Gender Characteristics of the Novel Coronavirus Infection (COVID-19) in Middle-Aged Adults

The aim of the study is to assess the gender-related specifics of the COVID-19 course in patients under 55 years of age.

Materials and Methods. This pilot single-center continuous retrospective non-randomized study was carried out in the repurposed infectious diseases hospital of the Privolzhsky Research Medical University (Nizhny Novgorod, Russia). The study inclusion criterion was the age of patients (up to 55 years) and confirmed coronavirus infection. In the groups based on gender differences (25 men, average age 44.0±7.8 years and 32 women, average age 41.9±9.1 years), we monitored complications of COVID-19 such as the transfer of patients to the ICU and the volume of lung damage (determined with CT scans).

Results. The course of COVID-19 in male patients younger than 55 was aggravated by concomitant diseases (γ=0.36; p=0.043), among which IHD (γ=1.00; p=0.003) and liver disease (γ=0.58; p=0.007) dominated. Frequency analysis confirmed the high prevalence of coronary artery disease in men (p=0.044). Significant differences between the gender-related groups were noted in the volume of lung lesions: at admission (p=0.050), during hospital treatment (p=0.019), and at discharge (p=0.044). Using the logistic regression method, a relationship was found between the transfer of male patients to ICU and the Krebs index [y= –2.033 + 1.154 male gender + 1.539 Krebs index (χ²=5.68; p=0.059)] and comorbidity [y= –2.836 + 1.081 male gender + 2.052 comorbidity (χ²=7.03; p=0.030)]. The influence of the Krebs index and the male gender on the excess volume of lung lesions was shown [y= –1.962 + 0.575 male gender + 1.915 Krebs index (χ²=7.78; p=0.021)].

Conclusion. In individuals under the age of 55 diagnosed with COVID-19, gender is of significant importance: in men, there is a more pronounced lesion of the lung parenchyma and a more significant change in laboratory parameters. Risk factors for a severe course of COVID-19 in men are coronary artery disease and hepatobiliary disorder. Calculating the Krebs index can be used to assess the risk of disease progression.

1. WHO. Weekly epidemiological update on COVID-19 — 25 May 2021. URL: https://www.who.int/publications/m/item/weekly- epidemiological-update-on-covid-19---25-may-2021.
2. Iba T., Connors J.M., Levy J.H. The coagulopathy, endotheliopathy, and vasculitis of COVID-19. Inflamm Res 2020; 69(12): 1181–1189, https://doi.org/10.1007/s00011-020-01401-6.
3. Wang D., Hu B., Hu C., Zhu F., Liu X., Zhang J., Wang B., Xiang H., Cheng Z., Xiong Y., Zhao Y., Li Y., Wang X., Peng Z. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020; 323(11): 1061–1069, https://doi.org/10.1001/jama.2020.1585.
4. Wu Z., McGoogan J.M. 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, https://doi.org/10.1001/jama.2020.2648.
5. Tsatsakis A., Calina D., Falzone L., Petrakis D., Mitrut R., Siokas V., Pennisi M., Lanza G., Libra M., Doukas S.G., Doukas P.G., Kavali L., Bukhari A., Gadiparthi C., Vageli D.P., Kofteridis D.P., Spandidos D.A., Paoliello M.M.B., Aschner M., Docea A.O. SARS-CoV-2 pathophysiology and its clinical implications: an integrative overview of the pharmacotherapeutic management of COVID-19. Food Chem Toxicol 2020; 146: 111769, https://doi.org/10.1016/j.fct.2020.111769.
6. Pagliaro P. Is macrophages heterogeneity important in determining COVID-19 lethality? Med Hypotheses 2020; 143: 110073, https://doi.org/10.1016/j.mehy.2020.110073.
7. Sze S., Pan D., Nevill C.R., Gray L.J., Martin C.A., Nazareth J., Minhas J.S., Divall P., Khunti K., Abrams K.R., Nellums L.B., Pareek M. Ethnicity and clinical outcomes in COVID-19: a systematic review and meta-analysis. EClinicalMedicine 2020; 29: 100630, https://doi.org/10.1016/j.eclinm.2020.100630.
