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Biomarkers for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a systematic review - PubMed

  • ️Sun Jan 01 2023

Biomarkers for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a systematic review

Rebekah Maksoud et al. BMC Med. 2023.

Abstract

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifaceted condition that affects most body systems. There is currently no known diagnostic biomarker; instead, diagnosis is dependent on application of symptom-based case criteria following exclusion of any other potential medical conditions. While there are some studies that report potential biomarkers for ME/CFS, their efficacy has not been validated. The aim of this systematic review is to collate and appraise literature pertaining to a potential biomarker(s) which may effectively differentiate ME/CFS patients from healthy controls.

Methods: This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Cochrane review guidelines. PubMed, Embase and Scopus were systematically searched for articles containing "biomarker" and "ME/CFS" keywords in the abstract or title and if they included the following criteria: (1) were observational studies published between December 1994 and April 2022; (2) involved adult human participants; (3) full text is available in English (4) original research; (5) diagnosis of ME/CFS patients made according to the Fukuda criteria (1994), Canadian Consensus Criteria (2003), International Consensus Criteria (2011) or Institute of Medicine Criteria (2015); (6) study investigated potential biomarkers of ME/CFS compared to healthy controls. Quality and Bias were assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Case Control Studies.

Results: A total of 101 publications were included in this systematic review. Potential biomarkers ranged from genetic/epigenetic (19.8%), immunological (29.7%), metabolomics/mitochondrial/microbiome (14.85%), endovascular/circulatory (17.82%), neurological (7.92%), ion channel (8.91%) and physical dysfunction biomarkers (8.91%). Most of the potential biomarkers reported were blood-based (79.2%). Use of lymphocytes as a model to investigate ME/CFS pathology was prominent among immune-based biomarkers. Most biomarkers had secondary (43.56%) or tertiary (54.47%) selectivity, which is the ability for the biomarker to identify a disease-causing agent, and a moderate (59.40%) to complex (39.60%) ease-of-detection, including the requirement of specialised equipment.

Conclusions: All potential ME/CFS biomarkers differed in efficiency, quality, and translatability as a diagnostic marker. Reproducibility of findings between the included publications were limited, however, several studies validated the involvement of immune dysfunction in the pathology of ME/CFS and the use of lymphocytes as a model to investigate the pathomechanism of illness. The heterogeneity shown across many of the included studies highlights the need for multidisciplinary research and uniform protocols in ME/CFS biomarker research.

Keywords: Biomarker; Chronic fatigue syndrome; Diagnostic test; Myalgic encephalomyelitis.

© 2023. The Author(s).

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest. The authors disclose Patent Cooperation Treaty application number WO2016176726A1 and Australian provisional application 2022902253.

Figures

Fig. 1
Fig. 1

PRISMA flow diagram of systematic search for biomarker systematic review

Fig. 2
Fig. 2

Postulated multidisciplinary pathway of ME/CFS. ME/CFS onset often occurs following an environmental trigger/s such as infection, trauma or chemical insult. ME/CFS is associated with genetic changes including SNPs in TRP and CHRM that are critical in cell signalling processes. In a two-step process, environmental triggers may result in upregulation of defected proteins that participate in these pathways and disruption of downstream signalling pathways involved in natural killer cell cytotoxicity and mitochondrial regulation. This can either directly affect different tissues and systems or indirectly through inflammatory pathways and cytokines. Cytokines and inflammation trigger epigenetic changes through mRNA or miRNA that further affect physiological function. Ca2+, calcium; CN, calcineurin, CaM, Camodulin, CHRM, cholinergic Receptor Muscarinic; cAMP, cyclic adenosine monophosphate, CREB, cyclic adenosine monophosphate response element-binding protein; DAG, diacylglycerol; DHEAs, dehydroepiandrosterone sulfate; DNA, Deoxyribonucleic acid; ERK, extracellular signal-regulated kinase; GDF15, growth/differentiation factor 15; IP3, inositol trisphosphate; IP3R, inositol trisphosphate receptor; IL, interleukin; mTOR, mammalian target of rapamycin; mRNA, messenger ribonucleic acid, MiRNA, micro ribonucleic acid; NFAT, nuclear factor of activated T D cells; PIP2, Phosphatidylinositol 4,5-bisphosphate; PLC, phospholipase C; PACAP, pituitary adenylate cyclase-activating peptide; STIM, stromal interaction molecule; TRP, Transient Receptor Potential; TRPM3, Transient Receptor Potential Melastatin 3; VIP, vasoactive intestinal peptide

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