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. Author manuscript; available in PMC: 2021 Mar 29.
Published in final edited form as: J Allergy Clin Immunol. 2020 Aug 24;146(5):1089–1096. doi: 10.1016/j.jaci.2020.08.015

Persistent, refractory, and biphasic anaphylaxis: A multidisciplinary Delphi study

Timothy E Dribin a,b, Hugh A Sampson c, Carlos A Camargo Jr d, David C Brousseau e, Jonathan M Spergel f, Mark I Neuman g,h, Marcus Shaker i,j, Ronna L Campbell k, Kenneth A Michelson g,h, Susan A Rudders l,m, Amal H Assa’ad b,n, Kimberly A Risma b,n, Mariana Castells o, Lynda C Schneider l,m, Julie Wang c, Juhee Lee f, Rakesh D Mistry p, David Vyles e, Lisa M Vaughn q, Daniel J Schumacher a,b, John K Witry r, Shiv Viswanathan r, Erica M Page s, David Schnadower a,b
PMCID: PMC8006564  NIHMSID: NIHMS1682582  PMID: 32853640

Abstract

Background:

The use of inconsistent definitions for anaphylaxis outcomes limits our understanding of the natural history and epidemiology of anaphylaxis, hindering clinical practice and research efforts.

Objective:

Our aim was to develop consensus definitions for clinically relevant anaphylaxis outcomes by utilizing a multidisciplinary group of clinical and research experts in anaphylaxis.

Methods:

Using Delphi methodology, we developed agenda topics and drafted questions to review during monthly conference calls. Through online surveys, a 19-member panel consisting of experts in allergy and/or immunology and emergency medicine rated their level of agreement with the appropriateness of statements on a scale of 1 to 9. A median value of 1.0 to 3.4 was considered inappropriate, a median value of 3.5 to 6.9 was considered uncertain, and a median value of 7.0 to 9.0 was considered appropriate. A disagreement index was then calculated, with values less than 1.0 categorized as “consensus reached.” If consensus was not reached after the initial survey, subsequent surveys incorporating the aggregate deidentified responses from prior surveys were sent to panel members. This process was repeated until consensus was reached or 4 survey rounds had been completed, after which the question was categorized as “no consensus reached.”

Results:

The panel developed outcome definitions for persistent, refractory, and biphasic anaphylaxis, as well as for persistent and biphasic nonanaphylactic reactions. There was also consensus among panel members regarding the need to develop an anaphylaxis severity grading system.

Conclusion:

Dissemination and application of these definitions in clinical care and research will help standardize the terminology used to describe anaphylaxis outcomes and serve as the foundation for future research, including research aimed at development of an anaphylaxis severity grading system.

Keywords: Anaphylaxis, biphasic anaphylaxis, biphasic nonanaphylactic reactions, Delphi, emergency department, persistent anaphylaxis, persistent nonanaphylactic reactions, refractory anaphylaxis

Anaphylaxis is a severe, systemic mast cell– and/or basophil-mediated reaction that occurs after exposure with an allergy-causing substance (eg, foods, medications, insect venom), whereas in other cases its etiology may be unknown or it may occur in relation to mast cell disorders.1,2 From 2008 to 2016 there were more than 400,000 emergency department (ED) visits for anaphylaxis in the United States. During this period, ED visit rates for anaphylaxis doubled among all age groups and tripled among children.3 These reactions impose a significant personal and financial burden on patients and families. In 2010 direct and indirect expenditures for anaphylaxis in the United States totaled $1.2 billion and $609 million respectively, and these costs have likely increased during the past decade.4

Prompt recognition and treatment of anaphylaxis with intramuscularly administered epinephrine are essential to mitigate reaction severity and prevent complications, including respiratory failure, cardiovascular collapse, and death. In 2006, the National Institute of Allergy and Infectious Diseases and Food Allergy and Anaphylaxis Network (NIAID/FAAN) developed a widely accepted definition of anaphylaxis for children and adults and established clinical diagnostic criteria (see Table I).1 The NIAID/FAAN guidelines have been instrumental in standardizing anaphylaxis diagnostic criteria, encouraging recognition and appropriate treatment, improving communication between health care providers and patients, and optimizing the care of patients with anaphylaxis across health care settings.2

TABLE I.

Clinical criteria for diagnosing anaphylaxis

Anaphylaxis is highly likely when any 1 of the following 3 criteria is fulfilled:

  1. Acute onset of an illness (within minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized hives; pruritus or flushing; swollen lips, tongue, and/or uvula)

    and at least 1 of the following:
    1. Respiratory compromise (eg, dyspnea, wheeze and/or bronchospasm, stridor, reduced peak expiratory flow, hypoxemia)
    2. Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], syncope, incontinence)
  2. Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (within minutes to several hours):
    1. Involvement of the skin and/or mucosal tissue (eg, generalized hives; itch and/or flush; swollen lips, tongue, and/or uvula)
    2. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, hypoxemia)
    3. Reduced blood pressure or associated symptoms (eg, hypotonia [collapse], syncope, incontinence)
    4. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
  3. Reduced blood pressure after exposure to known allergen for that patient (within minutes to several hours):
    1. For infants and children, low systolic blood pressure (age-specific) or a >30% decrease in systolic blood pressure*
    2. For adults, systolic blood pressure >90 mm Hg or a >30% decrease from that person’s baseline
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*

