Elevated Tryptase Research Articles

Hereditary alpha tryptasemia: elevated tryptase, female sex, thyroid disorders, and anaphylaxis

IntroductionThe clinical significance of elevated baseline serum tryptase (BST) in the absence of mast cell disorders or allergic reactions has long been unclear. Recently, a genetic variation of the TPSAB1 gene, which among others encodes for alpha tryptase, has been reported and named hereditary alpha tryptasemia (HaT). HaT has been linked to various manifestations, including severe allergic reactions. However, clinical studies are limited. In this study, we aimed to determine HaT prevalence and characterize its clinical manifestations in patients at a specialized allergy center.MethodsFrom January 2022 to December 2023, patients with elevated BST at least once were screened for HaT at the outpatient clinic. A control group included patients with a history of anaphylaxis undergoing specific Hymenoptera immunotherapy. TPSAB1 copy numbers, BST levels, and clinical parameters were assessed and analyzed.ResultsOf 47 patients with elevated BST (≥11.4 µg/L), 93% showed increased TPSAB1 copy numbers. Individuals diagnosed with HaT displayed a BST range between 12.3 and 28.4 µg/L, with 84.1% associated with TPSAB1 duplication and 15.9% with triplication. HaT predominated in women (86.4%) and was associated with thyroid disease (27.3%). Over half had a history of anaphylaxis (54.5%), which was mainly low-grade.DiscussionIn patients with elevated BST but no mastocytosis, the most likely cause of elevated BST was an increase in the copy number of the TPSAB1 gene. A heightened risk of anaphylaxis should be considered. Further research is needed to explore the predominance of women and the emerging link with thyroid disease.

Successful management of anaphylactic shock prior to elective cesarean delivery: a case report

BackgroundAnaphylactic cardiovascular collapse is complicated by aortocaval compression during pregnancy, exacerbated by neuraxial anesthesia. Despite recommendations to administer perioperative antibiotics before anesthesia, common practice in Japan involves administering them after anesthesia induction. We report a case of possible antibiotics-induced anaphylaxis just before anesthesia for cesarean delivery.Case presentationA 24-year-old woman at 37 weeks of gestation presented for a scheduled repeat cesarean under spinal anesthesia. After starting administration of cefazolin prior to anesthesia, she developed anaphylactic symptoms. Hypotension refractory to adrenaline necessitated conversion to an emergency cesarean section under general anesthesia. A neonate was delivered with favorable Apgar scores. Post-delivery, the mother’s hemodynamics stabilized significantly. Elevated plasma tryptase confirmed anaphylaxis. Both mother and infant were discharged without further complications.ConclusionsThis case emphasizes the importance of administering prophylactic antibiotic before anesthesia in mitigating severity of shock induced by anaphylaxis and the crucial role of prompt emergency cesarean in achieving successful outcomes.

Retesting Intervals for Tryptase

What Is the Issue? Tryptase is a serine protease primarily produced and released by mast cells. Tryptase measures are most used to diagnose and manage anaphylaxis and mastocytosis, and the timing of tryptase measurement is crucial for its utility. The clinical utility of tryptase remains unclear, and available evidence showed that more than 30% of patients with acute anaphylaxis did not exhibit an elevated tryptase level, which suggests that repeated tryptase testing may be overused in this population. Appropriate retesting intervals or frequency for tryptase retesting in patients with anaphylaxis or mastocytosis remain unclear. What Did We Do? To inform decisions about the use and timing of repeat tryptase testing for patients with confirmed or suspected anaphylaxis and patients with cutaneous or systemic mastocytosis, we identified and summarized related recommendations and publications on the potential biological or physiological factors that may impact retesting intervals in these populations. We searched key resources, including journal citation databases, and conducted a focused internet search for relevant evidence published since 2014. One reviewer screened articles for inclusion based on predefined criteria, critically appraised the included evidence-based guidelines, and narratively summarized the findings. What Did We Find? For patients with suspected anaphylaxis, identified guidelines suggest measuring tryptase levels 1 to 2 times during the event onset (e.g., immediately or within 4 hours) and 1 to 2 times after resolution of symptoms (e.g., after 24 hours) to establish baseline tryptase levels. These recommendations were based on very low certainty of evidence. For patients with systemic mastocytosis, 1 evidence-based guideline in Brazil recommends testing tryptase once a year, which is based on very low certainty of evidence. Baseline tryptase level varies very little over time within the same individual and is determined by their genetic background. For patients with anaphylaxis, the timing of the peak tryptase level is from 1 minute to 6 hours (median 30 minutes), and the half-life of serum tryptase is about 1.5 hours to 2.5 hours and needs up to 24 hours to return to baseline level. We did not find any recommendations that met our inclusion criteria regarding the minimum retesting interval for tryptase testing or the use of repeat or serial tryptase testing in patients with confirmed or suspected anaphylaxis or with cutaneous or systemic mastocytosis. What Does It Mean? The available recommendations suggest testing blood tryptase at the acute (1 or 2 times) and baseline phases (1 or 2 times) for patients with suspected anaphylaxis. There is little rationale for the ongoing monitoring of tryptase levels beyond the recommended 4 time points for patients with anaphylaxis. For patients with mastocytosis, the guidelines recommend retesting tryptase only once a year and do not support frequent repeat tryptase testing within a year. Decision-makers and clinicians should consider the cost of tryptase testing, potential burden on health care resources, local lab capacity, or accessibility of testing facilities when making decisions regarding tryptase retesting. Given the very low-quality evidence regarding measuring tryptase and the unclear utility of tryptase testing for patients with anaphylaxis, future research that focuses on the clinical utility of tryptase relative to clinical assessment for anaphylaxis is needed.

