Anaphylaxis

Ann Allergy Asthma Immunol 132 (2024) 124−176
Contents lists available at ScienceDirect
Practice Parameters
Anaphylaxis: A 2023 practice parameter update
David B.K. Golden, MDCM*; Julie Wang, MDy; Susan Waserman, MDz; Cem Akin, MDx;
Ronna L. Campbell, MD, PhDǁ; Anne K. Ellis, MD, MSc{; Matthew Greenhawt, MD, MBA, MSc#;
David M. Lang, MD**; Dennis K. Ledford, MDyy,zz; Jay Lieberman, MDxx;
John Oppenheimer, MDǁǁ; Marcus S. Shaker, MD, MSc{{,##; Dana V. Wallace, MD***;
Elissa M. Abrams, MD, MPHyyy; Jonathan A. Bernstein, MDzzz,xxx; Derek K. Chu, MD, PhDǁǁǁ;
Caroline C. Horner, MD, MSCI{{{; Matthew A. Rank, MD###; David R. Stukus, MD****; Collabo-
rators : Alyssa G. Burrows, BHSc, MSc{; Heather Cruickshank, BAz; Workgroup Contributors:
David B.K. Golden, MDCM*; Julie Wang, MDy; Cem Akin, MDx; Ronna L. Campbell, MD, PhDǁ;
Anne K. Ellis, MD, MSc{; Matthew Greenhawt, MD, MBA, MSc#; David M. Lang, MD**;
Dennis K. Ledford, MDyy,zz; Jay Lieberman, MDxx; John Oppenheimer, MDǁǁ;
Marcus S. Shaker, MD, MSc{{,##; Dana V. Wallace, MD***; Susan Waserman, MDz; Joint Task
Force on Practice Parameters Reviewers : Elissa M. Abrams, MD, MPHyyy;
Jonathan A. Bernstein, MDzzz,xxx; Derek K. Chu, MD, PhDǁǁǁ; Anne K. Ellis, MD{;
David B.K. Golden, MDCM*; Matthew Greenhawt, MD, MBA, MSc#;
Caroline C. Horner, MD, MSCI{{{; Dennis K. Ledford, MDyy,zz; Jay Lieberman, MDxx;
Matthew A. Rank, MD###; Marcus S. Shaker, MD, MSc{{,##; David R. Stukus, MD****;
Julie Wang, MDy
* 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 A B S T R A C T
Article history: This practice parameter update focuses on 7 areas in which there are new evidence and new recommendations.
Received for publication August 17, 2023. Diagnostic criteria for anaphylaxis have been revised, and patterns of anaphylaxis are defined. Measurement of
Received in revised form September 29, 2023. serum tryptase is important for diagnosis of anaphylaxis and to identify underlying mast cell disorders. In infants
Accepted for publication September 29, 2023.
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.
D.B.K. Golden et al. / Ann Allergy Asthma Immunol 132 (2024) 124−176 125
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 when and how to administer the EAI and whether and when to call
911 (emergency medical services [EMS]). Health care professionals
This practice parameter is not a comprehensive review of anaphy-
should consider a patient’s risk factors for severe anaphylaxis, their
laxis but focuses on 7 areas in which new evidence has emerged and
values and preferences, and the burden of both anaphylaxis and EAI
in which recommendations may now be different from previous
prescription when deciding whether to prescribe EAIs and the num-
practice parameters.
ber of EAIs to prescribe. If epinephrine is used promptly, immediate
Diagnosis activation of the EMS may not be required if the patient experiences
prompt, complete, and durable response to treatment. EMS should be
Accurate classification, criteria, and definitions for the diagnosis of
activated if anaphylaxis is severe, fails to resolve promptly, fails to
anaphylaxis are critical for proper treatment and consistency in
resolve completely or nearly completely, or returns or worsens after
research studies that would enable meaningful evidence analysis and
the first dose of epinephrine.
stronger recommendations. Revised criteria by the World Allergy
Organization (WAO), Brighton, and Delphi Consensus groups aim to
Beta-Blockers and Angiotensin-Converting Enzyme Inhibitors
create more universally accepted definitions and criteria for anaphy-
lactic reactions. Biphasic anaphylaxis is associated with greater sever- Both beta-blockers (BBs) and angiotensin-converting enzyme
ity of an initial reaction, persistence of the reaction, and use of more inhibitors (ACEIs) have been previously considered to be contraindi-
than one dose of epinephrine. Baseline serum tryptase (bST) level cated in patients at high risk for anaphylaxis because of increased
should be measured in patients presenting with a history of recur- risk of severe anaphylaxis. Larger and more focused studies have pro-
rent, idiopathic, or severe anaphylaxis, Hymenoptera venom anaphy- vided new insights into the relative risk of these medications and
laxis, or with suspected mastocytosis. Evaluation for hereditary have improved guidance on whether it is necessary to change or stop
a-tryptasemia (HaT) and clonal mast cell disease should be consid- these medicines in some patients. For most medical indications, the
ered if bST level is more than 8 ng/mL. Alpha-gal allergy can be a risk of stopping or changing the medication may exceed the risk of
cause of unexplained anaphylaxis. more severe anaphylaxis if the medication is continued, especially in
patients with insect sting anaphylaxis. Venom immunotherapy (VIT)
Infants and Toddlers may be considered for patients receiving BBs/ACEIs, with shared deci-
sion-making regarding the balance of benefits and harms. Patients
The diagnosis and treatment of anaphylaxis may be even more receiving maintenance-dose allergen immunotherapy (AIT) have
challenging in infants. As our understanding improves, so can our minimal increased absolute risk of severe anaphylactic reaction
recommendations for this important age group. In infants and tod- when receiving BBs/ACEIs and may consider continuing AIT and med-
dlers, patient age is not correlated with reaction severity, and ana- ications based on shared decision-making.
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. Mast Cell Disorders
Many mast cell disorders are associated with an inherently
Community Settings greater risk of anaphylaxis. Advances in recent years are beginning to
enable better recognition of the related phenotypes, application of
Anaphylaxis is most difficult to recognize and treat outside of new diagnostic methods, and targeting treatment to prevent anaphy-
health care facilities. Reactions may occur at home, school, work, din- laxis. The bST level should be measured in patients with severe insect
ing out, traveling, or in many other locations, and situations can be sting anaphylaxis, particularly among those who had hypotension
associated with different patient characteristics, causes, or available and/or absence of urticaria, in all cases of recurrent unexplained ana-
options for treatment or prevention. Patients at high risk for anaphy- phylaxis, and in patients with suspected mastocytosis. Evaluation for
laxis, and their caregivers, should be counseled regarding the carry- mastocytosis, including a bone marrow biopsy, should be considered
ing and using of epinephrine autoinjectors (EAIs) and the recognition for adult patients with severe insect sting anaphylaxis or recurrent
and avoidance of exposures. Childcare centers and schools should idiopathic anaphylaxis (IA), particularly those with a predictive Red
implement staff training and stock undesignated EAI that can be used Espanola MAstocitosis (REMA) score. New treatment modalities are
to treat any individual who experiences anaphylaxis. under investigation to prevent anaphylaxis in high-risk patients.
Epinephrine Autoinjectors Perioperative Anaphylaxis

The cardinal treatment of anaphylaxis is prompt epinephrine Continued study of anaphylaxis during and after surgical anesthe-
injection. The optimal prescribing and use of EAI devices require spe- sia has improved the recognition of the most common culprits and
cific counseling and training of patients and caregivers, including the approach to counseling for future surgery and anesthesia through
126 D.B.K. Golden et al. / Ann Allergy Asthma Immunol 132 (2024) 124−176
testing, challenge, or strategic avoidance, when necessary, based on serum total tryptase level at least 20% plus 2 ng/mL above the
availability of the materials and expertise. After perioperative ana- patient’s bST level may provide evidence of systemic mast cell activa-
phylaxis (POA), repeat anesthesia may proceed in the context of tion.
shared decision-making and based on the history and results of diag- For patients with a history of recurrent, idiopathic, or severe ana-
nostic evaluation. Immediate hypersensitivity skin testing (percuta- phylaxis, or with suspected mastocytosis, obtaining a bST level is
neous and intradermal) and/or in vitro-specific IgE testing should be advisable as elevated levels are found in patients with HaT and clonal
performed, if available, to all potential pharmacologic and nonphar- mast cell disease and are associated with more severe anaphylaxis.
macologic culprits used during the perioperative period. If testing is Adult patients with severe insect sting anaphylaxis or recurrent IA
not possible, we suggest referral to another center or if necessary, may require evaluation for mastocytosis, including a bone marrow
use of the most efficacious agents structurally dissimilar from the biopsy, especially if they have a predictive REMA score. Alpha-gal
most likely culprit. Challenges should be performed to all culprit allergy should be considered in patients who have recurrent IA and
agents to which skin and/or in vitro testing is negative, but if this is an appropriate exposure history.
not feasible, avoidance of culprit pharmacologic and nonpharmaco-
Infant Anaphylaxis
logic agents associated with POA may be considered if equally effica-
cious, structurally unrelated alternatives are available. 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-
Executive Summary
laxis diagnostic criteria. Therefore, the current NIAID/FAAN or WAO
Anaphylaxis is characterized as a life-threatening systemic allergic anaphylaxis criteria should be used to establish the diagnosis of ana-
reaction that can include a range of clinical signs and symptoms. phylaxis in infants/toddlers. These young children are unable to com-
Most definitions of anaphylaxis include vague words such as “gener- municate their symptoms to their caregivers, and many signs and
alized” and/or “systemic” and/or “multi-organ” but there are instan- symptoms of anaphylaxis can be indistinguishable from normal
ces where a single system is primarily affected. Although anaphylaxis infant behaviors or can be attributable to other conditions, so recog-
is not an infrequent occurrence, with a lifetime prevalence estimated nizing these symptoms as part of anaphylaxis requires astute clinical
at 1.6% to 5.1%, advancing the understanding of anaphylaxis has been skills. In this young age group, patient age is not correlated with reac-
hindered by the fact that several anaphylaxis criteria and grading sys- tion severity. When foods are introduced to young children, anaphy-
tems exist, which can result in differing clinical assessments and ren- laxis is not frequently reported as the first reaction and is far less
ders comparisons between research studies difficult. Consistency in common than mild-to-moderate, primarily cutaneous, reactions.
diagnosis and classification of anaphylaxis is critical for proper treat- Clinicians may prescribe either the 0.1 mg or the 0.15 mg EAI dose
ment and to facilitate research efforts. The 2006 National Institute of for infants/toddlers weighing less than 15 kg. Additional research is
Allergy and Infectious Diseases (NIAID) and Food Allergy and Ana- needed to address knowledge gaps in the epidemiology, classifica-
phylaxis Network (FAAN) defined anaphylaxis as one of several clini- tion, diagnosis, and management of anaphylaxis in infants and tod-
cal diagnostic scenarios. This set of criteria has been widely adopted dlers.
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-
Anaphylaxis in the Community Setting
ognizing that anaphylaxis courses can be variable, a Delphi
Consensus group defined parameters for biphasic, persistent, and Anaphylaxis is not always easy to recognize, and anaphylaxis
refractory anaphylaxis. Validation of the WAO criteria and Delphi occurring outside the medical setting can be particularly challenging
Consensus group definitions will be helpful in determining their clin- to manage. Most cases occur at home, but anaphylaxis has also been
ical utility. reported in community settings, including school, work, while dining
Having reliable predictors of anaphylaxis severity can help opti- out, and during travel. Given the unpredictability of anaphylaxis, at-
mize treatment, but severity of reactions is influenced by many dif- risk patients and their caregivers should be counseled on allergen
ferent factors related to the patient and the allergen. Biphasic avoidance strategies, identification of signs and symptoms of allergic
anaphylaxis is associated with greater severity of the initial reaction reactions, and advised to be prepared with EAIs at all times. Imple-
and requirement of more than one dose of epinephrine to treat the mentation of staff training and stocking undesignated EAIs at child-
initial symptoms. Although determining the diagnosis and severity care centers and schools may help improve anaphylaxis management
grading are not necessary for initiating treatment with epinephrine in these locations. Whereas current research does not support consis-
during an acute allergic reaction, establishing the anaphylaxis diag- tent benefits of site-wide food-specific prohibition in the manage-
nosis and severity using available criteria and grading systems is ment of food allergies in childcare centers and schools, there may be
important to communicate the clinical history and to counsel on specific circumstances in which implementation of allergen-
future management. Conversely, the use of epinephrine to treat an restricted zones (eg, milk-free table) may be appropriate, such as
allergic reaction does not confer a diagnosis of anaphylaxis. when there are students who lack the capacity to self-manage.
Diagnosing anaphylaxis relies on a thorough clinical history that Counseling patients on strategies to minimize allergen exposure
includes patient characteristics (eg, age, sex, medical and atopic his- and preparedness to manage allergic reactions while dining out, dur-
tory, concurrent medications), detailed description of the reaction ing travel, or activities in any community setting is important
(possible triggers, symptom pattern, timing of onset duration of because anaphylaxis can occur anywhere. Given that the risk of a
symptoms), concomitant factors (eg, exercise, viral infection, medica- severe food allergy reaction is primarily associated with ingestion of
tions, menstrual status, stress, food, alcohol), and response to treat- a food allergen rather than skin contact or inhalation, steps to pre-
ment. The diagnosis can be supported by an elevated acute serum vent unintentional allergen ingestion should be the main priority for
tryptase level. Although a tryptase level above the laboratory-defined these patients. Counseling should include discussions on labeling reg-
normal value (eg, >11.4 ng/mL in many laboratories) is informative, ulations (both United States and those from other countries relevant
many cases of anaphylaxis may not be associated with a tryptase ele- to the patient’s travel plans) that require disclosure of major aller-
vation above that level. Particularly in these situations, an acute gens on labels of prepackaged foods, while also noting that
restaurants are not required to declare ingredients or provide allergy use for anaphylaxis may improve clinical outcomes by decreasing
warnings for non-prepackaged foods. risk of biphasic reactions and the need for hospitalization. Therefore,
Management of anaphylaxis risk is a “shared responsibility” in the epinephrine should be administered at the first sign or symptom of
restaurant setting (ie, both the allergic diner and food service staff suspected anaphylaxis. However, there is no evidence that preemp-
have roles to play in keeping the diner safe), so clear communication tive use of epinephrine in an asymptomatic patient will prevent ana-
is essential. There is a lack of high-quality data on the effects of spe- phylaxis. Serious adverse reactions to intramuscular epinephrine are
cific strategies for safe dining, but patients may consider reviewing rare and should not pose a barrier to the prescription or early admin-
menu options to make informed choices, disclosing the allergy to a istration of EAIs when indicated. Immediate activation of EMS after
knowledgeable and responsible food service staff member before EAI use may not be required if the patient experiences prompt, com-
ordering their meal, informing dining companions of the food allergy, plete, and durable response to treatment and has access to additional
and avoiding situations where there may be a higher risk of cross- EAIs. Situations that would warrant EMS activation include severe
contact, such as buffets. anaphylaxis, symptoms that do not resolve promptly, completely, or
Clinicians should counsel patients on standard management prac- nearly completely, or symptoms that return or worsen.
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 Beta-Blockers and Angiotensin-Converting Enzyme Inhibitors
and a syringe in a cramped air cabin midflight during an acute reac-
Both BBs and ACEIs have been previously considered to be contra-
tion is challenging and could lead to delayed treatment. Importantly,
indicated in patients at high risk for anaphylaxis because their physi-
stock epinephrine is not available in airports or during transit
ological effects could theoretically increase the severity of
between travel destinations, so it is imperative that patients are pre-
anaphylaxis and affect the response to treatment. The BBs may
pared with their own EAIs at all times.
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-
Epinephrine Autoinjectors nin, promote vasodilation, and may have direct effects on mast cells.
With more recent data and availability of more cardioselective
Epinephrine is the first-line treatment for anaphylaxis, and EAIs
beta-blocking agents, shared decision-making is needed when
allow patients to have this emergency medication available outside the
assessing the risks of potential anaphylaxis while receiving the BBs/
medical setting. A patient’s risk factors for severe anaphylaxis, their
ACEIs, the cardiac risk of stopping the BBs/ACEIs, and alternative
values and preferences, and the burden of both anaphylaxis and EAI
medications or procedures. For patients with insect sting allergy who
prescription are important factors to consider when deciding whether
receive BBs/ACEIs, VIT may be considered as there seems to be little
to prescribe EAIs and how many EAIs to prescribe. There are no vali-
or no increased risk of reaction to VIT associated with these cardio-
dated risk-stratification algorithms in the research literature to guide
vascular medications. Similarly, AIT may be pursued in patients on
EAI prescription, but expert opinion suggests that patients with the fol-
BBs or ACEIs, but shared decision-making (regarding the potential
lowing are at higher likelihood of requiring treatment with their pre-
risk of a more severe reaction) is important when considering this
scribed EAI: history of systemic allergic reaction or anaphylaxis to their
treatment approach. Those on maintenance AIT have minimal
food allergen; IA; frequent allergen exposure through occupation or
increased risk of severe anaphylactic reaction when concurrently on
other activities (for venom, latex, drug allergy); prior systemic allergic
BBs/ACEIs. For planned procedures that carry a risk of anaphylaxis
reaction to AIT or VIT; venom allergy with honey bee as the trigger, ele-
(eg, radiocontrast media [RCM], challenge/desensitization, and infu-
vated bST level, older age, underlying cardiovascular disease (CVD);
sion), if the BBs/ACEIs cannot be safely interrupted, then shared deci-
venom-induced anaphylaxis not treated with VIT; exercise-induced
sion-making is critical to weigh the medical necessity of the
anaphylaxis; and cold-induced urticaria. Prescription of EAIs is advised
procedure against the relative risk of anaphylaxis and the possibility
for omalizumab and sublingual immunotherapy (SLIT) even though
of more severe reaction if the BBs/ACEIs are continued. Patients at
they cause anaphylaxis in less than 1% of all treated patients. Multiple
significant risk for recurrent and unexpected anaphylaxis (eg, severe
EAIs are commercially available, so dosage, needle length, affordability,
food allergy, mastocytosis, or mast cell activation syndrome [MCAS],
access, and patient treatment preferences should be taken into account
or recurrent IA) should receive counseling about the theoretical risk
when prescribing EAIs.
of more severe anaphylaxis and should avoid nonselective BBs or
The current standard practice is to treat anaphylaxis with a dosage
ACEIs, if possible. There is insufficient evidence to distinguish angio-
of epinephrine of 0.01 mg/kg, up to a maximum of 0.3 mg for children
tensin receptor blockers (ARBs) from ACEIs with regard to the poten-
and teenagers and 0.5 mg for adults. EAIs are only available in a limited
tial risk of more severe anaphylaxis.
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
Mastocytosis
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 Mastocytosis is a clonal disorder of mast cell proliferation and
& Immunology [AAAAI], American Academy of Pediatrics [AAP], Cana- is associated with episodic and chronic mast cell activation symp-
dian Society of Allergy and Clinical Immunology [CSACI], and European toms, including anaphylaxis. An estimated 40% to 50% of adults
Academy Allergy and Clinical Immunology [EAACI]) support switching and 10% of children with mastocytosis are at risk for anaphylaxis.
to 0.3 mg at 25 kg to limit underdosing in patients nearing 30 kg. The Risk factors for anaphylaxis associated with mastocytosis have
AAP supports the option to use the 0.1 mg dose (if available) for been identified as male sex, total serum IgE greater than 15 kU/L,
patients weighing 7.5 to 13 kg and the 0.15 mg dose for patients atopic background, and basal tryptase levels less than 42 ng/mL.
weighing 13 to 25 kg. However, the 0.1 mg EAI is not universally avail- Basal tryptase levels greater than 42 ng/mL are associated with
able, and the AAP and Joint Task Force on Practice Parameters (JTFPP) mastocytosis but are reported not to have markedly increased
support the use of 0.15 mg EAIs for young children less than 15 kg. risk for severe anaphylaxis.
Those prescribed EAIs should receive counseling and training on The World Health Organization (WHO) has updated classification
when and how to administer the device and steps to take after and diagnostic criteria for cutaneous and systemic mastocytosis. Key
administration. Available evidence suggests that early epinephrine presenting symptoms of systemic mastocytosis will overlap with
anaphylaxis but also may include the cutaneous symptoms (eg, urti- recommended because a “refractory period” may result in lack of
caria pigmentosa, blisters or bullae in infants, pruritus, urticaria, and skin testing response. Data reveal that graded challenge of agents
flushing), presyncope/syncope, constitutional symptoms (eg, fevers, with negative test results can proceed safely, though this procedure
weight loss, night sweats), bone pain, and prominent gastrointestinal may require coordination with an anesthesiologist, depending on the
symptoms, such as reflux, nausea, vomiting, diarrhea, and colic. On medication tested. If testing and challenge are not feasible, avoidance
physical examination, hepatosplenomegaly and lymphadenopathy of culprit pharmacologic and nonpharmacologic agents associated
may be prominent especially in patients with advanced disease. with POA may be considered if equally efficacious, structurally unre-
Although an elevated bST level (>20 ng/mL) is considered a signifi- lated alternatives are available.
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
Methods and Overview of the Practice Parameter Development
least 15 mast cells in aggregates is the major diagnostic criterion for
Process
diagnosis of systemic mastocytosis. Clinicians ordering a bone mar-
row biopsy should ask for staining for tryptase, CD25 immunohis- The purpose of this practice parameter is to evaluate current evi-
tochemistry and/or flow cytometry, the KIT D816Vmutation using a dence and provide guidance to health care practitioners on the diag-
highly sensitive allele-specific polymerase chain reaction (PCR) nosis and management of anaphylaxis. This updated practice
−based technique, and if there is peripheral eosinophilia, a FIP1L1- parameter focuses on topics selected by the workgroup as described
PDGRA mutational analysis. subsequently. By identifying knowledge gaps in the research litera-
There should be a high index of suspicion for mastocytosis in ture, these guidelines may also help researchers to direct their atten-
patients who have had severe insect sting anaphylaxis, particularly tion to topics on which more studies are needed. This practice
among those who had hypotension or absence of urticaria, and for parameter is meant to update the selected topics and to complement
patients with recurrent unexplained/IA. Recent studies suggest that our previous practice parameters on anaphylaxis but does not
in patients with insect sting anaphylaxis of any severity, bST levels entirely replace or supersede those documents which may be con-
greater than 8 ng/mL indicate increased risk of severe anaphylaxis to sulted for additional background discussion on anaphylaxis and for
stings, and evaluation for an underlying mast cell disorder (including guidance on topics not selected for review in the current update. This
HaT) may be warranted. Treatment with VIT reduces the frequency document is intended to be used by allergy/immunology specialists
and severity of reactions to stings in patients with mastocytosis, but and all health care providers who seek guidance on the evaluation
these patients have higher rates of systemic reactions to VIT injec- and management of patients with anaphylaxis.
tions (15% compared with 5% of patients on VIT who do not have Evidence has evolved since the previous anaphylaxis practice
mastocytosis). Patients with mastocytosis who have discontinued VIT parameters. Although the ideal type of reference would consist of a
(even after a 5-year course) remain at higher risk of relapse; there- randomized, double-blind, placebo-controlled study, the topic of this
fore, these patients should continue VIT indefinitely. practice parameter is represented by very few such studies. Conse-
For patients with mastocytosis and recurrent anaphylaxis despite quently, it was necessary to use observational studies, case series,
optimized prophylactic therapy with H1 and H2 antihistamines, off- basic laboratory reports, and expert review articles to develop a doc-
label treatment with omalizumab can be considered as studies report ument that addresses most of the issues included in this practice
that it provided improved control of symptoms and prevention of parameter. The references cited in this practice parameter represent
anaphylaxis. There is also evidence that mast cell cytoreduction the best quality and most relevant evidence for the discussion and
results in improvement of anaphylaxis in mastocytosis. 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-
Perioperative Anaphylaxis
tions for this document after input from the JTFPP and the Anaphy-
Perioperative anaphylaxis, which has a greater risk of death than laxis workgroup. Members of the JTFPP and Anaphylaxis workgroup
other types of anaphylaxis, occurs at a rate of 15.3 per 100,000 cases. received no compensation for their work related to this practice
Evaluation of POA is complicated by the fact that multiple agents are parameter. The practice parameter development process involved
usually administered simultaneously or in close succession. Studies several stages. A workgroup of experts was appointed by the JTFPP
suggest that antibiotics and paralytics (neuromuscular blocking on behalf of the AAAAI and ACAAI. The workgroup, co-chaired by
agents [NMBAs]) are the more common culprits. Rigorous evidence David Golden, MD, and Julie Wang, MD, developed a list of key clini-
on this topic is lacking because of the limitations resulting from the cal questions and topics to be addressed. The topics and questions
relatively rare occurrence of POA and inability to perform double- were selected to reflect the most significant advances and changes
blind studies because of ethical considerations. Therefore, the in the field that affect clinical practice. At least 3 workgroup mem-
strength of evidence is uniformly low to very low. bers were assigned to review and write each topic. They then per-
After POA, repeat anesthesia may proceed in the context of shared formed literature searches to determine the most up-to-date
decision-making and directed by history and results of diagnostic information for each consensus-based statement (CBS) and discus-
evaluation. Immediate hypersensitivity skin testing (percutaneous sion. Searches of the medical literature were performed using a vari-
and intradermal, if available) and/or in vitro-specific IgE testing ety of terms that were considered relevant for the topics under
should be performed to all potential pharmacologic and nonpharma- review in this practice parameter. Literature searches were per-
cologic culprits used during the perioperative period, including alter- formed on PubMed and in some cases also on MEDLINE, Medscape,
natives for anesthesia at the health care facility. Published resources Google Scholar, and the Cochrane Database of Systematic Reviews.
provide empirical, nonirritating concentrations for hypersensitivity The time frame for most searches was 2015 to 2022, but some topics
skin testing of potential culprit pharmacologic causes of POA. How- required searches for an expanded time frame from 1960 to the
ever, availability of drugs for testing is limited by the controlled present. The searches included only English-language articles. The
nature of many agents, and positive and negative likelihood ratios of draft topics were reviewed by the workgroup co-chairs with subse-
such testing have not been determined. Delaying immediate hyper- quent revision by the authors. Subsequently, all sections were
sensitivity skin testing for 4 to 6 weeks after anaphylaxis is generally reviewed and revised by the entire workgroup through several
rounds of electronic and teleconference reviews. The practice GRADE format, the rigor of the evidence collection and analysis is
parameter was then reviewed in detail by the JTFPP, and revisions, limited. The certainty of evidence for each recommendation is deter-
when needed, were made in conjunction with the workgroup. mined to be high, moderate, low, or very low based on the kind of
External review followed as described previously in the Resolving evidence that has been published (eg, randomized controlled trials,
Conflicts of Interest section. Permission was obtained for all tables observational studies, case series and reports) and factors that rate
and figures for which it was required. down or rate up the certainty of the evidence. The significance and
This practice parameter contains recommendations intended to implications of this rating are described in Table 2. The intended
optimize care of patients and to assist physicians and/or other health implications of these statements are similar to the GRADE format, but
care practitioners and patients to make decisions regarding evalua- the evidence basis is not necessarily as conclusive. When the JTFPP
tion and management of suspected anaphylaxis. This practice param- did not have adequate published evidence with which to make a rec-
eter was not intended to be a document using Grading of ommendation, but nonetheless recognized the need to provide guid-
Recommendations, Assessment, Development and Evaluation ance to the clinician, the CBSs were based on the collective expert
(GRADE) methodology, which was used for our previous focused ana- opinion and experience of the workgroup and JTFPP. Table 3 lists all
phylaxis consensus-based guideline. Because GRADE documents the recommendations.
require a comprehensive literature search, systematic review, and
meta-analysis for each question, it is beyond the scope and resources Main Text
of a traditional practice parameter to attempt to conduct a GRADE
Introduction and Background
analysis for the large number of the questions for which clinicians
would like an answer. In addition, for many questions, there is very Our understanding of anaphylaxis has grown steadily in recent
limited evidence, and the workgroup/JTFPP must rely on expert evi- years, but many important knowledge gaps remain.1 The previous
dence and opinion. Therefore, in this practice parameter, most rec- traditional practice parameter published in 2015 focused on the defi-
ommendations are made as CBSs, which are based on a recent nition of anaphylaxis, prescribing of EAIs, mast cell disorders, and
literature search of PubMed to update or add to the 2015 and 2020 unusual manifestations of anaphylaxis.2 It also provided updates on
Anaphylaxis practice parameter documents. For the non-GRADE the evaluation, management, and prevention of anaphylaxis, and
CBSs, the terminology used is intended to be transparent and consis- anaphylaxis to foods, drugs, biologicals, insect stings, seminal fluid,
tent with descriptions used across JTFPP Traditional and GRADE exercise, subcutaneous immunotherapy (SCIT), and POA.2 As evi-
guidelines. However, the use of this terminology does not imply that dence evolves in these areas and new observations are reported,
we are equating our recommendations to the rigor required in a there develops a need for updated recommendations. This 2023
GRADE guideline. update of the Anaphylaxis Practice Parameter addresses what is new
The strength of recommendation and the certainty of the evidence or changed since 2015. The JTFPP of the AAAAI and ACAAI also pub-
for each CBS were determined by the group, based on their assess- lished a GRADE guideline on anaphylaxis in 2020 with highly focused
ment of the anticipated benefits and harms, certainty (quality) of the questions and recommendations regarding the risk of biphasic ana-
evidence (including, when possible, magnitude of effect, indirectness, phylaxis and the use of antihistamines or corticosteroids to prevent
inconsistency, imprecision, and risk of bias), and contextual factors biphasic anaphylaxis or anaphylaxis owing to chemotherapy infu-
(resource allocation, costs, equity, feasibility, and acceptability). sions, aeroallergen rush immunotherapy, and RCM.3 This 2023
Although the consensus of the workgroup was not always unani- Update is meant to complement the 2020 GRADE guideline, not to
mous, the recommendations reflect the majority opinion, and points replace it or prior practice parameters.
of disagreement are clearly described in the text. The foundation for this practice parameter update is the library of
The strength of recommendation is determined to be either strong knowledge on anaphylaxis that was expertly reviewed in the 2020
or conditional based on published evidence, expert evidence, and GRADE guideline. This included the epidemiology and risk factors,
expert opinion. The significance and implications of this rating are burden of disease for the most common triggers, pathogenesis, treat-
described in Table 1. Although the terminology is modeled after the ment strategies, and paradigms, and other essential background
Table 1
Grading the Strength of Recommendations488
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.

Table 2
Grading the Certainty of Evidence for Each Recommendation489
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 Method Recommendation Strength of Certainty of

number recommendation evidence
Diagnosis of anaphylaxis
1 CBS We recommend obtaining a bST in patients presenting with a history of recurrent, idiopathic, or severe ana- Strong Moderate
phylaxis, particularly those presenting with hypotension.
2 CBS We suggest drawing an acute-phase tryptase level as early as possible during a suspected anaphylactic Conditional Moderate
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.
3 CBS We suggest clinicians consider evaluation for HaT 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 Conditional Moderate
patients with severe insect sting anaphylaxis or recurrent IA, particularly those with a predictive REMA
score.
5 CBS We suggest that clinicians consider alpha-gal allergy as a possible cause of recurrent IA in a patient with Conditional Moderate
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.
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- Conditional Very low
nephrine be used as a surrogate marker to establish a diagnosis of anaphylaxis.
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- Conditional Low
phylaxis in infants/toddlers, because there are no criteria specific to this age group.
9 CBS We suggest clinicians be aware that, in infants and toddlers, patient age does not correlate with reaction Conditional Very low
severity.
10 CBS We suggest clinicians be aware that anaphylaxis is unlikely to be the initial reaction to a food or medication Conditional Low
on first exposure in infants.
11 CBS We suggest clinicians be aware that parents of infants and toddlers may report age-specific symptoms that Conditional Very low
are less often reported by older children and adults.
12 CBS We suggest clinicians prescribe either the 0.1 mg or the 0.15 mg EAI dose for infants/toddlers weighing less Conditional Low
than 15 kg.
Anaphylaxis in community settings
13 CBS We recommend clinicians counsel patients at high risk of anaphylaxis to always carry self-injectable epi- Strong Very low
nephrine and teach patients proper indications and use.
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 Strong Moderate
and not contact or inhalation.
16 GRADE We suggest childcare centers and schools implement staff training for allergy and anaphylaxis manage- Conditional Very low
ment.
17 GRADE We suggest that childcare centers and schools not implement site-wide food-specific prohibition because Conditional Very low
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.
18 GRADE We suggest that childcare centers and schools stock undesignated EAIs that can be used to treat any indi- Conditional Very low
vidual on school grounds who experiences anaphylaxis.
19 CBS We suggest clinicians counsel patients that although US regulations require disclosure of major allergens on Conditional Very low
labels of prepackaged foods, they do not require restaurants to declare ingredients or provide allergy
warnings for non-prepackaged foods.
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- Conditional Very low
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.
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 Conditional Very low
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.
24 CBS We suggest that in jurisdictions where single-packs of EAIs are available, clinicians consider a patient’s risk Conditional Very low
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.
(continued)
Table 3 (Continued)

25 CBS We suggest that clinicians counsel patients and caregivers to give epinephrine at the first sign of suspected Conditional Very low
anaphylaxis.
We suggest that, in general, clinicians counsel patients or caregivers not to give epinephrine preemp-
tively to an asymptomatic patient.
26 CBS We suggest that clinicians counsel patients that immediate activation of EMS may not be required if the Conditional Very low
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.
27 CBS Serious adverse reactions to intramuscular epinephrine are very rare and should not pose a barrier to the Strong Low
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.
28 CBS We suggest that clinicians discuss the potential financial and psychosocial burdens of EAIs with patients Conditional Very low
while engaging in shared decision-making.
29 CBS When deciding which EAI to prescribe, we suggest that clinicians consider dosage, needle length, afford- Conditional Very low
ability, access, and patient treatment preferences.
30 CBS During visits with patients who have been prescribed EAIs, we recommend that clinicians routinely review Strong Low
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.
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 Conditional Low
BB or ACEI medications when the medical necessity of the daily medication outweighs the chance of
increased severity of anaphylaxis to a sting.
32 CBS We suggest that VIT may be prescribed for patients with a history of insect sting anaphylaxis who are Conditional Low
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.
33 CBS We suggest that, in most cases, treatment with BB or ACEI medication need not be changed or discontinued Conditional Moderate
in patients receiving maintenance VIT.
34 CBS We suggest use of initial AIT may be considered in patients who are treated with BB or ACEI medication, Conditional Low
with shared decision-making. It would be preferable to replace the BB or ACEI, if there is a safe and effec-
tive alternative.
35 CBS We suggest that patients receiving maintenance dose AIT have a minimal increased risk of a severe anaphy- Conditional Low
lactic reaction when on BB/ACEI medication and may consider continuing AIT and medications based on
shared decision-making.
36 CBS For planned procedures (eg, RCM, challenge/desensitization, and infusion), if the BB/ACEI medication can- Conditional Very low
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.
37 CBS We suggest that all patients at significant risk for recurrent and unexpected anaphylaxis (eg, those with Conditional Moderate
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.
Mastocytosis and anaphylaxis
38 CBS We recommend clinicians order a bone marrow biopsy with staining for tryptase, CD25 immunohis- Strong Moderate
tochemistry and flow cytometry, and the KIT D816V mutation when there is strong suspicion for systemic
mastocytosis.
39 CBS We recommend clinicians not rely on serum tryptase levels alone for diagnostic assessment of the likeli- Strong Moderate
hood that a patient does or does not have a clonal mast cell disorder.
40 CBS We recommend measurement of bST in: patients with severe insect sting anaphylaxis, particularly those Strong Moderate
who had hypotension and/or absence of urticaria; in all cases of recurrent unexplained anaphylaxis; and
in patients with suspected mastocytosis.
41 CBS We suggest clinicians consider evaluation for mastocytosis, including a bone marrow biopsy, for adult Conditional Moderate
patients with severe insect sting anaphylaxis or recurrent IA, particularly those with a predictive REMA
score.
42 CBS We suggest VIT be continued indefinitely in patients with mastocytosis and insect sting anaphylaxis due to Conditional Low
the increased risk of severe or fatal sting anaphylaxis if VIT is discontinued.
Perioperative anaphylaxis
43 CBS We suggest that immediate hypersensitivity skin testing (percutaneous and intradermal) and/or in vitro- Conditional Very low
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.
44 CBS We suggest that immediate hypersensitivity testing to suspected culprit (and alternative) agents be delayed Conditional Very low
after POA, unless repeat surgery cannot be postponed. If surgery with general anesthesia is needed
sooner, then testing may be performed when needed.
45 CBS We suggest that challenges be performed, when feasible, to all potential culprit agents to which skin and/or Conditional Very low
in vitro testing is negative, before or in conjunction with use of these agents for a future surgical proce-
dure.
46 CBS We suggest that repeat anesthesia may proceed in the context of shared decision-making and as directed by Conditional Low
history and results of diagnostic evaluation.
(continued)
Table 3 (Continued)

