Paediatric Meningitis in the Conjugate Vaccine Era and Development of a Novel Clinical Decision Model to Predict Bacterial Aetiology in 3,002 Children with Suspected Meningitis (preprint)

Background: Implementation of bacterial conjugate vaccines have resulted in dramatic reductions in bacterial meningitis globally. The aetiology of childhood meningitis in the conjugate vaccine era is not well-defined, and differentiating bacterial meningitis from other similar childhood illnesses is a major challenge. The aims of this study were to assess aetiology and clinical characteristics in childhood meningitis, and develop clinical decision rules to distinguish bacterial meningitis from other similar clinical syndromes.Methods: Children aged <16 years hospitalised with suspected meningitis/encephalitis were included. Meningitis was defined as identification of bacteria/viruses from CSF and/or a CSF WBC>5/μL. Aetiology and clinical and laboratory features were analysed. Two new clinical decision rules were developed to distinguish bacterial meningitis from aseptic or suspected meningitis.Findings: 3,002 children (median age 2·4 months, IQR: 1·0-12·7) were prospectively recruited at 31 UK hospitals. Overall 1,101/3,002 (36·7%) had meningitis, including 203 with a bacterial aetiology, 423 viral and 280 with no pathogen identified. Enterovirus was the most common pathogen in those aged < six months and 10-16 years, with N. meningitidis and/or S. pneumoniae commonest at age six months–nine years. The Bacterial Meningitis Score had a negative predictive value of 95·3%. We developed two clinical decision rules, that could be used either before (sensitivity 82%, specificity 71%) or after LP (sensitivity 84%, specificity 93%), to determine risk of bacterial meningitis.Interpretation: Bacterial meningitis comprised only 6% of children presenting to hospital with suspected meningitis/encephalitis. Our clinical decision rules provide important novel approaches to identify the children with bacterial meningitis.Funding: This independent research was supported by the UK Meningitis Research Foundation, Pfizer, and the National Institute for Health Research Programme Grants for Applied Research Programme (Understanding and improving the outcome of viral encephalitis, RP-PG-0108- 10048). MS is supported via salary awards from the BC Children’s Hospital Foundation and Michael Smith Health Research BC. TS is supported by the National Institute for Health and Care Research (NIHR) Health Protection Research Unit in Emerging and Zoonotic Infections (Grant Nos. IS-HPU- 1112-10117 and NIHR200907).Declaration of Interest: MS has been an investigator on projects funded by GlaxoSmithKline, Merck, Moderna, Pfizer, Sanofi-Pasteur, Seqirus, Symvivo and VBI Vaccines. All funds have been paid to his institute, and he has not received any personal payments. AJP was a member of the World Health Organization’s Strategic Advisory Group of Experts on Immunization until January 2022 and remains chair of the UK Department of Health and Social Care's Joint Committee on Vaccination and Immunisation (JCVI). AJP also reports providing advice to Shionogi on COVID-19, and funding from the National Institute for Health Research (NIHR), AstraZeneca, the Bill & Melinda Gates Foundation, Wellcome, the Medical Research Council, and the Coalition for Epidemic Preparedness Innovations (CEPI). Oxford University has entered into a partnership with AstraZeneca for the development of COVID-19 vaccines. TS is Director of The Pandemic Institute, which has received funding from Innova, CSL Seqirus, Aviva and DAM Health; was an advisor to the GSK Ebola Vaccine programme and the Siemens Diagnostic Programme; Co-Chaired the WHO Neuro-COVID task force and sat on the UK Government’s Advisory Committee on Dangerous Pathogens, and the Medicines and Healthcare Products Regulatory Agency (MHRA) Expert Working Group on Covid-19 vaccines. PH has been an investigator on projects funded by GlaxoSmithKline, Merck, Moderna, Pfizer, Sanofi- Pasteur, Novavax, Valneva, Minervax and AZ. All funds have been paid to his institute, and he has not received any personal payments. He is a member of the UK JCVI. All other authors have no COI to disclose.Ethical Approval: The study was approved by NRES Committee East Midlands - Nottingham 1 (Ref: 11/EM/0442).

