ABSTRACT
Introduction: Case definitions are used to guide clinical practice, surveillance, and research protocols. However, how they identify COVID-19-hospitalised patients is not fully understood. We analysed the proportion of hospitalised patients with laboratory-confirmed COVID-19, in the ISARIC prospective cohort study database, meeting widely used case definitions. Methods: Patients were assessed using the CDC, ECDC, WHO, and UKHSA case definitions by age, region, and time. Case fatality ratios (CFR) and symptoms of those who did and who did not meet the case definitions were evaluated. Patients with incomplete data and non-laboratory-confirmed test-result were excluded. Results: 263,218 of the patients (42%) in the ISARIC database were included. Most patients (90.4%) were from Europe and Central Asia. The proportions of patients meeting the case definitions were 56.8% (WHO), 74.4% (UKHSA), 81.6% (ECDC), and 82.3% (CDC). For each case definition, patients at the extremes of age distribution met the criteria less frequently than those aged 30 to 70 years; geographical and time variations were also observed. Estimated CFRs were similar for the patients that met the case definitions. However, when more patients did not meet the case definition, the CFR increased. Conclusions: The performance of case definitions might be different in different regions and may change over time. Similarly concerning is the fact that older patients often did not meet case definitions. While epidemiologists must balance their analytics with field applicability, ongoing revision of case definitions is necessary to improve patient care through early diagnosis and limit potential nosocomial spread.
Subject(s)
COVID-19ABSTRACT
BackgroundWhilst timely clinical characterisation of infections caused by novel SARS-CoV-2 variants is necessary for evidence-based policy response, individual-level data on infecting variants are typically only available for a minority of patients and settings. MethodsHere, we propose an innovative approach to study changes in COVID-19 hospital presentation and outcomes after the Omicron variant emergence using publicly available population-level data on variant relative frequency to infer SARS-CoV-2 variants likely responsible for clinical cases. We apply this method to data collected by a large international clinical consortium before and after the emergence of the Omicron variant in different countries. ResultsOur analysis, that includes more than 100,000 patients from 28 countries, suggests that in many settings patients hospitalised with Omicron variant infection less often presented with commonly reported symptoms compared to patients infected with pre-Omicron variants. Patients with COVID-19 admitted to hospital after Omicron variant emergence had lower mortality compared to patients admitted during the period when Omicron variant was responsible for only a minority of infections (odds ratio in a mixed-effects logistic regression adjusted for likely confounders, 0.67 [95% confidence interval 0.61 - 0.75]). Qualitatively similar findings were observed in sensitivity analyses with different assumptions on population-level Omicron variant relative frequencies, and in analyses using available individual-level data on infecting variant for a subset of the study population. ConclusionsAlthough clinical studies with matching viral genomic information should remain a priority, our approach combining publicly available data on variant frequency and a multi-country clinical characterisation dataset with more than 100,000 records allowed analysis of data from a wide range of settings and novel insights on real-world heterogeneity of COVID-19 presentation and clinical outcome.
Subject(s)
COVID-19ABSTRACT
Background Acute kidney injury (AKI) is one of the most common and significant problems in patients with Coronavirus Disease 2019 (COVID-19). However, little is known about the incidence and impact of AKI occurring in the community or early in the hospital admission. The traditional Kidney Disease Improving Global Outcomes (KDIGO) definition can fail to identify patients for whom hospitalisation coincides with recovery of AKI as manifested by a decrease in serum creatinine (sCr). We hypothesised that an extended KDIGO (eKDIGO) definition, adapted from the International Society of Nephrology (ISN) 0by25 studies, would identify more cases of AKI in patients with COVID-19 and that these may correspond to community-acquired AKI (CA-AKI) with similarly poor outcomes as previously reported in this population. Methods and findings All individuals recruited using the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC)–World Health Organization (WHO) Clinical Characterisation Protocol (CCP) and admitted to 1,609 hospitals in 54 countries with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection from February 15, 2020 to February 1, 2021 were included in the study. Data were collected and analysed for the duration of a patient’s admission. Incidence, staging, and timing of AKI were evaluated using a traditional and eKDIGO definition, which incorporated a commensurate decrease in sCr. Patients within eKDIGO diagnosed with AKI by a decrease in sCr were labelled as deKDIGO. Clinical characteristics and outcomes—intensive care unit (ICU) admission, invasive mechanical ventilation, and in-hospital death—were compared for all 3 groups of patients. The relationship between eKDIGO AKI and in-hospital death was assessed using survival curves and logistic regression, adjusting for disease severity and AKI susceptibility. A total of 75,670 patients were included in the final analysis cohort. Median length of admission was 12 days (interquartile range [IQR] 7, 20). There were twice as many patients with AKI identified by eKDIGO than KDIGO (31.7% versus 16.8%). Those in the eKDIGO group had a greater proportion of stage 1 AKI (58% versus 36% in KDIGO patients). Peak AKI occurred early in the admission more frequently among eKDIGO than KDIGO patients. Compared to those without AKI, patients in the eKDIGO group had worse renal function on admission, more in-hospital complications, higher rates of ICU admission (54% versus 23%) invasive ventilation (45% versus 15%), and increased mortality (38% versus 19%). Patients in the eKDIGO group had a higher risk of in-hospital death than those without AKI (adjusted odds ratio: 1.78, 95% confidence interval: 1.71 to 1.80, p-value < 0.001). Mortality and rate of ICU admission were lower among deKDIGO than KDIGO patients (25% versus 50% death and 35% versus 70% ICU admission) but significantly higher when compared to patients with no AKI (25% versus 19% death and 35% versus 23% ICU admission) (all p-values <5 × 10−5). Limitations include ad hoc sCr sampling, exclusion of patients with less than two sCr measurements, and limited availability of sCr measurements prior to initiation of acute dialysis. Conclusions An extended KDIGO definition of AKI resulted in a significantly higher detection rate in this population. These additional cases of AKI occurred early in the hospital admission and were associated with worse outcomes compared to patients without AKI.
