Epstein-Barr virus reactivation may contribute to long COVID fatigue
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Epstein-Barr virus replication may be a cofactor in a subgroup of patients who develop long COVID fatigue, although other potential contributing factors need to be evaluated as well, according to a letter published in Allergy.
Up to 10% of patients with COVID-19 develop long COVID, Johanna Rohrhofer, MS, PhD student with the Institute of Pathophysiology and Allergy Research, Medical University of Vienna, and colleagues wrote.
Although Epstein-Barr virus (EBV) has been associated with post-viral fatigue, the researchers said the mechanisms that lead to post-viral fatigue syndrome overall and in long COVID in particular are unresolved.
The researchers hypothesized that long COVID fatigue may be triggered by SARS-CoV-2 persistence in the gastrointestinal or respiratory tract after acute disease or by COVID-19-associated reactivation of EBV.
The study involved 30 patients (mean age, 37.73 years ± 9.96; 73.4% female) with long COVID experiencing persistent fatigue, post-exertional malaise, autonomic dysfunction and/or orthostatic intolerance.
The researchers collected stool, throat washings and blood samples from these patients between 74 and 471 days (median, 235 days) after the beginning of their acute SARS-CoV-2 infections.
The study also included 20 age-matched and sex-matched patients (mean age, 33.9 years ± 11.95; 65% female) who had fully recovered from acute SARS-CoV-2 infection as controls, with stool, throat washing and blood samples taken from them between 106 and 571 days (median, 275 days) after the beginning of their infections.
SARS-CoV-2 infections were mild in both groups and occurred between spring 2020 and autumn 2021. There were no hospitalizations for any of these patients.
The researchers did not find SARS-CoV-2 RNA in any of the throat washing or stool samples.
Also, there were no differences in SARS-CoV-2 IgA or IgG antibody titers between the cohorts. The researchers noted that 24 of the 30 patients with long COVID and 17 of 20 of the controls received COVID-19 vaccination after developing the disease but before the samples were taken.
The blood and stool samples all were negative for EBV, whereas the throat washing samples of 15 (50%) patients with long COVID and four (20%) controls were positive for EBV DNA (P = .0411). The load levels of EBV did not differ significantly between the groups.
Except for one patient in the control group, all the patients in the study had previous EBV infections. The researchers concluded that the EBV replication that they had observed was caused by EBV reactivation and not primary infection. Additionally, the groups did not have any differences in EBV-specific antibody titers.
Overall, the researchers said they did not detect any SARS-CoV-2 persistence in any of the study participants up to 10 weeks after infection, although the patients with vs. without long COVID fatigue had more EBV reactivation in their throat months after acute SARS-CoV-2 infection.
These findings indicate that cofactors in long COVID fatigue may include EBV replication, the researchers wrote, adding that they did not evaluate human leukocyte antigen subtype or other contributing factors.
The researchers acknowledged they could not confirm earlier reports of differences in EBV antibody profiles among patients with long COVID and that additional, larger studies are necessary to clarify the impact and mechanism of long COVID fatigue associated with EBV.
Perspective
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None of this is surprising. It is pretty clear from this report and others that SARS-CoV-2 infection may activate/reactivate EBV, although it is unclear whether and to what extent this activation plays a role in long COVID, such as onset, severity or duration of symptoms.
I think doctors generally should be cognizant of the fact that some people with COVID-19 develop long COVID. I know I am stating an obvious fact, but it is surprising how many patients are told that long COVID is in their head.
While we still do not fully understand the biology and mechanisms of long COVID, people need care and attention now, which starts with recognizing the entity and caring for these patients.
Health systems should, if they have not already, develop long COVID clinics. We also need a robust and coordinated research strategy to help us deepen our understanding of long COVID and develop treatment for it.
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