Introduction
Accumulating evidence indicates a central role of vascular endothelial injury and
immunothrombosis in the pathogenesis of severe COVID-19.
1
–3
Pulmonary perfusion
defects, representing micro- and macro-thromboses, are ubiquitous and extensive in
those
receiving intensive care.
4,5
The
perfusion abnormalities are also present in those receiving ward-based care, occupying
>20% of the lung volume.
5
While inflammatory and immunological drivers of COVID-196 remain highly
relevant to disease severity and outcomes, occlusive pulmonary vasculopathy appears
to play
a key pathophysiological role in disease progression and respiratory failure. In this
context, clinical risk stratification based on traditional models may be unsafe in
COVID-19.
This is consequent to the large reserve capacity of pulmonary perfusion, with respiratory
failure occurring as a late and pre-terminal event in progressive perfusion loss.
7
Current approach to COVID-19 risk stratification
The current approach to clinical risk stratification in COVID-19 largely follows the
model
for a lower-respiratory illness and relies on symptoms and signs of respiratory failure
(dyspnea and hypoxemia) to have a linear relationship with pathological progression.
The
World Health Organisation (WHO) defines mild COVID-19 as a limited upper respiratory
infection with no radiological abnormalities. Patients with radiological changes
with/without dyspnea, but no hypoxemia, have moderate disease, and those who develop
hypoxemia (SPO2 < 90%) have severe disease. Patients who develop acute
respiratory distress syndrome (ARDS) are deemed critically ill. Mild and moderate
disease
are managed expectantly with an advisory to monitor for symptom progression. If symptoms
worsen or hypoxemia occurs, hospitalization is advised, and supplemental oxygen is
provided
along with therapeutic agents. Critical illness is managed based on established ARDS
protocols. Venous thromboembolism prophylaxis is advised for hospitalized patients.
Clinicopathological discordance in COVID-19 and flaws in the current approach
A striking feature of COVID-19 is the rapid deterioration seen in the second week
of
illness after days of smoldering infection.
8
Respiratory failure progresses abruptly from the onset of hypoxemia or dyspnea. As
the clinical deterioration occurs around the time when adaptive immunity appears,
it was
initially postulated that the rapid deterioration, resulting in severe disease, occurs
due
to a dysregulated adaptive immune response. However, a fundamental assumption in this
hypothesis is that clinical deterioration mirrors pathological deterioration, and
that, this
occurs concurrently in COVID-19. This assumption has several flaws. First, in several
clinical conditions (e.g. coronary artery disease), pathology can progress significantly
before signs or symptoms appear. Second, in COVID-19, the pathological progression
is linear
from symptom onset in those who develop severe disease. This is best demonstrated
by
radiological features of ground-glass opacities (GGO) that occur in the first week
of
illness, that progresses to consolidation, while new GGO appear.
9
A dissociation between pathological deterioration and progression of respiratory
failure thus exists in COVID-19. This is atypical for pneumonia, but typical for disorders
of the pulmonary vasculature,
7
where a large reserve exists, that has to be compromised before the failure of gas
exchange can occur.
Additionally, while COVID-19 progresses from moderate to severe disease, it is observed
that hypoxemia typically precedes dyspnea.
10
Significant hypoxemia may occur with the patient unaware, without increased work of
breathing (“silent hypoxemia”). This is atypical for pneumonia, as for it to cause
profound
hypoxemia would require sufficient parenchymal involvement with alveolar exudate and
increased extravascular lung water. Dyspnea would therefore accompany severe hypoxemia.
This
conundrum may be resolved by realizing that pulmonary vascular occlusion is the major
determinant of COVID-19 progression.
11
In pulmonary vaso-occlusive disorders (except in post-capillary occlusion), lung
parenchymal injury is not necessary for impaired gas exchange, and profound hypoxemia
can
occur without dyspnea.
Due to this observed dissociation between pathological progression, arterial oxygenation,
and work of breathing, resulting from a dominant pathophysiological role of pulmonary
vasculopathy, a risk stratification approach based on the “pneumonia model” can be
unsafe in
COVID-19. For instance, home management of moderate disease may fail to detect disease
progression leading to hypoxemia, before the onset of dyspnea. Patients may therefore
present late to the emergency department followed by rapid clinical deterioration.
Furthermore, at the onset of hypoxemia and dyspnea, pathology would have progressed
significantly with the exhaustion of physiological reserves, and adverse outcomes
may ensue
despite supportive interventions.
Proposed approach to clinical risk stratification
The realization that thrombotic pulmonary vascular occlusion occurs early in susceptible
individuals and progresses in a linear fashion, and that respiratory failure is a
late
feature suggesting extensive vaso-occlusion, should transform our approach to the
disease. A
new risk stratification model based on the stage of pathological progression may be
more
appropriate in this situation (Fig.
