What We Know about Sting-Related Deaths? Human Fatalities Caused by Hornet, Wasp and Bee Stings in Europe (1994–2016)

Simple Summary Information about fatalities due to stinging insects is scarce. Hymenopteran-related deaths (n = 1691) in 32 European countries based on official registers over a 23-year period (1994–2016) are described. Male adults (25–64 years) were the most common group to be fatally injured and almost half of the fatalities were recorded at “unspecified places”. Fatalities per million inhabitants per year ranged from 0 to 2.24 with an average of 0.26. Geographic, environmental, and ecological factors influence the frequency of stings, and its subsequent reaction. It is necessary to produce and interpret knowledge using diverse sources and in an interdisciplinary way. As part of the One Health philosophy, people and hornets, wasps and bees, as well as the environment that they share are closely connected. Abstract Epidemiology of Hymenopteran-related deaths in Europe, based on official registers from WHO Mortality Database (Cause Code of Death: X23), are presented. Over a 23-year period (1994–2016), a total of 1691 fatalities were recorded, mostly occurring in Western (42.8%) and Eastern (31.9%) Europe. The victims tended to concentrate in: Germany (n = 327; 1998–2015), France (n = 211; 2000–2014) and Romania (n = 149; 1999–2016). The majority of deaths occurred in males (78.1%) between 25–64 years (66.7%), and in an “unspecified place” (44.2%). The highest X23MR (mortality rate) were recorded in countries from Eastern Europe (0.35) followed by Western (0.28), Northern (0.23) and Southern Europe (0.2). The countries with the highest and lowest mean X23MR were Estonia (0.61), Austria (0.6) and Slovenia (0.55); and Ireland (0.05), United Kingdom (0.06) and the Netherlands (0.06), respectively. The X23 gender ratio (X23GR; male/female) of mortality varied from a minimum of 1.4 for Norway to a maximum of 20 for Slovenia. Country-by-country data show that the incidence of insect-sting mortality is low and more epidemiological data at the regional level is needed to improve our understanding of this incidence. With the expansion of non-native Hymenopteran species across Europe, allergists should be aware that their community’s exposures are continually changing


Introduction
Anaphylaxis is an acute, life-threatening reaction that occurs shortly after contact with a trigger. It is classically defined as the most severe form of an allergic reaction, but it could also be induced by non-IgE-mediated pathways through the activation of mast cells − Country in which the fatality happened (n = 32) grouped into four regions (Eastern, Northern, Southern and Western Europe) (Figure 1). mortality ranged from 0.03 to 0.48 fatalities per 1,000,000 inhabitants per year, which is low but not negligible [21].
Information about the fatalities due to stinging insects is scarce. There is a need to improve the epidemiology of these deaths in order to get more accurate, informative and contemporary figures. Therefore, to fill this gap, the aim of the present study was to document and characterize the European deaths caused by Hymenoptera stings during a 23-year period (1994-2016).

Materials and Methods
The number of deaths related to hornet, wasp and bee stings (including yellow jackets) were obtained from the World Health Organisation (WHO) Mortality Database (MDB). Using X23 as diagnosis code, the MDB returned a file comprising individual data for all X23-related fatalities registered between 1994 and 2016, with both years included. For each observation, the following particular variables were obtained:  Country in which the fatality happened (n = 32) grouped into four regions (Eastern, Northern, Southern and Western Europe) ( Figure 1).  [24]. Countries were grouped in four regions, based on the "Standard Country or Area Codes for Statistical Use" (M49) [25], from United Nations geographic scheme for the continent of Europe (numerical code 150), created by the United Nations Statistics Division (UNSD).
The X23 gender ratio (X23GR) of mortality, was obtained by dividing ♂X23, by ♀X23: The X23 gender differential (X23GD) in mortality is the absolute difference between ♂X23 and ♀X23: The X23 mortality rates (X23MR) were on the basis of the yearly number of X23 deaths and the population size in each country: The X23MR were expressed in terms of annual rates (i.e., per year) and per 1,000,000 inhabitants. The X23GR, X23GD and X23MR were obtained both for countries and regions, as well as for each year and for the total years of the studied period. Countries censuses were obtained from the European Statistical System (ESS), produced by the statistical office of the European Union (EU) (Eurostat) in partnership with National Statistical Institutes and other national authorities in the EU Member States. The software, Gimp, was used to elaborate a map showing the spatial distribution of the average Hymenopteran sting-related deaths per 1,000,000 inhabitants (X23MR).

