Standardized indolent systemic mastocytosis evaluations across a health care system: implications for screening accuracy.

ABSTRACT: Timely diagnosis of systemic mastocytosis (SM) remains challenging because of care heterogeneity. We implemented a standardized approach for SM screening and diagnosis using a novel health care system-wide international screening registry. A retrospective analysis assessed rates of SM, cutaneous mastocytosis (CM), and molecular diagnoses before and 2 years after care standardization. The accuracy of individual and combined SM screening tests, basal serum tryptase (BST) ≥11.5 and ≥20.0 ng/mL, REMA ≥2, monomorphic maculopapular CM (MPCM), and elevated BST based upon tryptase genotype, was analyzed. Tryptase genotyping and high-sensitivity KIT p.D816V testing increased substantially 2 years after care standardization. SM diagnoses doubled from 47 to 94, and KIT p.D816V molecular diagnoses increased from 24 to 79. Mean BST and KIT p.D816V variant allele frequency values were significantly lower in patients diagnosed after standardization. Hereditary-alpha tryptasemia prevalence was increased in SM before care standardization (4/30 [13.3%]) but reflected the general population prevalence 2 years later at (5/76 [6.6%]). Elevated BST based upon genotype and BST ≥11.5 ng/mL had the highest sensitivities at 84.2% and 88.3%, respectively. The presence of monomorphic MPCM, elevated BST based upon tryptase genotype, and the combination of REMA ≥2 with elevated BST based upon tryptase genotype had specificities >90%. BST >20.0 ng/mL had low sensitivity and specificity and was not required to establish any indolent SM (ISM) diagnosis. Care standardization increased SM diagnosis rates, particularly in patients with low BSTs. Stratifying BST based upon genotype had the best overall sensitivity and specificity of any ISM screening test and improved the REMA score specificity.

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

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.

Prevention of Anaphylaxis Episodes in Idiopathic Anaphylaxis by Omalizumab.

INTRODUCTION: In 15-35 percent of patients with anaphylaxis, the triggering allergen cannot be found; therefore, a diagnosis of idiopathic anaphylaxis (IA) is made. We report on the outcomes in patients with IA treated with omalizumab. METHODS: We included consequent omalizumab-treated IA adult patients treated with omalizumab 300 mg every 4 weeks. RESULTS: Out of 7 patients, 6 were female, median age 40 years with the frequency of anaphylaxis episodes from 3 in 2 years to 5 in 4 months. Baseline tryptase ranged from 1.71 to 12.0 µg/L. An increase in tryptase during anaphylaxis was documented in 6 patients. Activating KIT p.D816V variant was detected in 2 patients. One patient also had hereditary alpha-tryptasemia (HαT). The duration of omalizumab treatment was 0.5-7.5 years. None of the patients have experienced an anaphylactic reaction since the start of treatment. Mild systemic reactions were reported in 6 patients (86%). The presence of underlying cMCD had no impact on the treatment outcome. CONCLUSION: All patients in our study had complete responses to omalizumab. The presence of KIT p.D816V and HαT did not influence the response to omalizumab treatment.

Interplay of clinical biomarkers in allergic asthma diagnosis and severity: A case-control study.

Given asthma's large phenotypic diversity, the study was aimed to use specific biomarkers to characterize Allergic asthma (AA) and its severity. Blood was collected from 42 healthy controls (HCs) and 96 patients with AA. Biomarkers related to blood cell number and function: total leukocyte count (TLCs), neutrophil, lymphocyte, monocyte, eosinophil, basophil, neutrophil-to-lymphocyte ratio (NLR), immunoglobulin E (IgE), tryptase and eosinophilic cationic protein (ECP) as well as remodelling biomarkers (Matrix metalloproteinase (MMP-9), (MMP-16), Fibroblast growth factor (FGF-18) and (FGF-23) and alpha-skeletal muscle actin-1 (ACTa-1) were measured. Significant differences were observed in hematological parameters with higher levels of total leukocytes, eosinophil, and basophil counts in the AA group compared to HCs. The disease group also had significantly higher levels of several serum biomarkers (IgE, TPs, ECP, MMP-9, MMP-16, FGF-18, FGF-23, and ACTa-1) compared to HC. Forced expiratory volume 1 (FEV1) and forced vital capacity (FVC) had a strong negative correlation with ECP, IgE, and ACTa-1. FEV1 was negatively correlated with MMP-16 and tryptase. Patients with AA have higher levels of several biomarkers, such as MMP-9, MMP-16, FGF-18, FGF-23, IgE, tryptase, and ACTa-1. In addition, IgE, tryptase, ACTa-1, and MMP-16 are related to lung function impairment in AA. This indicates that measuring multiple biomarkers may be of value in the future when diagnosing and monitoring AA.

