Effect of inhaled glucocorticoids in childhood on adult height

BACKGROUND: The use of inhaled glucocorticoids for persistent asthma causes a temporary reduction in growth velocity in prepubertal children. The resulting decrease in attained height 1 to 4 years after the initiation of inhaled glucocorticoids is thought not to decrease attained adult height. METHODS: We measured adult height in 943 of 1041 participants (90.6%) in the Childhood Asthma Management Program; adult height was determined at a mean (±SD) age of 24.9±2.7 years. Starting at the age of 5 to 13 years, the participants had been randomly assigned to receive 400 μg of budesonide, 16 mg of nedocromil, or placebo daily for 4 to 6 years. We calculated differences in adult height for each active treatment group, as compared with placebo, using multiple linear regression with adjustment for demographic characteristics, asthma features, and height at trial entry. RESULTS: Mean adult height was 1.2 cm lower (95% confidence interval [CI], -1.9 to -0.5) in the budesonide group than in the placebo group (P=0.001) and was 0.2 cm lower (95% CI, -0.9 to 0.5) in the nedocromil group than in the placebo group (P=0.61). A larger daily dose of inhaled glucocorticoid in the first 2 years was associated with a lower adult height (-0.1 cm for each microgram per kilogram of body weight) (P=0.007). The reduction in adult height in the budesonide group as compared with the placebo group was similar to that seen after 2 years of treatment (-1.3 cm; 95% CI, -1.7 to -0.9). During the first 2 years, decreased growth velocity in the budesonide group occurred primarily in prepubertal participants. CONCLUSIONS: The initial decrease in attained height associated with the use of inhaled glucocorticoids in prepubertal children persisted as a reduction in adult height, although the decrease was not progressive or cumulative. (Funded by the National Heart, Lung, and Blood Institute and the National Center for Research Resources; CAMP ClinicalTrials.gov number, NCT00000575.)

Patterns of Growth and Decline in Lung Function in Persistent Childhood Asthma

BACKGROUND: Tracking longitudinal measurements of growth and decline in lung function in patients with persistent childhood asthma may reveal links between asthma and subsequent chronic airflow obstruction. METHODS: We classified children with asthma according to four characteristic patterns of lung-function growth and decline on the basis of graphs showing forced expiratory volume in 1 second (FEV1), representing spirometric measurements performed from childhood into adulthood. Risk factors associated with abnormal patterns were also examined. To define normal values, we used FEV1 values from participants in the National Health and Nutrition Examination Survey who did not have asthma. RESULTS: Of the 684 study participants, 170 (25%) had a normal pattern of lung-function growth without early decline, and 514 (75%) had abnormal patterns: 176 (26%) had reduced growth and an early decline, 160 (23%) had reduced growth only, and 178 (26%) had normal growth and an early decline. Lower baseline values for FEV1, smaller bronchodilator response, airway hyperresponsiveness at baseline, and male sex were associated with reduced growth (P<0.001 for all comparisons). At the last spirometric measurement (mean [±SD] age, 26.0±1.8 years), 73 participants (11%) met Global Initiative for Chronic Obstructive Lung Disease spirometric criteria for lung-function impairment that was consistent with chronic obstructive pulmonary disease (COPD); these participants were more likely to have a reduced pattern of growth than a normal pattern (18% vs. 3%, P<0.001). CONCLUSIONS: Childhood impairment of lung function and male sex were the most significant predictors of abnormal longitudinal patterns of lung-function growth and decline. Children with persistent asthma and reduced growth of lung function are at increased risk for fixed airflow obstruction and possibly COPD in early adulthood. (Funded by the Parker B. Francis Foundation and others; ClinicalTrials.gov number, NCT00000575.

Association Between Pulmonary Function and Asthma Symptoms

Background: FEV1 as a percentage of predicted (FEV1%pred) is commonly measured in asthma clinical studies; however, reports vary on its association with asthma control instruments evaluating symptoms. Objective: Assess the association between FEV1%pred and Asthma Control Questionnaire (ACQ) scores in a managed-care population with persistent asthma. Methods: Retrospective analysis of survey responses and spirometry results of patients (aged ≥12 years) with persistent asthma from the Observational Study of Asthma Control and Outcomes was done. Eligible patients received 4 identical surveys including the 5-item ACQ (ACQ-5)/6-item ACQ (ACQ-6) and completed spirometry in parallel. Longitudinal analyses, comparisons of change over time, and fixed- and random-effects regression analyses were conducted, with/without adjustment for covariates. Results: There were 1748 survey responses with valid spirometry results. In unadjusted models, coefficients for ACQ-5/ACQ-6 scores were not statistically significant and coefficient of determination (R2) was low (0.03). When adjusted for covariates, ACQ-5 and ACQ-6 scores were significantly associated with FEV1%pred (P \u3c.001) and R2 increased to 0.11 and 0.12, respectively. In adjusted models, every 1-point increase in ACQ-5 and ACQ-6 scores was associated with a 1.7% and 1.9% decrease, respectively, in FEV1%pred. Change in FEV1%pred and change in ACQ-5/ACQ-6 scores were not significantly associated in regressions with/without covariates. Conclusions: The weak and statistically insignificant association between FEV1%pred and ACQ-5/ACQ-6 scores in unadjusted models suggests a high degree of unexplained variation between these measures. Results support the use of both symptoms and pulmonary function, rather than relying on one measure alone, to assess asthma control in clinical care and outcomes studies