Extending the role of tryptase in perioperative anaphylaxis: Predicting positive results in basophil activation tests

BackgroundBasophil activation tests (BAT) are useful in identifying culprits of perioperative anaphylaxis (PA), but its utility remains limited due to technical limitations, cost and availability. Being able to prioritize patients with likely higher yields for BAT would be useful in reducing costs and manpower. ObjectiveTo investigate if tryptase levels and clinical parameters may be useful for selecting patients for BAT. MethodsWe performed a ten-year retrospective study in Hong Kong to investigate the performance of BAT associated with tryptase levels (taking during PA) and other clinical parameters. ResultsOut of 90 patients, 70 (77.8%) showed significant tryptase elevation and 37 (41.1%) had positive BAT. BAT-positive patients presented with significantly higher absolute levels (15.9 μg/L vs 9.1 μg/L, p=0.018), absolute elevation (12.8μg/L vs 7.1 μg/L, p=0.012) and fold elevation (5.6- vs 4.1-fold, p=0.014) of acute tryptase; than negative BAT patients. Among patients with positive BAT, 94.6% (35/37) demonstrated elevated acute tryptase, significantly more than the BAT-negative group (66.0%, p<0.001). In regression analysis, tryptase elevation was the sole significant factor correlated to BAT positivity (OR=10.14 [95% CI=2.15-47.85], p=0.003). Overall, elevated acute tryptase demonstrated a sensitivity of 94.7% and a negative predictive value of 90.0% in predicting positive results with BAT. ConclusionWe observed that tryptase elevation is a very sensitive predictor of BAT positivity among patients with identified culprits of PA. Acute elevation of tryptase would not only aid in confirming anaphylaxis, but may also help guide the decision towards selecting labour-intensive and costly in vitro tests such as BAT.

Anaphylaxis in Practice: A Guide to the 2023 Practice Parameter Update

This review summarizes new research developments and clinical practice recommendations for the diagnosis and management of anaphylaxis presented in the Joint Task Force on Practice Parameters 2023 Anaphylaxis practice parameter Update. It is intended to serve as a high-level summary of the 2023 practice parameter, which makes clinically impactful recommendations based on evidence that has emerged since the 2015 practice parameter. We invite clinicians to explore the full 2023 practice parameter to understand the research methods and underlying evidence that have informed the recommendations summarized here. There are new and evolving diagnostic criteria for anaphylaxis, rules for defining elevated tryptase levels, and recognition of signs and symptoms particular to infants and toddlers. The administration of epinephrine should not be used as a surrogate to diagnose anaphylaxis. Risk factors for anaphylaxis should be assessed on a case-by-case basis. Patient counseling and shared decision-making are essential to support patients' treatment decisions and capacity to manage the risk of anaphylaxis at home and in other community settings. Activation of emergency medical services after home epinephrine administration may not be required in all cases, and patients should be engaged in shared decision-making to determine when home management may be appropriate.

Treating the untreatable: Somatoform disorder in an adolescent with organic symptoms mimicking idiopathic anaphylaxis

Idiopathic anaphylaxis (IA) is a rare life-threatening disorder that may present with severe symptoms similar to other forms of anaphylaxis. It is an exclusion diagnosis and requires careful consideration of all recognizable and rare causes of anaphylaxis. Psychiatric conditions, such as somatoform disorders, should be considered in the differential diagnosis when there is a paucity or absence of clinical signs. A 17-year-old female patient was admitted to the inpatient clinic for pediatric allergy due to recurrent anaphylaxis. In the last two years, the patient was administered intramuscular epinephrine more than 200 times and was admitted to the intensive care unit four times due to severe anaphylaxis. The attacks frequently appeared as flushing, itching, shortness of breath, and rarely hypotension, but without a defined trigger. The patient was diagnosed with IA and received oral steroids, omalizumab, and rituximab. However, none of her attacks were accompanied by elevated tryptase levels and the aforementioned pharmacotherapies did not prevent relapse. After psychiatric evaluation, somatoform disorders were suspected despite striking variations in the severity of the physical symptoms. The psychiatric diagnosis was also supported by a good response to fluoxetine and supportive individual psychotherapy. The patient is currently being followed up without any anaphylactic attacks. Somatoform disorders should be considered in the differential diagnosis of IA because of overlapping physical symptoms. In the clinical practice of diagnosing and managing IA, symptoms that are not only subjective but also objective and unresponsive to conventional treatments should alert physicians to the probability of the psychiatric condition and the requirement for psychiatric consultation.

