Bronchial Asthma, Second Edition

Severe Asthma (Fatal Asthma) 1

Bronchial Asthma

Bronchial Asthma Second Edition

D Behera MD (Medicine) FCCP FNCCP FICP FICA MNAMS (Medicine) Dip. NBE (Respiratory Medicine)

Professor Department of Pulmonary Medicine Postgraduate Institute of Medical Education and Research Chandigarh (India)

JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD New Delhi

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Bronchial Asthma © 2005, D Behera All rights reserved. No part of this publication should be reproduced, stored in a retrieval system, or transmitted in any form or by any means: electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the author and the publisher. This book has been published in good faith that the material provided by author is original. Every effort is made to ensure accuracy of material, but the publisher, printer and author will not be held responsible for any inadvertent error(s). In case of any dispute, all legal matters are to be settled under Delhi jurisdiction only.

First Edition: 2000 Second Edition: 2005 ISBN 81-8061-434-4

Typeset at JPBMP typesetting unit Printed at Gopsons Papers Ltd, A-14, Sector 60, Noida 201 301, India

Dedicated to the loving memory of my distinguished teacher late Dr SK Malik

VALLABHBHAI PATEL CHEST INSTITUTE UNIVERSITY OF DELHI, P.O. BOX NO. 2101 DELHI-110 007, INDIA Tel. (O) (R) Fax E-mail

Dr. V.K. Vijayan MD (Med), Ph D (Med), D Sc, FAMS FCAI, FNCCP (I), FICC, FCCP (USA)

Director

: 91-11-7666180 : 91-11-7667027 : 91-11-7667420 : [email protected]

July 8, 2004 Date: ...........................

Foreword The prevalence of bronchial asthma, a major public health problem is increasing worldwide. Several studies have demonstrated that there is an increase in morbidity and mortality from bronchial asthma. Over and under treatment of asthma may be responsible for high mortality rates. Until recently bronchospasm that results from hyperresponsiveness of the airways to multiplicity of stimuli has been regarded as the main cause of airway dysfunction in asthma. Bronchial asthma is now considered as a chronic inflammatory disease of the airways. This realization that inflammation is the key factor in the pathogenesis of asthma is reflected in the change in asthma therapy with emphasis on inhaled anti-inflammatory drugs. There are many controversies in the management of bronchial asthma especially the role of immunotherapy. Many new drugs are under development and yet there is no cure for asthma. In a country like India with different socio-cultural diversities and beliefs, the treatment of asthma varies and the existence of different systems of medicine in our country complicates the treatment issues. Prof D Behera, a renowned Pulmonologist of our country and Professor of Pulmonary Medicine at the Postgraduate Institute of Medical Education and Research, Chandigarh has taken up the challenge of bringing out the updated second edition of his book, “Bronchial asthma”. The tremendous response to the first edition of his book is a testimony to the academic excellence of this book. The second edition has 21 chapters including epidemiology, pathophysiology, clinical presentation, complications, management and various guidelines. This revised edition is a comprehensive review of bronchial asthma and provides practical information for Physicians and Pulmonologists who have to take appropriate diagnostic and therapeutic decisions in patients with bronchial asthma. I congratulate Dr Behera for his tireless efforts to bring out the second edition of this book.

Dr VK Vijayan Director

Preface to the Second Edition Bronchial asthma is a common respiratory disorder affecting approximately 3-5 percent of the population, although there is a wide variation in its prevalence in the world, even in the same country at different parts. Over the years our understanding about the disease has changed. One of the major changes in our thinking about the pathophysiology of the disease is that the disease is inflammatory in nature rather than the earlier simplistic view of it being a simple bronchospastic disorder. A number of cytokines and mediators take part in its causation. Accordingly the approach to management of asthma has also changed. A number of guidelines have come up in recent years and there is a constant renewal in some of the concepts. Although there is no guideline for adult Indian patients, the same is given for children. The chapter on bronchial asthma in children is not complete in all aspects, but it will give a brief account of the same for the pulmonary physician. This edition has brought out some of these changes. Further, the references are updated with Vancouver style. D Behera

Preface to the First Edition Bronchial asthma is a common disease affecting nearly 3 to 5 percent of the population. Although incidence- and prevalence-wise the disease is not more common than tuberculosis in this country, the major difference is its recurring nature with periods of remissions and exacerbation. In some cases life long, and in many cases most of the times, medications with anti-asthma drugs will be required for symptom-free life. This is a major contrast to tuberculosis where treatment for 6 to 9 months will cure the disease. Earlier concepts about bronchial asthma, that it is a bronchospastic disease, have changed in recent years, wherein it is proved that it is an inflammatory disease. A wide array of cells with a number of cytokines take active role in the pathophysiology of the disease. The idea of writing this book came to my mind while I was preparing for the second edition of my textbook entitled Pulmonary Medicine. I thought a chapter on Bronchial Asthma in a textbook may not give sufficient justification to cover the explosion of recent knowledge acquired about the disease, particularly our understanding of its pathophysiology and approach to management. D Behera

Contents 1. Epidemiology ........................................................................................................................ 1 2. Aetiology ............................................................................................................................... 14 3. Pathophysiology of Bronchial Asthma ............................................................................ 40 4. Pathology .............................................................................................................................. 86 5. Clinical Presentation of Bronchial Asthma ..................................................................... 92 6. Diagnosis of Bronchial Asthma ........................................................................................ 98 7. Prognosis of Bronchial Asthma ...................................................................................... 114 8. Complications of Bronchial Asthma .............................................................................. 117 9. Management of Bronchial Asthma ................................................................................ 127 10. Pharmacologic Management of Asthma ....................................................................... 134 11. Inhalation Therapy ........................................................................................................... 176 12. Therapeutic Approach in Patients with Asthma I. Chronic Bronchial Asthma ........................................................................................... 183 13. Therapeutic Approach in Patients with Asthma II. Acute Severe Asthma (SA) ......................................................................................... 208 14. Management of Asthma with Special Problems ......................................................... 235 15. New Treatment Modalities/Newer Drugs for Bronchial Asthma ............................ 247 16. New Guidelines for Asthma Management (Non-pharmacological Management) ............................................................................ 256 17. New Guidelines for Asthma Management (Pharmacological Management) ........ 265 18. New Guidelines for Asthma Management (Acute Asthma) ..................................... 276 19. Alternate Treatments in Asthma .................................................................................... 293 20. Severe Asthma (Fatal Asthma, Refractory Asthma) .................................................... 306 21. Asthma in Children .......................................................................................................... 314 Index ..................................................................................................................................... 337

1 Epidemiology DEFINITION Asthma is a disease whose presence dates back to at least the time of Hippocrates who noted a condition of ‘deep and heavy breathing’. The Greeks had labelled this condition as “asthma”, the meaning of which was panting. Bronchial asthma is difficult to define since it is not one homogenous condition and because there is no one objective measurement or series of measurements that can be used to make the diagnosis of asthma. A widely acceptable definition still remains elusive ever since it was first defined in 1959 by an expert study group during the CIBA Foundation Guest Symposium.1 The Global Initiative for Asthma (1995) defines asthma on the basis of its pathogenesis (vide infra). The clinician, immunologist, physiologist, and pathologist all have their own perspective of asthma, and all these perspectives are difficult to merge into a comprehensive definition sufficiently specific to exclude other diseases. Earlier definitions were non-specific and therefore the condition was both under and over-diagnosed.2,3 However, during the past one-decade there have been major changes in the concepts of pathophysiology of asthma. Whereas the condition was previously considered as a bronchospastic disorder only, it is now recognised that asthma is primarily an inflammatory disease. The current definition incorporates both of these components and a generally agreed-on working definition of asthma is as follows:4 “Bronchial asthma is a disease characterised by (i) airway obstruction (airway narrowing) that is reversible (but not completely so in some patients) either spontaneously or with treatment; (ii) airway inflammation; and (iii) airway hyperresponsiveness to a variety of stimuli”. Subsequently, the Consensus Report5 describes asthma as a “Chronic inflammatory disorder of the airways in susceptible individuals, inflammatory symptoms are usually associated with widespread but variable airflow obstruction and an increase in airway response to a variety of stimuli. Obstruction is often reversible, either spontaneously or with treatment.” PREVALENCE The prevalence of asthma is not exactly known. This is because the precise way how to define asthma in population studies is defined differently. Questionnaires are the most practical tools to use in screening population for asthma. Such questionnaires have been validated to assess the ability of individual questions and combination of questions to predict which individuals in the population have either clinical diagnoses of asthma or non-specific bronchial hyperreactivity to agents like methacholine or histamine.6 Unfortunately,

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Bronchial Asthma

physician-diagnosis of asthma and bronchial hyperreactivity are not particularly good “gold standards” for identifying asthma. While the former can miss milder forms of asthma, the later is present in many people without asthma.6-8 To avoid these limitations, many studies now use questionnaires.6,9-11 In general, questions about “ever having asthma”, “ever having asthma diagnosed by a physician”, and “having wheezing during the previous 12 months” have been the questions with best sensitivity and specificity for prediction of the flawed gold standards. These questionnaires, of course are being used most often in recent studies. However, earlier surveys will have flaws as mentioned, and the difference prevalence rates in different studies in the past can be explained in part due to these methodological difficulties. Nonetheless, in many countries, the prevalence of asthma has increased in recent decades.12,13 The disease has reached epidemic proportions affecting 155 million individuals in the world. About 15% (one out of seven) of children in United Kingdom wheeze and similar number suffers from the related disorders of atopic dermatitis. The prevalence has risen over the past 30 years all over the world particularly in all Westernised societies perhaps as a result of the loss of childhood infections.14 While asthma is one of the less common causes of death, the magnitude of the problem is evident from the fact that during a 10 years period from 1978 to 1987, there were 1,87,000 deaths in USA, Canada, England, Wales, France, West Germany, and Japan.15,16 Since the definition of asthma was varying, the available statistics is viewed with some skepticism. In general, it seems that asthma remains under diagnosed especially during childhood. There is some evidence that bronchial asthma is increasing in a number of countries particularly New Zealand, UK and USA.15,17 An estimated 10 million persons in the USA had asthma. In the general population, asthma prevalence rates increased 29% from 1980 to 1987. Bronchial asthma is the most common chronic respiratory disorder among all age groups with a reported prevalence of 5 to 10%.18 During the last decade, studies from different countries keeping appropriate statistics have reported a significant rise in asthma morbidity and mortality.18-28 In the United States, approximately 17 million people have asthma (and asthma related symptoms) account for 10 million missed school days, > 1.5 million emergency department visits, approximately 500,000 hospitalisations and > 5000 deaths annually. In 1998, the direct and indirect expenditures for the treatment of asthma in the United States were approximately $11.3 billion.29 The overall 1988 asthma death rate was 1.9/100,000 persons with much lower rates in persons younger than 45 years, rising dramatically with increasing age.18-30 Asthma is the most common chronic disease of children in USA.31,32 About 6 million children in the United States have asthma compared to 3.1 million in 1984, an increase of 80%. Annually, asthma accounts for 12 million primary care visits, 1.6 million emergency department visits, 11 million missed school days, 200,000 hospital admissions, and 150 paediatric deaths.33 Improved personal behaviour and medical care have a limited sustained impact on childhood asthma until basic environmental issues are modified.34 Various other statistics also prove that both asthma and allergic rhinitis have increased in recent years. The effect of these disorders on children and adults is considerable in terms of morbidity and lost productivity resulting from the disease and its treatment .35,36 In addition, hospitalisation due to asthma and deaths attributed to asthma are increasing, despite the availability of effective drugs.37 From 1982 to 1992, the overall annual age-adjusted prevalence rate of self reported asthma increased 42% (from 34.7 per 1,000 people to 49.4

Epidemiology 3 per 1,000 people). Even more alarming is the observation that during this period, the overall annual age-adjusted death rate for asthma increased 40%.38 One disadvantage with these statistics is that these are based on informations obtained by questionnaire and in most cases identical questions were not used at each survey.39 However, from available data, both morbidity and mortality from asthma in New Zealand are amongst the highest in the world.40 A survey of 12-year-old school children carried out in New Zealand and South Wales41 revealed a higher prevalence in the former (17%) than in the later (12%). New Zealand children were also more likely than the Wales children to have a history of “wheeze ever” (27% vs. 22%) and wheeze brought on by running (15% vs. 10.5%). The sex ratio of asthmatic and wheezy children was very similar in the two countries. The overall prevalence of asthma is estimated at 13.7%, bronchial hyperresponsiveness at 13.4%, and atopy at 31.1% in the age range of 13 to 18 years. The prevalence of bronchial hyperresponsiveness in those without asthma symptoms is 3%. Both current asthma symptoms and bronchial hyperresponsiveness are more common among females. In a study to determine the prevalence of asthma in cohorts of Finnish young men in the period 19261989, Haahtela et al42 found that during 1926-1961 the prevalence was steady at between 0.02 and 0.08%. Between 1961 and 1966, however, a continuous, linear rise began, the prevalence increasing from 0.29% in 1966 to 1.79% in 1989, that is, representing a six-fold increase. The rise is 20 folds compared with that in 1961. Much of this increase appears real and not merely due to an improvement in the methods of diagnosis over these years. A review of the available published figures for children in United Kingdom revealed prevalence for “wheeze in the previous year” of between 4.9 and 15% and “wheeze ever” between 9.9 and 24.9%. Figures for “asthma ever” varied between 1.2 and 5%. A simple flow diagram of the natural history of asthma17 based on the prevalence of childhood wheeze in Australia is shown in Figure 1.1.

Fig.1:1. Natural history of bronchial asthma in Australian children. The hatching represents the approximate percentages in each group who are atopic and who have bronchial hyperresponsiveness. The top line indicates the group who are atopic and who wheeze while the bottom line represents those without evidence of (a) allergy; (b) wheeze; (c) and persistent wheeze

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The Figure 1.1 also shows the approximate number of people entering adult life with persistent wheeze. This study showing natural history of asthma is based on the prevalence of atopy as measured by skin tests and the prevalence of childhood wheeze in Australia. A number of studies from around the world show that the prevalence of atopy is between 3050% in children.43-46 In addition, the number of children who have wheezed at sometime is around 25-30%.47-49 Most children with persistent wheeze are atopic.50,51 About 7% of the patients have persistent asthma as reported from Australia by Woolcock et al.18 Adequate prevalence data from most developing countries is not available either for children or adults. Although it is a general perception that bronchial asthma is a very common problem in India, apart from tuberculosis, authentic information is not available regarding its prevalence or incidence. Whatever data is available, it lacks the uniformity of definition, problems of sample size, and analytical methodology used. From different studies, the prevalence of asthma has been reported to be 1.2 to 6.2% in adults in the western world. In a survey of respiratory symptoms in India, the prevalence of asthma has been reported to be 0.6 and 3.2% in rural and urban women respectively. The same in urban males has been 4%.52-55 The prevalence was reported to be 1.76% in an urban population in the mid sixties.56 It was also reported by the same investigators that the prevalence in the morbidity surveys of government employees and their families in Delhi was 1.8%.56 However, in recent years two studies from Mumbai and Northern India are available.57,58 The study from Greater Mumbai revealed a prevalence of 3.5% by physician diagnosis and 17% using a very broad definition including those with asymptomatic bronchial reactivity. Prevalence of asthma in Mumbai was similar in males and females (3.8 and 3.4% respectively). In the North Indian survey, a validated questionnaire was used tested against physician—diagnosed asthma and the prevalence in the population was assessed.58 The true population prevalence was reported as 3.94% in urban and 3.99% in rural males and 1.27% in both urban and rural females. A recent study from Delhi59 estimated the risk of asthma in children to be very high.59 Prevalence of asthma symptoms in children was determined in the International Study of Asthma and Allergies in Childhood (ISAAC) in the age groups of 6-7 and 13-14 years using a standardised sample survey.60,61 Prevalence of “ever asthma” varied from 1.8 to 12.4% with an overall figure of 4.5%. The figure of “ever asthma” in 12 months is not strictly same as prevalence of asthma in adults. The overall prevalence of asthma in children of 10-18 years age at Chandigarh was 2%, using the same methodology as in adults.58,62 Since morbidity depends, at least partly, on prevalence, the trends should be similar. Other indices of morbidity such as days lost from work and restriction in lifestyle, nocturnal disturbances with symptoms and hospital admission rates confirm the trends and extent of problem due to asthma. It is clear that the most dramatic increase in admission to hospitals has been in children. All the data collected on the basis of above informations indicate continuing extensive morbidity from asthma, although more effective treatment may be modifying this. MORTALITY Statistics for deaths from asthma yield widely variable mortality rates between countries.15 Increasing asthma mortality was first highlighted in the early-mid 1960’s63,64 when there was a dramatic increase in asthma deaths in England and Wales, Australia and New Zealand. This was most apparent in children 10-14 years, but was also apparent for all age groups,

Epidemiology 5 particularly in 5-34 age group. The range of such mortality between 1985-1987 in 20 different countries has been depicted in Figure 1.2.15 The intriguing points about asthma mortality are that there are sizeable differences between countries and that death rates from asthma are gradually increasing in most western countries. An analysis of asthma mortality rates in Western countries as well as developed nations such as the United States, Canada, New Zealand, France, Denmark, and Germany has revealed a distinct rise in rates during the 20 years period prior to 1990. Recent trends, however, suggest a stabilisation of mortality rates due to asthma in United States. From 1977 to 1996, there was a rise in deaths due to asthma in the USA from 1,674 (0.8 per 100,000) to 5,667 (2.1 per 100,000).65 The mortality rate increased by 6.2% annually during the 1980’s and faster among subjects aged 5 to 14 years than those aged 15 to 34 years. Among Whites, the mortality has increased more in female subjects than male subjects. The death rates for asthma among African Americans is three times higher than among White Americans. The trend in other countries is less apparent.66-72 In some countries, the rates have doubled over the past 10 years. Two countries, the UK and New Zealand, have experienced “epidemics” of asthma deaths; one epidemic in 1960’s in the UK and two in New Zealand; one in the 1960’s and the other in the 1970’s. At the peak of the New Zealand epidemic in the 1970’s, the mortality rate for asthma was approximately 10 times the rate in the USA. However, the rate has shown a declining trend since 1979. However, this trend is less apparent in other countries.73,74 For example, asthma mortality rate in Israel during the years 1980 to 1997 was low and stable. Most of the patients still died outside the hospital. There was no difference in the asthma death rate and place of death between Jews and Arabs, suggesting that the population genetic predisposition is not likely to be a risk factor for mortality.75

Fig. 1.2: Asthma mortality in 20 different countries of the world. The rate is per 100,000 population (1985-1987)

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Bronchial Asthma

All statistics shown are derived from published population and mortality data available from the national statistics centres in each country. West Germany reported over 9 deaths per 100,000 followed by Norway, New Zealand, and Sweden. Netherlands, USA, and Hong Kong reported asthma mortality rates less than 2/100,000. The reasons for the trends in mortality due to asthma and for the sizeable differences between countries are not clear.76-79 The increase in mortality in most countries cannot be primarily due to an increase in the prevalence of asthma as the rise in mortality is disproportionately greater than that of the prevalence.80 In the last decade, though, the stabilisation of mortality, and even a decrease in mortality, from asthma has been reported.81-84 A number of reasons have been proposed including: (i) Partial contribution from the shift of International code of death (ICD-8 to ICD-9). Due to this, the term asthmatic bronchitis was coded as asthma rather than bronchitis; (ii) Shifts in physician diagnosis patterns, especially from bronchitis to asthma in the 0-5 years age group and from COPD to asthma in smokers past middle life. There is clearly some misclassification of asthma deaths with over-reporting over age 50 and under-reporting in the younger age groups; (iii) An increase in the prevalence and or severity of asthma; (iv) Increased diagnosis of asthma; and (v) Adverse drug effects. In the 60’s overuse of adrenaline in Europe and currently the use of fenoterol have been postulated to be contributory to the mortality due to asthma. However, these postulates have not been confirmed.85-89 Other possible contributors are delay in care, poor compliance, lack of access to health care, theophylline toxicity, besides the overuse of β-agonists.90-92 Most likely cause of the recent decline in asthma deaths is the more judicious use of prophylactic treatment, particularly inhaled steroids, as a possible factor.93,94 Race and socioeconomic status may influence the outcome of an asthma attack.95,96 Hospital admission rates for asthma are high and have increased in the last few decades.97,98 However, some patients die before they can receive medical care.98-100 The exact proportion of deaths occurring outside the hospital and its association with genetic, environmental or social factors is not clear. An estimated 15 million persons in the United States have bronchial asthma, and the number is increasing. Although asthma is generally treated in an outpatient basis, increased hospitalisation rates have been observed. Hospitalisation rates and episodes of asthma have increased in all age groups particularly in boys up to 4 years old.101 Hospitalisation rates are twice as common in African Americans as White Americans.102 Causes for the Increase in Asthma Mortality Besides the above mentioned reasons, many other causes have been advocated for the increase in asthma mortality and morbidity and they include allergen exposure, air pollution, medication use, inadequate access to health care, increased incidence of viral infections, and physician management of asthma (Discussed subsequently). The risk of death due to asthma appears to predominate in large urban areas with high rates of poverty. Risk of hospitalisation for children with asthma is 8.4 times greater in areas with population of lower socioeconomic status and 5.3 times greater in areas with a larger African American population.103 Lower socioeconomic status and African American race are strong risk factors for hospitalisation and mortality from asthma. NATURAL HISTORY OF BRONCHIAL ASTHMA Over the last few decades the natural evolution of asthma from childhood to adulthood has been the subject of many reviews and studies and more than 50 such well-designed

Epidemiology 7 publications highlight the subject.104 It was long believed that the prognosis for asthma originating in infancy or childhood was good, and that in most patients the symptoms would resolve by the age of puberty. However, a review of literature shows that not all patients become asymptomatic in adulthood. In fact, asthma symptoms persist in 30-80% of adult patients. Although epidemiological studies have shown a fair chance of either “remission” or a reduction in asthma symptoms between the ages of 10 and 20 years,105-108 and most population based and clinical studies have also shown a reduction in asthma symptoms with age, the relapse rates after a symptom-free interval is also high.107,109 It has also been shown that, even in the absence of asthma symptoms, subjects may still have obstructive lung functions and increased bronchial hyperresponsiveness.110-116 No definite information is available about the progression of asthma through childhood and adolescence.117 Martinez118 studied the natural history of wheezing in children aged 0-6 years and found that approximately half of the children experienced wheezing illness at sometime during the study period. In some of them wheezing occurred early in life but resolved by the age of three years (transient early wheezing), some experienced wheezing illness between the ages of three and six years (late onset wheezing) and others had wheezing illness throughout the entire study period (persistent wheezing). Different risk factors were associated with these results. Children with transient early wheezing had reduced pulmonary function, as measured by functional residual capacity shortly after birth and before any lower respiratory tract illness had occurred. The risk was also increased in children whose mothers smoked during pregnancy. Congenitally smaller airways may therefore predispose children to wheezing illness early in life. Children with late and persistent wheezing are more likely to be atopic as assessed by elevated serum IgE levels and skin test reactivity, asthmatic mothers, and their lung function decreased after the age of one till they are six years of age. This study suggests the presence of two distinct wheezing illnesses up to the age of six years. As discussed above, there are varying reports about the persistence/disappearance of asthma symptoms in adolescence. However, some reports suggest that up to 80% of asthmatics may become asymptomatic during puberty.119,120 In a cohort study of Australian school children121 tested initially at the age of 8-10 years and then again at 12-14 years of age, the persistence of bronchial hyperresponsiveness at 12-14 years of age was found to be related to the severity of disease at 8-10 years of age, the atopic status of the child, and parental history of bronchial asthma. Most of the children who had a slight or mild degree of bronchial hyperresponsiveness at 8-10 years of age lost their increased response by the age of 12-14 years. Only 15.4% of children with severe or moderate bronchial hyperresponsiveness at the initial assessment had normal levels of bronchial responsiveness at the later assessment. Whether the decline in reported symptoms is real or the result of the children increasingly denying their illness as they reach puberty remains to be clarified. The reduced bronchial responsiveness may favour the hypothesis of a real reduction in the activity of the disease or higher doses of the provocative agents like histamine or methacholine may be needed to provoke hyperresponsiveness in larger airways of rapidly growing children. As against the above figures, the prevalence of bronchial asthma in adolescents in 4 different countries 122 varied from 2.8 to 38% at different ages and is summarised in Table 1.1.123-126 This shows a significant number still will have asthma in adolescence.

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Bronchial Asthma Table 1.1: Prevalence of bronchial asthma in adolescents

Country New Zealand Australia Netherland Finland

Year of study 1991 1992 1989 1991

Age (years)

Prevalence (%)

12-15 12-15 10-23 15-16

32-38 16.5 19 2.8

Several other prospective studies,127-130 which separately examined subjects aged 10 to 19, 20 to 40, and over 60 years, revealed that asthma was frequently preceded by lower respiratory tract symptoms, sometimes for years. Among subjects who were diagnosed with asthma after age 60, one-third reported respiratory symptoms before age 16.130 Similarly 82.7% with asthma diagnosed between the ages of 5 and 11 years had lower respiratory tract symptoms before the age of 5 years.127 REFERENCES 1. CIBA Foundation Guest Symposium: Terminology, definitions, and classification of chronic pulmonary emphysema and related conditions. Thorax 1959;14:286-99. 2. American Thoracic Society: Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 1987;136:225-44. 3. American College of Chest Physicians, American Thoracic Society: Pulmonary terms and symbols. Chest 1975;67:583. 4. National Asthma Education Programme. Expert Panel Report. Guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute, National Institute of Health, Bethesda, Maryland, USA, Publication No. 91-3042A, June 1991. 5. International Consensus Report on the diagnosis and treatment of asthma. National Heart, Lung, and Blood Institute, National Institute of Health, Bethesda, Maryland, USA, 20892. Publication No. 92-3091, March, 1992. Eur Respir J 1992;5:601-841. 6. Toren K, Brisman J, Jarvholm B. Asthma and asthma like symptoms in adults assessed by questionnaire: A literature review. Chest 1993;104:600-05. 7. Pekkanon J, Pearce N. Defining asthma in epidemiological studies. Eur Respir J 1999;14:951-57. 8. Peat JK, Toelle BG, Marks GB et al. Continuing the debate about measuring asthma in population studies. Thorax 2001;56:406-11. 9. Burney PGJ, Chinn S, Britton JR et al. What symptoms predict bronchial response to histamine? Evaluation in a community survey of the bronchial symptoms questionnaire(1984) of the International Union Against Tuberculosis and Lung Disease. Int J Epidemiol 1989;18:165-73. 10. Jenkins MA, Clarke JR, Carlin JB et al. Validation of questionnaire and bronchial hyperresponsiveness against respiratory physician assessment in the diagnosis of asthma. Int J Epidemiol 1996;25:609-16. 11. Sistek D, Tschopp JM, Schindler C et al. Clinical diagnosis of current asthma: Predictive value of respiratory symptoms in the SPALDIA study. Eur Respir J 2001;17:214-19. 12. Gorgen PJ, Mullally DI, Evans R III. National survey of prevalence of asthma among children in the United States. 1976 to 1980. Pediatrics 1988;81:01-07. 13. Phelan PD. Asthma in children epidemiology. BMJ 1994;308:1584-85. 14. Strachan DP, Anderson HR, Limb SR et al. A national survey of asthma prevalence, severity and treatment in Great Britain. Arch Dis Child 1994;70:174-78. 15. Buist AS. Worldwide trends in asthma morbidity and mortality. Bull Int Union Tuberc Lung Dis 1991;66:77-78. 16. Sears MR. Worldwide trends in asthma mortality. Bull Int Union Tuberc Lung Dis 1991;66: 79-83.

Epidemiology 9 17. Woolcock AJ. Worldwide trends in asthma morbidity and mortality. Explanation of trends. Bull Int Union Tuberc Lung Dis 1991;66:85-89. 18. Woolcock AJ, Peat JK, Salome CM et al. Prevalence of bronchial hyperresponsiveness and asthma in a rural adult population. Thorax 1987;42:361-368. 19. Sears MR. International trends in asthma mortality. Allergy Proc 1991;12:155. 20. Jackson R, Sears MR, Beaglehole R et al. International trends in asthma mortality:1970 to 1985. Chest 1988;94:914-18. 21. Evans R, Mullally DI, Wilson RW et al. National trends in the morbidity and mortality of asthma in the US. Chest 1987;91(Suppl 6):65S-74S. 22. Sly RM. Mortality from asthma. 1979-1984. J Allergy Clin Immunol 1988;82:705-17. 23. Weiss KB, Wagener DK. Changing patterns of asthma mortality: Identifying target populations at high-risk. JAMA 1990;264:1683-87. 24. Gerjen PJ, Weiss KB. Changing patterns of asthma hospitalisation among children; 1979 to 1987. JAMA 1990;264:1688-92. 25. Weiss KB, Gergen PJ, Wagener DK. Breathing better or wheezing worse? The changing epidemiology of asthma morbidity and mortality. Annu Rev Public Health 1993;14:491-513. 26. Whitelaw WA. Asthma deaths. Chest 1991;99:1507-10. 27. Mao Y, Semenciw R, Morrison H et al. Increased rates of illness and death from asthma in Canada. Can Med Assoc J 1987;137:620-24. 28. Williams MH. Increasing severity of asthma from 1960-1987. N Engl J Med 1989;320:1015-16. 29. Center for Disease Control and Prevention. Forecasted state-specific estimates of self reported asthma prevalence – United States, 1998;MMWR Morb Mortal Wkly Rep 1998;47:1002-25. 30. Ehrlich RI, Bourne DE. Asthma deaths among coloured and white South Africans; 1962-88. Respir Med 1994;88:195-202. 31. Gergen PJ, Mullally DI, Evans R. National survey of prevalence of asthma among children in the United States 1976 to 1980. Pediatrics 1988;81:01-07. 32. Taylor WB, Newacheck PW. Impact of childhood asthma on health. Paediatrics 1992;90:657-62. 33. Centers for Disease Control and Prevention. Asthma mortality and hospitalisation among children and young adults 1980-1983. MMWR Morb Mort Wkly rep 1996;45:350-53. 34. Cloutter M, Wakefield D, Hall CB, Bailit H. Childhood asthma in an urban community. Prevalence, care system, and treatment. Chest 2002;122:1571. 35. Anderson HR, Bailey PA, Cooper JS et al. Morbidity and school absence caused by asthma and wheezing illness. Arch Dis Child 1983;58:777-84. 36. Vuurman EFPM, van Vaggel LMa, Uiterwijk MMC et al. Seasonal allergic rhinitis and antihistaminic effects on children’s learning. Ann Allergy 1993;71:121-26. 37. Turkeltaub PC, Gergen PJ. Prevalence of upper and lower respiratory conditions in the US population by social and environmental factors: Data from the Second National Health and Nutrition Examination Survey. 1976 to 1980 (NHANES II). Ann Allergy 1991;67(2 pt 1):147-54. 38. Asthma statistics in the United States from 1982 to 1992. MMWR 1995;43:952-55. 39. Costello J. Asthma-the problem and the paradox. Postgrad Med J 1991;67(Suppl 4):S1. 40. Shaw RA, Crane J, O’Donnell TV. Asthma symptoms, bronchial hyperresponsiveness and atopy in a Maori and European population. NZ Med J 1991;104:175. 41. Barry DM, Burr ML, Limb ES. Prevalence of asthma among 12 years old children in New Zealand and South Wales: A comparative survey. Thorax 1991;46:405. 42. Haahtela T, Lindholm H, Bjorksten F, Koskenvuo K, Laitinen LA. Prevalence of asthma in Finnish young men. Br Med J 1990;301:266. 43. Hurry VM, Peak JK, Woolcock AJ. Prevalence of respiratory symptoms, bronchial hyperresponsiveness and atopy in school going children living in the Villawood area of Sydney. Austr NZ J Med 1988;18:745-52. 44. Goodfrey RC, Griffiths M. The prevalence of immediate skin tests to Dermatophagoides pteronyssinus and grass pollen in school children. Clin Allergy 1976;6:79-82.

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45. Clifford RD, Howell JB, Radford M, Holgate ST. Association between respiratory symptoms, bronchial response to methacholin, and atopy in two age groups of school children. Arch Dis Child 1989;64:1133-39. 46. Burrows B, Lebowitz MD, Barbee RA. Respiratory disorders and allergy skin reactions. Ann Intern Med 1976;84:134-39. 47. Kaplan BA, Masci-Taylor CGN. Asthma and wheezy bronchitis in British National Sample. J Asthma 1987;24:289-96. 48. Schachter EN, Doyle CA, Beck GJ. A prospective study of asthma in a rural community. Chest 1984;85:623-30. 49. Sears MR, Jones DT, Holdaway MD et al. Prevalence of bronchial reactivity to inhaled methacholin in New Zealand children. Thorax 1986;41:283-89. 50. McNichol KH, Williams HE. Spectrum of asthma in children-II. Allergic components. Br Med J 1973;4:12-16. 51. Van Asperen PP, Kemp AS, Mukhi A. Atopy in infancy predicts the severity of bronchial hyperresponsiveness in later childhood. J Allergy Clin Immunol 1990;85:790-95. 52. Behera D, Jindal SK. Respiratory symptoms in Indian women using domestic cooking fuels. Chest 1991;100:385. 53. Behera D, Malik SK. Chronic respiratory disease in Chandigarh teachers- a follow up study. Ind J Chest Dis All Sci 1987;29:25. 54. Behera D, Malik SK. Chronic respiratory disease and ventilatory function in adult rural Oriya females. Lung India 1988;6:127. 55. Jindal, S.K., Bhaskar, BV and Behera, D: Respiratory disease pattern in a large referral hospital in India. Lung India 1989; 7: 119-21. 56. Viswanathan R, Prasad M, Thakur AK, Sinha SP, Prakash N, Mody RK et al. Epidemiology of asthma in an urban population; A random survey. J Ind Med Ass 1966;46:480. 57. Chougule R, Shetye VM, Parmer JR et al. Prevalence of respiratory symptoms, bronchial hyperreactivity and asthma in a mega city: Results of the European Community Respiratory Health Survey in Mumbai. Am J Respir Crit Care Med 1998;158:547-54. 58. Jindal SK, Gupta D, Aggarwal AN, Jindal RC, Singh V. Study of prevalence of asthma in adults in North India using a standardised questionnaire. J Asthma 2000;37:345-51. 59. Chhabra SK, Epidemiology of childhood asthma. Indian J Chest Dis Allied SS 1998; 40:179-94. 60. The International Study of Asthma and Allergies in Childhood (ISAAC)Steering Committee: Worldwide variations in the prevalence of symptoms of asthma, allergic rhino conjunctivitis, and atopic eczema: ISAAC. Lancet 1998;351:1225-32. 61. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee: Worldwide variations in the prevalence of symptoms of asthma, and allergies in childhood (ISAAC). Eur Respir J 1998;12:315-35. 62. Jindal SK. Asthma epidemiology in India. Chest2001; 2(Indian Edition):115. 63. Speizer FE, Doll R, Heaf P. Observations on recent increase in mortality from asthma. Br Med J 1968;1:335-39. 64. Fraser PM, Speizer FE, Water SDM, Doll R, Mann NM. The circumstances preceding death from asthma in young people in 1968-1969. Br J Dis Chest 1971;65:71-84. 65. Sly R. decreases in asthma mortality in the United States. Ann Allergy Asthma Immunol 2000;85:121-27. 66. Evans R, Mullally DI, Wilson RW et al. National trends in the morbidity and mortality of asthma in the US prevalence, hospitalisation, and mortality of asthma over two decades; 1965-1984. Chest 1987;91:65S-74S. 67. Buist AS. Asthma mortality: What have we learnt? J Allergy Clin Immunol 1989;84:275-83. 68. Sheffer AI, Buist AS. Proceedings of the asthma mortality task force. J Allergy Clin Immunol 1987;80:361-62.

Epidemiology 11 69. Khanna PM, Linger J. Asthma mortality and hospitalisation among children and young adults; United States, 1980-1993. JAMA 1996;275:1535-37. 70. Buist AS, Vollmer WM. Reflections in the rise in asthma morbidity and mortality. JAMA 19990;264:1719-20. 71. Burney P. Asthma deaths in England and Wales 1931-85: Evidence for a true increase in asthma mortality. J Epidemiol Community Health 1988;42:316-20. 72. Weiss KB, Wagener DK. Changing pattern of asthma mortality. JAMA 1990;264:1683-87. 73. Salas-Ramirez M, Sagura N, Martinez C. Trends in asthma mortality in Mexico. Bol Oficina Sanit Panam 1994, 116:298-306. 74. Molinari J, Chatkin J. Tendencia da mortalidade por asthma bronnquica no Rio Grande do Sul. J Pneumonol 1995;21:103-06. 75. Picard E, Barmeir M, Schwartz S et al. Rate and place of death from asthma among different ethnic groups in Israel. National trends 1980 to 1997. Chest 2002;122:1222-27. 76. Sears MR, Rea HH, De Boer G et al. Accuracy of certification of death due to asthma—A national study. Am J Epidemiol 1986;124:1004-11. 77. Hunt LW, Mair JE, Laplante JM et al. Causes of death in a population with asthma. Am Rev Respir Dis. 1989;139:A486. 78. Riou B, Barriot P. Accuracy of asthma mortality in France. Chest 1990;97:507-08. 79. World Health Organisation. Manual of the international statistical classification of diseases, injuries and causes of death: Based on the recommendation of the ninth revision conference, 1975. WHO, Geneva, 1979, Vol 1. 80. Garrett J, Kolbe J, Richards G et al. Major reduction in asthma morbidity and continued reduction in asthma mortality in New Zealand: What lessons have been learned? Thorax 1995;50:303-11. 81. Sly RM. Changing asthma mortality. Ann Allergy 1994;73:259-68. 82. Vergara C, Caraballo L. Asthma mortality in Colombia. Ann Allergy Asthma Immunol 1998;80:5560. 83. Pearce N, Beasley R, Crane J et al. End of the New Zealand asthma mortality epidemic. Lancet 1995;345:41-44. 84. Sly RM, O’Donnell R. Stabilisation of asthma mortality. Ann Allergy Asthma Immunol 1997;48:347-54. 85. Stolley PD, Schinnar R. Association between asthma mortality and isoprenol aerosols: A review. Preventive Med 1978;7:519-38. 86. Esdaile JM, Feinstein AR, Horwitz RI. Can general mortality data implicate a therapeutic agent? Arch Intern Med 1987;147:543-49. 87. Crane J, Flatt A, Jackson R et al. Prescribed fenoterol and death from asthma in New Zealand. Lancet 1989;1:917-22. 88. Poole C, Lanes SF, Walker AM et al. Fenoterol and fatal asthma. Lancet 1990;335:920. 89. Beasley R, Smith K, Pearce N et al. Trends in asthma mortality in New Zealand, 1908-1986. Med J Aust 1990;152:570-73. 90. Sly RM. Mortality from asthma. J Allergy Clin Immunol 1989;84:421-34. 91. Spitzer WO, Suissa S, Ernst P et al. The use of beta-agonists and the risk of death and near-death from asthma. New Engl J Med 1992;326:501-06. 92. Sly RM. O’Donnell R. Regional distribution of deaths from asthma. Ann Allergy 1989;62:347-54. 93. Goldman M, Rachmiel M,Gendler M et al. Decrease in asthma mortality rate in Israel from 19991-1995: Is it related to increased use of inhaled corticosteroids? J allergy Clin Immunol 2000;105:71-74. 94. Campbell MJ, Gogman GR, Holgate ST et al. Age, specific trends in asthma mortality in England and Wales, 1983-1995; Results of an observational study. BMJ 1997;314:1439-41. 95. Respiratory diseases disproportionately affecting minorities. The NHLBI Working Group. Chest 1995;108:1380-92.

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96. Lang D. Trends in US asthma mortality: Good news and bad news. Ann Allergy Asthma Immunol 1997;78:333-36. 97. Gergen PJ, Weiss KB. Changing patterns of asthma hospitalisation among children. 1979 to 1987. JAMA 1990;264:1688-92. 98. To T, Dick P, Feldman W et al. A cohort study in childhood asthma admissions and readmissions. Paediatrics 1996;98:191-95. 99. Jones AP, Bentham G. Health service accessibility and death from asthma in 401 local authority districts in England and Wales. 1988-92. Thorax 1997;52:218-22. 100. Capewell S. The continuing rise in emergency admissions. BMJ 1996;312:991-992. 101. Vollmer et al. Am Rev Respir Dis 1993;147:347 102. Osborne M. Clinical asthma: Will NAEP guidelines help? Pulm Perspectives 1994;11(1):1-3. 103. Castro M, Halstead J, Schechtman K et al. Risk factors for asthma morbidity and mortality in a large metropolitan city. J Asthma 2001;38:625-36. 104. Roorda RJ. Prognostic factors for the outcome of childhood asthma in adolescence. Thorax 1996;51(Suppl 1):S7-S12. 105. Peckham C, Butler N. A national study of asthma in childhood. J Epidemiol Community Health 1978;32:79-85. 106. Anderson HR, Bland JM, Patel S, Pekham C. The natural history of asthma in childhood. J Epidemiol Community Health 1986;40:121-29. 107. Bronniman S, Burros B. A prospective study of the natural history of asthma. Remissions and relapse rates. Chest 1986;90:480-84. 108. Aberg N, Engstrom I. Natural history of allergic diseases in children. Acta Paediatr Scand 1990;79:206-11. 109. Radford PG, Hopp RJ, Biven RE et al. Longitudinal changes in bronchial hyperresponsiveness in asthmatic and previously normal children. Chest 1992;101:624-29. 110. Friberg S, Bevegard S, Graff-Lonnevig V, Hallback I. Asthma from childhood to adulthood. A follow-up study of 20 subjects with special reference to work capacity and pulmonary gas exchange. J Allergy Clin Immunol 1989;84:183-90. 111. Ferguson AC. Persisting airway obstruction in asymptomatic children with asthma with normal peak expiratory flow rates. J Allergy Clin Immunol 1988;82:19-22. 112. Cooper DM, Cutz E, Levison H. Occult pulmonary abnormalities in asymptomatic asthmatic children. Chest 1977;71:361-65. 113. Blackhall M. Ventilatory function in subjects with childhood asthma who have become symptom free. Arch Dis Child 1970;45:363-65. 114. Cade JF, Pain MCF. Pulmonary function during clinical remission of asthma. How reversible is asthma? Aust NZ J Med 1973;3:545-51. 115. Strachan DP. The prevalence and natural history of wheezing in early childhood. J Royal Coll Gen Pract 1985;35:182-84. 116. Peat JK. Salome CM, Toelle BG, Bauman A, Woolcock AJ. Reliability of a respiratory history questionnaire and effect of mode of administration on classification of asthma in children. Chest 1992;102:153-57. 117. von Mutius E. Progression of allergy and asthma through childhood to adolescence. Thorax 1996;51(Suppl 1):S3-S6. 118. Martinez FD, Wright AL, Taussig LM et al. Asthma and wheezing in the first six years of life. N Engl J Med 1995;332:133-38. 119. Park Es, Golding J, Carswell F, Stewart-Brown S. Pre-school wheezing and prognosis at 10. Arch Dis Child 1986;61:642-46. 120. Balfour-Lynn. Childhood asthma and puberty. Arch Dis Child 1985;60:231-35. 121. Peat JK, Salome CM, Sedgewick CS, Kerrebijn J, Woolcock AJ. A prospective study of bronchial hyper responsiveness and respiratory symptoms in a population of Australian school children. Clin Exp Allergy 1989;19:299-306.

Epidemiology 13 122. Price JF. Issues in adolescent asthma: What are the needs? Thorax 1996;51(Suppl 1):S13-S17. 123. Robson B, Woodman K, Burgess C et al. Prevalence of asthma symptoms among adolescents in the Wellington region by area and ethnicity. NZ Med J 1993;106:239-41. 124. Forero R, Bauman A, Young L, Larkin P. Asthma prevalence and management in Australian adolescents; results from three community surveys. J adolescent Health 1992;13:707-12. 125. Kolnaar B, Beissel E, van-den-Bosch WJ et al. Asthma in adolescents and young adults: Screening outcome versus diagnosis in general practice. Fam Pract 1994;11:133-40. 126. Rimpela AH, Savonius B, Rimpela MK, Haahtela T. Asthma and allergic rhinitis among Finnish adolescents in 1977-1991. Scand J Soc Med 1995;23:60-65. 127. Dodge R, Martinez FD, Cline MG, Lebowitz MD, Burrows B. Early childhood respiratory symptoms and the subsequent diagnosis of asthma. J Allergy Clin Immunol 1996;95:48-54. 128. Dodge R, Burrows B, Lebowitz MD, Cline MG. Antecedent features of children in whom asthma develops during the second decade of life. J Allergy Clin Immunol 1993;92:744-49. 129. Dodge R, Cline MG, Lebowitz MD, Burrows B. Findings before the diagnosis of asthma in young adults. J Allergy Clin Immunol 1994;94:831-35. 130. Burrows B, Lebowitz MD, Barbee RA, Cline MG. Findings before the diagnosis of asthma among the elderly in a longitudinal study of a general population sample. J Allergy Clin Immunol 1991;88:870-77.

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2 Aetiology A number of factors are responsible either in the causation or exacerbation of bronchial asthma. A brief account of each of these factors will be discussed. ATOPY AND ALLERGY The association between asthma and allergy has long been recognised. It has been reported that 75-85% of patients with asthma have positive immediate skin reactions to common inhalant allergens. There are at least 6 major evidences to prove that most asthma in young people is due to exposure to allergens or to sensitisers. They are summarised below. i. Most people with asthma are atopic, which can be measured by skin tests or with measurements of specific IgE. In population studies and in clinical practice, it is clear that majority of young people are atopic. Furthermore, in most population studies of asthma, atopy has been found to be the most important single risk factor. House dust mite allergens appear to be the most common one associated with asthma. ii. Challenge with allergens in atopic asthmatics increases the severity of the disease. The stimulus is capable of increasing this for days and sometimes for weeks. This implies that allergens play a role in maintaining the disease. iii. Occupational asthma occurs due to allergens and sensitisers. In some healthy people, who are exposed to these agents, sensitisation occurs and is followed by episodic wheeze. Unless the subject is removed from the source, episodic symptoms continue, and with time become persistent. iv. It has been shown that subjects with apparently intrinsic asthma (normal skin tests), have higher levels of circulating IgE than the non-asthmatic population. v. Improvement in the symptomatology occurs on allergen withdrawal, which proves the causal relationship between the two. vi. Population studies have clearly demonstrated the association between atopy and asthma. It has been shown that in Indonesian children, there is less atopy and less asthma. Similarly studies from France have reported a lower prevalence of asthma where mites are less in number. There is a strong co-relation between allergic sensitisation to common aeroallergens and the subsequent development of asthma. There is also a strong association between allergen exposure in early life and sensitisation to these allergens, although it has not been possible to demonstrate an association between allergen exposure and the development of asthma.1

Aetiology 15 Some studies, however, challenged the assumption that childhood asthma is largely of allergic etiology.2 Pearce et al 3 reviewed the epidemiological evidence implicating aeroallergen exposure in the primary causation of asthma, and concluded that the available data do not indicate that aeroallergen exposure is a major risk factor. In a further study, they reported that atopy attributes only 38% to the causation of asthma.2 Some investigators have observed a weak and inconsistent association between atopy and asthma prevalence. On the contrary, recent studies suggest that among those reporting wheezing in the previous months have a stronger relationship with atopy for those reporting > 12 episodes of wheezing in the past 12 months compared to those reporting 1 to 3 episodes in the last 12 months.4 The proportion of “asthma-ever” attributable to atopy was 33%, while the proportion was 89% for those who were attending hospitals (indicating more severe form). Based on these findings, it is suggested that atopy contributes more to the frequent or severe asthma than to mild or infrequent asthma.4 These findings are consistent with other studies. The important association of atopy with childhood asthma is well recognised.5 A review of studies relating atopy to asthma notes that in cross-sectional studies conducted exclusively or predominantly in children, the proportion of cases attributable to atopy varied from 25 to 63%, with a weighted mean of 38%.6 Relationship of atopy and severity of asthma is a well-known fact.6 Atopy is also related to degree of bronchial hyperreactivity.7,8 Conversely, in patients having wheeze in the previous 12 months, bronchial hyperactivity is related to both atopy and measures of disease severity such as peak expiratory flow variability.9 Taken together these facts are strong evidence for the role of atopy in asthma. Even though not all asthmas are associated with or perpetuated by exposure to common airborne allergens, exposure to these agents plays a major role. Both indoor and outdoor allergen exposures have increased asthma morbidity. People now spend a substantial proportion of the time indoors. Most of the responsible allergens are probably prevalent inside the houses since this is where human beings spend most of their lives. The most important ones throughout the world appear to be the house dust mites, grass pollens, animal proteins, and moulds. Recent changes in housing styles in many western countries may have led to increased allergens levels. Houses tend to have less ventilation, making them more humid, and there has been widespread introduction of carpeted floors and pets living in the houses. Whereas house dust mite is the most important and common indoor allergen linked to asthma,10 Outdoor allergens such as grass pollen, soyabean dust and Alternaria alternate have been specifically linked to severe asthma exacerbations.11,12 There has also been spread of plants, cockroaches and perhaps mites. Moreover, the climate of a particular area may favour the availability of various allergens, which in part may be responsible for the difference in the prevalence of asthma in various countries. Another important factor is the way the allergen is handled. Pollutions add to the allergenicity of aeroallergens. The predominance of these allergens will of course depend upon various factors, particularly local. Studies in asthmatics of allergen skin reactivity, IgE antibody levels, and bronchial provocation have all helped establish the important role of allergens in many asthma exacerbations.13 Further, reducing the patient’s exposure to allergens can help bring asthma symptoms under control. A growing number of uncontrolled and controlled studies suggest that allergen eradication and avoidance measures lead to improvement in bronchial hyperresponsiveness, severity of symptoms, and requirements of asthma medications.14 Recent research suggests that for many allergic disorders associated with aeroallergens, the process of IgE sensitisation begins right early in life while the immune response is still

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developing. It has been shown that the level of dust mite allergen present in the home during the first year of life is a major factor in determining whether an infant born of an allergic mother who is genetically susceptible, did in fact develop allergy or asthma by the time they are 11 years of age. Moreover, the density of allergen (per gram of dust) is an important factor in determining the age of onset of first symptoms. Higher is the concentration of allergen earlier is the onset of disease. Allergenic pollens vary at different places. The predominant offending allergen will vary with locality, lifestyle, season, and climate. For example, in Delhi, Amarantus pollen is the most common offending allergen followed by Cassia siamea, Ricinus, Brassica, Imperata, Prosopis, Cenchrus, Cassia occidentalis, etc.15 Prosopis is the commonest antigenic pollen in Bikaner, Lucknow, and Varanasi.16-18 Brassica is the commonest pollen in Bhopal and Kanpur.19,20 On the other hand Parthenium is the commonest offending agent in Kolhapur .21 In the United kingdom, 50-75% of atopic asthmatics react to house dust mite, similar number to grass pollens, 35-55% to cat dander, 10-20% to dog dander, 10-20% to tree pollens, 10-15% to moulds, and fewer than 10% to food allergens.13 In contrast, keeping cats as pets, unlike in many western countries is not a common practice in India. Therefore, cat or dog dander allergy may not be that important in this country. On the other hand because of tropical climates, and peculiar habit of storage of food articles, cockroaches grow plenty in this country. Therefore, these might be an important allergen for people of India. The importance of allergy is different for different age groups. In infants, allergens play a less important role than other ages and viral respiratory infections are the principal triggers. Although allergic reactions to food can occur in infants, foods are not the common triggers. Studies in children suggest that allergy influences the persistence and severity of asthma. It is reported by several authors that severity of childhood asthma corelates with the number of positive immediate skin tests. Children with multiple positive skin tests are more likely to have daily rather than intermittent symptoms of asthma. The important allergens in children after infancy appear to be inhalants. Aeroallergens are important in patients whose disease has started before the age of 30 years or who are exposed to occupational allergens. Patient can also have allergy for the first time after the age of 30. However, in adults the intensity of allergic skin tests does not appear to be associated with increased severity of asthma. Food allergies are not common triggers for asthma in adults. The patient may have aspirin sensitivity, but it has no immunological basis. Different Allergens (Figs 2.1a to 2.1h) i. Important outdoor allergens include pollens and moulds. Pollen Particles greater than 10 micron in diameter are usually cleared in the nose and mouth and do not penetrate the lower respiratory tract. However, there are some plants, which produce allergen-containing particles that are less than 10 microns. Ragweed and grass pollination are definitely associated with asthma. Pollen allergy is usually season-related and is more closely linked to hay fever and allergic conjunctivitis. Mould Mould spores are generally smaller than pollen grains and are more likely to penetrate the lower respiratory tract. Mould spores exist primarily outdoors and tend to be seasonal. Some fungi sporulate on warm, dry summer days and others prefer the rainy season. The species of the fungus vary with the geographic distribution according to climatic conditions.

Aetiology 17

Fig. 2.1a: Dust during cleaning

Fig. 2.1c: Smoke

Fig. 2.1e: House dust mite in the bedding

Fig. 2.1b: Pollen

Fig. 2.1d: Domestic fuel

Fig. 2.1f: Perfumes

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Fig. 2.1g: Pets (Animal dander)

Fig. 2.1h: Mould in the wall

ii. Although house dust itself is not an allergen, there are allergic components in it. The most important ones are mites, animal danders, and cockroaches. House dust mite plays a major role in the causation of asthma, although it does not leave any immediately perceptible sting or bite. This is the agent most widely implicated in the pathogenesis and provocation of allergic asthma. They are arachnoids distantly related to ticks and spiders. They are ubiquitous, living in the house dust that provides both their shelter and food (scales of skin shed by humans). They occur in environments with sufficient humidity since they are quite dependent for survival on moisture from the atmosphere. Loss of water from the mite body constrains their growth, but mites are capable of extracting water vapour even from air that is only 50% saturated. Live mites are equipped with suckers at the tips of their legs, which make them difficult to remove by vacuuming. The commonest mite is Dermatophagoides pteronyssinus. Other species may also exist in small numbers. Mite antigen is found throughout the home, wherever human dander, the food for the mite, is found. High levels are found in mattresses, pillows, carpets, upholstered furnitures, bed covers, clothes, and soft toys. The principal allergen of the house dust mite is found in its faeces. A gram of dust may contain 1,000 mites and 250,000 faecal pellets. These pellets are quite large and 10-40 microns in size, similar to pollen grains and share some of the aerodynamic properties with them. Like larger pollen grains, they do not easily enter the lower respiratory tract and are rapidly cleared from the airway by

Aetiology 19 gravity. Mite antigen is readily demonstrated in the air during cleaning. Some mite allergens may be smaller that may be in the respirable range for the lower respiratory tract. The major allergens of house dust mites are probably digestive enzymes, collectively designated as group I allergens or Der p I, and there are now tests available to quantitate this. The improvement of asthma in children residing in high altitude where low humidity constrains dust mite growth or in patients admitted to the relatively dust-free environment of a hospital14 indicates the contribution of the house dust mite to asthma exacerbation. A study of children requiring hospitalisation for asthma found that the risk of re-admission was associated with continued exposure to high concentrations of mite allergen.22-28 Animal allergens Dogs, cats, and other pet animals including rodents are commonly kept in homes. Danders from these animals contribute greatly to the allergenic components of house dust. All warm-blooded pets can cause allergic reactions, including the birds and small rodents. Products made from feathers retain the allergens from bird. All breeds of cats produce common allergens, and cat saliva and cat danders are potent allergens. Dogs also produce common allergens, although minor breed differences may exist. For several reasons cat allergen is more likely to cause sensitisation than that of dogs. The major cat allergen is Fel d I, which is a protein secreted by the cat’s salivary, sebaceous, and lacrimal glands. The protein is very stable and loses none of its antigenic potency for at least a month. It is coated on to the fur by the usual grooming, and at the rate cats shed their fur and dander, a reservoir of the antigen rapidly accumulates in household furnishings. In addition, Fel d I, particles are less than 2.5 mm in diameter and flake-shaped, making them easily airborne and easily respirable. While air filtration can remove some of the allergens, little permanent reduction occurs unless carpets, furnishings, and other reservoirs of coated fur (the cat itself) are removed. It takes several months before the concentration of allergens in domestic dust falls after removal of the pet. A number of epidemiological studies suggest that close contact with a cat or dog in very early infancy reduces subsequent prevalence of allergy and asthma. This may be a consequence of high allergen exposure inducing tolerance.29-31 Cockroach allergen The cockroach appears to be important, particularly in warmer climates and inner side of the house in cooler climates. Cockroach allergy has been identified as an important cause of asthma. This form of asthma—“The cockroach asthma”—is a more severe form of the disease, having perennial symptoms, and high levels of IgE. Cockroaches produce several allergens, which produce sensitisation. Usually there is exposure to high levels of this allergen at homes. The important domestic species are Blattella germanica and Periplaneta American. Kinds of Allergens The allergens are Bla g 2 (inactive aspartic protease), Bla g 4 (calycin), Bla g 5 (glutathione – S-transferase), Bla g 6 (troponin), the Group I cross-reactive allergen Bla g 1 and Per a 1, Per a 3 (arylphorin), and Per a 7 (tropomyosin). Although elimination of cockroaches totally is difficult, development of cockroach allergens as recombinant proteins has led to better control of this form of asthma.32 Indoor moulds are prominent in environments with increased humidity. Bathrooms, kitchens, basement areas, and perspiration on pillows are

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the common sites of mould growth. Cockroach sensitivity in children has been associated with greater symptom frequency and more emergency department visits due to asthma.33-36 Similar observations are made for elderly patients with asthma also.37 Risk Allergens: Responsible for Acute Attacks Threshold concentrations of allergens that can be regarded as risk factors for acute attacks include: • 10 μg/g dust of group I mite allergen • 8 μg/g dust of Fel d I, the major cat allergen • 10 μg/g dust of Can f I, the major dog allergen • 8 μg/g dust of cockroach allergen FOOD ALLERGEN AND BREASTFEEDING In the first 1 or 2 years of life, food sensitivity is an important factor in the development of allergies. Breastfeeding has been advocated as a method of preventing allergy and asthma. With breastfeeding there is a decreased risk (about 20%) for development of asthma.38 Impact of exclusive breastfeeding in children at 6 years of age has shown that the introduction of milk other than breast milk before the age of 4 months of age is a significant risk factor for increased likelihood of bronchial asthma.39 However, another study has shown an increased risk of wheezing, particularly in asthmatic mothers and if the child is also atopic.40 There are some reports that regular consumption of oily fish is associated with a reduced risk for asthma in children, although subsequent studies have not shown clinical benefits of supplemental ω3 fatty acids over a 6 months period.41,42 Further, it has been hypothesised that decreased dietary antioxidant vitamin intake is associated with increased asthma.43 Higher concentrations of vitamin intake are associated with a decreased serum levels if IgE and a significant decrease of atopy.44 Recent experimental data showed a reduced risk with intake of lectins (wheat germ agglutinin from whole wheat products).45 INFECTION It has long been recognised that viral respiratory infections provoke and alter asthmatic responses. Over 80% of acute asthma exacerbations in school children and about 60% in adults result from viral infections, mostly common cold viruses. These observations have suggested that viral infections may be intimately involved in the development of asthma and allergy. The susceptibility of the asthmatic airway to viral inflammation is due to persistent allergic mast cell and eosinophil-derived inflammation stimulates the release of cytokines such as tumour necrosis factor-alpha, which cause an increase in the expression of receptors for human respiratory viruses on the airway lining epithelium. In case of most rhinoviruses, the receptor is an adhesion molecule (intracellular adhesion molecule-1). The Viral respiratory illnesses may produce their effect by causing epithelial damage, producing specific immunoglobulin IgE antibodies directed against respiratory viral antigens and enhancing mediator release. Once the virus enters the epithelial cells, it replicates and generates a wide variety of proinflammatory cytokines, which further enhance eosinophil and mast cell inflammation. Apart from aggravating clinical asthma, viral upper respiratory

Aetiology 21 infections increase airway responsiveness, which may persist for many weeks after the infection. Provocateurs of Asthma The principal infection provocateurs of asthma in childhood during the first 2 years of life are respiratory syncytial virus (RSV), parainfluenza virus, and rhinovirus. Influenza virus is much more common in older children and adults. Early hospitalisation for respiratory syncytial virus, croup, or bronchiolitis is associated with greater airway responsiveness and more frequent history of wheezing.46 Other microorganisms that can exacerbate bronchial asthma include Mycoplasma pneumoniae. Although bacterial infection i s no t a cause of such exacerbations, it has been reported recently that H.influenzae and other Gram-negative bacteria can synthesise histamine both in vivo and in vitro.47 The presence of this mediator may contribute to the bronchoconstriction and other effects of histamine that can accompany bronchial infection. Pseudomonas infection in cystic fibrosis is responsible for a hyperreactivity reaction in these patients. A recent study in 101 nonsmoking severe asthmatics shows association between accelerated loss of lung function and seropositivity to Chlamydia pneumoniae.48 Interestingly, in recent years it is also observed that some infections are protective of bronchial asthma. While viral infections can undoubtedly cause deterioration of established asthma, viral or bacterial infections during the first three years of life may serve a protective function against the development of allergic diseases. Possibly they evoke a Th1-like protective response with the generation of IFN-gamma and IL-2. Thus, if multiple infections occur during the first few years of life, high concentrations of these Th1 cytokines could inhibit the release of Th2 cytokines, thereby tuning the mucosal immune response away from allergen sensitisation. This hypothesis is supported from observations from an African study, where children infected with measles during the first year of life had a 63% lesser chance of developing positive skin tests to common aeroallergens. Similarly repeated vaccination with BCG exerted a protective effect against the development of allergy in young Japanese children. Both measles and BCG are potent stimulators of the Th1 cytokine response. Another support of this protective infection comes from observations comes from the fact that the increase in asthma and allergy with movement to urban areas may be related to a decrease in early exposure to parasitic infections. One study from slum are of Caracas, Venezuela showed that antihelminthic treatment causes a decrease in IgE level, but was accompanied by an increase in skin test reactivity to house dust mite. In contrast, in the untreated children, the parasitic colonisation continued, IgE levels increased but the dust mite sensitisation fell. It indirectly means that eradication of parasites or reduced opportunities for infection could, in part, explain the rural to urban differences in the prevalence of allergic diseases. These observations led to the “Hygiene hypothesis” of bronchial asthma. This suggests that early exposure to microbial products will switch off allergic responses preventing allergic disorders like asthma.49 Epidemiological studies comparing large populations who have or have not had such exposures support the hypothesis.50 The hygiene hypothesis explains that allergic diseases were prevented by infections in early childhood, transmitted by unhygienic contact with older siblings or acquired prenatally. Over the past century declining family size, improved household amenities, and higher standards of personal cleanliness may have resulted in more atopic diseases.49 It is further proposed that modern vaccinations, fears of germs and

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obsession with hygiene are depriving the immune system of input on which it is dependent. Recent data suggest that exposure of young children to older children at home or to children at day-care protects against the development of asthma and frequent wheezing later in childhood. A double blind placebo controlled trial using the probiotic. Lactobacillus CG, observed a reduced incidence of atopic eczema but no effect on IgE antibody sensitisation, important for bronchial asthma. However, this study has the limitation of small sample size and early age limit of interpretation.51 DRUGS About 5 to 20 per cent of adults with asthma will experience severe and even fatal exacerbations of bronchoconstriction after ingestion of aspirin or certain non-steroidal antiinflammatory drugs (NSAIDs). These drugs are as follows:52-58 • Aspirin • Ibuprofen • Indomethacin • Piroxicam • Sulindac • Tolmetin • Naproxen • Fenoprofen • Meclofanamate • Mefenamic acid • Diclofenac sodium The list is not complete and aspirin sensitivity implies cross-reactivity with other nonsteroidal medications. The prevalence increases with increasing severity of asthma. In these individuals, ingestion of aspirin is followed within 1 to 2 hours by the onset of bronchospasm, which may be accompanied by rhinitis and/or urticaria. An association between aspirin sensitivity in people with asthma and the presence of sinusitis and nasal polyps is often stressed. Although there is a statistical relation, many patients with nasal polyps are not aspirin sensitive, and many patients with asthma and aspirin sensitivity have not been found to have nasal polyps. It is likely that sinusitis, nasal polyps, and aspirin sensitivity all increase in prevalence with increasing severity of asthma and they are not causally related. Although the exact mechanism is not known, it is nonimmunologic and probably depends on inhibition of cyclo-oxygenase. Accordingly, the arachidonic acid metabolism proceeds via the lipo-oxygenase pathway producing leukotrienes (see pathogenesis). Although the exact pathogenesis of aspirin-induced asthma is unclear, studies have demonstrated that leukotrienes play an important role in airway narrowing and other signs in these patients. These observations are derived from the fact that urinary LTE4 is two-folds to ten-folds higher in these patients than in aspirin tolerant patients.59-61 Several leukotriene modifiers inhibit the asthma response in oral or inhaled bronchial provocation tests, such as aspirin and nonsteroidal anti-inflammatory drugs,62-64 and improve respiratory function by expanding the airway in patients with aspirin induced asthma.65 An additional hypothesis for the mechanism of aspirin sensitivity suggests that there is increased target organ sensitivity to leukotrienes. The inhibition of cyclo-oxygenase is a property common to all of the drugs producing this adverse reaction. Although analgesics not inhibiting this enzyme are generally considered to be safe, the most frequently employed alternative, acetaminophen, has been reported to cause asthma exacerbations in a few aspirin-sensitive patients. Other drugs that are known to exacerbate asthma include beta-blocker drugs (i.e. propranolol and nadolol). Eye drop preparations of this class of drugs also can induce asthma. Recently, inhaled verapamil, a calcium channel blocker, has been reported to induce severe bronchospasm in mild asthma.

Aetiology 23 EXERCISE-INDUCED ASTHMA66-71 Exercise-induced asthma’ (EIA) is often used to describe the asthma of persons in whom exercise is the predominant or even the only identified trigger to airflow obstruction. No available data support the concept that exercise-induced asthma represents a distinct pathologic or pathophysiologic entity. Exercise-induced bronchoconstriction is one manifestation of the asthmatic diathesis. Most, virtually all, people with asthma have airway hyperirritability that leads to exercise-induced asthma if the provocative stimulus - eucapnic voluntary hyperventilation- is appropriately intensified. Accordingly, this condition should be anticipated in all asthma patients. For some asthmatics, exercise is the only trigger. In addition, most patients in whom exercise is the predominant trigger, will have other additional sensitivities that either can be found in the clinical history or will evolve over time. It is estimated that approximately 40 per cent of children with allergic rhinitis, but without clinical asthma, have EIA. This situation probably holds true for adults. Untreated EIA can limit and disrupt normal life. Although individual episodes of EIA are short lived, the severity and impact is striking. During short (few minutes) periods of exercise, airways actually dilate. Exercise-induced asthma is the airway narrowing that occurs minutes after the onset of vigorous activity. Airway narrowing develops within 2-3 minutes after cessation of exercise. It generally reaches its peak about 5-10 minutes after cessation of activity and usually resolves spontaneously in the next 30-90 minutes or within a few minutes of administration of an inhaled beta-adrenergic bronchodilator. There are some reports now that a late phase of EIA exists.72,73 However, this phase is uncommon (EIA is a nonimmunologic form of asthma) and not severe unlike the late phase of allergen-induced asthma. Ambient air conditions during the post-exercise period also influence the degree of bronchoconstriction that develops. A rapid change to warm, moist air post-exercise tends to worsen the development of airflow obstruction.74 Some patients who engage in continuous, repetitive exercise periods, EIA diminishes or is completely abated during a refractory period that usually lasts 2 hours after an exercise challenge. This is referred to as “refractory period”. Because of this phenomenon, many asthmatic athletes report that a warm-up period of sub-maximal exercise helps to minimise exercise-induced symptoms.75 During sustained exercise they are often able to “work through’ initial respiratory symptoms, i.e. experience resolution of initial symptoms despite continued exercise. In contrast to asthma in general, which is characterised by both smooth muscle contraction and airway inflammation, exercise-induced asthma is due mainly to smooth muscle contraction. Therefore some investigators call this as airflow-induced bronchoconstriction (AIB) or exercise-induced bronchospasm (EIB). Although the exact mechanism of asthma is debated, it is generally established that EIA is due to loss of heat or water or both, from the lung during exercise resulting from hyperventilation of air that is cooler and dryer than that of the bronchial tree. The key aspects of the triggering stimulus are the level of ventilation during exercise and the temperature/water content of the inspired air.70 The higher the minute ventilation during exercise and the colder and drier the inspired air, the greater is the stimulus for bronchoconstriction. How this airway cooling causes bronchoconstriction, is not exactly clear. It has been suggested that heat and water loss leads to changes in airway fluid osmolarity which initiates mediator release that cause constriction in the smooth muscle. Some investigators believe that airway cooling triggers bronchoconstriction in asthmatic subjects, and a rewarming-induced hyperaemia and oedema results in airway

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obstruction. Another hypothesis put forth is that exercise-induced bronchoconstriction results from an imbalance between two opposing mechanisms: an excitatory pathway stimulated by airway drying and an inhibitory pathway initiated by airway cooling. It is speculated that cooling attenuates hypocapnia, hypertonic aerosol- and dry air-induced bronchospasm via a cold induced reduction in neuronal activity or mediator production and release. Effects of Exercise An athlete’s minute ventilation during exercise is determined in part by the workload undertaken as measured by oxygen consumption and in part by the degree of deconditioning as measured by minute ventilation. Thus, for all asthmatics, regular exercise that improves cardiovascular fitness and thereby increased oxygen extraction from the blood by exercising muscle can help reduce exercise-induced bronchoconstriction by lowering the level of ventilation needed during any given exercise task. Rate, depth, and pattern (I:E ratio) of breathing at a given level of ventilation during eucapnic voluntary hyperventilation are not important determinants of bronchoconstriction.71 To reduce/avoid EIA, avoidance of a cold/ dry environment is preferable. Swimming is the preferred exercise for persons with asthma because of this mechanism. Other inhaled irritants in the ambient air including high levels of air pollutants and smoke can also trigger asthma especially during exercise when larger than normal volumes of these irritants are inhaled. OCCUPATION AND ASTHMA Occupational asthma is the commonest industrial lung disease in the developed world with over 400 causes.76-78 It may account for about 10% of adult onset asthma.79 Environmental agents related to work place have been recognised as the causative agents for respiratory diseases for many centuries. Bernardino Ramazzini had recognised the importance of occupation in the causation of asthma as early as 1713 particularly in grain workers, bakers, millers, sulphur workers, and other occupations. With increased industrialisation, simple chemicals and organic compounds have been used more often with a consequent increase in new respiratory hazards, particularly occupational asthma. Occupational asthma may account for about 10% of adult onset asthma.79 It is now the commonest industrial lung disease in the developed world with over 400 causes.80-86 Agents causing occupational asthma are usually encountered in an industrial setting, but it is also possible for persons outside the working area to develop disease after contamination of their environment by a point source industrial chemical irritant or allergen. Industries in which asthma occurs include plastics and paint manufacturing, electronics, welding, metal refining, photography, health-related industries, antibiotics and cosmetic manufacturing, dyeing, forestry, and food processing. Asthma can also result from massive pollution due to transportation accidents or gross contamination of the local environment by manufacturing industries. It can also occur in more unrecognised ways like materials contaminating air conditioning system inlets from near by factories, or by contamination of workers or of their clothing. Thus the strict definition of occupational asthma as reversible obstructive airways disease contracted in the work place may underestimate the real extent of the problem.

Aetiology 25 Prevalence of Asthma in Workers Although the exact prevalence of occupational asthma is not known and will vary according to the setting in which it occurs, on the industrial agent involved, on the intensity of exposure, and on working conditions, industrial hygiene, and engineering factors; it is reported that between 5 to 15% of all cases of asthma in Japan are occupational. Bakers exposed to flour dust develop asthma at a rate of 10-30%, in washing powder industry, up to 60% of the workers become sensitised to Bacillus subtilis, and in the cotton industry the prevalence of byssinosis is 25-29% in workers exposed in the carding process and 10-29% in those exposed in the spinning process. Similarly 5% of the western red cedar workers, 6% of the animal handlers, 5% of the workers in plastics industry (volatile isocyanates), and 30-50% of those working in the metal industry using soluble platinum salts develop the disease. Agents capable of inducing occupational asthma can be vapours, gases, aerosols, or particulate matters and can range from very low molecular weight inorganic chemicals to complex organic macromolecules. Some of these agents are shown in Table 2.1. Table 2.1: Selective agents known to cause occupational asthma

Agents

Occupation

1. Natural organic environmental agents. Animal proteins (urine, danders) Shellfish, egg proteins, pancreatic enzymes papain, amylase B.subtilis enzymes Poultry mites, droppings, feathers Flour grain Storage mites, soyabean, wheat Midges Silk-worm moths and larvae Castor beans, Coffee seeds bean Colophony Wood dusts (red cedar, oak,mahogany, etc) Grain dust (moulds, insects, grain) Cotton dust Storage mites, fungi, ragweed, pollen

Laboratory workers/Veterinarians Food processing Detergent factory Poultry farmers Bakers Farmers Fish food manufacturing Silk workers Farmers Electric soldering Carpenters and Saw mill workers Shipping workers Cotton mill workers Granary workers

2. Organic chemicals. Isocyanates (TDI, MDI, HDI) Antibiotics, piperazine, methyl dopa Disinfectants Paraphenylene diamine Formaldehyde, ethylene diamine Furfuryl alcohol resin Dimethyl ethanolamine toluene di-isocyanate

Plastic and foam Manufacturing Hospital workers Fur dyeing Rubber processing Foundry workers Automobile painting

3. Inorganic chemicals. Platinum salts Nickel salts Cobalt salts Chromium salts Aluminium fluoride Persulphate Vanadium Stainless fumes

Refining Plating Diamond polishing Stainless steel welding Manufacturing Beauty shop Refinery workers Welding

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Occupational asthma can be mediated by any of the several, mechanisms. They include, reflex vagal bronchoconstriction in response to an irritant effect on specific receptors; inflammatory bronchoconstriction secondary to toxic concentration of gases (nonspecific complement activation, neuro-peptide release, disrupted cell membrane releasing arachidonic acid products); direct pharmacological reaction by agents such as organic insecticides (parasympathetic agonists) and beta-adrenergic blocking agents; or by immunologic mechanisms. Some agents also act via alternative path way of complement activation through an antibody-independent mechanism. TARTRAZINE AND SULPHITE SENSITIVITY Tartrazine is a yellow dye commonly employed in food and medications. Beginning in 1958, a number of reports appeared linking this agent with the occurrence of acute bronchoconstriction. The reaction is particularly noted in those with aspirin sensitivity. Although the exact prevalence is not known, there are reports of positive challenge in up to 22% of unselected asthma patients and 25-50% of those with aspirin sensitivity. It is not an inhibitor of cyclo-oxygenase. However, the incidence of tartrazine-induced asthma is very low and perhaps is limited to those rare individuals who appear to have an immunologically mediated sensitivity to the dye.87 Sulphiting agents88-90 have been used to preserve foods and beverages since ancient times. They maintain the crisp and fresh appearance of the foods, prevent browning, and control microbial growth and spoilage. The agents used include sulphur dioxide as well as the sodium and potassium salts of sulphite, bisulphite, and metabisulphite. All these agents release sulphur dioxide gas under suitable conditions of warmth and acidity. Major sources of exposure to sulphites are processed potatoes, shrimp, dried fruits, beer and wine. Another source of sulphite exposure for patients with asthma is medication. Sulphites are used to prevent oxidation of beta-adrenergic agonists. For this purpose, sulphites are contained in some nebuliser solutions, injected epinephrine, and injected local anaesthetics containing epinephrine. Except in vary rare individuals with true allergy to sulphites, the amount of injected solutions is inconsequential. However, the amount in the nebuliser solutions is sufficient to cause paradoxical bronchoconstriction or a blunted bronchodilator response in these subjects. Exposure to sulphites, particularly in restaurant salad bars in western countries, or after drinking wine or beer, has been reported to be responsible for fatal attacks of asthma and its use has been banned in many countries. Sulphur dioxide released in the mouth and stomach from sulphites has been incriminated as the cause of precipitation of asthma in a vast majority of patients. Sulphur dioxide is a known irritant and asthmatics are particularly susceptible. The levels released from food and beverages may be sufficient to account for the bronchoconstriction. However, all patients with asthma do not react adversely to sulphites. This may be due to varying extent of inhalation of liberated sulphur dioxide by different patients or there may be a subset of asthmatics, which have low levels of the enzyme sulphite oxidase. These patients will be able to metabolise sulphites to harmless sulphates. A small number of asthma patients may have true allergy to sulphites, in whom an immediate skin test reactivity can be demonstrated.

Aetiology 27 RHINITIS AND SINUSITIS A possible relation between sinusitis and activation of asthma has been postulated recently. A high incidence of radiographic evidence of sinusitis on the order of 40 to 60 % has been demonstrated in asthmatic patients. However, the question is, does this association represent an epiphenomenon? There is suggestive clinical evidence that sinusitis not only occurs in association with asthma but may also play some role in its pathogenesis. Studies of children and adults after medical or surgical therapy indicate that the asthmatic state may improve with proper management of the underlying sinusitis. It is also likely that nasal and sinus pathology can aggravate asthma, particularly if there is uncontrolled drainage of mucoid or mucopurulent material down the nasopharynx where it can contribute to cough and irritability of larynx. This material may also be aspirated into the lower respiratory tract, especially during sleep. It is also possible, but not proven, that sinus infection may aggravate asthma through reflex mechanisms.91-93 Although historically, it was believed that structurally and functionally there are differences within the respiratory tract which have been used as the basis for separating the airway into upper and lower respiratory tracts, it is now being appreciated that allergic rhinitis and bronchial asthma are considered as ‘one airway, and one disease’.94 The prevalence of asthma and allergic rhinitis is increasing in the general population, and a high proportion of new patients have coexisting upper and lower respiratory tract disease. It is estimated that 60 to 70% of patients who have asthma have also coexisting allergic rhinitis. During the past decade with increased understanding, current thinking is emerging that they should better be described as a continuum of inflammation involving one common airway. Traditional therapies originally indicated for allergic rhinitis and asthma are being reassessed to explore their potential utility in both these conditions. Recently, there has been a renewed interest in the role that histamine plays in lower airway disease, and interest in increasing in the theory that leukotrienes, which are more potent inflammatory mediators than histamine, play a role in upper airway disease as well. Because its important role in the pathogenesis of both airways disease, leukotriene receptor antagonists are recently have emerged as important therapeutic advances that have potential clinical utility in both asthma and allergic rhinitis. GASTRO-OESOPHAGEAL REFLUX (GER) A number of reports are available in the medical literature on the relationship between gastrooesophageal reflux (GER) and pulmonary disease. Since the late seventies, numerous investigators have reported on epidemiology, mechanisms and clinical trials in an effort to piece together the gastro-oesophageal reflux and asthma. Epidemiological evidence for the association suggest that about three-fourth of the asthmatics, independent of the use of bronchodilators, have acid gastro-oesophageal reflux, increased frequency of reflux episodes, or heart burn, and about 40 per cent have reflux oesophagitis. As early as 1967, Urschel and Paulson reported that of 636 patients scheduled for an operative treatment for GER, 60% also had pulmonary symptoms.95 Since then, many studies have shown a high prevalence of GER among patients with asthma.96,97 A recent report says that even asthmatics without having reflux symptoms have a high prevalence (62%) of abnormal results for 24-hours oesophageal tests.98 The simultaneous occurrence of GER and asthma suggests a causal

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relationship. The occurrence of GER after bedtime is strongly associated with asthma, respiratory symptoms, and obstructive sleep apnoea syndrome.99 Two separate mechanisms are involved in the gastro-oesophageal reflux and asthma relationship.99,100 i. Reflex vagal bronchoconstriction occurs secondary to stimulation of sensory nerve fibres in the lower oesophagus. This mechanism is supported by the findings that acid infusion of the oesophagus in asthmatic patients leads to increased airway resistance that rapidly reverses with antacids and infusion of acid into the lower oesophagus of asthmatic children during sleep induces bronchoconstriction. ii. The second proposed mechanism is micro-aspiration, particularly during sleep. This is supported by the findings of (a) a large vagally mediated increase in airway resistance with minute quantities of hydrochloric acid infused into the trachea of cats; (b) a high prevalence rate of hiatus hernia and gastro-oesophageal reflux in patients with bronchial asthma and (c) an incidence of gastro-oesophageal reflux in 63 per cent of children with asthma. The prevalence of gastro-oesophageal reflux is increased at least threefolds in both children and adults with bronchial asthma. The evidence for the relationship also has gained support from the results of clinical trials. iii. The partial narrowing or occlusion of the upper airway during sleep, followed by an increase in intrathoracic pressure, might predispose the patient to nocturnal GER and, consequently, to respiratory symptoms.99 Both medical treatment with antacids and postural therapy and surgical management of gastro-oesophageal reflux have resulted in improvement of asthma symptoms. However, other studies have not demonstrated such a beneficial effect.101-105 Prevalence of gastro-oesophageal reflux in asthmatics can be summarised as follows:106 • 57% of asthmatics have heartburn • 41% of asthmatics note reflux-associated respiratory symptoms • 82% of asthmatics have abnormal oesophageal acid contact times • 43% of asthmatics have oesophagitis • Heartburn is more prevalent in asthmatics over 65 years of age (35%) compared with asthmatics 18-34 years of age (23%) • Heartburn is associated with a higher rate of future asthma hospitalisation • Subjects reporting nocturnal GER have higher asthma prevalence rates and symptoms of obstructive sleep apnoea • Proximal oesophageal acid exposure is present in 48% of asthmatics • In children : abnormal oesophageal pH tests are present in 62% and GER is a risk factor for asthma (OR 1.9). PSYCHOLOGICAL FACTORS There has been a great deal of controversy regarding the cause and effect relationship of asthma and psychological factors. Many patients with asthma acknowledge that exacerbations are provoked by psychological events, such as shock, bereavement, or excitement. However, such factors are rarely the dominant cause of disease. Suggestion and hypnosis may have some beneficial effect in modifying the asthmatic reactions. Depression most often associated with asthma may be secondary to a chronic disease. In rare instances, patients commit suicide. Although the information linking depression and

Aetiology 29 increased death from asthma is derived from clinical reports, the association, however, is striking. In a review of cases in which children died suddenly and unexpectedly of asthma, there is clinical evidence that the children had expressed despair, hopelessness, a wish to die, and other evidence of depression. Other psychological problems that are documented as associated with those at increased risk of mortality include alcohol abuse, documented depression, recent family loss and disruption, recent unemployment, and schizophrenia. The severe asthmatic attack is very frightening and such patients are understandably anxious. Occasionally, psychological illness, family disputes or marital disharmony may be major factors in the aetiology of intractable asthma.107-109 POLLUTION Pollution with particulate matter adds to the allergenicity of aeroallergens. Passive smoking is known to be a risk factor110 and there is evidence that diesel fumes are associated with increased allergic responses. Similarly smokers have increased bronchial hyperreactivity to a variety of stimuli. A small increase in allergen exposure will make the airway more reactive, which will result in a large increase in severity and potential deaths. Ozone and other oxidants contained in photochemical smog which occurs in areas of high traffic density, high sunlight and temperature inversions as in Los Angeles and Athens, act as respiratory irritants and can exacerbate asthma. Similarly other atmospheric pollutants as in highly industrialised area containing sulphur dioxide and other smoke particulates can provoke asthma. Indoor air pollution due to cooking fuels such as gas, biomass, and kerosene contain oxides of nitrogen and are responsible for increased respiratory symptoms as reported in some studies.111 Other environmental pollutants such as diesel particulates, and noxious gases like ozone, sulphur dioxide, and nitrous oxides may be important in the development in young children.112 Air pollution is partly being incriminated as a possible contributing factor in the recent rise in the prevalence, morbidity and mortality of asthma globally.113 Although recent studies have not established a direct causal relation of air pollution and bronchial asthma, there is now substantial evidence that air pollution can contribute significantly to asthma morbidity and mortality. Ambient levels of air pollutants exacerbate mucosal inflammation in asthmatic airways, can affect lung function, and potentiate inhaled response to aeroallergens. Emissions from motor vehicles are a major source of these pollutants. Retrospective analysis of pollution episodes in the world history (Meuse Valley, Belgium -1930; Donnora, Pennsylvania-1948; London 1952) have identified a link between respiratory morbidity and mortality and high levels of sulphur dioxide and black smoke, although these studies were not primarily focussed to study the association between asthma and air pollution.114-116 Reports from the Tokyo-Yokohama area of Japan where USA soldiers were based, revealed many cases of asthmatic bronchitis characterised by cough, wheeze, and breathlessness associated with eosinophilia and positive skin prick tests. This area experienced smog as it was highly industrialised and surrounded by hills. These individuals experienced relief of their symptoms when they moved out to less polluted areas. This entity is known as “TokyoYokohama asthma”. However, since the levels of pollutants were not measured, this could not be attributed to any specific pollutant.117-119 Other studies from Yokkaichi, Japan,120 Birmingham, UK,121 Seattle,122 Utah valley,123 Southern Ontario and Toranto124-126 have shown

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positive correlations between asthma exacerbations and SO2, ozone, fine particulate matter, and sulphates.127-129 Indoor air pollution is a contributory factor in exacerbation of bronchial asthma.130 Environmental tobacco smoke is important in the development of childhood asthma and in the worsening of asthma in children and adults.131 The earlier and the greater the degree of environmental tobacco smoke, the greater the likelihood of asthma developing in children. In infants exposed to prenatal and postnatal cigarette smoking, have altered lung function.130,132,133 These limitations in lung functions may be secondary to smaller lung size, and less maturity of lungs secondary to in utero lung growth retardation because of persistent exposure of lungs to nicotine.134-136 Increased bronchial responsiveness after birth occurs in infants exposed to maternal smoking.137 Infants exposed to smoking are at increased risk of developing asthma later in life.138-146 It is, however, not clear whether increased bronchial reactivity after birth plays a role, if any, in the development of asthma. It is also not clear whether the increased bronchial reactivity in these infants is purely genetic, or whether it is the result of lung injury from exposure to cigarette smoke. Asthmatic smokers have increased hyperresponsiveness to methacholine.147 Asthmatic smokers have higher sputum total cell and neutrophil numbers and IL-8 concentrations compared to asthmatic nonsmokers. In contrast, sputum eosinophils and eosinophil-cationprotein levels are higher in nonsmoking than smoking asthmatics, suggesting a normalising effect of smoking on the Th1/Th2 balance. Thus upon the eosinophils inflammation, smoking induces neutrophilic airway inflammation in asthma.147 Further, smoking asthmatics show no improvement in lung function, airway hyperresponsiveness, and sputum eosinophilia on treatment with steroid inhalation.148 This decreased steroid responsiveness is responsible for the faster decline in FEV1 seen in smoking asthmatics. ENDOCRINAL FACTORS Although the exact role of hormones in asthma has not been defined, a number of patients complain of exacerbation of their symptoms during or preceding menstruation. Retrospective studies suggest that in approximately one-third of women, asthma becomes worse during pregnancy; in one-third, it becomes better; and in one-third, it remains unchanged. In women in whom asthma becomes worse during pregnancy, peak severity occurs at 29-36 weeks of gestation. Asthma becomes less severe during the last 4 weeks of pregnancy. The change in the severity of asthma during pregnancy is sometimes dramatic and tends to be consistent in subsequent pregnancies. Most patients return to a prepregnancy level of severity by 3 months of postpartum.149-152 There may be an improvement in airway responsiveness during pregnancy that is greatest in those with the most hyperresponsive airway initially. It is also reported that improvements in responsiveness are associated with improvements in clinical asthma severity. However, progesterone alone did not appear to be the sole contributor to these improvements. It is also suggested that oestrogen plays a role in the pathophysiology of asthma and long-term use and/or high doses of postmenopausal hormone therapy increase subsequent risk of asthma.153 Several observations have been made on the influence of thyroid hormones on asthma. Hyperthyroidism is accompanied by many manifestations suggesting over stimulation of the sympathetic system and this condition is a contraindication for use of β-2 agonists. One, therefore would expect that patients of bronchial asthma, who in addition develop hyperthyroidism, should either have a decreased requirements of bronchodilators or amelioration of their symptoms. However, the reverse has been observed. Asthmatics who develop

Aetiology 31 hyperthyroidism, do far worse than euthyroid asthmatics. In some hyperthyroid asthmatics following treatment of hyperthyroidism, not only asthma improves, but in rare instances they become completely asymptomatic. Similar discrepancies have also been observed in hypothyroidism. Various mechanisms such as changes in beta adrenoceptor activity and altered prostaglandin metabolism have been proposed to explain these observations. Bronchodilator response is impaired in the presence of excess thyroid hormones, which improves after euthyroid state is achieved.154 GENETICS AND ASTHMA Genetic factors play a contributing role in the pathogenesis of asthma.155 There are several studies indicating familial aggregation of asthma. It is a frequent clinical observation that asthma runs in families. Moreover, other atopic conditions like allergic rhinitis and atopic dermatitis are common among the family members of the asthma patients. The concordance of asthma in monozygotic (MZ) twins is reported to be significantly greater than that in dizygotic (DZ) twins. Though the dosage of inhaled antigens and other factors influence the likelihood of clinical disease, recent family studies suggest that atopy is dominantly inherited. Molecular genetic linkage studies indicate that the “atopy” gene locus is on chromosome 11.156-159 Cytokines are important components in the pathogenesis of asthma (see below). The genes for these cytokines are encoded in a small region in the long arm of chromosome 5 and a number of them are coordinately regulated. T cells that differentiate along this route and preferentially release cytokines of the IL-4 gene cluster are called Th2-like. These Th2like lymphocytes and their cytokines are over represented in tissue biopsy studies in patients with allergic diseases. The chromosome 5 contains an IL-4 gene cluster which encodes the allergic cytokines IL-3,4,5,9,13 and GM-CSF (granulocyte macrophage colony-stimulating factor). This gene is closely linked to inheritance of an increased IgE response and to increased bronchial hyperresponsiveness. Further, human genome studies have revealed that allergic diathesis is linked with a region on the long arm of chromosome 12 which contains the gene encoding interferon-γ) (INF-γ), which is a powerful suppressor of Th2 responses. It is established that there is a reciprocal relationship between Th2 and Th1 responses with IL-10 derived from Th2 cells inhibiting Th1 responses while INF-γ generated by Th1 cells inhibits Th2 responses. It is possible that, in allergic diseases like asthma, there is an increase in the expression of genes, which regulates Th2 cytokines, a decrease in expression of genes that regulate INF-γ production, or a combination of both.160 The other genetic component that plays an important role is the ability of a susceptible individual to recognise an environmental allergen as foreign and starts an allergic immune response. This component operates through the human lymphocyte antigen (HLA, or MHC class II) molecules HLA-DR, HLA-DP, HLA-DQ, which provide the mechanism for antigen recognition and presentation to and by T and B lymphocytes.160 Many candidate genes and positional cloning have recently been identified.161 The first genome-wide screen for linkages to asthma identifies linkages on chromosomes 4q,6 (near the major histocompatibility complex, (MHC), 7,11q containing FcεR1-β, 13q and 16. Linkages have been confirmed to chromosomes 4,11,13 and 16. Suggestive evidences are also found for linkages and replication for loci on chromosomes 5q, 12q, 19q, and 21q. Different linkages have been reported from different ethnic groups. The loci most consistently and robustly identified are on chromosomes 5, 6, 12 and 13.

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Various candidate genes those have been implicated in atopy and asthma are summarised in Table 2.2.162 Several studies have shown that polymorphisms in the β2 adrenergic receptor gene influences responsiveness to β-agonists. Similarly polymorphisms in the 5-lipoxygenase gene and the leukotriene C4 synthase gene have been associated with response to medications that target leukotriene metabolism. These findings suggest the potential for pharmacogenetic tailoring of therapy in individual asthmatic patients.163 Environmental risk factors for development of asthma are summarised in Table 2.3. Table 2.2: Candidate genes for asthma

Chromosome 1 5

6 11 12 13 14 16

Gene IL-10 IL-4 promoter IL-5 IL-9 IL-12B IL-13 GM-CSF CD 14 β2 adrenergic receptor TNF-α Human leukocyte antigens FcεR1-β, CC16 Interferon γ STAT 5 T-cell receptor α/β complex IL-4 receptor (IL-4α)

Table 2:3: Environmental risk factors for the development of bronchial asthma Allergens Pollutants

Infections

Dietary modifications

Food allergens Inhalant allergens Environmental tobacco smoke Diesel particulates Noxious gases (ozone, SO2, NO2) Viral Respiratory syncytial virus Parainfluenza virus Human rhinovirus Bacterial Mycobacterium Chlamydia Mycoplasma Lactobacillus ω3 fatty acids Vitamins Antioxidants Lectins

Aetiology 33 REFERENCES 1. Lau S, Illi S, Sommerfeld C et al. Early exposure to house-dust mite and cat allergens and development of childhood asthma: A cohort study. Multicentre Allergy Study Group. Lancet 2000;356:1392-97. 2. Pearce N, Pekkanen J, Beasley R. How much asthma is really attributable to atopy? Thorax 1999;54:268-72. 3. Pearce N, Douwes J, Beasley R. Is allergen exposure the primary cause of asthma. Thorax 2000;55:424-31. 4. Ponsonby AL, Garenby P, Glagow N, Mullins R, McDonald T, Hurwitz M. Which clinical subgroup within the spectrum of child asthma are attributable to atopy? Chest 2002;121:135-42. 5. Host A, Halken S. The role of allergy in childhood asthma. Allergy 2000;55:600-08. 6. Weissman DN. Epidemiology of asthma. Severity matters. Chest 2002;121:6-8. 7. Burrows B, sears MR, Flannery EM et al. Relations of bronchial responsiveness to allergy skin test reactivity, lung function, respiratory symptoms, and diagnoses in thirteen-year-old New Zealand children. J Allergy Clin Immunol 1995;95:548-56. 8. Soriano JB, Anto JM, Sunyer J et al. Risk of asthma in the general Spanish population attributable to specific immune response. Int J Epidemiol 1999;28:728-34. 9. Toelle BG, Peat JK, Salome CM et al. Toward a definition of asthma for epidemiology. Am Rev Respir Dis 1992;146:633-37. 10. Sporik K, Holgate ST, Platts-mills TA, Cogswell JJ. Exposure to house dust mite allergen (Derp I) and development of asthma in childhood. A prospective study. NEJM 1990; 323:502-07. 11. Anto JM, Sunyer J, Reed CE, et al. Preventing Asthma epidemics due to soyabean by dustcontrol measures. N Engl J Med 1993; 329:1760-63. 12. O’HallarenMT, Yaginger JW, Offord KP et al. Exposure to an aeroallergen as possible precipitating factor in respiratory arrest in young patients with asthma. N Engl J Med 1991;324:359. 13. Colloff MJ, Ayres J, Carswell F, Howarth PH, Merrett TG, Mitchell EB, Walshaw MJ, Warner JO, Warner JA, Woodcock AA. The control of allergens of dust mites and domestic pets: a position paper. Clin Exp Allergy. 1992; 22 Suppl 2:1-28. 14. Platts-Mills TA, Tovey ER, Mitchell EB, Moszoro H, Nock P, Wilkins SR. Reduction of bronchial hyperreactivity during prolonged allergen avoidance. Lancet. 1982; 2:675-8. 15. Shivpuri DN, Dua KL. Studies in pollen allergy in Delhi area. Part IV: Clinical investigations. Ind J Med Res 1983;51:68. 16. Gupta KD, Agarwal RG, Sulemani AA. Pollination calendar of allergenic plants of Bikaner (Rajsthan), Part 3; Investigations of pollens. J Asso Phys India 1969;17:225. 17. Agnihotri MS, Singh AB. Observations on pollinosis in Lucknow with special reference to offending factors. Aspects Allergy Appl Immunol 1971;5:135-45. 18. Jha VK, Sundaramma M, Mishra SK, Joshi M. Clinical study with some airborne pollens and dust as respiratory allergens Around Varanasi. Ind J Chest Dis 1975;10:155. 19. Tiwari UC. Studies in allergenic pollen in Bhopal atmosphere. Aspects Allergy Appl Immunol 1978;10:65-72. 20. Mittal OP, Katiyar SK. Results of intradermal tests by various allergens in cases of nasobronchial allergy in Kanpur. Aspects Allergy Appl Immunol 1978;11:188-97. 21. Chaubal PD, Gadve SB. Study of pollen allergy in Kolhapur during monsoon. Ind J Chest Dis 1984;26:38-40. 22. Sporik et al. Clin Exp Allergy 1993;23:740 23. Nelson HS. The atopic diseases. Ann Allergy 1985;55:441. 24. Zimmerman B, Feanny S, Reisman J et al. Allergy in asthma I. The dose relationship of allergy to severity of childhood asthma. J Allergy Clin Immunol 1988;81:63. 25. Martoin AJ, Landau LI, Phelan PD. Natural history of allergy in asthmatic children followed to adult life. Med J Aust 1981;2:470.

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Bronchial Asthma

26. Zimmerman B, Chambers C, Forsyth L. Allergy in asthma. II. The highly atopic infant and chronic asthma. J Allergy Clin Immunol 1988;81:71. 27. Inouye T, Tarlo S, Broder I et al. Severity of asthma in skin-test negative and skin-test positive patients. J Allergy Clin Immunol 1985;75:313, 28. Murray AB, Ferguson AC, Morrison B. The seasonal variation of allergic symptoms induced by house dust mites. Ann Allergy 1980;45:347. 29. Remes ST, Castro-Rodriguez JA, Holberg CJ et al. Dog exposure in infancy decreases the subsequent risk of frequent wheeze but not of atopy. J Allergy Clin Immunol 2001;108:509-15. 30. Hessaelmar B, Aberg N, Aberg B et al. Does early exposure to cat or dog protect against later allergy development? Clin Exp Allergy 1999;29:611-17. 31. Platts-Mills T, Vaughan J, Squillace S et al. Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a population based cross-sectional study. Lancet 2001;357: 752-56. 32. Arruda LK, Chapman MD. The role of cockroach allergens in asthma. Curr Opinion Pulm Med 2001;7:14-19. 33. Platts-Mills T, Vervloet D, Thomas W et al. Indoor allergens and asthma. Report of the third International workshop. J Allergy Clin Immunol 1997;100:S1-S24. 34. Rosenstreich D, Eggleston P, Kattan M et al. The role of cockroach allergy and exposure to cockroach allergen in causing morbidity among inner-city children with asthma,. New Engl J Med 1997;336:1356-63. 35. Eggleston P, Rosenstreich D, Lynn H et al. Relationship of indoor allergen exposure to skin test sensitivity in inner-city children with asthma. J Allergy Clin Immunol 1998;102:563-70. 36. Gelber L, seltzer I, Bouzoukis J et al. Sensitisation and exposure to indoor allergens as risk factors for asthma among patients presenting to hospital. Am Rev Respir Dis 1993;147:573-78. 37. Rogers L, Cassino C, Berger KL et al. Asthma in the elderly. Cockroach sensitisation and severity of airway obstruction in elderly nonsmokers. Chest 2002;122:1580-86. 38. Park JK, Li J. Reversing the trend: Reducing the prevalence of asthma. J Allergy Clin Immunol 1999;103:1-10. 39. Oddy WH, Holt PG, Sly PD et al. Association between breast-feeding and asthma in 6-year-old children: findings of prospective birth cohort study. BMJ 1999;319:815-19. 40. Wright AL, Holberg CJ, Taussig LM et al. Factors influencing the relation of infant feeding to asthma and recurrent wheeze in childhood. Thorax 2001;56:192-97. 41. Hodge L, Salome CM, Peat JK et al. Consumption of oily fish and childhood asthma risk. Med J Aust 1996;164:137-40. 42. Hodge L, Salome CM, Hughes JM et al. Effect of intake of dietary omega –3 and omega-6 fatty acids on severity of asthma in children. Eur Respir J 1998;11:361-65. 43. Britton JR, Pavord I, Richards K et al. Dietary antioxidant vitamins intake and lung function in general population. Am J Respir Crit Care Med 1995;151:1383-87. 44. Fogarty A, Lewis S, Weiss S et al. Dietary vitamin E, IgE concentrations and atopy. Lancet 2000;256:1573-74. 45. Watzl B, Neudecker C, Hansch GM et al. Dietary wheat germ agglutinin modulates albumininduced immune responses in Brown Norway rats. Br J Nutr 20001;85:483-90. 46. Bailey WC, Clark NM, Gotsch AR, et al. Asthma prevention. Chest 1992;102(Suppl):216S-231S. 47. Sheinman BD, Devalia JL, Crook SJ, Tabaqchali S. Synthesis of histamine by Haemophilus influenzae. Br Med J 1986;292:857. 48. Ten Brinke A, van Dissel JT, Sterk PJ et al. Persistent airflow limitation in adult onset nonatopic asthma is associated with serologic evidence of Chlamydia pneumoniae infection. J Allergy Clin Immunol 2001;107:449-54. 49. Holt PG, Sly PD, Bjorksten B. Atopic versus infectious diseases in childhood: A question of balance? Pediatr Allergy Immunol 1997;8:53-58.

Aetiology 35 50. Strachan DP. Family size, infection and atopy. The first decade of the “hygiene hypothesis”. Thorax 2000;55(Suppl 1):S2-S10. 51. Kallomaki M, Salminen S, Arvilommi H et al. Probiotics in primary prevention of atopic disease; a randomised placebo-controlled trial. Lancet 2001;357:1076-79. 52. Stevenson DD, Simon RO. Aspirin sensitivity: Respiratory and cutaneous manifestations, In. Middleton E, Reed C, Ellis EF et al (Eds). Allergy Principles and Practice, 3rd Ed, St Luis, CV Mosby, 1988. 53. Stevenson SD. Diagnosis, prevention and treatment of adverse reactions to aspirin and NSAIDs. J Allergy Clin Immunol 1984;74:617. 54. Ayers JG, Flemming DM, Whittington RM. Asthma death due to ibuprofen. Lancet. 1987;i:1082. 55. Raine JM, Palazzo MG, Kerr JH, Sleight P. Near fatal bronchospasm after oral nadolol in a young asthmatic and response to ventilation with halothane. Br Med J 19821;282:548. 56. McGarigle P, Tribe AE. Eye drop induced asthma. Med J Aust 1985;142:425. 57. Barnes PJ. Our changing understanding of asthma. Respiratory Med 1989;83(Suppl A):17. 58. Harman E, Hill M, Piper JA, Hendeles L. Inhaled verapamil-induced bronchoconstriction in mild asthma. Chest 1991;100:17. 59. Szceklik A, Stevenson DD. Aspirin induced asthma: Advances in pathogenesis and management. J Allergy Clin Immunol 1999;104:5-13. 60. Stevenson DD, Simon RA. Sensitivity to aspirin and nonsteroidal anti-inflammatory drugs. In: Middleton E, reed CE, Ellis EF et al, (Eds). Allergy: Principles and Practice. 5th Eds. St Louis, MO, Mosby, 1998;1225-34. 61. Smith CM, Hawksworth RJ, Thien FC et al. Urinary leukotriene E4 in bronchial asthma. Eur Respir J 1992;5:692-99. 62. Christie PE, Tagari P, Ford-Hutchinson AW et al. Urinary E4 concentrations increase after aspirin challenge in aspirin-sensitive asthma patients. Am Rev Respir Dis 1991;143:1025-29. 63. Yamamoto H, Nagata M, Kiramtsu K et al. Inhibition of analgesic-induced asthma by leukotriene receptor antagonist ONO-1078. Am J Respir Crit Care Med 1994;150:254-57. 64. Obase Y, Shimoda T, Tomari S, et al. Effects of pranlukast on chemical mediators in induced sputum on provocation tests in atopic and aspirin-intolerant asthmatic patients. Chest 2002;121:143-50. 65. Dahlen B, Nizankowska E, Szceklik A, et al. Benefits from adding the 5-lipoxygenase inhibitor zyluton to conventional therapy in aspirin-induced asthmatics. Am J Respir Crit Care Med 1998;157:1187-94. 66. Freed AN, Stream CE. Airway cooling: Stimulus specific modulation of airway responsiveness in the canine lung periphery. Eur Respir J 1991;4:568. 67. McFadden ER. Exercise and asthma. N Engl J Med 1987;317:502. 68. Anderson SD. Issues in exercise-induced asthma. J Allergy Clin Immunol 1985:76:763. 69. Godfrey S. Controversies in pathogenesis of EIA. Eur Respir J 1986;68:81. 70. McFadden ER Jr, Ingram RH Jr. Exercise-induced asthma: Observations on the initiating stimulus (Correction of published data) N Engl J Med. 1984; 311:1127-8. 71. Ingenito EP, Pichurko BM, Caeurfur J, Drazen JM, Ingram RH Jr., and Solway J. Breathing pattern after respiratory heat loss but not bronchoconstrictor response in asthma. Lung 1990; 168:23-34. 72. Rubinstein I, Levison H, Slutsky As et al. Immediate and delayed bronchoconstriction after exercise in patients with asthma. N Engl J Med 1987;317:482-85 73. Karjalainen J. Exercise response in 404 young men with asthma: No evidence for a late asthmatic reaction. Thorax 1991;46:100-04. 74. McFadden ER Jr, Kimberly AM, M. Lennes, Strohl KP. Post exertional airway rewarming and Thermal induced asthma. J Clin Invest 1986;78:18-25. 75. Reiff DB, Choudary NB, Pride NB, Ind PW. Effect of prolonged submaximal warm up exercise on exercise induced asthma. Am Rev Respir Dis 1989; 139:479-84.

36

Bronchial Asthma

76. Ross DJ. Ten-years of the SWORD project. Surveilance of work-related and occupational respiratory diseases. Clin Exp Allergy 1999;29:750-53. 77. Hendrick DJ, Burje PS,. Asthma. In. Hendrick DJ, Beckett W, Burge PS, charge A (Eds). Occupational disorders of the lung. Recognition, Management, and prevention. London WB Saunders, 2002:33-76. 78. Banks DE, Wang ML. Occupational asthma: “the big picture”. Occup Med 2000;15:335-58. 79. Meredith S, Nordman H. Occupational asthma: Measures of frequency from four countries. Thorax 1996;51:435-40. 80. Banks DE, deSazo RD. An overview of occupational asthma, principles of diagnosis and management. Immunol Allergy Pract 1985;7:122. 81. Brooks SM. Occupational asthma. Chest 1987;87:218S. 82. Chan-Yeung M, Lam S. Occupational asthma. Am Rev Respir Dis 1986;133:686. 83. Environmental and occupational asthma. Guest Editor Merchant JA. Chest 1990;98:146S. 84. Ross DJ. Twenty years of the SWORD project: Surveillance of work-related and occupational respiratory disease. Clin Expt Allergy 1999;29:750-53. 85. Hendrick DJ, Burge PS. Asthma. In. Hendrick DJ, Beckett W, Burge PS, Churg A (Eds). Occupational disorders of the lung: Recognition, management, and prevention. London WB Saunders, 2002;15:335-58. 86. Banks DE, Wang ML. Occupational asthma: The big picture. Occup Med 2000;15:335-58. 87. Stevenson DD, Simon RA, Lumry WR, Mathison DA. Adverse reactions to tartrazine. J Allergy Clin Immunol 1986;78:182-90. 88. Simon RA. Sulfite challenge for the diagnosis of sensitivity. Allergy Proc 1989;10:357-62. 89. Bush RK, Taylor SL, Busse W. A critical evaluation of clinical trials in reactions to sulfites. J Allergy Clin Immunol 1986;78:191-202. 90. Taylor SL, Bush RK, Selner JC et al. Sensitivity to sulfited foods among sulfite-sensitive subjects with asthma. J Allergy Clin Immunol 1988;81:1159-67. 91. Slavin RG. Sinusitis—Present state of the art. Allergy Proc 1991;12:163. 92. Rachelefsky GS, Katz RM, Siegel SC. Chronic sinus disease with associated reactive airway disease in children. Paediatrics 1984;73:526. 93. Mings R, Friedman WH, Linford PA, Slavin RG. Five year follow-up of the effects of bilateral intranasal sphino-ethmoidectomy in patients with sinusitis and asthma. Am J Rhinology 1987;79:247. 94. Grossman J. One airway, one disease. Chest 1997;111:11S-16S. 95. Uschel HC, Paulson DL. Gastroesopgeal reflux and hiatus hernia: Complications and therapy. Thorax Cardiovascular Surg1967;53:21-32. 96. Sontag SJ. Gastro-oesophageal reflux and asthma. Am J Med 1997;103(Suppl 1):84S-90S. 97. Harding SM, Sontag SJ. Asthma and gastrooesophageal reflux. Am J Gastroenterol 2000;95 (Suppl):S23-S32. 98. Harding SM, Guzzo MR, Richter JE. The prevalence of gastro-oesophageal reflux in asthma patients without reflux symptoms. Am J Respir Crit Care Med 2000;162:34-39. 99. Gislason T, Janson C, Vermeire P et al. Respiratory symptoms and nocturnal gastro-oesophageal reflux. A population-based study of young adults in three European countries. Chest 2002;121: 158-63. 100. Harding SM. Nocturnal asthma: Role of nocturnal gastresophageal reflux. Chronbiol Int 1999;16:641-62. 101. Nelson HS. Worsening asthma: is reflux esophagitis to blame? J Rev Respir Med 1990;11:827-44. 102. Sontag SJ. Gut feelings about asthma. The burp and the wheeze. Chest 1991;99:1321. 103. Mays EE. Intrinsic asthma in adults: Association with gastrooesophageal reflux. JAMA 1976;236:2626.

Aetiology 37 104. Field SK. Sutherland LR. Does medical antireflux therapy improve asthma in asthmatics with gastrooesophageal reflux. Chest 1998;114:275-83. 105. Field SK, Gelfand GAJ, McFadden SD. The effect of antireflux surgery in asthmatics with gastrooesophageal reflux. Chest 1999;116:766-74. 106. Harding SM. Acid reflux and asthma. Curr Opin Pulm Med 2003;9:42-45. 107. Miller BD. Depression and asthma: A potentially lethal mixture. J Allergy Clin Immunol 1987;80:481-86. 108. Strunk RC. Identification of the fatality-prone subjects with asthma. J Allergy Clint Immunol 1989;83:477-85. 109. Rea HH, Scragg R, Jackson R, Beaglehole E, Fenwick J, Southerland D. A case control study of deaths from asthma. Thorax 1986;41:833-39. 110. Gupta D, Aggarwal AN, Kumar R, Jindal SK. Prevalence of bronchial asthma and association with environmental tobacco exposure in adolescent school children in Chandigarh, North India. Journal of Asthma 2001; 38:501-07. 111. Behera D, Jindal SK. Respiratory symptoms in Indian women using domestic cooking fuels. Chest 1991;100:385. 112. Weiss ST, Tager IB, Schenker M et al. The health effects of involuntary smoking. Am Rev Respir Dis 1983;128:933-42. 113. Krishna MT, Chauhan AJ, Frew AJ. Air pollution and asthma: What is the association? Clin Asthma Rev 1997;1:7-12. 114. Department of Health, Committee on the Medical Effects of Air Pollutants. Asthma and Outdoor Air Pollution. HMSO, London 1995. 115. Ministry of Health. Mortality and Morbidity during the London Fog of 1952. HMSO, London 1954. 116. Schrenk HH, Heinmann H, Claydon GD, Gafarar WM, Wexler H. Air pollution in Donora PA: Epidemiology of the unusual smog episode of October 1948. Public Health Bulletin No 306. Washington D: Public Health Service 1949. 117. Phleps HW, Koike S. Tokyo-Yokohama asthma. The rapid development of respiratory distress presumably due air pollution. Am rev Respir Dis 1962;86:55-63. 118. Oshima Y, Ishizaka T, Miyamato T, Kabe J, Makino S. A study of Tokyo-Yokohama asthma among Japanese. Am Rev Respir Dis 1964;90:632-34. 119. Tremonti LP. Tokyo-Yokohama asthma. Ann Allergy 1970;28:590-95. 120. Kitagawa T. Cause analysis of Yokkaichi asthma episode in Japan. JAPCA 1984;34:743-46. 121. Walters S, Griffiths RK, Ayers J. Temporal association between hospital admissions for asthma in Birmingham and ambient levels of sulphur dioxide and smoke. Thorax 1994;49:79-83. 122. Schwartz J, Slater D, Larson TV, Pierson WE, Koenig JQ. Particulate air pollution and hospital emergency room visits for asthma in Seattle. Am Rev Respir Dis 1993;147:826-31. 123. Pope CA. Respiratory disease associated with community air pollution and a steel mill, Utah Valley. Am J Public Health 1989;79:623-28. 124. Bates DV, Sitzo R. Relationship between air pollutant levels and hospital admissions in Southern Ontario. Can J Public Health 1983;74:117-22. 125. Bates DV, Sitzo R. Air pollutant levels and hospital admissions in Southern Ontario: The acid summer haze effect. Environ Res 1987;43:317-31. 126. Bates DV, Sits R. The Ontario air pollution study; Identification of the causal agent. Environ Health Perspect 1989;79:69-72. 127. Committe of the Environmental and occupational health Assembly of the American Thoracic Society. Health effects of outdoor air pollution. Am J Respir Crit Care Med 1996;153:3-50. 128. Pande JN, Bhatta N, Biswas D, Pandey RM, Ahluwalia G, Siddaramaiah NH, Khilnani GC. Outdoor Air pollution and emergency room visits at a Hospital in Delhi. Indian J Chest Dis Allied Sci 2002; 44:13-19.

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129. Cunningham J, O’Connor GT, Dockery DW, Speizer FE. Environmental tobacco smoke, wheezing, and asthma in children in 24 communities. Am J Respir Crit Care Med 1996;153:218-24. 130. Martinez FD, Wright AL, Tausig LM et al. Asthma and wheezing in the first six years of life. New Engl J Med 1995;332:133-38. 131. Committee of the Environmental and occupational Health Assembly of the American Thoracic Society: Health of outdoor air pollution. Am J Respir Crit Care Med 1996;153:3-50. 132. Stick SM, Burton PR, Gurrin L et al. Effect of maternal smoking during pregnancy and a family history of asthma on respiratory function in newborn infants. Lancet 1996;348:1060-64. 133. Tager IB, Ngo L, Hanrahan JP. Maternal smoking during pregnancy: effects on lung function during the first 18 months of life. Am J Respir Crit Care Med 1995;152:977-83. 134. Chen MF, Kimizuka G, Wang NS. Human fetal lung changes associated with maternal smoking during pregnancy. Pediatr Pneumonol 1987;3:51-58. 135. Lieberman E, Torday J, Barbieri R et al. Association of intrauterine cigarette smoke exposure with indices of fetal lung maturation. Obstet Gynecol 1992;79:564-70. 136. Sheikh S, Goldsmith LJ, Howell L et al. Comparison of lung function in infants exposed to maternal smoking and in infants with a family history of asthma. Chest 2002;116:52-58. 137. Young S, Le Souef PN, Greelhoed GC et al. The influence of family history of asthma and parental smoking on airway responsiveness in early infancy. New Engl J Med 1991;324:1168-73. 138. Infante-Rivard C. Childhood asthma and indoor environmental risk factors. Am J Epidemiol 1003;137:834-44. 139. Arshad SH, hide DW. Effects of environmental factors on the development of allergic disorders in infancy. J Allergy Clin Immunol 1992;90:235-41. 140. Weitzman M, Gortmaker S, walker DK et al. Maternal smoking and childhood asthma. Pediatrics 1990;85:505-11. 141. Stoddard JJ, Miller T. Impact parental smoking on the prevalence of wheezing respiratory illness in children. Am J Epidemiol 1995;141:96-102. 142. Lewis S, Richards D, Bynner J et al. Prospective study of risk factors for early and persistent wheezing in childhood. Eur Respir J 1995;8:349-56. 143. Weiss ST. Environmental tobacco smoke and asthma. Chest 1993;104:991-92. 144. Martinez FD, Cline M, Burrows B. Increased incidence of asthma in children of smoking mothers. Pediatrics 1992;89:21-26. 145. Ehrlich RL, Tott DD, Jordan E et al. Risk factor for childhood asthma and wheezing: Importance of maternal and household smoking. Am J Respir Crit Care Med 1996;154:681-85. 146. Wright AL, Holberg C, Martinez FD et al. Relationship of parental smoking to wheezing and non-wheezing lower respiratory tract illness in infancy. J Pediatr 1991;118:207-14. 147. Chalmers DW, MacLeod KJ, Thomson L et al. Smoking and airway inflammation in patients with mild asthma. Chest 2001;120:1917-22. 148. Chalmers DW, MacLeod KJ, Little SA et al. Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma. Thorax 2002;57:226-30. 149. Stenius-Aarniala B, Piirila P, Teramo K. Asthma and pregnancy; a prospective study of 198 pregnancies. Thorax 1988;43:12-18. 150. Editorial. Pregnancy and the asthmatic. Respir Med 1991;85:451. 151. Schatz M, Harden KM, Forsythe A et al. The course of asthma during pregnancy, postpartum, and with successive pregnancies: a prospective analysis. J Allergy Clin Immunol 1988;81:509. 152. Schatz M, Zeiger RS, Harden KM et al. The safety of inhaled β-agonist bronchodilators during pregnancy. J Allergy Clin Immunol 1988;82:686. 153. Troisi RJ, Speizer FE, Willett WC, trichopoulos D, Rosner B. Menopause, postmenopausal estrogen preparations, and the risk of adult-onset asthma: A prospective cohort study. Am J Respir Crit Care Med 1995;152:1183-88.

