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1.
N Engl J Med ; 383(19): 1813-1826, 2020 11 05.
Article in English | MEDLINE | ID: covidwho-2292084

ABSTRACT

BACKGROUND: Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), no antiviral agents have yet been shown to be efficacious. METHODS: We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. RESULTS: A total of 1062 patients underwent randomization (with 541 assigned to remdesivir and 521 to placebo). Those who received remdesivir had a median recovery time of 10 days (95% confidence interval [CI], 9 to 11), as compared with 15 days (95% CI, 13 to 18) among those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P<0.001, by a log-rank test). In an analysis that used a proportional-odds model with an eight-category ordinal scale, the patients who received remdesivir were found to be more likely than those who received placebo to have clinical improvement at day 15 (odds ratio, 1.5; 95% CI, 1.2 to 1.9, after adjustment for actual disease severity). The Kaplan-Meier estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% with remdesivir and 15.2% with placebo by day 29 (hazard ratio, 0.73; 95% CI, 0.52 to 1.03). Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients who received placebo (31.6%). CONCLUSIONS: Our data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 ClinicalTrials.gov number, NCT04280705.).


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/therapeutic use , Administration, Intravenous , Adult , Aged , Alanine/administration & dosage , Alanine/adverse effects , Alanine/therapeutic use , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Betacoronavirus , COVID-19 , Coronavirus Infections/mortality , Coronavirus Infections/therapy , Double-Blind Method , Extracorporeal Membrane Oxygenation , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Oxygen Inhalation Therapy , Pandemics , Pneumonia, Viral/mortality , Pneumonia, Viral/therapy , Respiration, Artificial , SARS-CoV-2 , Time Factors , Young Adult , COVID-19 Drug Treatment
2.
Korean J Intern Med ; 38(3): 382-392, 2023 05.
Article in English | MEDLINE | ID: covidwho-2297857

ABSTRACT

BACKGROUND/AIMS: For patients hospitalized with coronavirus disease 2019 (COVID-19) who require supplemental oxygen, the evidence of the optimal duration of corticosteroid is limited. This study aims to identify whether long-term use of corticosteroids is associated with decreased mortality. METHODS: Between February 10, 2020 and October 31, 2021, we analyzed consecutive hospitalized patients with COVID-19 with severe hypoxemia. The patients were divided into short-term (≤ 14 days) and long-term (> 14 days) corticosteroid users. The primary outcome was 60-day mortality. We performed propensity score (PS) analysis to mitigate the effect of confounders and conducted Kaplan-Meier curve analysis. RESULTS: There were 141 (52%) short-term users and 130 (48%) long-term corticosteroid users. The median age was 68 years and the median PaO2/FiO2 at admission was 158. Of the patients, 40.6% required high-flow nasal cannula, 48.3% required mechanical ventilation, and 11.1% required extracorporeal membrane oxygenation. The overall 60-day mortality rate was 23.2%, and that of patients with hospital-acquired pneumonia (HAP) was 22.9%. The Kaplan-Meier curve for 60- day survival in the PS-matched cohort showed that corticosteroid for > 14 days was associated with decreased mortality (p = 0.0033). There were no significant differences in bacteremia and HAP between the groups. An adjusted odds ratio for the risk of 60-day mortality in short-term users was 5.53 (95% confidence interval, 1.90-18.26; p = 0.003). CONCLUSION: For patients with severe COVID-19, long-term use of corticosteroids was associated with decreased mortality, with no increase in nosocomial complications. Corticosteroid use for > 14 days can benefit patients with severe COVID-19.


Subject(s)
COVID-19 , Humans , Aged , Adrenal Cortex Hormones/adverse effects , Hospitalization , Kaplan-Meier Estimate , Respiration, Artificial , Retrospective Studies
3.
PLoS One ; 15(12): e0243762, 2020.
Article in English | MEDLINE | ID: covidwho-2279671

ABSTRACT

INTRODUCTION: Multiplex polymerase chain reaction (mPCR) for respiratory virus testing is increasingly used in community-acquired pneumonia (CAP), however data on one-year outcome in intensive care unit (ICU) patients with reference to the causative pathogen are scarce. MATERIALS AND METHODS: We performed a single-center retrospective study in 123 ICU patients who had undergone respiratory virus testing for CAP by mPCR and with known one-year survival status. Functional status including dyspnea (mMRC score), autonomy (ADL Katz score) and need for new home-care ventilatory support was assessed at a one-year post-ICU follow-up. Mortality rates and functional status were compared in patients with CAP of a bacterial, viral or unidentified etiology one year after ICU admission. RESULTS: The bacterial, viral and unidentified groups included 19 (15.4%), 37 (30.1%), and 67 (54.5%) patients, respectively. In multivariate analysis, one-year mortality in the bacterial group was higher compared to the viral group (HR 2.92, 95% CI 1.71-7.28, p = 0.02) and tended to be higher compared to the unidentified etiology group (p = 0.06); but no difference was found between the viral and the unidentified etiology group (p = 0.43). In 64/83 one-year survivors with a post-ICU follow-up consultation, there were no differences in mMRC score, ADL Katz score and new home-care ventilatory support between the groups (p = 0.52, p = 0.37, p = 0.24, respectively). Severe dyspnea (mMRC score = 4 or death), severe autonomy deficiencies (ADL Katz score ≤ 2 or death), and major adverse respiratory events (new home-care ventilatory support or death) were observed in 52/104 (50.0%), 47/104 (45.2%), and 65/104 (62.5%) patients, respectively; with no difference between the bacterial, viral and unidentified group: p = 0.58, p = 0.06, p = 0.61, respectively. CONCLUSIONS: CAP of bacterial origin had a poorer outcome than CAP of viral or unidentified origin. At one-year, impairment of functional status was frequently observed, with no difference according to the etiology.


