Fig : SARS-CoV-2 enters host cells through interaction of its spike protein with the entry receptor ACE2 in the presence of TMPRSS2 (far left). Proposed mechanisms for COVID-19 caused by infection with SARS-CoV-2 include (1) direct virus-mediated cell damage; (2) dysregulation of the RAAS as a consequence of downregulation of ACE2 related to viral entry, which leads to decreased cleavage of angiotensin I and angiotensin II; (3) endothelial cell damage and thromboinflammation; and (4) dysregulation of the immune response and hyperinflammation caused by inhibition of interferon signaling by the virus, T cell lymphodepletion, and the production of proinflammatory cytokines, particularly IL-6 and TNFα.
Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.
Main The coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), which is responsible for the disease COVID-19 (coronavirus disease 2019), has infected over 9.5 million people and has caused more than 480,000 deaths globally, as of 24 June 2020 (ref. 1). While SARS-CoV-2 is known to cause substantial pulmonary disease, including pneumonia and acute respiratory distress syndrome (ARDS), clinicians have observed many extrapulmonary manifestations of COVID-19. Our clinical experience and the emerging literature suggest that the hematologic, cardiovascular, renal, gastrointestinal and hepatobiliary, endocrinologic, neurologic, ophthalmologic, and dermatologic systems can all be affected (Supplementary Table)2,3,4,5,6. This pathology may reflect either extrapulmonary dissemination and replication of SARS-CoV-2, as has been observed for other zoonotic coronaviruses7, or widespread immunopathological sequelae of the disease. To provide a perspective on these extrapulmonary manifestations, we discuss the pathophysiology and clinical impact of COVID-19 on various organ systems, accompanied by insights from our experience at the Columbia University Irving Medical Center in New York City at the epicenter of the pandemic.
Pathophysiology SARS-CoV-2 seems to employ mechanisms for receptor recognition similar to those used by prior virulent coronaviruses such as SARS-CoV, the pathogen responsible for the SARS epidemic of 2003 (refs. 8,9,10,11). The coronavirus spike protein facilitates entry of the virus into target cells. The spike subunit of SARS-CoV and that of SARS CoV-2 engage ACE2 (angiotensin-converting enzyme 2) as an entry receptor (Fig. 1). In addition, cell entry requires priming of the spike protein by the cellular serine protease TMPRSS2 or other proteases12. Co-expression on the cell surface of ACE2 and TMPRSS2 is required for the completion of this entry process. In addition, the efficiency with which the virus binds to ACE2 is a key determinant of transmissibility, as shown in studies of SARS-CoV13. Recent studies have demonstrated higher affinity of binding of SARS-CoV-2 to ACE2 than of SARS-CoV to ACE2, which may partially explain the increased transmissibility of SARS-CoV-214,15,16.
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