COVID-19 in Patients with Diabetes: Clinical Course, Metabolic Status, Inflammation, and Coagulation Disorder

The aim of the investigation was to study the clinical course of COVID-19 in the presence of diabetes mellitus (DM) and elucidate possible mechanisms of their mutual aggravation.

Materials and Methods. The study included 64 patients with COVID-19; of them, 32 were with DM (main group) and 32 were DM-free (control group). The groups were formed according to the “case–control” principle. During hospitalization, the dynamics of clinical, glycemic, and coagulation parameters, markers of systemic inflammation, as well as kidney and liver functions were monitored and compared.

Results. Among patients with DM, the course of viral pneumonia was more severe, as evidenced by a 2.2-fold higher number of people with extensive (>50%) lung damage (p=0.05), an increased risk of death according to the CURB-65 algorithm (1.3-fold, p=0.043), and a longer duration of insufficient blood oxygen saturation (p=0.0004). With the combination of COVID-19 and DM, hyperglycemia is persistent, without pronounced variability (MAGE — 1.5±0.6 mmol/L), the levels of C-reactive protein (p=0.028), creatinine (p=0.035), and fibrinogen (p=0.013) are higher, manifestations of hypercoagulability persist longer, including slower normalization of antithrombin III (p=0.012), fibrinogen (p=0.037), and D-dimer (p=0.035).

Conclusion. The course of COVID-19 in patients with DM is associated with a high severity and extension of pneumonia, persistent decrease in oxygen supply, high hyperglycemia, accelerated renal dysfunction, systemic inflammation, and hypercoagulability.

1. Angelidi A.M., Belanger M.J., Mantzoros C.S. COVID-19 and diabetes mellitus: what we know, how our patients should be treated now, and what should happen next. Metabolism 2020; 107: 154245, https://doi.org/10.1016/j.metabol.2020.154245.
2. 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.
3. 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; https://doi.org/10.1001/jama.2020.2648.
4. Center for Disease Control and Prevention. Interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19). U.S. Department of Health & Human Services; 2020. URL: https://www.cdc.gov/coronavirus/2019-ncov/hcp/ clinical-guidance-management-patients.html.
5. Deng S.Q., Peng H.J. Characteristics of and public health responses to the coronavirus disease 2019 outbreak in China. J Clin Med 2020; 9(2): 575, https://doi.org/10.3390/jcm9020575.
6. Onder G., Rezza G., Brusaferro S. Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy. JAMA 2020; https://doi.org/10.1001/jama.2020.4683.
7. Grasselli G., Zangrillo A., Zanella A., Antonelli M., Cabrini L., Castelli A., Cereda D., Coluccello A., Foti G., Fumagalli R., Iotti G., Latronico N., Lorini L., Merler S., Natalini G., Piatti A., Ranieri M.V., Scandroglio A.M., Storti E., Cecconi M., Pesenti A.; COVID-19 Lombardy ICU Network; Nailescu A., Corona A., Zangrillo A., Protti A., Albertin A., Forastieri Molinari A., Lombardo A., Pezzi A., Benini A., Scandroglio A.M., Malara A., Castelli A., Coluccello A., Micucci A., Pesenti A., Sala A., Alborghetti A., Antonini B., Capra C., Troiano C., Roscitano C., Radrizzani D., Chiumello D., Coppini D., Guzzon D., Costantini E., Malpetti E., Zoia E., Catena E., Agosteo E., Barbara E., Beretta E., Boselli E., Storti E., Harizay F., Della Mura F., Lorini F.L., Donato Sigurtà F., Marino F., Mojoli F., Rasulo F., Grasselli G., Casella G., De Filippi G., Castelli G., Aldegheri G., Gallioli G., Lotti G., Albano G., Landoni G., Marino G., Vitale G., Battista Perego G., Evasi G., Citerio G., Foti G., Natalini G., Merli G., Sforzini I., Bianciardi L., Carnevale L., Grazioli L., Cabrini L., Guatteri L., Salvi L., Dei Poli M., Galletti M., Gemma M., Ranucci M., Riccio M., Borelli M., Zambon M., Subert M., Cecconi M., Mazzoni M.G., Raimondi M., Panigada M., Belliato M., Bronzini N., Latronico N., Petrucci N., Belgiorno N., Tagliabue P., Cortellazzi P., Gnesin P., Grosso P., Gritti P., Perazzo P., Severgnini P., Ruggeri P., Sebastiano P., Covello R.D., Fernandez-Olmos R., Fumagalli R., Keim R., Rona R., Valsecchi R., Cattaneo S., Colombo S., Cirri S., Bonazzi S., Greco S., Muttini S., Langer T., Alaimo V., Viola U. 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, https://doi.org/10.1001/jama.2020.5394.
