Mast Cell Activation Syndrome Research Articles

1194 Small Intestinal Bacterial Overgrowth Is Common in Mast Cell Activation Syndrome

INTRODUCTION: Mast cell activation syndrome (MCAS) often presents with symptoms of irritable bowel syndrome (IBS). MCAS is a multi-systemic disorder caused by inappropriate mast cell (MC) activation causing inflammatory and allergic symptoms. IBS can be associated with small intestinal bacterial overgrowth (SIBO). This study determined the prevalence of SIBO in MCAS. METHODS: Patients with refractory gastrointestinal (GI) symptoms were evaluated for MCAS and SIBO. MCAS was diagnosed if there were typical symptoms of mast cell (MC) activation in 2 or more organ systems plus 1 or more of the following: elevation of MC chemical mediator(s), clinical improvement with MC-directed therapy, and/or increased intestinal MC density. SIBO diagnosis was based on a lactulose breath test (LBT) with ≥20 ppm hydrogen rise from baseline within 90 minutes. These LBT results were compared to our prior study of healthy controls. The effect of co-morbid syndromes and medication use was analyzed. Antibiotic therapy effects were a secondary aim. This study was IRB approved. RESULTS: There were 139 MCAS subjects (116 F, 23 M, 46.6 ± 16.9 years) and 30 controls (19 F, 11 M, 44 ± 14.0 years). GI symptoms preceded other MCAS symptoms in 66.2%. Symptoms included abdominal pain (87.1%), bloating (74.8%), constipation (66.9%), diarrhea (63.3%), nausea (61.9%), heartburn (54.0%), and dysphagia (29.5%). In these MCAS patients Rome 4 criteria for IBS-mixed (39.6%), IBS-constipation (22.3%), and IBS-diarrhea (18.7%) were met. SIBO was present in 30.9% MCAS subjects vs. 10% in controls (P = 0.023). Methane excretion in a plateau pattern was common in MCAS: 10.1% had levels ≥10 ppm and 24.5% had levels 3-9 ppm. Higher methane levels were associated with IBS-constipation compared to SIBO positive subjects: 42.9% vs. 9.3% (P = 0.02). Postural orthostatic tachycardia syndrome, hypermobile Ehlers-Danlos syndrome, MC density and mediators, proton pump inhibitors, thyroid supplements, and statins were not associated with LBT changes. Antibiotics were prescribed for 74 subjects: 67.6% had marked improvement, 5.4% had partial improvement, and 21.6% had no improvement in GI symptoms. Adverse events led to cessation of antibiotics in 9.5%. CONCLUSION: SIBO with hydrogen and methane plateau patterns are common in MCAS subjects. MCAS could cause SIBO due to alterations of the GI immune system or altered motility by local release of MC mediators. Antibiotic therapy appears to improve GI symptoms in MCAS patients.

AAAAI Mast Cell Disorders Committee Work Group Report: Mast cell activation syndrome (MCAS) diagnosis and management

Our current recommendations for diagnosing and treating primary mast cell (MC) activation syndrome make use of the latest studies and consensus guidelines for clinically recognizing systemic anaphylaxis in real time, regardless of whether allergen-triggered or other pathways are involved; our current understanding of the biomarkers secreted by activated MCs that best discriminate this disorder from other conditions; and the therapeutic drugs that might selectively affect those mediators or MCs themselves.Finding familial or somatic mutations of genes that cause MCs to be hyperactivatable would extend our diagnostic tools and potentially indicate new therapeutic interventions, targeting either the mutated gene product or the associated molecular pathway. In conclusion, we trust that the clinical, laboratory, and therapeutic criteria for primary MC activation syndromes described herein will provide clinicians with practical criteria of sufficient sensitivity and specificity to diagnose most cases without overdiagnosing the disorder in patients who likely have other conditions.

