Abstract
Background: Many observations denote that we should deal with COVID-19 as a systemic disease.
Methods: In the following report, we briefly discuss observations denoting “the systemic” nature of COVID-19. Results: COVID-19 virology, the roles of ACE-2 receptor in COVID-19 pathogenesis, immunological aspects of the disease, endothelial dysfunction and coagulopathy, and autopsy studies denote the systemic nature of COVID-19. Conclusion: Thinking of COVID-19 as a systemic disease, we will implement our ways of understanding and hence dealing with that disease. The most important public health solution is an effective vaccine for the broad population remaining at risk. As patients with COVID-19 present a broad spectrum of clinical presentation and distinct phenotypes, different strategies of management should be customized to the specific individual phenotypes. Further researches are highly needed to clarify the concept of “Is COVID-19 a systemic disease?”. Until that time, we think that clinicians should deal with COVID-19 as a systemic disease.Keywords: COVID-19, systemic disease, immunity, pathobiology, ACE-2, coronavirus.
Graphical Abstract
[1]
Guan WJ, Ni ZY, Hu Y, et al. China Medical Treatment Expert Group for Covid-19. China medical treatment expert group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; 382(18): 1708-20.
[http://dx.doi.org/10.1056/NEJMoa2002032] [PMID: 32109013]
[http://dx.doi.org/10.1056/NEJMoa2002032] [PMID: 32109013]
[2]
Lan J, Ge J, Yu J, et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 2020; 581(7807): 215-20.
[http://dx.doi.org/10.1038/s41586-020-2180-5] [PMID: 32225176]
[http://dx.doi.org/10.1038/s41586-020-2180-5] [PMID: 32225176]
[3]
Shang J, Ye G, Shi K, et al. Structural basis of receptor recognition by SARS-CoV-2. Nature 2020; 581(7807): 221-4.
[http://dx.doi.org/10.1038/s41586-020-2179-y] [PMID: 32225175]
[http://dx.doi.org/10.1038/s41586-020-2179-y] [PMID: 32225175]
[4]
Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly E. The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade. Antiviral Res 2020; 176: 104742.
[http://dx.doi.org/10.1016/j.antiviral.2020.104742] [PMID: 32057769]
[http://dx.doi.org/10.1016/j.antiviral.2020.104742] [PMID: 32057769]
[5]
Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 2020; 181(2): 281-292.e6.
[http://dx.doi.org/10.1016/j.cell.2020.02.058] [PMID: 32155444]
[http://dx.doi.org/10.1016/j.cell.2020.02.058] [PMID: 32155444]
[6]
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(2): 271-280.e8.
[http://dx.doi.org/10.1016/j.cell.2020.02.052] [PMID: 32142651]
[http://dx.doi.org/10.1016/j.cell.2020.02.052] [PMID: 32142651]
[7]
Matsuyama S, Nao N, Shirato K, et al. Enhanced isolation of SARS-CoV-2 by TMPRSS2-expressing cells. Proc Natl Acad Sci USA 2020; 117(13): 7001-3.
[http://dx.doi.org/10.1073/pnas.2002589117] [PMID: 32165541]
[http://dx.doi.org/10.1073/pnas.2002589117] [PMID: 32165541]
[8]
Wang K, Gheblawi M, Oudit GY. Angiotensin converting enzyme 2: A double-edged sword. Circulation 2020; 142(5): 426-8.http://dx.doi.org/110.1161/CIRCULATIONAHA.120.047049
[http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047049] [PMID: 32213097]
[http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047049] [PMID: 32213097]
[9]
Bertram S, Heurich A, Lavender H, et al. Influenza and SARS-coronavirus activating proteases TMPRSS2 and HAT are expressed at multiple sites in human respiratory and gastrointestinal tracts. PLoS One 2012; 7(4): e35876.
[http://dx.doi.org/10.1371/journal.pone.0035876] [PMID: 22558251]
[http://dx.doi.org/10.1371/journal.pone.0035876] [PMID: 22558251]
[10]
Úri K, Fagyas M, Mányiné Siket I, et al. New perspectives in the renin-angiotensin-aldosterone system (RAAS) IV: Circulating ACE2 as a biomarker of systolic dysfunction in human hypertension and heart failure. PLoS One 2014; 9(4): e87845.
[http://dx.doi.org/10.1371/journal.pone.0087845] [PMID: 24691269]
[http://dx.doi.org/10.1371/journal.pone.0087845] [PMID: 24691269]
[11]
Grasselli G, Zangrillo A, Zanella A, et al. COVID-19 Lombardy ICU Network. 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): 1574-81.
[http://dx.doi.org/10.1001/jama.2020.5394] [PMID: 32250385]
[http://dx.doi.org/10.1001/jama.2020.5394] [PMID: 32250385]
[12]
Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet 2020; 395(10229): 1033-4.