Aetiology 39 154. Behera D, Roy R, Dash RJ, Jindal SK: Airway response to inhaled fenoterol in hyperthyroid patients before and after treatment. J Asthma 1992; 29:307, 369-74. 155. Meyers DA, Bleecker ER. Approaches to mapping genes for allergy and asthma. Am J Crit Care Med 1995;152:411-13. 156. Hopkin J. Genetics and lung disease. Advances in our understanding of emphysema, cystic fibrosis, and asthma. Br Med J 1991;302:1222. 157. Cookson WOCM, Hopkin JM. Dominant inheritance of atopic immunoglobulin-E responsiveness. Lancet 1988;i:86. 158. Cookson WOCM, Sharp P, Faux J, Hopkin JM. Linkage between immunoglobulin-E responsiveness underlying asthma and rhinitis and chromosome 11q. Lancet 1989;i:1292. 159. Nieminen MM, Kaprio J, Koskenvuo M. A population-based study of bronchial asthma in adult twin pairs. Chest 1991;100:70. 160. Holgate ST. Asthma and allergy: Interaction of immunology and environment. Pulmonary Perspectives 1997;14:4-6. 161. Cookson WOC. Asthma genetics. Chest 2002;121:7S-13S. 162. Sandford A, Pare P. The genetics of asthma: The important questions. Am J Respir Crit Care Med 2000;161:S202-S206. 163. Joos L, Sandford AJ. Genotype predictors of response to asthma medications. Curr Opin Pulm Med 2002;8:9-15.

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3 Pathophysiology of Bronchial Asthma Bronchial asthma is a disease characterised by wide variation over short periods of time in the resistance to flow in the airways. The hallmark of the disease is the airflow obstruction. Most asthma is of allergic origin. In this form, it is viewed as a sum of three features: the early asthmatic reaction (EAR); the late asthmatic reaction (LAR); and bronchial hyperresponsiveness, with varying contribution from each. The cellular response in LAR in non-allergic asthma is similar, but little is known of the underlying aetiology. Three factors narrow airway caliber to limit the flow: • Airway smooth muscle contraction; • Gland and epithelial secretions and exudation into the airway lumen; and • Inflammatory oedema and vasodilatation (hyperaemia). Early Asthmatic Reaction (EAR) In atopic individuals, bronchial challenge/inhalation of appropriate antigens will elicit an early response, which is maximum at 15 minutes and characterised by smooth muscle contraction, exudation of plasma, and mucus production. This reaches its peak in about thirty minutes and resolves within 90-180 minutes. This early reaction is IgE dependent and is the result of IgE binding to mast cells by its Fc portion and to specific antigens by its F(ab) portion. When IgE-sensitised mast cells are exposed to antigen against which the IgE molecule is directed, pre-formed and newly generated mediators are released.1 These can be detected in the blood as they overflow into the circulation, in bronchoalveolar lavage fluid, and as metabolites in the urine and include histamine, prostaglandin D2, and leukotriene C4 from airway mast cells.2 This early response is due to the release of histamine. This reaction can be prevented by pre-medication with sodium cromoglycate and nedocromil sodium and β-2 agonists,3 but not with steroids. Late Asthmatic Reaction (LAR) and Bronchial Hyperreactivity (BHR) The EAR is followed by a complete or partial recovery period over the next 1 to 2 hours and then by a further progressive fall in respiratory function, which is maximal between 6 to 12 hours. A further recovery occurs by 24 to 36 hours. This response can only be partially reversed by β-2 agonist, but pre-medication with cromolyn and corticosteroids inhibits this response. The LAR is also characterised by the release of inflammatory mediators into the same fluids. However, during this phase there is a striking infiltration of inflammatory

Pathophysiology of Bronchial Asthma 41 cells with activation of these cells which include eosinophils, neutrophils, and lymphocytes. This LAR is thought to be a primary mechanism responsible for airway (bronchial) hyperresponsiveness (BHR). The BHR is an exaggerated bronchoconstriction of smooth muscles and airway narrowing on exposure to small quantity of non-allergic stimulant that usually does not provoke such a reaction in normal subjects.4 The BHR usually precedes the onset of LAR.5 This may last for several days or occasionally weeks.6 The BAL fluid from these subjects contains increased eosinophils, eosinophilic cationic protein, CD4+ T lymphocytes, macrophages, monocytes, basophils, and neutrophils.3,6 The selective recruitment of these leucocytes into the airways during the LAR are probably due to the release of local and circulating messengers, i.e. cytokines from the cells in the airway mucosa in relation to allergen exposure with the subsequent effect of recruiting mature and precursor cells from the bone marrow and other sites of leucocyte sequestration.7 Mucosal oedema and vasodilatation are the important components of airway obstruction during the LAR and contraction of airway smooth muscle contribute substantially to the EAR. It is clear from studies in human and animals that the two phases of bronchoconstriction response to inhaled antigen have distinct characteristics. The immediate response to antigen occurs before airway inflammation is established histologically, is abolished or attenuated by prior bronchodilator drugs like β-2 adrenergic agonist, is sensitive to the effects of antiinflammatory drugs, and is not associated with an increased bronchial hyperreactivity. In contrast, the LAR is associated with histologic evidence of airway inflammation, is relatively resistant to bronchodilator drugs, is lessened by corticosteroids, and is associated with bronchial hyperreactivity. Rabbit experiments showed that if they are depleted of neutrophils and then exposed to inhaled antigen, there will be an immediate bronchoconstrictor response, but there will be no late bronchoconstriction, neither they develop bronchial hyperreactivity. These findings suggest that airway inflammation underlines the bronchial hyperreactivity characteristic of LAR. Non-immunologic causes of airway inflammation are also associated with the development of bronchial reactivity. Inhaled ozone and viral infections damage the bronchial epithelium, leading to an inflammatory response in the bronchial walls and bronchial hyperreactivity develops once airway inflammation become evident. Similarly neutropenic dogs do not develop hyperreactivity after exposure to ozone. All these support the hypothesis that inflammatory processes are important in the pathogenesis of bronchial hyperreactivity.8 The results of skin testing of allergic subjects indicate that isolated immediate hypersensitivity reactions occur in about 20% of positive challenges, isolated late phase reactions in 6-14%, and both reactions in 66 to 85%. Thus, it is apparent that both inflammation and bronchial hyperreactivity are important to bring about these changes. A series of events including cellular elements, mediators, and neuropeptides in a coordinated manner are responsible for the ultimate airway obstruction. A number of cells and chemical by-products take part in the pathogenesis of bronchial asthma to bring about changes outlined above. The stimulus/stimuli in a susceptible host starts the ball rolling so that a number of cells with their products cause various changes that are characteristic of bronchial asthma. The understanding and concept of pathogenesis of bronchial asthma has changed considerably over the past decade. Bronchial asthma is now considered as a heterogeneous disorder with multiple triggers. However, certain features are common to all asthmatics: Airway inflammation and hyperresponsiveness to a broad range of stimuli. It is also known over the last few years that there is a close relationship

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between airway inflammation and hyperresponsiveness. Exposure to oxidants, pollutants, viral infections, chemicals, and allergens are all associated with inflammation and these inflammatory stimuli are associated with airway hyperresponsiveness. Most studies have shown that airway inflammation precedes hyperresponsiveness and may be a prerequisite for the development of hyperresponsiveness and clinical bronchospasm. On the other hand, airway inflammation as in purulent bronchitis may be present without hyperresponsiveness or bronchospasm. Thus, airway inflammation, a hallmark of bronchial asthma is of a specific nature that differs from other types of inflammation. Bronchial asthma is now established as an inflammatory disease of the airways associated with inflammatory cell infiltration, epithelial damage, and subepithelial fibrosis. Bronchoalveolar lavage studies from patients with bronchial asthma have shown increased number of eosinophils, mast cells, epithelial cells, and various humoral and chemical mediators of asthma.9-15 Histopathological studies also have shown epithelial shedding and influx of eosinophils into the airway mucosa.16-18 Fresh biopsies from asthmatics of varying severity have shown epithelial changes, deposition of collagens, and influx of inflammatory cells even in patients with mild asthma.19 Further, presence of increased number of eosinophils in the sputum and peripheral blood of patients with bronchial asthma has been known for many years. It is also reported subsequently that eosinophils and mast cells increase quantitatively during exacerbations of asthma. Substantial data also support the role for both neutrophils and macrophages.20 Specific subtypes of lymphocytes (T-helpers2 [Th2]) may orchestrate a unique inflammatory response in the asthmatic lung and may significantly modulate the function not only of the inflammatory cells, but also non-inflammatory cells which include endothelial cells, platelets, sensory nerves, and airway epithelial cells.21 These non-inflammatory cells may contribute to the inflammatory response and may also directly participate in the regulation of normal airway tone. The function of these cells can be modulated in asthmatics and they may produce mediators with effects on airway function.22-31 INFLAMMATORY CELLS IN ASTHMA Mast Cells Mast cells have been recognised since a long time as the main effectors cells in early asthma reaction.32,33 Normal human respiratory tract contains large numbers of mast cells beneath the bronchial epithelium and alveolar walls. Increased numbers of mast cells and histamine (a product of mast cells) have been found in the bronchoalveolar lavage fluid obtained from patients with bronchial asthma.34,35 These calls are derived from CD34+ cells in the bone marrow.36 Based on the production of proteases, a number of subtypes of mast cells exist in human beings.37 A large number of biologically active molecules, both preformed, i.e. histamine, proteases38 and newly synthesised,39 are released from the mast cell during the allergic reaction when its high affinity, IgE receptors are cross-linked with antigen.40 After immunological activation, some populations of mast cells metabolise arachidonic acid, primarily through the cyclooxygenase pathway to prostaglandin (PGD2), and thromboxane A2, whereas other populations of mast cells metabolize arachidonic acid primarily through the 5'-lipooxygenase pathway to LTB4 and LTC4 (Fig. 3.1). All mast cells have secretory granules that contain large amounts of histamine, proteoglycans, heparin, and proteases. These preformed substances are exocytosed from the cell after immunologic

Pathophysiology of Bronchial Asthma 43

Fig. 3.1: Arachidonic acid metabolism and mediator release (LT- Leukotriene)

activation. It has been shown recently in experimental animals that certain activated mast cells also release transiently a large number of cytokines affect the tissue microenvironment during inflammation. These substances are GM-CSF, INF-γ, IL-1, IL-3-6, PAF, transforming growth factor, JE, and M1P1. These cytokines are capable of recruiting, priming and activating other cells involved in inflammation. Through the release of cytokines similar to those released from TH2 lymphocytes, it is possible that mast cells also play an important role in the development of LAR in addition to its primary role in EAR. It has been suggested that mast cells also possess anti-inflammatory properties through release of heparin and related proteolysis. The tissue damaging properties of cationic protein mediators released from eosinophils (see later) are neutralised by the highly anionic heparin. It has also been shown that heparin inhibits the increased vascular permeability induced by a wide range of agonists, can inhibit lymphocyte activation and trafficking and like glucocorticoids is capable of inhibiting delayed hypersensitivity responses. Thus, it is hypothesised that an imbalance between these inflammatory and anti-inflammatory substances will decide the final outcome. However, this has not yet been proven. Although mast cells are primary cells in EAR through IgE dependent release of spasmogenic mediators, they also have an important role in LAR as they also produce

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GM-CSF, interleukins, etc.41 although some other reports indicate that they are less likely to be involved in the chronic inflammatory response.42,43 Eosinophils44-47 The importance of eosinophils in the causation of bronchial asthma is evident in view of extensive tissue, blood and sputum eosinophilia in this disease. Biopsy studies both postmortem and during life have shown the presence of excess eosinophils in the bronchial mucosa of these patients. They also play a key role in asthma, and their presence in the airways characterises the inflammation of asthma, which has been termed as “chronic eosinophilic bronchitis”. The number of activated eosinophils is closely related to asthma severity and may be associated with epithelial shedding. Their development is dependent on T cell function. The IL-5 specifically stimulates eosinophil differentiation. They have receptors for IgG, IgA, and IgE on their cell surface. These cells are able to produce many mediators that are responsible for the disordered airway function characteristic of asthma. These substances include: • Platelet activating factor • LTB4 • LTC4 • PGE2 • 15-HETE • Oxygen radicals and • Four cytotoxic proteins48-51 i. Major basic protein (MBP) ii. Eosinophil cationic protein (ECP) iii. Eosinophil-derived neurotoxin (EDN) and iv. Eosinophil peroxidase (EPO). All these mediators are released by activated eosinophils. The release of these mediators results in bronchoconstriction, epithelial damage, and recruitment and priming of other inflammatory cells. Eosinophil maturation and priming are under the control of IL-3, IL-4, IL-5, and GM-CSF (Granulocyte macrophage-colony stimulating factor), cytokines released from a number of cell types in the airways including activated T cells of the TH2 type, and mast cells. Another molecule present in the eosinophils is the Charcot-Leydon crystal protein that possesses lysophospholipase activity. Eosinophils have characteristic granules and granule proteins. The granule is composed of a crystalloid core and a matrix. The above four proteins are present in the granules. The genes of these proteins are cloned and the cDNA for MBP specifies the existence of a proMBP molecule that is composed of an acid-rich portion and a basic MBP portion. EDN and ECP are both ribonucleases. In addition, ECP is a potent helminthotoxin. EPO is a member of the peroxidase multigene family that is composed of myeloperoxidase, thyroid peroxidase, and lactoperoxidase. The MBP is toxic to respiratory epithelium and is elevated in the sputum of patients with asthma. It has also been shown that MBP is deposited in the damaged areas in the epithelium. Not only MBP, but also ECP and EPO alone, as well as EPO in the presence of halide and hydrogen peroxidase, damage bronchial epithelium. Experimental studies have shown that eosinophil proteins, particularly MBP applied to respiratory epithelium stimulates smooth muscle contraction and also can increase the sensitivity of the smooth

Pathophysiology of Bronchial Asthma 45 muscle to acetylcholine, which suggests that eosinophil is an effector of the changes of bronchial hyperreactivity in vivo. Lymphocytes52-70 Although production of IgE by B lymphocytes is well known, the role of T lymphocytes in bronchial asthma had received little attention till recently.52,53 Chronic asthma, at least in part, represents a form of delayed-type hypersensitivity involving interactions between “activated” lymphocytes and eosinophils. There are a number of evidences to prove that these cells play important roles in this disease. i. T lymphocytes secrete lymphokines, IL-4, and interferon-γ, that closely regulate IgE production by B lymphocytes. While IL-4 stimulates, interferon-γ inhibits IgE synthesis. ii. IL-3, and IL-5, and GM-CSF regulate eosinophil production, and IL-3, and IL-4 are important regulators of mast cell and basophil production. iii. T cells are attracted to the bronchial mucosal surface to the site of inflammation by specific receptors both on themselves and on the mucosal capillary and endothelial venules. iv. Local accumulation of CD8+ cells in early phase reactions recovered in BAL fluid suggests that the subsequent late phase reaction may be in part, under the control of T cells. Although CD8+ cells are not a part of this reaction, it has been found that substantial infiltration of CD4 IL-2R+ lymphocytes, and activated (EG2+) eosinophils occurs in allergen-induced late phase reaction in atopic subjects. Recently it has been reported that a high percentage of these CD4+ cells are UCLH-1 or memory cells, that respond to recall antigens. v. Patients with acute severe asthma have activated CD4+ lymphocytes in their blood, the number of which returns to baseline value after successful treatment. The elevation is associated with increased serum concentration of IL-2 soluble receptors and INF-γ. These changes corelate well with the severity of disease. vi. Corticosteroid resistant asthmatics have chronically activated circulating T cells (IL-2R and HLA-DR positive). vii. More recently, direct evidence of T cell involvement in bronchial asthma is acquired by the study of mucosal biopsy specimens from volunteers. Electron microscopy has revealed elevated numbers of activated “irregular” lymphocytes in the bronchial mucosa. There is a significant increase in the number of IL-2R+ (CD25) cells both at the central and subsegmental airways. It is now well established that there are two types of T cells.54 They are Th1 and Th2, divided on the basis of lymphokines they secrete. While the Th1 cells secrete IL-2, interferonalpha and tumour necrosis factor-beta, the Th2 cells secrete IL-4,IL-5, IL-6, and IL-10, and IL-3 and GM-CSF are secreted by both. While INF-γ inhibits the development of Th2 cells,55 IL-10 inhibits Th1 proliferation.56 Details of such interaction are being discussed above under genetics and asthma. More recently, another stable phenotype among T-helper clones has been recognised both in mouse and man, which is called Th0. This subtype is characterised by an ability to generate a large variety of cytokines, including IL-4 and INF-γ, which are characteristic of either the Th1 or Th2 subset. Therefore, activated CD4+ cells are a feature of both active and chronic asthma, more so for the later, and their presence is associated with actively secreting eosinophils. T cells may be directly involved in eosinophil recruitment and activation by secreting various

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interleukins which favour the synthesis of IgE and activation of eosinophils and mast cells. There is a preferential expansion of type Th2 T cells secreting IL-3, IL-4, IL-5 and GM-CSF with fewer Th1 cells whose cytokine profile includes IL-2 and interferon-γ. Such a mechanism would explain the peculiarities of allergic inflammation involving isotype switching to IgE synthesis, and the preferential recruitment of eosinophils and mast cells. Lymphokines and various other cytokines that are relevant to airway inflammation in asthma are shown subsequently.57-68 Two important cytokines , that are particularly important in bronchial asthma are IL-4 and NF-KB.69,70 IL-4 is essential for IgE production. INF-γ diminishes cell processing necessary for IL-4 production.69 Thus, interplay of these cytokines will decide whether IL-4 producing cells will be produced, and, thus, whether IgE will be produced in response to various allergic stimuli. The role of transcription-factor NF-KB is emerging recently to play a key role in the pathogenesis of bronchial asthma. It is postulated that inflammatory signals activate transcription factors such as NF-KB and this in turn will switch on the inflammatory genes, which will lead on to the increased expression of inflammatory proteins. Corticosteroids are potent inhibitors of NF-KB and their antiinflammatory action is believed to be mediated through this mechanism.70 Thus, it may be summarised that T cell participation is an important event in allergic diseases and asthma. Th2 cells are more important by the way of production of various cytokines which are necessary for allergic responses. In contrast, Th1 cells are primarily responsible for classic delayed hypersensitivity. Products of Th1 type cells, principally INF-γ, inhibit or antagonize Th2 effector function. IL-4 induces IgE synthesis, and INF-γ is a strong inhibitor of this process. Such control establishes a model of how IgE can be tightly regulated in vitro. The Th2 pathway is also involved in regulation of eosinophilia, mast cell activity and IgE synthesis. The differentiation into Th1 and Th2 cells are again regulated by cytokines. While IL-4 may act directly on the precursor T cell to induce Th2 differentiation, interferon and transforming growth factor-beta TGF-β.71 While T cell sensitisation is an important factor in the development of IgE production to a particular antigen and T cell subsets are important in establishing the process of airway hyperresponsiveness. Experimental data have shown that the transfer of antigen-specific IgE, immediate cutaneous hypersensitivity, and increased airway responsiveness may be mediated, depending on the antigen, by specific Vβ expressing T cell subsets. While the precise mechanisms by which inflammatory cells are recruited into the lungs are not fully understood, increasingly available evidence suggest that the activation of antigen-specific CD4+ T cells of the type 2 T-helper (Th2) subset in the lungs, which results in IL-5 secretion, plays a major role in asthmatic airway inflammation.72 CD4+ T cell activation leading to cytokine production and effector function requires two signals from the antigen-presenting cell (APC). The first signal is triggered by the interaction between antigen-specific T cell receptor and peptide-major histocompatibility complex II complexes on APCs. The second signal or ‘co-stimulatory’ signal is triggered by CD80 (B7-1) and CD86 (B7-2) of the APC binding to the CD28 and cytotoxic T lymphocyte antigen (CTLA-4) of the T lymphocytes.73-76 In the absence of co-stimulatory signals, the T cell-dependent immune response is greatly diminished, or even eliminated.77 Thus, costimulatory signals may fulfill a valuable role in T lymphocyte activation, Type 1 T-helper (Th1) or Th2 cell differentiation, and the production of different cytokines.78 CTLA-4 is a second co-stimulatory molecule and is a homologue of CD28. It is expressed only on activated T cells, binds to accessory molecule B7,79 and mediates T cell-dependent

Pathophysiology of Bronchial Asthma 47 immune response. Signalling through CTLA-4 may down regulate Th1 cell proliferation by inhibiting the production of IL-2 and IL-2 receptor expression.80,81 However, the role of CTLA-4 remains uncertain, with some studies79 the CTLA-4 might also deliver a positive signal to Th2 cell activation. Disruption of this delicate balance of immune regulation could lead to autoimmune diseases or atopic diseases. Therefore, CTLA-4 is considered to be important in the development of many of the immunologic and physiologic features of asthma. Polymorphisms of the CLTA-4 gene, located on chromosome 2q33, could thus have effects on immune response. Three CTLA-4 genes are known at present.82-86 The CTLA-4 promoter (-318 C/T) T allele may serve as a clinically useful marker of severe asthma. This promoter polymorphism is associated with asthma severity, but not with asthma, atopy, or bronchial hyperresponsiveness. A significant association is found between severe asthma and bronchial hyperresponsiveness.85 Monocytes and Macrophages Several findings favour a role for macrophages in bronchial asthma.86-94 Firstly, after in vivo and in vitro contact with specific allergen or non-specific stimulus, alveolar macrophages from asthmatics have been shown to release lysosomal enzymes, prostaglandin (TxB2), leukotrienes, and platelet-activating factor (PAF). They are also able to generate oxygen free radicals, neutral proteases, and β-glucuronidase after non-specific stimulation. Some of these studies also have shown that macrophages from asthmatics are hyperactive and release more lipid-derived mediators than those from the normal subjects. Secondly, a subpopulation of peripheral blood monocytes and alveolar macrophages are IgE receptor positive.95,96 Whereas in normal healthy humans, only 5 to 10% of the alveolar macrophages and 10-15% of the peripheral monocytes are IgE Fc positive, these numbers increase dramatically in asthmatics. As many as 80% of the monocytes and up to 30% of the macrophages recovered from BAL fluid in mild asthmatics will be IgE receptor positive. The percentage may be still higher in severe forms of asthma. The macrophage IgE receptors (IgE FcR) has a low affinity for IgE compared to that of the mast cell. This lower affinity binding suggests that IgE immune complexes may be more important in activation of these cells compared to mast cells and basophils that are sensitised by monomeric IgE, because of their greater strength of binding to this FcR. Thirdly, it has been demonstrated that active macrophages are present at the air-surface interface of human airways as well as in alveoli. Therefore it is possible that these cells interact with any inhaled allergen. Fourthly, macrophages are capable of releasing several potent neutrophil chemotaxins. These include complement fragments, fibronectins, neutrophil attractant/activating protein1 (IL-8), and LTB4. IL-8 is also chemotactic for lymphocytes. The production of LTB4 from macrophages is greater on a nanogram per cell basis than other cells. LTB4 and PAF are chemo attractants for eosinophils. Macrophages produce histamine-releasing factor(s) that induce the release of histamine from basophils. Fifthly, macrophage function is altered by lymphokines, such as INF-γ. It is reasonable to hypothesize that this lymphokine and/or others, such as IL-4, may regulate the number of IgE FcRs on lung macrophages.

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Basophils Basophils are histamine releasing cells in the late phase reaction of asthma unlike mast cells, which release histamine in the early phase reaction. The spontaneous release of histamine is quite high by these activated basophils (20-40% of total). This release process has slow kinetics and is temperature dependent. Various cytokines (IL-1, IL-3, and histamine releasing factor) and PAF have an up regulatory/stimulatory effect on blood basophils. Any or all of these cytokines could prime the basophils such that they become responsive to very low concentrations of stimuli or some could directly trigger basophil mediator release. Epithelial Cells and Adhesion Molecules The infiltration of inflammatory cells into the airways is dependent on the expression of adhesion molecules on inflammatory cells and endothelial cells of the bronchial circulation.97 One consequence of inflammation is epithelial injury. Morphological studies have shown that asthma is associated with epithelial injury. These changes range from minor disruption of the epithelium with loss of ciliated cells to complete denudation of the epithelium. These structural changes in the epithelial barrier can lead to increased permeability to inhaled allergens, irritants, and inflammatory mediators. In addition, transudation of fluids and reduced clearance of inflammatory substances and respiratory secretions occur with disruption of epithelial mucociliary mechanisms. The epithelium also participates in mediator release and metabolism.98-101 They have the capacity to produce PGE2, PGF2α, 12-and 15-hydroxy eicosatetraenoic acid, GM-CSF, etc. The bronchial hyperresponsiveness in asthma is attributed to the epithelial cell damage. The airway epithelial cells have a protective role against various tachykinins. Currently, adhesion molecules are considered to be important in the causation of airway inflammation, although the specific mechanism is still under investigation.102-109 Adhesion of various inflammatory cells to the bronchial vascular endothelium is a key step in the initiation and propagation of inflammation. This is effected by the interaction of various adhesion molecules expressed on endothelial cells, epithelial cells, platelets, and leucocytes. These molecules are specific glycoproteins that are grouped into different families depending upon their molecular structure. These include integrins, immunoglobulin super gene family (intracellular adhesion molecule-ICAM, vascular cell adhesion molecule-VCAM; platelet endothelial adhesion molecule-PCAM), selectins (E-selectin like ELAM-1, and ECAM-1, P-selectin, L-selectin) and carbohydrates are important for lung inflammation. Expression of various adhesion molecules is regulated by various mediators of inflammation. Neutrophils Although neutrophils are found in large proportions in the bronchial wall and bronchoalveolar lavage fluid in bronchial asthma, it is not clear if they have any definite role to play in bronchial asthma. However, such neutrophils in bronchial asthma show increased expression of membrane complement receptors and enhanced toxicity for complement coated antigens. They also have ability to alter airway function. These finding suggest that neutrophils probably participate in inflammation of bronchial asthma.

Pathophysiology of Bronchial Asthma 49 CYTOKINES IN BRONCHIAL ASTHMA Cytokines are extracellular signalling proteins, usually less than 80 KD in size, and many are glycosylated. They are produced by different cell types. A detailed discussion on the role of different cytokines is given below. Various cytokines and their function are shown in Table 3.1.

Cytokines IL-1 IL-2 IL-3 IL-4 IL-5

IL-6 IL-8 IL-10

Table 3.1: Various cytokines, their source and function in the pathogenesis of bronchial asthma110 Origin Function Various cells Th2-cells Th2 cell, mast cells eosinophils T cell, mast cell T cell, mast cells,

Increased expression of endothelial adhesion molecules Eosinophil activation Eosinophil and neutrophil differentiation, activation, and eosinophils survival, eosinophil chemotaxis IgE synthesis, T cell growth, endothelial adhesion Eosinophil differentiation, maturation, activation, eosinophils, adhesion, priming and chemotaxis, basophil differentiation and priming, cofactor in IgE synthesis T cells T cell growth factor, eosinophil chemo-attractant Monocytes, T cells Neutrophil chemo-attractant and activator, fibroblasts inhibits IgE synthesis T cell Inhibition of Th1 cytokine, stimulates monocytes production T cells NK cell and T cell growth, IgE synthesis inhibition T cells Critical regulator of allergic response T cells, mast cells Granulocyte differentiation, activation, survival, macrophages, eosinophils, epithelial cells T cells Eosinophil and macrophage activation T cell and macrophage activation,

IL-12 IL-13 GM-CSF chemotaxis IFN-γ Tumour necrosis factor Platelet derived Monocytes, growth factor (PDGF) Macrophages

Fibrosis, Th2 cytokine inhibition

INFLAMMATORY MEDIATORS IN ASTHMA From the foregoing paragraphs it is apparent that a number of mediators released by different cells are important for various changes observed in bronchial asthma.111-116 They are generated by recruited cells and resident cells of the airways. These mediators cause contraction of airway smooth muscle, increased mucus secretion, microvascular leak, further recruitment and activation of various inflammatory cells, all essential changes in bronchial asthma. LEUKOTRIENES Of the many mediators that have been implicated in the asthmatic response, the sulphidopeptide leukotrienes are of interest because they have the potential of involvement in both aspects of the asthma syndrome, i.e. hyperresponsiveness, and inflammation. The original discovery of a slow-reacting substance was that of smooth muscle contractile activity distinct from histamine; it was distinguished from histamine on the basis that its effects were slow in onset and prolonged in duration.117 The subsequent isolation and elucidation

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of the structure of slow-reacting substance was identified as cysteinyl leukotrienes (LTC4, LTD4, LTE4) which are synthesised and exported into the microenvironment by a number of the above mentioned inflammatory cells, including mast cells and eosinophils.118-127 Furthermore, since plasma leakage is prominent in more severe asthma, it is likely that the vascular endothelium will be exposed to cells capable of donating LTA4. It is well established that the cysteinyl leukotrienes are formed when LTA4 exporting cells, such as polymorphonuclear leucocytes (neutrophils and eosinophils) provide LTA4 for effector cells such as vascular endothelial cells or platelets. As shown in Figure 3.2 arachidonic acid (AA) released from membrane phospholipids during cell activation may be oxidatively metabolised by the enzymes of the cyclooxygenase or lipooxygenase pathways.109 Arachidonate is presented to the 5-lipooxygenase enzyme by 5-lipooxygenase-activating protein (FLAP).120 This FLAP is a cofactor resident in the nuclear membrane. While cyclooxygenase pathway produces prostaglandins and thromboxane, the 5-lipooxygenase pathway generates 5-hydroperoxy-eicosatetraenoic acid (5-HPETE) or is converted enzymatically to the unstable intermediate LTA4. LTA4 is metabolised by an epoxide hydrolase to LTB4, or by a glutathion-S-transferase (LTC4 synthase) to LTC4.128 LTC4 is cleaved by glutamyl-transpeptidase to LTD4, which is converted by a peptidase to LTE4, these enzymes being ubiquitous in the tissues and circulation (Fig. 3.2). LTB4 is a potent chemo attractant for neutrophils, and the sulphidopeptide leukotrienes (LTC4, LTD4, and LTE4) are potent spasmogens for non-vascular smooth muscle and comprise the activity previously known as slow-reacting substance of anaphylaxis (SRS-A). The leukotrienes have profound biochemical and physiologic effects, even in Pico molar concentrations. The importance of leukotrienes has been suggested in a wide variety of disorders that include hepatorenal syndromes, myocardial ischaemia, and inflammatory conditions of bowel, skin and joints,122 besides their involvement principally in bronchial asthma.123 These include severe airway obstruction, i.e. bronchoconstriction,129 oedema,130 and increased secretion of bronchial mucus from submucosal gland secretion.131 The most

Fig. 3.2: Synthesis of leukotrienes and their function

Pathophysiology of Bronchial Asthma 51 prominent effect is their ability to mediate airway narrowing in normal subjects as well as in subjects with asthma. The airway obstruction is prolonged compared to that induced by histamine. LTC4 and LTD4 are approximately 3000 times more potent in contracting the airway compared to histamine in normal subjects. LT4 is also a potent bronchoconstrictor although 30-100 times less potent than the above two. LTE4 induces a state of enhanced airway responsiveness in asthmatics, but not in normal subjects. Inhalation of LTE4at doses that induce a small but significant contractile response enhances the response to subsequent administration of inhaled histamine. This enhancement is on the order of a four-fold shift in the histamine dose-response curve with the effect lasting approximately 24 hours with small effects persisting for up to a week. Thus a state of airway hyperresponsiveness is maintained. Leukotriene B4 (LTB4) is a potent chemotactic factor and is responsible, in part, for the recruitment of inflammatory cells to the airway and stimulation of secretion of inflammatory products. Their role in the smooth muscle contraction is controversial, although some studies suggest that they may increase airway smooth muscle responsiveness to subsequent stimulation. This can also modulate the immune response by inhibiting the capacity to mount a delayed hypersensitivity response.132 The cells producing leukotrienes are only macrophages, neutrophils, eosinophils, and mast cells that can synthesise them from the substrate arachidonic acid. However, subsequent enzymes like LTA4 hydrolase, and LTC4 synthase are more broadly distributed including non-inflammatory cells, airway epithelial cells and in the lung lining fluids. It is also now recognised that synthesis of leukotrienes in the lung may involve a single inflammatory cell type or an interaction between inflammatory and non-inflammatory cells termed “transcellular metabolism”. Some reports suggest that even transcellular metabolism may be the principal source of LTC4 in the lungs.133,134 These leukotrienes are recovered from nasal lavage fluid after inhalation challenge. Significantly larger quantities are also recovered from the BAL fluid from subjects with symptomatic asthma. Sulphidopeptide leukotrienes have been detected in the plasma during asthma attacks. Larger quantities of these substances have been recovered from the urine of asthma patients during acute spontaneous attacks than found in normal subjects. The recent development and usefulness of leukotriene receptor antagonists and synthesis inhibitors in bronchial asthma further emphasizes the role of these leukotrienes in the pathogenesis of this condition.135-138 Leukotrienes are important in asthma, and leukotriene modifiers modulate antigeninduced asthma. Leukotrienes participate in the pathogenesis of bronchial asthma besides the involvement eosinophilic airway inflammation.139 Overproduction of leukotrienes not only occurs in house dust mite provoked asthma, but also in aspirin induced bronchial asthma, although the mechanisms of such overproduction are different. While in the former the overproduction occurs with an antigen-antibody reaction, in aspirin-induced asthma, the overproduction is due to a shift to the 5-lipooxygenase series of the arachidonate cascade.140 Pranleukast, a leukotriene inhibitor suppresses the increased values of sputum eosinophil count and eosinophil cationic protein during house dust mite-induced asthma are suppressed by further, this drug increases FEV1 that falls during such provocation.140 The role of leukotrienes in the pathogenesis of aspirin-induced asthma comes from the fact that airway narrowing and other signs in these patients are associated with 2-10 fold higher values of LTE4 in the urine of these patients compared to aspirin tolerant patients.141-143

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Further, several leukotriene modifiers inhibit the asthma response in oral or inhaled bronchoprovocation by aspirin and other non-steroidal anti-inflammatory agents144,145 and improve respiratory function by bronchodilatation.146 Mast Cell Proteases As much as 70% of the weight of a mast cell consists of proteases that are enzymatically active at neutral pH. These cells express a complex array of proteases, which consist of serine proteases, tryptases, and chymase. These enzymes regulate neuropeptide regulation in the airways, smooth muscle contraction, and submucosal gland secretion.147-149 Histamine, another mast cell product has a well-established role in the pathogenesis of asthma. It induces bronchospasm, increases vascular and epithelial permeability, and increases the mucous glycoprotein secretion.150 Histamine The role of histamine in the pathogenesis of bronchial asthma is well established for a long time. Histamine induces bronchoconstriction, increases epithelial and vascular permeability, and increases the secretion of mucus glycoproteins.150 In patients of bronchial asthma, the levels of histamine are increased in blood and bronchoalveolar lavage fluid.151,152 Prostaglandins PGD2 and PGF2- A are very potent bronchoconstrictor agents. The former has greater bronchoconstrictor activity compared to that of the later or histamine.153 Both these prostaglandins also potentiates the bronchoconstricting activity of histamine and methacholine.155,156 On the other hand, PGE1 and PGE2 has bronchodilating effect. While Thromboxane A2 (TXA2) is a bronchoconstrictor, vasoconstrictor, and platelet aggregator, PGI2 is a bronchodilator, vasodilator and prevents platelet aggregation.156,157 Platelet-activating Factor (PAF) PAF has attracted attention as an important mediator of bronchial asthma.158-161 Recovery of this substance from bronchoaveolar lavage fluid in antigen exposed individuals supports such a role.162,163 It is an important mediator involved in the bronchial hyperresponsiveness in addition to having action of bronchoconstriction, stimulation of eosinophil and eosinophil accumulation in the airway, induction of airway microvascular leakage and oedema, and increased airway secretions and epithelial permeability. Bradykinin Bradykinin is another important inflammatory mediator in asthma and asthmatics have increased responsiveness to bradykinin,164 and the levels are found to be high in bronchoalveolar lavage fluid from these patients165 The substance causes bronchoconstriction, increases vascular permeability, has vasodilator activity, increases mucus secretion, activates C-fibre nerve endings, enhances neuropeptide release from sensory nerves, and increases cholinergic reflex.164, 166,167 Bradykinin mediates its effects through BK1 and BK2 receptors,166 although the effects on airways are primarily mediated via BK2 receptors. It also releases tachykinins from airway sensory nerves.

Pathophysiology of Bronchial Asthma 53 Cytokines Cytokines are extracellular signalling proteins, usually less than 80 kD in size and many are glycosylated. They are produced by different cell types involved in cell-to-cell interactions, having an effect on closely adjacent cells, and therefore function in a predominantly paracrine fashion. They may also act at a distance (endocrine) and may have effects on the cell of origin (autocrine). A classification according to function is proposed in Table 3.2. Table 3.2: Classification of cytokines and cytokine receptors

Cytokines Pro-inflammatory cytokines

IL-1α/β, TNFα/β, IL-6, IL-11, IFN-γ

Cytokines involved in atopy

IL-4, IL-13 (promoters); IFN-γ, IL-12 (inhibitors)

Cytokines of eosinophil chemo-attraction and activation

IL-2, IL-3, IL-4, IL-5, GM-CSF, RANTES, eotaxin, MCP-3, MCP-4

Th2 cytokines

IL-4, IL-5, IL-10, IL-13

Cytokines involved in T cell chemo-attraction

IL-16, RANTES, MIP-1α/β

Cytokines of neutrophil chemo-attraction and activation

IL-8, IL-1α/β, TNFα/β

Anti-inflammatory cytokines

IL-10, IL-4, IL-13, IL-12, IL-1ra

Growth factors

PDGF, TGF-β, FGF, EGF, TNF-α, SCF

Cytokine receptors Cytokine receptor super family

IL-2Rβ-and γ-chains, IL-4R, IL-3R α-and β-chains, IL-5 α-and β-chains, IL-6R, gp130, IL-12R, GM-CSFR; soluble forms by alternative splicing (e.g. IL-4R)

Immunoglobulin super family

IL-1R, IL-6R, PDGFR, M-CSFR

Protein kinase receptor super family

PDGFR, EGFR, FGFR

Interferon receptor super family

IFN-α/β receptor, IFN-γ receptor and IL-10 receptor

Never growth factor super family

NGFR, TNFR-1(p55), TNFR-II(p75)

Seven-transmembrane G-protein coupled receptor super family

Chemokine receptors

The effects of an individual cytokine may be influenced by other cytokines released simultaneously from the same cell or from target cells following activation by the cytokine, and are mediated by binding to cell surface high-affinity receptors usually present in low numbers, which can be up regulated with cell activation. The receptors for many cytokines have been regrouped into super families based on the presence of common homology regions (Table 3.3). Cytokines themselves may induce the expression of receptors which may change the responsiveness of both source and target cells. Some cytokines may stimulate their own production in an autocrine manner, where as others stimulate the synthesis of difference cytokines that have a feedback stimulatory effect on the first cytokine, resulting in an increase in its effects. The effects of cytokines are summarised in Table 3.3.168

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Cytokines Lymphokines IL-2 IL-3 IL-4

IL-5

IL-13

IL-15 IL-16 IL-17

Pro- inflammatory IL-1

TNF-α

IL-6

IL-9

IL-11

GM-CSF

Important cellular and mediator effects • • • • • • • • • • • • • • • • • • • • • •

Eosinophilia in vivo Growth and differentiation of T cells Eosinophilia in vivo Pluripotent haematopoietic factor ↑ Eosinophil growth ↑ Th2; ↓ Th1 ↑ IgE ↑ Mucin expression and goblet cells eosinophil maturation ↓ Apoptosis ↓ Th2 cells BHR Activates eosinophils ↓ apoptosis ↑ IgE ↑ mucin expression and goblet cells As for IL-2 Growth and differentiation of T cells Eosinophil migration Growth factor and chemotaxis of T cells (CD4+) T cell proliferation Activates epithelia, endothelial cells, fibroblasts

• ↑ adhesion to vascular endothelium; cosinophil accumulation in vivo • Growth factor for Th2 cells • B cell growth factor; neutrophil chemo-attractant; T cell and epithelial activation • BHR • Activation epithelium, endothelium, antigen-presenting cells; monocytes/macrophages • BHR • ↑ IL-8 from epithelial cells • ↑ MMPs from macrophages • T cell growth factor • B cell growth factor • ↑ IgE • ↑ Activated T cells and IgE from B cells • ↑ Mast cell growth and differentiation • ↑ Mucin expression and goblet cells • Causes eosinophilic inflammation and BHR • B cell growth factor • Activates fibroblast • BHR • Eosinophil apoptosis and activation; induces release of leukotrienes

Contd...

Pathophysiology of Bronchial Asthma 55 Contd... Cytokines

SCF

Important cellular and mediator effects • Proliferation and maturation of haematopoietic cells; endothelial cell migration • BHR • ↑ VCAM-1 on eosinophils • Growth factor for mast cells

Inhibitory cytokines IL-10 • • • • IL-1ra • • IFN-g • • • • • IL-18 • • • • Growth factors PDGF • • TGF-β • • • • •

↓ Eosinophil survival ↓ Th1 and Th2 ↓ Monocyte/macrophage activation; ↑ B cell; ↑ mast cell growth ↓ BHR ↓ Th2 proliferation ↓ BHR ↓ Eosinophil influx after allergen ↓ Th2 cells Activates endothelial cell, epithelial cells, alveolar macrophages/monocytes ↓ IgE ↓ BHR ↓ Via IFN-γ release Releases IFN-γ from Th1 cells Activates NK cells, monocytes ↓ IgE Fibroblast and airway smooth muscle proliferation Release of collagen ↓ T cell proliferation Blocks IL-2 effects Fibroblast proliferation Chemo-attractant for monocytes, fibroblasts, mast cells ↓ Airway smooth muscle proliferation

Inflammation and Cytokines in Asthma

Asthmatic Inflammation The chronic airway inflammation of asthma is characterised by an infiltration of T lymphocytes, eosinophils, macrophages/monocytes and mast cells, and sometimes neutrophils. An acute or chronic inflammation may be observed with acute exacerbations, with an increase in eosinophils and neutrophils in the airway submucosa and release of mediators, such as histamine and cysteinyl-leukotrienes, from eosinophils and mast cells to induce bronchoconstriction, airway oedema and mucus secretion. Changes in the resident cells are also observed, such as an increase in the thickness of the airway smooth muscle with hypertrophy and hyperplasia, more myofibroblasts with an increase in collagen deposition in the lamina reticularis, more vessels and an increase in goblet cell numbers in the airway epithelium. Cytokines play an integral role in the coordination and persistence of the inflammatory process in the chronic inflammation of the airways (Table 3.3).

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Th2-associated Cytokines CD4+ T lymphocytes of the asthmatic airways express Th2 cytokines including IL-3, IL-4, IL5, IL-10, IL-13 and GM-CSF. The primary signals that activate Th2 cells may be related to the presentation of a restricted panel of antigens in the presence of appropriate cytokines. Dendritic cells are ideally suited to being the primary contact between the immune system and external allergens. Co-stimulatory molecules on the surface of antigen-presenting cells, in particular B7.2/ CD28 interaction, may lead to proliferation of Th2 cells.169 With the expression of IL-4, synthesis of IgE by B lymphocytes on immunoglobulin isotype switching occurs.170 IgE produced in asthmatic airways binds to FcεRI receptors (high-affinity IgE receptors) on mast cells priming them for activation by antigen. The maturation and expansion of mast cells from bone marrow cells involve growth factors and cytokines such as SCF and IL-3 derived from structural cells. Bronchoalveolar mast cells from asthmatics show enhanced release of mediators such as histamine. Mast cells also elaborate IL-4 and IL-5.171 IL-4 also increases the expression of an inducible form of the low-affinity receptor for IgE (FcεRII or CD23) on B lymphocytes and macrophages.172 IL-4 drives the differentiation of CD4+ Th precursors to Th2- like cells. IL-18 is a cytokine with potent interferon (IFN)- γ-inducing activity. It is predominantly produced by activated macrophages and synthesised with IL-12 to induce (IFN)- γ synthesis from T lymphocytes, promoting differentiation of T cells to the Th1 subsets. The IL-18 levels are low in the BAL fluid of patients with bronchial asthma. This inherently low levels of IL18 may be associated with pathogenesis of asthmatic airway inflammation.173

Antigen presentation Cytokines may play an important role in antigen presentation (Fig. 3.3). Airway macrophages are usually poor at antigen presentation and suppress T cell proliferative responses (possible via release of cytokines such as IL-1 receptor antagonist), but in asthma there is reduced suppression after exposure to allergen.174 Both GM-CSF and IFN-γ increase the ability of macrophages to present allergen and express HLA-DR.175 IL-1 is important in activating T lymphocytes and is an important co-stimulator of the expansion of Th2 cells after antigen presentation.176 Airway macrophages may be an important source of first-wave cytokines, such as IL-1, TNF-α and IL-6, which may be released on exposure to inhaled allergens via FcεRI receptors. These cytokines, may then act on epithelial cells to release a second wave of cytokines, including GM-CSF, IL-8 and RANTES which then leads to influx of secondary cells, such as eosinophils, which themselves may release multiple cytokines. Eosinophil-associated cytokines The differentiation, migration and pathobiological effects of eosinophils may occur through the effects of GM-CSF, IL-3, IL-5 and certain chemokines such as eotaxin.177,178 IL-5 and eotaxin also induce the mobilisation of eosinophils and eosinophil precursors into the circulation.179 Mature eosinophils may show increase survival in bronchial tissue.180 Eosinophils themselves may also generate other cytokines such as IL-3, IL-5 and GM-CSF.181 Cytokines such as IL-4 may also exert an important regulatory effect on the expression of adhesion molecules such as VCAM-1, both on endothelial cells of the bronchial circulation and on airway epithelial cells. IL-1 and TNF-α increase the expression of ICAM-1 in both vascular endothelium and airway epithelium.182 Cytokines also play an important role in recruiting inflammatory cells to the airways.

Pathophysiology of Bronchial Asthma 57

Fig. 3.3: Cytokines and cell interaction in bronchial asthma

Airway wall remodelling cytokines Proliferation of myofibroblasts and the hyperplasia of airway smooth muscle may occur through the action of several growth factors such as PDGF and TGF-β. They may be released from inflammatory cells in the airways, such as macrophages and eosinophils, but also by structural cells, such as airway epithelium, endothelial cells and fibroblasts. These growth factors may stimulate fibrogenesis by recruiting and activating fibroblasts or transforming myofibroblasts. Epithelial cells may release growth factors, since collagen deposition occurs underneath the basement membrane of the airway epithelium.183 Growth factors may also stimulate the proliferation and growth of airway smooth muscle cells. PDGF and EGF are potent stimulants of human airway smooth muscle proliferation184 and these effects are mediated via activation of tyrosine kinase and protein kinase C. Cytokines, such as TNF-α and FGF may also play an important role in angiogenesis of chronic asthma. Oxygen Radicals Oxygen radicals have been indirectly implicated in the development of hyperresponsiveness. They are produced by neutrophils, eosinophils, and macrophages in the lungs. The relative importance of these substances in bronchial asthma is poorly defined.

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Nitric Oxide Although it is now well established that normal subjects have measurable concentrations of nitric oxide (NO.) in their expired air, in patients with bronchial asthma the peak or mixed expired NO are about 50% higher.185-187 Furthermore, compared with normal subjects, the airways of patients with asthma have up regulated expression of type II nitric oxide synthase, NOS.188 Taken together, these findings have led to the speculation that expired concentrations of NO reflect the inflammatory microenvironment of the asthmatic airway wall.189 Neurotrophins The neurotrophins are a family of peptides that promote survival, growth, and differentiation of neurons. They may also influence the function of non-neuronal cell types, including immune cells. The development and maintenance of asthma are thought to involve nervous system and the immune system, but the exact role that the neurotrophins play is unclear. The cellular sources of neurotrophins include mast cells, lymphocytes, macrophages, epithelial cells, smooth muscle cells, and eosinophils. The action of neurotrophin receptors like Trk (tyrosine kinase) acts possibly act in concert with known immune regulating factors to modulate the maturation, accumulation, proliferation, and activation of immune cells. Neurotrophins also can modulate afferent nerve function by stimulating the production of neuropeptides within airway afferent neurons. These neuropeptides may be released from the central terminals of airway afferent neurons, which leads to increased autonomic reflex activity, and increased reactivity in the airways.190 The role of different mediators is summarised in Table 3.4. Table 3.4: Role of mediators causing pathological changes in asthma Pathological changes Mediator implicated Bronchospasm Histamine (H1response) LTC4, LTD4, LTE4 Prostaglandins and TXA2 Bradykinin Platelet activating factor Acetylcholin Mucosal oedema Histamine (H1response) LTC4, LTD4, LTE4 Prostaglandin E Bradykinin Platelet activating factor Cellular infiltration Eosinophil chemotactic factor (airway hyperreactivity) Neutrophil chemotactic factor HETEs LTB4 Mucus secretion Histamine (H1response) LTC4, LTD4, LTE4 Prostaglandins generating Factor of anaphylaxis Prostaglandins HETEs Acetylcholin Macrophage mucus secretagauge Desquamation O–2, H2O2, OH– Proteolytic enzymes Basement membrane thickening O–2, Proteolytic enzymes

Pathophysiology of Bronchial Asthma 59 NEUROPEPTIDES IN ASTHMA There is increasing evidence that abnormal neurogenic mechanisms and neuropeptides contributing in the pathophysiology of bronchial asthma.191-197 Autonomic nerves regulate airways smooth muscle tone, mucous secretion, blood flow, vascular permeability, and migration and release of inflammatory cells.198,199 Neuropeptides are small amino acid components that are localised to neurons. Originally described in the gastrointestinal tract, neuropeptides were first termed “gut hormones”. Upon their discovery subsequently in brains, they were termed as “gut-brain hormones”. However, now it is established that these peptides are present throughout the body and may be produced by, localised to, cells other than cells of the nervous system. In the respiratory tract, they are located in neurons, neuroendocrine cells, and inflammatory cells. Neuroendocrine cells are granulated epithelial cells found throughout the conducting airways. They contain a number of peptides, including calcitonin, katacalcin, CGRP (calcitonin gene-related peptide), and bombesin. Neuropeptides such as VIP (vasoactive intestinal peptide) has been identified in various inflammatory cells including eosinophils, mast cells, and mononuclear and polymorphonuclear leucocytes. Once released these peptides act as either neurotransmitters, hormones, or mediators. They modulate airway caliber, vascular tone, mucus secretion, and vascular permeability. They are also capable of affecting inflammatory cell function by modulating mediator release and chemotactic responses. Their wide spread distribution and different physiological effects make neuropeptides excellent candidates to play important roles in asthma. The neural control of the airways is mediated by three pathways: cholinergic (parasympathetic); adrenergic (sympathetic); and the nonadrenergic noncholinergic (NANC) pathways.191 The cholinergic nervous system is considered excitatory in nature because it plays an important role in maintaining bronchial smooth muscle tone and in mediating acute bronchospastic responses. The system consists of vagal afferent fibres in and around the airway lumen that travels to the central nervous system and then terminate in efferent fibres. The later innervate airway smooth muscle. There are three types of pharmacologically defined muscarinic receptors, which are important in regulating the smooth muscle tone. The M1 receptor is located in the parasympathetic ganglia and facilitates vagal transmission. The M3 receptors are present in large airways and in some peripheral airways and are largely responsible for smooth muscle contraction. The M2 receptor functions as an autoreceptor in airway tissue, acting as a feedback-inhibitory receptor to reduce neurotransmission. Acetylcholin is the cholinergic messenger. Acetylcholin normally binds to the cholinergic receptor and causes release of cyclic 3',5'-guanosine monophosphate (cyclicGMP). This causes bronchoconstriction. Cholinergic nerves are the dominant neural bronchoconstrictor pathways for human lungs. Triggers like sulphur dioxide, prostaglandins, histamine, and cold air stimulate afferent receptors causing reflex bronchoconstriction. Inflammatory mediators like histamine, prostaglandins, and bradykinin stimulate irritant receptors and C-fibre endings in the airway leading to a reflex bronchoconstriction.200 Neurotransmitters like TxA2, PGD2, and tachykinins enhance Acetylcholine release from the postganglionic nerves in the airways. It is suggested that M2 autoreceptors are dysfunctional in bronchial asthma.201 The sympathetic nervous system in the bronchial tree is inhibitory because of its prominent airway relaxant effect. This is mediated by β-receptor stimulation and by cAMP. Adrenergic

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fibres represent only a minor component of the total nerve fibres in human airways. Although there is little or no direct sympathetic innervations of human airways, there are many αand β-adrenergic receptors that are important in regulating bronchomotor tone. Earlier it was believed the imbalance between cGMP and cAMP production was the underlying mechanism of bronchial asthma, (Yin-Yang hypothesis). The neurotransmitters for the NANC nervous system were initially thought to be purine nucleotides, such as adenosine and adenosine triphosphate and accordingly the NANC nerves were termed “purinergic”. However, now it is believed that the neurotransmitters are not purines, but peptides, and thus the nerves are “peptidergic”. Although a number of neurotransmitters have been identified, only VIP, peptide histidine methionine (PHM), and nitric oxide may be the neurotransmitters of the nonadrenergic inhibitory nervous system and thus are important endogenous bronchodilators.202,203 They also decrease mucus secretion and manifest anti-inflammatory actions. Deficiency of this system has been postulated to contribute to the development of bronchial hyperreactivity. Functional deficiencies of the system can result from blockade of nonadrenergic pathways at the level of ganglia or nerve endings; from deficiency of airway VIP or PHM receptors, or from enhanced breakdown of neuropeptides by peptidases released from inflammatory cells in the asthmatic airway. It has been demonstrated recently that there is a loss of VIP from pulmonary nerve fibres in asthmatics. Immunoreactive VIP is observed within nerves in more than 90% of lung sections from normal subjects but is not identified in any lung sections from patients with asthma. However, it is not clear whether it is a primary or secondary event. Other peptides such as substance P, neurokinin A (substance K, neuromodulin L) and calcitonin gene-related peptide (CGRP) are believed to be neurotransmitters of the noncholinergic excitatory system and thus act as endogenous bronchoconstrictors.204-209 These peptides also play a role in regulating mucus production, pulmonary vasomotor tone, mucosal permeability, and inflammatory cell function. A number of substances are known to release neuropeptides from these nerves include capsaicin (most potent), irritant gases, antigen, and various inflammatory mediators, including histamine, bradykinin, and prostaglandins. These neuropeptides have the remarkable ability to affect multiple cells in the airways and to provoke many responses including cough, mucus secretion, smooth muscle contraction, plasma extravasations, and neutrophil adhesion. This series of effects is termed as “neurogenic inflammation”.210-215 An enzyme neutral endopeptidase (NEP) exists on the surfaces of all lung cells. The enzyme inactivates the neuropeptides limiting their concentration. Angiotensin converting enzyme (ACE) also helps in the degradation of these neuropeptides. Thus neurogenic inflammatory responses are normally mild and probably protective in nature. It is proposed that in asthma, a decrease in the normal degradation process of substance P occurs by NEP or ACE. Cigarette smoke, respiratory viral infections, and inhalation of industrial pollutant toluene diisocyanate inhibit NEP and exaggerate neurogenic inflammation. In addition, there are reports that there are more substance P immunoreactive nerves in the lungs of patients with asthma compared to that in normal subjects. Therefore, in addition to the proposed changes in the cholinergic and adrenergic nervous systems, subjects with asthma have now been revealed to potentially have changes in their nonadrenergic inhibitory and noncholinergic excitatory nervous system. These changes will lead to an imbalance in the autonomic nervous system and predispose subjects with asthma towards bronchospasm (Fig. 3.4).

Pathophysiology of Bronchial Asthma 61

Fig. 3.4: Autonomic imbalance postulated for bronchial asthma

It is suggested that abnormal control of the airway is the underlying mechanism of bronchial hyperreactivity, with a preponderance of excitatory (cholinergic and α-adrenergic) or a deficiency of inhibitory (α-adrenergic) control. Bronchial Hyperreactivity Airway hyperresponsiveness to a large number of stimuli is a characteristic feature of asthma in humans. Various components of the tracheobronchial tree might contribute to this phenomenon, such as smooth muscle, the bronchial epithelium, various neurohumoral mechanisms and the mechanical linkage between the lung parenchyma and the airways including the baseline airflow obstruction. The degree of responsiveness can be further increased by a series of stimuli associated with inflammation in the periphery of the lung. Such stimuli actually induce an asthmatic state or heighten the vulnerability of asthmatics, making them more prone to overt attacks in response to minor stimuli that would be ordinarily tolerated. Depending upon the inciting stimulus, different cells and mediators may be playing a role in producing and perpetuating the inflammatory state and producing further increases in responsiveness. The level of airway responsiveness usually correlates with the clinical severity of asthma and medication requirement. The airways of asthmatic subjects are 14-fold, 15-fold, 5-fold, 9-fold, and 194-fold more responsive than were the airways of normal subjects to histamine, methacholine, LTC4, LTD4, and LTE4 respectively in a direct comparison of the potencies of these substances in six asthmatics and six controls.112 Further, cumulative data suggest that hyperresponsiveness to the leukotrienes may be more marked in the central rather than the peripheral airways of asthmatic subjects. Bisgard reported that the airways of 8 asthmatic subjects were more responsive to LTD4 than were those of 9 nonasthmatic controls; the relative differences in potencies between asthmatic and controls were 100- to 1000-fold when measured in terms of FEV1 but they were only 15fold differences in V30.216 Similarly Smith et al reported a 30% fall in V30 in response to LTD4

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was accompanied by a 60% fall in sGaw in asthmatic subjects but only a 30% fall in sGaw in normal controls.217 In another study Davidson et al reported a 30% fall in V30 induced by inhaled histamine was accompanied by a 10 and 13% fall in FEV1 in asthmatic and normal subjects, respectively. But when the same individuals inhaled LTE4, a 30% fall in V was accompanied by a 17% fall in FEV1 in asthmatic subjects and a 3% fall in FEV1 in normal controls.218 While FEV1 represents the central airway function, V30 represents small or peripheral airways function. The interaction of various factors and the pathophysiology of bronchial asthma is summarised in Figure 3.5. β AR) and Asthma Beta-adrenergic Receptors (β β ARs belong to the family of adrenergic receptors that use the endogenous catecholamines epinephrine and norepinephrine (and, to a lesser extent dopamine) as agonists. Nine different adrenergic receptor subtypes have been cloned.219 There are three β AR subtypes (β1, β2, β3) and they couple to the stimulatory G-protein, Gs, which results in activation of adenyl cyclase and increases in intracellular cAMP. The β2 AR is expressed to some extent in virtually every tissue in the body. In the lung, this is present in epithelium, smooth muscle of bronchi and bronchioles, submucosal glands, the endothelium and smooth muscle of pulmonary arteries, alveolar walls, immune cells including mast cells, macrophages, eosinophils, neutrophils, and lymphocytes. There are reports that β3AR also regulates bronchial smooth muscle tone in pharmacological in vivo studies. β2 AR has been studied extensively and thought to have important therapeutic implications. Recent genetic polymorphisms of the β2 AR have been identified in the population, which may be the basis of a more severe form of the disease or the basis of the heterogeneity of receptor expression and response to betaagonists observed clinically.220 Some of the important molecular domains that have been found to be important for receptor function have also been identified. Although a number of studies have addressed whether β2 AR are dysfunctional in asthma, there appears to be no consensus in this matter.221 It seems that beta-receptor dysfunction may not be the primary lesion in asthma. Perhaps this occurs as a secondary phenomenon in asthma either because of the drugs used and thus acquired or there may be a receptor mutation or polymorphism. Szentivanyi proposed in 1968 that asthma may be due to an inherited or acquired deficit in β-adrenoceptor function.222 Several lines of evidence suggest that the β2-adrenoceptor may be abnormal in asthma, making the β2-adrenoceptor gene an attractive candidate gene in this disease. Administration of β2-adrenoceptor agonists increases airway tone and responsiveness in patients with asthma.223 Bronchial or tracheal smooth muscle obtained at either autopsy or surgery from asthmatic patients show a deficit in β-adrenoceptor function.224-227 A large number of polymorphisms or point mutations have been described in the human β2-adrenoceptor gene. A restriction fragment length polymorphism (RFLP) of this gene has been reported using the restriction enzyme Ban I.228 Another biallelic polymorphism is reported using the restriction enzyme Fnu4HI,229 while subsequent investigations reported nine different point mutations within the coding region, four of which result in changes in amino acid residues 16, 27, 34 and 164.230 Moreover, cells transferred with β2-adrenoceptor complimentary DNA containing the mutations at amino acid positions 27 or 164 showed altered β-adrenoceptor function. Studies on the distribution of Ban I polymorphisms in South African asthmatics showed the presence of both these alleles in this group, but the genotypes were found with similar frequencies in

Pathophysiology of Bronchial Asthma 63

Fig. 3.5: Interaction of various factors in the causation of asthma

allergic and nonallergic subjects. Further studies on sequencing of the β2-adrenoceptor gene identified nine separate point mutations or polymorphisms, but there was no significant difference in the frequency of alleles between the asthmatic and nonasthmatic patients.230 Japanese investigation on family members of asthmatics found a higher prevalence of asthma in family members who lacked the 3.1 kb Ban I RFLP, but the findings were not sufficient to exclude genetic linkage to either methacholine responsiveness or allergy.231 Subsequent

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studies also showed that distribution of these alleles was not different between asthmatics and nonasthmatics,232 although it was not possible to exclude an association. In a more recent study to exclude genetic linkage between the β2-adrenoceptor gene and asthma, allergy, and methacholine airway hyperresponsiveness, indicated that these are not linked to a dominant β2-adrenoceptor gene with strong effect in families with an inherited pattern of asthma.233 Nitric Oxide (NO) and Bronchial Asthma185-188 Nitric oxide is synthesised from L-arginine by the enzyme NO synthase (NOS). Two forms of NO is known; iNOS (independent of Ca++) and cNOS (Ca++/calmodiulin-dependent, constitutive form). While the former is induced by TNF-alpha and beta, interferon gamma, endotoxins, interleukin-1 and other cytokines, stimulation of the later occurs through mediators like bradykinin, histamine, PAF, acetylcholine, and leukotrienes. Thus, it is obvious that NO has the potential to affect a number of cells critical for normal lung function and NO possibly plays a key role in the pathogenesis of asthma and its inhibitors may be useful therapeutically to treat asthma.221 Nitric oxide is present in the expired air of healthy individuals.234 It is a known bronchial smooth muscle relaxant. Thus its level should be reduced in bronchial asthma. But on the contrary, NO is higher in the expired air of asthmatics,185,235 and epithelial NOS is higher in the epithelial cells in them.236 This implies that NO may increase in asthma as a compensatory response to other factors, such as those that cause bronchoconstriction or inflammation. Further, elevated NO might exacerbate bronchial obstruction because NO relaxes vascular smooth muscle and thus, vascular engorgement which is an important pathogenetic mechanism. In addition, elevated NO may result in elevated NO reaction products, such as superoxides, particularly peroxynitrite, which may cause airway damage if excess. However, it is not clear whether elevated NO is part of the primary pathologic process in asthma or is a compensatory response. SUMMARY OF EVENTS LEADING TO AIRWAYS INFLAMMATION The pathogenesis of bronchial asthma is more clearly understood in extrinsic or allergic asthma and is summarised in Figure 3.6.237 Although the terms “intrinsic” and “extrinsic” no longer adequately reflect our knowledge of the clinical syndrome of asthma, recent advances in the understanding of its pathophysiology indicate that it is a heterogenous disorder with multiple triggers. There are, however, features, which are virtually common to all asthmatics. These include airways inflammation and hyperreactivity to a broad range of stimuli. The chronic allergic response is a continuous process of IgE generation, mast cell activation, and eosinophil recruitment. These processes are orchestrated by T lymphocytes. In atopic individuals, T lymphocytes receive an allergen-specific signal from highly specialised antigen presenting cells, called dendritic cells, at mucosal surfaces. Presentation of allergen peptides to the T cell usually occurs in local lymphoid tissue along with the essential engagement of co-stimulatory molecules (B7 and CD28) and results in the differentiation of the naive T cell to one that generates a range of cytokines which upregulate cells and antibodies involved in the allergic response. CD4+ lymphocytes of the Th2-type are activated and clonally expand after capture and processing of inhaled allergens like cigarette smoke, house dust mites, pollen, viral infection, fungi, etc. by the dendritic cells

Pathophysiology of Bronchial Asthma 65

Fig. 3.6: Pathogenesis of bronchial asthma

which migrate to the regional lymph nodes and present allergens, together with major histocompatibility antigen II, to lymphocytes.237,238 A number of cytokines are then released. The genes for these cytokines are encoded in a small region on the long arm of chromosome 5 and a number of them (IL-4, IL-5, and GMCSF) are coordinately regulated. While Th2 lymphocytes produce these cytokines, Th1 lymphocytes are involved in cell-mediated immunity. A number of Th2-derived cytokines are involved in mast cell, basophil, and eosinophil recruitment and maturation, IL-4 and IL-3 play a particularly important role in this arm of the immune process by interacting with B lymphocytes, they change the immunoglobulin isotope being secreted from the shortterm protective antibody IgM to the allergic antibody IgE. As with dendritic T cell interactions, effective signalling to β cells requires an interaction with the Th2 cell and

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involves antigen presentation and engagement of a second set of co-stimulatory molecules (CD40 and its ligand, CD40L). If T and B cell interact in the presence of antigen, IL-4 or IL-13, and co-stimulatory molecules, allergen-specific IgE is generated. If IL-4 or IL-3 is present, but cell-cell contact does not occur, only non-specific IgE is generated. Thus IgE has the important role of linking allergen recognition to cell signalling in a variety of cells, which release a range of active mediators. IL-4 produced by Th2 lymphocytes ‘fuels’ the inflammatory reactions in the airways and leads to production of further Th2 lymphocytes and to differentiation and maturation of IgE producing B lymphocytes. A strong genetic component plays important role in the form of an ability of a susceptible individual to recognise an environmental allergen as foreign and mounts an allergic immune response through the human lymphocyte antigen (HLA or MHC class II) molecules. The second component of the gene involves the genes responsible for cytokine response. Allergen specific IgE binds to IgE receptors on several inflammatory cell types such as eosinophils, mast cells, and macrophages. High affinity IgE receptors are an important link between the presence of specific antigen in the microenvironment and activation of mast cells and other cells. Antigen-specific IgE binds to effector cells via specific IgE receptors; when antigen binds an adequate number of these receptors to initiate receptor clustering, signal transduction occurs. The molecular nature of the IgE receptor has now been clearly defined;221 it is composed of four chains: an alpha chain, a beta chain, and two gamma chains. While the alpha chain binds IgE, it is thought that the gamma chains are the units that initiates intracellular signal transduction; however, the specific mechanisms of transduction are not established. The inflammatory cells then release various inflammatory mediators outlined above, which accentuates airways’ inflammation including the release of 5-lipooxygenase products and proteases. Leukotrienes along with other products cause bronchoconstriction and other changes characteristic of bronchial asthma. Mast cell proteases are also important players in the inflammatory process. Neutral endopeptidase (NEP) is a major enzyme of importance in limiting the biologic activity of small peptide mediators such as substance P or neurokinin A. The beta-adrenergic receptor and nitric oxide represent two effector mechanisms that are important in modifying the biology of an asthmatic response. Although smooth muscle constriction can lead to airways obstruction, it is now understood that nonmuscular airway obstruction is not less important. The importance of airway wall remodelling with thickening of the airway wall due to infiltration with inflammatory cells and alteration in the amount and type of collagen deposited in the airway is reflected in the enhanced degree of obstruction that is observed for a given level of smooth muscle activation in the remodelled wall. The wall is also thickened and obstructed due to the engorgement of the bronchial blood vessels. Such engorgement could account for a significant component of asthmatic airway narrowing under certain circumstances. The presence of intraluminal fluids including mucosubstances further obstruct airways and could make it more difficult for individuals to clear secretions from their airways. The relationship between airway inflammation and the development of airway hyperresponsiveness and clinical asthma has been well established during the last decade. Exposure to oxidant pollutants, some chemicals, antigens, and viral respiratory tract infections are all associated with inflammatory cell infiltration into the airway and these inflammatory stimuli are also associated with the development of airway hyperresponsiveness. Most studies have shown that airway inflammation precedes the development of hyperresponsiveness

Pathophysiology of Bronchial Asthma 67 and may be the prerequisite feature necessary for the development of both hyperresponsiveness and clinical bronchospasm. The relationship between airway inflammation, bronchial hyperreactivity and airway obstruction in asthma is shown in Figure 3.7. Although, approximately one-half of the children with wheezing in infancy and young childhood will no longer be wheezing at 6 years of age,239 a different type of observation has been noted in children with wheezing in their bronchoalveolar lavage fluid. Increased numbers of cells and increased neutrophils in BAL samples have been reported in children having wheezing.240-244 In contrast, BAL eosinophilia is a common finding in adults with asthma. Eosinophilia and elevated IgE levels have also been found in infants who subsequently develop asthma. It is possible that neutrophil-induced inflammation is important in the early stages of wheezing in infants. It is also possible that this neutrophil response may be a response to an unrecognised infection. While the pathogenesis of occupational asthma, intrinsic asthma and other forms of asthma is less clearly understood, these conditions are thought to involve a cytokine “cascade” similar to that involved in extrinsic or allergic asthma.237 The mechanisms of allergy in causing episodic and chronic asthma are shown in Figure 3.8. Aspirin Induced Asthma Patients with bronchial asthma and sensitivity to aspirin (ASA) and other nonsteroidal antiinflammatory drugs are often corticosteroid-dependent and have the accompanying symptoms of rhinosinusitis, rhinorrhoea, nasal congestion, anosmia, loss of taste, and recurrent severe nasal polyposis.245 Upon challenge with aspirin or other cyclooxygenase inhibitors these patients have increased cysteinyl leukotriene release as detected in urine,246,247 in nasal lavage,248,249 and in bronchial lavage fluids,250 in contrast to aspirin-tolerant subjects. These

Fig. 3.7: Interaction of various factors

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Fig. 3.8: Mechanisms of episodic and chronic asthma. (TH-:T-lymphocyte; MC-; Mast cell ; Ag-; Antigen)

observations conclude that cysteinyl leukotrienes are involved in aspirin-induced asthma (AIA). The mechanism of AIA is due to the inhibition of cyclooxygenase and bronchospasm is because of an increased generation of spasmogenic leukotrienes via lipooxygenase pathway. In patients with AIA, ingestion of aspirin is followed within 1 to 2 hours by the onset of bronchospasm, which may be accompanied by rhinitis and/or urticaria. Majority of these subjects can be desensitised by the administration of aspirin orally, which may lead to an improvement in the severity of asthma and of rhinitis. Further, inflammatory cell population in bronchial biopsies from aspirin-sensitive asthmatic patients demonstrates significantly greater numbers of mast cells and eosinophils per square millimetre of tissue than do similar biopsies from asthmatic subjects without aspirin sensitivity.251 Furthermore, the percentage of cells that immunostained for lipooxygenase and that are identified as eosinophils and mast cells are significantly increased in aspirin-sensitive patients. An additional hypothesis for the mechanism of aspirin sensitivity suggests that there is increased target organ sensitivity to leukotrienes.112 The recent development and usefulness of leukotriene receptor antagonists and synthesis inhibitors in bronchial asthma including that of aspirin-induced asthma further emphasizes the role of these leukotrienes in the pathogenesis of this condition.135-138 Leukotrienes are important in asthma, and leukotriene modifiers modulate antigen-induced asthma. Leukotrienes participate in the pathogenesis of bronchial asthma besides the involvement eosinophilic airway inflammation.139 Overproduction of leukotrienes not only occurs in house dust mite provoked asthma, but also in aspirin induced bronchial asthma, although the mechanisms of such overproduction are different. While in the former, the overproduction occurs with an antigen-antibody reaction, in aspirin-induced asthma, the overproduction is due to a shift to the 5-lipooxygenase series of the arachidonate cascade.140 Pranleukast a leukotriene inhibitor suppresses the increased values of sputum eosinophil count and eosinophil cationic protein during house dust mite-induced asthma are suppressed by further, this drug increases FEV1 that falls during such provocation.140 The role of leukotrienes in the pathogenesis of aspirin-induced asthma comes from the fact that airway

Pathophysiology of Bronchial Asthma 69 narrowing and other signs in these patients are associated with 2-10 fold higher values of LTE4 in the urine of these patients compared to aspirin tolerant patients.142-144 Further, several leukotriene modifiers inhibit the asthma response in oral or inhaled bronchoprovocation by aspirin and other non-steroidal anti-inflammatory agents144,145 and improve respiratory function by bronchodilatation.146 Virus-induced Asthma Viral infections have been considered to play a significant role in the development and consolidation of obstructive airway disease. This may occur by amplification of the response to cigarette smoke, induction of steroid resistance,252 enhanced sensitisation to inhaled allergens due to increased permeability and recruitment of dendritic cells,253 or reactivation of latent but persistent virus due to insufficient T-helper-1-type immune response and/or administration of corticosteroids.254 Viral respiratory infections increase symptoms of bronchial asthma in many patients.255 Rhinovirus increases airway responsiveness and also promotes the likelihood of a late allergic reaction to allergen.256,257 Enhanced airway responsiveness and the late allergic reaction persist for weeks beyond the viral infection. Lymphocytes are activated during incubation with rhinovirus and secrete cytokines, like γ -interferon. Although γ-interferon does not have any proinflammatory activity like those of Il-4 and 5, it does affect eosinophil function, including promotion of survival. Furthermore, γ-interferon can augment basophil mediator release. Thus, lymphocyte activation by virus may provide a very different cytokine profile and in this manner selectively enhances inflammation.71,258 Exercise-induced Asthma (EIA) Exercise-induced asthma is a temporary increase in the airway resistance following vigorous physical activity. Obstruction to airflow begins soon after cessation of exercise and peaks in 5-10 minutes.259 Most patients will recover completely in the next 30-60 minutes, but in few this EAR will be followed by a LAR several hours after the initial response subsides.260,261 Two major hypotheses have been put forward to explain the mechanism whereby water and heat loss by hyperventilation with exercise causes airway narrowing. i. The EIA is a consequence of thermodynamic events that occur within the tracheobronchial tree during or after hyperventilation that is associated with exercise.262 Because of this hyperventilation during exercise, there is a fall in the airway temperature and respiratory water loss, i.e. evaporation causes cooling.263 Mouth breathing to meet increased demand of oxygen further aggravates this factor because air bypasses the nasal air-conditioning mechanism. Thus, during re-warming of the airways by reactive hyperaemia of the bronchial circulation with subsequent airway oedema of the bronchial wall during the post-exercise period.264 Further, the event precipitates bronchoconstriction. The magnitude of bronchospasm is directly proportional to the heat loss from the respiratory tract required to bring the inspired air to alveolar conditions.265 Oedema due to hyperaemia of microcirculation may be the cause of bronchial obstruction developing after exercise. It is also possible that patients with EIA may have hyperplastic capillary bed that develop exaggerated hyperaemia and airway oedema leading on to bronchial obstruction.262 ii. The other mechanism of EIA may be as a result of water loss from mucosal surface and resulting increase in osmolarity of the fluid interface of the mucosal surface in the airways,

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Bronchial Asthma which may lead to mast cell and basophil degranulation and precipitating EIA.266,267 Exercise-induced bronchoconstriction, a feature of 70-80% of asthmatics,268 is triggered by drying of the bronchial epithelium due to airway water loss from the tracheobronchial tree.269-273 During exercise, the ventilation rate increases, and thus the respiratory tract needs to condition much larger volumes of air over a much shorter time during exercise compared with rest, and airway dehydration occurs with subsequent exercise-induced bronchoconstriction. The findings that269 inhaling fully humidified air at body conditions could prevent exercise-induced bronchoconstriction demonstrated the importance of water loss from the airway. It is also been recommended swimming as the exercise least troublesome to asthmatic patients because of the humidity of the inspired air, a phenomenon that is supported by comparative studies of diverse sporting activities.274,275

Since mast cell-derived mediators, such as histamine and leukotrienes, may cause not only airway smooth-muscle contraction, but also airway oedema, it is possible that both of these hypotheses are related to the airway narrowing following exercise in asthmatics. Exerciseinduced bronchospasm is, at least in part, due to bronchial microvascular phenomena such as vascular engorgement and plasma leakage that could thicken the mucosa and thereby narrow airway diameters, which could in turn amplify the effects of airway smooth muscle contraction. Various reports give conflicting results concerning the role of inflammation in EIA.276,277 However, some believe that EIA, to a larger extent, is mediated through the release of bronchoconstrictor substances from inflammatory cells in the airway wall. Leukotrienes seem to play a particularly important role in this response. This conclusion is arrived from observations made in antileukotriene drug studies in EIA.278,279 Similarly antileukotrienes are helpful in cold air-induced bronchial asthma280 highlighting the role of cold air in causing EIA. Further, eucapnic voluntary hyperventilation manoeuvres designed to simulate exerciseinduced bronchoconstriction in the laboratory, demonstrate that airway fluid-loss has a similar bronchoconstrictor effect to histamine.281-284 It is also demonstrated that the release of histamine, a potent bronchoconstrictor, and other pro-inflammatory bronchoconstrictor mediators, including cysteinyl-leukotrienes,285 from mast cells and other airway cells under hyperosmolar conditions.286-288 These findings underline the bronchoconstrictor potential of airway dehydration. Presence of thermally sensitive neural receptors in the airways of patients susceptible to EIA may be responsible for bronchoconstriction in response to cold air.267 Recently another hypothesis suggests that increased excessive production of nitric oxide during exercise289,290 increases airway vascular permeability, that co-relates with the severity of exercise-induced bronchoconstriction in asthmatics. Assessment of albumin flux in airway lining fluid stimulated by hypertonic saline solution is a sensitive predictor of the severity of this phenomenon.291 Occupational Asthma Bronchial hyperreactivity is a characteristic feature of occupational asthma.292 Specific inhalation challenge tests may induce any of the five types of reactions: (i) isolated early; (ii) isolated late; (iii) biphasic; (iv) continuous; or (v) atypical asthmatic reactions.293 An early reaction occurs within a few minutes after an inhalation challenge, reaches maximal intensity within 30 minutes, and ends within 60-90 minutes. An isolated late asthma reaction occurs 4-6 hours after the challenge, reaches maximal intensity within 8-10 hours, and ends after

Pathophysiology of Bronchial Asthma 71 24-48 hours. A biphasic reaction is an early reaction with spontaneous recovery followed by a late asthma reaction. In a continuous type of asthma reaction there will be no remission between the early and late reactions. Atypical reactions usually start 2 hours after a challenge and last for a few hours.294 Generally, IgE-dependent agents induce isolated early reactions or biphasic reactions, and IgE-independent agents will induce isolated late, biphasic or atypical asthma reactions. Occupational asthma induced by IgE-dependent agents is similar to allergic asthma.295 Most high-molecular-weight compounds (5000 or more daltons) induce asthma by producing specific IgE antibodies. These molecules such as proteins, glycoproteins and polysaccharides are usually complete antigens. Some low-molecular-weight molecules (<5000 daltons) like acid anhydrides and platinum salts act as haptens and induce specific IgE antibodies by combining with a body protein. The specific reaction between antigen and IgE gives rise to a cascade of events that is responsible for the activation of inflammatory cells. Both preformed and newly formed inflammatory mediators are released, and they orchestrate the inflammatory events already outlined above. However, for many low-molecular-weight molecules, such as isocyanates, specific IgE antibodies have not been identified or are found only in a small proportion of cases.296 Presence of these antibodies does not necessarily mean the cause of the disease, but may be the markers of exposure .297 In addition to IgE-mediated reactions, immunoglobulins of the IgG class, possibly IgG4, may be involved in immediate-type reaction. T lymphocytes may be directly involved in the inflammatory process.297,298 Pathologic airway changes are similar to those in patients with other forms asthma. Some of them include accumulation of inflammatory cells, mostly eosinophils, oedema, hypertrophy of smooth muscle, subepithelial fibrosis, and exudation of fluid and mucus.299-301 An increase in the activated eosinophils and T lymphocytes has been found in the mucosa and sub-mucosa, and mast cells increase in the epithelium.302 Animal models for pathogenic and immunologic mechanisms of bronchial asthma have also confirmed these observations.303 Some other mechanisms that are responsible for occupational asthma are as follows; (i) reflex vagal bronchoconstriction in response to an irritant-effect on specific receptors; (ii) inflammatory bronchoconstriction secondary to toxic concentrations of gases (nonspecific complement activation, neuropeptide release, perturbation of cell membrane releasing arachidonic acid products); (iii) a direct pharmacological reactions by agents like organic insecticides with anticholinergic activity (parasympathetic agonists) and beta-adrenergic blocking agents; (iv) or immunologic mechanism leading to allergic tissue injury.304 Irritant induced occupational asthma (Reactive airways dysfunction syndrome, RADS) is persistent asthma and airway hyperresponsiveness, which develops after acute inhalation of a respiratory irritant in toxic concentrations.305 The onset of respiratory symptoms and the presence of airway hyperresponsiveness within a few hours of exposure to an identifiable irritant distinguish this entity from hypersensitivity induced occupational asthma. This form of asthma is associated with the workplace, in which wheezing illness starts within 24 hours or less of a single large exposure to an irritant. The condition is inflammatory, but does not involve immunological recognition of the irritant, so that continued low-level exposure to the causative agent can be tolerated without problem. Bronchial biopsy studies in these individuals have shown bronchial epithelial cell injury with desquamation, and bronchial wall inflammation, with infiltration of plasma cells and lymphocytes, but not eosinophils.306307 The diagnosis is made by the presence of non-specific responsiveness and a compatible history. The prognosis varies, but most often the condition improves.

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Nocturnal Asthma Diurnal variations (circadian rhythm) is normally seen in healthy normal individuals as well as in patients with bronchial asthma. Lowest airways function during early in the morning and best during the mid-day and evening has been shown by various investigators.308-310 Frequent occurrence of nocturnal symptoms has been shown in many reports.311-313 Patients of bronchial asthma show a greater bronchial reactivity at 4 AM when compared to at 4 PM.314 It is also seen that majority of asthma deaths occur most often at night.315,316 Although mechanisms involved in nocturnal asthma are not clearly understood, multiple factors seem to be involved. In allergic individuals, allergen exposure during evening hours initiates a cascade of events to produce a LAR. Further, exposure to house-dust mite may precipitate an EAR, and these factors precipitate bronchoconstriction.317 Lowest levels of serum adrenaline and cortisol, and highest levels of histamine during night hours could be responsible for nocturnal episodes in asthmatic individuals318 The BAL fluid recovered from patients having nocturnal asthma shows greater number of eosinophils and neutrophils at 4 AM compared to that at 4 PM. This indirectly suggests worsening of inflammation during night319 Increased vagal tone at night or gastro-oesophageal reflux leading to increased vagal tone may further be contributory to increased bronchial reactivity and bronchial asthma at night. Changes of body temperature, i.e. lowering of temperature, and increased accumulation of secretions in the respiratory tract during sleep may be additional factors.320-321 REFERENCES 1. Barnes PJ, Chung KF, Page CP. Inflammatory mediators in asthma. Pharmacol Rev 1988;40: 49-84. 2. Holgate ST, Finnerty JP. Recent advances in the understanding the pathogenesis of asthma and its clinical consequences. Cl J Med 1988;249:5-9. 3. Cockcroft DW, Murdock KY. Comparative effects of inhaled salbutamol, sodium cromoglycate, and beclomethasone dipropionate on allergen-induced early asthmatic response, late asthmatic response, and allergen-induced increase in bronchial responsiveness to histamine. J All Clin Immunol 1987;79:734-40. 4. Postuma DS, Koeter GH, de Vries K. Clinical expression of airway hyperreactivity in adults. Clin Rev Allergy 1990;7:321-343. 5. Durham SR, Craddock CF, Cookson WOO, Benson MK. Increase in airway responsiveness to histamine precede allergen-induced late asthmatic response. J allergy Clin Immunol 1988;82: 764-70. 6. Metzger WJ, Zavala D, Richardson HB et al. Local allergen challenge and bronchoalveolar lavage of allergic asthmatic lungs: Description of the model and local airway inflammation. Am rev Respir Dis 1987;135:433-40. 7. Holgate ST. Pharmacological modulation of asthma in relation to mechanisms. All Proc 1991;12:151-54. 8. Madison JM. Chronic asthma in the adult: Pathogenesis and pharmacotherapy. Seminar Respir Med 1991;12:175-84. 9. Kelly C, Ward C, Stenton CS, Bird G, Hendrick DJ, Walters EH. Number and activity of inflammatory cells in bronchoalveolar lavage fluid in asthma and their relation to airway responsiveness. Thorax 1988;43:684-92. 10. Casale TB, Wood D, Richardson HB et al. Elevated bronchoalveolar lavage fluid histamine levels in allergic asthmatics are associated with methacholine bronchial hyperresponsiveness. J Clint Invest 1987;79:1197-1203.

Pathophysiology of Bronchial Asthma 73 11. Wardlan AJ, Dunnette S, Gleich GJ, Collins JV, Kay AB. Eosinophils and mast cells in bronchoalveolar lavage with mild asthma: Relationship to bronchial hyperreactivity. Am Rev Respir Dis 1983;137:62-69. 12. Liu MC, Blercker ER, Lichtensetein LM et al. Evidence of elevated levels of histamine, prostaglandin D2, and other bronchoconstricting prostaglandins in the airway of subjects with mild asthma. Am Rev Respir Dis 1990;142:126-32. 13. Diaz P, Galleguillos FR, Ganzales MC, Pantin C, Kay AB. Bronchoalveolar lavage in asthma; the effect of DSCG on leucocyte count, immunoglobulins and complement. J All Clin Immunol 1984;74:41-48. 14. Kirby JG, Hargreave FE, Gleich GJ, O’Byrne PM. Bronchoalveolar cell profiles of asthmatic and non-asthmatic subjects. Am Rev Respir Dis 1987;136:379-83. 15. Flint KC, Leung KBP, Hudspith BN et al. Bronchoalveolar mast cells in extrinsic asthma: A mechanism for initiation of antigen-specific bronchoconstriction. Br Med J 1985;291:923-26. 16. Haahtela T (editorial). The importance of inflammation in early asthma. Respir Med 1995;89: 461-62. 17. Glynn AA, Michaels L. Bronchial biopsy in chronic bronchitis and asthma. Thorax 1960;15: 142-53. 18. Dunnil MS, Massarella GR, Anderson JA. A comparison of the quantitative anatomy of the bronchi in normal subjects, in status asthmaticus, in chronic bronchitis and emphysem. Thorax 1969;24:176-79. 19. Laitinen LA, Heino M, Laitinen A, Kava T, Haahtela T. Damage of the airway epithelium and bronchial reactivity in patients with asthma. Am Rev Respir Dis 1985;131:599-606. 20. Bigby TD. Inflammatory mediators and asthma. Pulmonary Perspectives 1992;9(4):6-9. 21. Robinson et al. N Engl J Med 1992;326:298-304. 22. International symposium on airway hyperreactivity. AM Rev Respir Dis 1991;143:S3. 23. Johnston SL, Holgate S. The inflammatory response in asthma. Br J Hosp Med 1991;46:84. 24. Sheffer AL, Fink JN. Immunopharmacologic update. J Allergy Clin Immunol 1991;88:303. 25. Ingram RH Jr. Asthma and airway hyperresponsiveness. Annu Rev Med 1991;42:139. 26. Boushey HA, Holtzman MJ, Sheller JR, Nadel JA. Bronchial hyperreactivity. Am Rev Respir Dis 1980;121:1389. 27. Busse WW. The role of inflammation in asthma: a new focus. J Respir Dis 1989;10:72. 28. Djukanovic R, Roche WR, Wilson JW et al. Mucosal inflammation in asthma. Am Rev Respir Dis 1990;142:434. 29. Holgate ST, Beasley R, Twentymen OP. The pathogenesis and significance of bronchial hyperresponsiveness in airway disease. Clin Sci 1987;73:561. 30. Chanez P, Bousquet J, Couret I et al. Increased number of hypodense alveolar macrophages in patients with bronchial asthma. Am Rev Respir Dis 1991;144:923. 31. Page CP. Are mast cells bad? Postgrad Med J 1991;67(Suppl 4):S6. 32. Patterson NAM, Wassermann SI, Said JW, Austen KF. Release of chemical mediators from partially purified human lung mast cells. J Immunol 1976;117:1356-62. 33. Kay AB, Austen KF. The IgE mediated release of an eosinophil leucoyte chemotactic factor from human lungs. J Immunol 1971;107:899-902. 34. Tomioka M, Ida S, Shindoh Y, Ishizaka T, Takishima T. Mast cells in bronchoalveolar lumen of patients with bronchial asthma. Am Rev Respir Dis 1984;129:1000-05. 35. Walls AF, Djukanorie R, Walters C et al. Mast cell activation in atopic and intrinsic asthma. J allergy Clin Immunol 1991;87:215. 36. Krishenbaum AS, Goff JP, Kessler SW et al. The effect of IL-3 and stem cell factor on the appearance of mast cells and basophils from CD-34+ pleuripotent progenitor cells. J Immunol 1992;148: 772-77.

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37. Drazen JM, Evans JF, Stevens RL, Shipp MA. Inflammatory effector mechanisms in asthma. Am J Crit Care Med 1995;152:403-07. 38. Cruzen N, Rafferty P, Holgate ST. Effect of a cyclooxygenase inhibitor, flurbiprofen and a H1histamine receptor antagonist, terfenadine, alone and in combination on allergen induced bronchoconstriction in man. Thorax 1987;42:946-52. 39. Piacentinii GL, Kaliner M. The potential role of leukotrienes in bronchial asthma. Am Rev Respir Dis 1991;143:S96-S99. 40. Casale TB, Wood D, Richerdson HB et al. Direct evidence of a role for mast cells in the pathogenesis of antigen induced bronchoconstriction. J Clin Invest 1987;80:1507-11. 41. Romagnani S, Maggi E, Passonchi P, Macchia D, Piccini MP, Ricci M. Increased numbers of Th-2 like CD4+ T cells in target organs and in the allergen specific receptor of allergic patients— Possible role of IL-4 produced by non-T cells. Arch Allergy Appl Immunol 1991;94:133-36. 42. Barnes PJ. New concepts in the pathogenesis of bronchial hyperresponsiveness and asthma. J allergy Clin Immunol 1989, 83:1013-26. 43. Mcfadden ER, Gilbert IA. 1992-asthma. N Engl J Med 1992. 44. Bousquet J, Chanez P, Lacoste JY et al. Eosinophilic inflammation in asthma. N Engl J Med 1990;323:1033-39. 45. Ohashi Y, Matojima S, Fukuda T, Makano S. Airway hyperresponsiveness increased intracellular spaces of bronchial epithelium, and increased infiltration of eosinophils and lymphocytes in bronchial mucosa in asthma. Am Rev Respir Med 1992;145:1469-76. 46. Dunhil MS. The pathology of asthma with special reference to changes in the bronchial mucosa. J Clin Pathol 1960;13:27-33. 47. Dunhill MS, Massarella GR, Anderson JA. A comparison of the quantitative anatomy of the bronchi in the normal subjects, in chronic bronchitis, and in emphysema. Thorax 1969;24:176-79. 48. Filley WV, Holley KE, Kephart GM, Gleich GJ. Identification by immunofluorescence of eosinophil granule major basic protein in lung tissue of patients with bronchial asthma. Lancet 1982;ii:11-16. 49. Lam S, LeRice J, Philips D, Chan YM. cellular and protein changes in bronchial lavage fluid after late asthmatic reaction in patients with red cedar asthma. J Allergy Clin Immunol 1987;80:44-50. 50. DeMonchey JG, Kauffman HF, Venge P et al. Bronchoalveolar eosinophils during allergen induced late asthmatic reactions. Am Rev Respir Dis 1985;131:373-76. 51. Sedgwick JB, Calhoun GJ, Kita H, et al. Immediate and late airway response of allergic rhinitis patients to segmental antigen challenge. Characterisation of eosinophils and mast cell mediators. Am Rev Respir Dis 1991;144:1274-81. 52. Hamid Q, Azzawi M, Ying S et al. Expression of mRNA for interleukin 5 in mucosal bronchial biopsies from asthma. J Clin Invest 1991;87:1541-46. 53. Robinson DS, Homid Q, Ying S et al. Predominant Th2-like bronchoalveolar lavage T-lymphocyte population in atopic asthma. N Engl J Med 1992;326:298-304. 54. Mossman TR, Coffman RL. Th1 and Th2 cells; Different patterns of lymphokine secretion leads to different functional properties. Ann Rev Immunol 1989;7:145-73. 55. Gajewski TF, Joyce J, Pitch FW. Antiproliferative effect of interferon-gamma in immune regulation. III. differential secretion of Th1 and Th2 murine helper T lymphocyte clone using recombinants Il-2 and recombinant IFN-gamma. J Immunol 1989;143:15-22. 56. Fiorentino D, Bond HW, Mossman TR. Two types of mouse T-helper cells. IV. Th2 clones secret a factor that inhibits cytokine production by Th1 clones. J Exp Med 1989;170:2081-95. 57. De Prete G, Maggi E, Parrochi P et al. IL-4 is an essential factor for IgE synthesis induced in vitro by human T cells and their supernatants. J Immunol 1988;140:4193-98. 58. Spits H, Yessel Y, Takelsy Y et al. recombinant interleukin-4 promotes the growth of human T cells. J Immunol 1987;139:1142-47. 59. Schleimer RP, Sterbinsky SA, Kaiser J et al. IL-4 induces adherence of human eosinophils and

Pathophysiology of Bronchial Asthma 75

60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81.

basophils but not neutrophils to endothelium; association with expression of VCAM-1. J Immunol 1992;148:1086-92. Desermaux P, Janin A, Colombal JF et al. Interleukin-5 messenger RNA expression by eosinophils in the intestinal mucosa of patients with celiac disease. J Exp Med 1992;175:293-96. Campbell HD, Tucker WQJ, Hort Y et al. Molecular cloning, nucleotide sequence and expression of the gene encoding human eosinophil differentiation factor (IL-5). Proc Natl Acad Sci (USA) 1987;84:6629-33. Saito H, Hatake K, Dvorak AM et al. Selective differentiation and proliferation of haematopoitic cell induced by recombinant human interleukins. Proc Natl Acad Sci (USA) 1988;85:2288-92. Sonoda Y, Arai N, Ogawa M. Humoral regulation of eosinophilopoiesis in vitro; analysis of the targets of interleukin-3, granulocyte/macrophage colony stimulating factor (GM-CSF), and interleukin-5. Leukaemia 1989;3:14-18. Walsh GM, Hartnell A, Wardhwa AJ et al. IL-5 enhances the in vitro adhesion of human eosinophils, but not neutrophils, in a leukocyte integrin (CD11/18) dependant manner. Immunology 1990;71:258-65. Lopez AF, Sanderson CJ, Gamble JR, et al. Recombinant human interleukin-5 is a selective activator of human eosinophil function. J Exp Med 1988;167;219-24. Fugisawa T, Abu-ghazaleh R, Kita H, Sanderson CJ, Gleich GJ. Regulatory effect of cytokines on eosinophil degranulating. J Immunol 1990;140;642-46. Schmi R, Wardlaw AJ, Cornwell O et al. Interlukin-5 selectively enhances the chemotactic response of eosinophils obtained from normal but not from eosinophilic subjects. Blood 1992;79;2952-59. Pene I, Rousset F, Brier F et al. Interleukin-5 enhances IL-4 induced age production by normal human B cells; The role of soluble CD 23 antigen. Eur J Immunol 1988;18:929-35. NIH conference. Asthma. Ann Intern Med 1994;121:698-708. Barnes PJ. Molecular mechanisms of asthma: Order now emerging from chaos. (Amberson Lecture). ALA/ATS Daily Bulletin 1996;May 12:1,4. Busse WW, Coffman RL, Gelfand EW, Kay AB, Rosenwasser LJ. Mechanisms of persistent airway inflammation in asthma. A role for T cell and T cell products. Am J Crit Care Med 1995;152:388-93. Tsuyuki S, Tsuyuki J., Einsle K et al. Costimulation through B7-2 (CD86) is required for the induction of a lung mucosal T helper cell 2 (Th2) immune response and altered airway hyperresponsiveness, J Exp Med 1997;185:1671-1679. Weaver CT, Unanue ER. The costimulatory function of antigen-presenting cells. Immunol Today 1990;11:49-55. Schwartz RH. Costimulation of T-lymphocytes: The role of CD28, CTLA-4 and B7/BB1 in interleukin-2 production and immunotherapy. Cell 1992;71:1065-68. Jenkins MK, Johnson JG. Molecules involved in T cell costimulation. Curr Opin Immunol 1993;5:361-67. Jenkins MK. The role of cell division in the induction of clonal anergy. Immunol today 1992;13: 69-73. Keane-Myers A, Gause WC, Linsley PS et al. B7-CD28/CTLA-4 costimulatory pathways are required for the development of T-helper cell 2-mediated allergic airway responses to inhaled antigens. J Immunol 1997;158:2042-49. Le Gros G, Erb K, Harris N et al. Immunoregulatory networks in asthma. Clin Exp Allergy 1999;28:S92-S96. Djukanovic R. The role of costimulation in airway inflammation. Clin Exp Allergy 2000;30:S46S50. Krummel MF, Allison JP. CTLA-4 engagement inhibits accumulation and cell cycle progression upon activation of resting T cell. J Exp Med 1996;183:2533-40. Walunas TL, Bakker CY, Bluestone JA. CTLA-4 ligation blocks CD28-dependent T cell activation. J Exp Med 1996;183:2541-50.

76

Bronchial Asthma

82. Nisticio L, Buzzetti R, Pritchard LE. The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with type 1 diabetes. Hum Mol Genet 1996;5:1075-80. 83. Polymeropoulos MH, Xiao H, Rath DS et al. Dinucleotide repeat polymorphism at the human CTLA-4 gene. Nucleic Acids Res 1991;19:4018. 84. Deichman K, Heinzman A, Bruggenolt E et al. An Mse1 RFLP in the human CTLA-4 promoter. Biochem Biophys Res Commmun 1996;225:817-18. 85. Lee SY, Lee YH, Shin C et al. Association of asthma severity and bronchial hyperresponsiveness with a polymorphism in the cytotoxic T-lymphocyte antigen-4 gene. Chest 2002;122:171-76. 86. Fels AOS, Cohn ZA. The alveolar macrophage. J Appl Physiol 1986;60:353-69. 87. Sibille Y, Reynolds HY. Macrophages and polymorph nuclear neutrophils in lung defense and injury. Am Rev Respir Dis 1990;141:471-501. 88. Takemura R, Werb Z. Secretory products of macrophages and their physiological functions. Am J Physiol 1984;246:C1-C9. 89. Rich EA, Tweardy DJ, Fujiwara H, Ellner J. Spectrum of immunoregulatory functions and properties of human alveolar macrophages. Am Rev Respir Dis 1987;136:258-65. 90. Poulter LW, Power C, Burke C. The relationship between bronchial immunopathology and hyperresponsiveness in asthma. Eur Respir J 1990;3:792-799. 91. Crofton RW, Diesselhoff-den Dulk MMC, van Furth R. The origin, kinetics, and the characteristics of chuffer cells in normal steady state. J Exp Med 1978;148:1-17. 92. Meuret G, Schildkuecht O, Joder P, Senn H. Proliferation activity and bacteriostatic potential of human blood monocytes, macrophages and pleural effusions, ascites, and of alveolar macrophages. Blood 1980;40:17-25. 93. Van Furth R, Diesselhoff-den Dulk MMC, The kinetics of promonocytes and monocytes in the bone marrow. J Exp Med 1970;132:813-28. 94. Meuret G. The kinetics of mononuclear phagocytes in man. In: Schmalzl F, Han D, Schafer HE, (Eds). Hematology and Blood transfusion; Berlin: Springer vela; 1981; 27:11-22. 95. Joseph M, Tonnel AB, Capron A, Voisin C. Enzyme release and superoxide anion production by human alveolar macrophages stimulated with immunoglobulin E. Clin Exp Immunol 1980;40: 416-22. 96. Fuller RW, Morris PK, Richmond R et al. Immunoglobulin E-dependant stimulation of human alveolar macrophages: Significance in type I hypersensitivity. Clin Exp Immunol 1986;65: 416-26. 97. Albelda SM. Endothelial and epithelial cell adhesion molecules. Am J Respir Cell Mol Biol 1991;4:195-203. 98. Elia C, Bucca C, Rolla G, Scappaticci E, Cantino D. A freeze fracture study of human bronchial epithelium in normal, bronchitic, and asthmatic subjects. J Sub-microsc Cytol Pathol 1988;20: 509-17. 99. Jeffery PK, Wardlaw AJ, Nelson FC, Collins JV, Kay AB. Bronchial biopsies in asthma: An ultrastructural, quantitative study and correlation with hyperreactivity. Am Rev Respir Dis 1989;140:1745-53. 100. Churchil L, Chilton FH, Resau JH, Bascom R, Hubbard WC, Proud D. Cyclooxygenase metabolism of endogenous arachidonic acid by cultured human tracheal epithelial cells. Am Rev Respir Dis 1989;140:449-59. 101. Frossard N, Rhodenk J, Batrnes PJ. Influence of epithelium removal on guineapig airway response to tachykinins: Role of end peptidase and cyclooxygenase. J Pharmacol Exp Therap 1989; 248: 292-97. 102. Joseph M, Pilewski M, Steven MA. Adhesion molecules in the lung: An overview. Am Rev Respir Dis 1993; 148(Suppl):S31-S37. 103. Albelda SM, Buck CA. Integrins and other cell adhesion molecules. FASEB J 1990;4:2868-80.

Pathophysiology of Bronchial Asthma 77 104. Williams AF, Barelay AN. The immunoglobulin super gene family-domains for cell surface recognition. Ann Rev Immunol 1988;6:381-405. 105. Lasky LA. Selectins: Interpreters of cell-specific carbohydrate information during inflammation. Science 1992;258:964-69. 106. Berg EL, Robinson MK, Mansson O, Butcher EC, Magnani JL. A carbohydrate domain common to both Sialyl lea and Sialyl Lax is recognised by endothelial cell adhesion molecule (ELAM-1). Br J Boil Chem. 1991;266:14869-872. 107. McDonald JA. Receptors for extracellular matrix components. Am J Physiology 1989;257: L331-37. 108. Torsi MF, Stark JM, Smith CW et al. Induction of ICAM-1 expression on human airway epithelial cells by inflammatory cytokines: Effects on neutrophil-epithelial cell adhesion. Am J Respir Cell Mol Biol 1992;7:214-21. 109. Look DC, Rapp SR, Keller BT, Holtzmzn MJ. Selective induction of intercellular adhesion molecule1 by interferon-gamma in human airway epithelial cells. Am J physiology 1992;263:L79-l87. 110. Kumar S, Mohan A, Sharma SK, Pande JN. Recent concepts in the pathogenesis of bronchial asthma. Ind J Chest Dis All Sc 1997;39:27-45. 111. Lee TH, Arm J. Leukotrienes. Allergy Proc 1991;12:139-42. 112. Brown PH, Crompton GK, Greening AP. Proinflammatory cytokines in acute asthma. Lancet 1991;338:590. 113. Milgrom H. Asthma- something old, something new. Postgrad Med J 1991;67(Suppl 4):S13. 114. Jansen HM, Neijens HJ. Immunoregulation of asthma. Eur Respir J 1991;4(Suppl 13):3S. 115. Vercelli D, Geha RS. Regulation of IgE synthesis in humans: A tale of two signals. J Allergy Clin Immunol 1991;88:285. 116. Wenzel SE, Westcott JY, Smith HR, Larsen GL. Spectrum of prostanoid release after bronchoalveolar allergen challenge in atopic asthmatics and in control groups. Am Rev Respir Dis 1989;139:450. 117. Kellaway C.H, Trethewie R. The liberation of a slow reacting smooth muscle stimulating substance in anaphylaxis. Q J Exp Physiol 1940;30:121-45. 118. Taylor IK. Cysteinyl leukotrienes in asthma: Current state of therapeutic evaluation. Thorax 1995;50:1005-10. 119. Samuelsson B. Leukotrienes: Mediators of immediate hypersensitive reactions and inflammation. Science 1983; 220:568-75. 120. Lewis RA, Austen KF. The biologically active leukotrienes. J Clin Invest 1984;73:889-97. 121. Lewis RA, Austen KF, Soberman RJ. Leukotrienes and other products of lipoxygenase pathway. New Engl J Med 1990;323:645-55. 122. Barnes PJ, Chung KF, Page CP. Inflammatory mediators and asthma. Pharmacol Rev 1988;40: 49-84. 123. Piacentini GL, Kaliner MA. The potential roles of leukotrienes in bronchial asthma. Am Rev Respir Dis 1991;143:S96-S99. 124. Arm JP, Lee TH. Sulphidopeptide leukotrienes in asthma. Clin Sci 1993;84:501-10. 125. Dahlen SE, Hansson G, Hedquist P et al. Allergen challenge of lung tissue from asthmatics elicits bronchial contraction that co-related with the release of leukotrienes C4, D4, and E4. Proc Natl Acad Sci, USA 1983;80:1712-16. 126. MacGlashan DW, Schleimer RP, Peters SP et al. Generation of leukotrienes by purified human lung mast cells. J Clin Invest 1982;70:747-51. 127. Weller PF, Lee CW, Foster DW et al. Generation and metabolism of 5-lipoxygenase pathway leukotrienes by human eosinophils: Predominant production of leukotriene C4. Proc Natl Acad Sci USA. 1983;80:7626-30. 128. Lewis RA, Austen KF, Soberman RJ. Leukotrienes and other products of lipoxygenase pathway. New Engl J Med 1990;323:645-55.

78

Bronchial Asthma

129. Kern R, Smith LJ, Patterson R et al. Characterisation of the airway response to inhaled leukotriene D4 in normal subjects. Am Rev Respir Dis 1986;133:1127-32. 130. Soter NA, Lewis RA, Corey EJ, Austen KF. Local effects of synthetic leukotrienes (LTC4, LTD4, LTE4 and LTB4) in human skin. J Invest Dermatol 1983;80:115-19. 131. Coles SJ, Neill KH, Leid LM et al. Effects of leukotrienes C4 and D4 on glycoprotein and lysozyme secretion by human bronchial mucosa. Prostaglandins 1983;25:155-70. 132. O’Byrne PM, Leikauf GD, Aizwa H et al. Leukotriene B4 induces airway hyperresponsiveness in dogs. J Appl Physiol 1985;59:1941-46. 133. Black PN, Fuller RW, Taylor GW et al. Bronchial reactivity is not increased after inhalation of leukotriene B4 and prostaglandin D2. Br J Clin Pharmacol 1988;25:667P. 134. Bigby T. Inflammatory mediators and asthma. Pulm Perspectivs 1992;9(4):6-9. 135. Holgate ST, Bradding P, Sampson AP. Leukotriene antagonists and synthesis inhibitors: New directions in asthma therapy. J Allergy Clin Immunol 1996;98:1-13. 136. Fischer AR, McFadden CA, Frantz R, Awni WM, Cohn J, Drazen JM, Israel E. Effect of chronic 5-lipoxygenase inhibition on airway hyperresponsiveness in asthmatic subjects. Am J Respir Crit Care Med 1995;152:1203-07. 137. Wenzel SE. New approaches anti-inflammatory therapy for asthma. Am J Med 1998;104: 287-300. 138. Liu MC, Dube LM, Lancaster J et al. Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: A 6-month randomised multicentre trial. J Allergy Clin Immunol 1996;98:859-71. 139. Drazen JM, Israel F, O’Byrne PM. Treatment of asthma with drugs modifying the leukotriene pathway. N Engl J Med 1999;340:197-206. 140. Obase Y, Shimoda T, Tamari S et al. Effects of pranlukast on chemical mediators in induced sputum on provocation tests in atopic and aspirin-intolerant asthmatic patients. Chest 2002;121:14350. 141. Szczeklik A, Stevenson DD. Aspirin-induced asthma: Advances in pathogenesis and management. J Allergy Clin Immunol 1999;104:5-13. 142. Stevenson DD, Simon RA. Sensitivity to aspirin and nonsteroidal anti-inflammatory drugs: In: Middleton E, Reed CE, Ellis EF et al. (Eds). Allergy: Principles and Practice: 5th Edition. St Louis, MO: Mosby: 1998;1225-34. 143. Smith CM, Hawksworth RJ, Thien FC et al. Urinary leukotriene E4 in bronchial asthma. Eur Respir J 1992;5:693-99. 144. Christie PE, Tagari P, Ford-Hutchinson AW et al. Urinary leukotriene E4 concentrations increase after aspirin challenge in aspirin-sensitive asthmatic subjects. Am Rev Respir Dis 1991;143: 1025-29. 145. Yamamoto H, Nagata M, Kraits K et al. Inhibition of analgesic-induced asthma by leukotriene receptor antagonist ONO-1078. Am J Respir Crit Care Med 1994;150:254-57. 146. Dahlen B, Nizankowska E, Szczeklik A et al. Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-induced asthmatics. Am J Respir Crit Care Med 1998;157:1187-94. 147. Caughey GH. Roles of mast cell tryptase and chymase in airway function. Am J Physiol 1989;257:L39-46. 148. Nadel JA. Roles of mast cell proteases in airways. Drugs 1989;37:51-55. 149. Drazen JM, Evans JF, Stevens RL, Shipp MA. Inflammatory effector mechanisms in asthma. Am J Respir Crit Care Med 1995;152:403-07. 150. White MV, Slater JE, Kaliner MA. Histamine and asthma. Am Rev Respir Dis 1987;135:1165-76. 151. Simon RA, Stevenson DD, Arroyane CM, Tan EM. The relationship of plasma histamine to the activity of bronchial asthma. J Allergy Clin Immunol 1977;60:312-16. 152. Barnes PJ, Ind PW, Brown MJ. Plasma histamine and catecholamines in stable asthmatic subjects. Clin Sci 1982;62:661-65.

Pathophysiology of Bronchial Asthma 79 153. Hardy CC, Robinson C, Tattersfield AE, Holgate ST. The bronchoconstrictor effect of inhaled prostaglandin D2 in normal and asthmatic men. N Engl J Med 1984;311:209-13. 154. Walters EH, Parrish RW, Bevan C, Smoth AP. Induction of bronchial hyperresponsivity: Evidence for a role of prostaglandins. Thorax 1981;36:571-74. 155. Fuller RW, Dixon CMS, Dollery CT, Barnes PJ. Prostaglandins D potentiates airway responses to histamine and methacholine. Am Rev Respir Dis 1986;133:252-54. 156. Henderson WR (Jr). Eicosanoids and platelet activating factor in allergic respiratory disease. Am Rev Respir Dis 1991;143:S86-S90. 157. Henderson WR (Jr). Lipid derived and other chemical mediators of inflammation in the lung. J Allergy Clin Immunol 1987;79:543-53. 158. Hozawa S, Haruta Y, Ishioka S, Yamakido M. Effects of a PAF antagonist, Y-24180, on bronchial hyperresponsiveness in patients with asthma. Am J Respir Crit Care Med 1995;152:1198-1202. 159. Evans TW, Chung K, Rogers DF, Barnes PJ. Effect of platelet-activating factor on airway vascular permeability: possible mechanisms. J Appl Physiol 1987;63:479-84. 160. Wirtz H, Lang M, Sannwald U, Hahn H. Mechanism of platelet-activating factor (PAF)-induced secretion of mucus from tracheal submucosal glands in ferrets (abstract). Fed Proc 1986;45:486. 161. Wardlow AJ, Moqbel R, Cornwell O, Kay AB. Platelet-activating factor: A potent chemotactic and chemokinetic factor for human eosinophils. J Clin Invest 1986;78:1701-06. 162. Stenton Sc, Court EN, Kingston WP et al. Platelet-activating factor in bronchoalveolar lavage fluid from asthmatic subjects. Eur Respir J 1990;3:408-13. 163. Nakamura T, Morita Y, Kuriyama M, Ishitara K, Ito K, Miyamoto T. Platelet-activating factor in late asthmatic responses. Int Arch Allergy Appl Immunol 1987;82:57-61. 164. Simonsson BG, Skoogh BE, Bergh NP, Anderson R, Sredmyr N. In vivo and in vitro effect of bradykinin on bronchial motor tone in normal subjects and patients with airway obstruction. Respiration 1973;30:378-88. 165. Christiansen SC, Proud D, Sarnoff RB et al. Elevation of tissue kallikrein and kallidin in the airways of asthmatic subjects after endobronchial allergen challenge. Am Rev Respir Dis 1992;145:900-05. 166. Polosa R, Holgate ST. Comparative airway response to inhaled bradykinin, kallidin, and (des Arg) bradykinin in normal and asthmatic airways. Am Rev Respir Dis 1990;142:1367-71. 167. Regoli D, Barabe J. Pharmacology of bradykinin and related kinins. Pharmacol Rev 1980;32: 1-46. 168. Chung KF, Barnes PJ. Cytokines in asthma. Thorax 1999;54:825-57. 169. Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7 system of T cell co-stimulation. Annu Rev Immunol 1996;14:233-58. 170. Geha RS. Regulation of IgE synthesis in humans. J Allergy Clin Immunol 1992; 90:143-50. 171. Bradding P, Roberts JA, Britten KM et al. Interleukin 4, -5, and tumor necrosis factor-a in normal and asthmatic airways: Evidence for the human mast cell as a source of these cytokines. Am J Respir Cell Mol Biol 1994;10:471-80. 172. Vercelli D, Jabara HH, Lee BW et al. Human recombinant interleukin-4 induces FCeRH/CD23 on normal human monocytes. J Exp Med 1988;167:1406-16. 173. Ho LP, Davis M, Denison A et al. Reduced interleukin-18 levels in BAL specimens from patients with asthma compared to patients with sarcoidosis and healthy control subjects. Chest 2002;121:1421-26. 174. Spiteri M, Knight RA, Jeremi JY et al. Alveolar macrophage-induced suppression of T cell hyperresponsiveness in bronchial asthma is reversed by allergen exposure. Eur Respir J 1994;7:1431-38. 175. Fischer HG, Frosch S, Reske K et al. Granulocyte-macrophage-colony-stimulating factor activates macrophages derived from bone marrow cultures to synthesis of MHC class II molecules and to augmented antigen presentation function. J Immunol 1988;141:3882-88.

80

Bronchial Asthma

176. Chang TL, Shea CH, Urioste S et al. Heterogenicity of helper/inducer T lymphocytes: Lymphokine production and lymphokine responsiveness. J Immunol 1990;145:2803-08. 177. Sanderson CJ, Warren DJ, Strath M. Identification of a lymphokine that stimulates eosinophil differentiation in vitro. Its relationship to interleukin 3 and functional properties of eosinophils produced in cultures. J Exp Med 1985;162:60-74. 178. Hallsworth MP, Litchfield TM, Lee TH. Glucocorticoids inhibit granulocyte-macrophage-colonystimulating factor and interleukin 5 enhanced in vitro survival of human eosinophils. Immunology 1992;75:382-85. 179. Collins PD, Griffith-Johnson DA, Jose PJ et al. Co-operation between interleukin 5 and the chemokine, eotaxin, to induce eosinophil accumulation in vivo. J Exp Med 1995;182:1169-74. 180. Rothenberg ME, Owen WFJ, Siberstein DS. Human eosinophils have prolonged survival, enhanced functional properties and become hypodense when exposed to human interleukin. J Clin Invest 1988;81:1986-92. 181. Moqbel R, Hamid Q, Ying S et al. Expression of mRNA and immunoreactivity of the granulocyte/ macrophage colony-stimulating factor (GM-CSF) in activated human eosinophils. J Exp Med 1991;174:749-52. 182. Tosi MF, Stark JM, Smith CW et al. Induction of ICAM-1 expression on human airway epithelial cells by inflammatory cytokines. Effects on neutrophil-epithelial cell adhesion. Am J Respir Cell Biol 1992;7:214-21. 183. Brewster CEP, Howarth PH, Djukanovic R et al. Myofibroblasts and subepithelial fibrosis in bronchial asthma. Am J Respir Cell Mol Biol 1990;3:507-11. 184. Hirst SJ, Barnes PJ, Twort CHL. Quantifying proliferation of cultured human and rabbit airway smooth muscle cells in response to serum and platelet-derived growth factor. Am J Respir Cell Mol Biol 1992;7:574-81. 185. Massaro AF, Mehta S, Lilly CM, Kobazik L, Reilly JJ, Drazen JM. Elevated nitric oxide concentrations in isolated lower airway gas of asthmatic subjects. Am J Respir Crit Care Med 1996;153:1510-14. 186. Alving K, Weitzberg E, Lundberg JM. Increased amount of nitric oxide in exhaled air of asthmatics. Eur Respir J 1993;6:1368-70. 187. Kharitonov SA, Yates D, Robbins RA et al. Increased nitric oxide in exhaled air of asthmatic patients. Lancet 1994;343:133-35. 188. Hamid Q, Springall DR, Riveros-Moreno V et al. Induction of nitric oxide synthase in asthma. Lancet 1993;342:1510-13. 189. Ligget SB, Levi R, Metzger H. G-Protein coupled receptors, nitric oxide, and the IgE receptor in asthma. Am J Respir Crit Care Med 1995;152:394-402. 190. Carr MJ, Hunter DD, Undem BJ. Neurotrophins and asthma. Curr Opin Pulm Med 2001;7:1-7. 191. Barnes PJ. The third nervous system in the lung: Physiology and clinical perspectives. Thorax 1984;39:561-67. 192. Casale TB. Neuropeptides and the lung. J Allergy Clin Immunol 1991;88:1. 193. Casale TB, Neuromechanisms of asthma. Ann Allergy 1987;59:391. 194. Nadel JA. Neutral endopeptidase modulates neurogenic inflammation. Eur Respir J 1991;4:745. 195. Drazen JM, Israel E. Asthma: A solution to half the puzzle. Am Rev Respir Dis 1991;144:743. 196. Bleecker ER. Cholinergic and neurogenic mechanisms in obstructive airways disease. Am J Med 1986;81:93. 197. Kowalski ML, Diddier A, Kaliner MA. Neurogenic inflammation in the airways. Am Rev Respir Dis 1989;140:101. 198. Barnes PJ. Neural control of human airways in health and disease. Am Rev Respir Dis 1986;134:1289-1314. 199. Barnes PJ. Neural control of airway function: New perspectives. Mol Aspects Med 1990;11:351423. 200. Nadel JA, Barnes PJ, Holtzmzn MJ. Autonomic factors in the hyperreactivity of airway smooth

Pathophysiology of Bronchial Asthma 81

201. 202. 203. 204. 205. 206. 207. 208. 209. 210. 211. 212. 213. 214. 215. 216. 217. 218. 219. 220. 221. 222. 223. 224.

muscle. In: Hand book of physiology: The respiratory system III. American Physiology Society; 1986:693-702. Minett PAH, Lammers J, Dixon CMS, McCuska MT, Barnes PJ. A muscarinic agonist inhibits reflex bronchoconstriction in normal but not in asthmatic subjects. J Appl Physiol 1989;67: 2461-65. Palmer JB, Cuss FM, Barnes PJ. VIP and PHM and their role in nonadrenergic inhibitory responses in isolated human airways. J Appl Physiol 1986;61:1322-28. Belvisi MG, Stretton CD, Verlenden GM, Jacob MH, Barnes PJ. Inhibitory NANC nerves in human tracheal smooth muscle involvement of VIP and NO. Am Rev Respir Dis 1991;143:A355. Lundberg JM, Saria A, Lundblad L et al. Bioactive peptide in capsaici sensitive C-fibre afferents of airways, functional and pathophysiological implications, New York.; Marcel Decker; 1987: 417-45. Rogers DF, Belvisi MG, Arsudkij JB, Evans TW, Barnes PJ. Effects and interactions of sensory neuropeptides on airway microvascular leakage in guineapigs. Br J Pharmacol 1988;95:1109-16. Johnson AR, Aston J, Schulz WW, Erdos EG. Neutral metalloendopeptidases in human lung tissue and cultured cells. Am Rev Respir Dis 1985;132:564-68. Rogers DF, Arsudkij JB, Barnes PJ. Effects of tachykinins on mucus secretion on human bronchi in vitro. Eur J Pharmacol 1989;174:283-86. Mak JCM, Barnes PJ. Autoradiographic localisation of calcitonin gene-related peptide binding sites in human and guineapig lung. Peptides 1988;9:957-64. Barnes PJ. Neuropeptide and asthma. Am Rev Respir Dis 1991;143:S28-S33. Barnes PJ. Neurogenic inflammation and asthma. J Asthma 1992;29:165-80. Naline E, Devillier P, Drape G et al. Characterisation of neurokinin effects and receptor selectivity in human isolated bronchi. Am Rev Respir Dis 1989;140:679-86. Barnes PJ, Dewar A, Rogers DF. Human bronchial secretion: effect of substance P, muscarinic and adrenergic stimulation in vitro. Br J Pharmacol 1986;89:787P. Richardson PS, Webber SE. The control of mucus secretion in the airways by peptidergic mechanisms. Am Rev Respir Dis 1987;136:S72-S76. Fuller RW, Maxwell DL, Dixon CMS et al. The effects of substance P on cardiovascular and respiratory function in human subjects. J Appl Physiol 1987;62:1473-79. Sekizawa K, Tamaoki J, Graf PD et al. Enkephalinase inhibitor potentiates mammalian tachykininsinduced contraction in ferret trachea. J Pharmacol Exp Ther 1987;243:1211-17. Bisgaard H, Groth S, Madsen F. Bronchial hyperreactivity to leukotriene D4 and histamine in exogenous asthma. Br Med J 1985;290:1468. Smith LJ, Greenberger PA, Patterson R et al. The effect of inhaled leukotrienes in humans. Am Rev Respir Dis 1985;131:368. Davidson AB, Lee TH, Scanlon PD et al. Bronchoconstrictor effects of leukotriene E4 in normal and asthmatic subjects. Am rev Respir Dis 1987;135:333. Liggett SB, Raymond JR. Pharmacology and molecular biology of adrenergic receptors. In PM Bouloux, Editor, Catecholamines. WB Saunders, London, 1993;279-306. Reishaus E, Innis M, MacIntyre N, Liggett SB. Mutations in the gene encoding for the beta-2 adrenergic receptor in normal and asthmatic subjects. Am J Respir Cell Mol Biol 1993;8:334-39. Liggett SB, Levi R, Metzger H. G-protein coupled receptors, nitric oxide, and the IgE receptor in asthma. Am J Respir Crit Care Med 1995;152:394-402. Szentivanyi A. The β-adrenergic theory of the atopic abnormality in bronchial asthma. J Allergy 1968;42:203-32. McNeil RS. Effect of α–adrenergic blocking agent propranolol on asthmatics. Lancet 1964;2: 1101-02. Goldie RG, Spina D, Henry PJ et al. In vitro responsiveness of human asthmatic bronchus to carbachol, histamine, badrenoceptor agonists, and theophylline. Br J Clin Pharmacol 1986;22: 669-76.

