Allergy, Asthma, and Immune Deficiency (Primary Care Clinics in Office Practice, Volume 35-01)

ALLERGY, ASTHMA, AND IMMUNE DEFICIENCY ALLERGY, ASTHMA, AND IMMUNE DEFICIENCY ALLERGY, ASTHMA, AND IMMUNE DEFICIENC...

Author: Rohit Katial | Guest Editor

13 downloads 1251 Views 3MB Size Report

This content was uploaded by our users and we assume good faith they have the permission to share this book. If you own the copyright to this book and it is wrongfully on our website, we offer a simple DMCA procedure to remove your content from our site. Start by pressing the button below!

Report copyright / DMCA form

DOWNLOAD PDF

ALLERGY, ASTHMA, AND IMMUNE DEFICIENCY

ALLERGY, ASTHMA, AND IMMUNE DEFICIENCY

ALLERGY, ASTHMA, AND IMMUNE DEFICIENCY

ALLERGY, ASTHMA, AND IMMUNE DEFICIENCY

CONTENTS

Preface Rohit Katial Allergic Rhinitis Richard W. Weber

xi

1

Allergic rhinitis is common malady with a significant impact on quality of life. It can affect 25% to 35% of people, depending on the population studied. Costs for physicians’ visits and medications, and indirect costs of missed school and work and lost productivity, are estimated to be $2 billion annually in the United States. Pharmacotherapy is the most used therapeutic modality. Topical corticosteroids are the preferred method of treatment for seasonal and perennial allergic rhinitis. Antihistamines and antileukotrienes may be beneficial add-ons to topical steroids. Allergen avoidance is recommended, but may be difficult. Allergen immunotherapy is effective and should be considered with poor response to pharmacotherapy and avoidance.

The Diagnosis and Management of Acute and Chronic Sinusitis Roxanne S. Leung and Rohit Katial

11

Both acute and chronic sinusitis are common diseases associated with significant morbidity and consumption of health care dollars. Acute sinusitis is caused by an infectious process and can often be difficult to distinguish from a viral upper respiratory infection, as signs, symptoms, and even the results of most diagnostic tests overlap. In contrast, chronic sinusitis is an inflammatory disease and, contrary to common practice, long term antibiotics are likely not useful. This article reviews the diagnosis and management of both acute and chronic sinusitis and includes discussion of the

VOLUME 35

Æ NUMBER 1 Æ MARCH 2008

v

prevalence of disease, our current understanding of disease pathogenesis, diagnosis, and contemporary treatment.

Pediatric Asthma Lora J. Stewart

25

Asthma is one of the most common chronic illnesses affecting children. However, distinguishing true asthma from recurrent respiratory symptoms is often a challenge for primary care providers. Many risk factors can help predict persistent disease, including presence of allergies or eczema, family history, symptoms apart from obvious infection, and the severity of previous episodes. Because neither cure nor prevention is currently a viable option, the treatment is aimed at minimizing symptoms and maximizing asthma control.

Asthma Overview Ronald Balkissoon

41

This article presents our current understanding of the biological heterogeneity of asthma and reviews some of the key features of the latest proposed recommendations of the National Asthma Education and Prevention Program Guidelines. The diagnosis of asthma is based on such clinical features as variable airflow obstruction that is partially if not fully reversible and airway hyperresponsiveness that predisposes to episodic bronchospasm following exposure to a variety of triggers. The underlying inflammation and airway biology of asthma is heterogeneous and is part of the explanation for the variable response to therapy. New biologics that help to characterize patients according to their underlying biology will aid in making better choices for treatment. New asthma guidelines emphasize the importance of regular monitoring.

Making the Diagnosis of Occupational Asthma: When to Suspect It and What to Do Craig S. Glazer and Karin Pacheco

61

Although most adult patients seen by a clinician are employed, medical school curricula and residency training rarely cover occupational exposures and resultant diseases, even common ones that are encountered in a typical medical practice. This primer on occupational asthma is intended for the primary care clinician to provide the essential tools to diagnose and treat airways disease in the workplace. Using a case vignette format, we review the basic approach to suspecting and establishing a diagnosis of occupational asthma and address the thornier question of what to do about it. After reviewing this primer, the reader will be able to routinely include occupational asthma as part of the differential diagnoses in the adult patient with new or worsened asthma. vi

CONTENTS

Vocal Cord Dysfunction/Paradoxical Vocal Fold Motion Marcy Hicks, Susan M. Brugman, and Rohit Katial

81

Vocal cord dysfunction, also called paradoxical vocal cord motion, is a common mimicker of asthma, allergies, and severe upper airways obstruction with consequent misdiagnosis and mismanagement, and is frequently overlooked. Unfortunately, there is no unified understanding of this disorder, nor is there any consensus on its evaluation, etiology, or treatment. This article reviews the literature regarding the pathophysiology, causes, diagnosis, and treatment for this common disorder.

Atopic Dermatitis Peck Y. Ong and Mark Boguniewicz

105

Atopic dermatitis is a complex, chronic inflammatory skin disease. Affected individuals, particularly those with moderate to severe disease, often suffer from significant morbidity, such as sleep loss, skin infections, and school or work disruption. Treatment for these patients can be especially challenging. Restoring skin barrier function, eliminating allergic and nonallergic triggers, and properly using anti-inflammatory and antimicrobial medications are all important components of a comprehensive treatment plan. Wet wraps and systemic immunosuppressants are alternative treatments for patients with severe, refractory atopic dermatitis.

Food Allergy: Diagnosis and Management Dan Atkins

119

A rise in food allergy, accompanied by heightened public awareness, guarantees that clinicians will increasingly be consulted to accurately distinguish adverse reactions to foods from other disorders. The potential impact of inaccurately labeling a food as a cause of symptoms includes delaying appropriate treatment for another disorder or needlessly removing a food from the diet, with potential adverse nutritional and social consequences. When symptoms are triggered by food ingestion, determining the type of adverse reaction to the food responsible is important because of the implications regarding the mechanism involved, reproducibility, and the prognosis.

Urticaria Sheila M. Amar and Stephen C. Dreskin

141

Urticaria with or without angioedema is frequently encountered in primary care medicine. Although many patients and physicians think that urticaria is evidence of an IgE-mediated allergic reaction, often the etiology of urticaria is unknown. This uncertainty frequently results in patients enduring unnecessary lifestyle changes or extensive testing. In more persistent cases, patients achieve control of their disease only with the use of more toxic

CONTENTS

vii

medications, such as corticosteroids, and this can lead to a range of systemic complications. Acute urticaria is typically due to a hypersensitivity reaction while chronic urticaria has a more complex pathogenesis. Antihistamines remain the mainstay of symptomatic treatment for both.

Immunodeficiency Overview Yoshikazu Morimoto and John M. Routes

159

Primary immunodeficiencies are challenging in primary care settings, where clinicians often encounter patients with a history of recurrent infection. With advances in diagnostics and therapeutics, these disorders have been better understood and more successfully treated, yet their prognosis depends on early recognition of the disorder and initiation of the appropriate management. Because the primary care physician is most often the first physician encountered by a patient with immunodeficiency, primary care practitioners should be familiar with these rare but important disorders. This article provides an overview of the diagnosis and treatment of primary immunodeficiencies and two of the most common primary immunodeficiencies: common variable immunodeficiency and selective IgA deficiency.

Index

viii

175

CONTENTS

FORTHCOMING ISSUES June 2008 Kidney Diseases and Hypertension, Part I Edgar V. Lerma, MD, Guest Editor September 2008 Kidney Diseases and Hypertension, Part II Edgar V. Lerma, MD, Guest Editor December 2008 Wellness and Prevention Roger Zoorob, MD, MPH, and Vincent Morelli, MD, Guest Editors

RECENT ISSUES December 2007 Diabetes Management Jeff Unger, MD, Guest Editor September 2007 Mental Health Ralph A. Gillies, PhD, and J. Sloan Manning, MD, Guest Editors June 2007 Behavioral Pediatrics Donald E. Greydanus, MD, Helen D. Pratt, PhD, and Dilip R. Patel, MD, Guest Editors

THE CLINICS ARE NOW AVAILABLE ONLINE! Access your subscription at: http://www.theclinics.com

Prim Care Clin Office Pract 35 (2008) xi–xii

Preface

Rohit Katial, MD, FAAAAI, FACP Guest Editor

The discipline of allergy and immunology continues to grow, and the understanding of disease pathophysiology continues to expand as the scientiﬁc underpinnings of atopic diseases broaden. Allergic rhinitis (AR) is one of the most common chronic diseases signiﬁcantly aﬀecting the quality of life of 10% to 20% of the population. It also represents a prototypical immunoglobulin E-mediated disease that served as the framework for understanding the consequences of mast cell degranulation and its clinical impact. This eventually led the way for drug development that targets the complex pathways involved in cellular signaling and mediator release. The role of IgE has also been critical in understanding and subsequently managing atopic dermatitis (AD). This issue of Primary Care: Clinics in Oﬃce Practice covers the latest understanding of both AR and AD. One of the most important aspects of asthma diagnosis and management is a broad diﬀerential diagnosis and an understanding of the most current management guidelines. In 1991 the National Institutes of Health published the ﬁrst asthma guidelines, and, over the following 17 years, guideline updates have incorporated the most recent evidence and experience as it has become available. We currently await the most recent update to the asthma guidelines, which will be a complete rewrite. Some of the key changes are discussed in the adult and pediatric asthma articles in this issue. Additionally, this issue addresses vocal cord dysfunction, which is often misdiagnosed as asthma, as well as the role of occupational triggers in asthma.

0095-4543/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2007.10.001 primarycare.theclinics.com

xii

PREFACE

Finally, this issue includes other common allergic disorders: urticaria, food allergy, and acute versus chronic sinusitis. Sinusitis has been quite misunderstood and, in some cases, has led to the overuse of antibiotics. The sinusitis article focuses on the infectious nature of acute sinus disease while highlighting chronic hyperplastic sinus disease, an eosinophilic inﬂammatory disease or ‘‘asthma of the sinuses.’’ The last topic that this issue covers is primary immunodeﬁciency (PID). Although rare, PID has often been referred to as ‘‘experiments of nature,’’ and recently we have improved our understanding of the underlying mechanisms behind these diseases. This comprehensive review details how to recognize, diagnose, and treat PID. Overall, I hope this issue not only serves as a foundation for understanding common allergic and immunologic diseases seen in primary care practices but also presents the latest information. Rohit Katial, MD, FAAAAI, FACP National Jewish Medical and Research Center University of Colorado Health Sciences Center 1400 Jackson Street Denver, CO 80206, USA E-mail address: [email protected]

Prim Care Clin Office Pract 35 (2008) 1–10

Allergic Rhinitis Richard W. Weber, MD* National Jewish Medical and Research Center, The University of Colorado Health Sciences Center, 1400 Jackson Street, Room J326, Denver, CO 80206, USA

Allergic rhinitis is the most prevalent of the atopic disorders, aﬀecting 25% to 35% of persons, depending on the population studied. Atopy is an inherited disposition manifested by any, or all, of allergic rhinitis, asthma, or atopic eczema [1]. It is closely, if not invariably, linked to the generation of greater than normal amounts of speciﬁc allergic antibody, IgE. The atopic diseases have become more prevalent over the past century, although the exact reason for this increase is not clear. Considered by nonsuﬀerers to be a trivial disease, allergic rhinitis delivers a signiﬁcant personal impact on quality of life. It is responsible for an enormous economic burden because of the direct medical costs for physician visits and medication, and the indirect costs of missed work and school and lost productivity [2–4]. This cost in the United States has recently been estimated at more than 2 billion dollars annually and is now presumably even greater [5].

Pathogenesis IgE is a mucosal antibody, being produced by plasma cells beneath the mucosal surfaces of the eyes, the upper and lower airways, and the gut, similar to the distribution of IgA. IgE binds to speciﬁc, high-aﬃnity receptors on basophils and mast cells, designated FceRI. Bridging by allergen of two speciﬁc IgE molecules on the cell surface is suﬃcient to cause activation of these cells. The release of vasoactive mediators such as histamine, tryptase, leukotrienes, and prostaglandins, and several chemokines and cytokines, follows [6]. Symptoms of the immediate allergic (early-phase) reaction, including sneezing, itching, rhinorrhea, and nasal congestion, are due to the

* National Jewish Medical and Research Center, 1400 Jackson Street, Room J326, Denver, CO 80206. E-mail address: [email protected] 0095-4543/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2007.09.001 primarycare.theclinics.com

2

WEBER

former mediators. Chemotactic factors result in the recruitment of inﬂammatory cells such as basophils, eosinophils, and polymorphonuclear leukocytes. The inﬂux of these cells is accompanied by a fresh release of vasoactive substances, culminating in the delayed (late-phase) reaction with a recrudescence of symptoms. With a single allergen exposure, the early and late phases are easily discernible, the latter occurring 4 to 6 hours after the initial reaction [7]. With persistent exposure, such as with indoor allergens like dust mite or animal dander, the late-phase inﬂammatory process is ongoing, resulting in chronic symptoms. Well described with outdoor allergens such as pollens is the ‘‘priming eﬀect,’’ the persistence of inﬂammation from prior exposure resulting in greater sensitivity to further exposures, with lesser pollen amounts resulting in greater symptoms [8]. Increased IgE production is related to a shift of helper T cell cytokine release to a Th2 proﬁle. Three central cytokines to this allergic phenotype are IL-4, IL-13, and IL-5. The ﬁrst two cytokines cause isotype switch in B-cells to IgE production. IL-5 is crucial for eosinophil activation and persistence [6]. Once this shift to a Th2 proﬁle occurs, it tends toward self-perpetuation. Atopic persons may be genetically predisposed to the Th2 phenotype. Allergic rhinitis sensitization is almost always due to airborne, inhalant factors. These aeroallergens may emanate from indoor or outdoor sources and may be perennial, relatively constant, or have seasonal peaks. Outdoor sources are almost invariably of plant or fungal origin, usually pollen grains or mold spores. With frequently seen seasonal peaks, timing often aids in diagnosing the airborne culprit. Tree pollens pollinate in the winter into the early spring, although some trees shed pollen in the fall. Grasses generally pollinate from May into July, but have longer seasons in the southern states, and pollination is year-round in tropical or subtropical areas such as Hawaii and southern Florida. Some weeds overlap with the grasses, whereas most pollinate from July into the fall [9]. Indoor aeroallergens are more likely of animal origin: dust mite or cockroach emanations, or animal dander. Less likely, but possible, are symptoms due to mold spores, especially with water damage or high humidity. Although exposures are perennial in nature, these also have seasonal peaks: dust mite in late summer to early fall, cat and dog dander in late winter, and cockroach in summer [10]. A recent study has demonstrated that the allergens from dog and cat dander can be found in the dust of essentially all homes, whether pets are present or not [11].

Comorbid conditions and diﬀerential diagnosis Vasomotor rhinitis, better referred to as irritant rhinitis, is as frequent as allergic rhinitis, with nasal symptoms driven by perturbations in the environment. The cause of the increased susceptibility to irritants is not fully

ALLERGIC RHINITIS

3

understood, although the resultant release of mediators is similar to that seen with allergic rhinitis [12]. A variation of irritant rhinitis is ‘‘gustatory rhinitis,’’ where the eating act triggers rhinorrhea. Viral infection (upper respiratory infection) is perhaps the most common cause of nasal symptoms; other infectious agents are distinctly less common. Hormonal factors such as hypothyroidism and pregnancy may lead to worsened nasal congestion. Medication-induced nasal congestion was commonly seen with older antihypertensive agents, such as reserpine, and is certainly seen with topical alpha-adrenergic agonist overuse. Intolerance to aspirin and nonsteroidal anti-inﬂammatory drugs may manifest as either asthma or chronic sinusitis, or both. Vasculitides such as Wegener’s granulomatosis can present with chronic sinusitis. A World Health Organization expert panel published a position statement on allergic rhinitis and its impact on asthma (ARIA) [13]. Its scope is worldwide and it discusses resources with a global perspective. One of the major points is the frequent concordance of allergic rhinitis and asthma. It is crucial to suspect rhinitis and inﬂammation of the upper airway as an aggravator of asthma, and likewise, the lower airway should be evaluated in patients who have rhinitis. In keeping with the phraseology recommended by National Asthma Education and Prevention Program and Global Initiative for Asthma guidelines for the management of asthma, the position statement also suggested that ‘‘seasonal’’ and ‘‘perennial’’ be replaced by ‘‘intermittent’’ and ‘‘persistent.’’

Evaluation The evaluation of rhinitis is greatly advanced by a careful directed history: presence of itching and sneezing, severity, seasonality, progression of symptoms, identiﬁable triggers, occupational exposures, alleviating factors, and medication usage. Family history of atopic disease is helpful. Also important is the impact of disease and medication on daily activity. The presence of comorbid conditions is suggested by a history of headache, loss of smell and taste, purulent discharge, cough, chest tightness or wheezing, snoring, and sleep disturbance. Physical examination of the head may reveal characteristic ﬁndings. Dark discoloration under the eyes, or ‘‘allergic shiners,’’ is due to venous engorgement, and Dennie’s signs are folds under the eyes due to edema. The transverse crease across the bridge of the nose is seen in children who chronically push their palms upward under their noses in response to itching or rhinorrhea. The turbinates appearing edematous with a bluish mother-of-pearl hue was felt to be pathognomonic but may be seen in nonallergic rhinitis also. Likewise, turbinates may be engorged and erythematous. Cobble-stoning from lymphoid hyperplasia may be seen on the posterior pharynx. Chronic mouth breathing from nasal obstruction can cause the ‘‘allergic facies’’ in

4

WEBER

the developing facial features of children: open mouth with receding chin and overbite, elongation of the face, and arching of the hard palate [14]. Diagnosis, frequently determined by the appropriate history and ﬁndings (Box 1), is supported by the ﬁnding of speciﬁc IgE antibodies against airborne agents. Percutaneous (prick or puncture) skin testing remains the most speciﬁc and cost-eﬀective diagnostic modality, although improved cap-radioallergosorbent test (Cap-RAST) testing is approaching similar sensitivity. Intradermal skin testing is more sensitive but introduces a higher false-positive rate and is not felt to add any diagnostic value to prick testing of potent pollen extracts [15]. Intradermal testing with less potent extracts may, however, have a role.

Box 1. Diagnosis of allergic rhinitis Appropriate history of exacerbating factors Perennial or seasonal symptoms, with timing correlated to specific pollen or mold spore exposure Symptom triggering with identifiable agents such as animals Familial history of asthma, allergic rhinitis, or atopic eczema Medication and medical history Oral aggravators such as acetylsalicylic acid, nonsteroidal anti-inflammatory drugs, anti-hypertensive agents Topical aggravators such as alpha agonists Hypothyroidism Pregnancy Physical findings Rhinorrhea, clear or mucoid discharge Erythema of nasal mucosa Nasal congestion ‘‘Allergic facies’’ Collaborative findings Immediate hypersensitivity skin testing Serum specific IgE Comorbid conditions Sinusitis Nasal polyposis Asthma Eustachian tube dysfunction Serous otitis media

ALLERGIC RHINITIS

5

Pharmacotherapy Although perhaps not the most eﬀective mode of treatment, pharmacotherapy is the most used for allergic rhinitis (Box 2). H1 antihistamines have the largest market share of rhinitis remedies, although again, they are not the most eﬃcient. First generation oral H1 receptor antagonists have been available for a number of years, and many are over-the counter preparations. Typical beneﬁts are decreased sneezing, itching, and rhinorrhea, but oral antihistamines are notoriously ineﬀectual for nasal congestion. Side eﬀects include sedation and excessive dryness form anticholinergic eﬀects. Second-generation antihistamines have the advantage of less anticholinergic eﬀects and less sedation. Loratadine is available as an over-the-counter formulation, whereas others, such as fexofenadine,

Box 2. Treatment of allergic rhinitis Allergen avoidance Pharmacotherapy Topical corticosteroids as first-line monotherapy Mometasone Fluticasone Budesonide Triamcinolone Flunisolide Oral antihistamines used as add-on therapy or alone for mild symptoms Fexofenadine (second generation) Cetirizine (second generation) Loratadine (second generation) Hydroxyzine Chlorpheniramine Diphenhydramine Topical antihistamine (azelastine) Oral leukotriene modifiers (montelukast) as add-on only Oral decongestants Pseudoephedrine Phenylephrine Topical cromolyn Nasal saline irrigation Allergen immunotherapy Subcutaneous Sublingual or oral

6

WEBER

still require prescriptions. Cetirizine, the active metabolite of hydroxyzine, may be sedating and is typically dosed at bedtime. Topical azelastine is available as a nasal spray and as an ophthalmic preparation. In addition to typical antihistaminic eﬀects, it is modestly anti-inﬂammatory and improves nasal congestion, presumably through inhibition of intercellular adhesion molecule-1 (ICAM-1), lipoxygenase, and leukotriene C4 synthase [16]. It can cause sedation. Several topical ophthalmic antihistamine preparations are available for associated allergic conjunctivitis. The leukotriene receptor antagonists zaﬁrlukast and montelukast were Food and Drug Administration approved for asthma initially, but the latter has been approved for treatment of allergic rhinitis therapy also. A recent systematic review and meta-analysis, however, has shown this agent to be only modestly better than placebo, as eﬀective as antihistamines, and inferior to nasal corticosteroids in improving symptoms and quality of life in patients who have seasonal allergic rhinitis [17]. The use of leukotriene modiﬁers for treatment of uncomplicated allergic rhinitis is therefore of little beneﬁt. Using montelukast or zaﬁrlukast with zileuton in the treatment of rhinitis complicated by sinusitis with polyposis may have some rationale, although evidence-based data are still missing. Topical glucocorticoids are the most eﬀective pharmacotherapy for allergic rhinitis. Topical corticosteroids have been shown to decrease nasal Th2 cytokines, IgE, and eosinophils while having little impact on Th1 cytokines [18]. A meta-analysis has shown superiority over antihistamines in 15 of 16 controlled trials that evaluated symptoms such as rhinorrhea, congestion, and sneezing [19]. Another meta-analysis of nine studies again showed superiority of intranasal corticosteroids over topical antihistamines for nasal symptoms, and no diﬀerence for ocular symptoms [20]. Even if used on an as-needed basis only, nasal corticosteroids are superior to oral antihistamines for symptom relief [21]. In a short-term study, the combination of montelukast and cetirizine each once daily was shown to be as eﬀective as once-daily intranasal mometasone in improving nasal peak ﬂow and total nasal symptoms [22]. In contrast, other studies have shown superiority of intranasal corticosteroids over combination antihistamine and leukotriene modiﬁer therapy [23]. Although steroid potency based on receptor aﬃnity is important in the management of asthma, the dose response curves for most topical nasal corticosteroids is such that all preparations appear to be equally eﬀective. Choice is therefore predicated on patient preference, which is usually affected by the eﬀects of expedients. The most common side eﬀect is epistaxis. Septal perforation is reported, presumably due to topical vasoconstriction, but is exceedingly uncommon, and appears to be adverted by proper administration technique. Concern about systemic side eﬀects is generally not warranted. Fluticasone and mometasone have very low levels of systemic bioavailability by way of the nasal route, whereas those of budesonide, triamcinolone, beclomethasone, and ﬂunisolide are higher. Even so, reports of

ALLERGIC RHINITIS

7

adverse eﬀects are not common with nasal preparations [24]. For severe symptoms, oral steroids such as prednisone are sometimes used for very short periods to achieve quick improvement. The well-known complications of long-term oral therapy are not justiﬁable in the management of rhinitis. In some areas of the United States, intramuscular corticosteroids are considered the standard of care for severe symptoms induced by large exposures such as seen with mountain cedar fever. This practice is of debatable wisdom. Ipratropium bromide as a topical preparation is useful for rhinitis associated with more profuse rhinorrhea. It may be beneﬁcial in allergic rhinitis but has a larger role in nonallergic irritant rhinitis such as cold air–induced gustatory rhinitis, and the profuse rhinorrhea associated with viral upper respiratory infections. Ipratropium has no eﬀect on nasal congestion [25]. Methscopolamine is an oral quaternary ammonium anticholinergic used as a drying agent and found primarily in combination with antihistamines such as chlorpheniramine and decongestants such as phenylephrine. Cromolyn, a mast cell stabilizer, can be used as a topical nasal spray for allergic rhinitis but suﬀers from the need to use every 4 hours for optimal eﬃcacy. The use of decongestants is problematic; data on oral eﬃcacy are wanting, and the beneﬁt may be overridden by side eﬀects. The potential for signiﬁcant adverse reactions with overusage resulted in removal of phenylpropanolamine from the American market. Similar problems are arising with pseudoephedrine. Phenylephrine is most often found in combination products. Overusage of topical decongestants like neosynephrine and oxymetazoline results in well-described rebound nasal congestion. The use of saline nasal washes is highly recommended. A commercially available clear squeeze bottle with packets of sodium chloride and baking soda is eﬀective. This modality is especially useful in patients who have complicating chronic sinusitis but is also helpful for perennial allergic rhinitis. Considering ARIA and the one-airway concept, two issues arise. One is whether treatment of the upper airway truly impacts on the control of lower airway disease, speciﬁcally asthma. That this is so is suggested by reports such as that of Corren and colleagues [26], showing decreased emergency department treatment and hospitalization in asthmatic patients treated concomitantly for allergic rhinitis. The other issue is that economy of treatment would suggest using one agent to treat both the upper and lower airways; however, current oral agents such as montelukast are inadequate to the task [27,28]. Avoidance and environmental controls Although avoidance of outside aeroallergens frequently can be only achieved by remaining indoors, avoidance of indoor allergens is more amenable to intervention. Pets can be removed from the home, although levels of allergenic proteins may take months to subside [29]. And many pet owners choose not to remove an allergenic animal. The value of allergen-impermeable bedding linens is either supported or disavowed by

8

WEBER

contradictory studies [30,31]. Control of indoor humidity may provide the best avenue for dust mite and mold abatement. Cockroach control is very diﬃcult to achieve, and sublethal boric acid treatment may actually increase the release of cockroach allergen [32]. Allergen immunotherapy Allergen immunotherapy, administered by subcutaneous route, has been shown by double-blind placebo-controlled studies to be eﬀective in the treatment of allergic rhinoconjunctivitis. Extracts used include pollens such as short ragweed, timothy grass, other northern grasses, mountain cedar, and pellitory; fungi such as Alternaria and Cladosporium; house dust mites; and cat and dog dander [33,34]. Immunologic changes include induction of speciﬁc IgG, blunting of speciﬁc IgE, decreased end-organ responsiveness, decreased recruitment of eﬀector cells, shift from Th2 to Th1 cytokine proﬁle, and induction of T regulatory cells. The sublingual or oral route of administration has been studied extensively in Europe, requires a high dose of allergen, and appears to have an excellent safety proﬁle, but is less eﬀective than subcutaneous immunotherapy and is slower in onset of beneﬁt [35]. Biologic modiﬁers Omalizumab, the chimeric monoclonal antibody directed against IgE, has been shown to be eﬀective for allergic rhinitis, although it is currently approved only for use in steroid-requiring perennial allergic asthmatics [36,37]. It would be an exceedingly costly way of treating hay fever. However, those patients using it for asthma control could expect beneﬁt in concomitant allergic rhinitis symptoms. Considerations in pregnancy Older antihistamines like chlorpheniramine, hydroxyzine, and tripelennamine have been shown to be safe in pregnancy, and data are likewise reassuring for loratadine and cetirizine. Topical corticosteroids, especially after the ﬁrst trimester, appear safe; budesonide is category B. Cromolyn is category B also, and can be used for mild disease. Pseudoephedrine carries a category C, and oral decongestants are best avoided if possible [38]. Allergen immunotherapy with stable maintenance dosing has been shown to be safe. Summary Pharmacotherapy is the most used therapeutic modality in allergic rhinitis due to inhalant factors. Second-generation antihistamines are preferable because of decreased sedation and anticholinergic eﬀects. Topical

ALLERGIC RHINITIS

9

corticosteroids remain the best and preferred method of treatment for seasonal and perennial allergic rhinitis. The addition of antihistamines and antileukotrienes to topical steroids may be beneﬁcial because of a more rapid onset of eﬀect, and may be withdrawn as control is achieved. Allergen avoidance is recommended but may be diﬃcult, depending on the incriminating agent. Allergen vaccine immunotherapy is eﬀective and should be strongly considered in the face of poor response to pharmacotherapy and avoidance. The ARIA initiative reinforces the need always to think of lower airway inﬂammation when evaluating allergic rhinitis, and not to ignore the upper airway when dealing with asthma. Eﬀective pharmacotherapy of the entire airway still requires multiple agents.

References [1] Schwartz M. Heredity in bronchial asthma: a clinical and genetic study of 191 asthma probands and 50 probands with bakers’ asthma. Acta Allergol 1952;5:14S–126S. [2] Lamb CE, Ratner PH, Johnson CE, et al. Economic impact of workplace productivity losses due to allergic rhinitis compared with select medical conditions from an employer perspective. Curr Med Res Opin 2006;22:1203–10. [3] Kessler, Almeida DM, Berglund P, et al. Pollen and mold exposure impairs the work performance of employees with allergic rhinitis. Ann Allergy Asthma Immunol 2001;87:289–95. [4] Burton, Conti PJ, Chen CY, et al. The impact of allergies and allergy treatment on worker productivity. J Occup Environ Med 2001;43:64–71. [5] Nathan RA. The burden of allergic rhinitis. Allergy Asthma Proc 2007;28:3–9. [6] Abbas AK, Lichtman AH. Immediate hypersensitivity. In: Abbas AK, Lichtman AH, editors. Cellular and molecular immunology. 5th edition. Philadelphia: Elsevier Saunders; 2005. p. 432–52. [7] Walden SM, Proud D, Bascom R, et al. Experimentally induced nasal allergic responses. J Allergy Clin Immunol 1988;81:940–9. [8] Connell JT. Quantitative intranasal pollen challenges. III. The priming eﬀect in allergic rhinitis. J Allergy 1969;43:33–44. [9] Solomon WR, Weber RW, Dolen WK. Common allergenic pollen and fungi. In: Bierman CW, Pearlman DS, Shapiro GG, et al, editors. Allergy, asthma, and immunology from infancy to adulthood. Philadelphia: WB Saunders Company; 1996. p. 93–114. [10] Chew GL, Higgins KM, Gold DR, et al. Monthly measurements of indoor allergens and the inﬂuence of housing type in a northeastern US city. Allergy 1999;54:1058–66. [11] Arbes SJ Jr, Cohn RD, Yin M, et al. Dog allergen (Can f 1) and cat allergen (Fel d 1) in US homes: results from the national survey of lead and allergens in housing. J Allergy Clin Immunol 2004;114:111–7. [12] Togias A, Naclerio RM, Proud D, et al. Studies on the allergic and nonallergic nasal inﬂammation. J Allergy Clin Immunol 1988;81:782–90. [13] Bousquet J, Van Cauwenberge P, Khaltaev N. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 2001;108:S147–334. [14] Shapiro PA. Eﬀects of nasal obstruction on facial development. J Allergy Clin Immunol 1988;81:967–71. [15] The European Academy of Allergology and Clinical Immunology. Position paper: allergen standardization and skin tests. Allergy 1993;48:S48–82. [16] Ciprandi G, Pronzato C, Passalacqua G, et al. Topical azelastine reduces eosinophil activation and intercellular adhesion molecule-1 expression on the nasal epithelial cells: an antiallergy activity. J Allergy Clin Immunol 1996;98:1088–96.

10

WEBER

[17] Wilson AM, O’Byrne PM, Parameswaran K. Leukotriene receptor antagonists for allergic rhinitis: a systematic review and meta-analysis. Am J Med 2004;116:338–44. [18] Benson M, Strannega˚rd I-L, Strannega˚rd O¨, et al. Topical steroid treatment of allergic rhinitis decreases nasal ﬂuid Th2 cytokines, eosinophils, eosinophil cationic protein, and IgE but has no signiﬁcant eﬀect on IFN-g, IL-1b, TNF-a, or neutrophils. J Allergy Clin Immunol 2000;106:307–12. [19] Weiner JM, Abramson MJ, Puy RM. Intranasal corticosteroids versus oral H1 receptor antagonists in allergic rhinitis: systematic review of randomized controlled trials. Br Med J 1998;317:1624–9. [20] Yanez A, Rodrigo GJ. Intranasal corticosteroids versus topical H1 receptor antagonists for the treatment of allergic rhinitis: a systematic review with meta-analysis. Ann Allergy Asthma Immunol 2002;89:479–84. [21] Kaszuba SM, Baroody FM, deTineo M, et al. Superiority of an intranasal corticosteroid compared with an oral antihistamine in the as-needed treatment of seasonal allergic rhinitis. Arch Intern Med 2001;161:2581–7. [22] Wilson AM, Orr LC, Sims EJ, et al. Eﬀects of monotherapy with intra-nasal corticosteroid or combined oral histamine and leukotrienes receptor antagonists in seasonal allergic rhinitis. Clin Exp Allergy 2001;31:61–8. [23] Pullerits T, Praks L, Ristioja V, et al. Comparison of a nasal glucocorticoid, antileukotriene, and a combination of antileukotriene and antihistamine in the treatment of seasonal allergic rhinitis. J Allergy Clin Immunol 2002;109:949–55. [24] Pedersen S. Assessing the eﬀect of intranasal steroids on growth. J Allergy Clin Immunol 2001;108:S40–4. [25] Kaiser HB, Findlay SR, Georgitis JW, et al. Long-term treatment of perennial allergic rhinitis with ipratropium bromide nasal spray 0.06%. J Allergy Clin Immunol 1995;95:1128–32. [26] Corren J, Manning BE, Thompson SF, et al. Rhinitis therapy and the prevention of hospital care for asthma: a case-control study. J Allergy Clin Immunol 2004;113:415–9. [27] Perry TT, Corren J, Philip G, et al. Protective eﬀect of montelukast on lower and upper tract responses to short-term cat allergen exposure. Ann Allergy Asthma Immunol 2004;93:431–8. [28] Weber RW. Weaving a blanket to protect the entire airway: the goal of comprehensive therapy. Ann Allergy Asthma Immunol 2004;93:407–8. [29] Wood RA, Chapman MD, Adkinson NF, et al. The eﬀect of cat removal on allergen content in household-dust samples. J Allergy Clin Immunol 1989;83:730–4. [30] van den Bemt L, van Knappen L, de Vries MP, et al. Clinical eﬀectiveness of a mite allergenimpermeable bed-covering system in asthmatic mite-sensitive patients. J Allergy Clin Immunol 2004;114:858–62. [31] Horak F, Matthews S, Ihorst G, et al. Eﬀect of mite-impermeable mattress encasinfs and an education package on the development of allergies in a multinational randomized, controlled birth-cohort study –24 months results of the Study of Prevention of Allergy in Children in Europe. Clin Exp Allergy 2004;34:1220–5. [32] Zhang YC, Perzanowski MS, Chew GL. Sub-lethal exposure of cockroaches to boric acid pesticide contributes to increased Bla g 2 excretion. Allergy 2005;60:965–8. [33] Weber RW. Immunotherapy with allergens. JAMA 1997;278:1881–7. [34] Frew AJ. Immunotherapy of allergic disease. J Allergy Clin Immunol 2003;111:S712–9. [35] Cox LS, Linnemann DL, Nolte H, et al. Sublingual immunotherapy: a comprehensive review. J Allergy Clin Immunol 2006;117:1021–35. [36] Vignola AM, Humbert M, Bousquet J, et al. Eﬃcacy and tolerability of anti-immunoglobulin E therapy with Omalizumab in patients with allergic asthma and persistent allergic rhinitis: SOLAR. Allergy 2004;59:709–17. [37] Okubo K, Ogina S, Nagakura T, et al. Omalizumab is eﬀective and safe in the treatment of Japanes Cedar pollen-induced seasonal allergic rhinitis. Allergol Int 2006;55:379–86. [38] Incaudo GA, Takach P. The diagnosis and treatment of allergic rhinitis during pregnancy and lactation. Immunol Allergy Clin N Am 2006;26:137–54.

Prim Care Clin Office Pract 35 (2008) 11–24

The Diagnosis and Management of Acute and Chronic Sinusitis Roxanne S. Leung, MD, Rohit Katial, MD, FAAAAI, FACP* National Jewish Medical and Research Center, The University of Colorado Health Sciences Center, 1400 Jackson Street, Denver, CO 80206, USA

The objective of this article is to review the diagnosis and management of both acute and chronic sinusitis. Areas discussed include the prevalence of disease, our current understanding of disease pathogenesis, diagnosis, and contemporary treatment.

Prevalence and disease burden Sinusitis aﬀects an estimated 16% of the adult population in the United States, which translated into an astonishing 5.8 billion dollars of direct health care costs in 1996 [1]. The great majority of patients present to their primary care physician, resulting in approximately 18 million oﬃce visits a year. From 1990 through 1992, total restricted activity days numbered 73 million [2]. Degree of impairment from sinusitis is substantial, and is comparable to other chronic diseases, such as chronic obstructive lung disease, angina, and back pain [3].

Anatomy The sinuses are air-ﬁlled cavities, which are lined with classical, pseudostradiﬁed and ciliated columnar epithelium. The host defense system works to keep this pathogen free in a number of ways. In an immunocompetent host, secretory IgA and proper mucocilliary clearance through a patent ostium prevent local mucosal damage.

* Corresponding author. E-mail address: [email protected] (R. Katial). 0095-4543/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2007.09.002 primarycare.theclinics.com

12

LEUNG & KATIAL

Proper function of the sinuses involves several key points [4], including: (1) mucus that is of appropriate viscosity, composition, and volume, (2) normal mucociliary ﬂow, and (3) open ostia to allow adequate drainage and aeration.The cilia help to clear secretions by sweeping them toward a patent ostial opening and into the nasal cavity. In the maxillary sinuses, proper ciliary function is especially important because the direction of drainage is against the pull of gravity. The ostiomeatal complex (OMC) is a narrow drainage pathway located in the middle meatus, which allows ventilation of the anterior ethmoid, frontal, and maxillary sinus.

Deﬁnitions Sinusitis can be broadly deﬁned as inﬂammation of one or more of the paranasal sinuses. Classically, sinusitis is characterized as the following: Acutedsymptoms last less than 4 weeks Subacutedsymptoms last 4 to 8 weeks Chronicdsymptoms last longer than 8 weeks Recurrentdthree or more acute episodes a year Acute sinusitis can be further deﬁned as an infection of the paranasal sinuses, with accompanying symptoms present for more than 10 days and less than 4 weeks. To fully deﬁne chronic sinusitis has been diﬃcult. Because of the variation in clinical expression of the disease, and the discordance between patient symptoms and objective ﬁndings, no one set of diagnostic criteria has been agreed on by all clinicians. Furthermore, before much of the microbiologic or pathologic data regarding this disease had been shown, chronic sinusitis was thought to be a chronologic extension of acute sinusitis. However, it is now thought that chronic sinusitis is a much diﬀerent disease. In contrast to acute sinusitis, most chronic sinusitis is not an infectious disease and is better thought of as an inﬂammatory disease, much akin to asthma.

Pathogenesis and contributing factors Acute sinusitis Several factors promote the development of acute sinusitis. In most cases, bacterial sinusitis is preceded by a viral upper respiratory infection, which in turn leads to sinus inﬂammation and obstruction of the OMC. As a result, drainage and ventilation of the maxillary, anterior ethmoid, and frontal sinuses are compromised. Once this occurs, both the pH and oxygen content decrease, the cilia are less functional, mucosa are damaged, and the microenvironment becomes more susceptible to infection. Approximately 0.5% to 2% of viral sinusitis progress into bacterial infections [5]. To distinguish

ACUTE AND CHRONIC SINUSITIS

13

between bacterial and viral sinusitis can be diﬃcult. Typically viral sinusitis resolves in 7 to 10 days [6], whereas bacterial sinusitis remains persistent [7]. Rhinovirus is the most common viral pathogen and is easily transmissible. In a study of healthy volunteers, 95% of individuals challenged with intranasal rhinovirus drops became infected, and three quarters of them became symptomatic. Within 10 hours, newly replicating virus was found in the nasal secretions [8]. As conﬁrmed by sinus puncture, Streptococcus pneumoniae, Haemophilus inﬂuenza, and Moraxella catarrhalis make up the majority of the community acquired bacterial pathogens [9]. One possible mechanism for introduction of pathogens from the nasal passages into the sinuses may actually be through nose blowing. This processes creates a negative intranasal pressure with such force that nasal ﬂuid is propelled from the middle meatus into the sinus cavity [10]. Chronic sinusitis The pathogenesis of chronic sinusitis is poorly understood. The mechanisms that contribute to the chronicity of the disease include mucociliary dysfunction, mucostasis, hypoxia, and release of microbial products. However, the initial stimulus and subsequent perpetuation of these processes is unclear. Some theories have implicated anatomic, infectious, allergic, and inﬂammatory disease, but none have been proven. Unlike acute sinusitis, the role of ostiomeatal complex blockage is uncertain. In a comparison of CT scans between patients with chronic sinusitis and healthy controls, there was no diﬀerence in the patency of the ostiomeatal complex [11]. Also in contrast to acute sinusitis, the role of infection as the driving force behind most chronic sinusitis has been brought into question. While the most common pathogens in acute sinusitis include Streptococcus pneumoniae, Haemophilus inﬂuenzae, and Moraxella catarrhalis, pathogens found in chronic sinusitis are usually a mixture of aerobic and anaerobic bacteria, including Staphylococcus aureus and coagulase-negative Staphylococci. Whether these organisms are pathologic, or are merely colonizing agents, is diﬃcult to determine. Reports of the prevalence of anaerobic species diﬀer widely, and range from as high as 80% to 100% in children [12], or to as low as 0% to 25% in adults [13,14]. Furthermore, treatment with antibiotics tends to provide only transient beneﬁt. Granted, a small subset of patients with chronic sinusitis may be infectious in nature, but it is usually in association with an underlying immunodeﬁciency, such as immunoglobulin deﬁciency, HIV, cystic ﬁbrosis, or Kartagener syndrome [15]. Several other mechanisms of disease have been previously proposed. In these cases, the inﬂammatory response is against the microbe as an antigen, and not as an invasive pathogen per se. One theory proposes that immune hyperresponsiveness to colonizing bacteria, such as Staphylococcus aureus, may play a role in chronic sinusitis with polyps [16]. Yet another theory

14

LEUNG & KATIAL

proposes that colonizing fungi serve as the antigen, which will be discussed at the end of this article [17]. Regardless of the initial stimulus, the inﬂammatory process ensues, with a predominance of eosinophils. Furthermore, chronic sinusitis with and without polyps diﬀer in their speciﬁc histopathologic presentation. In nasal samples of patients with polyps, there were signiﬁcantly more eosinophils, plasma cells, and stromal edema compared with those without polyps. The investigators argued that because a substantial diﬀerence was found between these groups, they should be treated as separate entities, and not a continuum of one [18]. Perhaps an understanding of the pathophysiology of chronic sinusitis can be gleaned by its close association with other allergic diseases, such as allergic rhinitis, asthma, and aspirin sensitivity. Based on CT studies, anywhere from 74% to 90% of asthmatics have sinus mucosal abnormalities, albeit asymptomatic [19]. In addition, chronic sinusitis was associated with allergic rhinitis in 40% to 84% of adult patients [20]. Even so, a direct causal role between these diseases has never been shown. Lastly, gastroesophageal reﬂux (GERD) has been implicated as a cause of sinusitis. Gastric acid can reﬂux directly into the nasopharynx and, in theory, can cause inﬂammation of the sinus ostium, and pH probe studies have shown a much higher incidence of GERD in patients with chronic sinusitis. In an uncontrolled study of 19 adults with chronic sinusitis, 68% had symptoms of GERD, and 78% had abnormal esophageal pH probe results. After a subset of these subjects was treated with proton pump inhibitors, 67% had an improvement in sinus symptoms [21].

Diagnosis Physical examination The nasal mucosa is best visualized after application of a topical vasoconstrictive agent, such as oxymetazoine, and use of a nasal speculum. One approach to the exam should include notice of the color, edema, character of nasal secretions, presence of polyps, and structure of the nasal septum [22]. Purulent discharge from the middle meatus is highly predictive of bacterial sinusitis [23,24]. Palpation for tenderness of both the maxillary and frontal sinuses are helpful. Because a small proportion of cases of maxillary sinusitis may be caused by tooth infection, one should also check for maxillary teeth tenderness by tapping with a tongue blade [25]. Transillumination of the sinuses is an additional diagnostic test, and is limited to the frontal and maxillary sinuses, as other sinuses are too distal to examine. To examine the maxillary sinus, a light source is placed over the infraorbital rim, and light transmission is observed through the hard palate. The utility of this test is debatable [22].

ACUTE AND CHRONIC SINUSITIS

15

Imaging Imaging of the sinuses is usually reserved to conﬁrm the diagnosis, if history and physical are equivocal, or if conventional treatment has failed. Modalities include plain radiograph, CT, ultrasound, and MRI. Plain X-rays come in several views. The Caldwell (anterior-posterior), Waters (occipito-mental), and lateral ﬁlms provide views of the frontal sinus, maxillary, and sphenoid sinuses, respectively. Unlike the CT scan, the ethmoid sinus is not well visualized. Signiﬁcant opaciﬁcation or mucosal thickening and air-ﬂuid level are all signs of disease; however, there is no ability to predict the response to antibiotics based on the radiographic extent of disease. MRI is best used to evaluate soft tissue structures, and can distinguish between inﬂammatory and malignant disease. MRI is also useful to determine the extent of the complications of sinusitis, such as intracranial or orbital involvement. Ultrasound, although limited, is an alternative technique to evaluate the maxillary and frontal sinuses without exposure to ionizing radiation. This is an especially viable option for pregnant women. CT is the modality of choice, and is better able to evaluate the ethmoid sinuses compared with plain X-ray. CT is also much better than MRI for evaluation of boney structures. The ability to visualize detailed anatomy is helpful in preoperative planning. However, CT is unable to distinguish between viral or bacterial sinusitis. In one study, 31 healthy adult volunteers with ‘‘a fresh common cold,’’ 71% of whom described nasal or head congestion, underwent CT sinus imaging early on in their illness. Of the patients with congestion, 100% had an abnormality in one or more of their sinuses, compared with 56% of those who did not have congestion. Fourteen subjects returned for repeat imaging, and without interim antibiotics, 79% of the subjects showed either resolution or marked improvement [26]. In addition, a signiﬁcant number of patients have incidental mucosal changes on CT, in the absence of symptoms [27]. Moreover the extent of mucosal changes on CT does not correlate with severity of symptoms [28,29]. Culture Identiﬁcation of the pathologic organism is best done through maxillary sinus aspiration. After sterilization of the puncture site, usually through the lateral wall of the inferior meatus, contents of the maxillary sinus are aspirated. The invasive nature of this procedure often limits its use. As a less invasive approach, endoscopically obtained cultures of the middle meatus, may be a possible surrogate. However, the same organisms have been found to colonize the middle meatus in healthy children, as those with sinusitis, so the mere presence of the organism does not prove infection [30]. In adults, good correlation has been shown between endoscopically obtained cultures of the middle meatus, and those of direct antral culture [31].

16

LEUNG & KATIAL

Acute sinusitis The diagnosis of sinusitis is usually made on clinical grounds, which include both the history and physical examination and, if appropriate, diagnostic procedures. Symptoms of acute sinusitis often overlap with those of other diagnosis, such as allergic rhinitis and the common cold. Several studies have attempted to determine the relationship between the signs and symptoms of sinusitis, and benchmarks such as sinus puncture, CT, plain X-ray, and ultrasound. In a primary care clinic in Norway, 201 patients with a clinical diagnosis of acute sinusitis underwent CT scan. Of these patients, 63% met the clinic’s deﬁnition of acute sinusitis by having either an air ﬂuid level or total opaciﬁcation. The presence of two phases of illness, purulent rhinorrhea, erythrocyte sedimentation rate greater than 10 mm, and purulent secretion noted in the nasal cavity, were all independently associated with acute sinusitis, and a combination of three out of four of these criteria gave a speciﬁcity of 81% and a sensitivity of 66% [32]. Williams and colleagues [33] conducted a study of adult men who presented to a primary care clinic with either rhinorrhea, facial pain, or a self-suspected diagnosis of sinusitis, and compared their symptoms to ﬁndings of sinusitis on X-ray. The overall prevalence of sinusitis was 38%. They found the following symptoms were most sensitive: presence of colored discharge, cough, and sneezing with a sensitivity of 72%, 70%, and 70%, respectively. However, not surprisingly, the speciﬁcity of these symptoms was much less (52%, 44%, and 34% respectively). The most speciﬁc symptom (93%) was maxillary toothache; however, this was found in only a small subset of patients. Van Duijn and colleagues [32] reported a study of European patients who presented to their primary care providers. They compared an algorithm of ﬁve symptoms, which included preceding common cold, purulent rhinorrhea, pain on bending, unilateral maxillary pain, and pain in teeth, to ﬁndings on ultrasound, a technique primarily used in Europe. Even with this set of criteria, the proportion of correct diagnosis was a little over one half. In this study, the most sensitive indicator was history of preceding cold (85%), and most speciﬁc indicator was pain in teeth (83%). Perhaps the gold standard for the diagnosis of sinusitis is the ﬁnding of purulent material through maxillary sinus aspiration. In marked contrast to the studies discussed previously, Hansen and colleagues [34] found no independent association between purulent aspirate and the following symptoms: preceding upper respiratory tract infection, maxillary pain, tenderness of maxillary sinus, maxillary toothache, purulent nasal discharge, and visualization of purulent material on the posterior wall of the pharynx. In summary, there are no signs and symptoms of sinusitis that are both highly sensitive and speciﬁc. Most will agree that if symptoms persist beyond 7 to 10 days, a diagnosis of bacterial sinusitis should be entertained [35].

ACUTE AND CHRONIC SINUSITIS

17

Although rare, complications of acute sinusitis can occur through direct, local extension. With antibiotic treatment, complications occur with an estimated frequency of 1 per 10,000 cases [36]. Clinical presentation may include facial edema, cellulitis, orbital, visual, and meningeal involvement. In these cases, aggressive treatment, which may include surgical intervention, is warranted. Chronic sinusitis Unfortunately, clinical criteria to diagnose chronic sinusitis, as well as the predictive value of these criteria, are sorely lacking. Historically, the diagnosis of chronic sinusitis was based on several clinical symptoms, similar to the presentation of acute sinusitis, although often less dramatic; however, none of these symptoms are speciﬁc to sinusitis. In particular, headache, as the sole presenting symptom, is not likely chronic sinusitis. On the other hand, nasal endoscopy is useful. Evidence of nasal secretions, nasal polyps, and deformation of the middle meatus have been shown to distinguish patients with extensive sinus disease, as deﬁned by CT image criteria, compared with either the control group or to those with limited disease [37]. Plain X-rays are often insuﬃciently sensitive to diagnose chronic sinusitis and do not provide the anatomic detail required for preoperative evaluation. Although CT is recommended, this alone is still not evidence enough to make the diagnosis. CT should be performed at least 2 weeks after an upper respiratory infection, and more than 4 weeks after treatment of acute bacterial sinusitis, to evaluate underlying chronic disease. Therefore it is recommended that a combination of clinical signs and symptoms, nasal endoscopy, and CT be used to make the diagnosis of chronic sinusitis. Treatment Acute sinusitis The diagnosis of acute sinusitis prompts countless number of antibiotic prescriptions per year. Although the vast majority of cases of acute sinusitis resolve without treatment, antibiotics are prescribed for an estimated 85% to 98% of cases presented to a primary care clinic [9]. Antibiotics, compared with placebo, do reduce treatment failures in bacterial sinusitis by almost one half (from 31% to 16%) [38]. If culture results are unavailable, the antibiotic should target the most common bacterial pathogens. These include S. pneumoniae, H. inﬂuenzae, and M. catarrhalis. Antibiotic resistance is on the rise and almost half of S. pneumoniae is now resistant to penicillin, and the majority of both H. inﬂuenzae and M. catarrhalis are B-lactamase positive [39]. The choice of antibiotic should take into account a number of factors, such as geographic prevalence of resistance patterns, predicted eﬃcacy, cost, side eﬀects, and ease of ‘‘use.’’

18

LEUNG & KATIAL

The American College of Physicians published practice guidelines for the treatment of acute sinusitis [40]. This position publication was endorsed by a number of groups, including the Centers for Disease Control and Prevention, the American Academy of Family Physicians, the American College of Physicians, American Society of Internal Medicine, and the Infectious Disease Society of America. In this publication they give the following practice guidelines: 1. Sinus radiography is not recommended for the diagnosis of uncomplicated sinusitis. 2. Acute bacterial sinusitis does not require antibiotic treatment, especially if symptoms are mild or moderate. 3. Patients with severe or persistent moderate symptoms and speciﬁc ﬁndings of bacterial sinusitis should be treated with antibiotics. Narrowspectrum antibiotics (including amoxicillin, doxycycline and trimethoprim-sulfamethoxazole) are reasonable ﬁrst-line agents. Amoxicillin is a reasonable ﬁrst line antibiotic choice for both adults and children, unless there is a high prevalence of B-lactamase producing strains. The higher dose (90 mg/kg/day) is recommended for children at higher risk of amoxicillin resistance, such as those who attend day care, were recently treated with antibiotics, or are under the age of 2 years. The addition of potassium clavulanate can also counter this antibiotic resistance. The most common side eﬀects include abdominal cramping and diarrhea, which are quickly reversed upon discontinuation of the drug. Trimethoprim-sulfamethoxazole is an alternative antibiotic in penicillin-allergic individuals; however, up to 20% of S. pneumoniae may be resistant to this alternative. In a meta-analysis of several randomized trials, folate inhibitors were found to be as eﬀective as the newer, more costly antibiotics [38]; however, even the investigators cede the limitations of their data, so this should be interpreted with caution. In contrast to amoxicillin, doxycycline provides broader antibiotic coverage, including activity against B-lactamase producing strains of H. inﬂuenzae and M. catarrhalis. First generation cephalosporins, such as cephalexin and cefadroxil, do not provide adequate coverage against H. inﬂuenzae and should not be used. Second generation cephalosporins, such as cefuroxime axetil and cefprozil, as well as third generation cephalosporins, such as cefpodoxime axetil, and cefdinir, are appropriate choices. The ﬁrst ketolide, telithromycin, was initially indicated for acute sinusitis, but this was revoked after reports of severe hepatotoxicity. The ﬂuoroquinolones, including ciproﬂoxacin, levoﬂoxacin, and moxiﬂoxacin, oﬀer broadspectrum antimicrobial coverage, and are all indicated for acute sinusitis. Because of the concern for adverse eﬀect on the development of joints, these should be avoided in children. These medications can also prolong the QT interval, so should be used with caution in patients at risk for arrhythmia. No controlled studies have examined the length of treatment. Generally,

19

ACUTE AND CHRONIC SINUSITIS

antibiotics should be prescribed for 10 to 14 days, or 7 days after the patient is symptom free. If symptoms fail to improve in 48 to 72 hours, it is reasonable to switch to a second line antibiotic. The most commonly prescribed antibiotics are found in Table 1. In general, antihistamines are not recommended in the treatment of acute sinusitis unless the patient has underlying allergic rhinitis. However, antihistamines have been shown to decrease sneezing and rhinorrhea in the common cold [41,42]. Although topical and oral decongestants are often used in the treatment of the symptoms of sinusitis, no prospective trials have been performed. These agents do have a modest eﬀect in decreasing nasal airway resistance, and in theory may widen the ostia and improve nasal ventilation. Chronic use of topical decongestants beyond 3 to 5 days should be discouraged, as they may result in signiﬁcant rebound hyperemia and rhinitis medicamentosa. Nasal corticosteroids have been shown to decrease the inﬂammatory process of the nasal mucosa after nasal antigen challenge, and can modify both the early and late allergic response. As an extension, it is reasonable to consider that nasal corticosteroids may decrease the inﬂammatory response in sinusitis. Nasal corticosteroids have been studied as adjunctive therapy to antibiotic therapy and found signiﬁcant reduction in several symptom scores; in addition, they show no increase in adverse events [43].

