Early monocyte subset signatures predict outcomes in unvaccinated COVID-19 patients.

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is characterized by complex immune responses, with monocytes playing a central role in disease pathogenesis. Objective: This study aimed to evaluate the profiles of monocytes and their receptor expression during the first week of hospitalization in unvaccinated patients with COVID-19, stratified by clinical outcome: discharged or deceased. Methods: Peripheral mononuclear cells from hospitalized patients were analyzed by flow cytometry to characterize classical, intermediate, and non-classical monocytes, along with the expression of CD169, CD209, and TLR2, TLR3, TLR4, and TLR9. Result: Patients in whom death was the outcome exhibited a significant reduction in classical monocytes and an expansion of non-classical monocytes early during hospitalization. Additionally, non-classical monocytes from deceased patients showed increased expression of CD169 and greater intensity of CD209 expression. Enhanced expression of TLR2 across all monocyte subsets and increased TLR4 expression specifically in non-classical monocytes were also associated with mortality. Correlation network analysis revealed more complex and dysregulated interactions among monocyte subsets and immune markers in deceased patients compared with discharged individuals. Conclusion: Our findings demonstrate that, during the first week of hospitalization, alterations in monocyte distribution and activation status are strongly associated with COVID-19 severity. Increased expression of CD169, CD209, TLR2, and TLR4, particularly in non-classical monocytes, reflects heightened innate immune activation and may contribute to poorer disease outcomes. Collectively, these results highlight the potential of monocyte subsets and their associated receptors as early prognostic biomarkers and provide insight into the immunopathogenesis of severe COVID-19.