Publications
414 results found
Riley S, Eales O, Haw D, et al., 2021, REACT-1 round 10 report: Level prevalence of SARS-CoV-2 swab-positivity in England during third national lockdown in March 2021
BackgroundIn England, hospitalisations and deaths due to SARS-CoV-2 have been falling consistentlysince January 2021 during the third national lockdown of the COVID-19 pandemic. The firstsignificant relaxation of that lockdown occurred on 8 March when schools reopened.MethodsThe REal-time Assessment of Community Transmission-1 (REACT-1) study augmentsroutine surveillance data for England by measuring swab-positivity for SARS-CoV-2 in thecommunity. The current round, round 10, collected swabs from 11 to 30 March 2021 and iscompared here to round 9, in which swabs were collected from 4 to 23 February 2021.ResultsDuring round 10, we estimated an R number of 1.00 (95% confidence interval 0.81, 1.21).Between rounds 9 and 10 we estimated national prevalence has dropped by ~60% from0.49% (0.44%, 0.55%) in February to 0.20% (0.17%, 0.23%) in March. There weresubstantial falls in weighted regional prevalence: in South East from 0.36% (0.29%, 0.44%)in round 9 to 0.07% (0.04%, 0.12%) in round 10; London from 0.60% (0.48%, 0.76%) to0.16% (0.10%, 0.26%); East of England from 0.47% (0.36%, 0.60%) to 0.15% (0.10%,0.24%); East Midlands from 0.59% (0.45%, 0.77%) to 0.19% (0.13%, 0.28%); and NorthWest from 0.69% (0.54%, 0.88%) to 0.31% (0.21%, 0.45%). Areas of apparent higherprevalence remain in parts of the North West, and Yorkshire and The Humber. The highestprevalence in March was found among school-aged children 5 to 12 years at 0.41% (0.27%,0.62%), compared with the lowest in those aged 65 to 74 and 75 and over at 0.09% (0.05%,0.16%). The close approximation between prevalence of infections and deaths (suitablylagged) is diverging, suggesting that infections may have resulted in fewer hospitalisationsand deaths since the start of widespread vaccination.ConclusionWe report a sharp decline in prevalence of infections between February and March 2021.We did not observe an increase in the prevalence of SARS-CoV-2 following the reopening ofschools in England, although the decline of p
Gupta RK, Harrison EM, Ho A, et al., 2021, Development and validation of the ISARIC 4C Deterioration model for adults hospitalised with COVID-19: a prospective cohort study, The Lancet Respiratory Medicine, Vol: 9, Pages: 349-359, ISSN: 2213-2600
BackgroundPrognostic models to predict the risk of clinical deterioration in acute COVID-19 cases are urgently required to inform clinical management decisions.MethodsWe 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) among consecutively hospitalised adults with highly suspected or confirmed COVID-19 who were prospectively recruited to the International Severe Acute Respiratory and Emerging Infections Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) study across 260 hospitals in England, Scotland, and Wales. Candidate predictors that were specified a priori were considered for inclusion in the model on the basis of previous prognostic scores and emerging literature describing routinely measured biomarkers associated with COVID-19 prognosis. We used internal–external cross-validation to evaluate discrimination, calibration, and clinical utility across eight National Health Service (NHS) regions in the development cohort. We further validated the final model in held-out data from an additional NHS region (London).Findings74 944 participants (recruited between Feb 6 and Aug 26, 2020) were included, of whom 31 924 (43·2%) of 73 948 with available outcomes met the composite clinical deterioration outcome. In internal–external cross-validation in the development cohort of 66 705 participants, the selected model (comprising 11 predictors routinely measured at the point of hospital admission) showed consistent discrimination, calibration, and clinical utility across all eight NHS regions. In held-out data from London (n=8239), the model showed a similarly consistent performance (C-statistic 0·77 [95% CI 0·76 to 0·78]; calibration-in-the-large 0·00 [–0·05 to 0·05]); calibration slope 0·96 [0·91 to 1·01]), and greater net benefit than
Gardiner T, Cooke G, Fidler S, et al., 2021, The under-representation of BAME patients in the COVID-19 Recovery trial at a major London NHS Trust, JOURNAL OF INFECTION, Vol: 82, Pages: 105-107, ISSN: 0163-4453
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Cooke GS, 2021, Decentralisation, integration, and task-shifting: tools to accelerate the elimination of hepatitis C., The Lancet Global Health, Vol: 9, Pages: e375-e376, ISSN: 2214-109X
Bentzon AK, Panteleev A, Mitsura V, et al., 2021, Healthcare delivery for HIV‐positive people with tuberculosis in Europe, HIV Medicine, Vol: 22, Pages: 283-293, ISSN: 1464-2662
<jats:sec><jats:title>Background</jats:title><jats:p>In a 2013 survey, we reported distinct discrepancies in delivery of tuberculosis (TB) and HIV services in eastern Europe (EE) <jats:italic>vs</jats:italic>. western Europe (WE).</jats:p></jats:sec><jats:sec><jats:title>Objectives</jats:title><jats:p>To verify the differences in TB and HIV services in EE <jats:italic>vs</jats:italic>. WE.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Twenty‐three sites completed a survey in 2018 (EE, 14; WE, nine; 88% response rate). Results were compared across as well as within the two regions. When possible, results were compared with the 2013 survey.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Delivery of healthcare was significantly less integrated in EE: provision of TB and HIV services at one site (36% in EE <jats:italic>vs</jats:italic>. 89% in WE; <jats:italic>P</jats:italic> = 0.034), and continued TB follow‐up in one location (42% <jats:italic>vs</jats:italic>. 100%; <jats:italic>P</jats:italic> = 0.007). Although access to TB diagnostics, standard TB and HIV drugs was generally good, fewer sites in EE reported unlimited access to rifabutin/multi‐drug‐resistant TB (MDR‐TB) drugs, HIV integrase inhibitors and opioid substitution therapy (OST). Compared with 2013, routine usage of GeneXpert was more common in EE in 2018 (54% <jats:italic>vs</jats:italic>. 92%; <jats:italic>P</jats:italic> = 0.073), as was access to moxifloxacin (46% <jats:italic>vs</jats:italic>. 91%; <jats:italic>P</jats:italic> = 0.033), linezolid (31% <jats:italic>vs</jats:italic>. 64%; <jats:italic>P</jats:italic> = 0.217), and bedaqui
