Mast Cell Activation Syndrome Research Articles

Navigating environmental academia in a disabled body: an embodied autoethnography of ableism and advocacy

Disabled scholars are seriously underrepresented in academia and experience some of the highest rates of harassment of any protected class within the post-secondary educational system. This paper recounts my personal experience as someone living with Ehlers Danlos syndrome (EDS), postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and endometriosis. Focusing on lived examples of ableism and approaches to advocacy, I highlight barriers to disabled individuals within the academic field of environmental science. I further argue that the pervasiveness of ableism within the environmental field is especially insidious, as such barriers limit the ability of ∼1/5 of the population to contribute to addressing environmental degradation. This account provides insights to administrators seeking to improve their organization’s treatment of disabled faculty and staff, to faculty and staff seeking to improve their treatment of disabled colleagues, and to disabled scholars currently navigating an ableist education system and job market.

Breast Implant Illness May Be Rooted in Mast Cell Activation: A Case-Controlled Retrospective Analysis

Objective: To investigate the possible association between breast implant illness (BII) and mast cell activation syndrome (MCAS), which often manifests increased mast cells (MCs) in assorted tissues and may explain BII symptoms. Background: Mechanisms by which implants cause BII symptoms remain unclear, but BII and MCAS symptom profiles heavily overlap, warranting investigation of potential linkage. Methods: We retrospectively analyzed 20 implant patients who underwent explantation and total capsulectomy; 15 self-reported preoperatively they had BII (subject group); 5 felt they did not [control group 1 (CG1)]. Five prophylactic mastectomy patients constituted control group 2 (CG2). Subjects and CG1 patients completed BII symptom questionnaires preoperatively and multiple points postoperatively. With CD117 staining, average and maximum mast cell counts (MCCs) in resected tissues were determined. Results: Mean BII symptom score 2 weeks postexplantation was reduced by 77% (P < 0.0001), and 85% by 9 months. Analysis suggested BII in CG1 patients, too, who improved similarly. Among CG2 patients, healthy breast tissue showed mean and maximum MCCs of 5.0/hpf and 6.9/hpf. Mean and maximum MCCs in capsules in BII patients were 11.7/hpf and 16.3/hpf, and 7.6/hpf and 13.3/hpf in CG1 patients. All intergroup comparisons were significantly different (P < 0.0001). Conclusions: MCCs in peri-implant capsules in BII patients are increased; some implanted patients appear to have unrecognized BII. Given that neoantigenic/xenobiotic exposures commonly trigger dysfunctional MCs in MCAS to heighten aberrant mediator expression driving inflammatory and other issues, further investigation of whether BII represents an implant-driven escalation of preexisting MCAS and whether an MCAS diagnosis flags risk for BII seems warranted.

Complete remission with histamine blocker in a patient with intractable hyperadrenergic postural orthostatic tachycardia syndrome secondary to long coronavirus disease syndrome.

The COVID-19 pandemic caused by the novel severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), has emerged as a global public health concern and its sequels have barely started to outcrop. A good percentage of patients who suffered from COVID-19 are prone to develop long-COVID or post-COVID condition (PCC), a multisystemic, heterogeneous, chronic disorder. Patients with PCC may experience diverse manifestations, of which cardiovascular and neurological symptoms are among the most frequently reported. Indeed, dysautonomia presented as orthostatic intolerance has gained room following recent reports linking postural orthostatic tachycardia syndrome (POTS) with PCC. Disturbances in heart rate (HR) and blood pressure (BP) during postural changes are the cornerstones of orthostatic intolerance seen in patients suffering from PCC. A subtype of POTS, hyperadrenergic POTS, has been widely studied because of its association with mast cell activation syndrome (MCAS). Although a causative relationship between PCC, hyperadrenergic POTS, and MCAS remains unrevealed, these syndromes can overlap. We want to propose here a correlation produced by a close-loop mechanism with positive feedback established after SARS-CoV-2 infection in a previously healthy young patient.

