Real-Life Adherence to Venom Immunotherapy and Adrenaline Autoinjector.

INTRODUCTION: Venom immunotherapy (VIT) and adrenaline autoinjector (AAI) are important therapies in venom anaphylaxis. Adherence to VIT and AAI in patients with venom allergy has been evaluated in a few studies; however, solid data are lacking. This study aimed to evaluate VIT and AAI retrieval rates in patients with venom allergy with a special focus on adherence to treatment. Adherence was compared to subcutaneous immunotherapy (SCIT) with inhalant allergens. METHODS: This was a retrospective study among patients registered for allergen immunotherapy at the Allergy Center, Odense University Hospital, Denmark, from January 1, 2010, to December 31, 2014. Data on purchased immunotherapy and AAI were obtained from the Danish National Health Service Prescription Database. Multivariable logistic regression was used to analyze if allergen, age, sex, mastocytosis, and treatment site affected adherence. RESULTS: The 3-year adherence to VIT was 92.4% (244/264) compared to 87.4% (215/246) in SCIT with inhalant allergens, and the 5-year adherence to VIT was 84.1% (222/264) compared to 74.8% (184/246) in SCIT with inhalant allergens (p = 0.045). Females treated with VIT were more adherent than males (p = 0.45 [3-year], p = 0.008 [5-year]), whereas allergen, age, mastocytosis, or treatment site did not significantly affect adherence. Only 28.6% of patients (12/42) purchased an AAI after premature termination of VIT. CONCLUSION: In this register-based study, we found that the 3- and 5-year adherences to VIT and SCIT with inhalant allergens are at the upper end of the spectrum hitherto reported. Patients' 5-year adherence to VIT was higher than patients' 5-year adherence to SCIT with inhalant allergens. If VIT was prematurely terminated, less than 1/3 would have purchased an AAI.

Evaluation of the Cytokine Response Induced by Specific Allergen Immunotherapy in Patients with Vespa velutina Anaphylaxis.

INTRODUCTION: Changes in the cytokine profile from type 2 to type 1 together with the induction of regulatory cells are expected during hymenoptera venom immunotherapy (VIT). The present study was aimed to investigate the changes in type 1, type 2, and regulatory cytokines induced by a Vespula spp. VIT in patients with anaphylaxis to Vespa velutina. METHODS: Twenty consecutive patients with anaphylaxis due to Vespa velutina were treated with Vespula spp. VIT. Serum cytokines (IL-4, IL-5, IL-10, IL-13, and IFN-É£) were measured at baseline, 6, and 12 months after starting VIT. RESULTS: A significant increase in serum IFN-y was detected after 6 and 12 months of VIT. An increase in serum IL-10 and a decrease in IL-5 were observed after 12 months. IL-4 was undetectable all along the study, and an unexpected increase of IL-13 was present at 12 months of treatment. CONCLUSION: Vespula spp. VIT seems to be able to induce a shift to type 1 cytokine production measured through IFN-y levels and IL-10 production after, at least, 6 and 12 months of VIT, respectively.

A Retrospective Study of a Novel 3-Session Rush Venom Immunotherapy Protocol.

BACKGROUND: Venom-immunotherapy (VIT) is an effective treatment for life-threatening stinging-insect hypersensitivity. Rush VIT protocols allow patients to reach maintenance dosing faster, thereby conferring protection sooner. The published protocols vary in dosing regimens, monitoring parameters, and safety profiles. OBJECTIVE: We describe a novel 3-session outpatient rush VIT protocol with full therapeutic dosing achieved at the end of session 3. METHODS: We conducted a retrospective chart review of adult patients treated with rush VIT in an outpatient university allergy/immunology clinic. Demographic and clinical data, including the type of sting reaction, the number of venom allergens, and any systemic reactions (SR) during VIT were analyzed. RESULTS: Over a 14-year-period, 55 patients (28 females, 27 males) with a median age of 47 years underwent our VIT protocol. Forty-six patients (84%) tolerated the procedure without SR and 53 (96%) attained full maintenance dosing. All reactions during rush were World Health Organization grade 1 or 2. While the most common venom allergy was yellow jacket, most patients had multiple venom allergies and received therapy with more than 1 venom. Furthermore, ten patients were re-stung while on maintenance with only one patient having a mild SR. CONCLUSION: Our 3-session outpatient rush VIT protocol is effective and safe. The majority of patients had no SR and attained maintenance dosing. In comparison with other 3-session rush protocols, our protocol required non-invasive monitoring and patients achieved monthly maintenance dosing immediately upon completion.

