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Review 1: "Sex Differences in Symptomatology and Immune Profiles of Long COVID"

The reviewers found the study to be compelling, but they pointed out that more detail regarding the machine learning methods could help make this study reproducible and better understand the results.

Published onApr 17, 2024
Review 1: "Sex Differences in Symptomatology and Immune Profiles of Long COVID"
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key-enterThis Pub is a Review of
Sex differences in symptomatology and immune profiles of Long COVID
Sex differences in symptomatology and immune profiles of Long COVID

Summary Strong sex differences in the frequencies and manifestations of Long COVID (LC) have been reported with females significantly more likely than males to present with LC after acute SARS-CoV-2 infection1–7. However, whether immunological traits underlying LC differ between sexes, and whether such differences explain the differential manifestations of LC symptomology is currently unknown. Here, we performed sex-based multi-dimensional immune-endocrine profiling of 165 individuals8 with and without LC in an exploratory, cross-sectional study to identify key immunological traits underlying biological sex differences in LC. We found that female and male participants with LC experienced different sets of symptoms, and distinct patterns of organ system involvement, with female participants suffering from a higher symptom burden. Machine learning approaches identified differential sets of immune features that characterized LC in females and males. Males with LC had decreased frequencies of monocyte and DC populations, elevated NK cells, and plasma cytokines including IL-8 and TGF-β-family members. Females with LC had increased frequencies of exhausted T cells, cytokine-secreting T cells, higher antibody reactivity to latent herpes viruses including EBV, HSV-2, and CMV, and lower testosterone levels than their control female counterparts. Testosterone levels were significantly associated with lower symptom burden in LC participants over sex designation. These findings suggest distinct immunological processes of LC in females and males and illuminate the crucial role of immune-endocrine dysregulation in sex-specific pathology.

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.


Review: The manuscript investigates the immune and endocrine mechanisms underlying the increased susceptibility of females to long COVID (LC) as compared to males. It is a very interesting and timely study. Using data from medical records of patients with long COVID from the Mount Sinai Medical Center, the authors show that females with LC displayed a higher symptomatic burden which persisted even after accounting for age, BMI, and other comorbidities. Females with LC had higher overall frequencies of symptoms spanning multiple organ systems including changes in body temperature, cough, and neurological and neurocognitive symptoms such as headaches and confusion. Interestingly, symptom burden was higher in unvaccinated subjects. Standardized questionnaires also revealed significant differences in the severity scores between males and females with females reporting higher impact on overall health. Machine learning was used to analyze immune related differences between males and females. The analysis revealed that T cells from females displayed increased exhaustion while myeloid cells were reduced in males. Remarkably, testosterone levels correlated inversely with the symptoms in both sexes. This is a very important finding as several immune cells express androgen receptors and relatively little is known how their functions are modulated by testosterone. Interestingly, increased reactivity to latent herpes viruses such as CMV, HSV-2, EBV was also observed and were associated with reduced testosterone levels. The approach of using a combination of elegant statistical methods and machine learning shows how novel inferences can be derived from clinical data. Furthermore, uncovering of testosterone as a novel predictor LC symptom indicates a possibly novel therapeutic target to trat neurological pathologies associated with LC and maybe other diseases. Overall, this is an elegant study which brings to light some novel predictors of differences between immune response, increased reactivity to latent viruses and reduced testosterone levels in females accounting for the long COVID increase in females.

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