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses (preprint)

Neurological complications occur in a significant proportion of COVID-19 cases. In order to identify key biomarkers, we measured brain injury markers, inflammatory mediators, and autoantibodies in 203 participants admitted to hospital for management of COVID-19; 111 provided acute sera (1-11 days post admission) and 56 with COVID-19-associated neurological diagnoses provided convalescent sera (up to76 weeks post admission). Compared to 60 controls, brain injury biomarkers (total-Tau, GFAP, NfL, UCH-L1) were increased in acute sera, significantly more so for NfL and UCH-L1, in participants with altered consciousness. Total-Tau (tTau) and NfL remained elevated in convalescent sera, particularly following cerebrovascular and neuroinflammatory disorders. Acutely, inflammatory mediators (including IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) were higher in participants with altered consciousness and correlated with brain injury biomarker levels. Inflammatory mediators were lower in convalescent sera than acute sera. Levels of CCL2, CCL7, IL-1RA, IL-2Rα, M-CSF, SCF, IL-16 and IL-18 in individual participants correlated with tTau levels even at later time points. When compared to acute COVID-19 patients with a normal Glasgow Coma Scale score (GCS), network analysis showed significantly altered immune responses in patients with acute alteration of consciousness, and in convalescent patients who had suffered an acute neurological complication. The frequency and range of autoantibodies did not associate with neurological disorders. However, autoantibodies against specific antigens were more frequent in patients with altered consciousness in the acute phase (including MYL7, UCH-L1, GRIN3B, and DDR2), and in patients with neurological complications in the convalescent phase (including MYL7, GNRHR, and HLA antigens). In a novel low-inoculum mouse model of SARS-CoV-2, while viral replication was only consistently seen in mouse lungs, inflammatory responses were seen in both brain and lungs, with significant increases in CCL4, IFNγ, IL-17A, and microglial reactivity in the brain. Neurological injury is common in the acute phase of COVID-19 and we found brain injury markers persist during convalescence and may be driven by a para-infectious process involving a dysregulated host response.

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses (preprint)

We measured brain injury markers, inflammatory mediators, and autoantibodies in 203 participants with COVID-19; 111 provided acute sera (1-11 days post admission) and 56 with COVID-19-associated neurological diagnoses provided subacute/convalescent sera (6-76 weeks post-admission). Compared to 60 controls, brain injury biomarkers (Tau, GFAP, NfL, UCH-L1) were increased in acute sera, significantly more so for NfL and UCH-L1, in patients with altered consciousness. Tau and NfL remained elevated in convalescent sera, particularly following cerebrovascular and neuroinflammatory disorders. Acutely, inflammatory mediators (including IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) were higher in participants with altered consciousness, and correlated with brain injury biomarker levels. Inflammatory mediators were lower than acute levels in convalescent sera, but levels of CCL2, CCL7, IL-1RA, IL-2R, M-CSF, SCF, IL-16 and IL-18 in individual participants correlated with Tau levels even at this late time point. When compared to acute COVID-19 patients with a normal GCS, network analysis showed significantly altered immune responses in patients with acute alteration of consciousness, and in convalescent patients who had suffered an acute neurological complication. The frequency and range of autoantibodies did not associate with neurological disorders. However, autoantibodies against specific antigens were more frequent in patients with altered consciousness in the acute phase (including MYL7, UCH-L1, GRIN3B, and DDR2), and in patients with neurological complications in the convalescent phase (including MYL7, GNRHR, and HLA antigens). In a novel low-inoculum mouse model of SARS-CoV-2, while viral replication was only consistently seen in mouse lungs, inflammatory responses were seen in both brain and lungs, with significant increases in CCL4, IFN{gamma}, IL-17A, and microglial reactivity in the brain. Neurological injury is common in the acute phase and persists late after COVID-19, and may be driven by a para-infectious process involving a dysregulated host response.