Low systolic blood pressure for children is defined as less than 70 mm Hg from age 1 month to 1 year, less than 70 mm Hg plus twice the patient’s age from age 1 year to 10 years, and less than 90 mm Hg from age 11 years to 17 years. Reprinted with permission from Sampson et al.1

Although most anaphylactic reactions resolve promptly after treatment with epinephrine, patients may experience persistent or recurrent symptoms necessitating additional interventions. However, there are no uniformly accepted consensus-based definitions to describe these disparate clinical outcomes, limiting our understanding of their epidemiology and risk factors, as well as our ability to investigate or standardize their management.2,5 The lack of clear and objective definitions likely contributes to wide variability in reported rates of biphasic anaphylaxis (1%−19%) and inconsistent descriptions of predictors of biphasic anaphylaxis in recent studies.6–8

This gap presents a need to develop consensus definitions of anaphylaxis outcomes for application in clinical care and research, including persistent, refractory, and biphasic anaphylaxis, as well as for persistent and biphasic nonanaphylactic reactions. Such definitions will be instrumental when reporting outcomes in population- and patient-level studies, including trials comparing the efficacy of adjunctive and novel therapeutics. Therefore, the objective of this study was to develop consensus definitions for specific, clinically relevant anaphylaxis outcomes by utilizing a multidisciplinary group of clinical and research experts in anaphylaxis.

METHODS

Delphi group panel members

We convened a Delphi group consisting of a 19-member panel of experts in the field of anaphylaxis, including allergists and/or immunologists and general and pediatric emergency medicine specialists. Panel members were selected on the basis of their clinical expertise, prior published research, expert recommendations, and membership in national research networks and anaphylaxis interest groups. Three experts in qualitative and Delphi methodology were also included. Panel members engaged in monthly conference calls and surveys from September 2019 through March 2020 to develop consensus anaphylaxis outcome definitions. The institutional review board at Cincinnati Children’s Hospital Medical Center approved this study.

Literature search

We performed a literature review of the Embase, PubMed, Cochrane and Scopus databases for English articles from 1997 to August 2019 using the following search terms: anaphylaxis severity, anaphylaxis grading system, anaphylaxis grading scale, anaphylaxis grade, biphasic anaphylaxis, persistent anaphylaxis, refractory anaphylaxis, and protracted anaphylaxis (see Table E1 in the Online Repository at www.jacionline.org). Articles published before 1997 were also included if they were cited at least 5 times in references from the literature search. The primary investigator (T.D.) reviewed the literature search and excluded duplicate articles and articles not related to the study aims. Study panel members had access to relevant articles and were asked to review them before conference calls and before responding to survey questions. If a panel member believed that an important article was omitted from the literature search, the article was disseminated to all panel members and made available in a common online study folder that included all articles from the search.

Delphi surveys

The Delphi method is a structured group consensus technique with identified subject matter experts answering survey questions in iterative rounds. We used the approach by Fitch et al (the RAND/University of California Los Angeles appropriateness method),9 which has been used in similar studies.10,11 In each survey round, panel members were asked to rate each statement as to level of agreement (from 1 [indicating extremely inappropriate] to 9 [indicating extremely appropriate]) or as not applicable if panel members did not believe that they had the necessary expertise or background knowledge to rank a particular statement.10,11 Additionally, panel members were encouraged to submit free-text comments to clarify their response to every question, suggest additional questions, or recommend modifications to existing questions. A median appropriateness value of 1.0 to 3.4 was considered inappropriate, a median value of 3.5 to 6.9 was considered uncertain, and a median value of 7.0 to 9.0 was considered appropriate.10,11 A disagreement index (DI) was then calculated (see Table E2 in the Online Repository at http://www.jacionline.org), with a value less than 1.0 indicating consensus reached regarding the statement.10,11

If consensus for a question was not reached after the initial survey, subsequent surveys incorporating the aggregate deidentified responses from prior surveys were sent to panel members with the goal of narrowing responses to reach consensus. This process was repeated until consensus was reached for each statement or after 4 survey rounds. If no consensus was reached by the fourth round, the question was categorized as no consensus reached. After consensus was reached for individual questions pertaining to a topic (eg, biphasic anaphylaxis), a composite definition was created on the basis of responses from questions pertaining to the study topic. For an explanation of questions that the group considered when determining the need for and developing consensus outcome definitions, see the Supplemental Document in this article’s Online Repository (available at www.jacionline.org).

Conference calls

Three panel members (T.D., H.S., and D.S.) developed agenda topics and drafted questions to review during conference calls. Monthly conference calls with the full Delphi panel were designed to answer logistic questions related to study execution, review results from the prior survey rounds including questions for which the group did not reach consensus, and review and clarify questions. During calls, panel members also discussed relevant research and clinical experiences related to the questions. Audio recordings of the calls were made available to panel members who could not join the live calls. Qualitative themes discussed during calls related to specific questions and topics are presented in the Results section to provide a contextual framework for the definitions. Following conference calls, panel members were asked to review and/or revise questions, after which the primary investigator compiled revisions and incorporated them into a secure, anonymous online survey (Research Electronic Data Capture, Nashville, Tenn).12

RESULTS

All panel members (N = 19) participated in each Delphi round. An overview of questions related to each Delphi topic, including the median score, DI, number of survey rounds to reach (DI < 1.0) or not reach consensus (DI ≥ 1.0) on questions, and number of panel members for each round are listed in Table E3 in the Online Repository (at www.jacionline.org).

