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1.
J Clin Invest ; 132(4)2022 Feb 15.
Article in English | MEDLINE | ID: covidwho-1705312

ABSTRACT

Many SARS-CoV-2 neutralizing antibodies (nAbs) lose potency against variants of concern. In this study, we developed 2 strategies to produce mutation-resistant antibodies. First, a yeast library expressing mutant receptor binding domains (RBDs) of the spike protein was utilized to screen for potent nAbs that are least susceptible to viral escape. Among the candidate antibodies, P5-22 displayed ultrahigh potency for virus neutralization as well as an outstanding mutation resistance profile. Additionally, P14-44 and P15-16 were recognized as mutation-resistant antibodies with broad betacoronavirus neutralization properties. P15-16 has only 1 binding hotspot, which is K378 in the RBD of SARS-CoV-2. The crystal structure of the P5-22, P14-44, and RBD ternary complex clarified the unique mechanisms that underlie the excellent mutation resistance profiles of these antibodies. Secondly, polymeric IgG enhanced antibody avidity by eliminating P5-22's only hotspot, residue F486 in the RBD, thereby potently blocking cell entry by mutant viruses. Structural and functional analyses of antibodies screened using both potency assays and the yeast RBD library revealed rare, ultrapotent, mutation-resistant nAbs against SARS-CoV-2.


Subject(s)
Antibodies, Viral/immunology , Broadly Neutralizing Antibodies/immunology , COVID-19/immunology , COVID-19/virology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Animals , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/genetics , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/genetics , Antibody Affinity , B-Lymphocytes/immunology , Binding Sites/genetics , Binding Sites/immunology , Broadly Neutralizing Antibodies/blood , Broadly Neutralizing Antibodies/genetics , COVID-19/therapy , Cloning, Molecular , Disease Models, Animal , Humans , Immunization, Passive , Immunoglobulin G/immunology , In Vitro Techniques , Lung/virology , Mice , Mice, Inbred BALB C , Mutation , Neutralization Tests , Receptors, Virus/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
2.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-325143

ABSTRACT

Objectives: Although the respiratory and immune systems are the major targets of SARS-CoV-2, increasing evidence revealed that kidney injury was not rare in coronavirus disease 2019 (COVID-19). However, the incidences of kidney abnormalities were significantly different, from 0.5 to 75.4% in several reports. The association of kidney injury with prognosis remain controversial. Methods: : In this retrospective single center cohort study, laboratory confirmedCOVID-19inpatients with severe type were enrolled. Demographic, clinicaland laboratory data were collected. Association ofserum creatinine (SCr)with 28-days mortality in severe COVID-19 patients was analyzed. Results: : 18.79% (48/304) patients died during the first 28-days of hospitalization.Non-survivors had a significantly higher SCr levels than survivors (109.27μmol/L vs. 69.99μmol/L, P <0.001). The 28-days mortality in high SCr group (>76μmol/L) was significantly higher than that in low SCr group (31.7% vs. 7.5%, P <0.001). Multivariate logistic regression revealed that the independent risk factors of 28-days outcome included age(OR: 2.95, 95%CI: 1.08-8.05), WBC (OR: 6.09, 95%CI: 2.27-6.39), lymphopenia (OR: 3.49, 95%CI: 1.55-7.92), IL-6 (OR: 4.44, 95%CI: 1.64-11.99) and SCr (OR: 2.69, 95%CI: 1.18-6.11). Kaplan-Meier analysis demonstrated the survival disadvantage in patients with high SCr levels (>76μmol/L). ROC curve showed the SCr cut-off value for predicting 28-days death was 77.5 μmol/L, with the sensitivity of 68.8% and speciality of 74.1%. Conclusion: SCr was associated with poor prognosis and might be an independent risk factor for in-hospital death. The cut-off value of SCr for prognosis prediction was 77.5 μmol/L, with the sensitivity of 68.8% and speciality of 74.1%.

3.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-325142

ABSTRACT

Background: The 2019 novel coronavirus disease (COVID-19) spread in many countries.Data about viral shedding duration, particularly the prolonged ones of the pathogen SARS-Coronavirus-2 (SARS-CoV-2) is scarce. The longest viral RNA sheddingduration reported previously was 37 days. Herein, we report the clinical and immunologic features ofrecovered COVID-19cases with a medium viral RNA shedding duration of 44 days. Cases presentation: Nine laboratory-confirmed COVID-19 cases from Wuhan with viral RNA shedding duration more than 30 days were included in our study,5 of them were moderate.Althoughinflammatory markers were significantlyhigher, the medium duration in severepatients was similar to that in moderate patients (44.5days vs. 43.6days). Severepatients showed higher NK cells levels, although the T cells and B cells were lower as compared with moderate patients. Contrary to previous reports in influenza, prolonged viralshedding time did not cause poor prognosis in this study. Conclusions: : There could be characteristic immunological dysfunction in COVID-19 patients with prolonged viral shedding durationand interestingly, prolonged viral shedding duration seemed not to be related with poor prognosis.

