Expression of Inflammatory Markers in the Course of Acute Respiratory Viral Infections

Respiratory viral infections remain a major global public health challenge, causing substantial morbidity, hospitalization, and mortality, particularly among older adults and individuals with chronic medical conditions. Influenza viruses, respiratory syncytial virus (RSV), and SARS-CoV-2 are among the most clinically relevant respiratory pathogens worldwide and continue to impose a considerable burden on healthcare systems. Seasonal influenza epidemics affect up to 20% of the population annually, depending on circulating strains, and are responsible for an estimated 290,000 to 650,000 deaths globally each year. Although most infected individuals recover spontaneously within a few days, severe disease and complications are more common in adults aged 60 years or older, pregnant women, healthcare workers, young children, and individuals with underlying comorbidities. Current preventive strategies rely mainly on annual vaccination; however, vaccine effectiveness has remained limited in recent years due to viral antigenic drift and the continuous emergence of new strains. Although antiviral therapies are available for some respiratory viruses, their effectiveness is limited and treatment generally must be initiated within a narrow time window after symptom onset. Furthermore, currently available antiviral agents target virus-specific mechanisms, limiting their applicability across different respiratory pathogens. These limitations have stimulated interest in host-directed therapeutic strategies capable of modulating common immune pathways involved in viral pathogenesis. The programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint pathway has emerged as a potential regulator of antiviral immunity. PD-L1 is an immunoregulatory molecule that limits excessive immune activation and tissue damage by suppressing T-cell responses. While this mechanism is essential for maintaining immune homeostasis, excessive activation of the PD-1/PD-L1 pathway may contribute to impaired antiviral immunity, immune exhaustion, delayed viral clearance, and prolonged inflammation. Experimental and translational studies have demonstrated increased PD-L1 expression during acute respiratory viral infections, including influenza, RSV, and SARS-CoV-2. In influenza infection, PD-L1 upregulation has been associated with reduced CD8+ T-cell activity and impaired antiviral responses. Similar observations have been reported in SARS-CoV-2 and RSV infections, suggesting that modulation of this pathway may represent a common biological mechanism across multiple respiratory viruses. Preclinical studies have further suggested that PD-L1 expression follows a dynamic temporal pattern during infection, with expression levels increasing during the acute phase and subsequently declining during recovery. These findings raise the possibility that characterization of PD-L1 kinetics in humans may identify biologically relevant periods of immune dysregulation and help define potential therapeutic windows for future host-directed interventions. Despite increasing interest in the PD-1/PD-L1 pathway, its temporal behavior during naturally acquired respiratory viral infections in humans remains poorly understood. In particular, limited information is available regarding the relationship between PD-L1 expression, systemic inflammatory responses, and clinical outcomes in populations at highest risk for severe disease and complications. The AIRE-INT study seeks to generate clinical and biological data on PD-L1 expression and associated inflammatory responses during acute respiratory viral infections caused by influenza, RSV, and SARS-CoV-2. By improving understanding of immune checkpoint dynamics in naturally occurring infection, the study aims to contribute to the identification of biomarkers with potential prognostic and monitoring value and to provide foundational evidence for future research evaluating host-directed therapeutic approaches targeting the PD-1/PD-L1 pathway. The expected impact of this study is to provide a detailed characterization of PD-L1 kinetics and inflammatory responses during acute respiratory viral infections in older adults. The results may contribute to the identification of prognostic and monitoring biomarkers and establish the biological basis for future proof-of-concept clinical trials evaluating PD-L1-targeted therapies in respiratory viral infections. This study may ultimately support the development of innovative host-directed therapeutic strategies capable of acting across multiple respiratory viruses and extending the therapeutic window beyond currently available antiviral approaches.