The Prevalence Of Osteoporosis Is Low in Adult Cutaneous Mastocytosis Patients

BackgroundSystemic mastocytosis (SM) is a clonal disorder of mast cells frequently associated with vertebral osteoporosis (OP) and subsequent vertebral fractures. The natural history of this OP remains unclear. Importantly, we do not know whether OP represents an early event triggered alongside mast cell abnormalities, and whether mast cell clonality is sufficient to trigger osteoporosis. ObjectiveTo describe OP in patients with medullar clonality in cutaneous mastocytosis (CM) and monoclonal mast cell activation syndrome (MMAS) and to compare their osteoporosis characteristics to those of non-advanced SM patients (bone marrow mastocytosis (BMM) and indolent systemic mastocytosis (ISM)). MethodsWe retrospectively analyzed clinical, biological and densitometric data of 27 CM, 13 MMAS and 135 SM patients from the mastocytosis expert center (CEREMAST) in Toulouse. ResultsOP (respectively 3.7, 30.8 and 34.1%) and vertebral fractures (0.0, 15.4 and 20%) were less frequent in CM compared to MMAS and SM, despite the presence of clonal mast cells in the bone marrow. Most patients with OP and vertebral fractures in the non-SM groups had the usual risk factors for OP. Interestingly, the only non-SM patient with a typical SM-like OP had high bone marrow tryptase, developed bone marrow KIT mutation during follow-up, and had a family history of SM. Our data show that OP is not a common clinical finding in CM but is frequent in MMAS. When OP and fractures occur in CM and MMAS patients, they differ from the usual phenotype of SM bone fragility. ConclusionOur findings suggest that in most CM patients, the meaning and management of OP differs from that of OP in MMAS and non-advanced SM. Prospective longitudinal studies and the validation of predictors are needed to identify CM and MMAS patients developing SM-related OP.

Mast Cell Activation Syndrome and Gut Dysfunction: Diagnosis and Management.

Mast cell activation syndrome (MCAS) is a clinical disorder that may explain irritable bowel syndrome (IBS) type symptoms as well as other allergic symptoms experienced by an individual. The diagnosis and treatment of MCAS with specific focus on gastrointestinal (GI) manifestations is reviewed. Although biomarkers for MCAS remain elusive, testing for baseline serum tryptase will distinguish the type of mast cell disorder and urine tests for mast cell mediator metabolites may support the diagnosis. Endoscopy and Colonoscopy with biopsies is not used to diagnose MCAS but is important to rule out other conditions that may cause symptoms. There is increased awareness of the association between MCAS and autonomic dysfunction, small fiber neuropathy, and connective tissue disorders which all impact GI symptoms. MCAS is a disorder often of unknown etiology (idiopathic) and characterized by intermittent allergy type symptoms that affect multiple organ systems after exposure to a trigger. GI symptoms including abdominal cramping and loose stool are prominent and mimic those of IBS. Diagnostic testing is performed to assess for elevations in mast cell mediators during symptoms and to rule out other conditions. A comprehensive treatment plan includes medications that target mast cells, treatments for associated conditions including autonomic dysfunction, and management of comorbid psychiatric illness and nutritional deficits.

Mismatch between subjective and objective dysautonomia

Autonomic symptom questionnaires are frequently used to assess dysautonomia. It is unknown whether subjective dysautonomia obtained from autonomic questionnaires correlates with objective dysautonomia measured by quantitative autonomic testing. The objective of our study was to determine correlations between subjective and objective measures of dysautonomia. This was a retrospective cross-sectional study conducted at Brigham and Women’s Faulkner Hospital Autonomic Laboratory between 2017 and 2023 evaluating the patients who completed autonomic testing. Analyses included validated autonomic questionnaires [Survey of Autonomic Symptoms (SAS), Composite Autonomic Symptom Score 31 (Compass-31)] and standardized autonomic tests (Valsalva maneuver, deep breathing, sudomotor, and tilt test). The autonomic testing results were graded by a Quantitative scale for grading of cardiovascular reflexes, sudomotor tests and skin biopsies (QASAT), and Composite Autonomic Severity Score (CASS). Autonomic testing, QASAT, CASS, and SAS were obtained in 2627 patients, and Compass-31 in 564 patients. The correlation was strong between subjective instruments (SAS vs. Compass-31, r = 0.74, p < 0.001) and between objective instruments (QASAT vs. CASS, r = 0.81, p < 0.001). There were no correlations between SAS and QASAT nor between Compass-31 and CASS. There continued to be no correlations between subjective and objective instruments for selected diagnoses (post-acute sequelae of COVID-19, n = 61; postural tachycardia syndrome, 211; peripheral autonomic neuropathy, 463; myalgic encephalomyelitis/chronic fatigue syndrome, 95; preload failure, 120; post-treatment Lyme disease syndrome, 163; hypermobile Ehlers-Danlos syndrome, 213; neurogenic orthostatic hypotension, 86; diabetes type II, 71, mast cell activation syndrome, 172; hereditary alpha tryptasemia, 45). The lack of correlation between subjective and objective instruments highlights the limitations of the commonly used questionnaires with some patients overestimating and some underestimating true autonomic deficit. The diagnosis-independent subjective–objective mismatch further signifies the unmet need for reliable screening surveys. Patients who overestimate the symptom burden may represent a population with idiosyncratic autonomic-like symptomatology, which needs further study. At this time, the use of autonomic questionnaires as a replacement of autonomic testing cannot be recommended.

