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1.
BMC Pulm Med ; 21(1): 308, 2021 Sep 28.
Article in English | MEDLINE | ID: covidwho-1439539

ABSTRACT

BACKGROUND: Whether procalcitonin (PCT) or C-reactive protein (CRP) combined with certain clinical characteristics can better distinguish viral from bacterial infections remains unclear. The aim of the study was to assess the ability of PCT or CRP combined with clinical characteristics to distinguish between viral and bacterial infections in hospitalized non-intensive care unit (ICU) adults with lower respiratory tract infection (LRTI). METHODS: This was a post-hoc analysis of a randomized clinical trial previously conducted among LRTI patients. The ability of PCT, CRP and PCT or CRP combined with clinical symptoms to discriminate between viral and bacterial infection were assessed by portraying receiver operating characteristic (ROC) curves among patients with only a viral or a typical bacterial infection. RESULTS: In total, 209 infected patients (viral 69%, bacterial 31%) were included in the study. When using CRP or PCT to discriminate between viral and bacterial LRTI, the optimal cut-off points were 22 mg/L and 0.18 ng/mL, respectively. When the optimal cut-off for CRP (≤ 22 mg/L) or PCT (≤ 0.18 ng/mL) combined with rhinorrhea was used to discriminate viral from bacterial LRTI, the AUCs were 0.81 (95% CI: 0.75-0.87) and 0.80 (95% CI: 0.74-0.86), which was statistically significantly better than when CRP or PCT used alone (p < 0.001). When CRP ≤ 22 mg/L, PCT ≤ 0.18 ng/mL and rhinorrhea were combined, the AUC was 0.86 (95% CI: 0.80-0.91), which was statistically significantly higher than when CRP (≤ 22 mg/L) or PCT (≤ 0.18 ng/mL) was combined with rhinorrhea (p = 0.011 and p = 0.021). CONCLUSIONS: Either CRP ≤ 22 mg/L or PCT ≤ 0.18 ng/mL combined with rhinorrhea could help distinguish viral from bacterial infections in hospitalized non-ICU adults with LRTI. When rhinorrhea was combined together, discrimination ability was further improved.

2.
Am J Respir Crit Care Med ; 2021 Sep 17.
Article in English | MEDLINE | ID: covidwho-1430274

ABSTRACT

RATIONALE: Alteration of human respiratory microbiota had been observed in COVID-19. How the microbiota is associated with the prognosis in COVID-19 is unclear. OBJECTIVES: To characterize the feature and dynamics of the respiratory microbiota and its associations with clinical features in COVID-19 patients. Methods:We conducted metatranscriptome sequencing on 588 longitudinal oropharyngeal swab specimens collected from 192 COVID-19 patients (including 39 deceased patients), and 95 healthy controls from the same geographic area. Meanwhile, the concentration of 27 cytokines and chemokines in plasma was measured for COVID-19 patients. MEASUREMENTS AND MAIN RESULTS: The upper respiratory tract (URT) microbiota in COVID-19 patients differed from that in healthy controls, while deceased patients possessed a more distinct microbiota, both on admission and before discharge/death. The alteration of URT microbiota showed a significant correlation with the concentration of proinflammatory cytokines and mortality. Specifically, Streptococcus-dominated microbiota was enriched in recovered patients, and show high temporal stability and resistance against pathogens. In contrast, the microbiota in deceased patients was more susceptible to secondary infections, and became more deviated from the normality after admission. Moreover, the abundance of S. parasanguinis on admission was significantly correlated with prognosis in non-severe patients (lower vs. higher abundance, odds ratio=7.80, [95% CI 1.70-42.05]). Conclusions:URT microbiota dysbiosis is a remarkable manifestation of COVID-19; its association with mortality suggests it may reflect the interplay between pathogens, symbionts, and the host immune status. Whether URT microbiota could be used as a biomarker for the diagnosis and prognosis of respiratory diseases merits further investigation. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

3.
Clin Infect Dis ; 72(11): e901-e913, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1249298

ABSTRACT

There have been arguments on whether angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) treatment alters the risk of coronavirus disease 2019 (COVID-19) susceptibility and disease severity. We identified a total of 102 eligible studies for systematic review, in which 49 studies adjusting for confounders were included in the meta-analysis. We found no association between prior ACEI/ARB use and risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the general population (adjusted odds ratio [aOR], 1.00; 95% confidence interval [CI], .94-1.05). The risk of mortality (aOR, .87; 95% CI, .66-1.04) and severe outcomes (aOR, .95; 95% CI, .73-1.24) were also unchanged among COVID-19 patients taking ACEIs/ARBs. These findings remained consistent in subgroup analyses stratified by populations, drug exposures, and other secondary outcomes. This systematic review provides evidence-based support to current medical guidelines and position statements that ACEIs/ARBs should not be discontinued. Additionally, there has been no evidence for initiating ACEI/ARB regimen as prevention or treatment of COVID-19.


