Comparison of Multiple Breath Washout and Spirometry in Children with Primary Ciliary Dyskinesia and Cystic Fibrosis and Healthy Controls

Abstract

Rationale: In cystic fibrosis (CF), the lung clearance index (LCI), derived from multiple breath washout (MBW), is more sensitive in detecting early lung disease than FEV₁; MBW has been less thoroughly evaluated in young patients with primary ciliary dyskinesia (PCD).Objectives: Our objectives were 1) to evaluate the sensitivity of MBW and spirometry for the detection of mild lung disease in young children with PCD and CF compared with healthy control (HC) subjects and 2) to compare patterns of airway obstruction between disease populations.Methods: We used a multicenter, single-visit, observational study in children with PCD and CF with a forced expiratory volume in 1 second (FEV₁) greater than 60% predicted and HC subjects, ages 3-12 years. Nitrogen MBW and spirometry were performed and overread for acceptability. χ² and Kruskall-Wallis tests compared demographics and lung function measures between groups, linear regression evaluated the effect of disease state, and Spearman's rank correlation coefficient compared the LCI and spirometric measurements.Results: Twenty-five children with PCD, 49 children with CF, and 80 HC children were enrolled, among whom 17 children with PCD (68%), 36 children with CF (73%), and 53 (66%) HC children performed both acceptable spirometry and MBW; these children made up the analytic cohort. The median age was 9.0 years (interquartile range [IQR], 6.8-11.1). The LCI was abnormal (more than 7.8) in 10 of 17 (59%) patients with PCD and 21 of 36 (58%) patients with CF, whereas FEV₁ was abnormal in three of 17 (18%) patients with PCD and six of 36 (17%) patients with CF. The LCI was significantly elevated in patients with PCD and CF compared with HC subjects (ratio of geometric mean vs. HC: PCD 1.27; 95% confidence interval [CI], 1.15-1.39; and CF 1.24; 95% CI, 1.15-1.33]). Children with PCD had lower midexpiratory-phase forced expiratory flow % predicted compared with children with CF (62% [IQR, 50-78%] vs. 85% [IQR, 68-99%]; P = 0.05). LCI did not correlate with FEV₁.Conclusions: The LCI is more sensitive than FEV₁ in detecting lung disease in young patients with PCD, similar to CF. LCI holds promise as a sensitive endpoint for the assessment of early PCD lung disease.

Keywords: cystic fibrosis; lung clearance index; lung function; multiple breath washout; primary ciliary dyskinesia.

Figure 1.

Forest plots for (A) estimated ratio of geometric mean lung clearance index (LCI) with 95% confidence interval (CI) for children with primary ciliary dyskinesia (PCD) or cystic fibrosis (CF) compared with healthy control subjects (reference), from regression analyses of log-transformed LCI data, adjusted for height, sex, and age. (B) Estimated difference in mean spirometric measures (95% CI) between children with PCD or CF and healthy control subjects from regression analyses. *LCI 2.5 were log-transformed for linear regression because of nonnormality. The resulting exponentiated parameter estimate provides the ratio of the geometric mean of each outcome by disease group to that of healthy control subjects. For example, patients with PCD have a geometric mean LCI 2.5 that is 26% higher than that of healthy control subjects of the same age, height, sex, and ethnicity (95% CI, 15–37% higher). ^†Calculated using Global Lung Initiative equations. The results are interpreted as the difference in the mean measure between children with PCD or CF and healthy control subjects of the same age, height, sex, and ethnicity. For example, the mean forced expiratory volume in 1 second % predicted of children with PCD is 11.1% lower than that of healthy control subjects (95% CI, −17.6 to −4.7). FEF_25–75 = forced midexpiratory flow at 25–75% of the expiratory volume; FEV₁ = forced expiratory volume in 1 second; FVC = forced vital capacity.

Figure 2.

Lung clearance index versus forced expiratory volume in 1 second (FEV₁) z-score, stratified by disease status (primary ciliary dyskinesia, cystic fibrosis, healthy control). The lung clearance index did not correlate with FEV₁ (PCD, R  =  −0.24; P  = 0.36; CF, R  = −0.27, P  = 0.11; and HC, R  = −0.08; P = 0.57). CF = cystic fibrosis; HC = healthy control; LCI = lung clearance index; PCD = primary ciliary dyskinesia.