Subject(s)
Community-Acquired Infections/pathology , Pneumonia, Bacterial/pathology , Pneumonia, Viral/pathology , Activities of Daily Living , Aged , Aged, 80 and over , Community-Acquired Infections/microbiology , Community-Acquired Infections/mortality , Community-Acquired Infections/virology , Dyspnea/etiology , Female , Functional Status , Hospitalization , Humans , Intensive Care Units , Kaplan-Meier Estimate , Male , Middle Aged , Pneumonia, Bacterial/diagnosis , Pneumonia, Bacterial/microbiology , Pneumonia, Bacterial/mortality , Pneumonia, Viral/mortality , Proportional Hazards Models , Respiration, Artificial , Retrospective Studies , Severity of Illness Index
4.
Diabetes Obes Metab ; 25(7): 1950-1963, 2023 07.
Article in English | MEDLINE | ID: covidwho-2287843

ABSTRACT

AIM: To describe the Turkish generalized lipodystrophy (GL) cohort with the frequency of each complication and the death rate during the period of the follow-up. METHODS: This study reports on 72 patients with GL (47 families) registered at different centres in Turkey that cover all regions of the country. The mean ± SD follow-up was 86 ± 78 months. RESULTS: The Kaplan-Meier estimate of the median time to diagnosis of diabetes and/or prediabetes was 16 years. Hyperglycaemia was not controlled in 37 of 45 patients (82.2%) with diabetes. Hypertriglyceridaemia developed in 65 patients (90.3%). The Kaplan-Meier estimate of the median time to diagnosis of hypertriglyceridaemia was 14 years. Hypertriglyceridaemia was severe (≥ 500 mg/dl) in 38 patients (52.8%). Seven (9.7%) patients suffered from pancreatitis. The Kaplan-Meier estimate of the median time to diagnosis of hepatic steatosis was 15 years. Liver disease progressed to cirrhosis in nine patients (12.5%). Liver disease was more severe in congenital lipodystrophy type 2 (CGL2). Proteinuric chronic kidney disease (CKD) developed in 32 patients (44.4%) and cardiac disease in 23 patients (31.9%). Kaplan-Meier estimates of the median time to diagnosis of CKD and cardiac disease were 25 and 45 years, respectively. Females appeared to have a more severe metabolic disease, with an earlier onset of metabolic abnormalities. Ten patients died during the follow-up period. Causes of death were end-stage renal disease, sepsis (because of recurrent intestinal perforations, coronavirus disease, diabetic foot infection and following coronary artery bypass graft surgery), myocardial infarction, heart failure because of dilated cardiomyopathy, stroke, liver complications and angiosarcoma. CONCLUSIONS: Standard treatment approaches have only a limited impact and do not prevent the development of severe metabolic abnormalities and early onset of organ complications in GL.


Subject(s)
Diabetes Mellitus , Hypertriglyceridemia , Lipodystrophy, Congenital Generalized , Lipodystrophy , Myocardial Infarction , Renal Insufficiency, Chronic , Female , Humans , Turkey/epidemiology , Cohort Studies , Myocardial Infarction/complications , Renal Insufficiency, Chronic/complications , Kaplan-Meier Estimate , Hypertriglyceridemia/complications
5.
Curr Oncol ; 30(2): 2105-2126, 2023 02 08.
Article in English | MEDLINE | ID: covidwho-2229338

ABSTRACT

We address the problem of how COVID-19 deaths observed in an oncology clinical trial can be consistently taken into account in typical survival estimates. We refer to oncological patients since there is empirical evidence of strong correlation between COVID-19 and cancer deaths, which implies that COVID-19 deaths cannot be treated simply as non-informative censoring, a property usually required by the classical survival estimators. We consider the problem in the framework of the widely used Kaplan-Meier (KM) estimator. Through a counterfactual approach, an algorithmic method is developed allowing to include COVID-19 deaths in the observed data by mean-imputation. The procedure can be seen in the class of the Expectation-Maximization (EM) algorithms and will be referred to as Covid-Death Mean-Imputation (CoDMI) algorithm. We discuss the CoDMI underlying assumptions and the convergence issue. The algorithm provides a completed lifetime data set, where each Covid-death time is replaced by a point estimate of the corresponding virtual lifetime. This complete data set is naturally equipped with the corresponding KM survival function estimate and all available statistical tools can be applied to these data. However, mean-imputation requires an increased variance of the estimates. We then propose a natural extension of the classical Greenwood's formula, thus obtaining expanded confidence intervals for the survival function estimate. To illustrate how the algorithm works, CoDMI is applied to real medical data extended by the addition of artificial Covid-death observations. The results are compared with the estimates provided by the two naïve approaches which count COVID-19 deaths as censoring or as deaths by the disease under study. In order to evaluate the predictive performances of CoDMI an extensive simulation study is carried out. The results indicate that in the simulated scenarios CoDMI is roughly unbiased and outperforms the estimates obtained by the naïve approaches. A user-friendly version of CoDMI programmed in R is freely available.