Subject(s)
COVID-19 , Hypertension , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Humans , SARS-CoV-2
4.
Clin Infect Dis ; 72(10): e545-e551, 2021 05 18.
Article in English | MEDLINE | ID: covidwho-1232187

ABSTRACT

BACKGROUND: The characteristics of neutralizing antibodies (NAbs) and antibody against major antigen proteins related to clinical outcomes in severe coronavirus disease 2019 (COVID-19) patients were still less known. METHODS: NAbs and antibodies targeting nucleocapsid (N), spike protein (S), and the receptor-binding domain (RBD) in longitudinal plasma samples from the LOTUS China trial were measured by microneutralization assay and enzyme-linked immunosorbent assay (ELISA). Viral load was determined by real-time reverse transcription polymerase chain reaction (RT-PCR). A total of 576 plasma and 576 throat swabs were collected from 191 COVID-19 patients. Antibody titers related to adverse outcome and clinical improvement were analyzed. Multivariable adjusted generalized linear mixed model for random effects were developed. RESULTS: After day 28 post symptoms onset, the rate of antibody positivity reached 100% for RBD-immunoglobulin M (IgM), 97.8% for S-IgM, 100% for N-immunoglobulin G (IgG), 100% for RBD-IgG, 91.1% for N-IgM, and 91.1% for NAbs. The NAbs titers increased over time in both survivors and nonsurvivors and correlated to IgG antibodies against N, S, and RBD, whereas its presence showed no statistical correlation with death. N-IgG (slope -2.11, 95% confidence interval [CI] -3.04 to -1.18, P < .0001), S-IgG (slope -2.44, 95% CI -3.35 to -1.54, P < .0001), and RBD-IgG (slope -1.43, 95% CI -1.98 to -.88, P < .0001) were negatively correlated with viral load. S-IgG titers were lower in nonsurvivors than survivors (P = .020) at week 4 after symptoms onset. CONCLUSIONS: IgM and IgG against N, S, and RBD and NAbs developed in most severe COVID-19 patients and do not correlate clearly with clinical outcomes. The levels of IgG antibodies against N, S, and RBD were related to viral clearance.


Subject(s)
COVID-19 , Adult , Antibodies, Viral , Antibody Formation , China/epidemiology , Humans , Immunoglobulin M , SARS-CoV-2
5.
BMC Infect Dis ; 21(1): 341, 2021 Apr 12.
Article in English | MEDLINE | ID: covidwho-1181088

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that rapidly spreads worldwide and co-infection of COVID-19 and influenza may occur in some cases. We aimed to describe clinical features and outcomes of severe COVID-19 patients with co-infection of influenza virus. METHODS: Retrospective cohort study was performed and a total of 140 patients with severe COVID-19 were enrolled in designated wards of Sino-French New City Branch of Tongji Hospital between Feb 8th and March 15th in Wuhan city, Hubei province, China. The demographic, clinical features, laboratory indices, treatment and outcomes of these patients were collected. RESULTS: Of 140 severe COVID-19 hospitalized patients, including 73 patients (52.14%) with median age 62 years were influenza virus IgM-positive and 67 patients (47.86%) with median age 66 years were influenza virus IgM-negative. 76 (54.4%) of severe COVID-19 patients were males. Chronic comorbidities consisting mainly of hypertension (45.3%), diabetes (15.8%), chronic respiratory disease (7.2%), cardiovascular disease (5.8%), malignancy (4.3%) and chronic kidney disease (2.2%). Clinical features, including fever (≥38 °C), chill, cough, chest pain, dyspnea, diarrhea and fatigue or myalgia were collected. Fatigue or myalgia was less found in COVID-19 patients with IgM-positive (33.3% vs 50/7%, P = 0.0375). Higher proportion of prolonged activated partial thromboplastin time (APTT) > 42 s was observed in COVID-19 patients with influenza virus IgM-negative (43.8% vs 23.6%, P = 0.0127). Severe COVID-19 Patients with influenza virus IgM positive have a higher cumulative survivor rate than that of patients with influenza virus IgM negative (Log-rank P = 0.0308). Considering age is a potential confounding variable, difference in age was adjusted between different influenza virus IgM status groups, the HR was 0.29 (95% CI, 0.081-1.100). Similarly, difference in gender was adjusted as above, the HR was 0.262 (95% CI, 0.072-0.952) in the COX regression model. CONCLUSIONS: Influenza virus IgM positive may be associated with decreasing in-hospital death.


