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1.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-315248

ABSTRACT

Information with prolonged SARS-CoV-2 shedding among immunocompetent patients is limited. We describe a twice repositive 169-day prolonged SARS-CoV-2 shedding in an immunocompetent patient and explore potential factors from clinical, immunological and genomic perspectives. We found that continuous viral replication and infectivity could exist in an immunocompetent COVID-19 patient with high neutralizing antibody.

2.
Theranostics ; 12(1): 1-17, 2022.
Article in English | MEDLINE | ID: covidwho-1512993

ABSTRACT

Background: Administration of potent anti-receptor-binding domain (RBD) monoclonal antibodies has been shown to curtail viral shedding and reduce hospitalization in patients with SARS-CoV-2 infection. However, the structure-function analysis of potent human anti-RBD monoclonal antibodies and its links to the formulation of antibody cocktails remains largely elusive. Methods: Previously, we isolated a panel of neutralizing anti-RBD monoclonal antibodies from convalescent patients and showed their neutralization efficacy in vitro. Here, we elucidate the mechanism of action of antibodies and dissect antibodies at the epitope level, which leads to a formation of a potent antibody cocktail. Results: We found that representative antibodies which target non-overlapping epitopes are effective against wild type virus and recently emerging variants of concern, whilst being encoded by antibody genes with few somatic mutations. Neutralization is associated with the inhibition of binding of viral RBD to ACE2 and possibly of the subsequent fusion process. Structural analysis of representative antibodies, by cryo-electron microscopy and crystallography, reveals that they have some unique aspects that are of potential value while sharing some features in common with previously reported neutralizing monoclonal antibodies. For instance, one has a common VH 3-53 public variable region yet is unusually resilient to mutation at residue 501 of the RBD. We evaluate the in vivo efficacy of an antibody cocktail consisting of two potent non-competing anti-RBD antibodies in a Syrian hamster model. We demonstrate that the cocktail prevents weight loss, reduces lung viral load and attenuates pulmonary inflammation in hamsters in both prophylactic and therapeutic settings. Although neutralization of one of these antibodies is abrogated by the mutations of variant B.1.351, it is also possible to produce a bi-valent cocktail of antibodies both of which are resilient to variants B.1.1.7, B.1.351 and B.1.617.2. Conclusions: These findings support the up-to-date and rational design of an anti-RBD antibody cocktail as a therapeutic candidate against COVID-19.


Subject(s)
Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/pharmacology , COVID-19/drug therapy , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Monoclonal/metabolism , Antibodies, Neutralizing/chemistry , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/pharmacology , Binding Sites , Binding, Competitive , COVID-19/virology , Cricetinae , Cryoelectron Microscopy , Crystallography, X-Ray , Dogs , Epitopes , Female , Humans , Madin Darby Canine Kidney Cells , Neutralization Tests , Protein Domains , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism
4.
Dis Markers ; 2021: 5598824, 2021.
Article in English | MEDLINE | ID: covidwho-1262420

ABSTRACT

Assessing the length of hospital stay (LOS) in patients with coronavirus disease 2019 (COVID-19) pneumonia is helpful in optimizing the use efficiency of hospital beds and medical resources and relieving medical resource shortages. This retrospective cohort study of 97 patients was conducted at Beijing You'An Hospital between January 21, 2020, and March 21, 2020. A multivariate Cox proportional hazards regression based on the smallest Akaike information criterion value was used to select demographic and clinical variables to construct a nomogram. Discrimination, area under the receiver operating characteristic curve (AUC), calibration, and Kaplan-Meier curves with the log-rank test were used to assess the nomogram model. The median LOS was 13 days (interquartile range [IQR]: 10-18). Age, alanine aminotransferase, pneumonia, platelet count, and PF ratio (PaO2/FiO2) were included in the final model. The C-index of the nomogram was 0.76 (95%confidence interval [CI] = 0.69-0.83), and the AUC was 0.88 (95%CI = 0.82-0.95). The adjusted C-index was 0.75 (95%CI = 0.67-0.82) and adjusted AUC 0.86 (95%CI = 0.73-0.95), both after 1000 bootstrap cross internal validations. A Brier score of 0.11 (95%CI = 0.07-0.15) and adjusted Brier score of 0.130 (95%CI = 0.07-0.20) for the calibration curve showed good agreement. The AUC values for the nomogram at LOS of 10, 20, and 30 days were 0.79 (95%CI = 0.69-0.89), 0.89 (95%CI = 0.83-0.96), and 0.96 (95%CI = 0.92-1.00), respectively, and the high fit score of the nomogram model indicated a high probability of hospital stay. These results confirmed that the nomogram model accurately predicted the LOS of patients with COVID-19. We developed and validated a nomogram that incorporated five independent predictors of LOS. If validated in a future large cohort study, the model may help to optimize discharge strategies and, thus, shorten LOS in patients with COVID-19.


