Routine KIT p.D816V screening identifies clonal mast cell disease in patients with Hymenoptera allergy regularly missed using baseline tryptase levels alone

Šelb, Julij; Rijavec, Matija; Eržen, Renato; Zidarn, Mihaela; Kopač, Peter; Škerget, Matevž; Bajrović, Nissera; Luzar, Ajda Demšar; Park, Young Hwan; Liu, Yihui; Šerbec, Vladka Čurin; Zver, Samo; Košnik, Mitja; Lyons, Jonathan J.; Korošec, Peter

doi:10.1016/j.jaci.2021.02.043

Cited by 39 publications

(45 citation statements)

References 21 publications

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“…However, in selected cases, VIT should not be discontinued. The general consensus is that patients with an initial severe sting reaction and patients diagnosed with clonal mast cell disorder (often associated with elevated basal serum tryptase and KIT D816V mutation) should receive lifelong VIT [ 21 , 22 ]. Even though it is well documented that VIT provokes venom tolerance in the majority of treated patients, the exact underlying mechanism remains unclear.…”

Section: Venom Immunotherapymentioning

confidence: 99%

Hymenoptera Venom Immunotherapy: Immune Mechanisms of Induced Protection and Tolerance

Luzar

Korošec

Košnik

et al. 2021

Cells

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Hymenoptera venom allergy is one of the most severe allergic diseases, with a considerable prevalence of anaphylactic reaction, making it potentially lethal. In this review, we provide an overview of the current knowledge and recent findings in understanding induced immune mechanisms during different phases of venom immunotherapy. We focus on protection mechanisms that occur early, during the build-up phase, and on the immune tolerance, which occurs later, during and after Hymenoptera venom immunotherapy. The short-term protection seems to be established by the early desensitization of mast cells and basophils, which plays a crucial role in preventing anaphylaxis during the build-up phase of treatment. The early generation of blocking IgG antibodies seems to be one of the main reasons for the lower activation of effector cells. Long-term tolerance is reached after at least three years of venom immunotherapy. A decrease in basophil responsiveness correlates with tolerated sting challenge. Furthermore, the persistent decline in IgE levels and, by monitoring the cytokine profiles, a shift from a Th2 to Th1 immune response, can be observed. In addition, the generation of regulatory T and B cells has proven to be essential for inducing allergen tolerance. Most studies on the mechanisms and effectiveness data have been obtained during venom immunotherapy (VIT). Despite the high success rate of VIT, allergen tolerance may not persist for a prolonged time. There is not much known about immune mechanisms that assure long-term tolerance post-therapy.

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Section: Venom Immunotherapymentioning

confidence: 99%

Hymenoptera Venom Immunotherapy: Immune Mechanisms of Induced Protection and Tolerance

Luzar

Korošec

Košnik

et al. 2021

Cells

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“…Currently, no individual has been reported or observed with HaT and BST less than 6 ng/mL, including those with HVA. 13,15,30,31,36,37,42 The association between this genetic trait and severe venom anaphylaxis seems to be independent of concomitant clonal MC disease; however, the relatively high and unexpected prevalence of concomitant HaT and clonal MC disease (8.6%-15.8%) in different HVA cohorts suggests that the relative risk for severe HVA imparted by HaT and SM is additive. 13,14,16,[42][43][44] The ability to risk stratify individuals with venom allergy and identify those at risk for severe HVA is important not only for anticipatory counseling of patients but also for guiding therapy, as lifelong venom immunotherapy (VIT) is currently recommended for individuals with clonal MC disease and HVA.…”

Section: Hereditary Alpha-tryptasemia and Anaphylaxis Severity In Pat...mentioning

confidence: 99%

“…13,15,30,31,36,37,42 The association between this genetic trait and severe venom anaphylaxis seems to be independent of concomitant clonal MC disease; however, the relatively high and unexpected prevalence of concomitant HaT and clonal MC disease (8.6%-15.8%) in different HVA cohorts suggests that the relative risk for severe HVA imparted by HaT and SM is additive. 13,14,16,[42][43][44] The ability to risk stratify individuals with venom allergy and identify those at risk for severe HVA is important not only for anticipatory counseling of patients but also for guiding therapy, as lifelong venom immunotherapy (VIT) is currently recommended for individuals with clonal MC disease and HVA. 43,44 Because at the time of writing this manuscript, longitudinal data are lacking, the authors feel that it is prudent to continue lifelong VIT in patients with severe HVA and HaT, until such time that the long-term data become available.…”

