Şiddetli akut solunum yolu sendromu-koronavirüs-2 [severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)] enfeksiyonu damlacık yoluyla bulaşan bir solunum yolu hastalığı olarak ortaya çıkmasına rağmen, enfekte olan hastalarda solunum yolu dışındaki organlarda da çoklu organ tutulumları gözlenmiştir. Bu durum, SARSCoV-2'nin spike proteinin hücrelere girişi için anjiyotensin dönüştürücü enzim-2 [angiotensin converting enzyme-2 (ACE-2)] reseptörlerini kullanmasıyla ilişkilendirilmiştir. ACE-2 ekspresyonunun; akciğer, kalp, testis, ince bağırsak, tiroid, böbrek ve az miktarda beyinde olduğu bilinmektedir. Bu bilgiye dayanarak araştırmalar, SARS-CoV-2 enfeksiyonunda ACE-2 ekspresyonunun diğer organ ve sistemler üzerindeki etkilerine yoğunlaşmıştır. Enfeksiyon sürecinde proinflamatuar yanıtların ve ACE-2 ekspresyonundaki artışın çoklu organ tutulumuna yol açtığı öne sürülmüştür. Ağır hastalardaki çoklu organ tutulumları hastanede kalış süresini uzatmakta ve ölüm oranlarının artmasına sebep olmaktadır. SAR-CoV-2 enfeksiyonuna bağlı gelişen kalp yetersizliği, böbrek yetersizliği, sitokin fırtınası, pıhtılaşma bozuklukları ve organ yetersizlikleri ölümü hızlandırmaktadır. SARS-CoV-2 enfeksiyonunun tedavi stratejileri belirlenirken çoklu organ hasarının altında yatan mekanizmaların bilinmesi, hastalık prognozunun iyileştirilmesi açısından önem taşımaktadır. Bu derlemede SARS-CoV-2 enfeksiyonunun neden olduğu çoklu organ tutulumlarına neden olan mekanizmalar ele alınmıştır.
Anahtar Kelimeler: Şiddetli akut solunum yolu sendromu- koronavirüs 2; multipl organ yetersizliği; anjiyotensin dönüştürücü enzim-2
Although severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection appears as a respiratory tract disease transmitted through droplets, multiple organ involvements have also been observed in organs other than the respiratory tract in infected patients. This has been associated with SARS CoV-2's use of angiotensin converting enzyme-2 (ACE-2) receptors to enter the spike protein into cells. ACE-2 expression is known to occur in the lung, heart, testis, small intestine, thyroid, kidney and a small amount of the brain. Based on this information, research has focused on the effects of ACE-2 expression on other organs and systems in SARSCoV-2 infection. It has been suggested that pro-inflammatory responses and increase in ACE-2 expression during the infection process lead to multi-organ involvement. Multiple organ involvement in seriously ill patients prolongs the duration of hospital stay and causes an increase in mortality rates. Heart failure, kidney failure, cytokine storm, coagulation disorders and organ failure due to SARS-CoV-2 infection accelerate death. While determining the treatment strategies of SARS-CoV-2 infection, it is important to know the mechanisms underlying multiple organ damage in terms of improving the disease prognosis. In this review, the mechanisms that cause multiple organ involvement caused by SARS-CoV-2 infection are discussed.
Keywords: Severe acute respiratory syndrome coronavirus 2; multiple organ failure; angiotensin converting enzyme 2
- Robba C, Battaglini D, Pelosi P, Rocco PRM. Multiple organ dysfunction in SARS-CoV-2: MODS-CoV-2. Expert Rev Respir Med. 2020;14(9):865-8. [Crossref] [PubMed] [PMC]
- Lei F, Liu YM, Zhou F, Qin JJ, Zhang P, Zhu L, et al. Longitudinal association between markers of liver ınjury and mortality in COVID-19 in China. Hepatology. 2020;72(2):389-98. [Crossref] [PubMed] [PMC]
- World Health Organization [İnternet]. ©2021 WHO. WHO director-general's opening remarks at the media briefing on COVID-19 11 March 2020. Erişim linki: [Link] (Erişim tarihi: 15 Aralık 2020-15 December 2020).