Subject(s)
COVID-19/complications , Hospital Mortality , Influenza, Human/complications , Adult , Aged , Antibodies, Viral/blood , China , Coinfection/virology , Comorbidity , Female , Humans , Immunoglobulin M/blood , Male , Middle Aged , Retrospective Studies
6.
The Lancet ; 397(10270):220-232, 2021.
Article in English | APA PsycInfo | ID: covidwho-1164655

ABSTRACT

Presents a study which aims to examine consequences of COVID-19 in patients discharged from hospital for 6-months. This ambidirectional cohort study was done at Jin Yin-tan Hospital, the first designated hospital for patients with COVID-19 in Wuhan, Hubei, China. Clinical data for acute phase were retrieved from electronic medical records, including demographic characteristics, clinical characteristics, laboratory test results;and treatment. The disease severity was characterized by the highest seven-category scale during the hospital stay. Data were managed using REDCap electronic data capture tools in order to minimize missing inputs and allow for real-time data validation and quality control. Follow-up consultations were done in the outpatient clinic of Jin Yin-tan Hospital. All participants were interviewed face-to-face by trained physicians and asked to complete a series of questionnaires. For the symptom questionnaire, participants were asked to report newly occurring and persistent symptoms, or any symptoms worse than before COVID-19 development. A total of 2469 patients with COVID-19 were discharged from Jin Yin-tan Hospital between Jan 7, and May 29, 2020, and the follow-up study was done from June 16, 2020, to Sept 3, 2020. This is the largest cohort study with the longest follow-up duration assessing the health consequences of adult patients discharged from hospital recovering from COVID-19. (PsycInfo Database Record (c) 2021 APA, all rights reserved)

7.
Emerg Microbes Infect ; 10(1): 664-676, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1139855

ABSTRACT

Seasonal human coronaviruses (HCoVs) including HCoV-229E, -OC43, -NL63, and -HKU1 widely spread in global human populations. However, the relevance of humoral response against seasonal HCoVs to COVID-19 pathogenesis is elusive. In this study, we profiled the temporal changes of IgG antibody against spike proteins (S-IgG) of SARS-CoV-2 and seasonal HCoVs in 838 plasma samples collected from 344 COVID-19 patients. We tested the antigenic cross-reactivities of S protein between SARS-CoV-2 and seasonal HCoVs and evaluated the correlations between the levels of HCoV-OC43 S-IgG and the disease severity in COVID-19 patients. We found that SARS-CoV-2 S-IgG titres mounted until days 22-28, whereas HCoV-OC43 antibody titres increased until days 15-21 and then plateaued until day 46. However, IgG titres against HCoV-NL63, -229E, and -HKU1 showed no significant increase. A two-way cross-reactivity was identified between SARS-CoV-2 and HCoV-OC43. Neutralizing antibodies against SARS-CoV-2 were not detectable in healthy controls who were positive for HCoV-OC43 S-IgG. HCoV-OC43 S-IgG titres were significantly higher in patients with severe disease than those in mild patients at days 1-21 post symptom onset (PSO). Higher levels of HCoV-OC43 S-IgG were also observed in patients requiring mechanical ventilation. At days 1-10 PSO, HCoV-OC43 S-IgG titres correlated to disease severity in the age group over 60. Our data indicate that there is a correlation between cross-reactive antibody against HCoV-OC43 spike protein and disease severity in COVID-19 patients.


