The
lung pathology seen in patients with coronavirus disease 2019
(COVID-19) shows marked microvascular thrombosis and haemorrhage linked
to extensive alveolar and interstitial inflammation that shares features
with macrophage activation syndrome (MAS). We have termed the
lung-restricted vascular immunopathology associated with COVID-19 as
diffuse pulmonary intravascular coagulopathy, which in its early stages
is distinct from disseminated intravascular coagulation. Increased
circulating D-dimer concentrations (reflecting pulmonary vascular bed
thrombosis with fibrinolysis) and elevated cardiac enzyme concentrations
(reflecting emergent ventricular stress induced by pulmonary
hypertension) in the face of normal fibrinogen and platelet levels are
key early features of severe pulmonary intravascular coagulopathy
related to COVID-19. Extensive immunothrombosis over a wide pulmonary
vascular territory without confirmation of COVID-19 viraemia in early
disease best explains the adverse impact of male sex, hypertension,
obesity, and diabetes on the prognosis of patients with COVID-19. The
immune mechanism underlying diffuse alveolar and pulmonary interstitial
inflammation in COVID-19 involves a MAS-like state that triggers
extensive immunothrombosis, which might unmask subclinical
cardiovascular disease and is distinct from the MAS and disseminated
intravascular coagulation that is more familiar to rheumatologists.
The
coronavirus disease 2019 (COVID-19) pandemic and earlier coronavirus
outbreaks have been associated with adult respiratory distress syndrome
(ARDS) and worse outcomes in older patients.
The severity of systemic inflammation in response to human coronavirus
family members has features reminiscent of a cytokine storm or
macrophage activation syndrome (MAS), also known as secondary
haemophagocytic lymphohistocytosis (sHLH).
This response has inspired use of directed anticytokine therapies for
severe COVID-19 pneumonia, as these agents are known to be useful in
diseases on the MAS spectrum.
A key feature of sHLH or MAS is haemophagocytosis and an acute
consumptive coagulopathy, leading to disseminated intravascular
coagulation. Disseminated intravascular coagulation has also been
reported in COVID-19 pneumonia, but usually as a pre-terminal event.
In SARS, this process might involve phagocytosis of extravascular red
blood cells consequent to severe lung microvascular damage,
microhaemorrhage with physiological haemophagocytosis of extravascular
red blood cells, or possibly very advanced disease with frank MAS-like
pathology and disseminated intravascular coagulation (figure 1).
The hypercytokinaemia characteristic of sHLH or MAS is often associated
with extremely high serum ferritin concentrations (≥10 000–100 000
ng/mL), whereas in patients with COVID-19, serum ferritin concentrations
are typically in the 500–3000 ng/mL range, at least early in the
disease course. Another clear distinguishing feature of sHLH or MAS is
liver function derangement, which can contribute to coagulopathy
secondary to loss of liver synthetic function and is not typically seen
in patients with COVID-19 (figure 1).
Figure 1Early macrophage activation syndrome versus early COVID-19
Extensive
lung infiltration by macrophages and other immune cells leading to
diffuse alveolar damage has been reported in SARS pneumonia, with
similar findings emerging in patients with COVID-19 pneumonia.
The extensive nature of viral infection with severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) results in diffuse lung inflammation
that involves the large juxtaposed pulmonary vascular network.
The diffuse, slowly evolving COVID-19 pneumonia has similarities to a
MAS-like syndrome with regard to both clinical and laboratory features.
These clinical findings suggest that an initial pulmonary intravascular
coagulopathy occurs in patients with COVID-19 pneumonia that is distinct
from disseminated intravascular coagulation.
Herein, we propose a model for the pathophysiology of this pulmonary
intravascular coagulopathy and describe how extensive coronavirus
infection and age-related changes in immunity, combined with diffuse
pulmonary immunothrombosis, explain the cardiovascular mortality in
these patients (table 1).
Table 1Differences and similarities between DIC and PIC
DIC linked to HLH or MAS
PIC linked to COVID-19
Clinical features
Onset
Acute
Subacute
Hepatosplenomegaly
+++
..