- Surveillances V. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19)-China, 2020. China CDC Weekly. 2020;2(8):113-22.
- Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, et al. Extrapulmonary manifestations of COVID-19. Nat Med. 2020;26(7):1017-32. [Crossref] [PubMed]
- Xu X, Chen P, Wang J, Feng J, Zhou H, Li X, et al. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Sci China Life Sci. 2020;63(3):457-60. [Crossref] [PubMed] [PMC]
- Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020;46(4):586-590. Epub 2020 Mar 3. [Crossref] [PubMed] [PMC]
- Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426(6965):450-4. [Crossref] [PubMed] [PMC]
- Wu K, Peng G, Wilken M, Geraghty RJ, Li F. Mechanisms of host receptor adaptation by severe acute respiratory syndrome coronavirus. J Biol Chem. 2012;287(12):8904-11. [Crossref] [PubMed] [PMC]
- 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;1;202(5):756-9. Erratum in: Am J Respir Crit Care Med. 2021;203(6):782. [Crossref] [PubMed] [PMC]
- Danilczyk U, Sarao R, Remy C, Benabbas C, Stange G, Richter A, et al. Essential role for collectrin in renal amino acid transport. Nature. 2006;444(7122):1088-91. [Crossref] [PubMed]
- Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004; 203(2):631-7. [Crossref] [PubMed] [PMC]
- Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061-9. Erratum in: JAMA. 2021;325(11):1113. [Crossref] [PubMed] [PMC]
- Pan F, Ye T, Sun P, Gui S, Liang B, Li L, et al. Time course of lung changes at chest CT during recovery from coronavirus disease 2019 (COVID-19). Radiology. 2020;295(3):715-21. [Crossref] [PubMed] [PMC]
- Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005;11(8):875-9. [Crossref] [PubMed] [PMC]
- Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020;46(4):586-90. [Crossref] [PubMed] [PMC]
- Imai Y, Kuba K, Penninger JM. The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice. Exp Physiol. 2008;93(5):543-8. [Crossref] [PubMed] [PMC]
- Jia H. Pulmonary angiotensin-converting enzyme 2 (ACE2) and inflammatory lung disease. Shock. 2016;46(3):239-48. [Crossref] [PubMed]
- Nasir N, Farooqi J, Mahmood SF, Jabeen K. COVID-19-associated pulmonary aspergillosis (CAPA) in patients admitted with severe COVID-19 pneumonia: an observational study from Pakistan. Mycoses. 2020;63(8):766-70. [Crossref] [PubMed] [PMC]
- Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. Erratum in: Lancet. 2020;30. [Crossref] [PubMed] [PMC]
- Winkler ES, Bailey AL, Kafai NM, Nair S, McCune BT, Yu J, et al. SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function. Nat Immunol. 2020;21(11):1327-35. Erratum in: Nat Immunol. 2020;2. [Crossref] [PubMed] [PMC]
- Bonow RO, Fonarow GC, O'Gara PT, Yancy CW. Association of coronavirus disease 2019 (COVID-19) with myocardial injury and mortality. JAMA Cardiol. 2020;5(7):751-3. [Crossref] [PubMed]
- Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395(10234):1417-8. [Crossref] [PubMed] [PMC]
- Hui DS, I Azhar E, Madani TA, Ntoumi F, Kock R, Dar O, et al. The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health - the latest 2019 novel coronavirus outbreak in Wuhan, China. Int J Infect Dis. 2020;91:264-6. [Crossref] [PubMed] [PMC]
- Colantuoni A, Martini R, Caprari P, Ballestri M, Capecchi PL, Gnasso A, Lo Presti R, Marcoccia A, Rossi M, Caimi G. COVID-19 Sepsis and Microcirculation Dysfunction. Front Physiol. 2020;11:747. doi: 10.3389/fphys.2020. 00747. [Crossref] [PubMed] [PMC]
- Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol. 2020;20:355-62. [Crossref]
