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Objectives: Inhaled colistin is commonly used in patients with cystic fibrosis (CF), but only limited data are available to define its pharmacokinetic profile.Patients and methods: We performed a multicentre study in 30 CF patients to assess sputum, serum and urine concentrations after a single dose of 2 million units of colistin administered by inhalation. In a subgroup of patients we also compared the efficacy of two different nebulizers for administration of inhaled colistin.Results: Serum concentrations of colistin reached their maximum 1.5 h after inhalation and decreased thereafter. Serum concentrations were well below those previously reported for systemic application in all patients. A mean 4.3 ± 1.3% of the inhaled dose was detected in urine. Elimination characteristics did not differ significantly from those previously reported for systemic application. A positive correlation was found between forced expiratory volume in 1 s (FEV1) in per cent predicted and both AUC and maximal colistin concentrations in serum (Cmax). Maximum sputum concentrations were at least 10 times higher than the MIC breakpoint for Pseudomonas aeruginosa proposed by the British Society for Antimicrobial Chemotherapy. Although sputum drug concentrations decreased after a peak at 1 h, the mean colistin concentrations were still above 4 mg/L after 12 h. No differences were seen in polymyxin E sputum concentrations, for CF patients between the two nebulizer systems.Conclusions: The low systemic and high local concentrations of colistin support the use of inhaled colistin in CF patients infected with P. aeruginosa.

Abstract Background Pulmonary infections are associated with an increase in capillary permeability but information regarding age related differences in the local inflammatory response is lacking. To quantify the degree of capillary leakage during inflammation, the concentrations of the plasma proteins albumin, α ₁-antitrypsin, α ₂-macroglobulin and the locally produced proteins elastase, myeloperoxidase, lactoferrin and fibronectin were studied in the bronchoalveolar lavage (BAL) fluid of immunosuppressed children and adults with pneumonia. Methods Sixteen children aged 2–16 years and 15 adults who developed pneumonia while receiving immunosuppressive therapy for haematological malignancies were included in the study. Bronchoalveolar lavage was performed via a flexible bronchoscope with three aliquots of 1 ml/kg body weight in children and 200 ml in adults. Protein concentrations in BAL fluid were determined using highly sensitive immunoluminometric assays. Results Despite considerable variability, the median concentrations of all proteins in BAL fluid were significantly higher in both patient populations than in previously collected age adjusted reference values. The concentrations of serum derived proteins were significantly higher in children with pneumonia than in adult patients. In contrast, no differences were observed between the two groups for locally produced proteins. Conclusions These data suggest that the degree of protein exudation is more pronounced in immunosuppressed children with pneumonia than in adults in a similar clinical situation. This is in agreement with our studies in healthy individuals and may reflect a greater permeability of the alveolar-capillary membrane in children, regardless of disease status.

The therapeutic efficacy of oral N-acetylcysteine (NAC) and ambroxol as compared with the effect of placebos was studied in 36 cystic fibrosis (CF) patients with mild to moderate pulmonary disease. The patients were randomly assigned to one of three regimens, matched on the basis of age and Chrispin-Norman scores. The trial was conducted over a period of 12 weeks. Patients were assessed clinically and by extensive pulmonary function techniques (body-plethysmography, maximal expiratory flow-volume curves, trapped air determination). Although no clinical differences could be observed between the three groups, significant impairment in the placebo group was found for trapped air and FEV1 when compared to the active groups, suggesting a therapeutic effect of ambroxol and NAC in CF.

Although the activity of nitric oxide (NO) synthases are increased in lung tissue of patients with cystic fibrosis, the concentrations of nasal and exhaled NO have recently been found to be decreased in cystic fibrosis. This could either be due to reduced NO formation or metabolism of NO within airway fluids. In this study, the stable NO metabolites, nitrate and nitrite, were determined in the saliva and sputum of 18 stable cystic fibrosis patients, 21 cystic fibrosis patients during a pulmonary exacerbation, and in saliva and endotracheal secretions of normal controls. Median saliva concentrations of NO metabolites (nitrate plus nitrite) were 704 μmol/l (95% confidence interval (CI) 419 to 1477) in stable cystic fibrosis patients, 629 μmol/l (95% CI 382 to 1392) in cystic fibrosis patients presenting with pulmonary exacerbation, and 313 μmol/l (95% CI 312 to 454) in controls. Median sputum NO metabolite concentration in stable cystic fibrosis was 346 μmol/l (95% CI 311 to 504). This was not significantly different from cystic fibrosis patients presenting with pulmonary exacerbation (median 184 μmol/l, 95% CI 249 to 572), but significantly higher than in endotracheal secretions of controls (median 144 μmol/l, 95% CI 96 to 260). Sputum NO metabolite concentration in cystic fibrosis pulmonary exacerbation significantly increased during antibiotic treatment. A positive correlation was observed between sputum NO metabolites and lung function in stable cystic fibrosis, suggesting less airway NO formation in cystic fibrosis patients with more severe lung disease. These data indicate that decreased exhaled NO concentrations in cystic fibrosis patients may be due to retention and metabolism of NO within the airway secretions. However, sputum NO metabolites are not a useful marker of airway inflammation in cystic fibrosis lung disease.

