How does SARS-CoV-2 cause death in infected patients?

A review of postmortem studies and pathophysiological considerations has found how SARS-CoV-2, a respiratory virus that causes COVID-19, infects cells by binding to angiotensin-converting enzyme II (ACE2) receptors, producing cell death and ACE2 downregulation.

In combination with a dysregulated immune response, the virus then promotes a proinflammatory and prothrombic state that leads to respiratory and multiple organ failure (MOF).

“The contributions of pathology and forensic sciences during this pandemic have been paramount in order to determine an accurate cause of death and shed light on the pathogenesis of the disease, guide research, treatment and new discoveries,” said study author Angela M. Takano, senior consultant for the Department of Anatomical Pathology at Singapore General Hospital, Singapore.

Takano performed a literature search through PubMed to review the pulmonary pathology from postmortem studies and case reports of patients with COVID-19, perform clinicopathologic correlation, and hypothesize about pathogenetic mechanisms. She then sought to translate this knowledge into better prevention, management, and outcomes in the fight against the dreaded disease.

Takano’s main histopathologic findings in COVID-19 pneumonia were as follows: diffuse alveolar damage (DAD), organizing pneumonia, interstitial pneumonia, endotheliitis, thromboembolism associated with respiratory failure, and manifestations of thrombotic microangiopathy and hypercoagulable state. [Proc Singapore Healthc 2021;30:152-158]

In immunohistochemical and transmission electron microscopic studies, viral proteins and structures were noted within epithelial and endothelial cells. Moreover, reverse transcriptase polymerase chain reaction revealed the presence of viral RNA in nasopharynx and lung tissue postmortem.

A study by Ackermann and colleagues reported the presence of viral structures within damaged endothelial cells in the lung. This causes the cell to undergo pyroptosis, producing danger-related molecules, namely adenosine triphosphate and nucleic acids, and initiating the production of proinflammatory cytokines and chemokines that attract monocytes, macrophages, and T cells to the infection site. [N Engl J Med 2020;383:120-128]

“If the immune system is healthy and the viral inoculum is probably not too large, CD8+T cells recognize infected cells and eliminate them, CD4+ cells mediate immune response, antibodies bind and inactivate virus, while macrophages phagocytose apoptotic cells and neutralized virus, restoring the cell to a normal state in 80 percent of cases infected by the virus,” Takano said. [Int J Infect Dis 2020;97:290-292]

“In remaining patients, however, the immune response is dysfunctional and gives rise to excessive infiltration of monocytes, macrophages and T cells, systemic cytokine storm, pulmonary oedema and pneumonia, as well as widespread inflammation and multiorgan damage and MOF,” she added. [Nat Rev Immunol 2020;20:363-374]

In addition, the binding of SARS-CoV-2 to ACE2 receptors causes ACE2 downregulation, with an increase in oxidative stress and inflammation that leads to endothelial cell dysfunction and an upsurge in the Von-Willebrand factor, as well as the development of a procoagulant state with microthrombosis, angiogenesis, and direct damage to alveolar type II cells, Takano said. [Eur J Intern Med 2020;76:14-20]

“The inflammatory process, coupled with an inadequate clearance of the virus from infected cells, gives rise to DAD with its typical histologic findings—difficulty in gas exchange, hypoxaemia, and shortness of breath—which may progress to respiratory failure,” she added.