Allergy

The Allergy Report

Volume 1

Overview of Allergic Diseases:
Diagnosis, Management, and Barriers to Care Introduction Background Prevention Diagnostic Testing Management of Allergic Diseases
Environmental Control Pharmacologic Therapy Allergen Immunotherapy Patient Education

Recommendations for Policy and Interventions Volume 2

Diseases of the Atopic Diathesis
Introduction Rhinitis Asthma Atopic Dermatitis Associated Disease: Rhinosinusitis Associated Disease: Chronic or Recurrent Otitis Media Volume 3

Conditions That May Have an Allergic Component
Introduction Conjunctivitis Urticaria and Angioedema Contact Dermatitis Drug Reactions Food Reactions Insect Sting Reactions Latex Reactions Anaphylactic and Anaphylactoid Reactions

Copyright © 2000. The American Academy of Allergy, Asthma & Immunology, Inc. All rights reserved. The material contained in this publication is the exclusive property of the American Academy of Allergy, Asthma & Immunology, Inc. (“AAAAI”) and, as to copyrighted works of others which are contained herein, such other copyright owners. This work is protected under U.S. copyright law and other international treaties and conventions. Except as stated herein, none of the material contained in this publication may be copied, reproduced, distributed, republished, downloaded, displayed, posted or transmitted in any form or by any means, including, but not limited to, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of AAAAI or, as to copyrighted material of others, the copyright owner. Any inquiries regarding such permission should be directed to: Ms. Amy Stone American Academy of Allergy, Asthma & Immunology, Inc. 555 East Wells Street, Suite 1100 Milwaukee, WI 53202-3823 Phone: (414) 272-6071 Fax: (414) 272-6070 Certain material in this publication is taken or derived from NIH Publication Nos. 974051 (Guidelines for Diagnosis and Management of Asthma) (July 1997) and 97-4053 (Practical Guide for Diagnosis and Management of Asthma) (October, 1997) of the U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung and Blood Institute. AAAAI gratefully acknowledges the assistance of the Academic Services Consortium, University of Rochester, in the preparation of this publication. Permission is granted to display, copy, distribute and download the materials in this publication for personal, non-commercial use only provided that such materials are not altered or modified and AAAAI’s copyright notice is displayed thereon. DISCLAIMER: This publication and the material and information contained herein have been produced for informational purposes as a service to members and the general public and are provided “as is,” without warranty of any kind, either express or implied, including, without limitation, implied warranties of merchantability and fitness for a particular purpose. AAAAI shall not be liable for direct, indirect, special, incidental or consequential damages related to the user’s decision to use this publication or any material or information contained herein.

CONTENTS
Introduction ....................................................………………………………. 11 Conjunctivitis ..................................................…………………………….. 19
The Allergic Response in the Eye (Allergic Conjunctivitis).............……… 19 Classification of Allergic Conjunctivitis............……………………………… Seasonal Allergic Conjunctivitis..................………………………….. Perennial Allergic Conjunctivitis...............…………………………… Atopic Keratoconjunctivitis ..........................…………………………. Vernal Conjunctivitis ......................................………………………… Giant Papillary Conjunctivitis ....................…………………………… Contact Allergy..................................................………………………. Classification of Nonallergic Conjunctivitis ....……………………………… Bacterial Conjunctivitis ................................………………………….. Viral Conjunctivitis..........................................………………………… Chlamydial Conjunctivitis ............................………………………….. Diagnosing the Patient with Allergic Conjunctivitis ..........................……. Medical History ................................................……………………….. Ocular Examination........................................…………………………. Diagnostic Testing ............................................………………………. Skin Testing..................................................…………………… Differential Diagnosis (chart) ....................……………………………. 20 20 20 20 21 21 22 22 22 23 23 23 24 24 25 25 26

Managing the Patient with Allergic Conjunctivitis ........................……….. 28 Nonpharmacologic Management..............……………………………. 28 Pharmacologic Therapy ..............................………………………….. 28 Antihistamines ..........................................……………………. 28 Topical Vasoconstrictors ........................……………………... 28 Mast Cell Stabilizers ................................……………………… 29 Nonsteroid Anti-inflammatory Medications..................…….. 29 Corticosteroids ..........................................……………………. 29 Allergen Immunotherapy ............................…………………………… 29 Tips for Administering Eyedrops................…………………………… 31 Specialist Referral ........................................…………………………… 31 Opthalmic Preparations (chart)..................……………………………. 32 References ..............................................................…………………………… 33

Urticaria and Angioedema........................………………………………… 35
Urticaria ..................................................................……………………………. 35 Angioedema ..........................................................……………………………. 36 Pathology of Urticaria and Angioedema ....…………………………………… 36 Classification ..........................................................…………………………… 37 Chronic Urticaria ..........................................…………………………... 37 Physical Urticaria and Angioedema ......…………………………….... 37 Cold-induced Urticaria............................………………………. 38 Heat-induced Urticaria............................………………………. 39 Cholinergic Urticaria ..............................………………………. 39 Exercise-induced Anaphylaxis ..............……………………… 40 Dermographism (or dermatographism)………………………. 40 Delayed Pressure-induced Urticaria ..…………………………. 41 Solar-induced Urticaria ..........................……………………… 41 Aquagenic Urticaria ................................………………………. 41 Urticaria with Vasculitis ..............................…………………………… 41 Heredity Angioedema ..................................…………………………… 42 Acquired C1 -esterase Inhibitor Deficiency……………………………. 42 Diagnosing the Patient with Urticaria and Angioedema ..........................…43 Medical History ..............................................………………………….. 43 Physical Examination ..................................…………………………… 44 Diagnostic Testing ..........................................………………………… 44 Considerations for the Differential Diagnosis of Urticaria and Angioedema ……………………………………………………………… 46 Erythema Multiforme..............................………………………. 46 Bullous Pemphigoid ................................……………………… 46 Dermatitis Herpetiformis ......................……………………….. 46 Urticaria Pigmentosa ..............................………………………. 46 Managing the Patient with Urticaria and Angioedema......................……... 46 Nonpharmacologic Management..............…………………………….. 46 Avoidance....................................................…………………… 46

Palliative Measures ..................................…………………….. 46 Pharmacologic Management ....................……………………………. 47 Antihistamines ..........................................……………………… 47 Corticosteroids ..........................................…………………….. 47 Special Considerations for Managing Urticaria and Angioedema . 48 Papular Urticaria ......................................………………………. 48 Cold-induced Urticaria............................………………………. 48 Cholinergic Urticaria ..............................……………………… 48 Dermographism ........................................……………………… 48 Delayed Pressure-induced Urticaria ..…………………………. 48 Specialist Referral ........................................…………………………… 48 Features of common types of urticaria (chart).........................…….. 49 References ..............................................................…………………………… 50

Contact Dermatitis ......................................………………………………. 51
Mechanisms ............................................................…………………………… 51 Allergic contact dermatitis involves ........…………………………….. 51 Irritant Contact Dermatitis ........................…………………………….. 52 Diagnosing the Patient with Contact Dermatitis............……………………. 53 Medical History ..............................................…………………………. 53 Common Causes (chart) ........................………………………. 54 Physical Examination ..................................………………………….. 55 Most reported cases of contact dermatitis occur on the hands………………………………………………………………… 55 Eruptions may be broadly classified as acute or chronic .… 56 Urticaria reactions (wheal-and-flare responses)......………… 57 Differentiating Allergic and Irritant Contact Dermatitis ............…… 58 Irritant Contact Dermatitis....................………………………….58 Allergic Contact Dermatitis ..................………………………… 58 Clinical Features ......................................………………………. 59 Photosensitivity reactions are a type of contact dermatitis .. 60 Diagnostic Testing ..........................................………………………….61 Patch Testing ..............................................……………………. 61

Managing the Patient with Contact Dermatitis.........................…………….. 63 Nonpharmacologic Management..............…………………………….. 63 Pharmacologic Management ....................……………………………. 63 Acute Eruptions ........................................……………………… 63 Chronic or Subacute Dermatitis ..........………………………… 64 Severe and Chronic Dermatitis ............…………………………64 Special Considerations..................................…………………………. 65 Specialist Referral .........................................…………………………. 66 Topical corticosteroids (chart)....................…………………………… 67 References ..............................................................…………………………… 68

Drug Reactions ............................................………………………………. 69
Classification of Allergic Drug Reactions ..……………………………………70 IgE-mediated Reactions ..............................…………………………… 70 Cytotoxic/Cytolytic Reactions......................…………………………… 71 Immune Complex Reactions ......................……………………………. 71 T-cell-mediated Reactions ..........................…………………………………….72 Other Reactions ..............................................…………………………. 72 Delayed Dermatologic Reactions ........………………………………… 72 Drug-induced Fever ................................………………………………. 73 Hepatic Hypersensitivity Reactions ....……………………………….. 73 Pulmonary Hypersensitivity Reactions……………………………….. 73 Aseptic Meningitis from Drugs ............………………………………… 74 Nonimmunologic Drug Reactions ......…………………………………. 74 Multiple Drug Allergy Syndrome ........…………………………………. 74 Diagnosing Drug Allergy ....................................……………………………… 75 Medical History ..............................................………………………….. 75 Factors to consider ..................................……………………… 75 Concurrent disease and therapy may influence risk.......….. 75 Diagnostic Testing ..........................................………………………… 76 Skin Testing................................................…………………….. 76 Managing the Patient with Drug Allergy ......…………………………………. 77

Treatment of Severe Immediate or Accelerated Reactions ..……… 77 Treatment of Late Reactions ......................……………………………. 77 “Treating Through”........................................…………………………... 77 Premedication (radiocontrast media) ..……………………………….. 78 Desensitization for IgE-mediated Reactions...........…………………. 79 Desensitization for Non-IgE-mediated Reactions .......……………… 79 Specialist Referral ........................................…………………………… 79 Specific Considerations for Managing Drug Allergy Reactions......……… 80 Penicillin and Other Beta-lactam Antibiotics...………………………..80 Insulin Reactions ..........................................…………………………... 81 Sulfonamides ..................................................…………………………. 82 Local Anesthetic Agents ................................…………………………. 82 Radiocontrast Media ....................................…………………………… 82 Aspirin and NSAIDs ......................................………………………….. 82 Avian-based Vaccines....................................…………………………. 83 References ..............................................................…………………………… 85

Food Reactions ............................................………………………………. 87
Mechanisms of Food Reactions ......................……………………………….. 88 IgE-mediated Food Allergy Reactions......…………………………….. 89 The Oral Allergy Syndrome ........................……………………………. 90 Non-IgE-mediated Food Hypersensitivity…………………………….. 91 Food-induced Enterocolitis....................………………………. 91 Food-induced Proctocolitis....................………………………. 91 Food-induced Enteropathy ....................……………………… 91 Celiac Disease............................................……………………. 92 Allergic Eosinophilic Gastroenteritis ..………………………… 92 Food Intolerance ......................................……………………….93 Diagnosing the Patient with Food Allergy ...…………………………………. 93 Medical History ..............................................………………………….. 93 Diet diaries may be useful ....................…………………………94 Physical Examination ..................................…………………………… 95 Diagnostic Testing ..........................................………………………….95 Elimination Diets......................................………………………. 95 Skin and In Vitro Testing........................……………………….. 99

Double Blind, Placebo-Controlled Food Challenge (DBPCFC) ....................………………………. 100 Managing the Patient with Food Allergy ........……………………………….. 101 Nonpharmacologic Management..............…………………………….. 101 Pharmacologic Management ....................…………………………….. 102 Epinephrine................................................……………………... 102 Other treatments ......................................……………………… 102 General Considerations for Treating Food Allergy ............………... 103 Treating the Patient with a Suspected Food Allergy ..............................................……………………... 103 Treating Children with Food Allergy ..………………………… 103 Specialist Referral ........................................…………………………... 104 Patient Education ..........................................………………………….. 104 References ..............................................................…………………………… 105

Insect Sting Reactions ................................………………………………. 107
Reactions to Stinging Insects ..........................………………………………. 108 Immediate Local Reaction..........................……………………………. 108 Large Local Reaction....................................…………………………... 108 Anaphylaxis......................................................………………………… 109 Signs and Symptoms of Anaphylaxis..………………………... 109 Toxic Reaction ................................................…………………………. 110 Unusual (Delayed) Reactions ....................……………………………. 110 Diagnosing the Patient with Insect Sting Allergy................………………... 111 Medical History and Insect Identification ..................……………….. 111 Identifying stinging insects (Hymenoptera) (chart).......……. 112 Diagnostic Testing ..........................................………………………… 113 Managing the Patient with Insect Sting Allergy .......................……………. 113 Nonpharmacologic Management..............…………………………….. 113 Pharmacologic Management ....................…………………………….. 114 Immediate Local Reactions ..................………………………... 114

Oral Corticosteroids ................................……………………… 114 Epinephrine................................................……………………... 115 Venom Immunotherapy..........................……………………….. 117 Specialist Referral ......................................……………………………. 118 References ............................................................…………………………….. 119

Latex Reactions ..........................................……………………………… 121
Allergic Responses to Latex ..........................………………………………… 122 Types of Allergic Responses to Latex ......……………………………. 122 Diagnosing the Patient with Latex Allergy ..…………………………………. 123 Medical History ............................................…………………………… 123 Physical Examination ................................…………………………….. 124 Allergic Reactions ................................………………………… 124 Nonallergic Reactions ........................………………………….. 125 Diagnostic Testing ........................................………………………….. 125 Managing the Patient with Latex Allergy......…………………………………. 126 Avoidance ......................................................………………………….. 126 Avoiding natural latex products ........…………………………. 126 Additional avoidance measures for extremely allergic patients... …………………………………………………………… 127 Sources of latex exposure (chart)......…………………………. 129 Latex products and safe alternatives (chart)...........………… 130 References ............................................................…………………………….. 131

Anaphylactic and Anaphylactoid Reactions..............………. 133
Anaphylactic Reactions....................................……………………………….. 133 Possible Causes of Anaphylactic Reactions.....................…………. 133 Risk Factors for Anaphylaxis....................…………………………….. 134 Anaphylactoid Reactions ................................………………………………... 135 Possible Causes of Anaphylactoid Reactions.....................……….. 135

Diagnosing Anaphylactic/Anaphylactoid Reactions........................……… 136 Medical History ...........................................……………………………. 136 Signs and Symptoms of Anaphylactic/ Anaphylactoid Reactions....................………………………….. 136 Physical Examination ................................…………………………….. 138 Diagnostic Testing ........................................………………………….. 138 Specialist Referral ......................................……………………………. 139 Managing the Patient..........................................………………………………. 140 Managing Acute Events ..............................…………………………… 140 General considerations for treating an acute event..........…. 140 Hospitalize the patient who is unresponsive to initial Therapy ……………………………………………………………... 141 Preventing Events ........................................…………………………... 143 Patient Education is Essential. ................…………………………….. 143 Suggestions for reducing risk ..................…………………………….. 144 Special Considerations ......................................……………………………… 145 The Pregnant Patient ..................................……………………………. 145 Reactions in the Operating Room ..........……………………………… 145 Refractory Cases Due to Beta-adrenergic Blocking Agents ......…. 146 Exercise-induced Reactions ....................……………………………... 146 Idiopathic Reactions ..................................……………………………. 147 References ............................................................…………………………….. 148

Resource Organizations ..............................………………………… 149 Glossary............................................................………………….. 151

The Allergy Report
Introduction

T

o improve the health and well being of allergy sufferers, the American Academy of Allergy, Asthma, and Immunology (AAAAI) in partnership with the National Institute of Allergy and Infectious Diseases (NIAID) and 20 other medical associations, advocacy groups, and government agencies, has undertaken a comprehensive initiative – Allergic Disorders: Promoting Best Practice. The goal of this initiative is to ensure that a broad spectrum of healthcare providers learns about, understands, and implements clinical and best practice information for diagnosing and managing patients with allergic diseases. The Allergy Report represents the outcome of a first step of the initiative: development of an evidence-based, practical and easy-toaccess guide to allergic disorders to help family practice physicians, internists, pediatricians, nurse practitioners, school nurses, and others who manage or interact with patients with allergies. The Allergy Report provides guidance on the clinical management of allergic disorders, examines the barriers to effective care, and addresses future research needs for allergy mechanisms and clinical approaches to treatment. The Report is organized into three volumes. This Volume provides information on conditions in which there may be an allergic component, including: conjunctivitis, urticaria and angioedema, contact dermatitis, drug reactions, food reactions, insect sting reactions, latex reactions, and anaphylactic/anaphylactoid reactions. Volume 1 provides an overview of the allergic process, the principles in common to the diagnosis and management of all allergic diseases, and discusses potential interventions for improving care for patients with allergic disorders. Volume 2 focuses on the diseases of atopic diathesis (rhinitis, asthma, allergic dermatitis) and includes sections on two commonly associated diseases: rhinosinusitis and recurrent or chronic otitis media.

Introduction i

Overview of Sections of Volume 3: Conditions That May Have an Allergic Component Conjunctivitis
Conjunctivitis refers to a group of ocular disorders that result in inflammation of the conjunctiva. Conjunctivitis is the most common form of allergic eye disease with symptoms that can occur seasonally or perennially, depending on the allergens. Discussion includes differentiating allergic from nonallergic conjunctivitis, classification of other ocular conditions, and a protocol for management based on the severity of symptoms.

Urticaria and Angioedema
Urticaria and angioedema represent the same increase in vascular leakage (permeability) observed within minutes following injection of histamine. Urticaria, which occurs in the dermis, is characterized by pruritic and erythematous elevations (i.e., “rash”), and is usually associated with itching. Angioedema occurs in the deeper cutaneous layers, those containing fewer mast cells and sensory nerve endings. As a result, while angioedema is associated with swelling, the skin may appear normal, and the patient usually complains of pain or burning rather than itching. Angioedema most often involves the face, tongue, extremities, or genitalia whereas urticaria can occur virtually anywhere on the body. Considerations for diagnosis and management are given.

Contact Dermatitis
Contact dermatitis refers to a broad range of reactions resulting from the direct contact of an exogenous agent with the surface of the skin. It is the most common occupational disease and one of the most commonly acquired skin diseases in adults. Contact dermatitis comprises up to 40% of all occupational illnesses reported in the U.S. It accounts for about 90% of all occupational skin diseases. Discussion includes how to differentiate allergic contact dermatitis from irritant contact dermatitis, some common causes of contact dermatitis (including jobs with increased risk for developing the condition), and recommendations for diagnosis and treatment.

Introduction ii

Drug Reactions
Drug reactions can potentially result from any medication or biologic agent, and it is estimated that up to 10% of all adverse drug reactions are due to allergic responses. This section describes the different types of drug reactions that can occur, factors to consider in differential diagnosis, general principles of management, and recommendations for managing allergic reactions to specific drugs.

Food Reactions
Food reactions represent a group of disorders, some of which are characterized by immunologic responses to specific food proteins. The prevalence is greatest in the first few years of life and is higher in children with atopic disease. Approximately 35% of children with moderate to severe atopic dermatitis also have food allergy. This section describes the different types of food-related reactions, the common clinical manifestations of food allergy, techniques for diagnosing food allergy (including discussion of the role of elimination diets, food challenges), and considerations for management.

Insect Sting Reactions
Insect sting reactions should always be considered serious as the venom of the stinging insects (Hymenoptera) may cause anaphylaxis. This is in contrast to biting insects (e.g., mosquitoes, gnats) which can cause local allergy symptoms (e.g., swelling) but rarely are associated with severe systemic reactions. Clinical manifestations of insect stings, from mild to severe, are described along with recommendations for treatment and for prevention.

Latex Reactions
Latex reactions can be caused by an allergic response to the proteins in natural latex rubber or to the additives used in processing latex. The prevalence of latex allergy is increasing, and it is an important concern for both healthcare professionals and patients. This section describes the different types of allergic responses to latex, persons at increased risk for latex allergy, and provides suggestions for diagnosis and medical management. Sources of latex exposure, latex precautions, and tips for avoidance are included.

Introduction iii

Anaphylactic and Anaphylactoid Reactions
Anaphylaxis is a rapid, immune-mediated, systemic reaction to allergens to which the patient has been previously exposed. It has many etiologies. Anaphylactoid reactions look like anaphylaxis, but are not immune mediated. Anaphylaxis is the most severe form of allergic reaction and should always be considered a medical emergency. The reaction occurs rapidly, often dramatically, and is usually unanticipated. This section describes the anaphylactic reaction, its potential causes, differentiation from anaphylactoid reactions, management, and prevention.

Comment on Terminology
The Allergy Report represents the collaboration and team effort of 22 organizations (see page vii). Eight drafts of the document were developed, reviewed, and revised by some or all of the Task Force before the final sign-off and endorsement. Several terms had different definitions and/or interpretations by members of different groups. As a result, it was necessary for the Task Force to reach consensus on the following: Allergy: In most of The Allergy Report, the term: ❑ “Allergen” refers to substances that can induce IgE antibody responses.
❑ “Allergy” refers to IgE antibody responses to allergens. ❑ “Allergic disease” is the resulting clinical manifestations generated

by IgE antibody responses. Allergens include generally harmless materials such as: ❑ Pollens ❑ Cockroaches
❑ Mold spores ❑ Animal danders ❑ House dust mites ❑ Penicillin and other drugs ❑ Foods ❑ Latex ❑ Insect venoms

In several places in The Report, the terms “allergy” and “allergic disease” are more broadly encompassing and include altered immunologic reactivity that may be either IgE-mediated or non-IgE-mediated. The reader should note that this broader definition is used selectively.

Introduction iv

Examples of this can be seen in the following sections in this volume: ❑ Drug Reactions and Food Reactions describe clinical responses that are both IgE-mediated and non-IgE-mediated.
❑ Contact Dermatitis describes specific, non-IgE-mediated immune cell

reactions (i.e., T-cell responses to contact antigens). Another term that is frequently confused with “allergy” is “atopy.” Atopy refers to the genetic tendency to develop the “classical” allergic diseases, namely, allergic rhinitis, asthma, and atopic dermatitis. Atopy is typically associated with a genetically determined capacity to mount IgE responses to common allergens, especially inhaled allergens and food allergens. Recently, it has been shown that IgE responses to latex are more frequent in atopic families, and thus, latex allergy may be considered an atopic disease. In contrast, IgE responses to insect venom and drugs are not more common in atopic families. Hence, these disorders are considered allergic, but not atopic, diseases. Specialist: The Allergy Report identifies many clinical situations in which referral to a specialist is warranted. Specialists may include: ❑ Allergy/immunology specialists
❑ Dermatologists ❑ Infectious disease specialists ❑ Ophthalmologists ❑ Otolaryngologists ❑ Otolaryngologic allergy specialists ❑ Pulmonologists

In many cases, the type of specialist varies with the provider network and the geography/community. For example, the Asthma section (Volume 2) uses the term “asthma specialist” in the same manner used by the National Asthma Education and Prevention Program1 to refer to a fellowship-trained allergist or pulmonologist or, occasionally, other physicians with experience in asthma management developed through additional training and experience. Similar complexities exist in

1

Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma: Clinical Practice Guidelines. NIH Publication No. 97-4051, page 10.
Introduction v

identifying specialists for management of such diseases as atopic dermatitis, rhinosinusitis, otitis media, conjunctivitis, urticaria and angioedema, and contact dermatitis. Therefore, consultation or comanagement is recommended, as appropriate, with the type of specialist determined by the referring healthcare provider and taking into account the patient’s health insurance coverage and the healthcare resources available in the community. Allergies are the sixth leading cause of chronic disease in the United States, costing the healthcare system over $18 billion annually. Each year more than 50 million Americans suffer from allergic disease, and these numbers are increasing. On a daily basis, allergies cause time lost from work, school, and leisure activities and decrease productivity at work, in school, and at home; but they don’t have to! Learning what triggers allergies and understanding how to treat the diseases may make the difference between a chronic debilitating illness and a productive, healthy lifestyle. To help healthcare professionals bridge the gap between current knowledge and practice, The Allergy Report presents basic recommendations for the diagnosis and management of allergic diseases. It is the hope of the Task Force responsible for developing The Allergy Report, and those who have reviewed it, that this initiative will improve healthcare and productivity for patients with allergic diseases.

Acknowledgements
The Task Force acknowledges the support of Schering/Key, which provided an unrestricted educational grant for development, publication, and distribution of The Allergy Report.

Introduction vi

Chairs
Harold S. Nelson, M.D., FAAAAI American Academy of Allergy, Asthma and Immunology National Jewish Medical and Research Center Denver, CO Gary S. Rachelefsky, M.D., FAAAAI American Academy of Allergy, Asthma and Immunology Allergy Research Foundation, Inc. University of California at Los Angeles Los Angeles, CA

Task Force Members
John Bernick, M.D., Ph.D. American College of Occupational and Environmental Medicine A. Wesley Burks, M.D. American Academy of Pediatrics Don Cui, PA-C, C.M.C.M. American Academy of Physicians Assistants Mark Dykewicz, M.D., F.A.C.P . American College of Physicians/ American Society of Internal Medicine Ivor Emanuel, M.D. American Academy of Otolaryngic Allergy John Georgitis, M.D., F.C.C.P . American College of Chest Physicians Peter Gergen, M.D. Agency for Health Care Policy and Research James Hadley, M.D., F.A.C.S. American Academy of Otolaryngology/ Head and Neck Surgery Sharon Hipkins, R.N., M.S.N. Asthma and Allergy Foundation of America Joel Karlin, M.D. American Medical Association Monica Kraft, M.D. American Thoracic Society Barry Lampl, D.O. American Osteopathic College of Allergy and Immunology Doris Luckenbill, R.N., M.S., C.R.N.P . National Association of School Nurses Bryan Martin, D.O. American Osteopathic College of Allergy and Immunology

Introduction vii

Anne Muñoz-Furlong The Food Allergy Network Donna Nativio, Ph.D., C.R.N.P ., F.A.A.N. American College of Nurse Practitioners Marshall Plaut, M.D. National Institute of Allergy and Infectious Diseases, National Institutes of Health Stephen Redd, M.D. Centers for Disease Control and Prevention

Daniel Rotrosen, M.D. National Institute of Allergy and Infectious Diseases, National Institutes of Health Nancy Sander Allergy and Asthma Network Mothers of Asthmatics, Inc. William Storms, M.D. American College of Allergy, Asthma and Immunology Karen Tietze, Pharm.D. American Pharmaceutical Association Barbara Yawn, M.D. Specialist in Family Medicine

Outside Reviewers
The panel of content experts who reviewed the draft document included: Leonard Bielory, M.D., FAAAAI; S. Allan Bock, M.D., FAAAAI; William W Busse, M.D., FAAAAI; Harold M. Friedman, M.D.,FAAAAI; . Mitchell Friedlaender, M.D., FAAAAI; Anthony Gaspari, M.D.; David B. K. Golden, M.D., FAAAAI; Michael A. Kaliner, M.D., FAAAAI; Michael A. LeNoir, M.D.; Mark T. O'Hollaren, M.D., FAAAAI; Harold C. Pillsbury, III, M.D.; Thomas E. Platts-Mills, M.D., Ph.D., FAAAAI; Hugh Sampson, M.D., FAAAAI; Gail Shapiro, M.D., FAAAAI; F. Estelle R. Simons, M.D., FAAAAI; David Skoner, M.D.; Stuart Stoloff, M.D.; Abba Terr, M.D., FAAAAI; John Warner, M.D.; Jill Warner, Ph.D.; Robert Zeiger, M.D., Ph.D., FAAAAI.

Introduction viii

Conjunctivitis
❑ Conjunctivitis: o Refers to a group of ocular disorders that result

in inflammation of the conjunctiva.
o May be of allergic or nonallergic origin. ❑ The eye is a common target of allergic inflammatory

The conjunctiva is the most immunologically active tissue of the external eye. Conjunctivitis may be allergic or nonallergic.

disorders because of its:
o Marked vascularity. o Sensitivity of conjunctival vessels. o Direct contact with the environment.

Ocular allergy diseases include:
❑ Seasonal allergic conjunctivitis ❑ Perennial allergic conjunctivitis ❑ Atopic keratoconjunctivitis ❑ Vernal conjunctivitis ❑ Contact allergy ❑ Giant papillary conjunctivitis (hypothesized

Allergic conjunctivitis is the most common form of allergic eye disease.
❑ It may be seasonal or

allergic origin)

perennial, depending on the cause.

The Allergic Response in the Eye (Allergic Conjunctivitis)
❑ In response to various stimuli, the conjunctiva

undergoes a variety of morphological changes. o The type of response depends upon the nature of the stimulus. ❑ Seasonal and perennial allergic conjunctivitis are examples of immunological diseases initiated by an IgE-mediated reaction. o Airborne allergens (e.g., pollen, animal dander) dissolve in tear film, traverse the conjunctiva, and are processed to allergenic peptides that bind to IgE receptors on conjunctival mast cells.

Seasonal allergic conjunctivitis is the most common type of allergic conjunctivitis.

Conjunctivitis

1

o As in other tissues, the degranulation of mast cells

The allergic response in the eye is usually associated with other allergic disorders, most commonly allergic rhinitis.
❑ Treating associated

releases an array of inflammatory mediators ultimately resulting in the ocular allergic response. ❑ The ocular allergic response exhibits both early-phase and late-phase reactions similar to allergic reactions in other tissues (see Volume 1: Background, page 4). ❑ The allergic response in the eye is usually associated with other allergic disorders, most commonly allergic rhinitis.

