Meeghan A. Hart

Multicenter Evaluation of Infant Lung Function Tests as Cystic Fibrosis Clinical Trial Endpoints

RATIONALE The conducting of clinical trials in infants with cystic fibrosis (CF) has been hindered by lack of sensitive outcome measures. OBJECTIVES To evaluate safety, feasibility, and ability to detect abnormalities in lung function of serial pulmonary function tests (PFTs) in infants with CF. METHODS Multicenter observational study using a commercial device, rigorous training, ongoing quality control, and over-reading of data by an independent panel. Raised volume rapid thoracoabdominal compression technique and plethysmography were performed at enrollment and at 6 and 12 months, with an additional 1-month reproducibility visit. MEASUREMENTS AND MAIN RESULTS A total of 342 procedures were performed in 100 infants with CF at 10 centers. FRC measurements were acceptable at a higher proportion of study visits (89%) than raised volume (72%) or fractional lung volume (68%) measurements. Average Z scores for many parameters differed significantly from historical control values. Mean (95% confidence interval) Z scores were: -0.52 (-0.78 to -0.25) for forced expiratory flow at 75% (FEF₇₅) for FVC; 1.92 (1.39-2.45) for FRC; 1.22 (0.68-1.76) for residual volume; 0.87 (0.60-1.13) for FRC/total lung capacity; and 0.66 (0.27-1.06) for residual volume/total lung capacity. For future multicenter clinical trials using infant PFTs as primary endpoints, minimum detectable treatment effects are presented for several sample sizes. CONCLUSIONS In this 10-center study, key PFT measures were significantly different in infants with CF than in historical control subjects. However, infant PFTs do not yet appear ready as primary efficacy endpoints for multicenter clinical trials, particularly at inexperienced sites, based on acceptability rates, variability, and potentially large sample sizes required to detect reasonable treatment effects.

Sleep disordered breathing is associated with asthma severity in children

OBJECTIVE To examine the relationships among obesity, sleep-disordered breathing (SDB, defined as intermittent nocturnal hypoxia and habitual snoring), and asthma severity in children. We hypothesized that obesity and SDB are associated with severe asthma at a 1- year follow-up. STUDY DESIGN Children aged 4-18 years were recruited sequentially from a specialty asthma clinic and underwent physiological, anthropometric, and biochemical assessment at enrollment. Asthma severity was determined after 1 year of follow-up and guideline-based treatment, using a composite measure of level of controller medication, symptom burden, and health care utilization. Multivariate logistic regression was used to examine adjusted associations of SDB and obesity with asthma severity at 12-month follow-up. RESULTS Among 108 subjects (mean age, 9.1±3.4 years; 45.4% African-American; 67.6% male), obesity and SDB were common, affecting 42.6% and 29.6% of subjects, respectively. After adjusting for obesity, race, and sex, children with SDB had a 3.62-fold increased odds of having severe asthma at follow-up (95% CI, 1.26-10.40). Obesity was not associated with asthma severity. CONCLUSION SDB is a modifiable risk factor for severe asthma after 1 year of specialty asthma care. Further studies are needed to determine whether treating SDB improves asthma morbidity.

Obesity and obesity related co-morbidities in a referral population of children with asthma

Although there is mounting evidence that childhood obesity is a risk factor for incident asthma, it remains unclear if there is a distinct “asthma‐obesity” phenotype. This study characterized body composition, obesity related co‐morbidities, and traditional risk factors for asthma in a cohort of children referred for asthma management in a pulmonary clinic. We hypothesized that children with asthma and obesity would have distinct risk factors and co‐morbidities, particularly with respect to metabolic and sleep abnormalities.

Lung function distinguishes preschool children with CF from healthy controls in a multi-center setting.

Conducting clinical trials in cystic fibrosis (CF) preschoolers has been limited by lack of sensitive lung function measures performed across sites.

Analysis of the associations between lung function and clinical features in preschool children with cystic fibrosis.

To analyze cross‐sectional and longitudinal associations between lung function measures and clinical features in a cohort of preschool children with cystic fibrosis (CF).

Lung function from infancy to preschool in a cohort of children with cystic fibrosis

This study aimed to describe lung function in a cohort of children with cystic fibrosis (CF) who underwent infant pulmonary function tests (IPFTs) and preschool spirometry. Children performed up to four IPFTs (raised volume rapid thoracic compression technique) over 1 yr and five preschool spirometry tests over up to 2 yrs during participation in prospective, multicentre studies of infant and preschool lung function. All lung function data were reviewed centrally for measurement acceptability. 45 children had 252 acceptable measurements (137 IPFTs and 115 preschool spirometries) at ages 0.3–6.5 yrs. The median number of measurements per participant was 6 (range 3–9). Recent Pseudomonas aeruginosa infection was associated with 5.1% (95% CI 0.01–9.9%) lower forced expiratory volume in 0.5 s (FEV0.5) and 16.4% (95% CI 7.0–24.9%) lower forced expiratory flow at 25–25% of forced vital capacity (FEF25–75%), after adjustment for length, test type and centre. Recent cough was associated with 5.7% (95% CI 1.1–10.1%) lower FEV0.5 and 10.1% (95% CI 0.6–18.7%) lower FEF25–75%. Even after accounting for infection status, cough, sex, length, test type and centre, there was significant inter-individual variability in lung function (p<0.01 for each of FEV0.5, FEF25–75% and forced vital capacity). Recent P. aeruginosa infection and cough are associated with lower lung function in children with CF. Significant inter-individual variability in lung function remains to be explained.

Association of lung function, chest radiographs and clinical features in infants with cystic fibrosis

The optimal strategy for monitoring cystic fibrosis lung disease in infancy remains unclear. Our objective was to describe longitudinal associations between infant pulmonary function tests, chest radiograph scores and other characteristics. Cystic fibrosis patients aged ≤24 months were enrolled in a 10-centre study evaluating infant pulmonary function tests four times over a year. Chest radiographs ∼1 year apart were scored using the Wisconsin and Brasfield systems. Associations of infant pulmonary function tests with clinical characteristics were evaluated with mixed effects models. The 100 participants contributed 246 acceptable flow/volume (forced expiratory volume in 0.5 s (FEV0.5) and forced expiratory flow at 75% of the forced vital capacity (FEF75%)), 303 functional residual capacity measurements and 171 chest radiographs. Both Brasfield and Wisconsin chest radiograph scores worsened significantly over the 1-year interval. Worse Wisconsin chest radiograph scores and Staphylococcus aureus were both associated with hyperinflation (significantly increased functional residual capacity), but not with diminished FEV0.5 or FEF75%. Parent-reported cough was associated with significantly diminished forced expiratory flow at 75% but not with hyperinflation. In this infant cohort in whom we previously reported worsening in average lung function, chest radiograph scores also worsened over a year. The significant associations detected between both Wisconsin chest radiograph score and S. aureus and hyperinflation, as well as between cough and diminished flows, reinforce the ability of infant pulmonary function tests and chest radiographs to detect early cystic fibrosis lung disease. Infant pulmonary function tests and chest radiographs are able to detect early cystic fibrosis lung disease http://ow.ly/pv7pt

Assessing the relationship between obesity and asthma in adolescent patients: a review

The parallel rise in the prevalence of obesity and asthma over the last several decades has led to an extensive line of investigation into the relationship between these two conditions. This review will discuss evidence from laboratory-based studies, observational clinical studies, and clinical trials that suggests that obesity adversely influences asthma through multiple mechanisms. The effect of obesity on asthma during adolescence, including asthma incidence, the severity and control of existing asthma, lung function, and exacerbations, will be reviewed.