Anaphylaxis—a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis

Anaphylaxis is an acute, potential life-threatening systemic allergic reaction that may have a wide range of clinical manifestations. Severe anaphylaxis and/or the need for repeated doses of epinephrine to treat anaphylaxis are risk factors for biphasic anaphylaxis. Antihistamines and/or glucocorticoids are not reliable interventions to prevent biphasic anaphylaxis, although evidence supports a role for antihistamine and/or glucocorticoid premedication in specific chemotherapy protocols and rush aeroallergen immunotherapy. Evidence is lacking to support the role of antihistamines and/or glucocorticoid routine premedication in patients receiving low- or iso-osmolar contrast material to prevent recurrent radiocontrast media anaphylaxis. Epinephrine is the first-line pharmacotherapy for uniphasic and/or biphasic anaphylaxis. After diagnosis and treatment of anaphylaxis, all patients should be kept under observation until symptoms have fully resolved. All patients with anaphylaxis should receive education on anaphylaxis and risk of recurrence, trigger avoidance, self-injectable epinephrine education, referral to an allergist, and be educated about thresholds for further care. Anaphylaxis is an acute, potential life-threatening systemic allergic reaction that may have a wide range of clinical manifestations. Severe anaphylaxis and/or the need for repeated doses of epinephrine to treat anaphylaxis are risk factors for biphasic anaphylaxis. Antihistamines and/or glucocorticoids are not reliable interventions to prevent biphasic anaphylaxis, although evidence supports a role for antihistamine and/or glucocorticoid premedication in specific chemotherapy protocols and rush aeroallergen immunotherapy. Evidence is lacking to support the role of antihistamines and/or glucocorticoid routine premedication in patients receiving low- or iso-osmolar contrast material to prevent recurrent radiocontrast media anaphylaxis. Epinephrine is the first-line pharmacotherapy for uniphasic and/or biphasic anaphylaxis. After diagnosis and treatment of anaphylaxis, all patients should be kept under observation until symptoms have fully resolved. All patients with anaphylaxis should receive education on anaphylaxis and risk of recurrence, trigger avoidance, self-injectable epinephrine education, referral to an allergist, and be educated about thresholds for further care. The Joint Task Force on Practice Parameters would like to dedicate this guideline to Chitra Dinakar for her ongoing contributions and dedication to the field of allergy and immunology. Anaphylaxis is an acute, life-threatening systemic allergic reaction that may have a wide range of clinical manifestations.1Wood R.A. Camargo Jr., C.A. Lieberman P. Sampson H.A. Schwartz L.B. Zitt M. et al.Anaphylaxis in America: the prevalence and characteristics of anaphylaxis in the United States.J Allergy Clin Immunol. 2014; 133: 461-467Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar The clinical criteria proposed in 2006 by National Institute of Allergy and Infectious Diseases (NIAID) continue to provide a helpful framework in approaching patients with acute allergic symptoms, because diagnosis and management of anaphylaxis must occur rapidly and confirmatory testing for anaphylaxis has poor sensitivity.2Buka R.J. Knibb R.C. Crossman R.J. Melchior C.L. Huissoon A.P. Hackett S. et al.Anaphylaxis and clinical utility of real-world measurement of acute serum tryptase in UK emergency departments.J Allergy Clin Immunol Pract. 2017; 5: 1280-1287.e2Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar While NIAID anaphylaxis diagnostic criteria have a sensitivity of 95% with a specificity of 71% in an emergency department (ED) setting,3Loprinzi Brauer C.E. Motosue M.S. Li J.T. Hagan J.B. Bellolio M.F. Lee S. et al.Prospective validation of the NIAID/FAAN criteria for emergency department diagnosis of anaphylaxis.J Allergy Clin Immunol Pract. 2016; 4: 1220-1226Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar fulfilling diagnostic criteria is not a prerequisite for epinephrine administration in a patient experiencing an acute allergic reaction. The lifetime prevalence of anaphylaxis has been estimated at 1.6% to 5.1%.1Wood R.A. Camargo Jr., C.A. Lieberman P. Sampson H.A. Schwartz L.B. 