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Anaphylaxis—a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis

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Anaphylaxis is an acute, potential life-threatening systemic allergic reaction that may have a wide range of clinical manifestations. Severe anaphylaxis and/or the need for repeated doses of epinephrine to treat anaphylaxis are risk factors for biphasic anaphylaxis. Antihistamines and/or glucocorticoids are not reliable interventions to prevent biphasic anaphylaxis, although evidence supports a role for antihistamine and/or glucocorticoid premedication in specific chemotherapy protocols and rush aeroallergen immunotherapy. Evidence is lacking to support the role of antihistamines and/or glucocorticoid routine premedication in patients receiving low- or iso-osmolar contrast material to prevent recurrent radiocontrast media anaphylaxis. Epinephrine is the first-line pharmacotherapy for uniphasic and/or biphasic anaphylaxis. After diagnosis and treatment of anaphylaxis, all patients should be kept under observation until symptoms have fully resolved. All patients with anaphylaxis should receive education on anaphylaxis and risk of recurrence, trigger avoidance, self-injectable epinephrine education, referral to an allergist, and be educated about thresholds for further care.

Section snippets

Executive Summary

Anaphylaxis is an acute, life-threatening systemic allergic reaction that may have a wide range of clinical manifestations.1 The clinical criteria proposed in 2006 by National Institute of Allergy and Infectious Diseases (NIAID) continue to provide a helpful framework in approaching patients with acute allergic symptoms, because diagnosis and management of anaphylaxis must occur rapidly and confirmatory testing for anaphylaxis has poor sensitivity.2 While NIAID anaphylaxis diagnostic criteria

Introduction to and diagnosis of anaphylaxis

Anaphylaxis is an acute, life-threatening systemic allergic reaction associated with different mechanisms, triggers, clinical presentations, and severity.1 The wide range of clinical manifestations and complex underlying mechanisms of anaphylaxis contribute to the difficulty in establishing a definition and diagnostic criteria for anaphylaxis. The poor sensitivity of confirmatory laboratory testing further complicates accurate diagnosis of anaphylaxis. Furthermore, a lack of use of established

Epidemiology and risk factors

Prevalence estimates of anaphylaxis vary widely, and many studies suggest that the prevalence is increasing, particularly in developed countries. The lifetime prevalence of anaphylaxis has been estimated at 1.6% to 5.1%,1,4,11 with an incidence rate of 42 per 100,000 person-years, but estimates may be susceptible to ascertainment bias.59 Data from a European anaphylaxis registry revealed that over one-quarter of cases occurs in patients under 18 years of age.60 As indicated in an international

Prevalence

Food allergy (or presumed food allergy) is a leading cause of anaphylaxis presenting to US EDs, with an estimated 30,000 cases per year.96 Food allergy (assessed through a nationally representative Internet self-report study) is estimated to affect up to 8% to 11% of the US population.13, 14, 15 Food allergens may be attributed to upward of 50% of ED-reported anaphylaxis cases in developed countries, including the United States.97

Trends

According to the Centers for Disease Control and Prevention,

Pathogenesis of anaphylaxis

Data regarding pathophysiologic mechanisms and effector cells are limited on humans but mouse models have offered some insight.118 IgE binding and cross-linking of FcεRI on the surface of mast cells and basophils is an important mechanism in many cases of anaphylaxis. This causes the immediate release of preformed mediators, as well as de novo synthesis of inflammatory mediators.18 Interestingly, some patients with life-threatening anaphylaxis have low or undetectable circulating

Role of epinephrine

An understanding of the pathophysiology and effector cells involved in anaphylaxis reinforces the recommendation to use epinephrine as first-line treatment, while antihistamines and glucocorticoids are considered solely second-line therapy. Anaphylaxis is a clinical diagnosis that can present with any combination of symptoms affecting various organ systems.22 The clinical presentation and severity of symptoms differ among individuals and may change over time within the same individual.

