Publications
288 results found
Maher TM, Tudor VA, Saunders P, et al., 2024, Rituximab compared to intravenous cyclophosphamide in adults with connective tissue disease-associated interstitial lung disease: the RECITAL RCT, Efficacy and Mechanism Evaluation, Pages: 1-68, ISSN: 2050-4365
<jats:sec id="abs1-1"><jats:title>Background</jats:title><jats:p>Interstitial lung disease frequently complicates systemic autoimmune disorders including scleroderma, idiopathic inflammatory myositis and mixed connective tissue disease, resulting in considerable morbidity and mortality. Based on the results of trials undertaken in scleroderma, cyclophosphamide is the standard of care for individuals with severe or progressive connective tissue disease-associated interstitial lung disease. Observational studies suggest that the anti-CD20 monoclonal antibody, rituximab is an effective rescue therapy in treatment of refractory connective tissue disease-associated interstitial lung disease, but it has not been studied as first-line therapy in clinical trials.</jats:p></jats:sec><jats:sec id="abs1-2"><jats:title>Objectives</jats:title><jats:p>To compare the safety and efficacy of rituximab against that of cyclophosphamide as treatment for individuals with severe, progressive interstitial lung disease associated with scleroderma, idiopathic inflammatory myositis or mixed connective tissue disease.</jats:p></jats:sec><jats:sec id="abs1-3"><jats:title>Methods</jats:title><jats:p>This was a Phase IIb, multicentre, randomised, double-blind, double-dummy study assessing the superiority of rituximab compared with cyclophosphamide, conducted in rheumatology or interstitial lung disease units at 11 UK centres. The study recruited individuals with extensive and/or progressive connective tissue disease-associated interstitial lung disease, excluding those with significant comorbidities, including airflow obstruction. Participants were randomised 1 : 1 to receive either rituximab 1 g given intravenously, twice at an interval of 2 weeks, or intravenous cyclophosphamide given monthly for 6 months at a dose of 600 mg/m<jats:sup>2</jats:sup> body surf
Pocock SJ, Owen R, Gregson J, et al., 2024, Quantifying the benefit-risk trade-off for individual patients in a clinical trial: principles and antithrombotic case study., J Thromb Haemost
BACKGROUND: A treatment's overall favorable benefit-risk profile does not imply that every individual patient will benefit from the treatment. OBJECTIVES: To describe a statistical methodology for quantifying the benefit-risk trade-off in individual patients. METHODS: The method requires a large randomized controlled trial containing a primary efficacy outcome and a primary safety outcome, for instance, the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction 50 placebo-controlled trial of vorapaxar in 17 779 patients following myocardial infarction. Multivariate regression models predict each individual patient's risk of ischemic events (benefit) and major bleeding events (harm) based on their profile. Hence, each patient's predicted benefit from vorapaxar (reduction in ischemic events) and predicted risk (increase in bleeding events) were estimated. The relative importance of ischemic and bleeding events based on links to all-cause mortality was quantified, although the limitations of such weightings are noted. RESULTS: Overall results demonstrated both clear benefit and harm from vorapaxar. Substantial interindividual variation in both benefit and risk facilitated distinguishing patients with a favorable benefit-risk trade-off from those who did not. Such findings were applied to recommend vorapaxar in as many as 98.3% of patients in which a favorable mortality-weighted benefit-risk trade-off was present, in 77.2% of patients with ischemic benefit 20% greater than bleeding risk, or in as few as 45.5% of patients if an annual decrease in ischemic risk of ≥0.5% was also required. CONCLUSION: While overall randomized controlled trials of treatment benefit vs risk are valuable, models determining each individual patient's estimated absolute benefit and risk provide more useful insight regarding patient-specific benefit-risk trade-offs to better enable personalized therapeutic decis
Yap C, Rekowski J, Ursino M, et al., 2023, Enhancing quality and impact of early phase dose-finding clinical trial protocols: SPIRIT Dose-finding Extension (SPIRIT-DEFINE) guidance., BMJ, Vol: 383
Yap C, Solovyeva O, de Bono J, et al., 2023, Enhancing reporting quality and impact of early phase dose-finding clinical trials: CONSORT Dose-finding Extension (CONSORT-DEFINE) guidance., BMJ, Vol: 383
The CONSORT (CONsolidated Standards Of Reporting Trials) 2010 statement is the standard guideline for reporting completed randomised trials. The CONSORT Dose-finding Extension (DEFINE) extends the guidance (with 21 new items and 19 modified items) to early phase dose-finding trials with interim dose escalation or de-escalation strategies. Such trials generally focus on safety, tolerability, activity, and recommending dosing and scheduling regimens for further clinical development. These trials are often inadequately reported, hampering their informativeness and making evidence informed decisions difficult. The CONSORT-DEFINE guidance aims to develop an international, consensus driven guideline for reporting early phase dose-finding trials to promote transparency, completeness, reproducibility, and facilitate the interpretation of the results. The CONSORT-DEFINE guidance provides recommendations for essential items that should be reported in early phase dose-finding trials to promote greater clarity, reproducibility, informativeness, and usefulness of results.
