{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T05:10:33Z","timestamp":1777093833663,"version":"3.51.4"},"reference-count":37,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2023,11,15]],"date-time":"2023-11-15T00:00:00Z","timestamp":1700006400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004329","name":"Slovenian Research and Innovation Agency","doi-asserted-by":"publisher","award":["P3-0360"],"award-info":[{"award-number":["P3-0360"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hymenoptera venom\u2013triggered anaphylaxis (HVA) affects up to 8.9% of the general population and is the most frequent cause of anaphylaxis in adults, accounting for approximately 20% of all fatal anaphylaxis cases. Quite often, a fatal reaction is a victim\u2019s first manifestation of HVA. Mastocytosis represents one of the most important risk factors for severe HVA. We analyzed patients with documented fatal HVA for the presence of underlying clonal mast cell disorder (cMCD). Here, we report three cases of fatal HVA, with undiagnosed underlying cMCD identified by the presence of the peripheral blood and\/or bone marrow KIT p.D816V missense variant postmortem. In the first case, anaphylaxis was the initial episode and was fatal. In the other two cases, both patients were treated with specific venom immunotherapy (VIT), nevertheless, one died of HVA after VIT discontinuation, and the other during VIT; both patients had cardiovascular comorbidities and were taking beta-blockers and\/or ACE inhibitors. Our results point to the importance of screening all high-risk individuals for underlying cMCD using highly sensitive molecular methods for peripheral blood KIT p.D816V variant detection, including severe HVA and possibly beekeepers, for proper management and the need for lifelong VIT to prevent unnecessary deaths. Patients at the highest risk of fatal HVA, with concomitant cardiovascular and cMCD comorbidities, might not be protected from field stings even during regular VIT. Therefore, two adrenaline autoinjectors and lifelong VIT, and possibly cotreatment with omalizumab, should be considered for high-risk patients to prevent fatal HVA episodes.<\/jats:p>","DOI":"10.3390\/ijms242216368","type":"journal-article","created":{"date-parts":[[2023,11,15]],"date-time":"2023-11-15T10:51:37Z","timestamp":1700045497000},"page":"16368","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Fatal Hymenoptera Venom\u2013Triggered Anaphylaxis in Patients with Unrecognized Clonal Mast Cell Disorder\u2014Is Mastocytosis to Blame?"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2596-4952","authenticated-orcid":false,"given":"Matija","family":"Rijavec","sequence":"first","affiliation":[{"name":"University Clinic of Respiratory and Allergic Diseases Golnik, 4204 Golnik, Slovenia"},{"name":"Biotechnical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jezerka","family":"Inkret","sequence":"additional","affiliation":[{"name":"Institute of Forensic Medicine, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8978-6887","authenticated-orcid":false,"given":"Ur\u0161ka","family":"Bidovec-Stojkovi\u0107","sequence":"additional","affiliation":[{"name":"University Clinic of Respiratory and Allergic Diseases Golnik, 4204 Golnik, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanja","family":"Carli","sequence":"additional","affiliation":[{"name":"National Institute of Public Health, 1000 Ljubljana, Slovenia"},{"name":"Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nina","family":"Frelih","sequence":"additional","affiliation":[{"name":"University Clinic of Respiratory and Allergic Diseases Golnik, 4204 Golnik, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreja","family":"Kukec","sequence":"additional","affiliation":[{"name":"National Institute of Public Health, 1000 Ljubljana, Slovenia"},{"name":"Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Koro\u0161ec","sequence":"additional","affiliation":[{"name":"University Clinic of Respiratory and Allergic Diseases Golnik, 4204 Golnik, Slovenia"},{"name":"Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia"},{"name":"Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4701-7374","authenticated-orcid":false,"given":"Mitja","family":"Ko\u0161nik","sequence":"additional","affiliation":[{"name":"University Clinic of Respiratory and Allergic Diseases Golnik, 4204 Golnik, Slovenia"},{"name":"Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1111\/all.15032","article-title":"EAACI guidelines: Anaphylaxis (2021 update)","volume":"77","author":"Muraro","year":"2022","journal-title":"Allergy"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.jaci.2017.06.003","article-title":"The pathophysiology of anaphylaxis","volume":"140","author":"Reber","year":"2017","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1111\/cea.14264","article-title":"Clonal mast cell disorders and hereditary \u03b1-tryptasemia as risk factors for anaphylaxis","volume":"53","author":"Rijavec","year":"2023","journal-title":"Clin. Exp. Allergy"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"180","DOI":"10.18176\/jiaci.0310","article-title":"Hymenoptera venom allergy: Management of children and adults in clinical practice","volume":"29","author":"Pravettoni","year":"2019","journal-title":"J. Investig. Allergol. Clin. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1111\/j.1365-2222.2009.03324.x","article-title":"The natural history and epidemiology of insect venom allergy: Clinical implications","volume":"39","author":"Bonifazi","year":"2009","journal-title":"Clin. Exp. Allergy"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1111\/all.12475","article-title":"First European data from the network of severe allergic reactions (NORA)","volume":"69","author":"Worm","year":"2014","journal-title":"Allergy"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1016\/j.jaip.2017.06.031","article-title":"Fatal Anaphylaxis: Mortality Rate and Risk Factors","volume":"5","author":"Turner","year":"2017","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2644","DOI":"10.1111\/all.14352","article-title":"Fatal anaphylaxis in Italy: Analysis of cause-of-death national data, 2004\u20132016","volume":"75","author":"Corsi","year":"2020","journal-title":"Allergy Eur. J. Allergy Clin. Immunol."},{"key":"ref_9","unstructured":"Turner, P.J. (2021). Reference Module in Biomedical Sciences, Elsevier."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/j.iac.2023.04.011","article-title":"World Health Organization Classification and Diagnosis of Mastocytosis Update 2023 and Future Perspectives","volume":"43","author":"Valent","year":"2023","journal-title":"Immunol. Allergy Clin. N. Am."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1016\/j.jaci.2020.06.035","article-title":"Heritable risk for severe anaphylaxis associated with increased \u03b1-tryptase\u2013encoding germline copy number at TPSAB1","volume":"147","author":"Lyons","year":"2021","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/j.jaci.2021.02.043","article-title":"Routine KIT p.D816V screening identifies clonal mast cell disease in patients with Hymenoptera allergy regularly missed using baseline tryptase levels alone","volume":"148","author":"Rijavec","year":"2021","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1016\/j.jaip.2022.03.007","article-title":"Personalized Management Strategies in Mast Cell Disorders: ECNM-AIM User\u2019s Guide for Daily Clinical Practice","volume":"10","author":"Valent","year":"2022","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1159\/000113520","article-title":"Fatal anaphylactic sting reaction in a patient with mastocytosis","volume":"146","author":"Wagner","year":"2008","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/S0091-6749(97)70314-2","article-title":"Fatal anaphylaxis after a yellow jacket sting, despite venom immunotherapy, in two patients with mastocytosis","volume":"99","author":"Elberink","year":"1997","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1016\/j.jaip.2017.03.019","article-title":"Fatal Anaphylaxis to Yellow Jacket Stings in Mastocytosis: Options for Identification and Treatment of At-Risk Patients","volume":"5","author":"Vos","year":"2017","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/j.revmed.2021.08.005","article-title":"Fatal hymenoptera venom anaphylaxis by undetected clonal mast cell disorder: A better identification of high risk patients is needed","volume":"42","author":"Chatain","year":"2021","journal-title":"Rev. Med. Interne"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1016\/j.jaip.2017.11.025","article-title":"Anaphylactic Reactions After Discontinuation of Hymenoptera Venom Immunotherapy: A Clonal Mast Cell Disorder Should Be Suspected","volume":"6","author":"Bonadonna","year":"2018","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"110415","DOI":"10.1016\/j.forsciint.2020.110415","article-title":"Post mortem tryptase: A review of literature on its use, sampling and interpretation in the investigation of fatal anaphylaxis","volume":"314","author":"Garland","year":"2020","journal-title":"Forensic Sci. Int."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.forsciint.2017.12.035","article-title":"Post mortem tryptase cut-off level for anaphylactic death","volume":"284","author":"Tse","year":"2018","journal-title":"Forensic Sci. Int."