8. Zhang J., Wang X., Jia X., Li J., Hu K., Chen G., Wei J., Gong Z., Zhou C., Yu H., Yu M., Lei H., Cheng F., Zhang B., Xu Y., Wang G., Dong W. Risk factors for disease severity, unimprovement, and mortality in COVID-19 patients in Wuhan, China. Clin Microbiol Infect 2020; 26(6): 767–772, https://doi.org/10.1016/j.cmi.2020.04.012.
9. Liu Y., Mao B., Liang S., Yang J.W., Lu H.W., Chai Y.H., Wang L., Zhang L., Li Q.H., Zhao L., He Y., Gu X.L., Ji X.B., Li L., Jie Z.J., Li Q., Li X.Y., Lu H.Z., Zhang W.H., Song Y.L., Qu J.M., Xu J.F.; Shanghai Clinical Treatment Experts Group for COVID-19. Association between age and clinical characteristics and outcomes of COVID-19. Eur Respir J 2020; 55(5): 2001112, https://doi.org/10.1183/13993003.01112-2020.
10. Liu X., Lv J., Gan L., Zhang Y., Sun F., Meng B., Jheon A., Yan F., Li B., Xuan Z., Ma X., Wulasihana M. Comparative analysis of clinical characteristics, imaging and laboratory findings of different age groups with COVID-19. Indian J Med Microbiol 2020; 38(1): 87–93, https://doi.org/10.4103/ijmm.ijmm_20_133.
11. Liu K., Chen Y., Lin R., Han K. Clinical features of COVID-19 in elderly patients: a comparison with young and middle-aged patients. J Infect 2020; 80(6): e14–e18, https://doi.org/10.1016/j.jinf.2020.03.005.
12. Moreno Fernández-Ayala D.J., Navas P., López-Lluch G. Age-related mitochondrial dysfunction as a key factor in COVID-19 disease. Exp Gerontol 2020; 142: 111147, https://doi.org/10.1016/j.exger.2020.111147.
13. McGuire P.J. Mitochondrial dysfunction and the aging immune system. Biology (Basel) 2019; 8(2): 26, https://doi.org/10.3390/biology8020026.
14. López-Lluch G. Mitochondrial activity and dynamics changes regarding metabolism in ageing and obesity. Mech Ageing Dev 2017; 162: 108–121, https://doi.org/10.1016/j.mad.2016.12.005.
15. Meng Y., Wu P., Lu W., Liu K., Ma K., Huang L., Cai J., Zhang H., Qin Y., Sun H., Ding W., Gui L., Wu P. 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(4): e1008520, https://doi.org/10.1371/journal.ppat.1008520.
16. Haitao T., Vermunt J.V., Abeykoon J., Ghamrawi R., Gunaratne M., Jayachandran M., Narang K., Parashuram S., Suvakov S., Garovic V.D. COVID-19 and sex differences: mechanisms and biomarkers. Mayo Clin Proc 2020; 95(10): 2189–2203, https://doi.org/10.1016/j.mayocp.2020.07.024.
17. Trouillet-Assant S., Viel S., Gaymard A., Pons S., Richard J.C., Perret M., Villard M., Brengel-Pesce K., Lina B., Mezidi M., Bitker L., Belot A.; COVID HCL Study group. Type I IFN immunoprofiling in COVID-19 patients. J Allergy Clin Immunol 2020; 146(1): 206–208.e2, https://doi.org/10.1016/j.jaci.2020.04.029.
18. Webb K., Peckham H., Radziszewska A., Menon M., Oliveri P., Simpson F., Deakin C.T., Lee S., Ciurtin C., Butler G., Wedderburn L.R., Ioannou Y. Sex and pubertal differences in the type 1 interferon pathway associate with both X chromosome number and serum sex hormone concentration. Front Immunol 2019; 9: 3167, https://doi.org/10.3389/fimmu.2018.03167.
19. Wan Y., Shang J., Graham R., Baric R.S., Li F. Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus. J Virol 2020; 94(7): e00127-20, https://doi.org/10.1128/jvi.00127-20.