82

Bronchial Asthma

225. Bai TR. Abnormalities in airway smooth muscle in fatal asthma. Am Rev Respir Dis 1990;141: 552-57. 226. Bai TR. Abnormalities airway smooth muscle in fatal asthma: a comparison between trachea and bronchus. Am Rev Respir Dis 1991;143:441-43. 227. Cerrina J, Ladurie MLR, Labat C et al. Comparison of human bronchial muscle response to histamine in vitro with histamine and isoproterinol agonists in vitro. Am Rev Respir Dis 1986; 134:57-61. 228. Lentes KU, Berretinni WH, Hoche MR et al. A biallelic DNA polymorphism of the human β2-adrenergic receptor detected by Ban I-Adrbr-2. Nucleic Acids Res 1988;16:2359. 229. McQuitty CK, Emala CW, Hirshman CA et al. polymorphism in the human β2-adrenergic receptor gene detected by restriction endonuclear digestion with Fnu4HI. Hum Genet 1994;93:225. 230. Reihsaus E, Innis M, AacIntyre N et al. Mutations in the gene encoding for the β2-adrenergic receptor in normal and asthmatic subjects. Am J Respir Cell Biol 1993;8:334-39. 231. Ohe M, Munakata M, Hizawa N et al. β2-adrenergic receptor gene restriction fragment length polymorphism and bronchial asthma. Thorax 1995;50:353-59. 232. Taguchi H, Ohe M, Hizawa M. XV International Congress of Allergology and Clinical Immunology (abstract). ACI News 1994;89(Suppl 2):A317. 233. Emala CW, McQuitty CK, Eleff SM et al. Asthma, allergy, and airway hyperresponsiveness are not linked to the b2-adrenoceptor gene. Chest 2002;121:722-31. 234. Gustafsson LE, Leone AM, Persson MG, Wilklund NP, Moncada S. Endogenous nitric oxide is present in the exhaled air of rabbits, guinea pigs, and humans. Biochem Biophysics Res Comm 1991;181:852-57. 235. Springall DR, Hamid OA, Buttery LKD et al. Nitric oxide synthase induction in airways of asthmatic subjects. Am Rev Respir Dis 1993;147:A515. 236. Gaston B, Drazen J, Chee CBE, Wohl MEB, Stamler JS. Expired nitric oxide (NO) concentrations are elevated in patients with reactive airway disease. Endothelium 1993;1:87-92. 237. Pauwels R. Asthma: Managing the underlying disease. Eur Respir Rev 1994;4:291-94. 238. Holt PG. Regulation of antigen-presenting cell function(s) in lung and airway tissue. Eur Respir J 1993;6:120-29. 239. Martinez FD, Wright AL, Taussig LM et al. Asthma and wheezing in the first six years of life. N Engl J Med 1995;332:133-38. 240. Marguet C, jouen-Boedes F, Dean TP et al. Bronchoalveolar cell profiles in children with asthma, infantile wheezing, chronic cough, or cystic fibrosis. Am J Respir Crit Care Med 1999;159: 1533-40. 241. Schellhase DE, Pawcett DD, Schutze GE et al. Clinical utility of flexible bronchoscopy and bronchoalveolar lavage in young children with recurrent wheezing. J Pediatr 1998;132:312-18. 242. Krawiee ME, Westcott JY, Wei Chu H et al. Persistent wheezing in very young children is associated with lowered respiratory inflammation. Am J Respir Crit Care Med 2001;163: 1338-43. 243. Cloutier MM. Neutrophils or eosinophils in young children with wheezing. Chest 2002;122: 761-63. 244. Le Bourgeots M, Goncalves M, Le Clincher L et al. Bronchoalveolar cells in children , 5 years old with severe recurrent wheezing. Chest 2002;122:791-97. 245. Samter M, Biers RF. Intolerance to aspirin: clinical studies and consideration of its pathogenesis. Ann Intern Med 1968;6:975-83. 246. Christie PE, Tagari P, Ford-Hutchinson AW, et al. Urinary leukotriene E4 concentrations increase after aspirin challenge in aspirin-sensitive asthmatic subjects. Am Rev Respir Dis 1991;143: 1025-29. 247. Knapp HR, Sladek K, Fitzgerald GA. Increased excretion of leukotriene E4 during aspirininduced asthma. J lab Clin Med 1992;119:48-51.

Pathophysiology of Bronchial Asthma 83 248. Ferreri NR, Howland WC, Stevenson AD, Spiegelberg ML. Release of leukotrienes, prostaglandins and histamine into nasal secretions of aspirin-sensitive asthmatics during reaction to aspirin. Am Rev Respir Dis 1988;137:847-54. 249. Ortolani C, Mirone C, Fontana A, Folco GC et al. Study of mediators of anaphylaxis in nasal wash fluids after aspirin and sodium meta-bisulphite nasal provocation in intolerant rhinitic patients. Ann Allergy 1987;59:106-12. 250. Sladek K, Dworksi R, Soja J, et al. Eicosanids in bronchoalveolar lavage fluid of aspirin-tolerant patients with asthma after aspirin challenge. Am J Respir Crit Care Med 1994;149:940-46. 251. Nasser SMS, Pfister R, Christie PE, Sousa AR, et al. Inflammatory cell populations in bronchial biopsies from aspirin sensitive asthmatic subjects. Am J Respir Crit Care Med 1996;153:90-96. 252. Hogg JC. Role of latent viral infections in chronic obstructive pulmonary disease and asthma. Am J Respir Crit Care Med 2001;164:S71-S75. 253. Schwarze J, Gelfand EW. Respiratory viral infections as promoters of allergic sensitisation and asthma in animal models. Eur Respir J 2002;19:341-49. 254. ven HL. Role of persistent infection in the control and severity of asthma: focus on Chlamydia pneumoniae. Eur Respir J 2002;19:546-56. 255. Gypear D, Busse WW. Role of virus infection in asthma. Immunol Allergy Clin North Am 1993;13:745-68. 256. Lemanske RF, Jr, Dick EC, Swenson CA, Vrtis TF, Busse WW. Rhinovirus upper respiratory infection increases airway hyperreactivity and late asthmatic reactions. J Clin Invest 1989;83: 1-10. 257. Calhoune WJ, Swenson CA, Dick EA, et al. Experimental rhinovirus-16 infection potentiates histamine release after antigen bronchoprovocation in allergic subjects. Am Rev Respir Dis 1991;144:1267-73. 258. Huftel MA, Swenson CA, Borcherding WR et al. The effect of T cell depletion on enhanced basophil histamine release after in vitro incubation with live influenza A virus. Am J Respir Cell Mol Biol 1992;7:434-40. 259. Godfrey S. Exercise-induced asthma. In: Bierman CW, Perlmanlman DS, Ed: Allergic Disease from infancy to adulthood. Philadelphia; WB Saunders Co.; 1988;597-606. 260. Belcher NG, O’Hickey S, Arm JP et al. Pathogenic mechanisms of exercise-induced asthma and the refractory period. NER Allergy Proc 1988;9:199-201. 261. Lee TH, Nagacura T, Papageoriou N et al. Exercise-induced late asthmatic reaction with neutrophil chemotactic activity. N Engl J Med 1983;308:1502-05. 262. Gilbert IA, Fouke JM, McFadden ER Jr. Heat and water flux in the intrathoracic airways and exercise-induced asthma. J Appl Physiol 1987;631:681-91. 263. Godfrey S. Bronchial challenge by exercise or hypertension. In: spector Sl, Ed: provocative challenge procedures; background and methodology. New York, Futura Publishing Co; 1989; 365-94. 264. McFadden ER. Hypothesis: exercise-induced asthma as a vascular phenomenon. Lancet 1990;335:880-82. 265. McFadden ER Jr, Pichurko B, Bowman HF et al. Thermal mapping of the airways in humans. J Appl Physiol 1985;58:564-70. 266. Anderson SD. Is there a unifying hypothesis for exercise induced asthma? J Allergy Clint Immune 1984;73:660-65. 267. Anderson SD. Issues in exercise-induced asthma. J Allergy Clint Immune 1985;76:763-72. 268. Anderson SD, Silverman M, Godfrey S et al. Exercise-induced asthma – a review. Br J Dis Chest 1975;69:1-39. 269. Chen WY, Horton DJ,. Heat and water loss from the airways and exercise-induced asthma. Respiration 1977;34:305-13.

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Bronchial Asthma

270. Strauss RH, McFadden ER Jr., Ingram RH Jr et al. Influence of heat and humidity on the airway obstruction induced by exercise in asthma. J Clin Invest 1978;61:433-40. 271. Strauss RH, McFadden ER Jr., Ingram RH Jr et al. Enhancement of exercise-induced asthma by cold air. New Engl J Med 1977;297:743-47. 272. Deal EC Jr, McFadden ER Jr., Ingram RH Jr et al. Hyperapnea and heat flux: initial reaction sequence in exercise-induced asthma. J Appl Physiol 1979;46:476-83. 273. Anderson SD, Schoefield RE, Follet R et al. Sensitivity to heat and water loss at rest and during exercise in asthmatic patients. Eur J Respir Dis 1982;63:459-71. 274. Huang SW, Veiga R, Sila U et al. The effects of swimming on asthmatic children, participants in a swimming program in the city of Baltimore. J Asthma 1989;26:117-21. 275. Bar-Or O, Inbar O. Swimming and asthma: Benefits and deleterious effects. Sports Med 1992;14:397405. 276. Spector SL. Update on exercise-induced asthma. Ann Allergy 1993;71:571-77. 277. McFadden ER, Gilbert IA. Exercise-induced asthma. N Engl J Med 1994;330:1362-67. 278. Makkar HK, Lau LC, Thomson HW, Binks SM, Holgate ST. The protective effect of inhaled leukotriene D4 receptor antagonist ICi 204,219 against exercise-induced asthma. Am Rev Respir Dis 1993;147:1413-18. 279. Reiss TF, Bronsky E, Hendeles L et al. MK-0476, a potent leukotriene (LT)D4 antagonist, inhibits exercise-induced bronchoconstriction in asthmatics at the end of a once daily dosing schedule (abstract). Am J Respir Crit Care Med 1995;151:A377. 280. Glass M, Snadder LA, Israel E. Effect of the inhaled LTD4 receptor antagonist, ICI-204,219, on cold-air-induced bronchoconstriction in patients with asthma.(abstract). J Allergy Clin Immunol 1994;93:295A. 281. Scharf SM, Heimer D, Walters M. Bronchial challenge with room temperature isocapnic hyperventilation: a comparison with histamine challenge. Chest 1985;88:586-93. 282. Rosenthal RR. Simplified eucapnic voluntary hyperventilation challenge. J Allergy Clin Immunol 1984;73:676-79. 283. Argyros GJ, Phillips YY, Rayburn DB et al. Water loss without heat flux in exercise-induced bronchospasm. Am Rev Respir Dis 1993;147:1419-24. 284. Eliasson AH, Phillips YY, Rajagopal KR et al. Sensitivity and specificity of bronchial provocation testing: an evaluation of 4 techniques in exercise-induced bronchospasm. Chest 1992;102:347-55. 285. Anderson SD, Deviskas E, Smith CM. Exercise-induced asthma: a difference in opinion regarding the stimulus. Allergy Proc 1989;10:215-16. 286. Eggleston PA, Kagey-Sobotka A, Lichtenstein LM. A comparison of the osmotic activation of basophils and human lung mast cells. Am Rev Respir Dis 1987;135:1043-48. 287. Silber G, Proud D, Warner J et al. In vivo release of inflammatory mediators by hyperosmolar solutions. Am Rev Respir Dis 1988;137:606-12. 288. Moloney E, O’Sullivan S, Hogan T et al. Airway dehydration: A therapeutic target in asthma? Chest 2002;121:1806-11. 289. Barnes PJ, Belvisi MG. Nitric oxide and lung disease. Thorax 1993;48:1034-43. 290. Kanazawa H, Hirata K, Yoshikawa J. Role of endogenous nitric oxide in exercise-induced airway narrowing in patients with bronchial asthma. J Allergy Clin Immunol 2000;106:1081-87. 291. Kanazawa H, Asai K, Hirata K, Yoshikawa J. Vascular involvement in exercise-induced airway narrowing in patients with bronchial asthma. Chest 2002;122:166-70. 292. Lam S, Wong R, Chan-Yeung M. Nonspecific bronchial reactivity in occupational asthma. J Allergy Clin Immunol 1979;63:28-34. 293. Peppys J, Hutcheroft BJ. Bronchial provocation tests in etiologic diagnosis and analysis of asthma. Am Rev Respir Dis 1975;112:829-59. 294. Perrin B, Cartier A, Ghezzo H et al. Reassessment of the temporal patterns of bronchial obstruction after exposure to occupational sensitizing agents. J Allergy Clin Immunol 1991;87:630-39.

Pathophysiology of Bronchial Asthma 85 295. Chan-Yeung M, Malo JL. Occupational asthma. New Engl J Med 1995;333-107-12. 296. Mapp CE, Boschetto P, Dal Vecchio L, Maestrelli P, Fabbri LM. Occupational asthma due to isocyanate. Eur Respir J 1988;1:273-79. 297. Frew AJ, Chan H, Dryden P, Salari H, Lam S, Chan-Yeung M. Immunologic studies of the mechanisms of occupational asthma caused by western red cedar. J Allergy Clin Immunol 1993;92:466-78. 298. Kay AB, Corrigan CJ, Frew AJ. The role of cellular immunology in asthma. Eur Respir J 1991;13:105s-112s. 299. Kusaka Y, Nakano Y, Shirakawa Y, Morrimoto K. Lymphocyte transformation with cobalt in hard metal asthma. Ind Health 1989;27:155-63. 300. Saetta M, Di Stefano A, Maestrelli P et al. Airway mucosal inflammation in occupational asthma induced by toluene diisocyanate. Am Rev Respir Dis 1992;145:160-68. 301. Lam S, LeRiche J, Phillips D, Chan-Yeung M. Cellular and protein changes in bronchial lavage fluid after late asthmatic reaction in patients with red cedar asthma. J allergy Clin Immunol 1987;80:44-50. 302. Bentley AM, Maestrelli P, Saetta M et al. Activated T lymphocytes and eosinophils in the bronchial mucosa in isocyanate-induced asthma. J Allergy Clin Immunol 1992;89:821-29. 303. Karol MH. Animal models of occupational asthma. Eur Respir J 1994;7:555-68. 304. Soto-Aguilar MC, Salvaggio JE. Immunologic aspects of occupational asthma. Seminars Respir Med 1991;12:185-95. 305. Taylor AJN. Respiratory irritants encountered at work. Thorax 1996;51:541-45. 306. Brooks SM, Weiss MA, Bernstein IL. Reactive airways dysfunction syndrome (RADS). Persistent asthma syndrome after high level irritant exposure. Chest 1985;88:376-84. 307. Gautrin D, Boulat LP, Boulat M et al. Is reactive airway dysfunction syndrome a variant of occupational asthma? J Allergy Clin Immunol 1994;93:12-22. 308. Staudinger HW, Steinijsnd VW. Theophylline steady-state pharmacokinetics: Recent concepts and their application in the chrono-therapy of bronchial asthma. In: Lemmer B, Huller H, Ed; Clinical chronopharmacology, Clin Pharmacol 1996;6:136-47. 309. Gupta ML, behera D: Pattern of airflow obstruction in Bronchial Asthma—An observation on Home-Monitoring of Peak Expiratory Flow Rate. J Ass Phy India 1997;45:94-96. 310. Turner-Warwick M. Epidemiology of nocturnal asthma. Am J Med 1988;85:6-8. 311. Shah A. Bronchial asthma and sleep disturbances. Ind J Chest Dis All Sc 1997;39:77-79. 312. Meijer GG, Oosterhoff Y, Weersink EJM, Postma DS, Gerritsen J, van Aalderen WMC. Nocturnal dyspnoea: Prevalence in asthmatic children. Eur Respir J 1991;4:523S. 313. Martin RJ, Cicutoo LC., Ballard RD. Factors related to the nocturnal worsening of asthma. Am Rev Respir Dis 1990;141:33-38. 314. Hetzel MR, Clark TJH, Branthwaite MA. Asthma: Analysis of sudden deaths and ventilatory arrests in hospital. Br Med J 1977;1:808-11. 315. Robertson CF, Rubinfeld AR, Bowes G. Deaths from asthma in Victoria; A 12-months survey. Med J Austr 1990;152:511-17. 316. Mohiuddin AA, Martin RJ. Circadian basis of the late asthmatic response. Am Rev Respir Dis 1990;142:1153-57. 317. Barnes P, Fitzgerald G, Brown M, Dollery C. Nocturnal asthma and changes in circulatory epinephrine, histamine and cortisol. N Engl J Med 1980;303:263-67. 318. Martin RJ, Cicutto LC, Smith HR et al. Airways inflammation in nocturnal asthma. Am Rev Respir Dis 1991;143:351-57. 319. Chen WY, Chai H. Airway cooling and nocturnal asthma. Chest 1982;81;675-800. 320. Bush RK. Nocturnal asthma: Mechanisms and the role of theophylline in treatment. Postgrad Med J 1991;67(Suppl 4):S20. 321. Asthma: A nocturnal disease. Proceedings of a symposium. Am J Med 1988;85 (Suppl 1B):2.

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4 Pathology The earlier descriptions of histological changes in bronchial asthma relied on postmortem specimens taken from people dying in status asthmaticus. Since the 1960s, epithelial shedding and influx of eosinophils into the airway mucosa have been associated with bronchial asthma.1,2 Large segments of the airway from the major bronchi to the periphery are occluded with a mixture of tenacious secretion containing serum protein mixed with mucus and cellular debris. Crystalline material consisting largely of major basic protein derived from eosinophil granules (Charcot-Leyden crystals) may be present. There is oedema, dense eosinophilic infiltration, and epithelial denudation in the bronchial wall. Airway samples obtained at open lung biopsy show goblet cell hyperplasia, peribronchial smooth muscle hypertrophy and apparent basement membrane thickening. Further evidence of epithelial shedding in asthmatics is provided by the findings of clumps of epithelial cells in the sputum of such patients during acute attacks. The strips of epithelial cells are called Curschmann’s spirals. Clumps of cells (Creola bodies) or isolate metaplastic cells are common. However, no detailed pathological changes were available in milder forms of asthma before the use of fibreoptic bronchoscope (Fig 4.1a-c) Fibreoptic bronchoscopy has helped in sampling the bronchial mucosa as well as the submucosa from the subcarinal levels in asthmatics at various stages of their disease. In 1985, fresh biopsies were taken from eight asthmatics, with two of them having mild asthma, three having moderate and three with severe asthma.3 All of them showed virtual destruction and shedding of epithelium at the three airway levels studied. This was in contrast to perfectly intact epithelium found in a control subject. The most important observation was that epithelial changes and influx of inflammatory cells also existed in the two untreated patients who had mild disease both clinically and functionally. The existence of severe inflammatory changes is well known from necropsy studies on patients died of bronchial asthma. However, significant inflammation is also present in early asthma in patients with only a short duration of symptoms, or with mild disease.4-6 These bronchial mucosal biopsy findings resulted in surprising results. Biopsies taken from mild asthmatics requiring only occasional bronchodilators, showed them to be always abnormal compared to that from nonatopic normal individuals. Such changes included the presence of mast cells at various stages of degranulation, and a wide spread infiltration of eosinophils. Most of the eosinophils revealed the ultrastructural features of activation and degranulation. Eosinophils, neutrophils, and mononuclear cells were present in increased numbers in the postcapillary venules, and were frequently in close contact with the vascular endothelium. Another important observation was the presence of apparent thickening of the subepithelial basement membrane.7-9 Although the basement membrane is of normal thickness,

Pathology 87

Fig. 4.1a: Normal airway

Fig. 4.1b: Airway during an attack of bronchial asthma

Fig. 4.1c: Schematic representation of the airway in patients with bronchial asthma

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the subepithelial band consists of dense cross-linked collagen fibrils. Monoclonal antibody studies suggest that the sub-basement membrane band consists of types III and V collagen, together with fibronectin but not laminin. This suggests the fibroblastic origin of the band. Recent data further revealed an expanded network of subepithelial myofibroblasts with both contractile and collagen secreting properties. The number of myofibroblasts correlates with the degree of subepithelial thickening, suggesting a repair response secondary to chronic inflammation. Extensive collagen deposition within the bronchial mucosa might influence the mechanical properties of the airways and contribute towards bronchial hyperresponsiveness and irreversible airflow obstruction. The thickness of the reticular basement is increased even in mild asthma and is correlated with airway obstruction and hyperresponsiveness. It is therefore, suggested that anti-inflammatory treatment with inhaled steroids should be started in the early stage of bronchial asthma to prevent structural changes from occurring in the airway wall.10 Similar changes have been described in the asthmatic airway in childhood. Bronchial biopsy specimens from children show thickening and hyalinization of the basement membrane. The ciliated epithelial cells showed loss of cilia in some cases. Overactive fibroblasts are constant findings. There is submucosal infiltration with degranulating mast cells and lymphocytes. Eosinophils are present in some cases.11 AIRWAY REMODELLING Chronic inflammation in the airways leads to structural changes, including hypertrophy and hyperplasia of airway smooth muscle and thickening of the reticular layer of basement membrane. This later thickening is due to the deposition of collagen from activated myofibroblasts in response to cytokines and growth factors released during the inflammatory response.12 There is extensive deposition of collagen beneath the true basement membrane. Using immunostaining this collagen is identified as predominantly types III and V, but not type IV (basement membrane)13 collagen. Thus, the increased subepithelial collagen in asthma does not represent a thickening of the true basement membrane but rather collagen laid down by fibroblasts with the lamina propria. Although the factor(s) controlling the proliferation and collagen-secreting activities of the myofibroblasts is not known, these structural changes may underlie the progressive and irreversible airflow obstruction that is seen in patients with poorly controlled asthma over a period of time. The remodelling of airways in bronchial asthma involves structural changes in the epithelium, the myofibroblasts, and extracellular matrix including the basement membrane, and smooth muscle. This remodelling process is mainly caused by a complex interaction of inflammatory cells that are central to the pathogenesis of asthma with structural tissue cells. The inflammatory cells such as eosinophils, T cells, mast cells and macrophages together with structural tissue cells, play important effector role through the release of a number of cytokines, mediators, and chemokines. Remodelling of the airways in asthma involves structural changes in the epithelium, the myofibroblasts and extracellular matrix including basement membrane, and smooth muscle. This remodelling process is mainly orchestrated by a complex interaction of inflammatory cells that are central in the pathogenesis of asthma with structural tissue cells. Epithelial injury plays an important role in asthma airway remodelling.14 An intrinsically aberrant epithelium when injured by toxic mediators, cause the epithelium to be in a chronic state of

Pathology 89 increased injury and repair. Pro-fibrotic stimuli cause subsequent subepithelial basement membrane and submucosal alterations of collagen, elastin, and smooth muscle fibres. This interaction is called the epithelial mesenchymal trophic unit. Patients of asthma have increased goblet cell hyperplasia, and increased stored mucin in the airway epithelium. Airway inflammation and remodelling contribute significantly to the decline in lung function in bronchial asthma. Generally, lung function increases during childhood, levels off around 25-35 years of age, and declines after the age of 35 years. However, in asthmatic children the observation is different. A girl developing asthma at age of 7 years would have 5% reduction in FEV1 by age of 10 years and a 7% deficit by age of 15 years compared with children without asthma.15,16 Similar observations are made for adult asthmatics that may also have increased decline in lung function during their life.17 This enhanced decline in lung function is present in both sexes and is further enhanced by smoking. On this logic a 175 cm tall, nonsmoker, nonasthmatic man had an average FEV1 of 3.05 L, compared with the FEV1 of 1.99 L for a man of the same age and height who smoked and had asthma. Further, there may be a subset of nonsmoking asthmatics those have an excess overall decline in lung function. This may lead to severe, potentially life-threatening, irreversible airway obstruction without the presence of emphysema.18 Further, ongoing inflammation results in more severe airway hyperreactivity, and lower lung function as well as accelerated loss of FEV1. Airway Pathology during Asthma Remission Spirometric abnormalities and bronchial hyperresponsiveness to methacholine or cold air challenge during clinical remission of asthma are often observed.19,20 It is unclear whether these functional abnormalities reflect persistent activity of the airways inflammatory process or merely indicates structural changes of the airways as a consequence of childhood asthma. These structural changes (airway remodelling) are probably early events in the course of the disease that appear to progress. The process of remodelling leads to thickening of the airway wall.21-24 The exact physiologic consequences of airway wall thickening are not completely understood.25 If airway wall thickening is present in subjects in clinical remission of asthma, it could at least partly account for the functional abnormalities including bronchial hyperreactivity observed during remission. On the other hand, ongoing active airway inflammation will have substantial impact on the risk of relapse later in life. Therefore, subjects with subclinical airway inflammation could benefit from anti-inflammatory treatment.26-28 Elevated exhaled nitric oxide (eNO) levels and bronchial hyperreactivity during clinical remission have been demonstrated recently implying ongoing inflammation.29 Recent studies have shown that eosinophils, T cells, mast cells, and IL-5 are significantly elevated in the airway mucosa of subjects with bronchial asthma in remission compared with control subjects.13 Also blood eosinophil cell counts were higher in subjects with clinical remission. Blood eosinophil cell counts, exhaled nitric oxide (eNO) levels, and bronchial response to adenosine-5’-monophosphate correlated significantly with the quantity of tissue eosinophils. Significant airway remodelling was found in subjects in clinical remission. Matrix metalloproteinase-9 concentrations are increased in severe, persistent asthma and following airway challenge.30 These results indicate ongoing airway inflammation and airway remodelling in adolescents in clinical remission of atopic asthma. Subclinical airway inflammation may well determine the risk of an asthma relapse later in life.

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1. Glynn AA, Michaels L. Bronchial biopsy in chronic bronchitis and asthma. Thorax 1960;15:14253. 2. Dunhill MS, Massarella GR, Anderson JA. A comparison of the quantitative anatomy of the bronchi in normal subjects, status asthmaticus, in chronic bronchitis and emphysema. Thorax 1969;24:176-79. 3. Laitinen LA, Heino M, Laitinen A, Kava T, Haahtela T. Damage of the airway epithelium and bronchial reactivity in patients with asthma. Am Rev Respir Dis 1985;131:599-606. 4. Laitinen LA, Laitinen A, Heino M, Haahtela T. Eosinophilic airway inflammation during exacerbation of asthma and its treatment with inhaled corticosteroid. Am Rev Respir Dis 1992;42:423-27. 5. Laitinen LA, Laitinen A, Haahtela T. Airway mucosal inflammation even in patients with newly diagnosed asthma. Am Rev Respir Dis 1993;147:697-704. 6. Jeffrey PK, Wardlaw AJ, Nelson FC, Collins JV, Kay AB. Bronchial biopsies in asthma. An ultrastructural quantitative study and correlation with hyperreactivity. Am Rev Respir Dis 1989;140:1745-53. 7. Brewster CE, Howarth PH, Djukanovic R et al. Myofibroblast and subepithelial fibrosis in bronchial asthma. Am J Respir Cell Mol Biol 1990;3:507. 8. Reid LM. Workshop on pathology; summary of workshop manuscripts and discussion with recommendation from the panel. J Allergy Clin Immunol 1987;80(Suppl):403. 9. Cutz E, Levison H, Cooper DM. Ultrastructure of airways in children with asthma. Histopathology 1978:2:407. 10. Shiba K, Kasahara K, Nakajima H, Adachi M. Structural changes of the airway wall impair respiratory function, even in mild asthma. Chest 2002;122:1622-26. 11. Cokugras H, Akcakaya N, Seckin I, Camcroglu Y, Sarmurat M, Aksoy F. Ultrastructural examination of bronchial biopsy specimens from children with moderate asthma. Thorax 2001;56:25-29. 12. Djuknovie R, Roche WR, Wilson JW et al. Mucosal inflammation in asthma. Am Rev Respir Dis 1990;142:437-52. 13. Roche WR, Beasley R, Williams JH, Holgate ST. Subepithelial fibrosis in the bronchi of asthmatics. Lancet 1989;i:520-23. 14. Holgate ST, Davies DE, Lackie PM et al. Epithelial mesenchymal interactions in the pathogenesis of bronchial asthma. J Allergy Clin Immunol 2000;105: 193-204. 15. Weiss ST, Tosteson TD, Segal MR et al. Effect of asthma on pulmonary function in children. A longitudinal population based study. Am Rev Respir Dis 1‘992;145:58-64. 16. Roorda RJ, Germitsen J, van Aalderen WM et al. Follow up of asthma from childhood to adulthood: Influence of potential childhood risk factors on the outcome of pulmonary function and bronchial responsiveness in adulthood. J Allergy Clin Immunol 1994;93:575-84. 17. Lange P, Parmer J, Vestbo J et al. A 15-year follow up study of ventilatory function in adults with asthma. New Engl J Med 1998;339:1194-1200. 18. Nick HT, Hacken T, Postma Ds, Timens W. Airway remodelling and long-term decline in lung function in asthma. Curr Opin Pulm Med 2003;9;9-14. 19. Kerrebijn KF, Fioole AC, van Bentveld RD. Lung function in asthmatic children after year or more without symptom or treatment. Br Med J 1978;I:886-88. 20. Gruber W, Eber E, Steinbrugger B, Modl M, Weinhandle E, Zach MS. Atopy, lung function, and bronchial responsiveness in symptom-free pediatric asthma patients. Eur Respir J 1997;10:1041-45. 21. Sears MR. Consequences of long-term inflammation. The natural history of asthma. Clin Chest Med 2000;21:315-29.

Pathology 91 22. Gillis HL, Lutchen KR,. Airway remodelling in asthma amplifies heterogeneities in smooth muscle shortening causing hyperresponsiveness. J Appl Physiol 1999;86:2001-12. 23. Djukanovic R. Asthma: a disease of inflammation and repair. J Allergy Clin Immunology 2000;105:522-26. 24. Vignola AM, Chanez P, Bonsignore G, Godard P, Bousquet J. Structural consequences of airway inflammation in asthma. J Allergy Clin Immunol 2000;105:514-17. 25. Fahy JV, Corry DB, Boushey HA. Airway inflammation and remodelling in asthma. Curr Opin Pulm Med 2000;6:15-20. 26. Hodshino M, Takahashi M, Takai Y, Sim J. Inhaled corticosteroids decrease subepithelial collagen deposition by modulation of the balance between matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 expression in asthma. J Allergy ClinImmunol 1999;104:356-63. 27. Laitinen A, Altraza A, Kampe M, linden M, Virtanen I, Laitinen LA. Tenascin in airway basement membrane of asthmatics and decreased by an inhaled steroid. Am J Respir Crit Care Med 1997;156:951-58. 28. Van den Toorn LM, Prins JB, Overbeek SE, Hoogsteden HC, de Jongste JC. Adolescents in clinical remission of atopic asthma have elevated exhaled nitric oxide levels and bronchial hyperresponsiveness. Am J Respir Crit Care Med 2000;162;953-57. 29. Van den Toorn LM, Overbeek SE, de Jongste JC, Leman K, Hoogsteden HC, Prins JB. Airway inflammation is present during clinical remission of atopic asthma. Am J Respir Crit Care Med 2001;164:2107-13. 30. Mattos W, Lam S, Russell R et al. Matrix metalloproteinase-9 expression in asthma. Effect of asthma severity, allergen challenge, and inhaled corticosteroids. Chest 2002;122:1543-52.

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5 Clinical Presentation of Bronchial Asthma The clinical presentations of bronchial asthma are heterogeneous, falling into every age group from infancy to old age, and the spectrum of signs and symptoms varies in degree of severity from patient to patient, as well as within each patient, over time. Detailed clinical history taking is very important in the clinical diagnosis of bronchial asthma. The usual symptoms include cough, wheezing, shortness of breath, chest tightness, and modest degree of sputum production. The sputum is usually white or clear, and the patient may sometimes notice more solid or greenish streaks in it. Dry cough may be the only manifestation of asthma in some (cough variant asthma). It is estimated that about 10% of the population, i.e. double the number having overt asthma symptoms experience asthma-like symptoms.1 Conditions known to be associated with bronchial asthma include rhinitis, sinusitis, nasal polyposis, or atopic dermatitis. Between 60-78% of patients, who have asthma have coexisting allergic rhinitis.2 Further, allergic rhinitis has been recognised as a risk factor for asthma and between 20-38% of patients who have allergic rhinitis have coexisting asthma. Most patients will complain of the onset of an attack of bronchial asthma following allergic pharyngitis, in the form of sore throat, pain in the throat, itching, sneezing, running nose or a blocked nose. Viral infection of the upper airways is another important preceding event in many patients.3 The pattern of symptoms may be perennial, seasonal, or perennial with seasonal exacerbations. The symptomatology is generally episodic, although may be continuous or continuous with acute exacerbations. There is usually a circadian variation with more nocturnal symptoms.4 These nocturnal attacks wake the patient in early hours of morning and the patient feel the need to get out of bed and want to open the window for air. Exacerbation of symptoms, may occur after several minutes of usually unaccustomed exertion, increase in severity over a minute or two and wane over about half an hour. The precipitating event (discussed above under etiology) may or may not be evident from history. The incidence of IgE mediated allergy (allergic rhinitis, atopic dermatitis, hay fever) and bronchial asthma in close relatives is very high. The detailed medical history of the patient including other allergic disorders and in children history of early life injury to airways (bronchopulmonary dysplasia, history of pulmonary infiltrates, documented pneumonia, viral bronchiolitis, recurrent croup, symptoms of gastro-oesophageal reflux and passive exposure to smoking) may be rewarding.5 Many other risk factors discussed above like domestic dust mite, pollens, mould, furred animals, airborne irritants, tobacco smoke, are also capable of aggravating asthma and are known as asthma triggers as they can provoke

Clinical Presentation of Bronchial Asthma 93 asthma attacks. Other triggers include smoke from domestic cooking fuels, physical activity (running and other exercises), extreme emotional expressions (laughing or crying hard), cold air or weather changes, food additives, cold drinks, and drugs like aspirin. People with asthma may have one or more triggers, and different individuals have different triggers. Physical examination of chronic asthma (for acute attacks see later) should focus on the upper respiratory tract, the skin and the chest. The findings may reveal the presence of rhinitis and/or sinusitis in the form of purulent nasal discharge, pale nasal mucosa, postnasal drip, and nasal polyps. Flexural eczema may indicate the presence of atopic dermatitis. In children, there will be evidence of hyperinflation of the lungs with use of accessory muscles and appearance of hunched shoulders and “pigeon chest”. The intensity of the breath sounds in symptomatic asthma will be reduced and the expiratory phase is prolonged. Presence of rhonchi is a characteristic finding in asthma and will be present in most patients. However, neither its presence nor its absence will confirm or exclude bronchial asthma. Rhonchi may be heard in many other conditions including chronic bronchitis, pulmonary oedema, bronchial stenosis, foreign body aspiration, upper airway obstruction, aspiration pneumonia and pulmonary embolism, etc. It is often said that “all that wheezes is not asthma”. Moreover, wheezing is not a reliable sign of severity. Crepitations are not the findings of asthma unless there is secondary infection or a complication like allergic bronchopulmonary mycosis. CLASSIFICATION Intrinsic and Extrinsic Asthma Some investigators try to classify bronchial asthma into the intrinsic and extrinsic types. The intrinsic asthma usually has late onset with no history of atopy or allergy and is nonseasonal. The skin test for allergens is usually negative and the serum IgE level is often normal. The symptoms are generally severe, they do not respond well to conventional therapy and a greater likelihood that the patient will need maintenance oral steroids, to which the response is dramatic. A great majority of these patients have auto-antibodies to smooth muscle and among women, thyroid and gastric antibodies and antinuclear factor. Asthma associated with polyarteritis nodosa and aspirin-sensitive bronchial asthma are usually of intrinsic type. However, many do not agree with this classification in view of the recent understanding of the underlying pathogenesis of asthma. Moreover, history of allergy or the responsible allergen is not easy to find out always. Late Onset Asthma Late onset asthma is a much used but poorly defined term. The difficulty arises because of the lack of appreciation of the difference between truly late onset asthma and asthma that is recognised late.6,7 This is important because the missed asthmatic patient with long-standing under treated asthma is more likely to develop irreversible airflow obstruction. Although there is no agreeable definition of this entity, a reasonable definition would be “asthma with onset of symptoms in adult life in a patient with no pre-existing, persistent respiratory symptoms”. True onset of asthma is perhaps more common than it was appreciated and may affect one in 50 of the adult population, assuming a 5% prevalence of asthma overall. Asthma perhaps occurs more frequently in the elderly than is usually appreciated and

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may, therefore, be under diagnosed and under treated.8 Although several studies report the characteristics of older patients with asthma, few have described patients with onset of asthma after the age of 65 years. Available studies are limited by small number of patients.9,10 In a recent population based study, the incidence of asthma was found to be more common in the elderly.11 The age-and sex-adjusted incidence was 95/100,000 at or after the age of 65 years. Late onset asthma has sometimes been equated with intrinsic asthma, but in some patients there will be other important causes that must be recognised. Asthma induced by drugs, and occupational asthma may belong to this category. Asthma of adult onset may be the first sign of the development of polyarteritis nodosa. Women, who develop adult onset asthma more often than men, often give a history of asthma beginning at the menopause. Many patients report that their symptoms started after a respiratory tract infection. Occupational Asthma Occupational asthma is the most common occupational lung disease in developed world and accounts for 26-52% of all occupational lung diseases in UK, and Canada.12 About 15% of bronchial asthma are due to occupational exposure as reported from USA.13 About 250 agents have been identified that can cause occupational asthma and some of them are indicated in earlier in the section under aetiology. Isocyanates that are widely used in many industries are responsible for the most common form of the disease and the prevalence of isocyanate-induced asthma in exposed workers is close to 10%.14 There can be two categories of asthma related to the workplace. They are: occupational asthma and work-aggravated asthma. Occupational asthma is characterised by variable airflow limitation, bronchial hyperresponsiveness, or both, due to conditions in particular work environment, not to stimuli outside the workplace.15 On the other hand, workaggravated asthma is preexisting or concurrent asthma that is aggravated by irritants or physical stimuli in the workplace. Occupational asthma may develop in a person with preexisting asthma or concurrent asthma after workplace exposure. There is usually a latent period between the first exposure to the offending agent and the onset of asthma. This period may vary from a few weeks to over 20 years. Occupational asthma with latency includes all instances of immunologic asthma, although the immunologic mechanism has not been identified for all agents. The other type of occupational asthma is without a latent period and the worker develops symptoms immediately upon working with the same substance. This is usually due to exposure to high concentrations of irritant gases, fumes, or chemicals on one or several occasions-reactive airway dysfunction syndrome.16 Exposure is the most important determinant whether occupational asthma develops. Higher the degree of exposure to an agent, higher is the prevalence of occupational asthma. History of atopy and smoking are important determinants to induce occupational asthma that occurs through an IgE-dependent mechanism. The duration of exposure is not important. About 40% of patients with occupational asthma have symptoms within 2 years of exposure and in 20%, symptoms develop after 10 years of exposure.17 HLA class II alleles are involved in some cases of isocyanate-induced asthma. The patient usually complains of chest symptoms after working hours, in the evenings and at nights, but not during working hours at the onset of the illness. Improvement in symptoms occurs at weekends or during longer periods away from work and worsening on return to work suggests but does not

Clinical Presentation of Bronchial Asthma 95 confirm occupational asthma. Runny and itchy eyes and nose and sneezing often accompany respiratory symptoms. Peak flow monitoring is important to recognize this problem. Diagnosis of occupational asthma includes: a. Diagnosis of asthma and b. Establishment of a relation between asthma and work. The diagnosis of asthma is based on compatible history and the presence of variable airflow obstruction or, in the absence of airflow limitation, the presence of pharmacologically induced bronchial hyperresponsiveness. The number of criteria required to establish the relation to work depends on the purpose for which the diagnosis is made. They are more stringent if the diagnosis is required for medical purposes, and the relation to work should be objectively demonstrated. But for screening examinations in the workplace or for field epidemiological surveys, less stringent diagnostic requirements can increase the sensitivity of case detection. An occupational cause should be sought for all new onset asthma in adults. The disease should be suspected in a person exposed at work to agents known to cause occupational asthma. History of both past and current exposures is required to be obtained since previous exposure to such agents may have induced permanent asthma. Such list of agents is available.18 However, the inability to identify an agent should not rule out the diagnosis of occupational asthma. Detailed assessment of workplace exposure may help determine the specific type of occupational asthma. The history should include specific job duties and work processes for both the patient and the coworkers. A visit of the site by the physician may help to understand the work situation better. The diagnosis should always be confirmed by objective measurements. Various methods used to diagnose occupational asthma include questionnaire, immunological testing, bronchial responsiveness to methacholin or histamine, measurement of FEV1 before and after work, peak expiratory flow monitoring, specific inhalation challenges in a hospital laboratory, and serial FEV1 measurements at work under supervision. There are many advantages and disadvantages of all these tests. While questionnaire is simple and sensitive, it has a low specificity. Although immunological tests are simple and sensitive, they can only be used for high-molecular weight and some low-molecular weight agents. The test only identifies sensitisation, but not disease. Further, most of the allergens are not available commercially. Nocturnal Asthma Nocturnal asthma symptoms are frequent and about 39% of asthmatics awaken nightly, and 94% have nocturnal awakenings at least once a month. A number of mechanisms have been hypothesised to explain the phenomenon of nocturnal asthma including exposure to dust mite allergen, late-phase allergic reactions, effects of posture and sleep stages on airway tone, gastro-oesophageal reflux, impaired mucociliary clearance, airway cooling, and changes in circadian rhythms of circulating hormones (adrenaline and steroids). While no single mechanism can explain these changes, circadian rhythms may be particularly relevant. Normal airway tone increases during sleep and is magnified in asthmatics. Normally there is a rhythm city in the lung function parameters with maximum readings between 3-4 PM and the lowest being at 3-4 AM. This is exaggerated in asthmatics. Bronchial responsiveness to histamine and allergen challenge increases during sleep and mast cell mediator release

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is enhanced. Circulating eosinophils increase, which may allow their ingress into pulmonary tissue. Together with a decreased plasma catecholamine and cortisol levels all these factors may influence airway tone, inflammation, and responsiveness during sleep and produce the observed clinical picture. The characteristic symptomatology is described above. PATTERNS OF AIRFLOW OBSTRUCTION IN CHRONIC ASTHMA Chronic asthma may be classified according to patterns of variations in their airflow obstruction.18 1. “Brittle” asthma 2. “The morning dipper” 3. The irreversible asthma” a. A group never achieving a normal peak flow, but showing a reversible component, either spontaneously or after specific drug therapy. b. A subgroup having a reversible FVC, but irreversible FEV1 and PEFR. c. The “drifter”, having irreversible airflow obstruction gradually improving over weeks of intensive therapy. Brittle Asthma This is a form of intractable and persistent asthma resistant to all conventional therapy. There will be no wheeze at one moment, but gross wheezing may be present over a short period of time. Most often they are misunderstood to have deliberate or emotional asthma. Serial measurements of PEFR show a chaotic pattern, with normal to grossly abnormal patterns of airflow obstruction. They occur randomly throughout 24 hours. Low readings may reverse to normal with small doses of bronchodilators, but stabilisation is difficult. The salient feature of this asthma is their response to sympathomimetic drugs but without stabilisation. The patient may be atopic or non-atopic. Cromoglycate and steroid therapy will not be able to stabilize. These patients usually need frequent bronchodilators. However, not all patients are resistant to conventional therapy. Morning Dippers These are the patients who have worsening of their symptoms during early hours of the night and is discussed above. The rhythm city is maintained during the day and reduction occurs early in the morning. During day times, the patient may be completely normal and stable, so that no abnormality may be detected during the visit to the doctor. In children, the attack is usually worse around 2 AM and in adults it is variable increasing slowly and rapidly from midnight. Waking does not change the attack. It is observed in sleep workers that the attack is worse towards the end of sleeping hours. REFERENCES 1. National Asthma Programme in Finland 1994-2004. Ministry of Health and Social Welfare, Helsinki, 1994; quoted in Haahtela T. The importance of inflammation in early asthma. Respiratory Med 1995;89:461-62. 2. Braman SS, Barrows AA, deCotiis BA et al. Airway hyperresponsiveness in allergic rhinitis: A risk factor for asthma. Chest 1987;91:671-74.

Clinical Presentation of Bronchial Asthma 97 3. Steinium-Aarniale B. The role of infection in asthma. Chest 1987;91:157S. 4. Clark TJV. Diurnal rhythm of asthma. Chest 1987;91:137S. 5. Rachelefsky GS, Katz RM, Siegel SC. Chronic sinus disease with associated reactive airway disease in children. Paediatrics 1984;73:526. 6. Ayres JG. Late onset asthma. Br Med J 1990;300:1602. 7. Lee HY, Stretton TB. Asthma in the elderly. Br Med J 1972;4:93-95. 8. Banerjee DK, Lee GS, Malik SK, et al. Under diagnosis of asthma in the elderly. Br J Dis Chest 1987;81:23-29. 9. Burr ML, Charles TJ, Roy K et al. Asthma in the elderly: an epidemiological survey. BMJ 1979;1:1041-44. 10. Braman SS, Kaemmerlen JT, Davis SM. Asthma in the elderly: a comparison between patients with recently acquired and long-standing disease. Am Rev Respir Dis 1991;143:336-40. 11. Bauer BA, Reed CE, Yunginger JW, Wollan PC, Silverstein MD. Incidence and outcomes of asthma in the elderly. A population based study in Rochester, Minnesota. Chest 1997;111: 303-10. 12. Chan-Yeung M, Malo JL. Occupational asthma. New Engl J Med 1995;333:107-12. 13. Blane P. Occupational asthma in national disability survey. Chest 1987;92:613-17. 14. Chan-Yeung M, Malo JL. Epidemiology of occupational asthma. In: Busse WW, Holgate ST (Eds). Asthma and rhinitis. Boston; Blackwell Scientific Publications. 1995;44-57. 15. Bernstein IL, Chan-Yeung M, Malo JL, Bernstein DI. Definition and classification of asthma. In: Bernstein IL, Chan-Yeung M, Malo JL, Bernstein DI (Eds). Asthma in the workplace. New York: Marcel Dekker, 1993;1-4. 16. Brooks SM, Weiss MA, Bernstein IL. Reactive airway dysfunction syndrome (RADS): persistent asthma syndrome after high level irritant exposures. Chest 1985;88:376-84. 17. Malo JL, Ghezzo H, D’Aquino C, L’Archeveque J, Cartier A, Chan-Yeung M. Natural history of occupational asthma; relevance of type of agent and other factors in the rate of development of symptoms in affected subjects. J Allergy Clin Immunol 1992;90:937-44. 18. Turner Warwick M. On observing patterns of airflow obstruction in chronic asthma. Br J Dis Chest 1977;71:73-86.

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6 Diagnosis of Bronchial Asthma The diagnosis of asthma is a clinical one; there is no confirmatory diagnostic blood test, radiographic or histopathological investigation. In some people, the diagnosis can be corroborated by suggestive changes in lung function tests. The clinical diagnosis of asthma is not always simple and the absence of an agreed definition of the disease is a problem, with many descriptions existing. However, while making a diagnosis of bronchial asthma The International Consensus Report definition of asthma should be kept in mind which states that it is “a chronic inflammatory disorder of the airways…..in susceptible individuals, inflammatory symptoms are usually associated with widespread but variable airflow obstruction and an increase in airway response to a variety of stimuli. Obstruction is often reversible, either spontaneously or with treatment”. Some of the symptoms of asthma are shared with diseases of other systems. Even when the symptom of breathlessness is thought to be due to lung disease, there are numerous relatively common lung diseases and differentiation of an airway disorder needs to be made from both infections, and pulmonary thromboembolic disease and restrictive lung disorders. Features of an airway disorder such as cough, wheeze and breathlessness should be corroborated where possible by measurement of airflow limitation. They may be due either to a localised airway obstruction (e.g. tumour, foreign body, vocal cord dysfunction or post-tracheostomy stenosis), or to a generalised problem (such as asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, cystic fibrosis or obliterative bronchiolitis). Symptoms of Asthma To avoid misdiagnosis it is essential to remember that people with asthma may suffer from a variety of symptoms, none of which is specific for asthma: • Wheeze • Shortness of breath • Chest tightness • Cough The hallmark of asthma is that these symptoms tend to be: • Variable • Intermittent • Worse at night • Provoked by triggers including exercise

Diagnosis of Bronchial Asthma 99 When cough is the predominant symptom without wheeze, this is often refered to as cough variant asthma. Signs of Asthma During exacerbations, the patient will often have wheeze and reduced lung function, either reduced peak flow or an obstructive pattern on spirometry. The presence of wheeze (usually diffuse, polyphonic, bilateral and particularly expiratory) is a cardinal sign of asthma and, if present, should be documented in clinical notes. Outside acute episodes, there may be no objective signs of asthma. Patients who present with chronic asthma may have signs of hyperinflation with or without wheeze. Additional information which may contribute towards a clinical suspicion of asthma includes: personal or family history of asthma or other atopic condition (eczema, allergic rhinitis); worsening of symptoms after exposure to recognised triggers such as pollens, dust, feathered or furry animals, exercise, viral infections, chemicals, and environmental tobacco smoke; and worsening of symptoms after taking aspirin/non-steroidal antiinflammatory medication or use of β blockers. A good medical history is enough in most of the time to diagnose bronchial asthma. Particular attention should be paid to the precipitating and/or aggravating factors. Pattern of symptoms may be perennial, seasonal, or perennial with seasonal exacerbations. The symptoms may also be continuous, episodic, or continuous with acute exacerbations. The onset, duration, and frequency of symptoms like number of days per week or month are also important to note. Day-night (circadian) variation with special reference to nocturnal symptoms should be asked for in each case. This should also include the age of onset and age of diagnosis, progress of the disease, previous and present evaluation of the disease, treatment, and response to such therapy, living situation with home age, location, cooling, and heating (central with gas, oil, electric, or kerosene), wood burning fire place, type of domestic cooking fuel used, carpeting, and humidifier. Special attention should be paid in enquiring about the patient’s living room with particular reference to pillow, bed, floor covering, and dust collectors. Information regarding animals in home and exposure to cigarette smoke, direct or side stream, is important. The impact of disease on the patient including number of emergency department visits, hospitalisation, history of life-threatening acute exacerbations, ventilatory support, requirement of oral steroid therapy, number of school or work days missed, limitation of activity especially sports, nocturnal awakening and the effect on growth, development, behaviour, school or work achievements and lifestyles need to be assessed. Similarly, the impact on family including disruption of family life, effect on spouse and children, and economic impact needs assessment. Patient, parental, and spouse knowledge of asthma and belief in the chronicity of asthma and in the efficacy of treatment, ability of the patient and the family to cope with disease, level of family support and economic resources are helpful in planning out a management programme for the patient which is to be evaluated at the time of diagnosis. Any precipitating and/or aggravating factors like viral respiratory tract infections,1 exposure to environmental allergens, exposure to occupational chemicals or allergens, impact of environmental changes like moving into a new home, going on a vacation, and/or alterations in workplace, work process, or material used, exposure to irritants like tobacco smoke, strong odour, air pollutants like ozone, oxides of sulphur, occupational chemicals, vapors, gases and aerosols, emotional expressions like anger, laughter, frustrations, crying, fear, drugs like aspirin, beta blockers, nonsteroidal

100 Bronchial Asthma anti-inflammatory drugs, food additives like sulphites, change in weather, particularly exposure to cold air, exercise, endocrinal factors like menstruation, pregnancy, thyroid disease, etc. are very important to evaluate since they will be very helpful in identifying the possible agent/factor(s) that care responsible in causing the disease. Family history of allergic diseases, asthma in close relatives is important pointers. In the personal and past history, any previous allergic disease like chronic rhinitis, repeated throat infections, sneezing, dermatitis, gastrointestinal disturbances, adverse reaction to foods, history of pulmonary infiltrates, and history of smoking or passive smoking are important points to note. Diagnosis of allergy in an asthma patient requires a thorough history taking. For example, if the asthma worsens in certain months and other symptoms of allergy like allergic rhinitis, sneezing, itching, running nose and nasal obstruction occur at the same time, pollens and outdoor moulds are the responsible allergens. If symptoms appear when visiting a house where there are indoor pets or if the symptoms improve when the patient is away from home for a week or longer, animal dander is the offending agent. Further evidence of animal dander comes from the fact that eyes may itch and become red after handling the pet. If the pet licks the patient, a red, itchy welt develops. If symptoms are more where a carpet is being vacuumed and bed making makes asthma worse, most likely mites are the responsible antigens. Mould allergy is usual if symptoms develop around hay and on being exposed into a damp environment. If symptoms are related to certain job activities, either at work and they improve when away from work for a few days will indicate occupational asthma. Physical findings of bronchial asthma are already discussed above. Although recurrent episodes of cough and wheezing with breathlessness are almost always due to bronchial asthma in both children and adults, there are other causes of airways obstruction leading to wheezing. The diagnosis may be little more difficult in children and infants rather in adults. Laboratory Studies Spirometry should be undertaken to document severity of airflow obstruction and to establish acute bronchodilator responsiveness for all patients in whom the diagnosis of asthma is being considered. All patients suspected to have bronchial Asthma should have spirometry done at least for initial assessment. However, it is important to use an accurate spirometer and the procedure being done correctly.2 In bronchial asthma, typically one gets an obstructive pattern. Usually there will be a normal vital capacity with either impaired FEV1 or impaired MMEF.3 When the FEV1 is severely reduced with clear evidence of obstruction (FEV1/FVC ratio less than 75% predicted), the vital capacity can also be reduced due to severe obstruction alone which prevents all the air to be emptied out during forced expiration. The mid-expiratory flow rate is useful as a screening test but it is too sensitive to assess the severity of obstruction. The FEV1 is the single best measure of pulmonary function for assessing severity, although PEFR when measured accurately correlated well with FEV1. Bronchial asthma has a significant impact on lung function decline, although not as great as COPD. Decline in FEV1 in patients with bronchial asthma is significantly influenced by baseline FEV1, disease duration, and FEV1 variability. Moreover, the rate of FEV1 decline seems to increase in younger subjects only when the baseline function is poorer.4 The low FEV1 in bronchial asthma is due to increased resistance because of bronchoconstriction and remodelled airway walls. However, recently it is reported that measurement

Diagnosis of Bronchial Asthma 101 of maximum static pleural pressure at different lung volumes showed marked loss of lung recoil in patients with moderate and severe asthma.5 Loss of this elastic recoil accounted for more than half of the reduction in total maximum airflow in these patients. This low elastic recoil in patients of asthma is due to long-term corticosteroid therapy, which has known detrimental effect on connective tissue, smoking, mechanical fatigue due to the persistent stretch in over inflation, and altered surfactant levels. Further accumulation of inflammatory cells has been reported in the alveolar tissue of these patients.6 While complete spirometry can be done in a laboratory only, the patient can measure the peak expiratory flow rate (PEFR) himself. Such measurement has many benefits. It provides a simple, quantitative, reproducible measure of airway obstruction that can be obtained using inexpensive, portable peak flow meters. PEFR has a very good correlation with FEV1. This is almost analogous to measuring blood pressure with a sphygmomanometer. This simple objective measurement of lung function helps detecting early deterioration of lung function.7,8 The most common strategy employed to support a clinical diagnosis of asthma is to demonstrate the presence of an abnormal, short-term variable airflow obstruction. Spontaneous variable airflow obstruction can be assessed by using peak expiratory flow monitoring at home9 or treatment induced variable airflow obstruction can be assessed in the laboratory by measuring the bronchodilator response to β2-agonists or the bronchoconstrictor response to short-acting airway smooth muscle spasmogens like methacholine. Patients with stable asthma should be encouraged to measure their peak expiratory flow rates at least one or two days a week to detect any slow deterioration and to start recording it regularly if they develop a respiratory tract infection, increase in wheeze, or other symptoms of increasing airway obstruction. They should normally measure their PEFR twice daily, on waking and in the evening, before using a bronchodilator, and perhaps four times a day during exacerbations. On each occasion, three readings should be taken and the best recorded graphically for easy inspection. Patients at increased risk, who are those recently admitted to hospitals with acute asthma, brittle asthmatics, unstable asthma, those requiring varying doses of systemic steroids to control their symptoms, and those using home nebulizers should record their PEFR more often. Home recordings of PEFR should improve the detection of under treated asthma. Patients thought to overuse their β2-agonist inhalers may show previously unrecognised nocturnal asthma or pronounced morning dipping. Recordings may also allow unnecessary drugs to be withdrawn, thus reducing morbidity and cost of treatment. High dose corticosteroids required initially may not be necessary subsequently. Thus in summary, measurement of PEFR is valuable in medical care settings to: • Assess the severity of asthma as a basis for making treatment decisions, such as admission to or release from the hospital or initiation of oral steroids. • Monitor response to therapy during an acute exacerbation. • Monitor response to chronic therapy and provide objective justification for therapy to patients. • Diagnose exercise-induced asthma. • Detect asymptomatic deterioration in lung function in the office and intervene before it becomes more serious. • Monitor degree of airflow obstruction during a series of office visits to assess the overall success of therapy.

102 Bronchial Asthma The primary limitation of PEFR measurement is that it is effort dependent and valid measurements depend upon the patient’s willingness and ability to exhale as hard as possible. Adequate training and periodic checkups are necessary to verify the accuracy. In addition, PEFR measures only large airway function; therefore, patients with mild asthma whose pathophysiologic abnormalities are linked to the small airways may be under diagnosed if spirometry, which measures flow rates at low lung volumes (i.e., FEF50, FEF25-75), is not performed. • Other laboratory investigations for bronchial asthma include: • Complete and differential blood counts; chest X-ray (to rule out other causes of airway obstruction, and to detect associated complications); • Sputum examination and stain for eosinophils (sputum eosinophils are highly characteristic of asthma and neutrophils predominate in bronchitic sputum); nasal secretions and stain for eosinophils (neutrophilic nasal discharge indicates sinusitis); sputum differential eosinophil count is one of the most useful objective tests in patients with bronchial asthma10 and • Complete pulmonary function studies including flow-volume loops which may reveal the presence of upper airway obstruction. Determination of specific IgE antibodies to common inhalant allergens with skin tests or with in vitro test is useful to find out the role of allergy in the patient’s asthma. Incorporating a skin prick test using commonly inhaled allergens is a simple, safe, inexpensive, rapid, and most common way of assessing the contribution of atopy.11 The incidence of positive skin prick test result, at least to one aeroallergen in asthmatic adults residing in the UK, age range 18-50 years, was 90%,12 whereas a positive result has been found in 15-40% of normal individuals.13-15 Inclusion of this test in suspected asthma cases can reduce the cost of this process significantly, and the test can be used as a reliable method to predict the absence of asthma in young adults.16 OBJECTIVE TESTS Obstructive airways disease produces a decrease in peak expiratory flow (PEF) and forced expiratory volume in one second (FEV1). One or both of these should be measured, but may be normal if the measurement is made between episodes of bronchospasm. If they are repeatedly normal in the presence of symptoms, then a diagnosis of asthma must be in doubt. Variability of PEF and FEV1, either spontaneously over time or in response to therapy is a characteristic feature of asthma. Although the normal level of diurnal variability is open to question, sequential measurement of PEF may be useful in the diagnosis of asthma. Calculating variability may be done in one of several ways. A 20% or greater variability in amplitude % best with a minimum change of at least 60L/min, ideally for three days in a week for two weeks seen over a period of time, is highly suggestive of asthma.17-23 Many patients with asthma will demonstrate variability below 20%, making this a reasonably specific but insensitive diagnostic test. That is, marked variability of peak flow and easily demonstrated reversibility confirms a diagnosis of asthma, but smaller changes do not necessarily exclude the diagnosis.

Diagnosis of Bronchial Asthma 103 Diagnosis of Asthma Using PEF Amplitude % best Highest PEF Lowest PEF Amplitude Percentage PEF variability

= = = = =

(highest–lowest)/highest × 100 400 1/min 300 l/min 400 l/min – 300 l/min = 100 l/min (400-300)/400 × 100 = 25%

The objective measurements helpful in the diagnosis of asthma include: • > 20% diurnal variation on > 3 days in a week for two weeks (to be maintained in a diary) • or FEV1 > 15% (and 200 ml) increase after short acting β2-agonist (salbutamol 400 μg by metered dose inhaler (pMDI) +spacer or 2.5 mg by nebuliser) • or FEV1 > 15% (and 200 ml) increase after trial of steroid tablets (prednisolone 30 mg/ day for 14 days) • or FEV1 > 15% decrease after six minutes of exercise (running) • Histamine or methacholine challenge in difficult cases Methods for Measuring Reversibility • An increase after inhalation of a short acting β2-agonist (e.g. salbutamol 400 mg by metered dose inhaler (pMDI) +spacer or 2.5 mg by nebuliser) • An increase after a trial of steroid tablets (prednisolone 30 mg/day for 14 days) • A decrease after six minutes of exercise, e.g. running. A resting measurement is to be taken first and then the patient is to be asked to exercise for six minutes, a further reading is to be taken and then every 10 minutes for 30 minutes. As this procedure may rarely induce significant asthma, facilities for immediate treatment should be available. Objective tests should be used to try to confirm a diagnosis of asthma before long-term therapy is started. Each of the above methods can be used, measuring either PEF (a 20% change from baseline and at least 60 l/min) or FEV1 (15% change and at least 200 ml).24 Bronchodilators reduce hyperinflation. Measurements of lung volumes before and after bronchodilators add sensitivity when examining for bronchodilator responsiveness.25 Other investigations that may be helpful include rhinoscopy, sinus X-ray and bronchoprovocation tests,26,27 provocative challenge with occupational allergens and evaluation of pH for gastro-oesophageal reflux. Bronchoprovocation Test Bronchoprovocation test is indicated to assess the airway hyperresponsiveness in the form of increased bronchoconstrictor response to a variety of physical, chemical, or pharmacological stimuli.28-30 This can better be assessed in a specialised pulmonary testing facility using bronchial challenge or provocation techniques. The most commonly employed methods used to evaluate airway hyperresponsiveness include inhalation provocation with methacholine or histamine and exercise challenge. During such a test changes in pulmonary function are measured with serial spirometry after inhaling incremental doses of an agonist such as methacholine or histamine or after exercise.31 The results are then expressed either as the cumulative dose or the concentration of agonist that produces a 20% fall in FEV1 (PD20). Methacholine bronchoprovocation testing is frequently used to diagnose airway

104 Bronchial Asthma hyperresponsiveness and asthma. A > 20% reduction in FEV1 following methacholine administration is a common parameter used to determine airway hyperresponsiveness. Some observed that the slope of the decline of FEV1 with increasing dose of methacholine is a better way of measuring responsiveness because a value can be assigned to all subjects. Alternatively, a > 40% reduction in specific airway conductance (sGaw) can be used to determine airway hyperresponsiveness.32,33 Regardless of which test is selected, according to the American Thoracic Society guidelines, the changes in the test parameter following methacholine challenge must exceed 2 SDs or coefficients of variation for repeated measures in the same individual before a statistically significant change can be established.33 Although either of the two measurements is good enough, a substantial number of patients have a reduction in SGaw alone in response to methacholine, and this response is seen in patients with a higher FEF25-75 / FVC ratio.34 Large, central airway obstruction is best detected by SGaw measurements, while both large and small airway narrowing will affect measurements of FEV1. Methacholine responsiveness is often used to confirm asthma status in patients, and as a predictor of later development of respiratory disease.35,36 It is widely used in epidemiological studies, where a standardised tool for measurements of bronchial responsiveness to methacholine has been developed to estimate variation in prevalence of increased bronchial responsiveness and predictors of asthma in different groups.37 Various such predictors are the FEV1 and symptom status, female sex, smoking, atopy, occupational exposure, and geographical regions are associated with increased responsiveness. Smaller airways are more responsive than larger ones, and the reduction in responsiveness diminishes with each increase of lung size.38 Methacholine challenge testing may cause an acute episode of vocal cord adduction and thus, positive results may not reflect underlying reactive airways disease. However, a flattening or truncation of the inspiratory flow-volume loop after the patient undergoes methacholine testing is not diagnostic for the presence of inspiratory vocal cord adduction.39 Results of exercise provocation are expressed as the peak fall in FEV1 after exercise. Asthmatics respond to bronchoprovocation with greater degree of airflow obstruction than normal subjects.40 Other conditions that are associated with an increased bronchial hyperreactivity include allergic rhinitis, cystic fibrosis, COPD, normal persons after a viral upper respiratory tract infection or oxidant exposure, and smokers.40,41 Diurnal variation in the measurement of PEFR is an indirect but clinically useful way of the degree of bronchial hyperreactivity even if there may be some variation.42 Bronchial provocation test is helpful in the differential diagnosis of asthma when the respiratory history, physical findings, and PEFR variations are not adequate to confirm the clinical diagnosis. These situations include cough variant asthma and exercise-induced dyspnoea.28,43 There is no one test or set of tests that should be ordered for every patient. Selection of tests should be individualised. However, with careful attention to the history, physical examination, and laboratory results, a correct diagnosis of asthma will be made in virtually all instances. Asthma may be under diagnosed particularly in young children, if they only wheeze when they have respiratory infections which may be dismissed as wheezy bronchitis, asthmatic bronchitis, bronchitis, or pneumonia. Although recurrent episodes of cough and wheezing are almost always due to asthma in both children and adults, there are other

Diagnosis of Bronchial Asthma 105 causes of airway obstruction which produce similar symptoms that need to be excluded. In adults, such conditions include mechanical obstruction of the airways, laryngeal dysfunction, chronic bronchitis, pulmonary emphysema, congestive cardiac failure, pulmonary embolism, pulmonary infiltration with eosinophilia, and cough secondary to drugs. Of particular interest is the confusion with chronic bronchitis more so in elderly smokers. Presence of crepitations; absence of eosinophils in the nasal secretion, sputum, and blood eosinophilia; lack of good reversibility after bronchodilators; and an abnormal diffusion capacity favours chronic bronchitis with emphysema. Occasionally, it is not possible to differentiate the two conditions. Of all the battery of tests utilised to diagnose asthma (methacholine challenge testing, peak expiratory flow variability over a 2-week period, the FEV1/FVC ratio, the reversibility testing, and the differential count of eosinophils in blood and sputum), methacholine airway responsiveness and the sputum differential eosinophil count seems to be the most useful objective tests in patients with mild asthma. The sensitivity of these two tests are 91 and 72% respectively, and the specificity is 90 and 80% respectively.44 Increase bronchial responsiveness demonstrated by methacholine or histamine challenge is associated with symptomatic asthma, but is also common in the general population and in patients with COPD. However, failure to demonstrate hyperresponsiveness in an untreated person with suspected asthma should prompt reconsideration of the diagnosis. Other Tests Lung function tests may show changes suggestive of an alternative lung disease. For example, COPD may be suspected in the presence of obstructive spirometry, reduced diffusing capacity (CO uptake) and pressure dependent airway collapse on flow volume curves, but these changes are not diagnostic and do not exclude asthma, which may anyway coexist with other conditions. Failure to respond to asthma treatment should prompt a search for an alternative, or additional, diagnosis. Chest X-rays in all patients with atypical symptoms should be done. The differential diagnosis of bronchial asthma includes: COPD, cardiac diseases, laryngeal tumours, tracheal tumours, bronchogenic carcinoma, bronchiectasis, foreign body, interstitial lung disease, pulmonary embolism, aspirations, vocal cord dysfunction, pulmonary infiltrations with eosinophilia, cough due to drugs (beta blockers, ACE inhibitors) and hyperventilation. A detailed clinical history as well as investigations as outlined will be helpful in differentiating these conditions. In spite of a cautious and careful approach, there may be situations when one has to refer the case to a specialist for opinion and further investigations. These situations include: • Diagnosis unclear or in doubt • Unexpected clinical findings (like crepitations, collapse, effusion, cardiac murmur, clubbing, heart failure, cyanosis, etc.) • Spirometry or PEFR does not fit the diagnosis (like restrictive defect) • Suspected occupational asthma • Persistent shortness of breath (non-episodic, or without wheeze) • Unilateral or fixed wheeze • Stridor • Persistent chest pain or atypical features

106 Bronchial Asthma • Weight loss • Persistent cough or sputum production • Non-resolving pneumonia A suggested algorithm for the diagnostic work up in younger subjects with suspected asthma is shown in Figure 6.1. Cough, Wheezing, Dyspnoea

Spirometry with bronchodilators (Reversibility testing)

Positive

Negative

Skin testing

Positive

Exercise/Methacholine

Positive

Negative

Consider other diagnosis

Negative

Bronchial asthma Fig. 6.1: Diagnostic work-up for bronchial asthma

COPD and Bronchial Asthma Most often there is a confusion whether the patient is having bronchial asthma or COPD as both the conditions has similar symptoms like cough, wheezing and breathlessness. There are some similarities also between the two conditions. Tissue eosinophilia, sputum eosinophilia, increased bronchial hyperreactivity, inflammatory cells, cytokines, etc. can be similar in COPD, but the types of cells and degree of involvement differ. Because the overall prognosis and course of the disease are entirely different in both the conditions. Hence, the differentiation should always be made. It must, however, be possible that both conditions may coexist. The important differentiating points between the two are shown in Table 6.1.45 Diagnosis of Occupational Asthma Careful history and temporal relationship of symptoms with work place will clinch the diagnosis. However, it is important to establish objectively a relationship between work and asthma symptoms. Specific challenge tests of occupational exposure tests are often considered a reference standard for the diagnosis of occupational asthma. The various tests used are:

Diagnosis of Bronchial Asthma 107 Table 6:1: Important differentiating points between bronchial asthma and COPD

Parameter

Bronchial asthma

Clinical

• Young age of onset • Associated history of allergy (rhinitis, urticaria, eczema etc) • Episodic wheezing • Signs of hyperinflation unusual • Crepitations—unusual findings • Evidence of cor pulmonale—absent • Cyanosis—unusual except in acute severe asthma • Signs of hypercarbia unusual • Chest skiagram—frequently normal

Airflow obstruction

•

Postmortem

•

Sputum

• •

Surface epithelium Bronchiolar mucus cells Reticular basement membrane Congestion/oedema Bronchial smooth muscle Bronchial glands Cellular infiltrates

Cytokines

• • • •

COPD

• More older people • History of smoking, exposure to pollution • No history of allergy • Signs of hyperinflation (hyperresonant notes on percussion, obliteration of cardiac dullness, low, diaphragm) • Air entry diminished • Rhonchi and crepitation present • Cor pulmonale is a frequent complication • Cyanosis may be a finding • Signs of hypercarbia, frequent • Chest skiagram will show changes of COPD like increased lung volumes, tubular heart, low, flat diaphragms, attenuation of peripheral vessels, emphysematous bullae etc. Variable (irreversible component • Progressive deterioration of may be there in late stages) lung function Hyperinflation, mucus plugs • Excessive mucus (mucoid/ purulent) (exudates + mucus), • Small airway disease, Emphysema No or little emphysema Eosinophilia, metachromatic • Neutrophils (infective exacerbations) cells, creola bodies Fragility undetermined • Fragility loss Mucus metaplasia debated • Metaplasia/hyperplasia definite Homogenously thickened and • Variable or normal hyaline present Present • Variable/fibrotic Enlarged mass (large airways) • Enlarged (Small airways)

• Enlarged mass, but no change in mucin histochemistry • Predominantly CD3, CD4, CD25 (IL-2R)+, • Marked eosinophilia (activation) • Mast cells increase (Decrease in severe/fatal cases) • IL-4, IL-5, eotaxin, and RANTES gene expression

• Enlarged mass, increased acidic glycoprotein • Predominantly CD3, CD8, CD68, CD25, HLA-1 and HLA-DR+, • Mild eosinophilia except during exacerbations, • Mast cells increase in smokers • IL-4 and IL-5 gene expression RANTES only in exacerbations

108 Bronchial Asthma i. Measurement of lung function before and after a work shift. This is not very helpful in establishing a causal relationship between symptoms and work exposure. ii. Measurements of lung function (FVC and FEV1) when the patient has been away from the work environment for a period of time and again when he returns to work. An improvement in symptoms and lung functions away from work and recurrence of symptoms and deterioration in lung function after returning to work, confirms that the symptoms are related to the work environment. iii. Prolonged recording of PEFR by the patient at work and at home is a good method of establishing the causal relationship. The patient is asked to measure and record the PEFR every 2 hours from waking to sleep for at least 2 to 3 weeks at work, followed by at least 10 days off work. Different patterns of PEFR are described. The method has the disadvantage of falsification of data and inaccurate readings. iv. Serial measurements of nonspecific airway responsiveness in conjunction with prolonged recording of PEFR has been proposed as an additional test to provide objective evidence of sensitisation. Significant increases in airway responsiveness when away from work, associated with appropriate changes in PEFR, suggest an occupational relationship. Specific challenge tests are required to identify the substances in the work place causing the symptoms. However, this is time consuming and not devoid of danger. They should be performed by experienced personnel in hospital settings where resuscitation facilities are available and frequent observations can be made. Allergy skin tests with high molecular weight compounds may be useful in identifying the responsible agent. Animal products, flour, coffee, and castor bean produce immediate positive reactions on skin testing in sensitised subjects. Specific IgE antibodies to various occupational allergens may be demonstrated by RAST or by ELISA. Such specific antibodies against low molecular weight compounds conjugated to a protein like trimellite anhydride and isocyanate have been demonstrated in some exposed subjects. However, positive skin tests and the presence of IgE antibodies indicate sensitisation and may occur in exposed workers without asthma. The clinical investigation of occupational asthma is shown in Figure 6.2.46 Classification of Asthma Bronchial asthma can be defined as mild, moderate, and severe on severity of disease.47 This enables the clinician to categorize the overall assessment of a patient’s asthma and select appropriate therapy. The characteristics are shown in Table 6.2 and are recommended by the Expert Panel of the National Asthma Education Program by the National Heart, Lung, and Blood Institute, USA.47 The characteristics are general, and because asthma is highly variable, these characteristics may overlap. Furthermore, an individual may switch into different categories over time. Thus, severity of bronchial asthma, as defined by the National Asthma Education Programme (NAEP) Expert Panel of 1991, can be summarised as:

Mild: It is characterised by intermittent daytime symptoms up to two times in a week, brief wheezing, cough, or breathlessness with activity, and infrequent nocturnal cough or wheezing less than two times in a month. The FEV1 or PEFR is expected to be greater than 80% when asymptomatic and to vary 20% with symptoms.

Diagnosis of Bronchial Asthma 109

Fig. 6.2: Diagnostic work-up of occupational asthma

110 Bronchial Asthma Table 6.2: Classification of bronchial asthma

Characteristics Pretreatment Frequency of exacerbations

Mild Exacerbation of cough and wheezing no more often than 1-2 times/week

Moderate

Severe

Virtually daily. Exacerbations frequent. Often severe. Tends to have sudden severe urgent visits to emergency department or doctor’s office > 3/year Hospitalization > 2/yr Frequency of Few clinical Cough and low grade wheezing Continuous symptoms symptoms signs/symptoms between acute exacerbations of cough and wheezing between exacerbations almost often present always present Degree of Good. May not tolerate Diminished Very poor. Marked exercise vigorous exercise activity limitation tolerance like prolonged running Frequency of Not more than 1-2 2-3 times/week Considerable. Almost nocturnal times per month nightly sleep interrupasthma tion. Early morning chest tightness School or work Good May be affected Poor attendance Attendance > 80% predicted. 60-80% predicted. < 60% predicted. Pulmonary function PEFR Normal or minimal Airway obstruction Substantial degree of Spirometry airway obstruction. evident. Flow airway obstruction. Normal expiratory volume curve shows Flow volume flow volume curve. reduced expiratory flow curve shows Lung volumes at low lung volumes. marked concavity. not increased. Lung volumes often Spirometry may not be Usually a > 15% increased. Usually a normalised even with response to acute > 15% response to steroids. May have aerosol bronchoaerosol bronchosubstantial increase in dilator even with near dilator lung volumes and normal baseline marked unevenness values. of ventilation. Incomplete reversibility to acute aerosol bronchodilator Methacholine > 20 mg/ml Between 2-20 mg/ml < 2 mg/ml sensitivity (PC20)

After optimal treatment is established Response to Exacerbations respond and duration of to bronchodilators therapy. without the use of systemic steroids Regular therapy not required except for exacerbations

Exacerbations of cough and wheezing more frequent. Severe exacerbations infrequent. Urgent care treatment < 3/year

Periodic use of bronchodilators required during exacerbations for a week or more Steroids needed for short periods

Requires continuous multiple round-theclock drug therapy including daily steroids either aerosol or systemic in high doses

Diagnosis of Bronchial Asthma 111 Moderate: Moderate asthma is characterised by symptoms more than 1-2 times weekly affecting sleep and activity levels, exacerbations lasting several days, and occasional emergency care. The FEV1 or PEFR is expected to be 60-80% at baseline and vary between 20-30% with symptoms. Severe: This is characterised by continuous symptoms including nocturnal symptoms, limited activity levels, frequent exacerbations, and occasional hospitalisation, and emergency treatment. The FEV1 or PEFR is less than 60% at baseline and highly variable. The British Guidelines are parallel to the NAEP guidelines. However, the Global Strategy for Asthma Management and Prevention Workshop, a joint effort of the National Heart, Lung, and Blood Institute and the WHO, 1995 (NIH Publication No. 96-3659A) classifies severity of asthma into different (discussed subsequently). REFERENCES 1. Empey DW, Laitinen LA, Jacobs L, Gold WM, Nadel A. Mechanisms of bronchial hyperreactivity in normal subjects after upper respiratory tract infection. Am Rev Respir Dis 1976; 113:131. 2. Behera D. Normal values of Pulmonary Function Tests. In: Pulmonary functions tests in Health and Disease (Ed). PS Shankar. Indian College of Physicians, 1998; 150-59. 3. Wagner EM, Liu MC, Weinnman GG, Permutt S, Bleecker ER. Peripheral lung resistance in normal and asthmatic subjects. Am Rev Respir Dis 1990;141:584. 4. Cibella F, Cuttitta G, Bella V et al. Lung function decline in bronchial asthma. Chest 2002;122: 1944-48. 5. Gelb AF, Licuanan J, Shinar CM, Zamel N. Unsuspected loss of lung elastic recoil in chronic persistent asthma. Hest 2002;121:715-21. 6. Wassermann K. Is asthma another interstitial lung disease? Chest 2002;121:673-74. 7. Gupta ML, Behera D: Pattern of airflow obstruction in Bronchial Asthma—An observation on Home-Monitoring of Peak Expiratory Flow Rate. J Ass Phy India, 1997;45:94-96. 8. Clark TJH, Hetzel MR. Diurnal variation of asthma. Br J Dis Chest 1977;71:87-92. 9. Jamison JP, McKinley RK. Validity of peak expiratory flow rate variability for the diagnosis of asthma. Clin Sci 1993;85:367-71. 10. Hunter CJ, Brightling CE, Woltmann G, Wardlaw AJ, Pavord ID. A comparison of the validity of different diagnostic tests in adults with asthma. Chest 2002;121:1051-57. 11. Allergy skin testing. Board of Directors,; American Academy of Allergy and Immunology J Allergy Clin Immunol 1993;92:636-37. 12. Corne J, Smith S, Schreiber J et al. Prevalence of atopy in asthma. Lancet 1994;344:344-45. 13. Holt PG, Macaubas C, Stumbles PA et al. The role of allergy in the development of asthma. Nature 1999;402:B12-B17, 14. Holgate ST. The epidemic of allergy and asthma. Nature 1999;402:B2-B4. 15. Busse WW, Lemanske RF. Advances in immunology: Asthma. N Engl J Med 2001;344:350-62. 16. Graif Y, Yigla M, Tov N, Kramer MR. Value of a negative aeroallergen skin-prick test result in the diagnosis of asthma in young adults. Co-relative study with methacholine challenge testing. Chest 2002;122:821-25. 17. Higgins BG, Britton JR, Chinn S et al. The distribution of peak flow variability in a population sample. Am Rev Respir Dis 1989;140:1368-72. 18. Kesten S, Rebuck AS. Is the short-term response to inhaled beta-adrenergic agonist sensitive or specific for distinguishing between asthma and COPD! Chest 1994;105:1042-1045. 19. Thiadens HA, De Bock GH, Dekker FW et al. Value of measuring diurnal peak flow variability in the recognition of asthma: a study in general practice. Eur Respir J 1998;12:842-47.

112 Bronchial Asthma 20. Kunzli N, Stutz EZ, Perruchaoud AP et al. Peak flow variability in the SAPALDIA study and its validity in screening for asthma-related conditions. The SAPALDIA Team. Am J Respir Crit Care Med 1999;160:427-34. 21. Siersted HC, Mostgaard G, Hyldebrandt N et al. Interrelationships between diagnosed asthma, asthma like symptoms, and abnormal airway behaviour in adolescence. The Odense Schoolchild Study. Thorax 1996;51:503-09. 22. Quackenboss JL, Libowitz MD, Krzyzanoski M. The normal range of diurnal changes in peak expiratory flow rates. Relationship to symptoms, and respiratory disease. Am Rev Respir Dis 1991;143:323-30. 23. Reddel HK, Salome CM, Peat JK et al. Which index of peak expiratory flow is most useful in the management of stable asthma? Am J Respir Crit Care Med 1995;151:1320-25. 24. Tweeddale PM,Alexander F, McHardy GJ. Short-term variability in FEV1 and bronchodilator responsiveness in patients with obstructive ventilatory defects. Thorax 1987;42:487-90. 25. Newton MF, O’Donnell E, Forkert L. Response of lung volumes to inhaled salbutamol in a large population of patients with severe hyperinflation. Chest 2002;121:1042-50. 26. Anderson SD. Nonisotonic aerosol challenge in the evaluation of bronchial hyper-responsiveness. Allergy Proc 1991;12:143. 27. Boulet LP, Legris C, Thibault L, Turcotte H. Comparative bronchial response to hyperosmolar saline and methacholine in asthma. thorax 1987;42:953-58. 28. Boushey HA, Holtzman MJ, Sheller JR, Nadel JA. Bronchial hyper-reactivity. Am Rev Respir Dis 1980;121:389-414. 29. Hopp RJ, Townley RG, Biven RE, Bewtra AK, Nair NM. The presence of airway reactivity before the development of asthma. Am Rev Respir Dis 1990;141;2-8. 30. Jones A. Asymptomatic bronchial hyper-reactivity and the development of asthma and other respiratory tract illnesses. Thorax 1994;49;757-61. 31. Chatham M, Bleecker ER, Smith PL, Rosenthal RR, Mason P, Norman PS. A comparison of histamine, methacholine, and exercise airway reactivity in normal and asthmatic subjects. Am Rev Respir Dis 1982;126:235-40. 32. American Thoracic Society Guidelines for methacholine and exercise challenge testing, 1999. Am J Respir Crit Care Med 2000;161:309-329. 33. American Thoracic Society Guidelines for bronchial inhalation challenges with pharmacologic and antigenic agents. ATS News 1980 (Spring). 34. Parker AL, McCool FD. Pulmonary function characteristics in patients with different patterns of methacholine airway hyper-responsiveness. Chest 2002;121:1818-23. 35. Laprise C, Boulet LP. Asymptomatic airway hyper-responsiveness: A three year follow-up. Am J Respir Crit Care Med 1997;156:403-409. 36. Pattemore PK, Asher MH, Harrison AC et al. The interrelationship among bronchial hyperresponsiveness, the diagnosis of asthma, and asthma symptoms. Am Rev Respir Dis 1990;142: 549-554. 37. Burney PGJ, Luczynska G, Chinn S et al. The European Community Respiratory Health Survey. Eur Respir J 1994;7:954-60. 38. Schwartz J, Schindler C, Zemp E et al. Predictors of methacholine responsiveness in a general population. Chest 2002;122:812-20. 39. Perkins PJ, Morris MJ. Vocal cord dysfunction induced by methacholine challenge testing. Chest 2002;122:1988-93. 40. Hargreave FE, Ryan G, Thomson NC et al. Bronchial responsiveness to histamine or methacholine in asthma: Measurement and clinical significance. J Allergy Clin Immunol 1981;68:347-55. 41. Chatham M, Bleecker ER, Norman P, Smith PL, Mason P. A Screening test for airways reactivity. Chest 1982;82:15-18.

Diagnosis of Bronchial Asthma 113 42. Ryan G, Latimer KM, Dolovich J, Hargreave FE. Bronchial responsiveness to histamine: relationship to diurnal variation of peak flow rate, improvement after bronchodilator, airway caliber. Thorax 1982;37:423-29. 43. Galvez RA, McLaughlin FJ, Levison H. The role of the methacholine challenge in children with chronic cough. J Allergy Clin Immunol 1987;79:331-35. 44. Hunter CJ, Brightling CE, Voltman G et al. A comparison of the validity of different diagnostic tests in adults with asthma. Chest 2002;122:1051-57. 45. Jeffery P. Immunopathology: Comparison of COPD and asthma. In: Hansel TT, Barnes PJ (Eds): New Drugs for Asthma, Allergy, and COPD. Prog Respir Res. Basel, Karger, 2001; 31:24-29. 46. Chan-Yeung M, Malo JL. Occupational asthma. New Engl J Med 1995;333:107-12. 47. National Asthma Education Programme. Expert Panel Report. Guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute, National Institute of Health, Bethesda, Maryland, USA, Publication No. 91-3042A, June 1991.

114 Bronchial Asthma

7 Prognosis of Bronchial Asthma FACTORS FOR ASTHMA MORTALITY Although the possibility of asthma-related death exists for all patients with asthma, several studies have revealed factors associated with an increased risk of such deaths.1-6 Several studies from many countries of the world including Britain, New Zealand, United States, France, Germany, and Canada have shown increases over the last two decades in the incidence of deaths from asthma. The cause of such increase in deaths remains a puzzle. There are many hypotheses to explain this, but little emphasis has been placed on the possibility that confidence in better drug treatment may modify patient’s behaviour so as to place him at greater risk of illness. Excessive confidence in bronchodilator inhalers and nebulisers can make patients stay away from hospitals too long during acute attacks. It is also very likely that prevention of symptoms by use of antiasthma drugs could allow patients to spend more time in environments containing antigens or other agents that provoke asthma, resulting in more serious and long-lasting bronchial inflammation and reactivity. Some of these recognised factors that increases the susceptibility to death from asthma are as follows. Age and Ethnicity Asthma-related death rates are higher among older patients than in any other age group. Although the death rate is relatively low in younger patients, an increased trend in asthma deaths among these individuals between the age group of 5 to 34 years have been noted during the last 10 years. People in their late teens and early twenties, particularly members of minority groups, are over represented in asthma mortality statistics groups. AfricanAmericans have asthma related mortality rates that are higher than those of Caucasians, especially in relatively young age groups, and the mortality rate in this group has increased significantly during the past decade. In 1979, African-Americans of both sexes were about twice as likely to die of asthma as Caucasians. Previous Life-threatening Acute Asthma Exacerbations Individuals who have had acute exacerbations of asthma that resulted in respiratory failure and required intubation are at increased risk for subsequent fatal exacerbations. Those who have experienced respiratory acidosis without requiring intubation are also high-risk patients.

Prognosis of Bronchial Asthma 115 Hospital Admission for Asthma within the Last Year Those patients hospitalised for asthma within the last year have a greatly increased risk of dying from asthma when compared to severity-matched asthma patients in the community that have not been hospitalised. Those with more than two hospitalisations for status asthmaticus in spite of long-term oral steroid therapy are at the highest risk of dying from asthma. In some patients, deterioration during an acute exacerbation occurs very rapidly. Underestimation of the severity of such exacerbations may lead to a life-threatening delay in starting medical treatment or seeking medical care. Some patients may fail to appreciate a poor response to treatment during an acute exacerbation and may rely on frequent repetitive use of inhaled β2-agonist far in excess of recommended doses for therapy at home. This treatment may temporarily blunt symptoms but mask increasing inflammation and airway hyperresponsiveness, which may in turn, lead to abrupt and severe deterioration of lung function. Without the documented objective measures of pulmonary function or realisation by the patient and/or the physician of the severity of the disease, risk of death is increased. Psychological and Psychosocial Problems Depression leads to increased death particularly in children. Other psychological problems that have been documented as associated with those at increased risk include alcohol abuse, documented depression, recent family loss and disruption, recent unemployment, and schizophrenia. Patients who have experienced a life-threatening asthma exacerbation have been reported, on the whole, to deny that they are at risk of death. Following a near fatal exacerbation, they tend to either develop decompensating psychiatric disease and symptoms of extreme anxiety or develop even higher levels of denial. Some tend to minimise their symptoms and avoid access to health care. Other associations include life crises, family conflict, and social isolation. Regardless of the possible physiologic and psychological interactions that link anxiety, depression, and asthma fatality, it is evident that patients who have these psychological disruptions are at increased risk for death.7-15 Lack of Access to Medical Care Lack of access to medical care is another risk factor associated with asthma-related death. Patients of lower socioeconomic class are unable to obtain routine preventive asthma care. As a result, these patients seek help only when their asthma symptoms are severe and report to the emergency room for initial care.16 In rural areas, lack of access to adequate emergency care can result in life-threatening delay in medical treatment during exacerbations. Even in some urban centers, adequate facilities like ventilatory support are not available. Medication Use Medications, particularly steroids, are underused at the time of death. The controversy of the asthma mortality because of β-agonist use is still on.17-19

116 Bronchial Asthma REFERENCES 1. Wissow LS, Gittelsohn AM, Szklo M, Starfield B, Mussman M. Poverty, race, and hospitalisation for childhood asthma. Am J Public Health 1988;78:777. 2. Miller BD. Depression and asthma: A potentially lethal mixture. J Allergy Clin Immunol 1987;80:481. 3. Strunk RC. Identification of the fatally-prone subject with asthma. J Allergy Clin Immunol 1989;83:477. 4. Rea HH, Scragg R, Jackson R et al. A case-controlled study of deaths from asthma. Thorax 1986;41:833. 5. Benatar SR. Fatal asthma. N Engl J Med 1986;314:423. 6. Barriot P, Riou B. Prevention of fatal asthma. Chest 1987;92:460. 7. Campbell DA, McLennan G, Coates JR et al. A comparison of asthma deaths and near fatal asthma attacks in South Australia. Eur Respir J 1994;7:490-97. 8. Strunk RC, Mrazek DA, Fuhrmann GSW, LeBreque JF. Death from asthma in childhood. Can they be predicted? JAMA 1985;254:1193-98. 9. Wareham NJ, Harrison BDW, Jenkins PF, Nicholls J, Stableforth DE. A district confidential enquiry into death due to asthma. Thorax 1993;48;1117-20. 10. Campbell DA, Yellowlees PM, McLennan G, et al. Psychiatric and medical features of near fatal asthma. Thorax 1995;50;254-59. 11. Creer TL. Psychological factors and deaths from asthma; Creation and critique of a myth. J Asthma 1986;23;261-69. 12. Boseley CM, Fosbury JA, Cochrane GM. The psychological factors associated with poor compliance with treatment in asthma. Eur Respir J 1995;8;899-904. 13. Fitzgerald JM. Psychological barriers to asthma education. Chest 1994;1069(Suppl4):2S-3S. 14. Gibson GJ. Perception, personality, and respiratory control in life-threatening asthma. N Engl J Med 1994;330:1329-34. 15. Weiss KB, Wagener DK. Geographical variations in US asthma mortality: Small area analysis of exercise mortality, 1981-85. Am J Epidemiol 1990;132:s107. 16. Barger LW, Vollmer WM, Felt RW, Buist AS. Further investigations into the recent increase in asthma death rates; a review of 41 asthma deaths in Oregon in 1982. Ann Allergy 1988;60:31-39. 17. Crane J, Flatt A, Jackson R et al. Prescribed fenoterol and death from asthma in New Zealand, 1981-83: Case control study. Lancet 1989;1:917-27. 18. Crane J, Pearce N, Burgess C, Beasley R. Asthma and the beta agonist debate. Thorax 1995;50(Suppl 1):S5-S10. 19. Suissa S, Ernst P, Boivin JF et al. A cohort analysis of excess mortality in asthma and the use of inhaled beta agonists. Am J Respir Crit Care Med 1994;149:604-10.

Complications of Bronchial Asthma 117

8 Complications of Bronchial Asthma Infections, pneumothorax, pneumomediastinum, and atelectasis due to mucus plugging are the complications of acute bronchial asthma. Allergic broncho-pulmonary mycosis (ABPM) is an important complication of asthma.1 The most common fungus involved is Aspergillus fumigatus. Sensitisation to aspergillus antigens may occur in asthmatics without full-blown picture of ABPA. The prevalence of such sensitisation reportedly occurs in 20-50% of cases of bronchial asthma and the incidence of full-blown pictures of ABPA occurs in about 65 of cases, although higher figures have been reported.2-11 Other organisms that can cause such bronchopulmonary reactions include other species of Aspergillus, Candida albicans, Pseudoallescheria boydii, Stemphylium sp, Helminthosporium sp, Pseudomonas aeruginosa, Curvularia lunata, Drechslera hawaiiensis, Torulopsis glabrata, Rhizopus, Penicillium, Bipolaris, and Fusarium vasinifectum.12 Cor pulmonale secondary to bronchial asthma is extremely uncommon and in fact, the presence of this complication should be an indication that the underlying problem is not asthma. Respiratory failure is common during acute severe asthma. ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS (ABPA) Allergic bronchopulmonary aspergillosis is a complex hypersensitivity reaction to Aspergillus antigens because of the presence of the fungus in the bronchial tree and the disorder characterised by bronchospasm, pulmonary infiltrates, eosinophilia, and immunologic evidence of allergy to the antigens of Aspergillus species. Aspergillus fumigatus is the one responsible for the condition although other species may also be responsible. The first three cases were diagnosed in 1952 in England by Hinson et al.13 Subsequently the entity has been reported more frequently from that country as well as from other regions of the world like Australia,14 North America15 and parts of Asia.16 It was first reported from India in 197117 and a few case series have subsequently been documented.18-27 The disease is typically seen in patients with long-standing asthma or cystic fibrosis. The incidence of the condition in asthmatics is reported to vary from 3 to 20% of corticosteroid dependent asthma patients28 and 6% of patients with cystic fibrosis meet the diagnostic criteria of ABPA.29 Pathophysiology Patients with ABPA are usually atopic and have a history of bronchial asthma. The basic underlying pathophysiologic process in ABPA is a hypersensitivity reaction to the presence

118 Bronchial Asthma Flow Chart: Clinical spectrum of inhalation of Aspergillus spores Inhalation of Aspergillus

Colonisation

Normal host

No sequel

Cavitary lung disease

Aspergilloma

Chronic lung disease or mild immunocompromised

Chronic Nercotising Aspergillosis

Immunocompromised host

Invasive Pulmonary Aspergillosis

Asthma

ABPA

Colonisation

Tracheobronchitis

Ulcerative Tracheobronchitis Pseudomembranous tracheobronchitis

of fungus in the bronchial tree. Tissue invasion by the fungus usually does not occur. The factors favouring the initial colonisation of the bronchial tree are unclear. Other host factors, including cellular immunity, may contribute to the pathologic changes seen in ABPA.30,31 The changes brought about by the ensuing local immunologic reactions and the tenacious sputum of bronchial asthma favour the trapping of fungal spores and further colonisation. Antigenic material from the fungus stimulates production of IgE, IgG, and IgA antibodies. A number of immunologic reactions, notably type I (immediate) and type III (antigenantibody, immune complex) hypersensitivity reactions occur in this condition. The type I immediate hypersensitivity reaction is IgE mediated and account for the bronchospastic symptoms of the condition. Type III reactions mediated by IgG result in polymorph aggregation, inflammation of bronchial and peribronchial tissue and is responsible for the radiological features of ABPA. Both these reactions play a central role in the pathogenesis of ABPA.32,33 Recently a possible role of type IV hypersensitivity reaction has been inferred from the demonstration of in vitro lymphocyte transformation in response to Aspergillus antigens in patients with ABPA and the presence of parenchymal granuloma and mononuclear cell infiltration seen on histopathology. Alternate pathway complement

Complications of Bronchial Asthma 119 activation may also take part in the inflammatory response of ABPA. Long-standing involvement of the bronchial tree leads on to bronchiectasis, fibrosis, lung contraction, and lobar shrinkage. Lung biopsy in ABPA (done rarely as diagnosis is mainly clinical and laboratory findings) demonstrates different stages of chronic inflammatory process involving bronchial walls and peribronchial tissues. There is no tissue invasion by the fungus and granulomas may be seen. The most significant findings involve bronchi and bronchioles34 with bronchocentric granulomas and mucoid impaction. Other findings include granulomatous inflammation. The cellular infiltration consists of eosinophils, monocytes, plasma cells and multinucleated giant cells. The bronchi are dilated and are filled with tenacious exudates containing eosinophilic material and mycelia. In long-standing cases variable degrees of interstitial and alveolar fibrosis are seen. Presence of immune complexes has been demonstrated in some cases with immunofluorescent studies. Vasculitis is very rare. Bronchi contain tenacious mucus, fibrin, Curschmann’s spirals, Charcot-Leyden crystals, eosinophils, and mononuclear cells. Fungal hyphae may be seen in the bronchial lumen without tissue invasion.34 Clinical Features of ABPA The patient is usually an atopic individual with established bronchial asthma of many years. There is no clear relationship between exposure to antigens and the onset of symptoms. The onset is insidious with nonspecific complaints like anorexia, progressive fatigue, headache, generalised aches and pains, low grade fever, and loss of weight. The underlying asthma usually increases in frequency and severity with less degree of control with the usual anti-asthmatic medications. The increased frequency of wheezing is associated with intermittent or continuous sputum production. Rubbery golden-brown plugs of sputum production are characteristic of this condition and have been reported in 5 to 54% of cases. Expectoration of such plugs is associated with a dramatic improvement in symptoms particularly wheezing.35 These plugs consist of fungal hyphae with eosinophils and mucus. Cough is universal and dyspnoea may be present in a substantial number of cases. Haemoptysis has been reported in 34 to 85% of cases. Pleuritic chest pain may be present in about half of the patients and is usually localised to the side involved on chest X-ray. Chronic cases may present with symptoms compatible with bronchiectasis. Patients may exhibit minimal symptoms, yet demonstrate extensive pulmonary consolidation on chest radiography. Wheezing and diffuse crepitations are the common findings on chest examination. Five stages have been identified in patients with ABPA,36,37 which help to guide the management of the disease. It is not necessary for a patient to progress through all these stages. The stages are: • Stage I (Acute stage); • Stage II (Remission stage); • Stage III (Exacerbation stage); • Stage IV (Corticosteroid-dependent asthma stage); and • Stage V (Fibrotic stage).

Stage I The classic signs, symptoms, and laboratory findings present at diagnosis characterize the acute stage. Bronchial asthma, a markedly elevated IgE levels, peripheral eosinophilia, pulmonary infiltrates, and the presence of IgE and IgG antibodies to A.fumigatus characterize this stage. In practice, patients are rarely identified at this stage.

120 Bronchial Asthma

Stage II The remission stage is characterised by radiological clearing, a decline in total serum IgE levels, but not to the normal levels, eosinophilia is absent, control of respiratory symptoms, and a discontinuation of corticosteroid therapy over a six month period without recurrence of ABPA. Serum IgG antibodies to Aspergillus may be slightly elevated. Prolonged and permanent remissions may occur after treatment of the acute stage with steroids, and maintenance therapy is not required in these patients. In some, asthma may become refractory to aminophylline, β-agonists and Cromolyn and inhaled steroids may be necessary. Stage III The exacerbation stage is the one when the patent is a known case of ABPA and demonstrates all characteristics of the acute stage or when there is a two-fold rise in the total serum IgE levels in association with radiological finding in the absence of other causes of infiltrates like bacterial or viral pneumonias. Remission after an exacerbation is induced in these patients with corticosteroids and prolonged therapy is not necessary. Stage IV The corticosteroid-asthma stage is present when patients require oral steroid therapy to control asthma (steroid-dependent asthma) or to prevent recurrent exacerbations. The dose of steroids needed to control asthma usually is not sufficient for preventing the exacerbations of ABPA or the occurrence of both. Attempt to taper steroid therapy will result in worsening of symptoms and the development of pulmonary infiltrates. Stage V The fibrotic lung disease stage is present when there are extensive fibrotic changes on chest X-ray (end-stage lung disease) with irreversible obstructive lung disease on pulmonary testing. Steroid therapy is not able to reverse these changes completely. Dyspnoea, cyanosis, crepitations, clubbing, cor pulmonale, respiratory failure and death may occur in some patients. The serum IgE level and eosinophil count may be low or high. A minority of patients progress to this stage. ABPA may precede the clinical recognition of the disease for many years. Usually there are two sets of ABPA patients based on the onset of asthma before the age of 30 who have greater skin reactivity to other common allergens, and who show additional features of allergic disease such as eczema and allergic rhinitis. In the other subset of patients who have the onset of their asthma after the age of 30, generally have less cutaneous skin reactivity to common allergens and no other clinical symptom suggests allergic disease. Radiology The roentgenography changes in ABPA may be normal in early stages of the disease or they may be transient or permanent.38 (Figs 8.1 to 8.5 plate 1 and 2) During acute exacerbations, the typical changes are fleeting pulmonary infiltrates that tend to be in the upper lobe and central in location. Transient changes, which may clear with or without steroid therapy is due to parenchymal infiltrates, mucoid impactions or secretions in damaged bronchi. These transient findings include: i. Perihilar infiltrates simulating adenopathy; ii. Air-fluid levels from dilated central bronchi filled with fluid and debris; iii. Massive homogenous consolidation which may be unilateral or bilateral; iv. Radiographic infiltrates; v. “Tooth-paste shadows” due to impaction of mucus in the damaged bronchi; vi. “Gloved-finger” shadows due to distally occluded bronchi filled with secretions; and,

Complications of Bronchial Asthma 121 vii. Tram-line shadows, which are two parallel hairline shadows extending out from the hilum. Permanent changes include: i. Proximal bronchiectasis; ii. Parallel line shadows which are tram-line shadows resulting from bronchiectasis; and iii. Ring shadows which are dilated bronchi. Other rare findings may be cavitation, local emphysema, contracted upper lobes, honeycomb fibrosis, total lung collapse due to mucus impaction, and spontaneous pneumothorax. Normal chest X-ray does not exclude the diagnosis of ABPA. The chest CT may be more sensitive in demonstrating the above changes and has replaced the necessity of bronchography. Laboratory Findings Peripheral eosinophilia is common, and sputum contains eosinophils in most of the patients. Leucocytosis and raised ESR are found during acute episodes. The serological abnormalities include a marked increase in total serum IgE and specific IgE and IgG antibodies against A.fumigatus. The levels of both total and specific serum IgE levels are high during the development of pulmonary infiltrations; the levels decline after remission. Serial determination of total serum IgE may thus be helpful in detecting patients with ABPA or following the course of ABPA and determining the onset of an acute exacerbation.39 Occasionally, the serum IgE may be low. Skin testing with potent A.fumigatus extracts demonstrates an immediate wheal and flare reaction in most cases. This reaction is frequently followed by a late onset of erythema and edema occurring at the injection site over the next 4 to 6 hours. The reaction reaches its peak by 8 hours and subsides by 24 hours. These late reactions are due to deposits of IgG, IgM, IgA, and complement components. Serologic tests using double gel diffusion method reveal precipitating antibodies in most patients of ABPA. Radio immunoassay or ELISA techniques detects antibodies specific for Aspergillus belonging to several immunoglobulin classes. It has been demonstrated that up to 25% of patients of asthma have immediate skin reactivity to A.fumigatus and 10% demonstrate positive precipitating antibodies against this. Thus, neither of these parameters is specific for ABPA. Aspergillus can be cultured from sputum of nearly two-thirds of patients during acute episodes of ABPA. Repeated cultures are necessary to demonstrate the fungi. Bronchial challenges with A.fumigatus characteristically show a dual response in patients with ABPA. β-2 agonists can prevent the immediate reaction and the late reaction may be prevented by corticosteroids. Cromolyn sodium may prevent both types of reactions. However, bronchial challenge test is not required to confirm ABPA and may be risky. Abnormalities of pulmonary function tests in ABPA depend upon the stage at which they are performed. During the earlier stages of pure bronchospasm there will be an obstructive physiologic profile, whereas during the irreversible stages of the disease with bronchiectasis and fibrosis, the tests will reflect a restrictive physiologic profile. The degree of reversibility is much less compared to that in classic extrinsic-asthma. The diffusion capacity is reduced in most patients with a good correlation with the duration of the disease.

122 Bronchial Asthma Diagnosis There are no universally accepted criteria for the definite diagnosis of ABPA. Rosenberg et al35 have suggested the following which is accepted by most investigators. Greenberger and Patterson recently modified the diagnostic criteria for ABPA.39 They are listed in Tables 8.1 and 8.2. Table 8.1: Rosenberg criteria for diagnosis of ABPA

Primary 1. 2. 3. 4. 5. 6. 7. Secondary 1. 2. 3.

Episodic bronchial obstruction Peripheral blood eosinophilia Immediate skin reactivity to Aspergillus antigens Precipitating antibodies against Aspergillus antigens Elevated serum IgE History of infiltrates in the chest X-ray Central bronchiectasis

Aspergillus in sputum History of mucus plug expectoration Late skin (Arthus) reactivity to Aspergillus antigen

The diagnosis of ABPA is considered likely if the first six primary criteria are present; certain if all seven are present. Table 8.2: Modified diagnostic criteria of ABPA 1. 2. 3. 4. 5. 6. 7. 8.

Bronchial asthma Immediate skin reactivity to Aspergillus Serum precipitin to A.fumigatus Increased serum IgE and IgG to A.fumigatus Total serum IgE > 1000 ng/ml Current or previous pulmonary infiltrates Central bronchiectasis Peripheral eosinophilia (1,000 cells/μL)

Not all of these criteria need to be present to diagnose ABPA. Withholding therapy until the development of all clinical symptoms and evidence of bronchiectasis may lead to a missed diagnosis in a significant number of patients and to delayed treatment resulting in irreversible pulmonary damage. Therefore, ABPA may be subdivided into the following groups of patients with or without central bronchiectasis.40 A. Essential criteria for the diagnosis of ABPA with central bronchiectasis : Asthma, Immediate skin reactivity to Aspergillus antigen Serum IgE > 1000 ng/ml Central bronchiectasis B. Minimal criteria for the diagnosis of ABPA without central bronchiectasis: (labelled ABPA-seropositive) Asthma, Immediate skin reactivity to Aspergillus antigen Serum IgE > 1000 ng/ml History of pulmonary infiltrates Elevated levels of serum IgE and IgG antibodies to A.fumigatus

Complications of Bronchial Asthma 123 From a North Indian hospital (PGIMER, Chandigarh) a total of 651 patients with clinical suspicion of ABPA27 were reported during a period of 8 years (January 1991 to December 1998). Overall, 338 cases (52%) were positive either by sputum microscopy/culture (66 of 203 patients), by skin reactivity (150 of 309 cases), or by precipitating antibodies (122 of 338 cases) against Aspergillus species. However, in 89 patients, diagnosis was confirmed on the basis of Rosenberg’s criteria. Clinical profile and laboratory findings showed that the disease was more common among males. Poor control of asthma, constitutional symptoms, mucopurulent expectoration, increased dyspnoea or wheezing and rhonchi were the main presenting symptoms. Skin reactivity against aspergillin was seen in 73 (82%), precipitating antibodies against aspergillus species were positive in 64 (72%) and sputum microscopy/ culture was positive in 56 (63%) of these 89 patients. Central bronchiectasis and fleeting shadows were the most common radiological findings. Differential Diagnosis A number of disorders may be confused with ABPA. Tuberculosis, because of its similar upper lobe involvement on chest X-ray, may be the initial diagnosis. It is not uncommon to find patients receiving antitubercular therapy. A high degree of suspicion is necessary to avoid this confusion.19 History of asthma with such chest X-ray should arouse the suspicion. Repeated sputum examination will be negative for acid-fast bacilli. In that situation a diagnostic work-up for ABPA is warranted. Cystic fibrosis patients also may be confused with ABPA. In fact, these patients have a number of features in common with ABPA including isolation of the fungus from the sputum, bronchospasm, skin test reactivity and elevated serum IgE levels. However, the age of onset of cystic fibrosis, sweat chloride test, and other associated nonpulmonary features will help to distinguish the two conditions. Carcinoma of the lung, particularly, bronchoalveolar cell carcinoma, may some times be confused with ABPA particularly in elderly individuals. The other etiologies of eosinophilic pneumonias can usually be differentiated on clinical and immunological grounds. Although classically ABPA is caused by Aspergillus fumigatus, some cases can also be due to other species of Aspergillus. In recent years, allergic bronchopulmonary reactions have also been observed due to moulds or bacteria. Stemphylum species, Helminthosporium species, Pseudomonas aeruginosa, Curvularia lunata, Candida albicans, Dreschslera hawaiiensis, and Torulopsis globata are examples which have been shown to cause such reactions similar to ABPA in the lungs. Treatment Therapeutic approach to treat ABPA may be directed to achieve two goals: (i) to remove the source of antigenic stimulation by eliminating the fungus from the bronchial tree; and (ii) suppressing the bronchial hypersensitivity reactions and their associated local parenchymal changes. The first one was thought to be achieved by employing inhalation of anti-fungal agents such as amphotericin B, nystatin, natamycin, and cotrimazole. However this approach has now largely been abandoned because of frequent recurrences and because of the need for repetitive treatments more often. Oral corticosteroid therapy is the treatment of choice in ABPA. They act by suppressing the allergic inflammatory reaction by suppressing the immunologic response to aspergillus antigen and decrease sputum production. Because of the later effect the bronchus becomes

124 Bronchial Asthma less favourable for further fungal colonisation. Resolution of radiographic infiltrates and improvements in symptoms have been observed in most patients. Prednisone therapy maintains clinical improvement in over 80% of patients by relief of bronchospasm, clearing of pulmonary infiltrates, and decreasing serum IgE level and peripheral eosinophilia.41,42 The current treatment of exacerbation of ABPA consists of daily administration of prednisone in a dose of 0.5 mg/kg, given as a single morning dose for a period of two weeks and then gradually decreasing the dose.43 This dose is usually sufficient to improve pulmonary lesions in two weeks, at which time the same dosage is changed to a single alternate-day regimen. This dosage is maintained for a minimum of three months. Most patients, however, require more prolonged therapy to control their symptoms and minimize relapse.43,44 If the chest X-ray shows improvement and there is a substantial reduction in total serum IgE levels, slow reduction of prednisone, at a rate of 5 mg/day may be attempted. Treatment must be individualised depending upon the stage of ABPA, frequency of exacerbations, and severity of asthma. Monthly serum IgE levels are to be obtained, and when a twofold increase is present, a chest X-ray should be obtained to rule out exacerbation. Usually there is an exacerbation of symptoms during particularly seasons due to an increase in the fungal spores in the atmosphere. This varies with geographic locations and accordingly the steroid therapy should be reduced with caution during these months. The frequency of chest X-ray to be taken in following a patient of ABPA is not known. It is perhaps best to obtain the X-ray every three to six months during the first year of follow-up and on a yearly basis thereafter to avoid missing intercurrent pulmonary damage. Serum IgE levels should also be monitored regularly. Pulmonary function tests should be obtained yearly. Inhaled therapy may be beneficial, but its use is limited by the degree of obstruction and mucus plugging. Inhaled steroids are not helpful in preventing the progression of lung damage associated with ABPA.45,46 Since there are side effects associated with long-term use of corticosteroid therapy, including an increased risk of invasive aspergillosis,47 attempts were made to use alternative drugs. The role of itraconazole, an anti-fungal agent has been evaluated.48 When the drug is used in a dose of 200 mg twice daily for 4 months, 46% of the patients showed a significant response (a 50% reduction in corticosteroid dose, a decrease of at least 25% in the serum IgE level, and a 25% improvement in exercise tolerance or pulmonary function test results, or the resolution or absence of pulmonary infiltrates). The study concluded that patients with ABPA generally benefit from concurrent itraconazole therapy without much side effect and suggested that a lower dose of 200 mg daily is equally beneficial and may be used as a maintenance therapy to sustain remission. The disease has been seen throughout the world and has been a subject of extensive review from across the globe.49-53 REFERENCES 1. Bredin CP, Donnely S. Period prevalence of allergic bronchopulmonary mycosis in an outpatient population is over 1 percent. Eur Respir J 1991;4(Suppl 14):1715. 2. Aggarwal AK, Behera D, Malik SK, Kumar L, Talwar P. Skin hypersensitivity and precipitating antibodies against A.fumigatus in bronchial asthma. Lung India 1989;7:67-69. 3. Behera D, Guleria R, Jindal SK, Chakrabarti A, Panigrahi D. Allergy Bronchopulmonary Aspergillosis: A Retrospective study of 35 cases. Indian J Chest Dis All Sci 1994;36:173-79. 4. Malik SK, Talwar P. Allergic bronchopulmonary aspergillosis. Bull PGI 1980;14:95-98.

