Practice Parameters Anaphylaxis: A 2023 practice parameter update

Practice Parameters
Anaphylaxis: A 2023 practice parameter update
David B.K. Golden, MDCM*; Julie Wang, MD
y
; Susan Waserman, MD
z
; Cem Akin, MD
x
;
Ronna L. Campbell, MD, PhD
ǁ
; Anne K. Ellis, MD, MSc
{
; Matthew Greenhawt, MD, MBA, MSc 
# 
;
David M. Lang, MD**; Dennis K. Ledford, MD
yy,zz
; Jay Lieberman, MD
xx
;
John Oppenheimer, MD
ǁǁ
; Marcus S. Shaker, MD, MSc
{{,## 
; Dana V. Wallace, MD***;
Elissa M. Abrams, MD, MPH
yyy
; Jonathan A. Bernstein, MD
zzz,xxx
; Derek K. Chu, MD, PhD
ǁǁǁ
;
Caroline C. Horner, MD, MSCI
{{{
; Matthew A. Rank, MD 
### 
; David R. Stukus, MD****; Collabo-
rators ; Alyssa G. Burrows, BHSc, MSc
{
; Heather Cruickshank, BA
z
; Workgroup Contributors;
David B.K. Golden, MDCM*; Julie Wang, MD
y
; Cem Akin, MD
x
; Ronna L. Campbell, MD, PhD
ǁ
;
Anne K. Ellis, MD, MSc
{
; Matthew Greenhawt, MD, MBA, MSc 
#
; David M. Lang, MD**;
Dennis K. Ledford, MD
yy,zz
; Jay Lieberman, MD
xx
; John Oppenheimer, MD
ǁǁ
;
Marcus S. Shaker, MD, MSc
{{,## 
; Dana V. Wallace, MD***; Susan Waserman, MD
z
; Joint Task
Force on Practice Parameters Reviewers ; Elissa M. Abrams, MD, MPH
yyy
;
Jonathan A. Bernstein, MD
zzz,xxx
; Derek K. Chu, MD, PhD
ǁǁǁ
; Anne K. Ellis, MD
{
;
David B.K. Golden, MDCM*; Matthew Greenhawt, MD, MBA, MSc 
#
;
Caroline C. Horner, MD, MSCI
{{{
; Dennis K. Ledford, MD
yy,zz
; Jay Lieberman, MD
xx
;
Matthew A. Rank, MD
### 
; Marcus S. Shaker, MD, MSc
{{,## 
; David R. Stukus, MD****;
Julie Wang, MD
y
* Johns Hopkins School of Medicine, Baltimore, Maryland
y 
Icahn School of Medicine at Mount Sinai, New York, New York
z 
Division of Clinical Immunology and Allergy, McMaster University, Hamilton, Canada
x 
Division of Allergy and Clinical Immunology, Department of Medicine, University of Michigan, Ann Arbor, Michigan
ǁ 
Department of Emergency Medicine, Mayo Clinic, Rochester, Minnesota
{ 
Division of Allergy & Immunology, Department of Medicine, Queen’s University, Kingston, Canada
# 
Section of Allergy and Immunology, Children’s Hospital Colorado, Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado
** 
Department of Allergy and Clinical Immunology, Cleveland Clinic, Cleveland, Ohio
yy 
James A. Haley VA Hospital, Tampa, Florida
zz 
Morsani College of Medicine, University of South Florida, Tampa, Florida
xx 
The University of Tennessee Health Science Center, Memphis, Tennessee
ǁǁ 
Department of Internal Medicine, University of Medicine and Dentistry of New Jersey-Rutgers New Jersey Medical School, Newark, New Jersey
{{ 
Geisel School of Medicine, Hanover, New Hampshire
## 
Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire
*** 
Nova Southeastern University, Fort Lauderdale, Florida
yyy 
Department of Pediatrics and Child Health, Section of Allergy and Clinical Immunology, Children’s Hospital Research Institute of Manitoba, Winnipeg, Canada
zzz 
Division of Rheumatology, Allergy, and Immunology, University of Cincinnati College of Medicine, Cincinnati, Ohio
xxx 
Bernstein Allergy Group and Bernstein Clinical Research Center, Cincinnati, Ohio
ǁǁǁ 
Department of Medicine and Department of Health Research Methods, Evidence & Impact, McMaster University, Hamilton, Canada
{{{ 
Division of Allergy & Pulmonary Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
### 
Mayo Clinic in Arizona and Phoenix Children’s Hospital, Scottsdale and Phoenix, Arizona
**** 
Nationwide Children’s Hospital and The Ohio State University College of Medicine, Columbus, Ohio
A R T I C L E I N F O
Article history:
Received for publication August 17, 2023.
Received in revised form September 29, 2023.
A B S T R A C T
This practice parameter update focuses on 7 areas in which there are new evidence and new recommendations.
Diagnostic criteria for anaphylaxis have been revised, and patterns of anaphylaxis are defined. Measurement of
serum tryptase is important for diagnosis of anaphylaxis and to identify underlying mast cell disorders. In infants
and toddlers, age-specific symptoms may differ from older children and adults, patient age is not correlated with
Address correspondence to: David B.K. Golden, MDCM, or Julie Wang, MD, AAAAI/ACAAI Joint Task Force on Allergy-Immunology Practice Parameters, 555 E Wells Street, Suite
1100, Milwaukee, WI 53212. Email: [email protected]. Or: [email protected].
Previously published practice parameters and guidelines of the JTFPP are available at http://www.allergyparameters.org., http://www.AAAAI.org, and http://www.ACAAI.org.
https://doi.org/10.1016/j.anai.2023.09.015
1081-1206/© 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc.
ARTICLE IN PRESS
Ann Allergy Asthma Immunol 000 (2023) 1−53
Contents lists available at ScienceDirect

Accepted for publication September 29, 2023. 
reaction severity, and anaphylaxis is unlikely to be the initial reaction to an allergen on first exposure. Different
community settings for anaphylaxis require specific measures for prevention and treatment of anaphylaxis. Opti-
mal prescribing and use of epinephrine autoinjector devices require specific counseling and training of patients
and caregivers, including when and how to administer the epinephrine autoinjector and whether and when to
call 911. If epinephrine is used promptly, immediate activation of emergency medical services may not be
required if the patient experiences a prompt, complete, and durable response. For most medical indications, the
risk of stopping or changing beta-blocker or angiotensin-converting enzyme inhibitor medication may exceed
the risk of more severe anaphylaxis if the medication is continued, especially in patients with insect sting ana-
phylaxis. Evaluation for mastocytosis, including a bone marrow biopsy, should be considered for adult patients
with severe insect sting anaphylaxis or recurrent idiopathic anaphylaxis. After perioperative anaphylaxis, repeat
anesthesia may proceed in the context of shared decision-making and based on the history and results of diag-
nostic evaluation with skin tests or in vitro tests when available, and supervised challenge when necessary.
© 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc.
What Is New and What Is Different
This practice parameter is not a comprehensive review of anaphy-
laxis but focuses on 7 areas in which new evidence has emerged and
in which recommendations may now be different from previous
practice parameters.
Diagnosis
Accurate classification, criteria, and definitions for the diagnosis of
anaphylaxis are critical for proper treatment and consistency in
research studies that would enable meaningful evidence analysis and
stronger recommendations. Revised criteria by the World Allergy
Organization (WAO), Brighton, and Delphi Consensus groups aim to
create more universally accepted definitions and criteria for anaphy-
lactic reactions. Biphasic anaphylaxis is associated with greater sever-
ity of an initial reaction, persistence of the reaction, and use of more
than one dose of epinephrine. Baseline serum tryptase (bST) level
should be measured in patients presenting with a history of recur-
rent, idiopathic, or severe anaphylaxis, Hymenoptera venom anaphy-
laxis, or with suspected mastocytosis. Evaluation for hereditary
a-tryptasemia (HaT) and clonal mast cell disease should be consid-
ered if bST level is more than 8 ng/mL. Alpha-gal allergy can be a
cause of unexplained anaphylaxis.
Infants and Toddlers
The diagnosis and treatment of anaphylaxis may be even more
challenging in infants. As our understanding improves, so can our
recommendations for this important age group. In infants and tod-
dlers, patient age is not correlated with reaction severity, and ana-
phylaxis is unlikely to be the initial reaction to an allergen on first
exposure. Infants and toddlers may display age-specific symptoms
that are less often reported in older children and adults.
Community Settings
Anaphylaxis is most difficult to recognize and treat outside of
health care facilities. Reactions may occur at home, school, work, din-
ing out, traveling, or in many other locations, and situations can be
associated with different patient characteristics, causes, or available
options for treatment or prevention. Patients at high risk for anaphy-
laxis, and their caregivers, should be counseled regarding the carry-
ing and using of epinephrine autoinjectors (EAIs) and the recognition
and avoidance of exposures. Childcare centers and schools should
implement staff training and stock undesignated EAI that can be used
to treat any individual who experiences anaphylaxis.
Epinephrine Autoinjectors
The cardinal treatment of anaphylaxis is prompt epinephrine
injection. The optimal prescribing and use of EAI devices require spe-
cific counseling and training of patients and caregivers, including
when and how to administer the EAI and whether and when to call
911 (emergency medical services [EMS]). Health care professionals
should consider a patient’s risk factors for severe anaphylaxis, their
values and preferences, and the burden of both anaphylaxis and EAI
prescription when deciding whether to prescribe EAIs and the num-
ber of EAIs to prescribe. If epinephrine is used promptly, immediate
activation of the EMS may not be required if the patient experiences
prompt, complete, and durable response to treatment. EMS should be
activated if anaphylaxis is severe, fails to resolve promptly, fails to
resolve completely or nearly completely, or returns or worsens after
the first dose of epinephrine.
Beta-Blockers and Angiotensin-Converting Enzyme Inhibitors
Both beta-blockers (BBs) and angiotensin-converting enzyme
inhibitors (ACEIs) have been previously considered to be contraindi-
cated in patients at high risk for anaphylaxis because of increased
risk of severe anaphylaxis. Larger and more focused studies have pro-
vided new insights into the relative risk of these medications and
have improved guidance on whether it is necessary to change or stop
these medicines in some patients. For most medical indications, the
risk of stopping or changing the medication may exceed the risk of
more severe anaphylaxis if the medication is continued, especially in
patients with insect sting anaphylaxis. Venom immunotherapy (VIT)
may be considered for patients receiving BBs/ACEIs, with shared deci-
sion-making regarding the balance of benefits and harms. Patients
receiving maintenance-dose allergen immunotherapy (AIT) have
minimal increased absolute risk of severe anaphylactic reaction
when receiving BBs/ACEIs and may consider continuing AIT and med-
ications based on shared decision-making.
Mast Cell Disorders
Many mast cell disorders are associated with an inherently
greater risk of anaphylaxis. Advances in recent years are beginning to
enable better recognition of the related phenotypes, application of
new diagnostic methods, and targeting treatment to prevent anaphy-
laxis. The bST level should be measured in patients with severe insect
sting anaphylaxis, particularly among those who had hypotension
and/or absence of urticaria, in all cases of recurrent unexplained ana-
phylaxis, and in patients with suspected mastocytosis. Evaluation for
mastocytosis, including a bone marrow biopsy, should be considered
for adult patients with severe insect sting anaphylaxis or recurrent
idiopathic anaphylaxis (IA), particularly those with a predictive Red
Espanola MAstocitosis (REMA) score. New treatment modalities are
under investigation to prevent anaphylaxis in high-risk patients.
Perioperative Anaphylaxis
Continued study of anaphylaxis during and after surgical anesthe-
sia has improved the recognition of the most common culprits and
the approach to counseling for future surgery and anesthesia through
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testing, challenge, or strategic avoidance, when necessary, based on
availability of the materials and expertise. After perioperative ana-
phylaxis (POA), repeat anesthesia may proceed in the context of
shared decision-making and based on the history and results of diag-
nostic evaluation. Immediate hypersensitivity skin testing (percuta-
neous and intradermal) and/or in vitro-specific IgE testing should be
performed, if available, to all potential pharmacologic and nonphar-
macologic culprits used during the perioperative period. If testing is
not possible, we suggest referral to another center or if necessary,
use of the most efficacious agents structurally dissimilar from the
most likely culprit. Challenges should be performed to all culprit
agents to which skin and/or in vitro testing is negative, but if this is
not feasible, avoidance of culprit pharmacologic and nonpharmaco-
logic agents associated with POA may be considered if equally effica-
cious, structurally unrelated alternatives are available.
Executive Summary
Anaphylaxis is characterized as a life-threatening systemic allergic
reaction that can include a range of clinical signs and symptoms.
Most definitions of anaphylaxis include vague words such as “gener-
alized” and/or “systemic” and/or “multi-organ” but there are instan-
ces where a single system is primarily affected. Although anaphylaxis
is not an infrequent occurrence, with a lifetime prevalence estimated
at 1.6% to 5.1%, advancing the understanding of anaphylaxis has been
hindered by the fact that several anaphylaxis criteria and grading sys-
tems exist, which can result in differing clinical assessments and ren-
ders comparisons between research studies difficult. Consistency in
diagnosis and classification of anaphylaxis is critical for proper treat-
ment and to facilitate research efforts. The 2006 National Institute of
Allergy and Infectious Diseases (NIAID) and Food Allergy and Ana-
phylaxis Network (FAAN) defined anaphylaxis as one of several clini-
cal diagnostic scenarios. This set of criteria has been widely adopted
and validated. The 2007 Brighton Collaboration Anaphylaxis Working
Group created a definition specifically for anaphylaxis occurring as
an adverse event after an immunization. In an effort to further sim-
plify diagnosis, the WAO created a definition with only 2 criteria. Rec-
ognizing that anaphylaxis courses can be variable, a Delphi
Consensus group defined parameters for biphasic, persistent, and
refractory anaphylaxis. Validation of the WAO criteria and Delphi
Consensus group definitions will be helpful in determining their clin-
ical utility.
Having reliable predictors of anaphylaxis severity can help opti-
mize treatment, but severity of reactions is influenced by many dif-
ferent factors related to the patient and the allergen. Biphasic
anaphylaxis is associated with greater severity of the initial reaction
and requirement of more than one dose of epinephrine to treat the
initial symptoms. Although determining the diagnosis and severity
grading are not necessary for initiating treatment with epinephrine
during an acute allergic reaction, establishing the anaphylaxis diag-
nosis and severity using available criteria and grading systems is
important to communicate the clinical history and to counsel on
future management. Conversely, the use of epinephrine to treat an
allergic reaction does not confer a diagnosis of anaphylaxis.
Diagnosing anaphylaxis relies on a thorough clinical history that
includes patient characteristics (eg, age, sex, medical and atopic his-
tory, concurrent medications), detailed description of the reaction
(possible triggers, symptom pattern, timing of onset duration of
symptoms), concomitant factors (eg, exercise, viral infection, medica-
tions, menstrual status, stress, food, alcohol), and response to treat-
ment. The diagnosis can be supported by an elevated acute serum
tryptase level. Although a tryptase level above the laboratory-defined
normal value (eg, >11.4 ng/mL in many laboratories) is informative,
many cases of anaphylaxis may not be associated with a tryptase ele-
vation above that level. Particularly in these situations, an acute
serum total tryptase level at least 20% plus 2 ng/mL above the
patient’s bST level may provide evidence of systemic mast cell activa-
tion.
For patients with a history of recurrent, idiopathic, or severe ana-
phylaxis, or with suspected mastocytosis, obtaining a bST level is
advisable as elevated levels are found in patients with H
aT and clonal
mast cell disease and are associated with more severe anaphylaxis.
Adult patients with severe insect sting anaphylaxis or recurrent IA
may require evaluation for mastocytosis, including a bone marrow
biopsy, especially if they have a predictive REMA score. Alpha-gal
allergy should be considered in patients who have recurrent IA and
an appropriate exposure history.
Infant Anaphylaxis
With implementation of food allergy prevention guidelines, there
has been increased awareness and understanding of anaphylaxis in
the infant/toddler age group. Diagnosing anaphylaxis in infants and
toddlers can be challenging, and there are no age-specific anaphy-
laxis diagnostic criteria. Therefore, the current NIAID/FAAN or WAO
anaphylaxis criteria should be used to establish the diagnosis of ana-
phylaxis in infants/toddlers. These young children are unable to com-
municate their symptoms to their caregivers, and many signs and
symptoms of anaphylaxis can be indistinguishable from normal
infant behaviors or can be attributable to other conditions, so recog-
nizing these symptoms as part of anaphylaxis requires astute clinical
skills. In this young age group, patient age is not correlated with reac-
tion severity. When foods are introduced to young children, anaphy-
laxis is not frequently reported as the first reaction and is far less
common than mild-to-moderate, primarily cutaneous, reactions.
Clinicians may prescribe either the 0.1 mg or the 0.15 mg EAI dose
for infants/toddlers weighing less than 15 kg. Additional research is
needed to address knowledge gaps in the epidemiology, classifica-
tion, diagnosis, and management of anaphylaxis in infants and tod-
dlers.
Anaphylaxis in the Community Setting
Anaphylaxis is not always easy to recognize, and anaphylaxis
occurring outside the medical setting can be particularly challenging
to manage. Most cases occur at home, but anaphylaxis has also been
reported in community settings, including school, work, while dining
out, and during travel. Given the unpredictability of anaphylaxis, at-
risk patients and their caregivers should be counseled on allergen
avoidance strategies, identification of signs and symptoms of allergic
reactions, and advised to be prepared with EAIs at all times. Imple-
mentation of staff training and stocking undesignated EAIs at child-
care centers and schools may help improve anaphylaxis management
in these locations. Whereas current research does not support consis-
tent benefits of site-wide food-specific prohibition in the manage-
ment of food allergies in childcare centers and schools, there may be
specific circumstances in which implementation of allergen-
restricted zones (eg, milk-free table) may be appropriate, such as
when there are students who lack the capacity to self-manage.
Counseling patients on strategies to minimize allergen exposure
and preparedness to manage allergic reactions while dining out, dur-
ing travel, or activities in any community setting is important
because anaphylaxis can occur anywhere. Given that the risk of a
severe food allergy reaction is primarily associated with ingestion of
a food allergen rather than skin contact or inhalation, steps to pre-
vent unintentional allergen ingestion should be the main priority for
these patients. Counseling should include discussions on labeling reg-
ulations (both United States and those from other countries relevant
to the patient’s travel plans) that require disclosure of major aller-
gens on labels of prepackaged foods, while also noting that
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restaurants are not required to declare ingredients or provide allergy
warnings for non-prepackaged foods.
Management of anaphylaxis risk is a “shared responsibility” in the
restaurant setting (ie, both the allergic diner and food service staff
have roles to play in keeping the diner safe), so clear communication
is essential. There is a lack of high-quality data on the effects of spe-
cific strategies for safe dining, but patients may consider reviewing
menu options to make informed choices, disclosing the allergy to a
knowledgeable and responsible food service staff member before
ordering their meal, informing dining companions of the food allergy,
and avoiding situations where there may be a higher risk of cross-
contact, such as buffets.
Clinicians should counsel patients on standard management prac-
tices for allergic reactions, including having epinephrine readily
available. Although airplane emergency kits in the United States con-
tain epinephrine vials, drawing up appropriate doses using a needle
and a syringe in a cramped air cabin midflight during an acute reac-
tion is challenging and could lead to delayed treatment. Importantly,
stock epinephrine is not available in airports or during transit
between travel destinations, so it is imperative that patients are pre-
pared with their own EAIs at all times.
Epinephrine Autoinjectors
Epinephrine is the first-line treatment for anaphylaxis, and EAIs
allow patients to have this emergency medication available outside the
medical setting. A patient’s risk factors for severe anaphylaxis, their
values and preferences, and the burden of both anaphylaxis and EAI
prescription are important factors to consider when deciding whether
to prescribe EAIs and how many EAIs to prescribe. There are no vali-
dated risk-stratification algorithms in the research literature to guide
EAI prescription, but expert opinion suggests that patients with the fol-
lowing are at higher likelihood of requiring treatment with their pre-
scribed EAI: history of systemic allergic reaction or anaphylaxis to their
food allergen; IA; frequent allergen exposure through occupation or
other activities (for venom, latex, drug allergy); prior systemic allergic
reaction to AIT or VIT; venom allergy with honey bee as the trigger, ele-
vated bST level, older age, underlying cardiovascular disease (CVD);
venom-induced anaphylaxis not treated with VIT; exercise-induced
anaphylaxis; and cold-induced urticaria. Prescription of EAIs is advised
for omalizumab and sublingual immunotherapy (SLIT) even though
they cause anaphylaxis in less than 1% of all treated patients. Multiple
EAIs are commercially available, so dosage, needle length, affordability,
access, and patient treatment preferences should be taken into account
when prescribing EAIs.
The current standard practice is to treat anaphylaxis with a dosage
of epinephrine of 0.01 mg/kg, up to a maximum of 0.3 mg for children
and teenagers and 0.5 mg for adults. EAIs are only available in a limited
number of premeasured doses. Although the US Food and Drug Admin-
istration (US FDA) has approved 0.3 mg EAIs for patients weighing
above or equal to 30 kg, 0.15 mg EAIs for patients weighing 15 to
30 kg, and a 0.1 mg EAI (Auvi-Q) for patients weighing 7.5 to 15 kg,
multiple medical organizations (American Academy of Allergy, Asthma
& Immunology [AAAAI], American Academy of Pediatrics [AAP], Cana-
dian Society of Allergy and Clinical Immunology [CSACI], and European
Academy Allergy and Clinical Immunology [EAACI]) support switching
to 0.3 mg at 25 kg to limit underdosing in patients nearing 30 kg. The
AAP supports the option to use the 0.1 mg dose (if available) for
patients weighing 7.5 to 13 kg and the 0.15 mg dose for patients
weighing 13 to 25 kg. However, the 0.1 mg EAI is not universally avail-
able, and the AAP and Joint Task Force on Practice Parameters (JTFPP)
support the use of 0.15 mg EAIs for young children less than 15 kg.
Those prescribed EAIs should receive counseling and training on
when and how to administer the device and steps to take after
administration. Available evidence suggests that early epinephrine
use for anaphylaxis may improve clinical outcomes by decreasing
risk of biphasic reactions and the need for hospitalization. Therefore,
epinephrine should be administered at the first sign or symptom of
suspected anaphylaxis. However, there is no evidence that preemp-
tive use of epinephrine in an asymptomatic patient will prevent ana-
phylaxis. Serious adverse reactions to intramuscular epinephrine are
rare and should not pose a barrier to the prescription or early admin-
istration of EAIs when indicated. Immediate activation of EMS after
EAI use may not be required if the patient experiences prompt, com-
plete, and durable response to treatment and has access to additional
EAIs. Situations that would warrant EMS activation include severe
anaphylaxis, symptoms that do not resolve promptly, completely, or
nearly completely, or symptoms that return or worsen.
Beta-Blockers and Angiotensin-Converting Enzyme Inhibitors
Both BBs and ACEIs have been previously considered to be contra-
indicated in patients at high risk for anaphylaxis because their physi-
ological effects could theoretically increase the severity of
anaphylaxis and affect the response to treatment. The BBs may
reduce compensatory cardiovascular responses to anaphylaxis,
enhance the release of mast cell mediators, and interfere with the
effects of epinephrine. The ACEIs prevent the breakdown of bradyki-
nin, promote vasodilation, and may have direct effects on mast cells.
With more recent data and availability of more cardioselective
beta-blocking agents, shared decision-making is needed when
assessing the risks of potential anaphylaxis while receiving the BBs/
ACEIs, the cardiac risk of stopping the BBs/ACEIs, and alternative
medications or procedures. For patients with insect sting allergy who
receive BBs/ACEIs, VIT may be considered as there seems to be little
or no increased risk of reaction to VIT associated with these cardio-
vascular medications. Similarly, AIT may be pursued in patients on
BBs or ACEIs, but shared decision-making (regarding the potential
risk of a more severe reaction) is important when considering this
treatment approach. Those on maintenance AIT have minimal
increased risk of severe anaphylactic reaction when concurrently on
BBs/ACEIs. For planned procedures that carry a risk of anaphylaxis
(eg, radiocontrast media [RCM], challenge/desensitization, and infu-
sion), if the BBs/ACEIs cannot be safely interrupted, then shared deci-
sion-making is critical to weigh the medical necessity of the
procedure against the relative risk of anaphylaxis and the possibility
of more severe reaction if the BBs/ACEIs are continued. Patients at
significant risk for recurrent and unexpected anaphylaxis (eg, severe
food allergy, mastocytosis, or mast cell activation syndrome [MCAS],
or recurrent IA) should receive counseling about the theoretical risk
of more severe anaphylaxis and should avoid nonselective BBs or
ACEIs, if possible. There is insufficient evidence to distinguish angio-
tensin receptor blockers (ARBs) from ACEIs with regard to the poten-
tial risk of more severe anaphylaxis.
Mastocytosis
Mastocytosis is a clonal disorder of mast cell proliferation and
is associated with episodic and chronic mast cell activation symp-
toms, including anaphylaxis. An estimated 40% to 50% of adults
and 10% of children with mastocytosis are at risk for anaphylaxis.
Risk factors for anaphylaxis associated with mastocytosis have
been identified as male sex, total serum IgE greater than 15 kU/L,
atopic background, and basal tryptase levels less than 42 ng/mL.
Basal tryptase levels greater than 42 ng/mL are associated with
mastocytosis but are reported not to have markedly increased
risk for severe anaphylaxis.
The World Health Organization (WHO) has updated classification
and diagnostic criteria for cutaneous and systemic mastocytosis. Key
presenting symptoms of systemic mastocytosis will overlap with
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anaphylaxis but also may include the cutaneous symptoms (eg, urti-
caria pigmentosa, blisters or bullae in infants, pruritus, urticaria, and
flushing), presyncope/syncope, constitutional symptoms (eg, fevers,
weight loss, night sweats), bone pain, and prominent gastrointestinal
symptoms, such as reflux, nausea, vomiting, diarrhea, and colic. On
physical examination, hepatosplenomegaly and lymphadenopathy
may be prominent especially in patients with advanced disease.
Although an elevated bST level (>20 ng/mL) is considered a signifi-
cant contributory finding to the diagnosis, a tryptase elevation in iso-
lation is insufficient to make the diagnosis as this marker is not
specific for a mast cell disorder. A bone marrow biopsy revealing at
least 15 mast cells in aggregates is the major diagnostic criterion for
diagnosis of systemic mastocytosis. Clinicians ordering a bone mar-
row biopsy should ask for staining for tryptase, CD25 immunohis-
tochemistry and/or flow cytometry, the KIT D816Vmutation using a
highly sensitive allele-specific polymerase chain reaction (PCR)
−based technique, and if there is peripheral eosinophilia, a FIP1L1-
PDGRA mutational analysis.
There should be a high index of suspicion for mastocytosis in
patients who have had severe insect sting anaphylaxis, particularly
among those who had hypotension or absence of urticaria, and for
patients with recurrent unexplained/IA. Recent studies suggest that
in patients with insect sting anaphylaxis of any severity, bST levels
greater than 8 ng/mL indicate increased risk of severe anaphylaxis to
stings, and evaluation for an underlying mast cell disorder (including
H
aT) may be warranted. Treatment with VIT reduces the frequency
and severity of reactions to stings in patients with mastocytosis, but
these patients have higher rates of systemic reactions to VIT injec-
tions (15% compared with 5% of patients on VIT who do not have
mastocytosis). Patients with mastocytosis who have discontinued VIT
(even after a 5-year course) remain at higher risk of relapse; there-
fore, these patients should continue VIT indefinitely.
For patients with mastocytosis and recurrent anaphylaxis despite
optimized prophylactic therapy with H 
1 
and H 
2 
antihistamines, off-
label treatment with omalizumab can be considered as studies report
that it provided improved control of symptoms and prevention of
anaphylaxis. There is also evidence that mast cell cytoreduction
results in improvement of anaphylaxis in mastocytosis.
Perioperative Anaphylaxis
Perioperative anaphylaxis, which has a greater risk of death than
other types of anaphylaxis, occurs at a rate of 15.3 per 100,000 cases.
Evaluation of POA is complicated by the fact that multiple agents are
usually administered simultaneously or in close succession. Studies
suggest that antibiotics and paralytics (neuromuscular blocking
agents [NMBAs]) are the more common culprits. Rigorous evidence
on this topic is lacking because of the limitations resulting from the
relatively rare occurrence of POA and inability to perform double-
blind studies because of ethical considerations. Therefore, the
strength of evidence is uniformly low to very low.
After POA, repeat anesthesia may proceed in the context of shared
decision-making and directed by history and results of diagnostic
evaluation. Immediate hypersensitivity skin testing (percutaneous
and intradermal, if available) and/or in vitro-specific IgE testing
should be performed to all potential pharmacologic and nonpharma-
cologic culprits used during the perioperative period, including alter-
natives for anesthesia at the health care facility. Published resources
provide empirical, nonirritating concentrations for hypersensitivity
skin testing of potential culprit pharmacologic causes of POA. How-
ever, availability of drugs for testing is limited by the controlled
nature of many agents, and positive and negative likelihood ratios of
such testing have not been determined. Delaying immediate hyper-
sensitivity skin testing for 4 to 6 weeks after anaphylaxis is generally
recommended because a “refractory period” may result in lack of
skin testing response. Data reveal that graded challenge of agents
with negative test results can proceed safely, though this procedure
may require coordination with an anesthesiologist, depending on the
medication tested. If testing and challenge are not feasible, avoidance
of culprit pharmacologic and nonpharmacologic agents associated
with POA may be considered if equally efficacious, structurally unre-
lated alternatives are available.
Methods and Overview of the Practice Parameter Development
Process
The purpose of this practice parameter is to evaluate current evi-
dence and provide guidance to health care practitioners on the diag-
nosis and management of anaphylaxis. This updated practice
parameter focuses on topics selected by the workgroup as described
subsequently. By identifying knowledge gaps in the research litera-
ture, these guidelines may also help researchers to direct their atten-
tion to topics on which more studies are needed. This practice
parameter is meant to update the selected topics and to complement
our previous practice parameters on anaphylaxis but does not
entirely replace or supersede those documents which may be con-
sulted for additional background discussion on anaphylaxis and for
guidance on topics not selected for review in the current update. This
document is intended to be used by allergy/immunology specialists
and all health care providers who seek guidance on the evaluation
and management of patients with anaphylaxis.
Evidence has evolved since the previous anaphylaxis practice
parameters. Although the ideal type of reference would consist of a
randomized, double-blind, placebo-controlled study, the topic of this
practice parameter is represented by very few such studies. Conse-
quently, it was necessary to use observational studies, case series,
basic laboratory reports, and expert review articles to develop a doc-
ument that addresses most of the issues included in this practice
parameter. The references cited in this practice parameter represent
the best quality and most relevant evidence for the discussion and
recommendations made herein.
Development of these guidelines was funded by the JTFPP, which
is financially supported by the ACAAI and AAAAI. Leadership from
the ACAAI and AAAAI reviewed and approved the topics and ques-
tions for this document after input from the JTFPP and the Anaphy-
laxis workgroup. Members of the JTFPP and Anaphylaxis workgroup
received no compensation for their work related to this practice
parameter. The practice parameter development process involved
several stages. A workgroup of experts was appointed by the JTFPP
on behalf of the AAAAI and ACAAI. The workgroup, co-chaired by
David Golden, MD, and Julie Wang, MD, developed a list of key clini-
cal questions and topics to be addressed. The topics and questions
were selected to reflect the most significant advances and changes
in the field that affect clinical practice. At least 3 workgroup mem-
bers were assigned to review and write each topic. They then per-
formed literature searches to determine the most up-to-date
information for each consensus-based statement (CBS) and discus-
sion. Searches of the medical literature were performed using a vari-
ety of terms that were considered relevant for the topics under
review in this practice parameter. Literature searches were per-
formed on PubMed and in some cases also on MEDLINE, Medscape,
Google Scholar, and the Cochrane Database of Systematic Reviews.
The time frame for most searches was 2015 to 2022, but some topics
required searches for an expanded time frame from 1960 to the
present. The searches included only English-language articles. The
draft topics were reviewed by the workgroup co-chairs with subse-
quent revision by the authors. Subsequently, all sections were
reviewed and revised by the entire workgroup through several
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D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53 5

rounds of electronic and teleconference reviews. The practice
parameter was then reviewed in detail by the JTFPP, and revisions,
when needed, were made in conjunction with the workgroup.
External review followed as described previously in the Resolving
Conflicts of Interest section. Permission was obtained for all tables
and figures for which it was required.
This practice parameter contains recommendations intended to
optimize care of patients and to assist physicians and/or other health
care practitioners and patients to make decisions regarding evalua-
tion and management of suspected anaphylaxis. This practice param-
eter was not intended to be a document using Grading of
Recommendations, Assessment, Development and Evaluation
(GRADE) methodology, which was used for our previous focused ana-
phylaxis consensus-based guideline. Because GRADE documents
require a comprehensive literature search, systematic review, and
meta-analysis for each question, it is beyond the scope and resources
of a traditional practice parameter to attempt to conduct a GRADE
analysis for the large number of the questions for which clinicians
would like an answer. In addition, for many questions, there is very
limited evidence, and the workgroup/JTFPP must rely on expert evi-
dence and opinion. Therefore, in this practice parameter, most rec-
ommendations are made as CBSs, which are based on a recent
literature search of PubMed to update or add to the 2015 and 2020
Anaphylaxis practice parameter documents. For the non-GRADE
CBSs, the terminology used is intended to be transparent and consis-
tent with descriptions used across JTFPP Traditional and GRADE
guidelines. However, the use of this terminology does not imply that
we are equating our recommendations to the rigor required in a
GRADE guideline.
The strength of recommendation and the certainty of the evidence
for each CBS were determined by the group, based on their assess-
ment of the anticipated benefits and harms, certainty (quality) of the
evidence (including, when possible, magnitude of effect, indirectness,
inconsistency, imprecision, and risk of bias), and contextual factors
(resource allocation, costs, equity, feasibility, and acceptability).
Although the consensus of the workgroup was not always unani-
mous, the recommendations reflect the majority opinion, and points
of disagreement are clearly described in the text.
The strength of recommendation is determined to be either strong
or conditional based on published evidence, expert evidence, and
expert opinion. The significance and implications of this rating are
described in Table 1. Although the terminology is modeled after the
GRADE format, the rigor of the evidence collection and analysis is
limited. The certainty of evidence for each recommendation is deter-
mined to be high, moderate, low, or very low based on the kind of
evidence that has been published (eg, randomized controlled trials,
observational studies, case series and reports) and factors that rate
down or rate up the certainty of the evidence. The significance and
implications of this rating are described in Table 2. The intended
implications of these statements are similar to the GRADE format, but
the evidence basis is not necessarily as conclusive. When the JTFPP
did not have adequate published evidence with which to make a rec-
ommendation, but nonetheless recognized the need to provide guid-
ance to the clinician, the CBSs were based on the collective expert
opinion and experience of the workgroup and JTFPP. Table 3 lists all
the recommendations.
Main Text
Introduction and Background
Our understanding of anaphylaxis has grown steadily in recent
years, but many important knowledge gaps remain. 
1 
The previous
traditional practice parameter published in 2015 focused on the defi-
nition of anaphylaxis, prescribing of EAIs, mast cell disorders, and
unusual manifestations of anaphylaxis. 
2 
It also provided updates on
the evaluation, management, and prevention of anaphylaxis, and
anaphylaxis to foods, drugs, biologicals, insect stings, seminal fluid,
exercise, subcutaneous immunotherapy (SCIT), and POA. 
2 
As evi-
dence evolves in these areas and new observations are reported,
there develops a need for updated recommendations. This 2023
update of the Anaphylaxis Practice Parameter addresses what is new
or changed since 2015. The JTFPP of the AAAAI and ACAAI also pub-
lished a GRADE guideline on anaphylaxis in 2020 with highly focused
questions and recommendations regarding the risk of biphasic ana-
phylaxis and the use of antihistamines or corticosteroids to prevent
biphasic anaphylaxis or anaphylaxis owing to chemotherapy infu-
sions, aeroallergen rush immunotherapy, and RCM.
3 
This 2023
Update is meant to complement the 2020 GRADE guideline, not to
replace it or prior practice parameters.
The foundation for this practice parameter update is the library of
knowledge on anaphylaxis that was expertly reviewed in the 2020
GRADE guideline. This included the epidemiology and risk factors,
burden of disease for the most common triggers, pathogenesis, treat-
ment strategies, and paradigms, and other essential background
Table 1
Grading the Strength of Recommendations 
488
Strong recommendation
The workgroup and JTFPP are confident that the desirable effects of adherence to a recommendation outweigh the undesirable effects. This recommendation may be appropriate to
be used as a practice standard indicator. When making a strong recommendation, the wording is “We recommend” implying that the clinician would choose to follow the recom-
mendation in most circumstances.
The implications of a strong recommendation are the following:
 
For patients—Most people in this situation would want the recommended course of action and only a small proportion would not; request discussion if the intervention is not
offered.
 
