Fatal Anaphylaxis: Mortality Rate and Risk Factors

Up to 5% of the US population has suffered anaphylaxis. Fatal outcome is rare, such that even for people with known venom or food allergy, fatal anaphylaxis constitutes less than 1% of total mortality risk. The incidence of fatal anaphylaxis has not increased in line with hospital admissions for anaphylaxis. Fatal drug anaphylaxis may be increasing, but rates of fatal anaphylaxis to venom and food are stable. Risk factors for fatal anaphylaxis vary according to cause. For fatal drug anaphylaxis, previous cardiovascular morbidity and older age are risk factors, with beta-lactam antibiotics, general anesthetic agents, and radiocontrast injections the commonest triggers. Fatal food anaphylaxis most commonly occurs during the second and third decades. Delayed epinephrine administration is a risk factor; common triggers are nuts, seafood, and in children, milk. For fatal venom anaphylaxis, risk factors include middle age, male sex, white race, cardiovascular disease, and possibly mastocytosis; insect triggers vary by region. Upright posture is a feature of fatal anaphylaxis to both food and venom. The rarity of fatal anaphylaxis and the significant quality of life impact of allergic conditions suggest that quality of life impairment should be a key consideration when making treatment decisions in patients at risk for anaphylaxis. Up to 5% of the US population has suffered anaphylaxis. Fatal outcome is rare, such that even for people with known venom or food allergy, fatal anaphylaxis constitutes less than 1% of total mortality risk. The incidence of fatal anaphylaxis has not increased in line with hospital admissions for anaphylaxis. Fatal drug anaphylaxis may be increasing, but rates of fatal anaphylaxis to venom and food are stable. Risk factors for fatal anaphylaxis vary according to cause. For fatal drug anaphylaxis, previous cardiovascular morbidity and older age are risk factors, with beta-lactam antibiotics, general anesthetic agents, and radiocontrast injections the commonest triggers. Fatal food anaphylaxis most commonly occurs during the second and third decades. Delayed epinephrine administration is a risk factor; common triggers are nuts, seafood, and in children, milk. For fatal venom anaphylaxis, risk factors include middle age, male sex, white race, cardiovascular disease, and possibly mastocytosis; insect triggers vary by region. Upright posture is a feature of fatal anaphylaxis to both food and venom. The rarity of fatal anaphylaxis and the significant quality of life impact of allergic conditions suggest that quality of life impairment should be a key consideration when making treatment decisions in patients at risk for anaphylaxis. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI: In Practice Web site: www.jaci-inpractice.org/. The accompanying tests may only be submitted online at www.jaci-inpractice.org/. Fax or other copies will not be accepted.Date of Original Release: September 1, 2017. Credit may be obtained for these courses until August 31, 2018.Copyright Statement: Copyright © 2017-2019. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for 1.00 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Paul J. Turner, MD, PhD, Elina Jerschow, MD, Thisanayagam Umasunthar, MD, Robert Lin, MD, Dianne E. Campbell, MD, PhD, and Robert J. Boyle, MB, ChB, PhD (authors); Scott H. Sicherer, MD (editor)Learning objectives:1.To communicate risk estimates for fatal or near-fatal anaphylaxis to patients and caregivers.2.To evaluate a patient's risk for fatal or near-fatal anaphylaxis.3.To discuss the uncertainties in understanding fatal anaphylaxis.Recognition of Commercial Support: This CME has not received external commercial support.Disclosure of Relevant Financial Relationships with Commercial Interests: P. J. Turner has received research support from the Medical Research Council, NIHR/Imperial BRC, and EU FP7 Programme; and has received consultancy fees from UK Food Standards Agency. T. Umasunthar has received research support from Lincoln Medical. D. E. Campbell is employed by NSW Health; has received research support from the National Health and Medical Research Council, Australian Food Allergy Foundation, and the Allergy and Immunology Foundation of Australasia; and has received travel support from DBV. R. J. Boyle has received consultancy fees from Oval Technoloties and ALK Abello; and has provided expert testimony for Squitieri and Fearon. The rest of the authors declare that they have no relevant conflicts of interest. S. H. Sicherer disclosed no relevant financial relationships. Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI: In Practice Web site: www.jaci-inpractice.org/. The accompanying tests may only be submitted online at www.jaci-inpractice.org/. Fax or other copies will not be accepted. Date of Original Release: September 1, 2017. Credit may be obtained for these courses until August 31, 2018. Copyright Statement: Copyright © 2017-2019. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for 1.00 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Paul J. Turner, MD, PhD, Elina Jerschow, MD, Thisanayagam Umasunthar, MD, Robert Lin, MD, Dianne E. Campbell, MD, PhD, and Robert J. Boyle, MB, ChB, PhD (authors); Scott H. Sicherer, MD (editor) Learning objectives:1.To communicate risk estimates for fatal or near-fatal anaphylaxis to patients and caregivers.2.To evaluate a patient's risk for fatal or near-fatal anaphylaxis.3.To discuss the uncertainties in understanding fatal anaphylaxis. Recognition of Commercial Support: This CME has not received external commercial support. Disclosure of Relevant Financial Relationships with Commercial Interests: P. J. Turner has received research support from the Medical Research Council, NIHR/Imperial BRC, and EU FP7 Programme; and has received consultancy fees from UK Food Standards Agency. T. Umasunthar has received research support from Lincoln Medical. D. E. Campbell is employed by NSW Health; has received research support from the National Health and Medical Research Council, Australian Food Allergy Foundation, and the Allergy and Immunology Foundation of Australasia; and has received travel support from DBV. R. J. Boyle has received consultancy fees from Oval Technoloties and ALK Abello; and has provided expert testimony for Squitieri and Fearon. The rest of the authors declare that they have no relevant conflicts of interest. S. H. Sicherer disclosed no relevant financial relationships. Between 1.6% and 5.1% of US citizens are estimated to have experienced anaphylaxis,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 (256) Google Scholar a systemic hypersensitivity reaction that can be rapidly fatal. An estimated, 1% of hospitalizations and 0.1% of emergency department attendances for anaphylaxis have a fatal outcome.2Ma L. Danoff T.M. Borish L. 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The aim of this review is to provide clinicians with information that can be used to identify and counsel those individuals at risk of fatal anaphylaxis. We review the incidence and time trends of fatal anaphylaxis due to the 3 main causes (drugs, food, and insect venom) from recent studies and summarize risk factors for fatal anaphylaxis associated with these triggers. Drugs are the most common reported cause of fatal anaphylaxis in several countries, including Australia, New Zealand, United Kingdom, Brazil, and United States.5Tanno L.K. Ganem F. Demoly P. Toscano C.M. Bierrenbach A.L. Undernotification of anaphylaxis deaths in Brazil due to difficult coding under the ICD-10.Allergy. 2012; 67: 783-789Crossref PubMed Scopus (96) Google Scholar, 6Jerschow E. Lin R.Y. Scaperotti M.M. McGinn A.P. 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Fatal anaphylaxis in the United States, 1999-2010: temporal patterns and demographic associations.J Allergy Clin Immunol. 2014; 134: 1318-1328.e1317Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar The year 1999 was the first year when ICD-10 codes were used to record deaths in the US National Mortality database, raising the possibility of a code shift underlying the reporting increase.6Jerschow E. Lin R.Y. Scaperotti M.M. McGinn A.P. Fatal anaphylaxis in the United States, 1999-2010: temporal patterns and demographic associations.J Allergy Clin Immunol. 2014; 134: 1318-1328.e1317Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar A significant increase was also noted in an Australian ICD-10-based report, between 1997 and 2005,7Liew W.K. Williamson E. Tang M.L. Anaphylaxis fatalities and admissions in Australia.J Allergy Clin Immunol. 2009; 123: 434-442Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar and an overall rate of increase of 5.6% per year over the period 1997-2013.18Turner P.J. Campbell D.E. Epidemiology of severe anaphylaxis: can we use population-based data to understand anaphylaxis?.Curr Opin Allergy Clin Immunol. 2016; 16: 441-450Crossref PubMed Scopus (42) Google Scholar In contrast, an increase has not been reported in the United Kingdom, according to data from a national fatal anaphylaxis registry.14Turner P.J. Gowland M.H. Sharma V. Ierodiakonou D. Harper N. Garcez T. et al.Increase in anaphylaxis-related hospitalizations but no increase in fatalities: an analysis of United Kingdom national anaphylaxis data, 1992-2012.J Allergy Clin Immunol. 