Anaphylaxis-a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) ...
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Practice parameter
Anaphylaxis—a 2020 practice parameter update,
systematic review, and Grading of
Recommendations, Assessment, Development
and Evaluation (GRADE) analysis
Marcus S. Shaker, MD, MSc,a Dana V. Wallace, MD,b David B. K. Golden, MD,c John Oppenheimer, MD,d
Jonathan A. Bernstein, MD,e Ronna L. Campbell, MD, PhD,f Chitra Dinakar, MD,g Anne Ellis, MD,h
Matthew Greenhawt, MD, MBA, MSc,i David A. Khan, MD,j David M. Lang, MD,k Eddy S. Lang, MD,l
Jay A. Lieberman, MD,m Jay Portnoy, MD,n Matthew A. Rank, MD,o David R. Stukus, MD,p and Julie Wang, MD,q
Collaborators: Natalie Riblet, MD, MPH,r Aiyana M. P. Bobrownicki, MPH, MBA,r
Teresa Bontrager, RN, BSN, MSNed, CPEN,s Jarrod Dusin, MS, RD, LD,s Jennifer Foley, RT(R)(N), CNMT,s
Becky Frederick, PharmD,s Eyitemi Fregene, MD, MPH,r Sage Hellerstedt, MPH,r Ferdaus Hassan, PhD,s
Kori Hess, PharmD,s Caroline Horner, MD,t Kelly Huntington, RN, BSN, CPN,s Poojita Kasireddy, MPH,r
David Keeler, RN, BSN, CPN,s Bertha Kim, MPH,r Phil Lieberman, MD,m Erin Lindhorst, MS, RD, LD,s
Fiona McEnany, MPH,r Jennifer Milbank, MPH,r Helen Murphy, BHS RRT AE-C,s Oriana Pando, MPH,r Ami K. Patel, MPH,r
Nicole Ratliff, BS RT(R),s Robert Rhodes, MHA, RRT-NPS,s Kim Robertson, MBA, MT-BC,s Hope Scott, RN, CPEN,s
Audrey Snell, MS, RD, CSP, LD,s Rhonda Sullivan, MS, RD, LD,s Varahi Trivedi, MPH,r and Azadeh Wickham, MS, FNP-BCs
Chief Editors: Marcus S. Shaker and Dana V. Wallace
Workgroup Contributors: Marcus S. Shaker, Dana V. Wallace, Jonathan A. Bernstein, Ronna L. Campbell, Chitra Dinakar,
Anne Ellis, David B. K. Golden, Matthew Greenhawt, Jay A. Lieberman, Matthew A. Rank, David R. Stukus, and
Julie Wang
Joint Task Force on Practice Parameters Reviewers: Marcus S. Shaker, Dana V. Wallace, David B. K. Golden,
Jonathan A. Bernstein, Chitra Dinakar, Anne Ellis, Matthew Greenhawt, Caroline Horner, David A. Khan,
Jay A. Lieberman, John Oppenheimer, Matthew A. Rank, Marcus S. Shaker, David R. Stukus, and Julie Wang, Lebanon
and Hanover, NH; Fort Lauderdale, Fla; Baltimore, Md; Morristown, NJ; Cincinnati, Cleveland, and Columbus, Ohio; Rochester, Minn;
Stanford, Calif; Kingston, Ontario, and Calgary, Alberta, Canada; Denver, Colo; Dallas, Tex; Memphis, Tenn; Kansas City and St Louis, Mo;
Scottsdale, Ariz; and New York, NY
Anaphylaxis is an acute, potential life-threatening systemic doses of epinephrine to treat anaphylaxis are risk factors for
allergic reaction that may have a wide range of clinical biphasic anaphylaxis. Antihistamines and/or glucocorticoids are
manifestations. Severe anaphylaxis and/or the need for repeated not reliable interventions to prevent biphasic anaphylaxis,
From athe Section of Allergy and Clinical Immunology, Dartmouth-Hitchcock Medical University of Texas Southwestern Medical Center, Dallas; kthe Department of Allergy
Center, Geisel School of Medicine at Dartmouth, Lebanon; bthe Nova Southeastern and Clinical Immunology, Respiratory Institute, Cleveland Clinic; lthe Department of
Allopathic Medical School, Fort Lauderdale; cthe Division of Allergy-Clinical Emergency Medicine, Cumming School of Medicine, University of Calgary, mthe
Immunology, Johns Hopkins University, Baltimore; dthe Department of Internal Department of Pediatrics, The University of Tennessee Health Science Center, Mem-
Medicine, Pulmonary and Allergy, University of Medicine and Dentistry of New phis; nthe Pediatric Allergy and Immunology, Children’s Mercy Hospital, Kansas City
Jersey–Rutgers New Jersey Medical School and Pulmonary and Allergy Associates, School of Medicine; othe Division of Allergy, Asthma, and Clinical Immunology,
Morristown; ethe Department of Internal Medicine, Division of Immunology, Allergy Mayo Clinic in Arizona, Scottsdale; pthe Division of Allergy and Immunology,
Section, University of Cincinnati College of Medicine; fthe Department of Emergency Nationwide Children’s Hospital and The Ohio State University College of Medicine,
Medicine, Mayo Clinic, Rochester; gthe Allergy, Asthma, and Immunodeficiency, Columbus; qthe Division of Allergy and Immunology, Icahn School of Medicine at
Division of Pulmonary, Allergy, and Critical Care Medicine, Stanford University Mount Sinai, New York; rThe Dartmouth Institute for Health Policy and Clinical
School of Medicine; hthe Division of Allergy and Immunology, Department of Practice, Hanover; sthe Office of Evidence-Based Practice, Children’s Mercy Hospital,
Medicine, Queen’s University, Kingston; ithe Section of Allergy and Immunology, Kansas City; tthe Department of Pediatrics, Division of Allergy, Immunology, and
Children’s Hospital Colorado, University of Colorado School of Medicine, Denver; Pulmonary Medicine, Washington University School of Medicine, St. Louis.
