Lung clearance index predicts pulmonary exacerbations in young patients with cystic fibrosis

Abstract

RationaleThe lung clearance index (LCI) is a promising endpoint for use in cystic fibrosis (CF) clinical trials, but correlations with validated clinical endpoints have not yet been established. Objective This study aimed to demonstrate that, in young patients with CF, baseline LCI predicts subsequent pulmonary exacerbation (PE) and correlates with the respiratory domain of the CF Questionnaire-Revised (CFQ-R resp ). Methods Baseline LCI, forced expiratory volume in 1 s (FEV 1 ), CFQ-R resp and PEs over the subsequent year were prospectively recorded in 63 patients aged 5-19 years. The ability of baseline LCI to predict PE was assessed using negative binomial regression models and KaplanMeier plots. Results Twenty-six patients (41%) experienced 48 PEs. Baseline LCI and FEV 1 were predictors of PE. Compared with the quartile with the lowest LCI, the annual PE rate in increasing LCI quartiles was 2.9 (95% CI 0.5 to 16.5, p=0.238), 5.4 (95% CI 1.0 to 29.0, p=0.045) and 13.6 (95% CI 2.8 to 67.1, p=0.001). Similarly, time to first PE decreased with worsening LCI quartiles (log-rank test for trend, p<0.001). Furthermore, LCI correlated with CFQ-R resp (r=−0.43, p<0.001). In the subgroup of 53 patients with normal FEV 1 , LCI was a predictor of PE. In this subgroup, LCI also correlated with CFQ-R resp (r=−0.282, p=0.043). Conclusions Baseline LCI predicts PE in young patients with CF and correlates with CFQ-R resp , a validated patient-reported outcome, even in the subgroup with normal FEV 1 . These data further support the use of LCI as a surrogate outcome measure in CF clinical trials.

Multiple-Breath Washout as a Lung Function Test in Cystic Fibrosis. A Cystic Fibrosis Foundation Workshop Report

“…The majority of studies performed in subjects with CF are cross-sectional, where LCI is related to other measures of lung function (26,32), imaging (28,(33)(34)(35), or clinical status (36)(37)(38). These studies consistently demonstrate that, compared with healthy control subjects, LCI is abnormal in a significant proportion of preschool children with CF and in the majority of school-aged children and adults (32,33,35,39).…”

“…Increased LCI appears to predict those individuals who are more likely to have pulmonary exacerbations associated with infection (37), and LCI decreases when exacerbations are treated (45,46).…”

“…At these centers, MBW is performed on at least an annual basis; however, MBW may be performed more often if the physician is unclear about symptomatology and/or if symptoms are being reported by the patient or parents (weight deviation, loss of appetite, fatigue, irritability). Currently, an increase of 1 unit in the LCI value is considered a sign of deterioration in these centers (36,37). The medical history coupled with the LCI values is used as part of the clinical decision making for these patients.…”

Measurement of Serum Calprotectin in Stable Patients Predicts Exacerbation and Lung Function Decline in Cystic Fibrosis

“…Sputum high mobility group box 1 (HMGB1) levels may predict CF exacerbation (12), but this requires specialized sample processing that is not available in most clinics. The lung clearance index, a physiological measurement, also predicts exacerbation frequency and onset in children (13), but again requires specialized equipment. In contrast, calprotectin may be measured in serum with relative ease, underlined by its use in a pediatric study of azithromycin (14).…”

Validation of Multiple-Breath Washout Equipment: From Bench to Clinic and Possible Pitfalls

“…To date, measures obtained from the MBW have followed two parallel paths. First, the lung clearance index (LCI) has been shown to be a sensitive marker of cystic fibrosis and applicable in routine clinical practice or as study outcome in a predominantly paediatric population [1,2,3,4,5,6]. Other outcomes, such as the slope of phase III parameters (S acin and S cond ), have been found to predict disease course in asthmatic patients [7,8,9,10] and other respiratory conditions, but predominantly in adult populations [11,12,13].…”