Subject(s)
COVID-19 , Motivation , Humans , Survival Analysis , Kaplan-Meier Estimate , Algorithms
6.
Georgian Med News ; (330): 99-105, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-2125799

ABSTRACT

Coronavirus disease 2019 (Covid-19) active cases continue to demand the development of safe and effective treatments. This is the first clinical trial to evaluate the safety and efficacy of oral thymic peptides. ; We conducted a nonrandomized phase 2 trial with a historic control group to evaluate the safety and efficacy of a daily 250-mg oral dose of thymic peptides in the treatment of hospitalized Covid-19 patients. Comparisons based on standard care from registry data were performed after propensity score matching. The primary outcomes were survival, time to recovery, and number of participants with treatment-related adverse events or side effects by day 20. ; A total of 44 patients were analyzed in this study: 22 in the thymic peptide group and 22 in the standard care group. There were no deaths in the intervention group compared to 24% mortality in standard care by day 20 (log-rank P=0.02). Kaplan-Meier analysis showed a significantly shorter time to recovery by day 20 in the thymic peptide group than in the standard care group (median, 6 days vs. 12 days; hazard ratio for recovery, 2.75 [95% confidence interval, 1.34 to 5.62]; log-rank P=0.002). No side effects or adverse events were reported. ; In patients hospitalized with Covid-19, the use of thymic peptides resulted in no side effects, adverse events, or deaths by day 20. Compared with the registry data, a significantly shorter time to recovery and mortality reduction were measured.


Subject(s)
COVID-19 Drug Treatment , Peptides , Humans , Honduras , Kaplan-Meier Estimate , Peptides/adverse effects , Proportional Hazards Models
7.
In Vivo ; 36(6): 2986-2992, 2022.
Article in English | MEDLINE | ID: covidwho-2100684

ABSTRACT

BACKGROUND/AIM: To report long-term survival results after trimodal approach for locally advanced rectal cancer (LARC) in the Covid-19 era. We herein illustrate a clinical application of Covid-death mean-imputation (CoDMI) algorithm in LARC patients with Covid-19 infection. PATIENTS AND METHODS: We analyzed 94 patients treated for primary LARC. Overall survival was calculated in months from diagnosis to first event (last follow-up/death). Because Covid-19 death events potentially bias survival estimation, to eliminate skewed data due to Covid-19 death events, the observed lifetime of Covid-19 cases was replaced by its corresponding expected lifetime in absence of the Covid-19 event using the CoDMI algorithm. Patients who died of Covid-19 (DoC) are mean-imputed by the Kaplan-Meier estimator. Under this approach, the observed lifetime of each DoC patient is considered as an "incomplete data" and is extended by an additional expected lifetime computed using the classical Kaplan-Meier model. RESULTS: Sixteen patients were dead of disease (DoD), 1 patient was DoC and 77 cases were censored (Cen). The DoC patient died of Covid-19 52 months after diagnosis. The CoDMI algorithm computed the expected future lifetime provided by the Kaplan-Meier estimator applied to the no-DoC observations as well as to the DoC data itself. Given the DoC event at 52 months, the CoDMI algorithm estimated that this patient would have died after 79.5 months of follow-up. CONCLUSION: The CoDMI algorithm leads to "unbiased" probability of overall survival in LARC patients with Covid-19 infection, compared to that provided by a naïve application of Kaplan-Meier approach. This allows for a proper interpretation/use of Covid-19 events in survival analysis. A user-friendly version of CoDMI is freely available at https://github.com/alef-innovation/codmi.


Subject(s)
COVID-19 , Radiation Oncology , Humans , Kaplan-Meier Estimate , COVID-19/epidemiology , Survival Analysis , Algorithms
8.
EBioMedicine ; 76: 103856, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1894987

ABSTRACT

BACKGROUND: Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials in COVID19 without characterisation of Pharmacokinetics /Pharmacodynamics including safety data. One such drug is nafamostat mesylate. METHODS: We present the findings of a phase Ib/IIa open label, platform randomised controlled trial of intravenous nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), nafamostat or an alternative therapy. Nafamostat was administered as an intravenous infusion at a dose of 0.2 mg/kg/h for a maximum of seven days. The analysis population included those who received any dose of the trial drug and all patients randomised to SoC. The primary outcomes of our trial were the safety and tolerability of intravenous nafamostat as an add on therapy for patients hospitalised with COVID-19 pneumonitis. FINDINGS: Data is reported from 42 patients, 21 of which were randomly assigned to receive intravenous nafamostat. 86% of nafamostat-treated patients experienced at least one AE compared to 57% of the SoC group. The nafamostat group were significantly more likely to experience at least one AE (posterior mean odds ratio 5.17, 95% credible interval (CI) 1.10 - 26.05) and developed significantly higher plasma creatinine levels (posterior mean difference 10.57 micromol/L, 95% CI 2.43-18.92). An average longer hospital stay was observed in nafamostat patients, alongside a lower rate of oxygen free days (rate ratio 0.55-95% CI 0.31-0.99, respectively). There were no other statistically significant differences in endpoints between nafamostat and SoC. PK data demonstrated that intravenous nafamostat was rapidly broken down to inactive metabolites. We observed no significant anticoagulant effects in thromboelastometry. INTERPRETATION: In hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous nafamostat, and there were additional adverse events. FUNDING: DEFINE was funded by LifeArc (an independent medical research charity) under the STOPCOVID award to the University of Edinburgh. We also thank the Oxford University COVID-19 Research Response Fund (BRD00230).


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Benzamidines/therapeutic use , COVID-19 Drug Treatment , Guanidines/therapeutic use , Administration, Intravenous , Adult , Aged , Aged, 80 and over , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Benzamidines/adverse effects , Benzamidines/pharmacokinetics , Biomarkers/blood , Biomarkers/metabolism , COVID-19/mortality , COVID-19/virology , Drug Administration Schedule , Female , Guanidines/adverse effects , Guanidines/pharmacokinetics , Half-Life , Humans , Immunophenotyping , Kaplan-Meier Estimate , Male , Middle Aged , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Treatment Outcome , Viral Load
9.
Surgery ; 171(5): 1422-1426, 2022 05.
Article in English | MEDLINE | ID: covidwho-1829571