Mast Cell Activation Syndrome: Tools for Diagnosis and Differential Diagnosis

The current consensus diagnostic criteria for mast cell activation syndrome(s) (MCAS[s]) were first established in 2012 and updated in 2019. This diagnosis has been attached to multiple medical conditions not intended as part of the diagnosis. In this article, the diagnostic criteria are reviewed and other diseases in the differential diagnosis outlined. The goal of this review is to provide a tool for evaluation of patients with conditions that can mimic MCAS. Furthermore, the potential role for hereditary alpha-tryptasemia in this group of disorders is discussed.

A review of the dermatologic symptoms of idiopathic mast cell activation syndrome

Since the first reported cases in 2007, idiopathic mast cell activation syndrome has been increasingly recognized. Understanding of the cutaneous manifestations of this condition is imperative for dermatologists given the substantial clinical heterogeneity in its presentation and high estimated prevalence. A review of PubMed® and SCOPUS® databases was performed in order to investigate the most common dermatologic manifestations of idiopathic mast cell activation syndrome. Evidence to date suggests that flushing, pruritus, and clotting dysfunction or bleeding disorder are the most frequently observed dermatologic symptoms in idiopathic mast cell activation syndrome, while dermatographism has been identified as a common finding in patients as well. Mast cell activation syndromes have also been linked to connective tissue disorders, including an Ehlers-Danlos Syndrome-like phenotype possibly mediated by matrix metalloproteinases and tryptase released by mast cells. Current literature regarding dermatologic manifestations of idiopathic mast cell activation syndrome is limited by the heterogeneity of studies including clinical descriptions, inconsistency of diagnostic criteria implemented, and a paucity of literature available. This work provides a guide for dermatologists to strengthen diagnostic acuity for idiopathic mast cell activation syndrome, therefore contributing toward a goal of helping patients to receive timely, effective, and targeted therapy. J Drugs Dermatol. 2019;18(2):162-168.

Venom immunotherapy in patients with clonal mast cell disorders: IgG4 correlates with protection.

Patients with clonal mast cell disorders (cMCD), systemic mastocytosis (SM) and monoclonal mast cell activation syndrome (MMAS), represent an increased risk for Hymenoptera venom anaphylaxis (HVA). Lifelong venom immunotherapy (VIT) is recommended; however, its efficacy and safety are controversial. Hence, we sought to evaluate the efficacy and safety of VIT in HVA patients with cMCD. A retrospective study was conducted among 46 patients with Vespula venom allergy who had experienced severe HVA, 32 cMCD (22 with SM and 10 with MMAS) and 14 controls. There were no differences between cMCD patients and controls in age (58 vs 66) and duration of VIT (47 vs 48months), respectively. During VIT, 11 (34%) cMCD patients experienced adverse reactions (ARs) (7% in controls), including 1 anaphylaxis. There were 23 re-stings in 17 (53%) patients during VIT. Of episodes, four (17%) presented with anaphylaxis, 14 (60%) presented with local reaction, and five (23%) were asymptomatic. In 11 episodes (48%), the patient did not take epinephrine, of these 8 (73%) presented with local reaction, and 3 (27%) were asymptomatic. Patient-based protection from anaphylaxis was 76% (4/17) in cMCD vs. 100% in controls during VIT. The venom-specific IgG4 concentrations increased during VIT (P<.001) although tryptase and IgE were unaltered. Both safety and efficacy of VIT in cMCD patients were slightly reduced than controls. Severe ARs were rare. The elevated IgG4 levels may be a biomarker for efficacy of VIT in cMCD patients, as it correlates with protection from re-stings.