20. Zhao Y., Zhao Z., Wang Y., Zhou Y., Ma Y., Zuo W. Single-cell RNA expression profiling of ACE2, the receptor of SARS-CoV-2. Am J Respir Crit Care Med 2020; 202(5): 756–759, https://doi.org/10.1164/rccm.202001-0179le. Erratum in: Am J Respir Crit Care Med 2021; 203(6): 782.
21. Culebras E., Hernández F. ACE2 is on the X chromosome: could this explain COVID-19 gender differences? Eur Heart J 2020; 41(32): 3095, https://doi.org/10.1093/eurheartj/ehaa521.
22. Bukowska A., Spiller L., Wolke C., Lendeckel U., Weinert S., Hoffmann J., Bornfleth P., Kutschka I., Gardemann A., Isermann B., Goette A. 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, https://doi.org/10.1177/1535370217718808.
23. Asfahan S., Deokar K., Dutt N., Niwas R., Jain P., Agarwal M. Extrapolation of mortality in COVID-19: exploring the role of age, sex, co-morbidities and health-care related occupation. Monaldi Arch Chest Dis 2020; 90(2), https://doi.org/10.4081/monaldi.2020.1325.
24. Borghesi A., Zigliani A., Masciullo R., Golemi S., Maculotti P., Farina D., Maroldi R. Radiographic severity index in COVID-19 pneumonia: relationship to age and sex in 783 Italian patients. Radiol Med 2020; 125(5): 461–464, https://doi.org/10.1007/s11547-020-01202-1.
25. Bhopal S.S., Bhopal R. Sex differential in COVID-19 mortality varies markedly by age. Lancet 2020; 396(10250): 532–533, https://doi.org/10.1016/s0140-6736(20)31748-7.
26. Ministry of Health of the Russian Federation. Profilaktika, diagnostika i lechenie novoy koronavirusnoy infektsii (COVID-19). Vremennye metodicheskie rekomendatsii. Versiya 6 (28.04.2020) [Prevention, diagnosis and treatment of new coronavirus infection (COVID-19). Temporary guidelines. Version 6 (April 28, 2020)]. URL: https://roszdravnadzor.gov.ru/i/upload/images/ 2020/5/28/1590682537.35655-1-117450.pdf.
27. Ministry of Health of the Russian Federation. Profilaktika, diagnostika i lechenie novoy koronavirusnoy infektsii (COVID-19). Vremennye metodicheskie rekomendatsii. Versiya 7 (03.06.2020) [Prevention, diagnosis and treatment of new coronavirus infection (COVID-19). Temporary guidelines. Version 7 (June 3, 2020)]. URL: https://static-0.rosminzdrav.ru/ system/attachments/attaches/000/050/584/ original/03062020_МR_COVID-19_v7.pdf.
28. WHO. Klinicheskoe vedenie tyazheloy ostroy respiratornoy infektsii pri podozrenii na novuyu koronavirusnuyu (2019-nCoV) infektsiyu: vremennye rekomendatsii, 28 yanvarya 2020 g. [Clinical management of severe acute respiratory infection in suspected novel coronavirus (2019-nCoV) infection: temporary guidelines, January 28, 2020]. URL: https://apps.who.int/iris/bitstream/handle/ 10665/330893/WHO-nCoV-Clinical-2020.3 -rus.pdf?sequence=5&isAllowed=y.
29. Zhang C., Shi L., Wang F.S. Liver injury in COVID-19: management and challenges. Lancet Gastroenterol Hepatol 2020; 5(5): 428–430, https://doi.org/10.1016/s2468-1253(20)30057-1.
30. Ivashkin V.T., Sheptulin A.A., Zolnikova O.Yu., Okhlobystin A.V., Poluektova E.A., Trukhmanov A.S., Shirokova E.N., Gonik M.I., Trofimivskaya N.I. New coronavirus infection (COVID-19) and digestive system. Rossijskij zurnal gastroenterologii, gepatologii, koloproktologii 2020; 30(3): 7–13, https://doi.org/10.22416/1382-4376-2020-30-3-7.