Table 1 Oral antibiotics for sinusitis Antibiotic First line therapy Amoxicillin Second line therapy Amoxicillin/potassium clavulanate Azithromycin Cefdinir Cefpodoxime Cefprozil Cefuroxime Ciproﬂoxacin Clarithromycin Clindamycin Doxycycline Gatiﬂoxacin Levoﬂoxacin Sulfamethoxazole/ trimethoprim

Pediatric dosage

Adult dosage

45 mg/kg/day or 90 mg/kg/day divided

500 mg bid

22.5 mg/kg/day–45 mg/kg/day divided (Dose based on amoxicillin component) 10 mg/kg/day on day 1, then 5 mg/kg/day on days 2–5 14 mg/kg/day 10 mg/kg qd 15 mg/kg bid 15 mg/kg/day bid

500 mg–875 mg bid

7.5 mg/kg bid 8 mg/kg/day–20 mg/kg/day divided qid

6 mg/kg/day–12 mg/kg/day divided (based on trimethoprim)

500 mg qd on day 1, then 250 mg qd on days 2–5 300 mg bid 200 mg bid 250 mg–500 mg bid 250 mg bid 500 mg bid 500 mg bid 150 mg–450 mg qid 100 mg–200 mg qd 400 mg qd 500 mg qd 800/160 mg bid

20

LEUNG & KATIAL

However, it should be noted that nasal corticosteroids do not have a Food and Drug Administration-approved indication for treatment of acute sinusitis. Surgical intervention of acute sinusitis is rare, but may be needed in the case of complications of sinusitis, or in those patients who continue to have severe symptoms and are unresponsive to medical therapy. Chronic sinusitis Corticosteroids (CCSs) are potent anti-inﬂammatory agents, and as such, would seem to be a logical choice to treat chronic sinusitis. Although intranasal CCSs are unlikely to reach the paranasal sinuses, they do improve nasal congestion, which is often a signiﬁcant symptomatic component in chronic sinusitis. Intranasal CCSs have also been shown to shrink nasal polyps. These beneﬁts, combined with their relatively safe proﬁle, make topical intranasal steroids a reasonable adjunctive therapy. Systemic corticosteroids are also widely used in clinical practice. Recently, a double-blind placebo-controlled trial of prednisolone, 50 mg daily for 14 days versus placebo, demonstrated improvement of sinonasal polyposis as measured by symptom scores, nasal endoscopy, and MRI [44]. The use of antibiotic treatment in chronic sinusitis is quite controversial. Patients with chronic sinusitis may also present with acute bacterial sinusitis, and in these patients antibiotics are indicated. Immunocompromised patients are at higher risk of a chronic infectious process, and may need to be treated with antimicrobial therapy. However, often acute exacerbations may be caused by reasons noninfectious in nature, such as allergic or nonallergic rhinitis. In these cases, treating the underlying disease is more appropriate. Aspirin sensitivity is often present in patients with nasal polyps. In patients with aspirin-exacerbated respiratory disease (AERD), aspirin desensitization, followed by long term treatment (650 mg twice a day), have demonstrated improvement of clinical outcomes and decrease in the requirement for systemic corticosteroids [45]. Cysteinyl leukotrienes are proinﬂammatory mediators, and are especially elevated in patients with chronic sinusitis and AERD. Several pharmacologic agents target disruption of this pathway, and are collectively known as leukotriene modiﬁers. In a placebo controlled study of aspirin intolerant asthmatics, zileuton, one such leukotriene modiﬁer, reduced polyp size and restored the sense of smell [46]. Surgical management may be indicated in cases refractory to medical management. In a randomized controlled study comparing medical versus combined medical and surgical treatment of nasal polyposis, medical treatment alone was often suﬃcient to treat most symptoms. However, if the primary complaint is nasal obstruction, despite corticosteroid treatment, surgical intervention is indicated [47].

ACUTE AND CHRONIC SINUSITIS

21

The role of fungus in sinusitis Two speciﬁc cases of fungal sinusitis are worth mention. The ﬁrst, allergic fungal sinusitis (AFS) is a well known, distinct entity of sinusitis, and is best characterized as the upper airway equivalent to allergic bronchopulmonary aspergillosis. AFS is a noninvasive form of sinusitis, which is characterized by thick mucus, often described as peanut butter-like in consistency. Histologic ﬁndings include fungal hyphae and degranulating eosinophils embedded within mucinous material. Most patients also present with peripheral blood eosinophilia, nasal polyposis, and evidence of allergy to fungus (by skin testing or fungal antigen speciﬁc IgE). Treatment requires surgical debridement and corticosteroid therapy. An active controversy in the literature revolves around the role of fungi as a major contributor to the pathogenesis of most chronic sinusitis. Fungi are ubiquitous organisms, and one group has been able to collect and culture fungi in virtually all patients with chronic sinusitis. Surprisingly, a similarly high rate of colonization was found in healthy controls [48]. Therefore, the mere presence of fungi is not suﬃcient to cause disease. The investigators argue that in a susceptible host, an immunologic response is mounted, including the proliferation or recruitment of eosinophils, which results in the clinical expression of chronic sinusitis. If this were true, then eradication of the fungi should result in improvement in disease course. This has been investigated in several trials with mixed results. In a randomized placebo-controlled double-blind trial, 24 subjects completed 6 months of treatment with intranasal amphotericin B solution versus placebo. The treatment group exhibited both improved CT scores and endoscopy, but no change in symptoms over placebo [49]. In contrast, two European trials have shown no clinical beneﬁt [50,51]. Overall, there is not enough data to routinely justify nasal antifungal therapy, and the authors do not prescribe this in our clinical practice.

Summary In summary, acute and chronic sinusitis are common diseases and account for a signiﬁcant number of visits to the primary care oﬃce. Both are associated with signiﬁcant morbidity and consumption of health care dollars. Acute sinusitis is caused by an infectious process and can often be diﬃcult to distinguish from a viral upper respiratory infection, as signs, symptoms, and even the results of most diagnostic tests overlap. Treatment of choice is antibiotic therapy, and adjunctive therapy may or may not add beneﬁt. In contrast, chronic sinusitis is an inﬂammatory disease. Contrary to common practice, long term antibiotics are likely not useful. Instead, corticosteroids, both in intranasal form and, if necessary, oral systemic form, are more eﬃcacious. In select patients with nasal polyposis and AERD, both leukotriene modiﬁers and aspirin desensitization may be useful.

22

LEUNG & KATIAL

References [1] Ray NF, Baraniuk JN, Thamer M, et al. Health care expenditures for sinusitis in 1996: contributions of asthma, rhinitis, and other airway disorders. J Allergy Clin Immunol 1999;103: 408–14. [2] Anand VK. Epidemiology and economic impact of rhinosinusitis. Ann Otol Rhinol Laryngol 2004;193(Suppl):S3–5. [3] Glikilich RE, Metson R. The health impact of chronic sinusitis in patients seeking otolaryngologic care. Otolaryngol Head Neck Surg 1995;113:104–9. [4] Senior BA, Kennedy DW. Management of sinusitis in the asthmatic patient. Ann Allergy Asthma Immunol 1996;77:6–19. [5] Gwaltney JM. Acute community-acquired sinusitis. Clin Infect Dis 1996;23:1209–23. [6] Gwaltney JM Jr, Hendley JO, Simon G, et al. Rhinovirus infections in an industrial population. II. Characteristics of illness and antibody response. JAMA 1967;202:494–500. [7] Piccirillo JF. Acute bacterial sinusitis. N Engl J Med 2004;351:902–10. [8] Gwaltney JM Jr, Hayden FG. Psychological stress and the common cold. N Engl J Med 1992;326:644–6. [9] Anon JB, Jacobs MR, Poole MD, et al. Sinus and Allergy Health Partnership. Antimicrobial treatment guidelines for acute bacterial rhinosinusitis. Otolaryngol Head Neck Surg 2004;130(Suppl 1):S1–45. [10] Gwaltney JM Jr, Hendley JO, Philips CD, et al. Nose blowing propels nasal ﬂuid into the paranasal sinuses. Clin Infect Dis 2000;30:387–91. [11] Jones NS, Strobl A, Holland I. A study of the CT ﬁndings in 100 patients with rhinosiusitis and 100 controls. Clin Otolaryngol 1997;22:47–51. [12] Brook I, Yocum P, Shah K. Aerobic and anaerobic bacteriology of concurrent chronic otitis media with eﬀusion and chronic sinusitis in children. Arch Otolaryngol Head Neck Surg 2000;126(2):174–6. [13] Rontal M, Bernstein JM, Rontal E, et al. Bacteriologic ﬁndings from the nose, ethmoid, and bloodstream during endoscopic surgery for chronic rhinosinusitis: implications for antibiotic therapy. Am J Rhinol 1999;13(2):91–6. [14] Klossek JM, Dubreuil L, Richet H, et al. Bacteriology of chronic purulent secretions in chronic rhinosinuisitis. J Laryngol Otol 1998;112(12):1162–6. [15] Steinke JW, Borish L. The role of allergy in chronic rhinosinusitis. Immunol Allergy Clin N Am 2004;24:45–57. [16] Van Zele T, Gevaert P, Watelet JB, et al. Staphylococcus aureus colonization and IgE antibody formation to enterotoxins is increased in nasal polyposis. J Allergy Clin Immunol 2004; 114:981–3. [17] Shin S-H, Ponikau JU, Sherris DA, et al. Rhinosinusitis: an enhanced immune response to ubiquitous airborne fungi. J Allergy Clin Immunol 2004;114:1369–75. [18] Pozehl D, Moeller P, Riechelmann H, et al. Distinct features of chronic rhinosinusitis with and without nasal polyps. Allergy 2006;61:1275–9. [19] Borish L. Sinusitis and asthma: entering the realm of evidence-based medicine. J Allergy Clin Immunol 2002;109(4):606–8. [20] Smart BA. Pediatric Rhinosinusitis and Its Relationship to Asthma and Allergic Rhinitis. Pediatric Asthma, Allergy and Immunology 2005;18:88–98. [21] Dibaise JK, Huerter JV, Quigley EM. Sinusitis and gastroesophageal reﬂux disease. Ann Intern Med 1998;129:1078–83. [22] Williams JW, Simel DL. Does this patient have sinusitis? Diagnosing acute sinusitis by history and physical examination. JAMA 1993;270(10):1242–6. [23] Lindbaek M, Hjortdahl P. The clinical diagnosis of acute purulent sinusitis in general patienceda review. Br J Gen Pract 2002;52:491–5. [24] Lacroix JS, Ricchetti A, Lew D, et al. Symptoms and clinical and radiological signs predicting the presence of pathogenic bacteria in acute rhinosinusitis. Acta Otolaryngol 2002;122:192–6.

ACUTE AND CHRONIC SINUSITIS

23

[25] Loyal V, Jones J, Noyek A. Management of odotogenic maxillary sinus disease. Otolaryngol Clin North Am 1976;9:213–22. [26] Gwaltney JM Jr, Phillips CD, Miller RD, et al. Computed tomographic study of the common cold. N Engl J Med 1994;330:25–30. [27] Jones NS. CT of the paranasal sinuses: a review of the correlation with clinical, surgical and histopathological ﬁndings. Clin Otolaryngol 2002;27:11–7. [28] Bhattacharyya T, Piccirillo J, Wippold FJ. Relationship between patient-based descriptions of sinusitis and paranasal sinus computed tomographic ﬁndings. Arch Otolaryngol Head Neck Surg 1997;123(11):1189–91. [29] Mudgil SP, Wise SW, Hopper KD, et al. Correlation between presumed sinusitis-induced pain and paranasal sinus computed tomographic ﬁndings. Ann Allergy Asthma Immunol 2002;88:223–6. [30] Gordts F, Nasser IA, Clement PAR, et al. Bacteriology of the middle meatus in children. Int J Pediatr Otorhinolaryngol 1999;48:163–7. [31] Gold SM, Tami TA. Role of middle meatus aspiration culture in the diagnosis of chronic sinusitis. Laryngoscope 1997;107:1586–9. [32] Van Duijn NP, Brouwer HJ, Lamberts H. Use of symptoms and signs to diagnose maxillary sinusitis in general practice: comparison with ultrasonography. BMJ 1992;305: 684–7. [33] Williams JW Jr, Simel DL, Roerts L, et al. Clinical evaluation for sinusitis. Making the diagnosis by history and physical examination. Ann Intern Med 1992;117(9):705–10. [34] Hansen JG, Schmidt H, Rosborg J, et al. Predicting acute maxillary sinusitis in a general practice population. BMJ 1995;311(6999):233–6. [35] Sande MA, Gwaltney JM. Acute community-acquired bacterial sinusitis: continuing challenges and current management. Clin Infect Dis 2004;39:S151–8. [36] Balk EM, Zucker D, Engels EA, et al. Strategies for diagnosing and treating suspected acute bacterial sinusitis: a cost-eﬀectiveness analysis. J Gen Intern Med 2001;16:701–11. [37] ten Brinke A, Grootendorst D, Schmidt JT, et al. Chronic sinusitis in severe asthma is related to sputum eosinophilia. J Allergy Clin Immunol 2002;109(4):621–6. [38] de Ferranti SD, Ioannidis JP, Lau J, et al. Are amoxycillin and folate inhibitors as eﬀective as other antibiotics in acute sinusitis? A meta-analysis. BMJ 1998;317:362–7. [39] Jacobs MR, Bajaksouzian S, Zilles A, et al. Suceptibilities of Streptococcus pneumoniae and Haemophilus inﬂuenzae to 10 oral antimicrobial agents based o pharmacodynamic parameters: 1997 US surveillance study. Antimicrob Agents Chemother 1999;43:1901–8. [40] Snow V, Mottur-Pilson C, Hickner JM. Principles of appropriate antibiotic use for acute sinusitis in adults. Ann Intern Med 2001;134:495–7. [41] Gwaltney JM Jr, Druce HM. Eﬃcacy of brompheniramine maleate for the treatment of rhinovirus colds. Clin Infect Dis 1997;25:1188–94. [42] Turner RB, Sperber SJ, Sorrentino JV, et al. Eﬀectiveness of clemastine fumarate for treatment of rhinorrhea and sneezing associated with the common cold. Clin Infect Dis 1997;25: 824–30. [43] Meltzer EO, Charous BL, Busse WW, et al. Added relief in the treatment of acute recurrent sinusitis with adjunctive mometxone furate nasal spray. J Allergy Clin Immunol 2000;106: 630–7. [44] Hissaria P, Smith W, Wormald P, et al. Short course of systemic corticosteroids in sinuonasal polyposis: a double-blind, randomized, placebo-controlled trial with evaluation of outcome measures. J Allergy Clin Immunol 2006;118(1):128–33. [45] Stevenson DD, Hankammer MA, Mathison DA, et al. Aspirin desensitization treatment of aspirin sensitive rhinosinusitisdasthmatic patients: long term outcomes. J Allergy Clin Immunol 1996;98:751–8. [46] Dahlen B, Nizankowska E, Szczeklik A, et al. Beneﬁts from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-tolerant asthmatics. Am J Respir Crit Care Med 1998;157:1187–94.

24

LEUNG & KATIAL

[47] Blomqvist EH, Lundbald L, Anggard A, et al. A randomized controlled study evaluating medical treatment versus surgical treatment in addition to medical treatment of nasal polyposis. J Allergy Clin Immunol 2001;107(2):224–8. [48] Potikau JU, Sherris DA, Kern EB, et al. The diagnosis and incidence of allergic fungal sinusitis. Mayo Clin Proc 1999;74:877–84. [49] Ponikau JU, Sherris D, Weaver A, et al. Treatment of chronic rhinosinusitis with intranasal amphotericin B: a randomized, placebo-controlled, double-blind pilot trial. J Allergy Clin Immunol 2005;115(1):125–31. [50] Weschta M, Rimek D, Formanek M, et al. Topical antifungal treatment of chronic rhinosinusitis with nasal polyps: a randomized, double-blind clinical trial. J Allergy Clin Immunol 2004;113(6):1122–8. [51] Ebbens FA, Scadding GK, Badia L, et al. Amphotericin B nasal lavages: not a solution for patients with chronic rhinosinusitis. J Allergy Clin Immunol 2006;118(5):1149–56.

Prim Care Clin Office Pract 35 (2008) 25–40

Pediatric Asthma Lora J. Stewart, MD Premier Allergy and Asthma, 18525 E Smoky Hill Road, #C, P.C., Centennial, Colorado 80015, USA

Asthma is deﬁned as episodic and reversible airﬂow obstruction and is the most common chronic illness of childhood. According to estimates, 9 million children in the United States were aﬀected by asthma in 2002 [1]. When taken as a single group, asthma rates for children rose from 2001 until 2004. However, when evaluated by category, the rates during the period stabilized for white children and black girls, while increasing for black boys [2]. Additionally, the morbidity and mortality of asthma disproportionately aﬀects low-income, minority, and inner-city children. Acute asthma exacerbations are the third leading cause of pediatric hospitalizations and the estimated cost for pediatric asthma treatment is over $3 billion per year. Because of the magnitude of this burden, much attention has been placed on early diagnosis and prevention of pediatric asthma. Diagnosis of asthma in the pediatric patient presents a challenge, though, because only half of young children with recurrent wheeze are found to have true asthma. Multiple birth cohorts have supported this ﬁnding and have led to the description of diﬀerent childhood wheezing phenotypes: Transient wheezersdthose who have recurrent wheezing that remits Nonatopic wheezersdthose who are nonallergic and who often have wheezing that is associated with viral infections and that remits by age 5 to 6 years Persistent wheezersdthose who are atopic wheezers with persistence [3,4] Additionally, for some patients, the respiratory symptoms may remit only to relapse later in life. The recognition of these diﬀerent groups has prompted research into identifying and understanding the risk factors for developing persistent asthma.

E-mail address: [email protected] 0095-4543/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2007.09.007 primarycare.theclinics.com

26

STEWART

Risk factors for developing asthma in the pediatric patient Atopy The single greatest risk factor for developing asthma seen in infants and children is atopy or the genetic predisposition for allergic diseases. This includes both atopic dermatitis and allergies. The Tucson Birth Cohort demonstrated that the presence of eczema was a major risk factor in predicting the likelihood of persistent disease [3]. Based on this cohort, the Asthma Predictive Index (API) was developed (Table 1). The major risk factors (only one is required) include parental asthma and physician-diagnosed atopic dermatitis. Minor risk factors (two are required) include physiciandiagnosed allergic rhinitis, wheezing unrelated to colds, and blood eosinophilia (R4%). A subsequent study of children at risk for asthma, Prevention of Early Asthma in Kids (PEAK), demonstrated that allergic sensitization could be added to the aforementioned major risk factors in predicting persistent disease [5]. The importance of allergy in pediatric asthma is further supported by the so-called ‘‘atopic march,’’ as many children initially present with eczema with or without food allergies and then progress to develop asthma and ﬁnally allergic rhinitis. Viral illnesses Viral illnesses are tightly linked with asthma both as a risk factor and a trigger. Studies have shown that previous severe infection with respiratory syncytial virus (RSV), including hospitalization and/or oxygen requirement, is a risk factor for the development of asthma [6]. What remains unclear is whether RSV infection itself results in permanent damage leading to asthma Table 1 API criteria and modiﬁed API criteria APIa

Modiﬁed APIb

Major criteria

Parental history of asthma Physician-diagnosed atopic dermatitis

Minor Criteria

Physician-diagnosed allergic rhinitis Wheezing apart from viral illnesses Blood eosinophilia O4%

Parental history of asthma Physician-diagnosed atopic dermatitis Allergic sensitization to at least one aeroallergen Allergic sensitization to eggs, milk, or peanuts Wheezing apart from viral illnesses

a

Blood eosinophilia O4%

Data from Castro-Rodriquez JA, Holberg CJ, Wright AL, et al. A clinical index to deﬁne risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med 2000;162:1403–6. b Data from Guilbert TW, Morgan WJ, Zeiger RS, et al. Atopic characteristics of children with recurrent wheezing at high risk for the development of childhood asthma. J Clin Immunol 2004;114:1282–7.

PEDIATRIC ASTHMA

27

or if a child already predisposed to asthma is more likely to have a severe RSV infection. In either case, a history of a signiﬁcant RSV infection may support a prediction of persistent disease. Consequently, repeated viral illness exposure through siblings or daycare may actually lead to less atopy and asthma. Finally, viral illnesses are major triggers for acute asthma symptoms, particularly infection with rhinoviruses, and there is now evidence that patients with asthma lack normal defense mechanisms against rhinovirus infections [7,8]. Early allergen exposures Investigations into the role of early allergen exposure and its eﬀect on subsequent allergic sensitizations and asthma have had varied results. Several recent studies have presented conﬂicting results as to whether having a pet in the home is a risk factor for asthma or is protective against developing persistent disease. In one study of Swedish children, exposure to a dog or cat during the ﬁrst year of life resulted in lower allergic rhinitis and asthma rates [9]. The etiology of this protective eﬀect from domesticated pets is less clear. It may be the allergen pet dander itself or the endotoxin associated with the animals. Several studies have also demonstrated that being raised on a farm and being exposed to high levels of endotoxin protects against allergic disorders and wheeze [10,11]. Early exposure to high levels of dust mites and cockroach allergen is associated with increased rates of asthma in inner-city children [12–14]. Finally, skin test positivity to Alternaria species is associated with increased risk of persistent asthma [15].

Pathogenesis of asthma in pediatric patients Pediatric asthma, similar to asthma in adults, is characterized by episodic and reversible airﬂow obstruction. One diﬀerence seen between adult and pediatric asthmatic patients is that the vast majority of pediatric asthma is allergic. Inﬂammatory cells and airway structural changes are common in adult patients, but rare in pediatric patients. However, when inﬂammatory cells and airway structural changes are present in pediatric patients, there is an eosinophilic predominance in the airways of atopic persistent wheezing children [16,17]. This diﬀers from wheezing infants, in whom there is a neutrophilic predominance [18]. There is now evidence that the greatest loss of lung function occurs very early in life, often well before a persistent pattern of wheezing has been documented [3]. Additionally, a percentage of pediatric asthma patients have progressive loss of lung function despite currently recommended treatment [19]. Common triggers for pediatric asthma symptoms include viral illnesses, exercise, cold air, allergen exposure, and irritant exposure, including environmental tobacco smoke and air pollution. Finally, several comorbid diseases are seen in pediatric patients with asthma. Similar to adult patients, untreated or underrecognized gastroesophageal

28

STEWART

reﬂux disease is often found in pediatric patients with diﬃcult-to-control asthma. Persistent and untreated allergic rhinitis and sinusitis can also trigger persistent asthma symptoms.

Diagnosis of asthma in the pediatric patient The diagnosis of asthma in the pediatric patient is a challenge because many young children with asthma have only transient wheezing rather than persistent wheezing. Pediatric patients often appear well and without symptoms between episodes of wheezing or cough. Consideration of a diagnosis of asthma is often prompted by recurrent episodes of respiratory symptoms. Although there is no single diagnostic test for asthma at any age group, careful review of recent and past history, along with physical examination and selected evaluations, can help the clinician support a diagnosis of asthma. History Many aspects of current and past history as well as physical examination can help the clinician distinguish between transient wheezing and asthma in the young child and conﬁrm asthma in the older child. Although many parents confuse wheezing with upper airway congestion or noisy breathing, a history of previous physician-diagnosed wheezing is helpful to conﬁrm true wheeze. Most wheezing and coughing in children occur in association with viral illnesses, but wheezing or coughing apart from obvious infection, such as with exercise, activity, exposure to allergens, or exposure to environmental tobacco smoke, suggests more persistent disease. Additionally, cough that has responded to bronchodilator therapy is consistent with an asthma cough and frequent nocturnal cough may be associated with more severe asthma. Past medical history, including birth history, prematurity, and history of oxygen requirement or mechanical ventilation, documents important factors that can help clarify the condition of pediatric patients with recurrent respiratory symptoms, especially because often nonatopic infants can have bronchopulmonary dysplasia and airway hyperresponsiveness similar to asthma. Determining the severity of previous respiratory episodes, including urgent or emergent care, hospitalization, and hypoxia, helps the clinician quantify symptom control and potentially predict subsequent episodes. Previous response to therapy, including bronchodilators and steroids (both inhaled and systemic), can also help conﬁrm a diagnosis of asthma. Finally, previous history of other allergic conditions increases the risk for developing asthma. The evaluation of a child with recurrent respiratory symptoms should include a thorough review of the family medical history and environmental exposures. A history of physician-diagnosed asthma in a parent is an important risk factor for persistent wheezing in children. Reviewing the family history for the presence of other atopic disease, such as allergic rhinitis, food

PEDIATRIC ASTHMA

29

allergy, and eczema, help establish an atopic genetic background for the patient. An environmental history should document the presence of potential perennial allergens in the home, including furred and feathered pets; the use of allergen covers for mattresses and pillows; the frequency of cleaning bed linens; and the presence of carpets, upholstered furniture, and stuﬀed animals. Other potential sources of irritation in the home environment include tobacco smoke, cockroaches, ﬁreplaces, home heating systems, and home cooling systems. As mentioned above, children sensitized to certain allergens are more likely to have asthma. Examination When examining an asymptomatic pediatric patient with recurrent respiratory symptoms, the physical ﬁndings are likely normal, but evidence of allergic disease can help conﬁrm asthma. Speciﬁcally, an examination that ﬁnds nasal edema, rhinorrhea, enlarged turbinates, allergic shiners, and atopic dermatitis establishes allergy. On the other hand, cystic ﬁbrosis is suggested in the child with nasal polyps. The lung examination should include respiratory rate, auscultation, and oxygen saturation, all of which are likely normal. However, a normal lung examination does not exclude a diagnosis of asthma. It is during an acute episode that the respiratory examination is most helpful. The presence of wheeze, cough, diminished air movement, retractions, tachypnea, or hypoxia should be documented to help determine severity. In some children with signiﬁcant airway obstruction, wheezing is not appreciated until some bronchodilation has occurred. Diagnostic testing In the older child, lung function tests, such as peak expiratory ﬂow rate (PEFR) tests, spirometry measurements, lung volume measurements (body plethysmography), bronchodilator response tests, and bronchial challenges, can conﬁrm or exclude a diagnosis of asthma. Most of these testing options require patient participation and cooperation, making them impractical for the younger pediatric patient outside of a research setting where infant pulmonary function testing and ausculatory bronchial challenges can be completed. For the older child, PEFR testing is an easy and aﬀordable modality to test lung function. The PEFR represents the maximum expiratory ﬂow rate after the patient has inhaled to total lung capacity. The peak ﬂow meter is not only helpful in monitoring day to day lung function and variability, but also can be a tool to help guide treatment intervention. Additionally, the peak ﬂow meter can be used in the oﬃce or home to document response to bronchodilator therapy. Spirometry is a critical tool in evaluating a patient for asthma and can be adequately completed by patients as young as 5 to 6 years. As seen in Fig. 1, the ﬂow-volume loop can demonstrate obstruction in the asthmatic patient

30

STEWART

A

B

Expiratory Loop

Flow

“Scooped Out” Pattern Volume

Inspiratory Loop

Fig. 1. Flow-volume loops. (A) Normal ﬂow-volume loop. (B) ‘‘Scooped out’’ pattern seen with obstruction in the ﬂow-volume loop.

when compared with the loop seen in a patient without asthma. The forced expiratory volume in the ﬁrst second (FEV1) has been the main measure of airﬂow obstruction. According to previous guidelines, mild asthma is characterized by an FEV1 greater than 80%, moderate asthma by an FEV1 of 60% to 80%, and severe asthma by an FEV1 of less than 60%. Unfortunately, the FEV1 in pediatric patients likely underestimates the extent of the disease. The ratio of FEV1 to forced vital capacity is likely a better marker of obstruction in the pediatric patient [18]. According to the standard set by the American Thoracic Society, a diagnosis of asthma is supported when a reversal of airﬂow obstruction after bronchodilator therapy is 12% or more [20]. Additionally, the degree of reversibility may help the clinician determine asthma severity and correlate with underlying airway inﬂammation. Bronchial challenges, which can establish a diagnosis of asthma, include exercise and cold-air challenges as well as challenges with pharmacologic agents, such as methacholine, adenosine monophosphate, and histamine. These challenges typically involve a change in lung function (FEV1) of 20% or more after exposure to the trigger followed by reversal with bronchodilator medication. A challenge using methacholine is considered a ‘‘gold standard’’ for conﬁrming an asthma diagnosis with high sensitivity and speciﬁcity. Additionally, a negative methacholine challenge makes a diagnosis of asthma unlikely. Finally, formal evaluation of lung volumes, whether by helium dilution or body box plethysmography, can demonstrate hyperinﬂation and air trapping. Radiographic studies such as chest radiographs and chest CT scans of pediatric patients with recurrent respiratory symptoms are not routinely obtained during well periods. However, when they are obtained, they may show hyperinﬂation, ﬂattened diaphragms, and/or bronchial thickening. The usefulness of radiographic studies during acute wheezing episodes has been debated. Such studies are usually reserved for patients with signiﬁcant tachypnea, localized ﬁndings on auscultation, associated fever, or signiﬁcant hypoxemia. Additionally, radiographic studies can be useful to exclude alternate diagnoses, such as the presence of a foreign body or an anatomical abnormality.

PEDIATRIC ASTHMA

31

Conﬁrmation of allergic sensitizations, either by percutaneous skin-prick testing or radioallergosorbent testing of serum, can lend support to the diagnosis of asthma as well as identify potential triggers of recurrent respiratory symptoms. In the preschool child, sensitization is usually only seen to perennial allergens (pet dander, dust mite, mold, and cockroach) and food allergens, while the older child may be sensitized to seasonal and/or perennial allergens. Other laboratory results that suggest atopy include an elevated eosinophil count or an elevated serum IgE level, although these testing options are much less speciﬁc for asthma. An elevated eosinophil count is considered a minor criterion for predicting persistence as deﬁned by the API and modiﬁed API [21,22]. The diﬀerential diagnosis for the pediatric patient with recurrent respiratory symptoms is quite extensive (Box 1), but should be narrowed by a thorough history and physical. Additionally, the clinician should focus on common conditions, such as asthma, allergies, and gastroesophageal reﬂux disease, before focusing on less likely causes. In the preschool child with recurrent respiratory symptoms that have been unresponsive to conventional therapies, other causes should be considered, including tracheomalacia, airway compression due to congenital anomalies, tracheo-esophageal ﬁstulas, and foreign body aspiration. In the older patient, vocal cord dysfunction can mimic asthma symptoms, but does not respond to bronchodilator or steroid therapies. Diagnosis can be suspected by a history of inspiratory wheezing and truncation of the inspiratory loop on spirometry. The diagnosis is conﬁrmed by visualization of paradoxical movement of the vocal cords

Box 1. Differential diagnosis in pediatric patient with recurrent respiratory symptoms Young child (<5 years of age) Viral bronchiolitis Tracheomalacia Airway compression due to vascular malformations Foreign body aspiration Chronic aspiration Gastroesophageal reflux disease Tracheo-esophageal fistula Cardiac disease Primary immunodeficiency Cystic fibrosis Older child (>5 years of age) Vocal cord dysfunction Gastroesophageal reflux disease Cystic fibrosis

32

STEWART

during inspiration. In all pediatric patients with diﬃcult-to-control respiratory symptoms or with concomitant poor growth, cystic ﬁbrosis should be considered. Cystic ﬁbrosis typically presents with symptoms of failure to thrive and evidence of pancreatic insuﬃciency (malabsorption or diabetes) in combination with upper- and lower-respiratory symptoms. Cystic ﬁbrosis diagnosis can be conﬁrmed by an abnormal sweat chloride and/or demonstration of a cystic ﬁbrosis DNA mutation. A history of recurrent bacterial infections along with respiratory symptoms may prompt consideration for a primary immune deﬁciency or dysfunction. Patients with primary immunodeﬁciency typically present with infections that are not limited to the respiratory tract or have other abnormal ﬁndings on physical examination. However, when considering this diagnosis, radiographic and immune laboratory studies should be obtained. Treatment of asthma General treatment Treatment of asthma involves not only pharmacologic agents but also recognition and modiﬁcation of potential triggers. Typical triggers include environmental tobacco smoke, air pollution (both indoor and outdoor), and allergens. Ideally, in the case of a child with pet-dander allergy, the pet should be removed from the home. However, if pet removal is not feasible or likely, then, at the very least, the pet should not be allowed in the patient’s bedroom. Dust mite sensitivity should prompt the use of dust mite mattress and pillow covers, regular laundering of bed linens in hot water, and limiting the amount of upholstered furniture, carpeting, and stuﬀed animals in the child’s bedroom. Finally, parents of a child sensitized to seasonal allergens should be encouraged to keep the child in an air-conditioned environment during peak pollen times day and night. If the child cannot avoid seasonal allergens, allergy immunotherapy has been shown to modulate pediatric asthma [23]. The pediatric patient with asthma and his or her family should also be educated about all asthma triggers, including exercise and viral illnesses. Pretreatment with bronchodilator therapy before exercise or planned activity can decrease the likelihood of asthma symptoms. Additionally, a high level of vigilance when a pediatric patient begins to show signs and symptoms of a viral illness can allow detection of asthma symptoms earlier and permit timely intervention. Treatment for chronic asthma In 2002, the National Heart, Lung, and Blood Institute (NHLBI) published revised guidelines for the treatment of pediatric asthma [24]. These guidelines recommend treatment based on assessment and categorization of pediatric asthma as mild intermittent, mild persistent, moderate

PEDIATRIC ASTHMA

33

persistent, or severe persistent. Based on the category of severity, therapies are recommended in a step-wise fashion with inhaled corticosteroids the preferred treatment for mild persistent disease. Combination therapy with inhaled corticosteroids is recommended for moderate to severe persistent disease. Finally, the guidelines recommend using a higher dose of inhaled steroid to gain control and then step down therapy as tolerated. Updated guidelines are anticipated by late 2007 and will focus on assessing asthma control as a function of the severity and frequency of asthma symptoms. Medications for asthma treatment are generally categorized as controller therapy and rescue therapy. Controller therapies include inhaled corticosteroids, leukotriene-modifying medications, and long-acting beta-agonists (LABAs). The goal of controller therapy is to minimize symptoms, decrease rescue use of bronchodilators, improve lung function, and prevent exacerbations, all using the least amount of medication possible. Controller therapies Inhaled corticosteroids According to the NHLBI guidelines, inhaled corticosteroids are the preferred ﬁrst-line controller therapy for persistent asthma for all age groups. This recommendation is based on numerous studies demonstrating that inhaled corticosteroid treatment results in decreased asthma symptoms, decreased use of rescue bronchodilator, and decreased frequency of acute asthma symptoms [24]. The largest study demonstrating the beneﬁt of inhaled corticosteroids in pediatric patients with asthma was the Childhood Asthma Management Program (CAMP), which showed that regular treatment with inhaled corticosteroids was superior to both nedocromil and placebo [25]. The subjects receiving inhaled corticosteroids experienced fewer hospitalizations and emergent care visits, decreased symptoms and use of albuterol rescue therapy, and fewer episodes of acute asthma requiring oral prednisone. Initiation of inhaled corticosteroids should be prompted when a patient demonstrates persistent asthma symptoms. Based on the severity of symptoms, patients should initially receive low to moderate doses of inhaled corticosteroids and be monitored for response. If improvement in symptoms, lung function, and rescue bronchodilator use is seen, the dose should be maintained and then later decreased if tolerated. If control is not obtained, then a trial of either a higher dose of inhaled corticosteroids or the addition of a second agent should be considered. Currently, the guidelines leave this decision to the clinician, but recent studies have shown that there is signiﬁcant heterogeneity in response to medications by asthmatics. In fact, a recent study demonstrated that, with increased inhaled corticosteroid dose and the addition of LABAs, only two thirds of the subjects gained control [26]. Additionally, by recent studies have demonstrated the limitations of inhaled corticosteroids. For example, the PEAK study was unable to demonstrate asthma prevention [5]. In fact, no clear evidence thus far has

34

STEWART

shown that inhaled corticosteroid treatment alters the natural progression of asthma. Multiple preparations of inhaled corticosteroids exist, including nebulized hydroﬂuoroalkane (HFA) metered dose inhalers and dry powder inhalers. Dosing diﬀers according to delivery device and steroid (Table 2). The most common side eﬀects of inhaled corticosteroids are local and include hoarseness or dysphonia, cough, and oral candidiasis. The stringent use of mouth rinsing can dramatically reduce the likelihood of these symptoms, as does the use of a spacer device. When oral candidiasis occurs, it is easily managed with topical antifungal therapy. Systemic side eﬀects seen with inhaled corticosteroids are usually limited to patients receiving very high doses and are similar to the side eﬀects seen with systemic corticosteroids: adrenal suppression, growth suppression, decreased bone density, myopathy, and weight gain. Many parents express concern about the risk of growth suppression, and previous studies have shown that moderate doses of inhaled corticosteroids have a small but detectable eﬀect on growth in the ﬁrst year. This eﬀect is much less with low doses and the long-term eﬀect on adult height is virtually undetectable, but may be seen with higher doses [27,28]. This risk may be increased in patients who are concurrently treated with additional topical steroids for their skin or nasal mucosa [29]. Despite this low risk, vigilance in following linear growth is still recommended for children on any dose of inhaled corticosteroids. Titration to the lowest eﬀective dose of inhaled corticosteroids for optimal disease control minimizes the possibility of adverse side eﬀects. Leukotriene-modifying medications Leukotriene-modifying agents include receptor antagonists, such as montelukast, and 5-lipoxygenase antagonists, such as zileuton. Montelukast is available orally as 10-mg tablets, as 4- and 5-mg chewable tablets, and as granule pouches. All doses are given once daily. Children 6 to 23 months should receive the 4-mg oral granules, children 2 to 5 years should receive the 4-mg chewable tablet, children 6 to 14 years should receive the 5-mg chewable tablet, and patients 15 years and older should receive the 10-mg oral tablet. Montelukast is generally well tolerated with only rare drug interactions. However, according to the most recent asthma guidelines, inhaled corticosteroids are the preferred treatment and montelukast is considered an alternative treatment. A recent study demonstrated that the children with the best response to montelukast alone were younger and had a shorter disease duration [30]. Long-acting beta-agonists Salmeterol and formoterol are the two LABAs currently available as single agents and as combination therapy combined with inhaled corticosteroids. LABAs are recommended as combination therapy for patients who are not controlled by a single agent. LABAs should always be used in combination with anti-inﬂammatory medications and not as a single controller

Table 2 Comparative dosing for inhaled corticosteroids Low dose

Medium dose

High dose

0–4 years

5–11 years

0–4 years

5–11 years

0–4 years

5–11 years

Beclomethasone HFA 40 or 80 mcg/puﬀ Budesonide DPI 90,180 or 200 mcg/inhalation Budesonide Respules 0.25, 0.5 or 1 mg Flunisolide 250 mcg/puﬀ Flunisolide HFA 80 mcg/puﬀ Fluticasone HFA/MDI 44, 110, or 220 mcg/puﬀ Fluticasone DPI 50, 100 or 250 mcg/inhalation Mometasone DPI 200 mcg/ inhalation Triamcinalone acetonide 75 mcg/puﬀ

NA

80–160 mcg

NA

160–320 mcg

NA

O320 mcg

NA

180–400 mcg

NA

400–800 mcg

NA

O800 mcg

0.25–0.5 mg

0.5 mg

0.5–1 mg

1 mg

O1 mg

2 mg

NA NA 175 mcg

500–750 mcg 160 mcg 88–176 mcg

NA NA 176–352 mcg

1000–1250 mcg 320 mcg 176–352 mcg

NA NA O352 mcg

O1250 mcg O640 mcg O352 mcg

NA

100–200 mcg

NA

200–400 mcg

NA

O400 mcg

NA

NA

NA

NA

NA

NA

NA

300–600 mcg

NA

600–900 mcg

NA

O900 mcg

PEDIATRIC ASTHMA

Inhaled corticosteroid

Data from National Asthma Education and Prevention Program. Expert Panel Report 3: guidelines for the diagnosis and management of asthma. August 2007:1–417. Available at: www.nhlbi.nih.gov/guidelines. Accessed December 14, 2007.

35

36

STEWART

agent. This recommendation is based on multicenter trial data demonstrating that inhaled corticosteroids are superior to LABAs as a single agent [31,32]. Additionally, another multicenter trial demonstrated a trend of increased severe asthma exacerbations and asthma-related deaths in patients receiving LABAs compared with patients receiving no LABAs [33]. This trial then raised questions about the mechanism leading to increased asthma morbidity and mortality, but post hoc analysis has suggested that a lack of controller therapy may have contributed to the noted eﬀect. Subsequently, this information prompted the Food and Drug Administration to require the companies that produce salmeterol (Serevent), formoterol (Foradil Aerolizer), Advair Diskus, and Symbicort HFA to include additional warnings in the product information about the potential for severe asthma exacerbations and even death. Salmeterol is available as dry powder Diskus and is approved for use in patients 12 years and older as one inhalation twice daily. It is also available as combination therapy with ﬂuticasone in Advair Diskus available in three inhaled corticosteroid doses. Advair 100/50 is approved for one inhalation twice daily in patients 4 years and older and two higher strengths are approved for twice daily dosing in patients 12 years and older. Formoterol is available as a single agent with one inhalation twice daily using the Foradil Aerolizer for patients 5 years and older. Symbicort HFA, a combination medication device containing formoterol and budesonide, is available in two strengths, 40/4.5 mg and 80/4.5 mg). Both strengths are dosed two puﬀs twice daily to patients 12 years and older. A recent pediatric trial demonstrated that in patients with moderate to severe asthma, the addition of a LABA (salmeterol) to an inhaled corticosteroid (ﬂuticasone) was more beneﬁcial than twice the inhaled corticosteroid dose [34]. Omalizumab Omalizumab is an anti-immunoglobulin E monoclonal antibody approved for treatment of moderate-severe allergic asthma in patients 12 years and older. Treatment with omalizumab has been shown to decrease acute asthma exacerbations [35]. In addition to local reactions at the injection site, risks include anaphylaxis (about 1 in 1000), according to post-marketing data. Based on this risk, the Food and Drug Administration has recently added a ‘‘black box’’ warning to the packaging of omalizumab and is encouraging provision of the medication in sites with the ability to treat anaphylaxis, education of the patient on the signs and symptoms of anaphylaxis, and observation after each injection. The indications for omalizumab include the following: age 12 years or older, moderate to severe asthma, suboptimal control on inhaled corticosteroids, and allergic sensitizations. Rescue medications Rescue medications, as their name implies, are reserved for symptomatic treatment of asthma. There are currently two short-acting bronchodilators or beta-agonists available and both are available in HFA metered dose

PEDIATRIC ASTHMA

37

inhalers and via nebulization. Of note, all metered dose inhalers containing chloroﬂuorocarbons are being replaced by the more environmentally friendly HFA propellant. Albuterol exists as a 1:1 racemic mixture of R-albuterol and S-albuterol. These two enantiomers are mirror images of each other in terms of their molecular structure. R-albuterol is more biologically active with a higher binding aﬃnity [36]. Although S-albuterol was originally thought to be inert, in vitro studies have suggested the possibility of some deleterious eﬀects, including smooth muscle contraction, increased hyperresponsiveness, and increased mucin production. This information prompted the development of pure R-albuterol or levalbuterol, which was initially suggested to be superior to racemic albuterol in regards to symptom improvement and side eﬀect proﬁle (Note that the dosing of levalbuterol is half that of racemic albuterol.). Unfortunately, the results of several large studies have been conﬂicting and thus far there does not seem to be a clear advantage to levalbuterol that justiﬁes the added cost [37]. Treatment for exercise-induced bronchospasm The standard treatment for exercise-induced asthma symptoms has been pretreatment with short-acting bronchodilators or beta-agonists 10 to15 minutes before onset of activity. Recently, montelukast has been shown to be an alternative treatment when taken as a single dose 2 hours before onset of activity [38]. Treatment for acute asthma In addition to some deaths, acute asthma accounts for signiﬁcant morbidity and cost (emergent visits, hospitalizations, missed productivity). The mainstays of acute asthma treatment include bronchodilator therapy and systemic corticosteroids (oral or parenteral). Bronchodilator therapy should employ albuterol or levalbuterol with a dose not more than 10 mg per hour of albuterol or 5 mg per hour of levalbuterol. Recent studies have also demonstrated that albuterol metered dose inhalers used with spacer devices are at least comparable to nebulized delivery [39]. In addition to bronchodilator therapy, anticholinergic therapy with ipratropium bromide used in combination has been shown to decrease hospitalization rates in children [40]. The NHLBI Expert Panel Guidelines recommend the prompt initiation of oral corticosteroid therapy for all moderate to severe asthma exacerbations. This recommendation is based on evidence that oral corticosteroid therapy prevents hospital admissions and hastens recovery [24]. Additionally, oral corticosteroid treatment is preferred and is consider equally eﬀective when compared with the parenteral route. Although the exact dose necessary to treat an acute exacerbation has been debated, it remains largely empiric and, in the end, is left to the clinician. Generally, the dose of prednisone is 1 to 2 mg/kg/day divided once to twice

38

STEWART

daily for 4 to 10 days with a maximum daily dose of 60 to 80 mg. A taper is not necessary for this length of treatment, but longer courses should include one. Oral dexamethasone and methylprednisolone are considered acceptable alternatives as well. Recently, the use of inhaled corticosteroids during acute exacerbations has been debated. Inhaled corticosteroids decrease the risk of potential adverse side eﬀects compared with systemic corticosteroids. A recent meta-analysis of four studies comparing inhaled corticosteroids to oral systemic corticosteroids in the setting of acute asthma demonstrated no difference between the two interventions in regard to relapse rate, bronchodilator use, or adverse events. However, because of small numbers and possible limitation to mild asthma exacerbations, equivalency could not be claimed [41]. Finally, a pediatric study showed that, although inhaled corticosteroids were beneﬁcial, patients experienced a more rapid resolution of symptoms with systemic corticosteroids if improvement of lung function was the outcome [42]. While initiating or doubling the dose of inhaled corticosteroids during acute mild asthma exacerbation has emerged to be a common practice among practitioners in an attempt to prevent the need for systemic corticosteroid therapy or development of more severe symptoms, there is no clear consensus of the exact role inhaled corticosteroids should have in the management of exacerbations in general [43]. It is critical that after an acute exacerbation, patients have follow-up with their primary physician to discuss treatment and potential triggers. Acute asthma exacerbations are also an excellent opportunity to discuss asthma action plans. There is evidence that patients with written asthma plans and peak expiratory ﬂow monitors are less likely to visit the emergency department, be hospitalized, or have low lung function [44]. Prognosis for the pediatric patient with asthma Because asthma prevention is not currently a viable option, early diagnosis and adequate control should be the goals of treatment. It appears that young children with mild symptoms usually do not develop persistent disease, whereas young children with more severe respiratory symptoms, significant airway hyperresponsiveness, and other allergic diseases are more likely to have persistent disease. With many of the asthma cohort studies, the hope was that early intervention with anti-inﬂammatory medications would alter the natural history of asthma. Unfortunately, this has not been the case. The lingering question was: Perhaps intervention was started too late? This prompted the PEAK study, which enrolled young children at risk for asthma. Although the long-term follow-up is still in progress, it appears that even this early intervention with inhaled corticosteroids in at-risk children was unable to alter the natural progression [5]. Now we are left with early identiﬁcation with intervention and the end goal of asthma control. Primary care physicians play critical roles in achieving this objective as they frequently encounter patients with pediatric asthma. These physicians,

PEDIATRIC ASTHMA

39

in consultation with subspecialty professionals, have a unique opportunity to improve the course of this common pediatric disease. References [1] Bloom B, Dey AN, Freeman G. Summary health statistics for U.S. children: national health interview survey, 2005. National Center for Health Statistics. Vital Health Stat 2006;10(231):1–83. [2] Centers for Disease Control and Prevention. Morbidity Mortality Weekly Reports. MMWR 2006;55(7):185. [3] Taussig LM, Wright AL, Holberg CJ, et al. Tucson children’s respiratory study: 1980 to present. J Allergy Clin Immunol 2003;111:661–75. [4] Sears MR, Greene JM, Willan AR, et al. A longitudinal, population-based cohort study of childhood asthma followed to adulthood. N Engl J Med 2003;349:1414–22. [5] Guilbert TW, Morgan WJ, Zeiger RS, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 2006;354:1985–97. [6] Sigurs N, Gustafsson PM, Bjarnason R, et al. Severe respiratory syncytial virus bronchiolitis in infancy and asthma and allergy at age 13. Am J Respir Crit Care Med 2005;171:137–41. [7] Lemanske RF. Viral infections and asthma inception. J Allergy Clin Immunol 2004;114: 1023–6. [8] Wark PA, Johnston SL, Bucchieri F, et al. Asthmatic bronchial epithelial cells have a deﬁcient innate immune response to infection with rhinovirus. J Exp Med 2005;201:937–47. [9] Hesselmar B, Aberg N, Aberg B, et al. Does early exposure to cat or dog protect against later allergy development? Clin Exp Allergy 1999;29:611–7. [10] Braun-Fahrander C, Reidler J, Herz U, et al. Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med 2002;347:869–77. [11] Ernst P, Cormier Y. Relative scarcity of asthma and atopy among adolescents raised on a farm. Am J Respir Crit Care Med 2000;161:1563–6. [12] Rosenstreich DL, Eggleston P, Kattan M, et al. The role of cockroach allergy and exposure to cockroach allergen in causing morbidity among inner-city children with asthma. N Engl J Med 1997;336:1356–63. [13] Ligonjua AA, Carey VJ, Burge HA, et al. Exposure to cockroach allergen in the home is associated with incident doctor-diagnosed asthma and recurrent wheezing. J Allergy Clin Immunol 2001;107:41–7. [14] Eggleston PA, Rosenstreich D, Lynn H, et al. Relationship of indoor allergen exposure to skin test sensitivity in inner-city children with asthma. J Allergy Clin Immunol 1998;102:563–70. [15] Halonen M, Stern DA, Wright AL, et al. Alternaria as a major allergen for asthma in children raised in a desert environment. Am J Respir Crit Care Med 1997;155:1356–61. [16] Saglani K, Malmstrom AS, Pelkonen LP, et al. Airway remodeling and inﬂammation in symptomatic infants with reversible airﬂow obstruction. Am J Respir Crit Care Med 2005;171:722–7. [17] Krawiec ME, Westcott JY, Chu HW, et al. Persistent wheezing in very young children is associated with lower respiratory inﬂammation. Am J Respir Crit Care Med 2001;163:1338–43. [18] Le Bourgeois M, Goncalves M, Le Clainche L, et al. Bronchoalveolar cells in children !3 years old with severe recurrent wheezing. Chest 2002;122:761–3. [19] Covar RA, Spahn JD, Murphy JR, et al. Progression of asthma measured by lung function in the childhood asthma management program. Am J Respir Crit Care Med 2004;170:234–41. [20] Crapo RO, Casaburi R, Coates AL, et al. Guidelines for methacholine and exercise challenge testing 1999. Am J Respir Crit Care Med 2000;161:309–29. [21] Castro-Rodriguez JA, Holberg CJ, Wright AL, et al. A clinical index to deﬁne risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med 2000;162:1403–6. [22] Guilbert TW, Morgan WJ, Zeiger RS, et al. Atopic characteristics of children with recurrent wheezing at high risk for the development of childhood asthma. J Allergy Clin Immunol 2004;114:1282–7.