8. Fadini G.P., Morieri M.L., Longato E., Avogaro A. Prevalence and impact of diabetes among people infected with SARS-CoV-2. J Endocrinol Invest 2020; 43(6): 867–869, https://doi.org/10.1007/s40618-020-01236-2.
9. CDC COVID-19 Response Team. Preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease 2019 — United States, February 12–March 28, 2020. MMWR Morb Mortal Wkly Rep 2020; 69: 382–386, https://doi.org/10.15585/mmwr.mm6913e2.
10. Huang I., Lim M.A., Pranata R. Diabetes mellitus is associated with increased mortality and severity of disease in COVID-19 pneumonia — a systematic review, meta-analysis, and meta-regression. Diabetes Metab Syndr 2020; 14(4): 395–403, https://doi.org/10.1016/j.dsx.2020.04.018.
11. Puig-Domingo M., Marazuela M., Giustina A. COVID-19 and endocrine diseases. A statement from the European Society of Endocrinology. Endocrine 2020; 68(1): 2–5, https://doi.org/10.1007/s12020-020-02294-5.
12. Berbudi A., Rahmadika N., Cahyadi A.I., Ruslami R. Type 2 diabetes and its impact on the immune system. Curr Diabetes Rev 2020; 16(5): 442–449, https://doi.org/10.2174/1573399815666191024085838.
13. Delamaire M., Maugendre D., Moreno M., Le Goff M.C., Allannic H., Genetet B. Impaired leucocyte functions in diabetic patients. Diabet Med 1997; 14(1): 29–34, https://doi.org/10.1002/(SICI)1096-9136 (199701)14:129::AID-DIA3003.0.CO;2-V.
14. Hodgson K., Morris J., Bridson T., Govan B., Rush C., Ketheesan N. Immunological mechanisms contributing to the double burden of diabetes and intracellular bacterial infections. Immunology 2015; 144(2): 171–185, https://doi.org/10.1111/imm.12394.
15. Zykova S.N., Jenssen T.G., Berdal M., Olsen R., Myklebust R., Seljelid R. Altered cytokine and nitric oxide secretion in vitro by macrophages from diabetic type II-like db/db mice. Diabetes 2000; 49: 1451–1458, https://doi.org/10.2337/diabetes.49.9.1451.
16. Kulcsar K.A., Coleman C.M., Beck S.E., Frieman M.B. Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infection. JCI Insight 2019; 4(20): e131774, https://doi.org/10.1172/jci.insight.131774.
17. Chen X., Hu W., Ling J., Mo P., Zhang Y., Jiang Q., Ma Z., Cao Q., Deng L., Song S., Zheng R., Shicheng G., Ke H., Gui X., Lundkvist Å., Li J., Lindahl J.F., Xiong Y. Hypertension and diabetes delay the viral clearance in COVID-19 patients. medRxiv 2020, https://doi.org/10.1101/2020.03.22.20040774.