The aerobiology of SARS-CoV-2 in UK hospitals and the impact of aerosol generating procedures (preprint)

BackgroundSARS-CoV-2 nosocomial transmission to patients and healthcare workers (HCWs) has occurred throughout the COVID-19 pandemic. Aerosol generating procedures (AGPs) seemed particularly risky, and policies have restricted their use in all settings. We examined the prevalence of aerosolized SARS-CoV-2 in the rooms of COVID-19 patients requiring AGP or supplemental oxygen compared to those on room air. MethodsSamples were collected prospectively near to adults hospitalised with COVID-19 at two tertiary care hospitals in the UK from November 2020 - October 2021. The Sartorius MD8 AirPort air sampler was used to collect air samples at a minimum distance of 1.5 meters from patients. RT-qPCR was used following overnight incubation of membranes in culture media and extraction. ResultsWe collected 219 samples from patients rooms: individuals on room air (n=67), receiving oxygen (n=65) or AGP (n=67). Of these, 54 (24.6%) samples were positive for SARS-CoV-2 viral RNA. The highest prevalence was identified in the air around patients receiving oxygen (32.3%, n=21, CI95% 22.2 to 44.3%) with AGP and room air recording prevalence of (20.7%, n=18, CI95% 14.1 - 33.7%) and (22.3%, n=15, CI95% 13.5 - 30.4%) respectively. We did not detect a significant difference in the observed frequency of viral RNA between interventions. InterpretationSARS-CoV-2 viral RNA was detected in the air of hospital rooms of COVID-19 patients, and AGPs did not appear to impact the likelihood of viral RNA. Enhanced respiratory protection and appropriate infection prevention and control measures are required to be fully and carefully implemented for all COVID-19 patients to reduce risk of aerosol transmission.

National Trends in Youth Sport during the COVID-19 Pandemic: Understanding American Parents' Perceptions and Perspectives

American children participate relatively ubiquitously in youth sport and parents are intimately engaged in their participation. However, the onset of the novel coronavirus 2019 (COVID-19) has dramatically changed how families consume youth sport. Given this, it is important to explore the new and still-changing landscape of youth sport in the United States. The purpose of the present study was to better understand parent perceptions of the current state of youth sport in the United States amidst the backdrop of the COVID-19 pandemic. To address this purpose, a large and statistically representative subset of youth sport parents in the United States (N = 2603;Mage = 38.72) was recruited via Qualtrics panel to complete a study-designed instrument assessing their perceptions prior to, and during, COVID-19-related restrictions. Results highlight youth sport parents' COVID-19-related perspectives, as well as their perceptions of return-to-play protocols in various organizational, community, and sociodemographic contexts. The present work has the potential to shape the ways families engage with youth sport if and when COVID-19-related restrictions are ultimately lifted.

Functional Neurological Disorder After SARS-CoV-2 Vaccines: Two Case Reports and Discussion of Potential Public Health Implications (preprint)

The scientific community responded rapidly to the COVID-19 pandemic by developing novel SARS-CoV-2 vaccines that have been shown to be safe and effective. Global vaccination programs have been rolled out with variable progress. Some vaccines have been suspended for certain demographic groups in a number of countries as a result of rare associations with cerebral venous sinus thromboses. Vaccine programs are dependent on public trust, which may be affected by safety concerns and vaccine hesitancy, both of which can be fueled by misinformation.

Clinical Review of Cerebral Venous Thrombosis in the Context of COVID-19 Vaccinations: Evaluation, Management, and Scientific Questions (preprint)

Background: Vaccine induced immune medicated thrombocytopenia or VITT, is a recent and rare phenomenon of thrombosis with thrombocytopenia, frequently including cerebral venous thromboses (CVT), that has been described following vaccination with adenovirus vaccines ChAdOx1 nCOV-19 (AstraZeneca) and Ad26.COV2.S Johnson and Johnson (Janssen/J&J). The evaluation and management of suspected cases of CVT post COVID-19 vaccination are critical skills for a broad range of healthcare providers. Methods: A collaborative comprehensive review of literature was conducted among a global group of expert neurologists and hematologists. Findings: Strategies for rapid evaluation and treatment of the CVT in the context of possible VITT exist, including inflammatory marker measurements, PF4 assays, and non-heparin anticoagulation. Interpretation: There are many unanswered questions regarding cases of CVT, possibly in association with VITT. Public health specialists should explore ways to enhance public and professional education, surveillance, and reporting of this syndrome to reduce its impact on health and global vaccination efforts. Funding: None

