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Tuberculosis (TB) control programs prevent transmission of Mycobacterium tuberculosis by identifying and treating active cases of TB disease and ensuring that contacts of infectious cases are also identified, screened, and treated for active disease or latent infection. The chapter reviews the use of genotyping to investigate transmission as well as how genotyping methods have been applied to study transmission dynamics, lineage, recurrent TB disease, mixed infections, and laboratory contamination. A common outbreak investigation goal is to combine genotyping data with different sources of clinical, epidemiological, and programmatic data through partnerships that lead investigators to the best conclusions and public health action for control of recent transmission. Although spatial analyses of TB case distributions are common, they are heterogeneous in their methods and findings. The central problem with using genotype clustering to estimate recent transmission has been that clustered cases are not necessarily part of the same chain of transmission.

Mutations in the Trypanosoma brucei aquaporin AQP2 are associated with resistance to pentamidine and melarsoprol. We show that TbAQP2 but not TbAQP3 was positively selected for increased pore size from a common ancestor aquaporin. We demonstrate that TbAQP2’s unique architecture permits pentamidine permeation through its central pore and show how specific mutations in highly conserved motifs affect drug permeation. Introduction of key TbAQP2 amino acids into TbAQP3 renders the latter permeable to pentamidine. Molecular dynamics demonstrates that permeation by dicationic pentamidine is energetically favourable in TbAQP2, driven by the membrane potential, although aquaporins are normally strictly impermeable for ionic species. We also identify the structural determinants that make pentamidine a permeant but exclude most other diamidine drugs. Our results have wide-ranging implications for optimising antitrypanosomal drugs and averting cross-resistance. Moreover, these new insights in aquaporin permeation may allow the pharmacological exploitation of other members of this ubiquitous gene family.

Mutations in the Trypanosoma brucei aquaporin AQP2 are associated with resistance to pentamidine and melarsoprol. We show that TbAQP2 but not TbAQP3 was positively selected for increased pore size from a common ancestor aquaporin. We demonstrate that TbAQP2's unique architecture permits pentamidine permeation through its central pore and show how specific mutations in highly conserved motifs affect drug permeation. Introduction of key TbAQP2 amino acids into TbAQP3 renders the latter permeable to pentamidine. Molecular dynamics demonstrates that permeation by dicationic pentamidine is energetically favourable in TbAQP2, driven by the membrane potential, although aquaporins are normally strictly impermeable for ionic species. We also identify the structural determinants that make pentamidine a permeant although most other diamidine drugs are excluded. Our results have wide-ranging implications for optimising antitrypanosomal drugs and averting cross-resistance. Moreover, these new insights in aquaporin permeation may allow the pharmacological exploitation of other members of this ubiquitous gene family. African sleeping sickness is a potentially deadly illness caused by the parasite Trypanosoma brucei. The disease is treatable, but many of the current treatments are old and are becoming increasingly ineffective. For instance, resistance is growing against pentamidine, a drug used in the early stages in the disease, as well as against melarsoprol, which is deployed when the infection has progressed to the brain. Usually, cases resistant to pentamidine are also resistant to melarsoprol, but it is still unclear why, as the drugs are chemically unrelated. Studies have shown that changes in a water channel called aquaglyceroporin 2 (TbAQP2) contribute to drug resistance in African sleeping sickness; this suggests that it plays a role in allowing drugs to kill the parasite. This molecular 'drain pipe' extends through the surface of T. brucei, and should allow only water and a molecule called glycerol in and out of the cell. In particular, the channel should be too narrow to allow pentamidine or melarsoprol to pass through. One possibility is that, in T. brucei, the TbAQP2 channel is abnormally wide compared to other members of its family. Alternatively, pentamidine and melarsoprol may only bind to TbAQP2, and then 'hitch a ride' when the protein is taken into the parasite as part of the natural cycle of surface protein replacement. Alghamdi et al. aimed to tease out these hypotheses. Computer models of the structure of the protein were paired with engineered changes in the key areas of the channel to show that, in T. brucei, TbAQP2 provides a much broader gateway into the cell than observed for similar proteins. In addition, genetic analysis showed that this version of TbAQP2 has been actively selected for during the evolution process of T. brucei. This suggests that the parasite somehow benefits from this wider aquaglyceroporin variant. This is a new resistance mechanism, and it is possible that aquaglyceroporins are also larger than expected in other infectious microbes. The work by Alghamdi et al. therefore provides insight into how other germs may become resistant to drugs., This work was supported by the UK Medical Research Council (MRC) [grant G0701258 to HPdK] andby the US National Institutes of Health (NIH) [Grant No. GM111749 to DWB]. DC was supported byan MRC iCASE award [MR/R015791/1]. UZ acknowledges funding from the Scottish UniversitiesPhysics Alliance. AHA is funded through a PhD studentship from Albaha University, Saudi Arabia.GDC was funded by a PhD Studentship from Science Without Borders [206385/2014–5, CNPq,Brazil]. TS was funded via a Doctoral Training Programme of the MRC and the Cambridge Trust andSW was funded by a Sir Henry Dale fellowship of the Wellcome Trust and Royal Society. The authorsthank Dr Tansy Hammarton for the use of the CRK2 RNAi cell line and Prof David Horn for the use ofthe aqp1-3 null cell line. This work was supported by a grant from the Wellcome Trust (204697/Z/16/Z to MCF. The authors are grateful to Professor George Diallinas, University of Athens, Greece, forhis exceptionally insightful reviewer comments and have adopted several of his arguments inrevision.

