Sex differences in severity and mortality from COVID-19: are males more vulnerable?
ABSTRACT: Coronavirus disease 2019 (COVID-19) has shown high infection and mortality rates all over the world, and despite the global efforts, there is so far no specific therapy available for COVID-19. Interestingly, while the severity and mortality of COVID-19 are higher in males than in females, the underlying molecular mechanisms are unclear. In this review, we explore sex-related differences that may be contributing factors to the observed male-biased mortality from COVID-19. Males are considered the weaker sex in aspects related to endurance and infection control. Studies show that viral RNA clearance is delayed in males with COVID-19. A recent study has indicated that the testis can harbor coronavirus, and consequently, males show delayed viral clearance. However, the role of testis involvement in COVID-19 severity and mortality needs further research. Males and females show a distinct difference in immune system responses with females eliciting stronger immune responses to pathogens. This difference in immune system responses may be a major contributing factor to viral load, disease severity, and mortality. In addition, differences in sex hormone milieus could also be a determinant of viral infections as estrogen has immunoenhancing effects while testosterone has immunosuppressive effects. The sex-specific severity of COVID-19 infections indicates that further research on understanding the sex differences is needed. Inclusion of both males and females in basic research and clinical trials is required to provide critical information on sex-related differences that may help to better understand disease outcome and therapy.
Project description:The sex discordance in COVID-19 outcomes has been widely recognized, with males generally faring worse than females and a potential link to sex steroids. A plausible mechanism is androgen-induced expression of TMPRSS2 and/or ACE2 in pulmonary tissues that may increase susceptibility or severity in males. This hypothesis is the subject of several clinical trials of anti-androgen therapies around the world. Here, we investigated the sex-associated TMPRSS2 and ACE2 expression in human and mouse lungs and interrogated the possibility of pharmacologic modification of their expression with anti-androgens. We found no evidence for increased TMPRSS2 expression in the lungs of males compared to females in humans or mice. Furthermore, in male mice, treatment with the androgen receptor antagonist enzalutamide did not decrease pulmonary TMPRSS2. On the other hand, ACE2 and AR expression was sexually dimorphic and higher in males than females. ACE2 was moderately suppressible with enzalutamide therapy. Our work suggests that sex differences in COVID-19 outcomes attributable to viral entry are independent of TMPRSS2. Modest changes in ACE2 could account for some of the sex discordance.
Project description:Coronavirus disease-2019 (COVID-19) has poorer clinical outcomes in males compared to females, and immune responses underlie these sex-related differences in disease trajectory. As immune responses are in part regulated by metabolites, we examined whether the serum metabolome has sex-specificity for immune responses in COVID-19. In males with COVID- 19, kynurenic acid (KA) and a high KA to kynurenine (K) ratio was positively correlated with age, inflammatory cytokines, and chemokines and was negatively correlated with T cell responses, revealing that KA production is linked to immune responses in males. Males that clinically deteriorated had a higher KA:K ratio than those that stabilized. In females with COVID-19, this ratio positively correlated with T cell responses and did not correlate with age or clinical severity. KA is known to inhibit glutamate release, and we observed that serum glutamate is lower in patients that deteriorate from COVID-19 compared to those that stabilize, and correlates with immune responses. Analysis of Genotype-Tissue Expression (GTEx) data revealed that expression of kynurenine aminotransferase, which regulates KA production, correlates most strongly with cytokine levels and aryl hydrocarbon receptor activation in older males. This study reveals that KA has a sex-specific link to immune responses and clinical outcomes, in COVID-19 infection.
Project description:Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to the global coronavirus disease 2019 (COVID-19) pandemic. SARS-CoV-2 enters cells via angiotensin-Converting Enzyme 2 (ACE2) receptors, highly expressed in nasal epithelium with parallel high infectivity.1,2 The nasal epigenome is in direct contact with the environment and could explain COVID-19 disparities by reflecting social and environmental influences on ACE2 regulation. We collected nasal swabs from anterior nares of 547 children, measured DNA methylation (DNAm), and tested differences at 15 ACE2 CpGs by sex, age, race/ethnicity and epigenetic age. ACE2 CpGs were differentially methylated by sex with 12 sites having lower DNAm (mean=12.71%) and 3 sites greater DNAm (mean=1.45%) among females relative to males. We observed differential DNAm at 5 CpGs for Hispanic females (mean absolute difference=3.22%) and lower DNAm at 8 CpGs for Black males (mean absolute difference=1.33%), relative to white participants. Longer DNAm telomere length was associated with greater ACE2 DNAm at 11 and 13 CpGs among males (mean absolute difference=7.86%) and females (mean absolute difference=8.21%), respectively. Nasal ACE2 DNAm differences could contribute to our understanding COVID-19 severity and disparities reflecting upstream environmental and social influences.