ABSTRACT

BACKGROUND: To determine the impact of COVID-19 infection in patients with chronic limb-threatening ischemia, mainly the limb salvage estimates rate and the overall survival. METHODS: This was a retrospective, consecutive cohort study of chronic limb-threatening ischemia in patients with COVID-19 infection. RESULTS: Overall, 35 patients with chronic limb-threatening ischemia and COVID-19 infection were evaluated. The mean age of the patients was 72.51 years, and most of them were male (60%), with arterial hypertension (85.7%), followed by diabetes mellitus (80%) and tobacco user (71.4%). There was a higher prevalence of wound, ischemia and foot infection (WIfI) classification 4 with 58.8% and Rutherford grade 5 (74.3%). The factors related to overall mortality rate were: D-dimer >1,000 mg/dL (hazard ratio = 22.7, P < .001, confidence interval = 10.49-26.52), respiratory symptoms (hazard ratio = 16.6, P < .001, confidence interval = 9.87-20.90), chest computed tomography compromising higher than 50% of the pulmonary tract (hazard ratio = 16,0, P < .001, confidence interval = 10.41-20.55), acute kidney failure (hazard ratio = 21.58, P < .001, confidence interval = 16.5-30.5), chronic kidney disease (hazard ratio = 4.4, P = .036, confidence interval = 1.45-10.1), therapeutic anticoagulation (hazard ratio = 8.37, P = .004, confidence interval = 1.35-8.45), and WIfI classification (hazard ratio = 5.28, P = .022, confidence interval = 1.34-10.01). The following were related to limb loss: D-dimer >1,000 mg/mL (hazard ratio = 5.47, P = .02, confidence interval = 1.94-10.52), respiratory symptoms (hazard ratio = 5.42, P = .02, confidence interval = 1.87-10.90), and WIfI classification (hazard ratio = 4.44, P = .035, confidence interval = 1.34-8.01). CONCLUSION: This study concluded that COVID-19 has a catastrophic impact among patients with chronic limb-threatening ischemia. The main factors related to overall mortality were D-dimer >1,000 mg/dL, respiratory symptoms, chest computed tomography compromising higher than 50% of the pulmonary tract, acute kidney failure, chronic kidney disease, therapeutic anticoagulation, and WIfI classification. The factors related to limb loss were WIfI classification, D-dimer >1,000 mg/mL and respiratory symptoms.


Subject(s)
COVID-19 , Peripheral Arterial Disease , Wound Infection , Aged , Amputation, Surgical , Anticoagulants , COVID-19/complications , Chronic Limb-Threatening Ischemia , Cohort Studies , Female , Humans , Ischemia/surgery , Kaplan-Meier Estimate , Limb Salvage , Male , Peripheral Arterial Disease/surgery , Predictive Value of Tests , Retrospective Studies , Risk Factors , Time Factors , Treatment Outcome , Wound Healing , Wound Infection/diagnosis , Wound Infection/surgery
10.
PLoS One ; 17(4): e0267235, 2022.
Article in English | MEDLINE | ID: covidwho-1808573

ABSTRACT

BACKGROUND: Chromogranin A (CgA) and its fragment vasostatin I (VS-I) are secreted in the blood by endocrine/neuroendocrine cells and regulate stress responses. Their involvement in Coronavirus 2019 disease (COVID-19) has not been investigated. METHODS: CgA and VS-I plasma concentrations were measured at hospital admission from March to May 2020 in 190 patients. 40 age- and sex-matched healthy volunteers served as controls. CgA and VS-I levels relationship with demographics, comorbidities and disease severity was assessed through Mann Whitney U test or Spearman correlation test. Cox regression analysis and Kaplan Meier survival curves were performed to investigate the impact of the CgA and VS-I levels on in-hospital mortality. RESULTS: Median CgA and VS-I levels were higher in patients than in healthy controls (CgA: 0.558 nM [interquartile range, IQR 0.358-1.046] vs 0.368 nM [IQR 0.288-0.490] respectively, p = 0.0017; VS-I: 0.357 nM [IQR 0.196-0.465] vs 0.144 nM [0.144-0.156] respectively, p<0.0001). Concentration of CgA, but not of VS-I, significantly increased in patients who died (n = 47) than in survivors (n = 143) (median 0.948 nM [IQR 0.514-1.754] vs 0.507 nM [IQR 0.343-0.785], p = 0.00026). Levels of CgA were independent predictors of in-hospital mortality (hazard ratio 1.28 [95% confidence interval 1.077-1.522], p = 0.005) when adjusted for age, number of comorbidities, respiratory insufficiency degree, C-reactive protein levels and time from symptom onset to sampling. Kaplan Meier curves revealed a significantly increased mortality rate in patients with CgA levels above 0.558 nM (median value, log rank test, p = 0.001). CONCLUSION: Plasma CgA levels increase in COVID-19 patients and represent an early independent predictor of mortality.


Subject(s)
COVID-19 , Chromogranin A , Humans , Kaplan-Meier Estimate , Prognosis , Proportional Hazards Models
11.
Proc Natl Acad Sci U S A ; 119(12): e2200065119, 2022 03 22.
Article in English | MEDLINE | ID: covidwho-1740535

ABSTRACT

SignificanceConcern has increased about the pandemic potential of Nipah virus (NiV). Similar to SARS-CoV-2, NiV is an RNA virus that is transmitted by respiratory droplets. There are currently no NiV vaccines licensed for human use. While several preventive vaccines have shown promise in protecting animals against lethal NiV disease, most studies have assessed protection 1 mo after vaccination. However, in order to contain and control outbreaks, vaccines that can rapidly confer protection in days rather than months are needed. Here, we show that a recombinant vesicular stomatitis virus vector expressing the NiV glycoprotein can completely protect monkeys vaccinated 7 d prior to NiV exposure and 67% of animals vaccinated 3 d before NiV challenge.


