Updated guidance regarding the risk of allergic reactions to COVID-19 vaccines and recommended evaluation and management: A GRADE assessment and international consensus approach
2023; Elsevier BV; Volume: 152; Issue: 2 Linguagem: Inglês
10.1016/j.jaci.2023.05.019
ISSN1097-6825
AutoresMatthew Greenhawt, Timothy E. Dribin, Elissa M. Abrams, Marcus Shaker, Derek K. Chu, David B.K. Golden, Cem Akin, Aikaterini Anagnostou, Faisal ALMuhizi, Waleed Alqurashi, Peter D. Arkwright, James L. Baldwin, Aleena Banerji, Philippe Bégin, Moshe Ben‐Shoshan, Jonathan A. Bernstein, Theresa Bingemann, Carsten Bindslev‐Jensen, Kim Blumenthal, Aideen Byrne, J. Cahill, Scott B. Cameron, Dianne E. Campbell, Ronna L. Campbell, Michael Cavender, Edmond S. Chan, R. Sharon Chinthrajah, Pasquale Comberiati, Jacqueline J. Eastman, Anne K. Ellis, David M. Fleischer, Adam Fox, Pamela A. Frischmeyer‐Guerrerio, Rémi Gagnon, Lene H. Garvey, Mitchell H. Grayson, Ghislaine Annie Clarisse Isabwe, Nicholas Hartog, David Hendron, Caroline C. Horner, Johnathan O'B Hourihane, E.A. Ba, Manstein Kan, Blanka Kaplan, Constance H. Katelaris, Harold Kim, John M. Kelso, David A. Khan, David M. Lang, Dennis K. Ledford, Michael Levin, Phil Lieberman, Richard Loh, Douglas P. Mack, Bruce Mazer, K Mody, G. Mosnaim, Daniel Munblit, S. Shahzad Mustafa, Anil Nanda, Richard Nathan, John Oppenheimer, Iris M. Otani, Miguel Park, Ruby Pawankar, Kirsten P. Perrett, Jonny Peter, Elizabeth H. Phillips, Matthieu Picard, Mitchell M. Pitlick, Allison Ramsey, Trine Holm Rasmussen, Melinda M. Rathkopf, Hari Reddy, Kara Robertson, Pablo Rodríguez del Río, Stephen Sample, Ajay Sheshadri, Javed Sheik, Sayantani Sindher, Jonathan M. Spergel, Cosby A. Stone, David R. Stukus, Mimi L.K. Tang, James M. Tracy, Paul Turner, Timothy K. Vander Leek, Dana Wallace, Julie Wang, Susan Wasserman, David Weldon, Anna R. Wolfson, Margitta Worm, Mona‐Rita Yacoub,
Tópico(s)Drug-Induced Adverse Reactions
ResumoThis guidance updates 2021 GRADE (Grading of Recommendations Assessment, Development and Evaluation) recommendations regarding immediate allergic reactions following coronavirus disease 2019 (COVID-19) vaccines and addresses revaccinating individuals with first-dose allergic reactions and allergy testing to determine revaccination outcomes. Recent meta-analyses assessed the incidence of severe allergic reactions to initial COVID-19 vaccination, risk of mRNA-COVID-19 revaccination after an initial reaction, and diagnostic accuracy of COVID-19 vaccine and vaccine excipient testing in predicting reactions. GRADE methods informed rating the certainty of evidence and strength of recommendations. A modified Delphi panel consisting of experts in allergy, anaphylaxis, vaccinology, infectious diseases, emergency medicine, and primary care from Australia, Canada, Europe, Japan, South Africa, the United Kingdom, and the United States formed the recommendations. We recommend vaccination for persons without COVID-19 vaccine excipient allergy and revaccination after a prior immediate allergic reaction. We suggest against >15-minute postvaccination observation. We recommend against mRNA vaccine or excipient skin testing to predict outcomes. We suggest revaccination of persons with an immediate allergic reaction to the mRNA vaccine or excipients be performed by a person with vaccine allergy expertise in a properly equipped setting. We suggest against premedication, split-dosing, or special precautions because of a comorbid allergic history. This guidance updates 2021 GRADE (Grading of Recommendations Assessment, Development and Evaluation) recommendations regarding immediate allergic reactions following coronavirus disease 2019 (COVID-19) vaccines and addresses revaccinating individuals with first-dose allergic reactions and allergy testing to determine revaccination outcomes. Recent meta-analyses assessed the incidence of severe allergic reactions to initial COVID-19 vaccination, risk of mRNA-COVID-19 revaccination after an initial reaction, and diagnostic accuracy of COVID-19 vaccine and vaccine excipient testing in predicting reactions. GRADE methods informed rating the certainty of evidence and strength of recommendations. A modified Delphi panel consisting of experts in allergy, anaphylaxis, vaccinology, infectious diseases, emergency medicine, and primary care from Australia, Canada, Europe, Japan, South Africa, the United Kingdom, and the United States formed the recommendations. We recommend vaccination for persons without COVID-19 vaccine excipient