Diagnostic measures in patients with severe insect sting reactions and elevated baseline serum tryptase levels.

Mastocytosis or an elevated basal serum tryptase (bST) level are known risk factors for patients with insect venom allergy. We report on 3 patients with a history of severe anaphylactic insect sting reactions who underwent a detailed workup for insect venom allergy before starting venom immunotherapy. In addition to insect venom sensitization, an elevated concentration of bST (15.5, 20.8, and 23.2 µg/L) was found in all cases. There was no evidence of mastocytosis in the skin (MIS). Further testing revealed hereditary α-hypertryptasemia (HαT) in 2 patients and a D816V mutation by liquid biopsy in 1 patient, which is a minor diagnostic criterion for indolent systemic mastocytosis. Even without iliac crest puncture, causes of elevated bST can be narrowed down with minimally invasive diagnostic measures. As this has practical implications, patients with elevated bST should always undergo further work-up to determine the cause of this abnormal finding.

Mast cell disorders and Hymenoptera venom-triggered anaphylaxis: evaluation and management.

Patients with Hymenoptera venom allergy (HVA), especially those with severe anaphylaxis, frequently have concomitant clonal mast cell disease (MCD) in the form of systemic mastocytosis or monoclonal mast cell activation syndrome. Detection of clonal MCD is important since it will have significant consequences for management of HVA. Therefore, we recommend patients with HVA be systematically screened for clonal MCD. The pre-test probability of clonal MCD can be assessed in a stepwise fashion starting with examination of the skin for typical monomorphic maculopapular cutaneous mastocytosis (MPCM) lesions; measurement of the baseline serum tryptase (BST) and tryptase genotyping for patients with BST>11 ng/mL; followed by the REMA score which is calculated by utilizing anaphylaxis clinical features, BST, and patient sex. A bone marrow biopsy should be performed in patients with monomorphic MPCM, a REMA score ≥2, or an elevated BST based upon tryptase genotype. Patients with HVA and a clonal MCD should be treated with immunotherapy directed against the Hymenoptera venom for which they are sensitized. For this high-risk subgroup of HVA patients, it is recommended to continue immunotherapy for more than 5 years or indefinitely and to carry at least three epinephrine autoinjectors. Future studies should determine whether KIT D816V-selective tyrosine kinase inhibitors are effective at preventing or reducing severity of Hymenoptera-venom triggered anaphylaxis in patients with clonal MCD.

Evaluation of the relationship between mast cell activation and postural orthostatic tachycardia syndrome in children and adolescents.

OBJECTIVE: Postural orthostatic tachycardia syndrome (POTS) is one of the orthostatic intolerance syndromes that are common in young adolescents and impair quality of life. POTS is a multi-systemic disease. Many mechanisms have been defined in POTS etiology, such as autonomic denervation, hypovolemia, hyperadrenergic stimulation, low condition, and hypervigilance. Recently, mast cell activation (MCA) has also been on the agenda in etiology. There are few studies in the literature on the relationship between MCA and POTS in adulthood. However, data on children and adolescents is limited. In light of this information, we aimed to evaluate the relationship between POTS and MCA by measuring serum tryptase levels, a specific marker for MCA. METHODS: This prospective study included patients who were admitted to Kocaeli University Faculty of Medicine Hospital Pediatric Cardiology outpatient clinic for syncope-presyncope between November 2018 and August 2019. Patients who underwent the TILT-table test were enrolled in the study. Patients with structural heart disease or chronic heart disease were not included in this study. Serum tryptase levels were obtained from all patients before the TILT-table test, and serum tryptase levels were re-studied after the test was terminated in patients with positive TILT-table tests for POTS. Patients diagnosed with POTS were classified as Group 1, and other patients were classified as Group 2. RESULTS: Twenty-eight of the 58 patients included in the study (mean: 14.4±2.0 years; 38 girls, 20 boys) were diagnosed with POTS. The remaining 30 patients were diagnosed with vasovagal syncope and included in Group 2. The increase in mean heart rate during the test was 38±6 beats/min and 47.05%±15.65% in patients with POTS. Basal serum tryptase levels were not different between groups (3.2±1.3 ng/ml and 3.84±1.78 ng/ml, respectively; p=0.129), while serum tryptase levels (both baseline and after 45-60 min of the TILT-table test) were higher in patients presenting with symptoms related to MCA compared to others. CONCLUSION: In the literature, MCA was considered to be one of the mechanisms leading to POTS. Although other mechanisms, such as neuropathic and hypovolemic POTS, may be active in the patients, the symptoms of MCA in these patients should be routinely questioned.

