Assessment of low immunoglobulin levels and clinical manifestations in patients with mastocytosis.

Background: Patients with a low IgG level alone or with low IgA or IgM levels have been reported to be susceptible to respiratory tract infections and recurrent sinusitis. Patients diagnosed with CVID have a higher prevalence of autoimmune diseases and lymphoid malignancies. Mastocytosis is a myeloproliferative disease, not typically associated with autoimmune disease or frequent infections. Objective: We sought to determine the distribution of immunoglobulins in children and adults with mastocytosis. Evaluate the impact of low immunoglobulins on the clinical management of patients with mastocytosis. Methods: We performed a 10-year retrospective analysis on 320 adult and pediatric patients with mastocytosis for immunoglobulins using an electronic medical query. We identified 25 adults and 9 children with one or more low immunoglobulins. Patient records were examined for a history of infections and autoimmune disorders. Results: Serum immunoglobulins in children and adults with mastocytosis fell within a normal range. Among patients with low IgG levels alone or with low IgM and /or IgA, 20% had a history of infections and 20% of adults had autoimmune disorders. The most common infection was recurrent otitis media (OM). Conclusion: Patients with mastocytosis typically have normal immunoglobulins. With few exceptions, those with low immunoglobulins did not have frequent infections or autoimmune diseases. This data supports the conclusion that routine determination of immunoglobulins in patients with mastocytosis is not required and reserved for patients with clinical conditions, which might be related to an immunoglobulin deficiency.

Assessment of Osteoporosis and Fracture Risk in Mastocytosis within a North American Cohort.

BACKGROUND: Systemic mastocytosis (SM), a clonal expansion of mast cells affecting multiple organs including the skeletal system, puts patients at risk for osteoporosis and fractures. Various aspects of skeletal disease in SM have been reported among European cohorts. OBJECTIVE: To determine fracture prevalence and risk predictors in SM in a North American (NA) cohort and compare findings with studies of other populations. METHODS: Fifty patients, aged 25-74 years, were grouped based on fracture type and history. Data collected included laboratory findings and radiographic markers such as serum tryptase, bone turnover markers, dual-energy x-ray absorptiometry images, and trabecular bone scores. We performed univariate and multivariate analyses of these findings. RESULTS: Fracture history was found in 74% of patients. Significantly different median age, body mass index, dual-energy x-ray absorptiometry scores, and alkaline phosphatase levels were observed between fracture groups, consistent with French and Dutch studies. Significant findings included the difference in trabecular bone scores among fracture groups, the association between alkaline phosphatase and fracture type and occurrence, and the model for predicting fracture risk based on DXA spine T-scores, alkaline phosphatase, and age (81.3% accuracy and 77.1% sensitivity). CONCLUSIONS: Our findings in an NA cohort are in overall agreement with those reported in European studies of skeletal disease and fracture risk for individuals with SM. We include an interactive calculator designed from a predictive model based on the NA cohort, which may be used for improved screening for fracture risk.

An optimized protocol for the generation and functional analysis of human mast cells from CD34+ enriched cell populations.

The culture of mast cells from human tissues such a cord blood, peripheral blood or bone marrow aspirates has advanced our understanding of human mast cells (huMC) degranulation, mediator production and response to pharmacologic agents. However, existing methods for huMC culture tend to be laborious and expensive. Combining technical approaches from several of these protocols, we designed a simplified and more cost effective approach to the culture of mast cells from human cell populations including peripheral blood and cryopreserved cells from lymphocytapheresis. On average, we reduced by 30-50 fold the amount of culture media compared to our previously reported method, while the total MC number generated by this method (2.46±0.63×106 vs. 2.4±0.28×106, respectively, from 1.0×108 lymphocytapheresis or peripheral blood mononuclear blood cells [PBMCs]) was similar to our previous method (2.36±0.70×106), resulting in significant budgetary savings. In addition, we compared the yield of huMCs with or without IL-3 added to early cultures in the presence of stem cell factor (SCF) and interlukin-6 (IL-6) and found that the total MC number generated, while higher with IL-3 in the culture, did not reach statistical significance, suggesting that IL-3, often recommended in the culture of huMCs, is not absolutely required. We then performed a functional analysis by flow cytometry using standard methods and which maximized the data we could obtain from cultured cells. We believe these approaches will allow more laboratories to culture and examine huMC behavior going forward.

Assessment of clinical findings, tryptase levels, and bone marrow histopathology in the management of pediatric mastocytosis.