40

STEWART

[23] Moller C, Dreborg S, Ferdousi HA, et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol 2002;109:251–6. [24] National Institutes of Health. Expert panel report 2: guidelines for the diagnosis and management of asthma, June 2002. Available at: www.nhlbi.nih.gov/guidelines. Accessed December 14, 2007. [25] The Childhood Asthma Management Program Research Group. Long-term eﬀects of budesonide or nedocromil in children with asthma. N Engl J Med 2000;343:1054–63. [26] Bateman ED, Boushey HA, Bousquet J, et al. Can guideline-deﬁned asthma control be achieved? The Gaining Optimal Asthma Control study. Am J Respir Crit Care Med 2004; 170:836–44. [27] Simons FER. A comparison of beclomethasone, salmeterol and placebo in children with asthma. N Engl J Med 1997;337:1659–65. [28] Agertoft L, Pedersen S. Eﬀect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med 2000;343:1064–29. [29] Allen DB. Inhaled steroids for children: eﬀects on growth, bone and adrenal function. Endocrinol Metab Clin North Am 2005;34:555–64. [30] Zeiger RS, Szeﬂer SJ, Phillips BR, et al. Response proﬁles to ﬂuticasone and montelukast in mild-to-moderate persistent childhood asthma. J Allergy Clin Immunol 2006;117:45–52. [31] Lazarus SC, Boushey HA, Fahy JV, et al. Long-Acting [beta] 2-agonist monotherapy vs continues therapy with inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial. J Am Med Assoc 2001;285:2583–93. [32] Lemanske RF Jr, Sorkness CA, Mauger EA, et al. Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: a randomized controlled trial. J Am Med Assoc 2001;285:2594–603. [33] Nelson HS, Weiss ST, Bleecker ER, et al. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006;129:15–26. [34] Sorkness CA, Lemanske RF Jr, Mauger DT, et al. Long-term comparison of 3 controller regimens for mild-moderate persistent childhood asthma: the Pediatric Asthma Controller Trial. J Allergy Clin Immunol 2007;119:64–72. [35] Busse W, Corren J, Lanier BQ, et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol 2001;108:184–90. [36] Waldeck B. Enantiomers of bronchodilating B2-adrenoceptor agonists: Is there a cause for concern? J Allergy Clin Immunol 1999;103:742–8. [37] Nelson HS, Bensch G, Pleskow WW, et al. Improved bronchodilation with levalbuterol compared with racemic albuterol in patients with asthma. 1999;102:943–52. [38] Pearlman DS, van Adelsberg J, Philip G, et al. Onset and duration of protection against exercise-induced bronchoconstriction by a single oral dose of montelukast. Ann Allergy Asthma Immunol 2006;97:98–104. [39] Cates CJ, Crilly JA, Rowe BH. Holding chambers versus nebulizers for beta-agonist treatment of acute asthma. Cochrane Database Sys Rev 2006;2:CD000052. [40] Qureshis F, Zartisky A, Lakkis H. Eﬃcacy of ipratropium in severely asthmatic children. Ann Emerg Med 1997;29:205–11. [41] Aﬁlalo M, Guttman A, Colacone A, et al. Eﬃcacy of inhaled steroids (beclomethasone dipropionate) for treatment of mild to moderately severe asthma in the emergency department: a randomized clinical trial. Ann Emerg Med 1999;33:304–9. [42] Nakanishi AK, Klasner AK, Rubin BK. A randomized controlled trial of inhaled ﬂunisolide in the management of acute asthma in children. Chest 2003;124:790–4. [43] Harrison TW, Oborne J, Newton S, et al. Doubling the dose of inhaled corticosteroid to prevent asthma exacerbations: randomized controlled trial. Lancet 2004;363:271–5. [44] Gibson PG, Powell H, Coughlan J, et al. Self-management education and regular practitioner review for adults with asthma. Cochrane Database Syst Rev 2004;(1):CD001117.

Prim Care Clin Office Pract 35 (2008) 41–60

Asthma Overview Ronald Balkissoon, MD, MSc, DIH, FRCPC National Jewish Medical and Research Center, The University of Colorado School of Medicine, 1400 Jackson Street, Room J215, Denver, CO 80206, USA

In the United States, asthma aﬀects over 22 million people and accounts for over 4000 deaths every year [1]. Asthma is a clinical diagnosis based on a symptom complex of episodic shortness of breath typically associated with wheezing, chest tightness, and cough and with objective physiological evidence of variable and reversible airﬂow obstruction with bronchial hyperresponsiveness. Airway inﬂammation plays a key role in the pathogenesis of asthma and ongoing research indicates that the underlying biology of asthma is complex and heterogeneous. Airway remodeling is presumed to be a result of undertreatment of airway inﬂammation. However, several features of airway remodeling may not be a direct result of airway inﬂammation and may be driven by genetics and factors as yet unappreciated. Inhaled corticosteroids remain the mainstay controller maintenance therapy for most asthmatics while other anti-inﬂammatory medications, such as leukotriene receptor antagonists, 5 lipoxygenase inhibitors or anti-IgE agents, may be helpful for certain individuals. An assessment of the severity of a patient’s asthma is important as a basis for deciding on initial therapeutic interventions. However, for deciding if therapy needs to be stepped up or stepped down, it is important to establish a patient’s personal best and arrange subsequent follow-up to ensure the patient is optimally controlled. Researchers are now focused on improving our understanding of the biological heterogeneity of asthma and increasing our capability to biologically phenotype patients by assessment of airway inﬂammation and/or pharmacogenomics. These novel clinical assessment tools will allow for better individualized therapy for asthma patients. This article presents our current understanding of the biological heterogeneity of asthma and reviews some of the key features of the latest proposed recommendations of the National Asthma Education and Prevention Program Guidelines [2].

E-mail address: [email protected] 0095-4543/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2007.09.008 primarycare.theclinics.com

42

BALKISSOON

Burden of illness Asthma is one of the most common chronic medical conditions in the developed world and is increasing in its prevalence in less developed countries as well. In the United States, over 22.2 million people are diagnosed with asthma [3]. Over 12.2 million people suﬀer asthma exacerbations (requiring increased asthma therapy and/or additional interventions) each year [3]. The total annual costs of asthma in the United States in 2002 were estimated to be $16.1 billion of which $11.5 billion were direct costs related to medical expenses and $4.5 billion were indirect costs related to lost work productivity and school days as well as mortality. There were 24.5 million lost workdays and 12.8 million missed school days in 2003 due to asthma [4]. There were almost half a million hospitalizations related to asthma in 2002, which approximates to about 16 hospitalizations per 10,000 population in the United States compared with 19.8 for diabetes and 37.4 for coronary atherosclerosis [3]. There were over 4200 asthma deaths in 2002 [3,4], indicating that over 11 people per day die of asthma in the United States. Many of the asthma deaths occur in otherwise healthy young productive individuals. Many of these deaths were almost certainly preventable if patients were treated more aggressively for their asthma. Data from the Salmeterol Multicenter Asthma Research Trial (SMART) showed that a number of those whose death was related to asthma had low use of inhaled corticosteroids despite having severe asthma [5].

What is asthma? The clinical presentation of asthma includes typical symptoms of episodic dyspnea variably associated with other symptoms, such as chest tightness, wheezing, and coughing. Typical triggers for asthma symptoms include allergens, exertion, cold air, irritant exposures, and strong odors. The hallmark features of asthma include reversible airﬂow obstruction (O12% improvement in forced expiratory volume in 1 second [FEV1] with a minimum of 200-mL improvement postbronchodilator), bronchial hyperresponsiveness, and airway inﬂammation, which most often involves an elevation in sputum eosinophils [6] and or elevations in exhaled nitric oxide [6]. While these elements represent the clinical features that lead to the diagnosis of asthma, these clinical features are not unique or the sole domain of asthma and these clinical characteristics are seen in a wide assortment of respiratory disorders. The symptom complex, the physiological features, and even certain histological features found in asthma are also found in other obstructive airway diseases and even in interstitial lung diseases that have an obstructive component, such as sarcoidosis and hypersensitivity pneumonitis. Furthermore, bronchoscopic and sputum studies that have examined the inﬂammatory features of patients who have the clinical diagnosis of asthma reveal that there is indeed signiﬁcant heterogeneity in the magnitude and types

ASTHMA OVERVIEW

43

of inﬂammatory cells and mediators involved in various patients that ﬁt the clinical phenotype we refer to as asthma. This biological diversity is part of the explanation for the variable response to pharmacological and nonpharmacological interventions observed in the asthma population. Hence, it is best to think of asthma as a clinical diagnosis that has typical symptom and physiological features but also has several biological mechanisms that contribute to the ﬁnal clinical phenotype. There are several distinct clinical phenotypes of asthma (Box 1) and it is likely that these are the result of environmental factors and diﬀerent biological pathways being less or more active for diﬀerent clinical presentations [7]. We recognize early- versus lateonset asthma [8] and we know that most early-onset asthmatics have environmental allergies whereas late-onset asthmatics are less atopic yet tend to have higher eosinophil counts in sputum and/or bronchoalveolar lavage [9]. Some asthmatics appear to have primarily nocturnal asthma [10,11], exercise-induced asthma [12], or cough variant asthma [13] in isolation. These patients may have distinct biological characteristics that diﬀerentiate them from the more common group of asthmatics that have any or all of these features as a reﬂection of poorly controlled disease in general. Meanwhile, some people develop occupational asthma related to high molecular weight allergens (eg, ﬂour, latex, animal proteins) with classic IgE-mediated allergic reactions versus low molecular weight antigens, most often such chemicals as isocyanates or acid anhydrides where the precise mechanism is not as clear [14]. In addition, some individuals develop reactive airways dysfunction syndrome because of single or multiple high-dose exposures to irritants [15]. Finally, some patients have so-called ‘‘inner-city asthma’’ or ‘‘urban asthma,’’ which is based on reports of higher prevalence rates and more severe disease found in urban populations. This asthma most likely reﬂects a complex interaction of socio-economic, environmental, and, potentially, biological factors.

Box 1. Clinical heterogeneity of asthma Allergic versus nonallergic asthma Late- versus early-onset asthma Exercise-induced asthma Nocturnal asthma Cough variant asthma Work-related asthma Work-aggravated asthma Occupational asthma Large molecular weight (classic IgE) Low molecular weight (Non-IgE) Reactive airways dysfunction syndrome Inner-city (urban) asthma

44

BALKISSOON

Asthma among urban populations has gained recognition and is an area of focused research [16–18]. Pathogenesis/pathophysiology of asthma As previously stated, the pathogenesis of asthma is varied and there are several biological pathways, inﬂammatory cells, and mediators that play varying roles in diﬀerent patient phenotypes (Fig. 1) [19]. While several inﬂammatory cell types may play important roles in asthma, eosinophils have classically been identiﬁed as part of the most common histological pattern. However, the exact role of eosinophils and their importance remain controversial. Mast cells and basophils, when stimulated by allergen-induced release of IgE from activated B lymphocyte memory cells known as plasma cells, release a host of chemical mediators (interleukin-1, -2, -3, -4, and -5, as well as granulocyte-macrophage colony stimulating factor [GMCSF], interferon g [IFN-g], and tumor necrosis factor a [TNF-a]) that lead to bronchoconstriction and recruitment of other inﬂammatory cells, such as neutrophils, T-lymphocytes, and macrophages, which also release inﬂammatory mediators and contribute to the inﬂammatory soup. Interleukin-5 is of particular interest because it has a central role in the regulation of eosinophil production and release from the bone marrow. There are other chemokines, such as RANTES (regulated upon activation in normal T cells, expressed and secreted protein), eotaxin, and macrophage inﬂammatory protein-1a

Fig. 1. The inﬂammatory cascade of asthma is much more complex than this drawing indicates. Even so, the ﬁgure illustrates that several pathways are involved in the pathogenesis of asthma. GM-CSF, granulocyte macrophage colony-stimulating factor; IL, interleukin; MCP-1, monocyte chemotactic protein 1; RANTES, regulated upon activation in normal T cells, expressed and secreted protein; Th, T-helper lymphocytes; TNF, tumor necrosis factor.

ASTHMA OVERVIEW

45

that participate in the migration of these inﬂammatory cells to the airway. With such a diversity of cell types involved in the inﬂammatory process, it is easy to appreciate how there can be signiﬁcant heterogeneity in clinical presentation and response to therapy simply on the basis of the relative contribution of the various cell types and inﬂammatory pathways for any individual patient. While eosinophils have a central role in the pathogenesis of typical asthma, their exact role is still under investigation. Studies with a monoclonal antibody that binds to interleukin-5, thus blocking a potent stimulus for the maturation and release of eosinophils, have not shown that obstructing the release of eosinophils profoundly changes the severity of bronchial hyperresponsiveness or the clinical course for many asthmatics despite signiﬁcantly reducing the eosinophils seen in biopsy or induced sputum specimens [20]. T-helper (Th) lymphocytes are also recognized as having a central role in the inception and progression of asthma. It has been proposed that individuals predisposed to developing allergic asthma have an imbalance favoring Th-2 cells, which produce a family of cytokines that mediate allergic inﬂammation, including interleukin-4, -5, -6, -9, and -13, rather than favoring Th-1 cells, which normally produce cytokines to ﬁght infection, such as interleukin-2 and IFN-g. The hygiene hypothesis suggests that reduced exposure to other children, frequent antibiotic use, and reduced exposure to certain infections (eg, tuberculosis, measles, and hepatitis A) promote the development of a Th-2 phenotype more prone to respond to environmental allergens. This gene-by-environment interaction is oﬀered as a plausible explanation for the observed higher prevalence of asthma in Westernized countries [21,22]. Wenzel [23] have determined that some asthmatics have a neutrophil-predominant inﬂammatory pattern or no signiﬁcant inﬂammation at all but rather extensive smooth muscle hypertrophy and mucous gland hyperplasia. Kraft and others [24] have shown that some asthmatic patients have a small airway (bronchiolar) inﬂammation that may be diﬃcult to target with inhaled medication. Patients with severe persistent asthma and indeed fatal asthma have additional airway features, including mucous gland hyperplasia, mucous plugging, collagen deposition, basement membrane thickening, bronchial smooth muscle hypertrophy, new blood vessel growth, and goblet cell hyperplasia (Fig. 2). These are the key elements of what is referred to as airway remodeling. Much remains to be learned about the pathogenesis of airway remodeling and why some asthmatics are more prone to develop it than others. While undertreatment of the inﬂammatory component of asthma likely contributes to the development of airway remodeling, it is clear that other factors, particularly genetic predisposition and environmental exposures, may make some asthmatics more prone to develop airway remodeling [25]. Szeﬂer and colleagues [26] have shown that some patients have a relative insensitivity to the anti-inﬂammatory eﬀects of steroids. These ﬁndings and observations help us understand at least part of the reason why some

46

BALKISSOON

Fig. 2. Key elements for assessing asthma severity. (Adapted from National Heart, Lung, and Blood Institute. Expert panel report: guidelines for the diagnosis and management of asthma. 1991. Bethesda (MD): U.S. Department of Health and Human Services; 1991, National Institutes of Health publication 91–3042.)

asthmatics are more diﬃcult to control than others. By improving our understanding of this heterogeneity (Box 2) and ﬁguring out ways to assess it by noninvasive means, we will be able to biologically phenotype patients and tailor therapy accordingly.

Clinical assessment of asthma Assessing for the presence of asthma As noted above, patients suspected of having asthma typically present with a history of episodic shortness of breath associated with chest tightness and variable wheezing and coughing. Typically there are a number of triggers,

Box 2. Summary of variable biological characteristics in asthma Eosinophilic predominant Neutrophil predominant Noninflammatory (smooth muscle hypertrophy and mucous gland hyperplasia) Small airway predominant Beta-receptor polymorphisms Steroid insensitivity: Abnormal glucocorticosteroid absorption and/or metabolism Glucocorticoid receptor polymorphisms

ASTHMA OVERVIEW

47

such as extremes of air temperature and humidity; air pollution; strong odors, such as from perfume and cleaning agents; dust; and smoke. If individuals are known to be atopic, then exposure to common environmental allergens, such as trees, weeds, grasses, animal dander, mold, dust mites, and cockroaches, can be potent triggers for their symptoms, depending on their particular atopic proﬁle. Because between 10% and 20% of adult asthma may be work related [27], adult-onset asthmatics should always be asked regarding occupational exposures and hobbies that may expose them to potential allergens. For younger nonsmoking patients with a typical history, many clinicians make a diagnosis of asthma and start therapy without consulting other specialists. Many patients with this symptom complex are diagnosed with asthma by their primary care physicians without any physiological baseline assessment, such as pre- and postbronchodilator response. This is suboptimal. A baseline physiological assessment is essential for gathering data to establish severity as well as to assess when a patient has reached his or her personal best. Furthermore, a physiological assessment could reveal a nonobstructive pattern suggesting interstitial lung disease. Also, a physiological assessment could show that a patient’s degree of dyspnea is disproportionate to his or her spirometry, in which case other diagnoses should be considered and further testing performed. Diﬀerential diagnosis of asthma When patients ﬁrst present and, perhaps more importantly, when patients don’t respond optimally to asthma therapy, the provider must consider the conditions that may mimic or exacerbate asthma (Box 3). In the adult population, the most common conditions that need to be ruled out in asthmatics are allergic or nonallergic rhinitis with postnasal drainage, gastroesophageal reﬂux disease, and, in smokers who have smoked more than 10 packs per year,

Box 3. Differential diagnosis of asthma Chronic bronchitis Chronic obstructive pulmonary disease Postnasal drip Gastroesophageal reflux disease Paradoxical vocal fold motion disorder (vocal cord dysfunction) Aspiration Chronic mycoplasma infection Bronchiectasis Bronchiolitis (constrictive, obliterative, related to collagen vascular diseases) Hypersensitivity pneumonitis Sarcoidosis

48

BALKISSOON

chronic obstructive pulmonary disease. Patients with allergic rhinitis may have signiﬁcant postnasal drainage that leads to cough wheezing and shortness of breath that can mimic asthma. Patients with gastroesophageal reﬂux disease can have bronchoconstriction just as a result of acid reﬂuxed into the esophagus stimulating bronchoconstriction through a neural reﬂex, or they may induce bronchoconstriction as a result of reﬂuxate being aspirated into the lungs [28]. Paradoxical vocal fold motion disorder (PVFMD), also known as vocal cord dysfunction (VCD), may mimic or complicate asthma. The paradoxical closure of the vocal folds classically during inspiration, but also seen during expiration, is associated with cough wheezing and shortness of breath and often coexists with postnasal drip and gastroesophageal reﬂux disease [28]. Some patients who have PVFMD and laryngopharyngeal reﬂux (reﬂux into the throat) without frank gastroesophageal reﬂux disease may have PVFMD in isolation. Some such patients may microaspirate this reﬂuxate, leading to asthma symptoms or reports of recurrent pneumonia. In the past, we thought of chronic obstructive pulmonary disease patients as generally having a minimal bronchodilator response and no evidence of airway hyperresponsiveness. Now we recognize that many patients with a clinical history and histological features closely compatible with chronic obstructive pulmonary disease have higher signiﬁcant bronchodilator response, evidence of airway hyperresponsiveness, or both [29]. Truncated ﬂow-volume loops and laryngoscopic ﬁndings of paradoxical closure conﬁrm the diagnosis. Many lung conditions can have asthmatic features, including sarcoidosis, hypersensitivity pneumonitis, and, to a much lesser extent, other interstitial lung diseases. Bronchiectasis, a dilation of airways due to chronic inﬂammation causing destruction of the airway wall, can present with symptoms and objective physiological assessments similar to those of asthma. Allergic bronchopulmonary mycosis, chronic colonization of the airways leading to an allergic response, is often a complication of asthma but may also develop in patients who have bronchiectasis for other reasons, such as cystic ﬁbrosis, primary ciliary dyskinesia, and immunodeﬁciency states, such as common variable immunodeﬁciency, which render patients more susceptible to recurrent infections. Patients who have postinfectious bronchiolitis or bronchiolitis for any number of other reasons, underlying collagen vascular disease and certain prescription and illicit drugs may have a clinical presentation suggestive of asthma. Assessment of severity Because of the importance of an asthma diagnosis, the initial assessment of asthma severity should include an assessment of symptoms and lung function. Recommendations in this article follow the latest version of guidelines from the National Asthma Education and Prevention Program (NAEPP) (draft available for review online until March 2007 but currently unpublished) in preference over the last published update in 2002 [30]. In otherwise

ASTHMA OVERVIEW

49

healthy asthmatics, assessment of lung function often reveals normal values that may underestimate the severity of their disease. This means the assessment of symptoms, such as the frequency of nocturnal awakenings, the need for rescue short-acting beta-agonist, the amount of school or work missed, and impact on overall quality of life often reveals a greater severity than reﬂected by pre- or postbronchodilator spirometry. Fuhlbrigge and colleagues [31] conducted a telephone survey of over 42,000 households and found 3273 homes with asthmatic adults (O16 years old) who answered questions from the NAEPP Panel II Severity Criteria Questionnaire. Over 77.3% of the patients interviewed had moderate or severe persistent asthma, about 7.3% met criteria for intermittent asthma, and 15.4% meet the criteria for mild persistent asthma. It is still imperative, however, that asthmatics be assessed with objective measures of lung function, such as peak ﬂow monitoring and routine spirometry. Many clinicians rely on spirometry as the best or most objective assessment of asthma severity and/or control. However, studies have shown that simple spirometry has a poor correlation with symptoms [32]. Many factors likely contribute to this discordance between spirometry, symptoms, and the severity of asthma and these factors have varying importance from one patient to another. Patients vary in sensitivity to their own dyspnea [33,34]. Hence, some patients have signiﬁcant symptoms with relatively well preserved lung function, while others have minimal reported symptoms but signiﬁcantly reduced lung function. Also, some asthma patients who have well-preserved baseline lung function also have signiﬁcant bronchial hyperreactivity such that with various stimuli, such as irritant odors, particulate, allergens, or exercise, they can have profound bronchospasm with cough, chest tightness, wheezing, and shortness of breath, but because of a robust response to bronchodilator they return to normal or perhaps even supernormal baseline values. For some patients, asthma may aﬀect smaller airways more than large airways and severity may be underestimated because there is a poor correlation between FEV1 and small airway involvement. Hence, it is not enough to measure spirometry. One must evaluate several elements (as outlined above) to assess an asthmatic’s severity and level of control. The severity level is determined by assigning a severity level for each category (daytime symptoms, nocturnal symptoms, rescue albuterol use, corticosteroid use, spirometry, and peak ﬂow assessment) and identifying the highest severity level found in any of these categories. For example, a patient with perfectly normal lung function but daily symptoms and use of albuterol would be in the very severe category despite normal lung function. Assessing asthma risk In addition to assessing an asthmatic’s severity, it is also important to establish that person’s risk for serious adverse outcomes. Hence patients should be asked about the frequency and severity of exacerbations. These

50

BALKISSOON

questions should cover, for example, medication and medical attention requirements; stays in emergency rooms, hospital wards and intensive care units; and experience with ventilation. Furthermore, it is important to ask about the use of oral steroids and to include lung function in this assessment. Recent studies have suggested that measurements of inﬂammatory markers, such as sputum eosinophils and exhaled nitric oxide, might improve assessments of severity and risk for serious adverse outcomes [35]. Assessing control The goals of asthma therapy are to achieve total asthma control and to deﬁne the personal best for each individual patient. In working toward these goals, the principal aims are to reduce impairment and risk. Reducing impairment means to improve or minimize chronic symptoms and rescue inhaler use and to maintain lung function and activity levels while meeting the patient’s and his or her family’s expectations. Reduction of risk involves preventing exacerbations, minimizing urgent care visits or hospitalization, and preventing loss of lung function with optimum pharmacotherapy with minimal or no adverse eﬀects. The Asthma Control Test is a standardized questionnaire that has been validated and shown to be as instructive as spirometry and standard questions (Box 4). When assessing the degree of asthma severity and control, it is important to know whether or not the patient is on controller medication. If the patient is not on controller medications, then the clinician uses the criteria above to establish severity and degree of control. If the patient is on controller medications, then the clinician must also use the criteria outlined above but, in addition, include what level of controller medication is required to keep the patient under control or at his or her best level of control. Obviously the asthmatic who requires high-dose inhaled corticosteroids and long-acting betaagonists may achieve good control but is clearly severe when one takes into account the medication needed to keep at that level of control. A preliminary draft of the latest version of the NAEPP asthma guidelines has provided evidenced-based recommendations for the management of asthma for infants through adults [2]. The grading system proposed in the latest NAEPP guidelines is outlined in Box 5.

Asthma management for infants to age 11 For children from infancy through to the age of 4 (Box 6), there is A-level evidence that inhaled corticosteroids for patients with persistent asthma are safe and eﬀective ﬁrst-line therapy. Because few drugs are ever studied in this patient population, the level of evidence for use of long-acting betaagonists, montelukast, and oral steroids at higher severity stages is no higher than D. For children between ages of 5 to 11, studies have shown the beneﬁt of inhaled corticosteroids at all stages of therapy (level A evidence) and

51

ASTHMA OVERVIEW

Box 4. Asthma Control Test for patients 12 years old 1. In the past 4 weeks, how much of the time did your asthma keep you from getting as much done at work, school or at home? 1 All of the time 2 Most of the time 3 Some of the time 4 A little of the time 5 None of the time 2. During the past 5 weeks, how often have you had shortness of breath? 1 More than once a day 2 Once a day 3 Three to six times a week 4 Once or twice a week 5 Not at all 3. During the past 4 weeks, how often did your asthma symptoms (wheezing, coughing, shortness of breath, chest tightness, or pain) wake you up at night or earlier than usual in the morning? 1 Four or more nights a week 2 Two or 3 nights a week 3 Once a week 4 Once or twice 5 Not at all 4. During the past 4 weeks, how often have you used your rescue inhaler or nebulizer medication (such as albuterol)? 1 Three or more times per day 2 One or two times per day 3 Two or three times per week 4 Once a week or less 5 Not at all 5. How would you rate your asthma control during the past 4 weeks? 1 Not controlled at all 2 Poorly controlled 3 Somewhat controlled 4 Well controlled 5 Completely controlled

Score: _____ _____ _____ _____ _____ Score: _____ _____ _____ _____ _____

Score: _____ _____ _____ _____ _____

Score: _____ _____ _____ _____ _____ Score: _____ _____ _____ _____ _____

Level of control based on composite score: ‚20, controlled; 16–19, not well controlled; •15, very poorly controlled regardless of patient’s self assessment of control in question 5. Available at: http://www.nhlbi.nih.gov/guidelines/asthma/ epr3/resource.pdf. Accessed February 5, 2007. Courtesy of QualityMetric, Inc., Lincoln, RI; with permission. Copyright Ó 2002 QualityMetric Incorporated. Asthma Control Test is a trademark of QualityMetric Incorporated. Available at: http://www.asthmacontrol.com. Accessed December 14, 2006.

52

BALKISSOON

Box 5. Grading system for evidence-based recommendations Level A evidence: based on randomized, controlled trials with rich body of data Level B evidence: based on randomized, controlled trials with limited body of data Level C evidence: based on nonrandomized trials and observational studies Level D evidence: based on panel consensus judgment increasing doses of inhaled corticosteroids in combination with long-acting beta-agonists as preferred treatment for steps two through ﬁve (level B evidence). The use of these medications in addition to long-term oral steroids remains a consensus opinion because few studies are done on this patient population (Box 7). Asthma treatment for those 12 years or older For patients 12 years old and older, inhaled corticosteroids are the mainstay of therapy for all steps of asthma care with increasing doses through steps 2 to 6 (level A evidence) (Box 8). For patients with mild moderate Box 6. NAEPP draft guidelines for stepped approach to managing asthma in children aged 0 to 4 years Step 1 (intermittent asthma): short-acting beta-agonist as needed Step 2 (mild persistent asthma) Preferred: low-dose inhaled corticosteroid (supported by level A evidence) Alternatives: montelukast (supported by level A evidence) or cromolyn (supported by level B evidence) Step 3 (moderate to severe persistent asthma): medium-dose inhaled corticosteroid (supported by level D evidence) Step 4 (moderate to severe persistent asthma): medium-dose inhaled corticosteroid and either montelukast or long-acting beta-agonist (supported by level D evidence) Step 5 (moderate to severe persistent asthma): high-dose inhaled corticosteroid and either montelukast or long-acting beta-agonist (supported by level D evidence) Step 6 (moderate to severe persistent asthma): high-dose inhaled corticosteroid and either montelukast or long-acting beta-agonist and/or oral corticosteroid (supported by level D evidence)

ASTHMA OVERVIEW

53

Box 7. NAEPP draft guidelines for stepped approach to managing asthma in children aged 5 to 11 years Step 1 (intermittent asthma): short-acting beta-agonist as needed Step 2 (mild persistent asthma) Preferred: low-dose inhaled corticosteroid (supported by level A evidence) Alternatives: leukotriene receptor antagonist, cromolyn, or theophylline (each supported by level B evidence) Step 3 (moderate/severe persistent asthma): medium-dose inhaled corticosteroid alone or low-dose inhaled corticosteroid and either long-acting beta-agonist, leukotriene receptor antagonist, or theophylline (each supported by level B evidence) Step 4 (severe persistent) Preferred: medium-dose inhaled corticosteroid and long-acting beta-agonist (supported by level B evidence) Alternatives: medium-dose inhaled corticosteroid and either or zileuton, leukotriene receptor antagonist, or theophylline (each supported by level B evidence) Step 5 (severe persistent) Preferred: high-dose inhaled corticosteroid and long-acting beta-agonist (supported by level B evidence) Alternatives: high-dose inhaled corticosteroid and either leukotriene receptor antagonist or theophylline (each supported by level B evidence). Consider omalizumab for patients who have allergies. Step 6 (severe persistent) Preferred: high-dose inhaled corticosteroid, long-acting beta-agonist, and oral corticosteroid (supported by level D evidence) Alternatives: high-dose inhaled corticosteroid, either leukotriene receptor antagonist or theophylline, and oral corticosteroid (supported by level D evidence). Omalizumab may be considered for patients who have allergies.

asthma (stage 3) long-acting beta-agonists can be added to low-dose corticosteroids if moderate-dose corticosteroids cause too many side eﬀects or are poorly tolerated (level A evidence). When patients have more severe disease, long-acting beta-agonists are considered for adding to medium- to high-dose steroids (level B evidence). While it is possible to consider alternative agents for treatment of stage 2 asthma, none of the other agents oﬀered as alternatives (eg, cromolyn,

54

BALKISSOON

Box 8. NAEPP draft guidelines for stepped approach to managing asthma in patients aged 12 years and older Step 1 (intermittent asthma): short-acting beta-agonist as needed Step 2 (mild persistent asthma) Preferred: low-dose inhaled corticosteroid (supported by level A evidence) Alternatives: cromolyn, nedocromil, leukotriene receptor antagonist, or theophylline (each supported by level B evidence) Step 3 (moderate persistent asthma) Preferred: medium-dose inhaled corticosteroid alone or low-dose inhaled corticosteroid and long-acting beta-agonist (both supported by level A evidence) Alternatives: low-dose inhaled corticosteroid and either leukotriene receptor antagonist (supported by level A evidence), theophylline (supported by level B evidence), or zileuton (supported by level D evidence) Step 4 (severe persistent asthma): medium-dose inhaled corticosteroid and long-acting beta-agonist (supported by level B evidence) Step 5 (severe persistent asthma): high-dose inhaled corticosteroid and long-acting beta-agonist (supported by level B evidence). Consider omalizumab for patients who have allergies (supported by level B evidence). Step 6 (severe persistent asthma): high-dose inhaled corticosteroid, long-acting beta-agonist, and oral corticosteroid. Consider omalizumab for patients who have allergies.

nedocromil, leukotriene receptor antagonists, or theophylline) are as eﬀective as inhaled corticosteroids (level B evidence). The role of zileuton, a 5 lipoxygenase inhibitor that reduces the production of leukotriene B-4, remains less established but can be considered for patients who have not been optimally controlled on inhaled corticosteroids and long-acting betaagonists and/or leukotriene D-4 receptor antagonists, such as montelukast (level D evidence). Some work suggests 5 lipoxygenase inhibitors may not only be useful for patients with asthma associated with an eosinophilic inﬂammatory response but also for those with a neutrophilic response [36]. Omalizumab, the new anti-IgE agent, is recommended as adjunctive therapy for asthma patients with allergies who are not controlled on high-dose inhaled corticosteroids and long-acting beta-agonists (step 5) and/or oral steroids (step 6) (level B evidence).

ASTHMA OVERVIEW

55

Theophylline remains on the list of alternative therapies. Some evidence shows that theophylline may be able to augment steroid responsiveness through up-regulation of the histone deacetylases, which down-regulates expression of inﬂammatory genes [37]. However, ongoing concerns remain about the narrow therapeutic window for theophylline, which is why it remains a third-tier option for most physicians (level B evidence).

Safety issues Long-acting beta-agonists There has been concern recently regarding the safety of such long-acting beta-agonists as salmeterol and formoterol. SMART [5] examined the safety of salmeterol compared with placebo in over 26,000 patients. Patients who stated they had a diagnosis of asthma and were on at least one medication used for asthma (even a short-acting beta-agonist) could be entered into the trial. Patients who had never been on a long-acting beta-agonist were excluded. Patients were given medication for the study duration and were followed up only by telephone interview every 4 weeks over the 28 weeks of the study. This study raised concerns because there were increased respiratory deaths or life-threatening experiences noted in the African American male population using salmeterol compared with placebo (relative risk 4.1; 95% CI, 1.54–10.9). The study found that this group also tended to use oral steroids more frequently, to have more frequent and longer hospitalizations, to have higher rates of intubation, and to use less inhaled corticosteroids as maintenance therapy compared with the other groups studied. There are legitimate concerns about the overuse of beta-agonist medications causing adverse eﬀects and perhaps even attenuating the beta-receptor’s response to beta-agonists for a subset of asthma patients who have certain polymorphisms of the beta-receptor ARG-ARG [38]. However, the ﬁndings of SMART likely reﬂect suboptimal compliance with inhaled corticosteroids. The consequent ‘‘black box’’ warning imposed by the Food and Drug Administration in the United States emphasizes that patients should be optimized on inhaled corticosteroids before the use of long-acting beta-agonists is considered. Hence, while further studies are needed to clarify the safety of long-acting beta-agonists in asthma patients that have certain beta-receptor polymorphisms, the vast majority of asthma patients are likely to beneﬁt from the use of these medications when inhaled corticosteroids alone are unable to achieve total control or when there are intolerable side eﬀects from higher dose inhaled corticosteroids. Omalizumab Omalizumab, a highly humanized monoclonal antibody against IgE, has been shown to reduce exacerbations [39–41] and steroid requirements

56

BALKISSOON

[39–41] for patients with allergic asthma. Omalizumab has been recommended for use in patients who are not optimally controlled on standard therapies or have signiﬁcant side eﬀects from inhaled corticosteroids [42]. Because omalizumab is systemically delivered, this agent may be eﬀective in patients who have signiﬁcant smaller airway disease. Earlier in 2007, there were concerns raised regarding potentially signiﬁcant anaphylactic events [43–45] despite the molecule being approximately 95% humanized with a 5% complimentary determining region that is mouse derived. Xolair, a brand of omalizumab, received a ‘‘black box’’ warning that states it should be administered in a monitored medical setting with personnel trained and able to manage anaphylaxis, but there is no speciﬁc time requirement as to how long patients should be monitored.

Setting up patients with asthma action plans In devising asthma action plans for patients, perhaps the ﬁrst question to ask is: Which asthma patients need such a plan? There has been some debate as to whether plans make a diﬀerence and some studies have suggested that outcomes were not signiﬁcantly altered in groups given action plans compared with those that were not [46–48]. Nonetheless, it is likely that there are at least some patients for whom action plans are helpful, such as those who have frequent exacerbations and those who are poor perceivers or have diﬃculty with adherence or compliance. Asthma action plans should enable the patient and his or her family to deal with any asthma emergency, to detect early signs of an exacerbation, and to intervene promptly to prevent urgent or emergency care visits and hospitalizations. Asthma action plans should contain such information as (1) a list of triggers known to worsen the individual’s asthma, (2) typical symptoms that suggest a worsening of asthma, (3) peak ﬂow meter readings, and (4) measurements of a personal best and zones with green indicating 80% to 100% of personal best, yellow indicating 50% to 79% of personal best, and red indicating less than 50% of personal best. Peak ﬂow levels fall and symptoms dictate what actions should be taken, ranging from allergen avoidance, to increasing inhaled corticosteroids, to seeking immediate medical attention (Fig. 3) (refer to http://www.nationaljewish.org/pdf/ asthma-action-plan.pdf).

Summary The diagnosis of asthma is based on such clinical features as variable airﬂow obstruction that is partially if not fully reversible and airway hyperresponsiveness that predisposes to episodic bronchospasm following exposure to a variety of triggers, which diﬀer from patient to patient. The underlying inﬂammation and airway biology of asthma is heterogeneous and is part of

Fig. 3. National Jewish Medical and Research Center Asthma Action Plan. (Courtesy of National Jewish Medical and Research Center, Denver, CO; with permission.)

58

BALKISSOON

the explanation for the variable response to therapy. New biologics, such as anti-IgE agents, and other new techniques that help to characterize patients according to their underlying biology will aid in making better choices for treatment. The new NAEPP asthma guidelines emphasize the importance of regular monitoring of several factors, including daytime and nighttime symptoms; interference with school, work, and other activities; rescue albuterol use; exacerbations; personal assessment of level of control; and lung function, so that appropriate choices are made regarding stepping up or stepping down therapy. When feasible, assessment of airway inﬂammation by noninvasive measures, such as sputum eosinophils or exhaled nitric oxide, provide the earliest indications of worsening asthma and allow treatment interventions earlier, which ultimately may lead to fewer exacerbations and lower inhaled steroid requirements.

References [1] Getahun D, Demissie K, Rhoads GG. Recent trends in asthma hospitalization and mortality in the United States. J Asthma 2005;42(5):373–8. [2] National Institutes of Health/National Heart Lung and Blood Institute. NAEPP, National Asthma Education and Prevention Program Expert Panel report: guidelines for the diagnosis and management of asthma: update on selected topics 2007 (preliminary online version for review) 2007. Available at: www.nhlbi.nih.gov/guidelines/asthma. Accessed November 28, 2007. [3] Center for Disease Control and Prevention. Asthma prevalence, health care use and mortality, United States, 2003–2005 March 12, 2007. Available at: http://www.cdc.gov/nchs/ products/pubs/pubd/hestats/asthma/asthma.htm. Accessed March 12, 2007. [4] American Lung Association. Trends in asthma morbidity and mortality. 2006. American Lung Association Epidemiology and Statistics Unit Research Program Services. p. 1–40. [5] Nelson HS, Weiss ST, Bleecker ER, et al. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006;129(1):15–26. [6] Hargreave FE. Quantitative sputum cell counts as a marker of airway inﬂammation in clinical practice. Curr Opin Allergy Clin Immunol 2007;7(1):102–6. [7] Wenzel SE. Asthma: deﬁning of the persistent adult phenotypes. Lancet 2006;368(9537): 804–13. [8] Miranda C, Busacker A, Balzar S, et al. Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inﬂammation. J Allergy Clin Immunol 2004;113(1):101–8. [9] Wenzel S. Physiologic and pathologic abnormalities in severe asthma. Clin Chest Med 2006; 27(1):29–40. [10] Silkoﬀ PE, Martin RJ. Pathophysiology of nocturnal asthma. Ann Allergy Asthma Immunol 1998;81(5 Pt 1):378–83 [quiz: 384–7]. [11] Kraft M, Pak J, Martin RJ, et al. Distal lung dysfunction at night in nocturnal asthma. Am J Respir Crit Care Med 2001;163(7):1551–6. [12] Hilberg T. Etiology of exercise-induced asthma: physical stress-induced transcription. Curr Allergy Asthma Rep 2007;7(1):27–32. [13] Doan T, Patterson R, Greenberger PA. Cough variant asthma: usefulness of a diagnostictherapeutic trial with prednisone. Ann Allergy 1992;69(6):505–9. [14] Lemiere C. Diagnosing occupational asthma: insight from induced sputum. Can J Physiol Pharmacol 2006;84(1):1–4.

ASTHMA OVERVIEW

59

[15] Brooks SM, Hammad Y, Richards I, et al. The spectrum of irritant-induced asthma: sudden and not-so-sudden onset and the role of allergy. Chest 1998;113(1):42–9. [16] Busse WW, Mitchell H. Addressing issues of asthma in inner-city children. J Allergy Clin Immunol 2007;119(1):43–9. [17] Akerman M, Valentine-Maher S, Rao M, et al. Allergen sensitivity and asthma severity at an inner city asthma center. J Asthma 2003;40(1):55–62. [18] Eggleston PA. Environmental causes of asthma in inner city children. The National Cooperative Inner City Asthma Study. Clin Rev Allergy Immunol 2000;18(3):311–24. [19] Wenzel SE. Phenotypes in asthma: useful guides for therapy, distinct biological processes, or both? Am J Respir Crit Care Med 2004;170(6):579–80. [20] O’Byrne PM, Inman MD, Parameswaran K. The trials and tribulations of IL-5, eosinophils, and allergic asthma. J Allergy Clin Immunol 2001;108(4):503–8. [21] Holla AD, Roy SR, Liu AH. Endotoxin, atopy and asthma. Curr Opin Allergy Clin Immunol 2002;2(2):141–5. [22] Schaub B, Lauener R, von Mutius E. The many faces of the hygiene hypothesis. J Allergy Clin Immunol 2006;117(5):969–77 [quiz: 978]. [23] Wenzel S. Severe asthma in adults. Am J Respir Crit Care Med 2005;172(2):149–60. [24] Kraft M, Cairns CB, Ellison MC, et al. Improvements in distal lung function correlate with asthma symptoms after treatment with oral montelukast. Chest 2006;130(6): 1726–32. [25] Slade DJ, Kraft M. Airway remodeling from bench to bedside: current perspectives. Clin Chest Med 2006;27(1):71–85. [26] Szeﬂer SJ, Martin RJ, King TS, et al. Signiﬁcant variability in response to inhaled corticosteroids for persistent asthma. J Allergy Clin Immunol 2002;109(3):410–8. [27] Blanc PD, Toren K. How much adult asthma can be attributed to occupational factors? Am J Med 1999;107(6):580–7. [28] Balkissoon R. Vocal cord dysfunction, gastroesophageal reﬂux disease, and nonallergic rhinitis. Clin Allergy Immunol 2007;19:411–26. [29] Sciurba FC. Physiologic similarities and diﬀerences between COPD and asthma. Chest 2004; 126(Suppl 2):117S–124S [discussion: 159S–61S]. [30] National Institutes of Health/National Heart Lung and Blood Institute. NAEPP, National Asthma Education and Prevention Program Expert Panel report: guidelines for the diagnosis and management of asthma: update on selected topics 2002. Available at: www.nhlbi.nih. gov/guidelines/asthma. Accessed November 28, 2007. [31] Fuhlbrigge AL, Adams RJ, Guilbert TW, et al. The burden of asthma in the United States: Level and distribution are dependent on interpretation of the National Asthma Education and Prevention Program guidelines. Am J Respir Crit Care Med 2002;166(8):1044–9. [32] Lagerstrand L, Bylin G, Hedenstierna G, et al. Relationships among gas exchange, spirometry and symptoms in asthma. Eur J Med 1992;1(3):145–52. [33] Magadle R, Berar-Yanay N, Weiner P. The risk of hospitalization and near-fatal and fatal asthma in relation to the perception of dyspnea. Chest 2002;121(2):329–33. [34] Weiner P, Magadle R, Massarwa F, et al. Inﬂuence of gender and inspiratory muscle training on the perception of dyspnea in patients with asthma. Chest 2002;122(1):197–201. [35] Petsky HL, Kynaston JA, Turner C, et al. Tailored interventions based on sputum eosinophils versus clinical symptoms for asthma in children and adults. Cochrane Database Syst Rev 2007;2:CD005603. [36] Wenzel S, Busse W, Calhoun W, et al. The safety and eﬃcacy of zileuton controlled-release tablets as adjunctive therapy to usual care in the treatment of moderate persistent asthma: a 6-month randomized controlled study. J Asthma 2007;44(4):305–10. [37] Adcock IM, Ito K, Barnes PJ. Histone deacetylation: an important mechanism in inﬂammatory lung diseases. COPD 2005;2(4):445–55. [38] Wechsler ME, Lehman E, Lazarus SC, et al. Beta-adrenergic receptor polymorphisms and response to salmeterol. Am J Respir Crit Care Med 2006;173(5):519–26.

60

BALKISSOON

[39] Soler M, Matz J, Townley R, et al. The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur Respir J 2001;18(2):254–61. [40] Fahy JV. Anti-IgE: lessons learned from eﬀects on airway inﬂammation and asthma exacerbation. J Allergy Clin Immunol 2006;117(6):1230–2. [41] Rees PJ. Review: Omalizumab reduces exacerbation and steroid use in chronic asthma. Arch Dis Child Educ Pract Ed 2007;92(4):ep127. [42] Karpel J, Bukstein DA, LoNigro R. The appropriate omalizumab patient. Manag Care 2007;16(5):44–50. [43] Dreyfus DH, Randolph CC. Characterization of an anaphylactoid reaction to omalizumab. Ann Allergy Asthma Immunol 2006;96(4):624–7. [44] Price KS, Hamilton RG. Anaphylactoid reactions in two patients after omalizumab administration after successful long-term therapy. Allergy Asthma Proc 2007;28(3):313–9. [45] Varghese M, Lieberman P. The eﬀects of repeat omalizumab administration on skin test positivity and the assessment of the safety of administration in patients with positive skin tests to mouse antigen. Allergy Asthma Proc 2007;28(3):320–3. [46] Toelle BG, Ram FS. Written individualized management plans for asthma in children and adults. Cochrane Database Syst Rev 2002;3:CD002171. [47] Toelle BG, Ram FS. Written individualized management plans for asthma in children and adults. Cochrane Database Syst Rev 2004;2:CD002171. [48] Bhogal S, Zemek R, Ducharme FM. Written action plans for asthma in children. Cochrane Database Syst Rev 2006;3:CD005306.

Prim Care Clin Office Pract 35 (2008) 61–80

Making the Diagnosis of Occupational Asthma: When to Suspect It and What to Do Craig S. Glazer, MD, MSPHa, Karin Pacheco, MD, MSPHb,* a

Division of Pulmonary and Critical Care Medicine, University of Texas Southwestern, 5323 Harry Hines Boulevard, Dallas, TX 75390–8558, USA b Division of Environmental and Occupational Health Sciences, National Jewish Medical and Research Center, 1400 Jackson Street, G211, Denver, CO 80206, USA

Occupational asthma might be considered a silent disease: frequently seen but seldom considered. Although most adult patients seen by a clinician are employed, medical school curricula and residency training rarely cover occupational exposures and resultant diseases, even common ones that are encountered in a typical medical practice. Occupational asthma has been estimated to constitute an average of 15% of adult asthma, and an even higher component of new-onset asthma in adults. This primer on occupational asthma is intended for the primary care clinician to provide the essential tools to diagnose and treat airways disease in the workplace. Using a case vignette format, the basic approach to suspecting and establishing a diagnosis of occupational asthma is reviewed, and the thornier question of what to do about it is addressed. There are simple steps the clinician can take to establish the diagnosis, and occupational specialists are available to help along the way. Treatment of occupational asthma follows the same guidelines as treatment of nonoccupational asthma. An added feature of the diagnosis involves identifying the inciting exposure in the workplace, however, and removing and restricting the patient from direct or indirect contact. Further, the clinician must alert the designated occupational medicine specialist or health and safety oﬃcers that an occupational issue exists in the workplace and that other workers are at risk of similar disease. Although this may seem daunting, the primer provides a list of resources to contact for help. * Corresponding author. E-mail address: [email protected] (K. Pacheco). 0095-4543/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2007.09.010 primarycare.theclinics.com

62

GLAZER & PACHECO

Occupational asthma, similar to many other occupational diseases, can be a satisfying area of practice. Unlike other medical diagnoses, it provides a real opportunity for cure and prevention. This primer reviews the characteristics of primary, secondary, and tertiary prevention; eﬃcient approaches; and who and where to turn for help. It is hoped that after reviewing this primer, the reader will routinely include occupational asthma as part of his or her diﬀerential diagnosis in the adult patient with new or worsened asthma.

Question 1: how common is occupational asthma? Case presentation Mr. M is a 42-year-old nonsmoking man with no past medical history. He initially came to your oﬃce 2 years ago with complaints of intermittent dyspnea on exertion, cough, and wheeze. You diagnosed him with asthma and initiated therapy with an inhaled steroid and rescue Albuterol. Despite this, his symptoms progressively increased requiring a step up in therapy to a low-dose inhaled steroid and long-acting b-agonist combination (ﬂuticasone propionate, 100 mg, and salmeterol, 50 mg). He presents now with continued worsening. He is requiring his rescue Albuterol daily and is using more than one canister per month. In addition, he is waking up nightly with dyspnea and wheeze requiring his rescue inhaler for relief. You increase the dose of the inhaled steroid in the combination (ﬂuticasone propionate, 250 mg, and salmeterol, 50 mg) with better control of persistent symptoms. Mr. M has noticed that his nighttime asthma symptoms occur every night during the workweek, but rarely on weekends. He wonders if something at work could be triggering his symptoms. Discussion Is occupational asthma a potential cause of Mr. M’s new-onset and difﬁcult to control disease? The epidemiologic literature has addressed the question of frequency of occupational asthma in two diﬀerent ways. The ﬁrst is to determine the incidence or prevalence of occupational asthma within a population, relying primarily on reporting registries. Finland has a mandatory health reporting system and numerous other countries have voluntary reporting systems operational in at least portions of their countries [1–8]. Yearly rates of new-onset occupational asthma vary widely from 1.3 per 100,000 in South Africa, to 18 per 100,000 in Finland out of an estimated annual asthma incidence in Finland of 200 per 100,000, or 9% of all new-onset asthma. Registry data often underestimates the true incidence of occupational asthma, however, because of missed reporting and lack of physician recognition. Lack of physician recognition is especially problematic. For example, Milton and colleagues [9] reviewed the charts

DIAGNOSIS OF OCCUPATIONAL ASTHMA

63

of patients diagnosed with asthma by their primary care physician in a large health system. Only 15% of the charts documented an occupational history. Occupational asthma cannot be diagnosed if the physician does not ask about a patient’s occupation. In this study, after including the occupational history, the investigators estimated an annual incidence of occupational asthma of 40 per 100,000 [9]. Another approach avoids the problems of underreporting and lack of recognition of occupational asthma by determining the attributable risk of occupational asthma. The attributable risk is the proportion of all cases of asthma that can be attributed to workplace exposures [10]. To date, 24 diﬀerent studies that directly measured the attributable risk of occupational asthma estimated from 5% to 30% of all adult-onset asthma as caused by the workplace [11,12]. Three recent meta-analyses have reached a similar conclusion [13–15]: the attributable risk of adult asthma caused by one’s occupation is between 10% and 15%. One out of every 7 to 10 cases of adult asthma is caused by workplace exposures. The attributable risk is even higher if one considers only those patients with new-onset adult asthma. In the same study by Milton and colleagues [9], the authors performed a prospective cohort study of almost 80,000 adult members of a regional HMO seen over a 3-month period. They contacted all patients seen for asthma and found that of those people with new-onset asthma, 26% most likely had occupationally induced asthma [9]. Similarly, Johnson and colleagues [16] re-examined the asthmatics identiﬁed in the Canadian portion of the European Community Respiratory Health Survey and found that 36% of the cases of de novo asthma were likely related to work. Occupational asthma accounts for a signiﬁcant portion of adult asthma, especially new-onset adult asthma. It is a potential cause of Mr. M’s diﬃcult to control disease. Other clues that the diagnosis may be work related include asthma presenting in a patient of older age, or in the absence of typical risk factors, similar disease in coworkers, or failure to respond to appropriate therapy [17]. For example, Mr. M. has developed asthma at an unusual age, does not have a history of allergies or atopy, and has continued to worsen despite appropriate therapy. A list of clues to the diagnosis of occupational asthma is shown in Box 1.

Question 2: how does one take an occupational history? Case presentation Mr. M has worked as a cabinet and wood furniture maker for the last 15 years. Before this he worked as a salesperson and had no exposures. Over the last 5 years, he has owned his own business and works out of a small shop. He uses a variety of woods including Western red cedar. He buys some woods preprocessed and some with the bark still present. He

64

GLAZER & PACHECO

Box 1. Historical clues for the presence of occupational asthma History of present illness clues New-onset asthma Symptoms worse at work or at night on workdays (or with specific exposures) Improved symptoms on vacation, over weekends, or other times away from work Similar symptoms in exposed coworkers Presence of work-related rhinitis or conjunctivitis Failure to improve with appropriate therapy Occupational history clues Work in a high-risk industry (eg, health care, laboratory research, electronics, baking, painting, and so forth) Personal use of a known respiratory sensitizer Coworker use of a known respiratory sensitizer High levels of exposure Presence of risk factors Atopy Work-related rhinitis High exposure intensity Known sensitization to a workplace agent

works 10 hours per day, 5 or 6 days per week, and has four employees. He tells you one of his employees has also begun coughing at work. The only ventilation in his shop is the warehouse door, which they leave open when the weather is warm. He only wears a paper dust mask for protection. In addition to the woods, they use a variety of varnishes, epoxies and glues, and paints. Mr. M states that in retrospect his symptoms were worse on weekdays than weekends at the beginning of his illness. Now he is symptomatic throughout the week and the weekend, but he did feel better at the end of a 2-week vacation he took several months ago. Unfortunately, his symptoms began to worsen again soon after returning to work. Discussion A thorough occupational history starts with a detailed chronologic history of the patient’s jobs and exposures (see Box 1), beginning with work in high school and thereafter. In some patients with occupational asthma, the causative exposure may have occurred in a previous job. The exposure portion of the history should include the job title, employer, dates of employment, and a detailed description of a typical workday. This should

DIAGNOSIS OF OCCUPATIONAL ASTHMA

65

include both the tasks performed by the patient and tasks performed by surrounding coworkers. Whenever possible, determine what materials are used in the worksite. Use of known sensitizers is a helpful clue [17]. Obtaining material safety data sheets can be useful when the patient does not know what substances are used. Material safety data sheets, however, are often limited, frequently do not list sensitizing chemicals of interest, and should not be used to exclude a diagnosis of occupational asthma. The next step is to determine the temporal association between exposure and symptom onset. An exposure must precede symptom onset to be causative. Many patients are able to describe a day-to-day connection between symptoms or exacerbations and workplace exposures. The relationship may be rapid onset of symptoms after entering the workplace or beginning a speciﬁc job (immediate, or early onset asthma). With some kinds of exposures, symptoms may only come on in the evening after work (delayed or late-onset asthma). Nocturnal asthma symptoms that are worse on workdays are suggestive of occupational asthma. In addition, the temporal relationships may change with disease severity [18]. As the disease becomes more severe, symptoms may become more persistent, and patients may not improve at all after leaving exposure or improve only after prolonged absence from work. In addition, if one is evaluating a patient long after symptoms began they may no longer remember the temporal associations with work. If these factors are considered, the history is very sensitive for the detection of occupational asthma. Multiple studies have shown a sensitivity of approximately 90% [19–21]. The presence of risk factors is also a helpful clue, especially the presence of work-related rhinitis or conjunctivitis. Occupational rhinoconjunctivitis frequently coexists with or precedes the onset of occupational asthma [22–25]. The presence of occupational rhinoconjunctivitis is also associated with a ﬁvefold increased risk of subsequent development of occupational asthma especially in the ﬁrst 2 years postdiagnosis [26]. Mr. M is using a variety of known sensitizers including Western red cedar, varnishes and paints, and two-part glues and epoxies (some of which contain isocyanates on review of the material safety data sheets). His exposures in the shop clearly preceded the onset of symptoms; his symptoms do have a temporal association with the worksite, although the distinction with time oﬀ is becoming blurred; and there are other symptomatic coworkers. Taken together, his history is strongly suggestive of occupational asthma.