There was consensus that the 2006 NIAID/FAAN anaphylaxis criteria should be used to categorize anaphylaxis in all outcome definitions and that the definitions developed by the expert panel would apply to all age groups, including infants, children, and adults. Consensus was also reached that anaphylaxis is a clinical diagnosis, and thus, the definitions can apply to all cases of anaphylaxis that fulfill NIAID/FAAN criteria no matter the allergen, pathophysiologic response (eg, IgE-mediated vs non–IgE-mediated), underlying conditions, or comorbidities. There was consensus that the panel should develop outcome definitions for persistent anaphylaxis, refractory anaphylaxis, and biphasic anaphylaxis, as well as for persistent nonanaphylactic reactions, biphasic nonanaphylactic reactions, and should also develop an anaphylaxis severity grading system (see Table E3 in the Online Repository for question specific median appropriateness values and DI).

Consensus was also reached regarding the need to develop separate diagnostic criteria (other than the NIAID/FAAN anaphylaxis criteria1) for infant anaphylaxis, given that the NIAID/FAAN criteria may lack adequate sensitivity for diagnosing anaphylaxis in this age group. However, in the free-text option for this question, panel members responded that rather than development of separate criteria for infant anaphylaxis, the NIAID/FAAN criteria could be modified to include clinical features that are more sensitive for diagnosing anaphylaxis in infants.

Definition of persistent anaphylaxis

The definition for persistent anaphylaxis is shown in Table II. Panel members acknowledged that there are minimal data supporting a time threshold for classifying reactions as persistent, and thus the proposed time threshold is based on expert opinion, clinical expertise, and an extensive review of the literature. To account for this, panel members were asked to suggest time thresholds based on their review of the literature and clinical experience. Suggested time thresholds were 1, 2, 4, 6, 12, and 24 hours. After 2 Delphi rounds, there was consensus that to be categorized as persistent anaphylaxis, persistent symptoms must fulfill NIAID/FAAN anaphylaxis criteria and must last at least 4 hours.1 Additionally, there was agreement that the definition of persistent anaphylaxis was independent of the management of the initial reaction.

TABLE II.

Clinical criteria for diagnosing persistent, refractory, and biphasic anaphylaxis

Persistent anaphylaxis is highly likely when the following criterion is fulfilled*:

  • Presence of symptoms and/or examination findings that fulfill the 2006 NIAID/FAAN anaphylaxis criteria that persist for at least 4 hours.1

Refractory anaphylaxis is highly likely when both of the following 2 criteria are fulfilled†:

  1. Presence of anaphylaxis following appropriate epinephrine dosing and symptom-directed medical management (eg, intravenous fluid bolus for hypotension).

  2. The initial reaction must be treated with 3 or more appropriate doses of epinephrine (or initiation of an intravenous epinephrine infusion).‡

Biphasic anaphylaxis is highly likely when all of the following 4 criteria are fulfilled§:

  1. New /or recurrent symptoms and/or examination findings must fulfill the 2006 NIAID/FAAN anaphylaxis criteria.1

  2. Initial symptoms and/or examination findings must completely resolve before the onset of new or recurrent symptoms and/or examination findings.

  3. There cannot be allergen reexposure before the onset of new or recurrent symptoms and/or examination findings.

  4. New or recurrent symptoms and/or examination findings must occur within 1 to 48 hours from complete resolution of initial symptoms and/or examination findings.
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*

The diagnosis of persistent anaphylaxis is independent of the management of the initial reaction. For reactions that do not fulfill persistent anaphylaxis criteria, please refer to Table III (clinical criteria for diagnosing persistent nonanaphylactic reactions).

†

Refractory anaphylaxis is not dependent on the duration of symptoms and/or examination findings.

‡

Appropriate epinephrine dosing is 0.01 mg/kg of epinephrine intramuscularly, with a maximum single dose of 0.5 mg or manufacturer-recommended dosing for epinephrine autoinjectors.

§

The diagnosis of biphasic anaphylaxis is independent of management of the initial reaction. For reactions that do not fulfill biphasic anaphylaxis criteria, please refer to Table III (clinical criteria for diagnosing biphasic nonanaphylactic reactions).