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Blumenstock J.A. Davis M.M. et al.Prevalence and severity of food allergies among US adults.JAMA Netw Open. 2019; 2: e185630Crossref PubMed Scopus (56) Google Scholar while adverse drug reactions (ADRs) affect up to 10% of the population (and 20% of hospitalized patients), with hypersensitivity reactions (HSRs) accounting for 10% of all ADRs.16World Allergy OrganizationWhite Book on Allergy: Update 2013, Executive Summary. World Allergy Organization, Milwaukee, WI2013Google Scholar Although medical complexity increases for patients with prior HSRs to radiocontrast media (RCM), fortunately the prevalence of RCM ADRs has decreased in recent decades.17Macy E.M. 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Human IgE-independent systemic anaphylaxis.J Allergy Clin Immunol. 2016; 137: 1674-1680Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar Anaphylaxis involves additional cell types that may include neutrophils, monocytes, macrophages, and platelets and signaling through mediators that include complement components, cysteinyl leukotrienes (LTs), platelet activating factor, IL-6, IL-10, and TNF-receptor 1.20Stone S.F. Cotterell C. Isbister G.K. Holdgate A. Brown S.G. Emergency Department Anaphylaxis InvestigatorsElevated serum cytokines during human anaphylaxis: identification of potential mediators of acute allergic reactions.J Allergy Clin Immunol. 2009; 124: 786-792.e4Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar,21Brown S.G. Stone S.F. Fatovich D.M. Burrows S.A. Holdgate A. 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Case fatality and population mortality associated with anaphylaxis in the United States.J Allergy Clin Immunol. 2014; 133: 1075-1083Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar Antihistamine agents are considered second-line treatment for anaphylaxis, given their slow onset of action and inability to stabilize or prevent mast cell degranulation or to target additional mediators of anaphylaxis.32Church M.K. Church D.S. Pharmacology of antihistamines.Indian J Dermatol. 2013; 58: 219-224Crossref PubMed Scopus (19) Google Scholar Unlike epinephrine, antihistamines will not effectively treat cardiovascular and respiratory symptoms such as hypotension or bronchospasm. Although glucocorticoids are frequently used as an adjunctive therapy for anaphylaxis, evidence is lacking to support clinical benefit, and they should not be administered in place of epinephrine in the treatment of acute anaphylaxis.33Inagaki N. Miura T. Nagai H. Koda A. Inhibitory effects of glucocorticoids on increased vascular permeability caused by passive cutaneous anaphylaxis and some chemical mediators in rats.Jpn J Pharmacol. 1988; 46: 189-192Crossref PubMed Scopus (13) Google Scholar,34Choo K.J. Simons F.E. Sheikh A. Glucocorticoids for the treatment of anaphylaxis.Evid Based Child Health. 2013; 8: 1276-1294Crossref PubMed Scopus (16) Google Scholar Biphasic anaphylaxis is recurrent anaphylaxis occurring 1 to 72 hours after resolution of an initial anaphylactic episode, though an outside limit of 78 hours has also been suggested.35Pourmand A. Robinson C. Syed W. Mazer-Amirshahi M. Biphasic anaphylaxis: a review of the literature and implications for emergency management.Am J Emerg Med. 2018; 36: 1480-1485Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar,36Lieberman P. 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Do corticosteroids prevent biphasic anaphylaxis?.J Allergy Clin Immunol Pract. 2017; 5: 1194-1205Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar Despite a lack of clear evidence supporting the role of antihistamines and glucocorticoids in anaphylaxis, these agents continue to be routinely used in anaphylaxis management. To evaluate the role for these second-line, supplemental therapies, the Joint Task Force on Practice Parameters (JTFPP) undertook a systematic review and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis of antihistamines and glucocorticoids in anaphylaxis. Specifically, the JTFPP sought to better inform the practice of anaphylaxis prevention in 2 broad topic areas through (1) identification and mitigation of risk factors for biphasic anaphylaxis and (2) evaluation of the use of supplemental glucocorticoid and/or antihistamine premedication (see Box 1). Although the goal of the JTFPP was to rigorously evaluate the literature to form evidence-based recommendations, there are limits to the available evidence in human anaphylaxis due to ethical considerations and the absence of double-blind studies in a potentially fatal, acute condition. This GRADE analysis incorporated the balance of relative benefits and harms of treatments under consideration, the certainty of the evidence, and the impact of patient preferences and values. Box 