Early predictors for adult asthma and lung function abnormalities in infants hospitalized for bronchiolitis: a prospective 18- to 20-year follow-up.

In the present cohort, 85% of infants hospitalized for wheezing outgrew their symptoms until puberty, but 30-40% had asthma, depending on criteria, again in young adulthood. The aim of this study was to determine early predictors for adulthood asthma, bronchial reactivity, and lung function abnormalities in infants hospitalized for bronchiolitis. Fifty-two children hospitalized for bronchiolitis at < 2 years of age were restudied at the median age of 19 years. Wheezing histories and early risk factors for later asthma were recorded prospectively during infancy. The follow-up study consisted of a written questionnaire, physical examination, flow-volume spirometry, methacholine inhalation challenge, home peak expiratory flow monitoring, and skin-prick tests. In univariate analyses, parental asthma and repeated wheezing at age the age of 0-1 years and 0-2 years predicted adulthood asthma. Repeated wheezing at age the age of 0-1 years predicted later bronchial reactivity. Onset and recurrence of wheezing at < 1 year of age, parental atopy and asthma, and maternal smoking during infancy were related to subnormal lung function parameters. In multivariate logistic regression, adjusted for sex, age on admission, current smoking, and atopy in infancy and, currently, repeated wheezing both at < 1 year and < 2 years of age was an independent predictor for adulthood asthma. Parental asthma and repeated wheezing predict adulthood asthma in infants hospitalized for bronchiolitis, and maternal smoking predisposes them to lung function impairment in adulthood.

Hand-held turbine spirometer: agreement with the conventional spirometer at baseline and after exercise.

Portable hand-held spirometers are widely used in outpatient clinics and in field surveys when examining children for asthma. However, the validity of the results obtained from the hand-held spirometers has not been assessed in population-based studies. We evaluated the agreement between the forced expiratory volume (FEV1) values got by the conventional flow volume spirometer (FVS) and the pocket-sized turbine spirometer (TS) at baseline and after exercise, among the 212 children screened for asthma and asthma-like symptoms from a population of 1633 school-aged children. The comparison was made between and within three diagnostic groups: clinical asthma (n = 34), possible asthma (n = 31), and controls (n = 147). In general, the differences in FEV1 between the FVS and the TS were small. For all children, the mean difference in FEV1 and the limits of agreement (difference +/-2 s.d.) was 0.05 l (0.23 to -0.13) at baseline and 0.06 l (0.24 to -0.12) after exercise. No significant differences were observed in the agreement between the diagnostic groups. In conclusion, although FEV1 results obtained by the hand-held spirometer are not interchangeable with those by the conventional spirometer, they are in reasonable agreement. The agreement is similar both at baseline and after exercise, and is not influenced by the presence of asthma.

Asthma and lung function 20 years after wheezing in infancy: results from a prospective follow-up study.

OBJECTIVE: To determine the outcome until adulthood after wheezing in infancy, compared with pneumonia in infancy and with controls. DESIGN: An 18- to-20-year prospective cohort study. SETTING: Pediatric department at a university hospital, providing primary hospital care for a defined population. Patients Fifty-four children hospitalized for bronchiolitis and 34 for pneumonia at younger than 2 years, and 45 controls with no early-life wheezing or hospitalization, were studied at median age 19 years. MAIN OUTCOME MEASURES: A questionnaire on asthma symptoms and medication, physical examination, flow volume spirometry (FVS), methacholine inhalation challenge (MIC), home peak expiratory flow (PEF) monitoring, and skin prick testing (SPT) to common inhalant allergens. The 2 asthma definitions were physician-diagnosed asthma and previously diagnosed asthma with recent asthmatic symptoms (physician-diagnosed asthma included). RESULTS: By the 2 definitions, asthma was present in 30% (odds ratio [OR], 3.37; 95% confidence interval [CI], 1.12-10.10) and in 41% (OR 1.38; 95% CI, 0.37-5.21) in the bronchiolitis group, in 15% (OR, 5.50; 95% CI, 1.87-16.14) and in 24% (OR, 2.07; 95% CI, 0.59-7.22) in the pneumonia group, and in 11% in the control group. After bronchiolitis, the FVS values were forced vital capacity (FVC), 108% (SD, 13%) of predicted; forced expiratory volume in 1 second, 98% (SD, 12%); forced expiratory volume in 1 second divided by FVC, 91% (SD, 7.6%); midexpiratory flow at 50% of the FVC, 74% (SD, 19%); and midexpiratory flow at 25% of the FVC, 74% (SD, 22%). Bronchial reactivity by MIC was present in 25 (48%) of 52 subjects in the bronchiolitis group, in 13 (42%) of 31 in the pneumonia group, and in 14 (32%) of 44 in the control group. The prevalence of atopy (positive SPTs) was 48% to 63% in the 3 groups. In a logistic regression adjusted for atopy and smoking, infantile bronchiolitis was an independent risk factor for asthma by both definitions. CONCLUSION: The increased risk for asthma persists until adulthood after bronchiolitis in infancy.