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.

Elevated tryptase level in a child with idiopathic anaphylaxis: a case of hereditary alpha-tryptasemia

Hereditary alpha-tryptasemia (HαT) is an autosomal dominant disorder estimated to affect 5% of the population. High baseline tryptase level is a consistent finding, but there is a great variability of clinic manifestations, including no symptoms at all. We describe a case of HαT in a 5 years 8 months old girl manifesting with idiopathic anaphylaxis and elevated baseline tryptase level. As more cases of HαT are described, a better understanding of the clinical phenotype will be acquired.

Diagnostic Significance of Tryptase for Suspected Mast Cell Disorders.

Tryptase has proven to be a very useful and specific marker to demonstrate mast cell activation and degranulation when an acute (i.e., within 4 h after the event) and baseline value (i.e., at least 24 h after the event) are compared and meet the consensus formula (i.e., an increase of 20% + 2). The upper limit of normal determined by the manufacturer is 11.4 ng/mL; however, this boundary has been the subject of debate. According to ECNM and AIM experts, the normal range of baseline tryptase should be 1 to 15 ng/mL. A genetic trait, hereditary alpha tryptasemia, characterized by an increased alpha coding TPSAB1 copy number is associated with a baseline value above 8 ng/mL. Elevated tryptase can also be found in chronic kidney disease, obesity, and hematological neoplasms. A tryptase > 20 ng/mL serves as a minor criterion to diagnose systemic mastocytosis and an increase in tryptase > 20% + 2 during an acute event is a required criterion in the diagnosis of mast cell activation syndrome. The goal of this review is to demonstrate the (in)significance of tryptase using some clinical vignettes and to provide a practical guide on how to manage and interpret an elevated tryptase level.

Predictive Value of Elevated Tryptase and Mediator Symptoms in Systemic Mastocytosis - a Single Center Experience

Background: Systemic mastocytosis (SM) is a rare clonal hematologic disorder primarily driven by the KIT D816V mutation in almost all (95%) patients. These patients most often have elevated serum tryptase levels and can present with a wide spectrum of symptoms caused by mediator release from clonal mast cell degranulation (e.g., skin rash, anaphylaxis, diarrhea, and neurocognitive symptoms). However, these symptoms are similar in other non-clonal mast cell disorders such as idiopathic mast cell activation syndrome (MCAS) and hereditary alpha-tryptasemia (HaT). As such, many patients are referred to hematology for SM work-up based on elevated serum tryptase and mediator release symptoms. We evaluated a real-world single-center experience determining whether elevated serum tryptase, mediator release symptoms, and/or a history of anaphylaxis correlated with a diagnosis of SM. Methods: We conducted a retrospective chart review of patients referred to the Mastocytosis Clinic at Huntsman Cancer Institute at the University of Utah for a year between August 2022 and July 2023. Data were collected by chart review and analyzed for disease characteristics, laboratory values, and diagnostic outcomes. Findings/Results: There were a total of 37 patients referred to us during the designated time period with either a tryptase value greater than 10.9 ug/L or abnormal mast cells found on tissue biopsy (e.g., skin, colon, etc) with or without systemic mediator release symptoms. Patients did not have to have a history of anaphylaxis to be seen. Of these, 7 patients already had a known diagnosis of SM and had bone marrow biopsy at an outside institution. Of the 30 remaining patients, 19 (63%) patients reported a history of at least one mediator release symptom, defined as pruritus, flushing, syncope, bloating, nausea, vomiting, or diarrhea. The median serum tryptase level was 17.4 ug/L. (Range 2 - 317 ug/L). KIT D816V mutation was detected in the peripheral blood by digital droplet PCR in 7 (23.3%) patients. Diagnostic bone marrow was done in 19 patients wherein 6 (31.5%) of them met the WHO diagnostic criteria for SM. Of these patients, 5 patients tested positive for KIT D816V mutation on peripheral blood and 1 patient had KIT wild type. Two patients with KIT D816V mutations did not receive bone marrow biopsy as they had no mediator release symptoms. The remaining 13 patients had a bone marrow biopsy but did not have a diagnosis consistent with SM, although some had rare scattered mast cells identified in the marrow. They were all KIT D816V mutation negative and serum tryptase ranged from 2.7 - 43 ug/L. As of the date of data analysis, 4 (30.7%) patients tested positive for HaT; serum tryptase ranged from 20 - 26 ug/L in this cohort. Conclusion: While SM can have a variety of clinical manifestations, including elevated tryptase level and mediator release symptoms, the presence of KIT D816V in the peripheral blood is a strong predictor of SM diagnosis. Persistently elevated serum tryptase without the KIT D816V mutation may suggest the likelihood of HaT, while only mediator release symptoms with normal serum tryptase and without the KIT mutation is a strong negative predictor of SM and HaT.

