Since
the outbreak of coronavirus disease 2019 (COVID-19), clinicians have
tried every effort to understand the disease, and a brief portrait of
its clinical features have been identified. In clinical practice, we
noticed that many severe or critically ill COVID-19 patients developed
typical clinical manifestations of shock, including cold extremities and
weak peripheral pulses, even in the absence of overt hypotension.
Understanding the mechanism of viral sepsis in COVID-19 is warranted for
exploring better clinical care for these patients. With evidence
collected from autopsy studies on COVID-19 and basic science research on
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and
SARS-CoV, we have put forward several hypotheses about SARS-CoV-2
pathogenesis after multiple rounds of discussion among basic science
researchers, pathologists, and clinicians working on COVID-19. We
hypothesise that a process called viral sepsis is crucial to the disease
mechanism of COVID-19. Although these ideas might be proven imperfect
or even wrong later, we believe they can provide inputs and guide
directions for basic research at this moment.
The
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak,
which was first reported in Wuhan, China, in December, 2019, has had an
enormous impact on China and the whole world. The disease caused by
SARS-CoV-2 is named coronavirus disease 2019 (COVID-19). By March 19,
2020, the number of confirmed cases had increased to over 200 000.
Although most patients infected with SARS-CoV-2 had a mild illness,
about 5% of patients had severe lung injury or even multiorgan
dysfunction, resulting in a 1·4% case fatality ratio.
In
clinical practice, we noticed that many severe or critically ill
COVID-19 patients developed typical clinical manifestations of shock,
including cold extremities and weak peripheral pulses, even in the
absence of overt hypotension. Many of these patients showed severe
metabolic acidosis, indicating possible microcirculation dysfunction.
Moreover, some patients had impaired liver
and kidney function in addition to severe lung injury. These patients
met the diagnostic criteria for sepsis and septic shock according to the
Sepsis-3 International Consensus,
COVID-19 patients showed diffuse alveolar damage with the formation of
hyaline membranes, mononuclear cells, and macrophages infiltrating air
spaces, and a diffuse thickening of the alveolar wall. Viral particles
were observed in the bronchial and type 2 alveolar epithelial cells by
electron microscopy.
In addition, spleen atrophy, hilar lymph node necrosis, focal
haemorrhage in the kidney, enlarged liver with inflammatory cell
infiltration, oedema, and scattered degeneration of the neurons in the
brain were present in some patients.
and urine (Zhao J, Guangzhou Medical University, personal
communication) specimens from COVID-19 patients, suggesting that
multiple organ dysfunction in severe COVID-19 patients is at least
partially caused by a direct attack from the virus. However, there are
no reports about the post-mortem observations of the broad dissemination
of the viral particles by autopsy right now. Whether SARS-CoV-2 can
directly target organs other than the lung, especially those organs with
high expression of angiotensin-converting enzyme 2 (ACE2)
as possible alternative cell receptors for SARS-CoV-2, has to be
further investigated. In addition, the question of how the SARS-CoV-2
spreads to extrapulmonary organs remains an enigma. Genomic variation of
the circulating SARS-CoV-2 has been observed, and the difference in the
virulence needs further investigation.
It
has been shown that proinflammatory cytokines and chemokines including
tumour necrosis factor (TNF) α, interleukin 1β (IL-1β), IL-6,
granulocyte-colony stimulating factor, interferon gamma-induced
protein-10, monocyte chemoattractant protein-1, and macrophage
inflammatory proteins 1-α were significantly elevated in COVID-19
patients.
Like in a severe influenza infection, the cytokine storm might play an
important role in the immunopathology of COVID-19. Previous studies
revealed that lung epithelial cells, macrophages, and dendritic cells
all express cytokines to some extent during influenza infection via the
activation of pattern recognition receptors (including the Toll-like
receptors TLR3, TLR7, and TLR8), retinoic acid-inducible gene I, and the
NOD-like receptor family members.
However, little is known about the situation in COVID-19 at this
moment. It is crucial to identify the primary source of the cytokine
storm in response to SARS-CoV-2 infection and the virological mechanisms
behind the cytokine storm. It would also be relevant to elucidate the
kinetics of cytokine activation during SARS-CoV-2 infection: when were
the first cytokines released and what were they? Also, whether direct
virus-induced tissue damage, systemic cytokine storm, or the synergistic
effects of both, contributes to the multiple organ dysfunction of
severe COVID-19 patients remains to be addressed. Furthermore, it is
worth keeping track of whether blocking one of these proinflammatory
mediators would affect the clinical outcome. The anti-IL-6R monoclonal
antibody or corticosteroids have been proposed to alleviate the
inflammatory response. However, IL-6 might play an important role in
initiating a preliminary response against virus infection by promoting
neutrophil-mediated viral clearance, as one study revealed that IL-6 or
IL-6R deficiency led to persistence of influenza infection and
ultimately death in mice.
Yet
the dysregulated immune response also has an immune suppression stage
following the proinflammatory phase. It is characterised by sustained
and substantial reduction of the peripheral lymphocyte counts, mainly
CD4 T and CD8 T cells in COVID-19 patients, and is associated with a
high risk of developing secondary bacterial infection.
This condition, known as lymphopenia, was also found in severe
influenza and other respiratory viral infections. The degree of
lymphopenia has been shown to correlate with the severity of COVID-19.
