Evaluating the effect of short-course rifapentine-based regimens with or without enhanced behaviour-targeted treatment support on adherence and completion of treatment for latent tuberculosis infection among adults in the UK (RID-TB: Treat): protocol for an open-label, multicentre, randomised controlled trial.

INTRODUCTION: The successful scale-up of a latent tuberculosis (TB) infection testing and treatment programme is essential to achieve TB elimination. However, poor adherence compromises its therapeutic effectiveness. Novel rifapentine-based regimens and treatment support based on behavioural science theory may improve treatment adherence and completion. METHODS AND ANALYSIS: A pragmatic multicentre, open-label, randomised controlled trial assessing the effect of novel short-course rifapentine-based regimens for TB prevention and additional theory-based treatment support on treatment adherence against standard-of-care. Participants aged between 16 and 65 who are eligible to start TB preventive therapy will be recruited in England. 920 participants will be randomised to one of six arms with allocation ratio of 5:5:6:6:6:6: daily isoniazid +rifampicin for 3 months (3HR), routine treatment support (control); 3HR, additional treatment support; weekly isoniazid +rifapentine for 3 months (3HP), routine treatment support; weekly 3HP, additional treatment support ; daily isoniazid +rifapentine for 1 month (1HP), routine treatment support; daily 1HP, additional treatment support. Additional treatment support comprises reminders using an electronic pillbox, a short animation, and leaflets based on the perceptions and practicalities approach. The primary outcome is adequate treatment adherence, defined as taking ≥90% of allocated doses within the pre-specified treatment period, measured by electronic pillboxes. Secondary outcomes include safety and TB incidence within 12 months. We will conduct process evaluation of the trial interventions and assess intervention acceptability and fidelity and mechanisms for effect and estimate the cost-effectiveness of novel regimens. The protocol was developed with patient and public involvement, which will continue throughout the trial. ETHICS AND DISSEMINATION: Ethics approval has been obtained from The National Health Service Health Research Authority (20/LO/1097). All participants will be required to provide written informed consent. We will share the results in peer-reviewed journals. TRIAL REGISTRATION NUMBER: EudraCT 2020-004444-29.

Communicating uncertainty in epidemic models.

While mathematical models of disease transmission are widely used to inform public health decision-makers globally, the uncertainty inherent in results are often poorly communicated. We outline some potential sources of uncertainty in epidemic models, present traditional methods used to illustrate uncertainty and discuss alternative presentation formats used by modelling groups throughout the COVID-19 pandemic. Then, by drawing on the experience of our own recent modelling, we seek to contribute to the ongoing discussion of how to improve upon traditional methods used to visualise uncertainty by providing a suggestion of how this can be presented in a clear and simple manner.

Clinical Characteristics and Predictors of Outcomes of Hospitalized Patients With Coronavirus Disease 2019 in a Multiethnic London National Health Service Trust: A Retrospective Cohort Study.

BACKGROUND: Emerging evidence suggests ethnic minorities are disproportionately affected by coronavirus disease 2019 (COVID-19). Detailed clinical analyses of multicultural hospitalized patient cohorts remain largely undescribed. METHODS: We performed regression, survival, and cumulative competing risk analyses to evaluate factors associated with mortality in patients admitted for COVID-19 in 3 large London hospitals between 25 February and 5 April, censored as of 1 May 2020. RESULTS: Of 614 patients (median age, 69 [interquartile range, 25] years) and 62% male), 381 (62%) were discharged alive, 178 (29%) died, and 55 (9%) remained hospitalized at censoring. Severe hypoxemia (adjusted odds ratio [aOR], 4.25 [95% confidence interval {CI}, 2.36-7.64]), leukocytosis (aOR, 2.35 [95% CI, 1.35-4.11]), thrombocytopenia (aOR [1.01, 95% CI, 1.00-1.01], increase per 109 decrease), severe renal impairment (aOR, 5.14 [95% CI, 2.65-9.97]), and low albumin (aOR, 1.06 [95% CI, 1.02-1.09], increase per gram decrease) were associated with death. Forty percent (n = 244) were from black, Asian, and other minority ethnic (BAME) groups, 38% (n = 235) were white, and ethnicity was unknown for 22% (n = 135). BAME patients were younger and had fewer comorbidities. Although the unadjusted odds of death did not differ by ethnicity, when adjusting for age, sex, and comorbidities, black patients were at higher odds of death compared to whites (aOR, 1.69 [95% CI, 1.00-2.86]). This association was stronger when further adjusting for admission severity (aOR, 1.85 [95% CI, 1.06-3.24]). CONCLUSIONS: BAME patients were overrepresented in our cohort; when accounting for demographic and clinical profile of admission, black patients were at increased odds of death. Further research is needed into biologic drivers of differences in COVID-19 outcomes by ethnicity.

