BACKGROUND: The association between immune-cell-specific transcriptomic profiles and mortality in IPF is unknown. METHODS: We profiled peripheral blood mononuclear cells (PBMC) by single-cell RNA sequencing (scRNA-seq) and investigated which immune-cell-specific transcriptomic profile predicted IPF outcomes consistently. Prognostic accuracy was investigated in PBMC, Bronchoalveolar Lavage (BAL) and lung tissue. Findings were validated by flow cytometry, analysis of independent scRNA-seq datasets and cellular deconvolution. We investigated the function of this transcriptomic profile and its cellular source in lung tissue (overall sample size:1054, IPF:555, other:499). Connectivity map and LASSO regression were used to identify drug candidates and a subset of genes with prognostic potential, respectively. RESULTS: A 230-gene-up-score (Pittsburgh-PBMC) from CD14(+)CD163(-)HLA-DR(low) monocytes predicted mortality in Chicago PBMC cohort (HR: 6.58, 95%CI:2.15-20.13, p=0.001), in BAL pooled analysis (HR: 2.20, 95%CI: 1.44-3.37, p=0.0003) and negatively correlated with Forced Vital Capacity (FVC) in lung tissues (