Subject(s)
Henipavirus Infections/veterinary , Nipah Virus/immunology , Primate Diseases/prevention & control , Vaccines, Synthetic/immunology , Viral Vaccines/immunology , Animals , Antibodies, Neutralizing , Antibodies, Viral/immunology , Biomarkers , Genetic Vectors , Kaplan-Meier Estimate , Neutralization Tests , Outcome Assessment, Health Care , Primate Diseases/diagnosis , Primate Diseases/mortality , Primate Diseases/virology , Vaccination , Viral Load
12.
PLoS One ; 17(3): e0264178, 2022.
Article in English | MEDLINE | ID: covidwho-1731596

ABSTRACT

Renalase is a secreted flavoprotein with anti-inflammatory and pro-cell survival properties. COVID-19 is associated with disordered inflammation and apoptosis. We hypothesized that blood renalase levels would correspond to severe COVID-19 and survival. In this retrospective cohort study, clinicopathologic data and blood samples were collected from hospitalized COVID-19 subjects (March-June 2020) at a single institution tertiary hospital. Plasma renalase and cytokine levels were measured and clinical data abstracted from health records. Of 3,450 COVID-19 patients, 458 patients were enrolled. Patients were excluded if <18 years, or opted out of research. The primary composite outcome was intubation or death within 180 days. Secondary outcomes included mortality alone, intensive care unit admission, use of vasopressors, and CPR. Enrolled patients had mean age 64 years (SD±17), were 53% males, and 48% non-whites. Mean renalase levels was 14,108·4 ng/ml (SD±8,137 ng/ml). Compared to patients with high renalase, those with low renalase (< 8,922 ng/ml) were more likely to present with hypoxia, increased ICU admission (54% vs. 33%, p < 0.001), and cardiopulmonary resuscitation (10% vs. 4%, p = 0·023). In Cox proportional hazard model, every 1000 ng/ml increase in renalase decreased the risk of death or intubation by 5% (HR 0·95; 95% CI 0·91-0·98) and increased survival alone by 6% (HR 0·95; CI 0·90-0·98), after adjusting for socio-demographics, initial disease severity, comorbidities and inflammation. Patients with high renalase-low IL-6 levels had the best survival compared to other groups (p = 0·04). Renalase was independently associated with reduced intubation and mortality in hospitalized COVID-19 patients. Future studies should assess the pathophysiological relevance of renalase in COVID-19 disease.


Subject(s)
COVID-19/pathology , Monoamine Oxidase/blood , Adult , Aged , COVID-19/mortality , COVID-19/virology , Endothelium/metabolism , Endothelium/pathology , Female , Hospitalization , Humans , Intensive Care Units , Interleukin-6/blood , Kaplan-Meier Estimate , Male , Middle Aged , Proportional Hazards Models , Respiration, Artificial , Retrospective Studies , Risk Factors , SARS-CoV-2/isolation & purification , Severity of Illness Index
13.
N Engl J Med ; 386(9): 837-846, 2022 03 03.
Article in English | MEDLINE | ID: covidwho-1721750

ABSTRACT

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection and hospitalization in infants. Nirsevimab is a monoclonal antibody to the RSV fusion protein that has an extended half-life. The efficacy and safety of nirsevimab in healthy late-preterm and term infants are uncertain. METHODS: We randomly assigned, in a 2:1 ratio, infants who had been born at a gestational age of at least 35 weeks to receive a single intramuscular injection of nirsevimab or placebo before the start of an RSV season. The primary efficacy end point was medically attended RSV-associated lower respiratory tract infection through 150 days after the injection. The secondary efficacy end point was hospitalization for RSV-associated lower respiratory tract infection through 150 days after the injection. RESULTS: A total of 1490 infants underwent randomization: 994 were assigned to the nirsevimab group and 496 to the placebo group. Medically attended RSV-associated lower respiratory tract infection occurred in 12 infants (1.2%) in the nirsevimab group and in 25 infants (5.0%) in the placebo group; these findings correspond to an efficacy of 74.5% (95% confidence interval [CI], 49.6 to 87.1; P<0.001) for nirsevimab. Hospitalization for RSV-associated lower respiratory tract infection occurred in 6 infants (0.6%) in the nirsevimab group and in 8 infants (1.6%) in the placebo group (efficacy, 62.1%; 95% CI, -8.6 to 86.8; P = 0.07). Among infants with data available to day 361, antidrug antibodies after baseline were detected in 58 of 951 (6.1%) in the nirsevimab group and in 5 of 473 (1.1%) in the placebo group. Serious adverse events were reported in 67 of 987 infants (6.8%) who received nirsevimab and in 36 of 491 infants (7.3%) who received placebo. CONCLUSIONS: A single injection of nirsevimab administered before the RSV season protected healthy late-preterm and term infants from medically attended RSV-associated lower respiratory tract infection. (Funded by MedImmune/AstraZeneca and Sanofi; MELODY ClinicalTrials.gov number, NCT03979313.).