ABSTRACT
BackgroundAcute kidney injury (AKI) is one of the most common and significant problems in patients with COVID-19. However, little is known about the incidence and impact of AKI occurring in the community or early in the hospital admission. The traditional KDIGO definition can fail to identify patients for whom hospitalization coincides with recovery of AKI as manifested by a decrease in serum creatinine (sCr). We hypothesized that an extended KDIGO definition, adapted from the International Society of Nephrology 0by25 studies, would identify more cases of AKI in patients with COVID-19 and that these may correspond to community-acquired AKI with similarly poor outcomes as previously reported in this population. Methods and FindingsAll individuals in the ISARIC cohort admitted to hospital with SARS-CoV-2 infection from February 15th, 2020, to February 1st, 2021, were included in the study. Data was collected and analysed for the duration of a patients admission. Incidence, staging and timing of AKI were evaluated using a traditional and extended KDIGO (eKDIGO) definition which incorporated a commensurate decrease in serum creatinine. Patients within eKDIGO diagnosed with AKI by a decrease in sCr were labelled as deKDIGO. Clinical characteristic and outcomes - intensive care unit (ICU) admission, invasive mechanical ventilation and in-hospital death - were compared for all three groups of patients. The relationship between eKDIGO AKI and in-hospital death was assessed using survival curves and logistic regression, adjusting for disease severity and AKI susceptibility. 75,670 patients from 54 countries were included in the final analysis cohort. Median length of admission was 12 days (IQR 7, 20). There were twice as many patients with AKI identified by eKDIGO than KDIGO (31.7 vs 16.8%). Those in the eKDIGO group had a greater proportion of stage 1 AKI (58% vs 36% in KDIGO patients). Peak AKI occurred early in the admission more frequently among eKDIGO than KDIGO patients. Compared to those without AKI, patients in the eKDIGO group had worse renal function on admission, more in-hospital complications, higher rates of ICU admission (54% vs 23%) invasive ventilation (45% vs 15%) and increased mortality (38% vs 19%). Patients in the eKDIGO group had a higher risk of in-hospital death than those without AKI (adjusted OR: 1.78, 95% confidence interval: 1.71-1.8, p-value < 0.001). Mortality and rate of ICU admission were lower among deKDIGO than KDIGO patients (25% vs 50% death and 35% vs 70% ICU admission) but significantly higher when compared to patients with no AKI (25% vs 19% death and 35% vs 23% ICU admission) (all p values < 5x10-5). Limitations include ad hoc sCr sampling, exclusion of patients with less than two sCr measurements, and limited availability of sCr measurements prior to initiation of acute dialysis. ConclusionsThe use of an extended KDIGO definition to diagnose AKI in this population resulted in a significantly higher incidence rate compared to traditional KDIGO criteria. These additional cases of AKI appear to be occurring in the community or early in the hospital admission and are associated with worse outcomes than those without AKI. Author SummaryO_ST_ABSWhy was this study done?C_ST_ABSO_LIPrevious studies have shown that acute kidney injury (AKI) is a common problem among hospitalized patients with COVID-19. C_LIO_LIThe current biochemical criteria used to diagnose AKI may be insufficient to capture AKI that develops in the community and is recovering by the time a patient presents to hospital. C_LIO_LIThe use of an extended definition, that can identify AKI both during its development and recovery phase, may allow us to identify more patients with AKI. These patients may benefit from early management strategies to improve long term outcomes. C_LI What did the researchers do and find?O_LIIn this study, we examined AKI incidence, severity and outcomes among a large international cohort of patients with COVID-19 using both a traditional and extended definition of AKI. C_LIO_LIWe found that using the extended definition identified almost twice as many cases of AKI than the traditional definition (31.7 vs 16.8%). C_LIO_LIThese additional cases of AKI were generally less severe and occurred earlier in the hospital admission. Nevertheless, they were associated with worse outcomes, including ICU admission and in-hospital death (adjusted odds ratio: 1.78, 95% confidence interval: 1.71-1.8, p-value < 0.001) than those with no AKI. C_LI What do these findings mean?O_LIThe current definition of AKI fails to identify a large group of patients with AKI that appears to develop in the community or early in the hospital admission. C_LIO_LIGiven the finding that these cases of AKI are associated with worse admission outcomes than those without AKI, identifying and managing them in a timely manner is enormously important. C_LI
Subject(s)
Addison Disease , Kidney Diseases , Death , Acute Kidney Injury , COVID-19ABSTRACT
Background: The benefits of remdesivir in the treatment of hospitalized patients with Covid-19 remain debated with the National Institutes of Health and the World Health Organization providing contradictory recommendations for and against use. Methods: We performed a systematic review of randomized controlled trials (RCTs) of remdesivir for the treatment of hospitalized patients with COVID-19. The primary outcome was mortality, stratified by oxygen use (none, supplemental oxygen without mechanical ventilation, and mechanical ventilation). We conducted a frequentist random effects meta-analysis on the risk ratio (RR) scale and, to better contextualize the probabilistic benefits, we also performed a bayesian random effects meta-analysis on the risk difference scale. Results: We identified 8 randomized trials, totaling 9157 participants. The RR for mortality comparing remdesivir versus control was 0.71 (95% confidence interval [CI] 0.42-1.22; I2=0.0%) in the patients who did not require supplemental oxygen; 0.83 (95%CI 0.73-0.95; I2=0.0%) for nonventilated patients requiring oxygen; and 1.19 (95%CI 0.98-1.44 I2=0.0%) in the setting of mechanical ventilation. Using neutral priors, the probabilities that remdesivir reduces mortality were 74.7%, 96.9% and 8.9%, respectively. The probability that remdesivir reduced mortality by more than 1% was 88.1% for nonventilated patients requiring oxygen. Conclusion: Based on this meta-analysis, there is a high probability that remdesivir reduces mortality for nonventilated patients with COVID-19 requiring supplemental oxygen therapy.