Airway Responsiveness in Mild to Moderate Childhood Asthma: Sex Influences on the Natural History

Rationale: Airway responsiveness is a prognostic marker for asthma symptoms in later life

The Status of Asthma Control in the U.S. Adult Population

Treatment guidelines recognize the importance of achieving and maintaining asthma control. This study was designed to assess the prevalence of asthma control in a representative U.S. population. A survey regarding asthma and associated symptoms was sent to a representative national sample of 134,401 households managed by the National Family Opinion WorldGroup from May to July 2007. Subjects ≥18 years with current asthma were identified and completed the Asthma Control Test (ACT), a brief validated self-administered survey that assesses asthma control. Subjects with an ACT score of >19 have been defined as having well-controlled asthma (WCA) and those with a score of ≤19 were defined as having not welt-controlled asthma (NWCA). The prevalence of WCA was identified for the total population as well as subjects who currently were only using albuterol to control asthma symptoms. In addition, the frequency of past asthma exacerbations was studied and correlated with ACT. Surveys were returned by 81,505 households (61% return rate). A total of 10,139 adults self-reported having asthma and completed the ACT. Forty-one percent of these had NWCA and 39% of the subjects using albuterol as the only asthma medication had NWCA. Fifty-eight percent of subjects with NWCA in the total population had an asthma-related exacerbation (asthma-related oral corticosteroid use, emergency department, or hospitalization) in the previous year compared with 24% of subjects with WCA. This large representative national asthma sample using a validated asthma control instrument identified >40% of subjects with NWCA. In addition, subjects using albuterol monotherapy, who would be expected to have mild asthma and thus be well controlled, had a similar high prevalence of NWCA

A novel endpoint for exacerbations in asthma to accelerate clinical development : A post-hoc analysis of randomised controlled trials

Background: Occurrence of severe asthma exacerbations are the cornerstone of the evaluation of asthma management, but severe asthma exacerbations are rare events. Therefore, trials that assess drug efficacy on exacerbations are done late in clinical development programmes. We aimed to establish an endpoint capturing clinically relevant deteriorations (diary events) that, when combined with severe exacerbations, create a composite outcome (CompEx). CompEx needs to strongly mirror results seen with the severe exacerbation-validated outcome, to allow the design of clinical trials of shorter duration and that include fewer patients than trials assessing severe exacerbations. Methods: Data from 12 asthma trials of 6 months or 12 months duration and, with standardised collection of exacerbations and diary card variables, were used to construct and test CompEx. The study populations had a mean age of 35-53 years, 59-69% were female, and had a mean FEV1 percentage of predicted normal of 63-84%. With data from five trials, we established a series of diary events based on peak expiratory flow (P), reliever use (R), symptoms (S), awakenings (A), and threshold values for change from baseline and slopes to assess trends. For the development phase, we evaluated different variable combinations and deterioration criteria to select the most robust algorithm to define a diary event for the composite outcome. We defined a composite outcome, CompEx, as first occurrence of a diary event or a severe exacerbation. We assessed the performance of CompEx in seven trials by comparing the event frequency, treatment effect (hazard ratio; HR), and the sample size needed for future trials for the CompEx versus episodes of severe exacerbations. Findings: CompEx (based on PRS) was the algorithm that best fulfilled our two-set criteria. When censored at 3 months, CompEx resulted in 2·8 times more events than severe exacerbations, and while preserving the treatment effect observed on severe exacerbations (CompEx over severe exacerbation average HR 1·01). The increased number of events, together with the sustained treatment effect, resulted in a large net gain in power, with a 67% mean reduction in the number of patients required in a drug trial for severe exacerbations. In six of seven comparisons tested, CompEx reduced the sample size needed by at least 50%. Validation of independent test populations confirmed the ability of CompEx to increase event frequencies, preserve treatment effect, and reduce the number of patients needed. Interpretation: CompEx is a composite outcome for evaluation of new asthma therapies. CompEx allows design of shorter trials that require fewer patients than studies of severe exacerbations, while preserving the ability to show a treatment effect compared with severe exacerbations. Funding: AstraZeneca