j
the Department of Internal Medicine, Division of Allergy and Immunology,
1082
J ALLERGY CLIN IMMUNOL SHAKER ET AL 1083 VOLUME 145, NUMBER 4 although evidence supports a role for antihistamine and/or radiocontrast media anaphylaxis. Epinephrine is the first-line glucocorticoid premedication in specific chemotherapy pharmacotherapy for uniphasic and/or biphasic anaphylaxis. protocols and rush aeroallergen immunotherapy. Evidence is After diagnosis and treatment of anaphylaxis, all patients lacking to support the role of antihistamines and/or should be kept under observation until symptoms have fully glucocorticoid routine premedication in patients receiving low- resolved. All patients with anaphylaxis should receive education or iso-osmolar contrast material to prevent recurrent on anaphylaxis and risk of recurrence, trigger avoidance, Disclosure of potential conflict of interest: The JTFPP members and work group Milwaukee, WI 53202. E-mail: pflagg@aaaai.org); JTFPP.allergy@gmail.com. members’ conflict of interest disclosure forms can be found at www.allergyparameters. Previously published practice parameters of the Joint Task Force on Practice Parameters org. Jonathan Bernstein has received financial support from Sanofi, Regeneron, Astra- for Allergy & Immunology are also available at http://www.allergyparameters.org, Zeneca, Merck, Optinose, Takeda, CSL Behring, Biocryst, Pharming, the National In- http://www.AAAAI.org, and http://www.ACAAI.org. stitutes of Health, Taylor Francis, INEOS; is Editor in Chief of the Journal of Asthma, The Joint Task Force on Practice Parameters (JTFPP) is committed to ensuring that the INEOS Medical Immunosurveillance Director, Vice Chair and Lectureship Chair of practice parameters are based on the best scientific evidence at the time of publication, the American Academy of Allergy, Asthma & Immunology (AAAAI) Foundation, and that such evidence is free of commercial bias to the greatest extent possible. The Chairman of Allergists for Israel, American College of Asthma, Allergy, and Immu- JTFPP recognizes that experts in a field are likely to have interests that could come into nology (ACAAI) Asthma Chair, Scientific Chair, and Young Investigator Award Chair; conflict with the development of a completely unbiased and objective practice and serves of the Board of Directors and Scientific Committee of Interasma. Ronna parameter. To take advantage of their expertise, a process has been developed to Campbell has served as a peer reviewer for EB Medicine and an author for UpToDate. acknowledge potential conflicts of interest (COI) and attempt to prevent them from Chitra Dinakar has received financial support from Propeller Health, ACAAI (stipend influencing the final document in a negative way. To preserve the greatest transparency for Editorial Board of AllergyWatch), the American Association of Allergists of Indian regarding potential COI, all members of the JTFPP and the practice parameters work Origin; serves on the Board of Directors of the AAAAI and on the Medical Advisory groups will complete a standard potential COI disclosure form prior to the Board of Food Equity Initiative; is Assistant Editor of AllergyWatch. Anne Ellis has development of each document, which will be available for external review by the received financial support from ALK-Abello, AstraZeneca, Green Cross, Merck, No- sponsoring organization and any other interested individual. In addition, before vartis, Nuvo, Pediapharm, Pfizer, Kaleo, Novartis, Sanofi, Regeneron; serves on the confirming the selection of the work group chairperson and members, the JTFPP will Board of Directors of the Canadian Allergy Society of Allergy and Clinical Immu- discuss and resolve all relevant potential COI associated with this selection. Finally, all nology. David Golden has received financial support from Aquestive, Sandoz, ALK- members of parameter work groups will be provided a written statement regarding the Abello, Sandoz, Genentech, Stallergenes-Greer, and UpToDate. Matthew Greenhawt importance of ensuring that the parameter development process is free of commercial has received financial support from Aquestive, Merck, Allergenis, Allergy Therapeu- bias. During the review process there are additional measures to avoid bias. At the tics, Sanofi Genzyme, Genentech, Aravax, Prota, Before Brands, the Institute for Clin- workgroup level, all the sections are reviewed by all work group members to ensure ical and Economic Review, ACAAI, DBV, Intrommune; is supported by the Agency of that content is appropriate and without apparent bias. If a section is deemed to have Healthcare Research and Quality; has served on the advisory board of International apparent bias, it will be appropriately revised without the section author’s involvement, Food Protein-Induced Enterocolitis Syndrome Association, the Asthma and Allergy in an attempt to remove potential bias. In addition, the entire document is then Foundation of America, and the National Peanut Board; and is Associate Editor of reviewed by the JTFPP, and any apparent bias is acknowledged and removed at that the Annals of Allergy, Asthma, and Immunology. Caroline Horner has served as com- level. For each and every recommendation, a vote is required by the work group and mittee chair for the AAAAI Asthma Diagnosis and Treatment Interest Section, Interest JTFPP, and any member with any perceived COI is recused from that vote (and so Section Coordinating Committee, and In-Training Exam Coordinating Committee. explained in the document). Any dissenting votes that cannot be resolved are described David Khan has received financial support from UpToDate and Aimmune; serves on and explained in the document. In a final stage of review, the practice parameter is sent the Board of Directors of the AAAAI, ACAAI Chair of Literature Review, Co-Chair to invited expert reviewers for review, selected by the American Academy of Allergy, of Conjoint Board Review, Texas Allergy, Asthma, and Immunology Society Chair Asthma & Immunology (AAAAI) and the American College of Allergy, Asthma, and of Meetings Committee; and is Associate Editor of the Journal of Allergy and Clinical Immunology (ACAAI). The document is also posted on the AAAAI and ACAAI Immunology In Practice. Eddy Lang received an honorarium from the Joint Task Force websites for general membership and the public-at-large to review and offer comment. on Practice Parameters for Grading of Recommendations, Assessment, Development All reviewers must provide statements of potential COI. Although the JTFPP has the and Evaluation methods support. Jay Lieberman has received financial support from final responsibility for the content of the documents submitted for publication, each the ACAAI, Aquestive, Aimmune, DBV, Biotest Pharma, and Regeneron; is Associate reviewer’s comments will be discussed and reviewers will receive written responses to Editor of the Annals of Allergy, Asthma, and Immunology, Vice Chair for the ACAAI comments when appropriate. Food Allergy Committee, and Medical Director for Food Allergy Alliance of the Mid- Disclaimer: The AAAAI and the ACAAI have jointly accepted responsibility for estab- South. John Oppenheimer has received financial support from DBV, Teva Pharmaceu- lishing ‘‘Anaphylaxis—a 2019 practice parameter update, systematic review and tical Industries, GlaxoSmithKline adjudication/data safety monitoring board, Grading of Recommendations, Assessment, Development and Evaluation (GRADE) AstraZeneca, Novartis, and Sanofi; is Associate Editor of the Annals of Allergy, analysis.’’ This is a complete and comprehensive document and is current at the Asthma, and Immunology and AllergyWatch, an American Board of Internal Medicine time of publication. The medical environment is rapidly changing and not all recom- Council Member and American Board of Allergy and Immunology Liaison to the mendations will be appropriate or applicable to all patients and may change over time. American Board of Internal Medicine, UpToDate Reviewer, American College of Because this document incorporated the efforts of many participants, no single individ- Clinical Pharmacy Cough Guideline Committee Member, and WebMD Editor. Jay ual, including members serving on JTFPP, are authorized to provide an official AAAAI Portnoy has received financial support from Thermo Fisher Scientific, Kaleo, Teva or ACAAI interpretation of these practice parameters. Any request for information or Pharmaceutical Industries, Novartis, Hycor, and Boehringer-Ingelheim. Matthew interpretation of this practice parameter by the AAAAI or ACAAI should be directed to Rank has received financial support from the ACAAI, National Institutes of Health, the executive offices of the AAAAI and the ACAAI. These parameters are not designed and Levin Family Foundation; has served as Chair of the AAAAI Health outcomes, for use by the pharmaceutical industry in drug development or promotion. Education, Delivery, and Quality Interest Section; and is Research Director of the Contributors: The Joint Task Force has made a concerted effort to acknowledge all con- Phoenix Children’s Hospital Breathmobile. Marcus Shaker has received financial sup- tributors to this parameter. If any contributors have been excluded inadvertently, the port from the Eastern Allergy Conference and has a family member who is Chief Ex- Task Force will ensure that appropriate recognition of such contributions is made sub- ecutive Officer of Altrix Medical. David Stukus has received financial support from sequently. Aimmune, Before Brands, Abbott Nutrition, the American Academy of Pediatrics, Received for publication October 2, 2019; revised December 21, 2019; accepted for pub- ACAAI; has served as Committee Chair for the AAAAI and ACAAI. Dana Wallace lication January 2, 2020. has received financial support from Mylan, Kaleo, Optinose, ALK-Abello, Bryan, Available online January 28, 2020. and Sanofi; is Education Council Chair and Rhinitis/Sinusitis/Ocular Committee Chair Corresponding author: Marcus S. Shaker, MD, MSc, FAAAAI, FACAAI, FAAP, Section for the ACAAI; is Website Content Editor and ESP/WATS Committee Chair for the of Allergy and Clinical Immunology, Dartmouth-Hitchcock Medical Center, One World Allergy Organization. Julie Wang has received financial support from ALK- Medical Center Drive, Lebanon, NH 03756-0001. E-mail: Marcus.shaker@ Abello, Regeneron, DBV, Aimmune; is an UpToDate author; serves on the Executive dartmouth.edu. Committee of the American Academy of Pediatrics Section on Allergy and Immu- The CrossMark symbol notifies online readers when updates have been made to the nology; and serves as Vice Chair of the AAAAI Anaphylaxis, Dermatitis, Drug Allergy article such as errata or minor corrections Interest Section. David Lang declares that he has no relevant conflicts of interest. 0091-6749/$36.00 Reprints: Joint Task Force on Practice Parameters Liaison: Peris Flagg (American Acad- Ó 2020 American Academy of Allergy, Asthma & Immunology emy of Allergy, Asthma, and Immunology, 555 E. Wells Street, Suite 1100, https://doi.org/10.1016/j.jaci.2020.01.017
1084 SHAKER ET AL J ALLERGY CLIN IMMUNOL
APRIL 2020
self-injectable epinephrine education, referral to an allergist,
and be educated about thresholds for further care. (J Allergy Abbreviations used
Clin Immunol 2020;145:1082-123.) AAAAI: American Academy of Allergy, Asthma & Immunology
ACAAI: American College of Allergy, Asthma, and
Key words: Anaphylaxis, GRADE, epinephrine, risk factors, Immunology
biphasic, severity, glucocorticoids, antihistamines, pretreatment- ADR: Adverse drug reaction
radiocontrast media, chemotherapy, mAb, infliximab, allergen C3a (4a, 5a): Complement 3a (4a, 5a)
immunotherapy, systematic meta-analysis, evidence to recommenda- DHR: Drug hypersensitivity reaction
tions, guideline, practice parameter ED: Emergency department
EMS: Emergency medical services
FAAN: Food Allergy and Anaphylaxis Network
FIA: Food-induced anaphylaxis
The Joint Task Force on Practice Parameters would like to GRADE: Grading of Recommendations, Assessment, Develop-
dedicate this guideline to Chitra Dinakar for her ongoing ment and Evaluation
contributions and dedication to the field of allergy and H1 (2, 3, 4): Histamine 1 (2, 3, 4)
immunology. HSR: Hypersensitivity reaction
HVA: Hymenoptera venom allergy
I2: Inconsistency of studies’ results
IQR: Interquartile range
EXECUTIVE SUMMARY JTFPP: Joint Task Force on Practice Parameters
Anaphylaxis is an acute, life-threatening systemic allergic LL: Large local
reaction that may have a wide range of clinical manifestations.1 LT: Leukotriene
The clinical criteria proposed in 2006 by National Institute of NIAID: National Institute of Allergy and Infectious Diseases
Allergy and Infectious Diseases (NIAID) continue to provide a NNT: Number needed to treat
helpful framework in approaching patients with acute allergic NPV: Negative predictive value
symptoms, because diagnosis and management of anaphylaxis OR: Odds ratio
must occur rapidly and confirmatory testing for anaphylaxis has PAF: Platelet-activating factor
PEER: Patient expected event rate
poor sensitivity.2 While NIAID anaphylaxis diagnostic criteria
PRISMA: Preferred Reporting Items for Systematic Reviews and
have a sensitivity of 95% with a specificity of 71% in an Meta-Analyses
emergency department (ED) setting,3 fulfilling diagnostic criteria RCM: Radiocontrast media
is not a prerequisite for epinephrine administration in a patient RIT: Rush immunotherapy
experiencing an acute allergic reaction. RR: Relative risk
The lifetime prevalence of anaphylaxis has been estimated at
1.6% to 5.1%.1,4 Risk factors for severe anaphylaxis include
cardiovascular disease, asthma, older age, and additional underutilized.23-25 As a nonselective adrenergic agonist,
coexisting, comorbid conditions.5-9 Medications and stinging epinephrine works rapidly to increase peripheral vascular
insects are the leading triggers in adults, with foods and stinging resistance through vasoconstriction, to increase cardiac output,
insects the most frequently implicated triggers in children and ad- to reverse bronchoconstriction and mucosal edema, and to
olescents.1,10-12 Food allergy impacts 8% to 11% of children and stabilize mast cells and basophils.26,27 Despite underuse of
adults in the United States,13-15 while adverse drug reactions rapidly acting epinephrine as first-line treatment, fatal
(ADRs) affect up to 10% of the population (and 20% of anaphylaxis is a rare outcome, with population prevalence rates
hospitalized patients), with hypersensitivity reactions (HSRs) ac- between 0.47 and 0.69 per million persons (0.25%-0.33% of
counting for 10% of all ADRs.16 Although medical complexity anaphylaxis hospitalizations or ED visits).9,28-31 Antihistamine
increases for patients with prior HSRs to radiocontrast media agents are considered second-line treatment for anaphylaxis,
(RCM), fortunately the prevalence of RCM ADRs has decreased given their slow onset of action and inability to stabilize or
in recent decades.17 Systemic reactions to Hymenoptera venom prevent mast cell degranulation or to target additional mediators
occur in 0.5% to 3.3% of the US population, with most fatalities of anaphylaxis.32 Unlike epinephrine, antihistamines will not
occurring in patients who have no prior history of systemic effectively treat cardiovascular and respiratory symptoms such
allergic reaction to Hymenoptera.16 as hypotension or bronchospasm. Although glucocorticoids are
IgE binding and cross-linking of the high affinity IgE receptor frequently used as an adjunctive therapy for anaphylaxis,
(FcεRI) on the surface of mast cells and basophils is an important evidence is lacking to support clinical benefit, and they should
mechanism in many cases of anaphylaxis.18 Some patients with not be administered in place of epinephrine in the treatment of
anaphylaxis have low or undetectable circulating allergen- acute anaphylaxis.33,34
specific IgE.19 Anaphylaxis involves additional cell types that Biphasic anaphylaxis is recurrent anaphylaxis occurring 1 to 72
may include neutrophils, monocytes, macrophages, and platelets hours after resolution of an initial anaphylactic episode, though an
and signaling through mediators that include complement compo- outside limit of 78 hours has also been suggested.35,36 Estimates
nents, cysteinyl leukotrienes (LTs), platelet activating factor, IL- of biphasic anaphylaxis vary fromJ ALLERGY CLIN IMMUNOL SHAKER ET AL 1085
VOLUME 145, NUMBER 4
Box 1. Key questions assessed by this systematic review on anaphylaxis
Topic area 1. Identification and mitigation of risk factors for biphasic anaphylaxis
Question 1. What risk factors should clinicians take into consideration in determining the likelihood of biphasic anaphylaxis?
Topic area 2. Evaluation of the use of supplemental glucocorticoids and/or antihistamine premedication for the prevention of
anaphylaxis
Question 2. Should antihistamines and/or glucocorticoids be used to prevent biphasic anaphylaxis?