Serum dehydroepiandrosterone sulfate concentration as an indicator of adrenocortical suppression during inhaled steroid therapy in adult asthmatic patients.

OBJECTIVE: Supraphysiological doses of exogenous glucocorticosteroids cause adrenocortical suppression. Dehydroepiandrosterone sulfate (DHEA-S) is the most abundant adrenal androgen and estrogen precursor. We studied to what extent inhaled glucocorticosteroid therapy for asthma decreases serum DHEA-S concentrations. DESIGN AND METHODS: We measured serum DHEA-S and cortisol concentrations in 101 adult patients with newly detected mild asthma before and after 2 and 12 weeks of treatment with inhaled glucocorticosteroids. The patients were randomized to receive budesonide 200 microg/day (low dose group, n=50) or 800 microg/day (high dose group, n=51) in two parallel groups double-blindly. RESULTS: In the low dose group, serum DHEA-S concentrations decreased from the baseline by a mean of 8 % (95 % confidence interval (CI), 3-13 %, P<0.01) after 2 weeks of therapy, and by 2 % (95 % CI, 9 % decrease to 5 % increase, NS) after 12 weeks. In the high dose group, the respective decreases were 16 % (95 % CI, 10-21 %, P<0.001) and 18 % (95 % CI, 12-24 %, P<0.001). The difference between the treatment groups was significant at both 2 and 12 weeks. During the 12 week treatment period the baseline concentrations of serum cortisol did not decrease in the low dose group, while in the high dose group the decrease was significant at 12 weeks (P<0.01), but not at 2 weeks. The forced expiratory volume in 1 s improved equally well in both groups. CONCLUSIONS: Inhaled budesonide decreased serum DHEA-S concentrations, which may indicate adrenocortical suppression. Reduced adrenal production of androgen and estrogen precursors may increase the risk of osteoporosis especially in postmenopausal women.

Biochemical markers of bone metabolism in relation to adrenocortical and growth suppression during the initiation phase of inhaled steroid therapy.

Growth suppression is usually most evident during the first year of inhaled steroid therapy. Steroid-induced changes in bone metabolism may contribute to this growth suppression. The aim of the present study was to evaluate the changes in biochemical markers of bone metabolism in relation to adrenal and growth suppression during the initiation phase of inhaled steroid therapy. Seventy-five school-aged children with new asthma were enrolled into budesonide (BUD, n = 30), fluticasone propionate (FP, n = 30) or cromone (CROM, n = 15) treatment groups. BUD dose was 800 microg/d during the first two months and 400 microg/d thereafter. The respective FP doses were 500 and 200 microg/d. Biochemical markers of bone metabolism were measured before treatment and after 2 and 4 mo of therapy. In the control (CROM) group, the mean concentrations of serum osteocalcin (OC), carboxyterminal propeptide of type I procollagen (PICP) (formation markers) and type I collagen carboxyterminal telopeptide (ICTP) (degradation marker) tended to increase. In the BUD group, OC and PICP decreased during the 4 mo by a mean of 23% (p < 0.001) and 15% (p < 0.05), respectively, while ICTP did not change significantly. In the FP group, OC and ICTP decreased during the first 2 mo by a mean of 19% (p < 0.01) and 21% (p < 0.01), respectively, returning to the pretreatment level at 4 mo, while PICP tended to increase during the 4 mo (14%, p = 0.12). In the steroid treated children whose height SD score decreased during the first 12 mo of therapy, both OC and PICP decreased during the first 4 mo by a mean of 20% (p < 0.01) and 21% (p < 0.001), respectively. In those children who had no growth suppression, the changes were not significant: -4% in OC and +13% in PICP. Furthermore, in children who developed evidence of adrenocortical suppression (on the basis of a low-dose ACTH test), OC decreased more (23%, p < 0.01) than in those with normal adrenocortical function (10%, p = 0.06). In conclusion, both inhaled BUD and FP caused dose-dependent effects on biochemical markers of bone metabolism. The children who developed growth or adrenocortical suppression were likely to have changes also in bone metabolism.

