Background: A sensitive and valid non-invasive marker of early cystic fibrosis (CF) lung disease is sought. The lung clearance index (LCI) from multiple-breath washout (MBW) is known to detect abnormal lung function more readily than spirometry in children and teenagers with CF, but its relationship to structural lung abnormalities is unknown. A study was undertaken to determine the agreements between LCI and spirometry, respectively, with structural lung disease as measured by highresolution computed tomography (HRCT) in children and teenagers with CF. Methods: A retrospective study was performed in 44 consecutive patients with CF aged 5-19 years (mean 12 years). At an annual check-up inspiratory and expiratory HRCT scans, LCI and spirometric parameters (forced expiratory volume in 1 s (FEV 1 ) and maximal expiratory flow when 75% of forced vital capacity was expired (FEF 75 )) were recorded. Abnormal structure was defined as a composite HRCT score of .5%, the presence of bronchiectasis or air trapping .30%. Abnormal lung function was defined as LCI above the predicted mean +1.96 residual standard deviations (RSD), or FEV 1 or FEF 75 below the predicted mean 21.96 RSD. Sensitivity/specificity assessments and correlation analyses were done. Results: The sensitivity to detect abnormal lung structure was 85-94% for LCI, 19-26% for FEV 1 and 62-75% for FEF 75 . Specificity was 43-65% for LCI, 89-100% for FEV 1 and 75-88% for FEF 75 . LCI correlated better with HRCT scores (Rs +0.85) than FEV 1 (20.62) or FEF 75 (20.66). Conclusions: LCI is a more sensitive indicator than FEV 1 or FEF 75 for detecting structural lung disease in CF, and a normal LCI almost excludes HRCT abnormalities. The finding of an abnormal LCI in some patients with normal HRCT scans suggests that LCI may be even more sensitive than HRCT scanning for detecting lung involvement in CF.

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Background: Multiple breath inert gas washout (MBW) has been suggested as a tool for detecting early cystic fibrosis (CF) lung disease. A study was undertaken to compare the relative sensitivity of MBW and spirometry for detecting abnormal lung function in school age children with CF and to compare MBW results obtained from healthy children in the UK with those recently reported from Sweden. Methods: Forced expiratory volume in 1 second (FEV 1 ) and maximal expiratory flow when 25% of forced vital capacity remains to be expired (MEF 25 ) were compared with the lung clearance index (LCI) derived from sulphur hexafluoride MBW in 22 children with CF aged 6-16 years and in 33 healthy controls. Results: LCI was higher in children with CF than in healthy controls (mean difference 5.1 (95% CI of difference 4.1 to 6.1) and FEV 1 and MEF 25 z-scores were lower (mean difference 22.3 (95% CI 22.9 to 21.7) and 21.8 (95% CI 22.4 to 21.3), respectively; p,0.001 for all). There was a significant negative correlation between LCI and FEV 1 (r 2 = 0.62) and MEF 25 (r 2 = 0.46). However, while normal (>21.96 z-scores) FEV 1 and MEF 25 results were seen in 11 (50%) and 12 (53%) children with CF, respectively, all but one of these children had an abnormally increased LCI. LCI was repeatable in both groups (within subject CV for three measurements 6% for CF and 5% for healthy children). In healthy subjects LCI was independent of age and virtually identical in the British and Swedish children (mean difference 0.1 (95% CI 20.1 to 0.4), p = 0.38) Conclusions: MBW is reproducible between laboratories, generates normal ranges which are constant over childhood, and is more frequently abnormal than spirometry in children with CF.

The median age of the population with cystic fibrosis (CF) has increased worldwide, which has led to the suggestion that the prevalence of liver disease would increase. The aim of this study was to evaluate the natural history of CF‐associated liver disease over a 15‐year period in a well‐controlled population of patients with CF. During the years 1976 through 1993, 124 patients were followed up by yearly liver function tests (LFTs). Fifteen patients were followed up with liver biopsies throughout the whole study period. More than 50% of the patients had pathological LFTs in infancy, later being normalized. Approximately 25% of children 4 years of age or older had biochemical markers of liver disease during the study period. In about 10% of the patients, cirrhosis or advanced fibrosis was confirmed at biopsy and 4% of patients had cirrhosis with clinical liver disease. Severe liver disease developed mainly during prepuberty and puberty. Of the 15 patients prospectively followed up with liver biopsies, only 3 had progressive fibrosis. No specific risk factor was identified, but deficiency of essential fatty acids was found more often in patients with marked steatosis (P < .05). No patient developed clinical liver disease in adulthood and the histological changes in the liver biopsies were usually not progressive. Liver disease was no more frequent at the end of the study period although the median age of the patient population had increased. Modern treatment might positively influence liver disease because it seemed less common, less progressive, and less serious than previously reported.

