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, the clinicians 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, these physicians 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. They 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, they believe they can provide inputs and guide directions for basic research at this moment.

After the research, on the basis of observations from COVID-19 patients, they 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. 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.