Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): An Overview.
Deumer, Undine-Sophie, Varesi, Angelica, Floris, Valentina et al. · Journal of clinical medicine · 2021 · DOI
Quick Summary
ME/CFS is a long-term illness that causes extreme tiredness, worsening of symptoms after activity, and difficulty thinking clearly. Patients experience these symptoms very differently from one another, and currently there are no blood tests or physical exams that can definitively diagnose the condition. This review examines several potential causes, including past infections, genetic factors, hormone imbalances, and changes in gut bacteria, while exploring whether a simple blood test might someday help diagnose ME/CFS.
Why It Matters
This comprehensive review addresses a critical gap in ME/CFS medicine: the absence of diagnostic biomarkers and molecular consensus despite decades of research. By synthesizing multi-disciplinary evidence on potential disease mechanisms and highlighting non-coding RNA as a diagnostic tool, the review provides a roadmap for future research that could lead to objective diagnostic tests and better treatment strategies for patients currently diagnosed only by symptoms.
Observed Findings
- Multiple infectious agents, genetic factors, and hormonal abnormalities have been associated with ME/CFS in prior research, but findings vary significantly between patients.
- Post-exertional malaise is a distinguishing feature preventing sustained physical and cognitive activity in many patients.
- No single biomarker-based diagnostic test exists to date, making symptom-based consensus criteria necessary for diagnosis.
- Gut microbiota alterations appear implicated in disease progression based on literature synthesis.
- Non-coding RNAs show potential as future diagnostic biomarkers across heterogeneous patient populations.
Inferred Conclusions
- ME/CFS likely involves multiple overlapping biological pathways rather than a single disease mechanism, explaining observed heterogeneity.
- Development of objective biomarker-based diagnostics is necessary and feasible, with non-coding RNA as a particularly promising avenue.
- Future research must account for and characterize the substantial biological variation between individual ME/CFS patients.
- Infectious triggers, genetic susceptibility, hormonal dysregulation, and microbiota changes warrant continued investigation as potential contributors.
Remaining Questions
- Why do molecular signatures differ so substantially between patients with similar clinical presentations, and can these differences predict treatment response?
- Can non-coding RNA panels be developed, validated, and implemented as reliable clinical diagnostic biomarkers for ME/CFS?
- Which combination of infectious, genetic, hormonal, and microbiota factors determine disease onset, and are there modifiable therapeutic targets?
- What is the relationship between acute SARS-CoV-2 infection and post-viral ME/CFS-like illness, and are mechanisms identical to classical ME/CFS?
What This Study Does Not Prove
As a narrative review, this study does not establish causation for any proposed mechanism—it synthesizes existing correlational data. The heterogeneity acknowledged by the authors means no single mechanism proposed here likely explains all ME/CFS cases. The review does not provide new experimental evidence or validate any specific biomarker for clinical use.
Topics
Tags
Metadata
- DOI
- 10.3390/jcm10204786
- PMID
- 34682909
- Review status
- Editor reviewed
- Evidence level
- Early hypothesis, preprint, editorial, or weak support
- Last updated
- 7 April 2026