Setting Nearly 8% of adult tuberculosis (TB) cases in England, Wales and Northern Ireland (EW&NI) occur among health care workers (HCWs), the majority of whom are from high TB incidence countries. Objectives To determine if a TB cluster containing multiple HCWs was due to nosocomial transmission. Methods A cluster of TB cases notified in EW&NI from 2009 to 2014, with indistinguishable 24-locus mycobacterial interspersed repetitive unit-variable number of tandem repeats (MIRU-VNTR) profiles, was identified through routine national cluster review. Cases were investigated to identify epidemiological links, and occupational health (OH) information was collected for HCW cases. To further discriminate strains, typing of eight additional loci was conducted. Results Of the 53 cases identified, 22 were HCWs. The majority (n = 43), including 21 HCWs, were born in the Philippines. Additional typing split the cluster into three subclusters and seven unique strains. No epidemiological links were identified beyond one household and a common residential area. HCWs in this cluster received no or inadequate OH assessment. Conclusions The MIRU-VNTR profile of this cluster probably reflects common endemic strains circulating in the Philippines, with reactivation occurring in the UK. Furthermore, 32-locus typing showed that 24-locus MIRU-VNTR failed to distinguish strain diversity. The lack of OH assessment indicates that latent tuberculous infection could have been identified and treated, thereby preventing active cases from occurring.

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.

Background The incidence of TB has doubled in the last 20 years in London. A better understanding of risk groups for recent transmission is required to effectively target interventions. We investigated the molecular epidemiological characteristics of TB cases to estimate the proportion of cases due to recent transmission, and identify predictors for belonging to a cluster. Methods The study population included all culture-positive TB cases in London residents, notified between January 2010 and December 2012, strain typed using 24-loci multiple interspersed repetitive units-variable number tandem repeats. Multivariable logistic regression analysis was performed to assess the risk factors for clustering using sociodemographic and clinical characteristics of cases and for cluster size based on the characteristics of the first two cases. Results There were 10 147 cases of which 5728 (57%) were culture confirmed and 4790 isolates (84%) were typed. 2194 (46%) were clustered in 570 clusters, and the estimated proportion attributable to recent transmission was 34%. Clustered cases were more likely to be UK born, have pulmonary TB, a previous diagnosis, a history of substance abuse or alcohol abuse and imprisonment, be of white, Indian, black-African or Caribbean ethnicity. The time between notification of the first two cases was more likely to be

BACKGROUND: TB remains a major public health concern, even in low-incidence countries like the USA and the UK. Over the last two decades, cases of TB reported in the USA have declined, while they have increased substantially in the UK. We examined factors associated with this divergence in TB trends between the two countries.METHODS: We analysed all cases of TB reported to the US and UK national TB surveillance systems from 1 January 2000 through 31 December 2011. Negative binominal regression was used to assess potential demographic, clinical and risk factor variables associated with differences in observed trends.FINDINGS: A total of 259,609 cases were reported. From 2000 to 2011, annual TB incidence rates declined from 5.8 to 3.4 cases per 100,000 in the USA, whereas in the UK, TB incidence increased from 11.4 to 14.4 cases per 100,000. The majority of cases in both the USA (56%) and the UK (64%) were among foreign-born persons. The number of foreign-born cases reported in the USA declined by 15% (7731 in 2000 to 6564 in 2011) while native-born cases fell by 54% (8442 in 2000 to 3883 in 2011). In contrast, the number of foreign-born cases reported in the UK increased by 80% (3380 in 2000 to 6088 in 2011), while the number of native-born cases remained largely unchanged (2158 in 2000 to 2137 in 2011). In an adjusted negative binomial regression model, significant differences in trend were associated with sex, age, race/ethnicity, site of disease, HIV status and previous history of TB (pINTERPRETATION: To achieve TB elimination in the UK, a re-evaluation of current TB control policies and practices with a focus on foreign-born are needed. In the USA, maintaining and strengthening control practices are necessary to sustain the progress made over the last 20 years.