Project description:BACKGROUND:The reported national case fatality rates (CFRs) for coronavirus disease 2019 (COVID-19) shows a sex bias with males > females. The relative lengths of the index (2D) and ring (4D) fingers (digit ratio; 2D:4D) is a sexually dimorphic (males < females) proxy of fetal sex steroids (low 2D:4D indicates high prenatal testosterone/low prenatal estrogen). AIM:To examine sex-specific relationships of 2D:4D per nation with national values of COVID-19 CFRs. STUDY DESIGN:COVID-19 CFRs and the percent of male deaths were related to mean national (self-reported) 2D:4D by sex and hand from a large online survey (the BBC Internet Study). SUBJECTS:103,482 men and 83,366 women. OUTCOME MEASURES:Relationships of mean national 2D:4D with CFRs from 41 countries and with national male death rates from 16 countries. RESULTS:Male right and left hand 2D:4D showed positive relationships with CFR. These relationships remained significant after removing the influence of female 2D:4D. A positive association of male right and left 2D:4D was detected with the percentage of male deaths. CONCLUSIONS:At the national level, high mean 2D:4D (indicating low prenatal testosterone/high prenatal estrogen) is associated with high CFRs and percent male mortality. At the individual level, high 2D:4D may be a risk factor for severity of COVID-19 in males. We speculate that male 2D:4D is a negative correlate for expression of the SARS-CoV2 receptor (ACE2).
Project description:To determine what exacerbate severity of the COVID-19 among patients without comorbidities and advanced age and investigate potential clinical indicators for early surveillance, we adopted a nested case-control study, design in which severe cases (case group, n = 67) and moderate cases (control group, n = 67) of patients diagnosed with COVID-19 without comorbidities, with ages ranging from 18 to 50 years who admitted to Wuhan Tongji Hospital were matched based on age, sex and BMI. Demographic and clinical characteristics, and risk factors associated with severe symptoms were analysed. Percutaneous oxygen saturation (SpO2), lymphocyte counts, C-reactive protein (CRP) and IL-10 were found closely associated with severe COVID-19. The adjusted multivariable logistic regression analyses revealed that the independent risk factors associated with severe COVID-19 were CRP (OR 2.037, 95% CI 1.078-3.847, P = 0.028), SpO2 (OR 1.639, 95% CI 0.943-2.850, P = 0.080) and lymphocyte (OR 1.530, 95% CI 0.850-2.723, P = 0.148), whereas the changes exhibited by indicators influenced incidence of disease severity. Males exhibited higher levels of indicators associated with inflammation, myocardial injury and kidney injury than the females. This study reveals that increased CRP levels and decreased SpO2 and lymphocyte counts could serve as potential indicators of severe COVID-19, independent of comorbidities, advanced age and sex. Males could at higher risk of developing severe symptoms of COVID-19 than females.
Project description:The novel coronavirus disease (COVID-19) has become a global health crisis since its first appearance in Wuhan, China. Current epidemiological studies suggest that COVID-19 affects older patients with multiple comorbidities, such as hypertension, obesity, and chronic lung diseases. The differences in the incidence and severity of COVID-19 are likely to be multifaceted, depending on various biological, social, and economical factors. Specifically, the socioeconomic differences and psychological impact of COVID-19 affecting males and females are essential in pandemic mitigation and preparedness. Previous clinical studies have shown that females are less susceptible to acquire viral infections and reduced cytokine production. Female patients have a higher macrophage and neutrophil activity as well as antibody production and response. Furthermore, in-vivo studies of the angiotensin-converting enzyme 2 (ACE2) showed higher expression in the kidneys of male than female patients, which may explain the differences in susceptibility and progression of COVID-19 between male and female patients. However, it remains unknown whether the expression of ACE2 differs in the lungs of male or female patients. Disparities in healthcare access and socioeconomic status between ethnic groups may influence COVID-19 rates. Ethnic groups often have higher levels of medical comorbidities and lower socioeconomic status, which may increase their risk of contracting COVID-19 through weak cell-mediated immunity. In this article, we examine the current literature on the gender and racial differences among COVID-19 patients and further examine the possible biological mechanisms underlying these differences.