Countries and Study Period
The countries for which data are available, as well as the year period to which they correspond, are presented in Supplementary Table S2. Information was retrievable for a total of 32 countries and in the whole study period there was an annual variation in the data available and provided by each country: ≥20 years (n = 9): CZ, FI, HU, IS, NL, NO, SK, SE and CH.

Specific Locations where Hymenopteran Sting-Related Deaths Occurred
The X23 code extension to four-digit is fully available for most of the countries, with a total of 18 reporting case details. Conversely, three countries (FI, LV and SI) report all deaths without the four-digit extension. In seven countries (BE, BG, EE, LT, RS, SK and SE) both the X23 code with and without an extension to four-digit are used (Supplementary Table  S3). All countries register the highest number of deaths with the code X23.9 (unspecified place), except for Hungary, and Austria, where the code X23.0 (home) harbours the highest number of Hymenopteran sting-related death events. In general, the pattern observed for most countries, with a few exceptions is X23.9 > X23.0 > X23.8 >X23.4 > X23.7; with no recorded deaths labelled as X23.5 (trade and service area). Very little used codes are: (i) 1 death coded as X23.3 (sports and athletics area) and 1 death coded as X23.6 (industrial and construction area), both having place in Romania; and (ii) seven deaths coded as X23.2 (school, other institution and public administrative area) in Belgium (1), Czechia (1), Hungary (3), Poland (1) and Spain (1); and 8 deaths coded as X23.1 (residential institution) in Austria (1), Belgium (1), Czechia (3), Norway (1) and Poland (2).

Age Distribution of Hymenopteran Sting-Related Deaths
Adults (25-64 years) were the most common age group to be fatally injured by Hymenopteran stings. Lithuania is the only exception, with an equal rate of adults and seniors (65 years and older) Hymenopteran sting-related deaths, a total of three (Supplementary  Table S4). Only adult deaths were found in the following two countries: Ireland and Luxembourg. Children were recorded in 12 countries with the following distribution: RO (6), AT (3), HU (2) and CH (2), and CZ, FR, DE, IT, LT, PL, RS and SI with only one death.

Hymenopteran Sting-Related Deaths by Gender
The majority of deaths (n = 1691) in Europe occurred in males (Supplementary Table  S5). In fact, there are four countries with only male deaths, specifically, Greece and Portugal with nine male victims each; and Ireland and Luxembourg with two and one male victims, respectively. The X23 gender ratio (X23GR) of mortality varied from a min value of 1.4 for Norway to a maximum value of 20 for Slovenia, with a range of 18.6 for the whole dataset of countries. Obtained values for the calculated X23 gender differential (X23GD) varied between countries, being over 100 in Germany, France and Romania, with values of 157, 113 and 111, respectively.  Table 2). Results show that eight and twenty-one fatalities were recorded in children (0-14 years) and the youth group (15-24 years), respectively. Adults (25-64 years) and seniors (65 years and older) were the most common age groups to be fatally injured with a total of 1128 victims (66.7%) and 520 victims (30.8%), respectively ( Table 2). Fatal stings occurred mainly at home (29.4%) and at other specified places (11.2%), followed by on the street and highway (3.2%) and at farms (1.5%). However, 44.2% of the fatalities, a total of 748, are recorded at an "unspecified place". The ranked order of the place of ocurrence was: X23.9 (unspecified place) > X23.0 (home) > X23.8 (other specified places) for Europe and Northern Europe; X23.0 (home) > X23.9 (unspecified place) > X23.8 (other specified places) for Eastern Europe; and X23.9 (unspecified place) > X23.8 (other specified places) > X23.0 (home) for Southern Europe. Table 2. Absolute and relative frequency of the deaths due to hornet, wasp and bee stings in Europe and by European region: counts, X23 gender ratio of mortality (X23GR), X23 gender differential in mortality (X23GD), by age distribution and by place of occurrence.

Hymenopteran Sting-Related Deaths, X23 Mortality Rates (X23MR)
The mortality rates (X23MR) were calculated based on the population size of each country, the obtained results ranged from 0 to 2.24 with an average of 0.26 (Supplementary  Table S6). The country with the highest mean X23MR was Estonia (0.61) followed by Austria and Slovenia (0.6 and 0.55, respectively). The countries with the lowest X23MR values were Ireland (0.05), United Kingdom (0.06) and the Netherlands (0.06). The highest rates were recorded in countries from Eastern Europe (X23MR = 0.35) followed by Western (X23MR = 0.28), Northern (X23MR = 0.23) and Southern (X23MR = 0.2) Europe ( Figure 2).