Item does not contain fulltext BACKGROUND: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. METHODS: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. FINDINGS: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0.15, 95% CI 0.11 to 0.18), levofloxacin (0.15, 0.13 to 0.18), carbapenems (0.14, 0.06 to 0.21), moxifloxacin (0.11, 0.08 to 0.14), bedaquiline (0.10, 0.05 to 0.14), and clofazimine (0.06, 0.01 to 0.10). There was a significant association between reduced mortality and use of linezolid (-0.20, -0.23 to -0.16), levofloxacin (-0.06, -0.09 to -0.04), moxifloxacin (-0.07, -0.10 to -0.04), or bedaquiline (-0.14, -0.19 to -0.10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I(2) method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. INTERPRETATION: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. FUNDING: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

Objectives Tuberculosis (TB) is a serious re-emergent public health problem in the UK. In response to rising case incidence a National TB Strain-Typing Service based on molecular strain-typing was established. This facilitates early detection and investigation of clusters, targeted public health action, and prevention of further transmission. We review the added public health value of investigating molecular TB strain-typed (ST) clusters. Methods A structured questionnaire for each ST cluster investigated in England between 1 January 2010 and 30 June 2013 was completed. Questions related to epidemiological links and public health action and the perceived benefits of ST cluster investigation. Results There were 278 ST cluster investigations (CIs) involving 1882 TB cases. Cluster size ranged from 2 to 92. CIs identified new epidemiological links in 36% of clusters; in 18% STs were discordant refuting transmission thought to have occurred. Additional public health action was taken following 23% of CI. Conclusions We found positive benefits of TB molecular ST and CI, in identifying new epidemiological links between cases and taking public health action and in refuting transmission and saving resources. This needs to be translated to a decrease in transmission to provide evidence of public health value in this low prevalence high resource setting.

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. Electronic supplementary material The online version of this article (doi:10.1186/s12916-017-0864-y) contains supplementary material, which is available to authorized users.

Background In the European Union and European Economic Area only 38% of multidrug-resistant tuberculosis patients notified in 2011 completed treatment successfully at 24 months’ evaluation. Socio-economic factors and patient factors such as demographic characteristics, behaviour and attitudes are associated with treatment outcomes. Characteristics of healthcare systems also affect health outcomes. This study was conducted to identify and better understand the contribution of health system components to successful treatment of multidrug-resistant tuberculosis. Methods We selected four European Union countries to provide for a broad range of geographical locations and levels of treatment success rates of the multidrug-resistant tuberculosis cohort in 2009. We conducted semi-structured interviews following a conceptual framework with representatives from policy and planning authorities, healthcare providers and civil society organisations. Responses were organised according to the six building blocks of the World Health Organization health systems framework. Results In the four included countries, Austria, Bulgaria, Spain, and the United Kingdom, the following healthcare system factors were perceived as key to achieving good treatment results for patients with multidrug-resistant tuberculosis: timely diagnosis of drug-resistant tuberculosis; financial systems that ensure access to a full course of treatment and support for multidrug-resistant tuberculosis patients; patient-centred approaches with strong intersectoral collaboration that address patients’ emotional and social needs; motivated and dedicated healthcare workers with sufficient mandate and means to support patients; and cross-border management of multidrug-resistant tuberculosis to secure continuum of care between countries. Conclusion We suggest that the following actions may improve the success of treatment for multidrug-resistant tuberculosis patients: deployment of rapid molecular diagnostic tests; development of context-specific treatment guidance and criteria for hospital admission and discharge in the European context; strengthening patient-centred approaches; development of collaborative mechanisms to ensure cross-border care, and development of long-term sustainable financing strategies. Electronic supplementary material The online version of this article (doi:10.1186/s12889-017-4216-9) contains supplementary material, which is available to authorized users.

Background: Patients born outside the UK have contributed to a 20% rise in the UK's tuberculosis incidence since 2000, but their effect on domestic transmission is not known. Here we use whole-genome sequencing to investigate the epidemiology of tuberculosis transmission in an unselected population over 6 years. Methods: We identified all residents with Oxfordshire postcodes with a Mycobacterium tuberculosis culture or a clinical diagnosis of tuberculosis between Jan 1, 2007, and Dec 31, 2012, using local databases and checking against the national Enhanced Tuberculosis Surveillance database. We used Illumina technology to sequence all available M tuberculosis cultures from identified cases. Sequences were clustered by genetic relatedness and compared retrospectively with contact investigations. The first patient diagnosed in each cluster was defined as the index case, with links to subsequent cases assigned first by use of any epidemiological linkage, then by genetic distance, and then by timing of diagnosis. Findings: Although we identified 384 patients with a diagnosis of tuberculosis, country of birth was known for 380 and we sequenced isolates from 247 of 269 cases with culture-confirmed disease. 39 cases were genomically linked within 13 clusters, implying 26 local transmission events. Only 11 of 26 possible transmissions had been previously identified through contact tracing. Of seven genomically confirmed household clusters, five contained additional genomic links to epidemiologically unidentified non-household members. 255 (67%) patients were born in a country with high tuberculosis incidence, conferring a local incidence of 109 cases per 100000 population per year in Oxfordshire, compared with 3·5 cases per 100000 per year for those born in low-incidence countries. However, patients born in the low-incidence countries, predominantly UK, were more likely to have pulmonary disease (adjusted odds ratio 1·8 [95% CI 1·2-2·9]; p=0·009), social risk factors (4·4 [2·0-9·4]; p