Basophil Activation Test Predicts Cetuximab Anaphylaxis Severity in Alpha-Gal IgE-Positive Patients.

Upon first exposure to cetuximab, hypersensitivity reactions can occur. We aimed to assess the utility of the basophil activation test (BAT) to alpha-gal and cetuximab for predicting severe reactions. We prospectively recruited 38 patients and evaluated sIgE to alpha-gal in all patients before the first application of cetuximab. In all alpha-gal-sensitized patients, we evaluated skin tests to meat extracts, gelatine, and cetuximab and performed BAT with alpha-gal and cetuximab. In 24% (9/38) of patients, sIgE to alpha-gal was >0.10 kUA/L, and 8/9 reacted to the cetuximab. Basophil activation tests with alpha-gal were positive in all sensitized patients and were higher in those with severe reactions (18.3% in grade 4 [n = 4] vs. 1.8% in grade 2 [n = 3] or no reaction [n = 1] at 3.3 ng/mL of alpha-gal; p = 0.03). All patients with severe grade 4 reactions had a positive CD63 BAT response to cetuximab compared to patients with moderate or no reaction, who all had negative BAT (57.7% vs. 0.9% at 500 µg/mL, 63.2% vs. 4.1% at 100 µg/mL, 58.2% vs. 2.7% at 10 µg/mL, and 32.1% vs. 3.3% at 1 µg/mL of cetuximab, respectively; p ≤ 0.001). In summary, before initiating cetuximab treatment, sIgE to alpha-gal should be assessed in all patients. To predict the severity of the reaction and to assess the risk of cetuximab-induced anaphylaxis, we should perform BATs with alpha-gal or more discriminative BATs with cetuximab.

Alpha-Tryptase as a Risk-Modifying Factor for Mast Cell-Mediated Reactions.

PURPOSE OF REVIEW: To provide an overview on the current understanding of genetic variability in human tryptases and summarize the literature demonstrating the differential impact of mature tryptases on mast cell-mediated reactions and associated clinical phenotypes. RECENT FINDINGS: It is becoming increasingly recognized that tryptase gene composition, and in particular the common genetic trait hereditary alpha-tryptasemia (HαT), impacts clinical allergy. HαT has consistently been associated with clonal mast cell disorders (MCD) and has also been associated with more frequent anaphylaxis among these patients, and patients in whom no allergic trigger can be found, specifically idiopathic anaphylaxis. Additionally, more severe anaphylaxis among Hymenoptera venom allergy patients has been linked to HαT in both retrospective and prospective studies. An increased relative number of α-tryptase-encoding gene copies, even in the absence of HαT, has also been associated with systemic mastocytosis and has been shown to positively correlate with the severity of mast cell-mediated reactions to vibration and food. These findings may be due to increased generation of α/ß-tryptase heterotetramers and differences in their enzymatic activity relative to ß-tryptase homotetramers. HαT is a naturally occurring overexpression model of α-tryptase in humans. Increased relative α-tryptase expression modifies immediate hypersensitivity symptoms and is associated with more frequent and severe mast cell-mediated reactions, ostensibly due to increased α/ß-tryptase heterotetramer production.

Paediatric perioperative hypersensitivity: the performance of the current consensus formula and the effect of uneventful anaesthesia on serum tryptase.

