Causes of symptoms and symptom persistence in long COVID and myalgic encephalomyelitis/chronic fatigue syndrome.
Komaroff, Anthony L, Dantzer, Robert · Cell reports. Medicine · 2025 · DOI
Quick Summary
This review examines why long COVID and ME/CFS cause such severe, lasting symptoms. Researchers found that both conditions share similar biological problems, including immune system misbehavior, problems with blood vessel function, and issues with how cells produce energy. The study suggests that symptoms may come from both these biological problems and from ancient survival responses in the brain that were meant to protect us during serious illness.
Why It Matters
This comprehensive framework helps explain why ME/CFS symptoms persist for years and suggests specific biological targets for treatment. By identifying shared mechanisms between long COVID and ME/CFS, it could accelerate development of therapies and improve recognition that these are biomedical conditions, not psychological ones. Understanding that ancient protective brain circuits may be causing symptoms opens new therapeutic avenues that could potentially reduce suffering for millions of patients.
Observed Findings
- Multiple similar biological abnormalities identified in both long COVID and ME/CFS, including autoantibodies against neural targets, endothelial dysfunction, and acquired mitochondrial dysfunction
- Persistence of symptoms despite symptom severity, suggesting ongoing physiological processes rather than deconditioning or psychological causes
- Identification of neuroinflammation as a potential activator of ancient neural circuits responsible for sickness behavior and metabolic torpor
- Evidence that biological abnormalities reinforce each other, creating vicious cycles that perpetuate symptoms
- Persistence of infectious agents, their nucleic acids, and antigens identified as factors contributing to chronicity
Inferred Conclusions
- Neuroinflammation represents a promising therapeutic target that could interrupt the symptom-generating pathway in both long COVID and ME/CFS
- The chronicity of symptoms results from multiple reinforcing biological abnormalities rather than a single cause, requiring multi-targeted approaches
- Shared pathophysiological mechanisms between long COVID and ME/CFS suggest that therapeutic strategies developed for one condition may benefit patients with the other
- Ancient, evolutionarily conserved neural circuits controlling sickness behavior and torpor may be central to symptom generation and could be specifically targeted by therapeutics
Remaining Questions
- Which specific biological abnormalities are primary drivers of symptoms versus secondary consequences, and does this vary between patient subgroups?
- How can therapies be designed to target neuroinflammation specifically without affecting necessary protective immune responses?
- What are the precise mechanisms by which persistent infectious agents or their components maintain neuroinflammation and prevent symptom resolution?
- Are there biomarkers that can predict which patients will develop chronic symptoms versus recover, and can these guide personalized treatment strategies?
What This Study Does Not Prove
This review does not prove that any single mechanism causes all symptoms in all patients—ME/CFS and long COVID are likely heterogeneous conditions with multiple contributing factors. It does not establish causation through new experimental evidence, but rather synthesizes existing findings, and therefore cannot confirm which mechanisms are primary versus secondary. The article also does not demonstrate that targeting neuroinflammation will successfully treat these conditions in clinical practice.
Topics
Tags
Metadata
- DOI
- 10.1016/j.xcrm.2025.102259
- PMID
- 40744021
- Review status
- Editor reviewed
- Evidence level
- Established evidence from major reviews, guidelines, or evidence maps
- Last updated
- 7 April 2026