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.

/pdf/extrapulmonary-manifestations-of-covid-19-5gbdx3z1ea.pdf

Extrapulmonary manifestations of COVID-19.

Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis.

Coronavirus disease 2019 (COVID-19) is a novel, viral-induced respiratory disease that in ∼10-15% of patients progresses to acute respiratory distress syndrome (ARDS) triggered by a cytokine storm. In this Perspective, autopsy results and literature are presented supporting the hypothesis that a little known yet powerful function of neutrophils-the ability to form neutrophil extracellular traps (NETs)-may contribute to organ damage and mortality in COVID-19. We show lung infiltration of neutrophils in an autopsy specimen from a patient who succumbed to COVID-19. We discuss prior reports linking aberrant NET formation to pulmonary diseases, thrombosis, mucous secretions in the airways, and cytokine production. If our hypothesis is correct, targeting NETs directly and/or indirectly with existing drugs may reduce the clinical severity of COVID-19.

https://rupress.org/jem/article-pdf/217/6/e20200652/1414639/jem_20200652.pdf

Targeting potential drivers of COVID-19: Neutrophil extracellular traps.

COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection.

Angiotensin-converting enzyme 2 (ACE2) has been established as the functional host receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the current devastating worldwide pandemic of coronavirus disease 2019 (COVID-19). ACE2 is abundantly expressed in a variety of cells residing in many different human organs. In human physiology, ACE2 is a pivotal counter-regulatory enzyme to ACE by the breakdown of angiotensin II, the central player in the renin-angiotensin-aldosterone system (RAAS) and the main substrate of ACE2. Many factors have been associated with both altered ACE2 expression and COVID-19 severity and progression, including age, sex, ethnicity, medication, and several co-morbidities, such as cardiovascular disease and metabolic syndrome. Although ACE2 is widely distributed in various human tissues and many of its determinants have been well recognised, ACE2-expressing organs do not equally participate in COVID-19 pathophysiology, implying that other mechanisms are involved in orchestrating cellular infection resulting in tissue damage. Reports of pathologic findings in tissue specimens of COVID-19 patients are rapidly emerging and confirm the established role of ACE2 expression and activity in disease pathogenesis. Identifying pathologic changes caused by SARS-CoV-2 infection is crucially important as it has major implications for understanding COVID-19 pathophysiology and the development of evidence-based treatment strategies. Currently, many interventional strategies are being explored in ongoing clinical trials, encompassing many drug classes and strategies, including antiviral drugs, biological response modifiers, and RAAS inhibitors. Ultimately, prevention is key to combat COVID-19 and appropriate measures are being taken accordingly, including development of effective vaccines. In this review, we describe the role of ACE2 in COVID-19 pathophysiology, including factors influencing ACE2 expression and activity in relation to COVID-19 severity. In addition, we discuss the relevant pathological changes resulting from SARS-CoV-2 infection. Finally, we highlight a selection of potential treatment modalities for COVID-19. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

/pdf/angiotensin-converting-enzyme-2-ace2-sars-cov-2-and-the-4asxbnmbwa.pdf

Angiotensin?converting enzyme 2 (ACE2), SARS?CoV?2 and the pathophysiology of coronavirus disease 2019 (COVID?19)

Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.

SARS-CoV-2 has rapidly spread across the United States, causing extensive morbidity and mortality, though the histopathologic basis of severe disease cases has yet to be studied in detail. Over the past century, autopsy has contributed significantly to our understanding of numerous disease processes, but for several reasons, autopsy reports following deaths related to SARS- CoV-2 have thus far been limited across the globe. We report on the relevant cardiopulmonary findings in the first series of autopsies in the United States, with the cause of death being due to SARS-CoV-2 infection. These cases identify key pathologic states potentially contributing to severe disease and decompensation in these patients.

https://medrxiv.org/content/10.1101/2020.04.06.20050575v1.full.pdf

Pulmonary and Cardiac Pathology in Covid-19: The First Autopsy Series from New Orleans

The study of pulmonary samples from individuals who have died as a direct result of COVID-19 infection is vital to our understanding of the pathogenesis of this disease. Histopathologic studies of lung tissue from autopsy of patients with COVID-19 specific mortality are only just emerging. All existing reports have relied on traditional 2-dimensional slide-based histological methods for specimen preparation. However, emerging methods for high-resolution, massively multiscale imaging of tissue microstructure using fluorescence labeling and tissue clearing methods enable the acquisition of tissue histology in 3-dimensions, that could open new insights into the nature of SARS-Cov-2 infection and COVID-19 disease processes. In this article, we present the first 3-dimensional images of lung autopsy tissues taken from a COVID-19 patient, including 3D “virtual histology” of cubic-millimeter volumes of the diseased lung, providing unique insights into disease processes contributing to mortality that could inform frontline treatment decisions.

/pdf/multiscale-3-dimensional-pathology-findings-of-covid-19-5em8ak5izg.pdf

Multiscale 3-dimensional pathology findings of COVID-19 diseased lung using high-resolution cleared tissue microscopy

Unexpected Features of Cardiac Pathology in COVID-19 Infection.

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Papers

Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.

Pulmonary and Cardiac Pathology in Covid-19: The First Autopsy Series from New Orleans

Multiscale 3-dimensional pathology findings of COVID-19 diseased lung using high-resolution cleared tissue microscopy

Unexpected Features of Cardiac Pathology in COVID-19 Infection.