The Prevalence of Self-Reported Systemic Allergic Reaction to Hymenoptera Venom in Beekeepers Worldwide: A Systematic Literature Review and Meta-Analysis

Hymenoptera, including bees, wasps, ants and sawflies, comprises over 150,000 described species (1). Widely distributed across terrestrial ecosystems (2), this insect order is among the most species-rich and abundant, (3), playing crucial roles as pollinators, herbivores, and natural enemies within ecosystems (2). Despite their ecological significance, direct interactions with humans – often prompted by perceived threats from human activities or competition for food (4) – pose a risk of stinging and venom injection. The likelihood of encountering a specific stinging insect can vary depending on geographical, environmental, and ecological factors in the living environment, as well as the types of activities individuals engage in (5, 6).

In most healthy individuals without Hymenoptera venom allergy (HVA), a sting typically results in a well-tolerated, albeit temporarily painful local reaction, characterized by swelling, redness, and itching (7), usually resolving on its own within 24 to 48 hours (8). Conversely, for those sensitized to Hymenoptera venom, symptomatic allergic reaction (AR) may occur, with large local reaction (LLR) and systemic allergic reaction (SAR) as the most frequent clinical patterns. Medically important species capable of stinging and causing HVA belong to the Apidae, Vespidae, and Formicidae families (9).

Hymenopteras are also a leading cause of occupational anaphylaxis due to the heightened risk associated with exposure to repeated stings, a key factor in the development of AR (6). In terms of exposure intensity, certain population groups, particularly those in outdoor professions and specific occupational settings (6), face increased vulnerability to HVA. Beekeepers, in particular, face a specific risk (10), and epidemiological review findings have consistently reported higher estimated (self-reported) prevalence rates of SAR to bee venom in beekeepers (14%–30% (10); 4%–26% (11)) compared to the general population, affecting up to 3.3% of adults in the USA (12) and 8.9% in Europe (13).

However, none of the existing reviews (10, 11) systematically assessed observational studies among beekeepers worldwide, addressing the epidemiology of SAR to Hymenoptera venom. This study aims to fill this gap by conducting the first comprehensive systematic literature review and meta-analysis with the following objectives: 1) to assess the estimated prevalence of self-reported SAR to Hymenoptera venom in beekeepers worldwide, and 2) to explore whether geographical location and climate differences affect the estimated self-reported prevalence. Aligning with the observed population, we focused on the most common culprits of HVA among beekeepers (bee, wasp, hornet). In addition, our research specifically focuses on one species of bee, the honeybee (Apis mellifera), rather than bees in general, hereinafter referred to as the “bee”.

A comprehensive systematic literature review and meta-analysis were performed following the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement (14). The study protocol was preregistered in the International Prospective Register of Systematic Reviews (PROSPERO) under the identification number CRD42021260922 and is described elsewhere (15).

To the best of our knowledge, this systematic literature review and meta-analysis represents the first comprehensive attempt to estimate the global prevalence of self-reported SAR to Hymenoptera venom among beekeepers. Compared to the previous reviews, our findings (23.7%) align within the estimated clinical data on SAR, as objectively assessed by physicians (14%–21%) or assessed through interviews (30%), and self-reported data (4%–26%) (10, 11). The estimated lifetime prevalence of self-reported SAR (grades III–IV) to bee venom and overall one-year prevalence of self-reported SAR to bee venom were, as expected, lower, at 6.0% (95% CI: 3.0–11.7) and 7.3% (95% CI: 5.8–9.2), respectively. The observed heterogeneity across the studies was substantial, with I² values of 99% for estimated overall lifetime prevalence, and 93% for grades III–IV. The majority of studies were characterized by a high RoB.

Two major reasons could contribute to the observed heterogeneity in the study. Firstly, they may reflect methodological differences, including data collection technique, definition of AR and utilization of diverse classification systems for grading the severity of SAR across different regions (12, 25, 26).

