Salivary DNA Loads for Human Herpesviruses 6 and 7 Are Correlated With Disease Phenotype in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex chronic condition affecting multiple body systems, with unknown cause, unclear pathogenesis mechanisms, and fluctuating symptoms which may lead to severe debilitation. It is frequently reported to have been triggered by an infection, but there are no clear differences in exposure to, or seroprevalence of, any particular viruses between people with ME/CFS and healthy individuals. However, herpes viruses have been repeatedly hypothesized to underlie the chronic relapsing/remitting form of MS/CFS due to their persistence in a latent form with periodic reactivation. It is possible that ME/CFS is associated with herpes virus reactivation, which has not been detectable previously due to insufficiently sensitive testing methods. Saliva samples were collected from 30 people living with ME/CFS at monthly intervals for 6 months and at times when they experienced symptom exacerbation, as well as from 14 healthy control individuals. The viral DNA load of the nine humanherpes viruses was determined by digital droplet PCR. Symptoms were assessed by questionnaire at each time point. Human herpesvirus (HHV) 6B, HHV-7, herpes simplex virus 1 and Epstein-Barr virus were detectable within the saliva samples, with higher HHV-6B and HHV-7 viral loads detected in people with ME/CFS than in healthy controls. Participants with ME/CFS could be broadly separated into two groups: one group displayed fluctuating patterns of herpesviruses detectable across the 6 months while the second group displayed more stable viral presentation. In the first group, there was positive correlation between HHV-6B and HHV-7 viral load and severity of symptom scores, including pain, neurocognition, and autonomic dysfunction. The results indicate that fluctuating viral DNA load correlates with ME/CFS symptoms: this is in accordance with the hypothesis that pathogenesis is related to herpesvirus reactivation state, and this should be formally tested. Herpesvirus reactivation might be a cause or consequence of dysregulated immune function seen in ME/CFS. The sampling strategy and molecular tools developed here permit such large-scale epidemiological investigations.

Biomarkers in the diagnostic algorithm of myalgic encephalomyelitis/chronic fatigue syndrome

“…HHV-6 has long been considered as one of the ME/CFS trigger factors, and recent published data indicate that HHV6-B is associated with ME/CFS disease severity ( 19 ). The high HHV-6 load, as well as infection in active phase, has been described in patients with fibromyalgia as well ( 20 ).…”

Saliva antibody-fingerprint of reactivated latent viruses after mild/asymptomatic COVID-19 is unique in patients with myalgic-encephalomyelitis/chronic fatigue syndrome

“…High rate of active EBV infection has been reported, suggesting that at least in a subset of patients, EBV is important factor for the development of the disease ( 23 ). However, reports on no correlation to herpesvirus infection highlight that the issue is not yet clear ( 24 , 25 ) Additionally, viral loads for HHV6B and HHV7, were previously reported to be higher in saliva samples of patients with ME/CFS compared to healthy controls ( 26 ), whereas partial HHV6 reactivation has been demonstrated (HHV6 small noncoding RNA U14 in whole blood) in 40% of the patients ( 12 ).…”

A comparative study of valaciclovir, valganciclovir, and artesunate efficacy in reactivated HHV‐6 and HHV‐7 infections associated with chronic fatigue syndrome/myalgic encephalomyelitis

“…23 Numerous controlled clinical trials indicate herpesvirus reactivation in patients with CFS, confirmed by positive leukocyte PCR results. 3,7,8,[24][25][26][27][28] Another group of studies reports an abnormal immune response to activating proteins of the virus. They are associated with the active reproduction of viral particles in the human body (IgM, IgG to early antigen or p41/38 and IgG to dUTP HHV-6).…”