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1.
Sci Rep ; 11(1): 9609, 2021 05 05.
Article in English | MEDLINE | ID: covidwho-1217711

ABSTRACT

The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the defining global health emergency of this century. GC-376 is a Mpro inhibitor with antiviral activity against SARS-CoV-2 in vitro. Using the K18-hACE2 mouse model, the in vivo antiviral efficacy of GC-376 against SARS-CoV-2 was evaluated. GC-376 treatment was not toxic in K18-hACE2 mice. Overall outcome of clinical symptoms and survival upon SARS-CoV-2 challenge were not improved in mice treated with GC-376 compared to controls. The treatment with GC-376 slightly improved survival from 0 to 20% in mice challenged with a high virus dose at 105 TCID50/mouse. Most notably, GC-376 treatment led to milder tissue lesions, reduced viral loads, fewer presence of viral antigen, and reduced inflammation in comparison to vehicle-treated controls in mice challenged with a low virus dose at 103 TCID50/mouse. This was particularly the case in the brain where a 5-log reduction in viral titers was observed in GC-376 treated mice compared to vehicle controls. This study supports the notion that GC-376 represents a promising lead candidate for further development to treat SARS-CoV-2 infection and that the K18-hACE2 mouse model is suitable to study antiviral therapies against SARS-CoV-2.

2.
Journal of Genetics and Genomics ; 2021.
Article | WHO COVID | ID: covidwho-1213358

ABSTRACT

Gut microbial dysbiosis has been linked to many noncommunicable diseases However, little is known about specific gut microbiota composition and its correlated metabolites associated with molecular signatures underlying host response to infection Here we describe the construction of a proteomic risk score based on 20 blood proteomic biomarkers which have recently been identified as molecular signatures predicting the progression of the COVID-19 We demonstrate that in our cohort of 990 healthy individuals without infection, this proteomic risk score is positively associated with proinflammatory cytokines mainly among older, but not younger, individuals We further discover that a core set of gut microbiota can accurately predict the above proteomic biomarkers among 301 individuals using a machine learning model and that these gut microbiota features are highly correlated with proinflammatory cytokines in another independent set of 366 individuals Fecal metabolomics analysis suggests potential amino acid-related pathways linking gut microbiota to host metabolism and inflammation Overall, our multi-omics analyses suggest that gut microbiota composition and function are closely related with inflammation and molecular signatures of host response to infection among healthy individuals These results may provide novel insights into the cross-talk between gut microbiota and host immune system

3.
J Med Chem ; 2021 Apr 23.
Article in English | MEDLINE | ID: covidwho-1199254

ABSTRACT

The main protease (Mpro) of SARS-CoV-2 is a validated antiviral drug target. Several Mpro inhibitors have been reported with potent enzymatic inhibition and cellular antiviral activity, including GC376, boceprevir, calpain inhibitors II, and XII, with each containing a reactive warhead that covalently modifies the catalytic Cys145. Coupling structure-based drug design with the one-pot Ugi four-component reaction, we discovered one of the most potent noncovalent inhibitors, 23R (Jun8-76-3A) that is structurally distinct from the canonical Mpro inhibitor GC376. Significantly, 23R is highly selective compared with covalent inhibitors such as GC376, especially toward host proteases. The cocrystal structure of SARS-CoV-2 Mpro with 23R revealed a previously unexplored binding site located in between the S2 and S4 pockets. Overall, this study discovered 23R, one of the most potent and selective noncovalent SARS-CoV-2 Mpro inhibitors reported to date, and a novel binding pocket in Mpro that can be explored for inhibitor design.

