Sex-related differences in COVID-19 lethality.
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ABSTRACT:
SUBMITTER: Penna C
PROVIDER: S-EPMC7405496 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Men are consistently overrepresented in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and coronavirus disease 2019 (COVID-19) severe outcomes, including higher fatality rates. These differences are likely due to gender-specific behaviors, genetic and hormonal factors, and sex differences in biological pathways related to SARS-CoV-2 infection. Several social, behavioral, and comorbid factors are implicated in the generally worse outcomes in men compared with women. Underlying biological sex differences and their effects on COVID-19 outcomes, however, have received less attention. The present review summarizes the available literature regarding proposed molecular and cellular markers of COVID-19 infection, their associations with health outcomes, and any reported modification by sex. Biological sex differences characterized by such biomarkers exist within healthy populations and also differ with age- and sex-specific conditions, such as pregnancy and menopause. In the context of COVID-19, descriptive biomarker levels are often reported by sex, but data pertaining to the effect of patient sex on the relationship between biomarkers and COVID-19 disease severity/outcomes are scarce. Such biomarkers may offer plausible explanations for the worse COVID-19 outcomes seen in men. There is the need for larger studies with sex-specific reporting and robust analyses to elucidate how sex modifies cellular and molecular pathways associated with SARS-CoV-2. This will improve interpretation of biomarkers and clinical management of COVID-19 patients by facilitating a personalized medical approach to risk stratification, prevention, and treatment.
| S-EPMC7402208 | biostudies-literature
Project description:BackgroundMales and females differ in their immunological responses to foreign pathogens. However, most of the current COVID-19 clinical practices and trials do not take the sex factor into consideration.MethodsWe performed a sex-based comparative analysis for the clinical outcomes, peripheral immune cells, and severe acute respiratory syndrome coronavirus (SARS-CoV-2) specific antibody levels of 1558 males and 1499 females COVID-19 patients from a single center. The lymphocyte subgroups were measured by Flow cytometry. The total antibody, Spike protein (S)-, receptor binding domain (RBD)-, and nucleoprotein (N)- specific IgM and IgG levels were measured by chemiluminescence.ResultsWe found that male patients had approximately two-fold rates of ICU admission (4.7% vs. 2.7% in males and females, respectively, P = 0.005) and mortality (3% vs. 1.4%, in males and females, respectively, P = 0.004) than female patients. Survival analysis revealed that the male sex is an independent risk factor for death from COVID-19 (adjusted hazard ratio [HR] = 2.22, 95% confidence interval [CI]: 1.3-3.6, P = 0.003). The level of inflammatory cytokines in peripheral blood was higher in males during hospitalization. The renal (102/1588 [6.5%] vs. 63/1499 [4.2%], in males and females, respectively, P = 0.002) and hepatic abnormality (650/1588 [40.9%] vs. 475/1499 [31.7%], P = 0.003) were more common in male patients than in female patients. By analyzing dynamic changes of lymphocyte subsets after symptom onset, we found that the percentage of CD19+ B cells and CD4+ T cells was generally higher in female patients during the disease course of COVID-19. Notably, the protective RBD-specific IgG against SARS-CoV-2 sharply increased and reached a peak in the fourth week after symptom onset in female patients, while gradually increased and reached a peak in the seventh week after symptom onset in male patients.ConclusionsMales had an unfavorable prognosis, higher inflammation, a lower percentage of lymphocytes, and indolent antibody responses during SARS-CoV-2 infection and recovery. Early medical intervention and close monitoring are important, especially for male COVID-19 patients.