Adenopathy
++
..
Pulmonary involvement (%)
50%
100%
Thrombosis
Multi-organ clotting
Mainly lung (occasional CNS and peripheral thrombosis reported; related to DIC evolution?)
Bleeding
Generalised
Intrapulmonary microhaemorrhage
Active infection considerations
Yes usually for primary HLH; secondary HLH might not have driving infection
Thought to be ongoing alveolar infection
Laboratory parameters
Liver function
Decreased synthetic function including fibrinogen and other clotting factors; raised transaminase +++
Preservation of liver synthetic function; +/−
Anaemia
+++
−
Thrombocytopenia
+++
Normal or low
Immune cell cytopenia
++
No but lymphopenia is a feature of COVID-19 in general
Creatine kinase
+ (skeletal and cardiac origin)
+ (worse prognosis)
Troponin T
+
++ with high levels associated with worse outcome
Haemophagocytosis
Generalised to marrow, liver, and other sites detectable in >80%
Occasional intrapulmonary and regional lymph node haemophagocytosis reported
Evolution
DIC secondary to MAS
PIC might evolve into DIC; PIC might occur without MAS
Coagulation and immunology markers
Elevated prothrombin time or activated partial thromboplastin time
+++/+++
+ or normal
Fibrinogen levels
Decreased
Normal or slight increase
Fibrin degradation products or D-dimer
Increased
Increased
C-reactive protein
Elevated
Elevated
Ferritin elevation
+++
Elevated
Hypercytokinaemia
+++
++
Present
(+), usually present (++), frequently present (+++), or absent (−)
clinical features, laboratory parameters, and coagulation and immunology
markers. DIC=disseminated intravascular coagulation.
HLH=haemophagocytic lymphohistiocytosis. MAS=macrophage activation
syndrome. PIC=pulmonary intravascular coagulopathy. COVID-19=coronavirus
disease 2019.
Pulmonary vascular pathology patterns in SARS and COVID-19
Acute
respiratory infections are associated with a high risk of
cardiovascular-related death, especially in the weeks immediately after
infection, and particularly in older patients and those with
pre-existing cardiovascular disease. Severity of pneumonia in these
patients is linked to an increased risk of death.
Of particular note, one pathology study showed similar vascular changes
in post-mortem tissue from patients with bronchopneumonia not related
to SARS as was found in individuals who died from SARS,
Coronavirus
family members show tropism for angiotensin-converting enzyme 2 (ACE2)
on type II pneumocytes. This tropism, along with the close anatomical
juxtaposition of type II pneumocytes and the pulmonary vascular network,
and a severe multifaceted inflammatory reaction, is likely to drive the
generalised pulmonary hypercoagulable state seen in patients with
COVID-19 (figure 2).
Single-cell sequencing analysis has recently shown that most pulmonary
gene expression is confined to a small population of type II
pneumocytes, and ACE2 is largely absent from endothelial cells and
alveolar macrophages.
From a clinical perspective, the diffuse alveolar changes (determined
by CT scan) seen in patients with COVID-19 are distinct from
bronchopneumonia and show how SARS-CoV-2 interfaces with a large area of
the pulmonary microvasculature. This finding probably explains the
propensity for diffuse pathology in patients with COVID-19 pneumonia. In
these patients, extensive air space changes on CT are associated with a
worse prognosis compared with patients not showing these changes.
ACE2
has been shown to regulate innate immunity, and mice with a genetic
deletion of ACE2 developed more severe pulmonary inflammation after acid
inhalation than did wild-type mice.
These findings suggest that ACE2 downregulation could aggravate
inflammation over a wide alveolar capillary network. It was subsequently
shown that injecting the SARS spike protein led to similar lung
pathology in mice, probably due to internalisation of the ACE2 receptor
and subsequent inhibition of ACE2-mediated generation of the
immunoregulatory angiotensin (1–7) peptide, which signals via the MAS1
receptor.
