Respiratory support in patients with severe COVID-19 in the International Severe Acute Respiratory and Emerging Infection (ISARIC) COVID-19 study: a prospective, multinational, observational study

Invasive mechanical ventilation; COVID-19; Critical careVentilación mecánica invasiva; COVID-19; Cuidado críticoVentilació mecànica invasiva; COVID-19; Atenció críticaBackground Up to 30% of hospitalised patients with COVID-19 require advanced respiratory support, including high-flow nasal cannulas (HFNC), non-invasive mechanical ventilation (NIV), or invasive mechanical ventilation (IMV). We aimed to describe the clinical characteristics, outcomes and risk factors for failing non-invasive respiratory support in patients treated with severe COVID-19 during the first two years of the pandemic in high-income countries (HICs) and low middle-income countries (LMICs). Methods This is a multinational, multicentre, prospective cohort study embedded in the ISARIC-WHO COVID-19 Clinical Characterisation Protocol. Patients with laboratory-confirmed SARS-CoV-2 infection who required hospital admission were recruited prospectively. Patients treated with HFNC, NIV, or IMV within the first 24 h of hospital admission were included in this study. Descriptive statistics, random forest, and logistic regression analyses were used to describe clinical characteristics and compare clinical outcomes among patients treated with the different types of advanced respiratory support. Results A total of 66,565 patients were included in this study. Overall, 82.6% of patients were treated in HIC, and 40.6% were admitted to the hospital during the first pandemic wave. During the first 24 h after hospital admission, patients in HICs were more frequently treated with HFNC (48.0%), followed by NIV (38.6%) and IMV (13.4%). In contrast, patients admitted in lower- and middle-income countries (LMICs) were less frequently treated with HFNC (16.1%) and the majority received IMV (59.1%). The failure rate of non-invasive respiratory support (i.e. HFNC or NIV) was 15.5%, of which 71.2% were from HIC and 28.8% from LMIC. The variables most strongly associated with non-invasive ventilation failure, defined as progression to IMV, were high leukocyte counts at hospital admission (OR [95%CI]; 5.86 [4.83–7.10]), treatment in an LMIC (OR [95%CI]; 2.04 [1.97–2.11]), and tachypnoea at hospital admission (OR [95%CI]; 1.16 [1.14–1.18]). Patients who failed HFNC/NIV had a higher 28-day fatality ratio (OR [95%CI]; 1.27 [1.25–1.30]). Conclusions In the present international cohort, the most frequently used advanced respiratory support was the HFNC. However, IMV was used more often in LMIC. Higher leucocyte count, tachypnoea, and treatment in LMIC were risk factors for HFNC/NIV failure. HFNC/NIV failure was related to worse clinical outcomes, such as 28-day mortality.This work was supported by the UK Foreign, Commonwealth, and Development Office and Wellcome [215091/Z/18/Z] and the Bill & Melinda Gates Foundation [OPP1209135]; CIHR Coronavirus Rapid Research Funding Opportunity OV2170359; Grants from Rapid European COVID-19 Emergency Response research (RECOVER) [H2020 Project 101003589] and European Clinical Research Alliance on Infectious Diseases (ECRAID) [965313]; The Imperial NIHR Biomedical Research Centre; The Cambridge NIHR Biomedical Research Centre; and Endorsed by the Irish Critical Care-Clinical Trials Group, co-ordinated in Ireland by the Irish Critical Care-Clinical Trials Network at University College Dublin and funded by the Health Research Board of Ireland [CTN-2014-12]. This work uses Data/Materials provided by patients and collected by the NHS as part of their care and support #DataSavesLives. The Data/materials used for this research were obtained from ISARIC4C. The COVID-19 Clinical Information Network (CO-CIN) data was collated by ISARIC4C Investigators. Data and Material provision were supported by grants from: the National Institute for Health Research (NIHR; award CO-CIN-01), the Medical Research Council (MRC; Grant MC_PC_19059), and the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at the University of Liverpool in partnership with Public Health England (PHE), (Award 200907), Wellcome Trust [Turtle, Lance-fellowship 205228/Z/16/Z], NIHR HPRU in Respiratory Infections at Imperial College London with PHE (Award 200927), Liverpool Experimental Cancer Medicine Centre (Grant C18616/A25153), NIHR Biomedical Research Centre at Imperial College London (Award IS-BRC-1215-20013), and NIHR Clinical Research Network providing infrastructure support. This work was possible due to the dedication and hard work of the Norwegian SARS-CoV-2 study team and supported by grants from Research Council of Norway Grant No. 312780 and a philanthropic donation from Vivaldi Invest A/S owned by Jon Stephenson von Tetzchner; The dedication and hard work of the Groote Schuur Hospital Covid ICU Team, and supported by the Groote Schuur nursing and University of Cape Town registrar bodies coordinated by the Division of Critical Care at the University of Cape Town; and supported by the COVID clinical management team, AIIMS, Rishikesh, India

Lovastatin for adult patients with dengue: protocol for a randomised controlled trial.