Definition of refractory anaphylaxis

The definition of refractory anaphylaxis is shown in Table II. It took 3 Delphi rounds to determine whether reactions must be treated with 2 or 3 epinephrine doses to be categorized as refractory anaphylaxis. Consensus was reached that to be categorized as refractory anaphylaxis, the initial reaction must be treated with 3 or more appropriate doses of epinephrine (or initiation of an intravenous epinephrine infusion) in addition to symptom-directed medical management, such as an intravenous fluid bolus for hypotension or supplemental oxygen for hypoxia or shock. For this question, we intentionally did not include every possible symptom and/or therapy combination but instead included a general statement to reflect the need for patients to receive appropriate resuscitative and/or supportive therapies in addition to treatment with epinephrine. The group reinforced the idea that this statement does not mean that clinicians should delay or substitute treatment with epinephrine to administer other therapies (eg, inhaled β-agonists, intravenous fluid boluses); instead, it reflects the importance of ensuring that patients receive appropriate resuscitative efforts before reactions are classified as refractory. There was also agreement that the definition of refractory anaphylaxis was not dependent on the duration of symptoms and/or examination findings but instead depended on the persistence of anaphylaxis following appropriate epinephrine administration and medical management of specific symptoms and/or examination findings.

Definition of biphasic anaphylaxis

The composite definition of biphasic anaphylaxis is outlined in Table II. Panel members reached consensus that initial symptoms need to completely resolve before the onset of recurrent symptoms and that recurrent symptoms must fulfill NIAID/FAAN anaphylaxis criteria.1 Furthermore, there was agreement that the definition of biphasic anaphylaxis is independent of management of the initial reaction. Thus, initial reactions do not have to be treated with epinephrine for recurrent symptoms to be categorized as a biphasic anaphylaxis. During dialogue about this question, panel members agreed that anaphylactic reactions may resolve without treatment with epinephrine before medical provider evaluation. Thus, there would be no indication to administer epinephrine at the time of provider evaluation. If patients then developed recurrent symptoms that fulfilled biphasic anaphylaxis criteria, the reaction would appropriately be categorized as biphasic.

Consensus was reached that there should be minimum and maximum time thresholds from complete resolution of the initial symptoms to the onset of recurrent symptoms. Panel members noted that reducing the minimum time threshold (the threshold before which the presence of new or recurrent symptoms and/or examination findings would not be categorized as biphasic anaphylaxis) would increase the definition’s sensitivity whereas expanding the threshold would increase the definition’s specificity. In contrast, if the upper time threshold (the threshold after which the presence of new or recurrent symptoms and/or examination findings would not be categorized as biphasic anaphylaxis) was excessively long (eg, 1 week), it would decrease the definition’s specificity by including reactions that might not be related to the initial reaction but would instead represent discrete reactions. Panel members suggested lower (30, 60, 120, and 240 minutes) and upper (24, 36, 48, and 72 hours) time thresholds for classifying biphasic reactions on the basis of their review of the literature and clinical expertise. The final lower and upper time thresholds developed by the group were 1 hour or more (2 Delphi rounds were required to reach consensus) and 48 hours or less (3 Delphi rounds were required to reach consensus) respectively.

Definitions of persistent and biphasic nonanaphylactic reactions

The definitions of persistent and biphasic nonanaphylactic reactions are listed in Table III. The only difference between the definitions of persistent and biphasic nonanaphylactic reactions and persistent and biphasic anaphylaxis is that for the former definitions, persistent and recurrent symptoms do not fulfill the NIAID/FAAN anaphylaxis criteria.1

TABLE III.

Clinical criteria for diagnosing persistent and biphasic nonanaphylactic reactions

Persistent allergic reactions are highly likely when the following criterion is fulfilled*:

  • Presence of symptoms and/or examination findings that do not fulfill the 2006 NIAID/FAAN anaphylaxis criteria that persist for at least 4 hours.1

Biphasic allergic reactions are highly likely when all of the following 4 criteria are fulfilled†:

  1. New or recurrent symptoms and/or examination findings do not fulfill the 2006 NIAID/FAAN anaphylaxis criteria.1

  2. The initial symptoms and/or examination findings must be completely resolved before the onset of new or recurrent symptoms and/or examination findings.

  3. There can be no allergen reexposure before the onset of new or recurrent symptoms and/or examination findings.

  4. New and/or recurrent symptoms and/or examination findings must occur within 1 to 48 hours from complete resolution of initial symptoms and/or examination findings.
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*

The diagnosis of persistent allergic reaction is independent of management of the initial reaction.

†

The diagnosis of biphasic allergic reaction is independent of management of the initial reaction.

Definition of anaphylaxis not otherwise specified

Consensus was reached that anaphylaxis not otherwise specified is defined as anaphylactic reactions that do not fulfill the following clinical outcomes: fatal anaphylaxis, persistent anaphylaxis, biphasic anaphylaxis, persistent nonanaphylactic reactions, or biphasic nonanaphylactic reactions. However, the panel recognized that there is a spectrum of severity among patients with this label and that the definition can be applied only after 48 hours (the time at which reactions can no longer be classified as biphasic).

The outcome definitions shown in Fig 1 are not mutually exclusive, and a patient may fulfill more than 1 outcome through their clinical course; however, 1 outcome must always precede another. For example, a patient may have refractory anaphylaxis (for which symptoms completely resolve after treatment with 3 doses of intramuscularly administered epinephrine), and if the initial reaction lasts 4 hours, it would then fulfill persistent anaphylaxis criteria (this example would be categorized as refractory, persistent anaphylaxis).

FIG 1.

FIG 1.

