Chronic Fatigue Syndrome: From Clinical Observations to Unifying Hypotheses of Disease Mechanisms

Dear Colleagues,

Chronic fatigue syndromes (ICD-10 code G93.3) are one of the major mysteries of current medical science. While myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is still a very much debated condition, a similar set of post-viral fatigue symptoms is now appearing in the aftermath of COVID-19. There is no known cause or effective treatment. Therefore, the need for understanding the etiology and pathophysiologic mechanisms of fatigue syndromes has never before been as timely and urgent as today. Depending on the area of expertise, several theories of pathogenesis and pathophysiology have been proposed. In addition to earlier psychological theories, chronic (viral) infections, systemic inflammation, autoimmune diseases, and disorders of the autonomic nervous system dysautonomia are the most commonly proposed ones. Despite intensive current research and promising initiatives, none of the approaches has so far managed to result in effective therapies to cure or even systematically control the debilitating symptoms.

Epidemic outbreaks of ME/CFS have been described before. However, there is a risk that COVID-19 becomes the first pandemic that is followed by post-viral fatigue of a global range. This would result in significant individual suffering, a burden on healthcare systems, and decreased productivity of economies. We absolutely need to share and combine all our efforts that could contribute to further understanding the disease mechanisms, to get control over the current and future chronic fatigue pandemics.

More research into fatigue syndromes is urgently needed. Significant research is possible only if we have innovative theories or a hypothesis to test. Every clinician who has solid knowledge around basic sciences, an observational eye, and the ability to pay careful attention to patients’ symptoms and responses to medical treatments and nonmedical interventions may develop their own understanding of ME/CFS or post-COVID syndrome. If you have a novel idea regarding this issue, as well as the resources to investigate it further and perhaps submit a patent application for a potential treatment, then I would encourage you to do just that. However, if you still think that you have a good understanding or an idea arising from your clinical observations but do not think you could take it further by yourself, perhaps because the diagnostic testing you are proposing does not even exist yet, then you should consider that sharing your experience and thoughts could inspire other clinicians or researchers to combine your idea with their experience or take it forward to scientific testing or methodological development, for the benefit of all.

Therefore, I invite you to (1) describe those patient histories, status findings, laboratory tests, clinical investigations, and perhaps with surprising treatment outcomes that you are able to (2) evaluate against your literature review and combine into a unifying hypothesis of potential disease mechanisms. It could be an ambitious unifying hypothesis or just a smaller thought linking two or more things together. You may share potential (even hypothetical) biomarkers for diagnostic testing. Finally, based on your hypothesis, you may propose a treatment that either cures or alleviates the symptoms of chronic fatigue.

For your own credit, you may provide a name for your innovative hypothesis so that those who may subsequently test it can better refer to your innovation. Use of imagination, the most powerful innovation tool of human beings, is encouraged. However, to guarantee scientific credibility, your idea must arise from clinical observations. You should test your proposal against the current body of evidence (review section) before you liberate your creative mind for future projections.

I solicit papers addressing ME/CFS, post-COVID/long COVID syndrome or other conditions where long-term fatigue is a central clinical complaint. I encourage you to report on symptoms or signs that you think have so far received too little attention. You may report their frequency in your patient population and put them into a meaningful context of plausible disease mechanisms. You may present a single symptom, a single case, a set of symptoms or a series of cases that have inspired your hypothesis.

Dr. Olli J. Polo
Guest Editor

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