Molecular profiling in bee venom allergy: clinical and therapeutic characterization in a Portuguese cohort.

Summary: Background. Bee venom allergy (BVA) can trigger local and systemic allergic reactions, including anaphylaxis. Recently, the molecular sensitization profile has gained importance in the reaction's stratification and venom immunotherapy (VIT). Methods. Retrospective analysis of patients with hypersensitivity to BVA, confirmed by specific sIgE to Apis mellifera ≥0.35 kU/L and/or positive skin tests to bee venom commercial extract, evaluated in specialized consultation. Demographic, clinical, and laboratory data (including molecular Api m 1, 4, and 10) were analyzed, looking for risk factors associated with the severity of the index reaction and reactions during VIT. Results. 93 patients were included (55.9% male; median age of 46 years), 57.3% with atopic comorbidities, and 23.4% with cardiovascular comorbidities. The median specific IgE to Apis mellifera was 6.7 kU/L (IQR 1.0-20.3) kU/L. Regarding the molecular profile, the median IgE to Api m 1 was 0.5 kU/L (57.5% positive out of all measurements); Api m 4 - 0.01 kU/L (11.9% positive), and Api m 10 - 0.3 kU/L (50.0% positive). No patient was monosensitized to Api m 4. The median age of the most severe sting reaction was 36 (IQR 26-48) years, with a median severity (Müeller scale) of 3 (IQR 2-3). Forty-seven patients (50.5%) underwent VIT, with 35.6% of reactions recorded. Allergic reactions during VIT were recorded in 35.6% of cases. The severity of the index reaction correlated positively with older ages (p=0.040; r=0.249), in contrast to monosensitization to Api m 1, which was an independent predictor of milder reactions (p=0.015). Sensitization to Api m 10 was associated with a higher likelihood of reactions during VIT (p=0.038) but potentially less systemic reactions at re-stings (p=0.097). Conclusions. Molecular sensitization profile appears to be relevant not only to the severity of index reactions but also during VIT. Studies of a large cohort of patients with molecular profiles are essential to validate these results and improve the clinical and therapeutic approach to BVA.

The role of basophil activation test in venom immunotherapy: comparative evaluation with specific IgE and skin prick tests, innovative approaches.

Summary: Background. In diagnosing insect venom allergy and making immunotherapy decisions, clinical history, skin tests, and specific serum IgE levels are commonly utilized. This study aims to emphasize the clinical significance of using the basophil activation test in accurately identifying sensitivities in individuals with insect venom allergy and to compare its effectiveness with other testing methods. Methods. This study included a total of 43 patients, who experienced at least one systemic allergic reaction following insect stings and were deemed suitable for immunotherapy.Basophil activation test, specific serum IgE levels, and skin prick test results utilized in making immunotherapy treatment decisions were recorded. Results. Our study determined that the overall clinical sensitivities of the basophil activation test (BAT), specific serum IgE (spIgE), and skin prick test (SPT) for apis mellifera were 95.5%, 95.7%, and 48.4% respectively, while for vespula vulgaris, they were 83.3%, 100%, and 33.3%. Based on these results, the prediction of systemic reactions to bee stings is ordered as spIgE > BAT > SPT. Additionally, early-stage skin prick tests showed a sensitivity of 67% and specificity of 50% at a cut-off value of 1.5 mm, and 33% sensitivity and 83% specificity at 2.5 mm. Conclusions. This study demonstrates that the basophil activation test (BAT) can provide a high positive predictive value in immunotherapy treatment decisions and offer significant insights in clinical practices.

Blood Transcriptomics Identifies Multiple Gene Expression Pathways Associated with the Clinical Efficacy of Hymenoptera Venom Immunotherapy.

