Rationale: Reducing asthma exacerbation frequency is an important criterion for approval of asthma therapies, but the clinical features of exacerbation-prone asthma (EPA) remain incompletely defined.Objectives: To describe the clinical, physiologic, inflammatory, and comorbidity factors associated with EPA.Methods: Baseline data from the NHLBI Severe Asthma Research Program (SARP)-3 were analyzed. An exacerbation was defined as a burst of systemic corticosteroids lasting 3 days or more. Patients were classified by their number of exacerbations in the past year: none, few (one to two), or exacerbation prone (>3). Replication of a multivariable model was performed with data from the SARP-1 1 2 cohort.Measurements and Main Results: Of 709 subjects in the SARP-3 cohort, 294 (41%) had no exacerbations and 173 (24%) were exacerbation prone in the prior year. Several factors normally associated with severity (asthma duration, age, sex, race, and socioeconomic status) did not associate with exacerbation frequency in SARP-3; bronchodilator responsiveness also discriminated exacerbation proneness from asthma severity. In the SARP-3 multivariable model, blood eosinophils, body mass index, and bronchodilator responsiveness were positively associated with exacerbation frequency (rate ratios [95% confidence interval],

The phenotypic features of asthma differ by severity and with advancing age. With advancing age, patients with severe asthma are more obese, have greater airflow limitation, less allergen sensitization, and variable type 2 inflammation. Novel mechanisms besides type 2 inflammatory pathways may inform the severe asthma phenotype with advancing age.

Both human and mouse c-kit ligand induced differentiation of human mast cells in a long-term culture ofthe mononuclear cells of umbilical cord blood. Growth factor activity for human mast cells present in conditioned medium of BALB/3T3 fibroblasts was due to mouse c-kit ligand. Recombinant c-kit ligand induced differentiation and proliferation of mast cell progenitors in early stages of culture. However, apparent selective growth of mast cells by c-kit ligand in cord blood cell cultures is mainly due to the effect of the cytokine to selectively maintain survival of immature mast cells. Electron microscopic analysis indicated that human mast cells developed by c-kit ligand were similar to human mast cells in the lung and gut mucosa, while those developed in coculture of cord blood cells with Swiss albino/3T3 fibroblasts were similar to skin mast cells. This conclusion was supported by the fact that the majority of mast cells developed by c-kit ligand contained only tryptase in their granules, whereas those developed in the cocultures contained both tryptase and chymase. It was also found that mast cells developed by c-kit ligand were immature even after culture for 14 weeks. Nevertheless, these cells express FceRI, and could be sensitized with human IgE for anti-IgE-induced release of histamine, prostaglandin D2, and leukotriene C4.Several murine cytokines, such as interleukin (IL)-3, IL4, IL-9, and IL-10 promote differentiation and proliferation of mouse mast cells (1-4). In contrast, reproducible growth of human mature mast cells had not been achieved until 1989, when we succeeded in developing morphologically and functionally mature human mast cells in a long-term coculture of mononuclear cells of cord blood with Swiss albino/3T3 fibroblasts (5). Subsequent studies revealed that the culture supernatant of 3T3 fibroblasts contained growth factors that promote differentiation of human mast cells (6). Human mast cell growth-promoting activity could be enriched by fractionation of the culture supernatant with ammonium sulfate precipitation and by ion-exchange chromatography. The molecular size of the factor was estimated by gel filtration to be between 70 and 100 kDa (7).While our studies were in progress, a cytokine, c-kit ligand, was characterized and molecular cloning of the cytokine has been accomplished by several groups of investigators (8)(9)(10)(11)(12). The present experiments show that both human and murine c-kit ligand induce differentiation of cord blood cells to human mast cells in culture and provide evidence that human mast cell growth-promoting activity in culture supernatants of 3T3 fibroblasts is associated with murine c-kit ligand. MATERIALS AND METHODSCell Cutures and Microscopic Examination. Mononuclear cells were obtained from heparinized umbilical cord blood (5) and suspended in RPMI 1640 medium (GIBCO) supplemented with 10%o fetal bovine serum (FBS; GIBCO), 50 ,M 2-mercaptoethanol, 2 mM L-glutamine, 100 units of penicillin per ml, 50 ,ug of streptomycin per ml, and 25 ,ug of gentami...

Biomarkers of disease activity have come into wide use in the study of mechanisms of human disease and in clinical medicine to both diagnose and predict disease course; as well as to monitor response to therapeutic intervention. Here we review biomarkers of the involvement of mast cells, basophils, and eosinophils in human allergic inflammation. Included are surface markers of cell activation as well as specific products of these inflammatory cells that implicate specific cell types in the inflammatory process and are of possible value in clinical research as well as within decisions made in the practice of allergy-immunology.