Sex hormones in SARS-CoV-2 susceptibility: key players or confounders?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has a clear sex disparity in clinical outcomes. Hence, the interaction between sex hormones, virus entry receptors and immune responses has attracted major interest as a target for the prevention and treatment of SARS-CoV-2 infections. This Review summarizes the current understanding of the roles of androgens, oestrogens and progesterone in the regulation of virus entry receptors and disease progression of coronavirus disease 2019 (COVID-19) as well as their therapeutic value. Although many experimental and clinical studies have analysed potential mechanisms by which female sex hormones might provide protection against SARS-CoV-2 infectivity, there is currently no clear evidence for a sex-specific expression of virus entry receptors. In addition, reports describing an influence of oestrogen, progesterone and androgens on the course of COVID-19 vary widely. Current data also do not support the administration of oestradiol in COVID-19. The conflicting evidence and lack of consensus results from a paucity of mechanistic studies and clinical trials reporting sex-disaggregated data. Further, the influence of variables beyond biological factors (sex), such as sociocultural factors (gender), on COVID-19 manifestations has not been investigated. Future research will have to fill this knowledge gap as the influence of sex and gender on COVID-19 will be essential to understanding and managing the long-term consequences of this pandemic.

Development and validation of a prognostic model for the early identification of COVID-19 patients at risk of developing common long COVID symptoms.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic demands reliable prognostic models for estimating the risk of long COVID. We developed and validated a prediction model to estimate the probability of known common long COVID symptoms at least 60 days after acute COVID-19. METHODS: The prognostic model was built based on data from a multicentre prospective Swiss cohort study. Included were adult patients diagnosed with COVID-19 between February and December 2020 and treated as outpatients, at ward or intensive/intermediate care unit. Perceived long-term health impairments, including reduced exercise tolerance/reduced resilience, shortness of breath and/or tiredness (REST), were assessed after a follow-up time between 60 and 425 days. The data set was split into a derivation and a geographical validation cohort. Predictors were selected out of twelve candidate predictors based on three methods, namely the augmented backward elimination (ABE) method, the adaptive best-subset selection (ABESS) method and model-based recursive partitioning (MBRP) approach. Model performance was assessed with the scaled Brier score, concordance c statistic and calibration plot. The final prognostic model was determined based on best model performance. RESULTS: In total, 2799 patients were included in the analysis, of which 1588 patients were in the derivation cohort and 1211 patients in the validation cohort. The REST prevalence was similar between the cohorts with 21.6% (n = 343) in the derivation cohort and 22.1% (n = 268) in the validation cohort. The same predictors were selected with the ABE and ABESS approach. The final prognostic model was based on the ABE and ABESS selected predictors. The corresponding scaled Brier score in the validation cohort was 18.74%, model discrimination was 0.78 (95% CI: 0.75 to 0.81), calibration slope was 0.92 (95% CI: 0.78 to 1.06) and calibration intercept was -0.06 (95% CI: -0.22 to 0.09). CONCLUSION: The proposed model was validated to identify COVID-19-infected patients at high risk for REST symptoms. Before implementing the prognostic model in daily clinical practice, the conduct of an impact study is recommended.

Immunoreactivity of the SARS-CoV-2 entry proteins ACE-2 and TMPRSS-2 in murine models of hormonal manipulation, ageing, and cardiac injury.

Previous work indicates that SARS-CoV-2 virus entry proteins angiotensin-converting enzyme 2 (ACE-2) and the cell surface transmembrane protease serine 2 (TMPRSS-2) are regulated by sex hormones. However, clinical studies addressing this association have yielded conflicting results. We sought to analyze the impact of sex hormones, age, and cardiovascular disease on ACE-2 and TMPRSS-2 expression in different mouse models. ACE-2 and TMPRSS-2 expression was analyzed by immunostaining in a variety of tissues obtained from FVB/N mice undergoing either gonadectomy or sham-surgery and being subjected to ischemia-reperfusion injury or transverse aortic constriction surgery. In lung tissues sex did not have a significant impact on the expression of ACE-2 and TMPRSS-2. On the contrary, following myocardial injury, female sex was associated to a lower expression of ACE-2 at the level of the kidney tubules. In addition, after myocardial injury, a significant correlation between younger age and higher expression of both ACE-2 and TMPRSS-2 was observed for lung alveoli and bronchioli, kidney tubules, and liver sinusoids. Our experimental data indicate that gonadal hormones and biological sex do not alter ACE-2 and TMPRSS-2 expression in the respiratory tract in mice, independent of disease state. Thus, sex differences in ACE-2 and TMPRSS-2 protein expression observed in mice may not explain the higher disease burden of COVID-19 among men.