For clinicians—Most patients should receive the recommended course of action.
 
For policy makers—The recommendation can be adopted as a policy in most situations.
Conditional recommendation
The workgroup and JTFPP concluded that the desirable effects of adherence to a recommendation probably outweigh the undesirable effect but are not confident. When making a
conditional recommendation, the wording is “We suggest” implying that the clinician may choose to follow the recommendation but that decisions may vary based on contextual
factors.
The implications of a conditional recommendation are the following:
 
For patients—Most people in this situation would want the recommended course of action, but many would not.
 
For clinicians—Recognize that different choices will be appropriate for different patients and that you must help each patient to arrive at a management decision consistent
with their values and preferences. It is likely that shared decision-making will play a major role in arriving at the management decision.
 
For policy makers—Policy making will require substantial debate and involvement of many stakeholders.
Abbreviation: JTFPP, Joint Task Force on Practice Parameters.
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Table 2
Grading the Certainty of Evidence for Each Recommendation 
489
High = Large and robust randomized controlled trial(s) or systematic reviews and meta-analyses inform intervention effects. Further research is very unlikely to change our confi-
dence in the estimate of effect.
Moderate = The recommendation would likely be based on somewhat limited evidence, for example, randomized trials with study limitations. Further research is likely to have an
important impact on our confidence in the estimate of effect and may change the estimate.
Low = The recommendation would likely be based on very weak evidence, for example, mostly observational studies (nonrandomized studies) and registries. Further research is
very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low = The recommendation is based largely on very low quality studies and/or on expert opinion. Any estimate of effect is very uncertain.
Table 3
List of Recommendations
Section and
number
Method Recommendation Strength of
recommendation
Certainty of
evidence
Diagnosis of anaphylaxis
1 CBS We recommend obtaining a bST in patients presenting with a history of recurrent, idiopathic, or severe ana-
phylaxis, particularly those presenting with hypotension.
Strong Moderate
2 CBS We suggest drawing an acute-phase tryptase level as early as possible during a suspected anaphylactic
event (ideally within 2 hours after onset of symptoms). We suggest drawing a second tryptase measure-
ment at a later time as a baseline for comparison to determine whether there was a significant acute ele-
vation.
Conditional Moderate
3 CBS We suggest clinicians consider evaluation for H
aT in patients with elevated bST level (8 ng/mL or greater). Conditional Low
4 CBS We suggest clinicians consider evaluation for mastocytosis, including a bone marrow biopsy, for adult
patients with severe insect sting anaphylaxis or recurrent IA, particularly those with a predictive REMA
score.
Conditional Moderate
5 CBS We suggest that clinicians consider alpha-gal allergy as a possible cause of recurrent IA in a patient with
history of possible tick bite; when appropriate, check an alpha-gal IgE and advise a trial elimination of
mammalian meat if alpha-gal IgE sensitization is detected.
Conditional Moderate
6 CBS We suggest that meeting diagnostic criteria for anaphylaxis is not required before the use of epinephrine. Conditional Very low
7 CBS We suggest that neither the clinical decision to administer epinephrine nor the clinical response to epi-
nephrine be used as a surrogate marker to establish a diagnosis of anaphylaxis.
Conditional Very low
Anaphylaxis in infants and toddlers
8 CBS We suggest clinicians use current NIAID/FAAN or WAO anaphylaxis criteria to assist in the diagnosis of ana-
phylaxis in infants/toddlers, because there are no criteria specific to this age group.
Conditional Low
9 CBS We suggest clinicians be aware that, in infants and toddlers, patient age does not correlate with reaction
severity.
Conditional Very low
10 CBS We suggest clinicians be aware that anaphylaxis is unlikely to be the initial reaction to a food or medication
on first exposure in infants.
Conditional Low
11 CBS We suggest clinicians be aware that parents of infants and toddlers may report age-specific symptoms that
are less often reported by older children and adults.
Conditional Very low
12 CBS We suggest clinicians prescribe either the 0.1 mg or the 0.15 mg EAI dose for infants/toddlers weighing less
than 15 kg.
Conditional Low
Anaphylaxis in community settings
13 CBS We recommend clinicians counsel patients at high risk of anaphylaxis to always carry self-injectable epi-
nephrine and teach patients proper indications and use.
Strong Very low
14 CBS We recommend clinicians educate patients on avoidance of potential exposure to their allergen(s). Strong Very low
15 CBS We recommend clinicians educate patients that the main route of food-induced anaphylaxis is by ingestion
and not contact or inhalation.
Strong Moderate
16 GRADE We suggest childcare centers and schools implement staff training for allergy and anaphylaxis manage-
ment.
Conditional Very low
17 GRADE We suggest that childcare centers and schools not implement site-wide food-specific prohibition because
current research does not support consistent benefits. Special circumstances: It might be appropriate to
implement allergen-restricted zones (eg, milk-free table) when there are children who lack the capacity
to self-manage.
Conditional Very low
18 GRADE We suggest that childcare centers and schools stock undesignated EAIs that can be used to treat any indi-
vidual on school grounds who experiences anaphylaxis.
Conditional Very low
19 CBS We suggest clinicians counsel patients that although US regulations require disclosure of major allergens on
labels of prepackaged foods, they do not require restaurants to declare ingredients or provide allergy
warnings for non-prepackaged foods.
Conditional Very low
20 CBS We suggest clinicians counsel patients on safe practices for dining outside of the home. Conditional Very low
21 CBS We suggest that advising individuals at risk of anaphylaxis to wear or carry medical identification (eg, jew-
elry or wallet card) be considered optional. If it is worn or carried, the wording on medical alert jewelry or
wallet cards should be verified for accuracy by a health care professional.
Conditional Very low
22 CBS We suggest that keeping stock EAI in community settings be encouraged, if feasible. Conditional Very low
Epinephrine autoinjectors: when and how to prescribe
23 CBS We suggest clinicians routinely prescribe EAIs to patients at higher risk of anaphylaxis. When deciding
whether to prescribe EAIs to lower risk patients, we suggest that clinicians engage in a shared decision-
making process that considers the patients’ risk factors, values, and preferences.
Conditional Very low
24 CBS We suggest that in jurisdictions where single-packs of EAIs are available, clinicians consider a patient’s risk
factors for severe anaphylaxis, their values and preferences, and contextual factors when deciding
whether to prescribe only 1 vs multiple EAIs. We suggest they routinely prescribe more than one EAI
when patients have previously required multiple doses of epinephrine to treat an episode of anaphylaxis
and/or have a history of biphasic reactions.
Conditional Very low
(continued)
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D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53 7

Table 3 (Continued)
Section and
number
Method Recommendation Strength of
recommendation
Certainty of
evidence
25 CBS We suggest that clinicians counsel patients and caregivers to give epinephrine at the first sign of suspected
anaphylaxis.
We suggest that, in general, clinicians counsel patients or caregivers not to give epinephrine preemp-
tively to an asymptomatic patient.
Conditional Very low
26 CBS We suggest that clinicians counsel patients that immediate activation of EMS may not be required if the
patient experiences prompt, complete, and durable response to treatment with epinephrine, provided
that additional epinephrine and medical care are readily available, if needed. We suggest that clinicians
counsel patients to always activate EMS after epinephrine use if anaphylaxis is severe, fails to resolve
promptly, fails to resolve completely or nearly completely, or returns or worsens after a first dose of epi-
nephrine.
Conditional Very low
27 CBS Serious adverse reactions to intramuscular epinephrine are very rare and should not pose a barrier to the
prescription or early administration of EAIs when indicated. To manage the risk of adverse events, we
recommend that clinicians counsel patients and caregivers on the proper use of EAIs, the common
adverse effects, and the need for immediate evaluation and treatment when signs or symptoms of serious
adverse events develop.
Strong Low
28 CBS We suggest that clinicians discuss the potential financial and psychosocial burdens of EAIs with patients
while engaging in shared decision-making.
Conditional Very low
29 CBS When deciding which EAI to prescribe, we suggest that clinicians consider dosage, needle length, afford-
ability, access, and patient treatment preferences.
Conditional Very low
30 CBS During visits with patients who have been prescribed EAIs, we recommend that clinicians routinely review
the essentials of EAI carriage, storage, and use; encourage patients to regularly practice EAI administra-
tion with a trainer device; and discuss strategies to manage barriers to adherence that patients may have
experienced.
Strong Low
Beta-blocker and angiotensin-converting enzyme inhibitor medications
31 CBS We suggest that patients with a history of insect sting anaphylaxis who are not receiving VIT may continue
BB or ACEI medications when the medical necessity of the daily medication outweighs the chance of
increased severity of anaphylaxis to a sting.
Conditional Low
32 CBS We suggest that VIT may be prescribed for patients with a history of insect sting anaphylaxis who are
treated with BB or ACEI medication, with shared decision-making regarding the benefits and potential
harms of concurrent VIT treatment and medication, compared with withholding either the treatment or
the medication.
Conditional Low
33 CBS We suggest that, in most cases, treatment with BB or ACEI medication need not be changed or discontinued
in patients receiving maintenance VIT.
Conditional Moderate
34 CBS We suggest use of initial AIT may be considered in patients who are treated with BB or ACEI medication,
with shared decision-making. It would be preferable to replace the BB or ACEI, if there is a safe and effec-
tive alternative.
Conditional Low
35 CBS We suggest that patients receiving maintenance dose AIT have a minimal increased risk of a severe anaphy-
lactic reaction when on BB/ACEI medication and may consider continuing AIT and medications based on
shared decision-making.
Conditional Low
36 CBS For planned procedures (eg, RCM, challenge/desensitization, and infusion), if the BB/ACEI medication can-
not be safely interrupted, we suggest shared decision-making discussion of the medical necessity (bene-
fit) of the procedure, the relative risk of anaphylaxis, the possibility of more severe reaction if the
medication is continued, and the risk of stopping the medication.
Conditional Very low
37 CBS We suggest that all patients at significant risk for recurrent and unexpected anaphylaxis (eg, those with
severe food allergy, mastocytosis or MCAS, or recurrent IA) be counseled about the risk of more severe
anaphylaxis and consider avoiding, where possible, the use of nonselective BBs or ACEIs.
Conditional Moderate
Mastocytosis and anaphylaxis
38 CBS We recommend clinicians order a bone marrow biopsy with staining for tryptase, CD25 immunohis-
tochemistry and flow cytometry, and the KIT D816V mutation when there is strong suspicion for systemic
mastocytosis.
Strong Moderate
39 CBS We recommend clinicians not rely on serum tryptase levels alone for diagnostic assessment of the likeli-
hood that a patient does or does not have a clonal mast cell disorder.
Strong Moderate
40 CBS We recommend measurement of bST in: patients with severe insect sting anaphylaxis, particularly those
who had hypotension and/or absence of urticaria; in all cases of recurrent unexplained anaphylaxis; and
in patients with suspected mastocytosis.
Strong Moderate
41 CBS We suggest clinicians consider evaluation for mastocytosis, including a bone marrow biopsy, for adult
patients with severe insect sting anaphylaxis or recurrent IA, particularly those with a predictive REMA
score.
Conditional Moderate
42 CBS We suggest VIT be continued indefinitely in patients with mastocytosis and insect sting anaphylaxis due to
the increased risk of severe or fatal sting anaphylaxis if VIT is discontinued.
Conditional Low
Perioperative anaphylaxis
43 CBS We suggest that immediate hypersensitivity skin testing (percutaneous and intradermal) and/or in vitro-
specific IgE testing be performed, when available, to all potential pharmacologic and nonpharmacologic
culprits used during the perioperative period. If testing is not possible, we suggest referral to another
center or, if necessary, use of the most efficacious agents structurally dissimilar from the most likely cul-
prit.
Conditional Very low
44 CBS We suggest that immediate hypersensitivity testing to suspected culprit (and alternative) agents be delayed
after POA, unless repeat surgery cannot be postponed. If surgery with general anesthesia is needed
sooner, then testing may be performed when needed.
Conditional Very low
45 CBS We suggest that challenges be performed, when feasible, to all potential culprit agents to which skin and/or
in vitro testing is negative, before or in conjunction with use of these agents for a future surgical proce-
dure.
Conditional Very low
46 CBS We suggest that repeat anesthesia may proceed in the context of shared decision-making and as directed by
history and results of diagnostic evaluation.
Conditional Low
(continued)
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knowledge on anaphylaxis. In this document, we will update only
those areas in which new developments are relevant to the topics
under discussion. Our previous anaphylaxis practice parameters
remain an important resource for guidance on many clinical areas
that are not updated in the current document. 
2,3
This update focuses on selected topics based on the publication of
new and clinically important studies and on the knowledge gaps of
concern to members of the AAAAI/ACAAI and to our patients. 
4
Despite the advances in these areas, the body of evidence is still lim-
ited in relation to most questions and lacking for some. Clinically
important questions must often be addressed indirectly through sur-
rogate markers and outcomes, especially when there are low event
rates, and the only published studies are observational and do not
consistently report the same outcomes or use the same criteria. 
3
These realities of anaphylaxis research lead to low or very low cer-
tainty of evidence, even when there are moderate-to-large numbers
of patients studied. The goal of this workgroup was to identify the
best available evidence of the past 7 years for the specific topics of
interest and synthesize an expert assessment of the best clinical prac-
tices supported by this evidence.
Although the topics in this update are distinct, there are some
areas of overlap. Rather than eliminate all duplication, we felt that
the reader is better served by having all the relevant information pre-
sented when it supports a recommendation. However, the work-
group did make an effort to harmonize the recommendations across
all the topics.
Diagnosis of Anaphylaxis
Anaphylaxis is a systemic, usually multiorgan, potentially life-
threatening syndrome. The diagnosis is clinical—there are no quin-
tessential symptoms, findings, or laboratory markers. Through the
years, the absence of a reference standard for diagnosis has chal-
lenged the ability to formulate a consistently accurate, universally
accepted, evidence-based definition. Furthermore, the lack of a uni-
versal, standard, practical definition has contributed to both underdi-
agnosis and overdiagnosis, the former resulting in inadequate
treatment, with possible increased morbidity and mortality, and the
latter contributing to anxiety and unnecessary prescription of epi-
nephrine. 
5 
We will discuss and compare the definitions and criteria
for the diagnosis of anaphylaxis and the nomenclature for the clinical
patterns of anaphylactic reactions, which are summarized in the list
of Key Points in the Diagnosis of Anaphylaxis found in Box 1. There is
also a need for improved equity and inclusivity in the evaluation and
management of anaphylaxis. For example, increased mortality rate
has been noted in minorities with anaphylaxis, particularly those of
African American race, and outcomes in anaphylaxis are improved
with use of an interpreter for shared decision-making, when
indicated. 
6
As found in Table 4, the diagnosis of anaphylaxis over the years has
varied with the country of origin, group or entity from which it was
derived, and the intended application. 
7−21 
Although “multi-organ”
has been part of many definitions from 2004 to 2016, a single-organ
Table 3 (Continued)
Section and
number
Method Recommendation Strength of
recommendation
Certainty of
evidence
47 CBS We suggest that avoidance of culprit pharmacologic and nonpharmacologic agents associated with POA
may be considered, regardless of test results if challenge is not feasible and if equally efficacious, structur-
ally unrelated alternatives are available.
Conditional Low
48 CBS We offer no recommendation for or against the use of pretreatment before return to the operating room in
patients with negative cutaneous (percutaneous and intradermal) and/or in vitro-specific IgE testing (and
challenge when possible) result to all suspected POA culprit agents.
None Very low
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; AIT, allergen immunotherapy; BB, beta-blocker; bST, baseline serum tryptase; CBS, consensus-based statement; EAI,
epinephrine autoinjector; EMS, emergency medical services; FAAN, Food Allergy and Anaphylaxis Network; H
aT, hereditary a-tryptasemia; IA, idiopathic anaphylaxis; MCAS, mast
cell activation syndrome; NIAID, National Institute of Allergy and Infectious Disease; POA, perioperative anaphylaxis; RCM, radiocontrast media; REMA, Red Espanola MAstocitosis;
VIT, venom immunotherapy; WAO, World Allergy Organization.
Box 1 Key points of consensus in the definition, criteria, and
nomenclature of anaphylaxis
1. Anaphylaxis is a serious, systemic hypersensitivity reaction that
is usually rapid in onset and may cause death. Severe anaphy-
laxis is characterized by potentially life-threatening compro-
mise in respiration and/or the circulation, and it may occur
without typical skin features, circulatory shock, or compro-
mised breathing being present.
2. There are similarities and differences between the 2006 NIAID
and 2020 WAO anaphylaxis criteria. Further studies should be
conducted to validate the 2020 WAO anaphylaxis criteria.
3. Use of the 2007 Brighton Collaborative Criteria in establishing
the diagnosis of anaphylaxis may lead to overdiagnosis of
anaphylaxis.
4. Biphasic anaphylaxis is highly likely when the patient develops
anaphylaxis after initial signs and symptoms have completely
resolved for at least one hour before the onset of repeated ana-
phylaxis within 48 hours and without re-exposure to an aller-
gen trigger.
5. Biphasic anaphylaxis is unlikely when anaphylaxis is not severe
and the patient remains symptom-free for one hour of observa-
tion following resolution of initial anaphylaxis. Biphasic ana-
phylaxis is more likely to occur with increasing anaphylaxis
severity and in patients who have received more than one dose
of epinephrine for anaphylaxis treatment.
6. Persistent anaphylaxis is highly likely when anaphylaxis per-
sists for at least 4 hours.
7. Refractory anaphylaxis is highly likely when anaphylaxis con-
tinues despite appropriate epinephrine dosing and symptom-
directed medical management (e.g., intravenous fluid bolus for
hypotension). Refractory anaphylaxis increases the risk for ana-
phylaxis fatality.
8. Anaphylaxis severity is a continuum that results from a combi-
nation of risk factors, including those related to the allergen (e.
g., allergen dose and route of exposure) as well as the patient
(e.g., immune response, behaviors, concomitant medications,
and other patient specific factors and comorbidities).
9. Patients with severe anaphylaxis are more likely to demon-
strate hypotension and hypoxemia. Severe anaphylaxis is asso-
ciated with older age, pre-existing cardio-pulmonary disease,
and drug etiology.
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system may exhibit major involvement with more physiological dis-
ruption than others. For example, predominantly cardiovascular or
respiratory system involvement may be present in up to 14% and 31%
of patients, respectively, with only minor involvement of other sys-
tems. 
22 
Laryngeal, respiratory, and/or cardiovascular involvement is
common in fatal anaphylaxis. 
23
Most definitions of anaphylaxis include the word “generalized”
and/or “systemic” reaction; however, the ability of patients, care-
takers, or bystanders to understand these concepts is uncertain. The
WAO (2019 and 2020) anaphylaxis definition consisted of 2
sentences. 
18,19 
The first is similar to the 2006 NIAID definition but
with “systemic hypersensitivity” substituted for “allergic” to be more
precise (Table 4).
Given the need to facilitate recognition of anaphylaxis for treat-
ment with epinephrine, the NIAID and FAAN convened a multina-
tional and multidisciplinary symposium in 2005 to propose an
anaphylaxis definition and clinical diagnostic criteria 
10 
(Table 5).
These criteria have been widely adopted 
25 
and were found to be 95%
sensitive and 71% specific in a prospective validation study among
emergency department (ED) patients. 
26 
Knowledge deficits regarding
anaphylaxis recognition and treatment continue to be revealed. 
27,28
In an effort to simplify anaphylaxis diagnostic criteria, in 2019 the
WAO Anaphylaxis Committee proposed revisions to the definition for
the clinical diagnostic criteria for anaphylaxis, which was subse-
quently largely adopted by the WAO 2020 guidance (Table 5). 
18,19
With regard to the 2020 WAO criteria, although most cases of
anaphylaxis are likely to be categorized the same as the 2006 NIAID
criteria, there are several notable differences, mostly related to the
timing, the associated exposures, or the specific organ systems
involved. Some examples are listed here and found in Table 6.
1. Although the 2006 NIAID criteria include cases of isolated hypo-
tension, but not isolated respiratory reaction, after exposure to a
known allergen, the 2020 WAO criteria would include reactions
with acute-onset hypotension, including those with broncho-
spasm or laryngeal involvement (eg, stridor, vocal changes, or
odynophagia) after exposure to a known or highly probable aller-
gen in the absence of typical skin involvement. These criteria
exclude respiratory compromise triggered by common inhalant
allergens.
Table 4
Anaphylaxis Definitions 2001 to 2021
Country, region, or
organization
Date Definition Reference
EAACI 2001 Anaphylaxis is a severe, life-threatening, generalized or systemic hypersensitivity reaction Johansson et al,
7 
2001
ASCIA 2004 Anaphylaxis is a rapidly evolving generalized multisystem allergic reaction characterized by one or
more symptoms or signs of respiratory and/or cardiovascular involvement, and involvement of other
systems such as the skin and/or gastrointestinal tract.
Braganza et al, 
8 
2006 and
Brown et al, 
9 
2006
USA/NIAID 2006 Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death (see Table 5 for
NIAID anaphylaxis criteria)
Sampson et al, 
10 
2006
Brighton Collaboration
Working Group—
International
2007 Anaphylaxis is an acute hypersensitivity reaction with multiorgan system involvement that can present
as, or rapidly progress to, a severe life-threatening reaction. It may occur after exposure to allergens
from a variety of sources including food, aeroallergens, insect venom, drugs, and immunizations.
Anaphylaxis is set apart from simple allergic reactions (eg, urticaria, allergic rhinitis, asthma) by the
simultaneous involvement of several organ systems.
R
€
uggeberg et al, 
11 
2007
US JTFPP guidelines 2010 Anaphylaxis is an acute, life-threatening systemic reaction with varied mechanisms, clinical presenta-
tions, and severity that results from the sudden systemic release of mediators from mast cells and
basophils.
Lieberman et al, 
12 
2010
WAO 2011 Anaphylaxis is a serious life-threatening generalized or systemic hypersensitivity reaction and a serious
allergic reaction that is rapid in onset and might cause death.
Simons et al, 
13 
2011
Pakistan 2013 Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death. Khan et al, 
14 
2013
EAACI 2014 Anaphylaxis is a severe (potentially) life-threatening generalized or systemic hypersensitivity reaction.
This is characterized by being rapid in onset with life-threatening airway, breathing, or circulatory
problems and is usually, although not always, associated with skin and mucosal changes.
Muraro et al,
15 
2014
Germany 2016 Anaphylaxis is a severe, life-threatening, generalized or systemic hypersensitivity reaction. Grade 1:
local with no systemic symptoms. Grade 2: mild/moderate systemic reaction with skin and/or GI.
Grade 3: severe anaphylaxis, systemic with respiratory and/or cardiovascular involvement
Niggemann and Beyer, 
16
2016
ASCIA 2016 Any acute-onset illness with typical skin features (urticarial rash or erythema/flushing, and/or angioe-
dema), PLUS
involvement of respiratory and/or cardiovascular and/or persistent severe gastrointestinal symp-
toms; or any acute onset of hypotension or bronchospasm or upper airway obstruction where ana-
phylaxis is considered possible, even if typical skin features are not present.
ASCIA Clinical Update 
21
WHO ICD-11 2019 Anaphylaxis is a severe, life-threatening systemic hypersensitivity reaction characterized by being
rapid in onset with potentially life-threatening airway, breathing, or circulatory problems and is usu-
ally, although not always, associated with skin and mucosal changes.
World Health Organization
2021 
17
WAO 2019
2020
Anaphylaxis is a serious systemic hypersensitivity reaction that is usually rapid in onset and may cause
death. Severe anaphylaxis is characterized by potentially life-threatening compromise in breathing
and/or the circulation and may occur without typical skin features or circulatory shock being present.
Turner et al, 
18 
2019 and Car-
dona et al, 
19 
2020
EAACI 2020 Anaphylaxis is a severe allergic reaction. [Defined in the context of when to use epinephrine autoinjec-
tors]
Kraft et al, 
20 
2020
ASCIA 2021 Any acute-onset illness with typical skin features (urticarial rash or erythema/flushing and/or angioe-
dema), plus involvement of respiratory and/or cardiovascular and/or persistent severe gastrointesti-
nal symptoms; or any acute onset of hypotension or bronchospasm or upper airway obstruction
where anaphylaxis is considered possible, even if typical skin features are not present.
ASCIA, 
21 
2021
Brighton Collaboration
Working Group
2022 Anaphylaxis presents acutely and leads to a marked change in an individual’s previous stable condition
and is characterized by the following: rapid progression of symptoms and signs which typically
affects multiple body systems (skin/mucosa/respiratory/cardiovascular/gastrointestinal) at the same
time or sequentially but occurring in a short period of time (within 1 hour of onset of the first symp-
toms or signs).
Gold et al, 
24 
2022
Abbreviations: ASCIA, Australian Society of Clinical Immunology and Allergy; EAACI, European Academy Allergy and Clinical Immunology; GI, gastrointestinal; JTFPP, Joint Task Force on
Practice Parameters; NIAID, National Institute of Allergy and Infectious Disease; PP, practice parameter; WAO, World Allergy Organization; WHO, World Health Organization.
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10 D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53