There is

Review of evidence for supplemental therapies in anaphylaxis treatment

Despite a lack of clear evidence supporting the use of antihistamines and glucocorticoids in anaphylaxis, these treatments continue to be a part of anaphylaxis management in routine practice. While it is critical to ensure that use of these agents does not delay administration of epinephrine, the question of whether use of these therapies adds value in the management of anaphylaxis has not been subjected to rigorous methodologic assessment in previous anaphylaxis practice parameters. To

GRADE: From certainty of evidence to recommendations for diagnosis, treatment, or course of action

The strength of a recommendation indicates the extent to which one can be confident that adherence to the recommendation will do more good than harm. After the certainty of evidence is evaluated, and before recommending or suggesting in favor or against a certain diagnostic strategy, therapeutic approach, or course of action, the GRADE analysis continues to consider additional factors: balance of desirable and undesirable effects, certainty of evidence, safety of the intervention, cost,

Question 1. What risk factors should clinicians take into consideration in determining the likelihood of biphasic anaphylaxis?

Recommendation 1. We suggest that a clinician incorporate severity of anaphylaxis presentation and/or the administration of >1 dose of epinephrine for the treatment of initial anaphylaxis as a guide to determining a patient’s risk for developing biphasic anaphylaxis. Conditional recommendation. Certainty rating of evidence: very low.

Limitations

Unfortunately, the certainty of evidence around supplemental therapies in anaphylaxis management is very low. While early epinephrine is recommended by the JTFPP when anaphylaxis is recognized in any setting, whether clinicians should (or should not) also administer antihistamines and/or glucocorticoids is a question that has not been subjected to rigorous methodologic evaluation.

All patients with anaphylaxis should be educated regarding the risk for biphasic reactions, and self-injectable

Future directions

At present, high-certainty evidence is lacking to determine whether antihistamines and/or glucocorticoids provide benefit as supplemental therapies in anaphylaxis management in patients promptly and appropriately treated with epinephrine. In addition, it seems unlikely that antihistamine and/or glucocorticoid premedication is likely to offer clear benefit in the prevention of RCM anaphylaxis in patients with a history of immediate RCM hypersensitivity receiving an alternative low- or

Conclusions

Anaphylaxis is a multisystem allergic emergency. Early recognition and prompt administration of intramuscular epinephrine remain the cornerstone of management. Risk factors for biphasic reactions include severe anaphylaxis and/or the need for >1 dose of epinephrine. Additional biphasic anaphylaxis risk factors include wide pulse pressures, unknown anaphylaxis trigger, cutaneous signs and symptoms, and drug trigger in children. Although treatment of anaphylaxis in the United States also

References (265)

  • F.D. Finkelman et al.

    Human IgE-independent systemic anaphylaxis

    J Allergy Clin Immunol

    (2016)
  • S.F. Stone et al.

    Elevated serum cytokines during human anaphylaxis: identification of potential mediators of acute allergic reactions

    J Allergy Clin Immunol

    (2009)
  • S.G. Brown et al.

    Anaphylaxis: clinical patterns, mediator release, and severity

    J Allergy Clin Immunol

    (2013)
  • H.A. Sampson et al.

    Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network Symposium

    Ann Emerg Med

    (2006)
  • C. Curtis et al.

    Epinephrine preparedness in pediatric patients with food allergy: an ideal time for change

    Ann Allergy Asthma Immunol

    (2014)
  • M. Robinson et al.

    Factors associated with epinephrine administration for anaphylaxis in children before arrival to the emergency department

    Ann Allergy Asthma Immunol

    (2017)
  • W.K. Liew et al.

    Anaphylaxis fatalities and admissions in Australia

    J Allergy Clin Immunol

    (2009)
  • L. Ma et al.

    Case fatality and population mortality associated with anaphylaxis in the United States

    J Allergy Clin Immunol

    (2014)
  • N. Inagaki et al.

    Inhibitory effects of glucocorticoids on increased vascular permeability caused by passive cutaneous anaphylaxis and some chemical mediators in rats

    Jpn J Pharmacol

    (1988)
  • A. Pourmand et al.

    Biphasic anaphylaxis: a review of the literature and implications for emergency management

    Am J Emerg Med

    (2018)
  • P. Lieberman

    Biphasic anaphylactic reactions

    Ann Allergy Asthma Immunol

    (2005)
  • B.J. Stark et al.

    Biphasic and protracted anaphylaxis

    J Allergy Clin Immunol

    (1986)
  • A.K. Ellis et al.

    Incidence and characteristics of biphasic anaphylaxis: a prospective evaluation of 103 patients

    Ann Allergy Asthma Immunol

    (2007)
  • B.E. Grunau et al.