Yates T, Zaccardi F, Islam N, et al., 2021, Obesity, ethnicity and risk of critical care, mechanical ventilation and mortality in patients admitted to hospital with COVID-19: Analysis of the ISARIC CCP-UK cohort., Obesity (Silver Spring, Md.), Vol: 29, Pages: 1223-1230, ISSN: 1071-7323
OBJECTIVE: To investigate the association of obesity with in-hospital COVID-19 outcomes in different ethnic groups. METHODS: Patients admitted to hospital with COVID-19 in the United Kingdom through the Clinical Characterisation Protocol UK (CCP-UK) developed by the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) were included from 6th February to 12th October 2020. Ethnicity was classified as: white, South Asian, black and other minority ethnic groups. Outcomes were admission to critical care, mechanical ventilation and in-hospital mortality, adjusted for age, sex and chronic diseases. RESULTS: 54,254 (age = 76 years; 45.0% women) white, 3,728 (57 years; 41.1%) South Asian, 2,523 (58 years; 44.9%) black and 5,427 (61 years; 40.8%) other ethnicities were included. Obesity was associated with all outcomes in all ethnic groups, with associations strongest for black ethnicities. When stratified by ethnicity and obesity status, the OR for admission to critical care, mechanical ventilation and mortality in black ethnicities with obesity were 3.91 (3.13, 4.88), 5.03 (3.94, 6.63), 1.93 (1.49, 2.51) respectively, compared to white ethnicities without obesity. CONCLUSIONS: Obesity was associated with an elevated risk of in-hospital COVID-19 outcomes in all ethnic groups, with associations strongest in black ethnicities.
Joshi M, Archer S, Morbi A, et al., 2021, Perceptions on the Use of Wearable Sensors and Continuous Monitoring in Surgical Patients: Interview Study Among Surgical Staff (Preprint)
<sec> <title>BACKGROUND</title> <p>Continuous vital sign monitoring by using wearable sensors may result in the earlier detection of patient deterioration and sepsis. Few studies have explored the perspectives of surgical team members on the use of such sensors in surgical patients.</p> </sec> <sec> <title>OBJECTIVE</title> <p>This study aims to understand the views of surgical team members regarding novel wearable sensors for surgical patients.</p> </sec> <sec> <title>METHODS</title> <p>Wearable sensors that monitor vital signs (heart rate, respiratory rate, and temperature) continuously were used by acute surgical patients. The opinions of surgical staff who were treating patients with these sensors were collated through in-depth semistructured interviews to thematic saturation. Interviews were audio recorded, transcribed, and analyzed via thematic analysis.</p> </sec> <sec> <title>RESULTS</title> <p>A total of 48 interviews were performed with senior and junior surgeons and senior and junior nurses. The main themes of interest that emerged from the interviews were (1) problems with current monitoring, (2) the anticipated impact of wearables on patient safety, (3) the impact on staff, (4) the impact on patients overall, (5) potential new changes, and (6) the future and views on technology.</p> </sec> <sec> <title>CONCLUSIONS</title> <p>Overall, the feedback from staff who were continuously monitoring surgical pat
Pairo-Castineira E, Clohisey S, Klaric L, et al., 2021, Genetic mechanisms of critical illness in Covid-19, Nature, Vol: 591, Pages: 92-98, ISSN: 0028-0836
Host-mediated lung inflammation is present,1 and drives mortality,2 in critical illness caused by Covid-19. Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development.3 Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study(GWAS) in 2244 critically ill Covid-19 patients from 208 UK intensive care units (ICUs). We identify and replicate novel genome-wide significant associations, on chr12q24.13 (rs10735079, p=1.65 [Formula: see text] 10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), on chr19p13.2 (rs2109069, p=2.3 [Formula: see text] 10-12) near the gene encoding tyrosine kinase 2 (TYK2), on chr19p13.3 (rs2109069, p=3.98 [Formula: see text] 10-12) within the gene encoding dipeptidyl peptidase 9 (DPP9), and on chr21q22.1 (rs2236757, p=4.99 [Formula: see text] 10-8) in the interferon receptor gene IFNAR2. We identify potential targets for repurposing of licensed medications: using Mendelian randomisation we found evidence in support of a causal link from low expression of IFNAR2, and high expression of TYK2, to life-threatening disease; transcriptome-wide association in lung tissue revealed that high expression of the monocyte/macrophage chemotactic receptor CCR2 is associated with severe Covid-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms, and mediators of inflammatory organ damage in Covid-19. Both mechanisms may be amenable to targeted treatment with existing drugs. Large-scale randomised clinical trials will be essential before any change to clinical practice.