BACKGROUND: Dengue is the most important vector-borne viral infection of man, with approximately 2 billion people living in areas at risk. Infection results in a range of manifestations from asymptomatic infection through to life-threatening shock and haemorrhage. One of the hallmarks of severe dengue is vascular endothelial disruption. There is currently no specific therapy and clinical management is limited to supportive care. Statins are a class of drug initially developed for lipid lowering. There has been considerable recent interest in their effects beyond lipid lowering. These include anti-inflammatory effects at the endothelium. In addition, it is possible that lovastatin may have an anti-viral effect against dengue. Observational data suggest that the use of statins may improve outcomes for such conditions as sepsis and pneumonia. This paper describes the protocol for a randomised controlled trial investigating a short course of lovastatin therapy in adult patients with dengue. METHODS/DESIGN: A randomised, double-blind, placebo-controlled trial will investigate the effects of lovastatin therapy in the treatment of dengue. The trial will be conducted in two phases with an escalation of dose between phases if an interim safety review is satisfactory. This is an exploratory study focusing on safety and there are no data on which to base a sample size calculation. A target sample size of 300 patients in the second phase, enrolled over two dengue seasons, was chosen based on clinical judgement and feasibility considerations. In a previous randomised trial in dengue, about 10% and 30% of patients experienced at least one serious adverse event or adverse event, respectively. With 300 patients, we will have 80% power to detect an increase of 12% (from 10% to 22%) or 16% (from 30% to 46%) in the frequency of adverse events. Furthermore, this sample size ensures some power to explore the efficacy of statins. DISCUSSION: The development of a dengue therapeutic that can attenuate disease would be an enormous advance in global health. The favourable effects of statins on the endothelium, their good safety profile and their low cost make lovastatin an attractive therapeutic candidate. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number ISRCTN03147572

Electronic data collection, management and analysis tools used for outbreak response in low- and middle-income countries: a systematic review and stakeholder survey

BACKGROUND: Use of electronic data collection, management and analysis tools to support outbreak response is limited, especially in low income countries. This can hamper timely decision-making during outbreak response. Identifying available tools and assessing their functions in the context of outbreak response would support appropriate selection and use, and likely more timely data-driven decision-making during outbreaks. METHODS: We conducted a systematic review and a stakeholder survey of the Global Outbreak Alert and Response Network and other partners to identify and describe the use of, and technical characteristics of, electronic data tools used for outbreak response in low- and middle-income countries. Databases included were MEDLINE, EMBASE, Global Health, Web of Science and CINAHL with publications related to tools for outbreak response included from January 2010-May 2020. Software tool websites of identified tools were also reviewed. Inclusion and exclusion criteria were applied and counts, and proportions of data obtained from the review or stakeholder survey were calculated. RESULTS: We identified 75 electronic tools including for data collection (33/75), management (13/75) and analysis (49/75) based on data from the review and survey. Twenty-eight tools integrated all three functionalities upon collection of additional information from the tool developer websites. The majority were open source, capable of offline data collection and data visualisation. EpiInfo, KoBoCollect and Open Data Kit had the broadest use, including for health promotion, infection prevention and control, and surveillance data capture. Survey participants highlighted harmonisation of data tools as a key challenge in outbreaks and the need for preparedness through training front-line responders on data tools. In partnership with the Global Health Network, we created an online interactive decision-making tool using data derived from the survey and review. CONCLUSIONS: Many electronic tools are available for data -collection, -management and -analysis in outbreak response, but appropriate tool selection depends on knowledge of tools' functionalities and capabilities. The online decision-making tool created to assist selection of the most appropriate tool(s) for outbreak response helps by matching requirements with functionality. Applying the tool together with harmonisation of data formats, and training of front-line responders outside of epidemic periods can support more timely data-driven decision making in outbreaks