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Algorithm for applying the anaphylaxis outcome definitions in clinical care and research. Anaphylaxis not otherwise specified is defined as anaphylactic reactions that do not fulfill the following clinical outcomes: fatal anaphylaxis, persistent anaphylaxis, biphasic anaphylaxis, persistent nonanaphylactic reactions, or biphasic nonanaphylactic reactions. aThere can be no allergen reexposure before the onset of new or recurrent symptoms and/or examination findings. bAppropriate epinephrine dosing is 0.01 mg/kg of epinephrine intramuscularly, with a maximum single dose of 0.5 mg or the manufacturer-recommended dosing for epinephrine autoinjectors. cSymptom-directed medical management such as an intravenous fluid bolus for hypotension or albuterol for wheezing. dOutcome definitions are not mutually exclusive (eg, a patient who has refractory anaphylaxis may also have or develop persistent or biphasic anaphylaxis).

DISCUSSION

We convened a multidisciplinary panel of anaphylaxis experts to develop consensus anaphylaxis outcome definitions for persistent, refractory, and biphasic anaphylaxis, as well as for persistent and biphasic nonanaphylactic reactions. Although there was agreement that there is also a need to develop an anaphylaxis severity grading system and separate criteria for diagnosing infant anaphylaxis (or modify existing NIAID/FAAN criteria to include symptoms more specific for infant anaphylaxis)1, we believed that these topics were beyond the scope of this study and would be better addressed through future investigation that could expand upon or incorporate components of the definitions outlined in this study.

The study was conducted by using rigorous Delphi methodology previously applied in other clinical fields of medicine,9–11 and we included clinicians and researchers with expertise in Delphi methodology and qualitative research to ensure the appropriateness of methods and study procedures. This is the first study to evaluate the need for anaphylaxis outcome definitions on the basis of input from a multidisciplinary group of anaphylaxis experts, including allergists and/or immunologists and ED providers who care for children and adults.

This study advances the classification of anaphylaxis outcomes by defining not only persistent, refractory, and biphasic anaphylaxis but also persistent and biphasic allergic reactions that do not fulfill the NIAID/FAAN anaphylaxis criteria.1 We believed that these were necessary designations given that prior studies have categorized all biphasic reactions, no matter whether they fulfill NIAID/FAAN criteria, as biphasic anaphylaxis.6,13–15 This distinction is important to harmonize data about the prevalence and risk factors for biphasic anaphylaxis in clinical practice, given that clinicians may make different management decisions based on the risk of biphasic anaphylaxis versus biphasic nonanaphylactic reactions. Additionally, the outcome definitions apply only to anaphylactic reactions and thus cannot be used to describe clinical courses following nonanaphylactic reactions. For example, if a patient has a nonanaphylactic reaction and then develops recurrent symptoms that fulfill anaphylaxis criteria, the recurrent symptoms cannot be classified as biphasic anaphylaxis.

The definitions are designed to apply to both clinical care and research, and they are based on the best available, albeit limited evidence. Nonetheless, we believe that the definitions are pragmatic and also provide a nuanced approach for evaluating distinct, clinically important outcomes of patients with anaphylaxis. Thus, we do not anticipate significant barriers when applying the definitions to bedside care because they are based on important clinical questions and they incorporate reaction features that are easily ascertained during medical evaluation (eg, duration of symptoms, resolution of initial symptoms and/or examination findings).

During conference calls, panel members routinely stated that there is a lack of validated data to inform responses to many of the questions. Still, this study is a practical, necessary first step in standardizing the outcomes of patients with anaphylaxis. Application of the definitions in clinical care and research has the potential to improve communication among clinicians and patients and families and to standardize research outcomes. For example, if a patient develops isolated urticaria 2 hours after complete resolution of initial anaphylaxis symptoms, the reaction would be classified as anaphylaxis with a biphasic nonanaphylactic reaction, whereas a patient with anaphylaxis who requires 3 doses of epinephrine and who receives symptom-directed therapy would be described as having refractory anaphylaxis. These efforts may help better elucidate the true prevalence of persistent, refractory, and biphasic anaphylaxis, and they may be incorporated into study protocols to evaluate the efficacy of adjunctive anaphylaxis medications (eg, systemic steroids, antihistamines) and novel therapeutics.

There was robust discussion about whether definitions should apply to broad categories of patient ages and allergens or should instead be limited in scope. These were important questions given that reactions may be caused by allergens involving different pathophysiologic pathways necessitating tailored short- and long-term management decisions. Although there was uncertainty as to whether the definitions should apply to infants, consensus was ultimately reached that infants should be included; however, it is important to acknowledge that the sensitivity of these definitions may be lower in infancy because symptoms are more difficult to detect in this age group. Thus, these criteria should not dictate management decisions across all settings, and contextual clinical management remains paramount. Instead, the definitions are designed to standardize the terminology used to describe patient outcomes following anaphylactic reactions. This statement was instrumental to the study, given that we sought to develop definitions that clinicians and researchers alike would support to advance patient care and research, and thus would, we believe, lead to their widespread dissemination and application.

Panel members repeatedly emphasized that the definitions are not intended to dictate clinical care, given that there may be unique diagnostic and therapeutic decisions for specific allergens and patient presentations. Additionally, the definitions are not prescriptive to decision making about observation periods or need for hospitalization. For example, it may be reasonable for a patient with isolated oropharyngeal edema to have an extended observation period to ensure that he or she does not develop upper airway obstruction despite not fulfilling the criteria for persistent or refractory anaphylaxis. Similarly, a patient with anaphylaxis that lasts 3 hours may require hospitalization despite the reaction not fulfilling persistent anaphylaxis criteria.