Objective To review all notified cases of leprosy in England and Wales between 1953 and 2012. Design National surveillance study of all reported cases. Setting England and Wales. Outcome Number and characteristics of reported cases. Results During this period, a total of 1449 leprosy cases were notified. The incidence fell from 356 new cases notified between 1953 and 1962 to 139 new cases between 2003 and 2012. Where data were available, leprosy was more common in men, 15–45 year olds and those from the Indian subcontinent. There was considerable undernotification in 2001–2012. Conclusions The high level of under-reporting indicates a need for improved surveillance in the UK. Public Health England, in collaboration with the UK Panel of Leprosy opinion, has revised the UK Memorandum on Leprosy in order to provide updated guidance on diagnostic procedures, treatment, case management, contact tracing and notification.

Background The incidence of non-tuberculous mycobacteria (NTM) isolation from humans is increasing worldwide. In England, Wales and Northern Ireland (EW&NI) the reported rate of NTM more than doubled between 1996 and 2006. Although NTM infection has traditionally been associated with immunosuppressed individuals or those with severe underlying lung damage, pulmonary NTM infection and disease may occur in people with no overt immune deficiency. Here we report the incidence of NTM isolation in EW&NI between 2007 and 2012 from both pulmonary and extra-pulmonary samples obtained at a population level. Methods All individuals with culture positive NTM isolates between 2007 and 2012 reported to Public Health England by the five mycobacterial reference laboratories serving EW&NI were included. Results Between 2007 and 2012, 21,118 individuals had NTM culture positive isolates. Over the study period the incidence rose from 5.6/100,000 in 2007 to 7.6/100,000 in 2012 (p

Objectives To describe the burden of TB in healthcare workers (HCWs) in the UK and determine whether HCWs are at increased risk of TB due to occupational exposure. Methods Retrospective cohort analysis of national UK TB surveillance and genotyping data between 2009 and 2013. The rate of TB in HCWs compared with non-HCWs to calculate incidence rate ratios stratified by country of birth. Results 2320 cases of TB in HCWs were notified in the study period, 85% were born abroad. The TB rate in HCWs was 23.4 (95% CI 22.5 to 24.4) per 100 000 compared with 16.2 (95% CI 16.0 to 16.3) per 100 000 in non-HCWs. After stratifying by country of birth, there was not an increased TB incidence in HCWs for the majority of countries of birth, including in the UK-born. Using combined genotyping and epidemiological data, only 10 confirmed nosocomial transmission events involving HCWs were identified between 2010 and 2012. Of these, only two involved transmission to patients. Conclusions The lack of an increased risk of TB after stratifying by country of birth, and the very few transmission events involving nosocomial transmission in the UK suggests that TB in HCWs in the UK is not generally acquired through UK occupational exposure. The majority of cases in foreign-born HCWs are likely to result from reactivation of latent TB infection (LTBI) acquired abroad, and is not likely to be prevented by BCG vaccination in the UK. Testing and treatment of LTBI in HCWs with exposure to high TB burden countries should be the focus of occupational health prevention activities.

Due to an increase in bovine tuberculosis in cattle in the United Kingdom, we investigated the characteristics of Mycobacterium bovis infection in humans and assessed whether extensive transmission of M. bovis between humans has occurred. A cross-sectional study linking demographic, clinical, and DNA fingerprinting (using 15-locus mycobacterial interspersed repetitive-unit–variable-number tandem-repeat [MIRU-VNTR] typing) data on cases reported between 2005 and 2008 was undertaken. A total of 129 cases of M. bovis infection in humans were reported over the period, with a decrease in annual incidence from 0.065 to 0.047 cases per 100,000 persons. Most patients were born pre-1960, before widespread pasteurization was introduced (73%), were of white ethnicity (83%), and were born in the United Kingdom (76%). A total of 102 patients (79%) had MIRU-VNTR typing data. A total of 31 of 69 complete MIRU-VNTR profiles formed eight distinct clusters. The overall clustering proportion determined using the n − 1 method was 33%. The largest cluster, comprising 12 cases, was indistinguishable from a previously reported West Midlands outbreak strain cluster and included those cases. This cluster was heterogeneous, having characteristics supporting recent zoonotic and human-to-human transmission as well as reactivation of latent disease. Seven other, smaller clusters identified had demographics supporting recrudescence rather than recent infection. A total of 33 patients had incomplete MIRU-VNTR profiles, of which 11 may have yielded 2 to 6 further small clusters if typed to completion. The incidence of M. bovis in humans in the United Kingdom remains low, and the epidemiology is predominantly that of reactivated disease.