Question 3: is it necessary to conﬁrm the diagnosis of asthma, and if so, how? Case presentation You repeat Mr. M’s spirometry, which does reveal mild obstruction (forced expiratory volume in 1 second [FEV1]/forced vital capacity

66

GLAZER & PACHECO

ratio ¼ 68%, and FEV1 ¼ 70% predicted). He did not have a bronchodilator response on his present therapy. Conﬁrmation of asthma requires not just the presence of obstruction but also the presence of reversibility or bronchial hyperreactivity [27]. Mr. M undergoes a methacholine challenge. His provocative concentration of methacholine inducing a 20% fall in FEV1 (PC20) was 1 mg/mL, conﬁrming that he does have bronchial hyperreactivity and asthma [28]. Discussion There are several published guidelines for the diagnostic evaluation of occupational asthma including a recent Internet publication from the British Occupational Health Research Foundation (www.bohrf.org.uk/content/ asthma.htm) [18,29]. All of the guidelines recommend a stepwise approach to diagnosis. The ﬁrst step is to suspect the diagnosis and take an occupational history. The second step is conﬁrmation of asthma. This step is important for several reasons. As discussed later, the diagnosis can have signiﬁcant social consequences and although the occupational history is very sensitive, history alone is not suﬃcient to make the diagnosis [19–21]. There are several diseases that can mimic asthma, including vocal cord dysfunction, allergic rhinitis-sinusitis, and hypersensitivity pneumonitis, all of which require diﬀerent treatment approaches. Mr. M is at risk for all of these. Vocal cord dysfunction, the inappropriate adduction of the vocal cords during inspiration, and less commonly during expiration, is associated with exposure to irritant dusts and fumes in the workplace [30]. Wood dust exposure has been associated with sinus pathology [31–34]. Woodworker’s lung, a form of hypersensitivity pneumonitis, can occur in workers exposed to molds growing under the bark or contaminating sawdust that becomes wet [35,36]. Given the signiﬁcant medical, social, and economic consequences of this diagnosis and the potential for disease mimics, conﬁrmation of asthma is an important next step in the diagnosis of occupational asthma. One criteria for asthma, a greater than or equal to 12% and at least 200 mL improvement in the FEV1 following bronchodilator, can be seen on a single spirometry performed before and after treatment with a bronchodilator. Asthma can also be documented by a greater than or equal to 20% improvement in FEV1 following treatment with anti-inﬂammatory therapy. Airﬂow obstruction is not always present in occupational asthma, however, especially early in the disease or if some time has passed since the last exposure [37]. In that case asthma can be conﬁrmed by a methacholine challenge test to document the degree of bronchial hyperreactivity. This test measures the provocative dose of methacholine that induces a 20% fall in FEV1 (PC20). Asthmatics are deﬁned as having a PC20 FEV1 less than 4 mg/mL, whereas in normal individuals without asthma the PC20 is typically greater than 25 mg/mL

DIAGNOSIS OF OCCUPATIONAL ASTHMA

67

[28]. Patients with a PC20 between 4 and 25 mg/mL fall into an area of diagnostic uncertainty where test results should be interpreted in the context of the history, including workplace exposures; length of time in or out of exposure; and comorbidities, such as allergic rhinitis or a recent upper respiratory infection. Once asthma is conﬁrmed, the next diagnostic step is to conﬁrm an association between asthma and the workplace [18,29].

Question 4: how does one prove the association of the patient’s asthma with the workplace? Case presentation Mr. M was given a peak ﬂow meter and instructed in its use. He was then provided with a log in which to record his peak ﬂows a minimum of four times a day over 2 weeks at work and on weekends, and then during 2 weeks of vacation away from work. He is also instructed to continue his present dose of asthma medications throughout the time frame. The results are then graphed; after 2 weeks away from work his peak ﬂows increase significantly by more than 20% (from about 300 up to 500) and the amount of daily variability decreases markedly (from 20% down to 10%). This conﬁrms an objective relationship between work exposures and his asthma, and allows you conﬁdently to diagnose Mr. M with occupational asthma. Discussion Another approach to demonstrate the association of asthma with work is the speciﬁc inhalation challenge test. In this test, the individual is exposed to progressively increasing (but sub-irritant) concentrations of the chemical or substance in question. Patients with occupational asthma demonstrate a 20% fall in their FEV1, or a threefold decrease in the PC20 to methacholine [18,38]. Unfortunately, this test is only available at a few specialized centers. There is a risk of false-negative results because of use of the wrong chemical or concentration, too short duration of exposure to the chemical, or the patient has been out of exposure for too long and has temporarily lost his or her responsiveness. False-positive results are rare, and may be caused by irritation from the chemical or elicitation of vocal cord dysfunction misinterpreted as asthma. A diﬀerent option includes demonstrating immune sensitization to the workplace antigen in question and methacholine sensitivity or worsened pulmonary function at work. Patients who demonstrate sensitization to a workplace antigen and have a positive methacholine challenge for asthma have an 80% or greater chance of having occupational asthma to that allergen. Standardized reagents for most of the workplace antigens are rare, however, and variability in the antigen preparations limits sensitivity and may make

68

GLAZER & PACHECO

negative tests unreliable. For example, in one recent study of occupational asthma the potency of diﬀerent commercially available antigen preparations was so variable that the sensitivity of the test was only from 45% to 67% [39]. The most practical approach in most instances remains documentation of work-related changes in pulmonary function. Serial peak ﬂow recordings are most frequently used and the most easily accessible test. The currently recommended method is for the patient to record his or her peak ﬂow at least four times daily (on awakening, middle of work shift or lunch, end of work shift, and before bed). At each time point, patients should perform the maneuver three times and record each result in a log. The optimal duration of the recording is for at least 2 weeks at work and including the weekends, followed by 1 to 2 weeks away from work. At the end of the time period, the patient should return the log to their physician, who can then plot the highest value at each time point onto graph paper. The plots may be analyzed by visual inspection to look for greater than or equal to 20% diﬀerences in the peak ﬂow or variability on days at work versus days away from work [18]. The sensitivity is maximized with at least four measurements per day [40]. Speciﬁcity can increase with more readings per day; however, this is hard to do consistently and compliance with testing is often compromised. Peak ﬂow recordings are limited by patient reliability and compliance with performing and recording the readings [18]. Test quality is improved, however, when patients are given the instruction by the physician (as opposed to preprinted instruction forms) and when the patient records data in a dedicated log and not directly onto graph paper [41]. Despite these limitations, numerous studies have documented a sensitivity and speciﬁcity of peak ﬂow recordings in the range of 85% to 90% [18,19,40]. An algorithm for the diagnosis and treatment of occupational asthma is shown in Fig. 1.

Question 5: how does one treat occupational asthma? Case presentation A more detailed occupational history reveals that Mr. M began using Western red cedar 2 to 3 years before symptom onset, when he began to make custom furniture in addition to cabinets. Mr. M associated most of his chest symptoms to days when Western red cedar was used in his workshop. He stopped using Western red cedar and over the course of the next few months his symptoms stabilized, and the frequency of exacerbations markedly declined. Discussion The cornerstone of management of occupational asthma is removal of the exposure. In the case of Mr. M, the association of his symptoms with

69

DIAGNOSIS OF OCCUPATIONAL ASTHMA

Adult with new onset respiratory symptoms or exacerbation of pre-existing asthma NO workplace trigger Routine evaluation

YES workplace trigger

Medical, social and occupational history

NO asthma Consider other diagnosis Rhinosinusitis VCD GERD Chronic bronchitis Hypersensitivity pneumonitis, etc.

Confirm asthma Methacholine PC20FEV1≤4 mg/mL, or 12% / 200 mL FEV1 to bronchodilator, or > 20% variability in PFR over 24 hours

YES asthma NO workplace association Treat and follow, re-consider workplace association if history remains suggestive.

Confirm workplace association PFR 4x/d for 2 weeks at work and on weekends, and (if feasible) 2 weeks away. Skin test positive to workplace allergen AND methacholine positive. > 3-fold change PC20FEV1 between periods at and away from work, or Specific inhalation challenge if available.

Identify exposure Remove and restrict from exposure

YES workplace association Treat asthma Identify exposure(s) Consult occupational professional

Coworkers exposed or affected? Work with occupational medicine physician, and plant health & safety officers

Treat patient for asthma and follow.

Fig. 1. Approach to the diagnosis and care of a patient with occupational asthma. FEV1, forced expiratory volume in 1 second; GERD, gastroesophageal reﬂux disease; PFR, peak ﬂow recordings; VCD, vocal cord dysfunction.

the introduction of Western red cedar made this the most likely causative antigen. Most new-onset sensitization and disease occurs during the ﬁrst 4 to 5 years of workplace exposure [38,42], and the incidence of new sensitization is highest in the ﬁrst year of exposure. Delayed-onset sensitization (O10–15 years) does occur, but accounts for only 10% to 15% of disease [38]. Removing Western red cedar from the workplace eliminated the most likely causative exposure, and was the logical ﬁrst step. Mr. M was

70

GLAZER & PACHECO

also exposed to a number of other potential workplace asthmagens, however, including exotic woods, two-part glues, and paints, which should be considered if removing Western red cedar was not eﬀective in improving his asthma. Removing the exposure from the worksite, either by eliminating the agent or substituting an alternative, is the preferred approach to controlling patient exposures. Unfortunately, it is not always possible to remove the exposure. Then, the physician must consider removing the patient, which can have signiﬁcant social and economic consequences that the clinician must consider. Removal from exposure can be accomplished through engineering controls, such as improved ventilation. Respiratory protection may limit disease progression [43] but is often diﬃcult to implement for long periods of time at work. Another approach is administrative control, such as moving the process oﬀsite. The pharmacologic management of occupational asthma is identical to nonoccupational asthma [44]. Treatment with inhaled corticosteroids, while attempting to keep the worker in his or her job, can stabilize disease in some patients [45,46]. In this case, close follow-up and frequent monitoring of patient lung function is mandatory. Referral to an occupational disease specialist at this point is prudent. Disease progression can occur despite exposure reduction and pharmacologic therapy, and deaths have been reported in patients with occupational asthma and ongoing exposure [47–49].

Question 6: what are the social and economic costs to the patient of a diagnosis of occupational asthma? Case presentation Avoiding use of Western red cedar in his workshop has led to a signiﬁcant reduction in the custom furniture portion of Mr. M’s business. He was forced to consider laying oﬀ several of his employees because of his loss of business. Mr. M is especially concerned because he has two children approaching college age, and he is worried that he will be unable to fund their education. For these reasons, Mr. M contemplated reinstituting use of Western red cedar to recapture some of his business, but was reluctant to do so because he had been so sick at work before. He asks what he should do. Discussion Aside from medical concerns, occupational asthma has serious ﬁnancial and social consequences for the aﬀected workers, both for those who leave exposure and for those who remain in their jobs. One large well-designed study contacted 209 patients with occupational asthma an average of

DIAGNOSIS OF OCCUPATIONAL ASTHMA

71

3.1 years after the diagnosis [50]. Almost half (44%) had left their jobs and 25% were unemployed. Surprisingly, 32% remained exposed in the same jobs. Reduction in income was common (46%), although more prevalent in those who had left their jobs (82%) compared with those still employed (19%) in the same company. Risk factors for changing employers or becoming unemployed after diagnosis included having made a claim for compensation, working for a company with 50 or fewer employees, lower level of education, older age, and unmarried status. A smaller study of 25 patients with occupational asthma compared 13 patients out of exposure with 12 patients who continued to be exposed 1 year after diagnosis [46]. Asthma severity improved more markedly for those out of exposure, whereas pharmaceutical expenses were increased in those remaining in exposure. Socioeconomic status had deteriorated in 11: 9 of 13 out of exposure, who reported an average annual income loss of 27%, compared with 2 of 12 with less than 7.5% annual income loss. An excellent review of the socioeconomic eﬀects of work-related asthma found that from 25% to 41% of those aﬀected were not working [51]. Loss of income was reported by 75% of those removed from exposure, either by transfer to a diﬀerent job or by changing employers, compared with 42% to 55% of those remaining in exposure. About one third of the workers remained employed in the job associated with the onset of occupational asthma. Quality of life markers are consistently worse in those with occupational asthma and removed from their jobs, compared with paired subjects with a similar degree of asthma that was not work-related [52]. For these reasons, it is not surprising that many workers choose not to report their work-related symptoms, or remain in exposure despite medical advice.

Question 7: what are ways of reducing or minimizing these costs? Case presentation Mr. M is advised to consult an industrial hygienist to see if there were alternatives that would allow him to resume Western red cedar use. The consultant recommended installing a ventilated booth to allow his employees to work with cedar without contaminating the rest of the facility. The workplace was thoroughly cleaned and residual Western red cedar sawdust removed. Mr. M was able to resume red cedar use without his asthma worsening. He was able to avoid layoﬀs and continue to grow the custom furniture portion of his business without adversely aﬀecting his health. Discussion It is imperative that the physician understand the social and ﬁnancial costs to the patient of a diagnosis of occupational asthma. Losses of income and employment status are important considerations for all workers, and

72

GLAZER & PACHECO

are often more important than their medical conditions. The ability of the caregiver to help the patient requires attention to this aspect of the diagnosis. The physician should be prepared to work with the patient, health and safety oﬃcers at the worksite, and industrial hygienist consultants to reduce or eliminate workplace exposure. In some settings this may not be possible. For example, asthma deaths have been reported in patients with isocyanateinduced asthma who are medically treated and remain at work. In other situations, control of exposure may allow the patient to remain in the job, but requires vigilant medical follow-up. The best control of exposure is to discontinue the process or substitute another chemical without sensitizing or asthmagenic properties. For example, a sculptor with occupational asthma to the isocyanates used to make the rubber mold for bronze sculptures can substitute a silicone mold that does not have sensitizing properties or cause asthma. Alternatively, the process can be moved oﬀ-site, such that the patient is no longer exposed in the workplace. Administrative controls can be used to change the work process schedule, such that the patient’s shifts are scheduled for times when the chemical is not being used. As a last resort, the patient can be placed in ﬁt-tested respiratory protection, such as a powered air-purifying respirator or a dual cartridge mask, selected to exclude the chemical of concern. In general, these are not practical for periods of use longer than an hour or so: they can be hot, cumbersome, and impair the ability to talk to coworkers. It is important to note that many patients who remain in exposure worsen over time or fail to improve [53].

Question 8: once the patient is removed from exposure, is it necessary to continue medical follow-up? Case presentation After stabilizing during the ﬁrst 6 months out of exposure, Mr. M’s symptoms began to improve. After 1 year, his asthma therapy was stepped down and the long-acting b-agonist was eliminated. Mr. M continues to require treatment with low-dose inhaled corticosteroid, however, 3 years after removal from exposure. Discussion In most cases of occupational asthma, the asthma persists for years after the worker is removed from exposure to the inciting stimulus. These ﬁndings are documented for a variety of protein and chemical antigens, including red cedar, and show persistent disease in 30% to 80% of patients despite removal from exposure [54–59]. This is not to say that removal from exposure is not important [38,60]. Studies also show that in most workers removed from exposure, symptoms and bronchial hyperresponsiveness improve

DIAGNOSIS OF OCCUPATIONAL ASTHMA

73

[54,55,59,61]. In contrast, those who remain in exposure either do not improve or demonstrate disease progression [53–55,59,61]. Even with removal, the time course for improvement is slow. Natural history studies in snow crab processing workers with occupational asthma show that the FEV1 continues to improve over a year out of exposure before a plateau, and the reduction in bronchial hyperresponsiveness takes even longer [62]. More recent studies on patients with occupational asthma from a variety of exposures conﬁrm that bronchial hyperresponsiveness improves most signiﬁcantly in the ﬁrst 2.5 years out of exposure, but can demonstrate continued, although slower, improvement for many years thereafter [63,64]. The key message is that although cure is possible with removal from exposure early in the course of disease, most patients have persistent asthma requiring ongoing medical treatment and follow-up.

Question 9: does diagnosing occupational asthma in one patient have broader implications for one’s practice? Case presentation Mr. M comes to you after deciding to have his employees use Western red cedar again in the ventilated booth. He wants to know if there is anything he can do to prevent occupational asthma from developing in his exposed workers? You reply that occupational asthma is a preventable illness, and you make several recommendations. First, you ask about engineering controls in the booth and discover there is a movable exhaust over the mechanical saw and sander to limit exposure. You inform him this will help reduce exposure, and you then recommend a screening program for his workers including yearly symptom questionnaires and spirometry, because the chance for cure is best with early detection and diagnosis. You also recommend worker education of the health risks of the workplace exposures, so that employees come forward with symptoms soon after they appear. Discussion It is important to emphasize that occupational asthma is a preventable illness. Numerous studies show that the risk of disease correlates with level of exposure [42,65–76]. Many of these studies actually show that a high exposure dose is the strongest risk factor for the development of occupational asthma. Other studies suggest the possibility of a threshold dose below which sensitization and disease do not occur [67,77–79]. Exposure reduction oﬀers the potential for disease prevention. This theory has been put into practice with success at the level of individual institutions and entire industries. Fisher and colleagues [80] studied the eﬀects of several programmatic changes designed to reduce the exposure to laboratory animal antigen at a pharmaceutical company research institute.

74

GLAZER & PACHECO

The program included worker education and training; the mandatory use of respiratory protection; a medical surveillance symptom assessment; and radioallergosorbent test for animal allergens, performed annually and mandatory for all employees working with laboratory animals. The program also incorporated work-practice modiﬁcations, such as control of animal-stock density and instituting wet-shaving practices. Environmental controls included the use of ﬁlter-topped cages, high-eﬃciency particulate air-ﬁltered room ventilation, increased room air exchanges, and the use of dust-free bedding. Regular housekeeping routines ensured that the workplace was as clean and free from animal allergens as possible. They found a marked reduction in the incidence of laboratory animal allergy in the 2 years after the changes were instituted [80]. Similar results were seen at a teaching hospital and a dental school after changing their latex gloves from high-protein powdered gloves to low-protein powder-free gloves, an intervention that reduces the amount of airborne allergen [81,82]. The dental school study showed a 70% fall in the incidence of latex sensitization after the change [81]. In Germany, government regulations for hospitals required a shift to powder-free latex gloves, and the number of latex allergy cases reported to workers compensation fell dramatically [83]. The best example of the potential for exposure reduction and disease surveillance to prevent disease comes from the detergent industry. In the late 1960s, bacterial enzymes were added to detergents. Soon thereafter, the industry witnessed an astounding outbreak of occupational disease, with sensitization developing in about half the workforce and occupational asthma appearing in almost 20% of exposed workers [84,85]. The industry responded by altering work practices and encapsulating the enzymes, which resulted in a marked reduction of exposure levels. They also began an employee surveillance program to detect early disease and asymptomatic sensitization, because disease prognosis is improved with early detection and treatment [54,86–88]. The end result was a near total elimination of occupational asthma in enzyme workers [89,90]. The diagnosis of one patient with occupational asthma does have broader implications for one’s practice. The authors recommend initiating contact with the patient’s employer or designated occupational medicine provider (provided one is given permission by the patient). The goal is to work with the health and safety professionals of the company to identify and reduce relevant exposure levels to prevent further cases (ie, primary prevention) [38]. In addition, establishing a screening or surveillance program for the workforce may detect cases in coworkers at an earlier stage, where disease is more amenable to cure or improvement (ie, secondary prevention) [38]. Continued monitoring and care of the worker with disease (eg, Mr. M, the patient) constitutes tertiary prevention, and is a necessary component of the three-tiered approach to prevent asthma in the workplace. Box 2 contains a list of useful resources for the primary care practitioner of where to begin to initiate this cascade of prevention.

DIAGNOSIS OF OCCUPATIONAL ASTHMA

75

Box 2. Resources for the clinician Web sites for materials and identified asthmagens http://www.asmanet.com/asmapro/asmawork.htm http://www.ilpi.com/msds/index.html#General http://www.bohrf.org.uk/content/asthma.htm Texts ACCP consensus statement: assessment of asthma in the workplace. Chest 1995;108:1084–1117/update in 2007-8 Bernstein IL, Chan-Yeung M, Malo JL, et al. Asthma in the workplace. 3rd edition. New York: Taylor & Francis; 2006. Rom WN, Markowitz S. Environmental & occupational medicine. 4th edition. Lippincott, Williams & Wilkins; 2006. Rosenstock L, Cullen MR, Brodkin CA, et al. Textbook of clinical occupational and environmental medicine. 2nd edition. Philadelphia: WB Saunders; 2005. Web sites and consultants www.acoem.org/ American College of Occupational and Environmental Medicine. Top bar: Policies and position statements. Sidebar: Find an occupational medicine doctor (by city, state). www.aiha.org/ American Industrial Hygiene Association. Sidebar: Access to information – Consultants listing: search by city and state to find a certified industrial hygienist. www.thoracic.org/ American Thoracic Society. Top bar: Clinical information – environmental and occupational – Clinical cases, EOH statements. Cannot access membership list if not a member.

Summary Occupational asthma likely constitutes 15% of all asthma, and up to 30% of new-onset asthma in adults. Whereas the clinical presentation is similar to other types of asthma, making it diﬃcult to identify the work-related component, several features distinguish the history. Early in disease onset there is often an association with the workplace, although this relationship may wane over time and continued exposure. Asthma may begin soon after the introduction of a new process or chemical. The disease may develop in patients without other risk factors, and be diﬃcult to control despite appropriate therapy. Coworkers may be aﬀected. Occupational asthma management diﬀers from environmental asthma in two important ways. The ﬁrst is the emphasis on functional outcomes: the goal and mark of successful therapy are improved work capacity and return

76

GLAZER & PACHECO

to work. The second diﬀerence incorporates a public health approach to treatment. If the patient is exposed and has disease, then coworkers may also develop disease. Control of occupational asthma rests on control of exposure: restricting the patient from direct or indirect exposure to the inciting chemical or process. Wherever possible, the goal is to keep the patient at work, but not at risk of disease progression. Control of exposure also extends to other workers, and entails working with health and safety oﬃcials, human resources, and industrial hygiene to craft a solution for all exposed workers. Limitation of occupational asthma requires the three prongs of prevention: primary, secondary, and tertiary. These usually work backward in the typical clinical scenario. First, the patient with disease is diagnosed and treated (third-degree prevention); then other exposed coworkers are examined for disease (second-degree prevention); and ﬁnally the relevant exposure is identiﬁed and replaced or controlled (ﬁrst-degree prevention). Following the guidelines in this primer, the primary care physician, in partnership with occupational specialists, plays a pivotal role in the process of treatment and prevention of occupational asthma.

References [1] Meredith S, Nordman H. Occupational asthma: measures of frequency from four countries. Thorax 1996;51(4):435–40. [2] Nordman H, Karjalainen A, Keskinen H. Incidence of occupational asthma: a comparison by reporting systems. Am J Ind Med 1999;(Suppl 1):130–3. [3] McDonald JC, Keynes HL, Meredith SK. Reported incidence of occupational asthma in the United Kingdom, 1989–97. Occup Environ Med 2000;57(12):823–9. [4] Hnizdo E, Esterhuizen TM, Rees D, et al. Occupational asthma as identiﬁed by the Surveillance of Work-related and Occupational Respiratory Diseases programme in South Africa. Clin Exp Allergy 2001;31(1):32–9. [5] Ameille J, Pauli G, Calastreng-Crinquand A, et al. Reported incidence of occupational asthma in France, 1996–99: the ONAP programme. Occup Environ Med 2003;60(2): 136–41. [6] Rosenman KD, Reilly MJ, Kalinowski DJ. A state-based surveillance system for workrelated asthma. J Occup Environ Med 1997;39(5):415–25. [7] Toren K. Self-reported rate of occupational asthma in Sweden 1990–1992. Occup Environ Med 1996;53:757–61. [8] Provencher S, LaBreche F, De Guire L. Physician bases surveillance for occupational respiratory diseases: the experience of PROPULSE, Quebec, Canada. Occup Environ Med 1997; 54:272–6. [9] Milton DK, Solomon GM, Rosiello RA, et al. Risk and incidence of asthma attributable to occupational exposure among HMO members. Am J Ind Med 1998;33(1):1–10. [10] Gautrin D, Newman-Taylor AJ, Nordman H, et al. Controversies in epidemiology of occupational asthma. Eur Respir J 2003;22(3):551–9. [11] Karjalainen A, Kurppa K, Martikainen R, et al. Work is related to a substantial portion of adult-onset asthma incidence in the Finnish population. Am J Respir Crit Care Med 2001; 164(4):565–8. [12] Reijula K, Haahtela T, Klaukka T, et al. Incidence of occupational asthma and persistent asthma in young adults has increased in Finland. Chest 1996;110(1):58–61.

DIAGNOSIS OF OCCUPATIONAL ASTHMA

77

[13] Blanc PD, Toren K. How much adult asthma can be attributed to occupational factors? Am J Med 1999;107(6):580–7. [14] Balmes J, Becklake M, Blanc P, et al. American Thoracic Society Statement: occupational contribution to the burden of airway disease. Am J Respir Crit Care Med 2003;167(5):787–97. [15] Mannino D. How much asthma is occupationally related? Occup Med 2000;15:359–68. [16] Johnson AR, Dimich-Ward HD, Manfreda J, et al. Occupational asthma in adults in six Canadian communities. Am J Respir Crit Care Med 2000;162(6):2058–62. [17] Newman LS. Occupational illness. N Engl J Med 1995;333(17):1128–34. [18] Chan-Yeung M. Assessment of asthma in the workplace. ACCP consensus statement. American College of Chest Physicians. Chest 1995;108(4):1084–117. [19] Cote J, Kennedy S, Chan-Yeung M. Sensitivity and speciﬁcity of PC20 and peak expiratory ﬂow rate in cedar asthma. J Allergy Clin Immunol 1990;85(3):592–8. [20] Malo JL, Ghezzo H, L’Archeveque J, et al. Is the clinical history a satisfactory means of diagnosing occupational asthma? Am Rev Respir Dis 1991;143(3):528–32. [21] Vandenplas O, Cangh FB-V, Brumagne A, et al. Occupational asthma in symptomatic workers exposed to natural rubber latex: evaluation of diagnostic procedures*1. J Allergy Clin Immunol 2001;107(3):542–7. [22] Grammer LC, Ditto AM, Tripathi A, et al. Prevalence and onset of rhinitis and conjunctivitis in subjects with occupational asthma caused by trimellitic anhydride (TMA). J Occup Environ Med 2002;44(12):1179–81. [23] Slavin RG. Occupational rhinitis. Ann Allergy Asthma Immunol 2003;90(5 Suppl 2):2–6. [24] Ruoppi P, Koistinen T, Susitaival P, et al. Frequency of allergic rhinitis to laboratory animals in university employees as conﬁrmed by chamber challenges. Allergy 2004;59(3): 295–301. [25] Walusiak J, Hanke W, Gorski P, et al. Respiratory allergy in apprentice bakers: do occupational allergies follow the allergic march? Allergy 2004;59(4):442–50. [26] Karjalainen A, Martikainen R, Klaukka T, et al. Risk of asthma among Finnish patients with occupational rhinitis. Chest 2003;123(1):283–8. [27] U.S. Department of Health and Human Services, National Institutes of Health. Expert panel report 3: Guidelines for the diagnosis and management of asthma. Full report 2007. Bethesda (MD): National Heart, Lung, and Blood Institute; 2007. [28] Crapo RO, Casaburi R, Coates AL, et al. Guidelines for methacholine and exercise challenge testingd1999. This oﬃcial statement of the American Thoracic Society was adopted by the ATS board of directors, July 1999. Am J Respir Crit Care Med January 1 2000;161(1):309–29. [29] Tarlo SM, Boulet LP, Cartier A, et al. Canadian Thoracic Society guidelines for occupational asthma. Can Respir J 1998;5(4):289–300. [30] Perkner JJ, Fennelly KP, Balkissoon R, et al. Irritant-associated vocal cord dysfunction. J Occup Environ Med 1998;40(2):136–43. [31] Basomba A, Burches E, Almodovar A, et al. Occupational rhinitis and asthma caused by inhalation of Balfourodendron riedelianum (Pau Marﬁm) wood dust. Allergy 1991;46(4): 316–8. [32] Eire MA, Pineda F, Losada SV, et al. Occupational rhinitis and asthma due to cedroarana (Cedrelinga catenaeformis Ducke) wood dust allergy. J Investig Allergol Clin Immunol 2006; 16(6):385–7. [33] Fernandez-Rivas M, Perez-Carral C, Senent CJ. Occupational asthma and rhinitis caused by ash (Fraxinus excelsior) wood dust. Allergy 1997;52(2):196–9. [34] Hernandez M, Sanchez-Hernandez MC, Moreno V, et al. Occupational rhinitis caused by beech wood dust. Allergy 1999;54(4):405–6. [35] Belin L. Clinical and immunological data on ‘‘wood trimmer’s disease’’ in Sweden. Eur J Respir Dis Suppl 1980;107:169–76. [36] Halpin DM, Graneek BJ, Turner-Warwick M, et al. Extrinsic allergic alveolitis and asthma in a sawmill worker: case report and review of the literature. Occup Environ Med 1994;51(3): 160–4.

78

GLAZER & PACHECO

[37] Cartier A, L’Archeveque J, Malo JL. Exposure to a sensitizing occupational agent can cause a long-lasting increase in bronchial responsiveness to histamine in the absence of signiﬁcant changes in airway caliber. J Allergy Clin Immunol 1986;78(6):1185–9. [38] Bernstein I, Chan-Yeung M, Malo JL, et al, editors. Asthma in the workplace. 3rd edition. New York: Taylor and Francis; 2006. [39] Sander I, Merget R, Degens PO, et al. Comparison of wheat and rye ﬂour skin prick test solutions for diagnosis of baker’s asthma. Allergy 2004;59(1):95–8. [40] Anees W, Gannon PF, Huggins V, et al. Eﬀect of peak expiratory ﬂow data quantity on diagnostic sensitivity and speciﬁcity in occupational asthma. Eur Respir J 2004;23(5): 730–4. [41] Huggins V, Anees W, Pantin C, et al. Improving the quality of peak ﬂow measurements for the diagnosis of occupational asthma. Occup Med (Lond) 2005;55(5):385–8. [42] Gautrin D, Ghezzo H, Infante-Rivard C, et al. Natural history of sensitization, symptoms and occupational diseases in apprentices exposed to laboratory animals. Eur Respir J 2001;17(5):904–8. [43] Grammer LC, Shaughnessy MA, Henderson J, et al. A clinical and immunologic study of workers with trimellitic-anhydride-induced immunologic lung disease after transfer to low exposure jobs. Am Rev Respir Dis 1993;148(1):54–7. [44] National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma update on selected topicsd2002. J Allergy Clin Immunol 2002;110(5 Suppl):S141–219. [45] Marabini A, Siracusa A, Stopponi R, et al. Outcome of occupational asthma in patients with continuous exposure: a 3-year longitudinal study during pharmacologic treatment. Chest 2003;124(6):2372–6. [46] Moscato G, Dellabianca A, Perfetti L, et al. Occupational asthma: a longitudinal study on the clinical and socioeconomic outcome after diagnosis. Chest 1999;115(1):249–56. [47] Ortega HG, Kreiss K, Schill DP, et al. Fatal asthma from powdering shark cartilage and review of fatal occupational asthma literature. Am J Ind Med 2002;42(1):50–4. [48] Carino M, Aliani M, Licitra C, et al. Death due to asthma at workplace in a diphenylmethane diisocyanate-sensitized subject. Respiration 1997;64(1):111–3. [49] Ehrlich RI. Fatal asthma in a baker: a case report. Am J Ind Med 1994;26(6):799–802. [50] Ameille J, Pairon JC, Bayeux MC, et al. Consequences of occupational asthma on employment and ﬁnancial status: a follow-up study. Eur Respir J 1997;10(1):55–8. [51] Vandenplas O, Toren K, Blanc PD. Health and socioeconomic impact of work-related asthma. Eur Respir J 2003;22(4):689–97. [52] Dewitte JD, Chan-Yeung M, Malo JL. Medicolegal and compensation aspects of occupational asthma. Eur Respir J 1994;7(5):969–80. [53] Cote J, Kennedy S, Chan-Yeung M. Outcome of patients with cedar asthma with continuous exposure. Am Rev Respir Dis 1990;141(2):373–6. [54] Chan-Yeung M, Lam S, Koener S. Clinical features and natural history of occupational asthma due to western red cedar (Thuja plicata). Am J Med 1982;72(3):411–5. [55] Hudson P, Cartier A, Pineau L, et al. Follow-up of occupational asthma caused by crab and various agents. J Allergy Clin Immunol 1985;76(5):682–8. [56] Venables KM, Topping MD, Nunn AJ, et al. Immunologic and functional consequences of chemical (tetrachlorophthalic anhydride)-induced asthma after four years of avoidance of exposure. J Allergy Clin Immunol 1987;80(2):212–8. [57] Lozewicz S, Assouﬁ BK, Hawkins R, et al. Outcome of asthma induced by isocyanates. Br J Dis Chest 1987;81(1):14–22. [58] Mapp CE, Corona PC, De Marzo N, et al. Persistent asthma due to isocyanates. A follow-up study of subjects with occupational asthma due to toluene diisocyanate (TDI). Am Rev Respir Dis 1988;137(6):1326–9. [59] Burge PS. Occupational asthma in electronics workers caused by colophony fumes: follow-up of aﬀected workers. Thorax 1982;37(5):348–53.

DIAGNOSIS OF OCCUPATIONAL ASTHMA

79

[60] Paggiaro PL, Vagaggini B, Bacci E, et al. Prognosis of occupational asthma. Eur Respir J 1994;7(4):761–7. [61] Lam S, Wong R, Yeung M. Nonspeciﬁc bronchial reactivity in occupational asthma. J Allergy Clin Immunol 1979;63(1):28–34. [62] Malo J, Cartier A, Ghezzo H, et al. Patterns of improvement on spirometry, bronchial hyperresponsiveness, and speciﬁc IgE antibody levels after cessation of exposure in occupational asthma caused by snow-crab processing. Am Rev Respir Dis 1988;138:807–12. [63] Malo J-L, Ghezzo H. Recovery of methacholine responsiveness after end of exposure in occupational asthma. Am J Respir Crit Care Med 2004;169(12):1304–7. [64] Perfetti L, Cartier A, Ghezzo H, et al. Follow-up of occupational asthma after removal from or diminution of exposure to the responsible agent: relevance of the length of the interval from cessation of exposure. Chest 1998;114(2):398–403. [65] Cullinan P, Cook A, Nieuwenhuijsen MJ, et al. Allergen and dust exposure as determinants of work-related symptoms and sensitization in a cohort of ﬂour-exposed workers; a casecontrol analysis. Ann Occup Hyg 2001;45(2):97–103. [66] Gautrin D, Ghezzo H, Infante-Rivard C, et al. Incidence and determinants of IgE-mediated sensitization in apprentices: a prospective study. Am J Respir Crit Care Med 2000; 162(4 Pt 1):1222–8. [67] Grammer LC, Shaughnessy MA, Kenamore BD, et al. A clinical and immunologic study to assess risk of TMA-induced lung disease as related to exposure. J Occup Environ Med 1999; 41(12):1048–51. [68] Nieuwenhuijsen MJ, Putcha V, Gordon S, et al. Exposure-response relations among laboratory animal workers exposed to rats. Occup Environ Med 2003;60(2):104–8. [69] Houba R, Heederik D, Doekes G. Wheat sensitization and work-related symptoms in the baking industry are preventable: an epidemiologic study. Am J Respir Crit Care Med 1998;158(5 Pt 1):1499–503. [70] Heederik D, Venables KM, Malmberg P, et al. Exposure-response relationships for workrelated sensitization in workers exposed to rat urinary allergens: results from a pooled study. J Allergy Clin Immunol 1999;103(4):678–84. [71] Cullinan P, Lowson D, Nieuwenhuijsen MJ, et al. Work related symptoms, sensitisation, and estimated exposure in workers not previously exposed to laboratory rats. Occup Environ Med 1994;51(9):589–92. [72] Cullinan P, Cook A, Gordon S, et al. Allergen exposure, atopy and smoking as determinants of allergy to rats in a cohort of laboratory employees. Eur Respir J 1999;13(5): 1139–43. [73] Nieuwenhuijsen M, Heederik D, Doekes G, et al. Exposure-response relations of alphaamylase sensitisation in British bakeries and ﬂour mills. Occup Environ Med 1999;56(3): 197–201. [74] Houba R, Heederik DJ, Doekes G, et al. Exposure-sensitization relationship for alphaamylase allergens in the baking industry. Am J Respir Crit Care Med 1996;154(1): 130–6. [75] Barker RD, van Tongeren MJ, Harris JM, et al. Risk factors for sensitisation and respiratory symptoms among workers exposed to acid anhydrides: a cohort study. Occup Environ Med 1998;55(10):684–91. [76] Meredith SK, Bugler J, Clark RL. Isocyanate exposure and occupational asthma: a casereferent study. Occup Environ Med 2000;57(12):830–6. [77] Baur X, Chen Z, Liebers V. Exposure-response relationships of occupational inhalative allergens. Clin Exp Allergy 1998;28(5):537–44. [78] Baur X. New aspects on isocyanate asthma. Lung 1990;168(Suppl):606–13. [79] Musk AW, Venables KM, Crook B. Respiratory symptoms, lung function and sensitivity to ﬂour in a British bakery. Br J Ind Med 1989;46:636–42. [80] Fisher R, Saunders WB, Murray SJ, et al. Prevention of laboratory animal allergy. J Occup Environ Med 1998;40(7):609–13.

80

GLAZER & PACHECO

[81] Saary MJ, Kanani A, Alghadeer H, et al. Changes in rates of natural rubber latex sensitivity among dental school students and staﬀ members after changes in latex gloves. J Allergy Clin Immunol 2002;109(1):131–5. [82] Tarlo SM, Easty A, Eubanks K, et al. Outcomes of a natural rubber latex control program in an Ontario teaching hospital. J Allergy Clin Immunol 2001;108(4):628–33. [83] Allmers H, Schmengler J, Skudlik C. Primary prevention of natural rubber latex allergy in the German health care system through education and intervention. J Allergy Clin Immunol 2002;110(2):318–23. [84] Pepys J, Longbottom J, Hargreave F, et al. Allergic reactions of the lungs to enzymes of Bacillus subtilis. Lancet 1969;1:1181–4. [85] Flindt M. Pulmonary disease due to inhalation of derivatives of Bacillus subtilis containing proteolytic enzyme. Lancet 1969;1:1177–81. [86] Paggiaro PL, Chan-Yeung M. Pattern of speciﬁc airway response due to Western red cedar (Thuja plicata): relationship with length of exposure and lung function measurements. Clin Allergy 1987;17:333–8. [87] Tarlo SM, Banks D, Liss G, et al. Outcome determinants for isocyanate induced occupational asthma among compensation claimants. Occup Environ Med 1997;54(10):756–61. [88] Tarlo SM, Liss G, Corey P, et al. A workers’ compensation claim population for occupational asthma. Comparison of subgroups. Chest 1995;107(3):634–41. [89] Sarlo K, Kirchner DB. Occupational asthma and allergy in the detergent industry: new developments. Curr Opin Allergy Clin Immunol 2002;2(2):97–101. [90] Sarlo K. Control of occupational asthma and allergy in the detergent industry. Ann Allergy Asthma Immunol 2003;90(5 Suppl 2):32–4.

Prim Care Clin Office Pract 35 (2008) 81–103

Vocal Cord Dysfunction/Paradoxical Vocal Fold Motion Marcy Hicks, MSa,*, Susan M. Brugman, MDb, Rohit Katial, MD, FAAAAI, FACPc a

Department of Rehabilitation, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA b Division of Pulmonology, National Jewish Medical and Research Center, The University of Colorado Health Sciences Center, 1400 Jackson Street, Denver, CO 80206, USA c Division of Allergy and Clinical Immunology, National Jewish Medical and Research Center, The University of Colorado Health Sciences Center, 1400 Jackson Street, Denver, CO 80206, USA

Vocal cord dysfunction, often referred to as a mimicker of asthma [1–4], is as confusing as the plethora of labels attached to this disorder. Each subspecialty reporting on vocal cord dysfunction has attached its own descriptive name. For example, the medical community commonly refers to it as ‘‘vocal cord dysfunction,’’ whereas among speech-language pathologists it is known as ‘‘paradoxical vocal fold motion’’ (PVFM). A large number of labels (in excess of 70) have been used in the literature and include medical terms (paradoxical vocal fold movement disorder, paradoxical vocal cord movement, paradoxical vocal cord dysfunction, episodic paroxysmal laryngospasm) [5–8] and psychologically based terms (factitious asthma, Munchausen’s stridor, psychogenic stridor, and emotional laryngeal wheezing) [9–14]. PVFM is probably a more accurate term because it describes the dynamic, dysfunctional, and paradoxical movements of the vocal folds and better distinguishes this disorder from various organic pathologies that have been termed ‘‘vocal cord dysfunction’’ [15,16]. PVFM is used throughout this article. PVFM is a laryngeal disorder that aﬀects respiratory function and has gained signiﬁcant recognition over the past two decades. There are numerous case studies reporting PVFM as a masquerader of asthma, allergies, and severe upper airways obstruction with consequent misdiagnosis and mismanagement. The literature is replete with descriptions of PVFM * Corresponding author. E-mail address: [email protected] (M. Hicks). 0095-4543/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2007.09.005 primarycare.theclinics.com

82

HICKS

et al

presentations, patient proﬁles, and proposed etiologies. Unfortunately, there is no uniﬁed understanding of this disorder, nor is there any consensus on its evaluation, etiology, or treatment. This article addresses these issues and presents a coherent discussion and interpretation of the relevant literature and practice to date. It is hoped that the reader is left with useable knowledge and clinical decision-making skills to treat patients with PVFM. Description PVFM is an upper airway obstruction associated with the paradoxical adduction or closure of the vocal folds occurring primarily on inhalation and sometimes during exhalation [4,17–20]. The clinical presentation of PVFM ranges from mild dyspnea to acute, severe respiratory distress and is often mistaken for an asthma attack [6]. Patients complain of sudden onset of diﬃculty breathing, usually on inhalation, air hunger, tightness localized to the throat or neck, cough, and oftentimes stridor or laryngeal wheezing [4,20–22]. Other symptoms and signs include dry cough; chest tightness; neck or chest retractions; diﬃculty swallowing; globus pharyngeus sensation (sensation of a lump in the throat); choking; suﬀocating; intermittent aphonia (loss of voice) or dysphonia (deviant vocal quality); fatigue; chest pain; and throat clearing [18–25]. The acute presentation is frequently a frightening and emotional experience and may elicit panic and anxiety in some patients. Rarely, patients may exhibit no distress whatsoever (‘‘la belle indiﬀerence’’) while complaining of severe respiratory distress [26]. PVFM episodes frequently begin and end abruptly and may or may not be attributed to identiﬁable triggers. Self-reported triggers include upper respiratory infections; occupational exposures; eating; talking; laughing; singing; coughing; acid reﬂux; physical exertion; intense exercise; postnasal drip; weather changes; emotional stressors; perfumes and strong scents; fumes; solvents; smoke; air pollution; and, occasionally, unusual triggers (eg, certain brand of dry erase marker) [8,21]. Patients with PVFM may report a single initiating trigger but then ﬁnd that their PVFM is elicited by a number of previously benign irritants (priming eﬀect). In some cases, the trigger may be a generalized exposure in a group setting, which sets oﬀ a mass hysteria-like reaction [16,27]. PVFM patients are typically misdiagnosed as having refractory asthma with resultant mistreatment [20]. Patients with PVFM generally do not respond to pharmacologic treatment for asthma and frequently have severe side eﬀects from unnecessary medications and interventions including intubation and tracheostomy [20,28–30]. The degree of iatrogenic complications was well described by Newman and colleagues [20] in a group of 95 adults with PVFM. Patients were misdiagnosed with asthma for an average of 4.8 years, with 81% of them having been treated with daily prednisone at an average dose of 29.2 mg. Furthermore, these patients averaged 9.7

VOCAL CORD DYSFUNCTION

83

emergency room visits and 5.9 hospital admissions in the year before presentation and 28% of them had been intubated. Similar ﬁnding were reported by Andrianopoulos and colleagues [21] in 27 patients referred for PVFM, with 44% of them needlessly treated with systemic steroids and 52% with bronchodilators. Similarly to the study by Newman and colleagues [20], 25% of these patients were treated in emergency rooms or hospitalized and 7% underwent intubation or tracheostomy. The psychologic eﬀects of PVFM and the long-term prognosis may also be negatively aﬀected when the diagnosis is unrecognized and untreated [31]. The morbidity of this disorder is substantial and emphasizes the need for awareness and accurate diagnosis of PVFM. Epidemiology The incidence of PVFM is unknown, although the literature describes it in subpopulations of patients. In a prospective study, Kenn and colleagues [32] found PVFM in 2.8% of 1025 patients presenting to a pulmonary clinic complaining of dyspnea. In a retrospective study of 236 patients admitted to an inner city hospital asthma center for acute asthma exacerbations, Jain and colleagues [33] found a 2% incidence of PVFM. Other authors have reported various incidences in subgroups of patients. Newman and Dubester [4] reported 40% of adults diagnosed with refractory asthma and referred to a tertiary pulmonary center had PVFM, either as the sole diagnosis (10%) or in combination with asthma (30%). In a similar population of severe, asthmatic children, an incidence of PVFM was found in 14% [34]. Among healthy, physically active adolescents and young adults, the incidence has been variably reported to be 8% [35], 15% [30], and 27% [36]. PVFM is probably more common than is generally appreciated and the true incidence awaits further prospective research. The breakdown of PVFM patients along age and gender lines is likewise controversial. When ﬁrst described by Christopher and coworkers [1] in 1983, PVFM was understood to be a psychiatric disorder of women between 20 and 40 years of age who were medically savvy and victims of childhood or adult sexual abuse. A comprehensive review of the PVFM literature paints a diﬀerent picture [37]. Among the 1530 patients reported, 65% were adults and 35% were children (deﬁned as age !19 years). The age range was quite wide (0.02–82 years old), with median ages for pediatric patients being 14 years and for adult patients 36.5 years. A female preponderance was seen in all age groups with a ratio of 3:1 females to males. Another review corroborated these ﬁndings among 1161 patients with PVFM and found an even less impressive female preponderance (female/male ¼ 2:1) [38]. Furthermore, the belief that psychologic dysfunction is an underlying feature of all PVFM is not supported by the literature, which fails to document a greater incidence of such dysfunction in PVFM than in the general population [37]. Finally, the assumption that PVFM predominates among

84

HICKS

et al

individuals with a medical background is also refuted by the data [37]. As more thorough study is undertaken in this area, the clinical proﬁle of patients will be further reﬁned. Pathophysiology An understanding of PVFM is based on an appreciation for normal laryngeal physiology. The three basic functions of the larynx (protection, respiration, and phonation) are controlled by a complex interrelationship of neurosensory reﬂexes and the brainstem [39]. The protective function is solely an automatic, reﬂexive action, whereas both respiration and phonation are governed by involuntary (brainstem) and voluntary (cortical) neurons [39]. The most primitive and critical function of the larynx is pulmonary protection. This is subsumed by the glottic closure reﬂex, wherein the upper airway closes to prevent aspiration of food and liquid during deglutition and noxious fumes and particulates during respiration [39,40]. This sphincteric action involves adduction of three levels within the laryngeal framework and occurs sequentially from bottom to top. The ﬁrst level consists of the aryepiglottic folds adducting toward the midline of the glottic chink while the arytenoid cartilages fold in on the posterior glottis and the epiglottis inverts over the top of the anterior glottis. The second and third levels are then activated as the true vocal cords and then the false vocal cords adduct forcefully to seal the airway [39]. This highly choreographed reﬂex is mediated by the superior laryngeal, recurrent laryngeal, and vagal nerves [41]. Another critical component of airway protection is the cough reﬂex [42]. This reﬂex is triggered by stimulation of upper aerodigestive tract sensory receptors, which send aﬀerent information to the brainstem mediated through sensory neuropeptides [42]. Laryngeal sensory receptors fall into four functional categories: (1) cold (ﬂow) receptors, which respond to changes in temperature; (2) irritant receptors, which respond to mechanical deformation, and to irritants (including water) and aerosols; (3) pressure receptors, which respond to changes in laryngeal transmural pressure; and (4) drive receptors, which respond to laryngeal motion [13]. The irritant receptors are considered main players in the glottic reﬂex. The vocal folds abduct (open) into a V-shaped aperture, called the glottic ‘‘chink,’’ during inspiration (Fig. 1A) and adduct (close) into a narrower V or completely during expiration. Glottic widening begins just milliseconds before diaphragmatic activation to ensure unimpeded airﬂow as the respiratory muscles start to contract. The glottic chink achieves maximum width at mid-inspiration. This inspiratory movement is quite consistent within and among individuals, whereas expiratory laryngeal motion is quite variable. This vocal cord motion allows energy-eﬃcient control of airﬂow (small laryngeal muscles versus large respiratory muscles) and subtends other functions of the larynx including breath-holding, abdominal straining, vocalizing, and coughing [43].

VOCAL CORD DYSFUNCTION

85

Fig. 1. (A) Normal cords at mid-inspiration. (B) Complete vocal cord adduction in mid-inspiration (most common form of PVFM). (C) PVFM with chinking. (D) Periglottic structures prolapsing (functional laryngomalacia). (Adapted from Perkner JJ, Fennelly KP, Balkisoon R, et al. Irritant-associated vocal cord dysfunction. J Occup Environ Med 1998;40(2):136–43; and Brugman SM, Simons ST. Vocal cord dysfunction: don’t mistake it for asthma. Physician Sports Med 1998;26:36–4, 66, 67–74, 85; with permission.)

By deﬁnition, PVFM is the nonphysiologic, paradoxical closure of the true vocal folds on inspiration, with or without concomitant closure on expiration. The vocal folds may adduct along their entire length from anterior to posterior (Fig. 1B) or may adduct along the anterior two thirds of their length leaving a diamond-shaped posterior opening or chink (Fig. 1C) [1,44]. This chink pattern, initially thought to be pathognomonic of PVFM, has been seen in only 6% of cases reported in the literature [37]. Vocal fold adduction may occur for part or all of inspiration, although closure only at end-inspiration may be physiologic [45]. Expiratory-only closure of the vocal folds has been described as a PVFM variant [9,12]. Because this

86

HICKS

et al

pattern is physiologic during asthma, however, expiratory PVFM in the setting of asthma is a questionable diagnosis [45]. Other patterns of PVFM have been reported and include pharyngeal constriction [46], posterior arytenoids prolapse (Fig. 1D) [47], exercise-induced laryngomalacia [48], and laryngochalasia [49]. There is some controversy about whether these patterns are truly functional versus organic derivatives of upper airway obstruction. Yet, it points to the lack of consensus on the precise diagnostic features of PVFM, even though laryngoscopy is still considered the gold standard. At present, there is no protocol for laryngoscopy procedure or relevant ﬁndings in PVFM patients and there is still debate over how to or who should perform laryngoscopy (otolaryngologists, speech pathologists, pulmonologists, and so forth). Until agreement can be reached, PVFM diagnosis can be considered a multidisciplinary one with laryngoscopy as a primary tool. Diﬀerential diagnosis It is important to eliminate organic causes of upper airway obstruction when making a diagnosis of PVFM (Table 1). Most of these diseases can Table 1 Diﬀerential diagnosis of PVFM Infectious Inﬂammatory

Traumatic Neoplastic

Allergic

Neurologic

Pulmonary Congenial anomalies Psychiatric

Croup, epiglottis, laryngeal papillomatosis, pertussis, laryngitis, pharyngeal abscess, diphtheria, CMV Rheumatoid cricoarytenoid arthritis, Wegner’s granulomatosis Laryngeal sarcoid, relapsing polychondritis, Gulf War laryngotracheitis, World Trade Center cough Vocal cord or upper airway hemorrhage, caustic ingestion, thermal injuries, laryngeal fracture, inhalation injury Carcinoma of larynx or upper aerodigestive tract, cystic hygroma, hemangioma, rhabdomyosarcoma, teratoma, lymphoma, papilloma, goiter Spasmodic croup, hereditary angioedema, anaphylaxis, atypical asthma, exercise-induced asthma, exercise-induced anaphylaxis Brainstem anomalies or tumors, true laryngospasm, vocal cord paralysis/paresis, tic disorders, multiple sclerosis, postpolio syndrome, multiple system atrophy, myasthenia gravis, Meige syndrome, Gerhardt’s disease, Parkinson’s disease, diaphragmatic ﬂutter syndrome, respiratory spasmodic dysphonia, traction on recurrent laryngeal nerve (aortic aneurysm) Asthma, COPD, foreign body aspiration, gastric or laryngopharyngeal aspiration, hyperventilation syndrome Laryngomalacia, laryngeal cleft, intrathoracic vascular ring, subglottic stenosis, laryngeal web Munchausen’s syndrome, malingering, panic, anxiety disorder, somatization disorder

Abbreviations: CMV, cytomegalovirus; COPD, chronic obstructive pulmonary disease.

87

VOCAL CORD DYSFUNCTION

be easily diﬀerentiated on the basis of other corroborating ﬁndings. The characteristic presentation of abrupt, transitory airway compromise without hypoxemia that is typical of PVFM is rarely seen in these physical diseases. Perhaps the greatest mimic is asthma. Even more confounding is the fact that PVFM is frequently comorbid with asthma in as many as 40% of pediatric-aged patients and 38% of adults [20,50]. Sorting out these two diagnoses, particularly during exercise, and determining which process is active at any one time is challenging. There are ﬁndings in the clinical presentation that are helpful (Table 2). Neurologic abnormalities are the next most important class of diseases to rule out. Certainly, peripheral or central nerve damage can result in vocal cord paresis or paralysis and must be carefully sought. The importance of laryngoscopy to ensure normal vocal cord function during an asymptomatic period is essential. Tic disorders can also mimic PVFM, although a solitary respiratory tic emanating from the larynx is highly unusual. On occasion, Gillette de la Tourette’s syndrome can manifest as stridor as one element of numerous motor and vocal tics. The neurologic disorder that most closely approximates PVFM is respiratory laryngeal dystonia, which involves laryngeal muscle tremor during breathing but does not produce classic stridor. Another frequently mistaken diagnosis for PVFM is exercise-induced anaphylaxis. This rare disorder presents with angioedema, ﬂushing, pruritus, hypotension, urticaria, wheezing, and upper airway obstruction [51]. It is seen in a minority of individuals who exercise after eating certain foods, speciﬁcally shellﬁsh, eggs, celery, grapes, wheat, and peaches. A lack of conﬁrmatory history or physical ﬁndings on supervised exercise testing is suﬃcient to rule this out. Diagnosis The diagnosis of PVFM relies on four areas: (1) clinical history and physical examination, (2) pulmonary function testing, (3) measures of oxygenation, and (4) laryngoscopy (Box 1). Table 2 Diﬀerentiating PVFM from asthma during exercise

Female:male Chest tightness Throat tightness Stridor Onset of symptoms after beginning exercise (min) Recovery period (min) Refractory period Late-phase response Response to B2 agonists Nocturnal symptoms

PVFM

Asthma

3:1 þ þ !5 5–10

1:1 þ O10 15–60 þ þ þ þ

Abbreviation: PVFM, paradoxical vocal fold motion. Data from Brugman SM, Simons ST. Vocal cord dysfunction: don’t mistake it for asthma. Physician Sports Med 1998;26:36–4, 66, 67–74, 85.

