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.
Virus infection and COVID-19 pathogenesis in organs
In biopsy or autopsy studies, pulmonary pathology for both early and late phase 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. SARS-CoV-2 infectious virus particles have been isolated from respiratory samples, as well as from faecal
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) and organs with L-SIGN 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.
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
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.
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