Classification of Allergic Conjunctivitis
Seasonal Allergic Conjunctivitis
❑ The most common form of allergic conjunctivitis. ❑ Usually associated with allergic rhinitis. ❑ Signs and symptoms may include: o Bilateral ocular and periocular pruritus o Tearing o Burning and stinging o Pinkish or milky conjunctiva ❑ Symptoms are usually bilateral. ❑ Symptoms may persist throughout the allergy season

allergic rhinitis may improve allergic conjunctivitis.

Seasonal allergic conjunctivitis is rarely observed in the absence of allergic rhinitis.

but are subject to exacerbations and remissions.

Perennial Allergic Conjunctivitis
The symptoms of perennial allergic conjunctivitis are usually not as intense as the symptoms of seasonal allergic conjunctivitis.
(see Volume 1: Background, Common Allergens, page 12) ❑ Reflects sensitivity to allergens that are present throughout the entire year. ❑ Less prevalent than seasonal allergic conjunctivitis. ❑ Symptoms are usually milder than those of seasonal allergic conjunctivitis.

Atopic Keratoconjunctivitis
❑ Associated with atopic dermatitis of the eyelid and face. ❑ Signs and symptoms may include: o Redness o Pruritus o Burning o Tearing

2

Conjunctivitis

o Stringy, ropy discharge o Papillary hypertrophy of lower and upper tarsal

conjunctivae. o Corneal vascularization, ulceration and scarring, cataract, and punctate epithelial keratitis may occur but are not common. ❑ Age of onset is usually the late teens and early 20s. ❑ Patients often have a history of allergy, particularly allergic rhinitis and/or asthma.

Atopic keratoconjunctivitis is usually associated with atopic dermatitis affecting the face.
❑ Most often occurs in

Vernal Conjunctivitis
❑ Typically a childhood disease. ❑ Observed more often in males than in females. ❑ Commonly occurs during the spring and summer. ❑ Most patients have a personal history of atopic disease,

late adolescence and early adulthood. ❑ History of allergy, particularly allergic rhinitis and/or asthma, is common.

though vernal conjunctivitis is not IgE-mediated. ❑ Patient presents with chronic, bilateral inflammation of the conjunctivae. ❑ Other signs and symptoms may include: o Intense itching (patients vigorously rub their eyes) o Photophobia o Blurred vision o Blepharospasm o Stringy, ropy discharge o Giant papillae on the palpebral conjunctiva (“cobblestoning”) o Trantas’ dots (small white dots at the limbal conjunctiva, eosinophils) ❑ Patients often have a history of allergy, particularly allergic rhinitis and/or asthma. ❑ If untreated, corneal scarring can occur, leading to vision loss.

Vernal conjunctivitis usually occurs in children, most commonly in boys.
❑ Patient usually has a

history of allergy, particularly allergic rhinitis and/or asthma.

Vernal conjunctivitis can lead to corneal scarring with loss of vision, if not treated.

Giant Papillary Conjunctivitis
❑ Associated with contact lens use. ❑ Hypothesized to be an allergic reaction involving proteins

that adhere to the intraocular surfaces of contact lenses, ocular protheses, sutures, and cyanoacrylate adhesives.

Giant papillary conjunctivitis is associated with using contact lenses.
Conjunctivitis

3

❑ Signs and symptoms may include: o Mild pruritus o Occasional slight blurring of vision o Mild hyperemia o Abnormal thickening of the conjunctiva o Small strands of mucus o Macropapillae and giant papillae on the

upper tarsal conjunctiva o Opacification of the conjunctiva

Contact Allergy
Contact allergies affecting the eye are being observed more frequently due to increasing use of topical medications and contact lens solutions. Contact allergy of the eyelids may be caused by cosmetics applied to the hair, face, hands, or fingernails through inadvertent spreading. Preservatives in ophthalmic preparations associated with contact allergy:
❑ Benzalkonium chloride ❑ Thimerosal (merthiolate) ❑ Chlorobutanol ❑ Chlorhexidene ❑ Phenylmercuric nitrate
❑ Results from repeated exposure to various sensitizing

agents, such as ophthalmic medications, cosmetics, and preservatives in solutions (e.g., thimerosal). ❑ May involve the skin of the eyelid as well as the conjunctiva. ❑ Signs and symptoms may include: o Severe itching o Burning o Photophobia o Vasodilation and chemosis of the conjunctiva o Fine epithelial punctate keratitis o Occasionally, corneal opacity

Classification of Nonallergic Conjunctivitis
❑ Conjunctivitis of a nonallergic nature is often due

to infection: o Bacterial o Viral ❑ Determination of etiology is important.

Bacterial Conjunctivitis
❑ Characterized by: o Velvety, beefy-red conjunctiva o Serous, mucoid, or mucopurulent discharge ❑ Ocular pruritus is usually absent.

and acetate
4
Conjunctivitis

❑ Patients often complain of: o Unilateral or bilateral burning o Stinging o Foreign body sensation o Morning crustiness of the eyelids, causing difficulty

in eye opening ❑ Not seasonal ❑ Often preceded by, or associated with, infections of the upper respiratory tract, especially in children.

Viral Conjunctivitis
❑ Characterized by a watery discharge. ❑ Follicular hypertrophy and preauricular lymphadenopathy

Bacterial conjunctivitis is often preceded by, or associated with, upper respiratory infections, especially in children.

may be present upon ocular examination. ❑ Patients often complain of: o Unilateral or bilateral burning o Stinging o Foreign body sensation

Chlamydial Conjunctivitis
❑ Includes trachoma and inclusion conjunctivitis of adults

and newborns. ❑ Patient presents with: o Mucopurulent discharge lasting for more than 2 weeks. o Conjunctival follicles (not usually present in newborns).

Diagnosing the Patient with Allergic Conjunctivitis
❑ Many factors should be considered, including: o Age o Patient and family histories o Presenting clinical signs and symptoms ❑ It is important to remember that the presence and

The hallmark symptom of allergic ocular disorders is itching.

intensity of various symptoms can vary greatly.

Conjunctivitis

5

Medical History
❑ A complete medical and ocular history is essential.

Loss in visual acuity and eye pain may indicate conditions threatening to the patient’s vision (e.g., keratitis, uveitis, glaucoma).

Consider: o Patient and family history of allergic disease. ⇒ Particularly, the presence of allergic rhinitis. o Onset of symptoms: ⇒ Seasonal ⇒ Perennial o Specific exposures to: ⇒ Allergens ⇒ Irritants (particularly, occupational irritants) ⇒ Cosmetics and/or perfumes ⇒ Topical or systemic medications with the potential to cause ocular inflammation o Exposure to other persons with conjunctivitis. o A recent respiratory infection. o Recent trauma to the eye. o Use of contact lenses. o Use of ocular medications. ❑ Characteristic symptoms: o Itching o Stinging o Tearing o Burning o Redness o Ocular discharge o Irritation

Ocular Examination
❑ Note unilateral or bilateral presence of clinical signs. o Clinical signs most often occur bilaterally in allergic

conjunctivitis. ❑ Corneal involvement is rare, but scarring may occur in severe cases. ❑ Look for ocular discharge. o Allergic conjunctivitis is associated with a stringy or ropy discharge. ❑ Evaluate conjunctivae for edema and appearance. o Periorbital edema is most often observed in severe cases, usually involving the lower lids. ❑ Evaluation of conjunctival scrapings for cellular contents is a useful diagnostic tool for determining the basis of ocular inflammation.
6
Conjunctivitis

o Eosinophils suggest allergic conjunctivitis.

⇒ The absence of eosinophils does not rule out an allergic etiology. ⇒ Eosinophils may not be present in the upper layers of the conjunctiva. o Mast cells are often observed in patients with vernal keratoconjunctivitis. o Neutrophils usually indicate an infectious etiology, usually bacterial. o Mononuclear cells and lymphocytes are observed with viral infection.

Characteristic appearance of allergic conjunctivitis.
Reprinted from Wiley L, Arffa R, Fireman P Allergic . Immunologic Ocular Diseases. In: Fireman P Slavin R (eds). , Atlas of Allergies. 2nd ed. London: Mosby-Wolfe; 1996: 192. By permission of the publisher Mosby.

Diagnostic Testing
The general principles of diagnostic testing are included in Volume 1: Diagnostic Testing, page 31. Specific tests used for diagnosing conjunctivitis are included here.

Skin Testing
❑ Usually not required for seasonal allergic conjunctivitis

unless immunotherapy is contemplated. ❑ Limited testing may be helpful when there are conjunctival symptoms without any previous seasonal history. ❑ Can assist in confirming the diagnosis of, and directing environmental control measures for, perennial allergic conjunctivitis. ❑ Contact testing can be useful for patients with eyelid involvement. ❑ Referral to an allergy/immunology specialist for consultation and/or comanagement is recommended.
Conjunctivitis

7

8

Conjunctivitis

Differential diagnosis of conjunctival inflammatory disorders:
Type of Conjunctivitis Vernal Atopic KeratoGiant Papillary Contact Bacterial Viral Chlamydial

Allergic

Signs
Lymphocyte Lymphocyte Lymphocyte Lymphocyte PolymorphoEosinophil Eosinophil Eosinophil nuclear cell Monocyte Lymphocyte

Predominant cell type

Mast cell Eosinophil

Chemosis – ++ Stringy mucoid + + – ++ Stringy mucoid Clear white ± ++ ++ – – – – + –

+

±

±

±

–

±

Polymorphonuclear cell Monocyte Lymphocyte ± ++ ±

± ± +

Lymph node

–

Cobble stoning

–

Discharge

Clear mucoid

++ Clear mucoid ++ Mucopurulent Mucopurulent – – –

Eyelid involvement

–

Symptoms
++ ± + ± ± + ± ++ ++ + – – – + ± – + ± – + ±

Pruritus

+

Gritty sensation

±

Seasonal variation

+

+ = present; – = not present; ± = may or may not be present

Reproduced with permission from Gotto A, Current Practice of Medicine. Vol 2. Philadelphia: Current Medicine; 1999: 4.

When is it allergy?
❑ Ocular itching is a key distinguishing feature. o Differentiate from burning, scratchy, or sandy

eyes. ❑ Ocular discharge is mucoid, watery, or stringy. o Purulent and/or morning matting is common with infection. ❑ Lid involvement is usually associated with atopic or contact dermatitis. o Occasionally seen with seborrhea or rosacea. o Commonly associated with staphylococcal colonization. ❑ Patient has history of other allergic diseases: o Atopic dermatitis o Allergic rhinitis o Asthma

Ocular pruritus suggests allergy.

Symptoms suggesting nonallergic origin:
❑ Burning, scratchy,

sandy eyes ❑ Dandruff ❑ Rosacea

Masqueraders of ocular allergy:
❑ Infectious conjunctivitis (bacterial, viral,

chlamydial) ❑ Dry eye ❑ Blepharoconjunctivitis (inflammation of lid margin) ❑ Trauma ❑ Foreign substance ❑ Drug-related, toxic, or chemical reaction ❑ Neoplasm ❑ Nasolacrimal duct obstruction ❑ Uveitis ❑ Episcleritis or scleritis

Conjunctivitis

9

Managing the Patient with Allergic Conjunctivitis
Nonpharmacologic Management
Four general principles of allergy management
1. Avoid factors that cause symptoms. 2. Use appropriate medications. 3. Evaluate for immunotherapy. 4. Educate and follow-up.
❑ Avoiding the offending allergen(s) is critical. ❑ In some cases, physical removal of the antigens from

the eye by irrigation with a saline solution or artificial tears may provide temporary relief of symptoms. ❑ Cold compresses may provide symptomatic relief.

Pharmacologic Therapy
Antihistamines
❑ Can be administered orally or topically to relieve

Symptomatic relief may be provided by:
❑ Cold compresses. ❑ Irrigation with saline

solution or artificial tears.

Topical antihistamines provide rapid relief of acute ocular symptoms, particularly itching.

itching. ❑ Topical antihistamines provide rapid onset of relief for acute ocular symptoms, particularly ocular itching. ❑ Oral antihistamines often only partially relieve allergic ocular symptoms, but may be preferred by some patients. o Nonsedating antihistamines are preferred. o Sedating antihistamines are associated with drowsiness and may cause dryness of mucous membranes.

Topical Vasoconstrictors
❑ Topical decongestants do not treat the underlying

pathophysiology of ocular allergy, but can: o Decrease eye redness. o Relieve ocular itching. ❑ Indicated for the treatment of mild to moderate allergic conjunctivitis. ❑ Are often combined with antihistamines. ❑ Common side effects may include: o Transient stinging or burning on instillation o Decreased accommodation o Blurred vision

10

Conjunctivitis

Mast Cell Stabilizers
❑ Indicated for the relief of mild to moderate ocular

allergy. ❑ Most effective when administered prophylactically. o Some patients report an improvement of symptoms within 24 to 48 hours after initiating therapy with cromolyn. ❑ The most common side effect is transient burning or stinging upon administration. ❑ May be used in conjunction with a systemic antihistamine to treat more difficult cases of ocular allergy.

Nonsteroid Anti-inflammatory Medications
❑ Effective in relieving ocular itching associated with

seasonal allergic conjunctivitis.

Corticosteroids
❑ Use of topical corticosteroids is indicated for severe

cases of ocular allergy. o Patients should be closely monitored for: ⇒ Cataracts ⇒ Glaucoma ⇒ Superinfections of the cornea and conjunctivae (i.e., herpes). o Treatment with topical corticosteroids should be initiated and monitored by an ophthalmologist. ❑ Rarely, a short course (e.g., 5 to 7 days) of oral corticosteroids may be necessary for acute exacerbations of severe ocular symptoms.

Allergen Immunotherapy
❑ May be effective in reducing the symptoms of seasonal

and perennial allergic conjunctivitis. ❑ Should be reserved for patients with: o Severe disease o Significant associated rhinitis ❑ Referral to an allergy/immunology specialist for consultation and/or comanagement is recommended.

Conjunctivitis

11

General management of allergic conjunctivitis by symptom severity:
Mild Symptoms
❑ Avoidance

Moderate Symptoms
❑ Avoidance

Severe Symptoms
❑ Avoidance

measures ❑ Cold compresses and artificial tears ❑ Oral nonsedating antihistamine

measures ❑ Cold compresses and artificial tears ❑ Oral nonsedating antihistamine ❑ Topical antihistamine/ decongestant combination OR ❑ Topical antihistamine With or without: ❑ Topical mast cell stabilizer OR ❑ Topical NSAID ❑ Consider allergen immunotherapy

measures ❑ Cold compresses and artificial tears ❑ Oral nonsedating antihistamine ❑ Topical corticosteroid (with ophthalmologist consultation) ❑ Allergen immunotherapy

12

Conjunctivitis

Tips for administering eye drops:
❑ Lie down. ❑ Steady hand by resting it on face. ❑ Eyes open method: o Approach eye from side or top. o Keep eye open, and pull down lower lid,

forming a pouch. o Place drop into the pouch. o Look up to prevent blinking and draining of medicine. ❑ Eyes closed method: o Close eye. o Place drop on inside corner of eyelid. o Open eye slowly for drop to fall in. o Look up to prevent blinking and draining of medicine. ❑ When administering multiple eye medications, wait 5 to 15 minutes before delivering second medication to same eye in order to prevent dilution. ❑ Eye drop medical devices are available. ❑ Avoid contaminating eye dispenser from contact with eye, eyelid, eyelashes, or finger.

Specialist Referral
❑ Referral to an allergy/immunology specialist for

consultation and/or comanagement is recommended for patients having: o To undergo immunotherapy. o Skin testing for diagnosis. o Eye symptoms that do not resolve with treatment and that may be secondary to other allergic conditions (e.g., atopic dermatitis, contact dermatitis). ❑ Referral to an ophthalmologist for consultation and/or comanagement is recommended for patients having: o To use topical corticosteroids. o Severe symptoms of questionable allergic origin. o Difficult-to-control vernal conjunctivitis. o Difficult-to-control giant papillary conjunctivitis.
Conjunctivitis

13

Ophthalmic preparations for allergic conjunctivitis*:
Antihistamines Emedastine difumarate, 0.05% (Emadine®) Levocabastine hydrochloride, 0.05% (Livostin™) Antihistamine-vasoconstrictor combinations Pheniramine, 0.3%-naphazoline, 0.025% (Naphcon-A®, Opcon-A®, Occuhist®) Antazoline, 0.5%-naphazoline, 0.05% (Vasocon-A®) Mast cell stabilizers Cromolyn sodium, 4% (Crolom®) Lodoxamide tromethamine, 0.1% (Alomide®) Nedocromil, 2% (Alocril®) Cromolyn sodium, 4% (Opticrom®) Pemirolast, 0.1% (Alamast®) Antihistamine/mast cell stabilizers Ketotifen fumarate, 0.025% (Zaditor™) Olopatadine hydrochloride, 0.1% (Patanol®) Azelastine, 0.05% (Optivar®) Nonsteroid anti-inflammatory medications Ketorolac tromethamine, 0.5% (Acular®) Diclofenac sodium, 0.1% (Voltaren®)

Corticosteroids Dexamethasone, 0.1% Dexamethasone sodium phosphate, 0.05% Fluorometholone, 0.1%, 0.25% Fluorometholone acetate, 0.1% Loteprednol etabanate, 0.2% (Alrex®) Medrysone, 1% Prednisolone acetate, 0.12%, 0.125%, 1% Prednisolone sodium phosphate, 0.125%, 1%
*

This list is not all-inclusive; consult package inserts for full prescribing information.

14

Conjunctivitis

References
Abelson MB, Schaefer K. Conjunctivitis of allergic origin: immunologic mechanisms and current approaches to therapy. Surv Ophthalmol 1993; 38: S115-132. Bielory L. Allergic and immunologic disorders of the eye. In: Middleton E, Reed CE, Ellis EF, et al (eds). Allergy Principles and Practice, 5th ed. St. Louis:Mosby, 1998: 1148-1161. Foster CS. The pathophysiology of ocular allergy: current thinking. Allergy 1995; 50: S6-9. Friedlander MH. A review of the causes and treatment of bacterial and allergic conjunctivitis. Clin Therap 1995; 17: 800-810. Friedlander MH. Conjunctivitis of allergic origin: clinical presentation and differential diagnosis. Surv Ophthalmol 1993; 38: S105-114. Friedlander MH. Management of ocular allergy. Ann Allergy Asthma Immunol 1995; 75: 212-222. Hingorani M, Lightman S. Therapeutic options in ocular allergic disease. Drugs 1995; 50: 208-221. Jackson WB. Differentiating conjunctivitis of diverse origins. Surv Ophthalmol 1993; 38: S91-104. Lieberman PL, Blaiss MS. Allergic diseases of the eye and ear. In: Patterson R, Grammer LC, Greenberger PA (eds). Allergic Diseases - Diagnosis and Management, 5th ed. Philadelphia: Lippincott-Raven, 1997: 223-251. Titi MJ. A critical look at ocular allergy drugs. Am Fam Physician 1996; 53: 2637-2646.

Conjunctivitis

15

16

Urticaria and Angioedema
Urticaria
Urticaria is characterized by the appearance of pruritic, erythematous, cutaneous elevations that blanch with pressure, indicating the presence of dilated blood vessels and edema in the dermis. ❑ In its simplest form, urticaria is the same wheal-andflare reaction observed within minutes after histamine is injected into the skin. ❑ Urticaria may occur virtually anywhere on the body and is usually associated with itching. o Individual lesions usually resolve within 24 hrs. ❑ Acute urticaria is a self-limited disorder that usually lasts for a few days. o Commonly caused by an allergic reaction to a food or drug. o May be associated with a viral illness in children. ❑ Chronic urticaria lasts longer than 6 weeks. o 50% of chronic urticaria patients continue to have symptoms beyond 6 months. o 20% have problems for 10 years or more. o The cause is usually not identified.

Acute urticaria is very common, affecting 10% to 20% of the population at some time in their lives.
❑ Acute urticaria usually

lasts for a few days. ❑ Chronic urticaria lasts longer than 6 weeks.

Acute urticaria.
Photo provided by Anthony Gaspari, M.D., University of Rochester.

Urticaria and Angioedema

17

Angioedema
Angioedema is similar to urticaria but occurs in deeper skin layers.
❑ The area with Angioedema is caused by the same, or similar edematous process as urticaria, but angioedema extends into the deep dermis and/or subcutaneous tissue. ❑ Angioedema occurs in deeper skin layers which contain fewer mast cells and sensory nerve endings. ❑ Angioedema often involves the face, tongue, extremities, or genitalia. ❑ An area with angioedema shows swelling, but the skin may appear normal. o Lesions have little or no associated pruritus, and the swelling may be painful or burning in nature. o Swellings do not usually occur in dependent areas, are asymmetrically distributed, and are transient.
(A) (B)

angioedema shows swelling, but the skin may appear normal.

Urticaria and angioedema often occur together. Types of urticaria and angioedema:
❑ Acute ❑ Chronic ❑ Physical
o Cold-induced o Heat-induced o Cholinergic o Exercise-induced

(anaphylaxis) o Dermographism (dermatographism) o Delayed pressureinduced o Solar-induced o Aquagenic ❑ Urticaria with vasculitis ❑ Hereditary angioedema ❑ Acquired C1-esterase inhibitor deficiency

Facial angioedema following allergen exposure (A) and resolution after treatment (B).
Reprinted from Tharp M, Levine M, Fireman P Urticaria and angioedema. . In: Fireman P Slavin R (eds). Atlas of Allergies. 2nd ed. London: , Mosby-Wolfe; 1996: 250. By permission of the publisher Mosby.

Pathology of Urticaria and Angioedema
❑ Urticaria and angioedema are associated with the

release of various vasoactive mediators from activated cells or enzymatic pathways. o Histamine is the major mediator of these reactions. o The key mechanism of histamine release is the classic combination of an antigen with IgE antibody on the surface of mast cells and basophils. (See Volume 1: Background, page 5.)

18

Urticaria and Angioedema

o The major responses to histamine (and the other

mediators): ⇒ Itching ⇒ Vasodilation (erythema) ⇒ Increased vascular permeability ⇒ An axon reflex (increasing the extent of the reaction) ❑ Urticaria can be induced through allergen exposure by any route. o Allergic reactions to foods and drugs are common causes of acute urticaria. o In the majority of chronic urticaria cases, an inciting agent is not identified.

Urticaria can be induced through allergen exposure by any route.
❑ Allergic reactions to foods

Classification
Chronic Urticaria
❑ Lesions appear quickly and usually disappear in less

and drugs are common causes of acute urticaria.

than 24 hours. ❑ Characterized by a non-necrotizing perivascular mononuclear cell infiltrate with an accumulation of mast cells. ❑ Most cases are idiopathic (i.e., etiological factor unidentified): o An autoimmune origin is suspected. o IgG anti-IgE receptor antibodies are implicated as a potential cause. o Not associated with atopy.

Idiopathic urticaria is the most common chronic form of the disease. The lesions of chronic urticaria appear quickly and usually disappear within 24 hours.

Physical Urticaria and Angioedema
❑ Some types of urticaria or angioedema can be

reproducibly induced by: o Environmental factors (such as changes in temperature) o Direct stimulation of the skin by: ⇒ Pressure ⇒ Stroking ⇒ Vibration ⇒ Light ❑ Physical urticarias, except the delayed forms, typically last only 1 to 2 hours.

Most physical urticarias last only 1 to 2 hours.
❑ Delayed physical

urticarias can last longer.
Urticaria and Angioedema

19

Cold-induced Urticaria Cold-induced urticaria is caused by a rapid change in temperature, not by the absolute temperature.
❑ Follows exposure to a rapid change in ambient

Fatalities by drowning have been reported secondary to coldinduced hypotension.
❑ Patients should be

warned that swimming alone, or in cold water, is dangerous.

temperature. o It is the rapid change in temperature, not the absolute temperature, that induces the response. ❑ Response is characterized by rapid onset of: o Pruritus o Erythema o Edema (swelling) ❑ Swelling is usually confined to portions of the body in contact with the cold stimulus. o Swelling of the tongue and pharynx is less common. o Laryngeal edema and abdominal complaints are rare. ❑ Total body exposure, such as while swimming, may cause massive mediator release, resulting in hypotension. ❑ Symptoms may be maximal after the exposed area is warmed. ❑ Symptoms may occur while outside on cold, windy days, and while holding cold objects. ❑ Reported with diseases characterized by abnormal immunoglobulins with cold-dependent properties: o Cryoglobulinemia o Cold agglutinin disease o Cryofibrinogenemia o Paroxysmal cold hemoglobinuria ⇒ Most cases are idiopathic.

Positive ice cube test, demonstrating cold urticaria. 20
Photo provided by Anthony Gaspari, M.D., University of Rochester.
Urticaria and Angioedema

Heat-induced Urticaria
❑ May be localized or generalized (cholinergic). ❑ May occur alone or with other forms of physical allergy

(e.g., combined cold-induced urticaria, local heatinduced urticaria). o Pathogenesis of local heat-induced urticaria is unknown.

Cholinergic Urticaria
❑ Characterized by pruritus and small punctate wheals

surrounded by a prominent erythematous flare associated with: o Exercise o Hot showers o Sweating o Anxiety ❑ Lesions may affect the entire body except for the palms, soles, and axilla. ❑ Often remits within several years, but can last for more than 20 or 30 years.

Characteristic lesions of cholinergic urticaria.
Reprinted from Tharp M, Levine M, Fireman P Urticaria and . angioedema. In: Fireman P Slavin R (eds). Atlas of Allergies. , 2nd ed. London: Mosby-Wolfe; 1996: 260. By permission of the publisher Mosby.

Urticaria and Angioedema

21

Exercise-induced Anaphylaxis Exercise-induced anaphylaxis should be considered a MEDICAL EMERGENCY.
❑ Patients should (see Anaphylaxis, page 128). ❑ Caused by exercise. ❑ Characterized by hives, lesions larger than the small punctate lesions characteristic of cholinergic urticaria, and at times, angioedema. o May be associated with fatigue, diffuse warmth, and/or wheezing. o May be associated with hypotension and collapse. ❑ Food ingestion within 3 to 4 hours of excerise has been associated with increased risk. o Reactions may be IgE-mediated, related to a specific food, or may be a nonspecific effect of ingestion. ❑ Role of aspirin or NSAIDs in aggravating exerciseinduced anaphylaxis is unclear. ❑ Exercise should be discontinued at the onset of symptoms. ❑ Patients should avoid exercise during the postprandial period.

discontinue exercise at the first sign of symptoms. ❑ Patients need to avoid exercise during the postprandial period. ❑ Patients should not exercise alone.

Dermographism (or dermatographism)
❑ Gentle stroking of the skin provokes local pruritus,

erythema, and swelling within 5 to 15 minutes. ❑ Affects 2% to 5% of the population. ❑ Commonly seen in patients with chronic urticaria.

Dermatographism seen after light stroking of the skin.
Reprinted from Tharp M, Levine M, Fireman P Urticaria and angioedema. . In: Fireman P Slavin R (eds). Atlas of , Allergies. 2nd ed. London: Mosby-Wolfe; 1996: 260. By permission of the publisher Mosby.

22

Urticaria and Angioedema

Delayed Pressure-induced Urticaria
❑ Manifestations occur 4 to 6 hours after pressure

has been applied. ❑ Commonly seen in patients with chronic urticaria. ❑ Symptoms may occur on: o Skin covered by tight clothing. o Hands after activity such as hammering. o Feet after walking. o Buttocks after prolonged sitting.

Solar-induced Urticaria
❑ A rare disorder in which exposure to sun light

(at specific wavelengths) causes urticaria within 1 to 3 minutes.

Aquagenic Urticaria
❑ A rare form of urticaria with small wheals

(indistinguishable from those of cholinergic urticaria) after contact with water, regardless of its temperature. ❑ May occur with cholinergic urticaria. ❑ Histamine release into the circulation has been documented upon challenge with water.

Aquagenic urticaria is a rare form of urticaria that occurs after contact with water, regardless of its temperature. The lesions of urticaria with vasculitis may occur with:
❑ Serum sickness ❑ Systemic lupus

Urticaria with Vasculitis
❑ Lesions: o Usually last longer than 24 hours. o Are more prominent on lower extremeties. o Have a purpuric component. o Leave a stippling of hemosiderin pigment. o Are associated with constitutional symptoms,

including: ⇒ Arthralgia/arthritis ⇒ Gastrointestinal complaints ⇒ Low grade fever ⇒ Respiratory complaints

erythematosus (SLE) ❑ Viral infections (including hepatitis B and hepatitis C) ❑ Lyme disease

Urticaria and Angioedema

23

❑ May occur with: o Serum sickness o Systemic lupus erythematosus (SLE) o Viral infections (including hepatitis B and hepatitis C) o Lyme disease ❑ Biopsy of lesions shows necrotizing vasculitis involving

small venules (hypersensitivity angiitis). o Immunofluorescent studies demonstrate deposition of immunoglobulins and complement.