Title page Title Perspectives on COVID-19 testing policies and practices: a qualitative study with scientific advisors and NHS health care workers in England (preprint)

Background As COVID-19 death rates have risen and health-care systems have experienced increased demand, national testing strategies have come under scrutiny. Utilising qualitative interview data from a larger COVID-19 study, this paper provides insights into influences on and the enactment of national COVID-19 testing strategies for health care workers (HCWs) in English NHS settings during wave one of the COVID-19 pandemic (March-August 2020). We aim to inform COVID-19 learning and future pandemic diagnostic preparedness.Methods A remote qualitative, semi-structured longitudinal interview method was employed with a purposive snowball sample of senior scientific advisors to the UK Government on COVID-19, and HCWs employed in NHS primary and secondary health care settings in England. 24 interviews from 13 participants were selected from the larger project dataset. Framework analysis was informed by the non-adoption, abandonment, scale-up, spread, and sustainability of patient-facing health and care technologies implementation framework (NASSS) and by normalisation process theory (NPT).Results Our account highlights tensions between the communication and implementation of national testing developments; scientific advisor and HCW perceptions about infectiousness; and uncertainties about the responsibility for testing and its implications at the local level.Conclusions Consideration must be given to the implications of mass NHS staff testing, including the accuracy of information communicated to HCWs; how HCWs interpret, manage, and act on testing guidance; and the influence these have on health care organisations and services.

Frequency of neurological manifestations in COVID-19: a systematic review and meta-analysis of 350 studies (preprint)

ObjectiveTo summarize the frequency of neurological manifestations reported in COVID-19 patients and investigate the association of these manifestations with disease severity and mortality. DesignSystematic review and meta-analysis Eligibility criteriaStudies enrolling consecutive COVID-19 patients (probable or confirmed) presenting with neurological manifestations. Data sourcesPubMed, Medline, Cochrane library, clinicaltrials.gov and EMBASE from 31st December 2019 to 15th December 2020. Data extraction and analysisTwo authors independently screened titles and abstracts retrieved by literature search. Risk of bias was examined using Joanna Briggs Institute (JBI) scale. A random-effects meta-analysis was performed, and pooled prevalence and 95% Confidence Intervals (CI) were calculated for neurological manifestations. Odds ratio (OR) and 95%CI were calculated to determine the association of neurological manifestations with disease severity and mortality. Presence of heterogeneity was assessed using I-square, meta-regression, and subgroup analyses. Statistical analyses were conducted in R version 3.6.2. ResultsOf 2,455 citations, 350 studies were included in this review, providing data on 145,634 COVID-19 patients, 89% of whom were hospitalized. Forty-one neurological manifestations (24 symptoms and 17 diagnoses) were identified. Pooled prevalence of the most common neurological symptoms included: fatigue (32%), myalgia (20%), taste impairment (21%), smell impairment (19%) and headache (13%). A low risk of bias was observed in 85% of studies; studies with higher risk of bias yielded higher prevalence estimates. Stroke was the most common neurological diagnosis (pooled prevalence-2%). In COVID-19 patients aged >60, the pooled prevalence of acute confusion/delirium was 34% and the presence of any neurological manifestations in this age group was associated with mortality (OR 1.80; 95%CI 1.11 to 2.91). ConclusionsUp to one-third of COVID-19 patients analysed in this review experienced at least one neurological manifestation. One in 50 patients experienced stroke. In those over 60, more than one-third had acute confusion/delirium; the presence of neurological manifestations in this group was associated with near doubling of mortality. Results must be interpreted keeping in view the limitations of observational studies and associated bias. Systematic review registrationPROSPERO CRD42020181867. What is already known on this topicThe frequency of neurological manifestations including fatigue, myalgia, taste and smell impairments, headache and dizziness in COVID-19 patients has been reported in a few systematic reviews and meta-analyses. However, considerable heterogeneity has been observed in terms of methodological quality of the studies, severity of the disease, mean age and hospitalization status of the patients. The evidence regarding the frequency of neurological diagnoses including stroke, encephalitis, Guillain Barre syndrome (GBS) is also limited to case reports and case series and no data exists thus far on the pooled prevalence estimates for neurological diagnoses in COVID-19 patients. What this study addsTo the best of the authors knowledge, this is the largest systematic review and meta-analysis to date (including 350 studies with data on 145,634 cases) summarizing the evidence on the frequency of the full spectrum of neurological manifestations in COVID-19 patients in the overall, young and elderly populations. For the first time, our review reports the pooled prevalence of stroke in COVID-19 patients. Risk of bias, old age and disease severity were potential determinants of the frequency and nature of neurological manifestations as well as its association with mortality. Our review also highlights the need to develop reporting standards for studies describing the frequency of clinical features. Moreover, we note that this will be the first systematic review and meta-analysis on this subject to include studies reported in all languages.