Complications of Bronchial Asthma 125 5. Subramanium S, Viswanathan R. Allergic bronchopulmonary aspergillosis. Ind J Chest Dis 1972;14:72-77. 6. Shah JR. Allergic bronchopulmonary aspergillosis. J Ass Phys India 1971;19: 835-841. 7. Sandhu RS, Mishra SK, Randhawa HS, Prakash D. Allergic bronchopulmonary aspergillosis. in India. Scand J Respir Dis 1972;503:289-301. 8. Pamra SP, Khan ZU, Sandhu RS, Ilyas M. Allergic bronchopulmonary aspergillosis. Ind J Tubercl 1972;19:61-67. 9. Khan ZU, Sandhu RS, Randhwa HS et al. Allergic bronchopulmonary aspergillosis. A study of 46 cases with special reference to laboratory aspects. Scand J Respir Dis 1976;57:73-87. 10. Shivpuri DN, Aggarwal MK. Studies on the allergic fungal spores of Delhi., India, metropolitan area. J allergy 1969;44:204-13. 11. Chetty A, Bhargava S, Jain RK. Allergic bronchopulmonary aspergillosis in Indian children with bronchial asthma. Ann Allergy 1985;54:46-49. 12. Backman KS, Roberts M, Patterson R. Allergic bronchopulmonary mycosis caused by Fusarium vasinfectum. Am J Respir Crit Care Med 1995;152:1379-81. 13. Hinson KFW, Moon AJ, Plummer NS. Bronchopulmonary aspergillosis. A review and a report of eight cases. Thorax 1952;7:317-33. 14. Elder JL, Smith JT. Allergic bronchopulmonary aspergillosis. Med J Australia 1967;1:231-33. 15. Patterson R, Golbert F. Hypersensitivity disease of the Lung. University Michigan Med Centre J 1968;34:8-11. 16. Subramianiam S, Viswanathan R. Allergic aspergillosis. Ind J Chest Dis 1972;14:72-77. 17. Shah JR. Allergic bronchopulmonary aspergillosis. J Ass Phys Ind 1971;19:835-41. 18. Khan ZU, Sandhu RS, Randhawa HS, Menon MPS, Dusaj IS. Allergic bronchopulmonary aspergillosis: A study of 46 cases with special reference to laboratory aspects. Scand J Respir Dis 1976;57:73-87. 19. Behera D, Guleria R, Jindal SK, Chakrabarti A, Panigrahi D. Allergic bronchopulmonary aspergillosis: a retrospective study of 35 cases. Ind J Chest Dis All Sci 1994;36:173-79. 20. Bedi RS. Allergic bronchopulmonary aspergillosis: Review of 20 cases. Ind J Chest Dis All Sci 1994;36:181-86. 21. Shah A, Khan ZU, Chaturvedi S, Bazaz Malik G, Randhawa HS. Concomittant allergic Aspergillus sinusitis and allergic bronchopulmonary aspergillosis with familial occurrence of allergic bronchopulmonary aspergillosis. Ann allergy 1990;64:507-12. 22. Shah A, Khan ZU, Sircar M, Chaturvedi S, Bazaz Malik G, Randhawa HS. Allergic aspergillus sinusitis; an Indian report. Respir Med 1990;84:249-51. 23. Aggarwal AK, Behera D, Malik SK, Kumar L, Talwar P. Skin hypersensitivity and precipitating antibodies against A.Fumigatus in bronchial asthma. Lung India 1989;7:67-69. 24. Chetty A, Bhargava S, Jain RK. Allergic bronchopulmonary aspergillosis in Indian children with bronchial asthma. Ann Allergy 1985;54:46-49. 25. Sandhu RS, Mishra SK, Randhawa HS, Prakash D. Allergic bronchopulmonary aspergillosis in India. Scand J Respir Dis 1972;53:289-301. 26. Chakrabarti A, Sharma SC, Chander J. Epidemiology and pathogenesis of Para nasal sinus mycoses. Otolaryngol Head Neck Surg 1992;107:745-50. 27. Chakrabarti A, Sethi S, Raman DSV, Behera D. Eight-year study of allergic bronchopulmonary aspergillosis in an Indian teaching hospital. Mycoses 2002;45:295-99. 28. Basich JE, Graves TS, Baz MN et al. Allergic bronchopulmonary aspergillosis in corticosteroid dependent asthmatics. J Allergy Clin Immunol 1981;68:98-102. 29. Mrouch S, Spok A. Allergic bronchopulmonary aspergillosis in patients with cystic fibrosis. Chest 1994;105:32-36. 30. Knutsen AP, Slavin RG. Invitro T-cell response in patients with cystic fibrosis and allergic bronchopulmonary aspergillosis. J Lab Clin Med 1989;113:428-35.

126 Bronchial Asthma 31. Chauhan B, Santiago I, Kirschmann DA et al. The association of HLA-DR alleles and T-cell activation with allergic bronchopulmonary aspergillosis. J Immunol 1997;159:4072-76. 32. Wang JL, Patterson R, Rosenberg M et al. Serum IgE and IgG antibody activity against Aspergillus fumigatus as a diagnostic aid in allergic bronchopulmonary aspergillosis. Am Rev Respir Dis 1978;117:917-27. 33. Cockrill BA, Hales CA. Allergic bronchopulmonary aspergillosis. Ann Rev Med 1999;50:303-16. 34. Bosken CH, Myers JL, Greenberger PA et al. Pathologic features of allergic bronchopulmonary aspergillosis. Am J Surg Pathol 1988;12:216-22. 35. Rosenberg M, Patterson R, Mintzer R et al. Clinical and immunological criteria for the diagnosis of allergic bronchopulmonary aspergillosis. Ann Intern Med 1977;86:405-14. 36. Patterson R, Greenberger PA, Radin RC et al. Allergic bronchopulmonary aspergillosis: staging as an aid to management. Ann Intern Med 1982;96:286-91. 37. Patterson R, Greenberger PA, Hawig JM et al. Allergic bronchopulmonary aspergillosis; natural history and classification of early disease by serologic and roentgenographic studies. Arch Intern Med 1986;146:916-18. 38. Mintzer RA, Rogers LF, Kruglik GD et al. The spectrum of radiologic findings in allergic bronchopulmonary aspergillosis. Radiology 1978;127:301-07. 39. Greenberger PA, Patterson R. Diagnosis and management of allergic bronchopulmonary aspergillosis. Ann allergy 1986;56:444-48. 40. Greenberger PA. Immunologic aspects of lung diseases and cystic fibrosis. JAMA 1997;278: 1924-30. 41. Rosenberg M, Patterson R, Robert M et al. The assessment of immunologic and clinical changes occurring during corticosteroid therapy for allergic bronchopulmonary aspergillosis. Am J Med 1978;64:599-606. 42. Wang JL, Patterson R, Roberts M et al. The management of allergic bronchopulmonary aspergillosis. Am Rev Respir Dis 1979;120:87-92. 43. Capewell S, Chapman BJ, Alexander F et al. Corticosteroid treatment and prognosis in pulmonary eosinophilia. Thorax 1989;44:925-29. 44. Safirstein BH, D’Souza MF, Simon g et al. Five-year follow-up of allergic bronchopulmonary aspergillosis. Am Rev Respir Dis 1973;108:450-59. 45. British Thoracic Association. Inhaled beclamethasone dipropionate in allergic bronchopulmonary aspergillosis: Report to the Research Committee of the British thoracic Association. Br J Dis Chest 1979;79:349-56. 46. Soubani AO, Chandrasekar PH. The clinical spectrum of pulmonary aspergillosis. Chest 2002;121:1988-99. 47. Ganassinni A, Cazzadori A. Invasive pulmonary aspergillosis complicating allergic bronchopulmonary aspergillosis. Respir Med 1995;89:143-45. 48. Stevens DA, Schwartz HJ, Lee JY et al. A randomised trial of itraconazole in allergic bronchopulmonary aspergillosis. N Engl J Med 2000;342:756-62. 49. Davis SF, Sarosi GA. Role of serodiagnostic tests and skin tests in the diagnosis of fungal disease. Clin Chest Med 1987;8:135. 50. Pennington JE. Aspergillus lung disease. Med Clin North Am 1980;64:475. 51. Glimp RA, Bayer AS. Fungal pneumonias. Part 3. Allergic bronchopulmonary aspergillosis. Chest 1981;80:85 52. Ricketti AJ, Greenberger PA, Mintzer RA, Patterson R. Allergic bronchopulmonary aspergillosis. Chest 1984;86:773. 53. Fink JN. Allergic bronchopulmonary aspergillosis. Chest 1987;87(Suppl):81S.

Management of Bronchial Asthma 127

9 Management of Bronchial Asthma A number of guidelines on the management of bronchial asthma, both in children and adults are developed in recent years.1-11 They include those of the British Thoracic Society, NHLB, USA, and the Global Initiative for Asthma, etc. The recommendations are based on the same principle and basically the same. The goals of management of bronchial asthma as recommended by these agencies are as follows: i. To recognise asthma ii. To maintain a normal activity level including exercise. iii. To maintain a normal or near normal (best) pulmonary function rates. iv. To prevent chronic and troublesome symptoms like coughing or breathlessness in the night, early in the morning, or after exertion. v. To prevent recurrent exacerbations. vi. To minimise absence from work or school vii. To enable normal growth to occur in children, and viii. To use the least minimum drugs to avoid adverse reactions from medications used for asthma. Since bronchial asthma is a chronic condition with acute exacerbations, treatment requires a continuous care approach to control symptoms, to prevent exacerbations, to treat adequately such exacerbations, and to reduce chronic airway inflammation. Prevention of exacerbation is an important principle of therapy. This includes avoidance of triggers and allergens. Round-the-clock medication may be beneficial to many patients. Children and adults, who have poor exercise tolerance, recurrent symptoms, and frequent nocturnal attacks and patients with moderate asthma will often benefit from the regular administration and more aggressive use of antiasthma medication, particularly anti-inflammatory drugs. In contrast, patients with mild intermittent asthma with uninterrupted sleep at night, and good exercise tolerance may need only occasional treatment for the relief of symptoms. Periodic assessment of these patients is essential to assure that their therapy is appropriate. The treatment of asthma should also be based on the understanding of the underlying pathophysiologic mechanisms and the objective assessment of severity of the disease. It is now appreciated that asthma is an inflammatory disease and therapy should include antiinflammatory agents to reduce inflammation and to relieve or prevent symptomatic airway narrowing. Anticipatory or early interventions in treating acute exacerbations of asthma reduce the likelihood of developing severe airway narrowing.

128 Bronchial Asthma Thus, the integral components of asthma therapy include patient education, environmental control, and medication with the use of objective measures to monitor the severity of disease and the efficacy of therapy. The interrelationship of all these approaches is shown in Figure 9.1. Basically the treatment of asthma consists of both; i. Nonpharmacologic therapy and ii. Pharmacologic therapy. The optimal nonpharmacological treatment consists of i. Patient and family education; ii. Avoidance of agents that induce or trigger asthma like allergens, irritants like smoke, and reasonable attempts at reducing exposure to respiratory viruses; and iii. Immunotherapy. The pharmacologic therapy is used to treat reversible airflow obstruction and airway hyper-responsiveness. Medications include bronchodilators and antiinflammatory agents with some acting as both. NONPHARMACOLOGIC MANAGEMENT Patient and Family Education Patient education by the treating physician is a powerful tool for helping patients to gain self-confidence to control their asthma.12,13 Since much of the day-to-day responsibility for

Fig. 9.1: General principles of management of asthma

Management of Bronchial Asthma 129 managing asthma falls on the patient and the patient’s family, encouraging active participation in a partnership with the clinician can improve patient adherence to the treatment plan and stimulate family effort to improve control of asthma.14,15 In fact a patient is his best physician since he alone can recognise well about his illness, its progression, regression, response to treatment, and imminent acute attack. It should start at the time of diagnosis and should be continued throughout as an integral component during continued care. Family participation is an essential component of this programme. Establishment of a partnership with the patient, encouraging adherence to the treatment plan, teaching about the triggers (exercise, viral respiratory tract infections, allergens and irritants) and how to avoid, eliminate, or control them, explaining the patient regarding medications both preventive and rescue therapy, their adverse effects and educating about the adverse drug reactions are important components of this plan. Moreover teaching the patient how to recognise the severity of asthma and the appropriate time to seek medical advice during acute exacerbations are important. Giving information alone does not alter behaviour. Written and audiovisual reinforcement of spoken language further helps patient confidence. Giving these informations along with written self management plans will help the patient who may adjust treatment to keep themselves symptom free that reduces morbidity and health costs.16,17 Although now there is definite evidence of benefit from patient education and issuing of self management plans, certain areas like who need them, and what form they should take (number of action levels, thresholds for intervention) are poorly defined. Proper use of inhalers is very essential.18,19 Patient should demonstrate use of the metereddose inhaler to the physician, and the technique should be reviewed at every visit. Since home-monitoring of PEFR is an essential component of asthma management, the patient needs to be taught how to use a peak flow meter correctly and how to interpret it.20,21 Psychosocial issues as outlined above which increases asthma morbidity and mortality need to be taken care of. Management of Allergy Since allergy has a very significant role in the pathophysiology of asthma, interventions to control this are important. There can be two ways to approach this problem: (i) environmental controls; and (ii) immunotherapy.

Environmental Control Outdoor allergens like pollens and mould are best avoided by staying indoors particularly during the midday and afternoons. An air conditioned environment is the best way. Various nasal filters are available, which may be helpful to prevent penetration of allergens. However, this has not been proved to be very effective. Indoor allergen elimination is possible by paying special attention to the following. To avoid exposure to animal danders, the animal should be removed from the house. Removal of pets may not afford immediate relief even when followed by vigorous cleaning, since allergens continue to stay in the home for many months. Application of 3% tannic acid will denature and render such substances nonallergic. If the pet cannot be kept out of the house, there should be least contact with the patient and the animal should not be allowed at all to the bed room. Washing and bathing the pet frequently may reduce the amount of dander and dried saliva to be deposited on carpets and furnitures.22

130 Bronchial Asthma Reducing exposure to dust mites can be achieved by the following four plans of attack:23-25 a. By placing barriers between the patient and reservoirs of dust mite Elimination of mite exposure is possible by encasing the mattress in an airtight cover and encasing the pillow, particularly plastic mattress covers. These are not only inexpensive, but they effectively reduce dust mite exposure and clinical symptoms of asthma. Microporous covers are also available which allow passage of water vapour for patient comfort while excluding mites and their allergens. b. To kill and remove mites Regular washing of bedding and pillows by washing it at least once weekly. The bedding should be washed in hot water (>58°C) frequently. This kills mites and removes mites from an important exposure source. Ascaricides, tannic acid, dry heating, and liquid nitrogen have been used to kill mites, but they need further study particularly in terms of side effects to the patient and they need professional application.26 It is also important to remove the dead mites once they are killed, by vacuuming otherwise they continue to be the source antigen. HEPA filtration removes air-borne mites but leaves undisturbed the major reservoir antigen in carpets, beddings, and upholstery. c. Making the environment less hospitable for mites The patient should avoid sleeping or lying on upholstered furnitures. The carpets and other dust collectors that are laid on concrete are to be removed. Reduction of indoor humidity to less than 50% by air conditioning or mechanical ventilation are less favourable to the growth of mites. Although not so effective in removing live mites, regular vacuuming removes their food and shelter. d. To remove the patient to dust-free environment Although practically inconvenient and expensive, this is a very effective measure, and can be adopted whenever feasible while dust busting is completed at home. To prevent growth of moulds, special attention should be paid to areas with increased humidity. Such areas like bathrooms, kitchens, and basements require adequate ventilation and frequent cleaning using chlorine bleach. Sweat on foam pillows encourage mould growth. They should be encased or changed frequently. While cleaning, the patient should wear a dust mask. Climate control by air conditioning is beneficial, because it allows windows and doors to be closed and by reducing indoor humidity, discourages mould and mite growth. Humidifiers are potentially hazardous. If not cleaned regularly and properly, they facilitate the growth and aerosolise mould spores. A number of other devices are available for cleaning allergens from the indoor air. Two such major devices are mechanical filters and electrical filters. Other indoor irritants like tobacco smoke,27 wood smoke, strong odours or sprays (perfumes, talcum powders), household cleaning substances, and fresh paints irritate the airway and trigger asthma symptoms. Therefore, these should be avoided. Exposure to ozone and sulphur dioxide worsen asthma by interacting with allergens or other triggers and should be avoided as far as possible. Since occupational exposure is an important cause of bronchial asthma in adults, avoidance to such exposure is important. However, patients with suspected occupational asthma should not be advised to cease work until the diagnosis is proven and until all methods for reducing exposure at the work place have been explored. Specialist respiratory physician, occupational physicians, and employers will all need to be involved in this process.

Management of Bronchial Asthma 131 Immunotherapy Allergenic extract immunotherapy is in use since the early 1900’s in an attempt to protect against grass pollen. Allergy immunotherapy has been shown to reduce the symptoms of asthma in a number of double-blind studies with a wide variety of allergens, including house-dust , grass pollen , cat dander and cladosporium and alternaria.28-31 Such therapy reduces the late reaction to allergens in the lung, reduces asthma symptoms following injections. Long-term use also reduces bronchial hyperresponsiveness. These suggest that allergen immunotherapy can be employed to prevent the development of allergic inflammation and perhaps the resulting bronchial hyperresponsiveness.32-37 However, the British Thoracic Society guidelines recommends that hyposensitisation (immunotherapy) is not indicated in the management of bronchial asthma.9 This therapy is employed only after performing a careful diagnostic study of history and skin tests to identify possible offending inhalant allergens. The history of symptoms must correlate accurately with allergen exposure with confirmed IgE-mediated reactivity to one or more suspected allergens, usually by wheal and flare skin reactivity or by serology such as RAST. The decision regarding immunotherapy depends upon three important considerations. (i) It must be established that there is a clinically important allergic component to asthma. (ii) In patients with a significant allergic components who are not obtaining full clinical improvement with standard environmental control and medication, and (iii) Failure of maximal environmental control measures. Currently the methods and frequency of administration of allergenic extract immunotherapy vary considerably. The dosage and frequency vary considerably. The allergens used are often poorly standardised and characterised, and the methodology is illdefined. With most forms of allergenic extracts, the initial frequency of injections is usually once weekly, with doubling of the dosage at regular intervals and progression to a series of monthly maintenance injections, depending upon the antigen preparation employed and the individual patient requirements. The therapy is dose-dependent and specific for the allergen employed, the higher the dose, the greater the clinical improvement. Allergic signs and symptoms may develop subsequent to injections, manifested either as local or systemic anaphylactic reactions (rare). There are no well-defined guidelines regarding the duration of therapy. Most physicians attempt to discontinue therapy after three or four years of a successful regimen, The National Blood, Heart, and Lung Institute, USA1 recommends that once patient achieves maintenance levels of immunotherapy, the interval between injections should be extended, with a goal of monthly injections. If the patient’s symptoms improve, treatment is usually continued for 3-5 years, although under some circumstances more prolonged therapy at monthly intervals may be warranted. If there is no evidence of response following two allergy seasons after reaching the maintenance or highest level tolerated by the patient, immunotherapy should be discontinued. Allergy immunotherapy should be administered only under the direct supervision of a physician who is adequately trained. The mechanisms for clinical improvement are unknown, but one or more immunological changes may be responsible for such improvement. Among these changes are: a. A rise in serum IgG blocking antibodies; b. Suppression of the usual seasonal rise in IgE antibodies, which follows environmental exposure,

132 Bronchial Asthma c. An increase in blocking IgG and IgA antibodies in respiratory secretions, d. A reduced basophil reactivity to allergens, e. Reduced lymphocyte responsiveness to allergen, and f. An increase in specific T-suppressor cell generation. However, the problem of immunotherapy is the recognisation of the allergen. Most of the times, identification is not feasible and as mentioned, immunotherapy is only allergenspecific. The duration of treatment is often prolonged and costly. Moreover relapse occurs in most patients after discontinuation of therapy. Therefore, immunotherapy is not widely used as an important component in the management of bronchial asthma. REFERENCES 1. National Asthma Education Programme. Expert Panel Report. Guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute, National Institute of Health, Bethesda, Maryland, USA, Publication No. 91-3042A, June 1991. 2. Guidelines for the management of asthma in adults. 1-Chronic persistent asthma. Statement by the British Thoracic Society, Research Unit of the Royal College of Physicians of London, King’s Fund Center, National Asthma Campaign. BMJ 1990;301:651-53. 3. Guidelines for the management of asthma in adults. 2-Acute severe asthma. Statement by the British Thoracic Society, Research Unit of the Royal College of Physicians of London, King’s Fund Center, National Asthma Campaign. BMJ 1990;301:797-800. 4. Warner JO, Gotz M, Landau LI et al. Management of asthma: A consensus statement. Arch Dis Child 1989;64;1065-79. 5. International Paediatric asthma Consensus Group. Asthma, a follow-up statement. Arch Dis Child 1992;67:240-48. 6. International Consensus report on the diagnosis and management of asthma. Clin Exp Allergy 1992;22(Suppl):1-72. 7. British thoracic Society and others. Guidelines for the management of asthma: A summary. BMJ 1993;9:287-92. 8. The British Guidelines on Asthma Management. 1995 Review and Position Statement. Thorax 1997;52(Suppl 1): S2-S8. 9. British thoracic Society, British Paediatric Association, Royal College of Physicians of London, The King’s Fund Center, national asthma Campaign et al. Guidelines on the management of asthma. Thorax 1993;48:S1-S24. 10. British thoracic Society, British Paediatric Association, Royal College of Physicians of London, The King’s Fund Center, national asthma Campaign et al. Summary charts. BMJ1993;306:77682. 11. Global Initiative for Asthma. A practical guide for public health officials and health care professionals. US Department of Health and human services. NIH Publication No. 96-3659A, December 1995. 12. Brewis RAL. Patient education, self-management plans and peak flow measurements. Respir Med 1991;85:457. 13. Feldman CH, Clark NM, Evans D. The role of health education in medical management in asthma. Clin Rev Allergy 1987;5:195-205. 14. Mellians RB. Patient education is key to successful management of asthma. J Rev Respir Dis 1989;Suppl:S47-S52. 15. Clark NC. Asthma self-management education: Research and implications for clinical practice. Chest 1989;95:1110-13. 16. D’Souza W, Crane J, Burgess C, et al. Community-based asthma care; trial of a “credit card” asthma self-management plan. Eur Respir J 1994;7:1260-65.

Management of Bronchial Asthma 133 17. Iganacio-Gracia JM, Gonzalez-Santos P. Asthma self management education programme by home monitoring of peak expiratory flow. Am J Respir Crit Care Med 1995;151:353-59. 18. Shim C, Williams MH. The adequacy of inhalation of aerosol from canister nebullisers. Am J Med 1980;69:891-94. 19. Newman SP, Pavia D, Clarke SW. Simple instructions for using pressurised aerosol bronchodilators. J R Soc Med 1980;73:776-79. 20. Vathenen AS, Cooke NJ. Home peak flow meters. Br Med J 1991;302:738. 21. Mendoza GR. Peak flow monitoring. J Asthma 1991;28:161. 22. Glinert R, Wilson P, Wedner HJ. Fel; D1 is markedly reduced following sequential washing of cats. J Allergy Clin Immunol 1990;85:225. 23. Wallshaw MJ, Evans CC. allergen avoidance in house dust mite sensitive adult asthma. Q J Med 1986;58:199-215. 24. Ehnert B, Lau-Schadendorf S, Weber A, Buettner P, Sehou C, Wahn U. Reducing domestic exposure to dust mite allergen reduces bronchial hyper-reactivity in sensitive children with asthma. J Allergy Clin Immunol 1993;90:135-38. 25. Murray AB, Fergusson AC. Dust free bedroom in the treatment of asthmatic children with house dust mite allergy: A controlled trial. Paediatrics 1983;91:418-22. 26. Colloft MJ, Ayres J, Carswell F, et al. The control of dust mites and domestic pets: A position paper. Clin Exp Allergy 1992;22(Suppl 2):1-28. 27. Andrae S, Axelson O, Bjorksten B, Fredriksson M, Kiellman NM. Symptoms of bronchial hyper reactivity and asthma in relation to environmental factors. Arch Dis Child 1988;63:474-78. 28. Reid MJ, Moss RB, Hsu YP. Seasonal asthma in Northern California; allergy causes and efficacy of immunotherapy. J Allergy Clin Immunol 1986;78:590-600. 29. Aas K. Controlled trial of hyposensitisation to house dust. Acta Paediatrc Scand 1971;60:264-68. 30. Ohman JL Jr, Findlay SR, Leiterman KM. Immunotherapy in cat-induced asthma: Double-blind trial with evaluation of in vivo and invitro responses. J Allergy Clin Immunol 1984;74:230-39. 31. Horst M, Hejjaoui A, Horst V, Michel FB, Bousquet J. Double-blind, placebo-controlled rush immunotherapy with a standardised alternaria extract. J Allergy Clin Immunol 1990;85:460-72. 32. Lilja G, Sundin B, Graff-Lonnevig v, et al. Immunotherapy wit cat and dog dander extracts IV. Effect of 2 years treatment. J Allergy Clin Immunol 1989;83:37-44. 33. Bousquet J, Maasch HJ, Hejjaoui A et al. Double-blind, Placebo-controlled immunotherapy with mixed grass-pollen allergoids. III. Efficacy and safety of unfractionated and high-molecularweight preparations in rhinoconjunctivitis and asthma. J Allergy Clin Immunol 1989;84:546-56. 34. Boulet LP, Cartier A, Thomson NC et al. Asthma and increases in nonallergic bronchial responsiveness from seasonal exposure. J Allergy Clin Immunol 1983;71:399-406. 35. Van Bever HP, Stevens WJ. Suppression of late asthmatic reaction by hyposensitisation in asthmatic children allergic to house dust mites (Dermatophagoides pteronyssiunus). Clin Expt Allergy 1989;19:399. 36. Chapman MD. Use of nonstimulatory peptides: A new strategy for immunotherapy? J Allergy Clin Immunol 1991;88:300. 37. Hoshino K, Hawasaki A, Mizushima Y, Yano S. Effect of antiallergic agents and bronchial hypersensitivity in short-term bronchial asthma. Chest 1991;100:57.

134 Bronchial Asthma

10 Pharmacologic Management of Asthma The drugs used for the treatment of bronchial asthma are classified as: 1. Bronchodilators • β-adrenergic agonists • Anticholinergics • Methylxanthines (now can be classified as anti-inflammatory) 2. Anti-inflammatory agents • Corticosteroids • Cromolyn sodium or cromolyn-like compounds • Methylxanthines • Leukotriene antagonists • Miscellaneous compounds including antihistamines. METHYLXANTHINES Theophylline, the principal methylxanthine used in asthma therapy over the past six decades and the most widely prescribed anti-asthma treatment worldwide, is a dimethylxanthine similar in structure to the common dietary xanthines, caffeine and theobromine.1-3 Other substituted xanthines have also bronchodilator property and include: Dyphylline (dihydroxypropyl theophylline), Etophylline (β-hydroxyethyl theophylline), Proxyphylline (β-hydroxypropyl theophylline), and Enprophylline (3-propylxanthine). Many “salts” of theophylline preparations are commonly marketed and have been in use over many years. Aminophylline, the ethylenediamine salt is perhaps the commonest compound used in many countries. Other commonly salts include formulations with calcium salicylate, sodium glycinate, and choline (oxtryphylline). Mechanism of action of theophylline remains unclear despite the long history and widespread use of the drug.4 Various mechanisms proposed for the molecular mechanism of action has been proposed and are shown in Table 10.1. Phosphodiesterase Inhibition Earlier it was believed that theophylline acts as an anti-asthma drug as it relaxes bronchial smooth muscle. Although the exact mechanism of such relaxation was not known, in vitro, theophylline inhibits phosphodiesterase (PDE) which breaks down cyclic nucleotides in the cell, that results in delayed degradation of cAMP and cGMP. Several families of PDE

Pharmacologic Management of Asthma 135 Table 10.1: Mechanism of action of theophylline Phosphodiesterase inhibition Adenosine receptor antagonist Increase in circulating adrenaline Mediator antagonism (anti-inflammatory effect) Inhibition of calcium ion flux Effect on respiratory muscles

are now recognised,5 of which PDE III is predominant in airway smooth muscle relaxation and PDE IV is important in inflammatory cells.5-8 Theophylline is a nonselective PDE inhibitor. Such inhibition occurs at concentrations ten-fold higher than those usually attained clinically. Total PDE activity in human lung extracts is inhibited by only 5-20% at therapeutic concentrations of theophylline.9,10 However, this modest inhibition may be sufficient to cause a substantial increase in intracellular cyclic nucleotide levels in the presence of endogenous activators of adenylyl cyclase.11 Inhibition of PDE could also lead to synergistic interaction with β-agonists. Since there is some evidence that PDE levels may be higher in asthmatics than normal individuals, theophylline may have a greater than expected inhibitory effects on PDE in asthmatic airways than in normal airways. 12 Bronchodilating effects of theophylline appear to closely parallel the serum concentrations. Although a steady-state serum concentration between 10-20 μg/ml gives optimal effect, a more conservative approach would be to aim for levels between 5-15 mg/ml. Since there is a linear relationship between log serum concentration and bronchodilator effect within this range, the dose should be increased if symptoms persist and the patient is at the lower end of the serum concentration range. Adenosine Receptor Antagonism Adenosine causes bronchoconstriction in bronchial asthma both in vitro and clinically when given by inhalation.13,14 This involves the release of histamine and leukotrienes from airway mast cells. This bronchoconstricting effect of adenosine is prevented by theophylline.15 This shows that theophylline is capable of antagonising the effects of adenosine at therapeutic concentrations. Theophylline is a potent inhibitor of adenosine receptors (both A1 and A2 receptors) at therapeutic concentrations and this may be the basis of its bronchodilator effect.16 Since the potent bronchodilators enprophylline doxofylline, do not have action against adenosine receptors, adenosine antagonism may not be the exact cause of bronchodilatation. However, inhibition of different adenosine receptor types and subtypes may be important for this differential action. Increased Catecholamine Release Intravenous theophylline increases the secretion of adrenaline from the adrenal medulla.17,18 Although the increase is small, it may be important. Anti-inflammatory Effect Recent evidence shows that theophylline may also possess some anti-inflammatory activity.19 Theophylline reduces both bronchial hyper-reactivity20,21 and the inflammatory response. The anti-inflammatory effect has been shown both in vitro and in vivo studies. The effects

136 Bronchial Asthma include decreased mediator release from mast cells, decreased release of reactive oxygen species from macrophages, decreased cytokine release from monocytes, decreased basic protein release by eosinophils, decreased proliferation of T-lymphocytes, decreased release of ROS (reactive oxygen species), and inhibition of late response to allergens, increased + CD8 cells in peripheral blood and decreased T-lymphocytes in airways in asthmatic patients. Theophylline inhibits plasma exudation in guinea pigs.20 It also demonstrates immunomodulatory effects in vivo because of the inhibitory effects on T-lymphocytes. The antiinflammatory effect is seen in much lower concentrations than its bronchodilatory concentrations. Effect on Respiratory Muscles In addition to bronchodilatation, it improves respiratory function by increasing the strength and reducing the fatigue of respiratory muscles particularly diaphragm.21,22 A number of studies suggest that during various contractile maneuvers theophylline increases Pdi/Edi, where Pdi denotes intrathoracic pressure swings across the diaphragm which reflects muscle force and Edi is the electromyographic recordings taken at the skin surface opposite the diaphragm insertion to measure the nervous input to the muscle. The ratio represents force/ unit of input. Inhibition of Calcium Ion Flux and Other Extrapulmonary Effects Some evidence suggest that theophylline may interfere with calcium mobilisation in airway smooth muscle. Although it has no effect on entry of calcium ions through voltage-dependent channels, it may influence calcium entry via receptor-operated channels. Other possible effects may be release of calcium from intracellular stores or may have some effect ion phosphatidylinositol turnover which is linked to release of calcium ion from intracellular stores. Theophylline may increase calcium uptake into the intracellular stores also.23,24 The drugs also increase mucociliary clearance. Other pharmacological effects of theophylline include a transient diuretic effect, stimulation of the central nervous system, cerebral vascular constriction, gastric acid secretion, and inhibition of uterine contractions. These effects are of little clinical importance when appropriate doses are used for the treatment of asthma (or apnea of prematurity). Theophylline also exert activity on cardiac ventricular contractility. Theophylline is rapidly and completely absorbed from the gastrointestinal tract when it is administered in the form of solutions and tablets. Once absorbed, it is distributed rapidly through extracellular body fluid, and to some extent into intracellular space. Theophylline is then eliminated through multiple parallel pathways that include demethylation and oxidation. Approximately 90% of orally administered theophylline is metabolised in liver. The drug’s elimination is reduced by such factors as liver disease, congestive heart failure, sustained high fever, and with drugs like cimetidine, troleandomycin, and erythromycin. Therefore, the dose of the drug should be reduced in these circumstances. Cigarette and marijuana smoking, phenobarbital, phenytoin, and intravenous isoproterenol increases the elimination of the drug. Major changes in diet also have a potential effect with 25% increases in clearance associated with a low carbohydrate, high protein diet and about a 25% mean decrease in clearance associated with a high carbohydrate low protein diet. The drug is also eliminated rapidly from the body by some individuals, especially children. In obese individuals,

Pharmacologic Management of Asthma 137 with greater than 120% ideal body weight, initial theophylline should be calculated on the basis of ideal rather than actual body weight to avoid overdosing. Theophylline has long been marketed in a wide variety of formulations. The traditional preparation for oral and parenteral use has been theophylline with ethylenediamine known as aminophylline. Suppository and rectal solutions are also available. Fixed dose combinations of theophylline with ephedrine that were the most frequently used formulations previously were associated with synergistic toxicity while providing a small additive effect. They are now not been used. During the past decade, newer formulations have been developed with slower controlled release preparations because of unacceptable fluctuations during the use of plain tablets. Both twice-dosing and once-a day dosing are now available. Although once-a-day dosing may be satisfactory in adults who eliminate the drug slowly, substantial peak-to-trough differences in serum concentrations are found in individuals who eliminate the drug rapidly. Furthermore, intestinal transit time in some patients may be so rapid that sustained-release preparations designed to release drugs especially slowly with long absorption half-lives, will pass out of the gut before absorption is complete. These longer acting preparations may also be affected by the presence of food in the gut or by the fat content. In some cases, the rate of drug release is greatly accelerated, and in other cases drug absorption is impaired. Other products are relatively unaffected by food administration. One should be familiar with these properties of the product selected. Theophylline is used for the treatment of both acute and chronic asthma. In chronic asthma, the usual starting dose is 10 mg/kg/day up to 800 mg maximum dose. In children the starting dose is 10 mg/kg/day; with usual maximum is as; 1 year or more < 1 year

16 mg/kg/day 0.2(age in weeks) + 5 = mg/kg/day

For the management of acute asthma, the drug may have an additive effect on other medications. Intravenous aminophylline has been used in the management of acute severe asthma for over 50 years. However, its has been questioned recently in view of the risk of adverse effects compared with nebulised β-agonists. Intravenous aminophylline is less effective than nebulised β-agonists.25 Thus some authors recommend that the drug should be reserved for those patients who fail to respond to β-agonists. On the other hand, there are evidences to suggest that use of aminophylline in the emergency room reduces subsequent admissions to hospitals.26 There is no added advantage if aminophylline is used in addition to β-agonists. Use of intravenous aminophylline may increase the death rates.27 However, this is a drug which is cheap and still used as an important drug in many hospitals in the management of acute severe asthma. Whenever a decision is taken to use aminophylline intravenously, it should be given as a slow intravenous infusion with careful monitoring and a plasma theophylline concentration should be monitored, if possible, prior to infusion. The loading dose is aimed for a target serum concentration no higher than the mid point of the 10 to 20 μg/ml that is determined by multiplying the desired change in serum concentration by an average volume distribution of about 0.5 L/kg. In other words, each μg/ml increase in serum concentration requires 0.5 mg/kg of a loading dose. A repeat serum concentration 30 minutes after the loading infusion determines the need for an additional loading dose and provides a baseline for monitoring change during a subsequent maintenance infusion. A conservative maintenance infusion based on mean clearance and targeting a steady state serum concentration of 10 μg/ml is maintained with as follows:

138 Bronchial Asthma Infants under age 1 0.008 × age in weeks + 0.22 mg/kg/hr Children (1-9 years) 0.8 mg/kg/hr Children (9-16 years) 0.6 mg/kg/hr Adults 0.4 mg/kg/hr The adult dose should be decreased by one half for those with heart failure or liver disease. Subsequent infusion is adjusted according to the serum concentration. The other important use of theophylline is its use as maintenance therapy for chronic asthma. To attend an optimal dosage one should proceed with patience. Rapid attainment of therapeutic concentrations is associated with a high degree of minor complaints which may discourage the patient from continuing therapy. Therefore, the aim should be to attend such optimum concentration over a period of 1-2 weeks. Because of the variability in the rates of elimination, the final doses requirements are highly variable. While average doses are higher on a weight-adjusted basis for children than adults, considerable variability is observed at all ages. According to these principles the initiation of therapy should be at doses of 400 mg/day or 16 mg/kg/day, whichever is less. Since this dosage is low, adequate control of symptoms is not expected and for that period, another drug should be used for control of symptoms. The dose is then to be increased every three days to 600 mg/day for those more than 45 mg/kg or if the patient weighs less than 45 mg/kg, either 600 mg/kg or 16-20 mg/kg, whichever is less. After the next three days, the dose is to be increased to 800 mg/kg for those more than 45 kg in weight and if less than 45 kg in weight, the dose should be 800 mg/day or 18-24 mg/kg/day, whichever is less. The dose is then adjusted according to the serum concentration which should be measured about 4 hours after a dose when none have been missed or added for three days. Theophylline has little or no effect on bronchomotor tone in normal airways, but it reverses bronchoconstriction in asthmatics. The routine of theophylline in chronic stable asthma has recently been questioned.28-30 In various guidelines of management of bronchial asthma (discussed subsequently), theophylline is used as an additional bronchodilator if asthma remains difficult to control after moderate to high dose inhaled steroids. The recent use of salmeterol and formoterol may still threaten the position of theophylline. Nonetheless, the drug is cheap and is in use for several decades in many developing countries as a main stay of treatment. Monitoring serum concentrations is an important part of acute or chronic care of asthma. The frequency of measurements depend upon the specific clinical situation. Monitoring is required in those who fail to exhibit the expected clinical effect while receiving an appropriate therapeutic regimen and in patients who develop an adverse effect to an usual dose. It is useful to monitor serum theophylline concentrations when a patient begins his therapy and then at 6-12 months, as long as no adverse effects are observed. The therapeutic range of theophylline was based on measurements of acute bronchodilatation in response to the acute administration of theophylline.31 However, it is possible that the nonbronchodilator effects of theophylline may be exerted at lower plasma concentrations. Since side effects are also related to plasma concentration, these may be markedly reduced by aiming for plasma concentrations of 5-15 mg/l (28-55μM), rather than the previously recommended doses of 10-20 mg/l (55-110μM). This level should be in the steady state (at least 48 hours in the same dose). Improvements in slow-release preparations, including that of once-a-day products, have further improved the problem of fluctuations in plasma concentrations.

Pharmacologic Management of Asthma 139 Side Effects The signs and symptoms of theophylline intoxication involve many organ systems. The commonest toxicity are caffeine-like side effects including minor degrees of central nervous stimulation, headache, restlessness and nausea and vomiting or a queasiness of the stomach occur frequently after a loading dose and have no direct relationship to the serum concentration. Most patients rapidly acquire tolerance of these side effects when therapy is maintained and avoid them when the dose is gradually built up. As serum concentrations exceed 20 μg/ml, there is an associated progressively increasing risk of more serious side effects including seizures and death, most commonly when the level exceeds 40 μg/ml. The seizures may not be preceded by other central nervous system symptoms. Cardiopulmonary effects include tachycardia, and arrhythmias even at serum concentrations considered to be therapeutic. Multifocal atrial tachycardia may herald sudden cardiac death.32 Other adverse effects include stimulation of respiratory center causing tachypnoea, diuresis, relaxation of the detrusor muscle causing difficulty in urination in older men with prostatism, and important metabolic effects such as hyperglycaemia and hypokalaemia. The effect of theophylline on behaviour and learning of children have received attention recently. Because the drug stimulates the central nervous system, it may produce behaviour disturbances in children. Of more serious consequence are the reports that its use is associated with impairment of learning,33-35 although a carefully designed study could not confirm this.36 Some of the side effects of theophylline like central stimulation, gastric secretion, diuresis, and arrhythmias may be due to adenosin receptor antagonism and may, therefore, be avoided by drugs such as enprofylline, which has no significant adenosine antagonism at bronchodilator doses.37 However, the commonest side effects of theophylline like nausea, vomiting and headache are also seen with enprofylline.38 Prevention of toxicity is important by monitoring the serum concentrations and by aiming for lower plasma concentrations as indicated earlier to some extent, side effects may be reduced by gradually increasing the dose until therapeutic concentrations are achieved .39-41 Acute accidental or suicidal overdoses of theophylline are better tolerated than sustained high levels encountered due to uncontrolled therapy. Since theophylline-induced seizures are more dangerous including brain damage and death, an aggressive approach to the treatment of an overdose is necessary. Initial therapy with ipecac or other measures to induce vomiting removes remaining aminophylline in the stomach. Activated charcoal stops further absorption, and simultaneous administration of a cathartic such as sodium sulphate increases the transit time of charcoal and any remaining undisclosed drug. Repeated doses of activated charcoal increases the rate of elimination of theophylline already absorbed by two folds, possibly due to the result of a gastrointestinal dialysis. Extracorporeal charcoal haemoperfusion allows more rapid clearance. There are many factors which affect serum theophylline concentrations. These factors and actions to be taken are shown in Table 10.2. β-ADRENERGIC AGONISTS Normal β-adrenergic Receptor Physiology The autonomic nervous system is responsible for regulating the airway tone through the release of neurotransmitters that activate specific autonomic receptors. The autonomic

140 Bronchial Asthma Table 10.2: Factors affecting serum theophylline levels

Factor

Decreases

Increases

Action to be taken

Food

↓ or delays absorption

↑absorption (fatty foods)

Select appropriate preparation

Diet

↑metabolism (high protein)

↓metabolism (high carbohydrate)

Major changes in diet not advised

Systemic, febrile viral illness

↓metabolism

↓dose by 50%, if serum level not available

Hypoxia, cor pulmonale CCF, cirrhosis Age

↓metabolism

Decrease dose

↓metabolism (<6m, elderly)

Adjust dose as per serum levels increase dose

↓metabolism

Alternative H blockers (ranitidine/famotidine)

↓metabolism

Alternative antibiotic or adjust theophylline Alternative antibiotic or adjust theophylline ↑dose of theophylline

Phenobarbitone Phenytoin, Carbamazepine

↑metabolism (1-9 y) ↑metabolism

Cimetidine Macrolides: Erythromycin TAO, Clarithromycin Quinolones Ciprofloxacin, etc. Rifampicin

↑metabolism

Ticlopidine Smoking

↑metabolism

↓metabolism

↓metabolism

↓dose of theophylline ↑dose of theophylline advise to quit smoking

system is divided into the parasympathetic or cholinergic system, the sympathetic or adrenergic system, and the non-adrenergic non-cholinergic inhibitory system. Broadly speaking, while the parasympathetic system is responsible for bronchoconstriction mediated by cyclic 3'-5', guanosine monophosphate (GMP), the sympathetic system causes bronchodilatation via cyclic adenosine monophosphate (cAMP). The sympathetic system is further subdivided into alpha and beta components. Alpha receptor stimulation is associated with vasoconstriction and the inhibition of nonepinephrine release. Further, the β-adrenoreceptors are subdivided into β1- and β2-subgroups. β-receptors have both chronotropic and ionotropic effects on the heart, and β 2-adrenoreceptors mediate bronchodilatation.42 β-adrenergic receptors are integral membrane glycoproteins. They are oriented in the membrane in such a way that the adrenergic ligand binding sites expose directly to the extracellular space.43 Majority of the β2-receptors are located in glial cells, and on smooth muscle cells like vascular, bronchial, and uterine smooth muscle cells. The density of these cells in a particular site is important for physiologic responsiveness. Essential characteristics of β receptors are rapid and reversible kinetics of binding, strict specificity, stereospecificity, and affinity appropriate to the adenylate cyclase-coupled β-adrenergic receptors, and saturability.44 The general effect of activation of β2-receptors at smooth muscle sites is inhibitory, although this may not be an absolute rule. The effect in other tissues can stimulate various secretions like insulin. In humans, relaxation of central and peripheral

Pharmacologic Management of Asthma 141 airways is mediated entirely by β2 receptors. Increased bronchial reactivity could result from a decreased β-adrenergic or nonadrenergic inhibitory activity. Most probably it is caused by decreased responsiveness of β-adrenergic receptors.45 β-receptors mainly work through the enzyme adenylate cyclase activation and cyclic AMP formation. The enzyme adenylate cyclase is stimulated by catecholamines in virtually all tissues in which β-receptors can be found. The principal type of receptor coupling to adenylate cyclase by β2-adrenergic receptors is referred to as a “stoichiometric coupling”, in which the biological response elicited is directly proportional to the percentage of receptor occupied (occupancy theory). A reduction in receptor number will alter the sensitivity of the tissue to catecholamines. The tissue will require more drug to provide the same degree of receptor occupation as the receptor concentration is lowered. There is a general mechanism of hormone to receptor to adenylate cyclase interaction. Mammalian cells controlled by β-adrenergic hormones contain plasma membrane-bound adenylate cyclase and specific hormone receptors. These systems have a protein(s) which couples their receptors to the adenylate cyclase catalytic protein. This coupling protein contains a guanine nucleotide binding site, and is labelled as Ns. The interaction of the hormone, receptor, and guanine nucleotide binding protein with the adenylate cyclase catalytic unit and in the presence of magnesium ions, results in the formation of cAMP from adenosine triphosphate (ATP).46,47 Further, cAMP functions as a second messenger of catecholamine or hormonal action by modifying enzyme activities and permeability barriers. This is possible by the activation of protein kinases. These enzymes transfer terminal phosphate groups from ATP to amino acid residues of certain proteins.44 In bronchial smooth muscle, the kinases cause a reduction of calcium dependent coupling of actin and myosine and this results in smooth muscle relaxation. Thus, β2 agonists increase intracellular cAMP concentrations which are essential in the relaxation response. Recently, it has been become clear that β2 agonists may cause bronchodilatation, at least in part, via maxi-K channels in airway smooth muscle cells which are directly linked to relaxation.48-51 Maxi-K channels are opened by low concentrations of β2 agonists which are likely to be therapeutically relevant. There is now evidence that β receptors may be coupled directly to maxi-K channels via the alpha-subunit of Gs,48 and may therefore, induce relaxation without any increase in cAMP. The sympathomimetic bronchodilators are the keystone of therapy of bronchial asthma.52-62 Β-2 agonists are often the first and most commonly used drugs for the treatment of bronchial asthma. Modern bronchodilator therapy started in 1900 when the use of adrenal extract to treat asthma was described.42 In 1924, ephedrine was introduced into western medicine, although its parent plant, ma huang, was known to the Chinese for more than 5000 years. These drugs had both alpha and beta-adrenoceptor activity which were described by Ahlquist in 1948.42 The older sympathomimetic agents ephedrine, epinephrine, and isoproterenol have been generally replaced by the newer, longer acting, more β-2 specific bronchodilators. Nonetheless, they are still important antiasthma medications. Recognition of the pharmacologic differences between β1, β2, and α receptors has led to the development of adrenergic agonists that can preferably act on β2 receptors of bronchial smooth muscle with little direct stimulation of the β1 receptors of the myocardium. At present, β2 agonists or sympathomimetics, are the preferred and most effective bronchodilators available for the treatment of bronchial asthma and are often the first and most important drug to be used worldover.

142 Bronchial Asthma Biochemistry The β-adrenoceptor agonists are sympathomimetic amines whose parent compound is β-phenylethylamine. They consist of a benzene ring attached to an amine group by two carbon atoms. The distinctive features of different β-agonists depend on the basic structure, and on the substitution on the amine group in particular. Increasing the size of the terminal amino group substituent protects the drug against degradation by monoamine oxidase, and further increases the duration of bronchodilatation. 43 Modification of the phenylethylamine nucleus has helped to increase β2-specificity and duration of action. Catecholamines refer generically to all compounds containing a catechol nucleus (benzene with two adjacent hydroxyl groups) and an amine group. They have a relatively short halflife, because they are subject to removal by active uptake mechanisms and to rapid metabolism by catechol-o-methyltransferase (COMT) and monoamine oxidase (MAO). They are orally inactive because of their inactivation by gastrointestinal sulphatases. By modification of the 3,4-hydroxyl groups on the benzene ring, which are the sites of action of COMT, prolonged bronchodilating action and oral administration is possible. The various β2-agonists are shown in Table 10.3. Mechanisms of Action Sympathomimetic amines have six general types of action: peripheral excitatory, peripheral inhibitory, cardiac excitatory, metabolic, endocrine, and central nervous system actions. β2-agonists cause a direct relaxation of the pre-constricted or spontaneously contracting human bronchial smooth muscle. Their bronchodilator action is evident in normal persons, in patients with chronic obstructive pulmonary disease, and asthma. They cause a marked reduction in nonspecific bronchial reactivity to stimuli such as histamine, methacholine, or exercise. The mode of bronchodilatation seems to be due to a decrease in catecholamine-stimulated adenylate

Classification Ephedrine Catecholamines Epinephrine Isoproterenol Isoetharine Resorcinols Metaproterenol Terbutaline Fenoterol Saligenin Salbutamol Miscellaneous Bitolterol Pirbuterol Procaterol Long acting drugs Formoterol Salmeterol

Table 10.3: Adrenergic bronchodilators Receptor activity Availability

Duration of action(hours)

α, β1, β2.

Oral

2-3

α, β1, β2 β1, β2 (β1), β2

Injection, inhaler Oral, inhaler, Injection Inhaler

1-2 1-2 3

β2 β2 β2

Oral, inhaler Oral, inhaler, Injection Inhaler

3-5 4-6 4-6

β2

Oral, inhaler, Injection

4-6

β2 β2 β2

Inhaler Inhaler Oral, inhaler

6-8 4-6 6-8

β2 β2

Inhaler Inhaler

> 12 > 12

Pharmacologic Management of Asthma 143 cyclase activity. The final effect is an increase in cellular cyclic adenosine monophosphate. This effect derives from and is mediated through a plasma membrane-associated β-adrenergic receptor: the guanine nucleotide regulatory protein, which in turn activates adenylate cyclase and leads to generation of cAMP. β2-adrenoceptor agonists vary in their selectivity for β2adrenoreceptors, but none is β2-specific. They all stimulate β- receptors to a lesser but dosedependent extent. The duration of action is dose dependent, but to a limited extent. Since the human airway smooth muscle cells express β2-receptors from the trachea to the terminal bronchioles,63,64 these drugs as functional antagonists can prevent and reverse the effects of all substances,65 including leukotrienes, acetylcholine, bradykinin, prostaglandins, histamine and endothelins. Because of the widespread presence of β-receptors, the β2- agonists may affect many cells like stabilisation of mast cells,66 which may be the cause of effectiveness of these agents in blocking the bronchoconstricting effects of allergens, exercise, and fog. Further, β2-agonists inhibit cholinergic neurotransmission in the human airway, which can result in reduced cholinergic-reflex bronchoconstriction. The other mechanisms of action of β-agonists, although not proved conclusively, include, inhibition of mediator release, modulation of neural pathways, reduction of microvascular leak, and increased mucociliary clearance.67 Long acting β2-agonists, salmeterol xinafoate and formoterol fumarate, are currently available in many countries.68-70 They are available in inhaled forms. While salmeterol acts longer but is a partial agonist, formoterol is a nearly full agonist.71 Both provide effective bronchodilatation over a 12-hours period and thus, they are more useful for patients who have nocturnal asthma.72,73 Because these drugs have no anti-inflammatory effect, they should always be used with an inhaled glucocorticoid. Both drugs also protect against airways challenge with methacholine for a period of 12 hours.72,74 International guidelines have recommended both drugs to be added in the treatment of bronchial asthma. Several studies have demonstrated the superiority of salmeterol and formoterol to regular treatment with either salbutamol or placebo.75-77 Both these drugs differ pharmacologically, but there is no difference in the efficacy between the two drugs in any severity of bronchial asthma,78-80 although formoterol is more potent than salmeterol in vitro, with a faster onset but a shorter duration of action,81 but with similar bronchodilator action at 12h. Relative potency estimates show that 50 mg salmeterol corresponds to 9 mg formoterol.82 Optimal Pharmacological Profile of β-adrenoceptor Agonists They exhibit a range of physico-chemical properties, which arise from differences in molecular structure, and determine their pharmacological profiles with respect to affinity, efficacy, and duration of action at subtypes of β-adrenoceptors in a number of target cells. All β-agonists are racemic mixtures of optical isomers, there being two isomers, R and S in salmeterol and four isomers (RR, RS, SR, and SS) in fenoterol and formoterol. β-agonist activity resides predominantly in the R-form, which ranges from 40-fold to 1000-fold more potent than the S-isomer. At β2-adrenoceptors, salmeterol, formoterol, and fenoterol have a higher affinity than isoprenaline and salbutamol, the associated rank order of potency being: formoterol > salmeterol > fenoterol = isoprenaline > salbutamol. Fenoterol and formoterol are full agonists, and salmeterol and salbutamol are partial agonists, compared with isoprenaline. Salbutamol, and particularly salmeterol are weak and have low efficacy at β1 and β2-adrenoceptors, whereas formoterol and fenoterol are potent, full agonists. The functional β2-adrenoceptor

144 Bronchial Asthma selectivity is lowest for fenoterol and highest for salmeterol. β2-agonists such as salbutamol and fenoterol are hydrophilic and interact with the β-receptor directly, whereas formoterol is moderately lipophilic, and salmeterol is highly lipophilic, gaining access to the active site of the β2-adrenoceptor through the cell membrane. The rates of onset of action of salbutamol, fenoterol, and formoterol are more rapid than those of salmeterol. The duration of action is concentration-dependent for all β-agonists, with the exception of salmeterol, which appears to be intrinsically long-acting (salmeterol >> formoterol>fenoterol>salbutamol) due to additional exo-site binding in the β2-receptor protein. Aerosol or oral inhaled therapy is comparable or better than oral therapy in producing bronchodilatation and cause fewer systemic side effects such as cardiovascular stimulation, anxiety, and tremor. Inhaled therapy has a more rapid onset of action when compared with oral formulations and a similar duration of action, even when administered in substantially lower dosages. Furthermore, inhaled therapy appears superior to oral therapy because the latter causes more adverse effects and require higher doses to achieve similar effects. β2agonists are the medications of first choice for treatment of acute exacerbations and for the prevention of exercise-induced asthma. They can be used either intermittently to control episodic airway narrowing or chronically to aid in the control of persistent airway narrowing. Salbutamol inhalation reduces hyperinflation of the lungs. Measurements of lung volumes before and after bronchodilators add sensitivity when examining for bronchodilator responsiveness.83 Recently there is a trend to use more of inhaled form of these drugs rather than oral preparations because of adverse effects and slow onset of action. The advantage of slowrelease oral agents has been taken over by the introduction of long-acting inhaled β2- agonists, which are more effective in preventing induced bronchoconstriction than equivalent doses of oral β2-agonists.84 Further, inhaled drugs may reach superficial cells in the airways, such as mast cells and epithelial cells, that are less easily reached by oral drugs. Thus, nebulised β2-agonists are the first choice for acute severe asthma and may be life saving.85 Since the onset of action is rapid, and the therapeutic ratio of bronchodilatation to side effects is greatly improved, inhaled administration is preferred. Since there is a rapid action, this can be attributable to the direct effect of the drug on the smooth muscle β-adrenoceptor. When given by inhalation, all currently available β-agonists achieve a measurable effect within 5 minutes and by 10 minutes, 80-90% of the maximal response has actually been achieved.42 Another advantage of giving bronchodilators by inhalation is that they are not distributed to the rest of the body in large concentrations and therefore may be given in much smaller doses. The doses of some of these drugs are given in Table 10.4. Side Effects The predictable side effects of β-agonists include tachycardia, palpitation, dysrhythmia, hypokalemia, tremor, restlessness and rarely hypoxemia. Tremor, due to stimulation of β2adrenoceptors in skeletal muscles is a common side effect of these class of drugs. Tremor is inseparable from bronchodilator action, but, incidence usually declines with continued administration.86 Since the frequency of adverse effects are directly proportional to the plasma concentration, administration via inhalation results in less drug absorption and therefore fewer adverse effects than either oral or inject able routes. Although, the adrenergic aerosols are currently among the safest drugs available for asthma therapy, there are some

Pharmacologic Management of Asthma 145 Table 10.4: Dosage of sympathomimetic agents per treatment

Drug Adrenaline (1:1000) Isoproterenol Isoetharine Metaproterenol Salbutamol Terbutaline Bitolterol Formoterol Salmeterol

Subcutaneous (ml) 0.1-0.5 — — — 0.5 0.25-0.5 — — —

Metered dose inhaler or MDI (mg) 0.32-0.9 0.16-0.39 0.68-1.02 1.3-1.95 0.18-0.27 0.4-0.6 0.37-1.11 6-12 μg 50 μg

Nebulizer (mg)

Oral (mg)

2.5-22 0.63-3.8 1.25-5 10-15 — — — — —

— — — 5-20 2-4 2.5-5 — — —

areas of concern. Adverse drug reactions involving the cardiovascular system may also occur. Cardiovascular complications may result from decreased serum potassium levels or direct stimulation of the myocardium. Adverse reactions of the cardiovascular system may occur with the combination of systemic adrenergic agonists and theophylline. However, cardiac arrhythmias and myocardial ischaemia resulting from β-agonist therapy usually occurs in patients with preexisting cardiovascular disease, especially among the elderly. Very rarely, patients with asthma may experience paradoxical bronchoconstriction as a result of inhaled β-agonists administered by metered-dose inhalers (MDI). The paradoxical response is an abrupt worsening of asthma symptoms and/or a decrease in expiratory flow rates shortly after inhaling a therapeutic aerosol. It is not clear whether the reaction is due to the drug itself or due to another component or contaminant of the particular canister or batch of canisters or due to a hypersensitivity reaction to the hydrocarbon propellant. Very rarely lactic acidosis may occur. Several recent studies have suggested that regular use of β-agonists increases the responsiveness of airways to challenges with agents such as methacholine and histamine in children and adults. Similarly some recent reports associate the regular use of a potent inhaled β2-agonist with diminished control of asthma. Although the mechanisms of diminished control or increased hyperreactivity are not known, possibilities include the development of rebound airway hyperresponsiveness, increased bronchial secretions, or both. There are also some concern regarding damage to the mucosal epithelium due to repeated inhalation. There are controversies regarding the link between the use of fenoterol and increased asthma deaths in New Zealand. Another potential reason for increased asthma symptoms during prolonged therapy with these drugs may be the development of tolerance or subsensitivity resulting from downregulation of β-adrenoreceptors. This phenomenon is a tendency of biological responses to wane over time in the presence of a stimulus of constant intensity, and may develop to the antiasthmatic effects of inhaled β2-agonists.65,86 Although some evidences suggest that tolerance to the bronchoprotective effects of both short- and long-acting β2-agonists does develop,87-91 numerous other studies using a recommended dose of β-agonists by metered dose inhalers have failed to show the development of complete tolerance.92 Most studies suggest that clinically significant tolerance does not usually develop in patients with asthma. When tolerance develops, it is characterised by a small reduction in the bronchodilator response and by a slight shortening in the duration of action after inhaling a β-agonist. Thus, tolerance is not

146 Bronchial Asthma usually of major clinical significance and does not diminish the overall usefulness of inhaled β2-agonists in asthma therapy. It is possible, however, that receptor down-regulation could account for some of the diminished control of asthma and increased airway hyper-reactivity reported during chronic regular use of these drugs. Subsensitisation occurs because of the receptors in the tissue are exposed to persistent stimulation by agonists. The problem can occur at one or several different points in the formation of cAMP. It could occur at the level of the receptor, stimulatory or inhibitory, and/or involve down regulation mechanisms. These will involve an uncoupling of the hormone-receptor complex from the guanine nucleotide binding protein. Further, repeated exposure to catecholamines may reduce the number of β-receptors in the airways that are free to interact with catecholamine bronchodilators.43 Thus repeated administration of β-agonists makes the airways even less responsive. Tolerance is seen most commonly with triggers that operates through mast cell activation, such as adenosine, allergens, and exercise. Whether steroids protect against development tolerance is not known. The problem may be avoided by taking long acting β 2-agonists only at night. Recent studies of the polymorphism of human β2-receptors suggest that some forms of the receptors may be more likely to be down regulated.93 Patients having Arg-16 → Gly form of the receptor, which is more likely to be down regulated have more frequent asthma in the night.94 In contrast, the Gln→Glu form, resist down regulation and is having less airway hyperreactivity.95 There is some concern recently regarding the use of β2-agonists and excess asthma mortality. The two epidemics of asthma death recorded in the literature, one in several countries in the 1960’s and the other in New Zealand in the late 1970s, were associated with a rapid increase in the use of a β-agonist formulation delivering a high dose by metered-dose inhalers, isoprenaline in the 1960s and fenoterol in the late 1970s. Although, reports are conflicting, it seems likely that those epidemics were due to high-dose β2-agonist use. There is no epidemiological evidence to suggest that β-agonists have an appreciable effect on mortality outside these epidemics.96-101 Some Controversial Facts About β2-Agonists Despite the worldwide use and the significant contributions of inhaled synthetic sympathomimetic agents in the therapeutic management of bronchial asthma, the risk/benefit ratio of these agents have evoked controversy throughout the last half of the 20th century. Concerns about possible deleterious effects of the first reported from the United Kingdom, Australia and New Zealand in the mid-1960s, when a sudden increase in asthma mortality was attributed to overuse of a short-acting, dose-fortified formulation of isoproterenol.102 A similar phenomenon occurring a decade later in New Zealand appeared to be associated specifically with regular use of inhaled fenoterol, a more selective, relatively short-acting β2-agonist (SABA),.97 A Canadian retrospective case-control analysis of pressurised SABA in patients with asthma suggested that increased asthma mortality was not necessarily due to fenoterol alone but also occurred after overuse of any pressurised SABA of the same class.96 A subsequent meta-analysis of six similar surveys not only failed to confirm this conclusion but found that mortality was increased to a slight extent only in patients who used SABA on a regular basis.103 Even if this controversy keeps on appearing off and on, most clinicians believe that the mortality attributable to SABA is most likely based on over dosage and/or abuse by poorly controlled patients.104

Pharmacologic Management of Asthma 147 The above controversies led to more intensive exploration of the nonbronchodilator properties of SABAs and also long-acting β2-agonists (LABAs). The interactive effects of these agents as well as individual agents have been studied extensively. 105,106 Such investigations have revealed a complex and contradictory array of biological activities that encompass both proinflammatory and anti-inflammatory effects. As examples of antiinflammatory effects, β2-agonists are known to attenuate release of mediators from mast cells, suppress airway smooth muscle growth, and inhibit the function of immunocompetent lymphocytes. By contrast, the proinflammatory effects include suppression of interleukin12 production in antigen-presenting cells, intensification of the T-helper type 2 immune response, augmentation of eosinophil survival and enhancement of the late allergic response. SABAs may also favor the synthesis of receptors associated with neurogenic inflammation that could play a role in the phenomenon of increased airway hyperresponsiveness that has been noted after long-term use of these agents. Similar concerns were expressed about the LABAs. The lipophilic nature of these agents would enable them to partition into the outer phospholipid layer of cell membranes, where they have better access to receptors and downstream signalling cascades. Fortunately, downregulation of β2-agonist receptors on smooth muscle is not clinically relevant, presumably because of their overabundant distribution and relative refractoriness to tachyphylaxis in this tissue site. A number of studies in the mid 1980s and early 1990s demonstrated that regular use of SABAs increased airway hyperresponsiveness and actually worsen asthma control, and many asthma management guidelines recommended against their regular use over prolonged periods. Similar concerns were also expressed when LABAs were available, and in fact early clinical trials reported that both short-term and long-term use of LABAs dampened the β2-agonist protective effect against methacholine-induced bronchospasm without evidence of smooth muscle tachyphylaxis.90,107 However, more recent studies demonstrated that the LABA-induced protective effect against airway hyperresponsiveness was unimpaired after relatively long-term, continuous use of LABAs without evidence of a rebound effect after cessation of therapy.108,109 These contradictory results have been ascribed to patient-specific differences in sensitivity to the deleterious effects of bronchodilators, variability of allergic status among patient groups, or a masking activity of β2-agonists .110 The later effect might occur because these agents inhibit only the early allergic response and might exacerbate the ongoing inflammation associated with the late allergic response. A recent controlled study111 performed over a 6-week period using placebo or salmeterol that utilised a well-defined allergic phenotype of mild asthma, (pollen sensitive asthmatics), and a well-defined exposure period (a grass pollen season), measured both direct and indirect airway hyperresponsiveness using methacholine and adenosine monophosphate and exhaled NO was measured as an index of airway inflammation. Airway caliber (FEV1), airway hyperresponsiveness indices and exhaled NO were measured before the administration of salmeterol or placebo and at mid season. Patients receiving salmeterol experienced significant protection against a fall in FEV1 during the height of the allergy season. The increase in airway hyperresponsiveness showed only a small insignificant increase in the treated group compared to the placebo group. The result emphasised the difference between natural exposure and a single experimental allergen challenge studies reported earlier. There was a failure to detect a significant difference in adenosine monophosphate-induced airway responsiveness between salmeterol-treated and placebo-treated patients when they were challenged with the agent during the height of the pollen season. Since the adenosine monophosphate indirect

148 Bronchial Asthma challenge reflects bronchoconstriction caused by mast cell mediators, long-term salmeterol did not attenuate the chronic effects of mediators during the season and therefore did not function as an anti-inflammatory agent. The exhaled NO levels were increased both treatment arms during the height of the pollen season, but there was neither an augmentative nor inhibitory effect in the salmeterol group. These results strengthened the safety profile of salmeterol and indicated that long-term use of a LABA alone will not provide a clinically effective anti-inflammatory effect. Ultimately perhaps, the balance between the salutary and adverse effect of both SABAs and LABAs are tilted towards a more clinical benefit to the patient in the management of bronchial asthma. Anticholinergics Anticholinergics are the oldest forms of bronchodilator therapy for asthma and are recommended as early as the 17th century.112 The recreational and medicinal properties of atropine have been well-known to many cultures for many centuries. Atropine, in the form of the leaves and roots of Datura stramonium, was very well known to Indians for use in respiratory disorders, and it was introduced to Western medicine by the British military officers in the early 1800s, who in turn learnt its usefulness from Indians. At that time, stramonium, belladonna, and their alkaloid extract, atropine, had their place in most pharmacopoeias. Atropine was used for many years for the management of bronchial asthma. With the availability of potent β-adrenergic agonists in the 1920s, its use declined. In recent years there has been an increased interest in inhaled atropine sulphate, especially in patients with chronic bronchitis. Atropine is usually given as a powder nebuliser with a β-adrenergic agent. Its side effects include tachycardia, dryness of the oral mucosa, blurred vision, urinary retention, and constipation. The drug has a delayed onset of action. Atropine should not be used in patients with narrow angle glaucoma and prostatic hypertrophy. With the advent of newer more selective drugs without these unpleasant side effects of atropine, the later is almost no more used.112,113 The newer anticholinergic agents are watersoluble, quaternary ammonium compounds that are poorly absorbed, and when they are given by inhalation, they cause fewer systemic side effects.114-118 A better understanding of the cholinergic mechanisms that control airway caliber in health and disease and the development of newer synthetic analogs of atropine that are poorly absorbed, but retain the anticholinergic properties of the atropine, have revitalised the interest in anticholinergic therapy. Several anticholinergic agents that are in use worldwide include: • Atropine • Ipratropium bromide • Thiazinamum • Oxytropium bromide • Glycopyrrolate • Tiotropium bromide

Rationale for the Use of Anticholinergics To understand the rationale of use of these agents it is important to understand the mechanisms of bronchoconstriction and bronchodilatation that are mediated by the autonomic nervous system. The majority of the autonomic nerves in human airways are

Pharmacologic Management of Asthma 149 branches of the vagus nerve, the efferent paraganglionic fibres of which enter the lungs at the hilum and travel along the airways into the lungs.119 The efferent innervations is derived from the postganglionic fibres that end in the epithelium, submucosal glands, and smooth muscle of the airways as well as in the vascular structures. Thus, the release of acetylcholine at these sites results in smooth muscle contraction and the release of secretions from submucosal glands stimulated by their muscuranic receptors. Cholinergic pathways are important to regulate the acute bronchomotor responses, and many stimuli can provoke bronchoconstriction via vagal pathways. Anticholinergic medications antagonise transmission at the muscarinic receptors. They will only block reflex cholinergic bronchoconstriction and will have no effect on bronchoconstriction resulting from the action of, for example, histamine on the airways. Cholinergic-induced bronchoconstriction appears to involve primarily the larger airways, whereas β-agonist medications relax both large and small airway contraction equally. In humans, there are at least three pharmacologically distinct subtypes of muscarinic receptors within the airways, which are known as M1, M2, and M3 receptors.120 Recently, the types described are up to 5, M1 to M5. The M1 receptors are present within the parasympathetic ganglion and mediate increased cholinergic transmission. They may facilitate nicotineic transmission or be responsible for maintaining cholinergic tone. Inhibition would reduce cholinergic tone and thus would reduce bronchoconstriction. M1 receptors are also found on alveolar walls, although their function is unknown. Prejunctional M2 receptors on the postganglionic nerves act as negative feedback loop in neuronal transmission. They are activated by the release of acetylcholine and promote its reuptake, thereby limiting the degree of bronchoconstriction produced. These receptors are thought to be dysfunctional in asthma, resulting in exaggerated cholinergic reflexes. The loss of M2 receptor function has been demonstrated after viral infections. Similar changes can be seen after ozone exposure or antigen challenge.121 When the M2 receptors are dysfunctional, the resulting excessive concentrations of acetylcholine at the motor endplate can promote significant bronchoconstriction. Finally, M3 receptors are located on the airway smooth muscle. The receptor activation leads to a release of calcium ions from intracellular stores and a decrease in intracellular adenosine 3’,5’-cyclic monophosphate levels, resulting in the contraction of airway smooth muscle. M3 receptors also are located on submucosal glands, where they are likely to be involved in mucus secretion. Ipratropium bromide and oxytropium bromide are quaternary ammonium derivatives of atropine and are bronchoselective when delivered by inhalation.122,123 Ipratropium bromide is a muscarinic cholinergic antagonist that inhibits smooth muscle contraction by competing with the neurotransmitter acetylcholine at the muscarinic receptor.124 These drugs are thus less effective than inhaled β2-agonists because they counteract only cholinergic neural bronchoconstriction, which may be a relatively minor part of the broncho-constrictor mechanism in asthma. As discussed earlier, recently it is recognised that there are at least five subtypes of muscarinic receptors expressed in the airways.120, 125 The M3 receptors play the major role in causing bronchoconstriction, whereas the M2receptors mediate the feedback inhibition of acetylcholine release from airway sensory nerves.126 Atropine, ipratropium bromide and oxytropium bromide are nonselective antagonists and produce their beneficial effect by blocking M3 receptors. However by blocking prejunctional M2 receptors, they increase the release of acetylcholine and thus may have relatively deleterious effects.126 This may weaken the effect of the postjunctional M3 muscarinic receptor blockade on airway smooth

150 Bronchial Asthma muscle and submucosal glands. This suggests that antagonists that bind selectively to M1 and M3 receptors may be more effective in inhibiting cholinergic effects on the airways. The drugs also inhibit hypersecretion of mucus in the airways.127 The anticholinergic drugs act by reducing intrinsic vagal tone to the airways. They also block reflex bronchoconstriction caused by inhaled irritants. The agents also block postganglionic efferent vagal pathways. They are relatively free of systemic side effects because they are minimally absorbed into the systemic circulation and do not cross blood-brain barrier. The natural antichiolinergic, atropine, is rarely used in patients at the present time, however, this drug was used extensively as a nebulised solution by intensivists and emergency department specialists for years.128 It is readily absorbed across the oral and respiratory mucosa and when higher doses are used to maximize bronchodilator effect, the incidence of dry mouth, blurred vision, urinary retention, nausea and tachycardia may limit the usefulness of atropine. The principal anticholinergic agent is ipratropium bromide, a nonselective muscarinic antagonist.129,130 The drug is topically active, and the compound is poorly lipophilic and not significantly absorbed from the respiratory or GI tract. It has no or very little systemic effect. The drug has been found to be an effective bronchodilators in patients with COPD and selective patients with asthma both alone and when used in combination β2-agonists and theophylline. When used via MDI aerosol, the recommended dose of ipratropium bromide is 2 puffs (40 μg) 4 times daily. The drug has been shown to be effective during status asthmaticus when used in nebulised form in combination with β-adrenergics.131-133 It does not appear to affect mucus secretion and ciliary movement. Another significant advantage of ipratropium bromide in the critically ill asthma patients is the lack of tachycardia, which does occur with β2-agonist use.134 The only remarkable side effect is the inhibition of salivary secretions at high doses. It has no effect on urinary flow, or intraocular tension, and possible effects on the eye (glaucoma) can be prevented by using a mouth piece during nebulisation. The onset of action is 3 to 30 minutes with up to 50% of the response occurring in 3 minutes and 80% in 30 minutes, with a peak bronchodilator effect observed within 1 to 2 hours, and the duration of action is up to approximately 6 hours. These properties are ideal for acute asthma treatment. Oxytropium bromide is a quaternary ammonium anticholinergic compound that is based on scopolamine instead of atropine. It is also a nonselective muscarinic antagonist. The drug is used in a dose of 200-400 μg per day and is perhaps less effective in chronic asthma.134 It has a longer duration of action, up to 8 hours than ipratropium bromide, but has a slower onset of effect.135 The peak onset of action is 1-2 hours. In children ipratropium has bronchodilator action in acute exacerbations of asthma. However, the benefits of its use in day-to-day management of asthma in children and adults have not been established, although its use appears to be most effective in patients with COPD with partially reversible airflow obstruction. Tiotropium bromide is a recently developed, long acting, selective, anti-muscarinic medication. This agent is selective for both M1 and M3 receptors. In human bronchi, the drug has a similar inhibitory effect with a slow onset of action with the peak bronchodilator effect observed after 1.5 to 2 hours and a very prolonged effect compared to ipratropium bromide. The effect lasts for 10-15 hours.136,137 The drug has a prolonged inhibitory effect acetylcholine released from postganglionic nerve endings in the airways, probably via an inhibitory effect on M1 receptors. The drug is available as a lactose based powder formulation containing 18 mg of active substance and is used once daily.

Pharmacologic Management of Asthma 151 In certain clinical situations these drugs may be useful bronchodilators for the treatment of bronchial asthma.138 They are recommended for patients who cannot tolerate β-adrenergic agonists because of severe tremor or underlying cardiac disease and for patients with bronchospasm precipitated by β-adrenergic antagonists139 or acetylcholinesterase inhibitors. They can be used in combination with β-agonists. Corticosteroids Glucocorticosteroids are the most potent anti-inflammatory drugs useful in the treatment of bronchial asthma. With the realisation of the role of inflammation as an essential and important component of asthma, their frequent use is justified. Inhaled glucocorticosteroids have revolutionised the treatment of asthma and are highly effective in controlling asthma in all patients.140 Glucocorticosteroids are active against bronchial asthma, mainly through their antiinflammatory effects.141,142 The anti-inflammatory action of corticosteroids is as follows. The hormone penetrates freely into the cell and binds to the receptor forming an inactive complex, which is further activated or transformed to an active complex having an enhanced affinity for DNA forming the nuclear-bound complex. Then it is translocated to the nucleus where it binds to specific sequences (glucocorticoid-responsive element) on the upstream regulatory part of steroid-responsive gene.143 This complex then by binding to regulatory elements associated with certain genes, can activate or inhibit transcription of these genes. The hormone thereby increases or decreases the levels of mRNA and usually of the proteins that the genes encode. These proteins may be enzymes, secretory products, and regulators of various functions including transcription of other genes, which are the primary effectors of hormone actions. The particular genes and proteins regulated by corticosteroids depend on the type of cells. This may increases the production of a substance called lipocortin-1, which inhibits the enzyme phospholipase A2, an enzyme essential for activation of arachidonic acid metabolism. The complex may cause reduced transcription with inhibition of protein synthesis like cytokines. An important effect of steroids in asthma may be the inhibition of synthesis of key cytokines like IL-3, Il-5, and GM-CSF, which play significant role in perpetuating the inflammatory response.144 It is also likely that steroids act on many different cells of the airways. Although they do not reduce the release of mediators from mast cells themselves,145 they lead to a significant reduction in mast cell numbers, possibly due to inhibition of IL-3, which is necessary for mast cell survival in the airways.146 Steroids inhibit release of mediators by macrophages,147 but eosinophils are less responsive.148 But, eosinophil survival is markedly reduced due to blockage of the effect of cytokines like IL-3, Il-5, and GM-CSF.149 Inhaled steroids also reduce markedly the proportion of circulating low-density eosinophils in asthmatic patients through inhibition of IL-5 secretion.150 The other most important effect of steroids is on T lymphocytes where the synthesis of cytokines is reduced. Additional effects directly related to antiinflammatory action include reduced plasma exudation from postcapillary venules in the airways,151 and inhibition of mucus glycoprotein secretion.152 Further, inhaled steroid therapy causes a reduction in bronchial hyperresponsiveness to histamine and the underlying T-cell-dominated inflammation in the bronchial wall.153 Although the molecular mechanisms of the anti-inflammatory action of steroids are better understood,154 the key cellular targets in asthma have not yet been conclusively established. It appears that airway epithelial cells are important target cells and besides the above

152 Bronchial Asthma mentioned mechanisms including the inhibition of expression of cytokines like IL-1, IL-8, regulated on activation normal T-expressed and secreted (RANTES) and GM-CSF, they also inhibit lipid mediators,155 nitric oxide,156 and adhesion molecules.157 They also may inhibit the expression of inducible genes in airway epithelial cells by blocking key transcription factors such as nuclear factor-kappa B and activator protein-1.154 Thus, the important mechanisms of anti-inflammatory action of corticosteroids can be summarised as follows: i. Interference with arachidonic acid metabolism through alteration of lipocortin synthesis and that of the synthesis of leukotrienes, cytokines and prostaglandins. They inhibit the production of IL-1, collagenase, elastase, and plasminogen activator. ii. Prevention of the direct migration and activation of inflammatory cells. Dampening of the recruitment and activation of eosinophils results from their direct effect on these cells as well as upon T-lymphocytes, endothelial cells, and macrophages. Local activation of a variety of cell types including neutrophils, basophils, macrophages and possibly eosinophils by γ-interferon may be blocked by inhibition of this substance from T-lymphocytes by glucocorticoids. iii. Inhibition of cytokine gene transcription and translation leading to inhibition of cytokine secretion and increased intranuclear breakdown of these mediators. iv. Inhibition of cellular response to cytokines, such as increased release of mast cell mediators, expression of adhesion molecules, and prolonged survival of inflammatory cells. v. An acute anti-inflammatory action mediated via inhibition of microvascular leakage. Direct evidence for the anti-inflammatory effect of inhaled steroids is provided by biopsy studies in asthmatic patients. After regularly inhaling steroids over one to three months, bronchial biopsy shows many fewer eosinophils, mast cells, and lymphocytes,146, 153, 158 and in patients with mild inflammation of the airways, there is complete resolution. In biopsies of patients after ten years of inhaled steroids, inflammatory cells disappear completely, although basement membrane thickening may persist.159 Steroids facilitate the action of adrenergic bronchodilators, apparently by altering the ratio of α to β- adrenergic receptors on cell surface.160,161 Oral prednisolone therapy prevents the development of down regulation and subsensitivity of lymphocyte β2-adrenoceptors in subjects given long-term treatment with oral β2-agonists.162 Effects of corticosteroids in asthma patients are considerable.163-168 Treatment with inhaled corticosteroids improves FEV1, peak expiratory flow, and symptoms within weeks. Improvements in airways hyperresponsiveness are slower in onset, and gradual amelioration usually continues up to at least 1 year.164 Exacerbation rates are markedly reduced by treatment with inhaled corticosteroids in asthma.164,167,168 Some studies have even indicated that delayed introduction of inhaled corticosteroids results in an impaired response.169,170 Recent studies on the longterm effect in patients who are treated with terebutaline and beclomethasone dipropionate indicate that the initial improvement in lung function are well preserved over 5 years.171 Inhaled steroids prevent the accelerated decline of FEV1.172 The wide-ranging clinical benefits associated with corticosteroids are shown in Table 10.5. Corticosteroids can be administered parenterally, orally, or as aerosols. Because of the availability of inhaled steroids, there has been less fear now to treat patients with steroids

Pharmacologic Management of Asthma 153 Table 10.5: Clinical benefits of glucocorticosteroids * Improved pulmonary function Diurnal variability in pulmonary function Protection against antigen-induced bronchoconstriction Asthma exacerbation rate Hospital admission rate Asthma mortality rate * Prevention of long-term lung damage and therefore irreversible airflow obstruction The anti-inflammatory effects of glucocorticosteroids are shown in Figure 10.1: Glucocorticosteroids

Eosinophils Mast cells T-Lymphocytes Mucus secretion Plasma exudation Mediator formation

CYTOKINES

β-Adrenoceptors

INFLAMMATION Fig.10.1: Anti-inflammatory effects of glucocorticosteroids

either with a short course therapy or for longer times. It is now clear that the duration and severity of an acute asthma attack can be substantially reduced by therapy with corticosteroids. Early treatment of severe acute exacerbations of asthma with oral corticosteroids prevents progression of the exacerbation, decreases the need for emergency visits and hospitalisation, and reduces the morbidity of the illness. When oral steroids are used to treat acute severe asthma, the onset of action is gradual, occurring approximately 3 hours after administration with peak effectiveness occurring about 6-12 hours after administration. Acute short-term therapy is begun usually with a relatively high dose of 40-80 mg of prednisone daily and can be maintained up to 5-10 days or tapered over the same interval. Therapy with oral steroids should be maintained until peak expiratory flow rates are stable near the best predictable value. The major adverse effects associated with high-dose shortterm systemic therapy are: reversible abnormalities in glucose metabolism, increased appetite, fluid retention, weight gain, rounding of face, mood alteration, hypertension, peptic ulcer, and aseptic necrosis of the femur. In all patients requiring chronic maintenance therapy with steroids, a trial of inhaled steroids, which have minimal systemic side effects, should be attempted to see if oral corticosteroids could be reduced or eliminated. Oral therapy can be continued only if that shows to reduce chronic symptoms substantially or reduce the frequency of severe episodes.

154 Bronchial Asthma Oral steroids should not be used alone without maximising other forms of therapy. Long-term oral steroid therapy is associated with significant side effects such as osteoporosis, hypertension, Cushing’s syndrome, cataracts, myopathy, hypothalamo-pituitary-adrenal axis suppression, and in rare instances, impaired immune mechanisms. Therefore, prolonged use of oral steroids should be reserved for patients with severe asthma despite use of high-dose inhaled corticosteroids. The lowest possible drug dose should be employed including attempts of alternate-day therapy. The drug should be given as a single-morning dose and pulmonary function tests should be used to objectively assess efficacy. Inhaled steroids are safe and effective for the treatment of asthma. They are very effective in controlling the symptoms of asthma and usually achieve rapid control. As a companion drug to β2-agonists, inhaled steroids reduce symptoms, reduce the need for rescue bronchodilators, and improved lung function compared to regular treatment with β2-agonist alone.173 Inhaled steroids inhibit the late response reflecting inflammation to allergen and prevent the increase in airway hyperresponsiveness that follows allergen exposure.174 They also reduce AHR when given regularly, although the reduction takes place slowly over two months or more as the chronically inflamed airway heals slowly.175 When discontinued, symptoms and AHR revert to pretreatment levels.176 In patients with mild asthma treated with inhaled steroids for a long time, there may be long symptom free periods before recurrence.177 In patients with atopic asthma, changes in the bronchial eosinophils and lung function during steroid therapy occur , but independently.178 Some basic principles regarding inhaled corticosteroids include:179,180 • Both efficacy and side effects of aerosol glucocorticoids are dose dependent, and patients vary in their dose requirement. Patients with chronic asthma severe enough to need large oral maintenance doses are unlikely to respond adequately to inhaled treatment alone. • Aerosol treatment is not effective in acute severe asthma. • A part of the inhaled drug is absorbed resembling parenteral injection bypassing liver with reduced hepatic degradation of the active compound and able to produce systemic effects. • Aerosol treatment is more effective if divided into several doses throughout the day. The introduction of beclomethasone dipropionate to asthma therapy in the early 1970’s represented a major advance in asthma management. Various guidelines described subsequently advocate use of inhaled corticosteroids for longer periods of time than previously recommended in patients with mild asthma and at higher doses than previously considered feasible in patients with severe asthma. Inhaled corticosteroids are now gaining widespread acceptance as safe and effective agents for the management of childhood asthma. They are unique among anti-asthma medicines that no other anti-asthma drug currently available share such a wide ranging profile of clinical benefits. An important unresolved question is whether inhaled steroids exert a therapeutic effect on the airways through a systemic action. Since they reduce the number of circulating lowdensity eosinophils, it is suggested that inhaled steroids have an effect in the circulation or in the bone marrow.150 However, this phenomenon can be as a result of local airway effect through inhibition of synthesis of the eosinophil-stimulating cytokine IL-5 and RANTES. Studies in dogs have suggested that inhaled steroids affect the production of leucocyte progenitors in the bone marrow, but it is not clear whether this results from affecting the synthesis of some stimulatory factor in the airways or from the action of the systemically

Pharmacologic Management of Asthma 155 absorbed fraction of the inhaled steroid on the bone marrow.181 It is also uncertain whether steroids deposited in the proximal airways can be distributed via the airway circulation to the more distal airways. The inflammation of asthma affects the whole of the bronchial tree, from the large central airways down to the small peripheral airways.182,183 Steroid receptors, the site of action of inhaled corticosteroid therapy, are likewise located through out the bronchial tree.184 Various inhaled steroids available for clinical use include Beclomethasone dipropionate, betamethasone valerate, Budesonide, Flunisolide, Triamcinolone acetonide, Fluticasone propionate, Mometasone furoate, and Ciclesonide.185-189 Beclomethasone is the first inhaler steroid available nearly for the past 30 years and is used widely. The dose varies from < 400 μg per day to as high as 1600 μg depending upon the severity of bronchial asthma. Budesonide is a glucocorticoid aerosol with high ratio between topical and systemic corticosteroid effects.190,191 The drug is usually administered in a dose of 200-400 μg twice daily. Fluticasone propionate introduced in the 1990s, is one of the most potent inhaled steroids currently available, and is developed from the androstane 17 β-carboxylic acid and is a highly potent, selective anti-inflammatory steroid which binds with a high affinity to the glucocorticoid receptor of the human lung (18 times that of dexamethasone and 3 times that of budesonide). It has greater airway selectivity, rapid fast-pass metabolism (so less systemic side effects, and increased uptake and retention in the lungs as a result of its high lipophilicity. It is approximately 2-fold more potent than beclomethasone dipropionate and 4-fold more potent than budesonide.192 500 μg b.d. Fluticasone propionate is at least as effective as beclomethasone dipropionate 1000 μg b.d.193 Estimated clinical comparability of doses for inhaled corticosteroids are shown in Table 10.6. It is estimated that beclomethasone and budesonide achieve comparable effects at similar microgram doses by MDI. Beclomethasone has similar effects to twice the dose of triamcenoline acetonide on a microgram basis. However, fluticasone has effects similar to twice the dose of budesonide and beclomethasone when given via MDI in a microgram basis. Budesonide given by a Turbuhaler has effects similar to twice the dose delivered by MDI, implying greater bronchial delivery by the delivery device. These observations are made on the basis of clinical trials comparing effects in reducing symptoms and improving PEFR. The potency of a glucocorticosteroid is described by its receptor affinity and intrinsic activity. For all therapeutically used corticosteroids in asthma, the intrinsic activity directly corresponds to the receptor affinity, which is a compound-specific property. If the receptor activity of a corticosteroid is determined under standardised conditions (usually with dexamethasone as reference), the relative receptor affinity can be calculated and compared with other corticosteroids. The same is shown in Table 10.7.194 Table 10.6: Comparison of potency of inhaled corticosteroids

Drug Beclomethasone Budesonide Flunisolide Fluticasone Triamcinolone

Topical potency (skin blanching) 600 980 330 1,200 330

Corticosteroid receptor binding half-life (hrs) 7.5 5.1 3.5 10.5 3.9

Receptor binding affinity 13.5 9.4 1.8 18.0 3.6

156 Bronchial Asthma Table 10.7: Pharmacokinetic basis for evaluation of efficacy and safety of inhaled glucocorticosteroids

Glucocorticoid

Activation in the lung

Beclomethasone dipropionate Flunisolide Triamcinolone acetonide Budesonide Fluticasone propionate Mometasone furoate Ciclesonide

Relative receptor activity

Lung tissue affinity Oral bioavailability (%)

Expected theoretical therapeutic ratio

+

1345

High

41

Intermediate

– –

180 361

Low Low

20 23

Less favourable Less favourable

– –

935 1800

Medium/low High

11 <1

Intermediate Favourable

– +

1235* 1200

High High

<1 <1

Favourable Favourable

Receptor affinity are calculated with respect to dexamethasone as reference compound except * , which is based on that for fluticasone dipropionate 813.

Side Effects Although inhaled glucocorticoids have revolutionised the treatment of asthma being the most commonly and widely used anti-inflammatory drug treatment, which is highly effective in controlling asthma in all patients,140 concern has been expressed about their local and systemic side effects.195 The important local side effects of inhaled steroids are throat irritation, oropharyngeal candidiasis and dysphonia (huskiness) and only a minority of patients develop these complications (<5%). However, dysphonia is commonly seen (in more than 50%) if patients are given high-dose therapy. All these complications are caused by the active drug and not by the propellant and are clearly related to the daily dose, although other co-determinants are important. Dysphonia is common, whereas laryngeal thrush is extremely rare. The two are not causally related. The primary cause of husky voice is a steroid-induced dyskinesia of the voluntary musculature that control vocal cord tension. This can be alleviated by any thing that reduces the deposition of the drug around the larynx. These measures include reduction of the daily dose, slowing the speed of inhalation and/or by using a spacer, a longer post-inspiratory breath hold to reduce drug deposition during exhalation, and mouth rinsing immediately after inhaling the drug.196,197 The problem is more common, severe, and persistent in patients who use their voice maximum like preachers, teachers, singers, switch board operators, sports coaches or employees in a noisy work place. Compulsive throat clearing and hypothyroidism aggravates and perpetuates the huskiness. Voice rest may improve the condition in these patients. Candidiasis and thrush depend upon the frequency of dosing and the concomitant use of antibiotics and/or oral steroids. The Candida overgrowth occurs due to the inhibitory effect of the drug on the normal host defense functions of neutrophils, macrophages, and T-lymphocytes at the oral mucosal surface. A 12-hour interval between doses appears sufficient to allow temporary recovery of these functions and to prevent this complication. Spacers also markedly reduce the incidence of this complication. Other rare local complications include esophageal candidiasis; painful

Pharmacologic Management of Asthma 157 and protracted atrophic glossitis; chronic oesophagitis resulting from combined Candidaherpes simplex infection; reflex cough and bronchospasm; and nonspecific symptoms including nausea, headache, dry throat, gas, pruritus, rash, impaired taste or smell, abdominal pain, diarrhoea, constipation, and heartburn. Systemic bioavailability varies with the preparation selected. The systemic activity of any particular dose in different patients and patient groups depends largely on the fraction of the emitted dose that reaches the important absorptive surface in the lung periphery. This fraction is determined by the interaction of numerous factors, including variations in normal lung anatomy, the degree of pulmonary function impairment and presence or absence of associated chronic bronchitis, each of which reduces peripheral delivery of the inhaled drug, and in particular, by the inspiratory techniques used. There is some fear of systemic effects because of oral, gastrointestinal, and pulmonary absorption of the drugs.140,198 However, they are infrequent. Approximately 80% of an inhaled corticosteroid dose will be deposited in the mouth and subsequently swallowed, thus giving the potential for systemic adverse events during long-term therapy. This can be reduced by using a largevolume spacer and mouth rinsing or other steroid sparing agents like cromolyn sodium. Side effects can also be reduced by choosing a steroid such as budesonide or fluticasone propionate that undergoes extensive first-pass hepatic metabolism, allowing little of the drug to enter the systemic circulation. Then, the only source of systemic absorption will be from the fraction absorbed from lung deposits. The side effects may include bone and skin thinning, easy bruising, cataract formation, inhibition of longitudinal bone growth in children and suppression of adrenocortical function. Clinically significant adrenal suppression and altered bone metabolism are rare below 800 μg/day,199-201 but a minimum daily dose should be sought once clinical response has been achieved. Very large doses of inhaled drugs may cross the placental barrier as shown in experimental animals. Because of the importance of airway inflammation in the pathogenesis of asthma, inhaled corticosteroids are being used more frequently as primary therapy for moderate and severe asthma. This approach not only provides symptomatic benefit but also reduces airway hyperresponsiveness. CROMONES (CROMOLYN SODIUM AND NEDOCROMIL SODIUM) Cromolyn Sodium Cromolyn sodium is the best nonsteroidal anti-inflammatory drug for asthma available currently.202,203 This drug has been available for 35 years. When administered prophylactically, Cromolyn sodium inhibits early- and late phase allergen-induced airway narrowing and acute airway narrowing after exercise (less than inhaled adrenergic agents), exposure to cold dry air, and sulphur dioxide. They are also effective in controlling symptoms in patients with mild asthma.204 There is no way to predict reliably whether a patient will respond to Cromolyn sodium. A 4-6 week trial may be required to determine efficacy in individual patients. The drug is available in a capsule form (5 mg) taken as an inhaler as well as metered dose inhaler and even as a nebuliser solution. It controls the symptoms of bronchoial asthma and bronchial hyperresponsiveness and reduces the number of acute exacerbations with an acceptable safety profile.205-207 Cromolyn sodium produces only minimal side effects, such as occasional coughing upon inhalation of the powder formulation.

158 Bronchial Asthma Nedocromil Sodium This is a pyranoquinoline derivative and is shown to inhibit mediator release prophylactically in a variety of in vitro systems.208 It also inhibits allergen-induced acute and late-phase asthmatic reactions and modulates allergen-induced increases in bronchial hyperresponsiveness. It also reduces the acute airway narrowing response to exercise, hyperventilation, mist, and sulphur dioxide. Various clinical trials have proved that longterm therapy reduces nonspecific airway reactivity in atopic and nonatopic asthmatics. In clinical trials the drug has been used in a dose of 4 mg four times a day with most beneficial therapeutic effects. Therapy with nedocromil is not associated with any significant adverse effects. The drug, however, is not yet used extensively in clinical practice. Although the exact mechanism of action of cromones as anti-inflammatory drugs is not clear, it is believed that the drugs stabilise and prevent mediator release from mast cells.209-213 The drugs are also likely to affect several other inflammatory cells including sensory nerves.204,208 However, another study has found no evidence of a decrease of inflammatory cells after treatment with cromones.214 Other studies suggest that cromones may block swelling-dependent chloride channels.215 Additional chloride channels in mast cells, sensory nerves, and epithelial cells may be important. Advantages of cromones are that they control symptoms of asthma and effectively block bronchoconstriction induced by a number of agents and factors. Both drugs are safe and have no significant side effects.216 One study has found that nedocromil has steroid sparing effects but other studies have not confirmed this. The disadvantage of cromones are that they are weak anti-inflammatory drugs compared to inhaled steroids, and more costly. They appear to work best in patients with mild asthma, but not always. It is difficult to predict which patients will respond. Recent studies have shown that cromones may be most beneficial for patients whose predominant symptom is coughing. They may be considered as the first line therapy in children and as a prophylactic agent against allergen-induced asthma. The other disadvantage of these drugs is their short action, and therefore they are to be used four times a day which is an inconvenient regimen for long-term prophylaxis. Ketotifen Ketotifen is an orally active, prophylactic drug used in many countries in the management of asthma.217,218 Originally it was thought that the drug is a mast cell stabiliser that has the additional property of being a potent H1-receptor antagonist. Large double-blind, placebocontrolled trials have proved the efficacy of the drug in the prophylaxis of asthma particularly in children. Recent data suggests that the ability of the drug to act as a prophylactic agent is not related to its mast cell stabilising effect nor the H1-receptor antagonistic properties. The drug like many other prophylactic antiasthma drugs, inhibits PAF-induced eosinophil infiltration and bronchial hyperresponsiveness. The drug is most effective in mild asthma and require at least 4-12 weeks to show any clinically significant effect. It is given in a dose of 2-4 mg twice daily and this dose is roughly equivalent to 4 puffs of Cromolyn sodium. The major advantage of ketotifen over other prophylactic drugs is that it can be used orally. The major side effect of the drug is sedation.

Pharmacologic Management of Asthma 159 Antihistamines With the development of new classes of nonsedating antihistamines, there has been renewed interest in their use.219,220 The rationale for their use was that subjects with asthma demonstrate hyperresponsiveness airways to histamine and require only small quantities of this mediator to demonstrate changes in their pulmonary functions. These agents block the acute bronchoconstricting effect produced by inhaled histamine, but not that produced by methacholine. They have also bronchodilating action. The newer antihistamines also inhibit mediator release from in vitro cell systems. Clinical trials have shown their superiority over placebo in grass and pollen induced asthma. Most of these drugs (terfenadine, astemizole, azelastine and cetirizine) moderately inhibit the early asthmatic response. Only terfenadine inhibits exercise induced asthma. The drug also has some calcium channel blocking properties. Although some studies with H1 antihistamines in asthma have demonstrated some therapeutic benefits, their role and usefulness in treatment of asthma require additional studies and they are not recommended as anti-asthma drugs. Leukotriene Antagonists and Synthesis Inhibitors Cysteinyl leukotrienes (LT) play a significant part in the pathogenesis of bronchial asthma as discussed earlier.221-238 These leukotrienes are produced and released from proinflammatory cells, including eosinophils and mast cells, and are at least 1000 times more potent bronchoconstrictors than histamine or methacholine in normal subjects and patients with bronchial asthma. They mediate many of the pathophysiologic processes associated with asthma including microvascular leakage, bronchoconstriction and eosinophil recruitment into the airways. Since the structure of leukotrienes was described in 1979 ,239 attempts were made to modulate their pharmacological actions so that they can be of some clinical use by the way of blocking the leukotriene receptors or inhibition of their synthesis. The therapeutic strategies were i. Dietary provision of alternative fatty acid substrates within membrane phospholipids which will products with less proinflammatory activity,240 but the attempt was unsuccessful;241 ii. Pharmacological inhibition of specific enzymes, particularly 5-lipoxyenase; and iii. Modulation of end organ effects with selective cysteinyl leukotriene receptor antagonists.221,238 Generally four classes of drugs are currently under development and some of them are available for clinical use as anti-asthma or anti-inflammatory therapy, which interferes with LT synthesis or activity. They are depicted in Table 10.8 and Figure 10.2.242 Although a number of the above compounds were tried initially, only a few could be used clinically in human beings because of safety factors.243 Zafirlukast is active both orally and when administered by inhalation and is the most potent oral cysteinyl LT antagonist.244 Pranlukast, another orally active drug is marked in Japan in the mid-1995.245, 246 These drugs are at least 200 times more than the early LT antagonists and they cause a shift up to 100-fold in the bronchoconstrictor dose-response curve. They are very active in preventing bronchoconstriction induced by agonists both in healthy and asthmatic individuals. They also reduce bronchoconstriction induced by several natural triggers of asthma including exercise, cold air, allergen and aspirin. A single 20 mg oral dose of zafirlukast produces marked protection against exercise-induced bronchoconstriction with the maximum effect

160 Bronchial Asthma Table 10.8: The anti-leukotriene group of drugs

Name Leukotriene D4 antagonists Zafirlukast Probilukast Pranlukast Tomelukast Verlukast 5-Lipoxygenase inhibitors Zileuton FLAP Inhibitors

Compound ICI-204.219 SK and F 104353-Q ONO-1078 LY 171883 MK-679,-476,-571 A-64077, ABT-761, Z-D2138 MK-886, MK-0591, BAYx1005

Fig.10.2: The four groups of drugs directed against leukotriene synthesis and activity. Thick arrows shows sites of action that finally prevents the final pathophysiological activity

being observed 5-30 minutes after stimulation.247 400 μg of the drug inhaled also produced a similar degree of protection.248 In aspirin-induced asthma, where there is an increased production of cysteinyl LTs, the LT-antagonists improve lung function and inhibit bronchoconstriction induced by aspirin.249,250 Zafirlukast and pranlukast are well tolerated in clinical trials. Efficacy of objective and subjective measures in patients with symptoms are dose related and the greater response are achieved with 40 mg total dose of zafirlukast. Compared with placebo, significant improvement occurs in evening peak flow, a 30% reduction in rescue use of inhaled β2-agonists, a 46% reduction in night waking, and a 26% improvement in morning asthma and daily symptoms are observed.251 Doses up to 80 mg

Pharmacologic Management of Asthma 161 twice daily have been given to patients with beneficial effects increasing still further at the higher doses.252 Besides being effective in preventing bronchoconstriction due to various triggers, these drugs also affect eosinophil reflux, microvascular permeability, proliferation of airway smooth muscle cells in chronic severe asthma, mucus secretion, mucociliary transport, and interaction with nerves. The reported side effects of these drugs are: headache, dry mouth, and somnolence.251,253-255 The 5-lipoxygenase inhibitor zileuton is the best studied drug.256 Oral zyleuton in a dose of 800 mg inhibits the early response to allergen challenge and reduced LT synthesis. It also prevents the response to cold air challenge and to aspirin in aspirin-induced asthma. It also increases the FEV1. The drug is as effective as theophylline in moderate asthma. It helps in reducing the symptoms of asthma, β-agonist use, and inhaled steroid doses can also be reduced. The drug also has a steroid-sparing effect in severe asthma. The only disadvantage of zileuton is its relatively low potency and short half-life (2.5 hours). Therefore, dosing is to be made four times a day. Even if the drug appears to be safe in clinical trials, this is an antioxidant and potentially can interfere with redox reactions in other metalloenzymes. Of the above mentioned drugs, four oral antileukotriene drugs are now available for the treatment of asthma: monteleukast, zafirleukast, and pranleukast, and the 5-lipoxygenase inhibitor, zyluton. Clinical studies have shown improvement in FEV1, improvement in daytime and nocturnal asthma symptom scores, and reduction in reliever β2-agonist use in patients with patients treated with leukotriene antagonists.257,258 For this reason, recent asthma guidelines have recommended that antileukotrienes have a role in the management of bronchial asthma (see below). However, not all patients will show a significant clinical improvement. No factor has been identified to predict such a response except that cysteinyl leukotrienes release from leukocytes is correlated with leukotriene receptor antagonist response.259 In summary, while cysteinyl leukotrienes are important pro-inflammatory and bronchoconstrictor mediators in the pathogenesis of asthma, leukotriene receptor antagonists demonstrate hybrid anti-inflammatory and bronchodilatory properties.260 A meta-analysis found that these agents reduced exacerbations by 50% and reduced the requirement of additional asthma therapy.261 Another meta-analysis from 13 trials showed weighted estimated protection of leukotriene receptor antagonists amounted to a 0.85 doubling dose shift, thus the estimated protection amounted to almost one doubling dose reinforcing the role of these agents as anti-inflammatory therapy in asthma.262 Current International Guidelines recommend using an leukotriene receptor antagonist as first-line therapy in patients with mild, persistent asthma, or as second-line therapy in conjunction with inhaled corticosteroids, as an alternative to increasing the dose of inhaled corticosteroid. Further, leukotriene-receptor antagonists confers significant additive pro-inflammatory effects to therapy with a low-dose inhaled corticosteroid.263 Alternative Treatment for Oral Steroid Dependence Approximately 10% of patients with asthma have severe disease and require high doses of inhaled or oral glucocorticoids. Some of these patients may have more severe disease because of relative resistance to the effect of glucocorticoids.264 Although this group may constitute a very small proportion of the total cases, they consume more than 50% of the resources. They require more frequent medical attention, need more expensive drugs, more often hospitalised,

162 Bronchial Asthma and miss more time for work or school than patients with milder form of the disease. Treatment of patients with severe, persistent asthma who require high doses of systemic steroids presents a therapeutic challenge. Such high doses of steroids for longer periods of time have multiple systemic side effects. Several modalities of therapeutic regimens have been advocated/tried to help reduce oral steroid dependence in severe asthma. Some of these approaches are still experimental and should be used only in specialised centers. Before labelling someone having steroid resistance preventable factors need to be considered. These include poor compliance, occupational factors, gastro-oesophageal reflux, specific antigens, and dietary factors. Anxiety about asthma deaths might lead to overuse of steroids. Superimposed psychosocial factors and hyperventilation syndrome may cause further problem. Some patients are truly corticosteroid resistant, i.e. shows response to bronchodilators but none to corticosteroids.265,266 These patients should not be prescribed corticosteroids. Some patients having severe asthma and who show some response to steroids should not be labelled as steroid resistant cases, but as severe asthma only. Before attempting any of the following experimental drugs, a trial of high doses of inhaled corticosteroids (2 to 4 times the usual doses) is essential. This approach has the lowest incidence of adverse effects and has a high likelihood of clinical efficacy. In the steroid dependent asthma, a patient, treatment with high-dose inhaled corticosteroids should be maintained over a period of several weeks to months, and the dose of oral steroids should be reduced slowly while monitoring pulmonary function. This approach is often helpful. Various drugs have been proposed as alternatives to systemic steroids, including troleandomycin, gold, azathioprine, methotrexate, and cyclosporine, intravenous immunoglobulins, hydroxychloroquine, dapsone, inhaled frusemide, and intravenous magnesium sulphate. 267-270 Since asthmatic inflammation may be regulated by Th2 lymphocytes, some of these drugs which are immunosuppressive, act due to their action of inhibition of T-lymphocytes. Methotrexate is an antimetabolite which antagonizes folic acid by inhibiting dihydrofolate reductase. This interferes with thymidine synthesis and thus blocks DNA synthesis and cell division. At higher doses, it is an antineoplastic agent and in low doses (5-25 mg/ week) it acts as an anti-inflammatory and immuno-suppressive agent. The mechanism of action as an anti-inflammatory drug include inhibition of histamine release from basophils, inhibition of cytokine release (IL-1) from mononuclear cells, and reduction of neutrophil chemotaxis.271-273 Although some clinical trials have shown benefit from low dose methotrexate, (15 mg/wk) others do not support this.273-279 The drug is also found useful in children.280,281 There is significant reduction in steroid doses, when methotrexate is added in addition to subjective improvement. The common side effects are nausea, vomiting, hepatic dysfunction, alopecia, oral ulcers, and neutropenia. In spite of the controversy and confusion, the following provisional conclusion may be made from available literature: i. Methotrexate may be a steroid agent in some steroid-dependent patients; ii. No predictive factor could be found about the responders; iii. No consistent effect on airflow or bronchial responsiveness is expected; iv. To have an appreciable effect, the treatment may be continued for long periods (> 3 months) and unlikely to occur after 1 year; v. Steroid-sparing effect disappears on discontinuation of methotrexate; vi. Doses more than 15 mg/wk may have unacceptable side effects;

Pharmacologic Management of Asthma 163 vii. Steroid weaning should be done before methotrexate trial; and viii. The drug should be viewed as a risky preposition in comparison to long-term oral steroid therapy.282 Cyclosporin A is a fungal cyclic polypetide used mostly for transplant patients. It inhibits the activation of T lymphocytes and the synthesis and release of lymphokines like IL-2, IL-3, Il-4, IL-5, and TNF (tumor necrosis factor). It also inhibits histamine and LTC4 release from mast cells and basophils and inhibits neutrophil chemotaxis, monocytes-macrophages.283 Use of cyclosporin has shown some result.284,285 Hypertrichosis, hypertension, parasthesia, tremour, headache, and flue-like symptoms are some of the side effects of cyclosporin treatment. Cyclosporin appears to be a promising drug in the treatment of steroid-dependent bronchial asthma. Gold salts (auranofin) has anti-inflammatory properties and are commonly used for the treatment of rheumatoid arthritis. The drug has been shown to inhibit IgE-mediated release of histamine and LTC4 from basophils and mast cells.286 It also inhibits tracheal smooth muscle contraction in response to histamine and specific antigens in guinea pigs.287 Oral auranofin 3 mg twice daily has been found useful.288,289 Mucocutaneous reactions are the common side effects of gold therapy. Other agents like azathioprine,290 intravenous immunoglobulin,291 troleandomycin,292 colchicine,293,294 and hydroxychloroquine295 have been suggested to be alternatives in steroiddependent asthma. But the experience in clinical practice is not much, and they are not recommended for the routine use in these patients. REFERENCES 1. Weinberger M. The pharmacology and therapeutic use of theophylline. J Allergy Clin Immunol 1984;73:525. 2. Arkinstall WW. The role of theophyllines in a preventive approach for subjects with both mild and severe asthma. Postgrad Med J 1991;67(Suppl 4):S25. 3. Isles A, MacLeod SM, Levison H. Theophylline. New thoughts about an old drug. Chest 1982;82(Suppl):49S-54S. 4. Barnes PJ, Pauwels RA. Theophylline in the management of asthma: Time for reappraisal? Eur Respir J 1994;7:579-91. 5. Beavo JA, Reifsynder DH. Primary sequence of cyclic nucleotide phosphodiesterase isoenzymes and the design of selective inhibitors. Trends Pharmacol Sci 1990;11:150-55. 6. Nicholson CD, Challiss RAJ, Shahid M. Differential modulation of tissue function and therapeutic potential of selective inhibitors of cyclic nucleotide phosphodiesterase isoenzymes. Trends Pharmacol Sci 1991;12:19-27. 7. Trophy TJ, Undern RJ. Phosphodiesterase inhibitors; new opportunities for the treatment of asthma. Thorax 1991;46:499-503. 8. Giembycz MA. Could selective cyclic nucleotide phosphodiestrase inhibitors render bronchodilator therapy redundant in the treatment of bronchial asthma? Biochem Pharmacol 1992;43:2041-51. 9. Bergstrand H. Phosphodiesterase inhibition and theophylline. Eur J Respir Dis 1980;61(Suppl 109):37-44. 10. Polson JB, Kazanowski JJ, Goldman AL, Szentivanyl A. inhibition of human pulmonary phosphodiesterase activity by therapeutic levels of theophylline. Clin Exp Pharmacol Physiol 1978;5:535-39.

164 Bronchial Asthma 11. Kuehl FA, Zanetti ME, Soderman DD, Miller DK, Ham EA. Cyclic AMP-dependent regulation of lipid mediators in white cells. A unifying concept of explaining the efficacy of theophylline in asthma. Am Rev Respir Dis 1987;136:210-13. 12. Estenne M, Yernault J, de Troyer A. Effect of parenteral aminophylline on lung mechanics in normal humans. Am Rev Respir Dis 1980;121:967-71. 13. Cushley MJ, Tattersfield AE, Holgate ST. Adenoine-induced bronchoconstriction in asthma; antagonism by inhaled theophylline. Am Rev Respir Dis 1984;129:380-84. 14. Bjork T, Gustafsson LE, Dahlen SE. Isolated bronchi from asthmatics are hyperresponsive to adenosine, which apparently acts indirectly by liberation of leukotrienes and histamine. Am Rev Respir Dis 1992;145:1087-91. 15. Mann JS, Holgate ST. Specific antagonism of adenosine induced bronchoconstriction in asthma by oral theophylline. Br J Clin Pharmacol 1985;19:85-92. 16. Fredholm BB, Persson CGA. Xanthine derivatives as adenosine receptor antagonists. Eur J Pharmacol 1982;81:673-76. 17. Higbee MD, Kumar M, Galant SP. Stimulation of endogenous catecholamine release by theophylline, a proposed additional mechanism of theophylline effects. J Allergy Clin Immunol 1982;70:377-82. 18. Ishizaki T, Minegishi A, Morishita A et al. Plasma catecholamine concentration during a 72-hour aminophylline infusion in children with acute asthma. J Allergy Clin Immunol 1988;92: 146-54. 19. Jenne JW. Two roles for theophylline in the asthmatics? J Asthma 1995;32:89-95. 20. Cresioli S, Spinazzi A, Plebani M et al. Theophylline inhibits early and late asthmatic reaction induced by allergens in asthmatic subjects. Ann Allergy 1991;66:245-51. 21. Cresioli S, de Marzo N, Boschetto P et al. Theophylline inhibits late asthmatic reactions induced by toluene diisocyanate in sensitised subjects. Eur J Pharmacol Environ Toxicol 1992;228:45-50. 22. Erjefalt I, Persson CGA. Pharmacologic control of plasma exudation into tracheobronchial airways. Am Rev Respir Dis 1991;143:1008-14. 23. Decramer M, Deschepper K, Jiang T, Derom E. Effects of aminophylline on respiratory muscle interaction. Am Rev Respir Dis 1991;144:797. 24. Kolbeck RC, Spier WA, Carrier GO, Bransome ED. Apparent irrelevance of cyclic nucleotides to the relaxation of tracheal smooth muscle induced by theophylline. Lung 1979;156:173-83. 25. Bowler SD, Mitchell CA, Armstrong JG. Nebulised fenoterol and IV aminophylline in acute severe asthma. Eur J Respir Dis 1987;70:280-83. 26. Wrenn K, Slovis CM, Murphy F, Greenberg RS. Aminophylline therapy for acute bronchspastic disease in the emergency room. Ann Intern Med 1991;115:241-47. 27. Eason J, Makowe HLJ. Aminophylline toxicity: How many hospital deaths does it cause? Resp Med 1989;83:219-26. 28. Lam A, Newhouse MT. Management of asthma and chronic airflow limitation. Are methylxanthines obsolete? Chest 1990;98:44-52. 29. Trigg CJ, Davies RJ. Use of slow-release theophylline in asthma: It is justified? Respir Med 1990;84:1-3. 30. Marks MB. Theophylline: Primary or tertiary drug? A brief review. Ann Allergy 1987;59:85-89. 31. Mitenko PA, Ogilvie RI. Rational intravenous doses of theophylline. N Engl J Med 1973;289:60003. 32. Fittar G, Friedman HS. The arrhythmogenicity of theophylline. A multivariate analysis of clinical determinants. Chest 1991;99:1415. 33. Furukawa CT, Sapiro CG, Duhamel T et al. Learning and behavioural problems associated with theophylline therapy. Lancet 1985;1:621. 34. Furukawa CT, Duhamel T, Weimer L et al. Cognitive and behavioural findings in children taking theophylline. J Allergy Clin Immunol 1988;81:83-85.

Pharmacologic Management of Asthma 165 35. Rachelefsky WOJ, Adelson J, Mickey MR et al. Behavioural abnormalities and poor school performance due to oral theophylline use. Paediatrics 1986;78:1113-38. 36. Lindgren S, Loksin B, Stromquist A et al. Does asthma or treatment with theophylline limit children’s academic performance. N Engl J Med 1992;327:926-30. 37. Persson CGA. Development of safer xanthine drugs for the treatment of obstructive airway disease. J Allergy Clin Immunol 1986;78:817-24. 38. Chapman KR, Bryant D, Marlin GE et al. A placebo-controlled dose-response study of enprofylline in the maintenance therapy of asthma. Am Rev Respir Dis 1989;139:688-93. 39. Weinberger M. The pharmacology and therapeutic use of theophylline. J Allergy Clin Immunol 1984;73:525-40. 40. Weinberger M., Hendeles l. Sloe-release theophylline: Rationale and basis for product selection. N Engl J Med 1983;308:760-764. 41. Hendeles L, Weinberger M. Theophylline: A state of the art review. Pharmacotherapy 1983;3: 2-44. 42. Shenfield GM, Brogaden RN, Ward A. Pharmacology of bronchodilators. In: Bronchodilator therapy: The basis of asthma and chronic obstructive airways management., Cochrane GM Ed: ADIS Press Limited, Auckland, NZ, 1984. 43. Fraser CM, Potter PC, Venter JC, Nelson HS, Middleton E: Adrenergic agents. In: Middleton E et al, (Eds). Allergy: Principles and Preactice, Vol I, CV Mosby Company, St.louis,1988. 44. Szentivanyi A, Krzanowski JJ, Polson JB: The autonomic nervous system. In: Middleton E et al, (Eds). Allergy: Principles and Practice, Vol I, CV Mosby Company, St.louis,1988. 45. Holtzmzn MJ: Pathophysiology in asthma: An overview of mechanisms of bronchial hyperreactivity. In: Morley J (Eds). Bronchial hyperreactivity (Perspectives in asthma;1), Academic Press, London,1982. 46. Rang HP. Drug receptors. University Park Press, Baltimore, 1973. 47. Cooke BA: β−adrenoceptor-adenylate cyclase: Basic mechanisms of control. In: Morley J (Eds). Β-adrenoceptors in asthma (Perspectives in asthma;2), Academic Press London,1982. 48. Kume H, Graziano MP, Kotokoff MI. Stimulatory and inhibitory regulation of calcium-activated potassium channels by guanine nucleotide binding proteins. Proc Natl Acad Sci USA 1992;89:11051-55. 49. Jones TR, Charette L, Gracia ML, Kaczorowski GJ. Selective inhibition of relaxation of guinea-pig trachea by charybodotoxin, a potent Ca++-activated K+ channel inhibitor. J Pharmacol Exp Ther 1990;225:697-706. 50. Miura M, Belvisi MG, Stretton CD, Yacoub MH, Barnes PJ. Role of potassium channels in bronchodilator response in human airways. Am Rev Respir Dis 1992;146:132-36. 51. Jones TR, Charette L, Gracia ML, Kaczorowski GJ. Interaction of iberiotoxin with β−adrenoceptor agonists and sodium nitroprusside on guinea-pig trachea. J Appl Physio 1993;74:1879-84. 52. Rees J. β−2 agonists and asthma. Still the main stay of symptomatic treatment. Br Med J 1991;302:1166. 53. Meltzer DL, Kemp JP. β2-agonists: Pharmacology and recent developments. J Asthma 1991;28:17986. 54. Erjefalt I, Persson GA. Long duration and high potency of anti-exudative effects of fermoterol in Guinea-pig tracheobronchial airways. Am Rev Respir Dis 1991;144:788. 55. Kesten S, Chapman KR, Broder I et al. A three-month comparison of twice daily inhaled formoterol versus four times daily inhaled albuterol in the management of stable asthma. Am Rev Respir Dis 1991;144:622. 56. Gongora HC, Wisniewski AFZ, Tattersfield AE. A single dose comparison of inhaled albuterol and two formulations of salmeterol on airway reactivity in asthmatic subjects. Am Rev Respir Dis 1991;144:626. 57. Janson C. Plasma levels and effects of salbutamol after inhaled or IV administration in stable asthma. Eur Respir J 1991;4:544.