Subject(s)
COVID-19/therapy , Length of Stay , Nomograms , SARS-CoV-2 , Adult , Aged , Female , Humans , Male , Middle Aged , Proportional Hazards Models , Retrospective Studies
5.
Eur J Nutr ; 60(8): 4379-4392, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1245619

ABSTRACT

PURPOSE: Corticosteroid (CS) therapy for infectious and rheumatological diseases showed to decrease serum magnesium (Mg++) level and induce muscle atrophy in patients. The present study investigated the effects of Mg++ supplementation on preventing CS-induced muscle atrophy in an animal model, which provided experimental data for potential clinical translation. METHODS: Twelve 24-week-old male Sprague-Dawley rats were treated with lipopolysaccharide (LPS) and CS methylprednisolone (MPS) to induce muscle atrophy, with half of the rats also given daily 50 mg/kg Mg++ oral supplementation. Additional six rats without LPS + CS treatments were used as normal controls. After treatment for 6 weeks, serum was collected for Mg++ quantification, animal dual-energy X-ray absorptiometry (DXA) was performed for tissue composition, and the extensor digitorum longus (EDL) was collected for muscle functional test and histology including muscle fiber size, intramuscular fat infiltration and fiber typing. In vitro myotube atrophy model was used to study the in vitro effect associated with in vivo muscle atrophy. RESULTS: LPS + CS treatments induced hypomagnesemia while the serum Mg++ level was in normal range after Mg++ supplementation. DXA showed 53.0% lower fat percent and 29.7% higher lean mass in LPS + CS + Mg group when compared to LPS + CS group. Muscle functional test showed 22.2% higher specific twitch force and 40.3% higher specific tetanic force in LPS + CS + Mg group when compared to LPS + CS group. Histological analysis showed 4.1% higher proportion of muscle fibers area to total area and 63.6% lower intramuscular fat infiltration in EDL sections in LPS + CS + Mg group when compared to LPS + CS group. LPS + CS + Mg group had 33.0% higher area proportion and 29.4% higher cross-sectional area (CSA) of type IIb muscle fiber. Myoblast culture results showed that Mg++ supplementation group had larger myotube diameter. The mRNA expressions of the muscle atrophy marker genes MuRF1 and MAFbx were lower in Mg++ supplementation group both in vitro and in vivo. CONCLUSION: The current study demonstrated that Mg++ supplementation successfully alleviated CS-associated muscle atrophy in rats at both functional and morphology levels, indicating a translational potential for patients undergoing CS therapy. This study provided the evidence for the first time that Mg++ supplementation could prevent muscle atrophy-an adverse effect of CS therapy, currently also adopted for treating coronavirus disease 2019 (COVID-19).


Subject(s)
COVID-19 , Magnesium , Adrenal Cortex Hormones , Animals , Dietary Supplements , Disease Models, Animal , Humans , Male , Muscle Fibers, Skeletal , Muscle, Skeletal , Muscular Atrophy/chemically induced , Muscular Atrophy/drug therapy , Rats , Rats, Sprague-Dawley , SARS-CoV-2
6.
J Orthop Translat ; 23: 122-131, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-1026231