Subject(s)
Antibodies, Viral/blood , COVID-19/immunology , Coronavirus OC43, Human/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/pathology , Cross Reactions/immunology , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Male , Middle Aged , Severity of Illness Index , Young Adult
8.
Lancet ; 397(10270): 220-232, 2021 01 16.
Article in English | MEDLINE | ID: covidwho-1065678

ABSTRACT

BACKGROUND: The long-term health consequences of COVID-19 remain largely unclear. The aim of this study was to describe the long-term health consequences of patients with COVID-19 who have been discharged from hospital and investigate the associated risk factors, in particular disease severity. METHODS: We did an ambidirectional cohort study of patients with confirmed COVID-19 who had been discharged from Jin Yin-tan Hospital (Wuhan, China) between Jan 7, 2020, and May 29, 2020. Patients who died before follow-up, patients for whom follow-up would be difficult because of psychotic disorders, dementia, or re-admission to hospital, those who were unable to move freely due to concomitant osteoarthropathy or immobile before or after discharge due to diseases such as stroke or pulmonary embolism, those who declined to participate, those who could not be contacted, and those living outside of Wuhan or in nursing or welfare homes were all excluded. All patients were interviewed with a series of questionnaires for evaluation of symptoms and health-related quality of life, underwent physical examinations and a 6-min walking test, and received blood tests. A stratified sampling procedure was used to sample patients according to their highest seven-category scale during their hospital stay as 3, 4, and 5-6, to receive pulmonary function test, high resolution CT of the chest, and ultrasonography. Enrolled patients who had participated in the Lopinavir Trial for Suppression of SARS-CoV-2 in China received severe acute respiratory syndrome coronavirus 2 antibody tests. Multivariable adjusted linear or logistic regression models were used to evaluate the association between disease severity and long-term health consequences. FINDINGS: In total, 1733 of 2469 discharged patients with COVID-19 were enrolled after 736 were excluded. Patients had a median age of 57·0 (IQR 47·0-65·0) years and 897 (52%) were men. The follow-up study was done from June 16, to Sept 3, 2020, and the median follow-up time after symptom onset was 186·0 (175·0-199·0) days. Fatigue or muscle weakness (63%, 1038 of 1655) and sleep difficulties (26%, 437 of 1655) were the most common symptoms. Anxiety or depression was reported among 23% (367 of 1617) of patients. The proportions of median 6-min walking distance less than the lower limit of the normal range were 24% for those at severity scale 3, 22% for severity scale 4, and 29% for severity scale 5-6. The corresponding proportions of patients with diffusion impairment were 22% for severity scale 3, 29% for scale 4, and 56% for scale 5-6, and median CT scores were 3·0 (IQR 2·0-5·0) for severity scale 3, 4·0 (3·0-5·0) for scale 4, and 5·0 (4·0-6·0) for scale 5-6. After multivariable adjustment, patients showed an odds ratio (OR) 1·61 (95% CI 0·80-3·25) for scale 4 versus scale 3 and 4·60 (1·85-11·48) for scale 5-6 versus scale 3 for diffusion impairment; OR 0·88 (0·66-1·17) for scale 4 versus scale 3 and OR 1·77 (1·05-2·97) for scale 5-6 versus scale 3 for anxiety or depression, and OR 0·74 (0·58-0·96) for scale 4 versus scale 3 and 2·69 (1·46-4·96) for scale 5-6 versus scale 3 for fatigue or muscle weakness. Of 94 patients with blood antibodies tested at follow-up, the seropositivity (96·2% vs 58·5%) and median titres (19·0 vs 10·0) of the neutralising antibodies were significantly lower compared with at the acute phase. 107 of 822 participants without acute kidney injury and with estimated glomerular filtration rate (eGFR) 90 mL/min per 1·73 m2 or more at acute phase had eGFR less than 90 mL/min per 1·73 m2 at follow-up. INTERPRETATION: At 6 months after acute infection, COVID-19 survivors were mainly troubled with fatigue or muscle weakness, sleep difficulties, and anxiety or depression. Patients who were more severely ill during their hospital stay had more severe impaired pulmonary diffusion capacities and abnormal chest imaging manifestations, and are the main target population for intervention of long-term recovery. FUNDING: National Natural Science Foundation of China, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, National Key Research and Development Program of China, Major Projects of National Science and Technology on New Drug Creation and Development of Pulmonary Tuberculosis, and Peking Union Medical College Foundation.