| S-EPMC8256650 | biostudies-literature
Project description:IntroductionSince the first reports of COVID-19 cases, sex-discrepancies have been reported in COVID-19 mortality. We provide a detailed description of these sex differences in relation to age and comorbidities among notified cases as well as in relation to age and sex-specific mortality in the general Dutch population.MethodsData on COVID-19 cases and mortality until May 31st 2020 was extracted from the national surveillance database with exclusion of healthcare workers. Association between sex and case fatality was analyzed with multivariable logistic regression. Subsequently, male-female ratio in standardized mortality ratios and population mortality rates relative to all-cause and infectious disease-specific mortality were computed stratified by age.ResultsMale-female odds ratio for case fatality was 1.33 [95% CI 1.26-1.41] and among hospitalized cases 1.27 [95% CI 1.16-1.40]. This remained significant after adjustment for age and comorbidities. The male-female ratio of the standardized mortality ratio was 1.70 [95%CI 1.62-1.78]. The population mortality rate for COVID-19 was 35.1 per 100.000, with a male-female rate ratio of 1.25 (95% CI 1.18-1.31) which was higher than in all-cause population mortality and infectious disease mortality.ConclusionOur study confirms male sex is a predisposing factor for severe outcomes of COVID-19, independent of age and comorbidities. In addition to general male-female-differences, COVID-19 specific mechanisms likely contribute to this mortality discrepancy.
| S-EPMC9151564 | biostudies-literature
Project description:Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10-22 and P = 8.1 × 10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10-8) and ARHGAP33 (P = 1.3 × 10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.
| S-EPMC9652109 | biostudies-literature
Project description:Although some studies reported the comprehensive mRNA expression analysis of coronavirus disease 2019 (COVID-19) using blood samples to understand its pathogenesis, the characteristics of RNA expression in COVID-19 and sepsis have not been compared. We compared the transcriptome expression of whole blood samples from patients with COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and patients with sepsis caused by other bacteria who entered the intensive care unit to clarify the COVID-19-specific RNA expression and understand its pathogenesis. Transcriptomes related to mitochondria were upregulated in COVID-19, whereas those related to neutrophils were upregulated in sepsis. However, the transcriptomes related to neutrophils were upregulated in both COVID-19 and sepsis compared to in healthy controls, whereas the mitochondrial transcriptomes were upregulated in COVID-19 and downregulated in sepsis compared to in healthy controls. Moreover, sepsis showed sub-optimal intrinsic apoptotic features compared with COVID-19. The transcriptome expression of COVID-19 has been examined in vitro but has not been widely validated using human specimens. This study improves the understanding of the pathogenesis of COVID-19 and can contribute to the development of treatments.
2022-11-29 | GSE199816 | GEO
Project description:More men than women have died from COVID-19. Genes encoded on X chromosomes, and sex hormones may explain the decreased fatality of COVID-19 in women. The angiotensin-converting enzyme 2 gene is located on X chromosomes. Men, with a single X chromosome, may lack the alternative mechanism for cellular protection after exposure to SARS-CoV-2. Some Toll-like receptors encoded on the X chromosomes can sense SARS-CoV-2 nucleic acids, leading to a stronger innate immunity response in women. Both estrogen and estrogen receptor-? contribute to T cell activation. Interventional approaches including estrogen-related compounds and androgen receptor antagonists may be considered in patients with COVID-19.
| S-EPMC7347256 | biostudies-literature
Project description:AimTo examine the magnitude of sex differences in survival from the coronavirus disease 2019 (COVID-19) in Europe across age groups and regions. We hypothesized that men have a higher mortality than women at any given age but that sex differences will decrease with age as only the healthiest men survive to older ages.MethodsWe used population data from the Institut National D'Études Démographiques on cumulative deaths due to COVID-19 from February to June 2020 in 10 European regions: Denmark, Norway, Sweden, The Netherlands, England and Wales, France, Germany, Italy, Spain and Portugal. For each region, we calculated cumulative mortality rates stratified by age and sex and corresponding relative risks for men vs. women.ResultsThe relative risk of dying from COVID-19 was higher for men than for women in almost all age groups in all regions. The overall relative risk ranged from 1.11 (95% confidence interval, CI 1.01-1.23) in Portugal to 1.54 (95% CI 1.49-1.58) in France. In most regions, sex differences increased until the ages of 60-69 years, but decreased thereafter with the smallest sex difference at age 80+ years.ConclusionDespite variability in data collection and time coverage among regions, the study showed an overall similar pattern of sex differences in COVID-19 mortality in Europe.