2. Although both the 2006 NIAID and 2020 WAO criteria note that
symptom onset would be expected within “minutes to several
hours,” the 2019 WAO anaphylaxis committee guidance, which
informed the WAO 2020 criteria, also includes a footnote specifi-
cally noting that some reactions, such as those secondary to alpha-
gal or immunotherapy, may be delayed up to 10 hours in onset.
18
3. The 2006 NIAID criteria require “persistent” gastrointestinal
involvement to qualify as an anaphylaxis manifestation. In con-
trast, the 2020 WAO criteria require “severe” gastrointestinal
involvement so as to acknowledge that gastrointestinal manifes-
tations can be indicative of anaphylaxis without being persistent.
4. The WAO Anaphylaxis Committee drew attention to the discrep-
ancy internationally between the inclusion of gastrointestinal
involvement as a systemic manifestation of food-induced ana-
phylaxis. 
18 
Thus, the WAO 2020 anaphylaxis criteria include the
phrase, “especially after exposure to non-food allergens” when
referring to gastrointestinal organ system involvement as a sys-
temic manifestation of anaphylaxis. 
19
5. Finally, to simplify the definition, the 2020 WAO criteria essen-
tially combine the first and second (of 3) 2006 NIAID criteria,
creating a definition with only 2 criteria. Therefore, with the
2020 WAO definition, all anaphylaxis cases must have mucocuta-
neous symptoms except those that meet the second 2020 WAO
criterion (Table 5). For example, cases with dyspnea and persis-
tent vomiting after exposure to a “likely allergen” would meet
the 2006 NIAID second criteria but not the 2020 WAO criteria
owing to the absence of mucocutaneous involvement and
absence of manifestations meeting the second 2020 WAO crite-
rion. Furthermore, with the 2020 WAO definition, exposure to a
“likely” allergen would not be required for cases with only muco-
cutaneous and severe gastrointestinal involvement. For example,
cases with acute onset of mucocutaneous and severe gastrointes-
tinal manifestations in the absence of a “likely allergen” (eg,
childhood viral gastroenteritis with acute urticaria) would meet
the 2020 WAO criteria but not the original 2006 NIAID criteria.
Future validation of the 2020 WAO criteria will be helpful in
determining their clinical utility. Further multidisciplinary and inter-
national consensus on clinical diagnostic criteria will be important to
address how clinicians and researchers will: (1) classify isolated,
Table 5
NIAID and WAO Side-by-Side Comparison 
10,19
NIAID criteria (2006) WAO criteria (2020)
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
and at least one of the following:
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hyp-
oxemia)
b. Reduced BP 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 (minutes to several hours):
a. Involvement of the skin mucosal tissue (eg, generalized hives, itch-flush, swollen lips-
tongue-uvula)
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hyp-
oxemia)
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence)
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced blood pressure after exposure to known allergen for that patient (minutes to sev-
eral hours):
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in systolic
BP
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that person’s
baseline
Anaphylaxis is highly likely when any one of the following 2 criteria are fulfilled:
1. Acute onset of an illness (minutes to several hours) with involvement of the
skin, mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen
lips-tongue-uvula)
and at least one of the following:
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor,
reduced PEF, hypoxemia)
b. Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia
[collapse], syncope, incontinence)
c. Severe gastrointestinal symptoms (eg, severe crampy abdominal pain, repeti-
tive vomiting), especially after exposure to non-food allergens
2. Acute onset of hypotension or bronchospasm 
a 
or laryngeal involvement after
exposure to a known or highly probable allergen for that patient (minutes to
several hours), even in the absence of typical skin involvement.
a. Excluding lower respiratory symptoms triggered by common inhalant aller-
gens or food allergens perceived to cause “inhalational” reaction in the absence
of ingestion.
Abbreviations: BP, blood pressure; NIAID, National Institute of Allergy and Infectious Disease; PEF, peak expiratory flow; WAO, World Allergy Organization.
Table 6
Diagnosis of Anaphylaxis Based on NIAID or WAO Criteria for Multiple-Organ System Involvement
Organ system #1 Organ system #2 NIAID anaphylaxis? WAO anaphylaxis?
Skin/mucosal Respiratory Yes Yes
Skin/mucosal CV Yes Yes
Skin/mucosal GI Only if likely allergen exposure Yes
Respiratory CV Yes Only if known or highly probable allergen with hypotension, 
a 
bronchospasm,
b
or laryngeal involvement 
c
Respiratory GI Only if likely allergen exposure Only if known or highly probable allergen with bronchospasm 
b 
or laryngeal
involvement 
c
CV GI Only if likely allergen exposure Only if known or highly probable allergen with hypotension 
a
Hypotension 
a 
None Only if known allergen exposure Only if highly probable allergen exposure
Laryngeal involvement
c 
None No Only if highly probable allergen exposure
Bronchospasm 
b 
None No Only if highly probable allergen exposure
Abbreviations: BP, blood pressure; CV, cardiovascular; GI, gastrointestinal; NIAID, National Institute of Allergy and Infectious Disease; WAO, World Allergy Organization.
NOTE. GI involvement variably defined as “persistent” (NIAID) or “severe” (WAO).
a
Hypotension defined as a decrease in systolic BP greater than 30% from that person’s baseline, OR (1) Infants and children under 10 years: systolic BP less than (70 mm Hg + [2 £ age
in years]). (2) Adults and children above 10 years: systolic BP less than 90 mm Hg.
b
Excluding lower respiratory symptoms triggered by common inhalant allergens or food allergens perceived to cause “inhalational” reactions in the absence of ingestion.
c
Laryngeal symptoms include stridor, vocal changes, and odynophagia.
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D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53 11

acute, allergic, oropharyngeal, or laryngeal angioedema as this would
meet the 2020 WAO anaphylaxis diagnostic criteria but not the 2006
NIAID criteria; (2) define what constitutes “severe” gastrointestinal
symptoms; (3) determine whether or not gastrointestinal involve-
ment should be recognized as a systemic manifestation of anaphy-
laxis when accompanied by mucocutaneous involvement secondary
to food allergens; and (4) reach consensus with regard to other classi-
fication discrepancies noted previously.
Although both the 2006 NIAID and 2020 WAO criteria were devel-
oped for the diagnosis of anaphylaxis with any potential trigger, a
case definition for the diagnosis of anaphylaxis occurring as an
adverse event after an immunization was proposed by the Brighton
Collaboration Anaphylaxis Working Group in 2007. 
11 
The case defini-
tion included sudden onset, rapid progression, and multiple-organ
system involvement (Table 7). Diagnostic levels of certainty were
based on fulfilling major and minor criteria consisting of signs and
symptoms and tryptase level elevation. A study comparing the 2007
Brighton Criteria with the 2006 NIAID criteria reported a moderate
level of agreement between case definitions among a cohort of ED
patients; however, a discordant result between definitions was found
in 28.1% of the cases. 
29 
The 2007 Brighton Criteria differ from the
2006 NIAID and 2020 WAO criteria in notable ways. For example, lip
swelling is considered a major criterion for respiratory
involvement. 
19,29 
Thus, a patient with lip swelling and itchy eyes
would meet the case definition of anaphylaxis with level 2 diagnostic
certainty, potentially leading to overdiagnosis of anaphylaxis in the
setting of immunizations. 
30 
Application of the 2006 NIAID or 2020
WAO criteria may be more accurate, but further studies are needed
(Table 5).
31,32 
As a result of increased use during the COVID-19 pan-
demic, and debate regarding the Brighton Criteria performance in
assessing vaccine-associated anaphylaxis compared with NIAID or
WAO criteria, the Brighton Collaboration Anaphylaxis Working
Group published an updated and revised version 2 of the criteria in
late 2022 (Table 7). The revised criteria focus the major and minor
criteria on the reporting of observable clinical signs, rather than sub-
jective symptoms, and provide a clearer approach to the ascertain-
ment of levels of certainty. 
24 
These modified 2022 Brighton Criteria
may be more consistent with other common case definitions for ana-
phylaxis.
The course of anaphylaxis can be variable across patients and pop-
ulations, although one study has reported some consistency among
recurrent anaphylaxis for individual patients. 
33 
For most patients,
anaphylaxis is not persistent, refractory, or biphasic 
34−37 
; however,
these subtypes of anaphylaxis are not uncommon. 
34−45 
Biphasic ana-
phylaxis is more likely to occur with increasing anaphylaxis severity
and in patients who have received more than one dose of epineph-
rine for anaphylaxis treatment. 
3 
Additional risk factors for biphasic
anaphylaxis include a wide pulse pressure (resulting from early arte-
riolar dilation), unknown anaphylaxis trigger, cutaneous signs and
symptoms, and drug trigger in children. 
3,46,47 
Persistent, refractory,
and biphasic anaphylaxis may be defined by clinical criteria (Table 8).
Persistent anaphylaxis is highly likely when anaphylaxis persists for at
least 4 hours. 
34 
Refractory anaphylaxis is highly likely when anaphy-
laxis continues despite appropriate epinephrine dosing and symp-
tom-directed medical management (eg, intravenous fluid bolus for
hypotension). 
34 
Data from the European Anaphylaxis Registry sug-
gest that refractory anaphylaxis accounts for less than 0.5% of severe
anaphylaxis cases, with an associated drug etiology (particularly in
the perioperative/procedural setting) most frequently recognized. 
48
Refractory anaphylaxis increases the risk for anaphylaxis fatality
(26.2% vs 0.35% in a 2019 European registry, P < .0001). 
48,49 
Biphasic
anaphylaxis is highly likely when the patient develops anaphylaxis
after initial signs and symptoms have completely resolved for at least
1 hour before the onset of repeated anaphylaxis within 48 hours
without re-exposure to an allergen trigger. 
34 
In a meta-analysis that
included 2890 adult patients with anaphylaxis, the median
percentage of patients with biphasic anaphylaxis was 6.5% (range,
0.4%-20%). 
40 
The median duration between resolution of the initial
episode and the secondary reaction was 10.5 hours (range, 1.75
hours-17 hours). 
40 
These findings are in range with other studies of
biphasic anaphylaxis. 
3,43,44,50 
Notably, a 1-hour symptom-free obser-
vation after resolution of initial anaphylaxis was associated with a
95% negative predictive value (95% CI, 90.9%-97.3%) for biphasic ana-
phylaxis. 
40 
Persistent anaphylaxis is distinct from biphasic anaphy-
laxis because in persistent anaphylaxis there is no period of
resolution between an initial and a subsequent phase. 
34 
In 1 report of
108 episodes of pediatric anaphylaxis requiring hospital admission,
anaphylaxis was described as biphasic in 6%, protracted in 1%, and
fatal in 2% of patients. 
35 
Fatal anaphylaxis is a rare outcome. 
51,52 
In a
population-based epidemiologic study using 3 national databases,
the case fatality rate among patients hospitalized or with ED presen-
tations was between 0.25% and 0.33%. 
53
Reaction severity is a leading factor in the subsequent course of
anaphylaxis, and anaphylaxis severe enough to require hospitaliza-
tion has been reported to account for up to 22% in some case
series. 
3,54−56 
It is important to recognize that reaction severity is a
continuum that results from a combination of risk factors, including
those related to the allergen (eg, allergen dose and route of exposure)
and the patient (eg, immune response, behaviors, concomitant medi-
cations, and other patient-specific factors and comorbidities)
(Fig 1). 
57−60 
Patients with severe anaphylaxis are more likely to have
hypotension and hypoxemia, and severe anaphylaxis is associated
with older age, preexisting lung disease, and drug etiology. 
22 
Never-
theless, anaphylaxis is part of a spectrum of acute allergic reactions
that range from mild to fatal. 
18,61,62 
Understanding and communicat-
ing anaphylaxis severity is important for patients and their families,
primary care providers, emergency physicians, hospital physicians,
allergy specialists, school personnel, public health authorities, food
providers, and researchers. 
57 
Any definition of anaphylaxis severity
must clearly inform all stakeholders.
Multiple severity grading systems have been developed, 
16,57,63−65
and the term “severity” can have different meanings to patients, clini-
cians, and investigators. 
57,63 
In 1977, Ring and Messmer 
66 
proposed a
4-category classification system to describe severity of reactions to
colloid volume substitutes, but this system was not specific to ana-
phylaxis. The Ring and Messmer classification was subsequently
modified such that grade I represents isolated mucocutaneous
involvement, grade II mild-to-moderate severity multiorgan system
involvement, grade III life-threatening symptoms in a single-organ
system or more severe multiple-organ system involvement, and
grade IV cardiac or respiratory arrest. 
67,68 
Additional grading
schemes have been proposed through the years. An approach involv-
ing 5 categories proposed by Sampson for grading of food-induced
anaphylaxis was subsequently adopted by the EAACI in 2007. 
69,70 
In
2004, Brown
63 
proposed a simple classification system for the range
of hypersensitivity reactions, with mild reactions limited to cutane-
ous manifestations; moderate reactions characterized by features
suggesting respiratory, cardiovascular, or gastrointestinal involve-
ment; and the most severe grades characterized by hypoxia, hypo-
tension, and/or neurologic compromise (Table 9). Many clinicians
continue to use the 2010 WAO Subcutaneous Immunotherapy Sys-
temic Allergic Reaction Grading System, 
71 
often applying modifica-
tions based on age and allergen trigger. 
19,65,72 
Recently, the 2012
Consortium for Food Allergy Research Grading Scale for Systemic
Allergic Reactions, characterized by 5 severity levels, was updated
through a collaboration of expert opinion with industry input to con-
sider response to therapy in assignment of severity grade. 
73 
In addi-
tion, the Food Allergy Severity Score was recently developed using
the EuroPrevail outpatient clinical cohort of 8232 food allergy
reactions. 
74
There are limitations to existing anaphylaxis severity scoring sys-
tems. For example, the Brown severity grading system, developed
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Table 7
Case Definitions and Differences Between the 2007 (Version 1) and 2022 (Version 2) Brighton Collaboration Anaphylaxis Major and Minor Criteria
24
Brighton collaboration criteria version 1 (2007) Brighton collaboration criteria version 2 (2022) Comments
Definition Anaphylaxis is a clinical syndrome characterized
by sudden onset and rapid progression of signs
and symptoms involving multiple (≥2) organ
systems, as follows
Anaphylaxis presents acutely and leads to a
marked change in an individual’s previous sta-
ble condition and is characterized by the fol-
lowing: rapid progression of symptoms and
signs which typically affects multiple body sys-
tems (skin/mucosa/respiratory/cardiovascular/
gastrointestinal) at the same time or sequen-
tially but occurring over a short period of time
(within 1 h of onset of the first symptoms or
signs).
Sudden onset has been replaced with acutely in
BC-V2; a clearer description of rapid
progression has been provided; and multisys-
tem involvement is defined more clearly. Both
V1 and V2 require rapid progression for all lev-
els of diagnostic certainty.
Criteria
Major skin Generalized urticaria (hives) or generalized ery-
thema; angioedema, localized or generalized;
generalized pruritus with skin rash
Urticaria (hives) at a location other the vaccine
administration site; angioedema of the skin
(swelling) at a location other the vaccine
administration site; generalized (widespread)
erythema (redness) of the skin with itch
Removal of generalized as a descriptor for urti-
caria and angioedema. Urticaria and angioe-
dema at injection site are excluded.
Minor skin Generalized pruritus without skin rash; general-
ized prickle sensation; localized injection site
urticarial rah; red and itchy eyes
Generalized (widespread) erythema (redness) of
the skin with itch; red and/or itchy eyes, bilat-
eral and new onset; generalized (widespread)
erythema (redness) of the skin without itch
Removal of generalized pruritus without skin
rash, generalized prickle sensation, localized
injection site urticaria, as minor criteria. Inclu-
sion of new onset for red and/or itchy eyes.
Major respiratory Bilateral wheeze (bronchospasm); stridor; upper
airway swelling (lip, tongue, throat, uvula, or
larynx); respiratory distress—2 or more of the
following: tachypnea, increased use of acces-
sory respiratory muscles (sternocleidomastoid,
intercostal), recession, cyanosis, grunting
Expiratory wheeze documented by health care
professional which could be with/out stetho-
scope; inspiratory stridor documented by
health care professional which could be with/
out stethoscope; angioedema of the mucosa of
the upper airway—swelling of the tongue,
pharynx, uvula, and/or larynx unequivocally
documented by a health care professional—
this does not include isolated lip swelling; 2
indicators of respiratory distress: tachypnea,
cyanosis, measured hypoxia with oxygen satu-
rations < 90%, grunting, chest wall retractions,
increased use of accessory respiratory muscles
Inclusion of wheeze, stridor, upper airway swell-
ing documented by a health care professional.
Removal of lip swelling as a sign of upper air-
way angioedema. Inclusion of measured hyp-
oxia with oxygen saturations <90%.
Minor respiratory Persistent dry cough; hoarse voice; difficulty
breathing without wheeze or stridor; Sensation
of throat closure; sneezing, rhinorrhea
Cough and/or sneezing and/or runny nose new
onset and persistent
The minor symptoms (reported difficulty breath-
ing, sensation of throat closure) and signs
(hoarse voice) have been removed. Minor
respiratory symptoms (cough and/or sneezing
and/or runny nose) have been retained but it
has been specified that this should be new
onset and persistent.
Major cardiovascular Measured hypotension; clinical diagnosis of
uncompensated shock, indicated by the combi-
nation of at least 3 of the following: tachycar-
dia, capillary refill time >3 s, reduced central
pulse volume, decreased level of consciousness
or loss of consciousness
Measured hypotension. Loss of consciousness,
other than the brief, self-resolving loss of con-
sciousness typical of a vasovagal reaction
The clinical features of uncompensated shock
(other than hypotension or loss of conscious-
ness) have been removed as major criteria, to
simplify the criteria. Loss of consciousness has
been inserted as a major criterion of hypoten-
sion. To differentiate vasovagal syncope from
anaphylaxis, the caveat “other than the brief,
self-resolving loss of consciousness typical of a
vasovagal reaction” 
has been inserted.
Minor cardiovascular Reduced peripheral circulation as indicated by
the combination of at least 2 of the following:
tachycardia, a capillary refill time of >3 s with-
out hypotension, a decreased level of
consciousness
None All minor cardiovascular criteria have been
removed.
Major gastrointestinal None New-onset vomiting; new-onset diarrhea Diarrhea and vomiting have been included as
major criteria.
Minor gastrointestinal Diarrhea; abdominal pain; nausea; vomiting None All minor criteria have been removed.
Major laboratory None Elevated mast cell tryptase Mast cell tryptase has been included as a major
criterion and defined as either: > upper normal
limit for laboratory doing test; or >
(1.2 £ baseline tryptase) + 2 ng/mL.
Minor laboratory Elevated mast cell tryptase None
Level of certainty
Level 1 ≥1 major dermatologic and ≥1 major cardiovas-
cular and/or ≥1 major respiratory criterion
Major skin/mucosal and ≥1 major system
involvement including respiratory and/or car-
diac and/or gastrointestinal and/or laboratory
(continued)
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D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53 13

using a statistical analysis of the relationship between individual
reaction features and subsequent treatment with epinephrine and
patient outcomes, uses observable signs and symptoms without the
use of physiological measurements (eg, blood pressure and oxygen
saturation). 
63 
Grade 1 would not be considered anaphylaxis, whereas
grade 2 and grade 3 would fulfill the definition of anaphylaxis and
could be adopted as an indication to immediately administer epi-
nephrine in both the community and medical settings. 
63 
However,
such a grading system may not be ideal in real-time decision-making
as affected subjects may change from a less severe to more severe
grade quickly, arguing for consideration of epinephrine in milder
reactions if risk of progression is a concern. This may be particularly
relevant with rapid onset of signs or symptoms after exposure to a
suspected allergen. In an analysis of 259 food-induced anaphylaxis
episodes from 157 children, a 24.7% to 70.2% disagreement was
observed across multiple severity score rating systems. The authors
of this study highlighted that the presence of anaphylaxis is not req-
uisite for epinephrine use during an allergic reaction, and conversely,
use of epinephrine does not necessitate a diagnosis of anaphylaxis be
made. 
75
Table 7 (Continued)
Brighton collaboration criteria version 1 (2007) Brighton collaboration criteria version 2 (2022) Comments
Level 2 ≥1 major cardiovascular and ≥1 major respira-
tory criterion or ≥1 major cardiovascular or
respiratory criterion and ≥1 minor criterion
involving ≥1 different system (other than car-
diovascular or respiratory systems) or (≥1
major dermatologic) and (≥1 minor
cardiovascular and/or minor respiratory crite-
rion)
≥2 Major system involvement including respira-
tory and/or cardiac and/or gastrointestinal and/
or laboratory—excludes skin/mucosal involve-
ment and must be from different systems
Level 3 ≥1 Minor cardiovascular or respiratory criterion
and ≥1 minor criterion from each of ≥2 differ-
ent systems/categories
≥1 Major system involvement including respira-
tory, cardiac, gastrointestinal or
laboratory and ≥1 minor system involvement
from skin/mucosal or respiratory and must be
from different systems
Level 4 Reported anaphylaxis with insufficient evidence
to meet the case definition
Insufficient information provided for review to
meet any level of certainty. This may include
reports which document anaphylaxis without a
description of any signs and/or symptoms.
Level 5 Not stated Sufficient information provided for review and
determined not to meet case definition at any
level of certainty.
Table 8
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 anaphylaxis criteria that persist for at least 4 h.
Refractory anaphylaxis is highly likely when both of the following 2 criteria are fulfilled:
1. Presence of anaphylaxis after appropriate epinephrine dosing and symptom-directed medical management (eg, intravenous fluid bolus for hypotension).
2. The initial reaction has been treated with 3 or more appropriate doses of epinephrine (or initiation of an intravenous epinephrine infusion).
Biphasic anaphylaxis is highly like when all the 4 criteria are fulfilled:
1. New or recurrent symptoms and/or examination findings that fulfill anaphylaxis criteria
2. Initial symptoms and examination findings have completely resolved before the onset of new or recurrent symptoms or examination findings.
3. Absence of allergen or trigger re-exposure.
4. New or recurrent symptoms or examination findings occur within 1 to 48 h from complete resolution of the initial symptoms or examination findings.
NOTE. Adapted from Dribin et al. 
34
Figure 1. Risk factors for severe allergic reactions. Many factors may modulate between mild and severe allergic reactions.
Adapted with permission from Dubois et al
60 
and Smith et al. 
59
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In 2021, a severity grading system for allergic reactions proposed
by Dribin et al
61 
resulted from an expert consensus and synthesis of
the many prior grading scales with additional granularity but also
added some degree of complexity (Fig 2). An advantage of the 2021
grading system is that it allows grading of allergic reactions from
mild to severe with or without requiring a definition of anaphylaxis.
This system is clinically intuitive, but also quite nuanced, so it will
likely require the use of decision support tools or memory aids to be
most effective. Although derived from expert consensus of a 21-
member multidisciplinary panel, the 2021 grading system still
requires validation. Using a “Best-Worst Scaling” exercise, Stafford et
al 
76 
evaluated 10 severity grading systems, concluding that geo-
graphic location of the health care provider may affect severity
assessment and that all scoring systems have limitations in discrimi-
nating anaphylaxis severity.
Question: What is the role of serum tryptase measurements in
anaphylaxis diagnosis?
Recommendation 1 (CBS): We recommend obtaining a bST in
patients presenting with a history of recurrent, idiopathic, or
severe anaphylaxis, particularly those presenting with hypoten-
sion.
Strength of Recommendation: Strong
Certainty of Evidence: Moderate
Recommendation 2 (CBS): We suggest drawing an acute-phase
tryptase level as early as possible during a suspected anaphylactic
event (ideally within 2 hours after onset of symptoms). We sug-
gest drawing a second tryptase measurement at a later time as a
Table 9
2004 Brown Grading System for Hypersensitivity Reactions
Mild: Signs and symptoms isolated to the skin, such as generalized erythema, urticaria, periorbital edema, or angioedema
Moderate: Signs and symptoms suggesting respiratory, cardiovascular, or gastrointestinal involvement, such as dyspnea, stridor, dizziness (presyncope), diaphoresis, chest or throat
tightness, or abdominal pain
Severe: Signs and symptoms reflective of hypoxia, hypotension, and/or neurologic compromise, such as cyanosis or oxygen saturation ≤ 92%, hypotension (systolic blood pressure
<90 mm Hg in adults), confusion, collapse, altered level of consciousness, or incontinence.
NOTE. Adapted from Brown, 2004.
63
Figure 2. Anaphylaxis consensus severity grading system. BP, blood pressure; CV, cerebrovascular; FAAN, Food Allergy and Anaphylaxis Network; GI, gastrointestinal; HR, heart
rate; MAP, mean arterial pressure; NIAID, National Institute of Allergy and Infectious Diseases; SpO 
2 
, oxygen saturation.
Reproduced with permission from Dribin et al 2021.
61
The severity grading system is designed for use across the spectrum of acute allergic reactions as depicted by the vertical arrow (mild to life-threatening reactions), whether
they fulfill criteria for anaphylaxis or not.
** For patients with multiple symptoms, reaction severity is based on the most severe symptom; symptoms that constitute more severe grades always supersede symptoms
from less severe grades. The grading system can be used to assign reaction severity at any time during the course of reactions; reactions may progress rapidly (within minutes)
from one severity grade to another. The grading system does not dictate management decisions; reactions of any severity grade may require treatment with epinephrine.
y Patients with severe cardiovascular and/or neurologic involvement may have urinary or stool incontinence. However, the significance of incontinence as an isolated symptom
is unclear, and it is therefore not included as a symptom in the subgrading system.
yy Abdominal pain may also result from uterine cramping.
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baseline for comparison to determine whether there was a signifi-
cant acute elevation.
Strength of Recommendation: Conditional
Certainty of Evidence: Moderate
Recommendation 3 (CBS): We suggest clinicians consider eval-
uation for H
aT in patients with elevated bST level (8 ng/mL or
greater).
Strength of Recommendation: Conditional
Certainty of Evidence: Low
Recommendation 4 (CBS): We suggest clinicians consider eval-
uation for mastocytosis, including a bone marrow biopsy, for
adult patients with severe insect sting anaphylaxis or recurrent
IA, particularly those with a predictive REMA score.
Strength of Recommendation: Conditional
Certainty of Evidence: Moderate
The differential diagnosis and diagnostic workup for patients pre-
senting with suspected or presumed anaphylaxis is broad (Table 10,
Fig 3).
2 
Diagnostic workup relies on a thorough clinical history with
attention to patient age, sex, medical and atopic history, concurrent
medications, possible triggers, symptom pattern, timing of onset,
concomitant factors (eg, exercise, viral infection, medications, men-
strual status, stress), symptom duration, response to treatment (epi-
nephrine), and number of episodes, with very focused testing to
evaluate for IgE-mediated triggers (eg, skin and/or serum testing). 
2
As part of the diagnostic evaluation, it is imperative to confirm that
the events in question are indeed anaphylaxis, classically by finding
objective signs of mast cell activation on physical examination (eg,
urticaria, wheezing on lung auscultation, or hypotension) or by ele-
vated tryptase level to rule out mimickers of anaphylaxis
(Table 10). 
77,78 
One must realize that when evaluating for an elevated
acute tryptase level, a serum tryptase level above the laboratory-
defined normal value (eg, >11.4 ng/mL in many laboratory results)
may not detect all episodes of anaphylaxis. Rather, a change in tryp-
tase above a patient’s bST may offer a more sensitive assessment of
systemic mast cell activation. Expert consensus has suggested that an
acute serum total tryptase level at least 20% plus 2 ng/mL over the
patient’s bST level is evidence of systemic mast cell activation. 
79,80
Although this equation was proposed to aid in diagnosis of MCAS
rather than anaphylaxis, it has been validated in POA in 1 study, sug-
gesting a specificity of 91% and sensitivity of 78% (in this cohort, the
positive and negative predictive values were 98% and 44%, respec-
tively). 
77 
Questions remain regarding the overall utility of using this
equation for anaphylaxis in general (eg, what is the normal temporal
intrapersonal variance in tryptase and what is the value in food-
induced anaphylaxis). 
78 
For example, Mateja et al
80 
revealed that sig-
nificant variability may occur in bST levels and that among individu-
als with an elevated tryptase due to an underlying mast cell disorder,
one-quarter of individuals exceeded the 20% plus 2 ng/mL threshold
on serial asymptomatic measurements; they found that a ratio of
acute/baseline tryptase of 1.685 was able to better identify anaphy-
laxis (sensitivity 94.4%, specificity 94.4%). It has been suggested that
even more nuanced cutoff values could be tailored to the index of
clinical suspicion, 
80 
suggesting a cutoff ratio of 1.868 when clinical
suspicion of anaphylaxis is low and a ratio of 1.374 when clinical sus-
picion is high. An online calculator has been published to facilitate
use of this particular approach at https://triptase-calculator.niaid.nih.
gov. 
81 
Thus, currently, we do not recommend using the 20% plus
2 ng/mL equation alone to diagnose anaphylaxis.
Since publication of the 2015 anaphylaxis parameter, there are 2
updated considerations for evaluating patients with recurrent mast
cell-mediated symptoms/recurrent IA. The first is examination not
only for elevated bST level (as a marker for mast cell disease), but
when appropriate, for H
aT. HaT is an inherited increase in the
a-tryptase−encoding tryptase a/b-1 (TPSAB1) gene copy number
resulting in elevated bST level (usually >8 ng/mL).
82,83 
Evidence sug-
gests that TPSAB1 gene copy number encoding 
a-tryptase signifi-
cantly influences bST levels, and H
aT genotyping could be
considered in individuals with tryptase levels above 8 ng/mL. 
84,85
Incorporating copy number can be useful in determining whether
further evaluation of a clonal mast cell evaluation may be warranted
(https://bst-calculater.niaid.nih.gov). 
86 
HaT occurs in 5% to 7% of peo-
ple in the European and North American populations sampled, 
87 
and
although many individuals with H
aT are asymptomatic, there are
data to suggest that it is often accompanied by a wide range of symp-
toms consistent with mast cell mediator release. 
88 
However, in a ran-
dom biorepository population, there was no difference in the clinical
symptomatology or medical history of individuals with H
aT com-
pared with controls. 
89 
HaT has been reported more frequently in
patients with severe symptoms of anaphylaxis in patients with IgE-
mediated allergies (such as Hymenoptera venom allergy), with or
without mastocytosis, and thus should be considered in evaluation of
patients presenting with possible anaphylaxis. 
90,91 
Our understand-
ing of H
aT is incomplete, and at this point, the degree to which the
diagnosis alters management is uncertain. 
85,92 
Still, HaT should be
considered in the differential diagnosis of patients with elevated bST
level and recurrent or severe anaphylaxis.
Second, there have been scoring systems developed to help deter-
mine when patients with recurrent mast cell-mediated symptoms or
recurrent IA warrant bone marrow biopsy to look for underlying
mastocytosis or a clonal mast cell disorder. The first of these was pub-
lished from the Spanish Mastocytosis Network (referred to as the
REMA score) and described patients with severe systemic symptoms
of mast cell mediator release but without cutaneous lesions, includ-
ing many patients with insect venom anaphylaxis (Fig 4).
93 
A more
recent study in the United States describes the NICAS (NIH Idiopathic
Table 10
Anaphylaxis Differential Diagnosis
Anaphylaxis
 
Anaphylaxis due to known allergens—for example, foods, drugs, insect sting, latex
 
Anaphylaxis associated with physical stimuli—for example, exercise, cold, heat
 
Anaphylaxis associated with both—for example, food-dependent exercise induced
 
Idiopathic
Mastocytosis and mast cell activation syndromes, hereditary a-tryptasemia
Vasodepressor reactions
 
Vasovagal
Flushing syndromes
 
Neuroendocrine tumors, for example, carcinoid, pheochromocytoma
 
Vasoactive intestinal peptide-secreting tumor
Restaurant syndromes
 
Scombroidosis
 
Monosodium glutamate
Nonorganic causes
 
Anxiety/panic syndromes (may include pruritus, flushing, urticaria)
 
Munchausen syndrome (factitious anaphylaxis) or Munchausen by proxy
 
Vocal cord dysfunction syndrome
 
Undifferentiated somatoform anaphylaxis
 
Prevarication anaphylaxis
Miscellaneous
 
Hereditary angioedema accompanied by rash
 
Capillary leak syndrome
 
Vancomycin infusion reaction (“red man syndrome”)
 
