Acute Cardiovascular Events After COVID-19 in England in 2020: A Self-Controlled Case Series Study.

Purpose: To assess the risk of incident cardiovascular outcomes after COVID-19 by level of cardiovascular risk in waves one and two of the pandemic in England in 2020. Patients and methods: We conducted a self-controlled case-series study among adults aged 40-84 years with no pre-existing cardiovascular disease using linked data from the Clinical Practice Research Datalink. We generated season-adjusted incidence ratios (IRs) for first acute cardiovascular event after SARS-CoV-2 infection compared with baseline time before and >91 days after infection. We used composite and individual acute cardiovascular event outcomes including myocardial infarction, major ventricular arrhythmia, left ventricular heart failure, and ischemic stroke. We stratified by cardiovascular risk, using diagnosed hypertension and QRISK3 predicted risk, and by wave one and two of the pandemic. Results: We included 1762 individuals, 76.6% had a QRISK3 score ≥10% and 59.4% had hypertension. The risk of any cardiovascular event was elevated in the 1-7 days after infection (IR 7.14 [95% CI 6.06-8.41]) and, while the effect size tapered, the risk remained for 15-28 days after infection (1.74 [1.33-2.26]). Risks were similar for individual event type, differing by level of cardiovascular risk, and in wave one and two of the pandemic. . Conclusion: SARS-CoV-2 infection is associated with early elevations in the risk of first acute cardiovascular event, across cardiovascular risk levels and in both wave one and two of the pandemic. Prevention of COVID-19 is important to avert cardiovascular complications.

Severe COVID-19 outcomes by cardiovascular risk profile in England in 2020: a population-based cohort study.

Background: While cardiovascular disease (CVD) is a risk factor for severe COVID-19, the association between predicted cardiovascular risk and severe COVID-19 among people without diagnosed CVD is unclear. Methods: We carried out historical, population-based cohort studies among adults aged 40-84 years in England using linked data from the Clinical Practice Research Datalink. Individuals were categorized into: existing CVD, raised cardiovascular risk (defined using QRISK3 score ≥10%) and low risk (QRISK3 score <10%) at 12/03/2020. We described incidence and severe outcomes of COVID-19 (deaths, intensive care unit [ICU] admissions, hospitalisations, major adverse cardiovascular events [MACE]) for each group. Among those with a COVID-19 record to 31/12/2020, we re-classified cardiovascular risk at infection and assessed the risk of severe outcomes using multivariable Cox regression with complete case analysis. We repeated analyses using hypertension to define raised cardiovascular risk. Findings: Among 6,059,055 individuals, 741,913 (12.2%) had established CVD, 1,929,627 (31.8%) had a QRISK3 score ≥10% and 3,387,515 (55.9%) had a QRISK3 score <10%. Marked gradients were seen in the incidence of all severe COVID-19 outcomes by cardiovascular risk profile. Among those with COVID-19 (N = 146,760), there was a strong association between raised QRISK3 score and death: adjusted hazard ratio [aHR] 8.77 (7.62-10.10), N = 97,725, which remained present, though attenuated in age-stratified results. Risks of other outcomes were also higher among those with raised QRISK3 score: aHR 3.66 (3.18-4.21) for ICU admissions, 3.38 (3.22-3.56) for hospitalisations, 5.43 (4.44-6.64) for MACE. When raised cardiovascular risk was redefined by hypertension status, only the association with MACE remained: aHR 1.49 (1.20-1.85), N = 57,264. Interpretation: Individuals without pre-existing CVD but with raised cardiovascular risk (by QRISK3 score) were more likely to experience severe COVID-19 outcomes and should be prioritised for prevention and treatment. Addressing cardiovascular risk factors could improve COVID-19 outcomes. Funding: BMA Foundation for Medical Research/Rosetrees Trust, Wellcome, BHF.

Virulence Profiles and Genome-Wide Association Study for Ascochyta lentis Isolates Collected from Australian Lentil-Growing Regions.