Hereditary Angioedema
Episodes of hereditary angioedema may be associated with abdominal complaints which may lead to unnecessary surgery.
❑ Comanagement with
❑ Onset usually occurs in adolescence and early

an allergy/immunology specialist is recommended.

adulthood. ❑ Not associated with urticaria. o Not part of differential diagnosis of urticaria. ❑ Not pruritic. ❑ Episodes may be associated with abdominal complaints. o May lead to unnecessary surgical procedures. ❑ Acute episodes may be caused by trauma (e.g., accidents, dental work, surgery), but often no causal factor is identified. ❑ Comanagement with an allergy/immunology specialist is recommended.

Acquired C1 -esterase Inhibitor Deficiency
Patients with acquired C1-esterase inhibitor deficiency may have a similar presentation as hereditary angioedema, but this disease is not inherited.
❑ In adults, may be associated with lymphoma or other

malignancies. ❑ Due to decreased levels of C1-esterase inhibitor activity. ❑ Patients may have a similar presentation as hereditary angioedema, but this disease is not inherited.

24

Urticaria and Angioedema

Diagnosing the Patient with Urticaria and Angioedema
Medical History
❑ The history is critical. Consider: o Drug reactions o Reactions to foods o Inhalation, ingestion of, or contact with antigens o Infections (e.g., bacterial, fungal, viral, helminthic) o Insect bites (e.g., papular urticaria) o Collagen vascular diseases:

Urticaria may be associated with:
❑ Systemic lupus

⇒ Cutaneous vasculitis ⇒ Serum sickness ⇒ Systemic lupus erythematosus o Exacerbation by aspirin, NSAIDS, or food additives o Environmental or physical factors, including: ⇒ Cold ⇒ Heat ⇒ Pressure ⇒ Sun/UV ⇒ Water o Malignancy (e.g., lymphoma, Hodgkin’s disease) o Systemic mastocytosis o Thyroid disease

erythematosus ❑ Serum sickness ❑ Cutaneous vasculitis ❑ Lymphoma ❑ Hodgkin’s disease ❑ Thyroid disease

Recent viral upper respiratory tract infections, especially in children, are the most common cause of urticaria caused by infections.

Urticaria is rarely the sole sign of an underlying disease.

Typical lesions of urticaria.
Reprinted from Tharp M, Levine M, Fireman P Urticaria and . angioedema. In: Fireman P Slavin R (eds). Atlas of Allergies. , 2nd ed. London: Mosby-Wolfe; 1996: 250. By permission of the publisher Mosby.
Urticaria and Angioedema

25

❑ The lesions of urticaria: o Appear suddenly. o Are usually pruritic. o Rarely lasts longer than 24 hours (for individual

lesions). o May continue to recur for indefinite periods.

When diagnosing urticaria, the history is critical in terms of exposure to: Anything ingested (e.g., foods, medications, nutritional supplements) should be considered a potential cause of urticaria or angioedema. Is it urticaria?
❑ Did the lesions ❑ Foods ❑ Drugs ❑ Contact allergens ❑ Viral illness in children ❑ Insect bites ❑ Environmental and physical factors

Physical Examination
❑ A thorough physical examination is necessary to

appear suddenly? ❑ Are the lesions pruritic? ❑ Do individual lesions tend to resolve within 24 hours? ❑ Have lesions recurred over indefinite periods of time?

exclude diseases that are commonly associated with skin manifestations.

Diagnostic Testing
The general principles of diagnostic testing are included in Volume 1: Diagnostic Testing page 31. Specific tests used for diagnosing urticaria and angioedema are included here. ❑ Clues in the medical history and physical examination may suggest a need for further testing. o Selective laboratory testing should be based on the history and physical examination. ❑ Blood counts are usually normal. ❑ Consider infections (e.g., hepatitis, mononucleosis).

26

Urticaria and Angioedema

Diagnostic testing for patients with urticaria and angioedema:
For patients with suspected: Vasculitis with arthralgia Consider:
❑ CBC with differential ❑ Erythrocyte

sedimentation rate ❑ Blood urea nitrogen (BUN) ❑ Creatinine ❑ Urinalysis ❑ Possibly, antinuclear antibody titer (ANA) Physical-induced urticaria or angioedema Cold-induced urticaria
❑ Challenge testing to

document a reaction
❑ Testing for

cryoglobulinemia and cold agglutinins Food-induced uticaria
❑ Skin testing or in vitro

testing for suspect foods, THEN CONSIDER provocation tests with the specific foods Chronic urticaria in which the individual lesions: ❑ Commonly remain in the same location for longer than 24 hours. ❑ Have a pigmented or purpuric component. ❑ Are painful.
❑ 4 mm punch biopsy

Urticaria and Angioedema

27

Considerations for the Differential Diagnosis of Urticaria and Angioedema
Erythema Multiforme
❑ Presentation can range from urticarial lesions to overt

bullous lesions. ❑ Compared to urticarial lesions, the lesions of erythema multiforme typically: o Last longer. o Are peripherally distributed, except in severe cases.

Bullous Pemphigoid
❑ Is an autoimmune bullous eruption.

Dermatitis Herpetiformis
❑ Is an autoimmune vesiculobullous disorder. ❑ Lesions: o Are markedly pruritic. o Usually appear on elbows, knees, buttocks,

shoulders, sacral area.

Urticaria Pigmentosa
❑ A cutaneous disorder of mast cell hyperplasia. ❑ Characterized by “Darier’s sign.” o Individual lesions develop a wheal when the overlying

skin is stroked.

It may be difficult to identify and eliminate factors causing chronic urticaria. Four general princples of allergy management
1. Avoid factors that cause symptoms. 2. Use appropriate medications. 3. Evaluate for immunotheropy. 4. Educate and follow-up
28
Urticaria and Angioedema

Managing the Patient with Urticaria and Angioedema
Nonpharmacologic Management
Avoidance
❑ Minimize (ideally, avoid) exposure to causal factors as

demonstrated by history or challenge. Causal factors: o Increase the underlying inflammation (e.g., allergens, viral respiratory infections). o Provoke symptoms (e.g., exercise, cold air). ❑ Minimize (ideally, avoid) modulating factors (e.g., stress, exertion, alcohol). ❑ Patients with chronic urticaria usually should avoid ACE inhibitors, aspirin, and NSAIDs.

Palliative Measures
❑ A tepid shower or oatmeal bath may temporarily relieve

pruritus.

Pharmacologic Management
The most effective treatment for acute attacks of either urticaria or angioedema is epinephrine (see Anaphylaxis, page 122).

Antihistamines
❑ Oral H1-antihistamines are the treatment of choice for

the management of urticaria and angioedema. ♦ Nonsedating antihistamines are preferred. ♦ Clarinex® (desloratadine) is indicated for chronic idiopathic urticaria. ❑ For chronic urticaria, antihistamines can usually: ♦ Reduce the pruritus. ♦ Minimize lesions. ♦ Allow patients to be reasonably comfortable and to function normally. ❑ Adding other medications to the H1-antihistamines may be useful for some patients: ♦ H2-antihistamines ♦ Tricyclic antidepressants (doxepin) ♦ Leukotriene pathway modifiers ⇒ Further clinical studies are necessary to assess the role of leukotriene modifiers in therapy. ❑ If the patient is unresponsive to conventional antihistamines, consider referral to an allergy/immunology or dermatology specialist for evaluation and/or comanagement.

Oral H1-antihistamines are the treatment of choice for managing urticaria and angioedema.
❑ Nonsedating

antihistamines are preferred.

Newer H1-antihistamines Nonsedating:
❑ Fexofenadine ❑ Loratadine

Less-sedating:
❑ Cetirizine
(see Volume 1: Pharmacologic Therapy, page 51)

Corticosteroids
❑ If the combination of H1-antihistamines,

H2-antihistamines, and leukotriene pathway modifiers are not enough to control chronic urticaria, addition of an oral corticosteroid is indicated. ❑ An alternate-day regimen is effective in most patients, with the corticosteroid being slowly withdrawn. ❑ Continue medications which have been helpful, concomitant with the corticosteroid. ❑ Start tapering the corticosteroid dose as soon as the urticaria is under control: ♦ Usually within 3 weeks. ♦ Can be variable. ❑ Referral to an allergy/immunology or dermatology specialist for evaluation or comanagement is recommended.
Urticaria and Angioedema

29

Special Considerations for Managing Urticaria and Angioedema
Papular Urticaria
❑ Use local cold compresses. ❑ Apply calamine lotion and/or topical corticosteroids.

Cold-induced Urticaria
❑ Cyproheptadine is reported to be useful. ❑ Nonsedating antihistamines may be used if sedation

is a problem.

Cholinergic Urticaria
❑ Hydroxyzine is reported to be useful. ❑ Nonsedating antihistamines may be used if sedation

is a problem.

Dermographism
❑ Patients should wear loosely fitting clothing.

Delayed Pressure-induced Urticaria
❑ Antihistamines may have little effect. ❑ NSAIDs may help. ❑ Patients with severe disease often require

corticosteroids. ❑ Direct therapy toward chronic urticaria if the pressureinduced urticaria is associated with chronic disease.

Specialist Referral
❑ Referral to an allergy/immunology specialist and/or

dermatologist for evaluation, consultation, comanagement, or additional patient education is recommended when the patient: o Fails to respond to treatment. o Has complications. o Requires hospitalization. o Needs oral corticosteroid therapy. ❑ Referral to an allergy/immunology specialist for evaluation, consultation, or comanagement is recommended for: o Anaphylaxis (see Anaphylaxis, page 115) o Assistance with diagnostic testing of possible allergic factors.
30
Urticaria and Angioedema

Features of common types of urticaria:
Type of Urticaria Chronic idiopathic Principal Clinical Features Profuse or sparse generalized, pink or pale edematous papules or wheals, often annular with itching. Itchy, linear wheals with a surrounding bright-red flare at sites of scratching or rubbing. Itchy pale or red swelling at sites of contact with cold air, cold surfaces, or fluids. Associated Angioedema Diagnostic Test Special Considerations

+/–

Symptomatic dermatographism

_

Light stroking of skin causes an immediate wheal with itching. In most cases, 10 min application of ice produces wheal within 5 min after removal of ice. Application of pressure perpendicular to skin produces persistent red swelling after a latent period of 1 to 4 hr. 30 to 120 sec irradiation by a 2.5 kW solar simulator (290690 nm) produces wheals within 30 min. Exercise or a hot shower elicits eruption.

Wear loosefitting clothing.

Cold

+/–

Delayed Pressure

Large painful or itchy red swelling at sites of pressure (soles, palms, or waist), lasting ≥ 24 hr.

+

NSAIDs may help in mild to moderate cases; corticosteroids may be required.

Solar

Itchy pale or red swelling at site of exposure to ultraviolet or visible light.

+/–

Cholinergic

Itchy, monomorphic pale or pink wheals on trunk, neck, and limbs, and classic “pencil-erasersized” wheals.

+/–

Use hydroxyzine if other antihistamines are not effective.

+ = Associated with angioedema. +/– = May or may not be associated with angioedema. – = Not associated with angioedema.

Urticaria and Angioedema

31

References
Beltrani VS. Urticaria and angioedema. Dermatol Clinics 1996; 14: 171-198. Black AK, Greaves MW. Urticaria and angioedema. In: Kay AB (ed). Allergy and Allergic Diseases. Blackwell Science Ltd. (Vol 2). Malden, 1997: 1586-1607. Champion RH, Roberts SO, Carpenter RG, Roger JH. Urticaria and angioedema. A review of 554 patients. Br J Dermatol 1969; 81: 588-597. Charlesworth EN. Urticaria and angioedema: a clinical spectrum. Ann Allergy Asthma Immunol 1996; 76: 484-496. Cooper KD. Urticaria and angioedema: diagnosis and evaluation. Clin Rev Allergy 1991; 25: 166-176. Gannon T. Dermatologic emergencies: when early recognition can be lifesaving. Postgrad Med 96: 67-82. Ghosh S, Kanwar AJ, Kaur S. Urticaria in children. Ped Dermatol 1993; 10: 107-110. Greaves M, Lawlor F. Angioedema: manifestations and management. J Am Acad Dermatol 1991; 25: 155-165. Greaves MW. Chronic urticaria. N Engl J Med 1995; 332: 1767-1772. Huston DP Bressler RB. Urticaria and , angioedema. Med Clin N America 1992; 76: 805-840. Joint task force on practice parameters. Exercise-induced anaphylaxis. J Allergy Clin Immun. 1998; 101: S523-524. Juhlin L, Landor M. Drug therapy for chronic urticaria. Clin Rev Allergy 1992; 10: 349-369. Kaplan AP Urticaria and angioedema. . In: Kaplan AP (ed). Allergy, 2nd ed. Philadelphia: Harcourt Brace, 1997: 573-592. Kaplan AP Urticaria and angioedema. In: . Middleton E, Reed CE, Ellis EF, et al (eds). Allergy Principles and Practice, 5th ed. St. Louis: Mosby-Year Book, 1998: 1104-1122. Lehach JG, Rosenstreich DL. Clinical aspects of chronic urticaria. Clin Rev Allergy 1992; 10: 281-301. Leung DYM, Diaz LA, DeLeo V, Soter NA. Allergic and immunologic skin disorders. J Am Med Assoc 1997; 278: 1914-1923. Mahmood T. Urticaria. Am Fam Physician 1995; 51: 811-816. Ormerod AD. Urticaria: recognition, causes, and treatment. Drugs 1994; 48: 717-730. Soter NA. Acute and chronic urticaria and angioedema. J Am Acad Dermatol 1991; 25: 146-154. Tharp MD. Chronic urticaria: pathophysiology and treatment approaches. J Allergy Clin Immunol 1996; 98: S325-330. Wade JP Liang MH, Sheffer AL. Exercise, induced anaphylaxis: epidemiologic observations. Prog Clin Biolog Res 1989; 297: 175-182.

32

Urticaria and Angioedema

Contact Dermatitis
❑ Contact dermatitis refers to a broad range of

reactions resulting from direct contact of an exogenous agent with the surface of the skin.
o The agent can be an allergen or an irritant.

⇒ Once the inflammatory process has started,

the pathologies of both types of reactions are similar.
⇒ Microscopic and clinical findings are

Contact dermatitis is the most common occupational disease and one of the most commonly acquired skin diseases in adults.
❑ 30% to 40% of all

often identical.
❑ All age groups are affected. ❑ Precipitating factors may be found in any

occupational illness. ❑ 90% of occupational skin disease.

workplace, home, school, or play area.
o Of the more than 6 million chemicals in the

environment, about 3,000 are known contact allergens.
o Under certain specific circumstances, almost any

chemical can cause contact dermatitis.

Irritant responses account for 80% of contact dermatitis reactions. Allergic responses account for 20%. Of the more than 6 million chemicals in the environment, about 3,000 are known contact allergens.

Allergic contact dermatitis on the hand due to silvadene cream.
Photo provided by Anthony Gaspari, M.D., University of Rochester.

Mechanisms
Allergic contact dermatitis involves:
❑ Allergic response against hapten-self complex which is

recognized by the immune system as foreign. ❑ Immunologic memory and specificity. o T-cell-mediated inflammatory response to a chemically reactive hapten (i.e., the allergen). ⇒ Hapten reacts with protein to form antigen.
Contact Dermatitis

33

Irritant Contact Dermatitis
❑ Is not defined by a single clinical entity. ❑ Represents a clinical spectrum based on the: o Type of injury. o Dermatologic reaction to injury. ❑ Reaction involves mediator released by “nonspecifically”

activated T cells. o The stimulus comes into direct contact with the keratinocytes of the epidermis. o Does not involve haptens. o The inflammation is concentration dependent. o Many allergenic and nonallergenic substances can be irritants at high concentrations. o The reaction causes direct tissue injury.
Classification Allergic contact dermatitis % of Reactions 20% Causative Agent Allergen Mechanism
❑ Inflammatory

Irritant contact dermatitis

80%

Irritant

process resulting from T-cellmediated response to chemically reactive hapten. ❑ Antigen recognized by immune system is likely to be hapten-self complex. ❑ Direct tissue damage by an irritant. ❑ Concentration dependent toxic reaction.

34

Contact Dermatitis

Diagnosing the Patient with Contact Dermatitis
❑ Diagnosis is usually based on: o History o Distribution of the eruption o Diagnostic testing ❑ Early diagnosis and treatment are essential to: o Minimize disruption to everyday activities. o Prevent long-term skin sensitivity.

Medical History
❑ When diagnosing contact dermatitis, consider: o Age o Current and previous occupations o Hobbies, leisure activities o Use of cosmetics and skincare products o Application of cosmetics and skincare products to

When diagnosing contact dermatitis, ask the patient about:
❑ Hobbies ❑ Sports activities ❑ Gardening ❑ Home improvement

other people (e.g. cosmetologist) o Medications (topical and systemic) o Personal and family history of allergy o History of eczema and other atopic manifestations o Details of other skin conditions o Weather conditions (e.g., cold, wind, low humidity) ❑ Unless the cause is immediately obvious, identify all substances the patient applies topically, including: o Moisturizers o Shaving creams o Cosmetics o Shampoos o Skin creams o Soaps o Perfumes o Powders o Sunscreens o Medications o Hair dyes

projects ❑ Use of chemicals at work ❑ Painting ❑ Specific contact with: o Adhesives o Resins o Lubricating oils

Contact Dermatitis

35

Common causes of allergic contact dermatitis:
Substance Sources
Poison ivy, poison oak, mango Philodendron, hydrangea, chrysanthemum, tulip bulbs Metal alloys, hairpins, earrings, zippers, door handles, silverwork, hair dyes and bleaches, insecticides, fungicides Cement, leather, household cleaners, bleaches Cosmetics, fabrics, cigarettes, newsprint and newspaper, preservatives, cardboard, plywood, rubber cement, shoes Dyes, fungicides
*

Common causes of irritant contact dermatitis:
❑ Soaps ❑ Detergents ❑ Cleaners ❑ Alkalis (e.g., bleach) ❑ Benzocaine ❑ Antimicrobials ❑ Formalin ❑ Latex

Rhus (urushiol) Other plant-derived saps Nickel sulfate*

Potassium dichromate* Formaldehyde*

Ethylenediamine* Mercaptobenzothiazole Thiuram
*

Rubber products Fungicides, insecticides, rubber products Hair dyes, fur dyes, chemicals used in photographic work

Paraphenylenediamine*

*

Included in the screening tray for standard diagnostic testing.

Allergic contact dermatitis over temporal area secondary to nickel present in eyeglass frame.
Photo provided by Anthony Gaspari, M.D., University of Rochester.

36

Contact Dermatitis

Jobs with increased risks for developing allergic contact dermatitis:
Occupation Hairdressers Builders and plasterers Electronic assembly workers Healthcare workers Substance(s) Perm solutions, tints Chromate in cement and plaster Epoxy resins and hardeners

Mechanics and machinists Oils Antimicrobials, formalin, latex, benzocaine

Occupational allergic contact dermatitis to paraphenylenediamine (black/ brown hair dye) in hairdresser.
Photo provided by Anthony Gaspari, M.D., University of Rochester.

Physical Examination
Most reported cases of contact dermatitis occur on the hands.
❑ However, contact dermatitis can occur on any mucous

membrane or skin surface. ❑ Allergic or irritant contact eruptions may have an atypical appearance if superimposed on a pre-existing dermatosis. ❑ The eyelids, neck, and genitalia are among the most readily sensitized areas. o The palms, soles, and scalp are more resistant.

Contact Dermatitis

37

The hands are the most common sites of contact dermatitis.
❑ Causative agents may be

❑ Causative agents (i.e., allergens, irritants) may be

transferred to secondary body sites by the hands. o Nail polish allergy may present as eyelid, rather than finger, dermatitis.

transferred to secondary body sites by the hands.

Secondary site of contact dermatitis on the eyelids due to contact with nail polish on the patient’s hands.
Photo provided by Anthony Gaspari, M.D., University of Rochester.

Eruptions may be broadly classified as acute or chronic.
❑ However, no sharp delineation exists. ❑ The acute phase is marked by: o Multiple, severe vesicles or bullae filled with clear

fluid. ⇒ When vesicles rupture, oozing, eroded skin emerges (eczema). o Edema o Erythema o Secondary infection with gram positive bacteria frequently occurs. ❑ The subacute phase progresses with: o Increased erythema o Decreased edema o Papules replacing vesicles ❑ Chronic lesions show: o Minimal redness and swelling. o More pronounced scaling, hyperkeratosis, and lichenification of affected skin.

38

Contact Dermatitis

Characteristics of contact dermatitis lesions:
Acute Lesions
❑ Multiple,

Subacute Lesions

Chronic Lesions
❑ Less erythma ❑ Less edema ❑ Increased

❑ Increased erythema severe vesicles or bullae filled ❑ Decreased with clear fluid edema ❑ Edema ❑ Papules ❑ Erythema ❑ Secondary infection with gram positive bacteria is common

scaling ❑ Hyperkeratosis ❑ Lichenification

Urticaria reactions (wheal-and-flare responses) are now recognized as an important subtype of allergic contact reactions.
❑ The reported incidence of contact urticaria has

increased rapidly in the last few years. ❑ Many new cases are caused by natural rubber latex proteins. ❑ Latex allergy may also cause “hand and glove” contact dermatitis. (see Latex Reactions, page 103)

Positive scratch test to latex
Photo provided by Anthony Gaspari, M.D., University of Rochester.

Contact Dermatitis

39

Differentiating Allergic and Irritant Contact Dermatitis
It may be difficult to differentiate allergen and irritant eruptions, especially after they become chronic. Irritant contact dermatitis usually develops gradually, after repeated exposures.
❑ Causes a variety of
❑ However, they may present very different inflammatory

responses.

Irritant Contact Dermatitis
❑ Develops gradually in most instances, after repeated

symptoms other than pruritus (e.g., pain, stinging, burning).

exposures. ❑ The cutaneous response: o Can cause a variety of symptoms other than pruritus, such as: ⇒ Pain ⇒ Smarting ⇒ Stinging ⇒ Burning ⇒ Abnormal sensations (without shmulus) o Has sharply demarcated redness with: ⇒ Heat ⇒ Tenderness ⇒ Swelling o May have apparent necrosis in severe cases. ❑ Severe acute reactions caused by potent irritants, such as acids, often resemble burns. ❑ The patient usually can identify the contactant (i.e., the contacted substance) because eruptions develop rapidly.
Acute bullous contact dermatitis to rhus (allergic) complicated by self-treatment with bleach (irritant).
Photo provided by Anthony Gaspari, M.D., University of Rochester.

Allergic contact dermatitis often flares 24 to 48 hours after allergen exposure.
❑ Most patients complain

Allergic Contact Dermatitis
❑ Cutaneous reactions: o Often flare 24 to 48 hours after exposure to allergen. o Pruritus is a common complaint. ❑ Repeated exposures to allergens to which the patient is

of pruritus.
40
Contact Dermatitis

sensitive, or exposures to irritants (e.g., in the workplace), can obscure the pattern of response.

Clinical features of allergic and irritant contact dermatitis:
Clinical Feature Reaction delay after contact Sharp demarcation Time for clinical resolution after removal of agent Allergic Many hours to 5 to 6 days May occur Many days Irritant Usually within 48 hours Often typical Frequently diminished after 96 hours

❑ The severity of both allergic and irritant reactions is

determined by the: o Chemical nature of the contactant o Concentration o Duration of exposure o Site of exposure o Hydration of the skin o Degree of occlusion o Local trauma

Repeated exposures, multiple exposures, or mixed exposures (i.e., to allergens and irritants) can obscure the pattern of response, making diagnosis difficult.

The distribution of the eruption often provides the best clue to the cause of contact reactions.
❑ In most cases, the reaction is localized and most

pronounced at the point of maximum contact. ❑ Contactants carried as dust or aerosols often affect the ears, eyelids, face, neck, and other exposed areas. ❑ Liquid contactants often leave a characteristic drip or smear pattern on exposed skin. ❑ Cosmetics, skin care products, and topically applied Allergic contact dermatitis to medications often polysporin ointment around cause reactions in surgical incision. the areas of Photo provided by Anthony Gaspari, application. M.D., University of Rochester.

A widespread eruption can develop when:
❑ Irritation is severe. ❑ Allergic reactions

are strong. ❑ Antigen exposure is systemic.

A detailed diary of day-to-day activities may be helpful to identify patterns of exposure to allergens and irritants.
Contact Dermatitis

41

Most contact dermatitis reactions are localized and most pronounced at the point of maximum contact. Severe reactions may cause a widespread eruption:
❑ Severe irritation ❑ Strong allergic reactions ❑ Systemic antigen

❑ Work-related exposure is most often seen on the hands. ❑ Indirect contact with clothing or animal fur containing

the contactant may also cause eruptions. ❑ Systemic administration of medications previously used topically, and to which the patient is sensitized, may elicit a generalized eruption. ❑ Cross-contamination can occur. ❑ An allergen applied to a certain area may cause dermatitis at a distant site by inadvertent spreading (e.g., nail polish causing secondary dermatitis on face).

exposure

The pattern of the lesions often provides the best clue to the cause of contact reactions.

Left: Pruritic vesicles arranged linearly are characteristic of poison ivy dermatitis. Right: Poison ivy (rhus).
Reprinted from Slavin R. Allergic contact dermatitis. In: Fireman P Slavin R (eds). Atlas of Allergies. 2nd ed. London: , Mosby-Wolfe; 1996: 220. By permission of the publisher Mosby.

Photosensitivity reactions are a type of contact dermatitis.
❑ Systemic photosensitivity reactions: o Usually involve systemic drug exposure. o Are expressed symmetrically on sun-exposed skin. ❑ Contact photosensitivity reactions: o Involve topical contact with a photosensitizer. o Are expressed only on skin exposed to both the

photosensitizer and ultraviolet light.

42

Contact Dermatitis

❑ Phototoxic reactions: o Often resemble bad sunburn, BUT peak at 48 hours

Masqueraders of contact dermatitis:
❑ Atopic dermatitis ❑ Dyshidrotic eczema ❑ Psoriasis ❑ Fungal infections ❑ Seborrheic dermatitis ❑ Xerosis

rather than 12 to 24 hours as in sunburn. o The skin is usually tender and erythematous. o Severe phototoxic reactions can produce bullae. ❑ Photoallergens tend to produce an eczematous, pruritic dermatitis with photodistribution.

Contact photosensitivity reaction with after-shave fragrance as the photosensitizer.
Photo provided by Anthony Gaspari, M.D., University of Rochester.

Diagnostic Testing
The general principles of diagnostic testing are included in Volume 1: Diagnostic Testing, page 31. Specific tests used for diagnosing contact dermatitis are included here.

Patch testing can help identify or confirm most suspected T-cell-mediated, delayed hypersensitivity, contact allergens.
❑ These tests are especially useful when the distribution

of lesions suggests several possible sensitizing agents. ❑ Proper patient selection, correct choice of allergens at appropriate test concentrations, and interpretation of results require experience and a detailed knowledge of proper test procedures. ❑ Patch testing is usually reserved for patients with chronic, recurring, or unrelenting contact dermatitis and/or lichenification, because management depends on isolating and avoiding the antigen.

Patch testing is the gold standard for contact allergen identification.

Contact Dermatitis

43

❑ Three visits are required for patch testing: o Visit 1 – patch application o Visit 2 – patch removal (48 hours after application) o Visit 3 – test reading (72 to 96 hours after application) ❑ Refer for patch testing any patient with: o Contact dermatitis that fails to heal in three months,

especially involving the hands, face, ears, eyes, or anogenital area. o Leg ulcers. o Contact dermatitis from working with chemicals. ❑ The testing procedure should be deferred until the patient’s dermatitis is not severe. o Testing a patient with a flaring or severe dermatitis increases the risk of false-positive results and may significantly worsen the patient’s condition.

Patch text reaction to nickel.
Photo provided by Anthony Gaspari, M.D., University of Rochester.

Patch test reaction (also known as delayed type hypersensitivity) to glove material used in chemical processing of rubber.
Photo provided by Anthony Gaspari, M.D., University of Rochester.

44

Contact Dermatitis

Managing the Patient with Contact Dermatitis
❑ In most cases, contact dermatitis is localized and

subsides within 3 to 4 weeks following removal of the antigen, if identified. ❑ Treatment consists of three steps: 1. Minimize, (ideally, completely avoid) contact with the offending agent. 2. Treat the active dermatitis. 3. Prevent recurrence from re-exposure to the offending agent.

Three steps for treating contact dermatitis
1. Minimize contact. 2. Treat the active dermatitis. 3. Prevent re-exposure and recurrence.

Nonpharmacologic Management
❑ Patient counseling is critical for: o Learning how to minimize (ideally, avoid) contact

with allergens. o Finding substitutes for necessary products. o Protecting from re-exposure and recurrence. ❑ Patients should also protect their skin from other irritants while healing.

When treating dermatitis, liberal use of emollients is recommended to protect the recovering skin.
❑ Lubricating baths with

oatmeal or bath oils also are soothing to inflamed skin.