Clinical features, severity, and immunological changes during venom immunotherapy in children and adults.

Background: Hymenoptera venom allergy (HVA) is among the most common causes of severe allergic reactions worldwide. Objective: To investigate clinical features and factors that affect the severity of HVA and to determine the alterations in immunologic biomarkers after venom immunotherapy (VIT). Methods: Seventy-six adults and 36 children were prospectively investigated. We analyzed specific immunoglobulin E (sIgE) and sIgG4 levels of venom extracts and components (rApi m1, rApi m10, rVes v1, rVes v5, rPol d5) before and after the first year of VIT. Results: Although cardiovascular symptoms were more common in adults (p < 0.001), the skin was the most affected organ in children (p = 0.009). Serum basal tryptase (sBT) levels were higher in the adults than the children (p < 0.001). The absence of urticaria (odds ratio [OR] 4.208 [95% confidence interval {CI}, 1.395-12.688]; p = 0.011) and sBT ≥ 5.2 ng/mL (OR 11.941 [95% CI, 5.220-39.733]; p < 0.001) were found as the risk factors for grade IV reactions. During VIT, changes in sIgE levels were variable. In the Apis VIT group, we observed remarkable increases in sIgG4 levels in Apis extract and rApi m1 but not in Api m10. Vespula extract, rVes v1, and rVes v5 sIgG4 levels were significantly increased in Vespula VIT group, we also detected significant increases in the Polistes extract and rPol d5 sIgG4 levels, which were not observed in the Apis VIT group. In the patients who received both Apis and Vespula VIT, increases in sIgG4 levels were observed for both venoms. Conclusion: Adults and children can have different clinical patterns. After 1 year, VIT induced a strong IgG4 response. Although Apis immunotherapy (IT) induced Apis sIgG4, excluding Api m10, Vespula IT induced both Vespula and Polistes sIgG4.

Unraveling wasp sensitization in a patient with systemic mastocytosis by CAP-inhibition assay.

Systemic mastocytosis (SM) is a clonal mast cell disorder that can lead to potentially severe anaphylactic reactions. Hymenoptera sting is one of the most frequent triggers of anaphylaxis in these patients, and diagnosis of indolent SM (ISM) without skin involvement (ISMs) is not rare. In this subgroup of patients, venom immunotherapy (VIT) is an effective treatment decreasing subsequent systemic reactions, and lifelong administration is recommended. An individualized diagnosis is necessary to offer the most adequate VIT, and molecular diagnosis (MD) may be useful to discriminate between primary sensitization and cross-reactivity. Nevertheless, other techniques such as ImmunoCAP inhibition assays may be necessary to identify the genuine sensitization to offer the most suitable VIT. We present a male patient with an anaphylactic reaction following several wasp stings. The patient was diagnosed with ISM, and allergy to both Polistes dominula and Vespula sp venom was confirmed. In this scenario, MD did not discriminate between a genuine double sensitization and venom cross-reactivity between both vespids. Thus, CAP-inhibition assay was performed. This case indicated the importance of an accurate diagnosis of hymenoptera venom allergy (HVA). It also highlights the usefulness of CAP-inhibition assays when MD fails to distinguish between genuine double Polistes-Vespula sensitization and cross-reactivity.

Comparison of the diagnostic performance of tryptase and histamine for perioperative anaphylaxis: A multicenter prospective study.

