Proceedings from the Inaugural American Initiative in Mast Cell Diseases (AIM) Investigator Conference.

The American Initiative in Mast Cell Diseases (AIM) held its inaugural investigator conference at Stanford University School of Medicine in May 2019. The overarching goal of this meeting was to establish a Pan-American organization of physicians and scientists with multidisciplinary expertise in mast cell disease. To serve this unmet need, AIM envisions a network where basic, translational, and clinical researchers could establish collaborations with both academia and biopharma to support the development of new diagnostic methods, enhanced understanding of the biology of mast cells in human health and disease, and the testing of novel therapies. In these AIM proceedings, we highlight selected topics relevant to mast cell biology and provide updates regarding the recently described hereditary alpha-tryptasemia. In addition, we discuss the evaluation and treatment of mast cell activation (syndromes), allergy and anaphylaxis in mast cell disorders, and the clinical and biologic heterogeneity of the more indolent forms of mastocytosis. Because mast cell disorders are relatively rare, AIM hopes to achieve a coordination of scientific efforts not only in the Americas but also in Europe by collaborating with the well-established European Competence Network on Mastocytosis.

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.

Presentation of untreated systemic mastocytosis as recurrent, pulseless-electrical-activity cardiac arrests resistant to cardiac pacemaker.

Recurrent, pulseless-electrical-activity (PEA) cardiac arrests were the novel presentation of untreated systemic mastocytosis in an 85-year-old woman who lacked cutaneous findings of mastocytosis. Despite prior implantation of a dual-chamber cardiac pacemaker 3 weeks previously for similar spells, she experienced a PEA arrest accompanied by flushing, increased urinary N-methylhistamine excretion and serum tryptase values on the day of presentation to our clinic. Bone marrow biopsy findings conducted to rule out breast cancer metastases showed 30% mast cell infiltration, aberrant expression of CD25 and a positive c-kit Asp816Val mutation. Treatment with a combination of H1 and H2 receptor blockers reduced flushing and eliminated hypotension. Maintenance medication included aspirin, cetirizine, ranitidine, montelukast, oral cromolyn sodium and an epinephrine autoinjector (as needed). At 6-month follow-up, the patient remained free of PEA arrests, flushing, or any clinical signs of mastocytosis or mast cell degranulation. PEA cardiac arrests may therefore be a presenting sign of untreated systemic mastocytosis.

Systemic mastocytosis in the elderly.

"Later onset" of systemic mastocytosis (SM) has been associated with a poorer prognosis. We examined clinical and laboratory findings, associated disorders, and survival in an older mastocytosis population. After receiving Mayo Clinic Institutional Review Board approval, we identified 42 patients aged 70 years and older at the time of diagnosis of SM. Associated disorders, cytogenetic abnormalities, laboratory findings, and survival were recorded. Only 10 patients had no associated hematologic disorder. Single or multiple chromosomal abnormalities, exclusive of the KIT Asp816Val mutation, were detected in eight patients (19%). KIT Asp816Val mutation was present in 14 patients, negative in three, and not tested in 25. Slight to marked bone marrow hypercellularity was observed in 33 patients (79%). Concurrent hematologic abnormalities included chronic myelomonocytic leukemia (n = 7), acute myelocytic leukemia (n = 1), myelodysplastic syndrome (MDS; n = 7), eosinophilia (n = 7), myelofibrosis (n = 1), myeloproliferative disorder (n = 1), multiple myeloma (n = 1), B-cell lymphoma (n = 1), and thrombocytopenia (n = 4). Eight patients had a hematologic disorder that preceded the diagnosis of SM. Tryptase levels were elevated in 38 of 39 patients tested. Survival from the diagnosis of SM was poor for patients with associated thrombocytopenia, leukemias, and MDS. In conclusion, patients with SM diagnosed at age 70 or older have an increased risk of secondary hematologic disorders and abnormal laboratory findings. Cytogenetic abnormalities are common, and survival is short in many SM patients with associated leukemias, MDS, or eosinophilia.

Anaphylaxis: Advances in the Past 10 Years.