Subject(s)
COVID-19/complications , Quality of Life , Aged , COVID-19/epidemiology , COVID-19/psychology , COVID-19 Serological Testing/statistics & numerical data , China/epidemiology , Cohort Studies , Comorbidity , Fatigue/epidemiology , Fatigue/etiology , Female , Humans , Length of Stay/statistics & numerical data , Male , Middle Aged , Muscle Weakness/epidemiology , Muscle Weakness/etiology , Pandemics , SARS-CoV-2 , Severity of Illness Index , Sleep Wake Disorders/epidemiology , Sleep Wake Disorders/etiology , Surveys and Questionnaires
9.
Emerg Microbes Infect ; 9(1): 2707-2714, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-953975

ABSTRACT

To identify the association between the kinetics of viral load and clinical outcome in severe coronavirus disease 2019 (COVID-19) patients, a retrospective study was performed by involved 188 hospitalized severe COVID-19 patients in the LOTUS China trial. Among the collected 578 paired throat swab (TS) and anal swab (AS) samples, viral RNA was detected in 193 (33.4%) TS and 121 (20.9%) AS. A higher viral RNA load was found in TS than that of AS, with means of 1.0 × 106 and 2.3 × 105 copies/ml, respectively. In non-survivors, the viral RNA in AS was detected earlier than that in survivors (median of 14 days vs 19 days, P = 0.007). The positivity and viral load in AS were higher in non-survivors than that of survivors at week 2 post symptom onset (P = 0.006). A high initial viral load in AS was associated with death (OR 1.368, 95% CI 1.076-1.741, P = 0.011), admission to the intensive care unit (OR 1.237, 95% CI 1.001-1.528, P = 0.049) and need for invasive mechanical ventilation (OR 1.340, 95% CI 1.076-1.669, P = 0.009). Our findings indicated viral replication in extrapulmonary sites should be monitored intensively during antiviral therapy.


Subject(s)
Anal Canal/virology , COVID-19/virology , SARS-CoV-2/isolation & purification , Viral Load , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/mortality , Female , Humans , Male , Middle Aged , Pharynx/virology , RNA, Viral/analysis , Retrospective Studies , Time Factors , Virus Replication , Young Adult
10.
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
11.
Lancet ; 395(10236): 1569-1578, 2020 05 16.
Article in English | MEDLINE | ID: covidwho-824547

ABSTRACT

BACKGROUND: No specific antiviral drug has been proven effective for treatment of patients with severe coronavirus disease 2019 (COVID-19). Remdesivir (GS-5734), a nucleoside analogue prodrug, has inhibitory effects on pathogenic animal and human coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro, and inhibits Middle East respiratory syndrome coronavirus, SARS-CoV-1, and SARS-CoV-2 replication in animal models. METHODS: We did a randomised, double-blind, placebo-controlled, multicentre trial at ten hospitals in Hubei, China. Eligible patients were adults (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, with an interval from symptom onset to enrolment of 12 days or less, oxygen saturation of 94% or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less, and radiologically confirmed pneumonia. Patients were randomly assigned in a 2:1 ratio to intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2-10 in single daily infusions) or the same volume of placebo infusions for 10 days. Patients were permitted concomitant use of lopinavir-ritonavir, interferons, and corticosteroids. The primary endpoint was time to clinical improvement up to day 28, defined as the time (in days) from randomisation to the point of a decline of two levels on a six-point ordinal scale of clinical status (from 1=discharged to 6=death) or discharged alive from hospital, whichever came first. Primary analysis was done in the intention-to-treat (ITT) population and safety analysis was done in all patients who started their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04257656. FINDINGS: Between Feb 6, 2020, and March 12, 2020, 237 patients were enrolled and randomly assigned to a treatment group (158 to remdesivir and 79 to placebo); one patient in the placebo group who withdrew after randomisation was not included in the ITT population. Remdesivir use was not associated with a difference in time to clinical improvement (hazard ratio 1·23 [95% CI 0·87-1·75]). Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less (hazard ratio 1·52 [0·95-2·43]). Adverse events were reported in 102 (66%) of 155 remdesivir recipients versus 50 (64%) of 78 placebo recipients. Remdesivir was stopped early because of adverse events in 18 (12%) patients versus four (5%) patients who stopped placebo early. INTERPRETATION: In this study of adult patients admitted to hospital for severe COVID-19, remdesivir was not associated with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies. FUNDING: Chinese Academy of Medical Sciences Emergency Project of COVID-19, National Key Research and Development Program of China, the Beijing Science and Technology Project.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/therapeutic use , Aged , Alanine/adverse effects , Alanine/therapeutic use , Antiviral Agents/adverse effects , Betacoronavirus , COVID-19 , China , Double-Blind Method , Female , Humans , Infusions, Intravenous , Male , Middle Aged , Negative Results , Pandemics , SARS-CoV-2
12.
Clin Microbiol Infect ; 27(1): 112-117, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-802088