Autonomic dysfunction
NOTE. Adapted from Lieberman et al. 
2
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Clonal Anaphylaxis Score) score in patients with IA (none had venom
anaphylaxis; Fig 4).
94 
In this study, 14% of patients with IA were diag-
nosed with having a clonal mast cell disorder. The NICAS score incor-
porates evaluation of the KIT D816V mutation. Although evidence
suggests that in many patients with a clonal mast cell disorder even
the most sensitive test for this mutation in the peripheral blood may
have a negative result, 
95 
within the NICAS score the predictive value
may improve. The REMA score has been validated and modified in
other studies. 
96,97 
The scoring systems are established only in adults
and advise that male sex, lack of angioedema/urticaria, and presence
of hypotension/syncope during episodes suggest increased likelihood
for clonal disease, and thus consideration for biopsy. 
93,94,96,98 
How-
ever, bone marrow biopsy may be considered in patients with recur-
rent or severe anaphylaxis episodes outside of these scoring systems.
Question: In what settings should the clinician consider evalu-
ation of alpha-gal allergy?
Recommendation 5 (CBS): We suggest that clinicians consider
alpha-gal allergy as a possible cause of recurrent IA in a patient
with history of possible tick bite; when appropriate, check an
alpha-gal IgE and advise a trial elimination of mammalian meat if
alpha-gal IgE sensitization is detected.
Strength of Recommendation: Conditional
Certainty of Evidence: Moderate
There are accumulating data to suggest that alpha-gal allergy can
be a common hidden cause of recurrent anaphylaxis previously pre-
sumed to be idiopathic depending on geographic location. 
99,100 
As
with other allergies, alpha-gal asymptomatic sensitization occurs and
does not always equate to clinically reactivity. Clinical history (ana-
phylaxis occurring hours after consumption of red meat), geographic
location, exposure to ticks, and outdoor exposure should all be con-
sidered when deciding to order and interpret an alpha-gal IgE level.
For example, forest workers in the United States 
101 
and Germany 
102
were found to have sensitization rates (>0.1 kU/L) of 39.1% and
35.0%, respectively. However, in those cohorts, 0% and 2%, respec-
tively, had clinical symptoms of delayed anaphylaxis with mamma-
lian meat. In a South African cohort of patients with delayed meat
reactions, the alpha-gal IgE assay had good discriminatory properties
when compared with 26 healthy controls, with a positive predictive
value and negative predictive value of 92% and 83%, respectively, at a
value of greater than 1.0 kU/L in this sample (although these predic-
tive values may not be generalizable in other populations). 
103 
Thus,
when ordering the alpha-gal sIgE, the clinician should use the history
Figure 3. Diagnostic evaluation of the patient with a history of anaphylaxis.
5HIAA, 5-hydroxyindolacetic acid; AIT, allergen immunotherapy; EAI, epinephrine autoinjector; H
aT, hereditary a-tryptasemia; IA, idiopathic anaphylaxis; REMA, Red Espanola
MAstocitosis; VIP, vasoactive intestinal peptide.
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to assess the pretest likelihood of alpha-gal allergy and leverage
shared decision-making with the patient regarding a trial elimination
of (and subsequent challenge with) mammalian meat if the test result
is positive.
Question: Is the diagnosis of anaphylaxis required for adminis-
tration of epinephrine?
Recommendation 6 (CBS): We suggest that meeting diagnostic
criteria for anaphylaxis is not required before the use of epineph-
rine.
Strength of Recommendation: Conditional
Certainty of Evidence: Very Low
Question: Is administration of, or response to, epinephrine
necessary for the diagnosis of anaphylaxis?
Recommendation 7 (CBS): We suggest that neither the clinical
decision to administer epinephrine, nor the clinical response to
epinephrine, be used as a surrogate marker to establish a diagno-
sis of anaphylaxis.
Strength of Recommendation: Conditional
Certainty of Evidence: Very Low
Anaphylaxis continues to be under-recognized and undertreated
with epinephrine, both in the community and health care set-
tings 
27,104−114 
; however, evidence suggests more appropriate use in
locations with systems designed for recognition and treatment. 
105,115
Although all cases of anaphylaxis represent a systemic hypersensitiv-
ity reaction, not all systemic hypersensitivity reactions fulfill
diagnostic criteria for anaphylaxis (eg, generalized urticaria without
additional symptoms after any form of AIT). 
75 
The potential of pro-
gression from a non-anaphylactic systemic hypersensitivity reaction
to anaphylaxis to life-threatening anaphylaxis further obfuscates this
distinction. Thus, definitions incorporate severity (eg, hypotension or
respiratory distress) to distinguish anaphylaxis from non-anaphylac-
tic systemic hypersensitivity reactions at any point in time. 
10,19
There may be epidemiologic value in the separation of anaphy-
laxis from non-anaphylactic systemic hypersensitivity reactions. The
definition of anaphylaxis is often confused or intertwined with either
the criteria for the diagnosis of anaphylaxis or the severity grading of
an allergic or anaphylactic reaction. Diagnostic criteria and severity
grading are of greatest benefit when establishing a retrospective
diagnosis of anaphylaxis, particularly for use in research and epide-
miologic studies, and when trying to predict the risk of severe reac-
tion with future episodes of anaphylaxis. Still, severity assessment
continues to be an important, often implicit, driver of anaphylaxis
management by clinicians. Although the NIAID/FAAN criteria are
often used in clinical practice, their diagnostic precision is
imperfect. 
116
Anaphylaxis represents a high-grade systemic hypersensitivity
reaction. For real-time treatment decisions, withholding epinephrine
in the setting of systemic hypersensitivity reactions that do not yet
fulfill a particular set of diagnostic criteria for anaphylaxis may result
in progression of a systemic hypersensitivity reaction. 
61,117 
Thus,
meeting anaphylaxis diagnostic criteria is not requisite before epi-
nephrine use in treating a systemic hypersensitivity reaction. 
27 
Con-
versely, neither the clinical decision to administer epinephrine nor
the clinical response to epinephrine should be used as a surrogate
marker to establish a diagnosis of anaphylaxis. 
28 
Early epinephrine
Figure 4. Scoring systems to evaluate risk of a clonal mast cell disorder in anaphylaxis. NICAS, NIH Idiopathic Clonal Anaphylaxis Score; REMA, Red Espanola MAstocitosis
Reproduced with permission from Lieberman et al
98 
and Carter et al. 
94 
Adapted from Alvarez-Twose et al. 
93
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treatment of a systemic hypersensitivity reaction may be more effec-
tive than delayed treatment. 
118,119 
Intramuscular epinephrine is a
safe medicine with negligible toxicity at doses recommended for ana-
phylaxis treatment (0.01 mg/kg of a 1:1000 [1 mg/mL] solution to a
maximum of 0.5 mg in adults and 0.3 mg in prepubertal children). 
3
However, epinephrine use in patients before the development of any
symptoms is a low-value practice (providing uncertain benefit with
potential for harm at substantial cost) and is associated with a qual-
ity-of-life burden. 
120−122 
Notably, appropriate use of epinephrine
during anaphylaxis improves quality of life and self-efficacy.
123 
In
addition to epinephrine, other supportive therapies, such as intrave-
nous fluids and supplemental oxygen, may play an important role in
the treatment of anaphylaxis, even before the development of hypo-
tension. 
124 
Of note, use of epinephrine does not mandate universal
activation of EMS in the patient who experiences prompt, complete,
and durable response to treatment when access to advanced medical
care is readily available if needed. 
125−127 
Anaphylaxis preparedness
discussions that include shared decision-making may be useful to
help patients understand thresholds for further care (see further dis-
cussion with Recommendation 26).
128,129
A recent expert consensus of knowledge gaps in anaphylaxis was
published. 
4 
Further research efforts are expected to continue to
inform knowledge gaps in the area of anaphylaxis diagnosis. These
are summarized in Table 11.
Anaphylaxis in Infants and Toddlers
There is a dearth of quality data regarding the epidemiology of
anaphylaxis in infants and toddlers, though this has been a growing
area of interest in the past several years. The available data agree that
food is clearly the most common cause of anaphylaxis in this age
group and that this is consistent across the globe. 
130−134 
In addition,
the rate of presentation to the ED for anaphylaxis in this age groups
seems to be increasing (at least in the United States). 
130
Question: How should anaphylaxis be diagnosed in infants and
toddlers?
Recommendation 8 (CBS): We suggest that clinicians use cur-
rent NIAID/FAAN or WAO anaphylaxis criteria to assist in the diag-
nosis of anaphylaxis in infants/toddlers, because there are no
criteria specific to this age group.
Strength of Recommendation: Conditional
Certainty of Evidence: Low
Defining what age range constitutes infancy is poorly established
for the purposes of allergic diseases, including anaphylaxis. 
10,19 
A
recent expert panel consensus report recommended emphasizing
age rather than weight in defining “infant” and that their recommen-
dations should broadly apply to both infants and toddlers up to age
36 months. 
135 
This panel also recommended working within the
existing NIAID/FAAN criteria for anaphylaxis as there are no criteria
specific for infants that have been created by any allergy or emer-
gency medicine society or regulatory authority. However, the panel
recognized that as more data are collected regarding these unique
cases, specific age-based criteria for anaphylaxis may become war-
ranted. The panel also identified knowledge gaps in many areas
including the following: recognition of anaphylaxis cases using
claims data and issues that may occur with billing/coding inaccura-
cies; that epinephrine usage rates may not always correlate with ana-
phylaxis diagnosis; identifying risk factors that specifically
predispose infants (vs children of other ages) to anaphylaxis; how
best to recognize symptoms of anaphylaxis in nonverbal or minimally
verbal populations; establishing appropriate epinephrine dosing for
infants and toddlers; and lack of a standardized evaluation for
patients of this age. 
135
Question: Should age of the infant/toddler experiencing ana-
phylaxis be used as a predictor of reaction severity?
Recommendation 9 (CBS): We suggest clinicians be aware that,
in infants and toddlers, patient age does not correlate with reac-
tion severity.
Strength of Recommendation: Conditional
Certainty of Evidence: Very Low
Question: Should lack of prior exposure to an allergen be used
as a predictor for anaphylaxis risk?
Recommendation 10 (CBS): We suggest clinicians be aware that
anaphylaxis is unlikely to be the initial reaction to a food or medi-
cation on first exposure in infants.
Strength of Recommendation: Conditional
Certainty of Evidence: Low
Few nationally representative data exist studying anaphylaxis in
this age group. However, the Healthcare Cost and Utilization Project
Nationwide Emergency Department Sample (a large, national study
of temporal trends of presentation to US EDs from 2006 to 2015)
noted that the proportion of visits for anaphylaxis in infants
increased from approximately 20 to 50 per 100,000 visits through
this time period, whereas overall hospitalizations for anaphylaxis
presenting to the ED in this age range fell from 19% to 6%. 
136 
Private
insurance, male sex, and high income were key factors associated
with increased odds of being hospitalized after presenting to the ED
for anaphylaxis. However, data from the Healthcare Cost and Utiliza-
tion Project Nationwide Inpatient Sample reveal that general admis-
sion rates were stable in infants and toddlers during that same time
frame.
137 
Overall, fatality from anaphylaxis in any age is rare, and
exceptionally rare in infants, though few studies have explored this,
and there is a risk of omitted cases potentially confounding low esti-
mates.
Data from interventional clinical trials assessing the early intro-
duction of allergenic solid foods in high- and low-risk infants under
the age of 12 months have largely noted that anaphylaxis is an
uncommon manifestation of initial reactions, and overall, although
severe reactions occur, they are far less common than mild-to-mod-
erate, primarily cutaneous, reactions. 
138−144 
Data from an Australian
Table 11
Knowledge Gaps in the Diagnosis of Anaphylaxis
Future validation of the 2020 WAO criteria will be helpful in determining their clinical utility.
Further multidisciplinary and international consensus on clinical diagnostic criteria will be important to address how clinicians and researchers will: (1) classify isolated acute aller-
gic oropharyngeal or laryngeal angioedema as this would meet the 2020 WAO anaphylaxis diagnostic criteria but not the 2006 NIAID criteria; (2) define what constitutes “severe”
gastrointestinal symptoms; (3) determine whether or not gastrointestinal involvement should be recognized as a systemic manifestation of anaphylaxis when accompanied by
mucocutaneous involvement secondary to food allergens; and (4) reach consensus with regard to other classification discrepancies between the 2006 NIAID and 2020 WAO crite-
ria.
Further validate acute and bST levels informed by TPSAB1 copy number variation.
Better understand the role of third-party payor coverage of TPSAB1 copy number evaluation in influencing and informing evaluation of patients with suspected mast cell disorders.
Abbreviations: bST, baseline serum tryptase; NIAID, National Institute of Allergy and Infectious Disease; TPSAB1, tryptase a/b-1; WAO, World Allergy Organization.
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population-based, cross-sectional study of 12-month-old infants
revealed that fewer than 2.5% of all reactions after initial introduction
of the food were severe.
145 
A national Korean ED registry which
revealed that 9.7% of children aged below 24 months (n = 93 children
of 558 total participants) who presented with anaphylaxis had what
was considered by investigators to be a severe reaction. 
146 
No clinical
data or biomarkers provide a rationale for why reaction severity
should differ based on age, though cofactors that augment severity
may be more relevant in older individuals. There may be confounding
factors in different geographic locations or ethnic populations.
Question: Do infants and toddlers present with different signs
and symptoms of anaphylaxis compared with older children and
adults?
Recommendation 11 (CBS): We suggest clinicians be aware that
parents of infants and toddlers may report age-specific symptoms
that are less often reported by older children and adults.
Strength of Recommendation: Conditional
Certainty of Evidence: Very Low
Studies suggest that there are age-related symptom presentation
patterns for severe allergic reactions. 
147−149 
Retrospective studies
report that infants and young children more often have skin symp-
toms as compared with older children whereas infants less often
have respiratory symptoms. 
147,148 
Subjective symptoms are also
more often documented for older children, likely because infants are
unable to communicate these types of symptoms. A national parent
survey conducted by an advocacy group noted that most parents
reported skin symptoms and subtle behavioral signs (pulling/scratch-
ing/fingers in ear) as a sign of reactions more frequently in children
aged below 12 months as compared with older toddlers. 
150 
In infants,
behavioral manifestations may include unexplained behavioral
changes, such as withdrawal, inconsolable crying, irritability, or
clinging. 
135,150,151 
Some studies suggest that gastrointestinal symp-
toms may be a common presenting feature in infants, but those retro-
spective studies are limited by the differing definition of ages of
infants and young children and reflect self-reported as opposed to cli-
nician-observed symptoms.
Question: Should infants/toddlers be prescribed the 0.1 mg or
0.15 mg EAI?
Recommendation 12: We suggest clinicians prescribe either
the 0.1 mg or the 0.15 mg EAI dose for infants/toddlers weighing
less than 15 kg.
Strength of Recommendation: Conditional
Certainty of Evidence: Low
Epinephrine is the drug of choice for infant anaphylaxis, as it is at
any age. However, perhaps the most significant development in
infant/toddler anaphylaxis management has been the introduction of
a 0.1 mg EAI for infants weighing 7.5 to 15 kg where formerly only
0.15 mg and 0.3 mg doses were offered. 
135 
There is older literature
suggesting that epinephrine should be dosed at 0.01 mg/kg, but this
was derived empirically and represented an expert consensus
regarding an appropriate dose. 
2 
Thus, the actual necessary and suffi-
cient mg/kg dose is unknown, though the 0.01 mg/kg recommenda-
tion seems to be at least anecdotally supported by evidence of
efficacy. 
152 
No data suggest that the 0.15 mg dose was either ineffec-
tive or unsafe in this population, even when used at lower weights
(including <7.5 kg) where the dose may exceed 0.01 mg/kg. Thus, the
necessity of the 0.1 mg dose remains unclear, though this dosing
option exists (subject to insurance coverage) as a preference-sensi-
tive choice in children under 15 kg. 
2 
Data have emerged regarding
the importance of needle length in smaller infants or toddlers. Ultra-
sound-based evaluations of skin-to-bone distance suggest that longer
needles increase the risk of the needle hitting bone. This could lead to
impaired delivery of the epinephrine, increased pain and distress, or
needle embedment in bone requiring surgical extraction. 
153,154 
We
found only 1 case report of intraosseous injection of the femur, which
occurred when an EpiPen Jr. was administered to a female child
weighing 25 kg. 
155 
More research is needed to determine the true
risk of intraosseous injection and how it may affect the efficacy of
epinephrine if it occurs.
Research into infant/toddler anaphylaxis continues to evolve as
multiple knowledge gaps exist regarding its epidemiology, classifica-
tion, diagnosis, and management. These are noted in Table 12, with
recommendations to help guide future research.
Anaphylaxis in Community Settings
Question: What counseling and education should clinicians
provide to patients to help them manage the risk of anaphylaxis
in community settings?
Recommendation 13 (CBS): We recommend clinicians counsel
patients at high risk of anaphylaxis to always carry self-injectable
epinephrine and teach patients proper indications and use.
Strength of Recommendation: Strong
Certainty of Evidence: Very Low
Recommendation 14 (CBS): We recommend clinicians educate
patients on avoidance of potential exposure to their allergen(s).
Strength of Recommendation: Strong
Certainty of Evidence: Very Low
Recommendation 15 (CBS): We recommend clinicians educate
patients that the main route of food-induced anaphylaxis is by
ingestion and not contact or inhalation.
Strength of Recommendation: Strong
Certainty of Evidence: Moderate
Anaphylaxis is unpredictable and can occur anywhere, with most
cases occurring outside the medical setting. Although there are abun-
dant data addressing the frequency and management of anaphylaxis
owing to different allergen triggers, there are little data regarding the
frequency of anaphylaxis in specific community locations or on effec-
Table 12
Summary of Key Knowledge Gaps That Require Additional Research Related to Anaphylaxis in Infants and Toddlers
Lack of data on symptom presentation from well-defined infant anaphylaxis cohorts to better determine whether infants need separate clinical criteria to define anaphylaxis as
compared with older children, adolescents, and adults.
Lack of data to suggest that anaphylaxis in an infant is associated with changes in core body temperature.
Lack of data to determine whether needle length of available 0.1 mg and 0.15 mg autoinjectors provides more optimal intramuscular delivery of epinephrine.
Lack of data to determine whether potentially higher doses (eg, >0.01 mg/kg) of epinephrine delivered using a 0.15 mg autoinjector in an infant <10 kg lead to adverse effects.
Lack of long-term data on whether early introduction of allergenic foods in infants’ diets will lead to increase in severe allergic reactions and health care utilization.
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tive mitigation strategies by location. Despite the low quality of avail-
able evidence, the workgroup has judged that the desirable effects of
certain interventions clearly outweigh the undesirable effects. Thus,
we have issued strong consensus-based statements based on very
low- to moderate-quality evidence, similar to good practice state-
ments under the GRADE methodology.
Allergen avoidance is a key management strategy for anaphylaxis
prevention. Regarding food-induced anaphylaxis, nearly all reported
cases are triggered by ingestion of the allergen. Although contact
reactions can cause cutaneous symptoms, such as hives or redness at
the site of contact, the risk of anaphylaxis from isolated skin contact
(without oral transfer) is very low.
156 
Similarly, the risk of anaphy-
laxis due to inhalation of food allergen is very low but has been sus-
pected to occur if there is active aerosolization of the allergen (such
as steam from boiling milk) in close proximity. 
157 
Studies support
that casual skin contact or inhalation, as may occur in a community
setting, is unlikely to trigger anaphylaxis. 
158−160
Determining the frequency of anaphylaxis in different locations
outside the home is difficult, due in large part to variations in study
design and categorization of locations outside the home, including
missing information. Table 13 presents the calculated percentage
range and the average frequency of anaphylaxis in children and/or
adults by reported location. 
132,161−207 
The younger the population,
the higher the percentage of anaphylaxis events occurring in the
“home” location. 
192 
A study in which 89% of 5149 participants were
children reported that although the initial anaphylaxis event
occurred most often at home, subsequent anaphylaxis events increas-
ingly shifted to outside the home, in locations such as schools and
restaurants. 
205 
Although fatalities have been reported, they are
rare.
190 
Fatalities reportedly occurred in homes (21%-35%), schools
(10%-19%), restaurants (19%-20%), hospitals (6%), and unknown loca-
tions (36%-75%). The average and/or median age for all 265 reported
fatalities was early twenties. 
190
Anaphylaxis in Childcare Centers and Schools
The JTFPP endorses the following GRADE recommendations from
2021 guidelines for the management of allergic reactions in childcare
centers and schools. 
208
Question: Should childcare centers and schools implement
training for personnel in the management of food allergy, rather
than not implementing such training?
Recommendation 16 (GRADE): We suggest childcare centers
and schools implement staff training for allergy and anaphylaxis
management.
Strength of Recommendation: Conditional
Certainty of Evidence: Very Low
Question: Should childcare centers and schools prohibit spe-
cific foods site wide (eg, nut-free schools), rather than not imple-
ment such restrictions?
Recommendation 17 (GRADE): We suggest that childcare cen-
ters and schools not implement site-wide food-specific prohibi-
tion because current research does not support consistent
benefits. Special circumstances: It might be appropriate to imple-
ment allergen-restricted zones (eg, milk-free table) when there
are children who lack the capacity to self-manage.
Strength of Recommendation: Conditional
Certainty of Evidence: Very Low
Question: Should childcare centers and schools stock undesig-
nated EAIs that can be used to treat any individual on school
grounds who experiences anaphylaxis?
Recommendation 18 (GRADE): We suggest that childcare cen-
ters and schools stock undesignated EAIs that can be used to treat
any individual on school grounds who experiences anaphylaxis.
Strength of Recommendation: Conditional
Certainty of Evidence: Very Low
The authors of these recommendations from the 2021 GRADE
guideline for the prevention and management of allergic reactions in
childcare centers and schools found that approximately 1 in 10 aller-
gic reactions and cases of anaphylaxis in children occur in childcare
centers or schools. 
208 
Across studies, the median reported rate of ana-
phylaxis in childcare centers or schools was 19 per 100,000 students
per year (range: 8-118/100,000). 
208 
The GRADE guideline condition-
ally recommended that childcare centers and schools implement an
expert-designed allergy training program for personnel in combina-
tion with site-wide protocols for managing anaphylaxis and allergy
action plans for managing allergic reactions in children at risk of
Table 13
Frequency of Anaphylaxis in Different Locations
a
Population studied Home School/work Restaurant Other home
Children Studies, n 44 46 26 16
Average 
b 
57% 11% 8% 14%
Range 37%-92% 0%-28% 0%-17% 3%-34%
Adults Studies, n 4 3 3
Average 
b 
42% 3% 22%
Range 27%-60% 2%-5% 17%-33%
Age not specified
c 
Studies, n 8 8 7
Average 
b 
46% 9% 21%
Range 16%-68% 4%-21% 6%-51%
Average = average frequency of anaphylaxis across the number of studies. 
b
Range = range across the number of studies (wide range across the locations).
References for child. 
132,161−201,207
References for all ages. 
132,190,199,202−206
References for adults. 
197−199
a
In summarizing the location of possible or confirmed anaphylactic events in this table, we have omitted reported reactions that occurred in an “unknown” location. We have com-
bined reactions that occurred in the following locations under the following labels: school, preschool, or work under “school/work”; restaurant, bar, or takeout under “restaurant”;
and friend’s, relative’s, or neighbor’s home under “other home.” For the categories of “restaurant” and “other home,” we only included studies that reported data for these locations
or that accounted for 100% of reactions in other categories.
b 
Unweighted average may be misleading; note the range of averages across studies.
c 
When studies report the location of anaphylaxis for “all age groups,” the authors usually fail to report the location by age category.
ARTICLE IN PRESS
D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53 21

anaphylaxis. Staff training is linked to short-term improvements in
allergy-related knowledge, skills, and preparedness among childcare
and school personnel. 
208 
Limited, low-quality evidence suggests that
training and action plans may help reduce the rate of allergic reac-
tions and the need for epinephrine use in students. 
174,208−214
Studies have not consistently found that food bans improve qual-
ity of life
215 
or lower the risk of allergic reactions among
students. 
171,172,216 
Thus, the GRADE guideline conditionally recom-
mends that childcare centers and schools not implement site-wide
food prohibitions (eg, “nut-free schools”). The guideline also condi-
tionally recommends against classroom-level food bans and allergen-
free tables, except in cases when students lack the capacity to self-
manage avoidance and prevention strategies due to very young age
or cognitive or physical impairments. 
208
Additional common sense strategies for risk reduction have not
been formally evaluated but include washing hands before and after
eating, avoiding sharing foods and drinks with others, and checking
ingredient lists for allergens. Other steps that childcare centers and
schools can take include providing adult supervision during meals
and snacks, cleaning surfaces where food is prepared or eaten, and
taking steps to avoid students’ allergens when planning and imple-
menting classroom activities (eg, parties, crafts, science projects) or
field trips.
The 2021 GRADE guidelines also conditionally recommended that
childcare centers and schools stock undesignated EAIs that may be
used to treat anaphylaxis in any student, staff member, or other indi-
vidual that experiences anaphylaxis on site. 
208 
The US School Access
to Emergency Epinephrine Act encourages states to implement poli-
cies requiring schools to stock undesignated EAIs for use in emergen-
cies. Undesignated EAIs may be used in cases when student-specific
EAIs are unavailable, including treatment of individuals with no
known history of allergy (15%-31% of reported cases of epinephrine
use at childcare centers and schools are for those with no known
allergy). 
208 
At this time, not all states have laws that require schools
to have stock epinephrine available. 
217
Anaphylaxis in the Restaurant Setting
Question: What education should clinicians provide to patients
with food allergy regarding anaphylaxis in the restaurant setting?
Recommendation 19 (CBS): We suggest clinicians counsel
patients that although US regulations require disclosure of major
allergens on labels of prepackaged foods, they do not require res-
taurants to declare ingredients or provide allergy warnings for
non-prepackaged foods.
Strength of Recommendation: Conditional
Certainty of Evidence: Very Low
Recommendation 20 (CBS): We suggest clinicians counsel
patients on safe practices for dining outside of the home.
Strength of Recommendation: Conditional
Certainty of Evidence: Very Low
Training of restaurant staff is the mitigation strategy that has been
most often evaluated for the ability to reduce anaphylaxis in the res-
taurant setting. Knowledge gaps related to food allergy and anaphy-
laxis have been noted in restaurant and other food service staff, and
only a few staff receive specific training. 
218−220 
The effectiveness of
such training in reducing rates of anaphylaxis or improving responses
to reactions has not been studied.
Additional risk reduction strategies have been used or suggested
for the restaurant industry, but data are lacking on whether these
practices affect rates of anaphylaxis. The Food Allergen Labeling and
Consumer Protection Act of 2004 
221 
requires disclosure of major
allergens on packaged food items, but the law does not require res-
taurants or food establishments that prepare food to provide ingredi-
ent lists or allergy warnings to customers. Some cities and states in
the United States have enacted laws related to food allergy awareness
and/or signage, but these are not universal. A few restaurants list
allergens or ingredients on their menu or other signage, a practice
that seems to be increasingly adopted. 
218 
Policies and practices may
need to be updated for additional allergens such as sesame which
was recently added by the FDA to the list of allergens that require
special labeling.
Researchers have used data from a national voluntary online reg-
istry to characterize food-allergic reactions in restaurants. 
222 
Cafes,
fast food establishments, and Asian restaurants (as described by the
authors) were frequently identified as locations for reactions. Peanut,
tree nuts, and milk were the most common triggers. Approximately
half the reactions (53.9%) occurred despite a diner informing the res-
taurant staff of the food allergy, 26.6% occurred when food allergens
were declared on the menu, and 13.7% occurred even though the
menu declared allergens and food allergy was communicated to res-
taurant staff. More than a quarter of reactions were treated with epi-
nephrine (28% received 1 dose, 6.2% received 2 doses). Reactions
have also been reported after allergen exposures due to takeout
foods. 
223 
In an online survey of parents of children with food allergy
ordering takeout, the most common allergens triggering reactions
were milk, peanut, and wheat, which often seemed as “hidden aller-
gens” (eg, unlabeled, inapparent, or contaminant components). Take-
out orders from Asian restaurants were most frequently associated
with severe allergic reactions. Diners reported taking a variety of pre-
cautions, including writing the allergy in an online order, calling the
restaurant to discuss the order, and visually inspecting the dish; how-
ever, reactions still occurred. The number of precautions taken by
takeout diners who experienced reactions was no less than by those
who did not have reactions. An AAAAI workgroup on food allergy in
restaurants has provided guidance for practitioners, patients, and res-
taurant staff. 
224
Table 14 presents potential strategies for safe dining to be consid-
ered when counseling patients who have food allergy. Management
of anaphylaxis risk is a “shared responsibility” in the restaurant set-
ting (ie, both the allergic diner and food service staff have roles to
play in keeping the diner safe). Clear communication is essential.
There is a lack of high-quality data on specific strategies for safe din-
ing, but the concepts in this table provide a framework based on
expert opinion.
Currently, there are no US mandates for restaurants to have medi-
cal emergency kits with epinephrine on site. However, most states
have passed legislation that allows restaurants to keep stock epi-
nephrine on site. 
225 
Despite this, physicians continue to have med-
ico-legal concerns about prescribing stock epinephrine, which poses
a barrier to restaurants and other community settings that would like
to stock epinephrine. In countries such as Canada, where EAIs can be
purchased without a prescription, stock epinephrine programs in
community settings may be more feasible. 
226
Anaphylaxis Inflight
An allergic inflight emergency is estimated to occur once for every
37,750 flights and for less than or equal to 1 of 2 million passengers,
with emergency landings reported for less than 4.4% of these epi-
sodes. When patients with peanut and/or tree nut allergy have been
surveyed, 1.7% to 10.7% reported having experienced an allergic reac-
tion while on a commercial flight. 
227−229 
The nature of these reac-
tions and how many of them meet the criteria for anaphylaxis are
not clearly reported in published studies. Epinephrine administration
for inflight allergic reactions was reported to have occurred in 10% to
ARTICLE IN PRESS
22 D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53

15% of cases across studies, 
227−230 
although reports of symptoms sug-
gested that epinephrine might have been indicated in more
cases. 
228,230 
Food allergens are the primary trigger for inflight reac-
tions, with peanut implicated most frequently as the culprit food. 
227
−230 
It is possible that there is underreporting of inflight reactions
given past data that 29% to 50% of reactors notified airline personnel
of their reactions. 
227−229
Many airline passengers report using risk reduction strategies
similar to those used in restaurants, such as notifying flight attend-
ants of their allergy and bringing safe foods for flights. 
231 
A 2013
international study of inflight reaction found that certain reported
risk mitigation strategies were associated with lower odds of report-
ing an inflight allergic reaction. 
229 
However, no prospective studies
have evaluated whether implementation of these strategies lowers
the risk of anaphylaxis. Although airline pre-notification is often sug-
gested, it can potentially result in unintended consequences. The Air
Carrier Access Act of 1986 allows pilots to refuse boarding to a pas-
senger with an identified medical risk deemed significant enough to
pose a potential risk of flight diversion or danger to the passenger. 
232
Many airline websites provide some information for patients with
allergy; however, only a few offer allergen-free meals for preorder or
allow priority boarding. 
233
Anaphylaxis in Community Recreational Settings
Anaphylaxis can occur in recreational community settings, such as
parks and other outdoor spaces. In these settings, insect sting allergy
is a relevant exposure of concern (occupational exposures will not be
discussed in this section). In data from the European Anaphylaxis
Registry, 
234 
half of venom anaphylaxis cases occurred in gardens and
parks, 25% in public places or at work, and 25% in an unspecified loca-
tion. On the basis of patient questionnaires, insect sting anaphylaxis
occurs in 0.34% to 8.9% of the general population, 
235,236 
accounts for
1.5% to 50% of ED visits for anaphylaxis, 
51,235 
and is responsible for
13% to 33% of all fatal cases of anaphylaxis. 
51 
Measures for minimiz-
ing chances of insect stings have been suggested in the 2016 stinging
insect hypersensitivity practice parameters. 
237
There are other causes and settings for anaphylaxis related to
community recreational activities both indoors and outdoors, such as
food-dependent exercise-induced anaphylaxis and outdoor dining.
However, there are no data quantifying the frequency of these events
in the community setting. There is also limited information on the
location of drug reactions in the community setting. Allergy to beta-
lactam antibiotics and nonsteroidal anti-inflammatory drugs is most
common, and most reactions occurring outside the medical setting
are likely to occur in the home.
Table 14
Potential Expert Opinion-Based Strategies and Considerations for Safe Dining to Discuss With Patients Who Have Food Allergy
Potential strategies for safe dining to discuss with patients Comments
1. Attempt to determine the restaurant’s food allergy policy, menu
options, and possible accommodations.
This is an important step to help ensure those with food allergy have the information they need
to make safe, informed choices when dining out. This can be done by speaking to the restau-
rant or checking online resources.
2. Disclose allergy to a knowledgeable and responsible food service staff
member before ordering their meal; discuss which specific foods
and ingredients they must avoid; and receive assurance that the
utmost care will be taken to exclude these allergens and avoid
cross-contact.
When speaking with a knowledgeable and responsible food service staff member, the patient
or family should request information about all the ingredients in the menu selection and how
the food is prepared, before placing an order. If the diner feels that safe options are not avail-
able, they should seek alternative dining options.
3. Ensure that all dining surfaces have been cleaned between diners to
remove any food residue. This is generally the responsibility of the
restaurant, but some diners may feel more comfortable cleaning
table surfaces themselves, for example, using disposable cleaning
wipes.
Cleaning protocols across restaurants may vary. It is not unreasonable to inquire about the
cleaning process that the food service staff use between diners.
4. Carry a written list (eg, allergy cards) of food allergens and hidden
sources of these allergens to support communication with food ser-
vice staff. When dining in a restaurant where many food service
staff speak a different language from the patient (eg, foreign travel),
consider providing a translation of this list.
Allergy cards (eg, https://equaleats.com/) are used by some diners with food allergy to commu-
nicate their allergy to the food service staff. This can be a useful communication tool, espe-
cially when traveling or if there is a language difference between the diner and staff. It can
help clearly articulate the diner’s food allergy and can be shared with the food service staff in
both front- and back-of-house to ensure the proper information is shared with those prepar-
ing and serving food to the diner with allergy.
5. Inform dining companions of the food allergy and steps to take in the
event of an accidental ingestion and allergic reaction.
When eating with others, allergic diners should tell them in advance about their food allergy
and what to do in an emergency situation. It is important to share this information so dining
companions can help in case of an allergic reaction and assist with the epinephrine adminis-
tration and/or calling emergency services. Patients should let their dining companions know
where to locate their EAI (eg, patient’s purse) and provide instructions on how to use it.
6. Be aware that there is likely higher risk of exposure to certain aller-
gens at certain venues, including: peanut, and/or tree nut exposure
in Asian restaurants; exposure to peanut, tree nuts, and/or milk in
bakeries and ice cream shops; and seafood at restaurants that pre-
dominantly serve seafood. Practice extra vigilance or possibly avoid
such venues.
Be aware that there is likely higher risk of seafood exposure at res-
taurants that predominantly serve seafood and practice extra vigi-
lance or possible avoidance of those venues.
Patients with an allergy to peanuts, tree nuts, milk, or seafood should be cautious at food ser-
vice establishments that frequently serve their allergens because it may be very difficult to
find safe menu options. The potential for cross-contact may be higher in these establish-
ments because these allergens are more prevalent in the kitchen, and depending on the level
of training or knowledge of the food service staff, there may or may not be protocols in place
to minimize cross-contact. Asking the food service staff about their food allergy policy and
practices and their ability to provide accurate and complete ingredient disclosure is impor-
tant and will help diners with food allergy better understand the potential risks of eating at
these establishments or determine whether another option would be more appropriate.
7. Avoid buffets due to higher risk of cross-contact. Buffets are accessed by multiple diners who may not be cautious about avoiding cross-contact
between serving utensils, dishes, and so on.
8. Only eat food prepared specifically for the diner with allergy when
dining out.
Diners with food allergy should consider not sharing or sampling the food of dining compan-
ions because food service staff may have paid less attention to cross-contact.
9. Consider dining during off-peak hours. Diners with food allergy may consider eating out during “low-traffic” times (as opposed to the
lunch rush or a busy brunch hour), when food service staff may have more time to discuss
safe menu options and prepare the allergen-free food.
10. Follow general recommendations regarding anaphylaxis preparedness
and management.
When dining out, it is important to always be prepared to treat a reaction should it occur. As
such, diners with food allergy should always carry their EAIs with them when dining out.
Abbreviation: EAI, epinephrine autoinjector.
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D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53 23