Ascochyta lentis, the causal organism of Ascochyta blight (AB) of lentil (Lens culinaris), has been shown to produce an avirulence effector protein that mediates AB resistance in certain lentil cultivars. The two known forms of the effector protein were identified from a biparental mapping population between isolates that have reciprocal virulence on 'PBA Hurricane XT' and 'Nipper'. The effector AlAvr1-1 was described for the PBA Hurricane XT-avirulent isolate P94-24 and AlAvr1-2 characterized in the PBA Hurricane XT-virulent isolate AlKewell. Here, we performed a genome-wide association study to identify other loci associated with AB for a differential set of lentil cultivars from a diverse panel of isolates collected in the Australian lentil-growing regions from 2013 to 2020. The chromosome 3 AlAvr1 locus was strongly associated with the PBA Hurricane XT, 'Indianhead', and Nipper disease responses, but one other genomic region on chromosome 11 was also associated with the Nipper disease trait. Our results corroborate earlier work that identified the AlAvr1 locus for field-collected isolates that span the period before release and after widespread adoption of PBA Hurricane XT. A multiplex PCR assay was developed to differentiate the genes AlAvr1-1 and AlAvr1-2 to predict PBA Hurricane XT avirulence and pathotype designation in the diversity panel. Increasing numbers of the PBA Hurricane XT-virulent pathotype 2 isolates across that time indicate strong selection for isolates with the AlAvr1-2 allele. Furthermore, one other region of the A. lentis genome may contribute to the pathogen-host interaction for lentil AB.

Primary prevention of acute cardiovascular events by influenza vaccination: an observational study.

AIMS: Previous studies show a reduced incidence of first myocardial infarction and stroke 1-3 months after influenza vaccination, but it is unclear how underlying cardiovascular risk impacts the association. METHODS AND RESULTS: The study used linked Clinical Practice Research Datalink, Hospital Episode Statistics Admitted Patient Care and Office for National Statistics mortality data from England between 1 September 2008 and 31 August 2019. From the data, individuals aged 40-84 years with a first acute cardiovascular event and influenza vaccination occurring within 12 months of each September were selected. Using a self-controlled case series analysis, season-adjusted cardiovascular risk stratified incidence ratios (IRs) for cardiovascular events after vaccination compared with baseline time before and >120 days after vaccination were generated. 193 900 individuals with a first acute cardiovascular event and influenza vaccine were included. 105 539 had hypertension and 172 050 had a QRISK2 score ≥10%. In main analysis, acute cardiovascular event risk was reduced in the 15-28 days after vaccination [IR 0.72 (95% CI 0.70-0.74)] and, while the effect size tapered, remained reduced to 91-120 days after vaccination [0.83 (0.81-0.88)]. Reduced cardiovascular events were seen after vaccination among individuals of all age groups and with raised and low cardiovascular risk. CONCLUSIONS: Influenza vaccine may offer cardiovascular benefit among individuals at varying cardiovascular risk. Further studies are needed to characterize the populations who could derive the most cardiovascular benefits from vaccination.

Phenotypic and Genotypic Diversity of Ascochyta fabae Populations in Southern Australia.

Ascochyta fabae Speg. is a serious foliar fungal disease of faba bean and a constraint to production worldwide. This study investigated the phenotypic and genotypic diversity of the A. fabae pathogen population in southern Australia and the pathogenic variability of the population was examined on a differential set of faba bean cultivars. The host set was inoculated with 154 A. fabae isolates collected from 2015 to 2018 and a range of disease reactions from high to low aggressiveness was observed. Eighty percent of isolates collected from 2015 to 2018 were categorized as pathogenicity group (PG) PG-2 (pathogenic on Farah) and were detected in every region in each year of collection. Four percent of isolates were non-pathogenic on Farah and designated as PG-1. A small group of isolates (16%) were pathogenic on the most resistant differential cultivars, PBA Samira or Nura, and these isolates were designated PG-3. Mating types of 311 isolates collected between 1991 and 2018 were determined and showed an equal ratio of MAT1-1 and MAT1-2 in the southern Australian population. The genetic diversity and population structure of 305 isolates were examined using DArTseq genotyping, and results suggest no association of genotype with any of the population descriptors viz.: collection year, region, host cultivar, mating type, or PG. A Genome-Wide Association Study (GWAS) was performed to assess genetic association with pathogenicity traits and a significant trait-associated genomic locus for disease in Farah AR and PBA Zahra, and PG was revealed. The high frequency of mating of A. fabae indicated by the wide distribution of the two mating types means changes to virulence genes would be quickly distributed to other genotypes. Continued monitoring of the A. fabae pathogen population through pathogenicity testing will be important to identify any increases in aggressiveness or emergence of novel PGs. GWAS and future genetic studies using biparental mating populations could be useful for identifying virulence genes responsible for the observed changes in pathogenicity.