Retrospective Single Center Descriptive Analysis of a Cohort with Hypereosinophilia Evaluated in the Last Decade

BACKGROUND: Hypereosinophilia (HE) (&amp;gt;1,5x109/L eosinophils in peripheral blood (pb)) is an occasional cause of consultation in hematology. The etiologies are varied, the diagnostic process is wide and may include other specialties. In addition, the absence of prospective studies and large cohorts makes the diagnosis and management of these patients very challenging. OBJECTIVE: To describe the diagnostic process of a series of patients with HE evaluated in our center between 2013-2023. METHODS: Clinical-biological characteristics and diagnostic evaluations performed were registered. Clonal HE and reactive HE were compared using Fisher exact test and Mann-Whitney U. RESULTS: Sixty patients with HE (n=59) or tyrosine-kinase fusion genes eosinophilia related (n=1) were selected out of 109 patients with eosinophilia (&amp;gt;0.5x109/L and &amp;lt;1,5x109/L eosinophils in pb), detected in the last decade in our center. Characteristics of the study population and diagnostic tests conducted are summarized in Table 1. Interestingly, bone marrow data with cytogenetic study was made in up to 70% of patients. Despite extensive analysis of the PDGFRα rearrangement by FISH, other fusion genes were less evaluated and NGS studies were little used. Diagnostic studies for exclusion of secondary causes were carried out in more than 40% of patients ( Table 1). Fifteen percent of HE attended were a primary clonal entity whereas 73% were secondary/reactive: 5% due to allergy, 7% to asthma, 2% to drugs 2%,13% parasites, 25% other, 2% lymphoma, 8% were hypereosinophilic syndrome (HES)-lymphocytic variants, 8% HES-overlap, 3% associated hematologic neoplasm. Twelve of the patients couldn't be classified, which evidences the diagnostic complexity. Among the variables used in differential diagnosis of HE, those significantly associated with clonal HE compared to reactive HE in our series were: BM dysplasia (85.7% vs 14.3%, p&amp;lt;0.001), BM fibrosis (100% vs 0, p&amp;lt;0.001), abnormal karyotype (83.3% vs 16.7%, p&amp;lt;0.001), LDH (328 vs 188.5 U/L, p=0.028), cobalamins (&amp;gt;1476 vs 279 pmol/L, p=0.003), tryptase (16.6 vs 6.7 ug/L, p=0.019) and leucocytes (39.2 vs 10.2 x109/L, p=0.014). Other analytical parameters were significantly lower in clonal vs. reactive HE: hemoglobin (125 vs. 136 g/L, p=0.020) and platelets (121 vs. 260x109/L, p=0.004). It was noteworthy that the number of eosinophils did not help always to distinguish clonal vs. non-clonal entities. Patients diagnosed with a primary clonal HE were 9 (15%): 7 patients with rearrangement of PDGFRα, 1 patient with ETV6 and 1 with BCR::JAK2. The group of PDGFRα patients, all asymptomatic, showed a median diagnostic delay of 45 months (5.1-103) since the first hematological evaluation. Four out of 7 patients with PDGFRα showed hematological and cytogenetic response after a median of 3.37 months (0.95-78.2) from imatinib initiation. Two patients started imatinib recently (not evaluable) and one patient presented clonal evolution and transformation to the blastic phase after 10 years of disease. He has been treated with imatinib 400mg achieving hematological response. The overall survival of this subgroup was 80% CI 95% (62.8-97.2), with a median follow-up of 25.8 months. One patient with ETV6 rearrangement presented as acute leukemia and died after few days from diagnosis and the patient with BCR::JAK2 fusion gen also presented with acute leukemia is in complete remission after being treated with intensive induction chemotherapy and allogeneic hematopoietic cell transplantation. CONCLUSIONS: HE requires a wide diagnostic evaluation with a multidisciplinary approach and the development of working groups in order to avoid these inconclusive diagnosis (12% in our series) and the missing diagnostic tests. Our study suggests the association between elevated LDH, cobalamins and tryptase and clonal cause of HE, as well as a higher rate of fibrosis, medullary dysplasia and altered karyotypes in these patients, indicating the need to include these evaluations in the diagnostic process. The group of PDGFRα patients had good prognosis with imatinib, but one patient presented clonal evolution and blastic transformation, showing the clinical challenge of these entities.