When the outcome definitions were developed, a key concept was whether definitions were independent of the management of the initial reaction. The group reached consensus that for persistent and biphasic reactions, the diagnosis was not dependent on management of the initial reaction given that the definitions are intended to classify the presence or absence of symptoms in relation to the initial reaction. However, there was recognition that there is a subset of patients who have persistent anaphylactic reactions despite treatment with multiple doses of epinephrine and symptom-directed medical management, and thus, we developed a definition for refractory anaphylaxis. Although the definition introduces subjective elements such as treatment decisions, we believe that this is an important clinical and research distinction given that there is no precise estimate in the literature about the prevalence and risk factors for refractory or fatal anaphylaxis, or about how to optimize treatment strategies in this high-risk cohort.16

A fundamental theme of the definitions is the timing of new or recurrent symptoms and the duration of persistent anaphylaxis. Although there was agreement that definitions should include clear time delineations, it was acknowledged that there are insufficient data to inform these time periods. It was underscored that reducing or extending time thresholds would affect the prevalence of outcomes and the sensitivity and/or specificity of definitions. Similarly, shortening the asymptomatic period for biphasic anaphylaxis would be associated with an increased prevalence of these reactions and would also increase the definition’s sensitivity. In contrast, an excessively short asymptomatic period (eg, 1 minute) would not be clinically or biologically plausible and would reduce the definition’s specificity, whereas an excessively long minimal asymptomatic period (eg, 12 hours) would not have face validity for clinicians who would be reluctant to not categorize symptoms that recur after 4 or 6 hours as biphasic. To account for these scenarios, the group made a concerted effort to ensure that time thresholds be clinically and biologically plausible to ensure buy-in from clinicians and researchers alike, and it also agreed that for persistent anaphylaxis, symptoms and/or examination findings must last at least 4 hours, whereas for biphasic anaphylaxis, the asymptomatic period must last from 1 to 48 hours.

Limitations and future areas for research

This study is subject to limitations that are related mainly to the paucity of validated clinical or basic science research to support the criteria on which the definitions are based. We recognize that consensus was reached for definitions and time thresholds based on expert opinion using the best available evidence and not based on objective data such as trends in the level of anaphylaxis biomarkers (eg, tryptase) over time. This was required, as there are currently no biomarkers routinely used in clinical practice that correlate well with symptoms or clinical courses.16 Additionally, for the definitions of persistent and biphasic anaphylaxis, we were not able to provide an explanation of how the route of allergen exposure might elicit persistent or recurrent or new symptoms (eg, persistent allergen exposure in the gastrointestinal tract) or of how medications and their half-lives might affect symptom duration or recurrence. Although the definitions rely on the 2006 NIAID/FAAN anaphylaxis criteria,1 we recognize that there are new proposed anaphylaxis diagnostic criteria in the literature.17 The group reached consensus that the 2006 NIAID/FAAN criteria should be used given that they are broadly applied in clinical practice and research, have been validated in both retrospective and prospective studies, and have withstood the test of time since their inception.1,18,19 We believe that the definitions proposed in this study could be easily adopted based on modifications to the NIAID/FAAN criteria or new diagnostic criteria.

Despite these limitations, we believe that this study is foundational because it proposes definitions that have the potential to advance clinical care and research, including prospective cohort studies to evaluate the feasibility of applying the definitions in clinical and research settings and thereby determining the true prevalence of these reactions. Although we based the definitions on symptoms and examination findings, we are optimistic that this work reinforces the need to transition current clinical practice to a precision medicine model of care.20,21 Such a model would incorporate biomarkers, genetics, and epigenetics to enhance clinicians’ ability to accurately diagnose anaphylaxis, predict treatment responses and patient-specific risks of persistent or biphasic reactions, and develop targeted therapies to treat and prevent anaphylaxis among high risk individuals.

Finally, there is a need for a consensus anaphylaxis severity grading system for application in clinical care and research. The limitations of prior grading systems include the use of nonspecific terms to denote reaction severity and the inability to differentiate between clinically important phenotypes. Additionally, some grading systems are complex and difficult to remember (which precludes their use in clinical care), whereas others have limited relevance in research because they lack granularity or do not account for the totality of symptoms during the course of reactions.22–32 Thus, a consensus grading system must be clinically relevant for patients and families and must enable researchers to accurately categorize reaction severity when assessing the efficacy of current and novel therapies in clinical trials. Such a severity system could be incorporated into the outcome definitions outlined in this study to categorize the severity of persistent and biphasic anaphylaxis.

Conclusion

We have developed consensus definitions of persistent, refractory, and biphasic anaphylaxis, as well as definitions of persistent and biphasic nonanaphylactic reactions. Successful dissemination and application of these definitions in clinical care and research has the potential to standardize the terminology used to describe anaphylaxis outcomes among clinicians and patients. They can serve as a foundation for future research to evaluate the epidemiology of anaphylaxis, transform current clinical practice to a precision medicine model of care, and determine the efficacy of current and novel therapeutics. Additionally, this study supports the need to develop a consensus anaphylaxis severity grading system for application in clinical care and research.