| S-EPMC7755064 | biostudies-literature
Project description:COVID-19 has a clear sex disparity in clinical outcome. Globally, infection rates between men and women are similar; however, men are more likely to have more severe disease and are more likely to die. The causes for this disparity are currently under investigation and are most likely multifactorial. Sex hormones play an important role in the immune response with estrogen seen as immune boosting and testosterone as immunosuppressing. Additionally, an important protease involved in viral entry, TMPRSS2, is regulated by androgens. Many observational and prospective studies are ongoing or initiating to further examine the role of sex hormones in SARS-CoV-2 infection and if modulation of them is a realistic treatment option.
| S-EPMC7298487 | biostudies-literature
Project description:AbstractAlthough the number of deaths due to coronavirus disease 2019 (COVID-19) is higher in men than women, prior studies have provided limited sex-stratified clinical data.We evaluated sex-related differences in clinical outcomes among critically ill adults with COVID-19.Multicenter cohort study of adults with laboratory-confirmed COVID-19 admitted to intensive care units at 67 U.S. hospitals from March 4 to May 9, 2020. Multilevel logistic regression was used to evaluate 28-day in-hospital mortality, severe acute kidney injury (AKI requiring kidney replacement therapy), and respiratory failure occurring within 14 days of intensive care unit admission.A total of 4407 patients were included (median age, 62 years; 2793 [63.4%] men; 1159 [26.3%] non-Hispanic White; 1220 [27.7%] non-Hispanic Black; 994 [22.6%] Hispanic). Compared with women, men were younger (median age, 61 vs 64 years, less likely to be non-Hispanic Black (684 [24.5%] vs 536 [33.2%]), and more likely to smoke (877 [31.4%] vs 422 [26.2%]). During median follow-up of 14 days, 1072 men (38.4%) and 553 women (34.3%) died. Severe AKI occurred in 590 men (21.8%), and 239 women (15.5%), while respiratory failure occurred in 2255 men (80.7%) and 1234 women (76.5%). After adjusting for age, race/ethnicity and clinical variables, compared with women, men had a higher risk of death (OR, 1.50, 95% CI, 1.26-1.77), severe AKI (OR, 1.92; 95% CI 1.57-2.36), and respiratory failure (OR, 1.42; 95% CI, 1.11-1.80).In this multicenter cohort of critically ill adults with COVID-19, men were more likely to have adverse outcomes compared with women.
| S-EPMC8677989 | biostudies-literature
Project description:IntroductionSevere COVID-19 leads to important changes in circulating immune-related proteins. To date it has been difficult to understand their temporal relationship and identify cytokines that are drivers of severe COVID-19 outcomes and underlie differences in outcomes between sexes. Here, we measured 147 immune-related proteins during acute COVID-19 to investigate these questions.MethodsWe measured circulating protein abundances using the SOMAscan nucleic acid aptamer panel in two large independent hospital-based COVID-19 cohorts in Canada and the United States. We fit generalized additive models with cubic splines from the start of symptom onset to identify protein levels over the first 14 days of infection which were different between severe cases and controls, adjusting for age and sex. Severe cases were defined as individuals with COVID-19 requiring invasive or non-invasive mechanical respiratory support.Results580 individuals were included in the analysis. Mean subject age was 64.3 (sd 18.1), and 47% were male. Of the 147 proteins, 69 showed a significant difference between cases and controls (p < 3.4 × 10-4). Three clusters were formed by 108 highly correlated proteins that replicated in both cohorts, making it difficult to determine which proteins have a true causal effect on severe COVID-19. Six proteins showed sex differences in levels over time, of which 3 were also associated with severe COVID-19: CCL26, IL1RL2, and IL3RA, providing insights to better understand the marked differences in outcomes by sex.ConclusionsSevere COVID-19 is associated with large changes in 69 immune-related proteins. Further, five proteins were associated with sex differences in outcomes. These results provide direct insights into immune-related proteins that are strongly influenced by severe COVID-19 infection.
| S-EPMC9516500 | biostudies-literature