[http://dx.doi.org/10.1016/S0140-6736(20)30628-0] [PMID: 32192578]
[http://dx.doi.org/10.1016/S0140-6736(20)30628-0] [PMID: 32192578]
[13]
Rello J, Storti E, Belliato M, Serrano R. Clinical phenotypes of SARS-CoV-2: Implications for clinicians and researchers. Eur Respir J 2020; 55(5): 2001028.
[http://dx.doi.org/10.1183/13993003.01028-2020] [PMID: 32341111]
[http://dx.doi.org/10.1183/13993003.01028-2020] [PMID: 32341111]
[14]
He Z, Zhao C, Dong Q, et al. Effects of severe acute respiratory syndrome (SARS) coronavirus infection on peripheral blood lymphocytes and their subsets. Int J Infect Dis 2005; 9(6): 323-30.
[http://dx.doi.org/10.1016/j.ijid.2004.07.014] [PMID: 16095942]
[http://dx.doi.org/10.1016/j.ijid.2004.07.014] [PMID: 16095942]
[15]
Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet 2020; 395(10229): 1054-62.
[http://dx.doi.org/10.1016/S0140-6736(20)30566-3] [PMID: 32171076]
[http://dx.doi.org/10.1016/S0140-6736(20)30566-3] [PMID: 32171076]
[16]
Lippi G, Plebani M, Henry BM. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis. Clin Chim Acta 2020; 506: 145-8.
[http://dx.doi.org/10.1016/j.cca.2020.03.022] [PMID: 32178975]
[http://dx.doi.org/10.1016/j.cca.2020.03.022] [PMID: 32178975]
[17]
Wang F, Nie J, Wang H, et al. Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia. J Infect Dis 2020; 221(11): 1762-9.
[http://dx.doi.org/10.1093/infdis/jiaa150] [PMID: 32227123]
[http://dx.doi.org/10.1093/infdis/jiaa150] [PMID: 32227123]
[18]
Lovren F, Pan Y, Quan A, et al. Angiotensin converting enzyme-2 confers endothelial protection and attenuates atherosclerosis. Am J Physiol Heart Circ Physiol 2008; 295(4): H1377-84.
[http://dx.doi.org/10.1152/ajpheart.00331.2008] [PMID: 18660448]
[http://dx.doi.org/10.1152/ajpheart.00331.2008] [PMID: 18660448]
[19]
Sardu C, Gambardella J, Morelli MB, Wang X, Marfella R, Santulli G. Hypertension, thrombosis, kidney failure, and diabetes: Is COVID-19 an endothelial disease? A comprehensive evaluation of clinical and basic evidence. J Clin Med 2020; 9(5): E1417.
[http://dx.doi.org/10.3390/jcm9051417] [PMID: 32403217]
[http://dx.doi.org/10.3390/jcm9051417] [PMID: 32403217]
[20]
Santulli G, Morelli M, Gambardella J. Is endothelial dysfunction the concealed cornerstone of COVID-19? BMJ 2020; 368: m1091.
[http://dx.doi.org/10.1136/bmj.m1091]
[http://dx.doi.org/10.1136/bmj.m1091]
[21]
Mast AE. Tissue factor pathway inhibitor: Multiple anticoagulant activities for a single protein. Arterioscler Thromb Vasc Biol 2016; 36(1): 9-14.
[http://dx.doi.org/10.1161/ATVBAHA.115.305996] [PMID: 26603155]
[http://dx.doi.org/10.1161/ATVBAHA.115.305996] [PMID: 26603155]
[22]
Martin FA, Murphy RP, Cummins PM. Thrombomodulin and the vascular endothelium: Insights into functional, regulatory, and therapeutic aspects. Am J Physiol Heart Circ Physiol 2013; 304(12): H1585-97.
[http://dx.doi.org/10.1152/ajpheart.00096.2013] [PMID: 23604713]
[http://dx.doi.org/10.1152/ajpheart.00096.2013] [PMID: 23604713]
[23]
Godo S, Shimokawa H. Endothelial Functions. Arterioscler Thromb Vasc Biol 2017; 37(9): e108-14.
[http://dx.doi.org/10.1161/ATVBAHA.117.309813] [PMID: 28835487]
[http://dx.doi.org/10.1161/ATVBAHA.117.309813] [PMID: 28835487]
[24]
Zhang Y, Xiao M, Zhang S, et al. Coagulopathy and antiphospholipid antibodies in patients with Covid-19. N Engl J Med 2020; 382(17): e38.
[http://dx.doi.org/10.1056/NEJMc2007575] [PMID: 32268022]
[http://dx.doi.org/10.1056/NEJMc2007575] [PMID: 32268022]
[25]
Zhou B, She J, Wang Y, Ma X. Venous thrombosis and arteriosclerosis obliterans of lower extremities in a very severe patient with 2019 novel coronavirus disease: A case report. J Thromb Thrombolysis 2020; 50(1): 229-32.
[http://dx.doi.org/10.1007/s11239-020-02084-w] [PMID: 32306290]
[http://dx.doi.org/10.1007/s11239-020-02084-w] [PMID: 32306290]
[26]
Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020; 18(4): 844-7.
