Anaphylactic Reactions After Discontinuation of Hymenoptera Venom Immunotherapy: A Clonal Mast Cell Disorder Should Be Suspected.

Up to 75% of patients with severe anaphylactic reactions after Hymenoptera sting are at risk of further severe reactions if re-stung. Venom immunotherapy (VIT) is highly effective in protecting individuals with ascertained Hymenoptera venom allergy (HVA) and previous severe reactions. After a 3- to 5-year VIT course, most patients remain protected after VIT discontinuation. Otherwise, a lifelong treatment should be considered in high-risk patients (eg, in mastocytosis). Several case reports evidenced that patients with mastocytosis and HVA, although protected during VIT, can re-experience severe and sometimes fatal reactions after VIT discontinuation. To evaluate whether patients who lost protection after VIT discontinuation may suffer from clonal mast cell disorders. The survey describes the characteristics of patients who received a full course of VIT for previous severe reactions and who experienced another severe reaction at re-sting after VIT discontinuation. Those with a Red Española de Mastocitosis score of 2 or more or a serum basal tryptase level of more than 25 ng/mL underwent a hematological workup (bone marrow biopsy, KIT mutation, expression of aberrant CD25) and/or skin biopsy. Nineteen patients (mean age, 56.3 years; 89.5% males) were evaluated. All of them had received at least 4 years of VIT and were protected. After VIT discontinuation they were re-stung and developed, in all but 1 case, severe anaphylactic reactions (12 with loss of consciousness, in the absence of urticaria/angioedema). Eighteen patients (94.7%) had a clonal mast cell disorder, 8 of them with normal tryptase. Looking at this selected population, we suggest that mastocytosis should be considered in patients developing severe reactions at re-sting after VIT discontinuation and, as a speculation, patients with mastocytosis and HVA should be VIT-treated lifelong.

Bonadonna P ，Zanotti R ，Pagani M ，Bonifacio M ，Scaffidi L ，Olivieri E ，Franchini M ，Reccardini F ，Costantino MT ，Roncallo C ，Mauro M ，Boni E ，Rizzini FL ，Bilò MB ，Marcarelli AR ，Passalacqua G ... -  《-》

Clonal mast cell disorders in patients with severe Hymenoptera venom allergy and normal serum tryptase levels.

Systemic mastocytosis is a clonal mast cell (MC) disease that can lead to potentially fatal anaphylactic reactions caused by excessive MC mediator release. The prevalence of mastocytosis in patients with Hymenoptera venom allergy is high, and thus the disease should be suspected in patients with severe reactions caused by Hymenoptera stings and increased serum basal tryptase (SBT) levels. We sought to evaluate the presence of clonal MC disorders in patients seen at our mastocytosis center with Hymenoptera sting-induced anaphylaxis, documented hypotension, absence of urticaria pigmentosa, and normal SBT levels. Twenty-two patients with Hymenoptera sting-induced anaphylaxis, without skin lesions, and with tryptase levels of less than 11.4 ng/mL underwent bone marrow evaluation. Bone mineral density was assessed in those patients with ascertained mastocytosis. In 16 of 22 patients, a diagnosis of indolent mastocytosis could be established, and 1 patient had a monoclonal MC activation syndrome. Patients with mastocytosis had higher SBT levels (P = .03) but only rarely had angioedema/urticaria associated with hypotension (P = .004). The absence of urticaria or angioedema in severe reactions to Hymenoptera stings with hypotension might represent the most relevant factor in identifying patients with mastocytosis, regardless of their serum tryptase levels.

Zanotti R ，Lombardo C ，Passalacqua G ，Caimmi C ，Bonifacio M ，De Matteis G ，Perbellini O ，Rossini M ，Schena D ，Busa M ，Marcotulli MC ，Bilò MB ，Franchini M ，Marchi G ，Simioni L ，Bonadonna P ... -  《-》

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

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. 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. 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). 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.

Korošec P ，Sturm GJ ，Lyons JJ ，Marolt TP ，Svetina M ，Košnik M ，Zidarn M ，Kačar M ，Frelih N ，Lalek N ，Luzar AD ，Zver S ，Škerget M ，Czarnobilska E ，Dyga W ，Grle SP ，Samarzija M ，Arzt-Gradwohl L ，Čerpes U ，Porebski G ，Pevec B ，Schadelbauer E ，Kopač P ，Šelb J ，Rijavec M ... -  《-》

Hymenoptera venom immunotherapy and field stings.

Lang R ，Hawranek T 《JOURNAL OF INVESTIGATIONAL ALLERGOLOGY AND CLINICAL IMMUNOLOGY》

Predictors of clinical effectiveness of Hymenoptera venom immunotherapy.

Treatment failure during venom immunotherapy (VIT) may be associated with a variety of risk factors, of which the relative importance is unknown. Our aim was to evaluate the association of baseline serum tryptase concentration (BTC), mastocytosis in the skin (MIS) and of other parameters with the frequency of objective systemic reactions during in-hospital sting challenge (SC). In this observational retrospective study, we enrolled 1532 patients (1609 cases due to double SC) with established honeybee or vespid venom allergy who had undergone VIT and a subsequent SC. Data were collected on various putative risk factors. Adult-onset MIS and/or a BTC > 20.0 μg/L was defined as clinical indicators of systemic mastocytosis. Relative rates were calculated with logistic regression models. Ninety-eight patients (6.4%) presented with MIS and/or BTC > 20.0 μg/L. 104 cases (6.5%) developed objective generalized symptoms during SC. In the absence of MIS, a BTC ≤ 20 μg/L did not increase the risk for VIT failure. The most important factors associated with a worse outcome were ACE inhibitor medication (OR 5.24, 95% CI 1.83-13.00, P < 0.001), honeybee venom allergy (OR 5.09, 95% CI 3.17-8.15, P < 0.001), systemic allergic reaction during VIT (OR 3.07, 95% CI 1.79-5.14, P < 0.001), and a substantial likelihood to suffer from SM (OR 2.74, 95% CI 1.37-5.22, P = 0.003), whereas a double VIT (OR 0.51, 95% CI 0.27-0.90, P = 0.027) and a longer duration of therapy (OR 0.68 per treatment month, 95% CI 0.50-0.93, P = 0.017) reduced the failure rate. The magnitude of therapeutic success correlates with type of venom, duration of therapy, and venom dose. Adult-onset MIS and/or a BTC > 20 μg/L is a significant, albeit not the strongest determinant for VIT failure. According to its odds ratio, ACE inhibitor therapy appears to be associated with the highest risk for VIT failure.

Ruëff F ，Vos B ，Oude Elberink J ，Bender A ，Chatelain R ，Dugas-Breit S ，Horny HP ，Küchenhoff H ，Linhardt A ，Mastnik S ，Sotlar K ，Stretz E ，Vollrath R ，Przybilla B ，Flaig M ... -  《-》