Activin B is a novel biomarker for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) diagnosis: a cross sectional study

Abstract

BackgroundInvestigations of activin family proteins as serum biomarkers for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). CFS/ME is a disease with complex, wide-ranging symptoms, featuring persistent fatigue of 6 months or longer, particularly post exertion. No definitive biomarkers are available.MethodsA cross-sectional, observational study of CFS/ME patients fulfilling the 2003 Canadian Consensus Criteria, in parallel with healthy non-fatigued controls, was conducted. Comparisons with a previously defined activin reference population were also performed. For the total study cohort the age range was 18–65 years with a female: male participant ratio of greater than 3:1. All participants were assessed via a primary care community clinic. Blood samples were collected for pathology testing after physical examination and orthostatic intolerance assessment. Cytokines, activin A, activin B and follistatin were also measured in sera from these samples. All data were compared between the CFS/ME and control cohorts, with the activins and follistatin also compared with previously defined reference intervals.ResultsSerum activin B levels for CFS/ME participants were significantly elevated when compared to the study controls, as well as the established reference interval. Serum activin A and follistatin were within their normal ranges. All routine and special pathology markers were within the normal laboratory reference intervals for the total study cohort, with no significant differences detected between CFS/ME and control groups. Also, no significant differences were detected for IL-2, IL-4, IL-6, IL-10, IL-17A, TNF or IFN-gamma.ConclusionElevated activin B levels together with normal activin A levels identified patients with the diagnostic symptoms of CFS/ME, thus providing a novel serum based test. The activins have multiple physiological roles and capture the diverse array of symptoms experienced by CFS/ME patients.

Weighting of orthostatic intolerance time measurements with standing difficulty score stratifies ME/CFS symptom severity and analyte detection

“…From among a broad range of pathology test and cytokine assay results (Additional file 1: Table S2), only serum activin B was significantly different (p < 0.05) for the direct comparison between ME/CFS and study control (healthy) participants, as previously reported [24]. Individual participant serum and urine pathology results generally fell within the laboratory reference interval.…”

“…IL-10 has been implicated in the pathogenesis of ME/CFS [37, 38], but there is no evidence from this study for a relationship between IL-10 levels and presence/severity of ME/CFS symptoms. On the other hand, Activin B has been recently identified as significant when separating this ME/CFS cohort from the same study (healthy) controls, [24] a relationship that was also reflected by WST analysis.…”

“…Comparison of the criteria and analytes in those two groups found that no routine pathology marker was significantly different at p < 0.05, and found no patterns of abnormal results for ME/CFS patients when applying standard reference intervals [24, 27]. The calculation of a weighted standing time (WST), which combined the participant’s time standing (minutes) with a subjective standing difficulty score, measured as a component of orthostatic intolerance (OI) assessments by a specialist ME/CFS clinic with 20 years’ experience.…”

Cell-Based Blood Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

“…Accordingly, molecular biomarkers have been pursued across multiple areas of research. For example, the role of the immune system in ME/CFS has been studied for decades, raising cytokines as potential biomarkers of disease [8][9][10][11][12][13][14] whose clinical utility would be aided by their accessibility in blood. Other cytokine studies have utilised cerebrospinal fluid [15,16], the acquisition of which is more invasive than drawing blood, and so could be less amenable to a routine diagnostic test.…”

“…The ideal molecular biomarkers would be straightforward to sample and assess, and they also exhibit high sensitivity and specificity. For these reasons, the search for biomarkers has extended to investigating the utility of routine blood pathology tests, but the results are either inconsistent [9,10] or require further study [30]. The recent development of a nanoneedle bioarray to measure the electrical impedance of ME/CFS peripheral blood mononuclear cells (PBMCs) in plasma is highly promising, but requires identification of the underlying mechanism and proven specificity for ME/CFS [31].…”