Fatal anaphylaxis following a hornet sting in a yellow jacket venom-sensitized patient with undetected monoclonal mast cell activation syndrome and without previous history of a systemic sting reaction

IgE-mediated fatal anaphylaxis after Hymenoptera stings is a rare but well-recognized cause of sudden death. However, the number of cases might be underestimated as establishing the diagnosis of fatal anaphylaxis without a clinical history is not always straightforward due to reasons such as the nonspecificity of macroscopic and microscopic autopsy findings or the presence of accompanying, potentially lethal diseases. Here, we report a detailed clinical history, necropsy, and serology of a case of fatal Hymenoptera anaphylaxis in a patient without a previous history of Hymenoptera venom allergy suffering from an undetected monoclonal mast cell activation syndrome (MMAS).

The Relationship Between Hypermobile Ehlers-Danlos Syndrome (hEDS), Postural Orthostatic Tachycardia Syndrome (POTS), and Mast Cell Activation Syndrome (MCAS).

In recent years, an association between hypermobile Ehlers-Danlos syndrome (hEDS), mast cell activation syndrome (MCAS), and postural orthostatic tachycardia syndrome (POTS) has garnered attention and patients are increasingly presenting with this triad. However, a real relationship between these entities is unclear due to a lack of scientific validity. We conducted an extensive review of the literature using two different search strategies. A narrower strategy included 88 searches of various combinations of terms for each of the three conditions, yielding 19 unique papers. A broader search included 136 searches of various combinations of terms but included all forms of EDS and yielded 40 unique papers. Of these, only four and nine papers from the narrower and broader search strategies were original research articles. None of these papers resulted from a combination of the search terms for the three conditions. All three clinical entities are controversial in either existence or pathogenesis. MCAS is a poorly defined clinical entity, and many studies do not adhere to the proposed criteria when establishing the diagnosis. Patients previously diagnosed with EDS hypermobility type may not meet the new, stricter criteria for hEDS but may for a less severe hypermobility spectrum disorder (HSD). The pathophysiology of POTS is still unclear. An evidence-based, common pathophysiologic mechanism between any of the two, much less all three conditions, has yet to be described. Our review of the literature shows that current evidence is lacking on the existence of MCAS or hEDS as separate or significant clinical entities. Studies proposing a relationship between the three clinical entities are either biased or based on outdated criteria. The reason behind the purported association of these entities stems from an overlapping pool of vague, subjective symptoms, which is inadequate evidence to conclude that any such relationship exists.

Frequency of clonal mast cell diseases among patients presenting with anaphylaxis: A prospective study in 178 patients from 5 tertiary centers in Spain

Mast cell activation syndromes (MCAS) encompass a heterogeneous group of disorders characterized by clinical symptoms secondary to the systemic effects of mediators released by mast cells (MCs) on their activation, including anaphylaxis. MCAS can be classified into 3 categories:1,2 (1) primary (monoclonal) MCAS, which includes symptomatic patients with systemic mastocytosis (SM) and those in whom clonal MCs and up to 2 minor SM criteria are found but SM cannot be diagnosed; (2) secondary MCAS; and (3) idiopathic MCAS.

A review of the evidence for the existence of and relationship between hypermobile Ehlers-Danlos syndrome (hEDS), postural orthostatic tachycardia syndrome (POTS), and mast cell activation syndrome (MCAS)

Abstract The association of hypermobile Ehlers-Danlos syndrome (hEDS), mast cell activation syndrome (MCAS) and postural orthostatic tachycardia syndrome (POTS) is unclear. We conducted an extensive review of the literature using 2 different search strategies. A narrower strategy included 88 searches of various combinations of terms for each of the three conditions, yielding 19 unique papers. A broader search included 136 searches of various combinations of terms but included all forms of EDS and yielded 40 unique papers. Of these, only 4 and 9 papers from the narrower and broader search strategies were original research articles. None of these papers resulted from a combination of the search terms for the three conditions. All three clinical entities are controversial in either existence or pathogenesis. MCAS is a poorly defined clinical entity and many studies do not adhere to the proposed criteria when establishing the diagnosis. Patients previously diagnosed with EDS hypermobility type may not meet the new, stricter criteria for hEDS, but may for a less severe hypermobility spectrum disorder (HSD). The pathophysiology of POTS is still unclear. An evidence-based, common pathophysiologic mechanism between any of the two, much less all three conditions, has yet to be described. Our review of the literature shows that current evidence is lacking on the existence of MCAS or hEDS as separate or significant clinical entities. Studies proposing a relationship between the three clinical entities are either biased or based on outdated criteria. The reason behind the purported association of these entities stems from an overlapping pool of vague, subjective symptoms, which is inadequate evidence to conclude that any such relationship exists.

