Daly Cantave

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.

A distinct biomolecular profile identifies monoclonal mast cell disorders in patients with idiopathic anaphylaxis

Background: Clonal mast cell disorders are known to occur in a subset of patients with systemic reactions to Hymenoptera stings. This observation has prompted the question of whether clonal mast cell disorders also occur in patients with idiopathic anaphylaxis (IA). Objective: We sought to determine the prevalence of clonal mast cell disorders among patients with IA, criteria to identify those patients who require a bone marrow biopsy, and whether the pathogenesis of IA involves a hyperresponsive mast cell compartment. Methods: We prospectively enrolled patients with IA (≥3 episodes/y) who then underwent a medical evaluation that included a serum tryptase determination, allele‐specific quantitative PCR (ASqPCR) for the KIT D816V mutation, and a bone marrow examination. Mast cells were cultured from peripheral blood CD34+ cells and examined for releasability after Fc&egr;RI aggregation. Results: Clonal mast cell disease was diagnosed in 14% of patients referred with IA. ASqPCR for the KIT D816V mutation was a useful adjunct in helping identify those with systemic mastocytosis but not monoclonal mast cell activation syndrome. A modified overall clonal prediction model was developed by using clinical findings, a serum tryptase determination, and ASqPCR. There was no evidence of a hyperresponsive mast cell phenotype in patients with IA. Conclusion: Patients with clonal mast cell disease can present as having IA. Distinct clinical and laboratory features can be used to select those patients more likely to have an underlying clonal mast cell disorder (monoclonal mast cell activation syndrome or systemic mastocytosis) and thus candidates for a bone marrow biopsy.

Identification and analysis of peanut-specific effector T and regulatory T cells in children allergic and tolerant to peanut

Background Peanut allergy (PA) is potentially life‐threatening and generally persists for life. Recent data suggest the skin might be an important route of initial sensitization to peanut, whereas early oral exposure to peanut is protective. In mice regulatory T (Treg) cells are central to the development of food tolerance, but their contribution to the pathogenesis of food allergy in human subjects is less clear. Objective We sought to quantify and phenotype CD4+ peanut‐specific effector T (ps‐Teff) cells and peanut‐specific regulatory T (ps‐Treg) cells in children with and without PA or PS. Methods ps‐Teff and ps‐Treg cells were identified from peripheral blood of children with PA, children with PS, and nonsensitized/nonallergic (NA) school‐aged children and 1‐year‐old infants based on upregulation of CD154 or CD137, respectively, after stimulation with peanut extract. Expression of cytokines and homing receptors was evaluated by using flow cytometry. Methylation at the forkhead box protein 3 (FOXP3) locus was measured as a marker of Treg cell stability. Results Differential upregulation of CD154 and CD137 efficiently distinguished ps‐Teff and ps‐Treg cells. A greater percentage of ps‐Teff cells from infants with PA and infants with PS expressed the skin‐homing molecule cutaneous lymphocyte antigen, suggesting activation after exposure through the skin, compared with NA infants. Although ps‐Teff cells in both school‐aged and infant children with PA produced primarily TH2 cytokines, a TH1‐skewed antipeanut response was seen only in NA school‐aged children. The frequency, homing receptor expression, and stability of ps‐Treg cells in infants and school‐aged children were similar, regardless of allergic status. Conclusions Exposure to peanut through the skin can prime the development of TH2 ps‐Teff cells, which promote sensitization to peanut, despite the presence of normal numbers of ps‐Treg cells. Graphical abstract Figure. No Caption available.