Considerations for Causality Assessment of Neurological and Neuropsychiatric Complications of SARS-CoV-2 Vaccines: from Cerebral Venous Sinus Thrombosis to Functional Neurological Disorder (preprint)

Worldwide SARS-CoV-2 vaccination campaigns for prevention of COVID-19 are currently underway. In clinical trials and in open-label monitoring the vaccines have shown efficacy against COVID-19 and there have been limited and transient side effects. Previous vaccination campaigns have taught us that neurological adverse events to vaccinations can occur. In this review, we summarise what is already known about neurological and neuropsychiatric adverse events of COVID-19 vaccinations, and place this in the context of historical vaccination campaigns. There have been a number of neurological and neuropsychiatric adverse events following immunisation (AEFI) in association with SARS-CoV-2 vaccinations, however in each case there is either no definitive evidence currently to support causality or recognised adverse events are extremely rare. Causality assessment aids such as the Causality Assessment of an Adverse Event Following Immunization from the World Health Organisation and the Bradford Hill criteria may help us better understand potential neurological and neuropsychiatric adverse events to COVID-19 vaccinations. Functional neurological disorder (FND) can be precipitated by the process of vaccination and has previously been noted to potentially spread between individuals, particularly in younger communities. Importantly FND does not implicate the vaccine constituents and therefore should not hamper ongoing vaccination campaigns. Although neurological and neuropsychiatric AEFI may occur after SARS-CoV-2 vaccinations, at present there are no common causally associated neurological adverse events. It is likely that some patients will develop FND in response to vaccination, although this does not implicate vaccine constituents. In cases of future serious neurological or neuropsychiatric AEFIs, judicious and rapid assessment of causality must occur. In general, the benefits of ARS-CoV-2 vaccination at present outweigh the risks from a neurological standpoint, although in specific situations the risk-benefit ratio will vary depending on geographic and demographic factors as well as population risk factors. Ensuring as minimal disruption as possible to ongoing swift worldwide vaccination campaigns is essential to establish the herd immunity required to end the COVID-19 pandemic.

The neurology and neuropsychiatry of COVID-19: a systematic review and meta-analysis of the early literature reveals frequent CNS manifestations and key emerging narratives (preprint)

ObjectivesThere is accumulating evidence of the neurological and neuropsychiatric features of infection with SARS-CoV-2. In this systematic review and meta-analysis, we aimed to describe the characteristics of the early literature and estimate point prevalences for neurological and neuropsychiatric manifestations. MethodsWe searched MEDLINE, Embase, PsycInfo and CINAHL up to 18 July 2020 for randomised controlled trials, cohort studies, case-control studies, cross-sectional studies and case series. Studies reporting prevalences of neurological or neuropsychiatric symptoms were synthesised into meta-analyses to estimate pooled prevalence. Results13,292 records were screened by at least two authors to identify 215 included studies, of which there were 37 cohort studies, 15 case-control studies, 80 cross-sectional studies and 83 case series from 30 countries. 147 studies were included in the meta-analysis. The symptoms with the highest prevalence were anosmia (43.1% [35.2--51.3], n=15,975, 63 studies), weakness (40.0% [27.9--53.5], n=221, 3 studies), fatigue (37.8% [31.6--44.4], n=21,101, 67 studies), dysgeusia (37.2% [30.0--45.3], n=13,686, 52 studies), myalgia (25.1% [19.8--31.3], n=66.268, 76 studies), depression (23.0 % [11.8--40.2], n=43,128, 10 studies), headache (20.7% [95% CI 16.1--26.1], n=64,613, 84 studies), anxiety (15.9% [5.6--37.7], n=42,566, 9 studies) and altered mental status (8.2% [4.4--14.8], n=49,326, 19 studies). Heterogeneity for most clinical manifestations was high. ConclusionsNeurological and neuropsychiatric symptoms of COVID-19 in the pandemics early phase are varied and common. The neurological and psychiatric academic communities should develop systems to facilitate high-quality methodologies, including more rapid examination of the longitudinal course of neuropsychiatric complications of newly emerging diseases and their relationship to neuroimaging and inflammatory biomarkers.

