Consultation and referral guidelines citing the evidence: How the allergist-immunologist can help

Schatz, Michael; Leung, Donald Y.M.; Goldstein, Stanley

doi:10.1016/j.jaci.2005.10.047

« PreviousThe Journal of Allergy and Clinical Immunology
Volume 117, Issue 2, Supplement 3 , Pages S495-S523, February 2006

Consultation and referral guidelines citing the evidence: How the allergist-immunologist can help

AAAAI Consultation and Referral Guidelines Citing the Evidence Task Force Chair

AAAAI Consultation and Referral Guidelines Citing the Evidence Task Force Co-Chair

AAAAI Practice and Policy Division Chair

Guest Editors: Donald Leung, MD, PhD, FAAAAI, and Michael Schatz, MD, MS, FAAAAI

Article Outline

Preface
Introduction
- What is an allergist-immunologist?
- How the allergist-immunologist can help
Guide to the tables
Contributors
References

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Preface

Allergic diseases affect at least 20% of the population, which means that at least 56,284,381 Americans have allergic diseases. Although there are currently only 5400 board-certified allergist-immunologists in this country, their expertise and services are often underused. We believe a major part of this underuse is a result of physicians and patients not really knowing what allergist-immunologists do and how we can help. It is the main purpose of these guidelines to define both the expertise of the allergist-immunologist and under what circumstances they can be of added value in the treatment of patients.

These guidelines started as a presidential initiative designed to help the American Academy of Allergy, Asthma and Immunology (AAAAI) fulfill its mission of “the advancement of the knowledge and practice of allergy, asthma, and immunology for optimal patient care.” The guidelines were subsequently developed as summarized in Fig 1, with the input of many AAAAI committees and individuals who are acknowledged in this supplement. The guidelines were reviewed and approved by the AAAAI leadership and presented to the AAAAI membership for comments before being finalized. The guidelines will be regularly updated on our Web site (www.aaaaai.org).

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Fig 1.
A summary of the development of the Consultation and referral guidelines citing the evidence.

When one speaks of “referral,” there may be “business” or “turf” connotations. In an attempt to transcend such considerations, we based the consultation and referral guidelines on evidence that allergist-immunologist care improves patient outcomes. As described in the “Introduction,” this was either direct evidence that outcomes improved with allergist-immunologist care or evidence that diagnostic or therapeutic interventions performed by allergist-immunologists improved outcomes. Because there has been a paucity of controlled intervention trials addressing this issue, the evidence is often observational. Moreover, some of the rationale statements are only supported by consensus or expert opinion. Nonetheless, we believe that trying to provide a rationale for each guideline and citing the best available evidence is a step forward in creating rational, useful, and evidence-based guidelines for consultation and referral. We look forward to future studies that would increase the evidence base for such guidelines.

The title Consultation and referral guidelines sends another important message. Although some patients will require ongoing allergist-immunologist management, others might require just a single or a limited number of consultations. Still others might benefit from coordinated primary care and allergist-immunologist follow-up (co-management). We hope these guidelines will allow the allergist-immunologist to function optimally as a member of the health care team for the ultimate benefit of the patients we serve.

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Introduction

Allergic diseases affect more than 20% of the US population and are the sixth leading cause of chronic disease in the United States.¹ Allergic rhinitis alone leads to approximately 16.7 million office visits to health care providers each year,² and asthma causes nearly 2 million emergency department visits and 465,000 hospitalizations each year.³ Indirect costs from asthma are reported to be more than $4.6 billion.⁴

Allergies and asthma cause unnecessary deaths each year: about 100 persons in the United States die from food-related anaphylaxis,⁵ and another 40 die from insect sting–induced anaphylaxis.⁶ Asthma leads to about 4300 deaths each year.⁴ For many patients with asthma and allergic diseases, working with an allergist-immunologist can assist them in managing their disease and preventing morbidity and mortality.

What is an allergist-immunologist?

An allergist-immunologist is a physician who has been trained in either internal medicine or pediatrics and who has completed an additional 2 (or more) years of training in allergy and immunology at an accredited training program. Most are certified in internal medicine, pediatrics, or both and have passed the examination given by the American Board of Allergy and Immunology.

The allergist-immunologist is uniquely trained⁷ in the following:

•allergy testing (skin test, in vitro studies);

•history-allergy test evaluation;

•bronchoprovocation testing (eg, exercise and methacholine);

•environmental control instructions;

•inhalant immunotherapy;

•immunomodulator therapy (eg, anti-IgE, intravenous immunoglobulin);

•venom immunotherapy;

•food and drug challenges;

•drug desensitization;

•evaluation of immune competence;

•education (disease, medications, and monitoring); and

•management of chronic or recurrent conditions in which allergy is not always identified: rhinosinusitis, conjunctivitis, asthma, cough, urticaria-angioedema, eczema, anaphylaxis.

How the allergist-immunologist can help

This Consultation and referral guideline developed by the American Academy of Allergy Asthma and Immunology is designed to assist patients and health care professionals in determining when referral to an allergist-immunologist could be helpful. This referral might be a single or limited consultation, lead to co-management between a primary care provider and an allergist-immunologist, or require ongoing specialty care by the allergist-immunologist.

Providing information based on evidence to assist patients and health care providers in the decision-making process should benefit not only the individuals but our health care system as a whole. The evidence included in this guide is based on the following:

•diagnostic evidence: tests performed or interpreted by allergist-immunologists facilitate diagnosis;

•direct outcome evidence: evidence that intervention by an allergist-immunologist improves outcomes; and

•indirect outcome evidence: evidence that interventions performed by allergist-immunologists improve outcomes (evidence to support established pharmacologic management will generally not be reviewed).

The evidence cited for each allergic disease category is also graded according to the following system:

Ia.Meta-analysis of randomized controlled trials

Ib.Randomized controlled trial

II.Nonrandomized, controlled intervention study

III.Observational cohort or case-control study

IV.Review article, expert opinion.

This document includes specific referral guidelines for 14 categories of allergic diseases, along with the rationale for the referral, references, and the type and grade of evidence provided (Tables I-XIV). The tables are presented alphabetically for easy navigation and do not refer to the prevalence of the individual disease. This information will be regularly updated on the AAAAI Web site (http://www.aaaai.org/professionals/resources/rgce/).

Table I. Allergic bronchopulmonary aspergillosis

Referral guideline	Rationale	Evidence type
Patients with suspected or proven asthma or cystic fibrosis who have pulmonary infiltrates and peripheral blood eosinophilia	Allergen skin testing and in vitro tests, when correlated with history and other findings, can establish the diagnosis of ABPA.¹	Diagnostic

Patients with known ABPA for management	Allergist-immunologists are specifically trained to manage this disease,² and outcomes of such management have been reported by allergist-immunologists.³, ⁴, ⁵	Indirect outcome (ABPA management)

ABPA, Allergic bronchopulmonary aspergillosis.

REFERENCES

1Greenberger PA. Allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol 2002;110:685-92. Evidence grade: IV

2Core Curriculum Subcommittee of the Training Program Directors; American Academy of Allergy, Asthma and Immunology. Allergy and immunology core curriculum outline 1996. J Allergy Clin Immunol 1996;98:1012-5. 2002 update available at: http://www.aaaai.org/professionals/careers/training_programs.stm. Evidence grade: IV

3Patterson R, Greenberger PA, Radin R, et al. Allergic bronchopulmonary aspergillosis: staging as an aid to management. Ann Intern Med 1982;96:286-91. Evidence grade: III

4Patterson R, Greenberger PA, Halwig M, et al. Allergic bronchopulmonary aspergillosis. Natural history and classification of early disease by serologic and roentgenographic studies. Arch Intern Med 1986;146:916-8. Evidence grade: III

5Patterson R, Greenberger PA, Lee TM, et al. Prolonged evaluation of patients with corticosteroid-dependent asthma stage of allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol 1987;80:663-8. Evidence grade: III

Table II. Anaphylaxis (see also “Drug allergy” [Table VII], “Food allergy” [Table VIII], and “Insect hypersensitivity” [Table X] for anaphylaxis caused by these agents)

Referral guideline	Rationale	Evidence type
Individuals with a severe allergic reaction (anaphylaxis) without an obvious or previously defined trigger	After a severe allergic reaction without a known cause, a trigger should be identified if at all possible. An allergist-immunologist is the most appropriate medical professional to perform this evaluation,¹ which might include skin testing, in vitro tests, and challenges when indicated (including with exercise, see below). Major triggers for anaphylaxis are foods and food constituents, medications and biologic agents, latex, and insect stings.², ³, ⁴, ⁵, ⁶ Future avoidance of the identified triggers should prevent subsequent anaphylactic episodes.	Diagnostic
		Indirect outcome (trigger avoidance)
	Management of idiopathic anaphylaxis by an allergist-immunologist is associated with a reduction in hospitalizations and emergency department visits.⁷	Direct outcome (idiopathic anaphylaxis)

Persons with anaphylaxis attributed to food	Food allergy is the most common cause of anaphylaxis outside of the hospital setting.² ³ ⁵ Allergist-immunologists use diagnostic modalities to confirm the trigger and use their specific training¹ and clinical experience to educate patients regarding avoidance and immediate management to prevent potentially deadly outcomes.⁸	Diagnostic
Persons with anaphylaxis attributed to food		Indirect outcome (food avoidance, early interventions)

Exercise-induced anaphylaxis and food-dependent exercise-induced anaphylaxis	After an anaphylactic reaction that appears to have a significant relationship to exercise, it is crucial to be certain whether exercise is the cause and to determine whether a food might be involved.⁹, ¹⁰, ¹¹, ¹²	Diagnostic
		Indirect outcome (avoidance)

Drug-induced anaphylaxis	Allergist-immunologists use diagnostic agents to confirm the drug responsible for the reaction, if these agents are available (see “Drug allergy” [Table VII]).	Diagnostic

REFERENCES

1Core Curriculum Subcommittee of the Training Program Directors; American Academy of Allergy, Asthma and Immunology. Allergy and immunology core curriculum outline 1996. J Allergy Clin Immunol 1996;98:1012-5. 2002 update available at: http://aaaai.org/professionals/careers/training_programs.stm. Evidence grade: IV

2Cianferoni A, Novembre E, Mugnaini L, et al. Clinical features of acute anaphylaxis in patients admitted to a university hospital: an 11-year retrospective review (1985-1996). Ann Allergy Asthma Immunol 2001;87:27-32. Evidence grade: III

3Brown AF, McKinnon D, Chu K. Emergency department anaphylaxis: a review of 142 patients in a single year. J Allergy Clin Immunol 2001;108:861-66. Evidence grade: III

4Lee JM, Greenes DS. Biphasic anaphylactic reactions in pediatrics. Pediatrics 2000;106:762-6. Evidence grade: III

5Yocum MW, Butterfield JH, Klein JS, Volcheck GW, Schroeder DR, Silverstein MD. Epidemiology of anaphylaxis in Olmsted County: a population-based study. J Allergy Clin Immunol 1999;104:452-6. Evidence grade: III

6Akin C, Metcalfe DD. Systemic mastocytosis. Ann Rev Med 2004;55:419-32. Evidence grade: IV

7Wong S, Arnold PR, Yango C, Patterson R, Harris KE. Idiopathic anaphylaxis: a clinical summary of 175 patients. Arch Intern Med 1990;150:1323. Evidence grade: III

8Bock SA, Munoz-Furlong A, Sampson HA. Fatalities due to anaphylactic reactions to foods. J Allergy Clin Immunol 2001;107:191-3. Evidence grade: III

9Sheffer AL, Soter NA, McFadden ER Jr, Austen KF. Exercise-induced anaphylaxis: distinct form of physical allergy. J Allergy Clin Immunol 1983;71:311-6. Evidence grade: III

10Casale T. Exercise-induced anaphylaxis syndromes. JAMA 1986;255:2049-53. Evidence grade: III

11Romano A, Di Fonso M, Giuffreda F, et al. Food-dependent exercise-induced anaphylaxis: clinical and laboratory findings in 54 subjects. Int Arch Allergy Immunol 2001;125:264-72. Evidence grade: II

12Aihara Y, Takahashi, Y, Kotoyori T, et al. Frequency of food-dependent, exercise induced anaphylaxis in Japanese high school students. J Allergy Clin Immunol 2001;108:1035-9. Evidence grade: II

Table III, A. Asthma diagnosis

Referral guideline	Rationale	Evidence type
Patients with respiratory symptoms suggestive of asthma but with normal PFT results (FEV₁ >80% of predicted value) and no significant reversibility (<12% and 200-mL increase in FEV₁)	Allergists-immunologists perform methacholine challenges, which have a high sensitivity for current asthma.¹ ²	Diagnostic

Exercise-induced symptoms that are atypical or do not respond well to pretreatment with albuterol, nedocromil, or cromolyn	Further objective evaluation and confirmation with pulmonary function testing (including exercise challenge) in conjunction with appropriate allergist-immunologist evaluation will define diagnosis or differential diagnosis.³	Diagnostic

Subjects wishing to scuba dive with a history of asthma	There is a theoretic risk of increased barotraumas, as well as exercise-induced bronchospasm, in patients with asthma who scuba dive. Bronchoprovocation with exercise has been recommended to exclude asthma in scuba divers.⁴	Diagnostic
Subjects wishing to scuba dive with a history of asthma		Indirect outcome (scuba diving avoidance)

PFT, Pulmonary function test.

REFERENCES

1Hopp R, Bewtra AK, Nair NM, Townley RG. Specificity and sensitivity of methacholine inhalation challenge in normal and asthmatic children. J Allergy Clin Immunol 1984;74:154-58. Evidence grade: III

2Cockcroft DW, Berscheid BA, Murdock KY, Gore BP. Sensitivity and specificity of histamine PC₂₀ measurements in a random selection of young college students. J Allergy Clin Immunol 1992;89:23-30. Evidence grade: III

3Holzer K, Anderson SD, Douglass J. Exercise in elite summer athletes: challenges for diagnosis. J Allergy Clin Immunol 2002;110:374-80. Evidence grade: III

4Anderson SD, Brannan J, Trevillion L, Young I. Lung function and bronchial provocation tests for intending divers with a history of asthma. SPUMS J 1995;25:233-48. Evidence grade: IV

Table III, B. Asthma: environmental diagnosis and management

Referral guideline	Rationale	Evidence type
Patients with a history of seasonal or persistent asthma for evaluation of inhalant sensitization to confirm the diagnosis	Exposure to indoor and outdoor allergens can worsen asthma.¹, ², ³, ⁴, ⁵, ⁶, ⁷, ⁸, ⁹, ¹⁰, ¹¹, ¹², ¹³, ¹⁴, ¹⁵ Allergy cannot be diagnosed on the basis of history alone.¹⁶ Diagnosis is derived from correlation of clinical history and diagnostic tests,¹⁶ with which allergist-immunologists are expert.¹⁷	Diagnostic

Patients who need management and education concerning environmental triggers	Allergists have familiarity with the wide variety of both indoor and outdoor aeroallergen exposures that have been shown to affect asthma and respiratory function.¹⁷ Allergists are specifically trained to provide education regarding appropriate avoidance measures.¹⁷ Allergen avoidance can improve asthma.¹⁸, ¹⁹, ²⁰, ²¹, ²², ²³, ²⁴, ²⁵, ²⁶, ²⁷, ²⁸, ²⁹, ³⁰	Indirect outcome (avoidance)

Patients with asthma who experience a worsening of symptoms after a new pet has been introduced into the home	Exposure to furred pets in allergic patients can worsen asthma symptoms.³¹ ³² Avoidance of pets in allergic patients can improve asthma symptoms,³³ reduce airway responsiveness,³⁴ and reduce the need for inhaled corticosteroids.³⁴	Diagnostic
		Indirect outcome (avoidance)

REFERENCES

1Bjornsson E, Norback D, Janson C, et al. Asthmatic symptoms and indoor levels of micro-organisms and house dust mites. Clin Exp Allergy 1995;25:423-31. Evidence grade: III

2Marks GB, Tovey ER, Toelle BG, Wachinger S, Peat JK, Woolcock AJ. Mite allergen (Der p 1) concentration in houses and its relation to the presence and severity of asthma in a population of Sydney schoolchildren. J Allergy Clin Immunol 1995;96:441-8. Evidence grade: III

3Henderson FW, Henry MM, Ivins SS, et al. Correlates of recurrent wheezing in school-age children. Am J Respir Crit Care Med 1995;151:1786-93. Evidence grade: III

4Newson R, Strachan D, Archibald E, Emberlin J, Hardaker P, Collier C. Effect of thunderstorms and airborne grass pollen on the incidence of acute asthma in England, 1990-94. Thorax 1997;52:680-5. Evidence grade: III

5Marks GB, Colquhoun JR, Girgis ST, et al. Thunderstorm outflows preceding epidemics of asthma during spring and summer. Thorax 2001;56:468-71. Evidence grade: III

6Pollart SM, Reid MJ, Fling JA, Chapman MD, Platts-Mills TA. Epidemiology of emergency room asthma in northern California: association with IgE to rye-grass pollen. J Allergy Clin Immunol 1988;82:224-30. Evidence grade: III

7Subiza J, Cabrera M, Valdavieso R, et al. Seasonal asthma caused by airborne Platanus pollen. Clin Exp Allergy 1994;24:1123-9. Evidence grade: III

8Epton MJ, Martin IR, Graham P, et al. Climate and aeroallergen levels in asthma: a 12 month prospective study. Thorax 1997;52:528-34. Evidence grade: III

