Serum Tryptase Levels Research Articles

Osteoporosis in Systemic Mastocytosis: A Scoping Review

Background: Mastocytosis (MS) is a rare disease that can involve various organs, including the bone. Given the incidence of the disease in the global population, MS poses a challenge for physicians, and early therapeutic intervention in the initial stages could significantly impact the quality of life of affected patients. Objective: The aim of this scoping review was to provide an overview of secondary osteoporosis in systemic mastocytosis (SM), focusing on the heterogeneity of its manifestations, the benefits of early diagnosis, and appropriate pharmacological treatment. Design: A technical expert panel (TEP) consisting of 8 physicians with expertise in metabolic bone diseases conducted the review following the PRISMA-ScR model. A strength of this study is that it provides various therapeutic approaches for patients with bone involvement in SM, although the limited available literature on the topic constituted a limitation. The TEP sought evidence regarding the following diagnostic and therapeutic modalities in the management of SM: “bisphosphonate therapy”, “zoledronic acid therapy”, “denosumab therapy”, “IFN-alpha therapy”, and “IFN-alpha therapy in combination with pamidronate”. Results: Clinical data showed a correlation between densitometric outcomes, serum tryptase levels, and mast cell infiltration in the bone marrow, between increased bone mineral density and the presence of osteosclerosis in cases of advanced SM, between the severity of osteoporosis and hypertryptasemia, and also provided results on the long-term effects of bisphosphonate therapy, the therapeutic efficacy of zoledronic acid administration, the positive effect of denosumab on the reduction of serum tryptase levels (even if is proved in a limited numbers of cases) and the prevention of new fractures, and the effect of IFN-alpha in more severe cases of SM, either alone or in combination with pamidronate. Conclusions: Studies have demonstrated the effectiveness of various treatments depending on the form of mastocytosis, whether indolent systemic or advanced systemic, in the prognosis of the disease. However, this role should be further investigated in additional clinical studies, considering the limited data on the use of these interventions.

Gastrointestinal symptoms in children with mastocytosis

Introduction. Mastocytosis is a heterogeneous group of diseases characterized by the abnormal accumulation of clonal mast cells (MCs) in various tissues and organs, including skin, bone marrow, liver, spleen and lymph nodes. The clinical picture of cutaneous and indolent systemic mastocytosis is formed by a wide range of symptoms associated with activation of mast cells. Single European studies have demonstrated wide variability in the frequency of gastrointestinal symptoms (GI-symptoms)) in children with mastocytosis (from 15 to 50%).Aim. To analyze the frequency of mediator-related GI-symptoms in children with different subtypes and clinical forms of mastocytosis.Materials and methods. A prospective observational study included data from 289 children aged 3 to 17 years who were under observation at the Moscow Scientific and Practical Center of Dermatovenereology and Cosmetology. Symptoms were assessed using the Pediatric grade scale of symptoms of mastocytosis. Clinical manifestations of reactions caused by mast cell degranulation were compared with data from clinical and laboratory studies. The concentrations of tryptase and histamine in the blood serum of patients were determined. The incidence of organomegaly and mesenteric lymphadenitis in children with mediating symptoms and without symptoms was determined using ultrasound.Results. 67 (23.2%) patients had GI symptoms. More than half of the patients (51.6%) indicated abdominal pain, 32.3% reported diarrhea. The severity of pain symptoms correlated with the level of serum tryptase (ρ = 0.564, p < 0.01). The incidence of hepatomegaly and mesadenitis in children with GI- symptoms was 19.4% and 25.4%, respectively. In a comparative analysis in groups of children with and without GI symptoms, the differences in the number of identified cases of organomegaly and mesadenitis were statistically significant (p < 0.001). An increase in histamine levels in the blood was detected in half of the patients with complaints of heartburn and nausea.Conclusion. Our results demonstrated that a study of the level of serum tryptase, ultrasound of the abdominal organs and lymph nodes should be carried out in all children with mediator-related GI-symptoms regardless of the clinical form of mastocytosis.