Ward H, Atchison C, Whitaker M, et al., 2023, Design and implementation of a national program to monitor the prevalence of SARS-CoV-2 IgG antibodies in England using self-testing: the REACT-2 study, American Journal of Public Health, Pages: e1-e9, ISSN: 0090-0036
Data System. The UK Department of Health and Social Care funded the REal-time Assessment of Community Transmission-2 (REACT-2) study to estimate community prevalence of SARS-CoV-2 IgG (immunoglobulin G) antibodies in England. Data Collection/Processing. We obtained random cross-sectional samples of adults from the National Health Service (NHS) patient list (near-universal coverage). We sent participants a lateral flow immunoassay (LFIA) self-test, and they reported the result online. Overall, 905 991 tests were performed (28.9% response) over 6 rounds of data collection (June 2020-May 2021). Data Analysis/Dissemination. We produced weighted estimates of LFIA test positivity (validated against neutralizing antibodies), adjusted for test performance, at local, regional, and national levels and by age, sex, and ethnic group and area-level deprivation score. In each round, fieldwork occurred over 2 weeks, with results reported to policymakers the following week. We disseminated results as preprints and peer-reviewed journal publications. Public Health Implications. REACT-2 estimated the scale and variation in antibody prevalence over time. Community self-testing and -reporting produced rapid insights into the changing course of the pandemic and the impact of vaccine rollout, with implications for future surveillance. (Am J Public Health. Published online ahead of print September 21, 2023:e1-e9. https://doi.org/10.2105/AJPH.2023.307381).
Whitaker M, Davies B, Atchison C, et al., 2023, SARS-CoV-2 rapid antibody test results and subsequent risk of hospitalisation and death in 361,801 people, Nature Communications, Vol: 14, ISSN: 2041-1723
The value of SARS-CoV-2 lateral flow immunoassay (LFIA) tests for estimating individual disease risk is unclear. The REACT-2 study in England, UK, obtained self-administered SARS-CoV-2 LFIA test results from 361,801 adults in January-May 2021. Here, we link to routine data on subsequent hospitalisation (to September 2021), and death (to December 2021). Among those who had received one or more vaccines, a negative LFIA is associated with increased risk of hospitalisation with COVID-19 (HR: 2.73 [95% confidence interval: 1.15,6.48]), death (all-cause) (HR: 1.59, 95% CI:1.07, 2.37), and death with COVID-19 as underlying cause (20.6 [1.83,232]). For people designated at high risk from COVID-19, who had received one or more vaccines, there is an additional risk of all-cause mortality of 1.9 per 1000 for those testing antibody negative compared to positive. However, the LFIA does not provide substantial predictive information over and above that which is available from detailed sociodemographic and health-related variables. Nonetheless, this simple test provides a marker which could be a valuable addition to understanding population and individual-level risk.
Eales O, de Oliveira Martins L, Page A, et al., 2023, Dynamics and scale of the SARS-CoV-2 variant Omicron epidemic in England, Nature Communications, Vol: 13, ISSN: 2041-1723
The SARS-CoV-2 pandemic has been characterised by the regular emergence of genomic variants. With natural and vaccine-induced population immunity at high levels, evolutionary pressure favours variants better able to evade SARS-CoV-2 neutralising antibodies. The Omicron variant (first detected in November 2021) exhibited a high degree of immune evasion, leading to increased infection rates worldwide. However, estimates of the magnitude of this Omicron wave have often relied on routine testing data, which are prone to several biases. Using data from the REal-time Assessment of Community Transmission-1 (REACT-1) study, a series of cross-sectional surveys assessing prevalence of SARS-CoV-2 infection in England, we estimated the dynamics of England’s Omicron wave (from 9 September 2021 to 1 March 2022). We estimate an initial peak in national Omicron prevalence of 6.89% (5.34%, 10.61%) during January 2022, followed by a resurgence in SARS-CoV-2 infections as the more transmissible Omicron sub-lineage, BA.2 replaced BA.1 and BA.1.1. Assuming the emergence of further distinct variants, intermittent epidemics of similar magnitudes may become the ‘new normal’.
Atchison C, Whitaker M, Donnelly C, et al., 2023, Characteristics and predictors of persistent symptoms post COVID-19 in children and young people: a large community cross-sectional study in England, Archives of Disease in Childhood, Vol: 108, ISSN: 0003-9888
Objective: To estimate the prevalence of, and associated risk factors for, persistent symptoms post-COVID-19 among children aged 5–17 years in England.Design: Serial cross-sectional study.Setting: Rounds 10–19 (March 2021 to March 2022) of the REal-time Assessment of Community Transmission-1 study (monthly cross-sectional surveys of random samples of the population in England).Study population: Children aged 5–17 years in the community.Predictors: Age, sex, ethnicity, presence of a pre-existing health condition, index of multiple deprivation, COVID-19 vaccination status and dominant UK circulating SARS-CoV-2 variant at time of symptom onset.Main outcome measures: Prevalence of persistent symptoms, reported as those lasting ≥3 months post-COVID-19.Results: Overall, 4.4% (95% CI 3.7 to 5.1) of 3173 5–11 year-olds and 13.3% (95% CI 12.5 to 14.1) of 6886 12–17 year-olds with prior symptomatic infection reported at least one symptom lasting ≥3 months post-COVID-19, of whom 13.5% (95% CI 8.4 to 20.9) and 10.9% (95% CI 9.0 to 13.2), respectively, reported their ability to carry out day-to-day activities was reduced ‘a lot’ due to their symptoms. The most common symptoms among participants with persistent symptoms were persistent coughing (27.4%) and headaches (25.4%) in children aged 5–11 years and loss or change of sense of smell (52.2%) and taste (40.7%) in participants aged 12–17 years. Higher age and having a pre-existing health condition were associated with higher odds of reporting persistent symptoms.Conclusions: One in 23 5–11 year-olds and one in eight 12–17 year-olds post-COVID-19 report persistent symptoms lasting ≥3 months, of which one in nine report a large impact on performing day-to-day activities.