With regard to the definition of AR, variability in how studies categorized and reported AR was observed. With the exception of one study (23), the questionnaires did not distinguish between allergic and non-allergic reactions (i.e., systemic toxic reactions, psychogenic reactions), raising the potential for a false history of self-reported SAR to Hymenoptera venom. This is because psychogenic reactions, which can imitate the symptoms of SAR, are relatively common following insect stings (27), and the high estimated overall lifetime prevalence of self-reported SAR to bee venom among the British beekeepers (48.4%) (20) could be attributed to misinterpretations of anxiety or pain following bee stings. This difference is particularly noteworthy, since the British study included a substantial number of women compared to other studies (see Table 1). Gender differences in self-reported emotional experiences have been well-documented, with previous research indicating that women often report experiencing negative emotions (fear) more frequently and intensely than men (28). Moreover, in this study the absence of a reported response rate, coupled with insufficient information for recalculation, may have caused a selection-bias, as individuals who had experienced SAR might have been more inclined to complete the questionnaire, driven by their heightened awareness of the potential severity of SAR. This selective participation could have led to an overestimation of the overall lifetime prevalence of self-reported SAR to bee venom, particularly for mild grades (grade I: 233 out of 852 (27.3%); grade II: 111 out of 852 (13.0%)) (20). The phenomenon of overestimation in both parental and self-reported data is a well-documented issue in assessing the prevalence of food allergies (29), and has also been reported in the context of HVA. Studies conducted in Poland revealed an overestimation in the prevalence of LLR and mild SAR when comparing self-reported estimates to those objectively assessed by a physician (30).

Importantly, putting aside the fact that a classification other than Müller was used, a high estimated overall lifetime prevalence of self-reported SAR to bee venom (37.6%) was also reported by Ediger et al. (23). However, these results may actually reflect the incidence of new cases rather than the overall prevalence, as the authors observed the course of symptoms over the years following bee stings. Meanwhile, Münstedt et al. (19), aimed to report the incidence of bee venom allergy, but a detailed textual analysis revealed that they reported the prevalence instead. Compared to the other studies, the authors also reported the lowest overall lifetime prevalence of self-reported SAR to bee venom, partly attributed to variations in the age of participants, with the mean age being approximately a decade higher compared to the data from other studies (17, 18, 22,23,24). Nevertheless, an important shortcoming of the German study is its very low response rate (3.0%), which may affect the accuracy of the prevalence estimates.

Secondly, the observed heterogeneity might be attributed to genuine disparities in sting exposure across different regions, influenced by geographic locations, climate, and beekeeping practices (11, 12, 25, 26).

In relation to bee sting exposure, Bousquet et al. (31) noted a strong correlation between the degree of sensitization to bee venom and the annual number of bee stings. This correlation is most prominent when the annual number of stings falls below 25 and reaches an optimum when it exceeds 200 (31). Aligning with this data, the potential protective effect of higher sting frequencies, as observed in Turkish studies (18, 22), and less so in the Finnish beekeepers (17), may explain the lower estimated overall one-year prevalence of self-reported SAR to bee venom in Turkey (6.5% (18), 7.0% (22)) compared to Finland (9.4%) (17). However, in Bousquet et al.’s study (31) the specific selection criteria employed (exclusion of numerous allergic beekeepers and individuals with variations in the number of annual bee stings over the previous five years) may have influenced the study’s outcomes.

Nonetheless, an intriguing pattern emerges within the estimated lifetime prevalence of self-reported SAR to bee venom in grades III–IV (severe SAR). Studies consistently indicate a higher estimated prevalence of severe self-reported SAR to bee venom in colder European regions (Finland, Great Britain) (17, 20), and a lower one in warmer non-European ones (Mexico, Turkey) (21, 24). In the latter case, it is plausible that favourable climatic conditions permit beekeepers to be exposed to bees throughout most of the year (18, 22, 32), leading to a lasting form of immunological protection (33), presumably on an immunological basis. Notably, heavily exposed beekeepers exhibit higher levels of bee-venom specific IgG4 (sIgG4), reflecting their degree of exposure to stings and believed to induce immune tolerance while mitigating the inflammatory response (34). However, the results of one Turkish study led by Ediger et al. (23) deviate from this expected pattern. It is suggestive that these findings may not be solely attributable to geographic location and climatic conditions, as observed in other studies. Instead, it is conceivable that methodological concerns, as mentioned previously, could significantly impact the observed outcome. However, the risk of developing SAR to bee venom cannot be entirely ruled out, even among beekeepers with a history of numerous bee stings and no prior AR (35, 36).