Report of 3 Cases Diagnosed with Basal Cell Carcinoma and Systemic Mastocytosis with Favorable Prognosis

Abstract Introduction/Objective The co-existence of basal cell carcinoma (BCC) and systemic mastocytosis is an exceptionally rare clinical occurrence, and the prognosis is not well-documented. Understanding the clinical and histopathological features of this uncommon association is relevant for accurate diagnosis, management, and prognostication. Methods/Case Report We conducted a retrospective analysis of three cases of BCC with concurrent systemic mastocytosis that were identified in the pathology database of the University of Pennsylvania from 2010 to 2023. Patient demographics, clinical and histopathologic characteristics, and treatment outcomes were reviewed. Histopathologic assessment, immunohistochemistry, and C-KIT D816V mutation analysis (with an allele-specific PCR assay) were performed on biopsy material. Next-Generation Sequencing (NGS) was used to identify other hematologic neoplasm-associated mutations. Results (if a Case Study enter NA) All three cases were female with a median age of 55.3 years (50, 69, 47). In all three cases, atypical CD117+ tryptase+ CD25+ mast cells with mild to moderate pleomorphism were found in the dermis adjacent to the BCC cells. All three cases had bone marrow involvement. Serum tryptase levels were mildly elevated in all 3 patients (maximum 65.5 μg/L). All three cases harbor a C-KIT D816V mutation and a history of systemic glucocorticosteroids before the diagnosis of BCC. One of the cases was treated with phototherapy. NGS detected the following somatic mutations: Case #2 DNMT3A p.R882H c.2645G>A; Case #3 JAK2 V617F. Case #1 had multiple relapses of BCC, but a subsequent marrow biopsy did not identify any involvement by mastocytosis. Case #2 had mast cell leukemia, which typically has a poor prognosis; however, this patient has survived for several years. Case #3 had essential thrombocythemia and systemic mastocytosis with an associated hematological neoplasm, and her symptoms were stable. Treatment modalities for the three patients ranged from surgical excision to anti-mastocytosis therapy, with favorable outcomes (Table 1). Conclusion The coexistence of BCC with mastocytosis poses diagnostic challenges due to its infrequency and varied clinical presentations. Previous literature reports on treatments of mastocytosis such as phototherapy and steroids, which have been identified as risk factors for the development of basal cell carcinoma. However, recognizing this unique combination in clinical practice may aid in providing appropriate treatment strategies, ultimately leading to favorable patient outcomes.

Progression of Mast Cell Activation Syndrome to Systemic Mastocytosis

Abstract Introduction/Objective Mast cell activation syndrome (MCAS) is characterized by the abnormal release of mast cell mediators, leading to symptoms such as flushing, abdominal pain, and allergic reactions. In some cases, MCAS progresses to systemic mastocytosis (SM), a mast cell disorder marked by organ infiltration and dysfunction. However, predictors of MCAS progression to SM remain poorly understood, and long-term prognosis data are limited. Methods/Case Report We conducted a retrospective study of patients diagnosed with MCAS at Penn Medicine from January 1, 2019, through December 30, 2021. The primary endpoint was progression to SM, defined by World Health Organization criteria, with a secondary endpoint set for September 24, 2023. Results (if a Case Study enter NA) We identified 47 patients with MCAS (Table 1). Of these, 11 patients (23.4%) progressed to SM. Notably, all five patients with c-KIT mutations progressed to SM (100%, 5/5), while six out of 22 patients without c-KIT mutations also progressed (27.2%). Additionally, baseline serum tryptase levels were identified as a significant predictor of progression at two years. Conclusion The relative risk of progression varied depending on the subtype of MCAS, with higher rates observed in those with KIT D816V presence. Compared to the incidence of SM in the general population, our findings suggest a higher risk of progression from MCAS to SM, even without a c-KIT mutation. Identification of prognostic factors, such as specific genetic mutations and baseline serum tryptase levels, may aid in risk stratification and early intervention strategies for individuals with MCAS. HaT mutation testing should be considered in future studies on this topic. Our findings have important implications for the clinical management and understanding of MCAS progression to SM. Additionally, our data imply the importance of recognizing MCAS in the early phase and proper monitoring, considering the low rate of MCAS diagnosis. Patients with MCAS may need annual monitoring, including serum tryptase levels, to detect progression to SM and related complications. Early detection and intervention may improve outcomes and quality of life for individuals with MCAS.