Abstract 13185: Getting at the Heart of Allergies: A Case Series on Kounis Syndrome

Kounis Syndrome (KS) is a complex medical condition where acute coronary syndrome coincides with allergic reactions. KS presents a unique clinical challenge due to its varied presentation and simultaneous management of an allergic response and a cardiac event. This study aims to further our understanding of this underreported condition to improve outcomes in patients. We demonstrated the intricacies of KS by examining two case studies. In Case 1, a 51-year-old male suffered a myocardial infarction after a wasp sting. Workup revealed elevated tryptase levels and mastocytosis on bone marrow biopsy concerning for mast cell activation syndrome. In Case 2, a 48-year-old female was diagnosed with vasospastic angina exacerbated by exposure to various allergens and associated with elevated histamine levels. Both patients underwent coronary angiography which demonstrated no obstructive coronary artery disease. Functional coronary angiography with acetylcholine provocation confirmed a predisposition for coronary vasospasm. Both patients were treated with anti-anginals and antihistamines. A literature review was performed to describe the pathophysiology, diagnosis, and treatment of KS. The underlying pathophysiology includes mast cell degranulation, where the release of inflammatory mediators like histamine and tryptase provokes coronary vasospasm, plaque rupture, and thrombus formation. With prompt recognition and appropriate management, the prognosis of KS is favorable. A greater understanding of KS can support clinicians in delivering quality care for patients. Our cases demonstrate the importance of maintaining a high index of suspicion in patients exhibiting an acute allergic reaction with concurrent evidence of cardiac ischemia. While the current literature provides some management guidance, additional research is required to improve our mechanistic understanding, diagnostic criteria, and therapeutic strategies.

Liquid Biopsy Enhances Diagnostic Workup of Hereditary Alpha-Tryptasemia (HaT) and Systemic Mastocytosis (SM) in Patients with Mast Cell-Mediated Symptoms and Elevated Basal Tryptase Levels

Background and Objectives Hereditary alpha-Tryptasemia (HaT) and Systemic Mastocytosis (SM) both display elevated basal serum tryptase (BST) levels and share mast cell-mediated digestive, neuropsychiatric, cardiovascular, cutaneous and musculoskeletal symptoms. Lack of awareness and numerous differential diagnoses complicate and often delay diagnosis, while patients suffer from impaired quality of life and do not receive suitable treatment. HaT is defined by an autosomal dominant inherited amplification of an alpha-Tryptase encoding TPSAB1 gene and is found in 5-6% of the general population. SM is characterized by an activating cKIT D816V mutation that can be detected in 90% of patients. Currently, there is no test available to discriminate between HaT and SM. We aimed to establish a non-invasive blood test supporting the diagnostic workup of these still unrecognized entities. Methods We established a customized digital droplet (dd)PCR triplex assay to detect HaT and a highly sensitive ddPCR singleplex assay for cKIT D816V mutation. We designed a clinical assessment form to record the symptoms. We identified the frequency of HaT and cKIT D816V mutation in genomic DNA isolated from peripheral blood buffy coat samples in 112 patients presenting to our institution with suspected mast cell-mediated symptoms and highly normal (&amp;gt;8-11.4ng/ml) or elevated (&amp;gt;11.4 ng/ml) BST levels (prevalence cohort, Fig. 1). For symptom assessment, we performed blood testing and symptom assessment in these 112 patients and 34 additional patients presenting with suspected SM (n=146, symptom cohort, Fig. 2). As a control cohort we tested 62 age- and sex-matched patients presenting with BST levels &amp;lt; 6 ng/ml (thus not suspected to have HaT or SM). Results HaT accounted for 82 out of 112 cases (73.2%) of BST levels of 8 ng/ml or higher, while cKIT D816V indicating SM was identified in only 5 cases. In 28 patients (24,1%) no HaT genotype or cKIT D816V mutation was detected. One patient with negative cKIT D816V testing but clinical signs of SM was confirmed by bone marrow biopsy, increasing SM prevalence to 6/112 (5.4%). Interestingly the HaT and SM proportions increased to 91% (HaT) and 7.5% (SM) when higher BST cut-off level of 11.4 ng/ml and to 92,9% (HaT) and 28.6% (SM) when higher BST cut-off level of 20 ng/ml were used (Fig. 1). Of note, 21.4% of patients with BST &amp;gt; 20 ng/ml had both, HaT and SM, and no patient with BST &amp;gt;20 ng/ml was tested negative for HaT and SM. In the symptom cohort, we found significant differences in type and severity of symptoms between HaT, SM and the control group. The occurrence of digestive symptoms was up to twice as high in HaT or SM compared to the control group, for flatulence (HaT 83.5%; control group 53.2%) and diarrhea (SM 68.8%; control group 25.8%) or heartburn (SM 56.3%; control group 25.8%). Nausea was significantly more common in HaT (51.7%) than in SM patients (21.9%). HaT patients more frequently reported neuropsychiatric symptoms compared to control group and SM patients. This included memory impairment (HaT 45.9%; SM 23.3%; control group 16.1%) sleep disturbances (HaT 55.8%; SM 43.8%; control group 33.3%) and fatigue (HaT 67.4%; SM 50.0%; control group 37.7%). Conclusions Simultaneous, non-invasive testing for cKIT D816V and HaT in patients with suspected mast cell mediator symptoms allows discrimination of HaT from SM. Adding BST &amp;gt; 8 ng/ml and &amp;gt;11,4ng/ml to the diagnostic workup in symptomatic individuals increases the pretest probability to detect HaT to 73.8% and 91.0%. Diagnosed patients experience mental relieve through personal and medical acknowledgement of their symptoms and suitable treatment can be initiated. According to our results, HaT testing should be initiated in all individuals presenting with mast cell mediator symptoms and BST &amp;gt; 8 ng/ml, and cKIT testing should be initiated in patients with BST &amp;gt;11.4 ng/ml. In patients with BST &amp;gt;20 ng/ml, cKIT D816V positive blood testing or signs of advanced SM, bone marrow based diagnostic workup is still mandatory to cover diagnostic criteria for SM according to WHO.