Tu1845 – Identification of a Unique Population of Gi Mast Cells in a Subset of Patients with Mast Cell Activation Syndrome

Tu1845 – Identification of a Unique Population of Gi Mast Cells in a Subset of Patients with Mast Cell Activation Syndrome

The Role of KIT Mutations in Anaphylaxis.

Gain of function KIT mutations are detected in clonal mast cell diseases, namely mastocytosis and monoclonal mast cell activation syndrome. Timely diagnosis and treatment of these disorders are crucial because of their association with severe and life-threatening anaphylaxis. KIT mutations also have implications for targeted therapies of mast cell disorders. This review article strives to serve as an overview of the role of clonal mast cell disorders in anaphylaxis while elucidating current and future therapies. Clonal mast cell disease has been increasingly diagnosed in patients with severe hymenoptera allergy and those with recurrent unexplained anaphylaxis. The current state of knowledge of the epidemiology, pathophysiology, diagnosis, and treatment of mastocytosis with a particular focus on anaphylaxis and its triggers which are described in this context. Novel and forthcoming treatments are discussed including the relevance of KIT mutation status. This review provides an overview of the role of KIT mutations in mastocytosis and anaphylaxis, and highlights emerging therapies for mastocytosis, targeting these mutations.

Successful mast-cell-targeted treatment of chronic dyspareunia, vaginitis, and dysfunctional uterine bleeding

Dyspareunia, vaginitis and dysfunctional uterine bleeding (DUB) are common problems which, despite their polygenicity, commonly appear idiopathic and treatment-refractory. Mast cell (MC) activation syndrome (MCAS) is a newly-recognised, prevalent, chronic multisystem polymorbidity of general themes of inflammation ± allergic-type phenomena ± aberrant growth/development in assorted tissues. MCs produce significant quantities of heparin, too. As such, MCAS may underlie some cases of chronic dyspareunia, vaginitis or DUB. We report five such patients; all who responded well to MC-targeted treatment. We review aspects of MC biology and pathobiology of potential relevance to otherwise idiopathic persistent inflammatory or coagulopathic genital tract problems. Diagnostic testing for MCAS may be warranted in some patients with chronic dyspareunia, vaginitis or DUB (especially patients whose histories well fit the general profile of MCAS), and prospective therapeutic trials of MC-directed topical and/or systemic therapies may be warranted in such populations. Impact statement What is already known on this subject? Chronic, idiopathic, treatment-refractory female genital tract inflammation or bleeding are common problems for which mast cell (MC) disease, previously generally thought to consist of just rare cases of mastocytosis, and is seldom considered in the differential diagnosis. What do the results of this study add? The substantial prevalence of the newly recognised ‘mast cell activation syndrome’ (MCAS), featuring chronic inappropriate MC activation with little-to-no MC neoplasia, and its clinical presentation with chronic multisystem inflammation ± allergic-type phenomena ± aberrant growth/development in assorted tissues, raises the possibility that MCAS might underlie the aforementioned genital tract problems, especially in patients whose larger clinical presentations fit the MCAS profile. We report five example patients (among many more we have similarly treated) who enjoyed excellent responses to safe, inexpensive MC-targeted treatments, often given just intravaginally. What are the implications of these findings for clinical practice and/or further research? Our report identifies a potentially significant new MC-focused direction, of relevance to millions of affected women worldwide, for clinical treatment as well as for basic and clinical research, which historically has yielded major advancements disappointingly disproportionate to the scope of the affected population.