A mass threshold in the number density of passive galaxies at z∼\sim2

The process that quenched star formation in galaxies at intermediate and high redshift is still the subject of considerable debate. One way to investigate this puzzling issue is to study the number density of quiescent galaxies at z~2, and its dependence on mass. Here we present the results of a new study based on very deep Ks-band imaging (with the HAWK-I instrument on the VLT) of two HST CANDELS fields (the UKIDSS Ultra-deep survey (UDS) field and GOODS-South). The new HAWK-I data (taken as part of the HUGS VLT Large Program) reach detection limits of Ks>26 (AB mag). We select a sample of passively-evolving galaxies in the redshift range 1.4<z<2.5. Thanks to the depth and large area coverage of our imaging, we have been able to extend the selection of quiescent galaxies a magnitude fainter than previous analyses. Through extensive simulations we demonstrate, for the first time, that the observed turn-over in the number of quiescent galaxies at K>22 is real. This has enabled us to establish unambiguously that the number counts of quiescent galaxies at z~2 flatten and slightly decline at magnitudes fainter than Ks~22(AB mag.). We show that this trend corresponds to a stellar mass threshold $M_*10^{10.8}\,{\rm M_{\odot}}$ below which the mechanism that halts the star formation in high-redshift galaxies seems to be inefficient. Finally we compare the observed pBzK number counts with those of quiescent galaxies extracted from four different semi-analytic models. We find that none of the models provides a statistically acceptable description of the number density of quiescent galaxies at these redshifts. We conclude that the mass function of quiescent galaxies as a function of redshift continues to present a key and demanding challenge for proposed models of galaxy formation and evolution.Comment: Accepted for publication on Astronomy and Astrophysic

Clinical characteristics, risk factors and outcomes in patients with severe COVID-19 registered in the International Severe Acute Respiratory and Emerging Infection Consortium WHO clinical characterisation protocol: a prospective, multinational, multicentre, observational study

Respiratory infections and tuberculosisInfecciones respiratorias y tuberculosisInfeccions respiratòries i tuberculosiDue to the large number of patients with severe coronavirus disease 2019 (COVID-19), many were treated outside the traditional walls of the intensive care unit (ICU), and in many cases, by personnel who were not trained in critical care. The clinical characteristics and the relative impact of caring for severe COVID-19 patients outside the ICU is unknown. This was a multinational, multicentre, prospective cohort study embedded in the International Severe Acute Respiratory and Emerging Infection Consortium World Health Organization COVID-19 platform. Severe COVID-19 patients were identified as those admitted to an ICU and/or those treated with one of the following treatments: invasive or noninvasive mechanical ventilation, high-flow nasal cannula, inotropes or vasopressors. A logistic generalised additive model was used to compare clinical outcomes among patients admitted or not to the ICU. A total of 40 440 patients from 43 countries and six continents were included in this analysis. Severe COVID-19 patients were frequently male (62.9%), older adults (median (interquartile range (IQR), 67 (55–78) years), and with at least one comorbidity (63.2%). The overall median (IQR) length of hospital stay was 10 (5–19) days and was longer in patients admitted to an ICU than in those who were cared for outside the ICU (12 (6–23) days versus 8 (4–15) days, p<0.0001). The 28-day fatality ratio was lower in ICU-admitted patients (30.7% (5797 out of 18 831) versus 39.0% (7532 out of 19 295), p<0.0001). Patients admitted to an ICU had a significantly lower probability of death than those who were not (adjusted OR 0.70, 95% CI 0.65–0.75; p<0.0001). Patients with severe COVID-19 admitted to an ICU had significantly lower 28-day fatality ratio than those cared for outside an ICU.This work was supported by the UK Foreign, Commonwealth and Development Office and Wellcome (215091/Z/18/Z), the Bill and Melinda Gates Foundation (OPP1209135), Canadian Institutes of Health Research Coronavirus Rapid Research Funding Opportunity OV2170359, grants from Rapid European COVID-19 Emergency Response Research (Horizon 2020 project 101003589), the European Clinical Research Alliance on Infectious Diseases (965313), The Imperial National Institute for Health Research (NIHR) Biomedical Research Centre, and The Cambridge NIHR Biomedical Research Centre; and endorsed by the Irish Critical Care Clinical Trials Group, co-ordinated in Ireland by the Irish Critical Care Clinical Trials Network at University College Dublin and funded by the Health Research Board of Ireland (CTN-2014-12). Data and Material provision was supported by grants from: the NIHR (award CO-CIN-01), the Medical Research Council (grant MC_PC_19059), the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE) (award 200907), Wellcome Trust (Turtle, Lance-fellowship 205228/Z/16/Z), NIHR HPRU in Respiratory Infections at Imperial College London with PHE (award 200927), Liverpool Experimental Cancer Medicine Centre (grant C18616/A25153), NIHR Biomedical Research Centre at Imperial College London (award IS-BRC-1215-20013), and NIHR Clinical Research Network providing infrastructure support. This work was by Research Council of Norway grant number 312780, and a philanthropic donation from Vivaldi Invest A/S owned by Jon Stephenson von Tetzchner