In contrast to beekeeping in regions with milder climates, apiculture in Europe is inherently seasonal, characterized by the distinct absence of bee sting exposure during the winter months, with this seasonal break lasting from the end of October throughout the entire winter (33). Moreover, the length of the beekeeping season varies across the regions, i.e., in Finland it extends from May to August (17), while in France it spans from early spring to late fall (31). It is conceivable that the natural history of sting reactions may exhibit disparities between the northern and southern regions (17). Moreover, it is plausible that differences between countries may also be due to beekeeping with different subspecies of honeybees (e.g., Apis mellifera carnica, Apis mellifera ligustica, etc.), because they are not all equally aggressive. Although Richter (20) noted that beekeeping with a particular subspecies did not increase susceptibility to SAR (data not shown in the original article), future studies should incorporate species-specific behavioural trait data to gain further insights into this research area.

However, regardless of the location, the temporal gap between two working seasons may potentially attenuate the protective effect conferred by prior bee stings, consequently increasing the susceptibility to the development of AR (37). This aligns with the conclusions drawn from a literature review (10), as initial stings in spring were identified as a definitive risk factor for the onset of allergic bee sting reactions among beekeepers. Furthermore, Münstedt et al. (19), reported the occurrence of more severe non-allergic reactions to bee venom during the spring months when compared to later periods. It is also important to consider the impact of climate change, as the available data support the presence of positive correlations between climate change and HVA (38).

Knowing that factors such as geographical location, climate differences, temperature fluctuations, and insect behaviour patterns can heighten the risk of insect stings within this population group, targeted public health interventions are essential. This includes implementing comprehensive risk assessment and management strategies, as well as launching public health campaigns and educational initiatives aimed at raising awareness about SAR and promoting preventive measures.

For allergic beekeepers, the most critical measure to mitigate risk is to reduce exposure by considering cessation of beekeeping activities. However, our meta-analysis reveals that many allergic beekeepers continue beekeeping, thereby exposing themselves to recurrent and potentially life-threatening SAR. Therefore, allergologists, public health professionals, and occupational, traffic and sports medicine specialists should intensify efforts in counselling, emphasizing 1) the importance of wearing full protective equipment during all beekeeping activities, 2) self-medication in emergencies, including regular training in proper use of adrenaline autoinjectors, and 3) considering Venom Immunotherapy (VIT) as a causal treatment option when indicated. In particular, life-long VIT should be considered for individuals with inherited or acquired risk factors.

Finally, when considering the extent of exposure, the differences in beekeepers’ status (professional or hobbyist) may also affect the outcome. As only one study included professional beekeepers (17), it would be intriguing to investigate potential differences between these two groups in future research. Moreover, an important knowledge gap is the lack of information regarding the location of hives (i.e., in a rural or urban environment). Urban beekeeping considerations are essential for public safety, as the estimated prevalence of self-reported SAR to Hymenoptera venom among individuals living in close proximity to beehives remains unreported (11).

For future cross-sectional studies, detailed reporting of study design, settings, study participants, and the use of validated questionnaires should be employed to ensure high-quality assessment of the observed health outcomes. In order to reduce the overestimation of the self-reported data, the observed health outcomes should be confirmed by an allerogologist. In terms of data collection, comprehensive reporting of health outcomes should include essential elements such as the classification system used (e.g., Müller grading system), grade of SAR, identified culprit Hymenoptera species, type and number of bees causing AR, and the prevalence period. Standardizing these parameters will enhance data uniformity, completeness, and comparability across studies. Statistical analyses should employ multivariate regression models to control for potential confounders effectively. Furthermore, distinguishing between family members and first-degree relatives (parents, children, siblings) will provide valuable insights into the heritable risks associated with SAR.