Pharmacologic Management
Acute Eruptions
❑ Apply open wet compresses with tap water, saline,

or Domeboro solution (calcium, aluminum sulfate astringent) to the vesicular/bullous eruptions. ❑ Topical application of a Class I super-high-potency corticosteroid cream is often required. o Use the Class I topical corticosteroid for brief periods (usually 2 weeks). o Discontinue if dermatitis resolves. o Taper to a Class II or Class III topical corticosteroid if dermatitis is still present. ❑ Consider treating with oral corticosteroids, tapering course based on extent, severity, and patient contraindications. o Usual prednisone doses: ⇒ Adults: 0.5 to 1 mg/kg/day, tapering over 3 to 10 days depending on severity. ⇒ Children: 0.5 to 1 mg/kg/day, tapering over 3 to 5 days depending on severity.

Topical application of a Class I super-highpotency corticosteroid cream is often required for acute eruptions, but should only be used for short periods of time.
❑ Discontinue if dermatitis

resolves. ❑ Taper to a Class II or Class III topical corticosteroid if dermatitis is still present after 2 weeks. ❑ A short course of oral corticosteroid may be required for severe cases. ❑ Use an appropriate oral antibiotic if infection is present.
Contact Dermatitis

45

o Avoid recurrent use of oral corticosteroids. o If patient is nonresponsive following the course of

corticosteroid, consider referral to an allergy/immunology or dermatology specialist. ❑ Treat infection (if present) with appropriate oral antibiotics.

Chronic or Subacute Dermatitis
❑ Minimize exposure to the contactant.

When using a corticosteroid cream to treat chronic or subactute dermatitis:
❑ Avoid using:
o Class I, Class II, or

❑ Apply a topical corticosteroid: o Avoid use of Class I, Class II, or Class III corticosteroid

Class III creams on the face. o Class I or Class II creams on the axillae, breasts, and genitalia. ❑ Supervise the amount of topical corticosteroid dispensed. ❑ Assess response to treatment with follow-up visits.

creams on the face. o Abstain from using Class I or Class II topical agents on the axillae, breasts, and genitalia. o Supervise the amount of topical corticosteroid dispensed. o Assess response to treatment with follow-up visits.

Severe and Chronic Dermatitis
❑ Minimize exposure to contactants. ❑ Liberal use of medium- to high-potency topical

corticosteroids is sufficient in most cases. o Topical corticosteroid therapy should be tapered as the eruption clears and replaced with bland emollients. ❑ For very severe acute cases, oral corticosteroids (0.5 mg/kg/day) tapered over 5 to 14 days may be warranted. ❑ For severe chronic dermatitis, prolonged and aggressive topical corticosteroid treatment may be needed. ❑ Liberal use of emollients is recommended to protect the recovering skin. o Lubricating baths with oatmeal or bath oils are soothing to inflamed skin. ❑ Oral antihistamines can relieve associated pruritis. o Nonsedating antihistamines are preferred (see Volume 1: Pharmacologic Therapy, page 51). o Older sedating antihistamines may be used at night to relieve pruritus and help the patient sleep.

46

Contact Dermatitis

❑ Avoid topical calamine preparations containing

diphenhydramine as this agent can act as a contact sensitizer. ❑ Recalcitrant cases may require adjuvant therapy with psoralen and ultraviolet A (PUVA) or ultraviolet B (UVB). ❑ Tar has mild anti-inflammatory effects and can be useful, with topical corticosteroids, for treating chronic lichenified dermatitis. Use as: o A 5% crude coal tar in petrolatum. o OR tar bath oil soaks.

Avoid topical calamine preparations containing diphenhydramine as this agent can act as a contact sensitizer. General treatments for pruritus include:

Oral antihistamines can relieve the itching of contact dermatitis.
❑ Nonsedating antihistamines are preferred. ❑ Older sedating antihistamines may be used

❑ Calamine lotion ❑ Oatmeal baths ❑ Milk soaks

at night to relieve pruritus and help the patient sleep.

These treatments alone may be appropriate for children with self-limited allergic contact dermatitis (e.g., poison ivy).

Special Considerations for Managing Contact Dermatitis
❑ It is important to consider the vehicles used for topical

treatments. o Topical gels and ointments are best to use after the dermatitis has been dried by compresses (e.g., saline or Domeboro’s compresses). ⇒ Gels are drying and are preferred for acute vesicular dermatitis. ⇒ Ointments are best for chronic lichenified dermatitis. ⇒ Creams work well when a patient does not tolerate ointments for aesthetic reasons. ❑ Allergic contact dermatitis to topical medications can be a significant problem, due to preservatives. o If allergy to a topical cream is suspected, try a preparation without preservatives until the offending chemical is identified by patch testing.

Contact Dermatitis

47

Prolonged use of corticosteroid creams can lead to skin atrophy and other complications.
❑ Close follow-up is

o Some corticosteroid ointments lack preservatives and

important. ❑ Referral to a specialist is recommended.

may be useful. ⇒ Triamcinolone 0.1% ointment ⇒ Fluocinolone acetonide 0.025% ointment ⇒ Betamethasone valerate 0.1% ointment ❑ Topical corticosteroids can also act as sensitizers. o If topical corticosteroid therapy exacerbates the skin condition: ⇒ Consider topical corticosteroid allergy. ⇒ Confirm with patch testing.

Specialist Referral
❑ Referral to an allergy/immunology specialist and/or

dermatologist for consultation, comanagement, or additional patient education is recommended when the patient: o Requires diagnostic testing. o Fails to respond to treatment. o Has difficulty using topical treatments. o Has complications. o Requires prolonged treatment with topical corticosteroids. o Needs oral corticosteroid therapy. o Requires hospitalization.

48

Contact Dermatitis

Topical corticosteroids with potency rankings based on vasoconstrictor assays: (See Volume 2: Atopic Dermatitis, page 128,
for commonly used topical corticosteroids listed by brand name.) Group VII: Least Potent
Hydrocortisone hydrochloride 1.0%, 2.5% (cream, lotion, ointment) Hydrocortisone acetate 1.0%, (cream, lotion, ointment) Pramoxine hydrochloride 1.0% (cream, lotion, ointment)

Group VI
Alclometasone dipropionate 0.05% (cream, ointment) Betamethasone valerate 0.1% (lotion) Desonide 0.05% (cream) Fluocinolone acetonide 0.01% (cream, solution)

Group V
Betamethasone dipropionate 0.05% (lotion) Betamethasone valerate 0.1% (cream) Fluocinolone acetonide 0.025% (cream) Fluticasone propionate 0.05% (cream) Flurandrenolide 0.05% (cream) Hydrocortisone valerate 0.2% (cream) Prednicarbate 0.1% (cream)

Group IV
Hydrocortisone valerate 0.2% (ointment) Flurandrenolide 0.05% (ointment) Fluocinolone acetonide 0.025% (ointment) Mometasone furoate 0.1% (cream) Triamcinolone acetonide 0.1% (cream)

Least Potent
Group III Group II
Use after consultation with specialist

Moderately Potent

Group I: Most Potent
Most likely to cause side effects. Use only for short periods of time and on areas that are lichenified. DO NOT USE on face, diaper area, genitalia, axillae. Use after consultation with specialist.

Amcinonide 0.1% (cream, lotion) Betamethasone dipropionate 0.05% (cream) Betamethasone valerate 0.1% (ointment) Desoximetasone 0.05% (cream) Diflorasone diacetate 0.05% (cream) Fluocinonide 0.05% (cream) Halcinonide 0.1% (ointment, solution) Triamcinolone acetonide 0.1% (ointment)

Amcinonide 0.1% (ointment) Betamethasone dipropionate 0.05% (ointment) Desoximetasone 0.05% (gel) Fluocinonide 0.05% (gel, ointment, solution) Halcinonide 0.1% (cream) Mometasone furoate 0.1% (ointment)

Betamethasone dipropionate 0.05% augmented (cream, ointment) Clobetasol propionate 0.05% (cream, ointment) Halobetasol propionate 0.05% (cream, ointment)

Moderately Potent
Group VII agents are least likely to cause long-term side effects. Group I agents are most likely to cause long-term side effects.

Most Potent

w
49

Contact Dermatitis

w

References
Basketter D, Dooms-Goossens A, Karlberg A-T, Lepoittevin J-P The chemistry of . contact allergy: why is a molecule allergenic? Contact Dermatol 1995; 32: 65-73. Beltrani VS, Beltrani VP Contact dermatitis. . Ann Allergy Asthma Immunol 1997; 78: 160-175. Cohen DE, Brancaccio RR. What is new in clinical research in contact dermatitis. Dermatol Clinics 1997; 15: 137-148. Drake LA, Dinehart SM, Farmer ER, et al. Guidelines of care for the use of topical glucocorticosteroids. J Am Acad Dermatol 1996; 35: 615-619. Drake LA, Dorner W, Goltz RW, et al. Guidelines of care for contact dermatitis. J Am Acad Dermatol 1995; 32: 109-113. Funk JO, Maibach HI. Horizons in pharmacologic intervention in allergic contact dermatitis. J Am Acad Dermatol 1994; 31: 999-1014. Kalish RS. Contact dermatitis, and photoallergic reactions. In: Kaplan AP (ed). Allergy, 2nd ed. Philadelphia: W.B. Saunders, 1997: 603-619. Klaus MV, Wieselthier JS. Contact dermatitis. Am Fam Physician 1993; 48: 629-632. Leung DYM, Diaz LA, DeLeo V, Soter NA. Allergic and immunologic skin disorders. J Am Med Assoc 1997; 278: 1914-1923. Nasir A, Gaspari AA. Contact dermatitis: clinical perspectives and basic mechanisms. Clin Rev Allergy Immunol 1996; 14: 151-184. Shaw S. Managing contact dermatitis. The Practitioner 1996; 240: 16-24. Slavin RG. Contact dermatitis. In: Patterson R, Grammer C, Greenberger PA (eds). Allergic Diseases, 5th ed. Philadelphia: Lippincott-Raven, 1997: 413-424. Wolf JE. Contact dermatitis. In: Conn HF (ed). Conn’s Current Therapy. Philadelphia: WB Saunders, 1998: 845-846.

50

Contact Dermatitis

Drug Reactions
Allergic drug reactions are:
❑ Based on drug-specific immune mechanisms. ❑ Caused by a variety of drug classes. ❑ Present in a wide array of clinical syndromes. ❑ Able to affect any tissue or organ.

Any drug or biologic agent can potentially cause an adverse allergic reaction.
❑ Allergic drug reactions account for 5% to

10% of all adverse drug reactions.

The allergenic potential of drugs depends in part on their chemical properties.
❑ Higher molecular weight protein drugs are more

likely to produce allergic reactions:
o Insulin o Antisera o Recombinant proteins ❑ Low molecular weight drugs are usually haptens

The allergenic potential of drugs depends in part on their chemical properties.
❑ Many allergic reactions

to drugs are due to the metabolites rather than to the parent drug.

and must first combine with carrier proteins to induce an immune response:
o Antibiotics ❑ Drugs often induce an immune response, but only

a small number of patients actually experience clinical hypersensitivity reactions.

Dermatologic reactions represent the most common form of allergic drug reaction.
Drug Reactions

51

Classification of Allergic Drug Reactions
IgE-mediated Reactions
Most allergic drug reactions can be categorized as:
❑ IgE-mediated ❑ Cytotoxic/cytolytic ❑ Immune complex ❑ T-cell-mediated (see Anaphylactic and Anaphylactoid Reactions, page 115) ❑ Require the presence of IgE antibodies specific for the drug allergen. o Drug allergen binds to IgE antibodies that are bound to the surface of mast cells or basophils. o Antibody cross-linking o Cell activation o Mediator release ⇒ Preformed mediators: • Histamine • Heparin • Proteases (e.g. tryptase) • Eosinophil chemotactic factors • Neutrophil chemotactic factor ⇒ Newly formed mediators: • Leukotrienes • Prostaglandins • Thromboxanes • Platelet Activating Factor (PAF) ❑ Anaphylaxis is the classic clinical manifestation. o Any manifestation of anaphylaxis may occur singly or in combination: ⇒ Urticaria ⇒ Hypotension ⇒ Pruitus ⇒ Angioedema ❑ Examples of causative agents: o Penicillin (immediate reaction) o Blood products o Polypeptide hormones o Vaccines

IgE-mediated reactions require the presence of IgE antibodies specific for the drug allergen.
❑ Anaphylaxis is the

classic clinical manifestation.

52

Drug Reactions

Cytotoxic/Cytolytic Reactions
❑ IgG or IgM antibodies and complement interact with

a drug allergen that is associated with cell membranes, resulting in destruction of cells. ❑ Most often involves blood elements. ❑ Clinical manifestations: o Immune hemolytic anemia o Thrombocytopenia o Granulocytopenia ❑ Examples of causative agents: o Penicillin o Quinidine o Sulfonamides o Methyldopa

Cytotoxic/cytolytic reactions involve the interaction of IgG or IgM antibodies and complement with a drug allergen associated with cell membranes.
❑ Blood elements are

most frequently affected.

Immune Complex Reactions
❑ Drug combines with antibodies to form immune

complexes in the blood. o Deposit in blood vessels and basement membranes. o Result in local or disseminated inflammatory reactions. ❑ Complex formation can result in: o Platelet aggregation o Macrophage activation o Complement activation, leading to: ⇒ Vascular permeability changes ⇒ Mast cell activation ⇒ Production and release of inflammatory mediators and chemotactic agents. ⇒ Neutrophil influx • Toxic substances released from neutrophils result in local tissue destruction. ❑ Circulating immune complexes cause serum sickness reactions.

Drug-immune complex reactions cause serum sickness responses and druginduced lupus syndromes.

Drug Reactions

53

o Symptoms of serum sickness include:

⇒ Fever ⇒ Skin lesions ⇒ Lymphadenopathy ⇒ Arthralgias ⇒ Nephritis ⇒ Hepatitis ❑ Immune complex reactions also can cause druginduced lupus syndromes. o Examples of causative agents of drug-induced lupus: ⇒ Hydralazine ⇒ Procainamide ⇒ Isoniazid ⇒ Phenytoin

T-cell-mediated Reactions
❑ Mediated by lymphocytes. ❑ Require memory T cells specific for drug allergen. o Upon exposure to antigen, T cells become activated

Allergic contact dermatitis is the classic clinical manifestation of T-cell-mediated drug allergy reactions.

and produce an inflammatory response. ❑ Allergic contact dermatitis is the classic clinical manifestation.

Other Reactions
Delayed Dermatologic Reactions
❑ Clinical manifestations: o Macropapular, morbilliform, or erythematous rashes o Exfoliative dermatitis o Photosensitivity reactions o Eczema ❑ Examples of causative agents: o Penicillins o Sulfonamides

54

Drug Reactions

Drug-induced Fever
❑ May occur in response to an inflammatory process or

may be a manifestation of a drug reaction, such as a pharmacologic effect on: o CNS (resulting in altered temperature regulation) o Tissues ❑ Variable pattern of fever presentation: o Low grade and continuous o Spiking and intermittent ❑ Occurs most commonly with antibiotics. ❑ Generally improves or resolves within 48 to 72 hours of withdrawing the causative agent.

Drug-induced fever shows a variable pattern:
❑ Low grade and

continuous ❑ Spiking and intermittent

Hepatic Hypersensitivity Reactions
❑ Hepatocellular necrosis or hepatitis reactions: o Elevated serum transaminases o Hepatomegaly o Jaundice ❑ Cholestatic reactions: o Jaundice o Elevated serum alkaline phosphatase ❑ Examples of causative agents: o Phenothiazines o Sulfonamides o Halothane o Phenytoin o Isoniazid

Drug-induced fever occurs most commonly with antibiotics.
❑ Generally improves or

resolves within 48 to 72 hours of withdrawing the causative agent.

Pulmonary Hypersensitivity Reactions
❑ Alveolar or interstitial pneumonitis. ❑ Pneumonitis with associated fever, rash, eosinophilia. ❑ Examples of causative agents: o Nitrofurantoin o Sulfasalazine

Drug Reactions

55

Aseptic Meningitis from Drugs
❑ Causative agents: o NSAIDs o Radiocontrast media o Anti-CD3 ❑ Usually resolves within 48 hours of withdrawing the

agent.

Nonimmunologic Drug Reactions Nonimmunologic drug reactions have similar clinical manifestations as immunologic drug reactions but do not appear to involve an immunologically mediated reaction between drug and antibodies.
❑ First exposure to
❑ Similar clinical manifestations as immunologic drug

reactions. ❑ Do not appear to be initiated by an immunologically mediated reaction between drug and antibodies. ❑ Potential mechanisms include anaphylactoid reactions. (see Anaphylactic and anaphylactoid reactions, page 117) ❑ Exhibit “first-dose phenomenon:” o First exposure to therapeutic levels of the drug causes a reaction.

therapeutic levels of the drug can cause a reaction.

Examples of nonimmunologic drug reactions:
❑ Shock, urticaria, bronchospasm, and anaphylaxis

after radiocontrast media ❑ Aspirin- (or NSAID-) induced asthma ❑ Opiate-related urticaria ❑ Protamine-induced pulmonary hypertension ❑ NSAID-related urticaria ❑ Hemolytic anemia caused by primaquine ❑ Flushing during vancomycin infusion (“red man syndrome”)

Multiple Drug Allergy Syndrome
❑ Some patients react or perceive a reaction to multiple

drugs. ❑ These are difficult patients to evaluate and should be referred to an allergy/immunology specialist.

56

Drug Reactions

Diagnosing Drug Allergy
Medical History
❑ Investigation and identification of a drug responsible

for a suspected allergic reaction depends largely on circumstantial evidence and the clinical skills of the clinician. ❑ The most important consideration in evaluating a patient for possible drug allergy is a suspicion by the clinician that an unexplained symptom or sign may be due to a drug being administered. ❑ Obtain a complete history of all drugs the patient has taken within the past month and a history of any drug reactions. o Be aware of the drugs most frequently implicated in allergic reactions.

The most important consideration in evaluating possible drug allergy is a suspicion that an unexplained symptom or sign may be due to a drug being administered.
❑ The most useful

Factors to consider in differential diagnosis:
❑ Time of onset of reaction after starting the drug. ❑ Time of resolution after discontinuing the drug. ❑ Type of rash (pruritic/urticarial). ❑ Other system involvement (joints, lymph nodes, liver). ❑ Associated viral infections. ❑ Concurrent drug use. ❑ History of other drug reactions. ❑ Family history of drug allergy. ❑ Presence of chronic diseases. ❑ History of atopy.

diagnostic tool is recovery following discontinuation of treatment with the suspected drug.

Concurrent disease and therapy may influence the risk for adverse drug reactions. Patients who have:
❑ Systemic lupus erythematosus may have increased

prevalence of allergic drug reactions. ❑ AIDS are at significantly higher risk for cutaneous reactions from drugs. ❑ Received protamine-containing insulin (e.g., NPH-insulin) are at significantly greater risk of anaphylaxis from protamine reversal of heparinization used in cardiopulmonary bypass.

Patients who have received protaminecontaining insulin (e.g., NPH-insulin) are at significantly greater risk of anaphylaxis from protamine reversal of heparinization used in cardiopulmonary bypass.
57

Drug Reactions

Consider temporal course of reaction.
Reaction Type Immediate Accelerated Onset After Drug Typical Clinical Administration Manifestations Within the first hour 1 to 72 hours Anaphylaxis Urticaria and/or angioedema Rash Fever Rash Serum-sicknesslike reactions Fever

Late

More than 72 hours

Diagnostic Testing
The general principles of diagnostic testing are included in Volume 1: Diagnostic Testing, page 31. Specific tests used for diagnosing drug reactions are included here.

Skin Testing
❑ Referral to and/or consultation with an

Skin testing for drug allergy can be done for a limited number of agents:
❑ Penicillin ❑ Insulin ❑ Heterologous serum ❑ Streptokinase ❑ Chymopapain

A positive skin test suggests a diagnosis and may predict which persons are at greater risk of future reactions.

allergy/immunology specialist is recommended. ❑ Detects only IgE antibody. ❑ Preferable to in vitro tests for specific IgE because of its greater sensitivity and specificity. ❑ Limited number of agents can be reliably skin tested: o Penicillin o Insulin o Heterologous serum o Streptokinase o Chymopapain ❑ A positive test result: o Suggests a diagnosis. o May predict which persons are at greater risk of future reactions.

58

Drug Reactions

Managing the Patient with Drug Allergy
Treatment of Severe Immediate or Accelerated Reactions
❑ Administer epinephrine (if the reaction severity

dictates). ❑ Discontinue the drug. ❑ Prescribe antihistamines for urticarial reactions, angioedema, and pruritus. o Nonsedating antihistamines have less impact on the patient’s daily activities and are preferred. ❑ Oral corticosteroids may be considered.

Four general principles of allergy management
1. Avoid factors that cause symptoms. 2. Use appropriate medications. 3. Evaluate for immunotherapy. 4. Educate and follow-up.

Treatment of Late Reactions
❑ Discontinue all nonessential suspect drugs. o Allergic reactions may progress despite cessation of

the causative agent. ❑ For very mild maculopapular rashes, antihistamines alone may be adequate. ❑ For more severe rashes, those that progress, or those associated with other symptoms, treatment may include a short course of oral corticosteroids. ❑ A short course of oral corticosteroids may be used in combination with antihistamines for: o Serum-sickness-like reactions, including: ⇒ Fever ⇒ Nephropathy ⇒ Arthralgias ⇒ Neuropathy o Exfoliative dermatitis o More severe maculopapular rashes

“Treating Through”
❑ Continuing drug treatment in the presence of a

suspected allergic reaction to the drug. ❑ Consultation with an allergy/immunology specialist is recommended. ❑ For extreme circumstances (i.e., when the continued use of causative agent is essential), antihistamines and corticosteroids are given to suppress the allergic reaction.

“Treating through” is continuing drug treatment in the presence of a suspected allergic reaction to the drug.

Drug Reactions

59

❑ Potential risks: o Progression of skin rash to exfoliation or Stevens-

Johnson syndrome o Internal organ involvement (e.g., renal disease, liver disease, CNS disease) o Fatality

Premedication (radiocontrast media)
❑ Prophylactic administration of antihistamines and

corticosteroids alone, or in combination with beta-adrenergic agents, has been effective for reducing the incidence and severity of anaphylactoid reactions to radiographic contrast media. ❑ Consider for patients who: o Previously reacted to radiocontrast media. o Have a history of allergy and/or asthma. o Are receiving beta-adrenergic blockers or ACE inhibitors. o Have cardiovascular disease. ❑ Use of lower osmolality media is recommended for patients at risk. ❑ Patients should be informed that a reaction can still occur. ❑ Referral to an allergy/immunology specialist for comanagement of premedication is recommended.

Typical premedication schedule:
Time before procedure 13 hours 7 hours 1 hour Drug Adult Dose 50 mg po 50 mg po 50 mg po Child Dose* 0.5-1 mg/kg po max 50 mg 0.5-1 mg/kg po max 50 mg

Prednisone Prednisone Prednisone Diphenhydramine Ephedrine**

0.5-1 mg/kg po max 50 mg 50 mg po/im 1 mg/kg max 50 mg 25 mg po 0.5 mg/kg max 25 mg

*

Consensus of Task Force recommends protocol for children; no sciencebased evidence for dosages exists. These reactions are rare in children but isolated cases have been reported. Some schedules recommend albuterol 4 mg in place of ephedrine; either agent may be withheld should the patient have unstable angina, arrhythmia, or other cardiac risks. Use of an H2-blocker (e.g., cimetidine) 1 hour before procedure has been used as an optional additional therapy.

**

60

Drug Reactions

Desensitization for IgE-mediated Reactions
❑ Achieved by administering progressive doses of the

drug until a full therapeutic dose is clinically tolerated. ❑ Indicated for patients with established drug allergy where no substitute for the responsible drug is available and treatment is essential. ❑ Desensitization may be possible for some agents: o Antibiotics o Insulin ❑ Drug administration must be continued for full treatment course once desensitization has been achieved. ❑ MUST BE PERFORMED UNDER THE DIRECTION OF AN ALLERGY/IMMUNOLOGY SPECIALIST KNOWLEDGEABLE ABOUT THE PROCEDURE, and only in a medical facility where appropriate equipment and trained personnel are available to treat any reaction that may occur.

Desensitization for Non-IgE-mediated Drug Reactions
❑ Desensitization is successful for aspirin and NSAIDs. ❑ A prolonged desensitization (up to 1 month) has been

Referral to an allergy/immunology specialist for consultation or comanagement is recommended for patients being considered for desensitization for drug reactions. Initiation of desensitization should be administered:
❑ Under the direction of

successful for some reactions: o Aspirin o Sulfamethoxazole o Alloprinol o Sulfasalazine o Gold ❑ MUST BE PERFORMED UNDER THE DIRECTION OF AN ALLERGY/IMMUNOLOGY SPECIALIST KNOWLEDGEABLE ABOUT THE PROCEDURE, and only in a medical facility where appropriate equipment and trained personnel are available to treat any reaction that may occur.

Specialist Referral
❑ Referral to an allergy/immunology specialist for

consultation and/or comanagement is recommended for the patient who: o Fails to respond to treatment. o Has complications.

an allergy/immunology specialist. ❑ Only in a medical facility where appropriate equipment and trained personnel are available to treat any reaction that may occur.

Life threatening reactions can occur, but are rare.

Drug Reactions

61

o Experiences anaphylaxis. o Requires hospitalization. o Needs a premedication protocol. ❑ Referral should also be considered when needing

assistance with diagnosis and management, particularly for: o Testing and test interpretation o Desensitization o Patient education

Specific Considerations for Managing Drug Allergy
Penicillin and Other Beta-lactam Antibiotics
Penicillin reactions are the most common allergic drug reactions. Manifestations include:
❑ Urticaria ❑ Pruritis ❑ Morbilliform rash ❑ The reaction may also
❑ Penicillin reactions are the most common allergic

include: o Angioedema o Laryngeal edema o Wheezing o Anaphylaxis o Hypotension ❑ Serious non-IgEmediated reactions, e.g.: o Stevens-Johnson syndrome o Exfoliative dermatitis

drug reactions. o Skin tests and desensitization procedures are well established. ❑ The following mechanisms have been implicated: o IgE (most common) o Circulating immune complexes o Cytotoxic- and T-lymphocyte-mediated reactions ❑ If the patient has had a previous allergic reaction, an alternative compound should be considered. ❑ The most common manifestations are: o Urticaria o Pruritis o Morbilliform rash o The reaction may also include: ⇒ Angioedema ⇒ Laryngeal edema ⇒ Wheezing ⇒ Anaphylaxis ⇒ Hypotension o Serious non-IgE-mediated reactions, e.g.: ⇒ Stevens-Johnson syndrome ⇒ Exfoliative dermatitis ❑ Considerations for choosing another antibiotic include: o Types of symptoms o Causative organism

62

Drug Reactions

o Patient factors:

⇒ Severity of illness ⇒ Risk of treatment failure ⇒ Costs ❑ In vitro cross-reactivity between penicillin and some cephalosporins is well established, but the clinical relevance is not as clear. o Consider avoiding cephalosporins in penicillinsensitive patients. o Aztreonam, a monobactam, has antigenic crossreactivity with ceftazidime, but can generally be safely administered to patients with allergies to penicillins and other beta-lactams. o Allergic reactions to cephalosporins usually occur in the absence of penicillin allergy. ❑ A nonimmunologic rash (“a measles type of rash”) is frequently seen with ampicillin and amoxicillin. o Incidence is greater with: ⇒ Concomitant viral infections (e.g., infectious mononucleosis) ⇒ Chronic lymphocytic leukemia ⇒ Hyperuricemia ⇒ Allopurinol administration o This reaction is generally not associated with an increased risk for future reactions to these drugs. o Usually occurs towards the end of a course of treatment and resolves spontaneously.

Skin tests and desensitization procedures for penicillin reactions are well established. When choosing another antibiotic for a patient with penicillin allergy, consider the:
❑ Types of symptoms ❑ Causative organism ❑ Severity of illness ❑ Risk of treatment failure ❑ Cost

Insulin Reactions
❑ Have been reported with sources isolated from: o Beef o Pork o Human (recombinant) ❑ Frequently occur after reinstituting therapy, following

a gap in treatment. ❑ May involve insulin itself or formulation additives (e.g., protamine). ❑ Are local, occurring at injection site. o Generally mild; do not require treatment. o Reactions involving systemic response rarely occur.

Drug Reactions

63

Sulfonamides
❑ A wide variety of agents, including: o Antimicrobials o Diuretics o Oral hypoglycemics o Carbonic anyhdrase inhibitors ❑ Typically cause a delayed dermatologic reaction. ❑ Drug metabolites are believed to be involved.

Local Anesthetic Agents
❑ Most reactions result from: o Vasovagal responses o Inadvertent intravenous injections o Hysterical responses (e.g., anxiety) o Epinephrine side effects ❑ A cell-mediated hypersensitivity (e.g., allergic contact

An IgE-mediated immediate-type reaction is extremely rare with local anesthetic agents.
❑ Do not accept this

dermatitis) may occur. ❑ An IgE-mediated immediate-type reaction is extremely rare. o This diagnosis should not be accepted without confirmation by an allergy/immunology specialist.

Radiocontrast Media
❑ Immediate generalized reactions occur in 2% to 3% of

diagnosis without confirmation by an allergy/immunology specialist.

patients receiving conventional radiocontrast media through intravascular infusion. ❑ Reactions are nonimmunologic. ❑ There is no association between shellfish allergy and radiocontrast media sensitivity. ❑ Premedication treatment has successfully reduced or eliminated reactions (see page 60).