Anaphylaxis induced by indocyanine green during abdominal surgery: A case report

Since 2011, indocyanine green (ICG) has been increasingly used in surgery as a diagnostic tool. Although allergic reactions to this fluorescent dye are considered rare, they can result in anaphylactic shock. We report the case of a 33-year-old woman who developed anaphylaxis immediately after ICG administration during laparoscopic-assisted high anterior resection. The patient was treated with intravenous adrenaline, and the surgery continued. Elevated plasma histamine and serum tryptase levels immediately after ICG administration and intradermal testing identified ICG as the causative agent. The frequency of ICG use is increasing, and anesthesiologists should recognize ICG as a prevalent perioperative allergen.

Report of six cases with mast cell leukemia and a literature review

From October 2021 to February 2023, we retrospectively analyzed the clinical and laboratory data of six patients (three male and three female, median age: 54 years, age range: 29-73 years) with mast cell leukemia (MCL) diagnosed in the First Affiliated Hospital of Soochow University (The Mastocytosis Collaborative Network of China). All patients had acute MCL, with at least one C-finding present. The main clinical presentations were hypoalbuminemia (n=4), fatigue (n=3), fever (n=2), abdominal discomfort (n=2), osteolytic lesions (n=2), dizziness (n=1), skin flushing (n=1), and weight loss (n=1). Splenomegaly and lymphadenopathy were noted in six and three patients, respectively. Six patients were strongly positive for CD117, five were positive for CD30 and CD25, and four were positive for CD2. Four patients had a normal karyotype and two patients had an abnormal karyotype. Gene mutations were detected in 4/6 cases. The median serum tryptase level was 24.9 (range: 20.1-171.9) μg/L. Two patients were treated with venetoclax and azacitidine for induction (one patient achieved partial remission by combination with afatinib, while there was no remission after combination with dasatinib in the other patient). Two patients did not achieve complete remission despite treatment with cladribine and imatinib, respectively. One patient treated with interferon combined with glucocorticoids was lost to follow-up, and one patient abandoned treatment. The follow-up time ranged from 1.1 to 21.7 months. Three patients died and two survived. Overall, MCL is a rare subtype of systemic mastocytosis with heterogeneous clinical course, and these patients have poor outcome. A better understanding of the clinical characteristics, treatment, and prognosis of MCL is urgently needed.

Indolent systemic mastocytosis (ISM) without skin lesions as a recurrent anaphylaxis: a case report study

Introduction and importance: Mastocytosis encompasses a diverse range of disorders characterized by the clonal accumulation of mast cells in various tissues, including the skin, bone marrow, and gastrointestinal tract. Case presentation: This case report describes a 32-year-old male patient who presented with a history of recurrent anaphylactic attacks and elevated serum tryptase levels without apparent skin involvement. The diagnostic process and clinical implications of non-cutaneous mastocytosis are discussed in the context of existing WHO criteria. Clinical discussion: Mastocytosis, although a rare disease, carries the potential for severe complications and can present with atypical symptoms, thereby complicating its diagnosis and management. Consequently, the development of a reliable diagnostic and therapeutic strategy is of paramount importance. Conclusion: There is a pressing need to delve deeper into the investigation of the potential impacts and manifestations of mastocytosis to further our understanding and enhance patient care.

