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Semin Thromb Hemost 2021; 47(04): 341-347
DOI: 10.1055/s-0040-1715455
Commentary

COVID-19 and Sex-/Gender-Specific Differences: Understanding the Discrimination

Ariunzaya Amgalan
1   Georgetown University School of Medicine, Washington, District of Columbia
,
Ann Kinga Malinowski
1   Georgetown University School of Medicine, Washington, District of Columbia
,
Maha Othman
2   Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
3   Department of Biomedical and Molecular Sciences, School of Medicine, Queen's University, Kingston, Ontario, Canada
4   School of Baccalaureate Nursing, St. Lawrence College, Kingston, Ontario, Canada
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Coronavirus disease in 2019 (COVID-19), as caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been associated with significant morbidity and mortality worldwide. Although SARS-CoV-2 primarily targets the respiratory system, it can cause various hematological and hemostatic derangements, most notably coagulopathies in severe cases.[1] [4] Thrombocytopenia and elevations in fibrinogen and D-dimer have been reported to be prognostic indicators of COVID-19 severity and/or mortality.[2] [4] Changes in hemostatic parameters correlate with parallel rises in inflammatory markers such as cytokines and C-reactive protein (CRP).[4] Key mechanisms for SARS-CoV-2–induced coagulopathy include severe lung injury, alterations in the renin–angiotensin–aldosterone system (RAAS), and overactivation of the immune inflammatory pathways.[3] [4]

Of relevance to the current commentary, certain demographic and clinical factors, such as older age and preexisting comorbid conditions, can increase the risk of more severe infections.[5] [6] The number of COVID-19 cases is similar among males and females, as evidenced by data from over 700,000 confirmed COVID-19 cases collected by the World Health Organization (WHO).[7] However, a recent meta-analysis suggests that men are more likely to experience severe disease and mortality compared with women.[8] Yet, it is unclear whether the disparities in COVID-19 clinical outcomes are due to underlying sex-based biologic differences or gender-based behavioral differences. Exploration of the sex- and gender-based differences in SARS CoV-2 infection is vital, as these may carry potential implications for disease progression, outcome severity, vaccine response, therapeutic intervention and effectiveness, recruitment of males and/or females to clinical research studies, as well as identification of novel therapies for use in both sexes. In this report, we highlight those differences based on available evidence, attempt to explore and discuss possible underlying reasons, and provide our views for future research.



Publikationsverlauf

Artikel online veröffentlicht:
03. September 2020

© 2020. Thieme. All rights reserved.

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  • References

  • 1 Becker RC. COVID-19 update: COVID-19-associated coagulopathy. J Thromb Thrombolysis 2020; 50 (01) 54-67
    CrossrefPubMedGoogle Scholar
  • 2 Lippi G, Favaloro EJ. D-dimer is associated with severity of coronavirus disease 2019: a pooled analysis. Thromb Haemost 2020; 120 (05) 876-878
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 3 Henry BM, Vikse J, Benoit S, Favaloro EJ, Lippi G. Hyperinflammation and derangement of renin-angiotensin-aldosterone system in COVID-19: a novel hypothesis for clinically suspected hypercoagulopathy and microvascular immunothrombosis. Clin Chim Acta 2020; 507: 167-173
    CrossrefPubMedGoogle Scholar
  • 4 Amgalan A, Othman M. Hemostatic laboratory derangements in COVID-19 with a focus on platelet count. Platelets 2020; 31 (06) 740-745
    CrossrefPubMedGoogle Scholar
  • 5 Knight M, Bunch K, Vousden N. et al. Characteristics and outcomes of pregnant women admitted to hospital with confirmed SARS-CoV-2 infection in the UK: national population based cohort study. BMJ 2020; 369: m2107
    CrossrefPubMedGoogle Scholar
  • 6 Kayem G, Lecarpentier E, Deruelle P. et al. A snapshot of the COVID-19 pandemic among pregnant women in France. J Gynecol Obstet Hum Reprod 2020; 49 (07) 101826
    Google Scholar
  • 7 World Health Organization. SUBJECT IN FOCUS: WHO Global Case-Based Surveillance for Human Infection with Coronavirus Disease (COVID-19).; 2020. Accessed May 23, 2020 at: https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200418-sitrep-89-covid-19.pdf?sfvrsn=3643dd38_2
  • 8 Peckham H, de Gruijter N, Raine C. et al. Sex-bias in COVID-19: a meta-analysis and review of sex differences in disease and immunity. Nat Commun 2020; (epub ahead of print) DOI: 10.21203/RS.3.RS-23651/V1.