The novel avirulence effector AlAvr1 from Ascochyta lentis mediates host cultivar specificity of ascochyta blight in lentil.

Ascochyta lentis is a fungal pathogen that causes ascochyta blight in the important grain legume species lentil, but little is known about the molecular mechanism of disease or host specificity. We employed a map-based cloning approach using a biparental A. lentis population to clone the gene AlAvr1-1 that encodes avirulence towards the lentil cultivar PBA Hurricane XT. The mapping population was produced by mating A. lentis isolate P94-24, which is pathogenic on the cultivar Nipper and avirulent towards Hurricane, and the isolate AlKewell, which is pathogenic towards Hurricane but not Nipper. Using agroinfiltration, we found that AlAvr1-1 from the isolate P94-24 causes necrosis in Hurricane but not in Nipper. The homologous corresponding gene in AlKewell, AlAvr1-2, encodes a protein with amino acid variation at 23 sites and four of these sites have been positively selected in the P94-24 branch of the phylogeny. Loss of AlAvr1-1 in a gene knockout experiment produced a P94-24 mutant strain that is virulent on Hurricane. Deletion of AlAvr1-2 in AlKewell led to reduced pathogenicity on Hurricane, suggesting that the gene may contribute to disease in Hurricane. Deletion of AlAvr1-2 did not affect virulence for Nipper and AlAvr1-2 is therefore not an avirulence gene for Nipper. We conclude that the hemibiotrophic pathogen A. lentis has an avirulence effector, AlAvr1-1, that triggers a hypersensitive resistance response in Hurricane. This is the first avirulence gene to be characterized in a legume pathogen from the Pleosporales and may help progress research on other damaging Ascochyta pathogens.

Risk of acute respiratory infection and acute cardiovascular events following acute respiratory infection among adults with increased cardiovascular risk in England between 2008 and 2018: a retrospective, population-based cohort study.

BACKGROUND: Although acute respiratory infections can lead to cardiovascular complications, the effect of underlying cardiovascular risk on the incidence of acute respiratory infections and cardiovascular complications following acute respiratory infection in individuals without established cardiovascular disease is unknown. We aimed to investigate whether cardiovascular risk is associated with increased risk of acute respiratory infection and acute cardiovascular events after acute respiratory infection using 10 years of linked electronic health record (EHR) data in England. METHODS: In this retrospective, population-based cohort study we used EHRs from primary care providers registered on the Clinical Practice Research Datalink (CPRD) GOLD and Aurum databases in England. Eligible individuals were aged 40-64 years, did not have established cardiovascular disease or a chronic health condition that would make them eligible for influenza vaccination, were registered at a general practice contributing to the CPRD, and had linked Hospital Episode Statistics Admitted Patient Care data in England from Sept 1, 2008, to Aug 31, 2018. We classified cardiovascular risk on the basis of diagnosed hypertension and overall predicted cardiovascular risk, estimated by use of the QRISK2 risk-prediction tool (comparing a score of ≥10% [increased risk] with a score of <10% [low risk]). Using multivariable Poisson regression models, we calculated incidence rate ratios (IRRs) for systemic acute respiratory infection. Among individuals who had an acute respiratory infection, we used multivariable Cox regression to calculate hazard ratios (HRs) for the risk of acute cardiovascular events within 1 year of infection. FINDINGS: We identified 6 075 321 individuals aged 40-64 years with data in the CPRD and linked data in the Hospital Episode Statistics Admitted Patient Care database between Sept 1, 2008, and Aug 31, 2018. Of these individuals, 4 212 930 (including 526 480 [12·5%] with hypertension and 607 087 [14·4%] with a QRISK2 score of ≥10%) were included in the assessment of the incidence of acute respiratory infection. After adjusting for confounders (age, sex, ethnicity, socioeconomic status, body-mass index, alcohol consumption, smoking status, and consultation frequency in the hypertension analysis; and alcohol consumption and consultation frequency in the QRISK2 analysis), the incidence of acute respiratory infection was higher in individuals with hypertension than those without (IRR 1·04 [95% CI 1·03-1·05]) and higher in those with a QRISK2 score of 10% or higher than in those with a QRISK2 score of less than 10% (1·39 [1·37-1·40]). Of the 442 408 individuals who had an acute respiratory infection, 4196 (0·9%) had an acute cardiovascular event within 1 year of infection. After adjustment (for age, sex, ethnicity, socioeconomic status, body-mass index, alcohol consumption, and smoking status in the hypertension analysis; and for alcohol consumption in the QRISK2 analysis), hypertension (HR 1·98 [95% CI 1·83-2·15]) and a QRISK2 score of 10% or higher (3·65 [3·42-3·89]) were associated with a substantially increased risk of acute cardiovascular events after acute respiratory infection. INTERPRETATION: People with increased cardiovascular risk but without diagnosed cardiovascular disease, measured by diagnosed hypertension or overall predicted cardiovascular risk, could benefit from influenza and pneumococcal vaccine prioritisation to reduce their risk of both acute respiratory infection and cardiovascular complications following an acute respiratory infection. FUNDING: British Heart Foundation and the Wellcome Trust.