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antiviral Agents/therapeutic use , Infant, Premature, Diseases/prevention & control , Infant, Premature , Respiratory Syncytial Virus Infections/prevention & control , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Drug Administration Schedule , Female , Humans , Infant , Infant, Newborn , Injections, Intramuscular , Kaplan-Meier Estimate , Male
14.
PLoS One ; 17(2): e0264301, 2022.
Article in English | MEDLINE | ID: covidwho-1703889

ABSTRACT

Remdesivir (RDV) reduces time to clinical improvement in hospitalized COVID -19 patients requiring supplemental oxygen. Dexamethasone improves survival in those requiring oxygen support. Data is lacking on the efficacy of combination therapy in patients on mechanical ventilation. We analyzed for comparative outcomes between Corticosteroid (CS) therapy with combined Corticosteroid and Remdesivir (CS-RDV) therapy. We conducted an observational cohort study of patients aged 18 to 90 with COVID-19 requiring ventilatory support using TriNetX (COVID-19 Research Network) between January 20, 2020, and February 9, 2021. We compared patients who received at least 48 hours of CS-RDV combination therapy to CS monotherapy. The primary outcome was 28-day all-cause mortality rates in propensity-matched (PSM) cohorts. Secondary outcomes were Length of Stay (LOS), Secondary Bacterial Infections (SBI), and MRSA (Methicillin-Resistant Staphylococcus aureus), and Pseudomonas infections. We used univariate and multivariate Cox proportional hazards models and stratified log-rank tests. Of 388 patients included, 91 (23.5%) received CS-RDV therapy, and 297 (76.5%) received CS monotherapy. After propensity score matching, with 74 patients in each cohort, all-cause mortality was 36.4% and 29.7% in the CS-RDV and CS therapy, respectively (P = 0.38). We used a Kaplan-Meier with a log-rank test on follow up period (P = 0.23), and a Hazards Ratio model (P = 0.26). SBI incidence was higher in the CS group (13.5% vs. 35.1%, P = 0.02) with a similar LOS (13.4 days vs. 13.4 days, P = 1.00) and similar incidence of MRSA/Pseudomonas infections (13.5% vs. 13.5%, P = 1.00) in both the groups. Therefore, CS-RDV therapy is non-inferior to CS therapy in reducing 28-day all-cause in-hospital mortality but associated with a significant decrease in the incidence of SBI in critically ill COVID-19 patients.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Adrenal Cortex Hormones/therapeutic use , Alanine/analogs & derivatives , COVID-19 Drug Treatment , Adenosine Monophosphate/therapeutic use , Aged , Alanine/therapeutic use , COVID-19/complications , COVID-19/mortality , COVID-19/virology , Cohort Studies , Drug Therapy, Combination , Female , Hospital Mortality , Humans , Incidence , Kaplan-Meier Estimate , Length of Stay , Male , Middle Aged , Proportional Hazards Models , Pseudomonas Infections/diagnosis , Pseudomonas Infections/epidemiology , Pseudomonas Infections/etiology , Respiration, Artificial , SARS-CoV-2/isolation & purification , Staphylococcal Infections/diagnosis , Staphylococcal Infections/epidemiology , Staphylococcal Infections/etiology , Treatment Outcome
15.
Sci Rep ; 12(1): 2552, 2022 02 15.
Article in English | MEDLINE | ID: covidwho-1692551

ABSTRACT

There is a need for effective therapy for COVID-19 pneumonia. Convalescent plasma has antiviral activity and early observational studies suggested benefit in reducing COVID-19 severity. We investigated the safety and efficacy of convalescent plasma in hospitalized patients with COVID-19 in a population with a high HIV prevalence and where few therapeutic options were available. We performed a double-blinded, multicenter, randomized controlled trial in one private and three public sector hospitals in South Africa. Adult participants with COVID-19 pneumonia requiring non-invasive oxygen were randomized 1:1 to receive a single transfusion of 200 mL of either convalescent plasma or 0.9% saline solution. The primary outcome measure was hospital discharge and/or improvement of ≥ 2 points on the World Health Organisation Blueprint Ordinal Scale for Clinical Improvement by day 28 of enrolment. The trial was stopped early for futility by the Data and Safety Monitoring Board. 103 participants, including 21 HIV positive individuals, were randomized at the time of premature trial termination: 52 in the convalescent plasma and 51 in the placebo group. The primary outcome occurred in 31 participants in the convalescent plasma group and and 32 participants in the placebo group (relative risk 1.03 (95% CI 0.77 to 1.38). Two grade 1 transfusion-related adverse events occurred. Participants who improved clinically received convalescent plasma with a higher median anti-SARS-CoV-2 neutralizing antibody titre compared with those who did not (298 versus 205 AU/mL). Our study contributes additional evidence for recommendations against the use of convalescent plasma for COVID-19 pneumonia. Safety and feasibility in this population supports future investigation for other indications.


Subject(s)
COVID-19/therapy , Adult , COVID-19/mortality , COVID-19/pathology , COVID-19/virology , Double-Blind Method , Female , HIV Infections/complications , Hospitals, Public , Humans , Immunization, Passive , Kaplan-Meier Estimate , Male , Middle Aged , Placebo Effect , SARS-CoV-2/isolation & purification , Severity of Illness Index , South Africa , Treatment Outcome , COVID-19 Serotherapy
16.
N Engl J Med ; 386(9): 847-860, 2022 03 03.
Article in English | MEDLINE | ID: covidwho-1684178