166 Bronchial Asthma 58. Tinkelman DG, Berkowitz RB, Cole WQ III. Aerosols in the treatment of asthma. J Asthma 1991;28:243. 59. Woolcock AJ. Inhaled drugs in the prevention of asthma. Am Rev Respir Dis 1977;115:191. 60. Maesen FP, Costongs R, Smeetys JJ, Brobacher BJ, Zweers PGMA. The effect of maximal doses of fermoterol from a metered dose inhaler on pulse rates, ECG, and serum potassium concentrations. Chest 1991;99:1367. 61. Haahtela T, Jarvinen M, Kava T et al. Comparison of a β2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med 1991;325-88. 62. Nelson HS, Szefler S, Martin RJ. Regular inhaled β−adrenergic agonists in the treatment of bronchial asthma: Beneficial or detrimental? Am Rev Respir Dis 1991;144-249. 63. Carstairs JR, Nimmo AJ, Barnes PJ. Autoradiographic visualisation of β-adrenoceptor subtypes in human lung. Am Rev Respir Dis 1985;132:541-47. 64. Hamid QA, Mak JC, Sheppard MN et al. Localisation of β2-adrenoceptor messenger RNA in human and rat lung using in situ hybridisation: Correlation with receptor autoradiography. Eur J Pharmacol 1991;206:133-38. 65. Barnes PJ. β−adrenergic receptors and their regulation. Am J Respir Crit Care Med 1995;152: 838-60. 66. Butchers PR, Skidmore IF, Vardey CJ et al. Characterisation of the receptor mediating antianaphylactic effects of β-adrenoceptor agonists in human lung tissues in vitro. Br J Pharmacol 1980;71:663-67. 67. Devalia JL, Sapsford RJ, Rusznak C et al. The effects of salmeterol and salbutamol on cilliary beat frequency of cultured human bronchial epithelial cells in vitro. Pulm Pharmacol 1992;5: 257-63. 68. Boulet LP. Long versus short-acting β2-agonists. Drug 1994;47:207-22. 69. Rossi A, Kristufek P, Levine BE et al. Comparison of the efficacy, tolerability, and safety of formoterol dry powder and oral, slow-release theophylline in the treatment of COPD. Chest 2002;121:1058-69. 70. Moore RH, Khan A, Dickey BF. Long-acting inhaled β2-agonists in asthma therapy. Chest 1998;113:1095-1108. 71. Jeppsson AB, Kallstrom BL, Waldeck B. Studies on the interaction between formoterol and salmeterol in guinea pig trachea in vitro. Pharmacol Toxicol 1992;71:272-77. 72. Derom EY, Pauwels RA, Van der Straeten ME. The effect of inhaled salmeterol on methacholine responsiveness in subjects with asthma up to 12 hours. J Allergy Clin Immunol 1992;89:811-15. 73. Derom EY, Pauwels RA. Time course of bronchodilating effect of inhaled formoterol, a potent and long acting sympathomimetic. Thorax 1992;47:30-33. 74. Ramsdale EH, Otis J, Kline PA et al. Prolonged protection against methacholine induced bronchoconstriction by the inhaled β2-agonist formoterol. Am Rev Respir Dis 1991;143:998-1001. 75. Dahl R, Earnshaw JS, Palmer JBD. Salmeterol: A four week study of a long acting β-adrenoceptor agonist for the treatment of reversible airway disease. Eur Respir J 1991;4:1178-84. 76. Midgren B, Melander B, Persson G. Formoterol, a new long acting β2-agonist, inhaled twice daily, in stable asthmatic subjects. Chest 1992;101:1019-22. 77. Ulman A, Hedner J, Svedmyr N. Inhaled salmeterol and salbutamol in asthmatic patients: An evaluation of asthma symptoms and the possible development of tachyphylaxis. Am Rev Respir Dis 1990;142:571-75. 78. Campbell LM, Anderson TJ, Paraschak MR et al. A comparison of the efficacy of long-acting β2agonists: Eformoterol via Turbohaler and salmeterol via pressurised metered dose inhaler or Accuhaler, in mild to moderate asthmatics. Respir Med 1999;93:236-44. 79. Vervoet D, Ekstrom T, Pela R et al. A six-month comparison between formoterol and salmeterol in patients with reversible obstructive airways disease. Respir Med 1998 1998;92:836-42. 80. Nightingale J, Rogers DF, Barnes PJ. Comparison of the effects of salmeterol and formoterol in patients with severe asthma. Chest 2002;121:1401-06.

Pharmacologic Management of Asthma 167 81. Naline E, Zhang Y, Qian Y et al. Relaxant effects and duration of action of formoterol and salmeterol on the isolated human bronchus. Eur Respir J 1994;7:914-20. 82. Palmqvist M, Persson G, Lazer L et al. Inhaled dry powder formoterol and salmeterol in asthmatic patients: onset of action, duration of effect, and potency. Eur Respir J 1997;10:2484-89. 83. Newton MF, O’Donnell DE, Forkert L. Response of lung volumes to inhaled salbutamol in a large population of patients with severe hyperinflation. Chest 2002;121:1042-50. 84. Anderson SD, Seale JP, Rozea P et al. Inhaled and oral salbutamol in exercise-induced asthma. Am Rev Respir Dis 1976;114:493-500. 85. McFadden ER Jr, Hejal R. Emergency medicine: Asthma. Lancet 1995;345:1215-20. 86. Grove A, Lipworth BJ. Tolerance with β2-adrenoceptor agonists: Time for reappraisal. Br J Clin Pharmacol 1995;39:109-18. 87. Yates DH, Worsdell M, Sussman H et al. Regular formoterol treatment in mild asthma: Effect on bronchial reactivity during and after treatment (abstract). Am J Respir Crit CareMed 1995;151: A272. 88. O’Connor BJ, Aikman SL, Barnes PJ. Tolerance to the non-bronchodilator effects of inhaled β2agonists. N Engl J Med 1992;327:1204-08. 89. Cockroft D, McParland CP, Britton SA et al. Regular inhaled salbutamol and airway responsiveness to allergen. Lancet 1993;342:833-37. 90. Cheung D, Timmers MC, Zwinderman AH et al. Long-term effect of a long-acting β2-adrenoceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma. New Engl J Med 1992;327:1198-1203. 91. Ramage L, Lipworth BJ, Ingran CG et al. Reduced protection against exercise induced bronchoconstriction after chronic dosing with salmeterol. Respir Med 1994;88:363-68. 92. Tattersfied AE, Britton JR. β-adrenoceptor agonists. In: Barnes PJ (Eds). Asthma—Basic mechanisms and clinical management. Academic Press, London, 1988. 93. Green SA, Turki J, Innis M et al. Amino-terminal polymorphisms of the human β2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 1994;33:9414-19. 94. Turki J, Pak J, Green SA et al. Genetic polymorphism of the β2-adrenergic receptor in nocturnal and non-nocturnal asthma: Evidence that Gly16 correlates with thenocturnal phenotype. J Clin Invest 1995;95:1635-41. 95. Hall IP, Wheatley A, Wilding P et al. Association of Glu 27 β2-Adrenoceptor polymorphism with lower airway reactivity in asthmatic subjects. Lancet 1995;345:1213-14. 96. Speitzer WO, Suissa S, Ernst P et al. The use of β-agonists and the risk of death and near death from asthma. N Engl J Med 1992;326:501-06. 97. Crane J, Pearce N, Flatt A. et al. Prescribed fenoterol and death from asthma in New Zealand, 1981-83: A case control study. Lancet 1989;1:917-22. 98. Grainger J, Woodman K, Pearce N et al. Prescribed fenoterol and death from asthma in New Zealand, 1981-7: A further case control study. Thorax 1991;46:105-11. 99. Suissa S, Ernst P, Boivin J et al. A cohort analysis of excess mortality in asthma due to use of inhaled β-agonists. Am J Respir Crit Care Med 1994;149:604-10. 100. Barrett TE, Strom BL. Inhaled β-adrenergic receptor agonists in asthma: More harm than good? Am J Respir Crit Care Med 1995;151:574-77. 101. Crane J, Pearce N, Burgess C, Beasley R. Asthma and the β-agonist debate. Thorax 1995;50 (Suppl):S5-S10. 102. Speizer FE, Doll R, Heaf P. Observations on recent increase in mortality from asthma. BMJ 1968;1:335-39. 103. Muller MI, Mullen B, Carey M. The association between β2-agonist use and death from asthma. JAMA 1993;270:1842-45. 104. Bernstein IL. β2-agonists: déjà vu all over again. The second generation controversy. Chest 2002;122:763-65.

168 Bronchial Asthma 105. Greeen SA, Turki J, Bejarano P et al. Influence of β2-adrenergic receptor genotype on signal transduction in human airway smooth muscle cells. Am J Respir Cell Mol Biol 1995;13:25-33. 106. Barnes PJ. Scientific rationale for inhaled combination therapy with long-acting β2-3agonists and corticosteroids. Eur Respir J 2002;19:182-91. 107. Wong CS, Wahedna I, Pavord ID et al. Effects of budesonide and terbutaline on bronchial reactivity to allergy in subjects with mild atopic asthma. Thorax 1992;47:231P(Abstract). 108. Booth H, Fishwick K, Harkawat R et al. Changes in methacholine induced bronchoconstriction with the long acting β2-agonist salmeterol in mild to moderate asthmatic patients. Thorax 1993;48:1121-24. 109. Rosenthal RR, Busse WW, Kemp JP et al. Effect of long-term salmetrol therapy compared with as-needed albuterol use on airway hyperresponsiveness. Chest 1999;116:595-602. 110. Van Schayck CP, Cloosterman SGM, Hofland ID et al. How detrimental is chronic use of bronchodilators in asthma and chronic obstructive lung disease? Am J Respir Crit Care Med 1995;151:1317-19. 111. Prieto L, Gutierrez V, Torres V, et al. Effect of salmeterol on seasonal changes in airway responsiveness and exhaled nitric oxide in pollen-sensitive asthmatic subjects. Chest 2002;122:798805. 112. Gandevia B. Historical review of the use of parasympatholytic agents in the treatment of respiratory disorders. Postgrad Med J 1975;51(Suppl 7):13-20. 113. Gross NJ, Skorodin MS. Anticholinergic antimuscarinic bronchodilators. Am Rev Respir Dis 1984;129:856-70. 114. Mann JS, George CF. Anticholinergic drugs in the treatment of airway disease. Brit J Dis Chest 1985;79:209. 115. Ziment I, Au JP. Anticholinergic agents. Clin Chest Med 1986;7:454-58. 116. Weber R. Role of anticholinergics in asthma. Ann Allergy 1990;65:348-50. 117. Beakes DE. The use of anticholinergics in asthma. J Asthma 1997;34:357-68. 118. Ward MJ, Fentem PH, Roderick-Smith WH et al. Ipratropium bromide in acute asthma. BMJ 1981;282:598-600. 119. Richardson JB. Nerve supply to the lungs. Am Rev Respir Dis 1979;119:785-802. 120. Barnes PJ, Minette P, Maclagan J. Muscarinic subtypes in airways. Trends Pharmacol Sci 1988;9: 412-16. 121. Fryer AD, Jacoby DB. Effect of inflammatory cell mediators on M2 muscarinic receptors in the lungs. Life Sci 1993;52:529-36. 122. Baigelman W, Chodosh S. Bronchodilator action of the anticholinergic drug, ipratropium bromide, as an aerosol in chronic bronchitis and asthma. Chest 1977;71:324. 123. Frith PA, Jenner B, Dangerfield R, Atkinson J, Drennan C.. Oxytropium bromide. Dose-response and time-response study of a new anticholinergic bronchodilator drug. Chest 1986;89:249-53. 124. Storms WW, Bodman SF, Nathan RA et al. Use of ipratropium bromide in asthma. Am J Med 1986;81(Suppl 5A):61-66. 125. Barnes PJ. Muscarinic receptor subtypes in airways. Life Sci 1993;52:521-27. 126. Patel HJ, Barnes PJ, Takahasi T et al. Evidence for prejunctional muscarinic autoreceptors in human and guinea pig trachea. Am J Respir Crit Care Med 1995;152:872-78. 127. Tamaoki J, Chiyotani A, Tagaya E et al. Effect of long-term treatment with oxytropium bromide in airway secretion in chronic bronchitis and diffuse panbronchiolitis. Thorax 1994;49:545-48. 128. Seifkin AD,. Optimal pharmacologic treatment of the critically ill patients with obstructive airway disease. Am J Med 1996;100(Suppl):545-615. 129. Schlueter DP. Ipratropium bromide in asthma: A review of the literature. Am J Med 1986; 81(Suppl):55-59. 130. Chapman KR, Smith DL, Rebuck AS et al. Haemodynamic effects of inhaled ipratropium bromide alone and combined with an inhaled β-agonist. Am Rev Respir Dis 1985;132:845-47.

Pharmacologic Management of Asthma 169 131. O’Driscoll BR, Taylor RJ, Horsley MG et al. Nebulised salbutamol with and without ipratropium bromide in acute airflow obstruction. Lancet 1989;1:1418-20. 132. Rebuck AS, Chapman KR, Abboud R et al. Nebulised anticholinergic and sympathomimetic treatment of asthma and chronic obstructive airways disease in the emergency room. Am J Med 1987;82:59-64. 133. Cugell DW,. Clinical pharmacology and toxicology of ipratropium bromide. Am J Med 1986;81: 18-22. 134. Gross NJ. Ipratropium bromide. N Engl J Med 1988;319;486-94. 135. Peel ET, Cheong AB, Broderick N. A comparison of oxytropium bromide and ipratropium bromide in asthma. Eur Respir J 1984;65:106-08. 136. O’Connor BJ, Towse LJ, Barnes PJ. Prolonged effect of tiotropium bromide on methacholine induced bronchoconstriction in asthma. Am J Respir Crit Care Med 1996;154:876-80. 137. Disse B, Witek TJ Jr. Anticholinergics: Tiotropium. In: Hansel TT, Barnes PJ (Eds): New drugs for Asthma, Allergy and COPD. Prog Respir Res, Basel, Karger, 2001; 31,72-76. 138. Bethel RA, Irvin CG. Anticholinergic drugs and asthma. Semin Respir Med 1987;8:366-71. 139. Ind PW, Dixon CMS, Fuller RW, Barnes PJ. Anticholinergic blockade of β-blocker-induced bronchoconstriction. Am Rev Respir Dis 1989;139:1390-94. 140. Barnes PJ. Inhaled glucocorticosteroids for asthma. N Engl J Med 1995;332:868-70. 141. Corticosteroids: their biological mechanisms and application to the treatment of asthma. Am Rev Respir Dis 1990;141(Suppl):S2. 142. Kaliner M. Mechanisms of glucocorticoid action in bronchial asthma. J Allergy Clin Immunol 1985;76:321. 143. Beato M. Gene regulation by steroid hormones. Cell 1989;56:335-344. 144. Guyre PM, Girard MT, Morganelli P, Managaniello PD. Glucocorticoid effects on the production and action on immune cytokines. J Steroid Biochem 1988;30:88-93. 145. Schleimer RP. Effects of glucocorticoids on inflammatory cells relevant to their therapeutic applications in asthma. Am Rev Respir Dis 1990;141:559-69. 146. Laitinen LA, Laitinen A, Haahtela T et al. A comparative study of the effects of an inhaled corticosteroid, budesonide, and a β2-agonist , terbuline, on airway inflammation in newly diagnosed asthma. J Allergy Clin Immunol 1992;90:32-42. 147. Lee TH, Lane SJ. The role of macrophages in the mechanisms of airways inflammation in asthma. Am Rev Respir Dis 1992;145:527-30. 148. Kita II, Abu-Ghazaleh R, Sanderson CJ, Gleich GJ. Effect of steroids on immunoglobulin induced eosinophil degranulation. J Allergy Clin Immunol 1991;87:70-77. 149. Her E, Frazer J, Austen KF, Owen WF Jr. Eosinophil haemopoitins antagonise the programmed cell death of eosinophils. Cytokine and glucocorticoid effects on eosinophils maintained by endothelial cell-conditioned medium. J Clini Invest 1991;88:1982-87. 150. Evans PM, O’Connor B, Fuller RW, Barnes PJ, Chung KF. Effect of inhaled corticosteroids on peripheral eosinophil counts and density profiles in asthma. J Allergy Clin Immunol 1993; 91: 643-49. 151. Boschetto P, Rogewrs DF, Faibbri LM, Barnes PJ. Corticosteroid inhibition of airway microvascular leakage. Am Rev Respir Dis 1991;141:1044-1049. 152. Shimura S, Sasaki HT. Ikeda K, Yammauchi K, Sasaki H, Takishim T. Direct inhibitory action of glucocorticoid on glycoconjugate secretion from airway submucosal glands. Am Rev Respir Dis 1990;141:1041-9. 153. Burke C, Power CK, Norris A, Condez A, Schmekel B, Poulter LW. Lung function and immunopathological changes after inhaled corticosteroid therapy in asthma. Eur Respir J 1992;5:73-79. 154. Barnes PJ, Adcock IM. Anti-inflammatory action of steroids: Molecular mechanisms. Trends Pharmacol Sci 1993;14:436-41.

170 Bronchial Asthma 155. Mitchell JA, Belvisi MG, Akarasereenont P et al. Induction of cyclooxygenase-2 by cytokines in human pulmonary epithelial cells: Regulation by dexamethasone. Br J Pharmacol 1994;113: 1008-14. 156. Robbins RA, Barnes PJ, Springall DR et al. Expression of inducible nitric oxide synthase in human bronchial epithelial cells. Biochem Biophs Res Commun 1994;203:209-18. 157. Van de Stolpe A, Caldenhoven E, Raaijmakers JAM et al. Glucocorticoid-mediated repression of intercellular adhesion molecule-1 expression in human monocytic and bronchial epithelial cell lines. Am J Respir Cell Mol Biol 1993;8:340-47. 158. Djukanovie R, Wilson JW, Britten KM, et al. Effect of an inhaled corticosteroid on airways inflammation and symptoms in asthma. Am Rev Respir Dis 1992;145:669-74. 159. Lundgren R, Soderberg M, Horstedt P, Stenling R. Morphological studies of bronchial mucosal biopsies from asthmatics before and after ten years treatment with inhaled steroids. Eur Respir J 1988;1:883-89. 160. Barnes PJ, Dolery Ct, MacDernot J. Increased pulmonary alpha-adrenergic and reduced β2adrenergic receptors in experimental asthma 1980;285:569-71. 161. Mano K, Akharzadeh A, Kosesnadi K et al. The effect of hydrocortisone on β-adrenergic receptors in lung tissue. J Allergy Clin Immunol 1979;63:147. 162. Brodde OE, Brinkman M, Schermuth R et al. Terbutaline induced desensitisation of human lymphocyte β2-adrenoceptors: accelerated restoration of β-adrenergic responses by prednisolone and ketotifen. J Clin Invest 1985;76:1096-1101. 163. Kraan J, Koeter GH, van der Mark THW, et al. Changes in bronchial hyperreactivity induced by 4 weeks of treatment with antiasthma drugs in patients with allergic asthma: A comparison between budesonide and terbutaline. J Allergy Clin Immunol 1985;76:628-36. 164. Kerstjens HAM, Brand PLP, Hughes MD et al, and the Dutch chronic non-specific (CNSLD) study group. A comparison of the bronchodilator therapy with or without inhaled corticosteroid therapy for obstructive airways disease. N Engl J Med 1992;327:1413-19. 165. Kerrebijn KF, van Essen-Zandvliet EEM, Neijens HJ. Effect of long-term treatment with inhaled corticosteroids and beta-agonists on the bronchial responsiveness in children with asthma. J Allergy Clin Immunol 1987;79:653-659. 166. Juniper EF, Kline PA, Vanzieleghem MA et al. Long-term effect of budesonide on airway responsiveness and clinical asthma severity in inhaled steroid-dependent asthmatics. Eur Respir J 1990;3:1122-1127. 167. Juniper EF, Kline PA, Vanzieleghem MA et al. Effect of long-term treatment with an inhaled corticosteroid (budesonide) on airway hyperresponsiveness and clinical asthma in nonsteroiddependant asthmatics. Am Rev Respir Dis 1990;142:832-36. 168. Haahtela T, Jarvinen M, Kava T et al. Comparison of a agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med 1991;325:388-92. 169. Overbeek SE, Kerstjens HAM, Bogaard JM et al. Is delayed introduction of inhaled corticosteroids harmful in patients with obstructive airways disease (asthma and COPD)? The Dutch chronic non-specific lung disease (CNSLD) study group. Chest 1996;110:35-41. 170. Haahtela T, Jarvinen M, Kava T et al. Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma. N Engl J Med 1994;331:700-05. 171. Rob Douma W, Kerstjens HAM, Gooijer AD et al. Initial improvement in lung function and bronchial hyperresponsiveness are maintained during a 5 years of treatment with inhaled beclomethasione dipropionate and terbutaline. Chest 2002;121:151-57. 172. Dompeling E, van Schayck CP, van Grunsven PM et al. Showing the deterioration of asthma and chronic obstructive pulmonary disease observed during bronchodilator therapy in adding inhaled corticosteroids: A 4-year prospective study. Ann Intern Med 1993;118:770-78. 173. Haahtela T, Jarvinen M, Kava T et al. Comparison of a β2-agonist terbutaline with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med 1991;325:388-92.

Pharmacologic Management of Asthma 171 174. Cockcroft DW, Murdock KY. Comparative effects of salbutamol, sodium cromoglycate and beclomethasone dipropionate on allergen-induced early asthmatic response, late asthmatic response, and increased bronchial responsiveness to histamine. J Allergy Clin Immunol 1987;79:734-40. 175. Barnes PJ. Effect of corticosteroids on airway hyperresponsiveness. Am Rev Respir Dis 1990;141:S70-S76. 176. Vathenen AS, Knox AJ, Wisniewiski A, Tatterfield AE. Time course of change in bronchial reactivity with an inhaled corticosteroid in asthma. Am Rev Respir Dis 1991;143:1317-21. 177. Juniper EF, Kline PA, Vanzieleghem MA et al. Airway responsiveness and clinical asthma severity in steroid-dependent asthmatics. Eur Respir J 1990;3:1122-27. 178. Faul JL, Demers EA, Burke CM, Poulter LW. Alterations in airway inflammation and lung function during corticosteroid therapy for atopic asthma. Chest 2002;121:1414-20. 179. Clark TJH. Inhaled corticosteroid therapy: A substitute for theophylline as well as prednisolone? J Allergy Clin Immunol 1985;76:330.148.Reed CE. Aerosol steroids as primary treatment of mild asthma. N Engl J Med 1991;325:425. 180. Reed CE. Aerosol steroids as primary treatment of mild asthma. N Engl J Med 1991;325:425. 181. Wooley MJ, Denberg JA, Ellis R et al. Allergen-induced changes in bone marrow progenitors and airway responsiveness in dogs and the effect of inhaled budesonide on these parameters. Am J Respir Cell Mol Biol 1994;11:600-06. 182. Howarth P. The relevance of and site of airway inflammation in asthma and targeted aerosol delivery. Int J Clin Pract Suppl 1999;106:3-10. 183. Hamid Q, Song Y, Kotsimbos TC et al. Inflammation of small airways in asthma. J Allergy Clin Immunol 1997;100:44-51. 184. Adcock IM, Gilbey T, Gelder CM et al. Glucocorticoid receptor localisation in normal and asthmatic lung. Am J Respir Crit Care Med 1996;154:771-82. 185. Laursen LC, Taudorf E, Weeke B. High dose inhaled budesonide in treatment of severe steroiddependent asthma. Eur J Respir Dis 1986;68:19-28. 186. Nikolaizik WH, Marchant JL, Preece MA, Warner JO. Nocturnal cortisol secretion in healthy adults before and after inhalation of budesonide. Am J Respir Crit Care Med 1996;153:97-101. 187. Connett GJ, Warde C, Wooler E, Lenny W. Use of budesonide in severe asthmatics aged 1-3 years. Arch Dis Child 1993;69:351-55. 188. Vaz de azevedo M, Coelho M, Pinto Mendes JA, Bugalho de Almeida A. Can a low or moderate dose of inhaled budesonide replace oral non-steroidal anti-asthma treatment? J International Med Res 1991;19:280-88. 189. Tan KS, Grove A, Cargill RI, McFarlane LC, Lipworth BJ. Effects of inhaled fluticasone propionate and oral prednisolone on lymphocyte β2-adrenoceptor function in asthmatic patients. Chest 1996;109:343-47. 190. Clissold SP, Hell RC. Budesonide: A preliminary review of its pharmacodynamic properties and therapeutic efficacy in asthma and rhinitis. Drugs 1984;28:485-518. 191. Field HV, Jenkinson PMA, Frame MH, Warner JO. Asthma treatment with a new corticosteroid inhaler, budesonide, administered twice daily by spacer inhaler. Arch Dis Child 1982;57:864-66. 192. Johnson M. Development of fluticasone propionate and comparison with other inhaled corticosteroids. J Allergy Clin Immunol 1998;101:S434-S439. 193. Bootsman GP, Koenderman L, Dekhuijzen PNR et al. Effects of fluticasone propionate and beclomethasone dipropionate on parameters of inflammation in peripheral blood of patients with asthma. Allergy 1998;53:653-61. 194. Hogger P. Dose response and therapeutic index of inhaled corticosteroids in asthma. Curr Opin Pulm Med 2003;9:1-8. 195. Barnes PJ, Pedersen S. Efficacy and safety of inhaled steroids in asthma. Am Rev Respir Dis 1993;148(4 pt2):S1-S26.

172 Bronchial Asthma 196. Brown PH, Greening AP, Compton GK. Large volume spacer devices and the influence of high dose beclomethasone dipropionate on hypothalamo-pituitary-adrenal axis function. Thorax 1993;48:233-38. 197. Selroos O, Halme M. Effect of a volumetric spacer and mouth rinsing on systemic absorption of inhaled corticosteroids from a metered-dose inhaler and dry powder inhaler. Thorax 1991;46: 891-94. 198. Lipworth BJ. New perspectives on drug delivery and systemic bioactivity. Thorax 1995;50: 105-10. 199. Geddes DM. Inhaled corticosteroids: Benefits and risks. Thorax 1992;47:404-07. 200. Brown PH, Blundell G, Greening AP, Crompton GK. Screening for hypothalamo-pituitaryadrenal axis suppression in asthmatics taking high dose inhaled corticosteroids. Respir Med 1991;85:511. 201. Brown PH, Blundell G, Greening AP, Crompton GK. Hypothalamo-pituitary-adrenal axis suppression in asthmatics inhaling high dose corticosteroids. Respir Med 1991;85:501. 202. Shapiro GG, Coneg P. Cromolyn sodium: A review. Pharmacotherapy 1985;5:156-70. 203. Bernstein IL. Cromolyn sodium. Chest 1985:87:68S. 204. Hoag JE, McFadden ER Jr. Long-term effect of cromolyn sodium on nonspecific bronchial hype responsiveness: A review. Ann allergy 1991;66:53-63. 205. Schwartz HJ, Blumenthal M, Brady R et al. A comparative study of the clinical efficacy of nedocromil sodium and placebo: How does cromolyn sodium compare as an active control treatment? Chest 1996;109:945-52. 206. Furukawa CT, Shapiro GG, Bierman CW et al. A double blind study comparing the effectiveness of cromolyn sodium and sustained release theophylline in childhood asthma. Paediatrcs 1984;74:453-59. 207. Petty TL, Rollins DR, Christopher K et al. Cromolyn sodium is effective in adult chronic asthma. Am Rev Respir Dis 1989;139:694-701. 208. Thomson NC. Nedocromil sodium: an overview. Respir Med. 1989;83:269-76. 209. Petty TL, Rollins DR, Christopher K et al. Cromolyn sodium is effective in adult chronic asthmatics. Am Rev Respir Dis. 1989;139:694-701. 210. Eigen H, Reid JJ, Dahl R et al. Evaluation of the addition of cromolyn sodium to bronchodilator maintenance therapy in the long-term management of asthma. J Allergy Clin Immunol 1987;80:612-21. 211. Bel EH, Timmers MC, Hermmans J, Dijkman JH, Sterk PJ. The long-term effects of nedocromil sodium and beclomethasone dipropionate on bronchial responsiveness to methacholine in nonatopic asthmatic subjects. Am Rev Respir Dis 1990;141:21. 212. North American Tilade study group: A double blind multicentre group comparative study of the efficacy and safety of nedocromil sodium in the management of asthma. Chest 1990;97:1299. 213. Bone MF, Kubik MM, Keaney NP et al. Nedocromil sodium in adults with asthma dependent on inhaled corticosteroids: A double-blind, placebo controlled study. Thorax 1989;44:654-59. 214. Manolitsas ND, Wang J, Devalia JL et al. Regular albuterol, nedocromil sodium, and bronchial inflammation in asthma. Am J Respir Crit Care Med 1995;2152:1925-30. 215. Heinke S, Szues G, Norris A et al. Inhibition of volume activated chloride currents in endothelial cells by cromones. Br J Pharmacol 1995;115:1392-98. 216. Barnes PJ, Holgate ST, Lattinen LA et al. Asthma mechanisms, determinants of severity and treatment,: The role of nedocromil sodium. Clin Expt Allergy 1995;25:771-87. 217. Tinkelman DG, Moss BA, Bukantz SC et al. A multicentre trial of the prophylactic effect of ketotifen, theophylline and placebo in atopic asthma. J Allergy Clin Immunol 1985;76:487. 218. Magnussen H.The inhibitor effect of azelastine and ketotifen on histamine induced bronchoconstriction in asthmatic patients. Chest 1987;91:855. 219. Phillips G, Rafferty P, Beasley R, Holgate ST. Effect of oral terfenadine on the bronchoconstrictor response to inhaled histamine and adenosine-5'-monophosphate in nonatopic asthma. Thorax 1987;42:939.

Pharmacologic Management of Asthma 173 220. Bruttmann G, Pedrali P, Arendt C, Rihoux JP. Protective effect of cetrizine in patients suffering from pollen asthma. Ann Allergy 1990;64:224-28. 221. Taylor IK. Cysteinyl leukotrienes in asthma: Current state of therapeutic evaluation. Thorax 1995;50:1005-10. 222. Samuelsson B. Leukotrienes: Mediators of immediate hypersensitive reactions and inflammation. Science 1983; 220:568-75. 223. Lewis RA, Austen KF. The biologically active leukotrienes. J Clin Invest 1984;73:889-97. 224. Lewis RA, Austen KF, Soberman RJ. Leukotrienes and other products of lipoxygenase pathway. New Engl J Med 1990;323:645-55. 225. Barnes PJ, Chung KF, Page CP. Inflammatory mediators and asthma. Pharmacol Rev 1988;40: 49-84. 226. Piacentini GL, Kaliner MA. The potential roles of leukotrienes in bronchial asthma. Am Rev Respir Dis 1991;143:S96-S99. 227. Arm JP, Lee TH. Sulphidopeptide leukotrienes in asthma. Clin Sci 1993;84:501-510. 228. Dahlen SE, Hansson G, Hedquist P et al. Allergen challenge of lung tissue from asthmatics elicits bronchial contraction that correlated with the release of leukotrienes C4, D4, and E4. Proc Natl Acad Sci, USA 1983;80:1712-16. 229. MacGlashan DW, Schleimer RP, Peters SP et al. Generation of leukotrienes by purified human lung mast cells. J Clin Invest 1982;70:747-51. 230. Weller PF, Lee CW, Foster DW et al. Generation and metabolism of 5-lipoxygenase pathway leukotrienes by human eosinophils: Predominant production of leukotriene C4. Proc Natl acad Sci USA. 1983;80:7626-30. 231. Kern R, Smith LJ, Patterson R et al. Characterisation of the airway response to inhaled leukotriene D4 in normal subjects. Am rev Respir Dis 1986;133:1127-32. 232. Soter NA, Lewis RA, Corey EJ, Austen KF. Local effects of synthetic leukotrienes (LTC4, LTD4, LTE4 and LTB4) in human skin. J Invest Dermatol 1983;80:115-19. 233. Coles SJ, Neill KH, Leid LM et al. Effects of leukotrienes C4 and D4 on glycoprotein and lysozyme secretion by human bronchial mucosa. Prostaglandins 1983;25:155-70. 234. O’Byrne PM, Leikauf GD, Aizwa H et al. Leukotriene B4 induces airway hyper-responsiveness in dogs. J Appl Physiol 1985;59:1941-46. 235. Black PN, Fuller RW, Taylor GW et al. Bronchial reactivity is not increased after inhalation of leukotriene B4 and prostaglandin D2. Br J Clin Pharmacol 1988;25:667P. 236. Bigby T. Inflammatory mediators and asthma. Pulm Perspectives 1992;9(4):6-9. 237. Holgate ST, Bradding P, Sampson AP. Leukotriene antagonists and synthesis inhibitors: New directions in asthma therapy. J Allergy Clin Immunol 1996;98:1-13. 238. Fischer AR, McFadden CA, Frantz R, Awni WM, Cohn J, Drazen JM, Israel E. Effect of chronic 5-lipoxygenase inhibition on airway hyper-responsiveness in asthmatic subjects. Am J Respir Crit Care Med 1995;152:1203-07. 239. Murphy RC, Hammarstorm S, Samuelsson B et al. Leukotriene C: A slow-reacting substance from murine mastocytoma cells. Proc Natl Acad Sci USA 1979;76:4275-79. 240. Lee TH. pharmacological modulation of leukotriene and platelet-activating factor biosynthesis and activities by alternative dietary fatty acids. Clin Exp Allergy 1989;19:15-23. 241. Arm JP, Horton CE, Mencia-Huerta JM et al. Effects of dietary supplementation with fish oil lipids on mild asthma. Thorax 1988;43:84-92. 242. Miller BD. Depression and asthma: A potentially lethal mixture. J Allergy Clin Immunol 1987;80:481-86. 243. Hay DWP. Pharmacology of leukotriene receptor antagonists. More than inhibitors of bronchoconstriction. Chest 1997;111:35S-45S. 244. Krell RD, Aharony D, Buckner CK et al. The preclinical pharmacology of ICI 204,219, a peptide leukotriene antagonist. Am Rev Respir Dis 1990;141:978-87. 245. Miyamoto T. The clinical evaluation of a leukotriene antagonist, ONO-1078. Presented at the European Congress of Allergology and Clinical Immunology, May 1992; Paris, France.

174 Bronchial Asthma 246. Fujimura M, Sakahato S, Kamis Y, Matsuda T. The effect of a leukotriene antagonist ONO-1078 on bronchial hyperresponsiveness in patients with asthma. Respir Med 1993;87:133-38. 247. Finnerty JP, Wood-Baker R, Thomson H, Holgate ST. Role of leukotriene in exercise-induced asthma: Inhibitory effect of iCI 204219, a potent leukotriene D4 receptor antagonist. Am Rev Respir Dis 1992;145:746-49. 248. Makkar HK, Lau LC, Thomson HW, Binks SM, Holgate ST. The protective effect of inhaled leukotriene D4 antagonist ICI 204,219 against exercise-induced asthma. Am Rev Respir Dis 1993;147:1413-18. 249. Arm JP, Lee TH. Sulphidopeptide leukotrienes in asthma. Clin Sci 1993;84:501-10. 250. Dahlen B, Margolskee DJ, Zetterstrom O, Dahlen SE. Effect of the leukotriene antagonist MK-0679 on baseline pulmonary function in aspirin-sensitive asthmatic subjects. Thorax 1993;48:1205-10. 251. Spector SL, Smith LJ, Glass M. Accolate Asthma Trialist Group. Effects of 6 weeks of therapy with oral doses of iCI 204, 219, a leukotriene D4 receptor antagonist, in subjects with bronchial asthma. Am J Respir Crit Care Med 1994;150:618-23. 252. Spector S, Miller CJ, Glass M. Thirteen-week dose response study with Accolate (zafirlukast) in patients with mild to moderate asthma (abstract). Am J Respir Crit Care Med 1995;151:A379. 253. Specter SL, Glass M, Minkwitz MC. The effect of six-week therapy with oral doses of ICI 204,219 in asthmatics (abstract). Am Rev Respir Dis 1992;145:A16. 254. Specter SL, Glass M, Minkwitz MC. The effect of six-week therapy with oral doses of ICI 204,219 in asthmatics (abstract). Am Rev Respir Dis 1992;145:A16. 255. Barnes NC, Pujet JC. First clinical experience of the oral leukotriene antagonist, pranlukast (SB205312/ONO 1078) in North European patients with mild to moderate asthma (Abstract). Am J Respir Crit Care med 1995;151:A378. 256. Cohn J. Zileuton (A-64077): A 5-lipoxygenase inhibitor. In: Lewis A, Furst DE (Eds). Nonsteroidal anti-inflammatory drugs: Mechanisms and Clinical uses. 1994;367-90. 257. Barnes NC, Pujet JC. Pranlukast, a novel leukotriene receptor antagonist: Results of the first European, placebo controlled, multicenter clinical study in asthma. Thorax 1997;52:523-27. 258. Reiss TF, Chervinsky P, Dockhorn RJ et al. Monteleukast, a once daily leukotriene receptor antagonist, in the treatment of chronic asthma. Ann Intern Med 1998;158:1213-20. 259. Terasima T, Amakawa K, Matsumaru A, Yamaguchi K. Correlation between cysteinyl leukotriene release from leukocytes and clinical response to a leukotriene inhibitor. Chest 2002;122:1566-70. 260. Lipworth BJ. Leukotriene-receptor antagonists. Lancet 1999;353:57-62. 261. Barnes NC, Miller CJ. Effect of leukotriene-receptor antagonist therapy on the risk of asthma exacerbations in patients with mild to moderate asthma: An integrated analysis of zafirlukast trials. Thorax 2000;55:478-83. 262. Currie GP, Lipworth BJ. Bronchoprotective effects of leukotriene-receptor antagonists in asthma: A meta-analysis. Chest 2002;122:146-50. 263. Dempsey OJ, Fowler SJ, Wilson A et al. Effects of adding either a leukotriene-receptor antagonist or low-dose theophylline to a low or medium dose of inhaled corticosteroid in patients with persistent asthma. Chest 2002;122:151-59. 264. Barnes PJ, Adcock IM. Steroid-resistance in asthma. Q J Med 1995;88:455-68. 265. Schwartz HJ, Lowell FC, Melby JC. Steroid resistance in asthma. Ann Intern Med 1968;69: 493-99. 266. Carmichael J, Paterson IC, Diaz P et al. Corticosteroid resistance in chronic asthma. Br Med J 1981;282:1419-22. 267. Hill JM, Tattersfield E. Corticosteroid sparing agents in asthma. Thorax 1995;50:577-82. 268. Moss RB. Alternative pharmacotherapies for steroid-dependent asthma. Chest 1995;107:817-25. 269. Shiner RJ, Nunn AJ, Chung KF et al. Randomised, double-blind, placebo-controlled trial of methotrexate in steroid dependent asthma. Lancet 1990;336:137-40. 270. Alexander AG, Barnes NC, Kay AB. Trial of cyclosporin in corticosteroid-dependent chronic severe asthma. Lancet 1992;339:324-28.

Pharmacologic Management of Asthma 175 271. Hu S, Mitcho YL, Oronsky AL, Kerwar SS. Studies on the effect of methotrexate on macrophage function. J Rheumatol 1988;15:206-09. 272. Nolte H, Skov PS. Inhibition of basophil histamine release by methotrexate. Agents Actions 1988;23:173-76. 273. Mullarkey ME, Blumenstein BA, Andrade WP et al. Methotrexate in the treatment of corticosteroid-dependent asthma. N Engl J Med 1988;318:603-07. 274. Shiner RJ, Nunn AJ, Kan Chung K, Geddes DM. Randomised, double-blind, placebo controlled trial of methotrexate in steroid dependent asthma. Lancet 1990;336:137-40. 275. Dyer PD, Vaughan TR, Weber RW. Methotrexate in the treatment of steroid dependent asthma. J Allergy Clin Immunol 1991;88:208-12. 276. Stewart GE, Diaz JD, Locky RF, et al. Comparison of oral pulse methotrexate with placebo in the treatment of severe glucocorticoid-dependent asthma. J Allergy Clin Immunol 1994;94:482-89. 277. Erzurum SC, Leff JA, Cochran JE et al. Lack of benefit of methotrexate in severe steroid-dependent asthma. Ann Intern Med 1991;114:353-60. 278. Trigg CJ, Davies RJ. Comparison of methotrexate 30 mg per week with placebo in chronic severe asthma: A 12-week double-blind, cross-over study. Respir Med 1993;87:211-16. 279. Coffey MJ, Sanders G, Eschenbacher WL et al. The role of methotrexate in the management of steroid-dependent asthma. Chest 1994;105:649-50. 280. Stemple DA, Lammert J, Mullarke MF. Use of methotrexate in the treatment of steroid-dependent adolescent asthmatics. Ann allergy 1991;67:346-48. 281. Guss S, Portnoy J. Methotrexate treatment for severe asthma in children. Pediatrics 1992;89: 635-39. 282. Moss RB. Alternative pharmacotherapies for steroid-dependent asthma. Chest 1995;107:817-25. 283. Calderon E, Lockey RF, Bukantz Sc et al. Is there role for cyclosporin in asthma? J Allergy Clin Immunol 1992;89:629-36. 284. Alexander AG, Barnes NC, Kay AB. Trial of cyclosporin in corticosteroid-dependent severe asthma. Lancet 1992;339:324-28. 285. Szczeklik A, Nizankowaska F, Dworosky R et al. Cyclosporin for steroid dependent asthma. Allergy 1991;46:312-15. 286. Bernstein DI, Bernstein IL, Bodenheimer SS et al. An open study of auranofin in the treatment of steroid-dependent asthma. J Allergy Clin Immunol 1988;81:6-16. 287. Szczeklik A, Nizankowaska F, Dworosky R et al. Cyclosporin for steroid dependent asthma. Allergy 1991;46:312-315. 288. Muranaka MM, Miyamoto T, Shida T et al. Gold salt in the treatment of bronchial asthma—A double blind study. Ann allergy 1978;40:132-37. 289. Nierop G, Gijzel WP, Bel EH et al. Auranofin in the treatment of steroid dependent asthma: A double blind study. Thorax 1992;47:349-54. 290. Hodges NG, Brewis RAL, Howell JBL. An evaluation of azathioprine in severe chronic asthma. Thorax 1971;26:734-39. 291. Mazor BD, Giclas PC, Gelfand EW. Immunomodulatory effects of intravenous immunoglobulin in severe steroid dependent asthma. Clin Immunol Immunopathol 1989;53:S156-S163. 292. Spector SL, Katz FH, Farr RS. Troleandomycin: Effectiveness in steroid dependent asthma and bronchitis. J Allergy Clin Immunol 1974;54:367-79. 293. Ilfield D, Kivity S, Feirman E, Topilsky M, Rojkind M. Effect of invitro colchicine and oral theophylline on suppressor cell function of asthmatic patients. Clin Exp Immunol 1985;61: 360-67. 294. Schwartz YA, Kivity S, Ilfield DN, et al. A clinical and immunological study of colchicine in asthma. J Allergy Clin Immunol 1990;85:578-82. 295. Charous BL. Open study of hydroxychloroquine in the treatment of severe symptomatic or corticosteroid-dependent asthma. Ann Allergy 1990;65:53-58.

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11 Inhalation Therapy Current therapeutics emphasises the importance of effective delivery of a drug to its site of action—the Targeted Drug Delivery.1-6 The advantage of this approach is avoidance of unnecessary and undesirable exposure of tissues/organs not involved in the disease process to the drug. It is sufficient and advantageous to have the drug delivered only to the site where the drug is needed. Targeted delivery of the drug to the desired site of action means that smaller doses are enough to produce the desired effect and generalised systemic side effects can be eliminated or minimised and a rapid action of the drug can be obtained. The value of inhalation as a route of drug administration has been recognised for thousands of years by the ancient civilisation in India, China, the Middle East and as well as by Hippocrates and Galen. The Ayurvedic system of medicine advocated the use of datura smoked in a pipe for a variety of ailments and atropa belladonna was given by smoking as a standard remedy for asthma. Asthma cigarettes made from Datura leaves are also being used by herbalists. Bronchodilator aerosols have been in use since 1935. In the past adrenergic bronchodilators have been given by hand-held squeeze-bulb nebulisers. This was cumbersome, and modern pressurised aerosols were introduced in 1956 and constituted a breakthrough in inhalation treatment. In recent times, inhalation therapy for asthma has been developed to a high level of sophistication although they are simple to use. The key to inhalation therapy is the aerosol particle. An aerosol is a suspension of fine liquid or solid particles in air. The efficacy of an inhaled drug depends largely on how much of the drug is deposited in the peripheral airways. On the other hand, the deposition of inhaled particles is determined both by the physical characteristics of the air-borne particles and physiological parameters like airflow to the lungs. Particle size is an important determinant of aerosol deposition in the lungs. Most devices (discussed below) generate particles in the size range of 1-10 micron. Only particles in the size range of 2-5 micron can be inspired deep into the lungs; particles 5 micron or more in diameter are impacted in the throat or in larger airways. Particles less than 1 micron behave like a gas and are exhaled in the expired air. Most aerosols contain a wide range of particle sizes and are known as heterodisperse aerosols. The mass median aerodynamic diameter (MMAD) is the median diameter of the aerosol multiplied by the square root of particle density. MMAD is important as regards aerosol deposition rather than the particle sizes. The propellant surrounding the drug particles evaporates on emerging from the canister and the particle steadily decreases as the aerosol moves away from the canister. Other factors that count for aerosol deposition include velocity, inertial impaction, and gravitational sedimentation. However measurements using radioactive teflon particles labelled with technetium-99m with a gamma camera

Inhalation Therapy 177 have shown that about 10% of the drug released from an MDI is deposited in the lung. About 80% is deposited in the oropharynx and about 10% is trapped on the walls of the inhaler device. For the purpose of inhalation therapy an aerosol of the drug can be generated in three ways: i. Pressurised aerosol systems; ii. Dry powder system; iii. Nebulisers. Pressurised Aerosol Systems (Metered Dose Inhalers—MDIs) Most medications prescribed for the treatment of bronchial asthma for maintenance or rescue, are administered via a metered dose inhaler (MDI). In Pressurised aerosol systems or metered dose inhalers micronised finely powdered drug is dissolved or suspended in a liquid propellant mixture, and packed in a sealed container (Fig. 11.1). The liquid propellants are highly volatile chlorofluorocarbons, CFC, (Freons) with a high vapor pressure of about 400 kPa. These freons are gases at room temperature, have a low boiling point, are inert, noninflammable, and odourless. Some surfactant is added so that they are not clumped together. On actuation, propellants emerge and break up into aerosol particles each consisting of a drug particle surrounded by the propellant. The valve is metered so that each actuation releases a fixed amount of the drug-propellant mixture. Therefore, it is named as the metered dose inhaler (MDI). During recent years, CFCs have been criticised for their harmful effects on the environment, especially the depletion of the stratospheric ozone layer. The production and use of CFCs were banned by international treaty (the Montreal protocol) in 1987, although their use in medications is not as the amount for this use is very small. Such exemptions to the National and International bans were made for MDIs to allow time for comparative clinical trials of alternative propellants, as required by worldwide regulatory agencies. Although no deadline has been set for the United States, Canada aims to achieve total transition by 2005, and the European Commission predicts that there will be no need for CFC-based MDIs in the European Community by the year 2003. So far, the most promising alternative propellants for MDIs are derivatives of hydrofluoroalkane (HFA). The HFA agents lack chlorine, and thus have zero ozone depletion potential.7-9 Preclinical studies have

Fig. 11.1: Components of meter dose inhalers

178 Bronchial Asthma demonstrated the acceptability of these propellants in terms of pharmacology, toxicology, and safety.10 Clinical studies also have shown that these propellant are as equivalent or even better than those use CFCs as propellants.11-18 Clinical trials have demonstrated that the level of asthma control achieved with CFC-beclomethasone dipropionate may be obtained with approximately half the total daily dose of HFA- beclomethasone dipropionate. This is probably due to improved lung deposition with the extra fine aerosol of HFAbeclomethasone dipropionate compared with the suspension of CFC based aerosol lung deposition is also greater with HFA- beclomethasone dipropionate compared with CFCbeclomethasone dipropionate and CFC-fluticasone propionate. Deposition values are related to the particle size distribution of each inhaler, with the smaller particles of HFAbeclomethasone dipropionate providing the greatest lung deposition and least oropharyngeal deposition.19 Evaluation of adherence to treatment is one important step in asthma management. Patients tend to overestimate the usage of MDIs presumably secondary to recall bias or as an effort to avoid criticism Prescription refill histories as from the issuing authorities or verification of the medical bill of the patient and canister weighing are more objective measures, but they do not reflect pattern of usage. Electronic monitors are recently available for accuracy of MDI use.20 Dry Powder Inhalers In an attempt to overcome the coordination problem that is required for the successful use of the pressurised MDIs, a number of dry powder inhalers have been developed. In the dry powder system, micronised drug is mixed with a carrier substance (lactose) and the mixture is filled into a gelatin capsule. The capsule is loaded into the inhaler device and is cut open in the device before inhalation (Fig. 11.2). After piercing or fracturing the gelatin capsule, the patient only needs to do is to inhale through the device to draw the powder out of the capsule. The aerosol is generated by means of the energy contained in the inspired air. The air stream passes the powder in such a way that a turbulent flow is formed which breaks up the particles into a dust or aerosol. The higher the inspiratory flow rate (>60L/min), higher the number of respirable particles. Although it is easier to use than a MDI, it is less convenient because of the need to load the capsule before use. Because of a high flow rate, many patients, particularly children, cannot generate a sufficient inspiratory flow required to break up the aggregates during an acute attack. Thus, too large particles are unable to penetrate into lung periphery. Further, in the panic and distress of an acute situation, the patient may have difficulty in inserting the capsule into the device. Inhalation of the dry

Fig. 11.2: Dry powder system

Inhalation Therapy 179 powder may cause some irritation and cough in some patients. The gelatin capsules are subject to environmental influences of moisture and temperature during storage. This will make the capsule soggy and could not be broken by the system efficiently. Thus, they may be reserved for those who cannot master the technique of MDI. Recently, a multi-dose, ready to use, additive free dry powder inhaler effective at low inspiratory flow rates are available which can overcome the above difficulties. Different types of DPI such as Turbohalers, Diskhalers, and Accuhalers are available now. These devices have the advantage of being breath activated, and delivery of an accurate dose is less dependent on patient technique. Recently, new generation multi-dose dry powder inhaler (MDPI) is available, which has a triple inhalation control system, so that the patient has acoustic (click), visual (dose counter), and sensory (oropharyngeal sensation confirmation of dosing. Other mandatory features of the DPI are an accurate metering system, a dose counter, and a robust compact design. A unique feature in terms of cost and flexibility is that the inhaler utilises replaceable cartridges that contain up to 200 doses, with the future potential for a wide range of therapies.21 Nebulisers In nebulisation, small droplets are generated suitable for inhalation from a nebulising solution containing the drug. Two types of nebulisers are used for this purpose: a. the Jet nebuliser (Fig. 11.3) which is powered by compressed air or oxygen from a compressor or a cylinder; and b. the ultrasonic nebuliser which derives the energy required to make an aerosol from high frequency sound waves (Fig. 11.4). Nebulisers need a power source and use of nebulisers is time consuming. However, they are useful in very young children or adult patients who cannot manage the use of inhalers and for delivery of large doses of bronchodilators as in acute severe asthma. In addition they are used for delivery of drugs that cannot be formulated in a MDI because of technical reasons since very high doses cannot be packed and for bronchial challenge tests and lung ventilation scanning. The main advantage of nebulisers is the ease of use by patients. It can be inhaled with normal tidal breathing through a mouthpiece or a face mask. Since they can be driven by oxygen, this becomes an extra advantage in acute asthma. Moisture obtained from wet aerosol may be helpful in loosening the mucus. Nebulised bronchodilators can also be administered through pressure-cycled ventilators. Jet nebulisers driven by oxygen/compressed air needs a flow rate of at least 6-8 litres/min generate aerosol particles in the respirable range. The solution used for nebulisation needs to be diluted with isotonic and preservative-free solutions to reduce drug loss due to impacting of aerosols in the dead space of the apparatus. A minimum volume fill of 4 ml (drug + normal saline) with a flow of 6 litres/ min. is recommended to ensure a high aerosol output, small particle size, And short treatment time. In infants, the small minute volume of 3-3.5 litres compared to the nebuliser output of 6 litres/min limits the amount of the drug to be inhaled. Hence, they will need a higher dose. Other precaution to be taken is that the interior of the container be cleaned thoroughly after use to avoid bacterial (Pseudomonas aeruginosa) contamination and the air intake grill and filters to avoid Aspergillus contamination. The choice of the particular nebuliser is important as not all of them produce desired aerosols. As with MDI, only about 10-12% of the drug can reach the lungs, most of it being retained as

180 Bronchial Asthma

Fig. 11.3: Jet nebuliser

Fig. 11.4: Ultrasonic nebuliser

large droplets on the internal walls of the nebuliser itself. Thus, in an acute attack of bronchial asthma, a properly used MDI with a spacer is as effective/useful as a nebuliser. The main advantages of inhalation devices are the greater asthmatic effect (10-20 times of an oral dose is required to produce an equivalent response as by inhalers), rapid onset of action and response, self administration on demand. Short-term prophylaxis and lack of side effects are the other advantages. Various problems of inhaler use include Hand-Lung dyscoordination (failure of timing the inspiration with dose release), cold freon effect, inspiration and breath holding, and cough on inhalation of aerosol. All aerosolised medications that are used for the treatment of asthma are available as metered-dose inhalers (MDI) which are pressurised and propellant-powered; or jet and ultrasonic nebulisers which are electrically powered. The advantage of delivering drugs directly into the airways is that high concentrations of drug can be delivered to the airways, while systemic side effects are usually avoided. The major disadvantage of this mode of drug delivery is that training and skill are required to coordinate activation of the MDI with inhalation of the drug. Therefore, teaching of proper MDI techniques is very essential

Inhalation Therapy 181 since only about 10% of the inhaled dose penetrates the lower airways, even with optimal techniques. It is generally agreed that maximum delivery of aerosol into the airways is obtained by inhaling an aerosol bolus from functional residual capacity. A flow rate of less than 1 L/sec, with an inhalation time of over 5 second and a breath holding time of 10 seconds is believed to be the optimal technique. There are two different general approaches to inhalant techniques with MDI: the open mouth and closed mouth techniques. In the open mouth technique the inhaler is held approximately 4 cm in front of an open mouth. Other delivery devices which have been developed in an attempt to overcome the disadvantages of pressurised MDI include the Roto-Haler, Gentle-Haler, Autohaler, and Turbohalers. The most important device is the “spacer” which may be a cone spacer or a tube spacer. Spacer Devices Spacer device is an extension chamber interposed between the mouth piece of the MDI and the mouth of the patient (Fig. 11.5). This device allows time and distance for the aerosol to travel in space before it is inhaled. The particle size is reduced because of evaporation of the liquid propellant. The aerosol velocity is also reduced because of resistance offered by air in the space. Smaller particle size helps better deposition in the peripheral airways and reduces deposition in the oropharynx. The slowed down particles held in the chamber can be inhaled few seconds later after the release and there is no need of synchronisation of inspiration and actuation. This simplifies inhaler use and quite helpful in those who have coordination problems. Spacer devices are usually of two types: small volume spacers (tube spacers) and large volume spacers or valved spacers of the volume of about 750 ml. The aerosol cloud emerging from the MDI expands into a conical shape as it moves away. The conical shape of the spacer accommodates the enlarging cloud. The spacer is such that impaction loss on the walls is minimal. The one way valve opens during inspiration and closes during expiration. This helps retaining the modified aerosol in the chamber until it is emptied by inhalation. The expired air leaves the mouth piece through a side port. It is calculated by laser holography studies that one cubic millimeter of air within a spacer is about 5500 at the end of 5 seconds and is still 3300 after 30 seconds of actuation. The mass median diameter of the aerosol from an MDI is reduced from 8.4 to 4.9 microns making possible most of the particles to be in the respirable range. Lung deposition is increased by 133% and reduces throat deposition by 90%.

Fig. 11.5: Spacer

182 Bronchial Asthma REFERENCES 1. Hillman B. Aerosol deposition and delivery of therapeutic aerosols. J Asthma 1991;28:239. 2. Newman SP, Clarke SW. Therapeutic aerosols 1- Physical and practical considerations. Thorax 1983;38:881-86. 3. Newman SP. Aerosol deposition consideration in inhalation therapy. Chest 1985;88(Suppl):S15260S. 4. Sackner MA, Kim CS. Auxillary MDI delivery systems. Chest 1985;88(Suppl):S161-S69. 5. Newhouse MT, Dolovich MB. Control of asthma by aerosols. N Engl J Med 1986;315:870-74. 6. Summer W, Elston R, Tharpe L, Nelson S, Haponik EF. Aerosol bronchodilator delivery methods. Arch Intern Med 1989;149:618-23. 7. Noakes TJ. CFCs, their replacements and the ozone layer. J Aerosol Med 1995;8(Suppl):S3-S7. 8. Smith IJ. The challenge of reformulation. J Aerosol Med 1995;8(Suppl):S19-S27. 9. Fischer DA, Hales CS, Wang WC et al. Model calculations of the relative effects of CFCs and their replacements on global warming. Nature 1990;344:513-16. 10. CPMP on possible alternatives to CFCs. Scrip 1994;1943:26. 11. Furukawa C, Atkinson D, Forster TJ et al. Controlled trial of two formulations of cromolyn sodium in the treatment of asthmatic patients > 12 years of age. Chest 1999;116:65-72. 12. Busse WW, Brazinsky S, Jackobson K et al. Efficacy response of inhaled beclomethasone dipropionatein asthma is proportional to dose and is improved by formulation with a new propellant. J Allergy Clin Immunol 1999;104:1215-22. 13. Davies RJ, Stampone P, O’Conner BJ. Hydrofuoroalkane 134a beclomethasone dipropionate extrafine aerosol provides equivalent asthma control to chlorofluorocarbon beclomethasone dipropionate to approximately half the total daily dose. Respir Med 1998;92(Suppl A):23-31. 14. Gross G, Thompson PJ, Chervinsky P et al. Hydrofuoroalkane 134a beclomethasone dipropionate, 400 μg is as effective as chlorofluorocarbon beclomethasone dipropionate 800 μg for treatment of moderate asthma. Chest 1999;115:343-51. 15. Leach CL. Improved delivery of inhaled steroids to the large and small airways. Respir Med 1998;92(Suppl A):3-8. 16. Juniper EF, Price DB, Stampone PA et al. Clinically important improvements in asthma-specific quality of life, but no difference in conventional clinical indexes in patients changed from conventional beclomethasone dipropionate to approximately half the dose of extra fine beclomethasone dipropionate. Chest 2002;121:1824-32. 17. Langley SJ, Holden J, Derham A et al. Fluticasone propionate via the disk haler or hydrofluoroalkane-134a metered-dose inhaler on methacholine-induced airway hyper-responsiveness. Chest 2002;122:806-11. 18. Nayak A, Lanier R, Weinstein S et al. Efficacy and safety of beclomethasone dipropionate extra fine aerosol in childhood asthma. A 12-week, randomised, double-blind, placebo-controlled study. Chest 2002;122:1956-65. 19. Leach CL, Davidson PJ, Hasselquist BE, Boudreau RJ. Lung deposition of Hydrofluoroalkane 134a beclomethasone is greater than that of chlorofluorocarbon fluticasone and chlorofluorocarbon beclomethasone. Chest 2002;122:510-16. 20. Julus S, Sherman JM, Hendeles L. Accuracy of three electronic monitors for metered dose inhalers. Chest 2002;121:871-76. 21. Hansel TT, Kunkel G. New horizons in asthma therapy: The Novoliser dry powder inhaler. Curr Opinion Pulm Med 2001;7(Suppl 1):S1-S2.

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12 Therapeutic Approach in Patients with Asthma I. Chronic Bronchial Asthma Asthma is a chronic condition with acute exacerbations having variable course. The course of disease is not uniform with periods of exacerbations and remissions which varies from days to weeks to months to years. Management therefore, requires a continuous care approach to control symptoms, prevent exacerbations, and reduce chronic airway inflammation. The course of asthma varies among patients. The degree of an individual’s asthma severity may change from one season or year to the next. Therefore, specific asthma therapy must be selected to fit the need of individual patients. The therapy must be adaptable to change as the disease changes in the individual. Over the years a number of guidelines have been developed. Notable amongst them are those of the National Heart, Lung and Blood Institute of the NIH, USA, British Thoracic Society, Research Unit of the Royal College of Physicians of London, the King’s Fund Center, the National Asthma Campaign, Global Initiative for Asthma and WHO.1-11 The basic principles are the same in all these guidelines. Management of bronchial asthma can be divided into that for chronic asthma and acute severe asthma. CHRONIC BRONCHIAL ASTHMA—AIMS OF THERAPY The basic goals or aims of management of chronic asthma are: i. To recognise asthma and its severity ii. To abolish symptoms particularly those of the chronic troublesome ones like nocturnal cough and dyspnoea, and early morning symptoms iii. To maintain normal activity levels including exercise iv. To maintain a normal or near normal or the best possible long-term pulmonary functions v. To prevent recurrent exacerbations of asthma and the risk of severe attacks vi. To minimise absence from school or work vii. To enable normal growth to occur in children viii. To minimise the need for as needed (quick-relief) β2-agonist therapy ix. To avoid adverse effects from asthma medications x. To meet patients’ and families’ expectations of and satisfaction with asthma care.

184 Bronchial Asthma PRINCIPLES OF MANAGEMENT Certain basic principles of bronchial asthma needs to be considered before administering any specific therapeutic modalities. i. Since there are many conditions which mimic bronchial asthma, the diagnosis should be established. ii. It should also be realised that asthma is a chronic condition with acute exacerbations with varying periods of remissions. There is no cure of bronchial asthma but if the patient follows certain guidelines including medications, the disease can be controlled and the patient can lead life like a normal individual. Treatment requires a continuous care approach to control symptoms, to prevent exacerbations, and to reduce airways inflammation. iii. Asthma is an inflammatory disease and inflammation may continue even during periods of clinical remission and even in patients with mild asthma. Therefore antiinflammatory treatment is an essential component of management of bronchial asthma. iv. The severity of asthma must be evaluated by assessing the activity limitation, by evaluation of night time symptoms and by assessing pulmonary function. v. The therapy selected should not have adverse effects that are perceived by the patient to be worse than the underlying disease. The therapy is usually dictated by the severity of disease, medication tolerance, and sensitivity to environmental allergens. All these factors need to be incorporated in the formulation of therapy. vi. It is essential to deal with common asthma triggers. Environmental control measures must be under taken to avoid allergens. All types of smoking should be stopped and exposure to passive smoke should be eliminated. Inhaled β2−agonist or Cromolyn sodium or both taken prior to an anticipated encounter with a known trigger can prevent or diminish an asthmatic response. This is particularly true for exerciseinduced asthma. The same principle can also be applied to other situations, including exposure to antigens like animal danders, cold air, or other irritants. Both adults and children who has upper respiratory tract viral infections, and start to have acute asthma symptoms may need to add or increase anti-inflammatory asthma medications in order to control the asthma symptoms. Bacterial otitis and sinusitis should be treated with antibiotic therapy. Sometimes aggressive antiasthma therapy fails because an upper respiratory infection has been overlooked. Allergic and nonallergic rhinitis should be treated with antihistamines, Cromolyn sodium nasal spray, or topical nasal steroids. The patient must be taught to avoid: a. Beta blockers (tablets and eyedrops) are contraindicated. b. If aspirin or NSAIDs are known to induce asthma, they should be avoided. c. Allergens as outlined above (e.g.; house-dust mite, domestic pets, and pollens. should be avoided where relevant. d. Occupational causes must be considered and appropriate steps be taken. e. Active smoking should be avoided. f. Passive smoking should also be avoided. g. Prophylactic treatment for exercise or before exposure to triggers. vii. Anticipatory or early interventions in treating acute exacerbations of asthma reduce the likelihood of developing severe airway narrowing. viii. Asthma therapy has the following integral components:

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a. Patient education and family participation b. Avoidance of identified causes where possible c. Use of the lowest effective dose with a target of controlling asthma but with the minimum of short and long term side effects. The above three approaches are interrelated in the management and pathogenesis of bronchial asthma are shown in Figure 12.1. PATIENT EDUCATION Health education by the physician is a powerful tool for helping patients gain the motivation and skill to control their asthma.12-15 There is definite evidence of benefit from patient education and the issuing of self management plans. Management of asthma requires a partnership between the patient and family and the health care provider. It should be made clear from the very beginning that treatment and supervision are likely to be required over a prolonged period of time. Education should be the basis of sharing of information and the acquisition by the patient and family of understanding and skills. This will bring about appropriate change in behaviour only if patients and family are given adequate opportunity to express any fears or concerns, and time to discuss their expectations of both the disease and its treatment. Patients and parents require both verbal and written advice and many will require guided self management plans, so that the patient can keep well and adjust treatment according to a plan developed with the physician. Giving information alone does not alter behaviour, but written and audiovisual reinforcement of spoken message aids patient confidence. All patients should be given information about features which indicate when their asthma is worsening, and what to do under those circumstances. Giving those with asthma written self management plans so that they may adjust treatment to keep themselves well reduces morbidity and health costs.16,17

Fig. 12.1: Approach to therapy of bronchial asthma depending upon the aetiopathogenesis

186 Bronchial Asthma Various components of patient education plan includes: i. Establishing a partnership which improves the patient adherence to the treatment plan and stimulate family effort to improve control of patient’s asthma18,19 ii. Encouraging adherence to the treatment plan is the next step which can be achieved by clarifying patient’s expectations for treatment and answering questions,20 involving the patient and family in the development of a treatment plan, simplifying the treatment plan, providing the patient with diaries to record antecedents of asthma exacerbations, symptoms, actions taken, and peak expiratory flow rates. Further, an important question to be kept in mind whether that patient can afford to buy the medications prescribed, and if not, alternative therapies must be considered. Ignoring this fact is a very important cause of non-adherence to treatment prescribed. Evaluation of the result of treatment from time to time helps positive reinforcement plans. If the patient is not adhering to the treatment plan, then the cause for the same to be identified by asking the patient the likely problems and a possible solution for the same should be provided. iii. Various essentials of patient education includes the content of teaching both written and audiovisual, explaining to the patient about asthma like what is it, what are the key points about the symptoms and signs of asthma, the role of inflammation and the role of various medications, asthma triggers and how to avoid them, the need for treatment, how the medicines work, adverse effects of drugs and their prevention, preventive treatment, and early treatment during exacerbations, alleviating patient fears concerning medications, providing written guidelines, and steps to manage asthma episodes at home. iv. The correct use of inhalers should be demonstrated to the patient.21,22 Similarly, the patient should demonstrate the use of the MDI to the clinician. The patient’s MDI technique should be reviewed during each visit. When several inhalers are prescribed, labelling them is essential and also explaining when to use which one and which inhaler to be used first. v. The patient should be able to recognise the early warning symptoms or signs of airflow obstruction which will enable him to begin treatment immediately. Early warning signs include a peak flow level below 20% predicted or personal best level; cough or wheeze, particularly during daily activity; an individual pattern of early signs such as chest tightness, shortness of breath, or dark circles under the eyes in children. Indications of immediate report to emergency include cyanosis, difficulty in breathing, talking or walking, retraction of the chest, neck or ribs and nasal flaring, failure of medications to control worsening of symptoms, and a steady decline of PEFR. vi. Knowledge of the optimal use of home peak expiratory flow meter—both its recording and interpretation are now one of the essential components of asthma management. vii. Materials and guidelines for individuals and group education and support network are very helpful. The education must continue in a long-term basis. discussions, demonstration, group classes, and dramas help patients learn guided self-management skills. The most effective is for the health care professional to give information verbally, demonstrate techniques, and then provide reinforcement by several routes. The specific methods should be selected on the basis of patient and cultural preferences. Some patients benefit from joining asthma patient support groups or clubs. These groups vary from area to area, but most provide informative materials, group education, and

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mutual support. Group members exchange personal tips on managing asthma, making changes at home, and coping with the stress of a chronic disorder in the family. Currently asthma education worldwide websites are available. However, asthma education material contains many accessibility barriers, is highly variable in quality, and content, and takes little innovative use of technology. These informations currently available in the web fails to meet the information needs of the patient.23 The patient must be made to understand that there are new ways to manage their disease so that they can prevent problems, be free of symptoms both day and night, and live productive, active lives. They can learn to control their asthma, handle mild attacks promptly at home, and prevent serious attacks. Emergency visits should no longer be needed. Regular medical visits provide periodic opportunities to address concerns, solve problems, and reach agreement on long-term treatment. This is achieved by having the patient become actively involved as a partner in his or her care through guided self-management. Guided self-management means a patient can take medications correctly; understand the difference between quick-relief and long-term preventive medications, avoid triggers; monitor personal status using symptoms and if possible, PEFR indicators; recognise signs that asthma is worsening and take action; follow personalised action steps and stop attacks; and seek medical help at the appropriate time to stop serious attacks. Long-term asthma control requires a written management plan that describes what to do to prevent symptoms and attacks and what to do in case an attack occurs. An asthma management zone system is effective for guided self-management and should be included in the management plan. This system classifies levels of asthma control as different zones based on the frequency and severity of symptoms and peak expiratory flow measurements. The system then indicates the appropriate therapy for each zone. The zone system helps patients understand the chronic and variable nature of asthma, monitor their condition, identifies the earliest possible signs that day to day control of asthma is deteriorating, and act quickly to regain control. When PEFR readings are available, the patient’s current reading must be compared to his or her personal best—the highest PEFR value achieved when the patient’s asthma is under control—is his benchmark for asthma control. The patient then follows the prearranged action steps appropriate to each of the following three zones. Green zone It indicates all clear. Asthma is under control with no symptoms or interruption of activities or sleep. PEFR are usually 80-100 percent of personal best. The variability is less than 20%. If the patient has stayed for at least 3 months in this zone, a careful stepdown of the therapy can be considered as outlined below. Yellow zone This signals caution. Some mild asthma symptoms are present. PEFR readings are 60-80% of personal best. There is 20-30% variability. Readings in this zone indicates that an acute attack may be present for which a temporary increase in medication is needed, essentially β2−agonist inhalers for quick relief. The patient should develop a treatment plan with the physician. Also it is possible that an overall deterioration of asthma might have occurred that require further treatment. A short burst of corticosteroids will be required till the PEFR comes back to the green zone. In case the patient is taking inhaled steroids, that should be doubled for 12 weeks or until PEFR improves. Frequent fluctuations into the yellow zone may indicate poor control of asthma and the green zone therapy has to be increased. Red zone This indicates medical alert. Asthma symptoms are present even when the patient is at rest or interfere with activity. PEFR readings are below 60% of the personal best. The

188 Bronchial Asthma patient should follow medication plan. An inhaled short-acting β-agonist should be taken immediately. If the PEFR improves after initial bronchodilator therapy, the yellow zone actions should be continued. After the attack is controlled, the green zone therapy and patient adherence to the management plan should be reviewed and adjusted accordingly. IMMUNOLOGICAL MANAGEMENT Although the benefits of immunotherapy remains unproven, this form of therapy is still widely practiced by many physicians. Since allergy has a significant role in the pathophysiology of bronchial asthma, environmental control measures to avoid allergens is an important step in the control of bronchial asthma. The main method of identifying allergy is by clinical history. Skin prick tests and in vitro specific IgE measurements are rarely helpful in diagnosis and management and should be interpreted by a physician familiar with such tests. In general both active and passive smoking should be avoided. Outdoor Allergens Exposure to outdoor allergens is best reduced by remaining indoors, preferably in an air conditioned environment,24,25 particularly during the midday and afternoon when pollen and some mould spore counts are highest. Since there is a geographical and seasonal variation of pollens and other aeroallergens, knowledge of the same is helpful. Use of nasal filters or masks have been tried with little success. Pollen particles greater than 10 microns are usually cleared in the nose and mouth and do not generally penetrate the lower airway.26 However, some plants produce allergen containing particles that are in the respirable range like ragweed, and congress grass pollination, which are clearly associated with asthma. Mould spores are generally smaller than pollen grains and are more likely to penetrate the lower airway. Mould spores exist primarily out of doors and tend to be seasonal. Some fungi sporulate on worm, dry summer days; others in the rainy seasons. Keeping windows closed during seasons of high mould production will reduce exposure. Indoor Allergens Environmental control to reduce exposure to indoor allergens is a critical component of asthma management. House dust is an important source of indoor allergens. Although house dust per se is not an allergen, there are allergic components in house dust. The most important include mites, cockroach allergen, and animal danders.

Animal Allergens The best way to avoid animal allergens are just to remove the animal from the house (dog, cat, rodents, birds, etc). Removal of the animal may not afford immediate relief even when followed by vigorous cleaning as allergen has been shown to remain in the home for many months.27 Residual allergen can be denatured and rendered nonallergenic by application of 3% tannic acid solution. If the pet cannot be removed from the house, it should at least be kept out of the allergic person’s bedroom at all times. If the animal is in the bedroom at all, the dander and saliva will remain for a long time even after the pet leaves. Weekly washing of the pet may reduce the amount of dander and dried saliva deposited on carpets and furnishings. The

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most reliable reduction of exposure to allergens derived from furred pets is done by completely excluding the pet from the home and avoiding exposure to pets elsewhere. It is of course not possible always. It is important to make patients aware of the choices they are making like more medications, decrease in health related quality of life and to reexamine these choices on a regular basis. Patients are often interested in alternatives to excluding the pet from the home. In such a situation, there is hardly anything other than complete avoidance can benefit asthmatic patients with a documented pet allergy.28 Since there is a dose-response relationship between parameters of asthma control, and exposure to allergens, it seems reasonable to keep the cat out of the bedroom, living room, and play- room. Washing of pets as mentioned above has given variable results and must be repeated so frequently as to be impractical in most situations. Settled allergens will be removed by methods of removal of house dust (see on page 191). Cat and dog allergens, as opposed to dust mite allergen, are often found on small particles that are easily airborne. This renders the use of air filtration devices attractive. Due to small particle size of airborne allergens, HEPA cleaners are likely required. Significant health benefits are not documented despite the reduction in the amount of airborne particles,29 although an improvement in bronchial hyperresponsiveness has been found in cat allergic children.30 In a recent meta-analysis, it is reported that use of air filtration systems in patients with asthma or allergy showed a reduction in symptoms, but not of medication use, and no improvement in measures of peak flow.31

House-dust Mite House-dust mites are important causes of allergic asthma. They occur in environments with sufficient humidity since they are quite dependent for survival on moisture from atmosphere. Mite antigen is found throughout the home, wherever human dander, the food for the mite, is found. High levels are obtained in dust obtained from mattresses, pillows, carpets, upholstered furnitures, bedcovers, clothes, and soft toys.32 The principal allergen is found in the mite faeces. A gram of dust may contain 1,000 mites and 250,000 faecal pellets. These faecal pellets are quite large varying in size from 10-40 microns, and therefore do not easily penetrate the lower respiratory tract. Mite antigen is easily demonstrated in the air during housecleaning activities, but it is present in only very small amounts in undisturbed air.33 Some mite allergen is associated with smaller size particles that may be in the respirable range for the lower airways.34 House-dust mite control measures include encasing the mattress in an airtight cover; the pillows are also to be encased and be washed weekly; the bedding should be washed in water at 130° F or 55° C weekly and dry thoroughly in a hot dryer or in the sun; curtains and children’s soft toys are to be washed regularly; the patient should avoid sleeping or lying on upholstered furnitures; and carpets laid on concrete are to be removed, if possible the indoor humidity is to be reduced to less than 50%; carpets may be removed from the bedroom; and ascaricides may be useful in killing the mites.35-38 If carpet removal is not possible, vacuuming should be carried out with a high-efficiency particulate air (HEPA) vacuum cleaner with a double reservoir bag, preferably when the asthmatic patient is not present. Central vacuum cleaners exhausted to the outside are also likely to be effective.39 Such a multifaceted and concerted approach to reducing levels of dust mite allergen among asthmatic subjects with positive allergy skin test results to mite allergens, if successful, is clearly associated with improvement in the parameters of asthma control like symptoms, need for medications, measures of airflow, and measures of bronchial hyperresponsiveness.40

190 Bronchial Asthma

Cockroach Allergen It is important in warmer climates.41 The infested homes should be cleaned thoroughly and regularly. Pesticides and pesticide sprays are used to eliminate cockroaches. If sprays are used the patient should not be present at that time.

Indoor Moulds These are found in environments with increased humidity. Bathrooms, kitchens and basements require adequate ventilation and frequent cleaning using chlorine bleach if necessary. Dehumidifiers for damp basement areas should be considered, with humidity levels for less than 50% but above 25%. The unit should be cleaned regularly. Perspiration on foam pillows may encourage mould growth. Pillows should be encased or changed regularly.

Other Precautions Since vacuum cleaners are prone to mobilise fine respirable allergen particles, allergic patients should not vacuum or if they do so, they should use a dust mask, or use a vacuum cleaner with a high efficiency particulate air filter. Air conditioning is helpful since the windows and doors need to be closed and it reduces indoor humidity discouraging mould and mite growth. Humidifiers are potentially harmful. The patient should avoid tobacco smoke, both active and passive. Wood smoke and other smoke from domestic cooking should be avoided as they are known to increase respiratory symptoms. To avoid this, all furnaces and stoves are to be vented outside and the room is to be kept well-ventilated. Strong odours or sprays produced by cosmetics like perfumes, talcum powder, room deodorisers, frying, household cleaning products, and fresh paints irritate some patient’s airways and trigger asthma symptoms. Those affected by such odours should avoid them. Exposure to air pollutants like oxidants and sulphur oxides and ozone has been associated with worsening pulmonary function and increased airway hyperresponsiveness in persons with asthma. These environmental exposures may interact with allergens and other triggers in the causation of bronchial asthma. Other precipitating factors like gastroesophageal reflux, sulphite sensitivity, and medication sensitivities need to addressed in all patients. All patients with asthma deserve an allergy evaluation to identify sensitisation to common inhaled allergens. Avoidance of allergens to which a patient with asthma is sensitised is an integral and effective part of asthma management. Indoor allergens are of particular importance because of the most part of the time spent indoors. The indoor allergens most likely to be relevant are dust mites, cockroaches, and furred pets. Avoidance measures for dust mites,42 and cockroaches,42 are probably effective at improving asthma control if the measures are strictly adhered to. Air filtration devices are unlikely to be important or effective over and above the more usual measures, given the characteristic distribution of these allergens at home. Air filtration devices are effective at reducing levels of pet allergen in home and may improve asthma control when combined with exclusion of the pet from the bedroom. This is likely to be less effective than ridding off the pet from the home completely.43 IMMUNOTHERAPY The role of specific immunotherapy in asthma management is controversial and is under continual investigation. In fact, the British Thoracic guidelines clearly mentions that the

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hyposensitisation or immunotherapy is not indicated in the management of chronic bronchial asthma in adults.9 Currently available medications and avoidance strategies usually provide good control of asthma. Allergen avoidance is always the first recommendation for managing asthma symptoms. However, when avoidance is not possible and appropriate medications fail to control symptoms of allergic asthma, referral for allergy immunotherapy may be considered.1 Allergy immunotherapy has been shown to reduce symptoms of asthma with a variety of allergens including house dust,44 cat dander,45 grass pollen,46 and alternaria .47 They also reduce the threshold for skin or lungs to the allergen employed and the late reaction to allergens in the lungs are also reduced.48 However, their efficacy in the overall clinical management remains controversial. Response to allergy immunotherapy decreases with age and with lower baseline levels of pulmonary function.49 If immunotherapy is administered, it is recommended that once patient achieves maintenance levels of immunotherapy, the interval between injections should be extended, with a goal of monthly injections. If the patient’s symptoms improve, treatment is usually continued for 3-5 years, although under some situations more prolonged therapy at monthly intervals may be needed. If there is no evidence of response following two allergy seasons after reaching the maintenance or the highest level tolerated by the patient, immunotherapy should be discontinued. Allergy immunotherapy should only be administered in a physician’s office who is well versant with the therapy and where facilities and trained personnel are available to treat any life-threatening reaction that can occur, which is a very rare situation. PHARMACOLOGICAL THERAPY Pharmacological therapy for bronchial asthma is often described as “step care”, in which the number of medications and frequency of administration are increased or decreased as necessary. The possibility of toxicity is also increased with this approach. The patient must have medication, an inhaled β2−agonist, available for acute relief of symptoms. If symptoms occur frequently (more than two times a week), preventive therapy is necessary in addition to rescue treatment. Rescue treatment itself has a step-care pattern, adding medications as necessary to control symptoms. Increasing use of rescue treatment by the patient is an indication to review the medication plan and possibly to increase preventive therapy. As asthma is a chronic inflammatory condition, anti-inflammatory treatment should be given to most patients. Treatment is to be considered in a step-wise manner as shown in Figure 12.2. In addition to those depicted in the figure it is essential that: a. The patient should avoid provoking factors whenever possible b. Patient involvement and education should be an integral part c. The best inhaler device should be selected d. Treatment may be stepped up as necessary to achieve good response e. Treatment may be stepped down if control of asthma is good and f. A peak expiratory flow meter may be prescribed to monitor response to treatment. The patient should start treatment at the step most appropriate to the initial severity. A reuse course of prednisolone tablets will be necessary at any time and at any step A short “rescue” course of corticosteroid tablets may be needed at any time and at any step to gain control of asthma. The indications of rescue courses of steroids are as follows: • Symptoms and PEFR get progressively worse day-by-day • PEFR falls below 60% of the patient’s best

192 Bronchial Asthma Step V

Regular steroid tablets added Step IV

Step III

Step II

Regular inhaled anti-inflammatory agents Step I

Occasional use of relief oronchodilator Inhaled short acting beta agonists SOS. If needed > 1 daily, move to Step II. Before altering a step ensure that the patient is having the treatment and having proper inhalation.

Inhaled short acting beta agonists SOS plus beclomethasone or budesonide 100-400 mcg bd or fluticasone 50-200 mcg bd or cromoglycate or nedocromil. If no control, start inhaled steroids.

High dose inhaled steroids and regular bronchodilators

Inhaled shortacting beta agonists SOS plus beclomethasone or budesonide 800-2000 mcg od Inhaled shortor fluticasone acting beta 400-1000 mcg od agonists SOS + via spacer plus 1 beclomethasone or or > 1 of inhaled budesonide 400long-acting beta 1000 mcg od or agonist sustained fluticasone 400release theophyl1000 mcg od via line inhaled spacer plus 1 or > ipratropium or 1 of inhaled longoxytropium longacting beta agonist acting beta sustained release agonist tablet theophylline high dose inhaled inhaled ipratropium bronchodilators or oxytropium cromoglycate or long-acting beta nedocromil agonist tablet high dose inhaled bronchodilators cromoglycate or nedocromil

High dose inhaled steroids or low dose inhaled steroids + longacting inhaled beta agonist

Inhaled shortacting beta agonists SOS plus beclomethasone or budesonide 800-2000 mcg od or fluticasone 400-1000 mcg od via large volume spacer and one or more of the longacting bronchodilators plus regular prednisolone tablets in a single daily dose

Stepping down

Review every 3-6 months

Fig. 12.2: Step-care management of bronchial asthma (BTS)

• • • •

Sleep is disturbed by asthma symptoms Morning symptoms persist till midday Diminishing response to inhaled bronchodilators Emergency use is made of nebulised or injected bronchodilators. In an adult, 30-60 mg of prednisolone is given immediately. This dose is to be continued in a single morning dose till two days after control is achieved. The drug is then tapered.

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The appropriate treatment with different drugs in various steps are summarised below: Step 5 Addition of Regular Steroid Tablets Inhaled short-acting beta agonists as required with inhaled beclomethasone or budesonide 800-2000 μg daily or fluticasone 400-1000 μg daily by a large volume spacer and one or more of the long-acting bronchodilators with regular prednisolone in a single daily dose. Step 4 High dose inhaled steroids and regular bronchodilators Inhaled short-acting β-agonists as required with inhaled beclomethasone or budesonide 800-2000 μg daily or fluticasone 400-1000 μg daily through a large volume spacer plus a sequential therapeutic trial of one or more of inhaled long-acting beta agonist or sustained release theophylline or inhaled ipratropium or oxytropium or long-acting beta agonist tablets high dose inhaled bronchodilators or cromoglycate or nedocromil. Step 3 High dose inhaled steroids or low dose inhaled steroids plus long-acting inhaled beta agonist bronchodilator Inhaled short-acting beta agonists as required plus either beclomethasone or budesonide increased to 800-2000 μg daily or fluticasone 400-1000 μg daily through a large volume spacer or beclomethasone or budesonide 100-400 μg twice daily or fluticasone 50-200 μg twice daily. In a very small number of patients who experience side effects with high doses of inhaled steroids, either the long-acting inhaled beta agonist or a sustained release theophylline may be added to step 2 medications. Cromoglycate or nedocromil may also be tried. Step 2 Regular inhaled anti-inflammatory agents Inhaled short-acting beta agonists as required plus beclomethasone or budesonide 100-400 μg twice daily or fluticasone 50-200 μg twice daily. Alternatively, use cromoglycate or nedocromil sodium. If control is not achieved start inhaled steroids. Step 1 Occasional use of relief bronchodilators Inhaled short-acting beta-agonists as required for symptom relief are acceptable. If they are needed more than once daily move to step 2. Before altering a treatment step, it must be ensured that the patient is having the treatment and has a good inhaler technique. Any fear the patient might be having must be addressed. The possible outcome with various steps of treatment are shown below. Outcome of steps 1-3: Control of asthma Outcome of step 4-5: Best possible result • Minimal or no chronic symptoms • Least possible symptoms • No nocturnal symptoms • Least need for relief bronchodilators • Infrequent exacerbations • Least possible activity limitations • Minimal need of relief bronchodilators • Least possible variation in PEFR • No activity or exercise limitations • Best PEFR • PEFR variation < 20%, PEFR 80%/more • Least adverse reactions from drugs • Minimum side effects from drugs The expected line of therapy and possible outcome in different grades of asthma are depicted in Figure 12.3. For patients who have established control of their asthma, regular follow up visits at approximately 1 to 3 month intervals are necessary to review the treatment plan, the patients management techniques including use of medicines, peak flow measurements, etc. For many

194 Bronchial Asthma

Fig.12.3: Step-care management of asthma and expected outcome

patients with moderate to severe asthma, control of the disease as reflected in normalisation of pulmonary function and activity levels without symptoms, can be maintained with only continuous preventive therapy. The aim of therapy should be to use the minimum medication needed to maintain control with minimum risk for adverse effects. Reduction of therapy can be carefully considered if PEFR variability is less than 10% and there are no asthma symptoms for a reasonable period (2-3 days for the exacerbation in mild asthma, several weeks for moderate or severe asthma). If PEFR variability is greater than 10-20%, evaluation of the patient’s technique in using the medication, find out environmental aggravators and the patient’s efforts to control them will be necessary. The possibility of concomitant upper respiratory tract disease, and the possibility of increasing the dosage or change of medications may also need to be considered. Recently the Expert Panel Report 2 of the National Institute of Health has published guidelines for the diagnosis and management of bronchial asthma in adults and children .50 Although the basic principles of management are the same, some more facts have been highlighted. The basic components of management include: A. Measures of assessment and monitoring. The new guidelines includes additional goal of therapy to meet the expectations of the patient and its family with satisfaction. Periodic assessment of six domains of patient health is highlighted. These include signs and symptoms, pulmonary function, quality of life, history of exacerbations, pharmacotherapy, patient-provider communication and patient satisfaction. The panel also recommends home monitoring of PEFR from twice daily to once in the morning only. If the morning reading is less than 80% of the personal best PEFR, more frequent monitoring may be required. The use of the individual patient’s personal best PEFR is emphasised. It is emphasised that patients of all severity levels are to monitor symptoms to recognise early signs of deterioration. Sample questions to use in periodic assessments are also added. B. Control of factors contributing to asthma severity is important. Skin testing or in vitro testing is now specifically recommended for at least those patients with persistent asthma

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exposed to perennial indoor allergens. Adult patients with severe persistent asthma, nasal polyps, or a history of sensitivity to aspirin or non-steroidal anti-inflammatory drugs are to be counselled regarding the risk of severe and even fatal exacerbations from using these drugs. Routine use of chemicals to kill house-dust mite and denature the antigen is no longer recommended as a control measure. Patients should be treated for rhinitis, sinusitis, and gastro-oesophageal reflux. Annual influenza vaccinations are specifically recommended for patients with persistent asthma. Pneumococcal vaccination is considered not important. C. The importance of pharmacological therapy is very much there and is an important component of asthma management. However, medications are now categorised into two general classes; (a) long-term control medications; and (b) quick-relief medications. While the former are used to achieve and maintain control of persistent asthma, the later are used to treat acute symptoms and exacerbations. The most effective medications for long-term control are those having anti-inflammatory effects and include drugs like corticosteroids, long-acting β2-agonists, and leukotriene antagonists. The stepwise approach to asthma therapy emphasises initiating a higher level of therapy at the onset to establish prompt control and then stepping down. Corticosteroids are the most important anti-inflammatory drugs and include various inhaled forms as discussed earlier and systemic drugs like methylprednisolone, prednisolone, and prednisone. D. Education for a partnership in asthma care includes providing patients both a written treatment plan for daily self-management and a written action plan for management of exacerbations. However they do not replace, though supplement, the education by the physician. Patient education by the principal clinician as well as other members of the health care team is important. To enhance the delivery of education, detailed questions to elicit information and educational messages for each visit are to be provided. Key messages are to be reinforced during each visit. Further, it is necessary to evaluate the outcome in terms of patient perceptions of improvement, specially quality of life and the ability to engage in desired activities. Patient education for CFC-free inhalers is gaining importance in view of the ban on the use of CFC (chlorofluorocarbons). The Expert Panel50 has changed the classification of the severity of asthma from mild, moderate, severe to mild intermittent, mild persistent, moderate persistent, and severe persistent asthma. The clinical features before treatment are shown in Table 12.1. Stepwise management of bronchial asthma in adults and children over 5 years of age depending upon the above severity criteria as recommended by the NIH Expert Panel is shown in Table 12.2. GENERAL PRINCIPLES OF APPROACH TO TREATMENT OF CHRONIC PERSISTENT ASTHMA i. Treatment of chronic persistent asthma should be considered in a stepwise manner as described above with the patients starting treatment at the step most appropriate for the initial severity of their conditions. ii. The stepwise approach presents general guidelines to assist clinical decision making; it is not intended to be a specific prescription. iii. Since asthma is highly variable; clinicians should tailor specific medication plans to the needs and circumstances of individual patients.

196 Bronchial Asthma Table 12.1. Classification of severity (NIH, USA, 51)

Severity Step 4 Severe persistent

Symptoms

Night time symptoms

• Continuous symptoms • Frequent • Limited physical activity • Frequent exacerbations

Lung function • FEV1 or PEFR 60% or less than predicted • Variability of PEFR > 30%

Step 3 • Daily symptoms Moderate persistent• Daily use of inhaled β2-agonists • Exacerbations affect activity • Exacerbation 2 or more/week • May last days

• > 1 week

• FEV1 or PEFR >60% > or = 80% predicted • PEF variation > 30%

Step 2 Mild persistent

• Symptoms > 2/week, but < 1 day • Exacerbations may affect activity

• > 2 times a month

• FEV1 or PEFR 80% or more • PEF variation 20-30%

Step 1 Mild intermittent

• Symptoms 2 times or less per week • Asymptomatic and normal PEFR between exacerbations • Exacerbations brief

• 2 times or less per month

• FEV1 or PEFR 80% or more • PEF variation < 20%

Note: The presence of one of the features of severity is sufficient to place a patient in that category. An individual should be assigned to the most severe grade in which any feature occurs. The characteristics described above are general and may overlap in view of the variable nature of asthma. Patients at any levels of severity can have mild, moderate, or severe exacerbations. Some with intermittent asthma experience severe and life-threatening exacerbations separated by long periods of normal lung function and no symptoms. Table 12.2: Stepcare management of bronchial asthma50

Step

Long-term control

Step 4 Severe persistent

Daily medications • Anti-inflammatory Inhaled steroids (high dose and long-acting bronchodilators like long-acting inhaled or oral β2-agonist, sustained release theophylline • Oral corticosteroid

Step 3 Moderate Persistent

Daily medications Anti-inflammatory Inhaled steroid (medium

Quick relief

Education

Inhaled β2-agonists • • Intensity of treatment • will depend upon severity of exacerbations • Use of short-acting β2-agonists on a daily basis, or increasing use indicates the need for additional long-term control therapy • Inhaled β2• agonists sos • • Intensity of treatment

As in step 2 and 3 Individual education

Step 1 action plus Individual education if available

Contd...

Therapeutic Approach in Patients with Asthma (Chronic Bronchial Asthma) Contd... Step

Step 2 Mild persistent

Step 1 Mild intermittent

Long-term control dose) or low-medium dose and add a longacting bronchodilator, especially for nighttime symptoms: either long-acting inhaled β2-agonist, sustained release theophylline or long-acting β2-agonist tablets If needed: Anti-inflammatory: Inhaled corticosteroids (medium-high dose) and long-acting bronchodilators, especially for night-time symptoms; either long-acting inhaled β2-agonist, sustained release theophylline, or longacting β2-agonist tablets Daily medications: Anti-inflammatory Either inhaled steroid (low doses) or cromolyn or nedocromil Alternatively, sustained release theophylline. Leukotriene antagonists may also be tried for the patients of 12 yrs or >, although their role in therapy is not fully established. Daily medication not needed

Quick relief

197

Education

will depend upon • Review and update severity of exacerself management plan bations • Use of short-acting β2-agonists on daily basis indicate need for term-control therapy

Short-acting bronchodilator: • Inhaled β2agonist as needed. • Intensity of treatment will depend on exacerbation severity. • Use of short acting inhaled β2-agonists daily or increasing use indicates need for additional longterm control therapy. Short-acting bronchodilator: Inhaled β2agonist sos • Intensity of treatment will depend on severity of exacerbation • Use of above more than 2 times a week may need to start

• Step 1 action + teach self monitoring • Group education. • Review and update self manage ment plan.

• Teach basic facts of bronchial asthma • Teach inhaler spacer/ holding chamber technique • Discuss role of medication management plan • Develop self management plan

Contd...

198 Bronchial Asthma Contd... Step

Long-term control

Quick relief long-term control therapy

Step down Review treatment every 1-6 months a gradual stepwise reduction in treatment may be possible

Education • Develop action plan to when and how to take rescue actions • Discuss appropriate environment control measures

Step up If control is not maintained, consider step up. First, review patient medication technique adherence, and environment control

iv. The control should be gained as soon as possible and then the treatment is to be decreased to the least medications necessary to maintain control. Gaining control may be accomplished by either starting treatment at the step most appropriate to the initial severity of their condition or by starting a high level of therapy like a short course of oral corticosteroids may be needed at any time and at any step to control their asthma as mentioned above. Alternatively, a higher dose of inhaled corticosteroid may be used. v. Patients should avoid all known factors precipitating their asthma. They may be chemicals, certain drugs like aspirin and non-steroidal anti-inflammatory drugs. β−blockers are contraindicated in asthma. vi. A rescue course of systemic corticosteroids may be required at any step at any time. vii. Some patients with intermittent asthma experience severe and life-threatening exacerbations separated by long periods of normal lung function and no symptoms. This may be especially common with exacerbations provoked by respiratory infections. A short course of systemic corticosteroids is recommended in that situation. viii. At each step the patient should control his environment to avoid or control factors that make their asthma worse like allergens, irritants, etc. This requires specific diagnosis and education. ix. Referral to an asthma specialist for consultation or co-management is recommended if there are difficulties in achieving or maintaining control of asthma or if the patient requires step 4 care. Referral may be considered if the patient requires step 3 care. Quick-relief Medications Bronchodilators. Short-acting β2-agonists are the therapy of choice for relief of acute symptoms and prevention of exercise-induced asthma. They are the most effective medications for relieving acute bronchospasm. A β2-agonist such as salbutamol 100-200 μg or terbutaline 250-500 μg should be used as required rather than regularly. Patients should be encouraged to use the minimum dose to control their symptoms. They can be used 2 puffs three to four times a day. Salbutamol is also available as rotahalers with 100-200 mcg/capsule which can

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be used 1-2 capsules every 4-6 hours as needed and prior to exercise. Increasing use of these drugs or roughly use of more than one canister in one month indicates inadequate control of asthma and the need for initiating or intensifying anti-inflammatory therapy. Regularly scheduled or daily use of these drugs are generally not recommended. Solutions for use in nebulisers are also available (salbutamol 5 mg/ml or terbutaline 5 mg/ml) for use during acute exacerbations. Anticholinergic drugs like ipratropium bromide may provide additive benefit to inhaled β2-agonists in severe exacerbations. It may be an alternative bronchodilator for patients who do not tolerate inhaled β2-agonists. They may be used as regular maintenance therapy in step 4 (British Thoracic Society) patients who already require high dose inhaled steroids. The drug is also available in solution forms for nebulisation. The MDI dose is 20 mcg for each puff and 2-3 puffs are used every 6 hours. Although systemic corticosteroids are strictly not bronchodilators, they are used for moderate to severe exacerbations to speed recovery and prevention of exacerbations along with other medications. Long-term Control Medications Inhaled anti-inflammatory agents. Patients who need to inhale a bronchodilator more than once daily or who have night time symptoms require regular inhaled anti-inflammatory drugs. Various drugs that can be used include corticosteroids, sodium cromoglycate (5-20 mg four times a day), and nedocromil sodium (4 mg four times daily). Inhaled steroids are the drugs of choice since they are the most potent and effective anti-inflammatory drugs available currently for mild, moderate and severe persistent asthma. The small but potential risk of adverse reactions from the use of inhaled corticosteroids is well balanced by their efficacy. Inhaled form is used for the long-term control of asthma. Systemic corticosteroids are used in longterm therapy to gain prompt control of the disease and also to manage severe persistent asthma. Beclomethasone dipropionate or budesonide should be started in doses of 100-400 μg twice daily. As the severity increases, the doses are to be increased. Patients with nocturnal symptoms and more severe and persistent form of disease may need more frequent and higher doses. Once symptoms and PEFR are controlled, the dose should be reduced to be maintained with the minimum. High doses of inhaled steroids. If control is not achieved, spacers and higher doses are needed after checking the compliance and proper use of inhalers. When the dose exceeds 800 μg, a large volume spacer is recommended to reduce systemic and local effects. The delivery system is an important determinant of the systemic effects of inhaled corticosteroids. The Turbohaler delivers approximately twice as much inhaled steroid to the lung,52 and, therefore the dose may be halved when this device is used. The patient should also be advised to rinse mouth (rinse and spit) following inhalation. The lowest possible dose of inhaler should be used to maintain control. Current guidelines recommend that patients should double the dose of inhaled steroids temporarily if their asthma deteriorates or at the first sign of an upper respiratory tract infection. To maintain control asthma, particularly nocturnal symptoms, a long-acting inhaled β2-agonist is to be added to a low-to medium dose of inhaled corticosteroid rather than using a high dose. For children growth monitoring is essential. Inhaled corticosteroids are typically associated with a flat dose-response curve when traditional efficacy values are examined by measurement of FEV1. Thus, by increasing the

200 Bronchial Asthma dose of inhaled steroids in the asthma management is not necessary and preferably, add-on therapy should be used rather than increasing the dose of inhaled steroids.53 Estimated comparative daily doses for inhaled steroids are shown in Table 12.3. There is no indication at present for the routine investigation of, or prophylactic treatment for, osteoporosis in patients with low dose inhaled corticosteroids. However, in patients receiving high dose therapy (1000 mcg or more of beclomethasone or budesonide and 500 mcg or more of fluticasone per day), general measures to counteract osteoporosis such as regular exercise, hormone replacement therapy, smoking cessation, and adequate dietary calcium should be considered. For postmenopausal women, supplemental calcium in the dose of 1000-1500 mg per day may be required. In addition, vitamin D is to be administered in a dose of 400 units a day. Estrogen therapy will be required in these women when the dose exceeds 1000 mcg of inhaled corticosteroids per day. There is no published trial to show that nebulised budesonide is effective in adults. Inhaled fluticasone is as effective as beclomethasone and budesonide at half the dose when given by equivalent delivery systems.54-57 At equipotent doses the drug may have the potential for producing similar systemic effects. Cromolyn Sodium and nedocromil These are mild to moderate anti-inflammatory medications. They may be used as initial choice for long-term control therapy for children. They can also be used as preventive treatment prior to exercise or unavoidable exposure to known allergens. Nedocromil has an unpleasant taste. Cromolyn is available as 5 mg/puff. The dose is 1-2 puffs thrice or four times daily. They are also available as DPI- 20 mg/ capsule.Nedocromil is not available in India yet. Additional bronchodilators If adequate control of symptoms is not achieved with inhaled steroids 2 mg each day and standard doses of β2-agonists, a trial of additional ipratropium (80 μg four times daily), oral bronchodilators, or high doses of inhaled bronchodilators may be considered. Oral β2-agonists and xanthine derivatives should not be used as first line drugs. However in view of the cost factor, oral β2-agonists and xanthine derivatives are used often as the first line bronchodilators in some places. The main indication of methyl xanthines is the presence of symptoms, often nocturnal, which are not controlled by anti-inflammatory drugs and standard doses of inhaled β2-agonists. Table 12:3: Daily doses for inhaled corticosteroids

Drug

Low Dose

Medium Dose

High Dose

Beclomethasone (100,200 mcg/puff) (DPI same)

200-400 mcg

400-800 mcg

>800 mcg

Budesonide (200,400 mcg/puff)

200-400 mcg

400-600 mcg

>600 mcg

Flunisolide (250 mcg/puff)

500-1000 mcg

1000-2000 mcg

>2000 mcg

Fluticasone (50,125 mcg/puff) DPI same doses

50-250 mcg

250-660 mcg

> 660 mcg

Triamcenolone 100 mcg/puff

400-1000 mcg

1000-2000 mcg

>2000 mcg

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The addition of long-acting xanthine derivatives may be good enough to control symptoms. Sustained release theophylline is a mild to moderate bronchodilator used principally as adjuvant to inhaled corticosteroids for prevention of nocturnal symptoms. They may have mild anti-inflammatory effect also. Usual starting dose is 10 mg/kg of body weight up to a maximum of 800 mgm per day. Long-acting β2-agonists are to be used concomitantly with anti-inflammatory drugs (lowto-medium dose corticosteroid inhalers) for long-term control of symptoms, particularly nocturnal symptoms. They also prevent exercise-induced bronchospasm. Long-acting β2agonists are not to be used for the treatment of acute symptoms or exacerbations. High doses of inhaled bronchodilators should be considered only if the patient does not respond to standard doses. Daily use of long-acting β2-agonists should generally not exceed 80-100 mcg. Salmeterol is currently available in India and Formoterol is being tried for clinical use in this country. Oral sustained release salbutamol 8 mgs tablets are available which can be used twice daily. Leukotriene Modifiers These drugs may be considered as alternative therapy to low doses of inhaled corticosteroids or cromolyn or nedocromil in mild persistent asthma in patients 12 years or older. These drugs are not yet marketed in India. Further study and clinical experience are needed to help establish their role in asthma therapy. The leukotriene receptor antagonist is available in USA as 20 mg tablets and the adult dose is 40 mg daily (1 tablet twice daily). The 5-lipoxygenase inhibitor Zileuton is available as 300 and 600 mg tablets and the daily dose is 2400 mgs in four divided doses. Oral steroids Systemic corticosteroids are used in long-term therapy to gain prompt control of the disease (Rescue therapy) and also to manage severe persistent asthma. High doses of inhaled steroids should always be continued in patients receiving oral steroids. These patients need to be referred to a specialty clinic where additional measures can be considered. For long-term treatment of severe persistent asthma, single dose is to be administered in a.m. either daily or on alternate days which may produce less adrenal suppression. Short courses or “bursts” are effective for establishing control when initiating therapy or during a period of gradual deterioration. The burst should be continued till the patient achieves 80% of personal best PEFR or the symptoms resolve. This usually requires 3-10 days, but may require longer. The most commonly available oral corticosteroid is prednisolone, although methylprednisolone or prednisone can also be used. Prednisolone tablets are available in 5 mg, and 20 mg, tablets. For control of asthma symptoms, a dose of 10-60 mgms daily single doses may be required. For short-course “burst” 40-60 mgm per day as single or 2 divided doses may be given for 3-10 days. Alternative and Complementary Therapies Alternative and complementary therapies are sought most frequently for many chronic disabling conditions as a desperate (sometimes with true belief) measure as there is no definite “cure” for these conditions. These include back pain, anxiety, depression, arthritis, headaches, HIV infection, and chronic allergic disorders like allergic rhinitis, and asthma.58,59 These forms of treatment include acupuncture, homeopathy, fish therapy, other herbal therapy including ayurvedic drugs, ionisers, and antihistamines including ketotifen, chiropractice, megavitamins, and spiritual healing, which are tried by many but have not stood the test of controlled clinical trials, although some patients claim benefit. Results of a 1998 survey indicates that 42% of adults in the United States consult alternative medical practitioners and

202 Bronchial Asthma spend an estimated $27 billion annually on alternative medical therapies.58 Many physicians either practice for complimentary/alternative medicine themselves or refer patients for such treatment.60 Acupuncture is one of the oldest and most widespread complimentary techniques, although homeopathy and Aurvedic forms of therapy are other forms of therapy in many countries. The first documented history of acupuncture is ascribed to the legendary Yelloe Emperor (Huang Di) in China (circa 2000 BC). The first paragraph of the second part of his classic book Huang Di Nei Jing describes the desire of the benevolent emperor to relieve the suffering of his subjects affected with disease, instead of the use of poisons of medicine in favour of fine needles to harmonise the blood and Qi energy.61 British Medical Association has recently approved acupuncture for practice,62 and many medical schools in the USA offer elective courses in complimentary/alternative medicine.63 Traditional Chinese medicine has claimed the ability to favourably influence the course and symptoms of bronchial asthma. However, the published data on this subject are controversial. Real acupuncture has been shown to have an immediate effect,64-66 but not a lasting effect on asthma.67-69 Methacholine challenges and exercise have been shown to be affected. However, most studies performed to date are not controlled or cross-over in design.70,71 Immunomodulatory changes in lymphocyte subsets and cytokines have been shown to be affected by acupuncture. In a recent randomised cross over study, it was shown that a short course of acupuncture treatment in patients with moderate asthma resulted in no change in lung function, bronchial hyperreactivity, or patient symptoms.72 Thus, acupuncture may not be recommended for bronchial asthma, although still thousands of patients continue to seek for this form of therapy. If these modalities of complimentary/ alternative medicine are tried, then the conventional treatment should also be continued. Hyposensitisation or immunotherapy is not indicated in the management of asthma. Ascaricides may be effective in controlling number of mites but have not produce clinically relevant benefit. Referral to a Specialist Referral to a specialist should be considered for: i. Patients in whom there is a doubt about the diagnosis for example in elderly and smokers with wheeze; those with persistent unexplained persistent cough; and those with systemic symptoms like fever, rash, weight loss, or proteinuria that might suggest associated disorders such as systemic eosinophilia or vasculitis. ii. Patients with possible occupational asthma. iii. Patients with difficult asthma and management problems. Such patients include • those who are recently discharged from a hospital • those with catastrophic severe (brittle) asthma • those with continuing symptoms despite high doses of inhaled steroids • those being considered for long-term treatment with nebulised bronchodilators • pregnant women with worsening asthma, and • patients in whom asthma is interfering with their lifestyles despite changes in treatment. iv. Patients suspected to have developed complication like bronchopulmonary mycosis (i.e.; ABPA).

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These patients most often misdiagnosed as pulmonary tuberculosis. This complication may be suspected if the patient has uncontrolled symptoms, systemic symptoms, haemoptysis, weight loss, profuse expectoration, and infiltrates in chest skiagram. Assessment of Asthma Control Once a treatment plan is established for a patient of bronchial asthma, it is essential to assess the asthma control. Most asthma guidelines recommend assessing asthma control according to a series of criteria based on symptoms and pulmonary function.11,73 As the aim of asthma treatment is to minimise symptoms, rescue bronchodilator need, and exacerbations, while optimizing pulmonary function. Recently, methods for assessment of airway inflammation noninvasively have been developed, but they are not currently integrated into the assessment of asthma control.74,75 Studies or surveys on asthma generally use an all or none approach or a strictly qualitative evaluation of asthma control, without specific quantification of its magnitude or degree compared with optimal goals. Other means of assessing these parameters include evaluating or scoring each separate component of asthma control and comparing the effects of treatment or intervention on these specific parameters. This global assessment approach may overestimate the adequacy of asthma control by the physician and even more so, by the patient, and may consequentially contribute to the poor asthma control when current guideline criteria are used.76-78 Quantification of control with tools such as the validated questionnaire developed by Juniper et al79 are the common ones, but they are too exhaustive to be used by the busy clinician. A new, simple method of global assessment and quantification of asthma control has been developed.80 This easy-to-use asthma control scoring system is based on a percentage of optimal control. The percentage symptom score but not the global control score of this new method correlates with patient’s global assessment of asthma control. This method provides a percentage control for symptoms, baseline expiratory flows, and an optional parameter for airway inflammation assessed from induced sputum eosinophil count. REFERENCES 1. National Asthma Education Programme. Expert Panel Report. Guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute, National Institute of Health, Bethesda, Maryland, USA, Publication No. 91-3042A, June 1991. 2. Guidelines for the management of asthma in adults. 1-Chronic persistent asthma. Statement by the British Thoracic Society, Research Unit of the Royal College of Physicians of London, King’s Fund Center, National Asthma Campaign. BMJ 1990;301:651-53. 3. Guidelines for the management of asthma in adults. 2-Acute severe asthma. Statement by the British Thoracic Society, Research Unit of the Royal College of Physicians of London, King’s Fund Center, National Asthma Campaign. BMJ 1990;301:797-800. 4. Warner JO, Gotz M, Landau LI et al. Management of asthma: A consensus statement. Arch Dis Child 1989;64;1065-79. 5. International Paediatric Asthma Consensus Group. Asthma, a follow-up statement. Arch Dis Child 1992;67:240-48. 6. International Consensus report on the diagnosis and management of asthma. Clin Exp Allergy 1992;22(Suppl):1-72. 7. British thoracic Society and others. Guidelines for the management of asthma: A summary. BMJ 1993;9:287-92.

204 Bronchial Asthma 8. The British Guidelines on Asthma Management. 1995 Review and Position Statement. Thorax 1997;52(Suppl 1): S2-S8. 9. British thoracic Society, British Paediatric Association, Royal College of Physicians of London, The King’s Fund Center, national asthma Campaign et al. Guidelines on the management of asthma. Thorax 1993;48:S1-S24. 10. British thoracic Society, British Paediatric Association, Royal College of Physicians of London, The King’s Fund Center, national asthma Campaign et al. Summary charts. B M J 1 9 9 3 ; 3 0 6 : 776-82. 11. Global Initiative for Asthma. A practical guide for public health officials and health care professionals. US Department of Health and human services. NIH Publication No. 96-3659A, December 1995. 12. Brewis RAL. Patient education, self-management plans and peak flow measurements. Respir Med 1991;85:457. 13. Feldman CH, Clark NM, Evans D. The role of health education in medical management in asthma. Clin Rev Allergy 1987;5:195-205. 14. Mellians RB. Patient education is key to successful management of asthma. J Rev Respir Dis 1989;Suppl:S47-S52. 15. Clark NC. Asthma self-management education: Research and implications for clinical practice. Chest 1989;95:1110-13. 16. D’Souza W, Crane J, Burgess G et al. Community based asthma care: Trial of a “credit card” asthma self-management plan. Eur Respir J 1994;7:1260-65. 17. Ignacia-Garcia JM, Gonzalez-Santos P. Asthma self management education programme by home monitoring of peak expiratory flow. Am J Respir Crit Care Med 1995;151:353-59. 18. Schulman BA. Active patient orientation and outcomes in hypertensive treatment. Med Care 1979;17:267-80. 19. Clark NC. Asthma self-management education: Research and implications for clinical practice. Chest 1989;95:1110-13. 20. Korsch BM, Gozzi EK, Francis V. Gaps in doctor-patient communication. I. Doctor-patient interaction and patient satisfaction. Pediatr 1958;42:855-71. 21. Shim C, Williams MH. The adequacy of inhalation of aerosol from canister nebulisers. Am J Med 1980;69:891-94. 22. Newman SP, Pavia D, Clarke SW. Simple instructions for using pressurised aerosol bronchodilators. Jr Soc Med 1980;73:776-79. 23. Croft DR, Peterson MW. An evaluation of the quality and contents of asthma education on the World Wide Web. Chest 2002;121:1301-07. 24. Solomon WR, Burge HA, Bloise JR. Exclusion of particulate allergens by window air conditioners. J Allergy Clin Immunol 1980;65:305-08. 25. Koostra JB, Pasch R, reed CE. The effects of air cleaners on hay-fever symptoms in air-conditioned homes. J allergy Clin Immunol 1978;61:315-19. 26. Wilson AF, Novy HS, Berke RH, Sufprenant EC. Deposition of inhaled pollen and pollen extract in human airways. N Engl J Med 1973;288:1056-58. 27. Woods RA, Chapman MD, Adkinson FN Jr, Eggleston PA. The effect of cat removal on allergen content in household-dust samples. J Allergy Clin Immunol 1989;83:730-34. 28. Chapman MD, Wood RA. The role and remediation of animal allergens in allergic diseases. J Allergy Clin Immunol 2-001;107(3 Suppl):S414-S421. 29. Wood RA, Johnson EF, van Natta ML et al. A placebo controlled trial of a HEPA air cleaner in the treatment of cat allergy. Am J Respir Crit Care Med1998;158:115-20. 30. Van Der Heise S, van Aalderen WM, Kauffman HF et al. Clinical effects of air cleaners at homes of asthmatic children sensitised to pet allergens. J Allergy Clin Immunol 1999;104(2 pt 1):447-51.

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31. McDonald E, Cook D, Newman T et al. Effects of air filtration systems on asthma. A systematic review of randomised trials. Chest 2002;122:1535-42. 32. Tovey ER, Chapman MD, Platts-Mills TAE. Mite faeces are a major source of house-dust allergens. Nature 1981;289:592-93. 33. Platts-Mills TAE, de Weck AL. Dust-mite allergens and asthma: Worldwide problem. J Allergy Clin Immunol 1989;83:416-26. 34. Swanson MC, Campbell AR, Klauck MJ, Reed CE. Correlation between levels of mite and cat allergens in settled and airborne dust. J Allergy Clin Immunol 1989;83:776-83. 35. Walshaw MJ, Evans CC. Allergen avoidance in house dust mite sensitive adult asthma. Q J Med 1986;58:199-215. 36. Ehnert B, Lau-Sehadendorf S, Weber A, Buettner P, Sehou C, Wahn U. Reducing domestic exposure to dust mite allergen reduces bronchial hyperreactivity in sensitive children with asthma. J Allergy Clin Immunol 1993;90:135-38. 37. Murray AB, Fergusson AC. Dust free bed room in the treatment of asthmatic children with house dust mite allergy: A controlled trial. Pediatrics 1983;91:418-22. 38. Colloff MJ, Ayeres J, Carswell F et al. The control of dust mites and domestic pets: A position paper. Clin Exp Allergy 1992;22(Suppl 2):1-28. 39. Arlian LG, Platts-Mills TA. The biology of dust mites and the remediation of mite allergens in allergic diseases. J Allergy Clin Immunol 20-01;107(3 Suppl):S406-S13. 40. Custovic A, Simpson A, Chapman MD et al. Allergen avoidance in the treatment of asthma and atopic disorders. Thorax 1998;53:63-72. 41. Lan JL, Lee DT, Wu CH et al. Cockroach hypersensitivity: Preliminary study of allergic cockroach asthma in Taiwan. J Allergy Clin Immunol 1988;82:736-40. 42. Eggleston PA, Arruda LK. Ecology and elimination of cockroaches allergens in the home. J Allergy Clin Immunol 2001;107(3 Suppl):S422-S29. 43. Ernst P. Environmental measures and asthma. Chest 2002;122:1509-10. 44. Aas K. Controlled trial of hyposensitisation to house dust. Acta Pediat Scand 1971;60:264-68. 45. Ohman JL Jr, Findlay SR, Leiterman KM. Immunotherapy in cat-induced asthma: Double-blind trial with evaluation of in vivo and in vitro responses. J Allergy Clin Immunol 1984;74:230-39. 46. Reid MJ, Moss RB, Hsu YP. Seasonal asthma in northern California: Allergy causes and efficacy of immunotherapy. J Allergy Clin Immunol 1986;78:590-600. 47. Horst M, Hejjaoui A, Horst V, Michel FB, Bouquest J. Double-blind, placebo-controlled rush immunotherapy with a standardised alternaria extract. J Allergy Clin Immunol 1990;85:460-72. 48. Van Bever HP, Stevens WJ. Suppression of the late asthmatic reaction by hyposensitisation in asthmatic children allergic to house dust mites (dermatophagoides pteronyssiunus). Clin Exp Allergy 1989;19:399-404. 49. Bousquet J, Maasch HJ, Hejjaoui A et al. Double-blind, placebo-controlled immunotherapy with mixed grass-pollen allergoids. III. Efficacy and safety of unfractionated and high-molecularweight preparations in rhino conjunctivitis and asthma. J Allergy Clin Immunol 1989;84:546-56. 50. Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. American College of Allergy, Asthma and Immunology. National Heart, Lung and Blood Institute, National Institute of Health. NIH Publication No. 97-4051A, May 1997. 51. Glinert R, Wilson P, Wedner HJ. Fel; D1 is markedly reduced following sequential washing of cats. J Allergy Clin Immunol 1990;85:225. 52. Thorsson L, Edsbacker S, Conardson TB. Lung deposition of budesonide from turbohaler is twice that from a pressurised metered dose inhaler p-MDI. Eur Respir J 1994;7:1839-44. 53. O’Sullivan S, Cormican L, Murphy M et al. Effects of varying doses of fluticasone propionate on the physiology and bronchial wall immunopathology in mild-to-moderate asthma. Chest 2002;122:1966-72.