Transactivation assay for determination of glucocorticoid bioactivity in human serum.

We have developed a mammalian cell (COS-1) bioassay, which measures glucocorticoid bioactivity (GBA) directly from a small amount of human serum. The assay is based on the expression of human glucocorticoid receptor (GR) together with a coactivator protein and reporter plasmid containing GR response elements upstream of the luciferase gene. Ten microliters of human serum, in duplicate, are added directly to the cell culture medium, and GBA is derived from reporter gene activity. The assay differentiates between biopotencies of synthetic steroids, and importantly, mifepristone (RU486) is able to block glucocorticoid-induced response. The assay is sensitive (<15.6 nM cortisol in fetal calf serum) and precise, with the within- and between-assay coefficients of variation less than 8% and 10%, respectively. We measured serum GBA (bioassay) and cortisol (RIA) levels in 34 asthmatic children (age range, 5.7-14.2 yr) at baseline and after treatment with either inhaled budesonide (800 microg/d, n = 14), fluticasone propionate (500 microg/d, n = 14), or cromones (control group, n = 6). Pretreatment serum GBA and cortisol levels correlated strongly (r = 0.90, P < 0.0001, n = 34). Two months of treatment with inhaled budesonide resulted in excess GBA in circulation, which was not attributable to endogenous cortisol (P < 0.001). In the fluticasone propionate group, the presence of serum excess GBA was at the borderline of statistical significance (P < 0.08) after 2 months of inhalation therapy, and no excess GBA was detected in the cromone group. In conclusion, our bioassay enables measurement of mammalian cell response to bioactive glucocorticoids in circulation and provides a novel means to investigate patients receiving drugs acting through the GR.

Efficacy and safety of inhaled steroid and cromone treatment in school-age children: a randomized pragmatic pilot study.

In the treatment of asthma, inhaled steroids are more effective than cromolyn, whereas the latter offers extreme safety. The aim of the present pilot study was to evaluate, contemporarily, efficacy and safety aspects of different asthma treatment modalities. In 75 school-age children (mean age 9.5 years; range 5.5-14.7 years), treatment of asthma was started with budesonide (BUD, n = 30), fluticasone propionate (FP, n = 30) or cromones (CROM, n = 15). BUD was used at a dose of 800 microg/day during the first 2 months and at 400 microg/day thereafter. The respective FP doses were 500 and 200 microg/day. Efficacy of the treatment was assessed by measuring forced expiratory volume in 1 second (FEV1) and by evaluating the use of bronchodilators. Side-effects of the treatment were evaluated by following growth of the children and by performing low-dose adrenocorticotropin (ACTH) testing. At 4 months FEV1 had improved by a mean of 8.2% in the BUD group and by 5.4% in the FP group (p< 0.01 vs. baseline in both groups; NS between BUD and FP groups). The use of bronchodilators had decreased from five doses/week to one dose/week in the BUD group (p< 0.05), and from three doses/week to one dose/week in the FP group (p< 0.01) (NS between the groups). In the CROM group, the FEV1 value and the use of bronchodilators did not change. The treatment was unsuccessful on the basis of FEV1 decrease and increased bronchodilator use in, respectively, 30 and 15% of the BUD-, 20 and 7% of the FP-, and 50 and 47% of the CROM-treated children. Therefore, to prevent one treatment failure in the CROM group, between three and five children would need to move to treatment with steroids. The treatment had measurable systemic effects on the basis of height standard deviation (SD) score decrease and minor adrenocortical suppression in, respectively, 60 and 30% of the BUD-, 27 and 17% of the FP-, and 20 and 0% of the CROM-treated children. Therefore, to avoid systemic effects in one steroid-treated child, three BUD- and six to 14 FP-treated children would need to move to treatment with CROM. In conclusion, in school-age children asthma should be treated first with inhaled steroids. It is probable that the best combination of efficacy and safety can be achieved by using low steroid doses.