Tryptase levels in children with cutaneous mastocytosis: a prospective study

BACKGROUND: Serum tryptase levels are used as a diagnostic marker in mastocytosis and are considered an indicator of clonal mast cell (MC) load. AIMS: To analyze tryptase levels in children with different clinical types of cutaneous mastocytosis. MATERIALS AND METHODS:A single-center prospective study was conducted for the period 2022-2024. The results of examination of 202 children aged from 6 months to 17 years with a diagnosis of cutaneous mastocytosis, who were undergoing outpatient treatment at the Moscow scientific and practical Center of dermatovenereology and cosmetology, were analyzed. Serum tryptase levels were determined by enzyme immunoassay. RESULTS:The median basal tryptase level for the entire group (n=202) was 5.09 μg/L (range 1.3–57.0 μg/L). Serum tryptase values exceeding 11.0 μg/L were detected in 17.3% of patients, and 20.0 μg/L in 7.4%. The mean enzyme level in the control group was 2.55 μg/L. There were significant differences in tryptase concentrations between the maculopapular cutaneous mastocytosis (MPCM) and control groups (p=0.05). The median tryptase level in children with MPCM was 8.7 μg/L. The most pronounced differences were observed between the enzyme levels in children with the monomorphic type of MPCM and in the control group (p=0.01). Analysis of tryptase levels depending on gender and clinical type of MPCM showed that children and adolescents with the monomorphic type of MPCM had higher enzyme levels. CONCLUSIONS: Further studies are needed to determine which tryptase levels in children are indicative of MC activation and primary MC diseases. A detailed understanding of tryptase levels in children may facilitate the development of new specific therapeutic approaches to the management of various clinical forms of cutaneous mastocytosis.

Mastocytoma and juvenile xanthogranuloma in children

The growing number of children with rare diseases such as cutaneous mastocytoma and juvenile xanthogranuloma turning to dermatologists, as well as their clinical similarity, dictate the need for specialists to pay careful attention to these diseases. cutaneous mastocytoma is a clinical form of cutaneous mastocytosis. According to the WHO classification (2022), isolated (one focus) and multiple cutaneous mastocytoma (no more than three foci) are distinguished. juvenile xanthogranuloma belongs to the group of non-Langerhans cell histiocytosis, a broad group of related diseases characterized by the proliferation of histiocytes other than Langerhans cells. We describe a case of an unusual clinical course of solitary juvenile xanthogranuloma in a 3-year-old boy referred to Moscow Scientific and Practical Center of Dermatovenereology and Cosmetology with suspected cutaneous mastocytoma. The size, unusual shape, localization of the lesion and elevated levels of serum tryptase exceeding the age norm (<5 μg/l) determined the atypicality of this case. Dermoscopic examination revealed a central deep yellow coloration of the lesion in the center (the setting sun symptom), a vascular pattern and a clouds symptom. Pathological examination confirmed the diagnosis of juvenile xanthogranuloma. The article also reflects the results of a dynamic observation of a child with an isolated large-sized cutaneous mastocytoma. During the examination, an increase in tryptase levels (>20 μg/l), and AST values, as well as ultrasound signs of hepatomegaly were revealed. Features of the dermoscopic and pathomorphological picture demonstrated patterns characteristic of infiltration and increased activity of mast cells. Cutaneous mastocytoma and juvenile xanthogranuloma are rare and benign skin diseases that usually begin in childhood. Diagnosis of rare diseases often requires complex differential diagnosis. Features of the modern course of cutaneous mastocytoma and juvenile xanthogranuloma are an atypical clinical picture and a high risk of developing extracutaneous symptoms. The presented clinical cases demonstrate the need for interdisciplinary monitoring of patients with these diseases and change the stereotypes of treating them as independent and regressive processes without a trace.

Airway tryptase levels inform the lack of clinical efficacy of the tryptase inhibitor MTPS9579A in asthma.

Tryptase, a mast cell protease, has been identified as a potential therapeutic target in managing patients with refractory asthma. We assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of MTPS9579A, an anti-tryptase antibody, in a phase 2a randomized trial for patients with uncontrolled asthma and a phase 1c trial to understand activity within the lower respiratory tract. Phase 2a patients (n = 134) received 1800 mg MTPS9579A or placebo intravenously every 4 weeks for 48 weeks. The primary endpoint was time to the first composite exacerbation event. Phase 1c patients (n = 27) received one intravenous dose of 300 or 1800 mg MTPS9579A or placebo. Both trials measured MTPS9579A concentrations and effects on tryptase in serum and nasal lining fluid; phase 1c also analyzed bronchial lining fluid. MTPS9579A did not meet the primary endpoint (hazard ratio = 0.90; 95% CI: 0.55-1.47; p = 0.6835); exacerbation rates in the placebo group were low. Serum and nasal MTPS9579A pharmacokinetics and tryptase levels were consistent with data from healthy volunteers. However, in phase 1c patients, compared to nasal levels, MTPS9579A bronchial concentrations were 6.8-fold lower, and bronchial active and total tryptase levels were higher (119-fold and 30-fold, respectively). Pharmacokinetic/pharmacodynamic modeling predicted intravenous doses of 3800 mg every 4 weeks would be necessary to achieve 95% active tryptase inhibition from baseline. The MTPS9579A dose tested in the phase 2a study was insufficient to inhibit tryptase in bronchial lining fluid, likely contributing to the observed lack of efficacy.

