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Incidence of Fatal Anaphylaxis: A Systematic Review of Observational Studies Short title: Incidence of fatal anaphylaxis

BACKGROUND AND OBJECTIVES
Fatal anaphylaxis is very rare, with an incidence ranging from 0.5 to 1 deaths per million person-years. Objective: Based on a systematic review, we aimed to explain differences in the reported incidence of fatal anaphylaxis based on the methodological and demographic factors addressed in the various studies.


METHODS
We searched PubMed/MEDLINE, EMBASE, and the Web of Science for relevant retrospective and prospective cohort studies and registry studies that had assessed the anaphylaxis death rate for the population of a country or for an administrative region. The research strategy was based on combining "anaphylaxis" with "death", "study design", and "main outcomes" (incidence).


RESULTS
A total of 46 studies met the study criteria and included 16,541 deaths. The range of the anaphylaxis mortality rate for all causes of anaphylaxis was 0.002-2.51 deaths per million person-years. Fatal anaphylaxis due to food (range 0.002-0.29) was rarer than deaths due to drugs (range 0.004-0.56) or Hymenoptera venom (range 0.02-0.61). The frequency of deaths due to anaphylaxis by drugs increased during the study period (IRR per year, 1.02, 95%CI 1.00-1.04). We detected considerable heterogeneity in almost all of the meta-analyses carried out.


CONCLUSION
The incidence of fatal anaphylaxis is very low and differs according to the various subgroups analyzed. The studies were very heterogeneous. Fatal anaphylaxis due to food seems to be less common than fatal anaphylaxis due to drugs or Hymenoptera venom.

We performed a systematic review on fatal anaphylaxis in order to assess differences in the reported incidence of anaphylaxis according to the continent of origin, design used, diagnostic criteria, settings, and periods of publication.

Search strategy
We performed a search of PubMed/MEDLINE, EMBASE, and Web of Science. The search was based on titles and abstracts from studies in humans published in all languages. The last search was run on 31 June 2019 by 2 investigators (MATA and SPC). In order not to overlook published material, the articles cited in the selected articles and in review papers on the epidemiology of fatal anaphylaxis were reviewed to find other, missing articles not selected using our review strategy.
The search strategy followed that of Umasunthar et al [32]. We combined the term "anaphylaxis" with "death", "study design", and "main outcomes" (incidence) (Annex 1). This strategy was developed with the support of the librarian of Hospital Universitario Fundación Alcorcon (EGC).
Two investigators (SPC, MATA) performed the search independently. The abstract and title of each article were examined during identification and screening in order to choose articles that met the study criteria. Disagreements between reviewers were resolved by consensus and discussion.

Selection criteria
The study population assessed was the whole population of a country or administrative region with no restrictions on age or sex. The types of studies reviewed were observational studies, cohort studies, cross-sectional studies, and registry studies that had assessed the incidence of death due to anaphylaxis. The series included studies with all the major causes of anaphylaxis (food, drugs, Hymenoptera venom, and unknown) or series involving only a major cause of anaphylaxis.
We excluded studies with duplicate dates, studies in which quantitative data for the general population were missing, systematic reviews ± meta-analysis, non-original studies where deaths were not reported, and studies from a single hospital or several hospitals or forensic series that were not representative of the population of a large geographic area (at least a state, province, or administrative region).
We did not extend the analysis to the most specific frequent causes (milk, egg, peanuts, fish, penicillin, nonsteroidal anti-inflammatory drugs), because this would have dramatically increased the number of studies and the length of the paper. We believed our research needed to maintain its generalist perspective and not enter into the problems of very specific causes of anaphylaxis, which could prove controversial, as is the case with cross-reactivity and underlying mechanisms. In our opinion, each specific cause of fatal anaphylaxis would need a purpose-designed specific meta-analysis.

Data collection and extraction
We recorded the following: first author, country, year, criteria for establishing anaphylaxis as the cause of the death, cause of anaphylaxis, institutions and other settings where cases were collected, age groups, sex, codes used (both ICD 9 and ICD 10 codes were used to define all causes of anaphylaxis), study design, population number, duration of data collection, mortality incidence rate, and quality of studies (or risk of bias). One author obtained all the information (SPC) and the other checked its accuracy (MATA). Disagreement was resolved by consensus.
When the same group published several reports on the same exposure in different studies, duplication was ruled out if the study period was different and without overlaps.
Given that our study was a systematic review of published literature, it was not necessary to request approval from our local ethics committee.