Predictors of Clonality and Underlying Mastocytosis in Mast Cell Activation Syndromes.

Mast cell (MC) activation can present with a wide range of symptoms. The mechanisms that cause such activation are varied. One of them is the presence of clonal MCs which is defined, within other possible changes, by the presence of a somatic, activating mutation in the KIT gene. The clinical course and prognosis of patients with this underlying disease may be different from other causes of MC activation (MCA). For this reason, it is important to early diagnose, or at least suspect, which patients with MCA are due to clonal MCs. The diagnosis of clonality must be made in a comprehensive manner. However, this paper reviews chronologically each of the stages from the patient's first visit to the doctor's office which can be indicative of clonality: clinical presentation of MCA, physical examination, analytical determinations of tryptase, and/or KIT mutational analysis and bone involvement, among others. The different clonality predictive scores proposed are also reviewed and compared. Although the gold standard for the diagnosis of certainty of MC clonality is the performance of a bone marrow (BM) biopsy, there are clinical symptoms, signs, and biological parameters suggestive of clonality, as well as predictive scores, which can guide (or rule out) an early diagnosis and avoid unnecessary BM biopsies.

Urine Mast Cell Mediators in the Evaluation and Diagnosis of Mast Cell Activation Syndrome.

Mast cell activation syndrome is defined by severe, episodic, and recurrent symptoms induced by mast cell mediators with objective measurement of increase in biomarkers of mast cell activation and treatment response with mast cell therapies. Increase in serum tryptase from baseline during a mast cell activation episode is currently the most accepted biomarker measurement of mast cell release. However, during symptomatic episodes, serum tryptase can be difficult to obtain as it is a venipuncture procedure. Other objective measures of mast cell activation are needed to complement serum tryptase. Urine mast cell mediators can be collected at home and are non-invasive tests. There is emerging evidence for the utility of urine mast cell mediators including histamine, cysteinyl leukotrienes, and prostaglandins in the diagnosis of mast cell activation syndrome. In this review, clinically available urine mast cell mediators will be discussed including N-methylhistamine, leukotriene E4, and 2,3-dinor-11beta-prostaglandin F2 alpha. We discuss the rationale for the use of these urine mast cell mediators and examine the studies analyzing their performance for identifying mast cell activation.

Comprehensive Assessment of Nutrition and Dietary Influences in Hypermobile Ehlers-Danlos Syndrome-A Cross-Sectional Study.

Disorders of gut-brain interaction (DGBI) are common in patients with hypermobile Ehlers-Danlos syndrome/hypermobility spectrum disorder (hEDS/HSD). Food is a known trigger for DGBI symptoms, which often leads to dietary alterations and, increasingly, nutrition support. We aimed to explore dietary behaviors and influencing factors in patients with hEDS/HSD. In a cross-sectional study, patients with hEDS/HSD were recruited from Ehlers-Danlos Support UK (nontertiary) and tertiary neurogastroenterology clinics to complete questionnaires characterizing the following: dietary behaviors, nutrition support, DGBI (Rome IV), gastrointestinal symptoms, anxiety, depression, avoidant restrictive food intake disorder (ARFID), mast cell activation syndrome, postural tachycardia syndrome (PoTS), and quality of life. We used stepwise logistic regression to ascertain which factors were associated with dietary behaviors and nutrition support. Of 680 participants (95% female, median age 39 years), 62.1% altered their diet in the last year and 62.3% regularly skipped meals. Altered diet was associated with the following: reflux symptoms ( P < 0.001), functional dyspepsia ( P = 0.008), reported mast cell activation syndrome ( P < 0.001), and a positive screen for ARFID, specifically fear of eating and low interest ( P < 0.001). Approximately 31.7% of those who altered their diet required nutrition support. The strongest predictor of requiring nutrition support was a positive screen for ARFID, specifically fear of eating (OR: 4.97, 95% CI: 2.09-11.8, P < 0.001). Altered diet is very common in the patients with hEDS/HSD we studied and influenced by functional dyspepsia, reflux symptoms, and ARFID. Those with ARFID have a 4-fold increased risk of requiring nutrition support, and therefore, it is paramount that psychological support is offered in parallel with dietary support in the management of DGBI in hEDS/HSD.

