Upper respiratory virome signatures reflect COVID-19 severity and post-recovery shifts

Introduction Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection profoundly affects the upper respiratory tract, yet the dynamics of the resident virome across different stages of Coronavirus Disease 2019 (COVID-19) and recovery remain poorly understood. Methods This study profiled alterations in the virome and microbiome in 143 SARS-CoV-2–positive adults, stratified by disease severity (Non-Severe, Severe, Critical), compared with 96 RT-PCR–negative controls. Nasal and oral swabs underwent targeted viral enrichment and next-generation sequencing, followed by virome profiling. Results The respiratory virome of SARS-CoV-2-positive individuals was dominated by SARS-CoV-2, with co-detected viruses such as Human Mastadenovirus C, which increased with disease severity and persisting post-recovery. Alpha diversity was highest in Non-Severe cases and declined in Severe and Critical groups, suggesting increasing disruption of the virome with disease severity. Beta diversity showed clear separation between controls and cases, and across severity levels. LEfSe identified distinct viral signatures differentiating infection status, and logistic regression of key viral taxa accurately classified Critical versus post-recovery samples (AUC = 0.91). Although the study focused on viruses, bacterial taxa including Rothia mucilaginosa and Haemophilus parahaemolyticus were also detected with severity-linked variation, highlighting viral–bacterial interactions. Longitudinal paired analysis revealed consistent post-recovery enrichment of Streptococcus-specific bacteriophages across all severity groups, suggesting restoration of Streptococcus-associated phage dynamics during convalescence. Discussion Overall, this study reveals SARS-CoV-2–associated alterations in the respiratory virome and microbiome and highlights specific microbial taxa with potential as biomarkers for disease severity and post-infection recovery.