Anti-tuberculosis drug regimens are efficacious, but drug intolerance can be severe and may impact on treatment completion rates. The Enhanced Tuberculosis Surveillance (ETS) system is a case register of all new notifications of tuberculosis in England, Wales and Northern Ireland. We conducted a cohort study to estimate the incidence of, and risk factors for, drug intolerance reported through ETS between 2001 and 2010 and to assess its relationship with treatment non-completion. Reports of drug intolerance were found for 868/67 547 (1.28%) patients in the cohort, and important risk factors were female sex, older age, later case report year and white ethnicity. Drug intolerance was associated with an approximate fivefold increased odds of treatment non-completion (p

Whether the incidence of tuberculosis in HIV-positive people receiving long-term antiretroviral therapy (ART) remains above background population rates is unclear. We compared tuberculosis incidence in people receiving ART with background rates in England, Wales, and Northern Ireland.We analysed a national cohort of HIV-positive individuals linked to the national tuberculosis register. Tuberculosis incidence in the HIV-positive cohort (2007-11) was stratified by ethnic origin and time on ART and compared with background rates (2009). Ethnic groups were defined as follows: the black African group included all individuals of black African origin, including those born in the UK and overseas; the white ethnic group included all white individuals born in the UK and overseas; the south Asian group included those of Indian, Pakistani, and Bangladeshi origin, born in the UK and overseas; and the other ethnic group included all other ethnic origins, including black Afro-Caribbeans.The HIV-positive cohort comprised 79 919 individuals, in whom there were 1550 incident cases in 231 664 person-years of observation (incidence 6·7 cases per 1000 person-years). Incidence of tuberculosis in the HIV-positive cohort was 13·6 per 1000 person-years in black Africans and 1·7 per 1000 person-years in white individuals. Incidence of tuberculosis during long-term ART (≥5 years) in black Africans with HIV was 2·4 per 1000 person-years, similar to background rates of 1·9 per 1000 person-years in this group (rate ratio 1·2, 95% CI 0·96-1·6; p=0·083); but in white individuals with HIV on long-term ART the incidence of 0·5 per 1000 person-years was higher than the background rate of 0·04 per 1000 person-years (rate ratio 14·5, 9·4-21·3; p0·0001). The increased incidence relative to background in white HIV-positive individuals persisted when analysis was restricted to person-time accrued on ART with CD4 counts of at least 500 cells per μL and when white HIV-positive individuals born abroad were excluded.Tuberculosis incidence is unacceptably high irrespective of HIV status in black Africans. In white individuals with HIV, tuberculosis incidence is significantly higher than background rates in white people despite long-term ART. Expanded testing and treatment for latent tuberculosis infection to all HIV-infected adults, irrespective of ART status and CD4 cell count, might be warranted.Public Health England.

To the Editor: Multidrug-resistant tuberculosis (MDR-TB), defined as Mycobacterium tuberculosis resistant to at least isoniazid and rifampicin, is an increasing problem globally [1]. Children are not usually included in global surveys of MDR-TB incidence and prevalence [2] due to the diagnostic challenges of paucibacillary TB [3]. Data on the burden of MDR-TB in children are, therefore, lacking globally [1, 4, 5] and no published data from the UK exist. The current World Health Organization (WHO) [6] and National Institute for Clinical Excellence (NICE) [7] TB guidelines for the management of MDR-TB do not explicitly address paediatric disease. As a consequence, the complex management of this condition is left to individual clinicians' judgment. In general, childhood TB is paucibacillary, most cases are treated on clinical grounds without drug susceptibility testing [2], and correct and timely diagnosis of childhood MDR-TB is therefore challenging. There are limited data on the pharmacokinetics, dosing and safety of the many second-line drugs used to treat MDR-TB in children [5]. Our group is the first to review the management of a paediatric cohort with MDR-TB in the UK, and represents the largest available dataset from children with culture-confirmed MDR-TB from western …

Resistance to diminazene aceturate (Berenil) is a severe problem in the control of African trypanosomiasis in domestic animals. It has been speculated that resistance may be the result of reduced diminazene uptake by the parasite. We describe here the mechanisms by which [ 3 H]diminazene is transported by Trypanosoma brucei brucei bloodstream forms. Diminazene was rapidly accumulated through a single transporter, with a K m of 0.45 ± 0.11 μM, which was dose dependently inhibited by pentamidine and adenosine. The K i values for these inhibitors were consistent with this transporter being the P2/TbAT1 adenosine transporter. Yeast expressing TbAT1 acquired the ability to take up [ 3 H]diminazene and [ 3 H]pentamidine. TbAT1 -null mutants had lost almost all capacity for [ 3 H]diminazene transport. However, this cell line still displayed a small but detectable rate of [ 3 H]diminazene accumulation, in a nonsaturable manner. We conclude that TbAT1 mediates [ 3 H]diminazene transport almost exclusively and that this explains the observed diminazene resistance phenotypes of TbAT1 -null mutants and field isolates.

