Shared autonomic phenotype of long COVID and myalgic encephalomyelitis/chronic fatigue syndrome.
Novak, Peter, Systrom, David M, Witte, Alexandra et al. · PloS one · 2026 · DOI
Quick Summary
Researchers compared people with Long COVID and ME/CFS to healthy volunteers and found they share very similar patterns of nervous system dysfunction, including problems with blood flow to the brain when standing up, widespread autonomic problems, and nerve damage in the skin. While the two conditions show these striking similarities, the study couldn't identify a single test that clearly separates them from each other, suggesting they may develop through related mechanisms.
Why It Matters
This is one of the largest comparative autonomic studies in ME/CFS, providing objective physiological evidence that Long COVID and ME/CFS share common underlying mechanisms rather than being entirely separate diseases. These findings validate patients' reported symptoms through measurable autonomic and neurological abnormalities, strengthening the biological basis for both conditions and potentially opening pathways for shared diagnostic and therapeutic approaches.
Observed Findings
92% of Long COVID and 88% of ME/CFS patients showed reduced orthostatic cerebral blood flow velocity compared to controls
95% of Long COVID and 89% of ME/CFS patients demonstrated mild-to-moderate widespread autonomic failure
67% of Long COVID and 53% of ME/CFS patients had evidence of small fiber neuropathy on skin biopsy
96% of Long COVID and 92% of ME/CFS patients tested showed preload failure (reduced blood volume response)
hEDS patients exhibited more severe peripheral neurodegeneration than both Long COVID and ME/CFS groups
Inferred Conclusions
Long COVID and ME/CFS share a common autonomic phenotype characterized by cerebrovascular dysregulation, widespread autonomic dysfunction, and small fiber neuropathy, suggesting overlapping pathophysiology
Standard laboratory tests (metabolic, inflammatory, autoimmune, hormonal panels) do not reliably distinguish between Long COVID and ME/CFS, indicating these conditions may require specialized autonomic and neuropathological assessment
The distinct pattern observed in hEDS raises the possibility that Long COVID and ME/CFS represent shared but distinct syndromes rather than simple variants of a single disease
Remaining Questions
What are the primary pathophysiological mechanisms causing the shared autonomic and small fiber neuropathy findings in both conditions?
What This Study Does Not Prove
This study does not prove that Long COVID and ME/CFS are identical diseases—the overlapping findings may reflect distinct conditions with convergent pathophysiology or represent different manifestations of a shared process. The retrospective design and reliance on existing autonomic laboratory data cannot establish causation or determine whether these autonomic findings are primary drivers of symptoms or secondary consequences. The findings also cannot explain why some individuals develop these conditions after infection while others do not.