9Neas EM, Dockery DW, Burge H, Koutrakis P, Speizer FE. Fungus spores, air pollutants, and other determinants of peak expiratory flow rate in children. Am J Epidemiol 1996;143:797-807. Evidence grade: III

10Targonski PV, Persky VW, Ramekrishnan V. Effect of environmental molds on risk of death from asthma during the pollen season. J Allergy Clin Immunol 1995;95:955-61. Evidence grade: III

11Dales RE, Cakmak S, Burnett RT, Judek S, Coates F, Brook JR. Influence of ambient fungal spores on emergency visits for asthma to a regional children's hospital. Am J Respir Crit Care Med 2000;162:2087-90. Evidence grade: III

12Vervloet D, Charpin D, Haddi E, et al. Medication requirements and house dust mite exposure in mite sensitive asthmatics. Allergy 1991;46:554-8. Evidence grade: IV

13Kivity S, Solomon A, Soferman R, Schwarz Y, Mumcuoglu KY, Topilsky M. Mite asthma in childhood: a study of the relationship between exposure to house dust mites and disease activity. J Allergy Clin Immunol 1993;91:844-9. Evidence grade: III

14Custovic A, Taggart SCO, Francis HC, Chapman MD, Woodcock A. Exposure to house dust mite allergens and the clinical activity of asthma. J Allergy Clin Immunol 1996;98:64-72. Evidence grade: III

15Rosenstreich DL, Eggleston P, Kattan, et al. The role of cockroach allergy and exposure to cockroach allergen in causing morbidity among inner-city children with asthma. N Engl J Med 1997;336:1356-63. Evidence grade: III

16Host A, Andrae S, Charkin S, et al. Allergy testing in children: why, who, when and how. Allergy 2003;58:559-69. Evidence grade: IV

17Core Curriculum Subcommittee of the Training Program Directors; American Academy of Allergy, Asthma and Immunology. Allergy and immunology core curriculum outline 1996. J Allergy Clin Immunol 1996;98:1012-5. 2002 update available at: http://www.aaaai.org/professionals/careers/training_programs.stm. Evidence grade: IV

18Platts-Mills TA, Tovey ER, Mitchell EB, Moszoro H, Nock P, Wilkins SR. Reduction of bronchial hyperreactivity during prolonged allergen avoidance. Lancet 1982;2:675-8. Evidence grade: II

19Dorward AJ, Colloff MJ, MacKay NS, McSharry C, Thomson NC. House dust mite avoidance measures and adult atopic asthma. Thorax 1988;43:98-102. Evidence grade: IV

20Ehnert B, Lau-Schadendorf S, Weber A, Beuttner P, Schou C, Wahn U. Reducing domestic exposure to dust mite allergen reduces bronchial hyperreactivity in sensitive children with asthma. J Allergy Clin Immunol 1992;90:135-8. Evidence grade: Ib

21Boner AL, Niero E, Antolini I, Valetta EA. Pulmonary function and bronchial hyperreactivity in asthmatic children with house dust mite allergy during prolonged stay in the Italian Alps (Musirini 1756 m). Ann Allergy 1985;54:42-5. Evidence grade: III

22Grootendorst DC, Dahlen SE, Van Den Bos JW, et al. Benefits of high altitude allergen avoidance in atopic adolescents with moderate to severe asthma, over and above treatment with high dose inhaled steroids. Clin Exp Allergy 2001;31:400-8. Evidence grade: II

23Marks GB, Tovey ER, Green W, Shearer M, Salome CM, Wollcock AJ. The effect of changes in house dust mite allergen exposure on the severity of asthma. Clin Exp Allergy 1995;25:114-8. Evidence grade: III

24Carswell F, Birmingham K, Oliver J, Crewes A, Weeks J. The respiratory effects of reduction of mite allergen in the bedrooms of asthmatic children—a double-blind controlled trial. Clin Exp Allergy 1996;26:386-96. Evidence grade: Ib

25Halken S, Host A, Niklassen U, et al. Effect of mattress and pillow encasings on children with asthma and house dust mite allergy. J Allergy Clin Immunol 2003;111:169-76. Evidence grade: Ib

26Frederick JM, Warner JO, Jessop WJ, Enander I, Warner JA. Effect of a bed covering system in children with asthma and house dust mite hypersensitivity. Eur Respir J 1997;10:361-6. Evidence grade: III

27Shapiro GG, Wighton TG, Chinn T, et al. House dust mite avoidance for children with asthma in homes of low income families. J Allergy Clin Immunol 1999;103:1069-74. Evidence grade: IV

28Cloosterman SG, Scherner TR, Bul-Hofland ID, et al. Effect of house dust mite avoidance measures on Der p 1 concentrations and clinical condition of mild adult house dust mite-allergic asthmatic patients, using no inhaled steroids. Clin Exp Allergy 1999;29:1336-46. Evidence grade: III

29Warner JA, Frederick JM, Bryant TN, et al. Mechanical ventilation and high efficiency vacuum cleaning: a combined strategy of mite and mite allergen reduction in the control of mite-sensitive asthma. J Allergy Clin Immunol 2000;105:75-82. Evidence grade: Ib

30Van der Heide S, Kauffman HF, Dubois AE, de Monchy JG. Allergen reduction measures in houses of allergic asthmatic patients: effects of air-cleaners and allergen-impermeable mattress covers. Eur Respir J 1997;10:1217-23. Evidence grade: IV

31Sporik R, Ingram JM, Price W, Sussman JH, Honsinger RW, Platts-Mills TAE. Association of asthma with serum IgE and skin-test reactivity to allergens among children living at high altitude: tickling the dragon's breath. Am J Respir Crit Care Med 1995;151:1388-92. Evidence grade: IV

32Bollinger ME, Eggleston PA, Wood RA. Cat antigen in homes with and without cats may induce allergic symptoms. J Allergy Clin Immunol 1996;97:907-14. Evidence grade: III

33Van der Heide S, van Aalderen WMC, Kauffman HF, Dubois AEJ, de Monchy JGR. Clinical effects of air cleaners in homes of children sensitized to pet allergens. J Allergy Clin Immunol 1999;104:447-51. Evidence grade: Ib

34Shirai T, Matsui T, Suzuki K, Chida K. Effect of pet removal on pet allergic asthma. Chest 2005;127:1565-71. Evidence grade: III.

Table III, C. Asthma treatment: immunotherapy

Referral guideline	Rationale	Evidence type
Consider referral for allergen immunotherapy for asthmatic patients if there is a clear relationship between asthma and exposure to an unavoidable aeroallergen to which specific IgE antibodies have been demonstrated and the following:	The efficacy of allergen immunotherapy in the treatment of allergic asthma has been demonstrated in many double-blind, placebo-controlled studies to multiple allergens (eg, pollen, animal allergen, fungi, and dust mite).¹, ², ³, ⁴	Indirect outcome (immunotherapy)
•poor response to pharmacotherapy or avoidance measures;
•unacceptable side effects of medications;
•desire to avoid long-term pharmacotherapy;
•coexisting allergic rhinitis; and
•long duration of symptoms (perennial or major portion of the year).

Consider referral for children with allergic rhinitis because immunotherapy can potentially prevent the development of asthma	One study suggests that allergen immunotherapy has been shown to reduce the development of asthma in children with allergic rhinitis compared with a group of children treated with medication alone.⁵ Immunotherapy might also prevent the development of new allergen sensitivities.⁶, ⁷, ⁸	Indirect outcome (immunotherapy)

REFERENCES

1Joint Task Force on Practice Parameters. Allergen immunotherapy: a practice parameter. American Academy of Allergy, Asthma & Immunology. American College of Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol 2003;90(suppl 1):1-40. Evidence grade: IV

2Abramson MJ, Puy RM, Weiner JM. Is allergen immunotherapy effective in asthma? A meta-analysis of prospective, randomized double-blind, placebo-controlled studies. Am J Respir Crit Care Med 1995;151:969-74. Evidence grade: Ia

3Ross RN, Nelson HS, Finegold I. Effectiveness of specific immunotherapy in the treatment of asthma: a meta-analysis of prospective, randomized, double-blind, placebo-controlled studies. Clin Ther 2000;22:329-41. Evidence grade: Ia

4Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma (Cochrane Review). In: The Cochrane Library, Issue 2. Oxford: Update Software; 2002. Evidence grade: Ib

5Moller, C, Dreborg S, Ferdousi HA, et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT study). J Allergy Clin Immunol 2002;109:251-6. Evidence grade: Ib

6Purello-D'Ambrosio F, Gangemi S, Merendino RA, et al. Prevention of new sensitizations in monosensitized subjects submitted to specific immunotherapy or not. A retrospective study. Clin Exp Allergy 2001;31:1295-302. Evidence grade: III

7Des Roches A, Paradis L, Menardo JL, et al. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract VI. Specific immunotherapy prevents the onset of new sensitizations in children. J Allergy Clin Immunol 1997;99:450-3. Evidence grade: II

8Panjno GB, Barberio G, DeLuca F, Morabito L, Parmiani S. Prevention of new sensitization in asthmatic children monosensitized to house dust mites by specific immunotherapy. A six year follow-up study. Clin Exp Allergy 2001;31:1392-7. Evidence grade: II

Table III, D. Asthma treatment: prevention of morbidity

Referral guideline	Rationale	Evidence type
Patients with asthma who require emergency department care for an acute episode	Allergist care reduces subsequent asthma emergency department visits.¹, ², ³, ⁴, ⁵, ⁶, ⁷, ⁸, ⁹, ¹⁰, ¹¹	Direct outcome
	Allergist care reduces subsequent hospitalization.², ³, ⁴, ⁵, ⁶, ⁷, ⁸, ⁹, ¹⁰, ¹¹

Patients with uncontrolled asthma	Allergist care reduces asthma symptoms and improves physical functioning and asthma-related quality of life.¹ ³ ¹¹ ¹²	Direct outcome

Patients with persistent asthma, particularly moderate-to-severe persistent asthma	Inhaled corticosteroid use leads to reduction in asthma symptoms, exacerbations, hospitalizations, and asthma death.¹⁰	Indirect outcome (controllers)
	Allergist care is more likely to lead to use of asthma controller medications (particularly inhaled corticosteroids).⁵ ⁷ ¹⁰ ¹², ¹³, ¹⁴, ¹⁵
	Allergists administer anti-IgE, which prevents exacerbations, improves symptoms, and reduces the use of inhaled steroids in patients with moderate-to-severe asthma.¹⁶ ¹⁷	Indirect outcome (anti-IgE)

Patients who need education on asthma and guidance in techniques for self-management	Use of written action plans improves asthma self-management.³ ¹⁴ ¹⁵	Indirect outcome (education, action plan)
	Allergist care is more likely to lead to provision of a written management plan and objective monitoring of asthma with peak flow meters.³ ¹⁴ ¹⁵
	Asthma self-management education improves outcomes in children and adults.¹⁸ ¹⁹ Allergist care is associated with more effective self-management education and knowledge.³ ¹¹ ²⁰ ²¹

Patients who use excessive amounts of reliever medications	Excessive short-acting β-agonist use indicates uncontrolled asthma. Allergist care reduces overuse of short-acting β-agonists.¹⁴	Direct outcome

Patients with severe asthma	Allergist care reduces cost of care for asthma.⁶ ⁸ ⁹ ²²	Direct outcome

REFERENCES

1Moore C, Ahmed I, Mouallem R, May W, Ehlayel M, Sorensen R. Care of asthma: allergy clinic versus emergency room. Ann Allergy Asthma Immunol 1997;1997:373-90. Evidence grade: III

2Vilar M, Reddy B, Silverman B, et al. Superior clinical outcomes of inner city asthma patients treated in an allergy clinic. Ann Allergy Asthma Immunol 2000;84:299-303. Evidence grade: III

3Wu A, Young Y, Skinner E, et al. Quality of care and outcomes of adults with asthma treated by specialists and generalists in managed care. Arch Intern Med 2001;161:2554-60. Evidence grade: III

4Kelly C, Morrow A, Shults J, Nakas N, Strope G, Adelman R. Outcomes evaluation of a comprehensive intervention program for asthmatic children enrolled in Medicaid. Pediatrics 2000;105:1029-35. Evidence grade: II

5Zeiger R, Heller S, Mellon M, Wald J, Falkoff R, Schatz M. Facilitated referral to asthma specialist reduces relapses in asthma emergency room visits. J Allergy Clin Immunol 1991;87:1160-8. Evidence grade: Ib

6Westley CR, Spiecher B, Starr L, et al. Cost effectiveness of an allergy consultation in the management of asthma. Allergy Asthma Proc 1997;18:15-8. Evidence grade: III

7Sperber K, Ibrahim H, Hoffman B, Eisenmesser B, Hsu H, Corn B. Effectiveness of a specialized asthma clinic in reducing asthma morbidity in an inner-city minority population. J Asthma 1995;32:335-43. Evidence grade: II

8Weinstein AG, Faust D, McKee L, Padman R. Outcome of Short-term hospitalization for severe asthmatic children. J Allergy Clin Immunol 1992;90:66-75. Evidence grade: III

9Weinstein AG, McKee L, Stapleford J, Faust D. An economic evaluation of short-term inpatient rehabilitation for severe asthmatic children. J Allergy Clin Immunol 1996;98:264-73. Evidence grade: III

10Schatz M, Cook EF, Nakahiro R, Petitti D. Inhaled corticosteroids and allergy specialty care reduce emergency hospital use for asthma. J Allergy Clin Immunol 2003;111:503-8. Evidence grade: III

11Schatz M, Zeiger RS, Mosen D, et al. Improved asthma outcomes from allergy specialist care: a population-based cross-sectional analysis. J Allergy Clin Immunol 2005;116:1307-13. Evidence grade: III

12Vollmer W, O'Hollaren M, Ettinger K, et al. Specialty differences in the management of asthma: a cross-sectional assessment of allergists' patients and generalists' patients in a large HMO. Arch Intern Med 1997;157:1201-8. Evidence grade: II

13Stempel D, Carlson A, Buchner D. Asthma: benchmarking for quality improvement. Ann Allergy Asthma Immunol 1997;79:517-24. Evidence grade: III

14Diette G, Skinner E, Nguyen T, Markson L, Clark B, Wu A. Comparison of quality of care by specialist and generalist physicians as usual source of asthma care for children. Pediatrics 2001;108:432-7. Evidence grade: II

15Mahr T, Evans R. Allergist influence on asthma care. Ann Allergy 1993;71:115-20. Evidence grade: III

16Corren J, Casale T, Deniz Y, Ashby M. Omalizumab, a recombitant humanized anti-IgE antibody, reduces asthma-related emergency room visits and hospitalizations in patients with allergic asthma. J Allergy Clin Immunol 2003;111:87-90. Evidence grade: Ib

17Lanier BQ, Corren J, Lumry W, Liu J, Fowler-Taylor A, Gupta N. Omalizumab is effective in the long-term control of severe allergic asthma. Ann Allergy Asthma Imunol 2003;91:154-9. Evidence grade: Ib

18Wolf FM, Guevara JP, Grum CM, et al. Educational interventions for asthma in children. Cochrane Database Syst Rev 2003;(1):CD000326. Evidence grade: Ia

19Gibson PG, Powell H, Coughlan J, et al. Self-management education and regular practitioner review for adults with asthma. Cochrane Database Syst Rev 2003;(1):CD001117. Evidence grade: Ia

20Engel W, Freund DA, Stein JS, et al. The treatment of patients with asthma by specialists and generalists. Med Care 1989;27:306-14. Evidence grade: III

21Wolle JM, Cwi J. Physicians prevention-related practices in treating adult patients with asthma: results of a national survey. J Asthma 1995;32:309-18. Evidence grade: III

22Freund D, Stein J, Hurley R, Engel W, Woomert A, Lee B. Specialty differences in the treatment of asthma. J Allergy Clin Immunol 1989;84:401-6. Evidence grade: III

Table III, E. Asthma treatment: prevention of mortality

Referral guideline	Rationale	Evidence type
Patients with potentially fatal asthma (prior severe, life-threatening episode; prior intubation)	Improved pharmacologic therapy
	Inhaled steroids have been associated with significant reductions in risk for fatal and near-fatal exacerbation of asthma.¹	Indirect outcome (inhaled and oral steroids)
	Allergist-immunologists prescribe inhaled steroids more frequently than primary care physicians, and patients seen and managed by allergist-immunologists are more likely to be taking inhaled steroids regularly.², ³, ⁴, ⁵, ⁶
	Oral steroid use for attacks reduces the risk of fatal asthma.⁷, ⁸, ⁹
	Patients managed by allergist-immunologists are more likely to appropriately receive oral steroids.⁶ ¹⁰ ¹¹

	Immunologic therapy
	Allergens can trigger severe and fatal asthma episodes.¹²	Indirect outcome (avoidance, immunotherapy)
	Allergist-immunologists have expertise in performance and interpretation of skin tests for immediate hypersensitivity, education to encourage aeroallergen avoidance, and provision of inhalant allergen immunotherapy in properly selected patients.¹³
	Allergen immunotherapy provides significant clinical benefit,¹⁴ ¹⁵ including for Alternaria species,¹⁶ which has been associated with life-threatening asthma.¹²
	Anti-IgE therapy has been shown to improve outcomes in high-risk patients.¹⁷ ¹⁸
	Objective monitoring of “poor perceivers”
	A major factor contributing to risk for fatal asthma outcomes is underrecognition of asthma; some asthmatic patients are “poor perceivers.”¹⁹	Diagnostic
	Allergist-immunologists perform objective measurements of lung function more frequently than other physicians.²⁰ ²¹
	Action plans
	Action plans can reduce asthma mortality.⁷	Indirect outcome (action plans)
	Asthma specialists are more likely to provide action plans to their patients.²²