Between 2000 and 2012 the number of multidrug-resistant (MDR) tuberculosis cases in the UK increased from 28 per year to 81 per year. We investigated the proportion of MDR tuberculosis cases arising from transmission in the UK and associated risk factors.We identified patients with MDR tuberculosis notified in England, Wales, and Northern Ireland between Jan 1, 2004, and Dec 31, 2007, by linking national laboratory and surveillance data. Data for laboratory isolates, including drug sensitivities and 24-mycobacterial interspersed repetitive-unit-variable-number tandem repeat (MIRU-VNTR) typing were obtained routinely from the National Tuberculosis Reference laboratories as part of national tuberculosis surveillance. We investigated clusters of cases with indistinguishable MIRU-VNTR profiles to identify epidemiological links. We calculated transmission using the n-1 method and established associated risk factors by logistic regression. We also assessed the likelihood of transmission to additional secondary active tuberculosis cases, identified through conventional contact tracing.204 patients were diagnosed with MDR tuberculosis in the study period; 189 (92·6%) had an MIRU-VNTR profile. We identified 12 clusters containing 40 individuals and 149 unique strains. The proportion of cases attributable to recent transmission, on the basis of molecular data, was 15% (40 cases clustered-12 clusters/189 with a strain type). The proportion of cases attributable to recent transmission (ie, transmission within the UK) after adjustment for epidemiological links was 8·5% (22 cases with epidemiological links-six clusters/189 cases with a strain type). Being UK born (odds ratio 4·81; 95% CI 2·03-11·36, p=0·0005) and illicit drug use (4·75; 1·19-18·96, p=0·026) were significantly associated with clustering. The most common transmission setting was the household but 21 of 22 of epidemiological links were missed by conventional contact tracing. 13 secondary active tuberculosis cases identified by conventional contact tracing were mostly contacts of patients with MDR tuberculosis from countries of high tuberculosis burden. 11 (85%) of 13 shared the same country of birth as the index case, of whom ten did not share a strain type or drug resistance pattern.Transmission of MDR tuberculosis in the UK is low and associated with being UK born or illicit drug use. MIRU-VNTR typing with cluster investigation was more successful at identifying transmission events than conventional contact tracing. Individuals with tuberculosis who have had contact with a known MDR tuberculosis source case from a country of high tuberculosis burden should have drug-sensitivity testing on isolates to ensure appropriate treatment is given.Public Health England.

Introduction The incidence of nontuberculous mycobacteria (NTM) isolation from humans is increasing worldwide. In England, Wales and Northern Ireland (EW and NI) the reported rate of NTM more than doubled between 1996 and 2006. It is unclear if this trend has continued. We present an updated analysis with national NTM data from 2007 to 2012. Methods All individuals with culture positive NTM isolates between 2007–2012 reported to Public Health England by the five mycobacterial reference laboratories serving EW and NI, were included. The annual incidence of NTM was calculated based on the year of the first positive NTM isolate from each individual. Results 21,024 individuals had NTM culture positive samples. Over the study period the incidence rose from 5.57 (n = 3126) to 7.63 (n = 4454) per 100,000 population. The majority were male (57%) and older (71% >50 years of age). 77% of individuals had a pulmonary isolate – and here the incidence increased from 3.97 to 6.05 per 100,000 population between 2007 and 2012. In those with extra-pulmonary samples it remained stable at 1.61 per 100,000 population. In patients Table 1 indicates the seven most frequently reported organisms; M. avium-intracellulare (MAI) accounted for 35% of isolates (75% in people >50 years). 78% of these were from pulmonary samples. 42% of M. abscessus isolates were in patients 60 years. Conclusion The incidence of NTM has continued to rise since the last national survey. This represents an almost ten-fold increase since 1995. The majority of these are pulmonary isolates (in particular MAI). Possible explanations include greater awareness amongst clinicians leading to increased sampling, improvements in laboratory techniques for speciation or laboratory reporting practices. However, such a large increase most likely reflects a genuine rise in NTM infection in the population. Given this change in culture confirmation, it is imperative that a comprehensive clinical database is set up to provide national monitoring of clinically significant infections, and establish the true burden of disease present in EW and NI.

United Kingdom (UK) guidelines recommend at least 18 months treatment for patients with multidrug-resistant tuberculosis (MDR-TB). Prior to 2008, data on treatment outcome were only available at 12 months and therefore the proportion completing treatment was unknown. This retrospective-prospective cohort study reports on treatment outcomes for MDR-TB patients notified between 2004 and 2007 and examines factors associated with successful outcomes. 70.6% (144/204) completed treatment in 24 months or more, 6.9% (14) stopped treatment, 6.9% (14) died, 7.8% (16) were lost to follow up, 0.5% (1) relapsed and 4.4% (9) were transferred overseas. Following adjustment for age, being non-UK born, non-compliance and having co-morbidities, treatment with a fluoroquinolone (OR 3.09; 95% CI 1.21-7.88; p