Interactions between eosinophils and IL-5Rα–positive mast cells in nonadvanced systemic mastocytosis

Bidirectional interactions between eosinophils and mast cells (MCs) have been reported in various allergic diseases. Bone marrow (BM) eosinophilia, and to a lesser extent blood eosinophilia, is common in systemic mastocytosis (SM), but its significance remains unknown. To describe blood and BM eosinophil characteristics in SM. A large collection of BM biopsies was analyzed using immunohistochemical staining and whole-slide imaging. Eosinophil and extracellular granules were detected by eosinophil peroxidase (EPX) staining, and MCs by KIT staining. Complementary analyses were conducted using flow cytometry and immunofluorescence. Eosinophil infiltrates and large areas of eosinophil degranulation were observed within or around BM MC infiltrates in SM. EPX staining surface, highlighting intact eosinophils and eosinophil degranulation, was higher in non-advanced-SM (n=37 BM biopsies) compared to both controls (n=8, p=0.0003) and to advanced SM (n=24, p=0.014). In non-advanced SM, positive correlations were observed between serum tryptase levels and percentages of eosinophil counts in BM aspirations (Spearman r coefficient r=0.38, p=0.038), eosinophils count in BM biopsies (r=0.45, p=0.007), EPX staining (r=0.37, p=0.035) and eosinophil degranulation (r=0.39, p=0.023). Eosinophil counts in BM biopsies also correlated with MC counts (r=0.47, p=0.006) and KIT staining surface (r=0.49, p=0.003). BM MCs expressed interleukin-5 receptor and other usual eosinophil cytokine/chemokine receptors, and blood eosinophils display several increased surface markers compared to controls, suggesting an activated state. Our data suggest a possible crosstalk between MCs and eosinophils, supporting MC tryptase release and MC activation-related symptoms. This suggests a rationale for targeting eosinophils in non-advanced-SM not fully controlled by other therapies.

Perioperative anaphylaxis: updates on pathophysiology.

Perioperative anaphylaxis has historically been attributed to IgE/FcεRI-mediated reactions; there is now recognition of allergic and nonallergic triggers encompassing various reactions beyond IgE-mediated responses. This review aims to present recent advancements in knowledge regarding the mechanisms and pathophysiology of perioperative anaphylaxis. Emerging evidence highlights the role of the mast-cell related G-coupled protein receptor X2 pathway in direct mast cell degranulation, shedding light on previously unknown mechanisms. This pathway, alongside traditional IgE/FcεRI-mediated reactions, contributes to the complex nature of anaphylactic reactions. Investigations into the microbiota-anaphylaxis connection are ongoing, with potential implications for future treatment strategies. While serum tryptase levels serve as mast cell activation indicators, identifying triggers remains challenging. A range of mediators have been associated with anaphylaxis, including vasoactive peptides, proteases, lipid molecules, cytokines, chemokines, interleukins, complement components, and coagulation factors. Further understanding of clinical endotypes and the microenvironment where anaphylactic reactions unfold is essential for standardizing mediator testing and characterization in perioperative anaphylaxis. Ongoing research aims to elucidate the mechanisms, pathways, and mediators involved across multiple organ systems, including the cardiovascular, respiratory, and integumentary systems, which will be crucial for improving patient outcomes.

