Travelers' diarrhea

TRAVELERS’ DIARRHEA CHARLES D. ERICSSON, MD Professor of Medicine and Head Clinical Infectious Diseases University of Texas, Houston Medical School Houston, Texas

HERBERT L. DUPONT, MD Chief, Internal Medicine St. Luke’s Episcopal Hospital Director, Center for Infectious Diseases University of Texas, Houston School of Public Health Mary W. Kelsey Chair University of Texas, Houston Department of Medicine Baylor College of Medicine H. Irving Schweppe Jr, Chair and Vice Chairman Houston, Texas

PROF ROBERT STEFFEN, MD Head, Division of Communicable Diseases Director, World Health Organization Collaborating Centre for Travellers’ Health Institute of Social and Preventive Medicine University of Zurich Zurich, Switzerland

2003 BC Decker Inc Hamilton • London

BC Decker Inc P.O. Box 620, L.C.D. 1 Hamilton, Ontario L8N 3K7 Tel: 905-522-7017; 800-568-7281 Fax: 905-522-7839; 888-311-4987 E-mail: [email protected] www.bcdecker.com © 2003 BC Decker Inc All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by an means, electronic, mechanical, photocopying, recording, or otherwise, without prior written permission from the publisher. 03 04 05 06 /FP/9 8 7 6 5 4 3 2 1 ISBN 1-55009-219-7 Printed in Canada Sales and Distribution United States BC Decker Inc P.O. Box 785 Lewiston, NY 14092-0785 Tel: 905-522-7017; 800-568-7281 Fax: 905-522-7839; 888-311-4987 E-mail: [email protected] www.bcdecker.com

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Notice: The authors and publisher have made every effort to ensure that the patient care recommended herein, including choice of drugs and drug dosages, is in accord with the accepted standard and practice at the time of publication. However, since research and regulation constantly change clinical standards, the reader is urged to check the product information sheet included in the package of each drug, which includes recommended doses, warnings, and contraindications. This is particularly important with new or infrequently used drugs. Any treatment regimen, particularly one involving medication, involves inherent risk that must be weighed on a case-by-case basis against the benefits anticipated. The reader is cautioned that the purpose of this book is to inform and enlighten; the information contained herein is not intended as, and should not be employed as, a substitute for individual diagnosis and treatment.

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CONTENTS Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .v Chapter 1

PART ONE

Historical Perspective of Travelers’ Diarrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 Herbert L. DuPont, MD, Charles D. Ericsson, MD, and Robert Steffen, MD

ETIOLOGY AND PATHOGENESIS

Chapter 2

The Bacterial Pathogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10 Zhi-Dong Jiang, MD, PhD, Jean-Paul Butzler, MD, PhD, and Brett S. Lowe, MPhil

Chapter 3

The Viral Pathogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .29 Robert L. Atmar, MD, and Margaret E. Conner, PhD

Chapter 4

The Parasitic Pathogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .47 Pablo C. Okhuysen, MD, and A. Clinton White, MD

Chapter 5

Antimicrobial Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .58 Jordi Vila, MD, PhD, and Stuart B. Levy, MD, FAAM

Chapter 6

Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .76 Made Sujita, MD, PhD, María G. Marcano, MD, and James P. Nataro, MD, PhD

Chapter 7

Relative Importance of Pathogens and Noninfectious Causes . . . . . . . . . . . . . . .100 Javier A. Adachi, MD, Charles D. Ericsson, MD, and Herbert L. DuPont, MD

PART TWO

EPIDEMIOLOGY AND CLINICAL FEATURES

Chapter 8

Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .112 Robert Steffen, MD, and R. Bradley Sack, MS, MD

Chapter 9

Host Factors and Susceptibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .124 Andrew W. DuPont, MD, and Robin C. Spiller, MD, MSc, FRCP

Chapter 10

Clinical Features and Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .134 Niklaus Gyr, MD, MPH, TM, Gilbert Kaufmann, MD, and Phyllis E. Kozarsky, MD

PART THREE Chapter 11

PREVENTION

Diet and Education about Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .148 David R. Hill, MD, DTMH, and Frank von Sonnenburg, MD, MPH

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CONTENTS

Chapter 12

Prophylactic Use of Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .160 Charles D. Ericsson, MD, and Herwig Kollaritsch, MD

Chapter 13

Immunity and Immunoprophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .175 David B. Huang, MD, MPH, and Mary K. Estes, PhD

PART FOUR

TREATMENT

Chapter 14

General Principles in Self-Treating Travelers’ Diarrhea Abroad . . . . . . . . . . . . . .200 Alain Bouckenooghe, MD, MPH, DTMH and Bob Kass, MB, MRCP, MScMCH, FAFPHM

Chapter 15

Nonspecific Treatment: Diet, Oral Rehydration Therapy, Symptomatic Drugs . . . .217 Deborah Mills, MBBS, and David L. Wingate, MA, MSc, DM, FRCP

Chapter 16

Antimicrobial Treatment: An Algorithmic Approach . . . . . . . . . . . . . . . . . . . . . .227 Herbert L. DuPont, MD, and Leena Mattila, MD, PhD

PART FIVE

SPECIAL HOSTS AND POPULATIONS

Chapter 17

Special Hosts: Children, Pregnant Women, Immunocompromised Patients, the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .240 Richard A. Oberhelman, MD, Susan L. F. McLellan, MD, MPH, and Ronald H. Behrens, BSc, MB, ChB, MD, FRCP

Chapter 18

Diarrhea in Expatriates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .258 David R. Shlim, MD, and Prativa Pandey, MD

Chapter 19

Diarrheal Outbreaks Associated with Airline Flights . . . . . . . . . . . . . . . . . . . . . .269 Margot Mütsch, PhD, MPH, and Norman Noah, MB, BS, FRCP, FFPHM

Chapter 20

Diarrhea at Sea and Outbreaks Associated with Cruises . . . . . . . . . . . . . . . . . . .277 Roisin Rooney, MS, and Chiara deBernardis, MD

Chapter 21

Diarrhea in Military Populations: From Historical Considerations until Modern Times . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .286 C. Kenneth McAllister, MD, and Lynn Longmore Horvath, MD

Chapter 22

Persistent and Chronic Diarrhea in the Returning Traveler . . . . . . . . . . . . . . . . .294 Bradley A. Connor, MD, and Brian R. Landzberg, MD

Chapter 23

The Future of Travelers’ Diarrhea: Directions for Research . . . . . . . . . . . . . . . . .310 Robert Steffen, MD, Herbert L. DuPont, MD, and Charles D. Ericsson, MD

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .317

P R E FAC E Even in this new millennium, travelers’ diarrhea remains a very frequent health problem, with a substantial impact on professional and leisure travelers alike. Although substantial progress has been made in our understanding of the pathogenesis and management of travelers’ diarrhea, the hygiene conditions and infrastructure in many developing countries have not improved significantly. We have chosen thought leaders in their fields to tell this story in comprehensive detail. Some authors are established investigators; some are rising stars. We have tried further to balance perspectives by encouraging collaboration among experts around the world. Our aim is to convey an erudite history, a basic understanding of the discipline, state-of-the-art management recommendations, and thoughts for future research. We have a substantial understanding of the risks of acquiring travelers’ diarrhea and we continue to learn about differences in host susceptibility. Recent research questions the pivotal role of fluid replacement in the treatment of adults with travelers’ diarrhea. An increasing number of medications are available for symptomatic relief and for specific antimicrobial therapy against causal organisms. Modern molecular and genetic techniques promise to elucidate virulence properties of enteropathogens and protective antibody responses. Although vaccine development based on such basic research is at various levels of investigation, hopes are high for vaccines against some of the pathogens, particularly enterotoxigenic Escherichia coli. New production techniques offer the possibility of cheap vaccines, and vaccine delivered in food promises to bypass the cold chain that limits vaccination in some developing countries. Finally, the improving public health services around the world promise to address the root cause of travelers’ diarrhea, namely, fecal–oral contamination. We hope this book offers something useful to the travel medicine expert and generalist alike. Charles D. Ericsson, MD Herbert L. DuPont, MD Robert Steffen, MD March 2003

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CONTRIBUTORS

JAVIER A. ADACHI, MD Department of Microbiology and Medicine Universidad Peruana Cayetano Heredia Lima, Peru

HERBERT L. DUPONT, MD Department of Medicine Baylor College of Medicine Houston, Texas

ROBERT L. ATMAR, MD Department of Medicine Baylor College of Medicine Houston, Texas

CHARLES D. ERICSSON, MD Department of Medicine University of Texas, Houston Medical School Houston, Texas

RONALD H. BEHRENS, BSc, MB, ChB, MD, FRCP Department of Infectious and Tropical Diseases University of London, School of Hygiene and Tropical Medicine London, England

MARY K. ESTES, PhD Department of Molecular Virology and Microbiology and Medicine Baylor College of Medicine Houston, Texas

ALAIN BOUCKENOOGHE, MD, MPH, DTMH Department of Medicine Baylor College of Medicine Houston, Texas

NIKLAUS GYR, MD, MPH, TM Department of Medicine University Hospital Basel Basel, Switzerland

JEAN-PAUL BUTZLER, MD, PhD Department of Human Ecology Vrije Universiteit Brussel Brussels, Belgium

DAVID R. HILL, MD, DTMH Department of Medicine University of Connecticut, School of Medicine Farmington, Connecticut

MARGARET E. CONNER, PhD Department of Molecular Virology and Microbiology Baylor College of Medicine Houston, Texas

DAVID B. HUANG, MD, MPH Department of Internal Medicine Baylor College of Medicine Houston, Texas

BRADLEY A. CONNOR, MD Department of Medicine Weill Medical College of Cornell University New York, New York

ZHI-DONG JIANG, MD, PhD Center for Infectious Diseases University of Texas, School of Public Health Houston, Texas

CHIARA DEBERNARDIS, MD Division of Communicable Diseases University of Zurich/ISPM Zurich, Switzerland

BOB KASS, MB, MRCP, MScMCH, FAFPHM Chief Medical Advisor The Travel Doctor Group Adelaide, Australia

ANDREW W. DUPONT, MD Department of Internal Medicine University of Alabama at Birmingham (UAB) Birmingham, Alabama

GILBERT KAUFMANN, MD Department of Internal Medicine University Hospital Basel Basel, Switzerland

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CONTRIBUTORS

HERWIG KOLLARITSCH, MD Department of Specific Prophylaxis and Tropical Medicine University of Vienna Vienna, Austria PHYLLIS E. KOZARSKY, MD Department of Medicine Emory University, School of Medicine Atlanta, Georgia BRIAN R. LANDZBERG, MD Department of Medicine Weill Medical College of Cornell University New York, New York STUART B. LEVY, MD, FAAM Department of Molecular Biology and Microbiology and Medicine Tufts University, School of Medicine Boston, Massachusetts LYNN LONGMORE HORVATH, MD Department of Medicine Uniformed Services, University of Health Sciences Bethesda, Maryland BRETT S. LOWE, MPhil Head of Laboratory KEMRI-CGMRC/Wellcome Trust Collaborative Programme Kilifi, Kenya MARÍA G. MARCANO, MD Department of Medical Microbiology and Immunology Program Internacional, ICB Guadalajara, Jalisco, Mexico LEENA MATTILA, MD, PhD Department of Medicine Helsinki University Helsinki, Finland

DEBORAH MILLS, MBBS Medical Director The Travel Doctor TMUC Brisbane Brisbane, Australia MARGOT MÜTSCH, PhD, MPH Division of Communicable Diseases University of Zurich/ISPM Zurich, Switzerland JAMES P. NATARO, MD, PhD Department of Pediatrics University of Maryland, School of Medicine Baltimore, Maryland NORMAN NOAH, MB, BS, FRCP, FFPHM Department of Infectious and Tropical Diseases London School of Hygiene and Tropical Medicine London, England RICHARD A. OBERHELMAN, MD Department of Tropical Medicine Tulane University, School of Public Health and Tropical Medicine New Orleans, Louisiana PABLO C. OKHUYSEN, MD Department of Internal Medicine The University of Texas Health Science Center Houston, Texas PRATIVA PANDEY, MD Medical Director The CIWEC Clinic Travel Medicine Center Kathmandu, Nepal ROISIN ROONEY, MS Department of Public Health and Policy London School of Hygiene and Tropical Medicine London, England

C. KENNETH MCALLISTER, MD Department of Medicine University of Texas Health Science Center at San Antonio (UTHSCSA) San Antonio, Texas

R. BRADLEY SACK, MS, MD Department of International Health John Hopkins University, Bloomberg School of Public Health Baltimore, Maryland

SUSAN L. F. MCLELLAN, MD, MPH Department of Internal Medicine Tulane University, School of Medicine New Orleans, Louisiana

DAVID R. SHLIM, MD Medical Director Jackson Hole Travel and Tropical Medicine Jackson Hole, Wyoming

CONTRIBUTORS

ROBIN C. SPILLER, MD, MSc, FRCP University of Nottingham Nottingham, United Kingdom ROBERT STEFFEN, MD Division of Communicable Diseases University of Zurich/ISPM Zurich, Switzerland MADE SUJITA, MD, PhD Department of Internal Medicine Charles R. Drew University Los Angeles, California JORDI VILA, MD, PhD Department of Microbiology University of Barcelona, School of Medicine Barcelona, Spain

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FRANK VON SONNENBURG, MD, MPH Department of Tropical Medicine and Infectious Diseases University of Munich Munich, Germany A. CLINTON WHITE, MD Department of Internal Medicine Baylor College of Medicine Houston, Texas DAVID L. WINGATE, MA, MSc, DM, FRCP Wingate Institute Queen Mary, University of London London, England

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Chapter 1

HISTORICAL PERSPECTIVE T R AV E L E R S ’ D I A R R H E A

OF

Herbert L. DuPont, MD, Charles D. Ericsson, MD, and Robert Steffen, MD

The early history of the topic of travelers’ diarrhea is tied up with military campaigns, where soldiers classically have suffered more losses from diarrhea and dysentery than from war-related injury.1-3 With the early recognition of the common occurrence of diarrhea, when individuals traveled to specific tropical and semitropical cities or regions, have emerged popular and colorful terms denoting the disorder: “Delhi Belly,”“Turkey Trots,”“Montezuma’s Revenge,”“G.I.s,”“Turista,”“Casablanca Crud,” “Aztec Two-Step,” “Malta Dog,” “Singapore Shakes,” “Canary Disease,” “Gyppy (Egyptian) Tummy,” “Aden Gut,” “Basra Belly,” “Maladie de la Mer Rouge,” “Poonah Pooh,” “Hongkong Dog,” “Ho Chi Minh,”“Rangoon Runs,”“Tokyo Trot,”“San Franciscitis,”“Greek Gallop,”“Rome Runs,” and “Trotsky’s.” When considering the syndrome of travelers’ diarrhea, historical developments can be divided into at least seven phases: 1. 2. 3. 4. 5. 6. 7.

Definitions of populations at risk; Clinical description and epidemiologic features of the syndrome; Specific risk of illness by region and development of immunity; Sources and cause of the disease; Drug prevention; Drug therapy; and Current era of research including refinements in therapy, studies of genetic susceptibility, and immunoprophylaxis.

We will briefly consider the important defining studies of the first six areas.

DEFINITIONS OF POPULATIONS AT RISK In Table 1-1, the various groups at high risk for developing travelers’ diarrhea are outlined along with references dealing with a review of the setting. As stated earlier, military groups have frequently experienced enteric diseases while engaged in campaigns. Kean indicated that the outcome of competition of athletes participating in Olympic Games was often determined by the occurrence of diarrhea.4 Students to Mexico have served as a setting for the study of travelers’ diarrhea for nearly 50 years.4-9 Persons living for prolonged periods in foreign countries have frequently experienced

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Table 1-1. Historical Groups at Risk of Acquiring Travelers’ Diarrhea Population Military groups Olympic competitors Students Expatriates and missionaries Peace Corps volunteers Cruise participants, seafaring populations, and persons taking commercial flights Tourists and business persons

Reference 1–3 4 4, 8 11, 12 10 13–15 16, 17, 20

acute and recurrent diarrhea, whether they be expatriates, missionaries, or Peace Corps volunteers.10-12 Diarrhea has been an important problem of populations at sea, and an occasional problem among passengers on cruise ships as well as passengers undertaking commercial air travels.13-15 International travelers on pleasure and business are known to be at high risk for travelers’ diarrhea.16,17 The two key predictive factors for illness occurrence, known for many decades, are place of origin of the travelers and level of hygiene of the country to be visited. International travelers resemble the children of the host country in their intrinsic susceptibility to enteric infection. Invariably, there are high rates of infantile gastroenteritis in those areas at high risk for travelers’ diarrhea.

CLINICAL DESCRIPTION AND EPIDEMIOLOGIC FEATURES OF THE SYNDROME The first good clinical description of travelers’ diarrhea was by Kean in his classic article, in which he graphically described the illness and revealed the associated inconvenience (Table 1-2).4 From 1963 to 1983, epidemiologic features including timing of occurrence after reaching the high-risk area and risk factors were described.4,8,16 Illness was generally seen within the first week of arrival to the highrisk area, with nearly all cases occurring within the first 2 weeks. The illness lasted between 2 and 5 days and was self-limiting, the younger travelers were at greatest risk, and recurrences occurred in about 15% of travelers remaining in the area of risk for 5 weeks.8

SPECIFIC RISK OF ILLNESS BY REGION AND DEVELOPMENT OF IMMUNITY With the availability of published data describing the occurrence of diarrhea in visitors, it became clear that areas of the world varied in risk of illness acquisition. Based on this information, in 1981, we attempted to divide the world into three categories of risk: high, low, and intermediate.18 Specific rates of risk were later established by study of European travelers to various countries.19 The attack rate of diarrhea occurrence in high-risk regions, including Latin America, Southern Asia, and many parts of Africa, averaged 30 to 50%.5,8,9,16,17,20 The incidence rate for a 2-week stay often exceeds 60%.17

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Table 1-2. Clinical Description and Epidemiologic Features of the Syndrome Observation

Reference

Clinical description of the illness

4

Epidemiologic description of the disease

4, 8, 16

Relative risk of various regions of the world

16, 20

Natural immunity occurrence with time in the region

8, 19

Studies have been carried out on US students in Mexico for nearly five decades and a consistently high rate of diarrhea (33 to 60%) has been seen (Reference details in Table 1-3). The highest rates were seen when subjects were followed for 4 weeks prospectively by daily visit to the clinic rather than through self-reporting during the first 2 weeks after arrival in Mexico. High rates of illness have remained in US travelers to Mexico despite prevalent knowledge of the cause and reasons for the illness, and availability of modern concepts of food and personal hygiene. Studies of British military troops stationed in Egypt during the years 1939 to 1945 demonstrated that high rates of diarrhea occurred only during the first months after arrival, with very low rates of diarrhea occurring during the second year of observation.19 Similarly, the rate of illness in Mexico decreased by half as students from the United States remained in the area of risk for one semester.8 The occurrence of natural immunity by remaining in an area of risk has given hope for the development of a vaccine to prevent the illness.

SOURCES AND CAUSE OF THE DISEASE The old adage, “don’t drink the water” during trips to international settings, was questioned in 1976 and 1977 when diarrhea occurrence was associated with the place at which meals were eaten or by the specific food items consumed (Tables 1-4, 1-5).21,22 Pathogens important as causes of diarrhea were then found in food and it was shown that diarrheal rates were reduced in those careful about the food items selected.23,24 The first evidence, albeit indirect, that bacterial agents were the important causes of travelers’ diarrhea was seen in the effectiveness of antibacterial drugs in reducing the rate of occurrence of illness.

Table 1-3. Risk of Travelers’ Diarrhea Seen in US Students to Mexico Attending Summer Classes for at Least 14 Days Year

Length of Study (wk)

Location in Mexico

Method of Reporting Illness

Rate of Diarrhea (%)

Reference

1958

2

Mexico City

Self-reporting

33

5

1975

4

Cholula

Daily visits to clinic

40

8

1986-7

4

Guadalajara

Daily visits to clinic

50

9

2002

4

Guadalajara

Daily visits to clinic

60

Unpublished data, DuPont et al.

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Table 1-4. Food as the Source of Travelers’ Diarrhea and Enteric Infection Observation

Reference

Location of food consumption correlated with development of diarrhea in travelers

21

Observation that consumption of a specific food item could be correlated with occurrence of diarrhea

22

Important pathogens of travelers’ diarrhea were found in foods consumed by persons at risk

23

Illness could be prevented by exercising care in foods consumed

24

Kean and his colleagues sought to determine the cause of this disease that could be prevented by prophylactic drugs. Early on, his team failed to find conventional bacterial or parasitic agents as causes.7 In 1973, Gorbach teamed up with Kean, in an important study of US students in Mexico, finding that enterotoxigenic Escherichia coli (ETEC) was the cause of the illness in a majority of cases.25 Within the next decade, it became clear that ETEC was the major cause, but it was only one of a number of bacterial agents responsible for travelers’ diarrhea.26 Recently, another E. coli strain that shows aggregative adherence to tissue culture cells and is known as enteroaggregative E. coli has been shown to rival ETEC as a major cause of travelers’ diarrhea.27

DRUG PREVENTION Interestingly, the early drug evaluation of travelers’ diarrhea was for prevention, not for therapy. While there had been a number of empiric uncontrolled uses of antibacterial drugs in preventing the disorder, the earliest placebo-controlled trials were carried out by Kean and colleagues in 1958 and 1960.5,6 The drugs tested were iodochlorhydroxyquin (a halogenated quinoline), neomycin sulfate with kaolin and pectin versus a placebo in one study, and phthalylsulfathiazole and neomycin sulfate versus placebo in the other.5,6 Moderate protection was seen for neomycin and phthalylsulfathiazole but not for the quinoline. Later, doxycycline was used successfully in preventing diarrhea of international travelers.28 A Consensus Development Conference held in the United States in 1985 concluded

Table 1-5. Establishment of the Bacterial Etiology of Travelers’ Diarrhea Observation Antibacterial drugs prevented the illness

Reference 5, 6, 28

Conventional enteropathogens were not responsible for the illness

7

Enterotoxigenic E. coli (ETEC) found to cause most cases of illness

25

ETEC, enteroaggregative E. coli (EAEC), and a variety of bacterial agents caused most cases of the illness Antibacterial drugs effectively shortened the illness when given therapeutically

26, 27 26

Antibacterial resistance complicated therapy

30, 31

Immunity to ETEC occurs and ETEC diarrhea may be prevented passively by orally administered antibody or actively by an oral vaccine

36–38

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that, until we had completely safe drugs not likely to produce antimicrobial resistance, prophylactic drugs should not be employed routinely to prevent this disease.29 The concern was drug side effects, occurrence of drug resistance, and difficulty in defining who should receive prophylaxis.

DRUG THERAPY An important and logical observation was that antibacterial drugs would shorten the illness in travelers when used therapeutically.26 This has become the standard approach to managing the disease. The problem is that antibacterial resistance is becoming a problem worldwide, making it important to search for antibacterial drugs to treat the more severe cases.30,31 In addition to antibacterial agents, a number of symptom relief drugs emerged once the mechanisms of diarrhea were better appreciated. These include the antimotility agent loperamide, a calmodulin inhibiting drug named zaldaride, and a chloride channel blocker, SP-303.32-34 Recent refinements of therapy have notably included the combination of the symptomatic relief drug, loperamide, and an active antibacterial drug.35

IMMUNOPROPHYLAXIS The natural immunity that occurs as travelers remain at risk appears to be directed to ETEC.8,36 This observation has encouraged groups to pursue development of immunologic approaches to prevent travelers’ diarrhea. While theoretically promising, the approach of using passive protection with colostrum or bovine antibody has not yet been shown to be useful in travelers’ diarrhea.37 Much more successful so far has been the approach of active immunization, specifically with a whole ETEC cell (containing the colonization factors of the organism) and the similar binding subunit of cholera toxin in an oral vaccine that is given twice before travel.38 There is every reason to believe that a measure of the illness may some day be prevented by an effective ETEC vaccine.

REFERENCES 1. Davison WC. A bacteriological and clinical consideration of bacillary dysentery in adults and children. Medicine 1922;1:389–510. 2. Butler T, Middleton FG, Earnest DL, Strickland GT. Chronic and recurrent diarrhea in American servicemen in Vietnam. An evaluation of etiology and small bowel structure and function. Arch Intern Med 1973;132:373–7. 3. Cook GC. Influence of diarrhoeal disease on military and naval campaigns. J R Soc Med 2001;94:95–7. 4. Kean BH. The diarrhea of travelers to Mexico. Summary of five-year study. Ann Intern Med 1963;59:605–14. 5. Kean BH, Waters SR. The diarrhea of travelers II. Drug prophylaxis in Mexico. N Engl J Med 1959;261:71–4. 6. Kean BH, Schaffner W, Brennan RW, Waters SR. The diarrhea of travelers V. Prophylaxis with phthalylsulfathiazole and neomycin sulphate. J Am Med Assoc 1962;180:367–71.

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7. Varela G, Kean BH, Barrett EL, Keegan CJ. The diarrhea of travelers II. Bacteriologic studies of U.S. students in Mexico. Am J Trop Med 1959;8:353–7. 8. DuPont HL, Haynes GA, Pickering LK, et al. Diarrhea of travelers to Mexico: relative susceptibility of United States and Latin American students attending a Mexican university. Am J Epidemiol 1977;105:37–41. 9. Ericsson CD, DuPont HL, Mathewson JJ III. Epidemiologic observations on diarrhea developing in U.S. and Mexican students living in Guadalajara, Mexico. J Travel Med 1995;2:6–10. 10. Herwaldt BL, de Arroyave KR, Roberts JM, Juranek DD. A multiyear prospective study of the risk factors for an incidence of diarrheal illness in a cohort of Peace Corps volunteers in Guatemala. Ann Intern Med 2000;132:982–8. 11. Haberberger RL Jr, Lissner CR, Podgore IA, et al. Etiology of acute diarrhea among United States embassy personnel and dependents in Cairo, Egypt. Am J Trop Med Hyg 1994;51:870–4. 12. Shlim DR, Hoge CW, Rajah R, et al. Persistent high risk of diarrhea among foreigners in Nepal during the first 2 years of residence. Clin Infect Dis 1999;29:613–6. 13. Hershey R. The incidence and effects of travelers’ diarrhea in a seafaring population. J Maritime Policy Management 1980;7:147–54. 14. Merson MH, Tenney JH, Meyers JD, et al. Shigellosis at sea: an outbreak aboard a passenger cruise ship. 1975;101:165–75. 15. Tauxe RV, Tormey MP, Mascola L, et al. Salmonellosis outbreak on transatlantic flights; foodborne illness on aircraft: 1947–1984. Am J Epidemiol 1987;125:150–7. 16. Steffen R, Van der Linde F, Gyr K, Schar M. Epidemiology of diarrhea in travelers. J Am Med Assoc 1983;249:1176–80. 17. von Sonnenburg F, Tornieporth N, Waiyaki P, et al. Risk and aetiology of diarrhea at various tourist destinations. Lancet 2000;356:133–4. 18. DuPont HL, DuPont MW. Travel with health. New York: Appleton-Century-Crofts; 1981. 19. Bulmer E. A survey of tropical diseases as seen in the Middle East. Trans R Soc Trop Med Hyg 1944; 37:225–42. 20. Steffen R. Epidemiologic studies of travelers’ diarrhea, severe gastrointestinal infections and cholera. Rev Infect Dis 1986;8 Suppl 2:S122–30. 21. Tjoa W, DuPont HL, Sullivan P, et al. Location of food consumption and travelers’ diarrhea. Am J Epidemiol 1977;106:61–6. 22. Merson MH, Morris GK, Sack DA, et al. Travelers’ diarrhea in Mexico: a prospective study of physicians and family members attending a congress. N Engl J Med 1976;294:1299–305. 23. Wood LV, Ferguson LE, Hogan P, et al. Incidence of bacterial enteropathogens in foods from Mexico. Appl Environ Microbiol 1983;46:328–32. 24. Kozicki M, Steffen R, Schar M. “Boil it, cook it, peel it or forget it”: does this rule prevent travelers’ diarrhoea? Int J Epidemiol 1985;14:169–72. 25. Gorbach SL, Kean BH, Evans DG, et al. Travelers’ diarrhea and toxigenic Escherichia coli. N Engl J Med 1975;292:933–6. 26. DuPont HL, Reves RR, Galindo E, et al. Treatment of travelers’ diarrhea with trimethoprim/sulfamethoxazole and with trimethoprim alone. N Engl J Med 1982;307:841–4. 27. Adachi JA, Jiang Z-D, Mathewson JJ, et al. Enteroaggregative Escherichia coli as a major etiologic agent in travelers’ diarrhea in 3 regions of the world. Clin Infect Dis 2001;32:1706–9.

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28. Sack DA, Kaminsky DC, Sack RB, et al. Prophylactic doxycycline for travelers’ diarrhea: results of a prospective double-blind study of Peace Corps volunteers in Kenya. N Engl J Med 1978;298:758–63. 29. Travelers’ Diarrhea – Consensus Conference. J Am Med Assoc 1985;253:2700–4. 30. Kuschner RA, Trofa AF, Thomas RJ, et al. Use of azithromycin for the treatment of Campylobacter enteritis in travelers to Thailand, an area where ciprofloxacin resistance is prevalent. Clin Infect Dis 1995;21:536–41. 31. Gomi H, Jiang Z-D, Adachi JA, et al. In vitro antimicrobial susceptibility testing of bacterial enteropathogens causing travelers’ diarrhea in four geographic regions. Antimicrob Agents Chemother 2001;45:212–6. 32. Johnson PC, Ericsson CD, DuPont HL, et al. Comparison of loperamide with bismuth subsalicylate for the treatment of acute travelers’ diarrhea. J Am Med Assoc 1986;225:757–60. 33. DuPont HL, Ericsson CD, Mathewson JJ, et al. Zaldaride maleate (Zm), an intestinal calmodulin inhibitor, in the therapy of travelers’ diarrhea. Gastroenterology 1993;104:709–15. 34. DiCesare D, DuPont HL, Mathewson JJ, et al. A double-blind, randomized, placebo-controlled study of SP303 (Provir) in the symptomatic treatment of acute diarrhea among travelers to Jamaica and Mexico. Am J Gastroenterol 2002;97:2585–8. 35. Ericsson CD, DuPont HL, Mathewson JJ, et al. Treatment of travelers’ diarrhea with sulfamethoxazole and trimethoprim and loperamide. J Am Med Assoc 1990;263:257–61. 36. Brown MR, DuPont HL, Sullivan PS. Effect of duration of exposure on diarrhea due to enterotoxigenic Escherichia coli in travelers from the United States to Mexico. J Infect Dis 1982;145:582. 37. Tacket CO, Losonsky G, Link H, et al. Protection by milk immunoglobulin concentrate against oral challenge with enterotoxigenic Escherichia coli. N Engl J Med 1988;318:1240–3. 38. Peltola H, Siitonen A, Kyronseppa H, et al. Prevention of travelers’ diarrhoea by oral B-subunit/whole-cell cholera vaccine. Lancet 1991;338:1285–9.

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Par t One

Etiology and Pathogenesis

Chapter 2

T H E B A C T E R I A L PAT H O G E N S Zhi-Dong Jiang, MD, PhD, Jean-Paul Butzler, MD, and Brett S. Lowe, MPhil

Diarrhea is the most frequent health problem experienced by travelers from developed countries visiting developing countries, especially tropical areas of the world.1 Approximately one-third of these travelers develop diarrhea. A number of surveys carried out in different geographic areas have identified a range of bacterial, viral, and parasitic agents as being responsible for travelers’ diarrhea. Bacterial pathogens are responsible for fewer than 5% of cases of diarrheal illness in the United States.2 In contrast, however, bacteria are the etiologic agents in 50 to 80% of cases of diarrheal illness in developing countries.3 The bacterial etiology of travelers’ diarrhea, based on the results of studies in a variety of geographic areas, is outlined in Table 2-1.2,4-8 Escherichia coli is the most prevalent facultative gram-negative bacillus of the human intestinal flora and the most common cause of bacterial infectious diarrhea.9 There are six established categories of diarrheagenic E. coli, based on the pathogenic mechanisms of the different strains: enteropathogenic E. coli (EPEC), enterotoxigenic E. coli (ETEC), enteroinvasive E. coli (EIEC), enterohemorrhagic or Shiga toxin-producing E. coli (EHEC or STEC), diffusely adherent E. coli

Table 2-1. Bacterial Etiology of Travelers’ Diarrhea Bacteria

Prevalence

All forms of Escherichia coli Enterotoxigenic E. coli

Common*

Enteroaggregative E. coli

Common

Enteropathogenic E. coli

Uncommon‡

Enteroinvasive E. coli

Less common

Enterohemorrhagic E. coli

Uncommon

Shigella spp

Less common†

Salmonella spp

Less common

Vibrio spp

Uncommon

Campylobacter jejuni

Common to less common

Aeromonas hydrophila

Less common

Clostridium difficile

Uncommon

No pathogen identified

Common

*Common, the pathogen is the cause in 15% or more of cases. † Less common, the pathogen is the cause in 5 to 15% of cases. ‡ Uncommon, the pathogen is the cause in fewer than 5% of cases.

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(DAEC), and enteroaggregative E. coli (EAEC).9 DAEC and EAEC are the most newly recognized emerging pathogens within the diarrheagenic strains.

ENTEROTOXIGENIC E. COLI Enterotoxigenic E. coli are those strains of E. coli that elaborate at least one member of two defined groups of enterotoxins: heat-stable (ST) and heat-labile (LT) enterotoxins.10 ETEC has a worldwide distribution and is an important cause of diarrhea in children living in developing countries and in travelers visiting these areas.11,12

Epidemiology ETEC was first described as a potential pathogen in humans more than 40 years ago when E. coli from the stool of children with diarrhea were shown to elicit fluid secretion in ligated rabbit intestinal loops.13 DuPont and colleagues subsequently showed that ETEC strains were able to cause diarrhea in adult volunteers.14 Although the diarrhea produced by ETEC is usually less severe than that caused by another toxigenic organism, Vibrio cholerae 01, ETEC-associated morbidity and mortality exceed those of cholera on a worldwide basis due to the high frequency of infection.15 In developing countries of the tropics in particular, where ETEC is endemic, infection tends to be clustered around the warm, wet months, when multiplication of the bacteria in food and water is most efficient.10 ETEC is the predominant etiologic agent causing travelers’ diarrhea among adults from the developed world visiting such regions.16 Studies suggest that 20 to 60% of such travelers experience diarrhea, with typically 20 to 40% of cases being attributable to ETEC. Predictably, ETEC-caused travelers’ diarrhea occurs most commonly in the warm and wet months and among first-time travelers to the developing world.17 Furthermore, it is reported that children from these areas, under 3 years of age, experience two to three episodes of diarrhea annually due to infection with ETEC, although this incidence does decline in older children and adults.18,19 ETEC infection is spread through water or food contaminated by bacteria from feces of infected individuals.20,21 Sampling of food sources from areas of endemic infection has revealed high rates of ETEC contamination. The most effective means of combating the disease are better hygiene and separate systems for drinking water and sewage. In developing countries, improvement of sanitary conditions is a long-term solution to the problem. In the short term, the struggle against infantile diarrhea must be aimed at protecting children against existing sources of infection, such as by education of mothers and possibly through use of an effective vaccine.22

Microbiology and Identification E. coli is the type species of the genus Escherichia, which contains mostly motile gram-negative bacilli within the family Enterobacteriaceae.23 E. coli can easily be isolated from clinical specimens on general or selective media incubated at 37°C under aerobic conditions. This bacterium in stool is most often recovered on MacConkey or eosin–methylene blue agar. These media contain chemicals that inhibit gram-positive organisms and contain lactose, a disaccharide that permits a presumptive dif-

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ferentiation of lactose fermenters from nonlactose fermenters. They selectively grow members of the Enterobacteriaceae and permit differentiation of enteric organisms on the basis of morphology.24 Confirmation that the E. coli are ETEC relies on detection of the enterotoxins LT and/or ST. ST was initially detected in a rabbit ligated ileal loop assay, and then subsequently superceded, due to expense of the technique and lack of standardization, by the suckling mouse assay.24,25 The traditional bioassay for detection of LT employs cell culture: either the Y1 adrenal cell assay or the Chinese hamster ovary (CHO) cell assay. In the Y1 assay, ETEC culture supernatants are added to Y1 cells and the cells are examined for rounding.26 In the CHO cell assay, LT will cause elongation of the CHO cells.27 ETEC were among the first pathogenic microorganisms for which molecular diagnostic techniques were developed. As early as 1982, DNA probes were used for the detection of LT and ST encoding genes isolated from stool and environmental samples.28 Although the LT polynucleotide probe provides good sensitivity and specificity when labeled with radioisotopes, ST polynucleotide probes have had problems of poor sensitivity and specificity, due to the small size of the gene.29 For this reason, oligonucleotide probes that are generally more sensitive and specific for ST detection have been developed.30 For the detection of ST and LT by hybridization after incubation, lactose fermenting E. coli are transferred to a Whatman filter paper (#541). The bacteria transferred on the paper can be lysed, denatured, and hybridized with the probe in situ, and then a radiographic image is generated by exposure to x-ray film. Recommended oligonucleotide probes consist of the following sequences: ST-h, 5'-GCTGTGAATTGTGTTGTAATCC-3'; ST-p, 5'-GCTGTGAACTTTGTTGTAATCC-3'; and LT, 5'-GCGAGAGGAACACAAACCGG-3'.31

Pathogenesis and Virulence Factors Like most mucosal pathogens, E. coli can be said to follow a requisite strategy of infection: 1) colonization of the mucosal site, 2) elaboration of enterotoxins, and 3) development of a net secretory state. The LT is closely related in structure and function to the cholera enterotoxin (CT) expressed by Vibrio cholerae.32 The LT activates adenylate cyclase, which is located on the basolateral membrane of polarized intestinal epithelial cells, and leads to an increase in levels of intracellular cyclic adenosine monophosphate (cAMP).33,34 Although the stimulation of Cl–, as a result of increased intracellular levels of cAMP, is the classical explanation for the mechanism by which LT or CT causes diarrhea, there is increasing evidence that LT or CT could evoke an intestinal inflammatory response. 35 CT has been reported to stimulate production of the proinflammatory cytokine, interleukin-6 (IL-6), thereby activating the enteric immune system.36 In contrast to the large oligomeric LTs, the STs are small monomeric toxins. There are two unrelated classes of STs that differ in structure and mechanism of action. Genes for both classes are found predominantly on plasmids, and some ST-encoding genes have been found on transposons. ST-I toxin is produced by ETEC and several other gram-negative bacteria including Yersinia enterocolitica and V. cholerae non-01. ST-II has been found only in ETEC. The major receptor for ST-I is guanylate cyclase C (GC-C). GC-C is located in the apical membrane of intestinal epithelial cells, and binding of ligands to the extracellular domain stimulates the intracellular enzymatic activity. Binding of ST-I

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to GC-C stimulates GC activity, leading to an increase in intracellular cyclic guanosine monophosphate (cGMP) levels.37 This activity leads ultimately to stimulation of chloride secretion and/or inhibition of sodium chloride absorption, resulting in net intestinal fluid secretion. Unlike ST-I, ST-II induces histologic damage of the intestinal epithelium. The receptor for ST-II is unknown. Unlike the chloride secretion elicited by ST-I, ST-II stimulates the secretion of bicarbonate from intestinal cells.35 In order to colonize the intestine, ETEC isolates express fimbrial antigens on their surfaces called colonization factor antigens (CFAs).38 Initially, two colonization factor antigens, CFA/I and CFA/II, were described in ETEC isolated from humans, but others have since been identified.39,40 CFA/I is a rigid, rod-like fimbria, while CFA/II and CFA/IV may contain a mixture of rigid fimbriae and nonfimbrial antigens. The CFA/II was later shown to consist of three subcomponents: coli surface (CS) associated antigens CS1, CS2, and CS3.41 CS3 is present in all strains of the CFA/II group, either alone or in combination with CS1 or CS2. The best characterized colonization factors of ETEC are CFA/I, CFA/II, and CFA/IV. CFA/IV consists of three distinct antigens: CS4, CS5, and CS6.42 Similarly to CFA/II, CS6 can be produced alone or together with CS4 and CS5. The role of CFA/III in colonization has also been demonstrated recently.43

ETEC Vaccine Development Natural ETEC immunity develops and persists as people remain at risk of infection.44 This observation has given researchers encouragement that a protective ETEC vaccine may be produced to prevent the disease, and there are a number of vaccine candidates currently under development. Some of the most promising vaccine candidates use the cholera toxin B-subunit, which is immunologically and physiologically related to the LT of ETEC.45 The anti-LT immunity elicited is specific and does not appear to offer any cross protection against ST-only-producing ETEC. ST is not immunogenic unless coupled to a carrier and it has proven impossible to synthesize ST toxoids that induce a good neutralizing antibody response without residual toxicity.22 Approximately half of the ETEC isolated in one of the studies produced ST only and would not be expected to be prevented by an anti-LT vaccine.16 To be effective, vaccine candidates should probably contain a number of ETEC CFAs, which is the approach employed by the developers of the oral cholera toxin B-subunit vaccine. Defined CFAs are produced in over 50% of ETEC.16 CFA/II was found to be the principal adhesin type among ETEC studied in two South American countries, while a study carried out in Peru demonstrated the importance of CFA/IV.46-48 For a vaccine designed for Mombasa (Kenya), Goa (India), and Montego Bay (Jamaica), the preparation should optimally include CFA/II (CS3 is the most important) and CFA/IV (in particular, CS6) components.16 It is recommended, therefore, that an ETEC vaccine for widespread use in developing countries should contain CS6 and probably CS3 as part of a multivalent combination.

ENTEROAGGREGATIVE E. COLI Enteroaggregative E. coli is a recently recognized pathogen within the group of E. coli that causes diarrhea.49,50 EAEC strains are classified as non-EPEC and non-ETEC strains that show a characteristic (“stacked-brick”) aggregative adherence pattern to HEp-2 cells.51

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Epidemiology EAEC was first implicated as a cause of travelers’ diarrhea in 1985 by Mathewson and colleagues.49 Subsequent studies have further substantiated the pathogenic role of EAEC strains as etiologic agents in acute travelers’ diarrhea, in persistent diarrhea in children in developing regions, and in AIDSassociated chronic diarrhea.52-57 Adachi and colleagues demonstrated that up to 26% of travelers’ diarrhea from multiple regions of the world may be attributable to EAEC, making it a major cause of this illness.52 A recent study demonstrated that coinfection of EAEC with ETEC and occurrence of asymptomatic EAEC infection were common to travelers in developing regions. 58 It was not possible to define whether the EAEC was the true pathogen in these cases. However, 56% (90 of 162) of the diarrheal cases where EAEC was the sole pathogen explains the etiology of approximately 30% of the otherwise undiagnosed cases. EAEC as the causative agent was further substantiated by a previous observation that diarrhea, in subjects in whom no other pathogen was isolated, improved with antimicrobial therapy.59,60

Microbiology and Identification The term “enteroaggregative E. coli” describes those strains of E. coli that attach to HEp-2 cells in a solely adhesion pattern (“stacked-brick” arrangement) but do not belong to serotypes often associated with enteropathogenic E. coli. The HEp-2 adherence assay was originally reported by Cravioto and colleagues.61 The adhesion assay is performed by incubating fresh bacterial cultures with a monolayer of HEp-2 cells (ATCC, Rockville, MD, USA), then fixing and staining the monolayer and observing the pattern of bacterial adhesion. A sample is interpreted as positive for EAEC if it shows the characteristic “stacked-brick” aggregative appearance as described by Nataro and colleagues.62

Pathogenesis and Virulence Factors Strains of EAEC differ in their pathogenicity, although the mechanisms of pathophysiology and the virulence traits that enable the organism to cause diarrhea are not well understood.62 Host and environmental factors may influence the occurrence of EAEC diarrhea (eg, diet, inoculum size, genetic makeup, stress, relocation), and the specific role of defined EAEC virulence determinants in the pathogenicity of diarrhea in humans is currently under investigation.64 EAEC strains have been found in food in endemic areas, although as stated earlier, asymptomatic infection is commonly observed in these areas.58 The frequent occurrence of asymptomatic EAEC infection in travelers to Mexico and the lack of intestinal inflammatory markers have raised questions about pathogenicity in these cases. It has been shown that most EAEC strains possess a 60 to 65 MDa plasmid (designated pAA), which encodes several putative virulence factors, including the AA fimbria, characterized as AAF/I or AAF/II.65 AAF/II has been shown to mediate adherence to the intestinal mucosa.66 AAF/I related genes include aggA, which encodes the major fimbrial subunit; the corresponding AAF/II subunit has been designated aafA. Both AAF/I and AAF/II biogenesis require the action of the transcriptional activator aggR. It is notable, however, that many strains carrying the aggR gene express neither AAF/I

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15

nor AAF/II.65 In addition, plasmid carrying in many EAEC strains has the cryptic gene, aspU, which encodes a secreted protein. Okeke and colleagues demonstrated that those EAEC expressing AAF/II were strongly associated with diarrhea in children in Southwest Nigeria.67 In that study, EAEC strains positive for the AAF/II gene probe were 3.55 times more likely to be isolated from individuals with diarrhea than from asymptomatic control subjects. They proposed that AAF/II is a true marker of certain, if not all, pathogenic EAEC strains. AAF/II in these studies relates to aafA used in the present study, which is the AAF/II fimbrial antigen. Vila and colleagues found that infection with EAEC strains producing Shigella enterotoxin 1 was associated with travelers’ diarrhea.68 Further evidence that the recognized virulence factors of EAEC are prevalent in EAEC from patients with acute diarrhea, and that they are specific for EAEC, also exists.64 The most common virulence factors observed in this study were aggA and aggR, although an association between the expression of other virulence factors and human infection and diarrhea could not be ruled out.64 The variety of virulence factors of EAEC strains and the variability of their presence in infecting strains resemble the heterogeneity among colonization factor antigens in enterotoxigenic E. coli.16 Nataro and Kaper proposed a three-stage model of EAEC pathogenesis based on an in vitro study.9 Stage I involves initial adherence to the intestinal mucosa and/or the mucus layer with AAF/I and AAF/II, the leading candidates as the factors that facilitate initial colonization. Stage II involves enhanced mucus production, apparently leading to deposition of a thick mucus-containing biofilm that facilitates EAEC adhesion and may promote persistent colonization. Stage III, suggested from histopathologic and molecular evidence, includes the elaboration of an EAEC cytotoxin, which results in damage to intestinal cells.

Immunity and Cytokine Production It has been shown that strains of EAEC commonly induce an immune response in patients with travelers’ diarrhea (50%).50 In a separate study of US adult tourists visiting Mexico, it was observed that the number of subjects with EAEC colonization increased over time, while the number of EAEC diarrhea cases decreased with the time of stay.58 During the first 2 weeks of stay, subjects with EAEC diarrhea and EAEC colonization were more frequently identified than those with ETEC infection. However, the ratio of diarrhea cases to asymptomatic subjects by week was found to be similar for both pathogens (0.8 to 0.9 for EAEC vs 0.7 to 1.1 for ETEC).58 During the third and fourth weeks, the diarrhea to asymptomatic infection ratio for EAEC dropped eightfold compared with the first week of study, yet the absolute number of subjects with EAEC colonization increased. This implies that immunity to symptomatic disease occurs quite early, although it is unable to block actual enteric infection.58 These observations suggest that although travelers are commonly colonized by EAEC, as reported previously, there may be other factors involved in the development of EAEC diarrheal disease.69 Possible explanations for the relatively high prevalence of asymptomatic infections are a) the development of an acquired partial immunity to EAEC by the host, b) the presence of a heterogeneous group of EAEC strains with different capacities to colonize the intestinal lumen, or c) difference in

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virulence properties between strains of EAEC. These hypotheses could explain the following observations: prolonged EAEC colonization with increasing frequency as persons remain in Mexico, the dichotomy in the trends of EAEC infection and colonization, the presence of some cases with EAEC diarrhea preceded by EAEC colonization, and the lack of any repeated EAEC diarrhea episode in the same patient. Sutijia and Steiner and their colleagues have presented two possible mechanisms of anti-EAEC immunity; the development of anti-EAEC secretory immunoglobulin A, and the activation of cytokines and interleukins, although the actual protective role that these mechanisms may play remains unclear.50,70 It is clear that EAEC strains represent a group of heterogeneous diarrheagenic E. coli that share the distinctive aggregative adherence pattern to HEp-2 cells. A number of observations support this: 1) different EAEC strains have been shown to have variable virulence in volunteers; 2) the organisms have a variety of possible pathogenic factors, identified in a selected group of EAEC isolates; and 3) strains of EAEC infecting persons in a common geographic area are quite genotypically diverse as determined by pulse field gel electrophoresis and plasmid analysis.52,58,63,67 Recent studies have documented in vitro production of IL-8 by EAEC infected epithelial cells.70 These findings are reminiscent of inflammatory bowel disease, in which increased levels of fecal cytokines IL-1β, tumor necrosis factor-α (TNF-α), and IL-8 have been demonstrated.71-73 Elevated TNF-α and IL-6 levels in stool and in the serum of children with shigellosis have also been associated with disease complications.74 Evidence also exists to indicate that EAEC may produce inflammatory enteritis with secretion of IL-8.75 Diarrhea caused by a variety of inflammatory bacterial enteropathogens including EAEC, Shigella, and Salmonella in adults was associated with production of cytokines in diarrheal stools.76 In addition, Bouckenooghe and colleagues demonstrated that naturally occurring EAEC diarrhea in travelers was associated with another marker of intestinal inflammation, fecal lactoferrin, whilst IL8 was detected at ~200-fold higher concentrations in fecal samples from patients with diarrhea in whom the infecting strains of EAEC were positive for aggR, aafA, or any combination of virulence factors when compared with patients with diarrhea from whom nonadherent E. coli were identified.64,77 When the infecting EAEC isolates in patients with diarrhea were positive for aggR or aafA factors, they were more likely to be associated with an increased level of Interferon (IFN-γ) when compared with patients infected with EAEC without those virulence factors.64 Detection of high concentrations of fecal cytokines in patients with EAEC diarrhea suggests increased production and secretion from an inflamed bowel, although studies show that diarrhea in international travelers with EAEC infection may or may not be associated with intestinal release of markers of inflammation. Steiner and colleagues demonstrated that concentrations of IL-1β were elevated in EAEC infection, either in the presence or absence of symptoms.75 In the study by Nataro and colleagues, patients with EAEC had higher rates of IL-1β:IL-1ra ratios compared with uninfected controls.78 Jiang and colleagues showed that there was no significant elevation in fecal IL-1β for patients with diarrhea and infection with EAEC positive or negative for virulence factors.64 One possible explanation for the variation in intestinal markers of inflammation with EAEC-associated diarrhea may well be because not all strains are pathogenic.

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SHIGELLA SPP The Shigellae are an important cause of bacillary dysentery. Clinical features of shigellosis classically include watery or bloody diarrhea, abdominal pain, fever, and malaise. There are four species of Shigella: boydii, dysenteriae, flexneri, and sonnei.

Epidemiology In endemic areas, Shigella infection occurs predominantly in young children, although the peak incidence occurs in preschool children rather than in infants.79 The lower incidence rates in older children and adults suggest the presence of an exposure dependent immunity. This is highlighted in the fact that adult travelers to such endemic areas commonly acquire Shigella infection, as they are likely to be immunologically naive. Furthermore, the immunity acquired appears to be strain specific. This is supported by the observation that when a new Shigella serotype is introduced, which is serologically distinct from strains previously encountered, diarrheal diseases occur equally in all age groups.80 The Shigella spp are the cause of travelers’ diarrhea in up to 10% of travelers to developing countries.16 Approximately 14,000 laboratory confirmed cases of shigellosis and an estimated 448,000 total cases (mostly due to S. sonnei) occur in the United States each year.81 In the developing world, S. flexneri tends to predominate.81 Epidemics of S. dysenteriae type 1 have occurred in Africa and Central America with case fatality rates of 5 to 15%.82 Infection with Shigella readily spreads among individuals living in cramped, overcrowded conditions.83 Transmission is via the fecal–oral route, and the inoculum size needed to initiate infection can be as few as 200 or less organisms.82 It may be transmitted through contaminated food and water; however, person-to-person spread and transmission by flies may also occur, since so few organisms are necessary to cause disease.82 Clinical cases may excrete 105 to 108 organisms per gram of feces, and even convalescent carriers have in excess of 102 Shigella per gram of feces.83 The enteritis caused by Shigella spp varies in severity, with the diarrhea ranging from watery to dysenteric. Dysentery more commonly results from S. dysenteriae and S. flexneri infections, while S. boydii and S. sonnei usually produce a watery diarrhea. Patients with Shigella dysentery tend to have severe symptoms, usually with high fever, severe abdominal pain, and fractionated stools.

Microbiology and Identification Shigella are gram-negative, rod-shaped bacilli that lack flagellae. While they share many biochemical properties with E. coli, major phenotypic differences include their failure to ferment lactose within 24 hours, inability to produce gas, and their lack of motility. In order of decreasing bacterial recovery, rectal swab and stool and anal swabs are the specimens of choice.84 Blood, mucus, or pus, if present in the stool, are extremely productive and should be cultured. For optimal chances of isolating Shigella spp, a differential enteric agar medium and a moderately selective agar medium should be used.85 Xylose-lysine-deoxycholate (XLD) medium is especially good for isolating Shigella spp.

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The four Shigella species are also biochemically similar to each other, except for the inability of S. dysenteriae to ferment mannitol, the positive ornithine utilization by S. sonnei, and the ability of most S. sonnei to ferment lactose after several days in culture. Final identification to the species and group levels is usually accomplished by serology. Shigella spp are susceptible to changes in stool pH that occurs during prolonged transport, and a number of organisms may die under such conditions. If shigellosis is suspected, the stool specimen should be transported promptly to the laboratory or a suitable transport media should be used, such as Enteric Plus (Meridian Diagnostics, Cincinnati, OH, USA).

Pathogenesis and Virulence Factors Shigella possess specialized adaptive processes that enable them to co-opt epithelial cell functions to augment their penetration of the host intestinal epithelium. A necessary step in the successful colonization and ultimate production of disease is the ability of Shigella to adhere to host surfaces, which is an important determinant of virulence.86 Generally, binding to intestinal host cells is essential for Shigella to resist both the fluid flow of the luminal contents and the peristalsis of intestinal contraction. Once bound to the epithelial surface, Shigella may colonize and establish a permanent residence in the gut. Adhesion of the bacteria to host cells or surfaces is essential for the successful development of infection. A wide range of mammalian cell surface constituents, including glycoproteins and glycolipids, can serve as receptors for bacterial attachment.87 This process allows Shigella to invade epithelial cells via their basolateral pole and subsequently to spread laterally from one enterocyte to another. The accompanying inflammatory response this elicits is characterized by IL-8 production and polymorphonuclear leukocyte transmigration.88 The host cell is often an active participant in the adhesion process and does not function simply as an inert surface for attachment. The host has specialized strategies to resist such infections, often in response to these virulence factors or the damage caused by them. This interaction defines the disease process.89 Evidence for an essential role of a plasmid in entry came from the observation that a plasmid of 200 kb was present in invasive isolates of Shigella, and loss of this plasmid eliminated entry.90 The nucleotide sequence of the 30.5 kb region that is necessary for entry of Shigella into epithelial cells has been determined.91 The plasmid encodes the invasion plasmid antigens (ipa) operon, which includes IpaB, IpaC, and IpaD, the three proteins essential for invasion.92 In contrast to the pathogenic E. coli, flagellae and pili are not recognized to be the virulence factors for Shigella. It has been demonstrated that Shigella of all serogroups elaborate an exotoxin that exhibits cytotoxic, neurotoxic, and enterotoxic activities.93,94 There is sufficient evidence that Shiga toxin uses cytotoxic effects on intestinal epithelial cells, including human colonic cells in primary culture.96 However, the in vivo situation is much more complicated, since not only is there free toxin in the lumen, but Shigella also invades and multiplies with epithelial cells, making it difficult to distinguish between invasion and an elicited inflammatory response and the specific direct effects of the toxin.97

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SALMONELLA SPP (NONTYPHOIDAL SALMONELLA INFECTION) Nontyphoidal salmonellosis refers to disease caused by any serotype of organism in the genus Salmonella other than Salmonella typhi, the causative agent of typhoid fever. The most common manifestation of nontyphoidal salmonellosis is acute enterocolitis, although the organism can produce invasive infections leading to septicemia, and meningitis and fever that may be clinically indistinguishable from that caused by S. typhi.

Epidemiology Human salmonellosis is initiated by the ingestion of food or water that is contaminated with one or another Salmonella spp. Nontyphoidal Salmonella infection is widely distributed among different animal species but is particularly prevalent in animals raised for food. For example, Salmonella spp have previously been isolated from approximately 50% of commercially available chickens, from 20% of frozen egg whites, from a varying percentage of raw milk sources, and from ground beef used to make hamburgers.97,98 Food products also become contaminated during collection and processing via the food handlers. The Salmonella spp are the cause of travelers’ diarrhea in up to 10% of travelers to developing countries.16 Salmonella enterocolitis remains an important cause of infectious enterocolitis in developing countries, despite the public health measures that have decreased endemic fever and cholera. One of the major contributors to the persistence of the salmonellae as a major cause of diarrheal and invasive disease is the variety and abundance of animal reservoirs they are able to infect. Salmonella enterocolitis usually occurs after an incubation period of between 6 to 48 hours. There is a marked seasonal variation in the occurrence of Salmonella infection: in the USA, peak incidences in summer and fall are due to many small outbreaks of food poisoning (Salmonella infection accounts for 10 to 15% of food poisoning cases). Inadequate cooking practices that affect relatively large numbers of people are most common at these times (eg, at picnics and barbecues). The highest rates of Salmonella infection are observed in children under the age of 5 years, particularly infants, and in elderly individuals. The colossal scale of contamination of animals and associated food products cannot be overstated and, despite at times heroic public health efforts to limit human encounters with Salmonella in food, the major defense against human infection is appropriate food handling and cooking practices. Person-to-person spread via the fecal–oral route is also a major source of infection.99

Microbiology and Identification The salmonellae are gram-negative, flagellated, nonsporulating, aerobic bacilli. Isolation of salmonellae from stool is best performed on selective and differential media. Salmonella-Shigella (SS), Hektoen enteric (HE), and xylose-lysine-deoxycholate (XLD) agars are widely used to screen for Salmonella as they support the growth of the organism and are considered moderately selective media. The purpose of these selective media is to suppress the growth of other Enterobacteriaceae and dif-

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ferentiate among gram-negative bacteria based on their ability to ferment lactose. Hektoen enteric agar is a useful medium for stool cultures, since it demonstrates the production of hydrogen sulfideproducing organisms. Most salmonellae produce abundant hydrogen sulfide, form gas in glucose media, and do not ferment sucrose. The salmonellae are distinguished from several Proteus species by their inability to metabolize urea.

Pathogenesis and Virulence Factors The pathogenesis of Salmonella infection is not fully understood. The bacteria penetrate and damage the intestinal mucosa, are ingested by macrophages, and may multiply in a limited fashion in mesenteric lymphoid tissues. In severe invasive infection, bacteremia and focal infections in distant tissues occur. The process includes several distinct steps, no single one of which explains the entire pathogenic spectrum: 1. Attachment and penetration. Adhesins facilitate the attachment of Salmonella to intestinal mucosal cells, and may be necessary for mucosal invasion.100 2. Secretory response. The diarrhea associated with salmonellosis may reflect bacterial properties that cause fluid loss. Some invasive strains of Salmonella can cause fluid to accumulate in the rabbit ileal loop model, and the characteristics of the fluid suggest active secretion rather than just passive leaking through a damaged mucosa.101 This fluid accumulation is accompanied by high levels of tissue cAMP, is abolished by indomethacin, and suggests the presence of an enterotoxin.102 3. Inflammation and tissue destruction. The fever, bloody diarrhea, and evidence of colitis that often accompany a Salmonella infection may be the result of local inflammation, effects of bacterial endotoxin, or of specific cytotoxins that cause mucosal cell death.103 A cytotoxin in Salmonella has been identified that inhibits protein synthesis in cultured vero cells, in a manner analogous to the cytotoxins present in Shigella dysenteriae 1 and verotoxigenic Escherichia coli.104 A great deal of progress has been made in the understanding of the molecular basis of Salmonella entry into host cells. It is now evident that Salmonella entry is encoded on a 35 to 40 kb region of the Salmonella chromosome located at centisome 63.105 The similarity between the genetic bases of Salmonella and Shigella proteins that mediate the entry of these organisms into cultured epithelial cells has been demonstrated.106

CAMPYLOBACTER SPP Campylobacter jejuni has emerged as one of the most commonly identified bacterial causes of acute gastroenteritis worldwide.107-109 Although several Campylobacter species (C. upsaliensis, C. lari, C. concisus, C. jejuni, C. fetus subsp fetus, C. jejuni subsp doylei, C. hyointestinalis, and Arcobacter butzleri) have been shown to cause diarrhea, C. jejuni is by far the most frequently isolated species from humans.

Epidemiology The reported incidence of campylobacteriosis in most developed countries has risen substantially during the past 20 years. In these countries, Campylobacter enteritis affects people of all ages and

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is prominent in infants and young adults. In developing countries, campylobacteriosis is widespread and causes significant morbidity and even mortality. In these countries, the disease is confined to young children who develop immunity early in life through repeated exposure to infection.108 The high prevalence of the organism in the tropics and its short incubation period are reflected in its frequency as a cause of travelers’ diarrhea. A 1998 study from Austria found that C. jejuni was the most frequent bacterial cause of diarrhea among 322 travelers returning from destinations in Asia, Africa, and Latin America.110 During the last 10 years, Campylobacter has consistently been the leading cause of travelers’ diarrhea among US troops participating in military exercises in Thailand, with isolation rates as high as 39%. 109 In Sweden, over 70% of cases of Campylobacter enteritis were acquired outside the country.111 The infection is seasonal in temperate climates. About twice as many infections occur in summer than in winter. Campylobacteriosis is a zoonosis. The reservoir of infection is in wild and domestic animals, particularly birds. Chickens constitute by far the largest potential source of human infection. 107-109 Many cases of campylobacteriosis are associated with foreign travel, ranging from 3 to 50% or more of all cases depending on the country, and usually result from the consumption of contaminated food or water in the countries visited. Many risk factors for Campylobacter transmission have been identified. In developed countries, for example, handling and consumption of poultry meat are primary sources of infection and are likely to account for much of the increased incidence of campylobacteriosis. Other risk factors in developed countries include foods of animal origin, including raw milk, inadequately treated water, contact with farm animals and pets, and foreign travel. In developing countries, inadequately treated water and contact with farm animals are assumed to be the most important risk factors. The significance of different transmission pathways varies with time and location.112

Clinical Features Acute self-limited gastrointestinal illness characterized by diarrhea, fever, and abdominal cramps is the most common presentation of C. jejuni infection, but symptoms and signs are not so distinctive that the physician can differentiate it from illness caused by other organisms. The incubation period is commonly 2 to 5 days, but estimates have extended up to 10 days. The diarrhea remains for about 2 to 3 days, but abdominal discomfort may persist after the diarrhea has stopped. In a significant proportion of the patients, the stools contain fresh blood, pus, or mucus and this suggests colorectal inflammation.107-109 Local complications such as cholecystitis, pancreatitis, and peritonitis occur rarely. Extraintestinal manifestations, including sepsis, meningitis, septic arthritis, and osteomyelitis, have occasionally been described. Some patients develop erythema nodosum or reactive arthritis. It has been recognized that the paralytic condition, Guillain-Barré syndrome, is the most serious complication of Campylobacter infection.

Microbiology Campylobacter species are small, curved, or spiral-shaped gram-negative bacilli that exhibit rapid darting and spinning motions. The isolation of Campylobacter requires special selective techniques that depend either on differential filtration or direct plating on agar containing antibiotics.

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The plates must be incubated under conditions of reduced oxygen tension. C. jejuni and C. coli grow best at 42°C. Seventy-two to 96 hours are required for primary isolation from stool samples, and isolation from blood takes even longer. Because some non jejuni-coli Campylobacter species are susceptible to cephalothin (an antibiotic used in most selective media), the filter method and antibiotic-free media are recommended in addition to the selective medium. The minimal standards for identifying Campylobacter after primary isolation are colony morphology, gram stain response, motility, and an oxidase test. The hippurate hydrolysis test differentiates most C. jejuni strains from other Campylobacter species. For organisms other than C. jejuni and C. coli, including atypical C. jejuni strains, additional biochemical tests are required. Several molecular tests can further characterize the strains.

Treatment In general, Campylobacter enteritis has a very good prognosis, and the isolation of the organism from the stools does not warrant chemotherapy.107 In the absence of chemotherapy, feces remain positive for about 2 to 7 weeks after the illness. Antibiotic therapy is indicated in patients with Campylobacter infection who are acutely ill with enteritis, have persistent fever, bloody diarrhea, more than eight bowel movements per day or significant volume loss, or more than a 7-day history of diarrhea. HIV-infected individuals, immunocompromised persons, and pregnant women should receive antibiotic treatment. When antimicrobial therapy is indicated, erythromycin is the drug of choice, given its efficacy, low toxicity, and low cost.107 Fluoroquinolones such as ciprofloxacin have commonly been used for the treatment of infections caused by Campylobacter. Since the end of the 1980s, fluoroquinolone resistance has been reported from Europe and Asia, and since 1995, in the United States. The prevalence of fluoroquinolone-resistant C. jejuni in the United States was 0% in 1990, and increased to 13% in 1997 and to 18% in 1999, following the approval of fluoroquinolone use in poultry in 1995. In contrast, in Australia, where fluoroquinolones are not used in poultry, human isolates of Campylobacter remain susceptible to fluoroquinolones.112 One prevailing theory is that fluoroquinolone use in animal populations is leading to the rise of resistance of Campylobacter.115 Human use of this class of drugs may be an even greater stimulus for the development of resistance. For whatever reason for the emergence of resistance, Campylobacter strains are becoming resistant to fluoroquinolones throughout the world.

Pathogenesis The mechanisms by which C. jejuni cause disease are not well known. C. jejuni depend on flagellummediated motility to display full virulence. At least three mechanisms by which Campylobacter may induce illness can be postulated on the basis of clinical syndromes108,109,112: 1. C. jejuni may cause an enterotoxigenic-like illness with watery diarrhea, as seen in patients in developing countries. 2. The frequent finding of dysenteric stools suggests that mucosal damage due to an invasive process analogous to that seen in shigellosis is also important in the pathogenesis. Indeed, the fact that many patients have erythrocytes and leukocytes in their stools suggest colonic involvement.

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3. Extraintestinal translocation may occur, in which the organisms cross the intestinal mucosa and migrate via the lymphatic system to various extraintestinal sites, leading to sepsis, meningitis, cholecystitis, endocarditis, osteomyelitis, and septic arthritis.

Prevention Prevention depends upon the purification of all water supplies, the heat treatment of all milk sold for human consumption, the hygienic handling of all raw meats (especially poultry) in kitchens, and the control of infection at all stages of poultry production. In developing countries, penning chickens outside the home and preventing contact with their feces substantially reduces transmission of C. jejuni.109,111,113

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103. Giannella RA. Importance of the intestinal inflammatory reaction in Salmonella-mediated intestinal secretion. Infect Immun 1979;23:140–5. 104. Koo FCW, Peterson JW, Houston CW, Molina NC. Pathogenesis of experimental salmonellosis: inhibition of protein synthesis by cytotoxin. Infect Immun 1984;43:93–100. 105. Mills DB, Bajaj V, Lee CA. A 40 kilobase chromosomal fragment encoding Salmonella typhimurium invasion genes is absent from the corresponding region of the Escherichia coli K-12 chromosome. Mol Microbiol 1995;15:749–59. 106. Groisman EA, Ochman H. Cognate gene clusters govern invasion of host epithelial cells by Salmonella typhimurium and Shigella flexneri. EMBO J 1993;12:3779–87. 107. Butzler JP, Mégreaud F. In: Zinner SH, Young LS, Acar JF, Neu HC, editors. Expanding indications for the new macrolides, azalides and streptogramins. New York: Marcel Dekker; 1997. p. 237–49. 108. Butzler JP. Campylobacteriosis in humans in the increasing incidence of human campylobacteriosis WHO/CDS/CSR/APH 2001;7:38–41. 109. Allos BM. Campylobacter jejuni infections: update on emerging issues and trends. Clin Infect Dis 2001;32:1201–6. 110. Reinthaler FF, Feierl G, Stunzner D, Marth E. Diarrhea in returning Austrian tourists: epidemiology, etiology and cost-analysis. J Travel Med 1998;5:65–72. 111. Hoge CW, Gambel JM, Srijan A, et al. Trends in antibiotic resistance among diarrheal pathogens isolated in Thailand over 15 years. Clin Infect Dis 1998;26:341–5. 112. Tauxe R. Incidence, trends and sources in developed countries: an overview in the increasing incidence of human Campylobacteriosis. WHO/CDS/CSR/APH 2001;7:42–3.

Chapter 3

T H E V I R A L PAT H O G E N S Robert L. Atmar, MD, and Margaret E. Conner, PhD

Gastroenteritis is one of the most common afflictions of humanity.1 Enteric viruses are being increasingly recognized as important causes of this disease, but the true burden of viral origins is not known.2 Diarrhea also can be a common symptom of a number of nonenteric viral infections (eg, influenza, hepatitis); however, other clinical signs and symptoms usually suggest the presence of a nonenteric infection. This chapter will focus upon the enteric viruses that contribute to the worldwide burden of gastroenteritis.

HISTORICAL BACKGROUND Viruses have been suspected to be a cause of gastroenteritis for more than 50 years. In 1929, Zahorsky described an outbreak of epidemic nonbacterial gastroenteritis and proposed the name “winter vomiting disease.”3 During the 1930s and 1940s, no bacterial pathogen could be identified in the majority of outbreaks of gastroenteritis that were investigated by the New York State Department of Health. In 1947, Gordon and colleagues pooled stool filtrates, collected from two subjects in an outbreak of nonbacterial gastroenteritis, and used the pool as an experimental challenge inoculum to infect volunteers.4 Subjects developed an enteric illness within 1 to 5 days of inoculation. The agent could be passed serially through humans, suggesting that it was not a preformed toxin, and its ability to cause illness was lost following heat inactivation by autoclaving. No bacteria were isolated from the inocula, but attempts to grow a viral pathogen in embryonated chicken eggs failed. Outbreaks of nonbacterial gastroenteritis continued to occur without an etiologic agent being identified. One such outbreak occurred in a middle school in Norwalk, Ohio, during October 1968.5 This outbreak was associated with a 50% attack rate, involving both students and teachers, and a secondary attack rate of 32% among family contacts. Stools collected during the outbreak were used to make challenge inocula to infect human subjects.6 In 1972, Kapikian and colleagues were able to use a new diagnostic method, immunoelectron microscopy (IEM), to identify viral particles in the stools of volunteers infected with a passage of the Norwalk inoculum.7 This became the first clear evidence associating a virus with gastroenteritis. Over the next 4 years, all of the other recognized causes of viral gastroenteritis (Table 3-1) were identified by electron microscopy; these included rotavirus, enteric adenovirus, astrovirus, and “classical” calicivirus.8-12 Other viruses have also been detected in stool samples of persons with diarrhea. Some of these are recognized to cause diarrhea in animals (eg, toroviruses, pestiviruses, coronaviruses, picobirnaviruses); in addition, viruses from some of these families as well as the recently

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Table 3-1. Established and Candidate Viral Agents as Causes of Gastroenteritis in Humans Established Agents

Candidate Agents

Adenoviruses (Group F – enteric) Astroviruses Caliciviruses Noroviruses Sapoviruses Rotaviruses

Aichi virus (a picornavirus) Coronaviruses Pestiviruses Picobirnaviruses Toroviruses

described picornavirus, Aichi virus, are more prevalent in stool samples from persons with diarrhea than in samples from asymptomatic individuals. However, the role of these viruses as causes of gastroenteritis in humans remains to be determined.13 The remainder of this chapter will focus upon the four virus families that have clearly been established to cause gastroenteritis. Table 3-2 provides a comparison of many of the characteristics of these viruses.

CALICIVIRUSES Viral Characteristics and Biology Caliciviruses are nonenveloped, icosahedral viruses that have a single-stranded, positive-sense RNA genome.14 There are four genera within the family Caliciviridae: Norovirus, Sapovirus, Lagovirus, and Vesivirus. Currently, only animal strains are recognized to be members of the latter two genera, while noroviruses and sapoviruses contain both human and animal strains.

Table 3-2. Characteristics, Epidemiology, and Diagnosis of Enteric Viruses Recognized to Cause Diarrhea Calicivirus

Rotavirus

Astrovirus

Enteric Adenovirus

Family

Caliciviridae

Reoviridae

Astroviridae

Adenoviridae

Genome

ssRNA, positive dsRNA, segmented sense, polyadeny(11 segments) lated

ssRNA, positive sense, polyadenylated

dsDNA

Viral Particle Size

28–35 nm

75 nm

28–30 nm

65–80 nm

Age Groups Affected

All age groups

Predominantly children; also elderly and adults

Predominantly children; occasionally adults

Young children; other age groups uncommon

Diagnostic Assays

RT-PCR, EM, EIA

EIA, Latex agglutination, RT-PCR, EM, culture

RT-PCR, EIA, EM, culture

EIA, PCR, EM, culture

Likely to Cause Travelers Diarrhea?

Yes

Yes

No

No

dsDNA = double-stranded deoxyribonucleic acid; dsRNA = double-stranded ribonucleic acid; EIA = enzyme immunoassay; EM = electron microscopy; PCR = polymerase chain reaction; RT-PCR = reverse transcription-polymerase chain reaction; ssRNA = single-stranded ribonucleic acid.

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31

The name “calicivirus” is derived from the Latin word, calyx, meaning “cup” or “goblet,” a reference to the cup-like depressions that can be seen by electron microscopy (EM) on the surface of viral particles. Sapoviruses have the traditional calicivirus morphology. In contrast, noroviruses are less likely to have visible cup-like depressions, and many were previously identified morphologically as small round structured viruses (SRSVs). However, some noroviruses have the distinctive calicivirus EM appearance, so definitive classification of an individual virus strain is dependent upon sequencing data and phylogenetic analysis. Noroviruses have a genome that ranges in size from 7.5 to 7.7 kb and has three open reading frames (ORFs).15 The first ORF encodes a large polyprotein that is thought to be cleaved post-translationally into several nonstructural proteins, including a viral protease, polymerase, and helicase. The second ORF encodes the major structural protein (VP1), while the third ORF encodes a basic protein that is also a minor structural protein (VP2). The VP1 protein spontaneously assembles into virus-like particles (VLPs) when expressed in a baculovirus expression system.16 These VLPs are antigenically and morphologically similar to native virions and have been useful reagents because human caliciviruses cannot be propagated in vitro.17 Sapoviruses have a genomic organization similar to that of the noroviruses, with the exception that the VP1 gene is in the same ORF as those for the nonstructural proteins.18 The lack of a cell culture system has led to the use of other classification systems for characterization of norovirus and sapovirus strains. Both antigenic and genetic classification schemes have been used. Early studies relied on reactivity with human convalescent sera (eg, solid phase immune electron microscopy), but more recent methods have used hyperimmune animal sera generated against recombinant VLPs.19 However, sequence-based strain characterization is currently the most common means of strain classification. The norovirus and sapovirus genera can each be subdivided into two genogroups based upon phylogenetic analyses, and additional genogroups have been proposed for the noroviruses.20,21 The genogroups can be further subdivided into genetic clusters, or genotypes, based upon pairwise comparisons of the VP1 amino acid sequences of viral strains. How well the genetic classification scheme reflects biologic (ie, serotypic) differences between groups has not yet been determined.

Epidemiology Human caliciviruses infect persons of all ages. These viruses cause infection throughout the year, although there is a peak incidence during the cold-weather months.22 Noroviruses were previously referred to as “Norwalk-like” viruses and Norwalk virus is the prototype strain. Noroviruses are the major cause of epidemic nonbacterial gastroenteritis, being identified in 70 to >95% of outbreaks.23-25 In contrast, sapoviruses are only occasionally identified as the cause of an outbreak, and are instead more commonly recognized as causing diarrhea among young children.26,27 Noroviruses are the most common viral cause of gastroenteritis identified in recent community-based studies.28,29 Seroprevalence rates in developed countries increase during the first several years of life, reaching levels of 80 to 90% by young adulthood.30 Human caliciviruses are principally spread by the fecal–oral route, but airborne transmission (following exposure to a vomiting person) may also occur.31 Person-to-person spread and consumption of contaminated foods or water are common mechanisms by which infection is established, although

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fomites also may serve as the infection source. Some of the more common foods associated with norovirus infection include uncooked shellfish, salads, and cold foods.32 Recreational activities, including canoeing, rafting, and football, are another means by which viral transmission has occurred, either through consumption of contaminated water or by more direct exposure to ill participants.33,34 These viruses are relatively resistant to many disinfectants, making it difficult to eradicate them from the environment. This characteristic has led to continued virus transmission from contaminated environmental surfaces to guests and has necessitated the closure of hotels and cruise ships in order to decontaminate potentially contaminated areas.35,36 The importance of human caliciviruses on cruises may relate to potential for contaminated food and water or to the low viral inoculum required and high secondary rate of spread.

Clinical Manifestations and Immunity The acute onset of vomiting, nonbloody diarrhea, or both, is characteristic of human calicivirus infection. From human experimental infection studies, vomiting may be the predominant symptom in one person, while diarrhea without vomiting may occur in another individual infected with the same virus.6,37 Other associated symptoms may include nausea, anorexia, abdominal cramps, malaise, and low-grade fever. Up to one-third of individuals infected during experimental challenge studies are asymptomatic, while other individuals are not infected, even upon repeated challenge.37,38 The incubation period ranges from 1 to 2 days, and symptoms generally persist for 12 to 60 hours. In persons who do not become infected following exposure to virus, short-term, homologous immunity (6 to 14 weeks) is induced following infection.38 In some studies, higher levels of serum antibody have correlated with protection from illness.39,40 Natural resistance to infection, based upon expression of blood-group antigens (ABH, secretor status), may also influence the likelihood of symptomatic illness following exposure to virus.41,42

Diagnosis Several approaches can be used to diagnose human calicivirus infection. Electron microscopy, the first method used for detection of these viruses, is still used by many laboratories to screen stools for potential viral pathogens. However, the low number of noroviruses shed in stool makes direct EM relatively insensitive. The sensitivity can be increased somewhat with IEM, which uses specific antisera to aggregate viruses and make them easier to detect, but the antisera used in this assay are not widely available. Currently, the most common assay for human calicivirus diagnosis is the reverse transcriptionpolymerase chain reaction (RT-PCR).19 This assay uses virus-specific primers that target conserved regions of the genome (usually in the polymerase or VP1 genes) to make complementary DNA and to amplify portions of the virus genome. The specificity of the amplification is confirmed using probe hybridization or sequencing of the amplicons. Unfortunately, the sequence diversity of the human caliciviruses is such that no single primer pair can detect all viruses, and most laboratories will use separate primer pairs for genogroups I and II nororviruses and a third pair for sapoviruses.19 Antigen and antibody detection assays have also been investigated, but their use is largely restricted to research laboratories. Early generation antigen detection enzyme-linked immunosor-

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33

bent assays (ELISA) were too specific, only detecting viruses closely related to the antigen from which the hyperimmune sera were made. The recent description of more broadly reactive monoclonal antibodies suggests that a more broadly reactive antigen detection assay can be developed.43,44 Antibody assays have relied largely on the use of paired sera, making the assay of more use for epidemiologic studies rather than for evaluation of the individual patient.

Treatment and Prevention The illness caused by human caliciviruses is generally mild and self-limited, and treatment is supportive (eg, rehydration, analgesics, antiemetics). Recovery is the rule, although some patients become ill enough to require hospitalization for fluid replacement. Mortality is rare, but it has occurred as a result of aspiration and in the elderly. Currently, the principal means of prevention is avoidance of contaminated foodstuffs and water. The potential use of VLPs as a vaccine is being explored.45

ROTAVIRUSES Viral Characteristics and Biology Rotaviruses are nonenveloped, icosahedral viruses that have a double-stranded, segmented RNA genome. Rotavirus is a genus within the family Reoviridae, and there are both animal and human strains within the genus.46 The name “rotavirus” is derived from the Latin word, rota, meaning “wheel,” and refers to the morphologic appearance of the virus particle. The virus particle is made up of three layers of structural protein: VP1, VP2, and VP3 form the inner core; VP6, which makes up 50% of the total weight of the viral particle, forms the second layer; and VP4 and VP7 form the outer layer. The inner core layer encloses the eleven segments of the RNA genome. The segmented genome allows reassortment of virus genes to occur in cells that are coinfected with more than one virus strain. Rotaviruses are classified into different groups based upon the presence of cross-reactive antigenic epitopes on the VP6 protein. Group A rotaviruses are the major cause of human disease. Groups B and C rotaviruses are primarily animal pathogens that occasionally cause disease in humans, including a few large outbreaks, while other groups (D to F) infect only animals.47-49 The group A rotaviruses are further subdivided into serotypes based upon antigenic characteristics of the VP7 (G type) and VP4 (P type) proteins. Fourteen different G types and 20 P types have been identified, with at least 10 G types and 11 P types being found in humans.47 One of the viral proteins, nonstructural protein 4 (NSP4), has been found to be a viral enterotoxin.50 Its toxigenic effect is mediated through a calcium-dependent signaling pathway that leads to excess chloride secretion. The toxigenic properties of this protein are not the only means by which rotavirus causes diarrhea; villous shortening with malabsorption and activation of the enteric nervous system are also likely to have a role in the pathogenesis of disease.51-53

Epidemiology Rotavirus infection is the principal cause of dehydrating diarrhea of young children in the world. In the developing world, it is a major cause of mortality in the first years of life. In contrast, in the United States, there is little mortality associated with primary infection; nevertheless, primary infection

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leads to a significant use of medical resources due to doctor visits and hospitalizations.54 Almost all children are infected at least once by the age of 3 years, with the peak incidence occurring between ages 6 and 24 months. Infection in adults is recognized less frequently. It occurs following contact with a pediatric case, in foodborne or waterborne outbreaks, in travelers, in epidemics in closed populations (ie, institutionalized individuals), and as a sporadic cause of endemic disease.55 It was identified in 1% of 263 nonbacterial gastroenteritis outbreaks investigated by the Centers for Disease Control and Prevention between 1998 and 2000.56 All three of the rotavirus-associated outbreaks in the United States and several recent outbreaks in Japan were caused by viruses with a G2 serotype. 56 In children, the most common infecting serotypes are G1 to G4 and G9.57,58 The reasons for the predominance of G2 serotypes among outbreaks in adults are not clear, but possibilities include increased virulence of G2 viruses and lack of protective heterotypic immunity in affected individuals.56,59 Transmission of rotavirus infection is by the fecal–oral route. Fomites and contaminated foods and water all serve as vehicles for virus transmission. Rotaviruses survive less well in the environment than do caliciviruses, based on the observations that they are commonly found in shellfish and in sewage, but they are uncommonly identified as causes of foodborne or waterborne outbreaks.56,60,61 In the United States, there is a distinct winter seasonality, but in other parts of the world, autumn and spring peaks of infection occur, and in the tropics (within 10° of the equator), a seasonal trend often is not apparent.62

Clinical Manifestations and Immunity Diarrhea, vomiting, and fever are all common symptoms of rotavirus-associated gastroenteritis.56,63 Diarrhea is usually watery and is typically of longer duration (4 days or more) than that seen with norovirus-associated illness. Vomiting occurs in the first 1 to 2 days of illness, and fever may be as high as 39° to 40°C in young children.63,64 Volume depletion occurs frequently and is a reason that patients seek medical care. The overall illness tends to be somewhat more severe than that associated with norovirus infection, which may explain the relatively greater frequency of identification of rotavirus infection in persons seeking medical attention.29,65-67 Asymptomatic infection also occurs commonly, particularly in older children and adults. The incubation period is estimated to be 1 to 3 days.64 Repeated infection leads to protection from more severe disease.68 Serum antibody levels have been the best correlate of protection from disease, based upon a variety of studies in humans.69 Additional host factors, such as nutritional status, and virus factors also likely contribute to the development of symptomatic infection.56,64

Diagnosis Antigen detection assays are currently the principal means of diagnosis of rotavirus infections. Both ELISA and latex agglutination assays are used to detect shared epitopes on the VP6 protein of group A rotaviruses.70 In some laboratories, EM is used to screen stools that are negative in group A rotavirus antigen assays. Such a strategy allows the detection of groups B and C viruses that are missed by the group A-specific antigen detection assays. RT-PCR assays are also used for diagnosis of rotavirus infection, and group A rotaviruses may be isolated using cell culture. Serologic assays (eg,

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35

ELISA, neutralization assay) rely on the identification of fourfold or greater rises in serum antibody, restricting the usefulness of these assays to epidemiologic studies. Rotaviruses identified in stool specimens or isolated in cell culture may be further characterized using a variety of methods. The mobility of the RNA genome segments by polyacrylamide gel electrophoresis (PAGE) has been used to compare different rotavirus strains.71 G and P types can be characterized based upon the reactivity of the virus with a panel of monoclonal antibodies.71,72 More recently, sequencing of the VP4 and VP7 genes has been used to characterize the genetic variability of strains within a region and over time.71,73

Treatment and Prevention Treatment of rotavirus infection is supportive; no specific effective antiviral therapy is available. Therapy is targeted at maintaining volume status, and this is accomplished using either oral or intravenous rehydration.74,75 Early reinstitution of feeding during the illness (~24 hours after onset) does not prolong diarrhea and may shorten it. There are insufficient data available to show a clinical benefit from the use of antimotility agents, such as loperamide, hence such agents are not recommended for use in children.75 Passive immunotherapy with oral immunoglobulins has been used successfully to treat chronic rotavirus diarrhea in immunocompromised children but is not recommended for general use.76 Active immunization can prevent or ameliorate the severity of rotavirus-induced illness.77 However, a live, attenuated rotavirus vaccine was recently withdrawn from the market due to its association with the occurrence of intussusception within the first 2 weeks of the first dose of the vaccine.78 Other vaccines are currently being developed and are under evaluation. At present, the principal means of control of infection is hand-washing, cohorting of ill individuals, and disinfection of potential fomites.

ASTROVIRUSES Viral Characteristics and Biology Astroviruses are nonenveloped, icosahedral viruses that have a single-stranded, positive-sense genome. Astrovirus is a genus within the family Astroviridae, and there are both animal and humans strains that tend to cause species-specific disease. The name “astrovirus” is derived from the Greek word, astron, meaning “star,” and refers to the five- or six-point star-like appearance of the viruses as seen by EM. 79 The 6.8 kb astrovirus genome has three large ORFs: ORF1a, ORF1b, and ORF2. ORF1a encodes several nonstructural proteins, including a 3C-like serine protease, while ORF1b contains the RNAdependent RNA polymerase gene and is translated by ribosomal frameshifting. ORF2 is contained in both genomic and a subgenomic RNA, and it is translated into a precursor that is proteolytically cleaved into at least three capsid proteins. 79,80 Eight different human astrovirus antigenic types have been identified.81,82 Phylogenetic analysis of the capsid gene also yields the eight groups that correspond to the serologic classification.83,84 Although the different astrovirus types can be distinguished serologically, they also share a shared group antigen that makes their identification possible with monoclonal antibodies in an enzyme immunoassay.85

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Epidemiology Astroviruses are recognized to cause disease in four different groups of individuals: 1) infants and young children; 2) the immunocompromised; 3) the institutionalized elderly; and 4) otherwise healthy persons exposed to contaminated food or water.79 These viruses are one of the most common causes of viral diarrhea among infants and children. For example, in China, astroviruses were the second most common virus identified, after rotavirus, in children hospitalized for acute diarrhea.86 In several other studies, astroviruses have been identified in 2 to 6% of persons with acute gastroenteritis.28,29,66,67,87 Astroviruses have been associated with gastroenteritis in a number of groups with immunodeficiencies. These viruses have caused an outbreak of gastroenteritis in a bone marrow transplant unit and were one of the more commonly identified viruses in human immunodeficiency virus (HIV)infected patients with diarrhea.88,89 The severely immunocompromised (eg, bone marrow transplant, fludarabine-treated) patient may have protracted courses of diarrhea.90-92 Several outbreaks of astrovirus infection among the institutionalized elderly have been reported, with attack rates ranging from 12 to 100%.79,93 Several outbreaks of astrovirus infection among otherwise healthy persons have been reported.94-96 At least some of these outbreaks are thought to have been caused by contaminated food or water. However, none of the recent outbreaks of epidemic gastroenteritis investigated by the Centers for Disease Control and Prevention have been attributed to astrovirus infection.23 Furthermore, although astroviruses can be demonstrated to be common contaminants in uncooked shellfish, this foodstuff has rarely been documented to be a source of astrovirus infection.60,90 Thus, although astroviruses can cause either foodborne or waterborne disease, epidemic gastroenteritis caused by these viruses via this route of transmission appears to be uncommon. Astroviruses are spread by the fecal–oral route. Transmission is from person-to-person spread, by food or water, and possibly, by fomites. Infection occurs most commonly during the winter months in temperate climates and during the rainy season in the tropics.79,90 Type 1 astroviruses are the most prevalent worldwide, although in a given location, the predominant circulating serotype may vary over time.

Clinical Manifestations and Immunity Astrovirus causes a mild gastroenteritis, with diarrhea lasting a median of 3 days and vomiting occurring in 20 to 62% of cases.97 Low-grade fever may also occur in up to one-quarter of patients. Dehydration is much less common than is seen with rotavirus infections in the same age group, and the overall illness associated with astrovirus infection is milder than with rotavirus.98 The incubation period is estimated to be approximately 3 to 4 days, based upon experimental challenge studies, and to be as little as 24 to 36 hours, based upon epidemiologic investigations of epidemic disease.79 The epidemiologic pattern of disease, occurring primarily in young children and in the elderly, suggests that immunity develops, which protects older children and adults from symptomatic infection. In studies of experimental challenge of adults, the presence of serum antibody correlated with protection from infection.99 Clearance of infection in an immunocompromised patient following administration of intravenous gamma globulin also suggests a possible role of antibody in disease resolution.91

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37

Diagnosis RT-PCR is the most sensitive assay for the diagnosis of astrovirus infection. Primer pairs have been developed that target conserved areas of the genome, including a region in ORF1a just upstream of the putative protease domain, a region in ORF1b (the RNA-dependent RNA polymerase gene) and the 3' untranslated region.94,100,101 Sequencing of the RT-PCR products has been performed to further characterize detected strains. Antigen detection enzyme immunoassays (EIAs) are also used to diagnose astrovirus infection.79,84,85,97 The EIA is not generally available in the United States, but an astrovirus-specific EIA is commercially available in Europe. Astroviruses can also be typed using type-specific EIAs.84 Electron microscopy is the least sensitive, but one of the most commonly available techniques for diagnosing astrovirus infection.88 Astroviruses can be isolated in cell culture. A number of different cell lines have been used, but the intestinally-derived cell lines, CaCo-2 and T84, are among the most sensitive.102,103 A rapid shell vial assay, which relies on detection of viral replication by immunofluorescent staining 18 hours after inoculation, has also been described.103 Amplification of virus in cell culture prior to detection using RT-PCR assays is another strategy to diagnose astrovirus infection.104

Treatment and Prevention Treatment is supportive, and no specific therapy is available. If volume depletion occurs, oral or intravenous volume rehydration should be provided. An anecdotal report on the use of gamma globulin to resolve protracted illness in an immunocompromised patient requires confirmation in additional patients.91 Prevention is targeted toward maintenance of hygienic standards and disinfection of potential fomites. No vaccine is currently available.

ENTERIC ADENOVIRUSES Viral Characteristics and Biology Enteric adenoviruses are nonenveloped, icosahedral viruses that have a double-stranded DNA genome. They are members of the family Adenoviridae, which contains six subgroups (or subgenera), A through F, that cause human disease. The subgroup F adenoviruses are the enteric adenoviruses. Adenovirus types 40 and 41 are the two members of the subgroup F adenoviruses, and variants among each of these types have been described.105,106 The adenovirus genome is approximately 32 kb in size and encodes a number of structural and nonstructural proteins. DNA restriction patterns have been used to characterize and determine the relationships between viruses in the different subgroups.107 Another way in which the subgroups have been characterized is through their ability to hemagglutinate rat or monkey red blood cells. Group F adenoviruses partially hemagglutinate rat red blood cells.108 The adenovirus capsid is made up of 240 hexons and 12 pentons, with the latter present at the vertices of the virus particle. A protein fiber extends from the penton base. A knob region at the tip of the fiber interacts with cellular receptors as the initial event in infection. The hexon protein has a group-specific antigen that is shared by all of the human adenoviruses.108

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Epidemiology Seroepidemiologic studies indicate that enteric adenoviruses cause disease in both developed and developing countries.105,109 These viruses have been identified in 1 to 2% of cases of gastroenteritis in most studies, although higher frequencies have been reported. 28,29,66,67,87,110,111 Children under 2 years of age are the most likely to have infection and disease. Some HIV-infected patients with chronic diarrhea have adenoviruses present in their feces, but it is not clear whether the enteric adenoviruses have a specific role in causing diarrhea in this patient population.112,113 Such a role is suggested by a single case report that noted the prolonged excretion of adenovirus type 40 in the absence of other enteric pathogens in an AIDS patient with chronic diarrhea.114 Transmission is by person-to-person spread. Foodborne or waterborne transmission has not been demonstrated, and transmission to adults is uncommon. Unlike the other viral causes of gastroenteritis, there is no seasonal pattern of enteric adenovirus disease.105

Clinical Manifestations and Immunity Diarrhea and vomiting are the principal manifestations of enteric adenovirus infection. Adenovirusinfected patients are less likely to have high fever (over 39°C) than rotavirus-infected children (3% vs 42%, respectively), but their diarrhea tends to last longer (mean duration 10.8 days vs. 5.8 days in rotavirus-infected patients).115 The incubation period is approximately 1 week.105

Diagnosis Enzyme immunoassays to detect enteric adenoviruses are commercially available.105 These assays use a group-specific polyclonal antiserum to capture and monoclonal subgroup F-specific antibodies as the detector. Sensitivity and specificity of the assay are high.116 Electron microscopy is another common means for detection of adenoviruses in the stool. To confirm that the adenovirus is an enteric adenovirus, IEM must be performed using type- or subgroup-specific antisera. A number of nucleic acid detection methods for the enteric adenoviruses have been described. Dot blot hybridization was one of the initial assays used, but more recently, PCR assays have been developed.105,117,118 A multiplex PCR assay allows the distinction of subgroup F adenoviruses from those of other subgroups based on amplicon size.118 Although fastidious, the enteric adenoviruses can be isolated in cell culture and classified by type or subgroup using monoclonal antibodies or restriction analysis.105,119,120

Treatment and Prevention Similar to the other enteric viruses, treatment of enteric adenovirus infection is supportive. No specific antiviral therapy is available. Because of their relatively low impact as a cause of diarrhea, compared to other enteric pathogens, vaccine development for adenoviruses has not been a priority. Additional studies are needed to clarify the correlates and duration of immunity.

RELATIVE IMPORTANCE OF THE VIRAL PATHOGENS AS CAUSES OF DIARRHEA Table 3-3 shows the relative impact of the enteric viruses as causes of diarrhea in cohort studies in different settings (in the community, presenting for outpatient care, admitted to the hospital) from

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Table 3-3. Frequency of Identification of Enteric Viruses in Persons with Gastroenteritis in Different Settings Country Setting Calicivirus

United Kingdom 29

The Netherlands 28,67

France 66

Sweden 87

Community (%)

General Practice (%)

Community (%)

General Practice (%)

Outpatient (%)

Outpatient (%)

Inpatient (%)

7.5

7.3

22.4

7.5

14

2.8

2.7

Rotavirus

3.7

6.9

7.3

5.3

61

2.1

4.5

Astrovirus

2.0

2.6

2.0

1.5

6.3

1.8

1.9

Adenovirus

1.5

2.7

3.8

2.2

3.1

1.3

0.5

several countries. Although all of the enteric viruses were found in each of the countries studied, they are not all likely to be a burden to the traveler. This is because astroviruses and enteric adenoviruses cause the greatest disease burden in young children. Thus, the most likely viral agents to cause diarrhea in the traveler are the human caliciviruses and rotaviruses. This conclusion is borne out by observational studies of travelers’ diarrhea.121 However, a few recent studies have evaluated human caliciviruses and astroviruses as potential etiologic agents of travelers’ diarrhea (Table 3-4), and only one study has used the best diagnostic assay available (RT-PCR) for identification of human caliciviruses.127 Additional studies using newer diagnostic methods are warranted for the identification of potential viral etiologies of travelers’ diarrhea, especially given the large number of cases for which no enteric pathogen is identified (see Table 3-4). Furthermore, improved strategies to prevent or ameliorate disease caused by the human caliciviruses and rotaviruses are needed for travelers.

Table 3-4. Number (Frequency) of Enteric Viruses Identified* in Association with Travelers’ Diarrhea in Selected Studies Reported Since 1990 Traveler (Number)

Travel Location

Human Calicivirus

Rotavirus

Astrovirus

Enteric Adenovirus

No Pathogen

Military (183)

Egypt

NT†

NT

NT

NT

93 (51%)

Adult tourists (171)

Morocco

NT

5 (3%)

NT

0

70 (41%)

Petrucelli et al.124

Military (137)

Thailand

NT

2 (1%)

NT

NT

57 (42%)

Bourgeois et al.125

Military (289)

South America, West Africa

26 (9%)‡

31 (11%)

NT

NT

143 (49%)

Sharp et al.126

Military (113)

Somalia

NT

1 (1%)

NT

NT

39 (35%)

Oyofo et al.127

Military (49)

Southeast Asia

21 (43%)**

0

NT

NT

14 (29%)

Steffen et al.128

Adult tourists (322)

Jamaica

NT

26 (9%)

NT

10 (3%)

220 (68%)

Author Haberberger et al.122 Mattila et al.123

*Identification of viral pathogen performed using antigen detection assay, unless noted otherwise. †NT, not tested for this viral pathogen. ‡Antigen and antibody detection assays using human-based reagents. **RT-PCR used as the diagnostic test.

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ACKNOWLEDGMENTS This work was supported by Public Health Service grants DK58955 from the National Institute of Diabetes & Digestive & Kidney Diseases and AI24998 from the National Institute of Allergy and Infectious Diseases and the National Vaccine Program Office, grant CX 827430 from the Environmental Protection Agency, and by a Merit Review Grant to Margaret E. Conner from the Research Service, Department of Veterans Affairs.

REFERENCES 1. Guerrant RL, Hughes JM, Lima NL, et al. Diarrhea in developed and developing countries: magnitude, special settings, and etiologies. Rev Infect Dis 1990;12:S41–50. 2. Mead PS, Slutsker L, Dietz V, et al. Food-related illness and death in the United States. Emerg Infect Dis 1999;5:607–25. 3. Zahorsky J. Hyperemesis hiemis or the winter vomiting disease. Arch Pediatr 1929;46:391–5. 4. Gordon I, Ingraham HS, Korns RF. Transmission of epidemic gastroenteritis to human volunteers by oral administration of fecal filtrates. J Exp Med 1947;86:409–22. 5. Adler JL, Zickl R. Winter vomiting disease. J Infect Dis 1969;119:668–73. 6. Dolin R, Blacklow NR, DuPont H, et al. Transmission of acute infectious nonbacterial gastroenteritis to volunteers by oral administration of stool filtrates. J Infect Dis 1971;123:307–12. 7. Kapikian AZ, Wyatt RG, Dolin R, et al. Visualization by immune electron microscopy of a 27-nm particle associated with acute infectious nonbacterial gastroenteritis. J Virol 1972;10:1075–81. 8. Bishop RF, Davidson GP, Holmes IH, et al. Virus particles in epithelial cells of duodenal mucosa from children with viral gastroenteritis. Lancet 1973;i:1281–3. 9. Appleton H, Higgins PG. Viruses and gastroenteritis in infants. Lancet 1975;i:1297. 10. Madeley CR, Cosgrove BP. 28 nm particles in faeces in infantile gastroenteritis. Lancet 1975;ii:451–2. 11. Flewett TH, Bryden AS, Davies H, et al. Epidemic viral enteritis in a long-stay children’s ward. Lancet 1975;i:4–5. 12. Madeley CR, Cosgrove BP. Caliciviruses in man. Lancet 1976;i:199–200. 13. Kilgore PE, Glass RI. Viral gastroenteritis. In: Richman DD, Whitley RJ, Hayden FG, editors. Clinical virology. 2nd ed. Washington (DC): ASM Press; 2002. p. 45–57. 14. Green KY, Ando T, Balayan MS, et al. Caliciviridae. In: van Regenmortel M, Fauquet CM, Bishop DHL, et al, editors. Virus taxonomy: 7th report of the International Committee on Taxonomy of Viruses. Orlando (FL): Academic Press, Inc.; 2000. p. 725–35. 15. Katayama K, Shirato-Horikoshi H, Kojima S, et al. Phylogenetic analysis of the complete genome of 18 Norwalk-like viruses. Virology 2002;299:225–39. 16. Jiang X, Wang M, Graham DY, et al. Expression, self-assembly, and antigenicity of the Norwalk virus capsid protein. J Virol 1992;66:6527–32. 17. Green KY, Lew JF, Jiang X, et al. Comparison of the reactivities of baculovirus-expressed recombinant Norwalk virus capsid antigen with those of the native Norwalk virus antigen in serologic assays and some epidemiologic observations. J Clin Microbiol 1993;31:2185–91. 18. Liu BL, Clarke IN, Caul EO, et al. Human enteric caliciviruses have a unique genome structure and are distinct from the Norwalk-like viruses. Arch Virol 1995;140:1245–56.

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19. Atmar RL, Estes MK. Diagnosis of noncultivatable gastroenteritis viruses, the human caliciviruses. Clin Microbiol Rev 2001;14:15–37. 20. Green J, Vinje J, Gallimore CI, et al. Capsid protein diversity among Norwalk-like viruses. Virus Genes 2000;20:227–36. 21. Fankhauser RL, Monroe SS, Noel JS, et al. Epidemiologic and molecular trends of “Norwalk-like viruses” associated with outbreaks of gastroenteritis in the United States. J Infect Dis 2002;186:1–7. 22. Mounts AW, Ando T, Koopmans M, et al. Cold weather seasonality of gastroenteritis associated with Norwalk-like viruses. J Infect Dis 2000;181:S284–7. 23. Fankhauser RL, Noel JS, Monroe SS, et al. Molecular epidemiology of “Norwalk-like viruses” in outbreaks of gastroenteritis in the United States. J Infect Dis 1998;178:1571–8. 24. Vinje J, Koopmans MPG. Molecular detection and epidemiology of small round-structured viruses in outbreaks of gastroenteritis in The Netherlands. J Infect Dis 1996;174:610–5. 25. Inouye S, Yamashita K, Yamadera S, et al. Surveillance of viral gastroenteritis in Japan: pediatric cases and outbreak incidents. J Infect Dis 2000;181:S270–4. 26. Chiba S, Nakata S, Numate-Kinoshita K, et al. Sapporo virus: history and recent findings. J Infect Dis 2000;181:S303–8. 27. Rockx B, de Wit M, Vennema H, et al. Natural history of human calicivirus infection: a prospective cohort study. Clin Infect Dis 2002;35:246–53. 28. de Wit MA, Koopmans MP, Kortbeek LM, et al. Sensor, a population-based cohort study on gastroenteritis in The Netherlands: incidence and etiology. Am J Epidemiol 2001;154:666–74. 29. Wheeler JG, Sethi D, Cowden JM, et al. Study of infectious intestinal disease in England: rates in the community, presenting to general practice, and reported to national surveillance. The Infectious Intestinal Disease Study Executive. Br Med J 1999;318:1046–50. 30. Lopman BA, Brown DW, Koopmans M. Human caliciviruses in Europe. J Clin Virol 2002;24:137–60. 31. Chadwick PR, McCann R. Transmission of a small round structured virus by vomiting during a hospital outbreak of gastroenteritis. J Hosp Infect 1994;26:251–9. 32. Schwab KJ, Estes MK, Atmar RL. Norwalk and other human caliciviruses: molecular characterization, epidemiology, and pathogenesis. In: Cary JW, Linz JE, Bhatnagar D, editors. Microbial foodborne diseases: mechanisms of pathogenicity and toxin synthesis. Lancaster (PA): Technomic Publishing Company, Inc.; 2000. p. 469–93. 33. Gray JJ, Green J, Cunliffe C, et al. Mixed genogroup SRSV infections among a party of canoeists exposed to contaminated recreational water. J Med Virol 1997;52:425–9. 34. Becker KM, Moe CL, Southwick KL, et al. Transmission of Norwalk virus during a football game. N Engl J Med 2000;343:1223–7. 35. Cheesbrough JS, Green J, Gallimore CI, et al. Widespread environmental contamination with Norwalk-like viruses (NLV) detected in a prolonged hotel outbreak of gastroenteritis. Epidemiol Infect 2000;125:93–8. 36. McEvoy M, Blake W, Brown D, et al. An outbreak of viral gastroenteritis on a cruise ship. Commun Dis Rep CDR Rev 1996;6:R188–92. 37. Graham DY, Jiang X, Tanaka T, et al. Norwalk virus infection of volunteers: new insights based on improved assays. J Infect Dis 1994;170:34–43. 38. Parrino TA, Schreiber DS, Trier JS, et al. Clinical immunity in acute gastroenteritis caused by Norwalk agent. N Engl J Med 1977;297:86–9.

