From Acute Respiratory Viral Infection to Post-Viral Inflammation and Tissue Remodelling: Molecular Mechanisms and Therapeutic Perspectives

Abstract

Viral respiratory infections are among the most prevalent infectious diseases and have clinical effects that extend beyond the acute phase of viral replication. Inflammation is important for antiviral defence and tissue repair, but when excessive, prolonged, or incompletely resolved, it can contribute to persistent respiratory abnormalities. A growing number of studies suggest that post-viral respiratory disease is a multifactorial process involving several interacting pathways, including dysregulated innate immune signalling, epithelial injury, altered immune cell signalling, metabolic and mitochondrial dysfunction, oxidative stress, abnormal cell death, and impaired tissue repair.

This narrative review reviews the literature published in recent years (2020-2026) on the five major respiratory viruses linked to persistent inflammatory responses: SARS-CoV-2, influenza viruses, respiratory syncytial virus (RSV), rhinovirus, and adenovirus. Special emphasis on the role of viral recognition by pattern recognition receptors, interferon signalling, NF-κB and mitogen-activated protein kinase pathways, activation of inflammasomes, cellular interactions, mitochondrial dysfunction, immunometabolic changes, and tissue remodelling. We will evaluate evidence of a prolonged presence of viral material or altered host responses separately from evidence of continued productive viral replication.

No single mechanism in the available literature explains persistent respiratory disease. SARS-CoV-2 has shown ample evidence of post-acute inflammatory and immune abnormalities, whereas influenza, RSV, rhinovirus, and adenovirus exhibit unique patterns of epithelial injury, immune activation, recurrent inflammation, or persistence. More recent research suggests that respiratory viral infections may also affect epithelial progenitor cell behaviour and their role in subsequent tissue repair. The difference between active viral infection and post-viral inflammatory disease is important from a therapeutic point of view. When viral replication continues, direct antiviral therapy is relevant; when inflammation, tissue remodelling, or fibrosis continues, different approaches may be relevant. Future studies should include longitudinal clinical studies, along with single-cell, transcriptomic, proteomic, metabolic, and immunological assessments, to identify patients at risk for chronic respiratory disease and develop therapeutic interventions that target the disease's biological stage.

The main topics covered are respiratory viral infections, persistent inflammation, SARS-CoV-2, influenza, respiratory syncytial virus, rhinovirus, adenovirus, innate immunity, epithelial injury, airway remodelling, and fibrosis.