ABSTRACT

PURPOSE: The coronavirus disease 2019 (COVID-19) reminds us of the severe acute respiratory syndrome (SARS) outbreak in 2003, and up to date, corticosteroid is commonly administrated to severe patients with COVID-19. Osteonecrosis of the femoral head (ONFH) is a common disabling complication among convalescent SARS patients who received corticosteroid therapy. In China, a considerable number of convalescent SARS patients with steroid-associated ONFH had undergone conservative treatment by traditional Chinese medicine, and this study aims to evaluate the long-term results of a spleen-invigorating Huo-Gu formula (HGF) therapy in these patients. PARTICIPANTS AND METHODS: A total of 33 convalescent SARS patients (9 males and 24 females) with bilateral steroid-associated ONFH (66 hips) were enrolled in this study. All patients received oral HGF therapy for 6 months when they were confirmed the diagnosis of steroid-associated ONFH. They had been regularly followed up at an interval of 1 year. Harris hip score and medical imaging modalities, including plain radiography, computed tomography and magnetic resonance imaging, were performed to evaluate the outcomes. RESULTS: Based on average 14 years of follow-up of HGF therapy (ranging from 6 to 16 years), 38 hips (57%) among the 66 hips developed definite osteoarthritis, and 14 hips (26%) in 53 precollapse hips (Association Research Circulation Osseous [ARCO] Stage I or II) progressed to femoral head collapse (ARCO Stage III or IV). Only five patients (also 5 hips) underwent total hip arthroplasty, and the mean hip survival time was over 15 years by the Kaplan-Meier analysis. We observed a mean Harris hip score of 63 points, which represented the reserve of 55% in pain score and 70% in physical function score. The severity of groin pain was not correlated to the severity of osteoarthritis. CONCLUSION: Chinese herbal HGF therapy demonstrates beneficial effects on preventing femoral head collapse, delaying total hip arthroplasty, and maintaining physical function in the treatment of steroid-associated ONFH. HGF therapy might be therefore a good alternative for the treatment of steroid-associated ONFH secondary to rheumatologic and infection diseases. TRANSLATIONAL POTENTIAL OF THE ARTICLE: HGF therapy might be a good alternative for the treatment of steroid-associated ONFH secondary to rheumatologic and infectious diseases.

8.
Chin. J. Evid.-Based Med. ; 4(20): 373-377, 20200401.
Article in English | WHO COVID, ELSEVIER | ID: covidwho-627125

ABSTRACT

To prevent and control 2019 novel coronavirus pneumonia diseases (COVID-19), hundreds of medical teams and tens of thousands of medical professionals throughout the nation were transferred to Hubei to assist COVID-19 control efforts. Medical professionals were at high risk of novel coronavirus pneumonia infections. To ensure the prevention and control of infection in medical teams and prevent cross-infection among medical staff at the medical station, this management standard includes routine management standards, resident disinfection, personnel entry and exit process, and logistics support management, so as to provide reference for medical teams combating COVID-19 in the future.

9.
Front Cell Infect Microbiol ; 10: 318, 2020.
Article in English | MEDLINE | ID: covidwho-615471

ABSTRACT

Background: A novel enveloped RNA beta coronavirus, Corona Virus Disease 2019 (COVID-19) caused severe and even fetal pneumonia in China and other countries from December 2019. Early detection of severe patients with COVID-19 is of great significance to shorten the disease course and reduce mortality. Methods: We assembled a retrospective cohort of 80 patients (including 56 mild and 24 severe) with COVID-19 infection treated at Beijing You'an Hospital. We used univariable and multivariable logistic regression analyses to select the risk factors of severe and even fetal pneumonia and build scoring system for prediction, which was validated later on in a group of 22 COVID-19 patients. Results: Age, white blood cell count, neutrophil, glomerular filtration rate, and myoglobin were selected by multivariate analysis as candidates of scoring system for prediction of disease severity in COVID-19. The scoring system was applied to calculate the predictive value and found that the percentage of ICU admission (20%, 6/30) and ventilation (16.7%, 5/30) in patients with high risk was much higher than those (2%, 1/50; 2%, 1/50) in patients with low risk (p = 0.009; p = 0.026). The AUC of scoring system was 0.906, sensitivity of prediction is 70.8%, and the specificity is 89.3%. According to scoring system, the probability of patients in high risk group developing severe disease was 20.24 times than that in low risk group. Conclusions: The possibility of severity in COVID-19 infection predicted by scoring system could help patients to receiving different therapy strategies at a very early stage. Topic: COVID-19, severe and fetal pneumonia, logistic regression, scoring system, prediction.