The impact of HIV infection on tuberculosis transmission in a country with low tuberculosis incidence: a national retrospective study using molecular epidemiology.

BACKGROUND: HIV is known to increase the likelihood of reactivation of latent tuberculosis to active TB disease; however, its impact on tuberculosis infectiousness and consequent transmission is unclear, particularly in low-incidence settings. METHODS: National surveillance data from England, Wales and Northern Ireland on tuberculosis cases in adults from 2010 to 2014, strain typed using 24-locus mycobacterial-interspersed-repetitive-units-variable-number-tandem-repeats was used retrospectively to identify clusters of tuberculosis cases, subdivided into 'first' and 'subsequent' cases. Firstly, we used zero-inflated Poisson regression models to examine the association between HIV status and the number of subsequent clustered cases (a surrogate for tuberculosis infectiousness) in a strain type cluster. Secondly, we used logistic regression to examine the association between HIV status and the likelihood of being a subsequent case in a cluster (a surrogate for recent acquisition of tuberculosis infection) compared to the first case or a non-clustered case (a surrogate for reactivation of latent infection). RESULTS: We included 18,864 strain-typed cases, 2238 were the first cases of clusters and 8471 were subsequent cases. Seven hundred and fifty-nine (4%) were HIV-positive. Outcome 1: HIV-positive pulmonary tuberculosis cases who were the first in a cluster had fewer subsequent cases associated with them (mean 0.6, multivariable incidence rate ratio [IRR] 0.75 [0.65-0.86]) than those HIV-negative (mean 1.1). Extra-pulmonary tuberculosis (EPTB) cases with HIV were less likely to be the first case in a cluster compared to HIV-negative EPTB cases. EPTB cases who were the first case had a higher mean number of subsequent cases (mean 2.5, IRR (3.62 [3.12-4.19]) than those HIV-negative (mean 0.6). Outcome 2: tuberculosis cases with HIV co-infection were less likely to be a subsequent case in a cluster (odds ratio 0.82 [0.69-0.98]), compared to being the first or a non-clustered case. CONCLUSIONS: Outcome 1: pulmonary tuberculosis-HIV patients were less infectious than those without HIV. EPTB patients with HIV who were the first case in a cluster had a higher number of subsequent cases and thus may be markers of other undetected cases, discoverable by contact investigations. Outcome 2: tuberculosis in HIV-positive individuals was more likely due to reactivation than recent infection, compared to those who were HIV-negative.

Common Bacterial Infections and Risk of Dementia or Cognitive Decline: A Systematic Review.