47 CBS We suggest that avoidance of culprit pharmacologic and nonpharmacologic agents associated with POA Conditional Low
may be considered, regardless of test results if challenge is not feasible and if equally efficacious, structur-
ally unrelated alternatives are available.
48 CBS We offer no recommendation for or against the use of pretreatment before return to the operating room in None Very low
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.
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; HaT, 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.
knowledge on anaphylaxis. In this document, we will update only

those areas in which new developments are relevant to the topics Box 1 Key points of consensus in the definition, criteria, and
under discussion. Our previous anaphylaxis practice parameters nomenclature of anaphylaxis
remain an important resource for guidance on many clinical areas
that are not updated in the current document.2,3 1. Anaphylaxis is a serious, systemic hypersensitivity reaction that
This update focuses on selected topics based on the publication of is usually rapid in onset and may cause death. Severe anaphy-
new and clinically important studies and on the knowledge gaps of laxis is characterized by potentially life-threatening compro-
concern to members of the AAAAI/ACAAI and to our patients.4 mise in respiration and/or the circulation, and it may occur
Despite the advances in these areas, the body of evidence is still lim- without typical skin features, circulatory shock, or compro-
ited in relation to most questions and lacking for some. Clinically mised breathing being present.
important questions must often be addressed indirectly through sur- 2. There are similarities and differences between the 2006 NIAID
rogate markers and outcomes, especially when there are low event and 2020 WAO anaphylaxis criteria. Further studies should be
rates, and the only published studies are observational and do not conducted to validate the 2020 WAO anaphylaxis criteria.
3. Use of the 2007 Brighton Collaborative Criteria in establishing
consistently report the same outcomes or use the same criteria.3
These realities of anaphylaxis research lead to low or very low cer- the diagnosis of anaphylaxis may lead to overdiagnosis of
anaphylaxis.
tainty of evidence, even when there are moderate-to-large numbers
of patients studied. The goal of this workgroup was to identify the 4. Biphasic anaphylaxis is highly likely when the patient develops
anaphylaxis after initial signs and symptoms have completely
best available evidence of the past 7 years for the specific topics of
interest and synthesize an expert assessment of the best clinical prac- resolved for at least one hour before the onset of repeated ana-
phylaxis within 48 hours and without re-exposure to an aller-
tices supported by this evidence.
Although the topics in this update are distinct, there are some gen trigger.
5. Biphasic anaphylaxis is unlikely when anaphylaxis is not severe
areas of overlap. Rather than eliminate all duplication, we felt that
the reader is better served by having all the relevant information pre- and the patient remains symptom-free for one hour of observa-
tion following resolution of initial anaphylaxis. Biphasic ana-
sented when it supports a recommendation. However, the work-
group did make an effort to harmonize the recommendations across phylaxis is more likely to occur with increasing anaphylaxis
severity and in patients who have received more than one dose
all the topics.
of epinephrine for anaphylaxis treatment.
6. Persistent anaphylaxis is highly likely when anaphylaxis per-
sists for at least 4 hours.
Diagnosis of Anaphylaxis 7. Refractory anaphylaxis is highly likely when anaphylaxis con-
Anaphylaxis is a systemic, usually multiorgan, potentially life- tinues despite appropriate epinephrine dosing and symptom-
threatening syndrome. The diagnosis is clinical—there are no quin- directed medical management (e.g., intravenous fluid bolus for
tessential symptoms, findings, or laboratory markers. Through the hypotension). Refractory anaphylaxis increases the risk for ana-
years, the absence of a reference standard for diagnosis has chal- phylaxis fatality.
lenged the ability to formulate a consistently accurate, universally 8. Anaphylaxis severity is a continuum that results from a combi-
accepted, evidence-based definition. Furthermore, the lack of a uni- nation of risk factors, including those related to the allergen (e.
versal, standard, practical definition has contributed to both underdi- g., allergen dose and route of exposure) as well as the patient
agnosis and overdiagnosis, the former resulting in inadequate (e.g., immune response, behaviors, concomitant medications,
treatment, with possible increased morbidity and mortality, and the and other patient specific factors and comorbidities).
latter contributing to anxiety and unnecessary prescription of epi- 9. Patients with severe anaphylaxis are more likely to demon-
nephrine.5 We will discuss and compare the definitions and criteria strate hypotension and hypoxemia. Severe anaphylaxis is asso-
for the diagnosis of anaphylaxis and the nomenclature for the clinical ciated with older age, pre-existing cardio-pulmonary disease,
patterns of anaphylactic reactions, which are summarized in the list and drug etiology.
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 As found in Table 4, the diagnosis of anaphylaxis over the years has
African American race, and outcomes in anaphylaxis are improved varied with the country of origin, group or entity from which it was
with use of an interpreter for shared decision-making, when derived, and the intended application.7−21 Although “multi-organ”
indicated.6 has been part of many definitions from 2004 to 2016, a single-organ
Table 4
Anaphylaxis Definitions 2001 to 2021
Country, region, or Date Definition Reference

organization
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 Braganza et al,8 2006 and
more symptoms or signs of respiratory and/or cardiovascular involvement, and involvement of other Brown et al,9 2006
systems such as the skin and/or gastrointestinal tract.
USA/NIAID 2006 Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death (see Table 5 for Sampson et al,10 2006
NIAID anaphylaxis criteria)
Brighton Collaboration 2007 Anaphylaxis is an acute hypersensitivity reaction with multiorgan system involvement that can present € ggeberg et al,11 2007
Ru
Working Group— as, or rapidly progress to, a severe life-threatening reaction. It may occur after exposure to allergens
International 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.
US JTFPP guidelines 2010 Anaphylaxis is an acute, life-threatening systemic reaction with varied mechanisms, clinical presenta- Lieberman et al,12 2010
tions, and severity that results from the sudden systemic release of mediators from mast cells and
basophils.
WAO 2011 Anaphylaxis is a serious life-threatening generalized or systemic hypersensitivity reaction and a serious Simons et al,13 2011
allergic reaction that is rapid in onset and might cause death.
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. Muraro et al,15 2014
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.
Germany 2016 Anaphylaxis is a severe, life-threatening, generalized or systemic hypersensitivity reaction. Grade 1: Niggemann and Beyer,16
local with no systemic symptoms. Grade 2: mild/moderate systemic reaction with skin and/or GI. 2016
Grade 3: severe anaphylaxis, systemic with respiratory and/or cardiovascular involvement
ASCIA 2016 Any acute-onset illness with typical skin features (urticarial rash or erythema/flushing, and/or angioe- ASCIA Clinical Update21
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.
WHO ICD-11 2019 Anaphylaxis is a severe, life-threatening systemic hypersensitivity reaction characterized by being World Health Organization
rapid in onset with potentially life-threatening airway, breathing, or circulatory problems and is usu- 202117
ally, although not always, associated with skin and mucosal changes.
WAO 2019 Anaphylaxis is a serious systemic hypersensitivity reaction that is usually rapid in onset and may cause Turner et al,18 2019 and Car-
2020 death. Severe anaphylaxis is characterized by potentially life-threatening compromise in breathing dona et al,19 2020
and/or the circulation and may occur without typical skin features or circulatory shock being present.
EAACI 2020 Anaphylaxis is a severe allergic reaction. [Defined in the context of when to use epinephrine autoinjec- Kraft et al,20 2020
tors]
ASCIA 2021 Any acute-onset illness with typical skin features (urticarial rash or erythema/flushing and/or angioe- ASCIA,21 2021
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.
Brighton Collaboration 2022 Anaphylaxis presents acutely and leads to a marked change in an individual’s previous stable condition Gold et al,24 2022
Working Group 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).
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.
system may exhibit major involvement with more physiological dis- anaphylaxis recognition and treatment continue to be revealed.27,28
ruption than others. For example, predominantly cardiovascular or In an effort to simplify anaphylaxis diagnostic criteria, in 2019 the
respiratory system involvement may be present in up to 14% and 31% WAO Anaphylaxis Committee proposed revisions to the definition for
of patients, respectively, with only minor involvement of other sys- the clinical diagnostic criteria for anaphylaxis, which was subse-
tems.22 Laryngeal, respiratory, and/or cardiovascular involvement is quently largely adopted by the WAO 2020 guidance (Table 5).18,19
common in fatal anaphylaxis.23 With regard to the 2020 WAO criteria, although most cases of
Most definitions of anaphylaxis include the word “generalized” anaphylaxis are likely to be categorized the same as the 2006 NIAID
and/or “systemic” reaction; however, the ability of patients, care- criteria, there are several notable differences, mostly related to the
takers, or bystanders to understand these concepts is uncertain. The timing, the associated exposures, or the specific organ systems
WAO (2019 and 2020) anaphylaxis definition consisted of 2 involved. Some examples are listed here and found in Table 6.
sentences.18,19 The first is similar to the 2006 NIAID definition but
with “systemic hypersensitivity” substituted for “allergic” to be more 1. Although the 2006 NIAID criteria include cases of isolated hypo-
precise (Table 4). tension, but not isolated respiratory reaction, after exposure to a
Given the need to facilitate recognition of anaphylaxis for treat- known allergen, the 2020 WAO criteria would include reactions
ment with epinephrine, the NIAID and FAAN convened a multina- with acute-onset hypotension, including those with broncho-
tional and multidisciplinary symposium in 2005 to propose an spasm or laryngeal involvement (eg, stridor, vocal changes, or
anaphylaxis definition and clinical diagnostic criteria10 (Table 5). odynophagia) after exposure to a known or highly probable aller-
These criteria have been widely adopted25 and were found to be 95% gen in the absence of typical skin involvement. These criteria
sensitive and 71% specific in a prospective validation study among exclude respiratory compromise triggered by common inhalant
emergency department (ED) patients.26 Knowledge deficits regarding allergens.
Table 5
NIAID and WAO Side-by-Side Comparison10,19
NIAID criteria (2006) WAO criteria (2020)
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled: 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 1. Acute onset of an illness (minutes to several hours) with involvement of the
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula) skin, mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen
and at least one of the following: lips-tongue-uvula)
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hyp- and at least one of the following:
oxemia) a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor,
b. Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], reduced PEF, hypoxemia)
syncope, incontinence) 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 c. Severe gastrointestinal symptoms (eg, severe crampy abdominal pain, repeti-
patient (minutes to several hours): tive vomiting), especially after exposure to non-food allergens
a. Involvement of the skin mucosal tissue (eg, generalized hives, itch-flush, swollen lips-
tongue-uvula) 2. Acute onset of hypotension or bronchospasma or laryngeal involvement after
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hyp- exposure to a known or highly probable allergen for that patient (minutes to
oxemia) several hours), even in the absence of typical skin involvement.
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence) a. Excluding lower respiratory symptoms triggered by common inhalant aller-
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) gens or food allergens perceived to cause “inhalational” reaction in the absence
3. Reduced blood pressure after exposure to known allergen for that patient (minutes to sev- of ingestion.
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
Abbreviations: BP, blood pressure; NIAID, National Institute of Allergy and Infectious Disease; PEF, peak expiratory flow; WAO, World Allergy Organization.
2. Although both the 2006 NIAID and 2020 WAO criteria note that creating a definition with only 2 criteria. Therefore, with the
symptom onset would be expected within “minutes to several 2020 WAO definition, all anaphylaxis cases must have mucocuta-
hours,” the 2019 WAO anaphylaxis committee guidance, which neous symptoms except those that meet the second 2020 WAO
informed the WAO 2020 criteria, also includes a footnote specifi- criterion (Table 5). For example, cases with dyspnea and persis-
cally noting that some reactions, such as those secondary to alpha- tent vomiting after exposure to a “likely allergen” would meet
gal or immunotherapy, may be delayed up to 10 hours in onset.18 the 2006 NIAID second criteria but not the 2020 WAO criteria
3. The 2006 NIAID criteria require “persistent” gastrointestinal owing to the absence of mucocutaneous involvement and
involvement to qualify as an anaphylaxis manifestation. In con- absence of manifestations meeting the second 2020 WAO crite-
trast, the 2020 WAO criteria require “severe” gastrointestinal rion. Furthermore, with the 2020 WAO definition, exposure to a
involvement so as to acknowledge that gastrointestinal manifes- “likely” allergen would not be required for cases with only muco-
tations can be indicative of anaphylaxis without being persistent. cutaneous and severe gastrointestinal involvement. For example,
4. The WAO Anaphylaxis Committee drew attention to the discrep- cases with acute onset of mucocutaneous and severe gastrointes-
ancy internationally between the inclusion of gastrointestinal tinal manifestations in the absence of a “likely allergen” (eg,
involvement as a systemic manifestation of food-induced ana- childhood viral gastroenteritis with acute urticaria) would meet
phylaxis.18 Thus, the WAO 2020 anaphylaxis criteria include the the 2020 WAO criteria but not the original 2006 NIAID criteria.
phrase, “especially after exposure to non-food allergens” when
referring to gastrointestinal organ system involvement as a sys- Future validation of the 2020 WAO criteria will be helpful in
temic manifestation of anaphylaxis.19 determining their clinical utility. Further multidisciplinary and inter-
5. Finally, to simplify the definition, the 2020 WAO criteria essen- national consensus on clinical diagnostic criteria will be important to
tially combine the first and second (of 3) 2006 NIAID criteria, address how clinicians and researchers will: (1) classify isolated,
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 involvementc
Respiratory GI Only if likely allergen exposure Only if known or highly probable allergen with bronchospasmb or laryngeal
involvementc
CV GI Only if likely allergen exposure Only if known or highly probable allergen with hypotensiona
Hypotensiona None Only if known allergen exposure Only if highly probable allergen exposure
Laryngeal involvementc None No Only if highly probable allergen exposure
Bronchospasmb 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.
acute, allergic, oropharyngeal, or laryngeal angioedema as this would percentage of patients with biphasic anaphylaxis was 6.5% (range,
meet the 2020 WAO anaphylaxis diagnostic criteria but not the 2006 0.4%-20%).40 The median duration between resolution of the initial
NIAID criteria; (2) define what constitutes “severe” gastrointestinal episode and the secondary reaction was 10.5 hours (range, 1.75
symptoms; (3) determine whether or not gastrointestinal involve- hours-17 hours).40 These findings are in range with other studies of
ment should be recognized as a systemic manifestation of anaphy- biphasic anaphylaxis.3,43,44,50 Notably, a 1-hour symptom-free obser-
laxis when accompanied by mucocutaneous involvement secondary vation after resolution of initial anaphylaxis was associated with a
to food allergens; and (4) reach consensus with regard to other classi- 95% negative predictive value (95% CI, 90.9%-97.3%) for biphasic ana-
fication discrepancies noted previously. phylaxis.40 Persistent anaphylaxis is distinct from biphasic anaphy-
Although both the 2006 NIAID and 2020 WAO criteria were devel- laxis because in persistent anaphylaxis there is no period of
oped for the diagnosis of anaphylaxis with any potential trigger, a resolution between an initial and a subsequent phase.34 In 1 report of
case definition for the diagnosis of anaphylaxis occurring as an 108 episodes of pediatric anaphylaxis requiring hospital admission,
adverse event after an immunization was proposed by the Brighton anaphylaxis was described as biphasic in 6%, protracted in 1%, and
Collaboration Anaphylaxis Working Group in 2007.11 The case defini- fatal in 2% of patients.35 Fatal anaphylaxis is a rare outcome.51,52 In a
tion included sudden onset, rapid progression, and multiple-organ population-based epidemiologic study using 3 national databases,
system involvement (Table 7). Diagnostic levels of certainty were the case fatality rate among patients hospitalized or with ED presen-
based on fulfilling major and minor criteria consisting of signs and tations was between 0.25% and 0.33%.53
symptoms and tryptase level elevation. A study comparing the 2007 Reaction severity is a leading factor in the subsequent course of
Brighton Criteria with the 2006 NIAID criteria reported a moderate anaphylaxis, and anaphylaxis severe enough to require hospitaliza-
level of agreement between case definitions among a cohort of ED tion has been reported to account for up to 22% in some case
patients; however, a discordant result between definitions was found series.3,54−56 It is important to recognize that reaction severity is a
in 28.1% of the cases.29 The 2007 Brighton Criteria differ from the continuum that results from a combination of risk factors, including
2006 NIAID and 2020 WAO criteria in notable ways. For example, lip those related to the allergen (eg, allergen dose and route of exposure)
swelling is considered a major criterion for respiratory and the patient (eg, immune response, behaviors, concomitant medi-
involvement.19,29 Thus, a patient with lip swelling and itchy eyes cations, and other patient-specific factors and comorbidities)
would meet the case definition of anaphylaxis with level 2 diagnostic (Fig 1).57−60 Patients with severe anaphylaxis are more likely to have
certainty, potentially leading to overdiagnosis of anaphylaxis in the hypotension and hypoxemia, and severe anaphylaxis is associated
setting of immunizations.30 Application of the 2006 NIAID or 2020 with older age, preexisting lung disease, and drug etiology.22 Never-
WAO criteria may be more accurate, but further studies are needed theless, anaphylaxis is part of a spectrum of acute allergic reactions
(Table 5).31,32 As a result of increased use during the COVID-19 pan- that range from mild to fatal.18,61,62 Understanding and communicat-
demic, and debate regarding the Brighton Criteria performance in ing anaphylaxis severity is important for patients and their families,
assessing vaccine-associated anaphylaxis compared with NIAID or primary care providers, emergency physicians, hospital physicians,
WAO criteria, the Brighton Collaboration Anaphylaxis Working allergy specialists, school personnel, public health authorities, food
Group published an updated and revised version 2 of the criteria in providers, and researchers.57 Any definition of anaphylaxis severity
late 2022 (Table 7). The revised criteria focus the major and minor must clearly inform all stakeholders.
criteria on the reporting of observable clinical signs, rather than sub- Multiple severity grading systems have been developed,16,57,63−65
jective symptoms, and provide a clearer approach to the ascertain- and the term “severity” can have different meanings to patients, clini-
ment of levels of certainty.24 These modified 2022 Brighton Criteria cians, and investigators.57,63 In 1977, Ring and Messmer66 proposed a
may be more consistent with other common case definitions for ana- 4-category classification system to describe severity of reactions to
phylaxis. colloid volume substitutes, but this system was not specific to ana-
The course of anaphylaxis can be variable across patients and pop- phylaxis. The Ring and Messmer classification was subsequently
ulations, although one study has reported some consistency among modified such that grade I represents isolated mucocutaneous
recurrent anaphylaxis for individual patients.33 For most patients, involvement, grade II mild-to-moderate severity multiorgan system
anaphylaxis is not persistent, refractory, or biphasic34−37; however, involvement, grade III life-threatening symptoms in a single-organ
these subtypes of anaphylaxis are not uncommon.34−45 Biphasic ana- system or more severe multiple-organ system involvement, and
phylaxis is more likely to occur with increasing anaphylaxis severity grade IV cardiac or respiratory arrest.67,68 Additional grading
and in patients who have received more than one dose of epineph- schemes have been proposed through the years. An approach involv-
rine for anaphylaxis treatment.3 Additional risk factors for biphasic ing 5 categories proposed by Sampson for grading of food-induced
anaphylaxis include a wide pulse pressure (resulting from early arte- anaphylaxis was subsequently adopted by the EAACI in 2007.69,70 In
riolar dilation), unknown anaphylaxis trigger, cutaneous signs and 2004, Brown63 proposed a simple classification system for the range
symptoms, and drug trigger in children.3,46,47 Persistent, refractory, of hypersensitivity reactions, with mild reactions limited to cutane-
and biphasic anaphylaxis may be defined by clinical criteria (Table 8). ous manifestations; moderate reactions characterized by features
Persistent anaphylaxis is highly likely when anaphylaxis persists for at suggesting respiratory, cardiovascular, or gastrointestinal involve-
least 4 hours.34 Refractory anaphylaxis is highly likely when anaphy- ment; and the most severe grades characterized by hypoxia, hypo-
laxis continues despite appropriate epinephrine dosing and symp- tension, and/or neurologic compromise (Table 9). Many clinicians
tom-directed medical management (eg, intravenous fluid bolus for continue to use the 2010 WAO Subcutaneous Immunotherapy Sys-
hypotension).34 Data from the European Anaphylaxis Registry sug- temic Allergic Reaction Grading System,71 often applying modifica-
gest that refractory anaphylaxis accounts for less than 0.5% of severe tions based on age and allergen trigger.19,65,72 Recently, the 2012
anaphylaxis cases, with an associated drug etiology (particularly in Consortium for Food Allergy Research Grading Scale for Systemic
the perioperative/procedural setting) most frequently recognized.48 Allergic Reactions, characterized by 5 severity levels, was updated
Refractory anaphylaxis increases the risk for anaphylaxis fatality through a collaboration of expert opinion with industry input to con-
(26.2% vs 0.35% in a 2019 European registry, P < .0001).48,49 Biphasic sider response to therapy in assignment of severity grade.73 In addi-
anaphylaxis is highly likely when the patient develops anaphylaxis tion, the Food Allergy Severity Score was recently developed using
after initial signs and symptoms have completely resolved for at least the EuroPrevail outpatient clinical cohort of 8232 food allergy
1 hour before the onset of repeated anaphylaxis within 48 hours reactions.74
without re-exposure to an allergen trigger.34 In a meta-analysis that There are limitations to existing anaphylaxis severity scoring sys-
included 2890 adult patients with anaphylaxis, the median tems. For example, the Brown severity grading system, developed
Table 7
Case Definitions and Differences Between the 2007 (Version 1) and 2022 (Version 2) Brighton Collaboration Anaphylaxis Major and Minor Criteria24
Brighton collaboration criteria version 1 (2007) Brighton collaboration criteria version 2 (2022) Comments
Definition Anaphylaxis is a clinical syndrome characterized Anaphylaxis presents acutely and leads to a Sudden onset has been replaced with acutely in
by sudden onset and rapid progression of signs marked change in an individual’s previous sta- BC-V2; a clearer description of rapid
and symptoms involving multiple (≥2) organ ble condition and is characterized by the fol- progression has been provided; and multisys-
systems, as follows lowing: rapid progression of symptoms and tem involvement is defined more clearly. Both
signs which typically affects multiple body sys- V1 and V2 require rapid progression for all lev-
tems (skin/mucosa/respiratory/cardiovascular/ els of diagnostic certainty.
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).
Criteria
Major skin Generalized urticaria (hives) or generalized ery- Urticaria (hives) at a location other the vaccine Removal of generalized as a descriptor for urti-
thema; angioedema, localized or generalized; administration site; angioedema of the skin caria and angioedema. Urticaria and angioe-
generalized pruritus with skin rash (swelling) at a location other the vaccine dema at injection site are excluded.
administration site; generalized (widespread)
erythema (redness) of the skin with itch
Minor skin Generalized pruritus without skin rash; general- Generalized (widespread) erythema (redness) of Removal of generalized pruritus without skin
ized prickle sensation; localized injection site the skin with itch; red and/or itchy eyes, bilat- rash, generalized prickle sensation, localized
urticarial rah; red and itchy eyes eral and new onset; generalized (widespread) injection site urticaria, as minor criteria. Inclu-
erythema (redness) of the skin without itch sion of new onset for red and/or itchy eyes.
Major respiratory Bilateral wheeze (bronchospasm); stridor; upper Expiratory wheeze documented by health care Inclusion of wheeze, stridor, upper airway swell-
airway swelling (lip, tongue, throat, uvula, or professional which could be with/out stetho- ing documented by a health care professional.
larynx); respiratory distress—2 or more of the scope; inspiratory stridor documented by Removal of lip swelling as a sign of upper air-
following: tachypnea, increased use of acces- health care professional which could be with/ way angioedema. Inclusion of measured hyp-
sory respiratory muscles (sternocleidomastoid, out stethoscope; angioedema of the mucosa of oxia with oxygen saturations <90%.
intercostal), recession, cyanosis, grunting 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
Minor respiratory Persistent dry cough; hoarse voice; difficulty Cough and/or sneezing and/or runny nose new The minor symptoms (reported difficulty breath-
breathing without wheeze or stridor; Sensation onset and persistent ing, sensation of throat closure) and signs
of throat closure; sneezing, rhinorrhea (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 Measured hypotension. Loss of consciousness, The clinical features of uncompensated shock
uncompensated shock, indicated by the combi- other than the brief, self-resolving loss of con- (other than hypotension or loss of conscious-
nation of at least 3 of the following: tachycar- sciousness typical of a vasovagal reaction ness) have been removed as major criteria, to
dia, capillary refill time >3 s, reduced central simplify the criteria. Loss of consciousness has
pulse volume, decreased level of consciousness been inserted as a major criterion of hypoten-
or loss of consciousness 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 None All minor cardiovascular criteria have been
the combination of at least 2 of the following: removed.
tachycardia, a capillary refill time of >3 s with-
out hypotension, a decreased level of
consciousness
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- Major skin/mucosal and ≥1 major system
cular and/or ≥1 major respiratory criterion involvement including respiratory and/or car-
diac and/or gastrointestinal and/or laboratory
(continued)
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- ≥2 Major system involvement including respira-
tory criterion or ≥1 major cardiovascular or tory and/or cardiac and/or gastrointestinal and/
respiratory criterion and ≥1 minor criterion or laboratory—excludes skin/mucosal involve-
involving ≥1 different system (other than car- ment and must be from different systems
diovascular or respiratory systems) or (≥1
major dermatologic) and (≥1 minor
cardiovascular and/or minor respiratory crite-
rion)
Level 3 ≥1 Minor cardiovascular or respiratory criterion ≥1 Major system involvement including respira-
and ≥1 minor criterion from each of ≥2 differ- tory, cardiac, gastrointestinal or
ent systems/categories laboratory and ≥1 minor system involvement
from skin/mucosal or respiratory and must be
from different systems
Level 4 Reported anaphylaxis with insufficient evidence Insufficient information provided for review to
to meet the case definition 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
using a statistical analysis of the relationship between individual grade quickly, arguing for consideration of epinephrine in milder
reaction features and subsequent treatment with epinephrine and reactions if risk of progression is a concern. This may be particularly
patient outcomes, uses observable signs and symptoms without the relevant with rapid onset of signs or symptoms after exposure to a
use of physiological measurements (eg, blood pressure and oxygen suspected allergen. In an analysis of 259 food-induced anaphylaxis
saturation).63 Grade 1 would not be considered anaphylaxis, whereas episodes from 157 children, a 24.7% to 70.2% disagreement was
grade 2 and grade 3 would fulfill the definition of anaphylaxis and observed across multiple severity score rating systems. The authors
could be adopted as an indication to immediately administer epi- of this study highlighted that the presence of anaphylaxis is not req-
nephrine in both the community and medical settings.63 However, uisite for epinephrine use during an allergic reaction, and conversely,
such a grading system may not be ideal in real-time decision-making use of epinephrine does not necessitate a diagnosis of anaphylaxis be
as affected subjects may change from a less severe to more severe made.75
Figure 1. Risk factors for severe allergic reactions. Many factors may modulate between mild and severe allergic reactions.
Adapted with permission from Dubois et al60 and Smith et al.59
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
In 2021, a severity grading system for allergic reactions proposed Question: What is the role of serum tryptase measurements in
by Dribin et al61 resulted from an expert consensus and synthesis of anaphylaxis diagnosis?
the many prior grading scales with additional granularity but also
Recommendation 1 (CBS): We recommend obtaining a bST in
added some degree of complexity (Fig 2). An advantage of the 2021
patients presenting with a history of recurrent, idiopathic, or
grading system is that it allows grading of allergic reactions from
severe anaphylaxis, particularly those presenting with hypoten-
mild to severe with or without requiring a definition of anaphylaxis.
sion.
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 Strength of Recommendation: Strong
most effective. Although derived from expert consensus of a 21-
member multidisciplinary panel, the 2021 grading system still Certainty of Evidence: Moderate
requires validation. Using a “Best-Worst Scaling” exercise, Stafford et Recommendation 2 (CBS): We suggest drawing an acute-phase
al76 evaluated 10 severity grading systems, concluding that geo- tryptase level as early as possible during a suspected anaphylactic
graphic location of the health care provider may affect severity event (ideally within 2 hours after onset of symptoms). We sug-
assessment and that all scoring systems have limitations in discrimi- gest drawing a second tryptase measurement at a later time as a
nating anaphylaxis severity.
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; SpO2, 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.
baseline for comparison to determine whether there was a signifi- (Table 10).77,78 One must realize that when evaluating for an elevated
cant acute elevation. acute tryptase level, a serum tryptase level above the laboratory-
defined normal value (eg, >11.4 ng/mL in many laboratory results)
Strength of Recommendation: Conditional
may not detect all episodes of anaphylaxis. Rather, a change in tryp-
Certainty of Evidence: Moderate tase above a patient’s bST may offer a more sensitive assessment of
systemic mast cell activation. Expert consensus has suggested that an
Recommendation 3 (CBS): We suggest clinicians consider eval- acute serum total tryptase level at least 20% plus 2 ng/mL over the
uation for HaT in patients with elevated bST level (8 ng/mL or patient’s bST level is evidence of systemic mast cell activation.79,80
greater). Although this equation was proposed to aid in diagnosis of MCAS
Strength of Recommendation: Conditional 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
Certainty of Evidence: Low positive and negative predictive values were 98% and 44%, respec-
tively).77 Questions remain regarding the overall utility of using this
Recommendation 4 (CBS): We suggest clinicians consider eval-
equation for anaphylaxis in general (eg, what is the normal temporal
uation for mastocytosis, including a bone marrow biopsy, for
intrapersonal variance in tryptase and what is the value in food-
adult patients with severe insect sting anaphylaxis or recurrent
induced anaphylaxis).78 For example, Mateja et al80 revealed that sig-
IA, particularly those with a predictive REMA score.
nificant variability may occur in bST levels and that among individu-
Strength of Recommendation: Conditional als with an elevated tryptase due to an underlying mast cell disorder,
one-quarter of individuals exceeded the 20% plus 2 ng/mL threshold
Certainty of Evidence: Moderate
on serial asymptomatic measurements; they found that a ratio of
The differential diagnosis and diagnostic workup for patients pre- acute/baseline tryptase of 1.685 was able to better identify anaphy-
senting with suspected or presumed anaphylaxis is broad (Table 10, laxis (sensitivity 94.4%, specificity 94.4%). It has been suggested that
Fig 3).2 Diagnostic workup relies on a thorough clinical history with even more nuanced cutoff values could be tailored to the index of
attention to patient age, sex, medical and atopic history, concurrent clinical suspicion,80 suggesting a cutoff ratio of 1.868 when clinical
medications, possible triggers, symptom pattern, timing of onset, suspicion of anaphylaxis is low and a ratio of 1.374 when clinical sus-
concomitant factors (eg, exercise, viral infection, medications, men- picion is high. An online calculator has been published to facilitate
strual status, stress), symptom duration, response to treatment (epi- use of this particular approach at https://triptase-calculator.niaid.nih.
nephrine), and number of episodes, with very focused testing to gov.81 Thus, currently, we do not recommend using the 20% plus
evaluate for IgE-mediated triggers (eg, skin and/or serum testing).2 2 ng/mL equation alone to diagnose anaphylaxis.
As part of the diagnostic evaluation, it is imperative to confirm that Since publication of the 2015 anaphylaxis parameter, there are 2
the events in question are indeed anaphylaxis, classically by finding updated considerations for evaluating patients with recurrent mast
objective signs of mast cell activation on physical examination (eg, cell-mediated symptoms/recurrent IA. The first is examination not
urticaria, wheezing on lung auscultation, or hypotension) or by ele- only for elevated bST level (as a marker for mast cell disease), but
vated tryptase level to rule out mimickers of anaphylaxis when appropriate, for HaT. 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-
Table 10
cantly influences bST levels, and HaT genotyping could be
Anaphylaxis Differential Diagnosis
considered in individuals with tryptase levels above 8 ng/mL.84,85
Anaphylaxis Incorporating copy number can be useful in determining whether
Anaphylaxis due to known allergens—for example, foods, drugs, insect sting, latex
Anaphylaxis associated with physical stimuli—for example, exercise, cold, heat
further evaluation of a clonal mast cell evaluation may be warranted
Anaphylaxis associated with both—for example, food-dependent exercise induced (https://bst-calculater.niaid.nih.gov).86 HaT occurs in 5% to 7% of peo-
Idiopathic ple in the European and North American populations sampled,87 and
although many individuals with HaT are asymptomatic, there are
Mastocytosis and mast cell activation syndromes, hereditary a-tryptasemia
data to suggest that it is often accompanied by a wide range of symp-
Vasodepressor reactions
Vasovagal toms consistent with mast cell mediator release.88 However, in a ran-
dom biorepository population, there was no difference in the clinical
Flushing syndromes symptomatology or medical history of individuals with HaT com-
Neuroendocrine tumors, for example, carcinoid, pheochromocytoma
pared with controls.89 HaT has been reported more frequently in
Vasoactive intestinal peptide-secreting tumor
patients with severe symptoms of anaphylaxis in patients with IgE-
Restaurant syndromes mediated allergies (such as Hymenoptera venom allergy), with or
Scombroidosis without mastocytosis, and thus should be considered in evaluation of
Monosodium glutamate patients presenting with possible anaphylaxis.90,91 Our understand-
ing of HaT is incomplete, and at this point, the degree to which the
Nonorganic causes
Anxiety/panic syndromes (may include pruritus, flushing, urticaria) diagnosis alters management is uncertain.85,92 Still, HaT should be
Munchausen syndrome (factitious anaphylaxis) or Munchausen by proxy considered in the differential diagnosis of patients with elevated bST
Vocal cord dysfunction syndrome level and recurrent or severe anaphylaxis.
Undifferentiated somatoform anaphylaxis
Second, there have been scoring systems developed to help deter-
Prevarication anaphylaxis
mine when patients with recurrent mast cell-mediated symptoms or
Miscellaneous recurrent IA warrant bone marrow biopsy to look for underlying
Hereditary angioedema accompanied by rash mastocytosis or a clonal mast cell disorder. The first of these was pub-
Capillary leak syndrome lished from the Spanish Mastocytosis Network (referred to as the
Vancomycin infusion reaction (“red man syndrome”)
REMA score) and described patients with severe systemic symptoms
Autonomic dysfunction
of mast cell mediator release but without cutaneous lesions, includ-
ing many patients with insect venom anaphylaxis (Fig 4).93 A more
NOTE. Adapted from Lieberman et al.2 recent study in the United States describes the NICAS (NIH Idiopathic
Figure 3. Diagnostic evaluation of the patient with a history of anaphylaxis.