Mast Cell-Targeting Therapies in Mast Cell Activation Syndromes.

Provide an overview of the expanding landscape of mast cell (MC)-targeting treatments in mast cell activation syndromes (MCAS). Tyrosine-kinase inhibitors (TKIs) targeting wild-type and mutated KIT can efficiently induce MC depletion. Avapritinib and midostaurin can also temper IgE-mediated degranulation. Avapritinib has been recently approved by the FDA for the treatment of indolent systemic mastocytosis (ISM). Targeting activation pathways and inhibitory receptors is a promising therapeutic frontier. Recently, the anti Siglec-8 antibody lirentelimab showed promising results in ISM. MCAS is a heterogeneous disorder demanding a personalized therapeutic approach and, especially when presenting as anaphylaxis, has not been formally captured as outcome in prospective clinical trials with TKI. Long-term safety of TKI needs to be addressed. New drugs under investigation in diseasesin which non-neoplastic MCs play a pivotal role can provide important inputs to identify new efficient and safe treatments for MCAS.

Characterizing a new clinical phenotype: the co-existence of cerebral venous outflow and connective tissue disorders.

There is increasing recognition of connective tissue disorders and their influence on disease in the general population. A conserved clinical phenotype involving connective tissue disorders and idiopathic intracranial hypertension (IIH) and associated cerebral venous outflow disorders (CVD) has not been previously described. A single-institution retrospective review of a prospectively maintained database of patients with connective tissue disorders and CVD was performed. A total of 86 patients were identified. The majority of these patients carried a diagnosis of Ehlers-Danlos syndrome (55%) and most were non-obese (mean body mass index 29.7 kg/m2), Caucasian (90%) females (87%). Most prevalent presenting symptoms included pressure headache (98%), dizziness (90%), tinnitus (92%), and cognitive dysfunction (69%). Aside from CVD and IIH, the most common associated conditions were postural orthostatic tachycardia syndrome (POTS; 55.8%), cerebrospinal fluid (CSF) leaks (51.2%), dysautonomia (45.3%), cranio-cervical instability (37.2%), mast cell activation syndrome (25.6%), and tethered cord syndrome (23.3%). Allergies to medications (87.2%) and surgical tape (19.8%) were also frequent. Despite significantly lower opening pressures on lumbar puncture, headache severity and quality of life scores were reported with the same severity of classic IIH patients, suggesting an underlying hypersensitivity to intracranial pressures and cerebral venous congestion. There is a rare but conserved clinical phenotype that has not been described previously that presents with severe IIH symptoms in predominantly young, non-obese Caucasian women with a high associated incidence of dysautonomia, POTS, craniocervical instability, and CSF leaks, among others.

