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.

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.

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.

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.

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.

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.

Hematologic Malignancies Identified in Patients with Hypereosinophilia and Hypereosinophilic Syndromes.

BACKGROUND: Certain hematologic malignancies are associated with hypereosinophilia or tissue eosinophilia. It is unclear if patients with hypereosinophilia are more likely to develop one of these malignancies. OBJECTIVE: This study sought to quantify the specific hematologic malignancies that developed in patients with preexisting hypereosinophilia. METHODS: Adult patients with eosinophilia associated with the development of hematologic malignancy were identified by a retrospective review of the Mayo Clinic patient database between 2000 and 2013. RESULTS: Of 2642 patients identified with eosinophilia, hypereosinophilia, or hypereosinophilic syndrome, 25 (aged 28.8 to 86.1 years; 13 male; 12 female) had a diagnosis of either lymphoma or leukemia. The majority of these patients had non-Hodgkin lymphoma (17 of 25). T-cell-derived lymphomas were more common (12 of 17) than B-cell-derived lymphomas (4 of 17). In patients with leukemia (8 of 25), chronic lymphocytic leukemia (4 of 8) was most common, followed by chronic eosinophilic leukemia (3 of 8). Approximately 5.1% of patients with hypereosinophilia developed a hematologic malignancy. On average, the malignancy developed 30.0 ± 42.7 months after the onset of hypereosinophilia. CONCLUSIONS: The development of hematologic malignancies in this referral population with eosinophilia was rare (0.2%), but more common in those with hypereosinophilia (5.1%). Non-Hodgkin's lymphomas, particularly T-cell-derived malignancies, were most commonly diagnosed. Patients with preexisting hypereosinophilia were diagnosed with hematologic conditions that were rarer within the general population.

Mast cell activation syndrome: improved identification by combined determinations of serum tryptase and 24-hour urine 11ß-prostaglandin2α.

BACKGROUND: Mast cell activation syndrome (MCAS) describes patients with episodes of mast cell mediator release, with negative bone marrow biopsy results, and the failure to meet the criteria for systemic mastocytosis. OBJECTIVE: Identify elevation of mast cell mediators of patients with MCAS. METHODS: We performed a retrospective study of 25 patients with MCAS who were evaluated at Mayo Clinic from 2006 to 2012. Patients were reviewed for MCAS symptoms and mast cell mediators, including serum tryptase and 24-hour urine N-methyl histamine (N-MH) and 11ß-prostaglandin-F2α (11ß-PGF2α). The study was approved by the institutional review board. RESULTS: Urinary 11ß-PGF2α was the most frequently elevated product in MCAS of our 25-patient cohort. Flushing and pruritus had the greatest correlation with elevation of 24-hour urine 11ß-PGF2α value at baseline. The serum tryptase level was elevated in 10 patients, whereas the N-MH level was elevated with 2 patients. Eight of 9 patients with MCAS and with elevated 24-hour urine 11ß-PGF2α who underwent aspirin therapy and follow-up urinary studies had normalization of this mediator (1 patient did not have a follow-up urine study). Six of these 9 patients with MCAS who underwent aspirin therapy had symptomatic improvement. CONCLUSION: We recommend measurement of 24-hour urine 11ß-PGF2α and serum tryptase levels of patients with symptoms suggestive of MCAS. Measurement of 24-hour urine 11ß-PGF2α and serum tryptase levels can help avoid misdiagnosis and overinterpretation of MCAS symptoms in clinical practice. Given that an elevation of 24-hour urine N-MH level was found only in 2 patients, measurement of this mediator may be less helpful in diagnosing MCAS. We recommend aspirin therapy for patients with MCAS and with elevated 24-hour urine 11ß-PGF2α levels.

Mast cell sarcoma: clinical management.

Mast cell sarcoma is a disorder that results in abnormal mast cells as identified by morphology, special stains, and in some publications, c-kit mutation analysis. It affects animal species such as canines more commonly than humans. In humans it is a very rare condition, with variable clinical presentation. There is no standard therapy for the disorder. It can affect any age group. It is occasionally associated with systemic mastocytosis and/or urticaria pigmentosa. The prognosis of mast cell sarcoma in published literature is very poor in humans.

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.

The Melkersson-Rosenthal syndrome: a retrospective study of biopsied cases.

Melkersson-Rosenthal syndrome (MRS) is a rare neuromucocutaneous syndrome marked by the triad of recurrent nonpitting orofacial edema, fissured dorsal tongue (lingua plicata), and lower motoneuron facial paralysis. Large case series including treatment are limited. A retrospective records review was performed for the diagnoses Melkersson-Rosenthal syndrome, granulomatous cheilitis, and orofacial granulomatosis, confirmed by noncaseating granulomas on biopsy, at the Mayo Clinic in Rochester, Minnesota (1979-2009). There were 72 patients [51 women (71 %), mean age at presentation 39 years (range 8-79)] identified with facial edema with noncaseating granulomas on skin biopsy. Lingua plicata occurred in 34 cases (47 %, 95 % confidence interval 35.3-59.3 %). Unilateral or partial facial nerve palsy occurred in 14 cases (19.4, 95 % confidence interval 11.4-30.8 %). Comorbidities among those with facial edema included periodontal disease (n = 10, 14 %), history of allergic disease (n = 10, 14 %), Crohn's Disease (n = 6, 8 %), migraine headaches (n = 5, 7 %), and systemic lupus erythematosus (n = 2, 3 %). There were no patients who had low C1q or C4 levels among those who were tested. Overall, the full triad canonical of Melkersson-Rosenthal syndrome was observed in nine patients (seven female, median age at symptomatic presentation 35 years (range 10-74 years), 13 %, (95 % confidence interval 6.2-22.9 %) with a median time from first symptoms to diagnosis of 4 years (range 1-35). The medication treatments attempted in the nine patients with the full triad of symptoms included non-steroidal anti-inflammatory drugs, oral and intra-lesional steroids, metronidazole, dapsone, acyclovir, methotrexate, and thalidomide with no consistent treatment responses. The Melkersson-Rosenthal syndrome may present over the course of most of the lifespan and may require several years of observation to be diagnosed. Neurologists who observe a combination of facial edema and facial palsy in a patient should consider the diagnosis of MRS and proceed to a diagnostic skin biopsy and a trial of steroid treatment for their patient.

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.