ABSTRACT

OBJECTIVES: Use of corticosteroids is common in the treatment of coronavirus disease 2019, but clinical effectiveness is controversial. We aimed to investigate the association of corticosteroids therapy with clinical outcomes of hospitalized COVID-19 patients. METHODS: In this single-centre, retrospective cohort study, adult patients with confirmed coronavirus disease 2019 and dead or discharged between 29 December 2019 and 15 February 2020 were studied; 1:1 propensity score matchings were performed between patients with or without corticosteroid treatment. A multivariable COX proportional hazards model was used to estimate the association between corticosteroid treatment and in-hospital mortality by taking corticosteroids as a time-varying covariate. RESULTS: Among 646 patients, the in-hospital death rate was higher in 158 patients with corticosteroid administration (72/158, 45.6% vs. 56/488, 11.5%, p < 0.0001). After propensity score matching analysis, no significant differences were observed in in-hospital death between patients with and without corticosteroid treatment (47/124, 37.9% vs. 47/124, 37.9%, p 1.000). When patients received corticosteroids before they required nasal high-flow oxygen therapy or mechanical ventilation, the in-hospital death rate was lower than that in patients who were not administered corticosteroids (17/86, 19.8% vs. 26/86, 30.2%, log rank p 0.0102), whereas the time from admission to clinical improvement was longer (13 (IQR 10-17) days vs. 10 (IQR 8-13) days; p < 0.001). Using the Cox proportional hazards regression model accounting for time varying exposures in matched pairs, corticosteroid therapy was not associated with mortality difference (HR 0.98, 95% CI 0.93-1.03, p 0.4694). DISCUSSION: Corticosteroids use in COVID-19 patients may not be associated with in-hospital mortality.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , COVID-19/drug therapy , COVID-19/mortality , SARS-CoV-2/pathogenicity , Aged , Antiviral Agents/therapeutic use , COVID-19/pathology , China , Critical Illness , Drug Administration Schedule , Female , Hospital Mortality/trends , Hospitals , Humans , Length of Stay/statistics & numerical data , Male , Middle Aged , Proportional Hazards Models , Respiration, Artificial , Retrospective Studies , SARS-CoV-2/drug effects , Severity of Illness Index , Treatment Outcome
14.
Eur Respir Rev ; 29(157)2020 Sep 30.
Article in English | MEDLINE | ID: covidwho-662439

ABSTRACT

According to the Third International Consensus Definition for Sepsis and Septic Shock, sepsis is a life-threatening organ dysfunction resulting from dysregulated host responses to infection. Epidemiological data about sepsis from the 2017 Global Burden of Diseases, Injuries and Risk Factor Study showed that the global burden of sepsis was greater than previously estimated. Bacteria have been shown to be the predominant pathogen of sepsis among patients with pathogens detected, while sepsis caused by viruses is underdiagnosed worldwide. The coronavirus disease that emerged in 2019 in China and now in many other countries has brought viral sepsis back into the vision of physicians and researchers worldwide. Although the current understanding of the pathophysiology of sepsis has improved, the differences between viral and bacterial sepsis at the level of pathophysiology are not well understood. Diagnosis methods that can broadly differentiate between bacterial and viral sepsis at the initial stage after the development of sepsis are limited. New treatments that can be applied at clinics for sepsis are scarce and this situation is not consistent with the growing understanding of pathophysiology. This review aims to give a brief summary of current knowledge of the epidemiology, pathophysiology, diagnosis and treatment of viral sepsis.


