Herpesvirus testing in blood serum may distinguish subgroups of ME/CFS patients

Tiago Dias Domingues, Anna D Grabowska, Ji-Sook Lee, Jose Ameijeiras-Alonso, Francisco Westermeier, Carmen Scheibenbogen, Jacqueline M Cliff, Luis Nacul, Eliana M Lacerda, Helena Mouriño & Nuno Sepúlveda

Charité – Universitätsmedizin Berlin, Germany; London School of Hygiene and Tropical Medicine, UK; and others

Frontiers in Medicine, 2021 July 5; 8:686736

Key findings

  • It is still not clear whether there is any association between chronic herpesvirus infection and the development of ME/CFS.
  • Using serum samples from the UK ME/CFS Biobank, patients who reported an infection trigger, and that infection was confirmed by a lab test, were less likely to be positive for human cytomegalovirus, compared with healthy controls.
  • Patients who did not report an infection trigger for their disease were less likely than controls to be positive for Epstein-Barr virus or Varicella-Zoster virus.


This study was partially funded by ME Research UK with the financial support of The Fred and Joan Davies Bequest.


The evidence of an association between Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and chronic herpesviruses infections remains inconclusive. Two reasons for the lack of consistent evidence are the large heterogeneity of the patients’ population with different disease triggers and the use of arbitrary cutoffs for defining seropositivity. In this work we re-analyzed previously published serological data related to 7 herpesvirus antigens. Patients with ME/CFS were subdivided into four subgroups related to the disease triggers: S0 – 42 patients who did not know their disease trigger; S1 – 43 patients who reported a non-infection trigger; S2 – 93 patients who reported an infection trigger, but that infection was not confirmed by a lab test; and S3 – 48 patients who reported an infection trigger and that infection was confirmed by a lab test. In accordance with a sensitivity analysis, the data were compared to those from 99 healthy controls allowing the seropositivity cutoffs to vary within a wide range of possible values. We found a negative association between S1 and seropositivity to Epstein-Barr virus (VCA and EBNA1 antigens) and Varicella-Zoster virus using specific seropositivity cutoff. However, this association was not significant when controlling for multiple testing. We also found that S3 had a lower seroprevalence to the human cytomegalovirus when compared to healthy controls for all cutoffs used for seropositivity and after adjusting for multiple testing using the Benjamini-Hochberg procedure. However, this association did not reach statistical significance when using Benjamini-Yekutieli procedure. In summary, herpesviruses serology could distinguish subgroups of ME/CFS patients according to their disease trigger, but this finding could be eventually affected by the problem of multiple testing.

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