Evidence of Severe Acute Respiratory Syndrome Coronavirus 2 Replication and Tropism in the Lungs, Airways, and Vascular Endothelium of Patients With Fatal Coronavirus Disease 2019: An Autopsy Case Series

Bhatnagar, Julu; Gary, Joy; Reagan‐Steiner, Sarah; Estetter, Lindsey; Tong, Suxiang; Tao, Ying; Denison, Amy M.; Lee, Elizabeth; DeLeon-Carnes, Marlene; Li, Yan; Uehara, Anna; Paden, Clinton R.; Leitgeb, Brooke; Uyeki, Timothy M.; Martines, Roosecelis B; Ritter, Jana M.; Paddock, Christopher D.; Shieh, Wun‐Ju; Zaki, Sherif R.

doi:10.1093/infdis/jiab039

Cited by 93 publications

(102 citation statements)

References 34 publications

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“…However, multiple studies of kidney biopsies from COVID-19 patients failed to confirm SARS-CoV-2 infection in the glomerular endothelium by electron microscopy, IHC and in situ hybridization (ISH) 23 , 25 , 34 . In one autopsy study, ISH revealed SARS-CoV-2 RNA in the microvasculature of endothelial cells and vessel walls of brain stem, leptomeninges, lung, heart, liver, kidney, and pancreas 35 . A separate group identified SARS-CoV-2 RNA by ISH in the alveolar capillary endothelium but not in the endothelium of peripheral organs 16 .…”

Section: Endothelial Injury and Thrombosis In Covid-19: The Direct Viral Infection Hypothesismentioning

confidence: 99%

COVID-19 Vasculopathy: Mounting Evidence for an Indirect Mechanism of Endothelial Injury

Nicosia

Ligresti

Caporarello

et al. 2021

The American Journal of Pathology

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COVID-19 patients who are critically ill develop vascular complications characterized by thrombosis of small, medium and large vessels. Dysfunction of the vascular endothelium due to the SARS-CoV-2 infection has been implicated in the pathogenesis of the COVID-19 vasculopathy. Although initial reports suggested that endothelial injury was caused directly by the virus, recent studies indicate that endothelial cells do not express ACE2 – the receptor that SARS-CoV-2 uses to gain entry into cells – or express it at low levels and are resistant to the infection. These new findings, together with the observation that COVID-19 triggers a cytokine storm capable of injuring the endothelium and disrupting its antithrombogenic properties, favor an indirect mechanism of endothelial injury mediated, locally, by an augmented inflammatory reaction to infected nonendothelial cells such as the bronchial and alveolar epithelium and, systemically, by the excessive immune response to infection. Here we review the vascular pathology of COVID-19 and critically discuss the potential mechanisms of endothelial injury in this disease.

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Section: Endothelial Injury and Thrombosis In Covid-19: The Direct Viral Infection Hypothesismentioning

confidence: 99%

COVID-19 Vasculopathy: Mounting Evidence for an Indirect Mechanism of Endothelial Injury

Nicosia

Ligresti

Caporarello

et al. 2021

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…104,189 SARS-CoV-2 RNA has been detected in pancreatic tissue from COVID-19 deceased patients, albeit at lower viral loads than respiratory tissue. 190,191 Virus-infected cell clusters (identified by immunohistochemical staining) were mostly in the exocrine compartment in one study, but with proximity to the islets of Langerhans. Viral RNA has also been documented in the endothelium of pancreatic blood vessels.…”

Section: Kidney and Urinementioning

confidence: 90%

Pathophysiology of infection with SARS‐CoV‐2—What is known and what remains a mystery