18. Maffetone P.B., Laursen P.B. The perfect storm: coronavirus (COVID-19) pandemic meets overfat pandemic. Front Public Health 2020; 8: 135, https://doi.org/10.3389/fpubh.2020.00135.
19. Tikellis C., Thomas M.C. Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease. Int J Pept 2012; 2012: 256294, https://doi.org/10.1155/2012/256294.
20. AlGhatrif M., Cingolani O., Lakatta E.G. The dilemma of coronavirus disease 2019, aging, and cardiovascular disease: insights from cardiovascular aging science. JAMA Cardiol 2020, https://doi.org/10.1001/jamacardio.2020.1329.
21. Roca-Ho H., Riera M., Palau V., Pascual J., Soler M.J. Characterization of ACE and ACE2 expression within different organs of the NOD mouse. Int J Mol Sci 2017; 18(3): 563, https://doi.org/10.3390/ijms18030563.
22. Bindom S.M., Lazartigues E. The sweeter side of ACE2: physiological evidence for a role in diabetes. Mol Cell Endocrinol 2009; 302: 193–202, https://doi.org/10.1016/j.mce.2008.09.020.
23. Yang J.K., Lin S.S., Ji X.J., Guo L.M. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta Diabetol 2010; 47(3): 193–199, https://doi.org/10.1007/s00592-009-0109-4.
24. Varga Z., Flammer A.J., Steiger P., Haberecker M., Andermatt R., Zinkernagel A.S., Mehra M.R., Schuepbach R.A., Ruschitzka F., Moch H. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020; 395(10234): 1417–1418, https://doi.org/10.1016/S0140-6736(20)30937-5.
25. Diaz J.H. Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19. J Trav Med 2020; 27(3): taaa041, https://doi.org/10.1093/jtm/taaa041.
26. Pal R., Bhansali A. COVID-19, diabetes mellitus and ACE2: the conundrum. Diabetes Res Clin Pract 2020; 162: 108132, https://doi.org/10.1016/j.diabres.2020.108132.
27. 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.
28. Zhang Y., Zheng L., Liu L., Zhao M., Xiao J., Zhao Q. Liver impairment in COVID-19 patients: a retrospective analysis of 115 cases from a single center in Wuhan city, China. Liver Int 2020; 40(9): 2095–2103, https://doi.org/10.1111/liv.14455.
29. Abou-Ismail M.Y., Diamond A., Kapoor S., Arafah Y., Nayak L. The hypercoagulable state in COVID-19: incidence, pathophysiology, and management. Thromb Res 2020; 194: 101–115, https://doi.org/10.1016/j.thromres.2020.06.029.
30. Endokrinopatii i COVID-19. Neotlozhnye sostoyaniya, ikh profilaktika i lechenie. Rekomendatsii FGBU “NMITs endokrinologii” Minzdrava Rossii [Endocrinopathies and COVID-19. Emergencies, their prevention and treatment. Recommendations of the Federal State Budgetary Institution “National Medical Research Center of Endocrinology” of the Ministry of Health of Russia]. ENTs; 2020. URL: https://www.endocrincentr.ru/sites/default/files/all/ news2020/Institut%20Diabeta/COVID-19_enc2020-4.pdf.
31. Muniyappa R., Gubbi S. COVID-19 pandemic, corona viruses, and diabetes mellitus. Am J Physiol Endocrinol Metab 2020; 318(5): E736–E741, https://doi.org/10.1152/ajpendo.00124.2020.
32. Maddaloni E., Buzzetti R. COVID-19 and diabetes mellitus: unveiling the interaction of two pandemics. Diabetes Metab Res Rev 2020; e33213321, https://doi.org/10.1002/dmrr.3321.
33. 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.
34. Liu W., Li H. COVID-19: attacks the 1-beta chain of hemoglobin and captures the porphyrin to inhibit human heme metabolism. ChemRxiv 2020; https://doi.org/10.26434/chemrxiv.11938173.v7.