The diagnostic workup for systemic mastocytosis differs from consensus recommendations: Results of a worldwide survey

ObjectiveMastocytosis is a complex disorder affecting various organs. The diagnostic workup can be challenging and requires a multidisciplinary approach including the use of uncommon tests. To assess mastocytosis management around the globe, we conducted the first worldwide online survey for physicians. MethodsA 21-item questionnaire was sent out to the members of the World Allergy Organization (WAO), the Global Allergy and Asthma European Network (GA2LEN), the Urticaria (UCARE) and Angioedema (ACARE) Centers of Reference and Excellence, the German Society of Allergology and Clinical Immunology (DGAKI), and the European Mast Cell and Basophil Research Network (EMBRN) in April–June 2021. ResultsAcross 628 respondents from 79 countries 87.7% and 9.7% of physicians were allergists/clinical immunologists and/or dermatologists. Participating physicians were from all regions of the world (Europe, EU: 41.6%; North America, NA: 24.8%; Latin America, LA: 14.5%; Asia-Pacific, AP: 12.6%; and Africa/Middle East, AME: 6.5%). Only 2.2% of respondents worked at Specialized Mastocytosis Centers (SMCs) in North America or European Union. Physicians reported caring for 4 patients with mastocytosis per year, with higher numbers in European Union and Asia Pacific (5/year) compared to Latin America (2/year). Dermatologists and physicians who work at SMCs reported higher patient numbers (15/year and 80/year, respectively). Suspicion of mastocytosis in the allergology and dermatology community is commonly driven by anaphylaxis (82.9%), mastocytosis skin lesions (82.1%), or elevated tryptase levels (76.6%). Osteoporosis and gastrointestinal symptoms less often prompted suspicion of mastocytosis (21.4% and 49.9%, respectively). World Health Organisation (WHO)-diagnostic criteria and classification, regardless of the region, are only used by about 50% of physicians, with higher rates for SMCs (83.3%). Serum tryptase, bone marrow biopsy, and KIT D816V mutation analysis are included in the diagnostic workup by 90.9%, 61.5%, and 58.4% of physicians, respectively. The biggest challenges for the management of mastocytosis are the lack of more effective treatment options (51.1%), missing multidisciplinary networks (47.1%), and the lack of experience of specialists from other disciplines (39.0%). ConclusionsThe diagnostic workup for mastocytosis differs from consensus recommendations and varies between regions. This may be improved by establishing active multidisciplinary networks, increasing access to diagnostic procedures, consistently applying WHO criteria, and developing new Mastocytosis Centers of Reference and Excellence.

THU431 An Interesting Case Of Severe Osteoporosis In A Young Male

Abstract Disclosure: M. Bilbatua: None. M. Deshmukh: None. Background: Systemic Mastocytosis is a rare disorder in which Osteoporosis is seen in about 24% of cases. We describe a rare case of Secondary Osteoporosis in a young man caused by Systemic Mastocytosis. Case presentation: A 32-year-old male with no significant medical history was seen by Endocrinology for evaluation of Osteoporosis. Symptoms started after two episodes of falls which caused persistent pain. A CT scan of thoracic spine revealed chronic anterior wedge compression fracture of T5, T7 and T10 with approximately 5-10% loss of height. DEXA scan demonstrated T-score of -4.2 at L1-L4, T-score of -2.3 at left hip suggestive of severe Osteoporosis. The patient admitted to generalized flushing and itching after taking hot showers as well as intermittent episodes of palpitations. The patient was started on Calcitonin nasal spray daily for pain related to vertebral fracture. Testing for secondary causes of Osteoporosis showed a Total testosterone 410 ng/dL (250-1,100 ng/dL), PTH 16 pg/mL (16 - 77 pg/mL), TSH 1.88 mIU/L (0.40 - 4.50 mIU/L), Phosphorus 4.1 mg/dL (2.5 - 4.5 mg/dL), Magnesium 2 mg/dL (1.5 - 2.5 mg/dL), Alkaline phosphatase 66 U/L (36 - 130 U/L), Vitamin D 25 ng/mL (30 - 100 ng/mL), Calcium 9.3 mg/dL (8.6 - 10.3 mg/dL), Tryptase 64 mcg/L (&amp;lt;11.0 mcg/L), 5-HIAA 24H Ur mg/24H 3 (&amp;lt;=6.0 mg/24 h). Based on this, the patient was seen by Hematology/Oncology for evaluation on elevated tryptase levels. Bone marrow biopsy and aspirate was performed, demonstrating 20% Mast cells positive for CD 117, CD 25, patient was diagnosed with Mastocytosis and treatment with Midostaurin 100 mg PO twice daily and Zometa every 12 weeks was initiated. Improvement of Tryptase was noted within two months of treatment. Discussion: Systemic Mastocytosis is a rare disease often complicated by Osteoporosis of which around 37% of the patients will develop Osteoporotic fractures where Bisphosphonates are effective and have a role in the associated refractory bone pain. The pathophysiological mechanisms leading to osteoporosis in Systemic Mastocytosis are not well understood. Although rare, back pain secondary to osteoporotic vertebral fractures is often the major presenting symptom of Mastocytosis and it should be included in the differential diagnosis of idiopathic osteoporosis due to its significant morbidity. Presentation: Thursday, June 15, 2023