BACKGROUND: Diagnosing perioperative anaphylaxis (POA) is often challenging. Although a guideline recommends measuring tryptase rather than histamine, there is little evidence for this. We aimed to examine the diagnostic performance and appropriate timing of tryptase and histamine measurements for diagnosing anaphylaxis, and the association between Hypersensitivity Clinical Scoring Scheme (HCSS) scores and elevated biomarkers. METHODS: We measured tryptase and histamine levels thrice: 30 min, 2 h, and at least 24 h after an anaphylactic event for patients with suspected anaphylaxis, and at the induction of general anesthesia and 30 min and 2 h after the start of surgery for control patients without a reaction. Absolute values and the magnitude and rate of change from baseline were evaluated. We determined the thresholds of tryptase and histamine levels with the best diagnostic performance and compared their performance. RESULTS: Forty-five patients with perioperative anaphylaxis were included in this study. The control group included 30 patients with uneventful general anesthesia and 12 patients with a suspected but unconfirmed diagnosis of perioperative anaphylaxis. Comparison at the same measurement timings showed that tryptase generally had better diagnostic performance than histamine. Both showed better diagnostic performance when assessed using multiple measurements rather than a single measurement. The best diagnostic performance was seen with the percentage change in the higher tryptase value, whether measured at 30 min or 2 h after anaphylaxis onset, as compared to baseline. However, neither tryptase nor histamine levels correlated with HCSS scores. CONCLUSIONS: Overall, tryptase showed better diagnostic performance than histamine. When multiple tryptase measurements are possible, parameters calculated using two acute phase measurements and the baseline level have better diagnostic performance.

Tryptase: The Silent Witness of Past and Ongoing Systemic Events.

Introduction: Tryptase is an important biomarker widely used in the laboratory confirmation of severe hypersensitivity reactions, especially anaphylaxis. It also plays a crucial role in the diagnosis, risk stratification, management and prognostic evaluation of many other mast cell-related conditions. Aim: This paper aims to highlight the role of serum tryptase, both in allergic disorders and other mast cell-related conditions. Two clinical cases regarding timely serum tryptase acquisition (in drug hypersensitivity reactions during the imaging procedure and perioperative anaphylaxis) are meant to emphasize the clinical potential of this protease. Method: We performed a comprehensive literature search of the PubMed/Medline and Scopus databases. From a total of 640 subject related publications, dating from 1940 to 2024, 45 articles written in English were selected. Literature search results: Total serum tryptase is a simple, cost-effective analysis with a normal baseline tryptase (sBT) level below 8.4 µg/L. Elevated sBT can indicate hereditary alpha-tryptasemia (HαT), mastocytosis and other non-allergic disorders. Patients with higher sBT levels, especially with insect venom allergy, have an increased risk of severe reactions and thereby require a prolonged treatment. All immediate systemic hypersensitivity reactions require a correlation between serum acute tryptase (sAT) and sBT. According to the guidelines, measuring sAT 30 min to 2 h after the symptom onset and sBT 24 h after the resolution, using the 20 + 2 rule and an sAT/sBT ratio of 1.685, improves the diagnostic accuracy in anaphylaxis. Conclusions: Tryptase levels should be acquired in all cases with clinical suspicion of MC degranulation. Given the increasing clinical relevance, elevated baseline serum tryptase levels require a multidisciplinary approach and further investigation.

Hereditary α tryptasemia is a valid genetic biomarker for severe mediator-related symptoms in mastocytosis.

Mastocytosis is a hematopoietic neoplasm characterized by expansion of KIT D816V-mutated clonal mast cells in various organs and severe or even life-threatening anaphylactic reactions. Recently, hereditary α-tryptasemia (HαT) has been described as a common genetic trait with increased copy numbers of the α-tryptase encoding gene, TPSAB1, and associated with an increased basal serum tryptase level and a risk of mast cell activation. The purpose of our study was to elucidate the clinical relevance of HαT in patients with mastocytosis. TPSAB1 germline copy number variants were assessed by digital polymerase chain reaction in 180 mastocytosis patients, 180 sex-matched control subjects, 720 patients with other myeloid neoplasms, and 61 additional mastocytosis patients of an independent validation cohort. α-Tryptase encoding TPSAB1 copy number gains, compatible with HαT, were identified in 17.2% of mastocytosis patients and 4.4% of the control population (P < .001). Patients with HαT exhibited higher tryptase levels than patients without HαT (median tryptase in HαT+ cases: 49.6 ng/mL vs HαT- cases: 34.5 ng/mL, P = .004) independent of the mast cell burden. Hymenoptera venom hypersensitivity reactions and severe cardiovascular mediator-related symptoms/anaphylaxis were by far more frequently observed in mastocytosis patients with HαT than in those without HαT. Results were confirmed in an independent validation cohort. The high prevalence of HαT in mastocytosis hints at a potential pathogenic role of germline α-tryptase encoding TPSAB1 copy number gains in disease evolution. Together, our data suggest that HαT is a novel emerging robust biomarker in mastocytosis that is useful for determining the individual patient´s risk of developing severe anaphylaxis.

