ABSTRACT
BACKGROUND: Coronavirus disease 2019 (COVID-19) is a global pandemic that has caused more than 600 million cases and over six million deaths worldwide. Despite the availability of vaccination, COVID-19 cases continue to grow making pharmacological interventions essential. Remdesivir (RDV) is an FDA-approved antiviral drug for treatment of both hospitalized and non-hospitalized COVID-19 patients, albeit with potential for hepatotoxicity. This study characterizes the hepatotoxicity of RDV and its interaction with dexamethasone (DEX), a corticosteroid often co-administered with RDV for inpatient treatment of COVID-19. METHODS: Human primary hepatocytes and HepG2 cells were used as in vitro models for toxicity and drug-drug interaction studies. Real-world data from hospitalized COVID-19 patients were analyzed for drug-induced elevation of serum ALT and AST. RESULTS: In cultured hepatocytes, RDV markedly reduced the hepatocyte viability and albumin synthesis, while it increased the cleavage of caspase-8 and caspase-3, phosphorylation of histone H2AX, and release of ALT and AST in a concentration-dependent manner. Importantly, co-treatment with DEX partially reversed RDV-induced cytotoxic responses in human hepatocytes. Moreover, data from COVID-19 patients treated with RDV with and without DEX co-treatment suggested that among 1037 patients matched by propensity score, receiving the drug combination was less likely to result in elevation of serum AST and ALT levels (≥ 3 × ULN) compared to the RDV alone treated patients (OR = 0.44, 95% CI = 0.22-0.92, p = 0.03). CONCLUSION: Our findings obtained from in vitro cell-based experiments and patient data analysis provide evidence suggesting combination of DEX and RDV holds the potential to reduce the likelihood of RDV-induced liver injury in hospitalized COVID-19 patients.
Subject(s)
COVID-19 , Chemical and Drug Induced Liver Injury , Humans , COVID-19 Drug Treatment , Hepatocytes , DexamethasoneABSTRACT
Exhalation of infectious micrometer-sized particles has been strongly implicated in respiratory infection spread. An important fundamental question is then the fate of infectious exhaled particles in indoor spaces, i.e., whether they will remain suspended in an aerosol until ventilation leads to their clearance or whether they will deposit, and if so, on what surfaces in an indoor space. We investigated the interplay between deposition and ventilation using model experiments with a breathing simulator manikin in an office environment. The breathing simulator utilized physiologically correct exhalation and inhalation breathing waveforms as well as an anatomically correct manikin. The simulator output fluorescein-doped particles with a volume distribution spanning the 1-3 um range. The office environment was a 344 m3 room equipped with desks. Four different test conditions were created by changing the simulator location and via different air change rates and MERV ratings of filters in the HVAC system. We found that the rate of ventilation exceeds the rate of deposition on all surfaces (quantified by Stanton numbers, which were below unity) with several important exceptions: (1) surfaces close to (within 2 m) the simulator;and (2) non-passive surface exteriors (return grilles and diffusers). A detectable decrease in Stanton number with distance suggests that the room environment cannot be approximated as truly well-mixed. The finding of enhanced deposition on non-passive surfaces at all distances from the room highlights that infectious particles may preferentially deposit on such surfaces in indoor spaces. Finally, while our results highlight particular surfaces with enhanced deposition, our results confirm the importance of ventilation in a room as a means to reduce infectious aerosol particle concentrations, as in large part the clearance for particles appears to occur by ventilation.
ABSTRACT
In indoor environments with limited ventilation, recirculating portable air filtration (PAF) units may reduce COVID-19 infection risk via not only the direct aerosol route (i.e., inhalation) but also via an indirect aerosol route (i.e., contact with the surface where aerosol particles deposited). We systematically investigated the impact of PAF units in a mock classroom, as a supplement to background ventilation, on localized and whole-room surface deposition and particle concentration. Fluorescently tagged particles with a volumetric mean diameter near 2 μm were continuously introduced into the classroom environment via a breathing simulator with a prescribed inhalation–exhalation waveform. Deposition velocities were inferred on >50 horizontal and vertical surfaces throughout the classroom, while aerosol concentrations were spatially monitored via optical particle spectrometry. Results revealed a particle decay rate consistent with expectations based upon the reported clean air delivery rates of the PAF units. Additionally, the PAF units reduced peak concentrations by a factor of around 2.5 compared to the highest concentrations observed and led to a statistically significant reduction in deposition velocities for horizontal surfaces >2.5 m from the aerosol source. Our results not only confirm that PAF units can reduce particle concentrations but also demonstrate that they may lead to reduced particle deposition throughout an indoor environment when properly positioned with respect to the location of the particle source(s) within the room (e.g., where the largest group of students sit) and the predominant air distribution profile of the room.
ABSTRACT
Pseudoviruses are viral particles coated with a heterologous envelope protein, which mediates the entry of pseudoviruses as efficiently as that of the live viruses possessing high pathogenicity and infectivity. Due to the deletion of the envelope protein gene and the absence of pathogenic genes, pseudoviruses have no autonomous replication ability and can infect host cells for only a single cycle. In addition, pseudoviruses have the desired characteristics of high safety, strong operability, and can be easily used to perform rapid throughput detection. Therefore, pseudoviruses are widely employed in the mechanistic investigation of viral infection, the screening and evaluation of monoclonal antibodies and antiviral drugs, and the detection of neutralizing antibody titers in serum after vaccination. In this review, we will discuss the construction of pseudoviruses based on different packaging systems, their current applications especially in the research of SARS-CoV-2, limitations, and further directions.