5HIAA, 5-hydroxyindolacetic acid; AIT, allergen immunotherapy; EAI, epinephrine autoinjector; HaT, hereditary a-tryptasemia; IA, idiopathic anaphylaxis; REMA, Red Espanola
MAstocitosis; VIP, vasoactive intestinal peptide.
Clonal Anaphylaxis Score) score in patients with IA (none had venom Strength of Recommendation: Conditional
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 There are accumulating data to suggest that alpha-gal allergy can
suggests that in many patients with a clonal mast cell disorder even be a common hidden cause of recurrent anaphylaxis previously pre-
the most sensitive test for this mutation in the peripheral blood may sumed to be idiopathic depending on geographic location.99,100 As
have a negative result,95 within the NICAS score the predictive value with other allergies, alpha-gal asymptomatic sensitization occurs and
may improve. The REMA score has been validated and modified in does not always equate to clinically reactivity. Clinical history (ana-
other studies.96,97 The scoring systems are established only in adults phylaxis occurring hours after consumption of red meat), geographic
and advise that male sex, lack of angioedema/urticaria, and presence location, exposure to ticks, and outdoor exposure should all be con-
of hypotension/syncope during episodes suggest increased likelihood sidered when deciding to order and interpret an alpha-gal IgE level.
for clonal disease, and thus consideration for biopsy.93,94,96,98 How- For example, forest workers in the United States101 and Germany102
ever, bone marrow biopsy may be considered in patients with recur- were found to have sensitization rates (>0.1 kU/L) of 39.1% and
rent or severe anaphylaxis episodes outside of these scoring systems. 35.0%, respectively. However, in those cohorts, 0% and 2%, respec-
tively, had clinical symptoms of delayed anaphylaxis with mamma-
Question: In what settings should the clinician consider evalu-
lian meat. In a South African cohort of patients with delayed meat
ation of alpha-gal allergy?
reactions, the alpha-gal IgE assay had good discriminatory properties
Recommendation 5 (CBS): We suggest that clinicians consider when compared with 26 healthy controls, with a positive predictive
alpha-gal allergy as a possible cause of recurrent IA in a patient value and negative predictive value of 92% and 83%, respectively, at a
with history of possible tick bite; when appropriate, check an value of greater than 1.0 kU/L in this sample (although these predic-
alpha-gal IgE and advise a trial elimination of mammalian meat if tive values may not be generalizable in other populations).103 Thus,
alpha-gal IgE sensitization is detected. when ordering the alpha-gal sIgE, the clinician should use the history
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 al98 and Carter et al.94 Adapted from Alvarez-Twose et al.93
to assess the pretest likelihood of alpha-gal allergy and leverage diagnostic criteria for anaphylaxis (eg, generalized urticaria without
shared decision-making with the patient regarding a trial elimination additional symptoms after any form of AIT).75 The potential of pro-
of (and subsequent challenge with) mammalian meat if the test result gression from a non-anaphylactic systemic hypersensitivity reaction
is positive. to anaphylaxis to life-threatening anaphylaxis further obfuscates this
distinction. Thus, definitions incorporate severity (eg, hypotension or
Question: Is the diagnosis of anaphylaxis required for adminis-
respiratory distress) to distinguish anaphylaxis from non-anaphylac-
tration of epinephrine?
tic systemic hypersensitivity reactions at any point in time.10,19
Recommendation 6 (CBS): We suggest that meeting diagnostic There may be epidemiologic value in the separation of anaphy-
criteria for anaphylaxis is not required before the use of epineph- laxis from non-anaphylactic systemic hypersensitivity reactions. The
rine. 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
Certainty of Evidence: Very Low grading are of greatest benefit when establishing a retrospective
diagnosis of anaphylaxis, particularly for use in research and epide-
Question: Is administration of, or response to, epinephrine
miologic studies, and when trying to predict the risk of severe reac-
necessary for the diagnosis of anaphylaxis?
tion with future episodes of anaphylaxis. Still, severity assessment
Recommendation 7 (CBS): We suggest that neither the clinical continues to be an important, often implicit, driver of anaphylaxis
decision to administer epinephrine, nor the clinical response to management by clinicians. Although the NIAID/FAAN criteria are
epinephrine, be used as a surrogate marker to establish a diagno- often used in clinical practice, their diagnostic precision is
sis of anaphylaxis. imperfect.116
Anaphylaxis represents a high-grade systemic hypersensitivity
Strength of Recommendation: Conditional reaction. For real-time treatment decisions, withholding epinephrine
Certainty of Evidence: Very Low in the setting of systemic hypersensitivity reactions that do not yet
fulfill a particular set of diagnostic criteria for anaphylaxis may result
Anaphylaxis continues to be under-recognized and undertreated in progression of a systemic hypersensitivity reaction.61,117 Thus,
with epinephrine, both in the community and health care set- meeting anaphylaxis diagnostic criteria is not requisite before epi-
tings27,104−114; however, evidence suggests more appropriate use in nephrine use in treating a systemic hypersensitivity reaction.27 Con-
locations with systems designed for recognition and treatment.105,115 versely, neither the clinical decision to administer epinephrine nor
Although all cases of anaphylaxis represent a systemic hypersensitiv- the clinical response to epinephrine should be used as a surrogate
ity reaction, not all systemic hypersensitivity reactions fulfill marker to establish a diagnosis of anaphylaxis.28 Early epinephrine
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.
treatment of a systemic hypersensitivity reaction may be more effec- recognized that as more data are collected regarding these unique
tive than delayed treatment.118,119 Intramuscular epinephrine is a cases, specific age-based criteria for anaphylaxis may become war-
safe medicine with negligible toxicity at doses recommended for ana- ranted. The panel also identified knowledge gaps in many areas
phylaxis treatment (0.01 mg/kg of a 1:1000 [1 mg/mL] solution to a including the following: recognition of anaphylaxis cases using
maximum of 0.5 mg in adults and 0.3 mg in prepubertal children).3 claims data and issues that may occur with billing/coding inaccura-
However, epinephrine use in patients before the development of any cies; that epinephrine usage rates may not always correlate with ana-
symptoms is a low-value practice (providing uncertain benefit with phylaxis diagnosis; identifying risk factors that specifically
potential for harm at substantial cost) and is associated with a qual- predispose infants (vs children of other ages) to anaphylaxis; how
ity-of-life burden.120−122 Notably, appropriate use of epinephrine best to recognize symptoms of anaphylaxis in nonverbal or minimally
during anaphylaxis improves quality of life and self-efficacy.123 In verbal populations; establishing appropriate epinephrine dosing for
addition to epinephrine, other supportive therapies, such as intrave- infants and toddlers; and lack of a standardized evaluation for
nous fluids and supplemental oxygen, may play an important role in patients of this age.135
the treatment of anaphylaxis, even before the development of hypo-
Question: Should age of the infant/toddler experiencing ana-
tension.124 Of note, use of epinephrine does not mandate universal
phylaxis be used as a predictor of reaction severity?
activation of EMS in the patient who experiences prompt, complete,
and durable response to treatment when access to advanced medical Recommendation 9 (CBS): We suggest clinicians be aware that,
care is readily available if needed.125−127 Anaphylaxis preparedness in infants and toddlers, patient age does not correlate with reac-
discussions that include shared decision-making may be useful to tion severity.
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 Certainty of Evidence: Very Low
published.4 Further research efforts are expected to continue to
inform knowledge gaps in the area of anaphylaxis diagnosis. These Question: Should lack of prior exposure to an allergen be used
are summarized in Table 11. 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-
Anaphylaxis in Infants and Toddlers
cation on first exposure in infants.
There is a dearth of quality data regarding the epidemiology of
anaphylaxis in infants and toddlers, though this has been a growing Strength of Recommendation: Conditional
area of interest in the past several years. The available data agree that Certainty of Evidence: Low
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, Few nationally representative data exist studying anaphylaxis in
the rate of presentation to the ED for anaphylaxis in this age groups this age group. However, the Healthcare Cost and Utilization Project
seems to be increasing (at least in the United States).130 Nationwide Emergency Department Sample (a large, national study
of temporal trends of presentation to US EDs from 2006 to 2015)
Question: How should anaphylaxis be diagnosed in infants and noted that the proportion of visits for anaphylaxis in infants
toddlers? increased from approximately 20 to 50 per 100,000 visits through
Recommendation 8 (CBS): We suggest that clinicians use cur- this time period, whereas overall hospitalizations for anaphylaxis
rent NIAID/FAAN or WAO anaphylaxis criteria to assist in the diag- presenting to the ED in this age range fell from 19% to 6%.136 Private
nosis of anaphylaxis in infants/toddlers, because there are no insurance, male sex, and high income were key factors associated
criteria specific to this age group. with increased odds of being hospitalized after presenting to the ED
for anaphylaxis. However, data from the Healthcare Cost and Utiliza-
Strength of Recommendation: Conditional tion Project Nationwide Inpatient Sample reveal that general admis-
sion rates were stable in infants and toddlers during that same time
Certainty of Evidence: Low
frame.137 Overall, fatality from anaphylaxis in any age is rare, and
Defining what age range constitutes infancy is poorly established exceptionally rare in infants, though few studies have explored this,
for the purposes of allergic diseases, including anaphylaxis.10,19 A and there is a risk of omitted cases potentially confounding low esti-
recent expert panel consensus report recommended emphasizing mates.
age rather than weight in defining “infant” and that their recommen- Data from interventional clinical trials assessing the early intro-
dations should broadly apply to both infants and toddlers up to age duction of allergenic solid foods in high- and low-risk infants under
36 months.135 This panel also recommended working within the the age of 12 months have largely noted that anaphylaxis is an
existing NIAID/FAAN criteria for anaphylaxis as there are no criteria uncommon manifestation of initial reactions, and overall, although
specific for infants that have been created by any allergy or emer- severe reactions occur, they are far less common than mild-to-mod-
gency medicine society or regulatory authority. However, the panel erate, primarily cutaneous, reactions.138−144 Data from an Australian
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.
population-based, cross-sectional study of 12-month-old infants was derived empirically and represented an expert consensus
revealed that fewer than 2.5% of all reactions after initial introduction regarding an appropriate dose.2 Thus, the actual necessary and suffi-
of the food were severe.145 A national Korean ED registry which cient mg/kg dose is unknown, though the 0.01 mg/kg recommenda-
revealed that 9.7% of children aged below 24 months (n = 93 children tion seems to be at least anecdotally supported by evidence of
of 558 total participants) who presented with anaphylaxis had what efficacy.152 No data suggest that the 0.15 mg dose was either ineffec-
was considered by investigators to be a severe reaction.146 No clinical tive or unsafe in this population, even when used at lower weights
data or biomarkers provide a rationale for why reaction severity (including <7.5 kg) where the dose may exceed 0.01 mg/kg. Thus, the
should differ based on age, though cofactors that augment severity necessity of the 0.1 mg dose remains unclear, though this dosing
may be more relevant in older individuals. There may be confounding option exists (subject to insurance coverage) as a preference-sensi-
factors in different geographic locations or ethnic populations. tive choice in children under 15 kg.2 Data have emerged regarding
the importance of needle length in smaller infants or toddlers. Ultra-
Question: Do infants and toddlers present with different signs
sound-based evaluations of skin-to-bone distance suggest that longer
and symptoms of anaphylaxis compared with older children and
needles increase the risk of the needle hitting bone. This could lead to
adults?
impaired delivery of the epinephrine, increased pain and distress, or
Recommendation 11 (CBS): We suggest clinicians be aware that needle embedment in bone requiring surgical extraction.153,154 We
parents of infants and toddlers may report age-specific symptoms found only 1 case report of intraosseous injection of the femur, which
that are less often reported by older children and adults. occurred when an EpiPen Jr. was administered to a female child
weighing 25 kg.155 More research is needed to determine the true
Strength of Recommendation: Conditional risk of intraosseous injection and how it may affect the efficacy of
Certainty of Evidence: Very Low epinephrine if it occurs.
Research into infant/toddler anaphylaxis continues to evolve as
Studies suggest that there are age-related symptom presentation multiple knowledge gaps exist regarding its epidemiology, classifica-
patterns for severe allergic reactions.147−149 Retrospective studies tion, diagnosis, and management. These are noted in Table 12, with
report that infants and young children more often have skin symp- recommendations to help guide future research.
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 Anaphylaxis in Community Settings
unable to communicate these types of symptoms. A national parent Question: What counseling and education should clinicians
survey conducted by an advocacy group noted that most parents provide to patients to help them manage the risk of anaphylaxis
reported skin symptoms and subtle behavioral signs (pulling/scratch- in community settings?
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, Recommendation 13 (CBS): We recommend clinicians counsel
behavioral manifestations may include unexplained behavioral patients at high risk of anaphylaxis to always carry self-injectable
changes, such as withdrawal, inconsolable crying, irritability, or epinephrine and teach patients proper indications and use.
clinging.135,150,151 Some studies suggest that gastrointestinal symp-
Strength of Recommendation: Strong
toms may be a common presenting feature in infants, but those retro-
spective studies are limited by the differing definition of ages of Certainty of Evidence: Very Low
infants and young children and reflect self-reported as opposed to cli-
nician-observed symptoms. Recommendation 14 (CBS): We recommend clinicians educate
patients on avoidance of potential exposure to their allergen(s).
Question: Should infants/toddlers be prescribed the 0.1 mg or
0.15 mg EAI?
Certainty of Evidence: Very Low
Recommendation 12: We suggest clinicians prescribe either
the 0.1 mg or the 0.15 mg EAI dose for infants/toddlers weighing Recommendation 15 (CBS): We recommend clinicians educate
less than 15 kg. patients that the main route of food-induced anaphylaxis is by
ingestion and not contact or inhalation.
Epinephrine is the drug of choice for infant anaphylaxis, as it is at
any age. However, perhaps the most significant development in Anaphylaxis is unpredictable and can occur anywhere, with most
infant/toddler anaphylaxis management has been the introduction of cases occurring outside the medical setting. Although there are abun-
a 0.1 mg EAI for infants weighing 7.5 to 15 kg where formerly only dant data addressing the frequency and management of anaphylaxis
0.15 mg and 0.3 mg doses were offered.135 There is older literature owing to different allergen triggers, there are little data regarding the
suggesting that epinephrine should be dosed at 0.01 mg/kg, but this frequency of anaphylaxis in specific community locations or on effec-
Table 13
Frequency of Anaphylaxis in Different Locationsa
Population studied Home School/work Restaurant Other home
Children Studies, n 44 46 26 16
Averageb 57% 11% 8% 14%
Range 37%-92% 0%-28% 0%-17% 3%-34%
Adults Studies, n 4 3 3
Averageb 42% 3% 22%
Range 27%-60% 2%-5% 17%-33%
Age not specifiedc Studies, n 8 8 7
Averageb 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.
tive mitigation strategies by location. Despite the low quality of avail- Recommendation 16 (GRADE): We suggest childcare centers
able evidence, the workgroup has judged that the desirable effects of and schools implement staff training for allergy and anaphylaxis
certain interventions clearly outweigh the undesirable effects. Thus, management.
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. Certainty of Evidence: Very Low
Allergen avoidance is a key management strategy for anaphylaxis
prevention. Regarding food-induced anaphylaxis, nearly all reported Question: Should childcare centers and schools prohibit spe-
cases are triggered by ingestion of the allergen. Although contact cific foods site wide (eg, nut-free schools), rather than not imple-
reactions can cause cutaneous symptoms, such as hives or redness at ment such restrictions?
the site of contact, the risk of anaphylaxis from isolated skin contact Recommendation 17 (GRADE): We suggest that childcare cen-
(without oral transfer) is very low.156 Similarly, the risk of anaphy- ters and schools not implement site-wide food-specific prohibi-
laxis due to inhalation of food allergen is very low but has been sus- tion because current research does not support consistent
pected to occur if there is active aerosolization of the allergen (such benefits. Special circumstances: It might be appropriate to imple-
as steam from boiling milk) in close proximity.157 Studies support ment allergen-restricted zones (eg, milk-free table) when there
that casual skin contact or inhalation, as may occur in a community are children who lack the capacity to self-manage.
setting, is unlikely to trigger anaphylaxis.158−160
Determining the frequency of anaphylaxis in different locations Strength of Recommendation: Conditional
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 Question: Should childcare centers and schools stock undesig-
range and the average frequency of anaphylaxis in children and/or nated EAIs that can be used to treat any individual on school
adults by reported location.132,161−207 The younger the population, grounds who experiences anaphylaxis?
the higher the percentage of anaphylaxis events occurring in the
Recommendation 18 (GRADE): We suggest that childcare cen-
“home” location.192 A study in which 89% of 5149 participants were
ters and schools stock undesignated EAIs that can be used to treat
children reported that although the initial anaphylaxis event
any individual on school grounds who experiences anaphylaxis.
occurred most often at home, subsequent anaphylaxis events increas-
ingly shifted to outside the home, in locations such as schools and Strength of Recommendation: Conditional
restaurants.205 Although fatalities have been reported, they are
rare.190 Fatalities reportedly occurred in homes (21%-35%), schools Certainty of Evidence: Very Low
(10%-19%), restaurants (19%-20%), hospitals (6%), and unknown loca- The authors of these recommendations from the 2021 GRADE
tions (36%-75%). The average and/or median age for all 265 reported guideline for the prevention and management of allergic reactions in
fatalities was early twenties.190 childcare centers and schools found that approximately 1 in 10 aller-
Anaphylaxis in Childcare Centers and Schools gic reactions and cases of anaphylaxis in children occur in childcare
centers or schools.208 Across studies, the median reported rate of ana-
The JTFPP endorses the following GRADE recommendations from phylaxis in childcare centers or schools was 19 per 100,000 students
2021 guidelines for the management of allergic reactions in childcare per year (range: 8-118/100,000).208 The GRADE guideline condition-
centers and schools.208 ally recommended that childcare centers and schools implement an
Question: Should childcare centers and schools implement expert-designed allergy training program for personnel in combina-
training for personnel in the management of food allergy, rather tion with site-wide protocols for managing anaphylaxis and allergy
than not implementing such training? action plans for managing allergic reactions in children at risk of
anaphylaxis. Staff training is linked to short-term improvements in Consumer Protection Act of 2004221 requires disclosure of major
allergy-related knowledge, skills, and preparedness among childcare allergens on packaged food items, but the law does not require res-
and school personnel.208 Limited, low-quality evidence suggests that taurants or food establishments that prepare food to provide ingredi-
training and action plans may help reduce the rate of allergic reac- ent lists or allergy warnings to customers. Some cities and states in
tions and the need for epinephrine use in students.174,208−214 the United States have enacted laws related to food allergy awareness
Studies have not consistently found that food bans improve qual- and/or signage, but these are not universal. A few restaurants list
ity of life215 or lower the risk of allergic reactions among allergens or ingredients on their menu or other signage, a practice
students.171,172,216 Thus, the GRADE guideline conditionally recom- that seems to be increasingly adopted.218 Policies and practices may
mends that childcare centers and schools not implement site-wide need to be updated for additional allergens such as sesame which
food prohibitions (eg, “nut-free schools”). The guideline also condi- was recently added by the FDA to the list of allergens that require
tionally recommends against classroom-level food bans and allergen- special labeling.
free tables, except in cases when students lack the capacity to self- Researchers have used data from a national voluntary online reg-
manage avoidance and prevention strategies due to very young age istry to characterize food-allergic reactions in restaurants.222 Cafes,
or cognitive or physical impairments.208 fast food establishments, and Asian restaurants (as described by the
Additional common sense strategies for risk reduction have not authors) were frequently identified as locations for reactions. Peanut,
been formally evaluated but include washing hands before and after tree nuts, and milk were the most common triggers. Approximately
eating, avoiding sharing foods and drinks with others, and checking half the reactions (53.9%) occurred despite a diner informing the res-
ingredient lists for allergens. Other steps that childcare centers and taurant staff of the food allergy, 26.6% occurred when food allergens
schools can take include providing adult supervision during meals were declared on the menu, and 13.7% occurred even though the
and snacks, cleaning surfaces where food is prepared or eaten, and menu declared allergens and food allergy was communicated to res-
taking steps to avoid students’ allergens when planning and imple- taurant staff. More than a quarter of reactions were treated with epi-
menting classroom activities (eg, parties, crafts, science projects) or nephrine (28% received 1 dose, 6.2% received 2 doses). Reactions
field trips. have also been reported after allergen exposures due to takeout
The 2021 GRADE guidelines also conditionally recommended that foods.223 In an online survey of parents of children with food allergy
childcare centers and schools stock undesignated EAIs that may be ordering takeout, the most common allergens triggering reactions
used to treat anaphylaxis in any student, staff member, or other indi- were milk, peanut, and wheat, which often seemed as “hidden aller-
vidual that experiences anaphylaxis on site.208 The US School Access gens” (eg, unlabeled, inapparent, or contaminant components). Take-
to Emergency Epinephrine Act encourages states to implement poli- out orders from Asian restaurants were most frequently associated
cies requiring schools to stock undesignated EAIs for use in emergen- with severe allergic reactions. Diners reported taking a variety of pre-
cies. Undesignated EAIs may be used in cases when student-specific cautions, including writing the allergy in an online order, calling the
EAIs are unavailable, including treatment of individuals with no restaurant to discuss the order, and visually inspecting the dish; how-
known history of allergy (15%-31% of reported cases of epinephrine ever, reactions still occurred. The number of precautions taken by
use at childcare centers and schools are for those with no known takeout diners who experienced reactions was no less than by those
allergy).208 At this time, not all states have laws that require schools who did not have reactions. An AAAAI workgroup on food allergy in
to have stock epinephrine available.217 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
Anaphylaxis in the Restaurant Setting
of anaphylaxis risk is a “shared responsibility” in the restaurant set-
Question: What education should clinicians provide to patients ting (ie, both the allergic diner and food service staff have roles to
with food allergy regarding anaphylaxis in the restaurant setting? play in keeping the diner safe). Clear communication is essential.
There is a lack of high-quality data on specific strategies for safe din-
Recommendation 19 (CBS): We suggest clinicians counsel
ing, but the concepts in this table provide a framework based on
patients that although US regulations require disclosure of major
expert opinion.
allergens on labels of prepackaged foods, they do not require res-
Currently, there are no US mandates for restaurants to have medi-
taurants to declare ingredients or provide allergy warnings for
cal emergency kits with epinephrine on site. However, most states
non-prepackaged foods.
have passed legislation that allows restaurants to keep stock epi-
Strength of Recommendation: Conditional nephrine on site.225 Despite this, physicians continue to have med-
ico-legal concerns about prescribing stock epinephrine, which poses
Certainty of Evidence: Very Low a barrier to restaurants and other community settings that would like
Recommendation 20 (CBS): We suggest clinicians counsel to stock epinephrine. In countries such as Canada, where EAIs can be
patients on safe practices for dining outside of the home. purchased without a prescription, stock epinephrine programs in
community settings may be more feasible.226

Anaphylaxis Inflight
Training of restaurant staff is the mitigation strategy that has been
most often evaluated for the ability to reduce anaphylaxis in the res- An allergic inflight emergency is estimated to occur once for every
taurant setting. Knowledge gaps related to food allergy and anaphy- 37,750 flights and for less than or equal to 1 of 2 million passengers,
laxis have been noted in restaurant and other food service staff, and with emergency landings reported for less than 4.4% of these epi-
only a few staff receive specific training.218−220 The effectiveness of sodes. When patients with peanut and/or tree nut allergy have been
such training in reducing rates of anaphylaxis or improving responses surveyed, 1.7% to 10.7% reported having experienced an allergic reac-
to reactions has not been studied. tion while on a commercial flight.227−229 The nature of these reac-
Additional risk reduction strategies have been used or suggested tions and how many of them meet the criteria for anaphylaxis are
for the restaurant industry, but data are lacking on whether these not clearly reported in published studies. Epinephrine administration
practices affect rates of anaphylaxis. The Food Allergen Labeling and for inflight allergic reactions was reported to have occurred in 10% to
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 This is an important step to help ensure those with food allergy have the information they need
options, and possible accommodations. 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 When speaking with a knowledgeable and responsible food service staff member, the patient
member before ordering their meal; discuss which specific foods or family should request information about all the ingredients in the menu selection and how
and ingredients they must avoid; and receive assurance that the the food is prepared, before placing an order. If the diner feels that safe options are not avail-
utmost care will be taken to exclude these allergens and avoid able, they should seek alternative dining options.
cross-contact.
3. Ensure that all dining surfaces have been cleaned between diners to Cleaning protocols across restaurants may vary. It is not unreasonable to inquire about the
remove any food residue. This is generally the responsibility of the cleaning process that the food service staff use between diners.
restaurant, but some diners may feel more comfortable cleaning
table surfaces themselves, for example, using disposable cleaning
wipes.
4. Carry a written list (eg, allergy cards) of food allergens and hidden Allergy cards (eg, https://equaleats.com/) are used by some diners with food allergy to commu-
sources of these allergens to support communication with food ser- nicate their allergy to the food service staff. This can be a useful communication tool, espe-
vice staff. When dining in a restaurant where many food service cially when traveling or if there is a language difference between the diner and staff. It can
staff speak a different language from the patient (eg, foreign travel), help clearly articulate the diner’s food allergy and can be shared with the food service staff in
consider providing a translation of this list. 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 When eating with others, allergic diners should tell them in advance about their food allergy
event of an accidental ingestion and allergic reaction. 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- Patients with an allergy to peanuts, tree nuts, milk, or seafood should be cautious at food ser-
gens at certain venues, including: peanut, and/or tree nut exposure vice establishments that frequently serve their allergens because it may be very difficult to
in Asian restaurants; exposure to peanut, tree nuts, and/or milk in find safe menu options. The potential for cross-contact may be higher in these establish-
bakeries and ice cream shops; and seafood at restaurants that pre- ments because these allergens are more prevalent in the kitchen, and depending on the level
dominantly serve seafood. Practice extra vigilance or possibly avoid of training or knowledge of the food service staff, there may or may not be protocols in place
such venues. to minimize cross-contact. Asking the food service staff about their food allergy policy and
Be aware that there is likely higher risk of seafood exposure at res- practices and their ability to provide accurate and complete ingredient disclosure is impor-
taurants that predominantly serve seafood and practice extra vigi- tant and will help diners with food allergy better understand the potential risks of eating at
lance or possible avoidance of those venues. 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 Diners with food allergy should consider not sharing or sampling the food of dining compan-
dining out. 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 When dining out, it is important to always be prepared to treat a reaction should it occur. As
and management. such, diners with food allergy should always carry their EAIs with them when dining out.
Abbreviation: EAI, epinephrine autoinjector.
15% of cases across studies,227−230 although reports of symptoms sug- Anaphylaxis in Community Recreational Settings
gested that epinephrine might have been indicated in more
Anaphylaxis can occur in recreational community settings, such as
cases.228,230 Food allergens are the primary trigger for inflight reac-
parks and other outdoor spaces. In these settings, insect sting allergy
tions, with peanut implicated most frequently as the culprit food.227
−230 is a relevant exposure of concern (occupational exposures will not be
It is possible that there is underreporting of inflight reactions
discussed in this section). In data from the European Anaphylaxis
given past data that 29% to 50% of reactors notified airline personnel
Registry,234 half of venom anaphylaxis cases occurred in gardens and
of their reactions.227−229
parks, 25% in public places or at work, and 25% in an unspecified loca-
Many airline passengers report using risk reduction strategies
tion. On the basis of patient questionnaires, insect sting anaphylaxis
similar to those used in restaurants, such as notifying flight attend-
occurs in 0.34% to 8.9% of the general population,235,236 accounts for
ants of their allergy and bringing safe foods for flights.231 A 2013
1.5% to 50% of ED visits for anaphylaxis,51,235 and is responsible for
international study of inflight reaction found that certain reported
13% to 33% of all fatal cases of anaphylaxis.51 Measures for minimiz-
risk mitigation strategies were associated with lower odds of report-
ing chances of insect stings have been suggested in the 2016 stinging
ing an inflight allergic reaction.229 However, no prospective studies
insect hypersensitivity practice parameters.237
have evaluated whether implementation of these strategies lowers
There are other causes and settings for anaphylaxis related to
the risk of anaphylaxis. Although airline pre-notification is often sug-
community recreational activities both indoors and outdoors, such as
gested, it can potentially result in unintended consequences. The Air
food-dependent exercise-induced anaphylaxis and outdoor dining.
Carrier Access Act of 1986 allows pilots to refuse boarding to a pas-
However, there are no data quantifying the frequency of these events
senger with an identified medical risk deemed significant enough to
in the community setting. There is also limited information on the
pose a potential risk of flight diversion or danger to the passenger.232
location of drug reactions in the community setting. Allergy to beta-
Many airline websites provide some information for patients with
lactam antibiotics and nonsteroidal anti-inflammatory drugs is most
allergy; however, only a few offer allergen-free meals for preorder or
common, and most reactions occurring outside the medical setting
allow priority boarding.233
are likely to occur in the home.
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
Question: Should clinicians advise use of medical identification Epinephrine Autoinjectors: When and What to Prescribe
(eg, jewelry or wallet card) for individuals at risk of anaphylaxis?
Epinephrine is universally recommended as the first-line treat-
Recommendation 21 (CBS): We suggest that advising individu- ment for anaphylaxis.3 However, the rate of EAI prescription for
als at risk of anaphylaxis to wear or carry medical identification patients at risk of anaphylaxis remains suboptimal.111,247 Even when
(eg, jewelry or wallet card) be considered optional. If it is worn or clinicians prescribe EAIs, patients do not always adhere to their treat-
carried, the wording on medical alert jewelry or wallet cards ment plans, with researchers reporting suboptimal rates of EAI pre-
should be verified for accuracy by a health care professional. scription fills and refills, carriage, and use.111,247,248 This practice
parameter provides evidence-informed guidance for EAI prescription,
Strength of Recommendation: Conditional use, and patient education and counseling.
Question: Should clinicians take a risk-stratified approach to
Many people at risk of anaphylaxis use medical alert jewelry (or EAI prescription?
wallet cards) to declare their allergies; however, the information
listed varies across products and not standardized, and there is no Recommendation 23 (CBS): We suggest clinicians routinely
requirement for physician verification of accuracy.238,239 It is prescribe EAIs to patients at higher risk of anaphylaxis. When
unknown whether medical alert jewelry or wallet cards reduce the deciding whether to prescribe EAIs to lower risk patients, we sug-
risk of anaphylaxis or result in more rapid treatment. gest that clinicians engage in a shared decision-making process
that considers the patients’ risk factors, values, and preferences.

Stock Epinephrine in Community Settings
Question: Should stock epinephrine in community settings be Certainty of Evidence: Very Low
supported? Allergic reactions range in severity from mild skin manifestations
Recommendation 22 (CBS): We suggest that keeping stock EAI to life-threatening anaphylaxis. The severity of symptoms can vary
in community settings be encouraged, if feasible. from one reaction to another, but the pattern and sequence of symp-
toms are more reproducible.33 There are risk factors that significantly
Strength of Recommendation: Conditional 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
Studies reveal that in the United States, sports facilities, airports, which they may avoid causative agents or circumstances, and
and amusement areas are the most common places where automated whether they have completed AIT. Some subsets of patients have a
external defibrillators are used.240,241 Therefore, some people suggest higher frequency of anaphylaxis and/or greater severity of anaphy-
that these same locations should, ideally, have undesignated EAIs laxis compared with other patients. There are patients who feel a
available.242 All states have passed legislation that permits (but does substantial psychosocial burden from EAI prescriptions; for others,
not require) “entities” to stock undesignated epinephrine for emer- EAI prescriptions are linked to improved quality of life.249,250 When
gency use.225,243 “Entities” vary by state and may include camps, assessing the risk of anaphylaxis and weighing the potential benefits
theme parks, sports arenas, restaurants, childcare centers, and/or col- of EAI prescription, clinicians should consider a patient’s diagnosis,
lege campuses, and this legislation is often separate from a state’s history of allergic reaction, likelihood of allergen exposure, and other
school-entity stock epinephrine legislation. Although permitted, it is potential cofactors that could affect the likelihood of a poor outcome.
rare for community settings to have stock epinephrine available. For patients with food allergy, even small amounts of causative
There is a lack of data on the health effects, feasibility, and cost-effec- allergen may potentially trigger an allergic reaction—including ana-
tiveness of stocking epinephrine in community settings outside of phylaxis in some cases. Owing to the potential for cross-contamina-
schools. Some studies have explored people’s willingness to share tion of food products and gaps in food allergy knowledge among the
their epinephrine devices (proximity-based community response) as general public, reactions to causative foods may occur even when
another novel approach to facilitate rapid responses to anaphylaxis patients have taken steps to avoid the food. Food oral immunother-
in the community.234,244 Availability of stock EAI on airplanes has apy (OIT) is a relatively new and promising therapy for food allergy;
been found to be cost-effective and may be a safer option than stock however, safety and tolerability concerns continue to limit its use in
ampules and syringes in this setting.245,246 routine clinical practice. Many reactions to OIT are mild and resolve
Knowledge gaps related to anaphylaxis in community settings are without intervention or with antihistamine alone. However, virtually
listed in Table 15. The key points reviewed in this section are summa- all clinical trials report some severe allergic reactions.251 These are
rized in Table 16. most frequently reported during the dose escalation when treatment
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.
is initiated and during subsequent buildup dosing; however, home of uneventful doses. In 2007, this led the AAAAI and ACAAI’s Omalizu-
maintenance doses can also be associated with severe reactions, even mab Joint Task Force to recommend the prescription of EAIs to
with doses previously tolerated.252 In a recent systematic review and patients prescribed omalizumab.257 In a subsequent 2011 review, the
meta-analysis, high-certainty evidence revealed that although cur- Omalizumab Joint Task Force found that omalizumab-induced ana-
rent peanut OIT regimens effectively induce desensitization, they are phylaxis most often occurred within the first 3 injections and within
associated with considerably increased risk of allergic reactions, ana- 2 hours after injection.258 Another review found that 64% of the cases
phylaxis (22% with OIT vs 7% at baseline), and epinephrine use (risk occurred within 1 hour of injection, 69% occurred at the first or sec-
ratio = 2.7) compared with avoidance or placebo.253 For these rea- ond dose, and 43% occurred in patients with a history of prior ana-
sons, most clinicians still prescribe EAIs even to those who have suc- phylaxis unrelated to omalizumab.259 More recently, a retrospective
cessfully achieved a desensitization regimen. study of 91 patients with difficult-to-control asthma found that of
People with venom or insect bite/sting allergy can take steps to 10,472 injections of omalizumab, no anaphylaxis occurred.260 In
reduce their risk of exposure. However, they may still be bitten or another study, 0.17% (n = 6) of 3620 adult patients with severe
stung. VIT is considered nearly completely effective in preventing life- asthma experienced omalizumab-induced anaphylaxis in a treatment
threatening reactions to stings, although honey bee VIT and fire ant course of 52 months.261 Given the drug’s demonstrated, long-term
whole body extract immunotherapy offer less complete protection.237 safety and efficacy, the FDA approved home injection of omalizumab
It is typically easier for people with latex, drug, or RCM reactions in 2021 for patients with no known history of anaphylaxis to either
to avoid causative agents and circumstances. Most reactions to drugs omalizumab or other agents from the fourth dose onward if deter-
and RCM occur in health care settings, where health care professio- mined appropriate by a clinician. Although the FDA has not mandated
nals are equipped to administer epinephrine.254 However, in up to 1 EAI prescription for home injection of omalizumab, the package
in 10 cases of drug- or RCM-induced anaphylaxis, the patient experi- insert does indicate that the patient/caregiver should be able to rec-
ences a biphasic reaction, which is likely to occur outside of the ognize and treat anaphylaxis. Nevertheless, a cost-effectiveness anal-
health care setting.37,255 The JTFPP found that the greatest risk factor ysis revealed that for many patients, home injection of omalizumab
for biphasic reaction is an initial presentation that requires multiple is a cost-effective strategy.262
epinephrine doses to treat anaphylaxis (odds ratio [OR] = 4.82; 95% Other potential causes of anaphylaxis include SCIT and SLIT, which
CI, 2.70-8.58).3 provide effective therapies for the treatment of allergic rhinitis, con-
Some drugs have garnered special attention regarding the risk of junctivitis, and asthma. Rare cases of severe anaphylaxis due to SCIT
anaphylaxis. These include omalizumab, which the FDA approved in with aqueous allergen extracts have been identified, including very
2003 for moderate-to-severe persistent allergic asthma, in 2014 for rare cases of fatal anaphylaxis.263−265 Potential risk factors in SCIT-
chronic idiopathic urticaria, and in 2020 for nasal polyps. Until 2021, associated fatalities include uncontrolled asthma, prior systemic
omalizumab was only administered under medical supervision, but it reactions, administration during peak pollen season, suboptimal
is now approved for home-based treatment. Clinical trials among treatment of anaphylaxis, and dosing errors, to name a few. Although
patients with moderate-to-severe asthma initially reported a risk of most systemic reactions with SCIT occur within 30 minutes of admin-
omalizumab-induced anaphylaxis of 0.08%, which increased to 0.2% istration, approximately 15% occur after more than 30 minutes.
in post-marketing surveillance.256 Many of the reactions were Nearly all severe systemic reactions and fatal reactions with SCIT
reported to occur more than 2 hours after injection or after a number begin within the first 30 minutes after injections.266 Severe
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, not treated with a complete course of VIT
History of anaphylaxis, but on maintenance VIT or discon- Current VIT, with history of prior systemic reaction(s) to VIT
tinued VIT after more than 5 y of treatment with no high- Honey bee allergy
risk factors 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- History of prior systemic reaction(s) to AIT and/or relevant comorbidities
vant comorbidities (eg, asthma) (eg, asthma)
Abbreviations: AIT, aeroallergen immunotherapy; EAI, epinephrine autoinjector; VIT, venom immunotherapy.
patient’s risk factors for severe anaphylaxis, their values and pref-
anaphylaxis has also been rarely reported in large phase 3 clinical tri- erences, and contextual factors when deciding whether to pre-
als on SLIT, but with no reported fatalities. In clinical trials of SLIT for scribe only one vs multiple EAIs. We suggest that they routinely
seasonal and perennial allergic rhinitis, treatment-related adverse prescribe more than 1 EAI when patients have previously required
events have been reported at equal frequencies for subjects with and multiple doses of epinephrine to treat an episode of anaphylaxis
without asthma. More research is needed to evaluate the safety and and/or have a history of biphasic reactions.
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 Certainty of Evidence: Very Low
with epinephrine are rare.267 When administering SCIT or SLIT, clini-
cians must be aware of the potential risk of severe allergic reactions In some cases of anaphylaxis, symptoms only improve or resolve
and know how to manage them. Clinicians may elect to prescribe after multiple doses of epinephrine. Biphasic recurrence of signs and
EAIs to patients on SCIT, particularly those with a history of prior ana- symptoms may also occur and require additional doses of epineph-
phylaxis owing to any cause, prior systemic reactions to immuno- rine to treat. To manage the potential risk of anaphylaxis requiring
therapy, active asthma, or other potential high-risk factors. In a cost- more than 1 dose of epinephrine, regulatory agencies including the
effectiveness simulation, prescription of EAI to all patients on SCIT FDA have recommended that patients at risk of anaphylaxis carry 2
was not cost-effective compared with prescription only to patients EAIs at all times.271 In the United States, EAIs are currently only sold
with prior systemic reactions to SCIT.268 In the United States, the FDA in twin-packs, and thus, single doses cannot be prescribed. However,
mandates EAI prescription for patients on SLIT. However, in other some researchers have recently called into question the magnitude
countries, this is not an absolute requirement and is left to the discre- of health benefits and cost-effectiveness of universally prescribing
tion of the individual allergist and patient, unless mandated by local multiple EAIs.272 Shaker et al272 used Markov modeling to evaluate
regulators.269,270 and compare the cost-effectiveness of different prescribing strategies
We found no validated risk-stratification algorithms in the for patients with peanut allergy. They evaluated the following: (1)
research literature to guide EAI prescription. Drawing on clinical data routinely prescribing 2 EAIs to all patients with peanut allergy; (2)
and expertise, we present a list of examples of low-risk vs higher-risk prescribing 2 EAIs only to patients with a history of anaphylaxis; and
histories in Table 17. Higher-risk patients are more likely than low- (3) prescribing 2 EAIs only to patients with a history of anaphylaxis
risk patients to experience anaphylaxis and require treatment with that required multiple EAI doses to treat. The authors tested the
EAIs. The benefits of EAI prescription are also more likely to outweigh model in multiple economies and at different price points. They con-
the financial and psychosocial burdens (see Recommendation 28) for cluded that at current EAI prices in the United States (lowest esti-
higher-risk patients compared with low-risk patients. Some addi- mated retail price of $340 for a twin-pack) and with low reported
tional factors that are not included in the table may increase a rates of anaphylaxis requiring multiple doses to treat, universally
patient’s risk of severe anaphylaxis (eg, comorbid asthma) or the prescribing 2 EAIs is not cost-effective and has marginal health bene-
potential benefits of having epinephrine available should anaphylaxis fits compared with a risk-stratified approach.272 They found that uni-
occur (eg, residing, studying, working, or traveling in a location with versally prescribing multiple EAIs would only be cost-effective in the
long emergency response times). When a patient with no prior his- United States if the cost of a single EAI was less than $80 or the proba-
tory of anaphylaxis is admitted to the ED or visits a primary care pro- bility of needing a second dose to treat anaphylaxis exceeded 25%.
vider for anaphylaxis, they should be given a prescription for A risk-stratified approach may help clinicians evaluate a patient’s
epinephrine and recommendation for allergist assessment. Patients risk of requiring multiple EAI doses and guide shared decision-mak-
with iatrogenic anaphylaxis (eg, to RCM or drugs) may have less need ing around EAI prescription. A recent systematic review and meta-
for epinephrine prescription, but they will still benefit from allergist analysis found that 7.7% of anaphylaxis cases (all ages, all causes)
assessment to clarify their risk and provide counseling on possible were treated with multiple doses of epinephrine, including epineph-
precautions. rine administered in the community and/or health care settings.271 In
children, milk-induced reactions are more likely to require multiple
Question: How many EAIs should clinicians prescribe to each doses of epinephrine.207,273 Risk factors and cofactors for severe and
patient? fatal anaphylaxis are listed in Table 18.51,274−280 Consideration of
these factors may help inform shared decision-making around EAI
Recommendation 24 (CBS): We suggest that in jurisdictions prescription. However, it is important to note that the interaction
where single-packs of EAIs are available, clinicians consider a between these factors is complex and varies across patients and
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 Adolescence Older age Mast cell disorders

Cardiovascular diseases Uncontrolled asthma Male sex Infections
Respiratory diseases Alcohol consumption Hereditary a-tryptasemia Perimenstrual period
Antihypertensive drugs Peanut- or tree nut-induced reaction Mast cell disorders NSAIDs
Exercise Cardiovascular diseases Alcohol consumption
NSAIDs Psychological burden
Antihypertensive drugs Exercise
Unknown cause
Abbreviation: NSAIDs, nonsteroidal anti-inflammatory drugs.
exposures. Significant uncertainties limit one’s ability to reliably pre- fatal anaphylaxis found that the median time interval from allergen
dict the severity of future reactions. The presence of one or more of exposure to respiratory or cardiac arrest was 5 minutes in drug-
the factors in Table 18 does not necessarily indicate an absolute need induced anaphylaxis, 15 minutes in stinging insect venom-induced
for multiple EAIs, nor does the absence of these factors preclude the anaphylaxis, and 30 minutes in food-induced anaphylaxis.202 As sin-
possibility of a severe reaction requiring multiple doses of epineph- gle-arm observational studies, fatality case series are considered low-
rine to treat. Efforts to identify biomarkers that reliably predict the grade evidence and do not allow us to compare the odds of survival
severity of future reactions are ongoing. The JTFPP’s 2020 practice with epinephrine treatment vs without epinephrine treatment.
parameter update on peanut allergy diagnosis recommends against There is no evidence that preemptive use of epinephrine in
the use of skin prick test results, whole peanut serum-specific IgE, or asymptomatic patients prevents anaphylaxis. A 2018 analysis used
component-specific peanut sIgE to predict the severity of future reac- Markov modeling to evaluate the cost-effectiveness of preemptive
tions.281 One rationale for prescribing multiple EAIs is the potential epinephrine use in cases when a patient has a known ingestion to an
need for a backup unit if there is a misfire or misuse of the first allergen without symptoms.120 The absolute protective effect of pre-
unit.282 Misuse can be mitigated by early and repeated education on emptive epinephrine use in the absence of symptoms was low and
correct handling and use of the specific device dispensed to the not cost-effective.120 However, the authors note that advice regard-
patient. Furthermore, the potential for monitoring at home without ing preemptive epinephrine use may be patient preference sensitive.
activating EMS after administration of the first dose of epinephrine For example, although there is a lack of evidence on the benefits of
requires the availability of an additional dose of epinephrine (see preemptive epinephrine use, it is possible that a more proactive
Recommendation 26). approach might be appropriate for patients with a history of rapidly
The decision of when to prescribe multiple EAIs may be guided progressive near-fatal anaphylaxis or underlying mastocytosis. Clini-
not only by patients’ risk of severe anaphylaxis but also by their val- cians should engage patients in shared decision-making that consid-
ues, preferences, and contextual factors. In the United States, one of ers individual risk factors, values, and preferences.
the most pressing contextual constraints is that EAIs are currently
Question: When should EMS be activated after EAI use?
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 Recommendation 26 (CBS): We suggest that clinicians counsel
and from campus each day. Such children may require 2 or more EAIs patients that immediate activation of EMS may not be required if
to meet school requirements while also ensuring adequate access to the patient experiences prompt, complete, and durable response
epinephrine in other settings. Residing, working, or attending school to treatment with epinephrine, provided that additional epineph-
in a location with long emergency response times is another example rine and medical care are readily available, if needed. We suggest
of a contextual factor that may warrant the prescription of multiple that clinicians counsel patients to always activate EMS after epi-
EAIs. nephrine use if anaphylaxis is severe, fails to resolve promptly,
fails to resolve completely or nearly completely, or returns or
Question: What is the optimal timing for EAI administration in
worsens after a first dose of epinephrine.
relation to symptoms?
Recommendation 25 (CBS): We suggest that clinicians counsel
patients and caregivers to give epinephrine at the first sign of sus- Certainty of Evidence: Very Low
pected anaphylaxis.
Until recently, professional and patient organizations have gener-
We suggest that, in general, clinicians counsel patients or care- ally advised patients and caregivers to immediately seek emergency
givers not to give epinephrine preemptively to an asymptomatic care or activate EMS (ie, call 911) when anaphylaxis occurs, even if
patient. epinephrine is administered and symptoms resolve.286−288 However,
there is a lack of evidence revealing the benefits of universal EMS
Strength of Recommendation: Conditional activation. In 2019, Shaker et al125 modeled the health and economic
Certainty of Evidence: Very Low outcomes associated with reflex activation of EMS immediately after
epinephrine use, compared with a “watchful waiting” approach, in
There is a lack of high-quality evidence on the effects of early vs which patients or caregivers only activate EMS afer epinephrine
delayed epinephrine administration for anaphylaxis. However, the administration if signs and symptoms of anaphylaxis do not immedi-
available evidence suggests that early epinephrine use for anaphy- ately resolve completely or nearly completely. Assuming that reflex
laxis may help improve clinical outcomes. Studies have linked activation would lower the fatality risk by 10-fold, the authors found
delayed epinephrine use after an anaphylaxis to increased risk of that the cost of preventing 1 death through immediate activation
biphasic reactions3 and hospitalization.196,283,284 In fatality case was $1,349,335,651. Reflex activation would only be cost-effective if
series, most patients who died from anaphylaxis did not receive it reduced the fatality risk by 500-fold and if 75% of people who
timely treatment with epinephrine.119,202,203,285 One case series of received epinephrine required additional care in the ED—both of
Figure 5. General guidance for activation of EMS and administration of a second dose of epinephrine. EMS, emergency medical services.
which are unlikely. However, the authors also note that patient pref- had ready access to additional EAIs. Patients with a history of pro-
erences for EMS activation may vary, particularly among groups at gressively severe or biphasic reactions may require more careful or
high risk of severe or biphasic anaphylaxis. prolonged observation, as may those with comorbid conditions that
During the “stay at home” phase of the initial wave of the COVID- may affect response to anaphylaxis and treatment. The recommenda-
19 pandemic, concerns about the risk of infectious disease exposure, tions of Casale et al126 were proposed as an interim measure related
health care resource use, and the need for short-term health care ser- to factors affecting EDs and the population at large during that stage
vice rationing led allergy specialists to review and revise their recom- of the COVID-19 pandemic. More recently, Casale et al129 have re-
mendations around EMS activation.3,126 Casale et al126 implemented evaluated these recommendations for extended application beyond
many of the findings of Shaker et al125 when developing Food Allergy the contingencies of the pandemic and discuss the considerations for
Research and Education’s anaphylaxis management algorithm for the and against home management (Table 19).
COVID-19 context. For patients with a prior history of anaphylaxis To date, “immediate” and “prompt” anaphylaxis resolution times
that required treatment with multiple doses of epinephrine, intuba- have not been objectively defined. For epinephrine, researchers have
tion, and/or ventilation, Casale et al126 recommended that EMS not yet determined the optimal time to peak plasma concentration
should be immediately activated on recognition of anaphylaxis. For (Tmax), time to pharmacodynamic (PD) parameter response, nor the
patients they considered to be at lower risk, they recommended acti- optimal peak plasma concentration (Cmax) required for symptom
vating EMS when severe signs and symptoms do not promptly resolution. Classic epinephrine pharmacokinetic (PK) data suggest
resolve with epinephrine treatment. In the opinion of many members that the Tmax is not more rapid than 12 to 15 minutes, and more
of this panel, it is sufficient for severe signs and symptoms to resolve recent data suggest that this may more reliably occur at 15 to 25
even if some residual cutaneous symptoms remain (Fig 5). minutes.289 However, some PD data suggest that mean increases in
Casale et al126 recommended careful monitoring for recurrence, systolic blood pressure occur less than 5 minutes after intramuscular
with non-urgent follow-up care if there was prompt and complete epinephrine injection, and anecdotally, many clinicians have
resolution of severe symptoms after epinephrine use and if patients observed patients responding (sometimes completely) within a few
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, Being unaware of the allergic symptoms that warrant the use of EAI
availability of the anaphylaxis treatment plan
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 Concerns about the potential epinephrine adverse effects
anaphylaxis
Good adherence to previous treatment recommendations, for example, use EAI Poor adherence to previous treatment recommendations, for example, not administering
for anaphylaxis in the past or use of controller medications for chronic EAI for anaphylaxis in the past or not using controller medications for chronic conditions
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
minutes of injection. It is difficult to suggest a specific duration of evaluation and treatment when signs or symptoms of serious
time to wait before a second dose of epinephrine is administered and adverse events develop.
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, Certainty of Evidence: Low
or activate EMS (Fig 5):
Epinephrine is generally safe, and there are no absolute contrain-
dications to its use for anaphylaxis. Compared with intravenous
1) Observe at home if signs and symptoms that had emerged before administration, intramuscular epinephrine is associated with
epinephrine administration resolve within minutes of epineph- reduced risk of dosing errors and adverse events.291,292 The adverse
rine administration, without recurrence, or if the patient is effects associated with EAI use are typically mild and transient, with
asymptomatic. Patients with scattered residual hives or other 1 registry study reporting tremors, palpitations, and anxiety as the
rash (including erythema), even those with newly emerging but most common.292 A 2018 computer simulation study found that the
isolated hives or erythema without other symptoms occurring serious adverse event rate for EAI administration was only 0.73%.293
after epinephrine administration, may be observed at home pro- In rare cases, epinephrine use for allergic reactions can cause car-
vided no additional new symptoms develop. diac adverse events such as arrhythmias or myocardial infarction.294
2) Consider EMS activation and possibly a second dose of epineph- When cardiac adverse events do occur, they are rarely associated
rine, or may continue to observe at home if comfortable, if signs with intramuscular administration. One observational cohort study
and symptoms that had emerged before administration of the found that among patients treated with epinephrine in an ED,
first dose of epinephrine are improving or resolving within adverse cardiovascular events were reported in 4 of 316 (1.3%) intra-
minutes of epinephrine administration. For example, persistence muscular administrations.291 In a registry-based study in Spain,
of a mild sensation of globus, nausea, coughing, or stomachache potentially serious adverse events—including increased blood pres-
may be closely observed at home provided symptoms are sure, chest discomfort, and electrocardiogram changes—were
improving (not worsening and are perceived to be getting better) reported in 4 of 256 (1.6%) intramuscular or subcutaneous adminis-
and do not persist for longer than 10 to 20 minutes without trations.292 Retrospective cohort studies suggest that the risk of
observing additional signs of improvement. Multiple contextual adverse cardiac events after epinephrine use is higher in older
factors (Table 19) may influence a patient or caregiver’s decision patients (age ≥50 years).295,296 This may lead to reluctance to pre-
whether to administer a second dose of epinephrine and contact scribe or administer epinephrine to older adults or people with a his-
EMS or continue observing without further intervention. tory of cardiovascular conditions. However, those same populations
3) Activate EMS immediately and consider a second dose of epi- have increased risk of severe or fatal anaphylaxis.294,297,298 Thus, the
nephrine (do not observe at home) if signs and symptoms that authors of case reports, observational studies, and reviews have gen-
had emerged before epinephrine administration are not resolv- erally recommended prompt treatment of anaphylaxis with intra-
ing or are worsening. Particularly concerning symptoms would muscular epinephrine, even in people with advanced age or other
include respiratory distress, stridor, altered consciousness, car- cardiac risk factors.295,299−302 Clinicians should counsel patients with
diovascular instability, cyanosis, or incontinence not typical for cardiac risk factors to seek immediate evaluation and treatment if
their age. This would also include non-skin symptoms that fail to chest pain or other signs or symptoms of cardiac adverse events
resolve or worsen, including but not limited to repeated (>2 develop after epinephrine use.
total) episodes of vomiting, persistent hoarseness, cough, dys- Other potential adverse events after an EAI administration include
phagia, wheezing, or lightheadedness. 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-
The workgroup recognizes that perceptions of anaphylaxis sever- ting a bone.303,304 In a 2020 study using EpiPen trainer devices,
ity may vary from one individual and context to another. A guide to researchers found that administering an EAI with a “swing and jab”
severity grading of hypersensitivity (including non-anaphylactic) motion rather than a “place and press” technique may result in more
reactions is presented in Table 9. When developing an anaphylaxis leg movement and increased risk of laceration. More research is
management plan and determining an individualized set of condi- needed to evaluate strategies to reduce the risk of EAI-related lacera-
tions for when contacting EMS is recommended or may not be tion and other injuries. However, Brown et al303 have proposed sev-
required, clinicians should engage patients in a shared decision-mak- eral strategies which we present in Table 20.
ing process that considers individual risk factors, values, and prefer- Improper handling of EAIs can also lead to accidental injection
ences. Given variability in contextual factors, there is not likely a and needlestick injury, frequently in the thumb or other digit.305 One
single universal approach for all patients and contexts.290 registry study found that after unintentional exposures to EAIs, most
This recommendation assumes that epinephrine has been admin- people report only minor to moderate effects.305 In rare cases, digital
istered promptly “at the first sign of suspected anaphylaxis” (see Rec- ischemia after accidental injection into the thumb or other digit has
ommendation 25). Delay in administration may delay or impair the resulted in digital amputation.306 A 2020 review recommended oral
response to epinephrine and should be taken into account in deciding phentolamine as the most effective treatment for reducing
when to activate EMS.
Question: What are the adverse events associated with EAI Table 20
use? Are certain populations at increased risk of adverse events? Proposed Strategies to Reduce the Risk of EAI-Related Injury303
How should this inform EAI prescription and patient education? 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
Recommendation 27 (CBS): Serious adverse reactions to intra- motion rather than a swing and jab motion
muscular epinephrine are very rare and should not pose a barrier 3. Hold the EAI in place for the shortest period of time recommended by the
manufacturer
to the prescription or early administration of EAIs when indi-
4. Avoid reinserting the needle if it dislodges before the recommended hold time
cated. To manage the risk of adverse events, we recommend that passes
clinicians counsel patients and caregivers on the proper use of
EAIs, the common adverse effects, and the need for immediate Abbreviation: EAI, epinephrine autoinjector.
epinephrine-induced digital ischemia.306 Despite the low quality of anaphylaxis, number of food allergies, and atopic dermatitis.312 In
available evidence, the workgroup has judged that the desirable contrast, a 2022 French study found no association between the pro-
effects of certain interventions clearly outweigh the undesirable vision of an EAI and worse health-related quality of life,313 and a
effects. Thus, we have issued strong consensus-based statements 2021 Japanese study found no link between EAI possession and men-
based on very low-to-moderate quality evidence, similar to good tal health outcomes.314 Some evidence suggests that patient treat-
practice statements under the GRADE methodology. ment preferences, history of anaphylaxis, and baseline stress may
affect the burden of epinephrine prescription and its effects on qual-
Question: What are the burdens of EAI prescription? How
ity of life.121,315,316 Ward and Greenhawt121 specifically noted an
should this inform EAI prescription and patient education?
interaction effect; epinephrine use was associated with decreased
Recommendation 28 (CBS): We suggest that clinicians discuss quality of life in general but increased quality of life in caregivers of
the potential financial and psychosocial burdens of EAIs with patients where the device was reportedly used for presumed anaphy-
patients while engaging in shared decision-making. laxis. A 2020 study in the United States found that approximately 22%
of children with food allergy, 50% of adolescents, and 36% of parents
Strength of Recommendation: Conditional reported anxiety caused by EAIs.250
Question: What autoinjector characteristics should clinicians
Recognizing the financial and psychosocial burdens of treatment consider when prescribing EAIs?
is important for providing patient-centered care and addressing
Recommendation 29 (CBS): When deciding which EAI to pre-
potential barriers to treatment adherence. A 2018 survey of parents
scribe, we suggest that clinicians consider dosage, needle length,
of children with food allergy in the United States found that 97% felt
affordability, access, and patient treatment preferences.
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 Strength of Recommendation: Conditional
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 Multiple brands of EAIs are available in the United States, includ-
States than in many other countries. In the United States, the average ing the following: Auvi-Q (Kaleo), EpiPen/EpiPen Jr. (Mylan), and
wholesale price of 2 EpiPens increased dramatically from $113.27 in generic versions of EpiPen/EpiPen Jr. (Viatris, Teva) and Adrenaclick
2007 to $730.33 in 2016.310 In comparison, the average wholesale (Amneal). The FDA has also approved the Symjepi epinephrine injec-
prices of generic EAIs, epinephrine prefilled syringes, and ampules of tion device, a prefilled syringe without autoinjector functionality.
epinephrine are substantially lower.310,311 Some devices are available in other countries but not currently avail-
In addition to the financial burden, EAI prescription may also have able in the United States (eg, Anapen, Emerade, Jext). Devices vary in
psychosocial effects. Although some studies have found that patients their available doses, manufacturer-indicated weight class, and
with food allergy and their caregivers may have positive feelings design, including needle length (Table 21). They also vary consider-
about EAIs, other studies have found that EAI prescription is associ- ably in cost (Recommendation 28). When deciding which device to
ated with reduced quality of life.249,250 In a 2013 Australian study, prescribe, clinicians may consider these characteristics in relation to
health-related quality of life was worse in children with food allergy patient factors such as age, weight, sex, and insurance coverage.
who were provided an EAI, even after controlling for age, 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 Weight class supported by Needle lengthb Pressurec
manufacturera (kg) practice parametera (kg) (cm)
Adrenaclick 0.15 15-30 <25 1.17 High