35. Hussain A., Bhowmik B., do Vale Moreira N.C. COVID-19 and diabetes: knowledge in progress. Diabetes Res Clin Pract 2020; 162: 108142, https://doi.org/10.1016/j.diabres.2020.108142.
36. Philips B.J., Meguer J.X., Redman J., Baker E.H. Factors determining the appearance of glucose in upper and lower respiratory tract secretions. Intensive Care Med 2003; 29(12): 2204–2210, https://doi.org/10.1007/s00134-003-1961-2.
37. Hill M.A., Mantzoros C., Sowers J. Commentary: COVID-19 in patients with diabetes. Metabolism 2020; 107: 154217, https://doi.org/10.1016/j.metabol.2020.154217.
38. Bode B., Garrett V., Messler J., McFarland R., Crowe J., Booth R., Klonoff D.C. Glycemic characteristics and clinical outcomes of COVID-19 patients hospitalized in the United States. J Diabetes Sci Technol 2020; 14(4): 813–821, https://doi.org/10.1177/1932296820924469.
39. Marhl M., Grubelnik V., Magdič M., Markovič R. Diabetes and metabolic syndrome as risk factors for COVID-19. Diabetes Metab Syndr 2020; 14(4): 671–677, https://doi.org/10.1016/j.dsx.2020.05.013.
40. Jiang X., Coffee M., Bari A., Wang J., Jiang X., Huang J., Shi J., Dai J., Cai J., Zhang T., Wu Z., He G., Huang Y. Towards an artificial intelligence framework for data-driven prediction of coronavirus clinical severity. Comput Mater Continua (CMC) 2020; 63(1): 537–551, https://doi.org/10.32604/cmc.2020.010691.
41. Harris E.H. Elevated liver function tests in type 2 diabetes. Clin Diabetes 2005; 23(3): 115–119, https://doi.org/10.2337/diaclin.23.3.115.
42. Zhou F., Yu T., Du R., Fan G., Liu Y., Liu Z., Xiang J., Wang Y., Song B., Gu X., Guan L., Wei Y., Li H., Wu X., Xu J., Tu S., Zhang Y., Chen H., Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395(10229): 1054–1062, https://doi.org/10.1016/S0140-6736(20)30566-3.
43. Tsalamandris S., Antonopoulos A.S., Oikonomou E., Papamikroulis G.A., Vogiatzi G., Papaioannou S., Deftereos S., Tousoulis D. The role of inflammation in diabetes: current concepts and future perspectives. Eur Cardiol 2019; 14(1): 50–59, https://doi.org/10.15420/ecr.2018.33.1.
44. Wang T., Chen R., Liu C., Liang W., Guan W., Tang R., Tang C., Zhang N., Zhong N., Li S. Attention should be paid to venous thromboembolism prophylaxis in the management of COVID-19. Lancet Haematol2020; 7(5): e362-e363, https://doi.org/10.1016/S2352-3026(20)30109-5.
45. Ranucci M., Ballotta A., Di Dedda U., Bayshnikova E., Dei Poli M., Resta M., Falco M., Albano G., Menicanti L. The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome. J Thromb Haemost2020; 18(7): 1747–1751, https://doi.org/10.1111/jth.14854.
46. Song W.C., FitzGerald G.A. COVID-19, microangiopathy, hemostatic activation, and complement. J Clin Invest 2020; 130(8): 3950–3953, https://doi.org/10.1172/jci140183.

Belikina D.V., Malysheva E.S., Petrov A.V., Nekrasova T.A., Nekaeva E.S., Lavrova A.E., Zarubina D.G., Atduev K.A., Magomedova D.M., Strongin L.G. COVID-19 in Patients with Diabetes: Clinical Course, Metabolic Status, Inflammation, and Coagulation Disorder. Sovremennye tehnologii v medicine 2020; 12(5): 6, https://doi.org/10.17691/stm2020.12.5.01