1). Stage 1 denotes endothelial injury without thrombosis, as indicated by elevated
vascular injury markers or by abnormal global hemostatic assays that reveal a prothrombotic
state, but with no radiological changes. Though endothelial injury is not unique to
COVID-19, the extent and severity of endothelial damage, and evidence of viral cytopathic
effect, distinguishes it from other viral illnesses.
12
Various endothelial injury markers that have been associated with poor outcomes in
COVID-19 include thrombomodulin, P-selectin, and von Willebrand factor.
13
With the endothelial injury promoting a pro-thrombotic state, viscoelastic hemostatic
assays such as thromboelastogram,
14
rotational thromboelastometry, and clot wave analysis
15
could be utilized to demonstrate hypercoagulability in COVID-19. If performed early
in the disease course, these may identify patients who subsequently progress to diffuse
thrombosis. Stage 2 of early thrombosis is indicated by elevated markers of
thrombosis/fibrinolysis such as d-dimer, or radiological findings of sub-pleural GGO
with
corresponding perfusion defects, indicating microthrombosis. These perfusion defects
are
best appreciated on dual-energy computerized tomography
4
that concurrently demonstrates parenchymal and vascular pathology, and is much
superior to high resolution CT scan in this regard. Inflammatory markers such as C-reactive
protein, iterleukin-6, ferritin, and lactate dehydrogenase show a linear rise at this
stage
and is able to predict patients who are at risk of progression to severe disease.
16
Stage 3 is progressive pulmonary thrombosis characterized by hypoxemia on exertion
often without dyspnea. Some patients may not progress beyond this stage but continue
to have
exertional hypoxemia at hospital discharge despite otherwise being asymptomatic.
17
Stage 4 denotes extensive vascular occlusion with or without diffuse parenchymal
injury and characterized by rest hypoxemia requiring oxygenation support, at risk
of rapidly
progressing respiratory failure. As initial parenchymal injury is often limited, lung
mechanics are typically preserved during this stage of illness. Stage 5 is advanced
respiratory failure requiring ventilatory support, associated with diffuse alveolar
injury
and fulfilling the clinical criteria for ARDS.
Fig. 1.
Clinicopathological discordance in COVID-19 and options for risk stratification at
various stages of the disease progression. In pneumonia, there is concordance between
pathological progression and symptoms/signs of respiratory failure, as the dominant
pathology is alveolar exudate and the dominant mechanism of hypoxemia is alveolar
hypoventilation/shunting and venous admixing. This facilitates early clinical risk
stratification based on symptoms (dyspnea), arterial oxygen saturation, and radiological
features. However, in COVID-19, due to the dominant pathophysiological role of pulmonary
vascular occlusion in disease progression and abnormal gas exchange, there is
discordance between the extent of pathology and respiratory failure severity. Distinct
features include silent hypoxemia and rapidly progressing respiratory failure from
the
onset of hypoxemia and dyspnea. An alternate approach to risk stratification, that
employs endothelial and thrombotic biomarkers, tests of global hemostasis, perfusion
imaging, and dynamic measures of perfusion adequacy such as exercise oximetry may
help
identify pathological progression early and guide interventions. Early and appropriate
antithrombotic strategy based on pathological severity may alter the natural history
of
the disease with improvement in outcomes.
Identifying patients in stages 2 and 3, who may not have dyspnea but have progressive
pulmonary vascular occlusion, is critical, as it is plausible that providing definitive
antithrombotic treatment may prevent tissue infarction and mitigate lung injury.
Importantly, hemorrhagic pulmonary infarction is more common with small than large
vessel occlusion
18
and may explain peripheral wedge-shaped lung opacities of COVID-19. Additionally,
for
patients in stages 4 and 5, along with supportive care, early treatment of reversible
pathology of pulmonary micro- and macro-thromboses may be considered to improve gas
exchange
19,20
and limit lung injury.
Summary and conclusions
The current risk stratification approach that follows a pneumonia model may be
inappropriate for COVID-19, where pulmonary vascular occlusion appears to be the major
determinant of respiratory failure. Clinicopathological discordance in COVID-19 limits
early
clinical identification of pathological progression and necessitates a modified approach
to
risk stratification, informed by pulmonary perfusion physiology. If thrombosis is
a major
determinant of hypoxemia and disease progression in COVID-19, early antithrombotic
measures
could avert disordered gas exchange
20
and ischemic lung injury, with improvement in outcomes. To conclude, a proactive and
pathophysiological approach to risk stratification, with an intent to alter the natural
history of the disease, may be superior to a reactive approach in COVID-19.