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39. Nakata S, Chiba S, Terashima H, et al. Humoral immunity in infants with gastroenteritis caused by human calicivirus. J Infect Dis 1985;152:274–9. 40. Ryder RW, Singh N, Reeves WC, et al. Evidence of immunity induced by naturally acquired rotavirus and Norwalk virus infection on two remote Panamanian islands. J Infect Dis 1985;151:99–105. 41. Hutson AM, Atmar RL, Graham DY, et al. Norwalk virus infection and disease is associated with ABO histo-blood group type. J Infect Dis 2002;185:1335–7. 42. Marrionneau S, Ruvoen N, Le Moullac-Vaidye B, et al. Norwalk virus binds to histo-blood group antigens present on gastroduodenal epithelial cells of secretor individuals. Gastroenterology 2002;122:1967–77. 43. Hale AD, Tanaka RN, Kitamoto N, et al. Identification of an epitope common to genogroup I “Norwalklike viruses.” J Clin Microbiol 2000;38:1656–60. 44. Kitamoto N, Tanaka T, Natori K, et al. Cross-reactivity among several recombinant calicivirus virus-like particles (VLPs) with monoclonal antibodies obtained from mice immunized orally with one type of VLP. J Clin Microbiol 2002;40:2459–65. 45. Estes MK, Ball JM, Guerrero RA, et al. Norwalk virus vaccines; challenges and progress. J Infect Dis 2000;181:S367–73. 46. Estes MK. Rotaviruses and their replication. In: Knipe DM, Howley PM, editors. Fields virology. Vol 2. 4th ed. New York: Lippincott Williams & Wilkins; 2001. p. 1747–85. 47. Desselberger U, Iturriza-Gomara M, Gray JJ. Rotavirus epidemiology and surveillance. In: Chadwick D, Goode JA, editors. Novartis Foundation Symposium 238. Gastroenteritis viruses. New York: John Wiley & Sons, Inc.; 2001. p. 125–47. 48. Fang ZY, Ye Q, Ho MS, et al. Investigation of an outbreak of adult diarrhoea in China. J Infect Dis 1989;160:948–53. 49. Nilsson M, Svenungsson B, Hedlund K-O, et al. Incidence and genetic diversity of group C rotavirus among adults. J Infect Dis 2000;182:678–84. 50. Ball J, Tian P, Zeng C, et al. Age-dependent diarrhea induced by a rotavirus nonstructural glycoprotein. Science 1996;272:101–4. 51. Mavromichalis J, Evans N, McNeish A, et al. Intestinal damage in rotavirus and adenovirus gastroenteritis assessed by D-xylose malabsorption. Arch Dis Child 1977;52:589–91. 52. Hyams J, Krause P, Gleason P. Lactose malabsorption following rotavirus infection in young children. J Pediatr 1981;99:916–8. 53. Lundgren O, Peregrin AT, Persson K, et al. Role of the enteric nervous system in the fluid and electrolyte secretion of rotavirus diarrhea. Science 2000;287:491–4. 54. Matson DO, Estes MK. Impact of rotavirus infection at a large pediatric hospital. J Infect Dis 1990;162:598–604. 55. Hardy D. Epidemiology of rotaviral infection in adults. Rev Infect Dis 1987;9:461–9. 56. Griffin DD, Fletcher M, Levy ME, et al. Outbreaks of adult gastroenteritis traced to a single genotype of rotavirus. J Infect Dis 2002;185:1502–5. 57. Matson DO, Estes MK, Burns JW, et al. Serotype variation in group A rotaviruses in two regions of the USA. J Infect Dis 1990;162:605–14. 58. Griffin D, Kirkwood C, Parashar UD, et al. Surveillance of rotavirus strains in the United States: identification of unusual strains. J Clin Microbiol 2000;38:2784–7. 59. Cascio A, Vizzi E, Alaimo C, et al. Rotavirus gastroenteritis in Italian children: can severity of symptoms be related to the infecting virus? Clin Infect Dis 2001;32:1126–32.

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60. LeGuyader F, Haugarreau L, Miossec L, et al. Three-year study to assess human enteric viruses in shellfish. Appl Environ Microbiol 2000;66:3241–8. 61. Baggi F, Peduzzi R. Genotyping of rotaviruses in environmental water and stool samples in southern Switzerland by nucleotide sequence analysis of 189 base pairs at the 5’ end of the VP7 gene. J Clin Microbiol 2000;38:3681–5. 62. Cook SM, Glass RI, LeBaron CW, et al. Global seasonality of rotavirus infections. Bull WHO 1990;68:171–7. 63. Ruuska T, Vesikari T. Rotavirus disease in Finnish children: use of numerical scores for clinical severity of diarrhoeal episodes. Scand J Infect Dis 1990;22:259–67 64. Bass DM, Greenberg HB. Group A rotaviruses. In: Blaser MJ, Smith PD, Ravdin JI, et al, editors. Infections of the gastrointestinal tract. New York: Raven Press, Ltd.; 1995. p. 967–82. 65. Pang X-L, Janesuu J, Vesikari T. Human calicivirus-associated sporadic gastroenteritis in Finnish children less than two years of age followed prospectively during a rotavirus vaccine trial. Pediatr Infect Dis J 1999;18:420–6. 66. Bon F, Fascia P, Dauvergne M, et al. Prevalence of group A rotavirus, human calicivirus, astrovirus, and adenovirus type 40 and 41 infections among children with acute gastroenteritis in Dijon, France. J Clin Microbiol 1999;37:3055–8. 67. de Wit MAS, Koopmans MPG, Kortbeek LM, et al. Etiology of gastroenteritis in sentinel general practices in The Netherlands. Clin Infect Dis 2001;33:280–8. 68. Velazquez FR, Matson DO, Calva JJ, et al. Rotavirus infection in infants as protection against subsequent infections. N Engl J Med 1996;335:1022–8. 69. Jiang B, Gentsch JR, Glass RI. The role of serum antibodies in the protection against rotavirus disease: an overview. Clin Infect Dis 2002;34:1351–61. 70. Steele JC Jr. Rotavirus. Clin Lab Med 1999;19:691–703. 71. Ramachandran M, Gentsch JR, Parashar UD, et al. Detection and characterization of novel rotavirus strains in the United States. J Clin Microbiol 1998;36:3223–9. 72. Taniguchi K, Urasawa T, Morita Y, et al. Direct serotyping of human rotavirus in stools by an enzymelinked immunosorbent assay using serotype 1-, 2-, 3-, and 4-specific monoclonal antibodies to VP7. J Infect Dis 1987;155:1159–66. 73. Leite JP, Alfieri AA, Woods PA, et al. Rotavirus G and P types circulating in Brazil: characterization by RTPCR, probe hybridization, and sequence analysis. Arch Virol 1996;141:2365–74. 74. Avery ME, Snyder JD. Oral therapy for acute diarrhea: the underused simple solution. N Engl J Med 1990;323:891–4. 75. American Academy of Pediatrics, Provisional Committee on Quality Improvement, Subcommittee on Acute Gastroenteritis. Practice parameter: the management of acute gastroenteritis in young children. Pediatrics 1996;97:424–35. 76. Guarino A, Guandalini S, Albano F, et al. Enteral immunoglobulins for treatment of protracted rotaviral diarrhea. Pediatr Infect Dis J 1991;10:612–4. 77. Centers for Disease Control and Prevention. Rotavirus vaccine for the prevention of rotavirus gastroenteritis among children: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 1999;48(RR-2):1–20. 78. Murphy TV, Garguillo PM, Massoudi MS, et al. Intussusception among infants given an oral rotavirus vaccine. N Engl J Med 2001;344:564–72.

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79. Matsui SM. Astroviruses. In: Richman DD, Whitley RJ, Hayden FG, editors. Clinical virology. 2nd ed. Washington (DC): ASM Press; 2002. p.1075–86. 80. Bass DM, Qui S. Proteolytic processing of the astrovirus capsid. J Virol 2000;74:1810–4. 81. Lee TW, Kurtz JB. Prevalence of human astrovirus serotypes in the Oxford region 1976-92 with evidence for two new serotypes. Epidemiol Infect 1994;112:187–93. 82. Taylor MB, Walter J, Berke T, et al. Characterisation of a South African human astrovirus as type 8 by antigenic and genetic analyses. J Med Virol 2001;64:256–61. 83. Wang Q-H, Kakizawa J, Wen L-Y, et al. Genetic analysis of the capsid region of astroviruses. J Med Virol 2001;64:245–55. 84. Monroe SS, Holmes JL, Belliot GM. Molecular epidemiology of human astroviruses. In: Chadwick D, Goode JA, editors. Novartis Foundation Symposium 238. Gastroenteritis viruses. New York: John Wiley & Sons, Inc.; 2001. p. 237–45. 85. Hermann JE, Hudson RW, Perron-Henry DM, et al. Antigenic characterization of cell-cultivated astrovirus serotypes and development of astrovirus-specific monoclonal antibodies. J Infect Dis 1988;158:182–5. 86. Qiao H, Nilsson M, Abreu ER, et al. Viral diarrhea in children in Beijing, China. J Med Virol 1999;57:390–6. 87. Svenungsson B, Lagergren A, Ekwall E, et al. Enteropathogens in adult patients with diarrhea and healthy control subjects: a 1-year prospective study in a Swedish clinic for infectious diseases. Clin Infect Dis 2000;30:770–8 88. Cubitt WD, Mitchell DK, Carter MJ, et al. Application of electron microscopy, enzyme immunoassay, and RT-PCR to monitor an outbreak of astrovirus type 1 in a paediatric bone marrow transplant unit. J Med Virol 1999;57:313–21. 89. Grohmann GS, Glass RI, Pereira HG, et al. Enteric viruses and diarrhea in HIV-infected patients. N Engl J Med 1993;329:14–20. 90. Kurtz JB, Lee TW. Astroviruses: human and animal. Ciba Found Symp 1987;128:92–107. 91. Bjorkholm M, Celsing F, Runarsson G, et al. Successful intravenous immunoglobulin therapy for severe and persistent astrovirus gastroenteritis after fludarabine treatment in a patient with Waldenstrom’s macroglobulinemia. Int J Hematol 1995;62:117–20. 92. Coppo P, Scieux C, Ferchal F, et al. Astrovirus enteritis in a chronic lymphocytic leukemia patient treated with fludarabine monophosphate. Ann Hematol 2000;79:43–5. 93. Lewis DC, Lightfoot NF, Cubitt WD, et al. Outbreaks of astrovirus type 1 and rotavirus gastroenteritis in a geriatric in-patient population. J Hosp Infect 1989;14:9–14. 94. Belliot G, Laveran H, Monroe SS. Outbreak of gastroenteritis in military recruits associated with serotype 3 astrovirus infection. J Med Virol 1997;51:101–6. 95. Utagawa ET, Nishizawa S, Sekine S, et al. Astrovirus as a cause of gastroenteritis in Japan. J Clin Microbiol 1994;32:1841–5. 96. Oishi I, Yamazaki K, Kimoto T, et al. A large outbreak of acute gastroenteritis associated with astrovirus among students and teachers in Osaka, Japan. J Infect Dis 1994;170:439–43. 97. Walter JE, Mitchell DK. Role of astroviruses in childhood diarrhea. Curr Opin Pediatr 2000;12:275–9. 98. Guerrero ML, Noel JS, Mitchell DK, et al. A prospective study of astrovirus diarrhea of infancy in Mexico City. Pediatr Infect Dis J 1998;17:723–7. 99. Kurtz JB, Lee TW, Craig JW, et al. Astrovirus infection in volunteers. J Med Virol 1979;3:221–30.

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100. Lewis TL, Greenberg HB, Herrmann JE, et al. Analysis of astrovirus serotype 1 RNA, identification of the viral RNA dependent, RNA polymerase motif, and expression of a viral structural protein. J Virol 1994;68:77–83. 101. Jonassen TO, Monceyron C, Lee TW, et al. Detection of all serotypes of human astrovirus by the polymerase chain reaction. J Virol Methods 1995;52:327–34. 102. Willcocks MM, Carter MJ, Laidler FR, et al. Growth and characterization of human faecal astrovirus in a continuous cell line. Arch Virol 1990;113:73–81. 103. Brinker JP, Blacklow NR, Herrmann JE. Human astrovirus isolation and propagation in multiple cell lines. Arch Virol 2000;145:1847–56. 104. Mustafa H, Palombo EA, Bishop RF. Improved sensitivity of astrovirus-specific RT-PCR following culture of stool samples in CaCO-2 cells. J Clin Virol 1998;11:103–7. 105. Herrmann JE, Blacklow NR. Enteric adenoviruses. In: Blaser MJ, Smith PD, Ravdin JI, et al, editors. Infections of the gastrointestinal tract. New York: Raven Press, Ltd.; 1995. p. 1047–53. 106. van der Avoort HGAM, Wermenbol AG, Somerdijk TPL, et al. Characterization of fastidious adenovirus types 40 and 41 by DNA restriction enzyme analysis and by neutralizing monoclonal antibodies. Virus Res 1989;12:139–58. 107. Adrian T, Wadell G, Hierholzer JC, et al. Restriction enzyme analysis of adenovirus prototypes 1 to 41. Arch Virol 1986;91:277–90. 108. Ruuskanen O, Meurman O, Akusjarvi G. Adenoviruses. In: Richman DD, Whitley RJ, Hayden FG, editors. Clinical virology. 2nd ed. Washington (DC): ASM Press; 2002. p. 515–35. 109. Kidd AH, Banatvala JE, de Jong JC. Antibodies to fastidious faecal adenoviruses (species 40 and 41) in sera from children. J Med Virol 1983;11:333–41. 110. Tiemessen CT, Wegerhoff MJ, Erasmus MJ, et al. Infection by enteric adenoviruses, rotaviruses, and other agents in a rural African environment. J Med Virol 1989;28:176–82. 111. Cruz JR, Caceres P, Cano F, et al. Adenovirus types 40 and 41 and rotaviruses associated with diarrhea in children from Guatemala. J Clin Microbiol 1990;28:1780–4. 112. Janoff EN, Orenstein JM, Manischewitz JF, et al. Adenovirus colitis in the acquired immunodeficiency syndrome. Gastroenterology 1991;100:976–9. 113. Smith PD, Quinn TC, Strober W, et al. Gastrointestinal infection in AIDS. Ann Intern Med 1992;116:63–7. 114. Dionisio D, Arista S, Vizzi E, et al. Chronic intestinal infection due to subgenus F type 40 adenovirus in a patient with AIDS. Scand J Infect Dis 1997;29:305–7. 115. Uhnoo I, Olding-Stenkvist E, Kreuger A. Clinical features of acute gastroenteritis associated with rotavirus, enteric adenoviruses, and bacteria. Arch Dis Child 1986;61:732–8. 116. de Jong JC, Bijlsma K, Wermenbol AG, et al. Detection, typing and subtyping of enteric adenoviruses 40 and 41 from fecal samples and observation of changing incidence of infections with these types and subtypes. J Clin Microbiol 1993;31:1562–9. 117. Takiff HE, Seidlin M, Krause P, et al. Detection of enteric adenoviruses by dot-blot hybridization using a molecularly cloned viral DNA probe. J Med Virol 1985;16:107–18. 118. Xu W, McDonough MC, Erdman DD. Species-specific identification of human adenoviruses by a multiplex PCR assay. J Clin Microbiol 2001;38:4114–20. 119. Kidd AH, Madeley CR. In vitro growth of some fastidious adenoviruses from stool specimens. J Clin Pathol 1981;34:213–6. 120. Wigand R, Baumeister HG, Maass G, et al. Isolation and identification of enteric adenoviruses. J Med Virol 1983;11:233–40.

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121. Peltola H, Gorbach SL. Travelers’ diarrhea epidemiology and clinical aspects. In: DuPont HL, Steffen R, editors. Textbook of travel medicine and health. Hamilton (ON): BC Decker Inc.; 1997. p. 78–86. 122. Haberberger RL Jr, Mikhail IA, Burans JP, et al. Travelers’ diarrhea among United States military personnel during joint American-Egyptian armed forces exercises in Cairo, Egypt. Mil Med 1991;156:27–30. 123. Mattila L, Siitonen A, Kyronseppa H, et al. Seasonal variation in etiology of travelers’ diarrhea. J Infect Dis 1992;165:385–8. 124. Petruccelli BP, Murphy GS, Sanchez JL, et al. Treatment of travelers’ diarrhea with ciprofloxacin and loperamide. J Infect Dis 1992;165:555–60. 125. Bourgeois AL, Gardiner CH, Thornton SA, et al. Etiology of acute diarrhea among United States military personnel deployed to South American and West Africa. Am J Trop Med Hyg 1993;48:243–8. 126. Sharp TW, Thornton SA, Wallace MR, et al. Diarrheal disease among military personnel during Operation Restore Hope, Somalia, 1992–1993. Am J Trop Med Hyg 1995;52:188–93. 127. Oyofo BA, Soderquist R, Lesmana M, et al. Norwalk-like virus and bacterial pathogens associated with cases of gastroenteritis onboard a U.S. navy ship. Am J Trop Med Hyg 1999;61:904–8. 128. Steffen R, Collard F, Tornieporth N, et al. Epidemiology, etiology, and impact of travelers’ diarrhea in Jamaica. J Am Med Assoc 1999;281:811–7.

Chapter 4

T H E PA R A S I T I C PAT H O G E N S Pablo C. Okhuysen, MD, and A. Clinton White, MD

The vast majority of travelers’ diarrhea cases are acute in nature and tend to resolve within 5 to 10 days after the onset of symptoms. Common etiologic agents of acute travelers’ diarrhea are enterotoxigenic Escherichia coli, Campylobacter jejuni, and Shigella and Salmonella species. In this setting, the duration and severity of illness are shortened with antimicrobial treatment. Contrary to popular belief, only a small percentage of acute travelers’ diarrhea cases are due to parasites. Numerous studies have identified intestinal protozoa in only 0 to 12% of cases of acute travelers’ diarrhea.1 In contrast, intestinal protozoa are the most common agents identified in travelers with chronic or persistent diarrhea.2 The longer incubation period for parasitic agents and the self-limiting nature of bacterial causes of diarrhea are factors that are probably responsible for a more common presentation in the returning traveler than during travel. The most common parasitic agents identified are Giardia intestinalis, Cryptosporidium parvum, and Entamoeba histolytica. Smaller proportions are due to the Microsporidiae and Isospora belli. In recent years, Cyclospora cayetanensis has been recognized as a common cause of chronic diarrhea in returning travelers. The risk factors for acquisition of intestinal parasites have not been well defined. In general, length of stay, hygiene, and level of development in the host country have been thought to be associated with the acquisition of intestinal protozoa.3 For example, in studies done in Nepal, giardiasis was most commonly diagnosed in travelers with diarrhea lasting more than 2 weeks than in those with diarrhea of less than 2 weeks’ duration.4

GIARDIA Giardia lamblia, also known as G. intestinalis or G. duodenalis, can produce infection in humans and a number of animal hosts. In most series, it is the most common parasitic cause of diarrhea in travelers. Molecular analysis of Giardia isolates has shown that these parasites belong to distinct genotypes, some of which demonstrate host preferences and will likely result in the reclassification as new species.5,6 The majority of human infections fall into groups 1 and 3, also known as assemblages A and B.7 While there are no phenotypic characteristics that support this differentiation, there are conflicting reports on the differences that the distinct genetic isolates have on the ability to cause symptomatic infection. Older studies based on isoenzyme analysis failed to demonstrate clinical differences between isolates.8 A more recent study using restriction fragment length polymorphism–polymerase chain reaction (RFLP–PCR) and done on isolates from a small group of Dutch patients showed that individuals infected with Giardia belonging to assemblage A present with intermittent diarrhea and

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those infected with assemblage B present with chronic diarrhea.9 It remains to be shown if this observation applies to other regions of the world. Infections with Giardia occur worldwide but the risk may vary according to the region visited. Modes of transmission include fecal–oral, waterborne, and foodborne.10In a study done on German travelers who contracted giardiasis, Giardia was demonstrated to more likely be acquired during travel to the Indian subcontinent and Africa than to Asia or Latin America.11 Giardia trophozoites adhere to the intestinal mucosal via the ventral disk as well as parasite lectins.10,12 While not invasive, Giardia causes damage to the microvillus layer via mechanical effects and via elaboration of cytotoxic materials, including proteinases. Giardiasis is also characterized by a lymphocytic infiltration of the lamina propria, and cytokine activation may cause villus atrophy. Also, there is an association of Giardia infection with overgrowth of bacteria in the small intestines. These processes result in disaccharidase deficiencies and altered intestinal absorption, which characterize clinical giardiasis. Worldwide, most patients infected with Giardia are asymptomatic.10,12 When present, clinical symptoms follow an incubation period of 1 to 3 weeks. The main clinical manifestation of giardiasis is diarrhea. In most cases, the stools are described as foul-smelling and greasy. Accompanying symptoms may include malaise, flatulence, cramping, bloating, nausea, anorexia, and weight loss. Less common symptoms include vomiting, fever, and urticaria. Symptoms often last for over 10 days and may continue beyond 1 month. Until recently, stool examination for ova and parasites was the main method used to diagnose giardiasis.13 Both the motile trophozoite and cyst forms can be visualized with trichrome or iodine stains. However, examining multiple stool samples using a single stool examination is timeconsuming and the results are highly dependent on technician skill. Recently, antigen detection tests have largely replaced direct examination. 10,13 Both immunofluorescent and enzyme-linked immunosorbent assay (ELISA) techniques are commercially available; both are more sensitive than stool examination.14 Nitroimidazoles such as multiple doses of metronidazole or a single dose of tinidazole are the main treatments of choice for giardiasis.10,12,13 Isolates with decreased susceptibility to metronidazole have been described, but the clinical significance of this observation is unclear, although patients failing clinically often responded to alternative agents.12,15 Quinacrine is another effective treatment; however, it is no longer marketed in much of the world and may not be manufactured.12 Nitazoxanide is a broad-spectrum antiparasitic agent that is currently licensed in many parts of the world, including the US. In controlled trials, it was as effective as metronidazole in the treatment of giardiasis.16,17 It may also be effective in metronidazole-resistant cases.18,19 Albendazole, furazolidone, and paromomycin have activity in giardiasis, but are generally less effective.20 New targets may be identified as the parasite’s genome is analyzed.21

CRYPTOSPORIDIUM Cryptosporidium parvum is a protozoan parasite that preferentially infects the small bowel of many animal species including humans.22,23 Oocysts are resistant to water chlorination and can survive in aquatic environments for prolonged periods of time.24 At least two distinct transmission cycles

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occur in nature and are related to specific genotypes. Infections with genotype 1 demonstrate preference for causing infection in humans while genotype 2 favors a zoonotic transmission.25,26 In addition to genotypic differences, phenotypic differences have been demonstrated in vivo and in vitro, as determined by the variable degrees of infectivity in humans and in tissue culture systems, suggesting that additional genetic pleomorphisms within the known genotypes exist.26,27 C. parvum is transmitted via the fecal–oral route.28 Risk factors for transmission include contact with farm animals or pets, drinking untreated water, ingestion of contaminated food, and contact with patients or day care centers.29-31 As few as 10 oocysts can cause infection in healthy volunteers and perhaps even fewer in immunocompromised individuals.32 Healthy individuals can develop specific antibody responses after infection and those with preexisting antibodies to C. parvum are less susceptible to lower innocula.33,34 However, healthy adults may experience repeated infections.35 Few studies have been performed to assess the prevalence of cryptosporidiosis in long-term travelers. Cohort studies have documented extremely high infection rates among children in developing countries, with seroconversion in virtually all children by age 5.36–38 There are fewer data on the epidemiology in travelers, but cryptosporidiosis seems to be more common in long-term travelers. For example, a survey of Peace Corps volunteers residing in West Africa demonstrated 13.6% increases in seroprevalence over a 2-year period of time.39 Studies from Europe note an association with travel, particularly to Africa and Asia.2 Giardia and Cryptosporidium are important causes of diarrhea in travelers to Russia, particularly to St. Petersburg. They are presumably waterborne pathogens in this setting. Both should be considered in any traveler with protracted travelers’ diarrhea. Cryptosporidium multiplies in the intestinal microvillus layer. Infection causes villous atrophy, crypt hyperplasia, and infiltration of lymphocytes, neutrophils, plasma cells, and macrophages into the lamina propria.40 In immunocompromised patients, Cryptosporidium may be found in the entire gastrointestinal tract and within the epithelial cells of the biliary tree, the pancreatic duct, and the airways.41 Infection causes increases in intestinal permeability and chloride secretion, which are thought to result from the host inflammatory response.42,43 Control of infection depends on the host cellular immune response and the production of cytokines such as interferon gamma. Individuals with immunoglobulin A (IgA) deficiencies can develop chronic disease.44 Symptoms of cryptosporidial infection include watery stools, fatigue, abdominal pain, general malaise, and, in 20% of cases, nausea and vomiting. Low-grade fever can also occur. Many patients will have a relapsing course. In human immunodeficiency virus (HIV)-infected individuals, when CD4 (T cells) counts are >200/mL3, C. parvum infection resolves spontaneously. In the later stages of HIV disease (CD4 counts <100/mL3), chronic infection can lead to dehydration, malnutrition, wasting, and death.45 Patients with HIV should exert particular caution when traveling abroad to prevent cryptosporidiosis. Specifically, they should avoid drinking water that has not been boiled or purified and that is not available in sealed containers. Diagnosis depends on the identification of oocysts in stool. The organisms are 4 to 6 µm in diameter, approximately the size of yeast found in normal stool. Staining of a fresh fecal specimen with a modified acid-fast stain aids in the diagnosis but the level of sensitivity is low. Recently, a more sensitive, monoclonal-based direct immunofluorescence assay (DIFA) has been introduced but it also

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suffers from low sensitivity. Commercially available ELISAs have been recently introduced and are sensitive and specific.46,47 Nevertheless, since oocyst excretion can be variable in light infections, the analysis of several specimens may be necessary to confirm the diagnosis. Treatment in the immunocompetent host is primarily supportive since cryptosporidiosis is selflimited. In one randomized, placebo-controlled trial of normal children and adults, nitazoxanide decreased the duration of diarrhea and oocysts shedding.48 The dose used in the trial was 500 mg twice a day for 3 days, with doses of 200 mg and 100 mg twice a day in children. A randomized trial in HIV patients with cryptosporidiosis, conducted in Mexico, showed improvement with treatment of patients having CD4 cell counts above (but not in those with below) 50/mL3.49 Nitazoxanide is approved for use in some countries and has recently been licensed in the United States by the manufacturer, Romark Laboratories. A small study using bovine anti-Cryptosporidium immunoglobulin in healthy adults exposed to C. parvum demonstrated a decrease in parasite excretion but no significant decrease in diarrhea.50 Few options exist for AIDS patients, in whom highly active antiretroviral therapy fails or is not an option. AIDS patients treated by monotherapy with paromomycin have variable responses. An openlabel study of paromomycin and azithromycin demonstrated some efficacy in terms of symptoms and parasitic burden.51 Treatment of water and avoiding contaminated food are the main methods for prevention of cryptosporidiosis. Specifically, travelers should avoid drinking water that has not been boiled or filtered. Personal-use water filters should be capable of removing particles of 1 mm in diameter.52 Two analyses of studies of agents for prophylaxis of Mycobacterium avium have also suggested a protective effect for Cryptosporidium infection.53,54 Rifabutin was associated with protection in both studies. The studies differed on whether clarithromycin was effective.53 Patients with HIV should exert particular caution when traveling abroad to prevent contracting the disease.

CYCLOSPORA Unlike Cryptosporidium, which is readily infectious after excretion, Cyclospora cayetanensis requires sporulation in the environment before becoming infectious. This coccidian parasite has been found in developing countries, particularly in Nepal and Peru, and was previously referred to as a cyanobacteria-like body or CLB. It appears that humans are the only reservoir for infection since extensive evaluation of domestic animals has failed to reveal carriage in endemic regions.55 However, it is genetically related to Eimeria species (a common cause of infection in avian species), and it is possible that a yet unidentified avian reservoir exists. The vehicles of transmission are most likely contaminated water and food.56 Cases in developed countries have been acquired mostly during outbreaks that have been related to imported raspberries, or diagnosed in travelers returning from developing nations.57,58 Studies in developing countries like Peru and Haiti have demonstrated a high frequency of asymptomatic excretion in indigenous populations. After an incubation period of approximately 7 days (range 2 to 11 days), diarrhea occurs accompanied by cramping, abdominal pain, nausea, vomiting, fatigue, and occasionally, fever. In general, infection is self-limited in otherwise healthy adults, but

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diarrhea can be prolonged and appears to be more severe than that experienced with Cryptosporidium if untreated. In the immunocompromised host, infection with Cyclospora may also result in chronic diarrhea if left untreated and requires chronic suppressive therapy in some cases such as AIDS. Cyclospora should be considered the likely cause of persistent or recurrent diarrhea among international travelers to Nepal in the spring or summer months. It is also endemic and of potential importance to travelers to other areas of the world and should be considered because of the chronicity of symptoms. Cyclospora and Cryptosporidium show staining similarity, but Cyclospora oocysts are twice as large (8 to 10 µm vs 3 to 5 µm). It can be identified in fecal samples by autofluorescence at 330 to 380 nm under ultraviolet microscopy.59 A 10-day course of therapy with combined trimethoprim (TMP) and sulfamethoxazole (SMX) results in clinical improvement and eradication of this parasite.

ISOSPORA Isospora belli produces large, oval-shaped oocysts that sporulate outside the body. This process takes 2 to 3 days before the oocysts become infectious. The organism is endemic in tropical and subtropical environments, associated with outbreaks of diarrheal disease, and have also been implicated in travelers’ diarrhea. I. belli infection is confined to humans and, perhaps, to dogs. No other animal reservoir has been identified. Transmission is postulated to be associated with contaminated water, although not proven. The watery diarrhea caused by this organism suggests an enterotoxin, but no evidence for this molecule yet exists. The clinical features of I. belli infection in immunocompetent hosts are abdominal pain, cramping, nausea, and watery diarrhea, occasionally with eosinophilia. In immunodeficient hosts, prolonged diarrhea with malnutrition may occur. Several case reports have documented dissemination to the mesenteric lymph nodes or acalculous cholecystitis in advanced HIV infection. Oocysts can be visualized with an acid-fast stain. Symptomatic infection responds to treatment with combined TMP–SMX. In AIDS patients with recurrent disease, secondary prophylaxis with TMP–SMX and pyrimethamine–sulfadoxine prevents relapses. Nitazoxanide, a thiazolide compound, and its desacetyl derivative, tizoxanide, have antimicrobial properties against anaerobic bacteria, as well as against helminths and protozoa, and are promising agents in the treatment of Isospora infection and other parasitosis.

ENTAMOEBA Infections with E. histolytica and E. dispar are especially prevalent in Mexico, India, Africa, and Central and South America. The species are morphologically indistinguishable, but can be differentiated by zymodeme patterns, monoclonal antibodies, and DNA probes. Infections with E. dispar are characteristically asymptomatic, do not elicit a serologic response, and are responsible for the majority of infections with Entamoeba. In contrast, infections with E. histolytica result in symptomatic illness (80 to 98% of cases) or invasive disease (2 to 20%) and the production of serum anti-

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bodies. However, in indigenous populations, asymptomatic carriage of E. histolytica is common. Major routes of transmission are through contaminated water and food or by direct fecal–oral contact. Individuals at highest risk for infection include travelers to developing nations, immigrants or migrant workers, immunocompromised individuals, and individuals housed in mental institutions. E. histolytica releases a pore-forming protein, soluble toxic molecules, and increased concentrations of a cysteine proteinase, which can degrade matrix proteins. Host leukocytes, neutrophils, and macrophages also play a role in cell damage when they are lysed and release their toxic products. Ulcerative lesions in the intestinal mucosa and liver abscesses are characterized by a moderate inflammatory response. Advanced lesions have necrotic centers with amebas concentrated at the outer zone of normal tissue. E. histolytica can cause intestinal syndromes including the following: 1) a dysenteric syndrome with production of small volumes of bloody, mucoid stools without fecal leukocytes, 2) colitis characterized by ulcerations of the colonic mucosa with typical flask-shaped abscesses, or 3) the formation of a fibrotic mass in the intestinal wall (ameboma). Chronic amebic colitis is clinically indistinguishable from inflammatory bowel disease, and those receiving corticosteroids are at risk for toxic megacolon and perforation. Infective trophozoites can migrate hematogenously to the right lobe of the liver, causing abscess formation, abdominal pain, jaundice, and fever. Adjacent anatomical structures, such as the pulmonary parenchyma, peritoneum, and pericardium can become involved. Amebas can also disseminate to the brain. Immunosuppressed or malnourished individuals, those at the extremes of age, patients with malignancy, and women during pregnancy and postpartum stages are especially at risk for invasive amebiasis. Indications for surgical drainage of an amebic abscess include large dimensions, impending rupture, left lobe location, or lack of therapeutic response. Identification of E. histolytica cysts and trophozoites requires examination of a fresh stool and a trichrome stain. New fecal antigen detection methods (ELISA) may also prove useful. Periodic acid–Schiff (PAS) stained tissue obtained by colonoscopy may be required to confirm the diagnosis. An episode of dysentery may not necessarily precede abscess formation. Newer serologic assays may improve the detection of invasive disease. After invasive disease, immunity develops to the subsequent invasion of E. histolytica, but not to colonization, and is perhaps mediated by cellular mechanisms. The identification of cysts in an asymptomatic host should prompt treatment with diloxanide or paromomycin. Invasive diseases, such as severe colitis or parenchymal abscess, should be treated with metronidazole, followed by a luminal agent such as diloxanide or paromomycin to prevent future invasion with any remaining cysts. Tinidazole has also been found to be highly effective.

MICROSPORIDIA Microsporidia species are small obligate intracellular parasites that infect vertebrate and invertebrate hosts. Only a few of the over 1,000 species known to belong in this phylum have been identified as pathogenic agents for humans. Microsporidia species have been sporadically reported as a cause of chronic diarrhea in both otherwise healthy adults and HIV-infected patients after travel and should be a consideration in cases of chronic diarrhea. Two species are associated with enteric infection: Enterocytozoon bieneusi and Encephalitozoon intestinalis (formerly known as Septata intestinalis), the former being the more common.

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Microsporidia share several common characteristics, including specialized polar tubes, intracellular asexual reproduction, and the formation of thick-walled spores that are able to survive for months in the environment. E. bieneusi and E. intestinalis can be distinguished morphologically by electron microscopy of small bowel biopsies or by PCR techniques. To date, E. bieneusi has only been reported in humans, but it is apparently found worldwide.60 The prevalence in selected groups of HIV-infected patients in different countries has indicated a range of 1.7 to 30%. Microsporidia may rarely cause travelers’ diarrhea in healthy, nonimmunocompromised hosts. The epidemiology and pathogenesis in these cases are uncertain. Both E. bieneusi and E. intestinalis infections are identified by diarrhea in individuals with CD4 counts less than 100/mL3, and frequently, also in asymptomatic carriers. E. bieneusi infects the enterocytes of the proximal jejunum and occasionally spreads to the biliary tract. In comparison, E. intestinalis is found in enterocytes, macrophages, and fibroblasts and may also disseminate to the mesenteric nodes and kidney. Free and intracytoplasmic spores can be stained with Giemsa stain, Weber’s trichrome stain, or fluorochrome (calcofluor, Uvitex 2B) stains that have affinity for chitin, but identification of the specific species requires electron microscopy or PCR. Infection of immunocompetent individuals is selflimited. Preliminary data suggest that albendazole may be of use in the treatment of E. intestinalis and in Encephalitozoon infections. Fumagillin has been shown to be of use in AIDS-associated microsporidiosis.61

OTHER PROTOZOA The role of Dientamoeba fragilis as a causal agent of travelers’ diarrhea remains a subject of debate; some authorities suggest treatment of symptomatic infections. A number of nonpathogenic protozoa are commonly identified in travelers with acute or chronic diarrhea; however, their role as causative agents of diarrhea has not been established. Patients in whom parasites such as Entamoeba coli, Endolimax nana, and other species of Entamoeba are identified do not require specific treatment.

HELMINTHS AND DIARRHEA IN TRAVELERS Numerous helminths infect the human intestinal tract, and in many developing countries, the majority of the population is infected with one or more intestinal helminths. However, intestinal helminths are rarely identified as causes of diarrhea.62 Diarrhea is usually associated with heavy infection, which is not common in travelers. Trichinosis can present with a diarrheal illness, typically associated with eosinophilia. This is particularly true in cases acquired in Arctic regions.63 Illness can last for up to 14 weeks. Strongyloidiasis can be associated with diarrhea.64,65 In most patients with intact host defenses, gastrointestinal illness is mild. However, patients can develop hyperinfection, which can be associated with watery or bloody diarrhea and prominent gastrointestinal complaints. Hyperinfection primarily develops in patients with compromised host defenses, particularly due to corticosteroid therapy. There is no sensitive diagnostic test for chronic strongyloidiasis.66 Capillariasis may

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present with abdominal pain, diarrhea, and malabsorption.67 Heavy infection with Trichuris may present with bloody diarrhea. Acute schistosomiasis is characterized by a systemic febrile illness termed Katayama fever. Travelers typically present at between 2 and 8 weeks after exposure with a systemic illness. Prominent features can include urticaria, hematospermia, or spinal cord involvements.68 Gastrointestinal complaints are common and, in some cases, diarrhea may be the most prominent symptom. Chronic intestinal schistosomiasis is associated with a granulomatous inflammation, polyps in the intestine, and bloody diarrhea.69 Heavy infection with Hymenolepsis tapeworms is associated with diarrhea.

OTHER CONSIDERATIONS The evaluation of diarrhea in travelers who do not respond to antimicrobial therapy or who experience prolonged illness requires a careful parasitologic examination of repeated stool specimens. In cases where a specific agent cannot be identified, other considerations should be entertained, such as Brainerd diarrhea, Clostridium difficile antibiotic associated colitis, tropical sprue, celiac disease, postinfective irritable bowel syndrome, HIV infection, or inflammatory bowel disease, among others.

REFERENCES 1. Peltola H, Gorbach SL. Travelers’ diarrhea. In: DuPont HL, Steffen R, editors. Travel medicine. 2nd ed. London: BC Decker Inc.; 2001. p. 151–9. 2. Reinthaler FF, Feierl G, Stunzner D, Marth E. Diarrhea in returning Austrian tourists: epidemiology, etiology, and cost-analyses. J Travel Med 1998;5:65–72. 3. Shlim DR, Hoge CW, Rajah R, et al. Persistent high risk of diarrhea among foreigners in Nepal during the first 2 years of residence. Clin Infect Dis 1999;29:613–6. 4. Taylor DN, Houston R, Shlim DR, et al. Etiology of diarrhea among travelers and foreign residents in Nepal. J Am Med Assoc 1988;260:1245–8. 5. Monis PT, Andrews RH, Mayrhofer G, Ey PL. Molecular systematics of the parasitic protozoan Giardia intestinalis. Mol Biol Evol 1999;16:1135–44. 6. Adam RD. Biology of Giardia lamblia. Clin Microbiol Rev 2001;14:447–75. 7. Caccio SM, De Giacomo M, Pozio E. Sequence analysis of the [beta]-giardin gene and development of a polymerase chain reaction-restriction fragment length polymorphism assay to genotype Giardia duodenalis cysts from human faecal samples. Int J Parasitol 2002;32:1023–30. 8. Cedillo-Rivera R, Enciso-Moreno JA, Martinez-Palomo A, Ortega-Pierres G. Giardia lamblia: isoenzyme analysis of 19 axenic strains isolated from symptomatic and asymptomatic patients in Mexico. Trans R Soc Trop Med Hyg 1989;83:644–6. 9. Homan WL, Mank TG. Human giardiasis: genotype linked differences in clinical symptomatology. Int J Parasitol 2001;31:822–6. 10. Hill DR, Nash TE. Intestinal flagyllate and ciliate infections. In: Guerrant RL, Walker DH, Weller PF, editors. Tropical infectious diseases: principles and practice; 1999. p. 703–20. 11. Jelinek T, Loescher T. Epidemiology of giardiasis in German travelers. J Travel Med 2000;7:70–3. 12. Gardner TB, Hill DR. Treatment of giardiasis. Clin Microbiol Rev 2001;14:114–28.

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13. Hiatt RA, Markell EK, Ng E. How many stool examinations are necessary to detect pathogenic intestinal protozoa? Am J Trop Med Hyg 1995;53:36–9. 14. Aldeen WE, Carroll K, Robison A, et al. Comparison of nine commercially available enzyme-linked immunosorbent assays for detection of Giardia lamblia in fecal specimens. J Clin Microbiol 1998;36:1338–40. 15. Upcroft P, Upcroft JA. Drug targets and mechanisms of resistance in the anaerobic protozoa. Clin Microbiol Rev 2001;14:150–64. 16. Ortiz JJ, Ayoub A, Gargala G, et al. Randomized clinical study of nitazoxanide compared to metronidazole in the treatment of symptomatic giardiasis in children from Northern Peru. Aliment Pharmacol Ther 2001;15:1409–15. 17. Rossignol JF, Ayoub A, Ayers MS. Treatment of diarrhea caused by Giardia intestinalis and Entamoeba histolytica or E. dispar: a randomized, double-blind, placebo-controlled study of nitazoxanide. J Infect Dis 2001;184:381–4. 18. Abboud P, Lemee V, Gargala G, et al. Successful treatment of metronidazole- and albendazole-resistant giardiasis with nitazoxanide in a patient with acquired immunodeficiency syndrome. Clin Infect Dis 2001;32:1792–4. 19. Adagu IS, Nolder D, Warhurst DC, Rossignol JF. In vitro activity of nitazoxanide and related compounds against isolates of Giardia intestinalis, Entamoeba histolytica and Trichomonas vaginalis. J Antimicrob Chemother 2002;49:103–11. 20. Zaat JO, Mank TG, Assendelft WJ. A systematic review on the treatment of giardiasis. Trop Med Int Health 1997;2:63–82. 21. Adam RD. The Giardia lamblia genome. Int J Parasitol 2000;30:475–84. 22. Current WL, Reese NC, Ernst JV, et al. Human cryptosporidiosis in immunocompetent and immunodeficient persons: studies of an outbreak and experimental transmission. N Engl J Med 1983;308:1252–7. 23. Homan W, van Gorkom T, Kan YY, Hepener J. Characterization of Cryptosporidium parvum in human and animal feces by single-tube nested polymerase chain reaction and restriction analysis. Parasitol Res 1999;85:707–12. 24. Chauret C, Nolan K, Chen P, et al. Aging of Cryptosporidium parvum oocysts in river water and their susceptibility to disinfection by chlorine and monochloramine. Can J Microbiol 1998;44:1154–60. 25. Widmer G, Tchack L, Chappell CL, Tzipori S. Sequence polymorphism in the beta-tubulin gene reveals heterogeneous and variable population structures in Cryptosporidium parvum. Appl Environ Microbiol 1998;64:4477–81. 26. Widmer G, Tzipori S, Fichtenbaum CJ, Griffiths JK. Genotypic and phenotypic characterization of Cryptosporidium parvum isolates from people with AIDS. J Infect Dis 1998;178:834–40. 27. Okhuysen PC, Chappell CL, Crabb JH, et al. Virulence of three distinct Cryptosporidium parvum isolates for healthy adults. J Infect Dis 1999;180:1275–81 28. Koch KL, Phillips DJ, Aber RC, Current WL. Cryptosporidiosis in hospital personnel: evidence for personto-person transmission. Ann Intern Med 1984;102:593–6. 29. Meinhardt PL, Casemore DP, Miller KB. Epidemiologic aspects of human cryptosporidiosis and the role of waterborne transmission. Epidemiol Rev 1996;18:118–36. 30. Foodborne outbreak of cryptosporidiosis – Spokane, Washington, 1997. MMWR Morb Mortal Wkly Rep 1998;47:565–7. 31. Outbreak of cryptosporidiosis associated with a water sprinkler fountain – Minnesota, 1997. MMWR Morb Mortal Wkly Rep 1998;47:856–60.

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32. DuPont HL, Chappell CL, Sterling CR, et al. The infectivity of Cryptosporidium parvum in healthy volunteers. N Engl J Med 1995;332:855–9. 33. Chappell CL, Okhuysen PC, Sterling CR, et al. Infectivity of Cryptosporidium parvum in healthy adults with pre-existing anti-C. parvum serum immunoglobulin G. Am J Trop Med Hyg 1999;60:157–64. 34. Moss DM, Chappell CL, Okhuysen PC, et al. The antibody response to 27-, 17-, and 15-kDa Cryptosporidium antigens following experimental infection in humans. J Infect Dis 1998;178:827–33. 35. Okhuysen PC, Chappell CL, Sterling CR, et al. Susceptibility and serologic response of healthy adults to reinfection with Cryptosporidium parvum. Infect Immun 1998;66:441–3. 36. Checkley W, Gilman RH, Epstein LD, et al. Asymptomatic and symptomatic cryptosporidiosis: their acute effect on weight gain in Peruvian children. Am J Epidemiol 1997;145:156–63. 37. Dillingham RA, Lima AA, Guerrant RL. Cryptosporidiosis: epidemiology and impact. Microbes Infect 2002;4:1059. 38. Newman RD, Sears CL, Moore SR, et al. Longitudinal study of Cryptosporidium infection in children in northeastern Brazil. J Infect Dis 1999;180:167–75. 39. Ungar BL, Mulligan M, Nutman TB. Serologic evidence of Cryptosporidium infection in US volunteers before and during Peace Corps service in Africa. Arch Intern Med 1989;149:894–7. 40. Goodgame RW, Kimball K, Ou C-N, et al. Intestinal function and injury in AIDS-related cryptosporidiosis. Gastroenterology 1995;108:1075–82. 41. Laurent F, McCole D, Eckmann L, Kagnoff MF. Pathogenesis of Cryptosporidium parvum infection. Microbes Infect 1999;1:141–8. 42. Zhang Y, Lee B, Thompson M, et al. Lactulose-mannitol intestinal permeability test in children with diarrhea caused by rotavirus and cryptosporidium. Diarrhea Working Group, Peru. J Pediatr Gastroenterol Nutr 2000;31:16–21. 43. Kosek M, Alcantara C, Lima AA, Guerrant RL. Cryptosporidiosis: an update. Lancet Infect Dis 2001;1:262–9. 44. Jacyna M, Parkin J, Goldin R, Baron J. Protracted enteric cryptosporidial infection in selective immunoglobulin A and Saccharomyces opsonin deficiencies. Gut 1990;31:714–6. 45. Hashmey R, Smith NH, Cron S, et al. Cryptosporidiosis in Houston, Texas. A report of 95 cases. Medicine (Baltimore) 1997;76:118–39. 46. Garcia LS, Shimizu RY. Evaluation of nine immunoassay kits (enzyme immunoassay and direct fluorescence) for detection of Giardia lamblia and Cryptosporidium parvum in human fecal specimens. J Clin Microbiol 1997;35:1526–9. 47. Garcia LS, Shimizu RY, Bernard CN. Detection of Giardia lamblia, Entamoeba histolytica/Entamoeba dispar, and Cryptosporidium parvum antigens in human fecal specimens using the triage parasite panel enzyme immunoassay. J Clin Microbiol 2000;38:3337–40. 48. Rossignol JF, Ayoub A, Ayers MS. Treatment of diarrhea caused by Cryptosporidium parvum: a prospective randomized, double-blind, placebo-controlled study of Nitazoxanide. J Infect Dis 2001;184:103–6. 49. Rossignol JF, Hidalgo H, Feregrino M, et al. A double-‘blind’ placebo-controlled study of nitazoxanide in the treatment of cryptosporidial diarrhoea in AIDS patients in Mexico. Trans R Soc Trop Med Hyg 1998;92:663–6. 50. Okhuysen PC, Chappell CL, Crabb J, et al. Prophylactic effect of bovine anti-Cryptosporidium hyperimmune colostrum immunoglobulin in healthy volunteers challenged with Cryptosporidium parvum. Clin Infect Dis 1998;26:1324–9.

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51. Smith NH, Cron S, Valdez LM, et al. Combination drug therapy for cryptosporidiosis in AIDS. J Infect Dis 1998;178:900–3. 52. Kaplan JE, Masur H, Holmes KK. Guidelines for preventing opportunistic infections among HIV-infected persons–2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. MMWR Recomm Rep 2002;51:1–52. 53. Holmberg SD, Moorman AC, Von Bargen JC, et al. Possible effectiveness of clarithromycin and rifabutin for cryptosporidiosis chemoprophylaxis in HIV disease. HIV Outpatient Study (HOPS) Investigators. J Am Med Assoc 1998;279:384–6. 54. Fichtenbaum CJ, Zackin R, Feinberg J, et al. Rifabutin but not clarithromycin prevents cryptosporidiosis in persons with advanced HIV infection. Aids 2000;14:2889–93. 55. Eberhard ML, Nace EK, Freeman AR. Survey for Cyclospora cayetanensis in domestic animals in an endemic area in Haiti. J Parasitol 1999;85:562–3. 56. Sturbaum GD, Ortega YR, Gilman RH, et al. Detection of Cyclospora cayetanensis in wastewater. Appl Environ Microbiol 1998;64:2284–6. 57. Herwaldt BL, Beach MJ. The return of Cyclospora in 1997: another outbreak of cyclosporiasis in North America associated with imported raspberries. Cyclospora Working Group. Ann Intern Med 1999;130:210–20. 58. Drenaggi D, Cirioni O, Giacometti A, et al. Cyclosporiasis in a traveler returning from South America. J Travel Med 1998;5:153–5. 59. Varea M, Clavel A, Doiz O, et al. Fuchsin fluorescence and autofluorescence in Cryptosporidium, Isospora and Cyclospora oocysts. Int J Parasitol 1998;28:1881–3. 60. Orenstein JM, Zierdt W, Zierdt C, Kotler DP. Identification of spores of Enterocytozoon bieneusi in stool and duodenal fluid from AIDS patients. Lancet 1990;336:1127–8. 61. Molina JM, Tourneur M, Sarfati C, et al. Fumagillin treatment of intestinal microsporidiosis. N Engl J Med 2002;346:1963–9. 62. Hashmey R, Genta RM, White Jr AC. Parasites and diarrhea. II: Helminths and diarrhea. J Travel Med 1997;4:72–5. 63. MacLean JD, Viallet J, Law C, Staudt M. Trichinosis in the Canadian arctic: report of five outbreaks and a new clinical syndrome. J Infect Dis 1989;160:513–20. 64. Tsai HC, Lee SS, Liu YC, et al. Clinical manifestations of strongyloidiasis in southern Taiwan. J Microbiol Immunol Infect 2002;35:29–36. 65. Genta RM, Gatti S, Linke MJ, et al. Endemic strongyloidiasis in Northern Italy: clinical and immunologic aspects. Q J Med 1988;257:679–90. 66. Siddiqui AA, Berk SL. Diagnosis of Strongyloides stercoralis infection. Clin Infect Dis 2001;33:1040–7. 67. Cross JH. Intestinal capillariasis. Clin Microbiol Rev 1992;5:120–9. 68. Roca C, Balanzo X, Gascon J, et al. Comparative, clinico-epidemiologic study of Schistosoma mansoni infections in travellers and immigrants in Spain. Eur J Clin Microbiol Infect Dis 2002;21:219–23. 69. Guyatt H, Gryseels B, Smith T, Tanner M. Assessing the public health importance of Schistosoma mansoni in different endemic areas: attributable fraction estimates as an approach. Am J Trop Med Hyg 1995;53:660–7.

Chapter 5

A N T I M I C R O B I A L R E S I S TA N C E Jordi Vila, MD, PhD, and Stuart B. Levy, MD, FAAM

The incidence of travelers’ diarrhea ranges from 2% in low-risk geographical areas (the United States, Europe, Australia, and Japan) to 40% in high-risk geographical areas (Latin America, Southern Asia, and Africa).1,2 All travelers from industrialized countries to developing countries develop a relatively rapid change in their intestinal flora. The new organisms often include potential enteric pathogens. Diarrhea follows ingestion of an inoculum of virulent organisms sufficiently large to overcome individual defense mechanisms. In patients traveling to high-risk areas, more than 60% of diarrheal illnesses are caused by a bacterial pathogen. 3 Knowing the antibiotic susceptibility profile of these enteric pathogens can help control the disease. Since information on the antimicrobial resistance of bacteria causing travelers’ diarrhea is scarce, and considering that the highest risk areas are developing countries, resistance data on certain relevant enteropathogenic bacteria in these countries can be helpful in predicting resistance in travelers’ diarrhea pathogens.

FACTORS FAVORING THE DEVELOPMENT OF ANTIMICROBIAL RESISTANCE Antimicrobial resistance has increased drastically in recent years in both developed and developing countries and can be spread through international travel (Figure 5-1). It has rapidly become a leading public health concern. Enteric infectious disease organisms are among those which are most affected by antimicrobial resistance. The prevalence of antimicrobial resistance varies greatly between and within countries and between different pathogens. Three main factors favor the development of bacterial resistance to antibiotics in developing countries: 1. Less potent activity: Some of the antibiotics provided in developing countries have decreased potency because of degradation or adulteration of the drug, or because of the presence of a lower concentration of active substances.4-6 For instance, substandard concentrations of ampicillin and tetracycline have been found in Nigeria.7-8 Moreover, expired drugs, with altered or removed expiry dates, have also been detected in developing countries.9-11 Some drugs produced in industrialized countries have been found to have expired on distribution in developing countries. 12 Finally, the antibiotics provided to these countries may be poorly transported and stored, leading to drug inactivation.13-15 2. Lack of diagnostic laboratories: Most of the hospitals in developing countries do not have clinical microbiology laboratories to perform routine analyses for microbiological diagnosis. Therefore, they have no information about either the etiology of the infectious diseases or antimicrobial

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Figure 5-1. Main factors favoring the development of antibiotic resistance in bacteria.

susceptibility, both essential for clinical practice. Bacterial infections are often treated empirically with broad-spectrum antibiotics. Although they are not frequently performed, specific and periodic studies regarding the etiology and antimicrobial susceptibility of some important infectious disease agents would help clinicians decide on which antibiotics to choose to treat such infections.16,17 3. Over-the-counter availability: In most developing countries, antibiotics can be purchased without prescription in pharmacies, general stores, markets, and from street hawkers. Since many drugs are expensive, some patients purchase incomplete regimens whenever possible and discontinue treatment when the symptoms disappear.18 As in industrialized countries, unnecessary prescriptions of antibiotics, mainly in cases of acute infantile diarrhea and respiratory infections, have been reported in developing countries.19-22 Health care personnel, who frequently have minimal training, are scarce and cannot serve the entire population, especially in rural areas. Moreover, in general, there are no policies on the use of antibiotics in hospitals. The infection control practices in many hospitals in developing countries are suboptimal or nonexistent and often compromised by the lack of resources and personnel trained in controlling infections in hospitals.23

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T R AV E L E R S ’ D I A R R H E A

Finally, although it may not seem to be an important problem in developing countries, where the practice is less applied, the excessive use of antimicrobials, especially as growth promoters in animals destined for human consumption, presents a growing risk to human health due to the emergence of bacteria resistant to the antibiotics fed to animals, which can then be transferred to humans through the food chain. 24-26 Spread of antibiotics and resistant bacteria into the environment is also a contributor to the problem (see Figure 5-1). Spread is also associated with the use of contaminated water from sewage runoff.27

DISSEMINATION OF RESISTANT BACTERIA Bacteria resistant to antibiotics can spread locally and internationally. The latter can occur bidirectionally between developed and developing countries (see Figure 5-1). Given that resistance determinants are often located on genetic mobile elements, resistance can be transferred to other bacteria. The dissemination of nonpathogenic antibiotic resistant bacteria is also important because they can serve as reservoirs of resistance genes that may be transferred to pathogens. For instance, investigators described the spread of a plasmid carrying a gentamicin-resistance gene among enteric bacteria isolated in Venezuela and the United States.28 Apparently healthy people in developing countries carry potentially pathogenic antibiotic resistant organisms asymptomatically.17,29 Crowding and unhygienic conditions are important factors favoring the dissemination of resistant bacteria. In Nigeria, resistant Escherichia coli isolates from individuals in an urban metropolis were significantly more likely to be resistant to 4 to 6 of 7 antibiotics tested, than were strains from rural areas which were resistant to only 0 to 3 antibiotics.30 Similar findings were reported from Nepal.31 The low level of sanitation of many of the developing countries may also contribute to the spread of antimicrobial resistant bacteria.12 Finally, warm and humid tropical climates are conducive to the propagation of bacteria in food and water.32 Visitors to developing countries acquire antibiotic resistant bacteria mainly in the intestinal tract.33 Travelers from the United States to Mexico have acquired antimicrobial resistant bacteria without taking antibiotics and have returned to the United States with these resistant organisms.33 Foodborne bacteria, such as Shigella sonnei and Vibrio cholerae, have been transmitted by contaminated meals served during international flights or aboard cruise ships.34-36

DIARRHEAGENIC ESCHERICHIA COLI Five different types of E. coli, with different virulence traits, may be causes of diarrhea. These have been termed enterotoxigenic E. coli (ETEC), enteroaggregative E. coli (EAEC), enteropathogenic E. coli (EPEC), enteroinvasive E. coli (EIEC), and enterohemorrhagic E. coli or verotoxigenic E. coli (EHEC/VTEC).37,38

Enterotoxigenic E. coli ETEC are the most common causative agents of travelers’ diarrhea in all countries where surveys have been conducted. However, they are an important cause of diarrhea among children in the

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developing world, as well, usually at the time of weaning.37 Contaminated food and water are the usual sources for ETEC. Susceptibility data for ETEC in comparison with other enteric pathogens causing travelers’ diarrhea are scarce, since most clinical laboratories do not perform toxin detection tests. Overall, the percentages of resistance of ETEC bearing the stable (ST) or labile (LT) toxins or both are very similar, with figures above 40% for ampicillin, tetracycline, and trimethoprim–sulfamethoxazole. Chloramphenicol shows activity against ETEC with percentages of resistance ranging from 13 to 25% (Table 5-1). There are no significant statistical differences among the different geographical areas analyzed and among those causing travelers’ diarrhea in travelers abroad. Similar levels of resistance were observed among these recent reports and previously published studies in the 1980s.39-43 Nalidixic acid or ciprofloxacin show the best activity against these microorganisms. However, a trend to a rise in quinalone resistance has recently been described, possibly following the increase in the use of quinolones for other diseases resistant to quinolones. ETEC have been isolated from people who traveled to India.42 Nalidixic acid was introduced a few years ago as the firstline therapy for shigellosis in some areas of India and therefore ETEC strains resistant to nalidixic acid are now emerging. Diarrhea due to ETEC is usually short-lived, so treatment rarely is necessary. Still, studies in patients with travelers’ diarrhea show that about one-third of these patients needed antimicrobial therapy to control persistence or severity of symptoms.42 Antibiotics have been shown to decrease both the duration and intensity of ETEC illness.37 Bismuth subsalicylate or loperamide are effective in reducing diarrhea by 50 to 80%.1 Antibacterial agents are more effective, but the action is slower. Table 5-1. Frequency of Antimicrobial Resistance of Diarrheagenic Escherichia coli from Different Developing Countries and in Those Causing Travelers’ Diarrhea Resistance (%) Country

AMP

CHL

TET

SXT

NAL

CIP

Ref.

—

—

39

0

40

ETEC Mexico

—

—

81

31

Tanzania

84.1

25

68.2

79.5

2.3

Thailand

54

13

43

51

3

2

41

Vietnam

67

17

65

63

<1

<1

41

TD*

40.7

22.3

55.6

47

7.3

0.6

42

EAEC Nigeria

80.9

46.5

95.4

74.0

0

0

47

Tanzania

83.1

57

87.7

90.8

1.5

0

40

TD*

52

28

64

48

6

2

45

90.4

33.3

81

90.4

0

0

40

27

23

42

—

0

53

EPEC Tanzania Uruguay

100

*TD = ETEC and EAEC causing travelers’ diarrhea. AMP = ampicillin; CHL = chloramphenicol; CIP = ciprofloxacin; EAEC = enteroaggregative E. coli; EPEC = enteropathogenic E. coli; ETEC = enterotoxigenic E. coli; NAL = nalidixic acid; SXT = trimethoprim–sulfamethoxazole; TET = tetracycline.

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T R AV E L E R S ’ D I A R R H E A

The combination of an antimicrobial agent with loperamide is the best treatment option.44

Enteroaggregative E. coli EAEC has been found to rank second among the diarrheagenic E. coli causing travelers’ diarrhea.37,38 In a recent study, resistance of EAEC to ampicillin was found to be 52%, to tetracycline 64%, to trimethoprim–sulfamethoxazole 48%, and to chloramphenicol 28%, whereas only 6% and 2% of the tested EAEC were resistant to nalidixic acid and ciprofloxacin, respectively.45 The quinoloneresistant EAEC strains were isolated from patients with travelers’ diarrhea who have journeyed to India or to Mexico.45 Multidrug resistant EAEC have also been reported in Kenya, Nigeria, Tanzania, Mexico, Chile, Peru, and Thailand (see Table 5-1).40,46-48 Treatment of travelers with diarrhea caused by EAEC with ciprofloxacin led to significant reduction in the duration of post-treatment diarrhea, but a nonsignificant reduction in the mean number of unformed stools passed during 72 hours as compared to the placebo group.49 To resolve the problem of the increase in resistance and to keep antimicrobial agents such as third generation cephalosporins or fluoroquinolones for more severe infectious diseases, nonabsorbable antibiotics should be used. For example, rifaximin is a nonabsorbable antibiotic achieving concentrations of 4,000 to 8,000 µg/g in feces.50 The MIC50 and MIC90 of rifaximin for ETEC and EAEC were 8 and 16 mg/L, respectively.51 The concentrations of rifaximin achieved in the intestinal tract are more than tenfold higher than the MICs of rifaximin, suggesting that this antibiotic is also active in vivo. In fact, recent studies have shown encouraging clinical and microbiological outcomes of travelers’ diarrhea treated with rifaximin.52

Enteropathogenic E. coli EPEC cause diarrhea in infants in developing countries as well as in travelers.38,40,53 The percentages of antimicrobial resistance are similar to those described for the other diarrheagenic E. coli, with high level of resistance (above 23%) to ampicillin, tetracycline, and trimethoprim–sulfamethoxazole, moderate resistance to chloramphenicol, and almost no strains resistant to quinolones (see Table 5-1). Although antibiotics are often used to treat enteritis caused by EPEC, there is no definitive evidence that treatment shortens the clinical course.

Enteroinvasive E. coli EIEC are biochemically and genetically related to Shigella. Most clinical microbiology laboratories do not perform invasive tests on E. coli. However, using a polymerase chain reaction (PCR) technique to identify EIEC, a minor role in the etiology of travelers’ diarrhea has been shown.37,38 Therefore, susceptibility data for EIEC are scarcer than those for other enteropathogens; however, antibiotics are helpful in cases where diarrhea is severe.54

Verotoxin-producing/Enterohemorrhagic E. coli VTEC/EHEC, in particular, E. coli serotype O157:H7, are an important cause of diarrhea, which can sometimes be complicated by hemorrhagic colitis and hemolytic uremic syndrome (HUS).37 No systematic search for VTEC has been conducted in developing countries. Moreover, they are not

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A N T I M I C R O B I A L R E S I S TA N C E

highly prevalent as a cause of travelers’ diarrhea.38 Therefore, little susceptibility data are available. However, two strains of verotoxin-producing E. coli O-rough:K1:H7 causing travelers’ diarrhea were susceptible to ampicillin, chloramphenicol, and quinolones, whereas one was resistant to trimethoprim–sulfamethoxazole and both were resistant to tetracycline.55 In patients with infection caused by enterohemorrhagic E. coli O157:H7, recent data suggest that antibiotic treatment increases the risk of the hemolytic uremic syndrome.56

SHIGELLA SPP Shigella are a well-known cause of bacillary dysentery affecting 5 to 15% of travelers. Few of the infected travelers had dysentery, but most had watery diarrhea. There are four species of Shigella: Shigella dysenteriae, Shigella flexneri, Shigella boydii, and Shigella sonnei. Shigella spp are transmitted from person to person, although food and water can also be contaminated. Infection is possible due to the low inoculum required (as few as 10 microorganisms). The percentages of resistance to several antimicrobial agents in the three main species of Shigella isolated from different geographical areas (mainly developing countries) as well as a cause of travelers’ diarrhea are shown in Tables 5-2, 5-3, and 5-4. Overall, S. flexneri and S. dysenteriae are more resistant than S. sonnei, at least when ampicillin and chloramphenicol are tested. The prevalence of resistance to ampicillin for S. sonnei ranges from a low of 0% in Calcutta (India) to a high of 62% in Vietnam.41,58 Similarly, the rate of chloramphenicol resistance is very wide, being from 0% in Western Kenya or Tanzania to 44.3% in Korea. 59,61,63 In most of the geographic areas analyzed, the resistance to trimethoprim–sulfamethoxazole in three species of Shigella ranged from 55 to 100%, and was higher than that previously reported, showing a trend to an increase in resistance to these antimicrobial agents in Shigella spp clinical isolates.43 However, most of the scientific literature on antimicrobial resistance in Shigella spp do not

Table 5-2. Frequency of Antimicrobial Resistance of Shigella flexneri from Different Developing Countries and in Strains Causing Travelers’ Diarrhea Resistance (%) Country

AMP

CHL

TET

SXT

NAL

CIP

Ref.

Brazil

100

—

—

55

0

—

57

India

87

58

100

100

21

0

58

Kenya

94

90

99

88

2

0

59

Rwanda

83

80

—

75

0.5

0

60

Tanzania

92

92

99

92

0

0

61

Thailand

82

61

96

86

0

0

41

Vietnam

84

74

87

83

<1

0

41

TD*

40.7

22.3

55.6

47

0.6

62

7.3

*TD = S. flexneri causing travelers’ diarrhea. AMP = ampicillin; CHL = chloramphenicol; CIP = ciprofloxacin; NAL = nalidixic acid; SXT = trimethoprim–sulfamethoxazole; TET = tetracycline.

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T R AV E L E R S ’ D I A R R H E A

Table 5-3. Frequency of Antimicrobial Resistance of Shigella sonnei from Different Developing Countries and in Strains Causing Travelers’ Diarrhea Resistance (%) Country

AMP

CHL

TET

SXT

NAL

CIP

Ref.

India

0

25

100

100

25

0

58

Kenya

0

0

100

100

0

0

59

Korea

11.4

44.3

95

45.5

100

63

Rwanda

13

7

—

38

0

—

60

Tanzania

25

0

100

100

0

0

61

Thailand

4

3

92

97

0

0

41

Vietnam

62

36

60

67

<1

0

41

TD*

32

18

73

54

0

0

62

96.6

*TD = S. sonnei causing travelers’ diarrhea. AMP = ampicillin; CHL = chloramphenicol; CIP = ciprofloxacin; NAL = nalidixic acid; SXT = trimethoprim–sulfamethoxazole; TET = tetracycline.

analyze the epidemiological relationship among the isolates, and a predominant multiresistant clone is probably responsible for this high frequency of resistance.61 A large percentage of Shigella is multiresistant, with two predominant resistance phenotypes: those resistant to ampicillin, tetracycline, and trimethoprim–sulfamethoxazole; and those resistant to ampicillin, tetracycline, chloramphenicol, and trimethoprim–sulfamethoxazole. Although no resistance to fluoroquinolones, such as ciprofloxacin, has been detected, the percentage of resistance to nalidixic acid ranges from 0% in several geographical areas to 100% in strains of S. sonnei isolated in Korea.63 However, the latter figures may be attributed to the spread of a resistant clone. Moreover, a trend to quinolone resistance has been observed in S. dysenteriae strains isolated in Burundi.64 Treatment with specific antimicrobial agents is generally recommended in cases of shigellosis to reduce the period of illness and the duration of microorganisms shedding. Rifaximin may also be an alternative treatment since the MIC90 of this antimicrobial agent for S. flexneri and S. sonnei is 8 and 16 mg/L, respectively.51 Table 5-4. Frequency of Antimicrobial Resistance of Shigella dysenteriae from Different Developing Countries Resistance (%) Country

AMP

CHL

TET

SXT

NAL

CIP

Ref.

India

100

80

100

100

60

0

58

Kenya

100

100

92

100

4

0

59

Rwanda

100

100

—

68

20

0

60

Tanzania

100

100

100

100

0

0

61

Thailand

0

0

33

0

0

0

41

Vietnam

50

17

50

50

0

0

41

AMP = ampicillin; CHL = chloramphenicol; CIP = ciprofloxacin; NAL = nalidixic acid; SXT = trimethoprim–sulfamethoxazole; TET = tetracycline.

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A N T I M I C R O B I A L R E S I S TA N C E

CAMPYLOBACTER SPP Campylobacter species associated with gastrointestinal infectious diseases include Campylobacter jejuni, Campylobacter coli, Campylobacter lari, and Campylobacter upsaliensis. The most common species implicated are C. jejuni and C. coli. C. jejuni is a common cause of diarrhea throughout the world. Recent limited data have shown that C. jejuni is responsible for a small percentage of the reported cases of travelers’ diarrhea, some with bloody diarrhea.65 Campylobacter spp are found in foods primarily of animal origins, particularly poultry. The resistance frequency to ampicillin and tetracycline in C. jejuni causing travelers’ diarrhea is approximately 33%. Macrolides, either erythromycin or azithromycin, are the most active antibiotics against C. jejuni (Table 5-5). Among 15 of 16 Peruvian children presenting with C. jejunirelated dysentery, stools became normal within 5 days when treated with erythromycin, in contrast to only 6 of 12 children who received placebo.66 Studies in adults with enteritis caused by Campylobacter have indicated that treatment with either ciprofloxacin or azithromycin shortened the duration of symptoms.67 In general, resistance to quinolones in C. jejuni causing travelers’ diarrhea is around 12%, and in some areas such as Thailand, Mali, and Burkina-Faso (Ruiz, Personal communication, June 2002), resistance is above 50%.41 These high figures are similar to those found in some industrialized countries. At the end of the 1980s, several studies showed minimal resistance to fluoroquinolones among Campylobacter species.68 Recently, there has been a trend toward an increased frequency of quinolone resistance concomitant with the increased use of fluoroquinolones in humans and animals.69 Until a few years ago, if antimicrobial therapy was indicated for Campylobacter infections, erythromycin and fluoroquinolones were considered the drugs of choice. Since the symptoms of Campylobacter enteritis are clinically indistinguishable from those of enteritis caused by other bacteria, most physicians prescribed fluoroquinolones empirically, which covered all bacterial enteropathogens. However, due to the rapid increase in the isolation of fluoroquinolone-resistant Campylobacter strains, erythromycin should currently be considered as the drug of choice to treat Campylobacter infections. The severity of the illness may be lessened by the administration of antibiotics early during the course of the disease. Antimicrobial treatment may be appropriate for patients with high fever,

Table 5-5. Frequency of Antimicrobial Resistance of Campylobacter jejuni from Different Developing Countries and in Strains Causing Travelers’ Diarrhea Resistance (%) Country

AMP

A/C

TET

ERI

Thailand

—

—

—

Vietnam

—

—

—

TD*

33

0

37.5

AZIT

NAL

CIP

—

6

73

77

41

—

0

7

7

41

0

—

12.5

12.5

65

*TD = C. jejuni causing travelers’ diarrhea. A/C = amoxicillin plus clavulanic acid; AMP = ampicillin; AZIT = azithromycin; CIP = ciprofloxacin; ERI = erythromycin; NAL = nalidixic acid; TET = tetracycline.

Ref.

66

T R AV E L E R S ’ D I A R R H E A

bloody stools, and more than 8 stools within a 24-hour period. Immunocompromised hosts and patients with bacteremia should also be treated.70 Contrary to what was found with ETEC, EAEC, and Shigella spp, rifaximin did not show good activity against C. jejuni since the MIC50 and MIC90 were 256 and 512 mg/L, respectively.51

SALMONELLA SPP Salmonella gastroenteritis is a well-known disease that occurs throughout the world. In industrialized nations, this large group of organisms is the most common cause of outbreaks of foodassociated diarrhea. The proportion of travelers’ diarrhea caused by Salmonella in those patients traveling to developing countries varies but is not high.71 Salmonella is transmitted to humans by ingestion of the microorganism in contaminated food, although fecal–oral transmission from person to person has also been described. Between 1980 and 1984, the susceptibility data for Salmonella strains from different tropical countries were compiled to predict significant patterns or trends.43 The percentages of resistance to ampicillin, tetracycline, chloramphenicol, and trimethoprim–sulfamethoxazole were quite variable, with the lowest rates found in Sri Lanka, the percentages ranging from 3% (resistance to chloramphenicol) to 10% (resistance to trimethoprim).43 In recent studies (Table 5-6), the resistance to the above-mentioned antibiotics among Salmonella spp has also varied among the different developing countries, with Vietnam showing the lowest rate.41 Overall, the frequencies of resistance to ampicillin, trimethoprim–sulfamethoxazole, and tetracycline in Salmonella spp causing travelers’ diarrhea were 21, 21, and 32%, respectively, whereas resistance to chloramphenicol was only 11%. No resistance to fluoroquinolones or third generation cephalosporins was observed (see Table 5-6). The antimicrobial resistances of travel-related and non–travel-related isolates of Salmonella are very similar, with the exception of trimethoprim–sulfamethoxazole, which has a significantly higher resistance frequency in travel-related isolates.71 Antibiotic therapy is not recommended for most uncomplicated cases since infection is most often self-limited. The administration of antimicrobial agents may prolong shedding, and antimicrobial resistance to all agents that have been used for treatment has been seen. Antibiotics should

Table 5-6. Frequency of Antimicrobial Resistance of Salmonella spp from Different Developing Countries and in Strains Causing Travelers’ Diarrhea Resistance (%) Country

AMP

CHL

TET

SXT

NAL

CIP

Kenya

45

4

76

41

7

0

0

59

Thailand

28

26

59

37

21

<1

—

41

3

7

13

10

0

0

—

41

21

11

32

21

—

00

70

71

Vietnam TD*

CFX

Ref.

*TD = Salmonella spp causing travelers’ diarrhea. AMP = ampicillin; CFX = ceftriaxone; CHL = chloramphenicol; CIP = ciprofloxacin; NAL = nalidixic acid; SXT = trimethoprim– sulfamethoxazole; TET = tetracycline.

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67

be considered for infants of less than 2 months of age, the elderly, and patients with sickle cell disease, advanced HIV infection, high fever, evidence of focal infection outside the gastrointestinal tract, or bacteremia. When therapy is indicated, the choice of agents includes a third generation cephalosporin or one of the fluoroquinolones.

MISCELLANEOUS Other potential bacterial pathogens, including Aeromonas spp, Plesiomonas shigelloides, Yersinia enterocolitica, and Vibrio cholerae are known to cause travelers’ diarrhea at a low prevalence. Among the Aeromonas genospecies, those considered of clinical relevance are Aeromonas hydrophila, Aeromonas caviae, and Aeromonas veronii biotype sobria. A. veronii biotype sobria and Aeromonas caviae are most frequently related to travelers’ diarrhea (Vila, June 2002). Although only 18 Aeromonas spp were analyzed, a high level of resistance to ampicillin (100%) and a moderate level of resistance to chloramphenicol (31%), tetracycline (37.5%), and trimethoprim–sulfamethoxazole (12.5%) were observed, with no resistance to quinolones (Vila, June 2002). P. shigelloides have been suggested, but not firmly established, as a cause of gastrointestinal infection. These microorganisms have been found to be part of the normal gastrointestinal flora in up to 3% of individuals. Little is known about the antimicrobial resistance of P. shigelloides causing travelers’ diarrhea. The microorganism is variably susceptible in vitro to chloramphenicol, tetracycline, trimethoprim–sulfamethoxazole, aminoglycosides, fluoroquinolones, imipenem, and third generation cephalosporins, and is naturally resistant to several antimicrobial agents such as penicillins, and some cephalosporins such as cefoperazone, ceftazidime, and cefepime. 72 Y. enterocolitica are isolated as the cause of travelers’ diarrhea at a low prevalence.3 Therefore, there are not many reports on the antimicrobial susceptibility of this microorganism as a cause of travelers’ diarrhea. All the isolates were resistant to ampicillin, but susceptible to tetracycline, nalidixic acid, and ciprofloxacin. Resistance to chloramphenicol and trimethoprim–sulfamethoxazole was less frequent (8%) (Vila, June 2002). Although V. cholerae infections are important in some endemic areas, they have only been described in sporadic cases of travelers’ diarrhea. Historically, epidemics have been due to serogroup O1 strains. In the early 1990s, a new serotype strain, Bengal O139, began a new wave of cholera epidemics. The primary treatment of cholera is oral rehydration to replace the massive fluid loss that occurs. Antibiotics are also recommended to shorten the duration of illness and bacterial shedding. Currently, the treatment of choice is tetracycline, although trimethoprim–sulfamethoxazole or a fluoroquinolone may also be used. However, some isolates causing outbreaks as well as sporadic strains have been shown to be tetracycline or trimethoprim–sulfamethoxazole resistant, mainly when the outbreaks are caused by O139 strains.

GENETIC AND BIOCHEMICAL BASES OF ANTIMICROBIAL RESISTANCE IN ENTEROPATHOGENIC BACTERIA Bacteria have a number of genetic means by which they may acquire or share antibiotic resistance traits. A mutation in the cellular target for the antibiotic is one such mechanism, which is largely

68

T R AV E L E R S ’ D I A R R H E A

responsible for quinolone resistance. This resistance will generally rest with the organism, unless the bacterial species has the ability to pass on naked DNA, which is incorporated into a new host’s chromosome. Gene transfer by this process is called “transformation.” Among the species in which transformation is a common mechanism for gene transfer are Hemophilus influenzae and Streptococcus pneumoniae. Probably the most common mechanism for acquiring and transferring genes is through extrachromosomal pieces of DNA called “plasmids,” which replicate independently of the chromosome. Plasmids may contain many nonchromosomal genes, including the more recently acquired genes for antibiotic resistance. The resistance genes themselves may lie on even smaller pieces of DNA called “transposons” because they can independently move or transpose from one DNA vehicle (such as a plasmid) to another (such as a chromosome). Bacteriophages offer another means of spreading resistance genes. These bacterial viruses can pick up pieces of DNA from one organism (generally from the same species or genus) and transfer it to another. This process, called “transduction,” will often involve transposons, which then find a site to integrate into the new host genome. Most recently, a specialized kind of transposon called an “integron” has been discovered as the basis for multidrug resistance. In simple terms, this vehicle consists of an integrase and a single promoter upstream from a number of different genes that are members of cassettes integrated behind the single promoter. The acquisition of these different genes leads to a multidrug-resistance genetic element. Thus, bacteria causing travelers’ diarrhea have at their disposal any one or more of these many genetic mechanisms for acquiring drug resistance. Although no studies on the mechanisms of resistance to β-lactam antibiotics in ETEC strains have been published, we can assume that they are the same mechanisms of resistance as found in nonenteropathogenic E. coli. Most of the E. coli and Shigella spp strains synthesize low concentrations of the chromosomal AmpC cephalosporinase, which is not inhibited by clavulanic acid. 73 However, in less than 3% of the E. coli strains, this cephalosporinase is constitutively derepressed, generating a resistance pattern characterized by resistance to ampicillin, amoxicillin plus clavulanic acid, and first and second generation cephalosporins. In about 75% of the E. coli clinical isolates, the main mechanism of resistance to ampicillin is the production of a plasmid-mediated β-lactamase type TEM-1.74 Other β-lactamases such as OXA-1 have been found to have a prevalence of between 1 and 5% in E. coli strains resistant to ampicillin.74 The gene encoding the OXA-1 β-lactamase has been located in an integron.75 In Shigella spp, the main mechanism of resistance to β-lactam antibiotics is the synthesis of TEM-1-type and OXA-1-type β-lactamases (M. Navia, Personal communication, June 2002), with OXA-1 also being located in an integron, whereas TEM-1 would be plasmid-mediated.61 Overall, OXA-type β-lactamases are more prevalent in Shigella spp strains than those of TEM-1-type, and recently, an OXA-30 β-lactamase has been described in an S. flexneri strain.76 In Salmonella spp, and mainly in Salmonella typhimurium, OXA-1 and PSE-1 are the two β-lactamases that are more often detected (Table 5-7).77,78 Although the emergence of extended-spectrum variants of TEM and SHV enzymes extendedspectrum β-lactamases (ESBLs) is of great clinical concern, to date, this phenomenon either does not seem to be a problem in developing countries or it has not been studied in depth. Still, several

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extended-spectrum β-lactamases have been described in different countries. E. coli TLA-1 β-lactamase and VEB-1 β-lactamase, which have activity against ceftazidime, have been detected in Mexico and Vietnam/Thailand, respectively.79,80 Moreover, TEM-26 and SHV5 have also been described in E. coli strains isolated in South Africa.81 A SHV-11 β-lactamase found in an S. dysenteriae strain isolated in India has recently been described. This β-lactamase hydrolyzed oxacillin, cloxacillin, and oxyiminocephalosporins such as cefotaxime.82 A new family of ESBLs, displaying greater affinity for cefotaxime than ceftazidime (CTX-M) has been detected in E. coli, S. sonnei, and S. typhimurium in South America.83 Although β-lactamases constitute the major form of β-lactam resistance in E. coli and Shigella spp, other mechanisms of resistance such as decrease in outer membrane permeability, increase of active efflux systems, or decrease in the affinity for target penicillin binding proteins (PBPs) may also contribute to the increase of β-lactam resistance. Trimethoprim–sulfamethoxazole is one of the antibiotic therapies against which enteropathogens have developed increased frequency of resistance. Trimethoprim resistance may be due to the presence of one or more of the following four different mechanisms: auxotrophy in thymine/thymidine; impaired permeability; efflux pumps; alterations in chromosomal dihydrofolate reductase (DHFR); and/or presence of a plasmid-encoded trimethoprim-resistant gene, dfr. The latter mechanism is the most common mechanism of trimethoprim resistance.82 To date, at least twenty dfr genes have been reported.84 The corresponding enzymes differ, and thus can be distinguished by biochemical and biophysical properties. DHFR 1 is considered the most frequently found DHFR in Enterobacteriaceae. However, DHFR 5, DHFR 7, DHFR 12, and DHFR 15 have also been recently described in S. flexneri and S. sonnei (Navia, Personal communication, June 2002) and some of these genes are also integron-borne (see Table 5-7).61 The major mechanism of resistance to chloramphenicol is its inactivation by acetylation in a reaction catalyzed by chloramphenicol acetyltransferase.85 Three genetically distinct groups of chloramphenicol acetyltransferase have been found so far, some inducible and others constitutive. This mechanism has been described in both Shigella spp and Salmonella spp.61,77 The two most important mechanisms of tetracycline resistance involve an inducible active efflux system that prevents the intracellular accumulation of this antibiotic, and a protein that protects the ribosome from tetracycline inhibition. The latter is exemplified by tet(O), which was originally described in Campylobacter spp.86 Many genes encoding these efflux systems in gram-negative bacteria have been identified.86 Among them, tet(A), tet(B), tet(C), and tet(D) are frequently found in E. coli, Shigella spp, Salmonella spp, Aeromonas spp, P. shigelloides, and Vibrio spp.86 The majority of the Tet determinants are often associated with transferable genetic elements such as transposons. 87 Quinolone resistance has been steadily rising in the last few years.88 The main mechanisms of resistance to this family of antimicrobial agents are mutations in the gyrA and parC genes encoding the A subunits of the DNA gyrase and topoisomerase IV, which are the protein targets for quinolones; and reduced quinolone accumulation in the cells due to a decrease in drug permeability or to an increased efflux of the drug out of the cell.88 In ETEC and EAEC strains, a low level of resistance to ciprofloxacin and a high level of resistance to nalidixic acid have been associated with a mutation of the amino acid codon Ser-83 of the gyrA gene, which produces a change from Ser to Leu or Ala. Meanwhile, the high level of resistance to both ciprofloxacin and nalidixic acid is asso-

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Table 5-7. Main mechanisms of resistance to several antimicrobial agents and patterns of resistance in Escherichia coli, Shigella spp, and Salmonella spp Antimicrobial Agent

Mechanisms of Resistance

Resistant Patterns AMP


-Lactam Antibiotics

FOX

CXM

CTX

A) TEM-1, OXA-1, PSE-1

R

R

S

S

S

B) ESBLs (TLA-1, VEB-1, CTX-M)

R

R

S

R

R

NAL

CIP

A) Mutations in the gyrA gene

R

S

B) Mutations in the gyrA and parC genes

R

R

Trimethoprim

DHFR 1, 5, 7, 12, and 15

Chloramphenicol

CAT

Tetracycline

tet (A), tet (B), tet (C), tet (D)

Quinolones

TIC

AMP = ampicillin; TIC = ticarcillin; FOX = cefoxitin; CXM = cefuroxime; CTX = cefotaxime; NAL = nalidixic acid; CIP = ciprofloxacin.

ciated with a double mutation in the amino acid codons Ser-83 and Asp-87 of the gyrA gene plus a double mutation in the amino acid codons Ser-80 and Glu-84 of the parC gene.42 A similar mechanism can explain the quinolone resistance in Shigella spp and in Salmonella spp (see Table 5-7).78, 89 However, in C. jejuni, the situation is slightly different since a mutation in the gyrA gene (Thr86 to Ile or Lys) is enough to produce a high level of resistance to both ciprofloxacin and nalidixic acid.90 Recently, a multidrug efflux mechanism has been reported in C. jejuni.91 This active efflux system can explain the intrinsic resistance to several antimicrobial agents including quinolones. Therefore, in C. jejuni, which shows this basal intrinsic quinolone resistance, a mutation in the gyrA gene is enough to generate a high level of resistance to these antimicrobial agents, explaining the difference with Enterobacteriaceae. Multidrug efflux systems similar to that described above for C. jejuni have been shown in E. coli, Shigella spp, and Salmonella spp. Among the Enterobacteriaceae, the most in-depth studies have been performed on AcrAB, which consists of an inner membrane pump (AcrB) and an outer membrane protein (TolC) linked together by a membrane fusion protein (AcrA). This system affects a wide range of substrates such as quinolones, tetracycline, chloramphenicol, ampicillin, and rifampicin.92,93 Several transcriptional factors (eg, MarA, SoxS, and Rob) can induce expression of the AcrAB efflux pump.94

CONCLUSION Overall, drug resistance among bacteria associated with travelers’ diarrhea is increasing, particularly to inexpensive, first-line, broad-spectrum antibiotics. Notably, high levels of resistance to trimethoprim–sulfamethoxazole in many parts of the developing world now limit the use of these drugs for persons traveling to such areas. Furthermore, the introduction of newer drugs, such as fluoroquinolones, has been followed relatively quickly by the emergence and dissemination of resistant strains. Nonabsorbable antibiotics, such as rifaximin, may supplant “classical” antibiotic

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treatment, although more studies are needed to assure its reliability. However, in the meantime, azithromycin and new fluoroquinolones show promise as possible replacements for the older antimicrobial agents. Although drug prophylaxis against travelers’ diarrhea can be effective, it is not recommended except under special circumstances.95 Ultimately, the best solution is improvements in sanitary engineering and the development of safe water supplies.96 Antibiotics should be reserved for severe cases where studies have shown them to be effective. Avoidance of uncooked foods and nonsterile water is still sound advice for the international traveler. International harmonization of principles for prudent antimicrobial drug use should include monitoring and enforcement, as well as financial, educational, and technical assistance by industrialized countries to developing countries.97

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18. Lansang MA, Lucas-Aquino R, Tupasi TE, et al. Purchase of antibiotics without prescription in Manila, Philippines. Inappropriate choices and doses. J Clin Epidemiol 1990;43:61–7. 19. Guyon AB, Barman A, Ahmed JU, et al. A baseline survey on use of drugs at the primary health care level in Bangladesh. Bull World Health Organ 1994;72:265–71. 20. Bojalil R, Calva JJ. Antibiotic misuse in diarrhea. A household survey in a Mexican community. J Clin Epidemiol 1994;47:147–56. 21. Hui L, Li XS, Zeng XJ, et al. Patterns and determinants of use of antibiotics for acute respiratory tract infection in children in China. Pediatr Infect Dis J 1997;16:560–4. 22. Reyes H, Guiscafre H, Muñoz O, et al. Antibiotic noncompliance and waste in upper respiratory infections and acute diarrhea. J Clin Epidemiol 1997;50:1297–304. 23. Meers PD. Infection control in developing countries. J Hosp Infect 1988;11 Suppl A:406–10. 24. Rasniraul L, Suthienkul O, Echevarria PD, et al. Foods as a source of enteropathogens causing childhood diarrhea in Thailand. Am J Trop Med Hyg 1988;39:97–102. 25. Rahim Z, Aziz KM. Enterotoxigenic, hemolytic activity and antibiotic resistance of Aeromonas spp isolated from freshwater prawn marketed in Dhaka, Bangladesh. Microbiol Immunol 1994;38:773–8. 26. Barza M, Gorbach SL. The need to improve antimicrobial use in agriculture: ecological and human health consequences. Clin Infect Dis 2002;34 Suppl 3:S71–144. 27. Sokari TG, Ibiebele DD, Ottih RM. Antibiotic resistance among coliforms and Pseudomonas spp from bodies of water around Port Harcourt, Nigeria. J Appl Bacteriol 1988;64:355–9. 28. O’Brien T, Pla MP, Mayer KH, et al. Intercontinental spread of a new antibiotic resistance gene on an epidemic plasmid. Science 1985;230:87–8. 29. Lamikanra A, Fayinka ST, Olusanya OO. A study of low trimethoprim resistance in faecal isolates obtained from apparently healthy Nigerian students. FEMS Microbiol Lett 1989;50:275–8. 30. Lamikanra A, Okeke IN. A study of the effect of the urban/rural divide on the incidence of antibiotic resistance in Escherichia coli. Biomed Lett 1997;55:91–7. 31. Walson JL, Marshall B, Pokrel BM, et al. Fecal carriage of antibiotic resistance in Nepal reflects proximity to Katmandu. J Infect Dis 2001;184:1163–9. 32. Rosas I, Salinas E, Yela A, et al. Escherichia coli in settled-dust and air samples collected in residential environments in Mexico City. Appl Environ Microbiol 1997;63:4093–5. 33. Murray BE, Mathewson JJ, DuPont HL, et al. Emergence of resistant fecal Escherichia coli in travelers not taking prophylactic antimicrobial agents. Antimicrob Agents Chemother 1990;34:515–8. 34. Wenzel P. Airline travel and infection. N Engl J Med 1996;334:981–2. 35. Hedberg CW, Levine WC, White KE, et al. An international foodborne outbreak of shigellosis associated with a commercial airline. J Am Med Assoc 1992;268:3208–12. 36. Minoose A, Rickman L. Infectious diseases on cruise ships. Clin Infect Dis 1999;29:737–44. 37. Nataro JP, Kaper JB. Diarrheagenic Escherichia coli. Clin Microbiol Rev 1998;11:142–201. 38. Vargas M, Gascón J, Gallardo F, et al. Prevalence of diarrheagenic Escherichia coli strains detected by PCR in patients with travelers’ diarrhea. Clin Microbiol Infect 1998;4:682–8. 39. Jiang ZD, Mathewson JJ, Ericsson CD, et al. Characterization of enterotoxigenic Escherichia coli strains in patients with travelers’ diarrhea acquired in Guadalajara, Mexico, 1992–1997. J Infect Dis 2000;181:779–82. 40. Vila J, Vargas M, Casals C, et al. Antimicrobial resistance of diarrheagenic Escherichia coli isolated from children under the age of 5 years from Ifakara, Tanzania. Antimicrob Agents Chemother 1999;43:3022–4.

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41. Isenbarger DW, Hoge CW, Srijan A, et al. Comparative antibiotic resistance of diarrheal pathogens from Vietnam and Thailand, 1996–1999. Emerg Infect Dis 2002;8:175–80. 42. Vila J, Vargas M, Ruiz J, et al. Quinolone resistance in enterotoxigenic Escherichia coli causing diarrhea in travelers to India in comparison with other geographical areas. Antimicrob Agents Chemother 2000;44:1731–3. 43. Murray BE. Resistance of Shigella, Salmonella, and other selected enteric pathogens to antimicrobial agents. Rev Infect Dis 1986;8 Suppl 2:S172–81. 44. Ericsson CD, DuPont HL, Mathewson JJ, et al. Treatment of travelers’ diarrhea with sufamethoxazole and trimethoprim and loperamide. J Am Med Assoc 1990;263:257–61. 45. Vila J, Vargas M, Ruiz J, et al. Susceptibility patterns of enteroaggregative Escherichia coli associated with traveller’s diarrhoea: emergence of quinolone resistance. J Med Microbiol 2001;50:996–1000. 46. Sang WK, Oundo JO, Mwituria JK, et al. Multidrug-resistant enteroaggregative Escherichia coli associated with persistent diarrhea in Kenyan children. Emerg Infect Dis 1997;3:373–4. 47. Okeke IN, Lamikanra A, Czeczulin J, et al. Heterogeneous virulence of enteroaggregative Escherichia coli strains isolated from children in Southwest Nigeria. J Infect Dis 2000;181:252–60. 48. Yamamoto T, Echeverria P, Yokota T. Drug resistance and adherence to human intestines of enteroaggregative Escherichia coli. J Infect Dis 1992;165:744–9. 49. Glandt M, Adachi JA, Mathewson JJ, et al. Enteroaggregative Escherichia coli as a cause of traveller’s diarrhea: clinical response to ciprofloxacin. Clin Infect Dis 1999;29:335–8. 50. Jiang Z, Ke S, Palazzini E, et al. In vitro activity and fecal concentration of rifaximin after oral administration. Antimicrob Agents Chemother 2000;44:2205–6. 51. Sierra JM, Ruiz J, Navia MM, et al. In vitro activity of rifaximin against enteropathogens producing travelers’ diarrhea. Antimicrob Agents Chemother 2001;45:643–4. 52. DuPont HL, Jiang ZD, Ericsson CD, et al. Rifaximin versus ciprofloxacin for the treatment of traveller’s diarrhea: a randomized, double-blind clinical trial. Clin Infect Dis 2001;33:1807–15. 53. Torres ME, Pirez MC, Schelotto F, et al. Etiology of children’s diarrhea in Montevideo, Uruguay: associated pathogens and unusual isolates. J Clin Microbiol 2001;39:2134–9. 54. Gilligan PH. Escherichia coli. EAEC, EHEC, EIEC, ETEC. Clin Lab Med 1999;19:505–21. 55. Vila J, Vargas M, Ruiz J, et al. Isolation of verotoxin-producing Escherichia coli O-rough:K1:H7 from two patients with travelers’ diarrhea. J Clin Microbiol 1997;35:2279–82. 56. Wong CS, Jelacic S, Habeeb RL, et al. The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli 0157:H7 infections. N Engl J Med 2000;342:1930–6. 57. Lima AAM, Lima NL, Pinho MCN, et al. High frequency of strains multiply resistant to ampicillin, trimethoprim-sulfamethoxazole, streptomycin, chloramphenicol, and tetracycline isolated from patients with shigellosis in Northeastern Brazil during the period 1988 to 1993. Antimicrob Agents Chemother 1995;39:256–9. 58. Dutta S, Sinha T, Dutta P. Serotypes and antimicrobial susceptibility patterns of Shigella species isolated from children in Calcutta, India. Eur J Clin Microb Infect Dis 1998;17:298–9. 59. Shapiro RL, Kumar L, Phillips-Howard P, et al. Antimicrobial-resistant bacterial diarrhea in rural western Kenya. J Infect Dis 2001;183:1701–4. 60. Bogaerts J, Verhaegen J, Munyabikali JP, et al. Antimicrobial resistance and serotypes of Shigella isolates in Kigali, Rwanda (1983 to 1993): increasing frequency of multiple resistance. Diagn Microbiol Infect Dis 1997;28:165–71.

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61. Navia MM, Capitano L, Ruiz J, et al. Typing and characterization of mechanisms of resistance of Shigella spp isolated from feces of children under 5 years of age from Ifakara, Tanzania. J Clin Microbiol 1999;37:3113–7. 62. Vila J, Gascón J, Abdalla S, et al. Antimicrobial resistance of Shigella isolates causing travelers’ diarrhea. Antimicrob Agents Chemother 1994;38:2668–70. 63. Lee JC, Oh JY, Kim KS, et al. Antimicrobial resistance of Shigella sonnei in Korea during the last two decades. APMIS 2001;109:228–34. 64. Ries AA, Wells JG, Olivola MD, et al. Epidemic Shigella dysenteriae type 1 in Burundi: panresistance and implications for prevention. J Infect Dis 1994;169:1035–41. 65. Gallardo F, Gascón J, Ruiz J, et al. Campylobacter jejuni as a cause of traveller’s diarrhea: clinical features and antimicrobial susceptibility. J Travel Med 1998;5:23–6. 66. Salazar-Lindo E, Sack RB, Chea-Woo E, et al. Early treatment with erythromycin of Campylobacter jejuni-associated dysentery in children. J Pediatr 1986;109:355–60. 67. Kuschner Trofa AF, Thomas RJ. Use of azithromycin for the treatment of Campylobacter enteritis in travelers to Thailand, an area where ciprofloxacin resistance is prevalent. Clin Infect Dis 1995;21:536–41. 68. Goosens H, DeMol P, Coignan H, et al. Comparative in vitro activities of aztreonam, ciprofloxacin, norfloxacin, ofloxacin, HR 810 (a new cephalosporin), RU 28965 (a new macrolide) and other agents against enteropathogens. Antimicrob Agents Chemother 1985;27:388–92. 69. Endtz HP, Ruijs GJ, Van Klingeren B, et al. Quinolone resistance in Campylobacter isolates from man and poultry following the introduction of fluoroquinolones in veterinary medicine. J Antimicrob Chemother 1991;27:199–208. 70. Fields PI, Swerdlow DL. Campylobacter jejuni. Clin Lab Med 1999;19:505–21. 71. Vila J, Gascón J, Abdalla S, et al. Antimicrobial resistance of nontyphoidal Salmonella isolates in traveller’s diarrhea. J Travel Med 1995;2:45–7. 72. Stock I, Wiedemann B. Natural antimicrobial susceptibilities of Plesiomonas shigelloides strains. J Antimicrob Chemother 2001;48:803–11. 73. Normak S, Gundstrom T, Bergstrom S. Susceptibility to penicillins and cephalosporins in β-lactamase producing strains of Escherichia coli and relative amount of β-lactamase produced by these strains. Scand J Infect Dis 1980;25:23–9. 74. Liu PYF, Gur D, Hall LMC, Livermore DM. Survey of the prevalence of β-lactamases amongst 1,000 gram-negative bacilli isolated consecutively at the Royal London Hospital. J Antimicrob Chemother 1992;30:429–47. 75. Hall RM, Collins CM. Antibiotic resistance in gram-negative bacteria: the role of gene cassettes and integrons. Drug Resist Updates 1998;1:109–19. 76. Siu LK, Lo JYC, Yuen KY, et al. β-Lactamases in Shigella flexneri isolates from Hong Kong and Shanghai and a novel OXA-1-like β-lactamase, OXA-30. Antimicrob Agents Chemother 2000;44:2034–8. 77. Gallardo F, Ruiz J, Marco F, et al. Increase in the incidence of resistance to ampicillin, chloramphenicol and trimethoprim in clinical isolates of Salmonella serotype typhimurium with investigation of molecular epidemiology and mechanisms of resistance. J Med Microbiol 1999;48:367–74. 78. Ruiz J, Capitano L, Nuñez L, et al. Mechanisms of resistance to ampicillin, chloramphenicol and quinolones in multiresistant Salmonella typhimurium strains isolated from fish. J Antimicrob Chemother 1999;43:699–701. 79. Silva J, Aguilar C, Ayala G, et al. TLA-1: a new plasmid-mediated extended spectrum β-lactamase from Escherichia coli. Antimicrob Agents Chemother 2000;44:997–1003.

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80. Poirel L, Naas T, Guibert M, et al. Molecular and biochemical characterization of VEB-1, a novel class A extended spectrum β-lactamase encoded by an Escherichia coli integron gene. Antimicrob Agents Chemother 1999;43:573–81. 81. Pitout JDD, Thomson KS, Hanson ND, et al. β-Lactamases responsible for resistance to expandedspectrum cephalosporins in Klebsiella pneumoniae, Escherichia coli, and Proteus mirabilis isolates recovered in South Africa. Antimicrob Agents Chemother 1998;42:1350–4. 82. Ahamed J, Kundu M. Molecular characterization of the SHV-11 β-lactamase of Shigella dysenteriae. Antimicrob Agents Chemother 1999;43:2081–3. 83. Radice M, Power P, Di Conza J, Gutkind G. Early dissemination of CTX-M-derived enzymes in South America. Antimicrob Agents Chemother 2002;46:602–3. 84. Amyes SGB, Towner KJ. Trimethoprim resistance: epidemiology and molecular aspects. J Med Microbiol 1990;31:1–19. 85. Lovett PS. Translational attenuation as the regulator of inducible cat genes. J Bacteriol 1990;172:1–6. 86. Levy SB, McMurry LM, Barbosa TM, et al. Nomenclature for new tetracycline resistance determinants. Antimicrob Agents Chemother 1999;43:1523–4. 87. Chopra I, Roberts M. Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev 2001;65:232–60. 88. Vila J, Ruiz J, Navia MM. Molecular bases of quinolone resistance acquisition in gram-negative bacteria. Recent Results Devel Antimicrob Agents Chemother 1999;33:323–44. 89. Rahman M, Mauf G, Levy J, et al. Detection of 4-quinolone resistance mutations in the gyrA gene of Shigella dysenteriae type 1 by PCR. Antimicrob Agents Chemother 1994;38:2488–91. 90. Ruiz J, Goñi P, Marco F, et al. Increased resistance to quinolones in Campylobacter jejuni: a genetic analysis of gyrA gene mutations in quinolone-resistant clinical isolates. Microbiol Immunol 1998;42:223–6. 91. Lin J, Michel LO, Zhang Q. CmeABC functions as a multidrug efflux system in Campylobacter jejuni. Antimicrob Agents Chemother 2002;46:2124–31. 92. Ma D, Cook DN, Hearst JE, Nikaido H. Efflux pumps and drug resistance in gram-negative bacteria. Trends Microbiol 1994;2:489–93. 93. Nikaido H, Basina M, Nguyen VY, Rosenberg EY. Multidrug efflux pump AcrAB of Salmonella typhimurium excretes only those β-lactam antibiotics containing lipophilic side chains. J Bacteriol 1998;180: 4686–92. 94. Alekskun MN, Levy SB. The mar regulon: multiple resistance to antibiotics and other toxic chemicals. Trends Microbiol 1999;7:410–3. 95. DuPont HL, Ericsson CD, Johnson PC, et al. Prevention of travelers’ diarrhea by the tablet formulation of bismuth subsalicylate. J Am Med Assoc 1987;257:1347–50. 96. Juckett G. Prevention and treatment of travelers’ diarrhea. Am Fam Physician 1999;60:119–36. 97. Fidler DP. Legal issues associated with antimicrobial drug resistance. Emerg Infect Dis 1998;4:169–77.

Chapter 6

PAT H O G E N E S I S Made Sujita, MD, PhD, María G. Marcano, MD, and James P. Nataro, MD, PhD

The primary function of the small and large intestine mucosa is to absorb water and nutrients. The small intestine secretes water to maintain the fluidity of the intestinal content, acting as a mixer to combine food particles and enzymes, resulting in absorbable nutrients that are vital to our survival. In physiological conditions, however, absorption exceeds secretion. Enteric pathogens increase the net intestinal secretion of water and electrolytes, impair absorption of intraintestinal constituents, and alter intestinal motility, causing the passage of unformed stools. Knowledge of innate and acquired mucosal immunity, in addition to familiarity with the microorganism and host interaction, is important in understanding the pathogenesis and causes of infectious diarrhea. Further detail on host factors and susceptibility to enteric pathogens will be discussed in Chapter 9, “Host Factors and Susceptibility.” Microbial agents capable of producing infection of the gastrointestinal tract comprise a formidable list. These include pathogenic Escherichia coli, Salmonella spp, Shigella spp, Campylobacter spp, Vibrio parahemolyticus, Aeromonas spp, Rotavirus, and Norwalk virus, among others. Consideration of the pathogenesis of all known enteric pathogens is beyond the scope of this chapter. Our discussion will be limited to those that commonly cause travelers’ diarrhea. Both the species and strain of the organism are important in predicting the virulence of the microorganism. The majority of E. coli strains are normal aerobic colonic flora; they become pathogenic when they acquire genes or plasmids that encode various toxins or confer invasiveness. Six major pathotypes of E. coli are thought to be pathogenic for humans (a comprehensive review about diarrheagenic E. coli is published elsewhere).1 Transmissibility and the number of microorganisms consumed are important determinants for development of disease. Shigella spp are unusual, in that few microorganisms are required to cause disease. Experiments in volunteers have demonstrated that fewer than 200 viable cells of Shigella readily produce disease in healthy adults.2 This low infective dose of organism may allow the transmission of Shigella spp through flies, and explains how the illness can be transferred from person to person.3 The low infectious dose of some intestinal parasites in causing diarrhea is also well known. Only 10 to 100 cysts of Entamoeba histolytica and Giardia lamblia are required to cause diarrhea.4 Other organisms typically cause disease with relatively higher infectious doses. Over 107 of pathogenic Vibrio cholerae are required to be transmitted to cause disease in a person.

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PATHOGENESIS OF DIARRHEA Enteric pathogens cause diarrhea by various mechanisms, including adherence of the microorganism to the mucosal epithelial cell, invasion of the mucosa, and production of toxins. A microorganism may cause disease by using adherence and toxin production without invasion of mucosa. Others may employ invasion and toxin production to cause disease and overcome the host defenses. Pathogenic mechanism of these enteric pathogens is summarized in Table 6-1.

Adherence Microorganisms colonize the intestinal tract by adhering or attaching themselves to the intestinal mucosa, thereby evading peristalsis. Several adherence mechanisms have been described. First, bacterial surface protein on pili or fimbriae, expressed on pathogens such as enterotoxigenic E. coli (ETEC), confers binding of the organism to the cell wall of the enterocyte.5 These fimbriae bind to specific ligands on enterocytes in a lectin-like fashion.6 Second, a unique adherence is seen in enteropathogenic E. coli (EPEC) as it adheres to the enterocyte. EPEC causes the intestinal epithelial cell to lose their normal microvillus membrane surface. On electron microscopy, the apical surface membrane forms a protrusion with the appearance of a pedestal.1,7

Invasion of the Mucosa Enteric pathogens such as Shigella spp and some enteroinvasive strains of E. coli cause diarrhea by adhering to and invading the intestinal mucosa. Shigella is able to induce phagocytosis by the intestinal epithelial cells, by subverting the epithelial cell cytoskeleton.8 The Shigella organisms then lyse the phagosomes, multiply in the cytoplasm, and spread to contiguous epithelial cells. They induce polymerization of filamentous actin (F-actin) and thereby project themselves into adjacent host cells, causing destruction and inflammation of the mucosa.9 Shigella spp and some strains of E. coli are also able to produce cytotoxins, notably Shiga toxin. The absorption of Shiga toxin into the systemic circulation is responsible for the devastating hemolytic uremic syndrome.