Question: Should clinicians advise use of medical identification
(eg, jewelry or wallet card) for individuals at risk of anaphylaxis?
Recommendation 21 (CBS): We suggest that advising individu-
als at risk of anaphylaxis to wear or carry medical identification
(eg, jewelry or wallet card) be considered optional. If it is worn or
carried, the wording on medical alert jewelry or wallet cards
should be verified for accuracy by a health care professional.
Strength of Recommendation: Conditional
Certainty of Evidence: Very Low
Many people at risk of anaphylaxis use medical alert jewelry (or
wallet cards) to declare their allergies; however, the information
listed varies across products and not standardized, and there is no
requirement for physician verification of accuracy. 
238,239 
It is
unknown whether medical alert jewelry or wallet cards reduce the
risk of anaphylaxis or result in more rapid treatment.
Stock Epinephrine in Community Settings
Question: Should stock epinephrine in community settings be
supported?
Recommendation 22 (CBS): We suggest that keeping stock EAI
in community settings be encouraged, if feasible.
Strength of Recommendation: Conditional
Certainty of Evidence: Very Low
Studies reveal that in the United States, sports facilities, airports,
and amusement areas are the most common places where automated
external defibrillators are used. 
240,241 
Therefore, some people suggest
that these same locations should, ideally, have undesignated EAIs
available. 
242 
All states have passed legislation that permits (but does
not require) “entities” to stock undesignated epinephrine for emer-
gency use.
225,243 
“Entities” vary by state and may include camps,
theme parks, sports arenas, restaurants, childcare centers, and/or col-
lege campuses, and this legislation is often separate from a state’s
school-entity stock epinephrine legislation. Although permitted, it is
rare for community settings to have stock epinephrine available.
There is a lack of data on the health effects, feasibility, and cost-effec-
tiveness of stocking epinephrine in community settings outside of
schools. Some studies have explored people’s willingness to share
their epinephrine devices (proximity-based community response) as
another novel approach to facilitate rapid responses to anaphylaxis
in the community. 
234,244 
Availability of stock EAI on airplanes has
been found to be cost-effective and may be a safer option than stock
ampules and syringes in this setting. 
245,246
Knowledge gaps related to anaphylaxis in community settings are
listed in Table 15. The key points reviewed in this section are summa-
rized in Table 16.
Epinephrine Autoinjectors: When and What to Prescribe
Epinephrine is universally recommended as the first-line treat-
ment for anaphylaxis. 
3 
However, the rate of EAI prescription for
patients at risk of anaphylaxis remains suboptimal. 
111,247 
Even when
clinicians prescribe EAIs, patients do not always adhere to their treat-
ment plans, with researchers reporting suboptimal rates of EAI pre-
scription fills and refills, carriage, and use.
111,247,248 
This practice
parameter provides evidence-informed guidance for EAI prescription,
use, and patient education and counseling.
Question: Should clinicians take a risk-stratified approach to
EAI prescription?
Recommendation 23 (CBS): We suggest clinicians routinely
prescribe EAIs to patients at higher risk of anaphylaxis. When
deciding whether to prescribe EAIs to lower risk patients, we sug-
gest that clinicians engage in a shared decision-making process
that considers the patients’ risk factors, values, and preferences.
Strength of Recommendation: Conditional
Certainty of Evidence: Very Low
Allergic reactions range in severity from mild skin manifestations
to life-threatening anaphylaxis. The severity of symptoms can vary
from one reaction to another, but the pattern and sequence of symp-
toms are more reproducible. 
33 
There are risk factors that significantly
increase the relative risk of anaphylaxis, although the absolute risk
may remain small. A patient’s risk of anaphylaxis depends in part on
their specific diagnosis, history of prior reaction(s), the ease with
which they may avoid causative agents or circumstances, and
whether they have completed AIT. Some subsets of patients have a
higher frequency of anaphylaxis and/or greater severity of anaphy-
laxis compared with other patients. There are patients who feel a
substantial psychosocial burden from EAI prescriptions; for others,
EAI prescriptions are linked to improved quality of life.
249,250 
When
assessing the risk of anaphylaxis and weighing the potential benefits
of EAI prescription, clinicians should consider a patient’s diagnosis,
history of allergic reaction, likelihood of allergen exposure, and other
potential cofactors that could affect the likelihood of a poor outcome.
For patients with food allergy, even small amounts of causative
allergen may potentially trigger an allergic reaction—including ana-
phylaxis in some cases. Owing to the potential for cross-contamina-
tion of food products and gaps in food allergy knowledge among the
general public, reactions to causative foods may occur even when
patients have taken steps to avoid the food. Food oral immunother-
apy (OIT) is a relatively new and promising therapy for food allergy;
however, safety and tolerability concerns continue to limit its use in
routine clinical practice. Many reactions to OIT are mild and resolve
without intervention or with antihistamine alone. However, virtually
all clinical trials report some severe allergic reactions. 
251 
These are
most frequently reported during the dose escalation when treatment
Table 15
Knowledge Gaps for Anaphylaxis in the Community
Epidemiology - Accurate estimates of prevalence rates and causes of anaphylaxis in various community settings
- Standardized terminology for different locations (such as other homes, restaurants, and public and recreational settings) to facilitate aggregation
of data across studies
- Common definition of anaphylaxis across studies
Anaphylaxis prevention - Effective risk mitigation strategies for different community settings
Anaphylaxis management - Effective training programs for restaurant, airline, and other community workers to respond to anaphylaxis emergencies
- Feasible and cost-effective process for stocking EAIs in public locations
Abbreviation: EAI, epinephrine autoinjector.
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24 D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53

is initiated and during subsequent buildup dosing; however, home
maintenance doses can also be associated with severe reactions, even
with doses previously tolerated. 
252 
In a recent systematic review and
meta-analysis, high-certainty evidence revealed that although cur-
rent peanut OIT regimens effectively induce desensitization, they are
associated with considerably increased risk of allergic reactions, ana-
phylaxis (22% with OIT vs 7% at baseline), and epinephrine use (risk
ratio = 2.7) compared with avoidance or placebo. 
253 
For these rea-
sons, most clinicians still prescribe EAIs even to those who have suc-
cessfully achieved a desensitization regimen.
People with venom or insect bite/sting allergy can take steps to
reduce their risk of exposure. However, they may still be bitten or
stung. VIT is considered nearly completely effective in preventing life-
threatening reactions to stings, although honey bee VIT and fire ant
whole body extract immunotherapy offer less complete protection.
237
It is typically easier for people with latex, drug, or RCM reactions
to avoid causative agents and circumstances. Most reactions to drugs
and RCM occur in health care settings, where health care professio-
nals are equipped to administer epinephrine. 
254 
However, in up to 1
in 10 cases of drug- or RCM-induced anaphylaxis, the patient experi-
ences a biphasic reaction, which is likely to occur outside of the
health care setting. 
37,255 
The JTFPP found that the greatest risk factor
for biphasic reaction is an initial presentation that requires multiple
epinephrine doses to treat anaphylaxis (odds ratio [OR] = 4.82; 95%
CI, 2.70-8.58). 
3
Some drugs have garnered special attention regarding the risk of
anaphylaxis. These include omalizumab, which the FDA approved in
2003 for moderate-to-severe persistent allergic asthma, in 2014 for
chronic idiopathic urticaria, and in 2020 for nasal polyps. Until 2021,
omalizumab was only administered under medical supervision, but it
is now approved for home-based treatment. Clinical trials among
patients with moderate-to-severe asthma initially reported a risk of
omalizumab-induced anaphylaxis of 0.08%, which increased to 0.2%
in post-marketing surveillance. 
256 
Many of the reactions were
reported to occur more than 2 hours after injection or after a number
of uneventful doses. In 2007, this led the AAAAI and ACAAI’s Omalizu-
mab Joint Task Force to recommend the prescription of EAIs to
patients prescribed omalizumab. 
257 
In a subsequent 2011 review, the
Omalizumab Joint Task Force found that omalizumab-induced ana-
phylaxis most often occurred within the first 3 injections and within
2 hours after injection. 
258 
Another review found that 64% of the cases
occurred within 1 hour of injection, 69% occurred at the first or sec-
ond dose, and 43% occurred in patients with a history of prior ana-
phylaxis unrelated to omalizumab. 
259 
More recently, a retrospective
study of 91 patients with difficult-to-control asthma found that of
10,472 injections of omalizumab, no anaphylaxis occurred. 
260 
In
another study, 0.17% (n = 6) of 3620 adult patients with severe
asthma experienced omalizumab-induced anaphylaxis in a treatment
course of 52 months.
261 
Given the drug’s demonstrated, long-term
safety and efficacy, the FDA approved home injection of omalizumab
in 2021 for patients with no known history of anaphylaxis to either
omalizumab or other agents from the fourth dose onward if deter-
mined appropriate by a clinician. Although the FDA has not mandated
EAI prescription for home injection of omalizumab, the package
insert does indicate that the patient/caregiver should be able to rec-
ognize and treat anaphylaxis. Nevertheless, a cost-effectiveness anal-
ysis revealed that for many patients, home injection of omalizumab
is a cost-effective strategy. 
262
Other potential causes of anaphylaxis include SCIT and SLIT, which
provide effective therapies for the treatment of allergic rhinitis, con-
junctivitis, and asthma. Rare cases of severe anaphylaxis due to SCIT
with aqueous allergen extracts have been identified, including very
rare cases of fatal anaphylaxis. 
263−265 
Potential risk factors in SCIT-
associated fatalities include uncontrolled asthma, prior systemic
reactions, administration during peak pollen season, suboptimal
treatment of anaphylaxis, and dosing errors, to name a few. Although
most systemic reactions with SCIT occur within 30 minutes of admin-
istration, approximately 15% occur after more than 30 minutes.
Nearly all severe systemic reactions and fatal reactions with SCIT
begin within the first 30 minutes after injections. 
266 
Severe
Table 16
Key Points for the Clinician on Anaphylaxis in Community Settings
Epidemiology 
 
Anaphylaxis can occur anywhere.
 
Most cases of anaphylaxis occur at home, followed by school as the second most reported location for children and restaurants for adults.
Childcare centers and schools 
 
Implementation of training programs for childcare and school staff and provision of emergency plans by families may help reduce rates of aller-
gic events.
 
There is lack of evidence to support implementation of specific allergen restriction policies as a risk reduction strategy. Many strategies used by
families and schools are based on common sense approaches to minimize risk of allergen exposure.
 
Clinicians should prescribe EAIs and advise students at risk of anaphylaxis (and their families) to always have them available at their childcare
center or school, some of which may not have stock epinephrine on site.
Restaurants 
 
Restaurants are a location where accidental allergen ingestion can occur.
 
Clinicians should encourage education of food service staff to improve their knowledge of allergen-safe practices in food preparation, manage-
ment of allergic reactions, and disclosure of allergens on menus.
 
Clinicians should counsel patients to clearly communicate with food service staff to ensure that their food is allergen safe and to have their EAIs
available at all times as stock epinephrine is not available in most public locations.
Airplanes 
 
Anaphylaxis has been reported to occur in airplanes, most often to foods.
 
Clinicians should counsel patients on standard food allergy management practices. Given that the risk of severe reaction is primarily associated
with ingestion of a food allergen rather than skin contact or inhalation, steps to prevent unintentional allergen ingestion should be the main pri-
ority (eg, bring own safe food when traveling, read ingredient labels).
 
Although airplane emergency kits in the United States contain epinephrine (both 1:1000 w/v [1 mg/mL] and 1:10,000 w/v [0.1 mg/mL]), drawing
up appropriate doses using a needle and syringe in a cramped air cabin midflight is very challenging and could lead to delayed treatment.
 
Stock epinephrine is not available in airports or during transit between destinations. It is therefore imperative that patients are prepared with
their own EAIs at all times.
 
Patients should notify flight crew of any allergic reaction so that inflight assistance and ground-based medical support, if needed, can be
accessed.
Other community settings 
 
Anaphylaxis to drugs, insects, and food-dependent exercise-induced anaphylaxis and idiopathic anaphylaxis can occur outside the home, so
patients should be counseled on allergen avoidance and having epinephrine available.
Abbreviation: EAI, epinephrine autoinjector.
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D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53 25

anaphylaxis has also been rarely reported in large phase 3 clinical tri-
als on SLIT, but with no reported fatalities. In clinical trials of SLIT for
seasonal and perennial allergic rhinitis, treatment-related adverse
events have been reported at equal frequencies for subjects with and
without asthma. More research is needed to evaluate the safety and
efficacy of SLIT for food allergy, but studies to date suggest that
adverse events are typically limited to local oropharyngeal or gastro-
intestinal symptoms, and systemic reactions requiring treatment
with epinephrine are rare. 
267 
When administering SCIT or SLIT, clini-
cians must be aware of the potential risk of severe allergic reactions
and know how to manage them. Clinicians may elect to prescribe
EAIs to patients on SCIT, particularly those with a history of prior ana-
phylaxis owing to any cause, prior systemic reactions to immuno-
therapy, active asthma, or other potential high-risk factors. In a cost-
effectiveness simulation, prescription of EAI to all patients on SCIT
was not cost-effective compared with prescription only to patients
with prior systemic reactions to SCIT. 
268 
In the United States, the FDA
mandates EAI prescription for patients on SLIT. However, in other
countries, this is not an absolute requirement and is left to the discre-
tion of the individual allergist and patient, unless mandated by local
regulators. 
269,270
We found no validated risk-stratification algorithms in the
research literature to guide EAI prescription. Drawing on clinical data
and expertise, we present a list of examples of low-risk vs higher-risk
histories in Table 17. Higher-risk patients are more likely than low-
risk patients to experience anaphylaxis and require treatment with
EAIs. The benefits of EAI prescription are also more likely to outweigh
the financial and psychosocial burdens (see Recommendation 28) for
higher-risk patients compared with low-risk patients. Some addi-
tional factors that are not included in the table may increase a
patient’s risk of severe anaphylaxis (eg, comorbid asthma) or the
potential benefits of having epinephrine available should anaphylaxis
occur (eg, residing, studying, working, or traveling in a location with
long emergency response times). When a patient with no prior his-
tory of anaphylaxis is admitted to the ED or visits a primary care pro-
vider for anaphylaxis, they should be given a prescription for
epinephrine and recommendation for allergist assessment. Patients
with iatrogenic anaphylaxis (eg, to RCM or drugs) may have less need
for epinephrine prescription, but they will still benefit from allergist
assessment to clarify their risk and provide counseling on possible
precautions.
Question: How many EAIs should clinicians prescribe to each
patient?
Recommendation 24 (CBS): We suggest that in jurisdictions
where single-packs of EAIs are available, clinicians consider a
patient’s risk factors for severe anaphylaxis, their values and pref-
erences, and contextual factors when deciding whether to pre-
scribe only one vs multiple EAIs. We suggest that they routinely
prescribe more than 1 EAI when patients have previously required
multiple doses of epinephrine to treat an episode of anaphylaxis
and/or have a history of biphasic reactions.
Strength of Recommendation: Conditional
Certainty of Evidence: Very Low
In some cases of anaphylaxis, symptoms only improve or resolve
after multiple doses of epinephrine. Biphasic recurrence of signs and
symptoms may also occur and require additional doses of epineph-
rine to treat. To manage the potential risk of anaphylaxis requiring
more than 1 dose of epinephrine, regulatory agencies including the
FDA have recommended that patients at risk of anaphylaxis carry 2
EAIs at all times. 
271 
In the United States, EAIs are currently only sold
in twin-packs, and thus, single doses cannot be prescribed. However,
some researchers have recently called into question the magnitude
of health benefits and cost-effectiveness of universally prescribing
multiple EAIs. 
272 
Shaker et al
272 
used Markov modeling to evaluate
and compare the cost-effectiveness of different prescribing strategies
for patients with peanut allergy. They evaluated the following: (1)
routinely prescribing 2 EAIs to all patients with peanut allergy; (2)
prescribing 2 EAIs only to patients with a history of anaphylaxis; and
(3) prescribing 2 EAIs only to patients with a history of anaphylaxis
that required multiple EAI doses to treat. The authors tested the
model in multiple economies and at different price points. They con-
cluded that at current EAI prices in the United States (lowest esti-
mated retail price of $340 for a twin-pack) and with low reported
rates of anaphylaxis requiring multiple doses to treat, universally
prescribing 2 EAIs is not cost-effective and has marginal health bene-
fits compared with a risk-stratified approach.
272 
They found that uni-
versally prescribing multiple EAIs would only be cost-effective in the
United States if the cost of a single EAI was less than $80 or the proba-
bility of needing a second dose to treat anaphylaxis exceeded 25%.
A risk-stratified approach may help clinicians evaluate a patient’s
risk of requiring multiple EAI doses and guide shared decision-mak-
ing around EAI prescription. A recent systematic review and meta-
analysis found that 7.7% of anaphylaxis cases (all ages, all causes)
were treated with multiple doses of epinephrine, including epineph-
rine administered in the community and/or health care settings. 
271 
In
children, milk-induced reactions are more likely to require multiple
doses of epinephrine. 
207,273 
Risk factors and cofactors for severe and
fatal anaphylaxis are listed in Table 18.
51,274−280 
Consideration of
these factors may help inform shared decision-making around EAI
prescription. However, it is important to note that the interaction
between these factors is complex and varies across patients and
Table 17
Likelihood of Requiring Treatment With Prescribed EAI
Allergic condition Lower likelihood Higher likelihood
IgE-mediated food allergy 
 
History of prior systemic allergic reaction after exposure
Pollen food allergy syndrome 
 
No history of anaphylaxis to causative food 
 
History of anaphylaxis to causative food
Venom or insect bite/sting allergy 
 
History of only large local or cutaneous systemic reaction(s)
 
History of anaphylaxis, but on maintenance VIT or discon-
tinued VIT after more than 5 y of treatment with no high-
risk factors
 
History of anaphylaxis, not treated with a complete course of VIT
 
Current VIT, with history of prior systemic reaction(s) to VIT
 
Honey bee allergy
 
Elevated basal tryptase level
 
Frequent exposure
Latex allergy 
 
Low likelihood of exposure 
 
Occupational exposure
Drug allergy 
 
Low likelihood of exposure 
 
Occupational exposure (eg, compounding, mixing, or preparation of
medications)
Exercise-induced anaphylaxis 
 
All cases
Physical urticarias 
 
Cold induced
Aeroallergen immunotherapy 
 
No history of prior systemic reaction(s) to AIT and no rele-
vant comorbidities (eg, asthma)
 
History of prior systemic reaction(s) to AIT and/or relevant comorbidities
(eg, asthma)
Abbreviations: AIT, aeroallergen immunotherapy; EAI, epinephrine autoinjector; VIT, venom immunotherapy.
ARTICLE IN PRESS
26 D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53

exposures. Significant uncertainties limit one’s ability to reliably pre-
dict the severity of future reactions. The presence of one or more of
the factors in Table 18 does not necessarily indicate an absolute need
for multiple EAIs, nor does the absence of these factors preclude the
possibility of a severe reaction requiring multiple doses of epineph-
rine to treat. Efforts to identify biomarkers that reliably predict the
severity of future reactions are ongoing. The JTFPP’s 2020 practice
parameter update on peanut allergy diagnosis recommends against
the use of skin prick test results, whole peanut serum-specific IgE, or
component-specific peanut sIgE to predict the severity of future reac-
tions. 
281 
One rationale for prescribing multiple EAIs is the potential
need for a backup unit if there is a misfire or misuse of the first
unit. 
282 
Misuse can be mitigated by early and repeated education on
correct handling and use of the specific device dispensed to the
patient. Furthermore, the potential for monitoring at home without
activating EMS after administration of the first dose of epinephrine
requires the availability of an additional dose of epinephrine (see
Recommendation 26).
The decision of when to prescribe multiple EAIs may be guided
not only by patients’ risk of severe anaphylaxis but also by their val-
ues, preferences, and contextual factors. In the United States, one of
the most pressing contextual constraints is that EAIs are currently
only sold in twin-packs. Moreover, some children attend schools that
require them to store 1 or more EAIs on site rather than carry EAIs to
and from campus each day. Such children may require 2 or more EAIs
to meet school requirements while also ensuring adequate access to
epinephrine in other settings. Residing, working, or attending school
in a location with long emergency response times is another example
of a contextual factor that may warrant the prescription of multiple
EAIs.
Question: What is the optimal timing for EAI administration in
relation to symptoms?
Recommendation 25 (CBS): We suggest that clinicians counsel
patients and caregivers to give epinephrine at the first sign of sus-
pected anaphylaxis.
We suggest that, in general, clinicians counsel patients or care-
givers not to give epinephrine preemptively to an asymptomatic
patient.
Strength of Recommendation: Conditional
Certainty of Evidence: Very Low
There is a lack of high-quality evidence on the effects of early vs
delayed epinephrine administration for anaphylaxis. However, the
available evidence suggests that early epinephrine use for anaphy-
laxis may help improve clinical outcomes. Studies have linked
delayed epinephrine use after an anaphylaxis to increased risk of
biphasic reactions 
3 
and hospitalization. 
196,283,284 
In fatality case
series, most patients who died from anaphylaxis did not receive
timely treatment with epinephrine. 
119,202,203,285 
One case series of
fatal anaphylaxis found that the median time interval from allergen
exposure to respiratory or cardiac arrest was 5 minutes in drug-
induced anaphylaxis, 15 minutes in stinging insect venom-induced
anaphylaxis, and 30 minutes in food-induced anaphylaxis. 
202 
As sin-
gle-arm observational studies, fatality case series are considered low-
grade evidence and do not allow us to compare the odds of survival
with epinephrine treatment vs without epinephrine treatment.
There is no evidence that preemptive use of epinephrine in
asymptomatic patients prevents anaphylaxis. A 2018 analysis used
Markov modeling to evaluate the cost-effectiveness of preemptive
epinephrine use in cases when a patient has a known ingestion to an
allergen without symptoms. 
120 
The absolute protective effect of pre-
emptive epinephrine use in the absence of symptoms was low and
not cost-effective. 
120 
However, the authors note that advice regard-
ing preemptive epinephrine use may be patient preference sensitive.
For example, although there is a lack of evidence on the benefits of
preemptive epinephrine use, it is possible that a more proactive
approach might be appropriate for patients with a history of rapidly
progressive near-fatal anaphylaxis or underlying mastocytosis. Clini-
cians should engage patients in shared decision-making that consid-
ers individual risk factors, values, and preferences.
Question: When should EMS be activated after EAI use?
Recommendation 26 (CBS): We suggest that clinicians counsel
patients that immediate activation of EMS may not be required if
the patient experiences prompt, complete, and durable response
to treatment with epinephrine, provided that additional epineph-
rine and medical care are readily available, if needed. We suggest
that clinicians counsel patients to always activate EMS after epi-
nephrine use if anaphylaxis is severe, fails to resolve promptly,
fails to resolve completely or nearly completely, or returns or
worsens after a first dose of epinephrine.
Strength of Recommendation: Conditional
Certainty of Evidence: Very Low
Until recently, professional and patient organizations have gener-
ally advised patients and caregivers to immediately seek emergency
care or activate EMS (ie, call 911) when anaphylaxis occurs, even if
epinephrine is administered and symptoms resolve. 
286−288 
However,
there is a lack of evidence revealing the benefits of universal EMS
activation. In 2019, Shaker et al 
125 
modeled the health and economic
outcomes associated with reflex activation of EMS immediately after
epinephrine use, compared with a “watchful waiting” approach, in
which patients or caregivers only activate EMS afer epinephrine
administration if signs and symptoms of anaphylaxis do not immedi-
ately resolve completely or nearly completely. Assuming that reflex
activation would lower the fatality risk by 10-fold, the authors found
that the cost of preventing 1 death through immediate activation
was $1,349,335,651. Reflex activation would only be cost-effective if
it reduced the fatality risk by 500-fold and if 75% of people who
received epinephrine required additional care in the ED—both of
Table 18
Risk Factors and Cofactors Potentially Associated With Severe or Fatal Anaphylaxis
Drug-induced anaphylaxis Food-induced anaphylaxis Venom bite- or sting-induced anaphylaxis Non-trigger−related cofactors/risk factors
 
Age > 60 y
 
Cardiovascular diseases
 
Respiratory diseases
 
Antihypertensive drugs
 
Adolescence
 
Uncontrolled asthma
 
Alcohol consumption
 
Peanut- or tree nut-induced reaction
 
Exercise
 
Older age
 
Male sex
 
Hereditary 
a-tryptasemia
 
Mast cell disorders
 
Cardiovascular diseases
 
NSAIDs
 
Antihypertensive drugs
 
Mast cell disorders
 
Infections
 
Perimenstrual period
 
NSAIDs
 
Alcohol consumption
 
Psychological burden
 
Exercise
 
Unknown cause
Abbreviation: NSAIDs, nonsteroidal anti-inflammatory drugs.
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D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53 27

which are unlikely. However, the authors also note that patient pref-
erences for EMS activation may vary, particularly among groups at
high risk of severe or biphasic anaphylaxis.
During the “stay at home” phase of the initial wave of the COVID-
19 pandemic, concerns about the risk of infectious disease exposure,
health care resource use, and the need for short-term health care ser-
vice rationing led allergy specialists to review and revise their recom-
mendations around EMS activation. 
3,126 
Casale et al 
126 
implemented
many of the findings of Shaker et al 
125 
when developing Food Allergy
Research and Education’s anaphylaxis management algorithm for the
COVID-19 context. For patients with a prior history of anaphylaxis
that required treatment with multiple doses of epinephrine, intuba-
tion, and/or ventilation, Casale et al
126 
recommended that EMS
should be immediately activated on recognition of anaphylaxis. For
patients they considered to be at lower risk, they recommended acti-
vating EMS when severe signs and symptoms do not promptly
resolve with epinephrine treatment. In the opinion of many members
of this panel, it is sufficient for severe signs and symptoms to resolve
even if some residual cutaneous symptoms remain (Fig 5).
Casale et al 
126 
recommended careful monitoring for recurrence,
with non-urgent follow-up care if there was prompt and complete
resolution of severe symptoms after epinephrine use and if patients
had ready access to additional EAIs. Patients with a history of pro-
gressively severe or biphasic reactions may require more careful or
prolonged observation, as may those with comorbid conditions that
may affect response to anaphylaxis and treatment. The recommenda-
tions of Casale et al
126 
were proposed as an interim measure related
to factors affecting EDs and the population at large during that stage
of the COVID-19 pandemic. More recently, Casale et al 
129 
have re-
evaluated these recommendations for extended application beyond
the contingencies of the pandemic and discuss the considerations for
and against home management (Table 19).
To date, “immediate” and “prompt” anaphylaxis resolution times
have not been objectively defined. For epinephrine, researchers have
not yet determined the optimal time to peak plasma concentration
(Tmax), time to pharmacodynamic (PD) parameter response, nor the
optimal peak plasma concentration (Cmax) required for symptom
resolution. Classic epinephrine pharmacokinetic (PK) data suggest
that the Tmax is not more rapid than 12 to 15 minutes, and more
recent data suggest that this may more reliably occur at 15 to 25
minutes. 
289 
However, some PD data suggest that mean increases in
systolic blood pressure occur less than 5 minutes after intramuscular
epinephrine injection, and anecdotally, many clinicians have
observed patients responding (sometimes completely) within a few
Figure 5. General guidance for activation of EMS and administration of a second dose of epinephrine. EMS, emergency medical services.
Table 19
Considerations for and Against Home Management of Anaphylaxis
Considerations for home management Considerations against home management
 
Patients/caregivers engaged in shared decision process 
 
Patients/caregivers not comfortable with managing anaphylaxis without activating EMS/
ED
 
Immediate access to at least 2 EAIs 
 
No availability of EAIs or only 1 EAI
 
Immediate access to person(s) who can provide help if needed 
 
Being alone, without immediate access to person(s) who can provide help if needed
 
Clear understanding of the symptoms warranting the immediate use of EAI,
availability of the anaphylaxis treatment plan
 
Being unaware of the allergic symptoms that warrant the use of EAI
 
Familiarity with the EAI device administration technique 
 
Lack of technical proficiency with administration of EAI
 
Hesitance about the intramuscular injection (needle phobia)
 
Clear understanding of the benefits of early epinephrine treatment in
anaphylaxis
 
Concerns about the potential epinephrine adverse effects
 
Good adherence to previous treatment recommendations, for example, use EAI
for anaphylaxis in the past or use of controller medications for chronic
conditions
 
Poor adherence to previous treatment recommendations, for example, not administering
EAI for anaphylaxis in the past or not using controller medications for chronic conditions
 
History of severe/near-fatal anaphylaxis treated with more than 2 doses of epinephrine,
hospitalization, intubation
Abbreviations: EAI, epinephrine autoinjector; ED, emergency department; EMS, emergency medical services.
NOTE. Adapted from Casale et al. 
129
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28 D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53

minutes of injection. It is difficult to suggest a specific duration of
time to wait before a second dose of epinephrine is administered and
EMS is called. However, we recommend the following pragmatic
approach to gauge whether a reaction is resolving and as a guide for
when to observe at home, administer a second dose of epinephrine,
or activate EMS (Fig 5):
1) Observe at home if signs and symptoms that had emerged before
epinephrine administration resolve within minutes of epineph-
rine administration, without recurrence, or if the patient is
asymptomatic. Patients with scattered residual hives or other
rash (including erythema), even those with newly emerging but
isolated hives or erythema without other symptoms occurring
after epinephrine administration, may be observed at home pro-
vided no additional new symptoms develop.
2) Consider EMS activation and possibly a second dose of epineph-
rine, or may continue to observe at home if comfortable, if signs
and symptoms that had emerged before administration of the
first dose of epinephrine are improving or resolving within
minutes of epinephrine administration. For example, persistence
of a mild sensation of globus, nausea, coughing, or stomachache
may be closely observed at home provided symptoms are
improving (not worsening and are perceived to be getting better)
and do not persist for longer than 10 to 20 minutes without
observing additional signs of improvement. Multiple contextual
factors (Table 19) may influence a patient or caregiver’s decision
whether to administer a second dose of epinephrine and contact
EMS or continue observing without further intervention.
3) Activate EMS immediately and consider a second dose of epi-
nephrine (do not observe at home) if signs and symptoms that
had emerged before epinephrine administration are not resolv-
ing or are worsening. Particularly concerning symptoms would
include respiratory distress, stridor, altered consciousness, car-
diovascular instability, cyanosis, or incontinence not typical for
their age. This would also include non-skin symptoms that fail to
resolve or worsen, including but not limited to repeated (>2
total) episodes of vomiting, persistent hoarseness, cough, dys-
phagia, wheezing, or lightheadedness.
The workgroup recognizes that perceptions of anaphylaxis sever-
ity may vary from one individual and context to another. A guide to
severity grading of hypersensitivity (including non-anaphylactic)
reactions is presented in Table 9. When developing an anaphylaxis
management plan and determining an individualized set of condi-
tions for when contacting EMS is recommended or may not be
required, clinicians should engage patients in a shared decision-mak-
ing process that considers individual risk factors, values, and prefer-
ences. Given variability in contextual factors, there is not likely a
single universal approach for all patients and contexts. 
290
This recommendation assumes that epinephrine has been admin-
istered promptly “at the first sign of suspected anaphylaxis” (see Rec-
ommendation 25). Delay in administration may delay or impair the
response to epinephrine and should be taken into account in deciding
when to activate EMS.
Question: What are the adverse events associated with EAI
use? Are certain populations at increased risk of adverse events?
How should this inform EAI prescription and patient education?
Recommendation 27 (CBS): Serious adverse reactions to intra-
muscular epinephrine are very rare and should not pose a barrier
to the prescription or early administration of EAIs when indi-
cated. To manage the risk of adverse events, we recommend that
clinicians counsel patients and caregivers on the proper use of
EAIs, the common adverse effects, and the need for immediate
evaluation and treatment when signs or symptoms of serious
adverse events develop.
Strength of Recommendation: Strong
Certainty of Evidence: Low
Epinephrine is generally safe, and there are no absolute contrain-
dications to its use for anaphylaxis. Compared with intravenous
administration, intramuscular epinephrine is associated with
reduced risk of dosing errors and adverse events. 
291,292 
The adverse
effects associated with EAI use are typically mild and transient, with
1 registry study reporting tremors, palpitations, and anxiety as the
most common. 
292 
A 2018 computer simulation study found that the
serious adverse event rate for EAI administration was only 0.73%. 
293
In rare cases, epinephrine use for allergic reactions can cause car-
diac adverse events such as arrhythmias or myocardial infarction. 
294
When cardiac adverse events do occur, they are rarely associated
with intramuscular administration. One observational cohort study
found that among patients treated with epinephrine in an ED,
adverse cardiovascular events were reported in 4 of 316 (1.3%) intra-
muscular administrations. 
291 
In a registry-based study in Spain,
potentially serious adverse events—including increased blood pres-
sure, chest discomfort, and electrocardiogram changes—were
reported in 4 of 256 (1.6%) intramuscular or subcutaneous adminis-
trations. 
292 
Retrospective cohort studies suggest that the risk of
adverse cardiac events after epinephrine use is higher in older
patients (age ≥50 years). 
295,296 
This may lead to reluctance to pre-
scribe or administer epinephrine to older adults or people with a his-
tory of cardiovascular conditions. However, those same populations
have increased risk of severe or fatal anaphylaxis. 
294,297,298 
Thus, the
authors of case reports, observational studies, and reviews have gen-
erally recommended prompt treatment of anaphylaxis with intra-
muscular epinephrine, even in people with advanced age or other
cardiac risk factors. 
295,299−302 
Clinicians should counsel patients with
cardiac risk factors to seek immediate evaluation and treatment if
chest pain or other signs or symptoms of cardiac adverse events
develop after epinephrine use.
Other potential adverse events after an EAI administration include
lacerations and embedded needles. These injuries may result when a
patient or caregiver moves during administration, the device dis-
charges off center due to malfunction, or the needle bends after hit-
ting a bone. 
303,304 
In a 2020 study using EpiPen trainer devices,
researchers found that administering an EAI with a “swing and jab”
motion rather than a “place and press” technique may result in more
leg movement and increased risk of laceration. More research is
needed to evaluate strategies to reduce the risk of EAI-related lacera-
tion and other injuries. However, Brown et al
303 
have proposed sev-
eral strategies which we present in Table 20.
Improper handling of EAIs can also lead to accidental injection
and needlestick injury, frequently in the thumb or other digit. 
305 
One
registry study found that after unintentional exposures to EAIs, most
people report only minor to moderate effects. 
305 
In rare cases, digital
ischemia after accidental injection into the thumb or other digit has
resulted in digital amputation. 
306 
A 2020 review recommended oral
phentolamine as the most effective treatment for reducing
Table 20
Proposed Strategies to Reduce the Risk of EAI-Related Injury
303
1. Restrain the patient and firmly immobilize their leg before administering the EAI
2. Control the action of administration as much as possible, using a place and press
motion rather than a swing and jab motion
3. Hold the EAI in place for the shortest period of time recommended by the
manufacturer
4. Avoid reinserting the needle if it dislodges before the recommended hold time
passes
Abbreviation: EAI, epinephrine autoinjector.
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D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53 29

epinephrine-induced digital ischemia. 
306 
Despite the low quality of
available evidence, the workgroup has judged that the desirable
effects of certain interventions clearly outweigh the undesirable
effects. Thus, we have issued strong consensus-based statements
based on very low-to-moderate quality evidence, similar to good
practice statements under the GRADE methodology.
Question: What are the burdens of EAI prescription? How
should this inform EAI prescription and patient education?
Recommendation 28 (CBS): We suggest that clinicians discuss
the potential financial and psychosocial burdens of EAIs with
patients while engaging in shared decision-making.
Strength of Recommendation: Conditional
Certainty of Evidence: Very Low
Recognizing the financial and psychosocial burdens of treatment
is important for providing patient-centered care and addressing
potential barriers to treatment adherence. A 2018 survey of parents
of children with food allergy in the United States found that 97% felt
financially burdened by the cost of EAIs.
307 
The out-of-pocket costs of
EAIs vary, depending not only on the specific brand of EAI but also on
the patient’s drug coverage, their eligibility for manufacturers’ cou-
pons or other subsidies, and the pharmacy from which they purchase
the device. 
308,309 
The cost of EAIs is substantially higher in the United
States than in many other countries. In the United States, the average
wholesale price of 2 EpiPens increased dramatically from $113.27 in
2007 to $730.33 in 2016. 
310 
In comparison, the average wholesale
prices of generic EAIs, epinephrine prefilled syringes, and ampules of
epinephrine are substantially lower. 
310,311
In addition to the financial burden, EAI prescription may also have
psychosocial effects. Although some studies have found that patients
with food allergy and their caregivers may have positive feelings
about EAIs, other studies have found that EAI prescription is associ-
ated with reduced quality of life. 
249,250 
In a 2013 Australian study,
health-related quality of life was worse in children with food allergy
who were provided an EAI, even after controlling for age,
anaphylaxis, number of food allergies, and atopic dermatitis. 
312 
In
contrast, a 2022 French study found no association between the pro-
vision of an EAI and worse health-related quality of life, 
313 
and a
2021 Japanese study found no link between EAI possession and men-
tal health outcomes. 
314 
Some evidence suggests that patient treat-
ment preferences, history of anaphylaxis, and baseline stress may
affect the burden of epinephrine prescription and its effects on qual-
ity of life. 
121,315,316 
Ward and Greenhawt 
121 
specifically noted an
interaction effect; epinephrine use was associated with decreased
quality of life in general but increased quality of life in caregivers of
patients where the device was reportedly used for presumed anaphy-
laxis. A 2020 study in the United States found that approximately 22%
of children with food allergy, 50% of adolescents, and 36% of parents
reported anxiety caused by EAIs.
250
Question: What autoinjector characteristics should clinicians
consider when prescribing EAIs?
Recommendation 29 (CBS): When deciding which EAI to pre-
scribe, we suggest that clinicians consider dosage, needle length,
affordability, access, and patient treatment preferences.
Strength of Recommendation: Conditional
Certainty of Evidence: Very Low
Multiple brands of EAIs are available in the United States, includ-
ing the following: Auvi-Q (Kaleo), EpiPen/EpiPen Jr. (Mylan), and
generic versions of EpiPen/EpiPen Jr. (Viatris, Teva) and Adrenaclick
(Amneal). The FDA has also approved the Symjepi epinephrine injec-
tion device, a prefilled syringe without autoinjector functionality.
Some devices are available in other countries but not currently avail-
able in the United States (eg, Anapen, Emerade, Jext). Devices vary in
their available doses, manufacturer-indicated weight class, and
design, including needle length (Table 21). They also vary consider-
ably in cost (Recommendation 28). When deciding which device to
prescribe, clinicians may consider these characteristics in relation to
patient factors such as age, weight, sex, and insurance coverage.
Some patients may also prefer one device over another.
Table 21
Specifications for EAIs and Prefilled Epinephrine Injection Devices
Name Dosage (mg) Weight class specified by
manufacturer 
a 
(kg)
Weight class supported by
practice parameter 
a 
(kg)
Needle length 
b
(cm)
Pressure 
c
Adrenaclick 0.15 15-30 <25 1.17 High
0.3 ≥30 ≥25 1.17 High
Anapen 
d 
0.15 15-30 <25 1.0-1.5 High
0.3 ≥30 ≥25 1.0-1.5 High
Auvi-Q 0.1 7.5-15 <13 0.64-0.89 High
0.15 15-30 <25 1.14-1.4 High
0.3 ≥30 ≥25 1.47-1.73 High
Emerade 
d 
0.15 15-30 <25 1.5-1.67 Low
0.3 ≥30 ≥25 2.21-2.36 Low
0.5 >60 ≥45 2.21-2.36 Low
Epipen Jr. 0.15 15-30 ≤25 1.0-1.5 High
Epipen 0.3 ≥30 ≥25 1.3-1.8 High
Jext 
d 
0.15 15-30 ≤25 1.3 High
0.3 ≥30 ≥25 1.5 High
Symjepi 0.15 15-30 ≤25 Not published N/A
0.3 ≥30 ≥25 Not published N/A
Abbreviations: EAI, epinephrine autoinjector; N/A, not available.
a
The manufacturer-indicated weight classes for EAIs differ from recent recommendations from multiple professional organizations, which are described and endorsed in this prac-
tice parameter.
b 
Needle length may be an important consideration in young infants with low body mass, in women, and in adults with high body mass index (>25). Owing to the manufacturing
process, there is some variability in the length of EAI needles. The ranges reported in this table represent the lower and upper limits of needle lengths. 
317
c 
The average force required to activate an EAI varies from one brand to another. According to manufacturers’ specifications obtained by Dreborg and Kim, the mean activation force
in Newtons (N) is as follows: 27 N for Auvi-Q (range: 8.5-53 N), 20-22 N for EpiPen Jr. (range: 8.5-35 N), 20-21 N for EpiPen (range: 8.5-35 N), and 15-17 N for Emerade (range: 8-25
N). 
318
d
These devices are not currently available in the United States.
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30 D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53