REFERENCES

1Suissa S, Ernst P, Benayoun S, et al. Low-dose inhaled corticosteroids and the prevention of death from asthma. N Engl J Med 2000;343:332-6. Evidence grade: III

2Legorretta AP, Christian-Herman J, O'Connor RD, et al. Compliance with national asthma management guidelines and specialty care: a health maintenance organization experience. Arch Intern Med 1998;158:457-64. Evidence grade: III

3Hartert TV, Windom HH, Peebles RS, et al. Inadequate outpatient medical therapy for patients with asthma admitted to two urban hospitals. Am J Med 1996;100:386-94. Evidence grade: III

4Blais R, Gregoire JP, Rouleau R, et al. Ambulatory use of inhaled β2-agonists for the treatment of asthma in Quebec: a population based utilization review. Chest 2001;119:1316-21. Evidence grade: III

5Donahue JG, Fuhlbrigge AL, Finkelstein JA, et al. Asthma pharmacotherapy and utilization by children in 3 managed care organizations. J Allergy Clin Immunol 2000;106:1108-14. Evidence grade: III

6Schatz M, Cook EF, Nakahiro R, Petitti D. Inhaled corticosteroids and allergy specialty care reduce emergency hospital use for asthma. J Allergy Clin Immunol 2003;111:503-8. Evidence grade: III

7Abramson MJ, Bailey MJ, Couper FJ, et al. Are asthma medications and management related to deaths from asthma? Am J Respir Crit Care Med 2001;163:12-8. Evidence grade: III

8Leung FW, Santiago SM, Klaustermeyer WB. Corticosteroid therapy and death in cases of adult bronchial asthma. West J Med 1983;138:565-9. Evidence grade: III

9MRC: Controlled trial of effects of cortisone acetate in status asthmaticus. Lancet 1956;2:803-6. Evidence grade: Ib

10Engel W, Freund DA, Stein JS, Fletcher RH. The treatment of patients with asthma by specialists and generalists. Med Care 1989;27:306-14. Evidence grade: III

11Bucknall CE, Robertson C, Moran F, Stevenson RD. Differences in hospital asthma management. Lancet 1988;1:748-50. Evidence grade: III

12O'Hollaren MT, Yunginger JW, Offord KP, et al. Exposure to an aeoallergen as a possible precipitating factor in respiratory arrest in young patients with asthma. N Engl J Med 1991;324:359-63. Evidence grade: III

13Core Curriculum Subcommittee of the Training Program Directors; American Academy of Allergy, Asthma and Immunology. Allergy and immunology core curriculum outline 1996. J Allergy Clin Immunol 1996;98:1012-5 2002 update available at: http://www.aaaai.org/professionals/careers/training_programs.stm. Evidence grade: IV

14Joint Task Force on Practice Parameters. Allergen immunotherapy: a practice parameter. Ann Allergy Asthma Immunol 2003;90(suppl):S1-S40. Evidence grade: IV

15Abramson M, Puy R, Weiner J. Allergen immunotherapy for asthma. Cochrane Database Syst Rev 2003;4:CD001186. Evidence grade: Ia

16Horst M, Hejjaoui A, Horst V, et al. Double-blind, placebo-controlled rush immunotherapy with a standardized Alternaria extract. J Allergy Clin Immunol 1990;85:460-72. Evidence grade: Ib

17Bousquet J, Wenzel S, Holgate S et al. Predicting Response to omalizumab, and anti-IgE antibody, in patients with allergic asthma. Chest 2004;125:1378-86.Evidence grade: Ib

18Holgate S, Bousquet J, Wnezel S, et al. Efficacy of omalizumab, an anti-immunoglobulin E antibody, in patients with allergy asthma at risk of serious asthma-related morbidity and mortality. Curr Med Res Opin 2001;17:233-40. Evidence grade: Ia

19Kikuchi Y, Okabe S, Tamura G, et al. Chemosensitivity and perception of dyspnea in patients with a history of near-fatal asthma. N Engl J Med 1994;330:1329-34. Evidence grade: III

20Janson S, Weiss K. A national survey of asthma knowledge and practices among specialists and primary care physicians. J Asthma 2004;41:343-8. Evidence grade: III

21Freund DA, Stein J, Hurley R, et al. The Kansas City asthma care project: specialty differences in the cost of treating asthma. Ann Allergy 1988;60:3-7. Evidence grade: III

22Diette B, Skinner EA, Nguyen TT, et al. Comparison of quality of care by specialist and generalist physicians as usual source of asthma care for children. Pediatrics 2001;108:432-7. Evidence grade: III

Table III, F. Asthma treatment: adherence

Referral guideline	Rationale	Evidence type
Patients with asthma in whom adherence problems might be limiting optimal control	Patients with a visit to an allergist-immunologist in the prior year were significantly more likely to have been dispensed an optimally effective number of inhaled steroid canisters.¹	Direct outcome
	Specialty care is associated with more refills of anti-inflammatory medications.²
	Patient compliance with national asthma guidelines was higher in patients of specialists.³
	Misunderstanding of asthma controller medications, which was associated with decreased adherence, was more likely in patients not treated by specialists.⁴

REFERENCES

1Schatz M, Cook EF, Nakahiro R, Petitti D. Inhaled corticosteroids and allergy specialty care reduce emergency hospital use for asthma. J Allergy Clin Immunol 2003;111:503-8. Evidence grade: III

2Stempel DA, Carlson AM, Buchner DA. Asthma: benchmarking for quality improvement. Ann Allergy Asthma Immunol 1997;79:517-24. Evidence grade: III

3Meng YY, Leung KM, Berkbigler D, Halbert RJ, Legorreta AP. Compliance with US asthma management guidelines and specialty care: a regional variation or national concern? J Eval Clin Pract 1999;5:213-21. Evidence grade: IV

4Farber HJ, Capra AM, Finkelstein JA, et al. Misunderstanding of asthma controller medications: association with nonadherence. J Asthma 2003;40:17-25. Evidence grade: III

Table III, G. Occupational asthma

Referral guideline	Rationale	Evidence type
Patients with a history suggesting occupational asthma should undergo testing to confirm the diagnosis of asthma and referral to an allergist for evaluation to establish that the asthma is caused by or triggered by agents at the workplace and to initiate appropriate avoidance therapy.	History and physical examination are insufficient to confirm occupational asthma, and inaccurate conclusions can easily be drawn.¹ ² Allergists can interpret spirometry when performed as a baseline, with response to bronchodilator, serial assessment of spirometry or peak flows, and changes in methacholine response during work periods versus off-work periods.³, ⁴, ⁵, ⁶, ⁷, ⁸, ⁹	Diagnostic
		Indirect outcome (avoidance)
	Allergists can outline the algorithm for the clinical investigation of suspected occupational asthma and interpret other studies to confirm bronchial hyperresponsiveness, including challenges with methacholine, histamine, cold air, or exercise, yet realize that such study results might be negative if performed when the patient is off work and free of symptoms.³ ⁵ ⁸
	Allergists can review Material Safety Data Sheets and other specific details of the workplace obtained either through specific questioning, direct observation during an onsite work evaluation, or assistance in obtaining an industrial hygiene survey in an effort to identify exposure to possible causal agents. Allergists can arrange and interpret workplace challenges and be able to provide assistance in referring to centers that can perform specific agent laboratory challenges if indicated.³ ⁵ ⁷
	The importance of identifying the agent responsible for asthma is that continued exposure can lead to worsening asthma and possibly persistent disease, even after exposure ceases. Early accurate diagnosis and removal from further exposure to specific work sensitizers carries the best medical prognosis for those with occupational lung disease.¹⁰, ¹¹, ¹², ¹³, ¹⁴, ¹⁵, ¹⁶

Consider referral of a worker with asthma for evaluation of workplace exposures that could worsen or exacerbate the asthma.	Exposure to workplace irritants is a known cause of and known exacerbator of asthma.¹⁷	Indirect outcome (avoidance)

REFERENCES

1Malo JL, Ghezzo H, L'Archeveque J, Lagier F, Perrin B, Cartier A. Is the clinical history a satisfactory means of diagnosing occupational asthma? Am Rev Respir Dis 1991;143:528-32. Evidence grade: III

2Baur X, Huber H, Degens PO, Allmers H, Ammon J. Relation between occupational asthma case history, bronchial, methacholine challenge, and specific challenge test in patients with suspected occupational asthma. Am J Ind Med 1998;33:114-22. Evidence grade: III

3Core Curriculum Subcommittee of the Training Program Directors; American Academy of Allergy, Asthma and Immunology. Allergy and immunology core curriculum outline 1996. J Allergy Clin Immunol 1996;98:1012-5. 2002 update available at: http://www.aaaai.org/professionals/careers/training_programs.stm. Evidence grade: IV

4Moscato G, Godnic-Cvar J, Maestrelli P, Malo JL, Burge PS, Coifman R. Statement on self-monitoring of peak expiratory flows in the investigation of occupational asthma. J Allergy Clin Immunol 1995;96:295-301. Evidence grade: IV

5Vandenplas O, Binard-van Cangh F, Brumagne A, et al. Occupational asthma in symptomatic workers exposed to natural rubber latex: evaluation of diagnostic procedures. J Allergy Clin Immunol 2001;107:542-7. Evidence grade: III

6ACCP Consensus Committee. Assessment of asthma in the workplace. Chest 1995;108:1084-117. Evidence grade: IV

7Tarlo SM, Boulet LP, Cartier A, et al. Canadian Thoracic Guidelines on Occupational Asthma. Can Respir J 1998;5:289-300. Evidence grade: IV

8Cartier A, Pineau L, Malo JL. Monitoring of maximum expiratory peak flow rates and histamine inhalation tests in the investigation of occupational asthma. Clin Allergy 1984;14:193-6. Evidence grade: III

9Cockroft DW, Mink JT. Isocyanate-induced asthma in an automobile spray painter. Can Med Assoc J 1979;121:602-4. Evidence grade: III

10Moscato G, Dellabianca A, Perfetti L, et al. Occupational asthma. A longitudinal study on the clinical and socioeconomic outcome after diagnosis. Chest 1999;115:249-56. Evidence grade: III

11Paggiaro PL, Bacci E, Dente FL, Talini D, Giuntini C. Prognosis of occupational asthma induced by isocyanates. Bulletin Europeen de Physiopathologie Respiratoire 1987;23:565-9. Evidence grade: IV

12Gannon PF, Weir DC, Robertson AS, Burge PS. Health, employment, and financial outcomes in workers with occupational asthma. Br J Ind Med 1993;50:491-6. Evidence grade: III

13Chan-Yeung M, MacLean L, Paggiaro PL. Follow-up study of 232 patients with occupational asthma caused by western red cedar. J Allergy Clin Immunol 1987;79:792-6. Evidence grade: III

14Rosenberg N, Garnier R, Rousselin X, Mertz R, Gervais P. Clinical and socio-professional fate of isocyanate-induced asthma. Clin Allergy 1987;17:55-61. Evidence grade: III

15Tarlo SM, Banks D, Liss G, Broder I. Outcome determinants for isocyanate induced occupational asthma among compensation claimants. Occup Environ Med 1997;54:756-61. Evidence grade: III

16Perfetti L, Cartier A, Ghezzo H, Gautrin D, Malo JL. Follow-up of occupational asthma after removal from or diminution of exposure to the responsible agent: relevance of the length of interval from cessation of exposure. Chest 1998;114:398-403. Evidence grade: III

17Tarlo SM, Leung K, Broder I, Silverman F, Holness DL. Prevalence and characterization of asthmatics symptomatically worse at work among a general asthma clinic population. Chest 2000;118:1309-14. Evidence grade: III

Table IV. Conjunctivitis

Referral guideline	Rationale	Evidence type
Patients with prolonged or recurrent manifestations of allergic conjunctivitis	Allergy cannot be diagnosed on the basis of history alone.¹ Diagnosis is derived from a correlation of clinical history and diagnostic tests, with which allergist-immunologists are experienced.²Allergists can help to suspect and diagnose corneal involvement in vernal and atopic keratoconjunctivitis.³ ⁴	Diagnostic
Patients with comorbid conditions (eg, asthma, rhinitis, recurrent sinusitis)

Patients with symptoms interfering with quality of life, ability to function, or both	A thorough allergy evaluation will complement the patient history and aid in the development of specific treatment plans, including immunotherapy and environmental controls. These treatments can benefit patients with allergic conjunctivitis in terms of reduced symptoms, medication use, and cost. Allergen immunotherapy can be highly effective in controlling the symptoms of allergic conjunctivitis.⁵, ⁶, ⁷ Efficacy parameters include symptom and medication scores, conjunctival challenge, and immunologic cell markers and cytokine profiles. Allergen immunotherapy can provide lasting benefits after immunotherapy is discontinued.⁸, ⁹, ¹⁰	Indirect outcome (avoidance, immunotherapy)
Patients who have found medications to be ineffective or have had adverse reactions to previously prescribed medications		Indirect outcome (avoidance, immunotherapy)

REFERENCES

1Martin A, Gomez Demel E, Gagliardi J, et al. Clinical signs and symptoms are not enough for the correct diagnosis of allergic conjunctivitis. J Investig Allergol Clin Immunol 2003;13:232-7. Evidence grade: III

3Bonini Se, Lambiase A, Matricardi P, Rasi G, D'Amato M, Bonini St. Atopic and vernal keratoconjunctivitis: a model for studying atopic disease. Curr Probl Dermatol 1999;28:88-94. Evidence grade: IV

4Bonini St, Bonini SE, Lambiase A, et al. Vernal keratoconjunctivitis revisited. A case series of 195 patients with long term follow-up. Ophthalmology 2000;107:1157-63. Evidence grade: III

5Mimura T, Amano S, Funatsu H, et al. Correlations between allergen-specific IgE serum levels in patients with allergic conjunctivitis in the Spring. Ocul Immunol Inflamm 2004;12:45-51. Evidence grade: III

6Cakmak S, Dales RE, Burnett RT, et al. Effect of airborne allergens on emergency visits by children for conjunctivitis and rhinitis. Lancet 2002;359:947-8. Evidence grade: III

7Li JT, Lockey RF, Bernstein IL, Portnoy JM, Nickolas RA. Allergen immunotherapy: a practice parameter. Ann Allergy Asthma Immunol 2003;90(suppl 1):1-39. Evidence grade: IV

8Alvarez-Cuesta E, Cuesta-Herranz J, Puyana-Ruiz J, et al. Monoclonal antibody-standardized cat extract immunotherapy: risk benefit effects from a double-blind placebo study. J Allergy Clin Immunol 1994;93:556-66. Evidence grade: Ib

9Varney VA, Gaga M, Frew AJ, Aber VR, Kay AB, Durham SR. Usefulness of immunotherapy in patients with severe summer hay fever uncontrolled by antiallergic drugs. BMJ 1991;302:265-9. Evidence grade: Ib

10"Bachert C, van Cauwenberge P, Khaltaev N, et al. Allergic Rhinitis and its Impact on Asthma (ARIA). In collaboration with the World Health Organization. Allergy 2002;57:841-5. Evidence grade: IV

Table V. Cough

Referral guideline	Rationale	Evidence type
Patients with chronic cough of 3-8 weeks or more	Asthma, postnasal drainage, and gastroesophageal reflux disease are the most common causes of cough.¹ ² Spirometry and a chest radiograph have been suggested as the minimum investigations required in the evaluation of chronic cough.², ³, ⁴ Allergists have extensive training to evaluate the upper, as well as lower, airways in a patient with chronic cough.⁵	Diagnostic

Patients with coexisting chronic cough and asthma	Cough occurs in all asthmatic subjects.¹ However, cough alone is a poor marker of asthma, and asthma might be overdiagnosed in children with cough alone.³ The allergist can both provide expert consultation to ensure the diagnosis of asthma is correct and to maximize therapy in the asthmatic subject (see “Asthma” [Tables III, A, through III, G]).	Diagnostic
Patients with coexisting chronic cough and asthma		Indirect outcome (avoidance, pharmacologic, and immunologic therapy)

Patients with coexisting chronic cough and rhinitis	Postnasal drip is the single most common cause of chronic cough.¹ Allergy skin testing and history-testing correlation can differentiate allergic from nonallergic rhinitis (see “Rhinitis” [Table XIII, A]). Treatment of rhinitis can improve the cough.¹ Treatment of rhinitis by allergists improves patient outcomes (see “Rhinitis” [Table XIII, A]).	Diagnostic
Patients with coexisting chronic cough and rhinitis		Indirect outcome (avoidance, pharmacologic, and immunologic therapy)

Patients with chronic cough and tobacco use or exposure	Tobacco smoke exposure clearly increases cough prevalence and exacerbates any pulmonary condition.³ Chronic cough in cigarette smokers is dose related.⁴ Allergists can assist with active steps to minimize or eliminate tobacco smoke exposure.⁵	Indirect outcome (smoking cessation)

REFERENCES

1Irwin RS, Boulet L-P, Cloutier MM, et al. Managing cough as a defense mechanism and as a symptom. A consensus panel report of the American College of Chest Physicians. Chest 1998;114(suppl):131S-81S. Evidence grade: IV

2Kastelik JA, Aziz I, Ojoo JC, Thompson RH, Redington AE, Morice AH. Investigation and management of chronic cough using a probability-based algorithm. Eur Respir J 2005;25:235-43. Evidence grade: III

3Chang AB, Robertson CF. Cough in children. Med J Aust 2000;172:122-5. Evidence grade: IV

4Morice AH, Fontana GA, Sovijarvi ARA, et al. The diagnosis and management of chronic cough. Eur Respir J 2004;24:481-92. Evidence grade: IV