4.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-310860

ABSTRACT

Background: Coronavirus disease 2019 (COVID-19) is a current global pandemic. However, impact of recent influenza A virus infection on the clinical course and outcomes of severe COVID-19 adult inpatients needs to be further explored. Methods: : In this retrospective cohort study, severe, laboratory confirmed COVID-19 adult patients from Wuhan Tongji Hospital were included. Data were obtained from electronic medical records and compared between patients with and without recent influenza A virus infection. Results: : 200 patients were included, 51.5% with recent influenza A virus infection. Recent influenza A virus infection group presented with longer persistence of cough and sputum from illness onset (35.0 vs. 27.0 days, P = 0.018) and (33.0 vs. 26.0 days, P = 0.015), respectively. Median time of progression to critical illness from illness onset was shorter (day 11.5 vs. day 16.0, P = 0.034). Time to clinical improvement and length of hospital stay were longer in recent infection group (23.0 vs. 19.0 days, P = 0.044) and (22.0 vs. 18.0 days, P = 0.030), respectively. Conclusions: : Patients with recent influenza A virus infection showed a delay in time to clinical improvement and increased length of hospital stay. There is a high clinical need to improve the detection of common respiratory pathogens to identify co-infection during the epidemic of COVID-19.

5.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-309018

ABSTRACT

Background: Coronavirus Disease 2019 (COVID-19) is currently a global pandemic. Information about the death predicting of severe COVID-19 is not clear. Methods: : 151 in-patients from January 23th to March 8th 2020 were divided into severe and critically severe group, as well as survival and death group. The analysis of differences of clinical and imaging data were performed between groups. The logistic regression analysis of factors associated with death in COVID-19 were conducted, and the prediction model of death risk was developed. Results: : Many clinical and imaging indices were significantly different between groups, including the age, the epidemic history, the past medical history, the duration of symptoms prior to admission, blood routine, inflammatory related factors, Na + , myocardial zymogram, liver and renal function, coagulation function, fraction of inspired oxygen and complications. The proportion of patients in imaging stage III and comprehensive CT scores was increased significantly in death group. The area under receiver operating characteristic curve of the prediction model was 0.9593. Conclusions: : The clinical and imaging data reflect the severity of COVID-19 pneumonia. The prediction model of death risk might be a promising method to help clinicians to quickly identify and screen potential individuals who had a high-risk of death.

6.
Virol J ; 18(1): 117, 2021 06 04.
Article in English | MEDLINE | ID: covidwho-1259206

ABSTRACT

BACKGROUND: To date, specific cytokines associated with development of acute respiratory distress syndrome (ARDS) and extrapulmonary multiple organ dysfunction (MOD) in COVID-19 patients have not been systematically described. We determined the levels of inflammatory cytokines in patients with COVID-19 and their relationships with ARDS and extrapulmonary MOD. METHODS: The clinical and laboratory data of 94 COVID-19 patients with and without ARDS were analyzed. The levels of inflammatory cytokines (interleukin 6 [IL-6], IL-8, IL-10, and tumor necrosis factor α [TNF-α]) were measured on days 1, 3, and 5 following admission. Seventeen healthy volunteers were recruited as controls. Correlations in the levels of inflammatory cytokines with clinical and laboratory variables were analyzed, furthermore, we also explored the relationships of different cytokines with ARDS and extrapulmonary MOD. RESULTS: The ARDS group had higher serum levels of all 4 inflammatory cytokines than the controls, and these levels steadily increased after admission. The ARDS group also had higher levels of IL-6, IL-8, and IL-10 than the non-ARDS group, and the levels of these cytokines correlated significantly with coagulation parameters and disseminated intravascular coagulation (DIC). The levels of IL-6 and TNF-α correlated with the levels of creatinine and urea nitrogen, and were also higher in ARDS patients with acute kidney injury (AKI). All 4 inflammatory cytokines had negative correlations with PaO2/FiO2. IL-6, IL-8, and TNF-α had positive correlations with the APACHE-II score. Relative to survivors, non-survivors had higher levels of IL-6 and IL-10 at admission, and increasing levels over time. CONCLUSIONS: The cytokine storm apparently contributed to the development of ARDS and extrapulmonary MOD in COVID-19 patients. The levels of IL-6, IL-8, and IL-10 correlated with DIC, and the levels of IL-6 and TNF-α were associated with AKI. Relative to survivors, patients who died within 28 days had increased levels of IL-6 and IL-10.