    CrossrefPubMedGoogle Scholar
  • 9 The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19)—China, 2020. China CDC Weekly 2020; 2 (08) 113-122
    CrossrefPubMedGoogle Scholar
  • 10 Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020; 323 (13) 1239-1242
    CrossrefPubMedGoogle Scholar
  • 11 COVID-19 sex-disaggregated data tracker – Global Health 50/50. Accessed May 23, 2020 at: https://globalhealth5050.org/covid19/sex-disaggregated-data-tracker/#1587645651236-8a62beb3-4a03
    Google Scholar
  • 12 Michelozzi P, de'Donato F, Scortichini M. et al. Mortality impacts of the coronavirus disease (COVID-19) outbreak by sex and age: rapid mortality surveillance system, Italy, 1 February to 18 April 2020. Euro Surveill 2020; 25 (19) 2000620
    CrossrefPubMedGoogle Scholar
  • 13 Di Lorenzo G, Di Trolio R. Coronavirus disease (COVID-19) in Italy: analysis of risk factors and proposed remedial measures. Front Med (Lausanne) 2020; 7: 140
    CrossrefPubMedGoogle Scholar
  • 14 Di Stadio A, Ricci G, Greco A, de Vincentiis M, Ralli M. Mortality rate and gender differences in COVID-19 patients dying in Italy: a comparison with other countries. Eur Rev Med Pharmacol Sci 2020; 24 (08) 4066-4067
    PubMedGoogle Scholar
  • 15 Richardson S, Hirsch JS, Narasimhan M. et al; The Northwell COVID-19 Research Consortium. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA 2020; 323 (20) 2052-2059
    CrossrefPubMedGoogle Scholar
  • 16 Serge R, Vandromme J, Charlotte M. Are we equal in adversity? Does COVID-19 affect women and men differently?. Maturitas 2020; 138: 62-68
    CrossrefPubMedGoogle Scholar
  • 17 Grasselli G, Zangrillo A, Zanella A. et al; COVID-19 Lombardy ICU Network. Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy. JAMA 2020; 323 (16) 1574-1581
    CrossrefPubMedGoogle Scholar
  • 18 Garg S, Kim L, Whitaker M. et al. Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019 - COVID-NET, 14 states, March 1-30, 2020. MMWR Morb Mortal Wkly Rep 2020; 69 (15) 458-464
    CrossrefPubMedGoogle Scholar
  • 19 Meng Y, Wu P, Lu W. et al. Sex-specific clinical characteristics and prognosis of coronavirus disease-19 infection in Wuhan, China: a retrospective study of 168 severe patients. PLOS Pathog 2020; 16 (04) e1008520
    CrossrefPubMedGoogle Scholar
  • 20 Li X, Xu S, Yu M. et al. Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan. J Allergy Clin Immunol 2020; 146 (01) 110-118
    CrossrefPubMedGoogle Scholar
  • 21 Lechien JR, Chiesa-Estomba CM, Place S. et al; COVID-19 Task Force of YO-IFOS. Clinical and epidemiological characteristics of 1420 European patients with mild-to-moderate coronavirus disease 2019. J Intern Med 2020; 288 (03) 335-344
    CrossrefPubMedGoogle Scholar
  • 22 Luo H, Lie Y, Prinzen FW. Surveillance of coronavirus disease 2019 in general population using an online questionnaire: a report from 18161 respondents in China (preprint). JMIR Public Health Surveill 2020; 6 (02) e18576
    CrossrefPubMedGoogle Scholar
  • 23 Libert C, Dejager L, Pinheiro I. The X chromosome in immune functions: when a chromosome makes the difference. Nat Rev Immunol 2010; 10 (08) 594-604
    CrossrefPubMedGoogle Scholar
  • 24 Schurz H, Salie M, Tromp G, Hoal EG, Kinnear CJ, Möller M. The X chromosome and sex-specific effects in infectious disease susceptibility. Hum Genomics 2019; 13 (01) 2
    CrossrefPubMedGoogle Scholar
  • 25 Conti P, Younes A. Coronavirus COV-19/SARS-CoV-2 affects women less than men: clinical response to viral infection. J Biol Regul Homeost Agents 2020; 34 (02) 339-343
    Google Scholar
  • 26 vom Steeg LG, Klein SL. SeXX matters in infectious disease pathogenesis. PLoS Pathog 2016; 12 (02) e1005374
    CrossrefPubMedGoogle Scholar
  • 27 Amadori A, Zamarchi R, De Silvestro G. et al. Genetic control of the CD4/CD8 T-cell ratio in humans. Nat Med 1995; 1 (12) 1279-1283
