Anne L. Fuhlbrigge

Serum vitamin D levels and severe asthma exacerbations in the Childhood Asthma Management Program study

BACKGROUND Asthma exacerbations, most often caused by respiratory tract infections, are the leading causes of asthma morbidity and comprise a significant proportion of asthma-related costs. Vitamin D status might play a role in preventing asthma exacerbations. OBJECTIVES We sought to assess the relationship between serum vitamin D levels and subsequent severe asthma exacerbations. METHODS We measured 25-hydroxyvitamin D levels in sera collected from 1024 children with mild-to-moderate persistent asthma at the time of enrollment in a multicenter clinical trial of children randomized to receive budesonide, nedocromil, or placebo (as-needed beta-agonists): the Childhood Asthma Management Program. Using multivariable modeling, we examined the relationship between baseline vitamin D levels and the odds of any hospitalization or emergency department visit over the 4 years of the trial. RESULTS Thirty-five percent of all subjects were vitamin D insufficient, as defined by a level of 30 ng/mL or less 25-hydroxyvitamin D. Mean vitamin D levels were lowest in African American subjects and highest in white subjects. After adjusting for age, sex, body mass index, income, and treatment group, insufficient vitamin D status was associated with a higher odds of any hospitalization or emergency department visit (odds ratio, 1.5; 95% CI, 1.1-1.9; P = .01). CONCLUSION Vitamin D insufficiency is common in this population of North American children with mild-to-moderate persistent asthma and is associated with higher odds of severe exacerbation over a 4-year period.

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.).

Association of body mass with pulmonary function in the Childhood Asthma Management Program (CAMP)

Background: While increases in body mass index (BMI) have been associated with the incidence and prevalence of asthma, the mechanisms behind this association are unclear. Methods: We hypothesised that BMI would be independently associated with measures of asthma severity in a population of children with mild to moderate asthma enrolled in the Childhood Asthma Management Program (CAMP). A multivariable baseline cross sectional analysis of BMI with our outcomes of interest was performed. Results: BMI was generally not associated with symptoms, nor was it associated with atopy. While BMI was positively associated with the methacholine concentration that causes a 20% fall in forced expiratory volume in 1 second (PC20FEV1), this association did not persist after adjustment for FEV1. Increasing BMI was associated with increasing FEV1 (β = 0.006 l, 95% CI (0.001 to 0.01)) and forced vital capacity (FVC) (β = 0.012 l, 95% CI (0.007 to 0.017)). However, decrements in the FEV1/FVC ratio were noted with increasing BMI (β = −0.242, 95% CI (−0.118 to −0.366)). Thus, an increase in BMI of 5 units was associated with a decrease in FEV1/FVC of over 1%. Conclusions: Although the association of FEV1 and FVC with BMI did not support our initial hypothesis, the decrease noted in the FEV1/FVC ratio has potential relevance in the relationship between BMI and asthma severity.

Impact of inhaled antiinflammatory therapy on hospitalization and emergency department visits for children with asthma

