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In patients with cystic fibrosis, cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers, such as sweat chloride concentration and/or nasal potential difference, are used as end-points of efficacy in phase-III clinical trials with the disease modifying drugs ivacaftor (VX-770), VX809 and ataluren. The aim of this project was to review the literature on reliability, validity and responsiveness of nasal potential difference, sweat chloride and intestinal current measurement in patients with cystic fibrosis. Data on clinimetric properties were collected for each biomarker and reviewed by an international team of experts. Data on reliability, validity and responsiveness were tabulated. In addition, narrative answers to four key questions were discussed and agreed by the team of experts. The data collected demonstrated the reliability, validity and responsiveness of nasal potential difference. Fewer data were found on reliability of sweat chloride concentration; however, validity and responsiveness were demonstrated. Validity was demonstrated for intestinal current measurement, but further information is required on reliability and responsiveness. For all three end-points, normal values were collected and further research requirements were proposed. This body of work adds useful information to support the promotion of CFTR biomarkers to surrogate end-points and to guide further research in the area.

This European Respiratory Society task force has reviewed the evidence for paediatric medicines in respiratory disease occurring in adults and children. We describe off-licence use, research priorities and ongoing studies. Off-licence and off-label prescribing in children is widespread and potentially harmful. Research areas in asthma include novel formulations and regimens, and individualised prescribing. In cystic fibrosis, future studies will focus on screened infants and robust outcome measures are needed. Other areas include new enzyme and antibiotic formulations and the basic defect. Research into pneumonia should include evaluation of new antibacterials and regimens, rapid diagnostic tests and, in pleural infection, antibiotic penetration, fibrinolytics and surveillance. In uncommon conditions, such as primary ciliary dyskinesia, congenital pulmonary abnormalities or neuromuscular disorders, drugs indicated for other conditions (e.g. dornase alfa) are commonly used and trials are needed. In neuromuscular disorders, the beta-agonists may enhance muscle strength and are in need of evaluation. Studies of antibiotic prophylaxis, immunoglobulin and antifungal drugs are needed in immune deficiency. We hope that this summary of the evidence for respiratory medicines in children, highlighting gaps and research priorities, will be useful for the pharmaceutical industry, the paediatric committee of the European Medicines Agency, academic investigators and the lay public.

BACKGROUND: Published studies concerning the impact of specialist care on lung disease in cystic fibrosis remain limited and most are either biased due to comparison with historical controls and/or underpowered. METHODS: In this retrospective multicentric study, data from all CF children fulfilling the following criteria were collected: 1) Age 6-<18 at the end of 2003; 2) diagnosis before 8 y; 3) follow-up in an accredited CF Belgian centre; 4) at least 1 spirometry and respiratory culture available for 2003. Group A included children referred >/=2 years after the diagnosis. Patients from Group A were then matched with a single early referred patient on the basis of 2 criteria: same centre, as closest age as possible (Group B). RESULTS: Data from 217 children were collected (Group A: 67/217). Late referred patients had a lower FEV(1) (77.2%+/-22.4 vs 86.7% pred.+/-19.4, p=0.01) and a higher prevalence of Pseudomonas aeruginosa (38.6 vs 17.5%, p<0.05). CONCLUSION: In this population of CF children, a delay of 6.1 y (vs 0.1 y) between diagnosis and referral to a specialist clinic resulted in poorer respiratory outcome at age 13.

BACKGROUND: In patients with symptoms suggestive of cystic fibrosis (CF) and intermediate sweat chloride values (30-60 mmol/l), extensive CFTR gene mutation analysis and nasal potential difference (NPD) measurement are used as additional diagnostic tests and a positive result in either test provides evidence of CFTR dysfunction. To define the phenotype of such patients and confirm the validity of grouping them, patients with intermediate sweat chloride values in whom either additional CF diagnostic test was abnormal were compared with subjects in whom this was not the case and patients with classic CF. METHODS: The phenotypic features of four groups were compared: 59 patients with CFTR dysfunction, 46 with an intermediate sweat chloride concentration but no evidence of CFTR dysfunction (CF unlikely), 103 patients with CF and pancreatic sufficiency (CF-PS) and 62 with CF and pancreatic insufficiency (CF-PI). RESULTS: The CFTR dysfunction group had more lower respiratory tract infections (p = 0.01), more isolation of CF pathogens (p<0.001) and clubbing (p = 0.001) than the CF unlikely group, but less frequent respiratory tract infections with CF pathogens than the CF-PS group (p = 0.05). Patients in the CF-PS group had a milder phenotype than those with PI. Many features showed stepwise changes through the patient groups. CONCLUSION: Patients with intermediate sweat chloride values and two CFTR mutations or an abnormal NPD measurement have a CF-like phenotype compatible with CFTR dysfunction and, as a group, differ phenotypically from patients with intermediate sweat chloride values in whom further CF diagnostic tests are normal as well as from CF-PS and CF-PI patients.

Published studies concerning the impact of specialist care on lung disease in cystic fibrosis remain limited and most are either biased due to comparison with historical controls and/or underpowered., Journal Article, Multicenter Study, SCOPUS: ar.j, info:eu-repo/semantics/published

The source of acquisition of Pseudomonas aeruginosa in cystic fibrosis (CF) patients remains unknown. Patient-to-patient transmission has been well documented but the role of the environment as a source of initial infection is as yet unclear. In the present study, the origin of the first P. aeruginosa isolate in CF patients was investigated by comparing the P. aeruginosa genotype(s) from newly infected patients with genotypes of P. aeruginosa isolates from the home environment and from other patients from the same CF centre. A total of 50 newly infected patients were studied. P. aeruginosa could be cultured from 5.9% of the environmental samples, corresponding to 18 patients. For nine of these, the genotype of the environmental P. aeruginosa isolate was identical to the patient's isolate. In total, 72% of the environmental P. aeruginosa isolates were encountered in the bathroom. Patient-to-patient transmission within the CF centre could not be ruled out for three patients. In summary, a low prevalence of Pseudomonas aeruginosa was found in the home environment of the newly infected cystic fibrosis patients. The bathroom should be targeted in any preventive cleaning procedures. An environmental source of the new infection could not be ruled out in nine patients.

