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Review 1: "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 1: "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:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.



These study results are reliable: they are supported by adequate statistical treatment of data derived from the analysis of a medium sized cohort from clinical centers located in the same area. The strength of significance is just sufficient, and the authors investigate all combinations of covariates to determine their effects, as for the case of HIV positivity, forced into the model by oversampling through recruitment at a HIV outpatients clinic. There are some limitations, particularly the association with high IgG anti-NA and not with anti-EA(D) for EBV reactivation.

The explanation put forward by the authors, and schema in Figure 1, seems to be too much speculative, and therefore this must be clearly stated (no reference is even offered in support of the claim that IgG anti-NA >600 U is a surrogate markers defining EB reactivation) and the figure should be deleted or more clearly defined as merely hypothetical and not fully supported by data. The study does not sampled before 30 days from COVID-19 symptoms onset, and the number of longitudinal data is not reported, so we rely on one sample time per case, and this is another limitation of the study with reference to both antibody profile and cytokine markers.

This part of the report is therefore to be considered only Potentially informative, as discussed by the authors, and more studies are needed in order to provide supportive evidence. However many considerations are in keeping with .previous smaller studies, and only the protective role of CMV seropositivity represents a truly new finding, but in its case the evidence is too limited to be labelled as reliable.


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