[http://dx.doi.org/10.1111/jth.14768] [PMID: 32073213]
[http://dx.doi.org/10.1111/jth.14768] [PMID: 32073213]
[27]
Iba T, Levy JH, Warkentin TE, Thachil J, van der Poll T, Levi M. Scientific and standardization committee on dic, and the scientific and standardization committee on perioperative and critical care of the international society on thrombosis and haemostasis. diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation. J Thromb Haemost 2019; 17(11): 1989-94.
[http://dx.doi.org/10.1111/jth.14578] [PMID: 31410983]
[http://dx.doi.org/10.1111/jth.14578] [PMID: 31410983]
[28]
Dielis AW, Smid M, Spronk HM, et al. The prothrombotic paradox of hypertension: Role of the renin-angiotensin and kallikrein-kinin systems. Hypertension 2005; 46(6): 1236-42.
[http://dx.doi.org/10.1161/01.HYP.0000193538.20705.23] [PMID: 16286563]
[http://dx.doi.org/10.1161/01.HYP.0000193538.20705.23] [PMID: 16286563]
[29]
Risitano AM, Mastellos DC, Huber-Lang M, et al. Complement as a target in COVID-19? Nat Rev Immunol 2020; 20(6): 343-4.
[http://dx.doi.org/10.1038/s41577-020-0320-7] [PMID: 32327719]
[http://dx.doi.org/10.1038/s41577-020-0320-7] [PMID: 32327719]
[30]
Vabret N, Britton GJ, Gruber C, et al. Sinai Immunology Review Project. Sinai Immunology review project. Immunology of COVID-19: Current state of the science. Immunity 2020; 52(6): 910-41.
[http://dx.doi.org/10.1016/j.immuni.2020.05.002] [PMID: 32505227]
[http://dx.doi.org/10.1016/j.immuni.2020.05.002] [PMID: 32505227]
[31]
Maniatis NA, Orfanos SE. The endothelium in acute lung injury/acute respiratory distress syndrome. Curr Opin Crit Care 2008; 14(1): 22-30.
[http://dx.doi.org/10.1097/MCC.0b013e3282f269b9] [PMID: 18195622]
[http://dx.doi.org/10.1097/MCC.0b013e3282f269b9] [PMID: 18195622]
[32]
Poissy J, Goutay J, Caplan M, et al. Pulmonary embolism in COVID-19 patients: Awareness of an increased prevalence. Circulation 2020; 142(2): 184-6.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047430] [PMID: 32330083]
[http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047430] [PMID: 32330083]
[33]
Walborn A, Rondina M, Mosier M, Fareed J, Hoppensteadt D. Endothelial dysfunction is associated with mortality and severity of coagulopathy in patients with sepsis and disseminated intravascular coagulation. Clin Appl Thromb Hemost 2019; 25: 1076029619852163.
[http://dx.doi.org/10.1177/1076029619852163] [PMID: 31140293]
[http://dx.doi.org/10.1177/1076029619852163] [PMID: 31140293]
[34]
Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 2020; 18(5): 1094-9.
[http://dx.doi.org/10.1111/jth.14817] [PMID: 32220112]
[http://dx.doi.org/10.1111/jth.14817] [PMID: 32220112]
[35]
Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med 2020; 383(2): 120-8.
[http://dx.doi.org/10.1056/NEJMoa2015432] [PMID: 32437596]
[http://dx.doi.org/10.1056/NEJMoa2015432] [PMID: 32437596]
[36]
Buja LM, Wolf DA, Zhao B, et al. The emerging spectrum of cardiopulmonary pathology of the coronavirus disease 2019 (COVID-19): Report of 3 autopsies from Houston, Texas, and review of autopsy findings from other United States cities. Cardiovasc Pathol 2020; 48: 107233.
[http://dx.doi.org/10.1016/j.carpath.2020.107233] [PMID: 32434133]
[http://dx.doi.org/10.1016/j.carpath.2020.107233] [PMID: 32434133]
[37]
Nathan N, Prevost B, Corvol H. Atypical presentation of COVID-19 in young infants. Lancet 2020; 395(10235): 1481.
[http://dx.doi.org/10.1016/S0140-6736(20)30980-6] [PMID: 32353326]
[http://dx.doi.org/10.1016/S0140-6736(20)30980-6] [PMID: 32353326]
[38]
Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease 2019. Available from:
www.goldcopd.org
[39]
Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020; 395(10234): 1417-8.
[http://dx.doi.org/10.1016/S0140-6736(20)30937-5] [PMID: 32325026]
[http://dx.doi.org/10.1016/S0140-6736(20)30937-5] [PMID: 32325026]
[40]
Feldmann M, Maini RN, Woody JN, et al. Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed. Lancet 2020; 395(10234): 1407-9.
[http://dx.doi.org/10.1016/S0140-6736(20)30858-8] [PMID: 32278362]
[http://dx.doi.org/10.1016/S0140-6736(20)30858-8] [PMID: 32278362]