Tryptase in type I hypersensitivity.

Tryptase is currently the main mast cell biomarker available in medical practice. Tryptase determination is a quantitative test performed in serum or plasma for the diagnosis, stratification, and follow-up of mast cell-related conditions. The continuous secretion of monomeric α and ß protryptases forms the baseline tryptase level. Transient, activation-induced release of tryptase is known as acute tryptase. Because mast cells are tissue-resident cells, the detection of an acute tryptase release in the bloodstream is protracted, with a delay of 15 to 20 minutes after the onset of symptoms and a peak at approximately 1 hour. Constitutive release of tryptase is a marker of mast cell number and activity status, whereas transient release of mature tryptase is a marker of mast cell degranulation. Although consensual as a concept, the application of this statement in clinical practice has only been clarified since 2020. For baseline tryptase to be used as a biomarker, reference values need to be established. In contrast, defining a transient increase using acute tryptase can only be achieved as a function of the baseline status.

Hereditary alpha tryptasemia is not associated with specific clinical phenotypes.

BACKGROUND: Hereditary alpha tryptasemia (HαT) is found in approximately 7% of the population. Associations with a variety of clinical symptoms including gastric reflux, joint hypermobility, dysautonomia, flushing and pruritus, and hymenoptera allergy have variably been described in prior reports. However, our understanding of this genetic trait is limited by a paucity of published studies, referral bias, and conflicting findings at clinical presentation. OBJECTIVE: The purpose of this study was to assess the clinical phenotype of HαT in a random biorepository population and in patients with and without mastocytosis referred to the allergy clinic. METHODS: Tryptase copy number allele was assessed using digital droplet PCR. Participants with or without HαT were interviewed and examined by a clinician and surveyed regarding their medical history and symptomology. RESULTS: HαT was identified in 7.5% of the random biorepository samples and in 18% of patients with mastocytosis. There was no difference in the clinical symptomology or medical history of individuals with HαT compared to controls. Average baseline serum tryptase was higher in individuals with HαT compared to controls, but there was no difference in urinary mast cell activation products. CONCLUSIONS: Elevated baseline serum tryptase was the only consistent phenotypic marker for HαT in this study. There was a higher frequency of HαT in patients with mastocytosis than in the general population.

Diagnostic performance of serial serum total tryptase measurement to differentiate positive from negative allergy testing among patients with suspected perioperative hypersensitivity.

BACKGROUND: Serum total tryptase has been shown to increase during acute allergic reactions (acute tryptase, TA ); however, few studies have investigated the values of TA or a combination of TA and baseline tryptase (TB ) to discriminate positive from negative testing in perioperative hypersensitivity reaction (POH) allergy work-up. The aim of this study was to determine the diagnostic performance of TA in order to differentiate positive from negative allergy testing suspected POH and analyse the diagnostic performance of serial tryptase levels using several formulas. METHODS: All patients from the University hospital of Montpellier and Strasbourg, France, who presented with suspected POH and underwent complete drug allergy work-up between March 2011 and December 2019 with available TA and TB were included. Four formulas, including a change in TA  > 11 (F1), or >2 + 1.2 × TB (F2), or >3 + TB (F3), or >120%TB (F4), were applied. RESULTS: One hundred and sixty-two patients were included, and 131 of them (80.8%) had Grade III or IV reactions. Ninety patients had positive allergy testing. The optimal cut-off value of TA to distinguish positive from negative allergy testing patients was 9.8 µg/L with an AUC of 0.817 (95% CI: 0.752-0.882, p < .001). The 93% PPV threshold for TA was 33 µg/L (95.8% specificity). Paired tryptase levels according to formulas F2 and F3 yielded the highest Youden index (0.54 and 0.53, respectively). CONCLUSION: The optimal cut-off point for TA for distinguishing positive from negative allergy testing suspected POH was 9.8 µg/L. TA value of 33 µg/L was required to achieve >90% PPV.