206 Bronchial Asthma 54. Lundback B, Alexander M, Day J et al. Evaluation of fluticasone propionate (500 mcg per day) administered either as dry powder via diskhaler or pressurised inhaler and compared with beclomethasone dipropionate (1000 mcg/day) administered by pressurised inhaler. Respir Med 1993;87:609-20. 55. Gustaffson P, Tanakas J, Gold M, Primhak R, Radford M, Gillies E. Comparison of the efficacy and safety of inhaled fluticasone pripionate 200 mcg per day with beclomethasone dipropionate 2000 mcg per day in mild and moderate asthma. Arch Dis Child 1993;19:206-11. 56. Leblane P, Minks S, Keistinen T, Saaelainen PA, Ringdal N, Payne SL. A comparison of fluticasone propionate 200 mcg/day with beclomethasone dipropionate 400 mcg/day in adult asthma. Allergy 1994;49:380-85. 57. Conolly A. A comparison of fluticasone propionate 100 mcg twice daily with budesonide 200 mcg twice daily via their respective powder devices in the treatment of asthma. Eur J Clin Res 1996;7:15-29. 58. Eisenberg DM, Davis RB, Ettner SL et al. Trends in alternative medicine use in the United States. 1990-1997: Results of a follow-up national survey. JAMA 1998;280:1569-75. 59. Fairfield KM, Eisenberg DM, Davis RB et al. Patterns of use, expenditures, and perceived efficacy of complimentary and alternative therapies in HIV-infected patients. Arch Intern Med 1998; 158:2257-64. 60. Austin JA, Marie A, Pelletier KR et al. A review of the incorporation of complementary and alternative medicine by mainstream physicians. Arch Intern Med 1998;158:2303-10. 61. Wu JN. A short history of acupuncture. J Altern Complement Med 1996;2:19-21. 62. Silvert M. Acupuncture wins BMA approval. BMJ 2000;321:11. 63. Wetzel MS, Eisenberg DM, Kaptchuk TJ. Courses involving complementary and alternative medicine in US medical schools. JAMA 1998;280;784-87. 64. Yu DY, Lee SP. Effects of acupuncture on bronchial asthma. Clin Sci Mol Med 1976;51:503-09. 65. Virsik K, Kristufek D, Bangha O, et al. The effect of acupuncture on pulmonary function in bronchial asthma. Progr Respir Res 1980;14:271-75. 66. Takishima T, Mue S, Tamura G et al. The bronchodilating effect of acupuncture in patients with acute asthma. Ann Allergy 1982;48:44-49. 67. Christensen PA, Laursen LC, Tauderf E et al. Acupuncture and bronchial asthma. Allergy 1984;39:379-85. 68. Jobst K, Chen JH, McPherson K et al. Controlled trial of acupuncture for disabling breathlessness. Lancet 1986;2:416-19. 69. Biernacki W, Peake MD. Acupuncture in treatment of stable asthma. Respir Med 1998;92: 1143-45. 70. Lewth GT, Watkins AD. Unconventional therapies in asthma: An overview. Allergy 1996;51: 761-69. 71. Varon J, Fromm RE Jr, Marik PE. Acupuncture for asthma. Fact or fiction? Chest 2002;121: 1387-88. 72. Shapira MY, Berkman N, Ben-David G et al. Short-term acupuncture therapy is of no benefit in patients with moderate persistent asthma. Chest 2002;121:1396-1400. 73. Boulet LP, Becker A, Berube D et al. Canadian Asthma Consensus Report; 1999. Can Med Assoc J 1999;61(Suppl 11):S1-S62. 74. Jayaram L, Paramswaran K, sears MR et al. Induced sputum cell counts: Their usefulness in clinical practice. Eur Respir J 2000;16:150-58. 75. Kips JC, Pauwels RA. Use of induced sputum in the diagnosis and follow up of asthma and chronic obstructive pulmonary disease. Monaldi Arch Chest Dis 2000;55:93-95. 76. Boulet LP, Phillips R, O’Byrne P et al. Evaluation of asthma control by physicians and patients: Comparison with current guidelines. Can Respir J 2003.

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77. Rabe KF, Vermiere PA, Soriano JB et al. Clinical management of asthma in 1999: The asthma Insights and Reality in Europe (AIRE) study. Eur Respir J 2000;16:802-807. 78. Kips JC, Pauwels RA. Asthma control. Where do we fall? Eur Respir J 2000;16:797-98. 79. Juniper EF, O’Byrne PM, Guyatt GH et al. Development and validation of a questionnaire to measure asthma control. Eur Respir J 1999;14:902-07. 80. Boulet LP, Boulet V, Milot J. How should we quantify asthma control? A proposal. Chest 2002;122:2217-23.

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13 Therapeutic Approach in Patients with Asthma II. Acute Severe Asthma (SA) Definition The term status asthmaticus was previously used to describe a severe attack of asthma, which had continued for more than 24 hours. Although most severe attacks of asthma develop over days or weeks prior to presentation to medical care, all recent studies of asthma deaths have described patients who have died within hours or even minutes of the onset of symptoms. It is, therefore, not appropriate to include the duration of the attack in a definition of acute severe asthma. The most important aspect of such an attack is its severity. Another suggested definition of an acute asthmatic attack is severe airflow obstruction that had become unresponsive to the patient’s normal bronchodilator treatment. All patients with bronchial asthma are at risk of developing a severe asthma attack that places them at risk of developing respiratory failure—the disorder referred to as status asthmaticus.1-19 The attack can occur at any time and at any speed. In most cases of severe life-threatening asthma develops against a background of poorly controlled disease. However, in 10-20% of cases of fatal or near fatal asthma the onset appears to be sudden and unexpected, with death occurring at times within a couple of hours. Such episodes are called “Sudden asphyxic asthma”.20 This form is quite different from the more slowly progressive forms of airflow obstruction. These are accompanied pathologically by only mild inflammatory changes and little mucus plugging of the airways.21 This sudden and unexpected increased airflow obstruction results primarily from bronchial smooth muscle-mediated bronchospasm. An important feature of this near fatal asthma is that attacks are often recurrent and a previous life-threatening episode represents one of the most important factors predicting asthma deaths.22 Acute severe asthma said to “run to type”, meaning thereby, if hypercapnia develops during one severe attack, it is likely to recur in a subsequent episode.23 Both fatal and near fatal asthmatic attacks have similar features.24 Patients dying of sudden exacerbations of asthma have diminished eosinophils and increased neutrophils in the airway submucosa20 and less intraluminal mucus.25 This is in contrast with the relatively slower onset disease. Patients who develop progressive symptoms over days before finally presenting to the emergency room do so with respiratory distress. In these patients, inflammation of the airway wall and edema play a significant

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role. Yet many patients fail to perceive the severity to treat effectively their worsening airway inflammation.26 They fail to appreciate the severity of the final episode because of poor perception. Reduced chemosensitivity to hypoxia and blunted perception of dyspnoea perhaps predispose patients to fatal asthma.27 About 1.1 to 7.0% of patients with bronchial asthma die from an acute attack.28-30 It is difficult to predict which asthma patients will have a fatal or near-fatal asthma attack. In both these conditions (fatal and near-fatal asthma), there is a female predominance,31,32 history of frequent hospital admissions and emergency department visits, 33 noncompliance,34 psychosocial abnormalities,35 and socioeconomic factors linked to poverty.36 In addition, a significantly decreased response to inspiration against resistance and to hypoxic hypercapnia27 and a low perception of dyspnoea are other risk factors.37 In a case control study, the following eight variables were found to be associated with near-fatal asthma: history of seizures, conflict with parents and hospital staff, inappropriate self-care, decrement in prednisolone dose by 50%, use of inhaled beclomethasone, increased asthma symptoms during the week prior to discharge, depressive symptoms, and disregard of asthma symptoms.38 The variables associated with subsequent deaths include older age, female gender, smoking, labile asthma, poor compliance, and psychiatric treatment for anxiety or depression.39 In a recent unmatched, case-control study, the near fatal asthma was most often associated with the use of bronchodilators or corticosteroids during the last 12 months and these patients had nocturnal symptoms in the previous two weeks, more severe form of the asthma, and more likely to have had a previous intubation.40 Further, patients with near fatal asthma have more food allergies and onset of their episodes follows a visit to the bar, party or restaurant.41 This may be related to hypersensitivity to foods, such as nuts, or exposure to smoking exposure or substance abuse in this group.42 Another important contributory factor may be an inadequate access to health care facilities.43 Pathophysiology Abnormalities of gas exchange occur due to airways obstruction as a result of inflammation and bronchial smooth muscle contraction. Mucus plugging of both large and small airways is found at autopsy. Dead space increases as result of hypoperfusion of hyperinflated lung regions. Mechanical abnormalities of the lung include marked elevation of airways resistance, inspiratory transpulmonary pressure during quiet tidal breathing increases to as high as 50 cm H2O and expiration becomes active. Despite increased work of breathing, FEV1 is reduced to almost 10-20 percent of normal and PEFR is less than 100 L/min in severe cases. Expiratory time is prolonged and alveolar emptying is not complete at the end of expiration. Intrinsic or occult positive-end expiratory pressure (PEEPi) is the consequence of alveolar pressure not reaching atmospheric pressure under the condition of prolonged expiratory time. Abnormal circulatory effects of severe airways obstruction result mostly from pleural pressure excursions associated with breathing. During expiration, increases in intrathoracic pressure diminish blood return to the right heart. During inspiration, right ventricular volume may increase sufficiently to shift the interventricular septum towards the left ventricle compromising the volume of this chamber and resulting in incomplete filling. These cyclical events result in pulsus paradoxus. Additionally, large negative pleural pressure may directly impair left ventricular emptying by increasing left ventricular after load.44,45 Further, lung hyperinflation may represent a further after load on the right ventricle by

210 Bronchial Asthma increasing pulmonary artery pressure.46 During quiet breathing without airways obstruction, the pulsus measured as the maximal drop in systolic blood pressure during inspiration, is less than 10 mmHg. During severe asthma this may be greater than 15 mm Hg and is used as a measure of severity of asthma,47 although presently this is not included as a guideline in assessing the severity of asthma. Pulsus paradoxus may be faulty if the patient ceases making sufficient effort to cause large intrathoracic pressure swing, which is possible in a fatigued asthmatic unable to generate significant changes in the pleural pressure. Thus, the absence of a wide pulsus paradoxus does not always mean a mild attack.48,49 Further progression to ventilatory failure in status asthmaticus may result from respiratory muscle fatigue, increased work of breathing due to increased airways resistance, diaphragm failure as a force generator because of dynamic hyperinflation, and intrinsic PEEP associated with dynamic gas trapping. All these events are responsible for respiratory muscle fatigue. Lactate excess is thought to be due to increased muscle production, the action of catecholamines used during treatment, or diminished clearance related to hypoperfusion. Regardless of etiology, lactic acidosis is a metabolic marker which may be used to predict an increase risk of progression to ventilatory failure. Clinical Features The clinical presentation of a patient with status asthmaticus includes increased breathlessness, cough, wheezing, and chest tightness. The patient is typically anxious, breathless, fatigued, sitting upright in bed, and is preoccupied with the task of breathing. He is in apparent respiratory distress. Clinical signs include tachypnoea, tachycardia, hyperinflated lungs, wheeze, use of accessory muscles, pulsus paradoxus and diaphoresis. The absence of wheezing does not exclude a diagnosis of bronchial asthma and the classical sign of wheezing correlates poorly with the degree of airflow obstruction.50 Rather, a silent chest in a case of status asthmaticus indicates severe airway obstruction with little movement of air to produce respiratory sound. In the period immediately preceding respiratory arrest the chest may be completely silent. Presence of localised wheeze and crepitations may indicate mucus plugging, atelectasis, pneumonitis or some other cause. Adults with status asthmaticus who assume the upright position usually has a significantly higher pulse rate, respiratory rate, and pulsus paradoxus and a significantly low arterial oxygen tension, and low PEFR than patients who are able to lie supine. If upright patients are also diaphoretic, the PEFR is even lower.51 Use of sternocleidomastoid muscle indicates severe airways obstruction. Inability to lie supine, diaphoresis, impaired sensorium, inability to speak and use of accessory muscles are all signs severe disease. However, even patients with severe obstruction and exhaustion can lie down supine giving a false impression of less severe disease. The possible complications of bronchial asthma are shown in Table 13.1. While examining a patient of status asthmaticus clue for the possible complications should be looked for. Electrocardiogram (ECG) in such a patient will show tachycardia. Successful treatment of airflow obstruction is usually associated with a decrease in heart rate, although some improving patients may remain tachycardic because of the use of drugs. Successful therapy will reduce heart rate.52 The rhythm is usually sinus tachycardia. Rhythm abnormalities that are possible include supraventricular arrhythmias, and atrial, ventricular or combined arrhythmias.53 Patients with arrhythmias are usually older compared to patients without

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Table 13.1: Complications of acute bronchial asthma Pneumothorax Pneumomediastinum Subcutaneous emphysema Pneumopericardium Myocardial infarction Mucus plugging Atelectasis Drug toxicity (theophylline) Electrolyte imbalances (hypokalemia, hypophosphatemia, hypomagnesemia) Dehydration Myopathy Lactic acidosis Hypoxic brain injury

them. Status asthmaticus can cause right ventricular strain, which is usually transient and which resolves within hours of therapy.52,54 However, presence of right heart failure should suggest some other disease. The possibility of coronary ischaemia should be considered in older patients with coronary artery disease. Such patients with status asthmaticus are in increased risk of myocardial oxygen supply/demand imbalance when large decreases in intrathoracic pressure increases left ventricular after load and possibly decreased coronary blood flow.55 High dose beta agonists, theophylline and hypoxia can further tilt this balance. Although effort-dependent, objective physiologic measurements of airflow obstruction can be made by bedside determination of FEV1 and PEFR. In most patients PEFR can be measured more easily even if the maneuver is difficult in severely dyspnoic patients. In these cases, this may be deferred because deep inhalation may worsen bronchospasm56 and in rare cases, precipitate respiratory arrest.57 However, the measurements are safe in most patients. Measurement of arterial blood gas is essential in patients with status asthmaticus. The measurement is generally recommended when the FEV1 is less than 1 litre or PEFR is less than 120 L/min. Patients in the early stages of status asthmaticus will exhibit mild hypoxemia and respiratory alkalosis with low carbon dioxide tension. If respiratory alkalosis persists for hours to days, compensatory renal bicarbonate wasting may take place manifesting as a non-anion-gap metabolic acidosis. As the severity of obstruction increases, PaCO2 increases. This is because of patient exhaustion, inadequate alveolar ventilation, and/or an increase in physiologic dead space. Hypercapnia has a good correlation with FEV1 and usually does not occur unless the FEV1 is less than 25% of the predicted.58 Presence of hypercapnia, even normal PaCO2, indicates a severe degree of airflow obstruction and the possible need for mechanical ventilation. However, in certain situations, hypercapnia alone is not an indication for intubation. Such patients may respond to aggressive drug therapy.54,59 On the other hand the absence of hypercapnia does not exclude the possibility of severe airflow obstruction and impending respiratory arrest.3 Metabolic acidosis can occur in as high as 28% of patients with status asthmaticus.60 This may occur more likely in men and in patients with more severe degrees of airflow obstruction and hypoxemia. The possible cause is because of the elevated anion gap. Although the pathogenesis of lactic acidosis in this setting is not clearly understood, the possible mechanisms are:61

212 Bronchial Asthma • Increased work of breathing resulting in anaerobic metabolism, tissue hypoxia, intracellular alkalosis, decreased lactate clearance by the liver because of passive congestion in the setting of high intrathoracic pressure, and use of parenteral betaadrenergic agonists.62 Repeated blood gas sampling are not necessary to determine whether the patient is improving or deteriorating. In most cases important clinical signs described above will be sufficient to judge whether the patient is to be intubated or not. Patients who are deteriorating on these grounds to the point of respiratory arrest should be intubated whether or not the PaCO2 is rising. On the contrary, patients who are more comfortable on pharmacologic drug therapy are to continue with the same treatment despite an elevated PaCO2. Patients on mechanical ventilation will however, need serial measurement of arterial blood gas. Chest radiography has little role in the management of mild to moderate asthma like arterial blood gas. The benefits of routine chest skiagram are minimal and they contribute only 1-5% of studies where the treatment is influenced.63 Such changes include normal, hyperinflation, a minimal increase in interstitial markings. Other changes include focal/ major atelectasis, pneumonitis or one of the above described complications. However, chest skiagram is definitely indicated in patients with fever, purulent sputum, signs or symptoms of barotrauma, (chest pain, mediastinal crunch, subcutaneous emphysema, cardiovascular instability, or asymmetric breath sounds), suggestion of pneumonia, other localising chest signs, or when it is not clear that asthma is the cause of respiratory distress. Differential Diagnosis The differential diagnosis of severe dyspnoea with wheezing includes status asthmaticus, upper airways obstruction, foreign body aspiration, left ventricular failure or ischaemia, acute exacerbations of COPD, asthma complicated by pulmonary embolism, pneumonia or barotrauma. History and physical findings will differentiate many of these conditions. Assessment of Severity Assessment of severity of an acute asthma is very important since one has to decide whether the patient can be managed at home, or needs to be hospitalised or he is to be admitted to an intensive care unit with or without ventilatory support. It is necessary to manage a patient with acutely severe asthma with the same sense of emergency as for a 50-year old person with crushing substernal chest pain suspected of having myocardial ischaemia. The initial assessment should consist of a brief history pertinent to the exacerbation which include the time of onset and cause of present exacerbation; severity of symptoms including exercise limitation and disturbance of sleep, all current medication with the time of last administered medication and any recent use of systemic corticosteroids, prior hospitalisation, prior episodes of respiratory insufficiency, and significant prior cardiopulmonary disease. It generally requires an analysis of several factors, including the medical history, physical examination, bedside monitoring of airflow obstruction, response to initial therapy, arterial blood gas measurements, and radiographic studies. This multifactorial analysis is necessary because no single clinical measurements have been found to predict outcome reliably.64 A brief cardiopulmonary examination should be performed, with emphasis on findings relevant to assessing the severity or identifying complications (pneumonia, atelectasis, pneumothorax, and pneumomediastinum). The overall assessment of the patient should

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include alertness, colour, respiratory distress, and fluid status. Although wheezing is a prominent finding on chest auscultation, extremely severe obstruction may be accompanied by “silent chest”. Routine laboratory studies and sputum culture are not necessary for initial management of patients. A chest X-ray may be needed afterwards to identify any complication. Measurement of PEFR and FEV1 are very essential. Arterial blood gas should be obtained in all cases as far as possible, particularly if the patient is not able to perform pulmonary function tests or for whom intubation and mechanical ventilation are being considered. Various indices of acute severe asthma are shown in Table 13.2. Various clinical parameters helpful for the overall assessment of the patient are shown in Table 13.3. Table 13:2. Sherwood Jones’ index of severity of asthma Grade 1a

Able to carry out house work or job with moderate difficulty. Sleep occasionally disturbed.

Grade 1b

Able to carry out house work or job with great difficulty. Sleep frequently disturbed.

Grade 2a

Confined to a chair or bed but able to get up with moderate difficulty. Sleep disturbed. Little or no relief from inhalers.

Grade 2b

Confined to a chair or bed but able to get up with great difficulty. Unable to sleep. Pulse rate > 120/min.

Grade 3

Totally confined to a chair or bed. No asleep. No relief from inhaler. Pulse rate > 120/min.

Grade 4

Moribund. Table 13.3: Indices of acutely severe asthma

Symptoms/history Severe breathlessness, cough, chest tightness, and wheezing Difficulty in walking for 100 feet or more Speech fragmented by rapid breathing Syncope or near syncope Physical examination Pulsus paradoxus of > 12 mmHg Use of accessory muscles of respiration Diaphoresis, unable to lie supine Heart rate > 120/min Respiratory rate > 30/ min Silent chest Pulmonary functions FEV1 or PEFR , 30-50% baseline Failure of PEFR to improve at least 10% after initial treatment Arterial blood gas PO2 < 60 mmHg or O2 saturation of less than 90% PCO2 > 40 mmHg

214 Bronchial Asthma NIH Guidelines (1997) has classified severity of asthma exacerbations into four different categories according to the symptom and signs (Table 13.4), mild; moderate; severe and imminent respiratory arrest. Table 13.4: Classification of severity of asthma exacerbations (NIH, 1997)

Mild

Moderate

Severe

On walking; Can lie down

While talking; Prefers sitting

While at rest; Sits upright

Phrases May be agitated

Words Usually agitated

Usually agitated

Increased

Increased

Often > 30/min

Accessory muscles use; Suprasternal retractions

Usually not

Commonly

Usually

Paradoxical thoraco-abdominal movement

Wheeze

Moderate Only endexpiratory

Loud Throughout expiration

Usually loud Throughout inspiration and expiration

Absent

Pulse/min

< 100

100-120

> 120

Bradycardia

Pulsus paradoxus

Absent ± < 10 mm Hg

Often present 10-25 mm Hg

Present > 25 mm Hg

Absence suggests respiratory muscle fatigue

SYMPTOMS Breathless Talks in sentences Alertness

SIGNS: Respiratory rate

FUNCTIONAL ASSESSMENT: PEFR (% 80% predicted or % personal best)

Respiratory arrest imminent

Drowsy or confused

50-80%

<50% predicted or personal best or response lasts < 2 hours

PaO2 (air)

Normal Test usually not required

> 60 mmHg Test usually not necessary

< 60 mmHg May be cyanosed

and/or PaCO2

< 42 mmHg Test usually not required

< 42 mmHg Test usually not necessary

= or > 42 mmHg Possible respiratory failure

SaO2 (on air at sea level)

> 95% Test usually not required

91-95%

< 91%

Note: The presence of several parameters, but not all, indicates the general classification of the exacerbations.

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Recent data also showed that peak expiratory flow measurements must be interpreted in the light of other features of severity and the patient’s past history, particularly previous admissions to hospital, attendance at the emergency departments and current treatment, especially corticosteroids. Life-threatening asthma is one where the PEFR is less than 33% of the personal best. There is also a difference between a patient with PEFR of 50% who has been on prednisolone for a week and a patient who has a short history and has not yet started oral steroids. Similarly, pulsus paradoxus need not be measured as it adds nothing to the assessment and its interpretation is subject to many factors (BTS, 1995). Facilities for the monitoring of oxygen saturation should be available in all clinical areas that treat patients with acute asthma. Interpretation of saturation in patients who are on or who have recently been on oxygen, is difficult, but if the value is 92% or more and there is no feature of an imminently life-threatening attack, arterial puncture may be deferred (BTS, 1995). Therapeutic Management The best strategy for management of asthma exacerbations is early treatment to prevent deterioration and abort the exacerbation. Therefore early recognition of worsening lung function, prompt communication between the patient and the physician, appropriate intensification of antiasthma medication, and removal of the allergen or irritant are important components of management. Some patients are at increased risk for exacerbations and the category of high risk for asthma-related death includes patients who have history of : • Prior intubation for asthma, • Two or more hospitalisation for asthma in the past year, • Three or more emergency care visits for asthma in the past year, • Hospitalisation or emergency care visit within the past month’ • Current use of systemic steroids or recent withdrawal from systemic steroids, • Past history of syncope/hypoxic seizure due to asthma, • Prior admission to hospital based intensive care unit (ICU), and • Serious psychiatric disease or psychosocial problems. The basic principle of care of acute asthma exacerbations is the rapid reversal of airflow obstruction with relief of accompanying respiratory distress. This can be achieved by repetitive administration of inhaled β2-antagonists, early addition of systemic steroids, and correction of hypoxaemia. Some acute exacerbations can be managed at home, as an emergency outpatient basis, or the patient needs hospitalisation with or without admission into the intensive care unit (ICU). The primary goal of home management of acute exacerbations of asthma is to avoid delays in initiating antiasthma therapy by having the patient begin treatment at home. It is equally important that the patient does not delay seeking professional medical help if the asthma exacerbation is severe or if the response to therapy is not prompt and sustained. The initial treatment should consist of subcutaneous adrenaline (1:1000) in a dose of 0.5 ml slowly. This can be repeated every 20 minutes for three times. The drug should be avoided in patients with hypertension, and elderly individuals particularly with underlying heart disease. Although these drugs were commonly used as the first line therapy earlier, because of the availability of more β2-antagonist selective inhaled drugs recently, their use has declined dramatically. Subcutaneous adrenaline, terbutaline, or salbutamol has no

216 Bronchial Asthma advantage over inhaled β-agonists. However, there are situations when these drugs are very useful. These situations are: i. when the patient is unable to cooperate to inhale; ii. patients with impaired sensorium; and iii. patients with cardiopulmonary arrest.65-67 These drugs can also be tried in intubated patients not responding adequately to inhaled therapy. If parenteral β-agonists are used, potassium monitoring is essential to avoid hypokalemia, lactic acidosis, and cardiac arrhythmias. In very emergency cases, epinephrine may be delivered effectively through the endotracheal tube. Other injectable preparations that can be used include terbutaline and salbutamol.68 Some patients will not need further parenteral therapy and can be stabilised with oral or inhaled bronchodilators and steroids. There is no great advantage of more β2-specific drugs over subcutaneous epinephrine. Rather they cause more cardiovascular side effects like tachycardia for the same degree of bronchodilatation.69 Adrenaline is contraindicated during pregnancy because it is associated with congenital malformations and decreases uterine blood flow.70 Terbutaline is the preferred drug in this setting. However, terbutaline or salbutamol may inhibit uterine contractility at term. Routine use of infused β-agonists are not necessary and they have no extra advantage. On an individual basis however, intravenously administered β-agonists may be considered in patients below the age of 40 years who do not respond to inhaled or subcutaneous therapy, and in whom respiratory arrest is imminent or in whom persistent severe airflow obstruction is associated with alarming levels of lung hyperinflation during mechanical ventilation. In a recent meta-analysis, it is shown that the clinical benefit of intravenous β-agonists appears questionable, while the potential clinical risks are obvious. The only recommendations of intravenous β2-agonist use should be in those patients in whom inhaled therapy is not feasible.71,72 Inhalation of selective β2-agonist bronchodilators by nebulisation is favoured for both children and adults as the immediate and first-line therapy of status asthmaticus of all severity. The onset of action is very rapid and their side effects are usually tolerated. Salbutamol is the most commonly used drug. This has a slightly longer duration of action and it is more β2-selective. Long-acting β-agonists like salmeterol or formoterol are not indicated in acute asthma since their onset of action is very slow. Terbutaline (2.5-5 mg), or salbutamol 2.5-5 mg, or metaproterenol 15 mg or isoetharine 5 mg can be given 4-6 hourly diluted with normal saline. This dose can be used every twenty minutes for 1 hour (three doses) followed by administration every hourly during the first several hours of therapy. A single dose of 7.5 mg nebulised salbutamol and sequential doses of 2.5 mg nebulised salbutamol are clinically equivalent in the treatment of patients with moderate-to-severe acute asthma and result in similar disposition from the emergency room.73 Fewer doses can be given in patients with less severe airflow obstruction who demonstrate a good response. On the other hand, inhaled treatment can be given continuously to severely obstructed patients until an adequate clinical response is achieved or adverse effects limit further use. Prior use of inhaled drugs at home does not prevent further use in hospital. Lower doses are preferred initially but they can be repeated or increased if necessary. Larger and more frequent doses are necessary in acute asthma because the dose-response curve and duration of action of activity of these drugs are affected adversely by the degree of bronchoconstriction.74 Airway narrowing and the cooperation and breathing pattern of the patient may further reduce the dose of the drug delivered by inhalation.

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Recent studies have shown that in nonintubated patients, MDIs combined with a spacer are as useful/effective as that used by a nebulizer.75-78 Further, MDIs are more quicker action and cheaper still, many prefer the use of nebulizers as they need fewer instructions, less coordination is required and less supervision is necessary. Moreover, both the patient and physician feel satisfied psychologically. Both MDIs and nebulizers can also be used in patients on ventilators,79 although there are controversies regarding the optimal delivery of inhaled drugs in the intubated and/or mechanically ventilated patient, optimal ventilatory settings to be used during ventilation for drug delivery, ideal site on the ventilator circuit for connection of the nebulizer, and maximal acceptable drug dosage.80 Higher dosages are required to achieve physiologic effects than in nonintubated patients since pulmonary aerosol deposition is poor in these patients, in the range of 1.2-2.9%.81, 82 In recently extubated patients, MDIs can be used successfully. Inhaled β2-agonists are the drugs of choice with which to treat patients with acute severe asthma. In comparison to systemic approach, inhalation is associated with a more rapid onset of action, and fewer systemic side effects. There is a consensus that frequent intermittent nebulisation, every 20 minutes within the first hour, are appropriate, although continuous nebulisation also has been proposed. Since the late 1980s, there has been considerable clinical and academic interest in the use of continuous aerosolised bronchodilators for the treatment of acute asthma.83 A recent meta-analysis supports the equivalence of continuous and intermittent salbutamol nebulisation in the treatment of acute adult asthma.84 This method of therapy has potential advantage in terms of time, cost, and medication delivery. This feature may allow deeper penetration into the airways and greater reduction of bronchoconstriction. Furthermore, this may result in fewer side effects. In children, continuous salbutamol nebulisation is considered to be better than intermittent therapy.85-87 Since airway inflammation is an important component of airflow obstruction of bronchial asthma, treatment with corticosteroids is the most important and an integral part of managing a case of acute severe asthma. Ideally, an intensifying treatment of worsening of one’s asthma should start with aggressive use of corticosteroids, which both the patient and many physicians do not appreciate. If not intervened early, airway inflammation proceeds unchecked. Whether patients are using corticosteroids or not when they arrive in the emergency with severe attacks of asthma, the dose is inadequate. There is evidence to suggest that failure to use or under use of steroids contribute to asthma deaths.88 Benefits of steroids are well established in recently confirmed meta-analysis of large number of studies.89 The facts that emerge are that steroids given in the emergency room significantly reduce the rates of admission and the number of future relapses in the first 7-10 days. It did not matter whether steroids are given intravenously or orally even if intravenous therapy is preferred in patients at risk of intubation, as long as a minimum of 30 mg of prednisolone or its equivalent is given every 6 hourly. Lower doses are less effective and there will be no obvious benefit by giving higher doses.90-92 It is recommended that 150-225 mg/day of prednisolone or its equivalent is required to reach maximal therapeutic benefit. Either 40 mgms of intravenously administered methyl prednisolone every 6 hours or prednisolone 60 mg orally every 6-8 hours for 36-48 hours depending upon the condition of the patient will be most ideal. Corticosteroids both intravenous and oral should be started simultaneously. However, these drugs have a slow onset of action because of their intracellular mode of action whatever their route of administration. Intravenous administration speeds up their action marginally by about an hour. Hydrocortisone should be administered 200 mg intravenously

218 Bronchial Asthma initially followed by 100 mg every 4 hourly in place of methyl prednisolone because the later is costly. This can also be administered as an infusion in a dose of 0.5 mg/kg/hr. Prednisone in a dose of 40-60 mg should be administered from the first day for several days followed by tapering of the dosage according to the response. A meta-analysis has suggested that the administration of corticosteroids in addition to inhaled β2-agonists in patients with acute asthma on their arrival at the emergency department does not improve airflow obstruction nor reduces the need for hospitalisation.93 The failure of steroids to influence the early course of patients with acute asthma is due to the fact that it may take up to 24 hours for the effect of corticosteroids to become evident. However, other randomised, placebo-controlled trials94 have shown that high doses of inhaled glucocorticosteroids together with salbutamol in patients with acute asthma who are treated in the emergency department significantly improve pulmonary function when compared to the use of salbutamol alone. The difference becomes evident by 90 minutes. It is due to the fact that locally acting inhaled corticosteroids cause local vasoconstriction and thereby decrease edema formation and plasma exudation.95 However, glucocorticosteroids, either in inhaled form or oral form or parenteral form are the important mode of therapy for managing a case of acute bronchial asthma. Some studies have shown that after 48 hours of intravenous treatment with corticosteroids, the use of high-dose inhaled flunisolide (250 μg per activation, eight puffs twice daily is as effective as systemic corticosteroids, in adults hospitalised for a severe asthma exacerbation.96 A meta-analysis indicates that there is some evidence that therapy with high-dose inhaled corticosteroids (beclomethasone dipropionate, > 2,000 mg or equivalent per day) may replace therapy with oral corticosteroids following the emergency department discharge of patients who have been treated for an acute asthma exacerbation.97 However, this meta-analysis has not shown any concrete evidence to change the practice of administering oral prednisolone for a short while for 7-10 days at a dose of 40 mg per day, which is cheap, effective, and safe.98 Addition of inhaled corticosteroid (budesonide 1600 μg/day to oral corticosteroid reduces the number of relapses.95 If the patient continues to deteriorate despite treatment, with beta-agonists and steroids, the alternatives are to add nebulised ipratropium bromide 500 μg 6 hourly. The drug augments the bronchodilating effect of β2-agonists in acute asthma.99-101 The role for anticholinergic medications is not well-defined. Thus, the use of therapy with anticholinergics and β2-agonists, either simultaneously or in sequence, has produced positive as well as negative results in different trials. Most recent relevant reviews had proved that the use of multiple doses of ipratropium bromide are indicated in emergency department treatment of children and adults with severe acute asthma. The studies reported a substantial reduction in hospital admission (30-60%, number needed to treat 5-11) and significant difference in lung function favouring the combined treatment. No apparent increase in the occurrence of side effects was observed. The use of single-dose protocols of ipratropium bromide with β2-agonist treatment produced, particularly in children with more severe acute asthma, a moderate improvement in pulmonary function without reduction in hospital admission.; in adults, the evidence showed a similar increase in pulmonary function with an approximately 35% reduction in hospital admission rate. In patients with mild-to-moderate acute asthma, there is no apparent benefit adding a single dose of an anticholinergic medication.102 Theophylline: Aminophylline is commonly used as an important drug in many developing countries both as a maintenance drug in chronic asthma as well for treatment during an

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acute attack of bronchial asthma in the form of a continuous drip in many countries because of its lower cost and if given in proper doses, the drug is not all that unsafe. Moreover, other modalities may not be available at all places. However, the ready availability of beta agonists and their safety and quick onset of action has replaced theophylline therapy in acute asthma. The usual loading dose and maintenance dose is shown in the table below. In most situations roughly 250 mg, 400 mg, and 500 mg 8 hourly will be required for a small, medium or large person respectively for maintenance. Serum theophylline level should be obtained whenever possible. Use of theophylline confers additional benefit on beta agonists and parenteral steroid therapy.103 Further, administration of theophylline results in fewer hospitalisations.104 A recent analysis of the use of theophylline had concluded that there is inadequate evidence to support or reject the use of theophylline in the emergency setting.105 However, theophylline continues to be an important adjunct in the management of acute asthma particularly in the setting of poor or incomplete response to treatment with beta agonists and steroids and where economy is a consideration. Theophylline can be, and has been used, safely if attention is paid to the possible side effects, serum drug levels, and to factors that increase serum levels. Serum levels should be checked within 6 hours of intravenous loading to avoid toxic levels. High concentrations of oxygen (35%) will increase arterial PO2 and will not lead to carbon dioxide retention unless there is some other associated problem. Obstruction of peripheral airways will result in V/Q mismatch and hypoxemia. However, true shunt in acute asthma is only 1.5% of the pulmonary blood flow.106 Therefore, correction of hypoxemia requires only modest flow of oxygen, 1-3 L/min through a nasal cannula. Only a small proportion of patients below the age of 45 years develop hypoxaemia. Although there is a good correlation of FEV1 or PEFR with that of arterial oxygen tension, there is no cut-off value for either measurement to accurately predict hypoxaemia. The routine administration of low flow oxygen is an entirely safe practice that is recommended if routine pulse oxymetry is not available and if there is co-morbid condition such as coronary artery disease. Oxygen therapy improves oxygen delivery to the peripheral tissues including respiratory muscles, reverses hypoxic pulmonary vasoconstriction, airway bronchodilatation, and protection against the modest fall in PaO2 often seen after β2-agonist administration resulting from pulmonary vasodilatation and increased blood flow to low V/Q units. Since the attack is frightening reassurance to the patient is essential. Routine use of antibiotics is not necessary unless there is evidence of bacterial infection in form of fever, purulence of sputum or radiological evidence of consolidation. However, sputum that looks purulent, may be due to abundant eosinophils and not polymorphonuclear leukocytes. Adequate hydration should be maintained. Sedatives of all kinds should be avoided. Periodic assessment of progress of disease or the effect of therapy is very essential. There are reports supporting the usefulness of magnesium sulphate107-111 or heliox in the treatment of refractory bronchial asthma. This benefit has been described in patients with normal magnesium levels, although hypomagnesemia has been reported in 50% of patients with acute asthma.112 Magnesium was first reported as a treatment for acute bronchial asthma in 1936.113 It has since been shown to be a bronchodilator.114-116 Many case reports showed clinical benefits in patients with respiratory failure complicating bronchial asthma.117,118 Several trials in paediatric patients demonstrated a benefit from IV magnesium. 119,120 Many

220 Bronchial Asthma randomised trials of IV magnesium in acute asthma in adults have shown mixed results.121-123 A recent multicentric trial has shown that administration of 2g of IV magnesium sulphate improves pulmonary function when used as an adjunct to standard therapy in patients with very severe, acute asthma.124 The mechanism of action of magnesium is not known. One hypothesis is that magnesium inhibits calcium channels of airway smooth muscle and thus, interferes in calcium-mediated smooth muscle contraction. Magnesium decreases acetylcholine release at the neuromuscular junction, which may interfere with bronchoconstriction. Magnesium also reduces histamine-induced and methacholine-induced bronchoconstriction in asthmatics and affects respiratory muscle force generation. Although 1-2 gm of the drug is safe, care should be taken to monitor renal function. Further, hypotension, and loss of deep tendon reflexes can result from magnesium intoxication. Mild complications include flushing and mild sedation. The drug is not recommended for routine use. Heliox is a mixture of helium and oxygen (80:20,70:30, or 60:40) with a gas density less than that of air. It can be delivered through a tight fitting nonrebreathing face-mask in nonintubated patients and through the inspiratory limb of the ventilator circuit in mechanically ventilated patients. Because the mixture is lighter than air, airways resistance is decreased in bronchi with turbulent flow. This decreases the work of breathing and delays the inspiratory muscle fatigue until definite bronchodilator and anti-inflammatory therapy becomes effective.125,126 Drugs used in the treatment of status asthmaticus are shown in Table 13.5. Indications for Admission in the Intensive Care Unit Each patient should be assessed for response to treatment instituted initially in the emergency room. Patients who can be discharged include:127 • Significant improvement in shortness of breath • Improved air entry on clinical examination • PEFR or FEV1 greater than or equal to 70% predicted. Observation for a minimum period of 30 minutes after the last dose of β-agonist is administered is necessary to ensure stability before discharge. An incomplete response to treatment may be defined as the persistence of wheezing or shortness of breath and a PEFR or FEV1 between 40-70% of predicted. These groups of patients require ongoing treatment either in the emergency room or in the medical ward where facilities are available. Before discharge, these patients should be provided with a detailed follow-up plan which includes written medical instructions and a written plan of action to be followed if there is worsening of symptoms. Follow-up schedule should be made before the patient is sent home. However patients having the following problems should be admitted and observed for treatment in the intensive care unit. These are: • Patients with severe airflow obstruction; • Use of accessory muscles of respiration, • Pulsus paradoxus of > 12 mmHg • Diaphoresis • Inability to recline • Hypercapnia • PEFR < 40% predicted

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Table 13.5: Drugs used in status asthmaticus

Drug

Dosage/Mode of use

Adrenaline

0.3 ml of 1:1000 solution subcutaneous every 20 minutes 3 times. Terbutaline is favoured in pregnancy. The drug is to be avoided in patients with hypertension, older patients, and those with coronary artery disease.

Salbutamol

0.5 ml of 0.5% solution (2.5/5 mg) in 3 ml normal saline by nebulisation or 4 puffs by MDI with spacer every 20 min. for three doses; intubated patients can also given this drug.

Corticosteroids

Methyl prednisolone 60-125 mg given intravenously every 6 hours or prednisolone 30-40 mg orally every 6 hours. Hydrocortisone can also be given 200 mg start, followed by 100 mg every 6-8 hourly. The intravenous drugs are to be continued for at least for a period of 24-48 hours. Oral prednisolone is to be substituted as soon as possible. In fact, oral drugs are to be started simultaneously so that when the injectable steroids are withdrawn, they can take-over.

Anticholinergics Ipratropium bromide 0.5 mg by nebulisation hourly or 4-10 puffs by MDI with Spacer every 20 minutes for three doses. Theophylline - Loading dose:

No previous drug -6mg/kg of aminophylline (lean body weight) infused over 30 minutes or can be given slowly diluted with 25% of glucose over 20 minutes Already on theophylline: Reduce according to serum level as follows: If serum level is Cs mg/L, then Vol. of distribution (Vd) = 0.5L/kg × Wt (kg) Loading dose = Vd × desired change in serum level (mg/L) = Vd × (Cs desired -Cs known) For a patient of 50 kg Wt; with Cs of 8 mg/L and desired Cs of 18mg/L; Loading dose = 0.5 × 50 × (18 mg/L -8 mg/L) = 250 mg. Maintenance dose: Adults Smokers Liver disease Severe COPD CCF Viral illness Children drug interactions

Oxygen

Infusion Rate (mg/kg/hr) 0.5 0.8 0.4 0.4 0.2 0.4 0.9-1.2 As discussed in section under theophylline

1-3 l/min by nasal canula. Titration by pulse oxymetry

Unproved alternatives Magnesium 1 gm intravenously over 20 minutes (Total dose 2 gm). If hypomagnesemic, dose sulfate adjusted to normalize serum levels. Heliox

80:20, 70:30, or 60:40 helium:oxygen mixture by tight-fitting, nonrebreathing face mask. Higher helium concentrations are needed for maximal effect.

• Poor response to initial therapy • Less than 10% improvement in PEFR • Those deteriorate despite therapy • Respiratory arrest

222 Bronchial Asthma • Altered mental status • Cardiac toxicity • Tachyrrhythmias, Angina, Myocardial infarction Further, patients with imminently life-threatening features such as unconsciousness, confusion, drowsiness, hypoxia (PaO2 < 60 mmHg despite 60% oxygen) or patients with a raised PaCO2 should be admitted into the ICU. Similarly, patients whose condition is deteriorating and PaCO2 is rising need to be monitored in an intensive care unit. Mechanical Ventilation Many, but not all, of these patients will need ventilatory support. Patients receiving pharmacological therapy needs to be watched closely for the need for intubation in patients showing clinical deterioration. Indications for intubation will depend upon: a. Changes in posture, alertness, speech, use of accessory muscles, and respiratory rate, all of which indicates worsening respiratory failure. These signs do not need any arterial blood gas measurement or peak flow documentation; b. Fatigued patient despite PaCO2 levels c. Altered mental status despite PaCO2 levels d. PaCO2 is not an important predictor for intubation since patients who are more comfortable, better able to speak, and less respiratory distress can continue medical therapy despite a rise in PaCO2; Immediate intubation: e. Patients presenting with cardiopulmonary arrest f. Near cardiopulmonary arrest (patients unable to speak and/or gasping for air) g. Coma h. Significant obtundation A.

Non-invasive Ventilation

Non-invasive ventilation through face mask mechanical ventilation is an option used by some clinicians as a short-term ventilatory support in patients with hypercapnic ventilatory failure who are not i. Responding adequately to drug therapy; and ii. Where immediate intubation and mechanical ventilation is not indicated/required. Patients with encephalopathy or with a need of airway protection are not suitable for this form of therapy. Various advantages of noninvasive ventilation are; decreased need of anaesthesia, sedation, and paralysis, decreased incidence of nosocomial infections, decreased incidence of sinusitis and otitis, and better patient comfort.128-131 Usually a nasal CPAP of 5-7.5 cm H2O will be necessary. Potential disadvantages of this mode of ventilation include aspiration of gastric contents due to gastric insufflation, facial pressure necrosis, and less control of the patient’s ventilatory status. B. Intubation Once it is decided to ventilate the patient intubation should be done quickly by an experienced person as manipulation of the upper airways may precipitate laryngospasm. Oral intubation allows insertion of larger bore endotracheal tubes (8 mm or more), which has

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advantage of better suction and a decrease in airway resistance beneficial at high airflow. Nasal intubation is safe in most patients particularly if he is awake, breathless and in obese patients with short necks. Fibre optic guided intubation may be helpful in difficult cases. The disadvantage with the nasal route is that a smaller endotracheal tube can only be used and there is a high incidence of nasal polyps and sinusitis in them. C. Sedation Sedation will invariably be required in awake patients to prepare for intubation and to allow for effective mechanical ventilation (to avoid fighting the ventilator). Further, sedation improves patient comfort, facilitates various procedures, and decreases oxygen demand and consumption and decreased carbon dioxide production besides decreasing the risk of barotrauma. Various sedatives that can be used in status asthmaticus are shown in Table 13.6. D. Paralysis Muscle paralysis is required in patients fighting with the ventilator despite sedation and in those who continue to have asynchronous breathing which is a grave risk factor for generation of high airway pressure and loss of airway access. The decision, however, will be based on the clinician’s own judgment whether to use neuroparalytic agents or not to achieve a therapeutic strategy to maintain stable respiratory parameters. Paralysis further helps to reduce oxygen consumption, carbon dioxide production, and lactic aciodosis in addition to decreasing the risk of barotrauma with an overall augmentation of sedatives already used. Because the expiratory effort is eliminated, there is less airway collapse. The paralytic drugs of choice are vecuronium and atracurium. These are nondepolarising agents and are free of cardiovascular side effects, although larger doses may cause hypotension. The drugs are either given intermittently by bolus injection or by continuous Table 13.6: Sedatives that can be used in status asthmaticus

Drug

Dose

Comments

1 mg IV push slowly, can be repeated every 2-3 min. as needed.

Hypotension, respiratory depression

Ketamine

1-2 mg/kg IV at a rate of 0.5 mg/kg/min.

Sympathomimetic effects, respiratory depression, mood change, delirium

Propofol

60-80 mg/min IV up to 2 mg/kg followed by an infusion of 5-10 mg/kg/hr as needed

Respiratory depression

Before intubation Midazolam

After intubation for prolonged ventilation: Lorazepam Morphine sulphate Ketamine Propofol

1-5 mg/hr IV continuous infusion or bolus 1-5 mg/h IV continuous infusion 0.1-0.5 mg/kg IV 1-4.5 mg/kg/h IV

Drug accumulation Ileus As described above Seizures, hypertriglyceridemia

224 Bronchial Asthma intravenous infusions. The disadvantages of neuroparalytic agents in acute asthma are: difficulties in assessing the mental status, greater danger of developing deep vein thrombosis, disuse muscle atrophy and myopathy.132 The last complication is more pronounced in the presence of concomitant use of high dose steroids. E. Mechanical Ventilation Hypotension and hypoperfusion often follow intubation and positive pressure ventilation. Slowly bagging (4-6 breathes/min) with 100% oxygen for about 1 min will allow for prolonged expiratory time to decrease PEEPi which will result in a rise of blood pressure. If this occurs a fluid bolus of 0.5-1L of normal saline should be given every 10-20 minutes until adequate circulation is restored. The goals of mechanical ventilation in status asthmaticus are: • To achieve adequate alveolar ventilation; • Low levels of PEEPi; • Minimal circulatory compromise; • Low risk of barotrauma. The patient should initially be fully sedated and adequate muscle-relaxation be achieved to minimize airway pressures. Dynamic hyperinflation is often seen in these patients if an attempt is made to make them eucapnic. This can be prevented by using small tidal volumes and high inspiratory flow. Mechanical ventilation should be initiated with a tidal volume of 8 ml/kg, rate of 12-15/min, and inspiratory flow rate of 60L/min. Measurement of PEEPi in the sedated patient who has also received muscle relaxant, the expiratory limb of the ventilator is occluded at end expiration while omitting the subsequent breath. The proximal airway pressure rises to a plateau (PEEPi).133 If peak airway pressures exceed 55 cmH2O and PEEPi is greater than 15 cmH2O despite full sedation and muscle relaxation, tidal volume can be varied in 100-ml increments with corresponding changes in rate and flow in an attempt to optimize peak airway pressure (Ppk), PEEPi, and PCO2. In some patients, a high level of PCO2 in the range of 70-90 mmHg is the only way to bring Ppk below 55 cm H2O and PEEPi below 15 Cm H2O. This is known as “controlled hypoventilation”. This is preferable to the risk of barotrauma during an attempt to bring the PCO2 to normal, attempt to achieve this should never be tried. If associated acute respiratory acidosis is severe (pH < 7.2), bicarbonate infusion can be given to achieve a serum pH of approximately 7.25. External PEEP should not be used during ventilation of a patient of status asthmaticus as it can result in dangerous increases in lung volumes and pressures. Weaning from mechanical ventilation of the patient of status asthmaticus requires good planning. The paralytic agents should be discontinued briefly every 4 hours and readministered only if evidence of muscle activity is seen. While some patients with very labile asthma may respond to therapy within hours, more typically the patient will require 24-48 hours of aggressive bronchodilator therapy until airway pressures and PEEPi fall. Once this begins, improvement is usually rapid, with resolution of all dynamic hyperinflation by 12 hours. As airway pressures fall, sedatives, muscle relaxants, and bicarbonate infusions can be reduced to prepare the patient for a brief period of spontaneous ventilation and then extubation. Assessment of respiratory muscle strength should be made by determination of negative inspiratory pressure. If the patient has adequate muscle strength and no sign of respiratory failure emerge during the brief period of spontaneous breathing, extubation should be performed since the endotracheal tube itself can perpetuate bronchospasm. A

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quick return to spontaneous breathing can be achieved through a T-piece or by decreasing the respiratory rate on SIMV. The use of 5-8 cm H2O of pressure support helps overcome endotracheal tube resistance. Once the patient tolerates a trial of spontaneous breathing, quick extubation is done. Vigorous bronchodilator and chest physiotherapy should be continued in the ICU until the next day. During this period and following discharge from the ICU, a careful programme for education should be implemented to help the patient identify signs of worsening asthma and optimize the drug regimen to reduce/obviate future episodes of life-threatening asthma. F.

Inhalant Anaesthetics

Rarely, the above strategy fails to allow adequate ventilation at a safe level of lung inflation. In that situation inhalation of general anaesthetic is—halothane and enflurane—can be considered. These have bronchodilatation activity that can acutely reduce Ppk, and PaCO2.134,135 But the effect lasts as long as the drugs are in use. The bronchodilating effect are lost once the drugs are stopped. Inhalation of these drugs are. Inhalation of these drugs has significant cardiovascular side effects including myocardial depression, arterial vasodilatation, and arrhythmias. Recently, nitric oxide has been used to induce bronchodilatation, however, the experience is limited and at a dose of 80 ppm it exerts a weak bronchodilator effect in asthmatics.136 G.

Bronchoalveolar Lavage

Since mucus plugging is one of the notable features of status asthmaticus, all attempts should be made to remove the same from the respiratory tract to improve airflow. Strategies of mucus removal short of bronchodilators or steroids, like chest physiotherapy or mucolytics are not efficacious.137,138 Bronchoalveolar lavage using saline or acetylcystine, is being tried to remove mucus plug.139-143 Although there is improved airflow in intubated patients, the procedure is not without risk in intubated patients which further compromises the airway lumen. This will increase the expiratory airway resistance and may lead to high levels of lung hyperinflation. At present, BAL is not recommended as part of a routine management of patients with status asthmaticus. Hospital Discharge and Future Plan of Action After the patient has come out of the ICU, in the general ward itself the question of prevention and treatment of subsequent asthma attacks should be addressed. This process starts with extensive patient education, how to recognise the worsening of asthma and what to do at home in such an eventuality, and when to contact a physician or to visit the emergency department. Patients should be provided with written medication instructions as well as a written plan of action to be followed in the event of worsening of symptoms. The proper agents like inhaled medications with or without spacer as per the need. Their doses, frequency, etc. should be clearly explained. Similarly, any oral medication required is to be told to the patient in writing. It is important to explain also the purpose of such medication plans and the techniques are to be taught, particularly for inhalers. The importance of airway inflammation and use of anti-inflammatory drugs needs special explanation to the patient. When inhaled corticosteroids are prescribed, patients must be told not to expect immediate

226 Bronchial Asthma Assessment of severity: • PEFR measurement— < 50% personal best or predicted suggests severe exacerbation. • Signs and symptoms correlate poorly with severity • Accessory muscle use and suprasternal retractions suggest severe exacerbations.

Initial treatment: • Inhaled short-acting β2-agonist; up to three treatments of 2-4 puffs by MDI at 20-minutes intervals or single nebuliser treatment.

Good response

Incomplete response

Poor response

Mild episode

Moderate episode

severe episode

PEFR > 80% predicted or 50-80% predicted or personal best personal best

< 50% predicted or personal best

No wheezing or shortness Persistent wheezing and of breath shortness of breath

Marked wheezing and breathlessness

Response to β2-agonist sustained for 4 hours

Add oral steroid

Add oral corticosteroid

May continue above every Continue β2-agonist 3-4 hours for 24-48 hrs

Repeat β2-agonist immediately

For patients on inhaled corticosteroids, double dose for 7-10 days

• If distress is severe and non-responsive, consult physician and report to emergency.

Follow up with physician

Contact physician urgently the same day

Visit emergency department

Fig. 13.1: Home treatment of asthma exacerbations

relief of respiratory symptoms as they are not bronchodilators. Possible side effects of various drugs are to be told. The purpose and importance of peak flow measurements is to be explained. The technique of the manoeuvre, frequency of measurement maintaining a diary, timings of measurements are to be told. The patient should be told that it is to be measured at am and pm and the best of three readings each time is to be noted as the representative PEFR. Most important is to tell the patient what is the best for him and at what level of reading (severity) he should report to the physician. Appointments are to be made for followup care with primary clinician or asthma specialist. The patient should be given the date, time and location of appointment within seven days of hospital discharge. Before or at discharge the action plan has to be decided. The patient or its caregiver should be instructed on simple plan of action to be taken for symptoms, signs, and PEFR values suggesting recurrent airflow obstruction.

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ASSESSMENT IN HOSPITAL Acute severe asthma If SaO2 < 92% or if the patient has • PEFR 50% or less of predicted or any life-threatening features, ABG personal best measurement is essential • Cannot complete sentence in one breath Severe, life-threatening, if— • Respiration 25/min or more • Pulse > 110/min • Normal (36-45) or high PaCO2 • PaO2 < 60 mmHg irrespective of treatment with oxygen • A low pH Life-threatening features No other investigation is required for management • PEFR < 33% predicted or best • Silent chest, cyanosis, feeble respiratory effort • Bradycardia or hypotension • Exhaustion, confusion, or coma

IMP: Patients with severe or life-threatening attacks may not be distressed and may not have all these abnormalities. The presence of any one should alert the physician.

1. Immediate treatment • Oxygen 40-60%(CO2 retention is not a problem) • Salbutamol 5 mg or Terbutaline 10 mg by a nebuliser • Prednisolone tablet 30-60 mg or IV Hydrocortisone 200 mg or both if very ill • No sedatives of any kind • Chest radiograph to exclude pneumothorax If life-threatening features are present:• Add ipratropium 0.5 mg to the nebulised beta-agonist • IV aminophylline 250 mg over 20 min or Salbutamol or Terbutaline 250 mcg over 10 min. No bolus aminophylline to patients already taking oral theophylline.

2. Subsequent management: • If patient is improving: Continue • 40-60% oxygen • Prednisolone 30-60 mg orally daily or Hydrocortisone 200 mg 6 hrly. • Nebulised beta- agonist 4 hourly • If patient not improving after 15-30 min: • Continue oxygen and corticosteroids • Beta-agonists more frequently, up to every 15-30 min. • Add ipratropium bromide 0.5 mg to nebuliser and repeat every 6 hrly until patient is improving. • If patient is still not improving: • Aminophylline infusion (750-1500 mg/24 hrs for a small and large framed individual); serum level monitoring essential if continued for more than 24hr • Salbutamol or Terbutaline infusion as an alternative to aminophylline.

Contd...

228 Bronchial Asthma Contd... 3. • • • •

Monitoring treatment: Repeat measurement of PEFR 15-30 min after starting treatment Oxymetry Maintain SaO2 > 92% Repeat ABG within 2 hrs after treatment if: • initial PaO2 < 60 mmHg • PaCO2 normal or more than normal • Patient deteriorates • Record PEFR before and after treatment and at least 4 times daily throughout hospital stay.

Transfer to ICU accompanied by physician prepared to intubate if: • Deteriorating PEFR, • Worsening or persisting hypoxia • Hypercapnia • Exhaustion, feeble respiration, confusion, drowsiness • Coma or respiratory arrest

4. When discharged from hospital, patient should have: • Been on discharge medications for 24 hours and have had inhaler technique checked and recorded. • PEFR > 75% of predicted or personal best and diurnal variability of < 25% unless discharge is agreed with respiratory physician. • Treatment with oral and inhaled steroids in addition to bronchodilators. • Own peak flow meter and written self management plan • Physician follow-up planned within one week. • Follow-up visit to respiratory clinic within 4 weeks. • Cause of exacerbations is also to be determined. • Patient should be given details of record. Fig. 13.2: Hospital-based/emergency management of asthma exacerbations (British Guidelines1995)

Patients should be taught how to recognise early warning signs so that they may initiate appropriate treatment of their own. In general, warning signs of worsening airflow obstruction include: a 20% drop in PEFR below predicted or personal best; an increase in cough, shortness of breath, chest tightness, or wheeze. Although mild episodes may be treated by temporarily increasing the bronchodilator therapy, these alone are not sufficient to treat more severe forms of asthma. Inhaled β2-agonists at times give a false sense of security and delay the administration of anti-inflammatory therapy. Accelerated use of β2-agonists should be a warning sign that airway wall inflammation has worsened and corticosteroid therapy should be initiated. Patients with a history of sudden asphyxic asthma should also be given a kit of epinephrine for the immediate subcutaneous epinephrine. The guidelines of the NHLB Institute Expert Panel for management of acute exacerbations of bronchial asthma at different levels are summarised in Figures 13.1 and 13.2.139

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REFERENCES 1. Rebuck AS, Read J. Assessment and management of severe asthma. Am J Med 1971;51:788. 2. McFadden ER, Kiser R, deGroot WJ. Acute bronchial asthma: Relation between clinical and physiological manifestations. N Engl J Med 1973;288:221. 3. McFadden ER, Lyons HA. Arterial blood gas tension in asthma. N Engl J Med 1968;278:1027-32. 4. Nowak RM, Pensler MI, Parker DD. Comparison of peak expiratory flow and FEV1: admission criteria for acute bronchial asthma. Ann Emerg Med 1982;11:64. 5. Bucknall CE. Who needs referral to the hospital asthma specialist? Respir Med 1991;85:453. 6. Beasley R, Burgess C, Crane J, Bremner P, Pearce N. Respiratory arrest in near fatal asthma. N Engl J Med 1991;325:205. 7. Barnes PJ. A new approach to the treatment of asthma. N Engl J Med 1989;321:1517. 8. Reed CE. New therapeutic approaches in asthma. J Allergy Clin Immunol 1986;11:537. 9. Hargreave FE, DolorichJ, Newhouse MT. The assessment and treatment of asthma: A conference report. J Allergy Clin Immunol 1990;85:1098. 10. Whitelaw WA. Asthma deaths. Chest 1991;99:1507. 11. Robin ED. Risk-benefit analysis in chest medicine: Death from bronchial asthma. Chest 1988;93:614. 12. Shim CS, Williams MS. Evaluation of severity of asthma patient versus physician. Am J Med 1980;68:11. 13. McFadden ER Jr. Therapy of acute asthma. J Allergy Clin Immunol 19898;84:151. 14. White CS, Cole RP, Lubetsky HW, Austin JH. Acute asthma: Admission chest radiography in hospitalised adult patients. Chest 1991;100:14. 15. Daley J, Kopelman RI, Comeau E, Ginns LC, Rossing TH. Practice patterns in the treatment of acutely ill hospitalised asthmatic patients at three teaching hospitals. Variability in resource utilisation. Chest 1991;100:51. 16. Tattersfield AE. Current management of acute severe asthma. Br J Hosp Med 1991;46:38. 17. Jones Es. The intensive therapy of asthma. Proc R Soc Med 1971;64:1151. 18. Neville E, Gribbin H, Harrison BD. Acute severe asthma. Respir Med 1991;85:463. 19. Corbridge TC, Hall JB. The assessment and management of adults with status asthmaticus. Am J Respir Crit Care Med 1995;151:1296-16. 20. Wasserfallen JB, Schaller MD, Feihl F, Perret C. Sudden asphyxic asthma: A distinct entity? Am Rev Respir Med 1990;142:108-11. 21. Sur S, Crotty TB, Cephart GM et al. Sudden-onset fatal asthma: A distinct entity with few eosinophils and relatively more neutrophils in the airway submucosa? Am Rev Respir Dis 1993;148:713-19. 22. Rea HH, Scragg R, Jackson R et al. A case control study of death from asthma. Thorax 1986;41: 833-39. 23. Mountain RD, Sahn SA. Clinical features and outcome in patients with acute asthma presenting with hypercapnia. Am Rev Respir Dis 1988;138:535-39. 24. Campbell DA, McLennan G, Coates JR et al. A comparison of asthma deaths and near-fatal asthma attacks in South Australia. Eur Respir J 1994;7:490-97. 25. Reid LM. The presence or absence of bronchial mucus in fatal asthma. J Allergy Clin Immunol 1987; 80:415-16. 26. Gibson GJ. Perception, personality, and respiratory control in life-threatening asthma. Thorax 1995;50(Suppl 1):S2-S4, 27. Kikuchi Y, Okabe S, Tamura G et al. Chemosensitivity and perception of dyspnoea in patients with a history of near-fatal asthma. N Engl J Med 1994;330:1329-34. 28. Rackeman FM, Edwards MC. Asthma in children: A follow up study of 688 patients after an interval of 20 years. N Engl J Med 1952;246; 815-23 and 858-63.

230 Bronchial Asthma 29. Blair H. Natural history of childhood asthma: Twenty year follow-up. Arch Dis Child 1977;52: 613-19. 30. Ogilvie AG. Asthma: A study in prognosis of 1000 patients. Thorax 1962;17:183-189. 31. Ruffin RE, Latimer KM, Schembri DA. Longitudinal study of near fatal asthma. Chest 1991;99: 77-83. 32. Boulet LP, Deschenses F, Torcotte H et al. Near fatal asthma; clinical and physiological features, perception of bronchoconstriction, and psychological profile. J Allergy Clin Immunol 1991;88: 838-46. 33. Campbell DA, McLennan G, Coates JR et al. A comparison of asthma deaths and near fatal asthma attacks in south Australia. Eur Respir J 1994;7:490-497. 34. Sears M, Rea HH. Patients at risk for dying of asthma: The New Zealand experience. J Allergy Clin Immunol 1987;80:477-481. 35. Rea HH, Scragg R, Jackson R et al. A case control study of deaths from asthma. Thorax 1986;41: 833-39. 36. McDonald JB, Mcdonald ET, Seaton A et al. Asthma deaths in Cardiff 1963-74: 53 deaths in hospital. BMJ 1976;ii:721-23. 37. Magadle R, Berar-Yanay N, Weiner P. The risk of hospitalisation and near fatal and fatal asthma in relation to the perception of dyspnoea. Chest 2002;121:329-33. 38. Strunk R, Mrazek D, Furmann G et al. Physiologic and psychological characteristics associated with deaths due to asthma in childhood: A case-controlled study. JAMA 1985;254:1193-98. 39. Strunk R, Nicklas R, Milgrom H et al. Risk factors for fatal asthma: In: Sheffer A, (Ed). Fatal Asthma (vol 115). New York, NY Marcel Dekker, 1997; 115:31-44. 40. Mitchell I, Tough SC, Semple LK et al. Near-fatal asthma. A population based study of risk factors. Chest 2002;121:1407-13. 41. Sampson H, Mendelson L, Rosen J. Fatal and near fatal anaphylactic reaction to food in children and adolescents. N Engl J Med 1992;327:380-84. 42. Greenberger P, Miller T, Lifschultz B. Circumstances surrounding deaths from asthma in Cook County (Chicago), Illinois. Allergy Proc 1993;14:321-26. 43. Castro M. Near fatal asthma. What have we learned? Chest 2002;121:1394-95. 44. Scharf S, Brown R, Saunders N, Green L. Effects of normal and loaded spontaneous inspiration on cardiovascular function. J Appl Physiol 1979;47:582-90. 45. Scharf S, Brown R, tow D, Parisi A. Cardiac effects of increased lung volume and decreased pleural pressure. J Appl Physiol 1979;47:257-62. 46. Permutt S, Wise RA. Mechanical interaction of respiration and circulation. In: Fishman A (Ed). Handbook of Physiology; American Physiological Society. Williams and Wilkins., Baltimore. 1986; 3:647-56. 47. Knowles G, Clark TJH. Pulsus paradoxus as a valuable sign indicating severity of asthma. Lancet 1973;2:1356-59. 48. Kelson SG, Kelson DP, Fleegier BF, Jones RC, Rodman T. Emergency room assessment and treatment of patients with acute asthma. Am J Med 1978;64:622-28. 49. Fitzgerald JM, Hargreave FE. The assessment and management of acute life-threatening asthma. Chest 1989;95:888-94. 50. Shim CS, Williams MH. Relationship of wheezing to the severity of obstruction in asthma. Arch Intern Med 1983;143:890-92. 51. Brenner BE, Abraham E, Simon RR. Position and diaphoresis in acute asthma. Am J Med 1983;74:1005-09. 52. Grossman J. The occurrence of arrhythmias in hospitalised asthma patients. J Allergy Clin Immunol 1976;57:310-17. 53. Josephson GW, Kennedy HL, MacKenzie EJ, Gibson G. Cardiac dysrrhythmias during the treatment of acute asthma: A comparison of two treatment regimens by a double blind protocol. Chest 1980;78:429-35.

Therapeutic Approach in Patients with Asthma (Acute Severe Asthma) [SA]

231

54. Rebuck AS, read J. Assessment and management of severe asthma. Am J Med 1971;51:788-98. 55. Scharf S. Mechanical cardiopulmonary interaction with asthma. Clin Rev allergy 1985;4: 487-500. 56. Lim TK, Ang SM, Rossing TH, Ingenito EP, Ingram RH Jr. The effect of deep inhalation on maximal expiratory flow during intensive treatment of spontaneous asthmatic episodes. Am Rev Respir Dis 1989;140:340-43. 57. Lemarchand P, Labrune S, Herer B, Huchon GJ. Cardiorespiratory arrest following peak expiratory flow measurement during attacks of asthma. Chest 1991;100:1168-69. 58. Nowak RM, Tomalanovich MC, Sarkar DD, Kvale PA, Anderson JA. Arterial blood gases and pulmonary function testing in acute bronchial asthma: Predicting patient outcomes. JAMA 1983;249:2043-46. 59. Mountain RD, Sahn S. Clinical features and outcomes in patients with acute asthma presenting with hypercapnia. Am Rev Respir Dis 1988;138:535-39. 60. Mountain RD, Heffner JE, Brackett NC, Sahn SA. Acid-base disturbances in acute asthma. Chest 1990;98:651-655. 61. Appel D, Rubenstein R, Schrager K, Williams MH. Lactic acidosis in severe asthma Am J Med 1983;75:580-84. 62. O’Connel MB, Iber C. Continuous intravenous terbutaline infusions for adult patients with status asthmaticus. Ann Allergy 1990;64:213-18. 63. Findley LJ, Sahn SA. The value of chest roentgenograms in acute asthma in adults. Chest 1980;5:535-36. 64. Rodrigo G, Rodrigo C. Assessment of the patient with acute asthma in the emergency department; a factor analytic study. Chest 1993;104:1325-28. 65. Fanta CH, Rossing TH, McFadden ER. Treatment of acute asthma: Is combination therapy with sympathomimetics and methylxanthines indicated. Am J Med 1986;80:5-10. 66. Uden DL, Goetz DR, Kohen DP, Fifield GC. Comparison of nebulised terbutaline and subcutaneous epinephrine in the treatment of acute asthma. Ann Emerg Med 1985;14:229-32. 67. Becker AB, Nelson NA, Simons FER. Inhaled salbutamol (albuterol) vs injected epinephrine in the treatment of acute asthma in children. J Pediatr 1983;102:465-469. 68. Behera D, Malik SK and Jindal SK: Subcutaneous salbutamol in acute bronchial asthma. Ind J Chest Dis All Sci 1982; 24:290-92. 69. Amory DW, Burnham Sc, Chenery FW Jr. Comparison of the cardiopulmonary effects of subcutaneously administered epinephrine and terbutaline in patients with reversible a i r w a y obstruction. chest 1975;67:279-86. 70. Rosenfeld CR, Barton MD, Meschia G. Effects of epinephrine on distribution of blood flow in the pregnant woman. Am J Obstet Gynecol 1972;124:156-63. 71. Tracers AH, Rowe B, Barker S et al. The effectiveness of IV β-agonists in treating patients with acute asthma in the emergency department. A meta-analysis. Chest 2002;122:1200-07. 72. Varon J, Fromm RE Jr, Marik PE. IV 2β or not 2β, that is the question! Chest 2002;122:1116-17. 73. Cydulka RK, McFadden ER, Sarver JH, Emerman CL. Comparison of single 7.5 mg dose treatment vs sequential multidose 2.5 mg treatments with nebulised albuterol in the treatment of acute asthma. Chest 2002;122:1982-87. 74. Kelly HW. New β-2 agonist aerosols. Clin Pharmacol Ther 1985;4:393-403. 75. Idris AH, Mcdermott MF, Raucci JC, Morrabel A, McGorray S, Hendeles L. Emergency department treatment of severe asthma: metered dose inhaler plus holding-chamber is equivalent in effectiveness to nebulizer. Chest 1993;103:665-72. 76. Jasper AC, Mohsenifar Z, Kahan S, Goldberg HS, Koerner SK. Cost-benefit comparison of aerosl bronchodilator delivery methods in hospitalised patients. Chest 1987;91:614-18. 77. Newhouse MT. Emergency department management of life-threatening asthma: Are nebulizers obsolete? Chest 1993;103:661-63.

232 Bronchial Asthma 78. Newman KB, Milne S, Hamilton C, Hall K. A comparison of albuterol administered by metereddose inhaler and spacer with albuterol by nebulizer in adults presenting to an urban emergency department with acute asthma. Chest 2002;121:1036-41. 79. Harvey CJ, O’Doherty MJ, Page CJ, Thomas SHL, Nunan TO, Treacher DF. Effect of a spacer on pulmonary aerosol deposition from a jet nebulizer during mechanical ventilation. Thorax 1995;50:50-53. 80. Hess D. How should bronchodilators be administered to patients on ventilators. Respir Care 1991;36:399-404. 81. Thomas SHL, O’Doherry MJ, Fidler HM, Page CJ, Treacher DF, Nunan TO. Pulmonary deposition of a nebulised aerosol during mechanical ventilation. Thorax 1993;48:154-59. 82. Fuller HD, Dolovich MB, Posmituck G, Wong Pack W, Newhouse MT. Pressurised aerosol versus jet aerosol delivered to mechanically ventilated patients. Comparison of dose to the lung. Am rev Respir Dis 1990;141:440-44. 83. Olshaker J, Jerrand D, Barish RA et al. The efficacy and safety of a continuous albuterol protocol for the treatment of acute adult asthma attack. Am J Emerg Med 1993;11:131-33. 84. Rodrigo GJ, Rodrigo C. Continuous vs intermittent β-agonists in the treatment of acute adult asthma. A systemic review with meta-analysis. Chest 2002;122:160-165. 85. Khine H, Fuchs SM, Saville AL. Continuous vs intermittent nebulised albuterol for emergency management of asthma. Acad Emerg Med 1996;3:1019-24. 86. Papo M, frank J, Thompson AE. A prospective, randomised study of continuous versus intermittent nebulised albuterol for severe status asthmaticus in children. Crit Care Med 1993;21:1489-86. 87. Portnoy J, Aggarwal J. Continuous terbutaline nebulisation for the treatment of severe exacerbations of asthma in children. Ann Allergy 1988;60:368-71. 88. Benatar SR. Fatal asthma. N Engl J Med 1986;314:423-29. 89. Rowe BH, Keller JL, Oxman AD. Effectiveness of steroid therapy in acute exacerbations of asthma: a meta analysis. Am J Emerg Med 1992;10:301-10. 90. McFadden ER Jr. Dosages of corticosteroids in asthma. Am Rev Respir Dis 1993;147:1306-1310. 91. Haskel RJ, Wong EM, Hansen JE. A double-blind, randomised clinical trial of methyl prednisolone in status asthmaticus. Arch Intern Med 1983;143:1324-27. 92. Littenberg B, Gluck EH. A controlled trial of methyl prednisolone in the emergency treatment of acute asthma. N Engl J Med 1986;314:150-52. 93. Rodrigo G, Rodrigo C. Corticosteroids in the emergency department therapy of acute adult asthma: An evidence based evaluation. Chest 1999;116:285-95. 94. Rodrigo C, Rodrigo G. Inhaled flunisolide for acute severe asthma. Am J Respir Crit Care Med 1998;157:698-703. 95. McFadden ER. Inhaled glucocorticosteroids and acute asthma: Therapeutic breakthrough or nonspecific effect? Am J Respir Crit Care Med 1998;157:677-78. 96. Lee-Wong M, Dayrit FM, Kohli AR et al. Comparison of high-dose inhaled flunisolide to systemic corticosteroids in severe adult asthma. Chest 2002;122:1208-13. 97. Edmonds ML, Camargo CA Jr, Brenner BE, Rowe BH. Replacement of oral corticosteroids with inhaled corticosteroids in the treatment of acute asthma following emergency department discharge. Chest 2002;121:1798-1805. 98. Mark PE, Varon J. Oral vs inhaled corticosteroids following emergency department discharge of patients with acute asthma. Chest 2002;121:1735-36. 99. Rebuck AS, Chapman KR, Abboud R et al. Nebulised and sympathomimetic treatment of asthma and chronic obstructive airways disease in the emergency room. Am J Med 1987;82:59-64. 100. Bryant DH, Rogers P. Effects of ipratropium bromide solution nebulisation with and without preservatives in the treatment of acute and stable asthma. Chest 1992;102:742-47.

Therapeutic Approach in Patients with Asthma (Acute Severe Asthma) [SA]

233

101. Kelly HW, Murphy S. Should anticholinergics be used in acute severe asthma? Ann Pharmacothera 1990;24:409-14. 102. Rodrigo GJ, Rodrigo C. The role of anticholinergics in acute asthma treatment: An evidence based evaluation. Chest 2002;121:1977-1987. 103. Lalla S, Saleh A, Faroog J et al. Intravenous aminophylline in acute, severe bronchial asthma. Chest 1991;(Suppl):60S. 104. Wrenn K, Slovis CM, Murphy F, Greenberg RS. Aminophylline therapy for acute bronchospastic disease in the emergency room. Ann Intern Med 1991;115:241-47. 105. Littenberg B. Aminophylline in severe, acute asthma: A meta-analysis. JAMA 1988;259:16781684. 106. Rodriguez-Roisin R, Ballester E, Roca J, Torres A, Wagner PD. Mechanisms of hypoxia in patients with status asthmaticus requiring ventilation. Am Rev Respir Dis 1989;139:732-39. 107. Skobeloff EM, Spivey WH, McNamara RM, Greenspon L. Intravenous magnesium for the treatment of acute asthma in the emergency department. JAMA 1989;262:1210-13. 108. Noppen M, Vanmaele L, Impens N, Schandevyl W. Bronchodilating effect of intravenous magnesium sulfate in acute severe asthma. Chest 1990;97:373-76. 109. Rolla G, Bucca C, Caria E et al. Acute effects of intravenous magnesium sulfate on airway obstruction of asthmatic patients. Ann allergy 1986;61:388-91. 110. Okayama H, Aikawa T, Okayama M, Sasaki H, Mue S, Takishima T. Treatment of status asthmaticus with intravenous magnesium sulfate, J Asthma 1991;28:11-17. 111. Bloch H, Silverman R, Mancherje N, et al. Magnesium sulfate is a useful adjunct to standard therapy for acute severe asthma. Chest 1992;102(Suppl):83S. 112. Haury VG. Blood serum magnesium in bronchial asthma and its treatment by the administration of magnesium sulfate. J Lab Clin Med 1940;25:340-344. 113. Boselo SJ, Pla JC. Sulfato de magnesio en la crisis de asthma. Prensa Med Argent 1936; 23:1677-80. 114. Noppen M, Vanmaele I, Impens N et al. Bronchodilating effect of intravenous magnesium sulfate in acute severe bronchial asthma. Chest 1990;97:373-76. 115. Rolla G, Bucca C, Caria E et al. Acute effect of intravenous magnesium sulfate on airway obstruction of asthmatic patients. Ann allergy 1988;61:388-91. 116. Okayama H.Aikawa T, Okayama M et al. Bronchodilating effects of intravenous magnesium sulfate in bronchial asthma. JAMA 1987;257:1076-78. 117. McNamara RM, Spivey WH, Skobeloff E et al. Intravenous magnesium in the management of acute respiratory failure complicating asthma. Ann Emerg Med 1989;18:197-99. 118. Kuitert LM, Kletchko SL. Intravenous magnesium sulfate in life-threatening asthma. Ann Emerg Med 1991;20:1243-45. 119. Devi PR, Kumar L, Singhi S et al. Intravenous magnesium sulfate in acute severe asthma not responding to conventional therapy. Indian Paediatr 1997;34:389-97. 120. Clarallo L, Brousseau D, Reinert S. Higher-dose intravenous magnesium therapy for children with moderate to severe acute asthma. Arch Pediatr Adolesc Med 2000;154:979-83. 121. Blosch H, Silverman R, Mancherje N et al. Intravenous magnesium sulfate as an adjunct in the treatment of acute asthma. Chest 1995;107:1576-81. 122. Green SM, Rothrock SG. Intravenous magnesium for acute asthma: Failure decrease emergency treatment duration or need for hospitalisation. Ann Emerg Med 1992;21:260-65. 123. Tiffany BR, Berk WA, Todd IK et al. Magnesium bolus or infusion fails to improve expiratory flow in acute asthma exacerbations. Chest 1993;104:831-34. 124. Silverman RA, Osborn H, Runge J et al. IV magnesium sulfate in the treatment of acute severe asthma; a multicenter randomised controlled trial. Chest 2002;122:489-97. 125. Gluck EH, Onorato DG, Castriotta R. Helium-oxygen mixtures in intubated patients with status asthmaticus and respiratory acidosis. Chest 1990;98:693-98.

234 Bronchial Asthma 126. Manthouse CA, Hall JB, Melmed A et al. Heliox improves pulsus paradoxus and peak expiratory flow in nonintubated patients with severe asthma. Am J Respir Crit Care Med 1995;151:310-14. 127. National Asthma Education Programme. Expert panel report. Guidelines for the diagnosis and management of asthma. Bethesda, US Department of Health and Human Services. Publication No.91-3042. 128. Meduri GU, Abou-Shala N, Fox RC, Jones CB, Leeper KV, Wunderink RG. Non-invasive face mask mechanical ventilation in patients with acute hypercapnic respiratory failure. Chest 1991;100:445-54. 129. Shivram U, Miro AM, Cash ME, Finch PJP, Heurich AE, Kamolhz SL. Cardiopulmonary responses to continuous positive airway pressure in acute asthma. J Crit Care 1993;8:87-92. 130. Martin JG, Shore S, Engel LA. Effect of continuous positive airway pressure on respiratory mechanics and pattern of breathing in induced asthma. Am Rev Respir Dis 1982;126:812-17. 131. Mansel JK, Stogner SW, Norman JR. Face-mask CPAP and sodium bicarbonate infusion in acute severe asthma and metabolic acidosis. Chest 1989;96:943-44. 132. Pollard BJ. Which drug-steroid or benzylisoquinolium? Intensive Care Med 1993;19:46-60. 133. Pepe PE, Marini JJ, Occult end expiratory pressure ion mechanically ventilated patients with airflow obstruction. Am Rev Respir Dis 1982;126:166-70. 134. Saunier FF, Durocher AV, Deturck RA, Lefebvre MC, Wattell FE. Respiratory and haemodynamic effects of halothane in status asthmaticus. Intensive Care Med 1990;16:104-07. 135. Echeverria M, Gelb AW, Wexier HR, Ahmad D, Kenefick P. Enflurane and halothane in status asthmaticus. Chest 1986;89:153-54. 136. Hogman M, Frostell CG, Hedenstrom G. Inhalation of nitric oxide modulates adult human bronchial tone. Am Rev Respir Dis 1993;148:1474-78. 137. Falliers CJ, McCann WP, Chai H, Ellis EF, Yazdi N. Controlled therapy of iodotherapy for childhood asthma. J Allergy 1966;38:183-92. 138. Wanner A, Rao A. Clinical indications of and effects of bland, mucolytic, and antimicrobial aerosols. Am Rev Respir Dis 1980;122:79-87. 139. Helm WH, Barran KM, Mukerjeee SC. Bronchial lavage in asthma and bronchitis. Ann Allergy 1972;30:518-23. 140. Lang DM, Simon RA, Mathison DA, Tims RM, Stevensopn DD. Safety and possible efficacy of Fibre optic bronchoscopy with lavage in the management of refractory asthma with mucus impaction. Ann Allergy 1991;67:324-30. 141. Rogers RM, Shuman JF, Zubrow AB. Bronchoalveolar lavage in asthma. Chest 1973;63(Suppl): 62S-64S. 142. Smith DL, Desnazo RD. Bronchoalveolar lavage in bronchial asthma. Am Rev Respir Dis 1993;148:523-32. 143. Millman M, Millman FM, Goldstein IM, Mercandetti AJ. Use of acetylcystein in bronchial asthma: another look. Ann Allergy 1985;54:294-96.

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14 Management of Asthma with Special Problems EXERCISE-INDUCED ASTHMA (EIA) The term “exercise-induced asthma” (EIA) is often used to describe the asthma of persons in whom exercise is the predominant or at times the only identified trigger to airflow limitations. The goal of EIA is to enable patients to participate in any activity they choose without experiencing asthma symptoms and to enable the patient to achieve a normal exercise capacity. For some asthmatics, this goal means an ability to walk short distances and to work regularly without limitation due to breathlessness. While for other, like children and young adults, it implies the freedom to run about and to compete in sports without respiratory disability. For highly trained athletes with asthma, it means to compete at extremely high levels of physical activity and ventilatory performance. Therefore, the goals of managing asthma in relation to exercise are: (i) to maximise lung function prior to exercise, (ii) to protect bronchoconstriction during exercise. The presence or absence of bronchospasm induced by exercise can be established by spirometry before and after the exercise task in question. Some difficulty is encountered when the exercise cannot readily be performed in the laboratory. In that situation, the condition must be mimicked as closely as possible in the laboratory by having the patient exercise with a stationary bicycle or treadmill to the levels of ventilation and with inspired air temperature and humidity that simulates the actual exercising condition. Testing worldclass athletes in an otherwise well equipped pulmonary laboratory becomes still difficult because of difficulty in providing a sufficiently strenuous exercise work load. In this setting, eucapnic voluntary hyperventilation can be substituted for physical exertion, and the target level of ventilation to be sustained can be set without limit. Formal pulmonary evaluation before and after exercise can also be used effectively to evaluate the impact of preventive therapies. In athletes failing to respond to conventional prophylactic treatment, identical exercise challenges can be performed following administration of various medications in varied doses and combinations, thereby objectively assessing their success. Bronchoconstriction induced by exercise are generally rapidly eliminated by administration of inhaled β2-agonists. However, the bigger problem is preventing the development of significant airflow obstruction during and following exercise so as to minimise the impact of asthma on athletic participation and performance. Optimised control of asthma in general as outlined is the first step towards prevention. The less is the underlying bronchial hyperresponsiveness and higher the pre-exercise level of expiratory airflow, the less likely it is

236 Bronchial Asthma that a particular exercise task will provoke asymptomatic airflow obstruction. In some asthmatics, regular use of inhaled corticosteroids will be needed to achieve these goals. Inhaled corticosteroids are currently approved by the International Sports authorities for this purpose. Most patients with EIA are otherwise asymptomatic. In these patients, inhaled β2-agonists, used prior to exercise, will prevent EIA in more than 80% of subjects. These may be taken from less than 10 to 20 minutes prior to exercise in standard doses (1-2 inhalations) and are helpful for up to several hours. They provide excellent protection for 2 hours. Because they do not enhance exercise performance in any way other than prevention of air-flow obstruction, they are permitted and approved for use in world-class competitions. Fenoterol is an exception as its metabolite parahydroxyamphetamine, which is not allowed for athletes. The newer, longer-acting β-agonists, salmeterol and formoterol, offer effective prevention of exercise-induced symptoms for as long as 8 hours following a single, pre-exercise dose.1,2 Cromolyn sodium (2 puffs) before exercise is another acceptable pre-treatment, particularly in those who cannot tolerate beta-agonists. This drug is virtually devoid of any side effect. The peculiarity of the drug is that when used as an anti-inflammatory agent for chronic asthma, it takes several weeks for its effect. But as a prophylactic in EIA, a single dose prior to exercise is effective. Regular use of the drug does not enhance the protective action.3 The small percentage of patients who still encounter difficulty are helped by an increase in the dosage of β2-agonist or use of both this and Cromolyn. Many other drugs have been shown to inhibit the bronchoconstrictive effect of exercise. They are ipratropium bromide, theophylline, calcium channel blocking agents, nedocromil, terfenadine, leukotriene D4 antagonists and lipoxygenase inhibitors, inhaled frusemide4, and inhaled heparin5 are some of the conventional and newer therapies active in modifying the response to exercise. However, use of many of these are rarely required. Their use can be considered when conventional therapy with β-agonists and cromolyn fails. Patients who experience a refractory period during continuous exercise may benefit from a warm-up period before exercise utilising submaximal exercise and may not need repeated medications during periods of continuous exercise. They should avoid a sudden change to a warm, moist environment immediately after exercise which will help in modifying the post-exercise response. Specially designed low-resistance “heat and moisture exchange” face mask has been shown to help asthmatics in cold environments.6 Medications that are approved by the US Olympic Committee for use in competition include β2-agonists (aerosol or inhalant forms of salbutamol, bitolterol, and terbutaline), Cromolyn sodium, theophylline and inhaled steroids. PREGNANCY AND ASTHMA The natural history of asthma during pregnancy is variable. Several physiological changes occur during pregnancy that could worsen or improve asthma. However, it is not clear which are the factors that will decide the ultimate course. It is reported that symptoms of asthma worsens during pregnancy in 43% of patients and improves in 14%.7 In a perspective cohort study of 366 pregnancies in 330 women with asthma, the disease worsened during pregnancy in 35%.8 Other studies suggest that 11-18% of pregnant women with asthma will have at least one emergency department visit for acute asthma and of these, 62% will require hospitalisation.9,10 Exacerbations of asthma symptoms usually occurs during the

Management of Asthma with Special Problems 237 last trimester. In a large cohort study the most severe symptoms were experienced by patients between the 24th and 36th week of pregnancy. Thereafter symptoms decreased significantly in the last four weeks and 90% had no asthma symptoms during labor or delivery. Only two patients required additional medications beyond bronchodilators.8 Another study has also confirmed that during the last months of pregnancy asthma is least likely to exacerbate.11 Some other reports suggest that there is no change in the course of asthma during pregnancy.12 Women tend to follow the same pattern during all pregnancies with respect to the course of their asthma.13, 8 Women with extrinsic (atopic) asthma tend to have fewer symptoms during pregnancy than patients with intrinsic asthma.14 A cohort study comparing 198 pregnant women with asthma with 198 women without asthma observed that non-atopic patients with asthma tend to have more severe asthma. Pre-eclampsia was also more common in this group. However, with proper surveillance and treatment, pregnancy and delivery related complications could be avoided. A systematic review has shown that baseline asthma severity does determine what happens to asthma in pregnancy and asthma may affect the risk of adverse outcome.15 Severe asthma is likely to worsen during pregnancy than mild asthma.8 However, some patients with severe asthma may experience improvement, whilst symptoms may deteriorate in some with mild asthma. A meta-analysis of 14 studies concluded and agreed with the commonly quoted generalisation that during pregnancy about one-third of asthma patients experience an improvement in their asthma, one-third experience a worsening of symptoms, and one-third remains the same.16 During pregnancy 40% of the patients managed with the same asthma medications as before pregnancy; 18% needed less; and in 42% the need was more.17 Bronchial asthma in the mother has been associated with increased perinatal morbidity and mortality,18,19 and also with increased morbidity during infancy.18 Obstetric complications have been observed more often in asthmatics than in control subjects.18 Pre-eclampsia occurred more often in asthmatics than controls, especially in patients with severe asthma. Hypoglycemia occurred more often in infants of mothers with severe asthma than in infants of mothers with less severe disease. Uncontrolled asthma is associated with many maternal and fetal complications, including hyperemesis, hypertension, pre-eclampsia, vaginal hemorrhage, complicated labor, intrauterine growth retardation, pre-term birth, increased perinatal mortality, and neonatal hypoxia.20-23 A large Swedish population based study using record linkage data demonstrated increased risks for preterm birth, low birth weight, perinatal mortality, and pre-eclampsia in women with asthma. The risk of prematurity and low birth weight were higher in women with severe asthma necessitating admission.24 In contrast, if asthma is well controlled throughout pregnancy there is little or no increased risk of adverse maternal or fetal complications.9,10 Pregnancy, therefore, should be an indication for optimisation of therapy and maximising lung function in order to reduce the risk of acute exacerbations. Theophylline at term did not influence labor or delivery. Thus, severe asthma or systemic corticosteroid treatment or both during pregnancy seems to increase the incidence of mild pre-eclampsia in the mother and hypoglycaemia in the newborn.19 Poorly controlled asthma has adverse effect on the fetus, resulting in increased perinatal mortality, increased prematurity, and low birth weight. For this reason, the use of drugs to obtain optimal control of asthma is justified even when their safety in pregnancy has not been unequivocally proven. For most antiasthma drugs, clear documentation of teratogenic effects is lacking. On the other hand, these drugs have not yet been proved to be safe. Thus all drugs can be used without increased

238 Bronchial Asthma risk to the fetus25,26 except alpha-adrenergic compounds. Reports on the adverse effects of corticosteroids during pregnancy are contradictory. Apgar reported an increased incidence of cleft palate in two series of pregnancies in women treated with systemic corticosteroids in early pregnancy.27 The incidence of stillbirths was eight times higher in women having continuous steroid treatment than in a corresponding group of untreated women with the same diseases.28 However, the alarming findings in these studies may be a part of the underlying severe disease rather than the treatment.29 However, two other studies of pregnant asthmatic women, some having short-term and some long-term systemic corticosteroids, showed no complications attributable to steroid treatment.30,31 Thus, although the direct effects of systemic steroids on the fetus appears to be small, their indirect effects (hypertension, preeclampsia, hypoglycemia) may still form a risk for the infant. However, as an acute exacerbation of asthma carries even greater risks for the mother and child, systemic steroids should not be withheld when the need arises. Higher theopylline concentrations in the mother might be associated with complications of labor and delivery due to uterine atony. On the other hand, inhaled steroids may be quite safe in recommended doses. Immunotherapy should not be started during pregnancy, if that is considered. It is important to avoid fetal hypoxia during acute exacerbations. No special treatment is required for asthma during labor except for those who have received daily parenteral steroids for a week or three separate courses in the preceding year, in whom hydrocortisone supple-mentation (100 mg every 8 hours) should be given for the stress of delivery unless there is documentation of normal adrenal responsiveness. Terbutaline and salbutamol can cause delayed/poor uterine contraction during labor. During acute attacks, drug therapy should be the same as for the non-pregnant patient. Oxygen should be delivered to maintain saturation above 95%. Continuous fetal monitoring is recommended for severe asthma. In women with poor control of asthma, there should be close liaison between the respiratory physician and obstetrician. In general, the medicines used to treat patients of asthma are quite safe in pregnancy.32 The risk of harm to the fetus from severe or chronically under treated asthma outweighs any small risk from the medications used to control asthma. β2-agonists, corticosteroid inhalers are to be used as normal during pregnancy.33,34 No significant association has been demonstrated between major congenital malformations or adverse outcome and exposure to methylxanthines.32,35 Although there were some concerns of use of oral steroids during early pregnancy, they were unfounded and steroid tablets are to be used as normal when indicated during pregnancy for severe asthma and they should not be withheld because of pregnancy. Data regarding the safety of leukotriene antagonists are limited. Animal studies and postmarketing surveillance for zafirlukast and monteleukast are reassuring. There are concerns about animal data on zyleuton.36 Leukotriene antagonists should not be started during pregnancy. They may be continued in women who have demonstrated significant improvement in asthma control with these agents prior to pregnancy not achievable with other medications. Acute attacks of asthma are very rare in labor due to endogenous steroid production. In women receiving steroid tablets there is a theoretical risk of maternal hypothalamic-pituitaryadrenal axis suppression. Women with asthma may safely use all forms of pain relief in labor. In some studies there is an association between asthma and an increased caesarean section rate., which may not be conjectural. Risk of postpartum exacerbation of asthma is increased in women undergoing caesarean section. This may be related to the severity of asthma rather than caesarean section per se. The women should continue their usual asthma medications in labor. In the absence of acute severe asthma, caesarean section should be

Management of Asthma with Special Problems 239 reserved for usual obstetrics indications. If anaesthesia is required, regional blockade is preferable to general anaesthesia in women with asthma. Women receiving steroid tablets at a dose exceeding prednisolone 7.5 mg per day for more than two weeks prior to delivery should receive parenteral hydrocortisone 100 mg 6-8 hourly during labor. Prostaglandin F2α should be used with extreme caution in these women with asthma because of the risk of induction of bronchoconstriction. Antiasthma drugs may pass into the breast milk, and earlier, mothers have, therefore, been advised not to breastfeed. However, no evidence has shown that inhaled drugs or moderate doses of theophylline or systemic steroids taken by mouth by the lactating mother would be harmful to the infant.37 Breastfeeding, thus, is to be encouraged.19 All medications used to treat asthma including steroid tablets have been shown in early studies to be safe to use in nursing mothers.15 There is less data with newer agents. Less than 1% of the maternal dose of theophylline is excreted into the breast milk. Prednisolone is secreted in breast milk, but milk concentrations of prednisolone are only 5-25% of those in serum.16. The proportion of an oral or intravenous dose of prednisolone recovered in breast milk is less than 0.01%. For maternal doses of at least 20 mg once or twice daily, the nursing infant is exposed to minimal amounts of steroid with no clinically significant risk. Thus, asthma drugs should be used as normal during lactation, in line with manufacturer’s recommendations. SURGERY AND ASTHMA Possible intraoperative and postoperative complications can occur in patients of bronchial asthma because of bronchial hyper-reactivity, airflow obstruction, and mucus hypersecretion.38-40 Possible complications are many and may include the following. Acute attacks may be triggered during intubation which stimulates sensory receptors in the upper airway that can lead to reflex efferent neurotransmission via the vagus nerve, resulting in bronchial smooth muscle contraction. Increased airway obstruction may result due to suppressed cough and mucus plugging following surgery. This will result in ventilation-perfusion mismatching and may contribute to impaired gas exchange resulting in hypoxaemia and possibly hypercapnia during and following surgery. Severe airflow obstruction along with postoperative pain, can impair the effective cough. Retained airway secretion can further impair airflow and gas exchange. Further, mucus impaction can cause atelectasis and associated diminished respiratory excursion will result in respiratory infection and further impairment of gas exchange. The likelihood of these complications will depend upon the severity of the patient’s airway hyperresponsiveness, the degree of airways obstruction, and the amount of mucus plugging at the time of surgery. These variables can be assessed by history, physical examination, and spirometry. Other factors that influence the rate of postoperative complication include the type of surgery (thoracic and upper abdominal surgery have the greatest risk) and type of anaesthesia (general anaesthesia with endotracheal intubation carries the greatest risk). All patients with active asthma should undergo preoperative respiratory evaluation. Even asymptomatic patients with bronchial asthma should undergo evaluation as they may have significant airflow obstruction and bronchial hyper-responsiveness. Patients with moderate to severe disease, the evaluation should begin several days prior to surgery. When the asthma is uncontrolled, the patient should be hospitalised for a day or more prior to surgery for optimisation of lung function. Patients having frequent nocturnal awakening, frequent or

240 Bronchial Asthma continuous use of steroids, prior perioperative complications related to asthma, large volume of sputum production, and co-morbid cardiovascular disease are associated with a high risk for perioperative complications. Spirometry is the best way to assess the degree of airflow obstruction and all attempts should be made to achieve a normal or near normal lung function prior to surgery. Asthma patients experiencing wheezing, productive cough, chest tightness, or dyspnoea should receive intensified treatment of their asthma prior to elective therapy, even if this necessitates delay of surgery. An attempt should be made to improve lung function in patients with an FEV1 or PEFR < 80% of predicted or < 80% of their recent best value. Frequently a brief course of corticosteroids will be required to achieve this goal. Modification of anaesthetic approach may be possible in some at increased perioperative risk. Spinal, epidural, or local anaesthesia may in some cases be substituted for general anaesthesia and postoperative pain control may be achieved with epidural analgesia rather than parenteral narcotics. Even in the asymptomatic or minimally symptomatic patient, it is useful to administer an inhaled β2agonist bronchodilator immediately prior to surgery. Patients receiving daily medications for asthma should generally be maintained on these drugs. Intravenous aminophylline can be used to maintain therapeutic levels who are taking this drug, but are not permitted to take anything by mouth. The usual maintenance dose of theophylline is intravenous aminophylline of 0.6 mg/kg/hour by continuous infusion. Inhaled bronchodilators can be maintained during surgery even patients receiving general anaesthesia and mechanical ventilation. To prevent depressed adrenal-pituitary response to stress, intraoperative and postoperative steroid supplementation should be given to patients who have received systemic steroids for more than 2 weeks within the last 6 months or more than two courses of systemic steroids within the last 12 months. Patients who have been taking high-dose inhaled corticosteroids more than the conventional recommended doses, should also be considered at risk of relative adrenal-pituitary suppression and should be given perioperative steroid replacement therapy. The usual dose of replacement corticosteroid therapy during stress is 300 mg of hydrocortisone per day. Hydrocortisone of 100 mg each should be given intravenously on the day of surgery in the morning, intraoperatively, and postoperatively. The dose is then tapered over the next few days. Clearance of airways is an important aspect of postoperative care. OLDER PATIENTS WITH ASTHMA Although asthma affects all age groups, morbidity and mortality is particularly high in the elderly. In New York City, asthma-attributable mortality rates in adults > 65 years of age are six times higher than those in adults < 40 years of age.4 Whereas many factors contribute to the urban asthma problem, sensitisation to indoor allergens may play a particularly significant role. The presence of cockroach-specific serum IgE in a population of elderly urban patients with asthma, is associated with more severe asthma, as reflected by an increase in airway obstruction and hyperinflation.42 Asthma is frequently under diagnosed in the elderly because of a number of differential diagnosis, difficulty in measurement of lung function, and underreporting of symptoms.43 The later may occur because of reduced expectations or because of an age related reduction in perception of breathlessness.44 A similar age related difference in the physical signs associated with severe asthma may lead to underestimation of severity and under treatment.45 Simple tests of mental functioning may be necessary to ensure that elderly people with asthma are capable of acquiring the necessary skills for treating and monitoring their condition.46 Increased asthma mortality is more common in elderly patients

Management of Asthma with Special Problems 241 above the age of 55 years. This may be due to difficulty in diagnosis (COPD and congestive cardiac failure). The precise cause of severe airflow obstruction is difficult to diagnose at times. Some cases asthma diagnosed in older individuals may actually be a combination of asthma and COPD or of asthma and congestive heart failure. Further, coexistence of other diseases (myocardial ischaemia), can cause additional problems. For example, ischaemic heart disease in a case of bronchial asthma may be more dangerous because of associated hypoxaemia which could result in decreased myocardial oxygenation followed by myocardial infarction or rhythm disturbances. Frequent intake of drugs by people of this age are known to aggravate asthma (beta blockers for hypertension and eye drops, aspirin and other nonsteroidal anti-inflammatory drugs). Since arthritis is a known disease of this age, if the patient takes aspirin and other non-steroidal anti-inflammatory drugs may cause sudden and severe asthma exacerbations. Further, epinephrine and theophylline have the potential of precipitating the underlying heart disease. Although treatment of chronic and acute asthma exacerbations should be the same as per the recommended guidelines, certain special considerations are necessary in elderly individuals. All patients of asthma above the age of 55 years old should be evaluated for coexisting disease conditions. Particular attention should be given to the monitoring of hypoxemia if he has concomitant heart disease. Theophylline may increase the risk of urinary retention in older men with prostatism apart from its potential cardiac side effects. These patients should carefully be monitored for steroid side effects. Monitoring of hematocrit and blood sugar periodically is essential to rule out hyperglycemia, hypokalemia, and gastrointestinal bleeding. Eye examination is to be conducted annually to rule out cataract and glaucoma. Evaluation of possible alterations in calcium homeostasis is essential particularly in whom there is a greater concern of bone loss as in postmenopausal women. Anticholinergic bronchodilator therapy may have a greater role in this age group than in the younger patients.47 Oxygen should also be used with caution if there is associated COPD to avoid precipitation of carbon dioxide retention. Depression and other associated serious psychiatric illness needs detail assessment. Older individuals are more prone for depression, which in turn is identified as a risk factor for fatally-prone asthma. Family loss and disruption, difficult adjustments to retirement, and other psychosocial problems are more common in this age group. Certain other impairments more common in older individuals may interfere worth treatment. These include arthritis, which may require special devices such as a spacer to assist actuation. Nebulisers might be more useful. Patients with visual impairment may be unable to read the numbers on the peak flow meter in which colour codes might help. Further, there may be difficulty in reading instructions either on the drug or prescriptions given by the physician. Some other family member may be helpful in this situation. Patients with memory difficulties might forget to adhere to medical regimens that require several drugs and frequent schedules. Patients with hearing difficulties may not tell the health provider that they have not heard or understood the instructions. Asking the patients to state the information and/or instructions in their own words will help ensure understanding. OCCUPATIONAL ASTHMA The diagnosis should be suspected in all adults with airflow obstruction and with a positive history of high-risk occupations or exposures. Patients with pre-existing asthma aggravated non-specifically by dust and fumes at work (work aggravated asthma) should be distinguished from those with pre-existing asthma who become additionally sensitized to an occupational agent. The subject is usually better on days away from work and better on holidays. Although

242 Bronchial Asthma they are not specific for occupational asthma, but are important clues for investigation for an occupational agent. These symptoms are also present in asthmatics due to sensitizing agents at home and in those who do much less physical exertion. An accurate history taking is important which should include exposures to chemicals, organic dusts and other possible agents both at the current time as well as in the past. The diagnosis and management of occupational asthma are difficult and can be divided into three parts: • Confirming the diagnosis of asthma; • Confirmation of the relationship between asthma and work exposures; and • Finding the specific cause The first step is to confirm that the patient is having asthma by using standard measures like peak expiratory flow measurements, lung function tests, and reversibility testing. COPD and non-respiratory causes of breathlessness should be excluded. The next step is the establishment of a relationship between asthma and work exposure. These include serial measurements of PEFR at home, and at work, measurements of non-specific airway hyper reactivity after days at and away from work, measurements of specific IgE to an occupational agent, and specific bronchial provocation testing. The decision of making a case of occupational-induced asthma remains a matter of clinical judgment. Measurements of PEFR should be made every two hours from working to sleeping for four weeks keeping treatment constant and documenting times at work.48 Minimum standards for diagnostic sensitivity of > 70% and specificity of > 85% are (a) at least three days in each consecutive work period; (b) At least three series of consecutive days at work with three periods away from work (usually about three weeks); and (c) at least four evenly spaced readings per day. Nonspecific responsiveness measurements with methacholine or histamine can be undertaken after a period at end away from work exposure. A more than 3.2-fold changes in PC20 indicates a significant change outside the 95% confidence intervals for repeat measurements. The diagnostic sensitivity, however, is only 40%, which is substantially worse than serial PEFR measurements.49 The third step is identification of the cause of occupational asthma, which is often difficult. There should be information about the sources of exposure (risk assessment). IgE measurements are possible for most biological agents and a few low molecular weight chemicals. These include latex in health care workers, flour and enzymes in bakers, rodent urine extracts, and animal epithelia in laboratory animal workers and veterinary surgeons, and acid anhydrides in exposed workers. Carefully controlled exposure to workplace agents and suitable controls is the gold standard for diagnosis.50 Tests are difficult to do and are not widely available, and are not always possible for some types of workplace exposures. The ideal treatment for patients with occupational asthma with a latency period is removal from exposure. Early diagnosis and removal from exposure is associated with a favourable prognosis. Eliminating exposure should be tried. In some instances, reducing exposure by improving ventilation or providing a respirator may allow a person to return to the same job. However, once sensitisation occurs, bronchoconstriction will often be triggered by subsequent minimal exposure. Once well established, occupational asthma may not be completely reversible. Recovery, if occurs may take months to years after removal from exposure. A worker might be transferred to a job without exposure in the same company. Most people with occupational asthma have to be retained for a job with another employer in a different field. Before advising the worker to leave the job, attempt should be made to see if

Management of Asthma with Special Problems 243 changing the job process or activities can be changed to reduce exposure or if protective equipment is useful. When the employees have irritant-induced asthma, or work-aggravated asthma, employer should make every effort towards reasonable accommodation by improving the workplace as required. The physician should advise the patient regarding compensation as per the law of the particular country. If the patient returns to the same job, should have close medical follow-up. Worsening of asthma should lead to immediate removal from exposure. Pharmacological treatment of occupational asthma is similar to the treatment of patients with other forms of asthma. However, continuing monitoring is important. Although removal from the source of exposure lead to improvement, patients may continue to require medication and have airflow limitation or bronchial hyperresponsiveness for many months or years. Patients should be referred to compensation boards or similar other agencies. Patients should be evaluated for temporary impairment and disability when their asthma is under good control. Evaluation for potential permanent impairment and disability should take place after two years, when improvement in asthma has plateaued. Irritant-induced asthma (Reactive airway dysfunction syndrome—RADS) is another form of asthma associated with the workplace, in which a wheezing illness starts within 24 hours, and usually less than that, of a single large exposure to an irritant. The condition is inflammatory and does not involve immunological recognition of the irritant, so that continued low levels of exposure to the causative agent can be tolerated without problems. RADS is diagnosed by the presence of non-specific responsiveness and a compatible history. The prognosis varies, but there is a good likelihood of improvement. DRUG-INDUCED ASTHMA Even an initial reaction to aspirin or other nonsteroidal anti-inflammatory drug (NSAID) may be severe and an adverse reaction can occur at any time, typically following years of employing these drugs without difficulty. Therefore, all patients of asthma should avoid this group of drugs. Usually safe and alternative drugs are acetaminophen, sodium salicylate, or disalcid. Reaction to aspirin or an NSAID produce a refractory state lasting 2-7 days and do not occur if patients ingest the drugs on a daily basis.51 If the patient is avoiding these drugs, the initial dose in the form of a rapid graded challenge should be given in the presence of a physician. If the patient has severe asthma requiring steroids or has severe asthma with compromised pulmonary function, or if the patient reports a previous bronchoconstrictive reaction to these drugs, a more conservative treatment approach is indicated and should be undertaken by a physician familiar with the technique.51 Aspirin use may be a special problem in patients with nasal polyps, chronic rhino sinusitis, and steroid dependency. If there is a concern regarding the use of aspirin in these patients, a sensitivity challenge should be conducted. GASTRO-OESOPHAGEAL REFLUX AND ASTHMA The relationship of asthma to gastro-oesophageal reflux is a matter great debate, although most people now believe that this is an important precipitating factor for asthma.52,53 In some studies, medical and surgical treatment of gastro-oesophageal reflux has resulted in improvement in symptoms of oesophagitis and also a decrease in asthma symptoms,

244 Bronchial Asthma particularly those occurring in the night. On the other hand, other studies have failed to document similar benefits. Medical management of the reflux include elevation of the head of the bed 6-8 inches, eating smaller but frequent meals, avoiding food or drink between dinner and bed time, inhibition of gastric acid production using H2-antagonists and maintenance of lower oesophageal sphincter pressure by avoiding fatty meals, spices, ethanol, theophylline, caffeine, and avoiding drugs like metoclopromide that increase lower oesophageal sphincter pressure. Surgery is indicated for severely symptomatic oesophagitis that is not responsive to medical therapy, for complications like stricture, and for established pulmonary complications of nocturnal reflux. Since surgery is extensive and is not successful for everyone, emphasis should be on medical management. REFERENCES 1. Anderson SD, Rodwell LT, Toit JD, Young IH. Duration of protection by inhaled salmeterol in exercise-induced asthma. Chest 1991;100:1254-60. 2. Henriksen JM, Agertoff L, Pederson S. Protective effect and duration of action of inhaled fenoterol and salbutamol in exercise-induced asthma in children. J Allergy Clin Immunol 1992;89: 1176-82. 3. Rohr AS, Siegel SC, Katz RM et al. A comparison of inhaled albuterol and cromolyn in the prophylaxis of exercise induced bronchospasm. Ann Allergy 1987;59:107-09. 4. Bianco S, Robuschi M, Vaghi A, Pasorgikliom. Prevention of exercise induced bronchial asthma by inhaled frusemide. Lancet 1988;2:252-55. 5. Ahmed T, Garnigo J, Danta I. Preventing bronchoconstriction in exercise induced asthma with inhaled heparin. N Engl J Med 1993;329:90-95. 6. Nisar M, Spence DPS, West D, et al. A mask to modify inspired air temperature and humidity and its effects on exercise induced asthma. Thorax 1992;47:446-50. 7. Gluck JC, Gluck PA. The effects of pregnancy on asthma: A prospective study. Ann Allergy 1976;37:164-68. 8. Schatz M, Harden K, Forsythe A et al. The course of asthma during pregnancy, postpartum and with successive pregnancies: A prospective analysis. J allergy Clin Immunol 1988;81:509-17. 9. Schatz M, Zeiger RS, Hoffman CP et al. Potential outcome in the pregnancies of asthmatic women: A prospective controlled analysis. Am J Respir Crit Care Med 1995;151:1170-74. 10. Wandel OJ, Ramin SM, Barnett-Hamm C et al. Asthma treatment in pregnancy: A randomized controlled study. Am J Obstet Gynecol 1996;175:150-54. 11. Stenius-Armiala B, Hedman J, Terano KA. Acute asthma during pregnancy. Thorax 1996;51: 411-14. 12. Sims CD, Chamberlain GVP, de Swiet M. Lung function tests in bronchial asthma during and after pregnancy. Br J Obstet Gynaec 1976;83:434-37. 13. Schatz M, Harden K, Forsythe A et al. Course of asthma post-partum (PP) and during successive pregnancies; A prospective analysis (Abstract). J Allergy Clin Immunol 1986;77(Suppl):161. 14. Hiddlestone HJ. Bronchial asthma and pregnancy. N Z Med J 1964;63:521-23. 15. Schtz M. Interrelationship between asthma and pregnancy; a literature review. J Allergy Clin Immunol 1999;103:5330-35. 16. Juniper EF, Newhouse MT. Effect of pregnancy on asthma: a systematic review and metaanalysis. In Schatz m, Zeiger RS, Claman HC (Eds). Asthma and immunology of diseases in pregnancy and early infancy. New York, Marcel Dekker, 1993;401-27. 17. Stenius-Aarniala B, Piirila P, Teramo K. Asthma and pregnancy; A prospective study of 198 pregnancies. Thorax 1988;43:12-18.

Management of Asthma with Special Problems 245 18. Gordon M, Niswander KR, Berendes H, Kantor AG. Fetal morbidity following potentially anoxigenic obstetric conditions. VII. Bronchial asthma. Am J Obstet Gynaecol 1970;106:421-29. 19. Bahna SL, Bjerkedahl T. The course and outcome of pregnancy in women with bronchial asthma. Acta Allergol 1972;27:397-406. 20. Fitzsimons R, Greenberger PA, Patterson R. Outcome of pregnancy in women requiring corticosteroids for severe asthma. J Allergy Clin Immunol 1986;78:349-53. 21. Perlow JH, Montogomery D, Morgan MA et al. Severity of asthma and perinatal outcome. Am J Obstet Gynecol 1992;167:964-67. 22. Schatz M, Zeiger RS, Hoffman CP. Intrauterine growth is related to gestational pulmonary function in pregnant asthmatic women. Kaiser-Permanents Asthma and Pregnancy Study Group. Chest 1990;98:389-92. 23. Demissie K, Breckbridge MB, Rhods GG. Infant and maternal outcomes in the pregnancies of asthmatic women. Am J Respir Crit Care Med 1998;158:1091-95. 24. Kallen B, Rydhstroem H, Aberg A. Asthma during pregnancy: A population based study. Eur J Epidemiol 2000;16:167-71. 25. Spector SL. The treatment of the asthmatic during pregnancy and lactation. Ann allergy 1983;51:173-77. 26. Greenberger PA, Patterson R. Beclomethasone dipropionate for severe asthma during pregnancy. Ann Intern Med 1983;98:478-80. 27. Apgar V. The drug problem during pregnancy. Clin Obstet Gynec 1966;9:623-30. 28. Warrell DW, Taylor R. Outcome for the fetus of mothers receiving prednisolone during pregnancy. Lancet 1968;i:117-18. 29. Walsh SD, Clark FR. Pregnancy in patients on long-term corticosteroid therapy. Scot Med J 1967;12:302-06. 30. Schatz M, Patterson R, Zitz S, O’Rourke J, Melam H. Corticosteroid therapy for the pregnant asthmatic patient. JAMA 1975;233:804-07. 31. Fitzsimons R, Greenberger PA, Patterson R. Outcome of pregnancy in women requiring corticosteroids for severe asthma. J Allergy Clin Immunol 1986;78:349-53. 32. Schatz M, Zieger RS, Harden K et al. The safety of asthma and allergy medications during pregnancy. J Allergy Clin Immunol 1997;100:301-06. 33. Rayburn WF, Atkinson BD, Gilbert K et al. Short term effects of inhaled albuterol on maternal and fetal circulation. Am J Obstet Gynecol 1994;171:770-73. 34. Dombrowski M, Thom E, McNellis D. Maternal Fetal Medicine Units (MFMU) studies of inhaled corticosteroids during pregnancy. J Allergy Clin Immunol 1999;103:5356-59. 35. Stenius-Armiala B, Rikonen S, Terano K. Slow-release theophylline in pregnant asthmatics. Chest 1995;107:642-47. 36. The use of newer asthma and allergy medications during pregnancy. The American College of Obstetricians and Gynaecologists (ACOG) and the American College of Allergy, Asthma and Immunology (ACAAI). Ann Allergy Asthma Immunol 2000;84:475-80. 37. Chung KF, Barnes PJ. Prescribing in pregnancy. Treatment of asthma. Br Med J 1987;294:103-05. 38. Banatar SR. Anaesthesia for the asthmatic. S Afr Med J 1981;59:409. 39. Kingston HG, Hirshman CA. Perioperative management of the patient with asthma. Anaesth Analg 1984;63:844. 40. Oh SH, Patterson R. Surgery in corticosteroid-dependent asthmatics. J Allergy Clin Inmmunol 1974;53:345. 41. New York City department of Health. Asthma facts. New York, NY: New York City Department of Health, 2000. 42. Rogers L, Cassino C, Berger KL et al.Asthma in the elderly. Cockroach sensitization and severity of airway obstruction in elderly nonsmokers. Chest 2002;122:1580-86. 43. Dow L, Coggon D, Campbell MJ, Ormond C, Holgate ST. The interaction between immunoglobulin E and smoking in airflow obstruction in the elderly. Am Rev Respir Dis 992;146:402-07.

246 Bronchial Asthma 44. Connoly MJ, Crowley JJ, Chatran NB, Nielson CP, Vestel RE. Reduced subjective awareness of bronchoconstriction provoked by methacholine in elderly asthmatic and normal subjects as measure in a simple awareness scale. Thorax 1992;47:410-13. 45. Petheram IS, Jones DA, Collins JV. Assessment and management of acute asthma in the elderly: a comparison with the younger asthmatic. Postgrad Med J 1982;58:149-52. 46. Allien AC, Prior A. What determines whether an elderly patient can use a metered dose inhaler correctly? Br J Dis Chest 1986;80:45-59. 47. Ullah MI, Newman GB, Saunders KB. Influence of age on response to ipratropium bromide and salbutamol in asthma. Thorax 1981;36:523-29. 48. Burge PS, Pantin CF, Newton DT et al. Development of an expert system for the interpretation of serial peak expiratory flow measurements in the diagnosis of occupational asthma. Midlands Thoracic Society Research Group. Occup Med 1999;56:758-64. 49. Perrin B, Malo JL, l’Archeveque J et al. Comparison of monitoring of peak expiratory flow rates and bronchial responsiveness with specific inhalation challenges in occupational asthma. Am Rev Respir Dis 1990;141:A79. 50. Cartier A, Bernstein IL, Burge PS et al. Guidelines for bronchoprovocation on the investigation of occupational asthma. Report of the Subcommittee on Bronchoprovocation for Occupational Asthma. J Allergy Clin Immunol 1989;84:823-29. 51. Stevenson DD, Simon RO: Aspirin sensitivity: Respiratory and cutaneous manifestations, In: Middleton E, Reed C, Ellis EF et al (Eds): Allergy Principles and Practice, (3rd Ed). St. Louise, CV Mosby, 1988. 52. Larrin A, Carrasco E, Galleguillos F, Sepulveda R, Pope CE. Medical and surgical treatment of nonallergic asthma associated with gastroesophageal reflux. Chest 1991;99:1330. 53. Nelson HS. Worsening asthma: is reflux esophagitis to blame? J Rev Respir Dis 1990;11:827-44.