Subject(s)
Coronavirus Infections/epidemiology , Coronavirus Infections/pathology , Pneumonia, Viral/epidemiology , Pneumonia, Viral/pathology , Severity of Illness Index , Aged , Aged, 80 and over , Betacoronavirus/pathogenicity , COVID-19 , China , Comorbidity , Disease Progression , Female , Glomerular Filtration Rate/physiology , Humans , Leukocyte Count , Male , Middle Aged , Myoglobin/analysis , Neutrophil Infiltration/immunology , Neutrophils/immunology , Pandemics , Prognosis , Retrospective Studies , SARS-CoV-2
11.
J Infect Dis ; 222(1): 34-37, 2020 06 16.
Article in English | MEDLINE | ID: covidwho-599711

ABSTRACT

A major unanswered question in the current global coronavirus disease 2019 (COVID-19) outbreak is why severe disease develops in a small minority of infected individuals. In the current article, we report that homozygosity for the C allele of rs12252 in the interferon-induced transmembrane protein 3 (IFITM3) gene is associated with more severe disease in an age-dependent manner. This supports a role for IFITM3 in disease pathogenesis and the opportunity for early targeted intervention in at-risk individuals.


Subject(s)
Alleles , Betacoronavirus/genetics , Coronavirus Infections/genetics , Membrane Proteins/genetics , Pneumonia, Viral/genetics , Polymorphism, Single Nucleotide , RNA-Binding Proteins/genetics , Severity of Illness Index , Adult , Aged , Aged, 80 and over , COVID-19 , Cohort Studies , Coronavirus Infections/virology , Female , Genotype , High-Throughput Nucleotide Sequencing , Homozygote , Hospitalization , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/virology , Real-Time Polymerase Chain Reaction , SARS-CoV-2
12.
JCI Insight ; 5(13)2020 07 09.
Article in English | MEDLINE | ID: covidwho-541270

ABSTRACT

BACKGROUND: Identifying immune correlates of COVID-19 disease severity is an urgent need for clinical management, vaccine evaluation, and drug development. Here, we present a temporal analysis of key immune mediators, cytokines, and chemokines in blood of hospitalized COVID-19 patients from serial sampling and follow-up over 4 weeks. METHODS: A total of 71 patients with laboratory-confirmed COVID-19 admitted to Beijing You'an Hospital in China with either mild (53 patients) or severe (18 patients) disease were enrolled with 18 healthy volunteers. We measured 34 immune mediators, cytokines, and chemokines in peripheral blood every 4-7 days over 1 month per patient using a bioplex multiplex immunoassay. RESULTS: We found that the chemokine RANTES (CCL5) was significantly elevated, from an early stage of the infection, in patients with mild but not severe disease. We also found that early production of inhibitory mediators including IL-10 and IL-1RA were significantly associated with disease severity, and a combination of CCL5, IL-1 receptor antagonist (IL-1RA), and IL-10 at week 1 may predict patient outcomes. The majority of cytokines that are known to be associated with the cytokine storm in virus infections such as IL-6 and IFN-γ were only significantly elevated in the late stage of severe COVID-19 illness. TNF-α and GM-CSF showed no significant differences between severe and mild cases. CONCLUSION: Together, our data suggest that early intervention to increase expression of CCL5 may prevent patients from developing severe illness. Our data also suggest that measurement of levels of CCL5, as well as IL-1RA and IL-10 in blood individually and in combination, might be useful prognostic biomarkers to guide treatment strategies.


Subject(s)
Chemokine CCL5/immunology , Coronavirus Infections/immunology , Interleukin 1 Receptor Antagonist Protein/immunology , Interleukin-10/immunology , Pneumonia, Viral/immunology , Adult , Aged , Betacoronavirus , COVID-19 , Case-Control Studies , Coronavirus Infections/physiopathology , Cytokine Release Syndrome/immunology , Female , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Hospitalization , Humans , Immunoassay , Interferon-gamma/immunology , Interleukin-6/immunology , Longitudinal Studies , Male , Middle Aged , Pandemics , Pneumonia, Viral/physiopathology , SARS-CoV-2 , Severity of Illness Index , Tumor Necrosis Factor-alpha/immunology
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