    Incidence of clinically important biphasic reactions in emergency department patients with allergic reactions or anaphylaxis

    Ann Emerg Med

    (2014)
  • W. Alqurashi et al.

    Epidemiology and clinical predictors of biphasic reactions in children with anaphylaxis

    Ann Allergy Asthma Immunol

    (2015)
  • W. Alqurashi et al.

    Do corticosteroids prevent biphasic anaphylaxis?

    J Allergy Clin Immunol Pract

    (2017)
  • R.L. Campbell et al.

    Emergency department diagnosis and treatment of anaphylaxis: a practice parameter

    Ann Allergy Asthma Immunol

    (2014)
  • J.S. Klein et al.

    Underreporting of anaphylaxis in a community emergency room

    J Allergy Clin Immunol

    (1995)
  • S. Clark et al.

    Multicenter study of emergency department visits for insect sting allergies

    J Allergy Clin Immunol

    (2005)
  • P. Lieberman et al.

    Anaphylaxis—a practice parameter update 2015

    Ann Allergy Asthma Immunol

    (2015)
  • F.E. Simons et al.

    2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines

    World Allergy Organ J

    (2015)
  • P.J. Turner et al.

    The emperor has no symptoms: the risks of a blanket approach to using epinephrine autoinjectors for all allergic reactions

    J Allergy Clin Immunol Pract

    (2016)
  • M.S. Shaker

    An economic evaluation of prophylactic self-injectable epinephrine to prevent fatalities in children with mild venom anaphylaxis

    Ann Allergy Asthma Immunol

    (2007)
  • M. Shaker et al.

    The health and economic outcomes of peanut allergy management practices

    J Allergy Clin Immunol Pract

    (2018)
  • S. Lee et al.

    Predictors of biphasic reactions in the emergency department for patients with anaphylaxis

    J Allergy Clin Immunol Pract

    (2014)
  • T.H. Kim et al.

    Duration of observation for detecting a biphasic reaction in anaphylaxis: a meta-analysis

    Int Arch Allergy Immunol

    (2019)
  • S. Lee et al.

    Trends, characteristics, and incidence of anaphylaxis in 2001-2010: a population-based study

    J Allergy Clin Immunol

    (2017)
  • S. Celikel et al.

    Bee and bee products allergy in Turkish beekeepers: determination of risk factors for systemic reactions

    Allergol Immunopathol (Madr)

    (2006)
  • W.W. Decker et al.

    The etiology and incidence of anaphylaxis in Rochester, Minnesota: a report from the Rochester Epidemiology Project

    J Allergy Clin Immunol

    (2008)
  • M.P. Ross et al.

    Analysis of food-allergic and anaphylactic events in the National Electronic Injury Surveillance System

    J Allergy Clin Immunol

    (2008)
  • K.J. Allen et al.

    The epidemiology of IgE-mediated food allergy and anaphylaxis

    Immunol Allergy Clin North Am

    (2012)
  • S. Clark et al.

    Multicenter study of emergency department visits for food allergies

    J Allergy Clin Immunol

    (2004)
  • S.A. Rudders et al.

    Trends in pediatric emergency department visits for food-induced anaphylaxis

    J Allergy Clin Immunol

    (2010)
  • S. Clark et al.

    Epidemiology of anaphylaxis

    Immunol Allergy Clin North Am

    (2007)
  • L. Harduar-Morano et al.

    A population-based epidemiologic study of emergency department visits for anaphylaxis in Florida

    J Allergy Clin Immunol

    (2011)
  • L.M. Webb et al.

    Anaphylaxis: a review of 601 cases

    Ann Allergy Asthma Immunol

    (2006)
  • A. Banerji et al.

    Retrospective study of drug-induced anaphylaxis treated in the emergency department or hospital: patient characteristics, management, and 1-year follow-up

    J Allergy Clin Immunol Pract

    (2014)
  • R.L. Campbell et al.

    Prescriptions for self-injectable epinephrine and follow-up referral in emergency department patients presenting with anaphylaxis

    Ann Allergy Asthma Immunol

    (2008)
  • A. Gelincik et al.

    Anaphylaxis in a tertiary adult allergy clinic: a retrospective review of 516 patients

    Ann Allergy Asthma Immunol

    (2013)
  • L.B. Grabenhenrich et al.