Toxin Production Infectious diarrhea can be divided into two syndromes based on the pathogenesis of the microorganism interacting with the host intestinal mucosa. Noninflammatory diarrhea is generally caused by viruses or enterotoxin-producing bacteria. It affects primarily the small intestine rather than the large intestine. The pathogen adheres to the intestinal mucosa but does not invade or damage the enterocytes or epithelial cells. The fundamental pathogenetic mechanism involves a biochemical reaction inside the epithelial cells, which leads to excessive water excretion. In this type of diarrhea, fecal leukocytes may not present due to an absence of significant mucosal destruction.10 Inflammatory diarrhea is commonly caused by invasive or cytotoxin-producing bacteria and invasive protozoa; inflammatory diarrhea generally affects the large intestine. Here, the pathogen invades and disrupts colonic mucosal lining. The destruction of the mucosal lining leads to extrava-

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Table 6-1. Pathogenic Mechanism of Various Microorganisms Attachment, HEp-2 Cell Adherence

Pathogen ETEC

Invasiveness

Toxin Production

Primary Mechanism of Diarrhea

No

Yes (LT, ST)

Stimulation of cellular kinases

EPEC

Intimate attachment, localized adherence

No

No

Signal transduction

EHEC

Intimate attachment

Yes

Yes (Shiga toxin)

Selective killing of absorptive villus, inflammatory response

EAEC

Aggregative

Perhaps

Cytotoxin

Enhancement of mucous secretion, exfoliation of epithelial cells

Shigella spp

Yes

Yes (Shiga toxin)

Selective killing of absorptive villus, inflammatory response

Salmonella spp

Yes

Yes

Unclear, possible inflammatory response

Campylobacter spp

Yes

Cytotoxin

Enterocyte damage, inflammatory response

V. parahemolyticus

Yes

Cytotoxin

Unclear

Aeromonas spp

Yes

Yes

Unclear

Plesiomonas spp

Yes

Yes

Unclear

B. fragilis

Yes

Yes (BFT)

Stimulation of Cl– secretion

Rotavirus

No

Yes (NSP4)

Inhibition of Na+D-glucose symporter

Norwalk virus

No

No

Unclear

Cryptosporidium parvum

No

Yes

Reduction of nutrient transporters

Cyclospora

No

Unknown

Unclear

B. hominis

No

Unknown

Unclear

G. lamblia

No

No

Mechanical irritation, inflammatory response

E. histolytica

Yes

Yes

Degradation of matrix proteins, inflammatory response and mucosal ulceration

BFT = bacteroides fragilis toxin; EAEC = enteroaggregative E. coli; EHEC = enterohemorrhagic E. coli; EPEC = enteropathogenic E. coli; ETEC, enterotoxigenic E. coli; LT = heat-labile toxin; NSP4 = nonstructural protein 4; ST = heat-stable toxin.

sation of blood and serous fluid into the intestinal lumen. Microscopic examination of the stool reveals the presence of fecal leukocytes.10 Inflammatory diarrhea is the type of diarrhea that is more commonly associated with systemic manifestations of enteric disease. Patients with inflammatory diarrhea may have febrile illness and appear toxic.

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DIARRHEA DUE TO ENTEROTOXIGENIC E. COLI Perhaps the best known enteric pathogens causing travelers’ diarrhea are enterotoxigenic E. coli (ETEC) strains. After their ingestion into the host intestinal tract, ETEC adhere and colonize the surface of the intestinal mucosa through an array of colonization factor antigens (CFAs).11 Once on the intestinal mucosa, ETEC elaborate enterotoxins and diarrhea results. Two ETEC enterotoxins are known: heat-labile toxins (LT), inactivated by heating at 60°C for 30 minutes, and heat-stable toxins (ST). ETEC strains may express LT only, ST only, or both LT and ST. 12 LT has a structure and mechanism of action similar to cholera toxin.13 The toxins share many characteristic structures including similarity in protein sequence, primary receptor, and enzymatic activity.14 LT enterotoxins can be divided into two immunologically distinct serogroups, LT-I and LTII. LT-1 is expressed by ETEC strains pathogenic in human and animal. LT-II is secreted primarily by animal ETEC.1 LT-I is a protein of 86 kDa in size, composed of one 28 kDa subunit and 5 identical 11.5 kDa B subunits. The B subunits bind to their receptor, a GM1 ganglioside, on the host cell surface.15 GD1b ganglioside and some other glycoproteins may also act as LT receptors. 15 After binding to the host cell membrane, LT is endocytosed and translocated to the cytoplasm through trans-Golgi vesicular transport.16 Similar to cholera toxin, LT stimulates mucosal adenylate cyclase activity inside the cytoplasm of the epithelial cells, resulting in increased levels of the intracellular cyclic AMP, which then activates Protein A kinase.12,15 The activated Protein A kinase leads to the abnormal phosphorylation of chloride channels on the apical enterocyte membranes. This process leads to excessive Cl– secretion from the crypt epithelial cells and inhibition of NaCl absorption. The increase in luminal Cl– content draws water passively into the intestinal lumen.12 The ST of ETEC is a small monomeric toxin. It activates guanylate cyclase, and leads to increased intracellular cyclic GMP levels.12 The abnormal activation of guanylate cyclase allows stimulation of chloride secretion, resulting in net intestinal fluid secretion and diarrhea.

DIARRHEA DUE TO ENTEROPATHOGENIC E. COLI The mechanism of diarrhea due to enteropathogenic E. coli (EPEC) begins with a process called attaching and effacing (A/E). This A/E process comprises microvillus destruction and intimate adherence of EPEC to the intestinal epithelial cell, followed by an effacing process that is characterized by pedestal formation on the enterocyte membrane. The effacing process occurs due to polymerization of actin, a component of host cytoskeletal proteins. By using immunofluorescence actin staining, cytoskeletal changes, including accumulation of polymerized F-actin, can be seen directly beneath the adherent bacteria.17 EPEC is able to bind to the membrane of HEp-2 or HeLa cells in culture in a characteristic pattern called “localized adherence.” In this pattern, bacteria bind to localized areas of the cell surface, forming compact microcolonies or bacterial clusters.18 The localized adherence (LA) pattern is associated with the presence of a large EPEC adherence factor (EAF) plasmid, encoding bundleforming pili (BFP). BFP interconnect EPEC within microcolonies and function to maintain its stabilization.1

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After their adherence and attachment, EPEC activate a variety of signal transduction pathways. The bacterial genes responsible for this signal transduction activity are encoded on a 35 kb pathogenicity island called the locus of enterocyte effacement (LEE). 1 In vitro studies have also shown that EPEC strains are able to induce increases in intracellular calcium levels in cultured epithelial cells to which they are attached.19 Increases in intracellular calcium can inhibit Na+ and Cl– absorption and stimulate chloride secretion by enterocytes.20,21 The changes in calcium (Ca2+) metabolism mediate the intestinal secretory response due to EPEC infection.

DIARRHEA DUE TO ENTEROAGGREGATIVE E. COLI Enteroaggregative E. coli (EAEC) is an E. coli pathotype characterized by its distinctive aggregative or “stacked-brick pattern” (Figures 6-1, 6-2) of adherence to cultured human epithelial cells.22 After their ingestion, EAEC strains adhere to the intestinal mucosa through aggregative adherence fimbriae, followed by the formation of a mucus–bacteria biofilm on the intestinal mucosa. EAEC strains are able to enhance mucus secretion from the intestinal mucosa; secreted mucus apparently traps the EAEC bacteria in a mucus–bacteria biofilm.1,23 Once EAEC colonizes mucosa, it elaborates one or more enterotoxins, which lead to exfoliation of enterocytes and induction of a net secretory state.24 These toxins include the Pet cytotoxin, the ST-like toxin EAST1 and the Shigella enterotoxin 1 (ShET1).1,25,26 Pet is a member of the autotransporter family of secreted proteins. The toxin enters epithelial cells, where it acts to cleave the cytoskeletal protein spectrin.25 Cleavage of spectrin induces cell rounding and may induce intestinal secretion.

Figure 6-1. Aggregative pattern of adherence of EAEC in the HEp-2 assay. Note bacteria on the HEp-2 cells as well as on the glass surface.

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Figure 6-2. A “stacked-brick pattern” of EAEC adherence in the HEp-2 assay.

There is clinical evidence that EAEC infection may comprise a mild inflammatory enteritis; the EAEC flagellin has been suggested as the mediator of this effect.27

SHIGELLA Shigella infection is associated with a spectrum of watery to bloody diarrhea. There are four species of Shigella: Group A: Shigella dysenteriae (or Shiga bacillus, 13 serotypes) Group B: Shigella flexneri (6 serotypes, 15 subtypes) Group C: Shigella boydii (18 serotypes) Group D: Shigella sonnei (1 serotype) In developing countries, Shigella flexneri and Shigella dysenteriae type 1 are the predominant species causing diarrhea, whereas in developed countries, Shigella sonnei is the predominant isolate. Shigella boydii is most commonly encountered in the Indian subcontinent.28 Shigella dysenteriae and Shigella flexneri most commonly cause dysentery, while Shigella sonnei and Shigella boydii are more associated with watery diarrhea.29 Shigella is pathogenic only to humans and primates. Only a small inoculum is required to cause disease: as few as 10 to 100 organisms of Shigella dysenteriae type 1 are sufficient to cause clinical dysentery in healthy adults. Shigella is transmitted through contaminated food and water, person-to-person spread, and potentially, a fly vector. Shigella dysenteriae species produce a potent cytotoxin known as Shiga toxin. The physiopathologic effects of Shigella can be divided into three processes: 1) invasion of epithelial cells, 2) invasion of the underlying tissue, and 3) toxin production. These are described in the following sections.

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Invasion of Epithelial Cells The entry of Shigella occurs primarily via specialized structures known as M cells, which are devoid of brush border and associated with the mucosal lymphatic follicle.30 A number of plasmid- and chromosomal-encoded proteins facilitate the entry of all pathogenic Shigella into host epithelial cells. These proteins are the invasion plasmid antigens (ipa), surface presentation of invasion plasmid antigens (spa), membrane excretion of Ipa (mxi), and virulence (vir) proteins. The bacteria are thought to enter via the basolateral pole of epithelial cells. Through a process of transcytosis, they are deposited into the subepithelial space. Bacterial entry involves a complex of IpaB and IpaC proteins, secreted by a type III secretion system. This protein complex induces actin polymerization and introduces a series of plasmid-encoded proteins into the eukaryotic cell cytoplasm. Additionally, IpaA and IpgD are involved in the maturation of the entry focus, whereas the possible function of the other invasion plasmid antigens is unknown. After entry, Shigella escapes the phagocytic vacuole and moves through the cytoplasm via nucleation of actin filaments. These specialized actin filaments, induced by the IcsA protein, promote intracellular motility, thus facilitating cell-to-cell spreading.

Invasion of the Underlying Tissue Intercellular dissemination by Shigella is facilitated by the IpaB protein, which lyses the plasma membrane. In the lymphoid follicle, Shigella is phagocytosed by macrophages. The infected macrophages undergo apoptosis, resulting in the release of the bacteria, which then infect adjacent enterocytes at the basolateral surface. The apoptotic process is also mediated by the IpaB protein and occurs following activation of the cysteine protease caspase-1. The infected host cells produce an inflammatory response, which is mediated most importantly through interleukin-8 (IL-8) and interleukin-10 (IL-10) production. IL-8 and IL-10 are responsible for the chemotaxis of polymorphonuclear leukocytes, which cause disruption of the epithelial barrier’s integrity.31,32 Degeneration of the epithelium and inflammation of the lamina propia are pathognomonic of Shigella infection. These changes induce disruption of epithelial absorption, producing the characteristic diarrhea and abdominal cramps. Shigella may cause mucosal destruction in the form of ulcerations of the colonic mucosa, which explains the presence of blood in the stools.

Toxin Production Shigella dysenteriae type 1 produces a toxin referred to as Shiga toxin, which is active in Vero cells. Shiga toxin belongs to the family of A-B toxins, so named because they consist of two parts—an A subunit (active) and a B subunit (binding). Shiga toxin consists of one A subunit and five B subunits. The B component of the exotoxin binds to a receptor on the surface of the host cell. The exotoxin enters the host cell by endocytosis and a host cell target protein through adenosine diphosphateribosylation (ADP-ribosylation). Subunit A of Shiga toxin inactivates the 60S subunit of the host cell ribosomes and prevents the attachment of charged tRNA, resulting in inhibition of host cell protein synthesis and cell death. Shiga toxin increases release of tumor necrosis factor alpha (TNF-
) and IL-1, and appears to be responsible for hemolytic uremic syndrome. Shiga toxin has an enterotoxic, cytotoxic, or neurotoxic effect.

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SALMONELLA Salmonella ingested in food may survive the gastric acid barrier, travel through the mucus layer overlying the epithelium of the small intestine, and evade intestinal defenses such as specific IgA to result in infection. Salmonella interact with both the enterocytes and microfold cells that overlie the ileal Peyer’s patches. 33 Salmonella are then internalized and transported into the submucosal lymphoid tissue. They have the ability to induce enterocytes to take them into the cytoplasm, a process known as bacteria-mediated endocytosis. This process is an important pathway for invasive Salmonella to reach deeper tissues in vivo. Once Salmonella invade the intestinal epithelial barrier, the organisms interact with macrophages and lymphocytes in Peyer’s patches, which results in marked enlargement and necrosis of the lymphoid tissue.34 Invasion of epithelial cells also stimulates the release of proinflammatory cytokines which induce an inflammatory reaction. The acute inflammatory response causes diarrhea and leads to ulceration and destruction of the mucosa. From the submucosal lymphoid tissue or Peyer’s patches, the organism can enter the systemic circulation, causing fever and other systemic diseases. Salmonella are intracellular pathogens, able to invade and replicate in epithelial cells of the gut and in cultured cell lines. Salmonella survive and replicate in macrophages, but do not survive in neutrophils. The ability of Salmonella to survive within macrophages plays an important role in typhoid fever pathogenesis and spread of the organisms beyond the bowel to the systemic circulation, though unusual in nontyphoid Salmonella infection of competent hosts. In the bloodstream, the organisms are contained in the mononuclear cell fraction, especially tissue macrophages in the bone marrow, liver, and spleen. 35,36 Symptoms of typhoid fever occur due to the secretion of cytokines by macrophages in response to bacterial infection.36,37 The enlargement of the liver and the spleen found in patients with typhoid fever is probably related to S. typhi survival or replication within reticuloendothelial cells, recruitment of mononuclear cells, and the development of a cell-mediated immune response. Several genes of the salmonellae required for virulence have been identified. Chromosomal invasion (inv) genes are encoded on a pathogenicity island. Genes encoding macrophage survival have been identified on a second such island. These genes are controlled in part by phoP/phoQ, a twocomponent regulator that senses low Mg2+ inside the macrophage and turns on genes to allow survival in the macrophage.38 The same genes also encode resistance to cationic antimicrobial proteins and acid pH, and invasion of epithelial cells.38 Salmonella induce membrane ruffling in macrophages similar to that observed in enterocytes. They enter macrophages by induction of generalized macropinocytosis rather than by receptormediated endocytosis.39 Salmonella are initially internalized in membrane-bound vacuoles called macropinosomes, formed by fusion of the ends of membrane ruffles. After endocytosis, fusion with other macropinosomes can result in the formation of large vacuoles called spacious phagosomes.39 Salmonella then induce macrophage cell death, and this ability allows them to survive after phagocytosis and may contribute to the inflammation seen in lymphoid tissue. Salmonella’s ability to induce phagocytosis by macrophages and enterocytes would protect them from phagocytosis by neutrophils. The organisms are rapidly killed by neutrophils, with less than 10% of an initial inoculum

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surviving after phagocytosis.38 Bone marrow examination of children with typhoid fever and neutropenia reveals the presence of histiocytes that have internalized neutrophils, red blood cells, and platelets.40 Liver biopsy specimens from patients with typhoid show Kupffer’s cell hyperplasia and erythrophagocytosis.41 Therefore, Salmonella stimulation of hemophagocytosis may be an important mechanism in producing anemia, neutropenia, and thrombocytopenia in typhoid fever. The major surface molecules of Salmonella are important in pathogenesis. The Vi antigen of S. typhi prevents antibody-mediated opsonization, increases resistance to peroxide, and confers resistance to complement activation by the alternative pathway and to complement-mediated lysis.42 Vi antigen may therefore function to inhibit phagocytosis of the salmonellae by neutrophils while not interfering with the induction of phagocytosis by more permissive macrophages and epithelial cells. Moreover, the lipid A component of lipopolysaccharide is a potent toxin for mammalian cells, and lipopolysaccharide was an essential virulence determinant in S. typhimurium infection in an animal study.43 The mechanisms by which the nontyphoidal salmonellae cause gastroenteritis remain unclear. Cell-mediated immunity is important in controlling intracellular pathogens such as Salmonella. The risk of invasive salmonellosis is increased in patients with acquired immunodeficiency syndrome (AIDS), organ transplantation, and lymphoproliferative disease.44-46 Individuals deficient in the IL-12 receptor are also extremely susceptible to Salmonella infections.47 Interleukin-12 induces Th1-type cell responses and interferon-gamma production, which is important in resistance to salmonellosis. Patients who have splenic dysfunction, such as those with sickle cell disease, also have an increased incidence of salmonellosis.48

CAMPYLOBACTER Campylobacter inoculum required for illness is in the low to moderate level. In a volunteer study, subjects became ill after ingesting as few as 500 to 800 organisms.49 The rates of illness appeared to increase when inocula were ingested in a suspension buffered to reduce gastric acidity.50 Similar to S. typhimurium, C. jejuni is susceptible to hydrochloric acid.51 Milk and fatty foods that favor passage through the gastric acid barrier may permit some infections to occur at relatively low doses. C. jejuni infection of the gastrointestinal tract affects jejunum, ileum, and colon, with similar pathologic features in each. The affected intestine reveals diffuse, edematous, and exudative enteritis.52 Microscopic examination of the affected mucosa generally reveals a nonspecific colitis with an inflammatory infiltrate of neutrophils, mononuclear cells, and eosinophils in the lamina propria. Degeneration, atrophy, loss of mucus, crypt abscesses in the epithelial glands, and ulceration of the mucosal epithelium can be observed.53 C. jejuni is an invasive organism, demonstrated in animal and in vitro studies.54–56 Cell invasion and perhaps cytotoxin production with subsequent tissue destruction are likely to be key elements in pathogenesis. Enterocyte damage may be responsible for a loss of net fluid absorption and eventual perturbation of epithelial integrity, resulting in leakage of serous fluid that leads to diarrhea. Many C. jejuni O antigens possess sialic acid-containing structures.57 The antigen mimicry of C. jejuni’s sialic acid with human ganglioside GM1 and their presence in strains isolated from patients who developed the Guillain-Barré syndrome (GBS) suggest their role in inducing an autoimmune response that leads to motor neuron injury.57,58 It is estimated that one case of GBS occurs for every

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1,000 cases of campylobacteriosis.58 Up to 40% of patients with the syndrome have evidence of recent Campylobacter infection.58 Reiter’s syndrome has been associated with C. jejuni and C. fetus infections, perhaps through stimulation of autoimmune response due to cross reactivity of exogenous Campylobacter antigens with endogenous antigens.59

VIBRIO PARAHEMOLYTICUS V. parahemolyticus is a halophilic (salt requiring) gram-negative bacillus that lives in seawater. This organism is the most common cause of diarrhea after ingestion of seafood in the Northwest Pacific.60 V. parahemolyticus has caused outbreaks of diarrhea along the Atlantic and Gulf Coast of the United States and on Caribbean cruise ships.61,62 The pathogen is an invasive organism and can cause bacteremia, particularly in patients with an immunocompromised state such as those with leukemia and cirrhosis. Most of the reported bacteremia cases involved a history of ingestion of seafood or exposure to seawater. When ingested, V. parahemolyticus causes symptoms of watery diarrhea, often with abdominal cramping, nausea, vomiting, fever, and chills within 24 hours of ingestion. Illness is usually self-limited and lasts for about 3 days. Severe disease is rare and occurs more commonly in persons with immunodeficiency. V. parahemolyticus can also cause an infection of the skin when an open wound is exposed to warm seawater, although this is less common compared to V. vulnificus. Most people become infected by eating raw or undercooked shellfish, particularly oysters.63 There is very little study published about this organism, hence its mechanism to cause diarrhea and invasive disease is unclear.

AEROMONAS Aeromonas are ubiquitous inhabitants of fresh water. The organisms have been recovered from chlorinated tap water including hospital water supplies. Aeromonas increasingly have been associated with travelers’ diarrhea.64,65 Occasionally, they cause soft tissue infections and sepsis in immunocompromised hosts. Currently, there are 14 named species, but only 3 species (A. hydrophila, A. caviae, and A. veronii biovar sobria) cause disease in humans.66 The clinical manifestations of Aeromonas-associated diarrhea are varied. Diarrhea is usually watery and self-limited, but some patients may develop fever, abdominal pain, and bloody stools. Fecal leukocytes may be present. Occasionally, diarrhea may be severe or protracted, and hospitalization may be necessary. Chronic colitis following acute Aeromonas-associated diarrhea has been reported in adults.67 Aeromonas, particularly A. hydrophila, can cause soft tissue infections. Trauma followed by exposure to fresh water usually precedes infection. Cellulitis develops within 8 to 48 hours, and systemic signs and symtoms are common.68,69 The pathogenesis of diarrhea due to Aeromonas infection remains unclear.

PLESIOMONAS P. shigelloides is a water- and soil-associated organism that replicates at temperatures above 8°C. It is found primarily in freshwater or estuary environments within temperate and tropical climates but

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can exist in seawater during summer. The usual vehicles of transmission of Plesiomonas to humans are water, food such as oysters, shrimp, or chicken, and a variety of animals that may be colonized with the organism.70 Plesiomonas shigelloides has been implicated as a cause of travelers’ diarrhea.71,72 The clinical presentation of P. shigelloides-associated diarrhea varies from a mild self-limited illness to mucoid, bloody diarrhea with fecal leukocytes. A predominantly secretory diarrhea has been reported.70 Studies have found clinical illness compatible with invasive disease featuring abdominal pain, fever, bloody diarrhea, and fecal leukocytes.73 Bacteremia is rare and usually occurs in immunocompromised hosts.74 The mechanism of Plesiomonas in causing diarrhea remains unclear.

ROTAVIRUS Rotaviruses are the single most important cause of severe acute diarrhea in young children. Rotaviruses primarily infect and replicate in mature villous epithelial cells that line the small intestine and induce diarrhea.75,76 The virus outer capsid protein (vp4) attaches to the glycolipid receptor on the host cell surface and enters the cytoplasm by direct plasma membrane penetration.77-80 Several mechanisms of diarrhea due to Rotavirus have been proposed. A rotavirus nonstructural protein, NSP4, has been found to act as an enterotoxin. NSP4 is produced in the early replication cycle and is able to induce diarrhea in mice.81 The NSP4 enterotoxin activates a Ca2+-dependent signal transduction pathway or inhibits the Na+-D-glucose symporter and consequently impairs Cl– and Na+ transport into and out of epithelial cells, which results in diarrhea.81,82 The other proposed mechanism is the replication of rotaviruses in enterocytes of the small intestine causing atrophy of the villous cell, detachment of absorptive cells from the basement membranes, and hyperplasia of the crypt cells which subsequently leads to diarrhea.83 Rotavirus may also activate the enteric nervous system which then stimulates water secretion by intestinal cells, leading to diarrhea.84 Rotavirus infection can also cause a loss of intestinal permeability to macromolecules such as lactose, which is associated with decreased levels of intestinal disaccharidases.85,86 This Rotavirus-induced lactase deficiency may last for 10 to 14 days.85

NORWALK VIRUS Norwalk virus belongs to the Caliciviridae family. Unlike rotaviruses, which primarily infect children, Norwalk viruses infect any age group. Transmission can occur by drinking contaminated water. Any type of food that has contact with contaminated water can serve as a vehicle for outbreaks of Norwalk-related gastroenteritis. Outbreaks associated with swimming in pools or lakes in which ill individuals have been swimming have been reported, indicating the highly infectious nature of this virus.87,88 Norwalk viruses appear to be relatively resistant to inactivation by chlorine.89 Vomitus has been implicated as a vehicle of transmission, and virus has been detected in vomitus by electron microscopy and PCR.89-92 Nausea, vomiting, diarrhea, and abdominal cramps are prominent symptoms of Norwalk virus infection. Patients with Norwalk virus gastroenteritis may recover within 2 to 3 days without serious or long-term complication. Acute infection with Norwalk viruses generally results in a reversible

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histopathologic lesion in the jejunum.93,94 The infection apparently spares the stomach and rectum.95 Under microscopy, the infected villi are blunted, but the mucosa is otherwise intact. Round cell and polymorphonuclear leukocytic infiltration can be seen in the lamina propria. Under electron microscopy, the epithelial cells are intact, microvilli are shortened, and widened intercellular spaces can be observed. These histopathologic changes are temporary and generally resolved within 2 weeks after the onset of illness.94 During this acute episode of illness, a variable amount of intestinal fluid is produced. Diarrhea induced by the Norwalk virus can be associated with transient malabsorption of D-xylose and fat and with decreased activity of brush-border enzymes, including alkaline phosphatase and trehalase.93,96 Absorption and brush-border enzyme levels generally return to normal values within 2 weeks after the infection. Infection with the Norwalk virus has not been associated with detectable enterotoxin production. Adenylate cyclase levels in jejunal biopsy specimens appear to be normal during infection.97 The precise pathogenesis of Norwalk virus-induced diarrhea and vomiting remains unclear.

CRYPTOSPORIDIUM PARVUM Cryptosporidium is an intracellular protozoan parasite belonging to the phylum Apicomplexa, subclass Coccidia. Cryptosporidium can infect the respiratory or the gastrointestinal tracts of fish, birds, reptiles, and mammals. The distribution of Cryptosporidium infection is worldwide. Animals are the most likely reservoir for this parasite. Cryptosporidium causes diarrheal diseases in immunocompetent and immunocompromised patients. Genotype 1 causes human infection and genotype 2 is associated with zoonotic transmission.98 The parasite is transmitted via the fecal–oral route. The infection may be acquired through contaminated water, farm animals, person-to-person contact, contaminated raw foods, unpasteurized milk, and fruit and vegetables.99 Since 1980, Cryptosporidium had been recognized as a cause of travelers’ diarrhea in individuals returning from Russia. 100 There are also reports of disease acquired by travelers to the Caribbean, Mexico, Mauritius, Egypt, Central Africa, New Guinea, and Pakistan.101–103 The parasite undergoes asexual reproduction in the small intestine, and oocysts, each containing four sporozoites, are produced. The infected host excretes the sporulated oocysts by feces and respiratory secretions. A suitable host is infected following ingestion or inhalation of these sporulated oocysts. The excystation process occurs in the small intestine and is enhanced by proteolytic enzymes and bile salts. The four sporozoites are then released from each oocyst and parasitize the epithelial cells of the gastrointestinal tract or the respiratory tract. The released sporozoites invade the microvillous border of enterocytes and replicate either asexually to become merozoites, or sexually with the subsequent development of gametocytes in the brush-border epithelial cell surface. After fertilization of macrogamonts (female) by the microgametes (male), the oocysts are produced and the sporulation process occurs inside the infected host, whereafter the sporulated oocysts are excreted or begin a new cycle inside the host and autoinfection can occur.104 Data from 29 healthy volunteers revealed that the median infective dose of Cryptosporidium was 132 oocysts.105 It was agreed that a dose of 10 to 1,000 oocysts may be able to produce infection in

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50% of volunteers exposed.106 The incubation period is 1 to 2 weeks. Cryptosporidium infection is characterized by watery diarrhea with abdominal pain, nausea, weight loss, and occasionally, lowgrade fever. The mechanism by which Cryptosporidium causes diarrhea is poorly understood. Illness in humans is localized to the jejunum, but in immunocompromised patients, organisms may be found in the epithelium of the gastrointestinal tract from the pharynx to the rectum, and in the respiratory tracts from the sinuses to the lungs. Three important changes have been described of the enterocyte cytoskeleton in Cryptosporidium infection: 1) the microvilli are absent in the area of parasite invasion, 2) columnar epithelial cells shortened after the parasite invasion, and 3) there is development of a unique structure at the host–parasite interface during invasion. Cryptosporidium parvum induces a rearrangement of the host enterocyte cytoskeleton, reducing the membrane expression of nutrient transporters and causes impaired absorption and osmotic diarrhea.107 The voluminous watery diarrhea in Cryptosporidium infection is caused by hypersecretion of fluids and electrolytes due to a cholera-like cryptosporidial enterotoxin. Studies using piglet ileal mucosa and human jejunum showed that the loss of vacuolated villus tip epithelium is accompanied by an approximately 50% reduction in glucose-coupled sodium cotransport in the ileum.104 On the other hand, experimental studies have shown that these effects are due to the decrease in permeability to solute and macromolecules with impaired transcellular nutrient transport.108 In Cryptosporidium-infected piglet epithelium, glutamine drives Na+ and Cl– absorption. The absorption is inhibited by prostaglandins. There is an increase in macrophage-produced tumor necrosis factor (TNF) in the lamina propia of infected piglets. TNF does not directly affect epithelial transport, but when fibroblasts are present, a secretory effect is noted. This effect is inhibited by indomethacin. Researchers propose a prostaglandin-mediated secretory effect by crypt cells in a chloride secretory pathway and through the inhibition of neutral sodium chloride absorption by the Na+:H+ exchanger. Prostaglandin secretion occurs in the junctional or transitional epithelium during active cryptosporidial infection in children and in HIV-infected adults.104 All the inflammatory changes produce reduced xylose and B-12 absorption. In children and in HIV-infected patients, increased permeability to lactulose and mannitol has been described. CD4+ intraepithelial lymphocytes at the mucosal level are important in the control of cryptosporidial infection. These lymphocytes produce IFN-, which has a direct inhibitory effect on parasite development in enterocytes. IFN- inhibits the parasite’s development by inhibiting parasite invasion and modification of the intracellular Fe2+ concentration. In addition, infection results in increased intestinal expression of proinflammatory cytokines such as IL-12, IFN-, and TNF-
.109, 110 Secretory IgA is an important defense mechanism against Cryptosporidium infection. Production of IL-8 and GRO-
contributes to the mucosal inflammatory cell infiltrate in the underlying intestinal mucosa in vivo.111

CYCLOSPORA Cyclosporiasis was first described in 1977 in a study conducted in Papua New Guinea.112 There were few publications about this parasite infection until the 1990s when cases of diarrheal illness associ-

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ated with Cyclospora infection were more frequently reported. In 1994, the parasite was named Cyclospora cayetanensis. The species name of cayetanensis was derived from the name of the Peruvian university, Universidad Peruana Cayetano Heredia, where the principal studies of this species had been conducted.113 C. cayetenensis causes diarrhea among travelers and an opportunistic infection in those with HIV infection.114-116 Cyclospora oocysts are spherical, measuring about 8 to 10 microns in diameter. The oocyst contains two sporocysts that each hold two sporozoites, and are variably acid-fast.117 Oocysts in the environment are quite resilient, surviving freezing and chlorination.118,119 Transmission occurs by contaminated food and water.119-121 Cyclospora oocysts in freshly excreted stool are noninfectious. Under favorable condition, the oocysts require several days to weeks outside the host to sporulate and become infective.122 The incubation period of Cyclospora infection is between 1 and 11 days (average 1 week). The onset of illness is often abrupt and may be preceded by a flu-like illness. Watery diarrhea is invariably present, and in some patients, upper gastrointestinal symptoms may predominate.123,124 The diarrhea may be associated with general symptoms such as fatigue, anorexia, nausea, myalgia, abdominal cramps, and flatus.125 Fever occurs in approximately 25% of cases. Illness lasts from 2 to 7 weeks, and in patients with AIDS, the diarrheal illness tends to be more severe and lasts longer.126 Cyclospora can be detected in jejunal aspirates or in biopsy specimens of patients with diarrheal illness.127 They are generally located in the supranuclear location of the cytoplasm, distinguishing them from Cryptosporidium, which are found on the surface of the enterocytes. 128 Electron microscopy reveals the presence of the Cyclospora organisms and its various stages in the cytoplasm of jejunal epithelial cells.128 Under endoscopy, the small bowel may appear normal, but the histologic architecture of the small bowel is altered, with villous atrophy, infiltration of the lamina propria by inflammatory cells, and vascular dilatation.129 The pathogenesis of Cyclospora in causing diarrhea remains unclear. It is not known whether the diarrhea is due to enterocyte dysfunction or whether toxins are secreted.

BLASTOCYSTIS HOMINIS Blastocystis hominis is an intestinal protozoan measuring 3 to 30 microns. Three major forms are found in culture: vacuolar, granular, and ameboid.130 The smaller forms of the parasite, including a multivacuolar and cyst form, are more commonly detected in stool specimens.131,132 The prevalence of Blastocystis hominis infection is higher in developing countries (30 to 50%) than in developed countries (1.5 to 10%).133,134 While B. hominis can cause travelers’ diarrhea, based on our experience, it does so rarely. In fact, even if the organism is detected in the stool of a traveler presenting with diarrhea, it would be wise to consider other organisms first as the cause of the diarrhea. If the B. hominis are in heavy numbers and no other agent is found, and the patient fails to respond to antibacterial therapy, then it should be considered as the causative agent. Infection with B. hominis is associated with acute or chronic diarrhea, bloating, flatulence, abdominal cramps, and fatigue.135,136 Endoscopy and biopsy results reveal that B. hominis do not invade the colonic mucosa in human patients.133 Edema and inflammation of the intestinal mucosa may be observed.137 Several experimental studies

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support the pathogenicity of B. hominis, including work in animal models and cell cultures.138,139 The pathogenesis of this parasite in causing diarrhea is, however, still unclear.

GIARDIA Giardia lamblia (also known as Giardia intestinalis or G. duodenalis) is a protozoan flagellate that infects the small intestine of humans. Its mechanism of pathogenicity is poorly understood. Giardia is one of the most common causes of waterborne (drinking and recreational) and foodborne diseases, and infection in returning travelers in the United States.140,141 The parasite has a worldwide distribution but is more prevalent in warm climates. Giardia lamblia has a fecal–oral mode of transmission via cysts; oral ingestion of as few as 10 to 25 cysts is sufficient to cause infection.4 Infection by Giardia lamblia is generally luminal and self-limiting. 142 Giardia lamblia cysts germinate in the gastrointestinal tract and produce the symptoms of giardiasis. The clinical picture of symptomatic giardiasis is manifested by acute or chronic diarrhea associated with weight loss and growth retardation in children.143 A direct correlation exists between the genotype of Giardia lamblia and the type of clinical picture it manifests. Assemblage A isolates were detected in patients with intermittent diarrhea, while assemblage B isolates were associated with persistent diarrhea.144 The Giardia life cycle involves two stages: 1) the trophozoite, or freely living stage, and 2) the cyst. The ingested cyst, each of which produces two trophozoites, passes through the stomach and excystation takes place in the duodenum. The excystation releases the trophozoites. In vitro excystation can be induced after a brief exposure of the cysts to acidic pH or other sources of hydrogen ions. The breakdown of the cyst wall is believed be mediated by stimulation of parasite-derived proteases. Flagellar activity begins within 5 to 10 minutes following the acid treatment and the trophozoite emerges through a break in the cyst wall. The trophozoite undergoes cytokinesis (cell division without nuclear replication) within 30 minutes after emerging from the cyst, resulting in two binucleated trophozoites. In the lumen of the proximal small intestine, the trophozoites can be free or attached to the mucosa by a ventral sucking disk. Some of the trophozoites then undergo encystation when the parasites transit toward the colon. This encystation process is enhanced by multiple factors such as an alkaline pH and excess bile salts. Encystation is the completion of the life cycle, and new infectious cysts pass into the environment.145 Giardia lamblia attach to the brush border of enterocytes by either suction or a clasping mechanism and cause diffuse border microvillous alterations and disaccharidase deficiencies, which are responsible for intestinal malabsorption, particularly of fat and carbohydrates. Attachment of the large numbers of trophozoites to the brush border can produce a mechanical irritation or obstruct absorption. In Giardia infection, villus blunting (atrophy), crypt cell hypertrophy, and increased inflammatory cell infiltration in the lamina propria have been observed. The deficiencies of lactase and other enzymes in the microvilli suggest damage at the enzymatic level. There is a correlation between the infectious load and the extent of enzyme inhibition.146 Experimental giardiasis in immunocompetent mice showed that the enterocyte brush-border injury was mediated by T lymphocytes. The mechanisms of T cells’ effects on microvillus structure

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are unknown.147 The epithelial injury can be caused by a reduced transepithelial electrical resistance and is due, at least in part, to trophozoite products.148 The reduced absorption of solutes may lead to osmotic diarrhea. Giardia-induced lactose intolerance can occur and may persist for a variable time following elimination of the parasite. The immune response plays an important role in the host’s defenses against Giardia. It starts when Giardia are taken up and processed by macrophages residing in Peyer’s patches.149 Giardia reside strictly in the lumen of the intestine and do not invade the mucosa. IgA antibodies are important for controlling and clearing Giardia infection. The protective mechanism of IgA against Giardia lamblia probably prevents the trophozoites’ adherence to the intestinal mucosa. Cellular immunity including T lymphocytes and macrophages are components of the host’s immune response to Giardia infection. The cellular immune response helps to clear parasites by coordinating the production of anti-Giardia secretory IgA. Experimental Giardia infections in mice with ablation of CD4+ T cells and B cells led to chronic giardiasis.146 Polarized intestinal epithelial cells produce nitric oxide (NO). NO inhibits both encystation and excystation of Giardia and thus could interfere with parasite transmission.146 Normal flora have protective effects against Giardia lamblia infection. Experimental studies suggest that the resident flora block infection with this pathogen.150 On the other hand, recent experimental studies have shown that the intestinal microbiota are important for the pathogenicity, but not for the multiplication, of Giardia lamblia in the intestinal lumen.151

ENTAMOEBA HISTOLYTICA The robust E. histolytica cyst is the primary reason for the extensive prevalence of its infection throughout the world. The cysts move from one person to another through fecal contamination of water and vegetables or direct fecal–oral contact. The excreted cysts can survive for weeks in a hospitable environment. Ingestion of the cyst results in excystation in the small intestine and ends with trophozoite infection of the colon. Amebas invade the colonic epithelium directly.152,153 On light and electron microscopic studies, lysis of mucosal cells are found before amebic invasion or after contact with amebas.154 Amebic trophozoite membranes are coated with a glycocalyx layer. A lipid-anchored glycolipid called lipophosphoglycan (LPG) and a peptide-containing LPG (LPPG) play an important role for the invasiveness of the ameba.155 A direct correlation was observed between the relative abundance of LPG and LPPG in different amebic strains and their virulence. The glycolipids extracted from avirulent E. histolytica contained extremely low levels of LPG molecules and an LPPG of smaller molecular weight.155 E. histolytica release a pore-forming protein, soluble toxic molecules, and a cysteine proteinase that degrades matrix proteins. E. histolytica have the capacity to destroy leukocytes.156,157 Lysis of host neutrophils by E. histolytica results in the release of toxic nonoxidative neutrophil products that contribute to the destruction of host tissues.158,159 Macroscopically, ulcerative lesions in the intestinal mucosa can be observed, which are characterized by a moderate inflammatory response. Advanced lesions have necrotic centers, with ameba concentrated at the outer zone of normal tissue.

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E. histolytica infection can manifest as a dysenteric syndrome with production of small volumes of bloody, mucoid stools without fecal leukocytes. A more severe form of amebiasis colitis may occur which is characterized by ulcerations of the colonic mucosa with typical flask-shaped abscesses. Occasionally, the formation of a fibrotic mass (ameboma) may occur in the intestinal wall. Clinically, chronic amebic colitis may be indistinguishable from inflammatory bowel diseases (IBD). Misdiagnosis of amebiasis as IBD and treatment of patients with systemic steroids increase the risk for toxic megacolon and perforation. After invading the intestinal mucosa, E. histolytica can migrate hematogenously to the liver, causing abscess formation. Patients may present clinically with abdominal pain, jaundice, and fever. Adjacent internal organs, such as the pulmonary parenchyma, peritoneum, and pericardium, can be affected. Occasionally, E. histolytica may disseminate to the brain and cause brain abscess. Immunocompromised patients are especially at risk for this invasive form of amebiasis.

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118. Rabold JG, Hoge CW, Shlim DR, et al. Cyclospora outbreak associated with chlorinated drinking water [letter]. Lancet 1994;344:1360–1. 119. Huang P, Weber JT, Sosin DM, et al. The first reported outbreak of diarrheal illness associated with Cyclospora in the United States. Ann Intern Med 1995;123:409–14. 120. Hoge CW, Shlim DR, Rajah R, et al. Epidemiology of diarrhoeal illness associated with coccidian-like organisms among travelers and foreign residents in Nepal. Lancet 1993;341:1175–9. 121. Ortega YR, Roxas CR, Gilman RH, et al. Isolation of Cryptosporidium parvum and Cyclospora cayetanensis from vegetables collected in markets of an endemic region in Peru. Am J Trop Med Hyg 1997;57:683–6. 122. Taylor AD, Davis LJ, Soave R. Cyclospora review. Curr Clin Top Infect Dis. 1997;17:256–68. 123. Berlin OGW, Novak SM, Porschen RK, et al. Recovery of Cyclospora organisms from patients with prolonged diarrhea. Clin Infect Dis 1994;18:606–9. 124. Soave R. Cyclospora: an overview. Clin Infect Dis 1996;23:429–35. 125. Hoge CW, Shlim D, Echeverria P. Cyanobacterium-like Cyclospora species [letter]. N Engl J Med 1993;329:1504–5. 126. Wurtz RM, Kocka FE, Peters CS, et al. Clinical characteristics of seven cases of diarrhea associated with novel acid-fast organism in the stool. Clin Infect Dis 1993;16:136–8. 127. Bendall RP, Luca S, Moody A, et al. Diarrhoea associated with Cyanobacterium-like bodies: a new coccidian enteritis of man. Lancet 1993;341:590–2. 128. Sun T, Ilardi CF, Asnis D, et al. Light and electron microscopic identification of Cyclospora species in the small intestine. Evidence of the presence of asexual life cycle in human host. Am J Clin Pathol 1996;105:216–20. 129. Ortega YR, Nagle R, Gilman RH, et al. Pathologic and clinical findings in patients with cyclosporiasis and a description of intracellular parasite life-cycle stages. J Infect Dis 1997;176:1584–9. 130. Zierdt CH. Blastocystis hominis–past and future. Clin Microbiol Rev 1991;4:61–79. 131. Boreham PFL, Stenzel DJ. Blastocystis in humans and animals: morphology, biology and epizootiology. Adv Parasitol 1993;32:1–70. 132. Stenzel DJ, Boreham PFL, McDougall R. Ultrastructure of Blastocystis hominis in human stool samples. Int J Parasitol 1991;21:807–12. 133. Doyle PW, Helgason MM, Mathias RG, et al. Epidemiology and pathogenicity of Blastocystis hominis. J Clin Microbiol 1990;28:116–21. 134. Kain KC, Noble MA, Freeman HJ, et al. Epidemiology and clinical features associated with Blastocystis hominis infection. Diagn Microbiol Infect Dis 1987;8:235–44. 135. Keystone JS. Blastocystis hominis and traveler’s diarrhea. Clin Infect Dis 1995;21:102–3. 136. O’Gorman MA, Orenstein SR, Proujansky R, et al. Prevalence and characteristics of Blastocystis hominis infection in children. Clin Pediatr 1993;32:91–6. 137. Russo AR, Stone SL, Taplin ME, et al. Presumptive evidence for Blastocystis hominis as a cause of colitis. Arch Intern Med 1988;148:1064. 138. Phillips PB, Zierdt CH. Blastocystis hominis: pathogenic potential in human patients and gnotobiotes. Exp Parasitol 1976;39:358–64. 139. Walderich B, Bernauer S, Renner M, et al. Cytopathic effects of Blastocystis hominis on Chinese hamster ovary (CHO) and adeno carcinoma HT29 cell cultures. Trop Med Int Health 1998;3:385–90. 140. Taylor DN, Connor BA, Shlim DR, et al. Chronic diarrhea in the returned traveler. Med Clin North Am 1999;83:1033–53.

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141. Adkins H, Merrell B, O’Rourke T, Echeverria P. Travelers’ diarrhea among U.S. Navy and Marine Corps personnel during a Western Pacific deployment. Mil Med 1990;155:111–6. 142. Eckmann L, Laurent F, Langford TD, et al. Nitric oxide production by human intestinal epithelial cells and competition for arginine as potential determinants of host defense against the lumen-dwelling pathogen Giardia lamblia. J Immunol 2000;164:1478–87. 143. Hjelt K, Paerregaard A, Krasilnikoff PA. Giardiasis causing chronic diarrhea in suburban Copenhagen: incidence, physical growth, clinical symptoms and small intestine abnormality. Acta Paediatr 1992;81:881–6. 144. Homan WL, Mank TG. Human giardiasis: genotype linked differences in clinical symptomatology. Int J Parasitol 2001;31:822–6. 145. Katz DE, Taylor DN. Parasitic infections of the gastrointestinal tract. Gastroenterol Clin North Am 2001;30:797–815. 146. Eckman L, Gillin FD. Microbes and microbial toxins: paradigms for microbial-mucosal interactions I. Pathophysiological aspects of enteric infections with the lumen-dwelling protozoan pathogen Giardia lamblia. Am J Physiol Gastrointest Liver Physiol 2001;280:G1–6. 147. Scott KG. Jejunal brush border microvillous alterations in Giardia muris-infected mice: role of T lymphocytes and interleukin-6. Infect Immun 2000;68:3412–8. 148. Teoh DA, Kamieniecki D, Pang G, Buret AG. Giardia lamblia rearranges F-actin and alpha-actinin in human colonic and duodenal monolayers and reduces transepithelial electrical resistance. J Parasitol 2000;86:800–6. 149. Hill DR. Giardia lamblia. In: Mandell GL, Bennet JE, Dolin R, editors. Principles and practice of infectious diseases. Vol 2. 5th ed. Philadelphia: Churchill Livingstone Inc.; 2000. p. 2888–92. 150. Singer SM, Nash TE. The role of normal flora in Giardia infection in mice. J Infect Dis 2000;181:1510–2. 151. Torres MF, Uetanabaro AP, Costa AF, et al. Influence of bacteria from the duodenal microbiota of patients with symptomatic giardiasis on the pathogenicity of Giardia duodenalis in gonotoxemic mice. J Med Microbiol 2000;49:209–15. 152. Brandt H, Perez Tamayo R. Pathology of human amebiasis. Hum Pathol 1970;1:351–85. 153. Pittman FE, El Hashimi WK, Pittman JC. Studies of human amebiasis. II. Light and electromicroscopic observations of colonic mucosa and exudate in acute amebic colitis. Gastroenterology 1973;65:588–603. 154. Takeuchi A, Phillips BP. Electron microscopic studies of experimental Entamoeba histolytica infection in the guinea pig. I. Penetration of the intestinal epithelium by trophozoites. Am J Trop Med Hyg 1975;24:34–48. 155. Moody S, Becker S, Nuchamowitz Y, Mirelman D. Identification of significant variation in the composition of lipophosphoglycan-like molecules of E. histolytica and E. dispar. J Eukaryot Microbiol 1998;45:9S–12S. 156. Guerrant RL, Brush J, Ravdin JI, et al. Interaction between Entamoeba histolytica and human polymorphonuclear neutrophils. J Infect Dis 1981;143:83–93. 157. Ravdin JI, Murphy CF, Salata RA, et al. The N-acetyl-D-galactosamine-inhibitable adherence lectin of Entamoeba histolytica. I. Partial purification and relation to amoebic virulence in vitro. J Infect Dis 1985;151:804–15. 158. Tsutsumi V, Mena-Lopez R, Anaya-Velazquez F, et al. Cellular basis of experimental amebic liver abscess formation. Am J Pathol 1984;117:81–91. 159. Salata RA, Ravdin JI. The interaction of human neutrophils and Entamoeba histolytica increases cytopathogenicity for liver cell monolayers. J Infect Dis 1986;154:19–26.

Chapter 7

R E L AT I V E I M P O R TA N C E O F PAT H O G E N S A N D N O N I N F E C T I O U S C AU S E S Javier A. Adachi, MD, Charles D. Ericsson, MD, and Herbert L. DuPont, MD

Historically, diarrhea has affected virtually all forms of international travelers, business persons, and military personnel since early world history, with descriptions of travelers’ diarrhea being found in ancient sources including the Bible. However, the hypothesis that travelers’ diarrhea could be related to enteric pathogens was not well studied until Kean’s seminal studies in the 1950s and 1960s.1-4 Some of these studies showed that antimicrobial agents could prevent travelers’ diarrhea.2-4 Before this observation, travelers’ diarrhea had been attributed to factors such as ingestion of different kinds of food, change in the water, excessive exposure to sunlight, inhaled particles, stress, and other nonspecific travel related issues.1,4 Building on the observation that antimicrobials were effective in prevention of travelers’ diarrhea, Kean and Gorbach and colleagues went on to identify enterotoxigenic Escherichia coli (ETEC) as a bacterial cause of travelers’ diarrhea in Mexico.5 Since the publication of this observation in 1975, a flurry of studies, which are listed in recent reviews, have demonstrated the effectiveness of numerous antimicrobial agents in both the prevention and treatment of travelers’ diarrhea.6,7 Furthermore, many other infectious agents have been identified as causes of the syndrome, including other bacteria (Salmonella, Shigella, Campylobacter, Aeromonas, Plesiomonas, and most recently, enteroaggregative Escherichia coli (EAEC)), parasites (Giardia, Cryptosporidium, Entamoeba histolytica, and Cyclospora), and viruses (rotavirus, enteroviruses, and caliciviruses, including Norwalk).5,8-10 Since the incidence of travelers’ diarrhea reflects in large part the extent of environmental contamination with feces, etiologic agents are predominately those pathogens causing illness in native children in a specific region. Current studies have shown that infectious microorganisms are the primary cause of travelers’ diarrhea, and among them, bacterial enteric pathogens are the most common etiologic agents isolated. The list of etiologic agents changes as laboratory techniques identify new enteropathogens (Table 7-1). Approximately 60 to 80% of cases from recent research studies are associated with an identified pathogen.5,8,9,11 By comparison, 20 years ago, specific pathogens were found in only 20% of cases.12 One complicating issue in establishing etiology of travelers’ diarrhea is the observation that many travelers with diarrhea will have multiple pathogens identified in their stool samples.9,13 This has made determination of etiology difficult. One way we have tried to establish the etiologic importance of an enteropathogen in travelers with diarrhea is to demonstrate the development of a secretory IgA response to the agent identified in the infected or colonized stool. 14 The yield of causal enteropathogens has improved over the years through the recognition of EAEC as an important cause of travelers’ diarrhea and through the use of sensitive polymerase chain reaction techniques to look for ETEC, which has doubled the recovery of this important pathogen.15,16

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Table 7-1. Geographic Distribution of Pathogens in Travelers’ Diarrhea Given in Percentages Latin America References: 5, 8, 10, 16, 17, 41–44

Pathogen

Mexico

Asia References: 9, 10,

Caribbean References: 9, 11, 35

Africa References: 9, 10, 28

22–24, 27, 54, 55

All

Jamaica

All

India

Thailand

All

Kenya

All

Total

12–37

15–40

25

6–37

5–40

35

5–40

5–60

ETEC

38

15–60

EAEC

33

0–40

26

0–30

19

NR

0–20

NR

0–15

0–40

0–5

3

10–40

0–40

5

0–30

0–40

Campylobacter

0.9

0–5

5

Salmonella

4.6

0–15

8

0–15

10

1–30

0–30

3

5–25

0–30

Shigella

5.5

0–30

0.3

0–15

10

0–15

0–15

9

0–10

0–30

Others

0.9

0–5

0.3

0–5

15

3–55

0–40

7

0–10

0–40

Viruses

0

0–20

0–20

7

1–10

0–10

9

0–30

0–20

11

Rotavirus

0

0–20

8

0–20

5

1–8

0–10

6

0–30

0–20

Protozoa

1.4

0–5

1.5

0–5

9

1–12

0–10

0

0–10

0–10

NR

0–30

6

0–20

0–20

10–55

47

10–55

10–60

Mixed

18

0–20

5–10

0–10

No pathogen

35

20–60

42–68

20–70

11–27

37–45 10–55

EAEC = enteroaggregative E. coli; ETEC = enterotoxigenic E. coli; NR = not reported.

PATHOGEN-NEGATIVE AND MILD TRAVELERS’ DIARRHEA In recent studies conducted by our group, causative pathogens are still not identified in approximately 20% of cases. The likelihood that additional important bacterial causes of travelers’ diarrhea will be discovered now appears to be low, because that proportion of travelers’ diarrhea not associated with a currently recognized enteropathogen (as assessed in a full-service research laboratory that can recognize EAEC and maximize ETEC isolation) appears not to respond to treatment with an antimicrobial agent (R Infante, CD Ericsson, Z-D Jiang, HL DuPont, unpublished data). The proportion of diarrhea not associated with an enteropathogen or responsive to antimicrobial therapy deserves additional study. Perhaps new nonbacterial pathogens will be discovered, and search for new viruses, protozoa, and bacteria, including strict anaerobes, should continue. Perhaps a proportion of illness will be attributed to noninfectious causes. Regardless of the outcome of further research, the bottom line will remain that travelers’ diarrhea is predominately an infectious disease acquired largely by consumption of contaminated foods and beverages and caused predominately by bacterial agents. This observation explains the efficacy of numerous antimicrobial agents in the treatment and prevention of the syndrome. Among noninfectious factors that might cause minimal changes in stool consistency or frequency are changes in diet, stress, and excessive alcohol consumption.17-20 Changes in diet and stress are part of almost all trips, especially during travel to developing countries. Alcohol abuse, especially among younger travelers who are tempted to drink alcohol excessively owing to lack of age restrictions abroad, may also be a factor in some travelers.17-19 Changes in gastrointestinal habits that are possible among women during their menstrual period, might be confused with a mild case of travelers’ diarrhea.21 All these episodes of loose stools are occasionally bothersome, but most patients and experts would count these episodes as mild travelers’ diarrhea or no diarrhea at all.

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Logically, noninfectious causes of diarrhea might account relatively more often for less severe illness. A subject in most research protocols has passed at least three loose stools in a 24 hour period. In such studies, bacterial enteropathogens account for the majority of illness, and invasive enteropathogens are more common among those with more severe presentations. In a prospective study of travelers’ diarrhea in Mexico, in which passage of any number of unformed stools was tracked, about 40% of recently arrived US adults experienced episodes of passage of only one or two loose movements per day, and on average these episodes lasted only 1 or 2 days.17 Only about half of such subjects were able to submit an unformed stool for analysis, but typical bacterial enteropathogens were isolated from this group at about the same frequency as from subjects with more classic illness. The upshot is that a vast majority of diarrhea among travelers is mediated by enteropathogens.

GEOGRAPHIC PRESENCE OF SPECIFIC ENTEROPATHOGENS Most of the information we have on geographic association of enteropathogens in travelers comes from studies of single populations during limited time periods, in one limited area of the world. An ambitious study spearheaded by Robert Steffen was carried out in three different regions of the world to look at differences in clinical illness and etiology of illness during one time period.11 In one part of this study, Jiang and colleagues showed that the specific pathogens causing diarrhea in Goa, India, Montego Bay, Jamaica, and Mombasa, Kenya were similar, but that there were differences in pathogen prevalence rates.9 In Table 7-1, the distribution of etiologic microorganisms identified in cases of travelers’ diarrhea found in diverse areas of the world is presented. We included in the table recent data on the cause of travelers’ diarrhea in India and Thailand, because of unique pathogen profiles. In India, high frequencies of bacterial pathogens including ETEC, EAEC, Shigella, and Salmonella were found. 9 In Thailand, an important pathogen causing travelers’ diarrhea is fluoroquinolone-resistant Campylobacter jejuni.22-24 Fluoroquinolone resistance in prevalent Campylobacter is a growing problem worldwide. 22-26 In Table 7-2, we have focused on the unique geography–pathogen associations that should be considered in developing a therapeutic strategy for international travelers with diarrhea. Throughout the tropical and semitropical areas, bacterial agents are most important. The presence of parasitic agents should be strongly considered in travelers who acquire diarrhea while traveling to Nepal or Russia or in those with persistent (>14 days duration) or recurrent symptoms. Table 7-2. Associations between Geography and Pathogens Geographic Area

Organisms of Special Concern

All tropical and semitropical areas

Bacterial enteropathogens, particularly ETEC and EAEC

Nepal, Peru, and Haiti

Parasitic agents: Cyclospora, Giardia, and Cryptosporidium

Russia, particularly St. Petersburg

Cryptosporidium and Giardia

Thailand

Fluoroquinolone-resistant Campylobacter jejuni

EAEC = enteroaggregative E. coli; ETEC = enterotoxigenic E. coli.

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SPECIFIC ENTEROPATHOGENS Enterotoxigenic Escherichia coli In the mid-1970s, ETEC was found to be the most important cause of diarrhea among US students visiting Mexico.5,8 Later, ETEC was shown to be an important cause of travelers’ diarrhea worldwide, accounting for 5 to 60% of cases in all developing tropical and semitropical regions.9,27,28 ETEC also causes the majority of gastroenteritis in indigenous pediatric populations of developing countries, where contaminated food is the main source of infection.29-34 Enterotoxigenic E. coli is more prevalent in most regions of Latin America and the Caribbean than in Asia and Africa (see Table 7-1). In some parts of Asia (eg, Thailand), ETEC rates are lower than Campylobacter rates.22-24 Steffen and colleagues did not find a seasonal pattern for ETEC diarrhea in travelers to Jamaica, while Mattila and colleagues described in subtropical Morocco a higher prevalence in summer and fall (causing diarrhea in ~ 50% of cases) than in winter (with rates of diarrhea of ~ 15%).35,36 Similarly, in Mexico, there appeared to be a seasonal association, with ETEC being the most common pathogen in travelers with diarrhea in the rainy summer and nearly disappearing in the dry winter.37 Enterotoxigenic E. coli strains isolated from high-risk areas from diverse regions of the world may show different toxin types (heat-labile (LT) versus heat-stable (ST) production), colonization-factor antigens, plasmid contents, ribotypes, serotypes, and in-vitro susceptibility.38,39 ETEC strain variations between different regions, and also over different time periods, are important considerations in the development of an ETEC vaccine.

Enteroaggregative Escherichia coli HEp-2 cell adherent E. coli, referred to as enteroaggregative E. coli, were first described as a cause of travelers’ diarrhea by Mathewson and colleagues.15 EAEC were recently identified as the second most common cause of travelers’ diarrhea in a study of diarrhea in Guadalajara, Mexico, Ocho Rios, Jamaica, and Goa, India. EAEC accounted for an average of 26% of the diarrhea compared with 30% for ETEC.40 EAEC appears to account for at least a substantial part of the group of “no pathogens identified” that responded to treatment with antimicrobial drugs in earlier studies.41-44 Although initially the pathogenic role of these strains were not completely accepted by the medical literature, the current opinion is that EAEC are a group of bacteria that share a common phenotypic characteristic (aggregative adherence pattern to HEp-2 cells), but with unique virulence characteristics, and pathophysiologic and clinic features.45-48 EAEC commonly infect individuals asymptomatically, making it difficult to determine pathogenicity.13 Evidence would suggest that EAEC strains differ in their virulence properties and result in variation in the associated host inflammatory response.49 Travelers to high-risk areas are frequently exposed to the organism due to high rates of food contamination.34 On the basis of recent studies of prevalence, and good clinical response to the treatment with fluoroquinolones, EAEC have been demonstrated to be one of the two most important causes of travelers’ diarrhea.40,50 There are no adequate data available to define the seasonal pattern of EAEC diarrhea.

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Other Diarrheagenic E. coli Enteropathogenic and Shiga toxin-producing E. coli (EPEC and STEC, respectively) strains are not common causes of travelers’ diarrhea. Enteroinvasive E. coli strains have been shown to cause approximately 6% of travelers’ diarrhea in Mexico and constitute a potentially important cause of illness.51

Campylobacter jejuni As a cause of travelers’ diarrhea, C. jejuni is overall the third most common cause of infection (see Table 7-1), but there is great variation (0 to 40%) in prevalence, depending on the geographic area and the time of the year. Campylobacter was found to be the most common cause of travelers’ diarrhea in military populations in Thailand.22,23 A study in Finnish tourists visiting Morocco found that Campylobacter caused diarrhea more often in winter (10 to 15%) than summertime (3%).36 Similar results were found among US students visiting Mexico.37 C. jejuni is especially important in a region when its prevalence makes it a target to be included in the coverage of empiric antimicrobial therapy. C. jejuni is inherently resistant to trimethoprim–sulfamethoxazole, and currently, its resistance to fluoroquinolones is very high in Southeast Asia.24,25 In such regions, either azithromycin or rifaximin has become the empiric antimicrobial agent of choice for treatment of travelers’ diarrhea.

Salmonella Nontyphoid Salmonella is an occasional cause of travelers’ diarrhea, accounting for up to 3 to 30% of cases worldwide and for an even higher proportion of diarrhea in Asia and Africa, where it has been reported to be the second or third most common cause of travelers’ diarrhea.9 Similar to diarrheagenic E. coli, Salmonella strains have been found more often in summer and fall than in winter.36 The relative importance of Salmonella should also be taken into account when considering use of empiric antimicrobial therapy. Some authorities believe that nontyphoid Salmonella are preferentially managed without antibiotics to prevent prolonged excretion of the pathogen.52 Most feel that antimicrobial therapy is appropriate for treatment of travelers’ diarrhea when the etiology is uncertain, even recognizing that a measure of this illness is caused by strains of nontyphoid Salmonella.9,36 The major reservoir of nontyphoid Salmonella is food, not humans, and the prolongation of excretion stimulated by antimicrobial therapy is short lasting (~3 weeks) and of little consequence to the usual traveler.

Shigella The prevalence of shigellosis in travelers’ diarrhea (0 to 30%) is similar to Campylobacter.9,41,53 Geographically, shigellosis is more common in Mexico and India than in Jamaica (see Table 7-1).9 Although most of the data were collected in summertime, seasonal variations of shigellosis remain to be better studied. S. dysenteriae is a pathogen for which 3 or more days of antimicrobial therapy has been advised. Fortunately, S. dysenteriae is such a rare cause of travelers’ diarrhea that it has not driven the choice

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of a preferred treatment regimen, which arguably is a single dose of an antimicrobial agent for most illness.

Other Bacterial Pathogens Species of Aeromonas and Plesiomonas account for up to 10% of travelers’ diarrhea cases, and nonVibrio cholerae occur occasionally, particularly in coastal Asian regions.55 There are very few descriptions of V. cholerae as a cause of travelers’ diarrhea. By one calculation, the risk to travelers has been estimated to be 1 in 500,000 during a journey to an endemic area.56 A study in US persons staying in cholera-endemic Peru provided evidence that V. cholerae infection risk is actually higher, although much of the illness is less severe than classical cholera.57 Risk can be minimized by not ingesting undercooked seafood and not transporting raw seafood in luggage. The risk is so low that routine vaccination with cholera vaccine is not recommended for most travelers, although new vaccines that also protect against ETEC are likely to have a role in protection of travelers. Yersinia enterocolitica show a preference for the warmer months in more temperate climates. It is not found frequently in tropical and semitropical areas as being a cause of travelers’ diarrhea.9

Viral Enteric Pathogens Viral agents are well known causes of enteric disease in travelers. Usually, the enteric viruses produce gastroenteritis, with vomiting as the primary symptom, with or without watery diarrhea. Most of the cases are self-limited, although symptomatic antidiarrheal compounds may be helpful. Rotavirus, caliciviruses (eg, Norwalk virus) and enteroviruses (types 40 and 41) are the common viral pathogens, identified in 0 to 20% of the cases of travelers’ diarrhea, with no unique geographic distribution.9,58,59 Rotavirus is more common in the winter of temperate Australia, but seasonality is blunted and even lost in tropical and semitropical areas.60 Fortunately, viral causes of travelers’ diarrhea are not common enough in any region of the world to force reconsideration of an antimicrobial agent as empiric therapy.

Intestinal Protozoa Protozoal infection may be commensal or pathogenic to the human host. When illness is produced, it frequently is subacute or chronic. Protozoal enteric pathogens are identified in 0 to 5% of travelers with diarrhea.9,61,62 Giardia accounts for a small proportion (~2%) of travelers’ diarrhea cases, and along with Cryptosporidium, have been associated with tap water in St. Petersburg, Russia.61 Although Entamoeba histolytica is a common protozoal infection in endemic populations of Mexico, India, Africa, and Central and South America, it accounts for less than 1% of travelers’ diarrhea.63 The earlier reported prevalence of Cryptosporidium as a cause of travelers’ diarrhea is 1 to 2%, but the illness can be severe and lengthy. In Mexico, our group has continued to the present time to see Cryptosporidium cause diarrhea among travelers at this frequency (H.L. DuPont and C.D. Ericsson, unpublished data). C. parvum caused a large waterborne diarrheal outbreak in the United States, which underscores the importance of a clean water supply in any country. Cyclospora cayetanensis has been reported to cause diarrhea in travelers to Peru and Nepal.64,65

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GENERAL CONSIDERATIONS As a general concept, all travelers from industrialized areas developing diarrhea in high-risk tropical or semitropical regions should be considered to have a bacterial etiology for their illness. From the direct studies cited in this chapter and from the indirect evidence of favorable response to antibacterial drugs, we feel that approximately 80% of travelers’ diarrhea are caused by a bacterial agent. In Table 7-2, we focus on specific considerations for international travelers, based on associations between geography and pathogen. In addition, when travelers experience fever or dysentery, then invasive bacterial pathogens should be suspected. When chronic (>14 days) or recurrent symptoms occur, protozoal pathogens should be strongly suspected. The high frequency of protozoal pathogens, including Cyclospora, should be considered among travelers experiencing diarrhea during or after travel to Nepal, Peru, or Haiti. Diarrhea that occurs in St. Petersburg, Russia should be evaluated for Giardia or Cryptosporidium infection. A major public health problem exists in Thailand, where fluoroquinolone-resistant Campylobacter is an important pathogen, complicating recommendations about therapy. Noninfectious causes of mild diarrhea are inadequately studied, but even many of these cases are caused by recognized enteropathogens. In particular, the long-term or frequent traveler might be advised to consider not treating mild disease with an antimicrobial agent, in the hopes of acquiring immunity against the bacterial enteropathogens that do account for a proportion of such disease.

REFERENCES 1. Kean BH, Water SR. Incidence of diarrhea in travelers returning to the U.S. from Europe. AMA Arch Ind Health 1958;18:148–56. 2. Kean BH, Waters SR. The diarrhea of travelers. III. Drug prophylaxis in Mexico. N Engl J Med 1959;216:71–4. 3. Kean BH, Schaffner W, Brennan RW, Waters SR. The diarrhea of travelers. V. Prophylaxis with phthalylsulfathiazole and neomycin sulphate. J Am Med Assoc 1962;180:367–71. 4. Kean BH. The diarrhea of travelers to Mexico: summary of a five-year study. Ann Intern Med 1963;59:605–14. 5. Gorbach SL, Kean BH, Evans DG, et al. Travelers’ diarrhea and toxigenic Escherichia coli. N Engl J Med 1975;292:933–6. 6. DuPont HL, Ericsson CD. Prevention and treatment of travelers’ diarrhea. N Engl J Med 1993;328:1821–7. 7. Ericsson CD. Travelers’ diarrhea. Epidemiology, prevention and self-treatment. Infect Dis Clin North Am 1998;12:285–303. 8. DuPont HL, Olarte J, Evans DG, et al. Comparative susceptibility of Latin American and United States students to enteric pathogens. N Engl J Med 1976;295:1520–1. 9. Jiang Z-D, Lowe B, Verenkar MP, et al. Prevalence of enteric pathogens among international travelers with diarrhea acquired in Kenya (Mombassa), India (Goa) and Jamaica (Montego Bay). J Infect Dis 2002;185:497–502. 10. Black RE. Epidemiology of travelers’ diarrhea and relative importance of various pathogens. Rev Infect Dis 1990;12 Suppl 1:S73–9.

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11. von Sonnenburg F, Tornieporth N, Collard F, et al. Risk and etiology of diarrhoea at various tourist destinations. Lancet 2000;356:133–4. 12. Kean BH. Travelers’ diarrhea: an overview. Rev Infect Dis 1986;8 Suppl 2:111–25. 13. Adachi JA, Ericsson CD, Jiang Z-D, et al. Natural history of enteroaggregative and enterotoxigenic Escherichia coli infection among US travelers to Guadalajara, Mexico. J Infect Dis 2002;185:1681–3. 14. Sutjita M, Bouckenooghe AR, Adachi JA, et al. Intestinal secretory immunoglobulin: a response to enteroaggregative Escherichia coli in travelers with diarrhea. Clin Diag Lab Immunol 2000;7:501–3. 15. Mathewson JJ, Johnson PC, DuPont HL, et al. A newly recognized cause of travelers’ diarrhea: enteroadherent Escherichia coli. J Infect Dis 1985;151:471–5. 16. Caeiro JP, Estrada-Garcia MT, Jiang Z-D, et al. Improved detection of enterotoxigenic Escherichia coli among patients with travelers’ diarrhea, by use of the polymerase chain reaction technique. J Infect Dis 1999;180:2053–5. 17. Ericsson CD, DuPont HL, Mathewson JJ, et al. Epidemiologic observations on diarrhea developing in U.S. and Mexican students living in Guadalajara, Mexico. J Travel Med 1995;2:6–10. 18. Farmer RG, Gulya AJ, Whelan G. Travelers’ diarrhea: clinical observations. J Clin Gastroenterol 1981;3:27–9. 19. Rogers HL, Reilly SM. A survey of the health experiences of international business travelers. Part One: physiological aspects. Am Assoc Occup Health Nurses J 2002;50:449–59. 20. Herwaldt BL, de Arroyave KR, Roberts JM, Juranek DD. A multiyear prospective study of the risk factors for and incidence of diarrheal illness in a cohort of Peace Corps volunteers in Guatemala. Ann Intern Med 2000;132:982–8. 21. Moore J, Barlow D, Jewell D, Kennedy S. Do gastrointestinal symptoms vary with the menstrual cycle? Br J Obstet Gynaecol 1998;105:1322–5. 22. Kuschner R, Trofa AF, Thomas RJ, et al. Use of azithromycin for the treatment of Campylobacter enteritis in travelers to Thailand, an area where ciprofloxacin resistance is prevalent. Clin Infect Dis 1995;21:536–41. 23. Echeverria P, Jackson LR, Hoge CW, et al. Diarrhea in U.S. troops deployed to Thailand. J Clin Microbiol 1993;31:3351–2. 24. Hoge CW, Gambet JM, Srijan A, et al. Trends in antibiotic resistance among diarrhea pathogens isolated in Thailand over 15 years. Clin Infect Dis 1998;26:341–5. 25. Talsma E, Goettsch WG, Nieste HLJ, et al. Resistance in Campylobacter species: increased resistance to fluoroquinolones and seasonal variation. Clin Infec Dis 1999;29:845–8. 26. Segreti J, Gootz TD, Goodman LJ, et al. High-level quinolone resistance in clinical isolates of Campylobacter jejuni. J Infect Dis 1992;165:667–70. 27. Echeverria P, Blacklow NR, Sanford LB, et al. Travelers’ diarrhea among American Peace Corps volunteers in rural Thailand. J Infect Dis 1981;143:767–71. 28. Steffen R, Mathewson JJ, Ericsson CD, et al. Travelers’ diarrhea in West Africa and in Mexico: fecal transport systems and liquid bismuth subsalicylate for self-therapy. J Infect Dis 1988;157:1008–13. 29. Evans DG, Olarte J, DuPont HL, et al. Enteropathogens associated with pediatric diarrhea in Mexico City. J Pediatr 1977;91:65–8. 30. Pickering LK, Evans DJ Jr, Munoz O, et al. Prospective study of enteropathogens in children with diarrhea in Houston and Mexico. J Pediatr 1978;93:383–8.

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31. Long KZ, Wood JW, Garibay EV, et al. Proportional hazards analysis of diarrhea due to enterotoxigenic Escherichia coli and breast feeding in a cohort of urban Mexican children. Am J Epidemiol 1994;139:193–205. 32. Tjoa WS, DuPont HL, Sullivan P, et al. Location of food consumption and travelers’ diarrhea. Am J Epidemiol 1977;106:61–6. 33. Wood LV, Ferguson LE, Hogan P, et al. Incidence of bacterial enteropathogens in foods from Mexico. Appl Environ Microbiol 1983;46:328–32. 34. Adachi JA, Mathewson JJ, Jiang ZD, et al. Enteric pathogens in Mexican sauces of popular restaurants in Guadalajara, Mexico, and Houston, Texas. Ann Intern Med 2002;136:884–7. 35. Steffen R, Colland F, Tornieporth N, et al. Epidemiology, etiology, and impact of travelers’ diarrhea in Jamaica. J Am Med Assoc 1999;281:811–17. 36. Mattila L, Siitonen A, Kyronseppa H, et al. Seasonal variation in etiology of travelers’ diarrhea. FinnishMoroccan Study Group. J Infect Dis 1992;165:385–8. 37. Ericsson CD, DuPont HL. Travelers’ diarrhea: approaches to prevention and treatment. Clin Infect Dis 1993;16:616–26. 38. Jiang Z-D, Mathewson JJ, Ericsson CD, et al. Characterization of enterotoxigenic E. coli strains in patients with travelers’ diarrhea acquired in Guadalajara, Mexico, 1992–1997. J Infect Dis 2000;181:779–82. 39. Stenderup J, Orskov I, Orskov F. Changes in serotype and resistance pattern of the intestinal E. coli flora during travel: results from a trial of mecillinam as a prophylactic against travelers’ diarrhea. Scand J Infect Dis 1983;15:367–73. 40. Adachi JA, Jiang Z-D, Mathewson JJ, et al. Enteroaggregative Escherichia coli as a major etiologic agent in travelers’ diarrhea in three regions of the world. Clin Infect Dis 2001;32:1706–9. 41. DuPont HL, Reves RR, Galindo E, et al. Treatment of travelers’ diarrhea with trimethoprim/sulfamethoxazole and with trimethoprim alone. N Engl J Med 1982;307:841–4. 42. Ericsson CD, Johnson PD, DuPont HL, et al. Ciprofloxacin and trimethoprim/sulfamethoxazole as initial therapy for acute travelers’ diarrhea. A placebo-controlled randomized trial. Ann Intern Med 1987;106:216–20. 43. DuPont HL, Ericsson CD, Mathewson JJ, DuPont MW. Five vs three days of ofloxacin therapy for travelers’ diarrhea: a placebo-controlled study. Antimicrob Agents Chemother 1992;36:87–91. 44. DuPont HL, Ericsson CD, Mathewson JJ, et al. Oral aztreonam, a poorly absorbed yet effective therapy for bacterial diarrhea in US travelers to Mexico. J Am Med Assoc 1992;267:1932–5. 45. Vial PA, Mathewson JJ, DuPont HL, et al. Comparison of two assay methods for patterns of adherence to HEp-2 cells of Escherichia coli from patients with diarrhea. J Clin Microbiol 1990;28:882–5. 46. Nataro JP, Yikang D, Cookson S, et al. Heterogeneity of enteroaggregative Escherichia coli virulence demonstrated in volunteers. J Infect Dis 1995;171:465–8. 47. Czeczulin JR, Whittam TS, Henderson IR, et al. Phylogenetic analysis of enteroaggregative and diffusely adherent Escherichia coli. Infect Immun 1999;67:2693–9. 48. Jiang Z-D, Greenberg D, Nataro JP, et al. Rates of occurrence and pathogenic effect of enteroaggregative E. coli virulence factors in international travelers. J Clin Microbiol 2002;40:4185–90. 49. Greenberg DE, Jiang Z-D, Steffen R, et al. Markers of inflammation in bacterial diarrhea among travelers, with a focus on enteroaggregative Escherichia coli pathogenicity. J Infect Dis 2002;185:944–9. 50. Glandt M, Adachi JA, Mathewson JJ, et al. Enteroaggregative Escherichia coli as a cause of travelers’ diarrhea: clinical response to ciprofloxacin. Clin Infect Dis 1999;29:335–8.

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51. Wanger AR, Murray BE, Echeverria P, et al. Enteroinvasive Escherichia coli in travelers’ diarrhea. J Infect Dis 1988;158:640–2. 52. Neill MA, Opal SM, Heelan J, et al. Failure of ciprofloxacin to eradicate convalescent fecal excretion after acute salmonellosis: experience during an outbreak in health care workers. Ann Intern Med 1991;114:195–99. 53. Scerpella EG, Mathewson JJ, DuPont HL, et al. Shigella sonnei strains isolated from U.S. summer students in Guadalajara, Mexico, from 1986 to 1992. J Clin Microbiol 1994;32:2549–52. 54. Echeverria P, Sack RB, Blacklow NR, et al. Prophylactic doxycycline for travelers’ diarrhea in Thailand: further supportive evidence of Aeromonas hydrophila as an enteric pathogen. Am J Epidemiol 1984;120:912–21. 55. Sriratanaban A, Reinprayoon S. Vibrio parahaemolyticus: a major cause of travelers’ diarrhea in Bangkok. Am J Trop Med Hyg 1982;31:128–30. 56. Wittlinger F, Steffen R, Watanabe H, Handszuh H. Risk of cholera among Western and Japanese travelers. J Travel Med 1995;2:154–8. 57. Taylor DN, Rizzo R, Meza R, et al. Cholera among Americans living in Peru. Clin Infect Dis 1996;22:1108–9. 58. Bolivar R, Conklin RH, Vollet JJ, et al. Rotavirus in travelers’ diarrhea: study of an adult student population in Mexico. J Infect Dis 1978;137:324–7. 59. Johnson PC, Hoy J, Mathewson JJ, et al. Occurrence of Norwalk virus infection among adults in Mexico. J Infect Dis 1990;162:389–93. 60. Bishop RF. Natural history of human rotavirus infection. Arch Virol Suppl 1996;12:119–27. 61. Jokipii I, Pohjola S, Jokipii AMM. Cryptosporidiosis associated with traveling and giardiasis. Gastroenterology 1985;89:838–42. 62. Taylor DN, Houston R, Shlim DR, et al. Etiology of diarrhea among travelers and foreign residents in Nepal. J Am Med Assoc 1988;260:1245–8. 63. Frachtman RL, Ericsson CD, DuPont HL. Seroconversion to Entamoeba histolytica among short-term travelers to Mexico. Arch Intern Med 1982;142:1299. 64. Marshall MM, Naumovitz D, Ortega Y, et al. Waterborne protozoal pathogens. Clin Microbiol Rev 1997;10:67–83. 65. Hoge CW, Shlim DR, Rajh R, et al. Epidemiology of diarrhoeal illness associated with coccidian-like organism among travelers and foreign residents in Nepal. Lancet 1993;341:1175–9.

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Par t Two

Epidemiology and Clinical Features

Chapter 8

EPIDEMIOLOGY Robert Steffen, MD, and R. Bradley Sack, MS, MD

Travelers’ diarrhea (TD) has long been a problem for both civilian and military populations (see Chapter 1, “Historical Perspective of Travelers’ Diarrhea” and Chapter 21, “Diarrhea in Military Populations: From Historical Considerations until Modern Times”). Older data on TD were collected at a time prior to the availability of extensive diagnostic microbiological techniques; more recent data have defined the etiology of the disease, and therefore allowed the development of both preventive and treatment interventions. We will present data from both the old, classical surveys that are still valid, and newer studies that are more defined as to etiology and epidemiology. Perhaps in the future, we will have electronic networks (such as the one in Japan) that will give a more complete global picture of TD.1

DEFINITIONS Travelers’ diarrhea is, by definition, an illness that occurs during travel to developing countries, usually by persons from developed countries. The very high risk to developing the disease by these travelers is due to the fact that they are immunologically naïve, having never come in contact with these diarrhea pathogens in their home country. They have a disease that is in many ways similar in etiology to that experienced by the indigenous children of those countries. The most common cause of TD is known to be enterotoxigenic E. coli, which is also the most frequent bacterial cause of diarrhea in the children of the developing world. The rates of diarrheal disease among travelers are the highest of any population group, outside of common source outbreaks. The common definition of diarrhea, that is, output of more than 200 g of unformed feces per 24 hours, is not a practical definition for travelers. Also, the definition suggested by a National Institutes of Health Consensus Conference in 1985 to be “twofold or greater increase in the frequency of unformed bowel movements” has not been practical in questionnaire surveys.2 Over the years, case definitions for TD have varied between one to six unformed stools per day. Thus, it may be difficult to compare rates of TD in different studies because of the varying definitions used. The following definitions have been adopted in a recent multicentric study, which may provide some uniformity in the definition of TD in future studies:3,4 • Classic TD: passage of three or more unformed stools per 24 hours with at least one accompanying symptom, such as nausea, vomiting, abdominal cramps or pain, fever, and blood in stools. (This definition has usually been used in most studies over the past two decades.) • Moderate TD: passage of one to two unformed stools with at least one additional symptom, or more unformed stools without additional symptoms.

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• Mild TD: passage of one to two unformed stools without additional symptoms. These definitions of TD include all degrees of severity. Other symptoms that are sometimes included in the case definition include tenesmus, fecal urgency, malaise, and mucus in the stool (see Chapter 10, “Clinical Features and Syndromes”). The seriousness of TD in the past has usually been defined according to the number of unformed bowel movements per 24 hours (severe being usually ≥6 or ≥10), or by the incapacitation of the traveler. The latter may, of course, lead to some bias: someone on a tour may feel forced to change travel plans or to stay in the hotel more easily than someone on a beach vacation who always finds a toilet nearby. As per World Health Organization definitions, acute diarrhea defines an illness of less than 14 days; if the illness lasts 14 days or longer, it is categorized as persistent disease.5 The vast majority of TD is acute, with only about 1% being persistent.6-8 These entities, as well as the dysenteric forms of TD, will be discussed in more detail in Chapter 10, “Clinical Features and Syndromes.”

INCIDENCE RATES Despite the fact that slightly differing definitions have been used, and that often, only attack rates were given without precisely defining the duration of exposure, the world can generally be divided into three risk zones (Figure 8-1). These zones are based on the various studies summarized in Table 8-1, in which incidence rates per 2 weeks of stay are given.

Low risk: <8%

Intermediate risk: 8-20%

Figure 8-1. Risk areas for travelers’ diarrhea.

High risk: 20-90%

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Table 8-1. Observational Studies on TD Attack / Incidence Rates in Civilian Travelers Originating from Industrialized Countries at Various Destinations (*Incidence per 1 Week) Africa

Year

TD (%)

N at Risk

Reference

East Africa

1975–81

30

2,646

9

West Africa

1975–77

39

505

9

Tunisia

1975–77

48

988

9

Kenya

1977–78

43

42

10,11

Morocco

1977

54

24

12

Tunisia

1979/80

20

706

13

Egypt

1979/80

20

706

13

Morocco

1979/80

38

706

13

Egypt (Nile cruises)

1989–91

10–90

Egypt

1992

59

257

14

Tunisia

1992

40

2,695

14

Morocco

1992

30

1,639

14

Algeria

1992

13

728

14

West Africa

1995

27

141

15

East Africa

1995

26

383

15

West Africa

1991/92

25

53

16

Kenya

1997/8

55

15,181

4

Tunisia

1998

34

397

Steffen, on file

Morocco

1998

25

263

Steffen, on file

Americas

Year

TD (%)

N at Risk

Reference

Mexico

1957

33

1,000

17

Mexico

1975

40

55

18

Mexico

1975

29

133

19

Mexico

1976

49

121

20

Mexico (from Panama)

1979

36

64

21

Mexico

1975–81

31

1,104

9

Brazil

1975–81

33

1,305

9

South America (various)

1975–81

36

420

9

USA/Canada

1975–77

4 (control)

1,379

9

Mexico (Cuba)

1986/87

34

227

22

Mexico

1992

45

84

14

South America

1995

33

282

15

Central America

1995

33

120

15

Honduras

1980

54

22

23

Honduras

1984

100

22

24

Jamaica

1996/7

24

30,369

3

Brazil

1997

14

6,050

4

>500

Steffen, on file

Continued

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Table 8-1. Continued Asia

Year

TD (%)

N at Risk

Reference

Sri Lanka/Maldives

1975–81

35

1,371

9

Thailand

1975–81

22

1,838

9

Far East (various)

1975–81

31

2,470

9

Thailand

1984

24

33

25

Thailand

1981

57

35

26

Middle East

1991/92

48

30

16

Southeast Asia

1995

19

487

15

South Asia

1995

39

250

15

India (Goa)

1997/8

54

15,631

4

Turkey

1998

27

617

Steffen, on file

Europe

Year

TD (%)

N at Risk

Reference

Northern Europe

1953

35

26

27

Southern Europe

1953

67

127

27

Northern Europe

1970

4

1,551

28

Western Europe

1970

6

1,465

28

Southern Europe

1970

12

1,498

28

Spain

1979/80

<15

1,685

13

Canary Islands

1981

20

572

9

Rhodes

1981

13

987

9

Southern Europe

1984

15

720

29

Portugal

1998

9

560

Steffen, on file

Spain

1998

7

906

Steffen, on file

Greece

1998

7

1,398

Steffen, on file

Cyprus

1998

8

688

Steffen, on file

Italy

1998

4

113

Steffen, on file

• High risk, with incidence rates exceeding 20% (up to 90%) • Intermediate risk, with incidence rates exceeding 8% to 20% • Low risk, with incidence rates not exceeding 8% Various studies have demonstrated that TD is the most frequent health problem among travelers residing in industrialized countries when they visit developing countries.13,30 Depending on the duration of exposure abroad, travelers may have several episodes of TD.31 Travelers staying only within industrialized parts of the world have only a low risk of TD.32 Constipation may be a more frequent problem, for instance, among travelers crossing the Northern Atlantic.30 As will be discussed below, travelers originating in developing countries have a lower risk of infection.

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CAUSES Nearly all cases of TD result from the ingestion of fecally-contaminated food or beverage items. Also, swimming in contaminated water has been implicated as a cause of TD (this even without travel) within industrialized nations.33-35 Viral agents that cause TD (Calicivirus and Rotavirus), however, can also be spread by aerosols; this may occur when seasickness results in vomiting (see Chapter 20, “Diarrhea at Sea and Outbreaks Associated with Cruises”). In older publications, before the role of enteropathogens was recognized, a multitude of noninfective causes of TD were discussed. These included among others stress, ingested sand or dust, change of diet, particularly cold drinks, spices and oil, jet-lag, tiredness, and chilling of the abdomen.36 All these hypothetical causes have at best a minimal influence on the occurrence of TD; in up to 80% of cases, an enteropathogen can be identified. There are undoubtedly also additional viral and bacterial enteropathogens yet to be discovered. This is discussed in detail in Chapter 2, “The Bacterial Pathogens” and Chapter 7, “Relative Importance of Pathogens and Noninfectious Causes.” In the classical study by Kean, it has been determined that a warm climate per se was not the cause, since he detected a low attack rate of 8% in Americans visiting Hawaii.27 While a small amount of alcoholic beverages may have a small protective effect, overindulgence has been demonstrated to result in diarrhea, abroad as well as at home.

RISK FACTORS The risk of developing TD is determined through a multitude of travel-related, environmental, or host-related factors of varying importance.

Destination As mentioned above, the world of TD can be divided into three risk zones (see Figure 8-1). The studies in Table 8-1 clearly demonstrate how in the early studies conducted shortly after World War II, the whole of Europe initially was a high-risk destination; then, first Northern, and later Southern Europe become intermediate and low-risk destinations. However, even now, travel within France remains a risk for TD, with an odds ratio of 3.0 (1.6–5.7) as compared to staying at home.37 Developing countries essentially have constant high rates for TD; they all remain high-risk destinations.

Countr y of Origin Persons from developed countries, in which water and sanitation are optimal, have the highest risk of developing TD when visiting a country in the developing world, whereas persons from developing countries who visit other developing countries have a much lower incidence (Table 8-2)38-41 It is believed that such persons have developed immunity to most diarrheal pathogens due to continued exposure. In particular, individuals from the lower socioeconomic strata appear to be well protected.41,42 Of interest is the observation that British travelers to various locations in the developing world had significantly higher incidence rates as compared to other Europeans or North Americans; however, the reason for that remains unknown.4

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Table 8-2. Observational Studies on Travelers’ Diarrhea (TD) in Travelers Originating from Differing Risk Origins Attending Conventions Destination

Year

Lebanon (UN troops)

1958

Origin Northern Europe

1968

N at Risk

Reference

79

295

47

USA, Canada

75

70

South America

15

60

Southern Europe

13

51

9

100

USA, UK, Germany

≥40

175

India, Pakistan, Thailand

≤10

29

USA, Canada, N-Europe

≥44

745

France, S-Europe

Asia Teheran, Iran (medical congress)

TD (%)

38

Mexico City, Mexico (medical congress)

Mexico City, Mexico (students) London, UK (convention)

1970

1974

≤22

60

USA

25

197

Mexico

11

66

Europe

2

342

United Kingdom

4

143

39 40 32

Duration of Stay TD typically occurs most frequently during the first 2 weeks after arrival; the incidence rate then decreases with time. This has been often observed in the classical studies on American students in Mexico, and in Peace Corps volunteers and European tourists in Kenya (Figure 8-2).43 A lower risk

Figure 8-2. Cumulative incidence of TD with 95% confidence interval in Kenya (left) and Jamaica (right).

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T R AV E L E R S ’ D I A R R H E A

persists, however, throughout the duration of stay; long-term expatriate residents may also be affected by diarrheal illness.44,45

Travel Style and Standard of Accommodation Adventure travelers (backpackers) appear to be at greatest risk of infection, since they tend to more often consume inexpensive food and beverages from food handlers without high hygienic standards (eg, street vendors), and live in low-cost accommodations. The surveys conducted in Tunisia and recently on three continents have demonstrated up to fourfold and higher inter-hotel differences in the incidence rate of TD in one country or even within the same locality.4,29 As determined in Tunisia, individual hotels usually experienced a constant rate of TD among their guests, which was a mirror of the hygienic conditions at the respective facility, unless intensive action was taken.29 Various studies (usually unpublished data) have indicated that the hotel with the greatest number of star ratings is not necessarily the safest place to reduce the risk of TD. In the highest category, there is often a slightly increased risk as compared to three- or four-star resorts; this is explained by the fact that the risk of contamination increases as preparation and presentation of food becomes more complicated, since the number of persons actually touching food items increases. The same hypothesis has been suggested when it was found that persons who had their wedding and honeymoon in expensive hotels in Jamaica had a greater risk of TD as compared to those without such celebrations there.3 Data on travelers eating in local families are contradictory. Surveys on American students in Mexico and Central America, as well as on expatriate residents in Nepal, showed an increased risk.44,46,47 In contrast, a decreased risk was noted in Jamaica among those staying with family and friends. Eating outside the hotel did not influence the risk of TD significantly.3

Environment Bathing in contaminated water has been associated with enteric infection and diarrhea, even in the United Kingdom.33,35 The risk was greatest when submerging the head into the water, and smallest when the person went only knee-deep in the water.48 A particular problem is wilderness acquired diarrhea (sometimes abbreviated WAD), which may occur after drinking unpurified alpine or other mountain water.49 Aerogenic transmission of TD by viral infection is most likely to occur during cruises, where there are a large number of passengers in a confined space. Cruise ships are generally known to provide opportunities for outbreaks of diarrheal disease, because the same food may be served to large numbers of people, and any contaminated food could result in an epidemic. A large number of shipboard outbreaks of TD have been reported (see Chapter 20, “Diarrhea at Sea and Outbreaks Associated with Cruises”).

Seasonality On the basis of very few data, it seems that the incidence rate of TD is lower during the cool seasons. In Jamaica, the total TD attack rate exceeded 25% from May to October and was clearly below 20% from December to February.3 In a large survey conducted among package tourists going to different destinations, the incidence of TD increased between April and September, falling again in October.50

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This seasonal pattern is similar to that of diarrheal diseases among the children of those countries. Seasonal impacts on the etiology are described in Chapter 2, “The Bacterial Pathogens.”51

Gender No studies have reported a relevant gender related difference in the risk of acquiring TD.

Age Most studies report that the risk of TD is greatest among teenagers and young adults and that it decreases with age.3,14,30 Such an age related difference is found even when the population is stratified by hotel, by having all meals in the hotel, and by previous travel to developing countries. The most likely hypothesis is that young travelers have a greater and more exotic appetite and thus ingest a greater number of pathogens. TD additionally lasts longer in small children.29 Infants have a particularly high incidence rate of TD when visiting relatives, and in this group, the clinical course is often dramatic, frequently resulting in hospitalization.52,53

Compliance with Dietar y Recommendations It has sometimes been shown in prospective studies that avoidance of all potentially contaminated food and beverage items reduces the risk of TD; this risk increases continuously with the number of “dangerous” items ingested.54,55 Retrospective surveys that have been done, however, are generally more difficult to interpret and therefore not helpful. Travel health professionals must realize that despite their recommendations regarding food precautions, only a small proportion of travelers follows instructions carefully. According to three studies, only between 2 and 5% of all travelers were fully compliant, even in high-risk destinations such as India, Kenya, and Sri Lanka.4,54,55 Other host factors, notably preexisting illness such as lack of gastric-acid barrier, are discussed in Chapter 9, “Host Factors and Susceptibility.”

IMPACT AND OUTCOME The impact of TD is manyfold. Even a brief episode of severe TD may spoil a holiday or ruin a business trip.48 Incapacitation rates in patients with TD vary between 45% in high-risk destination India and 12% in intermediate-risk country Brazil. The mean duration of incapacitation varied between 12 hours in Jamaica and 3.5 days in West Africa.3,15 It appears that the number of pathogens ingested and the immunologic host defenses are the decisive factors for determining the presence or absence of disease and also for the severity thereof. Between 7 and 18% of patients with TD seek professional help abroad from doctors, nurses, or pharmacists, and up to 0.2% of patients are hospitalized abroad.4 The case fatality rate in TD is extremely low, but anecdotal cases with fatal outcome have been described.56 TD may become persistent in 1 to 2% of cases; these illnesses may be due to infectious causes such as Giardia or Cyclospora, but they may also indicate the onset of noninfectious gastrointestinal disease, such as irritable bowel disease or inflammatory bowel disease. Future studies need to analyze this problem more fully.

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Figure 8-3. Evolution of travelers’ diarrhea attack rates.

The most frequent reason for travelers seeking medical attention following a trip is diarrheal disease.15,29 Persons who had pretravel health advice have been shown to need fewer medical TD consultations as compared to travelers without pretravel medical advice.57

OUTLOOK TD will only decrease as water and sanitation facilities are improved in developing countries (see also Chapter 2 “The Bacterial Pathogens”). As demonstrated in Figure 8-3, the incidence rate of TD has not really decreased over the past decades. Among the developing countries, only in Tunisia and Jamaica have the Ministries of Health and of Tourism, working jointly to improve hygiene in tourist facilities, been able to drastically reduce the risk of TD in its visitors—at least, as long as an intense program was implemented.58 At several other destinations, the risk is actually increasing, which is probably the result of the rapid expansion of tourist facilities in places where water and sanitation are known to be inadequate. In contrast, those Southern European countries with a comparatively strong economy have at most sites successfully been able to reduce the risk of TD as compared to the post-World War II era. Improvements to the water supply and sewage disposal were, however, sometimes only instituted after major outbreaks of diarrhea.50

REFERENCES 1. Osaka K, Inouye S, Okabe N, et al. Electronic network for monitoring travellers’ diarrhoea and detection of an outbreak caused by Salmonella enteritidis among overseas travellers. Epidemiol Infect 1999;123:431–6. 2. Related articles on travelers’ diarrhea. NIH consensus development conference. J Am Med Assoc 1985;253:2700–4. 3. Steffen R, Collard F, Tornieporth N, et al. Epidemiology, etiology, and impact of traveler’s diarrhea in Jamaica. J Am Med Assoc 1999;281:811–7.

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4. von Sonnenburg F, Tornieporth N, Waiyaki P, et al. Risk and aetiology of diarrhoea at various tourist destinations. Lancet 2000;356:133–4. 5. DuPont HL, Capsuto EG. Persistent diarrhea in travelers. Clin Infect Dis 1996;22:124–8. 6. Addiss DG, Tauxe RV, Bernard KW. Chronic diarrhoeal illness in US Peace Corps volunteers. Int J Epidemiol 1990;19:217–8. 7. Steffen R, Rickenbach M, Wilhelm U, et al. Health problems after travel to developing countries. J Infect Dis 1987;156:84–91. 8. Taylor DN, Connor BA, Shlim DR. Chronic diarrhea in the returned traveler. Med Clin North Am 1999;83:1033–52, vii. 9. Steffen R, van der Linde F, Gyr K, Schär M. Epidemiology of diarrhea in travelers. J Am Med Assoc 1983;249:1176–80. 10. Sack DA, Kaminsky DC, Sack RB, et al. Enterotoxigenic Escherichia coli diarrhea of travelers: a prospective study of American Peace Corps volunteers. John Hopkins Med J 1977;141:63–70. 11. Sack DA, Kaminsky DC, Sack RB, et al. Prophylactic doxycycline for travelers’ diarrhea: results of a prospective double-blind study of Peace Corps volunteers in Kenya. N Engl J Med 1978;298:758–63. 12. Sack RB, Froehlich JL, Zulich AW, et al. Prophylactic doxycycline for travelers’ diarrhea: results of a prospective double-blind study of Peace Corps Volunteers in Morocco. Gastroenterology 1979;76:1368–73. 13. Peltola H, Kyrönseppä H, Hölsä P. Trips to the South – a health hazard. Morbidity of Finnish travellers. Scand J Infect Dis 1983;15:357–81. 14. Meuris B. Observational study of travelers’ diarrhea. J Travel Med 1995;2:11–5. 15. Bruni M, Steffen R. Impact of travel-related health impairments. J Travel Med 1997;4:61–4. 16. Cobelens FG, Leentvaar-Kuijpers A, Kleijnen J, Coutinho RA. Incidence and risk factors of diarrhoea in Dutch travellers: consequences for priorities in pre-travel health advice. Trop Med Int Health 1998;3:896–903. 17. Kean BH, Waters S. The diarrhea of travelers. Incidence in travelers returning to the United States from Mexico. Arch Industr Health 1958;18:148–50. 18. DuPont HL, Haynes GA, Pickering LK, et al. Diarrhea of travelers to Mexico. Relative susceptibility of United States and Latin American students attending a Mexican University. Am J Epidemiol 1977;105:37–41. 19. Gorbach SL, Kean BH, Evans DG, et al. Travelers’ diarrhea and toxigenic Escherichia coli. N Engl J Med 1975;292:933–6. 20. Merson MH, Morris GK, Sack DA, et al. Travelers’ diarrhea in Mexico. A prospective study of physicians and family members attending a congress. N Engl J Med 1976;294:1299–305. 21. Ryder RW, Oquist CA, Greenberg H, et al. Travelers’ diarrhea in Panamanian tourists in Mexico. J Infect Dis 1981;144:442–8. 22. Kollaritsch H. Traveller’s diarrhea among Austrian tourists in warm climate countries: I. Epidemiology. Eur J Epidemiol 1989;5:74–81. 23. Santosham M, Sack RB, Froehlich JL, et al. Biweekly prophylactic doxycycline for travelers’ diarrhea. In: Current Chemotherapy and Infectious Disease. Proceedings of the llth ICC and the l9th ICAAC American Society of Microbiology; 1980. p. 922–4. 24. Sack RB, Santosham M, Froehlich JL, et al. Doxycycline prophylaxis of travelers’ diarrhea in Honduras, an area where resistance to doxycycline is common among enterotoxigenic Escherichia coli. Am J Trop Med Hyg 1984;33:460–6.

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25. Echeverria P, Sack RB, Blacklow NR, et al. Prophylactic doxycycline for travelers’ diarrhea in Thailand: further supportive evidence of Aeromonas hydrophila as an enteric pathogen. Am J Epidemiol 1984;120:912–21. 26. Echeverria P, Blacklow NR, Sanford LB, Cukor GG. Travelers’ diarrhea among American Peace Corps volunteers in rural Thailand. J Infect Dis 1981;143:767–71. 27. Kean BH. The diarrhea of travelers to Mexico. Summary of five-year study. Ann Intern Med 1963;59:605–14. 28. Gangarosa EJ, Kendrick MA, Loewenstein MS, et al. Harry G. Armstrong lecture: global travel and travelers’ health. Aviat Space Environ Med 1980;51:265–70. 29. Steffen R. Epidemiologic studies of travelers’ diarrhea, severe gastrointestinal infections, and cholera. Rev Infect Dis 1986;8 Suppl 2:S122–30. 30. Steffen R, Van der Linde F, Meyer HE. Erkrankungsrisiken bei 10 500 Tropen- und 1300 Nordamerikatouristen. Schweiz Med Wschr 1978;108:1485–95. 31. Keskimaki M, Mattila L, Peltola H, Siitonen A. Prevalence of diarrheagenic Escherichia coli in Finns with or without diarrhea during a round-the-world trip. J Clin Microbiol 2000;38:4425–9. 32. Freedman BJ. Travellers’ diarrhoea: does it occur in the United Kingdom? J Hyg Camb 1977;79:73–5. 33. Balarajan R, Raleigh VS, Yuen P, et al. Health risks associated with bathing in sea water. Br Med J 1991;303:1444–5. 34. Outbreak of gastroenteritis associated with an interactive water fountain at a beachside park – Florida, 1999. MMWR Morb Mortal Wkly Rep 2000;49:565–8. 35. Keene WE, McAnulty JM, Hoesly FC, et al. A swimming-associated outbreak of hemorrhagic colitis caused by Escherichia coli O157:H7 and Shigella sonnei. N Engl J Med 1994;331:579–84. 36. Kershaw GR. Acute non-specific diarrhoea and dysentery. Local chilling of the abdomen as a causative factor. Br Med J 1947;1:717–9. 37. Yazdanpanah Y, Beaugerie L, Boelle PY, et al. Risk factors of acute diarrhoea in summer – a nation-wide French case-control study. Epidemiol Infect 2000;124:409–16. 38. Kean BH. Turista in Teheran. Travellers’ diarrhoea at the eighth international congresses of tropical medicine and malaria. Lancet 1969;13:583–4. 39. Loewenstein MS, Balows A, Gangarosa EJ. Turista at an international congress in Mexico. Lancet 1973;10:529–31. 40. DuPont HL, Olarte J, Evans DG, et al. Comparative susceptibility of Latin American and United States students to enteric pathogens. N Engl J Med 1976;295:1520–1. 41. Haneveld GT. Some epidemiological aspects of “travellers’ diarrhoea” in Lebanon. Trop Geogr Med 1960;12:339–44. 42. Ryder RW, Wells JG, Gangarosa EJ. A study of travelers’ diarrhea in foreign visitors to the United States. J Infect Dis 1977;136:605–7. 43. Angst F, Steffen R. Update on the epidemiology of traveler’s diarrhea in East Africa. J Travel Med 1997;4:118–20. 44. Hoge CW, Shlim DR, Echeverria P, et al. Epidemiology of diarrhea among expatriate residents living in a highly endemic environment. J Am Med Assoc 1996;275:533–8. 45. Shlim DR, Hoge CW, Rajah R, et al. Persistent high risk of diarrhea among foreigners in Nepal during the first 2 years of residence. Clin Infect Dis 1999;29:613–6.

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46. Tjoa WS, DuPont HL, Sullivan P, et al. Location of food consumption and travelers’ diarrhea. Am J Epidemiol 1977;106:61–6. 47. Ericsson CD, Pickering LK, Sullivan P, DuPont HL. The role of location of food consumption in the prevention of travelers’ diarrhea in Mexico. Gastroenterology 1980;79:812–6. 48. WHO. International travel and health. World Health Organization Geneva; 2002. p. 30–2. 49. Backer H. Wilderness acquired diarrhea. J Wilderness Med 1992;3:237–40. 50. Cartwright RY. Epidemiology of travellers’ diarrhoea in British package holiday tourists. PHLS Microbiol Digest 1992;9:121–4. 51. Mattila L, Siitonen A, Kyronseppa H, et al. Seasonal variation in etiology of travelers’ diarrhea. FinnishMoroccan Study Group. J Infect Dis 1992;165:385–8. 52. Hutchins P, Hindocha P, Phillips A, Walker-Smith JA. Travellers’ diarrhoea with a vengeance in children of UK immigrants visiting their parenteral homeland. Arch Dis Child 1982;57:208–11. 53. Pitzinger B, Steffen R, Tschopp A. Incidence and clinical features of traveler’s diarrhea in infants and children. Pediatr Infect Dis J. 1991;10:719–23. 54. Kozicki M, Steffen R, Schär M. ‘Boil it, cook it, peel it or forget it’: does this rule prevent travellers’ diarrhoea? Int J Epidemiol 1985;14:169–72. 55. Mattila L, Siitonen A, Kyronseppa H, et al. Risk behavior for travelers’ diarrhea among Finnish travelers. J Travel Med 1995;2:77–84. 56. Obana M, Suzuki A, Matsuoka Y, Irimajiri S. A fatal case of acute enteritis caused by Salmonella weltevreden after travel to Indonesia. Kansenshogaku Zasshi 1996;70:251–4. 57. McIntosh IB, Reed JM, Power KG. Travellers’ diarrhoea and the effect of pre-travel health advice in general practice. Br J Gen Pract 1997;47:71–5. 58. Cartwright RY, Chahed M. Foodborne diseases in travellers. World Health Stat Q 1997;50:102–10.

Chapter 9

H O S T FAC TO R S

AND

SUSCEPTIBILITY

Andrew W. DuPont, MD and Robin C. Spiller, MD, MSc, FRCP

Travelers from industrialized regions visiting developing tropical and subtropical regions with substandard hygienic conditions are exposed to prevalent enteropathogens in varying doses. Many become ill, but others exposed to the same pathogens remain asymptomatic with or without enteric infection. The variation in attack rate is only partially explained by the variation in dose and virulence of organisms ingested, suggesting important differences in host susceptibility. These host factors range from environmental to hygienic to genetic. Some risk factors are modifiable. This chapter identifies factors that influence the occurrence of enteric infection and illness among international travelers.