CME Exam: Mast Cell Activation Syndrome and Mastocytosis: Initial Treatment Options and Long-Term Management

CME Exam: Mast Cell Activation Syndrome and Mastocytosis: Initial Treatment Options and Long-Term Management

Insect Sting Anaphylaxis—Or Mastocytosis—Or Something Else?

Insect sting anaphylaxis and mast cell disorders are intertwined in a specific and unusual way. There may be specific subsets of clonal mast cell disorders that are predisposed to sting anaphylaxis. The clinical characteristics of the sting reactions should raise suspicion of underlying mastocytosis (eg, hypotension without hives especially in a male). A baseline serum tryptase level is helpful in the evaluation of patients with insect sting anaphylaxis because it correlates with important risks for these patients, and they have a high frequency of abnormally elevated baseline levels. Elevated baseline serum tryptase level has been reported to correlate with clonal mast cell disease in patients with insect sting anaphylaxis but may also indicate one of several possible underlying syndromes, including mast cell activation syndrome (MCAS), familial hypertryptasemia, and idiopathic anaphylaxis. There is some overlap in these conditions, so it is important to evaluate the clinical pattern at presentation as well as laboratory markers, and to consider bone marrow biopsy to make a final and specific diagnosis of clonal mast cell disease. The presence of venom-IgE does not prove that the patient's previous sting reactions were IgE-mediated, but even low levels of venom-IgE in patients with mastocytosis predispose to severe sting anaphylaxis. Evaluation of all these possible factors will affect the recommendation for venom immunotherapy.

Higher prevalence of vertebral fractures in systemic mastocytosis, but not in cutaneous mastocytosis and idiopathic mast cell activation syndrome

To describe osteoporosis (OP) and fragility fractures in mast cell disorders (MCDs). We retrospectively analyzed data concerning all successive patients with systemic mastocytosis (SM), cutaneous mastocytosis (CM), and mast cell activation syndromes (MCAS) diagnosed in our mastocytosis expert center between 2004 and 2015. We collected data concerning demographic profiles, clinical signs of MCD, osteoporosis, fractures, densitometry, and biological assessment of MCD. We compared CM and MCAS patients with SM patients with regard to the characteristics of OP and fragility fractures. We assessed 89 SM patients, 20 CM patients, and 20 MCAS patients. Osteoporosis was less frequent in CM (15.0%) and MCAS (10.0%) than in SM (44.9%). Similarly, fractures were less frequent in non-SM MCDs, respectively 5.0%, 5.0%, and 28.1%. SM patients displayed high prevalence of vertebral fractures (22.5%), mostly multiple. Conversely, in non-SM patients, vertebral fractures appeared to be uncommon (5%) and more frequently associated with risk factors for osteoporosis. SM is associated with multiple vertebral osteoporotic fractures, whereas CM and MCAS do not appear to be associated with this phenotype.

Increased prevalence of autonomic dysfunction due to postural orthostatic tachycardia syndrome in patients with eosinophilic gastrointestinal disorders.

Eosinophilic gastrointestinal disorders (EGIDs) have been linked with atopic conditions, connective tissue disorders, and autoimmunity, but the association between EGIDs and autonomic dysfunction has not been extensively described. We aimed to assess this association and determine the prevalence of autonomic dysfunction in our EGID population. In this retrospective cohort study, we analyzed adult patients in the University of North Carolina Eosinophilic Esophagitis (EoE)/EGID database who also had a diagnosis of comorbid autonomic dysfunction (postural orthostatic tachycardia syndrome [POTS] or gastroparesis). The electronic medical record was abstracted and disease characteristics summarized. We identified seven patients who had EGID and autonomic dysfunction. All had POTS and were Caucasian, and five (71%) were female; 2 also had gastroparesis. Onset of autonomic symptoms coincided with onset of EGID symptoms in 3 patients (43%) or with an acute EGID flare in 3. In no cases did successful control of EGID lead to improvement of autonomic symptoms. Two subjects (29%) had comorbid Ehlers-Danlos syndrome and mast cell activation syndrome. The prevalence of POTS in EGID patients was 7/560 (1.25%), compared to an estimated 0.17% prevalence of POTS in the general population. The prevalence of autonomic dysfunction was 5-10-fold higher in EGID than expected in the general population, suggesting an association between the two conditions, though the underlying mechanism is unclear. Providers should consider comorbid autonomic dysfunction in patients with EGID, particularly when symptoms persist despite treatment.

