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

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 de-identified 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; Delphi; biphasic anaphylaxis; biphasic nonanaphylactic reactions; emergency department; persistent anaphylaxis; persistent nonanaphylactic reactions; refractory anaphylaxis.

FIG 1.

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).