In the past 10 years, anaphylaxis has grown into its own special area of study within Allergy-Immunology, both at the bench and at the bedside. This review focuses on some of the most clinically relevant advances over the past decade. These include simplified and more inclusive diagnostic criteria for adults and children, uniform definition of biphasic anaphylaxis, and improved systems for objective severity grading. Studies reported in the past decade have led to improved understanding of normal and abnormal regulation of mast cell function, translating into better diagnostic and therapeutic approaches to patients with anaphylaxis. Research has provided improved recognition and treatment of mast cell disorders and has identified a new condition, hereditary α-tryptasemia, that may impact anaphylactic syndromes. We have learned to recognize new causes (α-gal), new pathways (Mas-related G protein-coupled receptor-X2), and many risk factors for severe anaphylaxis. The stability of epinephrine in autoinjectors was reported to be very good for several years after the labeled expiry date, and it can tolerate freezing and thawing. Repeated and prolonged exposure to excessive heat leads to degradation of epinephrine activity. New treatments to prevent severe anaphylaxis have been described, using new ways to block the IgE receptor or modulate intracellular signaling pathways.

Increased numbers of eosinophils, rather than only etiology, predict histologic changes in patients with esophageal eosinophilia.

BACKGROUND & AIMS: It can be a challenge to differentiate individuals with eosinophilic esophagitis (EoE) from those with gastroesophageal reflux disease (GERD). We investigated differences in histologic and eosinophil patterns and numbers of mast cells between patients with these disorders. METHODS: We performed histologic analyses and immunohistochemical assays for eosinophil-derived neurotoxin (EDN), major basic protein (MBP), and tryptase, using biopsy samples from 10 patients with GERD (positive results from a pH study and response to proton pump inhibitors), Barrett's esophagus, or EoE (negative results from a pH study and positive response to budesonide). Patients were matched for degree of eosinophilia. RESULTS: Samples from patients with EoE, GERD, or Barrett's esophagus had similar increases in concentrations of eosinophils. Patients with GERD or EoE did not differ in amount of basal zone hyperplasia, microabscesses, spongiosis, eosinophil distribution, maximum eosinophils/high-power field (HPF), or composite histologic scores. Samples from all 3 groups had high levels of EDN and MBP; the levels of eosinophil products were correlated (ρ = 0.93). Extracellular staining for EDN was greater than intracellular staining (2.67 of 3 vs 1.86 of 3); levels tended to be greater in samples from patients with EoE than GERD (P = .05) or Barrett's esophagus (P = .06). Detection of EDN correlated with peak numbers of eosinophils/HPF (ρ = 0.6 for intracellular and extracellular staining). Peak numbers of tryptase-positive mast cells/HPF were significantly greater in samples from patients with EoE than GERD or Barrett's esophagus (P = .01 and .005, respectively). The Spearman correlation between eosinophil and mast cell density was a ρ value of 0.2. CONCLUSIONS: Biopsy samples from patients with GERD and EoE, matched for esophageal eosinophilia, have similar changes in histology and levels of EDN and MBP, whereas mast cells from patients with EoE have higher levels of these products. The presence of esophageal eosinophils, rather than etiology, could be the most important determinant of epithelial response.

Eosinophilic esophagitis: allergic contribution, testing, and management.

Both basic science and clinical data indicate a strong role for allergy as a cause of eosinophilic esophagitis. As a result, one of the desired goals of therapy is identification and elimination of food antigens that trigger the allergic inflammatory pathway. Traditional methods for identification of causative food antigens include induction of symptoms with exposure to the antigen, demonstration of serum IgE antibodies against antigens and induction of immediate (IgE) or delayed (Th2) reactions against dermal instillation of antigens. Although some data support the use of these tests in patients with eosinophilic esophagitis, they are limited in this disease. This limitation results from an inability to provoke recognizable symptoms and a lack of concordance between allergies identified in the skin and the blood with the antigens that trigger esophageal disease. As a result, allergy therapy in eosinophilic esophagitis consists of global elimination of food antigens with an elemental diet or exclusion of the most common antigens. As compliance is difficult with these strategies, the mainstay of allergy therapy in eosinophilic esophagitis has become the use of medications that blunt the allergic pathway such as steroids with a future aimed toward more specific inhibitors of this pathway in eosinophilic esophagitis specifically.

