Reduction in circulating monocytes correlates with persistent post-COVID pulmonary fibrosis in multi-omic comparison of long-haul COVID and IPF

Rationale: Up to 30% of COVID-19 patients experience persistent sequelae, including dyspnea, restrictive physiology, and early radiographic signs of pulmonary fibrosis (PF). The mechanisms that provoke post-COVID progressive PF are poorly understood, and biomarkers to identify at-risk patients are urgently needed. Methods: We evaluated a cohort of 14 symptomatic COVID survivors with impaired respiratory function and imaging worrisome for developing PF, including bilateral reticulation, traction bronchiectasis and/or honeycombing, and compared these to Idiopathic Pulmonary Fibrosis (IPF) patients and age-matched controls without respiratory disease. We performed single-cell RNA-sequencing and multiplex immunostaining on peripheral blood mononuclear cells collected at the COVID-19 patients first visit after ICU discharge. Six months later, symptoms, restriction and PF improved in some (Early-Resolving COVID PF), but persisted in others (Late-Resolving COVID PF). Results: Circulating monocytes were significantly reduced in Late-Resolving COVID PF patients compared to Early-Resolving COVID PF and non-diseased controls. Monocyte abundance correlated with pulmonary function tests FVC and DLCO. Differential expression analysis revealed MHC-II class molecules were upregulated on the CD8 T cells of Late-Resolving COVID PF patients but downregulated in monocytes. IPF patients had a similar decrease in monocyte abundance and marked decrease in monocyte HLA-DR protein expression compared to Late-Resolving COVID PF patients. Conclusion: Circulating monocyte abundance may distinguish between patients whose post-COVID PF resolves or persists. Furthermore, fibrotic progression coincided with decreases in HLA-DR expression on monocytes, a phenotype previously associated with dampened antigen stimulation and severe respiratory failure.