Subject(s)
COVID-19ABSTRACT
Abstract Pakistan Registry of Intensive Care (PRICE) is a platform that has enabled standardized COVID-19 clinical data collection based on ISARIC/WHO Clinical Characterization Protocol. The near real-time data platform includes epidemiology, severity of illness, microbiology, treatment and outcomes of patients admitted with suspected or laboratory confirmed COVID19 infection to 67 intensive care and high dependency units across the country. Data has been extracted and analysed at regular intervals to inform stakeholders and improve care practices. This is our 28th report including all patients with suspected or confirmed COVID-19 from 26th March 2020 to 26th December 2021. Key findings from 8624 patients who met eligibility criteria, are as follows: [bullet] Median age of 60 years (IQR 50-70). [bullet] The most common symptoms were shortness of breath (n = 6428, 77.8%), fever (n = 6091, 73.8%), and Cough (n = 3354, 38.9%) [bullet] The most common comorbidity was hypertension followed by diabetes. [bullet] During the course of illness 2804 (32.6%) patients received non-invasive ventilation, whereas 2474 (28.8%) patients had mechanical ventilation as their highest organ support. In addition, 2246 (26.1%) patients needed haemodynamic support and 1249 (14.7%) patients required renal replacement therapy as their highest organ support. [bullet] Median APACHE II score was 18 [bullet] Overall mortality at ICU discharge was 39.2% [bullet] Increasing age and requirement for invasive mechanical ventilation were independent risk factors for mortality increased the risk of death
Subject(s)
Dyspnea , Fever , Diabetes Mellitus , Hypertension , Death , COVID-19ABSTRACT
BackgroundSeveral outpatient COVID-19 therapies have reduced hospitalization in randomized controlled trials. The choice of therapy may depend on drug efficacy, toxicity, pricing, availability, and access to administration infrastructure. To facilitate comparative decision making, we evaluated the efficacy of each treatment in clinical trials and then estimated the associated cost per hospitalization prevented. MethodsWherever possible, we obtained relative risk for hospitalization from published randomized controlled trials. Otherwise, we extracted data from press releases, conference abstracts, government submissions, or preprints. If more than one study was published, the results were meta-analyzed. Using relative risk, we estimated the number needed to treat (NNT), assuming a baseline hospitalization risk of 5%. Drug pricing was based on Canadian formularies, government purchases, or manufacturer estimates. Administrative and societal costs were not included. Results will be updated online as new studies emerge or final publication numbers become available. ResultsAt a 5% risk of hospitalization the estimated NNTs were: 87 for colchicine, 80 for fluvoxamine, 72 for inhaled corticosteroids, 24 for nirmatrelvir/ritonavir, 25 for sotrovimab, 24 for remdesivir, 29 for casirivimab/imdevimab, 29 for bamlanivimab/etesevimab and 52 for molnupiravir. Colchicine, fluvoxamine, inhaled corticosteroids, and nirmatrelvir/ritonavir had cost per hospitalization prevented point estimates below the CIHI estimated cost of hospitalization ($23000). InterpretationCanada is fortunate to have access to several effective outpatient therapies to prevent COVID-19 hospitalization. Given differences in efficacy, toxicity, cost and administration complexities, this assessment serves as one tool to help guide policy makers and clinicians in their treatment selection.
