Lights and Shadows of Long COVID: Are Latent Infections the Real Hidden Enemy?

Abstract

Long COVID-19 (LC) is a poorly understood, multifactorial condition that persists for at least three months following SARS-CoV-2 infection. The underlying pathophysiological mechanisms responsible for the wide range of associated symptoms-including fatigue, brain fog, and respiratory issues-remain unclear. However, emerging evidence suggests that the reactivation of latent viral infections, such as Epstein-Barr virus, cytomegalovirus, and varicella-zoster virus, may significantly contribute to the complexity of LC. These latent viruses can be reactivated by SARS-CoV-2, contributing to a chronic inflammatory state that prolongs symptomatology. This review confirms the potential involvement of latent viral infections in LC and examines whether these infections play an independent role or act synergistically with other factors. In addition, recent studies have highlighted viral persistence and immune dysregulation as key elements in LC. Our findings suggest that preventative strategies, including vaccination and antiviral treatments during the acute phase of COVID-19, show potential in reducing LC risk by preventing viral reactivation. However, tailored diagnostic and therapeutic strategies targeting these latent infections are urgently needed. Identifying biomarkers of viral reactivation, particularly for high-risk populations, could be considered another effective strategy to mitigate LC severity. Further research is crucial to better understand the interactions between SARS-CoV-2 and latent infections, and to improve the prevention and treatment of LC.

Keywords: COVID-19; EBV; HIV; Long COVID; SARS-CoV-2; VZV; latent viral infections; post-acute sequalae.

Figure 1

Long COVID symptoms clusters.

Figure 2

Summary of the probable pathophysiological mechanisms.