To the Editor: Described as a “template for success” by Hanekom et al. [1] the Beijing genotype of Mycobacterium tuberculosis has been associated with hypervirulence, drug resistance, evasion of the bacille Calmette–Guerin (BCG) vaccine and differential immunoregulation [1]. The genotype is itself diverse; accordingly the fact that specific traits have been associated with Beijing only in certain settings may be explained by the variation in the subtypes that predominate in each. We sought to explore the role that the Beijing genotype plays in the epidemiology of multidrug-resistant (MDR) tuberculosis (TB) in two very different epidemiological settings: England and Peru. In the UK nearly three quarters of TB disease occurs amongst migrants, which may result from latent M. tuberculosis infections acquired from high-burden countries of origin. Thus the distribution of lineages in the UK reflects a composite of the circulating strains in other nations. Whilst increasing levels of MDR-TB in the UK have triggered understandable concern, only a small fraction of cases of TB are MDR (in 2011 this was 1.0%) [2]. In contrast, the Peruvian TB epidemic is relatively “home-grown” and the prevalence of drug resistance is greater (in 2011 5.3% were MDR-TB) [2]. Our objectives were thus: 1) identify any association between the Beijing genotype and MDR in these two settings, and 2) to examine if trends in Beijing might explain changes in the prevalence of MDR-TB over time. Four datasets were used during this study: two English studies and two Peruvian studies. The English datasets were taken from Public Health England's Enhanced Tuberculosis Surveillance System and Mycobacterial Surveillance Network and were referred to as England 1 and England 2. England 1 consisted of 8 859 individuals diagnosed and 24-loci MIRU-VNTR (mycobacterial interspersed repetitive units variable number tandem repeats) strain-typed …

Background Migrants account for an increasing proportion of the UK population. They are at risk of acquiring infectious diseases in their country of origin (prior to migration or during return visits), during migration, as well as in their destination country. Migrants can therefore have different risk profiles to the indigenous population. Methods UK enhanced surveillance data for TB, HIV, malaria and enteric fever were analysed, with a focus on 2010, for migrant (non-UK born) populations. Results South Asia was the most common region of birth for TB and enteric fever cases (57 and 80% of migrant cases, respectively). SubSaharan Africa was the predominant region of birth for HIV in heterosexuals and malaria cases (80 and 75% of migrant cases, respectively). The majority of cases of TB, HIV in heterosexuals, malaria and enteric fever reported in the UK are migrants. Among UK-born cases, ethnic minorities are disproportionately represented. Conclusions This analysis highlights the importance of considering, and improving the recording of, country of birth as a risk factor for infection. Consideration of multiple health risks is of value for migrant patients, and this has implications for the design of improved preventative strategies.

BACKGROUND: We describe the identification of, and risk factors for, the single most prevalent Mycobacterium tuberculosis strain in the West Midlands region of the UK. METHODOLOGY/PRINCIPAL FINDINGS: Prospective 15-locus MIRU-VNTR genotyping of all M. tuberculosis isolates in the West Midlands between 2004 and 2008 was undertaken. Two retrospective epidemiological investigations were also undertaken using univariable and multivariable logistic regression analysis. The first study of all TB patients in the West Midlands between 2004 and 2008 identified a single prevalent strain in each of the study years (total 155/3,056 (5%) isolates). This prevalent MIRU-VNTR profile (32333 2432515314 434443183) remained clustered after typing with an additional 9-loci MIRU-VNTR and spoligotyping. The majority of these patients (122/155, 79%) resided in three major cities located within a 40 km radius. From the apparent geographical restriction, we have named this the "Mercian" strain. A multivariate analysis of all TB patients in the West Midlands identified that infection with a Mercian strain was significantly associated with being UK-born (OR = 9.03, 95%CI = 4.56-17.87, p65 years old (OR = 0.25, 95% CI = 0.09-0.67, p < 0.01). A second more detailed investigation analyzed a cohort of 82 patients resident in Wolverhampton between 2003 and 2006. A significant association with being born in the UK remained after a multivariate analysis (OR = 9.68, 95% CI = 2.00-46.78, p < 0.01) and excess alcohol intake and cannabis use (OR = 6.26, 95%CI = 1.45-27.02, p = .01) were observed as social risk factors for infection. CONCLUSIONS/SIGNIFICANCE: The continued consistent presence of the Mercian strain suggests ongoing community transmission. Whilst significant associations have been found, there may be other common risk factors yet to be identified. Future investigations should focus on targeting the relevant risk groups and elucidating the biological factors that mediate continued transmission of this strain.

A gene encoding a 352 amino acid protein with a putative signal sequence, transmembrane domain and thrombospondin structural homology repeat was identified in the genome of the human malaria parasite, Plasmodium falciparum and the rodent malaria parasite, Plasmodium berghei. The protein localises in the apical organelles of P. falciparum and P. berghei merozoites within intraerythrocytic schizonts and has, therefore, been termed the Plasmodium thrombospondin-related apical merozoite protein (PTRAMP). PTRAMP co-localises with the Apical Merozoite Antigen-1 (AMA-1) in developing micronemes and subsequently relocates onto the merozoite surface. Although the gene appears to be specific to the Plasmodium genus, orthologues are present in the genomes of all malaria parasite species examined suggesting a conserved function in host-cell invasion. PTRAMP, therefore, has all the features to merit further evaluation as a malaria vaccine candidate.

