- D1.519 - Safety of ultra-rush protocols in venom immunotherapy: a systematic review and meta-analysis of Portuguese data

Venom immunotherapy (VIT) is the only disease-modifying treatment for Hymenoptera venom allergy (HVA). The safety profile may be affected by patients’ and treatment characteristics, the latter including the venom source and extract, and updosing protocols.

This study aims to evaluate the safety of VIT build-up in Portugal.

Subanalysis of the systematic review on HVA in Portugal (PROSPERO CRD420251087328). Of 69 eligible studies published up to December 2024, 33 reported on safety aspects of VIT, and 16 specified the frequency of systemic reactions (SR) according to the build-up protocol.

Whenever possible, we performed a meta-analysis to evaluate the proportion of SR during VIT updosing, using a random-effects model with inverse variance weighting. Patients were grouped by study, build-up protocol, and venom used. Statistical analysis was performed using RStudio 2025.09.2 for macOS, with the meta package.

There was a total of 666 patients included in the 16 studies, all reporting the safety of the build-up phase of VIT with aqueous extracts: 14 studies with the original 6-step ultra-rush (UR) (2 in comparison with rush or semi-rush protocols), one study comparing the 6-step with a 5-step protocol, and one comparing the 5-step with a 4-step protocol.

The pooled proportion of SR to UR VIT was 0.33[95%CI 0.27-0.41] for the Apis-venom patients (330 patients from 9 study groups), 0.01[95%CI 0.00-0.04] for the Vespid-venom patients (277 patients from 22 study groups – 188 Vespula-, 71 Polistes- and 18 Vespa velutina-venom), and 0.22[95%CI 0.17-0.27] in the 468 patients from 8 studies reporting mixed Apis and Vespid-venom patients (ranging from 51.2% to 80.0% Apis-venom VIT).

Five studies reported the severity of SR with the UR protocol in a total of 76 patients, with 25 (32.9%) reporting a grade I SR, 34 (44.7%) a grade II, 17 (22.4%) a grade III, and none reporting a Mueller grade IV reaction.

The two studies comparing a rush or semi-rush protocol (n=28) with the UR protocol (n=31), demonstrated a comparable safety profile, with an odds-ratio of 1.11[95%CI 0.33-3.68], p = 0.87.

The findings contribute to the growing body of evidence supporting the use of accelerated VIT schedules in clinical practice, showing a particularly good safety profile of ultra-rush build-up in vespid-venom immunotherapy.