New Chronic Fatigue Syndrome Biomarkers in the Pipeline

Nicola M. Parry, DVM

July 31, 2017

Patients with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) have different circulating levels of two cytokines when compared with healthy individuals, a study has found. In addition, the circulating levels of 17 cytokines correlate with disease severity.

"Although only two cytokines were found to be different ([transforming growth factor-β (TGF-β)] higher and resistin lower) in ME/CFS patients compared with controls, 17 cytokines correlated with ME/CFS severity," the authors write. "Thirteen of these cytokines are proinflammatory and may contribute to many of the symptoms these patients experience for several years."

Jose G. Montoya, MD, from Stanford University School of Medicine in California, and colleagues published the results of their cross-sectional study online July 31 in the Proceedings of the National Academy of Sciences.

"There's been a great deal of controversy and confusion surrounding ME/CFS, even whether it is an actual disease," senior author Mark Davis, PhD, professor of immunology and microbiology and director of Stanford's Institute for Immunity, Transplantation and Infection, said in a news release. "Our findings show clearly that it's an inflammatory disease and provide a solid basis for a diagnostic blood test."

ME/CFS affects more than 1 million Americans and is characterized by unexplained chronic fatigue, as well as other symptoms including exertion intolerance, headaches, myalgias, and sleep and cognitive abnormalities. Although the pathogenesis of this disabling disorder remains incompletely understood, inflammation has long been considered to play a central role.

Surprisingly, however, traditional markers of inflammation that have been used in clinical practice, such as erythrocyte sedimentation rate and C-reactive protein, are rarely elevated in patients with ME/CFS. Nevertheless, studies have demonstrated changes in other inflammatory markers in this patient population.

For example, several studies have found increased numbers of circulating cytotoxic CD8+ cells expressing activation antigens in these patients; one study also described daily fluctuations of the pro-inflammatory adipokine leptin, and another study linked a distinct cytokine inflammatory profile with early disease.

The researchers therefore aimed to investigate whether patients with ME/CFS have an abnormal profile of circulating cytokines, and whether this profile correlates with disease severity and duration.

They analyzed blood samples from 192 ME/CFS patients and from 392 healthy individuals and performed immunological analyses of the samples, measuring the concentrations of 51 cytokines in each participant's blood.

When comparing patients with ME/CFS with healthy individuals, the investigators found differences in the circulating levels of only two of the 51 cytokines: TGF-β was increased (P = .0052) in patients with ME/CFS, and resistin was decreased (P = .0052). In addition, levels of resistin were significantly lower in patients with mild (P = .0370) and severe (P = .0208) ME/CFS.

Pro-inflammatory Cytokines Elevated

Concentrations of 17 cytokines correlated with disease severity, showing a statistically significant upward linear trend across the sequence of mild, moderate, and severe manifestations of ME/CFS: CCL11 (P = .0069), CXCL1 (P = .0266), CXCL10 (P = .0100), G-CSF (P = .0110), GM-CSF (P = .0063), interferon γ (P = .0101), interleukin 4 (IL-4; P = .0103), IL-5 (P = .0073), IL-7 (P = .0063), IL-12p70 (P = .0069), IL-13 (P = .0069), IL-17F (P = .0103), leptin (P = .0100), leukemia inhibitory factor (P = .0100), nerve growth factor (P = .0069), stem cell factor (P = .0145), and TGF-α (P = .0367).

Thirteen of these were pro-inflammatory. Elevations in these pro-inflammatory cytokines not only highlight the strong immune component of the disease but also likely contribute to many of the symptoms experienced by patients with ME/CFS, the authors write.

Although the researchers also examined the relationship between cytokine concentration and fatigue duration, they found that only the level of CXCL9 (monokine induced by interferon γ) inversely correlated with fatigue duration (P = .0123).

As TGF-β is predominantly considered to be an anti-inflammatory cytokine, the researchers explain that the elevated levels of TGF-β elevation in patients with ME/CFS may reflect down-regulatory activity by these patients' immune systems against continued inflammation. However, if this were true, TGF-β levels would be expected to correlate with ME/CFS severity, which was not the case in this study.

Thus, TGF-β may not always function to counteract inflammation. Instead, "its net effect may depend on the local immunological milieu at target tissues and the overall levels of TGF-β," they say.

Resistin has significant pro-inflammatory activity and is reportedly a marker of inflammation in patients with systemic lupus erythematosus and Crohn's disease. However, the authors are unclear why resistin levels showed an unusual trend, increasing in patients with mild to moderate ME/CFS, but decreasing in those with moderate to severe disease.

Acknowledging the cross-sectional design as one limitation of their study, the authors emphasize longitudinal studies are needed to determine whether patients with ME/CFS remain within their cytokine signature and disease severity category over time, or fluctuate among them.

"Future cytokine research in the peripheral blood of ME/CFS patients should embrace longitudinal designs and seek correlations with neuroradiology, neuroinflammation, and [cerebrospinal fluid]studies," the authors add.

One of the authors reported being a member of the Scientific Advisory Board of the Open Medicine Foundation. Another author reported having previously published with one of the manuscript reviewers. The other authors have disclosed no relevant financial relationships.

Proc Natl Acad Sci U S A. Published online July 31, 2017. Article

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