Eales O, Haw D, Wang H, et al., 2023, Dynamics of SARS-CoV-2 infection hospitalisation and infection fatality ratios over 23 months in England, PLoS Biology, Vol: 21, Pages: 1-21, ISSN: 1544-9173
The relationship between prevalence of infection and severe outcomes such as hospitalisation and death changed over the course of the COVID-19 pandemic. Reliable estimates of the infection fatality ratio (IFR) and infection hospitalisation ratio (IHR) along with the time-delay between infection and hospitalisation/death can inform forecasts of the numbers/timing of severe outcomes and allow healthcare services to better prepare for periods of increased demand. The REal-time Assessment of Community Transmission-1 (REACT-1) study estimated swab positivity for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in England approximately monthly from May 2020 to March 2022. Here, we analyse the changing relationship between prevalence of swab positivity and the IFR and IHR over this period in England, using publicly available data for the daily number of deaths and hospitalisations, REACT-1 swab positivity data, time-delay models, and Bayesian P-spline models. We analyse data for all age groups together, as well as in 2 subgroups: those aged 65 and over and those aged 64 and under. Additionally, we analysed the relationship between swab positivity and daily case numbers to estimate the case ascertainment rate of England's mass testing programme. During 2020, we estimated the IFR to be 0.67% and the IHR to be 2.6%. By late 2021/early 2022, the IFR and IHR had both decreased to 0.097% and 0.76%, respectively. The average case ascertainment rate over the entire duration of the study was estimated to be 36.1%, but there was some significant variation in continuous estimates of the case ascertainment rate. Continuous estimates of the IFR and IHR of the virus were observed to increase during the periods of Alpha and Delta's emergence. During periods of vaccination rollout, and the emergence of the Omicron variant, the IFR and IHR decreased. During 2020, we estimated a time-lag of 19 days between hospitalisation and swab positivity, and 26 days between deaths
Elliott P, Whitaker M, Tang D, et al., 2023, Design and implementation of a national SARS-CoV-2 monitoring programme in England: REACT-1 Study, American Journal of Public Health, ISSN: 0090-0036
Data System. The REal-time Assessment of Community Transmission-1 (REACT-1) Study was funded by the Department of Health and Social Care in England to provide reliable and timely estimates of prevalence of SARS-CoV-2 infection by time, person and place.Data Collection/Processing. The data were obtained by writing to named individuals aged 5 years and above in random cross-sections of the population of England, using the National Health Service (NHS) list of patients registered with a general practitioner (>99% coverage) as sampling frame. Data were collected 2-3 weekly approximately every month across 19distinct rounds of data collection from May 1, 2020 to March 31, 2022.Data Analysis/Dissemination. The data and study materials are widely disseminated via the study website, preprints, publications in peer-reviewed journals and the media. Data tabulations suitably anonymised to protect participant confidentiality are available on request to the study’s Data Access Committee.Implications. The study provided inter alia real-time data on SARS-CoV-2 prevalence over time, by area, and by socio-demographic variables; estimates of vaccine effectiveness; symptom profiles and detected emergence of new variants based on viral genome sequencing.
Atchison C, Moshe M, Brown J, et al., 2023, Validity of self-testing at home with rapid SARS-CoV-2 antibody detection by lateral flow immunoassay, Clinical Infectious Diseases, Vol: 76, Pages: 658-666, ISSN: 1058-4838
Background: We explore severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody lateral flow immunoassay (LFIA) performance under field conditions compared to laboratory-based ELISA and live virus neutralisation. Methods: In July 2021, 3758 participants performed, at home, a self-administered LFIA on finger-prick blood, reported and submitted a photograph of the result, and provided a self-collected capillary blood sample for assessment of IgG antibodies using the Roche Elecsys® Anti-SARS-CoV-2 assay. We compared the self-reported LFIA result to the quantitative Roche assay and checked the reading of the LFIA result with an automated image analysis (ALFA). In a subsample of 250 participants, we compared the results to live virus neutralisation. Results: Almost all participants (3593/3758, 95.6%) had been vaccinated or reported prior infection. Overall, 2777/3758 (73.9%) were positive on self-reported LFIA, 2811/3457 (81.3%) positive by LFIA when ALFA-reported, and 3622/3758 (96.4%) positive on Roche (using the manufacturer reference standard threshold for positivity of 0.8 U ml−1). Live virus neutralisation was detected in 169 of 250 randomly selected samples (67.6%); 133/169 were positive with self-reported LFIA (sensitivity 78.7%; 95% CI 71.8, 84.6), 142/155 (91.6%; 86.1, 95.5) with ALFA, and 169 (100%; 97.8, 100.0) with Roche. There were 81 samples with no detectable virus neutralisation; 47/81 were negative with self-reported LFIA (specificity 58.0%; 95% CI 46.5, 68.9), 34/75 (45.3%; 33.8, 57.3) with ALFA, and 0/81 (0%; 0.0, 4.5) with Roche. Conclusions: Self-administered LFIA is less sensitive than a quantitative antibody test, but the positivity in LFIA correlates better than the quantitative ELISA with virus neutralisation.
