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BACKGROUND: Obtaining accurate estimates of the risk of COVID-19-related death in the general population is challenging in the context of changing levels of circulating infection. METHODS: We propose a modelling approach to predict 28-day COVID-19-related death which explicitly accounts for COVID-19 infection prevalence using a series of sub-studies from new landmark times incorporating time-updating proxy measures of COVID-19 infection prevalence. This was compared with an approach ignoring infection prevalence. The target population was adults registered at a general practice in England in March 2020. The outcome was 28-day COVID-19-related death. Predictors included demographic characteristics and comorbidities. Three proxies of local infection prevalence were used: model-based estimates, rate of COVID-19-related attendances in emergency care, and rate of suspected COVID-19 cases in primary care. We used data within the TPP SystmOne electronic health record system linked to Office for National Statistics mortality data, using the OpenSAFELY platform, working on behalf of NHS England. Prediction models were developed in case-cohort samples with a 100-day follow-up. Validation was undertaken in 28-day cohorts from the target population. We considered predictive performance (discrimination and calibration) in geographical and temporal subsets of data not used in developing the risk prediction models. Simple models were contrasted to models including a full range of predictors. RESULTS: Prediction models were developed on 11,972,947 individuals, of whom 7999 experienced COVID-19-related death. All models discriminated well between individuals who did and did not experience the outcome, including simple models adjusting only for basic demographics and number of comorbidities: C-statistics 0.92-0.94. However, absolute risk estimates were substantially miscalibrated when infection prevalence was not explicitly modelled. CONCLUSIONS: Our proposed models allow absolute risk estimation in the context of changing infection prevalence but predictive performance is sensitive to the proxy for infection prevalence. Simple models can provide excellent discrimination and may simplify implementation of risk prediction tools.

Additional file 1. Supplementary materials

Caroline E Morton,1,2 Harriet J Forbes,1 Neil Pearce,3 Liam Smeeth,1 Charlotte Warren-Gash1 1Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK; 2EBM DataLab, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK; 3Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UKCorrespondence: Caroline E Morton MortonEBM DataLab, Nuffield Department of Primary Care Health Sciences, University of Oxford, Radcliffe Observatory Quarter, Woodstock Road, Oxford OX2 6GG, UKTel +44 1865 289300Email caroline.morton@phc.ox.ac.ukPurpose: To investigate the association between common infections and post-stroke dementia in a UK population-based cohort.Materials and Methods: A total of 60,392 stroke survivors (51.2% male, median age 74.3 years, IQR 63.9– 82.4 years) were identified using primary care records from the Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics (HES) with no history of dementia. Primary exposure was any GP-recorded infection (lower respiratory tract infection (LRTI), urinary tract infection (UTI) requiring antibiotics, skin and soft tissue infection requiring antibiotics) occurring after stroke. The primary outcome was incident all-cause dementia recorded in primary care records. In sensitivity analyses, we restricted to individuals with linked hospital records and expanded definitions to include ICD-10 coded hospital admissions. We used multivariable Cox regression to investigate the association between common infections and dementia occurring from 3 months to 5 years after stroke.Results: Of 60,392 stroke survivors, 20,969 (34.7%) experienced at least one infection and overall 4512 (7.5%) developed dementia during follow-up. Early dementia (3 months to 1-year post-stroke) risk was increased in those with at least one GP-recorded infection (HR 1.44, 95% CI 1.21– 1.71), with stronger associations when hospitalised infections were included (HR 1.84, 95% CI 1.58– 2.14). Late dementia (1– 5 years) was only associated with hospitalised, but not with GP-recorded, infections.Conclusion: There was evidence of an association between common infections and post-stroke dementia, strongest in the 3– 12 months following stroke. Better understanding of this relationship could help inform knowledge of pathways to dementia post-stroke and targeting of preventive interventions.Keywords: post-stroke dementia, infections, cohort study, electronic health records