allergy and revaccination after a prior immediate allergic reaction. We suggest against >15-minute postvaccination observation. We recommend against mRNA vaccine or excipient skin testing to predict outcomes. We suggest revaccination of persons with an immediate allergic reaction to the mRNA vaccine or excipients be performed by a person with vaccine allergy expertise in a properly equipped setting. We suggest against premedication, split-dosing, or special precautions because of a comorbid allergic history. Through March 2023, the novel severe acute respiratory syndrome novel coronavirus 2 (SARS-CoV-2) coronavirus and subsequent coronavirus disease 2019 (COVID-19) global pandemic has caused over 676 million infections and 6.8 million fatalities.1Johns Hopkins University Coronavirus Resource Center.https://coronavirus.jhu.edu/map.htmlDate accessed: October 28, 2022Google Scholar Multiple efficacious COVID-19 vaccines have been available since December 2020.2Status of COVID-19 vaccines within WHO EUL/PQ evaluation process. World Health Organization; 2022.https://extranet.who.int/pqweb/sites/default/files/documents/Status_COVID_VAX_02April2022.pdfDate accessed: April 13, 2022Google Scholar The rare occurrence of severe immediate allergic reactions to these vaccines raised initial concern about the potentially allergenic role of vaccine excipients, polyethylene glycol (PEG) in the mRNA vaccines and polysorbate 80 (PS) in the viral vector vaccines, and the need for allergy screening for possible risk factors for allergic reactions.3Banerji A. Wolfson A.R. Wickner P.G. Cogan A.S. McMahon A.E. Saff R. et al.COVID-19 vaccination in patients with reported allergic reactions: updated evidence and suggested approach.J Allergy Clin Immunol Pract. 2021; 9: 2135-2138Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 4Banerji A. Wickner P.G. Saff R. Stone Jr., C.A. Robinson L.B. Long A.A. et al.mRNA vaccines to prevent COVID-19 disease and reported allergic reactions: current evidence and suggested approach.J Allergy Clin Immunol Pract. 2021; 9: 1423-1437Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar, 5Greenhawt M. Abrams E.M. Shaker M. Chu D.K. Khan D. Akin C. et al.The risk of allergic reaction to SARS-CoV-2 vaccines and recommended evaluation and management: a systematic review, meta-analysis, GRADE assessment, and international consensus approach.J Allergy Clin Immunol Pract. 2021; 9: 3546-3567Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 6Klimek L. Jutel M. Akdis C.A. Bousquet J. Akdis M. Torres M.J. et al.ARIA-EAACI statement on severe allergic reactions to COVID-19 vaccines: an EAACI-ARIA Position Paper.Allergy. 2021; 76: 1624-1628Crossref PubMed Scopus (66) Google Scholar In mid-2021, a systematic review and meta-analysis facilitated preliminary GRADE (Grading of Recommendations Assessment, Development, and Evaluation)-based guidelines addressing immediate, presumed allergic, reactions following the mRNA COVID-19 vaccines (BNT162b2 or mRNA-1273), noting a rare incidence of immediate severe (eg, anaphylaxis) first-dose reactions (eg, occurring within 4 hours of administration as per the 2007 Brighton Collaboration criteria [BCC] definition),7Ruggeberg J.U. Gold M.S. Bayas J.M. Blum M.D. Bonhoeffer J. Friedlander S. et al.Anaphylaxis: case definition and guidelines for data collection, analysis, and presentation of immunization safety data.Vaccine. 2007; 25: 5675-5684Crossref PubMed Scopus (309) Google Scholar a low baseline PEG allergy prevalence, and poor test sensitivity for PEG as a skin testing reagent in assessing suspected non–COVID-19 vaccine and medication allergy.5Greenhawt M. Abrams E.M. Shaker M. Chu D.K. Khan D. Akin C. et al.The risk of allergic reaction to SARS-CoV-2 vaccines and recommended evaluation and management: a systematic review, meta-analysis, GRADE assessment, and international consensus approach.J Allergy Clin Immunol Pract. 2021; 9: 3546-3567Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar There were scant data available to analyze the risk of severe second-dose allergic reactions in individuals with first-dose reactions or to assess the predictive accuracy of vaccine or vaccine excipient skin testing for vaccine allergic reactions. Though immediate, severe COVID-19 vaccine allergic reactions occur rarely, many health authorities around the world contraindicate vaccinating persons with a history of allergy to the vaccine or its excipient.5Greenhawt M. Abrams E.M. Shaker M. Chu D.K. Khan D. Akin C. et al.The risk of allergic reaction to SARS-CoV-2 vaccines and recommended evaluation and management: a systematic review, meta-analysis, GRADE assessment, and international consensus approach.J Allergy Clin Immunol Pract. 