Eales O, Page AJ, Tang SN, et al., 2023, The use of representative community samples to assess SARS-CoV-2 lineage competition: Alpha outcompetes Beta and wild-type in England from January to March 2021., Microbial Genomics, Vol: 9, Pages: 1-14, ISSN: 2057-5858
Genomic surveillance for SARS-CoV-2 lineages informs our understanding of possible future changes in transmissibility and vaccine efficacy and will be a high priority for public health for the foreseeable future. However, small changes in the frequency of one lineage over another are often difficult to interpret because surveillance samples are obtained using a variety of methods all of which are known to contain biases. As a case study, using an approach which is largely free of biases, we here describe lineage dynamics and phylogenetic relationships of the Alpha and Beta variant in England during the first 3 months of 2021 using sequences obtained from a random community sample who provided a throat and nose swab for rt-PCR as part of the REal-time Assessment of Community Transmission-1 (REACT-1) study. Overall, diversity decreased during the first quarter of 2021, with the Alpha variant (first identified in Kent) becoming predominant, driven by a reproduction number 0.3 higher than for the prior wild-type. During January, positive samples were more likely to be Alpha in those aged 18 to 54 years old. Although individuals infected with the Alpha variant were no more likely to report one or more classic COVID-19 symptoms compared to those infected with wild-type, they were more likely to be antibody-positive 6 weeks after infection. Further, viral load was higher in those infected with the Alpha variant as measured by cycle threshold (Ct) values. The presence of infections with non-imported Beta variant (first identified in South Africa) during January, but not during February or March, suggests initial establishment in the community followed by fade-out. However, this occurred during a period of stringent social distancing. These results highlight how sequence data from representative community surveys such as REACT-1 can augment routine genomic surveillance during periods of lineage diversity.
Maher TM, Tudor VA, Saunders P, et al., 2023, Rituximab versus intravenous cyclophosphamide in patients with connective tissue disease-associated interstitial lung disease in the UK (RECITAL): a double-blind, double-dummy, randomised, controlled, phase 2b trial, The Lancet Respiratory Medicine, Vol: 11, Pages: 45-54, ISSN: 2213-2600
BACKGROUND: Rituximab is often used as rescue therapy in interstitial lung disease (ILD) associated with connective tissue disease (CTD), but has not been studied in clinical trials. This study aimed to assess whether rituximab is superior to cyclophosphamide as a treatment for severe or progressive CTD associated ILD. METHODS: We conducted a randomised, double-blind, double-dummy, phase 2b trial to assess the superiority of rituximab compared with cyclophosphamide. Patients aged 18-80 years with severe or progressive ILD related to scleroderma, idiopathic inflammatory myositis, or mixed CTD, recruited across 11 specialist ILD or rheumatology centres in the UK, were randomly assigned (1:1) to receive rituximab (1000 mg at weeks 0 and 2 intravenously) or cyclophosphamide (600 mg/m2 body surface area every 4 weeks intravenously for six doses). The primary endpoint was rate of change in forced vital capacity (FVC) at 24 weeks compared with baseline, analysed using a mixed-effects model with random intercepts, adjusted for baseline FVC and CTD type. Prespecified secondary endpoints reported in this Article were change in FVC at 48 weeks versus baseline; changes from baseline in 6 min walk distance, diffusing capacity of the lung for carbon monoxide (DLCO), physician-assessed global disease activity (GDA) score, and quality-of-life scores on the St George's Respiratory Questionnaire (SGRQ), King's Brief Interstitial Lung Disease (KBILD) questionnaire, and European Quality of Life Five-Dimension (EQ-5D) questionnaire at 24 and 48 weeks; overall survival, progression-free survival, and time to treatment failure; and corticosteroid use. All endpoints were analysed in the modified intention-to-treat population, which comprised all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT01862926). FINDINGS: Between Dec 1, 2014, and March 31, 2020, we screened 145 participants, of whom 101 participants were randomly allocated
Antcliffe DB, Burnham KL, Al-Beidh F, et al., 2022, Transcriptomic Signatures in Sepsis and a Differential Response to Steroids. From the VANISH Randomized Trial(vol 199, pg 980 year 2019), AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 206, Pages: 1572-1573, ISSN: 1073-449X
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Gordon A, 2022, Erratum: transcriptomic signatures in sepsis and a differential response to steroids. from the VANISH randomized trial., American Journal of Respiratory and Critical Care Medicine, Vol: 206, Pages: 1572-1573, ISSN: 1073-449X
Eales O, Wang H, Haw D, et al., 2022, Trends in SARS-CoV-2 infection prevalence during England’s roadmap out of lockdown, January to July 2021, PLoS Computational Biology, Vol: 18, Pages: 1-16, ISSN: 1553-734X
Background:Following rapidly rising COVID-19 case numbers, England entered a national lockdown on 6 January 2021, with staged relaxations of restrictions from 8 March 2021 onwards.Aim:We characterise how the lockdown and subsequent easing of restrictions affected trends in SARS-CoV-2 infection prevalence.Methods:On average, risk of infection is proportional to infection prevalence. The REal-time Assessment of Community Transmission-1 (REACT-1) study is a repeat cross-sectional study of over 98,000 people every round (rounds approximately monthly) that estimates infection prevalence in England. We used Bayesian P-splines to estimate prevalence and the time-varying reproduction number (Rt) nationally, regionally and by age group from round 8 (beginning 6 January 2021) to round 13 (ending 12 July 2021) of REACT-1. As a comparator, a separate segmented-exponential model was used to quantify the impact on Rt of each relaxation of restrictions.Results:Following an initial plateau of 1.54% until mid-January, infection prevalence decreased until 13 May when it reached a minimum of 0.09%, before increasing until the end of the study to 0.76%. Following the first easing of restrictions, which included schools reopening, the reproduction number Rt increased by 82% (55%, 108%), but then decreased by 61% (82%, 53%) at the second easing of restrictions, which was timed to match the Easter school holidays. Following further relaxations of restrictions, the observed Rt increased steadily, though the increase due to these restrictions being relaxed was offset by the effects of vaccination and also affected by the rapid rise of Delta. There was a high degree of synchrony in the temporal patterns of prevalence between regions and age groups.Conclusion:High-resolution prevalence data fitted to P-splines allowed us to show that the lockdown was effective at reducing risk of infection with school holidays/closures playing a significant part.