88

HICKS

et al

Box 1. Diagnostic indicators for PVFM 1. Clinical questionnaire Do you have more trouble getting air in or getting air out? Do you feel any tightness? Where is the tightness located? (throat, upper chest, lower chest) Do you hear any noises when you breathe in? Do you have numbness or tingling in your hands, feet, or lips? Do you feel lightheaded or dizzy? Have you passed out? Do symptoms come on rapidly? Do symptoms go away rapidly? Do your asthma medicines help? 2. Spirometry Saw-toothed, irregular, truncated, poorly reproducible inspiratory flow loops FEF50/FIF50 >1 Low FEV1 but normal FEV1/FVC ratio 3. Measures of oxygenation (during episodes) Pulse oximetry >90% Arterial PO >90 mm Hg Alveolar-arterial oxygen difference >15 mm Hg 4. Response to treatment No decrease in symptoms with >4 puffs of inhaled bronchodilator Worsening symptoms with inhaled medications No significant response to escalating asthma treatment, including inhaled corticosteroids 5. Presence of laryngopharyngeal irritants (gastroesophageal reflux disease/laryngopharyngeal reflux, postnasal drip)

Clinical history A careful clinical history may provide valuable information in diagnosing PVFM [13]. Certain symptoms and signs are more suggestive of PVFM than asthma or other respiratory conditions that have rapid onset and resolution (Box 2). Many patients point to or grab their throat when describing their respiratory symptoms, which may also diﬀerentiate upper from lower airway dysfunction [42,50]. Patients who have been treated for asthma may report a worsening of their symptoms with metered dose or powder inhalers, whereas nebulized medications can provide some relief [42]. Typically, patients are misdiagnosed as having asthma and are treated with intensive

VOCAL CORD DYSFUNCTION

89

Box 2. Symptoms of PVFM

Throat tightness Upper chest tightness Shortness of breath Tachypnea More difficulty getting air ‘‘in’’ than ‘‘out’’ Sensation of choking or suffocation Stridor Neck or chest retractions Pallor (without cyanosis) Hoarseness or aphonia Cough Lightheadedness Dizziness Heaviness of extremities Paresthesias of hands, feet, around mouth Near or total loss of consciousness

antiasthma medications, including systemic steroids, without improvement [20,37]. Symptoms of hyperventilation are quite common, occurring in 76% of patients diagnosed with PVFM in one study [52]. The clinical history may also point to risk factors and triggers for PVFM (Box 3), which may also help narrow the diagnosis. Pulmonary function testing A characteristic ﬁnding of nonorganic extrathoracic airway obstruction is a highly variable pattern of inspiratory ﬂow conﬁgurations (Fig. 2) [13,41].

Box 3. Risk factors for PVFM Female gender Gastroesophageal reflux disease Upper airway inflammation (rhinitis, sinusitis, allergies, recurrent viral infections) Prior traumatic event involving breathing (near-drowning, suffocation, witnessing severe asthma attack, and so forth) Playing a wind instrument Competitive athletics Excessive voice demands (singing, drama, public speaking) Severe emotional distress

90

HICKS

et al

Fig. 2. Flow volume loop showing forced expiratory ﬂow at 50% of the vital capacity (FEF50) and forced inspiratory ﬂow at 50% of the vital capacity (FIF50). A normal FEF50/FIF50 is usually !1 as shown by the line * to #. In PVFM, the FEF50/FIF50 ratio is O1, as shown by the line * to y.

A ﬂattening or truncation of the inspiratory ﬂow loop is often observed during an acute PVFM attack [4,41,42] and, in an appropriate clinical context, can diﬀerentiate PVFM from other laryngeal disorders [42]. Sequential inspiratory ﬂow volume loops are also nonreproducible and highly variable, which may be helpful in diagnosis [13,37]. The ﬂow volume loop may also be abnormal when patients are asymptomatic [20]. Organic laryngeal obstructions typically present with a ﬁxed truncation or ﬂattening of both inspiratory and expiratory loops [4]. Patients with asthma or accompanying closure of the vocal folds during expiration may have blunting of expiratory rather than inspiratory loops [41,53,54]. A helpful spirometric measure is the ratio between the forced expiratory ﬂow at 50% of the exhaled vital capacity and the forced inspiratory ﬂow at 50% of the inhaled vital capacity (FEF50/FIF50). Because normal inspiratory ﬂow is not limited by intrathoracic pressures like the expiratory ﬂow, this ratio is typically less than or equal to 1. In PVFM, this ratio often exceeds 1 and can frequently be estimated by observing the conﬁguration of the ﬂow-volume (see Fig. 2). This ratio is not typically observed in patients with both inspiratory and expiratory obstruction [13,55] and may be diﬃcult to interpret in cases of PVFM with comorbid asthma [13]. Another ﬁnding in PVFM is a decrease of greater than 25% in the maximum inspiratory ﬂow during histamine inhalation challenge [56]. Spirometry may be diﬃcult to interpret in patients with both PVFM and asthma. Methacholine and histamine have been used as irritant stimuli to provoke a PVFM attack separate from airway hyperactivity [17,57]. Patients with PVFM may exhibit ﬂattening of the inspiratory ﬂow-volume loop and

VOCAL CORD DYSFUNCTION

91

have a diagnostic laryngoscopy [41]. During bronchial provocation, lower airways hyperresponsiveness characteristic of asthma is diagnosed if the forced expiratory volume at 1 second (FEV1) is reduced by 20% or more when compared with baseline [1]. If there is normal lower airway response to methacholine challenge (PC20 FEV1 values of greater than 8 mg/mL) in patients with PVFM, then asthma can be ruled out [41]. In those patients who have both disorders, the bronchoprovocation is positive and the laryngoscopy can be positive or negative depending on whether associated PVFM is also elicited. Needless to say, the overlap of these two disorders makes the diagnosis complicated. If methacholine challenge fails to elicit PVFM in patients with a compelling history, a speciﬁc irritant challenge may be indicated [41,42]. Where exercise is the primary trigger, a graded exercise challenge on a bicycle ergometer or treadmill is helpful [4,18,30]. Measures of oxygenation A major diﬀerentiating feature of PVFM from other urgent respiratory disorders is the lack of cyanosis or evidence of low oxygen tensions. Over 75% of PVFM patients reported in the literature had normal oxygenation as measured by pulse oximetry or arterial blood gas sampling [37]. If a decreased PaO2 is seen on arterial blood gases, there is usually a corresponding increase in PaCO2, indicative of a breath-hold. Conversely, a low PaCO2 can be seen with an acute or compensated respiratory alkalosis because hyperventilation is frequently seen in conjunction with PVFM. The alveolar-arterial oxygen diﬀerence (PAO2-PaO2) calculated from arterial blood gases conﬁrms normal oxygen delivery and is typically less than 10 mm Hg [1]. This is in contrast to signiﬁcant acute asthma where PaO2 decreases in direct proportion to worsening airﬂow limitation and PAO2-PaO2 is elevated. The discrepancy between the apparent severe respiratory distress and normal measures of oxygenation may be a key discriminator for PVFM. Flexible laryngoscopy The gold standard for diagnosing PVFM is direct visualization using ﬂexible, transnasal laryngoscopy [13,17,20,29,38]. Paradoxic, inspiratory narrowing of the vocal cords during acute attacks is the most frequent ﬁnding. The controversy over the various patterns of inspiratory closure has been discussed previously in this article. Newman and colleagues [20] reported diagnostic laryngoscopic ﬁndings in 100% of PVFM patients while symptomatic and 60% of patients while asymptomatic. There is argument that ﬂexible laryngoscopy is invasive, somewhat uncomfortable, and may interfere with normal laryngeal function or induce PVFM. Until correlates of laryngeal closure are determined or noninvasive methods of examining the larynx are discovered, laryngoscopy remains the primary diagnostic tool.

92

HICKS

et al

Pulmonary function tests may or may not show signiﬁcant improvement (greater than 12% increase in FEV) after inhaled bronchodilators and their FEV and FEV/forced vital capacity ratio may be in the normal, low, or high range [42]. In patients with predominantly inspiratory PVFM, the ratio of forced expiratory to forced inspiratory ﬂows (liters per minute) at 50% of vital capacity is usually greater than 1 [13,28,42]. This ratio is not typically observed in patients with both inspiratory and expiratory obstruction [13,38,42] and may be diﬃcult to interpret in cases of PVFM with comorbid asthma [13]. Bucca and colleagues [56] demonstrated that a greater than 25% decrease in the maximum inspiratory ﬂow during histamine inhalation challenge was associated with changes in mid-inspiratory glottic area. Patients with pure PVFM have normal chest radiographs with no indication of hyperinﬂation [41,42]. Most patients with PVFM have normal oxygenation, as measured by pulse oximetry or arterial blood gas sampling [1,13] in contrast to asthma, where the alveolar-arterial oxygen diﬀerence is elevated [13]. The absence of an increase in PAO2-PaO2 gradient and when eosinophilia is not present during an acute attack is a vital indicator of PVFM. Both of these ﬁndings occur in greater than 90% of asthmatic attacks [53]. Methacholine or histamine may be used as irritant stimuli to invoke a PVFM attack separate from airway hyperactivity [17,57]. Patients with PVFM frequently show evidence of paradoxical vocal fold movement during the inspiratory or expiratory phase of breathing during laryngoscopy following methacholine challenge when compared with patients without PVFM [41]. During bronchial provocation, the test is considered positive for bronchial hyperactivity characteristic of asthma if the FEV1 is reduced by 20% or more when compared with baseline [1]. In many cases there is normal airway response to methacholine challenge with PC20 FEV, values of greater than 8 mg/mL in patients with PVFM [42]. A negative bronchial provocation helps to rule out asthma. If methacholine challenge fails to elicit PVFM in patients with a compelling history, a speciﬁc known irritant challenge may be indicated [41,58]. Provocation with exercise is required to elicit symptoms in those patients with exercise-induced PVFM [4,18,30].

Etiology The underpinnings of PVFM are poorly understood and more a matter of conjecture than of science. It is probably best to categorize them as a melding of psychologic, neurologic, and physiologic components. There are several proposed etiologies that merit discussion (Box 4). Upper airway hyperresponsiveness and exaggerated glottic closure reﬂex The upper airway may be rendered hyperresponsive by a number of factors including viral infections, allergic and nonallergic inﬂammation,

VOCAL CORD DYSFUNCTION

93

Box 4. Proposed etiologies of PVFM A. Upper airway hyperresponsiveness (irritable larynx syndrome [8]) secondary to Laryngopharyngeal reflux Inflammatory upper airway disease (allergic, nonallergic, viral rhinitis, sinusitis, postnasal drip) Toxic inhalation (occupational, accidental) B. Exaggerated glottic closure reflex C. Autonomic dysfunction of the larynx D. Primary psychiatric disorder Symptom amplification Panic or anxiety disorder Depression Conversion disorder (unresolved psychiatric conflicts) Stress

laryngopharyngeal or gastroesophageal reﬂux disease (GERD), prior episodic croup, and toxic inhalation exposures. Sensory receptors, particularly irritant receptors, densely populate the upper airway and provoke glottic closure and cough when stimulated [42]. It has been postulated that stimulation of irritants by the olfactory nerve or by sensory aﬀerent nerves in the upper and lower respiratory tract trigger the glottic closure and other reﬂexes and then paradoxical movement in the vocal folds [41]. After a priming insult, it is probable that the glottic closure reﬂex, which is initially adaptive, becomes activated by nonspeciﬁc irritants (smoke, fumes, GERD, and so forth) to perpetuate the clinical condition called PVFM [42]. Morrison and colleagues [8] deﬁned this as the ‘‘irritable larynx syndrome,’’ which they described as ‘‘hyperkinetic laryngeal dysfunction resulting from an assorted collection of causes in response to a deﬁnitive triggering stimulus.’’ They postulated that chronic noxious stimulation could promote hyperfunctional laryngeal symptoms caused by neural plastic changes in brainstem control centers. Although their theory has not been rigorously studied, it does parallel other authors’ speculations about upper airway hyperresponsiveness (UAWH). Several studies have looked at the association of UAWH and inﬂammatory or infectious conditions. Bucca and colleagues [59] studied UAWH and bronchial hyperresponsiveness in 106 nonasthmatic adults with acute exacerbations of their chronic sinusitis. A remarkable 86% of them had UAWH (termed ‘‘extrathoracic airways hyperresponsiveness’’), two thirds of whom also had bronchial hyperresponsiveness. Following 2 weeks of treatment with antibiotics and intranasal steroids, 76% of those with UAWH were resolved and another 21% were improved. There was also signiﬁcant

94

HICKS

et al

resolution and improvement of corresponding bronchial hyperresponsiveness in these same patients. They proposed that both UAWH and bronchial hyperresponsiveness ‘‘may be sustained by reﬂexes originating in pharyngeal receptors made hypersensitive by local seeding of the inﬂammatory process’’ [59]. In a similar study of 37 patients with episodic dyspnea and 9 controls, Bucca and colleagues [56] found that patients could be classiﬁed using histamine challenges as asthma only, asthma with UAWH, and UAWH alone. Those with UAWH as the only or contributing factor to their dyspnea had sinusitis. In a larger study by the same authors of 441 patients with asthmatic symptoms but without a prior diagnosis of asthma, 67% had UAWH [60]. The inﬂuence of concurrent upper respiratory tract diseases was also assessed and found to be substantial: postnasal drip (55%); pharyngitis (55%); laryngitis (40%); and sinusitis (32%). These studies provide strong support for the theory that laryngeal and pharyngeal bombardment by inﬂammatory cells and mediators from the upper airway causes mucosal damage, irritant sensory stimulation, and the glottic closure and similar reﬂexes that result in UAWH and PVFM. Further study is needed to corroborate and further elucidate this argument. Inhalational exposures, both occupational and accidental, have also been associated with PVFM [17,41,61,62]. The role of the upper airway as primary defender and gas ﬁlter places it in a vulnerable position when overwhelmed by inhalational agents. Precipitants are varied and include cleaning chemicals, soldering fumes, dust, organic solvents, machining ﬂuid, chlorine gas fumes, and smoke and particulates from ﬁres. Cough is also a frequent symptom in these cases. Perkner and colleagues [17] proposed that chest pain, chest tightness, and GERD symptoms distinguish between irritant and nonirritant PVFM. Another important cause of UAWH is GERD, and there are numerous studies to support this association. Canine models of GERD have indicated that a pH of 2.5 or less provokes laryngospasm through vagally mediated mechanisms and the sensitization of mucosal chemoreceptors [63]. Gastric reﬂux and upper airway secretions have been implicated in apnea in infants [64,65]. Likewise, Thatch [64] proposed that chronic or acute upper airway inﬂammatory processes may be responsible for hyperresponsive laryngeal chemoreﬂexes observed in infantile apnea. If chronic cough is accepted as another manifestation of UAWH, then several studies have conﬁrmed the association of GERD and UAWH. Palombini and colleagues [55] proposed a pathogenic triad of asthma, postnasal drip syndrome, and GERD as the most common causative factors of chronic cough. Other authors have reported similar ﬁndings [66]. For example, Altman and colleagues [42] found allergic rhinitis, cough-variant asthma, and GERD as the cause of chronic cough in 86% of adult patients. Vernigan and colleagues [24] reported on GERD and postnasal drip as underlying factors in PVFM. It is likely that chronic cough along with PVFM are manifestations of irritant-induced UAWH.

VOCAL CORD DYSFUNCTION

95

Autonomic dysfunction The role of viruses in inducing lower airways hyperresponsiveness is well documented [67]. Likewise, there is reason to believe that viruses can also induce UAWH. Ayres and Gabbott [68] proposed that PVFM may be caused by autonomic imbalance provoked by an inﬂammatory process in the upper airway. Laryngeal aﬀerents, stimulated by inﬂammatory products, link to more central brain regions in the medulla, midbrain, and the prefrontal cortex, causing a change in the sympathetic-parasympathetic nervous output. This could lead to a persistent ‘‘autonomic preset’’ whereby subsequent stimuli (eg, psychologic stressors, changes in ambient temperature, nonspeciﬁc irritants) induce cholinergically dominated reﬂexes. Such reﬂexes result in airway narrowing in the upper airway or in the lower airways in patients with asthma. Although only speculative at this point, such a theory seems plausible [68]. Psychologic considerations A number of studies suggest that psychologic factors may be operative in some cases of PVFM. The ﬁrst cases of psychologically driven PVFM may have been those of Dunglison in 1842 who described patients with ‘‘hysteric croup’’ (described disorders of the laryngeal musculature brought on by hysteria) [69]. Numerous other cases were reported in the late 1800s, then not again until Patterson’s seminal paper of Munchausen’s stridor in 1975 [10]. Because all of the early literature associated this disorder with mental diseases, it became known by a number of psychiatric names including psychogenic stridor, emotional laryngeal wheezing, laryngoneurosis, and factitious asthma [9–12]. In Christopher and coworkers’ [1] landmark citation in 1985, they reported on ﬁve patients with PVFM conﬁrmed by laryngoscopy. Evaluations on four of the ﬁve patients revealed psychiatric disorders ranging from ‘‘mild stress-related exacerbation of symptoms to obsessive-compulsive disorder.’’ Every one of these patients was reported to have varying degrees of secondary gain from their symptoms and it was suggested that they all suﬀered from a conversion disorder [1]. In a review of 48 PVFM patients in the military, Lacy and McManis [11] found 45 individuals to have a psychiatric disorder: 52% conversion disorder, 13% major depression, 10% factitious disorder, 4% obsessive-compulsive disorder, and 4% adjustment disorder. Several authors have postulated that the stridor in PVFM represents ‘‘unshed tears’’ or ‘‘symbolic crying’’ [70,71]. This supposition that PVFM is primarily a conversion disorder (patients unconsciously ‘‘convert’’ unresolved psychological conﬂict into medical illness) has not been supported in the literature. Neither has the belief that PVFM is a psychic accommodation to childhood abuse [1,72]. Some speciﬁc psychologic conditions have been linked to PVFM. Anxiety is widely accepted to be comorbid with

96

HICKS

et al

respiratory disorders with rates of 34% in adults and 25% in children [73,74]. Gavin and colleagues [34] reported a higher incidence of anxiety among adolescents with PVFM than among their age-matched peers with asthma. Panic disorder and hyperventilation syndrome were more often seen in PVFM patients as reported by Wamboldt and colleagues [75] in an uncontrolled study. Depression as a comorbid or underlying psychopathology has been reported [1,20]. An extensive review of PVFM patients found depression in only 13% and anxiety in 15%, although the number of patients who underwent psychologic evaluation was admittedly small [37]. It is also possible that symptoms of depression and anxiety are a result, rather than a cause, of chronic respiratory illness [4,17,22]. A ﬁnal psychologic cofactor with PVFM is stress. Certainly, other chronic medical problems are known to be inﬂuenced by emotional stresses including irritable bowel syndrome, migraine headaches, chronic abdominal pain, and coronary artery disease. An estimated 20% of PVFM attacks are triggered by stress in the general population and an indeterminate number of soldiers have experienced PVFM, especially as a reaction to combat [11,37]. Additionally, the achievement-oriented, competitive adolescents in whom PVFM is often seen corroborate the stress-PVFM association [13,76].

Treatment of paradoxical vocal fold motion Treatment for PVFM requires a multidisciplinary approach and is guided by the comorbidities present. The team may include the primary care physician, pulmonologist, allergist, otolaryngologist, gastroenterologist, neurologist, psychiatrist or psychologist, speech-language pathologist, athletic coach, or athletic trainer [5,42,77]. Medical intervention involves careful and compassionate disclosure of the diagnosis. Patient education is an especially important component of treatment. Describing normal laryngeal physiology and the paradoxical pattern of the vocal folds under various environmental exposures or stress augments the patient’s comprehension and acceptance of the condition. If the PVFM was diagnosed by laryngoscopy, viewing the videotape or DVD further enhances understanding and acceptance and allows the patient to visualize overcoming the laryngeal obstruction with breathing exercises [13]. Termination of unnecessary medications may be indicated for those patients misdiagnosed with asthma [1,22,38]. This should be done carefully, however, under medical supervision if underlying airway hyperactivity is suspected [38]. Medications can generally be tapered in those individuals with overtreated coexisting asthma [53]. Pharmacologic treatment and lifestyle modiﬁcations may be necessary when airway irritants, such as gastroesophageal reﬂux, laryngopharyngeal reﬂux, allergic and nonallergic rhinitis, and sinusitis, are identiﬁed [22].

VOCAL CORD DYSFUNCTION

97

Acute management The acute management of PVFM requires a conﬁrmed diagnosis and treatment should be directed toward relieving the airway obstruction [38]. The ﬁrst step is to reassure the patient that the condition is benign and that their oxygen levels are normal despite the intense dyspnea, while calmly validating their fears [2,13]. Morris and coworkers [38] found ample evidence of the eﬀectiveness of relieving acute airway symptoms with reassurance alone. Various nonspeech tasks optimize a wide-open airway and possibly abort PVFM attacks and include panting, sniﬃng, pursed lip breathing on exhalation, and nasal inhalation [21,54,78,79]. Heliox is a mixture of oxygen and helium in ratios of 80:20, 70:30, and 60:40 (helium to oxygen) [80] that has been found to be dramatically eﬀective in relieving acute presentations of PVFM [1,28,80–82] but not in all cases [81,83]. Heliox takes advantage of the lower density of helium compared with nitrogen and allows oxygen to ﬂow through occluded large airways by producing less turbulent ﬂow, hence decreasing the work of breathing [38,80]. As a therapeutic intervention, heliox does not relax the vocal folds, but relaxes the patient by decreasing the work of breathing, which then leads to relaxation of the vocal folds. In severe cases, sedation can be used because symptoms nearly always disappear with sleep or anxiolysis [13]. The use of benzodiazepines can be eﬀective in terminating PVFM episodes in patients presenting with acute symptoms [38]. A more invasive and least used treatment approach involves intralaryngeal injection of botulinum toxin. Botulinum toxin type A acts at nerve endings to prevent release of acetylcholine, resulting in chemical denervation, which paralyzes the vocal fold in the abducted (open) position [6,13,38]. Although this technique has been successful in treating adductor laryngeal breathing dystonia and spasmodic dystonia [13,22], it is infrequently used in the treatment of PVFM [38]. It should only be considered for the individual with severe protracted PVFM who does not respond to other treatment and for whom intubation or tracheostomy presents as the only option [6,13,84]. Chronic management Speech therapy is regarded as the primary therapy for PVFM and is considered by some physicians to be the cornerstone of treatment [4,11,13,20,25,28,29,53]. Speech therapists and vocal pathologists play an important role in long-term management of PVFM by providing respiratory retraining; assessment and diagnostic input; patient education; supportive counseling; management and suppression of laryngeal abusive behaviors (ie, cough and throat clearing); voice therapy; and desensitization to speciﬁc irritants [22,25,41]. Patients may also beneﬁt from psychotherapy or psychologic counseling and this is frequently used in conjunction with speech therapy [38]. Psychotherapeutic intervention in PVFM lacks systematic study

98

HICKS

et al

[13,22,38], but may be warranted in some PVFM cases and might range from assisting patients with stress management to coping with underlying psychopathology [22,85]. The use of surface electromyography biofeedback and hypnosis have been found to be eﬀective measures in some adolescents with PVFM [85,86]. Speech-language pathology assessment Assessment should begin with a comprehensive patient interview focusing on the patient’s knowledge of his or her symptoms and reason for referral. Many patients are unaware that speech-language pathologists specialize in diseases and disorders of the larynx, including upper airway obstruction and respiration. A careful and compassionate patient interview helps to establish rapport and trust between the patient and clinician [77]. Discrepant, inconsistent, or unrealized but pertinent information can emerge from this assessment [22]. The initial case history should also determine previously diagnosed or suspected respiratory disease; the patient’s knowledge of triggers and symptoms; what the patient is currently doing to resolve his or her symptoms; psychosocial aspects of the disorder (ie, anxiety or panic); eﬀectiveness of inhalers (when prescribed); changes in vocal quality; changes in swallowing; existence of laryngeal abusive behaviors; presence of laryngopharyngeal irritants (ie, postnasal drip, GERD, laryngopharyngeal reﬂux); and any contribution of the patient’s lifestyle to the disorder (ie, hydration, breathing pattern, vocal habits). The initial assessment should prompt any referrals to physicians or counselors if indicated. The patient should be provided education on normal laryngeal anatomy and physiology as it relates to breathing, vocalizing, swallowing, coughing, clearing, breath holding, and PVFM, and the paradoxical movement of the vocal folds during PVFM attacks. Knowledge of normal and abnormal physiology empowers the patient to accept and gain control over the disorder. Speech-language pathology treatment Treatment provided by the speech-language pathologists at the National Jewish Medical and Research Center is outlined next. It cannot be emphasized enough that treatment should be tailored to the speciﬁc needs of the patient and any one given treatment may not be helpful or suﬃcient. Patients are provided education on the role of laryngeal abusive behaviors (ie, cough and throat clearing) in PVFM and the rationale for prevention or minimization of these behaviors. Patients are provided demonstration of various cough suppression and throat clearing elimination techniques and are provided ample practice for appropriate return demonstration. They are then provided education on what is believed to be hypersensitivity in the larynx and hyperreaction of the protective nature of the vocal folds that occurs with PVFM. The patients are taught various

VOCAL CORD DYSFUNCTION

99

breathing techniques that are intended to provide immediate control or quick release over paradoxical movement in the vocal folds. The following techniques were developed by voice pathologist Fran Lowry, a revered colleague at the authors’ facility. (1) The patient is cued to lower their shoulders and place their hand on their mid-abdomen, which supports abdominal breathing and decreases upper body tension. (2) The patient is instructed to inhale quickly through the nose or the mouth for approximately 1 second. Patients are instructed to use whichever method of inhalation feels best. Many patients have coexisting sinus disease and cannot breathe in through their noses or sniﬀ secretions back into their throats triggering coughing or clearing. Sniﬃng in through the nose is noisy, so many patients prefer inhalation through the mouth. This inhalation technique assists with a forced abduction of the vocal folds. (3) Patients are instructed to breathe out through tightly pursed lips for 2 to 3 seconds. This pursed lip breathing technique creates a pressure behind the lips and through the pharynx that forcibly abducts the vocal folds. The timing of this technique is important in that breathing in too long forces a longer exhalation, which may create tension rather than release tension. The patients should be exhaling what they inhale. These techniques are then applied to symptom and trigger recognition, which allows the patient to prevent or control PVFM attacks at their ﬁrst onset and during exposure to known triggers, the caveat being that awareness of initial onset of symptoms and trigger identiﬁcation precedes initiation of these techniques. These techniques can provide immediate release of the vocal folds and decrease anxiety and panic that often accompanies attacks. Many patients can prevent or control their attacks during the ﬁrst visit. Patients are encouraged to practice ﬁve repetitions of this technique, 20 times daily when asymptomatic and at the ﬁrst onset of diﬃculty. This not only assists with laryngeal relaxation and retraining, but ensures an automatic response used by the patient during times of need. These techniques are frequently tailored or tweaked to meet the individual needs of patients. Patients who have a tendency toward hyperventilation or who have signiﬁcant anxiety or panic are instructed on controlled breathing exercises. These exercises focus on a more controlled pursed lip breathing pattern using abdominal support with focus directed at relaxation. The quick-release techniques are also used for desensitization to speciﬁc irritants and prevention or control during speciﬁc exercise triggers. Speciﬁc irritant challenges are extremely beneﬁcial because patients are taught control over and can frequently prevent episodes through progressive desensitization. Exercise challenges are provided for cycling, basketball, soccer, swimming, and running. All techniques and skills taught during these challenges are tailored toward individual requirements. The setting should resemble the environment where their symptoms are triggered (ie, indoors versus outdoors). Many athletes tax their bodies to physiologic limits and beyond. Care is directed at relieving upper and lower body tension and

100

HICKS

et al

any maladaptive patterns (ie, shallow breathing, posture, breath-holding) during their challenges. Patients are taught paced breathing techniques using abdominal support with attention toward awareness of initial onset of their symptoms. Patients use the quick-release techniques at initial onset of their symptoms at their current pace. If symptoms do not resolve at that pace, they back oﬀ until they can be resolved. Once symptoms subside, patients can resume the faster pace. Pacing skills are an important aspect in exercise challenges. Awareness of initial symptom onset ensures quick resolve and patients progress toward elimination or control of their symptoms. Summary It is reasonable to suggest that there are subgroups of PVFM and that one modality may not be suﬃcient in diagnosis or treatment. At the very least, there is a need to come together as health care professionals in terminology. There is a lack of suﬃcient knowledge regarding the relationship between psychologic and physiologic aspects of PVFM. Knowledge is needed regarding laryngeal sensitivity and its role in this perplexing disorder. Further research in treatment modalities is signiﬁcantly needed. Prospective and systematic study across disciplines and institutions is imperative.

References [1] Christopher KL, Wood RP, Eckert C, et al. Vocal cord dysfunction presenting as asthma. N Engl J Med 1983;308:1566–70. [2] Bahrainwala AH, Simon MR. Wheezing and vocal cord dysfunction mimicking asthma. Curr Opin Pulm Med 2001;7:8–13. [3] Mobeireek A, Alhamad A, Al-Subaei A, et al. Psychogenic vocal cord dysfunction simulating bronchial asthma. Eur Respir J 1995;8:1978–81. [4] Newman KB, Dubester SN. Vocal cord dysfunction: masquerader of asthma. Semin Respir Crit Care Med 1994;15(2):161–7. [5] Murry T, Tabaee A, Aviv JE. Respiratory retraining of refractory cough and laryngopharyngeal reﬂux in patients with paradoxical vocal fold movement disorder. Laryngoscope 2004;114:1341–5. [6] Maillard I, Schweizer V, Broccard A, et al. Use of botulinum toxin type A to avoid tracheal intubation or tracheostomy in severe paradoxical vocal cord movement. Chest 2000;118: 874–7. [7] Newsham KR, Klaben BK, Miller VJ, et al. Paradoxical vocal-cord dysfunction: management in athletes. J Athl Train 2002;37(3):325–8. [8] Morrison M, Rammage L, Emami AJ. The irritable larynx syndrome. J Voice 1999;13(3): 447–55. [9] Downing ET, Braman SS, Fox MJ, et al. Factitious asthma: physiological approach to diagnosis. JAMA 1982;248:2878–81. [10] Patterson R, Schatz M, Horton M. Munchausen’s stridor: non-organic laryngeal obstruction. Clin Allergy 1974;4:307–10. [11] Lacy TJ, McManis SE. Psychogenic stridor. Gen Hosp Psychiatry 1994;16:213–23.

VOCAL CORD DYSFUNCTION

101

[12] Rodenstein DO, Francis C, Stanescu DC. Emotional laryngeal wheezing: a new syndrome. Am Rev Respir Dis 1983;127:354–6. [13] Brugman, SM. What’s this thing called vocal cord dysfunction. Available at: http://www. chestnet.org/education/online/pccu/vol20/lessons25_27. Accessed July 30, 2007. [14] Gallivan G, Andrianopoulos M. Dysphonia due to paradoxical vocal fold movement/episodic paroxysmal laryngospasm. In: Sapienza CM, Casper J, editors. Vocal rehabilitation for medical speech-language pathology. Pro-ed inc; 2004. p. 165–208. [15] Filaire M, Mom T, Laurent S, et al. Vocal cord dysfunction after left lung resection for cancer. Eur J Cardiothorac Surg 2001;20(ER4):705–11. [16] Jones TF, Craig AS, Hoy D, et al. Mass psychogenic illness attributed to toxic exposure at a high school. N Engl J Med 2000;342:96–100. [17] Perkner JJ, Fennelly KP, Balkissoon R, et al. Irritant-associated vocal cord dysfunction. J Occup Environ Med 1998;40(2):136–43. [18] McFadden ER, Zawadski DK. Vocal cord dysfunction masquerading as exercise-induced asthma: a physiologic cause for choking during athletic activities. Am J Respir Crit Care Med 1996;153:942–7. [19] Reisner C, Nelson HS. Vocal cord dysfunction with nocturnal awakening. J Allergy Clin Immunol 1997;99:843–6. [20] Newman KB, Mason UG III, Schmaling KB. Clinical features of vocal cord dysfunction. Am J Respir Crit Care Med 1995;152:1382–6. [21] Andrianopoulos MV, Gallivan GJ, Gallivan KH. PVCM, PVCD, EPL, and irritable larynx syndrome: what are we talking about and how do we treat it. J Voice 2000;14(4): 607–18. [22] Mathers-Schmidt BA. Paradoxical vocal fold motion: a tutorial on a complex disorder and the speech-language pathologist’s role. Am J Speech Lang Pathol 2001;10:111–25. [23] Diamond E, Kane C, Dugan G. Presentation and evaluation of vocal cord dysfunction. Chest 2000;118(4):199S. [24] Vernigan AE, Theodoros DG, Gibson PG, et al. The relationship between chronic cough and paradoxical vocal fold movement: a review of the literature. J Voice 2006;20(3):466–80. [25] Vlahakis NE, Patel AM, Maragos NE, et al. Diagnosis of vocal cord dysfunction: the utility of spirometry and plethysmography. Chest 2002;122:2246–9. [26] Kissoon N, Kronick JB, Frewen TC. Psychogenic upper airway obstruction. Pediatrics 1988; 81(5):714–7. [27] Cairns-Pastor C. Condition has name, but still unsettling. Tampa Tribune. October 6, 2003. [28] Goldman J, Muers M. Vocal cord dysfunction and wheezing. Thorax 1991;46:401–4. [29] Patterson DL, O’Connell EJ. Vocal cord dysfunction: what have we learned in 150 years. Insights in Allergy 1994;9(6):1–9. [30] Morris MJ, Deal LE, Bean DR, et al. Vocal cord dysfunction in patients with exertional dyspnea. Chest 1999;116(6):1676–82. [31] Hayes JP, Nolan MT, Brennan N, et al. Three cases of paradoxical vocal cord adduction followed up over a 10-year period. Chest 1993;104(3):678–80. [32] Kenn K, Willer G, Bizer C, et al. Prevalence of vocal cord dysfunction in patients with dyspnea: ﬁrst prospective clinical study. Am J Respir Crit Care Med 1997;155:A965. [33] Jain S, Bandi V, Oﬃcer T, et al. Incidence of vocal cord dysfunction in patients presenting to emergency room with acute asthma exacerbation. Chest 1999;116(4):243S. [34] Gavin LA, Wamboldt M, Brugman S, et al. Psychological and family characteristics of adolescents with vocal cord dysfunction. J Asthma 1998;35(5):409–17. [35] Abu-Hasan M, Tannous B, Weinberger M. Exercise-induced dyspnea in children and adolescents: if not asthma then what? Ann Allergy Asthma Immunol 2005;94:366–71. [36] Seear MD, Wensley DW, West N. How accurate is the diagnosis of exercise-induced asthma amongst Vancouver schoolchildren? Doi:10.11.1136/adc.2004.063974. [37] Brugman S. The many faces of vocal cord dysfunction: what 36 years of literature tell us. Am J Respir Crit Care Med 2003;167:A588 [manuscript in progress 2007].

102

HICKS

et al

[38] Morris MJ, Allan PF, Perkins PJ. Vocal cord dysfunction: etiologies and treatment. Clinical Pulmonary Medicine 2006;13:73–86. [39] Sasaki CT, Weaver EM. Physiology of the larynx. Am J Med 1997;103:9S–18S. [40] O’Hollaren MT. Dyspnea originating from the larynx. Immunol Allergy Clin North Am 1996;16(1):69–76. [41] Balkissoon R. Occupational upper airway disease. Clin Chest Med 2002;23:717–25. [42] Altman KW, Simpson CB, Amin MR, et al. Cough and paradoxical vocal fold motion. Otolaryngol Head Neck Surg 2002;127(6):501–11. [43] McFadden R. Glottic function and dysfunction. J Allergy Clin Immunol 1987;79(5):707–10. [44] Wood RP, Milgrom H. Vocal cord dysfunction. J Allergy Clin Immunol 1996;98:481–5. [45] England SJ, Ho V, Zamel N. Laryngeal constriction in normal humans during experimentally induced bronchoconstriction. J Appl Physiol 1985;58(2):523–5. [46] Nagai A, Yamaguchi E, Sakamoto K, et al. Functional upper airway obstruction: psychogenic pharyngeal constriction. Chest 1992;101:1460–1. [47] Bittleman DB, Smith RJH, Weiler JM. Abnormal movement of the arytenoids region during exercise presenting as exercise-induced asthma in an adolescent athlete. Chest 1994;104: 615–6. [48] Smith RJH, Bent JP, Bauman NM, et al. Exercise-induced laryngomalacia. Ann Otol Rhinol Laryngol 1995;104:537–40. [49] Bjornsdottir US, Gudmundsson K, Hjartarson H, et al. Exercise-induced laryngochalasia: an imitator of exercise-induced bronchospasm. Ann Allergy Asthma Immunol 2000;85(5): 387–91. [50] Martin RJ, Blager FL, Gay ML, et al. Paradoxic vocal cord motion in presumed asthmatics. Semin Respir Med 1987;8(4):332–7. [51] Shadick NA, Liang MH, Partridge AJ, et al. The natural history of exercise-induced anaphylaxis: survey results from a 10-year follow-up study. J Allergy Clin Immunol 1999;104(1): 123–7. [52] Parker JM, Berg BW. Prevalence of hyperventilation in patients with vocal cord dysfunction. Chest 2002;122:185S–6S. [53] Brugman SM, Newman K. Vocal cord dysfunction. Medical/Scientiﬁc Update 1993;11(5): 1–6. [54] Bahrainwala AH, Simon MR, Harrison DD, et al. Atypical expiratory ﬂow volume curve in an asthmatic patient with vocal cord dysfunction. Ann Allergy Asthma Immunol 2001;86: 439–43. [55] Palombini BC, Castilhos Villanova CA, Araujo E, et al. A pathogenic triad in chronic cough: asthma, postnasal drip syndrome, and gastroesophageal reﬂux disease. Chest 1999;116: 279–84. [56] Bucca C, Rolla G, Scappaticci E, et al. Histamine hyperresponsiveness of the extrathoracic airway in patients with asthmatic symptoms. Allergy 1991;46(2):147–53. [57] Perkins PJ, Morris MJ. Vocal cord dysfunction induced by methacholine challenge testing. Chest 2002;122:1988–93. [58] Stanton AE, Bucknall CE. Vocal cord dysfunction. Breathe 2005;2(1):31–7. [59] Bucca C, Rolla G, Scappaticci E, et al. Extrathoracic and intrathoracic airway responsiveness in sinusitis. J Allergy Clin Imunol 1995;95(1):52–9. [60] Bucca C, Rolla G, Brussino L, et al. Are asthma-like symptoms due to bronchial or extrathoracic airway dysfunction. Lancet 1995;346:791–5. [61] Reddy PV, Solomon D, Truncale T. Vocal cord dysfunction after chlorine inhalation. Chest 2004;126(Suppl):999S. [62] Allan PF, Abouchahine S, Harvis L, et al. Progressive vocal cord dysfunction subsequent to a chlorine gas exposure. Doi:10.1016/j.jvoice.2005.04.003. [63] Loughlin CJ, Koufman JA, Averill DB. Acid-induced laryngospasm in a canine model. Laryngoscope 1996;106(12):1506–9.

VOCAL CORD DYSFUNCTION

103

[64] Thach BT. Reﬂux associated apnea in infants: evidence for a laryngeal chemoreﬂex. Am J Med 1997;103:120S–4S. [65] Orenstein SR. An overview of reﬂux-associated disorders in infants: apnea, laryngospasm, and aspiration. Am J Med 2001;111:60S–3S. [66] Millqvist E, Bende M, Lowhagen O. Sensory hyperreactivity: a possible mechanism underlying cough and asthma-like symptoms. Allergy 1998;53:1208–12. [67] Folkerts G, Busse WW, Nijkamp FP, et al. Virus-induced airway hyperresponsiveness and asthma. State of the art. Am J Respir Crit Care Med 1998;157:1708–20. [68] Ayres JG, Gabbott PLA. Vocal cord dysfunction and laryngeal hyperresponsiveness: a function of altered autonomic balance. Thorax 2002;57:284–5. [69] Dunglison R. Practice of medicine. Lea & Blanchard; 1842. p. 257–8. [70] Geist R, Tallett SE. Diagnosis and management of psychogenic stridor caused by a conversion disorder. Pediatrics 1990;86(2):315–7. [71] Starkman MN, Appelblatt N. Functional upper airway obstruction: a possible somatization disorder. Psychosomatics 1984;25:327–33. [72] Freedman MR, Rosenberg SJ, Schmaling KB. Childhood sexual abuse in patients with paradoxical vocal cord dysfunction. J Nerv Ment Dis 1991;179(5):295–8. [73] Yellowlees PM, Kalucy RS. Psychobiological aspects of asthma and the consequent research implications. Chest 1990;97:528–634. [74] Mrazek DA. Psychiatric complications of pediatric asthma. Ann Allergy 1992;69(4):285–90. [75] Wamboldt F, Balkissoon R, Amerigo P, et al. Diagnoses associated with persistent shortness of breath and upper airway dysfunction in patients with and without occupational or environmental exposure. Am J Respir Crit Care Med 2001;A55. [76] Brugman SM, Simons ST. Vocal cord dysfunction: don’t mistake it for asthma. Physician Sports Med 1998;26:63–4, 66, 67–74, 85. [77] Sandage MJ, Zelazny SK. Paradoxical vocal fold motion in children and adolescents. Lang Speech Hear Serv Sch 2004;35:353–62. [78] Pitchenik AE. Functional laryngeal obstruction relieved by panting. Chest 1991;100(5): 1465–7. [79] Blager FB. Paradoxical vocal fold movement: diagnosis and management. Curr Opin Otolaryngol Head Neck Surg 2000;8:180–3. [80] Weir M. Vocal cord dysfunction mimics asthma and may respond to heliox. Clin Pediatr 2002;41(1):37–41. [81] Weir M, Ehl L. Vocal cord dysfunction mimicking exercise-induced bronchospasm in adolescents. Pediatrics 1997;99:923–4. [82] Gose JE. Acute workup of vocal cord dysfunction. Ann Allergy Asthma Immunol 2003;91: 318. [83] Arndt GA, Voth BR. Paradoxical vocal cord motion in the recovery room: a masquerader of pulmonary dysfunction. Can J Anaesth 1996;43(12):1249–51. [84] Weiss TM. Vocal cord dysfunction: paradoxical vocal cord motion. A thorough review. Available at: http://www.utmb.edu/otoref/grnds/Vocal-Cord-2001-07/VCD-2htm. Accessed January 17, 2007. [85] Anbar RD, Hehir DA. Hypnosis as a diagnostic modality for vocal cord dysfunction. Pediatrics 2000;106(6):1–3. [86] Warnes E, Allen KD. Biofeedback treatment of paradoxical vocal fold motion and respiratory distress in an adolescent girl. J Appl Behav Anal 2005;38:529–32.

Prim Care Clin Office Pract 35 (2008) 105–117

Atopic Dermatitis Peck Y. Ong, MDa,*, Mark Boguniewicz, MDb a

Division of Clinical Immunology–Allergy, Childrens Hospital Los Angeles, University of Southern California Keck School of Medicine, 4650, Sunset Boulevard, MS# 75, Los Angeles, CA 90027, USA b Division of Pediatric Allergy-Immunology, National Jewish Medical and Research Center, The University of Colorado Health Sciences Center, 1400 Jackson Street, Denver, CO 80206, USA

Atopic dermatitis (AD) is a common chronic inﬂammatory skin disease in childhood, aﬀecting up to 17% of children in the United States [1]. This skin disease is characterized by intense puritus and cutaneous inﬂammation. The quality of life of aﬀected individuals can be signiﬁcantly affected, particularly in those with moderate to severe disease [2]. In addition, AD patients are predisposed to a variety of skin infections, including Staphylococcus aureus and herpes simplex virus. Up to 50% of children with AD go on to develop asthma [3]. AD also carries with it a signiﬁcant ﬁnancial burden to the family and society [4].

Pathogenesis The pathogenesis of AD is complex, involving genetic factors, skin barrier defects, and immune dysregulation (reviewed in reference [5]). The genetics of AD is an area of intense research. Genetic polymorphisms have been associated with chromosome 5q22-23, which contains a cluster of T helper type 2 (Th2) cytokine genes (IL-4 and IL-13). Those genes play a signiﬁcant role in IgE production and allergic sensitization. More recently, the association of AD with ﬁlaggrin gene mutations has pointed to the role of skin barrier defects in the pathogenesis of AD [6]. Filaggrin is a protein essential to the normal barrier function of the skin. Deﬁciency in this protein may contribute to the physical barrier defects in AD and predispose patients to increased transepidermal water loss, infections, and inﬂammation

* Corresponding author. E-mail address: [email protected] (P.Y. Ong). 0095-4543/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2007.09.006 primarycare.theclinics.com

106

ONG & BOGUNIEWICZ

associated with exposure of cutaneous immune cells to allergens [7]. A recent study showed that the level of ﬁlaggrin can be modulated by cytokines [8]. This may present speciﬁc therapeutic opportunities, although, at this time, maintaining a normal epidermal barrier is key.

Diagnosis There is currently no diagnostic laboratory test for AD. Although the majority of AD patients have elevated total serum IgE, up to 30% of these patients have normal total serum IgE and show no allergic sensitization to food or aeroallergens [9]. The diagnosis of AD is based on clinical criteria. Itch must be present for the diagnosis of AD. In addition, the patient should have three or more of the following criteria [10]: Visible rashes on the ﬂexural areas (elbows, back of knees, front of neck, or eyelids); in infants, the rash may be present on the cheeks or extensor areas of the knees or elbows History of rashes on the ﬂexural areas Personal or family history of respiratory allergies (asthma or allergic rhinitis) History of dry skin in the past year Onset before 2 years of age Ninety percent of AD patients have onset of the disease before 5 years. Therefore, new-onset AD in older children or adults should raise suspicion for other skin conditions. Box 1 shows the diﬀerential diagnosis of AD.

Management Basic skin care Daily skin care is key in the control of AD symptoms. The following list provides some of practical actions to take in the treatment of AD: Rather than soaps, use cleansers with minimal defatting activity and a neutral pH. Avoid alcohol and astringents in skin care products. Avoid wool clothing or other materials that may be irritating to the skin; cotton or cotton blends are generally preferred. Launder clothing to remove formaldehyde and other chemicals. Use liquid detergents, which are easier to rinse out than powder detergents. Add a second rinse cycle to facilitate further removal of detergents. Avoid extremes of environmental temperatures or humidity; prolonged exposure to sun may lead to overheating and evaporation, as well as perspiration, all of which can be irritating.

ATOPIC DERMATITIS

107

Box 1. Differential diagnosis of AD Dermatologic diseases Seborrheic dermatitis Irritant or allergic contact dermatitis Psoriasis Nummular pilaris Keratosis pilaris Lichen simplex chronicus Pityriasis rosea Nonbullous congenital ichthyosiform erythroderma Neoplastic diseases Cutaneous T cell lymphoma (mycosis fungocides, Sezary syndrome) Letterer-Siwe disease (Langerhans cell histiocytosis) Necrolytic migratory erythema associated with pancreatic tumor Immunodeficiencies Immune dysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) syndrome Hyper-IgE syndrome Wiskott-Aldrich syndrome Severe combined immunodeficiency syndrome Infectious diseases Human immunodeficiency virus–associated eczema Scabies Candidiasis Tinea vesicolor Congenital and metabolic disorders Netherton’s syndrome Phenylketonuria Zinc deficiency Essential fatty acid deficiency Histidine deficiency Infantile-onset multiple carboxylase deficiency

Use sunscreens with low irritancy potential, such as those made specifically for the face. After swimming, shower with a cleanser to remove chlorine or bromine. Avoid proven allergens (discussed further in the next sections). Most importantly, take time for daily skin care with hydration followed by moisturizers. The rationale and approach are discussed below.

108

ONG & BOGUNIEWICZ

Skin hydration and moisturizers Skin hydration is best accomplished through daily soaking baths for 10 to 20 minutes. It is important to remind patients and caregivers to apply a topical medication or moisturizer immediately after bathing. This is to seal in the water that has been absorbed into the skin and prevent evaporation that can lead to further drying of the skin. The combination of skin hydration and the use of a moisturizer may help to reestablish and preserve the skin barrier function. In addition, moisturizers can also decrease the need for topical corticosteroids [11]. Moisturizers are available as ointments, creams, lotions, and oils. Due to their occlusive nature, ointments are ideal for maintaining skin hydration after bathing or shower, but they may also trap perspiration, resulting in increased pruritus. Therefore, they may be more suitable for use in dry environments or in younger children or infants, who are generally more tolerable of the ‘‘greasy’’ feel. Lotions and creams, due to added preservatives or fragrances, may have more irritating eﬀects. In addition, lotions contain more water than creams and may therefore have a drying eﬀect through evaporation of their contents from the skin. Although oils (eg, mineral oil) can be applied easily, they often prove to be less eﬀective moisturizers based on their emollient properties and occasionally irritant potential. Ceramides are lipids important to the barrier function of the skin and are shown to be deﬁcient in AD skin. The use of a ceramide-dominant emollient has been found to decrease transepidermal water loss and the disease activity of AD in children [12]. Several ceramide-based creams are currently available and a new ceramide-containing cream, Epiceram, is expected to be available in 2007. In addition, nonsteroidal creams marketed as medical devices (thus requiring prescriptions) include Atopiclair and MimyX [13]. They have unique ingredients, diﬀerent proposed mechanisms of action, and do not have any restrictions for age or length of application. Control of pruritus Itch is usually the most distressing symptom of AD. Even patients whose AD is under good control may continue to be aﬀected by itch. First-generation antihistamines might be of beneﬁt primarily through their sedating eﬀects at bedtime. On the other hand, topical antihistamines and analgesics, due to their potential for contact allergy, should be avoided. There is increasing evidence that neuropeptides and opioid receptors are involved in the pathogenesis of itch in AD [14]. A recent placebocontrolled trial that included patients with AD showed that a cream containing naltrexone, an opioid receptor antagonist, was eﬀective in relieving pruritus [15]. In addition, the study showed that the clinical eﬃcacy of the medication correlated with changes in opiate receptor expression [15].

ATOPIC DERMATITIS

109

Management of sleep disturbance Sleep disturbance is a signiﬁcant problem in AD. Pharmacologic management for sleep disturbances in AD has recently been reviewed [16]. Doxepin is a tricyclic antidepressant with both H1 and H2 receptor antagonist activity and may be helpful to aid the sleep of AD patients [16]. In addition, doxepin possesses anxiolytic and antidepressant eﬀects, which may be helpful in select AD patients. However, the dose used to help with sedation is generally lower than the dose needed for antidepressant eﬀects, and patients may have diﬃculty tolerating daytime sedation with higher doses [16]. Other medications that may improve the sleep of AD patients include benzodiazepine and nonbenzodiazepine hypnotics, chloral hydrate, and clonidine [16]. However, there are limited data on the use of these medications in AD. Therefore, potential risks and beneﬁts of these medications need to be considered. Management of triggers and infections Food allergens About 30% to 40% of AD children with moderate to severe AD have immediate IgE-mediated food reactions [17]. Patients or families also describe delayed cutaneous reactions after ingesting certain foods. These reactions are more diﬃcult to reproduce or characterize as to mechanism of action. In children older than 1 year, negative allergy skin tests for foods have high negative predictive value (O95%), essentially ruling out IgE-mediated food allergy [18]. On the other hand, a positive skin test to a food allergen has a positive predictive value of only approximately 50% [18]. More recently, food-speciﬁc IgE levels measured by serum ImmunoCAP assay have been shown to have predictive values up to 95% for selected foods at speciﬁc levels [19]. These foods include cow’s milk, eggs, peanuts, and ﬁsh. However, it is crucial to recognize the limitations of this assay. It is especially important to note that the lower end of sensitivity for the assay is not zero, but less than 0.35kU/L. Rarely do patients still react at very low levels of food-speciﬁc IgE. In addition, speciﬁc IgE levels do not deﬁne severity of the clinical reaction. The clinical history of the patient remains important in conjunction with the use of in vivo or in vitro allergy tests. This is important because unnecessary limitation of diet based on testing can severely compromise the patient’s nutrition status. Ultimately, food challenges may be needed for diagnosing clinically relevant food allergies. These should be done with the involvement of an allergist familiar with the procedure. Foods that are conﬁrmed to cause allergic reactions should be eliminated from the patient’s diet as repeat ingestion may cause a spectrum of allergic reactions. The ImmunoCAP assay may also be useful in following the natural history of a patient’s food allergy with repeat measurements obtained approximately 12 months apart because most children become tolerant to cow’s milk and egg protein, as opposed to peanuts, tree nuts, ﬁsh, or shellﬁsh.