Allergen-specific venom immunotherapy (VIT) is a well-established therapy for Hymenoptera venom allergy (HVA). However, the precise mechanism underlying its clinical effect remains uncertain. Our study aimed to identify the molecular mechanisms associated with VIT efficiency. We prospectively included 19 patients with HVA undergoing VIT (sampled before the beginning of VIT, after reaching the maintenance dose, one year after finishing VIT, and after a sting challenge) and 9 healthy controls. RNA sequencing of whole blood was performed on an Illumina sequencing platform. Longitudinal transcriptomic profiling revealed the importance of the inhibition of the NFκB pathway and the downregulation of DUX4 transcripts for the early protection and induction of tolerance after finishing VIT. Furthermore, successful treatment was associated with inhibiting Th2, Th17, and macrophage alternative signalling pathways in synergy with the inhibition of the PPAR pathway and further silencing of the Th2 response. The immune system became activated when reaching the maintenance dose and was suppressed after finishing VIT. Finally, successful VIT restores the immune system's balance to a state similar to that of healthy individuals. Our results underline the important role of the inhibition of four pathways in the clinical effect of VIT: Th2, Th17, NFκB, and macrophage signalling. Two biomarkers specific for successful VIT, regardless of the time of sampling, were C4BPA and RPS10-NUDT3 and should be further tested as potential biomarkers.

Potential Cost Savings by Switching from Subcutaneous to Intralymphatic Insect Venom Immunotherapy.

INTRODUCTION: IgE-mediated bee venom allergy can be treated with allergen-specific immunotherapy (AIT). Subcutaneous immunotherapy (SCIT) is time and cost intensive due to the repeated consultations, but the costs are justified by the high risk of potentially life-threatening allergic reactions, including anaphylaxis. However, intralymphatic immunotherapy (ILIT) offers potential to reduce treatment costs due to a significant reduction in injections and a shorter duration of therapy. Therefore, we calculated the cost savings that arise when switching from SCIT to ILIT. METHODS: Treatment protocols for ILIT were based on previous ILIT studies. Treatment protocols for SCIT were based on routine treatment at the University Hospital Zurich (USZ). The treatment costs were calculated based on the internal hospital information system (KISIM). RESULTS: The calculations revealed a potential two-fold reduction in treatment costs if ILIT is used instead of SCIT in patients with bee venom allergy. The costs could be reduced from EUR 11,612.59 with SCIT to EUR 5,942.15 with ILIT over 5 years. CONCLUSIONS: This study shows that bee venom ILIT has a cost-benefit potential for health insurances and patients, which should encourage further ILIT studies and which should be taken into account when considering future implementation of ILIT in the standard care of venom allergy.

Influencing factors on the safety and effectiveness of venom immunotherapy.

BACKGROUND AND OBJECTIVE: The safety profile of venom immunotherapy (VIT) is a relevant issue and considerable differences in safety and efficacy of VIT have been reported. The primary aim of this study was to evaluate the safety of ACE inhibitors and beta-blockers during VIT, which has already been published. For a second analysis, data concerning premedication and venom preparations in relation to systemic adverse events (AE) during the up-dosing phase and the first year of the maintenance phase were evaluated as well as the outcome of field stings and sting challenges. METHODS: The study was conducted as an open, prospective, observational, multicenter study. In total, 1,425 patients were enrolled and VIT was performed in 1,342 patients. RESULTS: Premedication with oral antihistamines was taken by 52.1% of patients during the up-dosing and 19.7% of patients during the maintenance phase. Taking antihistamines had no effect on the frequency of systemic AE (p=0.11) but large local reactions (LLR) were less frequently seen (OR: 0.74; 95% CI: 0.58-0.96; p=0.02). Aqueous preparations were preferentially used for up-dosing (73.0%) and depot preparations for the maintenance phase (64.5%). The type of venom preparation neither had an influence on the frequency of systemic AE nor on the effectiveness of VIT (p=0.26 and p=0.80, respectively), while LLR were less frequently seen when depot preparations were used (p<0.001). CONCLUSION: Pretreatment with oral antihistamines during VIT significantly reduces the frequency of LLR but not systemic AE. All venom preparations used were equally effective and did not differ in the frequency of systemic AE.

The development of Jack Jumper ant venom immunotherapy: our 25 years' experience.

Jack Jumper ant venom allergy is a uniquely Australian medical issue. The stinging ant is a leading cause of insect venom allergy in south-eastern Australia. An effective venom immunotherapy-based treatment was successfully developed by the Tasmanian Jack Jumper Allergy Research group. This paper provides a synopsis of our 25 years' research journey in developing this evidence-based treatment modality.

Modified rush venom immunotherapy in dogs with Hymenoptera hypersensitivity.