COUNTRIES OF ORIGIN AND DESTINATION Rates of travelers’ diarrhea are influenced both by the traveler’s country of origin and their destination, with each being able to be categorized based on hygienic standards into low, moderate, and high risk with regard to rates of occurrence of diarrhea. The high-risk regions are in most countries of Latin America, Africa, and Southern Asia. Individuals from industrialized nations visiting high-risk regions experience an attack rate of diarrhea of about 40%, whereas persons from high-risk tropical areas visiting these same areas have a rate of illness of approximately 8%.1,2 This disparity in illness attack rates has been seen with travelers from Iran, Mexico, and South America in comparison with those from Northern Europe, the United States, Canada, and Australia (see Chapter 5 “Antimicrobial Resistance”).1-3 American students traveling to Mexico had the expected illness attack rate of 40% compared with students from Venezuela and Mexico who had lower rates of illness (14% and 11%, respectively), suggesting the development of protective immunity from previous exposure.2 It was also noted in this study that American students had a rate of recurrent illness of 15% during a 1-month time period, but the recurrence rate in Latin American participants was nonexistent. Students from the United States who remained in Mexico for a semester or longer acquired immunity, resulting in half the rate of diarrhea (20%) compared to the 40% attack rate seen with students newly arrived in Mexico.2 The fact that immunity develops during prolonged stay in a high-risk region has provided hope for the development of a protective vaccine in the control of travelers’ diarrhea. The areas of low risk have an incidence of diarrhea occurrence among travelers from other lowrisk regions of less than 8%.4 These regions include the United States, Canada, Northern and Central Europe, Australia, and New Zealand. The areas of intermediate risk include the Caribbean, Northern Mediterranean, Pacific, Israel, Japan, and South Africa.4 Some differences in illness attack

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rate may be seen among subsets of high-risk travelers. British travelers to India, Kenya, or Jamaica unexplainably had the highest rate of travelers’ diarrhea when compared to other at risk groups also traveling these regions.5 An interesting issue is the occurrence of diarrhea among persons from high-risk areas visiting low-risk areas. Two studies were designed to compare the incidence of diarrhea among international students and American students attending college in the United States for 1 month, either at southern California or southern Florida.6,7 No significant difference in illness attack rate was seen between the foreign and American students attending the same classes. The rates of illness were low and etiologic agents were not sought.6 It is assumed that much of the cases of diarrhea occurring among international visitors in the United States is related to psychological stress associated with a new environment (ie, a “functional” gastrointestinal disorder) or a combination of stress and exposure to a different microbial environment. The definition of diarrhea used in one of the studies—any increase in frequency or looseness of bowel movements—may have led to inclusion of a higher proportion of patients with a functional component of symptoms or those in whom changes in diet such as increased lactose consumption may have led to modest acceleration of colonic transit.6 Some studies have demonstrated an increased incidence of illness during certain seasons. The highest-risk months seen in Nepal were April through July.8 There appears to be some seasonal variation of illness attack rates in semitropical areas (ie, regions with at least some seasonal changes), specifically with respect to certain pathogens including enterotoxigenic Escherichia coli, although no seasonal pattern may be seen in more tropical areas.9–12

EFFECT OF CHILDHOOD EXPOSURE TO ENTERIC INFECTION Both innate and immune mechanisms of defense are enhanced by prior infection. Thus, exposure to Campylobacter in childhood leads to the development of mucosal antibodies, and subsequent exposure results in only a mild or asymptomatic infection. Those contracting Campylobacter for the first time as adults tend to have a much more severe illness, characterized by prolonged bloody diarrhea. Thus, individuals from the tropics may have superior immunity, both acquired and innate, and hence are less likely to suffer from symptomatic campylobacteriosis and travelers’ diarrhea.

LENGTH OF STAY The onset of travelers’ diarrhea is typically early in the course of the stay abroad.13 When comparing investigated regions of the world, including North America, the highest rate of symptom onset occurs on the third day, with symptoms typically lasting between 3 and 4 days. The time of onset for travelers with symptoms of fever, abdominal cramps, vomiting, and blood or mucus in stool did not significantly differ from travelers with diarrhea alone. The rate of travelers’ diarrhea decreases during the stay despite remaining at risk, suggesting an improved defense mechanism. In addition, with increased length of stay, there is a decreased duration and severity of symptoms when travelers

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become ill—also consistent with acquired immunity. This acquired immunity, however, appears to be short-lived, as previous trips to the tropics do not appear to reduce diarrheal incidence to a substantial degree. Travel to high-risk areas likely provides some protective immunity for less than 6 months.13 The risk of diarrhea decreases with the traveler’s length of stay in an endemic region. Among foreign residents in a highly endemic environment such as Nepal, the attack rate of diarrhea has been estimated to be 49% per month during the first 2 years of residency.8 This case-control study compared expatriate residents (median stay of 9 months) and tourists (median stay of 3 weeks) with diarrhea and asymptomatic residents and tourists. Enteric pathogens (enterotoxigenic Escherichia coli, Campylobacter, and Shigella predominantly) were identified in 64% of residents and 83% of tourists with diarrhea. Tourists with diarrhea were also more likely to have multiple pathogens than residents with diarrhea. Pathogens were found in the stool of 37% of asymptomatic residents and 52% of travelers without diarrhea, indicating a persistent widespread exposure. The decreased incidence of symptomatic disease and asymptomatic carrier rate in foreign residents was likely not due to acquired immunity alone. There was an increased incidence of illness with increased frequency of meals eaten in restaurants. Residents are more likely to have access to private kitchens and, therefore, eat fewer meals in restaurants compared to short-term travelers. In fact, residents with diarrhea ate a median of four meals in restaurants the previous week compared with a median of two meals for asymptomatic residents. In another study involving westerners living in Nepal, a bacterial pathogen was isolated from 47% of patients presenting with diarrhea.14 The most frequently isolated pathogens were enterotoxigenic E. coli (24%), Shigella (14%), and Campylobacter species (9%). Giardia was also common (12% of patients, 27% in patients with symptoms lasting more than 2 weeks). The isolation rates of bacterial pathogens decreased with length of stay. This was most significantly seen in isolation rates of Shigella, which was found in 21% of patients who had been in Nepal for less than 3 months compared to 8% in those staying in Nepal for more than 3 months. Rates of protozoal pathogens, on the other hand, were not significantly different in travelers compared to long-term residents.

TYPE OF TRAVEL AND LIVING ACCOMMODATIONS The attack rate of diarrhea appears to be greater in the more adventurous travelers.13 These travelers tend to stay in less expensive hotels, camps, or private accommodations, often living with the native population, as compared with other travelers. The adventure traveler tends to be more mobile, moving to multiple destinations. Beach or urban center vacationers, on the other hand, typically remain in one environment with limited if any excursions outside. The adventurous traveler tends to be younger and often has a less controlled eating pattern. Upscale hotels run by western companies are not always the safest places to stay, however. The rate of illness among travelers to the subtropics staying in four star hotels remains significant, probably because not all meals are eaten in these hotels and because the hygienic standards of the hotels are not always optimal.13

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AGE AND GENDER In multiple studies evaluating trends in the incidence of diarrhea with respect to gender, no predilection has been demonstrated. Age, on the other hand, has repeatedly been shown to influence rates of travelers’ diarrhea.3-15 The two peaks in rates of travelers’ diarrhea are 0 to 2 years of age and <30 years of age.8,14-16 Among resident expatriates living in Nepal, younger age (<30 years) was identified as a dominant risk factor for diarrhea.14 This trend has been demonstrated in younger travelers irrespective of duration of visit, type of travel (eg, more adventurous), and lower proportion of former visits to the tropics.8,15 In the subtropics, some of the specific hotels with a higher median age of visitors had a lower incidence of illness. In the tropics, older persons also had shorter duration of symptoms once illness occurred.13 The duration of diarrhea occurred in tropical areas was shown by Steffen and colleagues to range from 4.0 to 4.2 days for persons 30 years and younger, whereas the duration was 3.6 days for those aged 30 to 39 years and 2.9 to 3.2 days for all age groups older than 39 years.13 The higher rate of diarrhea among travelers younger than 30 years is likely to be due to multiple factors: more adventurous travel; decreased former international travel and decreased immunity; and increased quantity of food consumed with its attendant increased dose of enteropathogens.4,13,15

GASTRIC ACIDITY AND ITS NEUTRALIZATION For more than a century, investigators have supported the idea that decreased gastric acid secretion predisposes to enteric infections by bacterial pathogens. Although incompletely understood, gastric acidity has been thought to serve as a barrier for enteric pathogens, limiting the survival of ingested organisms and preventing the passage of viable organisms into the small intestine and colon. In support of this concept, many enteric bacteria are killed rapidly in an acidic environment.17,18 Studies have demonstrated the killing effect of normal gastric pH (<4.0) and the lack of bactericidal activity of achlorhydric gastric juice.18-20 In a small study of 25 patients by Gitelson, during an outbreak of cholera in the summer of 1970 in Jerusalem, 25% of patients studied were found to have undergone subtotal gastrectomy or vagotomy and pyloroplasty in the past.21 In the study, among 50 control patients admitted to the hospital with gastroenteritis in which a pathogen was not found (“nonspecific” gastroenteritis), none had had a previous gastric resection. In addition, during the convalescent phase of cholera, 16 of 21 patients had fasting gastric pH levels between 4.0 and 8.5, whereas the patients studied with “nonspecific” gastroenteritis had gastric pH levels between 1.0 and 4.0. It was also noted that cholera patients with higher gastric pH tended to have more severe disease, although it did not reach clinical significance. Numerous investigators have shown that subjects show greater susceptibility to enteric infection when they have altered gastric physiology or reduced stomach acid.22-36 Study of travelers with respect to diminished gastric acidity and susceptibility to diarrhea is lacking. It does appear intuitive that those with hypochlorhydria or achlorhydria would be at increased risk when traveling to the tropics. Even less information exists regarding the possible effects of medically induced alterations in gastric acidity. The widespread use of H2 antagonists and proton pump inhibitors could potentially pose a

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greater problem among travelers with respect to their risk of developing travelers’ diarrhea. In an evaluation of 108 travelers returning from Kenya who used antacids or H2 blockers, Hoffman found that only those who used Maalox had a significantly increased attack rate of travelers’ diarrhea compared to untreated controls (57% versus 26%).37 Persons using other antacids had a rate of 32%, and those who used H2 blockers had a similar rate of 36%. At the time of this study, omeprazole had only recently been introduced and only two of the five users developed travelers’ diarrhea. Risk factors in a group of Dutch travelers included a history of gastrointestinal surgery and current use of anti-acid medication, underscoring the importance of gastric acidity as a defense for travelers to high-risk areas.38 A case-control study by Neal and colleagues was conducted to assess whether H2 blockers were associated with Salmonella infection.39 Effects of use of H2 antagonists or antibiotics and previous gastric surgery were reviewed in 188 cases of Salmonella infection (stool culture positive, patients >45 years in age). The authors found that treatment with H2 antagonists in the past month was associated with a twofold increase in risk of Salmonella infection, and that recent antibiotic treatment was associated with a 50% increased risk. Previous gastric surgery was associated with a fivefold increased risk of infection. The increased risk seen with H2 antagonists was for concurrent use and not former use. None of these patients had been taking proton pump inhibitors. There are minimal data regarding the possible diminished bacterial killing effect of reduced gastric acid on enteric pathogens due to proton pump inhibitors and on the increased risk of diarrhea acquisition among travelers. Wingate reported a case of a 28-year-old male who was started on omeprazole 20 mg twice a day for esophagitis and who 10 days later developed acute gastroenteritis, which proved to be due to a strain of Salmonella.40 The patient completed the prescribed course of protonpump inhibitor (PPI) and was eventually changed to ranitidine. His esophagitis returned, however, and he was started on a second course of omeprazole. Within 1 week of restarting omeprazole, he had a second attack of acute gastroenteritis that was also attributable to a strain of Salmonella. Neal and colleagues conducted a case-control study on 211 patients, aged 45 and older, with Campylobacter gastroenteritis and found a tenfold increase in the occurrence of the enteric infection in those treated with omeprazole during the month prior to illness.41 The increased risk with omeprazole was significant only for current use. Interestingly, no significant association was seen with patients treated with H2 antagonists, possibly due to a decreased effect on gastric acidity compared with proton pump inhibitors.

BEVERAGE AND FOOD SELECTION It is well known that food is the major source of enteric infection among international travelers to tropical and semitropical areas.42,43 The risk of travelers’ diarrhea is clearly related to where persons eat their food.42-44 Even those travelers taking prophylactic drugs to prevent the illness will show a different rate of protection according to food consumption patterns.45 Eating foods with the locals and eating in local restaurants remain risk factors for illness among travelers and expatriates.44,46,47 It is possible to decrease the rate of illness by being careful about what is eaten, but travelers fail to heed the available recommendations.43

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GENETICS It is a common observation that certain persons remain well during international travel, trip after trip, while others recurrently are severely affected by bouts of illness during similar travels. It has been assumed that host genetics might some day explain these observations. The two major pathogens in travelers’ diarrhea appear to be enterotoxigenic E. coli (ETEC) and enteroaggregative E. coli (EAEC). In a porcine model, small bowel ETEC receptors, necessary for enteric infection and diarrhea, were genetically acquired.48 It is likely that in humans, ETEC receptors are either present or absent on a genetic basis. There is evidence in experimental Norwalk virus infection that lack of intestinal receptors relates to genetic resistance to illness following challenge.49 In these studies, volunteers challenged with Norwalk virus, with antiviral immunity to infection, lacked serum antibody to the virus, reflecting a prior nonexposure to the virus on a genetic basis. Volunteers with prior antibody development were more susceptible to experimental challenge-induced illness. In the case of EAEC diarrhea, the major mediator of symptoms may be intestinal interleukin-8 (IL-8) production.50,51 It has recently been shown that American travelers to Mexico were susceptible to EAEC diarrhea, based on genetic polymorphism in the promoter region of IL-8.52 There is a relationship between blood group type and certain enteric infectious diseases. Patients with blood type O show a decreased predisposition to cholera.53-55 Susceptibility to ETEC diarrhea is not affected by ABO blood type.56 Strong evidence exists that human blood groups contribute to mucosal infection by viral, bacterial, and parasitic infections, although the mechanism is not entirely clear.57 The protection may be associated with an as yet undetermined genetic factor related to blood type, such as receptors or inflammatory mediators. Genetics may explain the susceptibility and complications of a disease. It is known that persons who are HLA-B27 positive experience reactive arthritis following infection by Shigella flexneri, Campylobacter, and Yersinia.58-60

LONG-TERM CONSEQUENCES OF INFECTION Between 1 and 3% of travelers experiencing diarrhea will have illness lasting longer than a month. 61 In some studies, following certain forms of the diarrhea, the frequency of chronic gastrointestinal symptoms after a bout of diarrhea is even higher. Two studies reported that after a bout of enteric infection, between 7 and 17% of individuals with a normal previous bowel habit developed persistent bowel symptoms, compatible with irritable bowel syndrome (IBS).62,63 These investigators found that a substantial number (8 to 18%) had similar disturbed bowel function after the initial bout of diarrhea, which did not meet the threshold criteria for IBS. Symptoms of IBS, which consist largely of increased bowel frequency and loose stools, may persist for many years. These changes have been associated with an increase in enteroendocrine cells and mucosal lymphocytes.64 The resulting acceleration in colonic transit may facilitate subsequent expulsion of enteric pathogens and hence may be adaptive, though to the individual concerned, the change in bowel habit may seem to be a disorder. Further studies in the developing world would be valuable.

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IMMUNE STATUS When international travelers live in an area of risk, they develop protective immunity within months, presumably through repeated exposure to enteric pathogens found in food.2,44 The protective immunity that develops is most striking for enterotoxigenic E. coli.65 Other bacterial pathogens induce immunity through repeated exposure, as has been shown for strains of Shigella.66 Finding the development of immunity among international travelers has given hope for the development of vaccines to prevent disease.67

CONCLUSION The host is central to the occurrence of travelers’ diarrhea. The traveler’s behavior, through food and beverage selection and type of travel (business vs adventure) will determine if they will be exposed to enteric pathogens. Intrinsic susceptibility and immunity following exposure to many if not most pathogens will be determined by host genetics. Finally, prior exposure resulting in humoral and cellular immunity will result in organism-specific immunity. The limited immunity that occurs following exposure to the most common cause of travelers’ diarrhea seen in most regions (ie, enterotoxigenic E. coli) has given hope for the development of a vaccine that might control a measure of the disease immunologically.

REFERENCES 1. Kean BH. Turista in Tehran. Travelers’ diarrhea at the Eighth International Congresses of Tropical Medicine and Malaria. Lancet 1969;ii:583–4. 2. DuPont HL, Haynes A, Pickering LK, et al. Diarrhea of travelers to Mexico: relative susceptibility of United States and Latin American students attending a Mexican university. Am J Epidemiol 1997;105:37–41. 3. Loewenstein MS, Balows A, Gangarosa EJ. Turista at an International Congress in Mexico. Lancet 1973;1:529–31. 4. Steffen R. Epidemiologic studies of travelers’ diarrhea, severe gastrointestinal infections, and cholera. Rev Infect Dis 1986;8 Suppl 2:S122–30. 5. von Sonnenburg F, Tornieport N, Waiyaki P, et al. Risk and aetiology of diarrhea at various tourist destinations. Lancet 2000;356:133–4. 6. Dandoy S. The diarrhea of travelers: incidence in foreign students in the United States. California Med 1966;104:458–62. 7. Ryder RW, Wells JG, Gangarosa EJ. A study of travelers’ diarrhea in foreign visitors to the United States. J Infect Dis 1977;136:605–7. 8. Hoge CW, Shlim DR, Echeverria P, et al. Epidemiology of diarrhea among expatriate residents living in a highly endemic environment. J Am Med Assoc 1996;275:533–8. 9. Mattila L, Siitonen A, Kyronseppa H, et al. Seasonal variation in etiology of travelers’ diarrhea. J Infect Dis 1992;165:385–8. 10. Ericsson CD, DuPont HL. Travelers’ diarrhea: approaches to prevention and treatment. Clin Infect Dis 1993;16:616–26.

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11. Ericsson CD, DuPont HL, Mathewson JJ III. Epidemiologic observations on diarrhea developing in U.S. and Mexican students living in Guadalajara, Mexico. J Travel Med 1995;6–10. 12. Steffen R, Collard F, Tornieporth N, et al. Epidemiology, etiology, and impact of travelers’ diarrhea in Jamaica. J Am Med Assoc 1999; 281:811–7. 13. Steffen R, van der Linde F, Gyr K, Schar M. Epidemiology of diarrhea in travelers. J Am Med Assoc 1983;249:1176–80. 14. Taylor DN, Houston R, Shlim DR, et al. Etiology of diarrhea among travelers and foreign residents in Nepal. J Am Med Assoc 1988;260:1245–8. 15. Kean BH. The diarrhea of travelers to Mexico: summary of five-year study. Ann Intern Med 1963;59:605–14. 16. Pitzinger B, Steffen R, Tscopp A. Incidence and clinical features of travelers’ diarrhea in infants and children. Pediatr Infect Dis J 1991;10:719–23. 17. Garrod LP. A study of the bactericidal power of hydrochloric acid and of gastric juice. St Barthol Hosp J 1939:72:145–67. 18. Bartle HJ, Harkins MJ. The gastric secretion: its bactericidal value to man. Am J Med Sci 1925;169:373–88. 19. Arnold L. Host susceptibility to typhoid, dysentery, food poisoning and diarrhea. J Am Med Assoc 1927;89:789–91. 20. Giannella RA, Broitman SA, Zamcheck N. The gastric barrier to microorganisms in man: in vivo and in vitro studies. Gut 1972;13:251–6. 21. Gitelson S. Gastrectomy, achlorhydria, and cholera. Israel J Med Sci 1971;7:663–7. 22. Hornick RB, Music SI, Wenzel R, et al. The Broad Street pump revisited: response of volunteers to ingested cholera vibrios. Bull NY Acad Med 1971;47:1181–91. 23. Dubos RJ. Bacterial and mycotic infections in man. Philadelphia: JB Lippincott Co; 1958. 24. Pollitzer R. Cholera. Geneva: WHO; 1958. 25. Waddell WR, Kunz LJ. Association of Salmonella enteritis with operations on the stomach. N Engl J Med 1956;225:555–9. 26. Giannella RA, Broitman SA, Zamcheck N. Influence of gastric acidity on bacterial and parasitic enteric infections. Ann Intern Med 1973;78:271–6. 27. Giannella RA, Broitman SA, Zamcheck N. Salmonella enteritis 1: role of reduced gastric secretion in pathogenesis. Dig Dis 1971;16:1000–6. 28. Close AS, Smith MB, Koch ML, et al. An analysis of 10 cases of Salmonella infection on a general surgery service. Arch Surg 1960;80:972–6. 29. Sokol EM. Salmonella derby infections after gastrointestinal surgery. Mt Sinai J Med NY 1965;32:36–41. 30. Nordbring F. Contraction of Salmonella gastroenteritis following previous operation on the stomach. Acta Med Scand 1962;171:783–90. 31. Gray JA, Trueman AM. Severe Salmonella gastroenteritis associated with hypochlorhydria. Scott Med J 1971;16:255–8. 32. DuPont HL, Hornick RB, Snyder MJ, et al. Immunity in shigellosis. 1. Response of man to attenuated strains of Shigella. J Infect Dis 1972;125:5–11. 33. Hass J, Bucken EW. Zum krankheitswert der lamblien infektion. Dtsch Med Wochenschr 1967;92:1869–71. 34. Heremans PE, Huizenga KA, Hoffman HN, et al. Dysgammaglobulinemia associated with nodular lymphoid hyperplasia of the small intestine. Am J Med 1966;40:78–89. 35. Hoskins LC, Winawer SJ, Broitman SA, et al. Clinical giardiasis and intestinal malabsorption. Gastroenterology 1967;53:265–79.

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36. Hughes WS, Cerda JJ, Holtzapple P, et al. Primary hypogammaglobulinemia and malabsorption. Ann Intern Med 1971;74:903–10. 37. Hoffman A. Antacids and H2-blockers: risk of travelers’ diarrhea [dissertation]. University of Zurich; 1993. 38. Cobelens FG, Leentvaar-Kuijpers A, Kleijnen J, Coutinho RA. Incidence and risk factors of diarrhea in Dutch travellers: consequences for priorities in pre-travel health advice. Trop Med Int Health 1998;3:896–903. 39. Neal KR, Brij OS, Slack BCR, et al. Recent treatment with H2-antagonists and antibiotics and gastric surgery as risk factors for Salmonella infection. Br Med J 1994;308:176. 40. Wingate DL. Acid reduction and recurrent enteritis [letter]. Lancet 1990;335:222. 41. Neal KR, Scott HM, Slack RC, et al. Omeprazole as a risk factor for Campylobacter gastroenteritis: casecontrol study. Br Med J 1996;312:414–5. 42. Tjoa WS, DuPont HL, Sullivan P, et al. Location of food consumption and travelers’ diarrhea. Am J Epidemiol 1977;106:61–6. 43. Kozicki M, Steffen R, Schar M. “Boil it, cook it, peel it or forget it”: does this rule prevent travelers’ diarrhea? Int J Epidemiol 1985;14:169–72. 44. Wood LV, Ferguson LE, Hogan P, et al. Incidence of bacterial enteropathogens in foods from Mexico. Appl Environ Microbiol 1983;46:813–6. 45. Ericsson CD, Pickering LK, Sullivan P, DuPont HL. The role of location of food consumption in the prevention of travelers’ diarrhea in Mexico. Gastroenterology 1980;79:812–6. 46. Herwaldt BL, de Arroyave KR, Roberts JM, Juranek DD. A multiyear prospective study of the risk factors for and incidence of diarrheal illness in a cohort of Peace Corps volunteers in Guatemala. Ann Intern Med 2000;132:982–8. 47. Hoge CW, Shlim DR, Echeverria P, et al. Epidemiology of diarrhea among expatriate residents living in a highly endemic environment. J Am Med Assoc 1996:275:533–8. 48. Rutter JM, Burrows MR, Sellwood R, Gibbons RA. A genetic basis for resistance to enteric disease caused by E. coli. Nature 1975;257:135–6. 49. Parrino RA, Schreiber DS, Trier JS, et al. Clinical immunity in acute gastroenteritis caused by the Norwalk agent. N Engl J Med 1977;297:86–9. 50. Steiner T, Nataro JP, Poteet-Smith C, et al. Enteroaggregative Escherichia coli expresses a novel flagellin that causes IL-8 release from intestinal epithelial cells. J Clin Invest 2000;105:1769–77. 51. Greenberg DE, Jiang ZD, Steffen R, et al. Markers of inflammation in bacterial diarrhea among travelers with a focus on enteroaggregative Escherichia coli pathogenicity. J Infect Dis 2002;185:944–9. 52. Jiang ZD, Okhuysen PC, Guo DC, et al. Genetic susceptibility to enteroaggregative Escherichia coli diarrhea – polymorphism in interleukin-8 promoter region.[Submitted] 53. Chaudhuri A, De S. Cholera and blood groups. Lancet 1977;2:404. 54. Glass RI, Holmgren J, Haley CE, et al. Predisposition for cholera of individuals with O blood group. Possible evolutionary significance. Am J Epidemiol 1985;121:791–6. 55. Clemens JD, Sack DA, Harris JR, et al. ABO blood group and cholera: new observations on specificity of risk and modification of vaccine efficacy. J Infect Dis 1989;159:770–3. 56. Black RE, Levine MM, Clements ML, et al. Association between O blood group and occurrence and severity of diarrhea due to Escherichia coli. Trans R Soc Trop Med Hyg 1987;81:120–3.

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57. Moulds JM, Nowicki S, Moulds JJ, Nowicki BJ. Human blood groups: incidental receptors for viruses and bacteria. Transfusion 1996;35:362–74. 58. Keat A. Reiter’s syndrome and reactive arthritis in perspective. N Engl J Med 1983;309:1606–15. 59. Calin A, Fries JF. An experimental epidemic of Reiter’s syndrome revisited. Ann Intern Med 1976;84:564–6. 60. Sairanen E, Tilikainen A. HLA 27 in Reiter’s disease following shigellosis. Scand J Rheumatol. 1975;4 Suppl 8:30–41. 61. DuPont HL, Capsuto EG. Persistent diarrhea in travelers. Clin Infect Dis 1996;22:124–8. 62. Neal KR, Hebden J, Spiller R. Prevalence of gastrointestinal symptoms six months after bacterial gastroenteritis and risk factors for development of the irritable bowl syndrome: post survey of patients. Br Med J 1997;314:779–82. 63. Parry SD, Barton R, Welfare MR. Prevalence of pre-existing functional gastrointestinal disorders (FGID) in infectious diarrhoea (ID) subjects compared to a matched community control group. Gastroenterology 2001;120:A633. 64. Spiller RC, Jenkins D, Thornley JP, et al. Increased rectal mucosal enteroendocrine cells, T lymphocytes and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut 2000;47:804–11. 65. Brown MR, DuPont HL, Sullivan PS. Effect of duration of exposure on diarrhea due to enterotoxigenic Escherichia coli in travelers from the United States to Mexico. J Infect Dis 1982;145:582. 66. DuPont HL, Gangarosa EJ, Reller LB, et al. Shigellosis in custodial institutions. Am J Epidemiol 1970;92:172–9. 67. Peltola H, Siitonen A, Kyronseppa H, et al. Prevention of travelers’ diarrhoea by oral B-subunit/whole-cell cholera vaccine. Lancet 1991;338:1285–9.

Chapter 10

C L I N I C A L F E AT U R E S

AND

SYNDROMES

Niklaus Gyr, MD, MPH, TM, Gilbert Kaufmann, MD, and Phyllis E. Kozarsky, MD

DEFINITIONS Travelers’ diarrhea is defined as the occurrence of three or more watery or unformed stools per day during a journey, or any number of such stools, if accompanied by fever, abdominal cramps, or vomiting.1-3 It is usually an acute diarrhea characterized by a short duration of 3 to 4 days and uncommonly meets the criteria of persistent or chronic diarrhea that last for longer than 14 and 30 days, respectively. The symptoms are the consequence of bacterial colonization, the production of enterotoxins, and/or intestinal inflammation. Occasionally, travelers suffer from classical food poisoning, which is characterized by a rapid onset of nausea and vomiting that occur after ingestion of preformed neurotoxins.4 Common to all forms of classical food poisoning is the short duration of illness, usually lasting for fewer than 24 hours (Table 10-1).

EPIDEMIOLOGY Epidemiological data regarding travelers’ diarrhea have been presented before. In affected travelers, enterotoxigenic E. coli (ETEC) and enteroaggregative E. coli (EAEC) can be detected in 5 to 60% and 0 to 40%, respectively. Campylobacter jejuni is found in 0 to 40% of individuals visiting Asia and Africa.5,6 Further pathogens (see Chapter 7 “Relative Importance of Pathogens and Noninfectious Causes”) to be considered include Salmonella spp (infection rates of 0 to 30%), Shigella spp (0 to 30%), Plesiomonas shigelloides (0 to 13%), and Aeromonas spp (0 to 57%).6 In addition, a substantial proportion (5 to 15%) of affected individuals suffer from viral gastroenteritis, caused by Rotavirus or Norwalk virus.7 Occasionally, parasites are the culprits of travelers’ diarrhea, such as Giardia lamblia, Entamoeba histolytica, Isospora belli, Cryptosporidia, and Cyclospora cayetanensis.

Table 10-1. Characteristics of Food Poisoning Incubation Period (h)

Duration (h)

Clinical Symptoms

Staphylococcus aureus

1–6h

<24

Vomiting, diarrhea, fever

Clostridium perfringens

8–16h

<24

Diarrhea, abdominal cramps, nausea

Bacillus cereus

1–6h

<24

Vomiting, nausea, abdominal cramps

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ACUTE INFECTIOUS DIARRHEA Certain pathogens including Vibrio cholerae, ETEC, and enteropathogenic E. coli (EPEC) produce enterotoxins that affect the intestinal water balance and fluxes of electrolytes. Typically, this mechanism is not associated with an inflammation or invasion of the pathogen, but causes a cholera-like secretory diarrhea syndrome with voluminous watery stools (Table 10-2). In contrast, pathogens including Shigella spp, Salmonella spp, Campylobacter jejuni, Yersinia enterocolitica, enteroinvasive E. coli (EIEC), enterohemorrhagic E. coli (EHEC), and others cause mucosal damage, ulcers, and an acute inflammation of the lamina propria. The consequence is a dysentery syndrome with multiple, usually 10 to 30, small-volume bloody and purulent stools. This form of diarrhea is typically accompanied by abdominal cramps and tenesmus (Table 10-3). Certain pathogens such as C. difficile do not invade the mucosa, but damage the epithelium via secretion of cytotoxins. Frequently, a mixed picture of secretory and dysentery syndrome is observed, due to the fact that many invasive organisms causing dysentery also produce enterotoxins. Examples include Campylobacter jejuni, Salmonella spp, Yersinia enterocolitica, EIEC, and EHEC (see Table 10-3).

Cholera-like, Secretor y Syndrome Vibrio cholerae The classical example of a pathogen causing watery, secretory diarrhea is V. cholerae. Infections with Vibrio bacteria are acquired after ingestion of contaminated water, fish, and shellfish and are more frequently found in conditions of poor sanitation, although outbreaks of cholera have been reported in environments without pollution. The incubation period ranges from several hours to 5 days and depends on the inoculum size. V. cholerae infections can either be asymptomatic (25 to 66%), cause slightly watery stools, or result in severe dehydrating diarrhea. In milder forms, the loss of fluid does not exceed 1,000 mL per day. The illness is characterized by nausea, vomiting, and abdominal distension, followed by watery diarrhea and mild abdominal cramps, but tenesmus is absent. The diarrhea usually lasts for 2 to 4 days. In severe forms, large volumes of watery stool are evacuated within hours. The stool contains flecks of mucus, known as rice water stool that is associated with a high mortality of 50% in untreated individuals. Mild fever may occur, but signs of septicemia are absent. The major complication of Table 10-2. Characteristics of the Cholera-like Secretory Syndrome and the Dysentery Syndrome Dysentery Syndrome

Secretory Syndrome

Clinical Characteristics Stool volume

Small

Large

Stool Characteristics Pain Vomitus Tenesmus Fever Anatomic site

Bloody, purulent Left lower abdominal quadrant Rare Common Common Colon, ileum

Watery Periumbilical Common Absent Occasionally Small bowel

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Table 10-3. Pathogens Causing Infectious Diarrhea Watery Diarrhea

Dysentery

Viruses Rotavirus Norwalk virus

+ +

– –

Bacteria V. cholerae V. parahaemolyticus Aeromonas spp ETEC EPEC EIEC EHEC Shigella spp Salmonella spp Campylobacter spp Yersinia enterocolitica Plesiomonas shigelloides

+ + + + + + + + + + + +

– + – – – + + + + + + +

Protozoa Giardia lamblia Cryptosporidium parvum Microsporidia Isospora belli Cyclospora cayetanensis Entamoeba histolytica

+ + + + + +

+ + + + + +

cholera is rapid and extensive dehydration as a result of the massive loss of intestinal fluid. The maximum volume of stool is excreted after 24 hours, which can easily reach 500 to 1,000 mL per hour, resulting in a daily fluid loss of 15 to 20 liters. As a consequence, electrolyte disturbances, hypokalemia, and metabolic acidosis may develop. The clinical signs of severe dehydration include a reduced skin turgor, hoarseness, sunken bulbi, dry mucous membranes, washerwomen’s hands, missing pulses, cold extremities, hypothermia, hypovolemic shock, impaired renal function, and change of consciousness (Figure 10-1). Enterotoxigenic E. coli The most frequently found pathogen in travelers that causes a secretory syndrome is ETEC, which is acquired after ingestion of contaminated food and liquids. The organism passes the acid barrier of the stomach and colonizes the mucosa of the small bowel. It acts through its heat-labile and heatstable enterotoxins, but does not cause any damage to the mucosa, nor is it associated with bacteremia or a systemic illness.8 The incubation period ranges from 24 to 48 hours. The clinical picture is characterized by a distress of the upper intestinal tract, followed by watery diarrhea. Symptoms can be mild with only a few loose stools, but can also reach the severity of cholera, causing life-threatening dehydration, particularly in children. The heat-stable enterotoxin is usually associated with milder forms. ETEC infections are self-limited, lasting for 5 to 10 days.

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Figure 10-1. Child with cholera showing severe symptoms of dehydration.

Viral Gastroenteritis An incubation period of more than 14 hours and a duration of illness of less than 72 hours suggests a viral etiology of gastroenteritis.9 Viral gastroenteritis predominantly causes vomiting and watery diarrhea, as a result of the disruption of the mucosal structure and villous atrophy. In addition, malabsorption may occur and have an additional osmotic effect, contributing to the development of diarrhea. However, the exact pathogenesis of viral gastroenteritis is not known in detail. Rotavirus infections are usually observed in young children aged 3 to 15 months. Adults can acquire the infection from children and usually show milder forms. Travelers may be affected in up to 10% by rotavirus infection.10,11 The incubation period ranges from 1 to 3 days. The clinical picture is characterized by an abrupt onset of nausea and abdominal cramps, followed by watery diarrhea and vomiting. Low-grade fever develops in about half of affected individuals. The duration of symptoms ranges between 5 and 7 days. The Norwalk-like virus causes watery diarrhea in travelers after ingestion of contaminated water, salads, clams, and oysters.12 Typical symptoms include diarrhea (92%), nausea (88%), abdominal cramps (67%), vomiting (66%), and muscle aches (56%). In addition, headache and symptoms of the upper respiratory tract are common. The duration of illness usually does not exceed 24 to 48 hours.

Dysenter y Syndrome Shigellosis The classical Shigella enterocolitis causes a dysentery syndrome. It has frequently been reported in individuals working in refugee camps and institutional settings such as day care centers or prisons, but also occurs in travelers. Outbreaks have been associated with poor hygiene, inadequate water supplies, and crowded living conditions.

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The incubation period ranges from 36 to 72 hours. The clinical picture can vary from mild to severe forms of dysentery with systemic toxicity. The initial phase is characterized by fatigue, anorexia, watery diarrhea, and abdominal cramps. In 40% of cases, the body temperature is elevated, reaching 38° to 40°C. Within 24 hours, the abdominal pain wanders to the lower quadrants and the characteristics of diarrhea changes to multiple small-volume bowel movements. A third of affected individuals show the typical dysentery stool.13,14 Before and after bowel movements, strong tenesmus occurs. The infection is primarily located in the colon, but may spread to the terminal ileum. Endoscopically, the lamina propria of affected areas shows scattered ulcers. Shigella rarely penetrate beyond the intestinal mucosa and do not invade the blood stream. The average duration of symptoms is 7 days, but more severe cases can remain symptomatic for 3 to 4 weeks and are more likely to show a relapse of the infection. Malnutrition and S. dysenteriae type I infections have both been associated with a more severe course of the disease. Shigellosis may be complicated by toxic megacolon, colonic perforation, and large intestinal loss of protein. Extraintestinal manifestations include respiratory symptoms such as cough and coryza, hypoglycemia in children, and, in 18 to 45%, neurological alterations such as encephalitis, lethargy, and seizures. However, there is no evidence of a direct involvement of the central nervous system. Further potential complications include the hemolytic uremic syndrome, thrombocytopenia, and asymmetric arthritis of the larger joints.15 Shigella can persist in stool culture for up to 3 months after the disappearance of clinical symptoms. Chronic carriers, excreting bacteria for more than 1 year, have also been reported.

Overlap Syndrome Many pathogens such as Campylobacter jejuni cause dysentery as well as secretory diarrhea, producing an overlap syndrome. Campylobacter jejuni Campylobacter jejuni infections are acquired after ingestion of contaminated eggs, poultry, milk, or water. A direct contamination from infected animals has also been reported. Infants and immunodeficient patients appear to be particularly susceptible to this infection. A wide spectrum of symptoms is possible, ranging from asymptomatic infection to watery diarrhea or even dysentery.16 The prodromes include malaise, anorexia, headache, and myalgia. After an incubation period of 2 to 4 days, diarrhea and fever are found in 90% of affected individuals, while 70% experience abdominal pain and 50% have bloody stools. The fever can only be low grade or reach up to 40°C. In addition, vomiting may accompany the cardinal symptoms.17-19 The duration of illness usually does not exceed 7 days, but in up to 20% of cases, symptoms may persist for up to 3 weeks.16 In 16%, a prolonged carrier state is observed, lasting for 2 to 10 weeks. Possible complications include gastrointestinal hemorrhage, toxic megacolon, pancreatitis, cholecystitis, mesenteric adenitis, and appendicitis. Extraintestinal manifestations are rare and include osteomyelitis, hemolytic uremic syndrome, meningitis, endocarditis, septic arthritis, or Guillain-Barré syndrome, which is usually observed 1 to 3 weeks after onset of symptoms. Moreover, a reactive arthritis may

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develop, which predominantly affects individuals expressing the major histocompatibility complex HLA-B27. Recurrent infections of Campylobacter gastroenteritis are not uncommon.

Specific Diseases and Organisms Salmonellosis Salmonella infections are acquired after ingestion of contaminated water and uncooked food, especially meat, poultry, eggs, and dairy products. Patients receiving corticosteroid therapy or with AIDS, sickle cell anemia, malaria, leukemia, lymphomas, and other malignancy are at particular risk for Salmonella infections. Nontyphoid Salmonellosis The incubation period of nontyphoid salmonellosis ranges from 6 to 48 hours, but can occasionally reach 7 to 12 days. The initial symptoms are nausea and vomiting, followed by periumbilical abdominal pain, cramps in the right lower quadrant, and diarrhea. The diarrhea is often watery. However, in 50% of cases, a severe dysentery with bloody and purulent feces develops, which is usually accompanied by fever. The diarrhea disappears after 2 to 5 days, but tends to last longer if the colon is affected, frequently persisting for up to 3 weeks.20 Proctoscopy reveals hyperemia, mild edema, granularity, friability, and ulcerations of the mucosa. Potential complications include intestinal bleedings, septicemia, and toxic megacolon.21,22 Persistent fever usually suggests metastatic organ infection. The spectrum of metastatic Salmonella infections includes meningitis, arteritis, endocarditis, osteomyelitis, spondylodiscitis, and septic arthritis. Extraintestinal manifestations have been associated with a high mortality of 50%.23 The carrier rate is 2 to 6 cases per 1,000 infected individuals. Newborns, children, and patients older than 60 years are more likely to become chronic carriers. Enteric Fever Enteric fever is a severe and prolonged systemic illness, usually as a result of S. typhi infection (typhoid fever). The incubation period ranges from 7 to 14 days. The classical clinical course lasts for 4 weeks. In the first stage, patients suffer from unspecific symptoms such as low-grade fever, arthralgia, and headache. The second stage indicates systemic infection. The body temperature rises, reaching up to 40°C, the headaches become more intense, and patients suffer from abdominal pain in the right upper quadrant. Frequently, a relative bradycardia of less than 100 beats per minute is observed despite the high body temperature of 40°C. The abdominal skin may show the classic rash, characterized by light red, pinhead sized nonpruritic spots, known as rose spots. Bowel habits change in 50% of affected individuals, whereby constipation is more common than diarrhea. The size of lymphoid organs such as the spleen and lymph nodes increases due to hyperplasia of the reticuloendothelial system. In severe cases, the patient may enter the typhoidal state, which is characterized by fatigue, apathy, and anorexia. The third stage is characterized by more frequent bowel movements, declining body temperatures, but more intense abdominal pain in the ileocecal region. During this time, the stool resembles a

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greenish pea soup. Peyer’s patches are hyperplastic and may ulcerate. As a consequence, the bowel wall becomes thinner, which occasionally results in colonic perforation. After 6 weeks, 50% of affected individuals still harbor Salmonella in stool. Although this proportion declines to 5 to 10% at 3 to 6 months, 1 to 3% remain chronic carriers of Salmonella.24 Common intestinal complications include bleeding (20 to 25% of cases) and perforation (5%), both of which are usually noted in the third week. Systemic complications of typhoid fever include pneumonia, pleuritis, pyelonephritis, bone and joint infections, brain abscesses, necrotic cholecystitis, thromboembolic events, endocarditis, arteritis, and liver abscesses. Yersinia enterocolitica Yersinia enterocolitica infections have been described after ingestion of contaminated ice cream, milk, meat, and shellfish. In addition, person-to-person transmission has been reported. Yersinia enterocolitica is also found in freshwater streams as well as in lakes and has been isolated from a number of animals including puppies, cats, cows, chickens, and horses. The clinical course and severity depend on age and concomitant medical conditions. Acute enterocolitis is the most common manifestation found in two-thirds of patients. It frequently affects children under the age of 5 years. Typical symptoms include abdominal cramps (84%), watery or bloody diarrhea (75%), fever (43%), nausea (13%), and vomiting (8%).25-27 In older children and young adults, aphtous mouth ulcers, mesenteric adenitis, and terminal ileitis are common, often mimicking acute appendicitis. Symptoms disappear after 1 to 4 weeks, but can occasionally last longer. Postinfectious complications occur in 1 to 5% of patients and include myocarditis, glomerulonephritis, erythema nodosum (6%), and ankylosing spondylitis. Reactive arthritis or Reiter’s syndrome are found in 2 to 6% of cases and are associated with the major histocompatibility antigen HLA-B27. Yersinia bacteremia is uncommon, but may occasionally occur in patients with neoplasia, diabetes, anemia, or chronic liver disease. Metastatic infections have also been noted including osteomyelitis, endocarditis, meningitis, cutaneous infections, arthritis, pneumonia, and abscesses of the liver, kidney, spleen, and lung. Clostridium difficile Clostridium difficile is the major cause of antibiotic associated diarrhea and occasionally affects travelers. Antibiotics disrupt the normal bacterial flora and allow an overgrowth with Clostridium difficile, which may result in pseudomembranous colitis. Signs of pseudomembranous colitis are usually observed 4 to 9 days after initiation of antibiotics.28,29 The clinical symptoms vary from mild to severe diarrhea with more than 20 bowel movements per day.30 The stool is profuse, watery, and may occasionally contain blood and mucus.31 In addition, abdominal cramps and signs of systemic toxicity such as fever, anorexia, and malaise are observed.30,32 Proctoscopically, small 1 to 5 mm raised, whitish-yellow plaques or “pseudomembranes” are found without evidence of ulcers or erosions. Fulminant colitis develops in 1 to 3% of patients and may be complicated by toxic megacolon, bowel perforation, or death.33 Extraintestinal spread is rare, but can result in bacteremia, septic arthritis, and splenic abscesses.

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Enterohemorrhagic E. coli Enterohemorrhagic E. coli (EHEC) infections have been associated with the ingestion of contaminated hamburgers, milk, water, fruit, and vegetables.34,35 However, person-to-person transmission is possible. The clinical spectrum includes bloody or nonbloody diarrhea, abdominal cramps, nausea, vomiting, low-grade fever, and chills. Endoscopy usually reveals an inflamed mucosa with patchy erythema and submucosal edema in the ascending and transverse colon. The duration of uncomplicated illness ranges from 1 to 12 days. The development of fever, leukocytosis, and the decline in platelet count indicates the emergence of complications such as the hemolytic uremic syndrome (HUS) or thrombotic-thrombocytopenic purpura. HUS complicates 2 to 7% of EHEC infections, affecting mainly children younger than 5 years and elderly individuals. It was first described in two separate outbreaks in Michigan and Oregon in 1982 and has been associated with E. coli serotype O157:H7.36 HUS manifests itself 2 to 16 days after onset of gastrointestinal symptoms and is initially characterized by severe abdominal cramps and nonbloody diarrhea, which may become grossly bloody by the second and third days of illness. Half of the patients suffer from nausea and vomiting. In addition, low-grade fever may be present. The characteristic findings in the laboratory are microangiopathic hemolytic anemia, thrombocytopenia, and renal failure.37 In addition, neurologic complications develop in a quarter of patients, including seizures, coma, and hemiparesis. Half of the patients require dialysis due to progressive renal failure. In 75% of affected individuals, hemolysis reaches a level of severity that causes a rapid decline in hematocrit of more than 10% within 24 hours, urging the need for red cell transfusions. Hyperkalemia does not usually evolve, because of the concomitant gastrointestinal loss of potassium. The mortality reaches 3 to 5%, but higher rates of 16 to 35% have been reported in specific populations such as individuals in nursing homes. Vibrio parahaemolyticus V. parahaemolyticus is a common pathogen in countries where raw and undercooked seafood is consumed. In 90% of cases, explosive watery diarrhea is the cardinal symptom, which is accompanied by abdominal cramps, nausea, vomiting, and headache. Fever and chills occur in 25% of patients. Occasionally, patients present with a dysentery syndrome. Although hypotension and shock have been reported, these complications are rare and less severe than in patients with cholera. The duration of illness is short, ranging from 2 hours to 10 days. A carrier state is unknown. Cryptosporidia Cryptosporidium parvum is transmitted via the fecal–oral route, close contacts to animals or pets, and the ingestion of contaminated drinking water or food.38,39 A small number of 10 oocysts suffices for symptomatic infection in humans. After a short incubation period of 1 to 2 weeks, watery stools, abdominal pain and cramps, vomiting, fatigue, flatulence, general malaise, anorexia, nausea, and weight loss are observed. Fever is

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uncommon. Extraintestinal manifestations include acalculous cholecystitis and cholangitis. The illness is usually self-limited, but can last for 1 to 2 weeks. Isospora belli Isospora belli is endemic in tropical and subtropical areas. Transmission most likely occurs via contaminated water. The clinical features of I. belli infections include abdominal cramps, nausea, watery diarrhea, steatorrhea, headache, fever, malaise, vomiting, and occasionally eosinophilia. In the immunodeficient host, prolonged diarrhea, the dissemination of bacteria to mesenteric lymph nodes, and acalculous cholecystitis have been reported. The illness is usually self-limited. Cyclospora cayetanensis Cyclospora cayetanensis was previously referred to as Cyanobacteria-like pathogen. The transmission occurs via contaminated water and food.40 Outbreaks have also been traced back to the ingestion of raspberries.41 After an average incubation period of 7 days, affected individuals suffer from watery diarrhea, abdominal cramps, weight loss, nausea, vomiting, fatigue, muscle aches, and occasionally fever. Generally, the infection is self-limited, but can last for 6 to 12 weeks.42

CHRONIC DIARRHEA Chronic infectious diarrhea affects 0 to 12% of patients with travelers’ diarrhea and is mainly the result of parasitic infection. The pathogens most commonly detected are Giardia lamblia (1 to 12%), Entamoeba histolytica (2 to 11%), and Microsporidia. The main features are soft stools or watery diarrhea. A dysentery-like syndrome is occasionally observed in individuals with Entamoeba histolytica infections.

Giardia lamblia Giardia lamblia infects humans as well as animals. The ingestion of a small number of 10 to 100 cysts can either result in asymptomatic infection, in an acute self-limited diarrhea, or in a long-lasting intermittent diarrhea. After an incubation period of 1 to 2 weeks, a nonwatery, greasy, foul-smelling diarrhea without blood, abdominal cramps, nausea, vomiting, fever, and malaise are observed. Although acute symptoms disappear within 1 to 2 weeks, milder symptoms can persist, such as irregular bowel movements, soft stools, and flatulence. In addition, malabsorption, fatigue, anorexia, nausea, flatulence, weight loss, and large amounts of greasy stool are common. Extraintestinal manifestations are rare and include maculopapular rash, urticaria, polyarthritis, aphthous ulceration, and eosinophilia.

Entamoeba histolytica Entamoeba histolytica infections are highly prevalent in Mexico, India, Africa, and Central and South America. Individuals at highest risk are migrant workers in developing countries. The major routes of transmission are the consumption of contaminated water and food as well as direct fecal–oral contact. In addition, Entamoeba histolytica can be transmitted sexually.

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E. histolytica infections are symptomatic in 80 to 90% of cases and usually cause only mild symptoms. The incubation period is variable and ranges from 1 to 3 weeks. The number of bowel movements can be normal or can reach six or more stools per day. In addition, abdominal cramps in the right or left lower abdominal quadrant occur, independently of bowel movements. Two to 20% of affected individuals show an invasive form of the disease and suffer from severe dysentery with frequent small volumes of bloody mucoid stool. Endoscopy usually reveals ulcerations of the mucosa of the colon and typical flask-shaped abscesses. Occasionally, the formation of an inflammatory mass of the intestinal wall, called ameboma, can be found. Liver abscess is a typical complication of E. histolytica infection. Signs of liver involvement include anemia, fatigue, abdominal pain, jaundice, fever, and elevated liver function tests. Other complications include splenic abscess, brain abscess, empyema, and pericarditis.43 Individuals treated with corticosteroids are at increased risk for intestinal complications such as toxic megacolon and bowel perforation.

Microsporidia Microsporidia have sporadically been reported to be responsible for chronic diarrhea in travelers. Microsporidia are small intracellular parasites and are more commonly detected in immunodeficient individuals, particularly in HIV-1 infected patients. In humans, two species are associated with enteric infection including Enterocytozoon bieneusi and Encephalitozoon intestinalis. E. bieneusi infects enterocytes of the proximal jejunum and occasionally migrates to the biliary tract. E. intestinalis is located in enterocytes, macrophages, and fibroblasts, and is found in kidneys and mesenteric lymph nodes. The symptoms are usually watery diarrhea without abdominal pain, malabsorption, and weight loss. Complications include keratoconjunctivitis, sinusitis, peribronchitis, and myositis.

SPECIAL CONSIDERATIONS The normal enteric microflora plays an important role in reducing the number of intestinal pathogens. Alterations of the normal microflora allow an overgrowth with pathogenic organisms such as Pseudomonas, Klebsiella, Clostridium, and Candida. Infant botulism, nosocomial salmonellosis, and EPEC occur with increased frequency in newborns, who have not yet acquired the normal enteric microflora. Whether a person acquires a gastrointestinal infection largely depends on the inoculum size. A number of 100,000 to 100,000,000 pathogens are usually necessary to defeat the gastric barrier and the host’s immune response. However, Shigella and certain parasites such as Cryptosporidia can cause gastrointestinal infection after transmission of a small number of 10 to 100 organisms. The neutralization of gastric acid with antacids or proton blocking agents drastically reduces the number of organisms required for gastrointestinal infection.44 The reduction in gut motility increases the risk of bacterial overgrowth and toxic megacolon. Salmonella bacteremia is more likely to develop in patients who are treated with opiates.45 The use of antimotility drugs has also been associated with prolonged fever, reduced effectiveness of antibiotics, and a longer bacterial shedding in patients with Shigella infections.46 In addition, several case reports

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suggest that complications of Campylobacter and C. difficile infections occur more frequently when using antimotility agents.47 These drugs also appear to favor the development of HUS in patients with EHEC infections.48 Alterations of the immune system increase the risk of gastrointestinal infections. The lack of a sufficient number of neutrophils is associated with a defect in phagocytic activity, increasing the likelihood of gram-negative infections.49 Patients with advanced HIV-1 infection are particularly susceptible to Salmonella, Shigella, Cryptosporidia, Microsporidia, Mycobacteria, and Isospora belli infections. The host’s genotype may also be of importance. Individuals with blood group O appear to be more susceptible to cholera. In contrast, persons with blood group A are more likely to acquire G. lamblia infections.50,51 Young and old age represent further risk factors. Rotavirus infection and enteropathogenic E. coli (EPEC) predominantly affect young children, due probably to differences in gut mucus, cell-surface factors, microbial flora, and the expression of intestinal receptors for bacteria. Lew and colleagues reviewed 28,538 deaths due to infectious diarrhea and found that 51% were older than 74 years, indicating that elderly patients are more susceptible to serious complications of infectious diarrhea.52

DIFFERENTIAL DIAGNOSIS A number of noninfectious causes of diarrhea have to be considered in the differential diagnosis, including irritable bowel syndrome, inflammatory and ischemic bowel diseases, laxative abuse, Whipple’s disease, diverticulitis, appendicitis, adnexitis, celiac sprue, malabsorption, and diabetes. Travelers’ diarrhea may occasionally mask a more serious disease such as intestinal malignancy. In travelers returning from tropical areas, other systemic infections such as malaria should be considered in the differential diagnosis.

REFERENCES 1. Merson MH, Morris GK, Sack DA, et al. Travelers’ diarrhea in Mexico. A prospective study of physicians and family members attending a congress. N Engl J Med 1976;294:1299–305. 2. Sack RB. The epidemiology of diarrhea due to enterotoxigenic Escherichia coli. J Infect Dis 1978;137:639–40. 3. Baqui AH, Black RE, Yunus M, et al. Methodological issues in diarrhoeal diseases epidemiology: definition of diarrhoeal episodes. Int J Epidemiol 1991;20:1057–63. 4. Sugiyama H, Hayama T. Abdominal viscera as site of emetic action for staphylococcal enterotoxin in the monkey. J Infect Dis 1965;115:330–6. 5. Dupont HL, Haynes GA, Pickering LK, et al. Diarrhea of travelers to Mexico. Relative susceptibility of United States and Latin American students attending a Mexican university. Am J Epidemiol 1977;105:37–41. 6. Ericsson CD. Travelers’ diarrhea. Epidemiology, prevention, and self-treatment. Infect Dis Clin North Am 1998;12:285–303.

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7. Taylor DN, Echeverria P, Blaser MJ, et al. Polymicrobial aetiology of travelers’ diarrhoea. Lancet 1985;1:381–3. 8. Levine MM, Ferreccio C, Prado V, et al. Epidemiologic studies of Escherichia coli diarrheal infections in a low socioeconomic level peri-urban community in Santiago, Chile. Am J Epidemiol 1993;138:849–69. 9. DuPont HL. Guidelines on acute infectious diarrhea in adults. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 1997;92:1962–75. 10. DuPont HL, Ericsson CD. Prevention and treatment of travelers’ diarrhea. N Engl J Med 1993;328:1821–7. 11. Ryder RW, Oquist CA, Greenberg H, et al. Travelers’ diarrhea in Panamanian tourists in Mexico. J Infect Dis 1981;144:442–8. 12. Johnson PC, Hoy J, Mathewson JJ, et al. Occurrence of Norwalk virus infections among adults in Mexico. J Infect Dis 1990;162:389–93. 13. Gots RE, Formal SB, Giannella RA. Indomethacin inhibition of Salmonella typhimurium, Shigella flexneri, and cholera-mediated rabbit ileal secretion. J Infect Dis 1974;130:280–4. 14. DuPont HL, Hornick RB, Dawkins AT, et al. The response of man to virulent Shigella flexneri 2a. J Infect Dis 1969;119:296–9. 15. Barrett-Connor E, Connor JD. Extraintestinal manifestations of shigellosis. Am J Gastroenterol 1970;53:234–45. 16. Allos BM, Blaser MJ. Campylobacter jejuni and the expanding spectrum of related infections. Clin Infect Dis 1995;20:1092–9. 17. Blaser MJ, Wells JG, Feldman RA, et al. Campylobacter enteritis in the United States. A multicenter study. Ann Intern Med 1983;98:360–5. 18. Blaser MJ, Berkowitz ID, LaForce FM, et al. Campylobacter enteritis: clinical and epidemiologic features. Ann Intern Med 1979;91:179–85. 19. Lambert ME, Schofield PF, Ironside AG, Mandal BK. Campylobacter colitis. Br Med J 1979;1:857–9. 20. Mandal BK, Mani V. Colonic involvement in salmonellosis. Lancet 1976;1:887–8. 21. Bellary SV, Isaacs P. Toxic megacolon (TM) due to Salmonella. J Clin Gastroenterol 1990;12:605–7. 22. Deppisch LM, Crans CA. Salmonellosis: a cause of toxic megacolon. J Clin Gastroenterol 1990;12:483–5. 23. Cohen JI, Bartlett JA, Corey GR. Extra-intestinal manifestations of Salmonella infections. Medicine (Baltimore) 1987;66:349–88. 24. Kaye D, Merselis JG Jr, Connolly S, Hook EW. Treatment of chronic enteric carriers of Salmonella typhosa with ampicillin. Ann N Y Acad Sci 1967;145:429–35. 25. Lee LA, Gerber AR, Lonsway DR, et al. Yersinia enterocolitica O:3 infections in infants and children, associated with the household preparation of chitterlings. N Engl J Med 1990;322:984–7. 26. Vantrappen G, Ponette E, Geboes K, Bertrand P. Yersinia enteritis and enterocolitis: gastroenterological aspects. Gastroenterology 1977;72:220–7. 27. Vantrappen G, Geboes K, Ponette E. Yersinia enteritis. Med Clin North Am 1982;66:639–53. 28. Samore MH, DeGirolami PC, Tlucko A, et al. Clostridium difficile colonization and diarrhea at a tertiary care hospital. Clin Infect Dis 1994;18:181–7. 29. Johnson S, Clabots CR, Linn FV, et al. Nosocomial Clostridium difficile colonisation and disease. Lancet 1990;336:97–100. 30. Kelly CP, Pothoulakis C, LaMont JT. Clostridium difficile colitis. N Engl J Med 1994;330:257–62. 31. Spencer RC. The role of antimicrobial agents in the aetiology of Clostridium difficile-associated disease. J Antimicrob Chemother 1998;41 Suppl C:21–7.

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32. Gerding DN, Olson MM, Peterson LR, et al. Clostridium difficile-associated diarrhea and colitis in adults. A prospective case-controlled epidemiologic study. Arch Intern Med 1986;146:95–100. 33. Fekety R, Silva J, Kauffman C, et al. Treatment of antibiotic-associated Clostridium difficile colitis with oral vancomycin: comparison of two dosage regimens. Am J Med 1989;86:15–9. 34. Swerdlow DL, Woodruff BA, Brady RC, et al. A waterborne outbreak in Missouri of Escherichia coli O157:H7 associated with bloody diarrhea and death. Ann Intern Med 1992;117:812–9. 35. Spika JS, Parsons JE, Nordenberg D, et al. Hemolytic uremic syndrome and diarrhea associated with Escherichia coli O157:H7 in a day care center. J Pediatr 1986;109:287–91. 36. Riley LW, Remis RS, Helgerson SD, et al. Hemorrhagic colitis associated with a rare Escherichia coli serotype. N Engl J Med 1983;308:681–5. 37. Neill MA, Tarr PI, Clausen CR, et al. Escherichia coli O157:H7 as the predominant pathogen associated with the hemolytic uremic syndrome: a prospective study in the Pacific Northwest. Pediatrics 1987;80:37–40. 38. Deneen VC, Belle-Isle PH, Taylor CM, et al. Outbreak of cryptosporidiosis associated with a water sprinkler fountain–Minnesota, 1997. MMWR Morb Mortal Wkly Rep 1998;47:856–60. 39. Quinn K, Baldwin G, Stepak P, et al. Foodborne outbreak of cryptosporidiosis–Spokane, Washington, 1997. MMWR Morb Mortal Wkly Rep 1998;47:565–7. 40. Sturbaum GD, Ortega YR, Gilman RH, et al. Detection of Cyclospora cayetanensis in wastewater. Appl Environ Microbiol 1998;64:2284–6. 41. Herwaldt BL, Beach MJ. The return of Cyclospora in 1997: another outbreak of cyclosporiasis in North America associated with imported raspberries. Cyclospora Working Group. Ann Intern Med 1999;130:210–20. 42. Huang P, Weber JT, Sosin DM, et al. The first reported outbreak of diarrheal illness associated with Cyclospora in the United States. Ann Intern Med 1995;123:409–14. 43. Petri WA Jr. Recent advances in amebiasis. Crit Rev Clin Lab Sci 1996;33:1–37. 44. Hornick RB, Music SI, Wenzel R, et al. The Broad Street pump revisited: response of volunteers to ingested cholera vibrios. Bull N Y Acad Med 1971;47:1181–91. 45. Sprinz H. Pathogenesis of intestinal infections. Arch Pathol 1969;87:556–62. 46. DuPont HL, Hornick RB. Adverse effect of lomotil therapy in shigellosis. J Am Med Assoc 1973;226:1525–8. 47. Smith GS, Blaser MJ. Fatalities associated with Campylobacter jejuni infections. J Am Med Assoc 1985;253:2873–5. 48. Slutsker L, Ries AA, Greene KD, et al. Escherichia coli O157:H7 diarrhea in the United States: clinical and epidemiologic features. Ann Intern Med 1997;126:505–13. 49. Bodey GP, Buckley M, Sathe YS, Freireich EJ. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 1966;64:328–40. 50. Levine MM, Nalin DR, Rennels MB, et al. Genetic susceptibility to cholera. Ann Hum Biol 1979;6:369–74. 51. Zisman M. Blood-group A and giardiasis. Lancet 1977;2:1285. 52. Lew JF, Glass RI, Gangarosa RE, et al. Diarrheal deaths in the United States, 1979 through 1987. A special problem for the elderly. J Am Med Assoc 1991;265:3280–4.

Par t T hree

Prevention

Chapter 11

DIET

AND

E D U C AT I O N

ABOUT

RISKS

David R. Hill, MD, DTMH, and Frank von Sonnenburg, MD, MPH

“Boil it, cook it, peel it, or forget it.” This is the mantra of travel medicine specialists and all others who advise travelers about trying to avoid diarrhea during travel.1-3 Of the three potential modes of prevention, namely, dietary avoidance measures, chemoprophylaxis (either antibiotics or nonantimicrobial products), and immunoprophylaxis, care in food and liquid selection is the one that is universally accepted. Antibiotic prophylaxis is not recommended for most travelers, and except for some cross protection with the whole cell inactivated cholera vaccine against heat-labile (LT) toxinproducing Escherichia coli, immunoprophylaxis is not currently available.1,4 Although most people agree upon the importance of diet during travel, others, including some health care providers, feel that sampling the local diet is part of the pleasure of international travel. Each traveler will need to decide how motivated or able he or she is to follow the recommendations outlined in this chapter. This decision is likely to be based upon their willingness to accept a risk of diarrhea and how much their underlying health or travel plans will be affected by a diarrheal illness. Diet is not the only determinate for acquiring travelers’ diarrhea; several other risk factors are discussed in other sections of this book. These include the age and host characteristics of the traveler; the destination, duration, and season of travel; type of accommodation; and a history of previous travel or residence in developing regions. This chapter will focus on the role of diet in causing travelers’ diarrhea. Three essential questions arise when considering diet and education: • Which foods and liquids should be avoided? • Does avoidance decrease risk of diarrhea? • Do (can) travelers comply with avoidance measures?

THE RISK FROM FOOD AND LIQUIDS It was not until the early to mid-1970s, after enterotoxin-producing Escherichia coli were associated with the diarrhea of travelers to Mexico, that excellent epidemiologic studies on risk items and behavior were initiated.5-7 Some risk items have been identified by formal epidemiologic studies, some by culture, and others because of the pervasive opinion that poor sanitation in developing regions leads to near universal contamination of foods and water with enteric flora. The focus has also been on items that carry the most frequently implicated agents associated with travelers’ diarrhea: enterotoxigenic (ETEC), enteroaggregative, and other E. coli; Shigella spp; Salmonella enteritidis; Campylobacter; enteric viruses such as Norwalk-like viruses and rotavirus; and the protozoan parasites Giardia, Cryptosporidium, and Cyclospora. Measures taken to avoid these organisms will also help to

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prevent other less common but enterically transmitted microbes such as hepatitis A and E, Salmonella typhi and paratyphi, Brucella, intestinal nematodes such as ascaris and whipworm (Trichuris trichiura), tissue nematodes (eg, Trichinella), adult tapeworm infections (eg, Taenia solium and saginata), and the larval cestode infection, cysticercosis. Therefore, care in food and liquid selection should help to maintain the overall health of travelers. Table 11-1 lists items that have been implicated as a risk for travelers’ diarrhea, and therefore, should be avoided.

Food There are several stages during which food can become contaminated with enteric organisms of human or animal origin. Contamination may occur when leafy greens and vegetables are fertilized with “night soil” or when crops are watered with polluted water. Fruits such as strawberries and raspberries may be especially difficult to wash if they become contaminated, and others such as melons may have been injected with contaminated water to increase their weight.8 Products that are sold in a market can become contaminated if they lie on the market floor, are exposed to flies, or are handled by unsanitary fingers. Improper storage (ie, inadequate refrigeration) can lead to bacterial overgrowth in contaminated foods. Some sauces and toppings that use eggs or cream may not be pasteurized. If foods are insufficiently cooked or reheated prior to serving, any previous contamination will not be eliminated. Finally, foods may become contaminated if prepared by infected food handlers. Other agents are not strictly associated with travelers’ diarrhea; nevertheless, they are acquired following ingestion of undercooked fish, crustaceans, and meats. These foods may carry the intermediate lifecycle forms of Diphyllobothrium, Paragonimus, Clonorchis, Taenia, Trichinella, or the dormant cysts of Toxoplasma gondii. Shellfish may be contaminated with hepatitis A virus or vibrios if it has been harvested from polluted waters. Although ciguatera toxin poisoning is not an infectious disease,

Table 11-1. Dietary Items to Avoid During Travel Raw or undercooked meats, fish, or seafood Raw, ground grown vegetables and leafy greens (salads) Unpasteurized dairy products such as milk, custard, cream, ice cream, butter, cheese Foods containing raw or undercooked eggs Tap water and ice Noncarbonated bottled water Fruits that have been peeled (not by the traveler) Fruit juices Cold sauces and toppings such as mayonnaise, guacamole, spicy sauces Buffet food that has sat at room temperature for several hours Food that requires cold storage and then reheating Food that is served by street vendors

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it is acquired through ingestion of large reef fish (eg, barracuda, snapper, amberjack, sea bass, and grouper) in the Caribbean and South Pacific regions. Cooking will not destroy the heat-stable toxin, therefore, travelers should be aware of the potential risk from these fish. Other seafood toxins (eg, scromboid and puffer fish) may also be a risk. Food is most frequently implicated in the transmission of bacterial pathogens.9-11 A large body of literature that describes the risk, pathogens, and pattern of diarrhea came from the study of travelers to Mexico in the mid- and late 1970s. Although much of the early epidemiologic work defining this risk was done in Mexico, the findings from these studies are applicable throughout developing regions. In addition, regardless of whether a particular region is designated as high, moderate, or low risk for travelers’ diarrhea, nearly every country in the world will have areas where food and liquid sanitation may pose a risk to the traveler. The experience with foodborne outbreaks of enteric illness in the United States involving Listeria, Shiga toxin-producing E. coli, hepatitis A, and Cyclospora emphasizes this point.12 Therefore, all travelers should be thoroughly educated about food and liquid hygiene. A hierarchy has been established for the risk of diarrhea from eating in different settings. Tjoa and colleagues studied students newly arrived in Mexico and demonstrated that eating from street vendors carried the highest risk.10 In Guatemala, street vendor food and liquids were implicated in contributing to the spread of cholera in the early 1990s.13 In the study by Tjoa and colleagues, the next level of risk was eating in public restaurants and/or a school cafeteria; the lowest risk for diarrhea was eating in private homes. Nevertheless, depending upon the setting, foods taken in private homes may still be a source of diarrhea-producing organisms, and eating from street venders may not necessarily increase risk.11,14 Food items that cultured positive for enteric pathogens included watermelons (possibly injected with contaminated water), hamburger, mushrooms, dairy products, and ice that had been stored in an open market. 10 Even some cooked foods that may not have been served promptly after cooking, properly refrigerated, or sufficiently reheated were positive on culture. This data on risk was confirmed in a subsequent study, also carried out on students in Guadalajara, Mexico.15 In a prospective study of Peace Corps volunteers in Guatemala, there were several actions that correlated with an increased risk of diarrhea. These included eating in the home of a Guatemalan or in a small restaurant, eating fruit already peeled (not by the volunteer), eating ice cream, drinking water from an unknown source, and drinking iced beverages.16 For expatriates in Nepal, risk factors included eating in restaurants, eating restaurant take-out food that required reheating (such as quiche, lasagna, or casseroles), and drinking blended fruit drinks.17 Other food items that were implicated were salads, raw vegetables, and popular hot sauces (guacamole, green and red sauces) used in restaurants.7,18 In the study of Adachi and colleagues, even a low pH did not inhibit growth of diarrhea-producing E. coli.18 Environmental sources may contribute to diarrhea when there are conditions of crowding or high population densities and extensive contamination. This has occurred on cruise ships, as highlighted by recurrent outbreaks of Norwalk-like viral infection.19,20 In these cases, it is important to exercise strict hand-washing to prevent acquisition of the virus from environmental sources.

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Water and Other Liquids Although food has been documented to be the major source of pathogenic enteric organisms, water has also been suggested or implicated.16,21-23 It is likely that water is less frequently a vehicle for typical travelers’ diarrhea because many of the common bacterial pathogens, such as ETEC and Salmonella, require a large inoculum to establish infection. Unless the water is heavily contaminated, or has been contaminated with a small number of bacteria and left standing, such as in a holding tank or a homemade storage vessel, there will usually be dilution of the inoculum. Also, if a traveler has normal gastric acid, then the risk of a small inoculum, as may occur during teeth brushing, should not be enough to establish infection. If the water is frozen, the bacteria may be preserved, but there will be no multiplication. The most common causes of waterborne outbreaks of diarrheal illness in the United States (from water either intended for drinking or for recreation) are Giardia, Cryptosporidium, Shigella, E. coli O157:H7 (Shiga toxin-producing), and enteric viruses.24 Common to these agents is that they require a much lower inoculum to establish infection (often only one or two logs), and for the parasites and enteric viruses, they are relatively resistant to halogenation. In addition, Giardia cysts can survive in cold water for weeks.25 In areas such as Mexico, where ETEC predominates in the summer months, water was not seen to be an additional risk factor in early studies.7 Nevertheless, water has been associated with diarrhea in other studies, and if one shifts the focus of study from the summer season in Mexico to the winter months, then water has been associated with risk.16,22,23,26 In the study by Ericsson and colleagues, it was postulated that enteric viruses contributed to diarrhea and were waterborne.22 This would be consistent with the finding of decreased clearance of enteric viruses by water treatment plants and the more frequent contamination of samples during the winter months in Guadalajara.27 Water may be contaminated at its source, particularly if surface water is used. Municipal water supplies are often adequately chlorinated, but the water becomes contaminated following distribution and storage. This was found to be the case with water used by street vendors for making various drinks and fruit beverages; it was generally coliform-free at the source, but became contaminated as it was handled to prepare the drinks.28 Water can be a source of diarrhea on cruise ships that obtain water in foreign ports and do not adequately purify it.29 During the rainy season in many countries, flooding may wash ground contamination into surface water supplies or flood wells, leading to an increased incidence of diarrhea. The rainy season is also the period when diseases that require contact with contaminated water, such as leptospirosis, can be seen.30 The relative chlorine resistance of Cryptosporidium and Giardia can lead to diarrhea acquired during recreational activities such as swimming in fecally contaminated swimming pools or freshwater lakes.24 In addition to microbial contamination, water may contain chemical or other inorganic and organic substances such as arsenic, lead, and benzene, or herbicides and pesticides that might not be removed by routine treatment methods. Pathogenic enteric bacteria (ETEC, Salmonella, and Shigella) can survive in ice and multiply if the ice is placed in drinks with less than 80 proof alcohol.31 The viability of the bacteria declines if the

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ice remains frozen for more than 24 hours. If the ice has surface contamination, as may occur when a block has been left standing outside a restaurant, it can be a direct vehicle for transmission of enteric agents. What about bottled water and other beverages? The standards for purification of bottled water are not uniform, and thus noncarbonated bottled water, even if sealed, could potentially be contaminated.32 One investigation even documented Norwalk-like viral sequences in three brands of European mineral water for up to a year following bottling.33 The act of carbonation, probably by lowering the pH, should render carbonated bottled water safe. When a large inoculum of Salmonella, Shigella, or E. coli (2
106/mL) was added to different beverages (sour mix, cola, and beer) with an acidic pH, they all survived poorly at 48 hours.34 It appeared that the low pH was the common factor for poor survival since none of the bacteria would multiply in growth medium that had been rendered acidic. There were no bacteria recovered at 4 hours in wine. Milk and water supported growth.

DO AVOIDANCE MEASURES DECREASE RISK? It makes intuitive sense that being careful about food and liquids during travel should decrease the incidence of diarrhea. Several studies on travelers’ diarrhea have examined this directly or indirectly, and concluded that avoidance measures are not always associated with decreased risk.9,14,35-40 However, many of these studies are retrospective and rely upon recall of behavior rather than prospective recording of actions taken during travel. In one of the earliest studies to address this question, individuals who attended a congress in Mexico City, and who avoided salads, raw vegetables, peeled fruit, or untreated water, had the same incidence of diarrhea as those who did not practice any precautions.35 In another study from Mexico, only the ingestion of salads with raw vegetables was associated with diarrhea, and drinking untreated water or eating unpeeled fruits was not a risk for infection.7 For Finnish travelers to Morocco who made frequent dietary mistakes, there was a similar number of travelers with and without diarrhea who made the same errors.37 In a study of more than 16,000 predominantly Swiss travelers who visited multiple destinations, those who took at least three of the standard precautions actually had a slight, but increased risk of diarrhea.38 Visitors to Jamaica who ate meals outside of their tourist hotel had the same risk of diarrhea compared with those who took their meals in the hotels.39 Thirty-four percent of nearly 800 American travelers to many world destinations, who were provided both verbal and written pretravel information on avoidance measures, had moderate to severe travelers’ diarrhea, and another 11% had mild diarrhea.40 On the other hand, a prospective study of charter holiday tourists to Sri Lanka, and East or West Africa, who recorded in detail their dietary habits for the first few days of travel, documented that the more dietary mistakes committed, the higher the incidence of diarrhea.41 In a prospective study of Peace Corps volunteers that covered their entire service in Guatemala, several dietary errors were independently associated with an increased risk of diarrheal illness: water from an unknown source, eating in the home of a Guatemalan friend or family, eating in a small restaurant, eating peeled fruit, drinking iced beverages, eating ice cream, and traveling (and presumably eating) outside the area of residence.16 Therefore, if one was able to avoid the risk behavior, one had a lower incidence of diarrhea. Visitors to Jamaica, who stayed with family and friends and ate in their homes, had less diar-

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rhea compared with other visitors to the island.39 Students in Mexico, who were careful about water and ice consumption, had lower rates of diarrhea compared to newly arrived students who did not exercise these precautions.22 In retrospect, it appears that it is difficult to avoid diarrhea even if one is informed and careful. Thus, although the risk behaviors are identified, avoiding them does not guarantee a trip free from diarrhea. It is likely that the failure to decrease the incidence of diarrhea is secondary to widespread contamination of multiple food and drink items, not just those items that have been surveyed in published studies. How can one explain the occurrence of high rates of diarrhea despite adequate pretravel education? One possibility is that short-term travelers who receive advice before their trip tend to travel to higher risk destinations. This was documented in a retrospective study of British travelers.42 These findings do not imply that travelers should ignore the advice of “boil it, cook it, peel it, or forget it.” However, they should travel with the knowledge that preventive measures may not be effective, and be prepared to deal with diarrhea if it occurs.

DO (CAN) TRAVELERS PRACTISE AVOIDANCE MEASURES DURING TRAVEL? The information on whether or not travelers practise avoidance measures during travel is less encouraging. Whether intentionally or not, most travelers find it difficult to meticulously practise avoidance measures. In the previously quoted study on charter tourists to Sri Lanka or East or West Africa, 98% made at least one error in the first 72 hours.41 It was not known how many of these travelers had been counseled in care about foods and liquids. In a multicenter study of approximately 67,000 travelers to India, Kenya, Jamaica, and Brazil, more than 96% did not completely follow preventive measures.43 However, travelers to areas considered a higher risk for travelers’ diarrhea (eg, Kenya and India) did practise more preventive measures than those who traveled to areas perceived as a lower risk (eg, Jamaica and Brazil). Even travelers to Jamaica who received health advice did not always practise avoidance measures.39 Ninety-five percent of Finnish travelers to Morocco made a dietary error.37 In this same group, if a person had traveled overseas before, then there was an increased likelihood of eating potentially contaminated food items; those who traveled in the previous 12 months were more likely to make dietary errors than those who had not.37 On the other hand, in two studies of UK travelers, those who had sought pretravel advice worried more about food and liquid hygiene, or practised more preventive measures; however, their risk of diarrhea remained high.42,44 What about diarrhea in long-term travelers and expatriates? Do they need to continue to practise care in their dietary habits? There is conflicting information on whether the risk of travelers’ diarrhea decreases with increasing duration of residence in a developing region. In a study of American students in Puebla, Mexico, the incidence of diarrhea was 40% in those who were newly arrived compared with 20% in those who were living there year round.45 Additional episodes of diarrhea were also more common in new students (15% vs 4%). This finding was confirmed in a later study of American students in Guadalajara, Mexico.22 The decreased incidence of diarrhea suggested that partial immunity was developed to the etiologic agents. In support of this was the finding of elevated titers

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of anti-E. coli LT toxin antibody in year-round students.46 However, it may also be that long-term residents of endemic areas learn behaviors that allow them to remain well. This seemed to be the case with the follow-up study of students in Mexico, in whom a lower rate of diarrhea in the winter months correlated with decreased consumption of tap water and unsafe ice.22 In long-term residents of Kathmandu, Nepal, there remained a high risk of diarrhea—3.2 episodes of diarrhea per person per year.47 This was in an area where there was a wide variety of pathogens: E. coli (42% of persons affected), Cyclospora (32%), Giardia (16%), Shigella (16%), Campylobacter (10%), rotavirus (≥10%), and Entamoeba (6%). Only for ETEC did the incidence decrease with increasing duration of residence. In Peace Corps volunteers in Guatemala, the risk for all episodes of diarrhea decreased slightly over time, even though risk behavior remained about the same.16 However, the median time to acquisition of a parasite was 187 days (range, 14 to 7,452 days), indicating an ongoing risk for this type of intestinal infection with time.48 What is the message from the studies of long-term travelers and expatriates? There is an ongoing risk of diarrhea no matter how long one resides in a developing region. Although infection with ETEC may decrease with time, if there are multiple pathogens circulating in an area, which is the case for most areas of the world, then the traveler remains at risk for acquiring them.

SUMMARY AND RECOMMENDATIONS Advice and Education Based on the epidemiologic studies that have been reviewed, the dietary risk items or behavior are well described (see Table 11-1). In the pretravel session, the traveler should be advised to avoid these risk items and to try and choose food and beverages based on Table 11-2. Hand-washing should be emphasized, especially when there may be surface or environmental contamination with enteric pathogens. It can be demonstrated that straightforward, consistent education about risk and the importance of taking medication correlates with improved compliance with malaria chemoprophylaxis by travelers.49,50 Advice should be provided both verbally and in written form. In a survey of travel clinics worldwide, 97% of clinics gave verbal advice on travelers’ diarrhea and 91% provided it in written form.51 This knowledge can be incorporated by travelers, following their visit.52 Therefore, despite the

Table 11-2. Dietary Items that are Likely to be Safe to Ingest Cooked food that has been recently prepared and is steaming when served Dry items such as breads Fruit that can be washed off, dried, and peeled by the traveler Bottled, carbonated beverages (with an acidic pH): beer, soda, carbonated bottled water Coffee and tea (assumes that they have been heated above 70°C or brought to a boil) Wine Water brought to a boil and then properly stored Water that has been properly treated: halogenated and filtered (see text)

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information that many travelers do not exercise precautions in a consistent fashion, and those who do may still suffer from diarrhea, neither the traveler nor the travel health care professional should despair. The issue should be approached in a realistic fashion, understanding the potential benefits and difficulties of being careful about food and drink. It is the task of the travel medicine specialist to inform and educate and the responsibility of the traveler to act upon the information in accordance with their tolerance for becoming ill. There should be continued emphasis on trying to get travelers to seek pretravel care from established travel medicine services, and to train travel professionals to provide consistent education. Innovative educational strategies should also be developed. Compared with vaccination against vaccine-preventable disease, education is the most cost-effective and practical way to prevent illness.3,53,54 Education is particularly important for those who are at high risk for complications from diarrhea: pregnant women, the elderly, the very young, diabetics, those with cardiovascular or renal disease, and those who are immunocompromised.55 HIV/AIDS patients should be careful about their dietary habits during travel to avoid severe and chronic infection from Salmonella, Cryptosporidium, and Toxoplasma.56

Water Safety The provision of potable water, or water that can be drunk with a minimal risk for microbial contamination, is a universal goal. For the traveler, there are several ways to prepare water so that it is potable. Although bottled water is often safe, it is not reliably so. Therefore, it may be prudent to drink carbonated bottled water because of the added antibacterial effect of a lower pH and the reassurance that if the water remains carbonated at the time of opening, it is likely to have been prepared properly. To render surface or tap water safe for drinking, there are three standard methods that are comprehensively reviewed by Backer, and are outlined in Table 11-3.57 These methods are heat, filtration, and halogenation. Heat is the most reliable and will kill all bacterial, viral, and parasitic pathogens. However, it will not always be easy for the traveler to heat water. An electric heating element may be needed, and if the traveler is in a wilderness or rural setting, there has to be a source of fuel. In order to conserve resources, it is only necessary to bring water to a boil. The higher the temperature, the

Table 11-3. Water Disinfection Technique Heat* Filtration† Halogenation‡

Bacteria

Viruses

Giardia

Cryptosporidium

+ + +

+ – +

+ + d+**

+ + –

*Water should be brought to a boil (100°C). Water held for several minutes at temperatures of 70°C or higher should be potable. † The filter size should be ≤0.2 µm for bacteria and ≤1 µm for parasites. ‡ Concentrations of the halogen should be 1 to 10 mg/L for 30 to 60 minutes. There are several options: iodine tablets (tetraglycine hydroperiodide; eg, Globaline®, Potable-Aqua®, Coghlan’s®); tincture of iodine at 2%, 5 drops/L; chlorine tablets (AquaClear®); or chlorine bleach at 5 to 6%, 2 to 4 drops/L. The activity of chlorine varies more with changes in pH, turbidity, and temperature than iodine-based methods. **Giardia usually requires 5 to 8 mg/L of halogen and a longer contact time to be killed. Abbreviations: +: susceptible; –: not susceptible. Adapted from Backer.57

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shorter the period of time it takes to kill enteric organisms. Since most enterics are killed at 70°C, when they are maintained at this temperature for <1 minute to 10 minutes, the process and time that it takes to bring water to a boil (100°C) is sufficient to kill them.58–62 This is the concept behind pasteurization: the maintenance of a dietary product at a temperature below 100°C (usually 65° to 70°C) for a sufficient period of time to kill microbes. Tap water that is too hot to touch (60°C or cooler) may not be hot enough to render it potable.58,59 The Center for Disease Control and Prevention has taken a more conservative view and recommends boiling for one minute.63 Filtration, using a filter of an absolute micron size of 0.2 to 1 µm, will remove bacteria and parasitic cysts and ova because of their size.57 Standards for filters have been established by the National Sanitation Foundation International and can be viewed at . However, enteric viruses will not be reliably eliminated since they are too small to be filtered. Although some filters claim to remove viruses by viral adherence to the filter itself, this may not be the case for all products.64 In areas where water is a low risk for enteric viruses, such as in remote wilderness areas where the watershed is not contaminated with human waste, it may be possible to use filtration alone to purify water for drinking. For travel to all other developing regions, an additional purification process will be necessary. This process is usually halogenation. Halogenation can be performed before or after filtration, and once complete, the water may be passed through a carbon filter or have citric acid crystals added to render the taste more palatable. There is a hierarchy of susceptibility of organisms to halogenation: bacteria are the most sensitive (killed by a concentration of 0.1 to 1.0 mg/L), then viruses (0.5 to 5.0 mg/L), and finally parasitic cysts and ova (1 to ≥50 mg/L).57 While Giardia may be killed with a sufficient concentration of halogen over time, Cryptosporidium is highly resistant, and other agents such as Cyclospora and parasitic eggs are likely to be equally resistant.60,65,66,67,68 The efficacy of halogenation is also dependent upon temperature, contact time, turbidity, and pH, although iodine preparations are less subject to these factors compared with chlorine preparations. Thus, if the water is particularly cold, the contact time should be increased, or if it is turbid, the concentration should be increased. Filters with iodine resins are not reliably effective and should not be used. Water that has been rendered potable should be stored in a clean vessel that can be sealed against contamination. There should also be residual halogen so that bacteria that have not been eliminated will not multiply during storage. Use of iodine for short periods should not be problematic; however, some pregnant women and individuals with thyroid disease should not use iodine.69

REFERENCES 1. Gorbach SL, Edelman R, editors. Travelers’ diarrhea: National Institutes of Health Consensus Conference. Rev Infect Dis 1986;8 Suppl 2:S227–33. 2. DuPont HL, Ericsson CD. Prevention and treatment of travelers’ diarrhea. N Engl J Med 1993;328:1821–7. 3. Committee to Advise on Tropical Medicine and Travel (CATMAT). Statement on travellers’ diarrhea. An Advisory Committee Statement (ACS). Can Commun Dis Rep 2001;27:3–12. 4. Clemens JD, Sack DA, Harris JR, et al. Cross-protection by B subunit-whole cell cholera vaccine against diarrhea associated with heat-labile toxin-producing enterotoxigenic Escherichia coli: results of a largescale field trial. J Infect Dis 1988;158:372–7.

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5. Rowe B, Taylor J, Bettelheim KA. An investigation of travelers’ diarrhoea. Lancet 1970;1:1–5. 6. Gorbach SL, Kean BH, Evans DG, et al. Travelers’ diarrhea and toxigenic Escherichia coli. N Engl J Med 1975;292:933–6. 7. Merson MH, Morris GK, Sack DA, et al. Travelers’ diarrhea in Mexico: a prospective study of physicians and family members attending a congress. N Engl J Med 1976;294:1299–304. 8. Herwaldt BL. Cyclospora cayetanensis: a review, focusing on the outbreaks of cyclosporiasis in the 1990s. Clin Infect Dis 2000;31:1040–57. 9. Merson MH, Hughes JM, Wood BT, et al. Gastrointestinal illness on passenger cruise ships. J Am Med Assoc 1975;231:723–7. 10. Tjoa WS, DuPont HL, Sullivan P, et al. Location of food consumption and travelers’ diarrhea. Am J Epidemiol 1977;106:61–6. 11. Wood LV, Ferguson LE, Hogan P, et al. Incidence of bacterial enteropathogens in foods from Mexico. Appl Environ Microbiol 1983;46:328–32. 12. Centers for Disease Control and Prevention. Diagnosis and management of foodborne illnesses. A primer for physicians. MMWR Morb Mortal Wkly Rep 2001;50(No. RR-2):1–67. 13. Koo D, Aragon A, Moscoso V, et al. Epidemic cholera in Guatemala, 1993: transmission of a newly introduced epidemic strain by street vendors. Epidemiol Infect 1996;116:121–6. 14. Ryder RW, Oquist CA, Greenberg H, et al. Travelers’ diarrhea in Panamanian tourists in Mexico. J Infect Dis 1981;144:442–8. 15. Ericsson CD, Pickering LK, Sullivan P, DuPont HL. The role of location of food consumption in the prevention of travelers’ diarrhea in Mexico. Gastroenterology 1980;79:812–6. 16. Herwaldt BL, de Arroyave KR, Roberts JM, Juranek DD. A multiyear prospective study of the risk factors for and incidence of diarrheal illness in a cohort of Peace Corps volunteers in Guatemala. Ann Intern Med 2000;132:982–8. 17. Hoge CW, Shlim DR, Echeverria P, et al. Epidemiology of diarrhea among expatriate residents living in a highly endemic environment. J Am Med Assoc 1996;275:533–8. 18. Adachi JA, Mathewson JJ, Jiang ZD, et al. Enteric pathogens in Mexican sauces of popular restaurants in Guadalajara, Mexico, and Houston, Texas. Ann Intern Med 2002;136:884–7. 19. Centers for Disease Control and Prevention. “Norwalk-like viruses”: public health consequences and outbreak management. MMWR Morb Mortal Wkly Rep 2001;50(No. RR-9):1–17. 20. Centers for Disease Control and Prevention. Outbreaks of gastroenteritis associated with noroviruses on cruise ships – United States, 2002. MMWR Morb Mortal Wkly Rep 2002;51:1112–5. 21. Vollet JJ, Ericsson CD, Gibson G, et al. Human rotavirus in an adult population with travelers’ diarrhea and its relationship to the location of food consumption. J Med Virol 1979;4:81–7. 22. Ericsson CD, DuPont HL, Mathewson JJ. Epidemiologic observations on diarrhea developing in U.S. and Mexican students living in Guadalajara, Mexico. J Travel Med 1994;2:6–10. 23. Boccia D, Tozzi AE, Cotter B, et al. Waterborne outbreak of Norwalk-like virus gastroenteritis at a tourist resort, Italy. Emerg Infect Dis 2002;8:563–8. 24. Barwick RS, Levy DA, Craun GF, et al. Surveillance for waterborne-disease outbreaks – United States, 1997–1998. MMWR Morb Mortal Wkly Rep 2000;49(No. SS-4):1–35. 25. deRegnier DP, Cole L, Schupp DG, Erlandsen SL. Viability of Giardia cysts suspended in lake, river, and tap water. Appl Environ Microbiol 1989;55:1223–9. 26. Sanchez JL, Gelnett J, Petruccelli BP, et al. Diarrheal disease incidence and morbidity among United States military personnel during short-term missions overseas. Am J Trop Med Hyg 1998;58:299–304.

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27. Keswick BH, Gerba CP, DuPont HL, Rose JB. Detection of enteric viruses in treated drinking water. Appl Environ Microbiol 1984;47:1290–4. 28. Sobel J, Mahon B, Mendoza CE, et al. Reduction of fecal contamination of street-vended beverages in Guatemala by a simple system for water purification and storage, handwashing, and beverage storage. Am J Trop Med Hyg 1998;59:380–7. 29. Daniels NA, Neimann J, Karpati A, et al. Travelers’ diarrhea at sea: three outbreaks of waterborne enterotoxigenic Escherichia coli on cruise ships. J Infect Dis 2000;181:1491–5. 30. Centers for Disease Control and Prevention. Outbreak of acute febrile illness among participants in EcoChallenge Sabah 2000 – Malaysia, 2000. MMWR Morb Mortal Wkly Rep 2000;49:816–7. 31. Dickens DL, DuPont HL, Johnson PC. Survival of bacterial enteropathogens in the ice of popular drinks. J Am Med Assoc 1985;253:3141–3. 32. Harris JR. Are bottled beverages safe for travelers? Am J Public Health 1982;72:787–8. 33. Beuret C, Kohler D, Baumgartner A, Luthi TM. Norwalk-like virus sequences in mineral waters: one-year monitoring of three brands. Appl Environ Microbiol 2002;68:1925–31. 34. Sheth NK, Wisniewski TR, Franson TR. Survival of enteric pathogens in common beverages: an in vitro study. Am J Gastroenterol 1988;83:658–60. 35. Loewenstein MS, Balows A, Gangarosa EJ. Turista at an international congress in Mexico. Lancet 1973;1:529–31. 36. Chang TW. Traveler’s diarrhea [letter]. Ann Intern Med 1978;89:428–9. 37. Mattila L, Siitonen A, Kyrönseppä H, et al. Risk behavior for travelers’ diarrhea among Finnish travelers. J Travel Med 1995;2:77–84. 38. Steffen R, Van der Linde F, Gyr K, Schär M. Epidemiology of diarrhea in travelers. J Am Med Assoc 1983;249:1176–80. 39. Steffen R, Collard F, Tornieporth N, et al. Epidemiology, etiology, and impact of travelers’ diarrhea in Jamaica. J Am Med Assoc 1999;281:811–7. 40. Hill DR. Occurrence and self-treatment of diarrhea in a large cohort of Americans traveling to developing countries. Am J Trop Med Hyg 2000;62:585–9. 41. Kozicki M, Steffen R, Schär M. ‘Boil it, cook it, peel it or forget it’: does this rule prevent travellers’ diarrhoea? Int J Epidemiol 1985;14:169–72. 42. McIntosh IB, Reed JM, Power KG. Travelers’ diarrhea and the effect of pre-travel health advice in general practice. Br J Gen Prac 1997;47:71–5. 43. von Sonnenburg F, Tornieporth N, Waiyaki P, et al. Risk and aetiology of diarrhea at various tourist destinations [letter]. Lancet 2000;356:133–4. 44. Packman CJ. A survey of notified travel-associated infections: implications for travel health advice. J Pub Health Med 1995;17:217–22. 45. DuPont HL, Haynes GA, Pickering LK, et al. Diarrhea of travelers to Mexico. Relative susceptibility of United States and Latin American students attending a Mexican university. Am J Epidemiol 1977;105:37–41. 46. Evans DJ Jr, Ruiz-Palacios G, Evans DE, et al. Humoral immune response to the heat-labile enterotoxin of Escherichia coli in naturally acquired diarrhea and antitoxin determination by passive immune hemolysis. Infect Immun 1977;16:781–8. 47. Shlim DR, Hoge CW, Rajah R, et al. Persistent high risk of diarrhea among foreigners in Nepal during the first 2 years of residence. Clin Infect Dis 1999;29:613–6.

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48. Herwaldt BL, de Arroyave KR, Wahlquist SP, et al. Multiyear prospective study of intestinal parasitism in a cohort of Peace Corps volunteers in Guatemala. J Clin Microbiol 2001;39:34–42. 49. Phillips-Howard PA, Blaze M, Hurn M, Bradley DJ. Malaria prophylaxis: survey of the response of British travellers to prophylactic advice. Br Med J 1986;293:932–4. 50. Hill DR. Health problems in a large cohort of Americans traveling to developing countries. J Travel Med 2000;7:259–66. 51. Hill DR, Behrens RH. A survey of travel clinics throughout the world. J Travel Med 1996;3:46–51. 52. Genton B, Behrens RH. Specialized travel consultation. Part II: acquiring knowledge. J Travel Med 1994;1:13–5. 53. Behrens RH, Roberts JA. Is travel prophylaxis worth while? Economic appraisal of prophylactic measures against malaria, hepatitis A, and typhoid in travellers. Br Med J 1994;309:918–22. 54. Committee to Advise on Tropical Medicine and Travel (CATMAT). Guidelines for the practice of travel medicine. An Advisory Committee Statement (ACS). Can Commun Dis Rep 1999;25:1–6. 55. Guerrant RL, Van Gilder T, Steiner TS, et al. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis 2001;32:331–50. 56. Castelli F, Patroni A. The human immunodeficiency virus-infected traveler. Clin Infect Dis 2000;31:1403–8. 57. Backer H. Water disinfection for international and wilderness travelers. Clin Infect Dis 2002;34:355–64. 58. Bandres J, Mathewson JJ, DuPont HL. Heat susceptibility of bacterial enteropathogens. Implications for the prevention of travelers’ diarrhea. Arch Intern Med 1988;148:2261–3. 59. Groh CD, MacPherson DW, Groves DJ. Effect of heat on the sterilization of artificially contaminated water. J Travel Med 1996;3:11–3. 60. Ongerth JE, Johnson RL, MacDonald SC, et al. Backcountry water treatment to prevent giardiasis. Am J Public Health 1989;79:1633–7. 61. Fayer R. Effect of high temperature on infectivity of Cryptosporidium parvum oocysts in water. Appl Environ Microbiol 1994;60:2732–5. 62. Krugman S, Giles JP, Hammond J. Hepatitis virus: effect of heat on the infectivity and antigenicity of the MS-1 and MS-2 strains. J Infect Dis 1970;122:432–6. 63. Centers for Disease Control and Prevention. Health information for international travel, 2001–2002. Atlanta (GA): US Department of Health and Human Services; 2001. 64. Gerba CP, Naranjo JE. Microbiological water purification without the use of chemical disinfection. Wilderness Environ Med 2000;11:12–6. 65. Rice EW, Hoff JC, Schaefer FW 3rd. Inactivation of Giardia cysts by chlorine. Appl Environ Microbiol 1982;43:250–1. 66. Juranek DD. Cryptosporidiosis: sources of infection and guidelines for prevention. Clin Infect Dis 1995;21 Suppl 1:S57–61. 67. Centers for Disease Control and Prevention. Assessing the public health threat associated with waterborne cryptosporidiosis: report of a workshop. MMWR Morb Mortal Wkly Rep 1995;44(No. RR-6):1–19. 68. Carpenter C, Fayer R, Trout J, Beach MJ. Chlorine disinfection of recreational water for Cryptosporidium parvum. Emerg Infect Dis 1999;5:579–84. 69. Backer H, Hollowell J. Use of iodine for water disinfection: iodine toxicity and maximum recommended dose. Environ Health Perspect 2000;108:679–84.

Chapter 12

PROPHYLACTIC USE

OF

DRUGS

Charles D. Ericsson, MD, and Herwig Kollaritsch, MD

Options to prevent travelers’ diarrhea include avoidance of travel, risk factor education, with the aim of behavioral change related particularly to food and beverage selection (see Chapter 11 “Diet and Education About Risks”), immunologic protection with vaccines or immunoglobulin preparations (see Chapter 13, “Immunity and Immunoprophylaxis”), and chemoprophylaxis with various drugs.1-7 Educational efforts too frequently fail to substantially change risky behavior, and immunologic protection, while theoretically preferable, is still in the developmental stage. Furthermore, given the large number of organisms and strains that cause diarrhea, arguably immunoprotection will not be a comprehensive approach any time in the near future. Drugs will likely remain a viable option when prevention of travelers’ diarrhea is considered. Philosophically, prevention of travelers’ diarrhea with drugs must be weighed against current therapeutic options (see Chapter 14, “General Principles in Self-Treating Travelers’ Diarrhea Abroad,” Chapter 15, “Nonspecific Treatment: Diet, Oral Rehydration Therapy, Symptomatic Drugs,” and Chapter 16, “Antimicrobial Treatment: An Algorithmic Approach”).8-11 Therapy of travelers’ diarrhea with the combination of an antimicrobial agent and loperamide often limits the course and inconvenience of disease to a matter of hours.9,11,12 In the face of such therapeutic results, the use of drugs to prevent diarrhea becomes a matter of judgment. Highly respected authorities participating in a National Institutes of Health Consensus Development Conference in 1985 concluded that the prevention of diarrhea with drugs has very little role, if any, since travelers’ diarrhea is a self-limiting and nonfatal condition.13 A dissenting viewpoint is that the decision to use chemoprophylaxis should be a matter of assessing the risk status and preferences of an informed host, including an assessment of the criticality of remaining well during the travel. The potential benefits of chemoprophylaxis should be weighed against the risks and inconvenience of disease and comparative side effects and costs of drugs for both chemoprophylaxis and self-therapy. In this scheme, the authors still prefer to arm most travelers with medications for self-therapy and not to promote chemoprophylaxis. We will prescribe preventative drugs for the traveler who expresses the strong desire to use them, but we generally reserve recommending chemoprophylaxis only for special hosts and travel situations.

THE DRUGS Most of the drugs that are effective for chemoprophylaxis of travelers’ diarrhea are antimicrobial agents. Bismuth subsalicylate-containing preparations also have antimicrobial properties.14 The

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major reason such agents are effective is because travelers’ diarrhea is caused predominately by bacterial microorganisms. In early studies, the substantial proportion of travelers’ diarrhea for which no bacterial pathogen could be isolated responded to treatment with an antimicrobial agent. As a general rule, any antimicrobial agent that has proven to be effective in the treatment of travelers’ diarrhea should be effective in prevention. Although they are not technically drugs, Lactobacillus preparations and similar probiotics will also be considered as preventatives in this chapter. In earlier studies, a variety of agents have proven either ineffective or minimally effective in the prevention of travelers’ diarrhea.15,16 These include halogenated hydroxyquinoline, lactobacilli, and antimotility drugs.15 An agent called verum, the combination of tannalbuminate and ethacridin lactate, was found to be minimally effective, affording 36% protection.17 Activated charcoal was studied on the assumption that in a population in whom enterotoxigenic E. coli was a common cause of diarrhea, an agent that adsorbed enterotoxins might work. Activated charcoal was no more effective than placebo (HL DuPont, personal communication) and cannot be recommended even for its placebo effect because of the concern for nonspecific adsorption of medications. Polycarbophil, an absorbant agent that is indicated for management of constipation, failed to prevent diarrhea or to ameliorate its presentation (HL DuPont, personal communication). Although not studied in prevention of diarrhea, antimotility agents like loperamide, anticholinergics, and antisecretory agents such as zaldaride maleate, an intestinal calmodulin inhibitor, or racecadotril, an enkephalinase inhibitor, have no logical role in chemoprophylaxis of travelers’ diarrhea.

Antimicrobial Agents In sentinel early work, Ben Kean and colleagues showed that antimicrobial agents prevented travelers’ diarrhea.18,19 Agents such as phthalylsulfathiazole afforded 50% protection. Neomycin was minimally effective (13% protection) in one study but not in another. In a placebo-controlled trial, Turner compared Streptotriad, a combination of streptomycin and three sulfa compounds, with neomycin and the same three sulfa compounds and claimed statistical benefits only for the Steptotriad, but no data on illness attack rates were given.20 A series of studies by DA Sack and RB Sack and their colleagues demonstrated the benefits and limitations of doxycycline. Doxycycline was found to be efficacious in Peace Corps volunteers in Morocco and Kenya, but in Honduras, where enterotoxigenic E. coli were known to be resistant to doxycycline, the drug failed.21-23 Likewise, in Thailand, where enterotoxigenic E. coli were also known to be resistant to doxycycline, the drug afforded 59% protection against diarrhea, but these results were not statistically significant.24 Because doxycycline had a relatively long half-life (18 hours) and an enterohepatic circulation, the drug was administered biweekly. This regimen failed to adequately protect travelers.25 Because doxycycline resistance of enteropathogens has generally risen around the world, this drug is no longer promoted as an ideal agent for chemoprophylaxis of travelers’ diarrhea. One study, however, showed that doxycycline successfully treated shigellosis despite minimal inhibitory concentrations for some of the Shigella isolates that were considered resistant.26 Such results suggest that the high stool concentrations achieved by doxycycline might be effective against some organisms considered resistant by usual definitions. Doxycycline used for malaria prophylaxis,

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for instance, might afford a degree of protection against travelers’ diarrhea, but unfortunately, doxycycline is mostly used for malaria prophylaxis in Southeast Asia, a region well known for antimicrobial resistance of enteropathogens against tetracyclines. Studies by DuPont and colleagues showed the benefits of trimethoprim–sulfamethoxazole (TMP–SMX) and trimethoprim alone in the efficacious prevention of travelers’ diarrhea.27,28 While rising resistance worldwide has diminished the usefulness of either agent, these studies remain important for clarifying that a daily prophylactic dose of approximately half of a daily therapeutic dose should be effective in prevention.29-33 Black and colleagues showed that mecillinam afforded 75% protection against travelers’ diarrhea.34 The agent has never become routinely used and is not available in some locations like the United States. In a small study, Ericsson and colleagues showed that the nonabsorbable antimicrobial agent bicozamycin was 100% efficacious in prevention, but the drug was never fully developed for human use.35 Conceptually, a nonabsorbable antimicrobial agent might be particularly useful as a prophylactic agent, because side effects of such an agent should be minimal and they should be useful for certain patient groups like pregnant women and those on many other medications in whom the concern for drug–drug interactions is high. Two other nonabsorbable antimicrobial agents, aztreonam and rifaximin, have been studied for the treatment of travelers’ diarrhea, but neither has been studied for prevention.8,36,37 Aztreonam never became commercially available as an oral agent. Rifaximin would probably prove to be an excellent choice for prophylaxis, but what dose to use is an open question. A number of studies explored the efficacy of fluoroquinolones in prevention of travelers’ diarrhea.38-42 The efficacy of fluoroquinolones has been important to document because the efficacy of TMP–SMX has waned due to rising resistance worldwide. Specifically, norfloxacin and ciprofloxacin have proven efficacious in clinical trials.38,40-42 Given the efficacy of other fluoroquinolones (eg, ofloxacin, levofloxacin, and fleroxacin) in the treatment of travelers’ diarrhea, any fluoroquinolone should be efficacious in the prevention of travelers’ diarrhea.9-11,43,44 The newer fluoroquinolones are given once a day, and the assumption has been that the same dose would be appropriate for prophylaxis. Half doses of newer fluoroquinolones given once a day or full doses given every other day are logical considerations, but these regimens would need to be studied in clinical trials before they could be recommended. The placebo-controlled study published in 1994 by Heck and colleagues is the most recent assessment of prophylactic fluoroquinolones and compared TMP–SMX with ciprofloxacin.41 The population was adults traveling in Latin America and the Caribbean. TMP–SMX was only 51% protective while ciprofloxacin afforded 84% protection. Until recently, the argument against the routine choice of a fluoroquinolone as a prophylactic agent was that fluoroquinolones were the treatment of choice. TMP–SMX was recommended when antimicrobial prophylaxis was desired; a fluoroquinolone was reserved for self-therapy. With the availability of both azithromycin (see Chapter 16, “Antimicrobial Treatment: An Algorithmic Approach”) and rifaximin for treatment, a fluoroquinolone is probably the current agent of choice when chemoprophylaxis of travelers’ diarrhea is indicated.8,10,37,45

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Bismuth Subsalicylate Bismuth subsalicylate (BSS)-containing compounds (popularly marketed as Pepto-Bismol®) are effective in the prevention of travelers’ diarrhea.14,46-50 The drug has antisecretory, anti-inflammatory, and antimicrobial properties, and the latter most likely accounts for its efficacy as a preventative.14,48,51-53 When BSS dissociates in the mouth or in stomach acid, salicylate is released and nearly completely absorbed.54,55 The resultant insoluble bismuth salts appear to confer the antibacterial activity.48,53 At most, protection with BSS is about 62%.14,47,49,50 The products appear to protect best when given four times a day.2,3,14,48,50 The usual dose is two tablets chewed four times a day. The liquid preparation can be taken as 30 mL (one ounce) four times a day and is equally effective. When the same total dose that provided 62% protection was taken in two divided doses instead of four, protection decreased to 40%.49,50 The degree of protection conferred by BSS-containing compounds can be improved if travelers are careful about what and where they eat.56 The assumption has been that BSS must be ingested at the time contaminated food or beverage is ingested to be maximally effective. However, taking BSS only in relation to meals actually ingested has not been studied and should be discouraged, even though it might be successful. Chewing the usual prophylactic dose of BSS approximates taking 3 to 4 adult aspirins. 54,55 Tinnitus was no more common among subjects taking bismuth subsalicylate than among those taking placebo.46,47 Travelers should not take therapeutic doses of aspirin when they take BSS because of the risk of salicylate poisoning. Although the salicylate does not affect anticoagulation by warfarin as strongly as acetylsalicylic acid, the use of BSS is best avoided by persons needing anticoagulation. The use of BSS in areas highly endemic for Dengue fever might also be problematic. The concern is that Dengue infection concordant with aspirin use might confer a higher risk for hemorrhagic complications, but whether the same concern should be raised by use of salicylate in BSS is speculative. Bismuth toxicity is rare with ingestion of bismuth subsalicylate, because the bismuth salts formed during dissociation are largely insoluble and minimally absorbed.57 Blood levels were measured in adults who had been taking BSS prophylaxis for 3 weeks. The levels were miniscule and far below the level associated with bismuth encephalopathy.58 The same cannot be said for other bismuth salts (eg, subgallate and subnitrate) that must be avoided due to risk of encephalopathy. Some of the insoluble salts formed in the mouth and gut are black. To avoid developing a black tongue, travelers should brush their teeth and rinse their mouths after each dose and even consider gently brushing their tongues after their nighttime dose. Travelers should be informed that black stools can develop and be confused with melena. Finally, constipation with use of BSS was no more common than the risk among those study participants taking placebo. BSS has other limitations. BSS-containing products are not found in much of Europe, Australia, and New Zealand. Travelers from these regions would need to purchase the drug in the destination country. Chewing BSS tablets four times a day demands a high level of compliance. Furthermore, transient blackening of tongue and stools makes this approach to prophylaxis unattractive for many travelers.