110

ONG & BOGUNIEWICZ

Aeroallergens Although there is limited data on the role of domestic animals or pollens as triggers for AD, case reports and atopy patch testing suggest a role for these allergens in sensitized AD patients [20,21]. The best-studied aeroallergen in AD is house dust mite (HDM) [22]. However, blinded placebo-controlled studies have shown conﬂicting results on the role of HDM-control measures in AD [23,24]. Nevertheless, HDM control measures should be considered in sensitized patients, as these patients often have concurrent respiratory allergies or are at risk for developing these allergies [25]. The control measures include the use of HDM-proof encasings, frequent vacuuming (eg, once a week) and washing linens in hot water. At this time, speciﬁc allergen immunotherapy (‘‘allergy shots’’) is not indicated for AD, although limited studies suggest beneﬁt in HDM-sensitized adult AD patients [26]. Microbial pathogens S aureus can be cultured from the skin lesions of most AD patients [27]. AD patients are predisposed to colonization and infections by S aureus through deﬁciency in endogenous antimicrobial peptides as well as through a defective skin barrier [28]. S aureus from patients with AD typically secrete toxins that can cause T cell activation by acting as superantigens, which can exacerbate and perpetuate cutaneous inﬂammation [29]. AD patients also make speciﬁc IgE directed against these toxins, thus further triggering activation of mast cells and other IgE receptor–bearing cells in AD lesions [30]. Although AD patients are at risk for infections by S aureus, use of antibiotics in the absence of clinical signs of infection is not recommended because of the risk of bacterial resistance. A ﬁrst-generation cephalosporin, such as cephalexin, for 7 to 10 days for overt infections is eﬀective unless the patient is infected by a resistant strain of S aureus. Baths and cleansers as part of routine care can reduce S aureus colonization. Most AD patients do not tolerate harsh antiseptic cleansers, such as chlorhexidine or bleach baths, although some dermatologists recommend dilute bleach baths for AD patients with recurrent methicillin-resistant S aureus superinfections. Antibacterial cleansers, such as Lever 2000, can be considered, although some patients may still ﬁnd these to be irritating to their skin. The nose is a major reservoir of S aureus and intranasal mupirocin (Bactroban) applied twice daily for 5 to 7 days may eradicate S aureus and improve AD. Herpes simplex virus can cause life-threatening eczema herpeticum in AD patients. Therefore, physicians who treat AD must be vigilant for this infection. The infected area may not present with vesicular lesions or the area may appear as punched-out lesions with an erythematous base (Fig. 1). Ideally, viral polymerase chain reaction (PCR), Tczank smear, and/or culture should be obtained by unrooﬁng an intact vesicle because the yield from excoriated lesions is low. The mainstay of treatment is systemic acyclovir.

ATOPIC DERMATITIS

111

Fig. 1. Eczema herpeticum. (Courtesy of Ronald Ferdman, MD, Los Angeles, CA.)

Patients with disseminated lesions who appear toxic should be admitted to the hospital for intravenous acyclovir and antistaphylococcal antibiotic pending PCR and culture results. Patients with periocular or suspected ocular involvement should be evaluated by an ophthalmologist emergently. AD patients are also more susceptible to molluscum contagiosum (MC) virus infection. The lesions typically present as single or multiple ﬂesh-colored papules, which may be distributed on the trunk, extremities, or face. The treatment of MC depends on the location and number of the lesions, and the ability of the patient to tolerate painful procedures. If lesions are not periocular, they can be observed, as spontaneous resolution does occur. However, they are contagious and can spread through autoinoculation. In addition, they can occasionally scar with resolution. Treatment options include curettage under topical anesthetic cream, cryotherapy, cantharidin (a blistering agent), or topical imiquimod and tretinoin, although none of the treatments are currently approved by Food and Drug Administration for MC. Sensitization to the yeast Malassezia species has also been demonstrated in a subgroup of AD patients. Speciﬁc IgE levels to Malassezia furfur (previously known as Pityrosporum orbiculare) have been correlated with severity of AD [31]. Antifungal therapy has been shown to be eﬀective in a subgroup of AD patients in several studies, with most studies showing a correlation between response to antifungals and the levels of speciﬁc IgE [32]. However, the mechanism of antifungal therapy in AD remains to be clariﬁed. It is likely that antifungal therapy may exert anti-inﬂammatory eﬀects in addition to the fungicidal activity [32]. Further studies are needed to conﬁrm the use of antifungal agents in AD patients who are colonized by these organisms.

112

ONG & BOGUNIEWICZ

Anti-inﬂammatory treatment Topical corticosteroids Topical corticosteroids are the ﬁrst-line treatment for AD. They are available in potencies ranging from extremely high (class I) to low (class VII) (Box 2). In general, a corticosteroid formulated in an ointment base is more potent than one in a cream or lotion base. Ointment-based preparations are also more occlusive and have the fewest number of additives. They provide better delivery of the medication and decrease evaporative loss. Creambased preparations, however, may be better tolerated during conditions of excessive heat or humidity. Although lotions are easier to apply, they may contribute to irritation and xerosis. Solutions are useful for the scalp, although their high alcohol content can be irritating and drying. A lotion-based corticosteroid may be better tolerated. The choice of topical corticosteroid potency depends on the severity and distribution of AD. Although using the least potent corticosteroid is typically a good rule to follow, this approach should be balanced by the possibility that treatment with a preparation that is too weak may result in persistence or worsening of AD, which can in turn result in decreased adherence or the need for high-potency topical or systemic corticosteroids. A stepped approach starting with a mid-potency preparation (except for eczema involving the face, axillae, or groin) and, with clinical improvement, use of a lower-potency preparation may be a more eﬀective strategy. High-potency corticosteroids may be needed for severe hand and foot eczema. In general, use of topical corticosteroids under occlusion should be avoided. Prescribing topical corticosteroids in inadequate amounts can also contribute to suboptimal control of AD or nonadherence. The rule of thumb is that 30 g of medication are needed to cover the entire body of an average adult [33]. Therefore, patients with widespread disease need to be prescribed suﬃcient quantities of medication. In addition, obtaining medications in larger quantities may result in signiﬁcant savings for the patient. A major reason for treatment failure with topical corticosteroids is noncompliance as a result of parental or patient fear of side eﬀects [34], including skin atrophy, telangiectasias, and possibly systemic absorption resulting in hypothalamic-pituitary-adrenal (HPA) axis suppression. A study with ﬂuticasone propionate 0.05% cream (group V) in children as young as 3 months with AD showed that this medication was safe and eﬀective even when applied twice daily to the face and over signiﬁcant areas of the body for up to 1 month [35]. Studies using desonide 0.05% ointment (group V) or aqueous gel (group VI) found no evidence of HPA axis suppression in children with AD for up to 4 weeks of twice daily applications [36,37]. Topical calcineurin inhibitors Topical calcineurin inhibitors approved for AD include tacrolimus ointment (Protopic) 0.03% and pimecrolimus cream (Elidel) 1% (both for children 2 years and above), and tacrolimus ointment 0.1% (for adults). These

ATOPIC DERMATITIS

113

Box 2. Topical corticosteroid potency ranking Group I (most potent) Betamethasone dipropionate 0.05% (Diprolene; cream, ointment) Clobetasol propionate 0.05% (Temovate; cream, ointment) Diflorasone diacetate 0.05% (Psorcon; ointment) Halobetasol dipropionate 0.05% (Ultravate; cream, ointment) Group II Amcinonide 0.1% (Cyclocort; ointment) Betamethasone dipropionate 0.05% (Diprosone; cream, ointment) Desoximetasone (Topicort; 0.05% gel; 0.25% cream, ointment) Fluocinonide 0.05% (Lidex; solution, gel, cream, ointment) Halcinonide 0.1% (Halog; solution, cream, ointment) Mometasone furoate 0.1% (Elocon; ointment) Group III Amcinonide 0.1% (Cyclocort; lotion, cream) Betamethasone valerate 0.1% (Valisone; ointment) Diflorasone diacetate 0.05% (Florone; cream) Fluticasone propionate 0.005% (Cutivate; ointment) Group IV Triamcinolone acetonide 0.1% (Kenalog; cream, ointment) Fluocinolone acetonide 0.025% (Synalar; ointment) Mometasone furoate 0.1% (Elocon; lotion, cream) Group V Hydrocortisone valerate 0.2% (Westcort; cream, ointment) Betamethasone valerate 0.1% (Valisone; lotion, cream) Fluticasone propionate 0.05% (Cutivate; cream) Fluocinolone acetonide 0.025% (Synalar; cream) Desonide 0.05% (Tridesilon; ointment) Group VI Alclometasone dipropionate 0.05% (Aclovate; cream, ointment) Flucinolone acetonide 0.01% (Synalar; solution, cream) Desonide 0.05% (Tridesilon; cream, aqueous gel) Group VII (least potent) Hydrocortisone 1%/2.5% (Hytone; lotion, cream, ointment)

medications use diﬀerent anti-inﬂammatory mechanisms as compared with topical corticosteroids. Because they do not cause skin atrophy, these medications are especially useful for treatment of AD involving the face, including periocular and perioral areas [38]. However, based on animal studies and

114

ONG & BOGUNIEWICZ

case reports, the Food and Drug Administration has issued a ‘‘black box’’ warning for continuous use of both tacrolimus ointment and pimecrolimus cream because of concerns for possible development of malignancies. Since the issue of the warning, case-control studies involving up to 300,000 patients have not shown any association between the use of these medications and the risk of malignancy [39,40]. Systemic exposure in study animals treated with high oral doses or nonstandard formulations of pimecrolimus that result in immunosuppression and development of lymphoma have been 31 to 343 times higher than the highest individual systemic exposure ever observed among pediatric patients with extensive AD lesions treated with pimecrolimus cream [41]. The Topical Calcineurin Inhibitor Task Force of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology reviewed all available data and concluded that the risk/beneﬁt ratio of topical pimecrolimus and tacrolimus were similar to those of most conventional therapies for the treatment of chronic relapsing AD [42]. Therefore, as-needed use of these medications should continue to be considered in patients with persistent AD, especially on skin areas prone to develop atrophy from topical corticosteroids. Alternative and experimental treatments Treatments for patients with recalcitrant AD can be challenging [43]. Wet-wrap treatment with topical corticosteroids has been shown to be eﬃcacious although potential side eﬀects include secondary infection and HPA suppression. Therefore such treatments should be performed under the supervision of physicians who are familiar with them. A short course of an oral corticosteroid can also be considered for severe ﬂare of AD, but the corticosteroid dose should be tapered over 1 week to decrease the chance of a rebound eﬀect oﬀ the systemic corticosteroid [44]. Cyclosporin A and ultraviolet phototherapy have been shown to be eﬃcacious for severe AD, but their systemic side eﬀects (eg, renal toxicity with Cyclosporin A) and the risk of malignancy are of concern [43]. Other experimental treatments include mycophenolate mofetil, azathioprine, methotrexate, and intravenous immunoglobulin [43]. These treatments are also associated with significant systemic side eﬀects and therefore should only be considered for the most severe AD patients. Often, hospitalization of patients with a comprehensive approach, including addressing psychosocial aspects of this chronic relapsing disease, can lead to dramatic clinical improvement [45]. The use of probiotics to treat or prevent AD has been an area of controversy. To date, no convincing evidence shows that probiotics are eﬀective in AD [46]. Studies on the use of probiotics to prevent the development of AD have yielded conﬂicting results [47,48]. Evening primrose oil has also been shown to be ineﬀective in the treatment of AD [49]. There is also no convincing data to support the use of Chinese medicinal herbs in AD [50]. In addition, the potential side eﬀects of these medications are of concern [50].

ATOPIC DERMATITIS

115

Omalizumab or anti-IgE (Xolair) is approved for use in patients 12 years or older with allergic asthma that is inadequately controlled on high-dose inhaled or systemic corticosteroids. There have only been few case reports on the use of this medication in AD [51,52] and the results in these studies conﬂicted. Therefore, well-designed controlled trials are needed [53]. Finally, controlled studies with montelukast have not shown beneﬁt in AD [54].

Summary In conclusion, AD is a multifactorial, chronic inﬂammatory skin disease susceptible to numerous environmental triggers. Management of this condition should emphasize measures to preserve skin barrier function, elimination of triggers, and timely, consistent use of topical anti-inﬂammatory medications. Patients who repeatedly fail these interventions should be referred to a specialist for further evaluation and alternative treatment.

References [1] Laughter D, Istvan JA, Tofte SJ, et al. The prevalence of atopic dermatitis in Oregon schoolchildren. J Am Acad Dermatol 2000;43(4):649–55. [2] Paller AS, McAlister RO, Doyle JJ, et al. Perceptions of physicians and pediatric patients about atopic dermatitis, its impact, and its treatment. Clin Pediatr (Phila) 2002;41(5):323–32. [3] Lau S, Nickel R, Niggemann B, et al. The development of childhood asthma: lessons from the German Multicentre Allergy Study (MAS). Paedriatr Respir Rev 2002;3(3):265–72. [4] Su JC, Kemp AS, Varigos GA, et al. Atopic eczema: its impact on the family and ﬁnancial cost. Arch Dis Child 1997;76(2):159–62. [5] Leung DY, Boguniewicz M, Howell MD, et al. New insights into atopic dermatitis. J Clin Invest 2004;113(5):651–7. [6] Hoﬀjan S, Stemmler S. On the role of the epidermal diﬀerentiation complex in ichthyosis vulgaris, atopic dermatitis and psoriasis. Br J Dermatol 2007;157:441–9. [7] Hudson TJ. Skin barrier function and allergic risk. Nat Genet 2006;38:399–400. [8] Howell MD, Kim BE, Gao P, et al. Cytokine modulation of AD ﬁlaggrin skin expression. J Allergy Clin Immunol 2007;120:150–5. [9] Schmid-Grendelmeier P, Simon D, Simon HU, et al. Epidemiology, clinical features, and immunology of the ‘‘intrinsic’’ (non-IgE-mediated) type of atopic dermatitis (constitutional dermatitis). Allergy 2001;56:841–9. [10] Williams HC, Burney PG, Pembroke AC, et al. The U.K. Working Party’s Diagnostic Criteria for Atopic Dermatitis. III. Independent hospital validation. Br J Dermatol 1994;131: 406–16. [11] Lucky AW, Leach AD, Laskarzewski P, et al. Use of an emollient as a steroid-sparing agent in the treatment of mild to moderate atopic dermatitis in children. Pediatr Dermatol 1997; 14(4):321–4. [12] Chamlin SL, Kao J, Frieden IJ, et al. Ceramide-dominant barrier repair lipids alleviate childhood atopic dermatitis: changes in barrier function provide a sensitive indicator of disease activity. J Am Acad Dermatol 2002;47(2):198–208. [13] Abramovits W, Boguniewicz M. Adult Atopiclair Study Group. A multicenter, randomized, vehicle-controlled clinical study to examine the eﬃcacy and safety of MAS063DP (Atopiclair) in the management of mild to moderate atopic dermatitis in adults. J Drugs Dermatol 2006;5(3):236–44.

116

ONG & BOGUNIEWICZ

[14] Bigliardi-Qi M, Lipp B, Sumanovski LT, et al. Changes of epidermal mu-opiate receptor expression and nerve endings in chronic atopic dermatitis. Dermatology 2005;210(2): 91–9. [15] Bigliardi PL, Stammer H, Jost G, et al. Treatment of pruritus with topically applied opiate receptor antagonist. J Am Acad Dermatol 2007;56(6):979–88. [16] Kelsay K. Management of sleep disturbance associated with atopic dermatitis. J Allergy Clin Immunol 2006;118(1):198–201. [17] Eigenmann PA, Sicherer SH, Borkowski TA, et al. Prevalence of IgE-mediated food allergy among children with atopic dermatitis. Pediatrics 1998;101(3):E8. [18] Bock SA. Diagnostic evaluation. Pediatrics 2003;111(6 Pt 3):1638–44. [19] Sampson HA. Update on food allergy. J Allergy Clin Immunol 2004;113(5):805–19. [20] Endo K, Hizawa T, Fukuzumi T, et al. Keeping dogs indoors aggravates infantile atopic dermatitis. Arerugi 1999;48(12):1309–15. [21] Darsow U, Vieluf D, Ring J. Evaluating the relevance of aeroallergen sensitization in atopic eczema with the atopy patch test: a randomized, double-blind multicenter study. Atopy Patch Test Study Group. J Am Acad Dermatol 1999;40(2 Pt 1):187–93. [22] Beltrani VS. The role of house dust mites and other aeroallergens in atopic dermatitis. Clin Dermatol 2003;21(3):177–82. [23] Tan BB, Weald D, Strickland I, et al. Double-blind controlled trial of eﬀect of housedustmite allergen avoidance on atopic dermatitis. Lancet 1996;347:15–8. [24] Oosting AJ, de Bruin-Weller MS, Terreehorst I, et al. Eﬀect of mattress encasings on atopic dermatitis outcome measures in a double-blind, placebo-controlled study: the Dutch mite avoidance study. J Allergy Clin Immunol 2002;110(3):500–6. [25] Arshad SH, Bateman B, Sadeghnejad A, et al. Prevention of allergic disease during childhood by allergen avoidance: the Isle of Wight prevention study. J Allergy Clin Immunol 2007;119(2):307–13. [26] Werfel T, Breuer K, Rueﬀ F, et al. Usefulness of speciﬁc immunotherapy in patients with atopic dermatitis and allergic sensitization to house dust mites: a multi-centre, randomized, dose–response study. Allergy 2006;61:202–5. [27] Boguniewicz M, Sampson H, Leung SB, et al. Eﬀects of cefuroxime axetil on Staphylococcus aureus colonization and superantigen production in atopic dermatitis. J Allergy Clin Immunol 2001;108(4):651–2. [28] Ong PY, Ohtake T, Brandt C, et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 2002;347(15):1151–60. [29] Bunikowski R, Mielke ME, Skarabis H, et al. Evidence for a disease-promoting eﬀect of Staphylococcus aureus-derived exotoxins in atopic dermatitis. J Allergy Clin Immunol 2000;105(4):814–9. [30] Leung DYM, Harbeck R, Bina P, et al. Presence of IgE antibodies to staphylococcal exotoxins on the skin of patients with atopic dermatitis. Evidence for a new group of allergens. J Clin Invest 1993;92(3):1374–80. [31] Schmid-Grendelmeier P, Fluckiger S, Disch R, et al. IgE-mediated and T cell-mediated autoimmunity against manganese superoxide dismutase in atopic dermatitis. J Allergy Clin Immunol 2005;115:1068–75. [32] Boguniewicz M, Schmid-Grendelmeier P, Leung DYM. Atopic dermatitis. J Allergy Clin Immunol 2006;118(1):40–3. [33] Weston WL, Lane AT, Morelli JG. Color textbook of pediatric dermatology. 2nd edition. St. Louis (MO): Mosby; 1996. p. 358. [34] Zuberbier T, Orlow SJ, Paller AS, et al. Patient perspectives on the management of atopic dermatitis. J Allergy Clin Immunol 2006;118:226–32. [35] Friedlander SF, Hebert AA, Allen DB, Fluticasone Pediatrics Safety Study Group. Safety of ﬂuticasone propionate cream 0.05% for the treatment of severe and extensive atopic dermatitis in children as young as 3 months. J Am Acad Dermatol 2002;46(3):387–93.

ATOPIC DERMATITIS

117

[36] Lucky AW, Grote GD, Williams JL, et al. Eﬀect of desonide ointment, 0.05%, on the hypothalamic-pituitary-adrenal axis of children with atopic dermatitis. Cutis 1997;59(3):151–3. [37] Eichenﬁeld LF, Basu S, Calvarese B, et al. Eﬀect of desonide hydrogel 0.05% on the hypothalamic-pituitary-adrenal axis in pediatric subjects with moderate to severe atopic dermatitis. Pediatr Dermatol 2007;24(3):289–95. [38] Boguniewicz M, Fiedler VC, Raimer S, et al. A randomized, vehicle-controlled trial of tacrolimus ointment for treatment of atopic dermatitis in children. Pediatric Tacrolimus Study Group. J Allergy Clin Immunol 1998;102(4 Pt 1):637–44. [39] Margolis DJ, Hoﬀstad O, Bilker W. Lack of association between exposure to topical calcineurin inhibitors and skin cancer in adults. Dermatology 2007;214(4):289–95. [40] Arellano FM, Wentworth CE, Arana A, et al. Risk of lymphoma following exposure to calcineurin inhibitors and topical steroids in patients with atopic dermatitis. J Invest Dermatol 2007;127(4):808–16. [41] Paul C, Cork M, Ross AB, et al. Safety and tolerability of 1% pimecrolimus cream among infants: experience with 1133 patients treated for up to 2 years. Pediatrics 2006;117(1): e118–28. [42] Fonacier L, Spergel J, Charlesworth EN, et al. Report of the Topical Calcineurin Task Force of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol 2005;115:1249–53. [43] Akdis CA, Akdis M, Bieber T, et al, for the European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Group. Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report. J Allergy Clin Immunol 2006; 118:152–69. [44] Forte WC, Sumita JM, Rodrigues AG, et al. Rebound phenomenon to systemic corticosteroid in atopic dermatitis. Allergol Immunopathol (Madr) 2005;33:307–11. [45] Boguniewicz M. Atopic dermatitis. Immunol Allergy Clinics N Am 2002;22:1–178. [46] Williams HC. Two ‘‘positive’’ studies of probiotics for atopic dermatitis: or are they? Arch Dermatol 2006;142(9):1201–3. [47] Kalliomaki M, Salminen S, Arvilommi H, et al. Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. 2001;357:1076–9. [48] Taylor AL, Dunstan JA, Prescott SL. Probiotic supplementation for the ﬁrst 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: a randomized controlled trial. J Allergy Clin Immunol 2007;119(1): 184–91. [49] Williams HC. Evening primrose oil for atopic dermatitis. BMJ 2003;327:1358–9. [50] Zhang W, Leonard T, Bath-Hextall F, et al. Chinese herbal medicine for atopic eczema. Cochrane Database Syst Rev 2005;(2):CD002291. [51] Krathen RA, Hsu S. Failure of omalizumab for treatment of severe adult atopic dermatitis. J Am Acad Dermatol 2005;53(2):38–40. [52] Vigo PG, Girgis KR, Pfuetze BL, et al. Eﬃcacy of anti-IgE therapy in patients with atopic dermatitis. J Am Acad Dermatol 2006;55(1):168–70. [53] Beck LA, Saini S. Wanted: a study with omalizumab to determine the role of IgE-mediated pathways in atopic dermatitis. J Am Acad Dermatol 2006;55(3):540–1. [54] Veien NK, Busch-Sørensen M, Stausbøl-Grøn B. Montelukast treatment of moderate to severe atopic dermatitis in adults: a randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol 2005;53:147–9.

Prim Care Clin Office Pract 35 (2008) 119–140

Food Allergy: Diagnosis and Management Dan Atkins, MDa,b,* a

Department of Pediatrics, National Jewish Medical and Research Center, The University of Colorado, 1400 Jackson Street, Denver, CO 80206, USA b Department of Pediatrics, The Children’s Hospital, 13123 East 16th Avenue, Aurora, CO 80045, USA

A rise in food allergy, exempliﬁed by the doubling of self-reported peanut allergy among children in the United States from 1997 to 2002, accompanied by heightened public awareness, guarantees that clinicians will increasingly be consulted to accurately distinguish adverse reactions to foods from other disorders [1]. The potential impact of inaccurately labeling a food as a cause of symptoms includes delaying appropriate treatment for another disorder or needlessly removing a food from the diet, with potential adverse nutritional and social consequences. When symptoms are triggered by food ingestion, determining the type of adverse reaction to food responsible is important because of the implications regarding the mechanism involved, reproducibility, and the prognosis.

Deﬁnitions In a logical scheme developed as a framework for the categorization of food-induced reactions by mechanism, an adverse reaction to a food is the general term used to refer to any unpleasant reaction occurring as a result of food ingestion [2]. An adverse reaction to a food is further categorized into either a toxic or a nontoxic reaction [3]. In toxic reactions, the symptoms are caused by a toxin synthesized by the food or by an organism or substance contaminating the food. For example, individuals ingesting predatory reef ﬁsh, such as snapper, grouper, barracuda, or sea bass, contaminated with ciguatoxin, produced by the marine dinoﬂagellate Gambierdiscus toxicus, develop nausea, * Department of Pediatrics, National Jewish Medical and Research Center, The University of Colorado 1400 Jackson Street, Denver, CO 80206. E-mail address: [email protected] 0095-4543/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2007.09.003 primarycare.theclinics.com

120

ATKINS

vomiting, and diarrhea within minutes to hours later, followed by sensory disturbances, muscle aches, and fatigue that can last for months [4]. Although there is individual variability regarding sensitivity to diﬀerent toxins, one characteristic of toxic reactions is that they occur in virtually every person ingesting enough of the food containing the toxin [2]. Nontoxic reactions are further categorized into food intolerance or food allergy, depending upon whether the immune system is the primary cause of the reaction [3]. Reactions in which the immune system is not involved are categorized as examples of food intolerance. Categories of food intolerance include metabolic, pharmacologic, or idiosyncratic reactions. Individuals who are malnourished, ill, taking certain medications, or have acquired or inborn errors of metabolism are more likely to experience metabolic reactions to foods. One of the most commonly encountered examples of a metabolic reaction to a food is lactose intolerance, where a lactase-deﬁcient host, because of the inability to metabolize lactose, develops nausea, abdominal cramping, and diarrhea following the ingestion of lactose-rich dairy products [5]. Pharmacologic food reactions occur following the ingestion of foods containing pharmacologically active ingredients. For example, the ingestion of foods or beverages containing methylxanthines, such as caﬀeine or theobromine, may cause central nervous system stimulation, headache, and abdominal pain when ingested in large amounts or by sensitive individuals [6]. Idiosyncratic reactions resemble allergic reactions to foods but are not mediated by the immune system and result from a quantitatively abnormal response to a food or food additive that is not caused by a pharmacologic or physiologic eﬀect of the food. ‘‘Food allergy’’ is the term used to refer to those nontoxic reactions to foods primarily mediated by the immune system [3]. Allergic reactions to foods are further divided into IgE-mediated reactions, nonIgEmediated reactions, or combined reactions where both IgE- and nonIgEmediated mechanisms are implicated [7]. Disorders caused by IgE-mediated reactions to foods typically involve the gastrointestinal tract, the skin, and the respiratory tract. For example, IgE-mediated gastrointestinal disorders include pollen-food allergy syndrome and gastrointestinal anaphylaxis. Pollen-food allergy syndrome is encountered in patients sensitized to pollens containing allergens that cross react with those found in fresh fruits and vegetables [8,9]. Although the list of described pollen-food syndromes continues to grow, the more common clinically encountered examples include ragweed pollen sensitive patients, who experience symptoms with the ingestion of melons or banana; birch pollen sensitive patients, who experience symptoms when eating apple, hazelnut, celery, carrots, or raw potato; and mugwort pollen sensitive patients, who react upon ingesting fresh apples, celery, peanuts, or kiwi [10]. The syndrome was initially called ‘‘the oral allergy syndrome,’’ in reference to the typical pattern of rapid onset pruritus and mild edema localized to oropharyngeal tissues. Because some patients experience signiﬁcant laryngeal edema or symptoms extending beyond the oropharynx, including

FOOD ALLERGY

121

anaphylaxis, this name has been considered misleading and the pollen-food allergy syndrome has been proposed as a suitable alternative [11]. Gastrointestinal anaphylaxis presents with cramping abdominal pain, nausea, and vomiting occurring within minutes to hours after ingestion of the oﬀending food, and is often accompanied by cutaneous or respiratory symptoms. IgE-mediated cutaneous symptoms include acute urticaria, angioedema, generalized pruritus, and ﬂushing, whereas respiratory disorders mediated by IgE-mediated reactions to foods include acute rhinoconjunctivitis and acute onset bronchospasm. The most severe form of an IgE-mediated allergic reaction to a food is anaphylactic shock, in which multiple organ systems are involved, along with the presence of hypotension [6]. Examples of nonIgE-mediated allergic reactions to foods, considered to be cell mediated, that involve the gastrointestinal tract, include food protein-induced syndromes such as food protein-induced enterocolitis, food protein-induced proctocolitis, and food protein-induced enteropathy syndromes [12,13]. These disorders are seen primarily in infants or young children presenting with abdominal complaints, such as vomiting, cramping abdominal pain, diarrhea, and occasionally blood in the stool. Celiac disease, resulting from sensitivity to gliadin found in grains such as wheat, rye, and barley, is another example of a nonIgE-mediated gastrointestinal reaction to a food considered to be cell mediated [14,15]. Dermatitis herpetiformis and contact dermatitis are examples of cutaneous nonIgE-mediated reactions to food. Mixed IgE and cell mediated allergic reactions to foods are exempliﬁed by eosinophilic gut disorders, such as eosinophilic esophagitis and allergic eosinophilic gastroenteritis, or potentially other entities, such as atopic dermatitis or asthma [16]. As might be expected, most patients are unacquainted with the terms used in medical discussions of adverse reactions to foods and are unaware of the different types of these reactions. This is one of the reasons the public perceived prevalence of food allergy is signiﬁcantly higher than the true prevalence, as illustrated by a telephone poll revealing that as many as 25% of American households alter their diet because of a suspected food allergy in at least one family member [17]. Deﬁning terms and reviewing the diﬀerent types of adverse reactions to foods with patients early in the evaluation reduces the potential for misunderstanding and lays the framework for discussions about whether the diagnosis is food allergy, another type of adverse reaction to a food, or some other entity not related to food ingestion. Risk factors and prevalence Genetic and environmental factors have been proposed as capable of increasing the risk for the development of food allergy. The concordance rate of peanut allergy in 64% of monozygotic twins, versus 6.8% of dizygotic twins, in one study suggests a role for genetic inﬂuences in the development of food allergy [18]. Environmental factors, other than dietary factors that

122

ATKINS

have been suggested as potential but not proven risk factors, include Csection delivery [19,20], early multivitamin supplementation [21], antacid use, [22] and exposure to tobacco smoke early in life [23]. The foods most commonly implicated in allergic reactions include milk, egg, wheat, soy, peanut, tree nuts, ﬁsh, and shellﬁsh [16]. The documented prevalence of food allergy is highest in infants and young children, where it approaches 6% to 8% in children less than 3 years of age and decreases in older children, adolescents, and adults, so that overall approximately 4% of Americans are estimated to be food allergic [24,25]. This age-associated decrease in prevalence is attributed to the development of tolerance with age in most children allergic to cow’s milk, egg, wheat, and soy. Thus, the estimated prevalence of food allergy to milk and egg is higher in young children than adults, whereas the estimated prevalence of allergy to tree nuts, ﬁsh, and shellﬁsh is higher in adults than in young children [25]. For example, epidemiologic studies suggest that of the approximately 2.5% of infants allergic to cow’s milk, 80% will develop tolerance by 5 years of age [16]. Whereas it was previously considered that peanut allergy was rarely outgrown [26], more recent studies reveal that as many as 20% of peanut allergic infants and young children lose their clinical sensitivity over time [27,28]. Most children and adults with food allergy have a personal history of other allergic disease. Studies of children with moderate to severe atopic dermatitis reveal that approximately 35% are food allergic [29]. It has been estimated that from 2% to 8% of asthmatic children and adults experience respiratory symptoms triggered by allergic reactions to foods [30,31]. Although adult asthmatics often report that food additive ingestion triggers respiratory symptoms, a prevalence of less than 5% has been documented in well-controlled studies [30]. The severity of allergic reactions to foods varies from mild to life threatening. Of the cases of anaphylaxis treated in hospital emergency rooms, allergic reactions to foods are the most common cause encountered, accounting for from one third to one half of the cases seen [25]. It is estimated that approximately 200 deaths each year are attributable to food-induced anaphylaxis, with peanuts and tree nuts the most common cause of these fatal reactions [25,32]. An analysis of 32 cases of fatal allergic reactions to foods in the United States revealed that most of the victims were adolescents or young adults who knew they were allergic to the food that caused the reaction. Delays in the administration of epinephrine and concomitant asthma were other identiﬁed risk factors for fatal food-induced anaphylaxis in this group [32].

Diagnosis of food allergy History Accurately diagnosing patients complaining of adverse reactions to foods requires a certain amount of detective work that begins by obtaining

FOOD ALLERGY

123

a complete history. The initial step involves identifying the food or foods suspected of causing symptoms. Obtaining a list of all foods ingested within a few hours before the onset of the reaction is suggested when patients present with an acute reaction after a meal but are uncertain of the causative food. Foods eaten since the reaction in similar amounts without symptoms are removed from the list, whereas those foods not subsequently ingested remain suspect. Complaints of chronic symptoms not temporally associated with food ingestion, or symptoms reported to be signiﬁcantly delayed in onset after ingestion of the suspected food, often pose a diagnostic challenge. Determining the source, ingredients, and manner of preparation of the suspected food occasionally provides an explanation for a lack of reproducible symptoms with each exposure, or implicates a previously unsuspected food, food ingredient, or contaminant as the cause of reactions. All ingredients in suspected foods should be identiﬁed, and ingredient labels for processed foods should be examined for the presence of substances capable of causing reactions. Cooking denatures heat labile food allergens while others are heat stable. For example, patients who experience isolated oropharyngeal symptoms after ingesting raw fruits or vegetables, often report tolerating these foods when cooked [16,33]. Patients allergic to raw egg who tolerate cooked egg have been reported [34], as have patients who react to rare beef, but tolerate thoroughly cooked beef [35]. Occasionally, contamination of the suspected food with other food allergens, either intentionally as exempliﬁed by the addition of spices [36–38], or accidentally during meal preparation, is the cause of the reaction. The ability of nonfood allergens contaminating foodstuﬀs to cause reactions is exempliﬁed by reports of reactions in dust mite allergic individuals after the ingestion of dust mite contaminated pancakes, waﬄes or beignets [39], or latex as a contaminant in foods [40]. Obtaining a list of foods eliminated from the patient’s diet and documenting whether the elimination of these foods led to a reduction in symptoms provides useful information. The patient’s current diet should be thoroughly reviewed, not only for nutritional adequacy, but to determine whether the suspected food is being inadvertently ingested in signiﬁcant amounts (as a hidden ingredient in other foods), or whether a food with signiﬁcant immunologic cross reactivity to the suspected food remains in the diet. In some instances, patients thought to be on elimination diets continue to have symptoms because of the unrecognized continued ingestion of the culprit food as an ingredient in other foods. Alternatively, the ability to tolerate hidden sources of suspected foods in the diet raises suspicion as to whether these foods are truly causing symptoms. For example, a patient suspected of being milk allergic who tolerates goat’s milk should raise suspicion, given the documented extensive cross reactivity between homologous proteins in goat’s and cow’s milk [41]. Similarly, the patient considered to be wheat allergic, who tolerates spelt, may not be wheat allergic, given that spelt is an ancient variety of wheat [42].

124

ATKINS

After the foods suspected of causing symptoms are identiﬁed, a precise description of each previous reaction should be obtained, including the suspected route of exposure, the estimated dose, the symptoms experienced, the timing of symptom onset in relation to food exposure, and the severity of symptoms. In addition, the duration of the reaction, the treatment, the response to treatment, the reproducibility of reactions, and the date of the most recent reaction should be ascertained. While the majority of reactions to foods are caused by ingestion or topical contact, symptoms resulting from the inhalation or injection of food allergens have been documented [43]. Fortunately, unless a large surface area is exposed or the patient is exquisitely sensitive, contact reactions are generally localized to areas of contact and self-limited, rarely progressing to systemic reactions. For reactions triggered by ingestion, determining the amount of food ingested before each reaction provides one means of gaining insight about the patient’s level of sensitivity. In regards to reactions triggered by the ingestion of miniscule amounts of the oﬀending food, these place the patient at higher risk for more frequent reactions, and suggest the potential for more severe reactions if a larger dose of the food is ingested. Increasingly severe reactions following the ingestion of a similar amount, or symptoms caused by the ingestion of signiﬁcantly smaller portions, suggests an increasing level of sensitization. Alternatively, tolerating exposure to amounts of the food that previously caused reactions could be an indication that sensitivity to the food is waning. A dose response relationship in regard to the amount of food ingested and the severity of symptoms encountered is commonly observed in patients with allergic reactions to foods. For example, some children tolerate milligram amounts of egg as an ingredient in baked goods, but have signiﬁcant reactions when foods containing larger amounts of egg are ingested. Threshold doses and target organ involvement for speciﬁc foods vary considerably from patient to patient and among different foods in the patient with multiple food allergies. Studies attempting to determine the lowest threshold doses for allergic reactions to common foods allergens have documented patients with reactions after the ingestion of milligram amounts of these foods during blinded, placebo-controlled food challenges [44,45]. Allergic reactions to foods aﬀect diﬀerent target organs, either individually or in combination. The most often-involved target organs are the gastrointestinal tract, the skin, and the upper and lower respiratory tract. Although urticaria is frequently encountered in allergic reactions to foods, the lack of urticaria does not rule out an allergic reaction, as fatal allergic reactions to foods have been observed in the absence of urticaria. Fatalities from allergic reactions to foods are usually caused by extensive laryngeal edema, severe bronchospasm, or refractory hypotension. Most allergic reactions to foods begin within minutes to hours of ingestion of the oﬀending food, and last from approximately one to several hours, although cases of biphasic and protracted anaphylaxis to foods have been observed [46]. Often

FOOD ALLERGY

125

patients describe reactions that are similar in onset and progression when a comparable dose of allergen is ingested. Inconsistencies in the timing and severity of allergic reactions to the same food may result from a diﬀerence in the amount consumed, the manner of food preparation, the presence of other foods, or factors such as vomiting, which impact digestion or absorption, changes in the patient’s level of sensitivity, and the ingestion of medications such as antihistamines, that can mask symptoms. The time elapsed since the last reaction is of interest, as some patients develop tolerance after prolonged successful elimination of the food from their diet, whereas recent reactions document continued sensitivity. In rare instances, the ingestion of a food must be accompanied by another stimulus in order for a reaction to occur. For example, food-dependent exercise-induced anaphylaxis is an interesting form of anaphylaxis that occurs when the ingestion of a speciﬁc food is followed within several hours by exercise [47–49]. Ingestion of the speciﬁc food in the absence of exercise does not cause symptoms, even though the patient usually has a positive skin test to the food. Alternatively, exercise not preceded by ingestion of the speciﬁc oﬀending food is well tolerated, except in rare cases where the ingestion of any meal before exercise triggers symptoms. A wide variety of foods have been implicated in causing these reactions, such as ﬁsh, shellﬁsh, wheat, celery, mushrooms, and fruit [50,51]. The typical age of patients with food-dependent exercise-induced anaphylaxis extends from adolescence through the late thirties, with women outnumbering men. The mechanism responsible for these reactions remains to be deﬁned. This entity should be considered when reactions occur only following exercise preceded by food ingestion. Skin testing the patient to foods ingested shortly before the exercise preceding the reaction may aid in identiﬁcation of the oﬀending food [52,53]. Other factors that could cause confounding symptoms or impact the course of an allergic reaction, such as an acute illness, drug ingestion, alcohol ingestion, vigorous exercise, or psychologic distress, should be considered. A history of illness in others ingesting the same food raises concern about food poisoning rather than food allergy. Because most patients with food allergy have other family members with allergic disease and a personal history of other allergic disease, questioning to obtain this information is indicated. Studies examining fatal allergic reactions to foods suggest that food allergic patients with asthma are at higher risk for fatal or near-fatal reactions [32,46]. These same studies reveal that the majority of patients suffering from fatal allergic reactions to foods were aware of their food allergy and ingested the oﬀending food unknowingly. Physical examination The focus of the physical examination varies, depending upon the patient’s presenting symptoms, their acuity, chronicity, and the mechanism

126

ATKINS

suspected, based upon the history. In those patients presenting in the midst of an acute allergic reaction to a food, attention is directed to the upper and lower airway to determine whether signiﬁcant airway obstruction caused by laryngeal edema or bronchospasm is present or evolving, as severe laryngeal edema and bronchospasm refractory to treatment are common causes of death in food-induced anaphylaxis [32,46]. Continuous monitoring of the oxygen saturation during these reactions is required. Other airway ﬁndings, such as marked nasal congestion, repetitive sneezing, profuse clear rhinorrhea, hoarseness, stridor, coughing, accessory muscle use, nasal ﬂaring, and wheezing should be noted. Close monitoring of the vital signs and physical examination for changes suggestive of impending shock, such as delayed capillary reﬁll or changes in mental status, is indicated, as refractory shock is the other major cause of death in these reactions [54]. Cutaneous changes, including ﬂushing, generalized pruritus, angioedema, urticaria, and ﬂaring of eczema are often encountered, along with gastrointestinal ﬁndings of oropharyngeal edema, increased or decreased bowel sounds, abdominal tenderness, vomiting, or diarrhea. Physical ﬁndings, such as allergic shiners, conjunctival injection, clear rhinorrhea, nasal congestion with a pale, edematous nasal mucosa, a transverse nasal crease, wheezing, and xerosis or patches of eczema observed in a less acute setting, suggest the presence of other allergic disease and increase the likelihood of coexistent IgE-mediated sensitivity to foods. Occasionally, an associated physical ﬁnding may suggest a speciﬁc diagnosis or raise concern about more serious disease. For example, the presence of a rash consistent with dermatitis herpetiformis suggests a diagnosis of celiac disease. The diagnosis of dermatitis herpetiformis should be considered in the patient with ‘‘eczema’’ not responding to standard therapy, as mistaking dermatitis herpetiformis for eczema has been reported [55]. Careful monitoring of weight and growth parameters at each visit and over time is required for food allergic patients. Weight loss, or failure to thrive, is rarely encountered in patients with IgE-mediated reactions to few foods or those less pervasive in the diet. Alternatively, patients with nonIgE-mediated or mixed gastrointestinal allergy, young children with food refusal, or patients on severely restricted diets because of suspected or documented multiple food allergy may fail to maintain their weight. Although speciﬁc or multiple food refusal in young children with limited verbal ability is often attributed to behavioral issues, further questioning and a careful physical examination is indicated to rule out other potential causes. Infants and toddlers often shun foods to which they are allergic, as the ingestion of these foods causes oropharyngeal tingling and burning, a metallic taste, abdominal pain, or nausea. Children with active esophagitis or dysphagia may avoid solid foods swallowed as a ﬁrm bolus, because the resultant esophageal distention or spasm is painful. Other potential causes of food refusal in these children include chronic or intermittent aspiration resulting from swallowing disorders, or oral tactile defensiveness in which

FOOD ALLERGY

127

certain food textures are not tolerated. Continued weight loss, or failure to thrive and not responding to dietary intervention to provide adequate caloric intake, should prompt further evaluation to rule out other disease.

Evaluation of the food allergic patient Prick skin testing Skin testing to foods is essentially a bioassay that involves introducing miniscule amounts of food allergens into the patient’s epidermis and monitoring the result. If mast cells in the patient’s skin have IgE on their surface speciﬁc for the food being tested, binding of the food allergen by these IgE antibodies triggers mast cell degranulation, resulting in histamine release and mediator generation. The localized mediator release results in the rapid formation of a cutaneous wheal surrounded by an erythematous ﬂare. In the absence of IgE speciﬁc for the introduced food allergen, no reaction occurs. Glycerinated commercial food extracts are widely available for skin testing to many common food allergens. Fresh food extracts, prepared by crushing the fresh food in an aliquot of saline, are also occasionally used [56]. These fresh extracts can be further diluted if there is concern regarding exquisite sensitivity. Alternatively, the ‘‘prick to prick’’ technique can be employed, which involves ﬁrst pricking the food with the skin test device, immediately followed by pricking the patient’s skin [57]. These methods are useful when testing for sensitivity to fruits or vegetables containing labile allergens susceptible to degradation during the extraction process used in the preparation of commercial extracts, or when no commercial extract of the suspected food is available. Fresh extracts can also be prepared to verify the results obtained using a commercial extract when the history is highly suggestive, but the skin test to the commercial extract is negative. In addition, skin testing with freshly prepared extracts can provide a direction for further evaluation. Skin testing with fresh extracts prepared from foods or sauces from a restaurant meal thought to have caused a reaction can suggest which foods or ingredients are worthy of further investigation. The potential for irritant reactions exists, but can be ruled out by skin testing others not sensitive to the food with the same extract. After pricking the skin with a lancet or bifurcated needle through which a small drop of food allergen extract is applied to the back or forearm, any resultant wheal and erythema observed at the site after approximately 15 minutes is measured and recorded. A histamine skin test is applied as a positive control, with a saline skin test serving as the negative control. Based on initial studies performed in children by Bock and colleagues [58] in the late 1970s, a food skin test is deﬁned as positive if a wheal 3 mm in diameter larger than the negative saline control, is observed. Systemic symptoms resulting from prick or puncture skin testing are exceedingly rare. The use of intradermal skin testing to foods is discouraged, as it has been shown

128

ATKINS

to be less speciﬁc and carries a higher risk of systemic reactions [59]. Rather than routinely skin testing to a broad panel of food allergens, skin tests are selected based on foods suggested by the history or limited to the foods considered to be common food allergens. In general, the positive predictive accuracy of a properly performed food skin test is considered less than 40% when the 3-mm cutoﬀ for deﬁning a positive skin test is used, indicating that many individuals who have a positive skin test to a food can eat that food without ill eﬀects [58]. However, Sporik and colleagues [60], evaluating a large cohort of children with a median age of 3 years with skin testing followed by food challenges, were able to calculate skin test diameters to peanut (greater than 8 mm), cow’s milk (greater than 8 mm) and egg (greater than 7 mm) with positive predictive accuracies approaching 95%. Although their ﬁndings cannot be extrapolated to other populations because of potential diﬀerences in age, extracts, and technique used, they demonstrate that using a larger wheal diameter to deﬁne a positive skin test results in a decrease in sensitivity but an increase in speciﬁcity. As with other investigators, they found no correlation between skin test size and the severity of a reaction. Removing a previously tolerated food from the diet based on skin testing alone is rarely recommended. However, a positive skin test is useful for identifying foods worthy of further investigation and is highly suggestive of a diagnosis in situations when a patient experienced a signiﬁcant reaction following the ingestion of an isolated food. Alternatively, the negative predictive accuracy of a properly performed skin test is greater than 95% [61]. Thus, skin testing is a rapid, sensitive, eﬃcient method of ruling out IgE-mediated reactivity to a food when quality extracts are applied using proper technique, and the patient has not taken medications known to interfere with testing. Atopy patch testing Although prick skin testing and the measurement of serum food-speciﬁc IgE antibodies are indispensable in the evaluation of patients with IgE-mediated food allergy, these tests are not useful in identifying the responsible food in patients with nonIgE-mediated reactions where cell mediated immune mechanisms are involved. In an eﬀort to identify a test that might be predictive in these situations, the use of the atopy patch test (APT) has been explored in recent years in the evaluation of patients with atopic dermatitis [62], eosinophilic esophagitis [63], food protein-induced enterocolitis syndrome (FPIES) [64], and others with gastrointestinal symptoms suspected of being food-related, but not IgE-mediated [65]. The foods most commonly evaluated with the APT are milk, egg, soy, and wheat. The APT is performed by applying the intact food allergen to noninﬂamed skin on the back under occlusion in a small aluminium cup. After 48 hours the patch test is removed and the resulting reaction is assessed and recorded,

FOOD ALLERGY

129

initially at 20 minutes and again 24 hours after patch test removal. The reactions are graded based on the degree of erythema and the presence of papules or vesicles. Thus, the APT has been referred to as an epicutaneous patch test using allergens capable of causing IgE-mediated reactions, where the test sites are evaluated for an eczematous response after 24 to 72 hours. Although side eﬀects are uncommon, irritant reactions and contact urticaria have been reported [66]. The utility of the APT in the evaluation of food allergic patients remains a topic of debate [67–70]. At this point, the interest lies in the potential utility of this test as an aid in identifying the responsible foods in patients with nonIgE-mediated gastrointestinal disorders, such as FPIES, or mixed reactions involving both IgE and lymphocyte mediated mechanisms, as seen in eosinophilic esophagitis and atopic dermatitis. Aspects that hinder wider use of the APT include the lack of standardization of the procedure, including the lack of standardized reagents or how best to prepare them, in addition to the time and expertise required for the accurate performance of the test [66]. Laboratory testing While prick skin testing to foods determines the presence of food allergen-speciﬁc IgE bound to speciﬁc receptors on the surface of mast cells in a patient’s skin, laboratory assays have been developed that determine the presence and amount of food allergen-speciﬁc IgE circulating unbound in the serum. These assays are particularly useful when medications that impact skin testing cannot be discontinued, widespread skin disease is present, or some other circumstance, such as unavailability of an extract, precludes skin testing. In addition, these assays are used to further investigate situations involving a suggestive history but a negative skin test, or to determine the level of circulating food-speciﬁc IgE in the patient with a positive skin test, to aid in deciding whether a food challenge to document tolerance of the food is indicated. Although the sensitivity of skin testing and selected immunoassays is comparable [71], in the patient with a highly suggestive history and a negative immunoassay, if not already obtained, the performance of a skin test is advised before ingestion of the food is encouraged. Following the levels of food allergen-speciﬁc IgE in an individual patient over time can be used to evaluate whether sensitization to the food is increasing, stable, or waning. Food allergen-speciﬁc IgE levels aid in predicting the likelihood of a reaction, but do not predict reaction severity. One of the most widely used and evaluated immunoassays is the ImmunoCap radioallergosorbent test (CAP RAST) system, which measures the amount of circulating allergen-speciﬁc IgE in the serum in kilounits of allergen-speciﬁc IgE per liter (kUA/L). In 1997, in a retrospective study analyzing the sera of food allergic children in light of highly suggestive histories or the results of food challenges, Sampson and Ho [72] reported predictive threshold levels for several of the commonly allergenic foods, including

130

ATKINS

milk, egg, peanut, and ﬁsh. Patients with values higher than the calculated threshold values had a 95% likelihood of reacting upon ingestion of the food. In a subsequent prospective study, Sampson [73] evaluated 100 children by history, oral food challenges, and measure of allergen-speciﬁc IgE levels to egg, milk, peanut, soy, wheat, and ﬁsh. This study was undertaken to determine if the 95% predictive decision points for egg, milk, peanut, and ﬁsh determined in the previous study were accurate. Using the previously deﬁned predictive decision points, more than 95% of the food allergies to these foods in this population of patients were correctly identiﬁed. These diagnostic decision points have been further investigated and reﬁned, and their use in clinical settings has signiﬁcantly reduced the need for food challenges [25]. CAP RAST levels, above which 95% or more of children would be expected to react, have been reported for several of the major food allergens. Children less than 2 years of age with a CAP RAST to egg of greater 2 kUA/L or a CAP RAST to milk of greater than 5 kUA/L, have a greater than 95% chance of reacting on food challenges. For older children the decision points for foods commonly causing allergic reactions are as follows: egg 7 kUA/L, milk 15 kUA/L, peanut 14 kUA/L, tree nuts approximately 15 kUA/L, and ﬁsh 20 kUA/L. However, individual patient CAP RAST results often fall in an indeterminate zone below the diagnostic threshold but above the value predicting tolerance. In addition, because these decision points have been determined for a relatively small number of foods, threshold values for the suspected food may not have been established. As a result of these and other nuances, food challenges remain an important tool for documenting the association between the ingestion of a suspected food and the onset of symptoms. Elimination diets Elimination diets are used in both the diagnosis and treatment of patients suﬀering from adverse reactions to foods, regardless of the mechanism involved. During the diagnostic phase suspected foods are eliminated from the diet while the patient’s clinical course is carefully monitored for a reduction in or resolution of symptoms. A lack of signiﬁcant improvement prompts a search for additional oﬀending foods or potential causes other than foods. During the treatment phase, an elimination diet is constructed that removes all oﬀending foods from the diet while meeting the patient’s nutritional requirements and taste preferences. Elimination diets should be carefully constructed, as the overzealous elimination of foods unnecessarily from the diet has been associated with adverse physical and psychologic consequences [74,75]. Diﬀerent versions of elimination diets, which vary in regard to the number of foods removed, are used. Limited elimination diets involve the removal of only those foods for which there is a high level of suspicion, based either upon the history or the results of testing. These are the simplest

FOOD ALLERGY

131

to prepare and use when a single food not widely found in the diet is suspected, and become more diﬃcult to design as more foods or those pervasive in the diet come under suspicion. Oligoantigenic diets are constructed using only a few foods classically considered to rarely be allergenic. Elemental diets consist of an elemental formula, with or without the addition of a few foods considered to be safe. Oligoantigenic and elemental diets are used when there is uncertainty about which foods cause symptoms or when a large number of foods are suspected. Elemental diets are useful in young infants not yet on solids, but adherence to these diets is often diﬃcult to maintain beyond infancy. One food-associated disorder in which the use of elemental diets has been shown to be of particular beneﬁt is eosinophilic esophagitis, where improvement in 98% of patients placed on elemental diets has been reported [76]. When oligoantigenic and elemental diets are used, foods are added back to the diet individually at selected intervals, accompanied by symptom monitoring. Tolerated foods are left in the diet, while those associated with a return of symptoms are removed. When elimination diets are instituted for extended periods, care must be taken to ensure that the patient’s nutritional requirements are met. Children on dairy-free diets have been shown to have diﬃculty meeting their requirements for calcium, vitamin D, and phosphorous [75]. Consultation with a registered dietician to provide a nutritional assessment and patient education regarding label reading, food preparation, hidden sources of food allergens, and alternative nutrient sources is encouraged. Food challenges The goal of performing an oral food challenge is to document the presence or lack of clinical reactivity to a food. Oral food challenges are categorized into open, single-blind, placebo-controlled, or double-blind, placebo-controlled, depending upon who is aware of the contents of each dose given during the challenge. The type of oral food challenge selected for use depends upon the expected need to control for patient or observer bias. In a double-blind, placebo-controlled food challenge (DBPCFC) neither the patient nor the medical team involved in administering the challenge is aware of the contents of the challenge. The DBPCFC remains the gold standard for diagnosing food allergy, as it best controls for both patient and observer bias. Thus, the DBPCFC is the challenge of choice in the research setting. In a single-blind, placebo-controlled food challenge (SBPCFC) the medical staﬀ knows the contents of challenge doses, but the patient does not. SBPCFCs are performed to eliminate bias on the part of the patient and the patient’s family. In an open food challenge (OFC), because the food is provided in its usual edible form, both the patient and medical staﬀ knows which and how much food is being eaten. A beneﬁt of the OFC is the relative ease of performance, as masking the challenge food is unnecessary, thereby signiﬁcantly reducing preparation time.