Project description:Background:Whether there is sex-bias within the adverse outcomes associated with COVID-19 in the cancer population is unknown. In this regard, several published studies have examined this question, but the results are inconclusive and inconsistent. To evaluate the sex-difference in the risk of adverse outcomes associated with COVID-19 in the cancer population, we have conducted a systematic review and meta-analysis. Methods:Published articles evaluating adverse outcomes associated with COVID-19 in the cancer population from inception to June 2020 were identified by searching PubMed and EMBASE, ASCO 2020 Virtual Annual Conference, AACR 2020 COVID-19 and Cancer, ESMO conferences held from January to June 2020, and medRxiv and bioRxiv. Prospective or retrospective analyses in English, providing outcomes data with sex differences in the cancer population were included. The primary outcomes of interest were pooled ORs of severe illness, all-cause death, and the composite of severe illness and death attributable to COVID-19 in males versus females in cancer patients. Findings:Overall, 3968 patients (17 studies) were analyzed in retrospective study settings. Overall, pooled ORs of the composite of severe illness and all-cause death in the setting of COVID-19 in males versus females was 1.60 (95% CI, 1.38-1.85). The risk of severe illness or death were both independently increased in males versus females. Interpretation:Male sex was associated with a higher risk of severe illness and death attributable to COVID-19. This finding has implications in informing the clinical prognosis and decision making in the care of cancer patients. Funding:This study received no funding.
Project description:COVID-19 pandemia is affecting Countries worldwide with a gendered death excess as being a male represents, especially in the 50-69 years age group, an unfavourable factor. Females are constitutionally prone to defend themselves against pathogens with a stronger efficiency than males. As a fact, several genes involved into the regulation of the innate and adaptive immune response are strategically placed on the X-chromosome and, among them, pathogen-related receptors (PRRs), such as Toll-like receptor 7, suitable to recognize ssRNAs and trigger a gendered successful anti-viral fight. On the other hand, a more regulated IL-6 production and a more contained inflammation after the encounter of a pathogen supply score points in favour of the female sex in the view that an abnormal and exaggerated cytokine release does represent the hallmark of the deathful SARS-CoV-2 infection. The sex-prevalent expression of the attachment and permissive molecules ACE2 and TMPRSS2 further supports the concept of a male-oriented vulnerability. In this review, the possible role of biological and immunological sex differences into the higher morbidity and mortality of SARS-CoV-2 between females and males are discussed.
Project description:Sex-related differences in Coronavirus Disease (COVID-19) severity and mortality exist, with the male sex being a potential risk factor1. It was recently shown that patients with mild to moderate SARS-CoV-2 infection have elevated levels of inflammatory cytokines and chemokines, and sex-differences in these immune responses. In this study, we used an untargeted metabolomics workflow with multivariable logistic regression to identify metabolites that were associated with COVID-19 disease. Serum samples were analyzed from COVID-19 patients (n=22 women and n=17 men), and healthcare worker (HCW) controls that had no evidence of COVID-19 disease (n=10 women and n=10 men). We further investigated the sex differences in the associations between metabolites and immune markers, and found that the relevance of kynurenic acid, KYAT and AhR activation in COVID-19 could be of utmost importance.
Project description:The COVID-19 pandemic has spread across more than 200 countries and resulted in over 170,000 deaths. For unclear reasons, higher mortality rates from COVID-19 have been reported in men compared to women. While the SARS-CoV-2 receptor ACE2 and serine protease TMPRSS2 have been detected in lung and other tissues, it is not clear what sex differences may exist. We analyzed a publicly-available normal human prostate single-cell RNA sequencing dataset and found TMPRSS2 and ACE2 co-expressing cells in epithelial cells, with a higher proportion in club and hillock cells. Then we investigated datasets of lung epithelial cells and also found club cells co-expressing TMPRSS2 and ACE2. A comparison of ACE2 expression in lung tissue between males and females showed higher expression in males and a larger proportion of ACE2+ cells in male type II pneumocytes, with preliminary evidence that type II pneumocytes of all lung epithelial cell types showed the highest expression of ACE2. These results raise the possibility that sex differences in ACE2 expression and the presence of double-positive cells in the prostate may contribute to the observed disparities of COVID-19.