Riley S, Wang H, Eales O, et al., 2021, REACT-1 round 9 final report: Continued but slowing decline of prevalence of SARS-CoV-2 during national lockdown in England in February 2021
BackgroundEngland will start to exit its third national lockdown in response to the COVID-19 pandemicon 8th March 2021, with safe effective vaccines being rolled out rapidly against abackground of emerging transmissible and immunologically novel variants of SARS-CoV-2.A subsequent increase in community prevalence of infection could delay further relaxation oflockdown if vaccine uptake and efficacy are not sufficiently high to prevent increasedpressure on healthcare services.MethodsThe PCR self-swab arm of the REal-time Assessment of Community Transmission Study(REACT-1) estimates community prevalence of SARS-CoV-2 infection in England based onrandom cross-sections of the population ages five and over. Here, we present results fromthe complete round 9 of REACT-1 comprising round 9a in which swabs were collected from4th to 12th February 2021 and round 9b from 13th to 23rd February 2021. We also comparethe results of REACT-1 round 9 to round 8, in which swabs were collected mainly from 6thJanuary to 22nd January 2021.ResultsOut of 165,456 results for round 9 overall, 689 were positive. Overall weighted prevalence ofinfection in the community in England was 0.49% (0.44%, 0.55%), representing a fall of overone third from round 8. However the rate of decline of the epidemic has slowed from 15 (13,17) days, estimated for the period from the end of round 8 to the start of round 9, to 31 daysestimated using data from round 9 alone (lower confidence limit 17 days). When comparinground 9a to 9b there were apparent falls in four regions, no apparent change in one regionand apparent rises in four regions, including London where there was a suggestion ofsub-regional heterogeneity in growth and decline. Smoothed prevalence maps suggest largecontiguous areas of growth and decline that do not align with administrative regions.Prevalence fell by 50% or more across all age groups in round 9 compared to round 8, withprevalence (round 9) ranging from 0.21% in those aged 65 and over to 0
Ansari MA, Marchi E, Ramamurthy N, et al., 2021, In vivo negative regulation of SARS-CoV-2 receptor, ACE2, by interferons and its genetic control, Wellcome Open Research, Vol: 6, Pages: 47-47
<ns4:p><ns4:bold>Background</ns4:bold>: Angiotensin I converting enzyme 2 (ACE2) is a receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and differences in its expression may affect susceptibility to infection.</ns4:p><ns4:p> <ns4:bold>Methods</ns4:bold>: We performed a genome-wide expression quantitative trait loci (eQTL) analysis using hepatitis C virus-infected liver tissue from 190 individuals.</ns4:p><ns4:p> <ns4:bold>Results</ns4:bold>: We discovered that polymorphism in a type III interferon gene (<ns4:italic>IFNL4</ns4:italic>), which eliminates IFN-λ4 production, is associated with a two-fold increase in ACE2 RNA expression. Conversely, among genes negatively correlated with <ns4:italic>ACE2 </ns4:italic>expression, IFN-signalling pathways were highly enriched and <ns4:italic>ACE2 </ns4:italic>was downregulated after IFN-α treatment. Negative correlation was also found in the gastrointestinal tract where inflammation driven IFN-stimulated genes were negatively correlated with <ns4:italic>ACE2</ns4:italic> expression and in lung tissue from a murine model of SARS-CoV-1 infection suggesting conserved regulation of <ns4:italic>ACE2 </ns4:italic>across tissue and species.</ns4:p><ns4:p> <ns4:bold>Conclusions</ns4:bold>: We conclude that <ns4:italic>ACE2 </ns4:italic>is likely a negatively-regulated interferon-stimulated gene (ISG) and carriage of <ns4:italic>IFNL4 </ns4:italic>gene alleles which modulates ISGs expression in viral infection may play a role in SARS-CoV-2 pathogenesis with implications for therapeutic interventions.</ns4:p>
Moshe M, Daunt A, Flower B, et al., 2021, SARS-CoV-2 lateral flow assays for possible use in national covid-19 seroprevalence surveys (REACT2): diagnostic accuracy study, BMJ: British Medical Journal, Vol: 372, Pages: 1-8, ISSN: 0959-535X
Objective: To evaluate the performance of new lateral flow immunoassays (LFIAs) suitable for use in a national COVID-19 seroprevalence programme (REACT2).Design: Laboratory sensitivity and specificity analyses were performed for seven LFIAs on a minimum of 200 sera from individuals with confirmed SARS-CoV-2 infection, and 500 pre-pandemic sera respectively. Three LFIAs were found to have a laboratory sensitivity superior to the finger-prick sensitivity of the LFIA currently used in REACT2 seroprevalence studies (84%). These LFIAs were then further evaluated through finger-prick testing on participants with confirmed previous SARS-CoV-2 infection. Two LFIAs (Surescreen, Panbio) were evaluated in clinics in June-July, 2020, and a third LFIA (AbC-19) in September, 2020. A Spike protein enzyme-linked immunoassay (S-ELISA) and hybrid double antigen binding assay (DABA) were used as laboratory reference standards.Setting: Laboratory analyses were performed at Imperial College, London and University facilities in London, UK. Research clinics for finger-prick sampling were run in two affiliated NHS trusts.Participants: Sensitivity analysis on sera were performed on 320 stored samples from previous participants in the REACT2 programme with confirmed previous SARS-CoV-2 infection. Specificity analysis was performed using 1000 pre-pandemic sera. 100 new participants with confirmed previous SARS-CoV-2 infection attended study clinics for finger-prick testing.Main outcome measures: The accuracy of LFIAs in detecting IgG antibodies to SARS-CoV-2 in comparison to two in-house ELISAs.Results: The sensitivity of seven new LFIAs using sera varied between 69% and 100% (vs S-ELISA/hybrid DABA). Specificity using sera varied between 99.6% and 100%. Sensitivity on finger-prick testing for Panbio, Surescreen and AbC-19 was 77% (CI 61.4 to 88.2), 86% (CI 72.7 to 94.8) and 69% (CI 53.8 to 81.3) respectively vs S-ELISA/hybrid DABA. Sensitivity for sera from matched clinical samples performe