Aspirin and NSAIDs
❑ Reactions may consist of: o Urticaria o Angioedema o Rhinitis o Bronchospasm o Hypotension
64
Drug Reactions

❑ Aspirin sensitivity is: o Present in 9% to 20% of adult patients with asthma. o Present in 30% to 40% of patients with nasal asthma

Aspirin sensitivity is:
❑ Present in 9% to 20%

polyps and sinusitis. o Related to age of patient and severity of disease. ⇒ Less common in children. ❑ Reactions are nonimmunologic (anaphylactoid). o Evidence indicates an abnormal metabolism of the arachidonic acid pathway with increased leukotriene production. ❑ Some cases of acute urticaria and anaphylaxis may be specific for particular agents without cross reactivity with other NSAIDs. o These cases may reflect an immunologic mechanism. ❑ Oral desensitization has been successful for patients with aspirin/NSAID-induced bronchospasm. (see page 61) ❑ Agents that are usually tolerated by aspirin-sensitive patients: o Acetominophen o Nonacetylated salicylates (e.g., sodium salicylate, salsalate)

of adult patients with asthma. ❑ Present in 30% to 40% of patients with nasal asthma polyps and sinusitis. ❑ Less common in children.

Aspirin-sensitive patients may have cross-reactivity with other NSAIDs, especially those that alter arachidonic acid metabolism. Aspirinsensitive patients can usually tolerate:
❑ Acetominophen ❑ Nonacetylated salicylates

Avian-based Vaccines
❑ Adverse reactions have been attributed to proteins

(e.g., sodium salicylate, salsalate)

cross-reactive with egg. o Adverse reactions may also occur to hydrolyzed gelatin, sorbitol, and neomycin in some vaccines. o Most immediate sensitivity reactions to measles, mumps, rubella vaccine (MMR) appear to be due to other vaccine components. ❑ True anaphylactic reactions are rare. ❑ The 1997 Recommendation of the American Academy of Pediatrics Committee on Infectious Disease suggests that children with egg allergy may routinely be given MMR without prior skin testing. o Current MMR vaccines are derived from cultures that contain insignificant amounts of cross-reactive proteins to eggs. o If there is concern, skin testing should be considered. ⇒ Referral to and/or consultation with an allergy/immunology specialist is recommended.

Oral desensitization has been successful for patients with aspirin/NSAIDinduced bronchospasm.

Drug Reactions

65

Avoid influenza vaccines in persons who have severe systemic sensitivity to egg.

❑ Skin testing with yellow fever vaccines is recommended

The 1997 Recommendation of the American Academy of Pediatrics Committee on Infectious Disease suggests that children with egg allergy may routinely be given mumps, measles, rubella vaccine without prior skin testing.
❑ If there is concern, skin

before administration to patients with a history of systemic anaphylactic reactions following egg ingestion. o Referral to and/or consultation with an allergy/immunology specialist is recommended. ❑ Influenza vaccine should be avoided for patients with severe systemic sensitivity to eggs. o Skin testing has been used in this population but is not widely accepted. o Vaccine is generally not recommended in these patients because of the yearly requirement for vaccine and the high risk of reaction. o Patients with less severe reactions to egg or allergy reactions to feathers can still receive influenza and yellow fever vaccinations.

The Food and Drug Administration (FDA) maintains a surveillance system for adverse drug reactions.
❑ Clinicians should identify and report individual

testing should be considered. o Referral to and/or consultation with an allergy/immunology specialist is recommended.

reactions observed in patients receiving any drug. ❑ Clinicians who observe an adverse drug reaction should contact either the pharmaceutical manufacturer or the Office of Epidemiology and Biostatistics (HFN-700), Center for Drug Evaluation and Research, FDA, Parklawn Building, Rockville, MD 20857. o The FDA MEDWATCH telephone number is (800) FDA-1088.

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References
Adkinson NF. Drug allergy. In: Middleton E, Reed CE, Ellis EF, et al (eds). Allergy Principles and Practice, 5th ed. St. Louis: Mosby, 1998: 1212-1224. Almén T. The etiology of contrast medium reactions. Invest Radiol 1994; 29: S37-45. Anne S, Reisman RE. Risk of administering cephalosporin antibiotics to patients with histories of penicillin allergy. Ann Allergy Asthma Immunol 1995; 74: 167-170. Anonymous. General principles of prevention of allergic drug reactions. Allergy Proc 1994; 15: 245-264. Anonymous. Medication administration: how safe is your patient? Am J Nurs 1995; October: 44-60. Blaiss MS, deShazo RD. Drug allergy. Pediatr Clin North Am 1988; 35: 1131-1147. Cohan RH, Leder RA, Ellis JH. Treatment of adverse reactions to radiographic contrast media in adults. Radiol Clin North Am 1996; 34: 1055-1076. deShazo RD, Kemp SF. Allergic reactions to drugs and biologic agents. J Am Med Assoc 1997; 278: 1895-1906. DeSwarte RD, Patterson R. Drug allergy. In: Patterson R, Grammer LC, Greenberger PA (eds). Allergic Diseases, 5th ed. Philadelphia: Lippincott-Raven, 1997: 317-412. Dykewicz MS. Drug allergy. Compr Ther 1996; 22: 353-359. Enright, T.,Chua-Lim, A.,Duda, E.,Lim, DT. The role of a documented allergic profile as a risk factor for radiographic contrast media reaction. Ann Allergy 1989; 62: 302-305. Gleckman RA, Borrego F. Adverse reactions to antibiotics: clues for recognizing, understanding, and avoiding them. Postgrad Med 1997; 101: 97-108. Gorevic PD. Drug allergy. In: Kaplan AP (ed). Allergy, 2nd ed. Philadelphia: W.B. Saunders, 1997: 620-643. Greenberger PA. Halwig JM. Patterson R. WallemarkCB. Emergency administration of radiocontrast media in high-risk patients. J Allergy Clin Immunol 1986; 77: 630-634.
Drug Reactions

James, JM, Zeiger, RS, Lester, MR, et al. Safe administration of influenza vaccine to patients with egg allergy. J Pediatrics 1998; 133: 624-628. Joint task force on practice parameters. Ann Allergy Asthma Immunol 1998; 101: S491-S503. Joint task force on practice parameters. The diagnosis and management of anaphylaxis. J Allergy Clin Immunol 1998; 101: S465-582. Mathews KP Clinical spectrum of allergic . and pseudoallergic drug reactions. J Allergy Clin Immunol 1984; 74: 558-566. Patterson R. Diagnosis and treatment of drug allergy. J Allergy Clin Immunol 1988; 81: 380-384. Purdy BH, Philips DM, Summers RW. Desensitization for sulfasalazine skin rash. Ann Intern Med 1984; 100: 512-514. Stevenson D, Simon R. Sensitivity to aspirin and noncorticosteroidal anti-inflammatory drugs. In: Middleton E, Reed CE, Ellis EF, et al (eds). Allergy Principles and Practice, 5th ed. New York: Mosby, 1998: 1225-1234. Turner WM, Milstein JB. Drug-induced diseases. In: DiPiro JT, Talbert RL, Hayes PE, Yee GC, Posey LM (eds). Pharmacotherapy: a pathophysiologic approach. New York: Elsevier Science Publishing Co., Inc. 1989: 60-68. Volz MA, Nelson HS. Drug allergy: best diagnostic and treatment approaches. Postgrad Med 1990; 87: 137-149. Weiss ME. Drug allergy. Med Clin North Am 1992; 76: 857-882. Wheeler JG, Burks AW. What to do when you suspect antibiotic hypersensitivity: choose an alternative agent, or desensitization? J Respir Dis 1996; 17: 103-114.

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Food Reactions

F

ood allergy is a group of disorders characterized by immunologic responses to specific food proteins. ❑ Prevalence is greatest in the first few years of life. o Prevalence declines over the first decade of life. o Some infants “outgrow” their food allergy to: ⇒ Eggs ⇒ Milk ⇒ Soy o Allergies usually not outgrown include: ⇒ Peanuts ⇒ Tree nuts ⇒ Fish ⇒ Shellfish ❑ Children with atopic disease are more likely to have food allergies. o Seen in approximately 35% of children with moderate to severe atopic dermatitis. ❑ Six foods account for 90% of food allergy reactions in children: 1. Milk 2. Egg 3. Peanuts 4. Wheat 5. Soy 6. Tree nuts ❑ Four foods account for 90% of food allergy in adults: 1. Peanuts 2. Tree nuts 3. Fish 4. Shellfish ❑ Proteins identified as the major allergens found in foods: o Caseins and whey in cow milk. o Ovomucoid in egg whites. o Tropomycin in shellfish. ❑ The gastrointestinal tract has a barrier system to protect the body from ingested antigens. o Includes immunologic and physiologic barrier mechanisms: ⇒ Stomach acidity ⇒ Gastrointestinal enzymes ⇒ Mucin coat ⇒ Immunoglobulins

Any food may cause a food allergic reaction. The prevalence of food allergy is greatest in the first few years of life and declines over the first decade.

Children with atopic disease are more likely to have food allergies.

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69

o Gastrointestinal absorption increases with:

⇒ Rise in stomach pH. ⇒ Ingestion of alcohol.
o An immature gastrointestinal tract may increase

the susceptibility of children to food allergy reactions.

Some food allergies may be “outgrown.”
Sometimes “outgrown” Eggs Milk Soy Usually not “outgrown” Peanuts Tree nuts Fish Shellfish

Severe lifethreatening reactions are often associated with the ingestion of peanuts, tree nuts, fish, shellfish, eggs, and milk.

90% of food allergy reactions are caused by a limited number of foods.
In Children Milk Egg Peanuts Wheat Soy Tree Nuts In Adults Peanuts Tree nuts Fish Shellfish

Food is the leading cause of anaphylaxis in children.
❑ Also is commonly seen

in adults. ❑ Symptoms may subside and then recur hours later.

Mechanisms of Food Reactions
❑ Clinical manifestations of food allergy are dependent

upon the immunologic mechanism. o IgE-mediated reactions typically present with a rapid onset of signs/symptoms. o Other adverse food reactions (non-IgE-mediated reactions) may take hours or days to become evident.

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IgE-mediated Food Allergy Reactions
❑ Are the most studied and best defined food reactions. ❑ Arise when food allergens penetrate the gastrointestinal

barrier, initiating the classical immediate hypersensitivity chain of events. ❑ Frequently cause acute urticaria/angioedema. ❑ May contribute to the pathogenesis of atopic dermatitis. ❑ May cause life-threatening events without cutaneous responses. ❑ Signs/symptoms may occur within minutes to a couple of hours. o May be limited to local involvement (oropharynx and/or gastrointestinal tract), including: ⇒ Itching/tingling of the lips, palate, tongue, or throat ⇒ Swelling of the lips or tongue ⇒ Hoarseness and sensation of tightness in throat ⇒ Dysphonia ⇒ Nausea/vomiting ⇒ Colic or abdominal cramps ⇒ Diarrhea o May involve other areas: ⇒ Skin: • Urticaria/ angioedema • Atopic dermatitis • Flushing • Itching ⇒ Airways: • Chest tightness • Wheezing • Shortness of breath ⇒ Pharynx: • Tightness • Dysphonia • Tongue swelling • Vocal cord edema ⇒ Nose: • Nasal congestion • Itching • Rhinorrhea • Sneezing ⇒ Eyes: • Ocular itching • Tearing ⇒ Systemic: • Decreased blood pressure • Loss of consciousness

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71

❑ The most severe cases involve the cardiovascular and/or

respiratory systems, resulting in food-induced anaphylaxis. o These potentially fatal reactions are usually immediate. o Symptoms may subside only to recur several hours later. o See Anaphylaxis, page 115 for further information.

The Oral Allergy Syndrome
Symptoms of throat closing are a potential systemic and lifethreatening reaction and should not be confused with oral allergy syndrome, which is a mild selflimiting problem.
❑ Symptoms are associated with the ingestion of fresh

fruits and vegetables. o Symptoms generally have a rapid onset and resolution. o Characteristic symptoms include pruritus of the: ⇒ Lips ⇒ Palate ⇒ Tongue ⇒ Throat ❑ Confined to oropharynx. ❑ Frequently seen in patients with seasonal allergic rhinitis due to cross-reactivity between some pollens and foods. ❑ Symptoms of throat closing are a potential systemic and life-threatening reaction and should not be confused with symptoms of oral allergy syndrome, which is a self-limiting condition.

Cross-reactivity between some common allergens and foods may contribute to the oral allergy syndrome.
Allergen Ragweed pollen Birch pollen Mugwort pollen Latex
*

Foods Melons, banana Apple, carrot, hazelnut, potato, almond group* Celery, apple, kiwi Banana, kiwi, avocado, chestnut

Almond group includes pear, plum, nectarine, cherry, and apricot.

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Non-IgE-mediated Food Hypersensitivity
Non-IgE-mediated food hypersensitivity reactions include: ❑ Food-induced enterocolitis ❑ Food-induced proctocolitis ❑ Food-induced enteropathy ❑ Celiac disease ❑ Allergic eosinophilic gastroenteritis ❑ Food intolerance

Nonimmunologic food reactions that usually present in the first few months of life include food-induced:
❑ Enterocolitis ❑ Proctocolitis ❑ Enteropathy

Food-induced Enterocolitis
❑ Generally presents in infants between 1 week

and 3 months of age. ❑ Major symptoms are protracted vomiting and/or diarrhea. o Frequently results in dehydration. ❑ Cow milk, soy protein, or both are most often responsible. ❑ Similar, less severe reactions reported in adults. ❑ Symptoms usually resolve after 72 hours of allergen avoidance.

Food-induced Proctocolitis
❑ Presents during first few months of life. ❑ Hematochezia (gross or occult) is a distinguishing

feature. ❑ Cow milk or soy protein are usually implicated.

Food-induced Enteropathy
❑ Malabsorption syndrome. ❑ Presents in the first several months of life. ❑ Symptoms: o Protracted and/or greasy diarrhea o Vomiting o Failure to thrive

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73

❑ Cow milk sensitivity is the most frequent cause. o Other causes include:

⇒ Soy ⇒ Egg ⇒ Wheat ⇒ Rice ⇒ Chicken ⇒ Fish ❑ Intestinal lesions may require 6 to 18 months of allergen avoidance for complete resolution.

Celiac Disease Managing celiac disease requires lifelong elimination of gluten. Most infants with nonIgE-mediated reactions outgrow their adverse reactions to food.
❑ Celiac disease is
❑ Gluten-sensitive celiac disease produces a more

lifelong.

extensive enteropathy, leading to malabsorption. o Sensitivity is to gliadin: ⇒ The alcohol-soluble portion of gluten. ⇒ Found in wheat, oat, rye, and barley. ❑ Characteristic symptoms: o Diarrhea or frank steatorrhea o Abdominal distention and flatulence o Weight loss in adults o Occasional nausea and vomiting o Oral ulcers ❑ Lifelong elimination of gluten is necessary to: o Control symptoms. o Avoid risk of malignancy.

Allergic Eosinophilic Gastroenteritis
❑ Intolerance to multiple foods. o Multiple food allergies due to IgE- or

non-IgE-mediated mechanisms. ❑ Eosinophils infiltrate esophageal, gastric or intestinal walls. ❑ Characteristic symptoms: o Postprandial nausea and vomiting o Abdominal pain and diarrhea o Gastroesophageal reflux o Early satiety or refusal to eat o Weight loss o Growth failure in children ❑ Symptoms should subside within 3 to 6 weeks of allergen elimination, although gut histology may not return to normal for months.
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Food Intolerance
❑ Accounts for the majority of adverse food reactions. ❑ Not an immunologically mediated response. ❑ May include: o Abnormal metabolic responses (e.g., lactase

deficiency). o Unusual susceptibility to pharmacologic substances in certain foods (e.g., caffeine, tyramine).

Food intolerance accounts for the majority of adverse food reactions.

Diagnosing the Patient with Food Allergy
The diagnosis of food allergy is based on a thorough history, physical examination, and diagnostic testing, followed by food challenge and elimination diet.

Medical History
Consider:
❑ Personal and family history of allergy. ❑ Exposure to common allergenic foods. ❑ Presence of other allergic diseases, particularly: o Asthma o Rhinitis o Atopic dermatitis ❑ Quantity of the suspected food ingested. ❑ Length of time between ingestion and development

The double-blind, placebo-controlled food challenge (DBPCFC) is the gold standard for diagnosis, except for the patient with anaphylactic reactions to food. Food allergy often occurs in patients with a history of other allergic diseases, particularly:
❑ Asthma ❑ Rhinitis ❑ Atopic dermatitis

of symptoms. ❑ Types of symptoms when the food has been ingested in the past. ❑ Activities at the time of, or prior to, symptoms (e.g., exercise). o Food ingestion within 3 to 4 hours has been associated with increased risk of exercise-induced anaphylaxis. ⇒ Reactions may be IgE-mediated, requiring a specific food, or may be a nonspecific effect of ingestion. • Patient should not eat for more than 2 hours prior to exercising, if reaction is to a specific food. • Patient should not eat for 2 hours prior to exercising, if reaction is nonspecific. o See Anaphylaxis, page 115 for information on exercise-induced anaphylaxis. ❑ Length of time since last reaction.

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75

When taking a history for possible food sensitivity, consider the:
❑ Types of symptoms expressed. ❑ Relationship between symptom onset and ingestion. ❑ Time since the last reaction. ❑ Quantity of suspected food ingested when symptoms

occured. ❑ Activities at the time of (or prior to) symptoms.

Diet diaries may be useful. Diet diaries may be helpful for diagnosing food allergy. Have the patient record:
❑ All foods ingested,
❑ An adjunct to medical history. ❑ Record all foods eaten: o On a prospective basis for the patient with frequent

including anything just placed in mouth (e.g., chewing gum, mouthwash, toothpaste). ❑ Any symptoms experienced. ❑ Length of time from ingestion to symptoms.

symptoms. o 12 hours prior to symptoms for the patient who experiences problems infrequently. ❑ May detect an unrecognized association between a food and symptoms. ❑ Have the patient record: o Foods ingested, including anything just placed in mouth (e.g., chewing gum, mouthwash, toothpaste). o Any symptoms experienced. o Length of time from ingestion to symptoms.

Masqueraders of food allergy:
❑ Food intolerance (e.g., lactase deficiency) ❑ Hiatal hernia, gastrointestinal reflux disease ❑ Inflammatory bowel disease ❑ Pyloric stenosis ❑ Pancreatic insufficiency ❑ Gall bladder or peptic ulcer disease ❑ Toxins (e.g., scromboid, Clostridium botulinum) ❑ Bacteria, virus, or parasite infection ❑ Irritable bowel syndrome ❑ Severe headache to food additives

(e.g., nitrates, nitrites)

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Physical Examination
❑ Between reactions, there may be nothing unusual on

physical examination. ❑ During reactions, signs and symptoms may range from localized discomfort to anaphylaxis. ❑ Important clinical manifestations include: o Urticaria/angioedema o Skin pruritus o Atopic dermatitis o Asthma o Rhinitis ❑ Monitor height and weight percentiles in children. o This can be an indicator for failure to thrive in young children.

Diagnostic Testing
The general principles of diagnostic testing are included in Volume 1: Diagnostic Testing, page 31. Specific tests used for diagnosing food reactions are included here.

Monitoring height and weight in young children with food allergy is important.
❑ May indicate failure

to thrive.

Elimination Diets
❑ Elimination diets are therapeutic trials: o Use only for a limited period of time (10 to 14 days). o Monitor the outcomes closely. ❑ Why elimination diets fail: o The patient (and family/caregiver) does not receive

Elimination diets are therapeutic trials:
❑ Use only for a limited

adequate education before starting. o The patient does not adhere to the diet. o The patient is allergic to other foods not eliminated. o Coexisting disease masks a beneficial response. o The patient does not have food-induced disease. Basic Elimination Diet ❑ The use of a basic elimination diet may be helpful in assessing the role of food allergy. ❑ Patients responding to the basic elimination diet should be referred to an allergy/immunology specialist in a timely manner for appropriate counseling and possible open or double-blind food challenge. Targeted Elimination Diet ❑ Eliminate foods based on the patient’s history and/or the results of specific IgE tests to the foods in question (e.g., skin tests or in vitro tests).

period of time (10 to 14 days). ❑ Monitor the outcomes closely.

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77

❑ Interpret positive skin tests or in vitro tests for specific

allergens cautiously. ❑ Consultation with an allergy/immunology specialist is recommended. Using the Targeted Elimination Diet Eliminate specific foods based on patient history and/or tests

w
Patient improves

w
Symptoms persevere

w
Reintroduce suspect food to diet

w
Stop elimination diet; evaluate other reasons for illness

w
Symptoms reoccur

w
Re-eliminate suspect food

w
Perform double-blind food challenge

Severe elimination diets should be used for only short periods of time (i.e., < 1 to 2 weeks).

Severe Elimination Diet ❑ The use of a severe elimination diet may be warranted when: o Removal of suspected food(s) does not eliminate symptoms. o Multiple food sensitivities are suspected. o Food is unlikely to be causing symptoms (e.g., chronic urticaria). ❑ Should be used for only short periods of time (i.e., < 1 to 2 weeks).

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Implementation of the Severe Elimination Diet Elimination diet

w
Symptoms cease; begin normal diet

w
Symptoms persevere

w
Symptoms persevere

w
Symptoms cease

w
Stop elimination diet; evaluate other reasons for illness

w
Reinstate elimination diet

w
Symptoms cease

w
Reintroduce one food every 2 to 4 days

w

Symptoms reoccur

w
Symptoms abolished

w
Omit causal food; keep diary of events

w
Continue reintroducing foods

w w
Symptoms cease

w
List of tolerable and intolerable foods

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79

Some suggestions for food-sensitive patients who respond to:
Basic elimination diet ❑ Refer to a specialist in a timely manner for: o Appropriate counseling. o Possible open or double-blind food challenge. Targeted elimination diet ❑ Continue eliminating food(s). ❑ Avoid overzealous restriction of nonimplicated foods. ❑ Monitor weight (and height) regularly. ❑ Re-evaluate annually. o Re-evaluate children less than 2 years of age more frequently. ❑ Consider referral to a dietitian for education and help in managing diet.

Symptoms are due to specific food allergens.
❑ Patients occasionally

react to more than one food.

Sample elimination diet (foods permitted):
❑ Rice ❑ Puffed rice ❑ Rice flakes ❑ Rice crispies ❑ Canned pineapple ❑ Canned apricots ❑ Cranberries ❑ Peaches ❑ Pears ❑ Apples ❑ Lamb ❑ Chicken ❑ Asparagus ❑ Beets ❑ Carrots ❑ Lettuce ❑ Sweet potato ❑ Tapioca ❑ White vinegar ❑ Olive oil ❑ Honey (2 oz per day) ❑ Cane (or beet) sugar ❑ Salt

Adapted from: A. Bock et. al. J Allergy Clin Immunol 1988; 82: 986-987.

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Food Reactions

Sample severe elimination diets (foods permitted):
Infants < 3 months of age ❑ Milk substitute alone, such as: o Casein hydrolysates (e.g., Alimentum, Nutramigen) ® o Amino acid-derived formulas (e.g., Neocate , ® Vivonex ) Infants 3 to 6 months of age ❑ Milk substitute ❑ Rice cereal ❑ Applesauce ❑ Pears ❑ Carrots ❑ Squash ❑ Lamb Older children, adolescents, and adults ❑ Casein hydrolysate formulas or commercial elimination diets (e.g., Neocate® 1 Plus, Vivonex®) ❑ Rice or corn ❑ Applesauce
Adapted from: Metcalfe DD, Sampson HA, Simon RA. Food Allergy: Adverse Reactions to Foods and Food Additives. 2nd ed. Cambridge: Blackwell Science; 1997: 178.

Skin and In Vitro Testing
❑ Positive skin tests or in vitro tests for specific allergens

must be interpreted cautiously. o Consultation with an allergy/immunology specialist is recommended. ❑ IgE-mediated sensitivity to several fruits and vegetables are frequently not detected with commercially prepared reagents. o Test with fresh food. ❑ Children less than 1 year of age may have IgE-mediated food allergy in the absence of positive skin tests. o Children less than 2 years of age may have smaller wheals.

Some food groups (e.g., legumes, bony fish, cereal grains) contain allergens that frequently cross-react within the food group on immunological testing (e.g., skinprick test, in vitro tests), but rarely cross-react clinically.
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81

Some fruits and vegetables which may not be detected with commercially prepared reagents:
❑ Apples ❑ Oranges ❑ Bananas ❑ Pears ❑ Melons ❑ Potatoes ❑ Carrots ❑ Celery

Some patients present with a very strong positive history of food allergy but have negative skin and in vitro tests. These patients should be considered at risk.
❑ Treat with appropriate

❑ A positive skin test to a food to which the patient

measures including provision of injectable epinephrine.

In vitro tests (e.g., ELISA) are recommended over skin testing for patients with:
❑ Significant

dermatographism. ❑ Severe skin disease and limited surface area for skin testing. ❑ Suspected marked sensitivities to certain foods. ❑ Difficulty in discontinuing antihistamines or some antidepressants.
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Food Reactions

reported an anaphylactic reaction may be considered diagnostic. ❑ In vitro tests (e.g., ELISA) are recommended for patients with: o Significant dermatographism. o Severe skin disease and limited surface area for skin testing. o Suspected marked sensitivities to certain foods. o Difficulty in discontinuing antihistamines or some antidepressants. ❑ Confirm positive result with oral challenge and elimination diet. ❑ Some patients who present with a very strong positive history will have negative skin and in vitro tests. May indicate: o Nonimmunologically mediated reactions. o Poor quality test material. o In either instance, consider the patient at risk. ⇒ Treat with appropriate measures including provision of injectable epinephrine.

Double-Blind, Placebo-Controlled Food Challenge (DBPCFC)
❑ Considered the “gold standard” for diagnosing

food allergies. ❑ Used successfully in both children and adults. ❑ Selection of foods to be tested is based on history and/or diagnostic tests. ❑ Should be administered by an allergy/immunology specialist.

When evaluating patients for possible food allergy, referral to an allergy/ immunology specialist for consultation is recommended for:
❑ Diagnostic assessment of the patient who has: o Complications. o Severe or persistent disease. o Been admitted to the hospital. o Coexisting asthma, allergic rhinitis, atopic

❑ ❑ ❑

❑

dermatitis, or allergic conjunctivitis. o A history of anaphylaxis to food(s). Identification of causal factors. Targeted elimination diets. Open or single-blind food challenge. o Double-blind placebo-controlled food challenges, if indicated, in special circumstances. Test interpretation.

The double-blind, placebo-controlled food challenge (DBPCFC) is the "gold standard" for diagnosing food allergies.
❑ Used successfully in

both children and adults. ❑ Should be administered by an allergy/immunology specialist.

Managing the Patient with Food Allergy
Nonpharmacologic Management
❑ Strict avoidance of the offending food allergen(s) is the

Positive immunological tests for food allergens should be confirmed with an oral challenge and/or elimination diet. Four general principles of allergy management
1. Avoid factors that cause symptoms. 2. Use appropriate medications. 3. Evaluate for immunotherapy. 4. Educate and follow-up.

only proven therapy. ❑ Symptomatic reactivity to food allergens is often lost over time, except for: o Peanuts o Tree nuts o Fish o Shellfish

Providing a list of “allowed foods” may not be beneficial as ingredients frequently change. Instead, ENCOURAGE PATIENTS TO READ LABELS.

Strict avoidance of the foods to which the patient is sensitive is the only proven therapy for food allergy.
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83

Pharmacologic Management
Epinephrine is the treatment of choice for severe reactions to food. Patients with severe reactions should:
❑ Wear medical alert (see Anaphylactic/Anaphylactoid Reactions, page 122) ❑ Adult dose: 0.2 ml to 0.5 ml of a 1:1000 (wt/vol) dilution (0.2 to 0.5 mg) intramuscularly or subcutaneously. ♦ For serious reactions, use intramuscular administration. ⇒ Intramuscular administration is more rapidly absorbed. ♦ Dose may be repeated every 10 to 15 minutes for the first hour. ♦ If patient remains hypotensive, consider plasma volume expanders. ❑ Child dose: 0.01 mg/kg up to a maximum of 0.3 mg or 0.3 ml of 1:1000 (wt/vol) administered intramuscularly. ♦ Parents and caregivers of children under 30 pounds (13.6 kg) should be taught to administer epinephrine (1:1000) by syringe (0.01 mL/kg, maximum: 0.15 mL). ♦ Dose may be repeated every 15 minutes for up to 3 doses. ❑ Patients on beta-blockers are at higher risk of anaphylaxis because of the danger of epinephrine resistance. ♦ This may be countered with glucagon injection. ❑ Epinephrine kits (e.g., Epi Pen® auto-injector and Epi Pen Jr® auto-injector) are commercially available with preloaded syringes or automatic injector systems for self-injection by patients over 30 pounds. ❑ Delayed, biphasic, or prolonged anaphylaxis occurs in more than 20% of cases. ♦ This requires extended observation of all cases and extended treatment in some.

identification. ❑ Be taught to selfadminister epinephrine. ❑ Keep epinephrine and antihistamines readily available.