Theoretically, a similar mechanism could increase the proclivity
towards immunothrombosis in humans. In humans, the Middle East
respiratory syndrome coronavirus (MERS-CoV) principally uses the
dipeptidyl peptidase 4 (DPP4) receptor, which is not restricted to type
II pneumocytes; nonetheless, this virus results in clinical features and
pathology similar to SARS-CoV and SARS-CoV-2, including a high
mortality rate.
Analogous to ACE2, in some experimental systems the DPP4 receptor might
negatively regulate lymphocyte function, which could indicate a shared
coronavirus-specific mechanism that contributes to pulmonary
intravascular coagulopathy (panel).
The
SARS-CoV-2 and SARS-CoV virus genomes are highly homologous, and
patients infected with these viruses appear to share common clinical and
pathological features.
Initial post-mortem reports from three patients with SARS indicated not
only diffuse alveolar damage and small pulmonary vessel thrombosis and
haemorrhage, but also a more generalised small vessel thrombosis.
A study of pathological specimens from 20 patients with SARS showed the
presence of not only diffuse alveolar damage, but also fibrin thrombi,
small vessel occlusion, and pulmonary infarction in upwards of 80% of
cases.
A review of aggregated SARS pathology reports showed evidence for
vessel wall oedema, inflammatory cell infiltration into the walls of the
pulmonary microvasculature, marked haemorrhagic necrosis, and vessel
microthrombi mostly confined to the lung and pulmonary tissue
infarction, in the context of septal inflammation and diffuse alveolar
damage.
Some data have emerged from patients with COVID-19 pneumonia that show a
similar pulmonary vascular picture with blood vessel wall oedema,
modest vessel wall immune cell infiltration, hyaline thrombosis,
haemorrhagic change, and infarction.
Insufficient evidence for coronavirus myocarditis or coronary vasculitis
Myocarditis
might occur after severe respiratory viral pneumonia. Although this
outcome is relatively rare, it is well documented, especially in younger
women following influenza infection (table 2).
Understandably, increased cardiac enzymes in patients with COVID-19 has
been taken to potentially represent myocarditis or cardiac vasculitis
associated with viral infection. In SARS-CoV infection, however, most
evidence points away from cardiac involvement.
The ACE2 receptor is expressed on endothelial cells, and one in situ
hybridisation study suggested that pulmonary endothelial cells are
infected with SARS-CoV.
Cardiac
injury in >60% with avian influenza H7N9 infection suggesting that
cardiac disease linked to infection; also linked to history of
cardiovascular disease, but not male sex or diabetes (myocarditis is
well documented with influenza)
Pandemic
(H1N1) 2009 virus; cardiac injury in 46% of cases; mean age 34 years;
more common in women than in men; presumed myocarditis (no histology or
post-mortem data)
Furthermore,
a study in patients with SARS suggested a close link between infection
of pneumocytes and inflammatory cytokine expression in the same cells;
A
role for the ACE2 receptor in cardiovascular biology predates the link
between pulmonary pathology and COVID-19 pneumonia. Genetic deletion of
ACE2 in rodents was associated with ventricular contractility defects,
but there was no evidence of cardiomyopathy or fibrosis.
The link between ACE2 downregulation in lung tissue (either in
genetically manipulated mice or mice treated with SARS spike protein)
and increased inflammation suggests a relatively simple model, in which
coronavirus infection of ACE2-expressing cardiomyocytes or cardiac
endothelium might trigger a similar inflammatory pathology. In the most
comprehensive study of cardiac involvement in patients who died from
SARS, viral RNA was detectable in a third of post-mortem cardiac tissues
and was associated with both decreased ACE2 expression and increased
macrophage infiltration.
Overall autopsy reports, including those emerging in COVID-19, vary
from showing no clinically significant pathology or infiltrating
macrophages, and some reports of occasional infiltrating CD4 T cells.
The
cardiac pathology in COVID-19 pneumonia needs evaluation in view of
known cardiovascular comorbidities, including hypertension and pulmonary
intravascular coagulopathy, as well as the MAS-like state with
associated hypoxaemia and secondary pulmonary artery hypertension. The
hypercytokinaemia that is part of the MAS-like state could modify ACE2
expression independently of viraemia. One key cytokine characteristic of
MAS-like pathology, interferon-γ, has been shown to downregulate ACE2
expression on an epithelial cell line; however, this finding has not
been reported for heart cells.
