eNAMPT is a plasma biomarker of COVID-19 severity and ARDS progression linked to increased immune effector cell expression

Background The COVID-19 pandemic highlighted the critical unmet need for novel targets, biomarkers, and effective pharmacotherapies to reduce the severity/mortality of COVID pneumonia and progression to acute respiratory distress syndrome (ARDS). Extracellular NAMPT (eNAMPT) is a druggable DAMP and TLR4 ligand centrally involved in ARDS pathobiology. We explored the utility of plasma eNAMPT measurements as a potential COVID-19 biomarker linked to ARDS progression and disease severity and investigated the potential cellular source for eNAMPT release/secretion in COVID-19 subjects. Methods A plasma biomarker panel of inflammatory cytokines (IL-1β, IL-6, IL-8, IL-1RA, TNF-α), DAMPs (eNAMPT, MIF) and vascular proteins (ANG-2, PSGL-1) were evaluated in three distinct COVID-19-positive cohorts (Miami, Arizona, Tampa) (n = 277) and healthy control subjects (n = 214). Single-cell RNA sequencing (scRNA-seq) publicly available on peripheral blood mononuclear cells (PBMCs) in a subset of Tampa COVID-19 survivors (n = 18) and an autopsied COVID lung tissue database was separately analyzed for biomarker gene expression. Results Plasma biomarkers, including eNAMPT were significantly elevated in COVID-19 subjects compared to healthy controls (p < 0.0001), with IL-1RA, IL-6 and eNAMPT exhibiting the strongest diagnostic performance. Biomarker levels (all except IL-8, MIF) were higher in COVID-19 ARDS cases vs COVID-19 pneumonia (n = 154, AUC 0.71–0.79, p < 0.05) and were significantly elevated in COVID non-survivors (IL-6, IL-1RA, TNF-α, eNAMPT, ANG-2, PSGL-1) compared to survivors (p < 0.05). NAMPT gene expression was significantly upregulated in COVID-19 PBMCs compared with healthy controls, most evident within the CD14 + monocyte cluster. Relative to lung tissue from non-COVID-19 infected, NAMPT gene expression was increased in specific COVID-19 lung cell populations, including neutrophils, CD16 + monocytes, conventional dendritic cells (cDCs), fibroblasts, endothelium, and alveolar macrophages. Conclusion Our study corroborated the utility of this biomarker panel for diagnostic and severity assessment in COVID-19- associated ARDS and as a strategy for subject stratification in therapeutic trials of eNAMPT-neutralizing therapies. We further identified NAMPT expression in immune effector cells that correlates with COVID-19 severity and lethality. Together, these findings suggest NAMPT plays a key role in sustaining inflammatory activation and impairing lung regeneration in fatal COVID-19.