4.
J Med Virol ; 93(5): 2908-2917, 2021 05.
Article in English | MEDLINE | ID: covidwho-1196524

ABSTRACT

The aim is to explore the relation between inflammation-associated factors and in-hospital mortality and investigate which factor is an independent predictor of in-hospital death in patients with coronavirus disease-2019. This study included patients with coronavirus disease-2019, who were hospitalized between February 9, 2020, and March 30, 2020. Univariate Cox regression analysis and least absolute shrinkage and selection operator regression (LASSO) were used to select variables. Multivariate Cox regression analysis was applied to identify independent risk factors in coronavirus disease-2019. A total of 1135 patients were analyzed during the study period. A total of 35 variables were considered to be risk factors after the univariate regression analysis of the clinical characteristics and laboratory parameters (p < .05), and LASSO regression analysis screened out seven risk factors for further study. The six independent risk factors revealed by multivariate Cox regression were myoglobin (HR, 5.353; 95% CI, 2.633-10.882; p < .001), C-reactive protein (HR, 2.063; 95% CI, 1.036-4.109; p = .039), neutrophil count (HR, 2.015; 95% CI, 1.154-3.518; p = .014), interleukin 6 (Il-6; HR, 9.753; 95% CI, 2.952-32.218; p < .001), age (HR, 2.016; 95% CI, 1.077-3.773; p = .028), and international normalized ratio (HR, 2.595; 95% CI, 1.412-4.769; p = .002). Our results suggested that inflammation-associated factors were significantly associated with in-hospital mortality in coronavirus disease-2019 patients. C-reactive protein, neutrophil count, and interleukin 6 were independent factors for predicting in-hospital mortality and had a better independent predictive ability. We believe these findings may allow early identification of the patients at high risk for death, and can also assist in better management of these patients.


Subject(s)
/mortality , Hospitalization/statistics & numerical data , Inflammation/blood , Aged , Aged, 80 and over , Biomarkers/blood , /diagnosis , Female , Hospital Mortality , Humans , Male , Middle Aged , ROC Curve , Retrospective Studies , Risk Factors , Survival Rate
5.
Protein Cell ; 2021 Apr 17.
Article in English | MEDLINE | ID: covidwho-1188202

ABSTRACT

A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease (PLpro). Together with main protease (Mpro), PLpro is responsible for processing the viral replicase polyprotein into functional units. Therefore, it is an attractive target for antiviral drug development. Here we discovered four compounds, YM155, cryptotanshinone, tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC50 values ranging from 1.39 to 5.63 µmol/L. These compounds also exhibit strong antiviral activities in cell-based assays. YM155, an anticancer drug candidate in clinical trials, has the most potent antiviral activity with an EC50 value of 170 nmol/L. In addition, we have determined the crystal structures of this enzyme and its complex with YM155, revealing a unique binding mode. YM155 simultaneously targets three "hot" spots on PLpro, including the substrate-binding pocket, the interferon stimulating gene product 15 (ISG15) binding site and zinc finger motif. Our results demonstrate the efficacy of this screening and repurposing strategy, which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments.

6.
Frontiers in Cardiovascular Medicine ; 8, 2021.
Article | WHO COVID | ID: covidwho-1158347

ABSTRACT

Recent evidence indicates that a large proportion of deaths from coronavirus disease 2019 (COVID-19) can be attributed to cardiovascular disease, including acute myocardial infarction, arrhythmias and heart failure Indeed, severe infection increases the risk of heart failure among patients with COVID-19 In most patients, heart failure arises from complex interactions between pre-existing conditions, cardiac injury, renin-angiotensin system activation, and the effects of systemic inflammation on the cardiovascular system In this review, we summarize current knowledge regarding pathogen-driven heart failure occurring during treatment for COVID-19, the potential effects of commonly used cardiovascular and anti-infective drugs in these patients, and possible directions for establishing a theoretical basis for clinical treatment

7.
Applied Energy ; 291:116789, 2021.
Article | WHO COVID | ID: covidwho-1141609

ABSTRACT

Trombe wall is a simple and mature passive solar building design while its utilization of solar energy is limited to space heating Aerosol transmission, as a potential transmission pathway of COVID-19, poses a serious threat to the public health especially in a closed indoor environment The thermal disinfection of virus, which can be easily integrated into solar systems, seems to be a suitable method for controlling bioaerosols Therefore, a novel disinfected Trombe wall for virus inactivation and space heating is proposed, providing a potential way to fight the current COVID-19 pandemic After the proposal of the concept, its performance on space heating and virus inactivation was investigated through experimental and simulation methods The main results were as follows: (1) The average thermal efficiency was 0 457 and the average indoor temperature was 20 7 ℃, 1 9 ℃ higher than the ambient temperature (2) The maximum single-pass inactivation ratio was 0 893, 0 591 and 0 893 while the total production of clean air was 112 3, 63 8 and 114 7 m3 for SARS-CoV-1, SARS-CoV-2 and MERS-CoV, respectively (3) The increase of ambient temperature or solar irradiance may enhance the thermal efficiency while the former has little effect on the thermal disinfection process (4) Extending the height or narrowing the thickness of the duct by 40% may contribute to an increase in total production of clean air by 510 m3 or 681 m3 per unit area during the heating seasons, but the later may cause a larger decrease (about 8%) in the heat gain of indoor air

