Investigation of Long COVID Prevalence and Its Relationship to Epstein-Barr Virus Reactivation

Abstract

Coronavirus disease 2019 (COVID-19) patients sometimes experience long-term symptoms following resolution of acute disease, including fatigue, brain fog, and rashes. Collectively these have become known as long COVID. Our aim was to first determine long COVID prevalence in 185 randomly surveyed COVID-19 patients and, subsequently, to determine if there was an association between occurrence of long COVID symptoms and reactivation of Epstein-Barr virus (EBV) in 68 COVID-19 patients recruited from those surveyed. We found the prevalence of long COVID symptoms to be 30.3% (56/185), which included 4 initially asymptomatic COVID-19 patients who later developed long COVID symptoms. Next, we found that 66.7% (20/30) of long COVID subjects versus 10% (2/20) of control subjects in our primary study group were positive for EBV reactivation based on positive titers for EBV early antigen-diffuse (EA-D) IgG or EBV viral capsid antigen (VCA) IgM. The difference was significant (p < 0.001, Fisher's exact test). A similar ratio was observed in a secondary group of 18 subjects 21-90 days after testing positive for COVID-19, indicating reactivation may occur soon after or concurrently with COVID-19 infection. These findings suggest that many long COVID symptoms may not be a direct result of the SARS-CoV-2 virus but may be the result of COVID-19 inflammation-induced EBV reactivation.

Keywords: COVID-19; EBV; Epstein–Barr virus; Epstein–Barr virus reactivation; PACS; SARS-CoV-2; chronic COVID syndrome; coronavirus; long COVID; post-acute COVID-19 syndrome.

Figure A1

The relationship between EBV VCA IgG antibody titers and reported long COVID symptoms in the 68 subjects making up the primary and secondary groups was not significant (r = −0.014, p = 0.75).

Figure A2

The relationship between EBV nuclear antigen 1 (EBNA-1) IgG antibody titers and reported long COVID symptoms in the 68 subjects making up the primary and secondary groups was not significant (r = −0.23, p = 0.09).

Figure 1

The relationship between EBV early antigen-diffuse (EA-D) IgG antibody titers and reported long COVID symptoms in the 68 subjects making up the primary and secondary groups was significant (r = 0.34, p < 0.001).

Figure 2

The number of subjects reporting each of 13 clinical manifestations of long COVID, as reported by the 29 subjects from both our long-term and short-term long COVID groups who tested positive for Epstein–Barr virus (EBV) reactivation. The percent of subjects with EBV reactivation reporting each symptom was: fatigue 58.6%, insomnia 48.3%, headaches 44.8%, myalgia 44.8%, confusion/brain fog 41.4%, weakness 37.9%, rash 31.0%, pharyngitis 24.1%, abdominal pain 24.1%, tinnitus 24.1%, fever over 101° F 13.8%, neck lymphadenopathy 13.8%, and mild-to-moderate hearing loss 6.9%.

Figure 3

Skin manifestations of six long COVID subjects positive for EBV reactivation (two photos of each subject).

Figure 4

One subject experienced COVID toes at four months and another at nine months after testing positive for Coronavirus disease 2019 (COVID-19).

Figure 5

The dynamics of EBV viral capsid antigen (VCA) IgM titers, EBV early antigen-diffuse (EA-D) IgG titers, and serum EBV DNA over time after EBV infection or reactivation [14,26,27,28].

Figure 6

Primary inclusion: subjects were included only if they provided the requested background, including documentation of their COVID-19 diagnosis, most often in the form of SARS-CoV-2 polymerase chain reaction (PCR) results. Secondary inclusion: subjects were included only if between the ages of 21–74, with no exclusionary health conditions.