0.3 ≥30 ≥25 1.17 High
d
Anapen 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
Emeraded 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
Jextd 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.
Dosage of epinephrine after an injection, the initial plasma peak was similar
in both groups, and the overall bioavailability of epinephrine was
The current standard practice is to treat anaphylaxis with a dos-
higher in the overweight women.329 There is emerging evidence
age of epinephrine of 0.01 mg/kg, up to a maximum of 0.3 mg for
that the pharmacokinetics of epinephrine may vary between indi-
children and teenagers and 0.5 mg for adults. However, there is a
vidual patients and between different devices and methods used for
lack of robust data to substantiate this recommendation, and more
administration.289,330 This practice parameter addresses only
research is needed to determine the optimal dosing. EAIs are only
injectable epinephrine; noninjectable routes of administration have
available in a limited number of premeasured doses for manufac-
been developed and have been reported to have favorable pharma-
turer-specified weight classes (Table 21). In the United States, the
cokinetic and pharmacodynamic profiles, but no clinical evidence
FDA has approved 0.3 mg EAIs for patients weighing more than or
base was available at the time of the development of this practice
equal to 30 kg, 0.15 mg EAIs for patients weighing 15 to 30 kg, and a
parameter.
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-
Accessibility
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 Manufacturer shortages, patient drug coverage, and other factors
available in some countries for patients weighing more than 60 kg. may affect the accessibility of EAIs and influence providers’ prescrib-
Using dosages specified by manufacturers, patients will receive ing decisions.311,331 Clinicians may ask to review insured patients’
increasingly less than the recommended dose as their weight drug formularies to learn which EAIs are covered by their insurance.
increases.320 To limit underdosing, the AAAAI, AAP, CSACI, and EAACI Some uninsured or underinsured patients may be eligible for manu-
support switching to 0.3 mg at 25 kg.2,15,269,321 The CSACI advises facturer-sponsored coupons or financial assistance programs to help
that clinicians may consider prescribing a 0.5 mg EAI (not currently offset the cost of EAIs; however, these programs typically exclude
available in USA) for people weighing more than or equal to 45 kg.269 Medicare and Medicaid recipients. In the United States, EAIs are sold
Among teenagers, a small randomized trial of EAI administration only in packages of 2; the cost might be reduced, and access
found no significant adverse events following intramuscular self- improved, if they were available in single units. Clinicians may also
injection with 0.3 mg or 0.5 mg of epinephrine.322 The 0.5 mg dose consider prescribing generic EAIs as a more affordable alternative to
resulted in higher plasma catecholamine level than the 0.3 mg dose. 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
Needle Length and Pressure recently reviewed the available research on the clinical and cost-
effectiveness of EAIs vs manual epinephrine administration with an
When administering epinephrine for anaphylaxis, the standard
ampule/vial and syringe and found no relevant studies.332
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 Usability and Patient Preference
the muscle, but not so long that it strikes a bone or causes intraoss- Some people may find certain EAIs easier to use, more convenient,
eous injection. or otherwise more appealing than others. When researchers asked
The depth of delivery of epinephrine is affected by the pressure adults to simulate EAI administration with trainer devices, they found
with which it is delivered, including the pressure generated by the lower rates of error with Auvi-Q than with EpiPen Jr. or
device (propulsion) and the compression by the person administer- Anapen.333,334 A 2013 study in the United States also found that chil-
ing the injection.323,324 On the basis of ultrasound imaging measure- dren and caregivers expressed a preference for Auvi-Q over Epi-
ments of skin-to-bone and skin-to-muscle distance, Dreborg et Pen.335 Unlike other EAIs, Auvi-Q provides audio prompts to guide
al154,325 predicted that low-pressure EAIs (Emerade) posed no risk of administration. However, some patients or caregivers may prefer
intraosseous injection and low risk of subcutaneous injection. For other brands of EAI due to familiarity or other reasons. A 2022 study
high-pressure EAIs (Auvi-Q, EpiPen, Jext), they found that the risk in Ireland found that caregivers tended to prefer EpiPen over Anapen,
varied by demographics and device. They predicted that in children Emerade, and Jext.336 When asked why they preferred a particular
weighing less than 15 kg, the risk of intraosseous injection was lower brand, respondents said that they found it easy to administer, the
with Auvi-Q 0.1 mg, compared with EpiPen Jr. and Jext 0.15 mg; how- instructions on the label were clear and easy to follow, the manufac-
ever, Auvi-Q 0.1 mg posed higher predicted risk of subcutaneous turer provided helpful resources, and/or it was the brand they had
injection than other devices.154,325 In a follow-up study, they found been trained on by a health care professional.
that injecting EAIs through thick winter clothing increased the risk of
subcutaneous injection for all brands—and up to 100% for Auvi-Q Question: What counseling, education, and/or training on epi-
0.1 mg specifically.317 Counseling patients to remove heavy clothing nephrine should clinicians provide to patients and caregivers?
before administering EAIs may help mitigate the risk. Recommendation 30 (CBS): During visits with patients who
Dreborg et al154 predicted that the risk of intraosseous injection have been prescribed EAIs, we recommend that clinicians rou-
was low in children weighing 15 to 30 kg and negligible in adults. tinely review the essentials of EAI carriage, storage, and use;
Ultrasound imaging measurements suggest that among adults, the encourage patients to regularly practice EAI administration with
risk of subcutaneous injection is highest in obese women.325,326 a trainer device; and discuss strategies to manage barriers to
Both body mass index and sex differences in subcutaneous tissue adherence that patients may have experienced.
depth may affect the risk of subcutaneous injection because women
tend to have more subcutaneous fat on their thighs than men.326−328 Strength of Recommendation: Strong
However, Duvauchelle et al329 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- Many patients and caregivers do not administer epinephrine
tion (n = 10 of 12) compared with non-overweight men (n = 1 of when indicated, because of a variety of factors.247,337 These include
18).329 However, when the researchers evaluated the bioavailability suboptimal prescription and carriage of EAIs, gaps in knowledge and
lack of comfort in recognizing anaphylaxis and administering EAIs, Table 22

and fear that administering an EAI may cause harm. Multiple studies Summary of Key Knowledge Gaps Regarding Prescription and Use of Epinephrine That
reveal the benefits of clinician-provided education and counseling for Require Additional Research
improving EAI-related knowledge, skills, and comfort.338 However, a Lack of consistent definition of anaphylaxis and clinical criteria for diagnosis
single instructional session is not sufficient for sustained across scientific societies and professional organizations
Lack of validated biomarkers that reliably predict the severity of future allergic
improvement.339,340 More research is needed to identify the optimal
reactions
frequency of EAI education for patients and caregivers, but 1 study in Lack of validated risk-stratification algorithms for guiding EAI prescription
Turkey suggests that 6-month intervals may be appropriate.341 Lack of validated strategies to reduce the risk of EAI-related lacerations and other
Possessing an EAI trainer device and practicing its use on another injuries
Lack of high-quality evidence regarding the . . .
person have also been linked to increased rates of proper
○ effects of early vs delayed epinephrine administration for anaphylaxis
administration.342,343 Hands-on experience with administering ○ outcomes after reflex EMS activation vs watchful waiting after epinephrine
active EAIs is beneficial, too. When patients or caregivers adminis- administration for anaphylaxis
tered an EAI for an allergic reaction during a medically supervised ○ optimal epinephrine dosing
oral food challenge, they reported improved EAI confidence, knowl- ○ implications of EAI needle length
○ ideal frequency of EAI training for patients and caregivers
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- Abbreviations: EAI, epinephrine autoinjector; EMS, emergency medical services.
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 especially in patients with diabetes. By interfering with the body’s
Patients and caregivers may also benefit from reminders to natural renin-angiotensin-aldosterone system, ACEIs block the con-
replace EAIs after the devices have been used or expired. If they for- version of angiotensin I to angiotensin II, thereby preventing the
get to replace an expired EAI—or are unable to do so because of man- breakdown of bradykinin, promoting vasodilation, and may have
ufacturer shortages or other barriers—it is preferable to use the direct effects on mast cells. In both human and mouse models, BBs
expired device rather than no device at all to treat anaphylaxis. and ACEIs have been found to increase the severity of anaphylaxis
Recent studies have found that expired EAIs retain substantial epi- and may have an additive effect when used in combination (which
nephrine activity (80%-90%), well beyond their expiration dates.348 has become a common therapeutic approach in severe CVD).362 The
−350
Pediatric doses may degrade more quickly after expiration com- ARBs may blunt the cardiovascular adaptive compensatory response
pared with adult doses.350 to shock but do not directly affect the kinin system. There is not suffi-
Despite the revealed benefits of EAI education for patients and cient evidence to address whether ARBs are similar to ACEIs with
caregivers, provision of this support remains suboptimal.351,352 Clini- respect to the risk of severe anaphylaxis (see specific medications in
cian-reported barriers to providing EAI education and counseling subsequent discussion). Therefore, ARBs are not addressed in this
include lack of time, lack of training devices, lack of role clarity practice parameter, and anything stated about ACEIs should not nec-
around who is responsible for educating patients, and gaps in clini- essarily be construed to apply to ARBs.
cian knowledge, including confusion about the different brands of Although there is a widely held assumption that the use of BBs
EAIs.352−354 Proposed strategies to address these barriers include and ACEIs is contraindicated in all patients who are at risk for poten-
automated implementation of EAI teaching and comfort assessments tial anaphylactic reactions of any kind, there is conflicting evidence
during check-in at allergy clinics,351,355 provision of a dedicated phar- in the literature of the actual risk of these medications.297,363,364 This
macist who can provide counseling on medication,352 and provision has become a dilemma for an increasing proportion of patients in a
of EAI training for clinicians.356−360 Studies have found that in-person variety of clinical settings including AIT (both SCIT and SLIT), VIT,
training sessions,360 video education sessions,356,357 e-learning allergen skin testing, food anaphylaxis, RCM administration, drug
sessions,358,361 and mixed-method training approaches359 can help infusion/intravenous immunoglobulin (IVIG), MCAS, IA, and desensi-
improve EAI knowledge, skills, and confidence among clinicians and tization procedures. The perception of risk is based on data from
students. Some evidence suggests that training clinicians on strate- older studies where most of the BBs in use were nonselective (eg,
gies to identify and address psychosocial barriers to EAI adherence propranolol, nadolol), with many of the reports not taking into
may also yield benefits.353 Despite the low quality of available evi- account the confounder of cardiac comorbidities that could indepen-
dence, the workgroup has judged that the desirable effects of certain dently account for the increased risk of severe anaphylaxis.297 There
interventions clearly outweigh the undesirable effects. Thus, we have is also clinically significant medical risk in stopping or changing the
issued strong consensus-based statements based on very low-to- prescribed medications such that the risk of discontinuing the medi-
moderate quality evidence, similar to good practice statements under cation may far exceed the risk of more severe anaphylaxis.
the GRADE methodology. A systematic review and meta-analysis of observational studies of
Knowledge gaps regarding prescription and use of epinephrine for the relationship between anaphylaxis of all causes and use of BBs and
anaphylaxis are listed in Table 22. 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-
Beta-Blocker and Angiotensin-Converting Enzyme Inhibitors
nificantly increased. The quality of evidence was low, and it was not
BB medications are widely used for a variety of cardiovascular possible to adjust for CVD in their analysis because only 1 study had
conditions, including hypertension, arrhythmias, and congestive adjusted data. The authors noted that in the 3 studies that reported
heart failure, and for prevention of migraine and treatment of glau- severity of anaphylaxis in relation to CVD, the OR for severe anaphy-
coma. These medications have physiological effects that might affect laxis in relation to CVD was 3-fold higher than the OR in those receiv-
the severity of anaphylaxis and the response to treatment. BBs may ing BB treatment and 5 times higher than the OR in those on the
reduce compensatory cardiovascular responses to anaphylaxis, may ACEIs.297
enhance the release of mast cell mediators, and may interfere with Given the current propensity to use more cardioselective beta-
beneficial effects of endogenous and therapeutic epinephrine. ACEIs blocking agents (eg, metoprolol, atenolol), and the risk/benefit ratio
have similar uses to BBs for patients with cardiovascular conditions, for each of the interventions, we recommend a 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? All of these disease states have been found to derive Risks include poorly controlled heart rate, inadequate secondary preven-
Post-MI benefit from BB. tion of cardiac disease, and ongoing symptoms of CHF. Glaucoma often
CHF cannot be managed without ocular BBs but risk of systemic complica-
Tachyarrhythmia tions of beta-blockade extremely low. Minimal risk of avoiding BBs for
Migraine migraine prophylaxis as many alternatives now exist.
Glaucoma
Diabetes
What is the indication for the intervention? Benefit of skin testing includes accurate diagnosis. Risk of avoiding skin tests includes delayed/inaccurate diagnosis.
Skin test Benefit of environmental AIT is mainly improved QOL. Risk of avoiding AIT includes ongoing QOL burden if pharmacotherapy has
Initial AIT Benefit of VIT is reduction of morbidity and elimina- failed.
Mc AIT tion of mortality. Risks of avoiding VIT means ongoing risk of potentially life-threatening
Initial VIT anaphylaxis.
Mc VIT
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.
making discussion between patient, prescribers, and providers to differs, there has been little to differentiate their risks from each
convey the absolute and relative risk of the treatment/procedure other in the published reports.
while receiving the BB/ACEI medication, the risk of stopping the BB/ Although it is believed that there is less potential risk with beta-1-
ACEI medication, and alternative medications or procedures. Recom- selective blockers than with nonselective BBs, there are insufficient
mendation to the individual patient should include evaluation of data in the published reports to address this question. Still, when
many potential risk factors including the frequency of exposure (to possible, consideration should be given to managing patients at risk
the anaphylaxis trigger), predictability of exposure (expected vs for anaphylaxis with a cardioselective BB so as to minimize the risk,
unexpected), severity of underlying cardiovascular condition, addi- given the more targeted nature of these BBs, thus avoiding blockade
tive risk of BB plus ACEI medications, medical necessity, and benefit of the beta-2 adrenergic effects on the airways. Of note, this is a theo-
of the treatment/procedure. retical consideration which lacks high certainty supporting evidence.
There are also scant data on the relative risk of ACEIs and ARBs. In
Framework for Risk Assessment
1 study of angioedema (n = 4511 events), the adjusted OR compared
It is important to place the clinical questions described here in with BBs was 3.04 for ACEIs, 2.85 for the direct renin-inhibitor aliski-
appropriate context of both potential risks and benefits of these med- ren, and 1.16 for ARBs.365 In a study of cardiac catheterization, 70 epi-
ications in patients who are at risk for future anaphylaxis. A sample sodes of anaphylaxis occurred during 71,782 exposures; there was no
framework for this evaluation is found in Table 23. The clinician, the significant difference in the frequency of anaphylactic reactions
patient, and the prescriber (eg, cardiologist) must consider the bene- between controls, BB (mostly beta-1 selective), ACEI, or ARB medica-
fit of the medication for its prescribed indication, the benefit of the tions.366 In a study of systemic reactions to immunotherapy injec-
medical procedure or treatment that is said to be contraindicated, tions, there was no difference in the frequency of reaction between
the risk of stopping the prescribed medication, the risk of not having ACEI- and ARB-treated patients.367 It should not be assumed that
the medical procedure or treatment, and the risk of having the medi- ARBs carry the same potential risks as ACEIs, but there is not suffi-
cal procedure or treatment while continuing the prescribed medica- cient evidence to recommend either avoidance or safety of ARBs in
tion. patients at risk for anaphylaxis. Moreover, angioedema caused by
In most cases, the risk of stopping the BB or ACEI is greater than ACEI or ARB is likely due to a different mechanism than the angioe-
the risk of more severe anaphylaxis if the medication is continued. dema that occurs with anaphylaxis.
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
Stinging Insect Allergy and Venom Immunotherapy
decision-making often rests on the patient’s desire or need for the
procedure/treatment and their willingness to accept the potential Question: Should BB or ACEI be discontinued or changed in
risk of the medications. patients with a history of insect sting anaphylaxis who are not yet
However, the risk of anaphylaxis may be higher for some patients on VIT?
than others. The frequency of natural exposure to potential triggers
of anaphylaxis may be very low in some people (eg, insect sting), but Recommendation 31 (CBS): We suggest that patients with a
exposure occurs in all patients with food OIT and with food/drug history of insect sting anaphylaxis who are not receiving VIT may
challenges. The exposure is known with AIT/VIT, but the risk of ana- continue BB or ACEI medications when the medical necessity of
phylaxis is very low with these. The risk of foregoing certain proce- the daily medication outweighs the chance of increased severity
dures or treatments, such as AIT in many cases, may be relatively of anaphylaxis to a sting.
low; however, the risk of foregoing other procedures or treatments, Strength of Recommendation: Conditional
such as VIT for life-threatening sting anaphylaxis, may be signifi-
cantly higher. 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
Specific Medications ACEIs?
In this document, we will generally refer to BB and ACEI medica- Recommendation 32 (CBS): We suggest that VIT may be pre-
tions together. Although their mechanisms of action differ and the scribed for patients with a history of insect sting anaphylaxis who
rationale for their potential impact on outcomes of anaphylaxis are treated with BB or ACEI medication, with shared decision-
making regarding the benefits and potential harms of concurrent sting in 388 patients receiving BB and ACEI medications (OR = 1.14;
VIT treatment and medication, compared with withholding either 95% CI, 0.89−1.46; P = .29).298 In contrast to the earlier report of Nas-
the treatment or the medication. siri et al,362 the data in the study of Sturm et al298 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 al298 and
Certainty of Evidence: Low Francuzik et al378 revealed somewhat differing results with respect
to severity of anaphylaxis in patients receiving BBs or ACEIs, they
Question: In patients on maintenance VIT who are treated with both revealed that the risk of reaction related to medications corre-
BBs or ACEIs, should VIT be stopped or the medication discontin- lated very closely with the risk related to CVD and, therefore, could
ued? not be attributed directly to the medications. Kopac et al379 studied
Recommendation 33 (CBS): We suggest, in most cases, treat- biomarkers for severe insect sting anaphylaxis and found that the use
ment with BB or ACEI medication need not be changed or discon- of BBs or ACEIs was not associated with the severity of honey bee
tinued in patients receiving maintenance VIT. field sting reactions or adverse reactions to VIT.
The accumulated evidence now supports a modified approach to
Strength of Recommendation: Conditional 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
The potential for increased risk of anaphylactic reactions in does not seem to be any increased risk associated with cardiovascular
patients treated with BBs or ACEIs was first reported in relation to medications. It is important to acknowledge that patients with CVD
insect sting allergy and VIT 30 to 40 years ago. These early reports have an inherently increased risk of severe anaphylaxis, which is all
cited individual cases as examples of such risk but did not include the more reason to maintain treatment that is medically indicated to
any controls or data in larger populations.368−370 Mu € ller and Hae- mitigate that risk. Thus, it is believed to be safer for these patients to
berli371 recognized the importance of BBs in management of CVD and remain on appropriate BB or ACEI medications rather than to discon-
studied patients with CVD and BB treatment who received VIT. Dur- tinue these medications. Moreover, changing the medication may
ing VIT buildup, the BB was replaced by an alternative drug in most lead to increased morbidity or mortality from the underlying CVD,
but continued in some due to medical necessity; the BB was resumed which is estimated to exceed the risk of severe anaphylaxis that
during maintenance VIT in most cases. There were additional patients might result from staying on the medications. This was found to be
who had been started on a BB during maintenance VIT. Thus, 25 the case in an analysis simulating the life expectancy of patients with
patients were treated with a BB during VIT (all with history of severe peanut anaphylaxis and CVD.380 Although the prescribing physician
sting anaphylaxis). Systemic symptoms occurred in 12% of the may be consulted about the medical necessity of the BB or ACEI medi-
patients receiving a BB and in 11.6% of 138 patients with CVD who cation, they should only be changed when there is an alternative
were not receiving a BB. There was also no difference in the rate of medication that is safe and effective.
systemic reaction to stings during VIT in patients with CVD who were Decisions regarding VIT and continuing cardiovascular medica-
or were not treated with a BB. tions should occur in the context of shared decision-making that
Concern regarding BB and ACEI treatment in patients at risk for includes the relative indication for VIT (severity of previous sting
insect sting anaphylaxis was increased by the report of Rue €ff et al372 reaction and risk of future sting anaphylaxis), the medical necessity
of 962 patients with a history of sting anaphylaxis (52 on BB and 42 of the medication (eg, BBs for post-myocardial infarction, congestive
on ACEI) that revealed a significantly greater severity of sting ana- heart failure, high blood pressure, glaucoma, or migraine) and its
phylaxis in patients receiving a BB (34.6% severe vs 20.7% with no BB; benefit and risk, the values and preferences of the patient, and the
P = .024) or ACEI (42.9% severe vs 20.4% with no ACEI; P = .002). A relative efficacy of non-BB or non-ACEI alternatives. Underlying CVD
similar study by Stoevesandt et al373 found no correlation between is recognized in the Insect Allergy Practice Parameters as one of the
cardiovascular medications and the severity of sting anaphylaxis. high-risk factors that can support the prescription of VIT and the con-
Both groups published subsequent reports on patients receiving VIT tinuation of VIT indefinitely.237 Therefore, the recommendations for
revealing no increased risk of systemic adverse effects in patients patients with insect sting allergy may differ from those for other
receiving BB or ACEI medication.374−377 It is noteworthy that both immunotherapy patients.
Stoevesandt et al376 and Mu € ller and Haeberli371 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 Allergen Immunotherapy
issue of BB/ACEI treatment in patients experiencing insect sting ana- Question: Should patients who are treated with BB or ACEI
phylaxis with somewhat conflicting results. Francuzik et al378 medication initiate a course of AIT?
reported a case-control study of 12,874 cases of anaphylaxis from the
European Anaphylaxis Registry that characterized 3612 cases of Recommendation 34 (CBS): We suggest use of initial AIT may
venom anaphylaxis and 3605 matched cases of nonvenom anaphy- be considered in patients who are treated with BB or ACEI medica-
laxis. The study found a higher frequency of severe anaphylaxis and tion, with shared decision-making. It would be preferable to
cardiovascular symptoms in patients receiving BBs or ACEIs, but the replace the BB or ACEI, if there is a safe and effective alternative.
authors cautioned that the apparent effect of the medications corre- Strength of Recommendation: Conditional
lated closely with coexisting CVD, so that severe anaphylactic reac-
tions could not be attributed specifically to the medications.378 Certainty of Evidence: Low
Conversely, in the first prospective observational study and largest
Question: In patients on maintenance AIT who are treated with
study of its kind, Sturm et al298 enrolled 1425 patients with a history
BB or ACEI medication, should AIT be stopped or the medication
of sting anaphylaxis of whom 1342 began VIT. They found that there
discontinued?
was no increased frequency of anaphylaxis to VIT injections or to
stings during VIT in 338 patients treated with cardiovascular medica- Recommendation 35 (CBS): We suggest that patients receiving
tions (27.2% on antihypertensive drugs, 10.4% BB, 11.9% ACEI, 5.0% BB maintenance dose AIT have a minimal increased risk of a severe
and ACEI) and no increased severity of anaphylaxis to the pre-VIT anaphylactic reaction when on BB/ACEI medication and may
consider continuing AIT and medications based on shared deci- BB/ACEI medications during these procedures. In 2 case reports of
sion-making. 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-
Certainty of Evidence: Low tion. Drug desensitization procedures are usually performed because
of the lack of safe and effective alternatives to a medically necessary
Similar to the findings with VIT, the use of BBs or ACEIs in patients treatment. Thus, any potential risk associated with concomitant med-
undergoing SLIT has not been associated with increased severity or ications must be viewed in the context of the risk of foregoing the
frequency of systemic allergic reactions.381,382 Beta-blockers are not procedure or the risk of stopping the medication during the proce-
associated with increased frequency of systemic reaction to SCIT; dure.
however, evidence from VIT, cases reports, and a SCIT surveillance Radiocontrast media are agents given to increase the contrast in
program suggests that these medications may increase severity of an imaging study to allow visualization of internal structures. Similar
reaction in patients receiving SCIT.381−383 In fact, in a survey of the to other causes of anaphylaxis, there has been conflicting evidence
experience and opinion of physicians, 37.1% and 47.3% report pre- about whether BB and/or ACEI medications increase the severity of
scribing AIT in patients receiving BBs and ACEIs, respectively, and anaphylaxis after RCM administration. In a case-control study of
none reported major anaphylactic incidents during the course of the 34,371 intravenous RCM procedures by Lang et al,387 BB exposure
treatment.384 There is also no specific evidence related to the risk of and CVD were highly associated (X2 = 49; P < .001). Using a logistic
BB/ACEI medication during buildup SCIT compared with maintenance regression model with adjusted ORs, increased risk of bronchospasm
SCIT. However, when the baseline risk of reaction is higher (as is was associated with BB (OR = 3.73, 1.18-11.75; P = .025) and asthma
expected during the buildup schedule), then the risk of a more severe (OR = 16.49, 4.30-62.46; P = .001), independent of CVD. Of 21 reactors
reaction related to BB/ACEI medication might also be expected to be with CVD who did not have asthma, 10 were receiving BB; 9 of these
higher. 10 had bronchospasm compared with only 4 of 11 not receiving BB
The available evidence is not specific to SCIT but rather was com- (OR = 15.75; P = .023). Risk of a major and life-threatening reaction
mon to studies of many or all causes of anaphylaxis. The theoretical (hypotension with/without need for hospitalization) was associated
risk of BB treatment was not confirmed in a study of anaphylaxis in with CVD (OR = 7.71, 1.04-57.23; P = .046), independent of asthma or
the ED revealing they were not associated with an increased need for BB exposure. A more recent case-control study of patients receiving
epinephrine.363 However, a recent systematic review of anaphylaxis intra-arterial low-osmolality contrast during cardiac catheterization
of all causes found that the risk of severe anaphylaxis was signifi- found no increased rate of severe anaphylactic reactions in associa-
cantly increased but the incidence of new cases of anaphylaxis was tion with BBs (P = .40) or ACEIs (P = .14).366 However, in that study of
not.297 Furthermore, it was not possible to adjust for underlying CVD, 71,782 cardiac catheterizations, only 11 cases (0.015%) of severe ana-
and in fact, the risk of anaphylaxis was 3 to 5 times higher in patients phylaxis were observed—reflecting the substantial reduction in
with known CVD than in those taking BB/ACEI medication. It is severe adverse reactions with low osmolar contrast. Neither cardio-
important to note that although the relative risk may be increased, selective BBs (P = .2) nor non-cardioselective BBs (P = .5) influenced
the absolute risk remains very small. For example, the frequency of reaction severity.366
systemic reactions to SCIT is approximately 0.2% for each injection, Anaphylaxis can occur during IVIG infusions; however, this is a
most of which are mild-moderate (ie, severe reactions occur in <0.1% very rare complication (7.34 per 10,000 infusions).388−390 Patients
of injections).71 Even if the relative risk of a severe reaction is 2-fold receiving their initial IVIG treatment are considered at higher risk for
higher as reported in patients taking a BB or ACEI, the absolute risk adverse events and should be monitored closely at the slower than
would still be very low (<0.2%). There is a need for an individualized usual infusion rate.391 In a study of patients with idiopathic inflam-
risk-benefit discussion exploring both the potential risk of the medi- matory myopathy and concomitant heart failure, 75% of patients
cation and the importance to the patient of the immunotherapy receiving IVIG therapy were using BBs and/or ACEIs. In these patients,
treatment, including the patient’s history of anaphylaxis and associ- no cases of anaphylaxis were reported.389 Literature on the relative
ated risk factors, in the framework of the available evidence. risk of anaphylaxis in patients receiving IVIG while on BB or ACEI
medication is not available.
Planned Procedures: (eg, Drug Desensitization, Radiocontrast Media

Administration, Intravenous Immunoglobulin Infusion) Patients at Risk for Anaphylaxis (Unplanned Exposure or Unknown
Cause)
Question: For planned procedures where there is a risk of ana-
phylaxis, should BB or ACEI treatment be interrupted or contin- Question: In patients at significant risk for recurrent and unex-
ued? pected anaphylaxis due to unplanned exposure or unknown
cause, should BB or ACEI medication be stopped or continued?
Recommendation 36 (CBS): For planned procedures (eg, RCM,
challenge/desensitization, and infusion) if the BB/ACEI medication Recommendation 37 (CBS): We suggest that all patients at sig-
cannot be safely interrupted, we suggest shared decision-making nificant risk for recurrent and unexpected anaphylaxis (eg, those
discussion of the medical necessity (benefit) of the procedure, the with severe food allergy, mastocytosis or MCAS, or recurrent IA)
relative risk of anaphylaxis, the possibility of more severe reac- be counseled about the risk of more severe anaphylaxis, and con-
tion if the medication is continued, and the risk of stopping the sider avoiding, where possible, the use of nonselective BBs or
medication. ACEIs.
Strength of Recommendation: Conditional Strength of Recommendation: Conditional
Certainty of Evidence: Very Low Certainty of Evidence: Moderate
Drug desensitization is a safe and effective treatment option for Some conditions are associated with greater frequency or severity
patients with severe hypersensitivity to antibiotics, chemotherapies, of anaphylactic reactions, often at unpredictable times. Such patients
monoclonal antibodies, and other drugs such as aspirin. There is should be counseled to take special measures to mitigate this risk,
insufficient evidence to determine the relative risk associated with with increased caution regarding contributing factors (eg, alcohol,
vigorous exercise, medications), increased vigilance for the earliest severe, although the absolute risk of severe anaphylaxis remains
signs of the beginning of a reaction, and ready availability of treat- small and the risk of stopping or changing the medications may be
ment with epinephrine. This may apply to patients with IA, underly- greater than the risk of continuing them during any planned treat-
ing mast cell disorders, severe food allergy, or severe insect sting ment or procedure. The risk of severe anaphylaxis may be related
allergy (before VIT). There could reasonably be increased concern in more to age and underlying cardiovascular conditions than to the BB/
these patients for the potential risk associated with BB or ACEI medi- ACEI medications. In general, however, one should not assume auto-
cation. matically that these medications are absolutely contraindicated in
Idiopathic anaphylaxis is a diagnosis of exclusion and is based on this population. The discussion should include the prescribing physi-
the inability to identify a causal relationship between a trigger and cian (eg, cardiologist).
an anaphylactic event.392 Every effort should be made to identify a Patients taking BBs or ACEIs who are at risk for sting anaphylaxis
specific cause and any contributing factors or medications so as to but are not on VIT should be counseled about the increase in relative
improve further management and risk reduction. There are no spe- risk (but only a small increase in absolute risk) of a sting reaction
cific reports on the effects of BBs or ACEIs in patients with IA, but the being more severe and should discuss with the prescribing clinician
reported increased risk of severe reactions that has been associated whether alternative medications are equally safe and effective for
with BBs and ACEIs in anaphylaxis of all causes would be of concern their treatment. For patients on maintenance immunotherapy (VIT,
in patients with recurrent and unpredictable anaphylaxis. As in other SCIT, or SLIT), the risk of BB/ACEI therapy is minimal and no change
patients, the medical risk of changing or stopping the medication in medication is needed. Patients who need to begin VIT should be
must be weighed against the risk of more severe anaphylaxis if the counseled about the increase in relative risk (but only a small
medications are continued. increase in absolute risk) of a reaction to VIT injection during initial
Patients with severe food allergy have a greater chance of unex- buildup being more severe and the potential risks of the alternatives
pected severe reactions. An evidence review and meta-analysis of (changing the medications or foregoing VIT). For patients who wish
risk factors for severe reactions in food allergy noted that although to begin SCIT, the severity and history of their allergies, alongside the
BB or ACEI treatment may increase severity, they are less important efficacy of alternative pharmaceutical agents, should be considered
than age as a risk factor for severe anaphylaxis.393 Tenbrook et al380 when determining whether to proceed with SCIT and whether BBs
studied a simulated cohort of adults with peanut allergy and underly- and ACEIs are suitable treatment options. Patients at risk for anaphy-
ing CVD. This study developed a Markov model for patients with laxis from known exposures or unknown/unplanned exposures or
heart disease at risk for peanut anaphylaxis to compare their esti- procedures should be counseled about the increase in relative risk
mated life expectancy with and without BBs. For people with post- (but only a small increase in absolute risk) of a reaction being more
myocardial infarction or congestive heart failure, the benefits of BB severe and should discuss with the prescribing clinician whether
treatment outweighed the potentially increased likelihood of dying alternative medications are equally safe and effective for their treat-
from anaphylaxis, increasing estimated life expectancy by 9.4 and ment. Knowledge gaps related to use of BB or ACEI medication in
17.4 months, respectively. Quality-of-life outcomes were not evalu- patients at risk for anaphylaxis are listed in Table 24.
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
Mast Cell Disorders and Anaphylaxis
may be of consideration in patients with frequent episodes of IA for
whom triggers are not avoidable, in contrast with food-induced ana- Mastocytosis is a clonal disorder of mast cell proliferation and is
phylaxis in which the trigger is more easily recognized.394 Similar associated with episodic and chronic mast cell activation symptoms
analyses have not been conducted for IA, MCAS, alpha-gal allergy, or in most patients.396 Mast cell activation, in its most severe form, may
HaT. Overall, before stopping BBs in patients with a history of ana- present with anaphylaxis. It has been estimated that approximately
phylaxis, the relative risk of CVD without BB treatment must be 40% to 50% of adults and 10% of children with mastocytosis experi-
weighed against the risk of more severe anaphylaxis while on BB ence anaphylaxis.397 Risk factors for anaphylaxis associated with
treatment395 and requires a shared decision-making discussion. 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
Summary of Recommendations for Beta-Blocker/Angiotensin-Converting
patients with mastocytosis who lack skin lesions; however, it is not
Enzyme Inhibitor Medication
clear whether this finding is due to referral bias. Most anaphylaxis
In summary, clinicians should weigh the potential benefits and episodes associated with mastocytosis do not have a single identifi-
harms when considering the use of BBs and ACEIs in patients at risk able trigger and sometimes may be termed “unprovoked.” In patients
for anaphylaxis (Table 23). These medications are associated with an with mastocytosis, Hymenoptera venom allergy is the leading cause
increased relative risk that any anaphylactic reaction will be more 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.
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 organsa
b. KIT-activating KIT point mutation(s) at codon 816 or in other critical regions of KITb 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 CD30c
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 HaT, the tryptase level should be adjustedd
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 al403 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 HaT, the HaT-corrected tryptase level is 10 (30/3 = 10) and thus is
not a minor SM criterion.
prevalence of drug, food, and POA is also slightly increased in Table 26

