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

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease that is mainly diagnosed based on its clinical symptoms. Biomarkers that could facilitate the diagnosis of ME/CFS are not yet available; therefore, reliable and clinically useful disease indicators are of high importance. The aim of this work was to analyze the association between ME/CFS clinical course severity, presence of HHV-6A/B infection markers, and plasma levels of autoantibodies against adrenergic and muscarinic acetylcholine receptors. A total of 134 patients with ME/CFS and 33 healthy controls were analyzed for the presence of HHV-6A/B using PCRs, and antibodies against beta2-adrenergic receptors (β2AdR) and muscarinic acetylcholine receptors (M3 AChR and M4 AChR) using ELISAs. HHV-6A/B U3 genomic sequence in whole-blood DNA was detected in 19/31 patients with severe ME/CFS, in 18/73 moderate ME/CFS cases, and in 7/30 mild ME/CFS cases. Severity-related differences were found among those with a virus load of more than 1,000 copies/106 PBMCs. Although no disease severity-related differences in anti-β2AdR levels were observed in ME/CFS patients, the median concentration of these antibodies in plasma samples of ME/CFS patients was 1.4 ng/ml, while in healthy controls, it was 0.81 ng/ml, with a statistically significant increased level in those with ME/CFS (p = 0.0103). A significant difference of antibodies against M4 AChR median concentration was found between ME/CFS patients (8.15 ng/ml) and healthy controls (6.45 ng/ml) (p = 0.0250). The levels of anti-M4 plotted against disease severity did not show any difference; however, increased viral load correlates with the increase in anti-M4 level. ME/CFS patients with high HHV-6 load have a more severe course of the disease, thus confirming that the severity of the disease depends on the viral load—the course of the disease is more severe with a higher viral load. An increase in anti-M4 AchR and anti-β2AdR levels is detected in all ME/CFS patient groups in comparison to the control group not depending on ME/CFS clinical course severity. However, the increase in HHV-6 load correlates with the increase in anti-M4 level, and the increase in anti-M4 level, in turn, is associated with the increase in anti-β2AdR level. Elevated levels of antibodies against β2AdR and M4 receptors in ME/CFS patients support their usage as clinical biomarkers in the diagnostic algorithm of ME/CFS.

Tissue specific signature of HHV-6 infection in ME/CFS

“…Additionally, several recent studies have identified higher copy numbers of HHV-6 and EBV in ME/CFS patients compared to healthy controls ( Fevang et al, 2021 ; Lee et al, 2021 ; Gravelsina et al, 2022 ). Lee et al observed an association between HHV-6B and HHV-7 viral load and severity of ME/CFS symptoms by analyzing salivary viral load.…”

“…Lee et al observed an association between HHV-6B and HHV-7 viral load and severity of ME/CFS symptoms by analyzing salivary viral load. Gravelsina et al found a higher viral load of HHV-6B in peripheral blood mononuclear cells (PBMC) corresponding to the severity of ME/CFS symptoms, with 84.2% of patients with severe ME/CFS having a load greater than 1,000 copies per million PBMC compared to 57.1% of patients with mild ME/CFS and 11.1% of health controls ( Gravelsina et al, 2022 ). Fevang et al found a higher average copy number of EBV in the peripheral blood of ME/CFS patients compared to healthy controls, however the difference was not statistically significant ( Fevang et al, 2021 ).…”

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

“…During dormancy periods [ 139 ], and the IgG levels against HSV-1 are associated with brain fog, AD, schizophrenia, and bipolar disorders [ 140 ]. HHV-6 has also been linked to the development of encephalopathy, ME/CFS and other neurological disorders [ 141 ], and is known to infect CD4 + T-cells preferably, but also CD8 + , macrophages/monocytes and natural killer (NK) cells. HHV-6-infected cells affect immune responses [ 142 ].…”

From Viral Infection to Autoimmune Reaction: Exploring the Link between Human Herpesvirus 6 and Autoimmune Diseases

“…In a recent study, Gravelsina et al provided supportive evidence for the potential association of HHV-6 and ME/CFS and the disease’s autoimmune nature. The study investigated 134 ME/CFS patient serum samples and demonstrated that a higher HHV-6 load was associated with more severe disease and higher HHV-6 loads correlated with higher muscarinic acetylcholine receptor autoantibody levels [ 136 ]. A seminal study by Kasimir et al addressed a crucial shortcoming regarding research into HHV-6’s association with various diseases.…”