    Epinephrine in severe allergic reactions: the European Anaphylaxis Register

    J Allergy Clin Immunol Pract

    (2018)
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    Disclosure of potential conflict of interest: The JTFPP members and work group members’ conflict of interest disclosure forms can be found at www.allergyparameters.org. Jonathan Bernstein has received financial support from Sanofi, Regeneron, AstraZeneca, Merck, Optinose, Takeda, CSL Behring, Biocryst, Pharming, the National Institutes of Health, Taylor Francis, INEOS; is Editor in Chief of the Journal of Asthma, INEOS Medical Immunosurveillance Director, Vice Chair and Lectureship Chair of the American Academy of Allergy, Asthma & Immunology (AAAAI) Foundation, Chairman of Allergists for Israel, American College of Asthma, Allergy, and Immunology (ACAAI) Asthma Chair, Scientific Chair, and Young Investigator Award Chair; and serves of the Board of Directors and Scientific Committee of Interasma. Ronna Campbell has served as a peer reviewer for EB Medicine and an author for UpToDate. Chitra Dinakar has received financial support from Propeller Health, ACAAI (stipend for Editorial Board of AllergyWatch), the American Association of Allergists of Indian Origin; serves on the Board of Directors of the AAAAI and on the Medical Advisory Board of Food Equity Initiative; is Assistant Editor of AllergyWatch. Anne Ellis has received financial support from ALK-Abello, AstraZeneca, Green Cross, Merck, Novartis, Nuvo, Pediapharm, Pfizer, Kaleo, Novartis, Sanofi, Regeneron; serves on the Board of Directors of the Canadian Allergy Society of Allergy and Clinical Immunology. David Golden has received financial support from Aquestive, Sandoz, ALK-Abello, Sandoz, Genentech, Stallergenes-Greer, and UpToDate. Matthew Greenhawt has received financial support from Aquestive, Merck, Allergenis, Allergy Therapeutics, Sanofi Genzyme, Genentech, Aravax, Prota, Before Brands, the Institute for Clinical and Economic Review, ACAAI, DBV, Intrommune; is supported by the Agency of Healthcare Research and Quality; has served on the advisory board of International Food Protein-Induced Enterocolitis Syndrome Association, the Asthma and Allergy Foundation of America, and the National Peanut Board; and is Associate Editor of the Annals of Allergy, Asthma, and Immunology. Caroline Horner has served as committee chair for the AAAAI Asthma Diagnosis and Treatment Interest Section, Interest Section Coordinating Committee, and In-Training Exam Coordinating Committee. David Khan has received financial support from UpToDate and Aimmune; serves on the Board of Directors of the AAAAI, ACAAI Chair of Literature Review, Co-Chair of Conjoint Board Review, Texas Allergy, Asthma, and Immunology Society Chair of Meetings Committee; and is Associate Editor of the Journal of Allergy and Clinical Immunology In Practice. Eddy Lang received an honorarium from the Joint Task Force on Practice Parameters for Grading of Recommendations, Assessment, Development and Evaluation methods support. Jay Lieberman has received financial support from the ACAAI, Aquestive, Aimmune, DBV, Biotest Pharma, and Regeneron; is Associate Editor of the Annals of Allergy, Asthma, and Immunology, Vice Chair for the ACAAI Food Allergy Committee, and Medical Director for Food Allergy Alliance of the MidSouth. John Oppenheimer has received financial support from DBV, Teva Pharmaceutical Industries, GlaxoSmithKline adjudication/data safety monitoring board, AstraZeneca, Novartis, and Sanofi; is Associate Editor of the Annals of Allergy, Asthma, and Immunology and AllergyWatch, an American Board of Internal Medicine Council Member and American Board of Allergy and Immunology Liaison to the American Board of Internal Medicine, UpToDate Reviewer, American College of Clinical Pharmacy Cough Guideline Committee Member, and WebMD Editor. Jay Portnoy has received financial support from Thermo Fisher Scientific, Kaleo, Teva Pharmaceutical Industries, Novartis, Hycor, and Boehringer-Ingelheim. Matthew Rank has received financial support from the ACAAI, National Institutes of Health, and Levin Family Foundation; has served as Chair of the AAAAI Health outcomes, Education, Delivery, and Quality Interest Section; and is Research Director of the Phoenix Children’s Hospital Breathmobile. Marcus Shaker has received financial support from the Eastern Allergy Conference and has a family member who is Chief Executive Officer of Altrix Medical. David Stukus has received financial support from Aimmune, Before Brands, Abbott Nutrition, the American Academy of Pediatrics, ACAAI; has served as Committee Chair for the AAAAI and ACAAI. Dana Wallace has received financial support from Mylan, Kaleo, Optinose, ALK-Abello, Bryan, and Sanofi; is Education Council Chair and Rhinitis/Sinusitis/Ocular Committee Chair for the ACAAI; is Website Content Editor and ESP/WATS Committee Chair for the World Allergy Organization. Julie Wang has received financial support from ALK-Abello, Regeneron, DBV, Aimmune; is an UpToDate author; serves on the Executive Committee of the American Academy of Pediatrics Section on Allergy and Immunology; and serves as Vice Chair of the AAAAI Anaphylaxis, Dermatitis, Drug Allergy Interest Section. David Lang declares that he has no relevant conflicts of interest.