Question 3. Should antihistamine and/or glucocorticoid premedication be used to prevent index hypersensitivity/infusion reac-
tions to chemotherapy?
Question 4. Should antihistamine and/or glucocorticoid premedication be used to prevent recurrent HSRs to RCM?
Question 5. Should antihistamine and/or glucocorticoid premedication be used to prevent HSRs to allergen immunotherapy or
other agents?
Force on Practice Parameters (JTFPP) undertook a systematic 0.6; 95% CI, 0.38-0.96). Prompt and adequate treatment of
review and Grading of Recommendations, Assessment, anaphylaxis appears central to reducing biphasic anaphylaxis
Development and Evaluation (GRADE) analysis of antihista- risk, in the opinion of the JTFPP. While the possibility of biphasic
mines and glucocorticoids in anaphylaxis. Specifically, the JTFPP anaphylaxis should be emphasized in this higher risk group, it is
sought to better inform the practice of anaphylaxis prevention in 2 important to educate all patients regarding the chance of a
broad topic areas through (1) identification and mitigation of risk biphasic reaction as well as avoiding known triggers,
factors for biphasic anaphylaxis and (2) evaluation of the use of identification of symptoms of anaphylaxis, the use of
supplemental glucocorticoid and/or antihistamine premedication auto-injector epinephrine for the treatment of anaphylaxis, and
(see Box 1). Although the goal of the JTFPP was to rigorously timely follow-up with an allergist.
evaluate the literature to form evidence-based recommendations, Recommendation 2. We suggest extended clinical observa-
there are limits to the available evidence in human anaphylaxis tion in a setting capable of managing anaphylaxis (to detect a
due to ethical considerations and the absence of double-blind biphasic reaction) for patients with resolved severe anaphylaxis
studies in a potentially fatal, acute condition. This GRADE and/or those who need >1 dose of epinephrine. Conditional
analysis incorporated the balance of relative benefits and harms recommendation. Certainty rating of evidence: very low.
of treatments under consideration, the certainty of the evidence, While wide pulse pressures may be considered a marker for
and the impact of patient preferences and values. Box 2 provides severe anaphylaxis, the clinician may also consider extended
a summary of key clinical advice. observation for patients with an unknown anaphylaxis trigger and
children with a drug trigger. Incorporating cutaneous signs and
symptoms into a clinical decision for extended observation may
Question 1. What risk factors should clinicians take be limited by the common occurrence of cutaneous signs and
into consideration in determining the likelihood of symptoms in patients presenting with anaphylaxis. The estimated
biphasic anaphylaxis? number needed to monitor with extended observation to be able to
Recommendation 1. We suggest that a clinician incorporate detect 1 episode of biphasic anaphylaxis before discharge would
severity of anaphylaxis presentation and/or the administra- be 41 (range, 18-195) for patients with a more severe initial
tion of >1 dose of epinephrine for the treatment of initial presentation of anaphylaxis and 13 (range, 7-27) for patients with
anaphylaxis as a guide to determining a patient’s risk for multiple epinephrine doses. The implication for the clinician,
developing biphasic anaphylaxis. Conditional recommenda- based on this systematic review and meta-analysis, is that the
tion. Certainty rating of evidence: very low. patient presenting with severe anaphylaxis and/or requiring more
Even though the ability to accurately predict which patients aggressive treatment (eg, >1 dose of epinephrine) should be
with resolved initial anaphylaxis will experience biphasic considered for longer observation time for a potential biphasic
anaphylaxis is imperfect, an understanding of risk factors allows reaction following complete resolution of signs and symptoms. At
a more tailored approach to patient management. Risk factors also present, evidence is lacking to clearly define the optimal duration
provide useful parameters to incorporate into decision making of observation (eg, number of hours) that would prove to be cost-
regarding duration of observation following initial resolution of effective for patients with initial resolution of severe anaphylaxis
anaphylaxis. and/or those requiring multiple doses of epinephrine. However,
The JTFPP findings suggest biphasic anaphylaxis is associated for patients without severe risk features, discharge after a 1-hour
with a more severe initial presentation of anaphylaxis (odds ratio asymptomatic observation may be reasonable. If the clinical
[OR], 2.11; 95% CI, 1.23-3.61) or repeated epinephrine doses (ie, impression is that a patient has a higher risk of biphasic
>1 dose of epinephrine) required with the initial presentation reaction (ie, 17% or greater) or risk factors for anaphylaxis
(OR, 4.82; 95% CI, 2.70-8.58). Additional risk factors include fatality (eg, cardiovascular comorbidity, lack of access to
wide pulse pressure (OR, 2.11; 95% CI, 1.32-3.37), unknown epinephrine, lack of access to emergency medical services
anaphylaxis trigger (OR, 1.63; 95% CI, 1.14-2.33), cutaneous (EMS), poor self-management skills), then extended observation
signs and symptoms (OR, 2.54; 95% CI, 1.25-5.15), and drug of up to 6 hours or longer (including hospital admission) may be
trigger in children (OR, 2.35; 95% CI, 1.16-4.76). While presence appropriate. Regardless of severity, after diagnosis and treatment
of dyspnea on presentation was associated with a decreased risk of anaphylaxis, all patients should be kept under observation until
for anaphylaxis, overall confidence in this estimate was low (OR, signs and symptoms have fully resolved.1086 SHAKER ET AL J ALLERGY CLIN IMMUNOL
APRIL 2020
Box 2. Suggested key clinical advice
d Severe anaphylaxis and/or the need for >1 dose of epinephrine to treat anaphylaxis are risk factors for biphasic anaphylaxis.
Additional risk factors include wide pulse pressure, unknown anaphylaxis trigger, cutaneous signs and symptoms, and drug
trigger in children.
d Extended observation is suggested for patients with resolved severe anaphylaxis and/or those with need for >1 dose of
epinephrine.
d Antihistamines and/or glucocorticoids are not reliable interventions to prevent biphasic anaphylaxis but may be considered
as secondary treatment.
d Evidence supports a role for antihistamine and/or glucocorticoid premedication in specific chemotherapy protocols and rush
aeroallergen immunotherapy.
d Evidence is lacking to support the routine use of antihistamines and/or glucocorticoid premedication in patients receiving
low- or iso-osmolar contrast material to prevent recurrent RCM anaphylaxis.
d Administer epinephrine as the first-line pharmacotherapy for uniphasic and/or biphasic anaphylaxis.
d Do not delay the administration of epinephrine for anaphylaxis.
d After diagnosis and treatment of anaphylaxis, all patients should be kept under observation until symptoms have fully
resolved.
d All patients with anaphylaxis should receive education about anaphylaxis, risk of recurrence, trigger avoidance, self-
injectable epinephrine, and thresholds for further care, and they should be referred to an allergist for follow-up evaluation.
