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Sex differences in immune responses that underlie COVID-19 disease outcomes

Our take —

Men tend to have a more severe COVID-19 disease course than women, and it is thought that differences in the immune response to SARS-CoV-2 infection might contribute to this disparity. This study considered 39 patients (who were not in intensive care and who had not received anti-inflammatory treatment) hospitalized for COVID-19 at Yale-New Haven Hospital, and looked for differences in various facets of the baseline immune response between men and women. The authors found some differences by sex in inflammatory cytokines/chemokines and proportions of different types of immune cells, and found that women tended to have a more robust T-cell response than men. However, these data should be regarded as exploratory, given the small sample size and the inability to adjust for possible confounding variables.

Study design

Retrospective Cohort

Study population and setting

This study compared immune responses between men and women who were admitted to a single hospital (Yale-New Haven Hospital) with laboratory-confirmed SARS-CoV-2 infection between March 18 and May 9, 2020 (n=98). A subset of 39 patients (cohort A) were considered for the primary baseline analysis; these patients were not in intensive care, had not received tocilizumab, and had not received > 40 mg corticosteroid treatment before initial sample collection. The full cohort (cohort B), including those with more severe disease, was used in a secondary longitudinal analysis. An additional secondary analysis compared COVID-19 patients with health care workers (n=64), adjusting for age and BMI. The authors tested for sex differences in SARS-CoV-2 viral concentrations in saliva and nasopharyngeal swabs, plasma levels of IgG and IgM antibodies to SARS-CoV-2, plasma concentrations of 71 inflammatory cytokines and chemokines, proportions of peripheral blood mononuclear cells (PBMCs) represented by different cell types, and T cell phenotypes. Finally, the authors tested whether immune phenotypes correlated with disease outcomes, and whether these immune phenotypes and outcomes differed by sex.

Summary of Main Findings

There were no statistically significant differences between men and women with respect to concentrations of SARS-CoV-2 RNA or anti-SARS-CoV-2 S1-specific IgG or IgM antibodies. Concentrations of inflammatory cytokines and chemokines were also largely similar between men and women with COVID-19, both at baseline and over the course of the disease, with some exceptions (higher concentrations of IL-8 and IL-18 in men). In the full cohort (cohort B), men had lower counts and proportions of T cells in PBMCs. At baseline (cohort A), but not in the longitudinal data from the full cohort, women had larger populations of activated and terminally differentiated T cells than men. Men whose disease worsened tended to have less T-cell activation at baseline than men whose disease did not worsen; this association was not present in women. Increased age was associated with lower T-cell activation in men, but not in women.

Study Strengths

The authors measured a wide array of immune response markers.


The study population was small relative to the number of measured immune parameters, particularly in the baseline cohort, limiting the ability to appropriately adjust analyses for variables that may have confounded the observed associations between sex and immune response (e.g., comorbidities, treatments, timing of sample relative to probable date of infection). The timing of serial measurements was not consistent across patients and was not clearly reported. A key covariate, steroid use, may have been subject to misclassification (e.g., patients were classified as not being on steroids if they had not received steroids that day, but many commonly administered steroids have a half-life exceeding 24 hours). Categorizing variables that were originally measured on a continuous scale may have resulted in residual confounding.

Value added

This paper provides exploratory analysis related to sex differences in the immunologic and clinical response to COVID-19.

This review was posted on: 11 February 2021