RECOVERY Collaborative Group, Horby P, Lim WS, et al., 2021, Dexamethasone in hospitalized patients with Covid-19., New England Journal of Medicine, Vol: 384, Pages: 693-704, ISSN: 0028-4793
BACKGROUND: Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. METHODS: In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the final results of this assessment. RESULTS: A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.92 to 1.55). CONCLUSIONS: In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY Clin
Honeyford C, Costelloe C, Expert P, et al., 2021, Changes in Emergency Department attendances before and after COVID-19 lockdown implementation: a cross sectional study of one urban NHS Hospital Trust, Western Journal of Emergency Medicine : Integrating Emergency Care with Population Health, ISSN: 1936-900X
Ward H, Cooke G, Whitaker M, et al., 2021, REACT-2 Round 5: increasing prevalence of SARS-CoV-2 antibodies demonstrate impact of the second wave and of vaccine roll-out in England
BackgroundEngland has experienced high rates of SARS-CoV-2 infection during the COVID-19 pandemic, affecting in particular minority ethnic groups and more deprived communities. A vaccination programme began in England in December 2020, with priority given to administering thefirst dose to the largest number of older individuals, healthcare and care home workers.MethodsA cross-sectional community survey in England undertaken between 26 January and 8 February 2021 as the fifth round of the REal-time Assessment of Community Transmission-2 (REACT-2) programme. Participants completed questionnaires, including demographic details and clinical and COVID-19 vaccination histories, and self-administered a lateral flowimmunoassay (LFIA) test to detect IgG against SARS-CoV-2 spike protein. There were sufficient numbers of participants to analyse antibody positivity after 21 days from vaccination with the PfizerBioNTech but not the AstraZeneca/Oxford vaccine which was introduced slightly later.ResultsThe survey comprised 172,099 people, with valid IgG antibody results from 155,172. The overall prevalence of antibodies (weighted to be representative of the population of England and adjusted for test sensitivity and specificity) in England was 13.9% (95% CI 13.7, 14.1) overall, 37.9% (37.2, 38.7) in vaccinated and 9.8% (9.6, 10.0) in unvaccinated people.The prevalence of antibodies (weighted) in unvaccinated people was highest in London at 16.9% (16.3, 17.5), and higher in people of Black (22.4%, 20.8, 24.1) and Asian (20.0%, 19.0, 21.0) ethnicity compared to white (8.5%, 8.3, 8.7) people. The uptake of vaccination by age was highest in those aged 80 years or older (93.5%). Vaccine confidence was high with 92.0% (91.9, 92.1) of people saying that they had accepted or intended to accept the offer.Vaccine confidence varied by age and ethnicity, with lower confidence in young people and those of Black ethnicity. Particular concerns were identified around pregnancy, fertility and alle
Horby P, Lim WS, Emberson JR, et al., 2021, Dexamethasone in Hospitalized Patients with Covid-19, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 384, Pages: 693-704, ISSN: 0028-4793
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Riley S, Walters C, Wang H, et al., 2021, REACT-1 round 9 interim report: downward trend of SARS-CoV-2 in England in February 2021 but still at high prevalence
Background and Methods: England entered its third national lockdown of the COVID-19pandemic on 6th January 2021 with the aim of reducing the daily number of deaths andpressure on healthcare services. The real-time assessment of community transmission study(REACT-1) obtains throat and nose swabs from randomly selected people in England inorder to describe patterns of SARS-CoV-2 prevalence. Here, we report data from round 9aof REACT-1 for swabs collected between 4th and 13th February 2021.Results: Out of 85,473 tested-swabs, 378 were positive. Overall weighted prevalence ofinfection in the community in England was 0.51%, a fall of more than two thirds since our lastreport (round 8) in January 2021 when 1.57% of people tested positive. We estimate ahalving time of 14.6 days and a reproduction number R of 0.72, based on the difference inprevalence between the end of round 8 and the beginning of round 9. Although prevalencefell in all nine regions of England over the same period, there was greater uncertainty in thetrend for North West, North East, and Yorkshire and The Humber. Prevalence fellsubstantially across all age groups with highest prevalence among 18- to 24-year olds at0.89% (0.47%, 1.67%) and those aged 5 to12 years at 0.86% (0.60%, 1.24%). Largehousehold size, living in a deprived neighbourhood, and Asian ethnicity were all associatedwith increased prevalence. Healthcare and care home workers were more likely to testpositive compared to other workers.Conclusions: There is a strong decline in prevalence of SARS-CoV-2 in England among thegeneral population five to six weeks into lockdown, but prevalence remains high: at levelssimilar to those observed in late September 2020. Also, the number of COVID-19 cases inhospitals is higher than at the peak of the first wave in April 2020. The effects of easing ofsocial distancing when we transition out of lockdown need to be closely monitored to avoid aresurgence in infections and renewed pressure on health services.