2 provides a summary of key clinical advice.Box 1Key questions assessed by this systematic review on anaphylaxisTopic area 1. Identification and mitigation of risk factors for biphasic anaphylaxisQuestion 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 anaphylaxisQuestion 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 reactions 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? Topic area 1. Identification and mitigation of risk factors for biphasic anaphylaxisQuestion 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 anaphylaxisQuestion 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 reactions 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? Recommendation 1. We suggest that a clinician incorporate severity of anaphylaxis presentation and/or the administration of >1 dose of epinephrine for the treatment of initial anaphylaxis as a guide to determining a patient’s risk for developing biphasic anaphylaxis. Conditional recommendation. Certainty rating of evidence: very low. Even though the ability to accurately predict which patients with resolved initial anaphylaxis will experience biphasic anaphylaxis is imperfect, an understanding of risk factors allows a more tailored approach to patient management. Risk factors also provide useful parameters to incorporate into decision making regarding duration of observation following initial resolution of anaphylaxis. The JTFPP findings suggest biphasic anaphylaxis is associated with a more severe initial presentation of anaphylaxis (odds ratio [OR], 2.11; 95% CI, 1.23-3.61) or repeated epinephrine doses (ie, >1 dose of epinephrine) required with the initial presentation (OR, 4.82; 95% CI, 2.70-8.58). Additional risk factors include wide pulse pressure (OR, 2.11; 95% CI, 1.32-3.37), unknown anaphylaxis trigger (OR, 1.63; 95% CI, 1.14-2.33), cutaneous signs and symptoms (OR, 2.54; 95% CI, 1.25-5.15), and drug trigger in children (OR, 2.35; 95% CI, 1.16-4.76). While presence of dyspnea on presentation was associated with a decreased risk for anaphylaxis, overall confidence in this estimate was low (OR, 0.6; 95% CI, 0.38-0.96). Prompt and adequate treatment of anaphylaxis appears central to reducing biphasic anaphylaxis risk, in the opinion of the JTFPP. While the possibility of biphasic anaphylaxis should be emphasized in this higher risk group, it is important to educate all patients regarding the chance of a biphasic reaction as well as avoiding known triggers, identification of symptoms of anaphylaxis, the use of auto-injector epinephrine for the treatment of anaphylaxis, and timely follow-up with an allergist. Recommendation 2. We suggest extended clinical observation in a setting capable of managing anaphylaxis (to detect a biphasic reaction) for patients with resolved severe anaphylaxis and/or those who need >1 dose of epinephrine. Conditional recommendation. Certainty rating of evidence: very low. While wide pulse pressures may be considered a marker for severe anaphylaxis, the clinician may also consider extended 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 be limited by the common occurrence of cutaneous signs and symptoms in patients presenting with anaphylaxis. The estimated number needed to monitor with extended observation to be able to detect 1 episode of biphasic anaphylaxis before discharge would be 41 (range, 18-195) for patients with a more severe initial presentation of anaphylaxis and 13 (range, 7-27) for patients with multiple epinephrine doses. The implication for the clinician, based on this systematic review and meta-analysis, is that the patient presenting with severe anaphylaxis and/or requiring more aggressive treatment (eg, >1 dose of epinephrine) should be considered for longer observation time for a potential biphasic reaction following complete resolution of signs and symptoms. At present, evidence is lacking to clearly define the optimal duration of observation (eg, number of hours) that would prove to be cost-effective for patients with initial resolution of severe anaphylaxis and/or those requiring multiple doses of epinephrine. However, for patients without severe risk features, discharge after a 1-hour asymptomatic observation may be reasonable. If the clinical impression is that a patient has a higher risk of biphasic reaction (ie, 17% or greater) or risk factors for anaphylaxis fatality (eg, cardiovascular comorbidity, lack of access to epinephrine, lack of access to emergency medical services (EMS), poor self-management skills), then extended observation of up to 6 hours or longer (including