Sridhar

Nicholls

2021

Respirology

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Coronavirus disease 2019 (COVID-19), caused by coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused extensive disruption and mortality since its recent emergence. Concomitantly, there has been a race to understand the virus and its pathophysiology. The clinical manifestations of COVID-19 are manifold and not restricted to the respiratory tract. Extrapulmonary manifestations involving the gastrointestinal tract, hepatobiliary system, cardiovascular and renal systems have been widely reported. However, the pathophysiology of many of these manifestations is controversial with questionable support for direct viral invasion and an abundance of alternative explanations such as pre-existing medical conditions and critical illness. Prior research on SARS-Co-V and NL63 was rapidly leveraged to identify angiotensin-converting enzyme 2 (ACE2) receptor as the key cell surface receptor for SARS-CoV-2. The distribution of ACE2 has been used as a starting point for estimating vulnerability of various tissue types to SARS-CoV-2 infection. Sophisticated organoid and animal models have been used to demonstrate such infectivity of extrapulmonary tissues in vitro, but the clinical relevance of these findings remains uncertain. Clinical autopsy studies are typically small and inevitably biased towards patients with severe COVID-19 and prolonged hospitalization. Technical issues such as delay between time of death and autopsy, use of inappropriate antibodies for paraffin-embedded tissue sections and misinterpretation of cellular structures as virus particles on electron micrograph images are additional problems encountered in the extant literature. Given that SARS-CoV-2 is likely to circulate permanently in human populations, there is no doubt that further work is required to clarify the pathobiology of COVID-19.

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“…In one autopsy study in which immunochemistry analysis of lung sections was performed in patients with COVID-19, no evidence of SARS-CoV-2 infection in pulmonary endothelial cells was found [42]. However, a recent autopsy case series of COVID-19 showed that SARS-CoV-2 RNA was localized by in situ hybridization within the endothelium and tunica media of vessels in multiple organs, including the lung, kidney, brain, heart, liver, and pancreas, providing important evidence of direct SARS-CoV-2 infection of vascular endothelial cells in multiple organs [43]. Taken together, although further studies are needed for confirmation, the results of studies indicate that SARS-CoV-2 may directly infect vascular endothelial cells in multiple organs.…”

Section: Possibility Of Direct Sars-cov-2 Infection Of Endothelial Cellsmentioning

confidence: 99%

Pathophysiological Association of Endothelial Dysfunction with Fatal Outcome in COVID-19

Maruhashi

Higashi

2021

IJMS

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The outbreak of coronavirus disease 2019 (COVID-19) caused by the betacoronavirus SARS-CoV-2 is now a worldwide challenge for healthcare systems. Although the leading cause of mortality in patients with COVID-19 is hypoxic respiratory failure due to viral pneumonia and acute respiratory distress syndrome, accumulating evidence has shown that the risk of thromboembolism is substantially high in patients with severe COVID-19 and that a thromboembolic event is another major complication contributing to the high morbidity and mortality in patients with COVID-19. Endothelial dysfunction is emerging as one of the main contributors to the pathogenesis of thromboembolic events in COVID-19. Endothelial dysfunction is usually referred to as reduced nitric oxide bioavailability. However, failures of the endothelium to control coagulation, inflammation, or permeability are also instances of endothelial dysfunction. Recent studies have indicated the possibility that SARS-CoV-2 can directly infect endothelial cells via the angiotensin-converting enzyme 2 pathway and that endothelial dysfunction caused by direct virus infection of endothelial cells may contribute to thrombotic complications and severe disease outcomes in patients with COVID-19. In this review, we summarize the current understanding of relationships between SARS-CoV-2 infection, endothelial dysfunction, and pulmonary and extrapulmonary complications in patients with COVID-19.

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Evidence of Severe Acute Respiratory Syndrome Coronavirus 2 Replication and Tropism in the Lungs, Airways, and Vascular Endothelium of Patients With Fatal Coronavirus Disease 2019: An Autopsy Case Series

Cited by 93 publications

References 34 publications

COVID-19 Vasculopathy: Mounting Evidence for an Indirect Mechanism of Endothelial Injury

COVID-19 Vasculopathy: Mounting Evidence for an Indirect Mechanism of Endothelial Injury

Pathophysiology of infection with SARS‐CoV‐2—What is known and what remains a mystery

Pathophysiological Association of Endothelial Dysfunction with Fatal Outcome in COVID-19

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