31. Ilchenko L.Yu., Nikitin I.G., Fedorov I.G. COVID-19 and liver damage. Arhiv vnutrennej mediciny 2020; 10(3): 188–197, https://doi.org/10.20514/2226-6704-2020-10-3-188-197.
32. Youssef M., Hussein M.H., Attia A.S., Elshazli R.M., Omar M., Zora G., Farhoud A.S., Elnahla A., Shihabi A., Toraih E.A., Fawzy M.S., Kandil E. COVID-19 and liver dysfunction: a systematic review and meta-analysis of retrospective studies. J Med Virol 2020; 92(10): 1825–1833, https://doi.org/10.1002/jmv.26055.
33. Ye L., Chen B., Wang Y., Yang Y., Zeng J., Deng G., Deng Y., Zeng F. Prognostic value of liver biochemical parameters for COVID-19 mortality. Ann Hepatol 2020; 21: 100279, https://doi.org/10.1016/j.aohep.2020.10.007.
34. Gabarre P., Dumas G., Dupont T., Darmon M., Azoulay E., Zafrani L. Acute kidney injury in critically ill patients with COVID-19. Intensive Care Med 2020; 46(7): 1339–1348, https://doi.org/10.1007/s00134-020-06153-9.
35. Cheng Y., Luo R., Wang K., Zhang M., Wang Z., Dong L., Li J., Yao Y., Ge S., Xu G. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int 2020; 97(5): 829–838, https://doi.org/10.1016/j.kint.2020.03.005.
36. Xu P.P., Tian R.H., Luo S., Zu Z.Y., Fan B., Wang X.M., Xu K., Wang J.T., Zhu J., Shi J.C., Chen F., Wan B., Yan Z.H., Wang R.P., Chen W., Fan W.H., Zhang C., Lu M.J., Sun Z.Y., Zhou C.S., Zhang L.N., Xia F., Qi L., Zhang W., Zhong J., Liu X.X., Zhang Q.R., Lu G.M., Zhang L.J. Risk factors for adverse clinical outcomes with COVID-19 in China: a multicenter, retrospective, observational study. Theranostics 2020; 10(14): 6372–6383, https://doi.org/10.7150/thno.46833.
37. Hensel M., Grädel L., Kutz A., Haubitz S., Huber A., Mueller B., Schuetz P., Hügle T. Peripheral monocytosis as a predictive factor for adverse outcome in the emergency department: survey based on a register study. Medicine (Baltimore) 2017; 96(28): e7404, https://doi.org/10.1097/md.0000000000007404.
38. Potempa L.A., Rajab I.M., Hart P.C., Bordon J., Fernandez-Botran R. Insights into the use of C-reactive protein as a diagnostic index of disease severity in COVID-19 infections. Am J Trop Med Hyg 2020; 103(2): 561–563, https://doi.org/10.4269/ajtmh.20-0473.
39. Iba T., Levy J.H., Connors J.M., Warkentin T.E., Thachil J., Levi M. The unique characteristics of COVID-19 coagulopathy. Crit Care 2020; 24(1): 360, https://doi.org/10.1186/s13054-020-03077-0.
40. Eljilany I., Elzouki A.N. D-dimer, fibrinogen, and IL-6 in COVID-19 patients with suspected venous thromboembolism: a narrative review. Vasc Health Risk Manag 2020; 16: 455–462, https://doi.org/10.2147/vhrm.s280962.
41. Asakura H., Ogawa H. COVID-19-associated coagulopathy and disseminated intravascular coagulation. Int J Hematol 2021; 113(1): 45–57, https://doi.org/10.1007/s12185-020-03029-y.
42. Rostami M., Mansouritorghabeh H. D-dimer level in COVID-19 infection: a systematic review. Expert Rev Hematol 2020; 13(11): 1265–1275, https://doi.org/10.1080/17474086.2020.1831383.
43. Zhang L., Yan X., Fan Q., Liu H., Liu X., Liu Z., Zhang Z. D-dimer levels on admission to predict in-hospital mortality in patients with COVID-19. J Thromb Haemost 2020; 18(6): 1324–1329, https://doi.org/10.1111/jth.14859.