Flushing in children with cutaneous mastocytosis

Introduction. Flushing is a subjective feeling of warmth that is accompanied by redness of the skin on any part of the body, but mainly on the face, neck and upper trunk. Episodic flushing with other symptoms associated with mast cell mediators can be observed in 30–50% of children with cutaneous mastocytosis (CM).Aim. To analyze the frequency of flushing in children with various clinical forms of cutaneous mastocytosis. To study serum tryptase levels in children with flushing.Materials and methods. The study included data from 275 children aged from 6 months to 17 years inclusive, who were undergoing outpatient treatment and observation at the Moscow Scientific and Practical Center of Dermatovenereology and Cosmetology from March 2022 until January 2024. The concentration of tryptase in the blood was determined by immunofluo-rescence on a three-dimensional porous solid phase (ImmunoCAP technology, Pharmacia Diagnostics AB, Sweden). Polarization and immersion dermatoscopy with 20x magnification were performed.Results. Flushings were observed in 17.5% of patients out of 275 observed children with CM. The level of tryptase more than 15 µg/l was determined in 20.8% of children with flushing, above 11.0 µg/l – in 37.5%. Tryptase levels were higher than 8.0 µg/L in 22 (45.8%) patients. In 25.0% of patients with flushing, tryptase levels did not exceed 5 µg/L. The severity of the vascular pattern in lesions and apparently healthy skin was characteristic of patients with frequent or prolonged flushing and tryptase levels above 8.0 µg/L.Conclusion. This study was the first in the Russian Federation to demonstrate the prevalence of flushing in children with various clinical forms of cutaneous mastocytosis. The results showed that the assessment of serum tryptase levels should be performed in all children with flushing, regardless of the clinical form of mastocytosis, including those with isolated and multiple skin mastocytomas. Clinical laboratory and dermatoscopic monitoring are important for the development of individual therapeutic tactics and prevention of mediator reactions and anaphylaxis.

Comprehensive Review of Mastocytosis From Pathophysiology to Management Strategies

Introduction: Mastocytosis is a rare hematologic neoplasm characterized by the abnormal proliferation and accumulation of mast cells in various tissues. Its clinical manifestations vary widely, ranging from cutaneous lesions to systemic involvement with potentially life-threatening symptoms. Understanding the pathophysiology, diagnosis, and management of mastocytosis is crucial for improving patient outcomes. 
 
 Aim of the Study: The aim of this study was to provide a comprehensive overview of mastocytosis, including its epidemiology, risk factors, pathophysiology, clinical manifestations, diagnostic approaches, and management strategies. By synthesizing current knowledge on mastocytosis, this study aims to enhance understanding of the disease and guide clinical practice. 
 
 Description of the State of Knowledge: Mastocytosis is classified into cutaneous and systemic forms, with various subtypes based on clinical and histopathological features. Diagnosis relies on a combination of clinical suspicion, serum tryptase levels, histological examination of bone marrow biopsies, and genetic testing. Management strategies include symptomatic treatment, avoidance of triggers, and targeted therapies such as monoclonal antibodies and tyrosine kinase inhibitors. Advanced forms may require cytoreductive therapy or allogeneic hematopoietic stem cell transplantation (alloHSCT). 
 
 Conclusions: Despite advancements in diagnosis and treatment, achieving lasting remission in mastocytosis remains challenging, especially in advanced cases. Further research into the molecular mechanisms underlying the disease and the development of novel therapeutic modalities are needed to improve patient outcomes and quality of life.

Elderly Patients and Insect Venom Allergy: Are the Clinical Pictures and Immunological Parameters of Venom Allergy Age-Dependent?

Insect venom is one of the most common triggers of anaphylaxis in the elderly population. Venom immunotherapy (VIT) remains the only treatment for Hymenoptera venom allergy (HVA). However, little is known about the differences in indication for VIT in the group of patients aged 60 years and older. The objective of this study was to assess the clinical and diagnostic differences of HVA in elderly patients. The study compared data from patients aged ≥ 60 (N = 132) to data from patients aged from 11 to 60 years (N = 750) in terms of HVA severity, comorbidities, and immunological parameters, namely, intradermal testing (IDT), specific IgE (sIgE) levels against extracts and major allergenic molecules, and serum tryptase level (sBT). The severity of systemic HVA (I-IV Müller scale) did not differ between adults and seniors. However, the severity of cardiovascular reactions (IV) increased with age, while the frequency of respiratory reactions (III) decreased. No differences were found in the immunological parameters of sensitization IDT, venom-specific IgE concentrations, or sIgE against Api m 1, 2, 4, 5, and 10 between patients below and above 60 or 65 years of age. Differences were noted for sIgE against Ves v1 and Ves v5; they were higher and lower, respectively, in seniors. In the seniors group, sBT levels were higher. Elevated tryptase levels, along with the aging process, can represent a risk factor within this age category. Nevertheless, advanced age does not influence the immunological parameters of immediate HVA reactions, nor does it impact the diagnosis of HVA.

