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Rationale: Low vitamin D levels are associated with asthma and decreased airway responsiveness. Treatment with inhaled corticosteroids improves airway responsiveness and asthma control., Objectives: To assess the effect of vitamin D levels on prebronchodilator FEV(1), bronchodilator response, and responsiveness to methacholine (PC(20), provocative concentration of methacholine producing a 20% decline in FEV(1)) in patients with asthma treated with inhaled corticosteroids., Methods: We measured 25-hydroxyvitamin D levels in the serum of children with persistent asthma at the time of enrollment in the Childhood Asthma Management Program. We divided subjects into the vitamin D sufficiency (>30 ng/ml), insufficiency (20-30 ng/ml), and deficiency (<20 ng/ml) groups. Covariates included age, treatment, sex, body mass index, race, history of emergency department visits, hospitalizations, and season that vitamin D specimen was drawn. Our main outcome measures were change in prebronchodilator FEV(1), bronchodilator response, and PC(20) from enrollment to 8-12 months., Measurements and Main Results: Of the 1,024 subjects, 663 (65%) were vitamin D sufficient, 260 (25%) were insufficient, and 101 (10%) were deficient. Vitamin D-deficient subjects were more likely to be older, African American, and have a higher body mass index compared with the vitamin D-sufficient and insufficient subjects. In the inhaled corticosteroid treatment group, prebronchodilator FEV(1) increased from randomization to 12 months by 140 ml in the vitamin D-deficient group and prebronchodilator FEV(1) increased by 330 ml in the vitamin D insufficiency group and by 290 ml in the vitamin D sufficiency group (P = 0.0072), in adjusted models., Conclusions: In children with asthma treated with inhaled corticosteroids, vitamin D deficiency is associated with poorer lung function than in children with vitamin D insufficiency or sufficiency.

Rationale: Polymorphisms in the gene for transforming growth factor-beta1 (TGFB1) have been associated with asthma, but not with airway responsiveness or disease exacerbations in subjects with asthma., Objectives: To test for association between single nucleotide polymorphisms (SNPs) in TGFB1 and markers of asthma severity in childhood., Methods: We tested for the association between nine SNPs in TGFB1 and indicators of asthma severity (lung function, airway responsiveness, and disease exacerbations) in two cohorts: 416 Costa Rican parent-child trios and 465 families of non-Hispanic white children in the Childhood Asthma Management Program (CAMP). We also tested for the interaction between these polymorphisms and exposure to dust mite allergen on asthma severity., Measurements and Main Results: The A allele of promoter SNP rs2241712 was associated with increased airway responsiveness in Costa Rica (P = 0.0006) and CAMP (P = 0.005), and the C allele of an SNP in the promoter region (rs1800469) was associated with increased airway responsiveness in both cohorts (P

Rationale: Airway responsiveness is a prognostic marker for asthma symptoms in later life., Objectives: To evaluate characteristics responsible for persistence of airway responsiveness in children with asthma., Methods: A total of 1,041 children, initially aged 5-12 years, with mild to moderate persistent asthma enrolled in the Childhood Asthma Management Program (CAMP) were studied prospectively for 8.6 +/- 1.8 years with methacholine challenges yearly., Measurements and Main Results: Least squares geometric mean models were fit to determine effects of sex and age on airway responsiveness (provocative concentration producing 20% decrease in FEV(1) [PC(20)]). Multiple linear regression analysis was performed to determine factors at baseline and over time, which were associated with PC(20) at end of follow-up. A total of 7,748 methacholine challenges were analyzed. PC(20) increased with age, with boys having greater increase after age 11 years than girls (P < 0.001). The divergence coincided with the mean age for Tanner stage 2. Postpubertal girls had greater airway responsiveness, even after adjustment for FEV(1) and other potential confounders. Although multivariable regression analyses noted a variety of factors that influenced airway responsivness in both sexes, a history of hay fever (beta= -0.30, P = 0.005), respiratory allergy (beta= -0.32, P = 0.006), or recent inhaled corticosteroid usage (beta= -0.18, P = 0.02) were associated with decrements in final log PC(20) only in girls., Conclusions: Airway responsiveness (PC(20)) is more severe in the postpubertal female with asthma than in males. Although there are factors associated with airway responsiveness in both males and females, sex-specific factors may contribute to new insights into asthma pathogenesis.

Nedocromil sodium inhibits the response to exercise-induced asthma (EIA). Mannitol given as a powder by inhalation is an osmotic stimulus that identifies EIA. We studied the acute effect of nedocromil on airway responsiveness to mannitol in 24 asthmatic subjects. After a control day, nedocromil (8 mg) or its placebo was administered randomized, double blind, 10 min before a challenge with progressively increasing doses of mannitol. Nedocromil inhibited the response to mannitol and there was a significant increase in the dose of mannitol required to cause a 15% reduction in FEV(1) (PD(15)) after nedocromil 409 (316,503) mg compared with placebo 156 (106,229) mg (p < 0.001). In the presence of nedocromil 12 subjects no longer recorded a 15% decrease in FEV(1) in response to mannitol. The remaining 12 required a significantly greater dose of mannitol to achieve a 15% decrease in FEV(1) after nedocromil. Following nedocromil, a plateau in responsiveness to mannitol was observed in 14 subjects. Nedocromil significantly inhibits the responsiveness to inhaled mannitol in asthmatic subjects.

