Herpes Zoster: Epidemiological Links With Stroke and Myocardial Infarction.

Routine data from electronic health records (EHRs) provide insights into links between herpes zoster (HZ) and cardiovascular complications such as stroke or myocardial infarction (MI) in different populations worldwide. Evidence from large EHR studies using both self-controlled case series and traditional cohort designs suggests that there is a transient increase in the risk of stroke after HZ, which gradually resolves over 6-12 months. In these studies, herpes zoster ophthalmicus was associated with a higher risk of stroke than HZ at other sites. A larger effect size was seen in people aged under 40 years. Existing studies also suggest that HZ may have a triggering effect on MI, although fewer studies examined this outcome. Further evidence is needed on the effectiveness and cost-effectiveness of vaccine and antiviral drugs to reduce cardiovascular complications after HZ from studies that are designed to minimize selection biases and confounding by indication

Investigating the effects of population density of residence and rural/urban classification on rate of influenza-like illness symptoms in England and Wales.

BACKGROUND: Better understanding of risk factors for influenza could help improve seasonal and pandemic planning. There is a dearth of literature on area-level risk factors such as population density and rural/urban living. METHODS: We used data from Flusurvey, an online community-based cohort that records influenza events. The study outcome was symptoms of influenza-like illness (ILI). Multivariable Poisson regression analysis was used to explore associations of both population density and rural/urban status with rate of ILI symptoms and whether these effects differed by vaccination status. RESULTS: Of the 6177 study participants, the median age was 45 (IQR 32-57), 65.73% were female, and 66% reported at least one episode of ILI symptoms between 2011 and 2016. We found no evidence to suggest that the rate of ILI symptoms was higher in the medium [RR 1.02 (95% CI 0.95-1.09)] or high [RR 1.02 (95% CI 0.96-1.09)] population density group versus the low population density group. This was the same for the effect of urban living [RR 0.96 (95% CI 0.90-1.03)] versus rural living on symptom rate. There was weak evidence to suggest that the ILI symptom rate was lower in urban areas compared with rural areas among unvaccinated individuals only [RR 0.90 (95% CI 0.83-0.99)], whereas no difference was seen among vaccinated individuals [1.04 (95% CI 0.94-1.16)]. CONCLUSIONS: Although neither population density nor rural/urban status was associated with ILI symptom rate in this community cohort, future research that incorporates activity and contact patterns will help to elucidate this relationship further

Implications of using whole genome sequencing to test unselected populations for high risk breast cancer genes: a modelling study.

BACKGROUND: The decision to test for high risk breast cancer gene mutations is traditionally based on risk scores derived from age, family and personal cancer history. Next generation sequencing technologies such as whole genome sequencing (WGS) make wider population testing more feasible. In the UK's 100,000 Genomes Project, mutations in 16 genes including BRCA1 and BRCA2 are to be actively sought regardless of clinical presentation. The implications of deploying this approach at scale for patients and clinical services are unclear. In this study we aimed to model the effect of using WGS to test an unselected UK population for high risk BRCA1 and BRCA2 gene variants to inform the debate around approaches to secondary genomic findings. METHODS: We modelled the test performance of WGS for identifying pathogenic BRCA1 and BRCA2 mutations in an unselected hypothetical population of 100,000 UK women, using published literature to derive model input parameters. We calculated analytic and clinical validity, described potential health outcomes and highlighted current areas of uncertainty. We also performed a sensitivity analysis in which we re-ran the model 100,000 times to investigate the effect of varying input parameters. RESULTS: In our models WGS was predicted to identify correctly 93 pathogenic BRCA1 mutations and 151 BRCA2 mutations in 120 and 200 women respectively, resulting in an analytic sensitivity of 75.5-77.5 %. Of 244 women with identified pathogenic mutations, we estimated that 132 (range 121-198) would develop breast cancer, so could potentially be helped by intervention. We also predicted that breast cancer would occur in 41 women (range 36-62) incorrectly identified with no pathogenic mutations and in 12,460 women without BRCA1 or BRCA2 mutations. There was considerable uncertainty about the penetrance of mutations in people without a family history of disease and the appropriate threshold of absolute disease risk for clinical action, which impacts on judgements about the clinical utility of intervention. CONCLUSIONS: This simple model demonstrates the need for robust processes to support the testing for secondary genomic findings in unselected populations that acknowledge levels of uncertainty about the clinical validity and clinical utility of testing positive for a cancer risk gene

Investigating obesity as a risk factor for influenza-like illness during the 2009 H1N1 influenza pandemic using the Health Survey for England.