Spectrum, Risk Factors, and Outcomes of Neurological and Psychiatric Complications of COVID-19: A UK-Wide Cross-Sectional Surveillance Study (preprint)

Background: SARS-CoV2 is associated with neurological and psychiatric complications including cerebrovascular events, encephalopathy and peripheral nerve disease. Detailed clinical data, including factors associated with recovery, is lacking, hampering prediction modelling and targeted therapeutic interventions. We studied COVID-associated neurological and psychiatric complications, to investigate the key clinical features, including those associated with outcome.Methods: This UK-wide cross-sectional surveillance study of neurological and psychiatric complications of COVID-19 in adult hospitalised patients captured detailed data on demographics/risk factors, pre-COVID-19 Rockwood frailty score, comorbidities, neurological presentation and outcome. A priori clinical case definitions, based on criteria adopted by the World Health Organisation, were used, with cross-specialty independent adjudication for discrepant cases. Patients meeting multiple clinical case definitions were identified. Cases of stroke were compared to normative data during the equivalent time-period prior to the pandemic. Multivariable logistic regression was performed using demographic and clinical variables, to determine the factors associated with outcome.Findings: 267 cases were included. Cerebrovascular events were most frequently reported (131, 49%), followed by central disorders (95, 36%) including delirium (28, 11%), central inflammatory (25, 9%), psychiatric (25, 9%), and other encephalopathies (17, 7%), including a severe encephalopathy not meeting delirium criteria; and peripheral nerve-disorders (41, 15%). 27% of cerebrovascular events occurred in patients <60 years. Relative to those >60 years old, the younger patients presented with delayed onset from respiratory symptoms, higher rates of multi-vessel occlusion (31%) and more frequently had systemic thrombotic events. Nevertheless, in both younger and older stroke cases there was an association with conventional, modifiable, cerebrovascular risk factors. The timing of neurological presentation varied between disease groups. In 34 cases (13%), clinical case definitions overlapped, and these cases were more likely to require intensive care and ventilation. Regardless of clinical case definition, older age, a higher pre-COVID-19 frailty score, and a high admission white cell count independently associated with a poor outcome. Limited recovery was most common for those with cerebrovascular events. Interpretation: COVID-19 is associated with a broad spectrum of presentations throughout the nervous system, at varied time points relative to respiratory disease. Outcomes vary between disease groups, with cerebrovascular disease conferring the worst prognosis, but this effect was less marked than the pre-morbid factors of age and frailty. A severe encephalopathy occurs after COVID-19 and is associated with requiring intensive care and ventilation. COVID-19 is associated with large and multi-vessel stroke in young people, often with non-CNS thrombotic disease and requires further study. Nevertheless, conventional, modifiable risk factors were associated with stroke, even in younger people, suggesting the potential for public health intervention for this and future pandemics. These clinical data should be combined with blood and neuroimaging biomarkers so that patients can be stratified to targeted existing or novel therapeutics.