ABSTRACT

BACKGROUND: The Ad26.COV2.S vaccine was highly effective against severe-critical coronavirus disease 2019 (Covid-19), hospitalization, and death in the primary phase 3 efficacy analysis. METHODS: We conducted the final analysis in the double-blind phase of our multinational, randomized, placebo-controlled trial, in which adults were assigned in a 1:1 ratio to receive single-dose Ad26.COV2.S (5×1010 viral particles) or placebo. The primary end points were vaccine efficacy against moderate to severe-critical Covid-19 with onset at least 14 days after administration and at least 28 days after administration in the per-protocol population. Safety and key secondary and exploratory end points were also assessed. RESULTS: Median follow-up in this analysis was 4 months; 8940 participants had at least 6 months of follow-up. In the per-protocol population (39,185 participants), vaccine efficacy against moderate to severe-critical Covid-19 at least 14 days after administration was 56.3% (95% confidence interval [CI], 51.3 to 60.8; 484 cases in the vaccine group vs. 1067 in the placebo group); at least 28 days after administration, vaccine efficacy was 52.9% (95% CI, 47.1 to 58.1; 433 cases in the vaccine group vs. 883 in the placebo group). Efficacy in the United States, primarily against the reference strain (B.1.D614G) and the B.1.1.7 (alpha) variant, was 69.7% (95% CI, 60.7 to 76.9); efficacy was reduced elsewhere against the P.1 (gamma), C.37 (lambda), and B.1.621 (mu) variants. Efficacy was 74.6% (95% CI, 64.7 to 82.1) against severe-critical Covid-19 (with only 4 severe-critical cases caused by the B.1.617.2 [delta] variant), 75.6% (95% CI, 54.3 to 88.0) against Covid-19 leading to medical intervention (including hospitalization), and 82.8% (95% CI, 40.5 to 96.8) against Covid-19-related death, with protection lasting 6 months or longer. Efficacy against any severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was 41.7% (95% CI, 36.3 to 46.7). Ad26.COV2.S was associated with mainly mild-to-moderate adverse events, and no new safety concerns were identified. CONCLUSIONS: A single dose of Ad26.COV2.S provided 52.9% protection against moderate to severe-critical Covid-19. Protection varied according to variant; higher protection was observed against severe Covid-19, medical intervention, and death than against other end points and lasted for 6 months or longer. (Funded by Janssen Research and Development and others; ENSEMBLE ClinicalTrials.gov number, NCT04505722.).


Subject(s)
Ad26COVS1 , COVID-19/prevention & control , Vaccine Efficacy/statistics & numerical data , Ad26COVS1/adverse effects , Ad26COVS1/immunology , Adolescent , Adult , COVID-19/epidemiology , COVID-19/mortality , Double-Blind Method , Follow-Up Studies , Hospitalization/statistics & numerical data , Humans , Immunogenicity, Vaccine , Kaplan-Meier Estimate , Middle Aged , Patient Acuity , SARS-CoV-2 , Young Adult
17.
Biomolecules ; 12(2)2022 02 08.
Article in English | MEDLINE | ID: covidwho-1674482

ABSTRACT

A high proportion of critically ill patients with COVID-19 develop acute kidney injury (AKI) and die. The early recognition of subclinical AKI could contribute to AKI prevention. Therefore, this study was aimed at exploring the role of the urinary biomarkers NGAL and [TIMP-2] × [IGFBP7] for the early detection of AKI in this population. This prospective, longitudinal cohort study included critically ill COVID-19 patients without AKI at study entry. Urine samples were collected on admission to critical care areas for determination of NGAL and [TIMP-2] × [IGFBP7] concentrations. The demographic information, comorbidities, clinical, and laboratory data were recorded. The study outcomes were the development of AKI and mortality during hospitalization. Of the 51 individuals that were studied, 25 developed AKI during hospitalization (49%). Of those, 12 had persistent AKI (23.5%). The risk factors for AKI were male gender (HR = 7.57, 95% CI: 1.28-44.8; p = 0.026) and [TIMP-2] × [IGFBP7] ≥ 0.2 (ng/mL)2/1000 (HR = 7.23, 95% CI: 0.99-52.4; p = 0.050). Mortality during hospitalization was significantly higher in the group with AKI than in the group without AKI (p = 0.004). Persistent AKI was a risk factor for mortality (HR = 7.42, 95% CI: 1.04-53.04; p = 0.046). AKI was frequent in critically ill COVID-19 patients. The combination of [TIMP-2] × [IGFBP7] together with clinical information, were useful for the identification of subclinical AKI in critically ill COVID-19 patients. The role of additional biomarkers and their possible combinations for detection of AKI in ritically ill COVID-19 patients remains to be explored in large clinical trials.


Subject(s)
Acute Kidney Injury/diagnosis , Acute Kidney Injury/urine , COVID-19/diagnosis , COVID-19/urine , Critical Illness/mortality , Acute Kidney Injury/complications , Acute Kidney Injury/mortality , Adult , Aged , Biomarkers/urine , COVID-19/complications , COVID-19/mortality , Female , Humans , Insulin-Like Growth Factor Binding Proteins/urine , Kaplan-Meier Estimate , Lipocalin-2/urine , Longitudinal Studies , Male , Middle Aged , Prospective Studies , Risk Factors , Tissue Inhibitor of Metalloproteinase-2/urine
18.
Antimicrob Resist Infect Control ; 11(1): 27, 2022 02 05.
Article in English | MEDLINE | ID: covidwho-1673927

ABSTRACT

BACKGROUND: There is insufficient evidence regarding the role of respirators in the prevention of SARS-CoV-2 infection. We analysed the impact of filtering facepiece class 2 (FFP2) versus surgical masks on the risk of SARS-CoV-2 acquisition among Swiss healthcare workers (HCW). METHODS: Our prospective multicentre cohort enrolled HCW from June to August 2020. Participants were asked about COVID-19 risk exposures/behaviours, including preferentially worn mask type when caring for COVID-19 patients outside of aerosol-generating procedures. The impact of FFP2 on (1) self-reported SARS-CoV-2-positive nasopharyngeal PCR/rapid antigen tests captured during weekly surveys, and (2) SARS-CoV-2 seroconversion between baseline and January/February 2021 was assessed. RESULTS: We enrolled 3259 participants from nine healthcare institutions, whereof 716 (22%) preferentially used FFP2. Among these, 81/716 (11%) reported a SARS-CoV-2-positive swab, compared to 352/2543 (14%) surgical mask users; seroconversion was documented in 85/656 (13%) FFP2 and 426/2255 (19%) surgical mask users. Adjusted for baseline characteristics, COVID-19 exposure, and risk behaviour, FFP2 use was non-significantly associated with decreased risk for SARS-CoV-2-positive swab (adjusted hazard ratio [aHR] 0.8, 95% CI 0.6-1.0) and seroconversion (adjusted odds ratio [aOR] 0.7, 95% CI 0.5-1.0); household exposure was the strongest risk factor (aHR 10.1, 95% CI 7.5-13.5; aOR 5.0, 95% CI 3.9-6.5). In subgroup analysis, FFP2 use was clearly protective among those with frequent (> 20 patients) COVID-19 exposure (aHR 0.7 for positive swab, 95% CI 0.5-0.8; aOR 0.6 for seroconversion, 95% CI 0.4-1.0). CONCLUSIONS: Respirators compared to surgical masks may convey additional protection from SARS-CoV-2 for HCW with frequent exposure to COVID-19 patients.