132

ATKINS

In most clinical situations an OFC suﬃces when objective symptoms are used to determine if the challenge is positive. Oral food challenges are performed to address a variety of clinical questions. When the food responsible for a reaction remains unclear, even after a thorough history and attempts to document sensitization, or when more than one food is implicated based on the history and test results, food challenges are indicated to determine which, if any, of the suspected foods cause symptoms. Accurately identifying the causative food prevents future reactions and avoids the needless elimination of foods from the diet. Food challenges are also performed to prove that a food is not or is no longer the cause of symptoms. An example is the patient who has been inaccurately labeled as food allergic, despite an unconvincing history or suspicious skin test or immunoassay results. A food challenge is indicated for reassurance that the food can be safely returned to the diet. The majority of children, who as infants and toddlers were allergic to milk, egg, soy, or wheat, develop tolerance to these foods as they age. More recent studies have shown that 20% of children with allergic reactions to peanut in the ﬁrst years of life outgrow their sensitivity [28]. Children determined to be allergic to a speciﬁc food at an early age, and during the course of their initial evaluation have evidence of sensitization to other foods they have yet to eat, are often kept on diets eliminating these foods until they are older. A thorough exposure history, combined with information obtained from skin testing and immunoassay for the level of food allergen-speciﬁc IgE, is used to determine if and when to challenge children to these foods. Carefully performed food challenges safely determine when these foods can be added to the diet. When immune mechanisms other than IgE-mediated sensitivity are suspected, as exempliﬁed with FPIES, a food challenge may be the only accurate means of verifying the diagnosis [13]. Contraindications to the performance of food challenges are relatively few. The performance of a food challenge is not advised in a patient with a history of a previous life threatening reaction and no evidence to suggest a signiﬁcant decrease in the patient’s level of sensitivity to the food. Challenging a patient with unstable asthma is ill advised. Patients with severe eczema should have their eczema under control before being challenged. When a previous reaction was severe and the obvious causative food is rarely encountered in the diet, or if the patient dislikes the food and, if given the opportunity, would chose to avoid it, the potential beneﬁt is unlikely to outweigh the risks of challenge. Patients frightened by the consideration of a food challenge often beneﬁt from working with a psychosocial clinician before a food challenge is performed. Decisions about who should be challenged are ﬁnalized only after a thorough discussion with the patient or the patient’s family regarding the reasons for challenge, in addition to a review of the potential beneﬁts and risks. Although signiﬁcant risk can be associated with the performance of oral food challenges, a retrospective analysis of 253 failed food challenges to the common food allergens (milk, egg,

FOOD ALLERGY

133

peanut, soy, or wheat), performed in a tertiary care center, along with the experience of other centers that routinely perform these challenges, provide evidence that controlled oral food challenges are safe when performed in a medical setting, with the necessary medications and equipment, in addition to personnel experienced in the treatment of anaphylaxis [77]. Before beginning a challenge, the history of previous suspected reactions to the food is reviewed and an interim history is taken to verify that the patient is medically stable. The basic structure of a food challenge involves feeding gradually increasing doses of the suspected food at predetermined time intervals, until objective symptoms occur or a normal portion of the food ingested openly is tolerated. In blinded studies the challenge food is disguised in another food that the patient will ingest. Typical total doses are the normal age adjusted single serving amounts, or 8 g to 10 g when freeze-dried or powdered foods are used. When freeze-dried or concentrated foods are used, the potential for alteration of labile allergens must be taken into consideration. Standardized recipes for DBPCFC to milk, soy, cooked egg, raw whole egg, peanut, hazelnut, and wheat in their usual edible form, and validated by professional panelists in a food laboratory, have been published [78]. Although the dosing and interval between doses can be established based upon the patient’s history, diﬀerent schemes have been successfully used in diﬀerent centers [79,80]. If subjective symptoms are encountered after a dose, options include waiting longer before administering the next dose, repeating the previous dose, or stopping the challenge. A food challenge is completed when the patient has an obvious reaction or a normal portion of the food has been ingested openly without symptoms. The observation period following completion of the challenge depends upon several factors, including the immune mechanism involved, timing, severity and duration of previous reactions, whether the patient reacted and the severity of that reaction, in addition to the level of concern about biphasic anaphylaxis. Usually patients are observed until they have been asymptomatic for a couple of hours after a reaction, or for about two hours after the last dose if the food was tolerated. Patients with nonIgE-mediated reactions, such as the food-protein induced enterocolitis syndrome or other delayed reactions, are observed longer. The implications of the challenge results should be thoroughly reviewed with the patient and the patient’s family, and all questions thoroughly addressed. If the challenge is negative, including the challenged food regularly in the diet is encouraged. Management of the food allergic patient Current management of food-allergic patients consists of the dietary avoidance of causal foods and optimizing the prompt treatment of symptoms resulting from accidental exposure. An individualized approach, taking into consideration the immunologic mechanism involved, the age of the patient, the suspected degree of sensitivity, the number of implicated

134

ATKINS

foods, and the severity of previous reactions, is required. Dietary avoidance of implicated foods is accomplished through the design of a palatable, nutritionally adequate elimination diet, education regarding label reading, and a review of potential sources of accidental exposure. The ease of designing a single food elimination diet depends upon the pervasiveness of the offending food in the diet. Diets eliminating commonly encountered foods or multiple foods are best developed with the aid of a skilled dietician experienced in working with patients with food allergies. Reliable resources for obtaining further information, such as the Food Allergy and Anaphylaxis Network (www.foodallergy.org), should be provided. Wearing a medical information bracelet or necklace or carrying a card listing the patient’s allergies and other important medical information can save time, particularly when the patient is found unconscious or cannot communicate as a result of a reaction. A food allergy action plan should be developed that lists the steps to take in case of a reaction, including the order and doses of all medications to be administered, as well as contact information for family members and health care providers. This plan should be thoroughly reviewed with patients, their family members, and all other caretakers. Fatal allergic reactions to foods have been associated with the delayed administration of epinephrine [32,46]. As a result, an epinephrine autoinjector, along with instruction about when and how to use it, should be provided to those patients considered to be at risk for food-induced anaphylaxis. Features of the history that should prompt providing an epinephrine autoinjector include: a previous severe reaction or one involving the respiratory or cardiovascular system; generalized urticaria or angioedema during previous reactions; coexistent asthma; allergy to peanuts, nuts, ﬁsh, or shellﬁsh; or a history of other family members with severe allergic reactions to foods [81]. Injection of the epinephrine dose intramuscularly into the lateral thigh is recommended, based upon studies demonstrating improved absorption by this route over subcutaneous administration [82]. Currently, epinephrine autoinjectors are available in doses of 0.15 mg and 0.30 mg, with the 0.15-mg dose suggested by the manufacturer for patients weighing 15 kg to 30 kg, and 0.30-mg dose recommended for those over 30 kg, with the caveat that physician discretion regarding dosing is suggested based upon the history. Autoinjector use is preferred over the use of an epinephrine ampule and syringe, to avoid delay in administering the dose and reduce the potential for signiﬁcant errors in dosing [83]. Providing more than one autoinjector is generally recommended, particularly in situations where access to medical care is limited or could be delayed. Once an epinephrine autoinjector is used, emergency medical services should be notiﬁed for transport of the patient to the appropriate medical facility. Other medications commonly available to patients, for use in the immediate treatment of allergic reactions to foods, include oral antihistamines and inhaled bronchodilators. Antihistamines carried for the ﬁrst-aid

FOOD ALLERGY

135

treatment of allergic reactions should be chewable or liquid preparations, to reduce the time required for absorption. Appropriate doses of these medications and when to use them should be reviewed. The ﬁrst-aid treatment of food-induced anaphylaxis, including the rationale for epinephrine administration, has been reviewed by Simons [54]. Although epinephrine is the drug of choice for the treatment of anaphylactic reactions to foods, it does not reverse the symptoms of nonIgE-mediated reactions, such as food proteininduced enterocolitis, where the mainstay of therapy is ﬂuid replacement. Upon arrival at a medical facility for treatment of an allergic reaction to a food, the patient should be rapidly assessed and supportive care provided as indicated. Oxygen should be rapidly provided for any evidence of respiratory distress. If 10 to 15 minutes have elapsed since the initial dose, and the reaction persists or is progressing, another dose of epinephrine should be given. Patients presenting with hypotension should receive intravenous ﬂuids with consideration for instituting vasopressor therapy. If antihistamines have not been given or symptoms persist, an additional dose of antihistamine should be administered and use of an H2 blocker considered. Other supportive care, such as bronchodilator therapy for patients with bronchospasm, should be provided as indicated. Looking for factors that inhibit response to therapy, such as beta-blocker use, is encouraged in patients unresponsive to standard treatment. Intravenous glucagon may eﬀectively treat hypotension in patients on beta blocker therapy who are not responding to the vasopressor eﬀects of epinephrine [54]. Before the patient with food-induced anaphylaxis is released from medical care, the means for obtaining an epinephrine autoinjector should be provided, along with appropriate teaching and arrangement for follow-up with an allergist. Long term management of the food allergic patient involves monitoring for evidence of the development of tolerance, or for the acquisition of new food allergies, by obtaining interim histories regarding reactions to foods, and evaluating the results of immunoassays for food-speciﬁc IgE or skin testing as indicated. Other important aspects of long-term follow-up include analyzing the diet for nutritional adequacy, reviewing the ﬁrst-aid treatment of allergic reactions to foods, discussing patient concerns, and providing psychologic support. The psychologic impact on patients and their families is a frequently ignored aspect of food allergy, often successfully managed with appropriate psychosocial intervention, resulting in a signiﬁcant improvement in quality of life. Future directions Promising results observed in recent studies suggest that improved diagnostic methods and treatments other than merely avoiding the oﬀending food are forthcoming. For example, examination of speciﬁc epitopes, or the number of epitopes on speciﬁc food allergens recognized by a patient’s food-speciﬁc IgE, may improve the ability to predict the likelihood of the

136

ATKINS

eventual development of tolerance or the potential for severe reactions [84– 87]. In addition, a variety of immunotherapeutic approaches, including oral immunotherapy [88–90], sublingual immunotherapy [91], and immunotherapy using altered allergens administered with speciﬁc adjuvants [92] are under investigation, as are novel therapies, including treatment with humanized monoclonal anti-IgE antibodies [93] and a modiﬁed Chinese herbal therapy [94]. The ﬁndings of these, and other studies underway to better deﬁne the immune mechanisms involved in the development of oral tolerance as well as food allergy, suggest that viable therapies will become available within the next decade.

References [1] Sicherer SH, Munoz-Furlong A, Sampson HA. Prevalence of peanut and tree nut allergy in the United States determined by means of a random-digit dial telephone survey: a 5-year follow-up study. J Allergy Clin Immunol 2003;112(6):1203–7. [2] Anderson SA, Sogn DD, editors. Adverse reaction to food. AAAI and NIAID, NIH publication no. 84–2442, 1984. [3] Bruijnzeel-Koomen C, Ortolani C, Aas K, et al. Adverse reactions to food. Allergy 1995; 50(8):623–35. [4] Lawrence DT, Dobmeier SG, Bechtel LK, et al. Food poisoning. Emerg Med Clin North Am 2007;25:357–73. [5] Srimshaw NS, Murray EB. The acceptability of milk and milk products in populations with a high prevalence of lactose intolerance. Am J Clin Nutr 1988;48(Suppl 4):1079–159. [6] Nowak-Wegrzyn A, Sampson HA. Adverse reactions to foods. Med Clin North Am 2006; 90:97–127. [7] Scurlock AM, Lee LA, Burks AW. Food allergy in children. Immunol Allergy Clin N Am 2005;25:369–88. [8] Amlot PL, Kemeny DM, Sachary C, et al. Oral allergy syndrome (OAS): symptoms of IgEmediated hypersensitivity to foods. Clin Allergy 1987;17:33–42. [9] Ortolani C, Ispano M, Pastorello E, et al. The oral allergy syndrome. Ann Allergy 1988;61: 47–52. [10] Egger M, Mutschlechner S, Wopfner N, et al. Pollen-food syndromes associated with weed pollinosis: an update from the molecular point of view. Allergy 2006;61:461–76. [11] Ma S, Sicherer SH, Nowak-Wegryzyn A. A survey on the management of pollen-food allergy syndrome in allergy practices. J Allergy Clin Immunol 2003;112:784–8. [12] Nowak-Wegrzyn A, Sampson HA, Wood RA, et al. Food protein-induced enterocolitis syndrome caused by solid food proteins. Pediatrics 2003;111:829–35. [13] Sicherer SH. Food protein-induced enterocolitis syndrome: case presentations and management lessons. J Allergy Clin Immunol 2005;115:149–56. [14] Farrell RJ, Kelly CP. Celiac Sprue. N Engl J Med 2002;346:180–8. [15] McManus R, Kelleher D. Celiac diseasedthe villain unmasked. N Engl J Med 2003;348: 2573–4. [16] Sampson HA. Food allergy. Part 1: immunopathogenesis and clinical disorders. J Allergy Clin Immunol 1999;103:717–28. [17] Sloan AE, Powers ME. A perspective on popular perceptions of adverse reactions to foods. J Allergy Clin Immunol 1986;78:127–33. [18] Sicherer SH, Furlong TJ, Maes HH, et al. Genetics of peanut allergy: a twin study. J Allergy Clin Immunol 2000;106:53–6.

FOOD ALLERGY

137

[19] Eggesbo M, Botten G, Stigum H, et al. Is delivery by Cesarean section a risk factor for food allergy? J Allergy Clin Immunol 2003;112:420–6. [20] Laubereau B, Filipiak-Pittroﬀ B, Von Berg A, et al. Caesarian section and gastrointestinal symptoms, atopic dermatitis, and sensitization during the ﬁrst year of life. Arch Dis Child 2004;89:991–7. [21] Milner J, Stein DM, McCarter R, et al. Early infant multivitamin supplementation is associated with increased risk for food allergy and asthma. Pediatrics 2004;114:27–32. [22] Untersmayr E, Bakos N, Scholl I, et al. Anti-ulcer drugs promote IgE formation toward dietary antigens in adult patients. FASEB J 2005;19:656–8. [23] Kulig M, Luck W, Lau S. Eﬀect of pre- and postnatal tobacco smoke exposure on speciﬁc sensitization to food and inhalant allergens during the ﬁrst 3 years of life. Allergy 1999;54: 220–8. [24] Bock SA. Prospective appraisal of complaints of adverse reactions to foods in children during the ﬁrst 3 years of life. Pediatrics 1987;78:127–33. [25] Sampson HA. Update on food allergy. J Allergy Clin Immunol 2004;113:805–19. [26] Bock SA, Atkins FM. The natural history of peanut allergy. J Allergy Clin Immunol 1989;83: 900–4. [27] Hourihane JO, Roberts SA, Warner JO. Resolution of peanut allergy: case control study. BMJ 1998;316:1271–5. [28] Skolnick HS, Conover-Walker MK, Koerner CB, et al. The natural history of peanut allergy. J Allergy Clin Immunol 2001;107:367–74. [29] Eigenmann PA, Sicherer SH, Borkowski TA, et al. Prevalence of IgE-mediated food allergy among children with atopic dermatitis. Pediatrics 1998;101:e8. [30] James JM. Respiratory tract and food hypersensitivity. Immunol Allergy Clin N Am 1999; 19(3):519–32. [31] Novembre E, de Martino M, Vierucci A. Foods and respiratory allergy. J Allergy Clin Immunol 1988;81:1059–65. [32] Bock SA, Munoz-Furlong A, Sampson HA. Fatalities due to anaphylactic reactions to foods. J Allergy Clin Immunol 2110;107:191–3. [33] Fiocchi A, Restani P, Bernardo L, et al. Tolerance of heat-treated kiwi by children with kiwifruit allergy. Pediatr Allergy Immunol 2004;15:454–8. [34] Eigenmann PA. Anaphylactic reactions to raw eggs after negative challenges with cooked eggs. J Allergy Clin Immunol 2000;105:587–8. [35] Werfel SJ, Cooke SK, Sampson HA. Clinical reactivity to beef in children clinically allergic to cow’s milk. J Allergy Clin Immunol 1997;99:293–300. [36] Bock SA. Anaphylaxis to coriander: a sleuthing story. J Allergy Clin Immunol 1993;91: 1232–3. [37] Joseph BE. Caraway seed allergy: a case report. Ann Allergy 1995;74:55–6. [38] Boxer M. Cumin anaphylaxis: a case report. J Allergy Clin Immunol 1997;99:722–3. [39] Erben AM, Rodriguez JL, McCullough J, et al. Anaphylaxis after ingestion of beignets contaminated with Dermatophagoides farinae. J Allergy Clin Immunol 1993; 92:846–9. [40] Schwartz HJ. Latex: a potential hidden ‘‘food’’ allergen in fast food restaurants. J Allergy Clin Immunol 1995;95:139–40. [41] Belloni-Businco B, Paganelli R, Lucenti P, et al. Allergenicity of goat’s milk in children with cow’s milk allergy. J Allergy Clin Immunol 1999;103:1191–4. [42] Yunginger JW. Food ingredient labeling: how many ways can wheat be spelt? Allergy Proc 1994;15:219–20. [43] James JM. Allergic reactions to foods by inhalation. Curr Allergy Asthma Rep 2007;7(3): 167–74. [44] Taylor SL, Helfe SL, Bindslev-Jensen C, et al. Factors aﬀecting the determination of threshold doses for allergenic foods; how much is too much? J Allergy Clin Immunol 2002;109:24–30.

138

ATKINS

[45] Moneret-Vautrin DA, Kanny G. Update on threshold doses of food allergens: implications for patients and the food industry. Curr Opin Allergy Clin Immunol 2004;4:215–9. [46] Sampson HA, Mendelson LM, Rosen JP. Fatal and near-fatal anaphylactic reactions to food in children and adolescents. N Engl J Med 1992;327:380–4. [47] Maulitz RM, Pratt DS, Schocket AL. Exercise-induced anaphylactic reaction to shellﬁsh. J Allergy Clin Immunol 1979;63:433–4. [48] Roman A, Di Fonso M, Giuﬀreda F, et al. Food-dependent exercise-induced anaphylaxis: clinical and laboratory ﬁndings in 54 subjects. Int Arch Allergy Immunol 2001;125: 264–72. [49] Tewari A, Du Tiot G, Lack G. The diﬃculties of diagnosing food-dependent exercise-induced anaphylaxis in childhoodda case study and review. Pediatr Allergy Immunol 2006; 17:157–60. [50] Palosuo K, Varnonen E, Nurkkala J, et al. Transglutaminase-mediated cross-linking of a peptic fraction of w-5 gliadin enhances IgE reactivity in wheat-dependent exercise-induced anaphylaxis. J Allergy Clin Immunol 2003;111:1386–92. [51] Shimamoto SR, Bock SA. Update on the clinical features of food-induced anaphylaxis. Curr Opin Allergy Clin Immunol 2002;2:211–6. [52] Romano A, Di Fonso M, Giureda F, et al. Diagnostic work-up for food-dependent, exerciseinduced anaphylaxis. Allergy 1995;50:817–24. [53] Guinnepain MT, Eloit C, Raard M, et al. Exercise-induced anaphylaxis: useful screening of food sensitization. Ann Allergy Asthma Immunol 1996;77:491–6. [54] Simons FES. First-aid treatment of anaphylaxis to food: focus on epinephrine. J Allergy Clin Immunol 2004;113:837–44. [55] George DE, Browning JC, Hsu S. Medical pearl: dermatitis herpetiformisdpotential for confusion with eczema. J Am Acad Dermatol 2006;54:327–8. [56] Ortolani C, Ispano M, Pastorello EA. Comparison of results of skin prick tests (with fresh foods and commercial food extracts) and RAST in 100 patients with oral allergy syndrome. J Allergy Clin Immunol 1989;83:683–90. [57] Dreborg S, Coucard T. Allergy to apple, carrot and potato in children with birch pollen allergy. Allergy 1983;38:167–72. [58] Bock SA, Buckley J, Holst A, et al. Proper use of skin tests with food extracts in diagnosis of food hypersensitivity. Clin Allergy 1977;7:375–83. [59] Simons EER, Frew AJ, Ansotegui IJ, et al. Risk assessment in anaphylaxis: current and future approaches. J Allergy Clin Immunol 2007;120:S2–24. [60] Sporik R, Hill DJ, Hosking CS. Speciﬁcity of allergen skin testing in predicting positive open food challenges to milk, egg and peanut in children. Clin Exp Allergy 2000;30: 1540–6. [61] Sampson HA. Comparative study of commercial food antigen extracts for the diagnosis of food hypersensitivity. J Allergy Clin Immunol 1988;82:718–36. [62] Kerschenlohr K, Darsow U, Burgdorf WHC, et al. Lessons from atopy patch testing in atopic dermatitis. Curr Allergy Asthma Rep 2004;4:285–9. [63] Spergel JM, Beausoleil JL, Mascarenhas M, et al. The use of skin prick tests and patch tests to identify causative foods in eosinophilic esophagitis. J Allergy Clin Immunol 2002;109: 363–8. [64] Fogg MI, Brown-Whitehorn TA, Pawloski NA, et al. Atopy patch test for the diagnosis of food protein-induced enterocolitis syndrome. Pediatr Allergy Immunol 2006;17:351–5. [65] Mehl A, Rolinck-Werninghaus C, Staden U, et al. The atopy patch test in the diagnostic workup of suspected food-related symptoms in children. J Allergy Clin Immunol 2006; 118:923–9. [66] Spergel JM, Brown-Whitehorn T. The use of patch testing in the diagnosis of food allergy. Curr Allergy Asthma Rep 2005;5:86–90. [67] Isolauri E, Turjamaa K. Combined skin prick and patch testing enhances identiﬁcation of food allergy in infants with atopic dermatitis. J Allergy Clin Immunol 1996;97:9–15.

FOOD ALLERGY

139

[68] Roehr C, Reibel S, Ziegert M, et al. Atopy patch tests, together with determination of speciﬁc IgE levels, reduce the need for oral food challenges in children with atopic dermatitis. J Allergy Clin Immunol 2001;107:548–53. [69] Osterballe M, Andersen KE, Bindslev-Jensen C. The diagnostic accuracy of the atopy patch test in diagnosing hypersensitivity to cow’s milk and hen’s egg in unselected children with and without atopic dermatitis. J Am Acad Dermatol 2004;51:556–62. [70] Canini RB, Ruotolo S, Auricchio L, et al. Diagnostic accuracy of the atopy patch test in children with food-related gastrointestinal symptoms. Allergy 2007;62:738–43. [71] Sampson HA, Albergo R. Comparison of results of skin tests, RAST, and double-blind placebo-controlled food challenges in children with atopic dermatitis. J Allergy Clin Immunol 1984;74:26–33. [72] Sampson HA, Ho DG. Relationship between food-speciﬁc IgE concentrations and the risk of positive food challenges in children and adolescents. J Allergy Clin Immunol 1997;100: 444–51. [73] Sampson HA. Utility of food-speciﬁc IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol 2001;107:891–6. [74] Salman S, Christie L, Burks A, et al. Dietary intakes of children with food allergies: comparison of the Food Guide Pyramid and the Recommended Dietary Allowances. J Allergy Clin Immunol 2002;109:S214. [75] Christie L, Hine RJ, Parker JG, et al. Food allergies in children aﬀect nutrient intake and growth. J Am Diet Assoc 2002;102:1648–51. [76] Liacouras CA, Spergel JM, Ruchelli E, et al. Eosinophilic esophagitis: a 10-year experience in 381 children. Clin Gastroenterol Hepatol 2005;3:1198–206. [77] Perry TT, Matsui E, Conover-Walker MK, et al. Risk of oral food challenges. J Allergy Clin Immunol 2004;114:1164–8. [78] Vlieg-Boestra BJ, Bijleveld CMA, van der Heide S, et al. Development and validation of challenge materials for double-blind, placebo-controlled food challenges in children. J Allergy Clin Immunol 2004;113:341–6. [79] Bock SA, Sampson HA, Atkins FM, et al. Double-blind, placebo-controlled food challenge (DBPCFC) as an oﬃce procedure: a manual. J Allergy Clin Immunol 1988;82: 986–97. [80] Bendslev-Jensen C, Ballmer-Weber BK, Bengtsson U, et al. Standardization of food challenges in patients with immediate reactions to foods-position paper from the European Academy of Allergology and Clinical Immunology. Allergy 2004;59:690–7. [81] Sicherer SH, Teuber ST. Current approach to the diagnosis and management of adverse reactions to foods. J Allergy Clin Immunol 2004;114:1146–50. [82] Simons FER, Roberts JR, Gu X, et al. Epinephrine absorption in children with a history of anaphylaxis. J Allergy Clin Immunol 1998;101:33–7. [83] Simons FER, Chan ES, Gu X, et al. Epinephrine for out-of-hospital (ﬁrst aid) treatment of anaphylaxis in infants: is the ampule/syringe/needle method practical? J Allergy Clin Immunol 2001;108:1040–4. [84] Jarvinen KM, Beyer K, Vila L, et al. B-cell epitopes as a screening instrument for persistent cow’s milk allergy. J Allergy Clin Immunol 2002;110:293–7. [85] Cooke SK, Sampson HA. Allergenic properties of ovomucoid in man. J Immunol 1997;159: 2026–32. [86] Beyer K, Ellman-Grunther L, Jarniene KM, et al. Measurement of peptide-speciﬁc IgE as an additional tool in identifying patients with clinical reactivity to peanuts. J Allergy Clin Immunol 2003;112:202–7. [87] Shreﬄer WG, Beyer K, Chu TT, et al. Microarray immunoassay: association of clinical history, in vitro IgE function, and heterogeneity of allergenic peanut epitopes. J Allergy Clin Immunol 2004;113:776–82. [88] Patriarca G, Bucera E, Roncallo C, et al. Oral desensitizing treatment in food allergy: clinical and immunological results. Aliment Pharmacol Ther 2003;17:459–65.

140

ATKINS

[89] Meglio P, Bartone E, Plantamura M, et al. A protocol for oral desensitization in children with IgE-mediated cow’s milk allergy. Allergy 2004;59:980–7. [90] Buchanan AD, Green TD, Jones SM, et al. Egg oral immunotherapy in nonanaphylactic children with egg allergy. J Allergy Clin Immunol 2007;119:199–205. [91] Enrique E, Pineda F, Malek T, et al. Sublingual immunotherapy for hazelnut food allergy; a randomized, double-blind, placebo-controlled study with a standardized hazelnut extract. J Allergy Clin Immunol 2005;116:1073–9. [92] Nowak-Wegrzyn A. New perspectives for use of native and engineered recombinant food proteins in treatment of food allergy. Immunol Allergy Clin N Am 2007;27:105–27. [93] Leung DY, Sampson HA, Yunginger JW, et al. Eﬀect of anti-IgE therapy in patients with peanut allergy. N Engl J Med 2003;348:986–93. [94] Srivastava KD, Kattan JD, Zou ZM, et al. The Chinese herbal medicine formula FAHF-2 completely blocks anaphylactic reactions in a murine model of peanut allergy. J Allergy Clin Immunol 2005;115:171–8.

Prim Care Clin Office Pract 35 (2008) 141–157

Urticaria Sheila M. Amar, MDa,b, Stephen C. Dreskin, MD, PhDb,c,* a

Division of Allergy and Immunology, National Jewish Medical and Research Center, The University of Colorado, 1400 Jackson Street, K1001, Denver, CO 80206, USA b Division of Allergy and Immunology, University of Colorado at Denver and Health Sciences Center, 4200 E. 9th Avenue, Campus Box B164, Denver, Colorado 80262, USA c Allergy, Asthma, and Immunology Practice, University of Colorado Hospital, 1635 N. Ursula Street, Aurora, CO 80045, USA

Urticaria with or without angioedema is frequently encountered in primary care medicine. If the urticaria is of short duration, it is usually not of major clinical concern. Conversely, if urticaria persists, it can become a diﬃcult problem for both patients and physicians. Although many patients and physicians think that urticaria is evidence of an IgE-mediated allergic reaction, often the etiology of urticaria is unknown. This uncertainty frequently results in patients enduring unnecessary lifestyle changes or extensive testing. In more persistent cases, patients achieve control of their disease only with the use of more toxic medications, such as corticosteroids, and this can lead to a range of systemic complications. Although this disease typically is associated with a good prognosis, patients with severe urticaria can suﬀer signiﬁcant morbidity with a dramatic decline in their quality of life, productivity at work, and emotional well-being.

Deﬁnition Urticaria, or hives, are pruritic, edematous, erythematous lesions that are typically round or oval. Pale raised centers called wheals are usually prominent in lesions and vary in size from a few millimeters to a few centimeters (Fig. 1). Approximately 40% of patients with urticaria experience

* Corresponding author. Division of Allergy and Clinical Immunology, University of Colorado at Denver and Health Sciences Center, 4200 E. 9th Avenue, Campus Box B164, Denver, Colorado 80262. E-mail address: [email protected] (S.C. Dreskin). 0095-4543/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2007.09.009 primarycare.theclinics.com

142

AMAR & DRESKIN

Fig. 1. Urticaria (hives).

angioedema, which aﬀects deeper subdermal and/or submucosal sites and appears as brawny, nonpitting edema typically without well-deﬁned margins and without erythema. Unlike other forms of edema, angioedema is usually not distributed in dependent areas of the body and may involve the lips, tongue, eyelids, and genitalia [1]. Angioedema in the absence of urticaria is rare and should alert the practitioner to alternative diagnoses, such as hereditary or acquired angioedema (see below). Recurrent hives with or without angioedema lasting less than 6 weeks are considered to be acute and episodes lasting longer than 6 weeks are considered chronic [2]. This somewhat arbitrary distinction of 6 weeks becomes important in regards to potential mechanisms, approaches to evaluation, and options for treatment. Both urticaria and angioedema can peak within minutes to hours and last hours to days. In this article, the terms urticaria and urticaria with angioedema are used interchangeably. Clinical manifestations Cases Case 1 A 58-year-old male with a history of hypertension, coronary heart disease, and gout comes to his primary care physician’s oﬃce complaining of

URTICARIA

143

pruritis starting 5 days before and diﬀuse hives occurring 2 days before with new lesions continuing to occur. Each hive is intensely pruritic, lasts less than 24 hours, and leaves normal skin upon resolution. He denies any unusual food ingestions or changes in his environment (eg, soaps, shampoos). His medications include aspirin, 81 mg, once daily; hydrochlorothiazide, 25 mg, once daily; and extended-release metoprolol, 100 mg, once daily. He had an episode of gout the previous month with an elevated uric acid and was started on allopurinol approximately 6 days prior to his current visit. Case 2 A 25-year-old female with urticaria and angioedema for the past 2 months reports that hives occur on her chest, abdomen, and extremities on a daily basis and have been unresponsive to fexofenadine, 180 mg, once daily; and diphenhydramine hydrochloride, 25 mg, once nightly. Each lesion lasts 24 to 36 hours, is very pruritic, and leaves residual hyperpigmentation that slowly resolves. She is unable to associate the hives with ingestion of medications or foods or to changes in temperature or environment. On one occasion, she experienced angioedema of the tongue associated with mild shortness of breath and now carries a self-injectable epinephrine device. Because of the intense pruritis, especially at night, and the sedation associated with the use of diphenhydramine, she has been unable to sleep or concentrate and is worried about successfully ﬁnishing her semester in graduate school. Case 3 A 2-year-old girl is brought to the pediatrician’s oﬃce for an episode of hives involving the upper body and face that lasted 1 day the week before. Her mother reports that she developed hives while at a picnic outside in the park with friends. The hives resolved in a few hours and there was no wheezing, shortness of breath, or swelling. The mother is unaware of all the food her daughter ate at the picnic but reports that seafood and peanut butter cookies were present and her daughter had not eaten these in the past. Discussion of cases The above three cases highlight the varying manifestations of urticaria and angioedema. Patients often report pruritis that is poorly localized before the onset of hives, as in case 1. The intensity of the pruritis varies and can progress to an unbearable intensity that may cause patients to go the emergency room. Hives can occur over a short period of time, such as in case 3, or last for days to months, as in the other two scenarios. Hives are limited to the skin in contrast to angioedema, which occurs in deeper sites. If angioedema occurs near the laryngeal, pharyngeal, or lingual areas, as in case 2, airway compromise may occur, which can be life-threatening.

144

AMAR & DRESKIN

Patients with urticaria often have dramatic impairment in sleep due to either the pruritis or sedative eﬀects of antihistamines. Furthermore, chronic urticaria often diminishes quality of life and, in extreme cases, can lead to loss of employment and social isolation [3]. A good example of the morbidity associated with this disease is the fatigue and emotional discomfort experienced by the patient in case 2. Finally, although chronic urticaria is occasionally caused by ingestants or topical exposures, usually the cause of the urticaria is unknown. In spite of this, many patients continue to believe that something in their diet or environment is causing the hives. Even if the hives can be characterized as physical or autoimmune in nature, our lack of understanding of mechanisms and lack of speciﬁc treatments are often frustrating for patients and physicians.

Epidemiology An episode of urticaria with or without angioedema occurs in 15% to 25% of individuals at some time in life and is most often acute. Only 30% of these cases go on to become chronic [4]. Urticaria aﬀects both genders and all races. Acute urticaria is more common in children and young adults and chronic urticaria is more common in adults, aﬀecting women (w60%) more than men (w40%) [5,6].

Pathophysiology Mast cells are the primary eﬀector cells in urticaria and in most cases of angioedema. These cells are found in high numbers throughout the body and in many locations, such as the skin, subdermis, and mucosal surfaces. When mast cells are activated, there is a rapid release of histamine, leukotriene C4, and prostaglandin D2 [7,8]. The release of these mediators leads to vasodilatation and subcutaneous and intradermal leakage of plasma from postcapillary venules, which in turn lead to pruritis. There is also a more delayed (4–8 hour) secretion of inﬂammatory cytokines (tumor necrosis factor, interleukin 4, interleukin 5) that leads to an inﬂammatory inﬁltrate and longer-lasting lesions. Angioedema can involve a similar mechanism but the extravasation of ﬂuid is deeper in subdermal and/or submucosal sites. Chronic urticarial lesions are characterized by dense perivascular inﬂammatory inﬁltrate consisting of CD4- and CD8-positive T lymphocytes, eosinophils, basophils, and neutrophils [9–11]. A minority of patients with chronic urticaria have urticarial vasculitis with lesions characterized by vascular destruction, ﬁbrinoid necrosis, and immune complex deposition on microscopic examination (including immunoﬂuorescence) [12]. Many cases of acute urticaria and angioedema are allergic or IgE-mediated reactions and tend to be self-limited. Typically, acute urticaria is a hypersensitivity reaction to foods, drugs, or insect stings (Box 1). They can

URTICARIA

Box 1. Classification of urticaria I. Acute urticaria/angioedema A. Hypersensitivity reactions 1. Drug allergy 2. Food allergy 3. Insect allergy B. Idiopathic C. Pseudoallergic reactions 1. Drugs 2. Radiocontrast dye 3. Other foods D. Toxic reaction E. Contact urticaria 1. Latex 2. Animal saliva 3. Processing of foods or biologics F. Immune complex 1. Serum sickness 2. Transfusion-related 3. Postviral II. Chronic urticaria/angioedema A. Autoimmune B. Idiopathic C. Physical 1. Dermographism 2. Cholinergic 3. Exercise-induced anaphylaxis 4. Delayed pressure 5. Solar 6. Cold 7. Vibratory 8. Aquagenic D. Presumed immune complex–induced 1. Thyroid disease 2. Urticarial vasculitis 3. Malignancy-associated 4. Collagen vascular disease–associated E. Hypersensitivity reactions 1. Drug allergy 2. Food allergy III. Rare syndromes A. Urticaria pigmentosa and systemic mastocytosis B. Cold inflammatory disorders

145

146

AMAR & DRESKIN

also occur as an epiphenomena associated with inﬂammatory processes produced by viral illness, particularly in children. The most common culprit drugs include penicillins, sulfonamides, muscle relaxants, diuretics, and nonsteroidal anti-inﬂammatory drugs (NSAIDs). For instance, in case 1 above, the patient’s urticaria may be due to the initiation of allopurinol. In addition, his use of aspirin and metoprolol (non–IgE-mediated mechanism, see below) can exacerbate urticaria if he progresses into a more persistent form of the disease. The predominant foods that cause urticaria are milk, eggs, peanuts, tree nuts, ﬁnﬁsh, and shellﬁsh. These allergens lead to activation of mast cells by cross-linking IgE bound to the high-aﬃnity receptor for IgE (FceRI). In the pediatric case 3 above, the transient nature of the urticaria in the child may be due to ingestion of a food (eg, tree nuts or peanuts in the cookie, seafood) or to other causes (eg, insect bites, contact with pets). Sensitization to foods not previously eaten can occur in utero, during lactation, or from topical application (eg, lotions containing peanut products) [13]. Although uncommon, antioxidant food preservatives butylated hydroxyanisole and butylated hydroxytoluene have also been shown to exacerbate urticaria [14]. In contrast, other agents can cause acute urticaria and angioedema by an IgE-independent (pseudoallergic) mechanism. For instance, some drugs (eg, opioids, vancomycin, NSAIDS, beta-blockers), radiocontrast dye, viral infections (eg, hepatitis B, Epstein-Barr virus), or ingestion of ﬁsh contaminated by histamine-producing bacteria (eg, scombroid food poisoning) can produce urticaria by a non–IgE-mediated mechanism. NSAIDs can cause urticaria by either IgE-mediated or IgE-independent routes. In case 1 above, if cessation of allopurinol does not resolve the urticaria, the patient may have an IgE-independent cause of urticaria caused by his use of aspirin. Selective cyclooxygenase 2 inhibitors generally do not induce urticaria in patients who are sensitive to NSAIDs [15]. The two largest subgroups of patients with chronic urticaria are those with autoimmune urticaria and those with idiopathic urticaria with 35% to 40% of patients falling into each of these categories. The autoimmune subgroup is still being deﬁned and some investigators consider cases with evidence of autoimmunity to still be idiopathic. Both groups have symptoms in the absence of speciﬁc physical triggers, allergen exposures, or coexistent disease. Patients with autoimmune urticaria are characterized by the presence of IgG antibodies that can cross-link FceRI, whereas patients with idiopathic urticaria do not have evidence of autoimmunity [16]. In approximately 5% of patients with chronic urticaria and angioedema, symptoms may be related to ingestants (eg, foods, medicines, dietary supplements), contacts (eg, soaps, latex), infections (eg, multicellular parasites in endemic areas), hormonal changes, or systemic illness (eg, rheumatic disease, autoimmune thyroid disease, hepatitis) (see Box 1). There once was concern that chronic urticaria could be a manifestation of an occult neoplasm. Today, this is not a signiﬁcant concern and most experts, in the

URTICARIA

147

absence of ﬁndings in history and physical examination, recommend only age and risk factor-appropriate cancer screening. In approximately 20% of patients with chronic urticaria, a physical stimulus may be causal. The most common physical urticaria is dermographism (or dermatographism). With dermographism, wheals are created or ‘‘written’’ on the skin by stroking or scratching the skin. A linear response occurs on the skin after stroking because of reﬂex vasoconstriction. This linear response is followed by pruritis, erythema, and a linear wheal. In these patients, the primary stimulus may be dry skin. This leads to pruritis and scratching, which, in the dermographic individual, directly causes hives. Here, the best approach is to hydrate the skin or otherwise interrupt the initiating pruritis. Other physical stimuli include urticaria in response to heat, cold, sunlight, pressure, vibration, and water [17,18]. Some physical urticaria can have varying clinical manifestations [18]. Cholinergic urticaria occurs following exercise or exposure to heat and typically has a distinct clinical presentation involving diﬀuse erythema and elevated, pale monomorphic urticarial lesions that are a few millimeters in diameter. These lesions occur with rise of basal body temperature. In addition, patients with cholinergic urticaria can have more generalized cholinergic manifestations, such as wheezing, salivation, syncope, or lacrimation, although this is unusual [19]. Cold urticaria and solar urticaria usually manifest after exposure to a cold stimulus or sunlight and, in instances of massive total body exposure (eg, swimming, in the case of cold urticaria), hypotension or death can occur [20]. Delayed pressure urticaria usually manifests as angioedema 4 to 6 hours after pressure has been applied (eg, tight clothing, foot swelling after standing, buttock swelling after sitting) [21]. Although avoidance of inciting stimuli can prevent urticaria, this is frequently impossible and pharmacologic therapy is necessary. Urticaria can rarely be a manifestation of a systemic illness. Atypical lesions or associated symptoms may justify a more extensive evaluation. For example, if the hives exhibit a burning quality more than pruritis, last longer than 24 hours, or do not blanch to local pressure, urticarial vasculitis or another dermatologic condition should be suspected [12].

Diﬀerential diagnosis The diﬀerential diagnosis of urticaria includes the subgroups discussed above and in Box 1. Other conditions that may easily be confused with urticaria include diﬀuse pruritis complicated by dermographism, ﬂushing disorders, urticarial vasculitis, urticaria pigmentosa, systemic mastocytosis, exercise-induced anaphylaxis, exercise-induced food-associated anaphylaxis, and idiopathic anaphylaxis. Patients who present with angioedema without urticaria are rare and this should lead to consideration of hereditary angioedema, acquired angioedema, angioedema associated with angiotensin-converting

148

AMAR & DRESKIN

enzyme inhibitors, and primary vascular processes, such as the superior vena cava syndrome. Physical urticarias are usually easily identiﬁed by history, although occasionally there is some confusion. For example, solar urticaria must be distinguished from other types of light sensitivity (eg, from metabolic abnormalities or drug eﬀects). The following speciﬁc conditions may complicate or be confused with urticaria but often have atypical presentations. Urticarial vasculitis is suggested when the hives are more painful than pruritic, last longer than 24 hours, or leave a bruising or discoloration on the skin [12]. Systemic mastocytosis is a rare hyperplastic condition with increased numbers of atypical mast cells in the bone marrow, skin, and other organs. Patients can experience episodic ﬂushing, urticaria pigmentosa, prominent gastrointestinal symptoms, anaphylaxis, or neuropsychiatric symptoms. Urticaria pigmentosa is characterized by distinctive pigmented cutaneous lesions containing nests of mast cells [22,23]. Hereditary angioedema, acquired angioedema, and angioedema associated with angiotensin-converting enzyme inhibitors are characterized by episodic swelling without urticaria and generally are not associated with pruritis. Included in the diﬀerential for physical urticarias are several unusual systemic diseases. For instance, acquired cold urticaria must be distinguished from familial cold autoinﬂammatory syndrome, which is characterized by a cold-induced papular rash (not urticaria) and belongs to the group of hereditary periodic fever syndromes [24,25].

Diagnosis and evaluation Acute Patients are often able to identify a stimulus if the hives occur 5 to 30 minutes after ingestion of a food or drug. If the hives are short-lived or respond rapidly to over-the-counter antihistamines, patients do not typically seek medical care. Patients whose hives occur in the absence of an identiﬁable trigger and are recurrent in nature often come to the attention of physicians. The best initial approach to a patient with urticaria is a thorough history and physical (Fig. 2). History should include details of the hives in relation to medications (including herbals, supplements), foods, physical triggers, infections, occupational exposures, insect stings, and contact exposures as well as a complete review of systems. Physical examination should include at least examination of the skin, lymph nodes, eyes, joints, throat, neck, ears, lungs, heart, and abdomen to detect possible associated conditions [5]. Then, food supplements and drugs that are nonessential should be discontinued. Recently added drugs should be discontinued or replaced with a chemically unrelated agent. Often, no speciﬁc agent is found and the hives are treated symptomatically until they resolve spontaneously.

URTICARIA

149

Fig. 2. Evaluation of urticaria. BMP, basic metabolic panel; CBC, complete blood cell count; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; LFTS, liver function tests; UA, urinalysis.

Chronic As for acute urticaria, evaluation of chronic urticaria begins with a detailed history and physical examination. Because patients often do not have lesions when they are seen in the oﬃce, it is also important to determine if the rash is indeed urticaria before embarking on an extensive

150

AMAR & DRESKIN

evaluation. Not all dermatoses described by patients as hives are really urticaria [26]. The transient nature of the lesions is a good indication that the lesions are indeed urticaria and a photograph taken by the patient can be reassuring. Nonetheless, some skepticism is advised [26]. Key elements in the history are duration of the episodes, duration of individual lesions, nature of the lesions (eg, pruritic, painful), and presence of angioedema. In addition, a thorough medication history, including herbal remedies and supplements, should be taken. Some herbal products associated with urticaria include cranberry, echinacea, hypericum, willow, garlic, ginger, glucosamine, horseradish, phytoestrogen, propolis, royal jelly, and valerian [27,28]. In addition, topical use of herbal soaps may cause urticaria [29]. In approximately 95% of patients with chronic urticaria, neither the patient nor the physician can identify a speciﬁc ingestant or contactant causing hives. This is sometimes diﬃcult for patients and physicians to accept. Therefore, an unnecessarily extensive, invasive, and expensive investigation is pursued without successfully identifying a speciﬁc culprit [30]. Included in a detailed physical examination should be exclusion of possible physical triggers. For instance, for cold-induced urticaria, an ice cube challenge should be done by placing an ice cube on the patient’s skin for 5 minutes. Patients with cold-induced urticaria will develop hives upon rewarming of the skin [20]. Dermatographism can be tested by stroking the skin and observing for linear hives. Pressure-induced urticaria can be tested by applying pressure perpendicular to the skin (eg, a sandbag across the shoulder) and instructing the patient to observe for swelling 4 to 6 hours later. Aquagenic urticaria can be tested by applying water regardless of temperature to the skin. In addition, applying heat, vibration, and UV radiation may rule out other physical urticaria [18]. Although foods and drugs are uncommon causes of acute urticaria, many patients are not satisﬁed until these are ruled out. As in the evaluation of acute urticaria, patients must discontinue all unnecessary food supplements and drugs. Patients can then keep a food diary to identify suspect foods, which can then be eliminated. If patients are highly motivated, a trial of a very restrictive diet of lamb and rice can be implemented for 2 weeks while oﬀ all antihistamines. If the urticaria resolves, foods can be slowly reintroduced into the diet while monitoring for urticaria with the use of a food diary. This method rarely leads to identiﬁcation of a speciﬁc trigger of chronic urticaria in adults. Chronic infections have also been associated with urticaria. For example, Helicobacter pylori gastric infection, tinea pedis, cholecystitis, hepatitis, thyroiditis, sinus infections, and dental abscesses have been associated with urticaria. The association between antithyroid antibodies (antimicrosomal [peroxidase] and antithyroglobulin) that are most commonly seen in Hashimoto’s thyroiditis and chronic urticaria is particularly strong, although urticaria occurs only in a few patients with Hashimoto’s thyroiditis [31]. There are many reports, but no rigorous proof, that treatment of euthyroid

URTICARIA

151

urticaria patients who have antithyroid antibodies with l-thyroxine leads to resolution of the urticaria. In many of these cases, improvement of the urticaria appears to be coincidental. Nonetheless, some specialists do treat these patients with l-thyroxine [32]. In patients with chronic urticaria, some laboratory evaluation is warranted in addition to the history and physical examination. Physicians should obtain a complete blood count with diﬀerential, a basic metabolic panel, liver enzymes, and a urinalysis in all patients with chronic urticaria [5]. Some experts advocate measurements of erythrocyte sedimentation rate, thyrotropin, and antithyroid antibodies (antimicrosomal and antithyroglobulin thyroid antibodies). Most experts agree that further testing should be determined by speciﬁc positive ﬁndings from the history and physical examination [33]. For example, there is no need to obtain an antinuclear antibody titer in a patient with urticaria who has no signiﬁcant rheumatologic complaints or ﬁndings. If patients have atypical lesions or systemic symptoms, a referral to a specialist is appropriate. Additional tests, usually performed in specialty clinics, may be useful in patients with chronic urticaria. Some allergists order immediate hypersensitivity skin tests or IgE RAST tests for foods if the history is suggestive. Approximately 40% of patients with chronic urticaria have evidence of an autoimmune process that may contribute to their hives. An in vitro test for antibodies to the a subunit of the FceRI (FceRIa) can be ordered from specialized immunology laboratories. However, this test has not been approved by the Food and Drug Administration. Evidence of autoimmunity can also be demonstrated by the autologous serum skin test. In this test, a small amount (0.05 mL) of the patient’s serum is injected intradermally into the patient’s own skin (therefore, autologous). If a wheal and ﬂare develops, this is thought to be due to an antibody to either FceRIa or to IgE itself. A positive test may reassure the patient, prevent further anxiety, and avoid unnecessary testing to ﬁnd an external cause [34]. In addition, systemic symptoms may necessitate checking antinuclear antibody titer and complement studies. Lastly, a skin biopsy examined by standard staining and immunoﬂuoresecence can be useful to rule out urticarial vasculitis [12].

Treatment Acute Acute urticaria is generally self-limited. Antihistamines work well in patients with acute urticaria, especially if taken prophylactically (Table 1). First-generation antihistamines, such as diphenhydramine and hydroxyzine, often cause sedation and must be taken three or four times daily to be eﬀective. Second-generation antihistamines, such as cetirizine, fexofenadine, loratidine, and desloratidine, are taken once daily, are better tolerated, and are often eﬀective. Some patients beneﬁt from a second-generation

152

AMAR & DRESKIN

Table 1 Medications for acute urticaria Drug

Recommended dose for adults

H1-antihistamines Chlorpheniramine

Hydroxyzine HCL

4 mg every 4–6 h or sustained-release 8–12 mg every 8–12 h; max: 24 mg/d Initial: 4 mg three times daily; usual: 4–20 mg/d; max: 0.5 mg/kg/d 25–50 mg every 4–6 h; max: 300 mg/24h 25 mg every 6 h

Doxepin

10–150 mg/d

Loratidine

10 mg every day

Fexofenadine

180 mg every day

Cetirizine hydrochloride H2-antihistamines

10 mg every day

Ranitidine Cimetidine Famotidine Antileukotrienes

150 mg twice daily 400 mg twice daily 20 mg twice daily

Montelukast sodium Zaﬁrlukast Steroids

10 mg every day

Cyproheptadine

Diphenhydramine

Prednisone

Comments Mainstay of therapy; grade A recommendation [48–55] Sedating in 50%

Appetite stimulant; best for cold urticaria

Often used at 50 mg three to four times daily; best for cholinergic urticaria H1- and H2-blocking properties; sedating; appetite stimulant; higher doses have antidepressive and anxiolytic eﬀects Second generation; often used in higher doses for urticaria Second generation; often used in higher doses for urticaria Second generation, often used in higher doses for urticaria Not ﬁrst-line therapy; may provide small beneﬁt when used with H1-antihistamines; grade B recommendation [56–58]

Not ﬁrst-line therapy, may provide beneﬁt in combination with antihistamines; supporting evidence in: [59,60]. Opposing evidence in: [48].

20 mg twice daily

1 mg/kg in divided doses initially and quickly taper

Usually very eﬀective; should be used for severe episodes and avoid chronic use if possible; grade A recommendation [61] Flares may occur with cessation of steroids, especially with abrupt cessation

URTICARIA

153

antihistamine daily with a ﬁrst-generation drug given at bedtime for breakthrough symptoms. A brief course of corticosteroids may be needed for severe episodes [35]. Epinephrine (0.3 mL of 1:1000 intramuscularly) rapidly reverses the signs and symptoms of urticaria and angioedema. Patients with life-threatening angioedema or anaphylaxis should always have access to epinephrine and be instructed and prepared to use it if needed. Betablockers can interfere with the action of epinephrine and should be discontinued if it is safe to do so [36]. Chronic Management of chronic urticaria also includes H1-type antihistamines. In most cases of chronic urticaria, additional measures are needed to control symptoms. Some specialists empirically use antihistamines at doses twice those approved by the Food and Drug Administration. However, insurance companies often require prior authorization. Because 15% of the histamine receptors of the skin are of the H2-type, addition of H2-antihistamines (eg, ranitidine or famotidine) may be helpful in treatment of urticaria. Doxepin, a tricyclic antidepressant, has potent H1- and H2-antihistamine activity and can be used as well. The main drawback of this medication, sedation, can often be managed by starting at 10 mg every night and slowly increasing the dose to a maximal antihistamine dose of 75 to 125 mg every night. Additional issues with doxepin include dry mouth, urinary retention, and increased appetite. Mast cells release a variety of mediators in addition to histamine. Thus, antileukotriene medications may be added with some success. Severe symptoms may also require oral steroids to achieve control. However, because of the long-term side eﬀects, chronic use of steroids should be limited when possible [16]. Corticosteroids may be needed in delayed pressure urticaria. Sunscreen and avoidance are the most eﬀective treatments for solar urticaria. A specialized clinic can determine the wavelengths of light aﬀecting the skin and desensitization may be possible. In some instances, speciﬁc H1-type antihistamines may be more eﬃcacious for certain types of urticaria. For example, hydroxyzine is often used for cholinergic urticaria [37] and cyproheptidine for cold-induced urticaria [38,39]. Specialists who see patients with refractory urticaria often use a variety of anti-inﬂammatory, immunomodulatory, and antimetabolic medications [6,40]. Case reports suggest that hydroxychloroquine, nifedipine, sulfasalazine, dapsone, colchicine, cyclosporine, azathioprine, methotrexate, and intravenous immunoglobulin may be useful in selected patients. Of these, only cyclosporine has been shown to be eﬀective in double-blind, placebocontrolled studies [41,42]. Many of these medications are limited by their side eﬀect proﬁles. In addition to medications, prevention plays an important role in the management of urticaria. For instance, patients with physical urticaria

154

AMAR & DRESKIN

can minimize or avoid triggering factors. If a systemic disease is present, the urticaria may improve by treating the underlying disease, as in the case of thyroid disease. Other exacerbating factors that may be modiﬁable for some patients are anxiety, medications (eg, NSAIDs), or cutaneous vasodilatation (eg, from alcohol, hot showers, exercise). Psychosocial stress plays a large part in many patients by exacerbating urticaria, although the mechanism for this is unclear [43]. Overall urticaria patients should be encouraged to accept their illness and focus on achieving symptomatic control with the most eﬀective treatment while minimizing side eﬀects. Prognosis The prognosis of most patients with chronic urticaria is excellent. Although the data are variable depending upon the population studied, spontaneous resolution occurs within 12 months in up to half of patients. Within 5 years, approximately 20% of patients have resolution [5,6]. Others can have symptoms lasting decades. Most patients are well managed with nonsedating antihistamines and few patients require additional systemic immunomodulatory medications. Patients who had chronic urticaria with resolution may experience a recurrence after several years. Patients with physical urticaria, those with autoimmune urticaria, and those with a signiﬁcant component of pressureinduced urticaria have a more severe clinical course [44–46]. Summary Urticaria has been referred to as a ‘‘vexing’’ problem and remains so for both patients and physicians [47]. Acute urticaria is typically due to a hypersensitivity reaction while chronic urticaria has a more complex pathogenesis. Antihistamines remain the mainstay of symptomatic treatment for both. In severe cases, referral to a specialist is prudent for determining a speciﬁc cause when possible, maximizing control of the disease with fewer medications, and considering the use of more potent immunomodulatory medications. Further research is needed to elucidate the pathogenesis of ‘‘idiopathic’’ urticaria and to develop safe and eﬀective agents for this disease. References [1] [2] [3] [4]

Greaves M. Chronic urticaria. J Allergy Clin Immunol 2000;105:664–72. Greaves MW. Chronic urticaria. N Engl J Med 1995;332:1767–72. Weldon DR. Quality of life in patients with urticaria. Allergy Asthma Proc 2006;27:96–9. Kaplan AP. Urticaria and angioedema. In: Adkinson NF, Yunginger JW, Busse WW, et al, editors. Middleton’s allergy: principles and practice, vol. 2. Sixth edition. Philadelphia: Mosby; 2003. p. 1537–58. [5] The diagnosis and management of urticaria: a practice parameter part I: acute urticaria/angioedema part II: chronic urticaria/angioedema. Joint Task Force on Practice Parameters. Ann Allergy Asthma Immunol 2000;85:521–44.