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15 New Treatment Modalities/Newer Drugs for Bronchial Asthma A number of advances had taken place in the management of bronchial asthma and a number of national and international guidelines have been developed on this regard.1-10 The most recent one is the British Thoracic Society Guidelines-(2003).11 The main therapy consists of inhaled β2-agonists, and corticosteroids along with other supplementary drugs. All these guidelines emphasize that ‘add-on’ or adjunctive therapies to inhaled corticosteroids, including long acting β2-agonists and leukotriene antagonists, are clearly a better option for asthmatic persons receiving lower doses of inhaled corticosteroids than merely increasing the dose. A number of studies have demonstrated that in patients on moderate doses of inhaled corticosteroids, addition of a long acting β2-agonist to the regimen is a better option than merely increasing the dose of inhaled corticosteroids.12 The addition of a long acting β2agonist is also effective in reducing the number and severity of exacerbations.13 Combination therapy of inhaled corticosteroid and long-acting β2-agonist, salmeterol or formoterol delivered simultaneously by a single device may be beneficial.14 Although, current asthma therapy is effective and well-tolerated, there are certain limitations. There are still concerns about side effects of corticosteroids, particularly in children and in patients requiring very high doses of the drug. Many patients are also reluctant to take steroids because of the fear of side effects. In general there is a corticophobia in the mind of many. There are also concerns about the osteoporosis and fracture which is in direct correlation with the overall drug intake. Inhaled β2-agonists, although effective bronchodilators, there are concerns about side effects particularly tremor, tachycardia, and tachyphylaxis. Theophylline, similarly has potentially serious side effects. About ~5% of asthma patients are steroid-resistant. They do not respond to high doses of corticosteroid therapy. This group of patients will need some other forms of therapy. Thus, there is a need for the development of newer drugs for the treatment of asthma. It is now firmly established about the cellular and mediator basis of the inflammatory processes in bronchial asthma. This knowledge has been harvested through advancement in biotechnology, by which new treatment options are being provided.15 Currently, a number of different therapies are under investigation, and in some stages of clinical trial, which include: • Anti-immunoglobulin E (IgE) antibodies • Soluble interleukin-4 receptors (sIL-4Rs), and • Anti-interleukin-5 antibodies. The basis of these therapeutic strategies are depicted in Figure 15.1.

248 Bronchial Asthma Anti-immunoglobulin E (IgE) antibodies-(E25) Anti-IgE is a specific monoclonal antibody that inhibits IgE activity by binding both to circulating IgE and to IgE on the surface of B cells.16 However, it does not bind to IgE on the IgE receptors (both low-affinity and high-affinity types, Fcε receptors). They block the binding of IgE to its receptors on effector cells, like mast cells and basophils, but do not trigger the activation of these cells. The molecule is nonanaphylactogenic. It forms antiIgE-IgE complexes, which are central to the action of the drug. The maximum demonstrable size of these complexes is as hexamers, which consist of three molecules of soluble IgE and three molecules of anti-IgE. Soluble IgE has a half-life of only a few days. The half-life of the hexamer, on the other hand, is considerably longer, and it acts as a sump for the allergen, and also has a role in antigen presentation. They lower serum free IgE in rodents and block passive sensitisation of lung fragments by serum from sensitised individuals. Humanised version of murine monoclonal anti-IgE antibodies - rhuMab-E25 and CGP 51910- are developed by grafting the variable immunoglobulin region of murine origin onto a backbone of the constant region of human IgG1.17 This reduced the immunogenicity of the monoclonal antibody and thus, enabled examination of the role of IgE in human disease. The safety and efficacy profile of the anti-IgE antibody – E25, was studied by repeated injections of the antibody to allergic human subjects which did not provoke anaphylaxis and lowered the serum IgE levels by > 99%.18 The treatment also reduced basophil receptor density and histamine release by > 96% and 90% respectively. The effects were then examined to see the preventive effect on the allergen provoking bronchoconstriction. The drug had protective effects on both the early and late responses to allergen challenges.19,20 E25 treatment also reduced the number of circulating eosinophils and the increases in bronchial reactivity and in sputum eosinophilia provoked by allergen challenge. The drug also reduced the eosinophilic-inflammation of the airways provoked by antigen challenge in sensitised mice.21 The treatment also inhibited production of IL-4 and IL-5. Antigen

B-cell

IgE

IL-4

Mast cell

Th2

IL-5

Acute symptoms (early asthma reaction)

Eosinophil (Late asthma reaction)

Fig. 15.1: Therapeutic basis of anti-IgE antibody, IL-4 and IL-5

New Treatment Modalities/Newer Drugs for Bronchial Asthma 249 The first large scale clinical trial of the efficacy of the humanised, monoclonal anti-IgE antibody, E25, examined the effects of repeated dosing on the severity of allergic rhinitis,22 and showed beneficial results. When given as regular treatment to patients with moderate to severe asthma requiring regular treatment with corticosteroids, inhaled or oral, E25 showed safety and efficacy.23 The double blind, prospective study of 317 patients compared the effects of placebo with that of a low dose E25 (2.5 μg /kg/ngIgE/ml) or a high dose E25 (5.8 μg /kg/ngIgE/ml) as adjuvant therapy every two weeks for 20 weeks. In both active IgE treatment groups, serum free IgE dropped rapidly, and remained low throughout the study period, significantly improved the morning PEFR, quality of life scores, the need for rescue treatments, and the severity of asthma symptoms. There was a significant reduction in the reduction in dose for corticosteroid treatment. Apart from a slight increase in urticaria, adverse events were not more than those in the placebo group. Another large study also has shown E25 to be effective in adults and children with ragweed allergic rhinitis.24 Other studies of E25 in adults and asthma with moderate severity confirm the safety and efficacy in terms of a significant reduction in the frequency of exacerbations as an adjunct or during tapering off of steroids.25 The above clinical studies, thus shows that the monoclonal antiIgE antibody, E25 treatment, significantly improves asthma, but does not cure asthma. Development of more selective, apparently safe anti-IgE monoclonal antibody holds great promise not only as a research tool for defining the role of IgE in health and disease, but also as a novel therapeutic tool in the treatment of bronchial asthma. Soluble Interleukin-4 Receptors (sIL-4Rs) Interleukin-4 plays a number of important roles in the allergic process and is critically important for the development of allergic inflammation. Important functions include secretion of IgE by B lymphocytes, induction of VCAM-1 expression on vascular endothelium in promoting cellular inflammation by which it directs the migration of T lymphocytes, monocytes, basophils, and especially eosinophils to the site of inflammation. Other mechanisms of eosinophilic inflammation are increasing eotaxin expression, inhibition of eosinophil apoptosis, and mucus gene expression and hypersecretion. The most important of all these is the biological activity of its ability to drive the differentiation of Th-0 lymphocytes into Th-2 cells. It shares a number of activities with IL-13 and because of its ability to prevent apoptosis of T lymphocytes, it is important in allergic immune responses. The IL-4 levels are increased in the BAL fluid of allergic individuals, and peripheral blood mononuclear cells produce IL-4 in response to dust mite antigen. Aerosolised IL-4 significantly increases airway hyper-responsiveness in patients with mild asthma. Further, there is altered regulation of IL-4 in atopic individuals as well atopic individuals have higher number of T cells. In view of a wide variety of important contribution of IL-4 in asthma pathogenesis,26-41 anti- IL-antibody is an important target for asthma therapy. A soluble IL-4 receptor is currently under investigation for the treatment of bronchial asthma.40,41 Preclinical studies in mice has shown prevention of the development of allergenspecific IgE and reduction of eosinophilic inflammation. The drug is proved to be safe and effective in patients of bronchial asthma. In 25 patients of mild to moderate persistent asthma on inhaled corticosteroid therapy, were randomised to placebo or IL-4R at doses of 0.5 or 1.5 mg once by nebuliser42 and their steroid therapy was discontinued. There was no side effect of the drug, neither there was development of any antibody. Treatment with

250 Bronchial Asthma 1.5 mg IL-4R resulted in significantly better FEV1 at 2 hrs after treatment, and the improvement persisted till 2 weeks. Asthma symptom score also improved significantly. Bronchial reactivity to methacholine was reduced in 6 of the 8 patients tested. Its antiinflammatory effect was obvious by a reduction of exhaled NO scores. In further phase I/II randomised, double blind, placebo-controlled study in 62 patients with moderately severe persistent asthma, treatment was given with 0.75, 1.5, or 3.0 mg of IL-4R twice weekly by nebulisation or placebo administration.43 The steroid inhalation was discontinued. Il-4R was safe and well tolerated. Antibodies to IL-4R developed in <3% without any symptom. The results were similar to that of the earlier study. Thus, it is apparent that IL-4 receptor is potentially a safe and effective treatment for asthma without the use of corticosteroids. Once-weekly dosing targeting the lungs will improve patient compliance. Long-term disease progression can be prevented by IL-4 as it inhibits the central inflammatory process.41 Anti-interleukin-5 Antibodies Eosinophils are important in the inflammatory pathophysiology of bronchial asthma. Interleukin-5 is thought to be associated with the late stages of maturation and release of eosinophils that occur within the bone marrow in different allergic diseases. Two different monoclonal antibodies against IL-5 in clinical trials have shown that single intravenous infusion with 2.5 or 10 mg/kg reduced the eosinophil levels to low normal values in the blood and sputum from patients with asthma, which is maintained up to 4 months. No effect, however was noticed on bronchial hyperresponsiveness.44 Another study using a single dose of anti-IL-5 provided only a small increase in FEV1 in noneosinophilic bronchial asthma.45 Other Cytokine-directed Therapy a. TNF Antagonism. Based on findings from experimental animals and the presence of elevated TNF levels in patients with bronchial asthma, there is a rationale for TNF antagonism to be deployed in asthmatics. TNF seems to play an important role in determining the severity of asthma. TNF antagonism may be useful in treating cases of severe persistent asthma as well as acute severe asthma.46 b. Interleukin-13 antagonism. IL-13 plays an important role in the induction of airway hyperreactivity, mucus formation, and airway remodelling in animal models of pulmonary disease. There is an increased production of IL-13 in atopic and non-atopic asthma, atopic dermatitis, allergic rhinitis, and chronic sinusitis. Recent human genetic data also show association of genes of the IL-13 signalling pathway to allergic disease and bronchial asthma. These findings suggest the possible role of IL-13 antagonists in the treatment of bronchial asthma.47 c. IL-10 therapy. IL-10 deficiency is associated with several inflammatory diseases like bronchial asthma and cystic fibrosis. Animal studies have shown that endogenous IL-10 suppresses excessive inflammation in the lung. Clinical studies have shown that constitutive IL-10 protein concentrations are reduced in BAL fluid from asthmatic compared to normal subjects and the IL-10 production by monocytes is reduced. The effect of IL-10 may thus, provide a physiological form of anti-inflammatory therapy.48

New Treatment Modalities/Newer Drugs for Bronchial Asthma 251 d. Antihistamine drugs like H1- antihistamines (cetirizine, terfenadine, loratadine, astemizole, azelastine, fexofenadine, mizolastine etc.) are useful drugs for associated conditions like allergic rhinitis. They do not have any direct effect on bronchial asthma.49 Similarly, H3–antihistamines, particularly in combination with H1-antihistamines, are useful for the treatment of allergic rhinitis. This combination provides a better treatment approach for allergic nasal congestion without the hypertensive liability of current alpha-adrenergic agonist decongestive therapy.50 e. Other future targeted therapeutic approaches. Because of the role of a large number of cytokines and other mediators in the pathophysiology of bronchial asthma, theoretically there is a wide scope of manipulating these products, which can be used as anti-asthma therapy. These are i. Mediator inhibitors and agonists like kinin receptor antagonists, endothelin antagonists, tachykinin antagonists, selective iNOS inhibitors, mucus regulation, and P2Y receptor antagonists; ii. Allergen-and IgE-directed therapy; iii. T-cell immunomodulation like GATa-3, mycobacterial immunisation, macrocyclic immunosuppressants; iv. Chemokine receptor inhibition; v. Adhesion molecule inhibitors; vi. Inhibition of cell signalling; vii. Therapies acting on transcription and viii. Genetic therapy, which includes antisense therapy, ribozyme therapy and gene therapy. f. Vaccines for bronchial asthma. Asthma is not curable by the currently available drugs. However, some investigators believe that the disease is potentially curable through strategies that prevent or reverse the immunological abnormalities in atopy. There are several approaches to reduce the preponderance of Th2 cells in atopy by switching the balance in favour of Th1 cells. This can be achieved in animals by exposure to bacterial products such as BCG, Mycobacterium vaccae, or unmethylated cytosine-guanosine dinucleotidecontaining oligonucleotides (CpG ODN).51-53 This suggests that vaccination with allergens, immunomodulators and adjuvants may be a future strategy for the prevention or cure of asthma.54 PDE4 Inhibitors Phosphodiesterase 4 (PDE4) is present in a number of inflammatory cells responsible for the development of asthma. One of the mechanisms of action of theophylline for bronchodilatation is inhibition of PDE4. However, the potency of the drug is relatively poor at therapeutic concentrations. A number of highly selective PDE4 inhibitors have been developed to overcome this problem. Phosphodiesterase inhibition increases the intracellular levels of cyclic AMP, which is important for regulation of cell function.55,56 PDE4 inhibitors reduce eosinophil survival, inhibit eosinophil chemotaxis, degranulation, adhesion molecule expression, and leukotriene synthesis. Other functions of PDE4 inhibitors include attenuation of proliferation of mononuclear cells in atopic individuals and Th1 and Th2 cells. They also inhibit cytokine generation. Thus, PDE4 inhibition suppresses various characteristic features of inflammation including recruitment of inflammatory cells to the lungs, airway hyperreactivity, and airway edema.

252 Bronchial Asthma The drugs of this class include: • Rolipram, • Cilomilast , and • Roflumilast These drugs suppress various aspects of allergic inflammation. The orally active PDE4 selective inhibitor CDP840 when administered orally for 9.5 days, attenuates the development of the late asthmatic response in mild asthmatics while showing effect on the acute response and with no significant side effects.57 The inhibition of the late asthma response is due to their anti-inflammatory property and not due to bronchodilator action per se. Single oral administration of the drug is without any significant bronchodilator activity. Hence, it is suggested that a mixed PDE3/4 inhibitor would seem to be a better option provided that they have minimal side effects. Another PDE4 inhibitor RP73401 has also no acute effect.58 Roflumilast is more potent than CDP840 acts against late asthma response, suppresses the development of bronchial hyper-responsiveness following antigen challenge in asthma, and improves various indices of lung function, and effective in allergic rhinitis.59-61 Cilomilast, another orally active PDE4 inhibitor attenuates bronchoconstriction following exercise, and also various features of allergic rhinitis62 and improves various pulmonary function parameters. The drug is well tolerated up to a dose of 15 mg bid. Apart from the potential anti-inflammatory action, they perhaps act by suppression of neural reflexes by suppressing neuropeptide release from sensory C-fibres and inhibition of bronchoconstriction by vagal nerves. The major side effect of this class of drugs is gastrointestinal disturbances.63 REFERENCES 1. Guidelines for the management of asthma in adults. 1-Chronic persistent asthma. Statement by the British Thoracic Society, Research Unit of the Royal College of Physicians of London, King’s Fund Center, National Asthma Campaign. BMJ 1990;301:651-53. 2. Guidelines for the management of asthma in adults. 2-Acute severe asthma. Statement by the British Thoracic Society, Research Unit of the Royal College of Physicians of London, King’s Fund Center, National Asthma Campaign. BMJ 1990;301:797-800. 3. Warner JO, Gotz M, Landau LI et al. Management of asthma: A consensus statement. Arch Dis Child 1989;64;1065-79. 4. International Paediatric asthma Consensus Group. Asthma, a follow-up statement. Arch Dis Child 1992;67:240-48. 5. International Consensus report on the diagnosis and management of asthma. Clin Exp Allergy 1992;22(Suppl):1-72. 6. British thoracic Society and others. Guidelines for the management of asthma: A summary. BMJ 1993;9:287-92. 7. The British Guidelines on Asthma Management. 1995 Review and Position Statement. Thorax 1997;52(Suppl 1): S2-S8. 8. British thoracic Society, British Paediatric Association, Royal College of Physicians of London, The King’s Fund Center, national asthma Campaign et al. Guidelines on the management of asthma. Thorax 1993;48:S1-S24. 9. British thoracic Society, British Paediatric Association, Royal College of Physicians of London, The King’s Fund Center, National Asthma Campaign et al. Summary charts. BMJ 1993;306: 776-82. 10. Global Initiative for Asthma. A practical guide for public health officials and health care

New Treatment Modalities/Newer Drugs for Bronchial Asthma 253

11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31.

professionals. US Department of Health and human services. NIH Publication No. 96-3659A, December 1995. New British Guidelines on management of Asthma –Thorax 1993;58(Suppl 1):1-94. Shrewsbury S, Pyke S, Britton M. Meta-analysis of increased doses of inhaled steroid or addition of salmeterol in symptomatic asthma. (MIASMA). BMJ 2000;320:1368-73. Pauwels RA, Lofdahl CG, Postma DS et al. Effect of inhaled formoterol and budesonide on exacerbation of asthma. New Engl J Med 1997;337:1405-11. Kavuru M, Melamed J, Gross G, et al. Salmeterol and fruticasone propionate combined in a new powder inhalation device for the treatment of asthma: A randomised, double-blind, placebocontrolled trial. J Allergy Clin Immunol 2000;105:1108-16. Hansel TT, Barnes PJ (Editors); New drugs for asthma, allergy and COPD, In: Progress in Respiratory Research, 31, Basel: Karger;2001. Chang TW. The pharmacological basis of anti-IgE therapy. Nature Biotechnol 2000;18:157-62. Presta LG, Lahr SJ, shields RL, et al. Humanisation of an antibody directed against IgE. J Immunol 1993;151:2623-32. Mac-Glashan DW, Bochner BS, Adel man DC, et al. Down regulation of FceR1 expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J Immunol 1997;158:1438-45. Boulet LP, Chapman KR, Cote J, et al. Inhibitory effects of an anti-IgE antibody E25 on allergeninduced early asthmatic response. Am J Respir Crit Care Med 1997;155:1835-40. Fahy JV, Fleming HE, Wong HH, et al. The effect of an anti-IgE monoclonal antibody on the early- and late-phase responses to allergen inhalation in asthmatic subjects. Am J Respir Crit Care Med 1997;155:1828-34. Coyle AJ, Wagner K, Bertrand C, et al. Central role of immunoglobulin (Ig) E in the induction of lung eosinophil infiltration and T helper 2 cell cytokine production: Inhibition by a nonanaphylactogenic anti-IgE antibody. J Exp Med 1996;183:1303-10. Casale TB, Benstein IL, Busse WW et al. Use of an anti-IgE humanised monoclonal antibody in ragweed-induced allergic rhinitis. J Allergy Clin Immunol 1997;100:110-21. Milgrom H, Fick RB, Su JQ et al. Treatment of allergic asthma with monoclonal anti-IgE antibody. New Engl J Med 1999;341:1966-73. Casale T, Condemi J, Miller SD et al. rhu-MAB-E25 in the treatment of seasonal allergic rhinitis (SAR). Ann Allergy Asthma Immunol 1999;82:75. Boushey HA, Fick R, Fahy JV. Anti-IgE antibody. In. Hansel TT, Barnes PJ (Eds). New drugs for Asthma, Allergy and COPD, In: Progress in Respiratory Research, 31, Basel: Karger;2001,31: 201-05. Coffman RL, Ohara J, Bond MW et al. B cell stimulatory factor-1 enhances the IgE response of lipopolysaccharide–activated B cell. J Immunol 1986;136:4538-41. Pawankar R, Okuda M, Yssel H, et al. Nasal mast cells in perennial allergic rhinitis exhibit increased expression of the Fc epsilon R1, CD40L, IL-4, and IL-13, and can induce IgE synthesis in B cells. J Clin Invest 1997;99:1492-99. Moser R, Fehr J, Bruijnzeel P. IL-4 controls the selective endothelium-driven transmigration of eosinophils from allergic individuals. J Immunol 1992;149:1432-38. Dabbagh K, Takeyama K, Lee HM, et al. IL-4 induces mucin gene expression and goblet cell metaplasia in vitro and in vivo. J Immunol 1999;162:6233-37. Hsieh CS, Hiemberger AB, Gold JS, et al. Differential regulation of T helper phenotype development by interleukins 4 and 10 in an alpha beta T-cell receptor transgenic system. Proc Natl Acad Sci USA 1992;89:6065-69. Sedar RA, Paul WE, Davis MM, et al. The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+T cells from T cell receptor transgenic mice. J Exp Med 1992;176:1091-98.

254 Bronchial Asthma 32. Kopf M, Le Gros G, Bachmann M et al. Disruption of the mucin IL-4 gene blocks Th2 cytokines responses. Nature 1993;362:245-48. 33. Vella A, Teague TK, Ihle J et al. Interleukin 4 (IL-4) or Il-7 prevents the death of resting T cells: stat 6 is probably not required for the effect of IL-4. J Exp Med 1997;186:325-30. 34. Xie H, Seward RJ, Huber BT. Cytokine rescue from glucocorticoid induced apoptosis in T cells is mediated through inhibition of I kappa-Balpha. Mol Immunol 1997;34:987-94. 35. Haher S, Santos IM, Sole D, et al. Interleukin-4 and soluble CD23 serum levels in asthmatic atopic children. J Invest Allergol Clin Immunol 1995;5:251-54. 36. Walker C, Bauer W, Braun RK, et al. Activated T cells and cytokines in bronchoalveolar lavages from patients with various lung diseases associated with eosinophilia. Am J Respir Crit Care Med 1994;150:1038-48. 37. Leonard C, Tormey V, Burke C, et al. Allergen-induced cytokine production in atopic disease and its relationship to disease severity. Am J Respir Cell Mol Biol 1997;17:368-75. 38. Shi HZ, Deng JM, Xu H, et al. Effect of inhaled interleukin–4 on airway hyper-reactivity in asthmatics. Am J Respir Crit Care Med 1998;157:1818-21. 39. Parronchi P, De Carli M, Manetti R, et al. Aberrant interleukin(IL)-4 and IL-5 production in vitro by CD4+ helper T cells from atopic subjects. Eur J Immunol 1992;22:1615-20. 40. Chan SC, Brown MA, Wilcox TM et al. Abnormal IL-4 gene expression by atopic dermatitis T lymphocytes is reflected in altered nuclear protein interactions with IL-4 transcriptional regulatory element. J Invest Dermatol 1996;106:1131-1136. 41. Borish L, Agosti JM. Interleukin-4 antagonism. In: Hansel TT, Barnes PJ (Eds). New drugs for Asthma, Allergy and COPD, In: Progress in Respiratory Research;31, Basel: Karger;2001;31: 256-59. 42. Borish LC, Nelson H, Lanz MJ, et al. Interleukin-4 receptor in moderate atopic asthma: A phase I/II randomised, placebo-controlled trial. Am J Respir Crit Care Med 1999;160:1816-23. 43. Borish LC, Steinke JW, 2. Cytokines and chemokines. J Allergy Clin Immunol. 2003;111 (2 Suppl):S460-75. 44. Lecki MJ, ten Brinke A, Khan J, et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness and the late asthmatic response. Lancet 2000;356:2144-48. 45. Kipa JC, O’Conner BJ, Langley SJ et al. Results of a phase I trial with SCH55700, a humanised anti-IL-5 antibody in severe persistent asthma (Abstract). Am J Respir Crit Care Med 2000;161:A505. 46. McDonnell N, Abbott NN, Mohler KM et al. TNF antagonism. In: Hansel TT, Barnes PJ (Eds). New drugs for Asthma, Allergy and COPD, In: Progress in Respiratory Research; Basel: Karger;2001; 31:247-50. 47. Donaldson DD, Elias JA, Wills-Karp M. Interleukin-13 antagonism. In: Hansel TT, Barnes PJ (Eds). New drugs for Asthma, Allergy and COPD, In: Progress in Respiratory Research; Basel: Karger;2001,31:260-64. 48. Narula S, Cuss F. Interleukin-10. In. Hansel TT, Barnes PJ (Eds). New drugs for Asthma, Allergy and COPD, In: Progress in Respiratory Research, Basel: Karger;2001; 31:269-73. 49. De Vos C, Rihoux JP H-antihistamines. In: Hansel TT, Barnes PJ (Eds). New drugs for Asthma, Allergy and COPD, In: Progress in Respiratory Research, volume 31, Basel: Karger;2001;31:28132. 50. McLeod RL, Egan RW, Cuss FM et al. Histamine H3 antagonists. In: Hansel TT, Barnes PJ (Eds). New drugs for Asthma, Allergy and COPD, In: Progress in Respiratory Research, Basel: Karger;2001; 31:133-36. 51. Hertz U, Gerhold K, Gruber C et al. BCG infection suppresses allergic sensitisation and development of increased airway reactivity in an animal model. J Allergy Clin Immunol 1998;102:867-74.

New Treatment Modalities/Newer Drugs for Bronchial Asthma 255 52. Wang CC, Rook GA,. Inhibition of an established allergic response to ovalbumin in BALB/c mice by killed Mycobacterium vaccae. Immunology 1998;93:307-13. 53. Sur S, Wild JS, Chaudhury BK, et al. Long term prevention of allergic lung inflammation in a mouse model of asthma by CpG oligodeoxynecleotides. J Immunol 1999;162:6284-93. 54. Holt PG. A potential vaccine strategy for asthma and allied atopic diseases during infancy. Lancet 1994;344:456-58. 55. Torphy TJ. Phosphodiesterase isoenzymes: Molecular targets for novel anti-asthma agents. Am J Respir Crit Care Med 1998;157:325-32. 56. Essayan DM. Cyclic nucleotide phosphodiesterases. J Allergy Clin Immunol 2001;108:671-80. 57. Harbinson PL, McLeod D, Hawksworth R, et al. The effect of a novel orally active selective PDE4 isoenzyme inhibitor (CDP840) on allergen-induced response in asthmatic subjects. Eur Respir J 1997;10:1008-14. 58. Jonker GJ, Tijhuis GJ, de Monchery JGR. RP73401 (a phosphodiesterase IV inhibitor) single dose does not prevent allergen induced bronchoconstriction during the early phase reaction in asthmatics. Eur Respir J 1996;9:82S. 59. Nell H, Louw C, Leichtl S, et al. Acute anti-inflammatory effect of the novel phosphodiesterase 4 inhibitor roflumilast on allergen challenge in asthmatics after a single dose (abstract) Am J Respir Crit Care Med 2000;161:A200. 60. Leichtl S, Schmid-Wirlitsch C, Bredenbroker D, et al. Dose-related efficacy of once-daily roflumilast, a new, orally active, selective phosphodiesterase 4 inhibitor, in asthma (abstract) Am J Respir Crit Care Med 2002;165:A85. 61. Schmidt BM, Kusma M, Feuring M, et al. The phosphodiesterase 4 inhibitor roflumilast is effective in the treatment of allergic rhinitis. J Allergy Clin Immunol 2001;108:530-36. 62. Torphy TJ, Barmette MS, Underwood DC, et al. Airflow (SB 207499): A second generation phosphodiesterase 4 inhibitor for the treatment of asthma and COPD: From concept to clinic. Pulm Pharmacol Ther 1999;12:131-35. 63. Spina D. Theophylline and PD4 inhibitors in asthma. Curr Opin Pulm Med 2003;9:57-64

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16 New Guidelines for Asthma Management (Non-pharmacological Management) The British Thoracic Society has recommended the new guidelines for the management of bronchial asthma in 2003.1 The first British Guidelines on Asthma Management in adults were first published in 1990 after a joint initiative between the Thoracic Society, the Royal College of Physicians of London, the King’s Fund Center, and the National Asthma Campaign. These were updated in 1993 when the addition of childhood asthma and further updated in 1995. Simultaneously Guidelines were also developed by the American Physicians, by the Global Initiative for Asthma (GINA), the International Consensus Report and the WHO. These guidelines are already discussed earlier.2-12 The Scottish Intercollegiate Guidelines Network (SIGN) published its first asthma guidelines in 199613 and has subsequently published on primary care management of asthma in 199814 and management of acute asthma in 1999.15 Further, both the British Thoracic Society and the SIGN have recognised the need to update their asthma guidelines, using evidence-based methodology to cover all aspects of asthma care. The two organisations jointly produced the comprehensive new guideline, which was strengthened by collaboration with the National Asthma Campaign, the Royal College of Physicians of London, the Royal College of Paediatrics and Child Health, General Practice Airways Group, and the British Association of Accident and Emergency Medicine. The outcome is the new British Guideline on the Management of Asthma.1 One important and new feature in this new guideline is the levels of evidence and grades of recommendations used in these guideline. The panel of experts have taken into account the evidence-based medicine, a more scientific way of expressing a particular conclusion .16 However, it is emphasised that the grade of recommendation relates to the strength of the evidence and not necessarily the clinical importance of the recommendation in patient management. Where there are only low grade recommendations in important clinical areas, this should be seen as a stimulus for further research. The recommendations levels are graded into 8 subtypes (1++, 1+, 1-, 2++, 2+, 2-, 3, and 4) depending on whether the inference from high-level meta-analyses, systemic review of randomised controlled-trials (RCTs), RCTs with a very low-risk of bias, well-conducted meta-analysis, systemic reviews, RCTs with low-risk bias, meta-analyses, systemic reviews, or RCTs with high-risk of bias, High quality systemic reviews of case-control or cohort studies, High quality case control or

New Guidelines for Asthma Management (Non-pharmacological Management) 257 cohort studies with a very low-risk of confounding or bias or a high probability that the relationship is causal, well conducted case control or cohort studies with low-risk of confounding or bias and a moderate probability that the relationship is causal, case control or cohort studies with a high-risk of confounding or bias and a significant risk that the relationship is not causal, non-analytical studies like case reports, case series, and expert opinion. The grades of recommendations are from A-D depending on the levels of evidence. Good practice points are also given based on clinical experience of the guideline development group. NON-PHARMACOLOGICAL MANAGEMENT There is increasing interest in factors which, if avoided might facilitate the management of asthma, reducing the requirement for pharmacotherapy, and which may have the potential to modify fundamental causes of asthma. However, evidence has been difficult to obtain for many approaches and more studies are required. Primary Prophylaxis Primary prophylaxis is employed before there is any evidence of disease in an attempt to prevent its onset. A number of potential strategies are suggested.

Allergen Avoidance There is a strong correlation between allergic sensitisation to common aeroallergens and the subsequent development of asthma. There is also a strong association between allergen exposure in early life and sensitisation to these allergens, although it has not been possible to demonstrate an association between allergen exposure and the development of asthma. Majority of allergen avoidance studies focus on dietary manipulation to prevent atopic eczema and have paid little attention to aeroallergen avoidance. Two trials in progress are investigating the consequences of introducing house dust mite reduction in early pregnancy, and are following up the children born to the participating mothers. Although accurate asthma phenotyping is not possible in infancy, outcomes at one year of age indicate a modest but significant reduction in wheezing illnesses. Allergen avoidance after birth has been studied in a number of controlled (but no double blind) trials. There appears to be a transient reduction in the prevalence of atopic eczema in the first two years of life but no evidence of sustained benefit in relation to asthma. A number of epidemiological studies suggest that close contact with a cat or dog in very early infancy reduced subsequent prevalence of allergy and asthma. This may be a consequence of high allergen exposure inducing tolerance. However, no recommendations on prenatal or postnatal allergen avoidance can be made in relation to primary prevention of asthma.

Breastfeeding A systematic review and meta-analysis involving 8183 subjects followed for a mean of four years revealed a significant protective effect of breastfeeding against the development of asthma. The effect was greatest in children with a family history of atopy. In contrast, a more recent study in 1246 patients found that breastfeeding was associated with a reduced

258 Bronchial Asthma risk of infant wheeze, but also with an increased risk of asthma at six years. Thus, breastfeeding should be encouraged and its benefits include a protective effect in relation to early life wheezing.

Modified Infant Milk Formulae Trials of modified milk formulae using partial and extensive hydrolysates of whey or casein or soy formulae compared with conventional formulae have not shown any consistent significant long-term benefits in relation to asthma. Variation in study design, intervention used, co-interventions and outcome definition make meta-analysis problematical.

Other Dietary Modifications Limited epidemiological evidence suggests that fish oil consumption may protect against asthma in childhood. Trials of lipid supplementation during pregnancy and postnatally to prevent atopic disease are in progress.

Microbial Exposure The “hygiene hypothesis” suggests that early exposure to microbial products will switch off allergic responses preventing allergic diseases such as asthma. Epidemiological studies comparing large populations who have or have not had such exposures support the hypothesis. A double blind placebo trial of the probiotic, lactobacillus CG, reported a reduced incidence of atopic eczema but no effect on IgE antibody sensitisation. Small sample size and early outcome age limit the interpretation of this study. In the absence of good quality intervention studies, no recommendation can be made at present.

Immunotherapy and Primary Prevention Three observational studies, in over 8000 patients, have shown that immunotherapy in individuals with a single allergy reduces the numbers subsequently developing new allergies over a three to four years follow-up compared with contemporaneous untreated controls. No double blind placebo controlled trials of immunotherapy as primary prevention have been conduced, and at present immunotherapy cannot be recommended for primary prevention. Preliminary results from an ongoing parallel group study using contemporaneous untreated children as the control group for pollen immunotherapy in children with allergic rhinitis suggest a lower rate of onset of asthma in the treated group.

Avoiding Pollutants No evidence was found to support a link between exposure to environmental tobacco smoke and other air pollutants and the induction of atopic asthma. An early meta-analysis suggested an association between gas cooking and respiratory illness, but this has not been brought out in larger studies. Increased risk of infant wheeze is associated with smoking during pregnancy and maternal postnatal smoking. Pregnancy smoking affects an infant’s airway function, increasing susceptibility to wheeze. There are many other adverse effects on the young child of such exposures.

Pharmacotherapy There are some pharmacological trials of treatments designed to prevent onset of the disease. Children given ketotifen (206 infants, in two trials) showed significantly less asthma at one

New Guidelines for Asthma Management (Non-pharmacological Management) 259 and three years follow-up compared with those receiving placebo. In the third study, using cetirizien, 18 months’ treatment had no effect in the intention to treat population but significantly reduced asthma in children with atopic dermatitis sensitised to either grass pollen or house dust mite. Cetirizien had additional benefits for atopic dermatitis alone and reduced the frequency of urticaria. Secondary Prophylaxis

Allergen Avoidance Allergen avoidance measures may be helpful in reducing the severity of existing disease. Increasing allergen exposure in sensitised individuals is associated with an increase in asthma symptoms, bronchial reactivity and deterioration in lung function. Treatment requirements, hospital attendance and respiratory arrest are associated with increased exposure to high concentrations of indoor allergens. Threshold concentrations of allergens that can be regarded as risk factors for acute attacks include: • 10 μg/g dust of group l mite allergen • 8 μg/g dust of Fel d l, the major cat allergen • 10 μg/g dust of Can f l, the major dog allergen • 8 μg/g dust of cockroach allergen. Evidence that reducing allergen exposure can reduce morbidity and mortality is tenuous. In uncontrolled studies, children and adults have both shown benefit from exposure to a very low allergen environment. However, the benefits in such circumstances cannot be necessarily attributed to the allergen avoidance.

House dust mite control measures There have been two Cochrane reviews on house dust mite control measures and the management of asthma. The first concluded that current chemical and physical methods were ineffective and could not be recommended as prophylactic treatment for asthma patients with sensitivity to house dust mites. An amendment concluded that physical reduction methods may reduce asthma symptoms. The reviewed studies used various chemical, physical or combinations of methods to reduce mite exposure. The combined meta-analysis showed no difference in improvement in asthma between patients in experimental groups compared with controls. There was heterogeneity between studies with regard to intervention, and in some studies intervention allocation was not adequately concealed. Larger and more carefully controlled studies are required to demonstrate any clear benefit from house dust mite avoidance. At present, this does not appear to be a cost-effective method of achieving benefit. In committed families with evidence of house dust mite allergy and who wish to try mite avoidance, the following are recommended. • Complete barrier bed covering systems • Removal of carpets • Removal of soft toys from bed • High temperature washing of bed linen • Acaricides to soft furnishings • Dehumidification

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Other allergens Animal allergens, particularly cat and dog, are a potent cause of asthma symptoms. Observational studies have not found that removing a pet from a home improves asthma control. In a study in adults with cat sensitivity, randomisation to either bedroom air cleaner and covers for bedding or no active intervention with restriction of cats away from the bedroom, resulted in no differences between groups with regard to symptoms, peak flow, lung function of bronchial reactivity. Alternatively, there is a suggestion that maintaining a high exposure to cat allergen in the domestic environment might actually induce some degree of tolerance. Many experts still feel that removal of pets from the home of individuals with asthma who also have an allergy to that pet should be recommended. Cockroach allergy is not a common problem in some countries like UK, but important in some other areas. There is no conclusive evidence regarding the impact of cockroach allergen reduction on asthma symptoms. Although fungal exposure has been strongly associated with hospitalisation and increased mortality in asthma, to date no controlled trials have addressed fungal exposure reduction and asthma. Environmental Factors Smoking The association between passive smoking and respiratory health has been extensively reviewed. There is a direct causal relationship between parental smoking and lower respiratory illness in children up to three years of age. Infants whose mothers smoke are four times more likely to develop wheezing illnesses in the first year of life. The independent contributions of prenatal and postnatal maternal smoking to the development of asthma in children are difficult to distinguish. Maternal pregnancy smoking has been shown to have an adverse influence on lung development. There is little evidence that maternal pregnancy smoking has an effect on allergic sensitisation. Exposure to tobacco smoke in the home contributes to the severity of childhood asthma. A US Institute of Medicine review identified a causal relationship between environmental tobacco smoke (ETS) exposure and exacerbations of asthma in pre-school children. Average exposure is associated with a 30% increased risk of symptoms. One small study suggests that by stopping smoking, parents decrease the severity of asthma in their children. Parents who smoke should be advised about the dangers for themselves and their children and offered appropriate support to stop smoking. Starting smoking as a teenager increases the risk of persisting asthma. Only one study was identified that examined the incidence of asthma related to taking up smoking. This showed a relative risk of 2.1 for the development of asthma over six years in 14 years old children who have started to smoke. No studies were identified that directly related to the question of whether smoking affects asthma severity. One controlled cohort study suggested that exposure to passive smoke at home delayed recovery from an acute asthma attack. Studies of interventions designed to reduce environment tobacco smoke exposure in the home have been largely ineffective in reducing the degree of exposure and none were designed with primarily clinical (as opposed to smoking outcomes. In one observational study giving up smoking in adults was associated with improved severity of asthma scores. Smoking cessation should be encouraged as it is good for general health and may decrease asthma severity. Air pollution There is evidence that changing from a high particulate sulphur dioxide (coal burning) environment to a low sulphur dioxide/high diesel particulate environment

New Guidelines for Asthma Management (Non-pharmacological Management) 261 increases the incidence of asthma and atopy. In the UK, asthma is more prevalent in 12-14 years olds in non-metropolitan rather than metropolitan areas. However, many differences between environments might explain the variation in asthma and allergy risk. There is some laboratory evidence that various pollutants can enhance the response of patients with asthma to allergens, but there is no firm epidemiological evidence that this has occurred in the UK or elsewhere. Time series studies suggest that air pollution may provoke acute asthma attacks or aggravate existing chronic asthma, although the effects are minimal in comparison with factors such as infection. The short-term fluctuations in levels of air pollution currently encountered in the UK may be responsible for small changes in numbers of hospital admissions and emergency attendances for asthma. No evidence was identified regarding asthma and indoor air pollutants, such as volatile organic compounds, formaldehyde or nitrogen oxides. Further research in this area is required. Complementary and Alternative Medicine

Herbal and Traditional Chinese Medicine Currently available evidence does not allow any firm judgment to be made on herbal remedies in general or individual preparations in particular. Seventeen trials were identified but the combined results are inconclusive. Nine of the 17 trials reported some improvement in lung function, but it is not clear that the results reported would be generalised.

Acupuncture A Cochrane review of 21 trials raised many methodological concerns. Only seven trials (174 patients) achieved randomisation to active (i.e. recognised in traditional Chinese medicine to be of benefit in asthma) or sham acupuncture (i.e. points with no recognised activity) for the treatment of persistent or chronic asthma. Binding was a common problem, and only achieved for those making the observations. The difficulty in making sham acupuncture convincing and part of the holistic approach of traditional Chinese medicine was emphasised. There was wide inconsistency in methodology. Acute trials show that acupuncture has a beneficial effect, but this is less in magnitude than that achieved by inhaled bronchodilators or cromones. Demonstrating that this effect can be transferred to persistent asthma using regular treatment was achieved in one RCT reported in the Cochrane review. The Cochrane review found no evidence for a clinically valuable benefit from acupuncture, with no statistically significant improvement in lung function being demonstrated. More rigorous research methodology and attention to outcomes other than lung function are required.

Air Ionisers Ionisers are widely advertised and marketed as being of benefit to patients with asthma, however, there is no evidence that they are of value in ameliorating the symptoms of asthma or improving lung function. They do reduced mite allergen levels in the room in which they are used, and could be incorporated into a coordinated allergen avoidance programme, but this has not been formally tested. One study has raised concerns that ionisation may

262 Bronchial Asthma produce an increase in nocturnal cough. The use of ionisers cannot be encouraged, as there is no evidence of benefit and a suggestion of adverse effect.

Homeopathy A Cochrane review identified only three methodologically sound randomised controlled trials. In the first trials (24 patients), homeopathy improved symptom scored and forced vital capacity (FVC) but had no effect on FEV1 or bronchial reactivity. The second study demonstrated improvements in both active and placebo groups. The third, poorly reported, trial demonstrated an increase in lung function in patients receiving the active preparation. There is insufficient information regarding the value of homeopathy in the treatment of asthma. Large well designed trials using defined remedies and a spectrum of patients are warranted.

Hypnosis Studies of hypnosis in patients with asthma are generally poorly controlled and patient characteristics and outcome measured vary enormously. The conclusions from a critical review were that hypnosis may be effective for asthma with the biggest effect in susceptible subjects, but more randomised and appropriately controlled studies are required.

Manual Therapy including Massive and Spinal Manipulation A Cochrane review identified four relevant randomised controlled trials. The two trials of chiropractice suggest that there is no place for this modality of treatment in the management of asthma. No conclusions can be drawn on massage therapy.

Physical Exercise Training A Cochrane review has shown no effect of physical training on PEF, FEV1, FVC or VEmax. However, oxygen consumption, maximum heart rate, and work capacity all increased significantly. Most studies discussed the potential problems of exercise-induced asthma, nut none made any observations on this phenomenon. As physical training improves indices of cardiopulmonary efficiency, it should be seen as part of a general approach to improving lifestyle and rehabilitation in asthma, with appropriate precautions advised about exerciseinduced asthma.

Breathing Exercise Including Yoga and Buteyko The underlying principle of Yoga and Buteyko is to reduce hyperventilation by lowering respiratory frequency. A Cochrane review found no change in routine measures of lung function. Two studies reported a reduction in use of medication, and two a reduced frequency of attacks. At present it is not possible to make an evidence-based recommendation about breathing exercises for asthma.

Family Therapy A Cochrane review identified two trials, in 55 children showing that family therapy may be a useful adjunct to medication in children with asthma. Small study size limits the recommendations.

New Guidelines for Asthma Management (Non-pharmacological Management) 263 Dietary Manipulation

Minerals Low magnesium intakes have been associated with higher prevalence of asthma. An intervention study of magnesium supplementation has suggested a reduced rate of bronchial hyperresponsiveness and wheeze. Studies of sodium and antioxidant supplements such as selenium and vitamin C have produced little or no evidence of benefit amongst patients with asthma.

Fish Oils and Fatty Acids In vitro studies suggest that supplementing diet with the omega n-3 fatty acids found predominantly in fish oils might reduce the inflammation associated with asthma. Controlled clinical studies in small numbers have on the whole been negative, with a Cochrane review concluding that there was little evidence to recommend fish oil supplements in asthma. Weight Reduction in Obese Patients with Asthma A small randomised parallel group study has shown improved asthma control following weight reduction in obese patients with asthma. REFERENCES 1. New British Guidelines on Management of Asthma. Thorax 1993;58(Suppl 1):1-94. 2. Guidelines for the Management of Asthma in Adults. 1-Chronic persistent asthma. Statement by the British Thoracic Society, Research Unit of the Royal College of Physicians of London, King’s Fund Center, National Asthma Campaign. BMJ 1990;301:651-53. 3. Guidelines for the Management of Asthma in Adults. 2-Acute severe asthma. Statement by the British Thoracic Society, Research Unit of the Royal College of Physicians of London, King’s Fund Center, National Asthma Campaign. BMJ 1990;301:797-800. 4. Warner JO, Gotz M, Landau LI, et al. Management of Asthma: A consensus statement. Arch Dis Child 1989;64;1065-79. 5. International Paediatric Asthma Consensus Group. Asthma, a follow-up statement. Arch Dis Child 1992;67:240-48. 6. International consensus report on the diagnosis and management of asthma. Clin Exp Allergy 1992;22(Suppl):1-72. 7. British Thoracic Society and others. Guidelines for the management of asthma: A summary. BMJ 1993;9:287-92. 8. The British Guidelines on Asthma Management. 1995 Review and Position Statement. Thorax 1997;52(Suppl 1): S2-S8. 9. British Thoracic Society, British Paediatric Association, Royal College of Physicians of London, The King’s Fund Center, National Asthma Campaign, et al. Guidelines on the management of asthma. Thorax 1993;48:S1-S24. 10. British Thoracic Society, British Paediatric Association, Royal College of Physicians of London, The King’s Fund Center, National Asthma Campaign, et al. Summary charts. BMJ 1993;306:77682. 11. Global Initiative for Asthma. A practical guide for public health officials and health care professionals. US Department of Health and human services. NIH Publication No.1995;96:3659A,. 12. National Asthma Education and Prevention Program. Expert Panel Report II: Guidelines for the diagnosis and management of asthma. Bethesda, MD: National Institute of Health. 1997.

264 Bronchial Asthma 13. Scottish Intercollegiate Guidelines Network (SIGN). Hospital inpatient management of acute asthma attack. SIGN Publication No. 6, Edinburgh, SIGN, 1996. 14. Scottish Intercollegiate Guidelines Network (SIGN). Primary care management of asthma. SIGN Publication No. 33, Edinburgh, SIGN, 1998. 15. Scottish Intercollegiate Guidelines Network (SIGN). Emergency management of acute asthma. SIGN Publication No. 38, Edinburgh, SIGN, 1999. 16. Harbour R, Miller J. A new system for grading recommendations in evidence based guidelines. BMJ 2001;323:334-36.

New Guidelines for Asthma Management (Pharmacological Management) 265

17 New Guidelines for Asthma Management (Pharmacological Management) The aims of pharmacological management of asthma are: • The control of symptoms, including nocturnal symptoms and exercise-induced asthma • Prevention of exacerbations • Achievement of best possible pulmonary function • With minimal side effects. It is not appropriate to define a fixed level of lung function or symptom control which must be achieved, as individual patients will have different goals and may also wish to balance these aims against the potential side effects or inconvenience of taking the medication necessary to achieve “perfect” control. In general terms, control of asthma is assessed against these standards: • Minimal symptoms during day and night • Minimal need for reliever medication • No exacerbations • No limitation of physical activity • Normal lung function (in practical terms FEV1 and/or PEF>80% predicted or best) A stepwise approach aims to abolish symptoms as soon as possible and to optimise peak flow by starting treatment at the level most likely to achieve this. Patients should start treatment at the step most appropriate to the initial severity of their asthma. The aim is to achieve early control and to maintain control by stepping up treatment as necessary and stepping down when control is good. Before initiating a new drug therapy practitioners should check compliance with existing therapies, inhaler technique and eliminate trigger factors. All doses of inhaled steroids in this section refer to beclomethasone (BDP) given via a metered dose inhaler (pMDI). Adjustment may be necessary for fluticasone and/or other devices. STEP 1: MILD INTERMITTENT ASTHMA The following medicines act as short acting bronchodilators: • Inhaled short acting β2-agonists • Inhaled ipratropium bromide

266 Bronchial Asthma • β2-agonist tablets or syrup • Theophyllines Short acting inhaled β2-agonists work more quickly and/or with fewer side effects than the alternative. An inhaled short acting β2-agonist should be prescribed as short-term reliever therapy for all patients with symptomatic asthma. Frequency of Dosing of Inhaled Short Acting β2-Agonists There is no consistent evidence of any benefit or harm from regular (four times daily) use of short acting β2-agonists compared with “as required” (sos) use. Unless individual patients are shown to benefit from regular use of inhaled short acting β2-agonists, then “as required” use is recommended. Using two or more canisters of β2-agonists per month or > 10-12 puffs per day is a marker of poorly controlled asthma. Patients with high usage of inhaled short acting β2-agonists should have their asthma management reviewed. STEP 2: INTRODUCTION OF REGULAR PREVENTER THERAPY For steps 2, 3 and 4, treatments have been judged on their ability to improve symptoms, improve lung function, and prevent exacerbations, with an acceptable safety profile improvement of quality of life while important is the subject of two few studies to be used to make recommendations at present. Inhaled Steroids Inhaled steroids are the most effective preventer drug for adults and children for achieving overall treatment goals. They are the recommended preventer drug for adults and children for achieving overall treatment goals. The threshold for introduction of inhaled steroids has never been firmly established. There is strong evidence that patients requiring short acting β2-agonists more than two to three times a day should be treated with inhaled steroids, but patients with lower inhaler requirements may also benefit. Inhaled steroids should be started for patients with; • Recent exacerbations, • Nocturnal asthma, • Impaired lung function, or • Use of inhaled β2-agonists more than once a day.

Starting Dose of Inhaled Steroids In mild to moderate asthma, starting at very high doses of inhaled steroids and stepping down confers no benefit. Start patients at a dose of inhaled steroids appropriate to the severity of disease. In adults, a reasonable starting dose will usually be 400 μg per day and in children 200 μg per day. In children under 5 years of age, higher doses may be required if there are problems in obtaining consistent drug delivery. The dose is to be titrated to the lowest dose at which effective control of asthma is maintained.

Frequency of Dosing of Inhaled Steroids Current inhaled steroids are slightly more effective when taken twice rather than once daily. There is little evidence of benefit for dosage frequency more than twice daily. Initially,

New Guidelines for Asthma Management (Pharmacological Management) 267 the inhaled steroids are to be given twice daily. Once a day inhaled steroids at the same total daily dose can be considered if good control is established. Safety of Inhaled Steroids The safety of inhaled steroids is of crucial importance and a balance between benefits and risks for each individual needs to be assessed. Account should be taken of other topical steroid therapy when assessing systemic risk. There is little evidence that doses below 800 μg day cause any short-term detrimental effects apart from the local side effects of dysphonia and oral candidiasis. However, the possibility of long-term effects on bone has been raised. Cross-sectional studies have shown possible dose related reduction in bone density. Other studies have shown effects on adrenocortical function of uncertain significance. In children, inhaled stereoids of 400 μg day of beclomethasone dipropionate or equivalent may be associated with systemic side effects like growth retardation, and adrenal suppression. The later may manifest as hypoglycaemic episodes. The smallest dose of inhaled steroids required to maintain adequate asthma control must be used. At higher doses, add-on therapy like long acting β2-agonists should be considered. The height of the children should be monitored on a regular basis. Comparison of Inhaled Steroids Many studies comparing different inhaled steroids are of inadequate design and have been omitted from further assessment. In view of the clear differences between normal volunteers and asthma patients in the absorption of inhaled steroids, data from normal volunteers have not been taken into account. Only studies in which more than one dose of at least one of the inhaled steroids or both safety and efficacy has been studied together in the same trial were evaluated. Non-blinded studies also has to be considered because of the problems of obtaining competitors’ delivery devices. All comparison used BDP-CFC (chlorofluoro-carbons) as the reference. Beclomethasone dipropionate (BDP) and budesonide are approximately equivalent in clinical practice although there may be variations with different delivery devices. There is limited evidence from two open studies of less than ideal design that budesonide via the turbohaler is more clinically effective. However, at present a 1:1 ratio should be assumed when changing between BDP and budesonide. Fluticasone provides equal clinical activity to BDP and budesonide at half the dosage. The evidence that it causes fewer side effects at doses with equal clinical effect is limited. Other Preventive Therapies Inhaled steroids are the first choice preventive drugs. Alternative, less effective preventive therapies in patients taking short acting β2-agonists alone are: • Cromones (have an inconvenient dosing frequency). • Sodium cromoglycate is ineffective in children. • Nedocromil sodium is of benefit in 5-12 years old. • Leukotriene receptor antagonists have some beneficial effect (side effects are common and monitoring of plasma levels is required). • Long acting inhaled β2-agonists have some beneficial effects but they are not recommended as first line preventive therapy. • Antihistamines and ketotifen are ineffective.

268 Bronchial Asthma STEP 3: ADD-ON THERAPY Before initiating a new drug therapy one should recheck compliance, inhaler technique and eliminate trigger factors. The duration of a trial of add-on therapy will depend on the desired outcome. For instance, preventing nocturnal awakening may require a relatively short trial of treatment (days or weeks), whereas preventing exacerbations of asthma or decreasing steroid tablet use may require a longer trial of therapy (weeks or months). If there is no response to treatment the drug should be discontinued. CRITERIA FOR INTRODUCTION OF ADD-ON THERAPY No exact dose of inhaled steroid can be determined, the correct dose at which to add another therapy. The addition of other treatment options to inhaled steroids has been investigated at doses from 200-1000 μg in adults and up to 400 μg in children. Many patients will benefit more from add-on therapy than from increasing inhaled steroids above doses as low as 200 μg/day. Furthermore, at doses of inhaled steroid above 800 μg/day side effects become more frequent. An absolute threshold for introduction of add-on therapy in all patients cannot be defined. Thus, one should carry out a trial of other treatment before increasing the inhaled steroid dose above 800 μg/day in adults and 400 μg/day in children. Add-On Therapy Option for add-on therapy are summarised in Figure 17.1. In adult patients taking inhaled steroids at doses of 200-800 μg/day and in children taking inhaled steroids at a dose of 400 μg/day the following interventions are of value. First choice would be the addition of an inhaled long acting β2-agonists (LABA), which improves lung function and symptoms, and decreases exacerbation. The first choice as add-on therapy to inhaled steroids in adults and children (5-12 years) is an inhaled long acting β2-agonists. If, as may happen occasionally, there is no response to inhaled long acting β2-agonist, the LABA should be stopped and the dose of inhaled steroid to be increased to 800 μg/day (adults) or 400 μg/day (children) if not already on this dose. If there is a response to LABA, but control remains poor, one should continue with the LABA and increase the dose of inhaled steroid to 800 μg/day (adults) or 400 μg/day (children 5-12 years). • Leukotriene receptor antagonists provide improvement in lung function, a decrease in exacerbations, and an improvement in symptoms. • Theophylline improves lung function and symptoms, but side effects occur more commonly. • Slow release β2-agonists tablets also improve lung function and symptoms, but side effects occur more commonly. If control is still inadequate after a trial of LABA and after increasing the dose of inhaled steroid, one may consider a sequential trial of add-on therapy, i.e. leukotriene receptor antagonists, theophyllines, slow release β2-agonist tablets in adults. Addition of anticholinergics is generally of no value. Addition of cromones is of marginal benefit. In patients on inhaled steroids whose asthma is stable, no intervention has been consistently shown to decrease inhaled steroid requirement in a clinically significant manner compared to placebo.

New Guidelines for Asthma Management (Pharmacological Management) 269 Inadequate control on lowdose inhaled steroids Add inhaled long-acting β2agonist (LABA) Assess control of asthma Good response to LABA and good control: • Continue LABA

Benefit from LABA, but control still inadequate: • Continue LABA and • Increase inhaled steroid dose to 800 µg/day (adults) and 400 µg/ day (children, 5-12 years) If control still inadequate, go to step 4

No response to LABA: • Stop LABA • Increase inhaled steroid dose to 800 µg / day (adults) and 400 µg/day (children 5-12 years) Control still inadequate: Trial of other add-on therapy, e.g. leukotriene receptor antagonist or theophylline If control still inadequate go to step 4

Fig. 17.1: Summary of step 3: add-on therapy

Combination Inhalers There is no difference in efficacy in giving inhaled steroid and long acting β2-agonist in combination or in separate inhalers. STEP 4: POOR CONTROL ON MODERATE DOSE OF INHALED STEROID + ADD-ON THERAPY: ADDITION OF FOURTH DRUG In a small proportion of patients asthma is not adequately controlled on a combination of as required short acting β2-agonist, inhaled steroid (800 μg/day), and an additional drug, usually a long acting β2-agonist. There are very few clinical trials in this specific patient group to guide management. The following recommendations are based on extrapolation from trials of add-on therapy to inhaled steroids and on previous guidelines. If control remains inadequate on 800 μg daily in adults and 400 μg/day in children, of an inhaled steroid plus a long acting agonist, β2-agonist, the following interventions are to be considered: • Increase the inhaled steroids to 2000 μg/day in adults or 800 μg/day in children of 5-12 years of age. • Leukotriene receptor antagonists • Theophyllines • Slow release β2-agonist tablets, (caution needs to be taken in patients on long acting β2-agonist)

270 Bronchial Asthma There is no control trial indicating which of these is the best option. If a trial of an add-on treatment is ineffective, the drug is to be stopped, or in case of increased dose of inhaled steroid, the dose is to be reduced to the original dose). Before proceeding to step 5, the physician should consider referring the patient with inadequately controlled asthma, especially children, to specialist care. STEP 5: CONTINUOUS OR FREQUENT USE OF ORAL STEROIDS Prevention and Treatment of Steroid Tablet-induced Side Effects Patients on long-term steroid tablets (e.g. longer than three months) or requiring frequent courses of steroid tablets (e.g. three to four per year) will be at risk of systemic side effects • Blood pressure should be monitored • Diabetes mellitus may occur • Osteoporosis commonly occurs and should be monitored and treated. • Growth should be monitored in children • Cataracts should be screened for in children Steroid Tablet—Starting Medication The aim of treatment is to control the asthma using the lowest possible dose, or if possible, to stop long-term steroid tablets completely. Inhaled steroids are the most effective drug for decreasing requirement for long-term steroid tablets. There is limited evidence for the ability of long acting β2-agonists, theophyllines, or leukotriene receptor antagonists to decrease the requirements for steroid tablets, but they may improve symptoms and pulmonary function. In adults, the recommended method of eliminating or reducing the dose of steroid tablets is inhaled steroids, at doses of up to 2000 μg/day if required. In children of aged 5-12 years, doses above 1000 μg/day should be added cautiously. There is a role for a trial of treatment in adults with long acting β2-agonists, leukotriene receptor antagonists, and theophyllines for about six weeks. They should be stopped if no improvement in steroid dose, symptoms or lung function is detected. Immunosuppressants (methotrexate, cyclosporin and oral gold) decrease long-term steroid tablet requirements but all have significant side effects. There is no evidence of persisting beneficial effect after stopping them; and there is marked variability in response. Immunosuppressants (methotrexate, cyclosporin and oral gold) may be given as a three month trial, once other drug treatments have proved unsuccessful. Their risks and benefits should be discussed with the patient and their side effects carefully monitored. Treatment should be in a center with experience of using these medicine. Colchicine and intravenous immunoglobulin have not been shown to have any beneficial effect in adults. Continuous subcutaneous terbutaline infusion has been reported to be beneficial in severe asthma but efficacy and safety have not been assessed in randomised controlled trials. Steroid Formulations Prednisolone is the most widely used steroid for maintenance therapy in chronic asthma. There is no evidence that other formulations offer any advantage. Although popular in

New Guidelines for Asthma Management (Pharmacological Management) 271 paediatric practice, there are no studies to show whether alternate day steroids produce fewer side effects than daily steroids. β-Blockers β-blockers, including eye drops, are contraindicated in patients with asthma. Stepping Down Stepping down treatment once asthma is controlled is recommended, but often not implemented leaving some patients over treated. There is little evidence regarding the most appropriate way to step down treatment. Regular review of patients as treatment is stepped down is important. When deciding which drug to step down first and at what rate, the severity of asthma, the side effects of the treatment, the beneficial effect achieved, and the patient’s preference should all be taken into account. Patients should be maintained at the lowest possible dose of inhaled steroid. Reduction in inhaled steroid dose should be slow as patients deteriorate at different rates. Reductions should be considered every three months, decreasing the dose by approximately 25-50% each time. SPECIFIC MANAGEMENT PROBLEMS Onset of Exacerbation Asthma Although, recommended for both adults and children in previous guidelines and as part of asthma action plants, doubling the dose at the time of an exacerbation is of unproven value. In adult patients on a low dose (220 μg) of inhaled steroids, a five-fold increase in dose at the time of exacerbation leads to a decrease in the severity of exacerbations. This five-fold increase should not be extrapolated to higher doses of inhaled steroids. Exercise-induced Asthma For most patients exercise-induced asthma is an expression of poorly controlled asthma and regular treatment including inhaled steroids should be reviewed. The following medicines give protection against exercise-induced asthma: • Inhaled steroids • Short acting β2-agonists • Long acting β2-agonists • Theophyllines • Leukotriene receptor antagonists • Cromones • β2-agonist tablets The following medicines do not give protection against exercise-induced asthma at normal doses: • Anticholinergics • Ketotifen • Antihistamines Long acting β2-agonists and leukotriene antagonists provide more prolonged protection

272 Bronchial Asthma than short acting β2-agonists, but a degree of tolerance develops with LABA particularly with respect to duration of action. No tolerance has been demonstrated with leukotriene receptor antagonists. If exercise is a specific problem in patients taking inhaled steroids who are otherwise well controlled, the following therapies are to be considered: • Leukotriene receptor antagonists • Long acting β2-agonists • Cromones ` • Oral β2-agonists • Theophyllines Immediately before exercise, inhaled short acting β2-agonists are the drug of choice. Rhinitis Patients with asthma often have rhinitis. The most effective therapy is intranasal steroids. Treatment of allergic rhinitis has not been shown to improve asthma control. Allergic Bronchopulmonary Aspergillosis In adult patients with allergic bronchopulmonary aspergillosis (ABPA), itraconazole may decrease steroid tablet dose and improve asthma control. In adult patients with ABPA, a four-month trial of itraconazole should be considered. Careful monitoring of side effects, particularly hepatic dysfunction, is recommended. Aspirin Intolerant Asthma There are theoretical reasons to suggest that leukotriene receptor antagonists might be of particular value in the treatment of aspirin intolerant asthma. However, there is little evidence to justify managing patients with aspirin intolerant asthma in a different manner to patients tolerant of aspirin, apart from the rigorous avoidance of non-steroidal antiinflammatory medications. NOVEL THERAPIES Anti-IgE Monoclonal Antibody In highly selected patients an anti-IgE monoclonal antibody has some beneficial effect, but its role in the stepwise treatment of asthma is unclear. At present this drug does not have a license in many countries. Mometasone Mometasone is a new inhaled steroid and the relatively limited number of studies suggests it is equivalent to twice the dose of BDP-CFC. The relative safety of mometasone is not fully established. Tiotropium Bromide Tiotropium bromide is a once daily long acting anticholinergic agent. Its value in the treatment of asthma has not been evaluated.

New Guidelines for Asthma Management (Pharmacological Management) 273  STEP5: CONTINUOUS OR FREQUENT USE OF ORAL STEROIDS Use daily steroid tablet in lowest dose providing adequate control • Maintain high dose inhaled steroid of 2000 μg /day • Consider other treatments to minimize the use of steroid tablets STEP4: PERSISTENT POOR CONTROL Consider trials of: • Increasing inhaled steroid up to 2000 µg/ day • Addition of a fourth drug, e.g. leukotriene receptor antagonist, SR theophylline, β2-agonist tablet



STEP3: 1. 2. • •

•

ADD-ON THERAPY Add inhaled long acting β2-agonist (LABA)  Assess control of asthma: Good response to LABA – continue LABA Benefit from LABA but control still inadequate – continue LABA and increase inhaled steroid dose to 800 μg /day (if not already on this dose) No response to LABA-stop LABA and increase inhaled steroid to 800 μg /day if control still inadequate, institute trial of other therapies, e.g. leukotriene receptor antagonist or SR theophylline

STEP2: REGULAR PREVENTER THERAPY

 Add inhaled steroid 200-800 μg /day ;

400 μg /day is an appropriate starting dose in many patients Start at dose of inhaled steroids appropriate to severity

STEP1: MILD INTERMITTENT ASTHMA Inhaled short acting β2-agonist as required

Inhaled steroids indicate beclomethasone dipropionate or equivalent Step care management of bronchial asthma in adults.



274 Bronchial Asthma  STEP5: CONTINUOUS OR FREQUENT USE OF ORAL STEROIDS Use daily steroid tablet in lowest dose providing adequate control • Maintain high dose inhaled steroid of 800 μg /day • Refer patient for specialist care

STEP4: PERSISTENT POOR CONTROL Consider trials of: • Increase inhaled steroid up to 800 µg/ day



STEP3: 1. 2. • •

•

ADD-ON THERAPY Add inhaled long acting β2-agonist (LABA) Assess control of asthma: Good response to LABA—Continue LABA Benefit from LABA but control still inadequate  – continue LABA and increase inhaled steroid dose to 400 μg /day (if not already on this dose) No response to LABA-stop LABA and increase inhaled steroid to 400 μg /day if control still inadequate, institute trial of other therapies, e.g. leukotriene receptor antagonist or SR theophylline

STEP2: REGULAR PREVENTER THERAPY

 Add inhaled steroid 200-400 μg /day ; (Other preventer drugs if inhaled steroid cannot be used) 200 µg/day is an appropriate starting dose in many patients Start at dose of inhaled steroids appropriate to severity

STEP1: MILD INTERMITENT ASTHMA Inhaled short acting β2-agonist as required

Inhaled steroids indicate beclomethasone dipropionate or equivalent Step care management of bronchial asthma in children, aged 5-12 years.



New Guidelines for Asthma Management (Pharmacological Management) 275  STEP4: PERSISTENT POOR CONTROL • Refer to Paediatrician with respiratory specialization

STEP 3: ADD-ON THERAPY In children aged 2-5 years consider trial of leukotriene  receptor antagonist In children under 2 years consider proceeding to Step 4.

STEP 2: REGULAR PREVENTER THERAPY Add inhaled steroid 200-400 µg/day ; or  Leukotriene receptor antagonist if inhaled steroid cannot be used Start at dose of inhaled steroids appropriate to severity

STEP 1: MILD INTERMITTENT ASTHMA Inhaled short acting β2-agonist as required



Inhaled steroids indicate beclomethasone dipropionate or equivalent. Higher nominal doses may be required if drug delivery is difficult. Step care management of bronchial asthma in children less than 5 years.

276 Bronchial Asthma

18 New Guidelines for Asthma Management (Acute Asthma) Confidential enquires into over 200 asthma deaths in the UK have concluded that three important factors associated with the disease—the medical management and the patient’s behaviour or psychosocial status-contributed to the death. Most deaths occurred before admission to hospital.

Disease Factors Most patients who died of asthma had chronically severe asthma. In a minority the fatal attack occurred suddenly in a patient with only mild or moderately severe background disease.

Medical Management Many of the deaths occurred in patients who had received inadequate treatment with inhaled steroid or steroid tablets and/or inadequate objective monitoring of their asthma. Follow up was inadequate in some and others should have been referred earlier for specialist advice. There was widespread underuse of written management plans. Heavy or increasing use of β2-agonist therapy was associated with asthma death. Deaths have continued to be reported following inappropriate prescription of β-blocker therapy or heavy sedation. A small proportion of patients with asthma were sensitive to nonsteroidal anti-inflammatory agents; all asthma patients should be asked about past reactions to these agents.

Adverse Psychosocial and Behavioural Factors Behavioural and adverse psychosocial factors were recorded in the majority of patients who died of asthma. The most important are: I. A combination of severe asthma: • Previous near fatal asthma, e.g. previous ventilation or respiratory acidosis • Previous admission for asthma especially if in the last year • Requiring three or more classes of asthma medication

New Guidelines for Asthma Management (Acute Asthma) 277 • Heavy use of β2-agonist • Repeated attendances at emergency for asthma care especially in the last year • Brittle asthma. II Adverse behavioural or psychological features: • Non-compliance with treatment or monitoring • Failure to attend appointments • Self-discharge from hospital • Psychosis, depression, other psychiatric illness or deliberate self-harm • Current or recent major tranquilliser use • Denial • Alcohol or drug abuse • Obesity • Learning difficulties • Employment problems • Income problems • Social isolation • Childhood abuse • Severe domestic, marital or legal stress Case control studies support most of these observations. Compared with control patients admitted to hospital with asthma, those who died were significantly more likely to have learning difficulties; psychosis or prescribed antipsychotic drugs; financial or employment problems; repeatedly failed to attend appointments or discharged themselves from hospital; drug or alcohol abuse; obesity; or a previous near fatal attack. Compared with control patients with asthma in the community, patients who died had more severe disease; more likelihood or a hospital admission or visit to emergency department for their asthma in the previous year; more likelihood or a previous near fatal attack; poor medical management; failure to measure pulmonary function; and noncompliance. Health care professionals must be aware that patients with severe asthma and one or more adverse psychosocial factors are at risk of death. Studies comparing near fatal asthma with deaths from asthma have concluded that patients with near fatal asthma have identical adverse factors to those described above, and that these contribute to the near fatal asthma attack. Compared with patients who die, those with near fatal asthma are significantly younger, are significantly more likely to have had a previous near fatal asthma attack, are less likely to have concurrent medical conditions, are less likely to experience delay in receiving medical care, and more likely to have ready access to acute medical care. Not all patients with near fatal asthma require intermittent positive pressure ventilation. For those with near fatal asthma, adults as well as children, it is always wise to involve a close relative when discussing future management. Patients with brittle asthma should also be identified. Patients who have had near fatal asthma or brittle asthma should be kept under specialise supervision indefinitely. In the UK there is a peak of asthma deaths in young people (aged up to 44 years) in July and August and, in December and January in older people, and similar seasonal deaths might also be true for other countries.

278 Bronchial Asthma PREDICTION AND PREVENTION OF A SEVERE ASTHMA ATTACK Most (88-92%) attacks of asthma severe enough to require hospital admission develop relatively slowly over a period of six hours or more. In one study, over 80% developed over more than 48 hours. There should therefore be time for effective action and the potential to reduce the number of attacks requiring hospitalisation. There are many similarities between patients who die from asthma, patients with near fatal asthma and asthmatic controls who are admitted to hospital. A respiratory specialist should follow up patients admitted with severe asthma for at least one year after the admission. I. ACUTE ASTHMA IN ADULTS Recognition of Acute Asthma Definitions of increasing levels of severity of acute asthma exacerbations are as follows: Near fatal asthma Raised PaCO2 and/or requiring mechanical ventilation with raised inflation pressures Life threatening asthma Any one of the following in a patients with severe asthma: • PEF<33% best or predicted • Bradycardia • SpO2<92% • Dysrhythmia • PaO2<60 mmHg • Hypotension • Normal PaCO2 (4.6-6.0 kPa) • Exhaustion • Silent chest • Confusion • Cyanosis • Coma • Feeble respiratory effort Acute severe asthma Any one of • PEF 33-50% best or predicted • Respiratory rate > 25/min • Heart rate > 100/min • Inability to complete sentences in one breath Moderate asthma exacerbation • Increasing symptoms • PEF >50-75% best or predicted • No features of acute severe asthma Brittle asthma • Type 1: Wide PEF variability (> 40% diurnal variation for 50% of the time over a period > 150 days) despite intense therapy • Type 2: Sudden severe attacks on a background of apparently well controlled asthma. Predicted PEF values should be used only if the recent best PEF (within two years) is unknown. Self Treatment by Patients Developing Acute or Uncontrolled Asthma Many patients with asthma and all patients with severe asthma should have an agreed written action plan and their own peak flow meter, with regular checks of inhaler technique and compliance. They should know when and how to increase their medication and when

New Guidelines for Asthma Management (Acute Asthma) 279 to seek medical assistance. Asthma action plans have been shown to decrease hospitalisation for and deaths from asthma.

Initial Assessment All possible initial contact personnel, should be aware that asthma patients complaining of respiratory symptoms may be at risk and should have immediate access to a doctor or trained asthma nurse. The assessments required to determine whether the patients is suffering from an acute attack of asthma, the severity of the attack and the nature of treatment required are detailed above as well as follows: It may also be helpful to use a systematic recording process. Proformas have proved useful in the emergency settings. Clinical features

Clinical features, symptoms and respiratory and cardiovascular signs are helpful in recognising some patients with severe asthma, e.g. severe breathlessness (including too breathless to complete sentences in one breath), tachypnea, tachycardia, silent chest, cyanosis or collapse. None of these singly or together is specific and their absence does not exclude a severe attack

PEF or FEV1

Measurements of airway caliber improve recognition of the degree Or severity, the appropriateness or intensity of therapy, and decisions about management in hospital or at home. PEF or FEV1 are both useful and valid measures of airway caliber PEF is more convenient and cheaper. PEF expressed as a percentage of the patient’s previous best value is more useful clinically. PEF as a percentage of predicted gives a rough guide in the absence of a known previous best value. Different peak flow meters give different readings. Where possible the same or similar type of peak flow meter should be used.

Pulse oximetry

Measurement of oxygen saturation (SpO2) with a pulse oxymeter is necessary in acute severe asthma to determine the adequacy of oxygen therapy and the need for arterial blood gas (ABG) measurement. The aim of oxygen therapy is to maintain SpO2 > 92%.

Blood gases (ABG)

Patients with SpO2<92% or other features of the threatening asthma require ABG measurement.

Chest X-ray

Chest X-ray is not routinely recommended in patients in the absence of: • Suspected pneumomediastinum or pneumothorax • Suspected consolidation • Life threatening asthma • Failure to respond to treatment satisfactorily • Requirement for ventilation. Systolic paradox (pulsus paradoxus) has been abandoned as an indicator of the severity of an attack for pragmatic reasons.

Systolic paradox

280 Bronchial Asthma Prevention of Acute Deterioration A register of patients at risk may help primary care health professionals to identify patients who are more likely to die from their asthma. A system should be in place to ensure that these patients are contacted if they fail to attend for follow up.

Criteria for Admission One should refer to a hospital if one comes across any patients with features of acute severe or life threatening asthma. Other factors, such as failure to respond to treatment, social circumstances or concomitant disease, may warrant hospital referral.

Criteria for Admission Patients with any feature of a life threatening or near fatal attack should be admitted. Also patients with any feature of a severe attack persisting after initial treatment need to be admitted. Patients whose peak flow is greater than 75% best or predicted one hour after initial treatment may be discharged from emergency, unless they meet any of the following criteria, when admission may be appropriate: • Still have significant symptoms • Concerns about compliance • Living alone/socially isolated • Psychological problems • Physical disability or learning difficulties • Previous near fatal or brittle asthma • Exacerbation despite adequate dose steroid tablets pre-presentation • Presentation at night • Pregnancy Criteria for admission in adults are summarised subsequently. Treatment of Acute Asthma in Adults

Oxygen Patients with acute severe asthma are hypoxaemic. This should be corrected urgently using high concentrations of inspired oxygen (usually 40-60%) and a high flow mask such as a Hudson mask. Unlike patients with COPD there is little danger of precipitating hypercapnia with high flow oxygen. Hypercapnia indicates the development of near fatal asthma and the need for emergency specialist/anaesthetic intervention. Oxygen saturations of at least 92% must be achieved. In view of the theoretical risk of oxygen desaturaion while using air driven compressors to nebulise β2-agonist bronchodilators, oxygen-driven nebulisers are the preferred method of delivery in hospitals, ambulances and primary care. (in order to generate the flow rate of 61/min required to drive most nebulisers, a high flow regulator must be fitted to the oxygen cylinder). The absence of supplemental oxygen should not prevent nebulised therapy from being administered where appropriate. In hospital, ambulance and primary care, nebulised β2-agonist bronchodilators should be driven by oxygen. Outside hospital, high dose β2-agonist bronchodilators may be delivered via large

New Guidelines for Asthma Management (Acute Asthma) 281 volume spacers or nebulisers. Whilst supplemental oxygen is recommended, its absence should not prevent nebulised therapy being given if indicated.

β2-Agonist Bronchodilators In most cases of acute asthma, inhaled β2-agonist given in high doses act quickly to relieve bronchospasm with few side effects. There is no evidence for any difference in efficacy between salbutamol and terbutaline, although rarely patients may express a preference. In acute asthma without life threatening features, β2-agonist can be administered by repeated activations of a pMDI via an appropriate large volume spacer or by wet nebulisation driven by oxygen, if available. Inhaled β2-agonist are at least as efficacious and preferable to intravenous β2-agonist (meta-analysis has excluded subcutaneous trials) in adult acute asthma in the majority of cases. High-dose inhaled β2-agonist are to be used as first line agents in acute asthma and should be administered as early as possible. Intravenous β2-agonist should be reserved for those patients in whom inhaled therapy cannot be used reliably. In acute asthma with life threatening features the nebulised route (oxygen-driven) is recommended. Parenteral β2-agonists, in addition to inhaled β2-agonist may have a role in ventilated patients or those patient in extremes in whom nebulised therapy may fail; however there is limited evidence to support this. Continuous nebulisation of β2-agonist is at least as efficacious as bolus nebulisation in relieving acute asthma. Most cases of acute asthma will respond adequately to bolus nebulisation of β2-agonist. In severe asthma (PEF or FEV1 <50% best or predicted) and asthma that is poorly responsive to an initial bolus dose of β2-agonist, continuous nebulisation may be considered. Repeated doses of β2-agonist should be given at 15-30 minute intervals or continuous nebulisation of salbutamol at 5-10mg/hour (requires appropriate nebuliser) used if there is an inadequate response to initial treatment. Higher bolus doses, e.g. 10 mg of salbutamol, are unlikely to be more effective. Steroid Therapy Steroid tablets reduce mortality, relapses, subsequent hospital admission and requirement for β2-agonist therapy. The earlier they are given in the acute attack the better the outcome. Steroid tablets are to be given in adequate doses in all cases of acute asthma. Steroid tablets are as effective as injected steroids, provided tablets can be swallowed and retained. Doses of prednisolone of 40-50 mg daily or parenteral hydrocortisone 400 mg daily (100 mg sixhourly) are as effective as higher doses. For convenience, steroid tablets may be given as 2 × 25 mg tablets daily rather than 8-12 × 5 mg tablets. The duration of prednisolone 40-50 mg daily is for at least five days or until recovery. Following recovery from the acute exacerbation steroid tablets can be stopped abruptly and doses do not need tapering provided the patient receives inhaled steroids (apart from patients on maintenance steroid treatment or rare instances where steroids are required for three or more weeks). There is no evidence to suggest that inhaled steroids should be substituted for steroid tablets in the treatment of patients with acute severe, or life threatening asthma. Further randomised controlled trials to determine the role of inhaled steroids in these patients are required. Inhaled steroids do not provide benefit in addition to the initial

282 Bronchial Asthma treatment, but should be continued (or started as soon as possible) to form the start of the chronic asthma management plan.

Ipratropium Bromide Combining nebulised ipratropium bromide with a nebulised β2-agonist has been shown to produce significantly greater bronchodilation that a β2-agonist alone, leading to a faster recovery and shorter duration of admission. Anticholinergic treatment is not necessary and may not be beneficial in milder exacerbations of asthma or after stabilisation. Nebulised ipratropium bromide (0.5 mg 4-6 hourly) should be added to β2-agonist treatment for patients with acute severe or life threatening asthma or those with a poor initial response to β2-agonist therapy.

Intravenous Magnesium Sulphate A single dose of IV magnesium sulphate has been shown to be safe and effective in acute severe asthma. The safety and efficacy of repeated doses have not been assessed in patients with asthma. Repeated doses could give rise to hypermagnesaemia with muscle weakness and respiratory failure. Indications of giving a single dose of IV magnesium sulphate for patients are: • Acute severe asthma who have not had a good initial response to inhaled bronchodilator therapy • Life threatening or near fatal asthma IV magnesium sulphate (1.2- 2g IV infusion over 20 minutes) should only be used following consultation with senior medical staff. More studies are needed to determine the optimal frequency and dose of IV magnesium sulphate therapy.

Intravenous Aminophylline In acute asthma, the use of intravenous aminophylline is not likely to result in any additional bronchodilation compared to standard care with inhaled bronchodilators and steroid tablets. Side effects such as palpitations, arrhythmias and vomiting are increased if IV aminophyline is used. Intravenous aminophylline is to be used only after consultation with senior medical staff. Some individual patients with near fatal asthma or life threatening asthma with a poor response to initial therapy may gain additional benefit from IV aminophylline (5mg/kg loading dose over 20 minutes unless on maintenance oral therapy, then infusion of 0.5-0.7 mg/kg/h). Such patients are probably rare and could not be identified in a meta-analysis of trials involving 739 subjects. If IV aminophylline is given to patients, on oral aminophylline or theophylline, blood levels should be checked on admission. Levels should be checked daily for all patients on aminophylline infusions.

Leukotriene Receptor Antagonists There is no published study of the use of leukotriene receptor antagonists in the management of acute asthma.

New Guidelines for Asthma Management (Acute Asthma) 283 Antibiotics When an infection precipitates an exacerbation of asthma, it is likely to be viral in type. The role of bacterial infection has been overestimated. Routine prescription of antibiotics is not indicated for acute asthma.

Heliox The use of heliox (Helium/oxygen mixture in a ratio of 80:20 or 70:30) in acute adult asthma cannot be recommended on the basis of present evidence.

Intravenous Fluids There are no controlled trials or even observational or cohort studies of differing fluid regimes in acute asthma. Some patients with acute asthma require rehydration and correction of electrolyte imbalance. Hypokalaemia can be caused or exacerbated by β2-agonist and/or steroid treatment must be corrected.

Referral to Intensive Care Indications for admission to intensive care facilities or a high dependency unit include patients requiring ventilatory support and those with severe acute or life threatening asthma who are failing to respond to therapy, as evidenced by: • Deteriorating PEF • Persisting or worsening hypoxia • Hypercapnea • Arterial blood gas analysis showing fail in pH or rising H+ concentration • Exhaustion, feeble respiration • Drowsiness, confusion • Coma or respiratory arrest Not all patients admitted to the Intensive Care Unit (ICU) need ventilation, but those with worsening hypoxia or hypercapnea, drowsiness or unconsciousness and those who have had a respiratory arrest require intermittent positive pressure ventilation. Intubation in such patients is very difficult and should ideally be performed by an anaesthetist or ICU consultant. All patients transferred to intensive care units should be accompanied by a doctor suitably equipped and skilled to intubate if necessary. Non-invasive Ventilation Non-invasive ventilation (NIV) is now well established in the management of ventilatory failure caused by extrapulmonary restrictive conditions and exacerbations of COPD. Hypercapneic respiratory failure developing during the evolution of an acute asthmatic episode is regarded as an indication for urgent admission to the ICU. It is unlikely the NIV would ever replace intubation in these very unstable patients but it has been suggested that this treatment can be used safely and effectively. Future studies might usefully examine its role in the gradually training patient, but at present this treatment cannot be recommended outside randomised controlled trials.

284 Bronchial Asthma

Further Investigation and Monitoring Measurement and recording of PEF 15-30 minutes after starting treatment, and thereafter according to the response is necessary. Measurement and recording of PEF before and after nebulised or inhaled β2-agonist bronchodilator (at least four times daily) throughout the hospital stay and until controlled after discharge is quite helpful. Recording of oxygen saturation by oximetry and maintaining arterial SaO2 >92% is very helpful. Repeat measurements of blood gas tensions within two hours of starting treatment is indicated if: • The initial PaO2 is < 8 kPa unless SaO2 is >92%; or • The initial PaCO2 is normal or raised; or • The patient’s condition deteriorates One should ensure them again if the patient’s condition has not improved by 4-6 hours. • Measure and record the heart rate. • Measure serum potassium and blood concentrations. • Measure the serum theophylline concentration if aminophylline is continued for more than 24 hours (aim at a concentration of 55-110 μmol/l. Asthma Management Protocols and Proformas The use of structured proformas has been shown to facilitate improvements in the process of case in emergency departments and hospital wards and to improve patient outcomes. The use of this type of documentation can assist data collection aimed at determining quality of care and outcomes. Hospital Discharge and Follow-Up

Timing of Dsicharge There is no single physiological parameter that defines absolutely the timing of discharge form an admission with acute asthma. Patients should have clinical signs compatible with home management, be on medical therapy they can continue safely at home. Although diurnal variability of PEF is not always present during an exacerbation, evidence suggests that patients discharged with PEF<75% best or predicted and with diurnal variability >25% are at greater risk of early relapse and readmission.

Patient Education Following discharge from hospital or emergency departments, a proportion of patients reattend emergency departments, with more than 15% re-attending within two weeks. Some repeat attendees need emergency care, but many delay seeking help, and are under-treated and/or under-monitored. Prior to discharge, trained staff should give asthma education. This should include education on inhaler technique and PEF record keeping , with a written PEF and symptom based action plan being provided allowing the patient to adjust their therapy within recommendations. These measures have been shown to reduce morbidity after the exacerbation and reduce relapse rates. There is some experience of a discrete population of patients who inappropriately use emergency departments rather than the primary care services for their asthma care. For these groups there is a role for a trained asthma liaison nurse based in, or associated with the emergency department.

New Guidelines for Asthma Management (Acute Asthma) 285 Follow-Up A careful history should elicit the reasons for the exacerbation and explore possible actions, the patient should take to prevent future emergency presentations. Medication should be altered depending upon the assessment, and the patient provided with an asthma action plan aimed at preventing relapse, optimising treatment and preventing delay in seeking assistance in the future. Follow-up should be arranged prior to discharge with the patient’s general practitioner or asthma nurse within two working days; and with a hospital specialist asthma nurse or respiratory physician at about one month after admission. It is essential that the patient’s primary care practice is informed within 24 hours of discharge from emergency or hospital following an asthma exacerbation treated in hospital. Ideally this communication should be directly with a named individual responsible for asthma care within the practice, by means or fax or e-mail. ACUTE ASTHMA IN CHILDREN AGED OVER 2 YEARS Initial Assessment The details of criteria for assessment of severity of acute asthma attacks in children are: Acute severe Can’t complete sentences in one breath Or too breathless to talk or feed

Life threatening

Silent Chest Cyanosis Poor respiratory effort Hypotension Respiration >30 breaths/min aged>5 yrs Exhaustion >50 breaths/min aged 2-5 yrs Confusion Coma Before children can receive appropriate treatment for acute asthma in any setting, it is essential to assess accurately the severity of their symptoms. The following clinical signs should be recorded: • Pulse rate (increasing tachycardia generally denotes worsening asthma; a fall in heart rate in life threatening asthma is a pre-terminal event). • Respiratory rate and degree of breathlessness (i.e. too breathless to complete sentences in one breath or to feed). • Use of accessory muscles of respiration (best noted by palpation of neck muscles) • Amount of wheesing (which might become biphasic or less apparent with increasing airways obstruction). • Degree of agitation and conscious level (always give calm reassurance). Clinical signs correlate poorly with the severity of airways obstruction. Some children with acute severe asthma do not appear distressed. Objective measurements of PEF and SpO2 are essential. Suitable equipment should be available for use by all health professionals assessing acute asthma in both primary and secondary care settings. Low oxygen saturations after initial bronchodilator treatment selects a more severe group of patients. Intensive inpatient treatment for children with SpO2 <92% on air after initial bronchodilator treatment should be considered. Pulse

>120 in children aged > 5 years >130 in children aged 2-5 years

286 Bronchial Asthma Decisions about admission should be made by trained physicians after repeated assessment of the response to further bronchodilator treatment. A measurement of <50% predicted PEF or FEV1 with poor improvement after initial bronchodilator treatment is predictive of more prolonged asthma attack. An attempt has to be made to measure PEF or FEV1 in all children aged >5 years, taking the best of three measurements; ideally expressed as percentage of personal best for PEF (as detailed in a written action plan) or alternatively as percentage of predicted for PEF or FEV1. Chest X-rays and ABG measurements rarely provide additional useful information and are not routinely indicated. TREATMENT OF ACUTE ASTHMA IN CHILDREN AGED OVER 2 YEARS Emergency units attending to children with acute asthma should have a registered sick children’s nurse available on duty at all times and staff familiar with the specific needs of children. The use of proformas can increase the accuracy of severity assessment. An assessment driven algorithm has been shown to reduce treatment costs and hospital stay. The use of structured care protocols detailing bronchodilator usage, clinical assessment, and specific criteria for safe discharge is recommended. Oxygen Children with life threatening asthma or SpO2 < 92% should receive high flow oxygen via a tight fitting face mask or nasal cannula at sufficient flow rates to achieve normal saturations.

β2-Agonist Bronchodilators Inhaled β2-agonist are the first line treatment for acute asthma. pMDI + spacer is an effective alternative to nebulisers for bronchodilator inhalation to treat mild to moderate asthma. Children receiving β2-agonist via pMDI+ spacer are less likely to have tachycardia and hypoxia than when the same drug is given via a nebuliser. pMDI+ spacer are the preferred option in mild to moderate asthma. Information about implementing evidence-based guidelines using such devices has been published. Children aged < 3 years are likely to require a face mask connected to the mouthpiece of a spacer for successful drug delivery. Inhalers should be actuated into the spacer in individuals puffs and inhaled immediately by tidal breathing. Frequent doses of β2-agonist are safe for the treatment of acute asthma, although children with mild symptoms benefit from lower doses. Drug dosing is to be individualised according to severity and adjust according to the patient’s response. Two to four puffs repeated every 20-30 minutes according to clinical response might be sufficient for mild attacks although up to 10 puffs might be needed for more severe asthma. Children with acute asthma in primary care show have not improved after receiving up to 10 puffs of β2-agonist should be referred to hospital. Further doses of bronchodilator should be given as necessary, whilst awaiting transfer. Treatment of children should be given before they are transported to hospital by ambulance with oxygen and nebulised β2-agonist during the journey. Children with severe or life threatening asthma should be transferred urgently to hospital to receive frequent doses of nebulised β2-agonist (2.5-5 mg albuterol or 5-10 mg terbutaline). Doses can be repeated every 20-30, omits. Continuous nebulised β2-agonist are of no greater benefit than the use of frequent intermittent doses in the same total hourly dosage.

New Guidelines for Asthma Management (Acute Asthma) 287 IV Salbutamol The role of intravenous β2-agonist in addition to nebulised treatment remains unclear. One study has shown that an IV bolus of salbutamol given in addition to near maximal doses of nebulised salbutamol results in clinically significant benefits. The early addition of a bolus dose of intravenous salbutamol (15 μg/kg) can be an effective adjunct to treatment in severe cases. Continuous intravenous infusion should be considered when there is uncertainty about reliable inhalation or for severe refractory asthma. Doses above 1-2 μg/kg/min (200 μg/ml solution) should be given in a Paediatric intensive Care Unit (PICU) setting (up to 5 μg/kg/min) with regular monitoring of electrolytes. Steroid Therapy

Steroid Tablets The early use of steroids for acute asthma can reduce the need for hospital admission and prevent a relapse in symptoms after initial presentation. Benefits can be apparent within three to four hours. Prednisolone is to be given early in the treatment of acute asthma attacks. A soluble preparation dissolved in a spoonful of water is preferable in those unable to swallow tablets. The dose is 20 mg for children 2-5 years old and 30-40 mg for children > 5 years. Oral and intravenous steroids are of similar efficacy. Intravenous hydrocortisone (4 mg/kg repeated four hourly) should be reserved for severely affected children who are unable to retain oral medication. Larger doses do not appear to offer a therapeutic advantage for the majority of children. There is no need to taper the dose of steroid tablets at the end of treatment. A dose of 20 mg prednisolone for children aged 2-5 years and a dose of 30-40 mg for children > 5 years is appropriate. Those already receiving maintenance steroid tablets should receive 2 mg/kg prednisolone up to a maximum dose of 60 mg. The dose of prednisolone in children who vomit may be repeated and intravenous steroids in those who are unable to retain orally, ingested medication should be considered. Treatment for up to three days is usually sufficient but the length of course should be tailored to the number of days necessary to bring about recovery.

Inhaled Steroids There is insufficient evidence to support the use of inhaled steroids as alternative or additional treatment to steroid tablets for acute asthma. One need not initiate inhaled steroids in preference to steroid tablets to treat acute childhood asthma. Children with chronic asthma not receiving regular preventive treatment will benefit from initiating inhaled steroids as part of their long-term management. There is no evidence that increasing the dose of inhaled steroids is effective in treating acute symptoms, but it is good practice for children already receiving inhaled steroids to continue with their usual maintenance doses.

Ipratropium Bromide There is good evidence for the safety and efficacy of frequent doses of ipratropium bromide used in addition to β2-agonist for the first two hours of a severe asthma attack. Benefits are more apparent in the most severe patients. If symptoms are refractory to initial β2-agonist treatment, add ipratropium bromide (250 mg/dose mixed with the nebulised β2-agonist

288 Bronchial Asthma solution). Frequent doses up to every 20-30 minutes (250 μg/dose mixed with the β2-agonist solution in the same nebuliser) should be used early. The dose frequency should be reduced as clinical improvement occurs. Repeated doses of ipratropium bromide should be given early to treat children poorly responsive to β2-agonist. Children with continuing severe asthma despite frequent nebulised β2-agonist and ipratropium bromide and those with life-threatening features need urgent review by a specialist with a view to transfer to a High Dependency Unit or PICU.

IV Amniophylline There is no evidence that aminophylline is of benefit for mild to moderate asthma and side effects are common and troublesome. However, one well conducted study has shown evidence for benefit in severe acute asthma unresponsive to multiple doses of β2-agonist and steroids. Aminophylline is not recommended in children with mild to moderate acute asthma. However, one may consider aminophylline in a High Dependency Unit or PICU setting for children with severe or life-threatening bronchospasm unresponsive to maximal doses of bronchodilators and steroid tablets. A 5 mg/kg loading dose should be given over 20 minutes with ECG monitoring (omit in those receiving maintenance oral theophyllines) followed by a continuous infusion at 1 mg/kg/hour. Estimation of serum theophylline levels in patients already receiving oral treatment and in those receiving prolonged treatment will be necessary. Other Therapies There is no evidence to support the use of heliox or leukotriene receptor antagonists for the treatment of acute asthma in childhood. There is insufficient evidence to support or refute the role of antibiotics in acute asthma, but the majority of acute asthma attacks are triggered by viral infection. Antibiotics are not to be given routinely in the management of acute childhood asthma.

Intravenous Fluids Children with prolonged severe asthma not tolerating, oral fluids will require intravenous hydration. Two-third of the child’s maintenance requirement should be given because of the possibility of inappropriate antidiuretic hormone secretion. Serum electrolytes should be measured and hypokalamia corrected, if detected. ECG monitoring is mandatory for all intravenous treatments.

IV Magnesium Sulphate Intravenous magnesium sulphate is a safe treatment for acute asthma although its place in management is not yet established. Doses of up to 40 mg/kg/day (maximum 2g) by slow infusion has been used. Studies of efficacy for severe childhood asthma unresponsive to more conventional therapies have been inconsistent in providing evidence of benefit.

Further Investigation and Monitoring Children can be discharged when stable on 3-4 hourly inhaled bronchodilators that can be continued at home. PEF and/or FEV1 should be >75% of best or predicted and SpO2>94%.

New Guidelines for Asthma Management (Acute Asthma) 289 Adult studies show that “optimal care” comprising self-monitoring, regular review and a written asthma action plan can improve outcomes. Acute asthma attacks should be considered a failure of preventive therapy and thought should be given about how to help families avoid further severe episodes. Discharge plans should address the following: • Check inhaler technique • Consider the need for regular inhaled steroids • Provide a written asthma action plan for subsequent asthma with clear instructions about the use of bronchodilators, seeking urgent medical attention in the event of worsening symptoms and, if appropriate, starting a course of oral steroids • Arrange follow-up by a General Practitioner within one week • Arrange follow-up in a paediatric asthma clinic within one to two months. ASSESSMENT OF ACUTE ASTHMA IN CHILDREN AGED LESS THAN 2 YEARS The assessment of acute asthma in early childhood can be difficult. Intermittent wheesing attacks are usually due to viral infection and the response to asthma medication is inconsistent. Prematurity and low birth weight are risk factors for recurrent wheesing. The differential diagnosis of symptoms includes aspiration pneumonitis, pneumonia, bronchiolitis, tracheomalacia, and complications of underlying conditions such as congenital anomalies and cystic fibrosis. These guidelines are intended for those who are thought to have asthma causing acute wheeze. They should not be used as a guide for treating acute bronchiolitis. TREATMENT OF ACUTE ASTHMA IN CHILDREN AGED < 2 YEARS β2-Agonist Bronchodilators A trial of bronchodilator therapy should be considered when symptoms are of concern. If inhalers have been successfully administered but there is no response, review the diagnosis and consider the use of other treatment options. Oral β2-agonists have not been shown to affect symptom score or length of hospital stay for acute asthma in infancy when compared to placebo. Oral β2-agonists are not recommended for acute asthma in infants. Inhaled β2-agonists are the treatment of choice for the initial treatment of acute asthma. Close fitting face masks are essential for optimal drug delivery. The dose received is increased if the child is breathing appropriately and not taking large gasps because of distress and screaming. There is good evidence that pMD+ spacer is as effective as, if not better than, nebulisers for treating mild to moderate asthma in children aged <2 years. For mild to moderate acute asthma, a pMDI+ spacer is the optimal drug delivery device. Whilst β2-agonists offer marginal benefits to children aged < 2 years with acute wheeze, there is little evidence for an impact on the need for hospital admission or length of hospital stay. Steroid Therapy Steroid tablets in conjunction with β2-agonists have been shown to reduce hospital admission rates when used in the emergency department. Steroid tablets have also been shown to reduce the length of hospital stay. Steroid tablets are to be considered in infants early in the management of moderate to severe episodes of acute asthma in the hospital setting. One

290 Bronchial Asthma study has shown similar benefits when comparing oral and nebulised steroids for acute asthma. Steroid tablet therapy (10 mg of soluble prednisolone for up to three days) is the preferred steroid preparation for use in this age group. Ipratropium Bromide The addition of ipratropium bromide to β2-agonists for acute severe asthma may lead to some improvement in clinical symptoms and reduce the need for more intensive treatment. It does not reduce the length of hospital stay either in combination with β2-agonists or in comparison with placebo. Inhaled ipratropium bromide in combination with an inhaled β2-agonist may be considered for more severe symptoms. Further Investigation and Monitoring Many children with recurrent episodes of viral-induced wheesing in infancy do not go on to have chronic atopic asthma. The majority do not require treatment with regular inhaled steroids. Parents should be advised about the relationship between cigarette smoke exposure and wheezy illnesses. Referral to suitable agencies should be offered to those who wish to give up smoking. Parents of wheezy infants should receive appropriate discharge plans along similar lines to those given for older children. Management of acute severe asthma in adults and children is shown in the following diagrams. Management of acute severe asthma in adults in general practice Many deaths from asthma are preventable, but delay can be fatal. Factors leading to poor outcome include: • Doctors failing to assess severity by objective measurement • Patients or relatives failing to appreciate severity • Under use of corticosteroids Regard each emergency asthma consultation as for acute severe asthma until it is shown to be otherwise.

Assess and record: • Peak expiratory flow (PEF) • Symptoms and response to self treatment • Heart and respiratory rates • Oxygen saturation by pulse oxymetry, if available Patients with severe or life threatening attacks may not be distressed and may not have all the abnormalities listed below. The presence of any should alert the doctor.

Moderate asthma ↓

Acute Severe Asthma ↓

PEF > 50% best or predicted

PEF 33-50% best or predicted

Life Threatening Asthma ↓

Initial Assessment PEF < 33% best or predicted

Further Assessment • Speech normal • Respiration , 25/min • Pulse < 110/min

↓

• Can’t complete sentences • Respiration > 25/min • Pulse > 110/min

↓

• SpO2 < 92% • Silent chest, cyanosis, or feeble respiratory effort • Bradycardia, dysrrhythmia, or hypotension • Exhaustion, confusion or coma ↓

Contd...

New Guidelines for Asthma Management (Acute Asthma) 291 Contd... Management Treat at home Assess response to treatment ↓

Consider admission

Arrange immediate ADMISSION

↓

↓

Treatment • High-dose β2-bronchodilator: • ideally via oxygen-driven nebulizer (salbutamol 5 mg or terbutaline 10mg) • Or via spacer or air-driven nebulizer (1 puff 10-20 times) If PEF > 50-70% predicted: • Give prednisolone 40-50 mg • Continue or step up usual treatment If good response to first nebulised treatment (symptoms improved, respiration and pulse setting, and PEF > 50%) continue or step up usual treatment and continue prednisolone

• Oxygen 40-60% if available • High-dose β2-bronchodilator: • ideally via oxygen-driven nebulizer (salbutamol 5 mg or terbutaline 10mg) • Or via spacer (1 puff β2-agonist via a large volume spacer and repeat 10-20 times) or airdriven nebulizer • Prednisolone 40-50 mg or IV hydrocortisone 100 mg • If no response in acute severe asthma, Admit

↓ ↓ Admit to hospital if any: If admitted patient to hospital: • Life threatening features • Stay with patient till ambulance • Features of acute severe arrives asthma present after initial • Send written assessment and treatment referral details to hospital • Previous near-fatal asthma • Give high dose β2-bronchoLower threshold for admission if: dilator via oxygen-driven • Afternoon or evening attack, nebulizer in ambulance • Recent nocturnal symptoms or hospital admission • Previous severe attacks • Patient unable to assess own condition • Concern over social circumstances

• Oxygen 40-60% • Prednisolone 40-50 mg or IV hydrocortisone 100 mg immediately • High-dose β2-bronchodilator and ipratropium: • Ideally via oxygendriven nebulizer (salbutamol 5 mg or terbutaline 10 mg and ipratropium 0.5 mg) • Or via spacer (1 puff β2-agonist via a large volume spacer and repeat 10-20 times) or air-driven nebulizer ↓ Follow up after treatment or discharge from hospital: • General Practitioner review within 48 hr • Monitor symptoms and PEF • Check inhaler technique • Written asthma action plan • Modify treatment according to guidelines for chronic persistent asthma • Address potentially preventable contributors to admission

292 Bronchial Asthma Management of Acute Severe Asthma in Adults in Emergency Room Time

Measure PEFR and arterial saturation PEFR 33-75% best or predicted Moderate-Severe Features of severe asthma • PEF<50% best or predicted • RR > 25/min • Pulse > 110/min • Can not complete sentence in one breath

PEFR > 75% predicted Mild

5 min

15-30 min

Give usual bronchodilator

Clinically stable, PEF > 75%

Patient recovering and PEF > 75% 60 min

Give 5 mg salbutamol by oxygen-driven nebulizer if any life threatening feature

Clinically stable, PEF > 75%

No life threatening feature PEF 5075%

• • • •

Obtain senior ICU help now

Life threatening features OR PEF < 50%

No sign of severe asthma and PEF 50-75%

Sign of severe asthma or PEF < 50%

120 min

Immediate Management • High concentration O2 (60%) • Salbutamol 5 mg +ipratropium 0.5 mg by oxygen-driven nebulizer • Prednisolone 40-50 mg orally or IV hydrocortisone, 100 mg Monitor ABG. Markers of severity: • Normal or ↑ PaCO2 (35 mmHg) • Severe hypoxia (PaO2 < 60 mHg) • Low pH

Observe Monitor SpO2, RR and HR

Patient stable and PEF > 50%

PEFR < 33% best or predicted or any lifethreatening feature SpO2 < 92% Silent chest, Cyanosis, poor respiratory effort Bradycardia, arrhythmia, hypotension Exhustion, confusion, coma

Signs of severe asthma or PEF < 50%

Potential Discharge: Extended observation if β-agonist before presentation; Prednisolone 40-50 mg for 5 days; ensure inhaled drugs and technique; arrange GP follow-up with detailed instructions; referral in appropriate cases

• Give/repeat as above after 15 minutes • Continuous salbutamol nebulizer 5-10 mg/hr • Consider IV magnesium sulphate 1-2 gm/ 20 min. • Fluid/electrolyte balance monitoring (specifically K+) • Chest X-ray ADMIT Patient should be accompanied by a nurse or doctor at all times

Alternate Treatments in Asthma 293

19 Alternate Treatments in Asthma Standard asthma therapy, as defined by various management guidelines includes oral and inhaled corticosteroids, leukotriene antagonists, short-acting and long-acting β-agonists, cromolyn, theophyllines, and nedocromil. Although these agents are generally successful in controlling asthma symptoms, a small but significant number of patients will continue with persistent symptoms, frequent exacerbations, and no improvement in objective pulmonary function parameters despite maximum standard therapy. The long-term use of oral and high-dose inhaled corticosteroids is often associated with significant side effects. Thus there is need for alternate agents that are effective in the treatment of asthma. Alternate agents those have been evaluated in prospective randomized trials or have novel mechanisms of action are shown in Table 19.1.1-4 Table 19.1: Alternate agents for bronchial asthma Methotrexate Azathioprine Gold Hydroxychloroquine Troleandomycin Cyclosporine IVIG Inhaled heparin Inhaled furosemide Dapsone Anti-IgE and soluble interleukin (IL)-4 receptor therapy

Methotrexate

Mechanism of Action Methotrexate is a folate antagonist. It has anti-inflammatory properties at low doses. Therefore, it is widely used in a variety of autoimmune and inflammatory diseases, including severe steroid-dependent asthma. A number of potential reasons for its effectiveness have been proposed, the mechanism of action of methotrexate in asthma remains unclear. The drug inhibits leukotriene B4-mediated and leukotriene C5a-mediated neutrophil chemotaxis in vitro5 although inflammatory cell numbers in vivo appear to be unaltered during treatment.6 It affects function of many cytokines. The drug inhibits the expression of Ia, a

294 Bronchial Asthma marker of macrophage activation and monocyte IL-1 production, IL-6, IL-8, and histamine release, and platelet-activating factor-induced eosinophil chemotaxis.6-8 The inhibition of purine metabolism by methotrexate diminishes lymphocyte proliferation and antibody formation6 and increases in CD8+ T-suppressor cells and suppression of B-cell differentiation have been observed. No significant interference with steroid metabolism has been noted.9 Methotrexate may enhance the sensitivity of peripheral blood monocytes to glucocorticoids in cases of steroid-refractory asthma.10 A number of randomized trials11-21 have been made using methotrexate in bronchial asthma and three meta-analyses have been performed since then with mixed results.22-24 Of the 11 prospective randomized trials, 10 evaluated the use of oral or IM low-dose methotrexate vs placebo in steroid-dependent asthma patients using either parallel or crossover design. A three-arm study compared methotrexate, 15 mg weekly orally, with a single dose of triamcinolone, 360 mg IM, or placebo.20 Most trials required that patients had received a minimum of 12 months of long-term corticosteroid therapy to be eligible for enrolment (range, 5 months to 28 years). The majority received oral methotrexate, 15 mg weekly, and many used a variety of run-in periods to maximize asthma therapy prior to starting treatment. The duration of methotrexate therapy ranged from 12 to 24 weeks, with no further reported long-term follow-up. Most studies reported significant reductions in oral steroid use in their placebo groups, which was attributed to the close-interval followup and the education that patients received during enrolment. Others reported a statistically significant reduction in corticosteroid dose using methotrexate, some demonstrating reduction of mean oral corticosteroid use up to 50%.12 Other trials, however, could not demonstrate a significant difference in corticosteroid reduction between the methotrexate and placebo groups. Small patient numbers further limits the interpretation. Many trials had significant dropout rates. No statistically significant changes in peak flow, spirometry, or mean values for the dose of methacholine provoking a 20% fall in FEV1 were observed in patients taking methotrexate neither reduction in steroid-related side effects were reported.12-21 Although responses to methotrexate have been reported after 3 months in patients with immunologic diseases such as rheumatoid arthritis, treatment for 12 weeks may be insufficient to demonstrate an adequate therapeutic response in patients with asthma. Some studies reported statistically significant reductions in the baseline prednisone dose, with over half were weaned off all steroid therapy.25, 26 Common side effects of methotrexate include liver function test abnormalities, GI symptoms (including abdominal pain, nausea, and diarrhea), oral ulcers and stomatitis, constitutional symptoms (including fatigue and decreased concentration), headache, rash, and less common ones like opportunistic infections (Pneumocystis carinii pneumonia), increased incidence of bacterial pneumonia, disseminated varicella zoster. However, side effects were transient and reversible and only minimal from the administration of low-dose methotrexate. No bone marrow toxicity was observed at the dosages used, and follow-up was too short to address issues of potential hepatic fibrosis. Methotrexate competes with the hepatic metabolism of theophylline, with an average decrease in theophylline clearance of 19% in one case series. Methotrexate is well-known to cause a variety of pulmonary manifestations, including drug-induced hypersensitivity reaction, chronic pneumonitis and fibrosis, bronchiolitis

Alternate Treatments in Asthma 295 obliterans with organizing pneumonia, noncardiogenic pulmonary edema, and bronchospasm.27 Troleandomycin Troleandomycin (TAO) is a macrolide antibiotic and was first described as a treatment for steroid-dependent asthma in 197428 The drug is believed to have a synergistic effect when administered with oral corticosteroids. In vitro data using its parent compound, oleandomycin, at a concentration of 5 µg/mL demonstrated a 44% reduction in the concentration of methylprednisolone that was required to inhibit human lymphocyte blast transformation by 50% (p < 0.005).29 It is believed that Troleandomycin alters corticosteroid bioavailability by decreasing hepatic metabolism and excretion.30-32 Subjective patient improvement has not been correlated with evidence of infection using sputum culture, suggesting that a direct antimicrobial effect is less likely.28,32 Clinical efficacy data on troleandomycin showed improvement in clinical symptoms and/or a reduction in corticosteroid dosage in when used as 14 mg/kg/d TAO (maximum dose, 1 g.33-35 These benefits, however, were less convincingly demonstrated in another trial of TAO efficacy.36 The results were limited by significant patient The authors concluded that patients who had been randomized to TAO experienced no advantage and appeared to develop greater steroid-related side effects than did placebo subjects. Steroid-related side effects are common with the use of TAO, especially in earlier trials when patients were given doses of 1 g daily.33,34 Cushingoid features, weight-gain, fluid retention, and glucose intolerance were the most common findings. GI distress and hepatotoxicity, ranging from transient liver enzyme abnormalities37 to prolonged cholestasis38 and jaundice39 have been reported, predominantly at higher doses. The doses of theophylline and other medications with hepatic metabolism must be adjusted to avoid toxicity. Decreased IgG levels and one case of varicella zoster has been reported with its use. Gold Gold is an immunomodulatory agent that has been used commonly for the treatment of a variety of inflammatory and autoimmune conditions. Although the complete mechanism of anti-inflammatory activity is unknown, gold has been demonstrated to decrease neutrophil and macrophage phagocytosis, and lymphocyte reactivity to antigenic stimulation.40 It also inhibits antibody production and lysosomal enzyme release from phagocytic leukocytes.41 Gold inactivates C1 (complement), decreases prostaglandin and leukotriene production in vitro, and inhibits IgE-mediated release of histamine from isolated basophils and lung mast cells.40-44 The enhancement of eosinophil survival with IL-5 is inhibited by the presence of gold.45 The beneficial effects of gold in the treatment of asthma were reported as early as 1932. Improvements have been reported in bronchial reactivity and oral corticosteroid requirements have been decreased46-48 oral or parenteral gold treatment was used for 12 to 22 weeks. There have been three prospective randomized studies examining the efficacy of gold. Other studies have reported benefit. The Auranofin Multicenter Drug Trial49 has been the largest clinical trial to examine the efficacy of oral gold. After a 4-week observation period 275 patients with daily oral prednisone requirements of ≥ 10 mg mg were randomized

296 Bronchial Asthma to auranofin, 3 mg twice daily, or placebo for a period of 6 months. The results were limited by a significant patient dropout rate (auranofin group, 40%; placebo group, 46%) due to adverse effects, protocol violations, and voluntary withdrawals, and no intention-to-treat analysis was performed. No significant differences were found in symptoms or objective measurements of pulmonary function, although more patients treated with gold were able to reduce their daily oral corticosteroid dose by ≥ 50% compared to those receiving placebo (60% vs 32%, respectively; p < 0.001). Statistically significant reductions in serum IgE level (reduction, 44.63 IU/mL; p = 0.003) were also observed in the auranofin group. Gold has been associated with a variety of side effects, including GI upset and diarrhea, pruritic rash, cytopenias, oral ulcerations, proteinuria, and frank nephrotic syndrome. Nearly 40% of patients in the prospective randomized trials that were detailed earlier experienced.49-51 All side effects were self-limited with discontinuation or reduction of therapy. Some experts have argued that the relative lack of severe side effects with gold therapy, compared to methotrexate therapy, make it a preferable agent for the treatment of severe, glucocorticoid-dependent asthma, but no clear consensus exists on the issue. Cyclosporine Cyclosporine is an immunomodulatory and anti-inflammatory drug and is a fungal metabolite that is commonly used in organ transplantation. Cyclosporine binds to cyclophilin, inhibiting cytokine messenger RNA transcription and CD4+ T-cell activation.52 The drug also reduces the synthesis and release of inflammatory mediators from mast cells and basophils, and it decreases B-cell IgE synthesis and release.53 Cyclosporine has been demonstrated to reduce the macrophage synthesis of IL-1, tumor necrosis factor, superoxide, and hydrogen peroxide, and has been shown to decrease neutrophil chemotaxis and serum soluble IL-2 receptor concentrations.40,54 The production of granulocyte macrophage colony-stimulating factor (GMCSF) and IL-5 from stimulated monocytes is also reduced with drug therapy, inhibiting eosinophil proliferation and survival activity.55,56 Cyclosporine has been shown to block the late asthmatic reaction and to inhibit the production of eosinophil-related cytokines after allergen challenge.52,57 Statistically significant improvement in airway hyperreactivity has been observed in steroid-dependent asthma patients after 12 weeks of therapy with cyclosporine. Three prospective randomized trials that have examined the effect of cyclosporine in asthma patients, which have shown a 12% increase in morning peak expiratory flow rates (PEFRs) (p < 0.004), a 17.6% increase in FEV1 (p < 0.001), and a 48% reduction in exacerbations requiring increased steroid dosing (p < 0.02) compared to those receiving placebo. 58 In another study treatment with cyclosporine (initial dose, 5 mg/kg/d) for 36 weeks in resulted in a statistically significant reduction in the median daily prednisolone dosage (62% vs 25%, respectively; p = 0.043) along with improvements in PEFR.59 However, another study with a longer follow-up period demonstrated no statistically significant effects of cyclosporine using the objective markers of pulmonary function and steroid-sparing effects.60 The side effects of cyclosporine are dose-dependent nephrotoxicity, tremor, hirsutism, hypertension, gum hyperplasia, and infectious complications. The majority of these side effects are not observed in the low doses that were used in the trial listed above. Several patients experience hypertrichosis and a worsening of pre-existing hypertension that may result in the discontinuation of therapy. Treatment-limited neuropathy also has been observed.