Death Due to Furosemide Anaphylaxis and The Importance of Serum Tryptase Level in Diagnosing Anaphylaxis: A Case Report

Anaphylaxis is a severe systemic hypersensitivity reaction with a sudden onset and may result in death. In this study, we report the case of a 71-year-old female patient who died within seconds after the administration of intravenous furosemide in emergency service; she had high serum tryptase levels at postmortem examination and nonspecific findings at autopsy, and death due to anaphylaxis was reported. With this study, we wanted to point to the rare and potentially fatal drug anaphylaxis, such as furosemide anaphylaxis. Also, our results indicate the importance of serum tryptase levels in the diagnosis of death due to anaphylaxis.

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.

Tryptase in Acute Appendicitis: Unveiling Allergic Connections through Compelling Evidence.

The aetiology of acute appendicitis (AA), the most frequent abdominal surgical emergency, is still unclarified. Recent epidemiologic, clinical and laboratorial data point to an allergic component in the pathophysiology of AA. Mastocytes participate in the Th2 immune response, releasing inflammatory mediators from their granules upon stimulation by IgE-specific antigens. Among the well-known mediators are histamine, serotonin and tryptase, which are responsible for the clinical manifestations of allergies. We conducted a prospective single-centre study to measure histamine and serotonin (commercial ELISA kit) and tryptase (ImmunoCAP System) concentrations in appendicular lavage fluid (ALF) and serum. Consecutive patients presenting to the emergency department with a clinical diagnosis of AA were enrolled: 22 patients with phlegmonous AA and 24 with gangrenous AA The control group was composed of 14 patients referred for colectomy for colon malignancy. Appendectomy was performed during colectomy. Tryptase levels were strikingly different between histological groups, both in ALF and serum (p < 0.001); ALF levels were higher than serum levels. Tryptase concentrations in ALF were 109 times higher in phlegmonous AA (APA) (796.8 (194.1-980.5) pg/mL) and 114 times higher in gangrenous AA (AGA) (837.4 (272.6-1075.1) pg/mL) than in the control group (7.3 (4.5-10.3) pg/mL. For the diagnosis of AA, the discriminative power of serum tryptase concentration was good (AUC = 0.825), but discriminative power was weak (AUC = 0.559) for the differential diagnosis between APA and AGA. Mastocytes are involved in AA during clinical presentations of both phlegmonous and gangrenous appendicitis, and no significant differences in concentration were found. No differences were found in serum and ALF concentrations of histamine and serotonin between histological groups. Due to their short half-lives, these might have elapsed by the time the samples were collected. In future research, these determinations should be made immediately after appendectomy. Our findings confirm the hypersensitivity type I reaction as an event occurring in the pathogenesis of AA: tryptase levels in ALF and serum were higher among patients with AA when compared to the control group, which is in line with a Th2 immune response and supports the concept of the presence of an allergic reaction in the pathogenesis of acute appendicitis. Our results, if confirmed, may have clinical implications for the treatment of AA.