Background: Paired sampling of acute (aST) and basal (bST) serum tryptase has been recommended when investigating patients with a suspected perioperative hypersensitivity (POH) reaction. In the current consensus formula, an aST value exceeding (1.2×bST+2) confirms mast cell activation. The current consensus formula has been validated in adults but not in children. Methods: We prospectively included 96 children who underwent uneventful anaesthesia and sampled serum tryptase at baseline and 60-90 min after induction. Tryptase changes were then compared with those in 94 children with suspected POH who were retrospectively included from four reference centres in Belgium, France, and Denmark. Results: We observed a median decrease in serum tryptase during uneventful anaesthesia of 0.41 µg L-1 (-15.9%; P<0.001). The current consensus formula identified mast cell activation in 31.9% of paediatric POH patients. After generating receiver operating characteristic curves through 100 repeated five-fold cross-validation, aST>bST+0.71 was identified as the optimal cut-off point to identify mast cell activation. This new paediatric formula has higher sensitivity than the current consensus formula (53.2% vs 31.9%, P<0.001) with a specificity of 96.9%. Analysis in the subpopulation where a culprit was identified and in grade 3-4 reactions similarly yielded higher sensitivity for the new paediatric formula when compared with the current consensus formula (85.3% vs 61.8%; P=0.008 and 78.0% vs 48.8%; P<0.001, respectively). Internally cross-validated sensitivity and specificity were 53.3% and 93.3%, respectively. Conclusions: This is the first study suggesting the need for an adjusted formula in children to identify perioperative mast cell activation as tryptase is significantly lowered during uneventful anaesthesia. We propose a new formula (aST>bST+0.71) which performs significantly better than the current consensus formula in our multicentric paediatric population.

Anaphylaxis in Risky Populations.

Anaphylaxis should be clinically diagnosed with immediate recognition, whereas, despite advances in the field of allergy, the symptoms of anaphylaxis remain to be under-recognized, diagnosis is often missed, and treatment is often delayed. Anaphylaxis presents with symptoms in a spectrum of severity, ranging from mild objective breathing problems to circulatory shock and/or collapse. Indeed, anaphylaxis management frequently relies on a 'one-size-fits-all approach' rather than a precision medicine care model, despite the evidence that anaphylaxis is a heterogeneous condition with differences in causative agents, clinical presentation, and host susceptibility. The key important risk factors for severe anaphylaxis and mortality are certain age groups or certain stages of life (infants, elderly and pregnant women), augmenting factors (physical exercise, alcohol consumption, menstruation, acute infections), concurrent use of some medications (beta-adrenergic blockers (ß-blockers) and angiotensin-converting enzyme (ACE) inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), and proton pump inhibitors (PPIs), and concomitant diseases (i.e. asthma, cardiovascular disease, mastocytosis). The present review aims to collectively address the patient groups who are at high risk of having anaphylaxis, those who have a more severe course, those that are difficult to diagnose, and require a special approach in treatment. Therefore, the risky populations like the elderly, pregnant women, patients receiving ß- blockers or ACE inhibitors, those with concomitant cardiovascular diseases, asthma, and mastocytosis, or those having higher baseline serum tryptase levels are discussed, including their clinical presentations and treatment strategies. Additionally, anaphylaxis during the perioperative period is addressed.

Comparison of serum tryptase as a diagnostic oncological marker in canine versus human mast cell neoplasms.

Canine mast cell tumors (MCTs) are a promising translational model for human mast cell neoplasms with striking similarities such as the Darier's sign and mutations in the KIT gene. Whereas mast cell neoplasms are rare in humans, MCTs are the most frequent malignant neoplasms of the skin in dogs. In human systemic mastocytosis, serum tryptase is an important diagnostic criterion. Surprisingly, serum tryptase levels were not yet investigated in dogs with MCTs. Therefore, the aim of this study was to investigate whether serum tryptase levels in dogs with cutaneous MCTs were elevated compared to those of a non-MCT control group. As a secondary aim, it was investigated whether surgical manipulation caused an increase in serum tryptase in canine MCT patients. A total of 48 serum samples were collected from dogs with different grades of cutaneous MCTs (n = 24) and non-MCT controls (n = 24). In dogs with cutaneous MCTs, blood was collected prior to and within 1 h after surgery. Serum tryptase levels were measured using a commercially available canine-specific ELISA kit. No significant difference in serum tryptase levels was found between cutaneous MCT patients and non-MCT controls, nor in these levels before versus after surgery. Our findings in canine cutaneous MCTs are in accordance with human cutaneous mastocytosis, where serum tryptase levels tend to remain within the normal range. However, despite various similarities between aggressive mast cell tumors in dogs and humans, serum tryptase cannot be considered a diagnostic biomarker in dogs with cutaneous MCTs as part of a comparative oncologic strategy.