Subject(s)
COVID-19 , Drug-Related Side Effects and Adverse ReactionsABSTRACT
ObjectiveTo estimate pairwise associations between administration of tocilizumab, sarilumab and usual care or placebo with 28-day mortality, in COVID-19 patients receiving concomitant corticosteroids and non-invasive or mechanical ventilation, based on all available direct and indirect evidence. MethodsEligible trials randomized hospitalized patients with COVID-19 that compared either interleukin-6 receptor antagonist with usual care or placebo in a recent prospective meta-analysis (27 trials, 10930 patients) or that directly compared tocilizumab with sarilumab. Data were restricted to patients receiving corticosteroids and either non-invasive or invasive ventilation at randomization. Pairwise associations between tocilizumab, sarilumab and usual care or placebo for all-cause mortality 28 days after randomization were estimated using a frequentist contrast-based network meta-analysis of odds ratios (ORs), implementing multivariate fixed-effects models that assume consistency between the direct and indirect evidence. ResultsOne trial (REMAP-CAP) was identified that directly compared tocilizumab with sarilumab and supplied results on all-cause mortality at 28-days. This network meta-analysis was based on 898 eligible patients (278 deaths) from REMAP-CAP and 3710 eligible patients from 18 trials (1278 deaths) from the prospective meta-analysis. Summary ORs were similar for tocilizumab [0.82 [0.71-0.95, P=0.008]] and sarilumab [0.80 [0.61-1.04, P=0.09]] compared with usual care or placebo. The summary OR for 28-day mortality comparing tocilizumab with sarilumab was 1.03 [95%CI 0.81-1.32, P=0.80]. The P value for the global test for inconsistency was 0.28. ConclusionAdministration of either tocilizumab or sarilumab was associated with lower 28-day all-cause mortality compared with usual care or placebo. The association is not dependent on the choice of interleukin-6 receptor antagonist.
Subject(s)
COVID-19ABSTRACT
Background: Risk factors associated with mortality in patients with coronavirus disease 2019 (COVID-19) on mechanical ventilation are still not fully elucidated. Thus, we aimed to identify patient-level factors, readily available at the bedside, associated with the risk of in-hospital mortality within 28 days from commencement of invasive mechanical ventilation (28-day IMV mortality) in patients with COVID-19. Methods: Prospective observational cohort study in 148 intensive care units in the global COVID-19 Critical Care Consortium . Patients with clinically suspected or laboratory confirmed COVID-19 infection admitted to the intensive care unit (ICU) from February 2 nd through December 29th, 2020, requiring IMV. No study-specific interventions were performed. Patient characteristics and clinical data were assessed upon ICU admission, the commencement of IMV and for 28 days thereafter. We primarily aimed to identify time-independent and time-dependent risk factors for 28-day IMV mortality. Results: : A total of 1713 patients were included in the survival analysis, 588 patients died in hospital within 28 days of commencing IMV (34.3%). Cox-regression analysis identified associations between the hazard of 28-day IMV mortality with age (HR 1.27 per 10-year increase in age, 95% CI 1.17 to 1.37, P<0.001), PEEP upon commencement of IMV (HR 0.78 per 5-cmH 2 O increase, 95% CI 0.66-0.93, P=0.005). Time-dependent parameters associated with 28-day IMV mortality were serum creatinine (HR 1.30 per doubling, 95% CI 1.19-1.42, P<0.001), lactate (HR 1.16 per doubling, 95% CI 1.06-1.27 P=0.001), PaCO 2 (HR 1.31 per doubling, 95% CI 1.05-1.64, P=0.015), pH (HR 0.82 per 0.1 increase, 95% CI 0.74-0.91, P<0.001), PaO 2 /FiO 2 (HR 0.56 per doubling, 95% CI 0.50-0.62, P<0.001) and mean arterial pressure (HR 0.92 per 10 mmHg increase, 95% CI 0.88-0.97, P=0.002). Conclusions: : This international study establishes that in mechanically ventilated patients with COVID-19, older age and clinically relevant variables monitored at the bedside are risk factors for 28-day IMV mortality. Further investigation is warranted to validate any causative roles these parameters might play in influencing clinical outcomes.
Subject(s)
COVID-19ABSTRACT
Objective To determine and compare the effects of drug prophylaxis on severe acute respiratory syndrome coronavirus virus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (covid-19). Design Living systematic review and network meta-analysis. Data sources WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature to 19 January 2021, and six additional Chinese databases to 20 January 2021. Study selection Randomized trials in which people at risk of covid-19 were randomized to drug prophylaxis or no prophylaxis (standard care or placebo). Pairs of reviewers independently screened potentially eligible articles. Methods After duplicate data abstraction, we conducted random-effects bayesian network meta-analysis. We assessed risk of bias of the included studies using a modification of the Cochrane risk of bias 2.0 tool and assessed the certainty of the evidence using the grading of recommendations assessment, development and evaluation (GRADE) approach. Results The first iteration of this living network meta-analysis includes nine randomized trials: six addressing hydroxychloroquine (6,059 participants), one addressing ivermectin combined with iota-carrageenan (234 participants) and two addressing ivermectin alone (540 participants), all compared to standard care or placebo. Hydroxychloroquine has no important effect on admission to hospital (risk difference (RD) 1 fewer per 1,000, 95% credible interval (CrI) 3 fewer to 4 more, high certainty) or mortality (RD 1 fewer per 1,000, 95% CrI 2 fewer to 3 more, high certainty). Hydroxychloroquine probably has no important effect on laboratory-confirmed infection (RD 2 more per 1,000, 95% CrI 18 fewer to 28 more, moderate certainty), probably increases adverse effects leading to drug discontinuation (RD 19 more per 1,000, 95% CrI 1 fewer to 70 more, moderate certainty) and may have no important effect on suspected, probable or laboratory-confirmed infection (RD 15 fewer per 1,000, 95% CrI 64 fewer to 41 more, low certainty). Due to serious risk of bias and very serious imprecision, and thus very low certainty evidence, the effects of ivermectin combined with iota-carrageenan on laboratory-confirmed infection (RD 52 fewer per 1,000, 95% CrI 58 fewer to 37 fewer), and ivermectin alone on laboratory-confirmed infection (RD 50 fewer per 1,000, 95% CrI 59 fewer to 16 fewer) and suspected, probable or laboratory-confirmed infection (RD 159 fewer per 1,000, 95% CrI 165 fewer to 144 fewer) remain uncertain. Conclusion Hydroxychloroquine prophylaxis does not have an important effect on hospital admission and mortality, probably increases adverse effects, and probably does not have an important effect on laboratory-confirmed SARS-CoV-2 infection. Because of serious risk of bias and very serious imprecision, we are highly uncertain whether ivermectin combined with iota-carrageenan and ivermectin alone reduce the risk of SARS-CoV-2 infection. Systematic review registration This review was not registered. The protocol established a priori is included as a supplement. Funding This study was supported by the Canadian Institutes of Health Research (grant CIHR-IRSC:0579001321). Reader note This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.