hospital admission) may be appropriate. Regardless of severity, after diagnosis and treatment of anaphylaxis, all patients should be kept under observation until signs and symptoms have fully resolved. Recommendation. We suggest against administering glucocorticoids or antihistamines as an intervention to prevent biphasic anaphylaxis. Conditional recommendation. Certainty rating of evidence: very low. Although we suggest against the use of antihistamines and/or glucocorticoids as an intervention to prevent biphasic anaphylaxis, these may be considered for the secondary treatment of anaphylaxis.45Campbell R.L. Li J.T. Nicklas R.A. Sadosty A.T. Emergency department diagnosis and treatment of anaphylaxis: a practice parameter.Ann Allergy Asthma Immunol. 2014; 113: 599-608Abstract Full Text Full Text PDF PubMed Google Scholar In particular, antihistamines may treat urticaria and itching to improve comfort during anaphylaxis, but if used prior to epinephrine administration, antihistamine administration could lead to a delay in first-line treatment of anaphylaxis. The JTFPP analysis did not identify clear benefit in prevention of biphasic anaphylaxis from histamine 1 (H1) antihistamines (OR, 0.71; 95% CI, 0.47-1.06), H2 antihistamines (OR, 1.21; 95% CI, 0.80-1.83), or glucocorticoids (OR, 0.87; 95% CI, 0.74-1.02). An interaction was identified between age and glucocorticoid use, with glucocorticoids actually increasing risk for biphasic anaphylaxis in children (OR, 1.55; 95% CI, 1.01-2.38); however, a confounding effect of severity could not be excluded. At a biphasic anaphylaxis patient expected event rate (PEER) of 5%, the number needed to treat (NNT) for H1 antihistamines and glucocorticoids is 72 and 161 to prevent 1 episode of biphasic anaphylaxis, with significant uncertainty in the estimate. Recommendation. We suggest in favor of administering glucocorticoids and/or antihistamines to prevent anaphylaxis or infusion-related reactions when indicated for specific agents in chemotherapy protocols. Conditional recommendation. Certainty rating of evidence: very low. The JTFPP analysis did identify a significant change in rates of anaphylaxis and/or infusion reactions for some chemotherapy protocols. The use of premedication was associated with a decreased rate of HSRs for chemotherapy (OR, 0.49; 95% CI, 0.37-0.66). In contrast to chemotherapy premedication, benefit was not observed when using premedication to prevent anaphylaxis in the setting of infliximab without prior reaction to the administered agent (relative risk [RR], 1.58; 95% CI, 0.87-2.87). We did not evaluate premedication in the context of desensitization to chemotherapy agents and to monoclonal antibodies. Furthermore, the use of premedication in patients who had previously experienced anaphylaxis from these agents was not evaluated. Recommendation. We suggest against routinely administering glucocorticoids and/or antihistamines to prevent anaphylaxis in patients with prior radiocontrast HSRs when readministration of a low- or iso-osmolar, nonionic RCM agent is required. Conditional recommendation. Certainty rating of evidence: very low. The JTFPP analysis did not identify significant benefit from the use of premedication prior to RCM administration to prevent anaphylaxis (RR, 1.07; 95% CI, 0.67-1.71). The absence of benefit of premedication in patients with prior immediate HSRs to 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, where premedication may add value to management.17Macy E.M. Current epidemiology and management of radiocontrast-associated acute- and delayed-onset hypersensitivity: a review of the literature.Perm J. 2018; 22: 17-072PubMed Google Scholar Given the diversity of clinical circumstances evaluated and low confidence in the literature base, higher certainty evidence is needed to better inform practice, and future recommendations could potentially change as a result of new information. As such, clinicians may reasonably consider premedication in clinical circumstances associated with a high level of perceived risk of anaphylaxis or comorbidities associated with greater anaphylaxis fatality risk (such as underlying cardiovascular disease, use of beta-blockers, or prior severe anaphylaxis), although evidence is lacking to clearly support this practice. This analysis evaluated patients with both mild and severe prior RCM reactions, but we were unable to stratify prophylaxis by severity of index reaction. Furthermore, only low- and iso-osmolar nonionic radiocontrast agents were evaluated because these are the most commonly used agents