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This single-center prospective study included 154 hospitalized and 10 outpatient COVID-19 patients, 62 IPF patients, and 40 healthy volunteers, and evaluated biomarkers of alveolar epithelial cell dysfunction, extracellular matrix (ECM) and fibroblast dysfunction, and macrophage\/monocyte activation (Galectin-3, CXCL13). Findings were further validated in an independant confirmation cohort (DisCoVeRy trial). COVID-19 patients had higher levels of biomarkers compared to healthy controls, except for SP-D. Compared to IPF patients, COVID-19 patients had significantly higher plasma levels of OPN, Galectin-3 and CXCL13 at admission. Elevated CXCL13 and Galectin-3 levels in COVID-19 were associated with greater lung injury. Multivariate logistic regression and Kaplan Meier analysis confirmed the role of CXCL13 in predicting severe lung injury (odd ratio 3.17, 95% CI 1.03\u20139.76) and in-hospital mortality (p\u2009=\u20090.04), with consistent results observed in the confirmation cohort. 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