Subject(s)
Coronavirus Infections , Laboratory Infection , COVID-19ABSTRACT
Background: Neuromuscular blocking agents (NMBA) have been previously used in patients with acute respiratory distress syndrome (ARDS). It is unknown if NMBA are useful in COVID-19 patients who require invasive mechanical ventilation (IMV).Methods: We investigated use of NMBA in COVID-19 patients on IMV from February 1 to November 24, 2020, in 147 hospitals across 6 continents, comprising the COVID-19 Critical Care Consortium. We performed propensity score (PS) matched Cox proportional hazards analysis to appraise the impact of NMBA use for ≥2 days, continuously or discontinuously (treatment), vs. no use of NMBA or only upon commencement of IMV (control) on 28-day intensive care unit (ICU) mortality.Findings: 1548 (72%) patients received any NMBA therapy; 1165 (54%) of patients were stratified in the treatment group, with a median (IQR) time from ICU admission to commencement of NMBA therapy of 0 (0-2) days. The median (IQR) duration of NMBA therapy was 3 (2-6) days (N=1548). Upon commencement of IMV, patients who received NMBA therapy had a lower mean (±SD) PaO2/FiO2 (139±75 vs 157±93; P<0.001). After PS matching, Cox proportional hazard model demonstrated that NMBA therapy was significantly associated with higher 28-day ICU mortality (adjusted HR 2.20, 95% CI 1.67, 2.89, P<0.001). Sensitivity analyses testing various NMBA therapeutic regimens confirmed similar associations with mortality.Interpretation: Use of NMBA is common in COVID-19 patients on IMV and associated with a 2.2-fold increase in risk of 28-day mortality. Until further randomised evidence is available, NMBA should be applied cautiously in routine clinical practice.Funding Statement: University of Queensland, Wesley Medical Research, The Prince Charles Hospital Foundation, The Health Research Board of Ireland; Biomedicine international training research programme for excellent clinician-scientists; European Union’s research and innovation programme (Horizon 2020); la Caixa Foundation. Finally, Carol Hodgson is funded by a National Health and Medical Research Council Grant.Declaration of Interests: Dr. Li Bassi received research support from Fisher & Paykel outside the submitted work. Dr. Dalton has consulting from Innovative ECMO Concepts, Abiomed and Instrumentation Labs , none which affect the current work. Dr. Brodie receives research support from ALung Technologies and he has been on the medical advisory boards for Baxter, Abiomed, Xenios and Hemovent. Dr. Fan reports personal fees from ALung Technologies, Baxter, Fresenius Medical Care, Getinge, and MC3Cardiopulmonary outside the submitted work. Dr. Laffey reports consulting fees from Baxter and Cala Medical, both outside the submitted work. Dr Nichol is supported by a health Research Board of Ireland award (CTN-2014-012). Dr. Fraser receives research support from Fisher & Paykel outside the submitted work. Remaining authors do not have any competing interest to declare. Ethics Approval Statement: Participating hospitals obtained local ethics committee approval and a waiver of informed consent was granted in all cases.De-identified patient data were collected and stored via the REDCap (Vanderbilt/NIH/NCATS UL1 TR000445 v.10.0.23) electronic data capture tool, hosted at the University of Oxford, United Kingdom and University of Queensland.
Subject(s)
COVID-19 , Respiratory Distress SyndromeABSTRACT
BACKGROUND: Oral pathologists are involved in laboratory diagnosis and receive specimens of biopsy, oral cytologic smears and samples for hematology, biochemistry and microbiology and thus are at a risk for laboratory-acquired infections, which may occur inadvertently and can be considered as an occupational hazard. AIM AND OBJECTIVES: This study was conducted during the coronavirus disease (COVID-19) pandemic to assess the knowledge of oral pathologists and oral pathology postgraduate students regarding the safe laboratory practices, procedures and guidelines. MATERIALS AND METHODS: The study was a cross-sectional online questionnaire-based study. Questions were framed to evaluate the knowledge on specimen/sample collection, its handling, disposal and protective measures for laboratory personnel. The study population comprised oral pathologists and oral pathology postgraduate students of various dental colleges in India. A Google Doc format was used to create an effective computerized questionnaire system, and the link was forwarded to around 500 participants. The survey was fielded online between August 29, 2020, and September 5, 2020. Three hundred and twelve responses were received, which were downloaded as spreadsheets for subsequent data analysis. RESULTS: Mean value of right answers for the oral pathologists was 8.11 ± 2.02 and for postgraduate students was 7.38 ± 1.75. When the knowledge score between the two groups was compared, a statistically significant difference was found. CONCLUSION: This article compares and highlights the knowledge lacunae among the oral pathologists and oral pathologists postgraduate students in relation to guidelines to be followed for safety in the laboratory. Adhering to these biosafety regulations reduces occupational health hazards and enhances a safe working environment in the laboratory.