Objective. Although the efficacy of inhaled antiinflammatory therapy in improving symptoms and lung function in childhood asthma has been shown in clinical trials, the effectiveness of these medications in real-world practice settings in reducing acute health care use has not been well-evaluated. This study examined the effect of inhaled antiinflammatory therapy on hospitalizations and emergency department (ED) visits by children for asthma. Design. Defined population cohort study over 1 year. Setting. Three managed care organizations (MCOs) in Seattle, Boston, and Chicago participating in the Pediatric Asthma Care–Patient Outcome Research and Treatment II trial. Participants. All 11 195 children, between 3 to 15 years old, with a diagnosis of asthma who were enrolled in the 3 MCOs between July 1996 and June 1997. Outcome Measures. We identified children with 1 or more asthma diagnoses using automated encounter data. Medication dispensings were identified from automated pharmacy data. Multivariate logistic regression analysis was used to calculate effects of inhaled antiinflammatory therapy on the adjusted relative risk (RR) for hospitalization and ED visits for asthma. Results. Over 12 months, 217 (1.9%) of children had an asthma hospitalization, and 757 (6.8%) had an ED visit. After adjustment for age, gender, MCO, and reliever dispensing, compared with children who did not receive controllers, the adjusted RRs for an ED visit were: children with any (≥1) dispensing of cromolyn, 0.4 (95% confidence interval [CI]: 0.3, 0.5); any inhaled corticosteroid (ICS), 0.5 (95% CI: 0.4, 0.6); any cromolyn or ICS combined (any controller), 0.4 (95% CI: 0.3, 0.5). For hospitalization, the adjusted RR for cromolyn was 0.6 (95% CI: 0.4, 0.9), for ICS 0.4 (95% CI: 0.3, 0.7), and for any controller 0.4 (95% CI: 0.3, 0.6). A significant protective effect for both events was seen among children with 1 to 5 and with >5 antiinflammatory dispensings. When the analysis was stratified by frequency of reliever dispensing, there was a significant protective effect for controllers on ED visits for children with 1 to 5 and with >5 reliever dispensings and on the risk of hospitalization for children with >5 reliever dispensings. Conclusions. Inhaled antiinflammatory therapy is associated with a significant protective effect on the risk for hospitalization and ED visits in children with asthma. Cromolyn and ICSs were associated with similar effects on risks.asthma drug therapy, inhaled antiinflammatory agents, health maintenance organizations, hospitalization, emergency department.

Decreased response to inhaled steroids in overweight and obese asthmatic children

BACKGROUND The mechanisms and consequences of the observed association between obesity and childhood asthma are unclear. OBJECTIVES We sought to determine the effect of obesity on treatment responses to inhaled corticosteroids in asthmatic children. METHODS We performed a post hoc analysis to evaluate the interaction between body mass index (BMI) and treatment with inhaled budesonide on lung function in the Childhood Asthma Management Program trial. Participants were then stratified into overweight/obese and nonoverweight groups, and their response to inhaled budesonide was analyzed longitudinally over the 4 years of the trial. RESULTS There was a significant interaction between BMI and budesonide for prebronchodilator FEV(1)/forced vital capacity (FVC) ratio (P = .0007) and bronchodilator response (BDR; P = .049) and a nonsignificant trend for an interaction between BMI and budesonide on prebronchodilator FEV(1) (P = .15). Nonoverweight children showed significant improvement with inhaled budesonide in lung function (FEV(1), FEV(1)/FVC ratio, and BDR) during the early (years 1-2) and late (years 3-4) stages of the trial. Overweight/obese children had improved FEV(1) and BDR during the early but not the late stage of the trial and showed no improvement in FEV(1)/FVC ratio. When comparing time points at which both groups showed a significant response, the degree of improvement among nonoverweight children was significantly greater than in overweight/obese children at most visits. Nonoverweight children had a 44% reduction in the risk of emergency department visits or hospitalizations throughout the trial (P = .001); there was no reduction in risk among overweight/obese children (P = .97). CONCLUSIONS Compared with children of normal weight, overweight/obese children in the Childhood Asthma Management Program showed a decreased response to inhaled budesonide on measures of lung function and emergency department visits/hospitalizations for asthma.

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.).

Future Research Directions in Asthma. An NHLBI Working Group Report

Asthma is a common chronic disease without cure. Our understanding of asthma onset, pathobiology, classification, and management has evolved substantially over the past decade; however, significant asthma-related morbidity and excess healthcare use and costs persist. To address this important clinical condition, the NHLBI convened a group of extramural investigators for an Asthma Research Strategic Planning workshop on September 18-19, 2014, to accelerate discoveries and their translation to patients. The workshop focused on (1) in utero and early-life origins of asthma, (2) the use of phenotypes and endotypes to classify disease, (3) defining disease modification, (4) disease management, and (5) implementation research. This report summarizes the workshop and produces recommendations to guide future research in asthma.

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. 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.