at present. This recommendation does not apply to patients receiving high-osmolar contrast agents for whom prophylaxis may be appropriate in some circumstances. Recommendation. We suggest the administration of glucocorticoids and/or antihistamines as an intervention to prevent anaphylaxis in patients undergoing aeroallergen rush immunotherapy (RIT). Conditional recommendation. Certainty rating of evidence: very low. Evidence suggests that in the setting of aeroallergen RIT, premedication may provide value in reducing systemic reactions and anaphylaxis (immunotherapy analysis including RIT: RR, 0.62; 95% CI, 0.41-0.94). The evidence base for premedication before conventional aeroallergen immunotherapy is limited; however, 1 study46Ohashi Y. Nakai Y. Murata K. Effect of pretreatment with fexofenadine on the safety of immunotherapy in patients with allergic rhinitis.Ann Allergy Asthma Immunol. 2006; 96: 600-605Abstract Full Text PDF PubMed Scopus (41) Google Scholar suggested some benefit with fexofenadine pretreatment 2 hours before conventional immunotherapy using cedar pollen or dust mite allergens. The JTFPP is unable to exclude the possibility that specific situations and subpopulations may exist where premedication could provide benefit to immunotherapy in those with concomitant risk factors (eg, in situations associated with higher rates of systemic reactions). As such, clinicians may reasonably consider immunotherapy premedication in other clinical circumstances associated with a high level of perceived risk of anaphylaxis or comorbidities associated with greater anaphylaxis fatality risk (such as underlying cardiovascular disease or use of beta-blockers), although high-certainty evidence is lacking to support this practice. Good practice statement 1. Administer epinephrine as the first-line pharmacotherapy for uniphasic and/or biphasic anaphylaxis.Good practice statement 2. Do not delay the administration of epinephrine for anaphylaxis, as doing so may be associated with higher morbidity and mortality.Good practice statement 3. After diagnosis and treatment of anaphylaxis, all patients should be kept under observation in a setting capable of managing anaphylaxis until symptoms have fully resolved.Good practice statement 4. All patients with anaphylaxis should receive education on anaphylaxis, including avoidance of identified triggers, presenting signs and symptoms, biphasic anaphylaxis, treatment with epinephrine, and the use of epinephrine auto-injectors, and they should be referred to an allergist. Of note, there may be some circumstances where self-injectable epinephrine is deferred (ie, resolved anaphylaxis and drug trigger with high likelihood of successful avoidance) and shared decision making may play a role in some circumstances.Box 2Suggested key clinical advice•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.•Extended observation is suggested for patients with resolved severe anaphylaxis and/or those with need for >1 dose of epinephrine.•Antihistamines and/or glucocorticoids are not reliable interventions to prevent biphasic anaphylaxis but may be considered as secondary treatment.•Evidence supports a role for antihistamine and/or glucocorticoid premedication in specific chemotherapy protocols and rush aeroallergen immunotherapy.•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.•Administer epinephrine as the first-line pharmacotherapy for uniphasic and/or biphasic anaphylaxis.•Do not delay the administration of epinephrine for anaphylaxis.•After diagnosis and treatment of anaphylaxis, all patients should be kept under observation until symptoms have fully resolved.•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. •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.•Extended observation is suggested for patients with resolved severe anaphylaxis and/or those with need for >1 dose of epinephrine.•Antihistamines and/or glucocorticoids are not reliable interventions to prevent biphasic anaphylaxis but may be considered as secondary treatment.•Evidence supports a role for antihistamine and/or glucocorticoid premedication in specific chemotherapy protocols and rush aeroallergen immunotherapy.•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.•Administer epinephrine as the first-line pharmacotherapy for uniphasic and/or biphasic anaphylaxis.•Do not delay the administration of epinephrine for anaphylaxis.•After diagnosis and treatment of anaphylaxis, all patients should be kept under observation until symptoms have fully resolved.•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.