Crosstalk between Mast Cells and Eosinophils Can Contribute to Pathophysiology of Sickle Cell Anemia

Introduction: Sickle cell anemia (SCA) is characterized by a chronic inflammatory state as a result of cellular activation and biochemical mediator release. Mast cell (MC) activation syndrome is recognized as a factor in the morbidity of SCA patients (Afrin 2014); in SCA murine models, MC activation and MC extracellular trap formation (Vincent et al, 2013; Tran et al 2017) are associated with neurogenic inflammation and nociceptor activation. Allergic models showed that MC activation induces selective release of preformed or newly synthesized compounds; these dynamics exhibit features that could be associated with distinct patterns of MC-dependent inflammation (Gaudenzo et al, 2016), which is modulated by the engagement of additional surface receptors activated by signals from other cells. In these models, MC and eosinophils (Eos) coexist in inflamed tissues and bidirectional modulation occurs; in SCA, however, the role of both types of cells has not been fully determined. Methods and Results: In order to clarify the contribution of MC/Eos cross talk to the pathophysiology of SCA, we standardized in vitro models to study MC that were differentiated from CD34+ stem cells and freshly isolated Eos from SCA patients and healthy volunteers (HV). First, using FACS and image cytometry (ImageStream-X; Amnis Corporation), we characterized surface marker expression (adhesion, activation and MC-Eos receptors, Fig 1) and identified changes on expression patterns after short-term MC/Eos co-cultures. HV-MC and SCA-MC were obtained after 5 weeks; higher frequencies of CD117+ and CD63+ cells were found on SCA-MC cultures but no other differences for MC or Eos were detected by FACS. Differences in cell size and the expression pattern distributions of CD117, CD63 and CD200RI between HV-MC and SCA-MC were found by IC analysis (Ratio Discrimination (RD) >1). Incubation of HV-MC and SCA-Eos for 2 hours generated changes not only in CD63 (RD 1.1) and CD117 (RD 1.3), but also in CD48 marker pattern expression (RD 1.09). The effect was more evident in SCA-Eos/SCA-MC cocultures for CD48 (RD 2.3) and CD63 (RD 2.2). Secondly, we compared the ability of SCA-MC and HV-MC to induce functional responses on Eos by evaluating changes in the frequency of apoptotic and activated (non-circular) Eos (IC analysis: Nuclear Morphology and Circularity Morphology Features). After 24 hours of MC/Eos coculture, the ability of MC and MC culture supernatants to induce Eos chemotaxis was evaluated by trans-well assays. After 24 hours, the percentage of apoptosis of Eos in monoculture was low (HV-Eos 1.2±0.3; SCA-Eos 3.65±1.1). MC/Eos coculture decreased the frequency of apoptotic Eos; where the anti-apoptotic effect on SCA-Eos was higher (4.2 fold) than that of SCA-MC (2-fold). Eos monocultures showed lower frequencies of activated cells (% of Eos with Circularity Morphology Index <10: HV-Eos 9.1±3.4, SCA-Eos 13.0±6.5); MC/Eos cocultures of both SCA-MC and HV-MC increased (2-3.5 fold) the percentage of activated SCA-Eos in comparison with Eos monocultures. SCA-MC strongly increased activated SCA-Eos (3.5-fold) and HV-Eos (2.4-fold) (p<0.05, 95% CI 5.5-43.69). The greatest chemotactic effect was obtained using SCA-MC supernatant stimuli for both HV-Eos (396.0%±53.8) and SCA-Eos (300.2%±22.5) in comparison with basal (100%) and eotaxin-1 (100 ng/ml) controls (HV-Eos 257.8%±76.4; SCA-Eos 227.7%±12.1; Eos p=0.020; MC p=0.006; Interaction p=0.61). Finally, we studied the frequency of heterotypical (MC-Eos) conjugate formation by IC analysis and we measured the influence of Eos on MC degranulation dynamics using a colorimetric test (β-hexosaminidase, β-hex). MC/Eos conjugate formation was a rare event (less than 5% of images); there was no difference in the percentage of conjugates among MC types (data not shown). Degranulation of SCA-MC was characterized by higher β-hex activity (HV-MC 0.03±0.009; SCA-MC 0.34±0.11 Units/ml). β-hex activity was reduced when incubated with HV-Eos (0.19±0.12 Units/ml) and SCA-Eos (HV-MC 0.04±0.010 Units/ml). Conclusions: Our data indicated that mast cells and eosinophils interact to modulate the activities (cell activation, degranulation, apoptosis) of each other and can contribute to the perpetuation of the inflammatory response in SCA. These bidirectional interactions between mast cells and eosinophils might be important to the pathophysiology of SCA. Financial Support: FAPESP. [Display omitted] DisclosuresFertrin:Apopharma Inc.: Honoraria; Alexion Pharmaceuticals Brasil: Speakers Bureau.

