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 (FEV(0.5)) and 16.4% (95% CI 7.0-24.9%) lower forced expiratory flow at 25-25% of forced vital capacity (FEF(25-75%)), after adjustment for length, test type and centre. Recent cough was associated with 5.7% (95% CI 1.1-10.1%) lower FEV(0.5) and 10.1% (95% CI 0.6-18.7%) lower FEF(25-75%). 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 FEV(0.5), FEF(25-75%) 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.

Molecular epidemiological surveillance of multidrug-resistant Pseudomonas aeruginosa isolates in a pediatric population of patients with cystic fibrosis and determination of risk factors for infection with the Houston-1 strain.

Multiyear molecular epidemiological surveillance of multidrug-resistant Pseudomonas aeruginosa (MRPA) in a pediatric cystic fibrosis care center identified an endemic MRPA strain (Houston-1). Recent hospitalization was found to be a statistically significant risk factor for acquisition of the endemic strain. Multiple infection control improvements led to the reduced incidence of the Houston-1 strain in the CF population.

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.

Human metapneumovirus and respiratory syncytial virus infections in older children with cystic fibrosis.

BACKGROUND: Human metapneumovirus (hMPV) has been isolated from children with acute respiratory infection worldwide. Its epidemiology remains to be defined in children with cystic fibrosis (CF). We describe the epidemiology and clinical impact of hMPV in CF children and compared it to respiratory syncytial virus (RSV). METHODS: CF children ages 7-18 years were studied prospectively during the 1998 -1999 RSV season. Nasopharyngeal specimens were collected during acute respiratory illnesses and tested for respiratory viruses. Blood specimens were drawn early, mid, and end of the RSV season, and tested for serological evidence of hMPV and RSV infections. Rates of lower respiratory tract illnesses (LRTI) and hospitalizations for pulmonary exacerbations were compared during the time intervals they developed serological evidence of infection to their non-infection intervals. RESULTS: Six of 44 CF children had a virus positive respiratory illness in 56 LTRI events and 18 hospitalizations. Serological evidence of hMPV and RSV infections occurred in 16 and 20 CF children, respectively; 8 had infections with both viruses. A greater proportion of CF children had >or=1 LRTI during their infection intervals compared to their non-infection intervals (13/25 vs. 5/25; P=0.03). A trend for higher rates of LRTI was observed in the infection intervals compared to non-infection intervals (9.5 +/- 11.0 vs. 4.2 +/- 9.9 per 1,000 child-days; P=0.06), and it was significantly greater with a more conservative estimate (one event per child per interval; 7.4 +/- 7.7 vs. 2.6 +/- 5.4 per 1,000 child-days; P

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

OBJECTIVE: To analyze cross-sectional and longitudinal associations between lung function measures and clinical features in a cohort of preschool children with cystic fibrosis (CF). METHODS: Longitudinal eight-center observational study of children with CF aged 36-60 months at enrollment, who underwent semiannual pulmonary function tests (PFTs) for up to 2 years consisting of spirometry (all 8 sites), forced oscillometry (FO, 5 sites), and measures of thoracoabdominal asynchrony using respiratory inductive plethysmography (IP, 5 sites). RESULTS: Ninety-three subjects were enrolled; 181 acceptable spirometry measurements from 71 subjects, 128 FO from 47 subjects, and 142 IP from 50 subjects were available for analysis. Cross sectional analyses did not detect an association between any PFT parameter at enrollment and Pseudomonas aeruginosa (Pa) status, CF gene mutation class, Wisconsin cough score, Shwachman score, environmental tobacco smoke exposure, family history of asthma, or nutritional indices. In longitudinal analyses, Pa infection within 6 months preceding enrollment was associated with a significantly greater rate of decline in z-scores for forced expiratory flow between 25 and 75% of forced vital capacity (FEF(25-75) ) (-1.3 vs. -0.4 Z scores/year, P = 0.024) and greater thoracoabdominal asynchrony measured by IP (mean phase angle difference 4.6°, P = 0.004). No other significant longitudinal associations were observed. CONCLUSIONS: Prior Pa infection is associated with a greater rate of decline in FEF(25-75) z-score and mild thoracoabdominal asynchrony in preschool children with CF. In this multicenter US study, significant associations between other lung function measures and clinical features were not detected.

Immunogenicity of a new purified fusion protein vaccine to respiratory syncytial virus: a multi-center trial in children with cystic fibrosis.

A third generation, purified fusion protein (PFP-3) vaccine was developed to prevent severe respiratory syncytial virus (RSV) disease in high-risk groups. A phase II, multi-center, adjuvant-controlled trial was performed in RSV seropositive children with cystic fibrosis (CF); 151 received the adjuvant-control and 143 received the vaccine. Details of the vaccine-induced immune response are presented. At enrollment, RSV-specific, serum antibodies were comparable between both groups. A highly sensitive and specific serum antibody vaccine profile was established for the PFP-3 vaccine. At post-vaccination and end-of-study, RSV-specific, neutralizing antibody (Nt Ab) and binding antibody (Bd Ab) to the fusion (F) protein were significantly higher in PFP-3 vaccinees. After 28 days post-vaccination, Nt Ab and Bd Ab to F protein titers declined slowly at rates of 0.23 and 0.37 log2 per month, respectively. The PFP-3 vaccine-induced a robust immune response that lasted throughout the RSV season.