High burden of clonal mast cell disorders and hereditary α-tryptasemia in patients who need Hymenoptera venom immunotherapy

Peter Korošec; Gunter J Sturm; Jonathan J Lyons; Tinkara Pirc Marolt; Manca Svetina; Mitja Košnik; Mihaela Zidarn; Mark Kačar; Nina Frelih; Nika Lalek; Ajda Demšar Luzar; Samo Zver; Matevž Škerget; Ewa Czarnobilska; Wojciech Dyga; Sanja Popović Grle; Miroslav Samarzija; Lisa Arzt-Gradwohl; Urban Čerpes; Grzegorz Porebski; Branko Pevec; Eva Schadelbauer; Peter Kopač; Julij Šelb; Matija Rijavec

doi:10.1111/all.16084

High burden of clonal mast cell disorders and hereditary α-tryptasemia in patients who need Hymenoptera venom immunotherapy

Allergy. 2024 Mar 13. doi: 10.1111/all.16084. Online ahead of print.

Authors

Peter Korošec^{1

2

3}, Gunter J Sturm^{4

5}, Jonathan J Lyons⁶, Tinkara Pirc Marolt¹, Manca Svetina^{1

7}, Mitja Košnik^{1

8}, Mihaela Zidarn^{1

7

8}, Mark Kačar^{1

8}, Nina Frelih^{1

8}, Nika Lalek^{1

8}, Ajda Demšar Luzar^{1

7}, Samo Zver^{8

9}, Matevž Škerget^{8

9}, Ewa Czarnobilska¹⁰, Wojciech Dyga¹⁰, Sanja Popović Grle¹¹, Miroslav Samarzija¹¹, Lisa Arzt-Gradwohl⁴, Urban Čerpes⁴, Grzegorz Porebski¹⁰, Branko Pevec¹¹, Eva Schadelbauer⁴, Peter Kopač^{1

8}, Julij Šelb^{1

8}, Matija Rijavec^{1

7}

Affiliations

¹ University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia.
² Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
³ Faculty of Medicine, University of Maribor, Maribor, Slovenia.
⁴ Department of Dermatology and Venerology, Medical University of Graz, Graz, Austria.
⁵ Allergy Outpatient Clinic Reumannplatz, Vienna, Austria.
⁶ Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
⁷ Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia.
⁸ Medical Faculty, University of Ljubljana, Ljubljana, Slovenia.
⁹ The Department of Hematology, University Medical Center Ljubljana, Ljubljana, Slovenia.
¹⁰ Department of Clinical and Environmental Allergology, Jagiellonian University Medical College, Krakow, Poland.
¹¹ Clinic for Respiratory Diseases Jordanovac, University Hospital Centre Zagreb, Zagreb, Croatia.

PMID: 38477502
DOI: 10.1111/all.16084

Abstract

Background: In patients who require venom immunotherapy (VIT), there is a need to identify underlying mast cell (MC) disorders since these may affect the risk and severity of future sting reactions and the long-term effectiveness of VIT.

Methods: 1319 individuals with Hymenoptera venom allergy (HVA) who needed VIT from referral centers in Slovenia, Austria, Croatia, and Poland underwent examination for KIT p.D816V in peripheral blood leukocytes (PBL) using a highly sensitive PCR test and tryptase genotyping by digital droplet PCR. We also included 183 control individuals with large local reactions (LLRs) to Hymenoptera stings and with asymptomatic sensitization to Hymenoptera venoms.

Results: 285 of 1319 individuals recommended for VIT (21.6%) were positive for KIT p.D816V in PBL, preferably those who present with severe reaction (33.9% [n = 207 of 610] with Ring-Messmer grade 3-4 vs. 11% [n = 78 of 709] with Grade 1-2; p < .0001), whereas only 1.3% (n = 2 of 152) of controls with LLR and none with asymptomatic sensitization (n = 31) had KIT p.D816V. KIT p.D816V allelic burden was higher in those with severe reaction (median 0.018% [n = 207] in Grade 3-4 vs. 0.001% [n = 78] in Grade 1-2; p < .0001), and the majority had normal baseline serum tryptase levels (69% [n = 196 of 285]). All KIT p.D816V-positive individuals (n = 41) who underwent bone marrow (BM) biopsy were found to have underlying clonal diseases, principally BM mastocytosis. HαT was also associated with severe HVA and symptoms (p < .01), and remarkably, 31.0% (n = 31 of 100) were found to have concomitant KIT p.D816V. Concomitant HαT and KIT p.D816V showed an additive effect, and having both was associated with the highest risk for severe HVA, even higher than having either HαT or KIT p.D816V alone (OR = 3.8; p < .01).

Conclusions: By employing prospective universal tryptase genotyping and examination for KIT p.D816V in PBL in large HVA populations, we have demonstrated a high burden of clonal MC disorders and HαT in patients who require VIT.

Keywords: anaphylaxis; hereditary α-tryptasemia; hypersensitivity; immunotherapy; mast cell; mastocytosis; venom.

Abstract

Grants and funding