Quantifying the contribution of pathways of nosocomial acquisition of COVID-19 in English hospitals.

BACKGROUND: Despite evidence of the nosocomial transmission of novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in hospitals worldwide, the contributions of the pathways of transmission are poorly quantified. METHODS: We analysed national records of hospital admissions and discharges, linked to data on SARS-CoV-2 testing, using an individual-based model that considers patient-to-patient, patient-to-healthcare worker (HCW), HCW-to-patient and HCW-to-HCW transmission. RESULTS: Between 1 March 2020 and 31 December 2020, SARS-CoV-2 infections that were classified as nosocomial were identified in 0.5% (0.34-0.74) of patients admitted to an acute National Health Service trust. We found that the most likely route of nosocomial transmission to patients was indirect transmission from other infected patients, e.g. through HCWs acting as vectors or contaminated fomites, followed by direct transmission between patients in the same bay. The risk of transmission to patients from HCWs over this time period is low, but can contribute significantly when the number of infected inpatients is low. Further, the risk of a HCW acquiring SARS-CoV-2 in hospital is approximately equal to that in the community, thereby doubling their overall risk of infection. The most likely route of transmission to HCWs is transmission from other infected HCWs. CONCLUSIONS: Current control strategies have successfully reduced the transmission of SARS-CoV-2 between patients and HCWs. In order to reduce the burden of nosocomial COVID-19 infections on health services, stricter measures should be enforced that would inhibit the spread of the virus between bays or wards in the hospital. There should also be a focus on inhibiting the spread of SARS-CoV-2 between HCWs. The findings have important implications for infection-control procedures in hospitals.

The impact of the COVID-19 pandemic on patterns of attendance at emergency departments in two large London hospitals: an observational study.

BACKGROUND: Hospitals in England have undergone considerable change to address the surge in demand imposed by the COVID-19 pandemic. The impact of this on emergency department (ED) attendances is unknown, especially for non-COVID-19 related emergencies. METHODS: This analysis is an observational study of ED attendances at the Imperial College Healthcare NHS Trust (ICHNT). We calibrated auto-regressive integrated moving average time-series models of ED attendances using historic (2015-2019) data. Forecasted trends were compared to present year ICHNT data for the period between March 12, 2020 (when England implemented the first COVID-19 public health measure) and May 31, 2020. We compared ICHTN trends with publicly available regional and national data. Lastly, we compared hospital admissions made via the ED and in-hospital mortality at ICHNT during the present year to the historic 5-year average. RESULTS: ED attendances at ICHNT decreased by 35% during the period after the first lockdown was imposed on March 12, 2020 and before May 31, 2020, reflecting broader trends seen for ED attendances across all England regions, which fell by approximately 50% for the same time frame. For ICHNT, the decrease in attendances was mainly amongst those aged < 65 years and those arriving by their own means (e.g. personal or public transport) and not correlated with any of the spatial dependencies analysed such as increasing distance from postcode of residence to the hospital. Emergency admissions of patients without COVID-19 after March 12, 2020 fell by 48%; we did not observe a significant change to the crude mortality risk in patients without COVID-19 (RR 1.13, 95%CI 0.94-1.37, p = 0.19). CONCLUSIONS: Our study findings reflect broader trends seen across England and give an indication how emergency healthcare seeking has drastically changed. At ICHNT, we find that a larger proportion arrived by ambulance and that hospitalisation outcomes of patients without COVID-19 did not differ from previous years. The extent to which these findings relate to ED avoidance behaviours compared to having sought alternative emergency health services outside of hospital remains unknown. National analyses and strategies to streamline emergency services in England going forward are urgently needed.

Key epidemiological drivers and impact of interventions in the 2020 SARS-CoV-2 epidemic in England.