Evaluation and Classification of Mast Cell Disorders: A Difficult to Manage Pathology in Clinical Practice.

Mast cells are granulocytic immunomodulatory cells with an important role in physiologic and pathogenic processes due to their location at the junction between the internal and external environment and to their capacity to release a broad range of active mediators. Mast cells mediators have both pro-inflammatory and anti-inflammatory activities and are implicated in various and complex pathology. Mast cells disorders (MCDs) represent a heterogeneous pathology, with frequently difficult and challenging evaluation and diagnostic workup. MCDs can be primary, secondary to other diseases, or idiopathic. Increased research interest in this field was noted during the last decade and various classification criteria, as well as diagnostic and treatment recommendations, were proposed. The aim of this paper is to review the most recent published data on the classification and evaluation of mast cells disorders and to point out the main difficulties in diagnosing and managing these complex diseases in medical practice.

Irritable bowel syndrome and basal serum tryptase: correlation between subtype, severity, and comorbidities. A pilot study

Introduction: the activation of mast cells causes alterations in epithelial and neuromuscular function and is involved invisceral hypersensitivity and dysmotility in gastrointestinal functional disorders.Objectives: primary: to evaluate differences in basal serum tryptase (BST) between patients with irritable bowel syndrome (IBS) and healthy controls. Secondary: BST depending on IBS subtype (diarrhea: IBS-D; constipation: IBS-C), comorbidities and correlation with IBS severity and quality of life.Material and methods: a prospective control-case study in IBS patients (Rome IV criteria). BST (ImmunoCAP-Phadia,Sweden®), IBS Severity Score (IBSSS), pain, bloating and flatulence analogue scales, IBS quality of life (IBSQOL), andpatient health status (PHQ-9) were determined. BST is the primary variable to achieve the primary endpoint. Results: thirty-two patients were included, 21 (65.6 %) with IBS-D and 11 (34.4 %) with IBS-C; 32 controls were also included. Mean IBSSSS: 326.6 (± 71.4), IBSQOL: 76 (± 20.3), and PHQ9: 10.2 (± 5.9). BST was 4.8 ± 2.6 in IBS and 4.7 ± 2.6 in controls (p = 0.875). There were no differences in BST between IBS subtypes (4.7 ± 2.9 in IBS-D and 5 ± 1.8 in IBS-C; p = 0.315) or IBS severity (p = 0.662). However, BST was higher in patients with IBS and extraintestinal comorbidities compared to other patients and controls (p = 0.029). This subgroup also has more severe bloating (p = 0.021). There was no correlation between BST, quality of life (p = 0.9260), and health status (p = 0.3985).Conclusion: BST does not discriminate between IBS patients and controls. However, BST was higher in patients with IBS with extraintestinal comorbidities, which had more severe bloating. This finding is worthy of investigation. (AU)

Fatal Food Anaphylaxis: Distinguishing Fact From Fiction.