ABSTRACT
Background: Post-exposure prophylaxis (PEP) is a well-established strategy for the prevention of infectious diseases, in which recently exposed people take a short course of medication to prevent infection. The primary objective of the COVID-19 Ring-based Prevention Trial with lopinavir/ritonavir (CORIPREV-LR) is to evaluate the efficacy of a 14-day course of oral lopinavir/ritonavir as PEP against COVID-19 among individuals with a high-risk exposure to a confirmed case. Methods: : This is an open-label, multicenter, 1:1 cluster-randomized trial of LPV/r versus no intervention, using an adaptive approach to sample size calculation. Participants will be individuals aged >6 months with a high-risk exposure to a confirmed COVID-19 case within the past 7 days. A combination of remote and in-person study visits at days 1, 7, 14, 35 and 90 include comprehensive epidemiological, clinical, microbiologic and serologic sampling. The primary outcome is microbiologically confirmed COVID-19 infection within 14 days after exposure, defined as a positive respiratory tract specimen for SARS-CoV-2 by polymerase chain reaction. Secondary outcomes include safety, symptomatic COVID-19, seropositivity, hospitalization, respiratory failure requiring ventilator support, mortality, psychological impact, and health-related quality of life. Additional analyses will examine the impact of LPV/r on these outcomes in the subset of participants who test positive for SARS-CoV-2 at baseline. To detect a relative risk reduction of 40% with 80% power at α=0.05, assuming p 0 =15%, 5 contacts per case and intra-class correlation coefficient (ICC)=0.05, we require 110 clusters per arm, or 220 clusters overall and approximately 1220 enrollees after accounting for 10% loss-to-follow-up. We will modify the sample size target after 60 clusters, based on preliminary estimates of p0, ICC and cluster size and consider switching to an alternative drug after interim analyses and as new data emerges. The primary analysis will be a generalized linear mixed model with logit link to estimate the effect of LPV/r on the probability of infection. Discussion: Harnessing safe, existing drugs such as LPV/r as PEP could provide an important tool for control of the COVID-19 pandemic. Novel aspects of our design include the ring-based prevention approach, and the incorporation of remote strategies for conducting study visits and biospecimen collection. Trial registration: This trial was registered at www.clinicaltrials.gov (NCT04321174) on March 25, 2020. https://clinicaltrials.gov/ct2/show/NCT04321174
Subject(s)
COVID-19 , Respiratory Insufficiency , Communicable DiseasesABSTRACT
SARS-CoV-2 enters cells by binding to angiotensin-converting enzyme 2 (ACE2), and COVID-19 infection may therefore induce changes in the renin-angiotensin system (RAS). To determine the effects of COVID-19 on plasma RAS components, we measured plasma ACE, ACE2, and angiotensins I, (1-7), and II in 46 adults with COVID-19 at hospital admission and on days 2, 4, 7 and 14, compared to 50 blood donors (controls). We compared survivors vs. non-survivors, males vs. females, ventilated vs. not ventilated, and angiotensin receptor blocker (ARB) and angiotensin-converting enzyme (ACE) inhibitor-exposed vs. not exposed. At admission, COVID-19 patients had higher plasma levels of ACE (p=0.012), ACE2 (p=0.001) and angiotensin-(1-7) (p<0.001) than controls. Plasma ACE and ACE2 remained elevated for 14 days in COVID-19 patients, while plasma angiotensin-(1-7) decreased after 7 days. In adjusted analyses, plasma ACE was higher in males vs. females (p=0.042), and plasma angiotensin I was significantly lower in ventilated vs. non-ventilated patients (p=0.001). In summary, plasma ACE and ACE2 are increased for at least 14 days in patients with COVID-19 infection. Angiotensin-(1-7) levels are also elevated, but decline after 7 days. The results indicate dysregulation of the RAS with COVID-19, with increased circulating ACE2 throughout the course of infection.Clinical Trial Registration: https://clinicaltrials.gov/ Unique Identifier: NCT04510623
Subject(s)
COVID-19ABSTRACT
Background Heterogeneous respiratory system static compliance (CRS) values and levels of hypoxemia in patients with novel coronavirus disease (COVID-19) requiring mechanical ventilation have been reported in previous small-case series or studies conducted at a national level.Methods We designed a retrospective observational cohort study with rapid data gathering from the international COVID-19 Critical Care Consortium study to comprehensively describe the impact of CRS on the ventilatory management and outcomes of COVID-19 patients on mechanical ventilation (MV), admitted to intensive care units (ICU) worldwide.Results We enrolled 318 COVID-19 patients enrolled into the study from January 14th through September 31th, 2020 in 19 countries and stratified into two CRS groups. CRS was calculated as: tidal volume/[airway plateau pressure-positive end-expiratory pressure (PEEP)] and available within 48 h from commencement of MV in 318 patients. Patients were mean ± SD of 58.0 ± 12.2, predominantly from Europe (54%) and males (68%). Median CRS (IQR) was 34.1 mL/cmH2O (26.5–45.5) and PaO2/FiO2 was 119 mmHg (87.1–164) and was not correlated with CRS. Female sex presented lower CRS than in males (95% CI: -13.8 to -8.5 P < 0.001) and higher body mass index (34.7 ± 10.9 vs 29.1 ± 6.0, p < 0.001). Median (IQR) PEEP was 12 cmH2O (10–15), throughout the range of CRS, while median (IQR) driving pressure was 12.3 (10–15) cmH2O and significantly decreased as CRS improved (p < 0.001). No differences were found in comorbidities and clinical management between CRS strata. In addition, 28-day ICU mortality and hospital mortality did not differ between CRS groups.Conclusions This multicentre report provides a comprehensive account of CRS in COVID-19 patients on MV – predominantly males or overweight females, in their late 50 s – admitted to ICU during the first international outbreaks. Phenotypes associated with different CRS upon commencement of MV could not be identified. Trial documentation: Available at https://www.covid-critical.com/study.Trial registration ACTRN12620000421932.