Forced Expiratory Volume in 1 Second Percentage Improves the Classification of Severity Among Children With Asthma

OBJECTIVE. Spirometry is an important component of the National Asthma Education and Prevention Program guidelines for asthma, yet published data show variable associations between forced expiratory volume in 1 second percentage (FEV1%) predicted, symptoms and health care utilization. The objective of this analysis was to examine the association between FEV1% and future risk of exacerbations among a well-characterized population of children with asthma. METHODS. Using data that are available from the Childhood Asthma Management Program, we examined the relationship between prebronchodilator FEV1% and important clinical outcomes. Multiple observations of FEV1 were available for each patient; multivariate regression analysis, using a general estimating equation approach, was used to control for the correlation between repeated measurements among individuals and potential confounders. FEV1% was categorized into 4 levels and as a continuous variable. Outcomes of interest included mean symptom score (0–3), episode-free days, and asthma-related events (oral steroid use, emergency department visits, and hospitalizations) during the ensuing 4-month period. Our analysis was limited to the placebo group (N = 417). RESULTS. We observed a clear relationship between prebronchodilator FEV1% and important clinical outcomes. In multivariable models that simultaneously controlled for covariates of interest, age at baseline, time, previous event history, and nocturnal awakenings, a significant relationship between FEV1% and asthma symptoms and serious asthma exacerbations (oral steroids, emergency department visits, and hospitalizations) was observed. Compared with children with an FEV1% ≥100%, children with FEV1% 80% to 99%, 60% to 79%, and <60% were 1.3, 1.8, and 4.8, respectively, more likely to have a serious asthma exacerbation during the ensuing 4 months. CONCLUSIONS. In children with mild to moderate asthma, FEV1% predicted is independently associated with future asthma symptoms and health care utilization. Previous asthma-related hospitalizations and nocturnal symptoms also were independently associated with risk for future adverse events. FEV1 is an important component of asthma health status and asthma severity classification.

Predictors of Symptoms Are Different From Predictors of Severe Exacerbations From Asthma in Children

BACKGROUND Asthma therapy is typically prescribed and titrated based on patient or parent self-report of symptoms. No longitudinal studies have assessed the relationship between symptoms and severe asthma exacerbations in children. The goal of our study was (1) to assess the association of asthma symptoms with severe asthma exacerbations and (2) to compare predictors of persistent asthma symptoms and predictors of severe asthma exacerbations. METHODS The Childhood Asthma Management Program was a multicenter clinical trial of 1,041 children randomized to receive budesonide, nedocromil, or placebo (as-needed β-agonist). We conducted a post hoc analysis of diary cards that were completed by subjects on a daily basis to categorize subjects as having persistent vs intermittent symptoms. We defined a severe asthma exacerbation as an episode requiring ≥ 3 days use of oral corticosteroids, hospitalization, or ED visit due to asthma based on self-report at study visits every 4 months. RESULTS While accounting for longitudinal measures, having persistent symptoms from asthma was significantly associated with having severe asthma exacerbations. Predictors of having persistent symptoms compared with intermittent symptoms included not being treated with inhaled corticosteroids, lower FEV(1)/FVC ratio, and a lower natural logarithm of provocative concentration of methacholine producing a 20% decline in FEV(1) (lnPC(20)). Predictors of having one or more severe asthma exacerbations included younger age, history of hospitalization or ED visit in the prior year, ≥ 3 days use of oral corticosteroids in the prior 3 months, lower FEV(1)/FVC ratio, lower lnPC(20), and higher logarithm to the base 10 eosinophil count; treatment with inhaled corticosteroids was predictive of having no severe asthma exacerbations. CONCLUSIONS Patients with persistent symptoms from asthma were more likely to experience severe asthma exacerbations. Nevertheless, demographic and laboratory predictors of having persistent symptoms are different from predictors of severe asthma exacerbations. Although symptoms and exacerbations are closely related, their predictors are different. The current focus of the National Asthma Education and Prevention Program guidelines on the two separate domains of asthma control, impairment and risk, are supported by our analysis.