We fitted a model of SARS-CoV-2 transmission in care homes and the community to regional surveillance data for England. Compared with other approaches, our model provides a synthesis of multiple surveillance data streams into a single coherent modeling framework, allowing transmission and severity to be disentangled from features of the surveillance system. Of the control measures implemented, only national lockdown brought the reproduction number (Rt eff) below 1 consistently; if introduced 1 week earlier, it could have reduced deaths in the first wave from an estimated 48,600 to 25,600 [95% credible interval (CrI): 15,900 to 38,400]. The infection fatality ratio decreased from 1.00% (95% CrI: 0.85 to 1.21%) to 0.79% (95% CrI: 0.63 to 0.99%), suggesting improved clinical care. The infection fatality ratio was higher in the elderly residing in care homes (23.3%, 95% CrI: 14.7 to 35.2%) than those residing in the community (7.9%, 95% CrI: 5.9 to 10.3%). On 2 December 2020, England was still far from herd immunity, with regional cumulative infection incidence between 7.6% (95% CrI: 5.4 to 10.2%) and 22.3% (95% CrI: 19.4 to 25.4%) of the population. Therefore, any vaccination campaign will need to achieve high coverage and a high degree of protection in vaccinated individuals to allow nonpharmaceutical interventions to be lifted without a resurgence of transmission.

The J-IDEA Pandemic Planner: A Framework for Implementing Hospital Provision Interventions During the COVID-19 Pandemic.

BACKGROUND: Planning for extreme surges in demand for hospital care of patients requiring urgent life-saving treatment for coronavirus disease 2019 (COVID-19), while retaining capacity for other emergency conditions, is one of the most challenging tasks faced by health care providers and policymakers during the pandemic. Health systems must be well-prepared to cope with large and sudden changes in demand by implementing interventions to ensure adequate access to care. We developed the first planning tool for the COVID-19 pandemic to account for how hospital provision interventions (such as cancelling elective surgery, setting up field hospitals, or hiring retired staff) will affect the capacity of hospitals to provide life-saving care. METHODS: We conducted a review of interventions implemented or considered in 12 European countries in March to April 2020, an evaluation of their impact on capacity, and a review of key parameters in the care of COVID-19 patients. This information was used to develop a planner capable of estimating the impact of specific interventions on doctors, nurses, beds, and respiratory support equipment. We applied this to a scenario-based case study of 1 intervention, the set-up of field hospitals in England, under varying levels of COVID-19 patients. RESULTS: The Abdul Latif Jameel Institute for Disease and Emergency Analytics pandemic planner is a hospital planning tool that allows hospital administrators, policymakers, and other decision-makers to calculate the amount of capacity in terms of beds, staff, and crucial medical equipment obtained by implementing the interventions. Flexible assumptions on baseline capacity, the number of hospitalizations, staff-to-beds ratios, and staff absences due to COVID-19 make the planner adaptable to multiple settings. The results of the case study show that while field hospitals alleviate the burden on the number of beds available, this intervention is futile unless the deficit of critical care nurses is addressed first. DISCUSSION: The tool supports decision-makers in delivering a fast and effective response to the pandemic. The unique contribution of the planner is that it allows users to compare the impact of interventions that change some or all inputs.

Modelling intensive care unit capacity under different epidemiological scenarios of the COVID-19 pandemic in three Western European countries.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has placed enormous strain on intensive care units (ICUs) in Europe. Ensuring access to care, irrespective of COVID-19 status, in winter 2020-2021 is essential. METHODS: An integrated model of hospital capacity planning and epidemiological projections of COVID-19 patients is used to estimate the demand for and resultant spare capacity of ICU beds, staff and ventilators under different epidemic scenarios in France, Germany and Italy across the 2020-2021 winter period. The effect of implementing lockdowns triggered by different numbers of COVID-19 patients in ICUs under varying levels of effectiveness is examined, using a 'dual-demand' (COVID-19 and non-COVID-19) patient model. RESULTS: Without sufficient mitigation, we estimate that COVID-19 ICU patient numbers will exceed those seen in the first peak, resulting in substantial capacity deficits, with beds being consistently found to be the most constrained resource. Reactive lockdowns could lead to large improvements in ICU capacity during the winter season, with pressure being most effectively alleviated when lockdown is triggered early and sustained under a higher level of suppression. The success of such interventions also depends on baseline bed numbers and average non-COVID-19 patient occupancy. CONCLUSION: Reductions in capacity deficits under different scenarios must be weighed against the feasibility and drawbacks of further lockdowns. Careful, continuous decision-making by national policymakers will be required across the winter period 2020-2021.

