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

Background Long COVID (LC) is a post-infectious condition affecting millions worldwide, characterized by persistent multisystem symptoms. Women 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. Methods We analyzed 34 participants experiencing symptoms from 9 months to 5 years post-SARS-CoV-2 infection, hereafter called persistent LC (pLC), alongside 26 SARS-CoV-2–infected controls without persistent 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. Results Women with pLC exhibited higher symptom burden, particularly neurocognitive and neurosensory complaints, which increased with age and disease duration, whereas men showed no clear age- or duration-related patterns. Comorbidities, especially affecting endocrine, metabolic, and circulatory systems, were more frequent in women and correlated with symptom severity. Immune profiling revealed subtle but sex-specific differences: women had reduced CD8⁺ T cell cytotoxic function, lower NKG2D and granzyme K expression, increased sCD40L and sFAS, and decreased perforin, whereas men 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. Conclusions Persistent LC is characterized by sex-specific differences in symptom burden and immune profiles. Reduced cytotoxic CD8⁺ T cell function in women may contribute to viral persistence and neurological symptoms, whereas elevated inflammatory markers in men 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 pLC endotypes. Understanding these mechanisms may inform therapeutic strategies for LC and other post-viral and chronic inflammatory syndromes.