Serum tryptase levels in patients with psoriasis: a pilot study for a possible useful biomarker.

In psoriasis, biomarkers for disease prognosis and response to treatment may help clinicians to improve patient management. Hence, we decided to evaluate the role of serum tryptase (ST) in a sample of patients with psoriasis. We found higher levels of ST in patients with scalp psoriasis than in those without (6.1 vs. 4.6 ng/mL), in those with palmoplantar psoriasis than in those without (5.3 vs. 5 ng/mL) and, with less significance, in those with psoriatic arthritis than in those without (6.1 vs. 5.1 ng/mL).

Heritable risk for severe anaphylaxis associated with increased α-tryptase-encoding germline copy number at TPSAB1.

BACKGROUND: An elevated basal serum tryptase level is associated with severe systemic anaphylaxis, most notably caused by Hymenoptera envenomation. Although clonal mast cell disease is the culprit in some individuals, it does not fully explain this clinical association. OBJECTIVE: Our aim was to determine the prevalence and associated impact of tryptase genotypes on anaphylaxis in humans. METHODS: Cohorts with systemic mastocytosis (SM) and venom as well as idiopathic anaphylaxis from referral centers in Italy, Slovenia, and the United States, underwent tryptase genotyping by droplet digital PCR. Associated anaphylaxis severity (Mueller scale) was subsequently examined. Healthy volunteers and controls with nonatopic disease were recruited and tryptase was genotyped by droplet digital PCR and in silico analysis of genome sequence, respectively. The effects of pooled and recombinant human tryptases, protease activated receptor 2 agonist and antagonist peptides, and a tryptase-neutralizing mAb on human umbilical vein endothelial cell permeability were assayed using a Transwell system. RESULTS: Hereditary α-tryptasemia (HαT)-a genetic trait caused by increased α-tryptase-encoding Tryptase-α/ß1 (TPSAB1) copy number resulting in elevated BST level-was common in healthy individuals (5.6% [n = 7 of 125]) and controls with nonatopic disease (5.3% [n = 21 of 398]). HαT was associated with grade IV venom anaphylaxis (relative risk = 2.0; P < .05) and more prevalent in both idiopathic anaphylaxis (n = 8 of 47; [17%; P = .006]) and SM (n = 10 of 82 [12.2%; P = .03]) relative to the controls. Among patients with SM, concomitant HαT was associated with increased risk for systemic anaphylaxis (relative risk = 9.5; P = .007). In vitro, protease-activated receptor-2-dependent vascular permeability was induced by pooled mature tryptases but not α- or ß-tryptase homotetramers. CONCLUSIONS: Risk for severe anaphylaxis in humans is associated with inherited differences in α-tryptase-encoding copies at TPSAB1.

Patients with mast cell activation symptoms and elevated baseline serum tryptase level have unique bone marrow morphology.

BACKGROUND: Patients with mast cell (MC) activation symptoms and elevated baseline serum tryptase level (MCAS-T) may not necessarily have a clonal MC disorder. Many are diagnosed with hereditary α-tryptasemia (HαT), a genetic trait characterized by autosomal dominant inheritance of multiple copies of TPSAB1 encoding α-tryptase and increased risk for severe anaphylaxis. OBJECTIVE: The aim of our study was to identify and characterize bone marrow MC histopathologic features specific for MCAS-T. METHODS: A total of 43 patients with MCAS-T underwent evaluation, including bone marrow biopsy, for a MC disorder. The results of the work-up for clonal MC disorders such as systemic mastocytosis and monoclonal MC activation syndrome were negative. Bone marrow MC histopathology was reviewed to identify characteristic features of MCAS-T. A subgroup of patients was available for tryptase genotyping. RESULTS: Patients with MCAS-T showed unique morphologic and histologic features when compared with controls. MCs were larger (P < .01), hypogranular (P < .01), frequently detected in paratrabecular (P < .05) and perivascular (P < .01) locations, and associated with bone marrow eosinophilia (P < .01). A total of 10 patients who were available for tryptase genotyping were all confirmed to have HαT. This subgroup was representative of the larger MCAS-T cohort. CONCLUSION: We report unique bone marrow MC phenotypic and histopathologic changes in patients with MCAS-T. These morphologic changes are associated with an elevated tryptase level that has been confirmed to be caused by HαT in all patients available for testing.