Characteristics and outcomes of clinically diagnosed RT-PCR swab negative COVID-19: a retrospective cohort study.

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.

Optimizing Benefits of Testing Key Workers for Infection with SARS-CoV-2: A Mathematical Modeling Analysis.

BACKGROUND: Internationally, key workers such as healthcare staff are advised to stay at home if they or household members experience coronavirus disease 2019 (COVID-19)-like symptoms. This potentially isolates/quarantines many staff without SARS-CoV-2, while not preventing transmission from staff with asymptomatic infection. We explored the impact of testing staff on absence durations from work and transmission risks to others. METHODS: We used a decision-analytic model for 1000 key workers to compare the baseline strategy of (S0) no RT-PCR testing of workers to testing workers (S1) with COVID-19-like symptoms in isolation, (S2) without COVID-19-like symptoms but in household quarantine, and (S3) all staff. We explored confirmatory re-testing scenarios of repeating all initial tests, initially positive tests, initially negative tests, or no re-testing. We varied all parameters, including the infection rate (0.1-20%), proportion asymptomatic (10-80%), sensitivity (60-95%), and specificity (90-100%). RESULTS: Testing all staff (S3) changes the risk of workplace transmission by -56.9 to +1.0 workers/1000 tests (with reductions throughout at RT-PCR sensitivity ≥65%), and absences by -0.5 to +3.6 days/test but at heightened testing needs of 989.6-1995.9 tests/1000 workers. Testing workers in household quarantine (S2) reduces absences the most by 3.0-6.9 days/test (at 47.0-210.4 tests/1000 workers), while increasing risk of workplace transmission by 0.02-49.5 infected workers/1000 tests (which can be minimized when re-testing initially negative tests). CONCLUSIONS: Based on optimizing absence durations or transmission risk, our modeling suggests testing staff in household quarantine or all staff, depending on infection levels and testing capacities.

Comparison of molecular testing strategies for COVID-19 control: a mathematical modelling study.

BACKGROUND: WHO has called for increased testing in response to the COVID-19 pandemic, but countries have taken different approaches and the effectiveness of alternative strategies is unknown. We aimed to investigate the potential impact of different testing and isolation strategies on transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We developed a mathematical model of SARS-CoV-2 transmission based on infectiousness and PCR test sensitivity over time since infection. We estimated the reduction in the effective reproduction number (R) achieved by testing and isolating symptomatic individuals, regular screening of high-risk groups irrespective of symptoms, and quarantine of contacts of laboratory-confirmed cases identified through test-and-trace protocols. The expected effectiveness of different testing strategies was defined as the percentage reduction in R. We reviewed data on the performance of antibody tests reported by the Foundation for Innovative New Diagnostics and examined their implications for the use of so-called immunity passports. FINDINGS: If all individuals with symptoms compatible with COVID-19 self-isolated and self-isolation was 100% effective in reducing onwards transmission, self-isolation of symptomatic individuals would result in a reduction in R of 47% (95% uncertainty interval [UI] 32-55). PCR testing to identify SARS-CoV-2 infection soon after symptom onset could reduce the number of individuals needing to self-isolate, but would also reduce the effectiveness of self-isolation (around 10% would be false negatives). Weekly screening of health-care workers and other high-risk groups irrespective of symptoms by use of PCR testing is estimated to reduce their contribution to SARS-CoV-2 transmission by 23% (95% UI 16-40), on top of reductions achieved by self-isolation following symptoms, assuming results are available at 24 h. The effectiveness of test and trace depends strongly on coverage and the timeliness of contact tracing, potentially reducing R by 26% (95% UI 14-35) on top of reductions achieved by self-isolation following symptoms, if 80% of cases and contacts are identified and there is immediate testing following symptom onset and quarantine of contacts within 24 h. Among currently available antibody tests, performance has been highly variable, with specificity around 90% or lower for rapid diagnostic tests and 95-99% for laboratory-based ELISA and chemiluminescent assays. INTERPRETATION: Molecular testing can play an important role in prevention of SARS-CoV-2 transmission, especially among health-care workers and other high-risk groups, but no single strategy will reduce R below 1 at current levels of population immunity. Immunity passports based on antibody tests or tests for infection face substantial technical, legal, and ethical challenges. FUNDING: UK Medical Research Council.

Adapting hospital capacity to meet changing demands during the COVID-19 pandemic.

