Elevated risk of new-onset chronic fatigue syndrome/myalgic encephalomyelitis up to four years after SARS-CoV-2 infection.
Hadidchi, Roham, Patel, Bhakti, Madan, Japji et al. · Journal of translational medicine · 2025 · DOI
Quick Summary
This study found that people who had COVID-19 are more likely to develop ME/CFS in the years following infection compared to people who never had COVID-19. Women, and people with existing autoimmune or anxiety disorders, appear to be at higher risk. Importantly, having COVID-19 again did not increase the risk further, and blood tests during acute COVID were not able to predict who would later develop ME/CFS.
Why It Matters
This study provides long-term epidemiological evidence that SARS-CoV-2 infection is a significant risk factor for ME/CFS development, which is critical for post-COVID care guidelines and identifying vulnerable populations. Understanding risk factors helps clinicians screen and monitor high-risk patients, while the finding that certain comorbidities increase susceptibility may inform future mechanistic research into ME/CFS pathogenesis.
Observed Findings
COVID-19 patients (both hospitalized and non-hospitalized) had 1.46–1.56-fold increased risk of new-onset CFS/ME versus controls over 4-year follow-up.
Female sex, autoimmune disorders, liver disease, and anxiety disorders independently increased CFS/ME risk after COVID-19.
Reinfection with SARS-CoV-2 was not associated with additional CFS/ME risk.
Early COVID-19 vaccination (pre-2022) was associated with increased new-onset CFS/ME risk.
Acute-phase blood biomarkers (AST, creatinine, D-dimer, LDH, ferritin, hemoglobin, platelets, NLR, temperature) did not predict subsequent CFS/ME development.
Inferred Conclusions
SARS-CoV-2 infection is an independent risk factor for new-onset CFS/ME, regardless of hospitalization status.
Certain pre-existing conditions and female sex confer heightened susceptibility to post-COVID CFS/ME.
Simple acute-phase laboratory markers cannot identify which COVID-19 patients will develop CFS/ME, suggesting the pathogenic mechanism may involve more complex immunological or systemic dysregulation.
Ongoing surveillance and symptom management are needed for COVID-19 survivors, particularly those with comorbid autoimmune or anxiety disorders.
Remaining Questions
What This Study Does Not Prove
This observational study cannot establish causation definitively; unmeasured confounding variables may explain some associations. The mechanism by which COVID-19 leads to ME/CFS remains unclear, and the unexpected vaccination finding requires replication and mechanistic investigation before drawing conclusions. Additionally, the study did not assess post-COVID syndrome severity or distinguish CFS/ME from other forms of prolonged fatigue.
Tags
Symptom:Fatigue
Biomarker:Blood Biomarker
Phenotype:Infection-TriggeredLong COVID Overlap
Method Flag:PEM Not DefinedWeak Case DefinitionMixed Cohort
What is the biological mechanism by which SARS-CoV-2 infection precipitates ME/CFS, and why do certain comorbidities increase vulnerability?
Why was early vaccination associated with increased CFS/ME risk, and does this finding reflect confounding, selection bias, or a true biological interaction?
Are there more complex or dynamic biomarkers (immune profiling, proteomics, metabolomics) measured beyond acute infection that can predict CFS/ME development?
Do interventions targeting fatigue or immune dysregulation in high-risk COVID-19 survivors prevent or mitigate ME/CFS onset?