Recent research has revealed sex differences in Long COVID (LC), with females more frequently affected than males. Despite this, the underlying immunological traits contributing to these sex differences and their impact on LC symptoms remain unclear. This study reveals distinct immunological processes in females and males with LC, highlighting the role of immune-endocrine dysregulation in sex-specific pathology and suggesting potential avenues for tailored therapeutic approaches.1
Key findings from the study show that individuals with LC exhibit different symptom profiles and organ system involvement based on sex. Machine learning techniques identified distinct immune feature sets associated with LC in each sex. Specifically:1
- Males with LC displayed reduced frequencies of monocytes and dendritic cells, elevated levels of natural killer (NK) cells, and increased plasma cytokines like IL-8 and TGF-β family members.
- Females with LC had increased frequencies of exhausted and cytokine-secreting T cells, higher antibody reactivity to latent herpesviruses (EBV, HSV-2, CMV), and lower testosterone levels compared to control females. Notably, lower testosterone levels were associated with a reduced symptom burden in LC participants, regardless of sex.
Alba Azola, MD, lead author of the AAPM&R autonomic dysfunction guidance statement and a member of the Johns Hopkins Post-Acute COVID-19 Team, emphasizes individualized rehabilitation protocols to address the unique needs of each LC patient.
“I would say that the vast majority of the epidemiology work that has been published to date have all shown that the preponderance of female patients in those with Long COVID is typically about 70% female to male,” Azola stated. “This is not a surprise. A lot of other post-infectious illnesses that were seen before the pandemic have this preponderance of females, which historically has set the tone for a lot of the historic interpretation of this.”
To investigate this, the researchers conducted a sex-based, multi-dimensional immune-endocrine profiling study involving 165 individuals with and without LC. This exploratory, cross-sectional study aimed to identify key immunological traits responsible for biological sex differences in LC.1
Azola discussed the influence of hormonal changes on reproductive health and their potential impact on LC symptoms in women. “We know that there may be some changes in hormone balances that either predispose or lead to the sequelae of the infection itself. There are interactions between sex hormones and the immune system that could be playing a role. Testosterone interacts with the immune system by decreasing its activity, almost like an anti-inflammatory in some ways.”
3 Key Takeaways
- Males and females with LC exhibit different immune responses, with males showing reduced monocytes and dendritic cells and increased NK cells, while females have more exhausted T cells and higher reactivity to latent herpesviruses.
- Lower testosterone levels in females are associated with a reduced symptom burden in LC, indicating that hormonal differences significantly influence symptom severity.
- The study highlights the need for personalized therapeutic approaches tailored to the distinct immune and hormonal profiles of each gender to improve treatment outcomes for LC.
Additional findings from and new results from a recent study reveal that males generally experience more severe acute COVID-19 and higher mortality, while females are more likely to develop LC. This research emphasizes how sex-specific immune dysregulation affects LC development and persistence. During acute infection, males with LC showed a significant increase in TGF-β signaling within proliferating NK cells. In contrast, females exhibited elevated XIST expression and enhanced IL-1 signaling in monocytes at 12 months post-infection.2
Across both sexes, individuals with LC demonstrated common immune features, including reduced co-stimulatory signaling from monocytes and widespread upregulation of NF-κB transcription factors. Persistent LC in both males and females was marked by increased LAG3, indicating T cell exhaustion, decreased ETS1 expression, and elevated intracellular IL-4 levels in T cells.2
To further understand how sex-specific factors influence LC, Azola explains: “We know that Long COVID involves immune dysregulation, where the immune system is often overactive. We also know that hormonal changes can affect this, with impacts like earlier onset of menopause and cycle irregularities observed in many patients, though we don't have a lot of explicit data on the mechanisms behind these observations,” Azola stated.
Researchers utilized single-cell transcriptomics, single-cell proteomics, and plasma proteomics to analyze blood samples from 45 patients during acute SARS-CoV-2 infection, and at three and 12months post-infection. The cohort included individuals who either developed LC or fully recovered, allowing for comparative analysis of immune features across sexes.2
Overall, these studies align on the key aspects of LC, emphasizing the need for continued exploration into how sex-specific immune and endocrine responses contribute to LC symptomatology and tailored therapeutic approaches. They underscore the role of lower testosterone levels in females and suggest that immune and endocrine factors drive sex-specific LC symptomatology, pointing toward potential tailored treatments. Future research should investigate how sex-specific immune and endocrine differences influence LC symptoms to develop personalized therapies.
References
Silva J, Takahashi T, Wood J, et. al. Sex differences in symptomatology and immune profiles of Long COVID. medRxiv. March 4, 2024. Accessed September 12, 2024. https://www.medrxiv.org/content/10.1101/2024.02.29.24303568v2
Hamlin R, Pienkos S, Chan L, et. al. Sex differences and immune correlates of Long COVID development, persistence, and resolution. bioRxiv. Published June 19, 2024. Accessed September 12, 2024. https://www.biorxiv.org/content/10.1101/2024.06.18.599612v