2021; 9: 3546-3567Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar However, this may not be necessary in the majority of instances. Additional data have emerged since the 2021 publication, providing evidence to evolve recommendations made earlier in the pandemic. This updated guidance specifically focuses on the approach to assessing a patient with a history of mRNA COVID-19 excipient allergy or an immediate presumed allergic reaction to a dose of a mRNA COVID-19 vaccine, in determining whether an initial or additional doses should be given and how to assess such patients. Following previously published methodology,5Greenhawt M. Abrams E.M. Shaker M. Chu D.K. Khan D. Akin C. et al.The risk of allergic reaction to SARS-CoV-2 vaccines and recommended evaluation and management: a systematic review, meta-analysis, GRADE assessment, and international consensus approach.J Allergy Clin Immunol Pract. 2021; 9: 3546-3567Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar we convened an ad hoc international panel of 94 clinical experts in allergy, anaphylaxis, vaccinology, infectious diseases, emergency medicine, and primary care from Australia, Canada, Europe, Japan, South Africa, the United Kingdom, and the United States to evaluate the current evidence regarding mRNA COVID-19 vaccination or revaccination in the context of suspected immediate vaccine or excipient allergy, and the utility of approaches such as vaccine or excipient skin testing in evaluating persons with an immediate, presumed allergic reaction to a mRNA COVID-19 vaccine or excipient from a societal perspective. The choice of questions and topics addressed in this document were intended to update the 2021 review (including the limitations, table of knowledge gaps, and feedback received on this document), which was planned as a living systematic review. Final selection of topics addressed was at the purview of the senior authors (M.G., M.S., E.A., D.G., D.C.). Data sources included published systematic reviews and meta-analyses (through the fall of 2022) assessing the risk of initial- and recurrent-dose reactions, and the accuracy of vaccine and vaccine excipient allergy skin testing (prick and intradermal testing combined) in predicting these risks.5Greenhawt M. Abrams E.M. Shaker M. Chu D.K. Khan D. Akin C. et al.The risk of allergic reaction to SARS-CoV-2 vaccines and recommended evaluation and management: a systematic review, meta-analysis, GRADE assessment, and international consensus approach.J Allergy Clin Immunol Pract. 2021; 9: 3546-3567Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar,8Greenhawt M. Shaker M. Golden D.B.K. Abrams E.M. Blumenthal K.G. Wolfson A.R. et al.Diagnostic accuracy of vaccine and vaccine excipient testing in the setting of allergic reactions to COVID-19 vaccines: a systematic review and meta-analysis.Allergy. 2023; 78: 71-83Crossref PubMed Scopus (12) Google Scholar,9Chu D.K. Abrams E.M. Golden D.B.K. Blumenthal K.G. Wolfson A.R. Stone Jr., C.A. et al.Risk of second allergic reaction to SARS-CoV-2 vaccines: a systematic review and meta-analysis.JAMA Intern Med. 2022; 182: 376-385Crossref PubMed Scopus (52) Google Scholar A primary draft was developed by the senior authors using the GRADE format for evidence synthesis from an individual perspective with secondary consideration for the health care perspective (see Table E1 in this article’s Online Repository at www.jacionline.org).10Chu D.K. Golden D.B.K. Guyatt G.H. Translating evidence to optimize patient care using GRADE.J Allergy Clin Immunol Pract. 2021; 9: 4221-4230Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 11Brozek J.L. Akl E.A. Alonso-Coello P. Lang D. Jaeschke R. Williams J.W. et al.Grading quality of evidence and strength of recommendations in clinical practice guidelines. Part 1 of 3. An overview of the GRADE approach and grading quality of evidence about interventions.Allergy. 2009; 64: 669-677Crossref PubMed Scopus (495) Google Scholar, 12Brozek J.L. Akl E.A. Jaeschke R. Lang D.M. Bossuyt P. Glasziou P. et al.Grading quality of evidence and strength of recommendations in clinical practice guidelines: Part 2 of 3. The GRADE approach to grading quality of evidence about diagnostic tests and strategies.Allergy. 