Children at risk of anaphylaxis should have epinephrine available at:
❑ Home ❑ School ❑ Daycare

Other Treatments
❑ Less severe reactions (usually localized skin or

gastrointestinal symptoms) may be treated with oral antihistamines. ❑ Prophylactic pharmacologic management of food allergy has not been proven effective or safe (e.g., cromolyn).

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General Considerations for Treating Food Allergy
Treating the Patient with a Suspected Food Allergy
❑ Avoid suspected food(s) until tests are performed by

the specialist. ❑ In case a reaction occurs with an accidental exposure to the food, the patient should: o Self-administer epinephrine. o Be transported by ambulance to the nearest emergency department (even if symptoms subside).

Treating Children with Food Allergy
❑ Advise parents that childcare providers, school

personnel, and others who have regular contact with the child must be trained to: o Recognize symptoms, particularly those indicating anaphylaxis. o Administer epinephrine immediately for anaphylaxis. ❑ Immediate treatment is critical. o Make this clear to the child, the family, and all caregivers when food allergy is first diagnosed. ❑ Provide an action plan to the family. o Tell them to give a copy to the school, daycare center, and any caregivers. o Make sure a written plan of action is given and understood by school nurse. ❑ Inform the child, family, and caregivers that the child should not accept food from classmates/friends. ❑ Monitor regularly the weight and height of children on targeted elimination diets. ❑ Consider referral to educational support groups to educate and support the family regarding lifestyle changes. ❑ Have the child wear a medical alert bracelet or necklace.

Prophylactic pharmacologic management of food allergy with oral cromolyn sodium has not been proven effective or safe. A child with food allergy must not accept food from classmates or friends.
❑ The child, parents and

ALL caregivers need to understand this.

For children with food allergies, the parents, childcare providers, and school personnel should be included in patient education.
❑ School nurse should be

notified in writing of emergency plan and should ensure that all school personnel are familiar with it.
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85

Everyone who has regular contact with a child with food allergy should know how to:
❑ Recognize symptoms for anaphylaxis. ❑ Administer epinephrine.

Provide a written action plan to the family and tell them to give a copy to all caregivers (before and after school care, at school, at daycare).

Specialist Referral
❑ Referral to an allergy/immunology specialist for

consultation or comanagement is recommended when the patient has: o Failed to respond to treatment, including: ⇒ Medications (e.g., corticosteroids, antihistamines) ⇒ Elimination diet o Complications. o Persistent or chronic symptoms. o Anaphylaxis or history of anaphylaxis. o Required hospitalization. o Coexisting asthma, allergic rhinitis, atopic dermatitis, or allergic conjunctivitis. o A case that may require assistance with diagnosis and management: ⇒ Identification of causal factors ⇒ Targeted elimination diets ⇒ Food challenges ⇒ Test interpretation ⇒ Additional patient education

Patient Education
Patient education is critical and should include: For more information, please refer to the general educational tips included in the Patient Education Chapter of Volume 1, page 71.
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Food Reactions

❑ Allergen identification (e.g., how to read food labels). ❑ Avoidance strategies and counseling. ❑ Symptom recognition. ❑ Cautions regarding the possibility of a life-threatening

reaction. ❑ What to do in case of accidental ingestion. o Development of a treatment plan. o How to self-administer epinephrine.

References
Anderson J, Sogn D. Adverse reactions to foods. Bethesda MD:National Institute of Health; 1984. NIH Publication 84-2442. Anderson JA. Milestones marking the knowledge of adverse reactions to food in the decade of the 1980s. Ann Allergy 1994; 72: 143-154. Anderson JA. Milk, eggs and peanuts: food allergies in children. Am Fam Physician 1997; 56: 1365-1374. Anonymous. Advice from your allergist. Ann Allergy Asthma Immunol 1999; 82: 25-28. Bernhisel-Broadbent J, Scanlon SM, Sampson HA. Fish Hypersensitivity I. In vitro and oral challenge results in fish-allergic patients. J Allergy Clin Immunol 1992; 89: 730-737. Bernhisel-Broadbent J, Scanlon SM, Sampson HA. Fish Hypersensitivity II: J Allergy Clin Immunol 1992; 90: 622-629. Bindslev-Jensen C, Skov PS, Madsen F, Poulsen LK. Food allergy and food intolerance- what is the difference? Ann Allergy 1994; 72: 317-320. Bock SA. Food hypersensitivity. In: Fireman P Slavin RG. (eds). Atlas of Allergies, 2nd , ed. London:Mosby-Wolfe, Times-Mirror 1996; 205-217. Bock SA. The natural history of food sensitivity. J Allergy Clin Immunol 1982; 69: 173-177. Bock SA, Atkins FM. The natural history of peanut allergy. J Allergy Clin Immunol 1989; 83: 900-904. Bock SA, Sampson HA. Food allergy in infancy. Pediatr Clin North Am 1994; 41: 1047-1067. 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: 986-987. Bousquet J, Metcalfe DD, Warner JO. Food allergy position paper of the codex alimentarius. ACI Internatl 1997; 9: 10-21. Brigino E, Bahna SL. Clinical features of food allergy in infants. Clin Rev Allergy Immunol 1995; 13: 329-345. Burks AW, Sampson H. Food allergies in children. Curr Probl Pediatr 1993; 23: 230-252. Burks AW, Sampson HA. Diagnostic approaches to the patient with suspected food allergies. J Pediatr 1992; 121: S64-71. Eigenmann PA, Sampson HA. Adverse reactions to foods. In: Kaplan AP (ed). Allergy, 2nd ed. Philadelphia: W.B. Saunders, 1997: 542-565. Ferguson A. Definitions and diagnosis of food intolerance and food allergy: consensus and controversy. J Pediatr 1992; 121: S7-11. Halken S, Host A. Prevention of allergic disease: exposure to food allergens and dietetic intervention. Pediatr Allergy Immunol 1996; 7: S102-107. Hill DJ, Hosking CS. Some limitations of double-blind, placebo-controlled food challenges in young children. J Allergy Clin Immunol 1991; 87: 136-137 (letter). Jones SM, Magnolfi CF, Cooke SK, Sampson HA. Immunologic cross-reactivity among cereal grains and grasses in children with food hypersensitivity. J Allergy Clin Immunol 1995; 96: 341-351. Kitts D, Yuan Y, Joneja J, et al. Adverse reactions to food constituents: allergy, intolerance, and autoimmunity. Can J Physiol Pharmacol 1997; 75: 241-254. Klein GL. J Double-blind, placebocontrolled food challenge. J Allergy Clin Immunol 1991; 87: 139 (letter). Marks DR, Marks LM. Food allergy: manifestations, evaluation, and management. Postgrad Med 1993; 93: 191-201. Metcalfe DD, Sampson HA, Simon RA Food Allergy: Adverse reactions to foods and food additives. 2nd ed. Cambridge: Blackwell Science; 1997.

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Novembre E, Cianferoni A, Bernardini R, et al. Anaphylaxis in children: clinical and allergologic features. Pediatrics 1998; 101: e8. Plaut M. New directions in food allergy research. J Allergy Clin Immunol 1997; 100: 7-10. Sampson H. Food allergy. Part 1: Immunopathogenesis and clinical disorders. J Allergy Clin Immunol 1999; 103: 717-728. Sampson H. Food allergy. Part 2: Diagnosis and management. J Allergy Clin Immunol. 1999; 103: 981-989. 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: 444-451. Sampson HA. Adverse reactions to foods. In: Middleton E, Reed CE, Ellis EF, et al (eds). Allergy Principles and Practice, 5th ed. St. Louis: Mosby, 1998; 1162-1182. Sampson HA. Differential diagnosis in adverse reactions to foods. J Allergy Clin Immunol 1986; 78: 212-219. Sampson HA. Food allergy. In: Kay AB (ed). Allergy and Allergic Diseases Blackwell Science Ltd. (Vol 2). Malden, 1997: 961-980, 1517-1549. Sampson HA. Food allergy. J Am Med Assoc 1997; 278: 1888-1894. Sampson HA. Food sensitivity and the pathogenesis of atopic dermatitis. J Royal Society Med 1997; 90: 52-58. Steinman HA. "Hidden" allergens in foods. J Allergy Clin Immunol 1996; 98: 241-250. Watson WTA. Food allergy in children. Clin Rev Allergy Immunol 1995; 13: 347-359. Weber RW. Food additives and allergy. Ann Allergy 1993; 70: 183-190. Zeiger RS. Prevention of food allergy and atopic disease. J Royal Society Med 1997; 90: 21-33.

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Food Reactions

Insect Sting Reactions
❑ Biting insects occasionally cause local allergic

swelling (e.g., mosquito allergy), but systemic or anaphylactic reactions to biting insects are extremely rare.
❑ It is the stinging insects that can cause anaphylaxis. ❑ Stinging insects are all members of the

Biting insects rarely cause systemic or anaphylactic reactions.
❑ The stinging insects

can cause anaphylaxis.

Hymenoptera order which includes the apid, vespid, and formicid families.
o Apids

⇒ Honeybee ⇒ Bumblebee
o Vespids

Honeybees

⇒ Yellow jacket ⇒ Yellow-faced hornet ⇒ White-faced hornet ⇒ Paper wasp
o Formicids
Bumblebee

Stinging insects belong to the Hymenoptera order, and include the:
❑ Apid family ❑ Vespid family ❑ Formicid family

⇒ Fire ant ⇒ Harvester ant ❑ Stings cause a local painful
Yellow jacket

The distribution of Hymenoptera varies across the country.
❑ Yellow jackets are

reaction in most patients and can cause systemic reactions in certain individuals.
o Most of the systemic reactions

are classic IgE-mediated allergic reactions, resulting in anaphylaxis.

Yellow-faced hornet

responsible for most sting reactions in the United States. ❑ Wasps and fire ants are a major cause of sting reactions along the Gulf Coast.

Paper wasp
Insect Sting Reactions

89

o Some patients who present with a very strong

positive history may have negative skin and in vitro tests.
⇒ This may indicate nonimmunologically

mediated reactions or poor quality test material.
⇒ In either instance, consider the patient at risk

and treat with appropriate measures including provision of injectable epinephrine.
❑ There is significant cross-reactivity among vespid

venoms, but little cross-reactivity exists between vespid and honeybee venoms.
o Fire ant venoms contain allergens very distinct

from the others.

Reactions to Stinging Insects
Immediate Local Reaction
❑ Sometimes referred to as the “normal reaction.” ❑ Presents as pain, erythema, itching, and swelling at the

sting site. ❑ A transient response which usually disappears within several hours. ❑ The reaction to fire ant stings is different, occurring: o As clear vesicles usually developing within several hours, followed by a sterile pustule at 24 hours. o Primarily on lower limbs (i.e., areas in contact with the ground). o In a cluster or ring (the insect pivots about the mandibles and stings repeatedly). o As numerous stings (due to contact with multiple ants).

Large Local Reaction
❑ Extensive swelling and erythema from the sting site

over a large area. o Often involves most of an extremity. ❑ Swelling often peaks within 48 hours and may last as long as 7 to 10 days. ❑ Occasionally, fatigue, low grade fever, and nausea accompany the reaction.
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Insect Sting Reactions

Anaphylaxis
(see Anaphylactic/Anaphylactoid Reactions, page 118) ❑ Signs and symptoms (see below) arise distant from the site of the sting, unlike localized reaction. ❑ The clinical features of anaphylaxis from an insect sting are the same as anaphylaxis from other causes. o Symptoms generally start within 15 to 30 minutes. o Occasionally begin after 1 hour. o Rarely occur hours later. o More than 20% of anaphylaxis episodes have a delayed, prolonged, or biphasic component occurring 3 to 5 hours after the sting. ⇒ It is recommended that the patient be observed for 3 to 6 hours depending on severity of reaction. ❑ A severe reaction can occur at any age, but most deaths have occurred in adults. o Other than a prior systemic reaction, there are no clinical criteria or risk factors to identify people at potential risk for insect sting anaphylaxis.

Anaphylaxis to a stinging insect is:
❑ Always systemic. ❑ Usually generalized.
o May affect only

limited areas of body distant from site of sting.

Signs and Symptoms of Anaphylaxis
❑ The most common systemic signs and symptoms

Patients may have severe, but delayed, reactions to insect stings. The patient with an allergic response to an insect sting should be observed for 3 to 6 hours.

involve the skin and include: o Urticaria o Flushing o Pruritus o Angioedema ❑ More serious, life-threatening responses involve the respiratory and cardiovascular systems, including: o Laryngeal edema o Bronchoconstriction o Hypotension o Arrhythmia o Hypovolemic shock ❑ Gastrointestinal effects may be part of the anaphylactic reaction: o Abdominal cramping o Nausea o Vomiting o Diarrhea

Other than a prior systemic reaction, there are no clinical criteria or risk factors to identify people at potential risk for insect sting anaphylaxis.

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91

ANAPHYLAXIS IS ALWAYS A MEDICAL EMERGENCY! Be prepared for serious, life-threatening airway obstruction with the patient who shows:
❑ ❑ ❑ ❑ ❑ Hoarseness Difficulty talking Coughing Choking Throat tightness

Toxic Reaction
❑ Usually results from multiple simultaneous stings

but can occur with a single sting. ❑ Similar clinical characteristics as anaphylaxis. o Differentiation between a toxic reaction and anaphylaxis may be difficult. ❑ Some patients may develop IgE antibody after toxic reaction and may be at risk for developing an allergic reaction to subsequent single stings.

Unusual (Delayed) Reactions
❑ Serum sickness may occur 7 to 10 days after

an insect sting. o The symptoms of this type of reaction include: ⇒ Urticaria ⇒ Joint pain ⇒ Malaise ⇒ Fever ⇒ Cold urticaria (within days or weeks following sting, persisting for weeks to months) o Occasionally, these reactions are associated with an immediate anaphylactic reaction. ⇒ Patients who have had a serum sickness reaction may be at risk for an anaphylactic reaction after subsequent insect stings.

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Insect Sting Reactions

❑ In association with an insect sting, there have

been reports of: o Vasculitis o Nephrosis o Neuritis o Encephalitis

The causes have not been established for the isolated reactions of:
❑ Vasculitis ❑ Nephrosis ❑ Neuritis ❑ Encephalitis

Diagnosing the Patient with Insect Sting Allergy
Medical History and Insect Identification
❑ The medical history and identification of the stinging

insect are important diagnostic tools. ❑ Symptoms of an allergic reaction tend to occur within minutes after the insect sting. o Obtain information on prior exposure and/or reactions to stinging insects from the patient (or caregiver). ❑ A person may be allergic to the venom from one or all of the stinging insects. o It is important to identify the responsible insect to help avoid and/or treat reactions. ⇒ Identification is not always possible. ⇒ Nesting and behavior patterns may help distinguish between insects. ❑ Have the patient or caregiver describe the stinging insect, if possible: o What does it look like (e.g., color, pattern)? o Where does it live (eg., ground, tree)? o How did it behave (e.g., was it provoked, angry)? o Was the stinger left at site of sting (e.g., honeybee, yellow jacket)?

Identify the stinging insect by having the patient (or caregiver) describe:
❑ What it looks like

(eg., color, pattern). ❑ Where it lives (e.g., ground, tree). ❑ How it behaves (e.g., angry, provoked). ❑ Was stinger left at site of sting (e.g., honeybee, yellow jacket).

The honeybee always loses its sting apparatus in the sting process.
❑ Yellow jackets may

or may not lose their stinger.

Insect Sting Reactions

93

Identifying stinging insects (Hymenoptera):
Common Name Nesting and Behavior Patterns Domestic ❑ Exposure is very common due to their use for production of honey and for plant fertilization. honeybees ❑ Live in hives constructed by humans or nest in hollow trees. ❑ Generally docile; do not sting unless provoked. ❑ Always lose stinger. African honeybees
❑ Sometimes referred to as “killer bees.” o Venom is the same as the domestic honeybee. o Increased danger is due to their tendency to be more defensive, hostile,

Bumblebees

Yellow jackets

Hornets

Wasps

Fire ants

Harvester ants

and to swarm and sting in large numbers (often hundreds). ❑ Introduced into Brazil from Africa in 1956; gradually spread north. o Expected to continue moving northward, but do not survive well in colder areas. ❑ Nest underground with wax and loose fibrous material. ❑ Nests resemble bunches of grapes. ❑ Generally docile; do not sting unless provoked. ❑ Nest in ground or under logs. ❑ Construct nests from masticated wood with several layers of comb attached one below another. ❑ Activities such as mowing or gardening commonly disturb the nest. ❑ Very attracted to food. o Commonly found near garbage and picnic areas. ❑ Very aggressive; sting without provocation. ❑ Occasionally lose stinger. ❑ Increase in numbers in late summer and fall. ❑ Build nests resembling Japanese lanterns. ❑ Commonly seen in trees, shrubs, or roof soffits. ❑ Very sensitive to vibration. ❑ European hornets, the largest Hymenopteran, fly at night and are attracted to lights. ❑ Nests resemble honeycombs. o Usually found on roof overhangs, shaded areas (e.g., porches, decks), and behind shutters. ❑ Generally less aggressive than yellow jackets. ❑ Common throughout southeastern United States, especially along Gulf Coast. ❑ Build large underground nests best described as mounds. ❑ Found throughout southern and western United States, Mexico, and western Canada. ❑ Stings are more painful and toxic than fire ants, but fatalities are rare.

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Insect Sting Reactions

Diagnostic Testing
The general principles of diagnostic testing are included in Volume 1: Diagnostic Testing, page 31. Specific tests used for diagnosing insect stings are included here. ❑ Confirmation of an insect sting allergy may be made by detection of venom-specific IgE. ❑ There are several insect venoms available for immediate skin testing of insect sting allergy. ❑ An in vitro test should be used when: o Skin tests cannot be performed. o Skin test reaction is uncertain. o There is a very strong positive history of systemic reactions and/or anaphylaxis and negative skin tests for IgE antibody to the suspected allergens. ❑ Approximately 15% to 20% of patients with positive skin tests do not react to in vitro tests. ❑ Referral to an allergist/immunology specialist for skin testing is recommended.

Managing the Patient with Insect Sting Allergy
Nonpharmacologic Management
❑ If the stinging apparatus is detected in the skin within

20 seconds of being stung, remove it by flicking. o After 20 seconds, all the venom will have been released from the stinger, so there is no reason to remove it. o Honeybees always lose their stingers. o Yellow jackets may occasionally lose their stingers. ❑ Large local reactions may be treated with ice or cold compresses. ❑ Individuals at risk for anaphylaxis should take steps to minimize exposure to insect stings (see diagnosis for nesting and behavior patterns, page 94).

If possible, the stinger should be removed from the skin within 20 seconds of being stung.
❑ After 20 seconds,

all the venom has been expelled. ❑ Honeybees always lose their stingers. ❑ Yellow jackets may occasionally lose their stingers.

Ice or cold compresses may provide relief for large local insect sting reactions.
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95

Tips to Minimize Exposure to Insect Stings Four general principles of allergy management
1. Avoid factors that cause symptoms. 2. Use appropriate medications. 3. Evaluate for immunotherapy. 4. Educate and follow-up.
In general: ❑ Avoid bright colored clothing and flowery prints. ❑ Do not use scented cosmetics, hair care products, or perfumes. ❑ Have aerosol insecticide readily available. ❑ Keep outdoor garbage covered. ❑ Use caution when working in yard, in attic, and on roof eaves. When outside: ❑ Wear shoes. ❑ Do not drink sodas or sweetened drinks. ❑ Use caution when cooking or eating. ❑ Wear barrier coverings (long sleeves, pants, and gloves). ❑ Do not wear flower corsages or garlands.

For immediate local reactions, consider:
❑ Analgesics for pain. ❑ Ice to reduce swelling. ❑ Oral antihistamines

Pharmacologic Management
For immediate local reactions, little or no treatment is warranted.
❑ Analgesics may be used for pain. ❑ Ice may be used to reduce swelling. ❑ In addition to ice or cold compresses, large local

(preferably, nonsedating) for large local reactions.

A short (3- to 7-day) course of oral corticosteroids may be indicated for a patient who:
❑ Has extensive and

reactions may be treated with oral antihistamines and analgesics. o Oral antihistamines are helpful; nonsedating antihistamines are preferred.

Oral Corticosteroids
❑ A short (3- to 7-day) course of prednisone may be

painful swelling. ❑ Was stung on the head or neck area. ❑ Has had prior severe large local reactions.
96
Insect Sting Reactions

indicated when the: o Swelling is extensive and painful. o Sting is on the head or neck area, where direct compression can be of great concern. o Patient has had prior severe large local reactions. ⇒ Start corticosteroid preferably within 2 hours of the sting, as it is easier to prevent progression than to reverse it.

Epinephrine
For acute anaphylaxis, epinephrine hydrochloride is primary medical treatment (See Anaphylactic/Anaphylactoid Reactions, page 122) ❑ Adult dose: 0.2 ml to 0.5 ml of a 1:1000 (wt/vol) dilution (0.2 to 0.5 mg) intramuscularly or subcutaneously. o For serious reactions, use intramuscular administration. ⇒ Intramuscular administration is more rapidly absorbed. o Dose may be repeated every 10 to 15 minutes for the first hour. o If patient remains hypotensive, consider plasma volume expanders. ❑ Child dose: 0.01 mg/kg up to a maximum of 0.3 mg or 0.3 ml of 1:1000 (wt/vol) administered intramuscularly. o Parents and caretakers of children under 30 pounds (13.6 kg) should be taught to administer epinephrine (1:1000) by syringe (0.01 mL/kg, maximum: 0.15 mL). o Dose may be repeated every 15 minutes for up to 3 doses. ❑ For anaphylaxis resulting from subcutaneous injection, intramuscular injection, or insect stings, half the dose of aqueous epinephrine should be injected into the site to inhibit further absorption of the causative agent. ❑ Patients on beta-blockers are at higher risk of anaphylaxis because of the danger of epinephrine resistance. o This may be countered with glucagon injection. ❑ Delayed, biphasic, or prolonged anaphylaxis occurs in more than 20% of cases. o This requires extended observation of all cases and extended treatment in some.

Epinephrine is the primary treatment for acute anaphylaxis.

Unless medically contraindicated, emergency epinephrine should be prescribed for all patients who have had a systemic reaction to insect sting.

Patients using beta-blockers have greater risk for severe reactions from insect stings due to the possibility for epinephrine resistance.
❑ Patients using ACE-inhibitors may be at greater risk for severe reactions presumably due to effects on the metabolism of eicosanoids and polypeptides.
97

Insect Sting Reactions

Patients at risk of anaphylaxis should be:
❑ Taught to self-administer epinephrine. ❑ Advised to keep epinephrine and antihistamines readily available. ❑ Told to wear medical alert identification.

❑ Patients with severe reactions should: ♦ Wear medical alert identification. ♦ Be taught to self-administer epinephrine. ♦ Keep epinephrine and antihistamines readily

Children at risk of anaphylaxis should have epinephrine available at all times at:
❑ Home ❑ School ❑ Daycare

available. ♦ Call 911 following administration and wait for ambulance transport. ❑ Children at risk of anaphylaxis should have epinephrine available at: ♦ Home ♦ School ♦ Daycare ❑ Epinephrine kits (e.g., Epi Pen® auto-injector and Epi Pen Jr® auto-injector) are commercially available with preloaded syringes or automatic injector systems for self-injection by patients over 30 pounds.

After removing the protective cover, administer the auto-injector directly through clothing.

98

Insect Sting Reactions

Venom Immunotherapy
❑ Highly effective in preventing subsequent reactions

(especially if high dose is achieved). o Efficacy demonstrated for treating reactions to: ⇒ Honeybee ⇒ Yellow jacket ⇒ Hornet ⇒ Wasp o Subsequent episodes of anaphylaxis occur in less than 2% to 5% of patients on an appropriate maintenance dose. ⇒ Reactions that do occur tend to be milder. ❑ Institute venom immunotherapy in patients who have: o Experienced a systemic reaction after an insect sting, AND IgE sensitivity has been documented. ❑ Venom immunotherapy is not recommended for patients with: o A very strong positive history, but negative skin and in vitro tests. This may indicate: ⇒ Nonimmunologically mediated reactions. ⇒ Poor quality test material. o In either instance, consider the patient at risk. ⇒ Treat with appropriate measures including provision of injectable epinephrine.

Venom immunotherapy is highly effective in preventing subsequent allergic reactions to:
❑ Honeybee ❑ Yellow jacket ❑ Hornet ❑ Wasp

Fire ant immunotherapy uses whole body extract and is reasonably effective when adequate doses are administered.

Indications for venom immunotherapy in patients with positive venom skin tests:
Reaction to Sting Anaphylaxis: Severe Moderate Non-life-threatening cutaneous eruptions: Children (< 16 yr) Adults Large Local Reaction Normal Reaction Venom Immunotherapy

Yes Yes

No Yes Not required* No

* Systemic reactions to subsequent stings occur in 10% of children and adults.

Insect Sting Reactions

99

Referral to an allergy/immunology specialist for evaluation, consultation, and/or comanagement is recommended when the patient needs:
❑ Diagnostic testing ❑ Venom immunotherapy ❑ Patient education

Referral to an allergy/immunology specialist is not needed for patients with:
❑ Local reactions ❑ Delayed, nonsevere reactions (> 48 hours after sting) ❑ Mild, cutaneous reactions (in children) unless further patient/family education and reassurance are necessary.

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Insect Sting Reactions

References
Barnard JH. Studies of 400 Hymenoptera sting deaths in the United States. J Allergy Clin Immunol 1973; 52: 259-264. Brown H, Bernton HS. Allergy to the Hymenoptera. V. Clinical study of 400 patients. Arch Intern Med 1970; 125: 665-669. Dykewicz MS. Anaphylaxis and sting insect reactions. Comp Therapy 1996; 22: 579-585. Freeman TM. Immunotherapy for allergy to fire ant venom. Ann Allergy Asthma Immunol 1997; 78: 602. Fricker M, Helbling A, Schwartz L, Muller U. Hymenoptera sting anaphylaxis and urticaria pigmentosa: clinical findings and results of venom immunotherapy in ten patients. J Allergy Clin Immunol 1997; 100: 11-15. Golden D. Epidemiology of allergy to insect venoms and stings. Allergy Proc 1989; 10: 103-107. Golden DB, Marsh DG, Kagey-Sobotka A, et al. Epidemiology of insect venom sensitivity. J Am Med Assoc 1989; 262: 240-244. Graft D, Golden D, Reisman R, Valentine M, Yunginger J. The discontinuation of Hymenoptera venom immunotherapy. Report from the Committee on Insects of the American Academy of Allergy Asthma and Immunology. J Allergy Clin Immunol 1998; 101: 573-575. Graft DF, Schuberth KC, Kagey-Sobotka A, et al. A prospective study of the natural history of large local reactions after Hymenoptera stings in children. J Ped 1984; 104: 664-668. Hoffman DR, Jacobson RS. Allergens in Hymenoptera venom. XXVII: Bumblebee venom allergy and allergens. J Allergy Clin Immunol. 1996; 97: 812-821. Hoffman DR. Allergens in Hymenoptera venom. XXVI: The complete amino acid sequences of two Vespid venom phospholipases. Int Arch Allergy Immunol 1994; 104: 184-190. Hoffman DR. Allergens in Hymenoptera venom. XV. The immunologic basis of Vespid venom cross-reactivity. J Allergy Clin Immunol 1985; 75: 611-613. Hunt KJ, Valentine MD, Sobotka AK, et al. A controlled trial of immunotherapy in insect hypersensitivity. N Engl J Med 1978; 299: 157-161. Lantner R, Reisman RE. Clinical and immunologic features and subsequent course of patients with severe insect sting anaphylaxis. J Allergy Clin Immunol 1989; 84: 900-906. Lichtenstein LM, Golden DB. Postscript to bee stings: delayed "serum sickness". Hosp Pract (Off Ed) 1983; 18: 36, 40, 40A. Light WC, Reisman RE, Shimizu M, Arbesman CE. Unusual reactions following insect stings: clinical features and immunologic analysis. J Allergy Clin Immunol 1977; 59: 391-397. Lockey RF. Systemic reactions to stinging ants. J Allergy Clin Immunol 1974; 54: 132-146. Lockey RF, Turkeltaub PC, Baird-Warren IA, et al. The Hymenoptera venom study I, 1979-1982: Demographics and history-sting data. J Allergy Clin Immunol 1988; 82: 370381. Mauriello PM, Barde SH, Georgitis JW, Reisman RE. Natural history of large local reactions from stinging insects. J Allergy Clin Immunol 1984; 74: 494-498. McKenna WR. Killer bees: what the allergist should know. Pediatr Asthma Allergy Immunol 1992; 4: 275-285. Moffitt JE, Barker JR, Stafford CT. Management of imported fire ant allergy: results of a survey. Ann Allergy Asthma Immunol 1997; 79: 125-130. Oude Elberink JN, deMonchy JG, Kors JW, van Doormaal JJ, Dubois AE. Fatal anaphylaxis after a yellow jacket sting despite venom immunotherapy in two patients with mastocytosis. J Allergy Clin Immunol 1997; 99: 153-154.