Therefore, reported changes in the heart tissue, including endothelium,
could represent a cytokine and hypoxia effect rather than direct viral
infection.
Laboratory data indicate early pulmonary intravascular coagulopathy
The
key early laboratory observations in patients with COVID-19 pneumonia
include elevated plasma D-dimer concentrations in conjunction with
elevated cardiac markers, including brain natriuretic peptide, creatine
kinase, and troponin T.
Similarly, a 2020 study reported that elevated plasma levels of fibrin
degradation products, including D-dimers, constitutes a significant
independent biomarker of poor prognosis.
reported that 117 (68%) of 172 patients presenting with COVID-19 had
increased activation of coagulation, as indicated by elevated D-dimer
concentrations at presentation (>0·5 ug/mL). Importantly, D-dimer
concentrations above 1 μg/mL were associated with an 18 times increased
odds ratio for fatal outcome.
However, despite this increase in D-dimers, patients with COVID-19 do
not typically develop overt systemic disseminated intravascular
coagulation. In rare cases of COVID-19 in which overt disseminated
intravascular coagulation does develop, it tends to be restricted to
late-stage disease. This finding is reflected in the consistent
observation that platelet counts and fibrinogen concentration are not
substantially reduced in patients with COVID-19, despite marked
increases in D-dimer concentrations.
Fibrinogen generally remains elevated in these patients, consistent with an ongoing acute phase response.
Extensive pulmonary inflammation and thrombosis in COVID-19 pathology
Severe
COVID-19 sepsis is associated with a marked MAS-type picture, and
increased inflammatory markers and ferritin concentrations that
undoubtedly result in local activation of pulmonary vasculature
endothelial cells. For example, interleukin (IL)-1, IL-6, and tumor
necrosis factor have all been shown to trigger acute endothelial cell
activation.
Given the crucial roles played by endothelial cells in maintaining
normal haemostasis, regulating fibrinolysis, and determining vessel wall
permeability, local endothelial cell dysfunction in the pulmonary
microvasculature is likely to play an important role in the
thromboinflammatory processes that ultimately result in COVID-19
vasculopathy, ventilation perfusion mismatch, and a clinical phenotype
of refractory ARDS.
Additionally,
the MAS-like picture associated with COVID-19 pneumonia will trigger
expression of active tissue factor, both on endothelial cells and on
activated infiltrating macrophages and neutrophils.
The net effect will be local presentation of blood-borne tissue factor
within the lungs, which will further amplify activation of the
coagulation cascade. Importantly, endothelial cell disruption, tissue
factor expression, and activation of the coagulation cascade will all be
progressively exacerbated by development of local hypoxia,
establishing a deleterious positive thromboinflammatory feedback loop
within the small vessels of the lungs with thrombosis and haemorrhage (figure 3).
Beyond the coagulopathic changes occurring within the pulmonary
vasculature, a study of bronchoalveolar lavage showed that both severe
pneumonia and ARDS are associated with enhanced thrombin generation and
fibrin deposition within the bronchoalveolar system.
and are primarily driven by upregulation of tissue factor expression
within the alveoli, coupled with a reduction in fibrinolysis induced by
plasminogen activation inhibitor 1.
The biological mechanisms responsible for the extremely elevated plasma
D-dimer concentrations in patients with severe COVID-19, together with
the marked variations observed between individuals, are unclear.
Nonetheless, these data clearly suggest hyperactive fibrinolysis with
increased plasmin generation. Collectively, these findings have led to
the suggestion that elevated plasmin (and plasminogen) concentrations
might represent a risk factor for COVID-19 susceptibility.
Development
of hypoxaemia, secondary to ARDS that is induced by COVID-19, might
also activate the coagulation cascade and could be important in
endothelial dysfunction beyond the capillary network.
