Venom Allergy Study: Most Untreated Patients Avoid Severe Reactions

A retrospective observational study published in Allergy, Asthma & Clinical Immunology provides detailed insight into the natural course of Hymenoptera venom allergy among patients who decline venom immunotherapy (VIT). The research, conducted at the Allergy Centre Mainfranken in Germany, tracked 1,163 consecutive patients diagnosed with bee or vespid venom allergy between 2011 and 2021. Of these, 271 patients, representing 23.3% of the cohort, refused or postponed VIT for at least 12 months despite receiving a medical recommendation for treatment. The study aimed to identify factors associated with this refusal and to evaluate the clinical outcomes of these untreated individuals over a median follow-up period of five years.

The decision to decline VIT was influenced by specific demographic and clinical characteristics. Patients who refused treatment were significantly more likely to be female, with 53.1% of the decliners being women compared to 44.4% in the total cohort, a difference that was statistically significant with a P-value of 0.012. Furthermore, the severity of the initial sting-induced anaphylaxis was lower in the group that declined VIT. While patients who accepted treatment had a significantly higher frequency of moderate-to-severe reactions, 28.4% of those who declined had experienced only mild cutaneous symptoms, such as urticaria or angioedema, indicating a relative rather than absolute indication for therapy.

Among the 166 patients who agreed to follow-up counselling, the primary reasons for rejecting VIT were practical and perceptual rather than fear-based. The most frequently cited reason was that the treatment was considered too time-consuming or burdensome, reported by 39.8% of patients. An additional 24.1% perceived VIT as unnecessary for their condition. Only a minority, 6.6%, explicitly cited fear of side effects as their reason for refusal. This suggests that logistical challenges and a lack of perceived benefit are more significant barriers to adherence than anxiety about adverse reactions.

The study also assessed the safety behaviors of these untreated patients. A majority, 69.9%, reported routinely carrying an emergency kit containing an epinephrine autoinjector. This high rate of preparedness indicates that many patients who decline VIT are still engaged in managing their risk through alternative means. The researchers noted that the build-up phase of VIT, which at their centre is routinely carried out as a three-day inpatient rush protocol, may be difficult to reconcile with professional or family obligations, contributing to the perception of burden.

During the median five-year follow-up period, 39.2% of the 166 patients available for evaluation experienced one or more stings by the relevant Hymenoptera species. Of these 65 re-exposed patients, 52 tolerated the stings or developed only a large local reaction. Thirteen patients, representing 20% of those re-exposed, reported an anaphylactic sting reaction. Among these 13 cases, six reactions were classified as mild, five as moderate, and only two as severe. This corresponds to an overall rate of 7.8% for re-sting-induced anaphylaxis among the patients available for follow-up.

The severity of the relapse reactions was closely linked to the severity of the initial index sting. In no case did a severe grade 3 relapse reaction occur following an initially mild grade 1 reaction. This finding aligns with literature suggesting a correlation between the severity of previous anaphylactic sting reactions and that of future reactions. The data indicate that patients with milder initial reactions are less likely to experience severe outcomes upon re-exposure, even without immunotherapy.

The authors calculated a number needed to treat (NNT) of 17 to prevent one anaphylactic re-sting reaction, assuming a 5% reaction rate upon re-sting in individuals undergoing VIT. This calculation highlights the potential benefit of VIT in preventing systemic reactions. However, the observed relapse rate in the untreated group was lower than some historical data, which reported systemic anaphylactic sting reaction rates of up to 74% in adult patients. A 2012 Cochrane review had reported an overall relapse rate of 39.8% among untreated patients, suggesting that the risk may be lower than previously estimated in certain populations.

The study has several limitations that must be considered when interpreting the results. The retrospective design and reliance on routine patient care data introduce potential selection bias, as patients who accepted re-counselling may have done so because they experienced a re-sting. Additionally, self-reported field-sting data may be subject to response bias, and patients may have incorrectly identified the stinging insect. The study also noted that all reported re-sting reactions occurred in patients with Vespula venom allergy, meaning no conclusions can be drawn regarding the natural course of bee venom allergy in this specific cohort.

The findings suggest that a strictly binary classification of VIT as recommended or not recommended does not adequately capture the complex medical and personal considerations involved in patient care. The authors advocate for a nuanced approach to counselling, establishing a flexible decision zone where shared decision-making can guide the choice for or against VIT. This process should consider individual risk factors for severe anaphylaxis, the degree of sting exposure, and the patient’s personal needs, fears, and expectations.

By understanding the specific reasons for declining VIT, such as the perception of time burden, healthcare providers can implement targeted interventions to improve treatment adherence. Offering alternative up-dosing protocols, such as outpatient or clustered schedules, may address the logistical concerns that deter patients from starting treatment. The study underscores the importance of open discussion about treatment-related adverse effects and the benefits of VIT, framed in a way that enhances patient expectations and understanding of the therapy’s role in managing venom allergy.

