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 . 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. 1 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 2 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, 3 but SARS-CoV-2 infection appeared to be the sole cause in most of them. 1 Blood and lower respiratory tract specimen cultures turned out to be negative for bacteria and fungus in 76% sepsis patients in a COVID-19 cohort. 4 Therefore, viral sepsis would be more accurate to describe the clinical manifestations of severe or critically ill COVID-19 patients. 5 Understanding the mechanism of viral sepsis in COVID-19 is warranted for exploring better clinical care for these patients.
In biopsy or autopsy studies, pulmonary pathology for both early 6 and late phase 7 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. 8, 9 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. 8, 9 SARS-CoV-2 infectious virus particles have been isolated from respiratory samples, 10 as well as from faecal 11 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 dissemin ation 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) 12, 13 and organs with L-SIGN 14 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 obser ved, and the difference in the virulence needs further investigation. 15
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 chemo attractant protein-1, and macrophage inflam matory proteins 1-α were signifi cantly elevated in COVID-19 patients. 16, 17 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 recog nition receptors (including the Toll-like receptors TLR3, TLR7, and TLR8), retinoic acid-inducible gene I, and the NOD-like receptor family members. 18 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. Further more, 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 neutrophilmediated viral clearance, as one study revealed that IL-6 or IL-6R deficiency led to persistence of influenza infection and ultimately death in mice. 19 And the use of corticosteroids is still controversial. 20, 21 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. 4 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. 17 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, 22, 23 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, 24, 25 and SARS-CoV-2 RNA was also detected in blood samples. 16 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, 26 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. 13 Whether or not alveolar macrophages can phagocytise the viral particles and then transfer to lymphocytes is an open question in the field.
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) 27 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. 4 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, 13 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. 28 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, 29 although others argued that ACE inhibitors might enhance viral entry by regulating ACE2 levels. 30 However, there has been little clinical evidence on the risk of treating COVID-19 patients with ARB or ACE inhi bitors. Further research is needed to explore whether these drugs inhibit or aid viral entry.
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 epithelialendothelial (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 patho genesis 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.
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.
We declare no competing interests.