BACKGROUND: Hymenoptera envenomation occurs frequently in people and dogs and can trigger anaphylaxis. Venom immunotherapy (VIT) is the only preventive treatment for Hymenoptera hypersensitivity and is indicated for people with severe adverse reactions to insect stings. Rush VIT is an accelerated VIT protocol in people. This has not been reported in dogs. OBJECTIVES: The objective of the study was to evaluate the safety of modified rush VIT. ANIMALS: Twenty client-owned dogs with Hymenoptera hypersensitivity based on a history of adverse reactions to Hymenoptera envenomation and a positive intradermal test to honey bee and/or paper wasp venom. MATERIALS AND METHODS: Dogs received incremental doses of venom via subcutaneous injection one day per week for three consecutive weeks until the maintenance dose was achieved. Vital signs were recorded every 30 min prior to venom administration. Adverse reactions were categorised as localised or grade I-IV systemic reactions. RESULTS: Nineteen of 20 dogs (95%) completed rush VIT. One dog experienced a grade III systemic adverse reaction and was withdrawn from the study. No adverse reactions occurred in 10 of 20 dogs (50%). Localised and grade I-II systemic reactions occurred in nine of 20 dogs (45%), including nausea (n = 5), injection site pruritus (n = 3) and diarrhoea and lethargy (n = 1). CONCLUSIONS AND CLINICAL RELEVANCE: Modified rush VIT in dogs was well-tolerated and should be considered for dogs with Hymenoptera hypersensitivity. Larger studies are needed to evaluate the efficacy of VIT in dogs for preventing hypersensitivity reactions to insect stings.

Fatal Hymenoptera Venom-Triggered Anaphylaxis in Patients with Unrecognized Clonal Mast Cell Disorder-Is Mastocytosis to Blame?

Hymenoptera venom-triggered 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's 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.

The Lights and the Shadows of Controlled Sting Challenge With Hymenoptera.

Hymenoptera venom immunotherapy (VIT) is effective for protecting individuals with systemic allergic reactions caused by Hymenoptera stings. The need for a tool that shows the degree of protection afforded by VIT and the lack of useful biomarkers have made the sting challenge test (SCT) the gold standard for this disorder, although its use has both lights and shadows. SCT with Hymenoptera involves causing a real sting in a patient diagnosed with allergy to the venom of the stinging insect and who is undergoing treatment with specific immunotherapy. In Spain, SCT is included in the list of services offered by some hospitals and forms part of their daily clinical practice. This review aims to analyze the strengths and weaknesses of this test and to describe the standardized procedure and necessary resources, based on the experience of a group of Spanish experts and a review of the literature.

Prevalence of mastocytosis and Hymenoptera venom allergy in the United States.

BACKGROUND: Mastocytosis is a risk factor for Hymenoptera venom anaphylaxis (HVA). Current guidelines recommend measuring tryptase in patients with HVA and that those with mastocytosis pursue lifelong venom immunotherapy (VIT). Available data on HVA and mastocytosis largely derive from European single-center studies, and the prevalence of HVA with and without mastocytosis in the United States is unknown. OBJECTIVE: We sought to determine the prevalence of HVA and mastocytosis in the United States using an insurance claims database and evaluate the impact of mastocytosis on VIT in patients with HVA in a US cohort. METHODS: The IBM Watson Database, consisting of insurance claims from approximately 27 million US patients in 2018, was queried to identify patients with HVA and/or mastocytosis. Furthermore, a retrospective study of 161 patients undergoing VIT between 2015 and 2018 at the University of Michigan was conducted. RESULTS: In the IBM Watson Database, the prevalence of HVA was 167 per 100,000 (0.167%) and the prevalence of mastocytosis 10 per 100,000 (0.010%) overall and 97 per 100,000 (0.097%) among those with HVA. Mastocytosis showed a 9.7-fold increase among patients with HVA versus the general population. In the U-M cohort, 2.6% of patients with VIT had mastocytosis. Tryptase level did not correlate with venom reaction severity but was higher in patients with systemic VIT reactions. CONCLUSIONS: We observed a lower US HVA prevalence than previously reported. Mastocytosis was more common in US patients with HVA, though at lower rates than previously reported. In patients with VIT there was no correlation between tryptase level and reaction severity.

Venom Collection by Electrical Stimulation in the Invasive Species Polistes dominula Reared Using a Vespiculture Regime.