Eales O, Haw D, Wang H, et al., 2022, Quantifying changes in the IFR and IHR over 23 months of the SARS-CoV-2 pandemic in England
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>The relationship between prevalence of infection and severe outcomes such as hospitalisation and death changed over the course of the COVID-19 pandemic. The REal-time Assessment of Community Transmission-1 (REACT-1) study estimated swab positivity in England approximately monthly from May 2020 to 31 March 2022. This period covers widespread circulation of the original strain, the emergence of the Alpha, Delta and Omicron variants and the rollout of England’s mass vaccination campaign.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Here, we explore this changing relationship between prevalence of swab positivity and the infection fatality rate (IFR) and infection hospitalisation rate (IHR) over 23 months of the pandemic in England, using publicly available data for the daily number of deaths and hospitalisations, REACT-1 swab positivity data, time-delay models and Bayesian P-spline models. We analyse data for all age groups together, as well as in two sub-groups: those aged 65 and over and those aged 64 and under.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>During 2020, we estimated the IFR to be 0.67% and the IHR to be 2.6%. By late-2021/early-2022 the IFR and IHR had both decreased to 0.097% and 0.76% respectively. Continuous estimates of the IFR and IHR of the virus were observed to increase during the periods of Alpha and Delta’s emergence. During periods of vaccination rollout, and the emergence of the Omicron variant, the IFR and IHR of the virus decreased. During 2020, we estimated a time-lag of 19 days between hospitalisation and swab positivity, and 26 days between deaths and swab positivity. By late-2021/early-2022 these time-lags had decreased to 7 days for hospitalisations, and 18 days for deaths.</jats:
Chadeau-Hyam M, Tang D, Eales O, et al., 2022, Omicron SARS-CoV-2 epidemic in England during February 2022: A series of cross-sectional community surveys, The Lancet Regional Health Europe, Vol: 21, Pages: 1-11, ISSN: 2666-7762
BackgroundThe Omicron wave of COVID-19 in England peaked in January 2022 resulting from the rapid transmission of the Omicron BA.1 variant. We investigate the spread and dynamics of the SARS-CoV-2 epidemic in the population of England during February 2022, by region, age and main SARS-CoV-2 sub-lineage.MethodsIn the REal-time Assessment of Community Transmission-1 (REACT-1) study we obtained data from a random sample of 94,950 participants with valid throat and nose swab results by RT-PCR during round 18 (8 February to 1 March 2022).FindingsWe estimated a weighted mean SARS-CoV-2 prevalence of 2.88% (95% credible interval [CrI] 2.76–3.00), with a within-round effective reproduction number (R) overall of 0.94 (0·91–0.96). While within-round weighted prevalence fell among children (aged 5 to 17 years) and adults aged 18 to 54 years, we observed a level or increasing weighted prevalence among those aged 55 years and older with an R of 1.04 (1.00–1.09). Among 1,616 positive samples with sublineages determined, one (0.1% [0.0–0.3]) corresponded to XE BA.1/BA.2 recombinant and the remainder were Omicron: N=1047, 64.8% (62.4–67.2) were BA.1; N=568, 35.2% (32.8–37.6) were BA.2. We estimated an R additive advantage for BA.2 (vs BA.1) of 0.38 (0.34–0.41). The highest proportion of BA.2 among positives was found in London.InterpretationIn February 2022, infection prevalence in England remained high with level or increasing rates of infection in older people and an uptick in hospitalisations. Ongoing surveillance of both survey and hospitalisations data is required.FundingDepartment of Health and Social Care, England.