    CrossrefPubMedGoogle Scholar
  • 28 Villacres MC, Longmate J, Auge C, Diamond DJ. Predominant type 1 CMV-specific memory T-helper response in humans: evidence for gender differences in cytokine secretion. Hum Immunol 2004; 65 (05) 476-485
    CrossrefPubMedGoogle Scholar
  • 29 Hewagama A, Patel D, Yarlagadda S, Strickland FM, Richardson BC. Stronger inflammatory/cytotoxic T-cell response in women identified by microarray analysis. Genes Immun 2009; 10 (05) 509-516
    CrossrefPubMedGoogle Scholar
  • 30 Buckberry S, Bianco-Miotto T, Bent SJ, Dekker GA, Roberts CT. Integrative transcriptome meta-analysis reveals widespread sex-biased gene expression at the human fetal-maternal interface. Mol Hum Reprod 2014; 20 (08) 810-819
    CrossrefPubMedGoogle Scholar
  • 31 Pinheiro I, Dejager L, Libert C. X-chromosome-located microRNAs in immunity: might they explain male/female differences? The X chromosome-genomic context may affect X-located miRNAs and downstream signaling, thereby contributing to the enhanced immune response of females. BioEssays 2011; 33 (11) 791-802
    CrossrefPubMedGoogle Scholar
  • 32 Chamekh M, Deny M, Romano M. et al. Differential susceptibility to infectious respiratory diseases between males and females linked to sex-specific innate immune inflammatory response. Front Immunol 2017; 8: 1806
    CrossrefPubMedGoogle Scholar
  • 33 Sundrani DP, Roy SS, Jadhav AT, Joshi SR. Sex-specific differences and developmental programming for diseases in later life. Reprod Fertil Dev 2017; 29 (11) 2085-2099
    CrossrefPubMedGoogle Scholar
  • 34 Moulton VR. Sex hormones in acquired immunity and autoimmune disease. Front Immunol 2018; 9: 2279
    CrossrefPubMedGoogle Scholar
  • 35 Kadel S, Kovats S. Sex hormones regulate innate immune cells and promote sex differences in respiratory virus infection. Front Immunol 2018; 9: 1653
    CrossrefPubMedGoogle Scholar
  • 36 Zeng F, Dai C, Cai P. et al. A comparison study of SARS-CoV-2 IgG antibody between male and female COVID-19 patients: a possible reason underlying different outcome between sex. J Med Virol 2020; 25989
    PubMedGoogle Scholar
  • 37 Hoffmann M, Kleine-Weber H, Schroeder S. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181 (02) 271-280.e8
    CrossrefPubMedGoogle Scholar
  • 38 Sungnak W, Huang N, Bécavin C. et al; HCA Lung Biological Network. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med 2020; 26 (05) 681-687
    CrossrefPubMedGoogle Scholar
  • 39 TMPRSS2 transmembrane serine protease 2 [Homo sapiens (human)] - Gene - NCBI. Accessed May 25, 2020 at: https://www.ncbi.nlm.nih.gov/gene/7113
    Google Scholar
  • 40 Matsuyama S, Nao N, Shirato K. et al. Enhanced isolation of SARS-CoV-2 by TMPRSS2-expressing cells. Proc Natl Acad Sci U S A 2020; 117 (13) 7001-7003
    CrossrefPubMedGoogle Scholar
  • 41 Camostat Mesylate in COVID-19 Outpatients - Full Text View - ClinicalTrials.gov. Accessed June 5, 2020 at: https://clinicaltrials.gov/ct2/show/NCT04353284
    Google Scholar
  • 42 Brosnihan KB, Hodgin JB, Smithies O, Maeda N, Gallagher P. Tissue-specific regulation of ACE/ACE2 and AT1/AT2 receptor gene expression by oestrogen in apolipoprotein E/oestrogen receptor-α knock-out mice. Exp Physiol 2008; 93 (05) 658-664
    CrossrefPubMedGoogle Scholar
  • 43 Bukowska A, Spiller L, Wolke C. et al. Protective regulation of the ACE2/ACE gene expression by estrogen in human atrial tissue from elderly men. Exp Biol Med (Maywood) 2017; 242 (14) 1412-1423
    CrossrefPubMedGoogle Scholar
  • 44 Mohamad N-V, Wong SK, Wan Hasan WN. et al. The relationship between circulating testosterone and inflammatory cytokines in men. Aging Male 2019; 22 (02) 129-140
    CrossrefPubMedGoogle Scholar