Specific Venom Immunotherapy (VIT) is practiced with venom extracted from insects, and is the specific therapy used for patients highly allergic to social insect (Hymenoptera) stings. Due to the dramatic shortage of vespid species in the local environment, we coupled vespiculture techniques of Polistes paper wasps with a venom collection procedure based on the electrical stimulation of individuals from entire colonies. The procedure involves little to no disturbance of the individual insects, and at the same time, successfully allows for the extraction of venom containing all allergens necessary for VIT.

Venom immunotherapy and difficulties encountered before and during immunotherapy: Double sensitization, systemic reactions, treatment with omalizumab, and high dose VIT.

BACKGROUND: Venom immunotherapy (VIT) is the most effective treatment method to prevent recurrent systemic reactions to Hymenoptera stings. In this study, the demographic characteristics of VIT patients, the success rates of VIT, the difficulties we encountered during VIT, and solutions for these difficulties in our clinic were presented. METHODS: We retrospectively analyzed patients with venom allergy who applied venom immunotherapy between 2013- 2020. Data on age, gender, Hymenoptera species with the first reaction, grade of the reaction, beekeeping history, skin prick and specific IgE and component results, double sensitization, blood groups, and reactions with VIT and/or sting during built-up and maintenance periods were recorded. RESULTS: A total of 73 patients were enrolled in the study. The median time from the first sting reaction to the application to the allergy outpatient clinic was 12 (0.5-24) months. The first sting reaction of 38 (52.1%) of the patients was with honey bees, and 24 (32.9%) were with wasps. Double positivity was present in 29 (40%) of the patients in prick results and 26 (36%) serologically. There was no correlation between the severity of first reactions and Apis Mellifera or Vespula prick diameters (p = 0.643; r = -0.056; p = 0.462; r = 0.089, respectively). High-dose VIT was administered to 4 patients. Omalizumab has been used as an alternative agent to achieve the maintenance dose in 2 patients with frequent systemic reactions during VIT. DISCUSSION: Most patients were able to tolerate VIT. Double positivity is one of the most common difficulties before VIT. In patients who develop systemic reactions in the VIT maintenance phase, a maintenance dose increase should be considered in the maintenance phase. Adding omalizumab does not seem to be a permanent solution in patients who develop a severe systemic reaction.

Ischemic stroke as a rare complication of wasp venom allergy: two clinical scenarios.

Neurological complications after a single Hymenoptera insect sting are very rare. The authors of this paper describe two instances of cerebral ischemic stroke that occurred immediately after a wasp sting. Two distinct pathomechanisms involved in the cases are put forward. When diagnosing such cases, it is vital to rule out the possibility of an immunoglobulin E (IgE)-dependent reaction of hypersensitivity. However, if sIgE antibodies against wasp venom extract and/or its allergenic components are detected, after hospitalization the patient should be qualified for venom immunotherapy, which is the only efficient method of protection from severe allergic reactions caused by an insect sting. Although the incidence of ischemic stroke in patients stung by insects is very low, it is important to be aware of this complication. This will allow rapid implementation of appropriate diagnostics and treatment. The optimal stroke treatment (thrombolysis or mechanical thrombectomy) in these rare cases has not yet been established.

ß-blockers and ACE inhibitors are not a risk factor for severe systemic sting reactions and adverse events during venom immunotherapy.

BACKGROUND: There is controversy whether taking ß-blockers or ACE inhibitors (ACEI) is a risk factor for more severe systemic insect sting reactions (SSR) and whether it increases the number or severity of adverse events (AE) during venom immunotherapy (VIT). METHODS: In this open, prospective, observational, multicenter trial, we recruited patients with a history of a SSR and indication for VIT. The primary objective of this study was to evaluate whether patients taking ß-blockers or ACEI show more systemic AE during VIT compared to patients without such treatment. RESULTS: In total, 1,425 patients were enrolled and VIT was performed in 1,342 patients. Of all patients included, 388 (27.2%) took antihypertensive (AHT) drugs (10.4% took ß-blockers, 11.9% ACEI, 5.0% ß-blockers and ACEI). Only 5.6% of patients under AHT treatment experienced systemic AE during VIT as compared with 7.4% of patients without these drugs (OR: 0.74, 95% CI: 0.43-1.22, p = 0.25). The severity of the initial sting reaction was not affected by the intake of ß-blockers or ACEI (OR: 1.14, 95% CI: 0.89-1.46, p = 0.29). In total, 210 (17.7%) patients were re-stung during VIT and 191 (91.0%) tolerated the sting without systemic symptoms. Of the 19 patients with VIT treatment failure, 4 took ß-blockers, none an ACEI. CONCLUSIONS: This trial provides robust evidence that taking ß-blockers or ACEI does neither increase the frequency of systemic AE during VIT nor aggravate SSR. Moreover, results suggest that these drugs do not impair effectiveness of VIT. (Funded by Medical University of Graz, Austria; Clinicaltrials.gov number, NCT04269629).