8.
World J Gastroenterol ; 27(9): 835-853, 2021 Mar 07.
Article in English | MEDLINE | ID: covidwho-1138767

ABSTRACT

BACKGROUND: Liver injury is common and also can be fatal, particularly in severe or critical patients with coronavirus disease 2019 (COVID-19). AIM: To conduct an in-depth investigation into the risk factors for liver injury and into the effective measures to prevent subsequent mortality risk. METHODS: A retrospective cohort study was performed on 440 consecutive patients with relatively severe COVID-19 between January 28 and March 9, 2020 at Tongji Hospital, Wuhan, China. Data on clinical features, laboratory parameters, medications, and prognosis were collected. RESULTS: COVID-19-associated liver injury more frequently occurred in patients aged ≥ 65 years, female patients, or those with other comorbidities, decreased lymphocyte count, or elevated D-dimer or serum ferritin (P < 0.05). The disease severity of COVID-19 was an independent risk factor for liver injury (severe patients: Odds ratio [OR] = 2.86, 95% confidence interval [CI]: 1.78-4.59; critical patients: OR = 13.44, 95%CI: 7.21-25.97). The elevated levels of on-admission aspartate aminotransferase and total bilirubin indicated an increased mortality risk (P < 0.001). Using intravenous nutrition or antibiotics increased the risk of COVID-19-associated liver injury. Hepatoprotective drugs tended to be of assistance to treat the liver injury and improve the prognosis of patients with COVID-19-associated liver injury. CONCLUSION: More intensive monitoring of aspartate aminotransferase or total bilirubin is recommended for COVID-19 patients, especially patients aged ≥ 65 years, female patients, or those with other comorbidities. Drug hepatotoxicity of antibiotics and intravenous nutrition should be alert for COVID-19 patients.


Subject(s)
/complications , Liver Diseases/virology , Adult , Aged , Aged, 80 and over , /physiopathology , China/epidemiology , Female , Follow-Up Studies , Humans , Liver Diseases/diagnosis , Liver Diseases/mortality , Liver Diseases/physiopathology , Male , Middle Aged , Prognosis , Retrospective Studies , Risk Factors , Survival Analysis
9.
Gut Microbes ; 13(1): 1-21, 2021.
Article in English | MEDLINE | ID: covidwho-1121345

ABSTRACT

SARS-CoV-2 is the cause of the current global pandemic of COVID-19; this virus infects multiple organs, such as the lungs and gastrointestinal tract. The microbiome in these organs, including the bacteriome and virome, responds to infection and might also influence disease progression and treatment outcome. In a cohort of 13 COVID-19 patients in Beijing, China, we observed that the gut virome and bacteriome in the COVID-19 patients were notably different from those of five healthy controls. We identified a bacterial dysbiosis signature by observing reduced diversity and viral shifts in patients, and among the patients, the bacterial/viral compositions were different between patients of different severities, although these differences are not entirely distinguishable from the effect of antibiotics. Severe cases of COVID-19 exhibited a greater abundance of opportunistic pathogens but were depleted for butyrate-producing groups of bacteria compared with mild to moderate cases. We replicated our findings in a mouse COVID-19 model, confirmed virome differences and bacteriome dysbiosis due to SARS-CoV-2 infection, and observed that immune/infection-related genes were differentially expressed in gut epithelial cells during infection, possibly explaining the virome and bacteriome dynamics. Our results suggest that the components of the microbiome, including the bacteriome and virome, are affected by SARS-CoV-2 infections, while their compositional signatures could reflect or even contribute to disease severity and recovery processes.


Subject(s)
/microbiology , Dysbiosis/diagnosis , Gastrointestinal Microbiome , Adolescent , Adult , Aged , Aged, 80 and over , Animals , Anti-Bacterial Agents/therapeutic use , Case-Control Studies , China , Disease Models, Animal , Female , Genome, Viral , Humans , Male , Mice , Mice, Inbred C57BL , MicroRNAs , Middle Aged , Transcriptome
10.
Sci Rep ; 11(1): 5148, 2021 03 04.
Article in English | MEDLINE | ID: covidwho-1117663