Horby PW, Roddick A, Spata E, et al., 2021, Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial, The Lancet, Vol: 397, Pages: 605-612, ISSN: 0140-6736
BackgroundAzithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatory actions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.MethodsIn this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospital with COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients were randomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once per day by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatment groups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment and were twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants and local study staff were not masked to the allocated treatment, but all others involved in the trial were masked to the outcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.FindingsBetween April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) were eligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was 65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomly allocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall, 561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days (rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No
Elliott J, Whitaker M, Bodinier B, et al., 2021, Symptom reporting in over 1 million people: community detection of COVID-19
Control of the SARS-CoV-2 epidemic requires rapid identification and isolation of infectedindividuals and their contacts. Community testing in England (Pillar 2) by polymerase chainreaction (PCR) is reserved for those reporting at least one of four ‘classic’ COVID-19 symptoms(loss or change of sense of smell, loss or change of sense of taste, fever, new continuous cough). 1Detection of positive cases in the community might be improved by including additionalsymptoms and their combinations. We used data from the REal-time Assessment of CommunityTransmission-1 (REACT-1) study to investigate symptom profiles for PCR positivity at differentages. Among rounds 2–7 (June to December 2020), an age-stratified, variable selection approachstably selected chills (all ages), headache (5–17 years), appetite loss (18–54 and 55+ years) andmuscle aches (18–54 years) as jointly and positively predictive of PCR positivity together withthe classic four symptoms. Between round 7 (November to December 2020) and round 8(January 2021) when new variant B.1.1.7 predominated, only loss or change of sense of smell(more predictive in round 7) and (borderline) new persistent cough (more predictive in round 8)differed between cases. At any level of PCR testing, triage based on the symptoms identifiedhere would result in more cases detected than the current approach .
Ward H, Atchison C, Whitaker M, et al., 2021, SARS-CoV-2 antibody prevalence in England following the first peak of the pandemic., Nature Communications, Vol: 12, Pages: 1-8, ISSN: 2041-1723
England has experienced a large outbreak of SARS-CoV-2, disproportionately affecting people from disadvantaged and ethnic minority communities. It is unclear how much of this excess is due to differences in exposure associated with structural inequalities. Here we report from the REal-time Assessment of Community Transmission-2 (REACT-2) national study of over 100,000 people. After adjusting for test characteristics and re-weighting to the population, overall antibody prevalence is 6.0% (95% CI: 5.8-6.1). An estimated 3.4 million people had developed antibodies to SARS-CoV-2 by mid-July 2020. Prevalence is two- to three-fold higher among health and care workers compared with non-essential workers, and in people of Black or South Asian than white ethnicity, while age- and sex-specific infection fatality ratios are similar across ethnicities. Our results indicate that higher hospitalisation and mortality from COVID-19 in minority ethnic groups may reflect higher rates of infection rather than differential experience of disease or care.
Riley S, Eales O, Walters C, et al., 2021, REACT-1 round 8 final report: high average prevalence with regional heterogeneity of trends in SARS-CoV-2 infection in the community in England during January 2021
In early January 2021, England entered its third national lockdown of the COVID-19 pandemic to reduce numbers of deaths and pressure on healthcare services, while rapidly rolling out vaccination to healthcare workers and those most at risk of severe disease and death. REACT-1 is a survey of SARS-CoV-2 prevalence in the community in England, based on repeated cross-sectional samples of the population. Between 6th and 22nd January 2021, out of 167,642 results, 2,282 were positive giving a weighted national prevalence of infection of 1.57% (95% CI, 1.49%, 1.66%). The R number nationally over this period was estimated at 0.98 (0.92, 1.04). Prevalence remained high throughout, but with suggestion of a decline at the end of the study period. The average national trend masked regional heterogeneity, with robustly decreasing prevalence in one region (South West) and increasing prevalence in another (East Midlands). Overall prevalence at regional level was highest in London at 2.83% (2.53%, 3.16%). Although prevalence nationally was highest in the low-risk 18 to 24 year old group at 2.44% (1.96%, 3.03%), it was also high in those over 65 years who are most at risk, at 0.93% (0.82%, 1.05%). Large household size, living in a deprived neighbourhood, and Black and Asian ethnicity were all associated with higher levels of infections compared to smaller households, less deprived neighbourhoods and other ethnicities. Healthcare and care home workers, and other key workers, were more likely to test positive compared to other workers. If sustained lower prevalence is not achieved rapidly in England, pressure on healthcare services and numbers of COVID-19 deaths will remain unacceptably high.
Middleton P, Perez-Guzman PN, Cheng A, et al., 2021, Characteristics and outcomes of clinically diagnosed RT-PCR swab negative COVID-19: a retrospective cohort study, Scientific Reports, Vol: 11, Pages: 1-7, ISSN: 2045-2322
Patients with strong clinical features of COVID-19 with negative real time polymerase chain reaction (RT-PCR) SARS-CoV-2 testing are not currently included in official statistics. The scale, characteristics and clinical relevance of this group are not well described. We performed a retrospective cohort study in two large London hospitals to characterize the demographic, clinical, and hospitalization outcome characteristics of swab-negative clinical COVID-19 patients. We found 1 in 5 patients with a negative swab and clinical suspicion of COVID-19 received a clinical diagnosis of COVID-19 within clinical documentation, discharge summary or death certificate. We compared this group to a similar swab positive cohort and found similar demographic composition, symptomology and laboratory findings. Swab-negative clinical COVID-19 patients had better outcomes, with shorter length of hospital stay, reduced need for >60% supplementary oxygen and reduced mortality. Patients with strong clinical features of COVID-19 that are swab-negative are a common clinical challenge. Health systems must recognize and plan for the management of swab-negative patients in their COVID-19 clinical management, infection control policies and epidemiological assessments.