mastocytosis.402 Differential Diagnosis for Elevated Baseline Serum Tryptase Level
Systemic mastocytosis
Epidemiology, Classification, and Diagnosis
Hereditary a-tryptasemia
Question: What is the role of bone marrow biopsy and serum Mast cell activation syndrome
Anaphylaxis
tryptase level in evaluation of patients for possible mastocytosis?
Complement (and mast cell) activation-related pseudoallergy
Recommendation 38 (CBS): We recommend clinicians order a Myeloid neoplasm
Helminth infection
bone marrow biopsy with staining for tryptase, CD25 immunohis- Renal failure
tochemistry and flow cytometry, and the KIT D816V mutation Hypereosinophilic syndrome
when there is strong suspicion for systemic mastocytosis.
NOTE. Reproduced from Valent et al403 under Creative Commons Attribution-Non
Strength of Recommendation: Strong Commercial-No Derivatives License 4.0 (CCBY-NC-ND).
Recommendation 39 (CBS): We recommend clinicians not rely

on serum tryptase levels alone for diagnostic assessment of the mastocytosis. Skin findings of maculopapular cutaneous mastocyto-
likelihood that a patient does or does not have a clonal mast cell sis, also known as urticaria pigmentosa (hyperpigmented macules
disorder. that urticate when lightly stroked), are a hallmark of cutaneous mas-
tocytosis but also can be present in systemic mastocytosis, although
Strength of Recommendation: Strong 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
Updated classification and diagnostic criteria from the WHO for such as pruritus, urticaria, and flushing have been observed. Mastocy-
cutaneous and systemic mastocytosis are detailed in Table 25.403−405 tomas in children can resemble flesh-colored to slightly pigmented
Diagnosis requires at least 1 major and 1 minor or 3 of the 4 minor nodules and are considered a benign mast cell tumor, which can also
criteria. A bST in excess of 20 ng/mL is considered a significant con- urticate on being rubbed. Documentation of a thorough skin exami-
tributory finding to the diagnosis but must be supported by addi- nation with pertinent positive and negative findings is of high impor-
tional findings.403 Differential diagnoses of conditions which can be tance.403 Isolated cutaneous mastocytosis is very uncommon in
associated with elevated bST levels are listed in Table 26, and the cli- adults. The risk of anaphylaxis in children with cutaneous mastocyto-
nician should be aware that this marker is not specific for a mast cell sis (in whom systemic disease is uncommon) is believed to be much
disorder.403,406 Moreover, there should be awareness that the differ- less than in patients with systemic mastocytosis, ranging from 0% to
ential diagnosis of an elevated bST level includes HaT, which is an 9% in various studies, and mainly occurs in those with extensive skin
autosomal-dominant genetic variant caused by increased copy num- involvement and higher tryptase levels.408
bers of alpha tryptase genes encoded by TPSAB1 locus.83 Although Key presenting symptoms of systemic mastocytosis will overlap
the clinical significance of HaT is not fully understood, it may with anaphylaxis but also may include the aforementioned skin find-
increase the frequency and/or severity of anaphylactic reactions. HaT ings, presyncope/syncope, constitutional symptoms (eg, fevers,
is observed in 5% to 7% of the general population and is most fre- weight loss, night sweats), bone pain, and prominent gastrointestinal
quently asymptomatic but is reported in more than 15% of patients symptoms such as reflux, nausea, vomiting, diarrhea, and colic. On
with IA, mastocytosis, or insect sting anaphylaxis.91,407 It is not clear physical examination, hepatosplenomegaly and lymphadenopathy
whether this is because of selection bias or a yet to be defined mecha- may be prominent especially in patients with advanced disease. Mul-
nism affecting mast cell proliferation or activation. HaT is discussed tiple reviews detail the key presenting features of mast cell
in more detail in the Diagnosis section. disorders.396,403,404,409 Systemic mastocytosis can present in child-
A bone marrow biopsy revealing at least 15 mast cells in aggre- hood in approximately 10% of the cases and should remain in the dif-
gates is the major diagnostic criterion for diagnosis of systemic ferential if the child presents with the constellation of symptoms
detailed previously, displays increasing tryptase levels, and the cuta- Strength of Recommendation: Conditional
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- Anaphylaxis to insect stings has been found to have a unique asso-
making and scoring schemes for bone marrow biopsy are discussed ciation with mastocytosis.416 Furthermore, an unusually high fre-
in more detail in the Diagnosis section. However, the procedure is quency of clonal mast cell disorders has been found in patients with
necessary to document the key marrow pathology that defines the severe sting anaphylaxis.417,418 Venom anaphylaxis in patients with
condition and for staging to determine whether the disease is mastocytosis is associated with a unique clinical pattern of reaction
advanced. Although mast cell proliferation can be noted in most and with a unique phenotype of mastocytosis.419,420 The frequency
other affected organs, the marrow remains the most important area and clinical characteristics of mast cell disorders in patients with insect
for biopsy.404 The clinician may consider other less invasive tests sting allergy in the United States may differ from those in European
such as a blood count (looking for evidence of cytopenia and/or reports.421 The presentation of insect sting allergy that is most sugges-
eosinophilia), blood chemistry (looking for other evidence of end- tive of mastocytosis is a male who develops rapid-onset hypotensive
organ dysfunction), a bST (which is often but not always elevated in shock with no urticaria. Insect stings are the most common cause of
mastocytosis), or a peripheral blood KITD816V mutation analysis anaphylaxis in patients with mastocytosis. In one report, patients with
before deciding on a bone marrow biopsy.95,413 A KIT mutation analy- mastocytosis who had positive test results for venom IgE had a very
sis is also generally ordered with most bone marrow aspirates and is high risk (93%) of severe and life-threatening anaphylaxis to insect
more sensitive than peripheral blood mutational analysis.414 The KIT stings.422 This led the authors of that report to suggest that testing for
D816V mutation should be analyzed by a highly sensitive test (such venom IgE should be considered in all patients with mastocytosis and
as allele-specific PCR or digital droplet PCR) capable of detecting that those with positive test results should be offered VIT (even if they
mutation at a 0.1% or lower allelic frequency. These assays have 80% have never had a systemic reaction to a sting).422 However, there is no
to 90% sensitivity compared with bone marrow biopsy and more consensus among the experts regarding preemptive VIT, and prospec-
than 99% specificity. It is important to note that tests frequently used tive confirmation of this observation is needed.
in hematologic neoplasms based on next-generation sequencing are Early reports noted that elevated bST level is unusually common in
not sufficiently sensitive.414 Nonetheless, in a patient with symptoms patients with insect sting anaphylaxis.423−425 Recent studies suggest
suggestive of systemic mastocytosis, irrespective of a normal tryptase that in patients with insect sting anaphylaxis, bST levels greater than
level, a bone marrow biopsy is necessary to definitively rule in or rule 8 ng/mL indicate increased risk of severe anaphylaxis to stings and sug-
out the diagnosis. Clinicians ordering a bone marrow biopsy should gest an underlying mast cell disorder.378 Such patients should be moni-
ask for staining for tryptase, CD25 immunohistochemistry, and flow tored for possible progressive increase over a period of years in serum
cytometry, the KIT D816V mutation using a highly sensitive allele- tryptase levels. HaT is also found in a much higher proportion of
specific PCR or digital droplet PCR-based technique, and whether patients with sting anaphylaxis (10%-20%) than in the general popula-
there is peripheral eosinophilia, a FIP1L1-PDGRA mutational tion (6%).91 However, one study found venom anaphylaxis correlated
analysis.403,404 In some cases, biopsy of other extracutaneous organs with presence of D816V mutation-positive clonal mast cells rather
may be helpful, as described in WHO guidelines, most frequently by than HaT.413 In that population of patients with severe insect sting
gastrointestinal mucosal biopsy.415 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
Mastocytosis, Hymenoptera Anaphylaxis, or Idiopathic Anaphylaxis in patients with mastocytosis with insect sting anaphylaxis.237,401
Treatment with VIT reduces the frequency and severity of reactions to
Question: When should bST be measured? stings in patients with mastocytosis although not as efficiently as in
Recommendation 40 (CBS): We recommend measurement of other patients with insect sting allergy.426 During maintenance VIT,
bST in patients with severe insect sting anaphylaxis, particularly systemic reactions to stings occur in 5% to 15% of patients without mas-
those who had hypotension and/or absence of urticaria; in all tocytosis but in 25% of patients with mastocytosis.427 This still repre-
cases of recurrent unexplained anaphylaxis; and in patients with sents significant benefit because, without VIT, the risk of sting
suspected mastocytosis. 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
Strength of Recommendation: Strong 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,
Question: When should patients be evaluated for mastocyto- omalizumab has been reported to enable most patients to achieve
sis? maintenance dose.429,430 Mastocytosis is also associated with increased
risk of relapse if VIT is discontinued, with severe and even fatal sting
Recommendation 41 (CBS): We suggest clinicians consider
reactions despite completing the usual 5-year course of
evaluation for mastocytosis, including a bone marrow biopsy, for
treatment.422,426,431 It is, therefore, recommended that patients with
adult patients with severe insect sting anaphylaxis or recurrent
mastocytosis should continue VIT indefinitely.237,401
IA, particularly those with a predictive REMA score.
Certainty of Evidence: Moderate Clinical Presentation