Dosage
The current standard practice is to treat anaphylaxis with a dos-
age of epinephrine of 0.01 mg/kg, up to a maximum of 0.3 mg for
children and teenagers and 0.5 mg for adults. However, there is a
lack of robust data to substantiate this recommendation, and more
research is needed to determine the optimal dosing. EAIs are only
available in a limited number of premeasured doses for manufac-
turer-specified weight classes (Table 21). In the United States, the
FDA has approved 0.3 mg EAIs for patients weighing more than or
equal to 30 kg, 0.15 mg EAIs for patients weighing 15 to 30 kg, and a
0.1 mg EAI (Auvi-Q) for patients weighing 7.5 to 15 kg. 
319 
Clinical
experience suggests that infants tend to tolerate doses of epinephrine
higher than 0.01 mg/kg well, and the JTFPP’s 2020 anaphylaxis prac-
tice parameter update supports the use of 0.15 mg EAI for infants or
children weighing less than 15 kg. 
3 
A 0.5 mg EAI (Emerade) is also
available in some countries for patients weighing more than 60 kg.
Using dosages specified by manufacturers, patients will receive
increasingly less than the recommended dose as their weight
increases. 
320 
To limit underdosing, the AAAAI, AAP, CSACI, and EAACI
support switching to 0.3 mg at 25 kg. 
2,15,269,321 
The CSACI advises
that clinicians may consider prescribing a 0.5 mg EAI (not currently
available in USA) for people weighing more than or equal to 45 kg. 
269
Among teenagers, a small randomized trial of EAI administration
found no significant adverse events following intramuscular self-
injection with 0.3 mg or 0.5 mg of epinephrine. 
322 
The 0.5 mg dose
resulted in higher plasma catecholamine level than the 0.3 mg dose.
Needle Length and Pressure
When administering epinephrine for anaphylaxis, the standard
recommended route is intramuscular injection into the mid-outer
thigh.
320 
The mean needle length and pressure required to trigger an
EAI vary from one brand to another (Table 21).
323 
The needle should
ideally be long enough to penetrate the deep fascia of the thigh into
the muscle, but not so long that it strikes a bone or causes intraoss-
eous injection.
The depth of delivery of epinephrine is affected by the pressure
with which it is delivered, including the pressure generated by the
device (propulsion) and the compression by the person administer-
ing the injection. 
323,324 
On the basis of ultrasound imaging measure-
ments of skin-to-bone and skin-to-muscle distance, Dreborg et
al 
154,325 
predicted that low-pressure EAIs (Emerade) posed no risk of
intraosseous injection and low risk of subcutaneous injection. For
high-pressure EAIs (Auvi-Q, EpiPen, Jext), they found that the risk
varied by demographics and device. They predicted that in children
weighing less than 15 kg, the risk of intraosseous injection was lower
with Auvi-Q 0.1 mg, compared with EpiPen Jr. and Jext 0.15 mg; how-
ever, Auvi-Q 0.1 mg posed higher predicted risk of subcutaneous
injection than other devices. 
154,325 
In a follow-up study, they found
that injecting EAIs through thick winter clothing increased the risk of
subcutaneous injection for all brands—and up to 100% for Auvi-Q
0.1 mg specifically. 
317 
Counseling patients to remove heavy clothing
before administering EAIs may help mitigate the risk.
Dreborg et al 
154 
predicted that the risk of intraosseous injection
was low in children weighing 15 to 30 kg and negligible in adults.
Ultrasound imaging measurements suggest that among adults, the
risk of subcutaneous injection is highest in obese women. 
325,326
Both body mass index and sex differences in subcutaneous tissue
depth may affect the risk of subcutaneous injection because women
tend to have more subcutaneous fat on their thighs than men. 
326−328
However, Duvauchelle et al 
329 
found that intramuscular injection
does not seem to be an absolute requirement for EAI efficacy. Over-
weight women were more likely to experience subcutaneous injec-
tion (n = 10 of 12) compared with non-overweight men (n = 1 of
18). 
329 
However, when the researchers evaluated the bioavailability
of epinephrine after an injection, the initial plasma peak was similar
in both groups, and the overall bioavailability of epinephrine was
higher in the overweight women. 
329 
There is emerging evidence
that the pharmacokinetics of epinephrine may vary between indi-
vidual patients and between different devices and methods used for
administration. 
289,330 
This practice parameter addresses only
injectable epinephrine; noninjectable routes of administration have
been developed and have been reported to have favorable pharma-
cokinetic and pharmacodynamic profiles, but no clinical evidence
base was available at the time of the development of this practice
parameter.
Accessibility
Manufacturer shortages, patient drug coverage, and other factors
may affect the accessibility of EAIs and influence providers’ prescrib-
ing decisions. 
311,331 
Clinicians may ask to review insured patients’
drug formularies to learn which EAIs are covered by their insurance.
Some uninsured or underinsured patients may be eligible for manu-
facturer-sponsored coupons or financial assistance programs to help
offset the cost of EAIs; however, these programs typically exclude
Medicare and Medicaid recipients. In the United States, EAIs are sold
only in packages of 2; the cost might be reduced, and access
improved, if they were available in single units. Clinicians may also
consider prescribing generic EAIs as a more affordable alternative to
brandname EAIs or prescribing prefilled epinephrine syringes or epi-
nephrine ampules with empty syringes as an affordable alternative
to EAIs. The Canadian Agency for Drugs and Technologies in Health
recently reviewed the available research on the clinical and cost-
effectiveness of EAIs vs manual epinephrine administration with an
ampule/vial and syringe and found no relevant studies. 
332
Usability and Patient Preference
Some people may find certain EAIs easier to use, more convenient,
or otherwise more appealing than others. When researchers asked
adults to simulate EAI administration with trainer devices, they found
lower rates of error with Auvi-Q than with EpiPen Jr. or
Anapen.
333,334 
A 2013 study in the United States also found that chil-
dren and caregivers expressed a preference for Auvi-Q over Epi-
Pen.
335 
Unlike other EAIs, Auvi-Q provides audio prompts to guide
administration. However, some patients or caregivers may prefer
other brands of EAI due to familiarity or other reasons. A 2022 study
in Ireland found that caregivers tended to prefer EpiPen over Anapen,
Emerade, and Jext.
336 
When asked why they preferred a particular
brand, respondents said that they found it easy to administer, the
instructions on the label were clear and easy to follow, the manufac-
turer provided helpful resources, and/or it was the brand they had
been trained on by a health care professional.
Question: What counseling, education, and/or training on epi-
nephrine should clinicians provide to patients and caregivers?
Recommendation 30 (CBS): During visits with patients who
have been prescribed EAIs, we recommend that clinicians rou-
tinely review the essentials of EAI carriage, storage, and use;
encourage patients to regularly practice EAI administration with
a trainer device; and discuss strategies to manage barriers to
adherence that patients may have experienced.
Strength of Recommendation: Strong
Certainty of Evidence: Low
Many patients and caregivers do not administer epinephrine
when indicated, because of a variety of factors. 
247,337 
These include
suboptimal prescription and carriage of EAIs, gaps in knowledge and
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D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53 31

lack of comfort in recognizing anaphylaxis and administering EAIs,
and fear that administering an EAI may cause harm. Multiple studies
reveal the benefits of clinician-provided education and counseling for
improving EAI-related knowledge, skills, and comfort. 
338 
However, a
single instructional session is not sufficient for sustained
improvement. 
339,340 
More research is needed to identify the optimal
frequency of EAI education for patients and caregivers, but 1 study in
Turkey suggests that 6-month intervals may be appropriate. 
341
Possessing an EAI trainer device and practicing its use on another
person have also been linked to increased rates of proper
administration. 
342,343 
Hands-on experience with administering
active EAIs is beneficial, too. When patients or caregivers adminis-
tered an EAI for an allergic reaction during a medically supervised
oral food challenge, they reported improved EAI confidence, knowl-
edge, and skill that were sustained a year later. 
344,345 
Similarly, self-
injection with an empty syringe during a supervised clinic visit has
been linked to improved comfort with injection among at-risk ado-
lescents. 
346 
Seeing clinicians administer epinephrine for anaphylaxis
during health care encounters may also reinforce the importance of
epinephrine administration for patients and caregivers. 
347
Patients and caregivers may also benefit from reminders to
replace EAIs after the devices have been used or expired. If they for-
get to replace an expired EAI—or are unable to do so because of man-
ufacturer shortages or other barriers—it is preferable to use the
expired device rather than no device at all to treat anaphylaxis.
Recent studies have found that expired EAIs retain substantial epi-
nephrine activity (80%-90%), well beyond their expiration dates. 
348
−350 
Pediatric doses may degrade more quickly after expiration com-
pared with adult doses. 
350
Despite the revealed benefits of EAI education for patients and
caregivers, provision of this support remains suboptimal. 
351,352 
Clini-
cian-reported barriers to providing EAI education and counseling
include lack of time, lack of training devices, lack of role clarity
around who is responsible for educating patients, and gaps in clini-
cian knowledge, including confusion about the different brands of
EAIs. 
352−354 
Proposed strategies to address these barriers include
automated implementation of EAI teaching and comfort assessments
during check-in at allergy clinics, 
351,355 
provision of a dedicated phar-
macist who can provide counseling on medication, 
352 
and provision
of EAI training for clinicians. 
356−360 
Studies have found that in-person
training sessions, 
360 
video education sessions, 
356,357 
e-learning
sessions, 
358,361 
and mixed-method training approaches 
359 
can help
improve EAI knowledge, skills, and confidence among clinicians and
students. Some evidence suggests that training clinicians on strate-
gies to identify and address psychosocial barriers to EAI adherence
may also yield benefits. 
353 
Despite the low quality of available evi-
dence, the workgroup has judged that the desirable effects of certain
interventions clearly outweigh the undesirable effects. Thus, we have
issued strong consensus-based statements based on very low-to-
moderate quality evidence, similar to good practice statements under
the GRADE methodology.
Knowledge gaps regarding prescription and use of epinephrine for
anaphylaxis are listed in Table 22.
Beta-Blocker and Angiotensin-Converting Enzyme Inhibitors
BB medications are widely used for a variety of cardiovascular
conditions, including hypertension, arrhythmias, and congestive
heart failure, and for prevention of migraine and treatment of glau-
coma. These medications have physiological effects that might affect
the severity of anaphylaxis and the response to treatment. BBs may
reduce compensatory cardiovascular responses to anaphylaxis, may
enhance the release of mast cell mediators, and may interfere with
beneficial effects of endogenous and therapeutic epinephrine. ACEIs
have similar uses to BBs for patients with cardiovascular conditions,
especially in patients with diabetes. By interfering with the body’s
natural renin-angiotensin-aldosterone system, ACEIs block the con-
version of angiotensin I to angiotensin II, thereby preventing the
breakdown of bradykinin, promoting vasodilation, and may have
direct effects on mast cells. In both human and mouse models, BBs
and ACEIs have been found to increase the severity of anaphylaxis
and may have an additive effect when used in combination (which
has become a common therapeutic approach in severe CVD). 
362 
The
ARBs may blunt the cardiovascular adaptive compensatory response
to shock but do not directly affect the kinin system. There is not suffi-
cient evidence to address whether ARBs are similar to ACEIs with
respect to the risk of severe anaphylaxis (see specific medications in
subsequent discussion). Therefore, ARBs are not addressed in this
practice parameter, and anything stated about ACEIs should not nec-
essarily be construed to apply to ARBs.
Although there is a widely held assumption that the use of BBs
and ACEIs is contraindicated in all patients who are at risk for poten-
tial anaphylactic reactions of any kind, there is conflicting evidence
in the literature of the actual risk of these medications. 
297,363,364 
This
has become a dilemma for an increasing proportion of patients in a
variety of clinical settings including AIT (both SCIT and SLIT), VIT,
allergen skin testing, food anaphylaxis, RCM administration, drug
infusion/intravenous immunoglobulin (IVIG), MCAS, IA, and desensi-
tization procedures. The perception of risk is based on data from
older studies where most of the BBs in use were nonselective (eg,
propranolol, nadolol), with many of the reports not taking into
account the confounder of cardiac comorbidities that could indepen-
dently account for the increased risk of severe anaphylaxis. 
297 
There
is also clinically significant medical risk in stopping or changing the
prescribed medications such that the risk of discontinuing the medi-
cation may far exceed the risk of more severe anaphylaxis.
A systematic review and meta-analysis of observational studies of
the relationship between anaphylaxis of all causes and use of BBs and
ACEIs analyzed 22,313 episodes for severity and 18,101 episodes for
incidence. 
297 
Both BBs and ACEIs were associated with significantly
increased severity (OR = 2.19 and 1.56, respectively), but the inci-
dence of anaphylaxis (OR = 1.40 and 1.38, respectively) was not sig-
nificantly increased. The quality of evidence was low, and it was not
possible to adjust for CVD in their analysis because only 1 study had
adjusted data. The authors noted that in the 3 studies that reported
severity of anaphylaxis in relation to CVD, the OR for severe anaphy-
laxis in relation to CVD was 3-fold higher than the OR in those receiv-
ing BB treatment and 5 times higher than the OR in those on the
ACEIs. 
297
Given the current propensity to use more cardioselective beta-
blocking agents (eg, metoprolol, atenolol), and the risk/benefit ratio
for each of the interventions, we recommend a shared decision-
Table 22
Summary of Key Knowledge Gaps Regarding Prescription and Use of Epinephrine That
Require Additional Research
 
Lack of consistent definition of anaphylaxis and clinical criteria for diagnosis
across scientific societies and professional organizations
 
Lack of validated biomarkers that reliably predict the severity of future allergic
reactions
 
Lack of validated risk-stratification algorithms for guiding EAI prescription
 
Lack of validated strategies to reduce the risk of EAI-related lacerations and other
injuries
 
Lack of high-quality evidence regarding the . . .
○ effects of early vs delayed epinephrine administration for anaphylaxis
○ outcomes after reflex EMS activation vs watchful waiting after epinephrine
administration for anaphylaxis
○ optimal epinephrine dosing
○ implications of EAI needle length
○ ideal frequency of EAI training for patients and caregivers
Abbreviations: EAI, epinephrine autoinjector; EMS, emergency medical services.
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making discussion between patient, prescribers, and providers to
convey the absolute and relative risk of the treatment/procedure
while receiving the BB/ACEI medication, the risk of stopping the BB/
ACEI medication, and alternative medications or procedures. Recom-
mendation to the individual patient should include evaluation of
many potential risk factors including the frequency of exposure (to
the anaphylaxis trigger), predictability of exposure (expected vs
unexpected), severity of underlying cardiovascular condition, addi-
tive risk of BB plus ACEI medications, medical necessity, and benefit
of the treatment/procedure.
Framework for Risk Assessment
It is important to place the clinical questions described here in
appropriate context of both potential risks and benefits of these med-
ications in patients who are at risk for future anaphylaxis. A sample
framework for this evaluation is found in Table 23. The clinician, the
patient, and the prescriber (eg, cardiologist) must consider the bene-
fit of the medication for its prescribed indication, the benefit of the
medical procedure or treatment that is said to be contraindicated,
the risk of stopping the prescribed medication, the risk of not having
the medical procedure or treatment, and the risk of having the medi-
cal procedure or treatment while continuing the prescribed medica-
tion.
In most cases, the risk of stopping the BB or ACEI is greater than
the risk of more severe anaphylaxis if the medication is continued.
This is partially because of the low inherent risk of anaphylaxis with
most medical procedures and treatments and the relatively small
incremental risk associated with the medications. Thus, the clinical
decision-making often rests on the patient’s desire or need for the
procedure/treatment and their willingness to accept the potential
risk of the medications.
However, the risk of anaphylaxis may be higher for some patients
than others. The frequency of natural exposure to potential triggers
of anaphylaxis may be very low in some people (eg, insect sting), but
exposure occurs in all patients with food OIT and with food/drug
challenges. The exposure is known with AIT/VIT, but the risk of ana-
phylaxis is very low with these. The risk of foregoing certain proce-
dures or treatments, such as AIT in many cases, may be relatively
low; however, the risk of foregoing other procedures or treatments,
such as VIT for life-threatening sting anaphylaxis, may be signifi-
cantly higher.
Specific Medications
In this document, we will generally refer to BB and ACEI medica-
tions together. Although their mechanisms of action differ and the
rationale for their potential impact on outcomes of anaphylaxis
differs, there has been little to differentiate their risks from each
other in the published reports.
Although it is believed that there is less potential risk with beta-1-
selective blockers than with nonselective BBs, there are insufficient
data in the published reports to address this question. Still, when
possible, consideration should be given to managing patients at risk
for anaphylaxis with a cardioselective BB so as to minimize the risk,
given the more targeted nature of these BBs, thus avoiding blockade
of the beta-2 adrenergic effects on the airways. Of note, this is a theo-
retical consideration which lacks high certainty supporting evidence.
There are also scant data on the relative risk of ACEIs and ARBs. In
1 study of angioedema (n = 4511 events), the adjusted OR compared
with BBs was 3.04 for ACEIs, 2.85 for the direct renin-inhibitor aliski-
ren, and 1.16 for ARBs. 
365 
In a study of cardiac catheterization, 70 epi-
sodes of anaphylaxis occurred during 71,782 exposures; there was no
significant difference in the frequency of anaphylactic reactions
between controls, BB (mostly beta-1 selective), ACEI, or ARB medica-
tions. 
366 
In a study of systemic reactions to immunotherapy injec-
tions, there was no difference in the frequency of reaction between
ACEI- and ARB-treated patients. 
367 
It should not be assumed that
ARBs carry the same potential risks as ACEIs, but there is not suffi-
cient evidence to recommend either avoidance or safety of ARBs in
patients at risk for anaphylaxis. Moreover, angioedema caused by
ACEI or ARB is likely due to a different mechanism than the angioe-
dema that occurs with anaphylaxis.
Stinging Insect Allergy and Venom Immunotherapy
Question: Should BB or ACEI be discontinued or changed in
patients with a history of insect sting anaphylaxis who are not yet
on VIT?
Recommendation 31 (CBS): We suggest that patients with a
history of insect sting anaphylaxis who are not receiving VIT may
continue BB or ACEI medications when the medical necessity of
the daily medication outweighs the chance of increased severity
of anaphylaxis to a sting.
Strength of Recommendation: Conditional
Certainty of Evidence: Low
Question: Should VIT be recommended to patients with a his-
tory of insect sting anaphylaxis who are treated with BBs or
ACEIs?
Recommendation 32 (CBS): We suggest that VIT may be pre-
scribed for patients with a history of insect sting anaphylaxis who
are treated with BB or ACEI medication, with shared decision-
Table 23
Framework for Evaluation of the Benefit and Risk of BB or ACEI Medication in the Patient at Risk for Anaphylaxis
Clinical question Potential benefits of treatment Potential risks of no treatment
What is the indication for the medication?
Post-MI
CHF
Tachyarrhythmia
Migraine
Glaucoma
Diabetes
All of these disease states have been found to derive
benefit from BB.
Risks include poorly controlled heart rate, inadequate secondary preven-
tion of cardiac disease, and ongoing symptoms of CHF. Glaucoma often
cannot be managed without ocular BBs but risk of systemic complica-
tions of beta-blockade extremely low. Minimal risk of avoiding BBs for
migraine prophylaxis as many alternatives now exist.
What is the indication for the intervention?
Skin test
Initial AIT
Mc AIT
Initial VIT
Mc VIT
Benefit of skin testing includes accurate diagnosis.
Benefit of environmental AIT is mainly improved QOL.
Benefit of VIT is reduction of morbidity and elimina-
tion of mortality.
Risk of avoiding skin tests includes delayed/inaccurate diagnosis.
Risk of avoiding AIT includes ongoing QOL burden if pharmacotherapy has
failed.
Risks of avoiding VIT means ongoing risk of potentially life-threatening
anaphylaxis.
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; AIT, allergen immunotherapy; BB, beta-blocker; CHF, congestive heart failure; MI, myocardial infarction; QOL, qual-
ity of life; VIT, venom immunotherapy.
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D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53 33

making regarding the benefits and potential harms of concurrent
VIT treatment and medication, compared with withholding either
the treatment or the medication.
Strength of Recommendation: Conditional
Certainty of Evidence: Low
Question: In patients on maintenance VIT who are treated with
BBs or ACEIs, should VIT be stopped or the medication discontin-
ued?
Recommendation 33 (CBS): We suggest, in most cases, treat-
ment with BB or ACEI medication need not be changed or discon-
tinued in patients receiving maintenance VIT.
Strength of Recommendation: Conditional
Certainty of Evidence: Moderate
The potential for increased risk of anaphylactic reactions in
patients treated with BBs or ACEIs was first reported in relation to
insect sting allergy and VIT 30 to 40 years ago. These early reports
cited individual cases as examples of such risk but did not include
any controls or data in larger populations. 
368−370 
M
€
uller and Hae-
berli 
371 
recognized the importance of BBs in management of CVD and
studied patients with CVD and BB treatment who received VIT. Dur-
ing VIT buildup, the BB was replaced by an alternative drug in most
but continued in some due to medical necessity; the BB was resumed
during maintenance VIT in most cases. There were additional patients
who had been started on a BB during maintenance VIT. Thus, 25
patients were treated with a BB during VIT (all with history of severe
sting anaphylaxis). Systemic symptoms occurred in 12% of the
patients receiving a BB and in 11.6% of 138 patients with CVD who
were not receiving a BB. There was also no difference in the rate of
systemic reaction to stings during VIT in patients with CVD who were
or were not treated with a BB.
Concern regarding BB and ACEI treatment in patients at risk for
insect sting anaphylaxis was increased by the report of Ru
€
eff et al 
372
of 962 patients with a history of sting anaphylaxis (52 on BB and 42
on ACEI) that revealed a significantly greater severity of sting ana-
phylaxis in patients receiving a BB (34.6% severe vs 20.7% with no BB;
P = .024) or ACEI (42.9% severe vs 20.4% with no ACEI; P = .002). A
similar study by Stoevesandt et al 
373 
found no correlation between
cardiovascular medications and the severity of sting anaphylaxis.
Both groups published subsequent reports on patients receiving VIT
revealing no increased risk of systemic adverse effects in patients
receiving BB or ACEI medication. 
374−377 
It is noteworthy that both
Stoevesandt et al
376 
and M
€
uller and Haeberli 
371 
actually found a
lower incidence of adverse events in patients with CVD who were
treated with a BB or ACEI than in those who were not.
More recently, there have been 2 large studies that addressed the
issue of BB/ACEI treatment in patients experiencing insect sting ana-
phylaxis with somewhat conflicting results. Francuzik et al
378
reported a case-control study of 12,874 cases of anaphylaxis from the
European Anaphylaxis Registry that characterized 3612 cases of
venom anaphylaxis and 3605 matched cases of nonvenom anaphy-
laxis. The study found a higher frequency of severe anaphylaxis and
cardiovascular symptoms in patients receiving BBs or ACEIs, but the
authors cautioned that the apparent effect of the medications corre-
lated closely with coexisting CVD, so that severe anaphylactic reac-
tions could not be attributed specifically to the medications. 
378
Conversely, in the first prospective observational study and largest
study of its kind, Sturm et al
298 
enrolled 1425 patients with a history
of sting anaphylaxis of whom 1342 began VIT. They found that there
was no increased frequency of anaphylaxis to VIT injections or to
stings during VIT in 338 patients treated with cardiovascular medica-
tions (27.2% on antihypertensive drugs, 10.4% BB, 11.9% ACEI, 5.0% BB
and ACEI) and no increased severity of anaphylaxis to the pre-VIT
sting in 388 patients receiving BB and ACEI medications (OR = 1.14;
95% CI, 0.89−1.46; P = .29). 
298 
In contrast to the earlier report of Nas-
siri et al, 
362 
the data in the study of Sturm et al 
298 
did not reveal an
additive effect of BB and ACEI treatment on the frequency or severity
of anaphylaxis during VIT. Although the studies by Sturm et al 
298 
and
Francuzik et al 
378 
revealed somewhat differing results with respect
to severity of anaphylaxis in patients receiving BBs or ACEIs, they
both revealed that the risk of reaction related to medications corre-
lated very closely with the risk related to CVD and, therefore, could
not be attributed directly to the medications. Kopac et al 
379 
studied
biomarkers for severe insect sting anaphylaxis and found that the use
of BBs or ACEIs was not associated with the severity of honey bee
field sting reactions or adverse reactions to VIT.
The accumulated evidence now supports a modified approach to
patients with insect sting allergy who are treated with BBs or ACEIs.
Before VIT, there may be an increased severity of reaction to a sting
but not an increased chance of reaction. For patients on VIT, there
does not seem to be any increased risk associated with cardiovascular
medications. It is important to acknowledge that patients with CVD
have an inherently increased risk of severe anaphylaxis, which is all
the more reason to maintain treatment that is medically indicated to
mitigate that risk. Thus, it is believed to be safer for these patients to
remain on appropriate BB or ACEI medications rather than to discon-
tinue these medications. Moreover, changing the medication may
lead to increased morbidity or mortality from the underlying CVD,
which is estimated to exceed the risk of severe anaphylaxis that
might result from staying on the medications. This was found to be
the case in an analysis simulating the life expectancy of patients with
peanut anaphylaxis and CVD. 
380 
Although the prescribing physician
may be consulted about the medical necessity of the BB or ACEI medi-
cation, they should only be changed when there is an alternative
medication that is safe and effective.
Decisions regarding VIT and continuing cardiovascular medica-
tions should occur in the context of shared decision-making that
includes the relative indication for VIT (severity of previous sting
reaction and risk of future sting anaphylaxis), the medical necessity
of the medication (eg, BBs for post-myocardial infarction, congestive
heart failure, high blood pressure, glaucoma, or migraine) and its
benefit and risk, the values and preferences of the patient, and the
relative efficacy of non-BB or non-ACEI alternatives. Underlying CVD
is recognized in the Insect Allergy Practice Parameters as one of the
high-risk factors that can support the prescription of VIT and the con-
tinuation of VIT indefinitely. 
237 
Therefore, the recommendations for
patients with insect sting allergy may differ from those for other
immunotherapy patients.
Allergen Immunotherapy
Question: Should patients who are treated with BB or ACEI
medication initiate a course of AIT?
Recommendation 34 (CBS): We suggest use of initial AIT may
be considered in patients who are treated with BB or ACEI medica-
tion, with shared decision-making. It would be preferable to
replace the BB or ACEI, if there is a safe and effective alternative.
Strength of Recommendation: Conditional
Certainty of Evidence: Low
Question: In patients on maintenance AIT who are treated with
BB or ACEI medication, should AIT be stopped or the medication
discontinued?
Recommendation 35 (CBS): We suggest that patients receiving
maintenance dose AIT have a minimal increased risk of a severe
anaphylactic reaction when on BB/ACEI medication and may
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34 D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53