Development and validation of the 4C Deterioration model for adults hospitalised with COVID-19 (preprint)

Prognostic models to predict the risk of clinical deterioration in acute COVID-19 are required to inform clinical management decisions. Among 75,016 consecutive adults across England, Scotland and Wales prospectively recruited to the ISARIC Coronavirus Clinical Characterisation Consortium (ISARIC4C) study, we developed and validated a multivariable logistic regression model for in-hospital clinical deterioration (defined as any requirement of ventilatory support or critical care, or death) using 11 routinely measured variables. We used internal-external cross-validation to show consistent measures of discrimination, calibration and clinical utility across eight geographical regions. We further validated the final model in held-out data from 8,252 individuals in London, with similarly consistent performance (C-statistic 0.77 (95% CI 0.75 to 0.78); calibration-in-the-large 0.01 (-0.04 to 0.06); calibration slope 0.96 (0.90 to 1.02)). Importantly, this model demonstrated higher net benefit than using other candidate scores to inform decision-making. Our 4C Deterioration model thus demonstrates unprecedented clinical utility and generalisability to predict clinical deterioration among adults hospitalised with COVID-19.

Elevated antiviral, myeloid and endothelial inflammatory markers in severe COVID-19 (preprint)

The mechanisms that underpin COVID-19 disease severity, and determine the outcome of infection, are only beginning to be unraveled. The host inflammatory response contributes to lung injury, but circulating mediators levels fall below those in classical cytokine storms. We analyzed serial plasma samples from 619 patients hospitalized with COVID-19 recruited through the prospective multicenter ISARIC clinical characterization protocol U.K. study and 39 milder community cases not requiring hospitalization. Elevated levels of numerous mediators including angiopoietin-2, CXCL10, and GM-CSF were seen at recruitment in patients who later died. Markers of endothelial injury (angiopoietin-2 and von-Willebrand factor A2) were detected early in some patients, while inflammatory cytokines and markers of lung injury persisted for several weeks in fatal COVID-19 despite decreasing antiviral cytokine levels. Overall, markers of myeloid or endothelial cell activation were associated with severe, progressive, and fatal disease indicating a central role for innate immune activation and vascular inflammation in COVID-19.

Early clinical characteristics of Covid-19: scoping review (preprint)

ABSTRACT Background: The Coronavirus disease 2019 (covid-19) pandemic has spread rapidly across the globe. Accurate clinical characterisation studies are essential to informing research, diagnosis and clinical management efforts, particularly early in a pandemic. In this scoping review we identify the clinical characteristics of patients admitted to hospital in the early months of the pandemic, focusing on symptoms, laboratory and imaging findings, and clinical outcomes. Methods: A scoping review. MEDLINE, EMBASE and Global Health databases were searched studies published from January 1st 2020 to April 28th 2020. Studies which reported on at least 100 hospitalised patients with covid-19 of any age were included. Results: Of 1,249 studies identified through the search 78 studies were eligible for inclusion; one randomized control trial and 77 observational studies presenting data on 77,443 patients admitted with covid-19. Most studies were conducted in China (82%), 9% in the US and 10% in Europe and two studies were set in more than one country. No studies included patients from low and middle income countries. Coagulopathy was underrecognised as a complication in the early months of the pandemic. Use of corticosteroids varied widely, and the use of anticoagulants was reported in only one study. Fever, cough and dyspnoea are less common in older adults; gastrointestinal symptoms, as the only presenting feature may be underrecognised. The most common laboratory finding was lymphocytopenia. Inflammatory biomarkers were commonly elevated, including C-reactive protein and interleukin-6. Typical computed tomography findings include bilateral infiltrates however imaging may be normal in early disease. Data on clinical characteristics in children and vulnerable populations were limited. Conclusions: Clinical characterisation studies from early in the pandemic indicated that covid-19 is a multisystem disease, with biomarkers indicating inflammation and coagulopathy. However, early data collection on symptoms and clinical outcomes did not consistently reflect this wide spectrum. Corticosteroid use varied widely, and anticoagulants were rarely used. Clinicians should remain vigilant to the possibility of covid-19 in patients presenting without fever, cough and dyspnoea, particularly in older adults. Further characterisation studies in different at-risk populations is needed. Review registration: Available at https://osf.io/r2ch9 Keywords: Covid-19, clinical characteristics, symptoms, biochemical parameters, imaging, outcomes, pandemic research