ABSTRACT

This study aimed to clarify and provide clinical evidence for which computed tomography (CT) assessment method can more appropriately reflect lung lesion burden of the COVID-19 pneumonia. A total of 244 COVID-19 patients were recruited from three local hospitals. All the patients were assigned to mild, common and severe types. Semi-quantitative assessment methods, e.g., lobar-, segmental-based CT scores and opacity-weighted score, and quantitative assessment method, i.e., lesion volume quantification, were applied to quantify the lung lesions. All four assessment methods had high inter-rater agreements. At the group level, the lesion load in severe type patients was consistently observed to be significantly higher than that in common type in the applications of four assessment methods (all the p < 0.001). In discriminating severe from common patients at the individual level, results for lobe-based, segment-based and opacity-weighted assessments had high true positives while the quantitative lesion volume had high true negatives. In conclusion, both semi-quantitative and quantitative methods have excellent repeatability in measuring inflammatory lesions, and can well distinguish between common type and severe type patients. Lobe-based CT score is fast, readily clinically available, and has a high sensitivity in identifying severe type patients. It is suggested to be a prioritized method for assessing the burden of lung lesions in COVID-19 patients.


Subject(s)
/diagnostic imaging , Lung/diagnostic imaging , Radiography, Thoracic/methods , Tomography, X-Ray Computed/methods , Adult , Age Factors , Female , Humans , Male , Middle Aged , Retrospective Studies , Severity of Illness Index
11.
ACS Infect Dis ; 7(3): 586-597, 2021 03 12.
Article in English | MEDLINE | ID: covidwho-1108883

ABSTRACT

As the COVID-19 pandemic continues to unfold, the morbidity and mortality are increasing daily. Effective treatment for SARS-CoV-2 is urgently needed. We recently discovered four SARS-CoV-2 main protease (Mpro) inhibitors including boceprevir, calpain inhibitors II and XII, and GC-376 with potent antiviral activity against infectious SARS-CoV-2 in cell culture. In this study, we further characterized the mechanism of action of these four compounds using the SARS-CoV-2 pseudovirus neutralization assay. It was found that GC-376 and calpain inhibitors II and XII have a dual mechanism of action by inhibiting both viral Mpro and host cathepsin L in Vero cells. To rule out the cell-type dependent effect, the antiviral activity of these four compounds against SARS-CoV-2 was also confirmed in type 2 transmembrane serine protease-expressing Caco-2 cells using the viral yield reduction assay. In addition, we found that these four compounds have broad-spectrum antiviral activity in inhibiting not only SARS-CoV-2 but also SARS-CoV, and MERS-CoV, as well as human coronaviruses (CoVs) 229E, OC43, and NL63. The mechanism of action is through targeting the viral Mpro, which was supported by the thermal shift-binding assay and enzymatic fluorescence resonance energy transfer assay. We further showed that these four compounds have additive antiviral effect when combined with remdesivir. Altogether, these results suggest that boceprevir, calpain inhibitors II and XII, and GC-376 might be promising starting points for further development against existing human coronaviruses as well as future emerging CoVs.


Subject(s)
Antiviral Agents/pharmacology , Carbonates/pharmacology , Glycoproteins/pharmacology , Leucine/pharmacology , Oligopeptides/pharmacology , Proline/analogs & derivatives , Sulfonic Acids/pharmacology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , Caco-2 Cells , Cathepsin L/antagonists & inhibitors , Cell Line , Chlorocebus aethiops , Coronavirus 229E, Human/drug effects , Coronavirus NL63, Human/drug effects , Coronavirus OC43, Human/drug effects , Drug Combinations , HEK293 Cells , Humans , Middle East Respiratory Syndrome Coronavirus/drug effects , Proline/pharmacology , Serine Endopeptidases/metabolism , Vero Cells
12.
Journal of Global Health ; 10(2), 2020.
Article in English | WHO COVID | ID: covidwho-1106365

ABSTRACT

Background: To prevent the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), strict control of person-to-person transmission is essential Family transmission is the most common route of transmission;however, family transmission patterns and outcomes are not well understood

13.
Journal of the Korean Medical Association / Taehan Uisa Hyophoe Chi ; 64(2):152-158, 2021.
Article in Korean | WHO COVID | ID: covidwho-1094303