  • 45 Shivers KY, Amador N, Abrams L, Hunter D, Jenab S, Quiñones-Jenab V. Estrogen alters baseline and inflammatory-induced cytokine levels independent from hypothalamic-pituitary-adrenal axis activity. Cytokine 2015; 72 (02) 121-129
    CrossrefPubMedGoogle Scholar
  • 46 Bianchi VE. The anti-inflammatory effects of testosterone. J Endocr Soc 2018; 3 (01) 91-107
    CrossrefPubMedGoogle Scholar
  • 47 La Vignera S, Cannarella R, Condorelli RA, Torre F, Aversa A, Calogero AE. Sex-specific SARS-CoV-2 mortality: among hormone-modulated ACE2 expression, risk of venous thromboembolism and hypovitaminosis D. Int J Mol Sci 2020; 21 (08) 2948
    Google Scholar
  • 48 Rastrelli G, Di Stasi V, Inglese F. et al. Low testosterone levels predict clinical adverse outcomes in SARS-CoV-2 pneumonia patients. Andrology 2020; 12821
    PubMedGoogle Scholar
  • 49 Channappanavar R, Fett C, Mack M, Ten Eyck PP, Meyerholz DK, Perlman S. Sex-based differences in susceptibility to severe acute respiratory syndrome coronavirus infection. J Immunol 2017; 198 (10) 4046-4053
    CrossrefPubMedGoogle Scholar
  • 50 Schwartz DA, Graham AL. Potential maternal and infant outcomes from (Wuhan) coronavirus 2019-nCoV infecting pregnant women: lessons from SARS, MERS, and other human coronavirus infections. Viruses 2020; 12 (02) 194
    Google Scholar
  • 51 Jose RJ, Manuel A. COVID-19 cytokine storm: the interplay between inflammation and coagulation. Lancet Respir Med 2020; 8 (06) e46-e47
    CrossrefPubMedGoogle Scholar
  • 52 Beagley KW, Gockel CM. Regulation of innate and adaptive immunity by the female sex hormones oestradiol and progesterone. FEMS Immunol Med Microbiol 2003; 38 (01) 13-22
    CrossrefPubMedGoogle Scholar
  • 53 Salem ML. Estrogen, a double-edged sword: modulation of TH1- and TH2-mediated inflammations by differential regulation of TH1/TH2 cytokine production. Curr Drug Targets Inflamm Allergy 2004; 3 (01) 97-104
    CrossrefPubMedGoogle Scholar
  • 54 Sutton D, Fuchs K, D'Alton M, Goffman D. Universal screening for SARS-CoV-2 in women admitted for delivery. N Engl J Med 2020; 382 (22) 2163-2164
    CrossrefPubMedGoogle Scholar
  • 55 Leclerc PM, Dubois-Colas N, Garenne M. Hormonal contraception and HIV prevalence in four African countries. Contraception 2008; 77 (05) 371-376
    CrossrefPubMedGoogle Scholar
  • 56 Rotermann M, Dunn S, Black A. Oral contraceptive use among women aged 15 to 49: results from the Canadian Health Measures Survey. Stat Canada 2015; 26 (10) 21-28
    PubMedGoogle Scholar
  • 57 Sanal MG. RE: Oral contraceptive pills may be better and safe in the management of COVID-19 than chloroquine derivatives!. CMAJ 2020; 192 (17) E450-E453
    CrossrefPubMedGoogle Scholar
  • 58 Juurlink DN. Safety considerations with chloroquine, hydroxychloroquine and azithromycin in the management of SARS-CoV-2 infection. CMAJ 2020; 192 (17) E450-E453
    CrossrefPubMedGoogle Scholar
  • 59 Estrogen Patch for COVID-19 Symptoms - Full Text View - ClinicalTrials.gov. Accessed May 24, 2020 at: https://clinicaltrials.gov/ct2/show/NCT04359329
    Google Scholar
  • 60 Batlle D, Wysocki J, Satchell K. Soluble angiotensin-converting enzyme 2: a potential approach for coronavirus infection therapy?. Clin Sci (Lond) 2020; 134 (05) 543-545
    CrossrefPubMedGoogle Scholar
  • 61 Lei C, Fu W, Qian K. et al. Potent neutralization of 2019 novel coronavirus by recombinant ACE2-Ig. bioRxiv 2020; Doi: org/10.1101/2020.02.01.929976
    Google Scholar
  • 62 Patel SK, Velkoska E, Freeman M, Wai B, Lancefield TF, Burrell LM. From gene to protein-experimental and clinical studies of ACE2 in blood pressure control and arterial hypertension. Front Physiol 2014; 5: 227
    CrossrefPubMedGoogle Scholar