Anaphylaxis manifestations in mastocytosis frequently include
Question: Should patients with mastocytosis and insect sting
hypotension, syncopal or presyncopal episodes, flushing, tachycardia,
allergy be treated with VIT?
and gastrointestinal symptoms, such as cramping, diarrhea, nausea,
Recommendation 42 (CBS): We suggest VIT be continued indef- and vomiting. In contrast, urticaria, angioedema, and wheezing are
initely in patients with mastocytosis and insect sting anaphylaxis not observed frequently.93 All such patients should have a careful
due to the increased risk of severe or fatal sting anaphylaxis if VIT skin examination to look for the presence of maculopapular cutane-
is discontinued. ous lesions of mastocytosis (formerly known as urticaria
pigmentosa), although absence of maculopapular cutaneous lesions immunotherapy for food allergy.436 A randomized clinical trial
does not rule out mastocytosis. As described in the Diagnosis section revealed a promising trend, but the results were not significant in a
(and Fig 4), risk-stratification schemes for the probability of mastocy- small group of 19 patients with severe IA.437 A systematic review
tosis in patients presenting with mast cell activation symptoms have identified 12 studies with 35 subjects with IA treated with omalizu-
been proposed by REMA and NICAS.93,94,96 According to the REMA mab: 63% had a complete response and 28.5% had a partial
scheme, patients with a total score of 2 or greater have a high likeli- response.438 Most studies have used omalizumab dosing similar to
hood of having systemic mastocytosis (sensitivity 0.92, specificity that used for chronic idiopathic urticaria.
0.81) and should be considered for bone marrow biopsy. The NICAS In patients with mastocytosis, there are reports of improved con-
scoring system did not include patients with insect anaphylaxis, trol of symptoms and prevention of anaphylaxis with omalizu-
whereas the REMA system included all causes. mab.439−441 Carter et al442,443 reported on successful control of
Tryptase level is the most reliable surrogate marker of systemic anaphylaxis in 2 patients, with sustained results in long-term (12
mast cell burden and should be determined in all patients suspected year) follow-up. A recent systematic review found a total of 69
of having mastocytosis. A normal median tryptase level is approxi- patients with mastocytosis treated with omalizumab (13 cutaneous
mately 4.5 to 5 ng/mL in the general population. Elevated bST levels and 56 systemic); there was greater improvement in prevention of
can be found in chronic renal failure, myeloid disorders, and HaT. anaphylaxis (84%) than in other systemic symptoms (improved in
Although a cutoff level of “normal” tryptase has been suggested as 0%-43%).444
11.4 ng/mL in most commercial diagnostic tests, individuals without Omalizumab is not currently approved by the FDA in the United
an extra allele of TPSAB1 encoding alpha tryptase generally have States for this indication, and further well-designed studies are
tryptase levels of less than 8 ng/mL.432 See the Diagnosis section for needed, but off-label prescription may be considered in patients with
further discussion of serum tryptase testing. mastocytosis who have frequent episodes of anaphylaxis despite
More than 90% of patients with systemic mastocytosis have a optimal medical treatment. However, when there are signs of
somatic activation mutation in KIT gene in a single codon (D816V).433 increasing mast cell burden and uncontrolled symptoms, other treat-
Detection of this mutation in the peripheral blood is a marker of ment modalities, particularly tyrosine kinase inhibitors (TKIs), may
clonal mast cell disease (mastocytosis) and should be considered in be more likely to be effective.
patients presenting with recurrent anaphylaxis, especially associated
with hypotension. There are several assays commercially available to Mast Cell Cytoreduction and Tyrosine Kinase Inhibitors
measure this mutation; as mentioned previously, the most accurate There is evidence that mast cell cytoreduction (reduction of mast
results are obtained by a high sensitivity PCR droplet digital assay cell mass) results in improvement of anaphylaxis in mastocytosis. In
with a lower limit of detection of at least 0.1%. 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
Mast Cell Activation Syndromes
with mastocytosis results in constitutive activation of the tyrosine
These syndromes consisted of a broad range of disorders with var- kinase function of the molecule. As such, TKIs targeting D816V KIT
ious etiologies presenting with systemic mast cell activation. They have been considered a first-line approach for mast cell cytoreduc-
can be classified as primary (clonal; eg, mastocytosis), secondary (eg, tion, given toxicities associated with cladribine. Although cytoreduc-
IgE mediated), or idiopathic. Mast cell activation and mediator tive therapy has been traditionally reserved for patients with
release are the primary cause of the manifestations of anaphylaxis in advanced mastocytosis, recent emergence of TKIs with low toxicity
humans, and therefore, IA is a prototypical MCAS. Other presenta- profiles has made this treatment an attractive possibility for those
tions of mast cell activation not meeting the clinical definition of ana- presenting with mast cell activation symptoms inadequately con-
phylaxis are also included in MCAS. In patients who otherwise do not trolled with symptomatic therapies.446 Midostaurin and avapritinib
fulfill the clinical definition of anaphylaxis, a logical approach to diag- are the TKIs currently FDA approved for treatment of advanced mas-
nosis has been proposed to include the following 3 diagnostic criteria, tocytosis, conditions that are associated with decreased life expec-
all of which should be fulfilled: tancy (ie, aggressive systemic mastocytosis, systemic mastocytosis
with an associated hematologic neoplasm, and mast cell leukemia).
1. Symptoms consistent with mast cell activation in at least 2 differ- The mast cell cytoreductive effects of these TKIs are associated with
ent organ systems (cardiovascular, respiratory, naso-ocular, gas- symptom control of mast cell activation.447−449 Avapritinib is now
trointestinal, cutaneous); also FDA approved for indolent systemic mastocytosis, at a lower
2. Documentation of elevated mast cell mediator levels during an daily dose. Neither drug is approved for prevention of anaphylaxis.
episode (most specific marker is tryptase, and threshold levels Midostaurin is a multikinase inhibitor whose targets include wild-
have been described [see the Diagnosis section] for the minimal type and D816V-mutated KIT. It has been found to resolve anaphylac-
diagnostic increase in a post-event tryptase obtained within 4 tic episodes in 3 of 4 patients (75%) at 3 months and 2 of 2 patients
hours); and (100%) at 6 months in patients with advanced systemic mastocyto-
3. Positive response to mediator-targeting drugs.79,434,435 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
Chronic and nonspecific multiorgan symptoms and patients with
systemic mastocytosis revealed significant reduction of symptoms
multiple environmental and food intolerances without meeting these
due to mast cell activation, but nausea and vomiting are common
criteria should not be diagnosed with having MCAS.
adverse effects of the drug.451
Avapritinib, a selective D816V KIT inhibitor, is approved by the
Special Treatment Considerations of Anaphylaxis in Mastocytosis FDA for treatment of patients with advanced systemic
mastocytosis.448,449 Its use has been associated with mast cell cytore-
Omalizumab duction and improvement in mast cell activation symptoms including
There has been much interest in omalizumab as a potential thera- a case report describing successful cessation of recurrent anaphy-
peutic for patients who have recurrent anaphylaxis due to mastocy- laxis.452 Avapritinib has recently been approved by the FDA for symp-
tosis. Omalizumab reduces the risk of anaphylaxis during rush tomatic indolent systemic mastocytosis based on the results of a
immunotherapy for ragweed and Hymenoptera venom and during randomized controlled trial (ClinicalTrials.gov identifier:
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 HaT 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.
NCT03731260) of a lower daily dose that revealed reduction of mast level is not always increased in anaphylaxis, even in severe or fatal
cell activation symptoms and all measures of mast cell burden.453 reactions. A French study of POA reported an increase in serum tryp-
Avapritinib is contraindicated in patients with platelet counts of less tase level in 68% of suspected IgE-mediated POA but in only 4% of
than 50,000/mL. Other KIT D816V selective TKIs currently being eval- non−IgE-mediated POA.461 Elevations in serum tryptase level are
uated in clinical trials include elenestinib (BLU-263; NCT04910685) most often detected in cases of anaphylaxis that involve hypotension
and bezuclastinib (NCT05186753). In patients with mastocytosis and and in reactions that are IgE mediated.22,454,458,461 The sensitivity
recurrent episodes of anaphylaxis despite optimal medical therapy (64%) and specificity (89%) of elevated serum tryptase level (>11.4
with high-dose H1 antihistamines and H2 antihistamines (and possi- ng/mL)460 lead to a calculated positive likelihood ratio (LR) of 6 and a
bly a trial of omalizumab), consideration may be given to a trial of negative LR of 0.4. These LRs indicate that an elevated serum tryptase
avapritinib or compassionate use of midostaurin, or referral to a clini- level gives moderate support to the likelihood of POA, but a lack of
cal trial for a TKI, although neither is currently FDA approved specifi- increase in serum tryptase level should not be interpreted as ruling
cally for prevention of anaphylaxis. out a diagnosis of POA.
Knowledge gaps related to anaphylaxis in mastocytosis are listed Measurement of plasma histamine to confirm a diagnosis of ana-
in Table 27. 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
Perioperative Anaphylaxis
value.22,461
POA occurs at a rate of 15.3 per 100,000 cases, is associated with Interpretation of serum tryptase level is based on international
increased cost and prolonged length of hospital stay, and can result consensus recommendations noting a 1.2-fold increase plus 2 ng/mL,
in 2% excess mortality.454 POA has a greater risk of death than other consistent with degranulation of mast cells during the suspected
forms of anaphylaxis.455,456 In a multivariate analysis of POA cases, reaction.432 Because bST values may be more variable in patients
independent risk factors associated with a fatal outcome related to with mastocytosis or HaT, 1 study found optimal sensitivity and
NMBAs, despite treatment with epinephrine, were as follows: male specificity with a threshold acute/baseline tryptase level of 1.685
sex (OR = 2.5; 95% CI, 1.4-5.0; P = .0004), emergency surgery (further discussed in the Diagnosis section).80 The timing of obtaining
(OR = 2.6; 95% CI, 1.5-4.6; P = .0007), history of hypertension the serum sample is important. The concentration peaks within 30 to
(OR = 2.5; 95% CI, 1.5-4.4; P = .0010) or other CVD (OR = 4.4; 95% CI, 60 minutes of the reaction and then typically returns to baseline in
2.4-8.1; P < .0001), obesity (OR = 2.4; 95% CI, 1.1-5.3; P = .0376), and approximately 120 minutes (but up to 4 hours or more). Interpreta-
BB exposure (OR = 4.2; 95% CI, 1.8-9.8; P = .0011).457 Increased risk tion of tryptase levels obtained in proximity to death or postmortem
for POA has also been associated with transplant, cardiac, vascular, may be unreliable as nonspecific increases occur during ischemia.462
and hematologic procedures.454 Recent trends in POA include the rec- Tryptase is stable for as long as 1 year if a blood sample is frozen after
ognition of geographic variation in etiologic agents (perhaps based on processing. This could enable retrospective investigation of suspected
different preprocedure exposures to sensitizing factors), a declining POA.
incidence of POA due to latex, and a greater appreciation for reactions A 15-year Belgian survey identified 180 subjects with tryptase
related to antibiotics—particularly cefazolin.458−460 It is important to determinations from a total of 532 subjects with POA463; in 139
note that rigorous evidence on this topic is lacking due to the limita- (77%) with clinical POA, an increase of tryptase level
tions resulting from the relatively rare occurrence of POA and inabil- (>1.2 £ baseline + 2 mg/L) was observed. Severity of anaphylaxis was
ity to perform blinded studies due to ethical considerations. associated with a tryptase level exceeding the aforementioned
Therefore, the strength of evidence is uniformly low to very low. threshold (11.4 ng/mL), but the severity of POA did not correlate with
POA is usually due to immunologic or non-immunologic activa- the absolute tryptase value. Furthermore, an increase in tryptase did
tion of mast cells and, to a lesser extent, basophils. Measurement of not correlate with the identification of a culprit drug-specific IgE.
mast cell mediators, particularly more stable mediators such as tryp- Thus, the finding of elevated mast cell mediators implies that mast
tase, is a validated strategy to confirm involvement of mast cell cell/basophil degranulation occurred, although it does not provide
degranulation in the pathogenesis of POA.459,460 A retrospective information regarding the underlying mechanism of the reaction (ie,
study revealed that serious anaphylaxis during anesthesia was asso- IgE mediated or not IgE mediated). A number of perioperative drugs,
ciated with elevations in serum tryptase level (mean = 86.5 ng/mL); including paralytics (NMBAs), opioids, and antibiotics (eg, vancomy-
moreover, tryptase level elevation was not observed in a comparator cin), can induce mast cell degranulation independent of
group with cardiogenic or septic shock but no anaphylaxis who were IgE.22,459,460,464 To determine whether serum tryptase level is
resuscitated.459 These data imply that resuscitation itself cannot increased after POA, a repeat measurement should be performed
account for serum tryptase level elevation. However, serum tryptase when the patient has recovered to provide a baseline tryptase level
for comparison with the acute level and to determine whether tryp- Table 28
tase levels are persistently increased.432 The baseline level should be Recommended Concentrations for Skin Tests: Skin Prick Tests and Intradermal
determined even if the acute-phase tryptase result is normal. Diag- Tests458,466−470
nostic evaluation of patients with persistent elevations of tryptase Item for testing SPT concentration IDT concentration
level is discussed further in the Diagnosis section and the Mast Cell NMBAs
Disorders section. Atracurium466 1 mg/mL 0.01 mg/mL
Cisatracurium467 2 mg/mL 0.02 mg/mL
Question: Should immediate hypersensitivity skin testing or in Mivacurium468 0.2-1.0 mg/mL 0.002-0.01 mg/mL
vitro testing be performed with all potential culprit pharmaco- Pancuronium468 2-20 mg/mL 0.2-2 mg/mL
logic and nonpharmacologic agents, or should this be limited to Rocuronium467 10 mg/mL 0.05 mg/mL
Vecuronium467 1 mg/mL 0.01 mg/mL
the agents that are highly suspected?
Succinylcholine467 20 mg/mL 0.8 mg/mL
Recommendation 43 (CBS): We suggest that immediate hyper- (Suxamethonium)
Hypnotics466
sensitivity skin testing (percutaneous and intradermal) and/or in Etomidate 2 mg/mL 0.2 mg/mL
vitro-specific IgE testing be performed, when available, to all poten- Ketamine 10 mg/mL 1 mg/mL
tial pharmacologic and nonpharmacologic culprits used during the Propofol 10 mg/mL 1 mg/mL
perioperative period. If testing is not possible, we suggest referral Thiopental 25 mg/mL 2.5 mg/mL
Midazolam 5 mg/mL 0.05 mg/mL
to another center or, if necessary, use of the most efficacious agents
Opioidsa,466
structurally dissimilar from the most likely culprit. Alfentanil 0.5 mg/mL 0.05 mg/mL
Fentanyl 0.05 mg/mL 0.005 mg/mL
Strength of Recommendation: Conditional 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
Sugammadex467 100 mg/mL 50 mg/mL
POA is complicated by the fact that multiple agents are usually
b-lactams
administered simultaneously or in close succession. Epidemiologic Pen G (10,000 U/mL)458 Undiluted Undiluted
evidence supports the assertion that antibiotics and paralytics Benzylpenicilloyl Polylysine Undiluted Undiluted
(NMBAs) are the more common culprits,458,460 but the limited reli- (Prepen)458
ability and validity of testing to these agents make it incumbent to Ampicillin458 20 mg/mL 20 mg/mL
Cefazolin469,470 20 mg/mL, 33 mg/mL 20 mg/mL, 33 mg/mL
consider all potential causes.
Local anesthetics466 Undiluted 1/10
Depending on history or clinical suspicion is not reliable. When Heparins466 Undiluted 1/10
referring anesthetists at a Danish Anesthesia Allergy Center were Tranexamic acid466 Undiluted 1/10
asked to provide their pretesting causes for POA, these were not con- Protamine466 Undiluted 1/1000-1/10,000
Aprotinin466 1/5 1/500
firmed in 73% of the cases, resulting in a poor correlation between
Hyaluronidase466 Undiluted 1/10
clinical impression and the results of diagnostic evaluation.465 These Antiseptics466
data suggest that testing for all potential culprits is required in the Povidone iodine468 100 mg/mL Not recommended
evaluation of patients with POA. Furthermore, testing for available Chlorhexidine468 5 mg/mL 0.002 mg/mL
alternatives to highly suspected culprit agents may be considered. Dyes
Patent blue (25 mg/mL)468 1:10, Undiluted 1:100, 1:10
Because NMBAs are among the most common causes of POA and to
Isosulfan blue468 1:10 dilution, undiluted 1:1000, 1:100, 1:10
reduce the need for follow-up testing, the tests should include the Methylene blue468 Undiluted 0.1 mg/mL
potential culprit NMBA and any alternative NMBA agents available at Neostigmine467 1 mg/mL 0.2 mg/mL
that health care facility. Although of limited reliability, the negative Methohexital468 1 mg/mL 0.1 mg/mL
predictive value of the skin tests may assist in the choice of NBMA in
Abbreviations: IDT, intradermal test; NMBA, neuromuscular blocking agent; Pen G,
affected patients. penicillin G; PPL, penicilloyl polylysine; SPT, skin prick test.
Published resources provide empirical, nonirritating concentra- a
Hypersensitivity skin testing to opioids may be unreliable due to high rates of false-
tions for hypersensitivity skin testing of potential culprit pharmaco- positive results.
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- Availability of drugs for testing is limited by the controlled nature
exposure, although this has not been established, and non-IgE mech- of many agents used in anesthesia and distribution exclusively by
anisms can cause positive skin test responses. Immediate hypersensi- inpatient pharmacies. Albeit very small amounts of the drugs are
tivity skin testing to direct mast cell activators, such as opioids or needed for testing, the acquisition of samples is often unobtainable
vancomycin, may be unreliable due to high rates of false-positive due to geographic, logistic, and legal barriers. These issues are gener-
results. Avoidance of drugs with a positive skin test result would ally less of a problem in some integrated health care systems but can
likely be in a patient’s best health care interest, if equally efficacious, be very limiting in the more common scenarios of outpatient allergy/
structurally unrelated alternatives are available. Data reveal that immunology clinics not affiliated with or separated from large medi-
administration of agents with negative test results can proceed safely, cal centers. On the basis of availability and feasibility, a 3-tier recom-
suggesting that testing may be helpful in drug selection for subse- mendation may be considered:
quent anesthesia (Table 29).471−473 Just as we do with many other
allergens to which skin testing result is negative (eg, latex, lidocaine, 1) Testing is suggested.
chlorhexidine, povidone-iodine), as the sensitivity (or negative likeli- 2) If testing is not possible, referral to another center is suggested.
hood ratio) is not well established, we may carry out provocative 3) If referral is not possible or time constrained, avoid the most
challenges to definitively rule out IgE-mediated (allergic/anaphylac- likely culprits and use the most efficacious structurally dissimilar
tic) potential. For some agents (eg, NMBAs, midazolam, propofol), it agents.
would be appropriate for an anesthesiologist to administer them in a
graded dose (ie, “test dose”) fashion immediately before the planned Question: Should immediate hypersensitivity skin and/or in
procedure. vitro testing of suspected culprit (and alternative) agents be
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
471
Fisher et al, 2011 606 246 183 183 0
Guyer et al,472 2015 73 73 47 45 2
473
Miller et al, 2018 174 70 70 67 3
Total 853 389 300 295 5 (1.7%)
Abbreviation: POA, perioperative anaphylaxis.
performed as soon as possible or delayed 4 to 6 weeks after the Recommendation 45 (CBS): We suggest that challenges be
POA event? performed, when feasible, to all potential culprit agents to
which skin and/or in vitro testing is negative, before or in con-
Recommendation 44 (CBS): We suggest that immediate hyper-
junction with use of these agents for a future surgical proce-
sensitivity testing to suspected culprit (and alternative) agents be
dure.
delayed after POA, unless repeat surgery cannot be postponed. If
surgery with general anesthesia is needed sooner, then testing Strength of Recommendation: Conditional
may be performed when needed.
Just as the reference standard for diagnostic evaluation of anti-
Certainty of Evidence: Very Low biotic allergy is tolerance of a drug challenge, usually oral,479 sim-
ilarly, the reference standard for evaluation of POA also entails
Delaying immediate hypersensitivity skin testing for 4 to 6 weeks
after anaphylaxis is generally suggested. This is based on case series carrying out challenges to items for which skin and/or in vitro
testing result is negative. Unfortunately, oral challenge with most
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- perioperative agents is not feasible, potentially increasing the risk
of the challenge. The lack of validated testing for all agents other
lactic event based on a “refractory period,” characterized by lack of
immediate cutaneous response to a clinically relevant allergen, was than penicillin makes challenges necessary to verify tolerance. In
general, suspected agents with positive testing result are avoided
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- in favor of alternative agents that are structurally unrelated or
which have negative test results. Cross-reactivity among chemi-
tera systemic sting reaction. In 21% of the cases, the second
evaluation, performed 4 to 6 weeks after, was required to confirm cally related agents, such as paralytics/NMBAs, is suspected but
the diagnosis of Hymenoptera venom anaphylaxis. This phenomenon not documented. Direct mast cell activators, such as drugs bind-
may be due to a generalized mast cell hyporesponsiveness (a.k.a., ing to Mas-related G-protein coupled receptor member X2
“the empty mast cell syndrome”) or may be allergen specific after an (MRGPRX2), p-I receptors, or other inherent activating receptors,
anaphylactic reaction.477 also likely share cross-reactivity within the same class of pharma-
Variability in the results of evaluation after POA is supported by a ceuticals. These include fluoroquinolone antibiotics, opioids,
study that compared the results of skin testing at 2 time points in NMBAs, polymyxins, icatabant, vancomycin, and iopamidol RCM.
patients with POA,478 the first within 4 days of the reaction and the Immediate hypersensitivity skin testing to direct mast cell activa-
second, 4 to 8 weeks after POA. Of patients with positive skin test tors, such as opioids or vancomycin, may be unreliable due to
results implicating a specific drug, 15 had positive results at the first high rates of false-positive results.480 However, the role of
testing (4 days after POA), 22 at the second testing, 12 at both, 3 only MRGPRX2 receptor activation on mast cells as a cause of anaphy-
at the first testing, and 10 only at the second testing. On the basis of laxis is not certain.481
these data, the authors recommended that until an evaluation is com- Graded challenge with suspected agents for which skin testing
plete, agents statistically more likely to have caused the initial reac- result is negative may also be carried out in collaboration with an
anesthesiologist, and if necessary and feasible, in the operating
tion, even with a single negative test result, ideally should be avoided
during subsequent anesthesia. Testing to any POA-related agents room in conjunction with a planned procedure.482 For instance,
in cases for which challenge with a NMBA is indicated, this can
other than penicillin has not been clinically validated.
The limited information related to hyporesponsiveness for vari- be performed in partnership with the anesthesiologist involved
with managing the return to the operating room. This can be
able time periods after anaphylaxis coupled with the lack of validated
allergy testing for most agents used in anesthesia provides support accomplished through administration of a 10% “test dose” before
the procedure; if tolerated without untoward reaction after a
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 period of observation, full dosing can then be administered as
indicated.
after the sentinel POA, especially because the procedure resulting in
the POA is frequently aborted. If so, the risk of delay in testing should Question: Should patients with POA be advised to avoid repeat
be discussed with the patient, anesthesiologist, surgeon, and other anesthesia?
relevant health care providers to support a shared decision-making
process that includes the values and preferences of the patient (and Recommendation 46 (CBS): We suggest that repeat anesthesia
family). Furthermore, testing for available alternatives to highly sus- may proceed in the context of shared decision-making and as
pected culprit agents may be considered. Another consideration directed by history and results of diagnostic evaluation.
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. Certainty of Evidence: Low
Question: Should challenges be performed to potential POA Several studies have reported that repeat anesthesia after appro-
pharmacologic and nonpharmacologic culprits to which skin and/ priate evaluation of POA can be performed successfully with a very
or in vitro testing is negative? low rate of recurrence of POA.471−473 Fisher et al471 reported that of
606 patients who had POA, 183 of 246 (74%) who were contactable management strategies for the underlying disease process should be
underwent anesthesia subsequently without remarkable untoward considered and reviewed by the anesthesiologist, surgeon, allergist/
reaction. In a study by Guyer et al472 of 73 with POA, 47 (64%) had immunologist, and patient (and family). Perioperative latex avoid-
subsequent procedures with anesthesia; 45 tolerated these proce- ance should be considered if latex is suspected as the culprit agent
dures without complication, the 2 who developed recurrent hyper- and diagnostic evaluation including provocative latex challenges484
sensitivity reactions were found to have mast cell disorders. Miller et has not been performed. Latex mitigation or avoidance strategies are
al473 investigated 70 of 174 cases who underwent repeat anesthesia; generally available in facilities performing general anesthesia.
3 whom had recurrence of POA: 1 who was found to have a mast cell Question: If results of all immediate hypersensitivity skin testing
disorder and 2 who had incomplete referral information that led to (percutaneous and intradermal) and/or in vitro-specific IgE testing
offending drugs being omitted from diagnostic testing. This report (and challenge when possible) are negative to suspected POA culprit
emphasizes the importance of detailed information related to the agents, should pretreatment with H1 antihistamine and corticoste-
timing of drug dosing and onset of POA. As found in Table 29, com- roid, with or without H2 antihistamine and anti-leukotriene, be
bining these 3 reports leads to a rate of recrudescence of POA with administered before subsequent anesthesia?
subsequent anesthesia of 1.7%.471−473 These data support the conten-
Recommendation 48 (CBS): We offer no recommendation for
tion that most patients are able to undergo repeat anesthesia using a
or against the use of pretreatment before return to the operating
combination of skin and/or in vitro testing results, avoidance of most
room in patients with negative cutaneous (percutaneous and
likely culprits, or alternative anesthesia strategies.458 However, the
intradermal) and/or in vitro-specific IgE testing (and challenge
data cannot rule out the alternative possibility that most POA reac-
when possible) result to all suspected POA culprit agents.
tions are not reproducible, as has been found for messenger RNA
COVID-19 vaccines.483 Strength of Recommendation: None
Question: Should repeat anesthesia after POA be performed Certainty of Evidence: Very Low
with equally efficacious, structurally unrelated alternatives rather
than the suspected culprit agents with negative skin and/or in For a patient with POA and negative immediate hypersensitivity
vitro test results when challenge is not feasible? testing result followed by negative provocative challenge result, the
recommendation as to whether to recommend pretreatment with H1
Recommendation 47 (CBS): We suggest that avoidance of cul- antihistamine and corticosteroid, with/without H2 antihistamine and
prit pharmacologic and nonpharmacologic agents associated anti-leukotriene, before returning to the operating room fulfills equi-
with POA may be considered, regardless of test results if challenge poise criteria.485 The equipoise between pretreatment and no pre-
is not feasible and if equally efficacious, structurally unrelated treatment implies not only balance but also uncertainty. On the basis
alternatives are available. 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
Certainty of Evidence: Low of the potential for benefit compared with the potential for harm,
and allow the patient (and family) to participate in the medical deci-
When testing result for all potential culprits is negative, challenge
sion-making process by expressing their values and preferences.
is recommended but is not always feasible, and decisions must be
The value of pretreatment is based on indirect evidence, such as
made about the use of the potential culprits or unrelated alternative
prevention of non−IgE-mediated anaphylaxis with re-exposure to
drugs. Immediate hypersensitivity skin testing to penicillin is vali-
high-osmolar radioiodinated urographic contrast in prior reactors
dated; if testing result is positive to the beta-lactam only, and chal-
and prophylaxis of IgE-mediated anaphylaxis in association with
lenge for the other potential culprits is not feasible, it is acceptable to
rush immunotherapy.486,487 There is no direct evidence that premed-
use all perioperative drugs except for the beta-lactam. However, the
ication prevents anaphylaxis to the various factors that cause most
lack of validated testing for virtually all agents except for penicillin
cases of POA. There are potential harms of pretreatment that should
limits the predictive value of the testing. For patient safety, if chal-
also be considered.3 The panel viewed both premedication and no
lenges are not possible or feasible, alternative agents are preferable,
premedication as reasonable paths and recommended a shared deci-
if available and equally efficacious. Although alternative forms of
sion-making discussion between the patient, allergist/immunologist,
anesthesia, such as spinal or regional anesthesia, have been consid-
anesthesiologist, and surgeon.
ered and suggested, patients still may potentially require conversion
Knowledge gaps related to POA are listed in Table 30.
to general anesthesia and intubation. As a result, alternative
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.
Acknowledgments of the Joint Task Force on Practice Parameters; and research support
from DBV. Dr Wallace: consulting fees from AbbVie, Bryn, Sanofi, and
The Anaphylaxis Workgroup and the Joint Task Force on Practice
Kaleo. Dr Abrams: employee of Public Health Agency of Canada
Parameters acknowledge Jerrold H. Levy, MD, for expert review and
(PHAC); views expressed are my own and not those of PHAC. Dr
revision of the section on Perioperative Anaphylaxis; Rashi Ram-
Bernstein: principal investigator, consultant, and speaker for Novar-
chandi, BHSc, for assistance with initial preparation of the section on
tis, Genentech, AstraZeneca, Sanofi Regeneron, Takeda/Shire, CSL
Beta-Blockers and ACE Inhibitors; Adil Adatia, MD, and Nishi Parikh,
Behring, Pharming, BioCryst, and Merck; consultant for Kalvista,
BSc, for assistance with initial preparation of the section on Epineph-
Ionis, Celldex, Allakos, Amgen, Biomarin, and Blueprint Medicine;
rine Autoinjectors; and Erin P. Scott, PhD, for providing administra-
principal investigator and speaker for GlaxoSmithKline; speaker for
tive oversight and extensive editing and coordination throughout the
Optinose; consultant for Ono, Astria, Incyte, Cycle, and Escient; and
development, manuscript preparation, and final editing process.
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-
Disclosures
nologies; social media editor for the AAAAI; member, board of
The JTFPP members and workgroup members’ conflict of interest regents for the ACAAI; and Associate Editor, Annals of Allergy, Asthma
disclosure forms can be found at www.allergyparameters.org. Dr & Immunology. Heather Cruickshank: grant support from AllerGen
Golden: clinical trial support from Genentech, ThermoFisher, Novar- NCE and medical writer for Healthline Media. The remaining authors
tis, Pfizer, GlaxoSmithKline, and Regeneron; consulting fees from have no conflicts of interests to report.
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, Funding
and Siolta; consulting fees from ALK-Abello, Jubilant HollisterStier; The authors have no funding sources to report.
and royalties from UpToDate. Dr Waserman: consulting fees from
GlaxoSmithKline, Novartis, CSL Behring, Pfizer Canada, Sanofi Canada,
AstraZeneca, Takeda, ALK-Abello, Teva, Medexus, MiravoHealth, Resolving Conflicts of Interest
Mylan, Bausch Lomb, AbbVie, Avir Pharma, and Leo Pharma; research
funding from Pfizer Canada, ALK-Abello, Aimmune; and president of The JTFPP is committed to ensuring that the Practice Parameters
Canadian Allergy, Asthma and Immunology Foundation. Dr Akin: are based on the best scientific evidence at the time of publication
consulting fees from Blueprint Medicine, Cogent, and Novartis; and that such evidence is free of commercial bias to the greatest
research support from Blueprint Medicines and Cogent; and royalties extent possible. The JTFPP recognizes that experts in a field may have
from UpToDate. Dr Campbell: consulting fees from Bryn and royalties interests that could create a potential conflict of interest (COI) with
from UpToDate. Dr Ellis: advisory boards for ALK-Abello, AstraZeneca, the development of a completely unbiased and objective practice
Aralez, Bausch Health, Leo Pharma, Merck, Novartis, and Pfizer; parameter. To take advantage of their expertise, a process has been
speakers’ bureaus for ALK-Abello, AstraZeneca, Miravo, Medexus, and developed to acknowledge potential COI and attempt to prevent
Mylan; research support (paid to institution) from ALK-Abello, Aralez, them from influencing the final document in a negative way. The dis-
AstraZeneca, Bayer LLC, Medexus, Novartis, and Regeneron; indepen- closure and management of potential conflicts for all participants
dent consultant to Bayer LLC and Regeneron; and royalties from were conducted in accordance with JTFPP policies. To preserve the
UpToDate. Dr Greenhawt: consultant for Aquestive; advisory boards greatest transparency regarding potential COI, all members of the
for DBV Technologies, Sanofi/Regeneron, Nutricia, Novartis, Aques- JTFPP and the practice parameters workgroups complete a standard
tive, Allergy Therapeutics, AstraZeneca, ALK-Abello, and Prota; scien- potential COI disclosure form before the development of each docu-
tific advisory council (unpaid) for the National Peanut Board and ment.
medical advisory board (unpaid) of the International Food Protein During the review process, there are additional measures to avoid
Induced Enterocolitis Syndrome Association; Working Group Mem- bias. At the workgroup level, all the sections are reviewed by all
ber of the Brighton Collaboration Criteria Vaccine Anaphylaxis; senior workgroup members to ensure that content is appropriate and with-
associate editor for Annals of Allergy, Asthma & Immunology; member out apparent bias. If a section is deemed to have apparent bias, it will
of the Joint Task Force on Allergy Practice Parameters; and speaker be appropriately revised without the section author’s involvement, in
honoraria from ImSci, MedLearningGroup, RMEI Medical Education an attempt to remove potential bias. In addition, the entire document
and multiple state/local allergy societies. Dr Lang: honoraria, consul- is then reviewed by the JTFPP, and any apparent bias is removed at
tant, and/or clinical research support from AstraZeneca, Genentech, that level. The final document and all recommendations are reviewed
Novartis, and Sanofi-Regeneron; Guest Associate Editor of JACI:In and approved by the workgroup and JTFPP. Any member with a per-
Practice; and editorial board of DynaMed. Dr Ledford: contributor to ceived COI related to a specific recommendation was recused from
UpToDate for Perioperative Anaphylaxis; contributing editor for Ask voting on that recommendation. In a final stage of review, the prac-
the Expert (AAAAI); research support from AstraZeneca and Novartis tice parameter is sent to invited expert reviewers, selected by the
(paid to institution); consultant for AstraZeneca; speaker bureau/ AAAAI and the American College of Allergy, Asthma, and Immunology
honoraria from AstraZeneca, Genentech, GlaxoSmithKline, and (ACAAI). The document is also posted on the AAAAI and ACAAI web-
Sanofi/Regeneron; and legal opinion indoor fungal exposure, drug sites for general membership and the public-at-large to review and
allergy, anaphylaxis. Dr Lieberman: contracted research (paid to offer comment. Reviewers are also asked to provide statements of
institution) for Aimmune, DBV, Regeneron, and Novartis; adjudica- potential COI. Although the JTFPP has the final responsibility for the
tion/DSMB for AbbVie and Siolta; consultant/advisor for Aquestive, content of the documents submitted for publication, each reviewer’s
ALK-Abello, Novartis, and DBV. Dr Oppenheimer: Executive Editor of comments will be discussed and reviewers will receive written
Annals of Allergy, Asthma & Immunology; reviewer for UpToDate; responses to comments when appropriate.
adjudication and data safety monitoring board for AstraZeneca, Glax-
oSmithKline, and Sanofi; consultant for GlaxoSmithKline, Aquestive,
Disclaimer
and Aimmune; NIH grant for the IDEA study. Dr Shaker: editorial
board of The Journal of Allergy and Clinical Immunology: In Practice; The AAAAI and the ACAAI have jointly accepted responsibility for
associate editor of Annals of Allergy, Asthma & Immunology; member establishing the Anaphylaxis 2023: A Practice Parameter Update. The
document is current at the time of publication. The medical environ- 15. Muraro A, Roberts G, Worm M, Bilo MB, Brockow K, Fernandez Rivas M, et al.
ment is rapidly changing, and not all recommendations will be Anaphylaxis: guidelines from the European Academy of Allergy and Clinical
Immunology. Allergy. 2014;69(8):1026–1045.
appropriate or applicable to all patients and may change over time. 16. Niggemann B, Beyer K. Time for a new grading system for allergic reactions?
Because this document incorporated the efforts of many participants, Allergy. 2016;71(2):135–136.
no single individual, including members serving on the JTFPP, is 17. World Health Organization. ICD-11 for mortality and morbidity statistics. Avail-
able at: https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/
authorized to provide an official AAAAI or ACAAI interpretation of 1868068711. Accessed July 14, 2021.
these practice parameters. Any request for information or interpreta- 18. Turner PJ, Worm M, Ansotegui IJ, El-Gamal Y, Rivas MF, Fineman S, et al. Time to
tion of this practice parameter by the AAAAI or ACAAI should be revisit the definition and clinical criteria for anaphylaxis? World Allergy Organ J.
2019;12(10): 100066.
directed to the executive offices of the AAAAI and the ACAAI. These
19. Cardona V, Ansotegui IJ, Ebisawa M, El-Gamal Y, Fernandez Rivas M, Fineman S,
parameters are not designed for use by the pharmaceutical industry et al. World Allergy Organization anaphylaxis guidance 2020. World Allergy
in drug development or promotion. The JTFPP understands that the Organ J. 2020;13(10): 100472.
20. Kraft M, Do € lle-Bierke S, Turner PJ, Muraro A, Ferna
ndez-Rivas M, Grabenhenrich
cost of diagnostic tests and therapeutic agents is an important con-
L, et al. EAACI task force Clinical epidemiology of anaphylaxis: experts’ perspec-
cern that may appropriately influence the evaluation and treatment tive on the use of adrenaline autoinjectors in Europe. Clin Transl Allergy.
chosen for a given patient. The JTFPP recognizes that the emphasis of 2020;10:12.
our primary recommendations regarding a medication may vary, for 21. Australia Society of Clinical Immunology and Allergy. Acute management of ana-
phylaxis. Available at: https://www.allergy.org.au/hp//papers/acute-manage
example, depending on third-party payer issues and product patent ment-of-anaphylaxis-guidelines. Accessed July 13, 2021.
expiration dates. However, because a given test or intervention’s cost 22. Brown SG, Stone SF, Fatovich DM, Burrows SA, Holdgate A, Celenza A, et al. Ana-
is so widely variable, and there is a paucity of pharmacoeconomic phylaxis: clinical patterns, mediator release, and severity. J Allergy Clin Immunol.
2013;132(5):1141–1149.e5.
data, the JTFPP is not always able to consider cost when formulating 23. Greenberger PA, Rotskoff BD, Lifschultz B. Fatal anaphylaxis: postmortem find-
practice parameter recommendations. In extraordinary circumstan- ings and associated comorbid diseases. Ann Allergy Asthma Immunol. 2007;98
ces, when the cost benefit of an intervention is prohibitive as sup- (3):252–257.
24. Gold MS, Amarasinghe A, Greenhawt M, Kelso JM, Kochhar S, Y-H Thong B, et al.
ported by pharmacoeconomic data, commentary may be provided. Anaphylaxis: revision of the Brighton collaboration case definition. Vaccine.
2023;41(15):2605–2614.
25. Simons FE, Ebisawa M, Sanchez-Borges M, Thong BY, Worm M, Tanno LK, et al.
2015 update of the evidence base: World Allergy Organization anaphylaxis
Contributors
guidelines. World Allergy Organ J. 2015;8(1):32.
26. Loprinzi Brauer CE, Motosue MS, Li JT, Hagan JB, Bellolio MF, Lee S, et al. Prospec-
The JTFPP has made a concerted effort to acknowledge all contrib-
tive validation of the NIAID/FAAN criteria for emergency department diagnosis
utors to this parameter. If any contributors have been excluded inad- of anaphylaxis. J Allergy Clin Immunol Pract. 2016;4(6):1220–1226.
vertently, the JTFPP will ensure that appropriate recognition of such 27. Arga M, Topal E, Yilmaz S, Erdemli PC, Bicakci K, Bakirtas A. Healthcare workers;
contributions is made subsequently. knowledge level regarding anaphylaxis and usage of epinephrine auto-injectors.
Turk J Pediatr. 2021;63(3):372–383.
28. Bann MA, Carrell DS, Gruber S, Shinde M, Ball R, Nelson JC, et al. Identification and
validation of anaphylaxis using electronic health data in a population-based set-
References ting. Epidemiology. 2021;32(3):439–443.
1. Weiler CR, Schrijvers R, Golden DB. Anaphylaxis: advances in the past 10 years. J 29. Erlewyn-Lajeunesse M, Dymond S, Slade I, Mansfield HL, Fish R, Jones O, et al.
Allergy Clin Immunol Pract. 2023;11(1):51–62. Diagnostic utility of two case definitions for anaphylaxis: a comparison using a
2. Lieberman P, Nicklas RA, Randolph C, Oppenheimer J, Bernstein D, Bernstein J, retrospective case notes analysis in the UK. Drug Saf. 2010;33(1):57–64.
et al. Anaphylaxis−a practice parameter update 2015. Ann Allergy Asthma Immu- 30. Hourihane JO, Byrne AM, Blumchen K, Turner PJ, Greenhawt M. Ascertainment
nol. 2015;115(5):341–384. bias in anaphylaxis safety data of COVID-19 vaccines. J Allergy Clin Immunol Pract.
3. Shaker MS, Wallace DV, Golden DBK, Oppenheimer J, Bernstein JA, Campbell RL, 2021;9(7):2562–2566.
et al. Anaphylaxis: a 2020 practice parameter update, systematic review, and 31. Blumenthal KG, Banerji A. We should not abandon the Brighton Collaboration cri-
Grading of Recommendations, Assessment, Development and Evaluation teria for vaccine-associated anaphylaxis. Ann Allergy Asthma Immunol. 2022;129
(GRADE) analysis. J Allergy Clin Immunol. 2020;145(4):1082–1123. (1):17–19.
4. Dribin TE, Schnadower D, Wang J, Camargo Jr CA, Michelson KA, Shaker M, et al. 32. de Silva D, Singh C, Muraro A, Worm M, Alviani C, Cardona V, et al. Diagnosing,
Anaphylaxis knowledge gaps and future research priorities: a consensus report. J managing and preventing anaphylaxis: systematic review. Allergy. 2021;76
Allergy Clin Immunol. 2022;149(3):999–1009. (5):1493–1506.
5. Nowak R, Farrar JR, Brenner BE, Lewis L, Silverman RA, Emerman C, et al. Custom- 33. Slapnicar C, Lebovic G, McParland A, Dozois M, Vadas P. Reproducibility of symp-
izing anaphylaxis guidelines for emergency medicine. J Emerg Med. 2013;45 tom sequences across episodes of recurrent anaphylaxis. J Allergy Clin Immunol
(2):299–306. Pract. 2022;10(2):534–538.e1.
6. Davis CM, Apter AJ, Casillas A, Foggs MB, Louisias M, Morris EC, et al. Health dis- 34. Dribin TE, Sampson HA, Camargo Jr CA, Brousseau DC, Spergel JM, Neuman MI,
parities in allergic and immunologic conditions in racial and ethnic underserved et al. Persistent, refractory, and biphasic anaphylaxis: a multidisciplinary Delphi
populations: A Work Group Report of the AAAAI Committee on the Underserved. study. J Allergy Clin Immunol. 2020;146(5):1089–1096.
J Allergy Clin Immunol. 2021;147(5):1579–1593. 35. Lee JM, Greenes DS. Biphasic anaphylactic reactions in pediatrics. Pediatrics.
7. Johansson SG, Hourihane JO, Bousquet J, Bruijnzeel-Koomen C, Dreborg S, Haah- 2000;106(4):762–766.
tela T, et al. A revised nomenclature for allergy. An EAACI position statement 36. Mehr S, Liew WK, Tey D, Tang ML. Clinical predictors for biphasic reactions in
from the EAACI nomenclature task force. Allergy. 2001;56(9):813–824. children presenting with anaphylaxis. Clin Exp Allergy. 2009;39(9):1390–1396.
8. Braganza SC, Acworth JP, McKinnon DR, Peake JE, Brown AF. Paediatric emer- 37. Kim T-H, Yoon SH, Lee S-Y, Choi YH, Park CM, Kang H-R, et al. Biphasic and pro-
gency department anaphylaxis: different patterns from adults. Arch Dis Child. tracted anaphylaxis to iodinated contrast media. Eur Radiol. 2018;28(3):1242–1252.
2006;91(2):159–163. 38. Rohacek M, Edenhofer H, Bircher A, Bingisser R. Biphasic anaphylactic reactions:
9. Brown SG, Mullins RJ, Gold MS. Anaphylaxis: diagnosis and management. Med J occurrence and mortality. Allergy. 2014;69(6):791–797.
Aust. 2006;185(5):283–289. 39. Stark BJ, Sullivan TJ. Biphasic and protracted anaphylaxis. J Allergy Clin Immunol.
10. Sampson HA, Mun ~ oz-Furlong A, Campbell RL, Adkinson Jr NF, Bock SA, Branum A, 1986;78(1 Pt 1):76–83.
et al. Second symposium on the definition and management of anaphylaxis: 40. Kim TH, Yoon SH, Hong H, Kang HR, Cho SH, Lee SY. Duration of observation for
summary report−Second National Institute of Allergy and Infectious Disease/ detecting a biphasic reaction in anaphylaxis: a meta-analysis. Int Arch Allergy
Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. Immunol. 2019;179(1):31–36.
2006;117(2):391–397. 41. Ellis AK, Day JH. Incidence and characteristics of biphasic anaphylaxis: a prospec-
11. Ru€ ggeberg JU, Gold MS, Bayas JM, Blum MD, Bonhoeffer J, Friedlander S, et al. tive evaluation of 103 patients. Ann Allergy Asthma Immunol. 2007;98(1):64–69.
Anaphylaxis: case definition and guidelines for data collection, analysis, and pre- 42. Grunau BE, Li J, Yi TW, Stenstrom R, Grafstein E, Wiens MO, et al. Incidence of
sentation of immunization safety data. Vaccine. 2007;25(31):5675–5684. clinically important biphasic reactions in emergency department patients with
12. Lieberman P, Nicklas RA, Oppenheimer J, Kemp SF, Lang DM, Bernstein DI, et al. allergic reactions or anaphylaxis. Ann Emerg Med. 2014;63(6). 736-44.e2.
The diagnosis and management of anaphylaxis practice parameter: 2010 update. 43. Alqurashi W, Ellis AK. Do corticosteroids prevent biphasic anaphylaxis? J Allergy
J Allergy Clin Immunol. 2010;126(3). 477-80.e1-42. Clin Immunol Pract. 2017;5(5):1194–1205.
13. Simons FE, Ardusso LR, Bilo MB, El-Gamal YM, Ledford DK, Ring J, et al. World 44. Alqurashi W, Stiell I, Chan K, Neto G, Alsadoon A, Wells G. Epidemiology and clin-
Allergy Organization guidelines for the assessment and management of anaphy- ical predictors of biphasic reactions in children with anaphylaxis. Ann Allergy
laxis. World Allergy Organ J. 2011;4(2):13–37. Asthma Immunol. 2015;115(3):217–223.e2.
14. Khan NU, Shakeel N, Makda A, Mallick AS, Ali Memon M, Hashmi SH, et al. Ana- 45. Vezir E, Erkocoglu M, Kaya A, Toyran M, Ozcan C, Akan A, et al. Characteristics of
phylaxis: incidence, presentation, causes and outcome in patients in a tertiary- anaphylaxis in children referred to a tertiary care center. Allergy Asthma Proc.
care hospital in Karachi, Pakistan. QJM. 2013;106(12):1095–1101. 2013;34(3):239–246.
46. Alqurashi W, Alnaji F, Menon K. Refractory anaphylaxis: further considerations 74. Fernandez-Rivas M, Gomez Garcia I, Gonzalo-Fernandez A, Fuentes Ferrer M,
for emergency care providers. Ann Allergy Asthma Immunol. 2016;116(3):265– Dolle-Bierke S, Marco-Martin G, et al. Development and validation of the food
266. allergy severity score. Allergy. 2022;77(5):1545–1558.
47. Brown SG. The pathophysiology of shock in anaphylaxis. Immunol Allergy Clin 75. Blazowski L, Majak P, Kurzawa R, Kuna P, Jerzynska J. A severity grading system
North Am. 2007;27(2):165–175. of food-induced acute allergic reactions to avoid the delay of epinephrine admin-
48. Francuzik W, Do € lle-Bierke S, Knop M, Scherer Hofmeier K, Cichocka-Jarosz E, Gar- istration. Ann Allergy Asthma Immunol. 2021;127(4):462–470.e2.
cía BE, et al. Refractory anaphylaxis: data from the European Anaphylaxis Regis- 76. Stafford A, Bartra J, Aston A, Mills ENC, Fernandez-Rivas M, Turner PJ. Improving
try. Front Immunol. 2019;10:2482. severity scoring of food-induced allergic reactions: a global “best-worst scaling”
49. Park H, Kim SM, Kim WY. Cardiac arrest caused by anaphylaxis refractory to exercise. J Allergy Clin Immunol Pract. 2021;9(11):4075–4086.e5.
prompt management. Am J Emerg Med. 2022;61:74–80. 77. Baretto RL, Beck S, Heslegrave J, Melchior C, Mohamed O, Ekbote A, et al. Valida-
50. Chu DK, McCullagh DJ, Waserman S. Anaphylaxis for internists: definition, evalu- tion of international consensus equation for acute serum total tryptase in mast
ation, and management, with a focus on commonly encountered problems. Med cell activation: a perioperative perspective. Allergy. 2017;72(12):2031–2034.
Clin North Am. 2020;104(1):25–44. 78. De Schryver S, Halbrich M, Clarke A, La Vieille S, Eisman H, Alizadehfar R, et al.
51. Turner PJ, Jerschow E, Umasunthar T, Lin R, Campbell DE, Boyle RJ. Fatal anaphy- Tryptase levels in children presenting with anaphylaxis: temporal trends and
laxis: mortality rate and risk factors. J Allergy Clin Immunol Pract. 2017;5 associated factors. J Allergy Clin Immunol. 2016;137(4):1138–1142.
(5):1169–1178. 79. Valent P, Akin C, Arock M, Brockow K, Butterfield JH, Carter MC, et al. Definitions,
52. Jerschow E, Lin RY, Scaperotti MM, McGinn AP. Fatal anaphylaxis in the United criteria and global classification of mast cell disorders with special reference to
States, 1999-2010: temporal patterns and demographic associations. J Allergy mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol.
Clin Immunol. 2014;134(6):1318–1328.e7. 2012;157(3):215–225.
53. Ma L, Danoff TM, Borish L. Case fatality and population mortality associated 80. Mateja A, Wang Q, Chovanec J, Kim J, Wilson KJ, Schwartz LB, et al. Defining base-
with anaphylaxis in the United States. J Allergy Clin Immunol. 2014;133 line variability of serum tryptase levels improves accuracy in identifying anaphy-
(4):1075–1083. laxis. J Allergy Clin Immunol. 2022;149(3):1010–1017.e10.
is AT, Cardoso T. Anaphylactic reactions in the emergency department of a
54. Fro 81. National Institute of Allergy and Infectious Diseases. Total Rise in Peripheral
Portuguese tertiary hospital: clinical characterization and disease notification. Tryptase after Systemic Event (TRIPTASAE) Calculator. Available at: https://trip
Acta Med Port. 2019;32(2):91–100. tase-calculator.niaid.nih.gov. Accessed November 5, 2022.
55. Clark S, Wei W, Rudders SA, Camargo Jr. CA. Risk factors for severe anaphylaxis in 82. Lyons JJ. Hereditary alpha tryptasemia: genotyping and associated clinical fea-
patients receiving anaphylaxis treatment in US emergency departments and hos- tures. Immunol Allergy Clin North Am. 2018;38(3):483–495.
pitals. J Allergy Clin Immunol. 2014;134(5):1125–1130. 83. Lyons JJ, Yu X, Hughes JD, Le QT, Jamil A, Bai Y, et al. Elevated basal serum tryp-
56. Ghazali H, Gammoudi M, Yahmadi A, Chaaebeni G, Souyah A, Souissi S. Anaphy- tase identifies a multisystem disorder associated with increased TPSAB1 copy
laxis in an emergency department: epidemiology, clinical features and manage- number. Nat Genet. 2016;48(12):1564–1569.
ment. Tunis Med. 2017;95(1):45–52. 84. Lyons JJ, Greiner G, Hoermann G, Metcalfe DD. Incorporating tryptase genotyping
57. Muraro A, Fernandez-Rivas M, Beyer K, Cardona V, Clark A, Eller E, et al. The into the workup and diagnosis of mast cell diseases and reactions. J Allergy Clin
urgent need for a harmonized severity scoring system for acute allergic reactions. Immunol Pract. 2022;10(8):1964–1973.
Allergy. 2018;73(9):1792–1800. 85. Giannetti MP, Weller E, Bormans C, Novak P, Hamilton MJ, Castells M. Hereditary
58. Anagnostou K, Turner PJ. Myths, facts and controversies in the diagnosis and alpha-tryptasemia in 101 patients with mast cell activation-related symptomatol-
management of anaphylaxis. Arch Dis Child. 2019;104(1):83–90. ogy including anaphylaxis. Ann Allergy Asthma Immunol. 2021;126(6):655–660.
59. Smith PK, Hourihane JO, Lieberman P. Risk multipliers for severe food anaphy- 86. National Institute of Allergy and Infectious Diseases. Basal Serum Tryptase Clini-
laxis. World Allergy Organ J. 2015;8(1):30. cal Cut-Off Assigned by Locus Copy Number of UTR-Linked Element and Associ-
60. Dubois AEJ, Turner PJ, Hourihane J, Ballmer-Weber B, Beyer K, Chan CH, et al. ated TPSAB1-Encoded Replication (BST Calculator). Available at: https://bst-
How does dose impact on the severity of food-induced allergic reactions, and can calculater.niaid.nih.gov. Accessed November 5, 2022.
this improve risk assessment for allergenic foods?: report from an ILSI Europe 87. Robey RC, Wilcock A, Bonin H, Beaman G, Myers B, Grattan C, et al. Hereditary
Food Allergy Task Force Expert Group and Workshop. Allergy. 2018;73(7):1383– alpha-tryptasemia: UK prevalence and variability in disease expression. J Allergy
1392. Clin Immunol Pract. 2020;8(10):3549–3556.
61. Dribin TE, Schnadower D, Spergel JM, Campbell RL, Shaker M, Neuman MI, et al. 88. Giannetti MP, Godwin G, Weller E, Butterfield JH. Castells M. Differential mast cell
Severity grading system for acute allergic reactions: a multidisciplinary Delphi mediators in systemic mastocytosis and hereditary alpha-tryptasemia. J Allergy
study. J Allergy Clin Immunol. 2021;148(1):173–181. Clin Immunol. 2022;150(5):1225–1227.
62. Turner PJ, Baumert JL, Beyer K, Boyle RJ, Chan CH, Clark AT, et al. Can we identify 89. Chollet MB, Akin C. Hereditary alpha tryptasemia is not associated with specific
patients at risk of life-threatening allergic reactions to food? Allergy. 2016;71 clinical phenotypes. J Allergy Clin Immunol. 2022;149(2):728–735.e2.
(9):1241–1255. 90. Greiner G, Sprinzl B, Gorska A, Ratzinger F, Gurbisz M, Witzeneder N, et al. Hered-
63. Brown SG. Clinical features and severity grading of anaphylaxis. J Allergy Clin itary a tryptasemia is a valid genetic biomarker for severe mediator-related
Immunol. 2004;114(2):371–376. symptoms in mastocytosis. Blood. 2021;137(2):238–247.
64. Sampson HA, Gerth van Wijk R, Bindslev-Jensen C, Sicherer S, Teuber SS, Burks 91. Lyons JJ, Chovanec J, O’Connell MP, Liu Y, Selb J, Zanotti R, et al. Heritable risk for
AW, et al. Standardizing double-blind, placebo-controlled oral food challenges: severe anaphylaxis associated with increased a-tryptase-encoding germline
American Academy of Allergy, Asthma & Immunology-European Academy of copy number at TPSAB1. J Allergy Clin Immunol. 2021;147(2):622–632.
Allergy and Clinical Immunology PRACTALL consensus report. J Allergy Clin 92. Giannetti MP, Akin C, Hufdhi R, Hamilton MJ, Weller E, van Anrooij B, et al.
Immunol. 2012;130(6):1260–1274. Patients with mast cell activation symptoms and elevated baseline serum tryp-
65. Cox LS, Sanchez-Borges M, Lockey RF. World Allergy Organization systemic aller- tase level have unique bone marrow morphology. J Allergy Clin Immunol.
gic reaction grading system: is a modification needed? J Allergy Clin Immunol 2021;147(4):1497–1501.e1.
Pract. 2017;5(1):58–62.e5. 93. Alvarez-Twose I, Gonza lez de Olano D, Sa nchez-Mun ~ oz L, Matito A, Esteban-
66. Ring J, Messmer K. Incidence and severity of anaphylactoid reactions to colloid Lo pez MI, Vega A, et al. Clinical, biological, and molecular characteristics of clonal
volume substitutes. Lancet. 1977;1(8009):466–469. mast cell disorders presenting with systemic mast cell activation symptoms. J
67. Garvey LH, Dewachter P, Hepner DL, Mertes PM, Voltolini S, Clarke R, et al. Man- Allergy Clin Immunol. 2010;125(6):1269–1278.e2.
agement of suspected immediate perioperative allergic reactions: an interna- 94. Carter MC, Desai A, Komarow HD, Bai Y, Clayton ST, Clark AS, et al. A distinct bio-
tional overview and consensus recommendations. Br J Anaesth. 2019;123(1): molecular profile identifies monoclonal mast cell disorders in patients with idio-
e50–e64. pathic anaphylaxis. J Allergy Clin Immunol. 2018;141(1):180–188.e3.
68. Srivastava S, Huissoon AP, Barrett V, Hackett S, Dorrian S, Cooke MW, et al. Sys- 95. De Puysseleyr LP, Ebo DG, Elst J, Faber MA, Poorten MV, Van Gasse AL, et al. Diag-
temic reactions and anaphylaxis with an acute serum tryptase ≥14 mg/L: retro- nosis of primary mast cell disorders in anaphylaxis: value of KIT D816V in
spective characterisation of aetiology, severity and adherence to National peripheral blood. J Allergy Clin Immunol Pract. 2021;9(8):3176–3187.e3.
Institute of Health and Care Excellence (NICE) guidelines for serial tryptase meas- 96. Alvarez-Twose I, Gonzalez-de-Olano D, Sanchez-Munoz L, Matito A, Jara-Acevedo
urements and specialist referral. J Clin Pathol. 2014;67(7):614–619. M, Teodosio C, et al. Validation of the REMA score for predicting mast cell clonal-
69. Sampson HA. Anaphylaxis and emergency treatment. Pediatrics. 2003;111(6 Pt ity and systemic mastocytosis in patients with systemic mast cell activation
3):1601–1608. symptoms. Int Arch Allergy Immunol. 2012;157(3):275–280.
70. Muraro A, Roberts G, Clark A, Eigenmann PA, Halken S, Lack G, et al. The manage- 97. Gu€ len T, Ha €gglund H, Sander B, Dahle n B, Nilsson G. The presence of mast cell
ment of anaphylaxis in childhood: position paper of the European academy of clonality in patients with unexplained anaphylaxis. Clin Exp Allergy. 2014;44
allergology and clinical immunology. Allergy. 2007;62(8):857–871. (9):1179–1187.
71. Cox L, Larenas-Linnemann D, Lockey RF, Passalacqua G. Speaking the same lan- 98. Lieberman JA, Bingemann TA, Wang J. Diagnostic challenges in anaphylaxis. J
guage: the World Allergy Organization subcutaneous Immunotherapy Systemic Allergy Clin Immunol Pract. 2020;8(4):1177–1184.
Reaction Grading System. J Allergy Clin Immunol. 2010;125(3):569–574. 574.e1- 99. Carter MC, Ruiz-Esteves KN, Workman L, Lieberman P, Platts-Mills TAE, Metcalfe
574.e7. DD. Identification of alpha-gal sensitivity in patients with a diagnosis of idio-
72. Soller L, Abrams EM, Carr S, Kapur S, Rex GA, Leo S, et al. First real-world safety pathic anaphylaxis. Allergy. 2018;73(5):1131–1134.
analysis of preschool peanut oral immunotherapy. J Allergy Clin Immunol Pract. 100. Pattanaik D, Lieberman P, Lieberman J, Pongdee T, Keene AT. The changing face of
2019;7(8):2759–2767.e5. anaphylaxis in adults and adolescents. Ann Allergy Asthma Immunol. 2018;121
73. Chinthrajah RS, Jones SM, Kim EH, Sicherer SH, Shreffler W, Lanser BJ, et al. (5):594–597.
Updating the CoFAR grading scale for systemic allergic reactions in food allergy. J 101. Bellamy P, Sanderson WT, Winter K, Stringer JW, Kussainov N, Commins SP.
Allergy Clin Immunol. 2022;149(6):2166–2170.e1. Prevalence of alpha-gal sensitization among Kentucky timber harvesters and
forestry and wildlife practitioners. J Allergy Clin Immunol Pract. 2021;9 131. Dyer AA, Lau CH, Smith TL, Smith BM, Gupta RS. Pediatric emergency department
(5):2113–2116. visits and hospitalizations due to food-induced anaphylaxis in Illinois. Ann Allergy
102. Fischer J, Lupberger E, Hebsaker J, Blumenstock G, Aichinger E, Yazdi AS, et al. Asthma Immunol. 2015;115(1):56–62.
Prevalence of type I sensitization to alpha-gal in forest service employees and 132. Grabenhenrich LB, Dolle S, Moneret-Vautrin A, Kohli A, Lange L, Spindler T, et al.
hunters. Allergy. 2017;72(10):1540–1547. Anaphylaxis in children and adolescents: the European Anaphylaxis Registry. J
103. Mabelane T, Basera W, Botha M, Thomas HF, Ramjith J, Levin ME. Predictive val- Allergy Clin Immunol. 2016;137(4):1128–1137.e1.
ues of alpha-gal IgE levels and alpha-gal IgE: total IgE ratio and oral food chal- 133. Tsuang A, Chan ES, Wang J. Food-induced anaphylaxis in infants: can new evi-
lenge-proven meat allergy in a population with a high prevalence of reported dence assist with implementation of food allergy prevention and treatment? J
red meat allergy. Pediatr Allergy Immunol. 2018;29(8):841–849. Allergy Clin Immunol Pract. 2021;9(1):57–69.
104. Cha LM, Lee WS, Han MY, Lee KS. The timely administration of epinephrine and 134. Jiang N, Xu W, Xiang L. Age-related differences in characteristics of anaphylaxis
related factors in children with anaphylaxis. J Clin Med. 2022;11(19):5494. in Chinese children from infancy to adolescence. World Allergy Organ J. 2021;14
105. Prosty C, Colli MD, Gabrielli S, Clarke AE, Morris J, Gravel J, et al. Impact of reac- (11): 100605.
tion setting on the management, severity, and outcome of pediatric food-induced 135. Greenhawt M, Gupta RS, Meadows JA, Pistiner M, Spergel JM, Camargo Jr CA, et al.
anaphylaxis: a cross-sectional study. J Allergy Clin Immunol Pract. 2022;10 Guiding principles for the recognition, diagnosis, and management of infants
(12):3163–3171. with anaphylaxis: an expert panel consensus. J Allergy Clin Immunol Pract. 2019;7
106. De Filippo M, Votto M, Albini M, Castagnoli R, De Amici M, Marseglia A, et al. (4):1148–1156.e5.
Pediatric anaphylaxis: a 20-year retrospective analysis. J Clin Med. 2022;11 136. Robinson LB, Arroyo AC, Faridi MK, Rudders S, Camargo Jr. CA. Trends in US Emer-
(18):5285. gency Department visits for anaphylaxis among infants and toddlers: 2006-2015.
107. Ferdman RM. What is anaphylaxis? Pediatric residents’ perception and treatment J Allergy Clin Immunol Pract. 2021;9(5):1931–1938.e2.
of anaphylactic reactions. Clin Pediatr (Phila). 2021;60(1):25–31. 137. Robinson LB, Arroyo AC, Faridi MK, Rudders SA, Camargo Jr. CA. Trends in US hos-
108. Gonzalez-Díaz SN, Villarreal-Gonzalez RV, Fuentes-Lara EI, Salinas-Díaz MDR, de pitalizations for anaphylaxis among infants and toddlers: 2006 to 2015. Ann
Lira-Quezada CE, Macouzet-Sa nchez C, et al. Knowledge of healthcare providers Allergy Asthma Immunol. 2021;126:168–174.e3.
in the management of anaphylaxis. World Allergy Organ J. 2021;14(11): 100599. 138. Du Toit G, Roberts G, Sayre PH, Bahnson HT, Radulovic S, Santos AF, et al. Ran-
109. Jung WS, Kim SH, Lee H. Missed diagnosis of anaphylaxis in patients with pediat- domized trial of peanut consumption in infants at risk for peanut allergy. N Engl J
ric urticaria in the emergency department. Pediatr Emerg Care. 2021;37(4):199– Med. 2015;372(9):803–813.
203. 139. Perkin MR, Logan K, Tseng A, Raji B, Ayis S, Peacock J, et al. Randomized trial of
110. Maris I, Dolle-Bierke S, Renaudin JM, Lange L, Koehli A, Spindler T, et al. Peanut- introduction of allergenic foods in breast-fed infants. N Engl J Med. 2016;374
induced anaphylaxis in children and adolescents: data from the European Ana- (18):1733–1743.
phylaxis Registry. Allergy. 2021;76(5):1517–1527. 140. Palmer DJ, Metcalfe J, Makrides M, Gold MS, Quinn P, West CE, et al. Early regular
111. Miles LM, Ratnarajah K, Gabrielli S, Abrams EM, Protudjer JLP, Be gin P, et al. Com- egg exposure in infants with eczema: a randomized controlled trial. J Allergy Clin
munity use of epinephrine for the treatment of anaphylaxis: a review and meta- Immunol. 2013;132(2). 387-92.e1.
analysis. J Allergy Clin Immunol Pract. 2021;9(6):2321–2333. 141. Palmer DJ, Sullivan TR, Gold MS, Prescott SL, Makrides M. Randomized controlled
112. Muraro A, Worm M, Alviani C, Cardona V, DunnGalvin A, Garvey LH, et al. EAACI trial of early regular egg intake to prevent egg allergy. J Allergy Clin Immunol.
guidelines: Anaphylaxis (2021 update). Allergy. 2022;77(2):357–377. 2017;139(5):1600–1607.e2.
113. Nasr I, Mahdi AS, Al Shekaili J, Nasr I, Al Wahshi H, Al Juma S, et al. Real world 142. Natsume O, Kabashima S, Nakazato J, Yamamoto-Hanada K, Narita M, Kondo M,
management of anaphylaxis versus the National Institute for Health and Clinical et al. Two-step egg introduction for prevention of egg allergy in high-risk infants
Excellence (NICE) guidelines. Cureus. 2022;14(9):e29336. with eczema (PETIT): a randomised, double-blind, placebo-controlled trial. Lan-
114. Vamvakaris K, Koumpoura A, Farmaki M, Lakoumentas J, Pasioti M, Papadopoulos cet. 2017;389(10066):276–286.
N, et al. Diagnosis, management and prescription practices of adrenaline in chil- 143. Bellach J, Schwarz V, Ahrens B, Trendelenburg V, Aksunger O, Kalb B, et al. Ran-
dren with food-induced anaphylaxis: audit in a specialized pediatric allergy domized placebo-controlled trial of hen’s egg consumption for primary preven-
department. J Pers Med. 2022;12(9):1477. tion in infants. J Allergy Clin Immunol. 2017;139(5):1591–1599.e2.
115. Tsoulis M, Shaker M. The influence of systems and settings on the management 144. Wei-Liang Tan J, Valerio C, Barnes EH, Turner PJ, Van Asperen PA, Kakakios AM,
of anaphylaxis. J Allergy Clin Immunol Pract. 2022;10(12):3172–3173. et al. A randomized trial of egg introduction from 4 months of age in infants at
116. de Silva D, Singh C, Muraro A, Worm M, Alviani C, Cardona V, et al. Diagnosing, risk for egg allergy. J Allergy Clin Immunol. 2017;139(5):1621–1628.e8.
managing and preventing anaphylaxis: systematic review. Allergy. 2021;76 145. Soriano VX, Peters RL, Ponsonby AL, Dharmage SC, Perrett KP, Field MJ, et al. Ear-
(5):1493–1506. lier ingestion of peanut after changes to infant feeding guidelines: the EarlyNuts
117. Grabenhenrich LB, Dolle S, Rueff F, Renaudin JM, Scherer K, Pfohler C, et al. Epi- study. J Allergy Clin Immunol. 2019;144(5):1327–1335.e5.
nephrine in severe allergic reactions: the European Anaphylaxis Register. J 146. Jeong K, Ye YM, Kim SH, Kim KW, Kim JH, Kwon JW, et al. A multicenter anaphy-
Allergy Clin Immunol Pract. 2018;6(6):1898–1906.e1. laxis registry in Korea: clinical characteristics and acute treatment details from
118. Bautista E, Simons FE, Simons KJ, Becker AB, Duke K, Tillett M, et al. Epinephrine infants to older adults. World Allergy Organ J. 2020;13(8): 100449.
fails to hasten hemodynamic recovery in fully developed canine anaphylactic 147. Rudders SA, Banerji A, Clark S, Camargo Jr. CA. Age-related differences in the clin-
shock. Int Arch Allergy Immunol. 2002;128(2):151–164. ical presentation of food-induced anaphylaxis. J Pediatr. 2011;158(2):326–328.
119. Sampson HA, Mendelson L, Rosen JP. Fatal and near-fatal anaphylactic reactions 148. Samady W, Trainor J, Smith B, Gupta R. Food-induced anaphylaxis in infants and
to food in children and adolescents. N Engl J Med. 1992;327(6):380–384. children. Ann Allergy Asthma Immunol. 2018;121(3):360–365.
120. Shaker M, Greenhawt M. The health and economic outcomes of peanut allergy 149. Pouessel G, Beaudouin E, Tanno LK, Drouet M, Deschildre A, Labreuche J, et al.
management practices. J Allergy Clin Immunol Pract. 2018;6(6):2073–2080. Food-related anaphylaxis fatalities: analysis of the Allergy Vigilance Network
121. Ward CE, Greenhawt MJ. Treatment of allergic reactions and quality of life among database. Allergy. 2019;74(6):1193–1196.
caregivers of food-allergic children. Ann Allergy Asthma Immunol. 2015;114 150. Pistiner M, Mendez-Reyes JE, Eftekhari S, Carver M, Lieberman J, Wang J, et al.
