ABSTRACT
IntroductionOn the basis of the preliminary report from the RECOVERY trial, the use of dexamethasone or alternative corticosteroids (CS) is currently recommended in severe COVID-19 patients requiring supplemental oxygen. However, last updated recommendations have not taken a position either for or against the use of other immunomodulators such as tocilizumab (TCZ), with or without CS, since results are still limited. MethodsFrom March 17 to April 7, 2020, a real-world observational retrospective analysis was conducted at our 750-bed university hospital to study the characteristics and risk factors for mortality in patients with severe COVID-19 treated with TCZ +/-CS, in addition to standard of care (SOC). Data were obtained from routine clinical practice, stored in electronic medical records. The main outcome was all-cause in-hospital mortality. ResultsA total of 1,092 COVID-19 patients were admitted during the study period. Of them, 186 (17%) were treated with TCZ, of which 129 (87.8%) in combination with CS. Of the total 186, 155 (83.3 %) patients were receiving non-invasive ventilation when TCZ +/-CS was initiated. Mean time from symptoms onset and hospital admission to TCZ use was 12 ({+/-} 4.3) and 4.3 days ({+/-} 3.4), respectively. Overall, 147 (79%) survived and 39 (21%) died. By multivariate analysis, mortality was associated with older age (HR=1.09, p<0.001), chronic heart failure (HR=4.4, p=0.003), and chronic liver disease (HR=4.69, p=0.004). The use of CS, in combination with TCZ, was the main protective factor against mortality (HR=0.26, p<0.001) in such severe COVID-19 patients receiving TCZ. No serious superinfections were observed after a 30-day follow-up. ConclusionsIn severe COVID-19 patients receiving TCZ due to systemic host-immune inflammatory response syndrome, the use of CS in addition to TCZ therapy, showed beneficial effect in preventing in-hospital mortality.
Subject(s)
COVID-19ABSTRACT
There is an urgent need for anti-viral agents that treat SARS-CoV-2 infection. The shortest path to clinical use is repurposing of drugs that have an established safety profile in humans. Here, we first screened a library of 1,900 clinically safe drugs for inhibiting replication of OC43, a human beta-coronavirus that causes the common-cold and is a relative of SARS-CoV-2, and identified 108 effective drugs. We further evaluated the top 26 hits and determined their ability to inhibit SARS-CoV-2, as well as other pathogenic RNA viruses. 20 of the 26 drugs significantly inhibited SARS-CoV-2 replication in human lung cells (A549 epithelial cell line), with EC50 values ranging from 0.1 to 8 micromolar. We investigated the mechanism of action for these and found that masitinib, a drug originally developed as a tyrosine-kinase inhibitor for cancer treatment, strongly inhibited the activity of the SARS-CoV-2 main protease 3CLpro. X-ray crystallography revealed that masitinib directly binds to the active site of 3CLpro, thereby blocking its enzymatic activity. Mastinib also inhibited the related viral protease of picornaviruses and blocked picornaviruses replication. Thus, our results show that masitinib has broad anti-viral activity against two distinct beta-coronaviruses and multiple picornaviruses that cause human disease and is a strong candidate for clinical trials to treat SARS-CoV-2 infection.
Subject(s)
COVID-19 , NeoplasmsABSTRACT
SARS-CoV-2 enters cells via ACE-2, which binds the spike protein with moderate affinity. Despite a constant background mutational rate, the virus must retain binding with ACE2 for infectivity, providing a conserved constraint for SARS-CoV-2 inhibitors. To prevent mutational escape of SARS-CoV-2 and to prepare for future related coronavirus outbreaks, we engineered a de novo trimeric ACE2 (T-ACE2) protein scaffold that binds the trimeric spike protein with extremely high affinity (KD < 1 pM), while retaining ACE2 native sequence. T-ACE2 potently inhibits all tested pseudotyped viruses including SARS-CoV-2, SARS-CoV, eight naturally occurring SARS-CoV-2 mutants, two SARSr-CoVs as well as authentic SARS-CoV-2. The cryo-EM structure reveals that T-ACE2 can induce the transit of spike protein to "three-up" RBD conformation upon binding. T-ACE2 thus represents a promising class of broadly neutralizing proteins against SARS-CoVs and mutants.
Subject(s)
Severe Acute Respiratory SyndromeABSTRACT
The second half of the Spring 2020 semester has been an unprecedented time globally due to the ongoing coronavirus disease 2019 (COVID-19). COVID-19 pandemic has forced more than one billion students out of school, has disrupted the world and led all university courses switched to online instruction social distancing actions taken to limit the spread of the virus. The aim of the present study is to evaluate the pandemic related changes for undergraduate students, to assess their perspectives related to their learning, experiences in two courses, and to discuss the far-reaching potential implications for the upcoming summer and fall semesters. An electronic survey was conducted to gather data on the student perceptions and learning characteristics of this transition from face-to-face (F2F) to online at a medium-sized university in the Southeast in the Spring 2020 semester. Nearly 88% of the participants indicated that the COVID-19 pandemic impacted their education, while 19% indicated that they prefer online over F2F learning. Furthermore, the online modality significantly increased attendance in General Biology I. Our study also showed that the usage of live conferencing and digital applications increased due to the pandemic. The current research fills the gap in the existing literature by providing the first study on the effects of the ongoing COVID-19 pandemic on undergraduate learning and experiences in the most unique dual modality of the Spring 2020 semester.