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Lactobacillus and Other Probiotic Preparations Lactobacillus GG has demonstrated bile and acid resistance, propensity to adhere to intestinal lining better than earlier Lactobacillus strains, and production of an antibacterial substance.59 Presumably, these features would promote colonization resistance that might prevent the growth of potential enteropathogens to an effective pathogenic inoculum. Lactobacillus GG has shown promise in prevention of nosocomial, especially rotavirus, diarrhea.60 One recent controlled trial suggested lactobacilli had no role in the prevention of antibiotic-associated diarrhea61; however, a recent metaanalysis suggests there might be a role for lactobacilli.62 A recent large placebo-controlled study by Hilton of 245 travelers demonstrated that Lactobacillus GG afforded 47% protection.63 In an accompanying editorial, DuPont noted that protection was minimal and not as effective as other drugs like BSS or antimicrobials.64 DuPont felt the concept was worthy of further study. While not directly relevant to travelers, Lactobacillus GG was studied for its prevention of diarrhea in undernourished children in Peru. The incidence of diarrhea dropped from 6.02 episodes per child per year to 5.21.65 Although this was a statistically significant drop, this translates to only 13% protection against diarrhea. A mild but significant and dose-dependent protection against travelers’ diarrhea with a varying regional effect was reported for Saccharomyces boulardii, a medication often used for prevention of travelers’ diarrhea in German-speaking countries and in France.66 Use of other probiotics have either not been scientifically studied or failed to adequately prevent travelers’ or infectious diarrhea.67-70 What can be said is that these agents are safe, and if a traveler wishes to use them, the only significant risk might be complacency with proper food and beverage precautions.

THE CASE FOR CHEMOPROPHYLAXIS Hosts At Risk Populations known to be at highest risk for travelers’ diarrhea or at special risk for the consequences of diarrhea (Table 12-1) are those for whom the travel medicine practitioner might wish to offer chemoprophylaxis.6,71,72 Examples of hosts who are at increased risk of acquiring diarrhea are persons with decreased production of gastric acid and those taking potent, long-acting H2 blockers or proton pump inhibitors like omeprazole. Immunodeficient hosts might be considered for prophylaxis; they include patients with malignancy, transplants, on chemotherapy, IgA deficiency, and AIDS with CD4 counts less than 200 cells/mm3.73 Such AIDS patients are up to 100 times more at risk of acquiring salmonellosis than are persons with normal immune systems.72 Studies have found that children of less than 6 years of age are at greater risk of acquiring diarrhea, probably because of their tendency to mouth their environment. Pediatricians as well as travel medicine practitioners generally avoid any consideration of chemoprophylaxis in children, preferring instead to educate parents.74 Some hosts might suffer complications if they acquire travelers’ diarrhea. Patients with underlying gastrointestinal conditions such as Crohn’s disease, ulcerative colitis, or chronic diarrhea probably should receive chemoprophylaxis. Pregnant women might be considered for prophylaxis, but the choice of agent is problematic. Trimethoprim–sulfamethoxazole might be considered with the exception of women late in the third

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Table 12-1. Travelers to Consider for Chemoprophylaxis of Travelers’ Diarrhea with an Antimicrobial Agent At special risk for acquiring travelers’ diarrhea

Achlorhydria, including late stage AIDS Long-acting H2 blockers and proton pump inhibitors Immunodeficiency, including: • • • • •

At risk of complications of diarrhea

Malignancy Transplants On chemotherapy IgA deficiency AIDS with CD4 counts <200 cells/mm3

Underlying chronic gastrointestinal disease: • Crohn’s disease • Ulcerative colitis • Chronic diarrhea Elderly* Pregnancy** Extreme travel

*Recommendations limited by lack of data. **Recommendations limited by lack of data and potential adverse effects in pregnancy of the fluoroquinolones.

trimester (risk of kernicterus), but this agent is no longer highly efficacious. Fluoroquinolones are contraindicated in pregnancy, and while azithromycin or rifaximin would be safe considerations, the dose to use for prevention has not been determined. One approach is to advise the pregnant woman to postpone travel until after delivery and breast feeding, if possible, especially when she is contemplating travel to areas that also place her at risk of malaria. Elderly travelers might more easily become befuddled by a diarrheal illness and risk dehydration, particularly if they are also taking diuretics. Data to elucidate the actual risks of complications of diarrhea in the elderly and to guide the choice of chemoprophylaxis versus early self-treatment, are simply lacking. Travelers participating in “extreme” travel can be in the position of needing to remain physically fit to be able to return to civilization. They are often a trek of many days away from any medical care. Logically, such travelers might be considered for chemoprophylaxis. At the very least, they should be prepared to take an oral rehydration solution to avoid dehydration and carry antimicrobial agents and loperamide with them for early empiric treatment (see Chapter 14, “General Principles in SelfTreating Travelers’ Diarrhea Abroad”). Occasionally, travelers indicate that they intend to disregard advice on safe food and beverages in order to fully experience a new culture, or they express the desire to take prophylaxis even though they are not in a high-risk group. For these travelers, one could recommend BSS, if it is available, because of its predictably better adverse effects profile.

Criticality of Travel The concept of criticality of travel enters the decision on whether to advise chemoprophylaxis.2,3,5-7 For instance, cutting edge athletes must perform for their livelihood or in special competitions like

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the Olympics. Weighing the risks of side effects against the risk of not competing is subjective and is best accomplished in consultation with the athlete and the coaching staff, who might already have arranged a safe food and beverage supply and preparation. Business travelers or politicians on short important trips might take preventative medication. Should the trip of a honeymooning couple be considered critical? Unless the trip was short, such travelers probably can be best managed by arming themselves with medication for self-treatment. The bottom line is that criticality of a trip is a subjective decision that finally needs to be made by the informed traveler who has been thoroughly advised about the pros and cons of chemoprophylaxis. The culture of the traveler and provider probably influences the decision of whether to seek or offer chemoprophylaxis for diarrhea. For instance, North Americans typically take relatively short, 1-week vacations. Discounting a day of travel each direction and then changing or abandoning even 1 day’s itinerary means giving up about 20% of their vacation at the destination. North Americans are likely to be more interested in chemoprophylaxis than Europeans, who often take much longer vacations and in whom the fractional impact of illness is not as important.

THE CASE AGAINST CHEMOPROPHYLAXIS Adverse Drug Effects Potential adverse effects of drugs are a strong argument against routine chemoprophylaxis of travelers’ diarrhea. Major, potentially life-threatening side effects of the antimicrobial agents used for chemoprophylaxis have been estimated to occur at a rate of approximately 0.01% (Table 12-2).75 Severe reactions include death, anaphylaxis, and conditions like Stevens-Johnson syndrome that can occur in as many as 1 in 10,000 persons exposed to sulfonamide-containing products like TMP–SMX. The most common mild adverse effects, occurring in about 3% of persons, are transient rashes, vaginal candidiasis, and ironically, gastrointestinal upset. Sun sensitivity rash is a particular concern with doxycycline, but can also be seen with the fluoroquinolones. If millions of travelers each year to developing countries were routinely given prophylactic antimicrobial agents, then a few travelers might die to prevent a self-limited illness. This was the public health stance taken by the participants in the Consensus Development Conference when they decided not to recommend chemoprophylaxis at all.13 These experts even refused to condone the use of BSS because they felt travelers might decide to push the dose higher than the recommended dosage and risk salicylate poisoning. Furthermore, the risk of side effects of any prophylactic agent probably rises

Table 12-2. Comparative Efficacy and Adverse Effects of Fluoroquinolones and Bismuth Subsalicylate in the Prevention of Travelers’ Diarrhea Adverse Effects (%) Prophylactic Agent

Protection (%)

Minor

Bismuth subsalicylate

~62

1

0

Fluoroquinolone

~84

3

0.01

Adapted from Reves et al,75 with addition of newer fluoroquinolone efficacy data from Heck et al.41

Major

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when use of the agent is prolonged. At a minimum, these arguments support the concept that chemoprophylaxis, if used at all, should be reserved for at-risk hosts or special circumstances, and for only short periods of time. Adverse effects with BSS preparations are felt to be largely absent or minor.14,48 Adverse effects of antimicrobial agents used for diarrhea prophylaxis (whether TMP–SMX or fluoroquinolones) are predictably much more frequent and severe than those with BSS (see Table 12-2).75 For this reason, BSS should probably be the preferred chemoprophylactic agent when safety rather than best protection of an at-risk host is the driving issue. Adverse effects with Lactobacillus GG and other probiotics are essentially nonexistent.63 These agents might be ideal for a traveler who is not at excessive risk and who really could be well managed by preparing them for self-treatment, but who seems mostly to need the psychologic support offered by taking something prophylactically.

Overgrowth Syndromes and Promotion of Disease With use of antimicrobial agents, some women and men can develop oral thrush and some women may develop Candida vaginitis. Fortunately brief, 1- to 3-day courses of antibiotics for the treatment of travelers’ diarrhea minimizes the likelihood of such overgrowth syndromes from occurring, because colonization resistance is hardly affected. Overgrowth of Clostridium difficile with development of colitis theoretically might occur. Antibiotic-associated colitis has not been reported among travelers taking antimicrobials for diarrhea prophylaxis, and when tests for C. difficile cytotoxin was specifically included in evaluation of persistent diarrhea after antimicrobial treatment, it was not found (HL DuPont, personal communication). Nevertheless, concern for colitis invariably enters into the decision-making (and cost) associated with treating a traveler who develops diarrhea despite antimicrobial prophylaxis. Use of antimicrobials might promote the development of disease by certain enteropathogens, namely, Salmonella and Campylobacter. While the mechanism is not proven, it might be decreasing colonization resistance in the gut lumen that promotes invasion. Early studies suggest that use of agents with substantial antianaerobic activity might be more likely to disturb colonization resistance. This concept is supported lately by the observation that acquisition of vancomycin-resistant Enterococcus is facilitated by use of metronidazole.

Costs Reves and colleagues compared the costs of chemoprophylaxis with self-treatment of diarrhea with an antibiotic and concluded that prophylaxis was more cost-effective for travel lasting only a few days.75 Costs assigned to lost vacation (or business) time and the amortized costs of travel were the largest costs making chemoprophylaxis most cost-beneficial for short periods of travel. Since this study, however, self-therapy with the combination of an antimicrobial agent plus loperamide has limited the duration of the average case of travelers’ diarrhea to a matter of hours, so that time lost due to diarrhea is minimal. This makes self-therapy generally more cost-beneficial than prophylaxis, except perhaps for trips of a few days. Add to this the efficacy of single-dose antimicrobial agent therapy, and self-therapy is relatively even more cost-effective than prophylaxis.9,11,12,76 If vaccines that

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protect against common E. coli-mediated diarrhea are eventually used, then the overall risk of travelers’ diarrhea will be less—making self-treatment of diarrhea even more appealing from the perspective of cost.

Drug–Drug Interaction BSS is known to interfere with the absorption of doxycycline.77 If doxycycline were used for malaria prevention, regular use of BSS might lower circulating doxycycline levels and increase the risk of acquiring malaria. As a rule, the two agents should not be used together. If they must be used together, their administration should be separated by at least 2 hours.

Antimicrobial Agent Resistance Routine use of an antimicrobial agent in prevention of diarrhea might contribute to increased antimicrobial resistance in the region and lower or shorten the usefulness of the agent to treat syndromes that require antimicrobials for effective management. Antimicrobial resistance is high in most developing countries, and often occurs earlier than in developed countries.32 In countries where drugs can be bought without a prescription and used indiscriminately, widespread use of subtherapeutic doses of antimicrobials undoubtedly contributes to the level of antimicrobial resistance in a region. Compared to such widespread use by an indigenous population, a traveler’s contribution to the local bacterial ecology must be minuscule. A more scientific insight is offered by stool flora studies during antimicrobial prophylaxis. When TMP–SMX was used preventatively for 2 weeks, the concentration of gram-negative aerobic bacilli in stool were suppressed to very low levels only to be replaced by TMP–SMX-resistant flora, with total gram-negative aerobic bacilli rising back to preprophylaxis concentrations in stool.29 When norfloxacin was used in a similar study of prevention in the same location in Mexico, the concentration of gram-negative aerobic bacilli in stool was suppressed to very low levels and remained low until norfloxacin was discontinued; whereupon, concentrations of gram-negative aerobic bacilli in stool returned to normal with norfloxacin-sensitive organisms.38 The implication is that preventative antibiotic use did not foster de novo development of resistance flora but merely the acquisition from the environment of already resistant flora. When an agent like norfloxacin was used and the prevalent gram-negative aerobic bacilli were not resistant to norfloxacin, no acquisition of resistant flora occurred. These data are supported by a study of stool flora during the use of mecillinam prophylaxis in Mexico. Highly antibiotic resistant flora replaced the initial stool flora, but selection of mecillinam resistant flora was minimal.78 In Mexico, healthy persons acquired antibiotic-resistant flora despite not being on any antibiotics for treatment or prophylaxis, implying that the emergence of antibiotic resistant flora in travelers’ stools is, at least in part, a simple matter of acquiring the flora from the new environment.79 The conclusion is that preventative use of an antibiotic to which some of the prevalent flora is resistant might encourage dissemination of resistant flora in the local environment, although this effect must be very small compared to dissemination by the indigenous population. Use of an antimicrobial agent to which regional flora are not resistant is not likely to foster dissemination of resistance. Applied to the present, these data argue for the preferential use of fluoroquinolones, rather than TMP–SMX, for chemoprophylaxis.

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One cautionary note must be raised. Fluoroquinolone-resistant Campylobacter jejuni has been documented to emerge with treatment of an initially sensitive strain, with relapse or failure to control symptoms.80,81 Only a handful of cases have been described during or after a course of treatment with norfloxacin or ciprofloxacin. The risk of such occurrence during chemoprophylaxis is unknown but is probably highest in Southeast Asia where the prevalence of Campylobacter is relatively high. If azithromycin and rifaximin become better studied and fully available, then in this region of the world where Campylobacter is common, or in India where quinolone-resistant E. coli is more prevalent than in other regions of the world, azithromycin might be the prophylactic agent of choice with rifaximin as the treatment backup, or vice versa.33 In support of this approach is one study in which epidemic dysentery was successfully prevented by use of azithromycin.82 For the present, a fluoroquinolone is recommended for prophylaxis, with azithromycin as the most available treatment backup. An argument against chemoprophylaxis is that the traveler might be denied exposure to the common local enteropathogens to which they might acquire immunity. Conceptually, the approach of intentionally not preventing, or even treating, some diarrhea with an antimicrobial best applies to long-term travelers to a region. In a prospective study of US medical students in Mexico, the 1-month (August) incidence of diarrhea upon arrival was 34% and fell to 5% five months later (January) compared to another group of newly arrived students whose January incidence was 28%.83 Furthermore, in a prospective study, diarrhea in 44% of US students was very mild, characterized by only 1 to 2 unformed stools per 24 hours and lasting only a couple of days. Among this group, about half of the study participants submitted stools for culture and the usual assortment of enteropathogens was documented. Not all expatriates appear to experience a drop in the incidence of diarrhea with long-term stay. In Nepal, the overall incidence of diarrhea did not appear to drop over time, but these expatriates had a relatively high incidence of parasitic disease, while diarrhea mediated by enterotoxigenic E. coli did appear to wane. Taken together, these data support the concept that mild diarrhea should not be treated with an antimicrobial agent and, more importantly, that an antimicrobial agent for chemoprophylaxis should be used only for short periods of time. Finally, travelers must not become complacent with their eating and drinking habits while they take chemoprophylaxis. Not only do data indicate that chemoprophylaxis with BSS is more efficacious when travelers are careful with where they eat, but the concern is that travelers might place themselves at relatively high risk of parasitic disease if they become complacent.

PRACTICAL APPROACH TO CHEMOPROPHYLAXIS OF TRAVELERS’ DIARRHEA Table 12-3 indicates the drugs with proven activity in the prevention of travelers’ diarrhea that can be recommended at present. The efficacy of trimethoprim–sulfamethoxazole is probably low enough in many parts of the world that it soon might not be recommended at all. Our own choice, when maximal protection is a serious consideration, is a fluoroquinolone. Bismuth subsalicylate confers less protection and is not available in many regions of the world. Our algorithmic approach to chemoprophylaxis is shown in Figure 12-1. The algorithm clearly favors the use of self-therapy for most travelers except those deemed by the physician to be at high risk. We also recognize that some

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Table 12-3. Agents and their Doses Currently Recommended for Chemoprophylaxis of Travelers’ Diarrhea Agent

Dose

Comment

Bismuth subsalicylate (BSS)

2 tablets chewed four times per day

Limited availability in Europe, Australia, and New Zealand. Not as effective as fluoroquinolones.

Trimethoprim– Sulfamethoxazole (TMP–SMX)

1 double-strength tablet daily (160 mg TMP–800 mg SMX)

Efficacy may be less than that of BSS in most of the world due to antimicrobial resistance.

Fluoroquinolones* • Norfloxacin • Ciprofloxacin

400 mg daily 500 mg daily

The drugs of choice for prophylaxis of appropriate hosts. Azithromycin or rifaximin could be prescribed for self-treatment of diarrhea that is not prevented. If diarrhea persists, traveler should seek medical care.

*Other fluoroquinolones have not been studied, but single doses per day of ofloxacin (200 mg), levofloxacin (500 mg), gatifloxacin (400 mg), and moxifloxacin (400 mg) should be efficacious. The dose of ofloxacin is based on the proven efficacy of 200 mg twice a day for 3 days for treatment. The newer once-a-day fluoroquinolones probably would be efficacious at lower than their typical daily dose, but data are lacking.

travelers on short journeys have critically important reasons for remaining well during their travel. If a traveler with no special risks or critical reasons for remaining well raises the issue of prophylaxis, or simply wants preventative medications, we still prefer to educate them about the benefits of selftherapy and advise them to use this approach instead of chemoprophylaxis.

Figure 12-1. Algorithmic approach to chemoprophylaxis of travelers’ diarrhea.

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42. Rademaker CM, Hoepelman IM, Wolfhagen MJ, et al. Results of a double-blind placebo-controlled study using ciprofloxacin for prevention of travelers’ diarrhea. Eur J Clin Microbiol Infect Dis 1989;8:690–4. 43. Steffen R, Jori R, DuPont HL, et al. Fleroxacin, a long-acting fluoroquinolone, as effective therapy for travelers’ diarrhea. Rev Infect Dis 1989;11 Suppl:S1154–5. 44. Steffen R, Jori R, DuPont HL, et al. Efficacy and toxicity of fleroxacin in the treatment of travelers’ diarrhea. Am J Med 1993;94 Suppl 3A:S182–6. 45. Kuschner R, Trofa AF, Thomas RJ, et al. Use of azithromycin for the treatment of Campylobacter enteritis in travelers to Thailand, an area where ciprofloxacin resistance is prevalent. Clin Infect Dis 1995;21:536–41. 46. DuPont HL, Sullivan P, Evans DG, et al. Prevention of travelers’ diarrhea (emporiatric enteritis) by prophylactic administration of bismuth subsalicylate. J Am Med Assoc 1980;243:237–41. 47. DuPont HL, Ericsson CD, Johnson PC, et al. Prevention of travelers’ diarrhea by the tablet formulation of bismuth subsalicylate. J Am Med Assoc 1987;257:1347–50. 48. Ericsson CD. Bismuth subsalicylate in the treatment and chemoprophylaxis of travelers’ diarrhea in adults. Drug Therapy 1990;6:31–5. 49. Steffen R, DuPont HL, Heusser R, et al. Prevention of travelers’ diarrhea by the tablet form of bismuth subsalicylate. Antimicrob Agents Chemother 1986;29:625–7. 50. Steffen R. Worldwide efficacy of bismuth subsalicylate in the treatment of travelers’ diarrhea. Rev Infect Dis 1990;6:153–7. 51. Ericsson CD, Evans DG, DuPont HL, et al. Bismuth subsalicylate inhibits activity of crude toxins of Escherichia coli and Vibrio cholerae. J Infect Dis 1977;136:692–6. 52. Ericsson CD, Tannenbaum C, Charles TT. Antisecretory and anti-inflammatory properties of bismuth subsalicylate. Rev Infect Dis 1990;12 Suppl 1:S16–20. 53. Cornick NA, Silva M, Gorbach SL. In vitro antibacterial activity of bismuth subsalicylate. Rev Infect Dis 1990;12 Suppl 1:S9–10. 54. Pickering LK, Feldman S, Ericsson CD, Cleary TG. Absorption of salicylate and bismuth in children and adults from a bismuth subsalicylate containing compound (Pepto-Bismol). J Pediatr 1981;99:654–6. 55. Feldman S, Chen SL, Pickering LK, et al. Salicylate absorption from a bismuth subsalicylate antidiarrheal preparation (Pepto-Bismol). Clin Pharm Ther 1981;29:788–92. 56. Ericsson CD, Pickering LK, Sullivan P, DuPont HL. The role of location of food consumption in the prevention of travelers’ diarrhea in Mexico. Gastroenterology 1980;79:812–6. 57. Mendelowitz PC, Hoffman RS, Weber S. Bismuth absorption and myoclonic encephalopathy during bismuth subsalicylate therapy. Ann Intern Med 1990;112:140–1. 58. Ericsson CD, DuPont HL, Pickering LK. Bismuth preparations for diarrhea. J Am Med Assoc 1980;244:1435–6. 59. Silva M, Jacobus N, Deneke C, Gorbach S. Antimicrobial substance from a human Lactobacillus strain. Antimicrob Agents Chemother 1987;31:1231–3. 60. Szajewska H, Kotowska M, Mrukowicz JZ, et al. Efficacy of Lactobacillus GG in prevention of nosocomial diarrhea in infants. J Pediatr 2001;138:361–5. 61. Thomas MR, Litin SC, Osmon DR, et al. Lack of effect of Lactobacillus GG on antibiotic-associated diarrhea: a randomized, placebo-controlled trial. Mayo Clin Proc 2001;76:883–9. 62. D’Souza AL, Rajkumar C, Cooke J, Bulpitt CJ. Probiotics in prevention of antibiotic associated diarrhoea: meta-analysis. Br Med J 2002;324:1361.

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63. Hilton E. Lactobacillus GG in prevention of travelers’ diarrhea. J Travel Med 1997;4:41–3. 64. DuPont HL. Lactobacillus GG in prevention of travelers’ diarrhea: an encouraging first step. J Travel Med 1997;4:1–2. 65. Oberhelman RA, Gilman RH, Sheen P, et al. A placebo-controlled trial of Lactobacillus GG to prevent diarrhea in undernourished Peruvian children. J Pediatr 1999;134:15–20. 66. Kollaritsch H, Holst H, Grobara P, Wiedermann G. Prevention of travelers’ diarrhea by Saccharomyces boulardii: results of a placebo-controlled double blind study. Fortschr Med 1993;11:153–6. 67. Oksanen PJ, Salminen S, Saxelin M, et al. Prevention of travelers’ diarrhea by Lactobacillus GG. Ann Med 1990;22:53–6. 68. de dios Pozo-Olano J, Warram JH Jr, Gomez RG, Cavazos MG. Effect of a lactobacilli preparation on travelers’ diarrhea: a randomized, double-blind clinical trial. Gastroenterology 1978;74:829–30. 69. Szajewska H, Mrukowicz JZ. Probiotics in the treatment and prevention of acute infectious diarrhea in infants and children: a systematic review of published randomized, double-blind, placebo-controlled trials. J Pediatr Gastroenterol Nutr 2001;33 Suppl 2:S17–25. 70. Saavedra J. Probiotics and infectious diarrhea. Am J Gastroenterol 2000;95 Suppl 1:S16–8. 71. Ericsson CD. Travelers with pre-existing medical conditions. Int J Antimicrob Agents 2002.[In press] 72. Mileno DM, Bia FJ. Travel medicine: the compromised traveler. Infect Dis Clin North Am 1998;12:369–412. 73. Castelli F, Patroni A. The human immunodeficiency virus-infected traveler. Clin Infect Dis 2000;31:1403–8. 74. Frenck R, Ericsson CD. Protection of travelers. In: Long SS, Pickering LK, Prober CG, editors. Principles and practice of pediatric infectious diseases. New York: Churchill Livingstone, In.; 1997. p. 79–96. 75. Reves RR, Johnson PC, Ericsson CD, DuPont HL. A cost-effectiveness comparison of the use of antimicrobial agents for the treatment or prophylaxis of travelers’ diarrhea. Arch Intern Med 1988;148:2421–7. 76. Ericsson CD, Nicholls-Vasquez I, DuPont HL, et al. Optimal dosing of trimethoprim/sulfamethoxazole when used with loperamide to treat travelers’ diarrhea. Antimicrob Agents Chemother 1992;36:2821–4. 77. Ericsson CD, Feldman S, Pickering LK, Cleary TG. Influence of subsalicylate bismuth on absorption of doxycycline. J Am Med Assoc 1982;247:2266–7. 78. Gaarslev K, Stenderup J. Changes during travel in the composition and antibiotic resistance pattern of the intestinal Enterobacteriaceae flora: results from a study of mecillinam prophylaxis against travelers’ diarrhoea. Curr Med Res Opin 1985;9:384–7. 79. Huang DB, Jiang ZD, Ericsson CD, et al. Emergence of trimethoprim-resistant Escherichia coli in healthy persons in the absence of prophylactic or therapeutic antibiotics during travel to Guadalajara, Mexico. Scand J Infect Dis 2001;33:812–4. 80. Segreti J, Gootz TD, Goodman LJ, et al. High-level quinolone resistance in clinical isolates of Campylobacter jejuni. J Infect Dis 1992;165:667–70. 81. Adler-Mosca H, Luthy-Hottenstein Lucchini GM, et al. Development of resistance to quinolones in five patients with campylobacteriosis treated with norfloxacin or ciprofloxacin. Eur J Clin Microbiol 1991;10:953–7. 82. Shanks GD, Ragama OB, Aleman GM, et al. Azithromycin prophylaxis prevents epidemic dysentery. Trans R Soc Trop Med Hyg 1996;90:316. 83. Ericsson CD, DuPont HL, Mathewson JJ. Epidemiologic observations on diarrhea developing in U.S. and Mexican students living in Guadalajara, Mexico. J Travel Med 1994;2:6–10.

Chapter 13

IMMUNITY

AND

IMMUNOPROPHYLAXIS

David B. Huang, MD, MPH, and Mar y K. Estes, PhD

Gastrointestinal tract infections, especially infectious diarrhea, are an important cause of morbidity and mortality in developing countries. These infections occur worldwide during travel to underdeveloped countries with immediate and long-term consequences in people of all ages. The human gastrointestinal tract, an estimated 200 to 300 m2, is a major defensive barrier to the antigenic load it encounters. It can provide a hostile environment for most pathogenic microorganisms while maintaining homeostasis of normal flora. Immunity refers to the mechanisms used to protect a host against environmental agents that are foreign to the body. The mucosal surface is the first portal of entry for most infectious agents. Gastrointestinal immune mechanisms prevent infections by either innate or acquired immunity. Innate immunity is nonspecific and is not acquired through contact with an antigen. The gastrointestinal epithelium, hypersensitivity and complement activation, phagocytosis, and inflammation by leukocyte and serum protein products such as lysozomes and lactoferrin are examples of innate immunity. Acquired immunity is specific and requires contact with an antigen such that a local antibody is produced to a foreign antigen. Acquired immunity evokes antigen-specific secretory IgA, T cells, and B cells, and is elicited by active infection or administration of oral or parenteral vaccinations (Table 13-1).

ACTIVE AND PASSIVE IMMUNITY Active immunity is resistance after contact with foreign antigens. It can occur with either subclinical or clinical infection, immunizations with live or killed infectious agents, and exposure to microbial toxins. Active immunity provides resistance that is generally long-term but slow in onset. Immunity to gastrointestinal infections is complex and difficult given the many types of enteric pathogens. Essential properties to pathogenicity, regardless of the pathogen, include the production of toxin and the adherence ability to intestinal mucosa to induce malabsorption or secretory diarrhea. The rest of the intestinal antibodies target endotoxin, capsular material, and exotoxins, and may function with bactericidal, opsonic, or neutralizing effects. Macrophage, T cells, and plasma cells are concentrated in the lamina propria of the small intestine to provide cell-mediated immune responses.1 T cells in the lamina propria are mostly CD4 helper T cells, and intraepithelial lymphocytes are mostly CD8 cytotoxic T cells.2,3 Natural immunization occurs by subclinical and clinical infections and sensitization to noninfectious foreign antigens. Artificial immunization occurs by vaccination through live attenuated, killed, or inactivated microorganisms or toxoids.

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Table 13-1. Acquired and Innate Gastrointestinal Tract Immunity Acquired

Innate

Secretory IgA

Amount of gastric acid secretion

T cells

Intestinal motility

Helper

Mucous tissue integrity and secretion

Cytotoxic

Intestinal epithelium

B cells

Hypersensitivity reactions

Immunization

Complement

Oral Parenteral Breast-feeding

Antigen presenting cells and phagocytes Macrophages Leukocytes Leukocyte and Serum Protein Products Lysozomes Lactoferrin Proteases Nucleases Fibronectin Lipases Natural killer cells

Passive immunization is the acquisition of preformed immunoglobulins from another host that are passively transferred in serum or in colostrum to protect an individual from local intestinal and systemic pathogens. Passive immunization provides resistance that is short-term but prompt in onset. This type of immunization has a risk of hypersensitivity reactions, especially if the globulin products are from another species. Natural immunization is the transplacental passage of maternal IgG antibodies and the passage of immunological and antimicrobial factors through breast-feeding. Artificial immunization is the administration of antibodies produced in another host. Antitoxins to diphtheria, tetanus, and botulism, and preformed antibodies to rabies and hepatitis A and B viruses are examples. The protective ability of colostrum is correlated with its content of specific IgA antibody. Human milk also contains lactoferrin, lysozyme, phagocytes, and bacteriostatic properties.

GASTRIC ACID BARRIER A normal gastric acid barrier prevents most bacterial pathogens from reaching the intestinal tract. When this gastric acid barrier is disrupted (ie, antacids or gastric surgery), the susceptibility and severity of enteric bacterial and parasitic infections are increased. With normal gastric acidity (pH<4), 99.9% of ingested bacteria are killed within 30 minutes. In contrast, individuals who are achlorhydric show no reduction of bacterial inoculum after 1 hour. The increased normal bacterial flora in the upper small bowel contributes to the development of malabsorption and diarrhea syndromes.

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GASTROINTESTINAL EPITHELIUM The intestinal epithelium acts as a “first line” of defense and plays an important role in the immunocompetency of the gastrointestinal tract. This epithelium develops during the first trimester of mammalian fetal life and is influenced by diet, method of birth, and microbe–microbe and microbe–host interactions.4-8 The lymphatic tissue of the intestine reacts to antigenic stimuli by rapid development during the first days after birth. The intestinal epithelium is composed of mucin-containing columnar cells which possess cysteine residues that allow for the binding of IgA.9 These intestinal cells also have microvilli and granular inclusion lymphocytes, and are responsible for the synthesis and excretion of proteins such as the secretory protein associated with IgA. The columnar epithelium cells are also responsible for the transportation of luminal substances like carbohydrate, protein, fat, viruses, and bacteria across the cell and basement membrane. The microfold (M) cell is a specialized epithelial cell type that transports antigen to underlying aggregations of lymphoid cells and sensitizes precursors of mucosal antibody-forming cells within the Peyer’s patches. Antigens may also be retained within the mucosa or mesenteric lymphoid tissues, or reach portal or lymphatic vessels to return to the gut mucosal surfaces.10,11 Deposition in the gut leads to the production of IgA antibodies in the gut and secretions at sites, such as colostrum, lacrimal, and salivary secretions.12,13 Precursors of IgAproducing cells can migrate from the gut-associated lymphoid tissue (GALT) to secretory sites such as the breast, sweat glands, and the respiratory and genitourinary tracts. Epithelial cells also secrete cytokines such as IL-1
, IL-1, IL-6, IL-8, IL-10, monocyte chemoattractant protein-1 (MCP-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-
(TNF-
) and transforming growth factor- (TGF-).14 These mediators are proinflammatory and recruit inflammatory cells to mucosal infection sites. TGF-, secreted by macrophages, T cells, and epithelial cells, has been shown to enhance IgA production.15,16 The gastrointestinal mucus binds organisms and toxins and is continually being removed and renewed along with any adherent bacteria. Intestinal epithelial cells have a life cycle of about 2 to 5 days. The peristaltic movements of the gastrointestinal tract also enhance the removal of mucusbinding microbes. Antimotility agents used during acute infectious diarrhea cause stasis, leading to bacterial overgrowth syndromes, prolonged fever, and shedding in individuals infected with shigellosis. Colonization of pathogenic microorganisms and systemic infections can be reduced with the preservation of a normal distribution of enteric flora. Disturbance of this enteric microflora balance with use of antibiotics is associated with diarrhea and more aerobes such as Pseudomonas, Klebsiella, Clostridium, and Candida.

HYPERSENSITIVITY AND COMPLEMENT REACTIONS Hypersensitivity and complement reactions are responsible for resistance to microbial infection through the gastrointestinal tract. Four types of hypersensitivity reactions have been described.17 Type I reactions, also called “immediate hypersensitivity,” occur when an antigen combines with the antibody on the Fc surface of tissue mast cells and basophils. An intracellular reaction then occurs with subsequent release of histamine and other vasoactive substances responsible for vasoactive abil-

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ity, vasodilatation, smooth muscle contraction, and occasional systemic anaphylaxis. These IgEcontaining plasma cells are located in the nasal mucosa, tonsils, intestine, nasal fluid, saliva, and sputum. In gastrointestinal disorders, these responses are associated with some worm infestation and massive worm expulsion. Parasitic infections are often able to traverse the intestinal barrier into the blood or lymphatic circulation. IgE antibodies bind to surface proteins on worms. The surface of eosinophils binds IgE and causes release of major basic protein from eosinophils, which damages the surface of the worm. Hypersensitivity reactions toward ingestion of food antigens may also lead to IgE antibody production and symptoms including diarrhea, vomiting, urticaria, angioedema, and asthma. Mast cells, responsible for immediate hypersensitivity and allergic responses, are located at all levels of the intestinal tract. The physiological role of this system is still not completely understood but its role in gastrointestinal diseases such as parasitic infections, peptic ulcer disease, and celiac disease is now being better understood. Type II reactions, termed “cytotoxic hypersensitivity,” occur when complement-fixing antibodies attach to the antigens on the surface of the body’s own cells. Complement activation leads to the destruction and decreased life span of the host cell. Cytotoxic lymphocytes can also target and lyse these IgG antibody-coated cells. Hemolytic anemia, agranulocytosis, thrombocytopenia, transfusion, or Rh reactions can be caused by an autoimmune process, which allows antibody against self-antigens or against a drug or chemical. Examples of gastrointestinal cytotoxic hypersensitivity reactions include ulcerative colitis, Crohn’s disease, and pernicious anemia. With the formation of circulating antigen–antibody complexes, systemic symptoms such as iritis, dermatitis, and arthritis can develop. Type III reactions, called “immune complex hypersensitivity,” occur when an antigen and complement-fixing antibody complex is deposited in tissues. The result is increased capillary permeability, recruitment of phagocytes, and release of lysozymes from polymorphonuclear cells. Tissue destruction and release of inflammatory mediators occur. The antigen, complement, and antibody complexes are deposited in the walls of endarterioles on mucosal surfaces and in the renal glomeruli. The consequence includes vasculitis, arthritis, glomerulitis, and serum sickness. Type IV reactions, called “delayed hypersensitivity,” involve antigen and antigen-sensitive helper T lymphocytes. Macrophages and lymphocytes accumulate perivascularly and release large amounts of soluble mediators and lymphokines that alter capillary permeability and form granulomas. This reaction has been best described with the tuberculin intradermal skin test and contact hypersensitivity. The interaction between complement and IgA in the gastrointestinal tract is unclear. IgA antibody is unable to fix complement. Little complement is present in the external secretions of the gastrointestinal tract, and these proteins are prone to degradation and inactivation by proteolytic enzymes. If the antigen is able to traverse the intestinal mucosa, submucosal reactions involving complement factors are then activated. Complement functions occur by opsonization and lysis to clear antigens from the body. The complement system contains 20 serum proteins and glycoproteins. Activation of the complement system occurs by two pathways: the classical and alternative (properidin) pathways. Type II and III reactions rely on the complement activation system. Inflammatory peptides are released causing vasodilatation, capillary permeability, and attraction and disruption of neutrophil polymorphonuclear leuko-

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cytes. If the antibody or complement function fails, clearance of the antigen will be unsuccessful, and these circulating complexes may lodge in small vessels walls, which may then activate low-grade complement fixation, impair physiological function, and ultimately cause tissue destruction.

LEUKOCYTE AND SERUM PROTEIN PRODUCTS Lysozyme is a bacteriolytic enzyme produced by the antral glands of the gastric mucosa, Paneth’s cells, and Brunner’s glands of the small intestinal mucosa, neutrophilic granulocytes, and macrophages. This molecule is responsible for directly inhibiting bacterial growth and preventing microbial adhesion to epithelium by retaining antimicrobial peptides and secretory antibody close to the epithelial surface.18,19 Lactoferrin is an iron-binding protein that exerts a bacteriostatic and bactericidal effect on gram-positive and gram-negative bacteria by saturation with iron.20,21 Lactoferrin is produced in the antral glands of gastric mucosa and in neutrophilic granulocytes. Serum IgA antibodies enhance the bacteriostatic effect of lactoferrin by inhibiting bacterial production of ironchelating agents that may interfere with its function.22,23 Other degradative enzymes essential to the killing of microbes include proteases, nucleases, fibronectin, and lipases.

STRUCTURAL AND BIOLOGIC PROPERTIES OF IgA IgA was discovered in 1960 and found to be predominant in several external secretions such as saliva, colostrum, mucus, sweat, gastric fluid, and tears.24 Secretory IgA, an 11S dimer, is important against local infections, especially in the respiratory, gastrointestinal, and genitourinary tracts. In humans, more than 90% of plasma cells in the normal intestine secrete IgA, which serves as a major source of intestinal protection against pathogens. Secretory IgA, with a half-life of 5.5 days, consists of four light chains, one secretory component, and one J chain with a total molecular weight of 385,000 to 400,000 daltons (Figure 13-1). The J chain is covalently linked to the penultimate cysteine residue of the C-terminal alpha chain by disulfide bonds. The J chain is responsible for the attachment of the secretory component of IgA.25 The secretory component serves important roles in the transport of secretory IgA through the epithelial cells to the lumen and in the stabilization of the secretory IgA molecule from proteolysis in the gastrointestinal tract. Secretory antibodies are mainly of the IgA class. The IgA in secretions are dimeric, whereas serum IgA is monomeric. IgA plasma secreting cells are predominantly found in the gastrointestinal tract. The secretory form of IgA is responsible for protection against surface infections such as Vibrio cholerae, Escherichia coli, Salmonella, Shigella spp, and enteric viral infections.9 The gastrointestinal glandular epithelium, found at the bases of the intestinal villi and Peyer’s patches, is where the majority of IgA is synthesized. After synthesis, much of the IgA drains into the lymphatics and circulation, and returns to the mucosa and to areas associated with infection and inflammation. Transport of IgA occurs by passing through gaps in the basement membrane through a receptor-mediated mechanism. A special polymeric immunoglobulin receptor (pIgR), located on the basolateral membrane of intestinal cells, allows endocytosis of the dimeric IgA.26 IgA is then transmitted to the luminal surface across the apical portion of the cell via exocytosis.27

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Figure 13-1. Structure of serum IgA and secretory IgA. Note that both types of IgA have a J chain but only secretory IgA has a secretory component. Reproduced with permission from Stites and Terr.117

Two subclasses of IgA exist. IgA1, predominantly found in the serum, makes up 90 to 95% of total IgA. IgA2, about 5 to 10% of total IgA, is mainly found in breast and colostrum. In newborns, IgA is absent in peripheral lymphoid intestinal tissue. This immunoglobulin develops with the exposure to intestinal contents such as microbes and dietary antigens. The function of IgA is to provide protection against infections, such as bacteria, viruses, toxins, and other antigens at mucosal surfaces.28 Many immunization and vaccination principles have been used to enhance secretory IgA production to microbial agents. Secretory IgA is noninflammatory and does not opsonize, activate, or fix complement since it does not contain receptors for complement. As a result, the mucosal immune reaction favors immune exclusion over complement-activated inflammatory responses. It is an efficient agglutinating antibody, which functions primarily by blocking microbial or toxin adherence, preventing absorption to

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mucosal surfaces and providing bacteriostatic and bactericidal activity against gram-positive and gram-negative organisms in the presence of lysozyme. IgA is responsible for limiting the entry of foreign antigens through the epithelium by complexing with the antigen, thereby increasing its size and preventing it from transversing the epithelium. It also neutralizes toxins and limits the mobility of microbes. Dysregulation or dysfunction of this system could be responsible for entry of foreign antigens and stimulation of a systemic antibody response or a submucosal hypersensitive response. An ineffective IgA response is associated with an increased IgE and IgM response. Children with defective secretory IgA systems develop more extrinsic allergies later in life.29 Secretory IgA is also an efficient antiviral antibody, preventing viruses from entering host cells. Specific secretory antiviral antibodies may prevent infection; however, local antiviral secretory antibody is not confined to the IgA immunoglobulin class. An effective immune response can be mounted by IgM or IgG antibodies in patients with selective IgA deficiency. In addition, cytotoxic T cells can kill target cells infected with viruses to which the T cells have been sensitized and to which the target cells have identical class I major histocompatibility complex (MHC) antigens. Natural killer (NK) cells are responsible for killing virus and tumor-infected cells by secreting cytotoxins such as perforins and interferon. Interferon inhibits viral replication, induces blastogenesis, stimulates NK cell proliferation, and enhances NK cell cytotoxicity. Natural killer cells are large granular lymphocytes that make up 5 to 10 % of peripheral lymphocytes. They do not require recognition of MHC proteins, do not require prior exposure, and are not specific for any virus or tumor. The microecological system and the interactions between bacteria, viruses, and the host are complex, involving an immune system that must function against pathogens while preserving a symbiotic relationship with the normal flora. The predominant antibody produced in the gastrointestinal tract is IgA, which functions to neutralize bacteria and viruses, provide antitoxin activity, inhibit bacteria adherence to mucosal surfaces, and inhibit bacterial enzymes and antigen uptake.30-33 Pentameric secretory IgM and IgG, mainly derived from serum, appear at mucosal sites to a lesser extent. Most IgA are present in secretions such as tears, saliva, colostrum, sweat, and mucus, where it serves an important immunobiologic function of the GALT. The GALT is responsible for regulating positive protective immune responses and generating tolerance or nonresponsiveness. It is composed of the Peyer’s patches, macrophages, lamina propria lymphocytes, and intraepithelial lymphocytes.

PEYER’S PATCHES Much of the intestinal immunological response occurs at mucosal lymphoid tissue in the Peyer’s patches, appendix, and tonsils. These mucosal lymphoid aggregates contain lymphoepithelium infiltrated with lamina propria lymphocytes and intraepithelial lymphocytes. Peyer’s patches occur throughout the small intestine but are most prominent in the distal ileum. Three layers, the dome, lymphoid follicle, and thymus-dependent area, make up the Peyer’s patches. The dome area is heavily infiltrated with B lymphocytes (Figure 13-2) and the lymphoid follicle is rich in IgA. The epithelium of these cells stain with IgA and IgM antisera.34 Peyer’s patches also contain regulatory T cells that induce immature IgM-bearing B cells to switch isotype to IgA.35

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Figure 13-2. Light micrograph of section through mouse Peyer’s patch stained for B lymphocytes by an immunoperoxidase technique (using anti-B220 monoclonal antibody). Follicles (F) consist largely of B cells, and a few scattered B cells are present in interfollicular areas (I). V, villus. 50.

Antigens are taken up by the dome of lymphoid aggregate through specialized M cells. These cells contain little cytoplasm and cover epithelial cells, permitting lymphoid cells to approach the gut lumen very closely. The M cells function to maintain tight junctions with adjacent epithelial cells while preserving the integrity of the gut epithelium. These cells are involved with transport of antigenic material from the intestinal lumen to underlying lymphoid cells, coupling of IgA to the secretory component, and transporting secretory IgA into the lumen. After being processed in subepithelial macrophages, antigens are presented to sub- and intraepithelial T lymphocytes by class II MHC protein expressing antigen-presenting cells (APC). This complex stimulates serum antibody production, predominantly IgG or IgA, by plasma cells located mainly in the lamina propria and increased cell-mediated responses to antigenic stimulation. Studies have shown that transferring Peyer’s patch cells to lethally irradiated rabbits can lead to a re-population of the lamina propria of the intestine, mesenteric lymph nodes, and spleen with IgAproducing cells.36 Peyer’s patch cells are also responsible for draining lymphoid aggregates to local regions in the intestine and for the education of cells destined for formation of IgA antibody.

T CELLS AND B CELLS Thymus (T) cells and bursa (B) cells (the mammalian equivalent of the bursa of Fabricius in birds) are derived from primitive bone marrow stem cells of the reticuloendothelial cells. Large numbers of T and B cells are present in the mucosa of the gastrointestinal tract and exhibit remarkable diversity, long-term memory, and specificity against antigens. Once a microbe surpasses the physiochemical mucosal barriers and has invaded a host cell, both T cells and B cells recognize foreign antigens, activate immune cells to elicit a specific response, and target an infected cell for destruction.

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T cells migrate to and mature in the thymus gland, 1) acquiring the capacity to recognize class II MHC proteins that appear on antigen-presenting cells such as macrophages, and 2) differentiating into T cells that can express CD3, CD4, and CD8 molecules on their surface. T cells participate in cellmediated and delayed hypersensitivity reactions, rejection, and processing of antigens. Macrophages are responsible for phagocytosis, cleaving foreign protein into small peptides, and transporting these small peptides to the surface of the macrophage in association with the class II MHC proteins. Macrophages also produce cytokines such as IL-1, which activates helper T cells, and TNF, which is an inflammatory mediator. The APC class II MHC protein interacts with a helper T cell through an antigen-specific receptor. Interleukin production, mainly IL-1 (produced by macrophages) and IL-2 (produced by lymphocytes), stimulates APC helper T cell activation and clonal proliferation. T cells include both helper T cells (CD4) and cytotoxic T cells (CD8). The phenotypic distribution of CD4:CD8 T cells is 2:1. Helper T cells participate in antigen recognition and in regulatory functions of helper T cells and suppressor T cells through the production of interleukins. Cytotoxic T cells kill with or without antibody and are activated in response to virus-infected cells, which express viral envelope glycoprotein on their surfaces in association with class I MHC proteins. Cytotoxic T cells then bind the virus-infected cell by antigen-specific receptors to the viral antigen class I MHC protein complex. Perforins are then released which destroy the membrane of infected cells, or the induction of programmed cell death (apoptosis) occurs. B cells and plasma cells are found in the bone marrow and diffuse lymphoid structures of the gut, such as the Peyer’s patches, appendix, and tonsils. They are responsible for antibody-mediated responses and neutralizing toxins, viruses, and opsonizing bacteria. B cells form plasma cells, which secrete antibodies after antigens are processed by macrophages in association with class II MHC proteins. Helper T cells then produce IL-2, a T cell growth factor which activates CD4 and CD8 cells; IL-4, a B cell growth factor and facilitator of isotype switching from surface IgA-negative to surface IgA-positive B cell; IL-5, a B cell differentiation factor to help B cells develop into antibody producing plasma cells; and gamma interferon, which activates macrophages and increases expression of class II MHC. Some antigens are T cell-independent, such as polymerized macromolecules like bacterial capsular polysaccharide. B cells can also serve like an APC by internalizing immunoglobulins that bind with an antigen. The stimulation and differentiation of B cells into antibody-producing plasma cells require activated T cells interacting with a CD40 protein on the surface of resting B cells. In addition, an interaction between CD28 on T cells must occur with B7 proteins on antigen-presenting cells, and lymphocyte function-associated (LFA) antigen of T cells must bind to intracellular adhesion molecules (ICAM-1) on APCs. LFA belongs to a family of cell surface proteins called integrins. “Memory” B cells bear surface immunoglobulins of the same class and differentiate to plasma cells on re-encountering antigens. Response to infection, food antigens, and immunity from reinfection is dependent on both B and T cell populations. The proportion of B to T cell population is dependent on the type of infection. B cell response is induced by infections with viruses, and gram-positive and gram-negative bacteria, whereas T cell response is induced by infections with certain viruses, fungi, parasites, and intracellular bacteria such as mycobacterium.

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T CELL AND B CELL DEFICIENCY T cell deficiency prevents the development of cell-mediated reactions and is associated with recurrent infections with viruses, fungi, parasites, and intracellular bacteria. In children with T cell deficiencies, jejunal biopsies may show villous atrophy and vacuolated macrophages in the lamina propria. 37 Examples of T cell deficiencies include DiGeorge syndrome, chronic mucocutaneous candidiasis, and hyper-IgM syndrome. Deficiency of B cells will cause a failure of antibody production and predispose to recurrent infections with viruses, and gram-positive and gram-negative organisms, especially pyogenic bacteria like Staphylococci. Antibody deficiencies occur by decreased production through bone marrow failure, cytotoxic drugs, or increased loss through the kidney or gastrointestinal tract. The most common immunoglobulin deficiency is IgA, which occurs in 1 in 700 individuals.38 IgA plays an important immunological role in mucosal surfaces. Surprisingly, no increased susceptibility is noted in individuals deficient in IgA to gastrointestinal infections, presumably due to IgM combining with a secretory component and compensating for IgA in selective IgA deficiency. Mixed T and B cell deficiencies occur more often and include a variety of clinical syndromes such as Wiskott-Aldrich syndrome, ataxia-telangiectasia, and severe combined immunodeficiency (SCID) disorder. Hypofunction of both T and B cells, such as in SCID and sex-linked Bruton’s disease, is often characterized by diarrhea and malabsorption in addition to susceptibility to viral, fungal, parasitic, and bacterial infections. Other immunological defects in response to certain types of antigens involving the gastrointestinal system exist, such as complement and phagocyte deficiencies. Failure can cause increased susceptibility to specific types of infections, poor antigen clearance, and chronic persistence of a microorganism.39 Some immunological defects are acquired, such as untreated patients with acquired immunodeficiency syndrome. These patients commonly present with opportunistic infections caused by viruses, fungi, parasites, and bacteria. Severe intestinal presentations and recurrent enteric infections occur in HIV patients with cytomegalovirus, Entamoeba histolytica, Cryptosporidium, Microsporidium, Salmonella, Giardia lamblia, Campylobacter jejuni, Shigella spp, Mycobacterium, Cyclospora, and enteroaggregative Escherichia coli.40-43

ORAL AND PARENTERAL VACCINATION Vaccinations are the most effective way of controlling and eradicating infectious diseases. They represent the most cost-effective public health measure leading to improved health worldwide, in terms of both reduced morbidity and mortality. Vaccinations may be administered parenterally, orally, intranasally, transdermally, and rectally.44-46 Traditionally, parenteral immunizations have predominated. This method generally does not elicit an effective IgA response or local cell-mediated immunity. In contrast, mucosal vaccines are easy to administer, safer (decreased risk of transmission of bloodborne pathogens), and less costly than parenterally administered vaccines. IgA antibody synthesis occurs with oral immunization of microbes and food antigens. Immunity and tolerance are likely concurrently induced in Peyer’s patches, where suppressor, helper, and antibody precursor

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cells are stimulated.47 The antibody levels produced in secretions, however, do not correlate with those in serum. Oral immunization to poliovirus with the Sabin vaccine (ie, live-attenuated vaccine) has been shown to produce an IgA response in intestinal secretions, whereas parenteral immunization with the Salk vaccine (ie, killed vaccine) has not.48 Both forms of the polio vaccine are able to produce serum antibody. Similar results have been shown for Shigella, typhoid, and cholera.49 The ability of oral immunization to induce a secretory and serum immune response after mucosal contact with antigen appears to be a useful mechanism to exclude potentially harmful substances from the body.50 The serum immune response acts as a secondary defense to clear antigens that penetrate the barrier of the intestinal epithelium. Antibody production to vaccines is generally dependent on multiple factors such as the number and frequency of pathogens ingested, the route of entry, antigen, prior exposure, and the scheduling of immunizations (Table 13-2).51 Relatively large bacterial antigen doses are needed to induce enteric infections and a secretory response in the gut.49 The nature of the antigen and prior immunity are also strongly correlated to the ability of the antigen to reach the portal circulation or lymphatic system and cause a secretory response. Vaccinations with live-attenuated Vibrio cholerae, Escherichia coli, Salmonella typhimurium, and Shigella spp, produce greater immunogenicity than killed vaccinations.52-54 Some advantages exist with using killed vaccines (eg, safety); however, larger doses are needed to induce secretory responses compared to the use of live vaccines. The nature of the antigen (soluble or particulate) and the age of the host are also important. Particulate and insoluble antigens have been more effective in inducing secretory antibodies than soluble antigens. Age has effects on secretory antibody responses, the production of mucus in the gut, cell-surface factors, microbial flora environmental exposures, and

Table 13-2. Factors Influencing Secretory Antibody Responses Frequency of exposure Infection Immunizations Food antigens Dosage of antigen Nature of antigen Living/Killed Particulate Soluble/Insoluble Host factors Host species and age Personal hygiene and sanitation facilities Housing and population density Water sources Immunocompetency Phagocytic Humoral Cell-mediated Genetic differences Prior exposure Site of immunization

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specific immune factors. It is unknown if human IgA response shows any decrement with age, but it is likely that the secretory systemic immune system becomes less efficient with advanced age. In the elderly, there is reduced IgG response to certain antigens, decreased T cells, and delayed type hypersensitivity response. In aged mice, compared to young mice, impaired antigen-specific mucosal IgA and systemic IgG responses occur to ovalbumin and cholera toxin as adjuvant. These results suggest that mucosal immunity is down-regulated in aged mice.55 Prior exposure is important, as secretory responses are enhanced by prior systemic sensitization. Unfortunately, animal studies have shown that the duration of secretory responses after gut immunization are generally short lived. Following the migration of antigen-sensitive cells of Peyer’s patches to secretory tissues, plasma cells do not continue to secrete antibodies in the absence of any local or continued antigen challenge. Oral immunization is associated with a local immune response in the intestine. This local immune response has memory and is able to generate immune competent cells and serum antibodies with repeated challenges. Oral immunization may induce both a mucosal and systemic antibody response. The deposition of antigen directly onto intestinal mucous membranes leads to the formation of antibodies, particularly those of the IgA isotype. Systemic serum antibody response occurs by absorption of the antigen across the mucosa and reaching systemic antibody sites like Peyer’s patches. Parenteral immunization may also induce antibody production at mucosal surfaces and enhance responses to subsequent antigen exposures.56 The practical requirements for an oral immunogen include being 1) effective and able to protect against a range of agents in an endemic area; 2) stable without the use of refrigeration or complex administration schedules, especially those with repeated dosages or frequent boosters; 3) affordable; 4) easy to administer; and 5) able to meet safety requirements. Antigen exposure in the gastrointestinal tract may lead to immunization by hyporesponsiveness. Also known as oral tolerance, hyporesponsiveness refers to the loss of the ability to respond to a specific antigen on subsequent systemic challenge in both humoral and cellular arms of a normally functioning immune system, when an antigen continues to be present. Both the liver and the intestine play a part in the induction of oral tolerance by processing antigens, acting as a source of suppressor cells, and producing soluble mediators.57 Oral tolerance applies mainly to T cell-dependent antigens and results in decreased systemic helper T cell activity, antigen-mediated proliferation of T cells, and delayed hypersensitivity reactions.58 Suppressor-induced T cells in Peyer’s patches have been shown to mediate oral tolerance. These suppressor-inducer cells differ phenotypically from other T cells in Peyer’s patches and have been shown to produce IL-10 and TGF-, which mediate tolerance to luminal antigens.59,60 Factors that affect oral tolerance include whether the antigen is particulate or soluble, protease sensitive or resistant, or easily aggregated in the intestinal tract. Oral tolerance could be applied in principle as oral desensitization to prevent immunological responses to recurrent antigenic exposures; however, large doses of antigen and frequent administrations are often required. Other promising mucosal vaccination avenues being explored are the use of attenuated bacteria or viruses as antigen delivery vectors, the inclusion of immunizing antigens in lipid-based carriers such as liposomes or immune stimulating complexes (Iscoms), the genetic creation of transgenic plants expressing antigens, and the use of the mucosal adjuvants derived from bacterial toxins.

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Attenuated mutants of Salmonella have been used as antigen-delivery vectors of antigen strains.61-64 This mode of immunization is useful because of its bivalent vaccine nature, providing protection from both Salmonella infection and the foreign antigen used. The attenuated bacteria are able to invade epithelium and deliver the foreign antigen to lymphoid follicles present in the GALT. A prototype hybrid vaccine against Shigella and enterotoxigenic E. coli (ETEC) has similarly been developed with Shigella live vectors expressing relevant ETEC antigens.65,66 Antigens in lipid-based carriers are encapsulated and allow for controlled release for extended periods by protecting the antigen from degradation. The lipid-based carriers are composed of biodegradable polymer microspheres and have been shown to induce mucosal and systemic immune responses.67-69 Genetic transformations of plants using Agrobacterium T-DNA vectors, or viral vectors in which the plant virus encodes a foreign antigen, have been shown to produce serum and gut mucosal antigen-specific immune responses.70-72 Genetically created transgenic plants are inexpensive to grow and easy to deliver to the host. Mucosal adjuvants given with antigens allow for effective immune responses when challenged orally. Two potent mucosal immunogens are cholera toxin (CT) from Vibrio cholerae and heat-labile enterotoxin (LT) from enterotoxigenic E. coli. These two bacterial proteins are effective mucosal adjuvants for killed whole bacteria, fungi, and a number of inactivated viruses due to their ADPribosyltransferase activity.73,74 Both are composed of multisubunit toxins with A and B components. The A component has an A1 piece which catalyzes the ADP-ribosylation of the stimulatory GTPbinding protein in the adenylate cyclase enzyme complex. Increased intracellular levels of cAMP cause secretion of water and electrolytes into the small intestine. The B subunit is responsible for the binding to the host cell membrane receptor and facilitates the translocation of the A subunit through the cell membrane. However, the toxic potential has limited their practical use. A spontaneously arising toxin-negative variant of the ETEC strain, E1392/75-2A, has been found to confer 75% immunological protection against ETEC challenge when administered to volunteers.75 Genetically constructed live oral cholera vaccines have been made by deleting 94% of the gene for the enzymatically active A subunit for cholera toxin, thus making it well tolerated and immunogenic.76 Other virulence properties of bacteria have also been targeted. The fimbriae adherence capacity to mucosa through adhesins has been targeted for immunization in ETEC.77-81 The Vi antigen and the lipopolysaccharide cell wall of S. typhi and the O-specific polysaccharide conjugates of Shigella have also been targeted.82,83 Development of mucosal vaccines for induction of targeted immunity also includes cytokines of innate immunity, which influence the development of helper T cells. IL-12 and lymphotactin administered with a protein antigen have been shown to produce an antigenspecific mucosal IgA antibody repsonse.84

EXISTING AND FUTURE ENTERIC VACCINES Numerous attempts to develop oral vaccinations against enteric diseases such as Shigella spp, Salmonella typhi, Vibrio cholerae, enterotoxigenic E. coli, and rotavirus have been tried (Table 13-3). With increased understanding of the pathogenesis of enteric infections and characterization of the

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Table 13-3. Existing and Future Enteric Vaccine Characteristics

Existing Vaccines* Shigella spp

Salmonella typhi

Vibrio cholerae

Enterotoxigenic Escherichia coli

Antigenic Form

Live-attenuated

Live-attenuated

Live-attenuated

Inactivated

Mechanism of Action

Antibody against Vi and O antigens of the envelope LPS; deletions of htrA gene, which encodes a heat-shock protein

Antibody against inactivated cholera toxin (CT) and B (CT-B) subunit; bivalent CT-B subunit plus 01/0139 whole cell

Antibody against colonization factors (CFA), fimbrial, and other adhesive surfaces, and heat-labile and heatstable enterotoxins, and CT-B subunit – CFA

Infection Site Application Schedule

Deletions of aromatic metabolic pathways, subunit deletions of the gene for Shigella enterotoxin (ShET1 and ShET2) and the A subunit of the Shiga toxin; O antigenic polysaccharide chain linked to exoprotein A of Pseudomonas aeroginosa Colon Oral; parenteral 1 dose

Small intestine Oral Multiple to single doses

Small intestine Oral 2 doses

Protection Efficacy

— 43–74%

Small intestine Oral; parenteral 3 or 4 spaced doses every other day for oral; 1 dose for parenteral — 63–67% oral; 64–72% parenteral

— 85% at 6 months, 60% at 3 years, and >50% at 5 years postvaccination; 100% against classical V. cholerae and up to 60% against El Tor

— 20–79%

Duration

>7 months

Adverse Reactions

Self-limiting diarrhea

>7 years oral; 3 years parenteral Bacteremia

Future Vaccines Rotavirus Antigenic Form

Live-attenuated

Mechanism of Action

Viral neutralizing antibody against VP7 glycoprotein, VP4 hemagluttin spike, VP6 inner capsid protein, NSP4 glycoprotein Small intestine Oral 3 doses of 105 plaque-forming units/dose, each dose separated by minimum of 3 weeks — 48–80%; 70–95% against severe disease — Secretory diarrhea, intussusception

Infection Site Application Schedule Protection Efficacy Duration Adverse Reactions *Marketed or phase III.

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immunological parameters of mucosal protection, more vaccines will be developed to control these infections. The predominating Shigella spp serotypes that cause infection include Shigella dysenteriae type 1, Shigella flexneri types 1a, 2a, 3a, and 6, and Shigella sonnei. Specific genes responsible for Shigella species virulence factors have been targeted. The aromatic metabolic pathways have been genetically deleted, causing the inability of Shigella organisms to grow intracellularly. However, this method has had a fine balance between reactogenicity and immunogenicity and is thought to be not sufficient alone as an immunogenic live vaccine.85 Two Shigella enterotoxins, enterotoxin 1 (ShET1) and enterotoxin 2 (ShET2), have been targeted. ShET1 is found almost exclusively in S. flexneri type 2a, and ShET2 is found in all Shigella spp. Oral vaccines deleting ShET1, ShET2, and the A subunit of the Shiga toxin have been developed and are currently in clinical trials.85 In animal studies, Shigella lipopolysaccharide (LPS) up-regulates proinflammatory cytokines at the apical surface of the mucosa. Up-regulation of cytokines then signals an influx of immune cells from the basolateral surface. IgA antibodies are then directed against O antigen in the protection against Shigella.86 This property has been used by covalently linking the O antigenic polysaccharide chain of the LPS of Shigella spp to an immunogenic carrier protein such as exoprotein A of Pseudomonas aeruginosa. This attenuates the intrinsic noxious properties of LPS by its lipid A part and possibly boosts antibody levels.87 This method has been given parenterally (intramuscularly) to Israeli soldiers, with fourfold rises in serum IgA and IgG titers in 90% of individuals receiving the S. sonnei conjugate and in 73 to 77% of those receiving the S. flexneri conjugate.87 The protection efficacy against S. sonnei ranged from 43 to 74%, but it has only be assessed to 7 months.87 Longer efficacy trials are warranted. Other vaccination strategies to Shigella being tested include 1) modification of an E. coli strain to express Shigella flexneri 2a O antigen; 2) deletions of genes necessary for the organisms to proliferate in vivo after invasion; and 3) mutations that limit growth in human tissues and decrease intracellular spread from enterocyte to enterocyte.88 Live-attenuated Salmonella typhi cause bacteremia by rapidly crossing the intestinal mucosal layer with subsequent dissemination. The rapid crossing of the mucosa prevents any significant placebocontrolled, double-blind field trials in Nepal and South Africa.89,90 Serum IgA and IgG titers to the O antigen of the envelope LPS is associated with protection against Salmonella typhi.91 A licensed liveattenuated S. typhi strain, Ty21a, has been approved and is given in 3 or 4 spaced doses every other day. In a randomized, placebo-controlled field trial in Santiago, Chile, this vaccination had a protective efficacy of 67% and 63% over 3 and 7 years follow-up, respectively.91 Attempts have been made to develop a one-time oral dose, with limited success, due to the balance of immunogenicity and adverse effects. Adverse effects of Salmonella typhi vaccination include symptomatic and “silent” bacteremia. “Silent” bacteremia is defined as bacteremia that is transient and can be cleared without any antimicrobial treatment. Deletion of the htrA gene, which encodes a heat-shock protein of Salmonella typhi, is being developed as a single oral dose. In 22 human volunteers, this vaccination has been shown to be very promising since it results in increased serum IgA and IgG titers but does not have the adverse effects of bacteremia.92 Live-attenuated vaccination to V. cholerae prevents isolated gastrointestinal illnesses from developing. Salmonella typhi carries a capsular polysaccharide Vi antigen. This Vi antigen has been puri-

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fied and used as a parenteral polysaccharide vaccine with a protection efficacy of 64 to 72% for at least 2 years in randomized, placebo-controlled, double-blind field trials in Nepal and South Africa. A bivalent CT-B subunit plus 01/0139 whole cell oral inactivated vaccine was developed which elicited significant intestinal and systemic antibacterial immune responses in volunteers.93 These previously developed vaccines required multiple dosing. A recent single-dose oral live-attenuated vaccine, CVD 103-HgR, was developed to V. cholerae classical 01. CVD 103-HgR is an attenuated V. cholerae 01 form with deletion mutations in the genes encoding critical virulence factors. This vaccine was shown to be safe and immunogenic, with a protective efficacy of 100% against classical V. cholerae and up to 60% against El Tor cholera, and has a protective efficacy of at least 6 months.94 Other strains, such as serogroup 0139 Bengal, capable of causing epidemic cholera, are currently under study for vaccination development since no cross protection is developed with the other biotypes of cholera. Vaccines against ETEC have targeted these bacteria’s colonization factors (CFs) subunits of cholera toxin (CT) and CT-B.95 Two biotypes of cholera include classical 01 and El Tor. Three oral doses of an inactivated cholera B subunit whole cell vaccine has been shown to have a protective efficacy of 85% at 6 months, 60% at 3 years, and just below 50% at 5 years postvaccination.96 Protection appears to be mediated by secretory IgA antibody directed against fimbriae, other adhesive surfaces, and LT. Heatstable toxin (ST) does not elicit neutralizing antitoxin following natural infection. CFs allow bacteria to attach to the intestinal epithelial cell lining. There are numerous CF antigens and subcomponents, so a successful vaccine would have to require several of these. The LT and ST enterotoxins cause secretory diarrhea by inducing net secretion of electrolytes and water into the gut lumen. A CT-B subunit colonization factor antigen ETEC vaccine has been developed and is still in clinical trials. Preliminary data have shown that this vaccine is safe and elicits antibody responses in more than 70% of adults in Bangladesh with two oral doses.97 An oral inactivated rCT-B whole cell ETEC vaccine is currently been studied. Three studies have shown statistically nonsignificant protective efficacy in the range of 2079%. One study was terminated early due to poor enrollment. Two other studies are ongoing. Other vaccinations being developed include polymer-microencapsulated fimbrial antigens which protect the ETEC fimbriae from degradation by the gastric juice; inactivated fimbriated whole E. coli bacteria, given alone or with toxoids; and nonenterotoxigenic E. coli strains expressing CF fimbriae. A live-attenuated oral rotavirus vaccine was developed based on a rhesus rotavirus with the VP7 glycoprotein subunit of human rotavirus.98 This vaccination has been given to over 17,000 children in 9 countries with a protection efficacy of 48 to 80% against rotavirus infection and 70 to 95% against severe disease when given as 3 doses of 105 plaque forming units, each dose being separated by a minimum of 3 weeks.98-100 The VP4 hemagglutinin spike of rotavirus has also been targeted for virus neutralization.98 The VP6 inner capsid protein has been shown to elicit IgA antibodies which resolve chronic murine rotavirus infections.101 Nonstructural glycoprotein NSP4, responsible for rotavirus assembly, is responsible for inducing a secretory diarrhea by potentiating chloride secretion via a calcium-dependent signaling pathway. Antibodies to glycoprotein NSP4 have provided a protective effect against rotavirus infections.102 All of the above glycoproteins have a goal of producing virus neutralizing antibodies as potential candidates in inducing immunogenicity and protection against rotavirus infections.

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Vaccination remains the most realistic and cost-effective way of controlling enteric infections in endemic regions. Several promising enteric vaccines are in clinical trials as a result of the increasing knowledge developed in the past decade. With increased understanding and application of new technology to the health problems of developing countries, better vaccines and diagnostic tools will certainly be available in the near future.

MALNUTRITION AND SUSCEPTIBILITY TO GASTROINTESTINAL INFECTION There is a clear association between malnutrition and susceptibility to enteric infections.103,104 The severity of malnutrition and specific nutritional deficiencies have a significant influence on the immune system and can increase the susceptibility of attack rates and mortality from acute infectious diarrheal illnesses.104-106 Poor nutritional status is also associated with persistent diarrhea, defined as diarrhea lasting longer than 14 days. In 1973, Sirisinha found decreased concentrations of IgA in the secretions of children with protein calorie malnutrition.107 Serum IgA production seems to depend more on the nutritional state of the child than the other serum Ig classes. In addition, impaired T cell functions and innate defense factors contribute to the decreased resistance seen in malnutrition. The effects of malnutrition on the immune system complete a vicious cycle with gastrointestinal infections, especially acute infectious diarrhea, leading to increased anorexia, dehydration, persistent postinfective malabsorption, and exacerbating nutritional deficiencies.108-110 Thus, a bidirectional interaction exists between malnutrition and susceptibility to gastrointestinal infections. Breast-feeding has had a major impact in decreasing intestinal infections in infants, especially in developing countries. This protective effect is largely due to decreased intake of contaminated food and water.111-114 In addition, breast milk contains nutritional (eg, increased lactose, decreased protein, phosphate, and salt), immunological (eg, IgG, IgA, IgM, complement factors, lysozome, lactoferrin, macrophage, polymorphs, and lymphocytes), and other antimicrobiological properties (eg, antistaphylococcal factor, antibodies against rotavirus, and enterotoxins of V. cholerae and E. coli) not found in non-breast milk. Infants who are breast-fed have been shown to have less morbidity and mortality than those who are not breast-fed. With weaning, there is a significant increase in the risk of diarrhea illness.115,116

SUMMARY AND CONCLUSION The gastrointestinal tract is an organ involved in absorbing, processing, and transporting food into the body. It also functions as a major defensive barrier to external macromolecules and microbes. Both natural and acquired immunity are important in the pathogenesis and treatment of infectious and inflammatory gastrointestinal diseases. Specifically, the gastrointestinal epithelium, serum protein products, secretory IgA, T cells and B cells, and administration of oral and parenteral vaccinations are involved in preserving the gastrointestinal ecosystem, such that a state of controlled inflammation is established in adult hosts. With increased understanding of the gastrointestinal immune

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system and better technology, more effective strategies will be developed in facilitating mucosal immunization. In spite of the vast literature on the immunology of the gastrointestinal tract, there are still many aspects that remain incompletely understood. With advances in molecular biology, cloning techniques, and new assays to measure and quantitate mucosal immunological responses, fruitful and exciting developments will help answer questions and help prevent infections that use a mucosal surface as their portal of entry.

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80. Honda T, Arita M, Miwatani T. Characterization of new hydrophobic pili of human enterotoxigenic Escherichia coli: a possible new colonization factor. Infect Immun 1984;43:959–65. 81. Tacket CO, Maneval DR, Levine MM. Purification, morphology, and genetics of a new fimbrial putative colonization factor of enterotoxigenic Escherichia coli 0159:H4. Infect Immun 1987;55:1063–9. 82. Robbins PW, Uchida T. Determinants of specificity in Salmonella: changes in antigenic structure mediated by bacteriophage. Immunochemistry 1962;21:702. 83. Germanier R, Gurer E. Isolation and characterization of Gal E Mutant Ty 21a of Salmonella typhi: a candidate strain for a live, oral typhoid vaccine. J Infect Dis 1975;131:533. 84. Boyaka PN, Lillard JW Jr, McGhee J. Interleukin 12 and innate molecules for enhanced mucosal immunity. Immunol Res 1999;20:207–17. 85. Noriega F, Formal SB, Kotloff KL, Lindberg AA. Vaccines against Shigella infections Part ii: engineered attenuated mutants of Shigella as live oral vaccines. In: Levine MM, Woodrow GC, Kaper JB, Cobon GS, editors. New generation vaccines. 2nd ed. New York: Marcel Dekker, Inc.; 1997. p. 853. 86. Phalipon A, Kaufman M, Michetti P, et al. Monoclonal immunoglobulin A antibody directed against serotype-specific epitope of Shiglella flexneri lipopolysaccharide protects against murine experimental shigellosis. J Exp Med 1995;182:769–78. 87. Cohen D, Askenazi S, Green M, et al. Safety and immunogenicity of investigational Shigella conjugate vaccines in Israeli volunteers. Infect Immun 1996;64:4074–7. 88. Lindberg AA, Pal T. Strategies for development of potential candidate Shigella vaccines. Vaccine 1993;11:168–79 89. Klugman K, Gilbertson IT, Koomhof HJ, et al. Protective activity of Vi capsular polysaccharide vaccine against typhoid fever. Lancet 1987;2:1165–9. 90. Acharya IL, Lowe C, Thapa R, et al. Prevention of typhoid fever in Nepal with the Vi capsular polysaccharide to Salmonella typhi. A preliminary report. N Engl J Med 1987;317:1101–4. 91. Levine MM, Sztein MB. Human mucosal vaccines for Salmonella typhi infections. In: Kiyono H, Ogra PL, McGhee JR, editors. Mucosal vaccines. San Diego: Academic Press; 1996. p. 201–11. 92. Levine MM, Galen J, Barry E, Noriega F, et al. Attenuated Salmonella as live oral vaccines against typhoid fever and as live vectors. J Biotechnol 1996;44:193–6. 93. Jerborn M, Svennerholm AM, Holmgren J. Intestinal and systemic immune responses in humans after oral immunization with a bivalent B subunit–01/0139 whole cell cholera vaccine. Vaccine 1996;14:1459–65. 94. Taylor DN, Tacket CO, Losonsky G, et al. Evaluation of a bivalent (CVD 103-HgR/CVD 111) live oral cholera vaccine in adult volunteers from the United States and Peru. Infect Immun 1997;65:3852–6. 95. van Loon FPL, Clemens JD, Chakraborty J, et al. Field trial of inactivated oral cholera vaccines in Bangladesh: results from 5 years follow-up. Vaccine 1996;14:162–6. 96. Holmgren J, Svennerholm AM. Oral vaccines against cholera and enterotoxigenic Escherichia coli diarrhea. In: Kiyono H, Ogra PL, McGhee DR, editors. Mucosal vaccines. San Diego: Academic Press; 1996. p. 241–53. 97. World Health Organization. Global programme for vaccines and immunization. In: Vaccine research and development: report of technical review group meeting: 1997 June 9-10; Geneva. 98. Midthun K, Kapikian AZ. Rotavirus vaccines: an overview. Clin Microbiol Rev 1996;9:423–34. 99. Joensuu J, Koshenniemi E, Pang XL, Vesikari T. A randomized, double-blind, placebo controlled trial of rhesus human reassortant rotavirus vaccine for prevention of severe rotavirus gastroenteritis. Lancet 1997;350:1205–9.

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100. Perez-Schael I, Guntinas MJ, Perez M, et al. Efficacy of the rhesus rotavirus-based quadrivalent vaccine in infants and young children in Venezuela. N Engl J Med 1997;337:1181–7. 101. Burns JW, Siadat-Pajouh M, Krishnaney AA, Greenberg H. Protective effect of Rotavirus VP6-specific IgA monoclonal antibodies that lack neutralizing activity. Science 1996;272:104–7. 102. Ball JM, Tian P, Zeng CQ-Y, et al. Age dependent diarrhea induced by a rotaviral nonstructural glycoprotein. Science 1996;272:101–4. 103. Gontzea I. Nutrition and anti-infectious defense. Basel: Karger; 1974. 104. Guerrant RL, Scholring JB, McAuliffe JF. Diarrhea as a cause and effect of malnutrition: diarrhea prevents catch-up growth and malnutrition increases diarrhea frequency and duration. Am J Trop Med Hyg 1992;47:28–35. 105. Chen LC, Scrimshaw NS, editors. Diarrhea and malnutrition: interactions, mechanisms and interventions. New York: Plenum Press; 1983. 106. Scholring JB, Guerrant RL. Diarrhea and catch-up growth. Lancet 1990;335:599–600. 107. Sirisinha S, Suskind R, Edelman R, et al. Secretory and serum IgA in children with protein-calorie malnutrition. In: Mestecky J, Lawton AR, editors. The immunoglobulin A system. New York: Plenum Press; 1973. p. 389–98. 108. Gordon JE, Guzman MA, Ascoli W. Acute diarrhea disease in less developed countries: 2. Patterns of epideiological behaviour in rural Guatemalan villages. Bull World Health Organ 1964;31:9. 109. Bowie MD. Malnutrition and diarrhea. S Afr Med J 1960;34:344. 110. Schorling JB, McAuliffe JF, de Souza MA. Malnutrition is associated with increased diarrhea incidence and duration among children in an urban Brazilian slum. Int J Epidemiol 1990;19:728–35. 111. Welsh JK, May JT. Anti-infective properties of breast milk. J Pediatr 1979;94:1. 112. McClelland DBL, McGrath J, Samson RR. Antimicrobial factors in human milk: studies of concentration and transfer to the infant during the early stages of lactation. Acta Paediatr Scand 1978;27:1. 113. Arnold RR, Cole MF, McGhee JR. A bactericidal effect for human lactoferrin. Science 1977;197:263. 114. Hanson LA, Winberg J. Breast milk and defense against infection in the newborn. Arch Dis Childhood 1972;47:845. 115. Stoliar OA, Pelley RP, Kaniecki-Gree E. Secretory IgA against enterotoxins in breast-milk. Lancet 1976;1:1258. 116. Brown SE III, Sauer KT, Nations-Shields M. Comparison of paired whole milk and dried filter paper samples for antienterotoxin and anti-rotavirus activities. J Clin Microbiol 1982;16:103. 117. Stites D, Terr A, editors. In: Basic and clinical immunology. 7th ed. Chapter 5. Appleton & Lange; 1991. p. 333.

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Par t Fou r

Treatment

Chapter 14

G E N E R A L P R I N C I P L E S I N S E L F - T R E AT I N G T R AV E L E R S ’ D I A R R H E A A B R O A D Alain Bouckenooghe, MD, MPH, DTMH and Bob Kass, MB, MRCP, MScMCH, FAFPHM

Considerable variation in attitudes to the treatment of travelers’ diarrhea exists among health professionals. In a study of 542 medical practitioners, nurses, and pharmacists, Ian McIntosh and colleagues found a marked divergence to commonly held views on best practice.1 They concluded that current guidelines may be outdated, and by limiting the use of antidiarrheal agents, health professionals may inadvertently cause higher levels of morbidity. The study focused on the British National Formulary “best practice” for the treatment of acute diarrhea; the main points are highlighted below, although it needs to be emphasized that the controversial guidelines were meant for the treatment of acute diarrhea in general, not particularly travelers’ diarrhea. 1. “First line treatment should be to prevent fluid depletion, especially in the young and frail old” (comment: the main goal of treatment of travelers’ diarrhea in adults is to relieve symptoms and to shorten the time of discomfort). 2. “Antispasmodics should not be used for primary treatment” (comment: antispasmodics belong to several pharmacologic classes, and while anticholinergics are not to be used, this can not be fully generalized to all antimotility drugs). 3. “Antibacterial drugs are generally unnecessary even if a bacterial cause is suspected” (comment: there is ample evidence that antimicrobial therapy shortens and improves natural history of disease). 4. “Lactobacillus preparations are of no value” (comment: there is some remaining controversy). 5. “Absorbents such as kaolin are not recommended.” 6. “Antimotility drugs have a very limited role as adjuncts to fluid and electrolyte replacement” (challenge: strictly antimotility drugs have a very limited role but antisecretory effects are beneficial). The dilemma facing physicians and other health professionals is whether these general recommendations for acute diarrhea can or should be extrapolated to travelers’ diarrhea. While the management of fluid depletion is undeniably common to all scenarios, the causative organism is not, and neither is the personal situation of the patient. In the traveler, a bacterial cause is more likely and any morbidity may result in major inconvenience. While as health professionals we all ascribe to the principle of “primum non nocere” or do no harm, we must also consider other factors such as inappropriate prescribing and local medical conditions. If evidence can be found for

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a particular treatment reducing the length and degree of morbidity, then there is surely a place for the use of other medications apart from rehydration. Travelers diarrhea is the most common health problem faced by 30 to 70% of travelers from both developed and less developed countries.2 More detail on the epidemiology can be found in Chapter 8, “Epidemiology.” While the mortality from the disease is thankfully extremely low, morbidity is not. Illness can have significant impact on the outcome of the trip whether it is for pleasure or business. This chapter focuses on the steps that may be taken by the traveler to deal with the problem of diarrhea. Early intervention may be necessary and it is important that certain steps are followed. The number of organisms associated with travelers’ diarrhea continues to grow, and includes various bacteria, and occasionally, viruses and parasites.3 A change of dietary habits that comes with traveling, changes in alcohol consumption, irritable bowel syndrome, stress, and a variety of other contributory factors can also cause diarrhea. In general, most episodes of diarrhea associated with travel to developing regions of the world are caused by bacterial infections. Most cases of travelers’ diarrhea to high-risk areas are bacterial in origin, as illustrated by the fact that most travelers experience marked clinical improvement with use of antibiotics.4 Viral infections are ubiquitous, but of greater relative importance in industrialized regions. The incidence of parasites varies with the region considered. Low-risk regions (incidence below 8%) include the United States, Canada, Northern and Central Europe, Australia, New Zealand, and Japan; medium-risk areas (8 to 20%) include nations surrounding the Mediterranean Sea, Caribbean islands, South Africa, and Korea; high-risk regions include Africa, Asia, and Latin America.2 Travelers’ diarrhea is common and health care professionals providing pretravel health advice should have a good understanding of the disease process and its management. It is easy to recommend “seek medical attention” and this may sound always like the most prudent approach, yet • medical care may not be easily obtained in the region visited; • the practice of medicine and recommended treatment are not uniform throughout the globe and the traveler may be exposed to treatments that would not be desirable by guidelines of the host’s place of origin. For example, chloramphenicol may still be used for the treatment of diarrhea even in countries where the medication is currently banned; • not all medications may be available, or if available, questions may remain on quality of produced products and conditions of storage before sale. Fake drugs are a major problem in developing countries and in themselves pose a major health risk; • interruption of travel to seek medical care is not always needed, and even more often, is not desired from the traveler’s point of view as it can lead to loss of travel or business time. Pretravel advice is therefore important and should allow for self-treatment of diarrhea under specific circumstances. A traveler should be supplied with information on • what can be treated without seeking local help; • what cannot be safely self-treated by a nonprofessional (nonmedical) traveler; • what medication to carry;

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• when to get local care; and • when to repatriate. Some travelers have an increased risk to develop travelers’ diarrhea and may need more detailed pretravel counseling, while others are at risk for a particular subset of pathogens because of preexisting conditions. Examples are those patients infected with human immunodeficiency virus (HIV) and CD4 counts below 200 cells/mm3 who are at a hundredfold risk for Salmonella infections, travelers with achlorhydria, or travelers using acid reducing medication (particularly proton pump inhibitors).5,6

DEFINITIONS For study purposes, diarrhea is defined as output of more than 200 g of unformed feces per day or as decreased stool consistency (unformed or loose) and increased stool frequency (3 or more bowel movements in 24 hours). The clinical symptom of at least 3 unformed stools per day is a useful indicator for travelers considering therapy for diarrhea when symptoms are mild; for other cases with more explosive or distressing symptoms, therapy initiation after a second unformed bowel movement is arguably very reasonable. Diarrhea is acute if the onset is within the last 14 days, persistent if it lasts longer than 14 days, and chronic if it lasts longer than 30 days. The severity of diarrhea can be graded based on its clinical impact on the traveler. Diarrhea is mild if the number of bowel movements is 3 or less per 24 hours and if the symptoms allow the patient to have normal activities. Moderate diarrhea is the production of 4 or more unformed stools, often associated with intestinal and systemic symptoms (abdominal cramps, nausea, vomiting, tenesmus, fever below 101°F [38°C], malaise, dehydration), which characteristically force a change in activities. Severe diarrhea causes incapacitation. Severe diarrhea requires special attention to avoidance of dehydration, immediate empiric treatment and consideration of a medical work-up, and physician-directed treatment if the traveler is unable to take oral medications due to uncontrollable vomiting, has high fever or rigors, or self-treatment fails to control symptoms expeditiously.

SELF-TREATMENT OPTION In mild acute diarrhea with minimal fluid loss, consumption of water combined with a source of sodium chloride (like saltine crackers) or use of fruit juices will usually be enough to rehydrate most travelers. Caffeine-containing products are to be avoided as they may increase bowel peristalsis. Carbonated drinks constitute a reliable source of fluids as these are free of microorganisms, but these drinks may not be available and are also difficult to be tolerated in large quantities; so the availability of sufficient amounts of clean mineral water is desirable. Salty soup or broth is an excellent option, too.

Oral Rehydration Solutions Oral rehydration solutions (ORS) are very effective, particularly to prevent dehydration in children with acute diarrhea, and can also be used for the treatment of mild to moderate dehydration and

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maintenance of proper fluid balance.7 In healthy adult travelers, reversal of dehydration is usually achieved very quickly and use of ad lib fluids of any kind is as good as ORS.4,8 Fluid and electrolyte therapy are not of additional benefit for treatment of diarrhea in adults, if an antisecretory and antimotility agent like loperamide is used early on.9 ORS could be used as initial therapy in cases of severe dehydration, bloody diarrhea, very high stool volume output (>10 mL/kg/h), and intractable vomiting, if done under close supervision of a qualified health care provider who monitors hydration status, electrolyte balance, and clinical symptoms. These sicker patients may at times vomit a part of the fluids taken, but typically retain some, and with repeated consumption of small amounts of ORS may keep a positive fluid balance. Vomiting in this setting is often self-limiting within a few hours, and in these cases, oral fluids are sufficient as volume replacement therapy. However, intravenous rehydration is needed and medical care must be promptly sought when the vomiting is intractable or lasting longer than a few hours, or in cases where the stool output is very high or the dehydration so severe that attempts at oral hydration are not leading to a normal frequency of urination. Mild dehydration (3 to 5% fluid deficiency) can clinically be recognized by dry oral mucosa, small urine output, and increased thirst. Moderate dehydration (6 to 9% fluid deficiency) can be identified by very dry oral mucous membranes, sunken eyes, decreased skin turgor, sunken fontanelle in newborns and infants, very low urine output, and delayed capillary refill. Severe dehydration (>10% fluid deficiency) is noted by the same findings together with a rapid pulse, cyanosis, cold extremities, and mental status changes and these findings should always lead to prompt referral to a health care provider. ORS are available as prepackaged, ready-to-use solutions, with the advantage that they are premixed and not dependent on the availability of clean water. They are unfortunately difficult to carry in any useful quantity. ORS salts are available in small easy-to-carry packets; however, the salts must be mixed with the correct amount of clean water. World Health Organization (WHO) ORS contain 3.5 g sodium chloride, 1.5 g potassium chloride, 2.5 g sodium bicarbonate, and 20 g glucose in a liter of previously boiled and filtered (through filter device with pores sized 1 micron or less) clean water. Commercial solutions such as Ricelyte and Pedialyte have a somewhat lower sodium concentration, but are very convenient, albeit also somewhat more expensive. Homemade recipes should reflect the same mixes of ingredients. An example may be adding 1/4 teaspoon of salt and 1/4 teaspoon of baking soda to a glass with 8 ounces of water, and a spoonful of sugar or honey to a second glass with 8 ounces of fruit juice. A standard “pinch” is always difficult to reproduce. A traveler needs to know that not all ingredients are easily available everywhere; for example, in Mexico, sodium bicarbonate is only available at a pharmacy as a pharmaceutical grade chemical, so commercial products are the only approach in these circumstances. New commercial formulations include rice powder or other starches, which provide fluid, electrolytes, and calories, and may actually improve diarrhea, and the use of amino acids such as glutamine, which have the advantages stated for starches as well as reduced healing time of gut mucosa. 10 ORS without these complex carbohydrates lead to an increased stool output. Adult patients should drink 2 to 3 L fluid/day. For children with mild dehydration, the replacement rate with ORS should be 50 mL/kg over 4 hours, starting with a teaspoon and gradually increasing and reassessing; replacement can be held after 4 to 6 hours or when rehydrated. With moderate dehydration, the fluid

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replacement is 100 mL/kg over 4 hours, initially. With severe dehydration, intravenous fluid and electrolyte replacement is preferred, but 50 to 100 mg/kg can be given concurrently when the patient is stable. Once rehydration has been achieved, half to one cup of ORS along with ad lib water can be given for each loose bowel movement to maintain hydration. The ad lib fluid is prudent to avoid hypernatremia that has been reported with use of current formulation ORS in mild and moderate diarrhea; this issue has lead WHO to consider altering the ingredients of ORS in the near future and reduce salt and sugar content.11,12

Diet Rehydration is the first goal of therapy in all patients with intractable vomiting or severe diarrhea. The very young and elderly should be encouraged to drink fluids and to consume salt (eg, from saltine crackers and soups). Evidence that major dietary changes have a significant impact on the course of travelers’ diarrhea in otherwise healthy adult travelers is lacking. As far as dietary recommendations are concerned, patients should probably avoid dairy products for the first 2 days of illness, as transient lactase deficiency due to small bowel mucosal inflammation can perpetuate the symptoms when dairy products are consumed.2 Patients with diarrhea should continue to eat if hungry. Before diarrhea responds to therapy, suggested foods include soups, toast, bananas, and boiled and baked meats. Vegetables can be added to the diet when the diarrhea is improving. Food intake is important during bouts of diarrhea to encourage enterocyte repair and intestinal recovery from the inflammatory process. Early feeding does not prolong diarrhea. No caffeine or lactose should be used while stools are unformed. The diet should progress to complex carbohydrates, meat products, fruits, and vegetables if not yet started, when the diarrhea has resolved. It is important to emphasize that breast-fed infants should receive ORS and breast-feeding continued on demand. Likewise, bottle-fed babies need to be given formula on demand, probably by preference lactose-free formula, although there are no data proving superiority over milk based products in this age group. Children on solid diets are to be treated similarly to the adults.

Symptomatic Therapy Antimotility Agents Classes of antimotility agents are (Table 14-1) • the opiates (loperamide, diphenoxylate, codeine, tincture of opium), and • the anticholinergics (atropine, scopolamine). Fluid and electrolyte therapies are not of additional benefit for treatment of diarrhea in adults if an antisecretory and antimotility agent like loperamide is used early on.9 Antimotility drugs are of proven efficacy in prevention of dehydration and to reduce the symptoms of diarrhea, but they are contraindicated as sole therapy when the diarrhea is suspected to be exudative, whether dysenteric or nondysenteric inflammatory in nature. As sole therapy, these agents should only be used in nonfebrile, nondysenteric cases of acute diarrhea. The adult traveler should be made aware of the symptoms associated with inflammation or invasion and must avoid the sole use of antimotility medica-

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Table 14-1. Non-Antibiotic Self-Treatment Medications for Patients with Acute Travelers’ Diarrhea Medication

Daily Dose

Antimotility/antisecretory loperamide

4 mg initially, then 2 mg after each unformed stool, not to exceed 16 mg/d Children 5–8 y: 2 mg tablet or 2 teaspoons initially, then 1 teaspoon for each unformed stool, not to exceed 4 teaspoons (2 tablets)/24 h Children 8–10 y: 2 mg orally, not to exceed 3 doses/24 h 2 tablets (4 mg) PO every 4 h for maximal 48 h Contraindicated in children

Diphenoxylate–atropine

40 mg loading dose, then 20 mg q 6 h
7 doses

Zaldaride maleate

0.5-1.0 ml q 4–6 h

Intraluminal attapulgite

3 g start dose, then 3 g q 2 h after each loose stool to maximum of 9 g/d

Mixed bismuth subsalicylate

30 ml or 2 tablets of 262 mg q 30 min
5 doses; can repeat day 2 Children 6–9 y: 2/3 tablet or 10 ml PO q 30 min up to 8 doses/24 h Children 9–12 y: 1 tablet or 14 ml PO q 30 min up to 8 doses/24 h

PO = orally.

tion in these situations. The combination of an effective antibiotic with an antimotility/secretory medication is acceptable in cases of moderate to severe nondysenteric diarrhea (see Figure 14-1).13,14 Empiric self-medication with loperamide is recommended, except in the mentioned circumstances. Antimotility medication is not recommended in children under the age of 5 years (in case of diphenoxylate due to significant central nervous system penetration and side effects). It should be doseadjusted in children over the age of 5 years. A recent report indicated the probable safety of use of antimotility drugs in cases of shigellosis, and patients with Shigella dysentery using the combination of ciprofloxacin and loperamide in some studies were actually treated more effectively than patients treated with ciprofloxacin alone.15 Despite this apparent safety of intentional use of antimotility medication in these patients, we currently recommend to avoid their use. The risk of arming a traveler with loperamide and antibiotics that could be subsequently misused to self-treat dysentery is not of great concern if the traveler uses the combination; sole use of loperamide in the same circumstances would be a major error, against which the traveler must be cautioned. The opiates are the most effective class and loperamide is therefore the drug of choice. Diphenoxylate–atropine has antisecretory action with its antimotility activity, but anticholinergics are generally less favored for self-treatment due to their side effect profile, and the efficacy of anticholinergics as antimotility products is seriously questioned.16 For patients with moderate to severe diarrhea, without high fever or blood overtly visible in the stool, the combination of an antibiotic with an antimotility drug is the best treatment. In patients with high fever or bloody stools, use of an antibiotic alone is preferred (see below). Antisecretory Products Bismuth subsalicylate (BSS) has antisecretory and antimicrobial properties (see Table 14-1).

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This medication is available over the counter in North America, but is not easily available in many other countries, including Europe, Australia, and New Zealand. Bismuth subsalicylate is less useful than loperamide in the treatment of diarrhea and should not be combined with a fluoroquinolone because of its chelation capacity. The optional use of BSS should probably be limited to cases of mild nonexudative diarrhea, in which case, it can decrease by half the number of stools passed during illness.17 Bismuth subsalicylate should not be used when salicylates are contraindicated, and this includes situations such as when allergic reactions have occurred in the past, or in young children with febrile syndromes that could be due to influenza or varicella infection because of the association with Reye’s syndrome. The American Academy of Pediatrics also does not recommend routine use of BSS for treatment of children under 6 years of age. Zaldaride maleate, a benzimidazole, has antisecretory activity through its inhibition of intestinal calmodulin. A clinical trial of 20 mg zaldaride qid for 2 days for the treatment of travelers’ diarrhea (US students traveling to Mexico) decreased the severity and duration of diarrhea.18 In a placebocontrolled, blinded comparison trial, zaldaride was superior to placebo, but without a loading dose was less effective than loperamide, particularly in the first 24 hours. In a more recent trial with a loading dose of 40 mg followed by 20 mg qid, zaldaride was equally as effective as loperamide.19 At this time, zaldaride has not been widely marketed. Racecadotril is an enkephalinase inhibitor with antisecretory effect. It can be used in adults or children as an adjunct to oral rehydration therapy. Availability at this time is limited to some European countries. Intraluminal Products This group includes • bulking agents (psyllium); • absorbents (kaolin pectin, attapulgite, polycarbophil, methylcellulose, cholestyramine); and • probiotic bacterial agents (Lactobacillus acidophilus, Saccharomyces cerevisiae or boulardii, Streptococcus faecium). Absorbents have generally not proven to be very effective and are therefore not recommended. Psyllium may improve mild diarrhea but otherwise has no proven efficacy. Some probiotics have been found to be of some use in studies of pediatric diarrhea and cases of antibiotic-associated diarrhea, but data on the efficacy of probiotic agents in cases of acute travelers’ diarrhea are not available, and their availability is quite restricted.

Antibiotics Antibiotics are the cornerstone of the treatment and self-treatment of travelers’ diarrhea as they effectively reduce the length of illness. The various antibiotics that can be used for empiric therapy are found in Table 14-2. The quinolones, rifaximin, and depending upon geographic area, the macrolide and azalide groups, are preferred antibiotics for the treatment of acute travelers’ diarrhea. Several antibiotics that were once important are no longer recommended for empiric therapy due to increas-

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Table 14-2. Antibiotics That can be Considered for Self-Treatment of Acute Travelers’ Diarrhea Antibacterial

Adult Dose

Pediatric Dose

Notes

Ciprofloxacin

*500 mg bid
3 d *750 mg single dose

Safety unknown

Availability not uniform

Levofloxacin

*500 mg qid
3 d *500 mg single dose

Safety unknown

Availability not uniform

Ofloxacin

*200 mg bid
3 d *600 mg single dose

Safety unknown

Availability not uniform

Norfloxacin

*400 mg bid
3 d *800 mg single dose

Safety unknown

Availability not uniform

Fleroxacin

*400 mg PO qid
3 d *400 mg PO
1 dose

Safety unknown

Not available in the United States

Azithromycin

*500 mg qid
3 d *1,000 mg single dose

Loading dose 10 mg/kg/d, followed by 5 mg/kg/d

Preferred in regions where high Campylobacter spp (SE Asia) or for failure

Rifaximin

200 mg tid
3 d 400 mg bid
3 d

100 mg suspension qid
3d

First-line option, especially in regions with high Campylobacter spp

Erythromycin

500 mg PO bid
5 d

40 mg/kg/d PO in 4 doses
5 d

For Campylobacter enteritis

Doxycycline

300 mg once

Contraindicated under age 8 years

Treatment of Vibrio cholerae infection, increasing resistance for other indications

Nalidixic acid

1 g PO qid
3–5 d

Safety unknown

Increasing resistance, widely available first generation quinolone; not first choice

Trimethoprim– Sulfamethoxazole

*Once 2 DS (320 mg TMP and 1,600 mg SMX) *1 DS bid
3 d

(5 mg/kg TMP and 25 mg/kg SMX) bid
3–5 d

Cheap, but resistance very common

10–12 mg/kg/day PO in 2 divided 2 doses

Fairly effective and inexpensive oral option for MDR salmonellosis in children (although failure with Shigella reported)

Second line agents:

Cefixime

Additional agents for treatment of treatment failures: Metronidazole

250 mg qid
7 days

50 mg/kg/d in 4 doses
7d

For treatment of persistent diarrhea if not dysenteric

Tinidazole

2 g PO single dose 2 g PO qid
3d

50 mg /kg PO (2 g maximal)
1 dose 3-d course

For giardiasis; for amebiasis

Albendazole

400 mg/d
7 d

Furazolidone

100 mg PO qid
7–10 days

Quinacrine

100 mg PO tid
7 d

Effective for giardiasis 6–8 mg/kg PO in 4 divided doses
7–10 d

Contraindicated with G6PD deficiency; lower efficacy Very effective for Giardia, but GI tolerance less than metronidazole

DS = double strength; GI = gastrointestinal; G6PD = glucose-6-phosphate dehydrogenase; MDR = multidrug resistant; PO = orally; bid = twice daily; tid = three times daily; qid = four times daily; SMX = sulfamethoxazole; TMP = trimethoprim. *No longer available in the United States.

ing resistance problems (eg, TMP–SMX). There is more discussion in Chapter 16, “Antimicrobial Treatment: An Algorithmic Approach.” Figures 14-1 and 14-2 indicate the place of antibiotics for the self-treatment of travelers’ diarrhea.14,20-25

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Other Antiemetics consist mainly of phenothiazines. Examples of commonly available antiemetics are promethazine, prochlorperazine, hydroxyzine, trimethobenzamide, and droperidol. They can be administered by the oral, parenteral, or rectal route in cases of prolonged vomiting. Despite the efficacy of these drugs, there are strong concerns over their usage in self-therapy. There is significant central nervous system penetration with possible side effects that could further impair the traveler, and they may also obscure other underlying pathologies. Where vomiting is the dominant symptom, or if vomiting persists past a few hours, other medical conditions must be considered and medical help sought as soon as possible. Medications to delay gastric emptying and activated charcoal are important in cases of food poisoning, such as mushroom poisoning. The charcoal can interact with adsorption of antibiotics and should not be taken at the same time. Delaying gastric emptying, however, is preferably done in a medically controlled setting where it can be achieved by nasogastric tube placement with suctioning or by gastric lavage. Use of emetics can lead to airway aspiration and should not be done in a setting of self-treatment. Neither charcoal nor emetics have a place in treatment of infectious gastroenteritis.

RISKS AND DISADVANTAGES OF THE SELF-TREATMENT APPROACH The advantages of self-treatment to the traveler are apparent and are outlined in the introduction of this chapter. Typically, the traveler with diarrhea will benefit from a reduced number of bowel actions and shorter episode of diarrhea. The avoidance of potential toxic preparations by consuming only those preparations that the traveler carries is relevant, particularly when the travel occurs in regions where the local practice of medicine is significantly different from what the traveler is used to. Many travelers will choose the autonomy of self-treatment and the familiarity with medication at a time of sickness and discomfort, rather than explore local health care at that time. A potential drawback of self-treatment is that the subjective symptoms are an important factor in the algorithm proposed (see Figure 14-1), leading to possible overtreatment in some travelers. Travelers should be reminded that there are many other noninfectious causes of diarrhea that do not require use of antibiotics and some may experience adverse events while using antibiotics. Selection for resistant organisms with inappropriate use of antibiotics is a concern when that happens on a larger scale, but would probably not be of major importance in this discussion. Any medication not used during the travel may be kept and used upon return for an inappropriate indication.

SIGNS AND SYMPTOMS, AND IMPLICATIONS FOR SELF-TREATMENT When diarrhea is mild, 3 or more unformed stools are needed before considering interventions, but when symptoms are severe or explosive, prompt initiation of empiric self-therapy, even at the time of a second loose stool, is quite reasonable. Larger numbers of bowel movements tend to implicate more severe diarrhea. Presence of signs and clinical symptoms is helpful in the algorithm of decisions (see Figures 14-1, 14-2). It must be said

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Oral fluids: 2 glasses for every fluid bowel action1 Oral rehydration salts: adults 2–3 L per day, children 50 mL/kg over 4 h Diet: Yes: rice, pasta, potato, bananas, broth/soup No: dairy products, fatty foods, spicy foods

Mild diarrhea (3 or less unformed bowel movements in last 24 h, able to continue normal travel schedule and activities)

No need for additional therapy or consider (if need to travel) loperamide or bismuth subsalicylate

Moderate diarrhea (4 or more unformed stools in 24 h with at least 1 more symptom: abdominal cramps, nausea, vomiting, mucus in stool, tenesmus, or fever below 101°F; leading to some travel changes)

Mild-moderate: clinical signs are mild, no distress: 1 to 3 day antibacterial3 course +/– loperamide

Severe diarrhea2 (>6 stools and incapacitating) Fever (>101°F or bloody stools)

Antibacterial3 3 day therapy alone if fever or dysentery (otherwise, combination with loperamide acceptable)

Moderate-severe2: severe cramping, large number of watery bowel movements: 1 to 3 day antibacterial3 course + loperamide

If no improvement after 1 week: see Figure 14-2

Remarks 1. Use of ORS in mild/moderate adult TD cases is not superior to use of ad lib fluids of any nature. 2. For moderate-severe and severe diarrhea, medical care should be sought if available, and laboratory analysis is desirable. 3. For choice of antibacterial agent, see Chapter 16, “Antimicrobial Treatment: An Algorithmic Approach”; for doses, see Table 14-2. Figure 14-1. General algorithm for self-treatment of acute travelers’ diarrhea.

that the risks of “overtreatment” when the clinical signs are over-read by the traveler are minimal, and even more so with the single-dose antibiotic treatment approach. Fever may be an indication of an invasive enteric pathogen, although the specificity of this sign is not great. It has been well observed that a number of patients with enterotoxigenic E. coli, a classic example of a secretory diarrhea, can also have fever. Abdominal cramping is more severe and more common in the group of inflammatory diarrheas, and tenesmus is often associated with lower colonic inflammation. The presence of macroscopic blood or mucoid stools indicates dysentery. Nausea and vomiting are commonly associated with any gastroenteritis.

