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Review 2: "Impact of Pre-Existing Chronic Viral Infection and Reactivation on the Development of Long COVID"

Reviewers were mixed on the overall reliability of this preprint. There is agreement that the study results are supported by the data, but some concern over the suggested explanation for the results.

Published onAug 11, 2022
Review 2: "Impact of Pre-Existing Chronic Viral Infection and Reactivation on the Development of Long COVID"
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key-enterThis Pub is a Review of
Impact of Pre-Existing Chronic Viral Infection and Reactivation on the Development of Long COVID

ABSTRACTThe presence and reactivation of chronic viral infections such as Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human immunodeficiency virus (HIV) have been proposed as potential contributors to Long COVID (LC), but studies in well-characterized post-acute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited. In a cohort of 280 adults with prior 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 independently associated with serological evidence of recent EBV reactivation (early antigen-D [EA-D] IgG positivity) or high nuclear antigen IgG levels, but not with ongoing EBV viremia. Evidence of EBV reactivation (EA-D IgG) was most strongly associated with fatigue (OR 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR 0.52) and tended to have less severe (>5 symptoms reported) LC (OR 0.44). Overall, these findings suggest differential effects of chronic viral co-infections on the likelihood of developing LC and predicted distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted.SUMMARYThe authors found that Long COVID symptoms in a post-acute cohort were associated with serological evidence of recent EBV reactivation and pre-existing HIV infection when adjusted for participant factors, sample timing, comorbid conditions and prior hospitalization, whereas underlying CMV infection was associated with a decreased risk of Long COVID.

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.



There is a lot of interest at present in the potential role of Epstein-Barr virus (EBV) in long Covid. The issues are whether increased immune responses to EBV found in some patients are coincidental or significant and whether they are part of the mechanism of the long Covid symptoms or just a bystander effect of generally altered immune disfunction in long Covid patients.

This paper discusses these points and presents a good, clear analysis of 294 patients with ongoing long Covid symptoms 4 months after SARS-CoV-2 infection. The conclusion is that there is evidence for increased antibodies to EBV EA-D in some long Covid patients but also that EBV reactivation is not a pre-requisite for long Covid. Since long Covid symptoms are likely to have heterogeneous causes and mechanisms this is a reasonable conclusion and the authors correctly state that interventional studies will be required to determine the contribution of EBV reactivation to long Covid.

Although descriptive, this is a well presented, valuable and worthwhile study.

Minor points to be addressed:

  1. Table 1 is good but it does not allow the reader to know the distribution of the preexisting conditions in the patient cohort (were they all in different people, did the same 54 HIV+ people have most of the conditions etc?). It would be helpful to also have a more comprehensive supplementary table showing the distribution of the conditions in the patient population.

  2. Since only some of the patients have raised antibodies to EBV, should the title of the paper be “Evidence of recent EBV reactivation in some individuals experiencing long COVID” ? The current title seems to imply that they all have raised EBV antibodies.

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