Progression of Lung Disease in Preschool Patients with Cystic Fibrosis

Abstract

Rationale: Implementation of intervention strategies to prevent lung damage in early cystic fibrosis (CF) requires objective outcome measures that capture and track lung disease.

Objectives: To define the utility of the Lung Clearance Index (LCI), measured by multiple breath washout, as a means to track disease progression in preschool children with CF.

Methods: Children with CF between the ages of 2.5 and 6 years with a confirmed diagnosis of CF and age-matched healthy control subjects were enrolled at three North American CF centers. Multiple breath washout tests were performed at baseline, 1, 3, 6, and 12 months to mimic time points chosen in clinical care and interventional trials; spirometry was also conducted. A generalized linear mixed-effects model was used to distinguish LCI changes associated with normal growth and development (i.e., healthy children) from the progression of CF lung disease.

Measurements and main results: Data were collected on 156 participants with 800 LCI measurements. Although both LCI and spirometry discriminated health from disease, only the LCI identified significant deterioration of lung function in CF over time. The LCI worsened during cough episodes and pulmonary exacerbations, whereas similar symptoms in healthy children were not associated with increased LCI values.

Conclusions: LCI is a useful marker to track early disease progression and may serve as a tool to guide therapies in young patients with CF.

Keywords: cystic fibrosis; disease progression; lung clearance index; lung function.

Figure 1.

Summary of study population. Multiple breath washout tests were considered technically acceptable according to quality control review criteria (31) and if there were at least two technically acceptable trials in a test occasion. Percentages are calculated based on the total number of visits expected (468 cystic fibrosis, 438 healthy control subjects), with the exception of the percentage successful, which is calculated as number technically acceptable/number analyzed. CF = cystic fibrosis subjects; HC = healthy control subjects; MBW = multiple breath washout.

Figure 2.

Median lung clearance index values (interquartile range) for healthy control subjects (gray) and cystic fibrosis subjects (black) at each of the six study visits. Lung clearance index was significantly higher in the cystic fibrosis group compared with the healthy group at each visit.

Figure 3.

The average change in lung clearance index (LCI) in healthy control subjects (HC) and cystic fibrosis subjects (CF). Slope (LCI units/yr) estimates were derived from an interaction term between diagnosis group and age using a mixed-effects model with repeated measures of LCI where random intercepts and random slopes were specified. The rate of deterioration of LCI in children with cystic fibrosis was significantly different from that observed in health.

Figure 4.

The average change in z score for forced expiratory volume in t seconds, where t is either 0.75 or 1 (zFEV_t) in health and cystic fibrosis. Slope (zFEV_t/yr) estimates were derived from an interaction term between diagnosis group and age using a mixed-effects model with repeated measures of zFEV_t where random intercepts only were specified. Although the intercepts differed between health and cystic fibrosis, the rate of decline in zFEV_t was similar in both groups. CF = cystic fibrosis subjects; HC = healthy control subjects.

Figure 5.

Association between pulmonary symptoms and lung clearance index (LCI) in health (solid line) and cystic fibrosis (CF) (dashed line). Estimates (absolute LCI during symptomatic visits relative to asymptomatic visits) derived from a mixed-effects model of LCI, adjusted for age; symptoms were treated as time-varying covariates. Neither upper airway symptoms nor cough were associated with higher LCI values in healthy participants, whereas both cough and pulmonary exacerbation were associated with significantly higher LCI values in CF (Table 4). Upper airways symptoms were not associated with higher LCI values in CF. PEx = pulmonary exacerbation.

Figure 6.

Association between pulmonary symptoms and z scores for the forced expiratory volume in t seconds, where t is either 0.75 or 1 (zFEV_t) in health (solid line) and cystic fibrosis (dashed line). Estimates (absolute zFEV_t during symptomatic visits relative to asymptomatic visits) derived from a mixed-effects model of lung clearance index, adjusted for age; symptoms were treated as time-varying covariates. Visits when both healthy and patients with cystic fibrosis had both upper and lower airway symptoms had significantly lower zFEV_t values, as did pulmonary exacerbation visits. PEx = pulmonary exacerbation.