Risk and Protective Factors for Infection, Severe Disease, and Mortality in Epidemic Respiratory Viruses

The post-COVID pandemic era has witnessed a concerning resurgence of respiratory viruses, driving a global increase in acute respiratory infections. This trend may stem from relaxed non-pharmaceutical interventions, waning herd immunity, immunological imprinting limiting heterosubtypic protection, or viral antigenic evolution. This review aims to identify and characterize risk and protective factors associated with infection, hospitalization, severe illness, and mortality, while elucidating the drivers of the rising incidence of respiratory virus infections post-pandemic. Evidence on SARS-CoV-2 sublineages, influenza, respiratory syncytial virus, rhinovirus, adenovirus, human metapneumovirus, human parainfluenza virus, human coronaviruses, and cytomegalovirus has been collected and identified. Identified risk factors include demographic characteristics such as pediatrics and older age, male sex, race (Black, Hispanic, American Indian or Alaska native), preterm birth, and HLA-DQA1, IFNAR2, ST6GAL, and B3GALT5 genetic susceptibility. Behavioral, socioeconomic (low socioeconomic status, crowded living conditions), environmental influences (cold seasons, pollution), smoking, obesity and malnutrition could also exacerbate the risk of infection and adverse outcomes. Comorbidities, such as chronic conditions and immunocompromised states, significantly increase the risk of severe disease and hospitalization. Laboratory indices linked to severe disease outcomes include neutrophilia or neutropenia, lymphopenia, eosinopenia, and elevated C-reactive protein. Viral subtypes, viral load kinetics, vaccination status, and antiviral therapies further delineate risk profiles. Epithelial barrier impairment and underlying chronic airway diseases characterized by type 2 immunity also play a detrimental role in the development and severity of respiratory viral infections. Our findings highlight the need for stratified prevention strategies, which combine universal measures targeting shared determinants with virus-specific interventions addressing unique virological and transmission dynamics. It will provide a critical framework for optimizing precision public health strategies to counter repeated respiratory threats in the evolving post-COVID-19 pandemic landscape.