ABSTRACT

Amid the coronavirus disease 2019 (COVID-19) crisis, the core functions of an acute care hospital are to continuously provide essential clinical care services to patients from community at large The dual track healthcare system (DTHS) is a strategy for preventing the hospital infection and allocating the resources of an acute care hospital to treat COVID-19 patients while simultaneously providing indispensable clinical care services for non-COVID-19 patients The key elements of DTHS include compartmentalizing the space within independent buildings, allocating buffer zones for patients who have not been confirmed for COVID-19 infection but require inpatient treatment, delegating manpower with appropriate support, establishing competent in-house laboratory that enables universal COVID-19 screening via reverse transcriptase polymerase chain reaction and employing real-time communication technology The effectiveness of DTHS was confirmed through the results of questionnaire surveys of hospital patients and the research on the qualitative and quantitative changes in the provision of fundamental care services including both acute and continuous clinical care after the care for COVID-19 patients in the hospital With a potential for subsequent explosive community infections, the pandemic public health crisis rendered by COVID-19 will be prolonged Therefore, each acute care hospital should prepare its measures and strategies to mimic the DTHS for the maintenance of the hospital's core functions in anticipation of a revisit of the situation

15.
IEEE J Biomed Health Inform ; 25(5): 1336-1346, 2021 05.
Article in English | MEDLINE | ID: covidwho-1075741

ABSTRACT

Coronavirus disease 2019 (COVID-19) is one of the most destructive pandemic after millennium, forcing the world to tackle a health crisis. Automated lung infections classification using chest X-ray (CXR) images could strengthen diagnostic capability when handling COVID-19. However, classifying COVID-19 from pneumonia cases using CXR image is a difficult task because of shared spatial characteristics, high feature variation and contrast diversity between cases. Moreover, massive data collection is impractical for a newly emerged disease, which limited the performance of data thirsty deep learning models. To address these challenges, Multiscale Attention Guided deep network with Soft Distance regularization (MAG-SD) is proposed to automatically classify COVID-19 from pneumonia CXR images. In MAG-SD, MA-Net is used to produce prediction vector and attention from multiscale feature maps. To improve the robustness of trained model and relieve the shortage of training data, attention guided augmentations along with a soft distance regularization are posed, which aims at generating meaningful augmentations and reduce noise. Our multiscale attention model achieves better classification performance on our pneumonia CXR image dataset. Plentiful experiments are proposed for MAG-SD which demonstrates its unique advantage in pneumonia classification over cutting-edge models. The code is available at https://github.com/JasonLeeGHub/MAG-SD.

16.
Emerg Microbes Infect ; 10(1): 317-330, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1075417

ABSTRACT

Coronavirus disease 2019 (COVID-19) is an ongoing pandemic that lacks effective therapeutic interventions. SARS-CoV-2 infects ACE2-expressing cells and gains cell entry through either direct plasma membrane fusion or endocytosis. Recent studies have shown that in addition to ACE2, heparan sulfate proteoglycans (HSPGs) also play an important role in SARS-CoV-2 cell attachment by serving as an attachment factor. Binding of viral spike protein to HSPGs leads to the enrichment of local concentration for the subsequent specific binding with ACE2. We therefore hypothesize that blocking the interactions between viral spike protein and the HSPGs will lead to inhibition of viral replication. In this study, we report our findings of the broad-spectrum antiviral activity and the mechanism of action of lactoferrin (LF) against multiple common human coronaviruses as well as SARS-CoV-2. Our study has shown that LF has broad-spectrum antiviral activity against SARS-CoV-2, HCoV-OC43, HCoV-NL63, and HCoV-229E in cell culture, and bovine lactoferrin (BLF) is more potent than human lactoferrin. Mechanistic studies revealed that BLF binds to HSPGs, thereby blocking viral attachment to the host cell. The antiviral activity of BLF can be antagonized by the HSPG mimetic heparin. Combination therapy experiment showed that the antiviral activity of LF is synergistic with remdesivir in cell culture. Molecular modelling suggests that the N-terminal positively charged region in BLF (residues 17-41) confers the binding to HSPGs. Overall, LF appears to be a promising drug candidate for COVID-19 that warrants further investigation.