Subject(s)
Coronavirus Infections/epidemiology , Disease Outbreaks/statistics & numerical data , Respiratory Tract Infections/diagnosis , Respiratory Tract Infections/epidemiology , Sepsis/diagnosis , Sepsis/epidemiology , Cause of Death , China/epidemiology , Consensus , Coronavirus/isolation & purification , Coronavirus Infections/diagnosis , Coronavirus Infections/therapy , Female , Humans , Male , Respiratory Syncytial Viruses/isolation & purification , Respiratory Tract Infections/therapy , Risk Assessment , Sepsis/therapy , Shock, Septic/diagnosis , Shock, Septic/epidemiology , Shock, Septic/therapy , Survival Analysis
16.
Front Med ; 14(5): 601-612, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-632554

ABSTRACT

The possible effects of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) on COVID-19 disease severity have generated considerable debate. We performed a single-center, retrospective analysis of hospitalized adult COVID-19 patients in Wuhan, China, who had definite clinical outcome (dead or discharged) by February 15, 2020. Patients on anti-hypertensive treatment with or without ACEI/ARB were compared on their clinical characteristics and outcomes. The medical records from 702 patients were screened. Among the 101 patients with a history of hypertension and taking at least one anti-hypertensive medication, 40 patients were receiving ACEI/ARB as part of their regimen, and 61 patients were on antihypertensive medication other than ACEI/ARB. We observed no statistically significant differences in percentages of in-hospital mortality (28% vs. 34%, P = 0.46), ICU admission (20% vs. 28%, P = 0.37) or invasive mechanical ventilation (18% vs. 26%, P = 0.31) between patients with or without ACEI/ARB treatment. Further multivariable adjustment of age and gender did not provide evidence for a significant association between ACEI/ARB treatment and severe COVID-19 outcomes. Our findings confirm the lack of an association between chronic receipt of renin-angiotensin system antagonists and severe outcomes of COVID-19. Patients should continue previous anti-hypertensive therapy until further evidence is available.


Subject(s)
Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Betacoronavirus , Coronavirus Infections , Hypertension/drug therapy , Pandemics , Pneumonia, Viral , Antihypertensive Agents/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/physiology , COVID-19 , China/epidemiology , Comorbidity , Coronavirus Infections/mortality , Coronavirus Infections/physiopathology , Coronavirus Infections/therapy , Female , Hospital Mortality , Humans , Hypertension/epidemiology , Male , Middle Aged , Outcome and Process Assessment, Health Care , Pneumonia, Viral/mortality , Pneumonia, Viral/physiopathology , Pneumonia, Viral/therapy , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index
17.
Trials ; 21(1): 422, 2020 May 24.
Article in English | MEDLINE | ID: covidwho-342726

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by a novel corinavirus (later named SARS-CoV-2 virus), was fistly reported in Wuhan, Hubei Province, China towards the end of 2019. Large-scale spread within China and internationally led the World Health Organization to declare a Public Health Emergency of International Concern on 30th January 2020. The clinical manifestations of COVID-19 virus infection include asymptomatic infection, mild upper respiratory symptoms, severe viral pneumonia with respiratory failure, and even death. There are no antivirals of proven clinical efficacy in coronavirus infections. Remdesivir (GS-5734), a nucleoside analogue, has inhibitory effects on animal and human highly pathogenic coronaviruses, including MERS-CoV and SARS-CoV, in in vitro and in vivo experiments. It is also inhibitory against the COVID-19 virus in vitro. The aim of this study is to assess the efficacy and safety of remdesivir in adult patients with severe COVID-19. METHODS: The protocol is prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. This is a phase 3, randomized, double-blind, placebo-controlled, multicentre trial. Adults (≥ 18 years) with laboratory-confirmed COVID-19 virus infection, severe pneumonia signs or symptoms, and radiologically confirmed severe pneumonia are randomly assigned in a 2:1 ratio to intravenously administered remdesivir or placebo for 10 days. The primary endpoint is time to clinical improvement (censored at day 28), defined as the time (in days) from randomization of study treatment (remdesivir or placebo) until a decline of two categories on a six-category ordinal scale of clinical status (1 = discharged; 6 = death) or live discharge from hospital. One interim analysis for efficacy and futility will be conducted once half of the total number of events required has been observed. DISCUSSION: This is the first randomized, placebo-controlled trial in COVID-19. Enrolment began in sites in Wuhan, Hubei Province, China on 6th February 2020. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04257656. Registered on 6 February 2020.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/administration & dosage , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/adverse effects , Alanine/administration & dosage , Alanine/adverse effects , Antiviral Agents/adverse effects , Betacoronavirus/pathogenicity , COVID-19 , China , Clinical Trials, Phase III as Topic , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Double-Blind Method , Equivalence Trials as Topic , Female , Humans , Infusions, Intravenous , Male , Multicenter Studies as Topic , Pandemics , Patient Safety , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , Risk Assessment , Risk Factors , SARS-CoV-2 , Severity of Illness Index , Time Factors , Treatment Outcome
18.
N Engl J Med ; 382(19): 1787-1799, 2020 05 07.
Article in English | MEDLINE | ID: covidwho-9371