BACKGROUND: Bacterial infections may be associated with dementia, but the temporality of any relationship remains unclear. OBJECTIVES: To summarize existing literature on the association between common bacterial infections and the risk of dementia and cognitive decline in longitudinal studies. METHODS: We performed a comprehensive search of 10 databases of published and grey literature from inception to 18 March 2019 using search terms for common bacterial infections, dementia, cognitive decline, and longitudinal study designs. Two reviewers independently performed the study selection, data extraction, risk of bias and overall quality assessment. Data were summarized through a narrative synthesis as high heterogeneity precluded a meta-analysis. RESULTS: We identified 3,488 studies. 9 met the eligibility criteria; 6 were conducted in the United States and 3 in Taiwan. 7 studies reported on dementia and 2 investigated cognitive decline. Multiple infections were assessed in two studies. All studies found sepsis (n = 6), pneumonia (n = 3), urinary tract infection (n = 1), and cellulitis (n = 1) increased dementia risk (HR 1.10; 95% CI 1.02-1.19) to (OR 2.60; 95% CI 1.84-3.66). The range of effect estimates was similar when limited to three studies with no domains at high risk of bias. However, the overall quality of evidence was rated very low. Studies on cognitive decline found no association with infection but had low power. CONCLUSION: Our review suggests common bacterial infections may be associated with an increased risk of subsequent dementia, after adjustment for multiple confounders, but further high-quality, large-scale longitudinal studies, across different healthcare settings, are recommended to further explore this association.

A model of tuberculosis clustering in low incidence countries reveals more transmission in the United Kingdom than the Netherlands between 2010 and 2015.

Tuberculosis (TB) remains a public health threat in low TB incidence countries, through a combination of reactivated disease and onward transmission. Using surveillance data from the United Kingdom (UK) and the Netherlands (NL), we demonstrate a simple and predictable relationship between the probability of observing a cluster and its size (the number of cases with a single genotype). We demonstrate that the full range of observed cluster sizes can be described using a modified branching process model with the individual reproduction number following a Poisson lognormal distribution. We estimate that, on average, between 2010 and 2015, a TB case generated 0.41 (95% CrI 0.30,0.60) secondary cases in the UK, and 0.24 (0.14,0.48) secondary cases in the NL. A majority of cases did not generate any secondary cases. Recent transmission accounted for 39% (26%,60%) of UK cases and 23%(13%,37%) of NL cases. We predict that reducing UK transmission rates to those observed in the NL would result in 538(266,818) fewer cases annually in the UK. In conclusion, while TB in low incidence countries is strongly associated with reactivated infections, we demonstrate that recent transmission remains sufficient to warrant policies aimed at limiting local TB spread.

Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance.

INTRODUCTION: 2018 World Health Organization (WHO) guidelines for the treatment of isoniazid (H)-resistant (Hr) tuberculosis recommend a four-drug regimen: rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx), with or without H ([H]RZE-Lfx). This is used once Hr is known, such that patients complete 6 months of Lfx (≥6[H]RZE-6Lfx). This cohort study assessed the impact of fluoroquinolones (Fq) on treatment effectiveness, accounting for Hr mutations and degree of phenotypic resistance. METHODS: This was a retrospective cohort study of 626 Hr tuberculosis patients notified in London, 2009-2013. Regimens were described and logistic regression undertaken of the association between regimen and negative regimen-specific outcomes (broadly, death due to tuberculosis, treatment failure or disease recurrence). RESULTS: Of 594 individuals with regimen information, 330 (55.6%) were treated with (H)RfZE (Rf=rifamycins) and 211 (35.5%) with (H)RfZE-Fq. The median overall treatment period was 11.9 months and median Z duration 2.1 months. In a univariable logistic regression model comparing (H)RfZE with and without Fqs, there was no difference in the odds of a negative regimen-specific outcome (baseline (H)RfZE, cluster-specific odds ratio 1.05 (95% CI 0.60-1.82), p=0.87; cluster NHS trust). Results varied minimally in a multivariable model. This odds ratio dropped (0.57, 95% CI 0.14-2.28) when Hr genotype was included, but this analysis lacked power (p=0.42). CONCLUSIONS: In a high-income setting, we found a 12-month (H)RfZE regimen with a short Z duration to be similarly effective for Hr tuberculosis with or without a Fq. This regimen may result in fewer adverse events than the WHO recommendations.

