Evaluation of clinically relevant changes in the lung clearance index in children with cystic fibrosis and healthy controls

Abstract

BackgroundThe limits of reproducibility of the lung clearance index (LCI) are higher in children with cystic fibrosis (CF) compared with healthy children, and it is currently unclear what defines a clinically meaningful change.MethodsIn a prospective multisite observational study of children with CF and healthy controls (HCs), we measured LCI, FEV1% predicted and symptom scores at quarterly visits over 2 years. Two reviewers performed a detailed review of visits to evaluate the frequency that between visit LCI changes outside ±10%, ±15%, ±20% represented a clinically relevant signal. In the setting of acute respiratory symptoms, we used a generalised estimating equation model, with a logit link function to determine the ability of LCI worsening at different thresholds to predict failure of lung function recovery at follow-up.ResultsClinically relevant LCI changes outside ±10%, ±15% and ±20% were observed at 25.7%, 15.0% and 8.3% of CF visits (n=744), respectively. The proportions of LCI changes categorised as noise, reflecting biological variability, were comparable between CF and HC at the 10% (CF 9.9% vs HC 13.0%), 15% (CF 4.3% vs HC 3.1%) and 20% (CF 2.4% vs HC 1.0%) thresholds. Compared with symptomatic CF visits without a worsening in LCI, events with ≥10% LCI increase were more likely to fail to recover baseline LCI at follow-up.ConclusionThe limits of reproducibility of the LCI in healthy children can be used to detect clinically relevant changes and thus inform clinical care in children with CF.

Variability of clinically measured lung clearance index in children with cystic fibrosis

“…Further, the lack of a healthy control group limits our interpretation of whether the observed variability truly reflects a change in the disease state. However, current literature showed that the biological variability of LCI is similar between health and CF and that changes above can be interpreted as clinically and physiologically meaningful with similar thresholds as in our study 34,40 …”

“…To assess whether individual variability is an indicator of disease status not captured by other clinical signs and symptoms or based on systems dynamics, 33 longitudinal studies combining imaging, lung function, and assessment of lower respiratory tract inflammation and infection with longer observation periods are needed to understand the exact cause of this variability. Until further insight into individual variability is provided, we propose, in clinical surveillance, our population‐derived limit of 19% change in LCI being considered physiologically relevant, but as suggested by Perrem et al, 34 an increase in LCI should always be reviewed in the context of clinical signs and symptoms. An increase in LCI can result from functional (e.g., mucus plugging) or structural impairment within the lungs (e.g., chronic infection leading to bronchiectasis) 2,4,35,36 .…”

“…However, current literature showed that the biological variability of LCI is similar between health and CF and that changes above can be interpreted as clinically and physiologically meaningful with similar thresholds as in our study. 34,40…”

Impact of Reanalysis of Nitrogen Multiple-Breath Washout on its Relationship with Chest Magnetic Resonance Imaging Findings in Clinically Stable and Pulmonary Exacerbated Children with Cystic Fibrosis

“…This underlines the sustained sensitivity of N 2 MBW to detect response to treatment with the adapted software [6,10,31]. In comparison to previously published studies focusing on PEx and N 2 LCI pre , the intra-and interindividual variability of N 2 LCI cor in different health conditions was lower than of N 2 LCI pre in our study [32].…”

Migration is not the perfect answer: How the cross‐talk error correction for multiple breath nitrogen washout (MBWN2) parameters differs on directly collected vs. legacy data

“…We found approximately 40% of values directly collected in the corrected software were >10% higher than migrated values. Recently Perrem et al 2022, 8 demonstrated that a change in LCI 2.5 > 10% compared to previous values should be considered clinically relevant if there was a corresponding change in FEV 1 and/or symptoms (>15% in the absence of supportive clinical change). Therefore, in clinical practice, comparing collected versus migrated/rerun data an apparent “clinical change” may appear artefactually.…”