2015; 135: 956-963Abstract Full Text Full Text PDF PubMed Scopus (442) Google Scholar Problems with current ICD-10-based anaphylaxis mortality coding have been recently detailed.15Tanno L.K. Simons F.E.R. Annesi-Maesano I. Calderon M.A. Aymé S. Demoly P. Fatal anaphylaxis registries data support changes in the WHO anaphylaxis mortality coding rules.Orphanet J Rare Dis. 2017; 12: 8Crossref PubMed Scopus (31) Google Scholar Fig 1 shows the range of estimates for fatal drug anaphylaxis incidence. The risk of fatal drug anaphylaxis is seen to be low compared with other population mortality risks.Table IPopulation-based data for rate of fatal anaphylaxis triggered by drugsRegionData SourceTime periodTotal deathsRate of fatal drug anaphylaxis (per million/year)AgeGender predominanceLeading causal drugsRisk factors identifiedAuthorsAustraliaAustralian Bureau of Statistics and National Coroners Information System1997-2013147 cases in total84 (57%) triggered by drugs ICD code T88.61997: 0.052013: 0.13Median 66 (IQR 52-73; range 26-94)Male > femaleAntibiotics 43%General anesthetic 35%Radiocontrast 18%AgeCardiovascular disease 71%Known penicillin allergy 11% (33% of beta-lactam fatalities)Mullins et al 201611Mullins R.J. Wainstein B.K. Barnes E.H. Liew W.K. Campbell D.E. Increases in anaphylaxis fatalities in Australia from 1997 to 2013.Clin Exp Allergy. 2016; 46: 1099-1110Crossref PubMed Scopus (174) Google ScholarCanada (Ontario)Ontario Coroner's database1986-201192 total16 (17%) drugsCoroner reports searched; ICD codes not used0.1Mean 65 (range 39-86)38% maleAntibiotics 44%Radiocontrast 25%AgeKnown allergy to the drug in 1 of 5 cases with data available (20%)Xu et al 201412Xu Y.S. Kastner M. Harada L. Xu A. Salter J. Waserman S. Anaphylaxis-related deaths in Ontario: a retrospective review of cases from 1986 to 2011.Allergy Asthma Clin Immunol. 2014; 10: 38Crossref PubMed Scopus (86) Google ScholarFranceFrench National Pharmacovigilance Database∗Reported data were only on neuromuscular blocking agents.2000-201184 (0.04% of total anaphylaxis cases) Pharmacovigilance DatabaseNot calculatedMean age 59Male > femaleNot statedMale gender Hypertension and cardiovascular comorbiditiesObesityBeta-blocker useReitter et al 201413Reitter M. Petitpain N. Latarche C. Cottin J. Massy N. Demoly P. et al.Fatal anaphylaxis with neuromuscular blocking agents: a risk factor and management analysis.Allergy. 2014; 69: 954-959Crossref PubMed Scopus (83) Google ScholarUnited KingdomNational fatal anaphylaxis registry1992-2012479 total263 drugs (55% of total) ICD code T88.61992: 0.242012: 0.24Median 58 (range 56-61)Not statedNot statedOlder ageTurner et al 201514Turner P.J. Gowland M.H. Sharma V. Ierodiakonou D. Harper N. 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Epidemiology of severe anaphylaxis: can we use population-based data to understand anaphylaxis?.Curr Opin Allergy Clin Immunol. 2016; 16: 441-450Crossref PubMed Scopus (42) Google Scholar Older age has been consistently associated with higher fatal drug anaphylaxis rates.6Jerschow E. Lin R.Y. Scaperotti M.M. McGinn A.P. Fatal anaphylaxis in the United States, 1999-2010: temporal patterns and demographic associations.J Allergy Clin Immunol. 2014; 134: 1318-1328.e1317Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar, 7Liew W.K. Williamson E. Tang M.L. Anaphylaxis fatalities and admissions in Australia.J Allergy Clin Immunol. 2009; 123: 434-442Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar, 14Turner P.J. Gowland M.H. Sharma V. Ierodiakonou D. Harper N. Garcez T. et al.Increase in anaphylaxis-related hospitalizations but no increase in fatalities: an analysis of United Kingdom national anaphylaxis data, 1992-2012.J Allergy Clin Immunol. 2015; 135: 956-963Abstract Full Text Full Text PDF PubMed Scopus (442) Google Scholar In the United Kingdom, the mean age for fatal drug anaphylaxis was 58 years,14Turner P.J. Gowland M.H. Sharma V. Ierodiakonou D. Harper N. Garcez T. et al.Increase in anaphylaxis-related hospitalizations but no increase in fatalities: an analysis of United Kingdom national anaphylaxis data, 1992-2012.J Allergy Clin Immunol. 2015; 135: 956-963Abstract Full Text Full Text PDF PubMed Scopus (442) Google Scholar and in Australia, most drug anaphylactic fatalities occurred between 55 and 85 years.7Liew W.K. Williamson E. Tang M.L. Anaphylaxis fatalities and admissions in Australia.J Allergy Clin Immunol. 2009; 123: 434-442Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar This may be related to increased prevalence of drug allergy due to increased drug exposure, and increased cardiovascular vulnerability, in older age groups. No consistent gender predilection has been noted in studies on drug-associated anaphylaxis; however in the United States, a significant association with African American ethnicity has been noted.6Jerschow E. Lin R.Y. Scaperotti M.M. McGinn A.P. Fatal anaphylaxis in the United States, 1999-2010: temporal patterns and demographic associations.J Allergy Clin Immunol. 2014; 134: 1318-1328.e1317Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar The role of comorbidities as a purported risk for fatal drug anaphylaxis has not been supported in many studies, and such morbidities are of course common in older people. However, one recent study reported 71% of fatal drug anaphylaxis occurred in people with known cardiovascular disease, and 39% in those with known asthma or emphysema.11Mullins R.J. Wainstein B.K. Barnes E.H. Liew W.K. Campbell D.E. Increases in anaphylaxis fatalities in Australia from 1997 to 2013.Cl