Creating a web-based electronic tool to aid tuberculosis (TB) cluster investigation: data integration in TB surveillance activities in the United Kingdom, 2013 to 2016.

Molecular technology to identify relatedness between Mycobacterium tuberculosis complex isolates, representative of possible tuberculosis (TB) transmission between individuals, continues to evolve. At the same time, tools to utilise this information for public health action to improve TB control should also be implemented. Public Health England developed the Strain Typing Module (STM) as an integral part of the web-based surveillance system used in the United Kingdom following the roll-out of prospective 24 loci mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) strain typing. The creation of such a system required data integration and linkage, bringing together laboratory results and patient notification information. The STM facilitated widespread access to patient strain typing and clustering results for the public health community working in TB control. In addition, the system provided a log of cluster review and investigation decision making and results. Automated real-time data linkage between laboratory and notification data are essential to allow routine use of genotyping results in TB surveillance and control. Outputs must be accessible by those working in TB control at a local level to have any impact in ongoing public health activity.

A Quantitative Evaluation of MIRU-VNTR Typing Against Whole-Genome Sequencing for Identifying Mycobacterium tuberculosis Transmission: A Prospective Observational Cohort Study.

BACKGROUND: Mycobacterial Interspersed Repetitive Unit-Variable Number Tandem Repeat (MIRU-VNTR) typing is widely used in high-income countries to determine Mycobacterium tuberculosis relatedness. Whole-genome sequencing (WGS) is known to deliver greater specificity, but no quantitative prospective comparison has yet been undertaken. METHODS: We studied isolates from the English Midlands, sampled consecutively between 1 January 2012 and 31 December 2015. In addition to routinely performed MIRU-VNTR typing, DNA was extracted from liquid cultures and sequenced using Illumina technology. Demographic and epidemiological data for the relevant patients were extracted from the Enhanced Tuberculosis Surveillance system run by Public Health England. Closely related samples, defined using a threshold of five single nucleotide variants (SNVs), were compared to samples with identical MIRU-VNTR profiles, to samples from individuals with shared epidemiological risk factors, and to those with both characteristics. FINDINGS: 1999 patients were identified for whom at least one M. tuberculosis isolate had been MIRU-VNTR typed and sequenced. Comparing epidemiological risk factors with close genetic relatedness, only co-residence had a positive predictive value of over 5%. Excluding co-resident individuals, 18.6% of patients with identical MIRU-VNTR profiles were within 5 SNVs. Where patients also shared social risk factors and ethnic group, this rose to 48%. Only 8% of MIRU-VNTR linked pairs in lineage 1 were within 5 SNV, compared to 31% in lineage 4. INTERPRETATION: In the setting studied, this molecular epidemiological study shows MIRU-VNTR typing and epidemiological risk factors are poorly predictive of close genomic relatedness, assessed by SNV. MIRU-VNTR performance varies markedly by lineage. FUNDING: Public Health England, Health Innovation Challenge Fund, NIHR Health Protection Research Unit Oxford, NIHR Oxford Biomedical Research Centre.

Trends in, and factors associated with, HIV infection amongst tuberculosis patients in the era of anti-retroviral therapy: a retrospective study in England, Wales and Northern Ireland.