Alternate Treatments in Asthma 297 IVIG IVIG has been shown to reduce immediate skin test reactivity to allergens, to decrease total serum IgE levels, to inhibit lymphocyte activation and the production of IL-2 and IL-4 in vivo, and to suppress cytokine-dependent lymphocyte proliferation in vitro.61-63 IVIG also has been shown to increase lymphocyte sensitivity to the suppressive effects of dexamethasone, even in patients with prior documented steroid resistance.64 Monthly administration of high-dose IVIG resulted in a three-fold reduction in the oral glucocorticoid dose, a reduction in symptoms, and in improved PEFRs with decreases in serum total IgE levels and skin test reactivity to allergens.61 These steroid-sparing effects are observed both in adult and pediatric asthma patients.65,66 Other investigators have observed after 3 months of therapy a reduction of oral corticosteroid doses67, others failed to identify a significant difference in steroid dose reductions, pulmonary function testing results, or the number of clinical exacerbations among patients in the IVIG groups and the placebo group.68 The minor adverse effects of therapy include headache and nausea, which generally occur with the infusion and are self-limiting. Although current commercial preparations should have no risk of transmission of viral hepatitis, there remains the remote possibility of IVIG transmission of a yet-undefined viral illness. More serious reactions can be associated with patients who have IgA deficiency, and IVIG administration should be avoided in this population. It also has been rarely associated with interstitial nephritis and aseptic meningitis, as was mentioned above.68 Heparin Heparin is an endogenous glycosaminoglycan and is extensively used as an anticoagulant. Its flexible structure and high anionic charge allow heparin to interact with a variety of molecules in vivo and it is involved in airway inflammation. Elevated levels of heparin-like anticoagulants have been demonstrated in atopic asthma patient and have been induced in some patients after antigen inhalational challenge leading to further interest in investigating the role of heparin in this disease.69-71 Heparin binds and inhibits a variety of cytotoxic and inflammatory mediators, including eosinophilic cation protein and peroxidase.72 It also increases the association rate of secretory leukocyte protease inhibitor with human neutrophil elastase and cathepsin G, reducing their activity.73 Heparin has been associated with the inhibition of lymphocyte activation74, neutrophil chemotaxis75, smooth muscle growth, and vascular tone.76 It also reduces complement activation.77 It has been suggested78 that the sulfate groups on the heparin molecule may attenuate antigen-induced bronchoconstriction via the inhibition of inositol 1,4,5 triphosphate-dependent, IgE-mediated mast cell histamine release. Perhaps heparin is bound to cell surface proteins in the airway epithelium may modulate smooth muscle tone either by inhibiting inositol 1,4,5 triphosphate-mediated calcium release or by preventing C-fiber stimulation, decreasing bronchial responsiveness, and reducing airway hyperreactivity.69 Subjective improvements in asthma symptoms have been reported with the use of IV heparin.79-81 Inhaled heparin therapy administered at a maximum dose of 80,000 U preserved specific airway conductance (sGaw) better than did 20 mg inhaled cromolyn or placebo following exercise82 but not following histamine challengen.83-85 Conflicting data exist

298 Bronchial Asthma regarding the effects of heparin pretreatment on the early asthmatic response to inhaled allergen challenge (dust mite extract), with mild but statistically significant protective effects in FEV1 seen 7 to 8 h postchallenge (p < 0.05). Trials examining the effects of inhaled heparin on bronchoprovocation using methacholine also have yielded mixed results, with variable effects on the provocative concentration of methacholine causing a 20% fall in FEV1, but with no significant effects on FEV, airway resistance, or sGaw postchallenge. Two cases of corticosteroid-resistant asthma patients who responded to 100,000 U inhaled heparin during asthma exacerbations have been reported. No adverse effects associated with the use of inhaled heparin at the doses described above have been reported. Heparin inhalation alone has not been demonstrated to affect baseline FEV1 despite the frequent use of isotonic saline solution as its carrier. No bleeding complications have been reported, and no significant changes in serum partial prothrombin time or anti-factor Xa activity have been observed with unfractionated and low-molecularweight heparin, respectively. Furosemide and Other Diuretics Changes in water concentration and surface osmolarity of the airway epithelium are important contributing factors to exercise-induced bronchospasm that prompted the first use of inhaled frusemide (ie, furosemide) as a potential treatment for asthma.86 Furosemide is a loop diuretic that acts in the kidney by inhibiting the Na+/K+/2 Cl- cotransporter in the ascending limb of the loop of Henle. Despite early speculations about the effects of furosemide on airway water concentration, its mechanism of action does not appear to be related to the diuretic effects of the drug. Furosemide is not effective against asthma when administered orally at the usual diuretic doses and must be inhaled at relatively high doses (i.e. 20 to 40 mg) for significant antiasthma effects.86 Furosemide attenuates bronchoconstriction by reducing apical chloride channel activity and by decreasing the potential difference and short-circuit current in airway epithelial cells.87,88 The drug’s inhibition of chloride transport also appears to inhibit the release of eosinophil mediators89 and may be related to the modulatory effects observed on presynaptic neuropeptide release from noncholinergic, nonadrenergic sensory nerves and cholinergic neural responses in animal models.90 Furosemide acts by inhibiting the release of histamine and leukotrienes from passively sensitized human lung.91 Conflicting data exist regarding the effects of furosemide on airway prostaglandins. Furosemide is well-known to enhance renal synthesis of prostaglandin E292 and the stimulation of inhibitory prostaglandins from the airway epithelium may be the cause of its protective role in some challenges.93 Further, it is suggested that the drug inhibits the production of bronchoconstricting prostaglandins.94 Effects of cyclooxygenase inhibitors on the activity of furosemide have been mixed95,96 reinforcing the lack of clarity in this area. Other postulated mechanisms of action based on animal data include the reduction of airway temperature variation through local airway vasodilation following dry air challenge97 and the enhancement of paracellular water movement in response to an osmotic stimulus.98 However, other data have shown that furosemide has little99 or no effect100 on mucociliary clearance, an indirect measure of the rate of recovery of periciliary fluid volume after isocapnic hyperventilation. Furosemide appears to attenuate the effects of indirect bronchoconstrictor mechanisms, including early and late responses to allergen101 and the effects of exercise86 distilled water102 adenosine 5'-monophosphate103 sodium metabisulfite104,105, aspirin105 and propranolol.106

Alternate Treatments in Asthma 299 Bronchoconstrictors that work directly on airway smooth muscle like histamine 103 methacholine104,107 and prostaglandin F2α108 are not affected by furosemide. The similarities between the protective spectrum of furosemide and cromolyn have led to speculation about a common mechanism of action, although cromolyn has been shown to have a statistically greater protective effect on airway reactivity when equal doses of the two inhaled drugs were compared.109 Inhaled furosemide has been shown to inhibit the cough response induced by the inhalation of low-chloride-content solutions110 in healthy volunteers, but not in asthmatic patients.111 The presumed effect of the drug is due to changing the local concentration of chloride ions in the vicinity of myelinated afferent nerve fibers that are acting as cough receptors at the airway surface.112 A significant steroid-sparing effect using a combination of lysine acetylsalicylate (LASA) and furosemide is observedin severe steroid-dependent asthma for 10 to 28 weeks.113-115 Effect of inhaled furosemide in acute asthma exacerbations showed mixed results.115 Serial FEV1 measurements showed a mean increase of 14.9 ± 10.5% in FEV1 with furosemide therapy alone (difference not significant) compared to an increase of 42.9 ± 15.2% with metaproterenol therapy (p = 0.003) and no additive benefit with combination therapy.116 Others have reported similar results.117 Others reported statistically significant improvements in PEFRs (p < 0.05) in acute asthma exacerbations, FEV1 had increased by > 2 SDs compared to those receiving placebo, although no differences between the good responders and the poor responders could be identified.118 A follow-up case series119 reported clinical improvement in 9 of 11 patients with severe asthma exacerbations that were refractory to conventional medical therapy with the addition of inhaled furosemide. Furosemide can cause allergic reactions due to its incorporated sulfa moiety and has been reported to cause ototoxicity with high-dose rapid IV infusion. None of the clinical trials using inhaled furosemide have reported significant side effects, and no diuretic effect has been reported. CONCLUSION Standard anti-asthma therapy is highly successful in most patients. Therefore, the use of alternate agents for treating asthma should be reserved for the steroid-resistant asthma patient or for the steroid-dependent asthma patient in whom a thorough evaluation to exclude other diagnoses and exacerbating factors has been performed. Of all the agents that have been examined in prospective randomized trials, methotrexate and gold appear to be the most important in terms of steroid-sparing and side effect. Methotrexate has been shown to reduce oral corticosteroid requirements modestly in steroiddependent asthma patients in some short-term, randomized, clinical trials, although its mechanism of action remains unclear and the data examining this issue remain limited and conflicting. Two case series have suggested that long-term therapy with methotrexate may be required to demonstrate objective benefit. Gold also has significant steroid-sparing effects in patients with high daily corticosteroid requirements, but this conclusion must be made with caution due to the confounding effects of the high dropout rate in the Auranofin Multicenter Drug Trial. Side effects with gold therapy are common but generally are minor and self-limited with dose reduction or the cessation of therapy. Until further data from controlled clinical trials are available, however, it is unclear whether methotrexate or gold

300 Bronchial Asthma offers a significant risk/benefit ratio compared to close follow-up, intensive standard therapy, and patient education alone. Cyclosporine offers an attractive mechanism of action and reasonable efficacy data in two of three small prospective randomized trials, but it also carries with it a significant side effect profile. Because of the risk of permanent renal damage and the need for intensive monitoring, further studies with larger prospective randomized trials should be performed before cyclosporine is considered as an appropriate alternate agent for asthma therapy. Although troleandomycin (TAO) appears to be an effective methylprednisolone dosereducing agent, the drug has not been shown to significantly improve asthma control or to reduce steroid-related side effects, and it was associated with an increased rate of osteoporosis and hypercholesterolemia in one clinical trial. Data demonstrating the beneficial effects of IVIG also are limited, while cost, convenience, and a possible risk of aseptic meningitis are all potential detractors to this therapy. At this time, the use of TAO appears to offer no advantage over conventional asthma therapy and patient education, and therapy with IVIG should be limited to clinical trials. Although its postulated mechanism of action and effects on exercise-induced bronchospasm are intriguing, the majority of clinical data currently available on inhaled heparin therapy is limited to single-blind trials involving < 20 patients. The enoxaparin data suggest that the accepted dosing regimens may be too low to demonstrate a full therapeutic effect, and larger prospective placebo-controlled trials are needed to determine the efficacy, dose, and patient population that may benefit from this therapy. Furosemide and other loop diuretics appear to attenuate a variety of indirect bronchoconstrictor mechanisms, although their exact mechanism of action remains unknown. The fact that loop diuretics seem to have little direct effect on bronchial smooth muscle is a likely explanation for their lack of effect as a single agent or in combination with β-agonists alone in patients with asthma exacerbations. The current data and the lack of significant side effects make them potential steroid-sparing agents in the long-term treatment of mild persistentto-severe asthma. The current clinical data are limited, however, and larger randomized trials are necessary to confirm the efficacy of loop diuretics and their role in the treatment of asthma. REFERENCES 1. Niven AS, Argyros G. Alternate treatment in asthma. Chest 2003;123:1254-65. 2. Boushey HA. Experiences with monoclonal antibody therapy for allergic asthma. J Allergy Clin Immunol 2001;108:S77-S83. 3. Oettgen HC, Geha RS. IgE regulation and roles in asthma pathogenesis. J Allergy Clin Immunol 2001;107:429-40. 4. Mohapatra SS, San Juan HS. Novel immunotherapeutic approaches for the treatment of allergic diseases. Immunol Allergy Clin North Am 2000;20:625-42. 5. Suarez CR, Pickett WC, Bell DH, et al. Effect of low dose methotrexate on neutrophil chemotaxis induced by leukotriene B4 and complement C5a. J Rheumatol 1987;14:9-11. 6. Cronstein, BN Molecular mechanism of methotrexate action in inflammation. Inflammation 1992;16:411-423. 7. Lynch JP, McCune, WJ Immunosuppressive and cytotoxic pharmacotherapy for pulmonary disorders. Am J Respir Crit Care Med 1997;155:395-420. 8. Tsai JJ, Wang TJ, Wang SR. The inhibitory effect of methotrexate on PAF-induced neutrophil and eosinophil locomotion in asthmatic patients. Asian Pac J Allergy Immunol 1994;12:65-71

Alternate Treatments in Asthma 301 9. Glynn-Barmhart, AM Erzurum, SC Leff, JA, et al. Pharmacokinetics of low-dose methotrexate in adult asthmatics. Pharmacotherapy 1992;12:383-390. 10. Vrugt B, Wilson S, Bron A, et al. Low-dose methotrexate treatment in severe glucocorticoiddependent asthma: effect on mucosal inflammation and in vitro sensitivity to glucocorticoids of mitogen-induced T-cell proliferation. Eur Respir J 2000;15:478-85. 11. Mullarkey MF, Blumenstein BA, Andrade WP, et al. Methotrexate in the treatment of corticosteroid dependent asthma. N Engl J Med 1988;318,603-07. 12. Shiner RJ, Nunn AJ, Chung KF, et al. Randomized, double-blind, placebo controlled trial of methotrexate in steroid dependent asthma. Lancet 1990;336:137-40. 13. Erzurum SC, Leff JA, Cochran JE, et al. Lack of benefit of methotrexate in severe, steroiddependent asthma. Ann Intern Med 1991;114:353-60. 14. Dyer PD, Vaughan TR, Weber RW. Methotrexate in the treatment of steroid-dependent asthma. J Allergy Clin Immunol 1991;88:208-12. 15. Trigg, CJ, Davies, RJ Comparison of methotrexate 30 mg per week with placebo in chronic steroiddependent asthma: A 12-week double-blind, cross-over study. Respir Med 1993;87,211-16. 16. Taylor DR, Flannery EM, Herbison GP, et al. Methotrexate in the management of severe steroiddependent asthma. N Z Med J 1993;106:409-11. 17. Stewart GE, Diaz JD, Lockey RF, et al Comparison of oral pulse methotrexate with placebo in the treatment of severe glucocorticoid-dependent asthma. J Allergy Clin Immunol 1994;94: 482-89. 18. Coffey MJ, Sanders G, Eschenbacher WL, et al. The role of methotrexate in the management of steroid-dependent asthma. Chest 1994;105:117-21. 19. Kanzow G, Nowak D, Magnussen, H Short-term effects of methotrexate in severe steroiddependent asthma. Lung 1995;173:223-31. 20. Ogirala, RG, Sturm, TM, Aldrich, TK, et al. Single, high-dose intramuscular triamcinolone acetonide vs weekly oral methotrexate in life-threatening asthma: A double-blind study. Am J Respir Crit Care Med 1995;152,1461-66. 21. Hedman J, Seideman P, Albertioni F, et al. Controlled trial of methotrexate in patients with severe chronic asthma. Eur J Clin Pharmacol 1996;49:347-49. 22. Marin MG. Low-dose methotrexate spares steroid usage in steroid-dependent asthmatic patients: A meta-analysis. Chest 1997;112:29-33. 23. Aaron SD, Dales RE, Pham B. Management of steroid-dependent asthma with methotrexate: A meta-analysis of randomized clinical trials. Respir Med 1998;92:1059-65. 24. Davies H, Olson L, Gibson P. Methotrexate as a steroid sparing agent for asthma in adults (Cochrane Review). The Cochrane Library, Issue 4 2000 Update Software. Oxford: UK. 25. Mullarkey MF, Lammert JK, Blumenstein BA. Long-term methotrexate treatment in corticosteroid-dependent asthma. Ann Intern Med 1990;112:577-81. 26. Shiner RJ, Katz I, Shulimzon T, et al. Methotrexate in steroid-dependent asthma: Long-term results. Allergy 1994;49:565-68 27. Jones G, Mierins E, Karsh J. Methotrexate-induced asthma. Am Rev Respir Dis 1991;143:179-81. 28. Spector SL, Katz FH, Farr RS. Troleandomycin: Effectiveness in steroid-dependent asthma and bronchitis. J Allergy Clin Immunol 1974;54:367-79. 29. Ong KS, Grieco MH, Rosner W. Enhancement by oleandomycin of the inhibitory effect of methylprednisolone on phytohemagglutinin-stimulated lymphocytes. J Allergy Clin Immunol 1978;62:115-18. 30. Szefler SJ, Rose JQ, Ellis EF, et al. The effect of troleandomycin on methylprednisolone elimination. J Allergy Clin Immunol 1980;66:447-51. 31. Townley RG, Selenke WM. Metabolic effects of macrolide antibiotics on bronchial asthma, experimental anaphylaxis and corticosteroid metabolism: Ninth International Congress of Allergy (vol 144) 1967;90 Excerpta Medica. Hillsborough, NJ.

302 Bronchial Asthma 32. Itkin IH, Menzel ML. The use of macrolide antibiotic substances in the treatment of asthma. J Allergy 1970;45:146-62. 33. Siracusa A, Brugnami G, Fiordi T, et al. Troleandomycin in the treatment of difficult asthma. J Allergy Clin Immunol 1993;92:677-82. 34. Zeiger RS, Schatz M, Sperling W, et al. Efficacy of troleandomycin in outpatients with severe, corticosteroid-dependent asthma. J Allergy Clin Immunol 1980;66:438-46. 35. Wald JA, Friedman BF, Farr RS. An improved protocol for the use of troleandomycin (TAO) in the treatment of steroid-requiring asthma. J Allergy Clin Immunol 1986;78:36-43. 36. Nelson HS, Hamilos DL, Corsello PR, et al. A double-blind study of troleandomycin and methylprednisolone in asthmatic subjects who require daily corticosteroids. Am Rev Respir Dis 1993;147:398-404. 37. Dasgupta A, Marcoux JP Hepatic abnormalities associated with long-term use of troleandomycin in asthma: A case report. Ann Allergy 1978;41:297-98. 38. Larrey D, Amouyal G, Danan G, et al. Prolonged cholestasis after troleandomycin-induced acute hepatitis. J Hepatol 1987;4:327-29. 39. Uzzan B, Vassy R, Nicholas P, et al. Troleandomycin hepatotoxicity: A case report of overt jaundice and a placebo-controlled trial. Therapie 1993;48:61-62. 40. Ledford DK. Treatment of steroid-resistant asthma. Immunol Allergy Clin North Am 1996;16: 777-796. 41. Walz DT, DeMartino MJ, Griswold DE, et al. Biologic actions and pharmacodynamic studies of auranofin. Am J Med 1983;75,90-108. 42. Marone G, Columbo M, Galeone D, et al. Modulation of the release of histamine and aracidonic acid metabolites from human basophils and mast cells by auranofin. Agents Actions 1986;18: 100-02. 43. Parente J, Wong K, David P, et al. Effects of gold compounds on leukotriene B4, leukotriene C4 and prostaglandin E2 production by polymorphonuclear leukocytes. J Rheumatol 1986;3:47-51. 44. Bernstein DI, Berstein IL, Bodenheimer SS, et al. An open study of auranofin in the treatment of steroid-dependent asthma. J Allergy Clin Immunol 1988;81:6-16 45. Suzuki S, Okubo M, Kaise S, et al. Gold sodium thiomalate selectively inhibits interleukin-5mediated eosinophil survival. J Allergy Clin Immunol 1995;96:251-56. 46. Alvarez J, Szefler SJ. Alternative therapy in severe asthma. J Asthma 1992;29:3-11. 47. Honoma M, Tamura G, Shirato K, et al. Effect of an oral gold compound, auranofin, on nonspecific bronchial hyperresponsiveness in mild asthma. Thorax 1994;49:649-651. 48. Klaustermeyer WB, Noritake DT, Kwong FK, et al. Chrysotherapy in the treatment of steroiddependent asthma. J Allergy Clin Immunol 1987;79:720-25. 49. Bernstein IL, Bernstein DI, Dubb JW, et al. A placebo-controlled multicenter study of auranofin in the treatment of patients with corticosteroid-dependent asthma: Auranofin Multicenter Drug Trial. J Allergy Clin Immunol 1996;98:317-24. 50. Muranaka MM, Miyamoto T, Shida T, et al. Gold salt in the treatment of bronchial asthma: A double blind study. Ann Allergy 1978;40:132-37. 51. Nierop G, Gijzel WP, Bel EH, et al. Auranofin in the treatment of steroid dependent asthma: A double blind study. Thorax 1992;47:349-54. 52. Sihra BS, Kon OM, Durham SR, et al. Effect of cyclosporin A on the allergen-induced late asthmatic reaction. Thorax 1997;52:447-52. 53. Frew AJ, Plummeridge MJ. Alternative agents in asthma. J Allergy Clin Immunol 2001;108:3-10. 54. Alexander AG, Barnes NC, Kay AB, et al. Clinical response to cyclosporin in chronic severe asthma is associated with reduction in serum soluble interleukin-2 receptor concentrations. Eur Respir J 1995;8:574-78. 55. Sano T, Nakamura Y, Matsunaga Y, et al. FK506, and cyclosporin A inhibit granulocyte/ macrophage colony-stimulating factor production by mononuclear cells in asthma. Eur Respir J 1995;8:1473-79.

Alternate Treatments in Asthma 303 56. Mori A, Suko M, Nishizaki Y, et al. IL-5 production by CD4+ T cells of asthmatic patients is suppressed by glucocorticoids and the immunosuppressants FK506 and cyclosporine A. Int Immunol 1995;7:449-57. 57. Khan LN, Kon OM, MacFarlane A. Attenuation of the allergen-induced late asthmatic reaction by cyclosporin A is associated with inhibition of bronchial eosinophils, interleukin-5, granulocyte macrophage colony-stimulating factor and eotaxin. Am J Respir Crit Care Med 2000;162: 1377-82. 58. Alexander AG, Barnes NC, Kay AB. Trial of cyclosporin in corticosteroid-dependent chronic severe asthma. Lancet 1992;339:324-28. 59. Lock SH, Kay AB, Barnes NC. Double-blind, placebo-controlled study of cyclosporin A as a corticosteroid-sparing agent in corticosteroid-dependent asthma. Am J Respir Crit Care Med 1996;153:509-14. 60. Nizankowska E, Soja J, Pinis G, et al. Treatment of steroid-dependent bronchial asthma with cyclosporin. Eur Respir J 1995;8:1091-99. 61. Mazer BD, Gelfand EW. An open-label study of high dose intravenous immunoglobulin in severe childhood asthma. J Allergy Clin Immunol 1991;87:976-83. 62. Amran D, Renz H, Lack G, et al. Suppression of cytokine-dependent human T-cell proliferation by intravenous immunoglobulin. Clin Immunol Immunopathol 1994;73:180-86. 63. Leung DY, Burns J, Newburger J, et al. Reversal of immunoregulatory abnormalities in Kawasaki syndrome by intravenous gammaglobulin. J Clin Invest 1987;79:468-72. 64. Spahn JD, Leung DY, Chan MT, et al. Mechanisms of glucocorticoid reductions in asthmatic patients treated with intravenous immunoglobulin. J Allergy Clin Immunol 1999;103:421-26. 65. Jakobsson T, Croner S, Kjellman N, et al. Slight steroid-sparing effects of intravenous immunoglobulin in children and adolescents with moderately severe bronchial asthma. Allergy 1994;49:413-20. 66. Landwehr LP, Jeppson JD, Katlan MG. Benefits of high-dose IV immunoglobulin in patients with severe steroid-dependent asthma. Chest 1998;114:1349-56. 67. Salmun LM, Barlan I, Wolf HM, et al. Effect of intravenous immunoglobulin on steroid consumption in patients with severe asthma: A double-blind, placebo-controlled, randomized trial. J Allergy Clin Immunol 1999;103:810-15. 68. Kishiyama JL, Valacer D, Cunningham-Rundles C, et al. A multi-center, randomized, doubleblind, placebo-controlled trial of high-dose intravenous immunoglobulin for oral corticosteroiddependent asthma. Clin Immunol 1999;91:126-33. 69. Ragazzi E, Chinellato A. Heparin: pharmacological potentials from atherosclerosis to asthma. Gen Pharmacol 1995;26:697-701. 70. Lasser EC, Lang JH, Curd JG, et al. The plasma contact system in atopic asthma. J Allergy Clin Immunol 1983;72:83-88. 71. Lasser EC, Simon RA, Lyon SG, et al. Heparin-like anticoagulants in asthma. Allergy 1987;42: 619-25. 72. Motojima S, Frigas E, Wegering DA, et al. Toxicity of eosinophil cationic protein from guineapig tracheal epithelium in vitro. Am Rev Respir Dis 1989;139:801-05. 73. Fath MA, Wu X, Hileman RE, et al. Interaction of secretory leukocyte protease inhibitor with heparin inhibits proteases involved in asthma. J Biol Chem 1998;273:13563-569. 74. Lider O, Mekori YA, Miller T, et al. Inhibition of T lymphocyte heparanase by heparin prevents T cell migration and T cell-mediated immunity. Eur J Immunol 1990;20:493-99. 75. Matzner Y, Marx G, Drexler R, et al. The inhibitory effect of heparin and related glycosaminoglycans on neutrophil chemotaxis. Thromb Haemost 1984;52:134-37. 76. Karnovsky MJ, Edelman ER. Heparin/heparin sulphate regulation of vascular smooth muscle behavior. Black, J Page, CP (Eds). Airways and vascular remodeling in asthma and cardiovascular disease: Implications for therapeutic intervention. 1994,45-70 Academic Press. London, UK.

304 Bronchial Asthma 77. Ekre HPT, Fjellner B, Hagermark O. Inhibition of complement dependent experimental inflammation in human skin by different heparin fractions. Int J Immunopharmacol 1986;8: 277-86. 78. Ahmed T, Syriste T, Mendelssohn R, et al. Heparin prevents antigen-induced airway hyperresponsiveness: Interference with IP3-mediated mast cell degranulation. J Appl Physiol 1994;76:893-901. 79. Dolowitz DA, Dougherty TF. The use of heparin as an anti-inflammatory agent. Laryngoscope 1960;70:873-84. 80. Boyle JP, Smart RH, Shirey JK. Heparin in the treatment of chronic obstructive bronchopulmonary disease. Am J Cardiol 1964;14:25-28. 81. Fine NL, Shim C, Williams MH. Objective evaluation of heparin in the treatment of asthma. Am Rev Respir Dis 1968;98:886-87. 82. Ahmed T, Abraham WM, D’Brot, J. Effects of inhaled heparin on immunologic and nonimmunologic bronchoconstrictor responses in sheep. Am Rev Respir Dis 1992;145:566-70. 83. Ahmed T, Garrigo J, Danta I. Preventing bronchoconstriction in exercise-induced asthma with inhaled heparin. N Engl J Med 1993;329:90-95. 84. Garrigo J, Danta I, Ahmed T. Time course of the protective effect of inhaled heparin on exerciseinduced asthma. Am J Respir Crit Care Med 1996;153:1702-07. 85. Ahmed T, Gonzalez BJ, Danta I. Prevention of exercise-induced bronchoconstriction by inhaled low-molecular-weight heparin. Am J Respir Crit Care Med 1999;160:576-81. 86. Bianco S, Vaghi A, Robuschi M, et al. Prevention of exercise-induced bronchoconstriction by inhaled frusemide. Lancet 1988;2:252-55. 87. Welsh MJ. Inhibition of chloride secretion by furosemide in canine tracheal epithelium. J Membr Biol 1993;71:218-26. 88. Alton EW, Kingsleigh-Smith DJ, Munkonge FM, et al. Asthma prophylaxis agents alter the function of an airway epithelial chloride channel. Am J Respir Cell Mol Biol 1996;14:380-87. 89. Perkins R, Dent G, Chung KF, et al. Effect of anion transport inhibitors and extracellular Clconcentrations on eosinophil respiratory burst activity. Biochem Pharmacol 1992;107;481-88. 90. Elwood W, Lotvall JO, Barnes PJ, et al. Loop diuretics inhibit cholinergic and non-cholinergic erves in guinea pig airways. Am Rev Respir Dis 1991;143:1340-44. 91. Anderson SD, Wei HE, Temple DM. Inhibition by furosemide of inflammatory mediators from lung fragments [letter]. N Engl J Med 1991;324:131. 92. Miyanoshita A, Terada M, Endou H. Furosemide directly stimulates prostaglandin E2 production in the thick ascending limb of Henle’s loop. J Pharmacol Exp Ther 1989;251:1155-59. 93. Barnes PJ. Diuretics and asthma. Thorax 1993;48:195-96. 94. Levasseur-Acker GM, Molimard M, Regnard J, et al. Effect of furosemide on prostaglandin synthesis by human nasal and bronchial epithelial cells in culture. Am J Respir Cell Mol Biol 1994;10:378-83. 95. Pavord ID, Wisniewski A, Tattersfield AE. Inhaled furosemide and exercise induced asthma: Evidence of a role for inhibitory prostanoids. Thorax 1992;47:797-800. 96. O’Connor BJ, Barnes PJ, Chung KF. Inhibition of sodium metabisulphite induced bronchoconstriction by frusemide in asthma: Role of cyclooxygenase products. Thorax 1994;49:307-11. 97. Gilbert IA, Lenner KA, Nelson JA, et al. Inhaled furosemide attenuates hyperpnea-induced obstruction and intra-airway thermal gradients. J Appl Physiol 1994;76:409-15. 98. Freed AN, Taskar V, Schofield B, et al. Effect of furosemide on hyperpnea-induced airway obstruction, injury and microvascular leakage. J Appl Physiol 1996;81:2461-67. 99. Daviskas E, Anderson SD, Gonda I, et al. Mucociliatory clearance during and after isocapnic hyperventilation with dry air in the presence of frusemide. Eur Respir J 1996;9:716-24. 100. Hasani A, Pavia D, Spiteri MA, et al. Inhaled frusemide does not affect lung mucociliary clearance in health and asthmatic subjects. Eur Respir J 1994;7:1497-1500.

Alternate Treatments in Asthma 305 101. Bianco S, Pieroni MG, Refini RM, et al. Protective effect of inhaled furosemide on allergeninduced early and late asthmatic reactions. N Engl J Med 1989;321,1069-73. 102. Moscato G, Dellabianca A, Falagiani P, et al. Inhaled furosemide prevents both the bronchoconstriction and the increase in neutrophil chemotactic activity induced by ultrasonic “fog” of distilled water in asthmatics. Am Rev Respir Dis 1991;143:561-66. 103. O’Conner BJ, Chung KF, Chen-Worsdell, YM, et al. Effect of inhaled furosemide and bumetanide on adenosine 5'-monophosphate- and sodium metabisulfate-induced bronchoconstriction in asthmatic subjects. Am Rev Respir Dis 1991;143:1329-33. 104. Nichol GM, Alton EW, Nix A, et al. Effect of inhaled furosemide on metabisulfite- and methacholine-induced bronchoconstriction and nasal potential difference in asthmatic subjects. Am Rev Respir Dis 1990;142:576-80. 105. Vargas FS, Croce M, Teizeira LR, et al. Effect of inhaled furosemide on the bronchial response to lysine-aspirin inhalation in asthmatic subjects. Chest 1992;102:408-11. 106. Myers JD, Higham MA, Shakur BH, et al. Attenuation of propranolol-induced bronchoconstriction by furosemide. Thorax 1997;52:861-65. 107. Vaghi A, Robuschi M, Chilaris M, et al. Inhaled furosemide does not alter the bronchial response to methacholine in asthmatics. Eur Respir J 1988;1:85. 108. Stone RA, Yeo TC, Barnes PJ, et al. Frusemide inhibits cough but not bronchoconstriction to prostaglandin F2α in patients with asthma. Am Rev Respir Dis 1991;143:A548. 109. Stone RA, Barnes PJ, Chung KF. Effect of frusemide on cough responses to chloride-deficient solution in normal and mild asthmatic subjects. Eur Respir J 1993;6:862-67. 110. Siffredi M, Mastropasqua B, Pelucchi A, et al. Effect of inhaled furosemide and cromolyn on bronchoconstriction induced by ultrasonically nebulized distilled water in asthmatic subjects. Ann Allergy Asthma Immunol 1997;78:238-43. 111. Ventresca PG, Nichol GM, Barnes PJ, et al. Inhaled frusemide inhibits cough induced by lowchloride solutions but not by capsaicin. Am Rev Respir Dis 1990;142,143-46. 112. Stone RA, Barnes PJ, Chung KF. Effect of frusemide on cough response to low-chloride solution in subjects with mild asthma. Thorax 1991;46:752P. 113. Chung KF Furosemide and other diuretics in asthma. J Asthma 1994;31:85-92. 114. Bianco S, Robuschi M, Vaghi A, et al. Steroid sparing effect of inhaled lysine-aspirin and furosemide in steroid-dependent asthma. Melillo, G O’Byrne, PH Marone, G (Eds). Respiratory Allergy 1993,261-69 Elsevier. Amsterdam, the Netherlands. 115. Bianco S, Vaghi A, Robuschi M, et al. Steroid-sparing effect of inhaled lysine acetylsalicylate and furosemide in high-dose beclomethasone-dependent asthma. J Allergy Clin Immunol 1995;95,937-43. 116. Karpel JP, Dworkin F, Hager D, et al. Inhaled furosemide is not effective in acute asthma. Chest 1994;106:1396-1400. 117. Pendino JC, Nannini LJ, Chapman KR. Effect of inhaled furosemide in acute asthma. J Asthma 1998;35,89-93. 118. Ono Y, Kondo T, Tanigaki T, et al. Furosemide given by inhalation ameliorates acute exacerbations of asthma. J Asthma 1997;34:283-89. 119. Tanigaki T, Kondo T, Hayashi Y, et al. Rapid response to inhaled frusemide in severe acute asthma with hypercapnia. Respiration 1997;64:108-10.

306 Bronchial Asthma

20 Severe Asthma (Fatal Asthma, Refractory Asthma) INTRODUCTION Severe or fatal asthma or refractory asthma constitutes about <5% of all the asthmatics. The entity is poorly understood clinically, physiologically, and pathologically. Severe forms of the disease often remain refractory to the best current medical care. Although some patients with severe asthma have had severe disease for most of their lives, a second group develops severe disease in adulthood. It is not clear which genetic and environmental elements may be the most important in the development of severe disease. Physiologically, these patients often have air-trapping and may have loss of elastic recoil, as well. The pathology demonstrates a wide variety of findings, those include continued eosinophilic inflammation, structural changes, distal disease, and, in at least one third of patients, a different pathology. Treatment remains problematic. These patients respond poorly to the usual treatment and are very difficult to manage. Accordingly the cost of treatment is very high with poor outcomes. The introduction of high-potency inhaled corticosteroids (CS) had a marked impact on the numbers of patients who were dependent on therapy with oral CS. However, beyond those medications, little further progress has been made in understanding the disease and improving its treatment. Definition Severe or “refractory” asthma was defined by the workshop sponsored by the American Thoracic Society.1 This definition includes the following:

Major Criteria • Continuous high-dose inhaled corticosteroids or • Oral corticosteroids for > 50% of the previous year

Minor Criteria • • • •

Aspects of lung function, Exacerbations, Disease stability, Amount of additional medications For a diagnosis of fatal asthma at least one major and additional two of the seven minor criteria are to be fulfilled. Patients also must have had compliance and exacerbating factors

Severe Asthma (Fatal Asthma, Refractory Asthma) 307 should be fully addressed. These definitions are a guide, but the list of criteria still may not be definitive and may have many pitfalls. Some suggest that expanding the minor criteria requirements to three would likely improve the capture of those who fulfill the “spirit” of the definition, rather than the “letter” of the definition. Epidemiology Very little is known about the development of severe asthma. It is not clear whether most patients with severe asthma have a life-altering event in childhood that irreversibly alters their lungs, from which they will never recover, or whether they slowly but steadily decline over the years. It is also not certain whether those patients with a history of adult-onset disease actually have some level of asthma as children those were ignored, or if at all they have a more rapid decline in function once the asthma begins. No satisfactory answer to these questions has been found although some information has come from the large cohort of asthma patients studied in Melbourne, Australia followed for 35 years.2 Those data suggest that reduced lung function in childhood leads to reduced lung function in adulthood, although there is little “progressive decline” of the mean data. Two studies3,4 from Europe have suggested that late-onset asthma is associated with a more rapid decline in lung function. In the database of > 100 patients with severe asthma who were seen at National Jewish Medical and Research Center (Denver, CO), approximately two-thirds of patients had onset in childhood, and the remaining one third experienced onset after the age of 20 years.5 Existence of any distinct phenotypic differences in adult-onset and childhood onset asthma or severe asthma is not known. Aetiology Various risk factors for development of severe asthma are shown in Table 20.1. Table 20.1: Various risk factors for development of severe asthma

Genetic Mutations in both the interleukin-4 gene or the interleukin-4 receptor Non-T helper (Th) type 2 factors Transforming growth factor (TGF)-β1 Monocyte chemotactic protein-1 Environmental factors Allergens (house dust mite; cockroach; alternaria exposure) Smoking Pet allergy Infections Respiratory syncytial virus infections in childhood Mycoplasma and Chlamydia infections in adults Lung-externa factors Obesity (Increased body mass index) Gastroesophageal reflux disease Chronic sinusitis Compliance/adherence to medications Inadequate response to therapy

308 Bronchial Asthma As is the case for many diseases, risk factors can be divided into genetic and environmental. Unfortunately, asthma itself is a disease involving multiple genes. Severe asthma is not likely to be different and is less well-studied. There are reports6,7 of relevant mutations in both the interleukin-4 gene or the interleukin-4 receptor, some of which have been linked to loss of lung function, and others to near-fatal events. Interestingly, two non-T helper (Th) type 2 factors also have been associated with severity of asthma, transforming growth factor (TGF)β1 and monocyte chemotactic protein-1, both of which can promote fibrotic reactions.8,9 Whether mutations of the receptors for the primary treatments for asthma (β2 and glucocorticoid receptors [GRs]) decrease responsiveness to medications and influence outcomes is not yet clear. Environmental factors include both allergen and tobacco exposure, with the strongest data for house dust mite, cockroach, and Alternaria exposures.10-12 Additionally, many patients will continue to smoke or own a cat despite being aware of the negative effects.13 Infection also may contribute to severe disease, with respiratory syncytial virus infections implicated in childhood, while pathogens like Mycoplasma and Chlamydia may play a role in adults.4 Although not precisely “environmental,” additional “lung-external” factors may include obesity, gastroesophageal reflux disease, and chronic sinusitis. Epidemiologic study of patients with severe/difficult-to-treat asthma suggested that body mass index increases with increasing severity of disease and that 76% of the cohort of patients with severe disease were either overweight or obese.14 However, similar to gastroesophageal reflux disease and chronic sinusitis, the relationship of effective treatment of obesity to severity of disease is not clear. Another external factor related to severity of disease is compliance/adherence to medications. Studies15 have suggested that in children and adolescents, instability of disease is related to adherence to therapy with corticosteroids. Adherence to medication may be influenced by lack of responsiveness to medication. If the patient is receiving therapy with oral corticosteroids, the early-morning measurement of cortisol level can be helpful in determining compliance. If this is not helpful, then treatment trials with injectable longacting steroids, such as depomethylprednisolone or triamcinolone, can be informative.16 Physiology Progressive increase in airflow limitation, which is often irreversible leads to a more rapid decline in the FEV1, although there is poor correlation between FEV1 and disease symptoms .17 This may be true in some patients. Others may have severe airflow limitation at presentation, while others, particularly adults, may develop a more rapid decline in lung function over a 10-year-period of time.4 These changes are not completely irreversible. There may be irreversibility to current aggressive medical management. However, it does not necessarily mean the lungs are in a fixed fibrotic state. Airway hyperreactivity also plays a role in the severity of asthma. The provocative concentration causing a 20% fall in FEV1 with disease severity is often present but is poor indicators.18 This instability may be an important aspect to the symptomatology of a subgroup of patients with severe asthma, in whom continuous airflow limitation may play a role.19 FEV1 and airway reactivity changes do not adequately explain disease severity. It is possible that other physiologic factors, such as changes in elastic recoil and/or small airway physiology, are important. The elastic recoil properties of the lung in asthma patients are not normal.20,21 Compliance is increased in patients with moderate persistent asthma, although the precise pathologic mechanism behind the change is not clear. It is suggested that the airways and the parenchyma are more collapsible than are the airways in healthy

Severe Asthma (Fatal Asthma, Refractory Asthma) 309 individuals.22 The FVC1 slow vital capacity ratio is decreased in a group of patients with severe asthma who had persistent eosinophilia.23 These patients are at a higher risk of nearfatal events than those with a more normal (1:1) ratio. There is air-trapping in patients with severe asthma, without associated hyperinflation. Residual volumes are routinely > 200% of predicted in severe asthma, with only modestly increased thoracic gas volumes.23 Whether this increase in residual volume may be reflective of small airway disease. There is no correlation of physiologic measures with inflammatory or structural changes. Pathology Up to two-thirds of patients with severe asthma have persistent tissue eosinophils, despite continued therapy with high-dose systemic steroids. There are associated increases in T lymphocytes and markers for activation of a Th-2 pathway.23 This pattern of inflammation represents steroid resistance, whereas a Th-2 pattern of inflammation persists despite the presence of high-dose steroid therapy. This lack of effect is due to a number of factors those include high levels of proinflammatory mediators sequestering the glucocorticoid receptors (GR), diminished binding of the GR to the genome, or increased levels of an alternatively spliced GR (i.e. GR-β), which has lessened inhibitory capabilities.24-26 Other, non-Th-2, proeosinophilic factors also play a role in the process. These changes lead to poor/modified drug response in patients with more unstable asthma. The apparent progressive loss of lung function in more severe forms of asthma is due to structural or remodeling changes in the airways and perhaps the parenchyma as well although tthe precise changes are unclear. Numerous structures have been implicated, including the sub-basement membrane (SBM), epithelium, smooth muscle, nerves, and blood vessels. Although the SBM is thickened in asthma patients, the relationship to disease severity is unclear. Patients with severe asthma with persistent eosinophil levels had the thickest SBM when compared to those of healthy control subjects, patients with milder cases of asthma. This thickened SBM was seen in association with high numbers of TGF-β-positive cells in the submucosa.23,27 However, the absolute increase in thickness is small and cannot explain the increase in airflow limitation. It may be used as a marker for abnormalities in composition, distribution, or quantity of extracellular matrix elements in other regions of the airway or parenchyma. The epithelium is abnormal in asthma patients. There is an increase in the ratio of goblet cells to ciliated epithelial cells. Mucus plugging of the small and medium airways contributes further to airflow limitation and air trapping in patients with severe asthma. Other studies28,29 suggested alterations in epithelial growth factor receptor and TGF-β1 and/or TGF-β2 in asthma patients, which may contribute to inappropriate and inadequate repair process, augmenting goblet cell metaplasia and mucus production. The amount (and perhaps phenotypes) of smooth muscle in the airways of patients with severe asthma is also increased. Patients dying of status asthmaticus have increased smooth muscle mass in the airways from the largest airways to nearly the smallest.30 Relationship of increased airway smooth muscle to severity of disease is possible although relationship of any of these structural changes to functional changes is not very clear. In addition to airflow limitation, airtrapping, hyperresponsiveness, and loss of elastic recoil/collapsibility are important. Alterations in the alveolar attachments to the airways and the airways themselves play a role in collapsibility, but the cause of changes in elastic recoil is not clear.

310 Bronchial Asthma Elastin levels have been shown to be abnormal (i.e. decreased or disordered) in patients who have died of asthma. The numbers of proteolytic enzymes that alter elastin composition are increased in several instances in asthma.31,32 It is possible that changes in elastin composition, secondary to chronic inflammatory elements, contribute to the unique structural/functional relationships of patients with severe asthma. Physiologic and pathologic data suggest that inflammatory changes exist in the lung periphery. Autopsy studies33,34 have suggested that both increased inflammation and wall thickness may exist in patients who have died of asthma, as opposed to those with milder asthma and healthy control subjects. Studies35,36 of living asthma patients also have suggested that distal lung inflammation may be more important than proximal lung inflammation. These observations have implications for current drug therapy, as most inhaled medications are unlikely to reach the lung periphery in high amounts.37 These structural and inflammatory changes in the small airway and parenchyma may interact to a greater degree in the small airways than the large airways due to the smaller general mass of the airway structure. Classically bronchial asthma has continued eosinophilic inflammation but, patients with severe asthma have neutrophil predominance or very little inflammation23,38, 39 The patients without eosinophils also do not appear to have the same degree of collapsibility and have less severe asthma attacks, also supporting a different presentation for this disease subtype. Recently CT scan findings confuse the issue whether other, less well-defined obstructive diseases like bronchiolitis obliterans also could masquerade as severe asthma.40 Management The treatment of severe asthma remains difficult. Corticosteroids remain the drug of choice because of their broad and nonspecific effects, and there are few alternatives in existence. Leukotriene modifiers may be helpful in some cases, especially as a large percentage of patients with severe asthma may be aspirin-sensitive.41 Anti-IgE also appears to be efficacious in patients with more severe forms of asthma and may be of benefit in some of these patients.42 Other forms of therapy, such as cyclosporine and methotrexate have limited value.43 However, use of alternate agents in treating asthma patients, whose disease remains poorly controlled while receiving standard therapy, may be considered. It is important to recognize that the reasons for lack of response to treatment are numerous, and the clinical approach to the patient with poorly controlled asthma must be systematic and individualised. The objective confirmation of asthma and the exclusion of other pulmonary conditions with screening blood tests, chest radiograph, spirometry, bronchoprovocation challenge, and cardiopulmonary exercise testing is vital in any patient who does not respond to asthma therapy. It is of importance of maximising standard asthma therapy with close outpatient follow-up, patient education, and compliance monitoring. The treatment of concomitant gastroesophageal reflux44 and chronic sinusitis45,46 and the removal of environmental triggers of asthma have been shown to improve asthma control. Glucocorticoid absorption and metabolism can be affected by thyroid disease and a variety of drugs, including antacids, rifampin, cholestyramine, and numerous antiepileptic agents.47 The increased detection of Mycoplasma pneumoniae and Chlamydia pneumoniae by polymerase chain reaction in the airways of patients with chronic asthma has led to questions regarding their role in pathogenesis48 and several small case series49,50 have demonstrated statistically significant improvements in lung function and reductions in bronchial reactivity to histamine after treatment with macrolides. Due to the significant side effects of many alternate asthma

Severe Asthma (Fatal Asthma, Refractory Asthma) 311 therapies, it is essential to thoroughly address these issues before going for a novel treatment strategy. It is also important to distinguish the “difficult-to-manage” asthma patient from the patient who is steroid-resistant. This asthma subgroup, which was first described in 196851 is characterised by patients with larger than usual daily oral corticosteroid requirements and poor symptom control, a blunted eosinopenic response to cortisol-21-succinate, and increased clearance of cortisol. Other clinical characteristics that are associated with steroid resistance include African-American race, symptoms requiring oral glucocorticoid agents at an early age, and < 15% improvement in FEV1 following 7 to 14 days of treatment with high-dose (i.e. > 40 mg daily) oral glucocorticoids.52 The recognition and early identification of these patients may isolate a subgroup of patients who could benefit from early intervention with alternate asthma therapies with better long-term asthma control and reduction in corticosteroid side effects. REFERENCES 1. Wenzel SE, Fahy JV, Irvin CG, et al. Proceedings of the ATS Workshop on Refractory Asthma: Current understanding, recommendations and unanswered questions. Am J Respir Crit Care Med 2000;162:2341-51. 2. Oswald H, Phelan PD, Lanigan A, et al. Childhood asthma and lung function in mid-adult life. Pediatr Pulmonol 1997;23:14-20. 3. Ulrik CS, Lange P. Decline of lung function in adults with bronchial asthma. Am J Respir Crit Care Med 1994;150:629-34. 4. Ten Brinke A, van Dissel JT, Sterk PJ, et al. Persistent airflow limitation in adult-onset nonatopic asthma is associated with serologic evidence of Chlamydia pneumoniae infection. J Allergy Clin Immunol 2001;107:449-54. 5. Gibbs R, Miranda C, Wenzel S. Initial demographic information from an extensive data base of severe, steroid dependent asthmatics studied at National Jewish. Am J Respir Crit Care Med 2002;165,A119. 6. Sandford AJ, Chagani T, Zhu S, et al. Polymorphisms in the IL4, IL4RA, and FCERIB genes and asthma severity. J Allergy Clin Immunol 2000;106:135-40. 7. Burchard EG, Silverman EK, Rosenwasser LJ, et al. Association between a sequence variant in the IL-4 gene promoter and FEV1 in asthma. Am J Respir Crit Care Med 1999;160:919-22. 8. Pulleyn LJ, Newton R, Adcock IM, et al. TGF-β-1 allele association with asthma severity. Hum Genet 2001;109:623-27. 9. Szalai C, Kozma GT, Nagy A, et al. Polymorphism in the gene regulatory region of MCP-1 is associated with asthma susceptibility and severity. J Allergy Clin Immunol 2001;108:375-81. 10. Squillace SP, Sporik RB, Rakes G, et al. Sensitisation to dust mites as a dominant risk factor for asthma among adolescents living in central Virginia: Multiple regression analysis of a populationbased study. Am J Respir Crit Care Med 1997;156:1760-64. 11. Halonen M, Stern DA, Wright AL, et al. Alternaria as a major allergen for asthma in children raised in a desert environment. Am J Respir Crit Care Med 1997;155:1356-61. 12. Rosenstreich DL, Eggleston P, Kattan M, et al. The role of cockroach allergy and exposure to cockroach allergen in causing morbidity among inner-city children with asthma. N Engl J Med 1997;336:1356-63. 13. Siroux V, Pin I, Oryszczyn MP, et al. Relationships of active smoking to asthma and asthma severity in the EGEA study: Epidemiological study on the genetics and environment of asthma. Eur Respir J 2000;15:470-77. 14. Weiss ST, Tager IB, Speizer FE, et al. Persistent wheeze: Its relation to respiratory illness, cigarette

312 Bronchial Asthma

15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35.

smoking and level of pulmonary function in a population sample of children. Am Rev Respir Dis 1980;122:697-707. Milgrom H, Bender B, Ackerson L, et al. Noncompliance and treatment failure in children with asthma. J Allergy Clin Immunol 1996;98:1051-57. Ogirala RG, Sturm TM, Aldrich TK, et al. Single, high-dose intramuscular triamcinolone acetonide versus weekly oral methotrexate in life-threatening asthma: A double-blind study. Am J Respir Crit Care Med 1995;152:1461-66. Teeter JG, Bleecker ER Relationship between airway obstruction and respiratory symptoms in adult asthmatics. Chest 1998;113:272-77. Weiss ST, Van Natta ML, Zeiger RS. Relationship between increased airway responsiveness and asthma severity in the childhood asthma management program. Am J Respir Crit Care Med 2000;162:50-56. Chan MT, Leung DY, Szefler SJ, et al. Difficult-to-control asthma: Clinical characteristics of steroid-insensitive asthma. J Allergy Clin Immunol 1998;101:594-601. Woolcock AJ, Rebuck AS, Cade JF, et al. Lung volume changes in asthma measured concurrently by two methods. Am Rev Respir Dis 1971;104:703-09. Woolcock AJ, Read J. The static elastic properties in the lungs in asthma. Am Rev Respir Dis 1968;98:788-94. Gelb AF, Zamel N. Unsuspected pseudophysiologic emphysema in chronic persistent asthma. Am J Respir Crit Care Med 2000;162:1778-82. Wenzel SE, Schwartz LB, Langmack EL, et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med 1999;160:1001-08. Kam JC, Szefler SJ, Surs W, et al. Combination IL-2 and IL-4 reduces glucocorticoid receptorbinding affinity and T cell response to glucocorticoids. J Immunol 1993;151:3460-66. Lane SJ, Adcock IM, Richards D, et al. Corticosteroid-resistant bronchial asthma is associated with increased c-fos expression in monocytes and T lymphocytes. J Clin Invest 1998;102: 2156-64. Leung DY, Hamid Q, Vottero A, et al. Association of glucocorticoid insensitivity with increased expression of glucocorticoid receptor beta. J Exp Med 1997;186:1567-74. Minshall EM, Hogg JC, Hamid QA. Cytokine mRNA expression in asthma is not restricted to the large airways. J Allergy Clin Immunol 1998;101:386-90. Takeyama K, Fahy JV, Nadel JA. Relationship of epidermal growth factor receptors to goblet cell production in human bronchi. Am J Respir Crit Care Med 2001;163:511-16. Howat WJ, Holgate ST, Lackie PM. TGF-β isoform release and activation during in vitro bronchial epithelial wound repair. Am J Physiol 2002;282:L115-L23. James AL, Pare PD, Hogg JC. The mechanics of airway narrowing in asthma. Am Rev Respir Dis 1989;139:242-46. Vignola AM, Riccobono L, Mirabella A, et al. Sputum metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio correlates with airflow obstruction in asthma and chronic bronchitis. Am J Respir Crit Care Med 1998;158:1945-50. Lemjabbar H, Gosset P, Lamblin C, et al. Contribution of 92 kDa gelatinase/type IV collagenase in bronchial inflammation during status asthmaticus. Am J Respir Crit Care Med 1999;159:12981307. Carroll NG, Elliot J, Morton AR, et al. The structure of large and small airways in nonfatal and fatal asthma. Am Rev Respir Dis 1993;147:405-10. Carroll NG, Mutavdzic S, James AL. Distribution and degranulation of airway mast cells in normal and asthmatic subjects. Eur Respir J 2002;19:879-85. Kraft M, Djukanovic R, Wilson S, et al. Alveolar tissue inflammation in asthma. Am J Respir Crit Care Med 1996;154:1505-10.

Severe Asthma (Fatal Asthma, Refractory Asthma) 313 36. Balzar S, Wenzel SE, Chu HW. Transbronchial biopsy as a tool to evaluate small airways in asthma. Eur Respir J 2002;20:254-59. 37. Leach CL, Davidson PJ, Boudreau RJ. Improved airway targeting with the CFC-free HFAbeclomethasone metered-dose inhaler compared with CFC-beclomethasone. Eur Respir J 1998;12:1346-53. 38. Wenzel SE, Szefler SJ, Leung DYM, et al. Bronchoscopic evaluation of severe asthma: Persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit Care Med 1997;156: 737-43. 39. Louis R, Lau LCK, Bron AO, et al. The relationship between airways inflammation and asthma severity. Am J Respir Crit Care Med 2000;161:9-16. 40. Jensen SP, Lynch DA, Brown KK, et al. High-resolution CT features of severe asthma and bronchiolitis obliterans. Radiology 2000;217(suppl):595. 41. Virchow JC, Jr. Prasse A, Naya I, et al. Zafirlukast improves asthma control in patients receiving high-dose inhaled corticosteroids. Am J Respir Crit Care Med 2000;162:578-85. 42. Holgate S, Bousquet J, Wenzel S, et al. Efficacy of omalizumab, an anti-immunoglobulin E antibody, in patients with allergic asthma at high risk of serious asthma-related morbidity and mortality. Curr Med Res Opin 2001;17:233-40. 43. Wenzel S. Severe/Fatal Asthma. Chest 2003;123:405S-10S. 44. Irwin RS, Curley FJ, French CL. Difficult-to-control asthma: Contributing factors and outcome of a systematic management protocol. Chest 1993;103:1662-69. 45. Rachelefsky GS, Goldberg M, Katz RM, et al. Sinus disease in children with respiratory disease. J Allergy Clin Immunol 1978;61:310-14. 46. Rachelefsky GS, Katz RM, Siegel SC Chronic sinus disease with associated reactive airway disease in children. Pediatrics 1984;73:526-29. 47. Spahn JD, Covar R. Steroid-resistant asthma. Immunol Allergy Clin North Am 2001;21:569-87. 48. Kraft M, Cassell GH, Henson JE, et al. Detection of Mycoplasma pneumoniae in the airways of adults with chronic asthma. Am J Respir Crit Care Med 1998;158:998-1001. 49. Ekici A, Ekici M, Erdemoglu AK. Effect of azithromycin on the severity of bronchial hyperresponsiveness in patients with mild asthma. J Asthma 2002;39:181-85. 50. Kraft M, Cassell GH, Pak J, et al. Mycoplasma pneumoniae and Chlamydia pneumoniae in asthma: Effect of clarithromycin. Chest 2002;121:1782-88. 51. Schwartz HJ, Lowell FC, Melby JC. Steroid resistance in bronchial asthma. Ann Intern Med 1968;69:493-99. 52. Chan MTS, Leung DYM, Szefler SJ, et al. Difficult-to-control asthma: Clinical characteristics of steroid insensitive asthma. J Clin Immunol 1998;101:594-601.

314 Bronchial Asthma

21 Asthma in Children The previous chapters have dealt with bronchial asthma in general, which is applicable, both in cases of adult as well as childhood asthma. However, this chapter will highlight certain important points about childhood asthma. PREVALENCE International Scene A worldwide rise in the prevalence of asthma is being reported with increase in wheeze at an alarming rate of 5% per year. From 1983 onwards an increase in asthma mortality and morbidity has been noticed worldwide.1 Data on prevalence of bronchial asthma on children are few from most countries but many from countries like Australia and UK.2 Table 21.1 shows the prevalence of current asthma, diagnosed asthma, wheeze ever, airway hyperresponsiveness, and atopy in children. There are large differences in the prevalence among the rich, partly rich, and poor populations, with the highest prevalence found in Australia. It is possible that the differences may be as a consequence of responses to different allergens, to different allergen loads, or to other factors in the environment in the affluent and not-so-affluent populations. There are some suggestions that patients with high levels of parasitic infections are less atopic, although there is no convincing experimental confirmation. This protection of parasitic infections against asthma may be a cause of less prevalence of the later in many developing countries. Diet may also be a factor. Exposure to allergens may be important although the most common allergen, the house dust mite has been found everywhere it has been looked for. However, these mites are mainly found in bedding and it is possible that steeping on a bed rather than on a floor, which many poor children do, increases exposure to them. There was considerable concern that the prevalence of asthma and allergic diseases is increasing in Western and developing countries. However, the etiology of these conditions remains poorly understood, despite a large volume of clinical and epidemiological research within populations that has been directed at explaining why some individuals and not others develop asthma and allergies. Little is known about such worldwide variations in the prevalence of asthma and allergic diseases. More authentic data was available from the International Study of Asthma and Allergies in Childhood (ISAAC) designed in late 90’s.3 The study allowed comparisons between populations in different countries. ISAAC Phase One used standardized simple surveys conducted among representative samples of school children from centres in most regions of the world. Two age groups (13-14 years and

Asthma in Children 315 Table 21.1: Prevalence of asthma in children in different countries

Country

Number

Age

Current asthma

Diagnosed Wheeze asthma ever

Airway Hyperresponsiveness

Atopy (SPT)

Australia

1,487 1,217 1,575

8 to 10 8 to 11 8 to 11

5.4 6.7 9.9

11.10 17.3 30.8

21.7 26.5 40.7

10.1(H) 10.0 (1.1) 16.0 (H)

29.3 31.9 37.9

New Zealand

813 1,084 873

9 6 to 11 12

11.1 9.1 8.1

27.0 14.2 16.8

22.0 (M) 20.0 (H) 12.0 (E)

45.8

27.2 26.6

England Wales Germany Denmark Spain Indonesia China Papua New Guinea

1,613

8.0

965

5.3

1.2 7.9

5,768

9 to 11

4.2

14.8* 22.3

?(H) 8.0 (E) ?

527

7 to 16

5.3

2,216

9 to 14

?

406

7 to 15

1.2

2.3

14.5

2.2 (H)

11 to 17

1.9

2.4

6.3

4.1 (H)

?30

1.7

1.0 (H)

17

3,067

16.0 (H) ?

257

6 to 20

0

0

Kenya Australia Indigenous

402

9 to 12

3.3

11.4

Aborigines

215

7 to 12

0.1

0

31

6.9(E)

10.7 (E)

1.4

1.8(H)

20.5

• Current asthma: Airway hyperresponsiveness (AHR) + wheeze in the last 12 months; Diagnosed asthma: asthma ever diagnosed; H:histamine; M:methacholine; E: exercise; • All figures are a percentage of the population tested.

6-7 years) with approximately 3,000 children in each group were studied in each centre. The 13-14 years-old (n = 463,801) were studied in 155 centres (56 countries) and the 6-7 year-old (n=257,800) were studied in 91 centres (38 countries). There were marked variations in the prevalence of asthma symptoms with up to 15-fold differences between countries. The prevalence of wheeze in the last 12 months ranged from 2.1-32.2% in the older age group and 4.1-32.1% in the younger age group and was particularly high in English-speaking countries and Latin America. A video questionnaire completed in the older age group in 99 centres (42 countries) showed a similar pattern. The major differences between populations found in the International Study of Asthma and Allergies in Childhood Phase One are likely to be due to environmental factors. The results provide a framework for studies between populations in contrasting environments that are likely to yield new clues about the aetiology of asthma.3 Self completed wheezing questionnaire data in 13-14 years and 6-7 years old age group from different regions of the world are shown in Tables 21.2 and 21.3. The ISAAC study has demonstrated, by means of simple standardized questionnaires, that there are large variations in the prevalence of asthma symptoms throughout the world. The self-reported 12 months prevalence of wheezing among 13-14 years-old between countries

316 Bronchial Asthma Table 21.2: Twelve months prevalence of bronchial asthma (%) in school going children 13-14 years old age group

Region

Wheeze

≥4Attacks

Severe wheeze

Exercise wheeze

Night cough

Ever had asthma

Number studied

Africa

11.7

3.4

5.4

23.3

23.3

10.2

20,475

Asia Pacific Eastern Mediterranean

8 10.7

2.2 2.9

1.8 3.8

16 16.9

17.8 20.2

9.4 10.7

83,826 28,468

Latin America North America

16.9 24.2

3.4 7.6

4.5 9.2

19.1 30.9

28.6 33.7

13.4 16.5

52,549 12,460

Northern and Eastern Europe Oceania

9.2

1.9

1.8

12.3

12.2

4.4

60,819

29.9

9.9

8.1

39.0

29.3

25.9

31,301

South East Asia Western Europe

6.0 16.7

1.6 4.6

3.0 4.2

9.5 20.0

14.1 27.1

4.5 13.0

37,171 1,35,559

Grand Total (All World)

13.8

3.7

3.8

18.8

22.3

11.3

4,63,801

Table 21.3: Twelve months prevalence of bronchial asthma (%) in school going children 6-7 years old age group

Region

Wheeze

≥4Attacks

Severe wheeze

Exercise wheeze

Night cough

Ever had asthma

Number studied

Asia Pacific

9.6

2.2

1.5

5.0

17.6

10.7

39,476

Eastern Mediterranean Latin America North America

6.8

1.7

1.7

4.0

13.6

6.5

12,853

19.6 17.6

4.0 5.5

4.5 3.0

9.1 9.6

30.6 25.1

12.4 14.7

36,264 5,755

Northern and Eastern Europe Oceania

8.8

2.0

1.5

3.6

11.4

3.2

23,827

24.6

8.9

4.6

15.9

29.4

26.8

29,468

South East Asia Western Europe

5.6 8.1

1.5 1.9

1.9 1.5

3.6 3.7

12.3 16.1

3.7 7.2

31,697 68,460

11.8

3.1

2.4

6.2

19.1

10.2

2,57,800

Grand Total (All World)

ranged from 2.1% in Indonesia to 32.2% in the UK. Parental reported 12 months prevalence of wheezing in 6-7 years-old ranged from 4.1% in Indonesia to 32.1% in Costa Rica. The highest values for 12-moth prevalence of wheeze were found in developed English-speaking countries (e.g. Peru and Costa Rica). There were considerable variations within regions, e.g. the 12 months prevalence in the 13-14 years-old age group varied within Europe from <5% in Centres in Albania, Georgia, Greece, Italy, Romania, and Russia; to >30% in the UK; and within Latin America from <10% in centres in Argentina, Chile, and Mexico to >25% in centre in Brazil and Peru.

Asthma in Children 317 The analysis shows that there is consistently more variation between countries than within countries. Three countries with a very large number of centres were represented across the range of prevalence, India with 14 centres representing the low prevalence group, Italy with 14 centres representing the middle prevalence group and the UK with 15 centres representing the high prevalence group. However, it must be remembered that the countries, and centres within countries were self-selected, and it is possible that countries with larger within-country variation did not participate. The only other comparable international survey of asthma is the European Community Respiratory Health Survey (ECRHS),4,5 which studied males and females aged 20-44 years., mainly from European centres. Among the 13 centres 10 countries that were reported in both studies, the ranking of prevalence of wheeze in the last 12 months was similar, with the English-speaking countries (Australia, New Zealand, Republic of Ireland, and the UK) having the highest and Italy and Greece the lowest rates. Subsequent other studies from different parts of the world also show similar trends.6-14 Indian Scene The ISAAC data from 12 different parts of the country shows wide variability in the history of wheeze over a 12 months period in children between 13-14 years-old age group ( Table 21.4). In Akola the prevalence was 1.6% whereas the highest figures was reported from Kottayam (17.8%) in the South. The children from this town also had history of “Ever had asthma” of 12.4%. The prevalence was also the highest 24.6% from Kottayam in the 6-7 years-old age group (Table 21.5). There is a difference in the prevalence of asthma in children from Northern and Southern part of the country. From the Northern part of the country the figure varied between 5.4 to 6.9% in the 6-7 years-old age group. The figures from the Western part were less compared to those from the Northern and Southern regions.5 Another hospital based study from South India, Bangalore on 20,000 children under the age of 18 years from 1979, 1984, 1989, 1994 and 1999 in the city of Bangalore showed a prevalence of 9%, 10.5%, 18.5%, 24.5% and 29.5% respectively. The increased prevalence correlated well with demographic changes of the city. Further to the hospital study, a school survey in 12 schools on 6,550 children in the age group of 6 to 15 years was undertaken for prevalence of asthma and children were categorized into three group-depending upon the geographical situation of the school in relation to vehicular traffic and the socioeconomic group of children. Group I—children from schools of heavy traffic area showed prevalence of 19.34%, group II—children from heavy traffic region and low socioeconomic population had 31.14%, and group III—children from low traffic area school had 11.15% respectively. A continuation of study in rural areas showed 5.7% in children of 6-15 areas. The persistent asthma also showed an increase from 20% to 27.5% and persistent severe asthma 4% to 6.5% between 1994-99.15 Another study from Delhi in 1999 revealed the prevalence of current asthma was 11.9% while past asthma was reported by 3.4% of children. Exclusive exercise-induced asthma was reported by 2.1% while that associated with colds by 2.4% of children. Boys had significantly higher prevalence of current asthma as compared with girls (12.8% and 10.7%, respectively). Multiple logistic regression analysis showed that male sex, a positive family history of atopic disorders, and the presence of smokers in the family were significant factors influencing the development of asthma while economic class, air pollution (total suspended particulates), and type of domestic kitchen fuel were not. The prevalence of current asthma in children in Delhi is 11.9%. Significant risk factors for its development are male sex, a positive family history of atopic disorders, and the

318 Bronchial Asthma Table 21.4: Twelve months prevalence of bronchial asthma (%) in school going children 13-14 years old age group in different parts of India

Region

Wheeze

≥4Attacks

Severe wheeze

Exercise wheeze

Night cough

Ever had asthma

Number studied

Akola Bombay (Area 1)

1.6 1.9

0.5 1.2

1.0 1.0

2.7 2.6

3.8 6.5

2.6 3.6

2,138 4,225

Bombay (Area 2) Bombay (Area 3)

10.6 3.6

1.8 1.0

3.2 1.4

11.1 7.4

22.4 14.9

6.5 5.2

2,226 3,178

3.4 4.2

0.6 1.5

1.6 2.7

5.3 8.0

10.2 8.0

5.9 3.3

3,878 3,139

10.7 17.8

3.5 1.7

4.8 13.5

15.9 17.9

18.4 32.2

6.4 12.4

1,094 2,047

8.4 6.0

1.9 3.3

2.9 3.6

7.7 7.4

14.6 11.5

2.8 1.8

1,903 3,086

13.0 6.0

3.0 1.9

4.8 2.5

18.4 23.2

25.8 16.9

5.3 2.4

3,026 3,281

3.8 1.8

0.8 0.8

2.1 1.3

6.8 4.0

13.5 9.4

2.8 4.9

1,248 2,702

Borivali Chandigarh Jodhpur Kottayam Madras (Area 1) Madras (Area 2) New Delhi Neyveli Orissa Pune

Table 21.5: Twelve months prevalence of bronchial asthma (%) in school going children 6-7 years old age group in different parts of India

Region

Wheeze

≥4Attacks

Severe wheeze

Exercise wheeze

Night cough

Ever had asthma

Number studied

Akola Bombay (Area 1)

5.6 0.8

1.5 0.6

1.9 0,6

3.6 1.0

12.3 3.3

3.7 1.3

31,697 2,030

Bombay (Area 2) Bombay (Area 3)

3.8 1.8

1.3 0.7

1.6 0.7

3.0 1.8

12.6 8.3

3.8 2.3

3,967 3,568

Borivali Chandigarh

5.2 5.4

2.0 1.9

1.7 2.8

3.1 3.8

12.3 10.7

3.4 2.8

1,672 2,891

3.5 24.6

1.3 4.7

1.4 7.5

2.9 13.3

13.6 27.0

4.1 14.4

1,104 2,156

Madras (Area 1) Madras (Area 2)

7.2 8.5

2.1 2.4

1.4 2.5

2.5 3.8

16.4 15.4

1.4 2.2

1,406 2,491

New Delhi Neyveli

6.9 1.5

1.4 0.1

1.6 0.3

4.1 1.4

14.6 8.1

3.7 1.0

2,938 1,498

Orissa Pune

4.1 2.3

1.4 1.0

2.2 1.3

3.8 2.5

8.7 9.5

3.8 4.2

1,520 3,248

Jodhpur Kottayam

presence of smokers in the family.16 A more recent study from Chandigarh, North India examined the prevalence of asthma and its association with environmental tobacco smoke exposure among adolescent school children. Using a previously standardized questionnaire, data from 9,090 students in the 9 to 20 years age range were analyzed. There were 4,367 (48%) boys, in whom the observed prevalence of asthma was 2.6%. Among 4,723 (52%) girls, asthma

Asthma in Children 319 was present in 90 (1.9%) students. 31% students reported presence of one or more respiratory symptoms. More students with asthma had either parents or other family members smoking at home as compared to nonasthmatics (41% vs. 28%, p<0.0001). The odds ratio for being asthmatic for patients exposed to ETS compared to those not exposed to ETS was 1.78 (95% confidence interval 1.33-2.31). ETS was also positively associated with prevalence of all the respiratory symptoms, with odds ratios varying between 1.6 and 2.25.17 Risk Factors A number of risk factors have been identified for the causation of bronchial asthma in children. They include male sex a positive family history of atopic disorders, and the presence of smokers in the family,16 urbanization, air-pollution, environmental tobacco smoke,15,17 and other socio environmental factors.18 Intrauterine Exposure Some studies have suggested a link to maternal, not paternal, allergy in the development of allergy and asthma. While it has been suggested that preferential acquisition of the mother’s genes (genomic imprinting) may account for this phenomenon, such an occurrence is excessively uncommon and the intrauterine environment is a more likely cause. A positive relationship has been found between greater head circumference at birth and the later development of allergy and high serum IgE levels. At first, such an association may sound strange, but placental and nutritional factors that increase brain growth in the last trimester of pregnancy may well influence the maturation of the thymus gland, the origin of the immune system. It has been suggested that after 26 weeks gestation, the fetus adopts a T’hl immunephenotype, to prevent maternal rejection and that, in the last trimester, with increased IFN-γ production, this phenotype converts to a more T’hl picture. IL-4 is produced by the human amnion epithelium throughout pregnancy, and IL-10, a cytokine that inhibitors have been found in human placenta. If, on account of factors, the Th2 mode is maintained rather than converting to a T’hl mode, an allergic diathesis might be expected to occur. Such a mechanism might also be invoked as a factor in sudden infant death syndrome in which mast cell tryptase and eosinophils are encountered in the lung and circulation. It is also possible that allergens crossing the placenta may be involved in subsequent development of allergy and asthma since mothers exposed to high concentrations of allergens, such as birch pollen, during the last trimester of pregnancy are more likely to have children who develop allergy and asthma. It is not known, however, how minute amounts of allergen taken in by the mother can cross the placenta to sensitive offspring. However, it has been shown, that children who subsequently develop allergy or asthma, have impaired cord blood T-lymphocyte production of IFN-γ at birth in response to exposure to specific allergens. This impaired response suggests an impaired inhibitory mechanism for shutting down a Th2 response rather than one that primarily enhances it. Other environmental factors that may direct the placental-fetal relationship towards a Th2 response include young maternal age and smoking during pregnancy. Several studies have reported an increased prevalence of respiratory symptoms like cough, wheeze and reduction in lung function in children or adolescents who were born as premature infants or who had a low birth weight.19,20

320 Bronchial Asthma Viral Infection It has long been recognized that viral infections, especially the common cold viruses, can lead to deterioration of asthma lasting several weeks. In infants, respiratory syncytial virus (RSV) is responsible for most wheezing illnesses. These observations have suggested that viral infections may be intimately involved in the development of asthma and allergy. It has been shown that over 80% of acute asthma exacerbations in school children and about 60% in adults result from viral infections (mostly common cold viruses). One explanation of the susceptibility of the asthmatic airway to viral inflammation is that persistent allergic mast cell and eosinophil-driven inflammation stimulates the release of cytokines such as tumour necrosis factor-alpha, which cause an increase in the expression of receptors for human respiratory viruses on the airway lining epithelium. In the case of most rhinoviruses, the receptor is an adhesion molecule, intracellular adhesion molecule-1. Once the virus enters the epithelial cells, it replicates and is able to generate wide variety of proinflammatory cytokines, which further enhance eosinophil and mast cell inflammation. Protective Infections Curiously, an important additional socioeconomic factor may be a reduction in early childhood infections (viral, bacterial, or parasitic) associated with improved living conditions. While viral infections can undoubtedly cause deterioration of established asthma, there is evidence that viral or bacterial infection during the first 3 years of life may serve a protective function against the development of allergic diseases. One of the most consistent risk factors for allergy relates to family size. The prevalence of mucosal allergy and positive skin tests in children declines markedly in the last-born child with increasing numbers of siblings. A working hypothesis is that over the past 30 years, opportunities for acquiring infections from siblings or playmates in early childhood have declined with reduction in average family size, vaccination programs, and higher standards of personal hygiene. Most viruses and some bacteria are able to evoke a Thl like protective response with the generation of IFN-α and IL-12. Thus, if multiple infections occur during the first few years of life, high concentrations of these Th1, cytokines could inhibit the release of Th2 cytokines, thereby biasing the mucosal immune response away ‘for this hypothesis is seen in an African study of, from allergen sensitization. Support adolescents infected with measles during the first year of life compared to those vaccinated later. Those infected early had a 63% lesser chance of developing positive skin tests to common aeroallergens. Repeated Bacille Calmette-Guerin (BCG) vaccination in young Japanese children also exerts a protective effect against the development of allergy. Both measles and BCG are potent stimulators—of the Th1 cytokine response’. It has also been suggested that the increase in asthma and allergy with movements to urban centres may be related to the decrease in early exposure to parasitic infections common in some rural areas. One study tested the effect of anti-helminthic treatment on the allergic reactivity of children in a slum area of Caracas, Venezuela. One group was treated for 22 months while a second group who declined treatment was used as a control. Active treatment eliminated worms in children (from 68 to 5%) and resulted in a decrease in total serum IgE levels (from 2,543 to 1,124 IU/ml) but was accompanied by an increase in skin test reactivity to house dust mite (from 17 to 68%). In contrast, in the untreated group, parasite colonization continued to increase (43 to 70%), IgE levels increased (1,649 to 3,697 IU/ml), but dust mite

Asthma in Children 321 sensitization fell (26 to 16%). Further testing showed that polyclonal stimulation of IgE synthesis by the parasites resulted in mast cell receptor saturation and suppression of specific IgE antibody synthesis. From a public health stand point; high levels of nonspecific IgE may protect rural dwellers exposed to parasites from allergy and asthma. It follows that eradication of parasites or reduced opportunities for infection could, in part, explain the rural to urban differences in the prevalence of allergic diseases. Some investigators believe that early childhood respiratory symptoms are a risk factor for asthma.21 This inference however, is weakened by the possibility of recall bias. Perhaps, respiratory symptoms reported by parents very early in life are not significantly associated with future asthma, but those symptoms that begin at or persist through age 3 to 4 years are likely to be associated with asthma.22 Diet As societies become affluent, the dietary habits change and such changes are linked with increased prevalence of asthma observed in recent years.23-25 Prospective studies have shown that breastfeeding has a transient beneficial effect on the incidence of eczema, food allergy, atopic sensitization, and wheezing illness in the first three years of life.26,27 However, there is little evidence for a persistent protective effect of breastfeeding on the ‘incidence of childhood asthma.28-30 In the UK, the amount of salt eaten with food seems to be correlated with bronchial hyperreactivity and asthma mortality.31 The severity of asthma—not its inception—has been linked to increased salt intake, but only in males.32 Recent studies have shown lower prevalence of asthma and bronchial hyperresponsiveness in children with a high intake of fresh oily fish,33 a source of’ polyunsaturated oils. Other studies also have shown an association of a, high fish consumption and improved baseline FEV1.34 Children who eat fish regularly consume more omega-3 fatty acids, which may protect them from bronchial hyperresponsiveness. Air-Pollution Air-pollution has been cited as—a causal factor in the development of asthma. The US Environmental Protection Agency concludes that35 passive exposure to tobacco smoke is causally related to: i. An increased risk of lower respiratory tract infections, such as bronchitis and pneumonia in infants and young children, ii. A small but significant dose-dependent reduction in pulmonary function, and iii. Additional episodes and increased severity of asthma symptoms in asthmatic children. Exposure to tobacco smoke is also considered to be a risk factor for the development of new cases of asthma in children.36 Trucson Children’s Respiratory Study has shown that maternal smoking is related to both transient early wheezing and persistent wheezing.37 The role of sulphur dioxide and particulate matters in the causation of asthma is not well established.38-41 Traffic pollutions42 and effects of ozone may also be of consequence for childhood asthma.43 Evolution of Asthma Asthma may develop during the first few months of life, but it is often difficult to make a definite diagnosis until the child is older. In infants, the most common cause of wheezing is

322 Bronchial Asthma respiratory viral infections. However, there is a correlation of early wheeze with reduced lung function before the onset of symptoms, which suggests that small lungs may be responsible for some infant wheeze that resolves with the child’s growth. Those children with asthma continue to wheeze in later childhood. Recurring exacerbations of asthma may be associated with exposure to allergens. In the susceptible infant, atopy may predispose the airways to sensitization by environmental allergens or irritants and the child experiences recurrent episodes of wheezing. In particular, early exposure to Alternaria, housedust mite, and animal allergens in high quantities appears to be important as discussed above. During early childhood, wheezing and cough may occur at infrequent intervals. In some infants wheezing becomes more frequent and asthma is well established at an early age. It is reported that the majority of 7-years-old children with airway hyperresponsiveness suffered from atopy during their infancy.44 Asthma also affects development of the lung. Asthma in infancy can result in a decrease ‘in lung function by approximately 20% in adulthood,45 although subsequent studies did not confirm the same.46 The predominant feature associated with asthma in children is allergy, and house dust mite represent major allergens worldwide in, both affluent and partly affluent countries.47 The role of viral infection in the causation of asthma in older children is less clear, although in atopic children viral infection is clearly important triggers of asthma exacerbations. By the age of 8 years, a proportion of children develop airway hyperresponsiveness and the associated symptoms of moderate to severe persistent asthma, while others continue to have mild intermittent asthma.48 Lung growth is unaffected in most children with asthma, but it can be reduced throughout childhood and adolescence in those with severe and persistent symptoms. A longitudinal study in New Zealand concluded that improved spirometric function was impaired in children with airway hyperresponsiveness and/or allergy to house dust mite or cat allergen.49 Although childhood asthma has long been considered as a single, easily recognizable disease characterized by reversible airflow limitations,50 recent findings have challenged this concept. Martinez et al21 studied the natural history of children (0-6 years) and found that approximately half of them experienced wheezing at some time during the study period. They recognized three patterns of wheezing: 1. Transient early wheezing. Wheezing occurred in life but resolves by the age of three years 2. Late onset wheezing. Some experience wheezing between the ages of three and six years 3. Persistent wheezing. Wheezing illness throughout the entire study period. The outcomes of these patterns are associated with different risk factors. Children with transient early wheezing had reduced pulmonary function as measured by functional residual capacity shortly after—birth and before any lower respiratory tract illness had occurred. The risk also increases in children—of mothers who smoked during pregnancy, had lower lung function values compared to those whose mothers did not smoke. Thus, the authors concluded that congenitally smaller airways might predispose children to wheeze illness later in life. Persistent and late onset wheezing is more likely associated with atopy with their mothers being asthmatics. Lung function in persistent wheezers is also less. The long-term prognosis of childhood asthma is a matter of controversy and of major concern. It has often been believed that the child grows out of its asthma when he or she reaches adulthood (asthma disappears). However, epidemiological studies are less convincing.46,51,52 Although there are methodological difficulties it is estimated that asthma disappears in 30 to 50% of children at puberty, but often reappears in adult life. Up to

Asthma in Children 323 two-third of children with asthma continue to suffer from the disorder through puberty and adulthood. Even when asthma symptoms disappear, the lung function frequently remains altered or airway hyperresponsiveness or cough persists. The prognosis of asthma becomes worse when the child has eczema or there is a family history of eczema. Wheezing in the first year of life is not a prognostic indicator for asthma or for more severe asthma or for more severe asthma later in childhood. About 5 to10 % of children with asthma that is considered trivial will have severe-asthma in later life. Therefore, childhood asthma should never be neglected with the hope that the child will grow out of it. Children with mild asthma are likely to have a good prognosis, but those with a moderate to severe asthma probably continue to have some degree of airway hyperresponsiveness and will be at risk of the long-term effects of asthma throughout life.53 Some, clinical studies have reported that up to 80% of asthmatics become asymptomatic during puberty.54,55 In a cohort study of Australian school children56 tested initially at the age of 8 to 10 years and then again at 12-14 years of age, the persistence if bronchial hyperresponsiveness at 12 to 14 years of age was found to be related to the severity of disease at 8 to 10 years of age, the atopic status of the child, and the presence of asthma in the parents. Most of the children who had a slight or mild degree of bronchial hyperresponsiveness at 8 to 10 years of age lost their increased response by the age of 12-14 years. However, only 15.4% of children with severe or moderate bronchial hyperresponsiveness at initial assessment had normal levels of bronchial responsiveness at the later assessment. There are several factors why asthma often goes unrecognized and tends to be under treated in teenagers because usually this is a period of turmoil, awkwardness, rebelliousness, and intolerability.53-59 Notwithstanding the factors described above as the factors responsible for the induction of asthma in childhood, occurrence of asthma within families is the strongest risk factor for the development of asthma in children.60-63 DIAGNOSIS Various symptoms and signs of bronchial asthma are not different than those in adults as discussed earlier. However, in children there is more chance of under diagnosis in this age group. This is a frequent problem and occurs most often when young children who wheeze only when they have respiratory infections and are dismissed as having wheezy bronchitis, asthmatic bronchitis, bronchitis, bronchiolitis, or pneumonia, despite evidence that the signs and symptoms are most compatible with a diagnosis of bronchial asthma. Although, recurrent episodes of cough and wheezing are almost always due to asthma in both children and adults, it is to be remembered that all that wheezes is not asthma always. There are other causes of airways obstruction leading to wheezing. The differential diagnosis will be as follows. Infants and Children

Obstruction in the Large Airways 1. Foreign body in trachea, bronchus 2. Vascular rings 3. Laryngotracheomalacia

324 Bronchial Asthma 4. 5. 6. 7.

Enlarged lymph nodes or tumors Laryngeal webs Tracheal stenosis Bronchial stenosis

Obstruction Involving both Large and Small Airways 1. 2. 3. 4. 5. 6. 7. 8. 9.

Bronchial asthma Viral bronchiolitis Cystic fibrosis Chlamydia trachomatis infection Obliterative bronchiolitis Bronchopulmonary dysplasia Aspiration Vascular engorgements Pulmonary oedema

Miscellaneous 1. 2. 3. 4.

Primary ciliary dyskinesia syndrome Primary immune deficiency Congenital heart disease Congenital malformations causing narrowing of intrathoracic airways.

Asthma in childhood can present a particularly difficult problem largely because episodic wheezing and cough are among the most common symptoms encountered in childhood illnesses, particularly in the under-3-years-old. Although health care professionals are increasingly encouraged to make a positive diagnosis of asthma whenever recurrent wheezing, breathlessness, and cough occur (particularly if associated with nocturnal and early morning symptoms), the underlying nature of the disorder’s process may differ in infants from that in older children and adults. The use of the label “asthma” to describe such children has important clinical consequences. It implies a syndrome in which there is airway inflammation and for which there is a specific protocol of management. The younger the child, particularly below ages 5, the greater the possibility of an alternative diagnosis for recurrent wheeze as described above. Chest radiography is important as a diagnostic test to exclude alternative causes. Features such as a neonatal onset of symptoms, associated failure to thrive, vomitingassociated symptoms, and localized lung or cardiovascular signs all suggest an alternative diagnosis and indicate the need for investigations, such as a sweat test to exclude cystic fibrosis, measurements of immune function, and reflux studies. Among those with no alternative diagnosis, there is the possibility that the problem does not have a uniform underlying pathogenesis. Nonetheless, there are two general patterns of wheezing in infancy. Some infants who have recurrent episodes of wheeze associated with acute viral respiratory infections, often with a first episode in association with respiratory syncytial virus (RSV) bronchiolitis, come from nonatopic families and have no evidence of atopy themselves. These infants usually outgrow their symptoms in the preschool years and have no evidence of subsequent asthma, though they may have minor defects of lung function

Asthma in Children 325 and airway hyperresponsiveness. This syndrome may have more to do with airway geometry than airway inflammation, and thus may differ mechanistically from the more established chronic inflammatory condition that underlies asthma in older children and adults. Other infants with asthma have an atopic background often associated with eczema and develop symptoms later in infancy that persists through childhood and into adult life. In these children, characteristic features of airway inflammation can be found even in infancy. However, there are no practical clinical tests that can be done to establish the presence of airway inflammation. Only associated atopic problems can be used as a guide to prognosis. Early age (less than 2 years) of onset of wheeze is a poor predictor of continuing problem in later childhood. It is likely that the issue of asthma associated with recurrent virus-related episodes and the later development of persistent asthma requires further study. Apart from the confusion over aetiological mechanisms of asthma in childhood, there is also considerable reluctance in establishing a diagnosis and, as a consequence, initiating appropriate therapy. Because lower respiratory tract symptoms similar to symptoms of asthma are so common in childhood (and frequently occur in association with upper respiratory tract symptoms), either a correct diagnosis is not made or an inappropriate diagnosis is given, thereby, depriving the child of antiasthma medication. Although in these young children there is the possibility of over treatment, the episodes of wheezing may be foreshortened and reduced in intensity by the effective use of antiinflammatory drugs and bronchodilators rather than antibiotics, and it is for this reason that health care professionals are encouraged to use the word “asthma” rather than other terminology to describe this syndrome. Asthma in all age groups may present only as repeated coughing especially at night, with exercise, and with viral illness, but these are particularly common forms of presentation of asthma in childhood. The presence of recurrent nocturnal cough in an otherwise healthy child should raise awareness of asthma as a probable diagnosis. Although repeated infections of the sinuses, tonsils, and adenoids may explain nocturnal coughing, the occurrence of this symptom awaking the child in the early hours of the morning is almost always diagnostic of asthma. Under the age of 5 years, the diagnosis of asthma has to rely largely on clinical judgment based on a combination of symptoms and physical findings. Because the measurement of airflow limitation and airway hyperresponsiveness infants and small children requires complex equipment and is difficult, it can therefore only be recommended as a research tool. A trial of treatment is probably the most confident-way in which a diagnosis of asthma can be secured in children (and in many adults as well). Prognostic features include a family history of asthma or eczema and presence of eczema in a young child with respiratory symptoms. Children aged 4 to 5 can be taught to use a peak expiratory flow (PEF) meter and obtain reliable readings. However, unless there is careful parental supervision over when and how the measurements are made, PEF recording in childhood can be unreliable. Some children with asthma only present with exercise-induced symptoms. In this group, or when there is doubt over the existence of low-grade asthma in childhood, exercise testing is helpful. A 6-minute running protocol is easily performed in clinical practice, and when used in-conjunction with measurements of airflow limitation (FEV, or PEF), it can be most

326 Bronchial Asthma helpful in establishing a firm diagnosis, especially if the cough produced by the exercise is similar to that occurring spontaneously at night. MANAGEMENT OF ASTHMA IN CHILDREN Several guidelines have been published since 1990 with the aim of improving management of asthma both in children and adults. However, a systematic analysis of guidelines till 1995 had brought out several controversial-issues as well as gaps in knowledge. In May 1997, an expert committee of the National Heart Lung and Blood Institutes of USA published guidelines about management of asthma where they have tried to overcome many of the previous lapses. These guidelines along with the recent British thoracic society guideline have been discussed in previous chapters. The need for similar guidelines has always been felt amongst the physicians managing children in India, but no uniform guidelines are available for the disease as seen in India. It. was felt that the guidelines originating in India would have much more relevance to the ground situation and the status of health services. To setup the process of achieving consensus, towards suitable guidelines, a Consensus Conference was held on April 17 and 18, 1998 at the Advanced Paediatric Centre of the Post Graduate Institute of Medical Education and Research, Chandigarh in which, 15 experts who manage asthma patients and have published papers in this field, participated. Recent evidence was accessed using searches on Medline, Embase, Index Medicus, and Excerpta Medica. Some of the contentious issues were resolved with the help of the Cochrane Library.64 Since the consumer of health care in India is not sufficiently literate, physicians have been assigned a lot of responsibility in decision making for the patients. The guidelines are required to be updated periodically and provide flexibility to individualize patients. Since in a large area in our country, all the recommended modalities may not be available then suitable improvisations must be made. The objectives of the conference were: i. To reach at a uniform treatment approach towards children with asthma keeping in mind the limitations of resources in the Indian context and to develop guidelines based on available evidence for the pediatricians, and ii. To prepare a consensus document for management of children with asthma which would provide guidelines to a general pediatricians managing asthma in India. Various components discussed included pathogenesis, definition, classification of severity, measure of assessment and monitoring, referral, control of factors contributing to asthma in seventy, pharmacological therapy and education of patient, family and health professionals regarding asthma care. The Expert Group I recommended that for the diagnosis of asthma in children a detailed medical history, careful physical examination and peak-expiratory flow rate (PEFR) measurement to demonstrate obstruction with reversibility of variable airflow obstruction are needed. To establish the diagnosis of asthma the clinician must determine that: i. Episodic symptoms of airflow obstruction, more than 3 episodes are present ii. Airflow-obstruction is at least partially reversible iii. Alternative diagnoses are excluded.

Asthma in Children 327 Physicians who care for children with asthma should be well versed in PEFR monitoring. They should perform spirometery wherever possible. Measures of Assessment and Monitoring A child with asthma is to be monitored for clinical signs and symptoms of asthma with the help of asthma diary given to the patients/parents and record of PEFR with a standardized peak flow meter. PEFR must be monitored at the physician’s office, asthma clinics (where spirometry should be available) and in the emergency room, and patients must be encouraged and trained to monitor their PEFR at home once a day routinely and twice a day if the morning reading is abnormal to determine their PEFR variability. Patient’s personal best should be assessed and used subsequently. Spirometry has been kept optional, and emphasis must be given to patient’s quality of life. Emphasis must be on self-management but physician’s supervision must still be the prima mode. Patients must be given a written crisis management plan where literate. Otherwise verbal communication at each contact must continue. Classification of Asthma Severity Asthma severity classification was accepted as changed to be mild intermittent, mild persistent, moderate persistent and severe persistent asthma (Table 21.6). Since spirometry is not routinely available to pediatricians in this country it was felt that more emphasis be placed on PEFR measurement, especially at the physician’s office. Patient’s personal best be used as the standard but in its absence expected PEFR according to norms published on children in India must be used.65 It was also mentioned that a severe form of asthma requiring daily oral steroids or stronger treatments like immunosuppressants is extremely uncommon in Indian children, and most of the children get controlled with inhaled medications. Goals of Asthma Therapy The goals of asthma therapy are: • Prevent chronic and troublesome symptoms • Maintain near normal (PEFR) • Maintain normal activity levels (including exercise and physical activity) • Prevent recurrent exacerbations of asthma and minimize the need for emergency room visits and hospitalization • Provide optimal pharmacotherapy with minimal side effects • Meet patient’s and family’s expectations of satisfaction with asthma care. Pharmacological Therapy Pharmacological therapy is the cornerstone of management. It must be instituted with proper environmental control measures. Medications are classified into two broad categories: i. Long-term control medications or the preventatives, and ii. Medications or rescue medications. Long-term control medications, are, inflammatory compounds. Early intervention with inhaled steroids can improve control and normalize lung function, and preliminary studies show that it might prevent irreversible airway injury. These are to be administered with the help of a metered dose inhaler (MDI) and

328 Bronchial Asthma a spacer (in patients who cannot afford the spacers a home-made spacer can be used). Another cheaper alternative is a dry powder inhaler (transparent rotahaler). A step care approach management of asthma starting at a higher level and then stepping-down as control is established (Table 21.7). Table 21.8 gives details of assessment of severity of asthma in children and Figures 21.1 and 21.2 outline management of asthma exacerbation. Table 21.6: Classification of asthma severity

Guide

Symptoms

Night-time symptoms

Lung Function

Severe persistent Step 4

Continual symptoms

Frequent

PEFR < 60 % predicted

> 1 time/week

PEF>60 to <80% predicted

>2 time/month

PEF ≥80 % predicted

≤ 2 time/month

PEF ≥80 %

Moderate persistent step 3 Mild persistent step 2 Mild intermittent step 1

Limited physical activity Frequent exacerbations Daily symptoms Daily use of beta-agonist Exacerbation affecting activity, ≥ 2/weeks, lasting days Symptoms > 2/week But <1 /day Exacerbation may affect activity Symptoms ≤ 2/week Exacerbation brief, Asymptomatic between exacerbations

The presence of one of the features is sufficient to place a patient in that category. A child should be assigned to the most severe category in which any feature occurs. An individual classification may change over a period of time Table 21.7: Stepwise approach in long-term management of children with asthma

Grade

Long-term

Severe Daily therapy high dose inhaled, steroid pesistent (BDP 1200 μg or BUD>600 or FP* step 4 200-400 μg + Long acting beta sympathomimetic or SR Theophylline or oral steroids. For infants ≤ 2 years inhaled medication with spacer and/or mask Moderate Daily therapy. Medium-dose inhaled pesistent steroid (BDP 600-1200 μg or BUD step 3 400-600 or FP 100-200 μg) or Low-medium dose inhaled steroid + SR Theophylline or long acting beta sympathomimetic. For infants inhaled medication with spacer and mask Mild Daily medication NSAIDs like Cromolyn persistent (1-5 mg/dose Oh) or low-dose inhaled step 2 steroid (BDP 200-600 or BUD 100-400 or

Quick relief

Education

Short-acting broncho- Step 1 + selfdilator. Infants as monitoring in step 1 Group education

Short-acting broncho- Step 1 + selfdilator Infants as monitoring in step I education/ counselling

Short-acting broncho- Step 1 + selfdilator. Infants as in monitoring step 1 Group education

Contd...

Asthma in Children 329 Contd... Grade

Mild asduna, intermittent step 1

Long-term

Quick relief

Education

FP50-100 μg) and Theophylline 5-15 mg/kg spacer and mask for infants ≤ 2 years No daily medications needed Short acting bronchodilator, inhaled β2 agonists sos use of β2-agonist > 2 times/ week indicates need for preventative drugs. For infants (< 2 years) bronchodilator as needed for symptoms. Use facemask with holding chamber or nebuliser or oral β2agonist

Basic facts about inhaler technique, discuss role of medication, selfmanagement and action plans, environmental control

Abbreviation: BDP-beclomethasone dipropionate, BUD-budesonide, FP-fluticasone propionate, SR-sustained release, FP is recommended for children older than 4 years Table 21.8: Classifying severity of asthma exacerbations

Mild

Moderate

Severe

While at rest (infant—stops feeding)

Can lie down

While talking (infant—softer, shorter cry; difficult feeding) Prefers sitting

Phrases

Words

Symptoms Breathlessness While walking

Talks in sentences Alertness

May be agitated Usually agitated

Signs Respiratory rate Increased

Increased

ReiTiratory Arrest Imminent

Sits upright

Usually agitated

Drowsy/confused

Often >30/ m

(Guide to breathing rates in awake children): Age Normal rate < 2months < 60/niin < 2-12 months < 50/n-dn 1-5 years < 40/n-dn 6-8 years < 30/min Use of accessory muscles: Suprasternal retractions

Usually not

Commonly

Usually

Paradoxical thoracoabdominal movement

Contd...

330 Bronchial Asthma Contd... Mild

Moderate

Severe

ReiTiratory Arrest Imminent

Wheeze

Moderate often only end expiratory

Loud; throughout exhalation

Usually loud; throughout inhalation and

Absence of wheeze

Pulse/min

< 100

100-120

> 120

Bradycardia

(Guide to heart rate in normal children): Age Normal rate 2-12 months < 160 min 1-2 years < 120 min 2-8 years < 110 min

Ask and record

Examine for

1. 2. 3. 4.

1. Sensorium 2. Respiratory rate, heart rate, colour, use of accessory muscles, breath sounds intensity, wheeze 3. Saturation-SaO2 if pulse oxymeter is available 4. Peak expiratory flow rate

Duration of present episode Medications already being used Time of last aminophylline dose (if taking) Precipitating factors—infections, exercise, drugs, stress, seasonal, etc. 5. Severity of previous episodes of treatment required

Treatment Phase I—Ist one hour 1. Oxygen by mask to achieve saturation >90% (minimum 5 L/min through simple facemask) 2. Start β2 sympathomimetic nebulisation 0.15 mg/kg/dose (minimum dose 2.5 mg) every 20 min for 3 doses. For delivery dilute aerosols to minimum of 4 ml of saline at (flow of 6-8 1/minutes) or β2 sympathomimetic through MDI and spacer with/without facemask 4 to 8 puffs every 20 minutes (10-20 puffs in one hour). In case of nonavailability of nebuliser or MDI and spacer or where the patient cannot move the needle of the peak flowmeter—parenteral beta-agonists (adrenaline/terbutaline) should be given in the dose of 0.01mg/kg up to 0.3 to 0.5 mg every 20 minutes for 3 doses in the first hour subcutaneously. 3. All children presenting with acute exacerbation should receive systemic steroids. Prednisolone 2 mg/kg/dose or methylprednisolone 1-2 mg/kg/dose or hydrocortisone 10 mg/kg/dose. At the end of hour repeat assessment with more emphasis on symptoms and signs, PEFR done if possible. In interpreting PEFR value is compared with predicted value of Indian children or personal best of the child if available. From the assessment 2 groups are identified: A. Good response Physical examination normal (decrease in heart rate from the previous value, respiratory rate, pulses paradoxus <10 mm Hg, no usage of accessory muscles, alert sensorium) O2 saturation >90 per cent, PEFR>70%. B. Incomplete response/poor response Mild to moderately severe symptoms and signs (see Table No. 21.8) for mild, moderate and severe classification of symptoms signs, PEFR< 50 to < 70%.

Contd...

Asthma in Children 331 Contd... Phase II—Management A. Good response group - Discharge home,continue treatment with β2-agonist and course of oral systemic corticosteroid 1-2 mg/kg/day maximum 60 mg/day in a single or 2 divided doses for 3-10 days. - Patient education, review medicine use, initiate action plan, recommend close medical follow-up. B. Incomplete/Poor responders - Continue O2, β2-sympathomimetic inhalation every 20 mts Continuous nebulization can also be used under strict monitoring for heart rate and blood potassium levels. - Continue systemic steroids. - Add ipratropium bromide nebulization 250 micrograms every 20 mts for three doses, May mix in same nebulizer with β2-sympathomimetic. - If no response, aminophylline infusion, (0.25 mg/kg/hr) can be tried. - IV Magnesium sulphate 50% 50 mg/kg/dose IV infusion in 30 ml normal saline/30 mt can be given before transfer to ICU. Continue to assess every one—hour, continue same treatment for 4 hours. Improvement at end of 6 hours since initiation of treatment decrease the frequency of β2sympathomimetic inhalations every 1 to 4 hr as needed, Stop parenteral aminophylline, Continue systemic steroids 1-2 mg/kg/day in 2 divided doses for 3-10 days. If no deterioration continue same treatment. If deterioration, follow intensive care of the child with asthma in pediatric ICU for possible intubation and mechanical ventilation in presence of: i. Exhaustion, shallow respiration, confusion or drowsiness ii. Coma/respiratory arrest iii. Worsening or persisting hypoxia. Fig. 21.1: Management protocol for acute exacerbation of childhood asthma emergency room

Assess Severity Measure PEF: Value <50% personal best or predicted suggest severe exacerbation Note signs and symptoms: Degrees of cough, breathlessness, wheeze and chest tightness correlate imperfectly with severity of exacerbation. Accessory muscle use and suprasternal retraction suggests severe exacerbation. Initial Treatment Inhaled short-acting beta-agonist: Up to three treatments of 2-4 puffs by MDI at 20-minute intervals or single nebuliser treatment.

Good response

Incomplete response

Poor response

Mild episode PEF>80% predicted or personal best

Moderate episode PEF 50-80% predicted or personal best

Severe episode PEF<50% predicted or personal best

Contd...

332 Bronchial Asthma Contd... No wheezing or shortness of breath Response to β2-agonist sustained for 4 hours • May continue β2-agonist every 3-4 hours for 24-48 hours • For patients on inhaled corticosteroids, double dose for 7-10 days

Persistent wheezing or shortness of breath • Add oral corticosteroid • Continue β2-agonist

Marked wheezing or shortness of breath • Add oral corticosteroid • Repeat β2-agonist immediately • If distress is severe and nonresponsive, call your doctor and proceed to emergency department, consider calling ambulance

• Contact clinician for follow-up instructions

• Contact clinician urgently (this day) for instructions

• Proceed to emergency department

Fig. 21.2: Home treatment of asthma exacerbation in children

Referral Patients must be referred to a special clinic of asthma if any of the following problems arise: • Failure to meet the goals of therapy • Atypical signs or symptoms or uncertain diagnosis • Presence of complications • Need for additional diagnostic testing like skin tests, pulmonary function tests endoscopy, incremental growth assessment etc. • Severe symptoms such as step 4 care • Nonadherence to therapy • Need for good asthma education • Significant psychosocial or psychiatric problems Environmental Control and Prevention of Asthma

Allergen Avoidance Indoor allergens Cockroach, house dust mite, fungal spores, animals (pets) are the main sources. Skin testing can be used, for the diagnosis. Following control measures are suggested. Cockroaches Leave no food uncovered. Traps are better than the anticockroach chemicals. House dust mite Sun the bedding weekly. No carpets or stuffed, the house. Proper mapping of the country needs I to be done to see where dust mite is an important allergen-expected in warm, humid climate. Pets Pets like dogs, cats or birds should not be kept. Reports on pets are very few in this country. If pets are already in the house contact with the patients should be minimized or they should be kept out of the premises. Moulds or indoor fungal spores Prevent see page of water through rooms or walls during the rainy season. Keep rooms well ventilated and allow sunlight in.

Asthma in Children 333 Seasonal exposure to pollens and fungi can be reduced by keeping the doors and windows closed from every morning till evening. Wherever affordable, air-conditioning can be used. In case an allergen is found to contribute significantly to patient problem, he or she should be referred to a specialist for skin testing and if required, for immunotherapy. In children less than 5 to 6 years of age immunotherapy is avoided.

Irritants or Chemicals Avoid tobacco smoke, strong odours, fumes from various kinds of stoves/chullah, using kerosene, wood, cowdung. In high risk families (atopy on both sides or even one side), exclusive breastfeed to continue for 4 to 6 months and mother to avoid well-known allergenic food in diet while baby is exclusively breastfeed. Psychosocial Aspects of Asthma Management in Children Children with chronic illnesses are at an increased risk for developing psychological disturbances. Children with severe asthma have been found to be three times more likely to develop emotional/behavioural problems as compared to healthy children. It was decided at the meeting that the primary physician to the patient be able to deliver the necessary preventive services like explaining the basic facts about the disease and try to improve the quality of life by optimum care. Mental health workers can provide important services to asthmatic children, who have obvious psychological or behavioural problems, experience school difficulties and are noncompliant with treatments. Family therapy aimed at modifying family interaction problems and parent-child relationships can help in improved management of asthma and also improve the overall quality of life. Hence, family therapy is considered an adjunct to the conventional treatment in asthma in children with severe disease. It is important that psychologists be part of the multidisciplinary treating team in order to provide comprehensive services to children with asthma. Health Education The experts stressed the need for health education not only in asthma clinic or hospital but also on TV, radio and other communication media. The attitudes and practices concerning this disease demonstrate a high degree of ignorance and misinformation. Written material containing information regarding basic facts of asthma should be made available to the patient and the parent at the time of transmission of information regarding the diagnosis. Special measures were recommended to be taken to educate the people about the harms of passive smoking. Future Directions for Research The data presented indicates gross inadequacy of information regarding basic facts of asthma to patients and their parents. Intervention in the form of written material significantly improves the knowledge of these individuals. More studies need to be done to assess the knowledge, attitudes and practices of these patients and specific materials developed to improve the baseline information and change attitudes towards inhalational therapy. All the participants felt that there was a local social stigma attached to the disease, and parents of the patients

334 Bronchial Asthma were specially concerned about the inhalatinal therapy having potential for producing drug dependence. Why incidence of asthma is relatively less in India and the disese is less severe as compared to some of the Western countries, information regarding it is not available. More data need to be generated towards epidemiology of asthma in this country. Research into usefulness of yogic breathing exercises and role of Ayurveda needs to be evaluated, although at present they have no proven scientific value. REFERENCES 1. Global Strategy for Asthma Management and Prevention. NHLBI/WHO Workshop report. Global Initiative for Asthma. NIH Publication No. 95-3659; January 1995, reprinted 1996; Epidemiology; Chapter 2; 1-24. 2. Gergen Pj, Mullay DY, Evans R M. National Survey of prevalence of asthma among children in the United States, 1976 to 1980. Pediatrics 1988;81:1-7. 3. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Worldwide variations in the prevalence of asthma symptoms: The International study of Asthma: The International Study of Asthma and Allergies in Childhood (ISAAC). Eur Respir J 1998;12:315-335. 4. Burney PGJ. Luczynska C. Chinn S, Jarvis D. The European Community Respiratory Health Survey. Eur Respir J 1994; 7:954-60. 5. European Community Respiratory Health Survey (ECRHS). Variations in the prevalence of respiratory symptoms, self-reported asthma attacks, and use of asthma medication in the European Community Respiratory Health Survey (ECRHS). Eur Respir J 1996; 9:687-695. 6. Habbick BF, Pzzichini MM, Taylor B, Rennie D, Senthilselvan A, Sears MR. Prevalence of asthma, rhinitis and eczema among children in 2 Canadian cities: in International Study of Asthma and Allergies in Childhood. CMAJ. 1999; 160:1824-28. 7. Shamssain MH, Shamsian N. Prevalence and severity of asthma, rhinitis, and atopic eczema in 13 to 14 years-old schoolchildren from the northeast of England. An Allergy Asthma Immunol. 2001; 86:428-32. 8. EI-Sharif NS, Nemery B, Barghuthy F, Mortaja S, Qasrawi R, Abdeen Z. Geographical variations of asthma and asthma symptoms among schoolchildren aged 5 to 8 years and 12 to 15 years in Palestine: The International Study of Asthma and Allergies in Childhood (ISAAC). Ann Allergy Asthma Immunol. 2003; 90:63-71. 9. AI-Dawood K. Epidemiology of bronchial asthma among schoolboys in AI-Khobar city, Saudi Arabia: Cross-sectional study. Croat Med J 2000;41:437-41. 10. AI-Riyami BM, AI-Rawas OA, AI-Riyami AA, Jasim LG, Mohammed AJ. A relatively high prevalence and severity of asthma, allergic rhinitis and atopic eczema in schoolchildren in the Sultanate of Oman. Respirology 2003;8:69-76. 11. Trakultivakorn M. Prevalence of asthma, rhinitis, and eczema in Northern Thai children from Chiang Mai (International Study of aAsthma and Allergies in Childhood, ISAAC). Asian Pac J Allergy Immunol 1999; 17:243-48. 12. Shohat T, Golan G, Tamir R, Green MS, Livne I, Davidson Y, Harari G, Garty BZ. Prevalence of asthma in 13-14 years-old schoolchildren across Israel. Eur Respir J 2000;15:725-29. 13. Crane J, Mallol J, Beasley R, Stewart A, Asher MI. International study of Asthma and Allergies in Childhood Phase I study group. Agreement between written and video questions for comparing asthma symptoms in ISAAC. Eur Respir J 2003; 21:455-61. 14. Beasley R, Ellwood P, Asher I, International patterns of the prevalence of pediatric asthma in ISAAC program. Pediatr Clin North Am. 2003; 50:539-53. 15. Paramesh H. Epidemiology of asthma in India. Indian J Pediatr 2002;69:309-12.

Asthma in Children 335 16. Chhabra SK, Gupta CK, Chhabra P, Rajpal S. Risk factors for development of bronchial asthma in children in Delhi. Ann Allergy Asthma Immunol. 1999;83:385-90. 17. Gupta D, Aggarwal AN, Kumar R, Jindal SK. Prevalence of Bronchial Asthma and Association with Environmental Tobacco Smoke Exposure in Adolescent School Children in Chandigarh, North India. Journal of Asthma, 2001; 38:501-07. 18. Palmer LJ, Valinsky IJ, Pikora T, Zubrick SR, Landau LI. Environmental factors and asthma and allergy in schoolchildren from Western Australia. Eur Respir J. 1999;14:1351-57. 19. Chan KN, Elliman A, Bryan et al. Respiratory symptoms in children of low birth weight Arch Dis Child 1989; 64:1294-1304. 20. Chan KN, Noble-jamieson Cm, Elliman A et al. Lung function of children of low birth weightArch Dis Child 1989;1284-1393. 21. Burrows B, Taussig ML. “As the twig is bent, the tree inclines” (perhaps). Am Rev Respir Dis 19K-122:813-16. 22. Dodge R, Martinez FD, Chm MG et al. Early childhood respiratory symptoms and the subsequent diagnosis of asthma. J Allergy Clin Immunol 1996,98:48-54. 23. Roberson CF, Heycock E, Bishop J et al. Prevalence of asthma in Melbourne schoolchildrenchanges over 26 years. BMI 1991;302:1116-18. 24. Ninan T, Ryssekk G. Respiratory symptoms and atopy in Aberdeen school children -evidence from two surveys 25 years apart- BMI 1992;304:873-75. 25. Peat JK-van den Berg RK Green WF et al. Chanding prevalence of Asthma in Australian children. BMJ 1994;308:1591-96. 26. Chandra RK. Prospective studies of the effect of breast feeding on incidence of infection and allergy. Acta Paediatr Scand 1979;68:691-94. 27. Fergusson DK Horwood JL, Shannon FT et al. Breast feeding gastrointestinal and lower respiratory illness in the first two years. Aust Paediatr J 1981;17:191-95. 28. Burr ML, Limb ES, Maguire MJ et al. Infant feeding wheezing, and allergy—A prospective.study. Arch Dis Child 19930:724-28. 29. Poysa L, Korppi M, Remes K et al. Atopy in childhood and diet in infancy a nine years follow-up study-I-clinical manifestations. Allergy Proc 1991;12:107-11. 30. Rust GS, Thompson CJ, Minor P, Davis-Mitchell W, Holloway K, Murray V. Does breastfeeding protect children from asthma? Analysis of NHANES III survey data. J Natl Med Assoc. 2001; 93:139-49. 31. Burney P. A diet rich in sodium may potentiate asthma—epidemiology evidence for a new hypothesis. Chest l987;91(Suppl):143S-148S. 32. Carey OJ, Locke C, Cooksoh JB. Effect of alterations of dietary sodium on the severity of asthma In men. Thorax 1993;48:714-18. 33. Peat JK, Hodge T, Salome CM et al. Dietary fish intake and asthma in children. Am J Respir Crit Care Med :1995;151(Suppl):A469. 34. Schwartz J, Weiss ST. The relationship of dietary fish intake to level of pulmonary function in the first National Health and Nutrition Survey (NHNS). Eur Respir 1 1994;7:1821-24. 35. National Research Council, Environmental tobacco smke’- nwzsunng -exposures and assessing effects. Washington: National Academy Press, 1986. 36. Cunningham J, O’Connor GT, Dockery DW et at. Environmental tobacco smoke, wheezing and asthma children in 24 communities. Am I Respir Crit Care Med 1996;153:218-24. 37. Martinez FD, Wright AL, Taussig LM et al. Asthma and wheezing in the first six years of Iife: N 1995;332:133-38. 38. Von Mutius E, Sherrill DL, fritzsch C et al. Air-pollution and upper respiratory-symptoms in children from East Germany. Eur Respir j 1995;8:23-28. 39. Braback L, Breborowicz A, Knutpson A et al. Atopic sensitisation and respiratory symptoms, and Swedish school children. Clin Exp Allergy 1994;24:826-35.

336 Bronchial Asthma 40. Behera D, Sood P, Singhi S. Passive smoking, domestic fuels, and lung function in North India Children. Ind J Chest Dis All Sci 1998; 40:89-98. 41. Behera D, Sood P, Singhi S. Respiratory, symptoms in Indian children exposed to different cooking fuels. J Assoc Phys India 1998;46:182-18 42. Wjst M, Reitmeir P, Dold S et al. Road traffic and adverse effects on respiratory health in children. BMJ 1993;307:596-600. 43. Weinmann.GG, Bowes SK Gerbase MW et al. Response to acute ozone exposure in healthy men. Results of a screening procedure. Am I.Respir Crit Care Med 1995;151:33-40. 44. Clough JB, WAHom JD, Holgate ST. Effect of atopy on the natural history of flow, and bronchial, hyperresponsiveness in 7 and 8-years-old children with 4 Respir Dis 1991;143:755-60. 45. Martin AJ, Landau LI, Phelan PD. Lung functions in young adults who had asthma in childhood. Am Respir Dis 1980;122:609-16. 46. Gerritsen J. Prognosis of asthma from childhood to adulthood. Am Rev Respir Dis 1989;140: 1325-30. 47. Peat JK Wookock AJ. Sensitivity to common allergens; relation to respiratory symptoms and bronchial hyperesponsiveness in children from different climatic areas of Australia. Clin Expt Allergy 1991;21:573-81. 48. van Asperen PP, Kemp AS, Mukhi A. Atopy in infancy predicts the severity of bronchial hyperresponsiveness in later childhood. J Allergy Cline Immune 1990; 85:790-95. 49. Sherril D. The effect of airway hyperresponsiveness, wheezing and atopy on longitudinal pulmonary function in children—A six ear follow-up study. Pediatr Pulmonol 1992;13:78-85. 50. Murphy S. Asthma: An inflammatory disease: In Hillman BC (Ed): Paediatric Respiratory Disease: Diagnosis and Management. Philadelphia: WB Saunders, 1993;621-26. 51. von Mutius E. Progression of allergy and asthma through childhood to adolescence. Thorax 19%;51(Suppl 1):S3-S6. 52. Kelly WJ. Childhood asthma and adult lung function. Am Rev Respir Dis 1988;138:26-30. 53. Martin AJ, Landau LI, Phelan PD. Asthma from childhood at age 21—the patient and his (or her) disease. Br Med J 1982;284:380-82 54. Williams H, McNicol KN. Prevalence, natural history, and relationship of wheez bronchitis and asthma in children. An epiden-dologic study. Br Med J 1969;4:321-25. 55. Park ES, Golding J, Carswell F et al. Preschool wheezing and prognosis at 10. Arch Dis Child 1986;61:642-46. 56. Balfour-Lynn. Childhood asthma and puberty. Arch Dis Child 1985;60:231-35. 57. Peat JK, Salome CM, Segwick CS et al. A prospective study of bronchial hyperresponsiveness and respiratory symptoms in a population of Australian school children. Clin Expt Allergy 1989;19:299-306. 58. Roorda RJ. Prognostic factors for the outcome of childhood asthma in adolescence, Thorax 1996;51(Suppl 1):S7-Sl2. 59. Price JF. Issues in adolescent asthma: What are the needs? Thorax 1996;51(Suppl 1):Sl3-Sl7. 60. Ownby DR. Enviroronmental factors versus genetic determinants of childhood inhalant allergies. J Allergy Clin Immunol 1990;86:279-87. 61. Frischer T, Kuehr J, Meinert R et al. Risk factors for childhood asthma and recurrent wheezy bronchitis. Eur J Pediatr 1993;152:771-75. 62. Sherman CB, Tosteson TD, Tager IB et al. Early childhood predictors of asthma. Am I Epidemiol 1990;132:83-95. 63. Sibbald B, Horn MEC, Gregg 1. A family study of the genetic basis of asthma and wheezy bronchitis. Arch Dis Child 1980;55:354-57. 64. The Cochranc Library: Update Soft Ware, Oxford, UK. 65. Parmar V, Kumar L, Malik SK. Normal values of peak expiratory flow rate in healthy north Indian school children 6-16 years of age. Ind Pediatr 1977;14:591-94.

Index 337

Index A

B

D

Acupuncture 261 Acute severe asthma 208, 276 anti-immunoglobulin E 248, 272 assessment 212,226 in children 285 clinical features 210 complications 211 definition 208 differential diagnosis 212 indices 213 management 215, 290 pathophysiology 209 therapeutic approach 227 Add-on therapy 268 Adhesion molecules 48 Adrenergic bronchodilators 142 Allergens 16, 20, 188 Allergic bronchopulmonary aspergillosis 117, 272 Allergy 14, 129 management 129 Alternative and complementary therapies 201 Alternative treatment oral steroid dependence 161 Animal allergens 19 Anticholinergics 148 comparison 155 side effects 156 Antihistamines 159 Arachidonic acid 43 Aspirin 22, 67, 272 Assessment of asthma control 202 Asthma definition 1 sign 99 symptoms 98 Asthma remission 89 Atopy 14

β2-agonists 281 Basophils 48 Beta-adrenergic receptors 62, 139, 143 Bradykinin 52 Brittle asthma 96 Bronchial asthma aetiology 14 complication 117 diagnosis 98 epidemiology 1 management 127 pathology 86 pathophysiology 40 pharmacologic management 134 prognosis 114 Bronchial asthma, management 127, 235 acute severe asthma 208 diet modification 258 nonpharmacologic 128, 256, 257 pharmacologic 134, 191 step-care 192, 194, 196 Bronchial hyperreactivity 40, 61 Bronchoprovocation test 103

Dietary manipulation 263 Diuretics 298 Drug-induced asthma 243 Drugs 22 Dry powder inhalers (DPI) 178

C Childhood asthma 7 Chronic bronchial asthma 183 Chronic eosinophilic bronchitis 44 Complementary and alternative medicine 261 Corticosteroids 151 Cough variant asthma 92 Cromones 157 Cyclosporin 163, 296 Cytokines 49, 53, 55, 250

E Early asthmatic reaction 40 Endocrinal factors 30 Environmental factors 32, 129, 260 Environmental tobacco smoke 30 Eosinophils 44 Epithelial-mesenchymal trophic unit 89 Exercise-induced asthma 23, 69, 235, 271 Extrinsic asthma 93 F Fatal asthma 306 Food allergen 20 G Gastro-oesophageal (GER) 27, 243 Genes 32 Genetics 31 Gold salts 163, 295 Gut hormones 59

reflux

H Heparin 297 Histamine 52 Hospital discharge 284 House-dust mite 18, 189, 259 Hygiene hypothesis 258

338 Bronchial Asthma I

N

R

Immunotherapy 131,190 Infection 20,21 Inflammation 55, 64, 65 Inflammatory mediators 49 Inhalation therapy 176 Interleukin 249 Intrinsic asthma 93

Natural history 6 Nebulisers 179 Nedocromil sodium 158 Neural control 59 Neurogenic inflammation 60 Neuropeptides 59 Neutrophils 48 Neutrophins 58 New guidelines for asthma management 256, 265, 276 Newer drugs 247 Nitric oxide 58, 64 Nocturnal asthma 72, 95

Refractory asthma 306 Remodelling 57, 88 Rhinitis 27, 272

K Ketotifen 158 L Laboratory findings 100 Late asthmatic reaction 40 Late onset asthma 93 Leukotriene 43, 49 antagonists 159 Lymphocytes 45

O Objective tests 102 Occupational asthma 24, 70, 94, 106, 109, 241 Oxygen radicals 57

M Macrophages 47 Mast cells 42 Mechanical ventilation 224 Mediators 58 Metered dose inhalers 177 Methotrexate 162, 293 Methylxanthines 134 Monocytes 47 Morning dippers 96 Mortality 4,6,114 Mould 16

P Patient education 128, 185, 284 Phosphodiesterase inhibition 134, 251 Platelet 52 Pollen 16 Pollution 29, 260 Pregnancy 236 Prostaglandins 52 Provocateurs 21

S Secondary prophylaxis 259 Severe asthma 306 Sherwood-Jones index 213 Sinusitis 27 Smoking 260 Spacer devices 181 Status asthmatics 208 drugs 221 Step-care management 273, 274, 275 Sulphite sensitivity 26 Surgery 239 Sympathomimetic agents 145 T Tartrazine 26 Theophylline 140 Tiotropium 272 Tokyo-Yokohama asthma 29 Troleandomycin 295 V Ventilator 222 noninvasive 283 Virus-induced asthma 69 Y Yin-Yang hypothesis 60