URTICARIA

155

[6] Kozel MM, Sabroe RA. Chronic urticaria: aetiology, management and current and future treatment options. Drugs 2004;64:2515–36. [7] Jacques P, Lavoie A, Bedard PM, et al. Chronic idiopathic urticaria: proﬁles of skin mast cell histamine release during active disease and remission. J Allergy Clin Immunol 1992;89: 1139–43. [8] Maxwell DL, Atkinson BA, Spur BW, et al. Skin responses to intradermal histamine and leukotrienes C4, D4, and E4 in patients with chronic idiopathic urticaria and in normal subjects. J Allergy Clin Immunol 1990;86:759–65. [9] Natbony SF, Phillips ME, Elias JM, et al. Histologic studies of chronic idiopathic urticaria. J Allergy Clin Immunol 1983;71:177–83. [10] Elias J, Boss E, Kaplan AP. Studies of the cellular inﬁltrate of chronic idiopathic urticaria: prominence of T-lymphocytes, monocytes, and mast cells. J Allergy Clin Immunol 1986;78: 914–8. [11] Sabroe RA, Poon E, Orchard GE, et al. Cutaneous inﬂammatory cell inﬁltrate in chronic idiopathic urticaria: comparison of patients with and without anti-FceRI or anti-IgE autoantibodies. J Allergy Clin Immunol 1999;103:484–93. [12] Davis MD, Brewer JD. Urticarial vasculitis and hypocomplementemic urticarial vasculitis syndrome. Immunol Allergy Clin North Am 2004;24:183–213, vi. [13] Lack G, Fox D, Northstone K, et al. Factors associated with the development of peanut allergy in childhood. N Engl J Med 2003;348:977–85. [14] Goodman DL, McDonnell JT, Nelson HS, et al. Chronic urticaria exacerbated by the antioxidant food preservatives, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). J Allergy Clin Immunol 1990;86:570–5. [15] Zembowicz A, Mastalerz L, Setkowicz M, et al. Safety of cyclooxygenase 2 inhibitors and increased leukotriene synthesis in chronic idiopathic urticaria with sensitivity to nonsteroidal anti-inﬂammatory drugs. Arch Dermatol 2003;139:1577–82. [16] Kaplan AP. Chronic urticaria: pathogenesis and treatment. J Allergy Clin Immunol 2004; 114:465–74 [quiz 475]. [17] Wong RC, Fairley JA, Ellis CN. Dermographism: a review. J Am Acad Dermatol 1984;11: 643–52. [18] Dice JP. Physical urticaria. Immunol Allergy Clin North Am 2004;24:225–46. [19] Hirschmann JV, Lawlor F, English JS, et al. Cholinergic urticaria. A clinical and histologic study. Arch Dermatol 1987;123:462–7. [20] Wanderer AA. Cold urticaria syndromes: historical background, diagnostic classiﬁcation, clinical and laboratory characteristics, pathogenesis, and management. J Allergy Clin Immunol 1990;85:965–81. [21] Earley KW, Haag JR, Pontes O, et al. Gateway-compatible vectors for plant functional genomics and proteomics. Plant J 2006;45:616–29. [22] Golkar L, Bernhard JD. Mastocytosis. Lancet 1997;349:1379–85. [23] Brockow K. Urticaria pigmentosa. Immunol Allergy Clin North Am 2004;24:287–316. [24] Hoﬀman HM, Mueller JL, Broide DH, et al. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinﬂammatory syndrome and Muckle-Wells syndrome. Nat Genet 2001;29:301–5. [25] Wanderer AA, Hoﬀman HM. The spectrum of acquired and familial cold-induced urticaria/ urticaria-like syndromes. Immunol Allergy Clin North Am 2004;24:259–86. [26] Weldon D. When your patients are itching to see you: not all hives are urticaria. Allergy Asthma Proc 2005;26:1–7. [27] Mullins RJ, Heddle R. Adverse reactions associated with echinacea: the Australian experience. Ann Allergy Asthma Immunol 2002;88:42–51. [28] Dibbern DA Jr. Urticaria: selected highlights and recent advances. Med Clin North Am 2006;90:187–209. [29] Knight TE, Hausen BM. Melaleuca oil (tea tree oil) dermatitis. J Am Acad Dermatol 1994; 30:423–7.

156

AMAR & DRESKIN

[30] Kozel MM, Mekkes JR, Bossuyt PM, et al. The eﬀectiveness of a history-based diagnostic approach in chronic urticaria and angioedema. Arch Dermatol 1998;134:1575–80. [31] Leznoﬀ A, Josse RG, Denburg J, et al. Association of chronic urticaria and angioedema with thyroid autoimmunity. Arch Dermatol 1983;119:636–40. [32] Dreskin SC, Andrews KY. The thyroid and urticaria. Curr Opin Allergy Clin Immunol 2005; 5:408–12. [33] Dibbern D, Dreskin S. Urticaria and angioedema: an overview. Immunol Allergy Clin North Am 2004;24:141–62. [34] Yasnowsky K, Dreskin SC, Efaw B, et al. Chronic urticaria sera increas basophil CD203c surface expression. J Allergy Clin Immunol 2006;117:1430–4. [35] Kaplan AP. Clinical practice. Chronic urticaria and angioedema. N Engl J Med 2002;346: 175–9. [36] Howard PJ, Lee MR. Beware beta-adrenergic blockers in patients with severe urticaria! Scott Med J 1988;33:344–5. [37] Davis RS, Remigio LK, Schocket AL, et al. Evaluation of a patient with both aquagenic and cholinergic urticaria. J Allergy Clin Immunol 1981;68:479–83. [38] Sigler RW, Evans R 3rd, Horakova Z, et al. The role of cyproheptadine in the treatment of cold urticaria. J Allergy Clin Immunol 1980;65:309–12. [39] Wanderer AA, St Pierre JP, Ellis EF. Primary acquired cold urticaria. Double-blind comparative study of treatment with cyproheptadine, chlorpheniramine, and placebo. Arch Dermatol 1977;113:1375–7. [40] Shiekh J. Advances in the treatment of chronic urticaria. Immunol Allergy Clin North Am 2004;24:317–34. [41] Grattan CE, O’Donnell BF, Francis DM, et al. Randomized double-blind study of cyclosporin in chronic ‘idiopathic’ urticaria. Br J Dermatol 2000;143:365–72. [42] Vena GA, Cassano N, Colombo D, et al. Cyclosporine in chronic idiopathic urticaria: a double-blind, randomized, placebo-controlled trial. J Am Acad Dermatol 2006;55:705–9. [43] Shertzer CL, Lookingbill DP. Eﬀects of relaxation therapy and hypnotizability in chronic urticaria. Arch Dermatol 1987;123:913–6. [44] O’Donnell BF, Lawlor F, Simpson J, et al. The impact of chronic urticaria on the quality of life. Br J Dermatol 1997;136:197–201. [45] Kozel MM, Mekkes JR, Bossuyt PM, et al. Natural course of physical and chronic urticaria and angioedema in 220 patients. J Am Acad Dermatol 2001;45:387–91. [46] Sabroe RA, Seed PT, Francis DM, et al. Chronic idiopathic urticaria: comparison of the clinical features of patients with and without anti-FceRI or anti-IgE autoantibodies. J Am Acad Dermatol 1999;40:443–50. [47] Sheldon JM, Mathews KP, Lovell RG. The vexing urticaria problem: present concepts of etiology and management. J Allergy 1954;25:525–60. [48] Di Lorenzo G, Pacor ML, Mansueto P, et al. Randomized placebo-controlled trial comparing desloratadine and montelukast in monotherapy and desloratadine plus montelukast in combined therapy for chronic idiopathic urticaria. J Allergy Clin Immunol 2004;114:619–25. [49] Finn AF Jr, Kaplan AP, Fretwell R, et al. A double-blind, placebo-controlled trial of fexofenadine HCl in the treatment of chronic idiopathic urticaria. J Allergy Clin Immunol 1999; 104:1071–8. [50] Kalivas J, Breneman D, Tharp M, et al. Urticaria: clinical eﬃcacy of cetirizine in comparison with hydroxyzine and placebo. J Allergy Clin Immunol 1990;86:1014–8. [51] Brunet C, Bedard PM, Hebert J. Eﬀects of H1-antihistamine drug regimen on histamine release by nonlesional skin mast cells of patients with chronic urticaria. J Allergy Clin Immunol 1990;86:787–93. [52] Grant JA, Bernstein DI, Buckley CE, et al. Double-blind comparison of terfenadine, chlorpheniramine, and placebo in the treatment of chronic idiopathic urticaria. J Allergy Clin Immunol 1988;81:574–9.

URTICARIA

157

[53] Fox RW, Lockey RF, Bukantz SC, et al. The treatment of mild to severe chronic idiopathic urticaria with astemizole: double-blind and open trials. J Allergy Clin Immunol 1986;78: 1159–66. [54] Goldsobel AB, Rohr AS, Siegel SC, et al. Eﬃcacy of doxepin in the treatment of chronic idiopathic urticaria. J Allergy Clin Immunol 1986;78:867–73. [55] Bernstein IL, Bernstein DI. Eﬃcacy and safety of astemizole, a long-acting and nonsedating H1 antagonist for the treatment of chronic idiopathic urticaria. J Allergy Clin Immunol 1986;77:37–42. [56] Simons FE, Sussman GL, Simons KJ. Eﬀect of the H2-antagonist cimetidine on the pharmacokinetics and pharmacodynamics of the H1-antagonists hydroxyzine and cetirizine in patients with chronic urticaria. J Allergy Clin Immunol 1995;95:685–93. [57] Harvey RP, Wegs J, Schocket AL. A controlled trial of therapy in chronic urticaria. J Allergy Clin Immunol 1981;68:262–6. [58] Monroe EW, Cohen SH, Kalbﬂeisch J, et al. Combined H1 and H2 antihistamine therapy in chronic urticaria. Arch Dermatol 1981;117:404–7. [59] Bagenstose SE, Levin L, Bernstein JA. The addition of zaﬁrlukast to cetirizine improves the treatment of chronic urticaria in patients with positive autologous serum skin test results. J Allergy Clin Immunol 2004;113:134–40. [60] Erbagci Z. The leukotriene receptor antagonist montelukast in the treatment of chronic idiopathic urticaria: a single-blind, placebo-controlled, crossover clinical study. J Allergy Clin Immunol 2002;110:484–8. [61] Pollack CV Jr, Romano TJ. Outpatient management of acute urticaria: the role of prednisone. Ann Emerg Med 1995;26:547–51.

Prim Care Clin Office Pract 35 (2008) 159–173

Immunodeﬁciency Overview Yoshikazu Morimoto, MD, PhDa,*, John M. Routes, MDb a

Division of Allergy and Immunology, Department of Medicine, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA b Section of Allergy and Clinical Immunology, Medical College of Wisconsin, 9000 West Wisconsin Avenue, Suite 408, Milwaukee, WI 53226, USA

Primary immunodeﬁciencies (PIDs) occur in more than 1 in 2000 live births. These diseases are challenging in primary care settings where clinicians often encounter patients with a history of recurrent infection. It has been repeatedly documented that the diagnosis of PIDs is prone to be delayed because of their underrecognition. For example, it has been reported that the diagnosis of common variable immunodeﬁciency (CVID) took more than 10 years in 22.4% of the patients after the ﬁrst presentation of the symptoms [1]. Delay in diagnosis and inadequate treatment often result in irreversible complications and even death. Although many cases go undiagnosed, there are also many instances where incorrect diagnosis results in years of inappropriate treatment and failure to implement beneﬁcial treatment [2]. Making a correct diagnosis of PIDs in a timely fashion is crucial to limit their mortality and morbidity. The ﬁrst immunodeﬁciency disease, Bruton’s agammaglobulinemia (or X-linked agammaglobulinemia), was identiﬁed by Bruton [3] in 1952. Since then, more than 150 PIDs have been described. PIDs have helped clinicians understand the normal function of the immune system. In the 1960s, immunodeﬁciency disorders were categorized into those disorders that involved defects in humoral immunity and those disorders that involved defects in cell-mediated immunity [4]. Classiﬁcations of PIDs have become more complex (eg, humoral immunodeﬁciency, cellular immunodeﬁciency, combined immunodeﬁciency, phagocytic defects, and complement deﬁciency), reﬂecting an increasing array of PIDs that have been identiﬁed. Among PIDs,

* Corresponding author. E-mail address: [email protected] (Y. Morimoto). 0095-4543/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2007.09.004 primarycare.theclinics.com

160

MORIMOTO & ROUTES

antibody (humoral) deﬁciency is the most common, accounting for approximately half of all patients with PIDs [5]. This article overviews the diagnosis and treatment of PIDs. To describe speciﬁc immunodeﬁciency disorders further, two of the most common PIDs in primary care settings have been selected: selective IgA deﬁciency and CVID. Information that is not covered in this article can be obtained in updated classiﬁcations by an international committee of experts [4]. A published practice parameter also provides information for the diagnosis and management of PIDs [5]. Diagnosis of primary immunodeﬁciencies A general approach for the diagnosis of PIDs is shown in Fig. 1 [5]. The diagnosis of immunodeﬁciency begins with suspecting immunodeﬁciency disorders. The clinical spectrum of PIDs is broad, and the onset of clinical symptoms may be relatively minor. For example, immunodeﬁciency should be suspected if clinicians encounter a patient who has infections that do not completely clear with treatment or infections that require antibiotics treatment for longer than usual. In all cases, the possibility of secondary immunodeﬁciency underlying the patient’s illness should be ruled out, such as

Suspected primary immunodeficiency

Sinopulmonary bacterial infections only?

Emergency! Proceed immediately to referral

No

Yes c.

SCID a possibility? No

Yes

Is there an antibody deficiency?

Are there: a. Neisserial infections? b. Abscesses and/or fungi? c. i. Atypical mycobacteria? ii. Disseminated infection? iii. Opportunistic infection? a.

No

b.

Is there complement deficiency?

No

Is there a phagocyte defect?

No

Is there a cellular or combined defect?

Yes

Yes

Yes

No

Yes

Undefined immunodeficiency or other problem Proceed to referral/therapy

Fig. 1. General approach for the diagnosis of primary immunodeﬁciency. SCID, severe combined immunodeﬁciency. (Adapted from Bonilla FA, Bernstein IL, Khan DA, et al. Practice parameter for the diagnosis and management of primary immunodeﬁciency. Ann Allergy Asthma Immunol 2005;94(5 Suppl 1):S1–63; with permission.)

IMMUNODEFICIENCY OVERVIEW

161

from medications (eg, corticosteroids or other immunosuppressive medications) or infection (eg, HIV). Antibody deﬁciency, the most frequently encountered type of immunodeﬁciency, commonly presents with sinopulmonary bacterial infections. In severe forms of antibodies deﬁciencies, such as CVID, chronic lung disease, particularly bronchiectasis, is a common problem, leading to frequent hospitalizations [6]. Gastrointestinal diseases, malignancy, and autoimmune diseases are also relatively common in many of the PIDs including CVID. To identify and treat the immunodeﬁciency eﬀectively, it is important to conﬁrm the site of infection and organism whenever possible, because some forms of PIDs may present with distinct infectious complications. For example, speciﬁc defect in cell-mediated immunity may present with recurrent infections with pathogens that replicate intracellularly, such as mycobacteria or salmonella. In a case with natural killer cell dysfunction, recurrent severe herpesvirus infection may be observed. Terminal complement component deﬁciencies may be suggested by neisserial infections [5]. Infants or children with Pneumocystis carinii infection suggest complex defects that include signiﬁcant cellular immune dysfunction, such as hyper-IgM syndrome or severe combined immunodeﬁciency (SCID) [7]. The diagnosis of phagocytic defect (eg, chronic granulomatous disease [CGD]) should be considered in patients with cutaneous and deep-seated abscesses with catalase-positive organisms, such as Staphylococcus aureus. For primary care physicians, it is critical immediately to refer patients with suspected SCID to specialists to prevent severe complications and expedite bone marrow transplant (BMT) treatment [5]. Clinical presentation of SCID includes recurrent severe infection, failure to thrive, developmental delay, or absence of lymphadenopathy (or tonsillar tissue) despite serious infections. For evaluation of the patient’s immune system, screening tests are performed followed by more complex tests as indicated (Table 1) [8]. This approach ensures eﬃcient and thorough evaluation. Speciﬁc screening tests of immune function should be ordered based on history and physical examination. A complete blood count with diﬀerential should be performed on all patients. Quantitative immunoglobulin levels (IgG, IgA, and IgM) in serum should be measured on most patients, because the antibody deﬁciencies are the most common type of PIDs. A deﬁciency in one or more of serum immunoglobulin levels warrants referral to a clinical immunologist for deﬁnitive diagnosis. Further diagnostic studies are often helpful in the diagnosis of humoral immunity. For example, studies to determine the ability to make speciﬁc antibodies to protein antigens and polysaccharide antigens are typically performed. Absence of antibody responses to protein antigens, compared with polysaccharide antigens, may suggest more profound immunodeﬁciency [9]. To measure antibody responses to polysaccharide antigens, the pneumococcal vaccine without carrier proteins is often used. Of note,

162

MORIMOTO & ROUTES

Table 1 Screening tests for immune function Immune function

Enumeration/ﬂow cytometry

Functional tests

Cellular immunity

CBC with diﬀerentiala Enumeration of T cells (CD3) and NK cells (CD16 and CD56) Enumeration of B cells (CD19 or CD20)

Cutaneous delayed hypersensitivity Enzyme assays (ADA, PNP) FISH for 22q11 and 10p11 deletion NK cell cytolysis assay IgG, IgA, IgM levels Antibody response to immunization Oxidase function (NBT, DHR, chemiluminescence) Enzyme assays (MPO, G6PD) Phagocyte function AH50 (alternative pathway) CH50 (classical pathway)

B cells

PMN

CBC with diﬀerential LFA-1

Complement

Abbreviations: ADA, adenosine deaminase; CBC, complete blood count; DHR, dihydrorhodamine; FISH, ﬂuorescence in situ hybridization; G6PD, glucose-6-phosphate dehydrogenase; LFA-1, lymphocyte function antigen 1; MPO, myeloperoxidase; NK, natural killer; NPT, nitroblue tetrazolium; PMN, polymorphonuclear leukocytes; PNP, purine nucleoside 3 phosphorylase. a Preferred initial screening tests are underlined. Adapted from Folz RJ, Routes JM. Pulmonary complications of organ transplantation and primary immunodeﬁciencies. In: Mason RJ, Murray JF, Broaddus VC, et al, editors. Textbook of respiratory medicine. 4th edition. Philadelphia: Elsevier; 2005. p. 2165; with permission.

antibody responses to polysaccharide vaccines are not as useful in infants. Delays in the maturation of the immune system may result in the decreased ability to make antibodies to polysaccharide antigens up to age 5 [10]. Determination of antibody titers to diphtheria and tetanus toxoids is helpful to determine antibody responses to protein antigens. Antibody titers are determined before and 3 to 4 weeks postimmunization. Based on the results of the screening tests, further testings may be indicated, such as cellular immunity assays, lymphocyte subset analysis, and enzyme assays [10]. For example, profound hypogammaglobulinemia with serum IgG levels less than 200 to 300 mg/dL (or 100 mg/dL in an infant) should lead to the evaluation of cellular immune function and lymphocyte subset analysis [5]. Importantly, the basic screening test may not show signiﬁcant abnormalities in some cases of PIDs (eg, selective cellular immune defect or natural killer cell dysfunction) [5]; therefore, referral to a clinical immunologist is essential when the index of suspicion for immunodeﬁciency is high. In patients with abnormalities of humoral immunity, such as CVID or X-linked agammaglobulinemia, frequently performed tests in primary care settings that use speciﬁc antibody responses are inaccurate and may lead to false-negative results. Examples include serologic studies to detect infection to hepatitis A, hepatitis B, or HIV-1. Conversely, patients who remain seronegative despite evidence supporting the infection may need a work-up

IMMUNODEFICIENCY OVERVIEW

163

for an underlying immunodeﬁciency [11]. Patients with IgA deﬁciency may have false-positive serum pregnancy tests (b human chorionic gonadotropin assays) because of the presence of heterophile antibodies [12]. Signiﬁcant advances in the ﬁeld of immunodeﬁciency in the past decade include identiﬁcation of many associated genetic abnormalities. The molecular bases for many of the common PIDs have been identiﬁed [13]. The identiﬁcation and characterization of the gene defects in PIDs allow for a more complete understanding of the molecular basis of PIDs and lead to new strategies to treat successfully the speciﬁc disorder. Diagnosis at the genetic or molecular level is always desirable for several reasons: to establish unequivocal diagnosis, to permit accurate genetic counseling, to deﬁne better the genotype-phenotype associations, and for the best therapy of speciﬁc disorders now and in the future when gene-speciﬁc therapies may be available [5]. Treatment of primary immunodeﬁciencies General considerations for therapy of PIDs are shown in Fig. 2 [5]. Bone marrow transplant or stem cell transplant BMT and stem cell transplant (SCT) should be pursued expeditiously for SCID. BMT-SCT is the primary treatment of choice for SCID and is an alternative therapy for other PIDs, such as phagocyte defects (eg, CGD). Use of HLA-identical related donors is associated with the best prognosis. In one study, 92.3% of SCID patients survived after HLA-identical related donors BMT, whereas 80.5% survived after HLA-matched unrelated donors BMT, and 52.5% survived after HLA-mismatched related donors BMT [14]. In most cases, successful BMT-SCT led to excellent immune reconstitution with normal cellular and humoral immunity. Again, early diagnosis and immediate referral for BMT-SCT treatment is critical for patients with SCID, because it is associated with signiﬁcantly better outcome. Immunoglobulin replacement therapy Intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) is the treatment of choice for patients with signiﬁcant abnormalities in humoral immunity. IVIG or SCIG preparations are fractionated from a plasma pool of several thousand donors. It contains neutralizing antibodies against numerous bacterial and viral pathogens, reﬂecting the immunologic experience of the donor population [15]. Several studies have demonstrated that the administration of immunoglobulins, either subcutaneously or intravenously, reduces the frequency and severity of these viral and bacteria infections and markedly improves the morbidity and mortality in patients with humoral immunodeﬁciency. For example, regular IVIG therapy was shown to have signiﬁcantly reduced the incidence of pneumonia

164

MORIMOTO & ROUTES

SCID

Agammaglobulinemia and CVID

IVIG or SCIG

BMT/SCT (gene therapy)

Other humoral immunodeficiency

Antimicrobial prophylaxis

Immunization

Yes No

Significant antibody deficiency?

Complement or phagocyte defects

Cellular or nonSCID combined immunodeficiency

Fig. 2. General considerations for treatment of primary immunodeﬁciency. BMT, bone marrow transplant; CVID, common variable immunodeﬁciency; IVIG, intravenous immunoglobulin; SCID, severe combined immunodeﬁciency; SCIG, subcutaneous immunoglobulin; SCT, stem cell transplant. (Adapted from Bonilla FA, Bernstein IL, Khan DA, et al. Practice parameter for the diagnosis and management of primary immunodeﬁciency. Ann Allergy Asthma Immunol 2005;94(5 Suppl 1):S1–63; with permission.)

and hospital admission caused by infections in patients with CVID. One study showed that after starting treatment with IVIG (mean treatment period, 41.5 35.4 months), the annual incidence of pneumonia decreased from 80.5% to 34.6% and the rate of hospitalization from 88.5% to 46%. The incidence of pneumonia requiring treatment or hospitalization fell from 3.4 to 0.7 per year [16]. When immunoglobulin replacement therapy is begun, clinicians should continue to follow patients closely, because the maximal beneﬁcial eﬀects of IVIG or SCIG may be delayed in the ﬁrst year of therapy [17]. SCIG infusion is increasingly recognized as an eﬃcacious alternative to IVIG immunoglobulin [18]. Patients with serious side effects to previous IVIG therapy or blood transfusions can be safely treated with SCIG [19]. IVIG or SCIG is generally not appropriate for selective cellular, complement, or phagocyte defects. IVIG is indicated for SCID patients before BMT-SCT, however, and until a normal humoral immune status after BMT-SCT [5]. Antimicrobial treatment Antimicrobial therapy should be instituted early in patients with manifestations of infection. Appropriate cultures should be obtained whenever

IMMUNODEFICIENCY OVERVIEW

165

possible because opportunistic or unusual pathogens frequently cause infection in patients with PIDs. The choices and doses of antibiotics for a speciﬁc infection usually are similar to those used in immunocompetent patients, but therapy is frequently given for a longer duration. Prophylactic antibiotics are sometimes indicated for any pathogens to which the host is susceptible [5,10]. For example, patients with hyper-IgM syndrome are often prophylactically treated with trimethoprim-sulfamethoxazole, because such patients are susceptible to P carinii pneumonia. Also, for patients with signiﬁcant cellular immune defect, administration of P carinii pneumonia prophylaxis is indicated until T-cell function is restored by BMT-SCT or other therapy. Antimicrobial prophylaxis is essential for phagocyte defects and may be considered for complement deﬁciencies [5]. Immunization Immunization is also to be considered where appropriate. Inactivated or subunit vaccines may be administered to immunocompromised patients. Live vaccines should not be administered to patients with signiﬁcant cellular immunodeﬁciency. In general, decisions regarding the immunization of patients with PIDs should be addressed by the clinical immunologist. Other therapy Enzyme-replacement therapy can be used in an autosomal-recessive form of SCID caused by adenosine deaminase deﬁciency. Adenosine deaminase deﬁciency was the ﬁrst human enzyme deﬁciency eﬀectively treated with enzyme replacement [20]. The polyethylene glycol–conjugated adenosine deaminase has been used in over 150 patients worldwide. Overall, approximately two thirds of patients treated with polyethylene glycol–conjugated adenosine deaminase have survived, with most patients showing good clinical improvement [21]. Gene therapy has cured patients with X-linked SCID, adenosine deaminase deﬁciency, and X-linked CGD [22,23]. The ﬁrst successful human gene therapy for genetic disease occurred in males with mutations in the gene coding for the common g chain of the interleukin-2 receptor, which accounts for nearly 50% of SCID (X-linked SCID) [24]. More recently nine patients with SCID caused by adenosine deaminase deﬁciency were treated with gene therapy. Early results of this study suggest that the treatment is safe and that most have shown reconstitution of cellular and humoral immune function [21]. Gene therapy for two patients with X-linked CGD also resulted in a threefold to fourfold improvement of phagocytic cell function [23]. Despite these successful cases, the safety of the gene therapy has not yet been established. For example, three of the patients with X-linked SCID who were treated with gene therapy developed leukemia and one died. Genetic analysis of the leukemia in all three patients indicated a common molecular event. The retroviral vector inserted into the chromosome

166

MORIMOTO & ROUTES

and activated the transcription of LMO-2, a proto-oncogene whose increased expression led to the malignant transformation [25]. Studies are ongoing to improve the safety and eﬃcacy of gene therapy speciﬁcally to treat patients with PIDs who have mutations in a speciﬁc gene. Other treatments for PIDs, such as interferon-g treatment for CGD [26] and thymus transplantation for DiGeorge syndrome [27], are beyond the scope of this article.

Selective IgA deﬁciency Selective IgA deﬁciency is the most common PID, characterized by significant decrease (!10 mg/dL) or total absence of the IgA in the serum and secretions. The prevalence in whites is estimated around 1 in 300 to 500 live births. Because most of the patients are clinically asymptomatic, many people with this disease are unaware of its presence. It is unclear why some patients present with almost no symptoms and others with significant clinical symptoms. The lack of speciﬁc antibody responses, deﬁciency of IgG subclasses, or mannose-binding lectin has been reported to be associated with a clinically severe presentation [28,29]. Predominant symptoms of the selective IgA deﬁciency include sinopulmonary and gastrointestinal infections: this can be easily understood from the role of IgA in protecting the mucosal surface. The molecular basis for selective IgA deﬁciency is unknown. B cells from such patients, however, exhibit a defect of terminal B cell diﬀerentiation and do not mature into IgA-producing plasma cells. Selective IgA deﬁciency and CVID in some cases seem to be closely related diseases. Although uncommon, there are extended families with IgA deﬁciency and CVID, suggesting a common molecular basis. Unlike CVID, however, selective IgA deﬁciency makes speciﬁc antibodies in response to immunization or infection and does not exhibit signiﬁcant T-cell abnormalities, which frequently are present in patients with CVID [30]. These diﬀerences likely explain why the clinical course of selective IgA deﬁciency is more benign and lacks serious complications seen in patients with CVID, such as multisystemic granulomatous disease and malignancies. Complications of selective IgA deﬁciency There have been many diseases reported in association with selective IgA deﬁciency, particularly autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, and immune thrombocytopenic purpura. Allergies (eg, asthma or food allergy) are also more common among individuals with selective IgA deﬁciency. Celiac disease is also more common than in the general population. This disease has special signiﬁcance because it is usually diagnosed by detection of speciﬁc IgA antibodies that are lacking in patients with selective IgA deﬁciency [29].

IMMUNODEFICIENCY OVERVIEW

167

Treatment for selective IgA deﬁciency There is no speciﬁc treatment for patients with symptomatic selective IgA deﬁciency. Antibiotics are prescribed in those with acute infections. A significant proportion of IgA-deﬁcient individuals are reported to have anti-IgA antibodies in their serum. Blood or blood products given to IgA-deﬁcient individuals have been associated with severe, even fatal, transfusion reactions, but such reactions rarely occur [29].

Common variable immunodeﬁciency The prevalence of CVID is estimated about 1 in 25,000 to 50,000 people. Although the incidence of CVID is far less than that of selective IgA deﬁciency, CVID is the most common PID to require the regular care of a clinical immunologist. CVID is a heterogenous syndrome characterized by antibody deﬁciency and a decrease in serum IgG (and IgA, IgM) more than 2 SD below the mean for age. Typically, serum IgG level is less than 400 mg/dL and antigen-speciﬁc antibody responses are absent or reduced. In most cases the diagnosis of CVID is made during adulthood; the main clinical features of CVID are recurrent infections, especially respiratory and gastrointestinal tract infections. In one medical center, at onset of CVID, 67.2% of patients presented recurrent respiratory infections, 50% had infections of the lower respiratory tract, and 39.6% of the patients had gastroenteric infections [1]. Because CVID is a humoral immunodeﬁciency, its pathogenesis is considered to be primarily based on abnormalities of B cells. The precise immunodefect is still unclear, however, despite extensive research eﬀorts. Among others, memory B-cell population, characterized by CD27 expression, seems to play an important role in determining clinical features in CVID. Decreases in speciﬁc memory B-cell populations, known as ‘‘switched memory B cells,’’ are associated with more severe clinical complications in CVID [31]. CVID patients with decreased percentages of switched memory B cells have lower levels of serum IgG, less eﬀective pneumococcal vaccine antibody responses, and higher rates of clinical complications including autoimmune and granulomatous disease [32,33]. CVID also has been associated with cellular abnormalities, including proliferative defects, accelerated T-cell apoptosis, insuﬃcient production of interleukin-2 and -10, polarized Th-1–type response, and dendritic cell dysfunction [34]. CVID is considered a combination of humoral and cell-mediated deﬁciency, which explains not only why so many systems are aﬀected but also why standard therapy with IVIG is not always eﬀective [35]. In a small percentage of patients with CVID, the genetic defects have been deﬁned. Since 2003, four genetic mutations have been described in CVID patients: (1) inducible costimulatory receptor (ICOS), (2) transmembrane activator and calcium-modulator and cyclophilin-ligand interactor

168

MORIMOTO & ROUTES

(TACI), (3) B-cell activating factor belonging to the TNF family receptor (BAFF-R), and (4) CD19. The ﬁrst identiﬁed genetic defect speciﬁc to CVID was the ICOS deﬁciency. The homozygous deletion of the ICOS, a costimulatory T-cell molecule, causes results in the clinical phenotype described for CVID with a profound hypogammaglobulinemia and a disturbed B-cell homeostasis. Although human ICOS deﬁciency serves as a monogenic model for this complex syndrome [36], it only accounts for less than 1% of the CVID patients. Worldwide, there are now a total of nine patients diagnosed with ICOS deﬁciency most likely caused by a common founder [37]. TACI and BAFF-R, a member of the tumor necrosis factor receptor superfamily, are involved in the regulation of B-cell homeostasis and diﬀerentiation [38,39]. Mutations in the TACI were found to be present in 10% to 20% of patients with CVID. BAFF-R mutations were found in a patient with CVID and an unaﬀected relative [40]. Homozygous CD19 mutations have been reported in two families with CVID [39]. Despite the recent signiﬁcant advances in identiﬁcation of the aﬀected genes in CVID, genetic abnormalities have been associated with less than 15% to 25% of cases with CVID. Many distinct genetic abnormalities are likely responsible for this very heterogenous disease [41,42]. The identiﬁcation of these genetic abnormalities, however, shows the importance of the impaired terminal B-cell differentiation in pathogenesis of CVID. Further research will help unravel the intricate pathogenesis of CVID. Complications of common variable immunodeﬁciency To reduce the morbidity associated with immunodeﬁciency including CVID, there needs to be greater awareness of pulmonary complications. The most commonly observed pulmonary abnormalities in patients with CVID are bronchiectasis, probably from recurrent or chronic infection [43–45]. Early involvement by a clinical immunologist is essential to monitor lung function and initiate optimal therapy, to minimize the occurrence and progression of lung damage [46]. A normal chest radiograph does not exclude signiﬁcant pulmonary parenchymal disease and high-resolution CT scan should be part of the evaluation of all patients with immunodeﬁciency [43]. Pulmonary function tests may be abnormal in patients with a normal chest radiograph [10,43]. Complete pulmonary function tests and high-resolution CT scan of the chest should be performed at the time of diagnosis, and depending on the initial studies, periodically thereafter [47,48]. Other important complications of CVID include multisystemic granulomatous diseases, autoimmune disorders, splenomegaly, and certain malignancies [49]. Multisystemic granulomatous disease and lymphoproliferative disease (eg, B-cell lymphoma) are well-documented complications of CVID, and their presence is associated with signiﬁcant morbidity and early mortality [43,50]. In particular, granulomatous lung disease is common in patients with

IMMUNODEFICIENCY OVERVIEW

169

CVID. Patients who have CVID and granulomatous lung disease are at high risk for early mortality and B-cell lymphomas [43]. Although the lung is the most common organ system aﬀected, granulomas are also found frequently in other organs, including skin, liver, spleen, and the gastrointestinal tract. Infection with human herpes virus type 8 has been suggested to be an important factor in the pathogenesis of the granulomatous lung diseases and lymphoproliferative disorders in patients with CVID [51]. Gastrointestinal complications are also common in patients with CVID. In one study, 48% of CVID patients had gastrointestinal complaints. The most common symptom was chronic diarrhea [52]. Patients with CVID are more prone to infection with gastrointestinal pathogens, such as giardia, campylobacter, and other organisms. Infection must carefully be excluded as a cause of diarrhea. CVID patients can also develop an idiopathic inﬂammatory bowel disease, and ulcerative colitis and Crohn’s disease are more common in patients with CVID. The T cell–mediated defects of this immunodeﬁciency disorder are thought to contribute to the pathogenesis of these gastrointestinal disorders in CVID. IVIG alone is ineﬀective, and therapy with other immunomodulators may be needed to treat these gastrointestinal manifestations of CVID [35]. CVID is associated with autoimmune manifestations in 20% to 25% of patients [53]. The most common conditions are immune thrombocytopenic purpura and autoimmune hemolytic anemia. Although the etiology of increased autoimmunity in CVID remains elusive, certain genetic predispositions in combination with repeated antigen exposure and overall immune dysregulation inherent in CVID likely play a signiﬁcant role [54]. Treatment for common variable immunodeﬁciency The treatment of CVID is currently based on the early recognition of the condition and immunoglobulin replacement combined with prompt treatment of infections and complications. IVIG therapy can signiﬁcantly reduce the incidence of pneumonia and hospital admission caused by infections in patients with CVID [16,17]. Although the route of administration, dose, and frequency of administration of immunoglobulin still vary between institutions and countries [55], the dose of 400 mg/kg body weight IVIG every 3 to 4 weeks is a standard starting therapy for the treatment of patients with CVID [56]. Increased doses of IVIG may be indicated in patients with persistent infections. Other interventions aimed at overcoming the immunologic defects in CVID, such as interleukin-2 therapy, are being studied but there is as yet insuﬃcient evidence to support their routine use. The treatment of complications, such as suppurative lung disease associated with bronchiectasis, uses principles similar to those used for cystic ﬁbrosis. The mainstay of treatment of autoimmune disease in CVID patients is often high-dose IVIG and corticosteroids, although other therapies, including tumor necrosis factor antagonists and anti-CD20 immunomodulators,

170

MORIMOTO & ROUTES

have been successfully used [49,57,58]. Optimal treatment of granulomatous disease in CVID remains to be established. In general, immunoglobulin replacement or corticosteroids are not eﬀective. Tumor necrosis factor-a is elevated in the serum of patients with CVID and granuloma and may be involved in the pathogenesis of the disorder [59]. Therapy directed to antagonize tumor necrosis factor-a, such as inﬂiximab, a monoclonal antibody against tumor necrosis factor-a, has been reported to improve the granulomatous disease in patients with CVID [60–62]. Further studies are needed to delineate appropriate treatments for this disease [63]. Summary PIDs represent a challenge in their diagnosis and treatment. With the advance of the diagnostics and therapeutics, these disorders have been better understood and more successfully treated. Their prognosis depends on the early recognition of the disorders and initiation of the appropriate management. Primary care physicians are most often the ﬁrst physician for patients with immunodeﬁciency to encounter: they should be familiar with these rare but important disorders. References [1] De Santis W, Esposito A, Conti V, et al. [Health care and infective aspects in patients aﬀected by common variable immunodeﬁciency assisted in the Lazio Regional Authority Reference Centre for Primary Immunodeﬁciencies]. Infez Med 2006;14(1):13–23. [2] Buckley RH. Primary immunodeﬁciency or not? Making the correct diagnosis. J Allergy Clin Immunol 2006;117(4):756–8. [3] Bruton OC. Agammaglobulinemia. Pediatrics 1952;9(6):722–8. [4] Notarangelo L, Casanova JL, Conley ME, et al. Primary immunodeﬁciency diseases: an update from the International Union of Immunological Societies Primary Immunodeﬁciency Diseases Classiﬁcation Committee Meeting in Budapest, 2005. J Allergy Clin Immunol 2006;117(4):883–96. [5] Bonilla FA, Bernstein IL, Khan DA, et al. Practice parameter for the diagnosis and management of primary immunodeﬁciency. Ann Allergy Asthma Immunol 2005;94(5 Suppl 1): S1–63. [6] Cunningham-Rundles C, Bodian C. Common variable immunodeﬁciency: clinical and immunological features of 248 patients. Clin Immunol 1999;92(1):34–48. [7] Winkelstein JA, Marino MC, Ochs H, et al. The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine (Baltimore) 2003;82(6):373–84. [8] Folz RJ, Routes JM. Pulmonary Complications of Organ Transplantation and Primary Immunodeﬁciencies. In: Mason RJ, Murray JF, Broaddus VC, et al, editors. Textbook of respiratory medicine. 4th edition. Philadelphia: Elsevier Inc.; 2005. p. 2163–99. [9] Al-Herz W, McGeady SJ. Antibody response in common variable immunodeﬁciency. Ann Allergy Asthma Immunol 2003;90(2):244–7. [10] Cunningham-Rundles C. Immune deﬁciency: oﬃce evaluation and treatment. Allergy Asthma Proc 2003;24(6):409–15. [11] Padeh YC, Rubinstein A, Shliozberg J. Common variable immunodeﬁciency and testing for HIV-1. N Engl J Med 2005;353(10):1074–5.

IMMUNODEFICIENCY OVERVIEW

171

[12] Knight AK, Bingemann T, Cole L, et al. Frequent false positive beta human chorionic gonadotropin tests in immunoglobulin A deﬁciency. Clin Exp Immunol 2005;141(2):333–7. [13] Buckley RH. Pulmonary complications of primary immunodeﬁciencies. Paediatr Respir Rev 2004;5(Suppl A):S225–33. [14] Grunebaum E, Mazzolari E, Porta F, et al. Bone marrow transplantation for severe combined immune deﬁciency. JAMA 2006;295(5):508–18. [15] Simon HU, Spath PJ. IVIG: mechanisms of action. Allergy 2003;58(7):543–52. [16] Pourpak Z, Aghamohammadi A, Sedighipour L, et al. Eﬀect of regular intravenous immunoglobulin therapy on prevention of pneumonia in patients with common variable immunodeﬁciency. J Microbiol Immunol Infect 2006;39(2):114–20. [17] Busse PJ, Razvi S, Cunningham-Rundles C. Eﬃcacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeﬁciency. J Allergy Clin Immunol 2002;109(6):1001–4. [18] Radinsky S, Bonagura VR. Subcutaneous immunoglobulin infusion as an alternative to intravenous immunoglobulin. J Allergy Clin Immunol 2003;112(3):630–3. [19] Eijkhout HW, van den Broek PJ, van der Meer JW. Substitution therapy in immunodeﬁcient patients with anti-IgA antibodies or severe adverse reactions to previous immunoglobulin therapy. Neth J Med 2003;61(6):213–7. [20] Hershﬁeld MS, Buckley RH, Greenberg ML, et al. Treatment of adenosine deaminase deﬁciency with polyethylene glycol-modiﬁed adenosine deaminase. N Engl J Med 1987;316(10):589–96. [21] Booth C, Hershﬁeld M, Notarangelo L, et al. Management options for adenosine deaminase deﬁciency: proceedings of the EBMT satellite workshop (Hamburg, March 2006). Clin Immunol 2007;123(2):139–47. [22] Aiuti A, Slavin S, Aker M, et al. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science 2002;296(5577):2410–3. [23] Ott MG, Schmidt M, Schwarzwaelder K, et al. Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nat Med 2006;12(4):401–9. [24] Hacein-Bey-Abina S, Le Deist F, Carlier F, et al. Sustained correction of X-linked severe combined immunodeﬁciency by ex vivo gene therapy. N Engl J Med 2002;346(16):1185–93. [25] Hacein-Bey-Abina S, Von Kalle C, Schmidt M, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 2003;302(5644):415–9. [26] Marciano BE, Wesley R, De Carlo ES, et al. Long-term interferon-gamma therapy for patients with chronic granulomatous disease. Clin Infect Dis 2004;39(5):692–9. [27] Markert ML, Devlin BH, Alexieﬀ MJ, et al. Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants. Blood 2007;109(10):4539–47. [28] Santaella ML, Peredo R, Disdier OM. IgA deﬁciency: clinical correlates with IgG subclass and mannan-binding lectin deﬁciencies. P R Health Sci J 2005;24(2):107–10. [29] Latiﬀ AH, Kerr MA. The clinical signiﬁcance of immunoglobulin A deﬁciency. Ann Clin Biochem 2007;44(Pt 2):131–9. [30] Litzman J, Vlkova M, Pikulova Z, et al. T and B lymphocyte subpopulations and activation/ diﬀerentiation markers in patients with selective IgA deﬁciency. Clin Exp Immunol 2007; 147(2):249–54. [31] Detkova D, de Gracia J, Lopes-da-Silva S, et al. Common variable immunodeﬁciency: association between memory B Cells and lung diseases. Chest 2007;131:1883–9. [32] Ko J, Radigan L, Cunningham-Rundles C. Immune competence and switched memory B cells in common variable immunodeﬁciency. Clin Immunol 2005;116(1):37–41. [33] Viallard JF, Blanco P, Andre M, et al. CD8þHLA-DRþ T lymphocytes are increased in common variable immunodeﬁciency patients with impaired memory B-cell diﬀerentiation. Clin Immunol 2006;119(1):51–8. [34] Cunningham-Rundles C, Radigan L. Deﬁcient IL-12 and dendritic cell function in common variable immune deﬁciency. Clin Immunol 2005;115(2):147–53.

172

MORIMOTO & ROUTES

[35] Kalha I, Sellin JH. Common variable immunodeﬁciency and the gastrointestinal tract. Curr Gastroenterol Rep 2004;6(5):377–83. [36] Warnatz K, Bossaller L, Salzer U, et al. Human ICOS deﬁciency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeﬁciency. Blood 2006;107(8):3045–52. [37] Salzer U, Maul-Pavicic A, Cunningham-Rundles C, et al. ICOS deﬁciency in patients with common variable immunodeﬁciency. Clin Immunol 2004;113(3):234–40. [38] Schaﬀer AA, Salzer U, Hammarstrom L, et al. Deconstructing common variable immunodeﬁciency by genetic analysis. Curr Opin Genet Dev 2007;17(3):201–12. [39] Salzer U, Grimbacher B. TACItly changing tunes: farewell to a yin and yang of BAFF receptor and TACI in humoral immunity? New genetic defects in common variable immunodeﬁciency. Curr Opin Allergy Clin Immunol 2005;5(6):496–503. [40] Losi CG, Silini A, Fiorini C, et al. Mutational analysis of human BAFF receptor TNFRSF13C (BAFF-R) in patients with common variable immunodeﬁciency. J Clin Immunol 2005;25(5):496–502. [41] Weiler CR, Bankers-Fulbright JL. Common variable immunodeﬁciency: test indications and interpretations. Mayo Clin Proc 2005;80(9):1187–200. [42] Blanco-Quiros A, Solis-Sanchez P, Garrote-Adrados JA, et al. Common variable immunodeﬁciency. Old questions are getting clearer. Allergol Immunopathol (Madr) 2006;34(6): 263–75. [43] Bates CA, Ellison MC, Lynch DA, et al. Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeﬁciency. J Allergy Clin Immunol 2004;114(2): 415–21. [44] Aghamohammadi A, Pouladi N, Parvaneh N, et al. Mortality and morbidity in common variable immunodeﬁciency. J Trop Pediatr 2007;53(1):32–8. [45] Martinez Garcia MA, de Rojas MD, Nauﬀal Manzur MD, et al. Respiratory disorders in common variable immunodeﬁciency. Respir Med 2001;95(3):191–5. [46] Thickett KM, Kumararatne DS, Banerjee AK, et al. Common variable immune deﬁciency: respiratory manifestations, pulmonary function and high-resolution CT scan ﬁndings. QJM 2002;95(10):655–62. [47] Kainulainen L, Varpula M, Liippo K, et al. Pulmonary abnormalities in patients with primary hypogammaglobulinemia. J Allergy Clin Immunol 1999;104(5):1031–6. [48] de Gracia J, Vendrell M, Alvarez A, et al. Immunoglobulin therapy to control lung damage in patients with common variable immunodeﬁciency. Int Immunopharmacol 2004;4(6): 745–53. [49] Knight AK, Cunningham-Rundles C. Inﬂammatory and autoimmune complications of common variable immune deﬁciency. Autoimmun Rev 2006;5(2):156–9. [50] Busse PJ, Farzan S, Cunningham-Rundles C. Pulmonary complications of common variable immunodeﬁciency. Ann Allergy Asthma Immunol 2007;98(1):1–8, quiz 8–11, 43. [51] Wheat WH, Cool CD, Morimoto Y, et al. Possible role of human herpesvirus 8 in the lymphoproliferative disorders in common variable immunodeﬁciency. J Exp Med 2005;202(4): 479–84. [52] Khodadad A, Aghamohammadi A, Parvaneh N, et al. Gastrointestinal manifestations in patients with common variable immunodeﬁciency. Dig Dis Sci 2007;52(11):2977–82. [53] Giannouli S, Anagnostou D, Soliotis F, et al. Autoimmune manifestations in common variable immunodeﬁciency. Clin Rheumatol 2004;23(5):449–52. [54] Brandt D, Gershwin ME. Common variable immune deﬁciency and autoimmunity. Autoimmun Rev 2006;5(7):465–70. [55] Sewell WA, Buckland M, Jolles SR. Therapeutic strategies in common variable immunodeﬁciency. Drugs 2003;63(13):1359–71. [56] Favre O, Leimgruber A, Nicole A, et al. Intravenous immunoglobulin replacement prevents severe and lower respiratory tract infections, but not upper respiratory tract and non-respiratory infections in common variable immune deﬁciency. Allergy 2005;60(3):385–90.

IMMUNODEFICIENCY OVERVIEW

173

[57] El-Shanawany TM, Williams PE, Jolles S. Response of refractory ITP in a patient with common variable immunodeﬁciency (CVID) to treatment with rituximab. J Clin Pathol 2007;60:715–5. [58] Mahevas M, Le Page L, Salle V, et al. Eﬃciency of rituximab in the treatment of autoimmune thrombocytopenic purpura associated with common variable immunodeﬁciency. Am J Hematol 2006;81(8):645–6. [59] Mullighan CG, Fanning GC, Chapel HM, et al. TNF and lymphotoxin-alpha polymorphisms associated with common variable immunodeﬁciency: role in the pathogenesis of granulomatous disease. J Immunol 1997;159(12):6236–41. [60] Thatayatikom A, Thatayatikom S, White AJ. Inﬂiximab treatment for severe granulomatous disease in common variable immunodeﬁciency: a case report and review of the literature. Ann Allergy Asthma Immunol 2005;95(3):293–300. [61] Hatab AZ, Ballas ZK. Caseating granulomatous disease in common variable immunodeﬁciency treated with inﬂiximab. J Allergy Clin Immunol 2005;116(5):1161–2. [62] Lin JH, Liebhaber M, Roberts RL, et al. Etanercept treatment of cutaneous granulomas in common variable immunodeﬁciency. J Allergy Clin Immunol 2006;117(4):878–82. [63] Morimoto Y, Routes JM. Granulomatous disease in common variable immunodeﬁciency. Curr Allergy Asthma Rep 2005;5(5):370–5.

Wellness and Prevention, An Issue of Primary Care Clinics in Office Practice (The Clinics: Internal Medicine)

Evidence-Based Approaches to Common Primary Care Dilemmas Part II, An Issue of Primary Care Clinics in Office Practice (The Clinics: Internal Medicine)

Evidence-Based Approaches to Common Primary Care Dilemmas, Part I, An Issue of Primary Care Clinics in Office Practice (The Clinics: Internal Medicine) (Pt. 1)

Allergy, Asthma, and Immune Deficiency (Primary Care Clinics in Office Practice, Volume 35-01)

Wellness and Prevention, An Issue of Primary Care Clinics in Office Practice (The Clinics: Internal Medicine)

Behavioral Pediatrics, An Issue of Primary Care Clinics in Office Practice (The Clinics: Internal Medicine)

Emergency Medicine, An Issue of Primary Care Clinics in Office Practice (The Clinics: Internal Medicine)

Mental Health, An Issue of Primary Care Clinics in Office Practice (The Clinics: Internal Medicine)

Asthma Allergy book

Pediatric Allergy, Asthma and Immunology

Depression in Primary Care: Evidence and Practice

Anti-IgE Therapy in Asthma and Allergy

Evidence-Based Approaches to Common Primary Care Dilemmas Part II, An Issue of Primary Care Clinics in Office Practice (The Clinics: Internal Medicine)

Evidence-Based Approaches to Common Primary Care Dilemmas, Part I, An Issue of Primary Care Clinics in Office Practice (The Clinics: Internal Medicine) (Pt. 1)

Office orthopedics for primary care: diagnosis issue orthopedics, general practice

Allergy in Practice

Allergy in Practice

Allergy and Asthma Practical Diagnosis and Management

Essential Practice Guidelines in Primary Care

Current Practice Guidelines in Primary Care, 2005

CURRENT Practice Guidelines in Primary Care 2009

Allergy and Asthma Practical Diagnosis and Management

Allergy principles and practice

Prevention of Allergy and Allergic Asthma (Chemical Immunology & Allergy)

Asthma Care in the Community

Pharmacotherapy in Primary Care

Urogynecology in Primary Care

Urogynecology in Primary Care

Essential Practice Guidelines in Primary Care (Current Clinical Practice)

Essential Practice Guidelines in Primary Care (Current Clinical Practice)

Primary Care

Kidney Diseases and Hypertension, Part II, An Issue of Primary Care Clinics in Office Practice (The Clinics: Internal Medicine) (Pt. 2)

Allergy And Asthma in Modern Society: A Scientific Approach

Pediatric Primary Care Ill.Child Care

Allergy, Asthma, and Immune Deficiency (Primary Care Clinics in Office Practice, Volume 35-01)

Wellness and Prevention, An Issue of Primary Care Clinics in Office Practice (The Clinics: Internal Medicine)

Behavioral Pediatrics, An Issue of Primary Care Clinics in Office Practice (The Clinics: Internal Medicine)

Emergency Medicine, An Issue of Primary Care Clinics in Office Practice (The Clinics: Internal Medicine)

Mental Health, An Issue of Primary Care Clinics in Office Practice (The Clinics: Internal Medicine)

Asthma Allergy book

Pediatric Allergy, Asthma and Immunology

Depression in Primary Care: Evidence and Practice

Anti-IgE Therapy in Asthma and Allergy

Evidence-Based Approaches to Common Primary Care Dilemmas Part II, An Issue of Primary Care Clinics in Office Practice (The Clinics: Internal Medicine)

Evidence-Based Approaches to Common Primary Care Dilemmas, Part I, An Issue of Primary Care Clinics in Office Practice (The Clinics: Internal Medicine) (Pt. 1)

Office orthopedics for primary care: diagnosis issue orthopedics, general practice

Allergy in Practice

Allergy in Practice

Allergy and Asthma Practical Diagnosis and Management

Essential Practice Guidelines in Primary Care

Current Practice Guidelines in Primary Care, 2005

CURRENT Practice Guidelines in Primary Care 2009

Allergy and Asthma Practical Diagnosis and Management

Allergy principles and practice

Prevention of Allergy and Allergic Asthma (Chemical Immunology & Allergy)

Asthma Care in the Community

Pharmacotherapy in Primary Care

Urogynecology in Primary Care

Urogynecology in Primary Care

Essential Practice Guidelines in Primary Care (Current Clinical Practice)

Essential Practice Guidelines in Primary Care (Current Clinical Practice)

Primary Care

Kidney Diseases and Hypertension, Part II, An Issue of Primary Care Clinics in Office Practice (The Clinics: Internal Medicine) (Pt. 2)

Allergy And Asthma in Modern Society: A Scientific Approach

Pediatric Primary Care Ill.Child Care

Recommend Documents