Small intestinal immunopathology and GI-associated antibody formation in hereditary alpha-tryptasemia.

BACKGROUND: Hereditary alpha-tryptasemia (HαT) is characterized by elevated basal serum tryptase due to increased copies of the TPSAB1 gene. Individuals with HαT frequently present with multisystem complaints, including anaphylaxis and seemingly functional gastrointestinal (GI) symptoms. OBJECTIVE: We sought to determine the prevalence of HαT in an irritable bowel syndrome cohort and associated immunologic characteristics that may distinguish patients with HαT from patients without HαT. METHODS: Tryptase genotyping by droplet digital PCR, flow cytometry, cytometry by time-of-flight, immunohistochemistry, and other molecular biology techniques was used. RESULTS: HαT prevalence in a large irritable bowel syndrome cohort was 5% (N = 8/158). Immunophenotyping of HαT PBMCs (N ≥ 27) revealed increased total and class-switched memory B cells. In the small bowel, expansion of tissue mast cells with expression of CD203c, HLA-DR, and FcεRI, higher intestinal epithelial cell pyroptosis, and increased class-switched memory B cells were observed. IgG profiles in sera from individuals with HαT (N = 21) significantly differed from those in individuals with quiescent Crohn disease (N = 20) and non-HαT controls (N = 19), with increased antibodies directed against GI-associated proteins identified in individuals with HαT. CONCLUSIONS: Increased mast cell number and intestinal epithelial cell pyroptosis in the small intestine, and class-switched memory B cells in both the gut and peripheral blood associated with IgG reactive to GI-related proteins, distinguish HαT from functional GI disease. These innate and adaptive immunologic findings identified in association with HαT are suggestive of subclinical intestinal inflammation in symptomatic individuals.

Association of Elevated Serum Tryptase with Cutaneous Photodamage and Skin Cancers.

INTRODUCTION: Mast cells and their major protein, the serine proteinase tryptase, can be involved in cutaneous photodamage and carcinogenesis. The serum test of tryptase (S-tryptase) measures total tryptase protein (active tryptase and inactive protryptases), and S-tryptase is elevated in a variety of diseases, for example, in mastocytosis and α-tryptasemia. OBJECTIVES: The objective of this study is to study whether S-tryptase is a marker of cutaneous photodamage and carcinogenesis. METHODS: Adult subjects (n = 399, aged 21-79) evaluated to be at risk for skin cancers were recruited at the dermatological policlinic and examined for photodamage severity, mole count, actinic keratoses (AKs), skin cancers, and immunosuppression (IS). A blood sample was analyzed for S-tryptase using the ImmunoCAP® Tryptase fluoroenzymeimmunoassay. RESULTS: There was no difference in S-tryptase between non-IS (n = 321) and IS (n = 78) subjects or between genders. S-tryptase correlated slightly to photodamage and AKs in 321 non-IS subjects, and this association can be related, in part, to the age of subjects. In 34 subjects, S-tryptase was elevated (≥13.5 ng/mL), and in 20 males, but not in 14 females, the photodamage level was significantly (p = 0.031) more severe than in 179 males with normal S-tryptase. In contrast, there were more frequently subjects (n = 12) with past or present skin cancer (basal or squamous cell carcinoma or melanoma) in 14 females with elevated S-tryptase than in 186 female controls. So far, no explanation has been found for the elevated S-tryptase. CONCLUSION: There are significant associations between elevated S-tryptase and skin carcinogenesis, but the molecular mechanisms are unclear and gender differences can exist.

Basal Tryptase High Levels Associated with a History of Arterial Hypertension and Hypercholesterolemia Represent Risk Factors for Severe Anaphylaxis in Hymenoptera Venom-Allergic Subjects over 50 Years Old.

