Long COVID Symptoms – Such As Fatigue, Brain Fog, and Rashes – Likely Caused by Epstein-Barr Virus Reactivation

Reactivation of the Epstein-Barr virus (EBV) due to the inflammatory response to a coronavirus infection may be the cause of previously unexplained long-term COVID symptoms – such as fatigue, brain fog and skin rashes – which occur in approximately 30% of patients after recovery from the initial COVID-19 infection. The first evidence linking EBV reactivation to long-term COVID, as well as an analysis of long-term COVID prevalence, is outlined in a new long-term COVID study published in the journal Pathogens.

“We conducted EBV antibody testing on recovered COVID-19 patients, comparing the EBV reactivation rates of people with long-term COVID-19 symptoms with those without long-term COVID-19 symptoms,” said lead study author Jeffrey E. Gold of World Organization. “The majority of those with long-term COVID symptoms were positive for EBV reactivation, but only 10% of controls indicated reactivation.”

The researchers began by examining 185 randomly selected patients who had recovered from COVID-19 and found that 30.3% had long-term symptoms consistent with long-term COVID after initial recovery from SARS-CoV-2 infection. This included several patients with initially asymptomatic COVID-19 cases who later developed long-term COVID-19 symptoms.

The number of subjects who reported each of the 13 clinical manifestations of long-term COVID. Credit: Jeffrey E. Gold, Ramazan A. Okyay, Warren E. Light, and David J. Hurley

The researchers then found, in a subset of 68 COVID-19 patients randomly selected from those surveyed, that 66.7% of long-term COVID patients versus 10% of controls were positive for EBV reactivation based on positive EBV early antigen-diffuse (EA-D) IgG or EBV viral capsid antigen (VCA) IgM titers. The difference was significant (p < 0.001, Fisher's exact test).

“We found similar rates of EBV reactivation in those who had long-term COVID-19 symptoms for months to those with long-term COVID-19 symptoms who started just weeks after testing positive for COVID-19,” said co-author David J. Hurley, PhD, a professor and molecular microbiologist at the University of Georgia. “This indicated to us that EBV reactivation likely occurs concurrently or shortly after COVID-19 infection.”

The relationship between SARS-CoV-2 and EBV reactivation described in this study opens new possibilities for long-term diagnosis and treatment of COVID. The researchers indicated that it may be prudent to test patients newly positive for COVID-19 for evidence of EBV reactivation indicated by positive EBV EA-D IgG, EBV VCA IgM or serum EBV DNA tests . If patients show signs of EBV reactivation, they can be treated early to reduce the intensity and duration of EBV replication, which may help inhibit the development of long-term COVID.

“As there is mounting evidence to support a role for EBV reactivation in the clinical manifestation of acute COVID-19, this study further implicates EBV in the development of long-term COVID,” said Lawrence S. Young, PhD, a virologist at the University of Warwick, and Editor of Pathogens. “If a direct role for EBV reactivation in long-term COVID is supported by further studies, this would provide opportunities to improve rational diagnosis of this condition and to consider the therapeutic value of anti-herpes virus agents such as ganciclovir.”

Reference: “Exploring long-term COVID prevalence and its relationship to Epstein-Barr virus reactivation” by Jeffrey E. Gold, Ramazan A. Okyay, Warren E. Licht, and David J. Hurley, June 17, 2021, Pathogens.
DOI: 10.3390/pathogens10060763