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Pinnas JL, Strunk RC, Wang TM, et al. Harvester ant sensitivity: in vitro and in vivo studies using whole body extracts and venom. J Allergy Clin Immunol 1977; 59: 10-16. Portnoy J, Moffitt J, Golden D, et al. Stinging insect hypersensitivity: a practice parameter. J Allergy Clin Immunol 1999; 103: 963-980. Reisman R. Current concepts: insect stings. N Engl J Med 1994; 331: 523-527. Reisman R. Venom hypersensitivity. J Allergy Clin Immunol 1994; 94: 651-658. Reisman RE, Dvorin DJ, Randolph CC, et al. Stinging insect allergy: natural history and modification with venom immunotherapy. J Allergy Clin Immunol 1985; 75: 735-740. Reisman RE, Livingston A. Late-onset allergic reactions, including serum sickness, after insect stings. J Allergy Clin Immunol 1989; 84: 331-337. Reisman RE, Livingston A. Venom immunotherapy: 10 years of experience with administration of single venoms and 50 micrograms maintenance doses. J Allergy Clin Immunol 1992; 89: 1189-1195. Reisman RE, Wypych JI, Arbesman CE. Stinging insect allergy: detection and clinical significance of venom IgE antibodies. J Allergy Clin Immunol 1975; 56: 443-449. Rueff F, Przybilla B, Müller U, Mosbech H. The sting challenge test in Hymenoptera venom allergy. Position paper of the Subcommittee on Insect Venom Allergy of the European Academy of Allergology and Clinical Immunology. Allergy 1996; 51: 216-225.

Schumacher MJ, Tueten MS, Egen NB. Rate and quantity of delivery of venom from honeybee stings. J Allergy Clin Immunol 1994; 93: 831-835. Sobotka AK, Adkinson NF Jr, Valentine MD, et al. Allergy to insect stings. IV. Diagnosis by radioallergosorbent test (R.A.S.T.). J Immunol 1978; 121: 2477-2484. Stafford CT. Hypersensitivity to fire ant venom. Ann Allergy Asthma Immunol. 1996; 77: 87-99. Valentine MD, Schuberth KC, Kagey-Sobotka A, et al. The value of immunotherapy with venom in children with allergy to insect stings. N Engl J Med 1991; 323: 1601-1603. Valentine MD. Anaphylaxis and stinging insect hypersensitivity. J Am Med Assoc 1992; 268: 2830-2833. Valentine MD. Insect venom allergy: diagnosis and treatment. J Allergy Clin Immunol 1984; 73: 299-304. Van der Linden PW, Hack CE, Struyvenberg A, van der Zwan JK. Insect-sting challenge in 324 subjects with a previous anaphylactic reaction: current criteria for insect-venom hypersensitivity do not predict the occurrence and the severity of anaphylaxis. J Allergy Clin Immunol. 1994; 94: 151-159. Yunginger JW. Insect Allergy. In: Middleton, Reed, Ellis, et al (eds). Allergy Principles and Practice, 5th ed. St. Louis: Mosby, 1998: 1063-1072.

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Insect Sting Reactions

Latex Reactions

L

atex allergy is an allergic response to the proteins in natural latex rubber or to the additives used in processing latex. It has become an important health concern of healthcare professionals and patients.
o Healthcare workers (and other workers wearing

❑ Persons at increased risk for latex allergy include:

latex gloves)
o Rubber industry workers o Patients with a history of multiple surgeries o Patients with spina bifida and urogenital

The increasing prevalence of latex allergy is related to more frequent use of latex gloves resulting from universal precautions and changes in the manufacturing process.

abnormalities
o Condom users ❑ Latex sensitivity is of greater risk in, but not

limited to, atopic individuals.
❑ Routes of exposure to latex include: o Skin (e.g., gloves) o Mucous membranes (e.g., condoms, rubber tip

on barium enema applicator)
o Inhalation (e.g., powder containing latex particles

from gloves)
o Intravascular (e.g., medical devices such as

intravenous tubing injection ports)

Latex Reactions

103

Allergic Responses to Latex
Types of Allergic Responses to Latex
IgE-mediated Reactions T-cell-mediated Reactions
❑ Are usually

Irritant Reactions

Irritant reactions are important cofactors for developing allergic reactions to latex. Patients with IgEmediated reactions may develop lifethreatening anaphylaxis to latex. Latex-sensitive individuals may experience symptoms of asthma and rhinitis by inhalation of latex allergen-coated particles from natural rubber latex gloves.

❑ Common

manifestations are at sites of contact: skin, eyes, nose, lungs (may include anaphylaxis). ❑ Can mimic symptoms of other allergies caused by proteins.

❑ Do not involve local. immune system. ❑ Produce ❑ Due to repeated contact hand washing, dermatitis. and to detergents, chemicals, ❑ Often caused endotoxin, or by the powders in chemicals gloves. added to latex during ❑ Important comanufacturing. factor in development of allergic reactions.

❑ Sensitizing latex antigens may: o Be inhaled. o Penetrate the skin after being solubilized by sweat. o Enter the body through skin that has been inflamed

by a contact dermatitis reaction. ❑ Latex allergens are also absorbed onto powder inside gloves. o When gloves are donned or discarded, the powder particles become airborne. ❑ Protein content varies considerably among different latex-containing medical devices. o May vary between, or even within, individual latex production batches.

Routes of exposure to latex antigens include:
❑ Skin (e.g., gloves) ❑ Mucous membranes (e.g., condoms, rubber tip

on barium enema applicator) ❑ Inhalation (e.g., powder containing latex particles from gloves) ❑ Intravascular (e.g., medical devices such as intravenous tubing injection ports)
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Latex Reactions

Diagnosing the Patient with Latex Allergy
Medical History
It is important to ask the patient (or parents) about: ❑ Personal or family history of allergy, including: o Hay fever o Food allergy (especially reactions to avocado, banana, kiwi, and chestnut) o Childhood or adult eczema o Asthma ❑ Multiple surgeries ❑ Events associated with anaphylaxis, such as episodes of: o Urticaria or angioedema o Respiratory distress o Difficulty with ventilation o Hypotension ❑ Allergic or allergic-type reactions during dental procedures ❑ Radiologic procedures (e.g., barium enema) ❑ Obstetric or gynecologic procedures ❑ History of latex exposure, including: o Type of latex device o Nature and duration of exposure ❑ Work-related symptoms of possible latex allergy o Cutaneous symptoms, including: ⇒ Hand dermatitis ⇒ Eczema ⇒ Pruritus ⇒ Urticaria o Upper respiratory symptoms, including: ⇒ Rhinorrhea ⇒ Nasal pruritus ⇒ Sneezing o Lower respiratory symptoms, including: ⇒ Cough ⇒ Wheeze ⇒ Shortness of breath

Many healthcare workers report adverse, nonspecific, irritant reactions to gloves.
❑ Are not due to IgE

sensitivity. ❑ Do not imply risk of anaphylaxis.

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105

❑ Symptoms with use of latex products, such as: o Itchy hands o Localized angioedema o Possible anaphylactic reactions

Medical conditions associated with increased risk of latex allergy:
Spina bifida Urogenital anomalies Imperforate anus Tracheoesophageal fistula Multiple congenital deformities Ventriculoperitoneal shunt Cerebral palsy Quadriplegia Multiple surgeries Atopy Preterm infants

Physical Examination
Physical examination can distinguish allergic from nonallergic reactions.

Allergic Reactions Allergic reactions to latex can vary from a minor rash to anaphylaxis. IgE-mediated allergic reactions to latex occur within minutes. T-cell-mediated allergic reactions to latex have an onset of hours, and peak symptoms may occur for up to days later.
❑ Vary from minor skin rash (contact eczema) to

anaphylaxis. o Hypersensitivity may be immediate or delayed. IgE-mediated reactions (see Anaphylactic and Anaphylactoid Reactions, page 115): ❑ Immediate reaction. ❑ May be localized (common) or generalized (rare). Signs and symptoms of IgE-mediated latex reactions: ❑ Contact urticaria ❑ Dysphonia ❑ Allergic rhinitis ❑ Dyspnea ❑ Bronchospasm ❑ Stridor ❑ Erythema ❑ Hypotension ❑ Pruritus ❑ Tachycardia ❑ Generalized urticaria ❑ Shock

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Latex Reactions

❑ Angioedema

T-cell-mediated reactions: ❑ Onset of reaction may be within hours. o Peak symptoms may be up to days later. ❑ Signs and symptoms are indicative of physical and chemical damage to the skin (see Contact Dermatitis, page 33): o Erythema o Pruritus o Vesiculation or blistering

Nonallergic (or irritant) reactions are the most common reactions associated with exposure to latex products.

Nonallergic (Irritant) Reactions
❑ Are the most common reactions associated with

exposure to latex products. ❑ Are caused by chemicals (e.g., thiurams) used in manufacturing. ❑ Usually a mild chemical dermatitis. ❑ May be cofactors in development of allergic reactions.

Diagnostic Testing
The general principles of diagnostic testing are included in Volume 1: Diagnostic Testing, page 31. Specific tests used for diagnosing latex reactions are included here. ❑ Skin or in vitro testing can confirm IgE sensitivity to natural latex rubber. o Referral to an allergy/immunology specialist for evaluation is recommended. o Appropriate skin-testing materials for natural latex rubber are only available in certain medical centers. o Skin tests with high concentrations of natural rubber latex antigens can cause anaphylaxis. ⇒ Testing should be performed by physicians who are trained to do such tests safely and in facilities equipped for treating anaphylaxis. ❑ Patch tests can confirm delayed hypersensitivity to chemicals in natural rubber latex. ❑ In some patients with IgE sensitivity to natural rubber latex, clinically significant cross-reactivity has been demonstrated between latex and: o Avocado o Banana o Chestnut o Kiwi

Irritant reactions to latex do not involve the immune system but are important cofactors for developing allergic reactions.

Diagnosis is best made by the medical history and an index of suspicion.

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Skin tests with high concentrations of natural rubber latex antigens can cause anaphylaxis.
❑ Testing should be

❑ Some patients who present with a very strong positive

history will have negative skin and in vitro tests. o This may indicate nonimmunologically mediated reactions or poor quality test material. o In either instance, consider the patient at risk, and treat with appropriate measures including provision of injectable epinephrine.

performed by physicians who are trained to do such tests safely and in facilities equipped for treating anaphylaxis. ❑ Referral to an allergy/immunology specialist for evaluation is recommended.

Patients who present with very strong positive history of latex allergy, but negative skin and in vitro tests, should be considered at risk.
❑ Treat with appropriate

Positive scratch test to latex.
Photo provided by Anthony Gaspari, M.D., University of Rochester.

Managing the Patient with Latex Allergy
The medical management of latex allergy focuses on avoidance.
Avoiding skin or mucous membrane contact with natural rubber latex is essential.
❑ This includes but is not limited to: o Gloves o Tourniquets o Blood pressure cuffs o Catheters o Drains o EKG pads o Some adhesive bandages

measures, including provision of injectable epinephrine.

Four general principles of allergy management
1. Avoid factors that cause symptoms. 2. Use appropriate medications. 3. Evaluate for immunotherapy. 4. Educate and follow-up.

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Extremely allergic patients require additional avoidance measures.
❑ Includes abstention from: o Any airborne latex

⇒ It can cause respiratory distress or anaphylaxis. o Syringes with latex in the plungers o Medications stored in contact with latex o Some anesthesia equipment o Some endotracheal tubes o Injection ports in IV tubing o Ingestion of food prepared by worker(s) wearing latex gloves

Educate the patient and family about latex avoidance measures. Provide patient educational resources including:
❑ Videos ❑ Pamphlets ❑ Books ❑ Referrals to educational

support organizations

Communicate latex precautions to ALL healthcare professionals as soon as possible.
1. Alert ALL healthcare professionals (e.g., doctors, nurses, dentists) to the potential for natural rubber latex allergy. 2. Latex precautions (in writing) and alternative materials should be available BEFORE any procedure. 3. FLAG the patient’s chart for latex allergy. 4. Suggest that the patient wear medical alert identification. 5. Make certain that all personnel that may come in contact with the allergic patient are warned in advance and again immediately before the patient arrives. This is crucial for effective avoidance, and includes personnel in: o Procedure areas o Post anesthesia units o Special care units o Wards

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Avoidance: what can you do? To decrease the risk of latex reactions in your facility use powder-free, nonlatex gloves.
❑ Nonlatex gloves should be available for use on

sensitive patients. o Consider standard use of nonpowdered gloves or nonlatex gloves to: ⇒ Reduce occupational exposure. ⇒ Reduce chance of accidental patient exposure, especially in emergency room. ❑ Health providers using powdered latex gloves while caring for another patient should scrub their hands, arms, and faces thoroughly, and change outer garments before entering the treatment area of a patient with latex allergy. ❑ Provide lists of latex-free products for home and medical needs to your latex-sensitive patients. o Latex-free alternatives exist for almost all home and medical needs. o Lists of latex-free products are readily available. Provide these to your latex-sensitive patients. (see page 112) ❑ Educate your staff about latex allergy, including patient care and potential occupational risks.

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Latex Reactions

With repeated exposure, allergy to latex can worsen or become lifethreatening. Patients with significant IgE-mediated latex allergy should:
❑ Wear a medical alert bracelet or necklace for

emergency situations. ❑ Inform necessary people about their latex allergy: o Family o Healthcare workers o Employers o School personnel o Caregivers ❑ Have (and use) lists of latex-containing products and safe alternatives.

Some sources of latex exposure:
Medical Gloves Blood pressure cuffs Catheters Dental devices Face masks, straps Tourniquets Wound drains Injection ports Electrode pads Bulb syringes Bandages Rubber syringe stoppers Stethoscope tubing Household Balloons Condoms Dishwashing gloves Hot water bottles Rubber bands Shoe soles Erasers Swimming goggles/masks Toys Sports equipment Pacifiers Food handler wearing latex gloves

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Some latex products and suggested safe alternatives:
Latex Product Balloons Baby bath toys Belts for clothing Condoms Crib mattress pads Elastic bands Feeding nipples Gloves, household Halloween rubber masks Rubber boots Raincoats/slickers Sneakers Shoes with rubber bottoms Swim fins Swimming goggle rims Tooth massagers Racquet handles Telephone cords Thong sandals Safe Alternative Mylar balloons Plastic or cloth toys Leather or cloth belts Sheep cecum condoms (for birth control only) Heavy cotton pads Paper clips or twine Silicone nipples Cotton gloves Synthetic gloves Plastic masks or water-based paints Clear vinyl “rubbers” Nylon or synthetic waterproof coats Leather shoes Leather or synthetic bottoms Clear plastic fins Clear plastic rims Soft brushes Leather handles Clear cords Leather sandals

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Latex Reactions

References
AAAAI and ACAAI Joint Subcommittee. AAAAI and ACAAI joint statement concerning the use of powdered and nonpowdered natural rubber latex gloves. Ann Allergy Asthma Immunol 1997; 79: 487. Barton EC. Latex allergy recognition and management of a modern problem. Nurse Practitioner 1993; 18: 52-58. Bernstein M. An overview of latex allergy and its implications for emergency nurses. J Emerg Nurs1996; 22: 29-36. Iacobelli A, McCullough J, Ownby D. The prevalence of latex allergy in high-risk medical personnel (abstract). J Allergy Clin Immunol 1993; 91: 216. Kalish RS. Contact dermatitis and photoallergic reactions. In: Kaplan AP (ed). Allergy, 2nd ed. Philadelphia: WB Saunders, 1997: 603-610. Kam PCA, Lee MSM, Thompson JF. Latex allergy: an emerging clinical and occupational health problem. Anaesthesia 1997; 52: 570-575. Kellett PB. Latex allergy: a review. J Emerg Nurs 1997; 23: 27-36. Kelly KJ, Kurup VP Reijula KE, Fink JN. , The diagnosis of natural rubber latex allergy. J Allergy Clin Immunol 1994; 93: 813-816. Kelly KJ, Sussman G, Fink JN. Stop the sensitization. J Allergy Clin Inmmunol 98: 857-858. Kim KT, Safadi GS, Sheikh KM. Diagnostic evaluation of type I latex allergy. Ann Allergy Asthma Immunol 1998; 80: 66-70. Landwehr LP Boguniewicz M. Current . perspectives on latex allergy. J Pediatr 1996; 128: 305-312. Latex Hypersensitivity Committee. ACAAI position statement: Latex allergy - an emerging healthcare problem. Ann Allergy Asthma Immunol 1995; 75: 19-21. Senst BL, Johnson RA. Latex allergy. Am J Health Syst Pharm 1997; 54: 1071-1075. Slater JE. Latex allergy. J Allergy Clin Immunol 1994; 94: 139-149. Steelman VM Latex allergy precautions: a research-based protocol. Nursing Clinics North Am 1995; 30: 475-493. Sussman GL, Beezhold DH. Allergy to latex rubber. Ann Intern Med 1995; 122: 43-46. Sussman GL, Liss, GM, Deal K, et al. Incidence of latex sensitization among latex glove users. J Allergy Clin Immunol 1998; 101: 171-178. Tarlo SM, Wong L, Roos J, et al. Occupational asthma caused by latex in a surgical glove manufacturing plant. J Allergy Clin Immunol 1990; 85: 626-631. Turjanmaa K, Alenius H, Mäkinen-Kiljunen S, Reunala T, Palosuo T. Natural rubber latex allergy. Allergy 1996; 51: 593-602. Wolf JE. Contact dermatitis. In: Conn HF (ed). Conn’s Current Therapy. Philadelphia: WB Saunders, 1998: 845-846. Woods JA, Lambert S, Platts-Mills TAE, Drake DB, Edlich RF. Natural rubber latex allergy: spectrum, diagnostic approach, and therapy. J Emergency Med 1997; 15: 71-85. Young MA, Meyers M. Latex allergy: considerations for the care of pediatric patients and employee safety. Nursing Clin North Am 1997; 32: 169-182. Yunginger JW. Natural rubber latex allergy. In: Middleton E, Reed CE, Ellis EF, et al (eds). Allergy Principles and Practice, 5th ed. St. Louis: Mosby, 1998: 1073-1078.

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114

Anaphylactic and Anaphylactoid Reactions
Anaphylactic Reactions
naphylaxis is a rapid immune-mediated systemic reaction to allergens to which the patient has been previously exposed. ❑ The response has many etiologies. ❑ Results from immune-mediated (i.e., IgE-mediated) rapid release of potent mediators from: o Tissue mast cells o Peripheral blood basophils ❑ Other reactions (i.e., anaphylactoid reactions) can mimic anaphylaxis.

A

Anaphylaxis is the most severe form of allergic reaction. It:
❑ Occurs rapidly and

often dramatically. ❑ Is usually unanticipated. ❑ Should always be considered a MEDICAL EMERGENCY.

Possible Causes of Anaphylactic Reactions
❑ Medications o Antibiotics o General anesthetics o Insulin o Protamine o Progesterone ❑ Vaccines o Egg-based formulations are contraindicated for

Anaphylaxis is an immediate systemic reaction that:
❑ Results from

patients with severe systemic sensitivity to egg. o Reactions may also occur in response to: ⇒ Gelatin ⇒ Protein components ⇒ Preservatives (e.g., thimerosal) ❑ Latex ❑ Blood components or biological fluids (e.g., seminal fluid) ❑ Insect stings ❑ Allergen extracts

immune-mediated (i.e., IgE-mediated) rapid release of potent mediators from: o Tissue mast cells o Peripheral blood basophils ❑ Is dependent upon previous allergen exposure.

Anaphylactoid reactions can mimic anaphylaxis.

Anaphylactic and Anaphylactoid Reactions

115

❑ Anaphylaxis may also occur: o With exercise o Without definable causes (e.g., idiopathic

anaphylaxis)

Association of anaphylactic reactions with plasma histamine levels.

30 Histamine level (ug/ml)
116
Anaphylactic and Anaphylactoid Reactions

20

10

l k k he on dia ing oc oc ma sh adac tensi or sh car Sh N hy te Flu He o ere yp era Tac ev H S od d-m l Mi

Risk factors for anaphylaxis:
❑ Food allergy ❑ Asthma ❑ Prior history of reactions ❑ Beta-adrenergic blocker use ❑ Multiple antibiotic sensitivity ❑ Atopic background

Anaphylactoid Reactions
An anaphylactoid reaction is an immediate systemic reaction that mimics anaphylaxis but is not an IgE-mediated response. ❑ Clinically similar to anaphylaxis, but not mediated by antigen-antibody interactions. ❑ Adverse reactions may occur on first exposure to agents, since sensitization is not required. ❑ Reactions generally are dependent on systemic exposure, usually in amounts greater than those needed for anaphylaxis. ❑ Allergy skin tests to detect IgE-mediated reactions are not useful in predicting anaphylactoid reactions.

Anapylactoid reactions appear clinically similar to anaphylaxis but are not IgE-mediated.

When is it an anaphylactic or anaphylactoid reaction?
Anaphylactic Reactions Is sensitization required? Can reaction occur on first exposure? How much exposure is needed to elicit reaction? Is reaction predicted by allergy skin tests? Yes No Anaphylactoid Reactions No Yes

Very little

Usually more than for anaphylaxis No

Yes

Possible Causes of Anaphylactoid Reactions
❑ Medications (e.g., ACE inhibitors, narcotics, anesthetics,

NSAIDs) ❑ Blood components or biological fluids (e.g., gamma globulin) ❑ Diagnostic testing material (e.g., radiographic contrast material) ❑ Insect bites
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117

❑ Exercise ❑ Anaphylactoid reactions may also occur without

definable causes (e.g., idiopathic).

Diagnosing Anaphylactic/ Anaphylactoid Reactions
Medical History
❑ A history of recent antigen or substance exposure is an

important diagnostic tool. o Focus on possible causative agents immediately before the event. o Obtain information from individuals present at time of event (e.g., family members, medical personnel). ❑ Consider history of: o Asthma o Cardiac disease o Use of beta-adrenergic blockers

When is it lifethreatening?
Signs and symptoms of potentially life threatening anaphylactic/ anaphylactoid reactions include:
❑ Stridor ❑ Respiratory distress ❑ Wheezing ❑ Laryngeal edema ❑ Hypotension ❑ Cardiac arrhythmias ❑ Shock ❑ Syncope ❑ Seizures

Signs and Symptoms of Anaphylactic/Anaphylactoid Reactions
Common Initial Signs and Symptoms
❑ Sense of impending doom ❑ Generalized warmth or flush ❑ Tingling or pruritus: o Palms of the hands and/or soles of feet o Lips and genitalia o Axillae o Scalp ❑ Complaints of: o A lump in the throat o Throat tightness o Hoarseness or difficulty in swallowing o Inspiratory stridor o Chest tightness o Wheezing or shortness of breath

Laryngeal edema and cardiovascular collapse are of greatest concern.

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Anaphylactic and Anaphylactoid Reactions

Other Signs and Symptoms
❑ Cardiovascular symptoms: o Lightheadedness o Faintness o Syncope o Palpitations o Arrythmias ❑ Upper respiratory ❑ Gastrointestinal

symptoms: o Nasal congestion o Rhinorrhea o Sneezing o Stridor o Dysphonia o Difficulty swallowing

symptoms: o Bloating o Nausea o Vomiting o Cramps ❑ Lower airway obstruction: o Cough o Wheeze ❑ Skin symptoms: o Urticaria o Angioedema o Flushing

Anaphylactic/ anaphylactoid reactions are a MEDICAL EMERGENCY. Patients who do not have life-threatening symptoms on initial presentation may progress to anaphylaxis.

The onset and course of the response are variable. ❑ Signs and symptoms generally begin within seconds to minutes after exposure to the causative agent, but may be delayed for up to 2 hours. ❑ The response may be: o Biphasic ⇒ Signs and symptoms occur initially, then abate for several hours before returning. o Protracted ⇒ Signs and symptoms persist for several hours despite treatment.

Anaphylactic/ anaphylactoid symptoms usually begin within seconds to minutes after exposure to the inciting agent.
❑ BUT symptoms may

be delayed for up to two hours.

Anaphylactic and Anaphylactoid Reactions

119

Physical Examination
IMMEDIATELY ASSESS patients with cardiac and respiratory symptoms for airway obstruction, bronchospasm, or shock. Symptoms suggesting upper airway obstruction:
❑ Hoarseness ❑ Dysphonia ❑ Difficulty swallowing ❑ Drooling ❑ Change in voice ❑ Dysphagia ❑ Stridor Physical findings include: ❑ Flushing ❑ Urticaria ❑ Diffuse erythematous rash ❑ Swelling of the lips, tongue, uvula, or other areas ❑ Expiratory wheezing and/or inspiratory stridor ❑ Cyanosis ❑ Hypotension

Diagnostic Testing
The general principles of diagnostic testing are included in Volume 1: Diagnostic Testing, page 31. Specific tests used for diagnosing anaphylactic/anaphylactoid reactions are included here. ❑ Have patient keep food/situation diaries. ❑ Look for new ingestions and/or medications including: o OTC medications o Laxatives o Vitamins ❑ Measure serum tryptase levels during acute reaction. o Used in emergency room to differentiate anaphylaxis from other types of reactions. ⇒ Elevated tryptase levels support the diagnosis of anaphylaxis. ⇒ Serum tryptase levels should be obtained within 2 hours after the event. • There are isolated reports of elevated levels detected up to 5 hours after the event.

Symptoms suggesting lower airway obstruction:
❑ Wheezing ❑ Chest tightness ❑ Cough

When reviewing patient diaries, look for new ingestions and/or medications including:
❑ OTC medications ❑ Laxatives ❑ Vitamins

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Anaphylactic and Anaphylactoid Reactions

Masqueraders of anaphylactic/anaphylactoid reactions:
❑ Vasovagal syncope ❑ Syndromes associated with flushing

(e.g., metastatic carcinoid) ❑ Postprandial syndromes (e.g., scombroid poisoning) ❑ Systemic mastocytosis ❑ Panic attacks ❑ Vocal cord dysfunction syndrome ❑ Hereditary angioedema ❑ Angioedema secondary to ACE inhibitor ❑ Other causes of shock ❑ Other cardiovascular or respiratory events

Serum tryptase levels are used in the ER to differentiate anaphylaxis from other types of reactions.
❑ Elevated tryptase levels

support the diagnosis of anaphylaxis.

Specialist Referral
❑ Referral to an allergy/immunology specialist for

diagnosis, consultation, and possible comanagement is recommended for: o Patients with recurrent events. o Identifying causes not apparent from history. o Diagnostic testing and test interpretation. o Hymenoptera sensitivity requiring immunotherapy and/or education. o Pharmacologic intervention. o Additional education on avoidance measures and treatment. o Desensitization, if appropriate (e.g., antibiotic). ❑ Specialist evaluation may include: o Skin tests o Challenge tests

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Four general principles of allergy management
1. Avoid factors that cause symptoms. 2. Use appropriate medications. 3. Evaluate for immunotherapy. 4. Educate and follow-up.

Managing the Patient with Anaphylactic/Anaphylactoid Reactions
Managing Acute Events
❑ Treatment should follow an established protocol for the

Rapid therapy is crucial when treating an acute anaphylactic/ anaphylactoid event!
❑ The immediate goal is

management of anaphylactic/anaphylactoid reactions. o Clinical presentation is variable. o Treatment may need to be individualized for the patient’s particular symptoms and symptom severity. ❑ Rapid therapy is crucial! o The immediate goal is to maintain adequate airway and support blood pressure.

General considerations for treating an acute event:
❑ Place patient in recumbent position and

to maintain adequate airway and support blood pressure.

For children, intramuscular administration of epinephrine is preferred over subcutaneous injection.
❑ Recommendations for

using subcutaneous epinephrine injection are based on anecdotal experience. o Subcutaneous injection may be associated with delayed epineprhine absorption.
SOURCE: Simons et al. J Allergy Clin Immunol 1998; 101: 33-37.
Anaphylactic and Anaphylactoid Reactions

elevate lower extremities. ❑ Stay with the patient; monitor vital signs frequently. ❑ Administer epinephrine. o Adult dose: 0.2 ml to 0.5 ml of a 1:1000 (wt/vol) dilution (0.2 to 0.5 mg) intramuscularly or subcutaneously. ⇒ For serious reactions, use intramuscular administration. • Intramuscular administration is more rapidly absorbed. ⇒ Dose may be repeated every 10 to 15 minutes for the first hour. ⇒ If patient remains hypotensive, consider plasma volume expanders. o Child dose: 0.01 mg/kg up to a maximum of 0.3 mg or 0.3 ml of 1:1000 (wt/vol) administered intramuscularly. ⇒ Parents and caretakers of children under 30 pounds (13.6 kg) should be taught to administer epinephrine (1:1000) by syringe (0.01 mL/kg, maximum: 0.15 mL). ⇒ Dose may be repeated every 15 minutes for up to 3 doses.