2009; 64: 1109-1116Crossref PubMed Scopus (180) Google Scholar, 13Brozek J.L. Akl E.A. Compalati E. Kreis J. Terracciano L. Fiocchi A. et al.Grading quality of evidence and strength of recommendations in clinical practice guidelines. Part 3 of 3. The GRADE approach to developing recommendations.Allergy. 2011; 66: 588-595Crossref PubMed Scopus (182) Google Scholar This draft was revised iteratively by the work group, and a modified Delphi panel was used to rate agreement and consensus with the text and recommendations (1 = strongly disagree, 2 = disagree, 3 = neutral, 4 = agree, 5 = strongly agree, 80% threshold for agreement), as previously described.5Greenhawt M. Abrams E.M. Shaker M. Chu D.K. Khan D. Akin C. et al.The risk of allergic reaction to SARS-CoV-2 vaccines and recommended evaluation and management: a systematic review, meta-analysis, GRADE assessment, and international consensus approach.J Allergy Clin Immunol Pract. 2021; 9: 3546-3567Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar,14Harris P.A. Taylor R. Thielke R. Payne J. Gonzalez N. Conde J.G. Research electronic data capture (REDCap): a metadata-driven methodology and workflow process for providing translational research informatics support.J Biomed Inform. 2009; 42: 377-381Crossref PubMed Scopus (26948) Google Scholar The guidance statements and recommendations are presented in Table I. The GRADE strength of recommendations and certainty of evidence are summarized in Tables II and III, and the risk of bias assessment in Table E2 in this article’s Online Repository at www.jacionline.org (the risk of bias for any meta-analysis was included as it was originally published). The Evidence to Decision Framework in this article’s Online Repository (available at www.jacionline.org) provides a summary reflection of the evidence in the context of the clinical recommendation. The modified Delphi panel results for each recommendation are shown in Table E3 in this article’s Online Repository at www.jacionline.org. All questions presume a patient is seeking either initial mRNA-COVID-19 vaccination or revaccination after an immediate presumed allergic reaction to a prior dose, or that the patient is allergic to a vaccine excipient, in the setting of shared decision-making with a medical professional willing to provide supervised vaccination. A full description of the methods is detailed in in this article’s Online Repository.Table IGRADE recommendationsQuestionsRecommendationEvidence strengthEvidence certainty1. What is the risk of COVID-19 vaccine anaphylaxis in a patient with no history of anaphylaxis to a COVID-19 vaccine or its excipients?1a. For patients with no history of a previous allergic reaction to a COVID-19 vaccine or its excipients, the risk of first-dose COVID-19 vaccine-induced anaphylaxis is exceptionally low, and we recommend vaccination over either no vaccination or vaccine deferral.StrongHigh1b. For patients with a history of a severe allergic reaction, including anaphylaxis, unrelated to a mRNA COVID-19 vaccine or vaccine excipient, we suggest against additional postvaccination observation beyond standard wait time (eg, 15 minutes).ConditionalLow2. In patients without a history of anaphylaxis to a mRNA COVID-19 vaccine or its excipients, should allergy skin testing to mRNA COVID-19 vaccines or its excipients be performed prior to initial mRNA COVID-19 vaccination?2. For patients without a history of an immediate allergic reaction to mRNA COVID-19 vaccine or its excipients, we recommend against vaccine or vaccine excipient testing to attempt to predict the rare individual who will have a severe allergic reaction to a vaccine dose.StrongLow3. Can additional supervised doses of mRNA COVID-19 vaccines be administered to a patient who had an immediate allergic reaction of any severity following the first vaccine dose?3. We recommend that individuals who had an immediate allergic reaction of any severity to their first mRNA COVID-19 vaccine dose can receive additional doses, and those with a history of an immediate allergic reaction of any severity to its excipients can receive either their initial or additional mRNA COVID-19 vaccine doses.StrongModerate4. In a patient with a history of an immediate allergic reaction of any severity to a previous mRNA COVID-19 vaccine or its excipients, should allergy skin testing to mRNA COVID-19 vaccines or their excipients be performed to determine whether a future dose of vaccine should be withheld?4. For individuals with a history of an immediate allergic reaction to mRNA COVID-19 vaccine or