ObjectiveTo quantify inequalities in zoster vaccine uptake by determining its association with socio-demographic factors: age, gender, ethnicity, immigration status, deprivation (at Lower-layer Super Output Area-level), care home residence and living arrangements.MethodThis population-based cohort study utilised anonymised primary care electronic health records from England (Clinical Practice Research Datalink) linked to deprivation and hospitalisation data. Data from 35,333 individuals from 277 general practices in England and eligible for zoster vaccination during the two-year period (2013-2015) after vaccine introduction were analysed. Logistic regression was used to obtain adjusted odds ratios (aOR) for the association of socio-demographic factors with zoster vaccine uptake for adults aged 70 years (main target group) and adults aged 79 years (catch-up group).ResultsAmongst those eligible for vaccination, 52.4% (n = 18,499) received the vaccine. Socio-demographic factors independently associated with lower zoster vaccine uptake in multivariable analyses were: being older (catch-up group: aged 79 years) aOR = 0.89 (95% confidence interval (CI):0.85-0.93), care home residence (aOR = 0.64 (95%CI: 0.57-0.73)) and living alone (aOR = 0.85 (95%CI: 0.81-0.90)). Uptake decreased with increasing levels of deprivation (p-value for trendConclusionsInequalities in zoster vaccine uptake exist in England; with lower uptake among those of non-White ethnicities, and among those living alone, in a care home and in more deprived areas. Tailored interventions to increase uptake in these social groups should assist in realising the aim of mitigating vaccination inequalities. As care home residents are also at higher risk of zoster, improving the uptake of zoster vaccination in this group will also mitigate inequalities in zoster burden.

Objective: To investigate risk factors for postherpetic neuralgia, the neuropathic pain that commonly follows herpes zoster. Methods: Using primary care data from the Clinical Practice Research Datalink, we fitted multivariable logistic regression models to investigate potential risk factors for postherpetic neuralgia (defined as pain ≥90 days after zoster, based on diagnostic or prescription codes), including demographic characteristics, comorbidities, and characteristics of the acute zoster episode. We also assessed whether the effects were modified by antiviral use. Results: Of 119,413 zoster patients, 6,956 (5.8%) developed postherpetic neuralgia. Postherpetic neuralgia risk rose steeply with age, most sharply between 50 and 79 years (adjusted odds ratio [OR] for a 10-year increase, 1.70, 99% confidence interval 1.63–1.78). Postherpetic neuralgia risk was higher in women (6.3% vs 5.1% in men: OR 1.19, 1.10–1.27) and those with severely immunosuppressive conditions, including leukemia (13.7%: 2.07, 1.08–3.96) and lymphoma (12.7%: 2.45, 1.53–3.92); autoimmune conditions, including rheumatoid arthritis (9.1%: 1.20, 0.99–1.46); and other comorbidities, including asthma and diabetes. Current and ex-smokers, as well as underweight and obese individuals, were at increased risk of postherpetic neuralgia. Antiviral use was not associated with postherpetic neuralgia (OR 1.04, 0.97–1.11). However, the increased risk associated with severe immunosuppression appeared less pronounced in patients given antivirals. Conclusions: Postherpetic neuralgia risk was increased for a number of patient characteristics and comorbidities, notably with age and among those with severe immunosuppression. As zoster vaccination is contraindicated for patients with severe immunosuppression, strategies to prevent zoster in these patients, which could include the new subunit zoster vaccine, are an increasing priority.

OBJECTIVE: To investigate whether adults with atopic eczema are at an increased risk of cardiovascular disease and whether the risk varies by atopic eczema severity and condition activity over time.DESIGN: Population based matched cohort study.SETTING: UK electronic health records from the Clinical Practice Research Datalink, Hospital Episode Statistics, and data from the Office for National Statistics, 1998-2015.PARTICIPANTS: Adults with a diagnosis of atopic eczema, matched (on age, sex, general practice, and calendar time) to up to five patients without atopic eczema.MAIN OUTCOME MEASURES: Cardiovascular outcomes (myocardial infarction, unstable angina, heart failure, atrial fibrillation, stroke, and cardiovascular death).RESULTS: 387 439 patients with atopic eczema were matched to 1 528 477 patients without atopic eczema. The median age was 43 at cohort entry and 66% were female. Median follow-up was 5.1 years. Evidence of a 10% to 20% increased hazard for the non-fatal primary outcomes for patients with atopic eczema was found by using Cox regression stratified by matched set. There was a strong dose-response relation with severity of atopic eczema. Patients with severe atopic eczema had a 20% increase in the risk of stroke (hazard ratio 1.22, 99% confidence interval 1.01 to 1.48), 40% to 50% increase in the risk of myocardial infarction, unstable angina, atrial fibrillation, and cardiovascular death, and 70% increase in the risk of heart failure (hazard ratio 1.69, 99% confidence interval 1.38 to 2.06). Patients with the most active atopic eczema (active >50% of follow-up) were also at a greater risk of cardiovascular outcomes. Additional adjustment for cardiovascular risk factors as potential mediators partially attenuated the point estimates, though associations persisted for severe atopic eczema.CONCLUSIONS: Severe and predominantly active atopic eczema are associated with an increased risk of cardiovascular outcomes. Targeting cardiovascular disease prevention strategies among these patients should be considered.