Mycobacterium abscessus has been isolated increasingly often from the respiratory tracts of cystic fibrosis (CF) patients. It is not known whether these organisms are transmitted from person to person or acquired from environmental sources. Here, colony morphology and pulsed-field gel electrophoresis (PFGE) pattern were examined for 71 isolates of M. abscessus derived from 14 CF patients, three non-CF patients with chronic respiratory M. abscessus infection or colonization, one patient with mastoiditis, and four patients with infected wounds, as well as for six isolates identified as environmental contaminants in various clinical specimens. Contaminants and wound isolates mainly exhibited smooth colony morphology, while a rough colony phenotype was significantly associated with chronic airway colonization (P ‫؍‬ 0.014). Rough strains may exhibit increased airway-colonizing capacity, the cause of which remains to be determined. Examination by PFGE of consecutive isolates from the same patient showed that they all represented a single strain, even in cases where both smooth and rough isolates were present. When PFGE patterns were compared, it was shown that 24 patients had unique strains, while four patients harbored strains indistinguishable by PFGE. Two of these were siblings with CF. The other two patients, one of whom had CF, had not had contact with each other or with the siblings. Our results show that most patients colonized by M. abscessus in the airways have unique strains, indicating that these strains derive from the environment and that patient-to-patient transmission rarely occurs.

A significant increase in life expectancy in successive birth cohorts of people with cystic fibrosis (CF) is a result of more effective treatment for the disease. It is also now widely recognized that outcomes for patients cared for in specialist CF Centres are better than for those who are not. Key to the effectiveness of the specialist CF Centre is the multidisciplinary team (MDT), which should include consultants, clinical nurse specialist, microbiologist, physiotherapist, dietitian, pharmacist, clinical psychologist, social worker, clinical geneticist and allied healthcare professionals, all of whom should be experienced in CF care. Members of the MDT are also expected to keep up to date with developments in CF through continued professional development, attendance at conferences, auditing and involvement in research. Specialists CF Centres should also network with other Centres both nationally and internationally, and feed Centre data to registries in order to further the understanding of the disease. This paper provides a framework for the specialist CF Centre, including the organisation of the Centre and the individual roles of MDT members, as well as highlighting the value of CF organisations and disease registries.

Background: A study was undertaken to compare the ability of computed tomographic (CT) scores and pulmonary function tests to detect changes in lung disease in children and adults with cystic fibrosis (CF). Methods: CT scans and pulmonary function tests were retrospectively studied in a cohort of patients with CF aged 5-52 years for whom two or three CT scans at 3 year intervals were available, together with pulmonary function test results. All CT scans were scored by two observers. Pulmonary function results were expressed as percentage predicted and Z scores. Results: Of 119 patients studied, two CT scans were available in 92 patients and three in 24. CT (composite and component) scores and lung function both deteriorated significantly (p,0.02). Peripheral bronchiectasis worsened by 1.7% per year in children (p,0.0001) and by 1.5% per year in adults (p,0.0001). Bronchiectasis worsened in 68 of 92 patients while forced expiratory volume in 1 second (FEV 1 ) worsened in 54 of 92 patients; bronchiectasis also deteriorated in 27 patients with stable or improving FEV 1 . The CT score (and its components) and pulmonary function tests showed similar rates of deterioration in adults and children (p.0.09). Conclusion:The peripheral bronchiectasis CT score deteriorates faster and more frequently than lung function parameters in children and adults with CF, which indicates that pulmonary function tests and CT scans measure different aspects of CF lung disease. Our data support previous findings that the peripheral bronchiectasis CT score has an added value to pulmonary function tests in monitoring CF lung disease.

The ECFS-CTN Standardisation Committee has undertaken this review of lung clearance index as part of the group's work on evaluation of clinical endpoints with regard to their use in multicentre clinical trials in CF. The aims were 1) to review the literature on reliability, validity and responsiveness of LCI in patients with CF, 2) to gain consensus of the group on feasibility of LCI and 3) to gain consensus on answers to key questions regarding the promotion of LCI to surrogate endpoint status. It was concluded that LCI has an attractive feasibility and clinimetric properties profile and is particularly indicated for multicentre trials in young children with CF and patients with early or mild CF lung disease. This is the first article to collate the literature in this manner and support the use of LCI in clinical trials in CF.