its excipients, we recommend against performing skin testing using any mRNA-COVID-19 vaccine or its excipients for the purpose of risk assessment to determine whether they should receive a vaccine dose.StrongModerate5. In a patient with a history of an immediate allergic reaction of any severity to a previous mRNA COVID-19 vaccine or its excipients, what is the most appropriate setting for these individuals to receive their vaccination?5. We suggest referral to an allergist (or other clinician with expertise in the management of vaccine allergy and allergic reactions) for assessment and supervised vaccination of such individuals for their initial dose or for the subsequent dose after a reaction to a prior dose.ConditionalModerate6. Should a patient with a history of an immediate allergic reaction to the vaccine or vaccine excipient be premedicated prior to receiving their vaccine to prevent a severe allergic reaction?6. We suggest against routine H1-antihistamine or systemic corticosteroid premedication prior to vaccination to prevent anaphylaxis.ConditionalLow7. Should a patient with a history of an immediate allergic reaction to the vaccine or vaccine excipient receive their vaccine as a graded dose rather than a single dose?7. We suggest against graded dosing or stepwise desensitization compared to a single dose.ConditionalLowSummary of GRADE recommendations regarding the management of primary COVID-19 vaccination and mRNA-COVID-19 revaccination in persons with a known or suspected history of allergy to the vaccine excipients (primary, revaccination) or to the vaccine (revaccination). Open table in a new tab Table IIGRADE certainty of evidence table for questions regarding reaction incidenceFor questions related to reaction ratesNo. of studiesCertainty assessmentEffectCertaintyImportanceQuestion/outcome assessedStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsNo. of eventsNo. of individualsRate (95% CI)Question 1. What is the risk of COVID-19 vaccine anaphylaxis in a patient with no history of anaphylaxis to a COVID-19 vaccine or its excipients?47Observational studies and RCTsNot seriousNot serious∗Nonadjudicated rates yield estimates that are higher than adjudicated ones by about 5-fold.†One adjudicated study yielded a markedly higher estimate than all others. It also was the only study that was not a national pharmacovigilance study. Though it contributed to some heterogeneity, it was not felt that this was so serious to rate down for inconsistency because the (1) estimate of effect was still rare, (2) excluding this study, yielding a pooled estimate of 6.43 (95% CI: 3.57-11.56) events per million doses was not importantly different in terms of rarity, (3) that this study was balanced by other studies with 0 events, and (4) visual inspection did not reveal serious inconsistency.Not seriousNot seriousNone674 (208)‡Values in parentheses are data restricted to studies with 20,000 or more doses.57,089,598 (41,018,326)‡Values in parentheses are data restricted to studies with 20,000 or more doses.Event rate‡Values in parentheses are data restricted to studies with 20,000 or more doses. per 7.911,000,000 (4.02-15.59)⨁⨁⨁⨁HighCriticalQuestion 3. Can additional supervised doses of mRNA COVID-19 vaccines be administered to a patient who had an immediate allergic reaction of any severity following the first dose of the vaccine?a) What is the incidence of anaphylaxis to a second SARS-CoV-2 vaccination in persons who had an allergic reaction to their first dose?22Case studies and case reportsNot serious§Risk of bias addressed in subgroup and sensitivity analyses.Not seriousNot seriousNot seriousLarge effect of tolerating and residual confounding would suggest an effect of reacting when none was detectedA history of allergic reaction to previous COVID vaccination was a priori thought to guarantee a reaction to repeated doses, but far fewer than all individuals that received the second dose had an allergic reaction or anaphylaxis. Furthermore, those being revaccinated, after an initial allergic reaction, would be at higher likelihood to be intensely monitored for any possible allergic reaction, whereas those without any history of an allergic reaction would not be.613660.16% (0.01%-2.91%)⨁⨁⨁◯ModerateCriticalb) What is the incidence of anaphylaxis to a second SARS-CoV-2 vaccination in persons who had an anaphylaxis to their first dose?17Case studies and case reportsNot serious§Risk of bias addressed in subgroup and sensitivity analyses.Not seriousNot seriousNot