The mechanism underlying lymphopenia remains unknown. Previous studies
have shown that SARS-like viral particles and SARS-CoV RNA were detected
in T lymphocytes isolated from peripheral blood sample, spleen, lymph
nodes, and lymphoid tissue of various organs,
suggesting that SARS-CoV might be able to infect T cells directly. The
receptor-binding domains of the spike proteins between SARS-CoV-2 and
SARS-CoV show a high degree of consistency,
Therefore, it is reasonable to hypothesise that, in addition to the
activation-induced cell death induced by Fas and Fas ligand interaction
as well as TNF-related apoptosis-inducing ligand axis,
SARS-CoV-2 could directly infect lymphocytes, particularly T cells, and
initiate or promote the cell death of lymphocytes, which eventually
lead to lymphopenia and impaired antiviral responses. However, such a
hypothesis needs to be further investigated. It also needs to be
identified what types of cell death are happening in the lymphocytes
after SARS-CoV-2 infection. In addition, it is intriguing that the
lymphocytes lack ACE2 expression, suggesting an alternative mechanism by
which SARS-CoV-2 compromises T lymphocytes.
Whether or not alveolar macrophages can phagocytise the viral particles
and then transfer to lymphocytes is an open question in the field.
COVID-19 and abnormal coagulation
Studies
have revealed that 71·4% of non-survivors of COVID-19 matched the grade
of overt disseminated intravascular coagulation (≥5 points according to
the International Society on Thrombosis and Haemostasis criteria)
and showed abnormal coagulation results during later stages of the
disease; particularly increased concentrations of D-dimer and other
fibrin degradation products were significantly associated with poor
prognosis.
However, the concrete mechanisms for coagulopathy are not identified
yet. Whether SARS-CoV-2 is able to directly attack vascular endothelial
cells expressing high levels of ACE2,
and then lead to abnormal coagulation and sepsis, still needs to be
explored. Meanwhile, ACE2 is also an important regulator of blood
pressure. High expression of ACE2 in the circulatory system after
infection of SARS-CoV-2 might partially contribute to septic
hypotension.
Questions have been raised about using inhibitor therapy with
angiotensin II receptor blockers (ARB) and ACE inhibitors for COVID-19
patients with hypertension. Some researchers suggested that ACE
inhibitors might benefit these patients by reducing pulmonary
inflammation,
However, there has been little clinical evidence on the risk of
treating COVID-19 patients with ARB or ACE inhibitors. Further research
is needed to explore whether these drugs inhibit or aid viral entry.
Conclusion
On
the basis of observations from COVID-19 patients, we hypothesise that
in mild cases, resident macrophages initiating lung inflammatory
responses were able to contain the virus after SARS-CoV-2 infection;
both innate and adaptive immune responses were efficiently established
to curb the viral replication so that the patient would recover quickly.
However, in severe or critical COVID-19 cases, the integrity of the
epithelial–endothelial (air–blood) barrier was severely interrupted. In
addition to epithelial cells, SARS-CoV-2 can also attack lung capillary
endothelial cells, which leads to a large amount of plasma component
exudate in the alveolar cavity. In response to the infection of
SARS-CoV-2, alveolar macrophages or epithelial cells could produce
various proinflammatory cytokines and chemokines. Upon this change,
monocytes and neutrophils were then chemotactic to the infection site to
clear these exudates with virus particles and infected cells, resulting
in uncontrolled inflammation. In this process, because of the
substantial reduction and dysfunction of lymphocytes, the adaptive
immune response cannot be effectively initiated. The uncontrolled virus
infection leads to more macrophage infiltration and a further worsening
of lung injury. Meanwhile, the direct attack on other organs by
disseminated SARS-CoV-2, the immune pathogenesis caused by the systemic
cytokine storm, and the microcirculation dysfunctions together lead to
viral sepsis (figure).
Therefore, effective antiviral therapy and measures to modulate the
innate immune response and restore the adaptive immune response are
essential for breaking the vicious cycle and improving the outcome of
the patients.
FigureOccurrence and outcome of severe acute respiratory syndrome coronavirus 2 viral sepsis
Since
the outbreak of COVID-19, clinicians have tried every effort to
understand the disease, and a brief portrait of its clinical features
have been identified. However, there are still open questions about the
mechanisms of the observations. With evidence collected from autopsy
studies on COVID-19 and basic science research on SARS-CoV-2 and
SARS-CoV, we have put forward several hypotheses about SARS-CoV-2
pathogenesis after multiple rounds of discussion among basic science
researchers, pathologists, and clinicians working on COVID-19. We
hypothesise that a process called viral sepsis is crucial to the disease
mechanism of COVID-19. Although these ideas might be proven imperfect
or even wrong later on, we believe that they raise questions for future
research.
Future basic science
research is needed to explore whether SARS-CoV-2 directly attacks
vascular endothelial cells, and to examine the effect of SARS-CoV-2 on
coagulation and virus dissemination. Clinical trials and animal
experiments should be done to assess the effect of ARB and ACE
inhibitors on the outcome of SARS-CoV-2 infection in vivo. Efforts
should be made to confirm whether SARS-CoV-2 directly infects
lymphocytes, and how it influences the adaptive immune response. The
kinetics of the cytokine response during SARS-CoV-2 infection also need
further investigation. The efficacy of immunomodulatory therapies should
be assessed in randomised clinical trials.
Contributors
HL
did the literature search and drafted the paper. JX helped with the
literature search and revised the manuscript. BC put forward the
hypothesis and revised the manuscript. LL, DZ, JX, HD, NT, and XS
provided ideas about the mechanism of viral sepsis and revised the
paper.
Declaration of interests
We declare no competing interests.
Acknowledgments
We appreciate the advice and editing of this Hypothesis by Xuetao Cao in Nankai University.
30920-X&id=gr1.jpg){kind=link}
No hay comentarios:
Publicar un comentario