Supplementary Material

Supplemental materials

Clinical implications:

The anaphylaxis outcome definitions proposed in this study have the potential to improve and standardize the care of and research outcomes for patients with anaphylaxis.

Acknowledgments

Supported by the Division of Emergency Medicine, Cincinnati Children’s Hospital Medical Center.

Disclosure of potential conflict of interest: H. A. Sampson receives funding to his institution for grants from the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) and is employed part-time by and has received stock options from DBV Technologies. C. A. Camargo has consulted for Bryn Pharma and Kaleo. D. C. Brousseau receives funding from the NIH and Maternal and Child Health Bureau. J. M. Spergel has grant support from DBV Technology, AImmune, and NIH; he has consulted for Kaleo. M. Shaker has a brother who is chief executive officer of Altrix Medical. He is a member of the Joint Task Force on Practice Parameters and serves as an editorial board member for the Journal of Allergy and Clinical Immunology In Practice, Annals of Allergy, Asthma, and Immunology, and Journal of Food Allergy. R. L. Campbell has been a peer reviewer for EB Medicine and an author for UpToDate. K. A. Michelson receives funding from Agency for Healthcare Research and Quality. A. H. Assa’ad has research grants from NIH, Aimmune, DBV Technologies, Astellas, AbbVie, and Sanofi. M. Castells is the Brigham and Women’s Hospital principal investigator for the PIONEER BluPrint Clinical trial for Indolent Systemic Mastocytosis. L. C. Schneider has received research support from Regeneron Pharmaceuticals, DBV Technologies, Pfizer, and Genentech; in addition, he has consulted for Aimmune Therapeutics and is on the Medical Advisory Board of FARE (Food Allergy Research and Education). J. Wang receives research support from NIAID, Aimmune, DBV Technologies, and Regeneron, as well as consultancy fees from Aimmune, ALK-Abelló, DBV Technologies, and Genentech. R. Mistry receives funding from the NIAID. D. Schnadower receives funding from the NIH. The rest of the authors declare that they have no relevant conflicts of interest.

Abbreviations used

DI

Disagreement index

ED

Emergency department

NIAID/FAAN

National Institute of Allergy and Infectious Diseases and Food Allergy and Anaphylaxis Network