serious¶Imprecision in width of CIs and total sample size sufficient to prevent rating up certainty for considerations of residual confounding, but not to rate down; the qualitative effect of the incidence of repeat anaphylaxis being not very high (eg, 100%) is more certain than the quantitative estimate of a mean of 4.94%.Large effect of tolerating and residual confounding would suggest an effect of reacting when none was detectedA history of allergic reaction to previous COVID vaccination was a priori thought to guarantee a reaction to repeated doses, but far fewer than all individuals that received the second dose had an allergic reaction or anaphylaxis. Furthermore, those being revaccinated, after an initial allergic reaction, would be at higher likelihood to be intensely monitored for any possible allergic reaction, whereas those without any history of an allergic reaction would not be.¶Imprecision in width of CIs and total sample size sufficient to prevent rating up certainty for considerations of residual confounding, but not to rate down; the qualitative effect of the incidence of repeat anaphylaxis being not very high (eg, 100%) is more certain than the quantitative estimate of a mean of 4.94%.4784.94% (0.93%-22.28%)⨁⨁◯◯LowCriticalc) What is the incidence of mild allergic symptoms to a second SARS-CoV-2 vaccination in persons who had an allergic reaction to their first dose?22Case studies and case reportsNot serious§Risk of bias addressed in subgroup and sensitivity analyses.Not seriousNot seriousNot seriousLarge effect of tolerating and residual confounding would suggest an effect of reacting when none was detectedA history of allergic reaction to previous COVID vaccination was a priori thought to guarantee a reaction to repeated doses, but far fewer than all individuals that received the second dose had an allergic reaction or anaphylaxis. Furthermore, those being revaccinated, after an initial allergic reaction, would be at higher likelihood to be intensely monitored for any possible allergic reaction, whereas those without any history of an allergic reaction would not be.232136613.5% (7.66%-22.27%)⨁⨁⨁◯ModerateCriticalGRADE summary of the certainty of evidence for questions 1 and 3, which deal with the prevalence of first dose (all COVID-19 vaccine types) and incidence of second dose (mRNA-COVID-19 vaccine only) presumed allergic reactions.RCT, Randomized clinical trial; SARS-CoV-2, severe acute respiratory syndrome novel coronavirus 2.∗ Nonadjudicated rates yield estimates that are higher than adjudicated ones by about 5-fold.† One adjudicated study yielded a markedly higher estimate than all others. It also was the only study that was not a national pharmacovigilance study. Though it contributed to some heterogeneity, it was not felt that this was so serious to rate down for inconsistency because the (1) estimate of effect was still rare, (2) excluding this study, yielding a pooled estimate of 6.43 (95% CI: 3.57-11.56) events per million doses was not importantly different in terms of rarity, (3) that this study was balanced by other studies with 0 events, and (4) visual inspection did not reveal serious inconsistency.‡ Values in parentheses are data restricted to studies with 20,000 or more doses.§ Risk of bias addressed in subgroup and sensitivity analyses.|| A history of allergic reaction to previous COVID vaccination was a priori thought to guarantee a reaction to repeated doses, but far fewer than all individuals that received the second dose had an allergic reaction or anaphylaxis. Furthermore, those being revaccinated, after an initial allergic reaction, would be at higher likelihood to be intensely monitored for any possible allergic reaction, whereas those without any history of an allergic reaction would not be.¶ Imprecision in width of CIs and total sample size sufficient to prevent rating up certainty for considerations of residual confounding, but not to rate down; the qualitative effect of the incidence of repeat anaphylaxis being not very high (eg, 100%) is more certain than the quantitative estimate of a mean of 4.94%. Open table in a new tab Table IIIGRADE certainty of evidence table for questions regarding diagnostic test accuracyFor questions related to diagnostic testingQuestion/outcome assessedNo. of studies (No. of patients)Study designFactors that may decrease certainty of evidenceEffect per 1000 patients testedTest accuracy CoERisk of biasIndirectnessInconsistencyImprecisionPublication biasPretest probability 