Subject(s)
Coronavirus Infections , Craniosynostoses , Hypoxia , COVID-19ABSTRACT
Background: The coronavirus disease (Covid-19) pandemic has produced a large number of clinical trial reports with unprecedented rapidity, raising concerns about methodological quality and potential for research waste. Objectives: To describe the characteristics of randomized clinical trials (RCTs) investigating prophylaxis or treatment of Covid-19 infection and examine the effect of trial characteristics on whether the study reported a statistically significant effect on the primary outcome(s). Study Design: Meta-epidemiological study of Covid-19 treatment and prophylaxis RCTs. Eligibility criteria: English-language RCTs (peer-reviewed or preprint) that evaluated pharmacologic agents or blood products compared to standard care, placebo, or an active comparator among participants with suspected or confirmed Covid-19 or at risk for Covid-19. We excluded trials of vaccines or traditional herbal medicines. Information sources: We searched 25 databases in the US Centre for Disease Control Downloadable Database from January 1 to October 21, 2020. Trial appraisal and synthesis methods: We extracted trial characteristics including number of centres, funding sources (industry versus non-industry), and sample size. We assessed risk of bias (RoB) using the modified Cochrane RoB 2.0 Tool. We used descriptive statistics to summarize trial characteristics and logistic regression to evaluate the association between RoB due to the randomization process, centre status (single vs. multicentre), funding source, and sample size, and statistically significant effect in the primary outcome. Results: We included 91 RCTs (46,802 participants) evaluating Covid-19 therapeutic drugs (n = 76), blood products (n = 9) or prophylactic drugs (n = 6). Of these, 40 (44%) were single-centre, 23 (25.3%) enrolled < 50 patients, and 28 (30.8%) received industry funding. RoB varied across trials, with high or probably high overall RoB in 75 (82.4%) trials, most frequently due to deviations from the intended protocol (including blinding) and randomization processes. Thirty-eight trials (41.8%) found a statistically significant effect in the primary outcome. RoB due randomization (odds ratio [OR] 3.77, 95% confidence interval [CI], 1.47 to 9.72) and single centre trials (OR 3.15, 95% CI, 1.25 to 7.97) were associated with higher likelihood of finding a statistically significant effect. Conclusions: There was high variability in RoB amongst Covid-19 trials. RoB attributed to the randomization process and single centre status were associated with a three-fold increase in the odds of finding a statistically significant effect. Researchers, funders, and knowledge users should remain cognizant of the impact of study characteristics, including RoB, on trial results when designing, conducting, and appraising Covid-19 trials. Registration number: CRD42020192095
Subject(s)
COVID-19 , Coronavirus InfectionsABSTRACT
BACKGROUND WHO expert groups recommended mortality trials in hospitalized COVID-19 of four re-purposed antiviral drugs. METHODS Study drugs were Remdesivir, Hydroxychloroquine, Lopinavir (fixed-dose combination with Ritonavir) and Interferon-{beta}1a (mainly subcutaneous; initially with Lopinavir, later not). COVID-19 inpatients were randomized equally between whichever study drugs were locally available and open control (up to 5 options: 4 active and local standard-of-care). The intent-to-treat primary analyses are of in-hospital mortality in the 4 pairwise comparisons of each study drug vs its controls (concurrently allocated the same management without that drug, despite availability). Kaplan-Meier 28-day risks are unstratified; log-rank death rate ratios (RRs) are stratified for age and ventilation at entry. RESULTS In 405 hospitals in 30 countries 11,266 adults were randomized, with 2750 allocated Remdesivir, 954 Hydroxychloroquine, 1411 Lopinavir, 651 Interferon plus Lopinavir, 1412 only Interferon, and 4088 no study drug. Compliance was 94-96% midway through treatment, with 2-6% crossover. 1253 deaths were reported (at median day 8, IQR 4-14). Kaplan-Meier 28-day mortality was 12% (39% if already ventilated at randomization, 10% otherwise). Death rate ratios (with 95% CIs and numbers dead/randomized, each drug vs its control) were: Remdesivir RR=0.95 (0.81-1.11, p=0.50; 301/2743 active vs 303/2708 control), Hydroxychloroquine RR=1.19 (0.89-1.59, p=0.23; 104/947 vs 84/906), Lopinavir RR=1.00 (0.79-1.25, p=0.97; 148/1399 vs 146/1372) and Interferon RR=1.16 (0.96-1.39, p=0.11; 243/2050 vs 216/2050). No study drug definitely reduced mortality (in unventilated patients or any other subgroup of entry characteristics), initiation of ventilation or hospitalisation duration. CONCLUSIONS These Remdesivir, Hydroxychloroquine, Lopinavir and Interferon regimens appeared to have little or no effect on hospitalized COVID-19, as indicated by overall mortality, initiation of ventilation and duration of hospital stay. The mortality findings contain most of the randomized evidence on Remdesivir and Interferon, and are consistent with meta-analyses of mortality in all major trials. (Funding: WHO. Registration: ISRCTN83971151, NCT04315948)