Risk stratification of patients admitted to hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: development and validation of the 4C Mortality Score (preprint)

ObjectivesTo develop and validate a pragmatic risk score to predict mortality for patients admitted to hospital with covid-19. DesignProspective observational cohort study: ISARIC WHO CCP-UK study (ISARIC Coronavirus Clinical Characterisation Consortium [4C]). Model training was performed on a cohort of patients recruited between 6 February and 20 May 2020, with validation conducted on a second cohort of patients recruited between 21 May and 29 June 2020. Setting260 hospitals across England, Scotland, and Wales. ParticipantsAdult patients ([≥]18 years) admitted to hospital with covid-19 admitted at least four weeks before final data extraction. Main outcome measuresIn-hospital mortality. ResultsThere were 34 692 patients included in the derivation dataset (mortality rate 31.7%) and 22 454 in the validation dataset (mortality 31.5%). The final 4C Mortality Score included eight variables readily available at initial hospital assessment: age, sex, number of comorbidities, respiratory rate, peripheral oxygen saturation, level of consciousness, urea, and C-reactive protein (score range 0-21 points). The 4C risk stratification score demonstrated high discrimination for mortality (derivation cohort: AUROC 0.79; 95% CI 0.78 - 0.79; validation cohort 0.78, 0.77-0.79) with excellent calibration (slope = 1.0). Patients with a score [≥]15 (n = 2310, 17.4%) had a 67% mortality (i.e., positive predictive value 67%) compared with 1.0% mortality for those with a score [≤]3 (n = 918, 7%; negative predictive value 99%). Discriminatory performance was higher than 15 pre-existing risk stratification scores (AUROC range 0.60-0.76), with scores developed in other covid-19 cohorts often performing poorly (range 0.63-0.73). ConclusionsWe have developed and validated an easy-to-use risk stratification score based on commonly available parameters at hospital presentation. This outperformed existing scores, demonstrated utility to directly inform clinical decision making, and can be used to stratify inpatients with covid-19 into different management groups. The 4C Mortality Score may help clinicians identify patients with covid-19 at high risk of dying during current and subsequent waves of the pandemic. Study registrationISRCTN66726260

UK-Wide Surveillance of Neurological and Neuropsychiatric Complications of COVID-19: The First 153 Patients (preprint)

Background: Increasingly neurological complications of COVID-19 are identified, mostly in small series. Larger studies have been limited by both geography and specialty.Consequently, the breadth of complications is not represented. Comprehensive characterization of clinical syndromes is critical to rationally select and evaluate potential therapies.Methods: During the exponential pandemic phase, we developed coordinated online portals for rapid notification across the spectrum of major UK neuroscience bodies, representing neurology, stroke, psychiatry, and intensive care. Evidence of infection and clinical case definitions were applied prospectively. Cases were compared to overall Government Public Health COVID-19 reporting.Findings: Within three weeks, 153 cases were notified, both geographically and temporally representative of overall COVID-19 Public Health reports. Median (range) age was 71 (23-94) years. 77 (62%) had a cerebrovascular event: 57 (74%) ischemic strokes, nine (12%) intracerebral hemorrhages, and one CNS vasculitis.The second most common group were 39 (31%) who had altered mental status, including 16 (41%) with encephalopathy of whom seven (44%) had encephalitis. The remaining 23 (59%) had a psychiatric diagnosis of whom 21 (92%) were new diagnoses; including ten (43%) with psychosis, six (26%) neurocognitive (dementia-like) syndrome, and 4 (17%) an affective disorder. Cerebrovascular events predominated in older patients. Conversely, altered mental status, whilst present in all ages, had disproportionate representation in the young.Interpretation: This is the first nationwide, cross-specialty surveillance study of acute complications of COVID-19 in the nervous system. Alteration in mental status was common, reflecting encephalopathy/encephalitis and primary psychiatric diagnoses, often in young patients.These data provide valuable and timely information urgently needed by clinicians, researchers, and funders to inform immediate steps in COVID-19 neuroscience research and health policy throughout the areas of neurology and neuropsychiatry.