Discussion
There are limited studies of anaphylaxis epidemiology in general, and of insectvenom anaphylaxis in particular, and its impact is probably underestimated and largely unknown. One of the reasons is the difficult coding of the condition under the ICD-10 [26]. The WHO officially included allergic and hypersensitivity conditions as a disorder in the

Discussion
There are limited studies of anaphylaxis epidemiology in general, and of insect-venom anaphylaxis in particular, and its impact is probably underestimated and largely unknown. One of the reasons is the difficult coding of the condition under the ICD-10 [26]. The WHO officially included allergic and hypersensitivity conditions as a disorder in the ICD-11 in May 2019 [27][28][29]. The ICD-11 came into effect on January 2022, and the "Injury, poisoning or certain other consequences of external causes" is now chapter XXII, and "External causes of morbidity or mortality" is now chapter XXIII. The term "Contact with hornets, wasps and bees" was replaced to "Unintentionally stung or envenomated by animal" (code PA78). The different insects could be postcoordinated by the following extension codes: XE4D9 Bee, XE6LT Wasp and XE322 Hornet [30]. In adidition, it can be found "Allergic or hypersensitivity reactions to arthropods", represented by code 4A85.3. This includes both local cutaneous and systemic allergic and hypersensitivity reactions to contact with insects and other arthropods, with the following codes in this section: (a) systemic allergic reaction due to Hymenoptera venom (4A85.30), (b) cutaneous allergic or hypersensitivity reactions to Hymenoptera venom (4A85.31) and (c) cutaneous allergic or hypersensitivity reactions to arthropods (4A85.32).
The present study succeeded in gathering new and recent epidemiological information on Hymenopteran sting-related deaths in Europe. The majority of deaths occurred in adult males (25-64 years) at "unspecified places". The incidence observed in men may be related to different occupational roles and exposure degrees. This situation has been reported especially for beekeepers, electrical facility field workers, farming activities and forestry workers [31][32][33]. Moreover, mastocytosis, a risk factor for venom allergy, is more common in males than in females [34].
Related to the place of occurrence, almost half of the fatalities were recorded at "unspecified places". This makes it more difficult to develop prevention initiatives. Increased specificity in the place coding of deaths would help public health professionals target prevention interventions.
Hymenopteran-induced fatalities differ by age. The number of deaths clearly indicates that adult (1128 = 66.7%) and elderly (570 = 30.8%) people are at a higher risk agreeing with previous studies carried out in Costa Rica, South Korea and UK [35][36][37]. Children do not usually shown an anaphylactic reaction after Hymenopteran stings, being the LLR the most common presentation [38][39][40].
Honeybees and the business of apiculture have economic importance for agricultural production and beehive products. However, beekeepers and those living in proximity to hives are under sting risk [33]. In 2010 the total number of honeybee colonies in the European Union was close to 13.845.070, with a high heterogeneity distribution [48]. Spain, Greece and France have the highest density of colonies (≈10 colony/km 2 ); however, the countries located in the extreme north of Europe have the lowest density (1 colony/km 2 or less). There is not a high presence of beehives in either country with the highest X23MR in Estonia (X23MR = 0.61; 42,000 hives; 1 hives/km 2 ; 3.2 hives/100 inhabitants), Austria (X23MR = 0.6; 367,583 hives; 4.4 hives per km 2 and per 100 inhabitants) and Slovenia (X23MR = 0.55; 48,990 hives; 17.2 hives/km 2 ; 7.6 hives/100 inhabitants).
Although wasps are disliked by the general public, there is evidence and reasons to consider the regulatory, provisioning, supporting and cultural ecosystem services value of wasps on par with other insects such as bees [49,50]. Vespid species, populations, and ecosystems shown marked biogeographical differences throughout Europe [51]. It is necessary to point out that, within the past two decades, not-native species have been detected in Europe: (i) the yellow-legged Asian hornet (Vespa velutina Lepeletier 1836), found in southwestern France in 2004 [52]; (ii) the black shield hornet (Vespa bicolor Fabricius, 1787) found in 2013 in the community of Andalucía in Spain [53] and the (iii) American paper wasp (Polistes major major Palisot de Beauvois 1818) found in 2008 in Asturias in northern Spain [54]. In addition, some vespids have been translocated from certain European countries to others, such as (i) the Oriental hornet (Vespa orientalis Linnaeus 1771) naturally distributed in the south-eastern Europe, found in eastern Spain (Community of Valencia) in 2012 [55], in southern Spain in Algeciras in 2018 [56], in the Northern part of Bucharest in Romania in 2019 [57], in southern France in 2021 [58], and in the central-northern of Italy in the city of Florence in 2021 [59]; and (ii) Vespula and Dolichovespula species were confirmed in Iceland, Shetland, Orkney and the Faroe Islands [60]. In the entrance areas, the species have maintained stable populations, but they differ in their ability to propagate, highlighting the fact that the Vespa velutina is a highly invasive alien species.
With the expansion of the above mentioned non-native Hymenopteran species across Europe, allergists should be aware that their community's exposures are continually changing. In this way, the invasive Vespa velutina was identified as responsible for three-quarters of the Hymenoptera anaphylaxis patients reported during the last years in north-western Spain [61,62]. Invasive species have a major impact on human health, biodiversity and economics [63][64][65][66]. One Health philosophy has been adopted by the European Academy of Allergy and Clinical Immunology (EAACI). Such recognition led to the establishment of an independent Working Group (WG) within the EAACI solely dedicated to One Health in 2021 [67]. Because of the highly interdisciplinary nature of this WG, it is desirable that EAACI members work together with colleagues from a variety of fields. Veterinarians should play an important role in this work, based on their expertise, working closely with the beekeepers and recognizing the insects involved in the attacks. Lastly, descriptions of the stings have important value in this study since it has been reported that the identification of these insects performed by general population and allergy specialists is poor [40,68,69].