ABSTRACT

BACKGROUND: No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. METHODS: We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao2) to the fraction of inspired oxygen (Fio2) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir-ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first. RESULTS: A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Treatment with lopinavir-ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.31; 95% confidence interval [CI], 0.95 to 1.80). Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, -5.8 percentage points; 95% CI, -17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events. CONCLUSIONS: In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.).


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/isolation & purification , Coronavirus Infections/drug therapy , Cytochrome P-450 CYP3A Inhibitors/therapeutic use , Lopinavir/therapeutic use , Pneumonia, Viral/drug therapy , Ritonavir/therapeutic use , Adult , Aged , Antiviral Agents/adverse effects , Betacoronavirus/genetics , COVID-19 , COVID-19 Testing , Clinical Laboratory Techniques , Coronavirus Infections/diagnosis , Coronavirus Infections/mortality , Coronavirus Infections/virology , Cytochrome P-450 CYP3A Inhibitors/adverse effects , Drug Therapy, Combination , Female , Hospital Mortality , Humans , Intention to Treat Analysis , Lopinavir/adverse effects , Male , Middle Aged , Pandemics , Patient Acuity , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Proportional Hazards Models , Reverse Transcriptase Polymerase Chain Reaction , Ritonavir/adverse effects , SARS-CoV-2 , Time-to-Treatment , Treatment Failure , Viral Load
19.
Lancet ; 395(10229): 1054-1062, 2020 03 28.
Article in English | MEDLINE | ID: covidwho-6685

ABSTRACT

BACKGROUND: Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. METHODS: In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. FINDINGS: 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03-1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61-12·23; p<0·0001), and d-dimer greater than 1 µg/mL (18·42, 2·64-128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0-24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. INTERPRETATION: The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 µg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. FUNDING: Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.


Subject(s)
Coronavirus Infections/mortality , Organ Dysfunction Scores , Patient Care Planning , Pneumonia, Viral/mortality , Risk Assessment , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Betacoronavirus , COVID-19 , COVID-19 Testing , Cardiovascular Diseases/complications , China , Clinical Laboratory Techniques , Cohort Studies , Comorbidity , Coronavirus Infections/complications , Coronavirus Infections/diagnosis , Diabetes Complications , Disease Progression , Female , Fibrin Fibrinogen Degradation Products/analysis , Humans , Hypertension/complications , Male , Middle Aged , Mortality/trends , Pandemics , Patient Isolation , Pneumonia, Viral/complications , Pneumonia, Viral/diagnosis , Prognosis , Retrospective Studies , Risk Assessment/methods , Risk Factors , SARS-CoV-2 , Young Adult
20.
Lancet ; 395(10223): 497-506, 2020 02 15.
Article in English | MEDLINE | ID: covidwho-34

ABSTRACT

BACKGROUND: A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. METHODS: All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. FINDINGS: By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0-58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0-13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. INTERPRETATION: The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. FUNDING: Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.


Subject(s)
Coronavirus Infections/diagnosis , Coronavirus Infections/epidemiology , Pneumonia, Viral/diagnosis , Pneumonia, Viral/epidemiology , Adult , Age Distribution , Aged , COVID-19 , China/epidemiology , Comorbidity , Coronavirus Infections/complications , Coronavirus Infections/transmission , Cough/epidemiology , Cough/virology , Female , Fever/epidemiology , Fever/virology , Hospitalization/statistics & numerical data , Humans , Intensive Care Units/statistics & numerical data , Male , Middle Aged , Myalgia/epidemiology , Myalgia/virology , Pneumonia, Viral/complications , Pneumonia, Viral/transmission , Prognosis , Radiography, Thoracic , Respiratory Distress Syndrome/epidemiology , Respiratory Distress Syndrome/virology , Time Factors , Tomography, X-Ray Computed , Young Adult
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