Riley S, Wang H, Eales O, et al., 2021, REACT-1 round 8 interim report: SARS-CoV-2 prevalence during the initial stages of the third national lockdown in England, Publisher: Imperial College London
BackgroundHigh prevalence of SARS-CoV-2 virus in many northern hemisphere populations is causingextreme pressure on healthcare services and leading to high numbers of fatalities. Eventhough safe and effective vaccines are being deployed in many populations, the majority ofthose most at-risk of severe COVID-19 will not be protected until late spring, even incountries already at a more advanced stage of vaccine deployment.MethodsThe REal-time Assessment of Community Transmission study-1 (REACT-1) obtains throatand nose swabs from between 120,000 and 180,000 people in the community in England atapproximately monthly intervals. Round 8a of REACT-1 mainly covers a period from 6thJanuary 2021 to 15th January 2021. Swabs are tested for SARS-CoV-2 virus and patterns ofswab-positivity are described over time, space and with respect to individual characteristics.We compare swab-positivity prevalence from REACT-1 with mobility data based on the GPSlocations of individuals using the Facebook mobile phone app. We also compare resultsfrom round 8a with those from round 7 in which swabs were collected from 13th Novemberto 24th November (round 7a) and 25th November to 3rd December 2020 (round 7b).ResultsIn round 8a, we found 1,962 positives from 142,909 swabs giving a weighted prevalence of1.58% (95% CI, 1.49%, 1.68%). Using a constant growth model, we found no strongevidence for either growth or decay averaged across the period; rather, based on data froma limited number of days, prevalence may have started to rise at the end of round 8a.Facebook mobility data showed a marked decrease in activity at the end of December 2020,followed by a rise at the start of the working year in January 2021. Between round 7b andround 8a, prevalence increased in all adult age groups, more than doubling to 0.94%(0.83%, 1.07%) in those aged 65 and over. Large household size, living in a deprivedneighbourhood, and Black and Asian ethnicity were all associated with increasedprevalence. Both healthcare
Vollmer MAC, Glampson B, Mellan TA, et al., 2021, A unified machine learning approach to time series forecasting applied to demand at emergency departments, BMC Emergency Medicine, Vol: 21, Pages: 1-14, ISSN: 1471-227X
There were 25.6 million attendances at Emergency Departments (EDs) in Englandin 2019 corresponding to an increase of 12 million attendances over the pastten years. The steadily rising demand at EDs creates a constant challenge toprovide adequate quality of care while maintaining standards and productivity.Managing hospital demand effectively requires an adequate knowledge of thefuture rate of admission. Using 8 years of electronic admissions data from twomajor acute care hospitals in London, we develop a novel ensemble methodologythat combines the outcomes of the best performing time series and machinelearning approaches in order to make highly accurate forecasts of demand, 1, 3and 7 days in the future. Both hospitals face an average daily demand of 208and 106 attendances respectively and experience considerable volatility aroundthis mean. However, our approach is able to predict attendances at theseemergency departments one day in advance up to a mean absolute error of +/- 14and +/- 10 patients corresponding to a mean absolute percentage error of 6.8%and 8.6% respectively. Our analysis compares machine learning algorithms tomore traditional linear models. We find that linear models often outperformmachine learning methods and that the quality of our predictions for any of theforecasting horizons of 1, 3 or 7 days are comparable as measured in MAE. Inaddition to comparing and combining state-of-the-art forecasting methods topredict hospital demand, we consider two different hyperparameter tuningmethods, enabling a faster deployment of our models without compromisingperformance. We believe our framework can readily be used to forecast a widerange of policy relevant indicators.
Garvey LJ, Cooke GS, Smith C, et al., 2021, Decline in Hepatitis C Virus (HCV) Incidence in Men Who Have Sex With Men Living With Human Immunodeficiency Virus: Progress to HCV Microelimination in the United Kingdom?, Clinical Infectious Diseases, Vol: 72, Pages: 233-238, ISSN: 1058-4838
BACKGROUND: Modeling of the London hepatitis C virus (HCV) epidemic in men who have sex with men (MSM) and are living with human immunodeficiency virus (HIV) suggested that early access to direct-acting antiviral (DAA) treatment may reduce incidence. With high rates of linkage to care, microelimination of HCV within MSM living with HIV may be realistic ahead of 2030 World Health Organization targets. We examined trends in HCV incidence in the pre- and post-DAA eras for MSM living with HIV in London and Brighton, United Kingdom. METHODS: A retrospective cohort study was conducted at 5 HIV clinics in London and Brighton between 2013 and 2018. Each site reported all acute HCV episodes during the study period. Treatment timing data were collected. Incidence rates and reinfection proportion were calculated. RESULTS: A total of. 378 acute HCV infections were identified, comprising 292 first infections and 86 reinfections. Incidence rates of acute HCV in MSM living with HIV peaked at 14.57/1000 person-years of follow-up (PYFU; 95% confidence interval [CI], 10.95-18.20) in 2015. Rates fell to 4.63/1000 PYFU (95% CI, 2.60 to 6.67) by 2018. Time from diagnosis to starting treatment declined from 29.8 (2013) to 3.7 months (2018). CONCLUSIONS: We observed a 78% reduction in the incidence of first HCV episode and a 68% reduction in overall HCV incidence since the epidemic peak in 2015, which coincides with wider access to DAAs in England. Further interventions to reduce transmission, including earlier access to treatment and for reinfection, are likely needed for microelimination to be achieved in this population.