Question 2. Should antihistamines or protocols. The use of premedication was associated with a
glucocorticoids be used to prevent biphasic decreased rate of HSRs for chemotherapy (OR, 0.49; 95% CI,
anaphylaxis? 0.37-0.66). In contrast to chemotherapy premedication, benefit was
Recommendation. We suggest against administering not observed when using premedication to prevent anaphylaxis in
glucocorticoids or antihistamines as an intervention to the setting of infliximab without prior reaction to the administered
prevent biphasic anaphylaxis. Conditional recommendation. agent (relative risk [RR], 1.58; 95% CI, 0.87-2.87). We did not
Certainty rating of evidence: very low. evaluate premedication in the context of desensitization to
Although we suggest against the use of antihistamines and/or chemotherapy agents and to monoclonal antibodies. Furthermore,
glucocorticoids as an intervention to prevent biphasic the use of premedication in patients who had previously experi-
anaphylaxis, these may be considered for the secondary treatment enced anaphylaxis from these agents was not evaluated.
of anaphylaxis.45 In particular, antihistamines may treat urticaria
and itching to improve comfort during anaphylaxis, but if used
prior to epinephrine administration, antihistamine administration Question 4. Should antihistamine and/or
could lead to a delay in first-line treatment of anaphylaxis. The glucocorticoid premedication be used to prevent
JTFPP analysis did not identify clear benefit in prevention of recurrent HSRs to RCM?
biphasic anaphylaxis from histamine 1 (H1) antihistamines Recommendation. We suggest against routinely adminis-
(OR, 0.71; 95% CI, 0.47-1.06), H2 antihistamines (OR, 1.21; tering glucocorticoids and/or antihistamines to prevent
95% CI, 0.80-1.83), or glucocorticoids (OR, 0.87; 95% CI, anaphylaxis in patients with prior radiocontrast HSRs when
0.74-1.02). An interaction was identified between age and gluco- readministration of a low- or iso-osmolar, nonionic RCM
corticoid use, with glucocorticoids actually increasing risk for agent is required. Conditional recommendation. Certainty
biphasic anaphylaxis in children (OR, 1.55; 95% CI, 1.01-2.38); rating of evidence: very low.
however, a confounding effect of severity could not be excluded. The JTFPP analysis did not identify significant benefit from the
At a biphasic anaphylaxis patient expected event rate (PEER) of use of premedication prior to RCM administration to prevent
5%, the number needed to treat (NNT) for H1 antihistamines and anaphylaxis (RR, 1.07; 95% CI, 0.67-1.71). The absence of
glucocorticoids is 72 and 161 to prevent 1 episode of biphasic benefit of premedication in patients with prior immediate HSRs to
anaphylaxis, with significant uncertainty in the estimate. RCM who are receiving a different low- or iso-osmolar agent is
consistent with prior literature; however, it is important to
distinguish the immediate index reaction associated with RCM
from a severe, delayed, cutaneous T-cell-mediated reaction,
Question 3. Should antihistamine and/or where premedication may add value to management.17 Given
glucocorticoid premedication be used to prevent the diversity of clinical circumstances evaluated and low
index hypersensitivity/infusion reactions to confidence in the literature base, higher certainty evidence is
chemotherapy? needed to better inform practice, and future recommendations
Recommendation. We suggest in favor of administering could potentially change as a result of new information. As
glucocorticoids and/or antihistamines to prevent anaphylaxis such, clinicians may reasonably consider premedication in
or infusion-related reactions when indicated for specific clinical circumstances associated with a high level of perceived
agents in chemotherapy protocols. Conditional recommenda- risk of anaphylaxis or comorbidities associated with greater
tion. Certainty rating of evidence: very low. anaphylaxis fatality risk (such as underlying cardiovascular
The JTFPP analysis did identify a significant change in rates of disease, use of beta-blockers, or prior severe anaphylaxis),
anaphylaxis and/or infusion reactions for some chemotherapy although evidence is lacking to clearly support this practice.J ALLERGY CLIN IMMUNOL SHAKER ET AL 1087
VOLUME 145, NUMBER 4
This analysis evaluated patients with both mild and severe prior INTRODUCTION TO AND DIAGNOSIS OF
RCM reactions, but we were unable to stratify prophylaxis by ANAPHYLAXIS
severity of index reaction. Furthermore, only low- and Anaphylaxis is an acute, life-threatening systemic allergic
iso-osmolar nonionic radiocontrast agents were evaluated reaction associated with different mechanisms, triggers, clinical
because these are the most commonly used agents at present. presentations, and severity.1 The wide range of clinical
This recommendation does not apply to patients receiving manifestations and complex underlying mechanisms of
high-osmolar contrast agents for whom prophylaxis may be anaphylaxis contribute to the difficulty in establishing a definition
appropriate in some circumstances. and diagnostic criteria for anaphylaxis. The poor sensitivity of
confirmatory laboratory testing further complicates accurate
diagnosis of anaphylaxis. Furthermore, a lack of use of
Question 5. Should antihistamine and/or established diagnostic criteria plays a major role in the
glucocorticoid premedication be used to prevent underdiagnosis and inconsistent management of anaphy-
HSRs to allergen immunotherapy or other agents? laxis.47-49 In 2005, a multinational and multidisciplinary work
Recommendation. We suggest the administration of group that included allergist-immunologists, emergency
glucocorticoids and/or antihistamines as an intervention to physicians, pediatricians, critical care specialists, internists, and
prevent anaphylaxis in patients undergoing aeroallergen key stakeholders was assembled by the NIAID and Food Allergy
rush immunotherapy (RIT). Conditional recommendation. and Anaphylaxis Network (FAAN) to address the need for
Certainty rating of evidence: very low. universally accepted anaphylaxis diagnostic criteria. The
Evidence suggests that in the setting of aeroallergen RIT, diagnostic criteria proposed by this work group were published
premedication may provide value in reducing systemic reactions in 200622 and describe anaphylaxis as likely when 1 of 3 criteria
and anaphylaxis (immunotherapy analysis including RIT: RR, are fulfilled: (1) acute onset of an illness (minutes to hours) with
0.62; 95% CI, 0.41-0.94). The evidence base for premedication involvement of the skin, mucosal tissue, or both with either
before conventional aeroallergen immunotherapy is limited; how- respiratory involvement or reduced blood pressure and/or
ever, 1 study46 suggested some benefit with fexofenadine associated symptoms of end-organ dysfunction; or (2) 2 or
pretreatment 2 hours before conventional immunotherapy using ce- more of the following that occur rapidly after exposure to a likely
dar pollen or dust mite allergens. The JTFPP is unable to exclude allergen for the patient, including (i) involvement of skin-mucosal
the possibility that specific situations and subpopulations may exist tissue, (ii) respiratory involvement, (iii) reduced blood pressure or
where premedication could provide benefit to immunotherapy in associated symptoms, or (iv) gastrointestinal symptoms; or
those with concomitant risk factors (eg, in situations associated (3) reduced blood pressure as a result of exposure to a known
with higher rates of systemic reactions). As such, clinicians may allergen trigger. These criteria have since been recognized and
reasonably consider immunotherapy premedication in other clin- endorsed by the American Academy of Allergy, Asthma & Immu-
ical circumstances associated with a high level of perceived risk nology (AAAAI), American College of Allergy, Asthma, and
of anaphylaxis or comorbidities associated with greater anaphy- Immunology (ACAAI),50 and the World Allergy Organization.51
laxis fatality risk (such as underlying cardiovascular disease or The NIAID/FAAN criteria were developed to facilitate rapid
use of beta-blockers), although high-certainty evidence is lacking diagnosis of anaphylaxis. The criteria (shown in Fig 1) incorpo-
to support this practice. rate features related to the onset of the reaction, exposure to an