Subject(s)
/antagonists & inhibitors , Antiviral Agents/pharmacology , Coronavirus/drug effects , Heparan Sulfate Proteoglycans/metabolism , Lactoferrin/pharmacology , /drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , Cattle , Cell Line , Cells, Cultured , Drug Delivery Systems , Drug Synergism , Heparin/metabolism , Humans , Microbial Sensitivity Tests , Virus Attachment/drug effects
17.
Free Radic Biol Med ; 163: 153-162, 2021 02 01.
Article in English | MEDLINE | ID: covidwho-1065088

ABSTRACT

Nitric oxide (NO) is a free radical playing an important pathophysiological role in cardiovascular and immune systems. Recent studies reported that NO levels were significantly lower in patients with COVID-19, which was suggested to be closely related to vascular dysfunction and immune inflammation among them. In this review, we examine the potential role of NO during SARS-CoV-2 infection from the perspective of the unique physical, chemical and biological properties and potential mechanisms of NO in COVID-19, as well as possible therapeutic strategies using inhaled NO. We also discuss the limits of NO treatment, and the future application of this approach in prevention and therapy of COVID-19.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Anticoagulants/therapeutic use , Antiviral Agents/therapeutic use , Lung/drug effects , Nitric Oxide/therapeutic use , Administration, Inhalation , Anti-Inflammatory Agents/blood , Anticoagulants/blood , Antiviral Agents/blood , /pathology , Endothelial Cells/drug effects , Endothelial Cells/pathology , Endothelial Cells/virology , Humans , Inflammation , Lung/blood supply , Lung/virology , Mitochondria/drug effects , Mitochondria/virology , Nitric Oxide/blood , /pathogenicity , Severity of Illness Index , Vasodilation/drug effects
18.
Front Med ; 15(2): 252-263, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1053070

ABSTRACT

An unexpected observation among the COVID-19 pandemic is that smokers constituted only 1.4%-18.5% of hospitalized adults, calling for an urgent investigation to determine the role of smoking in SARS-CoV-2 infection. Here, we show that cigarette smoke extract (CSE) and carcinogen benzo(a)pyrene (BaP) increase ACE2 mRNA but trigger ACE2 protein catabolism. BaP induces an aryl hydrocarbon receptor (AhR)-dependent upregulation of the ubiquitin E3 ligase Skp2 for ACE2 ubiquitination. ACE2 in lung tissues of non-smokers is higher than in smokers, consistent with the findings that tobacco carcinogens downregulate ACE2 in mice. Tobacco carcinogens inhibit SARS-CoV-2 spike protein pseudovirions infection of the cells. Given that tobacco smoke accounts for 8 million deaths including 2.1 million cancer deaths annually and Skp2 is an oncoprotein, tobacco use should not be recommended and cessation plan should be prepared for smokers in COVID-19 pandemic.


Subject(s)
Pandemics , Adult , Animals , Epithelial Cells , Humans , Lung , Mice , Peptidyl-Dipeptidase A , Spike Glycoprotein, Coronavirus , Ubiquitin-Protein Ligases/genetics
20.
Chest ; 159(5): 1793-1802, 2021 05.
Article in English | MEDLINE | ID: covidwho-1046526

ABSTRACT

BACKGROUND: Corticosteroid therapy is used commonly in patients with COVID-19, although its impact on outcomes and which patients could benefit from corticosteroid therapy are uncertain. RESEARCH QUESTION: Are clinical phenotypes of COVID-19 associated with differential response to corticosteroid therapy? STUDY DESIGN AND METHODS: Critically ill patients with COVID-19 from Tongji Hospital treated between January and February 2020 were included, and the main exposure of interest was the administration of IV corticosteroids. The primary outcome was 28-day mortality. Marginal structural modeling was used to account for baseline and time-dependent confounders. An unsupervised machine learning approach was carried out to identify phenotypes of COVID-19. RESULTS: A total of 428 patients were included; 280 of 428 patients (65.4%) received corticosteroid therapy. The 28-day mortality was significantly higher in patients who received corticosteroid therapy than in those who did not (53.9% vs 19.6%; P < .0001). After marginal structural modeling, corticosteroid therapy was not associated significantly with 28-day mortality (hazard ratio [HR], 0.80; 95% CI, 0.54-1.18; P = .26). Our analysis identified two phenotypes of COVID-19, and compared with the hypoinflammatory phenotype, the hyperinflammatory phenotype was characterized by elevated levels of proinflammatory cytokines, higher Sequential Organ Failure Assessment scores, and higher rates of complications. Corticosteroid therapy was associated with a reduced 28-day mortality (HR, 0.45; 95% CI, 0.25-0.80; P = .0062) in patients with the hyperinflammatory phenotype. INTERPRETATION: For critically ill patients with COVID-19, corticosteroid therapy was not associated with 28-day mortality, but the use of corticosteroids showed significant survival benefits in patients with the hyperinflammatory phenotype.

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