Subject(s)
COVID-19 , DeathABSTRACT
The Spike protein of SARS-CoV-2, its receptor binding domain (RBD), and its primary receptor ACE2 are extensively glycosylated. The impact of this post-translational modification on viral entry is yet unestablished. We expressed different glycoforms of the Spike-protein and ACE2 in CRISPR-Cas9 glycoengineered cells, and developed corresponding SARS-CoV-2 pseudovirus. We observed that N- and O-glycans had only minor contribution to Spike-ACE2 binding. However, these carbohydrates played a major role in regulating viral entry. Blocking N-glycan biosynthesis at the oligomannose stage using both genetic approaches and the small molecule kifunensine dramatically reduced viral entry into ACE2 expressing HEK293T cells. Blocking O-glycan elaboration also partially blocked viral entry. Mechanistic studies suggest multiple roles for glycans during viral entry. Among them, inhibition of N-glycan biosynthesis enhanced Spike-protein proteolysis. This could reduce RBD presentation on virus, lowering binding to host ACE2 and decreasing viral entry. Overall, chemical inhibitors of glycosylation may be evaluated for COVID-19.
Subject(s)
COVID-19ABSTRACT
Background: Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aimed to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. Methods: Rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/). We systematically identified published and unpublished RCTs by September 14, 2020 (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, PubMed, Cochrane COVID-19 registry). All-cause mortality was extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine/chloroquine. Prespecified subgroup analyses included patient setting, diagnostic confirmation, control type, and publication status. Results: Sixty-two trials were potentially eligible. We included 16 unpublished trials (1596 patients) and 10 publications/preprints (6317 patients). The combined summary OR on all-cause mortality for hydroxychloroquine was 1.08 (95%CI: 0.99, 1.18; I-square=0%; 24 trials; 7659 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I-square=0%; 4 trials; 307 patients). We identified no subgroup effects. Conclusions: We found no benefit of hydroxychloroquine or chloroquine on the survival of COVID-19 patients. For hydroxychloroquine, the confidence interval is compatible with increased mortality (OR 1.18) or negligibly reduced mortality (OR 0.99). Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.
Subject(s)
COVID-19ABSTRACT
Severe COVID-19 is characterised by fever, cough, and dyspnoea. Symptoms affecting other organ systems have been reported. The clinical associations of different patterns of symptoms can influence diagnostic and therapeutic decision-making: for example, significant differential therapeutic effects in sub-groups of patients with different severities of respiratory failure have already been reported for the only treatment so far shown to reduce mortality in COVID-19, dexamethasone. We obtained structured clinical data on 68914 patients in the UK (the ISARIC Coronavirus Clinical Characterisation Consortium, 4C) and used a principled, unsupervised clustering approach to partition the first 33468 cases according to symptoms reported at recruitment. We validated our findings in a second group of 35446 cases recruited to ISARIC-4C, and in separate cohort of community cases. A core symptom set of fever, cough, and dyspnoea co-occurred with additional symptoms in three patterns: fatigue and confusion, diarrhoea and vomiting, or productive cough. Presentations with a single reported symptom of dyspnoea or confusion were common, and a subgroup of patients reported few or no symptoms. Patients presenting with gastrointestinal symptoms were more commonly female, had a longer duration of symptoms before presentation, and had lower 30-day mortality. Patients presenting with confusion, with or without core symptoms, were older and had a higher unadjusted mortality. Symptom clusters were highly consistent in replication analysis using a further 35446 individuals subsequently recruited to ISARIC-4C. Similar patterns were externally verified in 4445 patients from a study of self-reported symptoms of mild disease. The large scale of ISARIC-4C study enabled robust, granular discovery and replication of patient clusters. Clinical interpretation is necessary to determine which of these observations have practical utility. We propose that four patterns are usefully distinct from the core symptom groups: gastro-intestinal disease, productive cough, confusion, and pauci-symptomatic presentations. Importantly, each is associated with an in-hospital mortality which differs from that of patients with core symptoms. These observations deepen our understanding of COVID-19 and will influence clinical diagnosis, risk prediction, and future mechanistic and clinical studies.