BACKGROUND: HIV increases the progression of latent tuberculosis (TB) infection to active disease and contributed to increased TB in the UK until 2004. We describe temporal trends in HIV infection amongst patients with TB and identify factors associated with HIV infection. METHODS: We used national surveillance data of all TB cases reported in England, Wales and Northern Ireland from 2000 to 2014 and determined HIV status through record linkage to national HIV surveillance. We used logistic regression to identify associations between HIV and demographic, clinical and social factors. RESULTS: There were 106,829 cases of TB in adults (≥ 15 years) reported from 2000 to 2014. The number and proportion of TB patients infected with HIV decreased from 543/6782 (8.0%) in 2004 to 205/6461 (3.2%) in 2014. The proportion of patients diagnosed with HIV > 91 days prior to their TB diagnosis increased from 33.5% in 2000 to 60.2% in 2013. HIV infection was highest in people of black African ethnicity from countries with high HIV prevalence (32.3%), patients who misused drugs (8.1%) and patients with miliary or meningeal TB (17.2%). CONCLUSIONS: There has been an overall decrease in TB-HIV co-infection and a decline in the proportion of patients diagnosed simultaneously with both infections. However, high rates of HIV remain in some sub-populations of patients with TB, particularly black Africans born in countries with high HIV prevalence and people with a history of drug misuse. Whilst the current policy of testing all patients diagnosed with TB for HIV infection is important in ensuring appropriate management of TB patients, many of these TB cases would be preventable if HIV could be diagnosed before TB develops. Improving screening for both latent TB and HIV and ensuring early treatment of HIV in these populations could help prevent these TB cases. British HIV Association guidelines on latent TB testing for people with HIV from sub-Saharan Africa remain relevant, and latent TB screening for people with HIV with a history of drug misuse, homelessness or imprisonment should also be considered.

Understanding Tuberculosis Transmission in the United Kingdom: Findings From 6 Years of Mycobacterial Interspersed Repetitive Unit-Variable Number Tandem Repeats Strain Typing, 2010-2015.

Genotyping provides the opportunity to better understand tuberculosis (TB) transmission. We utilized strain typing data to assess trends in the proportion of clustering and identify the characteristics of individuals and clusters associated with recent United Kingdom (UK) transmission. In this retrospective cohort analysis, we included all culture-confirmed strain-typed TB notifications from the UK between 2010 and 2015 to estimate the proportion of patients that clustered over time. We explored the characteristics of patients in a cluster using multivariable logistic regression. Overall, 58.5% of TB patients were concentrated in 2,701 clusters. The proportion of patients in a cluster decreased between 2010 (58.7%) and 2015 (55.3%) (P = 0.001). Being a clustered patient was associated with being male and UK-born, having pulmonary disease, having a previous TB diagnosis, and having a history of drug misuse or imprisonment. Our results suggest that TB transmission in the UK decreased between 2010 and 2015, during which time TB incidence also decreased. Targeted cluster investigation and extended contact tracing should be aimed at persons at risk of being in a transmission chain, including UK-born individuals with social risk factors in clusters with a high proportion of patients having pulmonary disease.

The use of whole-genome sequencing in cluster investigation of a multidrug-resistant tuberculosis outbreak.

We used whole-genome sequencing (WGS) to delineate transmission networks and investigate the benefits of WGS during cluster investigation.We included clustered cases of multidrug-resistant (MDR) tuberculosis (TB)/extensively drug-resistant (XDR) TB linked by mycobacterial interspersed repetitive unit variable tandem repeat (MIRU-VNTR) strain typing or epidemiological information in the national cluster B1006, notified between 2007 and 2013 in the UK. We excluded from further investigation cases whose isolates differed by greater than 12 single nucleotide polymorphisms (SNPs). Data relating to patients' social networks were collected.27 cases were investigated and 22 had WGS, eight of which (36%) were excluded as their isolates differed by more than 12 SNPs to other cases. 18 cases were ruled into the transmission network based on genomic and epidemiological information. Evidence of transmission was inconclusive in seven out of 18 cases (39%) in the transmission network following WGS and epidemiological investigation.This investigation of a drug-resistant TB cluster illustrates the opportunities and limitations of WGS in understanding transmission in a setting with a high proportion of migrant cases. The use of WGS should be combined with classical epidemiological methods. However, not every cluster will be solvable, regardless of the quality of genomic data.

Reduction in tuberculosis incidence in the UK from 2011 to 2015: a population-based study.

