BACKGROUND Cystic fibrosis is a life-limiting disease that is caused by defective or deficient cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Phe508del is the most common CFTR mutation. METHODS We conducted two phase 3, randomized, double-blind, placebo-controlled studies that were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator, in patients 12 years of age or older who had cystic fibrosis and were homozygous for the Phe508del CFTR mutation. In both studies, patients were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary end point was the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at week 24. RESULTS A total of 1108 patients underwent randomization and received study drug. The mean baseline FEV1 was 61% of the predicted value. In both studies, there were significant improvements in the primary end point in both lumacaftor–ivacaftor dose groups; the difference between active treatment and placebo with respect to the mean absolute improvement in the percentage of predicted FEV1 ranged from 2.6 to 4.0 percentage points (P<0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (P<0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the lumacaftor–ivacaftor groups than in the placebo group; the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the lumacaftor–ivacaftor groups as well. The incidence of adverse events was generally similar in the lumacaftor–ivacaftor and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor–ivacaftor versus 1.6% among those who received placebo. CONCLUSIONS These data show that lumacaftor in combination with ivacaftor provided a benefit for patients with cystic fibrosis homozygous for the Phe508del CFTR mutation. (Funded by Vertex Pharmaceuticals and others; TRAFFIC and TRANSPORT ClinicalTrials.gov numbers, NCT01807923 and NCT01807949.)

Respiratory pathogens are frequently detected in samples from children with no respiratory symptoms. Symptomatic cases occurred more often in younger children and with detections of more than 1 respiratory pathogen.

The aim of this study was to evaluate the applicability of American Thoracic Society and European Respiratory Society criteria for spirometry in children.Maximal expiratory flow/volume (MEFV) measurements from 446 school-age children, experienced in performing MEFV manoeuvres, were studied and acceptability (start-of-test (backward extrapolated volume as a percentage of forced vital capacity (FVC) (Vbe%FVC) or as an absolute value (Vbe), end-of-test (forced expiratory time (FET)) and reproducibility criteria (absolute and percentage difference between best and second-best FVC and forced expiratory volume in one second (FEV1) (DFVC, DFVC %, DFEV1 and DFEV1 %)) were applied to these manoeuvres.The Vbe%FVC criterion was met by 91.5%, the Vbe v0.15 L criterion by 94.8% and the Vbe v0.10 L by 60.1% of children. Vbe v0.15 L appeared to be a more useful parameter than Vbe%FVC. The FET criterion was met by only 15.3% of children. DFVC v0.2 L and DFEV1 v0.2 L were met by 97.1% and 98.4%, and DFVC v0.1 L and DFEV1 v0.1 L by 79.8% and 84.3% of the children, respectively. These criteria appeared to be less useful compared to percentage criteria (DFVC % and DFEV1 %). Even experienced children did not meet all international criteria for spirometry. However, most of their MEFV curves are useful for interpretation.Based on the performance of these children, a re-evaluation of criteria for maximal expiratory flow/volume measurements in children is proposed.

The impulse oscillometry system (IOS) was introduced as a new technique to assess airflow obstruction in patients who are not able to perform forced breathing maneuvers, e.g., subjects with cerebral palsy or severe mental retardation, and young children. This study evaluates the sensitivity and specificity of IOS parameters to quantify changes in airflow obstruction in comparison with forced expiratory volume in the first second (FEV(1)) and peak expiratory flow (PEF) measurements. Measurements of FEV(1), PEF, and resistance (R) and reactance (X) at frequencies of 5-35 Hz were performed in 19 children with asthma before, during, and after methacholine challenge and subsequent bronchodilatation. All parameters changed significantly during tests. Values of R5 and R10 correlated with FEV(1) (r = -0.71 and -0.73, respectively, P < 0.001), as did values of X5 and X10 (r = 0.52 and 0.57, respectively, P < 0.01). Changes in R preceded changes in PEF and FEV(1) during methacholine challenge. The area under the receiver operating characteristic (ROC) curve to predict a 15% fall in FEV(1) showed better sensitivity and specificity for R5 (area under the curve, 0.85) compared to PEF (0.79) or R10 (0.73). We conclude that IOS parameters can be easily used as an indirect measure of airflow obstruction. This might be helpful in patients who are not able to perform forced breathing maneuvers. In individual subjects, R values measured at 5 Hz showed to be superior to PEF measurements in the detection of a 15% fall in FEV(1).

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These new paediatric reference equations provide accurate estimates of the range of normality for most commonly used pulmonary function indices, resulting in less underdiagnosis and overdiagnosis of pulmonary diseases.

Although there were no differences in the seasonal occurrences and distributions of polymerase chain reaction-detected respiratory viruses, acute respiratory illnesses were frequently associated with increased lower respiratory tract morbidity in young children with cystic fibrosis.

Aspergillus fumigatus is commonly found in the respiratory secretions of patients with cystic fibrosis (CF). Although allergic bronchopulmonary aspergillosis (ABPA) is associated with deterioration of lung function, the effects of A. fumigatus colonization on lung function in the absence of ABPA are not clear. This study was performed in 259 adults and children with CF, without ABPA. A. fumigatus colonization was defined as positivity of >50% of respiratory cultures in a given year. A cross-sectional analysis was performed to study clinical characteristics associated with A. fumigatus colonization. A retrospective cohort analysis was performed to study the effect of A. fumigatus colonization on lung function observed between 2002 and 2007. Longitudinal data were analysed with a linear mixed model. Sixty-one of 259 patients were at least intermittently colonized with A. fumigatus. An association was found between A. fumigatus colonization and increased age and use of inhaled antibiotics. In the longitudinal analysis, 163 patients were grouped according to duration of colonization. After adjustment for confounders, there was no significant difference in lung function between patients colonized for 0 or 1 year and patients with 2-3 or more than 3 years of colonization (p 0.40 and p 0.64) throughout the study. There was no significant difference in lung function decline between groups. Although colonization with A. fumigatus is more commonly found in patients with more severe lung disease and increased treatment burden, it is not independently associated with lower lung function or more severe lung function decline over a 5-year period.