inciting trigger, as well as signs and symptoms. Importantly, using
these criteria, anaphylaxis can be identified among patients lack-
ing hemodynamic compromise, patients lacking cutaneous
Additional good practice statements manifestations, and patients with mild presentations (eg, those
Good practice statement 1. Administer epinephrine as the with a rash and vomiting after exposure to a likely trigger). The
first-line pharmacotherapy for uniphasic and/or biphasic NIAID/FAAN anaphylaxis diagnostic criteria were prospectively
anaphylaxis. validated in patients seeking care for an allergic reaction and
Good practice statement 2. Do not delay the administration possible anaphylaxis in an ED setting and were shown to provide
of epinephrine for anaphylaxis, as doing so may be associ- a positive likelihood ratio of 3.26 and negative likelihood ratio of
ated with higher morbidity and mortality. 0.07.3 Thus, although these criteria are helpful clinically, they
Good practice statement 3. After diagnosis and treatment of should not replace clinician judgment. It is important to
anaphylaxis, all patients should be kept under observation in recognize, as acknowledged by those who developed the criteria,
a setting capable of managing anaphylaxis until symptoms that epinephrine administration is not limited to those patients
have fully resolved. meeting the NIAID/FAAN diagnostic criteria. For example, a
Good practice statement 4. All patients with anaphylaxis patient undergoing immunotherapy who immediately develops
should receive education on anaphylaxis, including avoid- generalized urticaria after an injection may appropriately receive
ance of identified triggers, presenting signs and symptoms, epinephrine if impending anaphylaxis is suspected, despite the
biphasic anaphylaxis, treatment with epinephrine, and the fact that the diagnostic criteria for anaphylaxis have not yet
use of epinephrine auto-injectors, and they should be been met. In such instances, management relies heavily on
referred to an allergist. Of note, there may be some clinical judgment. However, the role of preemptive epinephrine
circumstances where self-injectable epinephrine is deferred prior to the development of anaphylaxis has been questioned.52-54
(ie, resolved anaphylaxis and drug trigger with high likeli- Isolated allergen-associated urticaria, which may respond to
hood of successful avoidance) and shared decision making antihistamines, should be distinguished from anaphylaxis for
may play a role in some circumstances. which prompt epinephrine administration is indicated.1088 SHAKER ET AL J ALLERGY CLIN IMMUNOL
APRIL 2020
FIG 1. Clinical criteria for the diagnosis of anaphylaxis. Anaphylaxis is likely when 1 of 3 criteria are fulfilled:
(1) acute onset of an illness (minutes to hours) with involvement of the skin, mucosal tissue, or both with
either respiratory involvement or reduced blood pressure (BP)/associated symptom of end-organ
dysfunction; or (2) >_2 of the following that occur rapidly after exposure to a likely allergen for the patient,
including (i) involvement of skin-mucosal tissue, (ii) respiratory involvement, (iii) reduced blood pressure
or associated symptoms, or (iv) gastrointestinal symptoms; or (3) reduced blood pressure as a result of
exposure to a known allergen trigger. Adapted from Simons et al.61J ALLERGY CLIN IMMUNOL SHAKER ET AL 1089
VOLUME 145, NUMBER 4
Additionally, in the ED, a stable, asymptomatic patient who most often occurs at home.1 Medications most frequently
provides a history of symptoms meeting NIAID/FAAN implicated in the United States are antibiotics, nonsteroidal
anaphylaxis diagnostic criteria but whose symptoms have anti-inflammatory drugs, immunomodulators, and biological
completely resolved prior to arrival, should still be given an agents.63 In contrast, in Portugal, a review64 of 313 patients
anaphylaxis diagnosis despite the fact that epinephrine with a history of drug-induced anaphylaxis revealed the most
administration is no longer acutely indicated. common trigger to be nonsteroidal anti-inflammatory drugs,
Biphasic anaphylaxis is a well-recognized potential followed by antibiotics and anesthetics. An anaphylaxis registry65
complication of anaphylaxis and has been defined as recurrent of German-speaking countries (Germany, Austria, and
anaphylaxis after complete improvement; this has been reported Switzerland) reported the most common trigger to be insect
to occur between 1 and 78 hours after the onset of the initial venom, followed by food and drugs, respectively (when all age
anaphylactic reaction, and this must be clinically differentiated groups are considered). In studies of food-induced anaphylaxis
from a reaction that does not fully respond to initial treatment and (FIA), incidence ranges from as low as 1 per 100,000 to as high
persists or quickly returns.35,36,55,56 Some earlier studies of as 70 per 100,000 have been reported by using data from
biphasic reactions, prior to the NIAID/FAAN criteria, which hospitalizations, ED visits, and medical record reviews.66-68
included patients with severe anaphylaxis, reported rates of When examining anaphylaxis etiology, the proportion due to
biphasic anaphylaxis as high as 20%.37-39 More contemporary foods varied between 13% and 65% depending on age and
studies of biphasic anaphylaxis utilizing the NIAID/FAAN study.66-71 The specific trigger may not be identified during the
diagnostic criteria or similar criteria for diagnosis of both the acute anaphylactic event or in subsequent evaluations, especially
initial anaphylactic reaction and the biphasic reaction have if the reaction is occurring for the first time, and the trigger may
demonstrated lower rates of biphasic reactions closer to 4% to only be identified retrospectively at a follow-up evaluation. For
5% (range, 0.18%-14.7%).40-44 No studies have systematically example, 1 study72 of ED records in Florida found that only
evaluated therapies for the second-phase reaction; however, 37% of patients could pinpoint a specific trigger on initial
therapy for the second phase is similar to that for the initial presentation. Futhermore, initial suspected culprits are often not
phase.36 Optimal duration of extended observation following confirmed on subsequent allergy testing, which suggests caution
resolution of biphasic anaphylaxis is unknown.36 One recent in presumption of potential triggers and supports the necessity
meta-analysis57 of 12 studies including 2890 adult patients with of follow-up evaluation by an allergy specialist.47,73,74
anaphylaxis suggested the pooled negative predictive value With respect to treatment, delayed use of epinephrine has been
(NPV) of 1-hour observation was 95%, with an NPV for biphasic associated with increased risk for fatality, and several
anaphylaxis after > _6 hours of observation (following resolved observational studies and case reports series48,75-88 suggest a
anaphylaxis) of 97.3%. A recent cost-effectiveness analysis continued disparity between the diagnosis of anaphylaxis and
suggested that extended observation could be cost-effective frequency of appropriate epinephrine treatment. In 1 study76 of
(ie, not exceeding $10 million per death prevented) at high rates drug-induced anaphylaxis evaluated and managed in an ED,
of fatality risk reduction (76%) from an additional 5 hours of only 8% of patients received epinephrine. While early
asymptomatic observation.58 epinephrine is the bedrock of anaphylaxis management,
anaphylaxis fatality is fortunately a rare outcome. The overall
prevalence of fatal anaphylaxis in recent years in the United States
EPIDEMIOLOGY AND RISK FACTORS and United Kingdom is between 0.47 and 0.69 per million
Prevalence estimates of anaphylaxis vary widely, and many persons.8,9,28-30 The 3 leading causes of fatal anaphylaxis are
studies suggest that the prevalence is increasing, particularly in drugs (29%-58.5%),8,28,89,90 insect stings (3.3%-54%),8,28,89,90
developed countries. The lifetime prevalence of anaphylaxis has and food (2%-6.7%).8,28,90 While anaphylaxis-related
been estimated at 1.6% to 5.1%,1,4,11 with an incidence rate of 42 hospitalizations have increased, general case fatality rates have
per 100,000 person-years, but estimates may be susceptible to been stable in the range of 0.25% to 0.33% of hospitalizations