BACKGROUND: To calculate hospital surge capacity, achieved via hospital provision interventions implemented for the emergency treatment of coronavirus disease 2019 (COVID-19) and other patients through March to May 2020; to evaluate the conditions for admitting patients for elective surgery under varying admission levels of COVID-19 patients. METHODS: We analysed National Health Service (NHS) datasets and literature reviews to estimate hospital care capacity before the pandemic (pre-pandemic baseline) and to quantify the impact of interventions (cancellation of elective surgery, field hospitals, use of private hospitals, deployment of former medical staff and deployment of newly qualified medical staff) for treatment of adult COVID-19 patients, focusing on general and acute (G&A) and critical care (CC) beds, staff and ventilators. RESULTS: NHS England would not have had sufficient capacity to treat all COVID-19 and other patients in March and April 2020 without the hospital provision interventions, which alleviated significant shortfalls in CC nurses, CC and G&A beds and CC junior doctors. All elective surgery can be conducted at normal pre-pandemic levels provided the other interventions are sustained, but only if the daily number of COVID-19 patients occupying CC beds is not greater than 1550 in the whole of England. If the other interventions are not maintained, then elective surgery can only be conducted if the number of COVID-19 patients occupying CC beds is not greater than 320. However, there is greater national capacity to treat G&A patients: without interventions, it takes almost 10,000 G&A COVID-19 patients before any G&A elective patients would be unable to be accommodated. CONCLUSIONS: Unless COVID-19 hospitalisations drop to low levels, there is a continued need to enhance critical care capacity in England with field hospitals, use of private hospitals or deployment of former and newly qualified medical staff to allow some or all elective surgery to take place.

COVID-19 among people experiencing homelessness in England: a modelling study.

BACKGROUND: People experiencing homelessness are vulnerable to COVID-19 due to the risk of transmission in shared accommodation and the high prevalence of comorbidities. In England, as in some other countries, preventive policies have been implemented to protect this population. We aimed to estimate the avoided deaths and health-care use among people experiencing homelessness during the so-called first wave of COVID-19 in England-ie, the peak of infections occurring between February and May, 2020-and the potential impact of COVID-19 on this population in the future. METHODS: We used a discrete-time Markov chain model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that included compartments for susceptible, exposed, infectious, and removed individuals, to explore the impact of the pandemic on 46 565 individuals experiencing homelessness: 35 817 living in 1065 hostels for homeless people, 3616 sleeping in 143 night shelters, and 7132 sleeping outside. We ran the model under scenarios varying the incidence of infection in the general population and the availability of prevention measures: specialist hotel accommodation, infection control in homeless settings, and mixing with the general population. We divided our scenarios into first wave scenarios (covering Feb 1-May 31, 2020) and future scenarios (covering June 1, 2020-Jan 31, 2021). For each scenario, we ran the model 200 times and reported the median and 95% prediction interval (2·5% and 97·5% quantiles) of the total number of cases, the number of deaths, the number hospital admissions, and the number of intensive care unit (ICU) admissions. FINDINGS: Up to May 31, 2020, we calibrated the model to 4% of the homeless population acquiring SARS-CoV-2, and estimated that 24 deaths (95% prediction interval 16-34) occurred. In this first wave of SARS-CoV-2 infections in England, we estimated that the preventive measures imposed might have avoided 21 092 infections (19 777-22 147), 266 deaths (226-301), 1164 hospital admissions (1079-1254), and 338 ICU admissions (305-374) among the homeless population. If preventive measures are continued, we projected a small number of additional cases between June 1, 2020, and Jan 31, 2021, with 1754 infections (1543-1960), 31 deaths (21-45), 122 hospital admissions (100-148), and 35 ICU admissions (23-47) with a second wave in the general population. However, if preventive measures are lifted, outbreaks in homeless settings might lead to larger numbers of infections and deaths, even with low incidence in the general population. In a scenario with no second wave and relaxed measures in homeless settings in England, we projected 12 151 infections (10 718-13 349), 184 deaths (151-217), 733 hospital admissions (635-822), and 213 ICU admissions (178-251) between June 1, 2020, and Jan 31, 2021. INTERPRETATION: Outbreaks of SARS-CoV-2 in homeless settings can lead to a high attack rate among people experiencing homelessness, even if incidence remains low in the general population. Avoidance of deaths depends on prevention of transmission within settings such as hostels and night shelters. FUNDING: National Institute for Health Research, Wellcome, and Medical Research Council.