Other factors, including mechanical ventilation in patients progressing
to ARDS, might contribute to this picture. The role of vascular
microthrombi formation, or immunothrombosis, in containment of bacterial
infection and spread is well established, but its role in viral
infection is not so well known.
Likewise, the role of local pulmonary intravascular immunity and its
effects on the phenotype of pulmonary intravascular coagulopathy is
completely unknown.
Nevertheless, access to the circulation in an artificial adenovirus
model system triggers a MAS-like phenomenon with disseminated
intravascular coagulation.
The role of positive pressure ventilation as a factor driving release
of viral nucleic acids and proteins across damaged alveolar endothelial
cell barriers is another factor that needs consideration as a potential
iatrogenic contributor to immunothrombosis and poor outcomes.
Experimental
SARS models have shown that normal aged primates have a similar degree
of viral replication as younger primates, but that aged primates have
more pulmonary damage and lower activation of type 1 interferon
responsive gene pathways.
At the molecular level, aged primates showed exacerbated innate immune
responses associated with NF-kB pathway activation, such as elevated
IL-8 and expression of tissue factor, which activates the extrinsic
clotting pathway protein.
Viral or age-related impairment in type 1 interferon production appears
to be associated with a second wave of inflammatory cytokine production
and tissue factor expression that might substantially contribute to
pulmonary intravascular coagulopathy.
Implications of pulmonary intravascular coagulopathy
The
role of anticoagulation in the setting of COVID-19 pulmonary
intravascular coagulopathy is of considerable interest. Expert
recommendations for the use of anticoagulants have already been
published, reflecting the recognition of clotting dysregulation.
The potential relevance of anticardiolipin antibodies in the critical
care setting of COVID-19 is also recognised, but is of uncertain
clinical significance.
However, some data are available, mostly derived from prospective
cohort studies. In a study of nearly 450 patients with COVID-19, low
molecular weight heparin (mostly used in prophylactic doses rather than
therapeutic doses) did not confer an overall survival advantage.
However, the regimen was associated with improved survival in the group
with a high sepsis-induced coagulopathy score and in patients with
D-dimer concentrations that were more than six times the upper limit of
normal.
The role and timing of anticoagulation in this extensive virus-related
immunothrombosis, especially where pulmonary haemorrhaging occurs, needs
careful consideration. In disseminated intravascular coagulation,
thrombosis and bleeding might occur simultaneously, and the same
scenario also appears to arise in pulmonary intravascular coagulopathy (figure 3).
Given
the MAS-like pathology of COVID-19 pneumonia, the question arises
whether anticytokine therapy will ameliorate the diffuse
immunothrombosis process associated with severe cases. In the
translational setting, the use of the IL-1β blocker canakinumab is
associated with a decreased risk of all-cause cardiovascular mortality,
Unlike in low grade arterial inflammation in the absence of overt
infection, it is still unclear whether severe COVID-19-associated MAS
with pulmonary intravascular coagulopathy will be successfully targeted
with these strategies; ongoing viral infection might represent a major
hurdle in this context.
In the past year, it has also emerged that the coagulation and immune
systems are directly linked via thrombin cleavage of IL-1α from
macrophages and platelets.
This novel mechanism is of special interest with regard to anakinra,
which blocks both the IL-1α and IL-1β pathways, whereas monoclonal
antibodies (eg, canakinumab) selectively block IL-1β.
The
most crucial question for optimal therapeutic strategies is whether the
emergent early activation of coagulopathy and fibrinolysis in patients
with COVID-19 pneumonia is purely due to an appropriate immune response
to the virus, or whether there is a degree of excessive inflammation
that could be targeted to help prevent progression of pulmonary
intravascular coagulopathy. The potential survival advantage of drugs
pioneered to treat inflammatory and hyperinflammatory states needs to be
viewed from the perspective of severe diffuse pulmonary
immunothrombosis. The combination of immunomodulatory and anticoagulant
strategies in patients with high D-dimer concentrations and evidence of
myocardial stress warrants especially close attention. The use of Janus
kinase (JAK) pathway inhibition needs careful scrutiny given the
association between JAK inhibitors and thromboembolic disease.