- Eltzschig HK, Carmeliet P. Hypoxia and inflammation. N Engl J Med. 2011;364(7): 656-65. [Crossref] [PubMed] [PMC]
- Yau JW, Teoh H, Verma S. Endothelial cell control of thrombosis. BMC Cardiovasc Disord. 2015;15(1):1-11. [Crossref]
- Löf A, Müller JP, Brehm MA. A biophysical view on von Willebrand factor activation. J Cell Physiol. 2018;233(2):799-810. [Crossref] [PubMed]
- Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020;5(7): 811-8. Erratum in: JAMA Cardiol. 2020;5(7): 848. [Crossref] [PubMed] [PMC]
- Li X, Hu C, Su F, Dai J. Hypokalemia and clinical implications in patients with coronavirus disease 2019 (COVID-19). MedRxiv. 2020. [Link]
- Severino A, Narducci ML, Pedicino D, Pazzano V, Giglio AF, Biasucci LM, et al. Reversible atrial gap junction remodeling during hypoxia/reoxygenation and ischemia: a possible arrhythmogenic substrate for atrial fibrillation. Gen Physiol Biophys. 2012;31(4):439-48. [Crossref] [PubMed]
- Lazzerini PE, Boutjdir M, Capecchi PL. COVID-19, arrhythmic risk, and ınflammation: mind the gap! Circulation. 2020;142(1):7-9. [Crossref] [PubMed]
- Li B, Yang J, Zhao F, Zhi L, Wang X, Liu L, et al. Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China. Clin Res Cardiol. 2020;109(5):531-8. [Crossref] [PubMed] [PMC]
- Arentz M, Yim E, Klaff L, Lokhandwala S, Riedo FX, Chong M, et al. Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington state. JAMA. 2020;323(16):1612-4. [Crossref] [PubMed] [PMC]
- Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19. N Engl J Med. 2020;382(17):1653-9. [Crossref] [PubMed] [PMC]
- Cheng Y, Luo R, Wang K, Zhang M, Wang Z, Dong L, et al. Kidney impairment is associated with in-hospital death of COVID-19 patients. MedRxiv. 2020. [Crossref]
- Cheng Y, Luo R, Wang K, Zhang M, Wang Z, Dong L, et al. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int. 2020;97(5):829-38. [Crossref] [PubMed] [PMC]
- Su H, Yang M, Wan C, Yi LX, Tang F, Zhu HY, et al. Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China. Kidney Int. 2020;98(1):219-27. [Crossref] [PubMed] [PMC]
- Ding Y, He L, Zhang Q, Huang Z, Che X, Hou J, et al. Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways. J Pathol. 2004;203(2):622-30. [Crossref] [PubMed] [PMC]
- Wu H, Uchimura K, Donnelly EL, Kirita Y, Morris SA, Humphreys BD. Comparative analysis and refinement of human PSC-derived kidney organoid differentiation with single-cell transcriptomics. Cell Stem Cell. 2018;23(6):869-81.e8. [Crossref] [PubMed] [PMC]
- Pan XW, Xu D, Zhang H, Zhou W, Wang LH, Cui XG. Identification of a potential mechanism of acute kidney injury during the COVID-19 outbreak: a study based on single-cell transcriptome analysis. Intensive Care Med. 2020;46(6):1114-6. [Crossref] [PubMed] [PMC]
- Su H, Lei CT, Zhang C. Interleukin-6 signaling pathway and its role in kidney disease: an update. Front Immunol. 2017;8:405. [Crossref] [PubMed] [PMC]
- Nechemia-Arbely Y, Barkan D, Pizov G, Shriki A, Rose-John S, Galun E, et al. IL-6/IL-6R axis plays a critical role in acute kidney injury. J Am Soc Nephrol. 2008;19(6):1106-15. [Crossref] [PubMed] [PMC]
- 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):1339-48. [Crossref] [PubMed] [PMC]
- Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen 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):271-80.e8. [Crossref] [PubMed] [PMC]
- Leow MK, Kwek DS, Ng AW, Ong KC, Kaw GJ, Lee LS. Hypocortisolism in survivors of severe acute respiratory syndrome (SARS). Clin Endocrinol (Oxf). 2005;63(2):197-202. [Crossref] [PubMed] [PMC]