REFERENCES

  • 1.Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF, Bock SA, Branum A, 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. J Allergy Clin Immunol 2006;117:391–7. [DOI] [PubMed] [Google Scholar]
  • 2.Shaker MS, Wallace DV, Golden DBK, Oppenheimer J, Bernstein JA, Campbell RL, et al. Anaphylaxis–2020 practice parameter update, systematic review, and grading of recommendations, assessment, development and evaluation (GRADE) analysis. J Allergy Clin Immunol 2020;145:1082–123. [DOI] [PubMed] [Google Scholar]
  • 3.Michelson KA, Dribin TE, Vyles D, Neuman MI. Trends in emergency care for anaphylaxis. J Allergy Clin Immunol Pract 2020;8:767–8.e2. [DOI] [PubMed] [Google Scholar]
  • 4.Wolf R, Sclar DA, Marx M-E. Food allergy and anaphylaxis - 2051. Economic burden of anaphylaxis in the United States. World Allergy Organ J 2013;6:P134. [Google Scholar]
  • 5.Simons FER, Ardusso LRF, Bilò MB, El-Gamal YM, Ledford DK, Ring J, et al. World Allergy Organization guidelines for the assessment and management of anaphylaxis. World Allergy Organ J 2011;4:13–37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Alqurashi W, Stiell I, Chan K, Neto G, Alsadoon A, Wells G. Epidemiology and clinical predictors of biphasic reactions in children with anaphylaxis. Ann Allergy Asthma Immunol 2015;115:217–23.e2. [DOI] [PubMed] [Google Scholar]
  • 7.Lee S, Peterson A, Lohse CM, Hess EP, Campbell RL. Further evaluation of factors that may predict biphasic reactions in emergency department anaphylaxis Patients. J Allergy Clin Immunol Pract 2017;5:1295–301. [DOI] [PubMed] [Google Scholar]
  • 8.Lee S, Sadosty AT, Campbell RL. Update on biphasic anaphylaxis. Curr Opin Allergy Clin Immunol 2016;16:346–51. [DOI] [PubMed] [Google Scholar]
  • 9.Fitch K, Bernstein SJ, Aguilar MD, Burnand B, LaCalle JR, Lazaro P, et al. The RAND/UCLA appropriateness method user’s manual. Santa Monica, CA: RAND; 2001. [Google Scholar]
  • 10.Hopkins PM, Cooke PJ, Clarke RC, Guttormsen AB, Platt PR, Dewachter P, et al. Consensus clinical scoring for suspected perioperative immediate hypersensitivity reactions. Br J Anaesth 2019;123:e29–37. [DOI] [PubMed] [Google Scholar]
  • 11.Maverakis E, Wang EA, Shinkai K, Mahasirimongkol S, Margolis DJ, Avigan M, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis standard reporting and evaluation guidelines: results of a National Institutes of Health working group. JAMA Dermatol 2017;153:587–92. [DOI] [PubMed] [Google Scholar]
  • 12.Harris P, Taylor R, Thielke R, Payne J, Gonzalez N, Conde J. Research electronic data capture (REDCap)–a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inf 2009;42:377–81. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Lee S, Bellolio MF, Hess EP, Erwin P, Murad MH, Campbell RL. Time of onset and predictors of biphasic anaphylactic reactions: a systematic review and meta-analysis. J Allergy Clin Immunol Pract 2015;3:408–16.e2. [DOI] [PubMed] [Google Scholar]
  • 14.Lee JM, Greenes DS. Biphasic anaphylactic reactions in pediatrics. Pediatrics 2000;106:762–6. [DOI] [PubMed] [Google Scholar]
  • 15.Rohacek M, Edenhofer H, Bircher A, Bingisser R. Biphasic anaphylactic reactions: occurrence and mortality. Allergy Eur J Allergy Clin Immunol 2014;69:791–7. [DOI] [PubMed] [Google Scholar]
  • 16.Campbell RL, Li JTC, Nicklas RA, Sadosty AT. Emergency department diagnosis and treatment of anaphylaxis: a practice parameter. Ann Allergy Asthma Immunol 2014;113:599–608. [DOI] [PubMed] [Google Scholar]
  • 17.Turner PJ, Worm M, Ansotegui IJ, El-gamal Y, Rivas MF, Fineman S, et al. Time to revisit the definition and clinical criteria for anaphylaxis? World Allergy Organ J 2019;12(10):1–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Brauer CEL, Motosue MS, Li JT, Hagan JB, Bellolio MF, Lee S, et al. Prospective validation of the NIAID/FAAN criteria for emergency department diagnosis of anaphylaxis. J Allergy Clin Immunol Pract 2016;4:1220–6. [DOI] [PubMed] [Google Scholar]
  • 19.Campbell RL, Hagan JB, Manivannan V, Decker WW, Kanthala AR, Bellolio MF, et al. Evaluation of National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network criteria for the diagnosis of anaphylaxis in emergency department patients. J Allergy Clin Immunol 2012;129:748–52. [DOI] [PubMed] [Google Scholar]
  • 20.Castells M Diagnosis and management of anaphylaxis in precision medicine. J Allergy Clin Immunol 2017;140:321–33. [DOI] [PubMed] [Google Scholar]
  • 21.Muraro A, Lemanske RF, Castells M, Torres MJ, Khan D, Simon H, et al. Precision medicine in allergic disease-food allergy, drug allergy, and anaphylaxis-PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology. Allergy 2017;72:1006–21. [DOI] [PubMed] [Google Scholar]
  • 22.Brown SGA. Clinical features and severity grading of anaphylaxis. J Allergy Clin Immunol 2004;114:371–6. [DOI] [PubMed] [Google Scholar]
  • 23.Sampson HA, van Wijk RG, Carsten Bindslev-Jensen SS, Teuber SS, Burks AW, Dubois AEJ, et al. Standardizing double-blind, placebo-controlled oral food challenges: American Academy of Allergy, Asthma & Immunology - European Academy of Allergy and Clinical Immunology PRACTALL consensus report. J Allergy Clin Immunol 2012;130:1260–74. [DOI] [PubMed] [Google Scholar]
  • 24.Cox LS, Sanchez-Borges M, Lockey RF. World Allergy Organization systemic allergic reaction grading system: is a modification needed? J Allergy Clin Immunol Pract 2017;5:58–62.e5. [DOI] [PubMed] [Google Scholar]
  • 25.Muraro A, Fernandez-Rivas M, Beyer K, Cardona V, Clark A, Eller E, et al. The urgent need for a harmonized severity scoring system for acute allergic reactions. Allergy 2018;73:1792–800. [DOI] [PubMed] [Google Scholar]
  • 26.Niggemann B, Beyer K. Time for a new grading system for allergic reactions? Allergy 2016;71:135–6. [DOI] [PubMed] [Google Scholar]
  • 27.Burks AW, Jones SM, Wood RA, Fleischer DM, Sicherer SH, Lindblad RW, et al. Oral immunotherapy for treatment of egg allergy in children. N Engl J Med 2012; 367:233–43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Andorf S, Purington N, Block WM, Long AJ, Tupa D, Brittain E, et al. Anti-IgE treatment with oral immunotherapy in multifood allergic participants: a double-blind, randomised, controlled trial. Lancet Gastroenterol Hepatol 2018;3:85–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Sampson HA. Anaphylaxis and emergency treatment. Pediatrics 2003;111(suppl 3): 1601 LP–8 LP. [PubMed] [Google Scholar]
  • 30.Du Toit G, Roberts G, Sayre PH, Bahnson HT, Radulovic S, Santos AF, et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med 2015;372:803–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Ring J, Messmer K. Incidence and severity of anaphylactoid reactions to colloid volume substitutes. Lancet 1977;309:466–9. [DOI] [PubMed] [Google Scholar]
  • 32.Mueller HL. Further experiences with severe allergic reactions to insect stings. N Engl J Med 1959;261:374–7. [DOI] [PubMed] [Google Scholar]

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