Subject(s)
COVID-19/blood , Cytokine Release Syndrome/blood , Cytokines/blood , Respiratory Distress Syndrome/blood , Acute Kidney Injury/diagnosis , Aged , Blood Urea Nitrogen , COVID-19/pathology , Creatinine/blood , Cytokine Release Syndrome/diagnosis , Disseminated Intravascular Coagulation/blood , Disseminated Intravascular Coagulation/pathology , Female , Humans , Interleukin-10/blood , Interleukin-6/blood , Interleukin-8/blood , Male , Respiratory Distress Syndrome/pathology , Retrospective Studies , SARS-CoV-2 , Tumor Necrosis Factor-alpha/blood
7.
Chin Med J (Engl) ; 133(12): 1390-1396, 2020 Jun 20.
Article in English | MEDLINE | ID: covidwho-1050186

ABSTRACT

BACKGROUND: Critical patients with the coronavirus disease 2019 (COVID-19), even those whose nucleic acid test results had turned negative and those receiving maximal medical support, have been noted to progress to irreversible fatal respiratory failure. Lung transplantation (LT) as the sole therapy for end-stage pulmonary fibrosis related to acute respiratory distress syndrome has been considered as the ultimate rescue therapy for these patients. METHODS: From February 10 to March 10, 2020, three male patients were urgently assessed and listed for transplantation. After conducting a full ethical review and after obtaining assent from the family of the patients, we performed three LT procedures for COVID-19 patients with illness durations of more than one month and extremely high sequential organ failure assessment scores. RESULTS: Two of the three recipients survived post-LT and started participating in a rehabilitation program. Pearls of the LT team collaboration and perioperative logistics were summarized and continually improved. The pathological results of the explanted lungs were concordant with the critical clinical manifestation, and provided insight towards better understanding of the disease. Government health affair systems, virology detection tools, and modern communication technology all play key roles towards the survival of the patients and their rehabilitation. CONCLUSIONS: LT can be performed in end-stage patients with respiratory failure due to COVID-19-related pulmonary fibrosis. If confirmed positive-turned-negative virology status without organ dysfunction that could contraindicate LT, LT provided the final option for these patients to avoid certain death, with proper protection of transplant surgeons and medical staffs. By ensuring instant seamless care for both patients and medical teams, the goal of reducing the mortality rate and salvaging the lives of patients with COVID-19 can be attained.


Subject(s)
Betacoronavirus , Coronavirus Infections/complications , Lung Transplantation/methods , Pneumonia, Viral/complications , Pulmonary Fibrosis/surgery , Respiratory Distress Syndrome/surgery , Aged , COVID-19 , Coronavirus Infections/mortality , Extracorporeal Membrane Oxygenation , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/mortality , Pulmonary Fibrosis/mortality , Respiratory Distress Syndrome/mortality , SARS-CoV-2
8.
EBioMedicine ; 62: 103125, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-938894

ABSTRACT

BACKGROUND: The pharmacokinetics and appropriate dose regimens of favipiravir are unknown in hospitalized influenza patients; such data are also needed to determine dosage selection for favipiravir trials in COVID-19. METHODS: In this dose-escalating study, favipiravir pharmacokinetics and tolerability were assessed in critically ill influenza patients. Participants received one of two dosing regimens; Japan licensed dose (1600 mg BID on day 1 and 600 mg BID on the following days) and the higher dose (1800 mg/800 mg BID) trialed in uncomplicated influenza. The primary pharmacokinetic endpoint was the proportion of patients with a minimum observed plasma trough concentration (Ctrough) ≥20 mg/L at all measured time points after the second dose. RESULTS: Sixteen patients were enrolled into the low dose group and 19 patients into the high dose group of the study. Favipiravir Ctrough decreased significantly over time in both groups (p <0.01). Relative to day 2 (48 hrs), concentrations were 91.7% and 90.3% lower in the 1600/600 mg group and 79.3% and 89.5% lower in the 1800/800 mg group at day 7 and 10, respectively. In contrast, oseltamivir concentrations did not change significantly over time. A 2-compartment disposition model with first-order absorption and elimination described the observed favipiravir concentration-time data well. Modeling demonstrated that less than 50% of patients achieved Ctrough ≥20 mg/L for >80% of the duration of treatment of the two dose regimens evaluated (18.8% and 42.1% of patients for low and high dose regimen, respectively). Increasing the favipravir dosage predicted a higher proportion of patients reaching this threshold of 20 mg/L, suggesting that dosing regimens of ≥3600/2600 mg might be required for adequate concentrations. The two dosing regimens were well-tolerated in critical ill patients with influenza. CONCLUSION: The two dosing regimens proposed for uncomplicated influenza did not achieve our pre-defined treatment threshold.


Subject(s)
Amides , Influenza, Human/drug therapy , Oseltamivir , Pyrazines , Aged , Amides/administration & dosage , Amides/pharmacokinetics , Drug Therapy, Combination , Female , Humans , Influenza, Human/blood , Male , Middle Aged , Oseltamivir/administration & dosage , Oseltamivir/pharmacokinetics , Pyrazines/administration & dosage , Pyrazines/pharmacokinetics , Severity of Illness Index
9.
Am J Ther ; 2020 Jun 01.
Article in English | MEDLINE | ID: covidwho-189006
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