Immune mechanisms associated with sex-based differences in severe COVID-19 clinical outcomes

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Abstract

Background

Although biological males and females are equally likely to become infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), evidence has mounted that males experience higher severity and fatality compared to females.

Main

The objective of this review is to examine the existing literature on biological mechanisms underlying sex-based differences that could contribute to SARS-CoV-2 infection clinical outcomes. Sex-based differences in immunologic response and hormonal expression help explain the differences in coronavirus disease 2019 (COVID-19) outcomes observed in biological males and females. X inactivation facilitates a robust immune response to COVID-19 in females, who demonstrate a more profound antibody response and faster recovery when compared to males. Low testosterone levels also help explain the dysregulated inflammatory response and poor outcomes observed in some males with COVID-19. Gender differences in health expression and behaviors further compound these observed differences.

Conclusion

Understanding the biology of sex-based differences in COVID-19 severity and mortality could help inform preventative measures, treatment decisions, and development of personalized, sex-specific therapies.

Highlights

Although most COVID-19 patients develop only mild disease, some mount a pronounced inflammatory response that results in severe pneumonia, respiratory failure, and death.
Male sex is a known risk factor for severe outcomes in COVID-19.
Biological sex-based differences in COVID-19 severity and mortality are influenced by genetic and hormonal differences at the cellular and immunologic level.
Biological sex-based differences are further complicated by environmental factors, namely social and cultural norms, that define gender roles which impact risk of infection and severe outcomes.
Understanding sex-based differences in COVID-19 outcomes will help inform clinical decision algorithms and treatment strategies to optimize the care of COVID-19 patients.

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Most cited references 46

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Clinical Characteristics of Coronavirus Disease 2019 in China

Wei-jie Guan, Zheng-yi Ni, Yu Hu … (2020)

Abstract Background Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients. Methods We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. Results The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Conclusions During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.)

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Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Nanshan Chen, Min Zhou, Xuan Dong … (2022)

Summary Background In December, 2019, a pneumonia associated with the 2019 novel coronavirus (2019-nCoV) emerged in Wuhan, China. We aimed to further clarify the epidemiological and clinical characteristics of 2019-nCoV pneumonia. Methods In this retrospective, single-centre study, we included all confirmed cases of 2019-nCoV in Wuhan Jinyintan Hospital from Jan 1 to Jan 20, 2020. Cases were confirmed by real-time RT-PCR and were analysed for epidemiological, demographic, clinical, and radiological features and laboratory data. Outcomes were followed up until Jan 25, 2020. Findings Of the 99 patients with 2019-nCoV pneumonia, 49 (49%) had a history of exposure to the Huanan seafood market. The average age of the patients was 55·5 years (SD 13·1), including 67 men and 32 women. 2019-nCoV was detected in all patients by real-time RT-PCR. 50 (51%) patients had chronic diseases. Patients had clinical manifestations of fever (82 [83%] patients), cough (81 [82%] patients), shortness of breath (31 [31%] patients), muscle ache (11 [11%] patients), confusion (nine [9%] patients), headache (eight [8%] patients), sore throat (five [5%] patients), rhinorrhoea (four [4%] patients), chest pain (two [2%] patients), diarrhoea (two [2%] patients), and nausea and vomiting (one [1%] patient). According to imaging examination, 74 (75%) patients showed bilateral pneumonia, 14 (14%) patients showed multiple mottling and ground-glass opacity, and one (1%) patient had pneumothorax. 17 (17%) patients developed acute respiratory distress syndrome and, among them, 11 (11%) patients worsened in a short period of time and died of multiple organ failure. Interpretation The 2019-nCoV infection was of clustering onset, is more likely to affect older males with comorbidities, and can result in severe and even fatal respiratory diseases such as acute respiratory distress syndrome. In general, characteristics of patients who died were in line with the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia. Further investigation is needed to explore the applicability of the MuLBSTA score in predicting the risk of mortality in 2019-nCoV infection. Funding National Key R&D Program of China.

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Gender Differences in Patients With COVID-19: Focus on Severity and Mortality

Jian-Min Jin, Peng Bai, Wei He … (2020)

Objective: The recent outbreak of Novel Coronavirus Disease (COVID-19) is reminiscent of the SARS outbreak in 2003. We aim to compare the severity and mortality between male and female patients with COVID-19 or SARS. Study Design and Setting: We extracted the data from: (1) a case series of 43 hospitalized patients we treated, (2) a public data set of the first 37 cases of patients who died of COVID-19 and 1,019 patients who survived in China, and (3) data of 524 patients with SARS, including 139 deaths, from Beijing in early 2003. Results: Older age and a high number of comorbidities were associated with higher severity and mortality in patients with both COVID-19 and SARS. Age was comparable between men and women in all data sets. In the case series, however, men's cases tended to be more serious than women's (P = 0.035). In the public data set, the number of men who died from COVID-19 is 2.4 times that of women (70.3 vs. 29.7%, P = 0.016). In SARS patients, the gender role in mortality was also observed. The percentage of males were higher in the deceased group than in the survived group (P = 0.015). Conclusion: While men and women have the same prevalence, men with COVID-19 are more at risk for worse outcomes and death, independent of age.

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Author and article information

Contributors

Cosby G. Arnold:

ORCID: http://orcid.org/0000-0002-8109-0460

cosby.arnold@cuanschutz.edu

Anne Libby: anne.libby@cuanschutz.edu

Alexis Vest: alexis.vest@cuanschutz.edu

Andrew Hopkinson: andrew.hopkinson@cuanschutz.edu

Andrew A. Monte: andrew.monte@cuanschutz.edu

Journal

Journal ID (nlm-ta): Biol Sex Differ

Journal ID (iso-abbrev): Biol Sex Differ

Title: Biology of Sex Differences

Publisher: BioMed Central (London )

ISSN (Electronic): 2042-6410

Publication date (Electronic): 4 March 2022

Publication date PMC-release: 4 March 2022

Publication date Collection: 2022

Volume: 13

Electronic Location Identifier: 7

Affiliations

GRID grid.430503.1, ISNI 0000 0001 0703 675X, Department of Emergency Medicine, , University of Colorado-Anschutz Medical Campus, ; 12401 East 17th Avenue, 7th Floor, Aurora, CO 80045 USA

Author information

Cosby G. Arnold http://orcid.org/0000-0002-8109-0460

Article

Publisher ID: 417

DOI: 10.1186/s13293-022-00417-3

PMC ID: 8894555

PubMed ID: 35246245

SO-VID: f94b84ee-3212-4288-adfa-ba0e58c36039

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 8 October 2021

Date accepted : 22 February 2022

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000050, National Heart, Lung, and Blood Institute;

Award ID: 1F32HL160123-01

Award Recipient : Cosby G. Arnold

Custom metadata

ScienceOpen disciplines: Human biology

Keywords: sex,gender,sars-cov-2,covid-19

Data availability:

ScienceOpen disciplines: Human biology

Keywords: sex, gender, sars-cov-2, covid-19

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Immune mechanisms associated with sex-based differences in severe COVID-19 clinical outcomes

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Abstract

Background

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Highlights

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Novel Coronavirus Disease COVID-19

Most cited references 46

Clinical Characteristics of Coronavirus Disease 2019 in China

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Gender Differences in Patients With COVID-19: Focus on Severity and Mortality

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Cited by 17

Most referenced authors 1,807