Intervention trials and ventilation distribution in mild cystic fibrosis lung disease: will it all come out in the wash?

T he identification of clinically relevant end-points for use in clinical trials of new treatments in cystic fibrosis (CF) lung disease is an ongoing problem for physicians and researchers working in the field of CF care. Lung disease almost certainly starts in early infancy [1–6] and is progressive, leading to significant structural lung disease in the preschool years [7]. Despite this, the majority of young children with CF tend to have spirometry within the normal range at early school age [1, 8, 9]. It is well recognised that relying on spirometry alone to identify children at risk of progressive lung disease has significant limitations. This has led to renewed emphasis on the assessment of physiological outcomes in infancy and the preschool years, as well as increased focus on lung function tests that are more sensitive to early lung dysfunction than spirometry [10–13]. One such outcome is the assessment of ventilation inhomo-geneity obtained from the multiple breath inert gas washout test (MBW), the most commonly reported outcome being the lung clearance index (LCI). A significant advantage of this technique is that it can be applied from infancy through to adulthood, with only minor changes in equipment and methodology, particularly from the preschool years onwards [14–16]. The LCI has been shown to be abnormal in the presence of normal spirometry in both preschool children [7] and older children with CF [9, 17–22], suggesting that it is a more sensitive marker of early lung disease in such children. The LCI has also been found to be strongly associated with structural changes on computed tomography scans [19, 20, 21]. Nevertheless, there is limited evidence regarding the use of LCI as an outcome measure following therapeutic interventions in children with CF. ROBINSON et al. [23] demonstrated a small but significant group improvement in LCI of-0.48 (which equated to a mean reduction of 3.8%) following intravenous antibiotic treatment for a respiratory exacerbation in 28 school-aged children with CF, but noted marked heterogeneity of response between patients. FUCHS et al. [24] performed baseline MBW in 27 schoolchildren with CF, with measurements repeated 90 min later, after administrating chest physiotherapy to 16 of the patients, with no intervention in the remaining 11. Their results indicated that physiotherapy did not appear to have any significant effect either on mean LCI nor its within-test variability, although within-subject between-test changes in LCI over this period could be as high as 1.4. …