Herpesviruses Serology Distinguishes Different Subgroups of Patients From the United Kingdom Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Biobank

Abstract

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.

The Emerging Role of Gut Microbiota in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Current Evidence and Potential Therapeutic Applications

“…Similarly, pathogens such as Epstein-Barr Virus (EBV), Human Herpesvirus (HHV)-6, and Human Parvovirus B19 are suspected of contributing to the development of the disease via antiviral immune activation and systemic inflammation [ 23 , 24 , 25 , 26 , 27 , 28 , 29 ], but their necessity for ME/CFS development remains debated [ 30 ]. Indeed, several studies comparing ME/CFS cases with controls failed to support the hypothesis of involvement of a viral infection in disease pathogenesis [ 29 , 31 , 32 , 33 , 34 , 35 ]. Moreover, it should be noted that the vast majority of people recover from infections without consequences, therefore making it difficult to establish a clear correlation between infection and ME/CFS.…”

Lessons From Heat Stroke for Understanding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

“…Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multi-system disease of unclear etiology ( 6 – 10 ). The most common peri-onset events reported by patients are infection-related episodes, stressful incidents, and exposure to environmental toxins ( 11 ).…”

Revisiting IgG antibody reactivity to Epstein-Barr virus in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and its potential application to disease diagnosis

“…In conclusion, this study identified two candidate antigens whose antibodies could be used to identify ME/CFS patients with an infectious trigger. To strengthen our findings, two other cohorts of patients are currently studied, including the well-characterized ME/CFS patients with different disease triggers and healthy controls from the United Kingdom ME/CFS biobank (10).…”

“…However, given the vast number of infectious agents associated with ME/CFS (5,38), it is worth noting that this subgroup of patients could be further subdivided according to the nature of the causative infection. In this regard, the data about the infectious agents that could have initiated ME/CFS are either inconclusive or simply based on self-reported history in most patients, as demonstrated by the data from the United Kingdom ME/CFS Biobank, where only a minority of patients had their infection confirmed with the lab test (10). Secondly, the final classification model included non-trivial statistical interactions of antibodies against EBNA6_0070 with both age and gender.…”

“…However, the existing evidence remains inconclusive on whether the prevalence of these reactivations is either higher or lower in patients than in healthy controls (5). This conflicting evidence notwithstanding, ME/CFS patients show deficient B-and T-cell responses against EBV and altered antibody profiles when compared to healthy controls (10,(13)(14)(15). Finally, CD4+ T cells recognizing self-peptides on HLA-DR15, the strongest genetic risk factor for multiple sclerosis, have been shown to cross-react with peptides derived from EBV (16).…”