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Fe\u00e1s, X., Vidal, C., and Remesar, S. (2022). What We Know about Sting-Related Deaths? Human Fatalities Caused by Hornet, Wasp and Bee Stings in Europe (1994\u20132016). Biology, 11.","DOI":"10.20944\/preprints202112.0483.v1"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.jaip.2019.06.021","article-title":"Fatal anaphylaxis following a hornet sting in a yellow jacket venom-sensitized patient with undetected monoclonal mast cell activation syndrome and without previous history of a systemic sting reaction","volume":"8","author":"Blank","year":"2020","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"110814","DOI":"10.1016\/j.forsciint.2021.110814","article-title":"Fatal anaphylactic shock: A review of postmortem biomarkers and diagnostics","volume":"323","author":"Heldring","year":"2021","journal-title":"Forensic Sci. Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1628","DOI":"10.1111\/all.15645","article-title":"Fatal and near-fatal anaphylaxis: The Allergy-Vigilance\u00ae Network data (2002\u20132020)","volume":"78","author":"Pouessel","year":"2023","journal-title":"Allergy Eur. J. Allergy Clin. Immunol."},{"key":"ref_25","first-page":"4","article-title":"H\u03b1T is associated with increased risk for severe Hymenoptera venom-triggered anaphylaxis","volume":"278","author":"Rijavec","year":"2022","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3176","DOI":"10.1016\/j.jaip.2021.04.062","article-title":"Diagnosis of Primary Mast Cell Disorders in Anaphylaxis: Value of KIT D816V in Peripheral Blood","volume":"9","author":"Ebo","year":"2021","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e12174","DOI":"10.1002\/clt2.12174","article-title":"Detection of clonal mast cell disease in wasp venom allergic patients with normal tryptase","volume":"12","author":"Onnes","year":"2022","journal-title":"Clin. Transl. Allergy"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1016\/j.jaci.2019.07.037","article-title":"Detection of KIT D816V mutation in patients with severe anaphylaxis and normal basal tryptase\u2014First data from the Anaphylaxis Registry (NORA)","volume":"144","author":"Siebenhaar","year":"2019","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1111\/all.15584","article-title":"KITD816V mutation in blood for the diagnostic screening of systemic mastocytosis and mast cell activation syndromes","volume":"78","author":"Henriques","year":"2023","journal-title":"Allergy Eur. J. Allergy Clin. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"128","DOI":"10.5414\/ALX02196E","article-title":"Omalizumab ensures compatibility to bee venom immunotherapy (VIT) after VIT-induced anaphylaxis in a patient with systemic mastocytosis","volume":"5","author":"Jappe","year":"2021","journal-title":"Allergol. Sel."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1111\/all.13237","article-title":"Omalizumab prevents anaphylaxis and improves symptoms in systemic mastocytosis: Efficacy and safety observations","volume":"73","author":"Vestergaard","year":"2018","journal-title":"Allergy"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1046\/j.1365-2222.2000.00864.x","article-title":"Lessons for management of anaphylaxis from a study of fatal reactions","volume":"30","author":"Pumphrey","year":"2000","journal-title":"Clin. Exp. Allergy"},{"key":"ref_33","unstructured":"(2023, August 09). International Classification of Diseases (ICD) [Internet]. Available online: https:\/\/www.who.int\/standards\/classifications\/classification-of-diseases."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1016\/j.jaci.2008.11.018","article-title":"Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased serum tryptase levels","volume":"123","author":"Bonadonna","year":"2009","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.iac.2006.05.010","article-title":"Diagnostic Value of Tryptase in Anaphylaxis and Mastocytosis","volume":"26","author":"Schwartz","year":"2006","journal-title":"Immunol. Allergy Clin. N. Am."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1002\/ajh.23672","article-title":"Sensitive KIT D816V mutation analysis of blood as a diagnostic test in mastocytosis","volume":"89","author":"Kristensen","year":"2014","journal-title":"Am. J. Hematol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1038\/ng.3696","article-title":"Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number","volume":"48","author":"Lyons","year":"2016","journal-title":"Nat. Genet."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/22\/16368\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:23:35Z","timestamp":1760131415000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/22\/16368"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,15]]},"references-count":37,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["ijms242216368"],"URL":"https:\/\/doi.org\/10.3390\/ijms242216368","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,15]]}}}