WHAT APPEARS TO BE POSSIBLE CARCINOID IS IN FACT MAST CELL ACTIVATION SYNDROME

Introduction Mast cell activation syndrome (MCAS) has been increasingly used to define patients with episodic systemic symptoms secondary to mast cell activation that do not fit the criteria for systemic mastocytosis or monoclonal mast cell activation syndrome. Here we present a patient with MCAS with laboratory features of carcinoid syndrome. Case Description A 54-year old Caucasian female with allergic rhinitis, urticaria, flushing with and without eating, fogginess, polycythemia, and Graves disease s/p total thyroidectomy presented to establish care. Labs revealed elevated tryptase of 18 ng/mL, and an elevated 24-hour urine prostaglandin D2 of 388 ng. Bone marrow biopsy findings were normal. Serum 5-HIAA and chromogranin A were normal. However, her 24-hour urine 5-HIAA was persistently elevated. Further work up failed to reveal findings consistent with carcinoid syndrome, including negative chest and abdominal scans. Given a convincing history of venom hypersensitivity, skin tests were performed revealing positives to honeybee, wasp and mixed venom. Patient was started on oral cromolyn with improvement in her flushing symptoms. She initially experienced diarrhea and abdominal cramping which has now resolved. She has been doing well with immunotherapy for allergic rhinitis, and is currently waiting to start venom immunotherapy. Discussion Although our patient's work up revealed persistently elevated urine 5-HIAA consistent with carcinoid syndrome, further work up revealed a picture more consistent with mast cell disorder. This case emphasizes the importance of considering MCAS even in patients with laboratory markers seen in carcinoid syndrome. Mast cell activation syndrome (MCAS) has been increasingly used to define patients with episodic systemic symptoms secondary to mast cell activation that do not fit the criteria for systemic mastocytosis or monoclonal mast cell activation syndrome. Here we present a patient with MCAS with laboratory features of carcinoid syndrome. A 54-year old Caucasian female with allergic rhinitis, urticaria, flushing with and without eating, fogginess, polycythemia, and Graves disease s/p total thyroidectomy presented to establish care. Labs revealed elevated tryptase of 18 ng/mL, and an elevated 24-hour urine prostaglandin D2 of 388 ng. Bone marrow biopsy findings were normal. Serum 5-HIAA and chromogranin A were normal. However, her 24-hour urine 5-HIAA was persistently elevated. Further work up failed to reveal findings consistent with carcinoid syndrome, including negative chest and abdominal scans. Given a convincing history of venom hypersensitivity, skin tests were performed revealing positives to honeybee, wasp and mixed venom. Patient was started on oral cromolyn with improvement in her flushing symptoms. She initially experienced diarrhea and abdominal cramping which has now resolved. She has been doing well with immunotherapy for allergic rhinitis, and is currently waiting to start venom immunotherapy. Although our patient's work up revealed persistently elevated urine 5-HIAA consistent with carcinoid syndrome, further work up revealed a picture more consistent with mast cell disorder. This case emphasizes the importance of considering MCAS even in patients with laboratory markers seen in carcinoid syndrome.

