COVID-19: towards understanding of pathogenesis

Since the end of 2019, COVID-19 has caused considerable mortality and morbidity worldwide, and become a priority of the global society. Better understanding the pathogenesis of COVID-19 will provide important insight into its management. The pandemic of coronavirus disease 2019 (COVID-19) is spreading rapidly. Although the cause was quickly identified as a new coronavirus named SARS-CoV-2, our knowledge of this novel virus remains very limited. High infectivity of the virus, lack of effective antivirals and vaccines, and potentially large asymptomatic populations, have made management of COVID19 extremely challenging. In addition to rapid medical responses, continuous efforts to better understand the pathogenesis of this disease will undoubtedly enlighten the optimal management of the growing pandemic. SARS-CoV-2 belongs to the β-coronavirus family, and is partially related with the known SARS-CoV (~79% similarity) and MERS-CoV (~50% similarity) according to genome sequencing. Same as SARS-CoV, SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as its main receptor, which is broadly expressed in vascular endothelium, respiratory epithelium, alveolar monocytes, and macrophages. The main transmission route is through direct or indirect respiratory tract exposure. Of note, SARS-CoV-2 is capable of active replication in the upper respiratory tissues, as demonstrated by successful live virus isolation from throat swabs and detection of viral subgenomic messenger RNA (sgRNA) in cells of upper respiratory tract. Tropism of the upper respiratory tissue probably explains continuous pharyngeal shedding of the virus and a more efficient transmission of SARS-CoV-2 than SARS-CoV when symptoms are still minimal and restricted to the upper respiratory tract. Later in the disease course, COVID-19 resembles SARS in terms of viral replication in the lower respiratory tract, and generates secondary viremia, followed by extensive attack against target organs that express ACE2, such as heart, kidney, gastrointestinal tract and vast distal vasculature. This process of viral spreading correlates with the clinical deterioration, mainly taking place around the second week following disease onset. However, it has been generally recognized that disease exaggeration till the late stage is not only attributed to direct viral damage, but also a consequence of immune-mediated injury induced by SARS-CoV-2. Of note, two distinctive features have been noticed in severe and critical patients with COVID-19, progressive increase of inflammation and an unusual trend of hypercoagulation. Although the concept of inflammatory storm remains controversial, there is no doubt that immune-mediated inflammation plays an important role in the pathogenesis of COVID-19, just as it did in SARS. The progression of COVID-19 was associated with a continuous decrease in lymphocyte count and significant elevation of neutrophils. Meanwhile, inflammatory markers were markedly elevated including C-reactive protein, ferritin, interleukin (IL)-6, IP-10, MCP1, MIP1A, and TNFα. Reduced lymphocyte count and elevated levels of ferritin, IL-6 and D-dimer were reported in various studies to be associated with increased mortality of COVID-19. Mechanisms underlying the progressive lymphopenia in severe and critical COVID-19 patients remain unclear. Subset analysis showed a general decrease in B cells, T cells, and natural killer (NK) cells, which was more prominent in severe cases. Xu et al. reported increased level of CD8 T-cell activation (measured by proportions of CD38 and HLA-DR expression) despite the reduction in CD8 T-cell count in one critically ill COVID-19 patient. Lymphopenia was also an important feature of SARS patients, and decline of both CD4 and CD8 T lymphocytes often preceded the radiographic changes. Although direct infection of macrophages and lymphocytes by SARS-CoV was indicated by one study, rapid reduction of lymphocyte counts in SARS was further attributed to two mechanisms, redistribution of the circulating lymphocytes or depletion of lymphocytes through apoptosis or pyroptosis. Currently, no viral gene expression has been observed in peripheral blood mononuclear cells (PBMCs) of patients with COVID-19. However, Wang et al. indicated that T lymphocytes may be more permissive to SARS-CoV-2 than to SARS-CoV, possibly through an endocytosis pathway triggered by the spike protein. As ACE2 is not readily expressed on lymphocytes, the efficiency of membrane fusion and to what extent this may account for the overall loss of lymphocytes remain to be elucidated. Moreover, Xiong et al. reported upregulation of apoptosis, autophagy, and p53 pathways in PBMCs of COVID-19 patients. Zheng et al. suggested functional exhaustion of NK and CD8 T cells with increased expression of NKG2A in COVID-19 patients, which could be restored after recovery. These findings indicated that immune disturbance starts early in COVID-19, as a combined result of both direct and bystander effects. Although current observations revealed that these changes might be largely reversible, especially in mild or moderate cases, long-term followup is warranted for further evaluation of the immune function in recovered patients. We and others have noticed an exceptionally high proportion of aberrant coagulation in severe and critical patients with COVID-19. This was rare for other coronavirus infections, but has been reported in severe influenza. COVID-19 patients exhibited a hypercoagulable state, featured by prolonged prothrombin time, elevated levels of D-dimer and fibrinogen, and near normal activated partial thromboplastin time. A few patients would finally progress to overt disseminated intravascular coagulation (DIC). Tang et al. reported that 71.4% of non-survivors and 0.6% of survivors of COVID-19 showed evidence of overt DIC. Indeed, more patients exhibited latent DIC characterized by a hypercoagulable state, as demonstrated by fibrin thrombus formation in