Although there is a general perception that the prevalence of food allergy is increasing, data supporting this are limited. Food is the least common cause of fatal anaphylaxis, and fortunately, it is a very rare event; however, it is also unpredictable. There is widespread consensus that severe reactions cannot be predicted in a clinically meaningful way. Certain food triggers are more frequently associated with fatal anaphylaxis than others. In observational studies, peanut and tree nuts account for at least 30% to 50% of fatalities, with seafood and cow's milk also associated with fatal reactions. Fatal food-induced anaphylaxis is most likely to occur during adolescence and young adulthood, although the reasons for this are unclear. International guidelines agree that intramuscular (IM) epinephrine is the treatment of choice for managing food-triggered anaphylaxis and has a good safety profile when given by the IM route. However, fatalities still occur despite the timely administration of epinephrine. Food-allergic individuals must navigate a world that requires daily vigilance for allergens and preparedness for allergic reactions. Although the actual risk of fatal reactions is minimal, it is not zero, and severe reactions are unpredictable. Clinicians need to help patients better understand the very low but real risk of fatal reaction and enable them to lead as normal a life as possible through appropriate education, safety netting, and risk reduction.

[Utility of serum tryptase in Emergency Department patients with possible anaphylaxis].

Background Diagnosing anaphylaxis is often straightforward but can be challenging if the presentation is atypical. In patients with atypical symptoms suspected to be due to an acute allergic reaction, s-tryptase can give additional diagnostic information. Measuring s-tryptase is also helpful in diagnosing mastocytosis. Obtaining s-tryptase levels has been done in the emergency department (ED) at Landspitali since 2011. The aim of this study was to evaluate the benefit of obtaining s-tryptase levels in the ED. Methods With institutional review board approval, all cases where s-tryptase level was obtained in ED patients from 2011-2018 were retrospectively reviewed. A database was collected including information on patient demographics, presenting symptoms, treatment, diagnosis, s-tryptase level and follow up. Results A total of 214 patients had a s-tryptase level measured. Serum tryptase was elevated (>12 µg/L) in 36 cases. Females were 131 and average age 40.6 years. Of the patients, 86.4% had skin or mucosal symptoms, 48.1% cardiovascular symptoms, 49.5% respiratory symptoms and 36.0% had gastrointestinal symptoms. An allergist reviewed 126 returning patients and 65 were considered to have had an episode of anaphylaxis. Of those 65 were 4 patients which did not meet the diagnostic criteria for anaphylaxis but had raised s-tryptase levels. Sensitivity of s-tryptase measurement was 40.9% and specificity 97.1%. Conclusions Obtaining a s-tryptase level from ED patients with possible anaphylaxis seems to be useful in atypical cases. The measurement is specific but not sensitive. No cases of mastocytosis were identified in the patient cohort.

Hereditary Alpha-Tryptasemia: a Commonly Inherited Modifier of Anaphylaxis.

PURPOSE OF REVIEW: Hereditary alpha-tryptasemia (HαT) is an autosomal dominant genetic trait and a common cause of elevated basal serum tryptase in Western populations. It is a risk factor for severe anaphylaxis among individuals with venom allergy and an established modifier of anaphylaxis and mast cell mediator-associated symptoms among patients with systemic mastocytosis. Understanding the physiology of tryptases and how this may relate to the clinical features associated with HαT is the first step in identifying optimal medical management and targets for novel therapeutics. RECENT FINDINGS: HαT prevalence is increased in both clonal and non-clonal mast cell-associated disorders where it augments symptoms of immediate hypersensitivity, including anaphylaxis. The unique properties of naturally occurring α/ß-tryptase heterotetramers may explain certain elements of phenotypes associated with HαT, though additional mechanisms are being evaluated. This review provides an overview of the clinical and translational studies that have identified HαT as a modifier of mast cell-associated disorders and anaphylaxis and discusses mechanisms that may potentially explain some of these clinical findings.

Biomarkers of the Severity of Honeybee Sting Reactions and the Severity and Threshold of Systemic Adverse Events During Immunotherapy.