Risk of bias in individual studies
The quality of the studies and the presence of bias were assessed using the score

Summary measures
The crude anaphylaxis death rate was calculated as the number of deaths per million person-years with the 95% confidence interval (CI). When articles gave this rate, we included it. However, we frequently had to calculate this rate using the official web pages of the national statistics office of the country where the study was carried out.
The denominator of this rate was the product of the number of people in the country for the year placed in the middle of the study period multiplied by the number of years comprising this period. The web pages were accessed between September and December, 2019.
We compared crude anaphylaxis mortality rates for all types of anaphylaxis, major causes of anaphylaxis, anaphylaxis in different geographical areas, age ranges, grade of risk of bias, and origin of cases. We were unable to classify settings where the database was collected from various origins (national death certificates, forensic data, clinical registries), as some articles pooled data from several settings. Therefore, we report bivariate variables whose positive result depends on whether the publication states that the data originated in a specific setting, independently of whether data in the same article came from several sources. In the case of temporal trend studies, where data were grouped based on an arithmetic progression, the results were homogenized into a single scale that increased in steps of 1 year.
We attempted to perform a meta-analysis to calculate pooled statistics. However, we observed considerable heterogeneity, which was almost always higher than 90%. Therefore, we only report descriptive statistics (median, range, minimum and maximum), which were calculated using the statistical software application STATA-16.1  . The crude anaphylaxis death rates were transformed into their natural logarithms, and the standard error of the transformed rate was estimated using the inverse of the square root of the events in each study (1/√events). The heterogeneity of the studies was measured using the I 2 statistic (inconsistency) 25,30 . Given the very probable heterogeneity of the epidemiologic studies, we performed the meta-analysis using a random-effects model, following the approach of DerSimonian and Laird 34 . We plotted quantiles of estimates of crude anaphylaxis death rates against the quantiles of the normal distribution (Q-Q plot) to detect outliers. Finally, after recording a heterogeneity (I 2 ) lower than 50% in the principal causes of anaphylaxis (drugs, food, Hymenoptera venom) we carried out another systematic review and meta-analysis, in which we assessed the trends of the crude anaphylaxis death rate for the main causes in the last 35 years using a logarithmic transformation of the crude anaphylaxis mortality rate and its standard error. The risk ratios were calculated as a division of crude anaphylaxis death rates for exposure and non-exposure, and their 95% CI was calculated as a Poisson distribution using a tool in STATA- 16

Selection of studies
Our literature search revealed 2888 publications on fatal anaphylaxis ( Figure 1). After exclusion of duplicate studies, the number of publications decreased to 1565. A further 1345 articles were excluded during the screening phase that did not meet the inclusion criteria and the reviewers had no doubts about the lack of relevant data related to the objectives of the review. Six articles [6,[9][10][11]30,[36][37] were identified by checking the references of the excluded articles. Of the remaining 220 studies, 180 were excluded for various reasons (Figure 1). Therefore, 46 met our criteria  for the quantitative analysis (Table 1). Using a Q-Q plot with estimations of the model, we In the studies which assessed the crude anaphylaxis death rate, we observed symmetry in the smaller or in the larger study areas, although findings were widely dispersed ( Figure E2).

Characteristics of the studies
The 46 studies on fatal anaphylaxis carried out for all causes of anaphylaxis reported 16,541 deaths ( Table 2). Drugs were the most frequently reported cause of fatal anaphylaxis (4262), while foods were the least frequently reported cause (612). The authors did not estimate the accuracy of these data.  (Table 3). data on all age groups (80%), and some studies focused only on the pediatric population (20%).
Almost all studies were retrospective cohort studies (91.30%) ( Table 3). Thirteen publications (26.07% ) performed only 1 study, while the remaining articles had 2 or more substudies, depending on the main cause of anaphylaxis or the subgroup analyzed (age, gender, temporal trends) ( Table 3).

Risk of bias
According to the score of Hoy et al [33], 51.06% of publications had a low risk of bias, 29.53% a moderate risk, and 19.15% a high risk. The items for which the conditions were not fulfilled in most of the studies were the minimal likelihood of nonresponse (95.65%) and the length of the shortest period prevalence for the parameter of interest (91.30%) ( Table 2).

Incidence of fatal anaphylaxis according to all the main causes
Twenty-five studies assessed the crude anaphylaxis death rate according to all the main causes, revealing a range of 0.002 to 2.51 deaths per million person-years, with a median of 0.50. Six studies overcame the crude anaphylaxis mortality rate of 1 death per million person-years, The crude anaphylaxis death rate was higher in studies from Australia than in studies from Europe, North America, and Asia. The probability of differences was statistically significant (p<0.01, chi 2 ) for the crude anaphylaxis mortality rate on the different continents ( Figure 2a). The meta-analysis of the total group on the different continents revealed considerable heterogeneity (higher than 95%).

