Post infectious fatigue and circadian rhythm disruption in long-COVID and other infections: a need for further research.
Livieratos, Achilleas, Lockley, Steven W, Tsiodras, Sotirios · EClinicalMedicine · 2025 · DOI
Quick Summary
This article discusses how infections like COVID-19 can disrupt the body's internal 24-hour clock, leading to persistent fatigue and sleep problems. The authors explain that viral infections may damage the genes and cellular machinery that control our daily rhythms, trigger inflammation in the brain, and harm energy-producing structures in our cells. Understanding these mechanisms could help doctors develop better treatments for Long COVID and chronic fatigue syndrome.
Why It Matters
This article bridges understanding between Long COVID and ME/CFS by highlighting shared biological mechanisms of post-infectious fatigue and circadian disruption. For patients, identifying circadian dysregulation as a treatable target offers hope for interventions beyond symptom management. For researchers, the proposed multi-system model (genetic, mitochondrial, immune, epigenetic) suggests promising avenues for biomarker discovery and therapeutic development.
Observed Findings
Clock gene dysregulation (CLOCK, BMAL1, PER2) occurs in post-infectious conditions
Mitochondrial dysfunction impairs energy production in circadian dysregulation
Key inflammatory cytokines (IL-6, TNF-α) contribute to neuroinflammation
DNA methylation changes at clock-related loci occur, particularly in peripheral tissues
Sleep disturbances and chronic fatigue are mechanistically linked to circadian rhythm disruption
Inferred Conclusions
Circadian dysregulation is a multifactorial consequence of viral infection involving genetic, mitochondrial, immune, and epigenetic disruptions
Post-infectious fatigue and sleep disturbances in Long COVID and ME/CFS share common biological mechanisms
Further research is needed to clarify the relative importance and interaction of these mechanisms in driving fatigue
Circadian dysregulation represents a potential therapeutic target for post-infectious fatigue conditions
Remaining Questions
Which of the identified mechanisms (clock gene, mitochondrial, inflammatory, or epigenetic) are most critical in driving fatigue in individual patients?
What This Study Does Not Prove
This editorial does not present new experimental data or patient cohort findings—it is a literature synthesis. It does not establish which mechanisms are most important or how they interact in individual patients. It does not prove causation between circadian disruption and fatigue, only that they are mechanistically linked and frequently co-occur after infection.
Can measurement of clock gene expression or DNA methylation patterns predict symptom severity or treatment response?
Are there effective interventions that target circadian dysregulation specifically, and do they improve fatigue in Long COVID or ME/CFS?
How do these circadian mechanisms interact with other known abnormalities in ME/CFS (immune dysfunction, autonomic dysregulation, post-exertional malaise)?