5Core Curriculum Subcommittee of the Training Program Directors; American Academy of Allergy, Asthma and Immunology. Allergy and immunology core curriculum outline 1996. J Allergy Clin Immunol 1996;98:1012-5. 2002 update available at: http://www.aaaai.org/professionals/careers/training_programs.stm. Evidence grade: IV

Table VI, A. Atopic dermatitis

Referral guideline	Rationale	Evidence type
To confirm the diagnosis of atopic dermatitis in a patient with dermatitis	Allergist-immunologists are specifically trained to diagnose atopic dermatitis.¹ Defining IgE-mediated sensitivity (by means of skin or in vitro testing) is useful in the differential diagnosis.²	Diagnostic

To identify the role of dust mite allergy in patients with atopic dermatitis	Dust mite allergy can trigger atopic dermatitis. In such patients mite avoidance should be helpful.³, ⁴, ⁵, ⁶, ⁷, ⁸, ⁹, ¹⁰, ¹¹	Diagnostic
		Indirect outcome (mite avoidance)

To identify the role of food allergy in patients with atopic dermatitis	Approximately 35% of young children with moderate-to-severe atopic dermatitis have food allergy; the association appears less common in adults but is possible.¹², ¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷, ¹⁸, ¹⁹	Diagnostic
		Indirect outcome (food avoidance)

Patients whose atopic dermatitis responds poorly to treatment	Allergist-immunologists are specifically trained and experienced in managing atopic dermatitis in both children and adults.²⁰, ²¹, ²², ²³, ²⁴, ²⁵, ²⁶, ²⁷	Indirect outcome (pharmacologic therapy)

REFERENCES

1Core Curriculum Subcommittee of the Training Program Directors; American Academy of Allergy, Asthma and Immunology. Allergy and immunology core curriculum outline 1996. J Allergy Clin Immunol 1996;98:1012-5. 2002 update available at: http://www.aaaai.org/professionals/careers/training_programs.stm. Evidence grade: IV

2Schultz-Larsen F, Hanifin JM. Epidemiology of atopic dermatitis. Immunol Allergy Clin North Am 2002;22:1-24. Evidence grade: IV

3Platts-Mills TA, Mitchell EB, Rowntree S, Chapman MD, Wilkins SR. The role of dust mite allergens in atopic dermatitis. Clin Exp Dermatol 1983;8:233-47. Evidence grade: II

4Tupker RA, De Monchy JG, Coenraads PJ, et al. Induction of atopic dermatitis by inhalation of house dust mite. J Allergy Clin Immunol 1996;97:1064-70. Evidence grade: II

5Huang JL, Chen CC, Kuo ML, et al. Exposure to a high concentration of mite allergen in early infancy is a risk factor for developing atopic dermatitis: a 3-year follow-up study. Pediatr Allergy Immunol 2001;12:11-6. Evidence grade: III

6Wheatley LM, Platts-Mills TAE. In: Leung DYM, Greaves MW, editors. Allergic skin disease: a multidisciplinary approach. New York: Marcel Dekker; 2000. p. 423. Evidence grade: IV

7Palmer RA, Friedmann PS. Effect of house dust mite avoidance measures in children with atopic dermatitis. Br J Dermatol 2001;144:912-3. Evidence grade: Ib

8Ricci G, Patrizi A, Specchia F, et al. Effect of house dust mite avoidance measures in children with atopic dermatitis. Br J Dermatol 2000;143:379-84. Evidence grade: Ib

9Gutgesell C, Heise S, Seubert S, et al. Double-blind placebo-controlled house dust mite control measures in adult patients with atopic dermatitis. Br J Dermatol 2001;145:70-4. Evidence grade: Ib

10Tan BB, Weald D, Strickland I, et al. Double-blind controlled trial of effect of house dust-mite allergen avoidance on atopic dermatitis. Lancet 1996;347:15-8. Evidence grade: Ib

11Holm L, Bengtsson A, van Hage-Hamsten M, et al. Effectiveness of occlusive bedding in the treatment of atopic dermatitis-a placebo-controlled trial of 12 months' duration. Allergy 2001;56:152-8. Evidence grade: Ib

12Sampson HA, Albergo R. Comparison of results of skin tests, RAST, and double-blind, placebo-controlled food challenges in children with atopic dermatitis. J Allergy Clin Immunol 1984;74:26-33. Evidence grade: Ib

13Lever R, MacDonald C, Waugh P, et al. Randomized controlled trial of advice on an egg exclusion diet in young children with atopic eczema and sensitivity to eggs. Pediatr Allergy Immunol 1998;9:13-9. Evidence grade: Ib

14Woodmansee DP, Christiansen SC. Improvement in atopic dermatitis in infants with the introduction of an elemental formula. J Allergy Clin Immunol 2001;108:309. Evidence grade: III

15Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol 2001;107:891-6. Evidence grade: III

16Sicherer SH, Morrow EH, Sampson HA. Dose-response in double-blind, placebo-controlled oral food challenges in children with atopic dermatitis. J Allergy Clin Immunol 2000;105:582-6. Evidence grade: Ib

17Niggemann B, Reibel S, Roehr CC, et al. Predictors of positive food challenge outcome in non-IgE-mediated reactions to food in children with atopic dermatitis. J Allergy Clin Immunol 2001;108:1053-8. Evidence grade: Ib

18Eigenmann PA, Sicherer SH, Borkowski TA, Cohen BA, Sampson HA. Prevalence of IgE-mediated food allergy among children with atopic dermatitis. Pediatrics 1998;101:E8. Evidence grade: III

19Reekers R, Busche M, Wittmann M, Kapp A, Werfel T. Birch pollen-related foods trigger atopic dermatitis in patients with specific cutaneous T-cell responses to birch pollen antigens. J Allergy Clin Immunol 1999;104:466-72. Evidence grade: Ib

20Leung DY, Hanifin JM, Charlesworth EN, et al. Disease management of atopic dermatitis: a practice parameter. Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma and Immunology, the American College of Allergy, Asthma and Immunology, and the Joint Council of Allergy, Asthma and Immunology. Work Group on Atopic Dermatitis. Ann Allergy Asthma Immunol 1997;79:197-211. Evidence grade: IV

21Joint Task Force on Practice Parameters. Disease management of atopic dermatitis: an updated practice parameter. American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol 2004;93(suppl):S1-S21. Evidence grade: IV

22Hoare C, Li Wan Po A, Williams H. Systematic review of treatments for atopic eczema. Health Technol Assess 2000;4:1-191. Evidence grade: Ia

23Van Der Meer JB, Glazenburg EJ, Mulder PG, et al. The management of moderate to severe atopic dermatitis in adults with topical fluticasone propionate. The Netherlands Adult Atopic Dermatitis Study Group. Br J Dermatol 1999;140:1114-21. Evidence grade: Ib

24Devillers AC, de Waard-van der Spek FB, Mulder PG, et al. Treatment of refractory atopic dermatitis using ‘wet-wrap’ dressings and diluted corticosteroids: results of standardized treatment in both children and adults. Dermatology 2002;204:50-5. Evidence grade: II

25Sowden JM, Berth-Jones J, Ross JS, et al. Double-blind, controlled, crossover study of cyclosporin in adults with severe refractory atopic dermatitis. Lancet 1991;338:137-40. Evidence grade: Ib

26Salek MS, Finlay AY, Luscombe DK, et al. Cyclosporin greatly improves the quality of life of adults with severe atopic dermatitis. A randomized, double-blind, placebo-controlled trial. Br J Dermatol 1993;129:422-30. Evidence grade: Ib

27Harper JI, Berth-Jones J, Camp RD, et al. Cyclosporin for atopic dermatitis in children. Dermatology 2001;203:3-6. Evidence grade: IV

Table VI, B. Contact dermatitis

Referral guideline	Rationale	Evidence type
To confirm the diagnosis of and identify the cause of contact dermatitis	Allergist-immunologists are specifically trained to diagnose contact dermatitis.¹ More allergist-immunologists than dermatologists currently perform patch testing.² ³ If a cause is defined, avoidance therapy can be initiated.⁴, ⁵, ⁶, ⁷, ⁸, ⁹, ¹⁰, ¹¹, ¹², ¹³	Diagnostic
		Indirect outcome (avoidance)

REFERENCES

1Core Curriculum Subcommittee of the Training Program Directors; American Academy of Allergy, Asthma and Immunology. Allergy and immunology core curriculum outline 1996. J Allergy Clin Immunol 1996;98:1012-5. 2002 update available at: http://www.aaaai.org/professionals/careers/training_programs.stm. Evidence grade: IV

2Fonacier LS, Charlesworth EN, Mak WY, Bahna SL. American College of Allergy & Immunology (ACAAI) patch testing and allergic dermatologic disease survey: the use of this procedure and the effect of education on confidence, attitude and usage. Am J Contact Dermatitis 2002;14:164-9. Evidence grade: IV

3Fonacier LS, Charlesworth EN. Patch testing for allergic contact dermatitis in the allergist office. Curr Allergy Asthma Rep 2003;3:283-90. Evidence grade: IV

4Nettis E, Marcandrea M, Colandardi MC, Paradiso MT, Ferrannini A, Tursi A. Results of standard series patch testing in patients with occupational allergic contact dermatitis. Allergy 2003;58:1304-7. Evidence grade: III

5Mitchell EB, Crow J, Chapman MD, Jouhal SS, Pope FM, Platts-Mills TA. Basophils in allergen-induced patch test sites in atopic dermatitis. Lancet 1982;1:127-30. Evidence grade: III

6Lindberg M, Tammela M, Bostrom A, et al. Are adverse skin reactions to cosmetics underestimated in the clinical assessment of contact dermatitis? A prospective study among 1075 patients attending Swedish patch test clinics. Acta Derm Venereol 2004;84:291-5. Evidence grade: III

7Li LF, Sujan SA, Wang J. Detection of occupational allergic contact dermatitis by patch testing. Contact Dermatitis. 2003;49:189-93. Evidence grade: III

8Adams RM. Patch testing for occupational allergens and the evaluation of patients with occupational contact dermatitis. Allergy Proc 1990;11:117-20. Evidence grade: IV

9Rietschel RL, Mathias CG, Fowler JF, et al. Relationship of occupation to contact dermatitis: evaluation in patients tested from 1998 to 2000. Am J Contact Dermatitis 2002;13:170-6. Evidence grade: III

10Drake LA, Dorner RW, Goltz RW, et al. Guidelines for care of contact dermatitis. Committee on Guidelines of Care. J Am Acad Dermatol 1995;32:109-13. Evidence grade: IV

11Marks J, DeLeo V. Patch testing for contact and occupational dermatology. St Louis: Mosby; 1993. Evidence grade: IV

12Bernstein L, Storms W. Practice parameters for allergy diagnostic testing. Ann Allergy 1995;75:543-615. Evidence grade: IV

13Marks JG, Belsito DV, DeLeo VA, et al. North American Contact Dermatitis Group patch test results for the detection of delayed-type hypersensitivity to topical allergens. J Am Acad Dermatol 1998;38:911-8. Evidence grade: III

Table VII. Drug allergy

Referral guideline	Rationale	Evidence type
Patients with a history of penicillin allergy who have a significant probability of requiring future antibiotic therapy	The vast majority of patients with a history of penicillin allergy can safely use penicillins if an allergy evaluation, often including a penicillin skin test, is performed.¹	Diagnostic
		Indirect outcome (needed penicillin treatment)
	History alone is inadequate to rule out IgE-mediated allergy to penicillin.²
	Penicillin skin testing in advance of need does not cause significant resensitization.³, ⁴, ⁵, ⁶
	Patients who are shown not to be allergic to penicillin might be able to use more appropriate and potentially less toxic antibiotics, less expensive antibiotics, or both.⁷

Patients with a history of penicillin allergy in which a penicillin-class antibiotic is the drug of choice	Skin test responses might be negative in such patients, who can then safely receive penicillin.⁴ Antibiotic desensitization in patients with positive skin test responses renders them transiently tolerant and induces negative skin test responses, indicating blocking of mast cell–IgE activation events.⁸, ⁹, ¹⁰, ¹¹	Indirect outcome (needed penicillin treatment)

Patients with histories of multiple drug allergy-intolerance	Allergist-immunologists provide a comprehensive plan to evaluate the historical adverse drug reactions and provide suggestions on future therapies to minimize risks.¹², ¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷	Diagnostic
		Indirect outcome (treatment with needed medications)

Patients who might be allergic to protein-based biotherapeutics and require use of these materials	Allergist-immunologists perform skin testing with appropriate concentrations and techniques to determine current sensitivity.¹² ¹⁶, ¹⁷, ¹⁸, ¹⁹, ²⁰ For example, insulin desensitization allows for continued insulin therapy in patients with prior systemic reactions.²¹ ²²	Diagnostic
		Indirect outcome (treatment with needed biotherapeutics)

Patients with histories of adverse reactions to NSAIDs who require aspirin or other NSAIDs	Allergist-immunologists accurately diagnose NSAID sensitivity through challenge testing.²³	Diagnostic
	Allergist-immunologists perform aspirin desensitization in patients with documented aspirin sensitivity who require aspirin for other medical conditions.¹⁰ ²³	Indirect outcome (needed NSAID treatment)
	Desensitization in patients with aspirin-exacerbated respiratory disease can improve the control of both upper and lower respiratory tract disease in these patients.¹⁰ ²³ ²⁴	Indirect outcome (improved respiratory symptoms)

Patients who require chemotherapy medication for cancer or other severe conditions and have experienced a prior hypersensitivity reaction to those medications	Desensitization allows for transient tolerance to chemotherapy medications when there is no alternative treatment.²⁵, ²⁶, ²⁷	Indirect outcome (needed chemotherapy)

Patients with a history of possible allergic reactions to local anesthetics	Allergist-immunologists are able to perform skin testing and graded challenge to find a safe local anesthetic for future use. Virtually all patients with histories of reactions to local anesthetics can subsequently tolerate the same or an alternate agent.²⁸, ²⁹, ³⁰	Indirect outcome (needed local anesthetic treatment)

HIV-infected patients with a history of adverse reactions to TM-S who need this therapy	Graded TM-S challenges can identify patients who are not currently sensitive to the drug and allow patients with reactions during challenge to subsequently tolerate the drug and safely continue therapy.³¹, ³², ³³, ³⁴, ³⁵, ³⁶, ³⁷	Diagnostic
		Indirect outcome (needed TM-S therapy)

Patients with a history of reactions to induction agents or to nonpenicillin antibiotics	Allergist-immunologists provide a comprehensive plan to evaluate the historical adverse drug reactions and provide suggestions on future therapies to minimize risks.¹², ¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷	Diagnostic
		Indirect outcome (treatment with needed medications)

NSAID, Nonsteroidal anti-inflammatory drug; TM-S, trimethoprim-sulfamethoxazole.

REFERENCES

1Mendelson LM, Ressler C, Rosen JP, Selcow JE. Routine elective penicillin allergy skin testing in children and adolescents: study of sensitization. J Allergy Clin Immunol 1984;73:76-81. Evidence grade: II

2Solensky R, Earl HS, Gruchalla RS. Penicillin allergy: prevalence of vague history in skin test-positive patients. Ann Allergy Asthma Immunol 2000;85:195-9. Evidence grade: III

3Solensky R, Earl HS, Gruchalla RS. Lack of penicillin resensitization in patients with a history of penicillin allergy after receiving repeated penicillin courses. Arch Intern Med 2002;162:822-6. Evidence grade: II

4Macy E, Mangat R, Burchette RJ. Penicillin skin testing in advance of need: multiyear follow-up in 568 test result-negative subjects exposed to oral penicillins. J Allergy Clin Immunol 2003;111:1111-5. Evidence grade: III

5Nugent JS, Quinn JM, McGrath CM, Hrncir DE, Boleman WT, Freeman TM. Determination of the incidence of sensitization after penicillin skin testing. Ann Allergy Asthma Immunol 2003;90:398-403. Evidence grade: II

6Bittner A, Greenberger PA. Incidence of resensitization after tolerating penicillin treatment in penicillin-allergic patients. Allergy Asthma Proc 2004;25:16-4. Evidence grade: III

7Macy E, Burchette RJ. Oral antibiotic adverse reactions after penicillin testing: multi-year follow-up. Allergy 2002;57:1151-8. Evidence grade: III

8Naclerio R, Mizrahi EA, Adkinson NF Jr. Immunological observations during desensitization. J Allergy Clin Immunol 1983;71:294. Evidence grade: III

9Stark BJ, Earl HS, Gross GN, Lumry WR, Goodman EL, Sullivan TJ. Acute and chronic desensitization of penicillin-allergic patients using oral penicillin. J Allergy Clin Immunol 1987;79:523-32. Evidence grade: III

10Solensky R. Drug allergy: desensitization and treatment of reactions to antibiotics and aspirin. Clin Allergy Immunol 2004;18:585-606. Evidence grade: IV

11Borish L, Tamir R, Rosenwasser LJ. Intravenous desensitization to beta-lactam antibiotics. J Allergy Clin Immunol 1987;80:314-9. Evidence grade: III

12Core Curriculum Subcommittee of the Training Program Directors; American Academy of Allergy, Asthma and Immunology. Allergy and immunology core curriculum outline 1996. J Allergy Clin Immunol 1996;98:1012-5. 2002 update available at: http://www.aaaai.org/professionals/careers/training_programs.stm. Evidence grade: IV

13Demoly P, Kropf R, Bircher A, Pichler WJ. Drug hypersensitivity: questionnaire. Allergy 1999;54:999-1003. Evidence grade: IV

