Longitudinal Mediastinal Lymph Node Dynamics Associate with Mortality and Fibrosis Progression in Fibrotic ILD.

Abstract

Mediastinal lymph node (MLN) enlargement is common in fibrotic interstitial lung disease (ILD), yet its dynamic behavior and prognostic value are unclear. Do MLN size, count, and progression on HRCT associate with physiologic decline, fibrosis progression, and transplant-free survival (TFS), and do they improve risk models? Prospective cohort of patients with fibrotic ILD from a tertiary center (n=1,122) with independent replication (n=181). MLNs were scored using standardized radiologic criteria; fibrosis was quantified by deep texture analysis. Associations with outcomes were evaluated using Cox and linear mixed-effects models; model discrimination was assessed using Harrell's concordance index and net benefit by decision curve analysis. Baseline MLN enlargement (≥10 mm) occurred in 67% and was independently associated with worse TFS (HR 2.44; 95% CI, 2.01-2.96; P<0.0001). MLN progression (ΔMLN) was associated with excess mortality (adjusted HR 4.09; 95% CI, 2.34-7.17; P<0.001) and modified the association between fibrosis progression and survival (interaction HR 3.02; P=0.001). Fibrosis remained the stronger prognostic marker, but MLN metrics added complementary information within fibrosis strata and modestly improved discrimination when added to clinical models based on ILD-GAP or PPF status. Findings were directionally consistent in the independent replication cohort. MLN burden and progression are accessible, quantifiable imaging biomarkers associated with adverse outcomes in fibrotic ILD. Incorporating MLN metrics into existing clinical models improves risk discrimination and supports further evaluation of their role in ILD risk stratification. Pulmonary fibrosis (PF) encompasses a heterogeneous group of interstitial lung diseases (ILDs) marked by progressive matrix deposition, immune activation, impaired gas exchange, and increased mortality.^1-5 Although HRCT fibrosis and physiologic indices (FVC, DLCO) aid risk stratification, they incompletely capture disease biology. Mediastinal lymphadenopathy (MLN) is frequent in fibrotic ILD,^1-10 yet remains absent from current indices (ILD-GAP, 2022 ATS/ERS PPF criteria). ^11-13 Prior studies suggest that MLN enlargement correlates with disease severity, but these reports have been limited by cross-sectional designs, imaging heterogeneity, and incomplete adjustment for key covariates.^2,5,14-16 Prior literature has also raised the possibility that MLN features may vary by treatment exposure,² although this has not been evaluated in a prospectively followed, systematically phenotyped cohort. We therefore assessed whether MLN size, count, and longitudinal change associate with transplant-free survival (TFS) in fibrotic ILD, with independent validation in a replication cohort. Secondary objectives were to examine associations of MLN burden with fibrosis progression, physiologic decline, and treatment exposure, and to determine whether adding MLN metrics improves established clinical models including ILD-GAP and PPF.