  • 63 Gemmati D, Bramanti B, Serino ML, Secchiero P, Zauli G, Tisato V. COVID-19 and individual genetic susceptibility/receptivity: role of ACE1/ACE2 genes, immunity, inflammation and coagulation. Might the double X-chromosome in females be protective against SARS-CoV-2 compared to the single X-chromosome in males?. Int J Mol Sci 2020; 21 (10) E3474
    CrossrefPubMedGoogle Scholar
  • 64 Liu J, Ji H, Zheng W. et al. Sex differences in renal angiotensin converting enzyme 2 (ACE2) activity are 17β-oestradiol-dependent and sex chromosome-independent. Biol Sex Differ 2010; 1 (01) 6
    CrossrefPubMedGoogle Scholar
  • 65 Swärd P, Edsfeldt A, Reepalu A, Jehpsson L, Rosengren BE, Karlsson MK. Age and sex differences in soluble ACE2 may give insights for COVID-19. Crit Care 2020; 24 (01) 221
    CrossrefPubMedGoogle Scholar
  • 66 Chen J, Jiang Q, Xia X. et al. Individual Variation of the SARS-CoV2 Receptor ACE2 Gene Expression and Regulation. Preprints; 2020. Accessed May 24, 2020 at: www.preprints.org
    Google Scholar
  • 67 Khan A, Benthin C, Zeno B. et al. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit Care 2017; 21 (01) 234
    CrossrefPubMedGoogle Scholar
  • 68 Monteil V, Kwon H, Prado P. et al. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell 2020; 181 (04) 905-913.e7
    CrossrefPubMedGoogle Scholar
  • 69 Valdés G, Neves LAA, Anton L. et al. Distribution of angiotensin-(1-7) and ACE2 in human placentas of normal and pathological pregnancies. Placenta 2006; 27 (2-3): 200-207
    CrossrefPubMedGoogle Scholar
  • 70 Noymer A, Garenne M. The 1918 influenza epidemic's effects on sex differentials in mortality in the United States. Popul Dev Rev 2000; 26 (03) 565-581
    CrossrefPubMedGoogle Scholar
  • 71 Garenne M. Demographic evidence of sex differences in vulnerability to infectious diseases. J Infect Dis 2015; 211 (02) 331-332
    CrossrefPubMedGoogle Scholar
  • 72 Oakes JM, Fuchs RM, Gardner JD, Lazartigues E, Yue X. Nicotine and the renin-angiotensin system. Am J Physiol Regul Integr Comp Physiol 2018; 315 (05) R895-R906
    CrossrefPubMedGoogle Scholar
  • 73 Elgendy IY, Pepine CJ. Why are women better protected from COVID-19: Clues for men? Sex and COVID-19. Int J Cardiol 2020; DOI: 10.1016/j.ijcard.2020.05.026. (epub ahead of print)
    CrossrefPubMedGoogle Scholar
  • 74 Lippi G, Henry BM. Active smoking is not associated with severity of coronavirus disease 2019 (COVID-19). Eur J Intern Med 2020; 75: 107-108
    CrossrefPubMedGoogle Scholar
  • 75 Lippi G, Sanchis-Gomar F, Henry BM. Active smoking and COVID-19: a double-edged sword. Eur J Intern Med 2020; 77 (00) 123-124
    CrossrefPubMedGoogle Scholar
  • 76 Walter LA, McGregor AJ. Sex- and gender-specific observations and implications for COVID-19. West J Emerg Med 2020; 21 (03) 507-509
    CrossrefPubMedGoogle Scholar
  • 77 Suen LKP, So ZYY, Yeung SKW, Lo KYK, Lam SC. Epidemiological investigation on hand hygiene knowledge and behaviour: a cross-sectional study on gender disparity. BMC Public Health 2019; 19 (01) 401
    CrossrefPubMedGoogle Scholar
  • 78 Johnson HD, Sholcosky D, Gabello K, Ragni R, Ogonosky N. Sex differences in public restroom handwashing behavior associated with visual behavior prompts. Percept Mot Skills 2003; 97 (3, Pt 1): 805-810
    CrossrefPubMedGoogle Scholar
  • 79 Harris CR, Jenkins M. Gender differences in risk assessment: Why do women take fewer risks than men?. Judgment Decision Making 2006; 1 (01) 48-63
    CrossrefPubMedGoogle Scholar
  • 80 Karlberg J, Chong DSY, Lai WYY. Do men have a higher case fatality rate of severe acute respiratory syndrome than women do?. Am J Epidemiol 2004; 159 (03) 229-231
    CrossrefPubMedGoogle Scholar
  • 81 Jin J-M, Bai P, He W. et al. Gender differences in patients with COVID-19: focus on severity and mortality. Front Public Health 2020; 8: 152
    Google Scholar