ABSTRACTRNA of the newly identified human metapneumovirus (HMPV) was detected in nasopharyngeal aspirates of 11 of 63 (17.5%) young children with respiratory tract disease. Markers of infection caused by another member of the Pneumovirinaesubfamily of the family Paramyxoviridae, respiratory syncytial virus (RSV), were identified in 15 of these patients (23.8%). Three patients were simultaneously infected with HMPV and RSV. Studies of the clinical characteristics of HMPV-infected children did not reveal any difference between HMPV-infected patients and a control population of RSV-infected patients with regard to disease severity, but the duration of symptoms was significantly shorter for HMPV-infected patients. Phylogenetic analysis of the amplified viral genome fragments confirmed the existence and simultaneous circulation within one epidemic season of HMPV isolates belonging to two genetic lineages.

Airway S-nitrosothiols (SNOs) are naturally occurring bronchodilators. SNOs, nitrate, and nitrite were measured in bronchoalveolar lavage fluid of 23 patients with cystic fibrosis (CF) and mild pulmonary disease (aged 6-16 years) and 13 healthy children (aged 8-15 years). Concentrations of SNOs were decreased in the lower airways of patients with CF and mild pulmonary disease (median, range: 0, 0-320 nmol/L vs 80, 0-970 nmol/L) despite normal levels of the inert nitric oxide metabolites nitrate and nitrite (mean +/- SEM: 3.7 +/- 0.5 @mmol/L vs 4.8 +/- 0.9 @mmol/L). S-nitrosolation- mediated bioreactivities may be impaired by depletion of the CF airway SNO reservoir. (J Pediatr 1999;135:770-2)

ObjectiveTo evaluate the effects of lumacaftor/ivacaftor (LUM/IVA) combination therapy on lung morphology and physiology with computed tomography (CT) scanning in patients aged 6 to 11 years with cystic fibrosis (CF) homozygous for the F508del-CFTRmutation.MethodsBaseline CT scans were obtained in 19 patients (12 active treatment, 7 placebo) from the phase 3 LUM/IVA trial (NCT02514473), and 24 week CT scans were completed in 7 active treatment and 3 placebo patients. CT scans were obtained at total lung capacity and at residual volume (RV). CT scans were scored by 2 independent readers blinded to all patient and time point information using the Brody score, which evaluates the extent and severity of multiple aspects of CF lung disease, including bronchiectasis and air trapping. Scores are presented as mean (SD); no statistical testing was performed for this preliminary study.ResultsMean total CT score (sum of the subcomponent scores) decreased from 20.6 to 12.5 (mean change [SD], 8.1 [13.6]) in the LUM/IVA group and increased from 32.8 to 41.4 (8.6 [14.6]) in the placebo group. The mean bronchiectasis score decreased from 3.2 to 2.5 (0.7 [1.3]) in the LUM/IVA group and increased from 6.4 to 8.1 (1.7 [2.1]) in the placebo group. Additionally, the diameter of ectatic bronchi decreased in several patients on active treatment. The mean air trapping score decreased from 7.8 to 5.9 (mean difference [SD], 1.9 [6.8]) in the active group and increased from 9.8 to 14.5 (4.7 [11.7]) in the placebo group, as shown for 1 patient (figure 1).ConclusionThis is the first report to describe CT lung findings after CFTR corrector/potentiator therapy in patients aged 6 to 11 years homozygous for F508del. In this 24 week exploratory analysis, bronchiectasis and air trapping scores improved in patients treated with LUM/IVA and worsened in the placebo group. These data suggest that LUM/IVA treatment may reduce CF disease-related changes in lung morphology and/or physiology and support the need for further study.Please refer to page A257 for declarations of interest in relation to abstract S93.[Figure]

ObjectiveTo evaluate ultrashort echo time (UTE) magnetic resonance imaging (MRI) as a feasible endpoint in a multicenter trial using a subset of patients aged 6 to 11 years with cystic fibrosis (CF) homozygous for the F508delmutation treated with lumacaftor/ivacaftor (LUM/IVA) combination therapy (NCT02514473).MethodsUTE MRI scans were obtained at study baseline (n=10); a second scan was completed at week 24 in 9 subjects (4 active treatment, 5 placebo) at 3 institutions using MRI hardware from 2 vendors. One of the platforms was 3D radial UTE (Johnson et al. Magn Reson Med. 2013;70:1241–1250); the other was 3D “stack of stars” UTE (Lederlin et al. J Magn Reson Imaging. 2014;40:839–847). Scans were obtained during 5 min of tidal breathing without the use of intravenous contrast. MRI scans were scored by 2 independent readers using the Brody score after supervised training on UTE MRI scans. Readers were blinded to time point and treatment group. Scores are presented as mean (SD); no statistical testing was performed.ResultsDespite the lower image quality of MRI compared with computed tomography, potential treatment effects were seen on the UTE MRI images (figure 1A). Mean total Brody score decreased from 41.1 to 32.5 with treatment, a change from baseline (SD) of 8.4 (11.2) with active treatment, but increased from 31.3 to 34.6, a change from baseline of 3.3 (8.2) with placebo (figure 1B). Mucus plugging subscore decreased by 5.0 (5.1) from 8.5 to 3.5 with active treatment but increased by 1.4 (4.4) from 4.2 to 5.6 with placebo. There were no noticeable changes in other subscores (bronchiectasis, peribronchial thickening, parenchyma, or hyperinflation).[Figure]ConclusionIn this analysis from an exploratory substudy in patients with CF aged 6 to 11 years homozygous for F508del, UTE MRI was a feasible approach for detecting the effect of LUM/IVA, despite the small sample size, short duration of treatment, and limitations in image quality. As optimisation in UTE MRI technology improves image quality, monitoring disease course in patients with CF may improve.Please refer to page A259 for declarations of interest in relation to abstract P254.