Ashby D, 2022, Proposal of the vote of thanks for 'Statistics in times of increasing uncertainty', Sylvia Richardson's Presidential Address, JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES A-STATISTICS IN SOCIETY, Vol: 185, ISSN: 0964-1998
Eales O, Ainslie KEC, Walters CE, et al., 2022, Appropriately smoothing prevalence data to inform estimates of growth rate and reproduction number, Epidemics: the journal of infectious disease dynamics, Vol: 40, ISSN: 1755-4365
The time-varying reproduction number () can change rapidly over the course of a pandemic due to changing restrictions, behaviours, and levels of population immunity. Many methods exist that allow the estimation of from case data. However, these are not easily adapted to point prevalence data nor can they infer across periods of missing data. We developed a Bayesian P-spline model suitable for fitting to a wide range of epidemic time-series, including point-prevalence data. We demonstrate the utility of the model by fitting to periodic daily SARS-CoV-2 swab-positivity data in England from the first 7 rounds (May 2020–December 2020) of the REal-time Assessment of Community Transmission-1 (REACT-1) study. Estimates of over the period of two subsequent rounds (6–8 weeks) and single rounds (2–3 weeks) inferred using the Bayesian P-spline model were broadly consistent with estimates from a simple exponential model, with overlapping credible intervals. However, there were sometimes substantial differences in point estimates. The Bayesian P-spline model was further able to infer changes in over shorter periods tracking a temporary increase above one during late-May 2020, a gradual increase in over the summer of 2020 as restrictions were eased, and a reduction in during England’s second national lockdown followed by an increase as the Alpha variant surged. The model is robust against both under-fitting and over-fitting and is able to interpolate between periods of available data; it is a particularly versatile model when growth rate can change over small timescales, as in the current SARS-CoV-2 pandemic. This work highlights the importance of pairing robust methods with representative samples to track pandemics.
Maher T, Tudor V, Saunders P, et al., 2022, Rituximab versus Cyclophosphamide for the Treatment of Connective Tissue Disease Associated Interstitial Lung Disease (RECITAL): A Sub-group Analysis of a Multi-centre Randomised Controlled Trial, Publisher: WILEY, Pages: 5-7, ISSN: 2326-5191
Elliott P, Eales O, Bodinier B, et al., 2022, Dynamics of a national Omicron SARS-CoV-2 epidemic during January 2022 in England, Nature Communications, Vol: 13, ISSN: 2041-1723
Rapid transmission of the SARS-CoV-2 Omicron variant has led to record-breaking case incidence rates around the world. Since May 2020, the REal-time Assessment of Community Transmission-1 (REACT-1) study tracked the spread of SARS-CoV-2 infection in England through RT-PCR of self-administered throat and nose swabs from randomly-selected participants aged 5 years and over. In January 2022, we found an overall weighted prevalence of 4.41% (n=102,174), three-fold higher than in November to December 2021; we sequenced 2,374 (99.2%) Omicron infections (19 BA.2), and only 19 (0.79%) Delta, with a growth rate advantage for BA.2 compared to BA.1 or BA.1.1. Prevalence was decreasing overall (reproduction number R=0.95, 95% credible interval [CrI], 0.93, 0.97), but increasing in children aged 5 to 17 years (R=1.13, 95% CrI, 1.09, 1.18). In England during January 2022, we observed unprecedented levels of SARS-CoV-2 infection, especially among children, driven by almost complete replacement of Delta by Omicron.
Eales O, Martins LDO, Page AJ, et al., 2022, Dynamics of competing SARS-CoV-2 variants during the Omicron epidemic in England, Nature Communications, Vol: 13, ISSN: 2041-1723
The SARS-CoV-2 pandemic has been characterised by the regular emergence of genomic variants. With natural and vaccine-induced population immunity at high levels, evolutionary pressure favours variants better able to evade SARS-CoV-2 neutralising antibodies. The Omicron variant (first detected in November 2021) exhibited a high degree of immune evasion, leading to increased infection rates worldwide. However, estimates of the magnitude of this Omicron wave have often relied on routine testing data, which are prone to several biases. Using data from the REal-time Assessment of Community Transmission-1 (REACT-1) study, a series of cross-sectional surveys assessing prevalence of SARS-CoV-2 infection in England, we estimated the dynamics of England’s Omicron wave (from 9 September 2021 to 1 March 2022). We estimate an initial peak in national Omicron prevalence of 6.89% (5.34%, 10.61%) during January 2022, followed by a resurgence in SARS-CoV-2 infections as the more transmissible Omicron sub-lineage, BA.2 replaced BA.1 and BA.1.1. Assuming the emergence of further distinct variants, intermittent epidemics of similar magnitudes may become the ‘new normal’.
Eales O, Wang H, Bodinier B, et al., 2022, SARS-CoV-2 lineage dynamics in England from September to November 2021: high diversity of Delta sub-lineages and increased transmissibility of AY.4.2, BMC Infectious Diseases, Vol: 22, ISSN: 1471-2334
Background: Since the emergence of SARS-CoV-2, evolutionary pressure has driven large increases in the transmissibility of the virus. However, with increasing levels of immunity through vaccination and natural infection the evolutionary pressure will switch towards immune escape. Genomic surveillance in regions of high immunity is crucial in detecting emerging variants that can more successfully navigate the immune landscape. Methods: We present phylogenetic relationships and lineage dynamics within England (a country with high levels of immunity), as inferred from a random community sample of individuals who provided a self-administered throat and nose swab for rt-PCR testing as part of the REal-time Assessment of Community Transmission-1 (REACT-1) study. During round 14 (9 September - 27 September 2021) and 15 (19 October - 5 November 2021) lineages were determined for 1322 positive individuals, with 27.1% of those which reported their symptom status reporting no symptoms in the previous month.Results: We identified 44 unique lineages, all of which were Delta or Delta sub-lineages, and found a reduction in their mutation rate over the study period. The proportion of the Delta sub-lineage AY.4.2 was increasing, with a reproduction number 15% (95% CI, 8%-23%) greater than the most prevalent lineage, AY.4. Further, AY.4.2 was less associated with the most predictive COVID-19 symptoms (p = 0.029) and had a reduced mutation rate (p = 0.050). Both AY.4.2 and AY.4 were found to be geographically clustered in September but this was no longer the case by late October/early November, with only the lineage AY.6 exhibiting clustering towards the South of England.Conclusions: As SARS-CoV-2 moves towards endemicity and new variants emerge, genomic data obtained from random community samples can augment routine surveillance data without the potential biases introduced due to higher sampling rates of symptomatic individuals.