Incidence of fatal anaphylaxis in studies assessed according to subgroups
The range of the crude anaphylaxis mortality rate was 0.08-1.13 (median 0.60) in articles that reported data from national death certificate databases and 0.002-2.51 (median 0.35) in articles from the remaining settings, with non-significant results in the test of probability of differences (p= 0.24, chi 2 ). Within subgroups, heterogeneity was greater than 98%. The remaining studies, which were carried out in several settings (forensic series, hospital systems, other settings), also revealed considerable heterogeneity and non-significant differences between groups (Table 4). Likewise, for the other different subgroups (use of ICD-9-CM, ICD-10, or both and subgroups according to whether the risk of bias was low or moderate-high) also revealed marked heterogeneity within subgroups and no differences between them, although studies with a low risk of bias had higher median (0.56) than those with a moderate to high risk of bias (0.39) ( Table 4).
On the other hand, the studies carried out in pediatric and adolescent populations revealed lower crude anaphylaxis death rates (median 0.08, range 0.002-0.43) than studies involving all age groups (median, 0.59; range, 0.03-2.28), with statistically significant differences (p=0.03). Studies based only on adult populations were not available ( Figure 2b). Heterogeneity was very high in both age ranges for both subgroups.
We performed an additional assessment by grouping the different causes of anaphylaxis. Deaths caused by drugs and Hymenoptera venom ranged from 0.004 to 0.56 (median, 0.2) and from 0.02 to 0.61 (median, 0.14), respectively. The crude anaphylaxis mortality rate for foods was much lower than that of the other 2 causes (median, 0.04; range, 0.002-0.29). The difference was statistically significant (p < 0.01, chi 2 ). Intra-group heterogeneity was higher than 98% ( Figure 3).

Temporal trends for fatal anaphylaxis
We observed considerable heterogeneity (higher than 90%) in anaphylaxis overall and in the subgroup of fatal anaphylaxis due to unknown causes. Heterogeneity was lower than 50% in the remaining causes. We noted a positive trend in the crude anaphylaxis death rate for drugs, in which the IRR for fatal episodes increased during the study period (1.02 by year of follow-up). Differences in the IRR of the trend were observed J Investig Allergol Clin Immunol 2022; Vol. 32(4) © 2021 Esmon Publicidad doi: 10.18176/jiaci.0693

DISCUSSION
Our systematic review seems to confirm the extremely low frequency of fatal anaphylaxis. The high heterogeneity that we observed for studies assessing all causes of anaphylaxis was maintained in the different subgroups (sources, ages, continents).
Probably, one of the more reliable findings is that fatal anaphylaxis due to food is especially rare. We detected a slight increase in the crude rate of fatal anaphylaxis induced by drugs, as reported in recent years. The considerable heterogeneity of the meta-analyses prevented us from obtaining pooled estimated anaphylaxis death rates.

