In this study, we retrospectively analyzed the early clinical manifestations of 300 hospitalized COVID-19 patients. The main impressions of the early clinical manifestations are that there is no sex bias in the incidence; that rare upper respiratory symptoms, age and the lymphocyte counts relate to disease severity, peripheral pulmonary involvement and lymphopenia; and that multisystem damage occurs in some moderately ill patients without hypoxia. Although many papers have been published recently, the concrete pathogenesis of COVID-19 has not yet been identified. What could we learn from the early clinical features of COVID-19? Clinical features provide many clues for pathogenesis.
The mode of transmission of the virus is thought to be largely by inhalation of respiratory droplets. Did the virus in the affected lung lesion come from airway spread? Although the nasopharynx mucosa was believed as first infected with SARS-CoV-2, the symptoms involving the upper respiratory tract occur less often, which is consistent with previous reports [7, 11–13] and indicates that the upper respiratory tract inflammation was mild. Moreover, the distribution of lung lesions was characterized by subpleural and lateral zones in the early stage, which suggested that the infection did not spread along the airway. Transmission of SARS-CoV-2 through contaminated surfaces might be possible , while aerosols are currently not considered the primary mode of transmission . The above points suggested that the lung lesion may be infected as a result of SARS-CoV-2 moving along lymphatics or blood vessels, as well as invading other target tissues. We propose that the virus might pass through the mucous membranes of the nasal passages, larynx or skin and then enter the blood, causing viremia. The virus attacks the targets, including the lungs and T lymphocytes. It is very interesting to find that the virus could be detected in the upper respiratory tract with no symptoms and mild inflammation within the bronchi and bronchioles, along with prominent mucosal edema within the bronchial mucosa . It seems that the upper respiratory tract, trachea, bronchi and bronchioles were not the targets of the virus, although their mucous membrane expressed angiotensin converting enzyme II (ACE2).
The early pathogenesis of COVID-19 is still unclear. The primary cells affected by SARS-CoV-2 may be both alveolar cells and T lymphocytes. Apoptosis could be the main early event. The first evidence comes from clinical studies. The lymphocyte count is negatively related to disease severity and is commonly considered a marker of prognosis [2, 17, 18]. This phenomenon also suggests that alveolar cells and T lymphocytes are both targets of SARS-CoV-2, and the T lymphocytes count could reflect the alveolar cell counts. The main evidence should be derived from the histopathologic features: diffuse alveolar damage (DAD)  and T-lymphocyte apoptosis in lymphoid organs, especially the spleen [20, 21]. This is similar to MERS-CoV that can efficiently infect T cells from the peripheral blood and from human lymphoid organs and induce apoptosis in T cells, which involves the activation of both the extrinsic and intrinsic apoptosis pathways . The number of CD4-positive T cells and CD8-positive T cells in the spleen and lymph nodes decreased, they were degenerated and necrotic, and macrophages proliferated in the spleen.
The immune response may explain the early clinical manifestations. The initial symptoms are mainly fever, cough, andlymphopenia. Increased values of liver enzymes, lactate dehydrogenase (LDH), muscle enzymes, coagulation factors and C-reactive protein can be found in some mildly ill patients without hypoxia in the early stage, which means that these abnormal changes were not secondary damage from hypoxia or secondary infection. The possible pathogenesis may be damage from the virus directly or by immune response. The possibility of an immune response should be greater than the direct invasion of the virus. The most direct evidence is the result of autopsy. No SARS-CoV-2 was detected in the heart, liver, kidney, spleen, pancreas, or gastrointestinal tract by immunohistochemistry and PCR . Transcriptome sequencing of RNA isolated from bronchoalveolar lavage fluid (BALF) and peripheral blood mononuclear cell (PBMC) specimens of COVID-19 patients revealed distinct host inflammatory cytokine profiles to SARS-CoV-2 infection in patients and highlighted the association between COVID-19 pathogenesis and excessive cytokine release, such as that of CCL2/MCP-1, CXCL10/IP-10, CCL3/MIP-1A, and CCL4/MIP1B .
It has also been hypothesized that the virus might use ACE2 as a receptor, similar to SARS-CoV . ACE2 is also expressed on many different cell types, including cardiac, renal, intestinal, endothelial, and gut cells [26, 27]. As no virus was found in these tissues , the receptor for SARS-CoV-2 has not been fully elucidated. SARS-CoV-2 may use ACE2 for entry and the serine protease TMPRSS2 for S protein priming .
Our study has several limitations inherent to its design. First, this was a retrospective study with the potential of incomplete and possible variation of data recording from the primary care providers. Second, patients with mild disease were not included. Third, much larger cohorts are needed.
COVID-19 is a new disease, our knowledge is gradually updated based on the ongoing research findings and clinical practice experience. The current study is a start to our understanding of the clinical presentation and spectrum of the disease for greater precision of estimates and an initial step to performing prognostic and risk factor analyses. It was expected that the human-to-human transmission toxicity of COVID-19 would be reduced  because a genetic bottleneck of RNA viruses often occurs in the process of respiratory droplet transmission; however, the real world scenario is still serious. The spread of COVID-19 could not be stopped.