Impact of Pre-Existing Chronic Viral Infection and Reactivation on the Development of Long COVID

Abstract

Epstein-Barr virus (EBV) reactivation has been proposed as a driver of Long COVID (LC), but studies in well-characterized post-acute COVID-19 cohorts of individuals with and without Long COVID symptoms over a time course consistent with current case definitions of LC are limited. In a cohort of 294 hundred adults with a history of SARS-CoV-2 infection, we observed that LC symptoms such as fatigue and neurocognitive dysfunction at a median of 4 months following initial diagnosis were associated with serological evidence of recent EBV reactivation (early antigen-D IgG positivity or nuclear antigen IgG levels >600 U/mL), but not with ongoing EBV viremia.. Importantly, Long COVID was also observed in the small proportion without evidence of prior or recent EBV infection, suggesting that EBV reactivation is not a prerequisite for this condition. Overall, these findings expand our knowledge of the relationships between EBV reactivation and LC and suggest that further assessment during the acute phase of COVID-19 is warranted.

Epstein Barr Virus Reactivation during COVID-19 Hospitalization Significantly Increased Mortality/Death in SARS-CoV-2(+)/EBV(+) than SARS-CoV-2(+)/EBV(−) Patients: A Comparative Meta-Analysis

“…The EBV can reactivate in people with impaired immune systems, as well as when physiological stressors such as an acute infection are present. In previous research, EBV reactivation was shown to occur during acute SARS-CoV-2 infection as indicated by the presence of detectable circulating EBV DNA or viral capsid antigen (VCA) IgM-positive [ 17 ]. In the current work, through meta-analysis, we have shown that EBV reactivation in COVID-19 patients increased the mortality.…”

COVID-19, SARS-CoV-2 Vaccination, and Human Herpesviruses Infections

“…Latency is the outcome of virus host adaptation, in which herpesvirus genomes are maintained in a non-replicative state, hidden from the host’s immune response. Changes in the host’s immune status can result in a failure of the host to suppress herpesvirus replication with consequent disease manifestations [ 45 , 60 , 61 ]. Infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can have several clinical outcomes depending upon the host’s immunological response to infection [ 62 ], and treatments for COVID-19 can also be immunosuppressive.…”

Tissue injury and leukocyte changes in post-acute sequelae of SARS-CoV-2: review of 2833 post-acute patient outcomes per immune dysregulation and microbial translocation in long COVID

“…B-cell changes during PASC have also been described, including increases in activated (CD86 hi HLA-DR hi ) and double negative (IgD -/CD27 -/CD24 -/CD38 -) subsets. In addition, such B cell change is positively associated with high anti-spike antibody responses (indicating the persistent spike antigen) and responses against non-SARS-CoV2 antigens (indicating the reactivation of latent herpesvirus infections, such as Epstein-Barr Virus (EBV)) (17,84).…”

“…We examine potential factors contributing to tissue injury to look for common features among otherwise highly variable clinical presentations of PASC (Figure 1). The mechanistic contributions of comorbid conditions to PASC are not addressed here, although links between PASC symptoms, such as fatigue and neurocognitive function, have been previously associated with Epstein Barr Virus (EBV) reactivation and HIV co-infection, respectively (17). We also do not address specific conditions (i.e., obesity, diabetes, and aging-associated disorders) that may be linked to COVID-19 severity and the development of PASC.…”