Preprints in times of COVID19: The time is ripe for agreeing on terminology and good practices

Over recent years, the research community has been increasingly using preprint servers to share manuscripts that are not yet peer-reviewed. Even if it enables quick dissemination of research findings, this practice raises several challenges in publication ethics and integrity. In particular, preprints have become an important source of information for stakeholders interested in COVID19 research developments, including traditional media, social media, and policy makers. Despite caveats about their nature, many users can still confuse pre-prints with peer-reviewed manuscripts. If unconfirmed but already widely shared first-draft results later prove wrong or misinterpreted, it can be very difficult to unlearn what we thought was true. Complexity further increases if unconfirmed findings have been used to inform guidelines. To help achieve a balance between early access to research findings and its negative consequences, we formulated five recommendations: (a) consensus should be sought on a term clearer than \u27pre-print\u27, such as \u27Unrefereed manuscript\u27, Manuscript awaiting peer review or \u27\u27Non-reviewed manuscript ; (b) Caveats about unrefereed manuscripts should be prominent on their first page, and each page should include a red watermark stating \u27Caution-Not Peer Reviewed\u27; (c) pre-print authors should certify that their manuscript will be submitted to a peer-review journal, and should regularly update the manuscript status; (d) high level consultations should be convened, to formulate clear principles and policies for the publication and dissemination of non-peer reviewed research results; (e) in the longer term, an international initiative to certify servers that comply with good practices could be envisaged

Targeted ablation of oligodendrocytes induces axonal pathology independent of overt demyelination

The critical role of oligodendrocytes in producing and maintaining myelin that supports rapid axonal conduction in CNS neurons is well established. More recently, additional roles for oligodendrocytes have been posited, including provision of trophic factors and metabolic support for neurons. To investigate the functional consequences of oligodendrocyte loss, we have generated a transgenic mouse model of conditional oligodendrocyte ablation. In this model, oligodendrocytes are rendered selectively sensitive to exogenously administered diphtheria toxin (DT) by targeted expression of the diphtheria toxin receptor in oligodendrocytes. Administration of DT resulted in severe clinical dysfunction with an ascending spastic paralysis ultimately resulting in fatal respiratory impairment within 22 d of DT challenge. Pathologically, at this time point, mice exhibited a loss of ∼26% of oligodendrocyte cell bodies throughout the CNS. Oligodendrocyte cell-body loss was associated with moderate microglial activation, but no widespread myelin degradation. These changes were accompanied with acute axonal injury as characterized by structural and biochemical alterations at nodes of Ranvier and reduced somatosensory-evoked potentials. In summary, we have shown that a death signal initiated within oligodendrocytes results in subcellular changes and loss of key symbiotic interactions between the oligodendrocyte and the axons it ensheaths. This produces profound functional consequences that occur before the removal of the myelin membrane, i.e., in the absence of demyelination. These findings have clear implications for the understanding of the pathogenesis of diseases of the CNS such as multiple sclerosis in which the oligodendrocyte is potentially targeted

Association of Country Income Level With the Characteristics and Outcomes of Critically Ill Patients Hospitalized With Acute Kidney Injury and COVID-19