0.001%Pretest probability 1%Pretest probability 10%Question 2. In patients without a history of anaphylaxis to mRNA COVID-19 vaccine or its excipients, should allergy skin testing to mRNA COVID-19 vaccines excipients be performed prior to initial mRNA vaccination?Sn: 0.59 (95% CI: 0.44-0.72), Sp: 0.99 (95% CI: 0.98-1.00), Prevalence: 0.001%, 1%, 10%True positives (patients with excipient allergy)15 studies296 patientsCohort and case-control type studiesSerious∗These were all case reports, with nonrandom selection of cases and controls.Serious†Challenges to the agents were not performed to confirm accuracy of the testing.Not serious‡Different agents and methods were used for testing and reported positives from these tests.Not serious§Low numbers of cases were tested to derive these estimates.Publication bias strongly suspected all plausible residual confounding would reduce the demonstrated effect0 (0-0)6 (1-8)64 (5-76)⨁⨁◯◯LowFalse negatives (patients incorrectly classified as not having excipient allergy)0 (0-0)4 (2-9)36 (24-95)True negatives (patients without excipient allergy)995 (977-999)985 (967-989)896 (879-899)False positives (patients incorrectly classified as having excipient allergy)5 (1-23)5 (1-23)4 (1-21)Question 4. In a patient with a history of an immediate allergic reaction of any severity to a previous mRNA COVID-19 vaccine or its excipients, should allergy skin testing to mRNA COVID-19 vaccines or their excipients be performed to determine if a future dose of vaccine should be withheld?For any testing agent, combined: Sn: 0.03 (95% CI: 0.00-0.08), Sp: 0.98 (95% CI: 0.95-1), Prevalence second-dose reaction: 0.16%Pretest probability 0.16%True positives (vaccine allergic)20 studies93 patientsCohort and case seriesNot seriousNot seriousNot seriousSeriousBias is suspected as authors are more likely to report.None0 (0-0)⨁⨁⨁◯ModerateFalse negatives (misclassified not allergic)2 (2-2)True negatives (not vaccine allergic)20 studies485 patientsCohort and case series976 (944-996)False positives (misclassified vaccine allergic)22 (2-54)For either mRNA vaccine agent: Sn: 0.2 (95% CI: 0.01-0.52), Sp: 0.97 (95% CI: 0.9-1), Prevalence second-dose reactions: 0.16%Pretest probability 0.16%True positives (vaccine allergic)14 studies14 patientsCohort and case seriesNot seriousNot seriousNot seriousVery seriousBias is suspected as authors are more likely to report.None0 (0 to 0)⨁⨁◯◯LowFalse negatives (misclassified not allergic)2 (2-2)True negatives (not vaccine allergic)14 studies103 patientsCohort and case series964 (854-998)False positives (misclassified vaccine allergic)34 (0-144)For PEG: Sn: 0.02 (95% CI: 0-0.07), Sp: 0.99 (95% CI: 0.95-1), Prevalence second-dose reactions: 0.16%Pretest probability 0.16%True positives (vaccine allergic)19 studies46 patientsCohort and case seriesNot seriousNot seriousNot seriousSeriousBias is suspected as authors are more likely to report.None0 (0-0)⨁⨁⨁◯ModerateFalse negatives (misclassified not allergic)2 (2-2)True negatives (not vaccine allergic)19 studies251 patientsCohort and case series985 (947-998)False positives (misclassified vaccine allergic)13 (0-51)For PS: Sn: 0.03 (95% CI: 0-0.11) Sp: 0.97 (95% CI: 0.91-1), Prevalence second-dose reactions: 0.16%Pretest probability 0.16%True positives (vaccine allergic)13 studies33 patientsCohort and case seriesNot seriousNot seriousNot seriousSeriousBias is suspected as authors are more likely to report.None0 (0-0)⨁⨁⨁◯ModerateFalse negatives (misclassified not allergic)2 (2-2)True negatives (not vaccine allergic)13 studies131 patientsCohort and case series968 (914-998)False positives (misclassified vaccine allergic)30 (0-84)GRADE summary of the certainty of evidence for questions 2 and 4, which pertain to the diagnostic accuracy (sensitivity, specificity) of vaccine excipient testing as a screening measure prior to receiving an initial mRNA COVID-19 vaccine in persons without a history of allergic reaction to the vaccine or its excipients (question 2), or testing to either mRNA COVID-19 vaccine or the vaccine excipients in persons with a history of a reaction to an initial mRNA COVID-19 vaccine (question 4), as a means of predicting an allergic reaction to the vaccine dose.CoE, Certainty of evidence; Sn, sensitivity; Sp, specificity.∗ These were all case reports, with nonrandom selection of cases and controls.† Challenges to the agents were not performed to confirm accuracy of the testing.‡ Different agents and methods were
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