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The commentary titled “ACEIs and beta blockers as a risk factor for severe reactions to Hymenoptera venom, facts or fictions?”1Incorvaia C. Pucci S. Febo O.C. ACEIs and beta-blockers as a risk factor for severe reactions to Hymenoptera venom, facts or fictions?.J Allergy Clin Immunol. 2021; 147: 414-415Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar is of great interest, and we agree with the authors that the current state of knowledge regarding this topic is still controversial. The authors have accurately pointed out that previous reports support that angiotensin-converting enzyme inhibitors (ACEIs) and β-blockers are a risk factor for severe reactions to Hymenoptera venom. Previously, we have reported a similar observation in a larger cohort from the European Anaphylaxis Registry that was not restricted to Hymenoptera venom cases, using a different statistical approach.2Worm M. Francuzik W. Renaudin J.-M. Bilo M.B. Cardona V. Scherer Hofmeier K. et al.Factors increasing the risk for a severe reaction in anaphylaxis: an analysis of data from The European Anaphylaxis Registry.Allergy. 2018; 73: 1322-1330Crossref PubMed Scopus (115) Google Scholar Moreover, we were several years ago able to prove the influence of ACEIs and β-blockers in a mouse anaphylaxis model.3Nassiri M. Babina M. Dölle S. Edenharter G. Ruëff F. Worm M. Ramipril and metoprolol intake aggravate human and murine anaphylaxis: evidence for direct mast cell priming.J Allergy Clin Immunol. 2015; 135: 491-499Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar Although the effects of ramipril and metoprolol on the severity of anaphylaxis are small, we determined in vivo that their combined systemic application resulted in a significant core temperature drop in a systemic anaphylaxis mouse model. Moreover, the data were supported by in vitro results from human mast cells showing that these drugs alter the mast cells’ degranulation threshold.3Nassiri M. Babina M. Dölle S. Edenharter G. Ruëff F. Worm M. Ramipril and metoprolol intake aggravate human and murine anaphylaxis: evidence for direct mast cell priming.J Allergy Clin Immunol. 2015; 135: 491-499Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar Taking together these experimental data with our epidemiological findings we are convinced that a systemic intake of these drugs can impact the outcome of an anaphylactic reaction. We cannot however estimate the role of other factors such as the dose of the drugs, their selectivity, the genetic background of a given individual, and of course the impact of, generally speaking, any concomitant “cardiovascular dysfunctions.”4Francuzik W, Ruëff F, Bauer A, Bilo MB, Cardona V, Christoff G, et al. Phenotype and risk factors of venom-induced anaphylaxis: a case-control study of the European Anaphylaxis Registry [published online ahead of print June 22, 2020]. J Allergy Clin Immunol. https://doi.org/10.1016/j.jaci.2020.06.008.Google Scholar We hope to report in more detail about the origin of cardiovascular conditions in patients with venom-induced anaphylaxis. For this purpose, we included additional items into our questionnaire regarding this topic. As the authors suggested, we continue to intensively work on this fact or fiction controversy to obtain a more differentiated “key message” for clinicians (using a deeper analysis) to facilitate personalized recommendations. ACEIs and beta blockers as a risk factor for severe reactions to Hymenoptera venom, facts or fictions?Journal of Allergy and Clinical ImmunologyVol. 147Issue 1PreviewThe article by Francuzik et al,1 “Phenotype and risk factors of venom-induced anaphylaxis: a case-control study of the European Anaphylaxis Registry,” recently published in the journal raises the controversial issue that angiotensin-converting enzyme inhibitors (ACEIs) and β-blockers may increase the risk of severe reactions to Hymenoptera venom. Such risk has been initially suggested by Stumpf et al2 in 2006 by the results of a number of case reports, but was denied by others.3,4 The latest European Academy of Allergy and Clinical Immunology guidelines on venom immunotherapy (VIT) stated that the risk from ACEIs may have been overestimated because of the small populations, and that ACEI therapy may be continued during VIT, informing the patient about possible risk. Full-Text PDF