Introduction: Acute kidney injury (AKI) has been identified as one of the most common and significant problems in hospitalized patients with COVID-19. However, studies examining the relationship between COVID-19 and AKI in low- and low-middle income countries (LLMIC) are lacking. Given that AKI is known to carry a higher mortality rate in these countries, it is important to understand differences in this population.Methods: This prospective, observational study examines the AKI incidence and characteristics of 32,210 patients with COVID-19 from 49 countries across all income levels who were admitted to an intensive care unit during their hospital stay.Results: Among patients with COVID-19 admitted to the intensive care unit, AKI incidence was highest in patients in LLMIC, followed by patients in upper-middle income countries (UMIC) and high-income countries (HIC) (53%, 38%, and 30%, respectively), whereas dialysis rates were lowest among patients with AKI from LLMIC and highest among those from HIC (27% vs. 45%). Patients with AKI in LLMIC had the largest proportion of community-acquired AKI (CA-AKI) and highest rate of in-hospital death (79% vs. 54% in HIC and 66% in UMIC). The association between AKI, being from LLMIC and in-hospital death persisted even after adjusting for disease severity.Conclusions: AKI is a particularly devastating complication of COVID-19 among patients from poorer nations where the gaps in accessibility and quality of healthcare delivery have a major impact on patient outcomes

Neurological manifestations of COVID-19 in adults and children

Different neurological manifestations of coronavirus disease 2019 (COVID-19) in adults and children and their impact have not been well characterized. We aimed to determine the prevalence of neurological manifestations and in-hospital complications among hospitalized COVID-19 patients and ascertain differences between adults and children. We conducted a prospective multicentre observational study using the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) cohort across 1507 sites worldwide from 30 January 2020 to 25 May 2021. Analyses of neurological manifestations and neurological complications considered unadjusted prevalence estimates for predefined patient subgroups, and adjusted estimates as a function of patient age and time of hospitalization using generalized linear models. Overall, 161 239 patients (158 267 adults; 2972 children) hospitalized with COVID-19 and assessed for neurological manifestations and complications were included. In adults and children, the most frequent neurological manifestations at admission were fatigue (adults: 37.4%; children: 20.4%), altered consciousness (20.9%; 6.8%), myalgia (16.9%; 7.6%), dysgeusia (7.4%; 1.9%), anosmia (6.0%; 2.2%) and seizure (1.1%; 5.2%). In adults, the most frequent in-hospital neurological complications were stroke (1.5%), seizure (1%) and CNS infection (0.2%). Each occurred more frequently in intensive care unit (ICU) than in non-ICU patients. In children, seizure was the only neurological complication to occur more frequently in ICU versus non-ICU (7.1% versus 2.3%, P &lt; 0.001). Stroke prevalence increased with increasing age, while CNS infection and seizure steadily decreased with age. There was a dramatic decrease in stroke over time during the pandemic. Hypertension, chronic neurological disease and the use of extracorporeal membrane oxygenation were associated with increased risk of stroke. Altered consciousness was associated with CNS infection, seizure and stroke. All in-hospital neurological complications were associated with increased odds of death. The likelihood of death rose with increasing age, especially after 25 years of age. In conclusion, adults and children have different neurological manifestations and in-hospital complications associated with COVID-19. Stroke risk increased with increasing age, while CNS infection and seizure risk decreased with age.</p

Clinical presentations, diagnosis, mortality and prognostic markers of tuberculous meningitis in Vietnamese children: a prospective descriptive study

Background Tuberculous meningitis in adults is well characterized in Vietnam, but there are no data on the disease in children. We present a prospective descriptive study of Vietnamese children with TBM to define the presentation, course and characteristics associated with poor outcome. Methods A prospective descriptive study of 100 consecutively admitted children with TBM at Pham Ngoc Thach Hospital, Ho Chi Minh City. Cox and logistic regression were used to identify factors associated with risk of death and a combined endpoint of death or disability at treatment completion. Results The study enrolled from October 2009 to March 2011. Median age was 32.5 months; sex distribution was equal. Median duration of symptoms was 18.5 days and time from admission to treatment initiation was 11 days. Fifteen of 100 children died, 4 were lost to follow-up, and 27/81 (33 %) of survivors had intermediate or severe disability upon treatment completion. Microbiological confirmation of disease was made in 6 %. Baseline characteristics associated with death included convulsions (HR 3.46, 95CI 1.19–10.13, p = 0.02), decreased consciousness (HR 22.9, 95CI 3.01–174.3, p 5 years) and hydrocephalus were also associated with the combined endpoint of death or disability. Conclusions Tuberculous meningitis in Vietnamese children has significant mortality and morbidity. There is significant delay in diagnosis; interventions that increase the speed of diagnosis and treatment initiation are likely to improve outcomes