BACKGROUND: A biomarker that could identify individuals at high risk for severe honeybee sting allergic reaction and/or systemic adverse events (SAEs) during venom immunotherapy (VIT) would improve the management of patients with honeybee (HB) venom allergy. OBJECTIVE: To identify biomarkers for risk of severe sting reactions or SAEs during VIT. METHODS: We recruited 332 patients undergoing HB VIT. We ascertained predictors of the severity of the field-sting reaction and the severity and threshold of SAEs during VIT. We assessed the use of cardiovascular medications; baseline serum tryptase (BST) levels; specific IgEs to HB venom, rApi m 1, and rApi m 10; and basophil activation test (BAT) response. RESULTS: Significant and independent predictors of a severe HB field-sting reaction were age (P = .008), an absence of skin symptoms (P = .001), BST (P = .014), and BAT response at an HB venom concentration of 0.1 µg/mL (P = .001). Predictors of severe SAEs during HB VIT were age (P = .025), BST (P = .006), and BAT response (P = .001). BAT response was also an individual and significant predictor of any SAEs and SAEs at a low cumulative allergen dose (median, 55 µg) during VIT build-up (P < .001). The use of ß-blockers and angiotensin-converting-enzyme inhibitors and specific IgE levels were not associated with the severity of HB field-sting reactions or VIT SAEs. CONCLUSIONS: BST and basophil activation are independent risk factors for severe HB sting anaphylaxis and SAEs during HB VIT. BAT response was the best biomarker for any SAEs and a lower threshold of SAEs during HB VIT. These risk factors can help guide recommendations for VIT and overcome systemic reactions to HB VIT.

Increased TPSAB1 Copy Number in a Family With Elevated Basal Serum Levels of Tryptase.

Background: Some recent familial studies have described a pattern of autosomal dominant inheritance for increased basal serum tryptase (BST), but no correlation with mRNA expression and gene dose have been reported. Objective: We analyzed TPSAB1 mRNA expression and gene dose in a four-member family with high BST and in two control subjects. Methods: Blood samples were collected from the family and control subjects. Complete morphologic, immunophenotypical, and molecular bone marrow mast cell (MC) studies were performed. mRNA gene expression and gene dose were performed in a LightCycler 480 instrument. Genotype and CNV were performed by quantitative real-time digital PCR (qdPCR). Results: CNV analysis revealed a hereditary copy number gain genotype (3ß2α) present in all the family members studied. The elevated total BST in the family members correlated with a significant increase in tryptase gene expression and dose. Conclusions and Clinical Relevance: We present a family with hereditary α-tryptasemia and elevated BST which correlated with a high expression of tryptase genes and an increased gene dose. The family members presented with atypical MC-mediator release symptoms or were even asymptomatic. Clinicians should be aware that elevated BST does not always mean an MC disorder.

Chronic inducible urticaria subtypes in children: Clinical features and prognosis.

BACKGROUND: Chronic inducible urticaria (CIndU) is a subtype of chronic urticaria induced by a physical stimulus. OBJECTIVE: To evaluate the clinical features, prognostic factors, and natural course of childhood CIndU subtypes. METHODS: Patients (1-18 years old, n = 117) diagnosed with CIndU between March 2011 and March 2019 were analyzed. Patients (n = 101) were re-evaluated for the status of their CIndU at least 6 months after the initial evaluation. RESULTS: The study population comprised of 117 children with a median (inter-quartile range) age of 10.3 (6-14.8) years at admission and a male predominance (53%). Symptomatic dermographism was the most common type of CIndU, affecting 65% of the group, followed by cold urticaria and cholinergic urticaria, which affected 17% and 15.4%, respectively. Baseline serum tryptase levels in cholinergic urticaria and cold urticaria were higher than those in symptomatic dermographism [7.0 (3.3-10.7) µg/L, 4.2 (2.8-9.3) µg/L, and 2.7 µg/L (1.8-5.9), respectively; P = .020]. Recovery was observed in 9.6%, 25.3%, and 34.7% of the CIndU children after 12, 36, and 60 months, respectively. Of the patients with symptomatic dermographism, 40% had remission in 5 years, whereas this rate was only one-fifth in patients with cold urticaria. The worst prognosis was observed in patients with cholinergic urticaria. CONCLUSION: This study concluded that nearly one-third of children with CIndU recovered within 5 years and symptomatic dermographism has the best prognosis. Cholinergic urticaria is the CIndU type with the worst prognosis, male dominance, and highest baseline serum tryptase levels.