URINARY 2,3-DINOR-11SS-PROSTAGLANDIN F2A – CLINICAL UTILITY IN PEDIATRIC MAST CELL ACTIVATION SYNDROME

Introduction Mast cell activation syndrome (MCAS) is not well-described in children. Case Description 11-year old female presenting with recurrent episodes of facial flushing, nausea, abdominal cramping, and loose stools. Exacerbating factors include citrus fruits and dips, stressful situations, and surgeries. She has had no history of anaphylaxis. Her baseline tryptase was 2.1ng/mL. Her urine mast cell mediators during a mild episode were urinary 2,3-dinor-11β prostaglandin F2α (2,3-BPG) 8183pg/mg Cr, leukotriene E4 (LTE4) 51pg/mg Cr, and N-methylhistamine(NMH) 151 µg/g Cr. With use of cromolyn or Zyrtec, there was both symptomatic improvement and decrease in urinary 2,3-BPG. Discussion Children with MCAS have symptoms consistent with mast cell mediator release, elevation of mast cell mediators, and symptomatic resolution with medications which block mast cell mediator effects. The pattern of mast cell mediator elevation in children resembles adult MCAS. This case illustrates the clinical utility of urinary 2,3-BPG in the diagnosis and management of pediatric MCAS.

SCHNITZLER SYNDROME – IS ANTI-IL-1 THERAPY ALWAYS THE RIGHT CHOICE?

Introduction Schnitzler syndrome is a periodic fever syndrome presenting with urticarial skin rash, a monoclonal IgM component and at least two of the following: fever, joint or bone pain, lymphadenopathy, hepatosplenomegaly and elevated acute phase reactants. IL-1 is typically elevated, making anakinra a successful therapy. However, sarilumab (IL-6 antagonist) may be efficacious in certain patients. Case Description A 69-year-old female experienced monthly episodes of facial swelling and a non-pruritic, erythematous rash with high fevers, nausea, headache and neck pain over 1 year. During episodes, white cell count, neutrophils, monocytes, eosinophils, ESR and CRP were elevated but would resolve after episodes. Facial cellulitis, odontogenic and neurologic infections were excluded. Previous medical history was significant for breast cancer and uterine cancer in remission and Hashimoto's thyroiditis. Tryptase levels were normal, arguing against mast cell activation syndrome. Complement C2 (less than 1.3 mg/dL) and C4 (10mg/dL) levels were slightly low. The patient had normal immunoglobulin levels, IL-2, TNF-α, IL-1β levels and negative anti-SSA and anti-SSB, anti-Smith, anti- dsDNA, anti-mitochondrial and anti-actin antibodies but isolated elevated IL-6 levels and a monoclonal IgM component. Isolated elevated IL-6 made tocilizumab appropriate treatment with symptom resolution in days. However, after 4 months of therapy anaphylactic symptoms required changing to sarilumab with good effect. Discussion Although a decade older than expected and despite the presence of an atypical rash, symptoms were consistent with Schnitzler syndrome. Patients with elevated IL-6 levels who do not tolerate tocilizumab may respond well to other IL-6 antagonists such as sarilumab.