Eosinophilic gastrointestinal disorders (EGID) with peripheral eosinophilia: a retrospective review at Mayo Clinic.

BACKGROUND AND AIMS: Hypereosinophilic syndrome (HES) is defined by significant eosinophilia (>1,500 eos/µl), which often leads to end-organ damage/dysfunction. It is unclear if the presence of significant peripheral eosinophilia (>1,500 eos/µl) indicates a more aggressive form of eosinophilic gastrointestinal disorder (EGID). METHODS: A database query of the Mayo Clinic Rochester electronic records (1995-2008) was performed using several search terms for eosinophilic gastrointestinal disease, and 161 records were reviewed. Patients under 18 years age, those without Mayo-reviewed pathology specimens, those with eosinophilic esophagitis only, and/or those with evidence of secondary etiologies for GI eosinophilia were excluded. A total of 39 were found to have primary EGID. We compared individuals with biopsy-proven primary EGID based on whether they had significant peripheral eosinophilia (≥1,500 eos/µl) (group A) or not (group B). RESULTS: Group A tended to have more atopy (A: 12/15; B: 11/24; p = 0.03) and more extensive segmental involvement of the GI tract (p = 0.001). None with available studies had evidence of cardiac (A: 7/15; B: 6/24) or bone marrow (A: 10/15; B: 6/24) involvement. The two thromboembolic events in group A after diagnosis did not translate to significantly greater risk (HR = infinity, p = 0.13; group A vs. B). Doses of initial (A: 40 mg/day; B: 55 mg/day; p = 0.17) and maintenance prednisone (A; 8.75 mg/day; B: 7.5 mg/day; p > 0.90) were similar. Group A was significantly more likely to need maintenance prednisone (77 vs. 8%, p = 0.001), with a median treatment duration of 52 weeks. Recurrence of symptoms (and peripheral eosinophilia) during prednisone taper was common in both groups. Prednisone-sparing agents (hydroxyurea, imatinib mesylate, interferon (IFN)-α2b, anti-interleukin (IL-5) monoclonal antibody) were more commonly used in group A (73 vs. 8%; p < 0.0001). CONCLUSIONS: EGID with peripheral eosinophilia ≥1,500/µl is associated with atopy, greater GI segmental involvement, and uncertain risk of thrombosis. The common use of long-term steroids and variable responsiveness to nonsteroidal agents, particularly in group A, underscores the need for targeted therapies.

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.

The Utility of Measuring Urinary Metabolites of Mast Cell Mediators in Systemic Mastocytosis and Mast Cell Activation Syndrome.

Mast cells (MCs) leave evidence of their presence and activation. Aside from increased numbers of MCs in tissues, this evidence includes detecting elevated serum levels of tryptase and discovering increased excretion of urinary metabolites of prostaglandin (PG) D2, leukotriene (LT) C4, and/or histamine. The importance of measuring these nontryptase mediator metabolites has largely gone unnoticed. We reviewed the utility of quantitating urinary levels of MC mediator metabolites in systemic mastocytosis (SM) and MC activation disorders and summarized the relative production of these mediators by MCs and other cell types. Quantitation of urinary n-methyl histamine, 2,3-dinor-11ßPGF2α, and LTE4 offers a simple, noninvasive avenue to monitor their constitutive release as well as contemporaneous discharge during MC activation as well as supporting a diagnosis of SM. These increases can occur independently of or in addition to raised levels of tryptase. Quantitation of these mediator metabolites potentially offers targets for therapeutic intervention. Synthesis of PGD2, a product nearly exclusively of MCs, can be controlled with aspirin, histamine increase by H1 and H2 receptor blockade, and LTC4 by a 5-LO inhibitor or LT receptor antagonist. Although other sources are reported, the increase in MC numbers in SM supports this cell as the predominant origin of all 3 mediators.