Update on Insect Sting Anaphylaxis.

PURPOSE OF REVIEW: This review describes improvement in diagnostic accuracy, prediction of outcomes, identifying high-risk factors, and refinements of treatment that continue to evolve over the past 5-10 years. RECENT FINDINGS: The risk of anaphylaxis is relatively low (< 5%) in patients with previous large local reactions or strictly cutaneous systemic reactions, but much higher in those with moderate-to-severe anaphylaxis (40%-70%) or mastocytosis (> 90%). Use of recombinant venom allergens and basophil activation tests may improve diagnostic accuracy. Elevated serum tryptase (and possible mastocytosis) occurs in 10% of patients with insect sting allergy, and in 25% of those with hypotensive reactions. Rush VIT is proven safe and rapidly effective. There are known high-risk factors that justify treatment beyond 5 years. Diagnostic accuracy and prediction of risk have improved in recent years. There are still knowledge gaps related to prediction and management of risk with current diagnostic and therapeutic modalities.

A Review of Honeybee Venom Allergens and Allergenicity.

Honeybee venom is a source of proteins with allergenic properties which can result in in various symptoms, ranging from local reactions through to systematic life-threatening anaphylaxis, or even death. According to the World Allergy Organization (WAO), honeybee venom allergy is one of the most common causes of anaphylaxis. Among the proteins present in honeybee venom, 12 protein fractions were registered by the World Health Organization's Allergen Nomenclature Sub-Committee (WHO/IUIS) as allergenic. Most of them are highly immunogenic glycoproteins that cross-react with IgE and, as a consequence, may give false positive results in allergy diagnosis. Allergenic fractions are different in terms of molecular weight and biological activity. Eight of these allergenic fractions have also been identified in honey. This explains frequent adverse reactions after consuming honey in people allergic to venom and sheds new light on the causes of allergic symptoms in some individuals after honey consumption. At the same time, it also indicates the possibility of using honey as a natural source of allergen in specific immunotherapy.

Venom immunotherapy in patients with clonal mast cell disorders: IgG4 correlates with protection.

BACKGROUND: Patients with clonal mast cell disorders (cMCD), systemic mastocytosis (SM) and monoclonal mast cell activation syndrome (MMAS), represent an increased risk for Hymenoptera venom anaphylaxis (HVA). Lifelong venom immunotherapy (VIT) is recommended; however, its efficacy and safety are controversial. Hence, we sought to evaluate the efficacy and safety of VIT in HVA patients with cMCD. METHODS: A retrospective study was conducted among 46 patients with Vespula venom allergy who had experienced severe HVA, 32 cMCD (22 with SM and 10 with MMAS) and 14 controls. There were no differences between cMCD patients and controls in age (58 vs 66) and duration of VIT (47 vs 48 months), respectively. RESULTS: During VIT, 11 (34%) cMCD patients experienced adverse reactions (ARs) (7% in controls), including 1 anaphylaxis. There were 23 re-stings in 17 (53%) patients during VIT. Of episodes, four (17%) presented with anaphylaxis, 14 (60%) presented with local reaction, and five (23%) were asymptomatic. In 11 episodes (48%), the patient did not take epinephrine, of these 8 (73%) presented with local reaction, and 3 (27%) were asymptomatic. Patient-based protection from anaphylaxis was 76% (4/17) in cMCD vs. 100% in controls during VIT. The venom-specific IgG4 concentrations increased during VIT (P < .001) although tryptase and IgE were unaltered. CONCLUSION: Both safety and efficacy of VIT in cMCD patients were slightly reduced than controls. Severe ARs were rare. The elevated IgG4 levels may be a biomarker for efficacy of VIT in cMCD patients, as it correlates with protection from re-stings.