    Reprints: Joint Task Force on Practice Parameters Liaison: Peris Flagg (American Academy of Allergy, Asthma, and Immunology, 555 E. Wells Street, Suite 1100, Milwaukee, WI 53202. E-mail: [email protected]); [email protected].

    Previously published practice parameters of the Joint Task Force on Practice Parameters for Allergy & Immunology are also available at http://www.allergyparameters.org, http://www.AAAAI.org, and http://www.ACAAI.org.

    The Joint Task Force on Practice Parameters (JTFPP) is committed to ensuring that the practice parameters are based on the best scientific evidence at the time of publication, and that such evidence is free of commercial bias to the greatest extent possible. The JTFPP recognizes that experts in a field are likely to have interests that could come into conflict with the development of a completely unbiased and objective practice parameter. To take advantage of their expertise, a process has been developed to acknowledge potential conflicts of interest (COI) and attempt to prevent them from influencing the final document in a negative way. To preserve the greatest transparency regarding potential COI, all members of the JTFPP and the practice parameters work groups will complete a standard potential COI disclosure form prior to the development of each document, which will be available for external review by the sponsoring organization and any other interested individual. In addition, before confirming the selection of the work group chairperson and members, the JTFPP will discuss and resolve all relevant potential COI associated with this selection. Finally, all members of parameter work groups will be provided a written statement regarding the importance of ensuring that the parameter development process is free of commercial bias. During the review process there are additional measures to avoid bias. At the workgroup level, all the sections are reviewed by all work group members to ensure that content is appropriate and without apparent bias. If a section is deemed to have apparent bias, it will be appropriately revised without the section author’s involvement, in an attempt to remove potential bias. In addition, the entire document is then reviewed by the JTFPP, and any apparent bias is acknowledged and removed at that level. For each and every recommendation, a vote is required by the work group and JTFPP, and any member with any perceived COI is recused from that vote (and so explained in the document). Any dissenting votes that cannot be resolved are described and explained in the document. In a final stage of review, the practice parameter is sent to invited expert reviewers for review, selected by the American Academy of Allergy, Asthma & Immunology (AAAAI) and the American College of Allergy, Asthma, and Immunology (ACAAI). The document is also posted on the AAAAI and ACAAI websites for general membership and the public-at-large to review and offer comment. All reviewers must provide statements of potential COI. Although the JTFPP has the final responsibility for the content of the documents submitted for publication, each reviewer’s comments will be discussed and reviewers will receive written responses to comments when appropriate.

    Disclaimer: The AAAAI and the ACAAI have jointly accepted responsibility for establishing “Anaphylaxis—a 2019 practice parameter update, systematic review and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis.” This is a complete and comprehensive document and is current at the time of publication. The medical environment is rapidly changing and not all recommendations will be appropriate or applicable to all patients and may change over time. Because this document incorporated the efforts of many participants, no single individual, including members serving on JTFPP, are authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information or interpretation of this practice parameter by the AAAAI or ACAAI should be directed to the executive offices of the AAAAI and the ACAAI. These parameters are not designed for use by the pharmaceutical industry in drug development or promotion.

    Contributors: The Joint Task Force has made a concerted effort to acknowledge all contributors to this parameter. If any contributors have been excluded inadvertently, the Task Force will ensure that appropriate recognition of such contributions is made subsequently.

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