The source of acquisition of Pseudomonas aeruginosa in cystic fibrosis (CF) patients remains unknown. Patient-to-patient transmission has been well documented but the role of the environment as a source of initial infection is as yet unclear. In the present study, the origin of the first P. aeruginosa isolate in CF patients was investigated by comparing the P. aeruginosa genotype(s) from newly infected patients with genotypes of P. aeruginosa isolates from the home environment and from other patients from the same CF centre. A total of 50 newly infected patients were studied. P. aeruginosa could be cultured from 5.9% of the environmental samples, corresponding to 18 patients. For nine of these, the genotype of the environmental P. aeruginosa isolate was identical to the patient's isolate. In total, 72% of the environmental P. aeruginosa isolates were encountered in the bathroom. Patient-to-patient transmission within the CF centre could not be ruled out for three patients. In summary, a low prevalence of Pseudomonas aeruginosa was found in the home environment of the newly infected cystic fibrosis patients. The bathroom should be targeted in any preventive cleaning procedures. An environmental source of the new infection could not be ruled out in nine patients.

Despite absence of clear proof of efficacy, the use of inhaled corticosteroids (ICS) is widespread in cystic fibrosis (CF) patients. Therefore, the effect of ICS on lung function and other clinical variables was studied in 27 prepubertal CF children with mild to moderate lung disease. In a prospective double-blind case-controlled study, fluticasone propionate 500 μg or placebo were administered twice daily during 12 months. The mean (standard error of the mean, SEM) patient age was 8.2 (0.6) years in the placebo group and 9.0 (0.5) years in the fluticasone group. The mean (SEM) forced expiratory volume in 1 s (FEV1) was 91% (4%) in the placebo group and 86% (4%) in the fluticasone group. There was no statistically significant difference in the evolution of lung function and the number of respiratory exacerbations between groups. However, longitudinal growth in fluticasone patients was significantly slower than in placebo patients: 3.96 (0.29) cm versus 5.49 (0.38) cm [p<0.005, analysis of variance (ANOVA)] over the 12-month study duration. This resulted in a significant change in height standard deviation score (SDS) of -0.38 (0.09) in the fluticasone group versus -0.01 (0.07) in the placebo group (p<0.003, ANOVA). No catch-up growth was noted 1-2 years after discontinuation of inhaled steroids. The use of high-dose ICS in CF patients with mild lung disease may lead to persistent growth impairment. © 2006 Springer-Verlag., SCOPUS: ar.j, info:eu-repo/semantics/published

The current authors aimed to examine whether cystic fibrosis (CF) patients in Belgium shared Pseudomonas aeruginosa genotypes and to compare the genotypes of isolates from the same patients during two consecutive years. A Belgian databank of the P. aeruginosa genotypes of all colonised CF patients was created. Sputum samples from a total of 276 P. aeruginosa colonised patients during 2003, and from a subgroup of 95 patients in 2004, were analysed. Patients were asked about any social contact between each other by questionnaire. All P. aeruginosa isolates exhibiting different colonial morphology on McConkey agar were first genotyped using arbitrarily primed PCR, whereafter single representatives of each randomly amplified polymorphic DNA-type were further genotyped by fluorescent amplified fragment length polymorphism analysis. In the 213 patients from whom P. aeruginosa could be cultured (resulting in 910 isolates), a total of 163 genotypes were found. The majority (75%) of patients harboured only one genotype. In most of the limited number of clusters, previous contacts between patients could be suspected. In 80% of the patients studied during both years, P. aeruginosa genotype remained unchanged. In conclusion, most colonised cystic fibrosis patients harbour only one Pseudomonas aeruginosa genotype, despite showing different colonial morphotypes. The number of clusters is limited, and most patients seem to retain the same genotypic strain during both years.

The current authors aimed to examine whether cystic fibrosis (CF) patients in Belgium shared Pseudomonas aeruginosa genotypes and to compare the genotypes of isolates from the same patients during two consecutive years. A Belgian databank of the P. aeruginosa genotypes of all colonised CF patients was created. Sputum samples from a total of 276 P. aeruginosa colonised patients during 2003, and from a subgroup of 95 patients in 2004, were analysed. Patients were asked about any social contact between each other by questionnaire. All P. aeruginosa isolates exhibiting different colonial morphology on McConkey agar were first genotyped using arbitrarily primed PCR, whereafter single representatives of each randomly amplified polymorphic DNA-type were further genotyped by fluorescent amplified fragment length polymorphism analysis. In the 213 patients from whom P. aeruginosa could be cultured (resulting in 910 isolates), a total of 163 genotypes were found. The majority (75%) of patients harboured only one genotype. In most of the limited number of clusters, previous contacts between patients could be suspected. In 80% of the patients studied during both years, P. aeruginosa genotype remained unchanged. In conclusion, most colonised cystic fibrosis patients harbour only one Pseudomonas aeruginosa genotype, despite showing different colonial morphotypes. The number of clusters is limited, and most patients seem to retain the same genotypic strain during both years., Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published