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

## TL;DR

Long COVID affects women more than men, with persistent symptoms and immune differences that suggest the need for tailored treatments.

## Contribution

This study identifies sex-specific immune and symptom patterns in long COVID patients over extended periods.

## Key findings

- Females with long COVID experience higher symptom burden, including fatigue and neurocognitive issues, which worsen with age and disease duration.
- Immune profiling reveals sex-specific differences, such as reduced CD8⁺ T cell cytotoxicity in females and elevated TNF-α in males.
- Over half of participants reported functional impairments affecting work capacity, highlighting the socioeconomic impact of long COVID.

## Abstract

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.

The online version contains supplementary material available at 10.1186/s13293-026-00825-9.

Long COVID (LC) is a post-infectious condition affecting millions worldwide, marked by persistent, multisystem symptoms, with females disproportionately affected, particularly by neurocognitive and neurosensory complaints. Despite growing knowledge of short-term immune changes, the long-term clinical course, immune dysregulation, and sex-specific mechanisms remain poorly understood. In this study, we analysed 34 LC participants with persisting symptoms from 9 months to 5 years post-SARS-CoV-2 infection and compared them with 26 SARS-CoV-2–infected controls without symptoms. Participants underwent clinical assessment, symptom inventories, comorbidity analysis, and work capacity evaluation, while immune profiling included looking at specific immune cells and proteins in the blood. We looked into differences between males and females. We found that females with LC experienced more symptoms than males, especially fatigue, difficulty concentrating, and memory problems, and these symptoms tended to worsen with age and length of illness. Females also had more underlying health conditions, particularly related to metabolism, neurology, and circulation, which may contribute to their symptoms. Regarding the immune system, females showed changes in immune cells that help fight viruses, which could explain lingering symptoms and vulnerability to neurological issues, while males showed higher levels of general inflammation. More than half of participants reported difficulties with daily activities and work. These findings highlight that LC affects people differently based on sex, illness duration, and health history and underline the need for tailored approaches to treatment, better understanding of the disease, and strategies to support daily functioning and quality of life for those affected.

The online version contains supplementary material available at 10.1186/s13293-026-00825-9.

Prolonged Long COVID (LC) disproportionately affects females, who exhibit higher symptom burden, especially persistent fatigue and neurocognitive complaints, increasing with age and disease duration.Females with LC have more comorbidities, particularly in endocrine, metabolic, and circulatory systems, which may exacerbate symptoms through chronic inflammation and organ dysfunction.Immune profiling revealed sex-specific alterations: females display reduced CD8⁺ T cell cytotoxicity (lower granzyme K and NKG2D), increased sCD40L and sFAS, and decreased perforin, while males show elevated TNF-α.Over half of patients reported functional impairments affecting work capacity, underscoring the socioeconomic burden of LC.It emphasizes the need for sex- and duration-specific management strategies for LC.

Prolonged Long COVID (LC) disproportionately affects females, who exhibit higher symptom burden, especially persistent fatigue and neurocognitive complaints, increasing with age and disease duration.

Females with LC have more comorbidities, particularly in endocrine, metabolic, and circulatory systems, which may exacerbate symptoms through chronic inflammation and organ dysfunction.

Immune profiling revealed sex-specific alterations: females display reduced CD8⁺ T cell cytotoxicity (lower granzyme K and NKG2D), increased sCD40L and sFAS, and decreased perforin, while males show elevated TNF-α.

Over half of patients reported functional impairments affecting work capacity, underscoring the socioeconomic burden of LC.

It emphasizes the need for sex- and duration-specific management strategies for LC.

The online version contains supplementary material available at 10.1186/s13293-026-00825-9.