000804 - Anaphylaxis during honeybee venom immunotherapy despite proven sting tolerance: the impact of cold-chain breach

Venom immunotherapy (VIT) is safe and effective, adverse events are usually associated with mast cell disorders or immunological risk factors. Non-immunological determinants, such as extract stability and handling, are rarely reported as triggers for paradoxical systemic reactions in protected patients.

We present an adult patient with a Grade II systemic reaction to a honeybee sting (urticaria, angioedema and dyspnea). Serum analysis and skin test for hymenoptera venom were performed, confirming selective Apis mellifera sensitization (rApi m 1++, rApi m 2++, CCD–) with a normal baseline serum tryptase (4.2 µg/L). Venom immunotherapy with Apis mellifera venom (Abenox®, Roxall) was initiated, reaching a maintenance dose of 100 µg/4 weeks with good tolerance. To confirm efficacy, a controlled in-hospital sting challenge was performed after 13 months. The challenge was negative (only an expected local reaction), confirming clinical protection and supporting continuation of maintenance VIT. One month later, 10 minutes after the injection of maintenance dose the patient developed acute anaphylaxis (facial edema, dyspnea). The reaction resolved rapidly after intramuscular epinephrine and intravenous corticosteroids and antihistamines. Considering the discordance between the recent negative sting challenge (proven tolerance) and injection-induced anaphylaxis, a new blood panel was performed, showing an unchanged sensitization profile.

After excluding changes in the patient’s sensitization profile, a non-immunological cause was suspected: we looked into a possible damage or defect in the VIT extract. So as, VIT was resumed with a fresh vial from a new batch under supervision, with complete tolerance of the maintenance dose divided between arms within 30 minutes interval (0.5ml + 0.5ml). 

New interrogation of the patient revealed the vial had been accidentally stored at high temperatures (> 30ºC) for 48 hours, and, afterwards stored back in the fridge. The reaction was hypothesized to be related to the formation of immunogenic protein aggregates or neo-epitopes secondary to thermal instability of the extract.

This case highlights a rare "false failure" of VIT safety rather than efficacy. Unlike typical loss of potency, improper extract storage (cold-chain breach) may trigger anaphylaxis in tolerant patients, potentially due to protein aggregation increasing reactogenicity. It underscores the critical importance of cold-chain compliance and traceability as non-immunological safety determinants.