Mast cells, mediators, and symptomatic activation

&lt;abstract&gt; &lt;p&gt;Mast cells (MC) are central effectors of allergic disease and distinct subsets with varying amounts of tryptase, chymase, and carboxypeptidase A3, and cathepsin G is distributed throughout the body. Their involvement in a diverse range of non-allergic illnesses mediated by a complex range of preformed and newly synthesized mediators is now increasingly recognized. The latter especially include conditions under the umbrella term of mast cell activation syndrome. In allergic disease, much has been written about the mechanisms by which the early and rapidly acting mediators produce both localized and systemic allergic symptoms. The role of chymase is presently underappreciated but there is increased awareness that MCs contain significant amounts of preformed TNF alpha and synthesize and releases a wide range of inflammatory cytokines such as interleukins (IL) 1β, IL6, IL31, and IL33. These can aggravate itching and perpetuate inflammation and likely contribute to the late constitutional symptoms seen in allergic reactions. Importantly, their involvement helps to clarify the role of MCs in stress and non-parasitic infections. Presently, unexplained is the increasing incidence of significant acute allergic reactions within a relatively short time frame. In this context, there is increasing interest in the environmental, menstrual, endocrine, circadian, and psychological factors that influence MC activation as well as the endocrine pathways involving the renin angiotensin system that oppose hypotension. In non-allergic diseases with normal numbers of MCs, reduced thresholds for activation may be produced by various combinations of life and dietary factors. Diagnosing these conditions is difficult but may be helped by urinary analysis of prostaglandin metabolites. The investigation and management of mastocytosis with and without mutations of c-kit is also relevant to allergic disease and the new medications used may also be helpful in idiopathic anaphylaxis. This knowledge may open a new chapter in human diseases and mast cell regulation.&lt;/p&gt; &lt;/abstract&gt;

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.

Low Prevalence of Idiopathic Mast Cell Activation Syndrome Among 703 Patients With Suspected Mast Cell Disorders

BackgroundIdiopathic mast cell activation syndrome (iMCAS) is characterised by severe, episodic systemic mast cell (MC) activation and mediator-related symptoms, event-related increase in serum tryptase levels and response to MC-targeted therapies, in the absence of underlying IgE-mediated allergy or clonal MC disorder. Studies indicating its prevalence using evidence-based diagnostic criteria are currently lacking. ObjectiveThe present study aimed to assess prevalence, as well as clinical and laboratory features of patients with iMCAS. MethodsWe conducted a retrospective evaluation of the data from 703 consecutive patients (≥18 years old) who were referred to our centre based on suspected MC disorders. Patients underwent a thorough clinical work-up including patient history, allergy tests, KIT D816V mutation analysis and/or bone marrow investigation. Disease activity was prospectively assessed during follow-up visits. ResultsThirty-one cases with confirmed iMCAS were identified. Furthermore, hereditary alpha-tryptasemia was detected in three of the cases with baseline tryptase levels >8 ng/ml. The most common clinical presentation during the MCAS episodes was mucocutaneous symptoms in patients with iMCAS, especially urticaria/angioedema. However, these symptoms were less prevalent in clonal MCAS patients (p=0.015). The duration of diagnostic delay was significantly longer in iMCAS compared to cMCAS patients (p=0.02). ConclusionOverall prevalence of iMCAS was 4.4% in the entire cohort, which indicates that iMCAS is an uncommon condition. Screening suspected patients for the three diagnostic criteria and performing a comprehensive allergy work-up including laboratory tests and ultrasensitive mutation analysis of KIT D816V followed by applying recommended diagnostic algorithms is crucial for the diagnosis of iMCAS.

Recombinant Human Diamine Oxidase Against Histamine Induced Shock - Implications for Mast Cell Activation Syndrome

