The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),
has resulted in more than 5·7 million confirmed cases and 350 000 deaths globally
as of May 28, according to the Johns Hopkins University Coronavirus Resource Center.
Despite the vast number of reports on the epidemiology, immunology, radiology, and
management of COVID-19, few publications on the disease's pathology have so far been
available, and most have been single-case reports or small case series.1, 2, 3
Initial reports of the disease focused on older patients with comorbidities; however,
we are now witnessing cases in paediatric and young adult populations. The spectrum
of clinical manifestations documented in the literature mirrors this expanded view
of COVID-19 as well. In addition to pneumonia and respiratory failure, thromboembolic
events (sometimes clinically unsuspected at death) are common, according to a 12-case
autopsy series from Germany.
4
In addition, clinical studies have reported acquired coagulopathy in patients with
COVID-19,5, 6, 7 and a paediatric inflammatory syndrome linked to SARS-CoV-2 can also
cause life-threatening cardiac issues.
8
Angiotensin-converting enzyme 2 (ACE2) has been identified as a functional receptor
for SARS-CoV-2, allowing entry of the virus into host cells.
9
ACE2 is normally highly expressed in the lung, heart, ileum, kidney, and bladder.
In the lungs, ACE2 is heavily expressed on ciliated airway epithelial cells and alveolar
type 2 pneumocytes.
9
Endothelial cells, which comprise about a third of resident pulmonary cells, also
express ACE2.
9
Thus, it has been hypothesised that SARS-CoV-2 undergoes haematogenous dissemination
via infected pulmonary epithelium, followed by pulmonary endothelium. During this
process, endothelial injury—inciting the coagulation cascade—and subsequent microvascular
permeability occur. Levels of circulating ACE2 are higher in men than in women, which
might account for the differences in severity and mortality between sexes.
9
Whether SARS-CoV-2 can bind to other targets is not known.
The host immune response mediates inflammation and cellular antiviral activity in
a process crucial to the inhibition of viral replication and dissemination. However,
excessive immune responses can be harmful and cause severe symptoms, especially in
younger patients. Patients infected with SARS-CoV-2, and especially those requiring
escalated levels of care, are reported to have higher plasma levels of proinflammatory
cytokines.
9
Careful observation and descriptive studies are vital to understanding disease manifestations.
As integral members of care teams, pathologists work behind the scenes to form diagnoses
on the basis of tissue biopsies, or to ascertain cause of death through autopsies.
A thorough post-mortem evaluation can prove or disprove various postulated clinical
events, with the potential to offer invaluable insights into the mechanism of disease.
In The Lancet Infectious Diseases, Luca Carsana and colleagues
10
report the post-mortem findings from 38 autopsies done at two centres in northern
Italy. They found diffuse alveolar damage to be the predominant pattern of lung injury.
Although this series did not include any control cases (without COVID-19), diffuse
alveolar damage is known to be a common pathway in acute lung injury caused by any
severe infection. Thus, the additional unusual findings could be attributable to COVID-19.
Carsana and colleagues highlight that the prevalence and intensity of endothelial
necrosis, increased megakaryocytes in alveolar capillaries, and widespread arteriolar
fibrin–platelet thrombi are far more pronounced in cases of COVID-19 than in typical
cases of diffuse alveolar damage resulting from other causes. These histopathological
findings are substantiated by very high serum D-dimer levels, suggesting ante-mortem
disseminated intravascular coagulation. Adding to this theory, some patients with
COVID-19 present with ischaemic stroke
11
or deep vein thrombosis.
4
Despite these compelling findings, it is difficult to tease out the causal relationship
among disseminated intravascular coagulation, diffuse alveolar damage, and pulmonary
thrombotic microangiopathy. Regardless of the underlying mechanism, these findings
suggest that anticoagulation might be an important therapeutic strategy.
An additional compelling and unique aspect of this study is the ultrastructural demonstration
of coronavirus particles. The virions showed characteristic 13 nm projections and
were identified along the plasmalemmal membranes or in cytoplasmic vesicles within
type 1 and 2 pneumocytes, and rarely within alveolar macrophages. Notably, these virions
were not detected in the endothelial cells in this study, conflicting with the aforementioned
mechanism of SARS-CoV-2 dissemination via infected pulmonary epithelium and endothelium.
Also noteworthy is that co-infection with secondary microorganisms was uncommon in
this series, possibly because of the rapidity with which death can occur in cases
of COVID-19.
Despite the limitations inherent to retrospective descriptive studies, Carsana and
colleagues
10
provide valuable information, corroborating clinical observations of coagulopathy,
which could have implications on viable treatment strategies. Carsana and colleagues'
work to provide these valuable findings amid the ongoing crisis should be lauded.
© 2020 Oxford University Images/Science Photo Library
2020
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