Atchison C, Moshe M, Brown J, et al., 2022, Validity of self-testing at home with rapid SARS-CoV-2 antibody detection by lateral flow immunoassay, Publisher: medRxiv
<h4>ABSTRACT</h4> <h4>Background</h4> Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody lateral flow immunoassays (LFIA) can be carried out in the home and have been used as an affordable and practical approach to large-scale antibody prevalence studies. However, assay performance differs from that of high-throughput laboratory-based assays which can be highly sensitive. We explore LFIA performance under field conditions compared to laboratory-based ELISA and assess the potential of LFIAs to identify people who lack functional antibodies following infection or vaccination. <h4>Methods</h4> Field evaluation of a self-administered LFIA test (Fortress, NI) among 3758 participants from the REal-time Assessment of Community Transmission-2 (REACT-2) study in England selected based on vaccination history and previous LFIA result to ensure a range of antibody titres. In July 2021, participants performed, at home, a self-administered LFIA on finger-prick blood, reported and submitted a photograph of the result, and provided a self-collected capillary blood sample (Tasso-SST) for serological assessment of IgG antibodies to the spike protein using the Roche Elecsys® Anti-SARS-CoV-2 assay. We compared the self-administered and reported LFIA result to the quantitative Roche assay and checked the reading of the LFIA result with an automated image analysis (ALFA). In a subsample of 250 participants, we compared the results to live virus neutralisation. <h4>Results</h4> Almost all participants (3593/3758, 95.6%) had been vaccinated or reported prior infection, with most having received one (862, 22.9%) or two (2430, 64.7%) COVID-19 vaccine doses. Overall, 2777/3758 (73.9%) were positive on self-reported LFIA, 2811/3457 (81.3%) positive by LFIA when ALFA-reported, and 3622/3758 (96.4%) positive on Roche anti-S (using the manufacturer reference standard threshold for positivity of 0.8 U ml -1 ). Live virus neutra
Eales O, Wang H, Haw D, et al., 2022, Trends in SARS-CoV-2 infection prevalence during England’s roadmap out of lockdown, January to July 2021
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Following rapidly rising COVID-19 case numbers, England entered a national lockdown on 6 January 2021, with staged relaxations of restrictions from 8 March 2021 onwards.</jats:p></jats:sec><jats:sec><jats:title>Aim</jats:title><jats:p>We characterise how the lockdown and subsequent easing of restrictions affected trends in SARS-CoV-2 infection prevalence.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>On average, risk of infection is proportional to infection prevalence. The REal-time Assessment of Community Transmission-1 (REACT-1) study is a repeat cross-sectional study of over 98,000 people every round (rounds approximately monthly) that estimates infection prevalence in England. We used Bayesian P-splines to estimate prevalence and the time-varying reproduction number (<jats:italic>R</jats:italic><jats:sub><jats:italic>t</jats:italic></jats:sub>) nationally, regionally and by age group from round 8 (beginning 6 January 2021) to round 13 (ending 12 July 2021) of REACT-1. As a comparator, a separate segmented-exponential model was used to quantify the impact on <jats:italic>R</jats:italic><jats:sub><jats:italic>t</jats:italic></jats:sub> of each relaxation of restrictions.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Following an initial plateau of 1.54% until mid-January, infection prevalence decreased until 13 May when it reached a minimum of 0.09%, before increasing until the end of the study to 0.76%. Following the first easing of restrictions, which included schools reopening, the reproduction number <jats:italic>R</jats:italic><jats:sub><jats:italic>t</jats:italic></jats:sub> incre
Chadeau M, Eales O, Bodinier B, et al., 2022, Breakthrough SARS-CoV-2 infections in double and triple vaccinated adults and single dose vaccine effectiveness among children in Autumn 2021 in England: REACT-1 study, EClinicalMedicine, Vol: 48, Pages: 1-14, ISSN: 2589-5370
Background: Prevalence of SARS-CoV-2 infection with Delta variant was increasing in England in late summer 2021 among children aged 5 to 17 years, and adults who had received two vaccine doses. In September 2021, a third (booster) dose was offered to vaccinated adults aged 50 years and over, vulnerable adults and healthcare/care-home workers, and a single vaccine dose already offered to 16 and 17 year-olds was extended to children aged 12 to 15 years. Methods: SARS-CoV-2 community prevalence in England was available from self-administered throat and nose swabs using reverse transcriptase polymerase chain reaction (RT-PCR) in round 13 (24 June to 12 July 2021, N= 98,233), round 14 (9 to 27 September 2021, N = 100,527) and round 15 (19 October to 5 November 2021, N = 100,112) from the REACT-1 study randomised community surveys. Linking to National Health Service (NHS) vaccination data for consenting participants, we estimated vaccine effectiveness in children aged 12 to 17 years and compared swab-positivity rates in adults who received a third dose with those who received two doses. Findings: Weighted SARS-CoV-2 prevalence was 1.57% (1.48%, 1.66%) in round 15 compared with 0.83% (0.76%, 0.89%) in round 14, and the previously observed link between infections and hospitalisations and deaths had weakened. Vaccine effectiveness against infection in children aged 12 to 17 years was estimated (round 15) at 64.0% (50.9%, 70.6%) and 67.7% (53.8%, 77.5%) for symptomatic infections. Adults who received a third vaccine dose were less likely to test positive compared to those who received two doses, with adjusted odds ratio of 0.36 (0.25, 0.53). Interpretation: Vaccination of children aged 12 to 17 years and third (booster) doses in adults were effective at reducing infection risk. High rates of vaccination, including booster doses, are a key part of the strategy to reduce infection rates in the community.