14Gruchalla RS. Approach to the patient with multiple antibiotic sensitivities. Allergy Asthma Proc 2000;21:39-44. Evidence grade: IV

15Macy E. Multiple antibiotic allergy syndrome. Immunol Allergy Clin North Am 2004;24:533-43. Evidence grade: IV

16Vemuir P, Tripathi A. Keefe P. Individual drugs or problems: summary of useful techniques; IgE mediated reactions, presumptive or proven. Allergy Asthma Proc 2004;25:349-57. Evidence grade: IV

17Rotskoff B, Saltoun C, Su F, Greenberger PA. Individual drugs or problems: summary of useful techniques; drugs resulting in probable or possible immunologically mediated reactions. Allergy Asthma Proc 2004;25:449-60. Evidence grade: IV

18Grammer LC, Schafer M, Bernstein D, et al. Prevention of chymopapain anaphylaxis by screening chemonucleolysis candidates with cutaneous chymopapain testing. Clin Orthop 1988;234:12-5. Evidence grade: II

19Dykewicz MS, Kim HW, Orfan N, Yoo TJ, Lieberman P. Immunologic analysis of anaphylaxis to protamine component in neutral protamine Hagedorn human insulin. J Allergy Clin Immunol 1994;93:117-25. Evidence grade: III

20Leonard PA, Woodside KJ, Guliuzza KK, Sur S, Daller JA. Safe administration of a humanized murine antibody after anaphylaxis to a chimeric murine antibody. Transplantation 2002;74:1697-700. Evidence grade: III

21Grammer LC, Metzger BE, Patterson R. Cutaneous allergy to human (recombinant DNA) insulin. JAMA 1984;251:1459-60. Evidence grade: III

22Gossain VV, Rovner DR, Mohan K. Systemic allergy to human (recombinant DNA) insulin. Ann Allergy 1985;55:116-8. Evidence grade: III

23Simon RA, Prevention and treatment of reactions to NSAIDs. Clin Rev Allergy Immunol 2003;24:189-98. Evidence grade: IV

24Stevenson DD. Aspirin desensitization in patients with aspirin exacerbated respiratory disease. Clin Rev Allergy Immunol 2003;24:159-68. Evidence grade: IV

25Markman M, Kennedy A, Webster K, Kulp B, Peterson G, Belinson J. Paclitaxel-associated hypersensitivity reactions: experience of the gynecologic oncology program of the Cleveland Clinic Cancer Center. J Clin Oncol 2000;18:102-5. Evidence grade: III

26Robinson JB, Singh D, Bodurka-Bevers DC, Wharton JT, Gershenson DM, Wolf JK. Hypersensitivity reactions and the utility of oral and intravenous desensitization in patients with Gyn malignancies. Gynecol Oncol 2001;82:550-8. Evidence grade: III

27Lee CW, Matulonis UA, Castells MC. Carboplatinum hypersensitivity: a 6-hour 12 step protocol effective in 35 desensitizations in patients with gynecological malignancies and mast cell/IgE mediated reactions. Gynecol Oncol 2004;95:370-6. Evidence grade: III

28Gall H, Kaufmann R, Kalveram CM. Adverse reactions to local anesthetics: analysis of 197 cases. J Allergy Clin Immunol 1996;97:933-7. Evidence grade: III

29Schatz M. Skin testing and incremental challenge in the evaluation of adverse reactions to local anesthetics. J Allergy Clin Immunol 1984;74:606-16. Evidence grade: II

30Macy E, Schatz M, Zeiger RS. Immediate hypersensitivity to methylparaben causing false-positive results of local anesthetic skin testing or provocative dose testing. Permanente J 2002;6:17-21. Evidence grade: III

31Leoung GS, Stanford JF, Giordano MF, et al. American Foundation for AIDS Research (amfAR) Community-Based Clinical Trials Network. Trimethoprim-sulfamethoxazole (TMP-SMZ) dose escalation versus direct rechallenge for Pneumocystis carinii pneumonia prophylaxis in human immunodeficiency virus-infected patients with previous adverse reaction to TMP-SMZ. J Infect Dis 2001;184:992-7. Evidence grade: Ib

32Bonfanti P, Pusterla L, Parazzini F, et al. The effectiveness of desensitization versus rechallenge treatment in HIV-positive patients with previous hypersensitivity to TMP-SMX: a randomized multicentric study. Biomed Pharmacother 2000;54:45-9. Evidence grade: Ib

33Asar N, Daneshvar H, Beall G. Desensitization to trimethoprim/sulfamethoxazole in HIV-infected patients. J Allergy Clin Immunol 1994;93:1001-5. Evidence grade: III

34Nguyen M, Weiss PJ, Wallace MR. Two-day oral desensitization to trimethoprim-sulfamethoxazole in HIV-infected patients. AIDS 1995;9:573-5. Evidence grade: III

35Belchi-Hernandez J, Espinosa-Parra FJ. Management of adverse reactions to prophylactic trimethoprim-sulfamethoxazole in patients with human immunodeficiency virus infection. Ann Allergy Asthma Immunol 1996;76:355-8. Evidence grade: III

36Rich JD, Sullivan T, Greineder D, Kazanjian PH. Trimethoprim/sulfamethoxazole incremental dose regimen in human immunodeficiency virus-infected persons. Ann Allergy Asthma Immunol 1997;79:409-14. Evidence grade: III

37Demoly P, Messaad D, Sahla H, et al. Six-hour trimethoprim-sulfamethoxazole-graded challenge in HIV-infected patients. J Allergy Clin Immunol 1998;102:1033-6. Evidence grade: III

Table VIII. Food allergy

Referral guideline	Rationale	Evidence type
Persons who have limited their diet on the basis of perceived adverse reactions to foods or additives	After allergy evaluation, an estimated one third of perceived adverse reactions to foods and a small fraction of adverse reactions to additives are verified.¹, ², ³, ⁴, ⁵, ⁶ Evaluation by an allergist-immunologist is likely to result in an individual's ability to liberalize his or her diet (thereby likely improving nutrition and quality of life).	Indirect outcome (avoiding unnecessary diet restriction)

Persons with a diagnosed food allergy	The allergist-immunologist can apply and interpret diagnostic tests (skin prick tests, serum food-specific IgE assays, and oral food challenges) and advise patients on dietary avoidance and emergency care measures.² ⁵ ⁷ ⁸ These are important aspects of care because (1) many allergies are not permanent and should be monitored for resolution,² and (2) avoidance of allergenic foods and action taken in the event of exposure are difficult to undertake, are prone to errors, and can be dangerous, thus mandating proper education.⁹ ¹⁰	Diagnostic
Persons with a diagnosed food allergy		Indirect outcome (food avoidance, early pharmacologic treatment of reaction)

Atopic families with or expecting a newborn who are interested in identifying risks for and preventing allergy	Family history is the strongest predictor of allergy. A sibling born to a family who already has a child with peanut allergy has a risk for that allergy that is more than 10 times greater than that of the general population.¹¹ Specific guidelines are in place to approach potential allergy in a food allergy–prone child (eg, breast-feeding and avoidance of allergenic foods).¹² ¹³ Meta-analyses of studies shows breast-feeding and avoidance of cow's milk–soy in the first year might reduce the risk for allergic disease.¹⁴ ¹⁵ The allergist-immunologist can evaluate the risks and explain possible approaches.	Diagnostic
		Indirect outcome (prevention of sensitization)

Persons who have experienced allergic symptoms (urticaria, angioedema, itch, wheezing, and gastrointestinal responses) in association with food exposure	The allergist-immunologist can perform diagnostic tests, such as skin tests, serum IgE tests, and oral food challenges to determine the cause of the reaction.² ⁷ ⁸ ¹⁶	Diagnostic
		Indirect outcome (food avoidance)

Persons who experience an itchy mouth from raw fruits and vegetables	These symptoms are typical of pollen-food allergy syndrome, or oral allergy syndrome, which can sometimes progress to or overlap with more severe allergic reactions.¹⁷, ¹⁸, ¹⁹ The allergist-immunologist evaluates the reactions to determine the cause and to advise which foods to avoid, identify other potential problematic foods, and assess risks for a severe reaction.	Diagnostic
		Indirect outcome (food avoidance)

Infants with recalcitrant gastroesophageal reflux or older individuals with recalcitrant reflux symptoms, particularly if they experience dysphagia	Food allergy might be a cause of infantile reflux, and evidence of food responsiveness is high (about 40%) for children in whom symptoms do not respond well to standard therapies.²⁰ Older individuals might have reflux symptoms and possibly dysphagia caused by eosinophilic esophagitis, a disorder that is also commonly food responsive.²¹ ²²	Diagnostic
		Indirect outcome (food avoidance)

Infants with gastrointestinal symptoms, including vomiting, diarrhea (particularly with blood), poor growth, and/or malabsorption, whose symptoms are otherwise unexplained, not responsive to medical management, and/or possibly food responsive (even if screening allergy test results are negative)	There are a group of food-responsive gastrointestinal disorders of infancy (including food protein–induced enteropathy, enterocolitis, and proctocolitis) that can be diagnosed, treated, and monitored with modalities with which allergist-immunologists are expert, including elimination diets and oral food challenges.⁷ ²³, ²⁴, ²⁵, ²⁶ Most of the disorders affecting infants cannot be identified with simple screening tests.²³, ²⁴, ²⁵, ²⁶	Diagnostic
		Indirect outcome (food avoidance)

Persons with known eosinophilic inflammation of the gut	Eosinophilic gastroenteritis, esophagitis, and/or gastroenterocolitis might be food responsive.²¹ ²² Patients’ symptoms could improve after identification and elimination of causal foods,²² modalities for which the allergist-immunologist is expert.	Diagnostic
Persons with known eosinophilic inflammation of the gut		Indirect outcome (food avoidance)

REFERENCES

1Young E, Stoneham MD, Petruckevitch A, Barton J, Rona R. A population study of food intolerance. Lancet 1994;343:1127-30. Evidence grade: II

2Bock SA. Prospective appraisal of complaints of adverse reactions to foods in children during the first 3 years of life. Pediatrics 1987;79:683-8. Evidence grade: III

3Sloan AE, Powers ME. A perspective on popular perceptions of adverse reactions to foods. J Allergy Clin Immunol 1986;78:127-33. Evidence grade: III

4Altman DR, Chiaramonte LT. Public perception of food allergy. J Allergy Clin Immunol 1996;97:1247-51. Evidence grade: III

5Sampson HA, McCaskill CC. Food hypersensitivity and atopic dermatitis: evaluation of 113 patients. J Pediatr 1985;107:669-75. Evidence grade: III

6Young E, Patel S, Stoneham MD, Rona R, Wilkinson JD. The prevalence of reactions to food additives in a survey population. J R Coll Physicians Lond 1987;21:241-71. Evidence grade: III

7Core Curriculum Subcommittee of the Training Program Directors; American Academy of Allergy, Asthma and Immunology. Allergy and immunology core curriculum outline 1996. J Allergy Clin Immunol 1996;98:1012-5. 2002 update available at: http://www.aaaai.org/professionals/careers/training_programs.stm. Evidence grade: IV

8Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol 2001;107:891-6. Evidence grade: II

9Sicherer SH, Forman JA, Noone SA. Use assessment of self-administered epinephrine among food-allergic children and pediatricians. Pediatrics 2000;105:359-62. Evidence grade: III

10Bock SA, Munoz-Furlong A, Sampson HA. Fatalities due to anaphylactic reactions to foods. J Allergy Clin Immunol 2001;107:191-3. Evidence grade: III

11Sicherer SH, Furlong TJ, Maes HH, Desnick RJ, Sampson HA, Gelb BD. Genetics of peanut allergy: a twin study. J Allergy Clin Immunol 2000;106:53-6. Evidence grade: II

12American Academy of Pediatrics, Committee on Nutrition. Hypoallergenic infant formulas. Pediatrics 2000;106:346-9. Evidence grade: IV

13Muraro A, Dreborg S, Halken S, et al. Dietary prevention of allergic diseases in infants and small children. Part III: Critical review of published peer-reviewed observational and interventional studies and final recommendations. Pediatr Allergy Immunol 2004;15:291-307. Evidence grade: IV

14Gdalevich M, Mimouni D, David M, Mimouni M. Breast-feeding and the onset of atopic dermatitis in childhood: a systematic review and meta-analysis of prospective studies. J Am Acad Dermatol 2001;45:520-7. Evidence grade: Ia

15Osborn DA, Sinn J. Formulas containing hydrolysed protein for prevention of allergy and food intolerance in infants. Cochrane Database Syst Rev 2003;4:CD003664. Evidence grade: Ia

16Eigenmann PA, Sampson HA. Interpreting skin prick tests in the evaluation of food allergy in children. Pediatr Allergy Immunol 1998;9:186-91. Evidence grade: III

17Ortolani C, Ispano M, Pastorello EA, Ansaloni R, Magri GC. Comparison of results of skin prick tests (with fresh foods and commercial food extracts) and RAST in 100 patients with oral allergy syndrome. J Allergy Clin Immunol 1989;83:683-90. Evidence grade: III

18Ortolani C, Ispano M, Pastorello E, Bigi A, Ansaloni R. The oral allergy syndrome. Ann Allergy 1988;61:47-52. Evidence grade: III

19Crespo JF, Rodriguez J, James JM, Daroca P, Reano M, Vives R. Reactivity to potential cross-reactive foods in fruit-allergic patients: implications for prescribing food avoidance. Allergy 2002;57:946-9. Evidence grade: II

20Iacono G, Carroccio A, Cavataio F, et al. Gastroesophageal reflux and cow's milk allergy in infants: a prospective study. J Allergy Clin Immunol 1996;97:822-7. Evidence grade: II

21Orenstein SR, Shalaby TM, Di Lorenzo C, Putnam PE, Sigurdsson L, Kocoshis SA. The spectrum of pediatric eosinophilic esophagitis beyond infancy: a clinical series of 30 children. Am J Gastroenterol 2000;95:1422-30. Evidence grade: III

22Spergel JM, Beausoleil JL, Mascarenhas M, Liacouras C. The use of skin prick tests and patch tests to identify causative foods in eosinophilic esophagitis. J Allergy Clin Immunol 2002;109:363-8. Evidence grade: II

23Lake AM, Whitington PF, Hamilton SR. Dietary protein-induced colitis in breast-fed infants. J Pediatr 1982;101:906-10. Evidence grade: II

24Sampson HA, Anderson JA. Summary and recommendations: Classification of gastrointestinal manifestations due to immunologic reactions to foods in infants and young children. J Pediatr Gastroenterol Nutr 2000;30(suppl):S87-S94. Evidence grade: IV

25Sampson HA, Sicherer SH, Birnbaum AH. AGA technical review on the evaluation of food allergy in gastrointestinal disorders. Gastroenterology 2001;120:1026. Evidence grade: IV

26Sicherer SH, Eigenmann PA, Sampson HA. Clinical features of food protein-induced enterocolitis syndrome. J Pediatr 1998;133:214-9. Evidence grade: III

Table IX. Hypersensitivity pneumonitis

Referral guideline	Rationale	Evidence type
Early referral of patients with suspected hypersensitivity pneumonia to avoid continued environmental exposure resulting in permanent lung injury	Early accurate diagnosis and removal from further exposure to specific sensitizers carries the best medical prognosis for those with HP.¹, ², ³, ⁴ Allergists are trained and experienced in environmental exposure history, physical examination, and clinical and laboratory diagnosis of HP.⁵	Diagnostic
		Indirect outcome (avoidance)

Diagnostic consultation in patients found to have NSIP	Histologic diagnosis of HP varies from the acute stage, subacute stage, and chronic form. Findings of NSIP should initiate the diagnostic consideration of HP because avoidance of the offending antigen and pharmacologic therapy might result in resolution of the disease or stop the progression of disease.⁶	Diagnostic
Diagnostic consultation in patients found to have NSIP		Indirect outcome (avoidance and corticosteroids)

Patients with known HP for management	Allergist-immunologists are specifically trained to evaluate environmental exposures, evaluate immunologic results, and treat and follow HP, including oral corticosteroid treatment.⁵ ⁷, ⁸, ⁹, ¹⁰, ¹¹, ¹²	Indirect outcome (avoidance and corticosteroids)

HP, Hypersensitivity pneumonitis; NSIP, nonspecific interstitial pneumonia.