T-cell chronic active EBV diagnosed in a 65-year-old male presenting as idiopathic hypereosinophilic syndrome

A 65-year-old male from Nigeria, admitted with dehydration and painful oral ulcers, is seen by allergy/immunology for hypereosinophilia.The patient had idiopathic eosinophilia (mean 5,000 cells/uL) ongoing for nine years. There were no evident drug or infectious causes. The eosinophilia peaked at 28,000 cells/µL, accompanied by parotid swelling, pustular skin rash, and elevated serum-IgG4 level (400 mg/dL). Rheumatology evaluated for IgG4-related disease and hypereosinophilic syndrome. This work-up demonstrated elevated IgE (39,000 IU/mL) and tryptase (40 ng/mL) levels. Bone marrow biopsy showed a hypercellular marrow with erythroid hyperplasia and eosinophilia. Submandibular gland, skin, and excisional lymph node biopsies demonstrated IgGsecreting plasma cells, lymphocytic/eosinophilic infiltrates, and lymphoid hyperplasia, respectively. All biopsies stained negative for IgG4. Treatment for idiopathic hypereosinophilia was initiated with corticosteroids, rituximab, and mycophenolate mofetil (MMF). Symptomatic improvement was attained on MMF (1000 mg twice daily) with the addition of mepolizumab (300 mg every 4 weeks).He unfortunately progressed to high fevers with elevated ferritin (7,286 ug/L) and soluble IL-2Ra (31,276.7 pg/mL) levels. He did not meet full criteria for hemophagocytic lymphohistiocytosis and improved after corticosteroids. EBV PCR from blood was >220,000 IU/mL.Dedicated immune work-up showed a non-specific population of lymphocyte-like cells without clear lineage markers (CD2dim/- surface CD3-CD4-CD8-CD7-CD56-CD49d-CD294dim) on peripheral blood flow cytometry, with otherwise normal T, B, and NK cell enumeration. There was reduced cytotoxic killing function of CD8+ T cells and NK cells by chromium-51 release assay. Sorted peripheral blood mononuclear cells demonstrated positive EBV viral load in B cells (1,018,239 IU/mL), T cells (857,418 IU/mL),NK cells (237,459), and myeloid cells (532,641 IU/mL). EBV-encoded RNA was positive within lymph node T cells, most consistent with a diagnosis of T-cell CA-EBV. The Invitae 407 gene immunodeficiency panel was sent; however, a pathogenic variant was not identified. The patient was seen by hematology/oncology with plans for hematopoietic stem cell transplant. Unfortunately, he succumbed to complications from CA-EBV and multiorgan failure.We describe a male with lymphocytic-variant hypereosinophilic syndrome and a longstanding constellation of inflammatory and lymphoproliferative symptoms due to CA-EBV. His course initially eluded his care team and only after careful multidisciplinary discussion was a diagnosis reached.

Ten-year outcomes of Perioperative Anaphylaxis Workup Study in Hong Kong (PAWS-HK): Performance of diagnostic modalities