consider continuing AIT and medications based on shared deci-
sion-making.
Strength of Recommendation: Conditional
Certainty of Evidence: Low
Similar to the findings with VIT, the use of BBs or ACEIs in patients
undergoing SLIT has not been associated with increased severity or
frequency of systemic allergic reactions. 
381,382 
Beta-blockers are not
associated with increased frequency of systemic reaction to SCIT;
however, evidence from VIT, cases reports, and a SCIT surveillance
program suggests that these medications may increase severity of
reaction in patients receiving SCIT. 
381−383 
In fact, in a survey of the
experience and opinion of physicians, 37.1% and 47.3% report pre-
scribing AIT in patients receiving BBs and ACEIs, respectively, and
none reported major anaphylactic incidents during the course of the
treatment. 
384 
There is also no specific evidence related to the risk of
BB/ACEI medication during buildup SCIT compared with maintenance
SCIT. However, when the baseline risk of reaction is higher (as is
expected during the buildup schedule), then the risk of a more severe
reaction related to BB/ACEI medication might also be expected to be
higher.
The available evidence is not specific to SCIT but rather was com-
mon to studies of many or all causes of anaphylaxis. The theoretical
risk of BB treatment was not confirmed in a study of anaphylaxis in
the ED revealing they were not associated with an increased need for
epinephrine. 
363 
However, a recent systematic review of anaphylaxis
of all causes found that the risk of severe anaphylaxis was signifi-
cantly increased but the incidence of new cases of anaphylaxis was
not.
297 
Furthermore, it was not possible to adjust for underlying CVD,
and in fact, the risk of anaphylaxis was 3 to 5 times higher in patients
with known CVD than in those taking BB/ACEI medication. It is
important to note that although the relative risk may be increased,
the absolute risk remains very small. For example, the frequency of
systemic reactions to SCIT is approximately 0.2% for each injection,
most of which are mild-moderate (ie, severe reactions occur in <0.1%
of injections). 
71 
Even if the relative risk of a severe reaction is 2-fold
higher as reported in patients taking a BB or ACEI, the absolute risk
would still be very low (<0.2%). There is a need for an individualized
risk-benefit discussion exploring both the potential risk of the medi-
cation and the importance to the patient of the immunotherapy
treatment, including the patient’s history of anaphylaxis and associ-
ated risk factors, in the framework of the available evidence.
Planned Procedures: (eg, Drug Desensitization, Radiocontrast Media
Administration, Intravenous Immunoglobulin Infusion)
Question: For planned procedures where there is a risk of ana-
phylaxis, should BB or ACEI treatment be interrupted or contin-
ued?
Recommendation 36 (CBS): For planned procedures (eg, RCM,
challenge/desensitization, and infusion) if the BB/ACEI medication
cannot be safely interrupted, we suggest shared decision-making
discussion of the medical necessity (benefit) of the procedure, the
relative risk of anaphylaxis, the possibility of more severe reac-
tion if the medication is continued, and the risk of stopping the
medication.
Strength of Recommendation: Conditional
Certainty of Evidence: Very Low
Drug desensitization is a safe and effective treatment option for
patients with severe hypersensitivity to antibiotics, chemotherapies,
monoclonal antibodies, and other drugs such as aspirin. There is
insufficient evidence to determine the relative risk associated with
BB/ACEI medications during these procedures. In 2 case reports of
desensitization to penicillin and gemifloxacin, allergic reactions were
reported to be more severe with the use of BBs and ACEIs. 
385,386
However, observed associations must not be confused with causa-
tion. Drug desensitization procedures are usually performed because
of the lack of safe and effective alternatives to a medically necessary
treatment. Thus, any potential risk associated with concomitant med-
ications must be viewed in the context of the risk of foregoing the
procedure or the risk of stopping the medication during the proce-
dure.
Radiocontrast media are agents given to increase the contrast in
an imaging study to allow visualization of internal structures. Similar
to other causes of anaphylaxis, there has been conflicting evidence
about whether BB and/or ACEI medications increase the severity of
anaphylaxis after RCM administration. In a case-control study of
34,371 intravenous RCM procedures by Lang et al, 
387 
BB exposure
and CVD were highly associated (X 
2 
= 49; P < .001). Using a logistic
regression model with adjusted ORs, increased risk of bronchospasm
was associated with BB (OR = 3.73, 1.18-11.75; P = .025) and asthma
(OR = 16.49, 4.30-62.46; P = .001), independent of CVD. Of 21 reactors
with CVD who did not have asthma, 10 were receiving BB; 9 of these
10 had bronchospasm compared with only 4 of 11 not receiving BB
(OR = 15.75; P = .023). Risk of a major and life-threatening reaction
(hypotension with/without need for hospitalization) was associated
with CVD (OR = 7.71, 1.04-57.23; P = .046), independent of asthma or
BB exposure. A more recent case-control study of patients receiving
intra-arterial low-osmolality contrast during cardiac catheterization
found no increased rate of severe anaphylactic reactions in associa-
tion with BBs (P = .40) or ACEIs (P = .14). 
366 
However, in that study of
71,782 cardiac catheterizations, only 11 cases (0.015%) of severe ana-
phylaxis were observed—reflecting the substantial reduction in
severe adverse reactions with low osmolar contrast. Neither cardio-
selective BBs (P = .2) nor non-cardioselective BBs (P = .5) influenced
reaction severity.
366
Anaphylaxis can occur during IVIG infusions; however, this is a
very rare complication (7.34 per 10,000 infusions). 
388−390 
Patients
receiving their initial IVIG treatment are considered at higher risk for
adverse events and should be monitored closely at the slower than
usual infusion rate. 
391 
In a study of patients with idiopathic inflam-
matory myopathy and concomitant heart failure, 75% of patients
receiving IVIG therapy were using BBs and/or ACEIs. In these patients,
no cases of anaphylaxis were reported. 
389 
Literature on the relative
risk of anaphylaxis in patients receiving IVIG while on BB or ACEI
medication is not available.
Patients at Risk for Anaphylaxis (Unplanned Exposure or Unknown
Cause)
Question: In patients at significant risk for recurrent and unex-
pected anaphylaxis due to unplanned exposure or unknown
cause, should BB or ACEI medication be stopped or continued?
Recommendation 37 (CBS): We suggest that all patients at sig-
nificant risk for recurrent and unexpected anaphylaxis (eg, those
with severe food allergy, mastocytosis or MCAS, or recurrent IA)
be counseled about the risk of more severe anaphylaxis, and con-
sider avoiding, where possible, the use of nonselective BBs or
ACEIs.
Strength of Recommendation: Conditional
Certainty of Evidence: Moderate
Some conditions are associated with greater frequency or severity
of anaphylactic reactions, often at unpredictable times. Such patients
should be counseled to take special measures to mitigate this risk,
with increased caution regarding contributing factors (eg, alcohol,
ARTICLE IN PRESS
D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53 35

vigorous exercise, medications), increased vigilance for the earliest
signs of the beginning of a reaction, and ready availability of treat-
ment with epinephrine. This may apply to patients with IA, underly-
ing mast cell disorders, severe food allergy, or severe insect sting
allergy (before VIT). There could reasonably be increased concern in
these patients for the potential risk associated with BB or ACEI medi-
cation.
Idiopathic anaphylaxis is a diagnosis of exclusion and is based on
the inability to identify a causal relationship between a trigger and
an anaphylactic event. 
392 
Every effort should be made to identify a
specific cause and any contributing factors or medications so as to
improve further management and risk reduction. There are no spe-
cific reports on the effects of BBs or ACEIs in patients with IA, but the
reported increased risk of severe reactions that has been associated
with BBs and ACEIs in anaphylaxis of all causes would be of concern
in patients with recurrent and unpredictable anaphylaxis. As in other
patients, the medical risk of changing or stopping the medication
must be weighed against the risk of more severe anaphylaxis if the
medications are continued.
Patients with severe food allergy have a greater chance of unex-
pected severe reactions. An evidence review and meta-analysis of
risk factors for severe reactions in food allergy noted that although
BB or ACEI treatment may increase severity, they are less important
than age as a risk factor for severe anaphylaxis. 
393 
Tenbrook et al
380
studied a simulated cohort of adults with peanut allergy and underly-
ing CVD. This study developed a Markov model for patients with
heart disease at risk for peanut anaphylaxis to compare their esti-
mated life expectancy with and without BBs. For people with post-
myocardial infarction or congestive heart failure, the benefits of BB
treatment outweighed the potentially increased likelihood of dying
from anaphylaxis, increasing estimated life expectancy by 9.4 and
17.4 months, respectively. Quality-of-life outcomes were not evalu-
ated. 
380 
Furthermore, with the assumptions in this model, BBs were
preferred unless the annual rate of moderate-to-severe anaphylaxis
exceeded 6% for patients with post-myocardial infarction and 15% for
patients with congestive heart failure. The frequency of anaphylaxis
may be of consideration in patients with frequent episodes of IA for
whom triggers are not avoidable, in contrast with food-induced ana-
phylaxis in which the trigger is more easily recognized. 
394 
Similar
analyses have not been conducted for IA, MCAS, alpha-gal allergy, or
H
aT. Overall, before stopping BBs in patients with a history of ana-
phylaxis, the relative risk of CVD without BB treatment must be
weighed against the risk of more severe anaphylaxis while on BB
treatment 
395 
and requires a shared decision-making discussion.
Summary of Recommendations for Beta-Blocker/Angiotensin-Converting
Enzyme Inhibitor Medication
In summary, clinicians should weigh the potential benefits and
harms when considering the use of BBs and ACEIs in patients at risk
for anaphylaxis (Table 23). These medications are associated with an
increased relative risk that any anaphylactic reaction will be more
severe, although the absolute risk of severe anaphylaxis remains
small and the risk of stopping or changing the medications may be
greater than the risk of continuing them during any planned treat-
ment or procedure. The risk of severe anaphylaxis may be related
more to age and underlying cardiovascular conditions than to the BB/
ACEI medications. In general, however, one should not assume auto-
matically that these medications are absolutely contraindicated in
this population. The discussion should include the prescribing physi-
cian (eg, cardiologist).
Patients taking BBs or ACEIs who are at risk for sting anaphylaxis
but are not on VIT should be counseled about the increase in relative
risk (but only a small increase in absolute risk) of a sting reaction
being more severe and should discuss with the prescribing clinician
whether alternative medications are equally safe and effective for
their treatment. For patients on maintenance immunotherapy (VIT,
SCIT, or SLIT), the risk of BB/ACEI therapy is minimal and no change
in medication is needed. Patients who need to begin VIT should be
counseled about the increase in relative risk (but only a small
increase in absolute risk) of a reaction to VIT injection during initial
buildup being more severe and the potential risks of the alternatives
(changing the medications or foregoing VIT). For patients who wish
to begin SCIT, the severity and history of their allergies, alongside the
efficacy of alternative pharmaceutical agents, should be considered
when determining whether to proceed with SCIT and whether BBs
and ACEIs are suitable treatment options. Patients at risk for anaphy-
laxis from known exposures or unknown/unplanned exposures or
procedures should be counseled about the increase in relative risk
(but only a small increase in absolute risk) of a reaction being more
severe and should discuss with the prescribing clinician whether
alternative medications are equally safe and effective for their treat-
ment. Knowledge gaps related to use of BB or ACEI medication in
patients at risk for anaphylaxis are listed in Table 24.
Mast Cell Disorders and Anaphylaxis
Mastocytosis is a clonal disorder of mast cell proliferation and is
associated with episodic and chronic mast cell activation symptoms
in most patients. 
396 
Mast cell activation, in its most severe form, may
present with anaphylaxis. It has been estimated that approximately
40% to 50% of adults and 10% of children with mastocytosis experi-
ence anaphylaxis. 
397 
Risk factors for anaphylaxis associated with
mastocytosis include male sex, total serum IgE greater than 15 kU/L,
atopic background, and tryptase levels less than 42 ng/mL. 
398 
New
potential biomarkers for risk of anaphylaxis in patients with masto-
cytosis have been reported. 
399 
Anaphylaxis is also overrepresented in
patients with mastocytosis who lack skin lesions; however, it is not
clear whether this finding is due to referral bias. Most anaphylaxis
episodes associated with mastocytosis do not have a single identifi-
able trigger and sometimes may be termed “unprovoked.” In patients
with mastocytosis, Hymenoptera venom allergy is the leading cause
of IgE-mediated anaphylaxis in studies from Europe. 
400,401 
The
Table 24
Knowledge Gaps Related to Use of BB or ACEI Medication in Patients at Risk for Anaphylaxis
 
The true increased risk of more severe or treatment refractory anaphylaxis related specifically to treatment with BBs or ACEIs is unknown.
 
How much is the degree of severity of anaphylaxis experienced by patients related specifically to their underlying cardiovascular disease as opposed to their medication(s)?
 
Is there a difference in risk of anaphylaxis associated with selective BBs vs nonselective BBs?
 
Is there a difference in risk of anaphylaxis associated with ACEIs vs ARBs?
 
Does the risk depend on the cause of reaction or route of exposure?
 
Is the efficacy of epinephrine reduced by BBs?
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, beta-blocker.
ARTICLE IN PRESS
36 D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53

prevalence of drug, food, and POA is also slightly increased in
mastocytosis. 
402
Epidemiology, Classification, and Diagnosis
Question: What is the role of bone marrow biopsy and serum
tryptase level in evaluation of patients for possible mastocytosis?
Recommendation 38 (CBS): We recommend clinicians order a
bone marrow biopsy with staining for tryptase, CD25 immunohis-
tochemistry and flow cytometry, and the KIT D816V mutation
when there is strong suspicion for systemic mastocytosis.
Strength of Recommendation: Strong
Certainty of Evidence: Moderate
Recommendation 39 (CBS): We recommend clinicians not rely
on serum tryptase levels alone for diagnostic assessment of the
likelihood that a patient does or does not have a clonal mast cell
disorder.
Strength of Recommendation: Strong
Certainty of Evidence: Moderate
Updated classification and diagnostic criteria from the WHO for
cutaneous and systemic mastocytosis are detailed in Table 25. 
403−405
Diagnosis requires at least 1 major and 1 minor or 3 of the 4 minor
criteria. A bST in excess of 20 ng/mL is considered a significant con-
tributory finding to the diagnosis but must be supported by addi-
tional findings. 
403 
Differential diagnoses of conditions which can be
associated with elevated bST levels are listed in Table 26, and the cli-
nician should be aware that this marker is not specific for a mast cell
disorder. 
403,406 
Moreover, there should be awareness that the differ-
ential diagnosis of an elevated bST level includes H
aT, which is an
autosomal-dominant genetic variant caused by increased copy num-
bers of alpha tryptase genes encoded by TPSAB1 locus. 
83 
Although
the clinical significance of H
aT is not fully understood, it may
increase the frequency and/or severity of anaphylactic reactions. H
aT
is observed in 5% to 7% of the general population and is most fre-
quently asymptomatic but is reported in more than 15% of patients
with IA, mastocytosis, or insect sting anaphylaxis. 
91,407 
It is not clear
whether this is because of selection bias or a yet to be defined mecha-
nism affecting mast cell proliferation or activation. H
aT is discussed
in more detail in the Diagnosis section.
A bone marrow biopsy revealing at least 15 mast cells in aggre-
gates is the major diagnostic criterion for diagnosis of systemic
mastocytosis. Skin findings of maculopapular cutaneous mastocyto-
sis, also known as urticaria pigmentosa (hyperpigmented macules
that urticate when lightly stroked), are a hallmark of cutaneous mas-
tocytosis but also can be present in systemic mastocytosis, although
systemic forms can present with minimal or no cutaneous find-
ings.
403 
In infants, skin lesions may form blisters or bullae during dis-
ease flares especially in the first 3 years of life. Other skin findings
such as pruritus, urticaria, and flushing have been observed. Mastocy-
tomas in children can resemble flesh-colored to slightly pigmented
nodules and are considered a benign mast cell tumor, which can also
urticate on being rubbed. Documentation of a thorough skin exami-
nation with pertinent positive and negative findings is of high impor-
tance. 
403 
Isolated cutaneous mastocytosis is very uncommon in
adults. The risk of anaphylaxis in children with cutaneous mastocyto-
sis (in whom systemic disease is uncommon) is believed to be much
less than in patients with systemic mastocytosis, ranging from 0% to
9% in various studies, and mainly occurs in those with extensive skin
involvement and higher tryptase levels. 
408
Key presenting symptoms of systemic mastocytosis will overlap
with anaphylaxis but also may include the aforementioned skin find-
ings, presyncope/syncope, constitutional symptoms (eg, fevers,
weight loss, night sweats), bone pain, and prominent gastrointestinal
symptoms such as reflux, nausea, vomiting, diarrhea, and colic. On
physical examination, hepatosplenomegaly and lymphadenopathy
may be prominent especially in patients with advanced disease. Mul-
tiple reviews detail the key presenting features of mast cell
disorders. 
396,403,404,409 
Systemic mastocytosis can present in child-
hood in approximately 10% of the cases and should remain in the dif-
ferential if the child presents with the constellation of symptoms
Table 25
WHO-Proposed Refined Major and Minor SM Criteria
Major criterion Multifocal dense infiltrates of mast cells (≥15 mast cells in aggregates) in bone marrow biopsies and/or in sections of other extracutaneous organ(s)
Minor criteria a. ≥25% of all mast cells are atypical cells on bone marrow smears or are spindle shaped in mast cell infiltrates detected in sections of bone marrow or other
extracutaneous organs
a
b. KIT-activating KIT point mutation(s) at codon 816 or in other critical regions of KIT
b 
in bone marrow or another extracutaneous organ
c. Mast cells in bone marrow, blood, or another extracutaneous organ express one or more of CD2 and/or CD25 and/or CD30
c
d. bST concentration >20 ng/mL. In the case of an unrelated myeloid neoplasm, an elevated tryptase level does not count as an SM criterion. In the case of a
known H
aT, the tryptase level should be adjusted 
d
If at least 1 major and 1 minor or 3 minor criteria are fulfilled, the diagnosis is SM
Abbreviations: bST, baseline serum tryptase; HaT, hereditary a-tryptasemia; SM, systemic mastocytosis; WHO, World Health Organization.
NOTE. Reproduced from Valent et al
403 
under Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND).
a
In tissue sections, an abnormal mast cell morphology counts in both a compact infiltrate and a diffuse (or mixed diffuse + compact) mast cell infiltrate. However, the spindle-shaped
form does not count as an SM criterion when mast cells are lining vascular cells, fat cells, nerve cells, or the endosteal-lining cell layer. In the bone marrow smear, an atypical mor-
phology of mast cells does not count as SM criterion when mast cells are located in or adjacent to bone marrow particles. Morphologic criteria of atypical mast cells have been
described previously. 
405
b 
Any type of KIT mutation counts as minor SM criterion when published solid evidence for its transforming behavior is available. A list of such KIT mutations (including variants
in KIT codons 417, 501-509, 522, 557-560, 642, 654, 799, 816, 820, 822) is provided in Supplemental Digital Content, Table S6, http://links.lww.com/HS/A201 (KIT-activating muta-
tions are labeled in bold).
c 
All 3 markers fulfill this minor SM criterion when expression in mast cells can be confirmed by either flow cytometry or by immunohistochemistry or by both techniques.
d
Although the optimal way of adjustment may still need to be defined, one way is to divide the basal tryptase level by 1 plus the extra copy numbers of the alpha tryptase gene.
Example, when the tryptase level is 30 and 2 extra copies of the alpha tryptase gene are found in a patient with H
aT, the HaT-corrected tryptase level is 10 (30/3 = 10) and thus is
not a minor SM criterion.
Table 26
Differential Diagnosis for Elevated Baseline Serum Tryptase Level
Systemic mastocytosis
Hereditary 
a-tryptasemia
Mast cell activation syndrome
Anaphylaxis
Complement (and mast cell) activation-related pseudoallergy
Myeloid neoplasm
Helminth infection
Renal failure
Hypereosinophilic syndrome
NOTE. Reproduced from Valent et al 
403 
under Creative Commons Attribution-Non
Commercial-No Derivatives License 4.0 (CCBY-NC-ND).
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D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53 37

detailed previously, displays increasing tryptase levels, and the cuta-
neous lesions fail to regress by puberty. 
410−412
The decision to recommend bone marrow biopsy in a patient pre-
senting with anaphylaxis is not always straightforward. Decision-
making and scoring schemes for bone marrow biopsy are discussed
in more detail in the Diagnosis section. However, the procedure is
necessary to document the key marrow pathology that defines the
condition and for staging to determine whether the disease is
advanced. Although mast cell proliferation can be noted in most
other affected organs, the marrow remains the most important area
for biopsy. 
404 
The clinician may consider other less invasive tests
such as a blood count (looking for evidence of cytopenia and/or
eosinophilia), blood chemistry (looking for other evidence of end-
organ dysfunction), a bST (which is often but not always elevated in
mastocytosis), or a peripheral blood KITD816V mutation analysis
before deciding on a bone marrow biopsy. 
95,413 
A KIT mutation analy-
sis is also generally ordered with most bone marrow aspirates and is
more sensitive than peripheral blood mutational analysis. 
414 
The KIT
D816V mutation should be analyzed by a highly sensitive test (such
as allele-specific PCR or digital droplet PCR) capable of detecting
mutation at a 0.1% or lower allelic frequency. These assays have 80%
to 90% sensitivity compared with bone marrow biopsy and more
than 99% specificity. It is important to note that tests frequently used
in hematologic neoplasms based on next-generation sequencing are
not sufficiently sensitive. 
414 
Nonetheless, in a patient with symptoms
suggestive of systemic mastocytosis, irrespective of a normal tryptase
level, a bone marrow biopsy is necessary to definitively rule in or rule
out the diagnosis. Clinicians ordering a bone marrow biopsy should
ask for staining for tryptase, CD25 immunohistochemistry, and flow
cytometry, the KIT D816V mutation using a highly sensitive allele-
specific PCR or digital droplet PCR-based technique, and whether
there is peripheral eosinophilia, a FIP1L1-PDGRA mutational
analysis. 
403,404 
In some cases, biopsy of other extracutaneous organs
may be helpful, as described in WHO guidelines, most frequently by
gastrointestinal mucosal biopsy. 
415
Mastocytosis, Hymenoptera Anaphylaxis, or Idiopathic Anaphylaxis
Question: When should bST be measured?
Recommendation 40 (CBS): We recommend measurement of
bST in patients with severe insect sting anaphylaxis, particularly
those who had hypotension and/or absence of urticaria; in all
cases of recurrent unexplained anaphylaxis; and in patients with
suspected mastocytosis.
Strength of Recommendation: Strong
Certainty of Evidence: Moderate
Question: When should patients be evaluated for mastocyto-
sis?
Recommendation 41 (CBS): We suggest clinicians consider
evaluation for mastocytosis, including a bone marrow biopsy, for
adult patients with severe insect sting anaphylaxis or recurrent
IA, particularly those with a predictive REMA score.
Strength of Recommendation: Conditional
Certainty of Evidence: Moderate
Question: Should patients with mastocytosis and insect sting
allergy be treated with VIT?
Recommendation 42 (CBS): We suggest VIT be continued indef-
initely in patients with mastocytosis and insect sting anaphylaxis
due to the increased risk of severe or fatal sting anaphylaxis if VIT
is discontinued.
Strength of Recommendation: Conditional
Certainty of Evidence: Low
Anaphylaxis to insect stings has been found to have a unique asso-
ciation with mastocytosis.
416 
Furthermore, an unusually high fre-
quency of clonal mast cell disorders has been found in patients with
severe sting anaphylaxis.
417,418 
Venom anaphylaxis in patients with
mastocytosis is associated with a unique clinical pattern of reaction
and with a unique phenotype of mastocytosis.
419,420 
The frequency
and clinical characteristics of mast cell disorders in patients with insect
sting allergy in the United States may differ from those in European
reports.
421 
The presentation of insect sting allergy that is most sugges-
tive of mastocytosis is a male who develops rapid-onset hypotensive
shock with no urticaria. Insect stings are the most common cause of
anaphylaxis in patients with mastocytosis. In one report, patients with
mastocytosis who had positive test results for venom IgE had a very
high risk (93%) of severe and life-threatening anaphylaxis to insect
stings.
422 
This led the authors of that report to suggest that testing for
venom IgE should be considered in all patients with mastocytosis and
that those with positive test results should be offered VIT (even if they
have never had a systemic reaction to a sting).
422 
However, there is no
consensus among the experts regarding preemptive VIT, and prospec-
tive confirmation of this observation is needed.
Early reports noted that elevated bST level is unusually common in
patients with insect sting anaphylaxis.
423−425 
Recent studies suggest
that in patients with insect sting anaphylaxis, bST levels greater than
8 ng/mL indicate increased risk of severe anaphylaxis to stings and sug-
gest an underlying mast cell disorder.
378 
Such patients should be moni-
tored for possible progressive increase over a period of years in serum
tryptase levels. H
aT is also found in a much higher proportion of
patients with sting anaphylaxis (10%-20%) than in the general popula-
tion (6%).
91 
However, one study found venom anaphylaxis correlated
with presence of D816V mutation-positive clonal mast cells rather
than H
aT.
413 
In that population of patients with severe insect sting
anaphylaxis who had positive test results for D816V mutation by high
sensitivity PCR blood test, 28 of 34 (82%) had normal tryptase levels.
413
Although once considered too dangerous, VIT is now recommended
in patients with mastocytosis with insect sting anaphylaxis.
237,401
Treatment with VIT reduces the frequency and severity of reactions to
stings in patients with mastocytosis although not as efficiently as in
other patients with insect sting allergy.
426 
During maintenance VIT,
systemic reactions to stings occur in 5% to 15% of patients without mas-
tocytosis but in 25% of patients with mastocytosis.
427 
This still repre-
sents significant benefit because, without VIT, the risk of sting
reactions in patients with mastocytosis and prior systemic reaction to
a sting is more than 75%.
422 
There is also a higher frequency of systemic
reactions to VIT injections in patients with mastocytosis (15%) than in
those without mastocytosis (5%), and reactions can occur even during
maintenance VIT.
428 
In patients who have repeated reactions to VIT,
omalizumab has been reported to enable most patients to achieve
maintenance dose.
429,430 
Mastocytosis is also associated with increased
risk of relapse if VIT is discontinued, with severe and even fatal sting
reactions despite completing the usual 5-year course of
treatment.
422,426,431 
It is, therefore, recommended that patients with
mastocytosis should continue VIT indefinitely.
237,401
Clinical Presentation
Anaphylaxis manifestations in mastocytosis frequently include
hypotension, syncopal or presyncopal episodes, flushing, tachycardia,
and gastrointestinal symptoms, such as cramping, diarrhea, nausea,
and vomiting. In contrast, urticaria, angioedema, and wheezing are
not observed frequently. 
93 
All such patients should have a careful
skin examination to look for the presence of maculopapular cutane-
ous lesions of mastocytosis (formerly known as urticaria
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38 D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53

pigmentosa), although absence of maculopapular cutaneous lesions
does not rule out mastocytosis. As described in the Diagnosis section
(and Fig 4), risk-stratification schemes for the probability of mastocy-
tosis in patients presenting with mast cell activation symptoms have
been proposed by REMA and NICAS. 
93,94,96 
According to the REMA
scheme, patients with a total score of 2 or greater have a high likeli-
hood of having systemic mastocytosis (sensitivity 0.92, specificity
0.81) and should be considered for bone marrow biopsy. The NICAS
scoring system did not include patients with insect anaphylaxis,
whereas the REMA system included all causes.
Tryptase level is the most reliable surrogate marker of systemic
mast cell burden and should be determined in all patients suspected
of having mastocytosis. A normal median tryptase level is approxi-
mately 4.5 to 5 ng/mL in the general population. Elevated bST levels
can be found in chronic renal failure, myeloid disorders, and H
aT.
Although a cutoff level of “normal” tryptase has been suggested as
11.4 ng/mL in most commercial diagnostic tests, individuals without
an extra allele of TPSAB1 encoding alpha tryptase generally have
tryptase levels of less than 8 ng/mL. 
432 
See the Diagnosis section for
further discussion of serum tryptase testing.
More than 90% of patients with systemic mastocytosis have a
somatic activation mutation in KIT gene in a single codon (D816V). 
433
Detection of this mutation in the peripheral blood is a marker of
clonal mast cell disease (mastocytosis) and should be considered in
patients presenting with recurrent anaphylaxis, especially associated
with hypotension. There are several assays commercially available to
measure this mutation; as mentioned previously, the most accurate
results are obtained by a high sensitivity PCR droplet digital assay
with a lower limit of detection of at least 0.1%.
Mast Cell Activation Syndromes
These syndromes consisted of a broad range of disorders with var-
ious etiologies presenting with systemic mast cell activation. They
can be classified as primary (clonal; eg, mastocytosis), secondary (eg,
IgE mediated), or idiopathic. Mast cell activation and mediator
release are the primary cause of the manifestations of anaphylaxis in
humans, and therefore, IA is a prototypical MCAS. Other presenta-
tions of mast cell activation not meeting the clinical definition of ana-
phylaxis are also included in MCAS. In patients who otherwise do not
fulfill the clinical definition of anaphylaxis, a logical approach to diag-
nosis has been proposed to include the following 3 diagnostic criteria,
all of which should be fulfilled:
1. Symptoms consistent with mast cell activation in at least 2 differ-
ent organ systems (cardiovascular, respiratory, naso-ocular, gas-
trointestinal, cutaneous);
2. Documentation of elevated mast cell mediator levels during an
episode (most specific marker is tryptase, and threshold levels
have been described [see the Diagnosis section] for the minimal
diagnostic increase in a post-event tryptase obtained within 4
hours); and
3. Positive response to mediator-targeting drugs. 
79,434,435
Chronic and nonspecific multiorgan symptoms and patients with
multiple environmental and food intolerances without meeting these
criteria should not be diagnosed with having MCAS.
Special Treatment Considerations of Anaphylaxis in Mastocytosis
Omalizumab
There has been much interest in omalizumab as a potential thera-
peutic for patients who have recurrent anaphylaxis due to mastocy-
tosis. Omalizumab reduces the risk of anaphylaxis during rush
immunotherapy for ragweed and Hymenoptera venom and during
immunotherapy for food allergy. 
436 
A randomized clinical trial
revealed a promising trend, but the results were not significant in a
small group of 19 patients with severe IA. 
437 
A systematic review
identified 12 studies with 35 subjects with IA treated with omalizu-
mab: 63% had a complete response and 28.5% had a partial
response. 
438 
Most studies have used omalizumab dosing similar to
that used for chronic idiopathic urticaria.
In patients with mastocytosis, there are reports of improved con-
trol of symptoms and prevention of anaphylaxis with omalizu-
mab.
439−441 
Carter et al
442,443 
reported on successful control of
anaphylaxis in 2 patients, with sustained results in long-term (12
year) follow-up. A recent systematic review found a total of 69
patients with mastocytosis treated with omalizumab (13 cutaneous
and 56 systemic); there was greater improvement in prevention of
anaphylaxis (84%) than in other systemic symptoms (improved in
0%-43%). 
444
Omalizumab is not currently approved by the FDA in the United
States for this indication, and further well-designed studies are
needed, but off-label prescription may be considered in patients with
mastocytosis who have frequent episodes of anaphylaxis despite
optimal medical treatment. However, when there are signs of
increasing mast cell burden and uncontrolled symptoms, other treat-
ment modalities, particularly tyrosine kinase inhibitors (TKIs), may
be more likely to be effective.
Mast Cell Cytoreduction and Tyrosine Kinase Inhibitors
There is evidence that mast cell cytoreduction (reduction of mast
cell mass) results in improvement of anaphylaxis in mastocytosis. In
1 study, use of cladribine (an antimetabolite purine analogue) for
treatment of advanced or indolent mastocytosis resulted in complete
clearance of anaphylactic episodes. 
445 
D816V KIT mutation associated
with mastocytosis results in constitutive activation of the tyrosine
kinase function of the molecule. As such, TKIs targeting D816V KIT
have been considered a first-line approach for mast cell cytoreduc-
tion, given toxicities associated with cladribine. Although cytoreduc-
tive therapy has been traditionally reserved for patients with
advanced mastocytosis, recent emergence of TKIs with low toxicity
profiles has made this treatment an attractive possibility for those
presenting with mast cell activation symptoms inadequately con-
trolled with symptomatic therapies. 
446 
Midostaurin and avapritinib
are the TKIs currently FDA approved for treatment of advanced mas-
tocytosis, conditions that are associated with decreased life expec-
tancy (ie, aggressive systemic mastocytosis, systemic mastocytosis
with an associated hematologic neoplasm, and mast cell leukemia).
The mast cell cytoreductive effects of these TKIs are associated with
symptom control of mast cell activation. 
447−449 
Avapritinib is now
also FDA approved for indolent systemic mastocytosis, at a lower
daily dose. Neither drug is approved for prevention of anaphylaxis.
Midostaurin is a multikinase inhibitor whose targets include wild-
type and D816V-mutated KIT. It has been found to resolve anaphylac-
tic episodes in 3 of 4 patients (75%) at 3 months and 2 of 2 patients
(100%) at 6 months in patients with advanced systemic mastocyto-
sis. 
450 
It should be noted that these drugs require periodic monitoring
with complete blood cell count with differential and are contraindi-
cated in pregnancy. An open-label trial of midostaurin in indolent
systemic mastocytosis revealed significant reduction of symptoms
due to mast cell activation, but nausea and vomiting are common
adverse effects of the drug.
451
Avapritinib, a selective D816V KIT inhibitor, is approved by the
FDA for treatment of patients with advanced systemic
mastocytosis. 
448,449 
Its use has been associated with mast cell cytore-
duction and improvement in mast cell activation symptoms including
a case report describing successful cessation of recurrent anaphy-
laxis. 
452 
Avapritinib has recently been approved by the FDA for symp-
tomatic indolent systemic mastocytosis based on the results of a
randomized controlled trial (ClinicalTrials.gov identifier:
ARTICLE IN PRESS
D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53 39