Heffernan A, Ma Y, Nayagam S, et al., 2021, Economic and epidemiological evaluation of interventions to reduce the burden of hepatitis C in Yunnan province, China, PLoS One, Vol: 16, Pages: 1-17, ISSN: 1932-6203
BackgroundThe paradigm shift in hepatitis C virus (HCV) treatment options in the last five years has raised the prospect of eliminating the disease as a global health threat. This will require a step-change in the number being treated with the new direct-acting antivirals (DAAs). Given constrained budgets and competing priorities, policy makers need information on how to scale-up access to HCV treatment. To inform such decisions, we examined the cost effectiveness of screening and treatment interventions in Yunnan, China.Methods and findingsWe simulated the HCV epidemic using a previously published model of HCV transmission and disease progression, calibrated to Yunnan data, and implemented a range of treatment and screening interventions from 2019. We incorporated treatment, diagnosis, and medical costs (expressed in 2019 US Dollars, USD) to estimate the lifetime benefits and costs of interventions. Using this model, we asked: is introducing DAAs cost effective from a healthcare sector perspective; what is the optimal combination of screening interventions; and what is the societal return on investment of intervention? The incremental cost-effectiveness ratio (ICER) of switching to DAAs with a median cost of 7,400 USD (50,000 Chinese Yuan) per course is 500 USD/disability adjusted life year (DALY) averted; at a threshold of 50% of Yunnan gross domestic product (2,600 USD), switching to DAAs is cost effective 94% of the time. At this threshold, the optimal, cost-effective intervention comprises screening people who inject drugs, those in HIV care, men who have sex with men, and ensuring access to DAAs for all those newly diagnosed with HCV. For each USD invested in this intervention, there is an additional 0·80 USD (95% credible interval: 0·17–1·91) returned through reduced costs of disease or increased productivity. Returns on investment are lower (and potentially negative) if a sufficiently long-term horizon, encompassing the full stream
du Cros P, Khamraev A, Tigay Z, et al., 2021, Outcomes with a shorter multidrug-resistant tuberculosis regimen from Karakalpakstan, Uzbekistan, ERJ Open Research, Vol: 7, ISSN: 2312-0541
Background: In 2016, World Health Organization guidelines conditionally recommended standardised shorter 9-12-month regimens for multidrug-resistant (MDR) tuberculosis (TB) treatment. We conducted a prospective study of a shorter standardised MDR-TB regimen in Karakalpakstan, Uzbekistan. Methods: Consecutive adults and children with confirmed rifampicin-resistant pulmonary TB were enrolled between September 1, 2013 and March 31, 2015; exclusions included prior treatment with second-line anti-TB drugs, and documented resistance to ofloxacin or to two second-line injectable agents. The primary outcome was recurrence-free cure at 1 year following treatment completion. Results: Of 146 enrolled patients, 128 were included: 67 female (52.3%), median age 30.1 (interquartile range 23.8-44.4) years. At the end of treatment, 71.9% (92 out of 128) of patients achieved treatment success, with 68% (87 out of 128) achieving recurrence-free cure at 1 year following completion. Unsuccessful outcomes during treatment included 22 (17.2%) treatment failures with fluoroquinolone-resistance amplification in 8 patients (8 out of 22, 36.4%); 12 (9.4%) lost to follow-up; and 2 (1.5%) deaths. Recurrence occurred in one patient. Fourteen patients (10.9%) experienced serious adverse events. Baseline resistance to both pyrazinamide and ethambutol (adjusted OR 6.13, 95% CI 2.01; 18.63) and adherence <95% (adjusted OR 5.33, 95% CI 1.73; 16.36) were associated with unsuccessful outcome in multivariable logistic regression. Conclusions: Overall success with a standardised shorter MDR-TB regimen was moderate with considerable treatment failure and amplification of fluoroquinolone resistance. When introducing standardised shorter regimens, baseline drug susceptibility testing and minimising missed doses are critical. High rates globally of pyrazinamide, ethambutol and ethionamide resistance raise questions of continued inclusion of these drugs in shorter regimens in the absence of drug susceptibi
Barnacle JR, Cairney G, Rainsley J, et al., 2021, Changes in the hospital admission profile of COVID-19 positive patients at a central London trust., Journal of Infection, Vol: 82, Pages: 159-198, ISSN: 0163-4453
Cooke GS, Pett S, McCabe L, et al., 2021, Strategic treatment optimization for HCV (STOPHCV1): a randomised controlled trial of ultrashort duration therapy for chronic hepatitis C., Wellcome Open Res, Vol: 6, ISSN: 2398-502X
Background: The World Health Organization (WHO) has identified the need for a better understanding of which patients with hepatitis C virus (HCV) can be cured with ultrashort course HCV therapy. Methods: A total of 202 individuals with chronic HCV were randomised to fixed-duration shortened therapy (8 weeks) vs variable-duration ultrashort strategies (VUS1/2). Participants not cured following first-line treatment were retreated with 12 weeks' sofosbuvir/ledipasvir/ribavirin. The primary outcome was sustained virological response 12 weeks (SVR12) after first-line treatment and retreatment. Participants were factorially randomised to receive ribavirin with first-line treatment. Results: All evaluable participants achieved SVR12 overall (197/197, 100% [95% CI 98-100]) demonstrating non-inferiority between fixed-duration and variable-duration strategies (difference 0% [95% CI -3.8%, +3.7%], 4% pre-specified non-inferiority margin). First-line SVR12 was 91% [86%-97%] (92/101) for fixed-duration vs 48% [39%-57%] (47/98) for variable-duration, but was significantly higher for VUS2 (72% [56%-87%] (23/32)) than VUS1 (36% [25%-48%] (24/66)). Overall, first-line SVR12 was 72% [65%-78%] (70/101) without ribavirin and 68% [61%-76%] (69/98) with ribavirin (p=0.48). At treatment failure, the emergence of viral resistance was lower with ribavirin (12% [2%-30%] (3/26)) than without (38% [21%-58%] (11/29), p=0.01). Conclusions: Unsuccessful first-line short-course therapy did not compromise retreatment with sofosbuvir/ledipasvir/ribavirin (100% SVR12). SVR12 rates were significantly increased when ultrashort treatment varied between 4-7 weeks rather than 4-6 weeks. Ribavirin significantly reduced resistance emergence in those failing first-line therapy. ISRCTN Registration: 37915093 (11/04/2016).