(4):312–318.e2. Caregiver-reported presentation of severe Food-induced allergic reactions in
122. Turner PJ, DunnGalvin A, Hourihane JO. The emperor has no ymptoms: the risks infants and toddlers. J Allergy Clin Immunol Pract. 2021;9(1):311–320.e2.
of a blanket approach to using epinephrine autoinjectors for all allergic reactions. 151. Simons FE, Sampson HA. Anaphylaxis: unique aspects of clinical diagnosis and
J Allergy Clin Immunol Pract. 2016;4(6):1143–1146. management in infants (birth to age 2 years). J Allergy Clin Immunol. 2015;135
123. Burrell S, Patel N, Vazquez-Ortiz M, Campbell DE, DunnGalvin A, Turner PJ. Self- (5):1125–1131.
administration of adrenaline for anaphylaxis during in-hospital food challenges 152. Yuvaraj R, Murugappan M, Acharya UR, Adeli H, Ibrahim NM, Mesquita E. Brain
improves health-related quality of life. Arch Dis Child. 2021;106(6):558–563. functional connectivity patterns for emotional state classification in Parkinson’s
124. Ruiz-Garcia M, Bartra J, Alvarez O, Lakhani A, Patel S, Tang A, et al. Cardiovascular disease patients without dementia. Behav Brain Res. 2016;298(B):248–260.
changes during peanut-induced allergic reactions in human subjects. J Allergy 153. Kim H, Dinakar C, McInnis P, Rudin D, Benain X, Daley W, et al. Inadequacy of cur-
Clin Immunol. 2021;147(2):633–642. rent pediatric epinephrine autoinjector needle length for use in infants and tod-
125. Shaker M, Kanaoka T, Feenan L, Greenhawt M. An economic evaluation of imme- dlers. Ann Allergy Asthma Immunol. 2017;118(6):719–725.e1.
diate vs non-immediate activation of emergency medical services after epineph- 154. Dreborg S, Kim L, Tsai G, Kim H. Epinephrine auto-injector needle lengths: can
rine use for peanut-induced anaphylaxis. Ann Allergy Asthma Immunol. 2019;122 both subcutaneous and periosteal/intraosseous injection be avoided? Ann Allergy
(1):79–85. Asthma Immunol. 2018;120(6):648–653.e1.
126. Casale TB, Wang J, Nowak-Wegrzyn A. Acute at home management of anaphy- 155. Ibrahim M, Kim H. Unintentional injection to the bone with a pediatric epineph-
laxis during the COVID-19 pandemic. J Allergy Clin Immunol Pract. 2020;8 rine auto-injector. Allergy Asthma Clin Immunol. 2018;14:32.
(6):1795–1797. 156. Simonte SJ, Ma S, Mofidi S, Sicherer SH. Relevance of casual contact with peanut but-
127. Shaker MS, Oppenheimer J, Grayson M, Stukus D, Hartog N, Hsieh EWY, et al. ter in children with peanut allergy. J Allergy Clin Immunol. 2003;112(1):180–182.
COVID-19: pandemic contingency planning for the allergy and immunology 157. Roberts G, Golder N, Lack G. Bronchial challenges with aerosolized food in asth-
clinic. J Allergy Clin Immunol Pract. 2020;8(5):1477–1488.e5. matic, food-allergic children. Allergy. 2002;57(8):713–717.
128. Blaiss MS, Steven GC, Bender B, Bukstein DA, Meltzer EO, Winders T. Shared deci- 158. Perry TT, Conover-Walker MK, Pomes A, Chapman MD, Wood RA. Distribu-
sion making for the allergist. Ann Allergy Asthma Immunol. 2019;122(5):463–470. tion of peanut allergen in the environment. J Allergy Clin Immunol. 2004;113
129. Casale TB, Wang J, Oppenheimer J, Nowak-Wegrzyn A. Acute at-home manage- (5):973–976.
ment of anaphylaxis: 911: what is the emergency? J Allergy Clin Immunol Pract. 159. Johnson RM, Barnes CS. Airborne concentrations of peanut protein. Allergy
2022;10(9):2274–2279. Asthma Proc. 2013;34(1):59–64.
130. Motosue MS, Bellolio MF, Van Houten HK, Shah ND, Campbell RL. National trends 160. Brough HA, Makinson K, Penagos M, Maleki SJ, Cheng H, Douiri A, et al. Distribu-
in emergency department visits and hospitalizations for food-induced anaphy- tion of peanut protein in the home environment. J Allergy Clin Immunol.
laxis in US children. Pediatr Allergy Immunol. 2018;29(5):538–544. 2013;132(3):623–629.
161. Boros CA, Kay D, Gold MS. Parent reported allergy and anaphylaxis in 4173 South 192. Pouessel G, Jean-Bart C, Deschildre A, Van der Brempt X, Tanno LK, Beaumont P,
Australian children. J Paediatr Child Health. 2000;36(1):36–40. et al. Food-induced anaphylaxis in infancy compared to preschool age: a retro-
162. de Silva IL, Mehr SS, Tey D, Tang ML. Paediatric anaphylaxis: a 5 year retrospec- spective analysis. Clin Exp Allergy. 2020;50(1):74–81.
tive review. Allergy. 2008;63(8):1071–1076. 193. Rudders SA, Clark S, Camargo Jr. CA. Inpatient interventions are infrequent during
163. De Swert LFA, Bullens D, Raes M, Dermaux AM. Anaphylaxis in referred pediatric pediatric hospitalizations for food-induced anaphylaxis. J Allergy Clin Immunol
patients: demographic and clinical features, triggers, and therapeutic approach. Pract. 2017;5(5):1421–1424.e2.
Eur J Pediatr. 2008;167(11):1251–1261. 194. Thomson H, Seith R, Craig S. Inaccurate diagnosis of paediatric anaphylaxis in
164. Novembre E, Cianferoni A, Bernardini R, Mugnaini L, Caffarelli C, Cavagni G, et al. three Australian Emergency Departments. J Paediatr Child Health. 2017;53
Anaphylaxis in children: clinical and allergologic features. Pediatrics. 1998;101 (7):698–704.
(4):e8. 195. Wright CD, Longjohn M, Lieberman PL, Lieberman JA. An analysis of anaphylaxis
165. Katsunuma T, Akashi K, Watanabe M. Anaphylaxis in children: demographic and cases at a single pediatric emergency department during a 1-year period. Ann
clinical features and triggers. Allergy. 2014;69(suppl 99):273. Allergy Asthma Immunol. 2017;118(4):461–464.
166. Gaspar A, Santos N, Piedade S, Santa-Marta C, Pires G, Sampaio G, et al. One-year 196. Robinson M, Greenhawt M, Stukus DR. Factors associated with epinephrine
survey of paediatric anaphylaxis in an allergy department. Eur Ann Allergy Clin administration for anaphylaxis in children before arrival to the emergency
Immunol. 2015;47(6):197–205. department. Ann Allergy Asthma Immunol. 2017;119(2):164–169.
167. Orhan F, Canitez Y, Bakirtas A, Yilmaz O, Boz AB, Can D, et al. Anaphylaxis in Turk- 197. Civelek E, Erkocoglu M, Akan A, Ozcan C, Kaya A, Vezir E, et al. The etiology and
ish children: a multi-centre, retrospective, case study. Clin Exp Allergy. 2011;41 clinical features of anaphylaxis in a developing country: a nationwide survey in
(12):1767–1776. Turkey. Asian Pac J Allergy Immunol. 2017;35(4):212–219.
168. Tiyyagura GK, Arnold L, Cone DC, Langhan M. Pediatric anaphylaxis management 198. Uguz A, Lack G, Pumphrey R, Ewan P, Warner J, Dick J, et al. Allergic reactions in
in the prehospital setting. Prehosp Emerg Care. 2014;18(1):46–51. the community: A questionnaire survey of members of the anaphylaxis cam-
169. Mehl A, Wahn U, Niggemann B. Anaphylactic reactions in children: a question- paign. Clin Exp Allergy. 2005;35(6):746–750.
naire-based survey in Germany. Allergy. 2005;60(11):1440–1445. 199. Sheikh A, Dhami S, Regent L, Austin M, Sheikh A. Anaphylaxis in the community:
170. Masumoto N, Shibata R, Yohei A, Yuko A, Yoshitaka M, Naohiko T, et al. Immedi- a questionnaire survey of members of the UK Anaphylaxis Campaign. JRSM Open.
ate food-allergic children visited to our hospital emergency room. Allergy. 2015;6(7): 205427041559344.
2011;66(suppl 94):407. 200. Boyano-Martinez T, Garcia-Ara C, Pedrosa M, Diaz-Pena JM, Quirce S. Accidental
171. Cherkaoui S, Ben-Shoshan M, Alizadehfar R, Asai Y, Chan E, Cheuk S, et al. Acci- allergic reactions in children allergic to cow’s milk proteins. J Allergy Clin Immu-
dental exposures to peanut in a large cohort of Canadian children with peanut nol. 2009;123(4):883–888.
allergy. Clin Transl Allergy. 2015;5:e6. 201. Gold MS, Sainsbury R. First aid anaphylaxis management in children who were
172. Nguyen-Luu NU, Ben-Shoshan M, Alizadehfar R, Joseph L, Harada L, Allen M, et al. prescribed an epinephrine autoinjector device (EpiPen). J Allergy Clin Immunol.
Inadvertent exposures in children with peanut allergy. Pediatr Allergy Immunol. 2000;106(1 Pt 1):171–176.
2012;23(2):133–139. 202. Pumphrey RS. Lessons for management of anaphylaxis from a study of fatal reac-
173. Yu JW, Kagan R, Verreault N, Nicolas N, Joseph L, St Pierre Y, et al. Accidental tions. Clin Exp Allergy. 2000;30(8):1144–1150.
ingestions in children with peanut allergy. J Allergy Clin Immunol. 2006;118 203. Pumphrey RS, Gowland MH. Further fatal allergic reactions to food in the United
(2):466–472. Kingdom, 1999-2006. J Allergy Clin Immunol. 2007;119(4):1018–1019.
174. Clark AT, Ewan PW. Good prognosis, clinical features, and circumstances of pea- 204. Worm M, Moneret-Vautrin A, Scherer K, Lang R, Fernandez-Rivas M, Cardona V,
nut and tree nut reactions in children treated by a specialist allergy center. J et al. First European data from the network of severe allergic reactions (NORA).
Allergy Clin Immunol. 2008;122(2):286–289. Allergy. 2014;69(10):1397–1404.
175. Kilger M, Range U, Vogelberg C. Acute and preventive management of anaphy- 205. Sicherer SH, Furlong TJ, Mun ~ oz-Furlong A, Burks AW, Sampson HA. A voluntary
laxis in German primary school and kindergarten children. BMC Pediatr. registry for peanut and tree nut allergy: characteristics of the first 5149 regis-
2015;15:159.e7. trants. J Allergy Clin Immunol. 2001;108(1):128–132.
176. Rance F, Grandmottet X, Grandjean H. Prevalence and main characteristics of 206. Eigenmann PA, Pastore FD, Zamora SA. An Internet-based survey of anaphylactic
schoolchildren diagnosed with food allergies in France. Clin Exp Allergy. 2005;35 reactions to foods. Allergy. 2001;56(6):540–543.
(2):167–172. 207. Tsuang A, Menon NR, Bahri N, Geyman LS, Nowak-Wegrzyn ˛ A. Risk factors for
177. Andrew E, Nehme Z, Bernard S, Smith K. Pediatric anaphylaxis in the prehospital multiple epinephrine doses in food-triggered anaphylaxis in children. Ann Allergy
setting: incidence, characteristics, and management. Prehosp Emerg Care. Asthma Immunol. 2018;121(4):469–473.
2018;22(4):445–451. 208. Waserman S, Cruickshank H, Hildebrand KJ, Mack D, Bantock L, Bingemann T, et al.
178. Anvari S, Blackman A, Anagnostou A. Anaphylaxis: closer to home? Ann Allergy Prevention and management of allergic reactions to food in child care centers and
Asthma Immunol. 2017;119(suppl 19). https://doi.org/10.1016/j.anai.2017.08.077. schools: practice guidelines. J Allergy Clin Immunol. 2021;147(5):1561–1578.
(abstract). 209. Ewan PW, Clark AT. Long-term prospective observational study of patients with
179. Azevedo J, Gaspar A, Mota I, Correia M, Benito-Garcia F, Piedade S, et al. Anaphy- peanut and nut allergy after participation in a management plan. Lancet.
laxis induced by tree nuts in preschool age children. Allergy. 2017;72(suppl 2001;357(9250):111–115.
103):767. 210. Ewan PW, Clark AT. Efficacy of a management plan based on severity assessment
180. Carrillo E, Hern HG, Barger J. Prehospital administration of epinephrine in pediat- in longitudinal and case-controlled studies of 747 children with nut allergy: pro-
ric anaphylaxis. Prehosp Emerg Care. 2016;20(2):239–244. posal for good practice. Clin Exp Allergy. 2005;35(6):751–756.
181. De Schryver S, Clarke A, La Vieille S, Eisman H, Morris J, Lim R, et al. Food-induced 211. Kourosh A, Davis C. School staff food allergy (FA) education increases epinephrine
anaphylaxis to a known food allergen in children often occurs despite adult coverage and recognition of allergic reactions. J Allergy Clin Immunol. 2015;135
supervision. Pediatr Allergy Immunol. 2017;28(7):715–717. (2):AB211.
182. Dogru M, Bostanci I, Ozmen S, Ginis T, Senol HD. The features of anaphylaxis 212. Moneret-Vautrin DA, Kanny G, Morisset M, Flabbee J, Guenard L, Beaudouin E,
cases followed in the pediatric allergy clinic. Guncel Pediatr. 2017;15(1):12–18. et al. Food anaphylaxis in schools: evaluation of the management plan and the
183. Dubus J-C, Le ^ M-S, Vitte J, Minodier P, Boutin A, Carsin A, et al. Use of epinephrine efficiency of the emergency kit. Allergy. 2001;56(11):1071–1076.
in emergency department depends on anaphylaxis severity in children. Eur J 213. Patel D, Johnson G, Guffey D, Minard C, Davis C. Longitudianal effect of food
Pediatr. 2019;178(1):69–75. allergy education on epinephrine availability in public schools. J Allergy Clin
184. Esenboga S, Kahveci M, Cetinkaya PG, Sahiner UM, Soyer O, Buyuktiryaki B, et al. Immunol. 2014;133(2):AB288.
Physicians prescribe adrenaline autoinjectors, do parents use them when 214. Tsuang A, Atal Z, Demain H, Patrick K, Pistiner M, Wang J. Benefits of school nurse
needed? Allergol Immunopathol. 2019;48(1):3–7. training sessions for food allergy and anaphylaxis management. J Allergy Clin
185. Ito K, Ono M, Kando N, Matsui T, Nakagawa T, Sugiura S, et al. Surveillance of the Immunol Pract. 2019;7(1):309–311.e2.
use of adrenaline auto-injectors in Japanese children. Allergol Int. 2018;67 215. Patel DR, Upton JEM, Wang J, Harada L, Guffey D, Minard CG, et al. Quality of life
(2):195–200. for parents of children with food allergy in peanut-restricted versus peanut-free
186. Jeong K, Kim J, Ahn K, Lee SY, Min TK, Pyun BY, et al. Age-based causes and clini- schools in the United States and Canada. J Allergy Clin Immunol Pract. 2018;6
cal characteristics of immediate-type food allergy in Korean children. Allergy (2):671–673.e7.
Asthma Immunol Res. 2017;9(5):423–430. 216. Bartnikas LM, Huffaker MF, Sheehan WJ, Kanchongkittiphon W, Petty CR, Leibo-
187. Korematsu S, Fujitaka M, Ogata M, Zaitsu M, Motomura C, Kuzume K, et al. witz R, et al. Impact of school peanut-free policies on epinephrine administration.
Administration of the adrenaline auto-injector at the nursery/kindergarten/ J Allergy Clin Immunol. 2017;140(2):465–473.
school in Western Japan. Asia Pac Allergy. 2017;7(1):37–41. 217. Food Allergy & Anaphylaxis Connection Team. Government Relations: school
188. McWilliam VL, Koplin JJ, Field MJ, Sasaki M, Dharmage SC, Tang MLK, et al. Self- access to emergency epinephrine federal legislation. Available at: https://www.
reported adverse food reactions and anaphylaxis in the SchoolNuts study: a pop- foodallergyawareness.org/government-relations/school-access-to-emergency-
ulation-based study of adolescents. J Allergy Clin Immunol. 2018;141(3):982–990. epinephrine-act/. Accessed September 15, 2022.
189. Nogic C, Belousoff J, Krieser D. The diagnosis and management of children pre- 218. Young I, Thaivalappil A. A systematic review and meta-regression of the knowl-
senting with anaphylaxis to a metropolitan emergency department: a 2-year ret- edge, practices, and training of restaurant and food service personnel toward
rospective case series. J Paediatr Child Health. 2016;52(5):487–492. food allergies and celiac disease. PLoS One. 2018;13(9): e0203496.
190. Pouessel G, Turner PJ, Worm M, Cardona V, Deschildre A, Beaudouin E, et al. 219. Radke TJ, Brown LG, Hoover ER, Faw BV, Reimann D, Wong MR, et al. Food allergy
Food-induced fatal anaphylaxis: from epidemiological data to general prevention knowledge and attitudes of restaurant managers and staff: an EHS-net study. J
strategies. Clin Exp Allergy. 2018;48(12):1584–1593. Food Prot. 2016;79(9):1588–1598.
191. Pouessel G, Cerbelle V, Lejeune S, Leteurtre S, Ramdane N, Deschildre A, et al. 220. Loerbroks A, Tolksdorf SJ, Wagenmann M, Smith H. Food allergy knowledge, atti-
Anaphylaxis admissions in pediatric intensive care units: follow-up and risk of tudes and their determinants among restaurant staff: a cross-sectional study.
recurrence. Pediatr Allergy Immunol. 2019;30(3):341–347. PLoS One. 2019;14(4): e0214625.
221. US Food and Drug Administration. Food allergen labeling and consumer protec- 253. Chu DK, Wood RA, French S, Fiocchi A, Jordana M, Waserman S, et al. Oral immu-
tion act of 2004 (FALCPA). Available at: https://www.fda.gov/food/food-allergens notherapy for peanut allergy (PACE): a systematic review and meta-analysis of
gluten-free-guidance-documents-regulatory-information/food-allergen-label efficacy and safety. Lancet. 2019;393(10187):2222–2232.
ing-and-consumer-protection-act-2004-falcpa. Accessed September 15, 2022. 254. Regateiro FS, Marques ML, Gomes ER. Drug-induced anaphylaxis: an update on
222. Oriel RC, Waqar O, Sharma HP, Casale TB, Wang J. Characteristics of food allergic epidemiology and risk factors. Int Arch Allergy Immunol. 2020;181(7):481–487.
reactions in United States restaurants. J Allergy Clin Immunol Pract. 2021;9 255. Montan ~ ez MI, Mayorga C, Bogas G, Barrionuevo E, Fernandez-Santamaria R, Mar-
(4):1675–1682. tin-Serrano A, et al. Epidemiology, mechanisms, and diagnosis of drug-induced
223. Zhang S, Sicherer SH, Bakhl K, Wang K, Stoffels G, Oriel RC. Restaurant takeout anaphylaxis. Front Immunol. 2017;8:614.
practices of food-allergic individuals and associated allergic reactions in the 256. Corren J, Casale TB, Lanier B, Buhl R, Holgate S, Jimenez P. Safety and tolerability
COVID-19 era. J Allergy Clin Immunol Pract. 2022;10(1):315–317.e1. of omalizumab. Clin Exp Allergy. 2009;39(6):788–797.
224. Carter CA, Pistiner M, Wang J, Sharma HP. Food allergy in restaurants work group 257. Cox L, Platts-Mills TAE, Finegold I, Schwartz LB, Simons FER, Wallace DV, et al.
report. J Allergy Clin Immunol Pract. 2020;8(1):70–74. American Academy of Allergy, Asthma & Immunology/American College of
225. Food Allergy Research & Education. Public access to epinephrine. Available at: Allergy, Asthma and Immunology Joint Task Force Report on omalizumab-associ-
https://www.foodallergy.org/public-access-epinephrine. Accessed September ated anaphylaxis. J Allergy Clin Immunol. 2007;120(6):1373–1377.
15, 2022. 258. Cox L, Lieberman P, Wallace D, Simons FER, Finegold I, Platts-Mills T, et al. Ameri-
226. Waserman S, Avilla E, Harada L, Allen M, Isaranuwatchai W, Perdrizet J, et al. To can Academy of Allergy, Asthma & Immunology/American College of Allergy,
stock or not to stock? implementation of epinephrine autoinjectors in food estab- Asthma & Immunology omalizumab-Associated Anaphylaxis Joint Task Force fol-
lishments. J Allergy Clin Immunol Pract. 2019;7(2):678–680. low-up report. J Allergy Clin Immunol. 2011;128(1):210–212.
227. Sicherer SH, Furlong TJ, DeSimone J, Sampson HA. Self-reported allergic reactions 259. Lieberman PL, Jones I, Rajwanshi R, Rose n K, Umetsu DT. Anaphylaxis associated
to peanut on commercial airliners. J Allergy Clin Immunol. 1999;104(1):186–189. with omalizumab administration: risk factors and patient characteristics. J Allergy
228. Comstock SS, DeMera R, Vega LC, Boren EJ, Deane S, Haapanen LA, et al. Allergic Clin Immunol. 2017;140(6):1734–1736.e4.
reactions to peanuts, tree nuts, and seeds aboard commercial airliners. Ann 260. Di Bona D, Fiorino I, Taurino M, Frisenda F, Minenna E, Pasculli C, et al. Long-term
Allergy Asthma Immunol. 2008;101(1):51–56. “real-life” safety of omalizumab in patients with severe uncontrolled asthma: a
229. Greenhawt M, MacGillivray F, Batty G, Said M, Weiss C. International study of nine-year study. Respir Med. 2017;130:55–60.
risk-mitigating factors and in-flight allergic reactions to peanut and tree nut. J 261. Adachi M, Kozawa M, Yoshisue H, Lee Milligan K, Nagasaki M, Sasajima T,
Allergy Clin Immunol Pract. 2013;1(2):186–194. et al. Real-world safety and efficacy of omalizumab in patients with severe
230. Greenhawt MJ, McMorris MS, Furlong TJ. Self-reported allergic reactions to pea- allergic asthma: a long-term post-marketing study in Japan. Respir Med.
nut and tree nuts occurring on commercial airlines. J Allergy Clin Immunol. 2018;141:56–63.
2009;124(3):598–599. 262. Shaker M, Briggs A, Dbouk A, Dutille E, Oppenheimer J, Greenhawt M. Estimation
231. Barnett J, Botting N, Gowland MH, Lucas JS. The strategies that peanut and nut- of health and economic benefits of clinic versus home administration of omalizu-
allergic consumers employ to remain safe when travelling abroad. Clin Transl mab and mepolizumab. J Allergy Clin Immunol Pract. 2020;8(2):565–572.
Allergy. 2012;2(1):12. 263. Bernstein DI, Epstein TG. Managing risk of anaphylaxis in patients receiving aller-
232. Venter C, Sicherer SH, Greenhawt M. Management of peanut allergy. J Allergy Clin gen immunotherapy: assessing benefit versus risk. J Allergy Clin Immunol.
Immunol Pract. 2019;7(2):345–355.e2. 2022;149(3):884–886.
233. Seidenberg J, Stelljes G, Lange L, Blumchen K, Rietschel E. Airlines provide too lit- 264. James C, Bernstein DI. Allergen immunotherapy: an updated review of safety.
tle information for allergy sufferers!. Allergo J Int. 2020;29(8):262–279. Curr Opin Allergy Clin Immunol. 2017;17(1):55–59.
234. Gaziel Yablowitz M, Dolle S, Schwartz DG, Worm M. Proximity-based emergency 265. Sanchez-Borges M, Bernstein DI, Calabria C. Subcutaneous immunotherapy
response communities for patients with allergies who are at risk of anaphylaxis: safety: incidence per surveys and risk factors. Immunol Allergy Clin N Am.
clustering analysis and scenario-based survey sudy. JMIR Mhealth Uhealth. 2020;40(1):25–39.
2019;7(8):e13414. 266. Holland CL, Samuels KM, Baldwin JL, Greenhawt MJ. Systemic reactions to inhal-
235. Bilo MB, Bonifazi F. The natural history and epidemiology of insect venom ant immunotherapy using 1:1 target dosing. Ann Allergy Asthma Immunol.
allergy: clinical implications. Clin Exp Allergy. 2009;39(10):1467–1476. 2014;112(5):453–458.
236. Vega A, Castro L. Impact of climate change on insect-human interactions. Curr 267. Schworer SA, Kim EH. Sublingual immunotherapy for food allergy and its future
Opin Allergy Clin Immunol. 2019;19(5):475–481. directions. Immunotherapy. 2020;12(12):921–931.
237. Golden DBK, Demain J, Freeman T, Graft D, Tankersley M, Tracy J, et al. Stinging 268. Sun D, Cafone J, Shaker M, Greenhawt M. The cost-effectiveness of requiring uni-
insect hypersensitivity: a practice parameter update 2016. Ann Allergy Asthma versal vs contextual self-injectable epinephrine autoinjector for allergen immu-
Immunol. 2017;118(1):28–54. notherapy. Ann Allergy Asthma Immunol. 2019;123(6):582–589.
238. Le TA, Foreman C, Smith WB. The use of medical alert jewelry to communicate 269. Li LDX, Abrams EM, Lavine E, Hildebrand K, Mack DP. CSACI position statement:
allergy information. J Allergy Clin Immunol Pract. 2019;7(3):1083–1085. transition recommendations on existing epinephrine autoinjectors. Allergy
239. Rahman S, Walker D, Sultan P. Medical identification or alert jewellery: an oppor- Asthma Clin Immunol. 2021;17(1):130.
tunity to save lives or an unreliable hindrance? Anaesthesia. 2017;72(9):1139– 270. Quirt J, Gagnon R, Ellis AK, Kim HL. CSACI position statement: prescribing sublin-
1145. gual immunotherapy tablets for aeroallergens. Allergy Asthma Clin Immunol.
240. Berger S. Cardiopulmonary resuscitation and public access defibrillation in the 2018;14:1.
current era−can we do better yet? J Am Heart Assoc. 2014;3(2): e000945. 271. Patel N, Chong KW, Yip AYG, Ierodiakonou D, Bartra J, Boyle RJ, et al. Use of multi-
241. Murakami Y, Iwami T, Kitamura T, Nishiyama C, Nishiuchi T, Hayashi Y, et al. Out- ple epinephrine doses in anaphylaxis: a systematic review and meta-analysis. J
comes of out-of-hospital cardiac arrest by public location in the public-access Allergy Clin Immunol. 2021;148(5):1307–1315.
defibrillation era. J Am Heart Assoc. 2014;3(2): e000533. 272. Shaker M, Turner PJ, Greenhawt M. A cost-effectiveness analysis of epinephrine
242. Dudley LS, Mansour MI, Merlin MA. Epinephrine for anaphylaxis: underutilized autoinjector risk stratification for patients with food allergy: one epinephrine
and unavailable. West J Emerg Med. 2015;16(3):385–387. autoinjector or two? J Allergy Clin Immunol Pract. 2021;9(6):2440–2451.e3.
243. Food Allergy & Anaphylaxis Connection Team. Government Relations: stock epi- 273. Araki M, Hamahata Y, Usui M, Akashi M. Use of multiple doses of adrenaline for
nephrine entity laws. Available at: https://www.foodallergyawareness.org/govern food-induced anaphylaxis. Arerugi. 2018;67(6):751–758.
ment-relations/stock-epinephrine-entity-laws/. Accessed September 14, 2022. 274. Turner PJ, Gowland MH, Sharma V, Ierodiakonou D, Harper N, Garcez T, et al.
244. Khalemsky M, Schwartz DG, Silberg T, Khalemsky A, Jaffe E, Herbst R. Childrens’ Increase in anaphylaxis-related hospitalizations but no increase in fatalities: an
and parents’ willingness to join a smartphone-based emergency response com- analysis of United Kingdom national anaphylaxis data, 1992-2012. J Allergy Clin
munity for anaphylaxis: survey. JMIR Mhealth Uhealth. 2019;7(8):e13892. Immunol. 2015;135(4):956–963.e1.
245. O’Connor M, Winders T, Meadows JA. Epinephrine autoinjectors on airplanes. 275. De Feo G, Parente R, Cardamone C, Bucci T, Guerritore L, Triggiani M. Risk factors and
Ann Allergy Asthma Immunol. 2020;125(3):250–251. cofactors for severe anaphylaxis. Curr Treat Options Allergy. 2018;5(2):204–211.
246. Shaker M, Greenhawt M. Cost-effectiveness of stock epinephrine autoinjectors on 276. Worm M, Francuzik W, Renaudin JM, Bilo MB, Cardona V, Scherer Hofmeier
commercial aircraft. J Allergy Clin Immunol Pract. 2019;7(7):2270–2276. K, et al. Factors increasing the risk for a severe reaction in anaphylaxis: an
247. Lieberman JA, Wang J. Epinephrine in anaphylaxis: too little, too late. Curr Opin analysis of data from the European Anaphylaxis Registry. Allergy. 2018;73
Allergy Clin Immunol. 2020;20(5):452–458. (6):1322–1330.
248. Sicherer SH, Simons FER, SECTION ON ALLERGY AND IMMUNOLOGY. Epinephrine 277. Anagnostou A, Sharma V, Herbert L, Turner PJ. Fatal food anaphylaxis: distin-
for first-aid management of anaphylaxis. Pediatrics. 2017;139(3): e20164006. guishing fact from fiction. J Allergy Clin Immunol Pract. 2022;10(1):11–17.
249. Saleh-Langenberg J, Flokstra-de Blok BMJ, Goossens NJ, Kemna JC, van der Velde 278. Motosue MS, Bellolio MF, Van Houten HK, Shah ND, Campbell RL. Risk factors for
JL, Dubois AEJ. The compliance and burden of treatment with the epinephrine severe anaphylaxis in the United States. Ann Allergy Asthma Immunol. 2017;119
auto-injector in food-allergic adolescents. Pediatr Allergy Immunol. 2016;27 (4):356–361.e2.
(1):28–34. 279. Roberts G, Allen K, Ballmer-Weber B, Clark A, Crevel R, Dunn Galvin A, et al. Iden-
250. Miller J, Blackman AC, Wang HT, Anvari S, Joseph M, Davis CM, et al. Quality of life tifying and managing patients at risk of severe allergic reactions to food: report
in food allergic children: results from 174 quality-of-life patient questionnaires. from two iFAAM workshops. Clin Exp Allergy. 2019;49(12):1558–1566.
Ann Allergy Asthma Immunol. 2020;124(4):379–384. 280. Tan-Lim CSC, Castor MAR, Recto MST, Casis-Hao RJ, Nano ALM. Predictors of seri-
251. Feuille E, Nowak-Wȩgrzyn A. Oral immunotherapy for food allergies. Ann Nutr ous outcomes among patients with anaphylaxis seen in the Philippine national
Metab. 2016;68(Suppl 1):19–31. tertiary hospital. Asia Pac Allergy. 2021;11(1):e8.
252. Feuille E, Nowak-Wegrzyn A. Food protein-induced enterocolitis syndrome, 281. Greenhawt M, Shaker M, Wang J, Oppenheimer JJ, Sicherer S, Keet C, et al. Peanut
allergic proctocolitis, and enteropathy. Curr Allergy Asthma Rep. 2015;15 allergy diagnosis: a 2020 practice parameter update, systematic review, and
(8):50. GRADE analysis. J Allergy Clin Immunol. 2020;146(6):1302–1334.
282. Sicherer SH, Forman JA, Noone SA. Use assessment of self-administered epineph- 310. Pepper AN, Westermann-Clark E, Lockey RF. The high cost of epinephrine autoin-
rine among food-allergic children and pediatricians. Pediatrics. 2000;105 jectors and possible alternatives. J Allergy Clin Immunol. 2017;5(3):665–668.e1.
(2):359–362. 311. Westermann-Clark E, Pepper AN, Lockey RF. Anaphylaxis: access to epinephrine
283. Fleming JT, Clark S, Camargo CA, Rudders SA. Early treatment of food-induced in outpatient setting. Immunol Allergy Clin North Am. 2022;42(1):175–186.
anaphylaxis with epinephrine is associated with a lower risk of hospitalization. J 312. Pinczower GD, Bertalli NA, Bussmann N, Hamidon M, Allen KJ, Dunngalvin A,
Allergy Clin Immunol Pract. 2015;3(1):57–62. et al. The effect of provision of an adrenaline autoinjector on quality of life in chil-
284. Hochstadter E, Clarke A, De Schryver S, La Vieille S, Alizadehfar R, Joseph L, et al. dren with food allergy. J Allergy Clin Immunol. 2013;131(1). 238-40.e1.
Increasing visits for anaphylaxis and the benefits of early epinephrine adminis- 313. Frachette C, Fina A, Fontas E, Donzeau D, Hoflack M, Gastaud F, et al. Health-
tration: a 4-year study at a pediatric emergency department in Montreal, Canada. related quality of life of food-allergic children compared with healthy controls
J Allergy Clin Immunol. 2016;137(6):1888–1890.e4. and other diseases. Pediatr Allergy Immunol. 2022;33(1):e13663.
285. Bock SA, Munoz-Furlong A, Sampson HA. Fatalities due to anaphylactic reactions 314. Imai T, Hirano K, Ohzeki T. Association between allergic diseases and mental
to foods. J Allergy Clin Immunol. 2001;107(1):191–193. health among Japanese adolescents. Allergol Int. 2021;70(3):379–381.
286. Wang J, Sicherer SH, SECTION ON ALLERGY AND IMMUNOLOGY. Guidance on 315. Oude Elberink JNG, De Monchy JGR, Van Der Heide S, Guyatt GH, Dubois AEJ.
Completing a Written Allergy and Anaphylaxis Emergency Plan. Pediatrics. Venom immunotherapy improves health-related quality of life in patients aller-
2017;139(3): e20164005. gic to yellow jacket venom. J Allergy Clin Immunol. 2002;110(1):174–182.
287. American Academy of Allergy, Asthma & Immunology. Anaphlyaxis emergency 316. Chow C, Pincus DB, Comer JS. Pediatric food allergies and psychosocial function-
action plan. Available at: https://www.aaaai.org/aaaai/media/medialibrary/ ing: examining the potential moderating roles of maternal distress and overpro-
pdf%20documents/libraries/anaphylaxis-emergency-action-plan.pdf. Accessed tection. J Pediatr Psychol. 2015;40(10):1065–1074.
September 7, 2022. 317. Dreborg S, Tsai G, Kim H. Epinephrine auto-injector needle length: the impact of
288. Food Allergy Research & Education. Food allergy & anaphylaxis emergency care winter clothing. Allergy Asthma Clin Immunol. 2020;16. 24-24.
plan. Available at: https://www.foodallergy.org/living-food-allergies/food- 318. Dreborg S, Kim H. Authors’ response. Ann Allergy Asthma Immunol. 2018;121
allergy-essentials/food-allergy-anaphylaxis-emergency-care-plan. Accessed Sep- (5):644–645.
tember 15, 2022. 319. PR Newswire. U.S. FDA approves Kale o’s AUVI-QÒ (Epinephrine injection, USP) 0.1-
289. Tanimoto S, Kaliner M, Lockey RF, Ebisawa M, Koplowitz LP, Koplowitz B, et al. mg auto-injector for life-threatening allergic reactions in infants and small children.
Pharmacokinetic and pharmacodynamic comparison of epinephrine, adminis- Available at: https://www.prnewswire.com/news-releases/us-fda-approves-kaleos-
tered intranasally and intramuscularly: an integrated analysis. Ann Allergy auvi-q-epinephrine-injection-usp-01-mg-auto-injector-for-life-threatening-allergic-
Asthma Immunol. 2023;130(4):508–514.e1. reactions-in-infants-and-small-children-300559170.html. Accessed September 15,
290. Howe L, Franxman T, Teich E, Greenhawt M. What affects quality of life among 2022.
caregivers of food-allergic children? Ann Allergy Asthma Immunol. 2014;113 320. Brown JC. Epinephrine, auto-injectors, and anaphylaxis: challenges of dose,
(1):69–74.e2. depth, and device. Ann Allergy Asthma Immunol. 2018;121(1):53–60.
291. Campbell RL, Bellolio MF, Knutson BD, Bellamkonda VR, Fedko MG, Nestler DM, 321. Sicherer SH, Simons FER, Williams PV, Bahna SL, Chipps BE, Fasano MB. Self-
et al. Epinephrine in anaphylaxis: higher risk of cardiovascular complications injectable epinephrine for first-aid management of anaphylaxis. Pediatrics.
and overdose after administration of intravenous bolus epinephrine compared 2007;119(3):638–646.
with intramuscular epinephrine. J Allergy Clin Immunol Pract. 2015;3(1):76–80. 322. Patel N, Isaacs E, Duca B, Mohammed H, Nagaratnam N, Donovan J, et al. What
292. Cardona V, Ferre -Ybarz L, Guilarte M, Moreno-Perez N, Go mez-Galan C, Alcoceba- dose of epinephrine? Safety and pharmacokinetics of 0.5mg versus 0.3mg epi-
Borra s E, et al. Safety of adrenaline use in anaphylaxis: a multicentre register. Int nephrine by autoinjector in food-allergic teenagers: a randomized cross-over
Arch Allergy Immunol. 2017;173(3):171–177. trial. J Allergy Clin Immunol. 2020;145(2):AB6.
293. Shaker M, Toy D, Lindholm C, Low J, Reigh E, Greenhawt M. Summary and simu- 323. Song TT, Lieberman P. Epinephrine auto-injector needle length: what is the ideal
lation of reported adverse events from epinephrine autoinjectors and a review of length? Curr Opin Allergy Clin Immunol. 2016;16(4):361–365.
the literature. J Allergy Clin Immunol Pract. 2018;6(6):2143–2145.e4. 324. Worm M, Nguyen D, Rackley R, Muraro A, Du Toit G, Lawrence T, et al. Epi-
294. Lieberman P, Simons FER. Anaphylaxis and cardiovascular disease: therapeutic nephrine delivery via EpiPen(Ò ) Auto-Injector or manual syringe across par-
dilemmas. Clin Exp Allergy. 2015;45(8):1288–1295. ticipants with a wide range of skin-to-muscle distances. Clin Transl Allergy.
295. Kawano T, Scheuermeyer FX, Stenstrom R, Rowe BH, Grafstein E, Grunau B. Epi- 2020;10:21.
nephrine use in older patients with anaphylaxis: clinical outcomes and cardio- 325. Dreborg S, Tsai G, Kim H. Implications of variation of epinephrine auto-injector
vascular complications. Resuscitation. 2017;112:53–58. needle length. Ann Allergy Asthma Immunol. 2019;123(1):89–94.
296. O’Brien ME, Koehl JL, Raja AS, Erickson TB, Hayes BD. Age-related cardiovascular 326. Turk M, Turk G, Koc A, Karabiyik O, Yilmaz I. What should the optimal adrenaline
outcomes in older adults receiving epinephrine for anaphylaxis in the emergency auto-injector needle length be? Asthma Allergy Immunol. 2020;18(2):82–90.
department. J Allergy Clin Immunol Pract. 2019;7(8):2888–2890. 327. Song TT, Nelson MR, Chang JH, Engler RJ, Chowdhury BA. Adequacy of the epi-
297. Tejedor-Alonso MA, Farias-Aquino E, Pe rez-Ferna
ndez E, Grifol-Clar E, Moro- nephrine autoinjector needle length in delivering epinephrine to the intramus-
Moro M, Rosado-Ingelmo A. Relationship between anaphylaxis and use of beta- cular tissues. Ann Allergy Asthma Immunol. 2005;94(5):539–542.
blockers and angiotensin-converting enzyme inhibitors: a systematic review and 328. Tsai G, Kim L, Nevis IF, Dominic A, Potts R, Chiu J, et al. Auto-injector needle
meta-analysis of observational studies. J Allergy Clin Immunol Pract. 2019;7 length may be inadequate to deliver epinephrine intramuscularly in women
(3):879–897.e5. with confirmed food allergy. Allergy Asthma Clin Immunol. 2014;10(1):39.
298. Sturm GJ, Herzog SA, Aberer W, Alfaya Arias T, Antolín-Ame rigo D, Bonadonna P, 329. Duvauchelle T, Robert P, Donazzolo Y, Loyau S, Orlandini B, Lehert P, et al. Bio-
et al. b-blockers and ACE inhibitors are not a risk factor for severe systemic sting availability and cardiovascular effects of adrenaline administered by Anapen
reactions and adverse events during venom immunotherapy. Allergy. 2021;76 autoinjector in healthy volunteers. J Allergy Clin Immunol Pract. 2018;6(4):1257–
(7):2166–2176. 1263.
299. Nazir S, Lohani S, Tachamo N, Ghimire S, Poudel DR, Donato A. Takotsubo cardio- 330. Turner PJ, Muraro A, Roberts G. Pharmacokinetics of adrenaline autoinjectors.
myopathy associated with epinephrine use: a systematic review and meta-analy- Clin Exp Allergy. 2022;52(1):18–28.
sis. Int J Cardiol. 2017;229:67–70. 331. Ponda P, Russell AF, Yu JE, Land MH, Crain MG, Patel K, et al. Access barriers to
300. Saeed M, Khan mr, Khan Z, Bachan M. Epinephrine-induced ST-elevation myo- epinephrine autoinjectors for the treatment of anaphylaxis: a survey of practi-
cardial infarction (STEMI) in the setting of anaphylaxis. Chest. 2019;156:A352. tioners. J Allergy Clin Immunol Pract. 2021;9(10):3814–3815.e4.
(abstract). 332. Weir A, Arga ez C. Epinephrine auto-injectors for anaphylaxis: a review of the
301. Shrestha B, Kafle P, Thapa S, Dahal S, Gayam V, Dufresne A. Intramuscular epi- clinical effectiveness, cost-effectiveness, and guidelines. Ottawa, ON: Canadian
nephrine-induced transient ST-elevation myocardial infarction. J Investig Med Agency for Drugs and Technologies in Health. Available at: https://www.ncbi.
High Impact Case Rep. 2018;6: 2324709618785651. nlm.nih.gov/books/NBK563019/. Accessed September 15, 2022.
302. Ventura MT, Boni E, Taborda-Barata L, Blain H, Bousquet J. Anaphylaxis in elderly 333. Umasunthar T, Procktor A, Hodes M, Smith JG, Gore C, Cox HE, et al. Patients’ abil-
people. Curr Opin Allergy Clin Immunol. 2022;22(6):435–440. ity to treat anaphylaxis using adrenaline autoinjectors: a randomized controlled
303. Brown JC, Tuuri RE, Akhter S, Guerra LD, Goodman IS, Myers SR, et al. Lacerations trial. Allergy. 2015;70(7):855-863.
and embedded needles caused by epinephrine autoinjector use in children. Ann 334. Kessler C, Edwards E, Dissinger E, Sye S, Visich T, Grant E. Usability and prefer-
Emerg Med. 2016;67(3):307–315.e8. ence of epinephrine auto-injectors: Auvi-Q and EpiPen JR. Ann Allergy Asthma
304. Goldman RD, Long KC, Brown JC. Hooked epinephrine auto-injector devices in Immunol. 2019;123(3):256–262.
children: four case reports with three different proposed mechanisms. Allergy 335. Camargo CAJ, Guana A, Wang S, Simons FER. Auvi-Q versus EpiPen: preferences
Asthma Clin Immunol. 2020;16:1–6. of adults, caregivers, and children. J Allergy Clin Immunol Pract. 2013;1(3). 266-
305. Anshien M, Rose SR, Wills BK. Unintentional epinephrine auto-injector injuries: a 272.e1-3.
National Poison Center observational study. Am J Ther. 2019;26(1):e110–e114. 336. Cronin C, O’Kelly C, Keohane H, Flores Villarta L, Tobin C, Velasco R, et al. Is
306. Walsh K, Baker BG, Iyer S. Adrenaline auto-injector injuries to digits: a systematic switching of adrenaline auto injector devices a concern for anaphylaxis manage-
review and recommendations for emergency management. Surgeon. 2020;18 ment? A cross-sectional study. Allergies. 2023;3(2):105–114.
(5):305–310. 337. Prince BT, Mikhail I, Stukus DR. Underuse of epinephrine for the treatment of
307. Wang E, Plunk A, Morales M. Attitudes and beliefs toward epinephrine auto- anaphylaxis: missed opportunities. J Asthma Allergy. 2018;11:143–151.
injector price increase. Ann Allergy Asthma Immunol. 2018;121(5):S58. 338. Trujillo J, Cronin C. Benefit of educational intervention on autoinjector technique
308. Westermann-Clark E, Pepper AN, Lockey RF. Economic considerations in the for caregivers and paediatric patients with food allergies: a literature review.
treatment of systemic allergic reactions. J Asthma Allergy. 2018;11:153–158. Allergol Immunopathol (Madr). 2022;50(5):100–113.
309. Shaker M, Bean K, Verdi M. Economic evaluation of epinephrine auto-injectors 339. Segal N, Garty B-Z, Hoffer V, Levy Y. Effect of instruction on the ability to use a
for peanut allergy. Ann Allergy Asthma Immunol. 2017;119(2):160–163. self-administered epinephrine injector. Isr Med Assoc J. 2012;14(1):14–17.
340. Peterson LR, Cullinane CR, Kane MJ, Bubak ME. Outcomes of simulated use of 369. Ingall M, Goldman G, Page LB. Beta-blockade in stinging insect anaphylaxis. JAMA.
Epinephrine injection USP auto-injectors. J Allergy Clin Immunol. 2019;143 1984;251(11):1432.
(2):AB153. 370. Tunon-de-Lara JM, Villanueva P, Marcos M, Taytard A. ACE inhibitors and
341. Sirin Kose S, Asilsoy S, Tezcan D, Al S, Atay O, Kangalli O, et al. Is there an optimal anaphylactoid reactions during venom immunotherapy. Lancet. 1992;340
training interval to improve the correct use of adrenaline auto-injectors? Int Arch (8824):908.
Allergy Immunol. 2020;181(2):136–140. 371. Mu € ller UR, Haeberli G. Use of beta-blockers during immunotherapy for Hyme-
342. Southall K, Reyes JEM, Hazi A, Andre M, Virkud Y, Shreffler W, et al. Epinephrine noptera venom allergy. J Allergy Clin Immunol. 2005;115(3):606–610.
auto-injector parental survey and skills demonstration. J Allergy Clin Immunol. 372. Rue€ff F, Przybilla B, Bilo MB, Muller U, Scheipl F, Aberer W, et al. Predictors of
2020;145(2):AB232. severe systemic anaphylactic reactions in patients with Hymenoptera venom
343. Kaminski AE, Li Z, Dike NO, Gonzalez-Estrada A, Simon LV. Self vs partnered epi- allergy: importance of baseline serum tryptase-a study of the European Academy
nephrine autoinjector training, performance differences in an anaphylaxis simu- of Allergology and Clinical Immunology Interest Group on Insect Venom Hyper-
lation. Ann Allergy Asthma Immunol. 2021;126(3):304–306. sensitivity. J Allergy Clin Immunol. 2009;124(5):1047–1054.
344. Soller L, Teoh T, Baerg I, Wong T, Hildebrand KJ, Cook VE, et al. Extended analysis 373. Stoevesandt J, Hain J, Kerstan A, Trautmann A. Over- and underestimated param-
of parent and child confidence in recognizing anaphylaxis and using the epineph- eters in severe Hymenoptera venom-induced anaphylaxis: cardiovascular medi-
rine autoinjector during oral food challenges. J Allergy Clin Immunol Pract. 2019;7 cation and absence of urticaria/angioedema. J Allergy Clin Immunol. 2012;130
(2):693–695. (3):698–704.e1.
345. Soller L, Teoh T, Baerg I, Wong T, Chan ES. One-year sustained impact of super- 374. Rue€ff F, Vos B, Oude Elberink J, Bender A, Chatelain R, Dugas-Breit S, et al. Predic-
vised epinephrine autoinjector administration during food challenge on parent tors of clinical effectiveness of Hymenoptera venom immunotherapy. Clin Exp
confidence. Ann Allergy Asthma Immunol. 2020;125(6):705–707. Allergy. 2014;44(5):736–746.
346. Shemesh E, D’Urso C, Cr Knight, Rubes M, Picerno KM, Posillico AM, et al. Food- 375. Rue€ff F, Przybilla B, Bilo MB, Muller U, Scheipl F, Aberer W, et al. Predictors of side
allergic adolescents at risk for anaphylaxis: a randomized controlled study of effects during the buildup phase of venom immunotherapy for Hymenoptera
supervised injection to improve comfort with epinephrine self-Injection. J Allergy venom allergy: the importance of baseline serum tryptase. J Allergy Clin Immunol.
Clin Immunol Pract. 2017;5(2):391–397.e4. 2010;126(1):105–111.e5.
347. Chooniedass R, Temple B, Martin D, Becker A. A qualitative study exploring 376. Stoevesandt J, Hosp C, Kerstan A, Trautmann A. Hymenoptera venom immuno-
parents’ experiences with epinephrine use for their child’s anaphylactic reaction. therapy while maintaining cardiovascular medication: safe and effective. Ann
Clin Transl Allergy. 2018;8:43. Allergy Asthma Immunol. 2015;114(5):411–416.
348. Cantrell FL, Cantrell P, Wen A, Gerona R. Epinephrine concentrations in EpiPens 377. Stoevesandt J, Hain J, Stolze I, Kerstan A, Trautmann A. Angiotensin-converting
after the expiration date. Ann Intern Med. 2017;166(12):918–919. enzyme inhibitors do not impair the safety of Hymenoptera venom immunother-
349. Kassel L, Jones C, Mengesha A. Epinephrine drug degradation in autoinjector apy build-up phase. Clin Exp Allergy. 2014;44(5):747–755.
products. J Allergy Clin Immunol Pract. 2019;7(7):2491–2493. 378. Francuzik W, Rueff F, Bauer A, Bilo MB, Cardona V, Christoff G, et al. Phenotype
350. Kassel L, Jones C, Turin R, Daly M, Mengesha A. Enantiomeric degradation of epi- and risk factors of venom-induced anaphylaxis: a case-control study of the Euro-
nephrine in autoinjector products. J Allergy Clin Immunol Pract. 2022;10 pean Anaphylaxis Registry. J Allergy Clin Immunol. 2021;147(2):653–662.e9.
(9):2463–2465.e1. 379. Kopac P, Custovic A, Zidarn M, Silar M, Selb J, Bajrovic N, et al. Biomarkers of the
351. Patrawala M, Shih J. P353 epinephrine autoinjector education: a quality improve- severity of honeybee sting reactions and the severity and threshold of systemic
ment project. Ann Allergy Asthma Immunol. 2019;123(5):S54–S55. adverse events during immunotherapy. J Allergy Clin Immunol Pract. 2021;9
352. Samstein M, Li T, Cassara M, Jongco A. Adoption of 2016 EpiPen administration (8):3157–3163.e5.
instructions by pediatric emergency department staff. J Allergy Clin Immunol. 380. TenBrook Jr JA, Wolf MP, Hoffman SN, Rosenwasser LJ, Konstam MA, Salem DN,
2020;145:AB3. et al. Should beta-blockers be given to patients with heart disease and peanut-
353. Mahoney B, Walklet E, Bradley E, O’Hickey S. Improving adrenaline autoinjector induced anaphylaxis? A decision analysis. J Allergy Clin Immunol. 2004;113
adherence: a psychologically informed training for healthcare professionals. (5):977–982.
Immun Inflamm Dis. 2019;7(3):214–228. 381. Smith DM, Coop CA, Freeman TM. Beta-blockers and angiotensin-converting
354. Dua S, Lacquiere S, Doyle M. Anaphylaxis and adrenaline autoinjector training, enzyme inhibitors with sublingual immunotherapy: are risks related to individ-
where do the responsibilities lie: results from a UK general practice survey. ual product safety profile? Curr Opin Allergy Clin Immunol. 2020;20(4):401–406.
Allergy. 2021;76:639. 382. Greenhawt M, Oppenheimer J, Nelson M, Nelson H, Lockey R, Lieberman P, et al.
355. Ziyar A, Kwon J, Li A, Naderi A, Jean T. Improving epinephrine autoinjector usabil- Sublingual immunotherapy: a focused allergen immunotherapy practice param-
ity and carriage frequency among patients at risk of anaphylaxis: a quality eter update. Ann Allergy Asthma Immunol. 2017;118(3):276–282.e2.
improvement initiative. BMJ Open Qual. 2022;11(3): e001742. 383. Dhamija Y, Epstein TEG, Bernstein DI. Systemic allergic reactions and anaphylaxis
356. Chow TG, Bonnet E, Roman H, Bird JA. Efficacy of video-based training to improve associated with allergen immunotherapy. Immunol Allergy Clin North Am.
epinephrine autoinjector use competency. J Allergy Clin Immunol. 2019;143(2): 2022;42(1):105–119.
AB152. 384. Rodriguez Del Rio P, Pitsios C, Tsoumani M, Pfaar O, Paraskevopoulos G, Gawlik R,
357. Yuenyongviwat A, Wirodwanich T, Jessadapakorn W, Sangsupawanich P. Utility et al. Physicians’ experience and opinion on contraindications to allergen immuno-
of an educational video on epinephrine prefilled syringe usage for anaphylaxis: a therapy: the CONSIT survey. Ann Allergy Asthma Immunol. 2017;118(5):621–628.e1.
randomized control trial. Asia Pac Allergy. 2020;10(3). e32-e32. 385. Yilmaz I, Dogan S, Tutar N, Kanbay A, Buyukoglan H, Demir R. Biphasic anaphy-
358. Salter SM, Delfante B, de Klerk S, Sanfilippo FM, Clifford RM. Pharmacists’ laxis to gemifloxacin. Asia Pac Allergy. 2012;2(4):280–282.
response to anaphylaxis in the community (PRAC): a randomised, simulated 386. Goddet NS, Descatha A, Liberge O, Dolveck F, Boutet J, Baer M, et al. Paradoxical
patient study of pharmacist practice. BMJ Open. 2014;4(7): e005648. reaction to epinephrine induced by beta-blockers in an anaphylactic shock
359. Aguilera A, O’Neill M, Slaven J, Vitalpur G. Improving knowledge of epinephrine induced by penicillin. Eur J Emerg Med. 2006;13(6):358–360.
auto-injector use and peanut guidelines at an academic medical center. J Allergy 387. Lang DM, Alpern MB, Visintainer PF, Smith ST. Elevated risk of anaphylactoid
Clin Immunol. 2020;145(2). AB168-AB168. reaction from radiographic contrast media is associated with both beta-blocker
360. Kaur N, McCrossin T, Gunasekera H. Improving anaphylaxis management by exposure and cardiovascular disorders. Arch Intern Med. 1993;153(17):2033–
health care professional education and practical skills training in a regional cen- 2040.
tre. J Paediatr Child Health. 2017;53(10):1029–1030. 388. Kareva L, Mironska K, Stavric K, Hasani A. Adverse reactions to intravenous
361. Wright K, Cross S, Meyer R, Holloway J. The development and evaluation of Ana- immunoglobulins - our experience. Open Access Maced J Med Sci. 2018;6
phylaxis Toolkit, a competency based online education course for Allied Health- (12):2359–2362.
care Professionals (AHP’s): a pilot study. Clin Exp Allergy. 2021;51:1663. 389. Liu Y, Fang L, Chen W, Lin X, Wang Q, Zhu Y, et al. Clinical characteristics, treat-
362. Nassiri M, Babina M, Dolle S, Edenharter G, Rueff F, Worm M. Ramipril and meto- ment, and outcomes in patients with idiopathic inflammatory myopathy con-
prolol intake aggravate human and murine anaphylaxis: evidence for direct mast comitant with heart failure. Int Heart J. 2020;61(5):1005–1013.
cell priming. J Allergy Clin Immunol. 2015;135(2):491–499. 390. Martinez C, Wallenhorst C, van Nunen S. Intravenous immunoglobulin and the
363. White JL, Greger KC, Lee S, Kahoud RJ, Li JT, Lohse CM, et al. Patients taking beta- current risk of moderate and severe anaphylactic events, a cohort study. Clin Exp
blockers do not require increased doses of epinephrine for anaphylaxis. J Allergy Immunol. 2021;206(3):384–394.
Clin Immunol Pract. 2018;6(5):1553–1558.e1. 391. Arumugham VB, Rayi A. Intravenous immunoglobulin (IVIG). Treasure Island, FL:
364. Miller MM, Miller MM. Beta-blockers and anaphylaxis: are the risks overstated? J StatPearls; 2022.
Allergy Clin Immunol. 2005;116(4):931–933. 392. Burrows AG, Ellis AK. Idiopathic anaphylaxis: diagnosis and management. Allergy
365. Toh S, Reichman ME, Houstoun M, Ross Southworth M, Ding X, Hernandez AF, Asthma Proc. 2021;42(6):481–488.
et al. Comparative risk for angioedema associated with the use of drugs that tar- 393. Turner PJ, Arasi S, Ballmer-Weber B, Baseggio Conrado A, Deschildre A, Gerdts J,
get the renin-angiotensin-aldosterone system. Arch Intern Med. 2012;172 et al. Risk factors for severe reactions in food allergy: rapid evidence review with
(20):1582–1589. meta-analysis. Allergy. 2022;77(9):2634–2652.
366. Smith MA, Newton LP, Barcena Blanch MA, Cuervo-Pardo L, Cho L, Newton D, 394. Lenchner K, Grammer LC. A current review of idiopathic anaphylaxis. Curr Opin
et al. Risk for anaphylactic reaction from cardiac catheterization in patients Allergy Clin Immunol. 2003;3(4):305–311.
receiving beta-adrenergic blockers or angiotensin-converting enzyme-inhibitors. 395. Mu € ller UR. Cardiovascular disease and anaphylaxis. Curr Opin Allergy Clin Immu-
J Allergy Clin Immunol Pract. 2020;8(6):1900–1905. nol. 2007;7(4):337–341.
367. Carlson GS, Wong PH, White KM, Quinn JM. Evaluation of angiotensin-converting 396. Theoharides TC, Valent P, Akin C. Mast cells, mastocytosis, and related disorders.
enzyme inhibitor and angiotensin receptor blocker therapy in immunotherapy- N Engl J Med. 2015;373(19):1885–1886.
associated systemic reactions. J Allergy Clin Immunol Pract. 2017;5(5):1430–1432. 397. Brockow K, Jofer C, Behrendt H, Ring J. Anaphylaxis in patients with mastocyto-
368. Awai LE, Mekori YA. Insect sting anaphylaxis and beta-adrenergic blockade: a rel- sis: a study on history, clinical features and risk factors in 120 patients. Allergy.
ative contraindication. Ann Allergy. 1984;53(1):48–49. 2008;63(2):226–232.
398. Gu€ len T, Ljung C, Nilsson G, Akin C. Risk factor analysis of anaphylactic reactions 425. Ludolph-Hauser D, Rueff F, Fries C, Schopf P, Przybilla B. Constitutively raised
in patients with systemic mastocytosis. J Allergy Clin Immunol Pract. 2017;5 serum concentrations of mast-cell tryptase and severe anaphylactic reactions to
(5):1248–1255. Hymenoptera stings. Lancet. 2001;357(9253):361–362.
399. Gulen T, Teufelberger A, Ekoff M, Westerberg CM, Lyberg K, Dahlen SE, et al. Dis- 426. Niedoszytko M, Bonadonna P, Oude Elberink JN, Golden DB. Epidemiology, diag-
tinct plasma biomarkers confirm the diagnosis of mastocytosis and identify nosis, and treatment of Hymenoptera venom allergy in mastocytosis patients.
increased risk of anaphylaxis. J Allergy Clin Immunol. 2021;148(3):889–894. Immunol Allergy Clin North Am. 2014;34(2):365–381.
400. Schuch A, Brockow K. Mastocytosis and anaphylaxis. Immunol Allergy Clin North 427. Gonzalez de Olano D, Alvarez-Twose I, Esteban-Lopez MI, Sanchez-Munoz L, de
Am. 2017;37(1):153–164. Durana MD, Vega A, et al. Safety and effectiveness of immunotherapy in patients
401. Bonadonna P, Zanotti R, Muller U. Mastocytosis and insect venom allergy. Curr with indolent systemic mastocytosis presenting with Hymenoptera venom ana-
Opin Allergy Clin Immunol. 2010;10(4):347–353. phylaxis. J Allergy Clin Immunol. 2008;121(2):519–526.
402. Carter MC, Metcalfe DD, Matito A, Escribano L, Butterfield JH, Schwartz LB, et al. 428. Bonadonna P, Gonzalez-de-Olano D, Zanotti R, Riccio A, De Ferrari L, Lombardo C,
Adverse reactions to drugs and biologics in patients with clonal mast cell disor- et al. Venom immunotherapy in patients with clonal mast cell disorders: efficacy,
ders: a Work Group Report of the Mast Cells Disorder Committee, American safety, and practical considerations. J Allergy Clin Immunol Pract. 2013;1(5):474–478.
Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol. 2019;143 429. Galera C, Soohun N, Zankar N, Caimmi S, Gallen C, Demoly P. Severe anaphylaxis
(3):880–893. to bee venom immunotherapy: efficacy of pretreatment and concurrent treat-
403. Valent P, Akin C, Hartmann K, Alvarez-Twose I, Brockow K, Hermine O, et al. ment with omalizumab. J Investig Allergol Clin Immunol. 2009;19(3):225–229.
Updated diagnostic criteria and classification of mast cell disorders: a consensus 430. Kontou-Fili K. High omalizumab dose controls recurrent reactions to venom
proposal. Hemasphere. 2021;5(11):e646. immunotherapy in indolent systemic mastocytosis. Allergy. 2008;63(3):376–378.
404. Valent P, Akin C, Metcalfe DD. Mastocytosis: 2016 updated WHO classification 431. Oude Elberink JN, de Monchy JG, Kors JW, van Doormaal JJ, Dubois AE. Fatal ana-
and novel emerging treatment concepts. Blood. 2017;129(11):1420–1427. phylaxis after a yellow jacket sting, despite venom immunotherapy, in two
405. Valent P, Horny HP, Escribano L, Longley BJ, Li CY, Schwartz LB, et al. Diagnostic patients with mastocytosis. J Allergy Clin Immunol. 1997;99(1 Pt 1):153–154.
criteria and classification of mastocytosis: a consensus proposal. Leuk Res. 432. Vitte J, Sabato V, Tacquard C, Garvey LH, Michel M, Mertes PM, et al. Use and
2001;25(7):603–625. interpretation of acute and baseline tryptase in perioperative hypersensitivity
406. Valent P, Sperr WR, Sotlar K, Reiter A, Akin C, Gotlib J, et al. The serum tryptase and anaphylaxis. J Allergy Clin Immunol Pract. 2021;9(8):2994–3005.
test: an emerging robust biomarker in clinical hematology. Expert Rev Hematol. 433. Bibi S, Langenfeld F, Jeanningros S, Brenet F, Soucie E, Hermine O, et al. Molecular
2014;7(5):683–690. defects in mastocytosis: KIT and beyond KIT. Immunol Allergy Clin North Am.
407. Luskin KT, White AA, Lyons JJ. The genetic basis and clinical impact of hereditary 2014;34(2):239–262.
alpha-tryptasemia. J Allergy Clin Immunol Pract. 2021;9(6):2235–2242. 434. Valent P, Akin C, Bonadonna P, Hartmann K, Brockow K, Niedoszytko M, et al.
408. Brockow K, Plata-Nazar K, Lange M, Nedoszytko B, Niedoszytko M, Valent P. Proposed diagnostic algorithm for patients with suspected mast cell activation
Mediator-related symptoms and anaphylaxis in children with mastocytosis. Int J syndrome. J Allergy Clin Immunol Pract. 2019;7(4):1125–1133.e1.
Mol Sci. 2021;22(5):2684. 435. Gu€ len T, Akin C, Bonadonna P, Siebenhaar F, Broesby-Olsen S, Brockow K, et al.
409. Valent P, Akin C, Hartmann K, Nilsson G, Reiter A, Hermine O, et al. Advances in Selecting the right criteria and proper classification to diagnose mast cell activation
the classification and treatment of mastocytosis: current status and outlook syndromes: a critical review. J Allergy Clin Immunol Pract. 2021;9(11):3918–3928.
toward the future. Cancer Res. 2017;77(6):1261–1270. 436. Dantzer JA, Wood RA. Update on omalizumab in allergen immunotherapy. Curr
410. Carter MC, Clayton ST, Komarow HD, Brittain EH, Scott LM, Cantave D, et al. Opin Allergy Clin Immunol. 2021;21(6):559–568.
Assessment of clinical findings, tryptase levels, and bone marrow histopathology 437. Carter MC, Maric I, Brittain EH, Bai Y, Lumbard K, Bolan H, et al. A randomized
in the management of pediatric mastocytosis. J Allergy Clin Immunol. 2015;136 double-blind, placebo-controlled study of omalizumab for idiopathic anaphy-
(6):1673–1679.e3. laxis. J Allergy Clin Immunol. 2021;147(3):1004–1010.e2.
411. Klaiber N, Kumar S, Irani AM. Mastocytosis in children. Curr Allergy Asthma Rep. 438. Kaminsky LW, Aukstuolis K, Petroni DH, Al-Shaikhly T. Use of omalizumab for
2017;17(11):80. management of idiopathic anaphylaxis: a systematic review and retrospective
412. Broesby-Olsen S, Carter M, Kjaer HF, Mortz CG, Moller MB, Kristensen TK, et al. case series. Ann Allergy Asthma Immunol. 2021;127(4):481–487.
Pediatric expression of mast cell activation disorders. Immunol Allergy Clin North 439. Broesby-Olsen S, Vestergaard H, Mortz CG, Jensen B, Havelund T, Hermann AP,
Am. 2018;38(3):365–377. et al. Omalizumab prevents anaphylaxis and improves symptoms in systemic
413. Selb J, Rijavec M, Erzen R, Zidarn M, Kopac P, Skerget M, et al. Routine KIT p. mastocytosis: efficacy and safety observations. Allergy. 2018;73(1):230–238.
D816V screening identifies clonal mast cell disease in patients with Hymenop- 440. Distler M, Maul JT, Steiner UC, Jandus P, Kolios AGA, Murer C, et al. Efficacy of omali-
tera allergy regularly missed using baseline tryptase levels alone. J Allergy Clin zumab in mastocytosis: allusive indication obtained from a prospective, double-
Immunol. 2021;148(2):621–626.e7. blind, multicenter study (XOLMA study). Dermatology. 2020;236(6):529–539.
414. Arock M, Sotlar K, Akin C, Broesby-Olsen S, Hoermann G, Escribano L, et al. KIT 441. Lemal R, Fouquet G, Terriou L, Vaes M, Livideanu CB, Frenzel L, et al. Omalizumab
mutation analysis in mast cell neoplasms: recommendations of the European therapy for mast cell-mediator symptoms in patients with ISM, CM, MMAS, and
Competence Network on Mastocytosis. Leukemia. 2015;29(6):1223–1232. MCAS. J Allergy Clin Immunol Pract. 2019;7(7):2387–2395.e3.
415. Doyle LA, Sepehr GJ, Hamilton MJ, Akin C, Castells MC, Hornick JL. A clinicopatho- 442. Carter MC, Robyn JA, Bressler PB, Walker JC, Shapiro GG, Metcalfe DD. Omalizu-
logic study of 24 cases of systemic mastocytosis involving the gastrointestinal mab for the treatment of unprovoked anaphylaxis in patients with systemic mas-
tract and assessment of mucosal mast cell density in irritable bowel syndrome tocytosis. J Allergy Clin Immunol. 2007;119(6):1550–1551.
and asymptomatic patients. Am J Surg Pathol. 2014;38(6):832–843. 443. Constantine GM, Bressler PB, Petroni D, Metcalfe DD, Carter MC. Twelve-year fol-
416. Bonadonna P, Zanotti R, Pagani M, Caruso B, Perbellini O, Colarossi S, et al. How low-up of omalizumab therapy for anaphylaxis in 2 patients with systemic mas-
much specific is the association between Hymenoptera venom allergy and mastocytosis. J Allergy Clin Immunol Pract. 2019;7(4):1314–1316.
tocytosis? Allergy. 2009;64(9):1379–1382. 444. Jendoubi F, Gaudenzio N, Gallini A, Negretto M, Paul C, Bulai Livideanu C. Omali-
417. Bonadonna P, Perbellini O, Passalacqua G, Caruso B, Colarossi S, Dal Fior D, et al. zumab in the treatment of adult patients with mastocytosis: a systematic review.
Clonal mast cell disorders in patients with systemic reactions to Hymenoptera Clin Exp Allergy. 2020;50(6):654–661.
stings and increased serum tryptase levels. J Allergy Clin Immunol. 2009;123 445. Barete S, Lortholary O, Damaj G, Hirsch I, Chandesris MO, Elie C, et al. Long-term
(3):680–686. efficacy and safety of cladribine (2-CdA) in adult patients with mastocytosis.
418. Vazquez-Revuelta P, Gonzalez-de-Olano D. Prevalence of clonal mast cell disor- Blood. 2015;126(8):1009–1016.
ders in patients presenting with Hymenoptera venom anaphylaxis might be 446. Akin C, Arock M, Valent P. Tyrosine kinase inhibitors for the treatment of indolent
higher than expected. J Investig Allergol Clin Immunol. 2018;28(3):193–194. systemic mastocytosis: are we there yet? J Allergy Clin Immunol. 2022;149
419. Alvarez-Twose I, Zanotti R, Gonzalez-de-Olano D, Bonadonna P, Vega A, Matito A, (6):1912–1918.
et al. Nonaggressive systemic mastocytosis (SM) without skin lesions associated 447. Gotlib J, Kluin-Nelemans HC, George TI, Akin C, Sotlar K, Hermine O, et al. Efficacy
with insect-induced anaphylaxis shows unique features versus other indolent and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med.
SM. J Allergy Clin Immunol. 2014;133(2):520–528. 2016;374(26):2530–2541.
420. Gonzalez de Olano D, de la Hoz Caballer B, Nunez Lopez R, Sanchez Munoz L, Cue- 448. DeAngelo DJ, Radia DH, George TI, Robinson WA, Quiery AT, Drummond MW,
vas Agustin M, Dieguez MC, et al. Prevalence of allergy and anaphylactic symp- et al. Safety and efficacy of avapritinib in advanced systemic mastocytosis: the
toms in 210 adult and pediatric patients with mastocytosis in Spain: a study of phase 1 Explorer trial. Nat Med. 2021;27(12):2183–2191.
the Spanish network on mastocytosis (REMA). Clin Exp Allergy. 2007;37 449. Gotlib J, Reiter A, Radia DH, Deininger MW, George TI, Panse J, et al. Efficacy and
(10):1547–1555. safety of avapritinib in advanced systemic mastocytosis: interim analysis of the
421. Schuler CFt, Volertas S, Khokhar D, Yuce H, Chen L, Baser O, et al. Prevalence of phase 2 Pathfinder trial. Nat Med. 2021;27(12):2192–2199.
mastocytosis and Hymenoptera venom allergy in the United States. J Allergy Clin 450. Hartmann K, Gotlib J, Akin C, Hermine O, Awan FT, Hexner E, et al. Midostaurin
Immunol. 2021;148(5):1316–1323. improves quality of life and mediator-related symptoms in advanced systemic
422. Vos B, van Anrooij B, van Doormaal JJ, Dubois AEJ. Oude Elberink JNG. Fatal ana- mastocytosis. J Allergy Clin Immunol. 2020;146(2):356–366.e4.
phylaxis to yellow jacket stings in mastocytosis: options for identification and 451. van Anrooij B, Oude Elberink JNG, Span LFR, de Monchy JGR, Rosati S, Mulder AB,
treatment of at-risk patients. J Allergy Clin Immunol Pract. 2017;5(5):1264–1271. et al. Midostaurin in patients with indolent systemic mastocytosis: an open-label
423. Biedermann T, Rueff F, Sander CA, Przybilla B. Mastocytosis associated with phase 2 trial. J Allergy Clin Immunol. 2018;142(3):1006–1008.e7.
severe wasp sting anaphylaxis detected by elevated serum mast cell tryptase lev- 452. Kudlaty E, Perez M, Stein BL, Bochner BS, Kuang FL. Systemic mastocytosis with
els. Br J Dermatol. 1999;141(6):1110–1112. an associated hematologic neoplasm complicated by recurrent anaphylaxis:
424. Haeberli G, Bronnimann M, Hunziker T, Muller U. Elevated basal serum tryptase prompt resolution of anaphylaxis with the addition of avapritinib. J Allergy Clin
and Hymenoptera venom allergy: relation to severity of sting reactions and to Immunol Pract. 2021;9(6):2534–2536.
safety and efficacy of venom immunotherapy. Clin Exp Allergy. 2003;33(9):1216– 453. Akin C, Elberink HO, Gotlib J, Sabato V, Hartmann K, Broesby-Olsen S, et al. Pio-
1220. neer: a randomized, double-blind, placebo-controlled, phase 2 study of
avapritinib in patients with indolent or smoldering systemic mastocytosis (SM) 470. Empedrad R, Darter AL, Earl HS, Gruchalla RS. Nonirritating intradermal skin test
with symptoms inadequately controlled by standard therapy. J Allergy Clin Immu- concentrations for commonly prescribed antibiotics. J Allergy Clin Immunol.
nol. 2020;145(2):AB336. 2003;112(3):629–630.
454. Gonzalez-Estrada A, Carrillo-Martin I, Renew JR, Rank MA, Campbell RL, Volcheck 471. Fisher MM, Jones K, Rose M. Follow-up after anaesthetic anaphylaxis. Acta Anaes-
GW. Incidence of and risk factors for perioperative or periprocedural anaphylaxis thesiol Scand. 2011;55(1):99–103.
in the United States from 2005 to 2014. Ann Allergy Asthma Immunol. 2021;126 472. Guyer AC, Saff RR, Conroy M, Blumenthal KG, Camargo Jr CA, Long AA, et al. Com-
(2):180–186.e3. prehensive allergy evaluation is useful in the subsequent care of patients with
455. Gibbs NM, Sadleir PH, Clarke RC, Platt PR. Survival from perioperative anaphy- drug hypersensitivity reactions during anesthesia. J Allergy Clin Immunol Pract.
laxis in Western Australia 2000-2009. Br J Anaesth. 2013;111(4):589–593. 2015;3(1):94–100.
456. Harper NJN, Cook TM, Garcez T, Lucas DN, Thomas M, Kemp H, et al. Anaesthesia, 473. Miller J, Clough SB, Pollard RC, Misbah SA. Outcome of repeat anaesthesia after
surgery, and life-threatening allergic reactions: management and outcomes in investigation for perioperative anaphylaxis. Br J Anaesth. 2018;120(6):1195–1201.
the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121(1):172–188. 474. Aalto-Korte K, Makinen-Kiljunen S. False negative SPT after anaphylaxis. Allergy.
457. Reitter M, Petitpain N, Latarche C, Cottin J, Massy N, Demoly P, et al. Fatal anaphy- 2001;56(5):461–462.
laxis with neuromuscular blocking agents: a risk factor and management analy- BM, Rueff F, Mosbech H, Bonifazi F, Oude-Elberink JN. EAACI Interest Group
475. Bilo
sis. Allergy. 2014;69(7):954–959. on Insect Venom Hypersensitivity. Diagnosis of Hymenoptera venom allergy.
458. Gonzalez-Estrada A, Pien LC, Zell K, Wang XF, Lang DM. Antibiotics are an impor- Allergy. 2005;60(11):1339–1349.
tant identifiable cause of perioperative anaphylaxis in the United States. J Allergy 476. Goldberg A, Confino-Cohen R. Timing of venom skin tests and IgE determinations
Clin Immunol Pract. 2015;3(1). 101-5.e1. after insect sting anaphylaxis. J Allergy Clin Immunol. 1997;100(2):182–184.
459. Laroche D, Gomis P, Gallimidi E, Malinovsky JM, Mertes PM. Diagnostic value of 477. Mohamed OE, Baretto RL, Walker I, Melchior C, Heslegrave J, McKenzie R, et al.
histamine and tryptase concentrations in severe anaphylaxis with shock or car- Empty mast cell syndrome: fallacy or fact? J Clin Pathol. 2020;73(5):250–256.
diac arrest during anesthesia. Anesthesiology. 2014;121(2):272–279. 478. Lafuente A, Javaloyes G, Berroa F, Goikoetxea MJ, Moncada R, Nunez-Cordoba JM,
460. Mertes PM, Laxenaire MC, Alla F, Groupe d’Etudes des Re actions Anaphylactoïdes et al. Early skin testing is effective for diagnosis of hypersensitivity reactions
Peranesthe siques. Anaphylactic and anaphylactoid reactions occurring during occurring during anesthesia. Allergy. 2013;68(6):820–822.
anesthesia in France in 1999-2000. Anesthesiology. 2003;99(3):536–545. 479. Demoly P, Adkinson NF, Brockow K, Castells M, Chiriac AM, Greenberger PA, et al.
461. Mertes PM, Alla F, Trechot P, Auroy Y, Jougla E, Groupe d’Etudes des Re actions International Consensus on drug allergy. Allergy. 2014;69(4):420–437.
Anaphylactoïdes Peranesthe siques. Anaphylaxis during anesthesia in France: an 480. Mi YN, Ping NN, Cao YX. Ligands and signaling of mas-related G protein-coupled
8-year national survey. J Allergy Clin Immunol. 2011;128(2):366–373. receptor-X2 in mast cell activation. Rev Physiol Biochem Pharmacol.
462. Cuculo A, Summaria F, Schiavino D, Liuzzo G, Meo A, Patriarca G, et al. 2021;179:139–188.
[Tryptase levels are elevated during spontaneous ischemic episodes in 481. Kolkhir P, Ali H, Babina M, Ebo D, Sabato V, Elst J, et al. MRGPRX2 in drug allergy:
unstable angina but not after the ergonovine test in variant angina]. Cardio- what we know and what we do not know. J Allergy Clin Immunol. 2023;151
logia. 1998;43(2):189–193. (2):410–412.
463. Faber MA, Ebo DG, Bridts CH, Sabato VJ. Tryptase as a biomarker of mast cell acti- 482. Garvey LH, Ebo DG, Kroigaard M, Savic S, Clarke R, Cooke P, et al. The use of drug
vation in perioperative anaphylaxis: survey from a Belgium reference centre. J provocation testing in the investigation of suspected immediate perioperative
Allergy Clin Immunol. 2018;141(2):AB87. allergic reactions: current status. Br J Anaesth. 2019;123(1):e126–e134.
464. Fisher MM, Baldo BA. Mast cell tryptase in anaesthetic anaphylactoid reactions. 483. Chu DK, Abrams EM, Golden DBK, Blumenthal KG, Wolfson AR, Jr Stone CA, et al.
Br J Anaesth. 1998;80(1):26–29. Risk of second allergic reaction to SARS-CoV-2 vaccines: a systematic review and
465. Kroigaard M, Garvey LH, Menne T, Husum B. Allergic reactions in anaesthesia: are meta-analysis. JAMA Intern Med. 2022;182(4):376–385.
suspected causes confirmed on subsequent testing? Br J Anaesth. 2005;95 484. Kurtz KM, Hamilton RG, Adkinson Jr. NF. Role and application of provocation in
(4):468–471. the diagnosis of occupational latex allergy. Ann Allergy Asthma Immunol. 1999;83
466. ~ a I, Corominas M, Gastaminza G, Mayorga C, et al. Practi-
Laguna JJ, Archilla J, Don (6 Pt 2):634–639.
cal guidelines for perioperative hypersensitivity reactions. J Investig Allergol Clin 485. Elwyn G, Frosch D, Rollnick S. Dual equipoise shared decision making: definitions
Immunol. 2018;28(4):216–232. for decision and behaviour support interventions. Implement Sci. 2009;4:75.
467. Gonzalez-Estrada A, Carrillo-Martin I, Morgenstern-Kaplan D, Garzon-Siatoya 486. Greenberger PA, Patterson R, Tapio CM. Prophylaxis against repeated radiocon-
WT, Renew JR, Hernandez-Torres V, et al. The nonirritating concentrations of trast media reactions in 857 cases. Adverse experience with cimetidine and
neuromuscular blocking agents and related compounds. J Allergy Clin Immunol safety of beta-adrenergic antagonists. Arch Intern Med. 1985;145(12):2197–2200.
Pract. 2023;11(2):466–473.e5. 487. Portnoy J, Bagstad K, Kanarek H, Pacheco F, Hall B, Barnes C. Premedication
468. Ledford DL. Anaphylaxis evaluation and prevention of recurrent reactions. UpTo- reduces the incidence of systemic reactions during inhalant rush immunotherapy
Date. Available at: https://www.uptodate.com/contents/perioperative-anaphylaxis- with mixtures of allergenic extracts. Ann Allergy. 1994;73(5):409–418.
evaluation-and-prevention-of-recurrent-reactions. Accessed August 15, 2023. 488. Guyatt GH, Oxman AD, Kunz R, Falck-Ytter Y, Vist GE, Liberati A, et al. Going from
469. Uyttebroek AP, Decuyper II, Bridts CH, Romano A, Hagendorens MM, Ebo DG, evidence to recommendations. BMJ. 2008;336(7652):1049–1051.
et al. Cefazolin hypersensitivity: toward optimized diagnosis. J Allergy Clin Immu- 489. Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, et al. Grading quality
nol Pract. 2016;4(6):1232–1236. of evidence and strength of recommendations. BMJ. 2004;328(7454):1490.