Cann A, Clarke C, Brown J, et al., 2022, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody lateral flow assay for antibody prevalence studies following vaccination: a diagnostic accuracy study [version 2; peer review: 2 approved], Wellcome Open Research, Vol: 6, ISSN: 2398-502X
Background: Lateral flow immunoassays (LFIAs) are able to achieve affordable, large scale antibody testing and provide rapid results without the support of central laboratories. As part of the development of the REACT programme extensive evaluation of LFIA performance was undertaken with individuals following natural infection. Here we assess the performance of the selected LFIA to detect antibody responses in individuals who have received at least one dose of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. Methods: This was a prospective diagnostic accuracy study. Sampling was carried out at renal outpatient clinic and healthcare worker testing sites at Imperial College London NHS Trust. Two cohorts of patients were recruited; the first was a cohort of 108 renal transplant patients attending clinic following two doses of SARS-CoV-2 vaccine, the second cohort comprised 40 healthcare workers attending for first SARS-CoV-2 vaccination and subsequent follow up. During the participants visit, finger-prick blood samples were analysed on LFIA device, while paired venous sampling was sent for serological assessment of antibodies to the spike protein (anti-S) antibodies. Anti-S IgG was detected using the Abbott Architect SARS-CoV-2 IgG Quant II CMIA. A total of 186 paired samples were collected. The accuracy of Fortress LFIA in detecting IgG antibodies to SARS-CoV-2 compared to anti-spike protein detection on Abbott Assay Results: The LFIA had an estimated sensitivity of 92.0% (114/124; 95% confidence interval [CI] 85.7% to 96.1%) and specificity of 93.6% (58/62; 95% CI 84.3% to 98.2%) using the Abbott assay as reference standard (using the threshold for positivity of 7.10 BAU/ml) Conclusions: Fortress LFIA performs well in the detection of antibody responses for intended purpose of population level surveillance but does not meet criteria for individual testing.
Maher TM, Tudor V, Saunders P, et al., 2022, Rituximab versus Cyclophosphamide for the Treatment of Connective Tissue Disease Associated Interstitial Lung Disease ( RECITAL): A Multi-Centre Randomised Controlled Trial, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
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Elliott P, Eales O, Steyn N, et al., 2022, Twin peaks: the Omicron SARS-CoV-2 BA.1 and BA.2 epidemics in England
BACKGROUNDRapid transmission of the SARS-CoV-2 Omicron variant has led to record-breaking incidencerates around the world. Sub-lineages have been detected in many countries with BA.1replacing Delta and BA.2 replacing BA.1.METHODSThe REal-time Assessment of Community Transmission-1 (REACT-1) study has trackedSARS-CoV-2 infection in England using RT-PCR results from self-administered throat and noseswabs from randomly-selected participants aged 5+ years. Rounds of data collection wereapproximately monthly from May 2020 to March 2022.RESULTSIn March 2022, weighted prevalence was 6.37% (N=109,181), more than twice that inFebruary 2022 following an initial Omicron peak in January 2022. Of the lineagesdetermined by viral genome sequencing, 3,382 (99.97%) were Omicron, including 346(10.2%) BA.1, 3035 (89.7%) BA.2 and one (0.03%) BA.3 sub-lineage; the remainder (1, 0.03%)was Delta AY.4. The BA.2 Omicron sub-lineage had a growth rate advantage (compared toBA.1 and sub-lineages) of 0.11 (95% credible interval [CrI], 0.10, 0.11). Prevalence wasincreasing overall (reproduction number R=1.07, 95% CrI, 1.06, 1.09), with the greatestincrease in those aged 55+ years (R=1.12, 95% CrI, 1.09, 1.14) among whom estimatedprevalence on March 31, 2022 was 8.31%, nearly 20-fold the median prevalence since May1, 2020.CONCLUSIONSWe observed unprecedented levels of SARS-CoV-2 infection in England in March 2022 and analmost complete replacement of Omicron BA.1 by BA.2. The high and increasing prevalencein older adults may increase hospitalizations and deaths despite high levels of vaccination.(Funded by the Department of Health and Social Care in England.)
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