Conclusions
The most obvious shortcoming of the present investigation is that the hymenoptera species involved were not individually identified, with data provided by ICD-10 code. Knowledge about the presence of different stinging insects in Europe is important for diagnostic and therapeutic purposes. Our study has the advantage of using a large countrybased data set, which allow us to analyze time trends and age/gender distributions of hymenoptera sting-related deaths. However, epidemiological data at the regional level is needed to improve our understanding of Hymenoptera-sting incidence.
The frequency of stings and allergic reactions depends on different variables such as geographic, environmental, and ecological factors. When dealing with complicated challenges such as the health risks caused by native and not-native species of bee and wasp stings, it is necessary to produce, assemble and interpret information and knowledge using diverse sources and in an interdisciplinary way. As part of the One Health philosophy, people and animals as well as the environment that they share are closely connected. With the expansion of not-native Hymenopteran species across Europe, allergists should be aware that their community's exposures are continually changing and include these insects as causes of sting-related allergic reactions.
Supplementary Materials: The following are available online at https://www.mdpi.com/article/ 10.3390/biology11020282/s1, Supplementary Table S1: Place of occurrence code. The following categories are provided to be used as separate variables in addition to ICD categories W00-Y34 to identify the place of occurrence of the external cause where relevant. Supplementary Table S2: List of all European countries (n = 32) analyzed in the present study with their country code, dataset range and number of datasets. Supplementary Table S3: Absolute and relative frequency of the deaths due to hornet, wasp and bee stings by place of occurrence. Supplementary Table S4: Absolute and relative frequency of the deaths due to hornet, wasp and bee stings by age. Supplementary Table S5: Absolute and relative frequency of the deaths due to hornet, wasp and bee stings by gender; and the X23 gender ratio (X23GR) of mortality and the X23 gender differential (X23GD) in mortality. Supplementary  Table S6: Hymenopteran sting-related mortality rates (X23MR) during the studied period (1994-2016) calculated on the basis of the yearly population size of each country as reported on the census, as of 1 January of each year. The X23MR are expressed per year and per 1,000,000 inhabitants.
Author Contributions: Conceptualization, X.F.; methodology, X.F., C.V. and S.R.; writing-original draft preparation, X.F.; writing-review and editing, X.F., C.V. and S.R.; supervision and funding acquisition, C.V. All authors have read and agreed to the published version of the manuscript.

Funding:
The authors thank the Instituto de Salud Carlos III (Fondo de Investigaciones Sanitarias, Spanish Ministry of Health, PI19/01023) (Co-funded by the European Regional Development Fund "A way to make Europe") for the financial support. X.F. thanks Instituto de Salud Carlos III for a research contract (program number: RD16/0017/001).

Institutional Review Board Statement:
The study was conducted according to the guidelines of the Declaration of Helsinki. Institutional Review Board/Independent Ethics Committee (IRB/IEC) was not needed because the data are publicly available and contain no personal identifiers.

Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.