REFERENCES

1Weltermann BM, Hodgson M, Storey E, et al. Hypersensitivity pneumonitis: a sentinel event investigation in a wet building. Am J Ind Med 1998;34:499-505. Evidence grade: III

2Banaszak EF, Thiede WH, Fink JN. Hypersensitivity pneumonitis due to contamination of an air conditioner. N Engl J Med 1970;283:271-6. Evidence grade: III

3Kawai T, Tamura M, Murao M. Summer type hypersensitivity pneumonitis: a unique disease in Japan. Chest 1984;85:311-7. Evidence grade: IV

4Zacharisen M, Kadambi A, Schlueter D, et al. The spectrum of respiratory disease associated with exposure to metal working fluids. J Occup Environ Med 1998;40:640-7. Evidence grade: III

6American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement of American Thoracic Society (ATS) and European Respiratory Society (ERS). Am J Respir Crit Care Med 2001;161:646. Evidence grade: IV

7Tripathi A, Grammer LC. Extrinsic allergic alveolitis from a proteolytic enzyme. Ann Allergy Asthma Immunol. 2001;86:425-7. Evidence grade: IV

8Bernstein DI, Lummus ZL, Santilli G, et al. Machine Operator's lung, a hypersensitivity pneumonitis disorder associated with exposure to metalworking fluid aerosols. Chest 1995;108:636-41. Evidence grade: IV

9Dykewicz MS, Laufer P, Patterson R, Roberts M, Sommers HM. Woodman's disease: hypersensitivity pneumonitis from cutting live trees. J Allergy Clin Immunol 1988;81:455-61. Evidence grade: IV

10Malo JL, Zeiss CR. Occupational hypersensitivity pneumonitis after exposure to diphenylmethane diisocyanate. Am Rev Respir Dis 1982;125:113-6. Evidence grade: IV

11Vandenplas O, Malo JL, Dugas M, et al. Hypersensitivity pneumonitis-like reaction among workers exposed to diphenylmethane diisocyanate (MDI). Am Rev Respir Dis. 1993;147:338-46. Evidence grade: III

12Baur X. Hypersensitivity pneumonitis (extrinsic allergic alveolitis) induced by isocyanates. J Allergy Clin Immunol 1995;95:1004-10. Evidence grade: III

Table X. Insect hypersensitivity

Referral guideline	Rationale	Evidence type
Consider referral of patients with systemic reactions suspected or possibly caused by insect stings for accurate identification of specific allergen and consideration for venom immunotherapy (or whole-body extract in case of fire ant)	Up to 3% of the population is at risk for anaphylaxis to insect stings, with approximately 40 documented deaths annually.¹, ², ³, ⁴, ⁵, ⁶, ⁷, ⁸	Diagnostic
		Indirect outcome (avoidance, early pharmacologic treatment of reaction, immunotherapy)
	Patient identification of the specific insect species causing an allergic reaction is frequently incorrect.
	Allergy testing and history-test correlation can more accurately identify specific insects responsible for an allergic reaction and can be helpful in diagnosis, treatment, and avoidance recommendations.⁷ ⁹, ¹⁰, ¹¹, ¹², ¹³, ¹⁴, ¹⁵, ¹⁶
	Skin testing is generally preferred over in vitro testing for the initial evaluation of venom-specific IgE antibodies.⁴ ⁵ ¹³ ¹⁵ ¹⁷, ¹⁸, ¹⁹, ²⁰, ²¹
	Venom immunotherapy (or fire ant whole-body extract) greatly reduces the risk of systemic reactions in stinging insect–sensitive patients.² ³ ⁵ ⁸ ¹⁵ ²², ²³, ²⁴
	Venom immunotherapy can prevent death caused by subsequent stings in hypersensitive patients.³ ⁵ ¹⁵ ²⁵

Consider referral of patients with systemic reactions suspected or possibly caused by biting insects for accurate identification of specific allergen	Biting insects, such as Triatoma species and mosquitoes, have been identified as a cause of systemic reactions.²⁶, ²⁷, ²⁸, ²⁹, ³⁰	Diagnostic
		Indirect outcome (avoidance, appropriate pharmacologic therapy)
	RASTs and skin tests to Triatoma species salivary gland extracts and whole-body extracts of other biting insects have been used to identify antigen-specific IgE in sera of hypersensitive patients.³¹, ³², ³³, ³⁴, ³⁵, ³⁶, ³⁷, ³⁸, ³⁹, ⁴⁰
	Patient education by an allergist-immunologist, including the cause of the allergy, specific avoidance measures, recognition and treatment of anaphylaxis, and management of local side effects, might reduce patient anxiety and potentially reduce morbidity from future bites.²⁵, ²⁶, ²⁷, ²⁸, ²⁹

Consider referral of patients receiving venom (or fire ant whole-body extract) immunotherapy annually for review of interval history, tolerance of immunotherapy, need for repeat testing, and need for continued therapy	Regular review of interval history, immunotherapy dosing schedule, and adverse events can contribute to reduced complications of treatment.¹⁷ ¹⁸	Indirect outcome (avoidance, early pharmacologic therapy, immunotherapy)
	Regular review might identify new comorbidities or medications that increase the risk of poor outcomes from natural stings or insect immunotherapy reactions.¹⁷ ¹⁸ ⁴⁰, ⁴¹, ⁴², ⁴³, ⁴⁴
	Assessment of reactions to interval stings can be used to monitor the effectiveness of immunotherapy and might be cause for consideration of changes in dose and schedule.¹⁷ ¹⁸ ⁴⁵, ⁴⁶, ⁴⁷, ⁴⁸
	The interval between maintenance dose injections can be increased to 4-week intervals during the first year of immunotherapy and eventually to every 6-12 weeks in some patients.¹⁷ ¹⁸ ⁴⁸ ⁴⁹
	Many patients can safely discontinue venom immunotherapy after at least 3-5 years of treatment, although some patients might need to continue immunotherapy indefinitely. An allergist-immunologist with experience in treating patients with insect venom allergy is best suited to facilitate individualized patient decisions.¹⁷ ¹⁸ ⁵⁰, ⁵¹, ⁵², ⁵³, ⁵⁴, ⁵⁵, ⁵⁶, ⁵⁷, ⁵⁸, ⁵⁹, ⁶⁰, ⁶¹, ⁶²

REFERENCES

1Chafee FH. The prevalence of bee sting allergy in an allergic population. Acta Allergol 1970;25:292-3. Evidence grade: III

2Settipane GA, Boyd GK. Prevalence of bee sting allergy in 4,992 Boy Scouts. Acta Allergol 1970;25:286-7. Evidence grade: II

3Antonicelli L, Beatrice Bilo M, Bonifazi F. Epidemiology of Hymenoptera allergy. Curr Opin Allergy Clin Immunol 2002;2:341-6. Evidence grade: IV

4Golden DBK. Epidemiology of allergy to insect venoms and stings. Allergy Proc 1989;16:103-7. Evidence grade: IV

5Charpin D, Birnbaum J, Vervloet D. Epidemiology of Hymenoptera allergy. Clin Exp Allergy 1994;24:1010-5. Evidence grade: IV

6Barnard JH. Studies of 400 Hymenoptera sting deaths in the United States. J Allergy Clin Immunol 1973;52:259-64. Evidence grade: III

7DeShazo R, Butcher B, Barber W. Reactions to stings of the imported fire ant. N Engl J Med 1990;323:463-6. Evidence grade: III

8Freeman T, Hylander R, Ortiz A, Martin M. Imported fire ant immunotherapy: effectiveness of whole body extracts. J Allergy Clin Immunol 1992;90:210-5. Evidence grade: II

9Hunt K, Valentine M, Sobotka A, Liechtenstein L. Diagnosis of allergy stinging insects by skin testing with Hymenoptera venoms. Ann Intern Med 1976;85:56-9. Evidence grade: II

10Rueff F, Pryzbilla B, Muller 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;51:216-25. Evidence grade: IV

11Georgitis J, Reisman R. Venom skin tests in insect-allergic and insect-nonallergic populations. J Allergy Clin Immunol 1985;76:803-7. Evidence grade: II

12Golden DBK, Marsh DG, Friedhoff LR, et al. Natural History of Hymenoptera Venom Sensitivity in adults. J Allergy Clin Immunol 1997;100:760-6. Evidence grade: III

13Golden DBK, Kagey-Sobotka A, Norman PS, et al. Insect sting allergy with negative venom skin test responses. J Allergy Clin Immunol 2001;107:897-901. Evidence grade: III

14Moffitt J, Barker J, Stafford C. Management of imported fire ant allergy: results of a survey. Ann Allergy 1997;79:125-30. Evidence grade: III

15Oude Elberink JNG, Dubois AEJ. Quality of life in insect venom allergic patients. Curr Opin Allergy Clin Immunol 2003;3:287-93. Evidence grade: IV

16Reisman R. Insect stings. N Engl J Med 1994;331:523-7. Evidence grade: IV

17Stinging insect hypersensitivity: a practice parameter. Joint Task Force on Practice Parameters representing the American Academy of Allergy, Asthma & Immunology, the American College of Allergy, Asthma and Immunology, and the Joint Council on Allergy, Asthma and Immunology. J Allergy Clin Immunol 1999;103:963-80. Evidence grade: IV

18Stinging insect hypersensitivity: a practice parameter update. Joint Task Force on Practice Parameters representing the American Academy of Allergy, Asthma & Immunology, the American College of Allergy, Asthma and Immunology, and the Joint Council on Allergy, Asthma and Immunology. J Allergy Clin Immunol 2004;114:869-8. Evidence grade: IV

19Valentine M. Allergy to the stinging insects. Ann Allergy 1993;70:427-32. Evidence grade: IV

20Valentine M. Insect venom allergy: diagnosis and treatment. J Allergy Clin Immunol 1984;73:299-304. Evidence grade: IV

21Schwartz HJ, Lockey RF, Sheffer AL, et al. A multicenter study on skin-test reactivity of human volunteers to venom as compared with whole body Hymenoptera antigens. J Allergy Clin Immunol 1981;67:81-5. Evidence grade: II

22Hunt K, Valentine M, Sobotka A. A controlled trial of immunotherapy in insect hypersensitivity. N Engl J Med 1978;299:156-61. Evidence grade: II

23Triplett R. Sensitivity to the imported fire ant: successful treatment with immunotherapy. South Med J 1973;66:477-80. Evidence grade: III

24Valentine M, Schuberth K, Kagey-Sobotka A. The value of immunotherapy with venom in children with allergy to insect stings. N Engl J Med 1991;323:1601-3. Evidence grade: Ib

25Sasvary T, Muller U. Fatalities from insect stings in Switzerland 1978 to 1987 Schweiz. Med Wochenschr 1994;124:1887-94. Evidence grade: III

26Feingold BF, Benjamin E. Allergy to flea bites. Ann Allergy 1961;19:1275-89. Evidence grade: III

27Hoffman DR. Allergic reactions to biting insects. In: Monograph on insect allergy. 4th ed. In: Levin MI, Lockey RF, editors. Pittsburgh: Dave Lambert Associates; 2003. p. 161-203. Evidence grade: IV

28McCormack DR, Salata KF, Hershey JN, Carpenter GB, Engler RJ. Mosquito bite anaphylaxis: immunotherapy with whole body extracts. Ann Allergy Asthma Immunol 1995;74:39-44. Evidence grade: IV

29Rohr AS, Marshall NA, Saxon A. Successful immunotherapy for Triatoma protracta-induced anaphylaxis. J Allergy Clin Immunol 1984;73:369-75. Evidence grade: II

30Simons FER, Peng Z. Mosquito allergy. In: Levin MI, Lockey RF, editors. Monograph on insect allergy. 4th ed. Pittsburgh: Dave Lambert Associates; 2003. p. 161-203. Evidence grade: IV

31Gauci M, Lob RKS, Stone BF, Thong YH. Evaluation of partially purified salivary gland allergens from the Australian paralysis tick, Ixodes holocyclus, in diagnosis of allergy by RIA and skin prick test. Ann Allergy 1990;64:297-9. Evidence grade: III

32Hoffman DR. Biting-insect allergens. Clin Allergy Immunol 2004;18:355-68. Evidence grade: IV

33Peng Z, Lam H, Cheng XW, Cheen YL, Simons FER. Characterization and clinical relevance of two recombinant mosquito Aedes aegypti salivary allergens rAED a 1 and rAed a 2. J Allergy Clin Immunol 1998;101(suppl):S32. Evidence grade: III

34Peng Z, Yang M, Simons FER. Measurement of mosquito Aedes vexans salivary gland-specific IgE and IgG antibodies and the distribution of these antibodies in human sera. Ann Allergy Asthma Immunol 1995;74:259-64. Evidence grade: III

35Pinnas JL, Chen TMW, Hoffman DR. Evidence of IgE mediation of human sensitivity to reduviid bug bites. Fed Proc 1978;37:1555. Evidence grade: III

36Renula T, Brummer-Korvenkontio H, Palosuo K, et al. Frequent occurrence of IgE and IgG4 antibodies against saliva of Aedes communis and Aedes aegypti mosquitoes in children. Int Arch Allergy Immunol 1994;104:366-71. Evidence grade: III

37Renula T, Brummer-Korvenkontio H, Rasanen L, Francois G, Palosuo T. Passive transfer of cutaneous mosquito-bite hypersensitivity by IgE anti-saliva antibodies. J Allergy Clin Immunol 1994;94:902-6. Evidence grade: III

38Shan EZ, Taniguchi Y, Shimizu M, et al. Immmunoglobulins specific to mosquito salivary gland proteins in the sera of persons with common or hypersensitive reactions to mosquito bites. J Dermatol 1995;22:411-8. Evidence grade: III

39Trudeau WL, Fernandez-Caldas E, Fox RW, Brenner R, Lockey RF. Allergencicity of the cat flea (Ctenocephalides felis felis). Clin Exp Allergy 1993;23:377-83. Evidence grade: III

40Van Wye JE, Hsu Y—P, Lane RS, et al. IgE antibodies in tick bite induced anaphylaxis. J Allergy Clin Immunol 1991;88:968-70. Evidence grade: III

41Hepner M, Ownby D, Anderson J. Risk of severe reactions in patients taking beta blocker drugs receiving allergen immunotherapy injections. J Allergy Clin Immunol 1990;86:407-11. Evidence grade: II

42Hermann K, Ring J. The renin-angiotensin system in patients with repeated anaphylactic reactions during Hymenoptera venom hyposensitization and sting challenge. Int Arch Allergy Immunol 1997;112:251-6. Evidence grade: III

43Simon P, Potier J, Thebaud HE. Risk factors for acute hypersensitivity reactions in hemodialysis. Nephrologie 1996;17:163-70. Evidence grade: III

44Toogood J. Risk of anaphylaxis in patients receiving beta-blocker drug. J Allergy Clin Immunol 1988;81:1-5. Evidence grade: IV

45Golden D, Kagey-Sobotka A, Valentine M. Dose dependence of Hymenoptera venom immunotherapy. J Allergy Clin Immunol 1981;67:370-4. Evidence grade: II

46Rueff F, Wenderoth A, Przybilla B. Patients still reacting to a sting challenge while receiving conventional Hymenoptera venom immunotherapy are protected by increased venom doses. J Allergy Clin Immunol 2001;108:1027-32. Evidence grade: III

47Tracy J, Demain J, Quinn J, Hoffman D, Goetz D, Freeman T. The natural history of exposure to the imported fire ant (Solenopsis invicta). J Allergy Clin Immunol 1995;95:824-8. Evidence grade: II

48Reisman R, Livingston A. Venom immunotherapy: 10 years of experience with administration of single venoms and 50 micrograms maintenance dose. J Allergy Clin Immunol 1992;89:1189-95. Evidence grade: III

49Goldberg A, Confino-Cohen. Maintenance venom immunotherapy administered at 3- month intervals is both safe and efficacious. J Allergy Clin Immunol 2001;107:902-6. Evidence grade: II

50Golden D, Valentine M, Kagey-Sobotka A. Prolonged maintenance interval in Hymenoptera venom immunotherapy. J Allergy Clin Immunol 1981;67:482-4. Evidence grade: II

51Golden D, Kwiterovich K, Kagey-Sobotka A. Discontinuing venom immunotherapy, outcome after five years. J Allergy Clin Immunol 1996;97:579-87. Evidence grade: II

52Golden DBK, Kagey-Sobotka A, Lichtenstein LM. Survey of patients after discontinuing venom immunotherapy. J Allergy Clin Immunol 2000;105:385-90. Evidence grade: III

53Golden DBK, Kwiterovitch KA, Adisson BA, et al. Discontinuing venom immunotherapy: extended observations. J Allergy Clin Immunol 1998;101:298-305. Evidence grade: II

54Graft D, Golden D, Reisman R, Valentin M, Yunginger J. The discontinuation of Hymenoptera venom immunotherapy. J Allergy Clin Immunol 1998;101:573-5. Evidence grade: IV

55Hauguard L, Norregard O, Dahl R. In-hospital sting challenge in insect venom allergic patients after stopping venom immunotherapy. J Allergy Clin Immunol 1991;87:702-9. Evidence grade: III

56Keating M, Kagey-Sobotka A, Hamilton R, Yunginger J. Clinical and immunological follow-up of patients who stop venom immunotherapy. J Allergy Clin Immunol 1991;88:339-48. Evidence grade: III

57Lerch E, Muller U. Long-term protection after stopping immunotherapy. J Allergy Clin Immunol 1998;101:606-12. Evidence grade: II

58Light WC. Insect sting fatality 9 years after venom treatment (venom allergy, fatality). J Allergy Clin Immunol 2001;107:925. Evidence grade: III

59Muller U, Berchrold E, Helbring A. Honeybee venom allergy: results of a sting challenge 1 year after stopping successful immunotherapy in 86 patients. J Allergy Clin Immunol 1991;87:702-9. Evidence grade: II

60The diagnosis and management of anaphylaxis. Joint Task Force on Practice Parameters representing the American Academy of Allergy, Asthma & Immunology, the American College of Allergy, Asthma and Immunology, and the Joint Council on Allergy, Asthma and Immunology. J Allergy Clin Immunol 1998;101(suppl):S465-S528. Evidence grade: IV

61Reisman R. Duration of venom immunotherapy: relationship to the severity of symptoms of initial insect sting anaphylaxis. J Allergy Clin Immunol 1993;92:831-6. Evidence grade: II

62Ross RN, Nelson HS, Finegold I. Effectiveness of specific immunotherapy in the treatment of hymenoptera venom insensitivity: a meta-analysis. Clin Ther 2000;22:351-8. Evidence grade: II