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Acute Diarrhea

If no previous therapy: follow general algorithm (Figure 14-1)

Improved

Not improved

Advance diet

Is there fever?

YES Medical care should be sought. Next step only if access to health care is not possible. Always consider malaria and other differential diagnoses.

Empiric antiparasitic therapy: metronidazole 250 mg qid
7 d or tinidazole 2 g
3 d Add intraluminal therapy for ameba at end if diarrhea is resolved

NO Review diet recommendations. Avoid dairy products • If no antibiotic was used, take course (1 to 3 days) • If antibiotic was used, try another antibiotic (eg, if quinolones were used, try azithromycin) • Consider use of loperamide if no blood in stool

Continuous diarrhea after 3 more days?

YES

Not improving: Seek medical care

Empiric antiparasitic treatment (Giardia doses of therapy): metronidazole 250 mg qid
7 d or tinidazole 2 g
1 d or albendazole
5 d

Remarks 1. For choice of antibacterial agent, see Chapter 16, “Antimicrobial Treatment: An Algorithmic Approach.” 2. For doses, see also Table 14-2.

Figure 14-2. Algorithm for self-treatment of acute travelers’ diarrhea for adventurous travelers, hikers, and treatment failure.

Presence of a large number of bowel movements should be treated with a 3-day course of an antibiotic if not contraindicated, and use of antisecretory symptomatic medication in the absence of dysentery or fever is acceptable. Antisecretory medication should be avoided in cases of dysentery or severe diarrhea with fever at 101°F or more.

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Moderate nondysenteric diarrhea accompanied by at least one clinical sign (excluding fever) can be treated with a single or a 3-day course of quinolones, with optional combination with loperamide.13-15 A worsening of symptoms while following the treatment guidelines of the algorithm should lead to an adjustment of therapy. For example, a course of antibiotics should be started if an initially mild diarrhea became more severe.

ALGORITHMS FOR SELF-TREATMENT General Algorithm Empiric use of antibiotics is not needed for mild forms of travelers’ diarrhea, but are indicated in cases of an inflammatory diarrhea or a severe diarrhea of any mechanism and febrile dysentery. Antibiotics are optional in moderate noninflammatory forms of diarrhea (see Figure 14-1). They have been shown in most travelers to reduce the number of loose bowel movements and the length of time to the last unformed stool (as a marker of efficacy in clinical trials). If there is significant subjective discomfort, additional underlying medical problems, or a particular personal need for a traveler to reduce length of symptoms (eg, as with the traveler participating in important sports events, business travel, and significant inconvenience), then empiric use of antibiotics are to be considered. Three-day courses are preferred over 5-day courses, and single-dose courses can also be considered for less severe diarrheal cases or when a traveler feels fairly well at the time of the next dose with some antibiotics (see Table 14-2). High-dose azithromycin is only used in a one-dose therapy regime. Antibiotics with predictable activity against all bacterial pathogens are preferred. Antibiotic resistance is an ever-increasing challenge. Gut levels of the antimicrobials are relevant, so nonabsorbed or poorly absorbed antibiotics can be very effective. Antibiotic choices are shown in Table 14-2; Table 14-3 shows the antibiotic options for special pathogens or circumstances.22 Trimethoprim–sulfamethoxazole (TMP–SMX) and fluoroquinolones have been intensely studied. TMP–SMX is cheaper but there is considerable resistance, and it may be used for treatment of adults and children either as single dose or biq for 3 days; it is widely available. TMP–SMX is the drug of choice for cases of isosporiasis and cyclosporiasis. Fluoroquinolones are very effective, but more expensive, and may not always be available. A single tablet is affordable to all travelers. Quinolones are first-line therapy in most regions and can be used as a single dose, or in a 3-day course.2,4,22 A 3-day course is preferred if the diarrhea is severe or in cases of exudative diarrhea. Rising incidence of resistance of Campylobacter jejuni makes this antibiotic group only a second choice in regions and seasons where there is high incidence of this organism (eg, Southeast Asian region).26,27 Nalidixic acid, the first quinolone, is more readily available in many developing nations and in Europe, but is restricted in the United States. In children, TMP–SMX and furazolidone (for giardiasis) can be considered as they come in liquid formulations. Azithromycin is a first choice for empiric therapy in regions with high Campylobacter diarrhea incidence in travelers, and erythromycin is equally effective if a traveler has culture-proven Campylobacter infection.21 Erythromycin is not good for empiric treatment of travelers’ diarrhea as its gram-negative spectrum is limited.

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Table 14-3. Geographic Regions with Special Risks That will Influence Choice of Antibiotics Region

Pathogen

Antibiotic

Nepal, Peru, Guatemala

Cyclospora cayetanensis

TMP–SMX DS bid
7d

Russia, North America: hikers, Asia

Giardia

Metronidazole 250 mg tid
5 d; Tinidazole 2,000 mg qid
1 d; Quinacrine 100 mg tid
7 d; Furazolidone 100 mg qid
7–10 d; Albendazole 400 mg qid
7 d

Caribbean, India, Africa

Isospora

TMP–SMX DS bid
10 d

Southeast Asia

Campylobacter spp

Erythromycin 500 mg qid
5 d; Azithromycin 1 g
1 dose

St. Petersburg, Russia

Cryptosporidium, Giardia

None (self-limited disease in immunocompetent host)

Asia, Africa

Entamoeba

Metronidazole 250 mg qid
7 d

DS = double strength; bid = twice daily; tid = three times daily; qid = four times daily; SMX = sulfamethoxazole; TMP = trimethoprim.

Rifaximin, a poorly absorbed rifamycin derivative, can equally be used in adults and children. Preliminary reports are promising although it is currently not recommended in single-dose therapy.20 Rifaximin is available in Europe and several Latin American nations. Doxycycline is globally available and indications are that there may be place for its use in treatment of travelers’ diarrhea for the adult nonpregnant or lactating traveler. Rising resistance limits its use and its main benefit is in the treatment of Vibrio cholerae infections. Chloramphenicol is a broad-spectrum antibiotic, globally available, but not recommended for its safety profile. Progressive resistance is also making this drug gradually less effective, such as for resistant Salmonella.

Specific Groups For hikers, adventurous travelers, and patients who failed to improve over 72 to 96 hours after a first antibacterial therapy, the treatment algorithm is as per Figure 14-2. Treatment failure could indicate infection with a resistant organism such as Campylobacter or Cryptosporidium. Treatment failures with fever should be medically evaluated and not further treated empirically, as the differential diagnosis is broader and includes other infections such as malaria. Only when that is impossible (eg, hikers in remote areas, missionaries in the field with no local health care infrastructure close by), can empiric antiparasitic therapy with 7 days of metronidazole be given to treat possible ameba dysentery (less common Giardia infection as this typically is not accompanied by fever). Nitazoxanide, not available in the United States, is an antiparasitic and protozoal product that can be used in cases of Giardia and Cryptosporidium infection.28 Rifaximin has anti-Cryptosporidium activity, and tinidazole, albendazole, and quinacrine can be used for Giardia infections. Patients with persistent diarrhea should also have a medical evaluation and stool analysis done, if possible.23,24 In this group, Giardia in particular, as well as Cryptosporidium, Cyclospora, and Entamoeba (for travelers with prolonged stay in rural areas), are common. Empiric therapy with metronidazole 250 mg qid for 7 days can be considered. Alternatives to metronidazole include tinidazole, furazolidone (particularly in children), paromomycin (poor choice as it is not very effective but of use in

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pregnant women), albendazole (good efficacy), and quinacrine (not available in the United States). A proven ameba infection should be followed by a course of iodoquinol (adults: 650 mg PO tid
20 days; children: 30 to 40 mg/kg/d in 3 divided doses, maximally 2 g/d,
20 days), diloxanide furoate (adults: 500 mg PO tid
10 days; children: 20 mg/kg/d in 3 divided doses
10 days), or paromomycin (25 to 35 mg/kg/d PO in 3 divided doses
7 days) to eradicate the residual cystic form.

WHEN TO SEE A LOCAL MEDICAL CARE PROVIDER AND WHEN TO REPATRIATE The traveler should seek prompt medical care for • • • • •

very severe diarrhea or dysentery; severe vomiting or vomiting that continues beyond a few hours; significant dehydration; high fever; and any mental status changes.

Repatriation is indicated in • delayed improvement despite rehydration and antibiotic therapy; • persistent and chronic diarrhea, especially with significant loss of weight; and • persistent fever or mental status changes. Patients with severe diarrhea or dysentery need closer medical supervision, and in these cases, medical care should be obtained whenever possible. When significant dehydration or severe vomiting is noted, immediate movement to a location with better health facilities should be undertaken. Severe dehydration may warrant intravenous fluid and electrolyte replacement with monitoring. This is particularly true for children under 5 years of age as they are already more prone to dehydration by having a large surface to weight ratio, but can in rare cases also occur in older children or adults. Laboratory analysis of serum electrolytes and stool examinations may need to be done. The stool culture sample should be obtained before antibiotic therapy is introduced. If stool analysis cannot be done immediately, a stool sample can be kept refrigerated for further analysis within 24 hours. A clinical examination to exclude other possible diseases is important at this time. If the traveler is unable to find adequate medical care, the emphasis remains on staying hydrated and completing the course of medication. Adherence to the right diet should be verified; consumption of lactose containing products can prolong the symptoms, as occasionally a transient lactase deficient state in the small bowel occurs, as will consumption of lots of caffeine containing drinks. Only rarely will repatriation be needed, and it ought to be considered when improvement is delayed despite rehydration and antibiotic therapy. Carrying intravenous catheters, needles, etc. may be important when there are critical shortages in the host country, particularly in countries where HIV is prevalent. Travelers with persistent or chronic diarrhea, especially if accompanied by severe weight loss, persistent fevers, focal abdominal pains, mental status changes, and protracted vomiting, should be repatriated.23,24 A differential diagnosis should always, if appropriate for the geographic

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region, include malaria, for which empiric therapy is needed whenever suspected if immediate medical attention is not available. Repatriation insurance is very important, not only to cover the considerable expenses of an urgent repatriation, but also to allow quick intervention when needed. Giving financial guarantees to a company asked to help with repatriation can be very challenging when this has to be organized far away from the surroundings that a traveler is used to while feeling sick.

PERSONAL PHARMACY OF A TRAVELER AND THINGS TO BUY LOCALLY An appropriate medical kit includes medication for the self-treatment of diarrhea. Choice of the antibiotic depends on the region of travel. Travel to industrialized countries is typically low risk, and a reliable supply of medication is expected to be available (albeit not always the same medication as the traveler is used to getting at home). Travelers are advised to have a travel health insurance that would allow access to the local health care system, as cost can be an inhibiting factor. For travelers to medium- and high-risk countries, a personal supply of medication for at least one course of selftreatment, purchased at home before travel, is desirable. The cost should be low, as the supply of small Table 14-4. List of Medication and Items to be Carried by Travelers for Self-Treatment of Gastroenteritis Class

Importance

Product

Antibiotic

High for travel to developing regions or remote travel (missionaries, hikers, etc.)

A quinolone or rifaximin (at least one treatment dose); azithromycin; metronidazole or tinidazole

Antimotility/secretory medicine

High if antibiotics are carried

Yes: loperamide, zaldaride maleate; NO: diphenoxylate–atropine, bismuth subsalicylate

Antiemetic medication

Less important, supervision needed

Promethazine, prochlorperazine, hydroxyzine, trimethobenzamide or other (both PO and suppository)

Antipyretic

Important

Nonsteroidal anti-inflammatory drug of choice

ORS

Useful for remote travel

Prepackaged ORS liquid or solution (especially if traveling with children), or ingredients to make ORS

Supplies

Less important but of use for travel to remote developing regions

Needles for SQ, IM, and IV injections, syringes, intravenous catheters, tubing, thermometer

H2O disinfectant

High for remote travel, hikers

Water disinfectant of choice to use when reliably clean water is not available (eg, silver-based products, sodium chloride solutions, iodine solutions)

Water filtration system

High for long-term residents and remote travel to regions with clean water supply problems

Water filtration needs to be combined with disinfecting the water first or heating to boiling point; some filtration systems are small and easy to carry. Active cola filters can remove bad taste of disinfectants

Point of contact

High

Address, phone number, E-mail of health provider (in host country or at home) who will respond to urgent questions

Medical and repatriation insurance

High

Repatriation insurance is very important for rapid assistance in need

IM = intramuscular; IV = intravenous; ORS = oral rehydration solutions; PO = orally; SQ = subcutaneous.

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amounts may suffice (at least one course). Any medication that the traveler did not carry can be obtained locally, often at reduced price. In quite a number of countries, pharmacies can supply medication including antibiotics without a medical prescription. However, production quality control measures are not implemented stringently globally and fake drugs are a major problem. Brand products from reputable companies are preferred over generic products from obscure local companies, and one needs to watch for fake imitation products. Storage conditions can also affect activity of the medication and the expiration date should be verified. Table 14-4 includes medication the traveler may consider to carry as it relates to self-treatment of gastroenteritis.

REFERENCES 1. McIntosh IB, Swanson V, Howell K. Health professionals’ attitudes toward acute diarrhea management. J Travel Med 2001;8:60–5. 2. Murphy GS, Petrucelli BP, Kollaritsch H, Taylor DN. Treatment of travelers’ diarrhea. In: DuPont HL, Steffen R, editors. Textbook of travel medicine and health. 2nd ed. Hamilton (ON): BC Decker Inc.; 2001. 3. Hoge CW, Shlim DR, Echeverria P, et al. Epidemiology of diarrhea among expatriate residents living in a highly endemic environment. J Am Med Assoc 1996;275:533–8. 4. Ericsson CD. Travelers’ diarrhea: epidemiology, prevention, and self-treatment. Infect Dis Clin North Am 1998:12;285. 5. Mileno DM, Bia FJ. Travel medicine: the compromised traveler. Infect Dis Clin North Am 1998;12:369–412. 6. Castelli F, Patroni A. The human immunodeficiency virus-infected traveler. Clin Infect Dis 2000;31:1403–8. 7. Greenough WB. Oral rehydration therapy: something new, something old. Infect Dis Clin Pract 1998;7:97–100. 8. Ericsson CD, DuPont HL. Travelers’ diarrhea: approaches to prevention and treatment. Clin Infect Dis 1993;16:616–26. 9. Caeiro JP, DuPont HL, Albrecht H, Ericsson CD. Oral rehydration therapy plus loperamide versus loperamide alone in the treatment of travelers’ diarrhea. Clin Infect Dis 1999;28:1286–9. 10. Molina S, Vettorazzi C, Peerson JM, et al. Clinical trial of glucose-oral rehydration solution (ORS), rice dextrin-ORS, and rice flour-ORS for the management of children with acute diarrhea and mild or moderate dehydration. Pediatrics 1995;95:191–7. 11. World Health Organization. New formula for oral rehydration salts will save millions of lives: number of deaths and severity of illness will be reduced. Available at: http://www.who.int/inf/en/pr-2002-35.html (accessed August 20, 2002). 12. Hirschhorn N, Nalin DR, Cash RA, Greenough WB III. Formulation of oral rehydration solution. Lancet 2002;360:340–1. 13. Ericsson CD, DuPont HL, Mathewson JJ. Single dose ofloxacin plus loperamide compared with single dose or three days of ofloxacin in the treatment of travelers’ diarrhea. J Travel Med 1997;4:3–7. 14. Ericsson CD, DuPont HL, Mathewson JJ. Optimal dosing of ofloxacin with loperamide in the treatment of non-dysenteric travelers’ diarrhea. J Travel Med 2001;8:19–25.

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15. Murphy GS, Bodhidatta L, Echeverria P, et al. Ciprofloxacin and loperamide in the treatment of bacillary dysentery. Ann Intern Med 1993;118(8):582–6. 16. Reves R, Bass P, DuPont HL, et al. Failure to demonstrate effectiveness of an anticholinergic drug in the symptomatic treatment of acute travelers’ diarrhea. J Clin Gastroenterol 1983;5:223–7. 17. Johnson PC, Ericsson CD, DuPont HL, et al. Comparison of loperamide with bismuth subsalicylate for the treatment of acute travelers’ diarrhea. J Am Med Assoc 1986;255:757–60. 18. DuPont HL, Ericsson CD, Mathewson JJ, et al. Zaldaride maleate, an intestinal calmodulin inhibitor, in the therapy of travelers’ diarrhea. Gastroenterology 1993;104:709–15. 19. Silberschmidt G, Schick MT, Steffen R, et al. Treatment of travellers’ diarrhea: zaldaride compared with loperamide and placebo. Eur J Gastroentrol Hepatol 1995;7:871–5. 20. DuPont HL, Jiang Z-D, Ericsson CD, et al. Rifaximin versus ciprofloxacin for the treatment of travelers’ diarrhea: a randomized, double-blind clinical trial. Clin Infect Dis 2001;33:812–4. 21. Kuschner RA, Trofa AF, Thomas RJ, et al. Use of azithromycin for the treatment of Campylobacter enteritis in travelers to Thailand, an area where ciprofloxacin resistance is prevalent. Clin Infect Dis 1995;21:536–41. 22. DuPont HL, Ericsson CD. Prevention and treatment of travelers’ diarrhea. N Engl J Med 1993;328:1821–7. 23. DuPont HL, Capsuto EG. Persistent diarrhea in travelers. Clin Infect Dis 1996;22:124–8. 24. Taylor DN, Connor BA, Shlim DR. Chronic diarrhea in the returned traveler. Med Clin North Am 1999;83:1033–52. 25. Adachi JA, Ostrosky-Zeichner L, DuPont HL, Ericsson CD. Empirical antimicrobial therapy for travelers’ diarrhea. Clin Infect Dis 2000;31:1079–83. 26. Coker AO, Isokpehi RD, Thomas BN, et al. Human campylobacteriosis in developing countries. Emerg Infect Dis 2002;8:237–43. 27. Blaser MJ. Epidemiologic and clinical features of Campylobacter jejuni infections. J Infect Dis 1997;176 Suppl 2:S103–5. 28. Davila-Gutierrez CE, Vasquez C, Trujillo-Hernandez B, Huerta M. Nitazoxanide compared with quinfamide and mebendazole in the treatment of helminthic infections and intestinal protozoa in children. Am J Trop Med Hyg 2002;66:251–4.

Chapter 15

N O N S P E C I F I C T R E AT M E N T : D I E T, O R A L R E H Y D R AT I O N T H E R A P Y, S Y M P T O M AT I C D R U G S Deborah Mills, MBBS, and David L. Wingate, MA, MSc, DM, FRCP

Travelers are, by definition, away from home, and from the proximity and comfort of their usual health care resources; they are often also confronted by problems of access and communication with local health care professionals or by their total absence. Whether their activities are of a leisure or business nature, travelers tend to be tightly scheduled. Tourists are often booked into guided tours involving coach trips that are punctuated by sightseeing on foot, while business travelers may be locked into a round of meetings and conferences. These activities are interrupted by frequent and urgent calls to stool. Travelers’ accommodations may be ill suited, in terms of space, service, and toilet facilities, to the exigencies of acute diarrhea. At home, the context of travelers’ diarrhea is what determines the initial approach to treatment. The discomfort and inconvenience of illness is blunted by the opportunity to rest in familiar surroundings, with support of family and friends, easy access (directly or by proxy) to a familiar pharmacist, as well as a family physician on call. In general, the traveler is denied these benefits, and from this stems the imperative for pharmacological intervention. The urgency of such intervention (the looming return charter flight, or the crucial working lunch) combined with the difficulty of access to health care dictates the resort to self-medication. But what medication should be taken? Here, there is a potential dichotomy between differing evidence-based advice of physicians and actual practice. For example, there have been various learned caveats against the use of antidiarrheal agents, particularly the antimotility agents,1 but results of many treatment trials have supported the use of these agents that all along were very popular with travelers because of their rapid onset of effective control. Others favor antimicrobial agents (see Chapter 19, “Diarrheal Outbreaks Associated with Airline Flights”). Overall, the options available to the afflicted may be grouped under three headings; diet (control of food and fluid intake), oral rehydration therapy (ORT), and antidiarrheal drugs. The latter group is subdivided into two types of medication; drugs that modify the fluid secretion of the gut, and antibacterial agents. The efficacy of these regimens is shrouded in dogma based on misunderstanding of the pathophysiology of acute travelers’ diarrhea.

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LABORATORY INVESTIGATIONS Most episodes of travelers’ diarrhea are not a threat to life, and are self-limiting. In health, the daily volume of stool water is about 200 mL. This is the unabsorbed residue of a daily fluid intake of about 2 L, to which is added a further 8 L of salivary, gastric, and pancreatobiliary exocrine secretions. Doubling the stool volume will produce liquid stools, and dehydration is the logical consequence. The physiologic response to dehydration is thirst, and thirst is alleviated by fluid intake. This is not a problem for adults, but young children and the elderly are at greater risk. The exception is cholera. Cholera toxin converts the small intestine into a secretory organ, and stool volumes of up to 14 L in 24 hours occur in acute cholera. Although cholera outbreaks still can occur, nowadays they threaten indigenous populations rather than travelers, the latter being at such low risk that cholera vaccine is not routinely recommended and traveling with the wherewithal to replace huge fluid losses is not advocated. Thus, while the combination of liquid stools that may threaten continence, dehydration, and thirst is distressing, the initial approach to travelers’ diarrhea abroad and initially back home should be aimed at relieving symptoms. This is not only for the sake of greater comfort, but also, and more importantly, to enable the traveler to resume the activities that were the objective of the journey. Given the high probability that the illness will be short-lived and will subside without significant sequelae, measures aimed at the relief of symptoms are justified; laboratory investigations are likely to be negative since the common causes, diarrheagenic E. coli, are not often identifiable in developing countries or even back home. Thus, stool examination for bacterial and parasitic pathogens is not justified at the outset, and is indicated only if signs suggest a more severe or protracted illness, or in the face of an epidemic. Investigations of outbreaks of diarrhea are generally carried out only after many cases have occurred, following a specific flight or cruise (see Chapter 22, “Persistent and Chronic Diarrhea in the Returning Traveler” and Chapter 23, “The Future of Travelers’ Diarrhea: Directions for Research”). Algorithms for investigations in patients who have returned home and in whom symptoms persist have been described in Chapter 22, “Persistent and Chronic Diarrhea in the Returning Traveler.” The minority of cases that are caused by pathogens that can lead to systemic problems requiring medical intervention including antimicrobial agents (see Chapter 16, “Antimicrobial Treatment: An Algorithmic Approach”) will usually be unmasked by signs such as fever and passage of bloody stools. Chapter 16 also deals conceptually with treating travelers’ diarrhea with an antimicrobial agent, not only because a clinical syndrome like dysentery might dictate the use of such an agent, but also because using an antimicrobial agent empirically regardless of clinical presentation is a viable approach, since the majority of causes of travelers’ diarrhea are bacterial and amenable to antimicrobial therapy. This chapter will deal with three non-antimicrobial treatment options at the onset of illness: dietary measures, oral rehydration therapy (ORT), and drugs.

DIET The only consensus on diet is the primary need to maintain fluid intake and to provide at least limited calories.2–6 Oral rehydration solutions (developed for cholera; see below) are widely recom-

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mended, but glucose-containing fluids and electrolyte-rich soups are usually sufficient for adults.7 Dehydration is not the only consequence of diarrheal stools; there may also be a significant depletion of electrolytes that, if nothing else, contributes to the malaise of the patient. Electrolyte-rich fluids are helpful; coconut milk, broth, and tomato juice are examples. Cola and other soft drinks by themselves, although often used, are not recommended since they provide low levels of electrolytes and may contain caffeine, which stimulates intestinal motility. While there is controversy about the details of partial fasting and the resumption of solid food,2–6 most authorities feel that some food is necessary for most patients with acute diarrheal disease. Temporary fasting is logical if diarrhea is associated with excessive nausea and vomiting. Oral consumption can provide a stimulus for defecation, and avoiding large meals may diminish the gastrocolic response of an already hyperactive gut. There are sound physiological reasons for restricting the quantity of dietary intake at the onset of travelers’ diarrhea. Transit time through the gut is diminished, and food constituents that are normally digested and absorbed relatively slowly may, under these circumstances, escape processing and be ejected into the colon and then defecated as recognizable components of the last meal! Such undigested food may also undergo digestion by colonic flora, leading to an osmotic load that is, in itself, cathartic. It is particularly important to avoid fatty foods, as these stimulate the secretion of bile. Bile salts are normally absorbed in the terminal ileum, but in the presence of diarrhea, they may be washed past the terminal ileum into the colon, where they stimulate the secretion of water and sodium. The same effect may be produced by unabsorbed hydroxy fatty acids. Fortunately, there is often little need to advise sufferers on this point; the diarrhea is often accompanied by nausea and, in this state, fatty foods are unappealing. Solutes from food may be as effective as the solutes in oral rehydration solutions in encouraging net fluid absorption.8,9 In children, whether initially malnourished or not, early resumption of feeding and solid food intake has been reported to speed recovery.10,11 An injured gut requires calories (energy) for regeneration and efficient recovery. Although there is no evidence in adults that fasting or dieting is beneficial to the treatment of acute diarrhea, or that solid food hastens or retards recovery, appropriate feeding is recommended for all patients with diarrhea.2 Carbohydrates are normally rapidly broken down to disaccharide and monosaccharide sugars that are absorbed, for the most part, in the duodenum. Sugars do not exacerbate diarrhea, and for reasons to be explained in the next section, should be encouraged in reasonable quantities, to avoid osmotic overload. Complex carbohydrates are best avoided, particularly those that normally resist digestion in the small bowel and serve as substrates for colonic bacteria. Baked beans are unsuitable sustenance in travelers’ diarrhea. The form of the diarrhea generally determines the foods to take. During the early watery diarrheal phase, soups and broths with saltine crackers and toast are recommended. As stools start to take shape, more complex foods can be ingested such as boiled or baked fish, chicken, vegetables, rice, and bananas. When stools become formed, the diet can return to normal.

ORAL REHYDRATION THERAPY In assessing the value of ORT in combating travelers’ diarrhea, it is useful to review the history of this therapeutic approach. In the two decades between 1960 and 1980, there was a sustained research

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effort in major research centers in Europe and North America to elucidate the mechanisms of intestinal water and sodium absorption. Starting with experiments on isolated rodent intestine, extended into perfusion studies on volunteers, it became clear that absorption is enhanced by the presence of glucose and bicarbonate in the intestinal lumen. These data were used to develop the use of ORT in acute cholera. The intestinal secretion caused by the cholera vibrios is massive, and is the cause of death in this disease. However, the illness is short-lived, and provided that dehydration can be prevented by parenteral fluid administration, recovery is assured. The problem with cholera is that it afflicts people in poor communities that lack health care; for such people, intravenous fluid administration is an unattainable luxury. The solution to this problem was the provision of packets of glucose and sodium bicarbonate, to be added to the water given to cholera victims. This did not require medical resources and skills, but simply the distribution of packets of powder to be dissolved in drinking water. While cholera is not a hazard for travelers, pharmaceutical entrepreneurs realized that ORT might be marketed as a remedy for travelers’ diarrhea. This is a much larger market ready to pay higher prices, with the advantage that the solutes in ORT are in common usage, and thus escape the regulatory hurdles that meet drugs. Marketing of ORT for all forms of acute diarrhea is prevalent. The arguments for efficacy in this wider context are, however, syllogistic. ORT was developed to enhance survival in intense dehydrating diarrhea, but it was not intended or expected to abolish diarrhea altogether. In travelers’ diarrhea, where dehydration is not ordinarily a threat to life, the value of ORT is arguable. It may negate the physiologic effects of fluid loss and decrease the symptoms of dehydration, but it will not stop or shorten diarrhea.7,8 As a first line of management, it has little to offer other than ease of access, since it can be bought over the counter without the intervention of medical or nursing advice. On the other hand, ORT is of particular importance in pediatric, geriatric, and other patients, in whom dehydration could rapidly become critical. Also, having ORT with the traveler encourages the intake of fluids and salt; however, with proper instruction on taking fluids and salt from other sources, the need for access to ORT is minimal.

SYMPTOMATIC DRUGS Some authorities suggest refraining from treating travelers’ diarrhea; this is undoubtedly influenced by the commonly held view that diarrhea is a defense mechanism and as such should not be treated with antidiarrheal drugs that reduce stool output.12 These agents are believed to have the potential in invasive bacterial diarrhea to “keep toxins or pathogens inside the body, allowing greater contact time between invading pathogen and mucosal lining where they do more damage” and to “prolong illness by delaying pathogen secretion.”7,12 Reports of adverse outcomes attributed to pharmacologic treatment, in some cases for bloody diarrhea of unknown cause, with “fixed” doses of different antimotility and/or broad-spectrum antibiotics, have been cited in support of this hypothesis.1,13 Other studies were generated with high constant prophylactic or extremely high doses of antidiarrheals, inappropriate or irrelevant to clinical practice.14,15 One controlled study has been a powerful influence.16 In this study, a combination of diphenoxylate and atropine was given to a population of male prisoners deliberately infected with a strain of Shigella flexneri 2a. Close scrutiny of the report raises doubts about its relevance to the management of adult acute diarrhea of unknown cause. Treatment

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of the subjects was instituted “when they developed an oral temperature of 38.3°C, passed 5 or more unformed stools, or experienced dysentery (bloody mucoid stools).” The cohort of 25 infected subjects was divided into 4 treatment groups. One group received diphenoxylate and atropine plus oxolinic acid (a quinolone antimicrobial agent), whereas the other groups had either one or other or both of the active drugs replaced by placebo. Oxolinic acid or diphenoxylate and atropine therapy decreased diarrhea, but fever, which occurred in 15 out of 25 of the cohort, was markedly prolonged in 2 of the 4 febrile subjects treated with diphenoxylate and atropine alone, compared to the 11 febrile subjects in the other 3 treatment groups. Stool cultures were negative within 5 days in 4 of 6 treated with oxolinic acid alone, but in only 1 of 6 receiving oxolinic acid with diphenoxylate and atropine. The numbers were small and, perhaps for that reason, no statistical treatment was applied to the results of this study carried out more than 30 years ago. Moreover, there is no way of determining whether the adverse effects were due to diphenoxylate or atropine. As required by the World Health Organization, anticholinergic agents such as atropine were added to older antimotility agents such as diphenoxylate and atropine to avoid abuse and possible consequent dependence of the morphine type, but are not constituents of newer antidiarrheal drugs. Another older placebo-controlled study on the combination of difenoxin plus atropine similarly resulted in a greater number of unformed stools among dysenteric travelers’ diarrhea patients, while this compound was clearly beneficial among nondysenteric patients.17 Taking these studies into account, many believe that it is prudent to exclude persons suffering from high fever, bloody stools, or both (dysentery) from self-medication with antimotility agents as monotherapy. Yet, a body of data indicates little concern for prolongation of disease by loperamide therapy as long as the patient is either concurrently taking an antimicrobial or can take an antimicrobial agent in the event monotherapy is not giving an adequate response.18-21 The notion of diarrhea as a defense mechanism may seem to have at least a superficial logic when the cause is an invasive bacterial enteric pathogen. Yet, it is difficult to see how diarrhea can reverse adherence of a pathogen attached by fimbriae, diminish the secretion induced by a toxin bound to the intestinal mucosa, or in the case of viral diarrhea, enhance absorption by a damaged mucosa.2 There is no evidence to support such effects. In acquired immunodeficiency syndrome patients, or in experimental parasitic infections, with an altered immune response, diarrhea does not eliminate the pathogen.22 Moreover, the defense hypothesis is inappropriate to other causes of diarrhea, such as diabetes, stress, or hyperthyroidism, which may be unrelated to pathogens. Diarrhea may be a defense mechanism for milder expressions, but when dealing with severe diarrhea and certain purging cholera, this is not a defense mechanism but an illness that requires treatment. The mainstay of symptomatic treatment of acute diarrhea has been, for several centuries, oral opiate medication. Originally, these were infusions of morphine in the form of laudanum, later replaced by variants including mixtures of morphine and kaolin. The twentieth century brought radical changes in this tradition in two ways; first, the addictive potential of such medicines became socially unacceptable, and, secondly, the development of antibiotics raised the possibility of eradicating the pathogens rather than just addressing the symptoms. Drugs that are opiate analogues have replaced the use of morphine extracts; these are diphenoxylate and loperamide. Both drugs have an opiate effect on the gut, but do not affect the central

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nervous system unless given in excessive doses, and both have no addictive potential. Loperamide, the more recent drug, is more effective. Diphenoxylate has now been replaced by loperamide as the drug of choice for the treatment of travelers’ diarrhea, and was recently recommended by a working party as the first line treatment for the management of acute adult diarrhea.23 Loperamide is a peripherally acting opiate, which is devoid of abuse potential because it does not cross the blood-brain barrier and because it hardly reaches the systemic circulation due to extensive hepatic extraction and fecal excretion.4 It has multiple antisecretory actions, some of which are not mediated by opiate receptors.24,25 In healthy adults, a therapeutic 4 mg dose does not significantly slow orocecal transit.26,27 Higher or repeated doses increase the drug concentration in the enterohepatic circulation and retard jejunal or orocecal transit, but in diarrheal states, the therapeutic dosage normalizes transit.27,28 In comparative studies, loperamide alone or in combination with an antimicrobial agent resulted in significantly faster relief as compared to a variety of antimicrobials used alone.18–21,29 Evidence from controlled studies have shown that loperamide, either alone or in combination with antibiotics, has no untoward effects in infectious nondysenteric (without high fever or blood in stool) travelers’ diarrhea, even if caused by E. coli, Shigella, Campylobacter, or Salmonella,30,31 although treatment failures are common as loperamide fails to target the infecting organism. As monotherapy in mild febrile dysentery, loperamide does not seem to aggravate the disease, although it is no more effective than placebo.30,32,33 Larger studies would be needed to verify such safety in all cases. A single analysis demonstrated an increase in number of stools, when an older antimobility agent, olifenoxin, was compared to placebo among travelers’ diarrhea patients with fever.17 Used with antimicrobials, it reduces the number of unformed stools and shortens the duration of symptoms.30,33,34 When compared to the use of an antimicrobial agent alone, the combination of loperamide with an antimicrobial agent did not prolong fever or delay pathogen excretion.33 Loperamide is not recommended for use in children under the age of 2 years; however, in some countries, the contraindication includes older children.35 It is among children that the rare adverse central and peripheral (ileus) side effects have mainly occurred, probably due to immature hepatic function and blood-brain barrier, or inadvertent overdose.36 In adults, the safety profile of loperamide has been evidenced by more than two decades of experience and, recently, also by a controlled study in pregnancy.37 The few anecdotal reports of serious adverse events in travelers’ diarrhea patients after loperamide use show no consistent pattern.1 In DuPont’s classic study, bismuth subsalicylate was shown to be effective in the treatment of travelers’ diarrhea.38 Bismuth subsalicylate is an old and complex drug with multiple actions. It has antisecretory action,39 can inhibit the effects of and adsorb toxin in the laboratory,40 and most importantly, has antimicrobial effects. In a controlled study, 41 it was found to be not as effective as loperamide alone, and for that reason, it is generally reserved for treatment of mild diarrhea or not used at all when loperamide is available. In some countries, bismuth subsalicylate-containing products are not available, making it at best a second line drug for treatment. An exciting new development is the identification of a variety of novel antisecretory agents such as acetorphan (racecadotril), zaldaride and SP-303, which are more physiologic in reducing fluid loss and have no significant effect on gastrointestinal transit.3,4 The different mechanisms involved with

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these compounds, including enkephalinase inhibition, calmodulin inhibition, and chloride channel blockage, offer evidence of multifactorial pathways in intestinal secretion. The overall efficacy of the antisecretory drugs, in terms of reduction in stools passed, may be a bit less than that seen with the antimotility drugs, but they may eventually be of more value in acute diarrhea management. Antimotility drugs should remain the major therapeutic agents with many forms of chronic diarrhea. Older adsorbents include charcoal, pectins, tannin albuminate (plus ethacrine), clays (aluminum silicates and kaolin), or activated clays (attapulgite, diosmectite).4 These agents are not absorbed but bind water, thereby diminishing free stool water. They were included in traditional antidiarrheal opiate mixtures in the United Kingdom, such as “Mist Kaolin et Morph” or “Dr J Collis Browne’s Chlorodyne Linctus,” but the decline of these medications following the removal of the opiate components suggests that the adsorbent component was unimportant. These drugs help in better formation of stools but have little additional value in treating diarrhea. Activated charcoal similarly had no effect other than modifying stool formation slightly in patients with diarrhea compared with those randomized to receive a placebo (DuPont HL, Ericsson CD, unpublished data). Mild effects have been documented in a single adult study in nonbacterial diarrhea and in several studies in infants.4,42,43 Some comparative studies of adsorbents reported efficacy equal to loperamide, but lacked a placebo group and had multiple methodological flaws, such as a long pretreatment period, late efficacy assessment, or use of wrong loperamide dosages.44,45 Well-controlled trials favor loperamide over adsorbents.46,47 Overall, it seems that apart from low risk, adsorbents confer little, if any, benefit on adults suffering from acute diarrhea.

PROS AND CONS ANTIMICROBIAL DEBATE Some authorities suggest that empiric use of antibacterial drugs should be reserved for proven bacterial causes of diarrhea, and the use of such drugs when the pathogen is unknown and the diarrhea is mild in severity is open to criticism. First, it is not known if the pathogen is susceptible to the chosen antibiotic or whether the illness is caused by a viral or parasitic, rather than bacterial, pathogen, in which cases the drug would be ineffective. Secondly, in many cases, the onset of diarrhea marks the successful intestinal invasion of the pathogen, soon in most cases to be followed by host inactivation of the pathogen and natural remission of the illness. The arguments in favor of symptomatic therapy and against the routine use of antimicrobial agents, especially in milder forms of illness, and the rebuttal to the arguments are as follows. 1. Critique. The pathogens that cause travelers’ diarrhea are heterogeneous, and when the pathogen is unknown, the recommended antibacterial drug may not be active against the pathogen causing the diarrhea. Rebuttal. Throughout the world, the majority of causes of travelers’ diarrhea are bacterial, and antibiotic susceptibility profiles can be monitored for regions of the world so that an optimal choice can be made for empiric use. 2. Critique. Antimicrobials are ineffective in diarrhea caused by viruses, which are most relevant in diarrhea cases in industrialized areas and those occurring anywhere, when vomiting is the chief symptom.

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Rebuttal. Although antimicrobial agents are generally not advocated for empiric use in diarrhea occurring in industrialized regions of the world, viruses cause <10% of diarrhea cases among travelers in the developing world. Furthermore, vomiting can be a prominent feature of some illnesses like shigellosis, for which antibiotics are indicated. 3. Critique. The time course of action of antibiotics is slow, and they do not offer the rapid relief of symptoms, which is of such importance to the traveler. Rebuttal. Use of symptomatic therapy alone is accompanied by a degree of treatment failure. This is an argument for the use of the combination of an antimicrobial agent plus a fast-acting symptomatic agent. 4. Critique. While the indiscriminate use of antibiotics in the general community (where the enteric pathogens encounter travelers) would encourage the development of resistant strains of bacteria in the community, travelers represent a minor contribution to the overall reservoir of prevalent enteric pathogens. The travelers may, however, be reservoirs of their own organisms, for such infections as urinary tract infections and prostatitis, and transient resistance in them could produce difficulties with extraintestinal infection treatment. Rebuttal. This is an argument that favors the judicious use of antimicrobial agents and limits the use of antimicrobial agents to illness that is distressing or lingering despite symptomatic therapy. Since antimicrobial therapy is now administered as a single dose or at most 3 days, the duration of therapy is not long enough to promote resistance among fecal flora. These arguments apply most effectively to the limitation of the use of antibacterial drugs in the initial approach to mild illness or that associated with more vomiting than diarrhea. Antibiotics are of more obvious value when symptoms persist, and a bacterial pathogen is suggested by occurrence of high fever and dysentery in an outbreak where the pathogen has already been identified or other setting where bacterial agents are highly likely (eg, severe cases of travelers’ diarrhea). 48 For further discussion of the role of antimicrobial agents see Chapter 16, “Antimicrobial Treatment: An Algorithmic Approach.”

REFERENCES 1. Caumes E, Brousse G, Manceron V, et al. Surgical complications of travelers’ diarrhoea: four cases. In: Proceedings of the 6th Conference of the International Society of Travel Medicine; Montreal, Quebec, Canada; 1999. 2. Gorbach SL. Infectious diarrhea and bacterial food poisoning. In: Sleisenger MH, Fordtran J, editors. Gastrointestinal disease. Vol 2. Philadelphia: WB Saunders Co.; 1993. p. 1128–89. 3. Scarpignato C, Rampal P. Prevention and treatment of travellers’ diarrhoea: a clinical approach. Chemotherapy 1995;41 Suppl 1:48–81. 4. Schiller LR. Anti-diarrhoeal pharmacology and therapeutics [review]. Aliment Pharmacol Ther 1995;9:87–106. 5. DuPont HL. Infectious diarrhoea [review]. Aliment Pharmacol Therap 1994;8:3–13. 6. Farthing MJG, DuPont HL, Guandalini S, et al. Treatment and prevention of travelers’ diarrhoea. Gastroenterol Intern 1992;5:162–75.

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7. WHO Diarrhoeal Disease Control Programme. Drugs in the management of acute diarrhoea in infants and young children. World Health Organization; 1986. Report No.: WHO/CDD/CMT/86.1. 8. Caeiro JP, DuPont HL, Albrecht H, Ericsson CE. Oral rehydration therapy plus loperamide versus loperamide alone in the treatment of travelers’ diarrhoea. Clin Infect Dis 1999;28:1286–9. 9. Bastidas JA, Zinner MJ, Bastidas JA, et al. Influence of meal composition on canine jejunal water and electrolyte absorption. Gastroenterology 1992;102:486–92. 10. Cleason M, Merson M. Global progress in the control of diarrhoeal diseases. Pediatr Infect Dis J 1990;9:345–55. 11. Provisional Committee on Quality Improvement, Subcommittee on Acute Gastroenteritis. Practice parameter: the management of acute gastroenteritis in young children. Pediatrics 1996;97:424–33. 12. Swanson V, McIntosh IB, Howell K. A study of GP attitudes to acute diarrhoea management. Scottish Med Vol 1999;18:6–7. 13. Scully RE, Mark EJ, McNeely WF, McNeely B. Case records of the Massachusetts General Hospital. Case 25-1994. N Engl J Med 1994;330:1811–7. 14. Novak E, Lee JG, Seckman CE, et al. Unfavourable effect of atropine-diphenoxylate (Lomotil) in lincomycin caused diarrhoea. J Am Med Assoc 1976;235:1451–4. 15. Shoda R, Matsueda K, Sekigawa J, et al. Loperamide treatment exaggerates bacterial translocation and hypoglycemia in the rat model of lectin-induced diarrhoea [abstract]. Gastroenterology 1999;116:A931. 16. DuPont HL, Hornick AB. Adverse effect of Lomotil therapy in shigellosis. J Am Med Assoc 1973;226:1525–8. 17. Steffen R, Stransky M, Kozicki M. Vorbeugende Massnahmen gegen Reisediarrhöe. Schweiz Med Wschr 1984;114 Suppl 17:35–8. 18. Ericsson CD, DuPont HL, et al. Treatment of travelers’ diarrhea with sulfamethoxazole and trimethoprim and loperamide. J Am Med Assoc 1990;263:257–61. 19. Ericsson CD, Nicholls-Vasquez I, et al. Optimal dosing of trimethoprim/sulfamethoxazole when used with loperamide to treat travelers’ diarrhea. Antimicrob Agents Chemother 1992;36:2821–4. 20. Ericsson CD, DuPont HL, et al. Ofloxacin and loperamide in the treatment of travelers’ diarrhea. J Travel Med 1997;4:3–7. 21. Ericsson CD, DuPont HL, et al. Optimal dosing of ofloxacin with loperamide in the treatment of nondysenteric travelers’ diarrhea. J Travel Med 2001;6:19–25. 22. McKay DM, Benjamin M, Baca-Estrada M, et al. Role of T lymphocytes in secretory response to an enteric nematode parasite. Studies in athymic rats. Dig Dis Sci 1995;40:331-7. 23. Wingate D, Phillips SF, Lewis SJ, et al. Guidelines for adults on self-medication for the treatment of acute diarrhea [review]. Ailment Pharmacol Ther 2001;15(6):773–82. 24. Awouters F, Megens A, Verlinden M, et al. Loperamide. Survey of studies on mechanism of its antidiarrhoeal activity. Dig Dis Sci 1993;38:977–9. 25. Stoll R, Ruppin H, Domschke W. Calmodulin mediated effects of loperamide on chloride transport by brush border membrane vesicles from human ileum. Gastroenterology 1988;95:69–76. 26. Van Wyk M, Sommers DK, Steyn GW. Evaluation of gastrointestinal motility using the hydrogen breath test. Br J Clin Pharmacol 1985;20:479–81. 27. Kirby MG, Dukes GE, Heizer WD, et al. Effects of metoclopramide, bethanechol, and loperamide on gastric residence time, gastric emptying and mouth-to-caecum transit time. Pharmacotherapy 1989;9:226–31.

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28. Keeling WF, Harris A, Martin BJ. Loperamide abolishes exercise-induced orocecal liquid transit acceleration. Dig Dis Sci 1993;38:1783–7. 29. Steffen R, Heusser R, Tschopp A, DuPont HL. Efficacy and side-effects of six agents in the self-treatment of travelers’ diarrhoea. Travel Med Int 1988;6:153–7. 30. Ericsson CD, DuPont HL, Mathewson JJ, West S. Treatment of travelers’ diarrhea with sulfamethoxazole and trimethoprim and loperamide. J Am Med Assoc 1990;263:257–61. 31. Van Loon FPL, Bennish ML, Speelman P, Butler C. Double blind trial of loperamide for treating acute watery diarrhoea in expatriates in Bangladesh. Gut 1989;30:492–5. 32. Meuris B. Observational study of travelers’ diarrhea. J Travel Med 1995;2:11–5. 33. Murphy GS, Bodhidatta L, Echeverria P, et al. Ciprofloxacin and loperamide in the treatment of bacillary dysentery. Ann Intern Med 1993;118:582–6. 34. Taylor DN, Sanchez JL, Candler W, et al. Treatment of travelers’ diarrhea: ciprofloxacin plus loperamide compared with ciprofloxacin alone. Ann Intern Med 1991;11:731–4. 35. Kaplan MA, Prior MJ, McKonly K, et al. A multicentre randomized controlled trial of a liquid loperamide product versus placebo in the treatment of acute diarrhoea in children. Clin Paediatr 1999;38:579–91. 36. Litovits T, Clancy C, Korberly B, et al. Surveillance of loperamide ingestions: an analysis of 216 poison center reports. Clin Toxicol 1997;35:11–9. 37. Einarson A, Mastroiacovo P, Arbon J, et al. Prospective controlled multi-centre study of loperamide in pregnancy. Can J Gastroenterol 2000;14:185–7. 38. DuPont HL, Sullivan P, et al. Symptomatic treatment of diarrhea with bismuth subsalicylate among students attending a Mexican university. Gastroenterology 1977;73:715–8. 39. Ericsson CD, Tannenbaum C, et al. Antisecretory and anti-inflammatory properties of bismuth subsalicylate. Rev Infect Dis 1990;12 Suppl 1:S16–20. 40. Ericsson CD, Evans DG, et al. Bismuth subsalicylate inhibits activity of crude toxins of Escherichia coli and Vibrio cholerae. J Infect Dis 1977;136:692–6. 41. Johnson PC, Ericsson CD, et al. Comparison of loperamide with bismuth subsalicylate for the treatment of acute travelers’ diarrhea. J Am Med Assoc 1986;255:757–60. 42. Zaid MR, Hasan M, Khan AA. Attapulgite in the treatment of acute diarrhoea: a double-blind placebocontrolled study. J Diarrhoeal Dis Res 1995;13:44–6. 43. Madkour AA, Madina EM, el-Azouni OE, et al. Smectite in acute diarrhoea in children: a double-blind placebo-controlled trial. J Paediatr Gastroenterol Nutr 1993;17:176–81. 44. De Sola Pool N, Loeble K. A comparison of nonsystemic and systemic antidiarrheal agents in the treatment of acute nonspecific diarrhea in adults. Today’s Therapeutic Trends 1987;5:31–8. 45. Leber W. A new suspension form of smectite (liquid ‘diasorb’) for the treatment of acute diarrhoea: a randomized comparative study. Pharmatherapeutica 1988;5:256–60. 46. John GI. Symptomatic treatment of acute self-limiting diarrhoea in adults. Practitioner 1977;1311:396–9. 47. DuPont H, Ericsson CD, DuPont M, et al. A randomized, open-label comparison of non-prescription loperamide and attapulgite in the symptomatic treatment of acute diarrhea. Am J Med 1990;88:S20–3. 48. Manatsathit S, DuPont H, Farthing M, et al. Guideline for the management of acute diarrhea in adults. J Gastroenterol Hepatol 2002;17:54–71.

Chapter 16

A N T I M I C R O B I A L T R E AT M E N T : A N A LG O R I T H M I C A P P ROAC H Herbert L. DuPont, MD, and Leena Mattila, MD, PhD

Clinical studies carried out by our group and others provide evidence that bacterial enteropathogens are the most commonly identified agents in patients with travelers’ diarrhea, regardless of country or region being visited. Carefully conducted microbiologic assessments usually identify bacterial pathogens at a rate of about 50% of travelers’ diarrhea cases.1 The occurrence of bacterial pathogens is actually quite a bit higher, as evidenced by the obvious clinical response of the otherwise nondiagnosed illness to antibacterial drugs.2-4 Improved laboratory techniques will be required to detect conventional bacterial agents and to identify new ones.5,6 For these reasons, antibacterial agents represent the mainstay of therapy for travelers’ diarrhea. Antibacterial resistance is a growing problem in the world, limiting the value of established drugs and calling for the development of surveillance systems to monitor drug susceptibility patterns throughout the world.7-9 Also, enteropathogens may show seasonal patterns, which may influence recommendations on therapy.10,11

IN VITRO SUSCEPTIBILITY OF BACTERIAL PATHOGENS AND REGIONAL FACTORS We have been monitoring the susceptibility of enteric pathogens cultured from cases of travelers’ diarrhea to antibacterial drugs from diverse areas of the world for many years.8,12 Table 16-1 summarizes susceptibility data from a previous study of 284 bacterial pathogens isolated from international travelers to Goa, India, Ocho Rios, Jamaica, Guadalajara, Mexico, and Mombasa, Kenya during 1997.8 A number of antibacterial drugs have in vitro activity against a large number of bacterial enteropathogens found in diverse regions of the world. The group of drugs with potential in the management of travelers’ diarrhea include fluoroquinolones, third generation cephalosporins, azithromycin, furazolidone, and ampicillin. Doxycycline and rifaximin show higher but achievable minimal inhibitory concentrations (MICs). On the other hand, trimethoprim (TMP) plus sulfamethoxazole (SMX), ampicillin, and furazolidone are no longer appropriate treatments for travelers’ diarrhea because of widespread resistance to these drugs. The fluoroquinolones collectively represent the current treatment of choice for adult patients with acute travelers’ diarrhea acquired in Latin America, Africa, and the Indian subcontinent. Studies car-

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ried out in Thailand have shown a high rate of fluoroquinolone and macrolide resistance among prevalent strains of Campylobacter jejuni.7 The fluoroquinolone resistance among Campylobacter species has also increased in southern Europe.13 Fluoroquinolone resistance among Salmonella isolates has also increased, especially in Southeast Asia.9

IMPORTANT PHARMACOKINETICS OF ANTIBACTERIAL THERAPY In 1968, an important study was published by Haltalin and colleagues, where orally absorbed ampicillin was shown to be superior to orally poorly absorbed neomycin in the treatment of severe shigellosis in children in Dallas.14 The conclusion of the authors was that oral absorption of the drug is needed to have a cure for a mucosally-invasive bacterial diarrhea like shigellosis. Later studies with dysenteric shigellosis in a monkey model demonstrated that orally administered kanamycin was not effective in treating the disease, while another poorly absorbed drug, bicozamycin, was.15 Thus, the clinical dictum proposed in the original study may not be correct. It may only be that aminoglycosides are ineffective drugs in mucosally-invasive shigellosis independent of drug pharmacokinetics. Bicozamycin was later shown to be effective in travelers’ diarrhea and in shigellosis of travelers.16 When it was decided that bicozamycin would not be used in human medicine, a second poorly absorbed drug, aztreonam, was evaluated by our group.17 The drug had antimicrobial activity against bacterial enteropathogens in vitro and was highly active in shortening diarrhea of travelers, including that associated with the passage of numerous fecal leukocytes (inflammatory diarrhea). The pharmaceutical sponsor elected not to pursue development of the drug for this use. Rifaximin, a poorly absorbed rifamycin derivative, is the latest poorly absorbed drug to be evaluated in travelers’ diarrhea. We have tested rifaximin in the treatment of travelers’ diarrhea in Mexico and found it to be superior to TMP–SMX in shortening diarrhea.18 In Mexico and Jamaica, rifaximin was equivalent to ciprofloxacin in shortening travelers’ diarrhea and in curing illness.19 Most recently, we participated in a multicenter placebo-controlled study to demonstrate the effectiveness of rifaximin and to establish the proper dosing of the drug.20 Again, we found rifaximin to be effective in the therapy of travelers’ diarrhea, occurring in three very different regions of the world, including fecal-leukocytepositive inflammatory diarrhea. Intestinal levels of drug may be important in recovery of bacterial diarrhea and travelers’ diarrhea. Doxycycline and rifaximin both possess inhibitory activity against bacterial enteropathogens only at moderate levels of the drugs.8 Both drugs concentrate to extremely high levels in the intestinal tract, which explains their beneficial effect in bacterial diarrhea and travelers’ diarrhea.21,22

STANDARD THERAPY IN ADULTS Table 16-2 lists the various drugs and daily doses to employ in therapy of travelers’ diarrhea. The durations of recommended therapies are given in the algorithm (Figure 16-1). The fluoroquinolones currently represent the standard therapy because of their availability and activity against a majority of pathogens. There are pharmacokinetic differences in the fluoroquinolones that may or may not have clinical significance. Norfloxacin was the first developed. It is not well absorbed, leading to high

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Moderate* to Severe+ Diarrhea All subjects should receive fluids

Areas Other than Thailand and Adjacent Regions

Thailand and Adjacent Regions

Adults FQ 1–3 d or Rif 3 d, can add Loperamide

Children >2 yrs Azith 1–3 d or Rif 3 d or Cef 3–5 d, can add Loperamide if >5 yrs

Adults Azith 1–3 d or Rif 3 d, can add Loperamide

Children >2 yrs Azith or Rif 3 d or Cef 3–5 d, can add Loperamide if >5 yrs

Fail to respond, Azith 3 d

Fail to respond, seek medical attention from qualified pediatrician

Fail to respond, may use Metro or Tin or seek medical attention

Fail to respond, seek medical attention from qualified pediatrician

Fail to respond, may use Metro or Tin or seek medical attention

Infants ≤2 months age should receive ORT or fluids and salt only and seek medical attention if illness progressive Immunocompromised patients should be treated with antibacterial drugs for 5–7 d

*Forces change in itinerary + Disables requiring confinement to bed Azith = Azithromycin, Cef = Ceftriaxone, FQ = Fluoroquinolones, Metro = Metronidazole, ORT = Oral Rehydration Therapy, Rif = Rifaximin, Tin = Tinidazole Figure 16-1. Algorithm for management of travelers’ diarrhea according to age and destination (see Table 12-2 for drugs and daily doses).

fecal levels of the drug, which may be an advantage in infectious diarrhea management.23 Norfloxacin has been shown to be effective in shortening post-treatment diarrhea.4,24 A variety of clinical trials have shown that ciprofloxacin and fleroxacin are effective in shortening the illness of travelers’ diarrhea.25-27 Studies with ofloxacin demonstrated that 3 days was as good as 5 days of therapy and that a single dose was as effective as 3 days for treatment of travelers’ diarrhea.3,28 Newer fluoroquinolones such as levofloxacin have increased activity against gram-positive bacteria, a characteristic not useful in treating travelers’ diarrhea. However, levofloxacin can be given and is excellent in a single dose for most cases of travelers’ diarrhea.29 The specific daily dose of quinolone used in most studies has been the recommended regimen in treating a variety of infections (eg, 400 mg norfloxacin, 500 mg ciprofloxacin, and 500 mg levofloxacin). Considering the site of infection and the concentration of drug in the gut, future study may show that these doses can be reduced in cases of travelers’ diarrhea.

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The duration of therapy in travelers’ diarrhea is somewhat controversial. For the most part, travelers’ diarrhea is a mucosal surface bacterial infection analogous to urinary tract infections (UTIs). Many people recommend 3 days’ therapy for UTIs to prevent treatment failures. Studies have shown that single-dose therapy is adequate in most cases of travelers’ diarrhea.24,26,28-32 Our current recommendation is that travelers with diarrhea take 1 day’s therapy and see how they are feeling the next day. If they continue to have unformed stools and feel unwell, we recommend taking the drug on day 2. This can be repeated on the third day if illness has not been controlled, so that the maximum duration of therapy is 3 days. When given this way, the vast majority of travelers do not need to take the second or third day’s doses of antimicrobial. No data are available to establish the optimal timing of administration of antibacterial therapy in travelers’ diarrhea. Some experts in the field recommend initiating antimicrobial therapy with the passage of the first unformed stool by the traveler to assure maximal shortening of the illness. Arguing against this is knowledge that many travelers will pass only one or two unformed stools without developing significant illness without therapy. In the absence of data on this point, we recommend initiating therapy when the traveler feels he or she has a significant illness. This may be passage of one or two unformed stools with important associated symptomatology-associated complaints. The duration of post-treatment travelers’ diarrhea following initiation of effective antimicrobial therapy is about 24 hours. This is in contrast to an illness duration postplacebo treatment of 50 to 90 hours.2,3

COMBINED ANTIBACTERIAL AND ANTIMOTILITY THERAPY In 1986, we demonstrated that an antisecretory drug with rapid onset of action in relieving symptoms could be combined with curative antibacterial therapy, giving more effective results to treatment than when either of the drugs was used alone.33 Since then, we have carried out a number of trials showing that when loperamide is combined with an effective antibacterial drug, the combination shortened the duration of post-treatment diarrhea when compared with administration of the antibacterial agent alone.30-32 Clinically important additional improvement by using combination therapy with loperamide and an effective antibacterial drug has not been seen in all studies.34,35 The potential worsening of invasive diarrhea by using an antimotility agent appears to be lessened by combining the antimotility agent with an effective antibacterial drug.36 In one study of dysenteric shigellosis in Thai adults, loperamide was actually beneficial when combined with a fluoroquinolone in the treatment of the diarrhea.37

NEW AND OLD AGENTS WITH PROMISE Macrolides Azithromycin Azithromycin, an azalide antibiotic related to the macrolides, has a high degree of in vitro activity against bacterial pathogens (see Table 16-1). Azithromycin attains very high tissue levels, including

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Table 16-1. Antimicrobial Susceptibility: Minimal Inhibitory Concentration of 90% (MIC90) of 284 Bacterial Enteropathogens from Travelers with Diarrhea in India, Jamaica, Mexico, and Kenya, 1996–1998 Antibacterial

MIC90 (range)
g/ml

Trimethoprim

1,024

(1–>1,024)

Ceftriaxone

0.0625

(≤0.0156–8)

Ciprofloxacin

0.125

(≤0.0156–256)

Levofloxacin

0.5

(≤0.0156–64)

Amdinocillin

8

(≤0.0156–512)

Azithromycin

0.0625

(≤0.0156–16)

Doxycycline

64

(0.0312–512)

Rifaximin

32

(≤0.0156–1,024)

Adapted from Gomi et al.8

in the intestinal mucosa. In Thailand, where fluoroquinolone-resistant Campylobacter jejuni is a major pathogen, azithromycin was shown to be active in the management of the diarrhea of US servicemen stationed there.7,38 We recently carried out a large clinical trial comparing single-dose therapy with 1,000 mg azithromycin versus a single dose of 500 mg levofloxacin.29 The drugs were equivalent in all respects. Both shortened the duration of post-treatment diarrhea to about 1 day. In all probability, a dose of 500 mg per day for 1 to 3 days would be ideal for adults with travelers’ diarrhea (see Table 16-2). A 5-day course of azithromycin has also shown to be effective for the treatment of enteric fever due to multidrug-resistant and nalidixic acid-resistant serovar S. typhi.39 Roxithromycin and clarithromycin are other available macrolides for treatment of susceptible Campylobacter infections.40 Macrolides are still the traditional treatment for Campylobacter infections, although resistance occurs—at least in Thailand and Europe. When Campylobacter strains are resistant to both fluoroquinolones and macrolide-like drugs, the infection may be left untreated with antibacterial drugs, or other agents may be used if the organism is susceptible (eg, clindamycin or doxycycline).

Rifaximin Rifaximin is a rifamycin derivative, but it does not possess the rifampin-like property of stimulating the development of antibacterial resistance.19,41 As previously mentioned, rifaximin has been shown to be as effective as ciprofloxacin in the treatment of travelers’ diarrhea.19 The studies performed support two dosages of rifaximin for treatment of travelers’ diarrhea: 200 mg tid or 400 mg bid for 3 days. 18-20 As stated earlier and as shown in Table 16-1, the MIC 90 of rifaximin to bacterial enteropathogens averages 32
g/mL.8 When rifaximin is given for 3 days, the fecal concentrations of drug reach 8,000
g/g or more than 125 times the MIC90.22 We are currently planning studies with rifaximin to obtain more information about the drug in the treatment of infectious diarrhea due to invasive pathogens and in the treatment of frankly dysenteric diarrhea due to bacterial pathogens. Active plans are being pursued to make rifaximin generally available in many regions of the world, including the United States and Europe. When rifaximin is made available, it should become an important drug for treatment of travelers’ diarrhea.

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Table 16-2. Antidiarrheal Drugs Used in the Management of Travelers’ Diarrhea* Antibacterial

Adult Daily Dose

Children Daily Dose

Fluoroquinolone (FQ) Norfloxacin Ciprofloxacin Ofloxacin Levofloxacin Fleroxacin

400 mg bid 500 mg bid 200 mg bid 500 mg qid 400 mg qid

Not given Not given Not given Not given Not given

Azithromycin (A)

500 mg qid

10 mg/kg/d single dose day 1, 5 mg/kg/d subsequently

Rifaximin (Rif)

200 mg tid or 400 mg bid

100 mg in oral suspension qid

Ceftriaxone (Cef)

Not normally used

50 mg/kg once a day IM or IV for 3–5 days

Metronidazole (Metro)

250 mg qid for 7 days

50 mg/kg/d in 4 doses for 7 days

Tinidazole (Tin) Loperamide (Lo)

50 mg/kg in single dose (maximum 2 g) 2 g single dose, 4 mg initially, then 2 mg after each unformed stool, not to exceed 8 mg/d

If older than 5 years age, 1 caplet/ chew tablet or 2 teaspoons initially, then 1 teaspoon or 1/2 caplet after each unformed stool, not to exceed 6 teaspoons (3 caplets)/d (9–11 years age) or 4 teaspoons (2 caplets)/d (6–8 years age)

bid = twice daily; tid = three times daily; qid = four times daily; IM = intramuscular; IV = intravenous *See Figure 16-1 for duration for antibacterial therapy.

Pivamdinicillin Pivamdinicillin has been used in limited studies on the treatment of culture-proven shigellosis in children living in Bangladesh.42 The drug shows moderate activity against bacterial enteric pathogens from diverse regions of the world.8 It is not available in most parts of the world.

Third Generation Cephalosporins Parenterally administered third generation cephalosporins have been used in limited studies in children with bacterial diarrhea.43 Oral third generation cephalosporins have not been shown to be effective in treating shigellosis in adults.44 Clinical trials in the treatment of travelers’ diarrhea are needed.

Trimethoprim and Sulfamethoxazole Trimethoprim alone was effective in the early 1980s for treatment of travelers’ diarrhea, but resistance developed rapidly.2,8,12 The combination of 160 mg trimethoprim and 800 mg sulfamethoxazole for 1 to 5 days has shown to be effective in the treatment of travelers’ diarrhea, an outcome that is even further improved by the simultaneous use of loperamide in randomized and controlled studies.25,45 Resistance to TMP–SMX has increased and reduced its effectiveness. Rare hypersensitivity reactions to the sulfonamide moiety (eg, Stevens-Johnson syndrome) remain a concern.

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Doxycycline Doxycycline was evaluated early on as a prophylactic agent in the prevention of travelers’ diarrhea.46 Limited data exist on its value as a therapy of the illness.47 The moderately high MICs and high intestinal concentration of doxycycline suggest that the drug would be a suitable agent for treating the diarrhea of travelers, but widespread resistance has reduced its overall effectiveness.8,21,48,49 Doxycyline causes photosensitivity, a potential problem for travelers to the sunny tropics.

TREATMENT OF SPECIAL PATIENTS Infants and Children Children commonly experience travelers’ diarrhea. For infants under 2 years of age, oral fluid therapy is generally recommended as the optimal therapy. Symptomatic drugs and antimicrobial drugs are not usually recommended in this age group. For older children, antibacterial therapy may be useful in reducing the suffering from enteric symptoms and returning the children to normal activities. The fluoroquinolones are not generally used in children because of the rare possibility of developing joint abnormalities during active growth.50 Although not evaluated in children and requiring extrapolation from adult studies, we believe that an ideal approach for treatment of children with moderate to severe travelers’ diarrhea would be to administer 10 mg/kg azithromycin for day 1 and then 5 mg/kg/day on days 2 and 3, as needed (see Figure 16-1 and Table 16-2). An alternative would be a parenterally administered third generation cephalosporin or to use a pediatric suspension of rifaximin, if available.43 The dose of rifaximin used in children in most studies was 100 mg qid for 3 days (see Table 16-2).

Pregnant Women The same therapeutic dilemma for fluoroquinolones exists for pregnant women as for young children. For milder illness, oral fluid and salt therapy may be all that is needed. For more severe illness in a pregnant woman, third generation cephalosporins such as ceftriaxone (2 g once a day) or azithromycin (500 mg/day for 1 to 3 days) may be given. Although it is not, and will not, be initially approved for use in pregnant women, poorly absorbed rifaximin should be safe when available.

Immunosuppressed Patients Immunocompromised travelers are most likely to present with the same organisms that cause travelers’ diarrhea in travelers with normal immune systems. Moreover, some parasites such as Cryptosporidium, Isospora, or Microsporidium are more common in these patients. A major step forward in the management of advanced human immunodeficiency virus (HIV) infection has been the development of highly active antiretroviral therapy (HAART). Patients with AIDS can be rendered immune to many enteric pathogens while taking HAART. In advising HIV patients about travel, seeing that they are properly treated for the HIV infection is the most important thing. In a patient not on adequate treatment or in other patients with altered immunity (cancer or transplant patients), it is best to suggest that they not travel to developing tropical regions. If

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this is not possible, then they should be given adequate treatment to take in case they develop illness. Chemoprophylaxis could be considered for these persons, employing an active antibacterial drug such as a single daily tablet of a fluoroquinolone during the period of high risk.51 Bismuth subsalicylate (BSS) prophylaxis should be avoided in immunocompromised patients to prevent the development of bismuth encephalopathy, a rare problem in patients with AIDS taking large doses of BSS.52 In considering therapy of travelers’ diarrhea in a patient with altered resistance, we recommend giving them antimicrobial therapy for longer periods of time than would be the case for otherwise healthy persons. Rather than single-dose therapy, we would suggest that the immunocompromised patient with travelers’ diarrhea take 5 to 7 days of the antibacterial drug to be used (see Table 16-2 and Figure 16-1 for specific drug suggestions).

ANTIBACTERIAL TREATMENT FAILURES (CAUSE AND MANAGEMENT) Clinical treatment failures occur following self-treatment of travelers’ diarrhea. In Table 16-3, we list the possibilities to consider in these cases. The two most common explanations for patients failing to respond to treatment of travelers’ diarrhea with conventional therapy are the occurrence either of an enteric infection with fluoroquinolone-resistant Campylobacter or Salmonella species, or of a protozoal pathogen such as Giardia, Cryptosporidium, Cyclospora, Isospora, or Microsporidium. Approximately 3% of travelers will have diarrhea lasting longer than 1 month.53 Many of those patients will have diarrhea lasting 6 months or even longer. It is reasonable to believe that Brainerd diarrhea, a chronic form of idiopathic diarrhea seen following consumption of raw milk or untreated water, explains a portion of that illness.53-55 Patients with chronic diarrhea following travel should be worked-up for cause, including gastrointestinal endoscopy and biopsy of abnormal tissue, and if all studies are negative for potential etiologic agents, they can be assumed to have Brainerd diarrhea. In this case, they should receive symptomatic treatment, usually with loperamide, and be reassured that their illness will likely be self-limited.55,56 Occasionally, an episode of travelers’ diarrhea may trigger a prolonged bout of irritable bowel syndrome or underlying chronic inflammatory bowel disease.57,58

Table 16-3. Conditions to Consider in Patients with Travelers’ Diarrhea who Fail Fluoroquinolone Antimicrobial Therapy Condition to Consider

Recommendations

Occurrence of antibiotic-resistant enteric bacterial pathogen (eg, Campylobacter, or Salmonella)

Empiric therapy with azithromycin vs stool microbiology studies (culture and parasite examination)

Protozoal infection (Giardia, Cryptosporidium, Cyclospora, Isospora, or Microsporidium)

Stool parasite exam vs empiric therapy with metronidazole

Brainerd diarrhea

Diagnosis of exclusion after a negative gastrointestinal work-up, treated with reassurance and symptomatic drugs (usually loperamide)

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20. DuPont HL, Steffen R, Sack DA, et al. A randomized, double-blind, parallel, placebo-controlled study of rifaximin at 600 and 1200 mg/day in the treatment of bacterial infectious diarrhea in travelers. 7th Conference of the International Society of Travel Medicine, Innsbruck, Austria, May 27–31, 2001. 21. Heimdahl A, Kager L, Nord CE. Changes in the oropharyngeal and colon microflora in relation to antimicrobial concentrations in saliva and feces. Scand J Infect Dis Suppl 1985;44:52–8. 22. Jiang Z-D, Ke S, Palazzini E, et al. In vitro activity and fecal concentrations of rifaximin after oral administration. Antimicrob Agents Chemother 2000;44:2205–6. 23. Cofsky RD, DeBouchet L, Landesman SH. Recovery of norfloxacin in feces after administration of a single oral dose to human volunteers. Antimicrob Agents Chemother 1984;26:110–1. 24. Wistrom J, Jertborn M, Hedstrom SA, et al. Short-term self-treatment of travelers’ diarrhoea with norfloxacin: a placebo-controlled study. J Antimicrob Chemother 1989;23:905–13. 25. Ericsson CD, Johnson PC, DuPont HL, et al. Ciprofloxacin and trimethoprim/sulfamethoxazole as initial therapy for acute travelers’ diarrhea. A placebo-controlled randomized trial. Ann Intern Med 1987;106:216–20. 26. Salam I, Katelaris P, Leigh-Smith S, Farthing MJG. Randomized trial of single-dose ciprofloxacin for travelers’ diarrhoea. Lancet 1994;344:1537–9. 27. Steffen R, Jori R, DuPont HL, et al. Fleroxacin, a long-acting fluoroquinolone, as effective therapy for travelers’ diarrhea. Rev Infect Dis 1989;11 Suppl 5:S1154–5. 28. Ericsson CD, DuPont HL, Mathewson JJ. Single dose ofloxacin plus loperamide compared with single dose or three days of ofloxacin in the treatment of travelers’ diarrhea. J Travel Med 1997;4:3–7. 29. Adachi JA, Ericsson CD, Jiang Z-D, et al. Azithromycin is comparable to levofloxacin in the treatment of US travelers with acute diarrhea in Guadalajara, Mexico. 7th Conference of the International Society of Travel Medicine, Innsbruck, Austria, May 27–31, 2001. 30. Ericsson CD, DuPont HL, Mathewson JJ, et al. Treatment of travelers’ diarrhea with sulfamethoxazole and trimethoprim and loperamide. J Am Med Assoc 1990;263:257–61. 31. Ericsson CD, Nicholls-Vasquez I, DuPont HL, Mathewson JJ. Optimal dosing of trimethoprim/ sulfamethoxazole when used with loperamide to treat travelers’ diarrhea. Antimicrob Agents Chemother 1992;36:2821–4. 32. Ericsson CD, DuPont HL, Mathewson JJ. Optimal dosing of ofloxacin with loperamide in the treatment of non-dysenteric travelers’ diarrhea. J Travel Med 2001;8:19–25. 33. Ericsson CD, Johnson PC, DuPont HL, Morgan DR. Role of a novel antidiarrheal agent, BW942C, alone or in combination with trimethoprim/sulfamethoxazole in the treatment of travelers’ diarrhea. Antimicrob Agents Chemother 1986;29:1040–6. 34. Taylor DN, Sanchez JL, Chandler W, et al. Treatment of travelers’ diarrhea: ciprofloxacin plus loperamide compared with ciprofloxacin alone: a placebo-controlled, randomized trial. Ann Intern Med 1991;114:731–4. 35. Petruccelli BP, Murphy GS, Sanchez JL, et al. Treatment of travelers’ diarrhea with ciprofloxacin and loperamide. J Infect Dis 1992;165:557–60. 36. DuPont HL, Hornick RB. Adverse effect of lomotil therapy in shigellosis. J Am Med Assoc 1973;226:1525–8. 37. Murphy GS, Bodhidatta L, Echeverria P, et al. Ciprofloxacin and loperamide in the treatment of bacillary dysentery. Ann Intern Med 1993;118:582-6. 38. Kuschner RA, Trofa AF, Thomas RJ, et al. Use of azithromycin for the treatment of Campylobacter enteritis in travelers to Thailand, an area where ciprofloxacin resistance is prevalent. Clin Infect Dis 1995;21:536–41.

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39. Chinh NT, Parry CM, Ly NT, et al. A randomized controlled comparison of azithromycin and ofloxacin for treatment of multidrug-resistant or nalidixic acid-resistant enteric fever. Antimicrob Agents Chemother 2000;44:1855–9. 40. Endtz HP, Broeren M, Mouton RP. In vitro susceptibility of quinolone-resistant Campylobacter jejuni to new macrolide antibiotics. Eur J Clin Microbiol Infect Dis 1993:12:48–50. 41. Soro O, Pesce A, Raggi M, et al. Selection of rifampicin-resistant Mycobacterium tuberculosis does not occur in the presence of low concentrations of rifaximin. Clin Microbiol Infect 1997;3:147–51. 42. Salam AM, Dhar U, Khan WA, Bennish ML. Randomized comparison of ciprofloxacin suspension and pivamdinicillin for childhood shigellosis. Lancet 1998;15:522–7. 43. Eidlitz-Marcus T, Cohen YH, Nussinovitch M, et al. Comparative efficacy of two- and five-day courses of ceftriaxone for treatment of severe shigellosis in children. J Pediatr 1993;123:822–4. 44. Salam MA, Seas C, Khan WA, Bennish ML. Treatment of shigellosis: IV. Cefixime is ineffective in shigellosis in adults. Ann Intern Med 1995;123:505–8. 45. Ericsson CD, DuPont HL, Mathewson JJ, et al. Treatment of traveler’s diarrhea with sulfamethoxazole and trimethoprim and loperamide. J Am Med Assoc 1990;263:413–25. 46. Sack RB, Froehlich JL, Zulich AW, et al. Prophylactic doxycycline for travelers’ diarrhea: results of a prospective double-blind study of Peace Corps volunteers in Morocco. Gastroenterology 1979;76:1368–73. 47. Sack RB, Froehlich JL, Ørskov F, Ørskov I. Doxycycline is an effective treatment for travelers’ diarrhoea. J Diarrhoeal Dis Res 1986;4:144–8. 48. Sack RB, Santosham M, Froehlich JL, et al. Doxycycline prophylaxis of travelers’ diarrhea in Honduras, an area where resistance to doxycycline is common among enterotoxigenic Escherichia coli. Am J Trop Med Hyg 1984;33:460–6. 49. Arthur JD, Echeverria P, Shanks GD, et al. A comparative study of gastrointestinal infections in United States soldiers receiving doxycycline or mefloquine for malaria prophylaxis. Am J Trop Med Hyg 1990;43:608–13. 50. Gough A, Barsoum NJ, Mitchell L, et al. Juvenile canine drug-induced arthropathy: clinicopathological studies on articular lesions caused by oxolonic acid and pipemidic acids. Toxicol Appl Pharmacol 1979;51:177–87. 51. DuPont HL, Ericsson CD. Prevention and treatment of travelers’ diarrhea. N Engl J Med 1993;328:1821–7. 52. Mendelowitz PC, Hoffman RS, Weber S. Bismuth absorption and myoclonic encephalopathy during bismuth subsalicylate therapy. Ann Intern Med 1990;112:140–1. 53. DuPont HL, Capsuto EG. Persistent diarrhea in travelers. Clin Infect Dis 1996;22:124–8. 54. Mintz ED, Weber JT, Guris D, et al. An outbreak of Brainerd diarrhea among travelers to the Galapagos Islands. J Infect Dis 1998;177:1041–5. 55. DuPont HL. Persistent diarrhea in a traveling student. Gastrointest Dis Today 1993;2:1–6. 56. Afzalpurkar RG, Schiller LR, Little KH, et al. The self-limited nature of chronic idiopathic diarrhea. N Engl J Med 1992;327:1849–52. 57. Yanai-Kopelman D, Paz A, Rippel D, Potasman I. Inflammatory bowel disease in returning travelers. J Travel Med 2000;7:333–5. 58. Thornley JP, Jenkins D, Neal K, et al. Relationship of Campylobacter toxigenicity in vitro to the development of post infectious irritable bowel syndrome. J Infect Dis 2001;184:606–9.

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Par t Five

Special Hosts and Populations

Chapter 17

SPECIAL HOSTS: CHILDREN, PREGNANT W O M E N , I M M U N O C O M P R O M I S E D PAT I E N T S , T H E E L D E R LY Richard A. Oberhelman, MD, Susan L. F. McLellan, MD, MPH, and Ronald H. Behrens, BSc, MB, ChB, MD, FRCP

While most research studies of travelers’ diarrhea (TD) have focused on healthy adults, who comprise the vast majority of overseas travelers, there are increasing numbers of travelers in other groups that require special consideration. International air travel has increased by 36% between 1990 and 1999, and with this increase many more children are traveling overseas, posing special considerations for evaluation and management of TD.1 Pregnant women also deserve special consideration because of the risks of placental insufficiency with dehydration and limitations on drugs that can be used therapeutically. Immunocompromised hosts present other challenges, complicated by the fact that varying degrees and types of immune suppression make it impossible to define a single approach that is universally applicable. Special considerations for the evaluation, diagnosis, and management of TD in children, pregnant women, elderly travelers, and immunocompromised hosts are discussed in separate sections of this chapter. A summary of these special considerations for children, pregnant women, and human immunodeficiency virus (HIV)-infected travelers is presented in Table 17-1.

TRAVELERS’ DIARRHEA IN CHILDREN Epidemiology and Clinical Manifestations While there are very few published studies of the epidemiology of TD in children, there is indirect evidence to suggest that children are at increased risk for TD as compared to normal adults. Children from affluent societies in developed countries have very limited exposure to the bacterial and parasitic organisms prevalent in developing countries, so they rarely develop partial immunity from repeated early exposures to enteropathogens. Child travelers may also develop TD from organisms such as Rotavirus, which are common in developed countries as well, but cause relatively little TD in adults with prior immunity. While children from developing areas with poor sanitation may experience many more episodes of diarrhea and more adverse health consequences from diarrhea than children from developed areas traveling abroad, the child traveler is probably at increased risk of developing diarrhea with a given pathogen exposure than either children from developing countries or normal adult travelers.

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Table 17-1. Travelers’ Diarrhea in Children, Pregnant Women, and HIV-Infected Travelers: Summary of Recommendations for Evaluation, Diagnosis, and Management as Compared to Normal Adults* Risk of TD as Compared to Normal Adults

Morbidity from TD as Compared to Normal Adults

Children

Increased in some age groups, especially children under age 2 years and adolescents

Greater risk of severe dehydration and prolonged disease

Pregnant Women

Probably increased due to decreased gastric acidity and increased intestinal transit time

HIV-Infected Travelers

Increased when CD4 count is low, similar if CD4 count is normal

Special Host Group

Use of Oral Rehydration for TD

Use of NonAntimicrobial Drugs for TD

Common Etiologies of TD

Use of Antibiotics for TD Prophylaxis

Empiric Antibiotic Therapies for TD

Pathogens common in normal adults (ETEC, Shigella, Campylobacter) and other organisms (Rotavirus)

Usually not recommended due to limited data and rarity of situations with specific indications

Not recommended Recommended with Bismuth subif enteroaggregative WHO or low salicylate (BSS) E. coli O157 is a osmolarity safe and effective; possibility; Some solutions Antimotility agents recommend avoiding not recommended quinolones due to except for older potential toxicity; children and Azithromycin or adolescents rifaximin may be used

Increased risk of Similar to normal maternal and fetal adults; increased morbidity and risk of severe mortality from deinfection with hydration; Greater some nonenteric morbidity with gastrointestinal concomitant gastro- organisms intestinal dis(Hepatitis E, turbances from Listeria, pregnancy Toxoplasma)

Usually not recommended due to risk of drug exposure during pregnancy

Usually not recommended due to risk of drug exposure during pregnancy; Quinolones are contraindicated; Azithromycin or metronidazole (category B) may be used, if necessary

Greater risk of prolonged or severe diarrhea with certain pathogens (if CD4 is low), or development of systemic disease

Used more commonly than in normal adults if CD4 count is low and traveler is visiting areas with poor sanitation; Quinolones or azithromycin frequently used

As in normal adults, Recommended quinolones or with WHO or low azithromycin osmolarity solufrequently used tions (do not use same family of drugs used for prophylaxis); Suggest lab evaluation for bacterial and parasitic agents and consider empiric metronidazole if TD is refractory to routine antibiotic therapy

*Based on multiple sources referenced in the text.

Pathogens common in normal adults and other opportunistic infections (Cryptosporidium, Cyclospora, Giardia)

Recommended with BSS not recomWHO or low mended due to osmolarity solupotential fetal tions; Use lowtoxicity; Loposmolarity solueramide (category tions preferenB) may be used, tially after initial if necessary rehydration

BSS and antimotility agents may be used as in normal adults

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The few published studies on the subject suggest that the epidemiology of TD in children and adolescents is similar to that seen in adults, but varies somewhat by age group. Pitzinger and colleagues described the incidence, clinical features, and management of TD in a group of 363 children and young adults aged 0 to 20 years, recruited from the Zurich University Vaccination Center in Switzerland and traveling to a variety of destinations in developing countries.2 The duration of travel was less than or equal to 2 weeks in 41%, and in the remainder, the duration of travel varied from 3 to 28 weeks. Overall, 142 participants (39.1%) reported at least one episode of TD, an attack rate that is slightly higher than in adults from the same population. When stratified by age groups, the TD attack rate was significantly higher in the 0 to 2-year-old group (60%) than in all other age groups. The second highest rate was found in adolescents aged 15 to 20 years (44.8%), followed by the 7 to 14-yearold group (21.7%) and the 3 to 6-year-old group (17%). Multiple episodes of TD were reported in 28% of those who reported at least one episode. When calculated as incidence of TD per 14-day travel period, the lowest rates by far were reported for the 3 to 6-year-olds (8.5%). Significantly higher rates were found in the 0 to 2-year-old subjects (40%) and in adults aged 20 and older (22 to 36%). TD rates were highest in young infants in spite of the fact that their parents often claimed that they consistently practised dietary precautions. Most episodes (72%) were reported as watery diarrhea, and other common clinical features included abdominal cramping (43%) and vomiting (14%). Fever was reported by 14.1%, mucus in the stools by 4.9%, and blood in the stools by 2.1%. The mean duration of TD in this study was 11.5 days, although children aged 0 to 2 years often had a prolonged illness (mean duration 29.5 days). Twenty-seven patients (19.1%) were confined to a bed, 21 (14.9%) were evaluated by a physician, and 2 were hospitalized. Illness attack rates were highest for children traveling to North Africa (73%) and India (61%), whereas attack rates for children traveling to East or West Africa, Southeast Asia, or Latin America varied from 31 to 39%. Etiologic agents of TD cases were not reported in this study. In contrast to the extensive literature on TD in adults, the etiology of TD in children has not been well studied. While it is tempting to extrapolate based on numerous studies of endemic pediatric diarrhea in children from developing countries, the causes of TD may be quite different because of differing nutritional status, level of sanitation, and preexisting immunity. However, it is likely that many common causes of endemic diarrhea will also cause TD in child travelers, especially those that are foodborne or waterborne such as enterotoxigenic Escherichia coli, Shigella spp, and Campylobacter jejuni. In contrast, agents that are spread by direct fecal–oral contact linked to crowding in environments like day care centers, such as Rotavirus, may be less frequent causes of TD in children unless the child’s family are long-term travelers who have integrated more completely into the host country society.

Diagnostic Testing and Therapy Criteria for deciding which children should have a diagnostic evaluation for TD are similar to those for adults. Generally, stool culture and parasitologic evaluation are only recommended for children with frank dysentery, severe diarrhea, or persistent diarrhea lasting more than 14 days. The mainstay of therapy for TD in children, as for pediatric diarrhea in general, is oral rehydration therapy (ORT).3 This is the most important intervention regardless of the etiology of diarrhea. In determining how best to use ORT for TD in children, one must consider the type of solution to use, volume

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to deliver, and method of delivery. Current medical standards advocated by both the World Health Organization (WHO) and the American Academy of Pediatrics state that ORT should be used for mild, moderate, and severe dehydration. In general, intravenous hydration is only necessary for very severe dehydration (eg, >15% dehydration, often with relative hypotension) and in certain medical conditions such as stomatitis or altered mental status that can predispose to aspiration. While rehydration of children with mild dehydration can often be accomplished with commercially-produced low osmolarity solutions (eg, Pedialyte, Ricelyte in the United States), these formulas are designed primarily to maintain hydration. World Health Organization formula ORT, manufactured in many countries as salt solution packets to be mixed with appropriate volumes of water, is appropriate for treatment of diarrhea and dehydration regardless of the etiologic agent. Special ORT solutions may be better for diarrhea due to specific etiologies, such as low osmolarity ORT for viral gastroenteritis and rice-based ORT for cholera, but in practice, these special solutions are rarely available to travelers.4 ORT is usually administered by small, frequent sips using a cup and spoon, and target volumes to rehydrate children over 4 to 6 hours are based on clinical estimates of the degree of dehydration, ranging from 50 to 60 cc/kg (mild to moderate dehydration) to 80 to 100 cc/kg (moderate to severe dehydration). Further details on ORT may be found in Chapter 15, “Nonspecific Treatment: Diet, Oral Rehydration Therapy, Symptomatic Drugs.” One medical dilemma that has evolved in recent years is whether to use empiric antibiotics for treatment of dysentery of unknown etiology, because studies suggest that antibiotic treatment of inflammatory colitis due to E. coli O157 may predispose to hemolytic uremic syndrome (HUS).5 While there is no fail-safe approach to this dilemma, several facts and guidelines may be useful in making this decision. First, it is important to recognize that E. coli O157 is rarely described as an agent of TD, although by the same token, it is often not detected because special isolation techniques are required to identify it. Most E. coli O157 infections are associated with outbreaks and not sporadic cases of diarrhea. In contrast, common agents of dysentery such as Shigella and Campylobacter are often identified in cases of TD with dysentery. If possible, child travelers with dysentery should be seen by a local physician who will be more knowledgeable about the risk of E. coli O157 in the particular area. Certain geographical locations, such as Argentina, are associated with higher rates of E. coli O157 infections in children, and greater restraint in using empiric antibiotics should be used in these areas. If it is not a high-risk area and the case of dysentery is sporadic (or limited to a family cluster), then the next step is the feasibility of stool culture for E. coli O157 and for other bacterial agents (which, if found, would make E. coli O157 less likely). While culture for E. coli O157 is possible within 24 hours, laboratory resources for rapid detection (or any detection at all) is doubtful in most locations where TD is prevalent. If culture is obtainable and reliable, it may be advisable to wait for the culture result to initiate directed therapy. If no reliable culture is available and the traveler is not in a known high-risk area, then in most cases, it is reasonable to use empiric antibiotic therapy for shigellosis and/or campylobacteriosis, depending on the epidemiological associations. In general, Campylobacter is a more common etiology for dysentery in children under 12 months of age, while both Campylobacter and Shigella are common in older children and adolescents. Once a decision is made to treat a case of TD with antibiotics, the distinction between dysentery and watery diarrhea becomes less important since the agents used for empiric therapy should cover

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common causes of both types of diarrhea. Trimethoprim–sulfamethoxazole (TMP–SMX) has been the mainstay of antimicrobial therapy for TD in children for years, due to extensive experience in children and data from the 1980s suggesting efficacy against many pathogens causing TD. Widespread resistance to TMP–SMX makes it a poor choice for TD in both children and adults today. While reports from Thailand frequently reflect extremes for antimicrobial resistance of enteropathogens (and malaria parasites), it is still significant that a recent report from Thailand demonstrated TMP–SMX resistance in 90% of Shigella and 40% of enterotoxigenic E. coli and nontyphoidal Salmonella strains.6 Although resistance to TMP–SMX in other locations is likely to be less, it is still a poor choice based on average levels of resistance among common TD pathogens. Because of increasing resistance to TMP–SMX and the risk of rare but serious side effects (Stevens-Johnson Syndrome, blood dyscrasia), the Committee on Safety in Medicine (United Kingdom) recommends that use of this antibiotic combination be restricted to specific indications.7 One should keep in mind, however, that certain protozoan agents of TD are still treated preferentially with TMP–SMX, such as Cyclospora cayetanensis and Isospora belli. If not TMP–SMX, then what antibiotics should be used? Fluoroquinolones such as ciprofloxacin are standard empiric therapy in adults because they cover most of the common enteropathogens causing TD, but common pediatric practice precludes use of this category of antibiotic because of quinolone-associated cartilage toxicity in juvenile animals. However, the risk of this type of toxicity in children seems to be low, and some experts use short course fluoroquinolones (such as 5-day courses for TD) in children without concern.8 While cefixime is an attractive choice because of substantial safety data in children and studies showing efficacy in vitro and in vivo against most enterobacteriaciae (including TMP–SMX-resistant Shigella strains isolated from children), caution is warranted because it was ineffective against shigellosis in adults from Bangladesh.9-11 As in the case of other third generation cephalosporins, cefixime is ineffective against most Campylobacter strains, limiting its use for empiric treatment of TD. Cefixime is no longer manufactured in the United States, as of early 2003. Azithromycin appears to be a better choice, as it was found to be effective against Shigella, Campylobacter, and other enterobacteriaciae causing TD, but resistance is emerging in some locations.12,13 Rifaximin is a poorly absorbable rifamycin derivative that shows great promise as an agent for empiric treatment of TD in children, but it is still not commercially available in the United States as of mid-2002.14 Toxicity appears to be low and rifaximin has been shown to be more effective than TMP–SMX and paromomycin and as effective as ciprofloxacin and azithromycin against a variety of common TD pathogens in both children and adults.15-19 Rifaximin may become an important tool in the armamentarium of antibiotics for TD in children. Nonspecific therapies for TD in children have not been well studied and are generally not recommended. Bismuth subsalicylate may be effective for treatment of TD in children as it is in studies of adult travelers, and salicylate levels in Chilean children receiving therapeutic doses for diarrhea are well below therapeutic doses for aspirin.20,21 Salicylate toxicity has not been demonstrated in adults or children taking bismuth subsalicylate for TD and is probably not an appropriate concern. Synthetic opiates as antiperistaltic agents (eg, loperamide) are not advisable in young children for several reasons. Classic concerns include delayed clearance of organisms and microbial toxins, occult dehydration that can occur in the lumen of the bowel in spite of reduced stool volume, unpredictable

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neurologic toxicity in young children, and their role as a potential risk factor for HUS.22 In some cases, loperamide may be used in older children and adolescents, as it is in adults for symptomatic relief in difficult travel situations, such as long bus rides with limited restroom facilities.

Prevention Most experts on TD in children advocate good hygienic practices as the best method of preventing TD. Prophylactic antibiotics are usually not recommended for adults except in special situations where TD would be especially problematic, such as short business trips or special personal situations such as honeymoons. This type of special situation is rarely applicable to children, and antibiotics that have been studied for prevention of TD either have very limited efficacy with current antibiotic resistance patterns (TMP–SMX) or are not usually recommended for prolonged therapy in children (eg, fluoroquinolones). Bismuth subsalicylate may be effective but it has not been studied for prevention of TD in children. Probiotic agents such as Lactobacillus GG have been shown to significantly reduce diarrhea rates in undernourished Peruvian children, but studies of probiotics to prevent TD in adults have either shown no effect or only modest benefits. 23,24 Current evidence does not support the widespread use of commonly available probiotics for prevention of TD.

PREGNANT WOMEN The choice to travel while pregnant, especially to areas of poor sanitation, is one that should not be taken lightly. The well-being of both mother and child must be taken into consideration. The pregnant woman is in a state of relative immune deficiency, and is therefore more susceptible to certain infectious pathogens. The developing fetus also has specific risks.

Clinical Features The pregnant traveler is at increased risk of developing disease when exposed to TD pathogens because of both decreased gastric acidity and increased intestinal transit time. Gastroesophageal reflux, common during pregnancy, may lead the woman to use antacids frequently, contributing further to the increase in gastric pH. If she does become ill, preexisting nausea may increase her susceptibility to dehydration from even a mild diarrheal illness. Even low levels of nausea and dehydration can be difficult to tolerate for the pregnant woman. An empty stomach exacerbates morning sickness, so a woman also afflicted by nausea due to TD may find it particularly difficult to tolerate oral intake, resulting in greater volume deficits. The tendency of pregnant women to suffer from syncope is legendary, and is compounded by dehydration. More severe dehydration can put the woman at risk of shock and premature labor. In general, although the pregnant woman is more susceptible to severe dehydration and the consequences thereof, the bacterial agents of travelers’ diarrhea are unlikely to follow a more fulminant course. Entamoeba histolytica, however, is known to cause severe disease during pregnancy. In particular, the development of hepatic abscess is more ominous during pregnancy, as there is an increased risk for rupture.

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There are other enterically acquired pathogens that are worth mentioning here because they pose a special risk to the pregnant woman or her child, although they are not typically causes of travelers’ diarrhea. Chief among these is hepatitis E, which carries a fatality rate of 15 to 25% during pregnancy.25 No vaccine is available, and the only protection is meticulous care with food and water. Listeria monocytogenes leads to severe disease in the pregnant woman as well as the possibility of miscarriage. Toxoplasmosis is endemic in the tropics and can cause severe congenital problems for the unborn child.

Treatment and Prevention of TD in Pregnant Women As with other persons at special risk, the pregnant traveler should be scrupulously attentive to dietary hygiene. One unique issue for the pregnant woman is the use of iodine compounds for water treatment. The use of iodine-containing drugs and even topical iodine-containing antiseptics has been associated with reports of congenital hypothyroidism.26,27 Although brief exposure to iodine at the concentrations used for water purification is probably innocuous, repeated consumption of iodinated water may put the infant at risk for congenital hypothyroidism. Boiled water is most reliably safe. Immunization against hepatitis A and typhoid can be achieved with inactivated vaccines and is generally considered safe. The Vi capsular polysaccharide vaccine against typhoid is preferred because of the lower rate of febrile reactions. Oral killed vaccines against cholera are available outside of the United States and offer some cross-protection against travelers’ diarrhea, but they have not been tested for safety in pregnancy. Because of the need to maintain adequate placental blood flow, aggressive oral rehydration is the most important intervention for management of TD in pregnant women. Dehydration may result in premature labor or shock, so it should be avoided as much as possible. It is prudent for pregnant women traveling to isolated areas to carry packets of oral rehydration salts with them. Either standard WHO formula ORS or low osmolarity ORS may be used safely in pregnancy, although many experts suggest that women receiving the WHO formula should switch to a low osmolarity formula; that is, a maintenance solution with lower salt concentrations (eg, Pedialyte in bottles or Ceralyte 50 in packets to mix with water), after initial rehydration is complete to avoid fluid retention. Low osmolarity ORS solutions are not widely available in developing countries, so these should be purchased before traveling. Management of diarrheal disease in the pregnant woman is complicated by the concerns regarding teratogenicity of certain medications. For this reason, in any case of serious diarrheal illness, an attempt should be made to make a specific diagnosis if empiric therapy with a safe antimicrobial fails. Routine stool culture and parasitologic examinations are appropriate, and further investigation is warranted if the diarrhea does not improve. Comprehensive information on the safety of various drugs in pregnancy can be found in texts such as Drugs in Pregnancy and Lactation by Briggs and colleagues.28 Risk factor categories for use of drugs in pregnancy as defined by the US Food and Drug Administration are summarized in the footnote.* In general, it is recommended that the pregnant woman avoid the use of any unnecessary medications, and routine prophylactic antimicrobials are not recommended. Chemoprophylaxis with bis-

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muth salicylate is also to be avoided, as the salicylate is well absorbed and may have adverse effects on the fetus.29 Loperamide is a category B drug and can be used, if necessary. The fluoroquinolones and tetracyclines are contraindicated in pregnancy and should not be used for the self-treatment of diarrhea. Trimethoprim–sulfamethoxazole (TMP–SMX) is a category C drug, but has been used in early pregnancy (there is a risk of kernicterus in the newborn in late pregnancy). Amoxicillin (category B) is also commonly used in early pregnancy, but high levels of resistance to both TMP–SMX and amoxicillin have limited their utility. While erythromycin is effective against some Campylobacter strains, azithromycin is more commonly used due to increasing quinolone resistance and because it has reliable activity against other agents of TD. Azithromycin is a category B drug. Other options include the oral second and third generation cephalosporins, such as cefixime. Rifaximin and oral aztreonam are poorly absorbed antimicrobials that offer promise but have not been evaluated in pregnant women. However, rifaximin appears to be safe in animal studies, and intravenous aztreonam is a category B drug.30 Metronidazole is a category B drug and may also be used empirically for amebiasis and giardiasis, although some experts advise against its use in the first trimester. Paromomycin is thought to be safe in pregnancy and can be used as an alternative agent for amebiasis, but not giardiasis. Many other antiparasitics and antihelminthics, however, are contraindicated in pregnancy or should be used only if the benefit outweighs the risk.

TD IN THE ELDERLY TRAVELER Two notable trends in clinical practice are the increasing number of travelers with preexisting medical problems and the fact that many more “over 65’s” are exploring the wider world. These trends mean that travel advice needs to focus on the unique hazards faced by these groups and the interventions available to reduce their particular risks.

Epidemiology and Clinical Manifestations In general, age per se is not a contraindication to most travel or activities. However, with age comes an increasing likelihood of chronic medical conditions, from hypertension to diabetes. To a great extent, it is these medical conditions that dictate whether an elderly person will be at increased risk from diarrheal disease. The impact of these specific conditions are discussed later in the section, “Special Features of TD in Other Immunocompromised Hosts,” below.

*Risk factor categories for use of drugs in pregnancy (Federal Register 1980; 44:37434-67): Category A: Controlled studies failed to demonstrate risk to fetus, and the possibility of fetal harm appears remote. Category B: Animal studies suggest a potential risk in the first trimester, only it is not confirmed in pregnant women; studies in animals that did not demonstrate fetal risk have not been confirmed. Category C: Animal studies to suggest adverse effects on the fetus and humans are not available; studies in women and animals are also not available. Drugs should only be used if the potential benefit justifies the potential risk to the fetus. Category D: Positive evidence of human fetal risk exists, but benefits for use in pregnancy may be acceptable despite the risk in certain situations (eg, life threatening situation, serious disease without safer alternatives).

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If anything, it appears that the elderly may have a somewhat lower risk of developing travelers’ diarrhea than the younger set. In one cohort of 1,469 travelers, the highest rate of diarrhea was in the 15 to 34-year-old age group.31 A study of visitors to Paris seen in an emergency room found rates of gastrointestinal problems of persons over 60 to be close to half of those in the 20 to 39-year-old group.32 The same pattern was found in a multicenter study of travelers’ diarrhea carried out in Jamaica, Kenya, India, and Brazil, and in a study of travelers returning from southern Turkey.33,34 Decreased incidence in older age groups may be related to increased likelihood of past exposure to pathogens, with development of some degree of residual immunity; more cautious eating habits; or greater chance of traveling in luxury accommodations with controlled food sources. On the other hand, decreasing gastric acidity with age may allow a lower inoculum of a potential pathogen to result in disease. The deleterious consequences of diarrheal disease are often more pronounced in the elderly because of their increased susceptibility to dehydration and electrolyte imbalance. A tendency toward reduced renal function and decreased sensitivity to thirst may contribute to this susceptibility. Dehydration can compound the effects of heatstroke, to which older travelers are also more prone.35 The elderly traveler is also more likely to have underlying medical conditions, such as diabetes or heart disease, which may be adversely affected by dehydration, changes in caloric intake (due to nausea), or fever. Medications routinely taken by persons with underlying conditions such as hypertension may potentiate dehydration (diuretics), blunt the physiologic tachycardic response to volume deficit (beta-blockers), or predispose to renal insufficiency in the face of volume deficit (angiotensin converting enzyme [ACE]-inhibitors). In general, the pathogens causing diarrheal disease in the elderly are not significantly different from those affecting younger adults. In terms of other enterically-acquired pathogens, many elderly travelers may be immune to hepatitis A due to childhood infection. However, they are at much higher risk of severe disease due to Listeria monocytogenes.

Treatment and Prevention Avoiding severe dehydration and its consequences is probably the most important aspect of the management of acute diarrhea in the elderly. Oral rehydration therapy should be initiated aggressively. Intravenous hydration may be necessary if oral rehydration and maintenance fails. Laboratory evaluation for renal dysfunction and electrolyte disorders should be performed early if diarrhea is voluminous or lasts more than a day or two despite self-treatment. Antimotility agents can be used, but caution must be used as the development of ileus may be more likely. Diagnostic studies would be similar to those conducted in other adults (stool culture, parasitologic examination, toxin assay for C. difficile). However, in an elderly population, more consideration must be given to the possibility of a noninfectious cause, such as neoplasm or inflammatory bowel disease. Antibiotics recommended for self-therapy will be similar to those for other adults, with care to avoid potential drug interactions. Because the consequences of disease may be more severe in the elderly, older travelers should be encouraged to be particularly careful with dietary hygiene. They should travel with a well-prepared medical kit and specific instruction on the use of oral rehydration solutions and self-treatment. They

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should have appropriate medical insurance and should be encouraged to seek appropriate care early if self-treatment fails.

TD IN PERSONS WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION Diarrheal disease in the vulnerable immunocompromised traveler is a frequent and important concern, as the physiological consequences to the vulnerable traveler may lead to greater morbidity. Much of the data on diarrhea in immunocompromised travelers has been provided from studies in proxy populations, such as adults living in endemic regions or from studies of diarrheal illness in immunocompromised patients living in developed countries.