Antigen challenge causes beta2-adrenoceptor dysfunction in sensitized human bronchi (Am. J. Respir. Crit. Care Med. 1997;155:1230-1234). This study investigated whether the dysfunction can be prevented by anti-inflammatory agents. Human bronchial rings (2 to 4 mm) from surgery were passively sensitized to house dust mite and challenged (1) with allergen only, (2) with allergen plus indomethacin (10(-)5 M), (3) with allergen plus nedocromil sodium (10(-)7 M to 10(-)5 M), (4) with allergen plus the H1-receptor antagonist cetirizine (10(-)7 M to 10(-)5 M), and (5) with allergen plus the peptido-leukotriene receptor antagonist iralukast (10(-)7 M to 10(-)5 M). Rings were first contracted with 10(-)6 M carbachol and then relaxed with salbutamol (10(-)9 M to 10(-)4 M). The concentration-relaxation curve to salbutamol was shifted significantly to the right in the rings challenged with allergen only compared with control rings. In the rings challenged with allergen plus nedocromil sodium (10(-)6 M and 10(-)5 M) or iralukast (10(-)6 M and 10(-)5 M) the concentration-relaxation curves to salbutamol were significantly shifted to the left compared with rings challenged in saline alone, suggesting a protective effect against beta2-adrenoceptor dysfunction. Neither allergen plus cetirizine nor allergen plus indomethacin shifted significantly the concentration-relaxation curves to salbutamol compared with rings challenged in saline alone. We conclude that the release of peptido-leukotrienes may play a significant role in causing the allergen-induced beta2-receptor dysfunction in passively sensitized human bronchi.

The protective activity of nedocromil sodium and of sodium cromoglycate against aspirin-induced asthma has never been investigated in controlled studies. Because it has been reported that aspirin-induced platelet-mediated cytotoxic activity in vitro is inhibited after treatment in vivo with nedocromil but not with cromoglycate, we investigated whether these compounds also exhibit a different protective activity against aspirin-induced bronchoconstriction. Ten patients with aspirin-induced asthma underwent three bronchial challenges with a single dose of lysine acetylsalicylate (LASA) that caused a decrease in FEV1 of 25% or more in a preliminary dose-response test 30 min after inhalation of 4 mg nedocromil sodium, 10 mg sodium cromoglycate, or placebo. FEV1 and SRaw were recorded at intervals for 195 min. After placebo, LASA caused a maximal decrease in FEV1 of 42 +/- 4% of baseline. After cromoglycate and nedocromil the maximal decrease in FEV1 was reduced to 20 +/- 3% and 18 +/- 4%, respectively (p < 0.01 versus placebo for both treatments), without significant differences between the two treatments. Similar results were observed with SRaw. We conclude that, at the recommended therapeutic doses, sodium cromoglycate and nedocromil sodium are equally effective in attenuating aspirin-induced bronchoconstriction and that it is unlikely that platelet activation participates in the pathogenesis of aspirin-induced asthma.

Adult, nonsmoking patients with mild to moderate asthma were randomized to receive 4 mg nedocromil sodium (n = 13), 200 micrograms albuterol (n = 13), or placebo (n = 12) four times daily for 16 wk in a double-blind, double-dummy protocol. Before and after treatment, patients underwent histamine bronchial provocation, followed by fiberoptic bronchoscopy. Bronchial mucosal biopsy tissue and bronchoalveolar lavage fluid were examined in detail. Daily diary cards were kept by each patient. Compared with baseline, the numbers of total (EG1) and activated (EG2) eosinophils, expressed as cells per square millimeter of bronchial biopsy tissue, decreased after treatment with nedocromil sodium (pretreatment: EG1 = 152.2 +/- 42.5 and EG2 = 143.8 +/- 36.8; post-treatment: EG1 = 115.4 +/- 35.1 and EG2 = 104.9 +/- 31.6) and increased after treatment with albuterol (pretreatment: EG1 = 129.3 +/- 28.0 and EG2 = 127.5 +/- 30.2; post-treatment: EG1 = 238.0 +/- 55.0 and EG2 = 211.4 +/- 50.4). Although the changes between the active treatment groups were significantly different (p < 0.05), no such significant differences were found in eosinophil numbers before and after treatment when comparisons were made between either of the active treatment groups and the placebo group. Although not significant, the changes in concentration of eosinophil cationic protein in bronchoalveolar lavage reflected the changes seen in numbers of activated eosinophils. No treatment differences were detected for mast cell or lymphocyte numbers. There were no statistical differences between treatment groups for clinical findings, with the exception of evening peak flow, which was significantly increased (p < 0.05) in the albuterol group.(ABSTRACT TRUNCATED AT 250 WORDS)