Background and Objective:Mastocytosis patients suffer from a clonal increase in mast cells which produce and release excessive amounts of histamine even under stable conditions (Keyzer et al. 1983). Unfortunately, symptom control with new kinase inhibitors is variable and modest at best. Mast cell activation syndrome may further enhance histamine release which can result in recurrent shocks (Böhm et al. 2019), or severe, protracted anaphylaxis refractory to epinephrine (Grafeneder et al. 2022). Previously we demonstrated that recombinant human diamine oxidase (rhDAO) fully degrades 100-fold elevated histamine concentrations in plasma samples from mastocytosis patients. In vivo rhDAO, with a mutated heparin binding motif (mHBM), was able to digest massively increased histamine levels, thereby improving indirect measures of shock such as a temperature drop in mice (Karer et al. 2022). As mice are insensitive to histamine (intravenous LD50 of 385mg/kg in mice compared with 0.18mg/kg in guinea pigs), this unfortunately limits their translational value. To assess the therapeutic potential of rhDAO_mHBM, we tested its efficacy for the prevention and treatment of histamine induced shock in guinea pigs, the only histamine sensitive rodent species. Methods:Guinea pigs received continuous intravenous infusions of 8 µg/kg/min histamine to model its release from activated circulating basophils or subcutaneous injections of 1mg/kg histamine to mimic peripheral histamine release by mast cells. We used intramuscular injections of 5µg/kg adrenaline as a benchmark, because it is recommended in guidelines for the treatment of anaphylaxis, although its efficacy had never been proven. Infusions of rhDAO_mHBM were given either prophylactically before- or therapeutically after - symptom onset. Mean arterial pressure was measured intra-arterially and rhDAO_mHBM levels were quantified by enzyme immunoassay and histamine concentrations by a liquid chromatography -tandem mass spectrometry (LC-MS/MS) method. The primary outcome variable was prevention of shock as defined by a &amp;gt;=30% drop in mean arterial blood pressure. Results:Guinea pigs pretreated with 4 mg/kg rhDAO_mHBM showed lower mean heart rate (p&amp;lt;0.01) and higher body core temperatures at the end of the intravenous histamine infusions compared to controls (p&amp;lt;0.05). Histamine infusions increased median urinary excretion of histamine and N-methyl-histamine 8.6- and 4.0-fold (p&amp;lt;0.05), respectively. Pretreatment with 4 mg/kg rhDAO_mHBM reduced urinary histamine (p&amp;lt;0.01) and N-methyl-histamine (p&amp;lt;0.01) concentrations compared with controls. Subcutaneous injections of 1 mg/kg histamine induced shock within 20 minutes in all control animals, and the experiments had to be terminated prematurely in several animals. Intramuscular injection of 5mcg/kg adrenaline (similar to human adrenaline auto-injector doses) after symptom onset was unable to prevent shock, confirming its lack of efficacy demonstrated previously in an anaphylaxis model in dogs (Mink et al. 2004). In contrast, prophylactic infusions of 4-8mg/kg rhDAO_mHBM prevented hypotensive shock in all treated animals (p&amp;lt;0.01). After an initial histamine induced drop in blood pressure, 8mg/kg rhDAO_mHBM restored blood pressure and prevented shock in all animals when injected at the time of symptom occurrence (p&amp;lt;0.01 Chi2 test). Figure 1 demonstrates the median drop in blood pressure and development of shock (indicated by the dashed line) by subcutaneous injection of 1mg/kg histamine (black squares), and the prevention of shock by rhDAO-mHBM given before (blue up triangles) or after (red circles) histamine injections. Conclusion: This is the first demonstration of the beneficial effects of rhDAO_mHBM in a histamine-sensitive species. rhDAO_mHBM is a novel therapeutic approach targeting histamine excess which effectively prevented shock, in contrast to intramuscular epinephrine. As the mechanism of action is not species specific, these findings can be translated from guinea pigs to humans: it will help to select optimal dosing of rhDAO_mHBM during clinical development for the prophylaxis in - and treatment of - mastocytosis patients suffering from histamine induced symptoms or mast cell activation syndrome, or patients with anaphylaxis induced by asparaginase, plasma products or other medications.

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.

Chemical Intolerance and Mast Cell Activation: A Suspicious Synchronicity.

Background: Chemical Intolerance (CI) is characterized by intolerances for chemicals, foods, and drugs with multi-system symptoms. As yet, the biomechanism remains unclear. One study reported converging lines of evidence supporting a substantive association between mast cell activation syndrome (MCAS) and CI. The purpose of this study is to (1) confirm a previous report demonstrating that 60% of MCAS patients report CI and (2) examine the parallels between symptoms and intolerances in CI and MCAS. Methods: Five hundred forty-four MCAS patients were assigned a clinical MCAS score using a validated assessment instrument and were assessed for CI using the validated Quick Environmental Exposure Sensitivity Index. Results: Our outcomes confirm the previously published study where the majority of MCAS patients also have CI. There was a clear overlap between various ICD-10 diagnostic categories and CI symptoms, providing further support for a potential shared mechanism. Conclusions: Exposures to pesticides, volatile organic compounds, combustion products, and mold have previously been reported as initiators of CI. However, until recently, little was known about the biological mechanism involved that could explain the multisystem symptoms associated with CI. This paper addresses a newly identified biomechanism for disease, which may underlie a host of "medically unexplained symptoms" triggered by xenobiotics.

