Serum GDF15 adds prognostic value to forced vital capacity in fibrotic interstitial lung disease

BACKGROUND: Antifibrotic therapy slows fibrotic interstitial lung disease (ILD) progression. However, fibrotic ILD remains a major life-threatening condition, with associated morbidity and mortality increasing annually. Growth differentiation factor 15 (GDF15), a stress-responsive cytokine within the transforming growth factor beta superfamily, has garnered increasing attention regarding its association with cachexia and immunomodulation. It is also involved in cellular senescence and ageing, all of which have been implicated in the progression of lung fibrosis, METHODS: We measured serum GDF15 levels in 253 patients with fibrotic ILDs receiving antifibrotic therapy (discovery cohort, n = 91; validation cohort, n = 162) and 78 healthy controls. Associations with clinical parameters and survival were assessed. GDF15 expression in lung tissue was evaluated using histological analysis. RESULTS: Compared with healthy controls, serum GDF15 levels in patients with fibrotic ILDs were more than double. Although serum GDF15 levels were not associated with underlying aetiology or forced vital capacity (FVC), patients with higher GDF15 levels exhibited significantly shorter survival, independent of the gender-age-physiology-ILD index. A composite model incorporating FVC and serum GDF15 levels stratified patients into four distinct risk groups for mortality. GDF15 expression was more pronounced in epithelial foci within fibrotic and inflammatory regions, particularly in metaplastic epithelium, whereas histologically normal distal parenchyma did not express GDF15. CONCLUSIONS: Serum GDF15 provides independent and additive prognostic information beyond established clinical indices in fibrotic ILDs. These findings support the potential utility of GDF15 as a tool for improving prognostic assessment in patients receiving antifibrotic therapy. REGISTRATION: UMIN000039664, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000045245.