INDOLENT SYSTEMIC MASTOCYTOSIS MASQUERADING AS CHRONIC ANEMIA IN ULCERATIVE COLITIS: A CASE STUDY

Abstract BACKGROUND Anemia is a frequent systemic/extra-intestinal manifestation of inflammatory bowel disease (IBD). It has a complex multifactorial etiology which suppresses erythropoiesis due to pro-inflammatory mediators, myelosuppression, iron and micronutrient deficiency. It significantly impacts quality of life (QoL) and increases hospitalizations, length of hospital stays and mortality rates. It Is commonly thought to arise as a consequence of IBD or it’s related therapy. Current strategies are aimed at correction of anemia with low priority towards identifying a specific cause. Here, we represent a case of UC with chronic anemia secondary to systemic mastocytosis (SM). CASE A 41 y/o female with UC presents to the outpatient clinic with complaints of fatigue. Further questioning revealed a baseline of 1-2 formed bowel movements per day. She did not report any hematochezia or weight loss. She was managed on 300 mg of vedolizumab every 4 weeks. Prior failure to medications includes anti-tumor necrosis factor inhibitors and tofacitinib. Labs were consistent with albumin 4.5 mg/dL and CRP &amp;lt; 1 mg/dL. Iron studies revealed low iron, TIBC and ferritin levels. Fecal calprotectin measurements were not available due to patient non-compliance. Patient (Pt) was thought to have experienced a UC flare and colonoscopy was recommended. Colonoscopy was unrevealing with no sign of active disease on examination (Mayo Endo 0). Pt was referred to hematology where she underwent a bone marrow biopsy revealing multifocal dense infiltrates of mast cells (≥15 mast cells in aggregates) expressing CD2+ and CD 25+ with 25% showing atypical morphology in bone marrow biopsies. KIT D816V mutation was also positive. The serum tryptase level in this pt was 47.1ug/L. She was then placed on anti-histamines, proton pump inhibitors and steroid therapy. CONCLUSION SM is a clonal disorder of MC that infiltrates one or more organs. It almost always involves the bone marrow. Gastrointestinal (GI) symptoms are present in up to 80% patients. These symptoms are secondary to systemic effects of MC mediators. Incidence of SM in UC has never been established. SM has been shown to mimic Crohn’s disease and is difficult to differentiate based on clinical and endoscopic features. Furthermore, little is known regarding histopathological features of GI involvement in SM. The presence of chronic anemia despite adequate therapy in a clinically/endoscopically inactive UC patient should raise suspicion of other pathologic causes of anemia. Our case highlights the importance of diagnosing the specific cause of anemia in IBD as it may lead to inaccurate clinical judgements of disease flares leading to undue alteration in therapy.

One-Bag 8-Step Ferric Carboxymaltose Desensitization Protocol for Patients with a History of Hypersensitivity Reactions to Iron Preparations

Introduction: Iron deficiency is the most common cause of anemia in both sexes, although it is more common in women. Intravenous (IV) iron replacement is preferred in patients who cannot tolerate oral treatment or when iron stores need to be replenished rapidly. In this study, we wanted to share the ferric carboxymaltose (FCM) desensitization protocol that we self-created and successfully applied. Methods: This retrospective cross-sectional study included patients with a history of hypersensitivity reactions (HSRs) to IV or oral iron replacement and patients who were planned to receive IV iron replacement but were referred to the allergy clinic because of have risk factors (atopic diseases, history of HSR to other drugs, high serum tryptase levels, etc.) for HSRs. Before desensitization, some of the patients underwent skin tests (skin prick test and intradermal test) with FCM, and the results were recorded. Skin tests were not performed in patients with a history of drug use (antihistamine, systemic steroid, omalizumab, etc.) that affected the results of skin tests. All patients underwent a one-bag 8-step desensitization protocol with 500 mg FCM and were observed for 2 h after desensitization. Results: A total of 15 patients (14 females and 1 male) with a mean age of 41.13 ± 11.18 years were included in the study. When the patients were evaluated in terms of the risk of allergic reactions according to their clinical history, 8 patients had a history of anaphylaxis with iron preparations (FCM, n = 4; ferric hydroxide sucrose, n = 2; iron [II] glycine sulfate, n = 1; and iron [III] hydroxide polymaltose, n = 1), and 7 patients had a history of HSR other than anaphylaxis with iron preparations (urticaria, n = 6 [FCM, n = 2; iron (II) glycine sulfate, n = 2; and iron (III) hydroxide polymaltose, n = 2] and urticaria + angioedema [ferric hydroxide sucrose, n = 1]). Desensitization was successfully completed in all patients. No HSR was observed during or after the procedure in any of the patients. Conclusion: IV iron replacement is a very effective method, especially in cases where iron stores need to be replenished more rapidly. In patients with a history of iron HSR or at risk of developing HSR, replacement can be safely performed without an allergic reaction with successful desensitization protocols.