BackgroundStudies on perioperative anaphylaxis (PA) in Asia are lacking. Furthermore, allergy workup for PA has largely been limited to the “silver standard” of skin tests (ST). Using in vitro tests as an adjunct to ST may improve and overcome these diagnostic challenges. ObjectiveTo evaluate the clinical characteristics and diagnostic tests of patients with suspected PA through the Perioperative Anaphylaxis Workup Study in Hong Kong cohort. MethodsPatients with a diagnosis of PA over a 10-year period were recruited into the Perioperative Anaphylaxis Workup Study in Hong Kong. We reviewed the medical records, tryptase elevation, and diagnostic tests including ST, specific immunoglobulin E, and basophil activation tests (BAT). ResultsIn 151 patients with PA, diagnosis was reached in three-fourths of the cases (113/151, 74.8%). The most common culprits identified were neuromuscular blocking agents (25.8%), β lactams (17.2%) and chlorhexidine (13.9%). Severe anaphylaxis was associated with female sex, older age, elevated acute tryptase levels, and more cardiovascular manifestations during induction. Skin tests remained the most sensitive diagnostic modality overall (66.2%). BAT showed better performance for chlorhexidine and gelofusine anaphylaxis, with sensitivity of 80.0% and 79.6%, respectively. Specific Immunoglobulin E indicated even higher sensitivity (95.2%) than did ST (85.0%) and BAT (80.0%) for chlorhexidine anaphylaxis but performed poorly for other drugs. ConclusionNeuromuscular blocking agents remain the most common culprit in PA. There was a higher prevalence of gelofusine anaphylaxis in our cohort than was seen in the literature. Skin tests remain the most sensitive testing modality. In vitro tests for chlorhexidine and gelofusine showed promising results, but more studies to further elucidate its use are warranted.

Evidence of an Abnormal Mast Cell Marrow Compartment in Patients with Idiopathic Anaphylaxis

Patients presenting with anaphylaxis for unknown reasons and no clonal mast cell (MC) disease are diagnosed as having idiopathic anaphylaxis (IA) and exhibit elevations in total serum tryptase during episodes. It has been reported that patients with MC activation symptoms and elevated baseline tryptase associated with hereditary α-tryptasemia (HαT) exhibit unique bone marrow MC phenotypic and histologic changes. It is unknown whether patients with IA and/or IA/HαT have similar marrow morphology.

Mastocytosis: retrospective analysis of maculopapular cutaneous form

Introduction. The article presents the data of a retrospective analysis of the debut and clinical manifestations of the types of maculopapular cutaneous mastocytosis (МPCM) in 96 children, and the frequency of non-regression of skin rashes with age in 33 adults. Aim. To conduct a retrospective analysis of the onset, clinical manifestations and dynamics of maculopapular cutaneous mastocytosis (MPCM). Materials and methods. Outpatient records of 96 children and 33 adults, who were treated and monitored at the Moscow Scientific and Practical Center of Dermatovenereology and Cosmetology, were statistically analyzed. Results. Monomorphic type of MPCM was diagnosed in 28 (29.2%) patients, polymorphic – in 68 (70.8%) patients. In 92.6% of children with a polymorphic type and in 35.7% with a monomorphic type, the rash debuted at the age of two years. The clinical picture of the monomorphic type was dominated by multiple small brown or yellow-brown spots. Rashes in the polymorphic type were spread, represented by brown or reddish-brown spots, papules, plaques ranging in size from several millimeters to several centimeters. The positive phenomenon of Unna-Darier was determined in 82.3% of cases. In patients with polymorphic type, the general population level of tryptase (&lt;11.4 µg/l) was determined significantly more often than in patients with monomorphic type (p &lt; 0.05). Elevated tryptase level was found in 53.6% of children and 69.7% of adults with monomorphic rashes. Pruritus was the most common cutaneous symptom, occurring in 49.0% of children. Bullous eruptions developed only in patients with polymorphic type. The most frequently reported systemic manifestations were gastrointestinal symptoms and headaches. Conclusions. The obtained results suggest that patients with early onset of the disease with polymorphic and variable lesions show a more favorable outcome.

Prevalence and Variability of Allergen-Specific Immunoglobulin E in Patients with Elevated Tryptase Levels.

BACKGROUND In this paper we report on the link between increased tryptase levels and prevalence of allergen-specific immunoglobulin E (IgE) in patients with anaphylaxis. The main aim of the study was to assess the corelation between elevated tryptase levels and allergen-specific immunoglobulin E (IgE) in anaphylactic reactions, mastocytosis, and other types of allergic reactions. MATERIAL AND METHODS We enrolled 60 adult patients, aged 18-68 years (mean age 45±8 years). The subjects were divided into 3 groups (20 patients in each group) according to the serum tryptase changes: group 1 consisted of patients with anaphylaxis (serum tryptase level ≥11.4 µg/l), group 2 consisted of patients with mastocytosis (serum tryptase level ≥20.0 µg/l), and group 3 consisted of patients with other allergic reactions with no anaphylaxis as an atopic control group (serum tryptase level <11.4 µg/l). The test material was venous blood serum samples. The allergen-specific IgE assay was carried out by immunoblot. Tryptase concentration was determined by immunoenzymatic assay. RESULTS Allergen-specific IgE was found in 73% of all subjects: 75% in the anaphylactic group, 55% in the mastocytosis group, and 90% in the atopic control group. Polysensitization was common and was significantly different among groups. In the atopic group, there were more patients allergic to 4-7 allergens (P<0.05). CONCLUSIONS We did not find a strong correlation between allergen-specific IgE levels and elevated tryptase levels.