44. Wang P., Sha J., Meng M., Wang C., Yao Q., Zhang Z., Sun W., Wang X., Qie G., Bai X., Liu K., Chu Y. Risk factors for severe COVID-19 in middle-aged patients without comorbidities: a multicentre retrospective study. J Transl Med 2020; 18(1): 461, https://doi.org/10.1186/s12967-020-02655-8.
45. Li Y., Zhao K., Wei H., Chen W., Wang W., Jia L., Liu Q., Zhang J., Shan T., Peng Z., Liu Y., Yan X. Dynamic relationship between D-dimer and COVID-19 severity. Br J Haematol 2020; 190(1): e24–e27, https://doi.org/10.1111/bjh.16811.
46. Hayıroğlu M.İ., Çınar T., Tekkeşin A.İ. Fibrinogen and D-dimer variances and anticoagulation recommendations in COVID-19: current literature review. Rev Assoc Med Bras (1992) 2020; 66(6): 842–848, https://doi.org/10.1590/1806-9282.66.6.842.
47. Wool G.D., Miller J.L. The impact of COVID-19 disease on platelets and coagulation. Pathobiology 2021; 88(1): 15–27, https://doi.org/10.1159/000512007.
48. Tripodi A., Caldwell S.H., Hoffman M., Trotter J.F., Sanyal A.J. Review article: the prothrombin time test as a measure of bleeding risk and prognosis in liver disease. Aliment Pharmacol Ther 2007; 26(2): 141–148, https://doi.org/10.1111/j.1365-2036.2007.03369.x.
49. Kaptanoglu L., Kurt N., Sikar H.E. Current approach to liver traumas. Int J Surg 2017; 39: 255–259, https://doi.org/10.1016/j.ijsu.2017.02.015.
50. Iba T., Levy J.H., Levi M., Thachil J. Coagulopathy in COVID-19. J Thromb Haemost 2020; 18(9): 2103–2109, https://doi.org/10.1111/jth.14975.
51. Colling M.E., Kanthi Y. COVID-19-associated coagulopathy: an exploration of mechanisms. Vasc Med 2020; 25(5): 471–478, https://doi.org/10.1177/1358863x20932640.
52. Perico L., Benigni A., Casiraghi F., Ng L.F.P., Renia L., Remuzzi G. Immunity, endothelial injury and complement-induced coagulopathy in COVID-19. Nat Rev Nephrol 2021; 17(1): 46–64, https://doi.org/10.1038/s41581-020-00357-4.
53. Stenmark K.R., Frid M.G., Gerasimovskaya E., Zhang H., McCarthy M.K., Thurman J.M., Morrison T.E. Mechanisms of SARS-CoV-2-induced lung vascular disease: potential role of complement. Pulm Circ 2021; 11(2): 20458940211015799, https://doi.org/10.1177/20458940211015799.
54. Emami A., Javanmardi F., Pirbonyeh N., Akbari A. Prevalence of underlying diseases in hospitalized patients with COVID-19: a systematic review and meta-analysis. Arch Acad Emerg Med 2020; 8(1): e35.
55. Fang X., Li S., Yu H., Wang P., Zhang Y., Chen Z., Li Y., Cheng L., Li W., Jia H., Ma X. Epidemiological, comorbidity factors with severity and prognosis of COVID-19: a systematic review and meta-analysis. Aging (Albany NY) 2020; 12(13): 12493–12503, https://doi.org/10.18632/aging.103579.
56. Ejaz H., Alsrhani A., Zafar A., Javed H., Junaid K., Abdalla A.E., Abosalif K.O.A., Ahmed Z., Younas S. COVID-19 and comorbidities: deleterious impact on infected patients. J Infect Public Health 2020; 13(12): 1833–1839, https://doi.org/10.1016/j.jiph.2020.07.014.