BackgroundHerpesviruses induce a range of inflammatory effects potentially contributing to an increased risk of stroke.ObjectivesTo investigate whether patients with infection, or reactivation of, human herpesviruses are at increased stroke risk, compared to those without human herpesviruses.Data sourcesSix medical databases and grey literature sources from inception to January 2017.Study eligibility criteriaStudies where the exposure was any human herpesvirus and the outcome was stroke. We included randomised controlled trials, cohort, case-control, case-crossover and self-controlled case series designs.MethodsMeta-analyses when sufficiently homogeneous studies were available. Quality of evidence across studies was assessed.ResultsWe identified 5012 publications; 41 met the eligibility criteria. Across cohort and self-controlled case series studies, there was moderate quality evidence that varicella infection in children was associated with a short-term increased stroke risk. Zoster was associated with a 1.5-fold increased stroke risk four weeks following onset (summary estimate: 1.55, 95%CI 1.46-1.65), which resolved after one year. Subgroup analyses suggested post-zoster stroke risk was greater among ophthalmic zoster patients, younger individuals and those not prescribed antivirals. Recent infection/reactivation of cytomegalovirus and herpes simplex viruses, but not past infection, was associated with increased stroke risk; however the evidence across studies was mainly derived from small, very low quality case-control studies.ConclusionsOur review shows an increased stroke risk following zoster and suggests that recent infection or reactivation of other herpesviruses increases stroke risk, although better evidence is needed. Herpesviruses are common and potentially preventable; these findings may have implications for reducing stroke burden.

BACKGROUND: Some malignancies are known to be associated with increased risk of herpes zoster, but little is known about how associations between cancer and subsequent zoster risk vary by cancer site, by time since cancer diagnosis, and by age. METHODS: An age-, sex-, calendar time-, and practice-matched case-control study, nested in the broadly UK representative Clinical Practice Research Datalink (CPRD) primary care database, was analysed using conditional logistic regression to estimate the association between 21 of the most common specific malignancies and subsequent zoster risk. We adjusted for comorbid conditions and other potential confounders, and investigated effect modification by age and time since malignancy diagnosis. RESULTS: A total of 192 081 adult zoster patients and 732 035 controls were included. Malignancy overall was positively associated with zoster risk (adjusted OR 1.29, 95% CI 1.27-1.32), and the association was especially strong for haematological malignancies (OR 2.46, 2.33-2.60). Among specific malignancies, there was evidence that oral, oesophageal, stomach, colorectal, lung, breast, ovarian, prostate, kidney, bladder, and CNS cancers, as well as lymphoma, myeloma, and leukaemia were associated with increased zoster odds (P⩽0.05 in each case), but the magnitude of associations varied widely. The association was typically strongest within 2 years of malignancy diagnosis and decreased with older age for both haematological and solid malignancies. CONCLUSIONS: Several cancers were associated with an increased risk of zoster, particularly within the first 2 years after diagnosis and among younger individuals. Knowledge that patients with a recent diagnosis of cancer are at high risk of zoster may encourage initiation of antiviral therapy earlier in the course of zoster when the benefits are greater. Evaluation of whether patients diagnosed with cancer would benefit from early zoster vaccination is warranted.

INTRODUCTION: After primary infection, human herpesviruses establish latency and persist lifelong. Periodic virus reactivation can lead to serious inflammatory complications. Recent research suggests that herpesvirus reactivation may also be linked to acute stroke. An improved understanding of this relationship is vital to inform public health prevention strategies. We will review the evidence regarding the role of human herpesviruses in triggering stroke. METHODS AND ANALYSIS: A systematic literature review of published and grey literature studies with a human herpesvirus (infection or reactivation) as an exposure and stroke as an outcome will be carried out. Randomised controlled trials, cohort, case-control, case crossover and self-controlled case series designs will be eligible; no restrictions will be placed on publication status, language and geographical or healthcare setting. The Cochrane Central Register of Controlled Trials, Embase, Global Health, Medline, Scopus and Web of Science will be searched from dates of inception to January 2017. A prespecified search strategy of medical subject headings and free text terms (in the title and abstract) for human herpesviruses AND stroke will be used. Two reviewers will independently screen titles and abstracts for eligible studies, followed by full-text screening. The reviewers will then extract data from the eligible studies using standardised, pilot-tested tables and assess risk of bias in individual studies, in line with the Cochrane Collaboration approach. The data will be synthesised in a narrative format, and meta-analyses considered where there are sufficient data. Quality of evidence will be assessed in line with theGrading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. ETHICS AND DISSEMINATION: As this is a systematic review, ethical approval is not required. The results will be submitted for peer-review publication and presented at national conferences. A lay and short summary will be disseminated on appropriate webpages. PROSPERO REGISTRATION NUMBER: CRD42017054502.