A93-10 Neutrophilic Dysregulated Host Response Is Seen in Idiopathic Pulmonary Fibrosis and Is Associated With Reduced Transplant-free Survival

Introduction We recently described a framework to quantify immune dysregulation in peripheral blood using cell-specific gene expression scores across the severity spectrum in sepsis (Moore et al, Nature Medicine). Given the associations between elevated neutrophil proportion in blood and bronchoalveolar lavage fluid and poor outcomes in idiopathic pulmonary fibrosis (IPF), we investigated whether the myeloid dysregulation score (MDS), which includes neutrophil-specific genes, generalizes to IPF and whether this differs depending on the collection technique. Methods We calculated the MDS at baseline in bulk RNA sequencing data from whole blood (containing all peripheral blood cells, including neutrophils) or peripheral blood mononuclear cell (PBMC) samples for 409 subjects (295 IPF patients, 114 healthy) in four publicly available IPF datasets (GSE93606, GSE33566, GSE38958, and GSE28042) and assigned high versus low myeloid dysregulation using median a threshold. We determined the difference in MDS between IPF patients and controls at baseline using Wilcoxon rank sum-test. When available, we assessed the correlation between forced vital capacity (FVC) and MDS using Spearman correlation. Using Kaplan-Meier estimator, we evaluated survival in cohorts with complete outcome information stratified by high versus low MDS. Results Of the 409 subjects, PBMCs or whole blood samples were available for 209 and 200 patients, respectively. 171 of 295 IPF patients had outcomes available. Of the combined 409 individuals in the four cohorts, MDS was significantly higher in IPF patients than healthy controls (p = 6.1e-06). This difference was significant in the whole blood cohort (p = 1.5 x 10-7) but not the PBMC cohort (p = 0.2). MDS was inversely correlated with baseline FVC (r = -0.1883, p = 0.026). In the whole blood cohort, transplant-free-survival within the first year was significantly higher for patients with low MDS than those with high MDS at baseline (HR = 4.4, 95% CI 1.4-14.0, p = 0.005), but not in the PBMC cohort (p > 0.9). Conclusion MDS in peripheral blood, which was derived predominantly in sepsis, is associated with severity and outcomes in IPF. The prognostic association is seen only in whole blood and not PBMCs, suggesting neutrophils may be associated with disease severity and outcomes in IPF. These results support shared immune dysregulation in sepsis and IPF that may contribute to disease trajectory in both conditions.