Longitudinal changes in KL6 levels predict acute exacerbation in fibrotic interstitial lung disease

Abstract

Krebs von den Lungen-6 (KL-6) levels are potentially indicative markers of prospective acute exacerbation (AE) in interstitial lung disease (ILD); however, their longitudinal trends have not been sufficiently investigated. We investigated the predictive ability of patient-specific changes in serum KL-6 levels for predicting AE in patients with fibrotic ILD. We included patients with fibrotic ILDs from the RWD database in Japan who received antifibrotic therapy and had at least two serum KL-6 values during the follow-up. The outcome was AE defined based on primary diagnoses, emergency admission, and pulse/high-dose steroids on the day of or after admission. We used the joint regression model integrating longitudinal and survival analyses to assess the predictive ability of each patient's serial serum KL-6 measurements for AE. Among 939 patients with fibrotic ILDs, 194 (21%) patients experienced AE during follow-up (event rate, 0.13/person-year; 1-year incidence, 35%). The AE hazard ratio comparing patients with differing cumulative serum KL-6 levels was 1.54 (95% confidence interval: 1.20-1.98, p < 0.001). In conclusion, AE in fibrotic ILD patients on antifibrotic therapy may be predicted by high baseline KL-6 levels and their increasing trend. Serial KL-6 monitoring can serve as a valuable tool in a multifaceted approach.

Keywords: Acute exacerbation; Fibrotic interstitial lung disease; Interstitial lung disease exacerbation; Interstitial pneumonia; KL-6; Serum Krebs von Den Lungen-6.

Fig. 1

Study overview. The index date referred to when a patient with a disease code related to interstitial pneumonia was prescribed anti-fibrotic therapy. The patient was tracked until acute exacerbation or censoring, and serial results of serum Krebs von den Lungen-6 levels until the end of follow-up were collected. The changes in serum KL-6 levels were modelled by longitudinal analysis, and the association with the hazard of acute exacerbation was modelled with survival analysis through a joint regression model.

Fig. 2

Flow diagram of patient selection. Overall, 41,658 patients with a disease code of interstitial lung disease (ILD) were identified; among them, 1,112 patients received antifibrotic therapy. After excluding 173 patients with ≤ 1 measurement of Krebs von den Lungen-6 levels, 939 patients with fibrotic ILDs were included in the final analysis.

Fig. 3

Spaghetti plots of Krebs von den Lungen-6 (KL-6) levels. (a) Individual-level trajectories of KL-6 levels from the index date, along with a smoothing line for the average trend. On average, patients with acute exacerbation (AE) have higher serum KL-6 values over time than those without. (b) Individual-level trajectories of serum KL-6 from the end of the follow-up. A slight increasing trend in the serum KL-6 is observed before AE, and the trend before censoring is flat.