Incidence of fatal anaphylaxis and its causes
The crude anaphylaxis mortality rate ranged from 0.002 per million person-years to 2.51 per million person-years [42,57], although these figures probably underestimate and overestimate, respectively, the incidence of death due to anaphylaxis. However, these figures do show how uncommon fatal anaphylaxis actually is.
It is difficult to determine the reliability of the data we collected for review. Experts agree that studies underestimate the true crude anaphylaxis death rate. In cases where coding systems such as the ICD-9 or the ICD-10 are used, Tanno et al [27] showed that the codes for anaphylaxis in these systems are not reliable because they include only anaphylactic shock and omit other mechanisms of death [38]. Likewise, the use of ICD-9 for coding of anaphylaxis is subject to variability between coders, low internal validity, and intermediate positive predictive value [59]. Furthermore, knowledge of anaphylaxis is very poor among professionals not working directly in allergy. Finally, unidentified cases of fatal anaphylaxis may include persons dying from acute asthma due to food allergy or sudden death from unrecognized insect stings [26]. Our data highlight the need for an improvement in how national death certificates are completed.
Despite improvements in the coding of anaphylaxis in ICD- 11 [27], it seems unlikely that, outside the focus on allergic diseases, physicians' knowledge of the condition will improve or physicians will complete death certificates more appropriately.
It is also important to determine the most reliable source of data. However, we found crude anaphylaxis death rates to be very similar in meta-analyses of national death certificates and hospital systems. We also found that these sources overlapped with other sources of data. Our findings are limited by the fact that we cannot analyze groups J Investig Allergol Clin Immunol 2022; Vol. 32 (4) © 2021 Esmon Publicidad doi: 10.18176/jiaci.0693 from a single source (e.g., only hospitals, only forensic reports). Likewise, we did not observe differences in the ranges of crude anaphylaxis mortality rates for the different decades of publication.
According to the groups of studies reported in our review, it seems that studies carried out with people aged <19 years will always have a lower crude anaphylaxis death rate than studies performed in people of all ages (including children and adults). This finding of our review is associated with the finding that old age is a clear risk factor for severe and fatal anaphylaxis [1][2][3][4][5].
Our systematic review revealed significant differences between continents, with the highest crude anaphylaxis mortality rates in Australia and closer crude anaphylaxis death rates between North America and Europe. It is noteworthy that in Australia, studies on fatal anaphylaxis have traditionally reported high rates [18,22].
Our systematic review also found the crude anaphylaxis mortality rate to differ widely according to the main cause. The lower crude anaphylaxis death incidence rates for foods compared with the remaining main causes of anaphylaxis may be the most reliable finding of our review, owing to the fact that it is routinely repeated in studies on the incidence of fatal anaphylaxis. Oral intake may be less dangerous than parenteral intake, probably because lower human tryptase-containing mast cells from the small bowel mucosa61 or younger age may better compensate for the hemodynamic changes induced by anaphylaxis in older patients [62].
In their meta-analysis, Umasunthar et al [32] found that the crude anaphylaxis mortality rate due to food was 1.81 per million person-years with food allergy when the prevalence of food allergy was 3%. The extrapolated estimation of the crude anaphylaxis death rate in the general population was 0.045, which is well within the range of food-induced fatal anaphylaxis studies in our review (0.02-0.29). However, the meta-analysis of Umasunthar et al [32] also revealed considerable heterogeneity (I2>85%), which would also limit the reliability of a pooled estimation of fatal anaphylaxis due to foods in this study.

Temporal trends
Our meta-analysis only revealed a slight increase in the crude anaphylaxis mortality rate by year during the study period among people who died from anaphylaxis induced by drugs, but not other causes. Our meta-analysis did not reveal considerable heterogeneity in the known causes of anaphylaxis (under 50%). However, several recent studies have reported a positive trend towards an increase in the anaphylaxis mortality rate for food [22] and the frequency of fatal anaphylaxis in the adult population [23]. Negative trends were reported in France [13] and Ontario (Canada) [17]. It is possible that the pooled crude anaphylaxis death rate in known causes of anaphylaxis is more influenced by older studies than by the most recent publications.
On the other hand, the increase in fatal anaphylaxis due to drugs can be explained by the frequency of poly-medication among elderly patients (antibiotics, nonsteroidal antiinflammatory drugs, iodinated contrast media, and cancer treatments).

Limitations and conclusions
The main limitation of our study, as previously mentioned, is the marked heterogeneity in almost all of the meta-analyses carried out and reproduced by other previous metaanalyses on anaphylaxis [32,63]. This considerably limits the reliability of our study for estimation of a pooled crude anaphylaxis death rate. Despite the analysis of subgroups, we are not able to explain the reasons for this heterogeneity.
In addition, other causes not explored in our review may contribute to the heterogeneity of the studies, for example, different rules are applied to code the cause of death (even if ICD-9 or 10 are used) in the different countries. In addition, geographic areas are too large and include countries with different allergens or populations with different ages 63 .
It is interesting to consider whether we should have included studies with 0 cases of deaths 64 . However, some studies with 0 deaths will not be as powerful for detection of cases of fatal anaphylaxis as studies from a single hospital. This high power is accomplished in many of the studies recovered by our search strategy, such as studies based on death certificates from a whole country or a large administrative territory.
Consequently, studies from a single hospital or outpatient allergy clinic and insufficiently powered studies should be excluded if they do not report cases of deaths.
For the small studies with cases of fatal anaphylaxis collected in our review, these cover In summary, our findings are consistent with those reported in epidemiologic studies performed during the last 30 years. The considerable heterogeneity of our systematic review on the crude anaphylaxis death rates was maintained in the different subgroups we explored. Finally, the incidence of fatal anaphylaxis due to foods is lower than the incidence of fatal anaphylaxis due to other causes.        Table 2. Crude anaphylaxis death rate in the 46 studies collected for the meta-analysis. *PICU: pediatric intensive care unit.