Clinical and epidemiological characterization of viral respiratory pathogens
Background: Acute respiratory infections (ARIs) are a leading cause of morbidity and mortality worldwide with sub-Saharan Africa accounting for approximately 50% of the 5.8 million ARI-related deaths globally.   Despite this substantial burden, pathogen-based surveillance remains limited in these regions. The post-pandemic phase presents a unique epidemiological landscape, with SARS-CoV-2 transitioning towards endemicity and potentially interacting with other circulating respiratory pathogens. This study aimed to characterize viral ARI etiology, clinical outcomes, and the influence of SARS-CoV-2 serostatus and malaria co-infection in the immediate post-pandemic period in a rural Ghanaian setting. Methods: We conducted a prospective-observational study at a district hospital in Ghana between May 2022 to September 2023. Adults with acute respiratory infection were enrolled, and nasopharyngeal swabs were tested using a multiplex PCR panel detecting 22 respiratory — mainly viral — pathogens. SARS-CoV-2 serostatus and malaria infection status were determined and broader clinical parameters examined. Clinical severity was assessed using the PRIEST score, and participants were followed up for 28 days to evaluatesymptom resolution. Multivariable logistic regression identified potential predictors of hospitalization. Results: Among 347 participants, the most frequently detected respiratory pathogens were rhinovirus/enterovirus (12.4%, n=43), acute SARS-CoV-2 (11.0%, n=38), and influenza A (6.3%, n=22). Among all participants 79.8% (n=277) of the participants were seropositive for SARS-CoV-2 and 28.5% (n=99) were carrying malaria parasites. Hospitalization rates were comparable across SARS-CoV-2 serostatus, acute infection, and malaria status groups (25-30%). Higher PRIEST scores predicted hospitalization (OR: 1.50, 95% CI: 1.32-1.74), while COVID-19 vaccination was protective (OR: 0.41, 95% CI: 0.18-0.93). Participants with acute SARS-CoV-2 infection experienced delayed symptom resolution. Conclusion: Post-pandemic ARI etiology in rural Ghana exhibits a diverse viral profile, with rhinovirus/enterovirus, SARS-CoV-2 and influenza A predominating. Clinical outcomes were more strongly associated with high PRIEST scores than with specific pathogens, with vaccination providing significant protection against hospitalization. While this study did not identify pathogen-specific associations with clinical severity, sustained surveillance remains important for detecting shifts in viral circulation and informing tailored public health responses.