Riley S, Walters C, Wang H, et al., 2020, REACT-1 round 7 updated report: regional heterogeneity in changes in prevalence of SARS-CoV-2 infection during the second national COVID-19 lockdown in England, REACT-1 round 7 updated report: regional heterogeneity in changes in prevalence of SARS-CoV-2 infection during the second national COVID-19 lockdown in England, London, Publisher: Imperial College London
BackgroundEngland exited a four-week second national lockdown on 2nd December 2020 initiated in response to the COVID-19 pandemic. Prior results showed that prevalence dropped during the first half of lockdown, with greater reductions in higher-prevalence northern regions.MethodsREACT-1 is a series of community surveys of SARS-CoV-2 RT-PCR swab-positivity in England, designed to monitor the spread of the epidemic and thus increase situational awareness. Round 7 of REACT-1 commenced swab-collection on 13th November 2020. A prior interim report included data from 13th to 24th November 2020 for 105,122 participants. Here, we report data for the entire round with swab results obtained up to 3rd December 2020.ResultsBetween 13th November and 3rd December (round 7) there were 1,299 positive swabs out of 168,181 giving a weighted prevalence of 0.94% (95% CI 0.87%, 1.01%) or 94 per 10,000 people infected in the community in England. This compares with a prevalence of 1.30% (1.21%, 1.39%) from 16th October to 2nd November 2020 (round 6), a decline of 28%. Prevalence during the latter half of round 7 was 0.91% (95% CI, 0.81%, 1.03%) compared with 0.96% (0.87%, 1.05%) in the first half. The national R number in round 7 was estimated at 0.96 (0.88, 1.03) with a decline in prevalence observed during the first half of this period no longer apparent during the second half at the end of lockdown. During round 7 there was a marked fall in prevalence in West Midlands, a levelling off in some regions and a rise in London. R numbers at regional level ranged from 0.60 (0.41, 0.80) in West Midlands up to 1.27 (1.04, 1.54) in London, where prevalence was highest in the east and south-east of the city. Nationally, between 13th November and 3rd December, the highest prevalence was in school-aged children especially at ages 13-17 years at 2.04% (1.69%, 2.46%), or approximately 1 in 50.ConclusionBetween the previous round and round 7 (during lockdown), there was a fall in prevalence of SARS-C
Riley S, Eales O, Walters C, et al., 2020, REACT-1 round 7 interim report: fall in prevalence of swab-positivity in England during national lockdown, Publisher: Cold Spring Harbor Laboratory
Background The second wave of the 2020 COVID-19 pandemic in England has been characterized by high growth and prevalence in the North with lower prevalence in the South. High prevalence was first observed at younger adult ages before spreading out to school-aged children and older adults. Local tiered interventions were in place up to 5th November 2020 at which time a second national lockdown was implemented.Methods REACT-1 is a repeated cross-sectional survey of SARS-CoV-2 swab-positivity in random samples of the population of England. The current period of data collection (round 7) commenced on 13th November 2020 and we report interim results here for swabs collected up to and including 24th November 2020. Because there were two distinct periods of growth during the previous round 6, here we compare results from round 7 (mainly) with the second half of round 6, which obtained swabs between 26th October and 2nd November 2020. We report prevalence both unweighted and reweighted to be representative of the population of England. We describe trends in unweighted prevalence with daily growth rates, doubling times, reproduction numbers (R) and splines. We estimated odds ratios for swab-positivity using mutually-adjusted multivariable logistic regression models.Results We found 821 positives from 105,123 swabs giving an unweighted prevalence of 0.78% (95% CI, 0.73%, 0.84%) and a weighted prevalence of 0.96% (0.87%, 1.05%). The weighted prevalence estimate was ∼30% lower than that of 1.32% (1.20%, 1.45%) obtained in the second half of round 6. This decrease corresponds to a halving time of 37 (30, 47) days and an R number of 0.88 (0.86, 0.91). Using only data from the most recent period, we estimate an R number of 0.71 (0.54, 0.90). A spline fit to prevalence showed a rise shortly after the previous period of data collection followed by a fall coinciding with the start of lockdown. The national trends were driven mainly by reductions in higher-prevalence northern regi
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