Prevention of mast cell activation disorder-associated clinical sequelae of excessive prostaglandin D(2) production.

BACKGROUND: Patients with systemic mastocytosis have increased numbers of mast cells in the bone marrow and other organs, such as the liver, spleen, gastrointestinal tract and skin. Symptoms result from the local and remote effects of mediator release from mast cells and from the local effects of increased mast cell numbers in various organs. Patients with mast cell activation experience many of the same clinical symptoms as do patients with systemic mastocytosis from chronic or spontaneous release of mast cell mediators. We report 4 patients with mast cell activation symptoms from selective release of prostaglandin (PG) D(2), but not histamine, and their improvement with aspirin therapy. METHODS: Bone marrow biopsy specimens obtained from 4 patients with symptoms suggestive of mastocytosis were examined by tryptase immunostaining. Baseline levels of serum tryptase and urinary 11beta-PGF(2)(alpha) and N-methylhistamine were obtained. In 2 of the 4 patients, urinary 11beta-PGF(2)(alpha) and N-methylhistamine samples were also measured during acute symptoms. RESULTS: Baseline increase in urinary excretion of the PGD(2) metabolite 11beta-PGF(2)(alpha) was found in 2 patients. In the remaining 2 patients, baseline levels of urinary 11beta-PGF(2)(alpha) and N-methylhistamine were normal, but during acute symptoms, the excretion of 11beta-PGF(2)(alpha) increased markedly. Treatment with aspirin resulted in normalization of 11beta-PGF(2)(alpha) excretion in the 2 patients with elevated baseline levels and in prevention of symptoms in all 4 patients. CONCLUSIONS: These results suggest that mast cell activation may be manifested by a selective excessive release of PGD(2). These patients respond to administration of aspirin but not to antihistamines.

Eosinophilic esophagitis: is it all allergies?

Eosinophilic esophagitis (EE) is an increasingly recognized disorder in the adult population, most often manifested by symptoms of dysphagia and food impaction. Mechanisms involving eotaxin-3, interleukin 5, and signal transducer and activator of transcription 6 have been studied and may represent future therapeutic targets. Patients commonly have a personal and family history of atopy, and both food allergies and aeroallergens have also been investigated as triggers of EE. Traditional allergy-testing methods, including skin prick testing and specific IgE testing, have been used to identify food and environmental allergies. However, new studies suggest that patch testing could add to diagnostic accuracy in EE because the disorder might not be a classic type I allergic response. Although studies of treatment of adults with EE have thus far focused on swallowed fluticasone proprionate, many trials in children have assessed the efficacy of food elimination and elemental diets. These diets, which have been extremely successful in reducing symptoms, have also been shown to induce histological improvement and remission. No similar studies have been conducted in adults; the tolerability of such an intervention may prove more difficult in this population. This article reviews the underlying pathophysiology of EE and describes evolving options for more accurately identifying food and environmental allergies. We also discuss the pediatric trials using food elimination and avoidance diets and suggest that this type of intervention may be an important area of future research in the adult population.

Hypereosinophilic syndrome: endomyocardial biopsy versus echocardiography to diagnose cardiac involvement.