122

o For anaphylaxis resulting from subcutaneous

injection, intramuscular injection, or insect stings, half the dose of aqueous epinephrine should be injected into the site to inhibit further absorption of the causative agent. o Patients on beta-blockers are at higher risk of anaphylaxis because of the danger of epinephrine resistance. ⇒ This may be countered with glucagon injection. ❑ Maintain the airway. ❑ Administer oxygen: usually 8 to 10 L/min o Lower concentrations may be appropriate in patients with COPD. ❑ Administer antihistamine, usually parenterally. o For adults: 25 to 50 mg diphenhydramine. o For children: 1.0 to 2.0 mg/kg diphenhydramine (50mg maximum). o May continue with oral diphenhydramine every 4 to 6 hours as necessary. o Addition of H2 antihistamine may be of benefit (e.g., cimetidine, 300 mg slow IV). ❑ Treat hypotension with intravenous fluids or colloid replacement. o Consider vasopressors. ❑ Treat bronchospasm with an inhaled beta2-agonist. ❑ Consider systemic corticosteroids if initial response is inadequate or reaction is severe.

Immediate goals for treating anaphylactic/ anaphylactoid reactions:
❑ Maintain an adequate

airway. ❑ Support blood pressure.

Stay with the patient! Monitor vital signs frequently! Epinephrine is the single most important agent for treating anaphylactic/ anaphylactoid reactions.

Patients with severe reactions should:
❑ Wear medical alert

Hospitalize the patient who is unresponsive to initial therapy.
❑ Monitor the patient in a medical setting for several

hours after apparent recovery to ensure that a late response does not occur away from medical care. ❑ There is potential for biphasic reactions. ❑ “Protracted” anaphylaxis may occur in which hypotension, bronchospasm, or laryngeal edema persist for many hours despite treatment. ❑ Biphasic and protracted anaphylaxis can lead to death, even though the patient survives the first several hours after the reaction.

identification. ❑ Be taught to selfadminister epinephrine. ❑ Keep epinephrine and antihistamines readily available. ❑ Call 911 following administration and wait for ambulance transport.

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Patients at risk for anaphylactic/ anaphylactoid reactions, and/or their caretakers, should carry with them AT ALL TIMES injectable epinephrine, oral antihistamine, and a tourniquet (for stings if necessary). Monitor the patient in a medical setting for several hours after apparent recovery.
❑ Biphasic and protracted
❑ Epinephrine kits (e.g., Epi Pen® auto-injector and

anaphylaxis can lead to death, even though the patient survives the first several hours after the reaction. ♦ Biphasic reaction: symptoms abate and then recur after several hours. ♦ Protracted reaction: hypotension, bronchospasm, or laryngeal edema persist for many hours despite treatment.

Epi Pen Jr® auto-injector) are commercially available with preloaded syringes or automatic injector systems for self-injection by patients over 30 pounds. ♦ Patient education and instruction in using these devices are required. ❑ After using a device, the patient should call 911 and be transported to the hospital for further definitive therapy. ❑ Children at risk for anaphylaxis should have injectable epinephrine available at their schools and child care facilities. ❑ Medical alert identification is essential to alert emergency personal about allergies in an unconscious patient.

After removing the protective cover, administer the auto-injector directly through clothing.
Anaphylactic and Anaphylactic and Anaphylactoid Reactions Anaphylactoid Reactions

124

Preventing Anaphylactic/ Anaphylactoid Events
❑ As in all allergic diseases, avoidance of a known antigen

is the best prevention. ❑ Avoidance measures should be individualized. Consider: o Age o Activities o Occupation o Hobbies o Residential conditions o Access to medical care

Patient education is critical and should include:
❑ Allergen identification. ❑ Avoidance strategies and

The risk of unpredictable anaphylaxis is increased in people suffering from allergies to:
❑ Food ❑ Insect venom ❑ Latex ❑ Parenteral drugs, vaccines, or diagnostic agents

counseling. ❑ Symptom recognition. ❑ Cautions regarding the possibility of lifethreatening reactions. ❑ What to do in case of accidental ingestion. ❑ Self-administration of epinephrine.

Patient Education is Essential
❑ Every patient at risk for anaphylactic/anaphylactoid

reactions should have an action plan. ❑ Education should cover several topics. o Symptom recognition: ⇒ Cautions regarding the possibility of lifethreatening reactions. o Treating an acute reaction: ⇒ What to do in case of accidental ingestion. ⇒ Self-administration of epinephrine. o Allergen identification, including: ⇒ Hidden allergens. ⇒ Cross-reactions to allergens. o Avoidance strategies and counseling. o Risks of future reactions. ⇒ Unforeseen risks during medical procedures. Please refer to the general educational tips included in the Patient Education Chapter of Volume 1, page 71, for further information.

For children with anaphylactic reactions, the child, parents, caregivers, and school personnel should be included in patient education.

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Suggestions for reducing the risk of anaphylactic/anaphylactoid reactions: Consider referral to an allergy/ immunology specialist for consultation and/or comanagement for:
❑ Patients with recurrent ❑ Require the patient to carry, at all times, a bracelet, necklace, or wallet card containing a statement of their condition. ❑ Know the patient’s allergy and medical history. Have medical record documentation. ❑ Be familiar with the patient’s concurrent therapy. ❑ Administer drugs orally rather than parenterally, if possible. ❑ Observe immunotherapy patients in the physician’s office for 20 to 30 minutes after injection. ❑ Withhold immunotherapy when patients are having significant asthma or allergic rhinitis. ❑ Pretreat patients who have a history of anaphylactoid reactions (e.g., to radiographic contrast media), if use of the offending agent is essential (see Drug Reactions, page 59). ❑ Have patients with idiopathic anaphylaxis, or those at risk of accidental exposure to known anaphylactic agents, carry an emergency treatment kit. ❑ Educate patients, families, and caregivers about risk. ❑ Consider referral to educational support groups to educate and support the family about lifestyle changes.

events. ❑ Identifying causes not apparent from history. ❑ Diagnostic testing and test interpretation. ❑ Hymenoptera sensitivity requiring immunotherapy and/or education. ❑ Pharmacologic intervention. ❑ Additional education on avoidance measures and treatment. ❑ Desensitization, if appropriate (e.g., antibiotic).

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Special Considerations for Managing Anaphylactic/ Anaphylactoid Reactions
The Pregnant Patient
❑ Both mother and fetus are at risk. ❑ Uterine cramping may occur in patients experiencing

anaphylaxis, which may mimic preterm labor or miscarriage. o However, miscarriage and preterm delivery are not common complications of anaphylaxis. ❑ For the pregnant patient experiencing anaphylaxis, epinephrine remains the treatment of choice.

For the pregnant patient experiencing anaphylaxis, epinephrine remains the treatment of choice.

Reactions in the Operating Room
❑ This is a particularly difficult setting in which to evaluate

anaphylaxis. o Patients may be intubated and sedated; obtaining a history may be impossible. o Patients are often exposed to a wide variety of agents, including: ⇒ Antibiotics ⇒ Muscle relaxants ⇒ Opiates ⇒ Neuromuscular-blocking drugs ⇒ Latex ⇒ Plasma expanders ⇒ Protamine ❑ Many of the clinical clues to impending reactions are not available. o The first sign may be hypotension or difficulty ventilating an unconscious patient. ❑ A history of a reaction during an operative procedure requires full investigation before subsequent procedures. o It is essential that different classes of drug are chosen for subsequent interventions to reduce the risk of repeated anaphylaxis.

A history of anaphylaxis during an operative procedure requires full investigation before subsequent procedures.

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Refractory Cases Due to Betaadrenergic Blocking Agents
❑ Patient may be unresponsive to usual doses used to

treat allergic reaction. ❑ 1 mg glucagon administered intravenously may be used. o A continuous infusion of 1 to 5 mg of glucagon per hour may be needed.

Exercise-induced Reactions
Anaphylaxis has been associated with many physical activities.
o Jogging o Racquet sports o Brisk walking o Skiing o Bicycling o Aerobic exercise
❑ Initial symptoms: o Fatigue o Diffuse warmth o Pruritus o Erythema o Urticaria o Wheezing ❑ Symptoms may progress to: o Angioedema o Gastrointestinal symptoms o Laryngeal edema

Patients who have experienced exercised-induced anaphylaxis should:
❑ Be cautioned to not

o Hypotension o Vascular collapse ❑ Associated factors: o Food ingestion within 3 to 4 hours of exercise

exercise alone. ❑ Wear medical alert identification. ❑ Discontinue exercise at the first sign of symptoms. ❑ Carry epinephrine, and administer it at the first sign of symptoms.

has been associated with increased risk. ⇒ Elimination of the food may allow the patient to exercise. ⇒ Reactions may be IgE-mediated, requiring a specific food, or may be a nonspecific effect of ingestion. • Patient should not eat for more than 2 hours prior to exercising, if reaction is to a specific food. • Patient should not eat for 2 hours prior to exercising, if reaction is nonspecific. o Higher incidence of personal and/or family atopy. o Role of aspirin or NSAIDs in aggravating exerciseinduced anaphylaxis is unclear.

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❑ Exercise should be discontinued at the onset of

symptoms. o Some patients should avoid exercise during the immediate post-prandial period. ❑ Patients should carry epinephrine and administer it at the first sign of symptoms. ❑ Prophylactic treatment is generally not useful. ❑ Patients who have experienced exercised-induced anaphylaxis should be cautioned to not exercise alone. ❑ Medical alert identification should be carried. ❑ The acute management of exercise-induced anaphylaxis is the same as treatment of anaphylaxis from other causes; the patient must be prepared to treat themselves!

Idiopathic Reactions
❑ Diagnose by exclusion where neither a causative

allergen nor physical factor can be identified. o Same signs/symptoms as with other anaphylactic/ anaphylactoid reactions. ❑ The acute treatment of symptoms is similar to that of other anaphylactic/anaphylactoid reactions. ❑ Patient education and psychological support are very important. ❑ Chronic oral corticosteroid treatment is sometimes necessary. ❑ Comanagement with an allergy/immunology specialist is necessary.

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References
Atkinson TP Kaliner MA. Anaphylaxis. Med , Clin North Am 1992; 76: 841-855. Burnstein M. Rubinow A. Shalit M. Cyclic anaphylaxis associated with menstruation. Ann Allergy 1991; 66: 36-38. Corren J, Schocket AL. Anaphylaxis: a preventable emergency. Postgrad Med 1990; 87: 168-178. Dykewicz MS. Anaphylaxis and stinging insect reactions. Compr Ther 1996; 22: 579-585. Friday GA, Fireman P Anaphylaxis. Ear Nose . Throat J 1996; 75: 21-24. Friday GA, Fireman P Anaphylaxis. In: . Fireman P Slavin R, (eds). Atlas of Allergies. , 2nd ed. London: Mosby-Wolfe; 1996: 57-73. James JM, Zeiger RS, Lester MR, et al. Safe administration of influenza vaccine to patients with egg allergy. J Pediatrics 1998; 133: 624-628. Joint Task Force on Practice Parameters. The diagnosis and management of anaphylaxis. J Allergy Clin Immunol 1998; 101: S465-528. Kemp SF, Lockey RF, Lieberman P et al. , Arch Intern Med 1995; 155: 1749-1754. Laroche D, Vergnaud M, Sillard B, Soufarapis H, Bricard H. Biochemical markers of anaphylactoid reactions to drugs. Anesthesiology 1991; 75: 945-949. Lieberman P Anaphylaxis and . anaphylactoid reactions. In: Middleton E, Reed CE, Ellis EF, et al (eds). Allergy Principles and Practice, 5th ed. St. Louis: Mosby, 1998: 1079-1092. McGrath KG. Anaphylaxis. In: Patterson R, Grammer LC, Greenberger PA (eds). Allergic Diseases, 5th ed. Philadelphia: LippincottRaven, 1997: 439-458. Meggs WJ, Pescovitz OH, Metcalfe D, et al. Progesterone sensitivity as a cause of recurrent anaphylaxis. N Engl J Med 1984; 311: 1236-1238. Orfan NA, Stoloff RS, Harris KE, et al. Idiopathic anaphylaxis: total experience with 225 patients. Allergy Proc 1992; 13: 35-43. 130
Anaphylactic and Anaphylactic and Anaphylactoid Reactions Anaphylactoid Reactions

Physicians' Desk Reference. 53rd ed. Oradell, NJ: Medical Economics Company, Inc, 1999. Saryan JA, O’Loughlin JM. Anaphylaxis in children. Pediatr Ann 1992; 21: 590-598. Stark BJ, Sullivan TJ. Biphasic and protracted anaphylaxis. J Allergy Clin Immunol 1986; 78: 76-83. Wade JP Liang MH, Sheffer AL. Exercise, induced anaphylaxis. Epidemiologic observations. Prog Clin Biol Res 1989; 297: 175-182. Wasserman SI. Anaphylaxis. In: Kaplan AP (ed). Allergy, 2nd ed. Philadelphia: W.B. Saunders, 1997: 1550-1572. Wyatt R. Anaphylaxis: how to recognize, treat, and prevent potentially fatal attacks. Postgrad Med 1996; 100: 87-99. Yunginger JW. Anaphylaxis. Ann Allergy 1992; 69: 87-99. Yunginger JW. Anaphylaxis. Curr Prob Pediatr 1992; March: 130-146.

Resource Organizations
Contact the organizations listed below for information and helpful ideas.
Allergy and Asthma Network/ Mothers of Asthmatics, Inc. 2751 Prosperity Ave., Suite 150 Fairfax, VA 22030 Phone: 1-800-878-4403 www.aanma.org American Academy of Allergy, Asthma and Immunology 611 East Wells Street Milwaukee, WI 53202 (800) 822-ASMA or (414) 272-6071 www.aaaai.org American Academy of Pediatrics 141 Northwest Point Boulevard Elk Grove Village, IL 60007-1098 (800) 433-9016 or (847) 228-5005 www.aap.org American Association for Respiratory Care 11030 Ables Lane Dallas, TX 75229 (972) 243-2272 www.aarc.org American College of Allergy, Asthma and Immunology 85 West Algonquin Road, Suite 550 Arlington Heights, IL 60005 (800) 842-7777 or (847) 427-1200 www.acaai.org The American Lung Association For the affiliate nearest you, call (800) LUNG USA www.lungusa.org Asthma and Allergy Foundation of America 1125 Fifteenth St, N.W Suite 502 ., Washington, DC 20005 Phone: 1-800-7-ASTHMA www.aafa.org Centers for Disease Control and Prevention 1600 Clifton Road Atlanta, GA 30333 (800) 311-3435 The Food Allergy Network 10400 Eaton Pl., Suite 107 Fairfax, VA 22030 Phone: 1-800-929-4040 www.foodallergy.org Healthy Kids: The Key to Basics Educational Planning for Students with Chronic Health Conditions 79 Elmore Street Newton, MA 02459-1137 (617) 965-9637 E-mail: [email protected] Immune Deficiency Foundation 25 W Chesapeake Ave., Suite 206 . Towson, MD 21204 Phone: 1-800-296-4433 www.primaryimmune.org National Heart, Lung and Blood Institute (National Asthma Education and Prevention Program) P Box 30105 .O. Bethesda, MD 20824 Phone: (301) 251-1222 www.nhlbi.nih.org National Institute of Allergy and Infectious Diseases Building 31, Room 7A-50 National Institutes of Health Bethesda, MD 20892 Phone: (301) 496-5717 www.niaid.nih.gov

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U.S. Department of Education Office for Civil Rights, Customer Service Team Mary E. Switzer Building 330 C Street, S.W . Washington, DC 20202-1328 (800) 421-3481 or (202) 205-5413 www.ed.gov/offices/OCR U.S. Environmental Protection Agency Indoor Environments Division 401 M Street, S.W (6604J) . Washington, DC 20460 (202) 233-9370 Indoor Air Quality Information Clearinghouse (800) 438-4318 www.epa.gov/iaq

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Glossary
AAAAI: American Academy of Allergy, Asthma and Immunology. Airway wall “remodeling”: structural changes that are unlikely to be reversible, resulting from continued inflammation observed in chronic asthma. Permanent changes include continued loss of epithelial cells, deposition of subbasement membrane collagen, and increased muscle mass and blood vessels. Allergen immunotherapy (allergy vaccine therapy): a form of long-term therapy consisting of repeated, controlled administration of specific allergens to patients with IgE-mediated conditions to reduce disease severity from natural exposure to these allergens. Allergen: the source of an allergy-producing substance, the allergy-producing substance itself, or one or more of the specific proteins that make up the substance and provoke the immune response, including IgE antibodies. They are often common, usually harmless substances such as pollen, mold spores, animal dander, dust, foods, insect venoms, and drugs. Allergic diseases: represent the clinical manifestations of adverse immune responses (including IgE responses), following repeated contact with usually harmless substances such as pollen, mold spores, animal dander, dust, foods, insect venoms, and drugs; include diseases of the atopic diathesis as well as diseases which may have an allergic component. Allergy: an acquired potential to develop immunologically mediated adverse reactions to normally innocuous substances upon re-exposure to the sensitizing allergen (including IgE antibody responses to allergens), causing the release of inflammatory mediators. Anaphylactoid reaction: an immediate systemic reaction that mimics anaphylaxis but is not an IgE-mediated response. Anaphylaxis: is the most severe form of allergic reaction. It is a rapid, immune-mediated, systemic reaction to allergens to which the patient has been previously exposed. It has many etiologies, resulting from immune-mediated (i.e., IgE-mediated) rapid release of potent mediators from tissue mast cells and peripheral blood basophils. The reaction occurs rapidly and often dramatically, and is usually unanticipated. Signs and symptoms arise systemically and may include faintness, syncope, severe difficulty breathing, and throat closing. Symptoms generally start within 15 to 30 minutes from exposure to allergen, occasionally begin after 1 hour, and rarely occur hours later. Other reactions (i.e., anaphylactoid reactions) can mimic anaphylaxis. Anaphylaxis is always a medical emergency! See also exercise-induced anaphylaxis, anaphylactoid reaction, and idiopathic anaphylactic/anaphylactiod reactions.

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Angioedema: swelling in the deep cutaneous layer, but the skin may appear normal. Antihistamines: drugs that inhibit allergy symptoms by blocking the actions of histamine at the H1 receptor. Older sedating antihistamines cause drowsiness and/or loss of concentration and may affect psychomotor performance. Nonsedating antihistamines have poor penetration of the CNS, resulting in no sedative or psychomotor adverse effects. Asthma: is a chronic inflammatory disease of the airways characterized by airway obstruction, which is at least partially reversible with or without medication, and manifests increased bronchial responsiveness to a variety of stimuli. Atopic dermatitis: is a chronic or recurrent atopic inflammatory skin disease that usually begins in the first few years of life. It is often the initial clinical manifestation of an atopic predisposition, with many children later developing asthma and/or allergic rhinitis. Atopy: the genetic tendency to develop the “classical” allergic diseases, namely, allergic rhinitis, asthma, and atopic dermatitis. Atopy is typically associated with a genetically determined capacity to mount IgE responses to common allergens, especially inhaled allergens and food allergens. Beta2-agonists: drugs that are used in the treatment of asthma for short-acting quick relief, long-term 12-hour control, and for preventing exercise-induced bronchospasm. The bronchial smooth muscle relaxes in response to beta2adrenergic receptor stimulation. Chlorofluorocarbon (CFC): propellant used in MDIs to deliver inhaled asthma medications. Other propellants (HFA-134) will be replacing CFCs in the future because CFCs deplete the ozone layer. Conjunctivitis: a group of ocular disorders that result in inflammation of the conjunctiva. May be of allergic or nonallergic origin. Contact dermatitis: refers to a broad range of reactions resulting from the direct contact of an exogenous agent (allergen or irritant) with the surface of the skin. Corticosteroids: medications related to cortisone with anti-inflammatory effects useful in many allergic conditions. Newer preparations for lung, nasal, and skin use minimize risk for side effects. Cromolyn sodium/Nedocromil sodium: are topical nonsteroid antiinflammatory agents. DBPCFC: double-blind, placebo-controlled food challenge. Considered the “gold standard” for diagnosing food allergies.

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Decongestants: are sympathomimetic drugs that relieve symptoms of nasal congestion or blockage by constricting the capacitance vessels in the turbinates. Desensitization: a medical procedure utilized to reduce or eliminate sensitivity to certain drugs. Desensitization for IgE-mediated drug reactions is achieved by administering progressive doses of the drug until a full therapeutic dose is clinically tolerated. Indicated for patients with established drug allergy where no substitute for the responsible drug is available and treatment is essential. Desensitization for non-IgE-mediated drug reactions is successful for aspirin and NSAIDs. Domeboro’s solution: calcium acetate, aluminum sulfate astringent used to dry oozing dermatitis. Dry-powder inhaler (DPI): delivery mechanism without propellant for inhaled asthma medications that are in powdered form. Early phase reaction (immediate hypersensitivity reaction): an immunological reaction that occurs within minutes of subsequent exposure of the IgE antibody to the allergen in sensitized individuals. With repeat exposure of allergen, multiple IgE-FcεR-complexes are cross-linked resulting in immediate hypersensitivity reactions (i.e., mast cells degranulate releasing histamine, leukotrienes, cytokines, and proteases). Eczema: is an inflammatory disease of the skin with lesions that can be erythematous, edematous, papular, crusting, lichenified, scaling, itching, burning, and sometimes skin discoloration can occur. Elimination diet: a restricted diet used for food allergy for a limited period of time (10 to 14 days) to evaluate the patient. Specific foods may be eliminated (e.g., targeted elimination diet) or basic/severe elimination diet protocols may be utilized in more complicated situations. Epicutaneous (patch) testing: a form of allergy skin testing that identifies or confirms suspected T-cell-mediated, delayed hypersensitivity, contact allergens in contact eczematous dermatitis. Exercise-induced anaphylactic/anaphylactoid reactions: a generalized reaction with initial symptoms of fatigue, diffuse warmth, pruritus, erythema, urticaria, and/or wheezing occurring during or immediately following exercise. Reactions may be associated with prior ingestion of food and/or analgesics. Exercise-induced bronchospasm (EIB): Smooth muscle contraction in the lungs caused by a loss of heat, water, or both from the airways during exercise due to increased ventilation and inhalation of cool, dry air relative to the air within the lungs. FDA: Food and Drug Administration.

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Food allergy: a group of disorders characterized by immunologic responses to specific food proteins. Any food may cause a food allergic reaction. The prevalence is greatest in the fist few years of life and declines over the first decade. Hepa-filters: high efficiency particulate air filter. Idiopathic anaphylactic/anaphylactoid reactions: a generalized reaction that is diagnosed by exclusion when neither a causative allergen nor physical factor can be identified. Immediate local reaction: describes an insect sting reaction and is sometimes referred to as the “normal reaction.” Presents as pain, erythema, itching, and swelling at the sting site. It is a transient response that usually disappears within several hours. In vitro: refers to a lab test (e.g., ELISA) to diagnose allergens that a person is sensitized to. Ipratropium bromide: used as adjunct therapy to bronchodilators in the treatment of acute asthma exacerbations. Affects are primarily due to anticholinergic action on bronchial smooth muscle. Also used to control rhinorrhea in a patient with nonallergic rhinitis. Large local reaction: describes an insect sting reaction that displays extensive swelling and erythema, extending from the sting site over a large area and often involves most of an extremity. Swelling often peaks within 48 hours and may last as long as 7 to 10 days. Occasionally, fatigue, low-grade fever, and nausea accompany the reaction. Late phase reaction: an immunological reaction that begins 2 to 4 hours following exposure to allergen and can last for 24 hours before subsiding. Inflammatory leukocytes (e.g., neutrophils, basophils, eosinophils) are involved but the late response is primarily mediated by eosinophils in atopic individuals. These inflammatory cells release cytokines and chemokines during the response. Latex allergy: an allergic response to the proteins in natural latex rubber or to the additives used in processing latex. Leukotriene modifiers: a group of drugs that may be used as long-term control medications for the treatment of mild persistent asthma. May be considered as alternative therapy to low doses of inhaled corticosteroids in mild persistent asthma, but the position of leukotriene modifiers in therapy has not been fully established.

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Long-term control medications: drugs that are taken daily on a long-term basis to achieve and maintain control of persistent asthma. Examples include inhaled corticosteroids, long-acting bronchodilators (e.g., beta2-agonists), plus other long-term control medications (e.g., methylxanthines [theophylline], leukotriene pathway modifiers). Mast cell stabilizer: a group of drugs that exhibit anti-inflammatory properties (e.g., cromolyn sodium, nedocromil sodium). The mechanism of action of these drugs remains uncertain. Metered-dose inhaler (MDI): propellant-driven delivery mechanism for inhalation of asthma medications. MMR: measles, mumps, and rubella vaccine. NIAID: National Institute of Allergy and Infectious Diseases. Nonallergic (or irritant) reaction: reactions that do not involve the immune system but can be important cofactors for developing allergic reactions. Oral allergy syndrome: a self-limiting condition associated with the ingestion of fresh fruits and vegetables that does not display symptoms of throat closing; appears to be a cross sensitivity to pollens that the individual is allergic to. Otitis media: an acute or chronic inflammation of the middle ear. Patch testing: see epicutaneous (patch) testing. Peak expiratory flow (PEF): a measurement of pulmonary function that is not as sensitive as FEV1 for diagnosing airflow obstruction; primarily a measurement of large airway function. Peak flow meters are designed as monitoring, not diagnostic, tools. Prick/puncture test: are a test used to confirm hypersensitivity to a wide variety of allergens, the most convenient and specific method for detecting IgE antibodies. Primary prevention: focuses on blocking sensitization and development of IgE-mediated response. Quick-relief medications: a group of drugs that give prompt relief of bronchoconstriction and accompanying acute asthma symptoms: coughing, wheezing, shortness of breath or rapid breathing, chest tightness. Examples including short acting beta2-agonists and anticholinergics.

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Rhinitis: inflammation of the mucous membranes of the nose with symptoms of sneezing, itching, nasal discharge, and congestion. The etiology can be allergic, nonallergic, or both. Seasonal allergic rhinitis is an IgE-mediated reaction of the nasal mucosa to one or more seasonal allergens. Perennial allergic rhinitis is an IgE-mediated reaction to allergens that show little or no seasonal variation. It is persistent, chronic, and generally less severe than seasonal. Rhinosinusitis: is an inflammation of the paranasal sinuses that occurs with rhinitis. It rarely appears in the absence of nasal inflammation, commonly occurring in patients with perennial allergic and nonallergic rhinitis and in patients with moderate to severe asthma. Acute rhinosinusitis is a common infection that lasts for up to 3 weeks and often follows a viral upper respiratory tract infection. Suspect if symptoms worsen after 5 days or persist after 7 days. Recurrent acute rhinosinusitis is characterized by four or more episodes of acute rhinosinusitis per year separated by at least 8 weeks of symptom-free intervals. Subacute (persisting acute) rhinosinusitis lasts between 3 weeks and 3 months. Chronic rhinosinusitis is a complex of symptoms associated with inflammation of the sinuses characterized by persistent symptoms of acute rhinosinusitis lasting longer than 3 months, a lack of response to treatment, and a positive imaging study. Secondary prevention: attempts to block the expression of the disease, despite sensitization. Short-acting beta2-agonists: a group of drugs that relax bronchial smooth muscle, resulting in bronchodilation usually within 5 to 10 minutes of administration. They are most effective medication for relieving acute bronchospasm, and are the therapy of choice for relieving acute symptoms and preventing exercise-induced bronchospasm. Using more than two times per week, other than for prevention of exercise-induced asthma, is an indicator for initiating or increasing anti-inflammatory therapy. Increasing use indicates inadequate control of asthma and the need to intensify long-term control therapy. Specialist: use of specialists in this document may include: ❑ Allergy/immunology specialists ❑ Dermatologists ❑ Infectious disease specialists ❑ Ophthalmologists ❑ Otolaryngologic allergy specialists ❑ Otolaryngologists ❑ Pulmonologists In many cases, the type of specialist varies with the provider network and the geography/community. For example, the Asthma section (Volume 2) uses the term “asthma specialist” in the same manner used by the National Asthma

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Education and Prevention Program1 to refer to a fellowship-trained allergist or pulmonologist or, occasionally, other physicians with experience in asthma management developed through additional training and experience. Similar complexities exist in identifying specialists for management of such diseases as atopic dermatitis, rhinosinusitis, otitis media, conjunctivitis, urticaria and angioedema, and contact dermatitis. Therefore, consultation or comanagement is recommended, as appropriate, with the type of specialist determined by the referring healthcare provider and taking into account the patient’s health insurance coverage and the healthcare resources available in the community. Spirometry (FEV1): pulmonary measurements made with a spirometer to evaluate airway obstruction, and if so, whether it is reversible with a bronchodilator. It is mandatory to diagnose and characterize asthma severity. Targeted elimination diet: an elimination diet with foods eliminated based on results from specific IgE tests (e.g., skin tests or in vitro tests) or from a suggestive history given by patient and/or parent. Tertiary prevention: targets the control of factors that increase symptoms. Theophylline: a drug with long-term control properties for asthma. It displays bronchodilation, respiratory stimulation, and may attenuate airway hyperreactivity. Treating through: continuing drug treatment in the presence of a suspected allergic reaction to the drug. Urticaria: a skin disease that occurs in the dermis, is characterized by pruritic, erythematous, and cutaneous elevations (i.e., “rash”) that blanch with pressure, indicating the presence of dilated blood vessels and edema in the dermis. Individual lesions last less than 24 hrs. Acute urticaria is a self-limited disorder that usually lasts for a few days. Chronic urticaria lasts longer than 6 weeks.

1

Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma: Clinical Practice Guidelines. NIH Publication No. 97-4051, page 10.
Glossary

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