BACKGROUND: Following nearly two decades of increasing tuberculosis in the UK, TB incidence decreased by 32% from 2011 to 2015. Explaining this reduction is crucial to informing ongoing TB control efforts. METHODS: We stratified TB cases notified in the UK and TB cases averted in the UK through pre-entry screening (PES) between 2011 and 2015 by country of birth and time since arrival. We used population estimates and migration data to establish denominators, and calculated incidence rate ratios (IRRs) between 2011 and 2015. We calculated the contribution of changing migrant population sizes, PES and changes in TB rates to the reduction in TB notifications. RESULTS: TB IRRs fell in all non-EU migrant and UK-born populations between 2011 and 2015 (0.61; 95% CI 0.59 to 0.64 and 0.78; 0.73 to 0.83 respectively), with the greatest decrease in recent non-EU migrants (0.54; 0.48 to 0.61). 61.9% of the reduction in TB notifications was attributable to decreases in TB rates, 33.4% to a fall in the number of recent/mid-term non-EU migrants and 11.4% to PES. A small increase in notifications in EU-born migrants offset the reduction by 6.6%. CONCLUSIONS: Large decreases in TB rates in almost all populations accounted for the majority of the reduction in TB notifications, providing evidence of the impact of recent interventions to improve UK TB control. The particularly large decrease in TB rates in recent non-EU migrants provides evidence of the effectiveness of screening interventions that target this population. These findings will inform ongoing improvements to TB control.

Acquired Resistance to Antituberculosis Drugs in England, Wales, and Northern Ireland, 2000-2015.

Among tuberculosis (TB) patients, acquired resistance to anti-TB drugs represents a failure in the treatment pathway. To improve diagnosis and care for patients with drug-resistant TB, we examined the epidemiology and risk factors associated with acquired drug resistance during 2000-2015 among TB patients in England, Wales, and Northern Ireland. We found acquired resistance in 0.2% (158/67,710) of patients with culture-confirmed TB. Using multivariate logistic regression, we identified the following factors associated with acquired drug resistance: having pulmonary disease; initial resistance to isoniazid, rifampin, or both; a previous TB episode; and being born in China or South Africa. Treatment outcomes were worse for patients with than without acquired resistance. Although acquired resistance is rare in the study area, certain patient groups are at higher risk. Identifying these patients and ensuring that adequate resources are available for treatment may prevent acquisition of resistance, thereby limiting transmission of drug-resistant strains of mycobacteria.

Recent household transmission of tuberculosis in England, 2010-2012: retrospective national cohort study combining epidemiological and molecular strain typing data.

BACKGROUND: We estimate the proportion of tuberculosis (TB) in England due to recent household transmission, identify factors associated with being a household transmitter, and investigate the impact that identification of a case has on time to treatment of subsequent cases. METHODS: TB cases notified between 2010 and 2012 in England in the same household as another case were identified; 24 locus MIRU-VNTR strain typing (ST) was used to identify household cases with likely recent transmission. Treatment delay in index and subsequent cases was compared. Risk factors for being a household transmitter were identified in univariable and multivariable analyses. RESULTS: Overall, 7.7% (1849/24,060) of TB cases lived in a household with another case. We estimate that 3.9% were due to recent household transmission. ST data was unavailable for 67% (1242) of household pairs. For those with ST data, 64% (386) had confirmed, 11% probable (66) and 25% (155) refuted household transmission. The median treatment delay was 65 days for index cases and 37 days for subsequent asymptomatic cases. Risk factors for being a household transmitter included being under 25 years old, UK-born with Black African, Indian or Pakistani ethnicity, or born in Somalia or Romania. CONCLUSIONS: This study has a number of implications for household TB contact tracing in low incidence countries, including the potential to reduce the diagnostic delay for subsequent household cases and the benefit of using ST to identify when to conduct source contact tracing outside the household. As 25% of TB cases in households had discordant strains, households with multiple TB cases do not necessarily represent household transmission. The additional fact that 25% of index cases within households only had extra-pulmonary TB demonstrates that, if household contact tracing is limited to pulmonary TB cases (as recently recommended in UK guidelines), additional cases of active TB in households will be missed. Our finding that no lineage of TB was associated with recent household transmission and with no increased transmissibility in the Beijing lineage compared to others, suggests that the lineage need not impact contact tracing efforts. Improvements in contact tracing have the potential to reduce transmission of TB in low incidence countries.