OBJECTIVE: To compare echocardiograms and endomyocardial biopsies to diagnose cardiac involvement in hypereosinophilic syndrome. METHODS: We examined the agreement between echocardiography and endomyocardial biopsies to detect cardiac involvement in hypereosinophilic syndrome by reviewing cases identified as hypereosinophilia or hypereosinophilic syndrome in Mayo Clinic databases from January 1978 through June 2009. Single-organ cases of eosinophilia such as eosinophilic fasciitis and eosinophilic gastroenteritis were excluded. We recorded echocardiogram and endomyocardial biopsy results including biopsy staining for eosinophil granule major basic protein (if performed). Clinical and laboratory features documented included presenting symptom(s), maximum total eosinophil count, dose of prednisone (if any) and eosinophil count at the time of endomyocardial biopsy, cardiac enzymes, serum tryptase level, electrocardiogram result, the result of testing for the FIP1L1-PDGFRA fusion gene, complications associated with the biopsy procedures and available follow-up information. RESULTS: From a total of 387 patients' records screened 288 met the criteria for hypereosinophilic syndrome and of these 240 had echocardiograms. Among these patients there were 138 normal echocardiograms, 67 had echocardiograms without findings of hypereosinophilic syndrome but with one or more other abnormalities, and 35 had echocardiograms with findings consistent with hypereosinophilic syndrome. Twenty-five patients from this group of 35 patients had both echocardiogram and endomyocardial biopsy. In 15 patients there was agreement between both endomyocardial biopsy and echocardiography as to the presence (n = seven) or absence (n = eight) for findings of cardiac involvement. In 10 of 25 patients test results diverged: 3 patients with positive echocardiographic changes did not have confirmatory findings by endomyocardial biopsy and seven patients with positive biopsy findings had echocardiograms without findings of hypereosinophilic syndrome. CONCLUSIONS: Echocardiograms and endomyocardial biopsies agree for presence or absence of cardiac involvement 60% of the time. Endomyocardial biopsy detected cardiac involvement in 7 patients in whom the echocardiogram was negative for findings of hypereosinophilic syndrome.

Genetic test indications and interpretations in patients with hereditary angioedema.

Patients with hereditary angioedema (HAE) present with recurrent, circumscribed, and self-limiting episodes of tissue or mucous membrane swelling caused by C1-inhibitor (CI-INH) deficiency. The estimated frequency of HAE is 1:50,000 persons. Distinguishing HAE from acquired angioedema (AAE) facilitates therapeutic interventions and family planning or testing. Patients with HAE benefit from treatment with attenuated androgen, antifibrinolytic agents, and C1-INH concentrate replacement during acute attacks. HAE is currently recognized as a genetic disorder with autosomal dominant transmission. Other forms of inherited angioedema that are not associated with genetic mutations have also been identified. Readily available tests are complement studies, including C4 and C1-esterase inhibitor, both antigenic and functional C1-INH. These are the most commonly used tests in the diagnosis of HAE. Analysis of C1q can help differentiate between HAE and AAE caused by C1-INH deficiency. Genetic tests would be particularly helpful in patients with no family history of angioedema, which occurs in about half of affected patients, and in patients whose C1q level is borderline and does not differentiate between HAE and AAE. Measuring autoantibodies against C1-INH also would be helpful, but the test is available in research laboratories only. Simple complement determinations are appropriate for screening and diagnosis of the disorder.

Tolerance and Efficacy with Simultaneous Use of Two Monoclonal Antibodies for a Patient with Hypereosinophilic Syndrome and Ulcerative Colitis.

The development and utilization of monoclonal antibodies (mAbs) have been of great interest in all fields of medicine. A substantial increase in the production and development of mAbs has occurred because these biologic agents are proving to be effective and less toxic given their targeted mechanism of action. However, data are limited on coadministration of two or more mAbs. With the increasing availability of mAbs and the comorbidities of some patients, assessment is needed of the ability to safely use multiple mAbs for an individual patient. Although the efficacy of coadministered mAbs may be inferred from their specific targets, we could find no literature reporting such a finding. Herein, we report our experience using two different classes of mAbs to treat hypereosinophilic syndrome and ulcerative colitis in a single patient.

Common variable immunodeficiency: test indications and interpretations.

Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder that can present with multiple phenotypes, all of which are characterized by hypogammaglobulinemia, in a person at any age. A specific genetic defect that accounts for all CVID phenotypes has not been identified, and it is likely that several distinct genetic disorders with similar clinical presentations are responsible for the observed variation. In this review, we summarize the known genetic mutations that give rise to hypogammaglobulinemia and how these gene products affect normal or abnormal B-cell development and function, with particular emphasis on CVID. Additionally, we describe specific phenotypic and genetic laboratory tests that can be used to diagnose CVID and provide guidelines for test interpretation and subsequent therapeutic intervention.