Section: Hereditary Alpha-tryptasemia and Anaphylaxis Severity In Pat...mentioning

confidence: 99%

“…16 Nevertheless, recent studies revealed an increased prevalence of HaT only among individuals with severe HVA (principally Mueller grade IV), with a prevalence that that was roughly doublethe expected prevalence in the general population or in overall cohorts of patients with venom allergy (from 5.5% to approximately 10%). 13,42 Thus, HaT does not seem to contribute to the development of sensitization to Hymenoptera venom but rather modifies the clinical outcome, potentially by unique activities of a/b-tryptase heterotetramers that may increase vascular permeability and anaphylaxis severity. 13,19 Given the high frequency (81% and 82%) of detecting HaT among those with HVA, 13,42 elevated BST and no evidence of clonal MC disease, and recent observations that HaT is the most common cause (65%) of elevated BST levels in patients with HVA, 42 we recommend that tryptase genotyping be considered in the clinical workup of all individuals with HVA and BST levels greater than 8 ng/mL and those with a history of severe venom anaphylaxis and a normal BST level of 6 to 8 ng/mL.…”

Section: Hereditary Alpha-tryptasemia and Anaphylaxis Severity In Pat...mentioning

confidence: 99%

“…13,42 Thus, HaT does not seem to contribute to the development of sensitization to Hymenoptera venom but rather modifies the clinical outcome, potentially by unique activities of a/b-tryptase heterotetramers that may increase vascular permeability and anaphylaxis severity. 13,19 Given the high frequency (81% and 82%) of detecting HaT among those with HVA, 13,42 elevated BST and no evidence of clonal MC disease, and recent observations that HaT is the most common cause (65%) of elevated BST levels in patients with HVA, 42 we recommend that tryptase genotyping be considered in the clinical workup of all individuals with HVA and BST levels greater than 8 ng/mL and those with a history of severe venom anaphylaxis and a normal BST level of 6 to 8 ng/mL. Currently, no individual has been reported or observed with HaT and BST less than 6 ng/mL, including those with HVA.…”

Section: Hereditary Alpha-tryptasemia and Anaphylaxis Severity In Pat...mentioning

confidence: 99%

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Clinical relevance of inherited genetic differences in human tryptases

Glover

Carter

Korošec

et al. 2021

Annals of Allergy, Asthma & Immunology

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Detection of clonal mast cell disease in wasp venom allergic patients with normal tryptase

Onnes

Alheraky

Nawijn

et al. 2022

Clinical & Translational All

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Background: Clonal mast cell disease (CMD) is an underlying aggravating condition in wasp venom allergy (WVA) which requires a different treatment strategy. CMD is increasingly recognized in patients with normal basal serum tryptase (bsT). However, methods to identify at risk patients have not yet been assessed in large cohorts of WVA patients with normal bsT. Methods: This retrospective study evaluated the reliability of the REMA score in detecting CMD in a cohort of grade IV WVA patients with normal bsT and assessed the added value of other clinical parameters, KIT D816V mutation analysis in peripheral blood (PB) and the diagnosis of hereditary alpha tryptasemia (HAT). All patients had a conclusive bone marrow evaluation that demonstrated or excluded underlying CMD.Results: In total 35 CMD and 96 non-CMD patients were included. REMA score had a sensitivity of 72% (95% CI 56%-88%) and specificity of 79% (95% CI 70%-87%) in this cohort. Loss of consciousness during systemic reaction and bsT between 6.3 and 11.4 ng/ml were additional parameters independently associated with CMD.Sensitivity of KIT in PB was relatively low, 56% (95% CI 36%-75%), but had added value as screening method in patients with a low REMA score due to 100% specificity. Conclusion:The REMA score is a relatively reliable method to detect patients at risk of CMD among WVA patients with normal bsT. KIT mutation analysis in PB could serve as additional screening method in patients with low REMA scores. K E Y W O R D Sinsect venom, KIT D816V analysis in peripheral blood, mastocytosis, REMA score, tryptaseThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Routine KIT p.D816V screening identifies clonal mast cell disease in patients with Hymenoptera allergy regularly missed using baseline tryptase levels alone

Cited by 39 publications

References 21 publications

Hymenoptera Venom Immunotherapy: Immune Mechanisms of Induced Protection and Tolerance

Hymenoptera Venom Immunotherapy: Immune Mechanisms of Induced Protection and Tolerance

Clinical relevance of inherited genetic differences in human tryptases

Detection of clonal mast cell disease in wasp venom allergic patients with normal tryptase

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