Epidemiology and Clinical Features The traveler infected with HIV faces several issues with regard to diarrheal disease. Depending on the degree of immune compromise, the traveler may have increased susceptibility to intestinal pathogens, reduced ability to tolerate diarrhea and dehydration, increased likelihood of severe manifestations, and increased risk of chronic manifestations from certain TD agents. On the other hand, an HIVinfected person whose virus is well suppressed and whose immune status is relatively stable may be considered to be at only mildly increased risk from foodborne infection. The primary indicator of risk faced by the HIV-infected traveler is the degree of immunodeficiency due to HIV infection. The patient whose CD4 cell count remains in the normal to nearnormal range may have little increased risk of immediate disease due to diarrheal pathogens. However, once the CD4 count begins to drop, the risk of suffering symptomatic disease from an exposure may increase. Adults whose CD4 cells are less than 200 fulfill the criteria for acquired immune deficiency syndrome (AIDS) and are at significantly increased risk for infection and disease due to both common and opportunistic pathogens. Although many HIV-infected persons travel, it is difficult to find any studies that address the actual incidence of travel-related illness in this population. However, knowledge of the underlying defect in AIDS and the prevalence of specific pathogens in diverse geographic areas allows us to predict common problems. Patients with HIV and AIDS are at increased risk of infectious disease, primarily as a result of decreased cell-mediated immunity, although decreased humoral immunity occurs. A reduction in gastric acidity may also play a role in increased rates of infection and disease in patients with AIDS, as achlorhydria frequently is a consequence of chronic HIV infection and may permit the development of disease with a low inoculum of organisms. The consequences of even the typical travelers’ diarrhea may be more profound for the HIVinfected patient. Borderline nutritional status may be further compromised if appetite is suppressed. For patients taking antiretroviral therapy, absorption may be diminished by rapid intestinal transit time, or the traveler may not be able to tolerate his or her usual drug regimen due to nausea. Many antiretrovirals must be taken with food for appropriate absorption. Persons taking indinavir, a protease inhibitor, are susceptible to the development of renal stones if they become dehydrated. The specific agents of travelers’ diarrhea in the HIV or AIDS patient will include all of the same pathogens known to cause diarrhea in healthy travelers, but the risks of both infection and of severe

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disease may be higher. Common bacterial pathogens seem to be an important cause of chronic as well as acute diarrhea for persons with AIDS in the developing world, and the HIV-infected traveler would certainly be at risk from these.36,37 In a study of Shigella isolates in San Francisco, HIV infection was found to be a significant risk for shigellosis. HIV-infected persons were also more likely to be hospitalized.38 Campylobacter has been found to occur in HIV positive patients at rates of 39 times the general population in Los Angeles, and salmonellosis has been seen to be 20 times more prevalent.39,40 These studies included many homosexual men, and the role of sexual activity in the spread of these diseases was not well defined. However, in some heterosexual African populations, nontyphoidal Salmonella were the most common cause of severe bacterial infections in HIV-infected patients, suggesting that these organisms may pose an increased risk for HIV positive travelers to developing countries.41 In the developed world, nontyphoidal Salmonella infections have been recognized as a cause of recurrent disease and invasive infection in AIDS patients.42,43 Certain coccidian parasites are also more likely to cause serious disease in patients who are immunocompromised. HIV-infected patients who have low (<200) CD4 counts are well known to be at risk for chronic, debilitating diarrhea from Isospora belli and Cryptosporidium parvum.44 These parasites, as well as Microsporidium, are common causes of chronic diarrhea in AIDS patients in the developing world.45,46 Cyclospora cayetanensis is also known to cause acute and chronic diarrhea in travelers and may affect HIV-infected patients more profoundly.47 Both Isospora and Cyclospora are susceptible to treatment with trimethoprim–sulfamethoxazole, so persons with AIDS who are taking this medication as prophylaxis against Pneumocystis carinii pneumonia may have some protection against these two agents as well. Chronic diarrhea due to Cryptosporidium parvum, however, is refractory to most forms of therapy unless the person’s immune status improves with antiretroviral therapy. Giardia lamblia is a common cause of diarrhea in the HIV-infected person, even without a history of travel. As it is one of the most common protozoan intestinal parasites, it should be looked for in any HIV-infected patient with persistent diarrhea. Entamoeba histolytica or E. dispar as well as Giardia have been reported to occur in higher frequency among men with male sexual partners, so behavioral factors may have a role in the prevalence of these pathogens.48 Although invasive and unusual presentations of amebiasis are occasionally reported in AIDS patients, it appears that the spectrum of disease due to E. histolytica is similar to that in non-AIDS patients.49 The same appears to be true of Strongyloides stercoralis. This helminth has sometimes been reported to occur in higher frequency in persons infected with HIV, but other studies have not found an increased prevalence of Strongyloides carriage or disease in such patients, and Strongyloides does not seem to be a common cause of severe illness in areas highly endemic for both diseases.49-51 However, infection with Strongyloides may result in persistent autoinfection, which (although asymptomatic) can set the stage for subsequent disseminated disease when triggered by other conditions. The most important of these is exposure to corticosteroids, which are indicated in the treatment of several HIV-related conditions, including severe Pneumocystis carinii pneumonia and drug reactions. With regard to other helminth infections, although there is evidence for some interesting

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immunologic interactions, there is currently no good evidence suggesting higher prevalence or increased severity of disease in HIV-infected persons.52

Treatment and Prevention HIV-infected travelers should be scrupulous about following dietary guidelines to avoid enteric pathogens, in particular avoidance of inadequately treated water, undercooked meats, and raw unpeeled fruits and vegetables. Since iodination without filtration may not remove protozoan agents such as Cryptosporidium, HIV positive travelers with low CD4 counts should be careful to use bottled water that is adequately treated. Inactivated parenteral vaccines are available against Hepatitis A and typhoid, and these should be safe for the HIV-infected traveler to receive, although data are lacking and the response to vaccine may not be reliable if the patient is severely immunocompromised. Live vaccines, such as oral typhoid vaccine and the oral cholera vaccine available in Europe, should be avoided, although they are felt to be probably safe if the traveler has no AIDS-defining conditions.53 For relatively immunocompromised HIV-infected travelers, it may be appropriate to prescribe an antimicrobial to be taken routinely for the prevention of travelers’ diarrhea. This strategy is generally recommended only if the length of travel is less than 3 weeks, but in fact, persons with HIV infection frequently are prescribed antimicrobials for opportunistic infections for considerably longer, without ill effect. In some cases, the HIV-infected traveler will already be taking some form of antimicrobial for the prevention of opportunistic infection, such as trimethoprim–sulfamethoxazole to prevent Pneumocystis carinii, or azithromycin for prophylaxis against Mycobacterium aviumintracellulare. In all cases, the traveler should be thoroughly counseled about the use of oral rehydration solutions, antiperistaltics such as loperamide, and standby therapy for diarrhea, as well as indications to seek medical care. Appropriate antimicrobials for prophylaxis or self-treatment will be similar to those recommended for non–HIV-infected travelers. The fluoroquinolones have been the most commonly recommended agents for this use in recent years due to evidence of the development of resistance to earlier compounds in many of the agents of travelers’ diarrhea.54 However, in some areas of the world (such as Southeast Asia), fluoroquinolone-resistant Campylobacter is becoming prevalent.55 For travelers going to these areas, especially during winter or dry season, azithromycin may be a more appropriate choice.54 In general, the antimicrobials used in the prevention and self-treatment of travelers’ diarrhea should not have significant interactions with most antiretrovirals, but travelers taking such medication should be prepared to discuss the issue of potential drug interactions with the health care providers they may seek out overseas. The approach to diagnosis and therapy of TD in HIV-infected travelers will initially be similar to that in other travelers. Empiric antimicrobial therapy with a quinolone or azithromycin is reasonable early in the course of relatively mild illness. If an HIV-infected traveler is taking antibiotic chemoprophylaxis, empiric treatment for TD should not be done with a drug in the same class of antibiotics used for prophylaxis. However, in many cases, it will be appropriate to aggressively seek

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the etiologic agent, especially if the diarrhea threatens to become chronic. Stool cultures may reveal nontyphoidal Salmonella, which would warrant antimicrobial therapy in the AIDS patient to avoid recurrent bacteremia and invasive complications. A finding of Cryptosporidium would prompt an aggressive approach to management of the underlying HIV infection, as specific therapy for this pathogen is disappointing. Isospora and Cyclospora, although self-limited in the normal host, may cause chronic diarrhea in the AIDS patient and warrant treatment with trimethoprim— sulfamethoxazole. A combination of albendazole and ornidazole has also been used to treat Isospora.56 Diagnosis of coccidian parasites may require the use of special techniques such as acidfast stain of the stool or immunofluorescence. If an empiric course with fluoroquinolones or azithromycin is unsuccessful and no diagnosis is immediately forthcoming, then an empiric course of metronidazole is reasonable since Clostridium difficile, E. histolytica, and Giardia are all potential pathogens and may be difficult to detect. Newer stool antigen tests for the two protozoans may help in this regard. If diarrhea persists, then colonoscopy and specialist consultation are appropriate, as the differential diagnosis of diarrhea in the setting of HIV infection becomes very broad and may in the end be unrelated to prior travel.

SPECIAL FEATURES OF TD IN OTHER IMMUNOCOMPROMISED HOSTS Disorders of the Stomach Gastric acid is one of the more important barriers to enteric infection and the low pH present in the stomach is capable of killing many enteric pathogens within minutes of exposure. Any interference with the production of gastric acid secretion either pharmacologically or surgically can increase the risk of bacterial and parasitic infections.57,58 The most detailed study of susceptibility to enteric infection in the presence of reduced gastric acid was undertaken by Evans and colleagues, who demonstrated that patients suffering from enterotoxigenic Escherichia coli (ETEC) or cholera diarrhea had significantly lower gastric acid levels than control subjects, and that low acid was associated with more severe disease.59 Somewhat unexpectedly, low gastric acid in this study did not appear to influence susceptibility to shigellosis, amebic dysentery, giardiasis, or hookworm infestation. In a case-control study of 743 Dutch travelers, Cobelens and colleagues described how previous gastric surgery and recent treatment for gastrointestinal disorders were significant risk factors associated with developing diarrhea during travel.60 A similar effect was noted in travelers using antacids, but the confidence limits on the odds ratio were too large to be reliable. The interpretation of this data suggests that travelers with reduced gastric acid secretion are significantly more susceptible to infections with the toxinproducing ETEC and cholera, but susceptibility to other pathogens has not been confirmed.

Diabetes Diabetic patients have a relatively high rate of gastrointestinal disorders even in the absence of travel. In the general population, type 2 diabetics are reported to be twice as likely to have watery loose stools than controls.61 However, this association is likely to be consequent to poor glycemic control or medication, especially metformin, rather than following an increase in infections of the intestinal tract.62

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Information on specific gastrointestinal infections of diabetic travelers is not readily available, but there is no clear reason to suspect a widely different spectrum of pathogens. The diabetic patient is at risk of both hyperglycemia and hypoglycemia as a consequence of the rigors of travel, and dehydration makes glucose concentrations more difficult to control. The diabetic who develops diarrhea must be prepared to monitor glucose levels more frequently and adjust insulin doses, if necessary. A switch to short-acting insulin preparations for the duration of an acute illness might be appropriate, especially if nausea and vomiting result in decreased caloric intake. As hypoglycemia is more immediately life threatening than hyperglycemia, the diabetic traveler should carry rapid sources of glucose, and consider a glucagon emergency kit. Maintenance of hydration is particularly important in this population. In diabetics, cereal-based ORS preparations can generally be used much the same as in nondiabetics, as they are very effective and unlikely to influence glucose metabolism. However, the diabetic traveler should not be dissuaded from using glucose-containing oral rehydration solutions if these are more easily available. A study of diabetic patients with diarrhea in Bangladesh showed no difference in blood glucose levels, stool output, or duration of recovery in patients receiving standard WHO ORS formulation versus those receiving rice-powder or glycine-containing rehydration solutions.63

Inflammator y Bowel Disease Inflammatory bowel disease (IBD) may be either unmasked (following an episode of TD) or exacerbated (following an acute intestinal infection), but there is no published evidence that travelers with IBD are at higher risk of or suffer from a more severe or prolonged diarrheal illness.64 However, an infection with an invasive pathogen would be a significant risk factor for an exacerbating quiescent IBD. On these grounds, it would be rational to prescribe chemoprophylaxis to travelers with IBD, recognizing and discussing the small but important risk of precipitating C. difficile colitis.

Travelers Receiving Immunosuppressive Therapy Studies of immunosuppressed and malnourished individuals, children, and adults have identified invasive disease from Entamoeba histolytica as being more frequent. The groups most at risk are those at the extremes of age, patients with malignancy, and women who are pregnant or in postpartum stages.65 In the immunocompromised host, infections with Cyclospora and Cryptosporidium species, if untreated, result in chronic and sometimes severe watery diarrhea.65 No published data have suggested an increased risk of TD in persons with solid organ transplants. However, the use of broadspectrum antibiotics, which is not infrequent in this group of travelers, is associated with an increased risk of C. difficile colitis. Other causes of infection in this group include Cryptosporidium and enteroviruses. Noninfectious diarrhea is probably more frequent and this may be a graft versus host reaction. Unusual pathogens such as Cytomegalovirus can be expected in these immunosuppressed travelers, especially in persons on high-dose corticosteroids.

Travelers with Cardiac Disease or Diuretic Therapy Cardiac disease and diuretic therapy pose additional challenges for the management of TD, although there is no evidence that they significantly alter the risk of infection with specific TD-associated

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pathogens. Low osmolality ORT (ie, 45 or even 30 mmol Na+-containing ORT solutions) is as effective as standard 90 mmol Na+ WHO solutions in most cases, and should be used preferentially in these patients. If carbohydrate is given without sodium, an osmotic drain of water into the lumen can occur, causing further dehydration and potassium loss. Any ORT must be supplemented with potassium in cardiac patients, as homemade ORT often does not contain adequate potassium unless specifically supplemented. Low osmolarity ORT is not likely to be dangerous for cardiac patients, as significant sodium will have been lost with the diarrhea. Examples of low osmolarity solutions are described in the section on pregnant women, above. Dysrhythmias are more likely in cardiac patients with TD because of K+ loss, possibly complicated by malabsorption of cardiac medication. Most experts do not suggest changing medications for cardiac patients with TD, especially diuretics, and some suggest taking extra doses of cardiac drugs if torrential diarrhea or vomiting occur soon after taking a dose.

REFERENCES 1. Statistical Abstract of the United States. US Census Bureau; 2001. p. 667. 2. Pitzinger B, Steffen R, Tschopp A. Incidence and clinical features of travelers’ diarrhea in infants and children. Pediatr Infect Dis J 1991;10:719–23. 3. Hirshhorn N, Greenough WB. Progress in oral rehydration therapy. Sci Am 1991;264:50. 4. Thillainayagam AV, Hunt JB, Farthing MJ. Enhancing clinical efficacy of oral rehydration therapy: is low osmolarity the key? Gastroenterology 1998;114:197–210. 5. Acheson DWK, Sears CL. Dangers of empiric ciprofloxacin in the treatment of acute inflammatory diarrhea in children [letter]. Pediatr Infect Dis J 2001;20:817–8. 6. Hoge CW, Gambel JM, Srijan A, et al. Trends in antibiotic resistance among diarrheal pathogens isolated in Thailand over 15 years. Clin Infect Dis 1998;26:341–5. 7. British National Formulary (BNF); 2002. Section 5.1.8. Available at: http://www.bnf.org/webnf/lform1/ bnf/index.html (last accessed, September 1, 2002). 8. Schaad UB. Use of quinolones in pediatrics. Eur J Clin Microbiol Infect Dis 1991;10:355–60. 9. Ashkenazi S, Amir J, Wiasman Y, et al. A randomized double-blind study comparing cefixime and trimethoprim–sulfamethoxazole in the treatment of childhood shigellosis. J Pediatr 1993;123:817–21. 10. Fuchs PC, Jones RN, Barry AL, et al. In vitro evaluation of cefixime (FK027, FR17027, CL284635): spectrum against recent clinical isolates, comparative antimicrobial activity, beta-lactamase stability, and preliminary susceptibility testing criteria. Diagn Microbiol Infect Dis 1986;5:151–62. 11. Salam MA, Seas C, Khan WA, Bennish ML. Treatment of shigellosis: IV. Cefixime is ineffective in shigellosis in adults. Ann Intern Med 1995;123:505-8. 12. Khan WA, Seas C, Dhar U, et al. Treatment of shigellosis: V. Comparison of azithromycin and ciprofloxacin: a double-blind, randomized, placebo-controlled trial. Ann Intern Med 1997;126:697–703. 13. Hoge CW, Gambel JM, Srijan A, et al. Trends in antibiotic resistance among diarrheal pathogens isolated in Thailand over 15 years. Clin Infect Dis 1998;26:341–5. 14. Gillis JC, Brogden RN. Rifaximin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic potential in conditions mediated by gastrointestinal bacteria. Drugs 1995;49:467–84. 15. DuPont HL, Jiang ZD, Ericsson CD, et al. Rifaximin vs. ciprofloxacin for the treatment of travelers’ diarrhea: a randomized, double-blind clinical trial. Clin Infect Dis 2001;33:1807–15.

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16. Gomi H, Jiang ZD, Adachi JA, et al. In vitro antimicrobial susceptibility testing of bacterial enteropathogens causing travelers’ diarrhea in four geographic regions. Antimicrob Agents Chemother 2001;45:212–6. 17. Beseghi U, De’Angelis GL. Comparison of two non-absorbable antibiotics for treatment of bacterial enteritis in children. Eur Rev Med Pharmacol Sci 1998;2:131–6. 18. DuPont HL, Ericsson CD, Mathewson JJ, et al. Rifaximin: a nonabsorbed antimicrobial in the therapy of travelers’ diarrhea. Digestion 1998;59:708–14. 19. Frisari L, Viggiano V, Pelagalli M. An open, controlled study of two non-absorbable antibiotics for the oral treatment of paediatric infectious diarrhoea. Curr Med Res Opin 1997;14:39–45. 20. Figueroa-Quintanilla D, Salazar-Lindo E, Sack RB, et al. A controlled trial of bismuth subsalicylate in infants with acute watery diarrheal disease. N Engl J Med 1993;328:1653–8. 21. Soriano-Brucher H, Avendano P, O’Ryan M, et al. Bismuth subsalicylate in the treatment of acute diarrhea in children: a clinical study. Pediatrics 1991;87:18–27. 22. Bell BP, Griffin PM, Lozano P, et al. Predictors of hemolytic uremic syndrome in children during a large outbreak of Escherichia coli O157:H7 infections. Pediatrics 1997;100:E12. 23. Oberhelman RA, Gilman RH, Taylor DN, et al. A placebo-controlled trial of Lactobacillus GG to prevent diarrhea in Peruvian children. J Pediatr 1999;134:15–20. 24. Alvarez M, Oberhelman RA. Probiotic agents and infectious diseases: a modern perspective on a traditional therapy. Clin Infect Dis 2001;32:1567–76. 25. Mast EE, Krawczynski K. Hepatitis E: an overview. Annu Rev Med 1996;47:257. 26. Crepin G, Delahousse G, Decocq J, et al. Danger of iodine drugs in the pregnant woman [in French]. Phlebologie 1978;31:279–85. 27. Stubbe P, Heidemann P, Schurnbrand P, Ulbrich R. Transient congenital hypothyroidism after amniofetography. Eur J Pediatr 1980;135:97–9. 28. Briggs GG, Freeman RK, Yaffe SJ, editors. Drugs in pregnancy and lactation. 4th ed. Baltimore: Williams and Wilkins; 1994. 29. Samuel B, Barry M. The pregnant traveler. Infect Dis Clin North Am 1998;12:325–54. 30. Bertoli D, Borelli G. Fertility study of rifaximin (L/105) in rats. Chemioterapia 1986;5:204–7. 31. Evans MR, Shickle D, Morgan MZ. Travel illness in British package holiday tourists: prospective cohort study. J Infect 2001;43:140–7. 32. Fisch A, Prazuck T, Semaille C, et al. Emergency consultations of foreign tourists in Paris in the month of August. 5 years of prospective surveillance (1992-1996) [in French]. Bull Soc Pathol Exot 1998;91(5 Pt 1–2):461–3. 33. Steffen R. La turista: acquisitions et lecons tirees d’enquetes recentes [in French]. Bull Soc Pathol Exot 1998;91(5 Pt 1–2):450–1. 34. Oksanen PJ, Salminen S, Saxelin M, et al. Prevention of travelers’ diarrhoea by Lactobacillus GG. Ann Med 1990;22:53–6. 35. Dessery BL, Robin MR, Pasani W. The aged, infirm, or handicapped traveler. In: DuPont HL, Steffen R, editors. The textbook of travel medicine. Hamilton (ON): BC Decker Inc; 1997. 36. Clerinx J, Bogaerts J, Taelman H, et al. Chronic diarrhea among adults in Kigali, Rwanda: association with bacterial enteropathogens, rectocolonic inflammation, and human immunodeficiency virus infection. Clin Infect Dis 1995;21:1282–4. 37. Orenstein JM, Kotler DP. Diarrheogenic bacterial enteritis in acquired immune deficiency syndrome: a light and electron microscopy study of 52 cases. Human Pathol 1995;26:481–92.

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38. Baer JT, Vugia DJ, Reingold AL, et al. HIV infection as a risk factor for shigellosis. Emerg Infect Dis 1999;5:820–3. 39. Sorvillo FJ, Lieb LE, Waterman SH. Incidence of campylobacteriosis among patients with AIDS in Los Angeles County. J Acquir Immune Defic Syndr Hum Retrovirol 1991;4:598–602. 40. Celum CL, Chaisson RE, Rutherford GW, et al. Incidence of salmonellosis in patients with AIDS. J Infect Dis 1987;156:998–1002. 41. Attia A, Huet C, Anglaret X, et al. HIV-1-related morbidity in adults, Abidjan, Cote d’Ivoire: a nidus for bacterial diseases. J Acquir Immune Defic Syndr 2001;28:478–86. 42. Vincent D, Petit JC, Pradalier A, et al. Manifestation of AIDS by recurrent Salmonella infection [in French] [letter]. Ann Med Intern 1989;140:215–7. 43. Tocalli L, Nardi G, Mammino A, et al. Salmonellosis diagnosed by the laboratory of the ‘L. Sacco’ Hospital of Milan (Italy) in patients with HIV disease. Eur J Epidemiol 1991;7:690–5. 44. Lindsay DS, Dubey JP, Blagburn BL. Biology of Isospora spp from humans, nonhuman primates, and domestic animals. Clin Microbiol Rev 1997;10:19–34. 45. Lebbad M, Norrgren H, Naucler A, et al. Intestinal parasites in HIV-2 associated AIDS cases with chronic diarrhoea in Guinea-Bissau. Acta Tropica 2001;80:45–9. 46. Maiga I, Doumbo O, Dembele M, et al. Human intestinal microsporidiosis in Bamako (Mali): the presence of Enterocytozoon bieneusi in HIV seropositive patients [in French]. Sante 1997;7:257–62. 47. Masuda G, Ajisawa A, Imamura A, et al. Cyclosporiasis: four case reports with a review of the literature [in Japanese]. Kansenshogaku Zasshi - J Jp Assoc Infect Dis 2002;76:416–24. 48. Junod C. Comparative results of coprological tests for the detection of intestinal amebae and flagellates in 200 male homosexuals. An appraisal of the risk of amebiasis [in French]. Bull Soc Pathol Exot Filiales 1983;76(5 Pt 2):805–17. 49. Lucas SB. Missing infections in AIDS. Trans R Soc Trop Med Hyg 1990;84 Suppl 1:34–8. 50. Feitosa G, Bandeira AC, Sampaio DP, et al. High prevalence of giardiasis and stronglyloidiasis among HIVinfected patients in Bahia, Brazil. Brazil J Infect Dis 2001;5:339–44. 51. Dias RM, Mangini AC, Torres DM, et al. Occurrence of Strongyloides stercoralis in patients with acquired immunodeficiency syndrome (AIDS) [in Portuguese]. Rev Inst Med Trop Sao Paulo 1992;34:15–7. 52. Plourde PJ. Interactions between HIV and helminthic diseases. In: Ronald AR, editor. Opportunistic complications of HIV; classical tropical diseases 5. No. 4. Bala Cynwyd (PA): Meniscus Health Care Communications; 1997. p. 93. 53. Anonymous. Statement on travellers and HIV/AIDS. Can Med Assoc J 1995;152:379–80. 54. Ericsson CD. Travelers’ diarrhea. Infect Dis Clin North Am 1998;12:285–303. 55. Engberg J, Aarestrup FM, Taylor DE, et al. Quinolone and macrolide resistance in Campylobacter jejuni and C. coli: resistance mechanisms and trends in human isolates. Emerg Infect Dis 2001;7:24–34. 56. Dionisio D, Sterrantino G, Meli M, et al. Treatment of isosporiasis with combined albendazole and ornidazole in patients with AIDS [letter]. AIDS 1996;10:1301–2. 57. Larner AJ, Hamilton MI. Infective complications of therapeutic gastric acid inhibition [review]. Aliment Pharmacol Ther 1994;8:579–84. 58. Giannella RA, Broitman SA, Zamcheck N. Influence of gastric acidity on bacterial and parasitic enteric infections: a perspective. Ann Intern Med 1973;78:271–6. 59. Evans CA, Gilman RH, Rabbani GH, et al. Gastric acid secretion and enteric infection in Bangladesh. Trans R Soc Trop Med Hyg 1997;91:681–5.

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60. Cobelens FG, Leentvaar-Kuijpers A, Kleijnen J, Coutinho RA. Incidence and risk factors of diarrhoea in Dutch travelers: consequences for priorities in pre-travel health advice. Trop Med Int Health 1998;3:896–903. 61. Bytzer P, Talley NJ, Leemon M, et al. Prevalence of gastrointestinal symptoms associated with diabetes mellitus: a population-based survey of 15,000 adults. Arch Int Med 2001;161:1989–96. 62. Lysy J, Israeli E, Goldin E. The prevalence of chronic diarrhea among diabetic patients. Am J Gastroent 1999;94:2165–70. 63. Haider R, Azad Khan AK, Roy SK, et al. Management of acute diarrhoea in diabetic patients using oral rehydration solutions containing glucose, rice, or glycine. Br Med J 1994;308:624–6. 64. Yanai-Kopelman D, Paz A, Rippel D, Potasman I. Inflammatory bowel disease in returning travelers. J Travel Med 2000;7:333–5. 65. Okhuysen PC. Travelers’ diarrhea due to intestinal protozoa. Clin Infect Dis 2001;33:110–4.

Chapter 18

DIARRHEA

IN

E X PAT R I AT E S

David R. Shlim, MD, and Prativa Pandey, MD

Expatriates face the same issues as all travelers in terms of the risk of travelers’ diarrhea (TD), with the additional concerns of confronting a constant risk of TD over time, and determining whether immunity eventually plays a role in decreasing either the frequency or severity of diarrhea. The term “expatriate,” for the purposes of this chapter, is meant to include any person from a developed country who takes up residence in a developing country. Expatriates live differently within a foreign country than most short-term travelers. They usually have their own homes and kitchens and are exposed to restaurant food less often. However, because some expatriates may have official roles, either as diplomats, aid workers, or business people, they may be required to eat out more often at official functions, and in local homes. Few studies have focused on the etiology and risk factors for diarrhea in expatriates, but the studies that have been done, especially in Nepal, have shed some light on the issues mentioned above.

THE RISK OF DIARRHEA IN EXPATRIATES Most studies of the incidence of TD are done on populations of short-term travelers.1 Thus, we obtain a glimpse of the risk of TD in a limited period of time, usually 2 weeks or less. Since the incidence of TD in these studies is often 30 to 70%, one could calculate very high annual rates of TD if this incidence was consistent.2 If a traveler runs a 30% risk of TD in a 2-week period, this would predict an annual incidence of 7 episodes per person per year. A 2-year study of 36 Peace Corps volunteers in Guatemala found that the incidence of diarrhea was 4.7 episodes of diarrhea per person per year, but that the risk decreased over the 2-year period. The rate was 6.1 for the first 6-month period, but had dropped to 3.6 by the start of the second year in the country.2 In Nepal, the rate of diarrhea was addressed in two ways. In one study, 70 expatriates were approached, outside of the clinic setting, who had resided in Nepal between 2 and 23 months (median 10 months). Forty-nine percent recalled having an episode of diarrhea in the past month, and 74% recalled having diarrhea in the past 3 months. This latter figure would predict an annual incidence of 3 episodes of diarrhea per person per year.3 In the second Nepal study, a cohort of 77 expatriates in Kathmandu, who had moved to Nepal within the past year, were recruited. They were asked to submit a stool sample every time they had a new episode of TD, and they were contacted by telephone every 2 weeks to see if an episode had been

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missed. Using the conservative numerator of episodes for which stool samples were actually obtained, the annual incidence of TD in this cohort was 3.3 episodes per person per year.4 The figure of 3.3 episodes of diarrhea per person per year is remarkably comparable to most studies have been done on children under the age of 5 years in developing countries, including Nepal, where the annual incidence is 4.2 episodes of diarrhea per child per year.5 This means that despite pretravel counseling and the efforts that almost all expatriates make to avoid drinking tap water and eating unwashed vegetables, the annual rate of diarrhea in Nepal is no different than a child born in that same country.

ETIOLOGY OF DIARRHEA IN EXPATRIATES The etiology of TD in multiple studies of travelers around the world has been remarkably consistent.2 Enterotoxigenic E. coli (ETEC) is always the most frequently isolated pathogen (17 to 70%), followed by Campylobacter spp (1 to 39%) and Shigella spp (0 to 30%).2 Additional pathogens found include Salmonella spp (1 to 33%), and a handful of other bacterial pathogens that are usually found in less than 5% of samples. Intestinal viral pathogens are usually found in less than 8% of samples.6 Protozoal pathogens are relatively uncommon in short-term travelers with diarrhea. In longitudinal studies of expatriates, the order in which bacterial pathogens are acquired does not appear to be random. ETEC is usually the first pathogen to be acquired, and the incidence drops off dramatically after the first year. In a study of American Embassy personnel in Egypt, ETEC was rarely detected in longer-term expatriates.7 This was also true for a cohort of US citizens residing in Lima, Peru.8 In Nepal, the risk of ETEC infection was double in the first 2 months of residence compared to the next 3 months.9 The risk of Shigella and Campylobacter infections remained stable over a 1-year period in Nepal, but in Thailand, the risk of Campylobacter decreased in a population of expatriates in their second year.10,11 Protozoal pathogens become more important with continual exposure over time. In a Peace Corps study in Guatemala, the median length of time in the country until infection by the first protozoal pathogen was over 8 months.12 Overall, G. lamblia was found in 12% of Peace Corps volunteers, and Entamoeba histolytica or E. dispar was found in about 5% of volunteers. In a study of protozoal pathogens among 251 expatriates followed for a year in Bangladesh, the incidence of G. lamblia was 11.8%, and the incidence of E. histolytica or E. dispar was 8.6%.13 These figures are similar to G. lamblia and E. histolytica or E. dispar infection rates among expatriates in Nepal.14 A pathogen that still causes consternation when found in the stool is Blastocystis hominis. This organism has been studied for over 80 years, but it is still unresolved as to whether it is pathogenic. The organism is commonly found in Nepal. In a case-control study among 301 foreigners in Nepal, B. hominis was found in 30% of 189 diarrhea cases and in 36% of 112 asymptomatic controls.15 There was no significant difference between the numbers of B. hominis found in the stools of case subjects and control subjects, when B. hominis was the only pathogen found in the stools. In addition, the presence of B. hominis in the stool exam of the diarrhea cases did not make it less likely that another pathogen would be found in the same stool. Efforts to eradicate B. hominis have not led to conclu-

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sive results. The patient may become asymptomatic while B. hominis persists in the stool, or B. hominis might be eliminated with no clinical improvement in the patient. It appears to be safe to ignore B. hominis as a pathogen, and continue to look for and treat other causes of diarrhea when B. hominis is present in the stool exam. Cryptosporidium is a rare pathogen among expatriates in Nepal, with fewer than five cases per year. This finding is consistent with other studies of diarrhea in travelers, although unpublished results of new PCR techniques suggest that the prevalence of this organism in fecal samples may be higher than previously thought (Pablo Okhuysen, MD, personal communication).2 Unlike C. cayetanensis, there was no seasonal pattern to the few Cryptosporidium infections in Nepal. One final pathogen that occasionally causes persistent low-grade diarrhea in expatriates is Dientamoeba fragilis. This organism is actually a flagellate without flagellae, and can be mistaken on the stool exam for an amebic trophozoite. The symptoms associated with D. fragilis tend to consist of low-grade, intermittent loose stools, with mildly increased gas, and mild fatigue. Treatment with 250 mg tetracycline qid for 10 days results in resolution of these symptoms and eradication of the organism.

HELMINTHS Intestinal helminths rarely cause any symptoms in expatriates, although there is widespread awareness and concern about infestations. The passage of a visible adult worm often causes great consternation. Some expatriates regularly “de-worm” themselves and their families every 6 to 12 months with mebendazole. A study in Peace Corps volunteers in Nepal found that only 4% of stool exams were positive for any of three helminths. Cumulatively, however, 19% of volunteers became infested with a helminth during their 2-year tour of duty.16 The three main types of worms that are found most often in expatriates are the roundworm, Ascaris lumbricoides, the whipworm, Trichuris trichiura, and the hookworms, Necator americanus and Ancylostoma duodenale. None of these species are capable of reproducing within the intestinal tract, so the load of expatriate infection is generally extremely small. Worm eggs, when found, are usually an incidental finding during a stool exam for an acute diarrheal episode. Treatment with mebendazole or albendazole is then appropriate. The beef and pork tapeworms, Taenia saginata and Taenia solium, are very rare in expatriates in Nepal, but are occasionally found. Found slightly more often than the pork and beef tapeworms is the dwarf tapeworm, Hymenolepsis nana. None of the tapeworms appeared to cause any distress in the expatriates we treated. Taenia solium pose a risk of cysticercosis, so treatment of infection with either tapeworm (the species cannot be differentiated at the egg level) should be carried out promptly. Rarely, expatriates become infected with Strongyloides stercoralis, which can complete its life cycle within the intestine, and lead to persistent infections that can last indefinitely.17 In addition, when the host becomes immunocompromised for some season, the worms can migrate out of the intestine, causing severe problems. Unlike the other intestinal helminths, Strongyloides can occasionally present with low-grade symptoms. In routine blood screening, Strongyloides is the one worm out of the group mentioned here that should be considered when eosinophilia is noted.

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RISK FACTORS FOR DIARRHEA IN EXPATRIATES The traditionally listed risk factors for acquiring diarrhea in developing countries have always included uncooked vegetables, unpeeled fruits, and untreated water.19 However, epidemiologic evidence is lacking over the fact that travelers who make greater efforts to avoid eating contaminated foods are protected from TD.19 There are a number of studies that noted an increased risk of diarrhea based on the locale where food is obtained.20,21 In all of these studies, the risk of diarrhea is least in one’s own home, greater in restaurants, and greatest in food stalls on the street. In a study in Kathmandu, eating in a restaurant just four times in the week prior to coming to the clinic significantly predicted that the person would enter the study as a diarrhea patient, rather than a control.4 Younger expatriates were more likely to present with TD than older expatriates in the Nepal casecontrol study, and the length of time that one had resided in Nepal was inversely proportional to the risk of diarrhea (Table 18-1). Expatriates have control over their home kitchen environments, and can take measures to safeguard their food chain. Foods sold in markets in developing countries are likely to be contaminated with potential enteropathogens, but proper handling in the expatriate kitchen can minimize the risk.23 Water can be boiled and stored for drinking in clean dispensers. Counters and utensils can be regularly cleaned, and staff can be taught the need for hand-washing. Vegetables and fruits can be disinfected by soaking in iodine solutions. When these rules are followed, illness acquired at home is uncommon. In addition to being able to afford refrigerators and freezers, expatriates can often afford back-up generators or battery systems to supply power during inevitable power cuts. However, expatriates will always want to eat out in restaurants, both for the chance to eat local and varied cuisine, and to fulfill social obligations. In addition, expatriates may be invited to attend local feasts and celebrations, which may be particularly high risk for diarrhea. Rather than urge expatriates to avoid these activities, it is important to make sure that they have a method for diagnosing and treating diarrheal illness when it occurs.

DIAGNOSIS AND TREATMENT OF EXPATRIATE DIARRHEA The risk of acquiring TD in an expatriate may exceed 100% in the first months of their stay. Thus, there will always be a need to be able to diagnose and treat inevitable illness. If a reliable expatriate clinic is available, then the person can obtain reliable stool examination and advice, and eventually develop the skills of self-diagnosis and treatment in the country. If there is only local medical care available, the quality and availability of the care will vary widely, both between countries and within the same country. Some aid workers work in remote, inaccessible areas, while others are in the capital cities. Local medical care has not proven itself to be reliable in most countries for the diagnosis and treatment of TD. The local laboratories have a tendency to both misdiagnose and overdiagnose protozoal pathogens. The treatment approach tends toward a shotgun rather than a pistol, with multiple medications prescribed for a single episode. For these reasons, many expatriates may have better results with self-diagnosis and treatment.

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Table 18-1. Risk Factors for Expatriate Diarrhea from a Case-Control Study in Nepal Resident Cases (n=69)

Resident Controls (n=87)

p-Value

9%

9%

NS

Ate unpeeled fruit

39%

37%

NS

Ate raw vegetables

38%

32%

NS

Risk Factor Drank untreated water

Took ice in drink

9%

12%

NS

Ate at least one meal in restaurant during week

96%

83%

.013

Ate quiche or lasagna

22%

7%

.007

Drank blended fruit and yogurt drink

32%

9%

.004

33 (27–43)

40(32–46)

.003

9 (4.5–19.5)

23 (8–67)

<.0001

Median age in years (IQR) Mean duration living in Nepal in months (IQR) IQR = interquartile range; NS = not significant.

In order for self-diagnosis and treatment to be effective, the main etiology of the diarrhea should be known, there should be a definable clinical syndrome, and treatment should be simple to apply. In the case of TD, the etiology is almost 80% bacterial. The clinical syndrome associated with bacterial diarrhea can be defined as “the sudden onset of relatively uncomfortable diarrhea.” This is in contrast to protozoal diarrhea, which is usually more gradual in onset and not as severe. The treatment of most bacterial pathogens is a fluoroquinolone antibiotic for 1 to 2 days. In areas where resistance to fluoroquinolones is known to be higher than usual, azithromycin can be used.21 By using an antibiotic to treat episodes of diarrhea that have acute onset and are relatively uncomfortable, most expatriates will be able to manage most of their diarrheal episodes at home. If the symptoms are less severe, but more persistent, then a protozoal pathogen can be suspected. The use of tinidazole, available in most countries, and now available in the United States through selected pharmacies, simplifies the empiric treatment of suspected G. lamblia or E. histolytica infections. If the person’s symptoms consist of a gradual onset of four to five loose stools per day with increased intestinal “churning,” and gas, along with mild to moderate fatigue, then G. lamblia infections can be suspected. If the symptoms consist of bouts of crampy diarrhea for 1 day interspersed with 1 to 2 days of no diarrhea, along with fatigue and gradual weight loss, then an E. histolytica infection can be suspected. If a reliable medical resource is available, the expatriate can seek medical evaluation before treatment. But if the person is living in a remote area, or in a country where reliable medical care is not available, then there is a role for empiric self-treatment. Treatment will either cure the problem or it will not. Complications from failed empiric treatment are extremely rare. If the problem is not cured, then further evaluation is warranted. In Nepal, Haiti, Peru, and Guatemala, C. cayetanensis has been shown to be a recurrent, seasonal risk.22 The symptoms of C. cayetanensis are distinctive. The onset of diarrhea is sudden, and often severe, with multiple crampy watery stools. Fever is present during the first 1 to 3 days of onset in 30% of patients.23 This initial severe bout of diarrhea subsides spontaneously, evolving into a syndrome of intermittent diarrhea, nausea, and persistent fatigue and anorexia. Untreated, the mean

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length of illness is 6 weeks, with a range of 2 to 12 weeks.24 The organism is effectively treated with cotrimoxazole, double-strength, bid for 7 days.24 For patients who may be allergic to a component of cotrimoxazole, there is no reliable alternative. Many other drugs have been tried unsuccessfully.25 The report of success using ciprofloxacin against C. cayetanensis in patients in Haiti has not been replicated in Nepal.25 For the expatriate with persistent diarrhea, fatigue, and weight loss, who does not respond to empiric treatment, the person should be evaluated for malabsorption. Tropical sprue is an illness that is characterized by gradual damage to the upper intestinal mucosa, leading to malabsorption with consequent diarrhea and weight loss. The nonmetabolizable sugar D-xylose is readily absorbed by a functioning intestinal mucosa. The D-xylose absorption test can be used to determine intestinal integrity. A decrease in absorption suggests the possibility of tropical sprue. If biopsy is not readily available, a trial of treatment can be undertaken with tetracycline and folic acid. A simplified schedule of 500 mg tetracycline twice a day (instead of 250 mg qid) can be used. Folic acid is given as 5 mg twice a day. The response to treatment is dramatic—the person begins to improve within days. Treatment is then continued for 6 weeks, as shorter treatments have been associated with relapse. One of the key points in evaluating someone with a complaint of persistent diarrhea is to get a detailed history. Often, patients will connect a series of isolated episodes of diarrhea into one long illness. A patient may present with a chief complaint of diarrhea for 1 month. The history might be as follows: “I had diarrhea for 2 days, 4 weeks ago. I got better, but then it recurred 10 days later. I took some antibiotics, and felt better for 2 weeks, but it came back last night.” Acute episodes of diarrhea that resolve for at least 5 days do not usually recur. The patient in the example has experienced three unrelated episodes of diarrhea, not persistent diarrhea for a month. The doctor can focus on the episode that began the night before. It should be noted that many expatriates living in high-risk countries for TD will not have completely normal stools during the majority of their overseas stay. Repeated insults to the intestine may alter the functioning for an extended period of time, leading to looser than normal stools, floating stools, or increased gas. If the person is otherwise functioning well, without fatigue or weight loss, it is not usually fruitful to pursue these symptoms. Reassurance has worked well for this patient population in Nepal. It should also be borne in mind, however, that expatriates often spend their entire working career in developing countries. As they age, they are also susceptible to noninfectious related diseases, such as colon cancer, or the development of celiac sprue. The treating physician needs to exercise judgment as to when to continue the work-up for weight loss and fatigue beyond the investigation for enteric pathogens. For example, blood in the stool unassociated with acute dysentery symptoms should always be investigated for cancer, using the same criteria that one would for a patient who was not overseas.

ANTIBIOTIC RESISTANCE The issue of antibiotic resistance among enteric pathogens may ultimately be more important to long-term expatriates. From a practical point of view, if the bacteria are becoming resistant over time, empiric antibiotic therapy may need to be changed to achieve the same results.26 Resistance to cotri-

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moxazole, once the drug of choice for TD, is now greater than 90% among Shigella strains in Thailand.27 Campylobacter isolates went from zero resistance to ciprofloxacin before 1991 to 84% resistant in 1995. Fifteen percent of ETEC isolates were resistant to azithromycin by 1995.32 Even protozoal pathogens are beginning to show resistance to long available treatments, with several case reports of giardiasis resistant to both metronidazole and albendazole.28,29 Expatriates living and working in remote areas may only infrequently seek prophylactic medical advice, unlike tourists who may see a travel health practitioner prior to each trip. Thus, expatriates may continue to rely on older antibiotics out of habit. The use by expatriates of antibiotics to treat enteric pathogens probably does not help induce resistance in the pathogens. Expatriates comprise tiny proportions of the population in a developing country, and could not be expected to change the available bacterial pool for that country. Only when the antibiotics used to treat enteropathogens are in widespread use within a given country does antibiotic resistance become problematic.

SEASONALITY OF DIARRHEA RISK The risk of diarrhea is not consistent throughout the calendar year in many developing countries in which seasonality has been studied. The highest-risk time of year in Asian countries is usually the dry season, right before the monsoon rains. The dry season was also associated with higher diarrhea risk among expatriates in Ethiopia.30 In Nepal, the seasonal difference in risk is striking, with a doubling of risk in the second quarter of the year, April to June.4 This increased risk of enteric pathogens in the spring was also true for Salmonella typhi, Salmonella paratyphi, and hepatitis A infections. Thus, some expatriates who move to Nepal in September or October will have relatively few incidents of diarrhea until the following spring. The hot, dry seasons in several countries, including Nepal, coincide with the time of maximum fly populations. The role of flies as vectors of diarrheal disease is recently being re-evaluated.31,32 Efforts to exclude flies from kitchen environments may be an effective way to decrease diarrheal disease during the high-risk season. The coccidian pathogen C. cayetanensis is the only pathogen in Nepal (besides Vibrio cholerae, which has not proven to be a risk for expatriates) that disappears completely from the environment for several months a year.33 The risk of C. cayetanensis begins in late April, peaks in mid-June through mid-July, and then drops off rapidly, with the last few cases usually diagnosed in October or November. The risk of C. cayetanensis, however, for newly arrived expatriates, was highly significant, outstripping the risk of ETEC in the months in which C. cayetanensis was prevalent. Overall, 32% of the expatriate cohort studied in Nepal had a C. cayetanensis infection in their first year, surpassed only by ETEC (at 42%), which has a year-round risk.5

EVIDENCE FOR IMMUNITY IN EXPATRIATES One of the worst events in the life of an expatriate is the sudden onset of severe gastrointestinal symptoms, including fever, vomiting, abdominal cramps, and profuse watery diarrhea. The symptoms can

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be so uncontrollable that patients may have to sit on a toilet for hours, vomiting into a waste basket, wracked by abdominal cramps, shaking with fever, and growing faint with dehydration. It became evident, after a number of years working in Nepal, that longer-term residents were no longer at risk for such severe bouts of gastroenteritis. The correlation of decreased risk of severe symptoms with a longer stay in the country suggests that partial immunity is playing a role. Antibodies are known to be generated by diarrheal pathogens. The questions that are unanswered are how quickly one begins to show a protective effect of immunity, how long the protection may last, and how much cross-protection there may be between serotypes of the same organism. The Peace Corps study in Guatemala demonstrated that the incidence of diarrhea was highest in the first 6-month period (6.1 episodes of diarrhea per person), less in the second 6-month period (5.2 episodes of diarrhea per person), and then stabilized at 3.6 episodes of diarrhea per person.3 Haneveld reported that the annual rates for diarrhea in US troops in the Mediterranean area, from 1942 to 1945, declined from a high of 196 per 1,000 to 79 per 1,000 in the fourth year.34 ETEC infections were much less common in a cohort of American expatriates who lived in Lima, Peru.10 A study in Mexico calculated the odds ratio (OR) of diarrhea for students who had been living in Mexico for a year or longer, compared to newly arriving students, to be 0.37 (95% CI, 0.18 to 0.77).35 For expatriates who had lived in Nepal for at least 1 year, the OR for their risk of diarrhea was nearly identical at 0.36 (95% CI, 0.18 to 0.74).5 Figure 18-1 shows the likely influence of immunity on the OR of appearing as a diarrhea case at a clinic in Kathmandu during a case-control study. Expatriates who presented to the clinic with diarrhea were enrolled as cases and compared to patients who presented to the clinic with a complaint other than diarrhea (and had not had diarrhea for at least 2 weeks). The graph shows the decreasing likelihood of enrolling a person as a case the longer that they had lived in Nepal, a decrease that continued to be evident for up to 6 years of residence.4 In practice, expatriates become less fearful about diarrhea and appear to suffer less severe consequences over a residence period of several years. Although not clear, there may be evidence that expatriates who move between developing countries

Figure 18-1. Decrease in odds ratio for diarrhea (relative to baseline) for increasing duration of time living in Nepal among 69 expatriate residents with diarrhea compared with 87 asymptomatic expatriate resident controls.

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may not bring all of their immunity with them and therefore be at risk of infection in the country they move to. Someone who moves to Nepal after several years in Kenya, for example, may be exposed to specific serotypes and strains that were not circulating in Kenya. In addition, they may face specific pathogens, like C. cayetanensis, that were not a risk in their previous posting.

SUMMARY Expatriates, unlike short-term tourists, face a continued risk of diarrheal disease over a prolonged period of time. The risk may vary seasonally. Maintaining a clean home kitchen environment may be one of the best protective measures against TD. Restaurant eating is the main risk factor for diarrhea in expatriates. Since diarrhea appears to be unavoidable, despite the best efforts of the expatriate, a strategy for diagnosis and treatment needs to be available, whether this entails access to adequate medical care, or self-diagnosis and treatment. Immunity does occur, but is acquired slowly with continuous exposure. One of the major benefits of immunity is decreased severity of disease when it does occur.

REFERENCES 1. Peltola H, Gorbach SL. Travelers’ diarrhea: epidemiology and clinical aspects. In: DuPont HL, Steffen R, editors. Textbook of travel medicine and health. 2nd ed. Hamilton (ON): BC Decker Inc.; 2001. 2. Herwaldt BL, de Arroyave KR, Roberts JM, Juranek DD. A multiyear prospective study of the risk factors for and incidence of diarrheal illness in a cohort of Peace Corps volunteers in Guatemala. Ann Intern Med 2000;132:982–8. 3. Hoge CW, Shlim DR, Echeverria P, et al. Epidemiology of diarrhea among expatriate residents living in a highly endemic environment. J Am Med Assoc 1996;275:533–8. 4. Shlim DR, Hoge CW, Rajah R, et al. Persistent high risk of diarrhea among foreigners in Nepal during the first two years of residence. Clin Infect Dis 1999;29:613–6. 5. Ministry of Health. Nepal fertility, family planning, and health survey (NFHS, 1991) 1993. Kathmandu, Nepal: His Majesty’s Government, Ministry of Health; 1993. 6. Taylor DN, Houston R, Shlim DR, et al. Etiology of diarrhea among travelers and foreign residents in Nepal. J Am Med Assoc 1988;260:1245–8. 7. Haberberger RL, Lissner CR, Podgore JK, et al. Etiology of acute diarrhea among United States Embassy personnel and dependents in Cairo, Egypt. Am J Trop Med Hyg 1994;51:870–4. 8. Pazzaglia G, Escamilla J, Batchelor R. The etiology of diarrhea among American adults living in Peru. Mil Med 1991;156:484–7. 9. Shlim DR. Travelers’ diarrhea. Wilderness Environ Med 1999;10:165–70. 10. Gaudio PA, Echeverria P, Hoge CW, et al. Diarrhea among expatriate residents in Thailand: correlation between reduced Campylobacter prevalence and longer duration of stay. J Travel Med 1996;3:77–9. 11. Herwaldt BL, de Arroyave KR, Wahlquist SP, et al. Multiyear prospective study of intestinal parasitism in a cohort of Peace Corps volunteers in Guatemala. J Clin Microbiol 2001;39:34–42. 12. Speelman P, Ljungstrom I. Protozoal enteric infections among expatriates in Bangladesh. Am J Trop Med Hyg 1986;35:1140–5.

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13. Taylor DN, Houston R, Shlim DR, et al. Etiology of diarrhea among travelers and foreign residents in Nepal. J Am Med Assoc 1988;260:1245–8. 14. Shlim DR, Hoge C, Rajah R, et al. Is Blastocystis hominis a cause of diarrhea in travelers? A prospective controlled study in Nepal. Clin Infect Dis 1995;21:97–101. 15. Houston R, Schwartz E. Helminithic infections among Peace Corps volunteers in Nepal. J Am Med Assoc 1990;263:373–4. 16. Gill GV, Bell DR. Strongyloides stercoralis infection in former Far East prisoners of war. Br Med J 1979;12:572–4. 17. Kozicki M, Steffen R, Schar M. “Boil it, cook it, peel it, or forget it”: does this rule prevent travelers’ diarrhoea? Int J Epidemiol 1985;14:169–72. 18. Steffen R, van der Linde F, Byr K, Schar M. Epidemiology of diarrhea in travelers. J Am Med Assoc 1983;249:1176–80. 19. Tjoa WS, DuPont HL, Sullivan P, et al. Location of food consumption and travelers’ diarrhea. Am J Epidemiol 1977;106:61–6. 20. Ericsson CD, Pickering LK, Sullivan P. The role of location of food consumption in the prevention of travelers’ diarrhea in Mexico. Gastroenterology 1980;79:812–6. 21. Kuschner RA, Trofa AF, Thomas RJ, et al. Use of azithromycin for the treatment of Campylobacter enteritis in travelers to Thailand, an area where ciprofloxacin resistance is prevalent. Clin Infect Dis 1995;21:536–41. 22. Herwaldt BL. Cyclospora cayetanensis: a review, focusing on the outbreaks of cyclosporiasis in the 1990s. Clin Infect Dis 2000;31:1040–57. 23. Shlim DR, Cohen MT, Eaton M, et al. An alga-like organism associated with an outbreak of prolonged diarrhea among foreigners in Nepal. Am J Trop Med Hyg 1991;45:383–9. 24. Hoge CW, Shlim DR, Ghimire M, et al. Placebo-controlled trial of co-trimoxazole for the treatment of C. cayetanensis infections among travelers and foreign residents in Nepal. Lancet 1995;345:691–3. 25. Shlim DR, Pandey P, Rabold JG, et al. An open trial of trimethoprim versus C. cayetanensis infections. J Travel Med 1997;4:44–5. 26. Isenbarger DW, Hoge CW, Srijan A, et al. Comparative antibiotic resistance of diarrheal pathogens from Vietnam and Thailand, 1996–1999. Emerg Infect Dis 2002;8:175–80. 27. Hoge CW, Gambel JM, Srijan A, et al. Trends in antibiotic resistance among diarrheal pathogens isolated in Thailand over 15 years. Clin Infect Dis 1998;26:341–5. 28. Nash TE, Ohl CA, Subramanian G, et al. Treatment of patients with refractory giardiasis. Clin Infect Dis 2001;33:22–8. 29. Abboud P, Lemee V, Gargala G, et al. Successful treatment of metronidazole- and albendazole-resistant giardiasis with nitazoxanide in a patient with acquired immunodeficiency syndrome. Clin Infect Dis 2001;32:1792–4. 30. Brickfield FX, Gebreegzi M, Beyenne A. Incidence of protozoal diarrheal disease in an expatriate community in Addis Ababa. Ethiop Med J 1996;34:107–17. 31. Cohen D, Green M, Block C, et al. Reduction of transmission of shigellosis by control of houseflies (Musca domestica). Lancet 1991;337:993–7. 32. Chavasse DC, Shier RP, Murphy OA, et al. Impact of fly control on childhood diarrhoea in Pakistan: community-randomised trial. Lancet 1999;353:22–5.

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33. Hoge CW, Shlim DR, Rajah R, et al. The epidemiology of diarrheal illness associated with a coccidian-like organism among travelers and foreign residents in Nepal. Lancet 1993;341:1175–9. 34. Haneveld GT. Some epidemiologic aspects of “travelers’ diarrhoea” in Lebanon. Trop Geogr Med 1960;12:339–44. 35. DuPont HL, Haynes GA, Pickering LK, et al. Diarrhea in travelers to Mexico: relative susceptibility of United States and Latin American students attending a Mexican university. Am J Epidemiol 1977;105:37–41.

Chapter 19

D I A R R H E A L O U T B R E A K S A S S O C I AT E D AIRLINE FLIGHTS

WITH

Margot Mütsch, PhD, MPH, and Norman Noah, MB, BS, FRCP, FFPHM

Diarrhea represents a significant in-flight medical event and is considered to be the most common infectious disease related to air travel. The first regular airline passenger service with meals served aboard was initiated between England and France in 1919. Since then, mass tourism has dictated a need for mass catering allied to food manufacturing units.1 The complexity of the production chain and the time difference between the preparation of food on land and serving it on-board are important and essential features of airline catering. Add to this the limited kitchen facilities (especially for refrigeration) on aircraft and it comes as no surprise that flight catering is a higher risk operation than most other types of catering. This chapter gives an overview of the available data on air travel-associated diarrheal events for selected industrialized countries between 1985 and 2000.

IMPORTANCE AND BURDEN OF GASTROENTERITIS ASSOCIATED WITH AIRLINE FLIGHTS Gastroenteritis associated with air travel is important for several reasons. It might affect the flight crew, with particularly potentially serious consequences if the pilot and copilot were both afflicted. Passengers invariably travel for a reason, commonly business or tourism, and the burden on them, whether it be lost business or a spoilt holiday, could be considerable. If the incubation period is shorter than the flight time, then the burden on the passenger may be intolerable—up to 400 passengers with diarrhea and/or vomiting competing for an inadequate number of cramped toilets is a nightmarish image. In-flight catering is nowadays highly specialized and efficient. A single large catering operation may produce many thousands of meals a day, with the propensity to produce a large number of ill people should a lapse in hygiene occur.2 In the British Airways outbreak of 1984, which was caused by aspic contaminated with Salmonella and affected mainly first class and Concorde passengers, at least 29 flights and an estimated 2,747 passengers were affected.3 The comment was made by one of the teams of investigators that the investigation paralleled a major aircraft disaster in the number of national and international agencies involved and in the variety of disciplines engaged.4 In the 1988 outbreak of foodborne shigellosis, 240 passengers were affected on 219 flights to 24 states and one district of the United States, as well as at least four other countries.5

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A further consideration is that passengers with diarrhea may infect other passengers, most probably through using the airplane toilet. A passenger who has contracted gastroenteritis on holiday and not on board the airplane could still infect others on the same flight. This is more likely to happen with the low-dose organisms, such as Norwalk-like viruses (NLV), hepatitis A, and Shigella. Such outbreaks, which also have medium to long incubation periods, are unlikely to be detected, which probably explains why so few have been reported. NLV infection, for example, has recently been causing large outbreaks on board cruise ships, having persisted from one cruise to another, and another outbreak was attributed to airborne transmission after someone vomited on a coach.6 Similar transmissions associated with aircraft will undoubtedly have occurred, and will continue to occur, undetected. Moreover, it is impossible for afflicted passengers to wash their hands efficiently using the spring loaded taps that most airline toilets have. The mechanisms for case-to-case transmission of pathogens are undoubtedly present.

OBSTACLES IN THE DETECTION OF IN-FLIGHT DIARRHEAL OUTBREAKS It is important to state at the outset that much of the data on gastroenteritis associated with airline flights are serious underestimates. The difficulty in recognizing an outbreak is particularly likely to occur with long–incubation-period infections. Many passengers may not attribute their symptoms to food served on-board or to another source on an aircraft, especially if they have just arrived from abroad and are unaware that others have also been affected. Unless there is a group traveling together, the chances of an outbreak being recognized are much diminished. People will disperse to various parts of the country or other countries, complicating both recognition and investigation. In an outbreak of shigellosis caused by sandwiches made in an airline flight kitchen, the outbreak was only recognized because an index outbreak occurred among players and staff of an American football team. Further investigation then revealed that 240 cases had occurred on 219 flights to various destinations. Tauxe and Hedberg and their colleagues noted that recognition of such outbreaks is greatly improved by the presence of one or more of the following factors3,5: • • • • •

An attack rate greater than 20% A short incubation period A severe or notifiable illness such as typhoid or cholera Geographically clustered distribution of passengers affected Well-known persons involved in an index outbreak, such as from politics, culture, or sports

Additionally, increased vigilance of public health officers could help to detect an outbreak early and facilitate rapid response. The importance of the seriousness of an infection is exemplified by the recognition of one case of botulism, following a flight from Zurich to London in 1987.7 The botulism occurred in a 49-year-old man from his eating two spoonfuls of a rice salad as part of a kosher meal, served on board to him and three other members of his family. Fortunately, as the dish in question smelled unwholesome, it was not eaten by the man’s family members, so he was the only one affected. Fortunately also for him,

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the diagnosis was suspected early. He was treated and survived after needing respiratory support for 173 days. A further reason for the poor reporting of airline-associated gastroenteritis is that airline companies could hesitate to explore outbreaks because of unfavorable media coverage, damage to their reputation, and an adverse financial impact.8

FREQUENCY OF GASTROENTERITIS Gastrointestinal events were listed among the top three to four most important in-flight medical incidents evaluated in selected industrialized countries from 1985 to 2000. Their frequency varied broadly between 3 and 28% depending on study population and case definition. The mean was 12% of all the medical incidents investigated. Bearing particularly in mind that it is more likely to be under-reported than most other airline medical incidents, gastroenteritis is rated clearly as the most common infectious disease connected to air travel (Table 19-1).15-19 The overall trend does not indicate a marked change in the incidence of gastroenteritis. In contrast, the number of in-flight medical emergencies generally is believed to have increased.11, 20 Although deaths have occurred, fortunately, diarrheal outbreaks associated with airline flights do not usually have serious consequences.3,4,21-23 Nevertheless, gastrointestinal complaints accounted for 7 out of 90 flight diversions (8%) according to a US study.13 Although few recent data are available, gastroenteritis is reported to be the leading cause of inflight aircrew incapacitations. Symptoms may significantly impair the cockpit crew members’ performances, therefore during critical flight phases, instant treatment is especially paramount.24, 25

Table 19-1. In-Flight Gastrointestinal Incidents Compared to Other Medical Events, 1985–2000 Rank Order of All Incidents

Region

Data Collection

USA

Passengers reports

Oct 1985 – Mar 1986

44/260 (17)

2

Speizer, 19899

Prospective survey

Sep 1986 – Aug 1987

29/190 (15)

2

Cummins, 198910

Airline or EMS* reports 1990 – 1993

Unknown/14,334

8

DeJohn, 199711

Airline reports

1996

314/10,471 (3)

9

Rayman, 199812

EMS* reports

Oct 1996 – Sep 1997

90/1,132 (8)

5

DeJohn, 200213

EMS* reports

1989 – 1999

61/380 (16)

2

Szmajer, 200114

Apr 1990 – Mar 1991

257/2,139 (12)

2

Harding, 199315

Airline reports

Jan – Sep 2000

255/910 (28)

1

Dowdall, 200016

Reports requiring physicians visit

1993

59/454 (13)

3

Donaldson, 199617

Airline reports

Jan 1995 – May 1999

10/201 (5)

4

Han, 200018

Europe

Asia, Australia

*EMS = emergency medical service.

Study Period

No. Gastrointestinal per Total Incidents (%)

Reference

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Aircrews now get different meals from passengers to avoid simultaneous contraction of gastrointestinal infections. Diarrhea and vomiting aboard are usually managed using oral antiemetics, rehydration solutions, and antidiarrheal agents. Mild symptoms can thus be reduced by trained cabin crew personnel if medication is available in the medical kit; sometimes, fellow passengers offer medication. The range of drugs available in airline medical kits varies widely, and can sometimes be extensive.26

REPORTED OUTBREAKS FROM 1985 TO 2000 Twenty-three in-flight outbreaks were reported worldwide from 1947 through 1984.3 Between 1985 and 2000, 10 outbreaks involving 10 or more persons were reported (Table 19-2). This resulted in 0.6 reported disease outbreaks per year in both time intervals. A review of the 1947 to 1984 outbreaks is given by Tauxe.3 We summarize here the 10 reported investigations for the 1985 to 2000 period. Table 19-2 presents an overview of in-flight diarrheal disease outbreaks reported between 1985 and 2000 in indexed sources.2,5,21,27-32 The gastrointestinal events described in Table 19-1 cannot be linked to the outbreaks presented in Table 19-2 due to their being from a different study population. Table 19-2. Foodborne Outbreaks Associated with Meals Served on Aircraft, 1985–2001 No. Infected Passengers (No. Passengers at Risk)

No. Infected Crew Members

Year of Outbreak

Food Origin

1985

Faro, Portugal

Salmonella enteritidis

—

Mousse with cream

At least 30

—

WHO, 198927

1986

Helsinki, Finland

Salmonella infantis

Median 44 h

Multiple

91 (350)

—

Hatakka, 199228

1988

Twin Cities, USA

Shigella sonnei

12–96 h

Cold dishes

240

9

Hedberg, 19925

1989

Palma de Mallorca, Spain

Salmonella enteritidis

—

Unknown

80

—

Hatakka, 200029

1991

Greece

Salmonella

2–4 h

Unknown

415

—

Lambiri, 199530

1991

Los Angeles, USA

Staphylococcus aureus

2–4 h

Chocolate cake

25

1

Sockett, 19932

1991

Melbourne, Australia

Norwalk-like virus

—

Orange juice

3,053

—

Lester, 199131

1992

Lima, Peru

Vibrio cholerae O1

0–6 d after arrival

Seafood

80 (336)

—

EberhartPhillips, 199621

1993

Charlotte, USA

Enterotoxigenic E. coli

—

Cold dishes

56

—

CDC, 199432

1997

Canary Islands, Spain

Salmonella enteritidis FT1

— —

Chocolate eclair

455

—

Hatakka, 200029

Detected Pathogen

Onset Interval

Vehicle

Reference

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While isolated cases among passengers in Table 19-1 mostly suggest a preflight source of infection, an in-flight food source was suspected or detected in the clusters described in Table 19-2. No waterborne pathogen transmission has been documented. The most common agents associated with the outbreaks were bacteria, which were similar to those reported in the previous period: Salmonella species followed by Vibrio cholerae and Staphylococcus aureus.2,3,21,27-30 The emerging pathogens enterotoxin-producing Escherichia coli and Norwalk-like viruses were also documented.31,32 The most risky food products were also similar in the two periods—cold dishes containing salads, meat or seafood components, or desserts (see Table 19-2). In general, contaminated raw materials or lapses in the food processing steps, such as insufficient refrigeration or infected food handlers, could be identified as causes of microbiological contamination. These are common to the most important transmission factors for foodborne outbreaks in general.33 In 1992, a cholera epidemic struck Latin America. On one flight, 80 passengers traveling from Lima to Los Angeles were affected (see Table 19-2). There is clearly potential for airline-associated spread of such infections from epidemic areas to other parts of the world.21 Single travelers with cholera were also documented to have come from Ecuador and The Philippines to the United States.34 A key point seems to be the location of the food manufacturing units. In one study of 1,012 hot meals prepared in 33 countries for serving on board aircraft, significant differences were detected in the microbiological quality of the meals, depending on the food processing country.35,36 In this respect, tropical manufacturing sites seem to present a higher risk of causing in-flight diarrheal outbreaks.

CONCLUSION Close to 1.7 billion passengers travel on commercial airlines each year.37 The health of both passengers and crew members has not yet received the close and systematic attention it needs.38 So far, there has been no standardized data collection of passengers requiring medical assistance, and therefore, the total number of passengers asking for medical treatment is unknown. Furthermore, in view of the incubation period of gastrointestinal infections, symptoms may occur long after the passenger has left the airport. Attempts are in progress to establish an international, voluntary database of in-flight medical incidents.8 The International Air Transport Association (IATA) annually organizes expert meetings on “Cabin Health” and is thus obviously concerned about this issue. Currently, the available data are limited to anecdotal reports of diarrheal outbreaks or gastrointestinal symptoms recorded as isolated in-flight medical events. These were reported to the airline, to Emergency Medical Services, or to airport medical services, or detected by national surveillance systems. Data collection methods as well as case definitions are very heterogeneous; cases, for instance, are often described as gastrointestinal incidents without further specification, or alternatively as symptoms such as vomiting, nausea, diarrhea, and fever. The World Health Organization (WHO) has established guidelines for hygiene and sanitation in aviation, which are currently being updated and are scheduled to be published in 2003.39 Additionally, microbiological quality standards and control measures for aircraft food are provided by major

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affiliations such as the Association of European Airlines (AEA), and even stricter standards are often demanded by many airlines. 29,40 Based on the available reports, no decrease in the frequency of flight-associated foodborne gastrointestinal illness could be observed in recent decades, despite the implementation of improved and continuous quality assurance of the entire food-handling chain. Theoretically, this can be explained by a greatly increased volume of air traffic, or by improved detection or reporting. Alternatively, persistent difficulties in critical steps of the food supply cascade cannot be ruled out; for example, contaminated raw material may be processed or mistakes may occur in food preparation on-board. As shown in Table 19-2, except for the transmission of V. cholerae, there were no outbreaks originating in developing countries, which is rather surprising. This could be a reporting artifact. Moreover, airlines often ferry critical food items from industrialized countries to serve them on the return flight. Possibly, the lack of outbreaks reported since 1997 reflects a new, more hygienic era, but this also may be the consequence of a time delay in reporting. There will often be patients with diarrhea on-board, usually undetected. One would expect this to be particularly frequent with a flight originating in a developing country. Unless fundamental hygienic rules are broken, such patients should pose no risk to fellow passengers. Nevertheless, given the toilet facilities usually available on-board, the variation in hygiene practices between individuals generally, and the high infectiousness of some organisms, particularly NLV and Shigella, there is undoubtedly a potential risk to other passengers. The ultimate goal must be to avoid flight-related outbreaks. Every in- or post-flight disease outbreak is a public health challenge that needs prompt detection and investigation, which will depend on coordinated surveillance by public health institutions.5 Prevention strategies should therefore encompass the whole setting. Catering companies delivering food to airlines need continuously to control every step of the food supply cascade, as recommended by the WHO and other expert groups.39,40 Knowledge from previous outbreaks of critical food items, such as seafood or cold desserts, could facilitate early identification and response to illness among airplane passengers. Moreover, these meal components should be targeted with high priority to implement and control for stricter food hygiene in order to eliminate them as transmission vehicles of foodborne disease outbreaks. Considering the enormous number of meals prepared and served under less than ideal conditions, the actual incidence of food poisoning originating from an aircraft flight, even allowing for underdetection, is almost certainly very low. Nevertheless, outbreaks of gastroenteritis originating from an aircraft flight can have serious consequences, and more importantly, they are preventable.

REFERENCES 1. Jones P, Kipps M. Flight catering: an introduction. In: Jones P, Kipps M, editors. Flight catering. International Flight Catering Association (IFCA). London: Addison Wesley Longman; 1995. p. 1–11. 2. Sockett P, Ries A, Wieneke A. Food poisoning associated with in-flight meals. Commun Dis Rep CDR Rev 1993;3:R103–4. 3. Tauxe RV, Tormey MP, Mascola L, et al. Salmonellosis outbreak on transatlantic flights; foodborne illness on aircraft: 1947–1984. Am J Epidemiol 1987;125:150–7.

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4. Burslem CD, Kelly MJ, Preston FS. Food poisoning – a major threat to airline operations. J Soc Occup Med 1990;40:97–100. 5. Hedberg CW, Levine WC, White KE, et al. An international foodborne outbreak of shigellosis associated with a commercial airline. J Am Med Assoc 1992;268:3208–12. 6. Chadwick PR, Walker M, Rees AE. Airborne transmission of a small round structured virus. Lancet 1994;343:171. 7. Colebatch JG, Wolff AH, Gilbert RJ, et al. Slow recovery from severe foodborne botulism. Lancet 1989;2(8673):1216–7. 8. Goodwin T. In-flight medical emergencies: an overview. Br Med J 2000;321:1338–41. 9. Speizer C, Rennie CJ III, Breton H. Prevalence of in-flight medical emergencies on commercial airlines. Ann Emerg Med 1989;18:26–9. 10. Cummins RO, Schubach JA. Frequency and types of medical emergencies among commercial air travelers. J Am Med Assoc 1989;261:1295–9. 11. DeJohn C, Veronneau S, Hordinsky J. In-flight medical care: an update. U.S. Federal Aviation Administration Civil Aeromedical Institute, February 1997. Report No. DOT/FAA/AM-97-2. 12. Rayman RB. Aerospace medicine. J Am Med Assoc 1998;279:1777–8. 13. DeJohn C, Veronneau S, Wolbrink A, et al. An evaluation of in-flight medical care in the US. Aviat Space Environ Med 2002;73:580–6. 14. Szmajer M, Rodriguez P, Sauval P, et al. Medical assistance during commercial airline flights: analysis of 11 years experience of the Paris Emergency Medical Service (SAMU) between 1989 and 1999. Resuscitation 2001;50:147–51. 15. Harding RM, Mills FJ. Medical emergencies in the air. In: Aviat Med 3rd edition. British Medical Journal. London, 1993;7–24. 16. Dowdall N. Is there a doctor on the aircraft? Top 10 in-flight medical emergencies. Br Med J 2000;321:1336–7. 17. Donaldson E, Pearn J. First aid in the air. Austr N Z J Surg 1996;66:431–4. 18. Han HM, Cheae DH, Kim JH. In-flight medical emergencies in civil airline [abstract]. Aviat Space Environ Med 2000;71:330. 19. Maloney SA, Cetron MS. Investigation and management of infectious diseases on international conveyances. In: DuPont HL, Steffen R, editors. Textbook of travel medicine and health. 2nd ed. Hamilton (ON): BC Decker Inc; 2001. 20. Gendreau MA, DeJohn C. Responding to medical events during commercial airline flights. N Engl J Med 2002;346:1067–74. 21. Eberhart-Phillips J, Besser RE, Tormey MP, et al. An outbreak of cholera from food served on an international aircraft. Epidemiol Infect 1996;116:9–13. 22. Johnston R. Clinical aviation medicine: safe travel by air. Clin Med JRCPL 2001;1:385–8. 23. Munk MD. In-flight medical emergencies. J Emerg Med Services 1997;22;64–72. 24. Beers KN, Mohler SR. Food poisoning as in-flight safety hazard. Aviat Space Environ Med 1985;56:594–7. 25. Masterton RG, Green AD. Dissemination of human pathogens by air travel. J Appl Bact 1991;70 Suppl:31–8. 26. Lyznicki JM, Williams MA, Deitchman SD, Howe JP III. In-flight medical emergencies. Aviat Space Environ Med 2000;71:832–8. 27. World Health Organization (WHO). Food safety microbiological quality of airline meals. Wkly Epidemiol Rec 1989;42:324–7.

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28. Hatakka M. Salmonella outbreak among railway and airline passengers. Acta Vet Scand 1992;33:253–60. 29. Hatakka M. Hygienic quality of foods served on aircraft [Master thesis]. Helsinki, Finland: University of Helsinki; 2000. p. 11–7. 30. Lambiri M, Mavridou A, Papadakis JA. The application of hazard analysis critical control point (HACCP) in a flight catering establishment improved the bacteriological quality of meals. J Roy Soc Health 1995:26–30. 31. Lester R, Stewart T, Carnie J, et al. Air travel-associated gastroenteritis outbreak. Comm Dis Intell 1991;15:292–3. 32. Centers for Disease Control and Prevention. Foodborne outbreaks of enterotoxigenic Escherichia coli – Rhode Island and New Hampshire, 1993. MMWR Morb Mortal Wkly Rep 1994;43:81–9. 33. World Health Organization (WHO). WHO surveillance programme for control of foodborne infections and intoxications in Europe. Geneva, Switzerland; 1995. 34. Centers for Disease Control and Prevention. Cholera associated with international travel 1992. MMWR Morb Mortal Wkly Rep 1992;41:134–5. 35. Hatakka M. Microbiological quality of hot meals served by airlines. J Food Prot 1998;61:1052–6. 36. Hatakka M. Microbiological quality of cold meals served by airlines. J Food Safety 1998;18:185–95. 37. International Air Transport Association (IATA). Aviation information and research: world air transport statistics. 45th ed. Montreal, Geneva, London; 2001, p. 8–9. 38. Committee on Science and Technology. Air travel and health. 5th Report. London: United Kingdom House of Lords; 2000. http:///www.parliament.the-stationery-office.co.uk/pa/Id199900/Idselect/Idsctech/ 121/12102.htm (accessed May 28, 2002). 39. Bailey J. Guide to hygiene and sanitation in aviation. Geneva, Switzerland: World Health Organization (WHO); 1977. 40. The Association of European Airlines (AEA). Hygiene guidelines. Brussels, Belgium; 1996, p. 1–24.

Chapter 20

D I A R R H E A AT S E A A N D O U T B R E A K S A S S O C I AT E D W I T H C R U I S E S Roisin Rooney, MS, and Chiara deBernardis, MD

Cruise ships are floating resorts that have rapidly expanded in number and passenger capacity since 1990 and continue to do so as the popularity of cruise ship vacations continues to increase. Some carry over 5,000 passengers and crew per sailing, and the newest additions feature “resort style” amenities such as multiple dining venues, speciality restaurants, and expansive spa and fitness facilities. The International Council of Cruise Lines estimates that almost 9.8 million people sailed on cruise ships in the year 2000 and this number is forecast to grow to 20.7 million in 2010.1 Travelers’ diarrhea has been a frequent problem in the early cruises.2 The first systematic investigations took place between 1972 and 1973.3 Over one hundred outbreaks of infectious diseases, particularly gastrointestinal disease, were reported to be associated with ships between 1970 and 2000.4-9 Gastrointestinal diseases are of particular public health importance, as ships are isolated communities with crowded living accommodation, shared sanitary facilities, and common water supplies. Such conditions could facilitate the spread of infectious diseases. The magnitude of outbreaks and sporadic cases of infection around the world is unknown, as surveillance systems are very variable in both the collection of data and the reporting of results. However, reported clusters of infection associated with ships demonstrate that passengers, and sometimes crew, are potential groups of susceptible persons at risk of disease.9 An increasing proportion of the population of many countries are elderly and a growing number of persons are immunosuppressed as a result of a variety of factors such as human immunodeficiency virus infection and various therapies. These people are at increased risk of foodborne and waterborne diseases, which may not present a major problem in the general population but which can have devastating consequences for vulnerable subgroups.10 The ship environment presents the opportunity for the secondary spread of pathogens that may have been introduced initially by foodborne or waterborne routes. Among travelers going to developing countries, gastrointestinal illness is the most frequent health problem, with an overall prevalence of 41%.11,12 A Spanish epidemiological study demonstrated that travellers on a cruise ship and trekkers have the highest attack rates of diarrhea.11 The Indian subcontinent, the Middle East, and North African countries were high-risk destinations.11,12 Outbreaks of infectious diseases on passengers ships can not only have serious health consequences for passengers and crew but also could result in high economic costs to an industry relying heavily on tourism.

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FOODBORNE DISEASES Foodborne illnesses comprise the various acute syndromes that result from ingestion of contaminated foods. These can fall under any of the following three classifications: • Intoxications caused by ingestion of foods containing either poisonous chemicals or toxins produced by microorganisms; • Toxin-mediated infections caused by bacteria that produce enterotoxins (ie, toxins that affect water, glucose, and electrolyte transfer) during their colonization and growth in the intestinal tract; and • Infections caused when microorganisms invade and multiply in the intestinal mucosa or other tissues.13 Manifestations range from slight discomfort to acute illness to severe reactions that may result in death or chronic sequelae, depending upon the nature of the causative agent, number of pathogenic microorganisms or concentration of poisonous substances ingested, and host susceptibility and reaction.13 A number of outbreaks of foodborne disease have been reported to be associated with cruises. Table 20-1 lists the pathogens and toxins in outbreaks of foodborne disease associated with ships.4 Factors contributing to these outbreaks have included infected food handlers, inadequate temperature control, cross contamination, and inadequate heat treatment. “Outbreak One. An Outbreak of Multi–Antibiotic-Resistant Shigella on a Cruise Ship14 An outbreak of multiple drug resistant Shigella flexneri 4a occurred on a ship in 1989. It affected almost 72 passengers. Thirteen people were hospitalized, and the illness was prolonged in many passengers because

Table 20-1. Foodborne Disease Outbreaks Associated with Ships Organism/Toxin Bacteria Salmonella species Shigella species Escherichia species Vibrio species Staphylococcus aureus Clostridium perfringens

No. of Outbreaks 14 8 9 6 2 1

Parasites Cyclospora Trichinella

1 1

Viruses Norwalk-like virus

6

Chemical food poisoning Ciguatera fish poisoning

2

Unknown Total

3 53

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the pathogen was multidrug resistant. An epidemiologic study implicated German salad as the source of the infection. It was suspected that the pathogen was spread by an infected food handler. This food handler may have been from or had visited a country where multiple antibiotic resistant Shigella was common. Some illness also could have been caused by secondary, person-to-person spread of the Shigella, since as few as 10 Shigella organisms can cause illness. During an environmental inspection of the ship, it was found that toilet and hand-washing facilities were limited for the galley staff. Only one sanitary convenience was available for over 100 food handlers. This outbreak underscores the need to ensure that adequate sanitary facilities are provided for food handlers, that food handlers maintain a high standard of personal hygiene, and most importantly, that infected food handlers are excluded from work until all symptoms have cleared.”

The continuing problem of foodborne gastrointestinal disease in settings such as cruise ships underscores the need for basic hygienic control for food handlers and food preparation areas. Other important factors in the prevention of foodborne disease are • • • • •

Time and temperature control; Control of cross contamination; Adequate heat treatment; Safe raw ingredients from reliable sources; and Exclusion of infected food handlers from work.

The above should be supported by the implementation of a Hazard Analysis Critical Control Point (HACCP) system. Such a system should be used as a tool to help determine critical control points specific to a particular menu; that is, the stages in the preparation and cooking of food, which must be controlled to ensure the safety of the food. Once identified, a monitoring system can be set up for each critical control point to ensure that correct procedures are maintained and action taken if control point criteria are not achieved. The chief advantage of HACCP is that it is proactive; it aims to prevent problems from occurring. The reason that HACCP is more effective is that its emphasis is upon prevention. The principles of HACCP have been described by Codex.15 Additional information is available from publications by the International Commission for Microbiological Specifications for Food, the National Advisory Committee on Microbiological Criteria for Foods, International Life Sciences Institute (ILSI) Europe, and others.16-18 The principles of HACCP are summarized in Table 20-2.

WATERBORNE DISEASES Waterborne illnesses result either from ingestion of contaminated water or ice, contact with water (eg, bathing, wading, swimming, ocular exposure), or inhalation of aerosols generated from water that contains etiologic agents.20 Illnesses acquired by ingestion are classified as the following: • Intoxications caused by either chemical substances or preformed toxins produced by microorganisms; these may affect the gastrointestinal tract or other organs;

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Table 20-2. Principles of HACCP Principle

Subject

Action

1

Hazard analysis (HA)

Construct a flow diagram of the process stages. Identify and list all of the potential hazards.

2

Identification of the critical control points (CCPs)

Identify the CCPs using a decision tree. Specify the systems of control.

3

Establishing critical limits

Target values and critical limits must be set for each CCP.

4

Monitoring

Continual or regular registering at each CCP to verify maintenance of control.

5

Correction

Establish protocols for: i) when a CCP is moving toward loss of control; ii) when a CCP is already out of control.

6

Verification

Establish systems to confirm the correct functioning of HACCP.

7

Documentation

Establish documentation regarding all of the procedures and records necessary for the implementation and operation of the above principles.

Adapted from Kirby.19

• Infections caused by microorganisms that elaborate enterotoxins (ie, toxins that affect tissues of intestinal mucosa, usually by interfering with salt and water transport) during their growth in the intestinal tract; and • Infections caused by microorganisms that invade the intestinal tract and may travel to and affect other tissues.20 The importance of water as a vehicle for infectious disease transmission on ships has been clearly documented. In general terms, the greatest microbial risks are associated with ingestion of water that is contaminated with human and animal excreta. However, chemical outbreaks of water poisoning have also occurred on ships.4 Waterborne transmission on board ships, by ingestion of the pathogens listed in Table 20-3, has been confirmed by epidemiologic evidence.4 In some waterborne outbreaks, no known agents were identified. Factors contributing to the outbreaks included contaminated source water, inadequate residual disinfection, contamination during loading, defective and poorly designed potable water storage tanks, cross connections during storage/distribution, and defective back flow preventers on equipment such as ice machines and dishwashers. “Outbreak Two. Waterborne Outbreak of Enterotoxigenic Escherichia coli on a Ship21 In 1984, almost 300 passengers and crew were affected in a large outbreak on a cruise ship. Investigators found a significant association between consumption of cabin tap water and reported illness in passengers. Enterotoxigenic Escherichia coli (ETEC) were isolated from passengers and crew, and coliforms were found in the main water storage tank. Contamination of inadequately chlorinated water by sewage was the most likely source of infection. A water engineer carried out an investigation of the ship’s water and sewage systems while the ship was sailing for its annual refit. This inspection revealed problem areas such as a

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Table 20-3. Pathogens/Toxins in Outbreaks of Waterborne Disease Associated with Ships Organism/Toxin Bacteria Salmonella species Shigella species Escherichia species Parasites Cryptosporidium Giardia

No. of Outbreaks 2 1 7 1 1

Viruses Norwalk-like virus

4

Chemical food poisoning

1

Unknown

5

Total

22

manual chlorination system on loading water; a loose inspection cover with a poor seal on a potable water tank over which bilge water flowed; and sewage and water pumps, which if ineffective, could lead to sewagecontained bilge water touching the potable water pumps. In addition, when the ship went into dry dock, a leak in one tank was found, caused by loose rivets in the base of the tank. Contaminated seawater could enter through the loose plates, which would happen whenever there was pressure difference between the tank and the seawater, most likely when the ship approached port and at a time when the seawater was most likely to be polluted. Fecal samples taken from affected passengers revealed several serogroups of ETEC. And one water sample taken from a potable water tank had a high coliform count that implied sewage contaminated water supply. Furthermore, the manual chlorination system did not ensure that all water was adequately chlorinated. Following these findings, it was recommended that automatic proportional chlorination pumps be installed as soon as possible. The damaged water tanks and inefficient sewage pipes were repaired. In the 2 months following the repair and review of the water systems, the reported illness dropped to the preoutbreak levels of less than 2%.”

The traditional approach to assuring the safety of water on board ships relied on sampling the end product. However, Water Safety Plans (WSPs) are a tool that could help ship operators manage water safety on board the ship and ensure that future outbreaks are prevented. WSPs can cover both design (materials and construction) and operation. They comprise three essential actions, which are the responsibility of the ship owner and shipmaster, in order that drinking water is safe: • A system assessment • Effective monitoring • Management

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This approach builds on the HACCP system, which has gained the approval of the food industry for controlling food quality. The purpose of system assessment is to determine whether a system has control measures in place that would ensure water quality is consistently maintained on the ship. This assessment involves understanding the characteristics of the drinking water system, what hazards may arise, how these create risks, and the processes and practices that affect drinking water quality. These hazards should be monitored on a routine basis. Management includes control measures, corrective action, and verification. Control measures are actions, activities, and processes applied to prevent or minimize hazards from occurring or to reduce them. WSPs should include the following: • Assessment of source water loaded onto the ship for the prevention or reduction of pathogen contamination; • If source water is contaminated, the selection and operation of treatment processes that are controlled by monitoring parameters that are critical to achieving the target level of pathogen reduction; • The prevention of contamination by pathogens in the storage and distribution system; and • The prevention of contamination during production (desalination).

OUTBREAKS OF VIRAL GASTROENTERITIS ON CRUISE SHIPS Norwalk-like viruses (NLV) (also called noroviruses) are the most common cause of outbreaks of viral gastroenteritis on cruise ships. Person-to-person spread is the most common mode of transmission. However, the virus can be spread via contaminated food or water or by contact with contaminated surfaces or fomites.22 Outbreaks often affect both passengers and crew, sometimes with very high attack rates. The infection usually lasts 12 to 60 hours and is characterized by sudden onset of nausea, vomiting, and watery diarrhea.23 Although the infection is normally self-limiting and usually mild, elderly passengers, children, and people with severe underlying medical conditions might be at increased risk of complications.24 Recurrences of infection on successive cruises are common. Outbreaks may continue because groups of new susceptible passengers are introduced on a regular basis, so that rather than running its course, the outbreak continues over a period of several cruises. Bridging between groups may occur by a reservoir of illness in the crew or by failure to decontaminate the environment. Thirteen outbreaks of NLV, spread mainly by person to person, were reported to be associated with ships between 1970 and 2000.4 “Outbreak Three. Outbreak of NLV on a Cruise Ship25 In 1988, an outbreak due to Norwalk-like virus occurred on a cruise ship and affected 265 (25%) passengers. This virus caused recurrent outbreaks on the cruise and the main mode of transmission was personto-person spread. The epidemiologic investigation implicated vomitus in the transmission of viral gastroenteritis. Contaminated bathrooms may have been important vehicles for person-to-person spread of the infection. The risk of gastroenteritis among passengers who had shared toilet facilities was twice that of those who had a private bathroom, and the rate of illness was related to the number of passengers sharing

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a communal bathroom. Index cases who had vomited in their cabins were more likely to have had cabinmates who subsequently became ill than were index cases who had not vomited. Person-to-person contact or droplet spread was suspected on this ship, because great efforts have been made to clean the vessel after the previous outbreak. The causal agent may have been introduced by a passenger or crew member and then spread by person-to-person contact, by surface contamination in communal bathrooms, and by general crowding on board the ship. The investigators recommended that preventive measures should focus on cleaning toilets in public bathrooms during an outbreak. They advised that the vomitus be regarded as infectious and be treated with the same precautions as fecal material. They recommended that all surfaces likely to have become contaminated be disinfected. Recommendations made to the ships’ management emphasized repeated and thorough clean-up and disinfection of communal bathrooms, rapid disinfection of rooms where people were ill, and improved early surveillance of illness by not charging for physician visits for gastroenteritis. No recurrence of disease was reported on the next three cruises.”

In 2002, the Centers for Disease Control and Prevention (CDC) investigated 21 outbreaks of acute gastroenteritis on 17 cruise ships. Nine of these outbreaks were confirmed by laboratory analysis of stool specimens to be associated with Norwalk-like viruses.24 This increase in reported NLV outbreaks might suggest a genuine increase on cruise ships or it could be due to improved surveillance of outbreaks by CDC and the application of sensitive molecular assays.24 Consecutive and prolonged outbreaks on ships suggest that NLVs survive well in this environment. An effective cleaning and disinfection program is essential to control outbreaks. Objects that are frequently handled, such as taps, door handles, and toilet or bath rails, should be thoroughly cleaned and disinfected. Contaminated hard surfaces should be washed with detergent and hot water, using disposable cloths, and then disinfected with 0.1% hypochlorite solution. Cloths should be disposed of as clinical waste.26 Other control measures on cruise ships may include removing the ship for 7 to 10 days from service for aggressive cleaning, quarantine of ill crew members and passengers until symptom-free for 72 hours, and reinforcement of water and food sanitation practices.24 Hypochlorite is not generally recommended for disinfecting carpets and soft furnishings, as prolonged contact is required and many such items are not bleach resistant. Steam cleaning may be used for carpets and soft furnishings, provided they are heat tolerant (some carpets are “bonded” to the underlying floor with heat sensitive materials). However, in-use tests with steam cleaners have shown failure to achieve temperatures of 60°C within carpets. Vacuum cleaning carpets and buffing floors have the potential to recirculate NLVs and are not recommended. Nondisposable mop heads should be laundered as a hot wash. Contaminated carpets should be cleaned with detergent and hot water, and then disinfected with hypochlorite (if bleach resistant) or steam cleaned.25

REGULATORY CONTROL In the United States, the CDC established the Vessel Sanitation Program (VSP) in the early 1970s as a cooperative activity with the cruise ship industry.27 The program assists the cruise ship industry in fulfilling its responsibility for developing and implementing comprehensive sanitation programs in

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order to minimize the risk of gastrointestinal diseases. The VSP reviews plans for new and renovated vessels, conducts on-site shipyard construction inspections, and provides training several times each year for shore side and shipboard management personnel. In order to monitor and learn from outbreaks that still do occur, the VSP continually monitors reports of diarrheal illness on each ship and almost always conducts an investigation when the master of a ship reports 3% or more of the passengers have reported symptoms of gastrointestinal illness to the ship’s medical staff or master of the ship. On cruises lasting from 3 days to 2 weeks and having at least 100 passengers, gastrointestinal illness outbreaks investigated by the CDC decreased from 8.1 to 3.0 per 10 million passenger days between 1975 to 1979 and 1980 to 1993, respectively.7 In addition, the percentage of ships with acceptable levels of sanitation has increased dramatically.28 This trend continued until the year 2001. Because of the rapidly growing cruise industry, continuing effort is needed to guarantee sanitary measures on ships and to safeguard the health of travelers and crew, as well as preventing the spread of infections from one country to another. This effort should not be limited to the United States. The World Health Organization (WHO) is working closely with the CDC, other regulators, ship builders, ship owners, and seafarers, associations in updating the 1967 WHO Guide to Ship Sanitation.29 This Guide is referenced under the International Health Regulations 1981 (also being extensively revised). The primary aim of the revised Guide is the protection of public health, and it is intended to be used as the basis for the development of national approaches to controlling the hazards that may be encountered on ships, as well as providing a framework for policy making and local decision making. The Guide may also be used as reference material for regulators, ship operators, and ship builders, as well as a checklist for understanding and assessing the potential health impacts of projects involving the design of ships. The Guide is due for publication in 2003 and will include chapters on water safety, food safety, swimming and spa pools, waste management, rodent and vermin control, outbreak investigation, and management and port health inspection and audit.

REFERENCES 1. Crye JM. Testimony. Before: The subcommittee on Commerce, Trade and Consumer Protection. House Energy and Commerce Committee, October 17th 2001. Available at: http://www.iccl.org/ (accessed January 15, 2002). 2. De Las Casas C, Adachi J, DuPont H. Travelers’ diarrhoea [review]. Aliment Pharmacol Ther 1999;13:1373–8. 3. Merson MH, Hughes JM, Wood BT, et al. Gastrointestinal illness on passenger cruise ships. J Am Med Assoc 1975;231:723–5. 4. WHO. Sanitation on ships. Compendium of outbreaks of foodborne and waterborne and Legionnaires’ disease associated with ships, 1970– 2000. WHO/WSH/01.4; 2001. 5. Dannenberg AL, Yashuk JC, Filedman RA. Gastrointestinal illness on passenger cruise ships, 1975–1978. Am J Public Health 1982;72:484–8. 6. Addis DG, Yashuk JC, Clapp DE, Blake PA. Outbreaks of diarrhoeal illness on passenger cruise ships, 1975–85. Epidemiol Infect 1989;103:63–72. 7. Koo D, Maloney K, Taux R. Epidemiology of diarrhoeal disease outbreaks on cruise ships 1986 through 1993. J Am Med Assoc 1996;275:545–7.

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8. DiGiovanna T, Rosen T, Forsett R, et al. Shipboard medicine. A new niche for emergency medicine. Ann Emerg Med 1993:22:1639. 9. Minooee A, Rickman LS. Infectious diseases on cruise ships. Clin Infect Dis 1999;29:737–44. 10. De Louvois J, Dadswell J. Emerging pathogens and drinking water supply. London: Public Health Laboratory Services; 1998. 11. Gascon J, Ruiz L, Canela J, et al. Epidemiology of travelers’ diarrhea in Spanish tourists traveling in developing countries. Med Clin 1993;100:365–7. 12. Steffen R. Travel medicine – prevention based on epidemiological data. Trans R Soc Trop Med Hyg 1991;85:156–62. 13. International Association of Milk, Food and Environmental Sanitarians, Inc. Procedures to investigate foodborne illness. 5th ed. Iowa: IAMFES; 1999. 14. Lew JF, Swerdlow DL, Dance ME, et al. An outbreak of shigellosis aboard a cruise ship caused by a multiple antibiotic-resistant strain of Shigella flexneri. Am J Epidemiol 1991;134:413–9. 15. Codex Alimentarius Commission, Committee on Food Hazards. Guidelines for the application of the hazard analysis critical control point (HACCP) system. ALINORM 93/13A, Appendix II. Rome: Food and Agriculture Organization/World Health Organization; 1993. 16. International Commission for Microbiological Specifications for Food. Microorganisms in foods. 4. Application of the hazard analysis critical control point (HACCP) system to ensure microbiological safety and quality. Oxford: Blackwell Scientific Publications; 1988. 17. National Advisory Committee on Microbiological Criteria for Foods. Hazard analysis and critical control point system. Report of the National Advisory Committee on microbiological criteria for food. USDA; 1992. 18. ILSI Europe. A simple guide to understanding and applying the hazard analysis critical control point. Washington: Concept ILSI Press; 1993. 19. Kirby R. HACCP in practice. Food Control 1994;5. 20. International Association of Milk, Food and Environmental Sanitarians, Inc. Procedures to investigate waterborne illness. 5th ed. Iowa: IAMFES; 1996. 21. O’ Mahony M, Noah ND, Evans B, et al. An outbreak of gastroenteritis on board a cruise ship. J Hyg (Lond) 1986;97:229–36. 22. Centers for Desease Control and Prevention. Norwalk-like viruses: public health consequences and outbreak management. MMWR Morb Mortal Wkly Rep 2001;50(No. RR-9). 23. Kaplan JE, Gary GW, Baron RC, et al. Epidemiology of Norwalk gastroenteritis and the role of Norwalk virus in outbreaks of acute, nonbacterial gastroenteritis. Ann Intern Med 1982;96:756–61. 24. Cramer EH, Forney D, Dannenberg MD, et al. Outbreaks of gastroenteritis associated with Noroviruses on cruise ships – United States. MMWR Morb Mortal Wkly Rep 2002;51:1112–5. 25. Ho MS, Glass RI, Monroe SS, et al. Viral gastroenteritis aboard a cruise ship. Lancet 1989;2:961–4. 26. Chadwick PR, Beards G, Brown D, et al. Management of hospital outbreaks of gastro-enteritis due to SRSV. J Hosp Infect 2000;45:1–10. 27. Korcok M. Sick at sea: outbreaks prompt reinstatement of cruise ship inspections. Can Med Assoc J 1987;136:1298–300. 28. Nguyen CH. A cost-effectiveness analysis of the vessel sanitation program. U.S. Department of Health and Human Services Document. Centers for Disease Control and Prevention; 1997. 29. Lamoureux VB. Guide to ship sanitation. Geneva: WHO; 1967. Reprinted with amendments in 1987.

Chapter 21

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When physicians use the term “travelers’ diarrhea,” they are generally referring to an attack of “Montezuma’s Revenge” that has suddenly ruined a vacation in a tropical destination. However, travelers’ diarrhea can be a serious illness. It does not selectively afflict those on a holiday as a mere inconvenience. In fact, military personnel have frequently been victims of travelers’ diarrhea throughout both historical and modern times, with sometimes devastating consequences. No one has more eloquently stated the enormous impact of diarrhea on military populations than Sir William Osler: “Dysentery has been more fatal to armies than powder and shot.” 1

HISTORICAL CONSIDERATIONS Though it remains a formidable foe in modern times, diarrhea has had devastating effects on soldiers throughout military history. Diarrhea and dysentery have been major causes of morbidity and mortality in every military campaign. The effects of diarrhea are noted as early as biblical times, where a diarrheal illness is described in David’s lament from Psalms 22:15 (Bible: King James Version): “I am poured out like water, and all my bones are out of joint; my heart is like wax; it is melted in the midst of my bowels.” Throughout the history of war, infections have taken more lives than battlefield injuries during times of war. The ratio of soldiers killed by infectious diseases to those killed by battle wounds was 8:1 during the Napoleonic Wars, and 3:1 during the Crimean War 50 years later.2 Once basic sanitation principles were embraced during the American Civil War, the infections mortality was reduced to 2:1. However, over 500,000 soldiers died secondary to infectious disease during the Civil War. Of these deaths, diarrhea accounted for 21,000, while typhoid fever resulted in 35,000 deaths.2 Typhoid fever also felled such notables as Stephan Douglas and the Hero of Little Round Top, Joshua L. Chamberlain.3 Early military physicians perceived the role of dietary changes in precipitating diarrhea, calling it “the bloody flux.” Diarrhea was also thought to be secondary to cold exposure, dampness, and even unsuitable food. The seasonal production of vectors, flies, and such, were ultimately recognized as being more important causes of diarrhea.4

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John Pringle, the father of military hygiene, defined dysentery as diarrhea with blood in the stool. He steered physicians away from “purging and bleeding” to prevention through field sanitation.4 During the 1860s, Jonathan Letterman and the US Sanitary Commission propagated sanitation during the American Civil War, by directing appropriate sanitation, quarantines in camp, and Letterman’s triage system, ultimately saving countless patient lives.5 During Letterman’s tenure as the Chief Medical Officer of the Army of the Potomac, the ratio of deaths from disease to those from battle improved over that of prior wars. Great military leaders of the past and present have realized that diarrhea often makes victory most elusive: “Dysentery of this Arabian coast used to fall like a hammer blow and crush its victims…and left men curiously tired.” 6 T. E. Lawrence (Lawrence of Arabia)

DIARRHEA DURING MODERN WARFARE In World War II, diarrheal illness contributed to a major allied victory—a turning point in the war. During the campaign for El Alamein, 50% of German soldiers suffered from dysentery. Ultimately, a combination of dysentery and Field Marshall Montgomery’s strategy produced a victory. The wars of the post-1940 era have also revealed ongoing problems with diarrhea. Fifty-five percent of American soldiers in the Korean War developed diarrhea upon arriving in the theater.7 The prevalence of diarrhea in American troops in Vietnam approached 30%. During the Vietnam War, diarrhea exceeded even malaria as the most common cause of hospitalization for US soldiers.8 Another modern war experience has recently further chronicled diarrhea’s debilitation role. The Russian-Afghanistan War data reveals that little effort was given to field sanitation among Russian soldiers. The prevalence of diarrhea was normally 30% during this campaign and increased up to 70% during the summer months.9 While diarrhea remained a problem during the Persian Gulf War, for perhaps the first time in military history, there was not a major loss of manpower. One might conclude that this was due to antibiotic prophylaxis, but it was more likely due to vastly improved sanitation and attention to personal hygiene. The Persian Gulf War provided an ideal opportunity to analyze the incidence, risk factors, and pathogens associated with infectious diarrhea in modern military campaigns. Hyams and colleagues surveyed 2,022 US soldiers deployed to the Persian Gulf from 1990 to 1991.10 Fifty-seven percent of the troops reported at least one episode of diarrhea. Contaminated water, which was so often implicated as the cause of diarrhea in past wars, was an unlikely etiology. Supplies of potable water were plentiful either from bottled sources or reverse-osmosis units. Fresh produce and dairy products were highly desired by troops, but difficult to provide. Supplies of these products generally came from local producers in the Middle East or Asia, and ensuring the safety of these items was not fully possible. Unfortunately, eating raw vegetables, especially salad, was associated with the highest risk of developing diarrhea. Enterotoxigenic E. coli (ETEC) was isolated from the culture of the lettuce in one military food-preparation facility.10

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In 1990, Wasserman and colleagues reviewed the charts of 6,772 sick-call visits.11 One unit reported a less than 3% incidence of diarrhea. This was likely attributable to the fact that the unit provided its troops with no fresh vegetables and enforced strict hand-washing near the latrines and the dining facilities. However, one squadron was noted to have an isolated outbreak of diarrheal illness. It was later determined that this squadron was the only one to eat fresh vegetables during a special Christmas dinner.11 Although bacteria comprise the majority of diarrheal pathogens in soldiers, it is important to recognize that viral etiologies may also play a role in diarrhea among military populations. During Operation Desert Storm, paired sera from 404 US military personnel were tested for serologic evidence of Norwalk virus. At least a fourfold increase in antibody was detected in 23% of patients with vomiting, 12% of patients with diarrhea and vomiting, and 6.5% of patients with diarrhea alone.12 Despite the knowledge of infectious diarrhea’s impact on centuries of military campaigns, diarrhea continues to afflict troops around the world. The multinational military campaign in Afghanistan initiated in 2001 is not without exception. A group of British soldiers became acutely ill with fever accompanied by severe diarrhea and vomiting in May of 2002. The gastroenteritis was quite severe, necessitating hospitalization in all afflicted, as well as ventilatory support for two patients. Eleven soldiers were ultimately evacuated out of Afghanistan to England, but not before three health care providers were also exposed. The British field hospital was temporarily closed to all but those with gastroenteritis in order to contain the outbreak. Analysis of stool specimens was performed in England, and Norwalk-like virus (NLV) was detected. NLV is a particular problem among military personnel, because it is extremely contagious, has a prolonged asymptomatic shedding period, and is relatively resistant to chlorination and environmental conditions. Twenty-nine soldiers and health care workers were ultimately affected, but all of the patients rapidly recovered.13 However, this small outbreak essentially incapacitated the unit’s ability to operate, and cost the British government an extraordinary amount of money in order to quarantine, evacuate, treat, and investigate the illness.

DIARRHEA DURING PEACEKEEPING MISSIONS Over the past 50 years, the United Nations (UN) has had a great impact on the role of a soldier. The UN essentially created the “Peacekeeping Soldier” and with this role came many of the risks of war, including infectious diarrhea. Sanchez and colleagues reported the incidence of diarrhea among US troops during 11 overseas peacekeeping missions from 1981 to 1990.14 During that time, the incidence of diarrhea varied widely, affecting between 1 and 52% of deployed troops. Factors associated with increased risk of diarrhea included location of deployment, food, and beverages, particularly ice.14 US troops deployed to Beirut, Lebanon, in 1982 also suffered from a tremendous amount of diarrheal illness. Diarrhea accounted for 96.5% of the infectious diseases presenting to the clinic from the 32nd Marine Amphibious Unit.15 Peacekeeping missions followed in Somalia from 1992 to 1994. Multiple nations participated in Operation Restore Hope, and diarrhea spared no one. Italian soldiers reported 55% were affected by at least one episode of diarrhea.16 During Operation Restore Hope, less than 15% of US troops expe-

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rienced one episode of diarrhea. However, severe diarrheal illness represented 16% (61 of 381) of all hospital admissions.17

DIARRHEA AT HOME Military populations are at risk for infectious diarrhea even when not at war. By virtue of living in close quarters, recruits are at increased risk for outbreaks of infectious diarrhea. An outbreak of gastroenteritis was reported from a military training facility in El Paso, Texas, during 1998. The outbreak resulted in hospitalization of 99 of 835 (12%) soldiers from one unit. Norwalk-like virus was ultimately determined to be the cause of this outbreak of gastroenteritis.18

PREVENTION OF DIARRHEA IN MILITARY DEPLOYMENTS Employment of preventative measures is extremely effective in decreasing infectious diarrhea rates during deployment. Hygiene may be the most effective method of diarrhea prevention. However, hand-washing, reliable sources of potable water, and sanitation are often simply not compatible with the austere environment of soldiers on the battlefield. Therefore, military physicians have attempted to improve hygiene measures as well as develop other methods to prevent diarrhea. Bismuth preparations were the first prophylactic medications employed. The preparations are only marginally effective. Furthermore, they are cumbersome to take with liquid formulations and dosing schedules of up to four times daily, limiting the usefulness of these compounds in mobile military populations. Doxycycline and trimethoprim–sulfamethoxazole (TMP–SMX) have both been demonstrated to have a role in diarrhea prevention. A direct comparison of these two agents was conducted in 1990 among naval personnel during a port call in Rio de Janeiro, Brazil. The participants were instructed to start their respective prophylactic therapy the night before and throughout the duration of the port call for a total of 6 days. Doxycycline and TMP–SMX were both found to be equally effective in diarrhea prevention. Side effects were minimal, with none reported in the doxycycline group and 3% with minor side effects in the TMP–SMX group.19 Along the Thai-Myanmar border, doxycycline potentially has dual benefits since it may be used for both malaria and diarrhea prophylaxis. A cautionary letter was published in 1988 by Taylor and colleagues, who noted their observations in military populations stationed in the region.20 Fifty percent (14/28) of the US soldiers who developed diarrhea while using doxycycline for malaria prophylaxis ultimately grew C. jejuni. The group theorized that the use of doxycycline malaria prophylaxis may actually be increasing the likelihood of developing diarrhea with resistant Campylobacter spp.20 This observation led to a double-blind study performed at the Armed Forces Research Institute of Medical Sciences in Bangkok, Thailand. Diarrhea incidence was monitored in 253 US soldiers using either doxycycline or mefloquine malaria prophylaxis. There was no significant difference in the incidence of diarrhea in either group, with 49% in the doxycycline group and 48% in the mefloquine group reporting at least one episode of diarrhea by the end of the 5-week trial. However, the percentage of multidrug resistant pathogenic bacteria isolated from the participants in the doxycycline

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group increased to 93%.21 As drug resistance increases, the role for both doxycycline and TMP–SMX will be less useful in travelers’ diarrhea prophylaxis. Fluoroquinolone prophylaxis of travelers’ diarrhea has had the best results over the past decade in both civilian and military populations. One of the first studies to illustrate the use of norfloxacin in diarrhea prophylaxis was published in 1990, in which 222 US military personnel in Egypt took part in a double-blinded randomized trial comparing the effectiveness of diarrhea prophylaxis with norfloxacin and placebo. Acute diarrhea was noted in only 2% (2/105) of those using norfloxacin prophylaxis, but in 26% (30/117) taking a placebo.22 A combination of hygiene measures and antibiotic prophylaxis has a potentially useful role in short-term military missions. This is demonstrated quite well by a real life scenario of British and Australian medical teams involved in Operation Safe Haven in 1991 in Northern Iraq, immediately following the Persian Gulf War. Thirty-six British and 72 Australian soldiers all had similar vaccinations and shared the same living area, food, and water. However, the Australian soldiers also took doxycycline 100 mg daily and enforced strict hand-washing and plate-washing. Over a 5-week period, the incidence of diarrhea between the two groups was noted to be markedly different. Sixty-nine percent of the British soldiers experienced at least one episode of diarrhea versus 36% of the Australian soldiers. In addition, the British soldiers had significantly more stools per day, longer duration of diarrhea, and more total days of incapacitation.23 One wonders which had the greater impact—doxycycline or hygiene measures? A study of 432 stool specimens collected during the Persian Gulf War may shed light on this question. Less than 50% of the specimens grew a bacterial pathogen, potentially indicating a greater incidence of viral etiologies. The bacterial pathogens isolated were most commonly ETEC, followed by Shigella spp. In this study, 63% of ETEC and 68% of Shigella spp were resistant to tetracycline.10 It seems clear that strict enforcement of hygiene measures were likely the biggest factor in preventing disease amongst the Australian troops. Although antibiotic prophylaxis may be helpful in some select settings, in prolonged military deployments, daily antibiotics for diarrhea prophylaxis may be difficult to adhere to and cost-prohibitive. Vaccinations for travelers’ diarrhea would be highly advantageous for both travelers and military populations. Ideally, physicians would provide one vaccine to prevent all future episodes of travelers’ diarrhea. Unfortunately, vaccines for travelers’ diarrhea pose a developmental challenge: A separate vaccine is needed for each virus, bacteria, and even each serotype in many cases. The cholera and typhoid fever vaccines are currently the only diarrhea vaccines available; the rotavirus vaccine has recently been removed from the market. There is, however, hope on the horizon. The military currently has active research programs dedicated to the development of Campylobacter spp, ETEC, and Shigella spp pre-deployment vaccines. The ETEC, Shigella flexneri, and Shigella sonnei vaccines are all in Phase I trials. ETEC, like cholera, may provide up to 3 years of protective immunity. The Shigella spp vaccines may only provide 1 year of protection. Campylobacter spp and S. dysenteriae vaccines are in development, but not yet in Phase I trials. It is likely there will be several pre-deployment vaccines available for routine use within the next decade (Daniel Scott, private communication, September 2002).

