Integrated immune, hormonal, and transcriptomic profiling reveals sex-specific dysregulation in long COVID patients with ME/CFS.
Shahbaz, Shima, Osman, Mohammed, Syed, Hussain et al. · Cell reports. Medicine · 2025 · DOI
Quick Summary
This study examined blood and immune system samples from Long COVID patients with ME/CFS, comparing men and women. The researchers found that women had stronger inflammatory responses, with changes in immune cells and hormones that may contribute to fatigue and cognitive symptoms. Men showed different patterns, including lower testosterone levels. These sex-based differences suggest that treatments may need to be tailored differently for men and women.
Why It Matters
This is the first comprehensive sex-disaggregated immune and molecular analysis of Long COVID/ME/CFS, revealing that women and men experience fundamentally different biological disease mechanisms. Identifying sex-specific biomarkers and immune signatures has direct implications for diagnosis, prognosis, and development of targeted therapeutic interventions, addressing a critical gap in precision medicine for ME/CFS.
Observed Findings
Female Long COVID/ME/CFS patients showed a shift toward myelopoiesis with reduced lymphocytes and increased neutrophils/monocytes compared to males.
RegulatoryT cells were depleted in female patients, suggesting reduced immune suppression capacity.
Elevated CD71+ erythroid cells and disrupted erythropoiesis were observed in females and correlated with fatigue severity.
Females demonstrated stronger pro-inflammatory cytokine profiles and markers of gut barrier dysfunction compared to males.
Transcriptomic analysis revealed neuroinflammatory gene signatures in female patients associated with cognitive symptom severity.
Inferred Conclusions
Long COVID with ME/CFS exhibits distinct sex-specific immune, hormonal, and transcriptional dysregulation patterns.
Females experience more severe systemic inflammation, myeloid activation, and neuroinflammatory responses compared to males.
Identified biomarkers can distinguish female from male Long COVID/ME/CFS and correlate with sex-specific clinical symptoms.
Sex-tailored therapeutic approaches, potentially including hormone replacement therapy and immune modulation, may be necessary for effective treatment.
Remaining Questions
Do the identified immune and hormonal alterations directly cause ME/CFS symptoms, or are they secondary responses to viral infection or other triggers?
What This Study Does Not Prove
This study does not prove that the observed immune and hormonal changes cause ME/CFS symptoms—it shows associations only. The cross-sectional design cannot establish whether these alterations are primary disease drivers or secondary consequences of illness. It also does not demonstrate that hormone replacement therapy or immune-targeted treatments will be clinically effective, only that dysregulation exists.