Long-term sex differences in symptoms and immune profile in long COVID

Long COVID (LC) is a post-infectious condition affecting millions worldwide, characterized by persistent multisystem symptoms. Females are disproportionately affected, reporting higher symptom burden, particularly neurocognitive and neurosensory complaints. While short-term immunopathology has been described, the long-term clinical course, immune dysregulation, and sex-specific underpinnings remain poorly understood.

We analyzed 34 participants experiencing persisting symptoms from 9 months to 5 years post-SARS-CoV-2 infection, alongside 26 SARS-CoV-2-infected controls without symptoms. Clinical assessments, symptom inventories, comorbidity analysis, and work capacity evaluation were performed. Immune profiling included flow cytometry of CD4⁺ and CD8⁺ T cells, NK cells, and B cells, as well as quantification of plasma cytokines, soluble factors, and cytotoxic molecules, analyzed in a sex-disaggregated manner.

Females with LC exhibited higher symptom burden, particularly persistent fatigue, neurocognitive and neurosensory complaints, which increased with age and tended to increase with disease duration, whereas males showed no clear age- or duration-related patterns. Comorbidities, especially affecting endocrine, metabolic, and circulatory systems, were more frequent in females and aligned with symptom severity. Immune profiling revealed subtle but sex-specific differences: females had reduced CD8⁺ T cell cytotoxic profile, lower NKG2D and granzyme K expression, increased sCD40L and sFAS, and decreased perforin, whereas males displayed elevated TNF-α. NK cell function, B cells, and humoral immunity remained largely intact. Over half of participants reported functional impairments affecting work capacity.

Even though our cohort is small it suggests that prolonged LC is characterized by sex-specific differences in symptom burden and immune profiles. Reduced cytotoxic CD8⁺ T cell profile in females may contribute to viral persistence and neurological symptoms, whereas elevated inflammatory markers in males suggest distinct immune pathways. These findings highlight the need for sex- and duration-specific management strategies, the identification of biomarkers, and the development of personalized therapies targeting specific LC endotypes.