Graphical abstractDipyridamole bound to the SARS-CoV-2 protease Mpro after identified via the virtual screening and bioassay validation, and thus suppressed viral replication in vitro. As a result, dipyridamole supplementation was associated with significantly decreased concentrations of D-dimers, increased lymphocyte and platelet recovery in the circulation, and markedly improved clinical outcomes in comparison to the control patients.Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause acute respiratory distress syndrome, hypercoagulability, hypertension, and multiorgan dysfunction.Effective antivirals with safe clinical profile are urgently needed to improve the overall prognosis. In an analysis of a randomly collected cohort of 124 patients with Corona Virus Disease 2019 , we found that hypercoagulability as indicated by elevated concentrations of D-dimers was associated with disease severity. By virtual screening of a U.S. Food and Drug Administration (FDA) approved drug library, we identified an anticoagulation agent dipyridamole (DIP) in silico, which suppressed SARS-CoV-2 replication in vitro. In a proof-of-concept trial involving 31 patients with COVID-19, DIP supplementation was associated with significantly decreased concentrations of D-dimers (P<0.05), increased lymphocyte and platelet recovery in the circulation, and markedly improved clinical outcomes in comparison to the control patients. In particular, all 8 of the DIP-treated severely ill patients showed remarkable improvement: 7 patients (87.5%) achieved clinical cure and were discharged from the hospitals while the remaining 1 patient (12.5%) was in clinical remission.

The human coronavirus HCoV-19 infection can cause acute respiratory distress syndrome 47 (ARDS), hypercoagulability, hypertension, extrapulmonary multiorgan dysfunction. Effective 48 antiviral and anti-coagulation agents with safe clinical profiles are urgently needed to improve the 49 overall prognosis. We screened an FDA approved drug library and found that an anticoagulant agent 50 dipyridamole (DIP) suppressed HCoV-19 replication at an EC50 of 100 nM in vitro. It also elicited 51 potent type I interferon responses and ameliorated lung pathology in a viral pneumonia model. In 52 analysis of twelve HCoV-19 infected patients with prophylactic anti-coagulation therapy, we found 53 that DIP supplementation was associated with significantly increased platelet and lymphocyte counts 54 and decreased D-dimer levels in comparison to control patients. Two weeks after initiation of DIP 55 treatment, 3 of the 6 severe cases (60%) and all 4 of the mild cases (100%) were discharged from the 56 hospital. One critically ill patient with extremely high levels of D-dimer and lymphopenia at the time 57 of receiving DIP passed away. All other patients were in clinical remission. In summary, HCoV-19 58 infected patients could potentially benefit from DIP adjunctive therapy by reducing viral replication, 59 suppressing hypercoagulability and enhancing immune recovery. Larger scale clinical trials of DIP 60 are needed to validate these therapeutic effects.61 62

Background: The pandemic of COVID-19 poses a challenge to global healthcare. The mortality rates of severe cases range from 8.1% to 38%, and it is particularly important to identify risk factors that aggravate the disease. Methods: We performed a systematic review of the literature with meta-analysis, using 7 databases to identify studies reporting on clinical characteristics, comorbidities and complications in severe and non-severe patients with COVID-19. All the observational studies were included. We performed a random or fixed effects model meta-analysis to calculate the pooled proportion and 95% confidence interval (CI). Measure of heterogeneity was estimated by Cochran's Q statistic, I 2 index and P value. Results: A total of 4881 cases from 25 studies related to COVID-19 were included. The most prevalent comorbidity was hypertension (severe: 33.4%, 95% CI: 25.4%–41.4%; non-severe 21.6%, 95% CI: 9.9%–33.3%), followed by diabetes (severe: 14.4%, 95% CI: 11.5%–17.3%; non-severe: 8.5%, 95% CI: 6.1%–11.0%). The prevalence of acute respiratory distress syndrome, acute kidney injury and shock were all higher in severe cases, with 41.1% (95% CI: 14.1%–68.2%), 16.4% (95% CI: 3.4%–29.5%) and 19.9% (95% CI: 5.5%–34.4%), rather than 3.0% (95% CI: 0.6%–5.5%), 2.2% (95% CI: 0.1%–4.2%) and 4.1% (95% CI: −4.8%–13.1%) in non-severe patients, respectively. The death rate was higher in severe cases (30.3%, 95% CI: 13.8%–46.8%) than non-severe cases (1.5%, 95% CI: 0.1%–2.8%). Conclusion: Hypertension, diabetes and cardiovascular diseases may be risk factors for severe COVID-19.