INTRODUCTION: Allergy to Hymenoptera venom (HV) may lead to life-threatening anaphylaxis. Some of the factors influencing the symptom's severity are still undetermined. The aim of this study was to identify the clinical aspects associated with the most severe reactions in a population with HV allergy, by comparing clinical and immunochemical biomarkers between patients with previous local large reactions (LLRs) and systemic reactions (SRs). METHODS: We selected adult patients with a history of HV allergy, with positive diagnostic tests and a correlation with one single Hymenoptera species. Age, gender, atopy, serum basal tryptase (sBT) value, total IgE, venom-specific IgE, history of hypertension, cardiovascular diseases, and hypercholesterolemia were compared between patients with previous LLRs and SRs. RESULTS: 460 adult patients (381 SRs, 79 LLRs) were included. Age (p = 0.0097), male gender (p < 0.0001), arterial hypertension (p = 0.046), hypercholesterolemia (p = 0.009), and higher sBT levels (p = 0.0004) were significantly associated with severe reactions as independent variables. Moreover, considering the previous variables as risk factors, there was a significant and progressive increase in the odds of being Mueller III + IV as the number of positive variables increased. Patients with sBT ≥6.4 ng/mL adjusted for any of the positive variables had increased the risk of Mueller grade IV reaction (p < 0.0001). CONCLUSION: According to our results, older age, male gender, arterial hypertension, hypercholesterolemia, and increased levels of sBT ≥6.4 ng/mL are risk factors for severe anaphylaxis to HV in adults. Atopy and allergic asthma do not increase the risk of HV-induced SRs.

Systemic mastocytosis in adults: 2021 Update on diagnosis, risk stratification and management.

OVERVIEW: Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in extra-cutaneous organs. DIAGNOSIS: The major criterion is presence of multifocal clusters of spindled MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC CD25 expression, and presence of KITD816V mutation. RISK STRATIFICATION: Establishing SM subtype as per the World Health Organization classification system is an important first step. Broadly, patients either have indolent/smoldering SM (ISM/SSM) or advanced SM, the latter includes aggressive SM (ASM), SM with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL). Identification of poor-risk mutations (ie, ASXL1, RUNX1, SRSF2, NRAS) further refines the risk stratification. Recently, clinical and hybrid clinical-molecular risk models have been developed to more accurately assign prognosis in SM patients. MANAGEMENT: Treatment goals for ISM patients are primarily directed towards anaphylaxis prevention/symptom control/osteoporosis treatment. Patients with advanced SM frequently need MC cytoreductive therapy to ameliorate disease-related organ dysfunction. High response rates have been seen with small-molecule inhibitors that target mutant-KIT, including midostaurin (Food and Drug Administration approved) or avapritinib (investigational). Other options for MC cytoreduction include cladribine or interferon-α, although head-to-head comparisons are lacking. Treatment of SM-AHN primarily targets the AHN component, particularly if an aggressive disease such as acute myeloid leukemia is present. Allogeneic stem cell transplant can be considered in such patients, or in those with relapsed/refractory advanced SM. Imatinib has a limited therapeutic role in SM; effective cytoreduction is limited to those with imatinib-sensitive KIT mutations.

Inherited and acquired determinants of serum tryptase levels in humans.

OBJECTIVE: To aid the clinician in correctly interpreting serum tryptase levels. DATA SOURCES: Primary peer-reviewed literature. STUDY SELECTIONS: Clinical and basic science peer-reviewed studies characterizing the genetic and physiological bases for tryptase generation, secretion, and elevation, including those describing serum tryptase levels in population-based cohort studies. RESULTS: Clinically measured basal serum tryptase (BST) consists of ostensibly inactive alpha- and beta-tryptase precursors. The autosomal dominant genetic trait hereditary alpha-tryptasemia is the most often cause for elevated BST levels, with other acquired causes, such as renal failure and clonal myeloid diseases being far less common. Acute increases in serum tryptase levels resulting from release of mature tryptase from secretory granules is specific to mast cell degranulation but is not detected in all cases of systemic anaphylaxis. CONCLUSION: Understanding the differences and distinguishing between acute increases in serum tryptase and chronic elevations in BST owing to inherited or acquired conditions is critical in the correct interpretation of this useful clinical biomarker.