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TREATMENT OF DIARRHEA IN MILITARY DEPLOYMENTS Measures to prevent diarrhea are not 100% effective and diarrhea will most certainly occur in the military setting. Effective therapies are still needed. Oral rehydration remains the cornerstone of diarrhea therapy. The glucose-electrolyte solution, developed throughout a lifetime of research and dedication by Captain Robert Allan Phillips, has saved millions of lives worldwide.24 Although initially developed to combat cholera, oral rehydration therapy can be used to treat all causes of diarrhea. Antimotility agents, such as loperamide, have a role in controlling the symptomatology of mild, noninvasive diarrhea. Viral etiologies of diarrhea may be quite easily treated with a combination of both antimotility agents and oral rehydration. Therapy of invasive bacterial diarrhea is more complicated and may require antibiotics to shorten the duration of the illness. Of the bacterial etiologies of diarrhea, ETEC and Shigella spp are most commonly isolated in military populations. Invasive bacterial diarrhea is often associated with fever, abdominal pain, and more than four episodes of bloody diarrhea per day. Doxycycline and TMP–SMX were once reliable therapies for these organisms, but increasing resistance has made these drugs less optimal choices over the past decade. A reasonable first line choice of therapy in a patient with this constellation of symptoms is 1 to 3 days of fluoroquinolone therapy. Many clinicians currently recommend a combination of fluoroquinolone and an antimotility agent. However, Taylor and colleagues demonstrated that 90% of patients with travelers’ diarrhea will fully recover within 48 hours whether treated with either a fluoroquinolone alone or in combination with an antimotility agent.25 Fluoroquinolone monotherapy is likely all that is necessary for resolution of invasive bacterial diarrhea at this time, but unfortunately, antibiotic resistance is increasing. The concern over antibiotic resistance is particularly evident in Asia, where Campylobacter spp are often more commonly isolated than either ETEC or Shigella spp. Campylobacter spp have demonstrated a marked increase in resistance to fluoroquinolones. Current experts recommend azithromycin for therapy of Campylobacter spp diarrheal infections.9

SUMMARY The modern soldier has to fight a battle far different from his ancestors, but in many ways, life on the battlefield is improved. Clean water and food supplies accompanied by proper hygiene have truly helped decrease, but not eradicate, the incidence of infectious diarrhea in military populations in recent times. However, the increase in drug resistant organisms may make the pathogens that are able to cause disease much more difficult to treat in the future. Military strategists can only hope that effective vaccines will be available before widespread antibiotic resistance develops in diarrheal pathogens.

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REFERENCES 1. Osler W. The principles and practice of medicine. New York: Appleton; 1892. p. 130. 2. Sartin JS. Infectious diseases during the civil war: the triumph of the “third army.” Clin Infect Dis 1993;16:580–4. 3. McAllister CK. Fire, blood and the lion of the union: Joshua Chamberlain’s civil war ailments. The Pharos of Alpha Omega Alpha 1998;61:40–1. 4. Cook GC. Influence of diarrhoeal disease on military and naval campaigns. J R Soc Med 2001;94:95–7. 5. Bollet AJ. Civil war medicine: challenges and triumphs. Tucson, Arizona: Galen Press, Ltd; 2001. p. 283–386. 6. Lawrence TE. Seven pillars of wisdom. Hants, England: Castle Hill Press; 1926. p. 23–5. 7. Kilpatrick ME. Diarrhoel disease: current concepts and future challenges—a military perspective. Trans R Soc Trop Med Hyg 1993;87:47–8. 8. Sheehy TW. Enteric disease among United States troops in Vietnam. Gastroenterology 1968;55:105–12. 9. Wallace MR, Hale BR, Utz GC, et al. Endemic infectious diseases of Afghanistan. Clin Infect Dis 2002;34: S171–207. 10. Hyams KC, Bourgeois AL, Merrell BR, et al. Diarrheal disease during operation Desert Shield. N Engl J Med 1991;325:1423–8. 11. Wasserman GM, Martin BL, Hyams KC, et al. A survey of outpatient visits in a United States army forward unit during operation Desert Shield. Mil Med 1997;162:374–9. 12. Hyams KC, Malone JD, Kapikian AZ, et al. Norwalk virus infection among Desert Storm troops. J Infect Dis 1993;167:986–7. 13. Brown D, Gray J, MacDonald P, et al. Outbreak of acute gastroenteritis associated with Norwalk-like viruses among British military personnel: Afghanistan, May 2002. MMWR Morb Mortal Wkly Rep 2002;51:477–9. 14. Sanchez JL, Gelnett J, Petruccelli BP, et al. Diarrheal disease incidence and morbidity among United States military personnel during short term missions overseas. Am J Trop Med Hyg 1998;58:299–304. 15. Daniell FD, Crafton LD, Walz SE, et al. Field preventive medicine and epidemiological surveillance: the Beirut, Lebanon experience, 1982. Mil Med 1985;150:171–6. 16. Cali G. The Italian army medical corps in the United Nations “peacekeeping” operations: Somalia and Mozambique, December 1992–December 1994. Med Trop 1996;56:400–3. 17. Sharp TW, Thornton SA, Wallace MR, et al. Diarrheal disease among military personnel during operation Restore Hope, Somalia, 1992–1993. Am J Trop Med 1995;52:188–93. 18. Arness M, Canham M, Geighner B, et al. Norwalk-like viral gastroenteritis in U.S. Army Trainees – Texas, 1998. MMWR Morb Mortal Wkly Rep 1999;48:225–7. 19. Hipskind JE. A prophylactic program to prevent travelers’ diarrhea in United States naval personnel comparing doxycycline and trimethoprim-sulfamethoxazole. Mil Med 1993;158:141–4. 20. Taylor DN, Pitarangsi C, Echeverria P, Diniega BM. Campylobacter enteritis during doxycycline prophylaxis for malaria in Thailand. Lancet 1988;2:578–9. 21. Arthur JD, Echeverria P, Shanks GD, et al. A comparative study of gastrointestinal infections in United States soldiers receiving doxycycline or mefloquine for malaria prophylaxis. Am J Trop Med Hyg 1990;43:608–13.

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22. Scott DA, Harberberger RL, Thornton SA, Hyams KC. Norfloxacin for the prophylaxis of travelers’ diarrhea in U.S. military personnel. Am J Trop Med Hyg 1990;42:160–4. 23. Rudland S, Little M, Kemp P, et al. The enemy within: diarrheal rates among British and Australian troops in Iraq. Mil Med 1996;161:728–31. 24. Savarino SJ. A legacy in 20th-century medicine: Robert Allan Phillips and the taming of cholera. Clin Infect Dis 2002;35:713–20. 25. Taylor DN, Sachez JL, Chandler W, et al. Treatment of travelers’ diarrhea: ciprofloxacin plus loperamide compared with ciprofloxacin alone. Ann Intern Med 1991;114:731–4.

Chapter 22

PERSISTENT THE

CHRONIC DIARRHEA R E T U R N I N G T R AV E L E R AND

IN

Bradley A. Connor, MD, and Brian R. Landzberg, MD

Most cases of travelers’ diarrhea (TD) are acute in nature and will resolve within a week of onset of symptoms. However, travel medicine practitioners and others who care for returning travelers have increasingly recognized subacute or chronic diarrheal syndromes in some returning travelers. Some cases of TD persist for weeks, months, or even years, and the importance of chronic diarrhea as a presenting complaint is now well established in the post-travel setting. There are limited data on the incidence, natural history, and predisposing factors for persistent travelers’ diarrhea (PTD), and an analysis of this condition is hampered by a lack of uniformity in defining this syndrome. Travelers’ diarrhea, defined as diarrhea that develops while abroad in, or shortly upon return from, a developing country, may be divided into acute and chronic types, usually based upon a symptom duration of less than or greater than 4 weeks, respectively. The term “persistent diarrhea” has been used to describe a syndrome lasting more than 14 days, particularly in children.1,2 In this chapter, we will use the terms “chronic” and “persistent” travelers’ diarrhea interchangeably to describe a syndrome of at least 3 weeks duration, although we prefer the term “persistent,” as it is appropriately less precise and implies a process which began acutely but lingered unexpectedly. In addition, many patients with PTD report diarrhea itself as a relatively minor complaint, suffering more from associated cramping pain, bloating, excessive flatulence, or tenesmus, and even constipation, all of which will be included hereunder in the rubric of PTD. An overview of several studies found that between 3 and 10% of travelers may have diarrhea lasting more than 2 weeks and that 0.8 to 3% of travelers will have symptoms lasting more than a month.3-6 PTD also poses a large problem for the military; 16% of 1,163 returned Gulf War veterans reporting chronic diarrhea (defined as 3 or more loose stools in 24 hours lasting more than 6 months) compared with 3% of 2,538 nondeployed military personnel.7 Interestingly, no infectious cause was found in the vast majority of these patients.

PATHOGENETIC MECHANISMS Persistent Infection or Infestation The causes of infectious diarrhea in travelers often resemble those acquired by the indigenous children of the developing world, as both groups are newly exposed to the pathogens of the environment and therefore lack the ability to mount relevant anamnestic responses.8 (Table 22-1)

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Table 22-1. Differential Diagnosis of Persistent Traveler’s Diarrhea Persistent Infections or Infestations

Postinfectious Processes

Chronic Gastrointestinal Diseases Unmasked by an Enteric Infection

Protozoans

Postinfectious malabsorption

Idiopathic inflammatory bowel disease

Helminths

Disaccharide intolerance

Ulcerative colitis

Bacteria (esp. C. difficile)

Bacterial overgrowth

Crohn’s disease

Unknown pathogen

Postinfectious irritable bowel syndrome

Microscopic colitis

Brainerd diarrhea

Celiac sprue

Tropical sprue

Colorectal malignancy Acquired immunodeficiency syndrome

Parasites Parasites, as a group, are the pathogens most likely to be isolated from patients with PTD, with their probability relative to bacterial infections increasing with increasing duration of symptoms. In a study of travelers to Nepal, protozoans were detected in 10% of travelers with gastrointestinal symptoms lasting less than 14 days and in 27% of patients with symptoms lasting more than 14 days.9,10 After passing the 2-month mark of symptom duration, however, it becomes decreasingly likely that one will encounter a persistent parasite and more likely that one is dealing with a postinfectious phenomenon. Parasites of the proximal small bowel are an especial concern when malabsorption is present in the presenting clinical syndrome. A review of all gastrointestinal parasitology would obviously exceed the scope of this chapter; however, a discussion of the parasites most likely to be encountered in PTD follows. Giardia lamblia G. lamblia is by far the most commonly encountered pathogen in patients with PTD. Untreated, symptoms may last for months, even in the immunocompetent host, and tend to localize to the upper gastrointestinal tract.11,12 The diagnosis can often be made through stool microscopy; however, as the parasite infests the very proximal small bowel, it is often too degraded prior to defecation to be recognized at microscopy, and therefore, upper gastrointestinal endoscopy and duodenal aspiration and biopsy may be necessary to make the diagnosis. First line therapy for Giardia consists of metronidazole 250 mg thrice daily for 7 days, although occasionally, a repeat course may be required. Outside the United States, tinidazole is most often used in a single dose of 2 g, which may be repeated the next day. Recently, metronidazole resistance has been reported. Albendazole 400 mg daily for 7 days, which has cured 100% of children tested, has encountered more mixed success in travelers.13,14 Quinacrine 100 mg tid has also been used as treatment with moderate success. Entamoeba histolytica Infection with E. histolytica may produce symptoms ranging from acute to chronic and may vary from mild diarrhea to severe, even fatal, colitis. Overestimations of the prevalence of E. histolytica as a cause of TD and PTD have probably occurred due to the existence of E. dispar, a morphologically indistinguishable and nonpathogenic protozoan, which seems to vastly outnumber its pathogenic

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cousin in stool isolate prevalence, by a factor of 10:1.15,16 Diagnosis is typically made by finding cysts or trophozoites in stool microscopy specimens or by blood serology. Patients with an asymptomatic cyst passage are usually treated with a luminal cystocidal agent alone, such as paromomycin 500 mg tid for 10 days, iodoquinol 650 mg tid for 20 days, or diloxanide furoate. For symptomatic disease, therapy consists of metronidazole 750 mg tid for 10 days (or tinidazole 2 g daily for 3 days) followed by a luminal cystocidal agent. Dientamoeba fragilis D. fragilis is a relatively rare cause of PTD, generally diagnosed by stool microscopy. It is effectively treated by iodoquinol 650 mg tid for 20 days or tetracycline 500 mg qid for 10 days.17 Microsporidia Several case reports have identified Microsporidia, including Enterocytozoan bieneusi and Encephalitozoan intestinalis, in patients with PTD.18,19 Cyclospora cayetanensis In the patient with PTD acquired in the late spring and early summer months, Cyclospora cayetanensis should be an immediate consideration. Although it has only been relatively recently recognized as a pathogen, it is quite prevalent, and in the premonsoon season in Nepal, for example, it is responsible for one-third of all reported diarrhea cases.20-22 In the data from Nepal and Peru, before effective antibiotic therapy was known (trimethoprim–sulfamethoxazole double strength tablet bid for 7 to 10 days), cases of diarrhea typically lasted 6 or more weeks.23 Symptoms are usually upper gastrointestinal and associated with profound fatigue, anorexia, weight loss, and malabsorption.24 Although it is twice as large as Cryptosporidium, detection of the 8 to 10 micron protozoan often requires obtaining a modified acid-fast stain of the stool. Trimethoprim–sulfamethoxazole is now seldom used for treating diarrhea, thus patients with cyclosporiasis are likely to seek care after having failed multiple empiric therapy regimens. Alternative therapies for those allergic or refractory to trimethoprim– sulfamethoxazole are sorely lacking. Cryptosporidium parvum A 1993 waterborne outbreak affecting 400,000 Milwaukee residents demonstrated that C. parvum was not only an opportunistic pathogen causing diarrhea in AIDS patients, but could affect the immunocompetent patient as well.25 C. parvum has been reported as a cause of PTD in travelers from Egypt, Mauritius, Russia, and elsewhere.26,27 Like Cyclospora, C. parvum is more easily found upon acid-fast staining of stool specimens. In the immunocompetent patient, a self-limited illness, usually lasting less than 1 month, is observed. Although no widely effective therapy exists for this illness, paromomycin has been met with some success in AIDS patients and immunocompetent travelers. Isospora belli I. belli has been reported as a cause of diarrhea in travelers returning to the United States from the Caribbean, India, and West Africa.28 Like the previous two protozoans, acid-fast staining of the stool

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is helpful. Successful therapy generally includes a 10-day course of trimethoprim–sulfamethoxazole double strength qid or pyrimethamine–sulfadiazine. Bacteria Enterobacteriaciae Enterobacteriaciae, such as enterotoxigenic Escherichia coli, Campylobacter, and Salmonella, which play the major role in acute TD, are probably a relatively uncommon cause of PTD as a persistent or recurrent infection.29,30 Salmonella and Shigella, however, have both been reported to result in a carrier state with recrudescence of symptoms days to weeks later. Enteroadherent E. coli, a distinct subset of E. coli, have been implicated as an important cause of chronic diarrhea in children, AIDS patients, and travelers.31-36 Quinolones have been used safely and effectively as treatment in affected travelers.37,38 Aeromonas, Plesiomonas, and Yersinia enterocolitica infections have also been reported in patients with PTD.39,40 Clostridium difficile C. difficile is an extremely important pathogen and should not be overlooked in the patient with PTD. Like amebiasis, it is capable of causing a wide range of clinical presentations, varying from acute to chronic disease and from mildly increased stool frequency to bloody diarrhea with toxic megacolon. Consequently, the initial work-up of PTD should always include a C. difficile stool toxin assay.41 Many PTD patients have taken malaria prophylaxis including mefloquine, chloroquine, or doxycycline, or antibiotics for acute TD, which place them at risk for C. difficile.42 First line therapy consists of either metronidazole or oral vancomycin, and is generally successful, although recurrence may occur in 10% of patients or more. Unknown Pathogens A category of PTD syndromes exist in which diarrhea seems to both clinically and epidemiologically resemble a persistent infectious disease, yet for which present day research has failed to find a responsible pathogen. This is, however, a subset, which will certainly shrink in the future as diagnostic techniques, such as new stains, polymerase chain reaction, and enzyme-linked immunosorbent assay, improve and our knowledge of emerging pathogens increases. For example, cases of TD due to Campylobacter jejuni, Cryptosporidium parvum, enteroadherent E. coli, and Cyclospora cayetanensis were included in this category until the relatively recent recognition of these organisms as common human pathogens in 1977, 1982, 1985, and 1991, respectively.43-46 Tropical Sprue Tropical sprue identifies a syndrome of PTD typically marked by malabsorption, steatorrhea, fatigue, and deficiencies of vitamins absorbed in both the proximal and distal small bowel (folate and B12, respectively). It most commonly affects longer-term travelers and expatriates in certain endemic areas of the tropics, although short-term travelers are still at risk for it.47 It occurs more commonly in travelers with close contact with the indigenous population, often follows an acute infectious diarrhea, and is seen in household and seasonal epidemics. It has long been suggested to reflect an

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infectious process, although a century of work has accomplished little in identifying a particular pathogen. In our personal experience with travelers returning to New York, the incidence of tropical sprue among patients with PTD has declined dramatically over the years. This observation has been made by other centers as well, including the Canadian International Water and Energy Consultants (CIWEC) clinic in Nepal, geared toward the care of travelers and expatriates, where the diagnosis is made only five to six times among approximately 1,500 patients presenting with diarrhea per year.48 When the diagnosis has been well established by evidence of malabsorption and histological evidence of villous blunting, and other diagnoses such as celiac sprue have been ruled out, therapy should be initiated with tetracycline 250 mg qid for at least 6 weeks with folate supplements. Shorter courses, bid dosing, and substitution with doxycycline have also been tried successfully. Empiric therapy for this should be discouraged because the incidence has recently been so low, and because the course of treatment is so prolonged. Brainerd Diarrhea Brainerd diarrhea was first described in 1983 when an epidemic of chronic diarrhea occurred in Brainerd, Minnesota, in which the unpasteurized milk of a local dairy was epidemiologically identified as the source.49 Although presumably infectious, extensive microbiological analysis has failed to identify a responsible pathogen and no antimicrobial agents have been found to be effective. Seven subsequent Brainerd epidemics have been reported since its initial description, including six in the United States, and one on a cruise ship in the Galapagos Islands of Ecuador.50-52 The watery diarrhea, associated with urgency, frequency (10 to 20 stools per day), cramping, weight loss, and a waxing and waning pattern, lasts from 2 to 42 months. At 1 year follow-up of the initial outbreak, 12% of patients were subjectively normal, 40% were improved, and 48% had unrelenting diarrhea. Biopsy specimens of the colon revealed a prominence of intraepithelial lymphocytes without markers, consistent with lymphocytic or collagenous colitis. It is unknown whether this entity reflects a frequent cause of sporadic PTD.

Postinfectious Processes Postinfectious Malabsorptive States Malabsorption due to persistent infection or infestation of the proximal small bowel, such as giardiasis or tropical sprue, is readily recognized and understood by most clinicians. Less consideration, however, is made to the common issue of malabsorption that persists after an acute infection (such as a bacterial or viral gastroenteritis) has cleared. Disaccharidases, such as the enzymes used to digest lactose and sucrose, normally reside in the brush border overlying the intestinal epithelium. Any acute inflammatory process will readily disrupt the fragile brush border, leaving the patient with transient lactose and sucrose intolerance, which may take several weeks to resolve.53,54 In some patients with underlying subclinical disaccharidase deficiency, a more permanent lactose intolerance may be seen following gastroenteritis. Exacerbation of symptoms with dairy products and concentrated sweets may not be elicited unless specifically queried and may not even be apparent to the patient. Secondary bacterial overgrowth is another possible sequela of an acute self-limited enteric infection, stemming from the changes in bowel motility following acute TD, which can result in stasis. This

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typically results in a combined osmotic and secretory diarrhea, accompanied by malabsorption. This diagnosis should be entertained in the setting of positive fecal fat analysis and D-xylose testing, in which both noninvasive and endoscopic duodenal sampling have failed to find a persistent pathogen. The diagnosis is confirmed by lactulose hydrogen breath testing or quantitative bacterial counts of small bowel fluid (latter difficult to obtain), and usually responds to antibiotic therapy including tetracyclines, amoxicillin-clavulanate, or quinolones.55,56 The prevalence of bacterial overgrowth in the PTD setting is unknown, and many of these patients may be cured by tetracycline empirically administered for tropical sprue. Postinfectious Irritable Bowel Syndrome (PIBS) Short, self-limited, enteric infections may result in longstanding neurogastroenterological changes and dysmotility. For example, it has long been known that postviral gastroparesis is an important subset of symptomatic delayed gastric emptying, though it is generally quite underdiagnosed, except in the hands of gastrointestinal motility sub-subspecialists. Similarly, an enteric infection of the type acquired in travel may leave the host with important changes in the enteric nervous system, visceral sensation, and altered gastrointestinal motility. Campylobacter, perhaps the most common cause of bacterial gastroenteritis, has long been recognized to produce chronic gastrointestinal symptoms meeting the criteria for irritable bowel syndrome (IBS). A study of 38 patients, followed in two outbreaks of Salmonella enteritidis phage type 4, found approximately one-third to develop chronic IBS.57 In this study, patients who developed IBS were more likely to have had a severe initial infective illness, but whether this reflects an increased dose of organism or host factors was unclear. The study also demonstrated abnormally increased rectal sensitivity and decreased rectal compliance in a manner similar to what has been seen in 58% of IBS patients in general, suggesting they may constitute a pathophysiologically distinct subset of the IBS population.58,59 Is PIBS different from IBS? Clinically, the syndromes are similar; both are defined by the absence of constitutional symptoms or weight loss, and the presence of abdominal pain that is associated with an alteration of bowel habits and relieved by defecation. Both IBS and PIBS can be subcategorized into syndromes of diarrhea predominance, constipation predominance, and pain-gas-bloat predominance, with patients in the latter two groups often not suffering from diarrhea at all. Divergently, however, our unpublished clinical experience with this syndrome suggests men and women to be equally likely to develop PIBS, whereas IBS is much more prevalent in women, demonstrating a ratio of at least 2:1. PIBS has also been known on occasion to respond to antibiotics; however, in such cases, there clearly exists the possibility that a persistent infection was missed and the diagnosis of PIBS was made in error. While there exist virtually no published data on antibiotic therapy in this group of patients, our own experiences, as well as that shared with us by colleagues seeing a large volume of such patients, include many anecdotes of such patients responding to transient antibiotic therapy that was often intended for another purpose such as an intercurrent urinary tract or upper respiratory infection. Why is it important to give this entity a name and definition? From the physician’s standpoint, once a diagnosis has been made, attention can be appropriately focused away from diagnostic efforts

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and onto symptomatic therapy and reassurance, the importance of which cannot be overstated. Psychologically, patients need to have a diagnosis and they find comfort in one. Many sufferers are consumed with the concern of harboring a parasite, or worse, an intestinal cancer. All too often, we have seen such patients who, desperate to have an explanation for their symptoms, fall prey to practitioners who may provide false diagnoses of parasites from in-office stool microscopy and dispense potentially harmful and unnecessary drug therapy. Finally, from a more global perspective, giving this syndrome a name may help facilitate research in the area, which is sorely lacking.

Chronic Gastrointestinal Diseases Unmasked by an Enteric Infection Traveler’s diarrhea has an important potential to uncover latent noninfectious gastrointestinal disease. In the case of celiac sprue (gluten-sensitive enteropathy) and colonic adenocarcinoma, it seems likely that the acute infection acquired in travel is not causative, but merely superimposed on diseased bowel with impaired reserve function or friability, leading to persistent diarrhea or bleeding, which brings the patient to medical attention. In the case of inflammatory bowel disease, it remains somewhat unclear if the TD is only unmasking the chronic disease or actually initiating it. Idiopathic Inflammatory Bowel Disease A diagnosis of IBD was made in 25% of patients in a retrospective British review of 129 cases of bloody diarrhea acquired in or within 2 weeks upon return from a tropical sojourn.60 These patients denied gastrointestinal complaints predating travel, begging the question of whether the infection acquired in travel was actually responsible for the initiation of the autoimmune cascade of IBD. As many of the prevailing hypotheses of the pathogenesis of IBD begin with an initiating antigenic pathogen in the setting of an alteration in intestinal permeability and a genetically determined imbalance of pro- and anti-inflammatory responses, such a scenario would seem plausible. The most common form of inflammatory bowel disease (IBD) uncovered in this setting is ulcerative colitis; however, Crohn’s disease and microscopic colitides, including collagenous and lymphocytic colitis, have also been seen.61 In microscopic colitis, an underdiagnosed entity, a normal gross colonoscopic examination is found; however, random biopsy specimens will evince the underlying inflammatory process. In cases of suspected ulcerative colitis, diligence should be taken to rule out amebic colitis with stool analysis and serology. Celiac Sprue Celiac sprue, or gluten-sensitive enteropathy, is a disease of the small bowel, in which genetically susceptible individuals sustain villous atrophy and crypt hyperplasia in response to exposure to antigens found in many grains (Figure 22-1), classically leading to malabsorptive diarrhea. From studies of healthy blood donors, however, we know that clinically apparent disease with malabsorptive diarrhea accounts for only the tip of the celiac sprue iceberg, with the majority of cases being subclinical or presenting with associated symptoms of osteoporosis, anemia, and the like.62 As 1 in 250 healthy Americans seem to harbor latent celiac disease, based on the screening of blood bank donations, it is important to consider the unmasking of this entity by an enteric superinfection in patients with

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Figure 22-1. Low power light photomicrograph of a duodenal biopsy specimen revealing a markedly blunted villus with crypt hyperplasia, consistent with sprue.

PTD. The disease is diagnosed by compatible gross and microscopic duodenal examination and by the presence of antiendomysial, antigliadin, antitissue trans glutaminase, and antireticulin antibodies, and is treated by a very effective, if difficult to maintain, gluten-free diet.63,64 Colorectal Malignancy Colorectal cancer must be a consideration in patients with PTD, particularly those passing blood per rectum or found to have fecal occult blood or new iron deficiency anemia.65 This is especially true if hematochezia persists after the diarrhea has resolved. In any such patient over the age of 50 years, a full colonoscopy should be performed, even if the symptoms seem consistent with infectious colitis. Colorectal cancer is too prevalent in the United States, with the average lifetime risk of the individual approaching 6%, and the consequences of missing an early diagnosis too great not to request a complete colonic luminal evaluation in the older patient. In the patient younger than 40 years of age, the prevalence of cancer is substantially lower and flexible sigmoidoscopy or expectant management may be reasonable options.

CLINICAL APPROACH Histor y and Physical Examination A complete history and physical examination remain the most important diagnostic tools in evaluating patients with PTD. It is first necessary to establish the diagnosis of a chronic or persistent diarrhea. For example, a complaint of PTD of 8 weeks of diarrhea may, upon further questioning, become in actuality three separate episodes of acute diarrhea, the most recent of which brings the patient to the office, changing the differential diagnosis considerably. In eliciting the history of present illness, therefore, it is critical to listen for gaps in wellness; a hiatus of 5 to 7 days without diarrhea suggests

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that an infection may have cleared and a new one had begun.66 In addition, vomiting and fever usually occur at the onset of enteric infections, so that if a patient reports weeks of diarrhea followed by the initiation of vomiting and fever, then the likelihood is that the patient suffers from a new superimposed acute infection, rather than a chronic one. Recall that travelers may develop multiple enteric infections, as suggested in a study of travelers to Nepal, in which 17% were diagnosed with more than one stool pathogen.67 Also important to consider is the season in which the patient traveled, Cyclospora being most prevalent in the spring and early summer. The history should be used to anatomically localize the pathology to either small or large bowel. Diarrhea that is large volume but relatively infrequent should suggest a small bowel process. Under normal circumstances, only at most 1.5 L of stool (of the 9 L that pass through the alimentary canal) pass from normal small bowel through the ileocecal valve per day. In addition, the noninflamed colon has the capacity to serve as a reservoir for liters of stool, explaining the relatively infrequent but high volume pattern to the bowel movements in patients with a small bowel cause of diarrhea. Other symptoms localizing to the upper gastrointestinal tract include nausea, vomiting, eructation, and pyrosis. Symptoms such as copious flatus, or stools that are foul smelling, floating, or associated with oil droplets, suggest a small bowel process associated with malabsorption. The frequent, relatively small volume diarrhea associated with infraumbilical cramping implies a colonic process (like Brainerd diarrhea), in which additional symptoms of tenesmus, bloody mucus, or frank hematochezia would herald a colitis or dysentery. Fever, sweats, or chills would favor the presence of a continued invasive pathogen, but may also be seen in unmasked idiopathic inflammatory bowel disease or cancer. Weight loss raises a concern for an ongoing infectious, malabsorptive, inflammatory, or malignant process and should be seen as inconsistent with merely functional syndromes such as PIBS, as would symptoms that awaken the patient from sleep. Bacterial infections will generally be abrupt and severe in onset, with a steady daily pattern. The symptoms of protozoan illnesses tend to be milder at onset, beginning with the passage of a few loose movements per day. They will also tend to be intermittent, with a few days on and a few days off, as is typically seen with Entamoeba and Cyclospora. Giardiasis tends to behave more like a bacterial process in its consistency of symptoms. It is also important in the history to inquire about any preceding gastrointestinal symptoms, even if patients are slow to offer them. These are often found in patients with unmasked idiopathic IBS or PIBS. Family history of gastrointestinal ailments and personal history of nonsteroidal antiinflammatory drug use or smoking patterns may influence the likelihood of IBD. If no evidence of malabsorption or constitutional symptoms exists, then the diagnosis of PIBS should be considered. Often, a physician will be the second or third one to encounter the patient, and it is important to be aware of all preceding diagnostic and therapeutic management, including pre-, intra- and posttravel care. Many of these patients have taken antibacterial agents, malarial prophylaxis, and the like, predisposing them to antibiotic associated diarrhea and C. difficile in addition to gastrointestinal side effects of the medications, apart from changes in bowel flora. The particular antibiotics given are important. Did they include broad gram-negative coverage, like a quinolone? Did the patient take trimethoprim–sulfamethoxazole, which would have covered Cyclospora? Physical examination, though less helpful than history in these patients, remains important. Observed weights (especially serial) and assessments of temporal wasting and skin turgor provide

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useful insights into the nutritional and volume status of the patient. Marked lower abdominal tenderness should raise concern for the presence of colitis, be it infectious, ischemic, or idiopathic IBS. Mild tenderness in the left lower quadrant may be seen in PIBS, as it is with IBS, relating to spasm of the sigmoid colon. Epigastric and right upper quadrant tenderness may be seen in giardial infections, but is neither specific nor sensitive. Edema may be seen in the presence of either malabsorption or protein-losing enteropathy. Any physical examination findings other than mild left lower quadrant tenderness probably preclude the diagnosis of PIBS. Fecal occult blood testing and testing for fecal leukocytes are also useful, and if positive, suggest the presence of an invasive or inflammatory, typically colonic, pathogen or process. The former should, in an older patient, alert the clinician to the alternative possibility of an unmasked gastrointestinal malignancy and lead to colonoscopic evaluation. The latter is unnecessary when gross or occult blood is present in the stool, as it will always be positive in that setting, regardless of the presence of an inflammatory process.

NONINVASIVE LABORATORY WORK-UP Stool Studies Stool studies should be the first diagnostic step in the evaluation of PTD, after the history and physical examination. These may be very helpful when positive, but are notoriously insensitive. Upper gastrointestinal parasites are often missed, and pathogenic bacteria are often misclassified as normal flora unless examined in specialized laboratories. We generally recommend at least three ova and parasite examinations with wet prep, trichrome stain, and modified acid-fast stain, in addition to culture and C. difficile toxin assay. A large retrospective review of stool microscopy specimens submitted to the Kaiser Permanente system in California found that the sending of three specimens rather than one increased the yield for E. histolytica, G. lamblia, and D. fragilis by 22.7%, 11.3%, and 31.1% respectively.68 Acid-fast staining is very helpful in the detection of Cyclospora, Cryptosporidium, and Isospora spp and is not performed unless specifically requested in most laboratories. Concentration of the stool will also increase the yield of finding these protozoans. Antigen assays, such as the one that exists for G. lamblia, appear to only minimally heighten sensitivity. The accuracy of fecal light microscopy is exquisitely dependent on the skill, experience, and integrity of the technician reading the slides. Another potential pitfall here is the detection of nonpathogenic protozoans, often identified in avid travelers to developing countries. The finding of these organisms has frequently led to inappropriate and unnecessary attention, patient angst, and drug therapy. These protozoans, several of which have been listed in Table 22-2, are clinically irrelevant, and are harmful to the patient only in distracting the clinician from further work-up and in iatrogenic complications of unneeded therapy.

Blood Testing As in the work-up of any chronic diarrheal illness, reasonable laboratory evaluation for PTD would begin with a complete blood count with differential. Eosinophilia would suggest the presence of a lingering parasitic infestation, recalling that this is seen with invasive helminths and not protozoans. Leukocytosis with neutrophilia favors a bacterial process, and when marked (greater than 20,000

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Table 22-2. Nonpathogenic Protozoans Blastocystis hominis Iodamoeba butschlii Entamoeba spp (non-histolytica) E. hartmanni E. moshkovskii E. coli E. dispar (distinguished from histolytica only with specialized analysis) Endolimax nana Chilomastix mesnili Enteromonas hominis

cells/dL) suggests C. difficile infection. Lymphocytosis may be seen in viral processes. Although neither sensitive nor specific, an elevated erythrocyte sedimentation rate or C-reactive protein may be seen in either an infectious or inflammatory process and should direct the differential diagnosis away from PIBS. Abnormalities in albumin or prothrombin time may be seen in malabsorption or malnutrition. Abnormally low values for iron or folate suggest a process in the proximal small bowel, whereas deficiency in vitamin B12 generally stems from ileal disease relating to the area or normal absorption. The presence of both B12 and folate deficiency should raise suspicion for tropical sprue in its typical ability to involve wide-reaching segments of the alimentary canal. A fecal fat assessment may be useful in screening for malabsorption or maldigestion; however, a D-xylose test is indicated as the confirmatory, noninvasive test for small bowel malabsorption. After drinking a 25 g bolus of D-xylose, the patient may either submit a 5 hour urine collection, or have a venous sample drawn. A normal result is excretion of greater than 20% of the xylose load into the urine. Markedly positive results (ie, those less than 15%) are typically seen in tropical sprue. Other reasonable blood work includes an electrolyte panel, thyroid function tests, and amebic, HIV, and celiac serologies.

ENDOSCOPIC EVALUATION We believe that most patients with PTD who have had unrevealing noninvasive evaluation as elaborated above should be considered for an endoscopic evaluation, although empiric therapy is an equally acceptable first line approach, such as for parasitic illnesses like Giardia or bacterial illness. There are no randomized data on the subject of empiric therapy versus endoscopic evaluation for PTD, and advantages and disadvantages exist for both approaches. The argument for empiric therapy is the avoidance of procedures that carry some cost and some minimal risk. On the other hand, the use of antimicrobials or antiparasitic agents, when no pathogen has been documented, may confuse rather than clarify the issue. These medications, in addition to the risk of allergic reaction and other side effects particular to the individual drugs, alter bowel flora and may muddle the picture by

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introducing antibiotic-associated diarrhea, with or without pseudomembranous colitis. In addition, a lack of response to an empiric course of therapy may simply reflect antibiotic resistance rather than an incorrect diagnosis.69 There exist selected groups of patients, in whom an endoscopic evaluation is strongly indicated, including patients failing one or two unsuccessful empiric courses, all patients older than 50 years with occult or gross fecal blood, and patients with malabsorptive symptoms or signs. Endoscopy provides a sensitive means of identifying a lingering parasitic infestation or tropical sprue, as well as identifying underlying structural gastrointestinal processes including idiopathic inflammatory bowel disease, celiac sprue, and colorectal carcinoma. It also provides an objective marker to follow in patients with persistent symptoms. From an evidence-based medicine standpoint, it demonstrates a useful diagnostic yield in the work-up of chronic diarrhea in general; however, the yield in PTD remains poorly studied.70 The choice of upper gastrointestinal endoscopy versus colonoscopy (or sigmoidoscopy) returns us to the importance of the medical history, using the clues as described above for localizing a process to the small or large bowel, as well as the presence of fecal fat or leukocytes. Of key importance is that the endoscopist should take biopsies and aspirates of the duodenum at esophagogastroduodenoscopy and of the colon (and possibly terminal ileum) at lower endoscopy, regardless of the presence of gross mucosal disease, as the changes may be only visible at the microscopic level. The role for evaluation of these specimens by transmission electron microscopy remains unclear. Presently, it is to be considered an investigational tool, to be used by those with research interests in the area.

THERAPY Empiric anti-infective therapy is both a useful diagnostic and therapeutic tool. A response to a quinolone or macrolide would simultaneously support the diagnosis of and treat bacterial disease. A response to a nitroimidazole might be similarly useful in clinically suspected giardiasis or amebiasis, as would trimethoprim–sulfamethoxazole for suspected cyclosporiasis. In the patient with diarrhea associated with upper gastrointestinal symptoms and without malabsorption, we would recommend an empiric course of metronidazole to cover giardiasis. Symptomatic therapy is another important aspect of the clinical management of PTD, particularly in PIBS, and begins with diet modifications. Due to the compromise of the brush border with a transient enteric infection, a trial should be undertaken of sequential avoidance of dairy products, sorbitol-containing products, fruit juices, concentrated sweets, and high fat items, in that order. In patients with colitis, a low residue, low fiber diet should be advised. Based upon the nature of the symptoms, antispasmodics and other drugs useful in IBS, such as hyoscyamine, chlordiazepoxide, clinidium, limbitrol, and fiber in the form of psyllium or methylcellulose, may be helpful. For the patient with predominant symptoms of diarrhea, loperamide, diphenoxylate, and tincture of opium are invaluable. Probiotics such as Lactobacillus and Saccharomyces boulardii seem to improve symptoms in some of these patients as well.71 In patients with PIBS, remember that reassurance and emotional support are as important as dietary recommendations and drug therapy.

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REFERENCES 1. American Gastroenterological Association Medical Position Statement. Guidelines for the evaluation and management of chronic diarrhea. Gastroenterology 1999;116:1461–3. 2. International Working Group on Persistent Diarrhoea. Evaluation of an algorithm for the treatment of persistent diarrhea: a multicenter study. Bull WHO 1996;74:478. 3. Merson MH, Morris GK, Sack DA. Travelers’ diarrhea in Mexico: a prospective study of physicians and family members attending a congress. N Engl J Med 1976;294:1299. 4. Addis DG, Tauxe RV, Bernard KW. Chronic diarrheal illness in U.S. Peace Corps volunteers. Int J Epidemiol 1990;19:217–8. 5. Steffen R, van der Linde F, Gyr K, Schar M. Epidemiology of diarrhea in travelers. J Am Med Assoc 1983;249:1176–80. 6. Dupont HL, Capsuto EG. Persistent diarrhea in travelers. Clin Infect Dis 1996;22:124–8. 7. Fukuda K, Nisenbaum R, Stewart G. Chronic multi-system illness affecting Air Force veterans of the Gulf War. J Am Med Assoc 1998;280:981. 8. Shlim DR, Hoge CW, Rajah R, et al. Persistent high risk of diarrhea among foreigners in Nepal during the first 2 years of residence. Clin Infect Dis 1999;29:613–6. 9. Hoge CW, Shlim DR, Echevarria P. Epidemiology of diarrhea among expatriate residents living in a highly endemic environment. J Am Med Assoc 1996;275:533–8. 10. Taylor DN, Houston R, Shlim DR. Etiology of diarrhea among travelers and foreign residents in Nepal. J Am Med Assoc 1988;260:1245–8. 11. Wright SG, Tomkins AM, Ridley DS. Giardiasis: clinical and therapeutic aspects. Gut 1977;18:343–50. 12. Ortega YR, Adam R. Giardia: overview and update. Clin Infect Dis 1997;25:545–50. 13. Kollaritsch H, Jeschko E, Wiedermann G. Albendazole is highly effective against cutaneous larva migrans but not against Giardia infection: results of an open pilot trial in travelers returning from the tropics. Trans R Soc Trop Med Hyg 1993;87:689. 14. Dutta AK, Phadke MA, Bagade AC. A randomized multicentre study to compare the safety and efficacy of albendazole and metronidazole in the treatment of giardiasis in children. Indian J Pediatr 1994;61:689. 15. Jackson TF. Entamoeba histolytica and Entamoeba dispar are distinct species; clinical, epidemiological and serological evidence. Int J Parasitol 1998;28:181. 16. Reed SL. Amebiasis: an update. Clin Infect Dis 1992;14:385–91. 17. Cuffari C, Oligny L, Seidmen EG. Dientamoeba fragilis masquerading as allergic colitis. J Pediatr Gastroenterol Nutr 1998;26:16. 18. Raynaud L, Delbac F, Broussolle V. Identification of Encephalitozoon intestinalis in travelers with chronic diarrhea by specific PCR amplification. J Clin Microbiol 1998;36:37. 19. Wanke CA, DeGirolami P, Federman M. Enterocytozoon bieneusi infection and diarrheal disease in patients who were not infected with human immunodeficiency virus: case report and review. Clin Infect Dis 1996;23:816. 20. Hoge CW, Shlim DR, Rajah R, et al. Epidemiology of diarrheal illness associated with coccidian-like organism among travelers and foreign residents in Nepal. Lancet 1993;341:1175–8. 21. Connor BA. Cyclospora infection: a review. Ann Acad Med Singapore 1997;26:532–6. 22. Connor BA. Cyclospora. In: Blaser MJ, et al, editors. Infections of the gastrointestinal tract. 2nd ed. Maryland: Lippincott, Williams and Wilkins; 2002.

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23. Hoge CW, Shlim DR, Ghimire M, et al. Placebo-controlled trial of co-trimoxazole for Cyclospora infections among travelers and foreign residents in Nepal. Lancet 1995;345:691–3. 24. Connor BA, Shlim DR, Scholes JV, et al. Pathologic changes in the small bowel in nine patients with diarrhea associated with a coccidian-like body. Ann Intern Med 1993;119:377–82. 25. MacKenzie WR, Hoxie NJ, Proctor ME, et al. A massive outbreak in Milwaukee of Cryptosporidium infection transmitted through the public water supply. N Engl J Med 1994;331:161. 26. Gatti S, Cevini C, Bruno A, et al. Cryptosporidiosis in tourists returning from Egypt and the island of Mauritius. Clin Infect Dis 1993;16:344–5. 27. Jokipii AMM, Hemila M, Jokipii L. Prospective study of acquisition of Cryptosporidium, Giardia lamblia, and gastrointestinal disease. Lancet 1985;1:487–9. 28. Shaffer N, Moore L. Correspondence – chronic travelers’ diarrhea in a normal host due to Isospora belli. J Infect Dis 1989;159:596–7. 29. Steffen R, van der Linde F, Gyr K, Schar M. Epidemiology of diarrhea in travelers. J Am Med Assoc 1983;249:1176–80. 30. Katelaris PH, Farthing MJ. Travelers’ diarrhea: clinical presentation and prognosis. Chemotherapy 1995;41 Suppl 1:40. 31. Baqui AH, Sack RB, Black RE. Enteropathogens associated with acute and persistent diarrhea in Bangladeshi children less than five years of age. J Infect Dis 1992;166:72. 32. Bhan MK, Raj P, Levine MM. Enteroaggregative Escherichia coli associated with persistent diarrhea in a cohort of rural children in India. J Infect Dis 1989;159:1061–4. 33. Black RE. Persistent diarrhea in children of developing countries. Pediatr Infect Dis J 1993;12:751. 34. Matthewson JJ, Jiang ZD, Zumla A. Hep 2 cell adherent Escherichia coli in patients with human immunodeficiency virus-associated diarrhea. J Infect Dis 1995;171:1636. 35. Cohen MB, Hawkins JA, Weckbach LS. Colonization by enteroaggregative Escherichia coli in travelers with and without diarrhea. J Clin Microbiol 1993;31:351–3. 36. Gascôn J, Vargas M, Quinté L. Enteroaggregative Escherichia coli strains as a cause of travelers’ diarrhea: a case control study. J Infect Dis 1998;177:1409–12. 37. Glandt M, Adachi JA, Mathewson JJ, et al. Enteroaggregative Escherichia coli as a cause of travelers’ diarrhea: clinical response to ciprofloxacin. Clin Infect Dis 1998;29:335–8. 38. Boockenooghe AR, DuPont HL, Jiang ZD, et al. Markers of enteric inflammation in enteroaggregative Escherichia coli diarrhea in travelers. Am J Trop Med Hyg 2000;62:711–3. 39. Rautelin H, Hanninen ML, Sivonen A. Chronic diarrhea due to a single strain of Aeromonas caviae. Eur J Clin Microbiol Infect Dis 1995;14:51. 40. Rautelin H, Sivonen A, Kuikka A. Enteric Plesiomonas shigelloides infections in Finnish patients. Scand J Infect Dis 1995;27:495. 41. Bartlett JG. Antibiotic associated diarrhea. Clin Infect Dis 1992;15:573–9. 42. Golledge CL, Riley TV. Clostridium difficile-associated diarrhea after doxycycline malaria prophylaxis. Lancet 1995;345:1377–8. 43. Skirrow MB. Campylobacter enteritis: a “new” disease. Br Med J 1977;2:9–11. 44. Centers for Disease Control and Prevention. Cryptosporidiosis: an assessment of chemotherapy of males with acquired immunodeficiency syndrome (AIDS). MMWR Morb Mortal Wkly Rep 1982;31:589–92. 45. Mathewson JJ, Johnson PC, DuPont HL, et al. A newly recognized cause of travelers’ diarrhea: enteroadherent Escherichia coli. J Infect Dis 1985;151:471–5.

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46. Hoge CW, Shlim DR, Rajah R, et al. Epidemiology of diarrheal illness associated with coccidian-like organism among travelers and foreign residents in Nepal. Lancet 1993;341:1175–8 47. Tomkins AM, James WPT, Walters JH, Cole ACE. Malabsorption in overland travelers to India. Br Med J 1974;3:380–4. 48. Shlim DR. Tropical sprue as a cause of travelers’ diarrhea [response to Letter to the Editor]. Wilderness Environ Med 2000;11:140–1. 49. Osterholm MT, MacDonald KL, White KE. An outbreak of a newly recognized chronic diarrhea syndrome associated with raw milk consumption. J Am Med Assoc 1986;256:484–90. 50. Parsonnet J, Trock SC, Bopp CA. Chronic diarrhea associated with drinking untreated water. Ann Intern Med 1989;110:985–91. 51. Parsonnet J, Wanke CA, Hack H. Idiopathic chronic diarrhea. In: Blaser MJ, Smith PD, Ravidin JI, editors. Infections of the gastrointestinal tract. New York: Raven Press; 1995. p. 311–23. 52. Mintz ED, Weber JT, Guris D. An outbreak of Brainerd diarrhea among travelers to the Galapagos Islands. J Infect Dis 1998;177:1041. 53. Montgomery RD, Beale DJ, Sammons HG, Schneider R. Postinfective malabsorption: a sprue syndrome. Br Med J 1973;2:265–8. 54. Greene HL, McCabe DR, Merenstein GB. Protracted diarrhea and malnutrition in infancy: changes in intestinal morphology and disaccharidase activities during treatment with total intravenous nutrition or elemental diets. J Pediatr 1975;87:695. 55. Attar A, Flourie B, Rambaud JC, et al. Antibiotic efficacy in small intestinal bacterial overgrowth-related chronic diarrhea: a crossover, randomized trial. Gastroenterology 1999;117:794-7. 56. Bhatnagar S, Bhan MK, George C. Is small bowel bacterial overgrowth of pathogenic significance in persistent diarrhea? Acta Paediatr Suppl 1992;381:108. 57. McKendrick MW, Read NW. Irritable bowel syndrome-post Salmonella infection. J Infect 1994;29:1–3. 58. Bergin AJ, Donnelly TC, McKendrick MW, Read NW. Changes in anorectal function in persistent bowel disturbance following Salmonella gastroenteritis. Eur J Gastroenterol Hepatol 1993;5:617–20. 59. Prior A, Sorial E, Sun WM, Read NW. Irritable bowel syndrome: differences between patients who show rectal sensitivity and those who do not. Eur J Gastroenterol Hepatol 1993;5:343–9. 60. Harries AD, Myers B, Cook GC. Inflammatory bowel disease: a common cause of bloody diarrhea in visitors to the tropics. Br Med J 1985;291:1686–7. 61. Case Records of the Massachusetts General Hospital: Case 29–1992. N Engl J Med 1992;327:182–91. 62. Trevisiol C, Not T, Berti I, et al. Screening for celiac disease in healthy blood donors at two immunotransfusion centres in northeast Italy. Ital J Gastroenterol Hepatol 1999;31:584–6. 63. Ferreira M, Davies SL, Butler M, et al. Endomysial antibody: is it the best screening test for celiac disease? Gut 1992;33:1633–7. 64. Ladinser B, Rossipal E, Pittschieler K. Endomysium antibodies in celiac disease: an improved method. Gut 1994;35:776–8. 65. Case Records of the Massachusetts General Hospital: Case 33–1993. N Engl J Med 1993;329:561–8. 66. Taylor DN, Connor BA, Shlim DR. Chronic diarrhea in the returned traveler. Med Clin North Am 1999;83:1033–52. 67. Taylor DN, Houston R, Shlim DR. Etiology of diarrhea among travelers and foreign residents in Nepal. J Am Med Assoc 1988;260:1245. 68. Hiatt RA, Markell EK, Ng E. How many stool examinations are necessary to detect pathogenic intestinal protozoa? Am J Trop Med Hyg 1995;53:36–9.

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69. Talsma E, Goettsch WE, Nieste HLJ, et al. Resistance in Campylobacter species: increased resistance to fluoroquinolones and seasonal variation. Clin Infect Dis 1999;29:845–8. 70. Shah RJ, Fenoglio-Preiser C, Bleau BL, Gianella RA. Usefulness of colonoscopy with biopsy in the evaluation of patients with chronic diarrhea. Am J Gastroenterol 2001;96:1091–5. 71. Kirchhelle A, Fruhwein N, Toburen D. Treatment of persistent diarrhea with S. boulardii in returning travelers: results of a prospective study. Fortschr Med 1996;114:136.

Chapter 23

T H E F U T U R E O F T R AV E L E R S ’ D I A R R H E A : DIRECTIONS FOR RESEARCH Robert Steffen, MD, Herbert L. DuPont, MD, and Charles D. Ericsson, MD

What does the future hold for travelers’ diarrhea? Can we beat this health problem once and for all? The elements are here. We know the reasons for the problem, and well known and effective public health principles are available for implementation. Despite knowing the solution, the short-term outlook unfortunately is not so bright. Better understanding and technologic advances promise hope for the longer term future of travelers to developing regions of the world. Before we predict what might be useful for the affluent traveler, we should remember that travelers’ diarrhea, as we discuss it in industrialized nations, is just the tip of an iceberg. We tend to neglect the fact that, in the developing world, the same syndrome affects infants who are as equally nonimmune as travelers. Two million children die each year in developing countries from diarrheal diseases, making it the second most serious killer of children under 5 years of age worldwide— before the propagation of oral rehydration solutions, this loss was even much higher.1 We fervently hope that advances in prevention and treatment of travelers’ diarrhea can have a positive impact on infant mortality in developing countries. On reviewing the basics of how to prevent infections (Figure 23-1), we learn that we can try to eliminate the source, interrupt transmission, or make the human host invulnerable or tolerant to infection. In the case of travelers’ diarrhea, these interventions are aimed at preventing fecally contaminated food or beverages from causing harm to travelers. Theoretically, various options can be considered for an intervention at each of the three targets; these are discussed in this chapter.

ELIMINATE THE SOURCE: ENVIRONMENTAL CONTROL Currently, water and food frequently become fecally contaminated in developing countries. Causes include improper treatment of sewage water, as recently exemplified in India,2 or admixture of sewage into drinking water, a risk that is amplified when rusty pipes leak or when overflow occurs after heavy rains.3 In many regions of the developing world, vegetable plantations are irrigated with potentially contaminated water, and in many instances, with human manure. Unless subsidy to cover the costs of an alternative fertilizer is offered, farmers are not likely to modify their behavior and stop spreading cheap fecal waste-containing human enteric pathogens over their acres. To guarantee clean water in the developing world, the public health infrastructure must be improved. This is a formidable task. In tourist destinations like Acapulco where infrastructure had

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Figure 23-1. Basics on Prevention of Infections.

been built to support a thriving tourist trade, the fragility of the infrastructure was readily exposed by a hurricane that placed both local residents and tourists immediately in danger due to lack of clean water. Initiatives are being undertaken by the World Health Organization and other institutions to improve public health infrastructure in the developing world, but due to insufficient funds, such lofty goals are likely not to be achieved in the next few decades. Even reaching the limited goal of assuring clean water in and around the main tourist destinations and large cities visited by business travelers is hampered by the incapacity of the local tourism industry and governments to partner and offer necessary financial support. Cost-sharing may be wishful thinking unless the parties are willing to think outside their immediate priorities and realize that it might be necessary to spend money to make even more through profits and increased tax revenues, realized by an increase in tourism prompted by the realization that the destination is safer.

ELIMINATE TRANSMISSION If the source of enteric pathogens cannot soon be eliminated, perhaps a coordinated effort by local authorities and hotel and restaurant owners might improve hygienic conditions and eliminate transmission of the organisms. In Hong Kong, for instance, food and beverage managers of all five-star hotels decided some years ago to import all vegetables and seafood from Australia and New Zealand to deal with complaints about travelers’ diarrhea. Apparently, this was effective. Although a more ideal solution might have been to clean up the local food sources, the success of this approach underscores what can be achieved by affluent industries when the motivation is strong enough. Jamaica has solicited expert advice about how to deal with the issue of travelers’ diarrhea among tourists and has

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developed a more fundamental approach to the problem by intensive education of the personnel handling food preparation at the various resort locations and by monitoring of food handling practices. So far, however, there are no published results, but the program appears to have been at least partially successful. Even if food and beverages are not primarily contaminated, they can become secondarily contaminated. This may occur by flies, by improperly washed hands during food preparation, and by cross contamination of food during preparation or storage. To eliminate all flies that may land on food is probably a hopeless task in most developing countries. Even attempts to minimize contamination via flies are likely not to be very successful, except possibly for the pathogens infectious in very low dose (Shigella, Cryptosporidium, Giardia, Shiga toxin-producing E. coli, or Norwalk virus), until fecal contamination of the environment is fundamentally controlled. On the other hand, food handlers in large hotels in Tunisia were commanded to wash hands and to observe other fundamental rules of hygiene. Reduced rates of travelers’ diarrhea resulted, but rates still exceeded 20%.4 In Mexico, public service announcements about hand-washing and avoiding street vendors now appear on television. Clearly, an effort to change hygienic behavior is underway; yet, the practice of storing leftovers at room temperature persists in many households as an ingrained habit, despite the availability of refrigerators. We have found that the hot sauces maintained on tabletops in Mexican restaurants are frequently contaminated with diarrhea-causing bacteria, even with a low pH. This clearly relates to inadequate refrigeration between customers. Future generations must be educated from infancy to wash hands after using the toilet and prior to touching food. Observing how many people (including some infectious disease physicians!) in industrialized lands do not comply with hand-washing rules, we can be skeptical about the long-term success of efforts to modify hand-washing behavior in developing countries without extensive and effective peer and governmental pressure. Yet, while we cannot currently count on much behavioral change among travelers, their ingrained behavior at home combined with excellent public health services does suffice to keep the diarrhea attack rate minimal during non-outbreak periods in industrialized countries. Perhaps achieving a critical mass of behavioral change within a local population is all that will be necessary to achieve substantial public health benefit for both indigenous persons and travelers in developing countries. With current educational efforts, perhaps at least a partial improvement in the overall diarrhea attack rate might be realized.

RISK REDUCTION IN THE HOST Four strategies to reduce risk of infection are reduction of exposure, identification of the highest risk travelers for special counseling and treatment, development of immunity, and use of prophylactic medication. Only a minority among travelers abstains from all potentially contaminated food and beverage items. Attempts to convince travelers of safe food and beverage choices have not met with measurable success. As medical educators, we probably ought to collaborate more closely with behavior modification specialists and psychologists to achieve better success in education directed at behavioral change. Yet, despite a 54% attack rate per month, US travelers in Mexico rarely develop

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amebiasis, despite the fact that the disease is endemic in the poorest element of the indigenous population. This observation shows that it is possible to reduce one form of enteric illness through improved eating patterns that differ fundamentally from those of an indigenous person. Clearly, there are grades of hygiene within these local settings. These questions illustrate a primary research need: we should learn far more about risk factors of infection. Our current methods are comparatively crude. A more fundamental question emerges if we consider that our role as medical advisors is to assess risk and benefit of any health strategy. While behavioral modification might lower risk of travelers’ diarrhea, the question is whether this really is considered a benefit in the traveler’s mind, if it means avoiding a substantial part of the local cuisine. Many travelers would argue that consumption of various kinds of local food is part of the travel adventure. Travelers seem quite content to accept a degree of risk of travelers’ diarrhea, especially when current self-treatment regimens appear highly effective. A potentially valuable approach to pursue through research is to develop simple field adapted methods to evaluate food for microbial contaminates prior to consumption. Increased knowledge of virulence factors and microbial products and improved screening methods should allow this in the future. Theoretically, travelers could rapidly check their food by dipstick before eating. Perhaps future research should investigate a paradigm shift: teaching the traveler how to eat risky foods while minimizing the consequences. Not only will the development of safer chemoprophylactic agents and more comprehensive vaccines have a role here, but host susceptibility will enter the equation as well. As we understand the genetics of host susceptibility better, we might be able to predict who has the “iron stomach” and can eat risky food more or less with impunity, and who should consider being vaccinated, changing their habits, including carrying out travel only to more hygienic environments or taking chemoprophylaxis, if they wish to minimize their chance of illness in a highrisk area. Research has already shown that there is a relationship between blood type and susceptibility to cholera, and persons with specific single nucleotide polymorphism in the promoter region of Interleukin 8 (an important mediator of intestinal inflammation) appear to be unusually susceptible to enteroaggregative E. coli diarrhea. With additional work looking at the genetics of cyclic nucleotides for enterotoxigenic E. coli (ETEC) or receptors for other pathogens, we should be able to identify the most susceptible hosts, which will aid in pretravel counseling. A concept that has not been studied, but which might be effective based on the success of singledose antibiotic treatment, is post-exposure prophylaxis with a single dose of an antibiotic after the traveler has ingested a particularly risky meal. This approach might be particularly popular with the traveler who by and large is savvy about avoiding risky foods, but who occasionally wants to be adventurous or is exposed to a set menu containing risky items that cannot easily be refused without offending a local host. In view of the multitude of pathogens associated with travelers’ diarrhea, it appears impossible to develop a single vaccine that offers protection against all of them. Consequently, the protective efficacy of vaccines against travelers’ diarrhea will be far lower than a vaccine that is directed against a single organism. A vaccine developed to protect against the most frequent pathogen, ETEC, unfortunately failed to show efficacy at various study destinations in East Africa and Latin America, largely due to

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lack of immunogenicity to the heat-stable enterotoxin (ST) and failure to include the important colonization factor antigens in the vaccine (unpublished data). An older oral cholera vaccine developed in Sweden, Dukoral®, has been shown to protect against heat-labile (LT) toxin-producing E. coli.5 If we assume a destination with a 60%6 incidence rate of travelers’ diarrhea, one quarter may be caused by ETEC,7 which corresponds to an overall 15% ETEC diarrhea incidence. If we continue to assume that 50% of the ETEC produce only heat-stable toxin, against which the vaccine is ineffective, we are left with a 7.5% incidence of ETEC pathogens against which the vaccine could be effective. Since Dukoral® showed a 60% protective efficacy against heat-labile toxin-producing E. coli, this vaccine would prevent approximately 5% of all travelers’ diarrhea. However, it would be beneficial to 3% of all travelers, which is more than any other vaccine. While this is only a first step, the hope is that a travelers’ diarrhea vaccine cocktail, directed to multiple pathogenic microbes, might offer better protective efficacy. Potential components of such a cocktail have been described in Chapter xxx. Taking the longer view, exciting prospects for cheap vaccines based on DNA technology are emerging. Theoretically, it might soon be possible to make enough cheap vaccine to immunize populations in developing countries against a number of pathogens. Since much of the risk to tourists arises from human transmission of fecal pathogens via hands or use of feces as fertilizer, an immunized population is less likely to shed pathogens in stool and less likely to contaminate their environment. Furthermore, genetic engineering already permits delivery of immunogenic microbial antigens in foodstuffs. The day may come when children are vaccinated by eating immune-enhancing bananas!8 This approach bypasses the necessity of a cold chain that limits the use of vaccines in many parts of the world. While most effort is being directed towards active immunization strategies, there still remains the possibility that passive immunity might be an appropriate future direction for immunologic control of travelers’ diarrhea. Bovine antibody, made by immunization of cows with microbial products, can be given orally to subjects during high-risk travel. Lastly, what about prophylactic medication? As mentioned in Chapter 16, only antimicrobials are importantly effective, and they are not recommended for all travelers. Considering the lack of compliance with antimalarials, compliance with regular intake of a prophylactic antidiarrheal might be even less satisfactory, although since eating is a daily habit for travelers, they might be reminded more easily by their daily behavior to take preventive medication. While the ideal agent would probably be a long-acting antimicrobial that could be ingested no more than weekly, no such agent currently exists. A more practical solution would be use of a nonabsorbable antibiotic with its reduced potential for adverse reactions. Such an agent would need to be taken daily since it would regularly be eliminated in the course of normal defecation. Other than safety, the other advantage of a poorly absorbed drug is that it would have value only in enteric infectious diseases, hence development of resistance would be less likely because of limited use, and the public health significance of resistance would be minimal. Regardless of whether an ideal prophylactic agent can be engineered, it will need to be very safe, since travelers’ diarrhea is basically a self-limiting disease for which self-treatment of the syndrome is already safe and effective.

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CONCLUSION We are pessimistic about the short-term prospects for environmental control or interruption of infectious agent transmission.9 In fact, as traveling hosts become even more susceptible, new pathogens might even emerge.10 We do not envision a public health breakthrough that would result in the disappearance of travelers’ diarrhea within the next few years. Nevertheless, the “Parkinsonian approach” of progressing with little steps should not be abandoned. Ideally, public health authorities in countries that host or generate tourists, the travel industry, and travel health professionals should work together to obtain funding to support a better public health infrastructure, primarily at places visited by large numbers of tourists. Perhaps the impact of expertise and capital devoted to public health regions of excellence at touristic destinations would spill over and improve health at the provincial and regional levels. Means should be searched for to have a greater impact with hygienic education programs. Until these long-term measures succeed, we will need to rely largely upon (self-)treatment and, to a lesser extent, prophylaxis options. In the longer term, we predict that breakthroughs in cheap vaccine production and novel delivery systems will await only the political will to pay for and use them to have a major worldwide impact. New insights into host susceptibility promise to allow practitioners to identify prospectively who might best benefit from vaccination or chemoprophylaxis.

REFERENCES 1. Victora CG, Bryce J, Fontaine O, Monasch R. Reducing deaths from diarrhoea through oral rehydration therapy. Bull WHO 2000;78(10):1246–55. 2. Vaidya SR, Chitambar SD, Arankalle VA. Polymerase chain reaction-based prevalence of hepatitis A, hepatitis E and TT viruses in sewage from an endemic area. J Hepatol 2002;37:131–6. 3. Tramarin A, Fabris P, Bishai D, et al. Waterborne infections in the era of bioterrorism. Lancet 2002;360:1699. 4. Cartwright RY, Chahed M. Foodborne diseases in travelers. World Health Stat Q 1997;50(1–2):102–10. 5. Peltola H, Siitonen A, Kyronseppa H, et al. Prevention of travelers’ diarrhea by oral B-subunit/whole-cell cholera vaccine. Lancet 1991;338(8778):1285–9. 6. Von Sonnenburg F, Tornieporth N, Waiyaki P, et al. Risk and aetiology of diarrhoea at various tourist destinations. Lancet 2000;356(9224);133–4. 7. Jiang Z, Greenberg D, Nataro JP, et al. Rate of occurrence and pathogenic effect of enteroaggregative Escherichia coli virulence factors in international travelers. J Clin Microbiol 2002;40(11):4185–90. 8. Richter L, Mason HS, Arntzen CJ. Transgenic plants created for oral immunization against diarrheal disease. J Travel Med 1996;3:52–6. 9. Kaferstein FK, Motarjemi Y, Bettcher DW. Food-borne disease control: a transnational challenge. Emerg Infect Dis 1997;3:503–10. 10. Morris JG, Morris P. Emergence of new pathogens as a function of changes in host susceptibility. Emerg Infect Dis 1997;3:435–41.

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INDEX In this index, page numbers followed by the letter “f ” designate figures; page numbers followed by the letter “t” designate tables; “See also” cross-references designate related topics or more detailed lists of subtopics.

Abscess Entamoeba infection, 51–52 hepatic, 143, 245 Absorption, of antibiotics vs. efficacy, 228 Acetorphan (racecadotril), 222–223 Acquired immunodeficiency syndrome (AIDS). See HIV/AIDS Acr membrane fusion proteins, 70t Activated charcoal, 161, 208, 223 Active immunity, 175, 176t Acute infectious diarrhea, 134t, 135–142, 136t Campylobacter jejuni, 138 cholera-like secretory syndrome, 135t, 135–137 Clostridium difficile, 140 Cryptosporidia spp, 141 dysentery syndrome, 135t, 137–138 enteric/typhoid fever, 139 enterohemorrhagic E. coli, 141 enterotoxigenic E. coli, 136 Isospora belli, 142 nontyphoid salmonellosis, 139 overlap syndrome, 138 salmonellosis, 139 shigellosis, 137–138 Vibrio cholerae, 135–136 Vibrio parahemolyticus, 141 viral gastroenteritis, 137 Yersinia enterocolitica, 140 Adenoviruses, enteric, 37–38, 39t Adherence, 77 localized, 78t, 79 Adsorbents, 205t, 206, 223 Adventure travel, as risk factor, 118 Adverse drug effects. See also Antimicrobial resistance; Drug interactions bismuth subsalicylate, 166t, 166–167 Aeromonas hydrophila, 85 Aeromonas spp. pathogenesis, 85 prevalence, 105 resistance in, 67 Africa compliance studies, 152–153 Entamoeba spp, 51–52 parasitic infections, 142 prevalence, 103 shigellosis, 17 Age. See also Children; Elderly immune response and, 185–186 as risk factor, 119, 127 Airline outbreaks, 269–274 epidemiology, 271t, 271–273, 272t importance and burden, 269–270 obstacles in detection, 270–271 Albendazole in giardiasis, 48

in Microsporidia, 53 in self-treatment failures, 207t Albendazole resistance, 264 Amebiasis, 52, 91–92 in pregnancy, 247 Ameboma, 52, 92 American Academy of Pediatrics, oral rehydration guidelines, 243 Amino acids, in self-treatment, 203 Ampicillin pharmacokinetics, 228 resistance, 62, 65 Ancyclostoma duodenale, 260 Antacids, as risk factor, 128 Antibiotic-associated diarrhea, 140 Anticholinergics, 205t, 221 Antiemetics, 208 Antigen-antibody response, 181, 185t Antigens, major histocompatibility complex (MHC), 181 Antimicrobial agents, 227–234. See also specific drugs absorption vs. efficacy, 228 with antimotility agents, 230 azithromycin, 230–231, 231t bacterial susceptibility and regional factors, 227–228 cephalosporins, 232 in chemoprophylaxis, 161–162 doxycycline, 231t, 233 nonspecific, 223–224 pharmacokinetics, 228 pivamdinicillin, 232 promising, 230–233, 231t, 232t rifaximin, 231, 231t self-administered, 206–207, 207t for special patients, 233–234 standard therapy in adults, 228–230, 229f, 232t TMP–SMX, 232 treatment failures, 234, 234t Antimicrobial resistance, 58–71 Aeromonas spp, 67 Campylobacter jejuni, 22, 211 Campylobacter spp, 65t, 65–66 chemoprophylaxis as promoting, 168–169 chlorine in rotaviruses, 86 dissemination of resistant bacteria, 59f, 60 enteroaggregative E. coli, 62 enteroinvasive E. coli, 62 enteropathogenic E. coli, 62 enterotoxigenic E. coli, 60–62 in expatriates, 263–264 factors favoring, 58–60, 59f genetic and bacterial bases, 67–70, 70t Plesiomonas shigelloides, 67 Salmonella spp, 66t, 66–67 Shigella spp, 63t, 63–64, 64t verotoxin-producing/enterohemorrhagic E. coli, 62–63 Vibrio cholerae, 67

318

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Yersinia enterocolitica, 67 Antimotility drugs. See also Opiates and specific drugs complications and, 143 in self-treatment, 204–205, 205t Antisecretory agents, 205t, 205–206, 222–223. See also Anticholinergics Arctic, trichinosis in, 53 Argentina, E. coli O157 in, 243 Arthritis, reactive, 140 Ascaris lumbricoides, 260 Asia, prevalence, 103 Aspirin, drug interactions, 163 Astroviruses, 35–37, 39t Ataxia-telangiectasia, 184 At-risk populations, 1–2, 2t, 164–165, 165t Atropine plus oxolinic acid, 221 Australia, rotavirus in, 105 Austria, C. jejuni in, 21 Avoidance measures practice of, 153–154 as risk reducer, 152–153 Azithromycin, 65, 169, 230–231, 231t in Campylobacter resistance, 211 in children, 233, 244 in pregnancy, 233, 247 in self-treatment, 207t single-dose, 231 Azithromycin resistance, 264 Aztreonam, 162 pharmacokinetics, 228 in pregnancy, 247 Bacteremia, silent, 189 Bacterial pathogens, 10–23 Campylobacter spp, 20–23 enteroaggregative E. coli, 13–16 enterotoxigenic E. coli, 11–13 pathogenesis, 79–86 in persistent diarrhea, 297 prevalence, 10t, 10–11 Salmonella spp (nontyphoidal), 19–20 Shigella spp, 17–18 susceptibility to antibiotics, 227–228 Bangladesh, 244 B cell deficiency, 184 B12 deficiency, 304 Bengal O139 V. cholerae, 67 Beta-lactam resistance, 68–69 Beverages, risk from, 151–152, 154t Bicozamycin, 162, 228 Bismuth subsalicylate adverse drug effects, 166t, 166–167 in chemoprophylaxis, 163, 169–170, 170t in nonspecific treatment, 222 in self-treatment, 205–206 with doxycyclines, 168 Bismuth subsalicylate resistance, 168 Blastocystis hominis, 89–90, 259 Blood testing, 303–304 Bovine anti-Cryptosporidium immunoglobulin, 50 Brainerd diarrhea, 234, 234t, 298 Brazil compliance studies, 153 multicenter study of elderly, 248 Breast-feeding, 191, 204

British National Formulary “best practice,” 200–202 British travelers compliance studies, 153 incidence rates, 116 Bruton’s disease, 184 Bulking agents, 205t, 206 Caliciviruses, 30t, 30–33, 39t, 105. See also specific organisms Calmodulin inhibitors, 161, 206 Campylobacter jejuni, 20–23 clinical manifestations, 138–139 fluoroquinolone-resistant, 22, 70t, 102, 104, 169, 231 Campylobacter spp, 20–23 geographic risk areas, 212t in HIV/AIDS, 250 immunity to, 125 in irritable bowel syndrome, 299 in military populations, 289–290 in Nepal, 126 overgrowth of, 167 pathogenesis, 84–85 resistance in, 65t, 65–66 Candidiasis, 166 Capillariasis, 53–54. See also Helminths Cardiac disease, 253–254 Caribbean, prevalence, 103 Cause. See Etiology CD proteins, 183 Cefixime in children, 244 in pregnancy, 247 in self-treatment, 207t Cefotaxime resistance, 69 Ceftadazine resistance, 69 Ceftriaxone, in pregnancy, 233 Celiac sprue, 300–301, 301f Cellulitis, 85 Central America accommodations and risk, 118 Entamoeba spp, 51–52 parasitic infections, 142 prevalence, 105 shigellosis, 17 Cephalosporinase, 68 Cephalosporin resistance, 66 Cephalosporins, 232 in children, 233 in pregnancy, 233 Charcoal, activated, 161, 208, 223 Chemoprophylaxis antimicrobial agents, 161–162 bismuth subsalicylate, 163 contraindications/disadvantages, 166t, 166–169 contraindications in pregnancy, 246–247 drugs used in, 160–164 history, 4–5 in HIV/AIDS, 251 indications for, 164–66, 165t Lactobacillus and other probiotics, 174 practical approach to, 169–170, 170f, 170t Children, 174, 240–245, 241t antimicrobials in, 233 astroviruses in, 36 diagnostic testing and therapy, 242–245 Southwest Nigerian study, 15

INDEX

epidemiology, 240–242 prevention, 245 typhoid fever in, 84 Chloramphenicol, 61, 212 Chloramphenicol resistance, 62, 69 Chlorine resistance, 151 in Norwalk virus, 86 Cholera-like secretory syndrome, 135t, 135–137 Cholera toxin, 186–188, 188t, 190 Chronic diarrhea, 294–309. See also Persistent diarrhea Ciprofloxacin, 61, 65. See also Fluoroquinolones in children, 244 pharmacokinetics, 228, 229 as preventative, 162 in self-treatment, 207t Ciprofloxacin resistance, 62, 169 Clarithromycin, 231 Climate. See also Seasonality etiologic role, 116 Clinical description, 2, 3t Clinical manifestations, 134–144 acute infectious diarrhea, 134t, 134–142. See also Acute infectious diarrhea astroviruses, 36 caliciviruses, 32 Campylobacter spp, 21 definitions, 134 enteric adenoviruses, 38 epidemiology, 134 in HIV/AIDS, 249–251 in pregnancy, 245–246 rotaviruses, 34 Clostridium difficile clinical manifestations, 140 in immunocompromised individuals, 253 overgrowth of, 167 in persistent diarrhea, 297 Colonization factor antigens (CFAs), 13 Colorectal malignancy, 301 Complement reactions, 177–179 Contraindications/disadvantages, of chemoprophylaxis, 166t, 166–169 Corticosteroids, 52–53 Costs, of chemoprophylaxis, 167–168 Cotrimoxazole, 263–264 Country of origin, as risk factor, 124–125 Cruise ship outbreaks, 85, 118, 277–285 epidemiology, 278t, 278–279 foodborne diseases, 278t, 278–279 regulatory control, 283–284 viral pathogens, 282–283 waterborne diseases, 279–282, 281t Cryptosporidium parvum pathogenesis, 87–88 in persistent diarrhea, 296 Cryptosporidium spp, 48–50 chlorine resistance, 151 clinical manifestations, 141–142 geographic risk areas, 212t halogenation and, 156 in HIV/AIDS, 250, 252 in immunocompromised individuals, 253 prevalence, 105 Cyclospora cayetanensis, 50–51, 89 ciprofloxacin in, 263

319

clinical manifestations, 142 geographic risk areas, 212t in HIV/AIDS, 250 in persistent diarrhea, 296 prevalence, 105, 106 seasonality, 264 Cyclospora spp, 50–51 halogenation and, 156 in immunocompromised individuals, 253 pathogenesis, 88–89 Cytokine production, enteroaggregative E. coli (EAEC), 15–16 Cytokines, 177 Defense hypothesis, 221 Definitions, 202 National Institutes of Health Consensus Conference, 112 World Health Organization (WHO), 113 Dengue fever, 163 Destination, as risk factor, 124–125 Diabetes mellitus, 252–253 Diagnosis astroviruses, 37 caliciviruses, 32–33 in children, 242–245 enteric adenoviruses, 38 rotaviruses, 34 Diarrhea chronic, 234, 234t. See also Persistent diarrhea classification, 202 persistent, 234, 234t, 294–305 Dientamoeba fragilis, 53, 296 in expatriates, 260 Diet, 218–219 as prophylactic measure, 148–156 as risk factor, 128 in self-treatment, 204 Dietary compliance, risk and, 119 Dietary education, 154t, 154–155 Difenoxin, in nonspecific treatment, 221 Diloxanide, in Entamoeba infection, 52 Diuretic therapy, 253–254 Doxycycline, 212, 231t, 233 in military populations, 290 pharmacokinetics, 228 in prevention, 4–5, 161–162 in self-treatment, 207t Drug interactions aspirin, 163 bismuth subsalicylate with tetracyclines, 168 Drug therapy. See also Antimicrobial agents and specific drugs history, 5 preventive, 160–170. See also Chemoprophylaxis Duration of antibiotic therapy, 230 Duration of stay, 117–118, 125–126, 169, 242 Dysentery stool, 137 Dysentery syndrome, 135t, 137–138, 141 in Entamoeba infection, 52 E. coli O157:H7, 62–63 Education, dietary, 154t, 154–155 Egypt, British military study, 3 Eimeria spp, 50 Elderly, 241t, 247–249 astroviruses in, 36

320

INDEX

clinical manifestations in, 247–248 epidemiology, 247–248 treatment and prevention, 248–249 ELISA in parasitic infections, 48 of rotaviruses, 34–35 Encephalitozoon intestinalis (Septata intestinalis), 52–53 Endolimax nana, 53 Endoscopic evaluation, 304–305 Entamoeba coli, 53 Entamoeba dispar, 51–52 Entamoeba histolytica, 51–52, 142–143, 263 geographic risk areas, 212t pathogenesis, 91–92 in persistent diarrhea, 295–296 in pregnancy, 245 prevalence, 105 Entamoeba spp, 51–52 Enteric adenoviruses, 37–38, 39t Enteroaggregative E. coli (EAEC), 13–16 epidemiology, 14 genetic factors, 129 immunity and cytokine production, 15–16 microbiology and identification, 14 pathogenesis, 14–15, 80f, 80–81, 81f prevalence, 103 resistance in, 62 Enterocytozoon bieneusi, 52–53 Enterohemorrhagic E. coli (EHEC), 141 Enteroinvasive E. coli (EIEC), 62 Enteropathogenic E. coli (EPEC) pathogenesis, 79–80 prevalence, 104 resistance in, 62 Enterotoxigenic E. coli (ETEC), 4, 11–13 airline outbreaks, 273 clinical manifestations, 136 epidemiology, 11 genetic factors, 129 immunity to, 5 microbiology and identification, 11–12 in Nepal, 126 pathogenesis, 12–13, 78t, 79 prevalence, 103 resistance in, 60–62 vaccine development, 13 vaccines, 187, 188t, 190 Environment, as risk factor, 118 Environmental control, 310–311 Environmental sources, 150 Enzyme-linked immunosorbent assay. See ELISA Epidemiology, 2–3, 3t, 112–121 airline outbreaks, 271t, 271–273, 272t astroviruses, 36 caliciviruses, 31–32 Campylobacter spp, 20–21 causes, 116 children, 240–242 cruise ship outbreaks, 278t, 278–279 definitions, 112–113 enteric adenoviruses, 38 enteroaggregative E. coli (EAEC), 14 enterotoxigenic E. coli (ETEC), 11 in HIV/AIDS, 249 impact and outcome, 119–120, 120f

incidence rates, 113F, 113–115, 114–115t outlook, 120 risk factors, 116–119, 117f, 117t rotaviruses, 33–34 Salmonella spp (nontyphoid), 19 Shigella spp, 17 Erythromycin in Campylobacter, 65, 211 in self-treatment, 207t Escherichia coli O157, in children, 243–244 Escherichia coli spp, resistance mechanisms, 70t Ethiopia, seasonality in, 264 Etiology, 3–4, 4t, 116 in expatriates, 259–260 Expatriates, 258–268 antibiotic resistance in, 263–264 diagnosis and treatment in, 261–263 etiology in, 259–260 helminths in, 260 immunity in, 264–265, 265f prevention in, 261 risk factors for, 261, 262t risk in, 258–259 seasonality and, 264 Fecal fat assessment, 304 Fever, 209 Filtration, 156 Fish and shellfish, 149–150 Fleroxacin pharmocokinetics, 229 in self-treatment, 207t Fluoroquinolone resistance, 22, 61, 62, 65–67, 70–71, 104, 211, 231 Fluoroquinolones adverse drug effects, 166t, 166–167 in chemoprophylaxis, 170t in children, 233, 244 contraindications in pregnancy, 247 geographic factors in susceptibility, 227–228 in military populations, 290 pharmocokinetics, 228–229 in pregnancy, 233 as preventative, 4, 162 in self-treatment, 211 in V. cholerae, 67 Folate deficiency, 304 Folic acid, 263 Foodborne diseases, cruise ship outbreaks, 278t, 278–279 Food sources, 3–4, 4t France, epidemiology of enteric viruses, 39t Fumagillin, in AIDS-associated microsporidiosis, 53 Furazolidone in giardiasis, 48 in self-treatment failures, 207t G. duodenalis. See Giardia lamblia G. intestinalis. See Giardia lamblia Gastric acid barrier, 176 immunodeficiency and, 252 Gastric acidity, as risk factor, 127–128 Gastrointestinal epithelium, immune functions, 177 Genetic bases, of resistance, 67–70, 70t Genetic factors, in susceptibility, 129 Geographical prevalence, 2–3, 3t

INDEX

Geographic risk areas, 113f, 113–114t, 212t Giardia lamblia, 47–48, 142, 264 in HIV/AIDS, 250 in Nepal, 126 pathogenesis, 90–91 in persistent diarrhea, 295 prevalence, 105, 106 waterborne, 150 Giardia spp. chlorine resistance, 150 geographic risk areas, 212t halogenation and, 156 Goa. See India Guatemala, 150 Peace Corps studies, 152, 154, 258, 259, 265 Guillain-Barré syndrome, 84–85 Gut-associated lymphoid tissue (GALT), 177, 181 Haiti Cyclospora spp, 50–51 pathogens present, 102t Halogenation, 155t, 155–156 Hazard Analysis Critical Control Point (HACCP) System, 279 H2 blockers, as risk factor, 128 Helminths, 52–54. See also Parasitic pathogens and specific organisms in expatriates, 260 Hemolytic uremic syndrome, 62, 63, 141, 243 HEP-2 adherence assay, 14 HEP-2 cell adherent E. coli. See Enteroaggregative E. coli Hepatic abscess, 143, 245 Hepatitis A, 149, 150, 246 Hepatitis E, 149, 246 High- and low-risk regions, 2–3, 3t, 113f, 113–114t, 124–125, 201, 212t Highly active antiretroviral therapy (HAART), 233–234 Hippurate hydrolysis test, 22 Historical perspective, 1–5 military populations, 286–287 viral pathogens, 29–30, 30t HIV/AIDS astroviruses and, 36 clinical manifestations, 249–251 Cryptosporidium in, 50 epidemiology, 249 highly active antiretroviral therapy (HAART), 233–234 microsporidiosis, 53 prevention in, 155, 251–252 as risk factor, 143, 164, 184 as Salmonella risk factor, 139 treatment in, 251 HLA-B27, 140 Host factors and susceptibility, 124–130 age and gender, 127 childhood exposure, 125 countries of origin and destination, 124–125 duration of stay, 125–126 food and beverage selection, 128 gastric acidity, 127–128 genetics, 129 immune status, 130 long-term consequences of infection, 129 travel style and accommodations, 126 Human immunodeficiency virus (HIV). See HIV/AIDS Hymenolepsis, 54

Hymenolepsis nana, 260 Hyperinfection, in strongyloidiasis, 53 Hypersensitivity, 177–178 cytotoxic (type II), 178 delayed (type IV), 178 immediate (type I), 177–178 immune complex (type III), 178 to sulfonamides, 232 Hyporesponsiveness (oral intolerance), 186 Ice, contaminated, 150 IgA, 177–192, 180f IgA deficiency, 184 IgG, 176, 178, 181–182, 186, 189–190 IgM, 181 IL-1-β, 16, 177 IL-2, 183 IL-4, 183 IL-6, 16, 177 IL-8, 16, 177 IL-10, 177, 186 IL-12 receptor deficiency, 84 Immune stimulating complexes (Iscoms), 186 Immunity, 17, 84, 125, 130, 175–184. See also Immunoprophylaxis active, 175, 176t astroviruses, 36 complement reactions, 177–179 enteric adenoviruses, 38 enteroaggregative E. coli (EAEC), 15–16 in expatriates, 264–265, 265f gastric acid barrier, 176 gastrointestinal epithelium, 177 hypersensitivity, 177–178 IgA, 177–192, 180f leukocyte and serum protein products, 179 malnutrition and, 191 passive, 175–176, 176t Peyer’s patches, 181–182, 182f rotaviruses, 34 T cell and B cell (cellular immunity), 182–183 T cell and B cell deficiency, 184 Immunodeficiency severe combined (SCID), 184 special features in, 252–254 Immunoglobulins. See also Ig entries bovine anti-Cryptosporidium, 50 Immunoprophylaxis, 184–191 enteric vaccines, 187–191, 188t enterotoxigenic E. coli (ETEC), 13 military populations, 290 oral and parenteral, 184–187 rotaviruses, 35 Immunosuppression. See also HIV/AIDS antimicrobials in, 233–234 astroviruses and, 36 as diarrhea risk factor, 143 as C. jejuni risk factor, 138 Immunosuppressive therapy, 253 Impact and outcome, 119–120, 120f Incidence rates, 113F, 113–115, 114–115t India, 13 compliance studies, 153 Entamoeba spp, 51–52 multicenter study of elderly, 248

321

322

INDEX

parasitic infections in, 142 pathogens present in, 102 prevalence, 104, 105 Indications, for chemoprophylaxis, 164–66, 165t Infection, long-term consequences as risk factor, 129 Inflammatory bowel disease (IBD), 92, 234, 253, 300 differential diagnosis, 52 In-flight outbreaks, 269–276. See also Airline outbreaks Integrions, 68 Interferon-g, 84 Interleukins. See IL entries Intracellular adhesion molecules (ICAMs), 183 inv genes, 83 Iodine exposure, 246 Iodochlorhydroxyquin, 4 Iran, incidence rates, 117t Irritable bowel syndrome, postinfectious, 129, 299–300 Isospora belli, 51 clinical manifestations, 142 in HIV/AIDS, 250, 252 in persistent diarrhea, 296–297 Isospora spp, 51 geographic risk areas, 212t Jamaica, 13 accommodations and risk, 118 compliance study, 152–153 incidence rates, 117f multicenter study of elderly, 248 pathogens present in, 102 prevalence, 103, 104 seasonality, 118–119 Kanamycin, 228 Katayama fever, 54 Kenya, 13 incidence rates, 117f pathogens present in, 102 resistance studies, 66t Lactase deficiency, in rotavirus infection, 86 Lactobacillus. See also Probiotics adverse drug effects, 167 Lactoferrin, 176t, 179 Latex agglutination assay, 30t, 34 Lebanon, incidence rates, 117t Levofloxacin pharmocokinetics, 229 in self-treatment, 207t Listeria monocytogenes, in pregnancy, 246 Liver abscess, 143, 245 Localized adherence, 78t, 79 Loperamide. See also Antimotility agents in nonspecific treatment, 221–222 Low- and high-risk regions, 113f, 113–114t, 124–125, 201, 212t Lymphocyte function-associated antigen (LFA), 183 Lysozyme, 179 Major histocompatibility complex (MHC) antigens, 181 Malabsorptive states, in persistent diarrhea, 298–299 Malaria, doxycycline prophylaxis, 161 Malignancy, colorectal, 301 Malnutrition, 191 M cells, 177

Mecillinam, 162, 168 Metronidazole in Entamoeba infection, 52 in parasitic infections, 48 in pregnancy, 247 in self-treatment failures, 207t Metronidazole resistance, 264 Mexico, 14, 148, 150–152 accommodations and risk, 118 Entamoeba spp, 51–52 incidence rates, 117t mecillinam prophylaxis and resistance, 168 parasitic infections, 142 prevalence, 102–105 resistance studies, 60, 69 seasonality, 169 student studies, 3, 3t, 4, 103, 153–154, 265 tourist studies, 15 waterborne pathogens, 151 Microbiology astroviruses, 35 caliciviruses, 30t, 30–31 Campylobacter spp, 21–22 enteric adenoviruses, 37 enteroaggregative E. coli (EAEC), 14 enterotoxigenic E. coli (ETEC), 11–12 rotaviruses, 33 Salmonella spp (nontyphoid), 19–20 Shigella spp, 17–18 Microsporidium, 52–53, 143, 296 in HIV/AIDS, 250 Military populations, 3, 286–291 history, 286–287 at home, 289 immunoprophylaxis, 290 in modern warfare, 287–288 in peacekeeping missions, 288–289 prevention, 289–290 treatment, 291 Mombasa. See Kenya Montego Bay. See Jamaica Morocco compliance studies, 152–153 prevalence, 103 Mucosal invasion, 77 Mycobacterium avium, 50, 251 Nalidixic acid, 61 in self-treatment, 207t, 211 National Institutes of Health Consensus Development Conference, 4–5, 166–167 definitions, 112 Necator americanus, 260 Neomycin, 161 Nepal accommodations and risk, 118 Blastocytis hominis in, 259–260 Cryptosporidium in, 260 Cyclospora spp in, 51 duration of stay study, 126, 169 enterotoxigenic E. coli in, 126 expatriates in, 258–260, 265 helminths in, 260 pathogens present, 102t prevalence, 105, 106

INDEX

seasonality in, 264 Netherlands, epidemiology of endemic viruses, 39t Neurologic toxicity, 84–85, 138, 245 Nigeria, 15, 58. See also Africa resistant bacteria in, 58, 60 Nitazoxanide in Cryptosporidium, 50 in Isospora, 51 in Giardia, 48 Nitozoxanide, in parasitic infections, 50 Nitromidazoles. See also specific agents in parasitic infections, 48 Noninfectious causes, 101–102 Nonpathogenic protozoans, 304t Nonspecific therapies, 216–224 in children, 244–245 diet, 218–219 empiric antibiotics, 223–224 laboratory investigations, 218–219 oral rehydration therapy, 219–220 symptomatic drugs, 220–223 Norfloxacin, 162 pharmocokinetics, 228–229 in self-treatment, 207t Norfloxacin resistance, 168, 169 Noroviruses. See Norwalk-like virus North America, length of stay, 125–126 Norwalk-like virus, 31 airline outbreaks, 273 clinical manifestaions, 137 cruise ship outbreaks, 282–283 pathogenesis, 86–87 NSP4 protein, 86 Ofloxacin, in self-treatment, 207t Omeprazole, as risk factor, 128 Opiates (synthetic), 205t in children, 244–245 in nonspecific treatment, 221–222 Salmonella bacteremia and, 143 Oral intolerance (hyporesponsiveness), 186 Oral rehydration therapy, 202–204, 219–220 in children, 242–243 in elderly, 248 in pregnancy, 246 Overgrowth syndromes, 167 Overlap syndrome, 138–142 Over-the-counter availability, resistance and, 59 OXA-1 lactamases, 68 Papua New Guinea, cyclosporiasis, 88–89 Parasitic pathogens, 47–54 Blastocystis hominis, 89–90 Cryptosporidium, 48–50, 87–88 Cyclospora, 50–51, 88–89 Dientamoeba fragilis, 53 Endolimax nana, 53 Entamoeba, 51–52 Entamoeba coli, 53 Entamoeba histolytica, 91–92 Giardia lamblia, 47–48, 90–91 helminths, 52–54 in HIV/AIDS, 250 Isospora, 51 Microsporidia, 52–53

pathogenesis, 87–92 in persistent diarrhea, 295–297 prevalence, 105 TMP–SMX in, 244 waterborne, 150 Paris, emergency room study, 248 Paromomycin in Cryptosporidium, 50 in Entamoeba infection, 52 in giardiasis, 48 Passive immunity, 175–176, 176t Pathogenesis, 76–92 Aeromonas, 85 Blastocystis hominis, 89–90 Campylobacter spp, 22–23, 84–85 Crytosporidium parvum, 87–88 Cyclospora, 88–89 Entamoeba histolytica, 91–92 enteroaggregative E. coli (EAEC), 14–15, 80f, 80–81, 81f enteropathogenic E. coli (EPEC), 79–80 enterotoxigenic E. coli (ETEC), 12–13, 78t, 79 general microbial, 77–79, 78t Giardia lamblia, 90–91 Norwalk virus, 86–87 Plesiomonas, 85–86 rotaviruses, 86 Salmonella spp, 20, 83–84 Shigella spp, 18, 81–82 Vibrio parahemolyticus, 85 Pathogens bacterial, 10–23. See also Bacterial pathogens and specific organisms geographic distribution, 101t, 102, 102t parasitic, 47–54. See also Parasitic pathogens and specific organisms relative importance, 100–106 viral, 29–39. See also Viral pathogens and specific organisms Peace Corps studies, 150, 152, 154, 258, 259, 265 cryptosporidiasis, 49 PeptoBismol. See Bismuth subsalicylate Persistent diarrhea, 294–309 clinical approach, 301–303 endoscopic evaluation, 304–305 laboratory work-up, 303–304 pathogenetic mechanisms, 294–301, 295t treatment, 305 Personal pharmacy, for self-treatment, 214t, 214–215 Peru Cyclospora spp, 50–51 pathogens present, 102t prevalence, 105 Peyer’s patches, 181–182, 182f, 186 Pharmacokinetics, of antimicrobial agents, 228 Phenothiazines, as antiemetics, 208 Phthalylsulfathiazole, 161 Pivamdinicillin, 232 Plaques (pseudomembranes), 140 Plesiomonas shigelloides, 85–86 pathogenesis, 85–86 prevalence, 105 resistance in, 67 Pneumocytis carinii, 250, 251 Polyacrylamide gel electrophoresis (PAGE), rotaviruses, 35 Polycarbophil, 161

323

324

INDEX

Polymerase chain reaction (PCR), 32 astroviruses, 37 enteric adenoviruses, 38 Postinfectious irritable bowel syndrome, 299–300 Postinfectious processes, in persistent diarrhea, 298–300 Potency, antimicrobial resistance and, 58 Pregnancy, 241t, 245–247 antimicrobials in, 233 clinical manifestations, 245–246 risk factor categories for drugs, 247 treatment and prevention, 246–247 Prevention, 148–197. See also Chemoprophylaxis; Immunoprophylaxis astroviruses, 37 caliciviruses, 33 Campylobacter spp, 23 chemoprophylaxis, 160–170 in children, 245 diet and risk education, 148–156 drug. See Chemoprophylaxis in elderly, 248–249 enteric adenoviruses, 38 for expatriates, 261 in HIV/AIDS, 251–252 immunity and immunoprophylaxis, 175–192 military populations, 289–290 in pregnancy, 246–247 rotaviruses, 35 Probiotics, 205t, 206 adverse drug effects, 167 Proton pump inhibitors, as risk factor, 127–128 Protozoal pathogens. See Parasitic pathogens and specific organisms Protozoans, nonpathogenic, 304t Pseudomembranes, in antibiotic-associated diarrhea, 140 Pyloroplasty, as risk factor, 127 Quinacrine in parasitic infections, 48 in self-treatment failures, 207t Quinolone-resistant Campylobacter jenuni, 102, 169 Quinolones. See Fluoroquinolones; Fluroquinolone resistance and specific drugs Racecadotril, 161, 206 Reactive arthritis, 140 Regulatory control, cruise ships, 283–284 Reiter’s syndrome, 85, 140 Repatriation, indications for, 213–214 Research directions, 310–315 environmental control, 310–311 risk reduction in host, 312–315 transmission, 311–312 Restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR), 47–48 Rice water stool, 135 Rifabutin, in cryptosporidiasis, 50 Rifaximin, 62, 64, 66, 162, 212, 231t, 231 in children, 232t, 233, 244 pharmacokinetics, 228 in pregnancy, 233, 247 in self-treatment, 207t Risk advice and education, 154t, 154–155 avoidance measures and, 152–153

from food, 148–150, 149t from water and other liquids, 151–152 Risk areas, 113f, 113–114t Risk factor categories, for drugs in pregnancy, 247 Risk factors, 116–119, 117f, 117t age, 119 country of origin, 116 destination, 116 duration of stay, 117–118 environment, 118 for expatriates, 261, 262t gender, 119 seasonality, 118–119 travel style and mode of accommodation, 118 Risk reduction, 311–315 Risks and disadvantages, of self-treatment, 208 Rotaviruses, 33–35, 39t chlorine in, 86 clinical manifestations, 137 pathogenesis, 86 prevalence, 105 vaccines, 188t, 190 Roxithromycin, 231 RT-PCR. See Polymerase chain reaction Russia Cryptosporidium, 87 parasitic infections, 49 pathogens present in, 102t prevalence, 105, 106 Saccharomyces boulardii, 164 Salmonella bacteremia, opiate therapy and, 143 Salmonella enteritidis, in irritable bowel syndrome, 299 Salmonella spp, 19–20, 70t airline outbreaks, 273 omeprazole as risk factor, 128 overgrowth of, 167 pathogenesis, 83–84 prevalence, 104 resistance in, 66t, 66–67 Salmonella typhi clinical manifestations, 139 vaccines, 187, 188t, 189 Salmonellosis clinical manifestations, 139 nontyphoid, 139 Sapovirus, 31 Schistosomiasis, 54 Seasonality, 103, 118–119, 169 expatriates and, 263–264 salmonellosis in United States, 19 Secretory IgA, 176t, 179–181, 180f Self-treatment, 200–216 activated charcoal, 208 algorithms, 211–213 antibiotics, 206–207, 207t antiemetics, 208 antimotility agents, 204–205, 205t British National Formulary “best practice,” 200–202 definitions, 202 diet, 204 for expatriates, 263 medical care or repatriation indications, 213–214 oral rehydration solutions, 202–204 personal pharmacy and equipment, 214t, 214–215

INDEX

risks and disadvantages, 208 signs and symptoms, 208–211, 209f, 210f symptomatic therapy, 204–206, 205t Septata intestinalis (Encephalitozoon intestinalis), 52–53 Serum IgA, 180, 180f, 189, 191 Severe combined immunodeficiency (SCID), 184 Shellfish, 149–150 Shiga toxin, 82, 104 Shigella boydii, 81 Shigella dysenteriae, 17, 81 prevalence, 104–105 resistance in, 64t Shigella flexneri, 17, 81 resistance in, 63, 63t Shigella sonnei, resistance in, 64t Shigella spp, 17–18 in Nepal, 126 pathogenesis, 81–82 prevalence, 104–105 resistance in, 63t, 63–64, 64t resistance mechanisms, 70t vaccines, 187, 188t, 189 Shigellosis in Bangladesh, 244 clinical manifestations, 137–138 doxycycline prophylaxis, 161 in HIV/AIDS, 250 Signs and symptoms, for self-treatment, 208–211, 209f, 210f Silent bacteremia, 189 South Africa, resistance studies, 69 South America, 13 Entamoeba sp, 51–52 parasitic infections in, 142 prevalence, 103, 105 SP-303, 222–223 Sprue celiac, 300–301, 301f tropical, 297–298 Sri Lanka, 152, 153 Stacked-brick adhesion pattern, 13, 14 Staphylococcus aureus, airline outbreaks, 273 Stevens-Johnson syndrome, 232 Stool dysentery, 137 rice water, 135 Stool studies, 303 Streptotriad (streptomycin/sulfa), 161 Strongyloides stercoralis, 260 in HIV/AIDS, 250–251 Strongyloidiasis, 53. See also Helminths Susceptibility, 124–133. See also Host factors and susceptibility Sweden C. jejuni in, 21 epidemiology of enteric viruses, 39t Switzerland, Zurich University Vaccination Center study, 242 Symptomatic therapy, in self-treatment, 204–206, 205t Taenia saginata, 260 Taenia solium, 260 T cell and B cell deficiency, 184 T cells cytoxic (TD8), 183 helper (CD4), 183 T cells and B cells (cellular immunity), 182–183 Teratogenicity, 246

325

Tetracycline resistance, 61t, 61–63, 63t, 64t, 65t, 66t, 67, 69, 70t Tetracyclines, 61–70 with bismuth subsalicylate, 168 contraindications in pregnancy, 247 with folic acid, 263 in V. cholerae, 67 Thailand, 21 antibiotic resistance, 231 expatriates in, 259 pathogens present in, 102, 102t prevalence, 106 resistance studies, 61t, 62t, 64t, 65t, 66t, 69 TMP–SMX resistance in, 244 Tinidazole, in self-treatment failures, 207t Tinnitus, 163 TMP–SMX, 232 in Campylobacter resistance, 211 in chemoprophylaxis, 170t in HIV/AIDS, 250 hypersensitivity to, 232 in Isospora 51 in pregnancy, 247 as preventative, 162 in self-treatment, 207t, 211 in V. cholerae, 67 vs. ciprofloxacin, 162 TMP–SMX resistance, 61t, 62, 63t, 64t, 66t, 67–69, 70t, 244 Toxin production, 77–79 Toxoplasmosis, in pregnancy, 246 Transformation, 68 Transforming growth factor-b, 177 Transmission, reduction of, 310–311 Transposons, 68 Travelers’ diarrhea, classification, 112–113 Travel style and mode of accommodation, as risk factors, 118 Treatment, 200–237. See also individual subtopics antimicrobials, 227–234 astroviruses, 37 caliciviruses, 33 Campylobacter spp, 22 in elderly, 248–249 enteric adenoviruses, 38 in expatriates, 261–263 in HIV/AIDS, 251 military populations, 291 nonspecific therapies, 217–225 of persistent diarrhea, 305 in pregnancy, 246–247 rotaviruses, 35 self-treatment principles, 200–215 Trichinosis, 53. See also Helminths Tricuris trichiura, 260 Trimethoprim–sulfamethoxazole. See TMP–SMX Tropical sprue, 295t, 297–298 Tumor necrosis factor, 16, 82, 88 Turkey, 248 Typhoid fever, 83–84. See also Salmonella clinical manifestations, 139 United Kingdom environmental risks, 118 epidemiology of enteric viruses, 39t incidence rates, 117t United States Cryptosporidium parvum outbreak, 105

326

INDEX

gentamicin-resistance gene, 60 salmonellosis in, 19 student studies, 125 Vibrio parahemolyticus, 85 Vaccination. See Immunoprophylaxis Vagotomy, as risk factor, 127 Venezuela, gentamicin-resistance gene, 60 Verotoxin-producing/enterohemorrhagic E. coli, resistance, 62–63 Verum, 161 Vessel Sanitation Program, 283–284 Vibrio cholerae, 12 airline outbreaks, 273 clinical manifestations, 135–136 prevalance, 105 resistance in, 67 vaccines, 188t, 189–190 Vibrio parahemolyticus clinical manifestations, 141 pathogenesis, 85 Vibrio vulnificus, 85 Vietnam, resistance studies, 61t, 63t, 64t, 65t, 66t, 69 Viral pathogens, 29–39 astroviruses, 35–37, 39t caliciviruses, 30t, 30–33, 39t clinical manifestations, 137 cruise ship outbreaks, 282–283 enteric adenoviruses, 37–38, 39t history, 29–30, 30t importance compared, 38–40, 39t pathogenesis, 86–87 prevalence, 105

rotaviruses, 33–35, 39t, 188t Virulence factors enteroaggregative E. coli (EAEC), 14–15 enterotoxigenic E. coli (ETEC), 12–13 Salmonella spp (nontyphoid), 20 Shigella spp, 18 vp4 protein, 86 Water risk from, 118, 151–152, 154t safety precautions, 155t, 155–156 Waterborne diseases, cruise ship outbreaks, 279–282, 281t Water Safety Plans, 281–282 WHO Guide to Ship Sanitation, 284 Wilderness-acquired diarrhea (WAD), 118 Wiskott-Aldrich syndrome, 184 World Health Organization (WHO) atropine policy, 221 definitions, 113 oral rehydration guidelines, 243 oral rehydration solution, 203 D-Xylose absorption test, 263, 304 Yersinia enterocolitica, 12 clinical manifestations, 140 prevalance, 105 resistance in, 67 Zaldaride maleate, 161, 205t, 206, 222–223 Zurich University Vaccination Center study, 242