(176) How frequently should the lung clearance index be measured in children with cystic fibrosis?

Background: The lung clearance index (LCI) can identify individuals with CF at risk of subsequent lung function decline [1]. Some CF centers have implemented LCI measurements as part of a routine annual assessment, but it is currently unclear what the optimal monitoring frequency is and whether more frequent LCI measurements (e.g., every 3 or 6 months) would enhance the detection of otherwise clinically stable individuals with deteriorating lung function.

Methods: In a prospective longitudinal study, school-age children with CF (98 subjects) were followed and LCI was measured every 3 months for 2 years. Study visits were categorized as clinically stable (i.e., respiratory symptoms judged to be representative of a participant’s baseline) or as acute respiratory event visits (i.e., increased respiratory symptoms). The baseline LCI for each study visit to calculate a relative change was defined as an LCI measurement from a stable visit 3 months, 6 months, or 12 months before. A significant change was defined as an LCI increase of 10%, a threshold than can identify clinically meaningful changes in LCI [1]. We used generalized estimating equation models (GEE) for linear and binary outcomes to determine whether different testing intervals impacted the magnitude of LCI change between stable visits or the proportion of visits associated with a ≥10% worsening in LCI, respectively.

Results: On average, LCI changes between stable visits were similar when a 3-month (0.22%; 95% CI -1.2% to 1.6%; reference group), 6-month (0.45% ;95% CI -0.1% to 2.0%; p=0.85) or 12-month (1.44%; 95% CI -0.13% to 3.0%; p=0.33) baseline was used to calculate changes. On an individual level, a similar proportion of stable visits were associated with a ≥10% increase in LCI when different baseline LCI values were used to calculate changes (3-month baseline (reference group) n=259; 13.2% (95% CI 8.8% to 17.7%), 6-month baseline n=204; 16.5% (95% CI 11.1% to 21.9%) p=0.31, 12-month baseline n=171; 19.8% (95% CI 14.0% to 25.6%) p=0.052). However, significantly more acute respiratory event visits (including treated and untreated events) qualified as a ≥10% worsening in LCI when the baseline was defined as a stable visit 6-months (n=109; 44.0%; 95% CI 34.2% to 53.8%; p=0.008) or 12 months (n=94; 42.8%; 95% CI 32.3% to 53.1%; p=0.019) before, compared to 3 months (n=140; 28.7%; 95% CI 20.7% to 36.7%).

Conclusions: Compared with annual monitoring, more frequent LCI testing in clinically stable children does not increase the detection of significant LCI changes. However, if LCI is being used to define lung function worsening with acute respiratory events, shorter intervals between tests increase the precision of classifying events with worsened lung function.

Acknowledgements: Funding for the study was obtained from the Cystic Fibrosis Foundation(award no RATJEN16A0), Cystic Fibrosis Canada (Grant ID: 3187) and the Cystic Fibrosis Foundation Therapeutics Development Network National Resource Center (Center for Pediatric Lung Function).

References:

1. Horsley AR, Belcher J, Bayfield K, et al. Longitudinal assessment of lung clearance index to monitor disease progression in children and adults with cystic fibrosis. Thorax 2021;:thoraxjnl-2021-216928. doi:10.1136/thoraxjnl-2021-216928


2. Perrem L, Stanojevic S, Solomon M, et al. Evaluation of clinically relevant changes in the lung clearance index in children with cystic fibrosis and healthy controls. Thorax 2022 (in press).