Predicting progressive phenotype in patients with fibrotic interstitial lung disease

<bold>Background:</bold> Progressive fibrotic interstitial lung disease (PF-ILD) refers to a heterogeneous group of patients who show a worsening of their underlying condition despite optimal treatment. Predictors of this progression remain unknown. <bold>Aim:</bold> we aimed to investigate if any histological, molecular, radiological, or clinical features can predict a progressive phenotype in patients with fibrotic ILD. <bold>Methods:</bold> 215 patients with fibrotic interstitial lung disease other than IPF and CTD-ILD were followed in our ILD clinic between Jan2016 and May2023. Based on slides and tissue block availability, 48 patients were definitively enrolled. Progression was defined according to the recent guidelines. Clinical, radiological, and functional data were also collected retrospectively and correlated with tissue morphological and molecular cytokine profile. <bold>Results:</bold> 15 patients resulted as progressors (PF-ILD) and 33 as non-progressors (NP-ILD). Age at diagnosis [63(59-66)vs.62(54-72) years; p=0.80] and gender (60%vs.67%; p=0.70) were similar between the two groups. PF-ILD showed, at CT scan, a higher prevalence of bronchiectasis (80%vs.27%;p=<0.001) and lower functional parameters [FVC: 2.42Lvs.3.37L;p=0.004; TLC: 3.83Lvs.4.65L;p=0.027] at diagnosis. In lung specimens, we found a significant overexpression of IL9 in the PF-ILD compared to the NP-ILD group (p=0.049). Using Boruta algorithm analysis, higher lymphoid aggregates and bronchiectasis at diagnosis were two independent predictors of progression. Furthermore, patients with progressive phenotype showed lower survival for all causes of mortality (p=0.024). <bold>Conclusions:</bold> high n° of lymphoid aggregates, tissue IL9 aberrant expression and traction bronchiectasis seem to be associated with a higher risk of progression in patients with fibrotic ILD.