A randomized double-blind, placebo-controlled study of omalizumab for idiopathic anaphylaxis.

BACKGROUND: Idiopathic anaphylaxis (IA) is a diagnosis of exclusion, thus taking away the option of therapeutic management focused on eliminating the inciting agent. Epinephrine and antihistamines followed by systemic corticosteroids are the mainstays of therapy for acute events. There is no prophylactic therapy that reliably prevents anaphylaxis. OBJECTIVE: We sought to determine the efficacy of omalizumab in the management of patients with frequent episodes of IA in a double-blind, placebo-controlled trial. METHODS: We prospectively enrolled 19 patients with frequent IA (≥6 episodes/y) who then underwent a medical evaluation that included a serum tryptase determination, mutational analysis for KIT D816V, and bone marrow evaluation to rule out a clonal mast cell disorder. Computer-generated random numbers were provided by the study pharmacist. The primary end point was anaphylactic events in the 6 months after baseline. Sixteen patients completed the primary trial. RESULTS: No statistically significant difference was demonstrated between the placebo and treated groups. There was a trend for efficacy in the treatment group, particularly after 60 days. Overall, the safety profile was favorable without long-term side effects. CONCLUSIONS: Omalizumab was safely administered to a difficult-to-treat patient population with IA. The efficacy results trended modestly in favor of the treatment group, but no statistically significant differences were detected.

Vibratory Urticaria Associated with a Missense Variant in ADGRE2.

Patients with autosomal dominant vibratory urticaria have localized hives and systemic manifestations in response to dermal vibration, with coincident degranulation of mast cells and increased histamine levels in serum. We identified a previously unknown missense substitution in ADGRE2 (also known as EMR2), which was predicted to result in the replacement of cysteine with tyrosine at amino acid position 492 (p.C492Y), as the only nonsynonymous variant cosegregating with vibratory urticaria in two large kindreds. The ADGRE2 receptor undergoes autocatalytic cleavage, producing an extracellular subunit that noncovalently binds a transmembrane subunit. We showed that the variant probably destabilizes an autoinhibitory subunit interaction, sensitizing mast cells to IgE-independent vibration-induced degranulation. (Funded by the National Institutes of Health.).

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.

Detection of KIT D816V in peripheral blood of children with manifestations of cutaneous mastocytosis suggests systemic disease.

The use of allele-specific quantitative polymerase chain reaction to identify KIT D816V in the peripheral blood of adults with mastocytosis has been reported to have value in the diagnosis, assessment of disease burden and management of this disease. To examine the value of this assay in children with cutaneous manifestations of mastocytosis, we assessed data on 65 patients with all variants of paediatric-onset mastocytosis, including those known to have systemic disease, to correlate KIT mutation status with clinical findings, serum tryptase levels and bone marrow histopathology. We found that KIT D816V was not identified in the peripheral blood of children known to have only cutaneous disease (specificity 100%) but was found in those known to have both cutaneous and systemic/probable systemic disease (sensitivity of 85·2%). These findings were the basis of the development of an algorithm to assist in the decision for when to perform a bone marrow biopsy in children presenting with cutaneous manifestations of mastocytosis.

Hematopoietic prostaglandin D synthase defines a proeosinophilic pathogenic effector human T(H)2 cell subpopulation with enhanced function.

BACKGROUND: IL-5(+) pathogenic effector T(H)2 (peT(H)2) cells are a T(H)2 cell subpopulation with enhanced proinflammatory function that has largely been characterized in murine models of allergic inflammation. OBJECTIVE: We sought to identify phenotype markers for human peT(H)2 cells and characterize their function in patients with allergic eosinophilic inflammatory diseases. METHODS: Patients with eosinophilic gastrointestinal disease (EGID), patients with atopic dermatitis (AD), and nonatopic healthy control (NA) subjects were enrolled. peT(H)2 and conventional T(H)2 (cT(H)2) cell phenotype, function, and cytokine production were analyzed by using flow cytometry. Confirmatory gene expression was measured by using quantitative RT-PCR. Prostaglandin D2 levels were measured with ELISA. Gut T(H)2 cells were obtained by means of esophagogastroduodenoscopy. RESULTS: peT(H)2 cells were identified as chemoattractant receptor-homologous molecule expressed on T(H)2 cells-positive (CRTH2(+)), hematopoietic prostaglandin D synthase-positive CD161(hi) CD4 T cells. peT(H)2 cells expressed significantly greater IL-5 and IL-13 than did hematopoietic prostaglandin D synthase-negative and CD161(-) cT(H)2 cells. peT(H)2 cells were highly correlated with blood eosinophilia (r = 0.78-0.98) and were present in 30- to 40-fold greater numbers in subjects with EGID and those with AD versus NA subjects. Relative to cT(H)2 cells, peT(H)2 cells preferentially expressed receptors for thymic stromal lymphopoietin, IL-25, and IL-33 and demonstrated greater responsiveness to these innate pro-TH2 cytokines. peT(H)2 but not cT(H)2 cells produced prostaglandin D2. In patients with EGID and those with AD, peT(H)2 cells expressed gut- and skin-homing receptors, respectively. There were significantly greater numbers of peT(H)2 cells in gut tissue from patients with EGID versus NA subjects. CONCLUSION: peT(H)2 cells are the primary functional proinflammatory human T(H)2 cell subpopulation underlying allergic eosinophilic inflammation. The unambiguous phenotypic identification of human peT(H)2 cells provides a powerful tool to track these cells in future pathogenesis studies and clinical trials.

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.

sCD14 and Intestinal Fatty Acid Binding Protein Are Elevated in the Serum of Patients With Idiopathic Anaphylaxis.

BACKGROUND: Intestinal epithelial integrity compromise has been identified in gastrointestinal (GI), atopic, and autoimmune diseases. OBJECTIVE: Episodes of idiopathic anaphylaxis (IA) are often accompanied by GI manifestations. We, therefore, sought to determine whether surrogate markers of GI permeability were aberrant in this patient population. METHODS: Serum concentrations of zonulin, intestinal fatty acid binding protein (I-FABP), and soluble CD14 (sCD14) measured in 54 patients with IA were compared with concentrations in healthy controls (HCs); and correlated with clinical and laboratory parameters. RESULTS: The I-FABP was elevated in sera of patients with IA compared with HCs (median 1,378.0 pg/mL vs 479.0 pg/mL, respectively; P < .001). The sCD14 was also elevated compared with HCs (median 2,017.0 ng/mL and 1,189.0 ng/mL, respectively; P < .001), whereas zonulin was comparable between patients with IA and HCs (median 49.6 ng/mL vs 52.4 ng/mL, respectively; P = .40). The I-FABP was elevated in patients with IA who experienced vomiting and/or diarrhea compared with patients with IA who did not (P = .0091). CONCLUSIONS: The I-FABP and sCD14 are elevated in the serum of patients with IA. Elevations in these biomarkers of IA provides evidence that increased GI permeability, as is observed in other allergic conditions such as food allergy, is a common finding in those with IA and offers possible insight into the pathogenesis of this disease.