Anaphylaxis

Uploaded by

Copyright:

Available Formats

Anaphylaxis

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Anaphylaxis

Uploaded by

Copyright:

Available Formats

Ann Allergy Asthma Immunol 132 (2024) 124−176

Contents lists available at ScienceDirect

Anaphylaxis: A 2023 practice parameter update

Epinephrine Autoinjectors Perioperative Anaphylaxis

The implications of a strong recommendation are the following:

The implications of a conditional recommendation are the following:

Abbreviation: JTFPP, Joint Task Force on Practice Parameters.

Section and Method Recommendation Strength of Certainty of

Section and Method Recommendation Strength of Certainty of

Section and Method Recommendation Strength of Certainty of

knowledge on anaphylaxis. In this document, we will update only

Country, region, or Date Deﬁnition Reference

NIAID criteria (2006) WAO criteria (2020)

Organ system #1 Organ system #2 NIAID anaphylaxis? WAO anaphylaxis?

Skin/mucosal Respiratory Yes Yes

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

NOTE. Adapted from Dribin et al.34

NOTE. Adapted from Brown, 2004.63

Figure 3. Diagnostic evaluation of the patient with a history of anaphylaxis.

Recommendation 10 (CBS): We suggest clinicians be aware that

Population studied Home School/work Restaurant Other home

Average = average frequency of anaphylaxis across the number of studies.b

Certainty of Evidence: Very Low

Potential strategies for safe dining to discuss with patients Comments

Abbreviation: EAI, epinephrine autoinjector.

Abbreviation: EAI, epinephrine autoinjector.

Strength of Recommendation: Conditional

Epidemiology Anaphylaxis can occur anywhere.

Abbreviation: EAI, epinephrine autoinjector.

Allergic condition Lower likelihood Higher likelihood

Age > 60 y Adolescence Older age Mast cell disorders

Abbreviation: NSAIDs, nonsteroidal anti-inﬂammatory drugs.

Considerations for home management Considerations against home management

Adrenaclick 0.15 15-30 <25 1.17 High

Abbreviations: EAI, epinephrine autoinjector; N/A, not available.

lack of comfort in recognizing anaphylaxis and administering EAIs, Table 22

Clinical question Potential beneﬁts of treatment Potential risks of no treatment

Question: Should VIT be recommended to patients with a his-

Planned Procedures: (eg, Drug Desensitization, Radiocontrast Media

Strength of Recommendation: Conditional Strength of Recommendation: Conditional

Certainty of Evidence: Very Low Certainty of Evidence: Moderate

prevalence of drug, food, and POA is also slightly increased in Table 26

Certainty of Evidence: Moderate

Recommendation 39 (CBS): We recommend clinicians not rely

Strength of Recommendation: Conditional

Certainty of Evidence: Moderate Clinical Presentation

Abbreviation: POA, perioperative anaphylaxis.

You might also like