Table XI. Occupational allergic diseases

Referral guideline	Rationale	Evidence type
Workers (1) who anticipate being exposed to an agent or agents to which they are at risk of allergy development or (2) who are presently being exposed to and are at risk for an allergic reaction to an agent, including rhinitis, conjunctivitis, asthma or eczema, should be referred to an allergist-immunologist for assessment to determine whether the worker might be susceptible to rhinitis, asthma, dermatitis, urticaria, or anaphylaxis from the exposure. An example is a worker who will be exposed to latex and has spina bifida, congenital urogenital tract abnormalities, or a worker with a past history suggestive of latex allergy.	Workers with congenital urogenital tract abnormalities, patients with spina bifida, health care workers, and rubber workers have a very high prevalence of latex allergy.¹, ², ³, ⁴, ⁵	Diagnostic
		Indirect outcome (avoidance)
	Workers with an allergy who might not be able to prevent exposure or are prone to accidental exposure should be educated on self-treatment of asthma, rhinitis, urticaria, eczema, and anaphylaxis and have appropriate medications to use to control symptoms and signs. Specifically, if the patient has a history of anaphylaxis, prescribing and educating the patient on the proper use of an EpiPen or similar device for self-administration of epinephrine might be life saving. Allergist-immunologists are specifically trained to educate patients regarding self-treatment of such reactions.⁶

Workers in whom the cause of occupationally induced lung disease, including asthma or hypersensitivity pneumonitis, skin disease, or upper respiratory disease, such as rhinitis or conjunctivitis, is unable to be determined on the basis of history alone, or objective evidence is necessary to confirm cause and effect between exposure and disease.	Skin testing and RAST testing often can identify the cause of a hypersensitivity reaction.⁷	Diagnostic
		Indirect outcome (avoidance)
	Continued exposure to an allergen might result in progressive lung volume loss, which could be irreversible.⁸
	In most cases avoidance of the identified agent is the optimal treatment for occupational diseases.⁹
	Correlation of the history with the results of IgE testing helps prevent inappropriate avoidance, which might be suggested by RASTs alone.¹⁰ ¹¹ In cases in which the cause cannot be isolated adequately on the basis of history, skin tests, or RASTs, inhalation challenge, which is the gold standard, can be arranged to provide objective evidence of a hypersensitivity reaction.¹²

Workers with occupationally induced rhinoconjunctivitis	Workers with rhinoconjunctivitis are at an increased risk of asthma. Early avoidance might decrease the risk of further respiratory disease.¹³ By means of history, skin tests, and/or RASTs and correlating the history and objective findings, the causative agent can often be identified, allowing appropriate avoidance and preventing possible loss of occupation or serious lung disease.¹⁴ Prognosis of occupationally induced respiratory disease is dependent on the extent and duration of exposure.¹⁵	Diagnostic
Workers with occupationally induced rhinoconjunctivitis		Indirect outcome (avoidance)

Referral to an allergist-immunologist for career counseling should be considered for adolescents with allergic disease who might be considering careers with exposure to animals or other allergens.	On the basis of history and relevant studies, allergist-immunologists can assess the future relative risks of such patients in the workplace.⁷ ¹⁶ These individuals can then be aware of any degree of increased risk of sensitization and be able to modify career plans with suitable advice.	Indirect outcome (avoidance)

Workers in occupations with animal exposure who experience rash, upper respiratory tract symptoms, eye symptoms, or lung symptoms	Upper respiratory and lower respiratory tract, skin, and eye symptoms might be due to allergic sensitization to the animals. Allergy testing can confirm sensitization and lead to appropriate interventions.¹⁶	Diagnostic
		Indirect outcome (avoidance)

Persons with occupational exposure to food proteins and chronic skin symptoms, respiratory symptoms, or both, attributable to the work environment	Occupational disease might be related to exposure to food proteins, such as wheat (“Baker's” asthma), or food handling (contact urticaria, contact dermatitis) that is diagnosed through modalities available to the allergist-immunologist.⁷ Avoidance is the treatment of choice.¹⁷ ¹⁸	Diagnostic
		Indirect outcome (avoidance)

REFERENCES

1Yassin MS, Sanyura S, Lierl MB, et al. Evaluation of latex allergy inpatients with meningomyelocele. Ann Allergy 1992;69:207-11. Evidence grade: III

2Liss GM, Sussman GL, Deal K, et al. Latex allergy: epidemiological study of 1351 hospital workers. Occup Environ Med 1997;54:335-42. Evidence grade: III

3Wartenberg D. Invited commentary: assessing latex allergy using data from HNANES III. Am J Epidemiol 2001;153:523. Evidence grade: IV

4Rueff F, Kienitz A, Schopf P, et al. Frequency of natural rubber allergy in adults is increased after multiple operative procedures. Allergy 2001;56:889-94. Evidence grade: III

5Tarlo SM, Easty A, Eubanks K, et al. Outcomes of a natural rubber latex control program in an Ontario teaching hospital. J Allergy Clin Immunol 2001;108:628-33. Evidence grade: III

6Hamilton RG, Adkinson NF Jr. Diagnosis of natural rubber latex allergy: multicenter latex skin testing efficacy study. J Allergy Clin Immunol 1998;102:482-90. Evidence grade: III

8Perfetti L, Cartier A, Ghezzo H, Gautrin D, Malo JL. Follow-up of occupational asthma after removal from or diminution of exposure to the responsible agent. Chest 1998;114:398-403. Evidence grade: III

9Vedal S, Chan-Yeung M, Enarson D, et al. Symptoms and pulmonary function in western red cedar workers related to duration of employment and dust exposure. Arch Environ Health 1986;41:179-183. Evidence grade: III

10Bernstein JA, Bernstein DI, Stauder T, Lummus Z, Bernstein IL. A cross sectional survey of sensitization to Aspergillus oryzae derived lactose in pharmaceutical workers. J Allergy Clin Immunol 1999;103:1153-7. Evidence grade: III

11Chan-Yeung M, Malo JL. Occupational asthma. N Engl J Med 1995;333:107. Evidence grade: IV

12Vandenplas O, Malo JL. Inhalation challenge with agents causing occupational asthma. Eur Respir J 1997;10:2612-29. Evidence grade: IV

13Malo JL, Lemiere C, Desjardins A, Cartier A. Prevalence and intensity of rhino-conjunctivitis in subjects with occupational induced asthma. Eur Respir J 1997;10:1513-5. Evidence grade: III

14Rodier F, Gautrin D, Ghezzo H, Malo JL. Incidence of occupational rhinoconjunctivitis and risk factors in animal-health apprentices. J Allergy Clin Immunol 2003;112:1105-11. Evidence grade: III

15Nguyen B, Ghezzo H, Malo, JL, Gautrin D. Time course of onset of sensitization to common and occupational inhalants in apprentices. J Allergy Clin Immunol 2003;111:807-12. Evidence grade: III

16Sjostedt L, Willers S. Predisposing factors in laboratory animal allergy: a study of atopy and environmental factors. Am J Ind Med 1989;16:199-208. Evidence grade: III

17Carmona JGB, Picon SJ, Sotillos MG, Gaston PR. Occupational asthma in the confectionary industry caused by sensitivity to egg. Allergy 1992;47:190-1. Evidence grade: III

18Thiel H, Ulmer W. Baker's asthma: development and possibility for treatment. Chest 1980;78:400-5. Evidence grade: III

Table XII. Primary immune deficiency

Referral guideline	Rationale	Evidence type
Any of the following warning signs:	Frequent infection, unusual infections, or unusual complications of usual infections are the most frequent presentation of immune deficiency.¹, ², ³, ⁴, ⁵, ⁶, ⁷ Advanced diagnostic strategies are necessary to ensure appropriate diagnosis and treatment.¹ ⁶, ⁷, ⁸ Allergist-immunologists are trained to diagnose and treat primary immunodeficiency.⁹	Diagnostic
•8 or more new infections within 1 year;
•2 or more serious sinus infections within 1 year;
•2 or more months on antibiotics with little or no effect;
•2 or more pneumonias within 1 year;	Immunologic therapy improves immunity,¹⁰ ¹¹ reduces infections,¹², ¹³, ¹⁴ improves organ function,¹⁵ prevents complications,¹ improves quality of life,¹⁶ and might be curative¹⁷ ¹⁸ in patients with primary immune deficiencies.	Indirect outcome (immunologic therapy)
•failure of an infant to gain weight or grow normally;
•recurrent deep skin or organ abscesses;
•persistent thrush in the mouth or elsewhere on skin after age 1 year;
•need for intravenous antibiotics to clear infections;
•2 or more deep-seated infections;
•a family history of immune deficiency

REFERENCES

1Practice parameter for the diagnosis and management of primary immunodeficiency. Joint Task Force on Practice Parameters representing the American Academy of Allergy, Asthma & Immunology, the American College of Allergy, Asthma and Immunology, and the Joint Council on Allergy, Asthma and Immunology. Ann Allergy 2005;94(suppl):S1-S62. Evidence grade: IV

2Ballow M. Primary immunodeficiency disorders: antibody deficiency. J Allergy Clin Immunol 2002;109:581-91. Evidence grade: IV

3Buckley RH. Primary cellular immunodeficiencies. J Allergy Clin Immunol 2002;109:747-57. Evidence grade: IV

4International Union of Immunological Societies. Primary immunodeficiency diseases. Report of an IUIS Scientific Committee. Clin Exp Immunol 1999;118(suppl 1):1-28. Evidence grade: IV

5Arnaiz-Villena A, Rodriguez-Gallego C, Timon M et al. Diseases involving the T-cell receptor/Cd3 complex. Crit Rev Oncol Hematol 1995;19:131-47. Evidence grade: IV

6Champi C. Primary immunodeficiency disorders in children: prompt diagnosis can lead to lifesaving treatment. J Pediatr Health Care 2002;16:16-21. Evidence grade: IV

7Fleisher TA. Evaluation of the potentially immunodeficient patient. Adv Intern Med 1996;41:1-30. Evidence grade: IV

8Wasserman RL, Sorensen RU. Evaluating children with respiratory tract infections: the role of immunization with bacterial polysaccharide vaccine. Pediatr Infect Dis J 1999;18:157-63. Evidence grade: III

9Core Curriculum Subcommittee of the Training Program Directors; American Academy of Allergy, Asthma and Immunology. Allergy and immunology core curriculum outline 1996. J Allergy Clin Immunol 1996;98:1012-5. 2002 update available at: http://www.aaaai.org/professionals/careers/training_programs.stm. Evidence grade: IV

10Hershfield MS. PEG-ADA replacement therapy for adenosine deaminase deficiency: an update after 8.5 years. Clin Immunol Immunopathol 1995;76(suppl):S228-S232. Evidence grade: III

11Cunningham-Rundles C, Bodian C, Ochs HD, et al. Long-term low-dose IL-2 enhances immune function in common variable immunodeficiency. Clin Immunol 2001;100:181-90. Evidence grade: II

12Nydahl-Persson K, Petterson A, Fasth A. A prospective, double-blind, placebo-controlled trial of i.v. immunoglobulin and trimethoprim-sulfamethoxazole in children with recurrent respiratory tract infections. Acta Paediatr 1995;84:1007-9. Evidence grade: Ib

13Gallin JI, Alling, DW, Malech HL, et al. Itraconazole to prevent fungal infections in chronic granulomatous disease. N Engl J Med 2003;348:2416-22. Evidence grade: Ib

14Busse PJ, Razvi S, Cunningham-Rundles C. Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeficiency. J Allergy Clin Immunol 2002;109:1001-4. Evidence grade: III

15de Gracia JM, Vendrell, A, Alvarez E, et al. Immunoglobulin therapy to control lung damage in patients with common variable immunodeficiency. Int Immunopharmacol 2004;4:745-53. Evidence grade: II

16Gardulf A, Nicolay U, Math D, et al. Children and adults with primary antibody deficiencies gain quality of life by subcutaneous IgG self-infusions at home. J Allergy Clin Immunol 2004;114:936-42. Evidence grade: II

17Horwitz ME, Barrett AJ, Brown MR, et al. Treatment of chronic granulomatous disease with nonmyeloablative conditioning and a T-cell-depleted hematopoietic allograft. N Engl J Med 2001;344:881-8. Evidence grade: II

18Buckley RH, Schiff SE, Schiff RI, et al. Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med 1999;340:508-16. Evidence grade: III

Table XIII, A. Rhinitis

Referral guideline	Rationale	Evidence type
Patients with prolonged or severe manifestations of rhinitis with comorbid conditions (eg, asthma or recurrent sinusitis); with symptoms interfering with quality of life, ability to function, or both; or who have found medications to be ineffective or have had adverse reactions to medications¹, ², ³	Allergist-immunologist care for rhinitis is associated with improved quality of life, compliance, and satisfaction with care.⁴ ⁵	Direct outcome
	Allergy cannot be diagnosed on the basis of history alone.⁶ Allergist-immunologists are highly trained to interpret the clinical history and allergy diagnostic test results in both upper and lower airway conditions.⁷	Diagnostic
	Allergist-immunologists have familiarity with the wide variety of both indoor and outdoor aeroallergen exposures that have been shown to affect the upper respiratory tree and have the expertise to provide avoidance education.⁷	Indirect outcome (avoidance)
	Allergen immunotherapy can be highly effective in controlling the symptoms of allergic rhinitis.⁸ Allergen immunotherapy might provide lasting benefits after immunotherapy is discontinued.⁹	Indirect outcome (immunotherapy)

Patients with nasal polyps	Allergist-immunologists are specifically trained and experienced in the medical management of nasal polyps, including intranasal steroids, oral steroids, and treatment of complicating sinusitis¹ ⁷	Indirect outcome (pharmacologic therapy)

In addition to the above guidelines, consider referral of the child with allergic rhinitis because of the potential preventive role of allergen immunotherapy in progression of allergic disease.	Allergen immunotherapy has been shown to reduce development of new sensitizations and asthma in children with allergic rhinitis compared with children with allergic rhinitis treated with medication alone.¹⁰	Indirect outcome (immunotherapy)

REFERENCES

1Diagnosis and management of rhinitis: parameter documents. Joint Task Force on Practice Parameters representing the American Academy of Allergy, Asthma & Immunology, the American College of Allergy, Asthma and Immunology, and the Joint Council on Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol 1998;81(suppl):478-518. Evidence grade: IV

2Practice parameters for allergen immunotherapy. Joint Task Force on Practice Parameters representing the American Academy of Allergy, Asthma & Immunology, the American College of Allergy, Asthma and Immunology and the Joint Council on Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol 2003;90(suppl):S1-S40. Evidence grade: IV

3Bousquet J, van Cauwenberge P, Khaltaev N. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 2001;108:S147-334. Evidence grade: IV

4Demoly P, Allaert FA, Lecasble M, PRAGMA. ERASM, a pharmacoepidemiologic survey on management of intermittent allergic rhinitis in every day general medical practice in France. Allergy 2002;57:546-54. Evidence grade: III

5Bagenstose SF, Bernstein JA. Treatment of chronic rhinitis by an allergy specialist improves quality of life outcomes. Ann Allergy Asthma Immunol 1999;83:524-8. Evidence grade: III

6Williams PB, Ahlstedt S, Barnes JH, Soderstrom L, Portnoy J. Are our impressions of allergy test performances correct? Ann Allergy Asthma Immunol 2003;91:26-33. Evidence grade: III

8Bousquet J, Lockey R, Malling HJ. Allergen immunotherapy: therapeutic vaccines for allergic diseases. A WHO position paper. J Allergy Clin Immunol 1998;102:558-62. Evidence grade: IV

9Durham SR, Walker SM, Varga EM, et al. Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med 1999;341:468-75. Evidence grade: Ib

10Moller C, Dreborg S, Ferdousi HA, et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT study). J Allergy Clin Immunol 2002;109:251-6. Evidence grade: Ib

Table XIII, B. Sinusitis

Referral guideline	Rationale	Evidence type
Patients with chronic rhinosinusitis of any type	This set of conditions related to chronic inflammation of the sinus and contiguous nasal mucosa often coexists with allergic rhinitis.¹ Allergist-immunologist care is associated with improved outcomes.²	Direct outcome
	Allergy immunotherapy is demonstrated to improve outcomes in patients with concomitant allergic rhinitis.³	Indirect outcome (immunotherapy)

Patients with chronic or recurrent infectious rhinosinusitis	Many patients with this condition have humoral immunodeficiency, cystic fibrosis, fungal sinusitis, or granulomatous diseases.¹ Allergist-immunologists are trained in the evaluation and management of these disorders.⁴	Diagnostic
		Indirect outcome (avoidance, pharmacologic, and immunologic therapy)

Patients with chronic eosinophilic rhinosinusitis	This is a chronic inflammatory disease with characteristics of allergic inflammation.¹ It often coexists with aspirin sensitivity, asthma, and sinus-nasal polyposis.⁵ ⁶ Allergist-immunologists are experts in allergic inflammation and can evaluate and treat both environmental allergy and aspirin sensitivity.⁴	Diagnostic
Patients with chronic eosinophilic rhinosinusitis		Indirect outcome (avoidance, pharmacologic, and immunologic therapy)

Patients with allergic fungal rhinosinusitis	This is a chronic inflammatory disease with characteristics of IgE and eosinophilic inflammatory response to fungi in sinuses.⁷ ⁸ Evaluation involves allergy skin testing and other laboratory testing.⁹ Management involves medical management, allergen immunotherapy, and surgery.⁹ ¹⁰ Allergist-immunologists are experts in the evaluation and management of allergic diseases, including allergy immunotherapy.⁴	Diagnostic
Patients with allergic fungal rhinosinusitis		Indirect outcome (pharmacotherapy, immunotherapy)

REFERENCES

1Steinke JW, Borish L. The role of allergy in chronic rhinosinusitis. Immunol Allergy Clin North Am 2004;24:45-57. Evidence grade: IV