BACKGROUND: Following the 2009 H1N1 influenza pandemic, obesity was shown to be associated with severe influenza outcomes. It remains unclear whether obesity was a risk factor for milder influenza-like illness (ILI). OBJECTIVES: To determine whether obesity was associated with an increased risk of self-reported ILI during the 2009 H1N1 influenza pandemic using Health Survey for England (HSE) 2010 cross-sectional data. METHODS: This study used HSE data collected from English households between January and December 2010. Weight and height measurements were taken by trained fieldworkers to determine obesity. ILI was defined as a positive response to the question "Have you had a flu-like illness where you felt feverish and had a cough or sore throat?" with illness occurring between May and December 2009. Multivariable logistic regression was used to evaluate the association between obesity and ILI. RESULTS: The study comprised 8407 participants (6984 adults, 1436 children), among whom 24.7% (95% CI: 23.6-25.9) were classified as obese. Of obese participants, 12.8% (95% CI: 11.1-14.8) reported ILI compared to 11.8% (95% CI: 10.8-12.8) of non-obese participants. The adjusted OR for ILI associated with obesity was 1.16 (95% CI: 0.98-1.38, P=.093). For adults and children, the adjusted ORs were 1.16 (95% CI: 0.97-1.38, P=.101) and 1.26 (95% CI: 0.72-2.21, P=.422), respectively. CONCLUSION: Household survey data showed no evidence that obesity was associated with an increase in self-reported ILI during the 2009 H1N1 influenza pandemic in England. Further studies using active prospective ILI surveillance combined with laboratory reporting would reduce bias and improve accuracy of outcome measurements

Laboratory-confirmed respiratory infections as triggers for acute myocardial infarction and stroke: a self-controlled case series analysis of national linked datasets from Scotland

While acute respiratory tract infections can trigger cardiovascular events, the differential effect of specific organisms is unknown. This is important to guide vaccine policy.Using national infection surveillance data linked to the Scottish Morbidity Record, we identified adults with a first myocardial infarction or stroke from January 1, 2004 to December 31, 2014 and a record of laboratory-confirmed respiratory infection during this period. Using self-controlled case series analysis, we generated age- and season-adjusted incidence ratios (IRs) for myocardial infarction (n=1227) or stroke (n=762) after infections compared with baseline time.We found substantially increased myocardial infarction rates in the week after Streptococcus pneumoniae and influenza virus infection: adjusted IRs for days 1-3 were 5.98 (95% CI 2.47-14.4) and 9.80 (95% CI 2.37-40.5), respectively. Rates of stroke after infection were similarly high and remained elevated to 28 days: day 1-3 adjusted IRs 12.3 (95% CI 5.48-27.7) and 7.82 (95% CI 1.07-56.9) for S. pneumoniae and influenza virus, respectively. Although other respiratory viruses were associated with raised point estimates for both outcomes, only the day 4-7 estimate for stroke reached statistical significance.We showed a marked cardiovascular triggering effect of S. pneumoniae and influenza virus, which highlights the need for adequate pneumococcal and influenza vaccine uptake. Further research is needed into vascular effects of noninfluenza respiratory viruses

Validity of Acute Cardiovascular Outcome Diagnoses Recorded in European Electronic Health Records: A Systematic Review.

BACKGROUND: Electronic health records are widely used in cardiovascular disease research. We appraised the validity of stroke, acute coronary syndrome and heart failure diagnoses in studies conducted using European electronic health records. METHODS: Using a prespecified strategy, we systematically searched seven databases from dates of inception to April 2019. Two reviewers independently completed study selection, followed by partial parallel data extraction and risk of bias assessment. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value estimates were narratively synthesized and heterogeneity between sensitivity and PPV estimates were assessed using I2. RESULTS: We identified 81 studies, of which 20 validated heart failure diagnoses, 31 validated acute coronary syndrome diagnoses with 29 specifically recording estimates for myocardial infarction, and 41 validated stroke diagnoses. Few studies reported specificity or negative predictive value estimates. Sensitivity was ≤66% in all but one heart failure study, ≥80% for 91% of myocardial infarction studies, and ≥70% for 73% of stroke studies. PPV was ≥80% in 74% of heart failure, 88% of myocardial infarction, and 70% of stroke studies. PPV by stroke subtype was variable, at ≥80% for 80% of ischaemic stroke but only 44% of haemorrhagic stroke. There was considerable heterogeneity (I2 >75%) between sensitivity and PPV estimates for all diagnoses. CONCLUSION: Overall, European electronic health record stroke, acute coronary syndrome and heart failure diagnoses are accurate for use in research, although validity estimates for heart failure and individual stroke subtypes were lower. Where possible, researchers should validate data before use or carefully interpret the results of previous validation studies for their own study purposes

Varicella and herpes zoster vaccine development: lessons learned.

INTRODUCTION: Before vaccination, varicella zoster virus (VZV), which is endemic worldwide, led to almost universal infection. This neurotropic virus persists lifelong by establishing latency in sensory ganglia, where its reactivation is controlled by VZV-specific T-cell immunity. Lifetime risk of VZV reactivation (zoster) is around 30%. Vaccine development was galvanised by the economic and societal burden of VZV, including debilitating zoster complications that largely affect older individuals. Areas covered: We describe the story of development, licensing and implementation of live attenuated vaccines against varicella and zoster. We consider the complex backdrop of VZV virology, pathogenesis and immune responses in the absence of suitable animal models and examine the changing epidemiology of VZV disease. We review the vaccines' efficacy, safety, effectiveness and coverage using evidence from trials, observational studies from large routine health datasets and clinical post-marketing surveillance studies and outline newer developments in subunit and inactivated vaccines. Expert commentary: Safe and effective, varicella and zoster vaccines have already made major inroads into reducing the burden of VZV disease globally. As these live vaccines have the potential to reactivate and cause clinical disease, developing alternatives that do not establish latency is an attractive prospect but will require better understanding of latency mechanisms