Julij Šelb1, Matija Rijavec2, Renato Eržen1, Mihaela Zidarn1, Peter Kopač1, Matevž Škerget3, Nissera Bajrović1, Ajda Demšar Luzar4, Young Hwan Park5, Yihui Liu5, Vladka Čurin Šerbec6, Samo Zver3, Mitja Košnik1, Jonathan J Lyons5, Peter Korošec7. 1. University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia; Medical Faculty, University of Ljubljana, Ljubljana, Slovenia. 2. University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia; Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia. 3. Medical Faculty, University of Ljubljana, Ljubljana, Slovenia; Department of Hematology, University Medical Center Ljubljana, Ljubljana, Slovenia. 4. University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia. 5. Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. 6. Department of Research and Development, Blood Transfusion Centre of Slovenia, Ljubljana, Slovenia. 7. University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia. Electronic address: peter.korosec@klinika-golnik.si.
Abstract
BACKGROUND: Clonal mast cell disorders and elevated basal serum tryptase (BST) levels with unknown cause(s) are associated with severe Hymenoptera venom-triggered anaphylaxis (HVA). However, some individuals with clonal disease have a normal BST level (<11.4 ng/mL). OBJECTIVE: Our aim was to evaluate whether screening for KIT p.D816V in the blood is a useful clinical tool to risk-stratify patients with venom allergy. METHODS: We prospectively recruited 374 patients with Hymenoptera allergy and no overt signs of mastocytosis who were referred to our center during the years 2018 and 2019. KIT p.D816V was determined in their peripheral blood by quantitative PCR, and tryptase genotyping was performed by droplet digital PCR. RESULTS: In all, 351 patients (93.9%) had normal levels of BST, and KIT p.D816V was detected in 8% of patients (28 of 351), predominantly in patients with the most severe Mueller grade IV anaphylaxis (18.2% [24 of 132] vs 1.8% in patients with lower grades [4 of 88 with grade III and 0 of 131 with other grades]; P < .001). In grade IV patients with a normal BST level, KIT p.D816V was associated with more severe symptoms, including a significantly higher frequency of loss of consciousness (58.3% [14 of 24] vs 34.3% [37 of 108]; P = .03) and absence of skin symptoms (41.7% [10 of 24] vs 15.7% [17 of 108]; P = .004). Among patients with a normal BST level, KIT p.D816V (OR = 10.25 [95% CI = 3.75-36.14]; P < .0001) was the major risk factor associated with severe HVA. Hereditary α-tryptasemia (HαT) due to increased germline copies of TPSAB1 encoding α-tryptase was the most common cause (65.2% [15 of 23]) of elevated BST level in patients with HVA, and together with KIT p.D816V, it accounted for 90% of BST level elevations (20 of 23) in patients with HVA. CONCLUSION: These results indicate that routine KIT p.D816V screening identifies clonal disease in high-risk patients with HVA who are regularly missed when BST level is used alone.
BACKGROUND: Clonal mast cell disorders and elevated basal serum tryptase (BST) levels with unknown cause(s) are associated with severe Hymenoptera venom-triggered anaphylaxis (HVA). However, some individuals with clonal disease have a normal BST level (<11.4 ng/mL). OBJECTIVE: Our aim was to evaluate whether screening for KITp.D816V in the blood is a useful clinical tool to risk-stratify patients with venom allergy. METHODS: We prospectively recruited 374 patients with Hymenoptera allergy and no overt signs of mastocytosis who were referred to our center during the years 2018 and 2019. KITp.D816V was determined in their peripheral blood by quantitative PCR, and tryptase genotyping was performed by droplet digital PCR. RESULTS: In all, 351 patients (93.9%) had normal levels of BST, and KITp.D816V was detected in 8% of patients (28 of 351), predominantly in patients with the most severe Mueller grade IV anaphylaxis (18.2% [24 of 132] vs 1.8% in patients with lower grades [4 of 88 with grade III and 0 of 131 with other grades]; P < .001). In grade IV patients with a normal BST level, KITp.D816V was associated with more severe symptoms, including a significantly higher frequency of loss of consciousness (58.3% [14 of 24] vs 34.3% [37 of 108]; P = .03) and absence of skin symptoms (41.7% [10 of 24] vs 15.7% [17 of 108]; P = .004). Among patients with a normal BST level, KITp.D816V (OR = 10.25 [95% CI = 3.75-36.14]; P < .0001) was the major risk factor associated with severe HVA. Hereditary α-tryptasemia (HαT) due to increased germline copies of TPSAB1 encoding α-tryptase was the most common cause (65.2% [15 of 23]) of elevated BST level in patients with HVA, and together with KITp.D816V, it accounted for 90% of BST level elevations (20 of 23) in patients with HVA. CONCLUSION: These results indicate that routine KITp.D816V screening identifies clonal disease in high-risk patients with HVA who are regularly missed when BST level is used alone.
Authors: Sarah C Glover; Melody C Carter; Peter Korošec; Patrizia Bonadonna; Lawrence B Schwartz; Joshua D Milner; George H Caughey; Dean D Metcalfe; Jonathan J Lyons Journal: Ann Allergy Asthma Immunol Date: 2021-08-13 Impact factor: 6.248
Authors: Aubri M Waters; Hyun J Park; Andrew L Weskamp; Allyson Mateja; Megan E Kachur; Jonathan J Lyons; Benjamin J Rosen; Nathan A Boggs Journal: J Allergy Clin Immunol Pract Date: 2022-01-12
Authors: Merel C Onnes; Abdulrazzaq Alheraky; Martijn C Nawijn; Tim E Sluijter; André B Mulder; Suzanne Arends; Hanneke N G Oude Elberink Journal: Clin Transl Allergy Date: 2022-09-07 Impact factor: 5.657