Subject(s)
COVID-19/prevention & control , Health Personnel , Masks , Respiratory Protective Devices , Adolescent , Adult , Aerosols , Aged , COVID-19/epidemiology , Female , Humans , Infection Control/methods , Kaplan-Meier Estimate , Logistic Models , Male , Middle Aged , Prospective Studies , Seroconversion , Switzerland , Young Adult
19.
J Cardiothorac Vasc Anesth ; 36(8 Pt B): 2935-2941, 2022 08.
Article in English | MEDLINE | ID: covidwho-1665734

ABSTRACT

OBJECTIVES: Cardiac injury has been reported in up to 20%-to-30% of patients with COVID-19, and severe disease can lead to cardiopulmonary failure. The role of mechanical circulatory support in these patients remains undetermined. The authors here aimed to determine the characteristics and outcomes of patients with COVID-19 requiring venoarterial extracorporeal membrane oxygenation (VA ECMO) or veno-arterial-venous (VAV) ECMO support. DESIGN AND SETTING: A multicenter, retrospective case series. PARTICIPANTS: The cohort consisted of adult patients (18 years of age and older) with confirmed COVID-19 requiring VA ECMO or VAV ECMO support in the period from March 1, 2020, to April 30, 2021. Outcomes were recorded until July 31, 2021. MEASUREMENTS AND MAIN RESULTS: To show factors related to death during hospitalization, patients were grouped as survivors and nonsurvivors. Kaplan-Meier analysis was used to estimate 90-day in-hospital mortality. Overall, 37 patients from 12 centers comprised the study cohort. The median patient age was 44 years old (interquartile range [IQR], 35-52), and 12 (32%) were female patients. The duration of ECMO support ranged from 2-to-132 days. At the end of the follow-up period, 13 patients (35%) were discharged or transferred alive, and 24 patients (65%) died during the hospitalization. The cumulative in-hospital mortality at 90 days was 64% (95% confidence interval: 47-81). During the time from intubation to VA ECMO or VAV ECMO initiation (1 day [IQR 0-7.5] v 6 days [IQR 2.5-14], p = 0.0383), body mass index (32 [IQR 26-36] v 37 [IQR 33-40], p = 0.009), and baseline C-reactive protein (7.15 v 38.9 mg/dL, p = 0.009) were higher in those who expired. CONCLUSION: Only one-third of the patients with COVID-19 requiring VA ECMO or VAV ECMO survived to discharge. Close monitoring of at-risk patients with early initiation of ECMO with circulatory support may further improve outcomes.


Subject(s)
COVID-19 , Extracorporeal Membrane Oxygenation , Adolescent , Adult , COVID-19/therapy , Female , Hospital Mortality , Humans , Kaplan-Meier Estimate , Male , Retrospective Studies
20.
J Korean Med Sci ; 37(4): e29, 2022 Jan 24.
Article in English | MEDLINE | ID: covidwho-1648601

ABSTRACT

BACKGROUND: Several studies have recently suggested that liver disease and cirrhosis were risk factors for poor outcomes in patients with coronavirus disease 2019 (COVID-19) infections. However, no large data study has reported the clinical course of COVID-19 patients with chronic hepatitis B virus (HBV) infections. This study investigated whether HBV infection had negative impacts on the clinical outcomes of COVID-19 patients. METHODS: We performed a nationwide population-based cohort study with 19,160 COVID-19-infected patients in 2020 from the Korean Health Insurance Review and Assessment database. The clinical outcomes of COVID-19 patients with chronic HBV infections were assessed and compared to those of non-HBV-infected patients. RESULTS: Of the 19,160 patients diagnosed with COVID-19, 675 (3.5%) patients had chronic HBV infections. The HBV-infected patients were older and had more commodities than the non-HBV infected COVID-19 patients. During the observation period, COVID-19-related mortality was seen in 1,524 (8.2%) of the non-HBV-infected 18,485 patients, whereas 91 (13.5%) in HBV-infected 675 patients died of COVID-19 infection. Compared to patients without HBV infections, a higher proportion of patients with chronic HBV infections required intensive care unit (ICU) admission and had organ failures. However, odds ratios for mortality, ICU admission, and organ failure were comparable between the two groups after adjusting for age, sex, and comorbid diseases including liver cirrhosis and hepatocellular carcinoma. CONCLUSION: COVID-19-infected patients with HBV infections showed worse clinical courses than non-HBV-infected COVID-19 patients. However, after adjustment, chronic HBV infection itself does not seem to affect the clinical outcomes in COVID-19 patients.


Subject(s)
COVID-19/epidemiology , COVID-19/mortality , Hepatitis B, Chronic/epidemiology , Hepatitis B, Chronic/mortality , Antiviral Agents/therapeutic use , COVID-19/therapy , Cell Line, Tumor , Comorbidity , Female , Hepatitis B virus , Hepatitis B, Chronic/therapy , Humans , Kaplan-Meier Estimate , Length of Stay/statistics & numerical data , Male , Middle Aged , Organ Dysfunction Scores , SARS-CoV-2 , Treatment Outcome
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