The study was conducted at the Allergy Centre Mainfranken, a tertiary referral centre in Germany that receives patients from a radius of approximately 100 kilometres. The cohort comprised 1,163 consecutive patients diagnosed with Hymenoptera venom allergy between 2011 and 2021. Diagnosis was confirmed through a history of sting-induced anaphylaxis alongside sensitisation verified by intradermal testing, serological detection of venom-specific IgE, or basophil activation testing. Venom immunotherapy was recommended for patients with a history of moderate-to-severe systemic sting reactions. For those with mild anaphylaxis, the treatment was advised based on individual assessment of risk factors for severe reactions, such as elevated serum tryptase levels, underlying mastocytosis, advanced age, or increased exposure to stings. Each patient received detailed medical counselling, an allergy ID card, a printed emergency action plan, and an emergency kit for self-administration including an epinephrine autoinjector.

Patients were classified as untreated or having declined treatment if they had neither initiated VIT nor scheduled an appointment for treatment initiation within 12 months following allergy testing and counselling. These individuals were offered follow-up counselling sessions in person or by telephone. During these consultations, patients were re-advised to undergo VIT, and their reasons for refusal, perception of risks, and potential future sting reactions were explored using a standardised questionnaire. The study also inquired about the occurrence and outcome of field stings from bees or vespids and whether patients carried an emergency kit. As part of the follow-up process, patients received refresher training on the correct use of the epinephrine autoinjector. Complete data from 166 of the 271 patients who declined treatment were available for retrospective evaluation, while 105 patients were lost to follow-up.

Anaphylaxis in the study was classified as mild, moderate, or severe according to a modified version of the grading system proposed by Muraro et al. Mild reactions were characterised by symptoms largely limited to skin and mucous membranes. Moderate reactions involved objective extracutaneous involvement of cardiovascular, respiratory, gastrointestinal, or neurological systems. Severe reactions were defined by serious systemic symptoms such as oxygen desaturation, severe hypotension, loss of consciousness, or cardiac arrest. Large local reactions were defined as exceeding 10 cm in diameter and lasting more than 24 hours. Statistical analyses were performed using SPSS version 29, with the Mann-Whitney U test applied to compare two independent groups for interval-scaled data. The Chi-square test or Fisher’s exact test was used to analyse categorical data, with a P value of less than 0.05 considered statistically significant.

The total cohort had a median age of 45 years, with a range of 4 to 84 years at the time of the index sting. No significant difference in age was observed between patients who received VIT and those who declined treatment. Similarly, there were no statistically significant differences between the two groups in terms of diagnosis, which included Vespula venom allergy, bee venom allergy, or double allergy, or history of cardiovascular comorbidities. Male patients predominated in the total group and the group receiving VIT, with males comprising 55.6% and females 44.4%. In contrast, the group that declined treatment included a significantly higher proportion of females, at 53.1%. The two groups also differed significantly with respect to the severity of the index sting-induced anaphylactic reaction, with patients receiving VIT having a significantly higher frequency of moderate-to-severe reactions.

Among the 166 patients available for follow-up evaluation, the median time interval from the initial diagnosis and counselling to the last documented patient contact was five years, with a range of one to 11 years. During this period, 65 patients, representing 39.2% of the available cohort, had experienced one or several stings by the relevant Hymenoptera species. Fifty-two of these patients, representing 80% of those re-exposed, tolerated the field stings or developed only a large local reaction. The remaining 13 patients, representing 20% of those re-exposed, experienced re-sting-induced anaphylaxis. All patients who developed re-sting reactions had initially been diagnosed with Vespula venom allergy. One female patient experienced a grade 2 reaction to a bee sting two years after her initial reaction to a Vespula sting, although no sensitisation to bee venom had been detected in the initial allergy testing. All other patients reacted to vespid field stings.

The severity of the re-sting reactions varied, with six classified as mild, five as moderate, and two as severe. This corresponds to 3.1% of re-exposed patients and 1.2% of those available for follow-up. In three cases, the field sting-induced anaphylaxis was more severe than the index sting, in four cases it was less severe, and in the remaining six cases it was unchanged. The study noted that in no case did a severe grade 3 relapse reaction occur following an initially mild grade 1 reaction. This observation aligns with literature suggesting a correlation between the severity of previous anaphylactic sting reactions and that of future reactions. The authors suggested that withholding VIT may be justifiable when the informed patient explicitly opts against it, provided that a careful evaluation of risk factors for severe sting reactions is conducted to identify patients who should be prioritised for treatment.

Subject of Research: Clinical outcomes and patient characteristics of Hymenoptera venom-allergic patients who decline venom immunotherapy

Article Title: Declining venom immunotherapy: patient characteristics and clinical outcomes

Article References: Ueberschaar, S., Trautmann, A., & Stoevesandt, J. (2026). Declining venom immunotherapy: patient characteristics and clinical outcomes. Allergy, Asthma & Clinical Immunology, 22(1), Article 38. https://doi.org/10.1186/s13223-026-01046-w

Image Credits: AI Generated

DOI: 10.1186/s13223-026-01046-w

Keywords: venom immunotherapy, Hymenoptera allergy, anaphylaxis, patient adherence, clinical outcomes, retrospective study, allergy management, epinephrine autoinjector, Declining, venom, immunotherapy, patient