- Nardo AD, Schneeweiss-Gleixner M, Bakail M, Dixon ED, Lax SF, Trauner M. Pathophysiological mechanisms of liver injury in COVID-19. Liver Int. 2021;41(1):20-32. [Crossref] [PubMed] [PMC]
- Wong SH, Lu RN, Sung JJ. Covid-19 and the digestive system. J Gastroenterol Hepatol. 2020;35(5):744-8. [Crossref]
- Xie H, Zhao J, Lian N, Lin S, Xie Q, Zhuo H. Clinical characteristics of non-ICU hospitalized patients with coronavirus disease 2019 and liver injury: a retrospective study. Liver Int. 2020;40(6):1321-6. [Crossref] [PubMed] [PMC]
- Li Y, Xiao SY. Hepatic involvement in COVID-19 patients: Pathology, pathogenesis, and clinical implications. J Med Virol. 2020;92(9):1491-4. Epub 2020 May 13. [Crossref] [PubMed]
- 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 centre in Wuhan city, China. Liver Int. 2020;40(9):2095-2103. [Crossref] [PubMed]
- Weisberg IS, Jacobson IM. Cardiovascular diseases and the liver. Clin Liver Dis. 2011; 15(1):1-20. [Crossref] [PubMed]
- van Deursen VM, Damman K, Hillege HL, van Beek AP, van Veldhuisen DJ, Voors AA. Abnormal liver function in relation to hemodynamic profile in heart failure patients. J Card Fail. 2010;16(1):84-90. [Crossref] [PubMed]
- Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, et al. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. 2020;77(6):683-690. [Crossref] [PubMed] [PMC]
- Desforges M, Le Coupanec A, Dubeau P, Bourgouin A, Lajoie L, Dubé M, et al. Human coronaviruses and other respiratory viruses: underestimated opportunistic pathogens of the central nervous system? Viruses. 2019; 12(1):14. [Crossref] [PubMed] [PMC]
- Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV-2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol. 2020;92(6):552-5. [Crossref] [PubMed] [PMC]
- Chen Y, Chen L, Deng Q, Zhang G, Wu K, Ni L, et al. The presence of SARS-CoV-2 RNA in the feces of COVID-19 patients. J Med Virol. 2020;92(7):833-40. [Crossref] [PubMed]
- Abdennour L, Zeghal C, Dème M, Puybasset L. Interaction cerveau-poumon [Interaction brain-lungs]. Ann Fr Anesth Reanim. 2012; 31(6):e101-7. [Crossref] [PubMed]
- Guo YR, Cao QD, Hong ZS, Tan YY, Chen SD, Jin HJ, Tan KS, Wang DY, Yan Y. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak - an update on the status. Mil Med Res. 2020;7(1):11. [Crossref] [PubMed] [PMC]
- Liu W, Han R, Wu H, Han D. Viral threat to male fertility. Andrologia. 2018;50(11):e13140. [Crossref] [PubMed]
- Xu J, Qi L, Chi X, Yang J, Wei X, Gong E, et al. Orchitis: a complication of severe acute respiratory syndrome (SARS). Biol Reprod. 2006;74(2):410-6. [Crossref] [PubMed] [PMC]
- Wang Z, Xu X. scRNA-seq profiling of human testes reveals the presence of the ACE2 receptor, a target for SARS-CoV-2 ınfection in spermatogonia, leydig and sertoli cells. Cells. 2020;9(4):920. [Crossref] [PubMed] [PMC]
- Li D, Jin M, Bao P, Zhao W, Zhang S. Clinical characteristics and results of semen tests among men with coronavirus disease 2019. JAMA Netw Open. 2020;3(5):e208292. Erratum in: JAMA Netw Open. 2020;3(6): e2010845. [Crossref] [PubMed] [PMC]
- Xu J, Xu Z, Jiang Y, Qian X, Huang Y. Cryptorchidism induces mouse testicular germ cell apoptosis and changes in bcl-2 and bax protein expression. J Environ Pathol Toxicol Oncol. 2000;19(1-2):25-33. [PubMed]
- Corona G, Baldi E, Isidori AM, Paoli D, Pallotti F, De Santis L, et al. SARS-CoV-2 infection, male fertility and sperm cryopreservation: a position statement of the Italian Society of Andrology and Sexual Medicine (SIAMS) (Società Italiana di Andrologia e Medicina della Sessualità). J Endocrinol Invest. 2020;43(8): 1153-7. [Crossref] [PubMed] [PMC]
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