ascertainment bias.59 Data from a European anaphylaxis registry or ED presentations for anaphylaxis.31 However, in contrast to
revealed that over one-quarter of cases occurs in patients under 18 other causes of fatal anaphylaxis, drug-induced anaphylaxis rates
years of age.60 As indicated in an international consensus on have increased.8 In the United Kingdom, fatal drug anaphylaxis
anaphylaxis document, cardiovascular disease and asthma are has been reported to be mostly due to general anesthetics,91
well-recognized risk factors for severe anaphylaxis.5 Additional whereas antibiotics predominate in Australia28 and France.92
risk factors potentially associated with severe or fatal anaphylaxis A review by Pichichero et al93 described the population incident
include older age, mast cell disorder, and beta-blocker or risk of anaphylaxis to penicillin between 0.004% and 0.015%
angiotensin-converting enzyme inhibitor use.6-9 Atopy is a risk with a fatality rate of 0.0002% to 0.0015%. The UK fatal
factor for anaphylaxis triggered by food, exercise, and latex.61 anaphylaxis registry reported that while those dying from food
While 1 survey62 of Turkish beekeepers (n 5 29 subjects with anaphylaxis often have a prior history of a food reaction, those
systemic reactions, 9 with anaphylaxis, of 444 subjects with a his- with fatal Hymenoptera venom and drug anaphylaxis usually do
tory of a sting exposure in the prior 12 months) suggested atopic not.91,94 Additional observational case series have shown patients
disease as a risk factor for systemic reactions (OR, 3.3; 95% CI, dying from food anaphylaxis often have a history of previous
1.2-8.7), it has not been otherwise established that atopic disease food-induced allergic reactions.28,38,95 Notably, respiratory arrest
increases the risk for Hymenoptera sting-associated anaphylaxis. may occur more commonly with foods (86% of fatalities in the
Medications and stinging insect venom are leading causes of UK registry), with shock more common in fatalities due to
adult anaphylaxis,1 while foods and stinging insect venom are the medications and venom reactions.91 It is important to note that
most common triggers of anaphylaxis in children and most fatal reactions are unpredictable and statistically occur
adolescents.10-12 In the middle-age adult population, anaphylaxis very rarely; however, appropriate trigger identification after1090 SHAKER ET AL J ALLERGY CLIN IMMUNOL
APRIL 2020
recovery from a severe reaction may decrease the risk for a reaction are prescribed an epinephrine auto-injector and have it
subsequent severe reaction, including fatality.94 Referral to an available when needed.95,105 Prevalence estimates and mean costs
allergy specialist after recovery from anaphylaxis is for office, inpatient, and ED visits have the largest effect on total
recommended to confirm the diagnosis, evaluate for potential societal direct costs. Indirect costs have been estimated at $115
triggers, and educate the patient on the risk of future reactions million104 with morbidity-related costs accounting for 85% of
and measures to reduce that risk, including self-injectable indirect costs, resulting from disease-related sick days (lost
epinephrine access and auto-injector education. productivity and wages).104 Simulations from probabilistic
sensitivity analyses have generated mean annual direct costs of
$307 million and indirect costs of $203 million in the United
BURDEN OF DISEASE States.104 While evidence suggests that activation of EMS and
Food-induced anaphylaxis prolonged ED observation of resolved food anaphylaxis is a
Prevalence. Food allergy (or presumed food allergy) is a low-value practice, prompt EMS activation is appropriate for
leading cause of anaphylaxis presenting to US EDs, with an patients who do not immediately completely respond to timely
estimated 30,000 cases per year.96 Food allergy (assessed through epinephrine, or for recurrence of symptoms.106
a nationally representative Internet self-report study) is estimated
to affect up to 8% to 11% of the US population.13-15 Food allergens
may be attributed to upward of 50% of ED-reported anaphylaxis Drug-induced anaphylaxis
cases in developed countries, including the United States.97 ADRs may affect up to one-tenth of the general population and
Trends. According to the Centers for Disease Control and up to 20% of all hospitalized patients. More than 10% of all ADRs
Prevention, rates of food allergies in US children increased by are drug hypersensitivity reactions (DHRs). In a systematic
about 50% between 1997 and 2011.98 Whereas Clark et al99 review, 53 observational studies were synthesized to estimate
reported stable trends in the frequency of US ED visits for food that 8% of patients self-report drug allergy, and that 11% of
allergy in the period of 2001 to 2009, they did find a statistically self-reported drug allergy is reported to be anaphylaxis.107 The
significant decline among individuals > _18 years of age. In a most common DHR involves antibiotics such as penicillins,
retrospective cohort study100 of 37 pediatric hospitals from cephalosporins, sulfonamides, aspirin, and other nonsteroidal
2007 to 2012, an increasing rate of FIA-related ED visits was anti-inflammatory drugs. DHRs can be severe and life-
reported but without any increase in the proportion of ED patients threatening and are associated with significant mortality rates.
hospitalized or admitted to the intensive care unit. This decrease The incidence of anaphylaxis due to medication triggers is
in the proportional rate of ED visits to utilization of inpatient and increasing over time.59 DHRs have a significant socioeconomic
intensive care unit facilities may be due to the increased impact related to both direct costs (management of reactions
utilization of ED or inpatient observation units, as approximately and hospitalizations) and indirect costs (missed work and/or
36% of US EDs reported having observation units in 2007.101 school days; alternative drugs); however, there is, overall, a major
More recently, Motosue et al102 reported a fourfold increase in gap in the literature for summarizing the economic burden of
FIA-related ED visits for adolescents from 2005 through 2014. DHRs.16 A US nationwide cross-sectional telephone self-
Economic burden. Food allergies can burden patients and reported survey1 reported a prevalence of anaphylaxis in the
families by affecting finances, social relationships, and personal general population of 1.6% with medications being the most
perceptions of health.103 Patients with food allergies and their common trigger (35%). Excluding pediatric cohorts (where
families experience anxiety and other stresses that affect food is the most common trigger), medications are the most
quality of life given the risk of potentially severe reactions and frequent cause of fatal anaphylaxis in reports from the United
inability to completely control these risks.16 The impact of food States, as well as the United Kingdom, Australia, and New
allergies is not limited to just the patients and their families but Zealand.8,16 Perioperative anaphylaxis presents unique
can also lead to a significant economic effect on society and the challenges. Recently, the 6th National Audit Project of the Royal
health care system. Food-induced anaphylaxis can result in College of Anaesthetists reviewed 266 reports of grades 3 to 5
prehospital emergency care by ambulance personnel, ED visits, anaphylaxis across all UK National Health Service hospitals
hospitalizations, or even death. Mild as well as more over the course of 1 year, reporting prompt recognition and
severe allergic reactions require comprehensive evaluation, treatment of anaphylaxis in 83% of cases.108 Cardiac arrest
including diagnostic studies, and regular follow-up outpatient occurred in 15% of cases reviewed, with fatalities occurring in
visits.104 3.8% of patients.108 Risk factors for perioperative anaphylaxis
In 2011, Patel et al104 estimated total annual direct medical fatality included older age and cardiovascular disease.108
costs of food allergy and anaphylaxis at $225 million (2007 US ADRs from RCM occur less frequently now than they did prior
dollars). Office visits accounted for 52.5% of direct medical costs, to 1990 when patients received high-osmolar, ionic RCM. Prior
