Distinct plasma immune signatures in ME/CFS are present early in the course of illness.

Observed Findings

• Early ME/CFS cases showed simultaneous activation of both pro-inflammatory and anti-inflammatory cytokines, suggesting dysregulated immune balance.
• Immune signature alterations were prominent in early disease (<5 years or estimated onset) but absent in longer-duration ME/CFS cases.
• Cytokine alterations correlated more strongly with illness duration than with objective measures of illness severity.
• Intercytokine regulatory networks showed dissociation in early ME/CFS, indicating breakdown in normal immune regulation.
• Findings were consistent across two large multicenter cohorts when controls were matched for season, geographic site, age, and sex.

Inferred Conclusions

• ME/CFS has a dynamic immunopathology that evolves over the course of illness, with distinct immune activation patterns present early that are not maintained chronically.
• The inability to find consistent biomarkers in previous studies may reflect failure to account for illness duration and sampling timing.
• Early diagnosis of ME/CFS may be possible through identification of these early plasma immune signatures.
• Intervention strategies may need to target the early immunological phase of disease when these distinct patterns are most prominent.

Remaining Questions