Postural orthostatic tachycardia syndrome after COVID-19 vaccination

There is an association between coronavirus disease 2019 (COVID-19) mRNA vaccination and the incidence or exacerbation of postural orthostatic tachycardia syndrome (POTS). The purpose of this study was to characterize patients reporting new or exacerbated POTS after receiving the mRNA COVID-19 vaccine. We prospectively collected data from sequential patients in a POTS clinic between July 2021 and June 2022 reporting new or exacerbated POTS symptoms after COVID-19 vaccination. Heart rate variability (HRV) and skin sympathetic nerve activity (SKNA) were compared against those of 24 healthy controls. Ten patients (6 women and 4 men; age 41.5 ± 7.9 years) met inclusion criteria. Four patients had standing norepinephrine levels > 600 pg/mL. All patients had conditions that could raise POTS risk, including previous COVID-19 infection (N = 4), hypermobile Ehlers-Danlos syndrome (N = 6), mast cell activation syndrome (N = 6), and autoimmune (N = 7), cardiac (N = 7), neurological (N = 6), or gastrointestinal conditions (N = 4). HRV analysis indicated a lower ambulatory root mean square of successive differences (46.19 ±24 ms; P = .042) vs control (72.49 ± 40.8 ms). SKNA showed a reduced mean amplitude (0.97 ± 0.052 μV; P = .011) vs control (1.2 ± 0.31 μV) and burst amplitude (1.67 ± 0.16 μV; P = .018) vs control (4. 3 ± 4.3 μV). After 417.2 ± 131.4 days of follow-up, all patients reported improvement with the usual POTS care, although 2 with COVID-19 reinfection and 1 with small fiber neuropathy did have relapses of POTS symptoms. All patients with postvaccination POTS had pre-existing conditions. There was no evidence of myocardial injuries or echocardiographic abnormalities. The decreased HRV suggests a sympathetic dominant state. Although all patients improved with guideline-directed care, there is a risk of relapse.

Abstract 15090: Postural Orthostatic Tachycardia Syndrome After COVID-19 Vaccination

Background: COVID-19 vaccination may be associated with postural orthostatic tachycardia syndrome (POTS) incidence, but little is known of who is at risk, their autonomic state, or how they respond to therapy. Methods: This prospective cohort study analyzed clinical data of 10 POTS clinic patients with new-onset or worsening POTS after COVID-19 vaccination. We also compared heart rate variability (HRV, via spot and ambulatory electrocardiograms (ECGs)) and skin sympathetic nerve activation (SKNA) with 24 healthy controls. Results: Patient mean age was 41.5±7.9 years with equal gender balance. Ambulatory ECG showed no major arrhythmias. Mean standing norepinephrine level was 638.2±395.3 pg/mL, with 4 patients &gt;600 pg/mL. All patients had conditions that could raise POTS risk: prior COVID-19 infection (N=4); hypermobile Ehlers-Danlos syndrome (N=6); mast cell activation syndrome (N=3 found pre-POTS, N=3 post-POTS); and autoimmune (N=7), cardiac (N=7), neurologic (N=6), or gastrointestinal conditions (4). HRV analysis indicated lower spot (36.09 ms±49.2) and ambulatory root mean square of successive differences (46.19 ms±24, p=0.042) vs control (72.49 ms±40.8). SKNA showed a reduced mean amplitude (0.97uV±0.052, p=0.011) vs control (1.2 uV±0.31) and burst amplitude (1.67 uV±0.16, p=0.018) vs control (4.3 uV±4.3). All patients received guideline-based POTS care. After 417.2±131.4 days of follow-up, 3 patients were on ivabradine, 2 on beta blockers, 2 on midodrine, 5 on antihistamines, 4 on mast cell stabilizers, and 1 on prednisone. All patients reported improvement, although 2 with COVID-19 reinfection and 1 with small fiber neuropathy did have relapses of POTS symptoms. Conclusion: POTS patients with post-vaccine onset or exacerbation had histories of potential predisposing conditions. These suggest a potential screening approach, though referral bias is possible. Elevated standing norepinephrine levels, decreased HRV, and decreased pRR50 support a sympathetic-dominant state. Though only 2/10 patients stayed on beta blockers, 8/10 did at least transiently use them. Reduced average SKNA and burst-to-mean amplitude ratio suggest the presence of peripheral autonomic neuropathy. Patients responded to standard POTS therapy.

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.