and the remaining was split among ED visits (20%), inpatient hos- ADRs to RCM can contribute to burden of disease by creating
pitalizations (11.8%), outpatient department visits (3.9%), ambu- medical complexity associated with premedication; however,
lance runs (3%), and epinephrine devices (8.7%). Children while glucocorticoid premedication has become common
accounted for 46.6% of the total inpatient costs, 31.5% of the practice for patients with prior RCM hypersensitivity, evidence
ED visit costs, 67.3% of the office visit costs, and 97.7% of the supporting the use of prophylaxis in high-risk patients receiving
total outpatient department visit costs. US national estimates for low- or iso-osmolar, nonionic contrast agents is lacking. ADRs
epinephrine auto-injector use after a suspected reaction triggered associated with RCM do not relate to iodine, and the term
by a food allergy obtained from the published literature suggest ‘‘iodine allergy’’ should not be used in the context of RCM
that between 30% and 86% of patients at risk for a severe allergic reactions.J ALLERGY CLIN IMMUNOL SHAKER ET AL 1091
VOLUME 145, NUMBER 4
Insect-venom anaphylaxis occurring in patients receiving chemotherapy suggests a mixed
Hymenoptera venom allergy (HVA) describes both anaphy- type of reaction with both features of IgE and non-IgE-
lactic and nonanaphylactic HSRs to stings. Reaction types dependent anaphylaxis.120 Cytokine storm-like reactions have
include sting-induced large local (LL) or systemic allergic recently been described for patients with chemotherapy-induced
reactions. LL reactions last over 24 hours in which signs and anaphylaxis.120
symptoms are confined to tissues contiguous with the sting site. In Animal and human studies have linked multiple mediators to
contrast to LL reactions, acute onset systemic reactions involve the signs and symptoms of anaphylaxis. The most important
generalized signs and symptoms and include a spectrum of effector cells involved in anaphylaxis are mast cells, but
manifestations, ranging from mild urticarial reactions to life- basophils, neutrophils, monocytes, macrophages, and platelets
threatening anaphylaxis. It is estimated that 2% to 3% of adults have also been implicated.118,121 Histamine is an important medi-
and up to 1% of children have had a systemic reaction to a sting, ator of anaphylaxis, and studies have demonstrated that intrave-
and LL reactions occur in >5% of adults.109 In a review of 10 nous histamine can induce symptoms of anaphylaxis, including
studies published between 2001 and 2009, Bilo et al110 found flushing, airway obstruction, systemic hypotension, and tachy-
that 23% of 2577 cases of anaphylaxis were caused by an insect cardia.122,123 While histamine appears to play a significant role,
sting. Fatal anaphylaxis can result from HVA; the reported other mediators have also been implicated. Therefore, pharmaco-
average of 40 deaths per year in the United States is highly logic targeting of histamine alone (eg, administration of antihista-
suspected to underestimate the true event rate.53,111 Even the first mines) is not appropriate and is thus considered second-line
reaction can be fatal, but no validated screening test is available treatment for anaphylaxis and should not be used in place of
because of the very high frequency of asymptomatic sensitization epinephrine. Given the slow onset of antihistamine agents, inef-
(>20% of adults have detectable venom-specific IgE).112,113 fectiveness in treating cardiovascular and respiratory symptoms
Patients often express fears of anaphylaxis because of their family such as hypotension or bronchospasm, and the inability to stabi-
history or atopic history, but HVA has not been shown to be lize or prevent mast cell degranulation, these agents should not
familial.112 delay definitive treatment of anaphylaxis.
Patients often present with concern about potential anaphylaxis Elevated tryptase levels have been less consistently found in
after having LL or generalized cutaneous systemic reaction.114 patients presenting with anaphylaxis, particularly in cases
The morbidity of living with HVA may be underestimated.114 triggered by allergic response to food.124 While the positive pre-
Fear of life-threatening anaphylaxis whenever one is outdoors, dictive value of an elevated serum tryptase is high (93%), the NPV
and the burden of ensuring that injectable epinephrine is readily of a serum tryptase is low (17%).2 However, several studies125-129
accessible at all times, affects the daily activities and level of have reported an association between elevation of tryptase and
stress in affected individuals.115 Even people with nonanaphylac- severity of anaphylaxis from food and other causes. In a study20
tic (LL or cutaneous systemic) reactions to stings share the same of prospectively recruited ED patients with anaphylaxis,
concerns and can be impacted as severely as the patients with mediators in addition to tryptase correlated with hypotension, a
anaphylactic reactions.114 These concerns persist in these mild symptom of severe anaphylaxis. These included histamine,
reactors even though their risk of severe anaphylaxis is quite IL-6, IL-10, and TNF-receptor 1.20,21 Several other mediators
low, and the prescription of injectable epinephrine is not have been shown to be important in murine models of
cost-effective in such cases.53 Whether it is mild or severe, anaphylaxis, but their contribution in human anaphylaxis has
HVA impairs long-term quality of life and may be a cause of not been clearly demonstrated—these include platelet-
substantial socioeconomic impairment.116 HVA can impact activating factor (PAF), cysteinyl LTs, and anaphylatoxins. PAF
career choices, especially in beekeepers, groundskeepers, is a lipid-derived mediator elevated in serum of patients with
gardeners, and greenhouse workers.117 HVA has important cold urticaria during cold challenge.130 The role of PAF is
adverse consequences in terms of employment, earning capacity, supported by studies demonstrating that injection of PAF into
and leisure and sporting activities.117 For these reasons, the skin of healthy volunteers can induce early wheal and flare
discussion of HVA usually includes not only anaphylactic, but and late-phase flare responses.131 These responses are not
also mild systemic and nonanaphylactic reactions.109 associated with increased dermal histamine levels,132 suggesting
that the effects of PAF are independent of mast cell degranulation.
While some evidence suggests antihistamine attenuation of
PATHOGENESIS OF ANAPHYLAXIS experimental intradermally injected PAF-mediated wheal and
Data regarding pathophysiologic mechanisms and effector flare response, antihistamines had no protective effect against
cells are limited on humans but mouse models have offered PAF-mediated bronchoconstriction during PAF bronchial provo-
some insight.118 IgE binding and cross-linking of FcεRI on the cation.133 Associations have been noted with increased PAF in
surface of mast cells and basophils is an important mechanism cases of anaphylaxis.125 In 1 study,134 increased PAF levels
in many cases of anaphylaxis. This causes the immediate release demonstrated the highest correlations with severe anaphylaxis
of preformed mediators, as well as de novo synthesis of inflamma- (when compared with histamine and tryptase levels), with PAF el-
tory mediators.18 Interestingly, some patients with life- evations in 20%, 67%, and 100% of patients with grades 1, 2, and
threatening anaphylaxis have low or undetectable circulating 3 allergic reactions, respectively (grade 1: acute allergic reactions
allergen-specific IgE and mouse models have demonstrated a po- with cutaneous signs and symptoms only; grade 2: mild to mod-
tential role for IgG-dependent anaphylaxis.19 Furthermore, the erate anaphylaxis; grade 3: severe anaphylaxis). Data to support
complement (C) system, anaphylatoxins C3a, C4a, C5a, and neu- the role of cysteinyl LTs stem from studies showing that intrader-
trophils119 have also been shown to be involved in anaphylaxis in mal injection of LTB4, LTC4, and LTD4 can induce wheal and
human subjects. Lastly, a newly recognized form of anaphylaxis flare responses135 and aerosolized LTC4 and LTD4 can triggerYou can also read