NCT03731260) of a lower daily dose that revealed reduction of mast
cell activation symptoms and all measures of mast cell burden. 
453
Avapritinib is contraindicated in patients with platelet counts of less
than 50,000/
mL. Other KIT D816V selective TKIs currently being eval-
uated in clinical trials include elenestinib (BLU-263; NCT04910685)
and bezuclastinib (NCT05186753). In patients with mastocytosis and
recurrent episodes of anaphylaxis despite optimal medical therapy
with high-dose H 
1 
antihistamines and H 
2 
antihistamines (and possi-
bly a trial of omalizumab), consideration may be given to a trial of
avapritinib or compassionate use of midostaurin, or referral to a clini-
cal trial for a TKI, although neither is currently FDA approved specifi-
cally for prevention of anaphylaxis.
Knowledge gaps related to anaphylaxis in mastocytosis are listed
in Table 27.
Perioperative Anaphylaxis
POA occurs at a rate of 15.3 per 100,000 cases, is associated with
increased cost and prolonged length of hospital stay, and can result
in 2% excess mortality. 
454 
POA has a greater risk of death than other
forms of anaphylaxis. 
455,456 
In a multivariate analysis of POA cases,
independent risk factors associated with a fatal outcome related to
NMBAs, despite treatment with epinephrine, were as follows: male
sex (OR = 2.5; 95% CI, 1.4-5.0; P = .0004), emergency surgery
(OR = 2.6; 95% CI, 1.5-4.6; P = .0007), history of hypertension
(OR = 2.5; 95% CI, 1.5-4.4; P = .0010) or other CVD (OR = 4.4; 95% CI,
2.4-8.1; P < .0001), obesity (OR = 2.4; 95% CI, 1.1-5.3; P = .0376), and
BB exposure (OR = 4.2; 95% CI, 1.8-9.8; P = .0011). 
457 
Increased risk
for POA has also been associated with transplant, cardiac, vascular,
and hematologic procedures. 
454 
Recent trends in POA include the rec-
ognition of geographic variation in etiologic agents (perhaps based on
different preprocedure exposures to sensitizing factors), a declining
incidence of POA due to latex, and a greater appreciation for reactions
related to antibiotics—particularly cefazolin. 
458−460 
It is important to
note that rigorous evidence on this topic is lacking due to the limita-
tions resulting from the relatively rare occurrence of POA and inabil-
ity to perform blinded studies due to ethical considerations.
Therefore, the strength of evidence is uniformly low to very low.
POA is usually due to immunologic or non-immunologic activa-
tion of mast cells and, to a lesser extent, basophils. Measurement of
mast cell mediators, particularly more stable mediators such as tryp-
tase, is a validated strategy to confirm involvement of mast cell
degranulation in the pathogenesis of POA. 
459,460 
A retrospective
study revealed that serious anaphylaxis during anesthesia was asso-
ciated with elevations in serum tryptase level (mean = 86.5 ng/mL);
moreover, tryptase level elevation was not observed in a comparator
group with cardiogenic or septic shock but no anaphylaxis who were
resuscitated. 
459 
These data imply that resuscitation itself cannot
account for serum tryptase level elevation. However, serum tryptase
level is not always increased in anaphylaxis, even in severe or fatal
reactions. A French study of POA reported an increase in serum tryp-
tase level in 68% of suspected IgE-mediated POA but in only 4% of
non−IgE-mediated POA. 
461 
Elevations in serum tryptase level are
most often detected in cases of anaphylaxis that involve hypotension
and in reactions that are IgE mediated. 
22,454,458,461 
The sensitivity
(64%) and specificity (89%) of elevated serum tryptase level (>11.4
ng/mL) 
460 
lead to a calculated positive likelihood ratio (LR) of 6 and a
negative LR of 0.4. These LRs indicate that an elevated serum tryptase
level gives moderate support to the likelihood of POA, but a lack of
increase in serum tryptase level should not be interpreted as ruling
out a diagnosis of POA.
Measurement of plasma histamine to confirm a diagnosis of ana-
phylaxis is generally not recommended as this is complicated by the
rapid degradation and decline of blood values after POA; however, in
the rare circumstance in which a blood sample is obtained within 30
minutes of POA, a plasma histamine determination may be of
value. 
22,461
Interpretation of serum tryptase level is based on international
consensus recommendations noting a 1.2-fold increase plus 2 ng/mL,
consistent with degranulation of mast cells during the suspected
reaction. 
432 
Because bST values may be more variable in patients
with mastocytosis or H
aT, 1 study found optimal sensitivity and
specificity with a threshold acute/baseline tryptase level of 1.685
(further discussed in the Diagnosis section). 
80 
The timing of obtaining
the serum sample is important. The concentration peaks within 30 to
60 minutes of the reaction and then typically returns to baseline in
approximately 120 minutes (but up to 4 hours or more). Interpreta-
tion of tryptase levels obtained in proximity to death or postmortem
may be unreliable as nonspecific increases occur during ischemia. 
462
Tryptase is stable for as long as 1 year if a blood sample is frozen after
processing. This could enable retrospective investigation of suspected
POA.
A 15-year Belgian survey identified 180 subjects with tryptase
determinations from a total of 532 subjects with POA 
463 
; in 139
(77%) with clinical POA, an increase of tryptase level
(>1.2 £ baseline + 2 
mg/L) was observed. Severity of anaphylaxis was
associated with a tryptase level exceeding the aforementioned
threshold (11.4 ng/mL), but the severity of POA did not correlate with
the absolute tryptase value. Furthermore, an increase in tryptase did
not correlate with the identification of a culprit drug-specific IgE.
Thus, the finding of elevated mast cell mediators implies that mast
cell/basophil degranulation occurred, although it does not provide
information regarding the underlying mechanism of the reaction (ie,
IgE mediated or not IgE mediated). A number of perioperative drugs,
including paralytics (NMBAs), opioids, and antibiotics (eg, vancomy-
cin), can induce mast cell degranulation independent of
IgE. 
22,459,460,464 
To determine whether serum tryptase level is
increased after POA, a repeat measurement should be performed
when the patient has recovered to provide a baseline tryptase level
Table 27
Knowledge Gaps Related to Anaphylaxis in Mastocytosis
 
What are the mechanisms of mast cell activation in mastocytosis, and why are certain clinical presentations (such as hypotension) more prevalent than others (such as urticaria
and angioedema)?
 
Are TPSAB1 copy number variations truly a modifying factor of severity of mast cell activation symptoms, and if so, what are the mechanisms for it?
 
In determining whether H
aT is a risk factor for anaphylaxis in general (and for which triggers), prospective studies should be designed in which basal tryptase levels are not
known at the time of patient recruitment.
 
Can D816V KIT tyrosine kinase inhibitors be used as a prophylactic strategy in patients who have mastocytosis with recurrent anaphylaxis refractory to or intolerant of mainte-
nance anti-mediator therapies?
 
Is VIT indicated in patients with a history of venom anaphylaxis and negative IgE testing result? If so, to which venoms?
 
Is preemptive venom testing (and VIT if positive) indicated in all patients with mastocytosis?
 
What is the diagnostic sensitivity of high-sensitivity peripheral blood D816V KIT mutation testing as a screening strategy for underlying mastocytosis in different clinical sce-
narios and basal tryptase levels?
 
Are new treatment modalities effective to prevent anaphylaxis?
Abbreviations: HaT, hereditary a-tryptasemia; TPSAB1, tryptase a/b-1; VIT, venom immunotherapy.
ARTICLE IN PRESS
40 D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53

for comparison with the acute level and to determine whether tryp-
tase levels are persistently increased. 
432 
The baseline level should be
determined even if the acute-phase tryptase result is normal. Diag-
nostic evaluation of patients with persistent elevations of tryptase
level is discussed further in the Diagnosis section and the Mast Cell
Disorders section.
Question: Should immediate hypersensitivity skin testing or in
vitro testing be performed with all potential culprit pharmaco-
logic and nonpharmacologic agents, or should this be limited to
the agents that are highly suspected?
Recommendation 43 (CBS): We suggest that immediate hyper-
sensitivity skin testing (percutaneous and intradermal) and/or in
vitro-specific IgE testing be performed, when available, to all poten-
tial pharmacologic and nonpharmacologic culprits used during the
perioperative period. If testing is not possible, we suggest referral
to another center or, if necessary, use of the most efficacious agents
structurally dissimilar from the most likely culprit.
Strength of Recommendation: Conditional
Certainty of Evidence: Very Low
POA is complicated by the fact that multiple agents are usually
administered simultaneously or in close succession. Epidemiologic
evidence supports the assertion that antibiotics and paralytics
(NMBAs) are the more common culprits, 
458,460 
but the limited reli-
ability and validity of testing to these agents make it incumbent to
consider all potential causes.
Depending on history or clinical suspicion is not reliable. When
referring anesthetists at a Danish Anesthesia Allergy Center were
asked to provide their pretesting causes for POA, these were not con-
firmed in 73% of the cases, resulting in a poor correlation between
clinical impression and the results of diagnostic evaluation. 
465 
These
data suggest that testing for all potential culprits is required in the
evaluation of patients with POA. Furthermore, testing for available
alternatives to highly suspected culprit agents may be considered.
Because NMBAs are among the most common causes of POA and to
reduce the need for follow-up testing, the tests should include the
potential culprit NMBA and any alternative NMBA agents available at
that health care facility. Although of limited reliability, the negative
predictive value of the skin tests may assist in the choice of NBMA in
affected patients.
Published resources provide empirical, nonirritating concentra-
tions for hypersensitivity skin testing of potential culprit pharmaco-
logic causes of POA, as found in Table 28.
458,466−470 
The positive and
negative LRs of such testing have not been determined. A positive
skin test result implies greater risk for IgE-mediated reaction with re-
exposure, although this has not been established, and non-IgE mech-
anisms can cause positive skin test responses. Immediate hypersensi-
tivity skin testing to direct mast cell activators, such as opioids or
vancomycin, may be unreliable due to high rates of false-positive
results. Avoidance of drugs with a positive skin test result would
likely be in a patient’s best health care interest, if equally efficacious,
structurally unrelated alternatives are available. Data reveal that
administration of agents with negative test results can proceed safely,
suggesting that testing may be helpful in drug selection for subse-
quent anesthesia (Table 29). 
471−473 
Just as we do with many other
allergens to which skin testing result is negative (eg, latex, lidocaine,
chlorhexidine, povidone-iodine), as the sensitivity (or negative likeli-
hood ratio) is not well established, we may carry out provocative
challenges to definitively rule out IgE-mediated (allergic/anaphylac-
tic) potential. For some agents (eg, NMBAs, midazolam, propofol), it
would be appropriate for an anesthesiologist to administer them in a
graded dose (ie, “test dose”) fashion immediately before the planned
procedure.
Availability of drugs for testing is limited by the controlled nature
of many agents used in anesthesia and distribution exclusively by
inpatient pharmacies. Albeit very small amounts of the drugs are
needed for testing, the acquisition of samples is often unobtainable
due to geographic, logistic, and legal barriers. These issues are gener-
ally less of a problem in some integrated health care systems but can
be very limiting in the more common scenarios of outpatient allergy/
immunology clinics not affiliated with or separated from large medi-
cal centers. On the basis of availability and feasibility, a 3-tier recom-
mendation may be considered:
1) Testing is suggested.
2) If testing is not possible, referral to another center is suggested.
3) If referral is not possible or time constrained, avoid the most
likely culprits and use the most efficacious structurally dissimilar
agents.
Question: Should immediate hypersensitivity skin and/or in
vitro testing of suspected culprit (and alternative) agents be
Table 28
Recommended Concentrations for Skin Tests: Skin Prick Tests and Intradermal
Tests 
458,466−470
Item for testing SPT concentration IDT concentration
NMBAs
Atracurium 
466 
1 mg/mL 0.01 mg/mL
Cisatracurium 
467 
2 mg/mL 0.02 mg/mL
Mivacurium 
468 
0.2-1.0 mg/mL 0.002-0.01 mg/mL
Pancuronium 
468 
2-20 mg/mL 0.2-2 mg/mL
Rocuronium 
467 
10 mg/mL 0.05 mg/mL
Vecuronium 
467 
1 mg/mL 0.01 mg/mL
Succinylcholine 
467
(Suxamethonium)
20 mg/mL 0.8 mg/mL
Hypnotics
466
Etomidate 2 mg/mL 0.2 mg/mL
Ketamine 10 mg/mL 1 mg/mL
Propofol 10 mg/mL 1 mg/mL
Thiopental 25 mg/mL 2.5 mg/mL
Midazolam 5 mg/mL 0.05 mg/mL
Opioids 
a,466
Alfentanil 0.5 mg/mL 0.05 mg/mL
Fentanyl 0.05 mg/mL 0.005 mg/mL
Remifentanil 0.05 mg/mL 0.005 mg/mL
Sufentanil 0.05 mg/mL 0.0005 mg/mL
Morphine 1 mg/mL 0.01 mg/mL
Sugammadex
467 
100 mg/mL 50 mg/mL
b-lactams
Pen G (10,000 U/mL) 
458 
Undiluted Undiluted
Benzylpenicilloyl Polylysine
(Prepen)
458
Undiluted Undiluted
Ampicillin 
458 
20 mg/mL 20 mg/mL
Cefazolin 
469,470 
20 mg/mL, 33 mg/mL 20 mg/mL, 33 mg/mL
Local anesthetics 
466 
Undiluted 1/10
Heparins
466 
Undiluted 1/10
Tranexamic acid 
466 
Undiluted 1/10
Protamine 
466 
Undiluted 1/1000-1/10,000
Aprotinin 
466 
1/5 1/500
Hyaluronidase 
466 
Undiluted 1/10
Antiseptics
466
Povidone iodine 
468 
100 mg/mL Not recommended
Chlorhexidine 
468 
5 mg/mL 0.002 mg/mL
Dyes
Patent blue (25 mg/mL) 
468 
1:10, Undiluted 1:100, 1:10
Isosulfan blue 
468 
1:10 dilution, undiluted 1:1000, 1:100, 1:10
Methylene blue
468 
Undiluted 0.1 mg/mL
Neostigmine 
467 
1 mg/mL 0.2 mg/mL
Methohexital
468 
1 mg/mL 0.1 mg/mL
Abbreviations: IDT, intradermal test; NMBA, neuromuscular blocking agent; Pen G,
penicillin G; PPL, penicilloyl polylysine; SPT, skin prick test.
a
Hypersensitivity skin testing to opioids may be unreliable due to high rates of false-
positive results.
ARTICLE IN PRESS
D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53 41

performed as soon as possible or delayed 4 to 6 weeks after the
POA event?
Recommendation 44 (CBS): We suggest that immediate hyper-
sensitivity testing to suspected culprit (and alternative) agents be
delayed after POA, unless repeat surgery cannot be postponed. If
surgery with general anesthesia is needed sooner, then testing
may be performed when needed.
Strength of Recommendation: Conditional
Certainty of Evidence: Very Low
Delaying immediate hypersensitivity skin testing for 4 to 6 weeks
after anaphylaxis is generally suggested. This is based on case series
and case reports of insect allergy, drug allergy, and POA. 
474,475 
Addi-
tional support for delaying the timing of skin testing after an anaphy-
lactic event based on a “refractory period,” characterized by lack of
immediate cutaneous response to a clinically relevant allergen, was
provided by Goldberg and Confino-Cohen. 
476 
In their study, skin test-
ing was performed within 1 week and 4 to 6 weeks after a Hymenop-
tera systemic sting reaction. In 21% of the cases, the second
evaluation, performed 4 to 6 weeks after, was required to confirm
the diagnosis of Hymenoptera venom anaphylaxis. This phenomenon
may be due to a generalized mast cell hyporesponsiveness (a.k.a.,
“the empty mast cell syndrome”) or may be allergen specific after an
anaphylactic reaction. 
477
Variability in the results of evaluation after POA is supported by a
study that compared the results of skin testing at 2 time points in
patients with POA, 
478 
the first within 4 days of the reaction and the
second, 4 to 8 weeks after POA. Of patients with positive skin test
results implicating a specific drug, 15 had positive results at the first
testing (4 days after POA), 22 at the second testing, 12 at both, 3 only
at the first testing, and 10 only at the second testing. On the basis of
these data, the authors recommended that until an evaluation is com-
plete, agents statistically more likely to have caused the initial reac-
tion, even with a single negative test result, ideally should be avoided
during subsequent anesthesia. Testing to any POA-related agents
other than penicillin has not been clinically validated.
The limited information related to hyporesponsiveness for vari-
able time periods after anaphylaxis coupled with the lack of validated
allergy testing for most agents used in anesthesia provides support
for a recommendation to delay testing, if possible. 
476−478 
However,
there may be a need for repeat anesthesia sooner than 4 to 6 weeks
after the sentinel POA, especially because the procedure resulting in
the POA is frequently aborted. If so, the risk of delay in testing should
be discussed with the patient, anesthesiologist, surgeon, and other
relevant health care providers to support a shared decision-making
process that includes the values and preferences of the patient (and
family). Furthermore, testing for available alternatives to highly sus-
pected culprit agents may be considered. Another consideration
would be to seek an alternative management strategy or use drugs
structurally unrelated to the agents to which the patient was exposed
in the POA event.
Question: Should challenges be performed to potential POA
pharmacologic and nonpharmacologic culprits to which skin and/
or in vitro testing is negative?
Recommendation 45 (CBS): We suggest that challenges be
performed, when feasible, to all potential culprit agents to
which skin and/or in vitro testing is negative, before or in con-
junction with use of these agents for a future surgical proce-
dure.
Strength of Recommendation: Conditional
Certainty of Evidence: Very Low
Just as the reference standard for diagnostic evaluation of anti-
biotic allergy is tolerance of a drug challenge, usually oral, 
479 
sim-
ilarly, the reference standard for evaluation of POA also entails
carrying out challenges to items for which skin and/or in vitro
testing result is negative. Unfortunately, oral challenge with most
perioperative agents is not feasible, potentially increasing the risk
of the challenge. The lack of validated testing for all agents other
than penicillin makes challenges necessary to verify tolerance. In
general, suspected agents with positive testing result are avoided
in favor of alternative agents that are structurally unrelated or
which have negative test results. Cross-reactivity among chemi-
cally related agents, such as paralytics/NMBAs, is suspected but
not documented. Direct mast cell activators, such as drugs bind-
ing to Mas-related G-protein coupled receptor member X2
(MRGPRX2), p-I receptors, or other inherent activating receptors,
also likely share cross-reactivity within the same class of pharma-
ceuticals. These include fluoroquinolone antibiotics, opioids,
NMBAs, polymyxins, icatabant, vancomycin, and iopamidol RCM.
Immediate hypersensitivity skin testing to direct mast cell activa-
tors, such as opioids or vancomycin, may be unreliable due to
high rates of false-positive results. 
480 
However, the role of
MRGPRX2 receptor activation on mast cells as a cause of anaphy-
laxis is not certain. 
481
Graded challenge with suspected agents for which skin testing
result is negative may also be carried out in collaboration with an
anesthesiologist, and if necessary and feasible, in the operating
room in conjunction with a planned procedure. 
482 
For instance,
in cases for which challenge with a NMBA is indicated, this can
be performed in partnership with the anesthesiologist involved
with managing the return to the operating room. This can be
accomplished through administration of a 10% “test dose” before
the procedure; if tolerated without untoward reaction after a
period of observation, full dosing can then be administered as
indicated.
Question: Should patients with POA be advised to avoid repeat
anesthesia?
Recommendation 46 (CBS): We suggest that repeat anesthesia
may proceed in the context of shared decision-making and as
directed by history and results of diagnostic evaluation.
Strength of Recommendation: Conditional
Certainty of Evidence: Low
Several studies have reported that repeat anesthesia after appro-
priate evaluation of POA can be performed successfully with a very
low rate of recurrence of POA. 
471−473 
Fisher et al
471 
reported that of
Table 29
Rate of Recurrence of POA
Citation Cases of (suspected) POA Contactable and confirmed POA cases Cases of subsequent anesthesia Procedures performed without POA Recurrent POA
Fisher et al, 
471 
2011 606 246 183 183 0
Guyer et al, 
472 
2015 73 73 47 45 2
Miller et al, 
473 
2018 174 70 70 67 3
Total 853 389 300 295 5 (1.7%)
Abbreviation: POA, perioperative anaphylaxis.
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42 D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53

606 patients who had POA, 183 of 246 (74%) who were contactable
underwent anesthesia subsequently without remarkable untoward
reaction. In a study by Guyer et al 
472 
of 73 with POA, 47 (64%) had
subsequent procedures with anesthesia; 45 tolerated these proce-
dures without complication, the 2 who developed recurrent hyper-
sensitivity reactions were found to have mast cell disorders. Miller et
al 
473 
investigated 70 of 174 cases who underwent repeat anesthesia;
3 whom had recurrence of POA: 1 who was found to have a mast cell
disorder and 2 who had incomplete referral information that led to
offending drugs being omitted from diagnostic testing. This report
emphasizes the importance of detailed information related to the
timing of drug dosing and onset of POA. As found in Table 29, com-
bining these 3 reports leads to a rate of recrudescence of POA with
subsequent anesthesia of 1.7%. 
471−473 
These data support the conten-
tion that most patients are able to undergo repeat anesthesia using a
combination of skin and/or in vitro testing results, avoidance of most
likely culprits, or alternative anesthesia strategies. 
458 
However, the
data cannot rule out the alternative possibility that most POA reac-
tions are not reproducible, as has been found for messenger RNA
COVID-19 vaccines. 
483
Question: Should repeat anesthesia after POA be performed
with equally efficacious, structurally unrelated alternatives rather
than the suspected culprit agents with negative skin and/or in
vitro test results when challenge is not feasible?
Recommendation 47 (CBS): We suggest that avoidance of cul-
prit pharmacologic and nonpharmacologic agents associated
with POA may be considered, regardless of test results if challenge
is not feasible and if equally efficacious, structurally unrelated
alternatives are available.
Strength of Recommendation: Conditional
Certainty of Evidence: Low
When testing result for all potential culprits is negative, challenge
is recommended but is not always feasible, and decisions must be
made about the use of the potential culprits or unrelated alternative
drugs. Immediate hypersensitivity skin testing to penicillin is vali-
dated; if testing result is positive to the beta-lactam only, and chal-
lenge for the other potential culprits is not feasible, it is acceptable to
use all perioperative drugs except for the beta-lactam. However, the
lack of validated testing for virtually all agents except for penicillin
limits the predictive value of the testing. For patient safety, if chal-
lenges are not possible or feasible, alternative agents are preferable,
if available and equally efficacious. Although alternative forms of
anesthesia, such as spinal or regional anesthesia, have been consid-
ered and suggested, patients still may potentially require conversion
to general anesthesia and intubation. As a result, alternative
management strategies for the underlying disease process should be
considered and reviewed by the anesthesiologist, surgeon, allergist/
immunologist, and patient (and family). Perioperative latex avoid-
ance should be considered if latex is suspected as the culprit agent
and diagnostic evaluation including provocative latex challenges 
484
has not been performed. Latex mitigation or avoidance strategies are
generally available in facilities performing general anesthesia.
Question: If results of all immediate hypersensitivity skin testing
(percutaneous and intradermal) and/or in vitro-specific IgE testing
(and challenge when possible) are negative to suspected POA culprit
agents, should pretreatment with H 
1 
antihistamine and corticoste-
roid, with or without H 
2 
antihistamine and anti-leukotriene, be
administered before subsequent anesthesia?
Recommendation 48 (CBS): We offer no recommendation for
or against the use of pretreatment before return to the operating
room in patients with negative cutaneous (percutaneous and
intradermal) and/or in vitro-specific IgE testing (and challenge
when possible) result to all suspected POA culprit agents.
Strength of Recommendation: None
Certainty of Evidence: Very Low
For a patient with POA and negative immediate hypersensitivity
testing result followed by negative provocative challenge result, the
recommendation as to whether to recommend pretreatment with H 
1
antihistamine and corticosteroid, with/without H 
2 
antihistamine and
anti-leukotriene, before returning to the operating room fulfills equi-
poise criteria. 
485 
The equipoise between pretreatment and no pre-
treatment implies not only balance but also uncertainty. On the basis
of the core principle of equipoise, 
485 
we must acknowledge that we
do not know what is best for patient care outcomes and recommend
this decision be based on an individualized and careful consideration
of the potential for benefit compared with the potential for harm,
and allow the patient (and family) to participate in the medical deci-
sion-making process by expressing their values and preferences.
The value of pretreatment is based on indirect evidence, such as
prevention of non−IgE-mediated anaphylaxis with re-exposure to
high-osmolar radioiodinated urographic contrast in prior reactors
and prophylaxis of IgE-mediated anaphylaxis in association with
rush immunotherapy. 
486,487 
There is no direct evidence that premed-
ication prevents anaphylaxis to the various factors that cause most
cases of POA. There are potential harms of pretreatment that should
also be considered. 
3 
The panel viewed both premedication and no
premedication as reasonable paths and recommended a shared deci-
sion-making discussion between the patient, allergist/immunologist,
anesthesiologist, and surgeon.
Knowledge gaps related to POA are listed in Table 30.
Table 30
Knowledge Gaps in Perioperative Anaphylaxis
Knowledge gap
 
Positive and negative likelihood ratios for skin testing to pharmacologic and nonpharmacologic agents implicated as causes of perioperative anaphylaxis have not been deter-
mined by challenge with culprit agents.
 
Necessity of avoidance of potentially “cross-reacting agents.” Can alternatives in the same chemical class be substituted with or without specific testing?
 
Develop in vitro-specific IgE and basophil activation tests and other methodologies to improve diagnostics and biomarkers of perioperative anaphylaxis.
 
Improving access to culprit agents so that all allergy/immunology providers can perform a comprehensive evaluation.
 
Optimal timing of evaluation. Additional evidence to support the value of testing in closer proximity of the event would be useful.
 
If the assessment of perioperative anaphylaxis is negative or not possible, it would be useful to know if any pretreatments reduce risk of POA.
 
Methods for determining if non-IgE mechanisms (eg, MRGPRX2) are responsible for POA and strategies for future anesthesia if non-IgE mechanisms suspected. If anaphylaxis
occurs through MRGPRX2 receptors, should all MRGPRX2 activators be avoided after POA with suspected MRGPRX2 mechanism? Does pretreatment reduce severity of
MRGPRX2-mediated anaphylaxis?
Abbreviations: MRGPRX2, Mas-related G-protein coupled receptor member X2; POA, perioperative anaphylaxis.
ARTICLE IN PRESS
D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53 43

Acknowledgments
The Anaphylaxis Workgroup and the Joint Task Force on Practice
Parameters acknowledge Jerrold H. Levy, MD, for expert review and
revision of the section on Perioperative Anaphylaxis; Rashi Ram-
chandi, BHSc, for assistance with initial preparation of the section on
Beta-Blockers and ACE Inhibitors; Adil Adatia, MD, and Nishi Parikh,
BSc, for assistance with initial preparation of the section on Epineph-
rine Autoinjectors; and Erin P. Scott, PhD, for providing administra-
tive oversight and extensive editing and coordination throughout the
development, manuscript preparation, and final editing process.
Disclosures
The JTFPP members and workgroup members’ conflict of interest
disclosure forms can be found at www.allergyparameters.org. Dr
Golden: clinical trial support from Genentech, ThermoFisher, Novar-
tis, Pfizer, GlaxoSmithKline, and Regeneron; consulting fees from
Aquestive, Novartis, ThermoFisher, ALK-Abello, Allergy Therapeutics;
and royalties from UpToDate. Dr Wang: clinical trials support (money
to institution) from NIH, Aimmune, DBV Technologies, Regeneron,
and Siolta; consulting fees from ALK-Abello, Jubilant HollisterStier;
and royalties from UpToDate. Dr Waserman: consulting fees from
GlaxoSmithKline, Novartis, CSL Behring, Pfizer Canada, Sanofi Canada,
AstraZeneca, Takeda, ALK-Abello, Teva, Medexus, MiravoHealth,
Mylan, Bausch Lomb, AbbVie, Avir Pharma, and Leo Pharma; research
funding from Pfizer Canada, ALK-Abello, Aimmune; and president of
Canadian Allergy, Asthma and Immunology Foundation. Dr Akin:
consulting fees from Blueprint Medicine, Cogent, and Novartis;
research support from Blueprint Medicines and Cogent; and royalties
from UpToDate. Dr Campbell: consulting fees from Bryn and royalties
from UpToDate. Dr Ellis: advisory boards for ALK-Abello, AstraZeneca,
Aralez, Bausch Health, Leo Pharma, Merck, Novartis, and Pfizer;
speakers’ bureaus for ALK-Abello, AstraZeneca, Miravo, Medexus, and
Mylan; research support (paid to institution) from ALK-Abello, Aralez,
AstraZeneca, Bayer LLC, Medexus, Novartis, and Regeneron; indepen-
dent consultant to Bayer LLC and Regeneron; and royalties from
UpToDate. Dr Greenhawt: consultant for Aquestive; advisory boards
for DBV Technologies, Sanofi/Regeneron, Nutricia, Novartis, Aques-
tive, Allergy Therapeutics, AstraZeneca, ALK-Abello, and Prota; scien-
tific advisory council (unpaid) for the National Peanut Board and
medical advisory board (unpaid) of the International Food Protein
Induced Enterocolitis Syndrome Association; Working Group Mem-
ber of the Brighton Collaboration Criteria Vaccine Anaphylaxis; senior
associate editor for Annals of Allergy, Asthma & Immunology; member
of the Joint Task Force on Allergy Practice Parameters; and speaker
honoraria from ImSci, MedLearningGroup, RMEI Medical Education
and multiple state/local allergy societies. Dr Lang: honoraria, consul-
tant, and/or clinical research support from AstraZeneca, Genentech,
Novartis, and Sanofi-Regeneron; Guest Associate Editor of JACI:In
Practice; and editorial board of DynaMed. Dr Ledford: contributor to
UpToDate for Perioperative Anaphylaxis; contributing editor for Ask
the Expert (AAAAI); research support from AstraZeneca and Novartis
(paid to institution); consultant for AstraZeneca; speaker bureau/
honoraria from AstraZeneca, Genentech, GlaxoSmithKline, and
Sanofi/Regeneron; and legal opinion indoor fungal exposure, drug
allergy, anaphylaxis. Dr Lieberman: contracted research (paid to
institution) for Aimmune, DBV, Regeneron, and Novartis; adjudica-
tion/DSMB for AbbVie and Siolta; consultant/advisor for Aquestive,
ALK-Abello, Novartis, and DBV. Dr Oppenheimer: Executive Editor of
Annals of Allergy, Asthma & Immunology; reviewer for UpToDate;
adjudication and data safety monitoring board for AstraZeneca, Glax-
oSmithKline, and Sanofi; consultant for GlaxoSmithKline, Aquestive,
and Aimmune; NIH grant for the IDEA study. Dr Shaker: editorial
board of The Journal of Allergy and Clinical Immunology: In Practice;
associate editor of Annals of Allergy, Asthma & Immunology; member
of the Joint Task Force on Practice Parameters; and research support
from DBV. Dr Wallace: consulting fees from AbbVie, Bryn, Sanofi, and
Kaleo. Dr Abrams: employee of Public Health Agency of Canada
(PHAC); views expressed are my own and not those of PHAC. Dr
Bernstein: principal investigator, consultant, and speaker for Novar-
tis, Genentech, AstraZeneca, Sanofi Regeneron, Takeda/Shire, CSL
Behring, Pharming, BioCryst, and Merck; consultant for Kalvista,
Ionis, Celldex, Allakos, Amgen, Biomarin, and Blueprint Medicine;
principal investigator and speaker for GlaxoSmithKline; speaker for
Optinose; consultant for Ono, Astria, Incyte, Cycle, and Escient; and
royalties from UpToDate, British Medical Journal, Taylor & Francis,
and Elsevier. Dr Stukus: consultant for ARS Pharmaceuticals, Before
Brands, Novartis, and ParentMD; research support from DBV Tech-
nologies; social media editor for the AAAAI; member, board of
regents for the ACAAI; and Associate Editor, Annals of Allergy, Asthma
& Immunology. Heather Cruickshank: grant support from AllerGen
NCE and medical writer for Healthline Media. The remaining authors
have no conflicts of interests to report.
Funding
The authors have no funding sources to report.
Resolving Conflicts of Interest
The 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 may have
interests that could create a potential conflict of interest (COI) 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 COI and attempt to prevent
them from influencing the final document in a negative way. The dis-
closure and management of potential conflicts for all participants
were conducted in accordance with JTFPP policies. To preserve the
greatest transparency regarding potential COI, all members of the
JTFPP and the practice parameters workgroups complete a standard
potential COI disclosure form before the development of each docu-
ment.
During the review process, there are additional measures to avoid
bias. At the workgroup level, all the sections are reviewed by all
workgroup members to ensure that content is appropriate and with-
out 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 removed at
that level. The final document and all recommendations are reviewed
and approved by the workgroup and JTFPP. Any member with a per-
ceived COI related to a specific recommendation was recused from
voting on that recommendation. In a final stage of review, the prac-
tice parameter is sent to invited expert reviewers, selected by the
AAAAI and the American College of Allergy, Asthma, and Immunology
(ACAAI). The document is also posted on the AAAAI and ACAAI web-
sites for general membership and the public-at-large to review and
offer comment. Reviewers are also asked to 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 the Anaphylaxis 2023: A Practice Parameter Update. The
ARTICLE IN PRESS
44 D.B.K. Golden et al. / Ann Allergy Asthma Immunol 00 (2023) 1−53

document is current at the time of publication. The medical environ-
ment 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 the JTFPP, is
authorized to provide an official AAAAI or ACAAI interpretation of
these practice parameters. Any request for information or interpreta-
tion 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. The JTFPP understands that the
cost of diagnostic tests and therapeutic agents is an important con-
cern that may appropriately influence the evaluation and treatment
chosen for a given patient. The JTFPP recognizes that the emphasis of
our primary recommendations regarding a medication may vary, for
example, depending on third-party payer issues and product patent
expiration dates. However, because a given test or intervention’s cost
is so widely variable, and there is a paucity of pharmacoeconomic
data, the JTFPP is not always able to consider cost when formulating
practice parameter recommendations. In extraordinary circumstan-
ces, when the cost benefit of an intervention is prohibitive as sup-
ported by pharmacoeconomic data, commentary may be provided.
Contributors
The JTFPP has made a concerted effort to acknowledge all contrib-
utors to this parameter. If any contributors have been excluded inad-
vertently, the JTFPP will ensure that appropriate recognition of such
contributions is made subsequently.
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