Some
bleeding complications outside of the lung have been described in
patients with COVID-19; this response is perhaps unsurprising in the few
cases of pulmonary intravascular coagulopathy that progress to systemic
disseminated intravascular coagulation. Reports of acute necrotising
encephalopathy, which is associated with haemorrhage, are also emerging.
Given that ACE2 is expressed on endothelial cells, the notion of
thrombosis outside either pulmonary or disseminated intravascular
coagulopathy needs further consideration.
This
pulmonary intravascular coagulopathy model has implications for
understanding cardiovascular mortality in the COVID-19 pandemic. This
model shifts the focus away from COVID-19-related myocarditis or
coronary vascular involvement, with cardiac injury secondary to viral
infection of myocytes or endothelial cells expressing ACE2, and towards a
scenario of multisite pulmonary vascular thrombosis with progressive
myocardial ischaemia. The immunothrombotic pathology that evolves over
several days in some patients with COVID-19 pneumonia is likely to
manifest in individuals with underlying cardiovascular risk factors such
as obesity, hypertension, and type 2 diabetes, and pathology will be
compounded by the cardiac ischaemia that accompanies development of
ARDS. Cardiovascular mortality is higher in men than in women aged 30–64
years in many different populations.
The COVID-19 pandemic, characterised by profound immunological changes
that constitute a pulmonary MAS-like picture, is revealing a large
burden of subclinical cardiovascular disease among patients predisposed
to disease, by slowly triggering an extensive pulmonary
immunothrombosis. Our model offers a different and robust alternative to
the proposed effects of medications on ACE2 expression with resulting
increased viral infectivity.
It is also important to determine the degree to which COVID-19-mediated
diffuse alveolar damage with development of ARDS in the absence of
coagulopathy might also contribute to outcomes, because emerging
post-mortem reports do not report this pathology in all cases.
Diffuse
pulmonary intravascular coagulopathy is not unique to the MAS-like
pattern of inflammation. Diffuse alveolar infection, activation of
innate immune mechanisms, dysregulation of ACE2 protein expression, and
marked adaptive antiviral immune responses could contribute to extensive
pulmonary immunothrombosis without a clinically evident MAS (panel).
Will this translate into differential effectiveness, if any, of
immunosuppressive therapy between the MAS-like subgroup of patients and
individuals without MAS? Ultimately, the tropism of COVID-19 for type II
pneumocytes, along with evidence for extensive microvascular thrombosis
during a global pandemic in patients without natural immunity, suggests
an explanation for the increased cardiovascular mortality that has been
recognised for some time in other settings of respiratory infection. We
believe that this pulmonary intravascular coagulopathy, or pulmonary
immunovascular coagulopathy, is the best explanation for the COVID-19
pneumonia risk factors for poor survival (eg, cardiovascular disease) in
the present scenario, in which little evidence exists for systemic
viraemia early in the COVID-19 disease course.
We
searched PubMed using the search terms “COVID-19 pneumonia”,
“SARS-CoV-2”, “SARS” and “pulmonary thrombosis”, “embolism”. We also
searched for D-dimer, fibrinogen, creatine kinase “CK“, and troponin and
reviewed publications that reported data on these parameters. We also
searched for articles on immunothrombosis and cytokines. We limited our
search to articles that were published in English between Dec 22, 2019,
and April 22, 2020.
Contributors
DM
and CB developed the initial concepts for this Viewpoint. JSO and KS
contributed to first draft writing. DM and CB wrote the final draft. DM,
CB, and JSO did the literature review and critically revised the
Viewpoint. KS made the figures. JSO and KS edited the Viewpoint. PE
edited and approved the final draft. All authors have participated
sufficiently in this work, take public responsibility for the content,
and have made substantial contributions to this research. This
manuscript has not been submitted to another journal and has not been
published in whole, or in part, elsewhere previously.
Declaration of interests
DM
has received honoraria and grant funding from Novartis and Sobi, and
honoraria from Roche. All other authors declare no competing interests.
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