2McNally PA, White MV, Kaliner MA. Sinusitis in an allergist's office: analysis of 200 consecutive cases. Allergy Asthma Proc 1997;18:169-75. Evidence grade: III

3Nathan RA, Santilli J, Rockwell W, Glassheim J. Effectiveness of immunotherapy for recurring sinusitis associated with allergic rhinitis as assessed by the Sinusitis Outcomes Questionnaire. Ann Allergy Asthma Immunol 2004;92:668-72. Evidence grade: III

4Core Curriculum Subcommittee of the Training Program Directors; American Academy of Allergy, Asthma and Immunology. Allergy and immunology core curriculum outline 1996. J Allergy Clin Immunol 1996;98:1012-5. 2002 update available at: http://www.aaaai.org/professionals/careers/training_programs.stm. Evidence grade: IV

5Borish L. Sinusitis and asthma: entering the realm of evidence-based medicine. J Allergy Clin Immunol 2002;109:606-8. Evidence grade: IV

6Szczeklik A, Stevenson DD. Aspirin-induced asthma: advances in pathogenesis, diagnosis, and management. J Allergy Clin Immunol 2003;111:913-21. Evidence grade: IV

7Schubert MS. Allergic fungal sinusitis: pathogenesis and management strategies. Drugs 2004;64:363-74. Evidence grade: IV

8Schubert MS, Goetz DW. Evaluation and treatment of allergic fungal sinusitis. I. Demographics and diagnosis. J Allergy Clin Immunol 1998;102:387-94. Evidence grade: IV

9Schubert MS, Goetz DW. Evaluation and treatment of allergic fungal sinusitis. II. Treatment and follow-up. J Allergy Clin Immunol 1998;102:395-402. Evidence grade: IV

10Mabry RL, Marple, BF, Folker RJ, Mabry CS. Immunotherapy for allergic fungal sinusitis: three years’ experience. Otolaryngol Head Neck Surg 1998;119:648-51. Evidence grade: III

Table XIV. Urticaria and angioedema (see also “Anaphylaxis” [Table II]), “Drug allergy” [Table VII], and “Food allergy” [Table VIII])

Referral guideline	Rationale	Evidence type
Patients with acute urticaria or angioedema without an obvious or previously defined trigger	After a severe allergic reaction without a known cause, a trigger should be identified, if at all possible.¹ An allergist-immunologist is the most appropriate medical professional to perform this evaluation,² which might include a detailed history, physical examination, skin testing, in vitro testing, and challenges when indicated.	Diagnostic
	Future avoidance of the identified triggers should prevent subsequent anaphylactic episodes.	Indirect outcome (avoidance)

Patients with acute urticaria or angioedema caused by a presumed food or drug with need for diagnostic confirmation or assistance with avoidance procedures	See “Food allergy” (Table VIII) and “Drug allergy” (Table VII)	Diagnostic
		Indirect outcome (avoidance)

Patients with chronic urticaria or angioedema (ie, those with lesions recurring persistently over a period of 6 weeks or more)	Allergists and dermatologists have more expertise in caring for patients with urticaria than other specialists.³ Chronic urticaria often has an autoimmune pathogenesis.⁴ Consultation with an allergist-immunologist would include (1) reviewing possible causative factors (medications, supplements, dietary factors, animal exposures, and physical factors), (2) possible skin testing, (3) possible physical challenges, (4) recommended changes in ingestants or contactants, and (5) optimal pharmacotherapy.¹, ², ³, ⁴, ⁵, ⁶, ⁷, ⁸ Allergy-immunology specialists are also knowledgeable of the minimal benefit of multiple laboratory tests in urticaria with an otherwise normal examination.¹, ², ³	Diagnostic
		Indirect outcome (avoidance, pharmacotherapy)

Patients who might have urticarial vasculitis or urticaria with systemic disease (vasculidities, connective tissue disease, rarely malignancies):	Allergist-immunologist training and expertise should allow appropriate differential diagnosis, determination of the need for biopsy, elimination of a specific inciting agent, and optimal pharmacotherapy.² ⁵ ⁹ ¹⁰	Diagnostic
		Indirect outcome (avoidance, pharmacotherapy)
a. Lesions last more than 24 hours; leave ecchymotic, purpuric, or hyperpigmented residua on or under the skin; or are associated with pain or burning
b. Patients who have typical urticaria-angioedema but have signs and symptoms suggestive of systemic illness
c. Patients whose symptom control requires regular steroid use

Patients with chronically recurring angioedema without urticaria	Such patients might have hereditary or acquired angioedema, paraproteinemia, or B-cell malignancies. Allergist-immunologist expertise should allow optimal differential diagnosis, determination of the need for hematology-oncology evaluation, and pharmacologic therapy of hereditary or acquired angioedema caused by C1 esterase inhibitor deficiency.¹¹, ¹², ¹³	Diagnostic
		Indirect outcome (pharmacotherapy)

Patients with suspected or proved cutaneous or systemic mastocytosis	Allergist-immunologists are trained to diagnose and treat this disease.² ¹⁴, ¹⁵, ¹⁶	Diagnostic
		Indirect outcome (pharmacotherapy)

REFERENCES

1Joint Task Force on Practice Parameters. The diagnosis and management of urticaria: a practice parameter part I: acute urticaria/angioedema part II: chronic urticaria/angioedema. Ann Allergy Asthma Immunol 2000;85(suppl):521-44. Evidence grade: IV

3Henderson RL Jr, Fleischer AB Jr, Feldman SR. Allergists and dermatologists have far more expertise in caring for patients with urticaria than other specialists. J Am Acad Dermatol 2000;43:1084-91. Evidence grade: III

4Kaplan AP. Chronic urticaria: pathogenesis and treatment. J Allergy Clin Immunol 2004;114:465-74. Evidence grade: IV

5Dibbern DA, Dreskin SC. Urticaria and angioedema: an overview. Immunol Allergy Clin North Am 2004;24:141-62. Evidence grade: IV

6Finn AF Jr, Kaplan AP, Fretwell R, Qu R, Long J. A double-blind, placebo-controlled trial of fexofenadine HCI in the treatment of chronic idiopathic urticaria. J Allergy Clin Immunol 1999;104:1071-8. Evidence grade: Ib

7Kalivas J, Breneman D, Tharp M, Bruce S, Bigby M. Urticaria: clinical efficacy of cetirizine in comparison with hydroxyzine and placebo. J Allergy Clin Immunol 1990;86:1014-8. Evidence grade: Ib

8Greene SL, Reed CE, Schroeter AL. Double-blind crossover study comparing doxepin with diphenhydramine for the treatment of chronic urticaria. J Am Acad Dermatol 1985;12:669-75. Evidence grade: Ib

9Davis MD, Brewer JD. Urticarial vasculitis and hypocomplementemic urticarial vasculitis. Immunol Allergy Clin North Am 2004;24:183-213. Evidence grade: IV

10Mehregan DR, Hall MJ, Gibson LE. Urticarial vasculitis: a histopathologic and clinical review of 72 cases. J Am Acad Dermatol 1992;26:441-8. Evidence grade: III

11Cicardi M, Zingale LC, Pappalardo E, Folcione A, Agostoni A. Autobodies and lymphoproliferative diseases in acquired C1 inhibitor deficiencies. Medicine (Baltimore) 2003;82:274-81. Evidence grade: III

12Agostoni A, Aygoren-Pursun E, Binkley K, et al. Hereditary and acquired angioedema: Problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol 2004;114(suppl):S51-S131. Evidence grade: IV

13Gelfand JA, Sherins RJ, Alling DW, Frank MM. Treatment of hereditary angioedema with danazol. Reversal of clinical and biochemical abnormalities. N Engl J Med 1976;295:1444-8. Evidence grade: Ib

14Brockow, K. Urticaria pigmentosa. Immunol Allergy Clin North Am 2004;24:287-316. Evidence grade: IV

15Akin C, Metcalfe DD. Systemic mastocytosis. Annu Rev Med 2004;55:419-32. Evidence grade: IV

16Valent P, Sperr WR, Schwartz LB, Horny HP. Diagnosis and classification of mast cell proliferative disorders: delineation from immunologic diseases and non-mast cell hematopoietic neoplasms. J Allergy Clin Immunol 2004;114:3-12. Evidence grade: IV

Back to Article Outline

Guide to the tables

1.Allergic bronchopulmonary aspergillosis

2.Anaphylaxis (systemic allergic reaction)

3.Asthma

A.Asthma diagnosis

B.Environmental diagnosis and management

C.Asthma treatment: immunotherapy

D.Asthma treatment: prevention of morbidity

E.Asthma treatment: prevention of mortality

F.Asthma treatment: adherence

G.Occupational asthma

4.Conjunctivitis

5.Cough

6.Dermatitis

A.Atopic

B.Contact

7.Drug allergy

8.Food allergy

9.Hypersensitivity pneumonitis

10.Insect hypersensitivity

11.Occupational allergic diseases

12.Primary immune deficiency

13.Rhinitis-rhinosinusitis

A.Rhinitis

B.Sinusitis

14.Urticaria-angioedema

Back to Article Outline

Contributors

Guest Editors

Donald Leung, MD, PhD

Department of Pediatrics

National Jewish Medical and Research Center

Denver, Colo

Michael Schatz, MD, MS

Department of Allergy

Kaiser Permanente

San Diego, California

The following individuals have contributed to the development and review of the consultation and referral guidelines:

Allen Adinoff, MD, Rhinosinusitis Committee

Cem Akin, MD, Anaphylaxis Committee

Jintanat Ananworanich, MD, HIV Committee

Andrea Apter, MD, Adherence Committee

Jose Arias, Jr, MD, Insect Allergy Committee

Amal Assa'ad, MD, Adverse Reactions to Foods Committee

Hyacinth Bacchus, NP, Adherence Committee

Leonard Bacharier, MD, Pharmacotherapeutics Committee

Christopher Baliga, MD, HIV Committee

Mark Ballow, MD, Primary Immune Deficiency Committee

Charles Barnes, PhD, Aerobiology Committee

Olga Belostotsky, MD, PhD, Autoimmunity Committee

Bruce Bender, PhD, Adherence Committee

Jonathan Bernstein, MD, Occupational Diseases Committee

Leonard Bielory, MD, Aerobiology Committee

R. Matthew Bloebaum, MD, HIV Committee

Vincent Bonagura, MD, HIV Committee

S. Allan Bock, MD, Anaphylaxis Committee

Sergio Bonini, MD, Immuno-Ophthalmology Committee

John Brannan, PhD, Asthma Diagnosis Committee

Robert Bush, MD, Allergic Bronchopulmonary Aspergillosis (ABPA) Committee

Carlos Camargo, Jr, MD, DrPH, Asthma Mortality Committee

Deborah Cesarone, RN, Adherence Committee

Ernest Charlesworth, MD, Eczema/Atopic Dermatitis Committee

Donald Cockcroft, MD, Asthma Diagnosis Committee

Leslie Coleman, MD, Insect Allergy Committee

Monroe Coleman, MD, Insect Allergy Committee

Linda Cox, MD, Immunotherapy and Allergy Diagnostics Committee

Timothy Craig, DO, Occupational Diseases Committee

Carla Davis, MD, HIV Committee

Jeffrey Demain, MD, Insect Allergy Committee

Chitra Dinakar, MD, Adherence Committee

Stephen Dreskin, MD, PhD, Urticaria and Angioedema Committee

Peyton Eggleston, MD, Indoor Allergen Committee

Yehia El-Gamal, MD, PhD, HIV Committee

Renata Engler, MD, Insect Allergy Committee

Reza Farid, MD, Insect Allergy Committee

Warren Filley, MD, Aerobiology Committee

Luz Fonacier, MD, Eczema/Atopic Dermatitis Committee

Theodore Freeman, MD, Insect Allergy Committee

Marianne Frieri, MD, PhD, Autoimmunity Committee

Arnon Goldberg, MD, Insect Allergy Committee

David Golden, MD, Insect Allergy Committee

Alan Goldsobel, MD, Rhinosinusitis Committee and Cough Task Force

David Graft, MD, Insect Allergy Committee

Frank Graziano, MD PhD, HIV Committee

George Green, MD, Adherence Committee

Leonardo Greiding, MD, Asthma Diagnosis Committee

Sudhir Gupta, MD PhD, HIV Committee

Miles Guralnick, Insect Allergy Committee

Robert Hamilton, PhD, Insect Allergy Committee

Zeev Handzel, MD, HIV Committee

Frederick Hargreave, MD, Asthma Diagnosis Committee

Pia Hauk, MD, Insect Allergy Committee

Vivian Hernandez-Trujillo, MD, Anaphylaxis Committee

Donald Hoffman, PhD, Insect Allergy Committee

Russell Hopp, DO, Asthma Diagnosis Committee

Elliot Israel, MD, Pharmacotherapeutics Committee

Carol Jones, RN, AE-C, Adherence Committee

Christine Joseph, PhD, Adherence Committee

Sunil Joshi, MD, Insect Allergy Committee

Lynda Kabbash, MD, Insect Allergy Committee

Steven Kagen, MD, Insect Allergy Committee

Andrea Keane-Myers, PhD, Immuno-Ophthalmology Committee

Pramod Kelkar, MD, Cough Task Force

Kevin Kelly, MD, Latex Allergy Committee

James Kemp,MD, Adherence Committee

Stephen Kemp, MD, Anaphylaxis Committee

Lisa Kobrynski, MD, Adherence Committee

David Lang, MD, Asthma Mortality Committee

Tao Tuan Le, MD, Adherence Committee

Francesca Levi-Schaffer, PhD, Pharmacotherapeutics Committee

Macy Levine, MD, Insect Allergy Committee

Jerome Listernick, MD, Insect Allergy Committee

Eric M. Macy, MD, Adverse Reactions to Drugs and Biologicals Committee

Shailee Madhok, MD, HIV Committee

Theron McCormick, MD, HIV Committee

Louis Mendelson, MD, Immunotherapy and Allergy Diagnostics Committee

Henry Milgrom, MD, Adherence Committee

John Moffitt, MD, Insect Allergy Committee

Elsie Morris, MD, Occupational Diseases Committee

Anne Munoz-Furlong, MA, Anaphylaxis Committee

Ramasamy Muthiah, PhD, Insect Allergy Committee

Christian Nageotte, MD, Insect Allergy Committee

Robert Nathan, MD, Adherence Committee

Michael Nelson, MD, PhD, Insect Allergy Committee

Lenora Noroski, MD, HIV Committee

Jordan Orange, MD, PhD, Primary Immune Deficiency Committee

Nancy Ostrom, MD, Pharmacotherapeutics Committee

Susan Pacheco, MD, HIV Committee

Savita Pahwa, MBBS, HIV Committee

Mary Paul, MD, HIV Committee

Wanda Phipatanakul, MD, MS, Indoor Allergen Committee

Jacob Pinnas, MD, Pharmacotherapeutics Committee

Riccardo Polosa, MD, PhD, Asthma Diagnosis Committee

James Quinn, MD, Insect Allergy Committee

Christopher Randolph, MD, Sports Medicine Committee

Robert Reisman, MD, Insect Allergy Committee

Clement Ren, MD, Pharmacotherapeutics Committee

Richard Rosenthal, MD, Asthma Diagnosis Committee

Donald Russell, MD, Urticaria and Angioedema Committee

Hugh Sampson, MD, Anaphylaxis Committee

Mark Sands, MD, Asthma Diagnosis Committee

Howard Schwartz, MD, Insect Allergy Committee

Elizabeth Secord, MD, Primary Immune Deficiency Committee and HIV Committee

Scott Sicherer, MD, Adverse Reactions to Foods Committee and Anaphylaxis Committee

Raymond Slavin, MD, MS, Allergic Bronchopulmonary Aspergillosis (ABPA) Committee

Brian Smart, MD, Rhinosinusitis Committee

Roland Solensky, MD, Adverse Reactions to Drugs and Biologicals Committee

Maria Soto-Aguilar, MD, Autoimmunity Committee

Jonathan Spergel, MD, PhD, Eczema/Atopic Dermatitis Committee

Gordon Sussman, MD, Anaphylaxis Committee

Michael Tankersley, MD, Cough Task Force

Susan Tarlo, MD, BS, Occupational Diseases Committee

Clifford Tepper, MD, Insect Allergy Committee

Abba Terr, MD, HIV Committee

Suzanne Teuber, MD, Adverse Reactions to Foods Committee

Stanislaus Ting, MD, Adherence Committee

Stuart Tousman, PhD, Adherence Committee

Robert Townley, MD, Asthma Diagnosis Committee

James Tracy, DO, Insect Allergy Committee

Richard Wasserman, MD, PhD, Primary Immune Deficiency Committee

Richard Weber, MD, Aerobiology Committee

Andrew Weinstein, MD, Adherence Committee and Pharmacotherapeutics Committee

Paul Williams, MD, Pharmacotherapeutics Committee

Robert Wood, MD, Indoor Allergen Committee

Osman Yusuf, MD, MCPS, MSc, Adherence Committee

Michael Zacharisen, MD, Occupational Diseases Committee

Back to Article Outline

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Disclosure of potential conflict of interest: M. Schatz has received grants from GlaxoSmithKline and Sanofi-Aventis and is on the speakers’ bureau for AstraZeneca and Merck. D. Leung—none disclosed.Reprint requests: Lauri Sweetman, American Academy of Allergy, Asthma and Immunology, 611 E Wells St, Milwaukee, WI 53202. E-mail: lsweetman@aaaai.org.

PII: S0091-6749(05)02579-0

doi:10.1016/j.jaci.2005.10.047

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