BACKGROUND: The management of children with pediatric mastocytosis poses a challenge. This is because there is limited information as to the application of clinical and laboratory findings and bone marrow histopathology as they relate to medical intervention and communication. OBJECTIVE: We sought to examine clinical aspects of pediatric mastocytosis in relationship to serum tryptase levels and bone marrow pathology to provide practical guidance for management. METHODS: Between 1986 and 2012, 105 children were evaluated at the National Institutes of Health. Organomegaly was confirmed by means of ultrasound. Baseline tryptase levels and at least 1 subsequent tryptase measurement was available in 84 and 37 of these children, respectively. Fifty-three children underwent a bone marrow examination. These data were used to examine relationships between clinical findings, tryptase levels, and marrow histopathology. RESULTS: In patients with high tryptase levels and severe mediator symptoms, all with organomegaly had systemic disease, and none without organomegaly had systemic disease. Serum tryptase levels differed significantly between patients with urticaria pigmentosa and those with diffuse cutaneous (P < .0001) and systemic mastocytosis (P < .0001) and in all 3 categories versus control subjects (P < .0001). Tryptase levels and symptoms decreased over time in most patients, and tryptase levels correlated with bone marrow mast cell burden in patients with systemic mastocytosis (P < .0001). There was a significant relationship between clinical resolution and the percentage decrease in tryptase levels (P = .0014). CONCLUSIONS: The majority of children experienced major or complete disease resolution (57%), whereas the remainder exhibited partial improvement. Organomegaly was a strong indicator of systemic disease. Serum tryptase levels furthered classification and reflected clinicopathologic findings, while sequential tryptase measurements were useful in supplementing clinical judgment as to disease course.

Risk assessment in anaphylaxis: current and future approaches.

Risk assessment of individuals with anaphylaxis is currently hampered by lack of (1) an optimal and readily available laboratory test to confirm the clinical diagnosis of an anaphylaxis episode and (2) an optimal method of distinguishing allergen-sensitized individuals who are clinically tolerant from those at risk for anaphylaxis episodes after exposure to the relevant allergen. Our objectives were to review the effector mechanisms involved in the pathophysiology of anaphylaxis; to explore the possibility of developing an optimal laboratory test to confirm the diagnosis of an anaphylaxis episode, and the possibility of improving methods to distinguish allergen sensitization from clinical reactivity; and to develop a research agenda for risk assessment in anaphylaxis. Researchers from the American Academy of Allergy, Asthma & Immunology and the European Academy of Allergology and Clinical Immunology held a PRACTALL (Practical Allergy) meeting to discuss these objectives. New approaches being investigated to support the clinical diagnosis of anaphylaxis include serial measurements of total tryptase in serum during an anaphylaxis episode, and measurement of baseline total tryptase levels after the episode. Greater availability of the test for mature beta-tryptase, a more specific mast cell activation marker for anaphylaxis than total tryptase, is needed. Measurement of chymase, mast cell carboxypeptidase A3, platelet-activating factor, and other mast cell products may prove to be useful. Consideration should be given to measuring a panel of mediators from mast cells and basophils. New approaches being investigated to help distinguish sensitized individuals at minimum or no risk from those at increased risk of developing anaphylaxis include measurement of the ratio of allergen-specific IgE to total IgE, determination of IgE directed at specific allergenic epitopes, measurement of basophil activation markers by using flow cytometry, and assessment of allergen-specific cytokine responses. Algorithms have been developed for risk assessment of individuals with anaphylaxis, along with a research agenda for studies that could lead to an improved ability to confirm the clinical diagnosis of anaphylaxis and to identify allergen-sensitized individuals who are at increased risk of anaphylaxis.

Assessment of the extent of cutaneous involvement in children and adults with mastocytosis: relationship to symptomatology, tryptase levels, and bone marrow pathology.

BACKGROUND: Cutaneous involvement occurs in most patients with systemic mastocytosis. OBJECTIVE: We sought to determine whether the extent of cutaneous involvement is predictive of systemic disease. METHODS: In a prospective survey of 48 adults and 19 children, the extent and density of cutaneous lesions were compared with patient history, symptoms, internal organ involvement, serum total mast cell tryptase level, and bone marrow pathology. RESULTS: Cutaneous lesions in children were of a greater mean and maximum diameter, but similar in extent and density compared with lesions in adults. In adults with skin lesions, the extent of lesions correlated to disease duration. Adults with extensive cutaneous disease experienced more pruritus and flushing. Fatigue, splenomegaly, and hepatomegaly were more frequent in adults without cutaneous involvement; and in those with a greater density of lesions and disease duration. Increased tryptase levels were found in children and adults with systemic disease and correlated to skin lesion density and bone marrow pathology. CONCLUSION: An examination of the extent and density of cutaneous lesions in adults helps identify those with more extensive extracutaneous disease and, thus, requiring a more thorough evaluation.