57. Sanyaolu A., Okorie C., Marinkovic A., Patidar R., Younis K., Desai P., Hosein Z., Padda I., Mangat J., Altaf M. Comorbidity and its impact on patients with COVID-19. SN Compr Clin Med 2020; 2: 1069–1076, https://doi.org/10.1007/s42399-020-00363-4.
58. Yang J., Zheng Y., Gou X., Pu K., Chen Z., Guo Q., Ji R., Wang H., Wang Y., Zhou Y. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis. Int J Infect Dis 2020; 94: 91–95, https://doi.org/10.1016/j.ijid.2020.03.017.
59. Ebrahimi M., Saki Malehi A., Rahim F. COVID-19 patients: a systematic review and meta-analysis of laboratory findings, comorbidities, and clinical outcomes comparing medical staff versus the general population. Osong Public Health Res Perspect 2020; 11(5): 269–279, https://doi.org/10.24171/j.phrp.2020.11.5.02.
60. Zaki N., Alashwal H., Ibrahim S. Association of hypertension, diabetes, stroke, cancer, kidney disease, and high-cholesterol with COVID-19 disease severity and fatality: a systematic review. Diabetes Metab Syndr 2020; 14(5): 1133–1142, https://doi.org/10.1016/j.dsx.2020.07.005.
61. Guan W.J., Liang W.H., Zhao Y., Liang H.R., Chen Z.S., Li Y.M., Liu X.Q., Chen R.C., Tang C.L., Wang T., Ou C.Q., Li L., Chen P.Y., Sang L., Wang W., Li J.F., Li C.C., Ou L.M., Cheng B., Xiong S., Ni Z.Y., Xiang J., Hu Y., Liu L., Shan H., Lei C.L., Peng Y.X., Wei L., Liu Y., Hu Y.H., Peng P., Wang J.M., Liu J.Y., Chen Z., Li G., Zheng Z.J., Qiu S.Q., Luo J., Ye C.J., Zhu S.Y., Cheng L.L., Ye F., Li S.Y., Zheng J.P., Zhang N.F., Zhong N.S., He J.X.; China Medical Treatment Expert Group for COVID-19. Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis. Eur Respir J 2020; 55(5): 2000547, https://doi.org/10.1183/13993003.00547-2020.
62. Peckham H., de Gruijter N.M., Raine C., Radziszewska A., Ciurtin C., Wedderburn L.R., Rosser E.C., Webb K., Deakin C.T. Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission. Nat Commun 2020; 11(1): 6317, https://doi.org/10.1038/s41467-020-19741-6.
63. Long L., Zeng X., Zhang X., Xiao W., Guo E., Zhan W., Yang X., Li C., Wu C., Xu T., Zhan C., Chen Y., Jiang M., Zhong N., Lai K. Short-term outcomes of COVID-19 and risk factors for progression. Eur Respir J 2020; 55(5): 2000990, https://doi.org/10.1183/13993003.00990-2020.
64. Cai J., Li H., Zhang C., Chen Z., Liu H., Lei F., Qin J.J., Liu Y.M., Zhou F., Song X., Zhou J., Zhao Y.C., Wu B., He M., Yang H., Zhu L., Zhang P., Ji Y.X., Zhao G.N., Lu Z., Liu L., Mao W., Liao X., Lu H., Wang D., Xia X., Huang X., Wei X., Xia J., Zhang B.H., Yuan Y., She Z.G., Xu Q., Ma X., Wang Y., Yang J., Zhang X., Zhang X.J., Li H. The neutrophil-to-lymphocyte ratio determines clinical efficacy of corticosteroid therapy in patients with COVID-19. Cell Metab 2021; 3(2): 258–269.e3, https://doi.org/10.1016/j.cmet.2021.01.002.

Nekaeva E.S., Bolshakova A.E., Malysheva E.S., Galova E.A., Makarova E.V., Nekrasova T.A., Polyakova I.V., Bedretdinova Z.S., Belikina D.V., Lavrenyuk A.A., Fomin I.V. Gender Characteristics of the Novel Coronavirus Infection (COVID-19) in Middle-Aged Adults. Sovremennye tehnologii v medicine 2021; 13(4): 16, https://doi.org/10.17691/stm2021.13.4.02