Introduction The London Borough of Newham consistently has the highest incidence of tuberculosis (TB) in the UK (≈120/100,000), with case numbers continuing to rise. We sought to investigate social risk factors for TB as compared with the general population in this borough. Methods Of 242 adult patients diagnosed with TB in 2012 at the Newham Chest Clinic 170 (70.3%) completed a structured interview assessing for social risk factors. Demographic data was obtained from hospital records. TB case data was compared with 2011 census data using Fisher’s exact test or t-tests as appropriate. Results Data directly comparable to 2011 census data is summarised in Table 1. Cases had a mean of 3.43 (95% CI 3.07–3.8) household contacts, 2.28 (1.41–3.16) non-household family contacts and 2.02 (1.71–2.33) close friends. Household and family contacts were almost exclusively of the same ethnicity as the cases, but with 18.4% of household contacts and 49.2% of family contacts being UK born, compared with 7.7% of cases. The majority of friends were of the same ethnicity (86%) with 18.4% UK born, 89.4% of cases had no close friends from a different ethnic group. None of the cohort reported alcohol or drug abuse or had been in prison in the last 5 years, one was currently homeless. Fifteen (8.8%) reported recent visitors from abroad and 61 (38.9% of foreign born) reported returning to their country of birth for greater than three weeks, with 75.4% having returned within the last two years, a further eleven had travelled to a high incidence country in the last ten years, six of whom were UK born travelling to their parents’ country of birth. Conclusions In this high incidence area of an otherwise low incidence country TB is significantly more common in those of South-Asian birth and ethnicity. It is more common in young adults who have lived in the UK between two and five years and work in unskilled jobs or are unemployed. This picture is likely driven by TB reactivation in new immigrants accompanied by a lack of social mixing and suggesting the influence of relative poverty in the development of TB.

Multidrug-resistant (MDR) tuberculosis is a public health emergency and a challenging scenario for both patients and clinicians. In 2012, there were more than 450 000 incident cases and 170 000 deaths worldwide. Treatment of MDR tuberculosis is complex and expensive (€100 000 or more for drugs for one patient), especially its most severe, extensively drug-resistant forms. Treatment is long (at least 2 years), the drugs are toxic (specific expertise is needed to manage adverse reactions), and the outcomes are poor (with low success and high death rates). New drugs will soon be available that will probably shorten and simplify treatment for MDR tuberculosis and increase effectiveness, and public health strategies have been developed to prevent the occurrence of drug resistance. The traditional approach of national tuberculosis programmes, focused on tuberculosis control (ie, rapid diagnosis and early, effective treatment of newly detected infectious cases), which was advocated by the WHO Stop TB Strategy, will soon be replaced by the post-2015 strategy focused on the concept of tuberculosis elimination (ie, fewer than one new sputum smear-positive tuberculosis case per 1 million population). Whereas traditional contact tracing (eg, looking for the contacts of individuals with tuberculosis and MDR tuberculosis in progressive circles) recommends identification and treatment of latently infected individuals and additional tuberculosis cases, new approaches recommend genotypic identification of the causative strain, monitoring of the epidemic, and initiation of adequate measures to manage it. One such approach is mycobacterial interspersed repetitive-unit-variable-number tandem repeat (MIRU-VNTR) strain typing. In The Lancet Infectious Diseases, Laura F Anderson and colleagues report an assessment of transmission of MDR tuberculosis in the UK between 2004 and 2007, using the 24-loci MIRU-VNTR method together with epidemiological data collected through the national surveillance system and an ad-hoc cluster investigation questionnaire. The scope was to identify the relative frequency of MDR tuberculosis cases transmitted nationwide. 204 patients were diagnosed with MDR tuberculosis in the study period of whom 189 (92·6%) had an MIRU-VNTR profile. 15% of these cases were clustered. Furthermore, Anderson and colleagues analysed the risk factors associated with MDR tuberculosis transmission: being born in the UK (odds ratio 4·81; 95% CI 2·03—11·36, p=0·0005) and having a history of illicit drug use (4·75; 1·19—18·96, p=0·026) significantly increased the probability of transmission. Most cases (21 of 22) were transmitted in the household. The occurrence of MDR tuberculosis transmission in the UK is lower than in other European and non-European settings, probably as a consequence of scarce transmission occurring between specific population groups. The study is an excellent example of nationwide implementation of one of the European Centre for Disease Prevention and Control (ECDC) recommendations to eliminate tuberculosis in the European Union. Moreover, the identification of risk factors allows the prioritisation of the public health investigations, reducing the probability of transmission related to health-care system delay. The core strength of the study is the high proportion of MDR tuberculosis cases assessed with the novel diagnostic approach (ie, 24-loci MIRU-VNTR) and the ability to increase sensitivity compared with the traditional epidemiological investigations. However, other more sensitive techniques such as whole genome sequencing analysis could also have increased the ability to identify additional epidemiological links, which means that a potential underestimation of MDR tuberculosis transmission should be considered. Low culture confirmation (about 60% in the UK) could also have underestimated the true prevalence of transmission. Molecular methods have several public health applications, including identification of outbreaks, population groups at highest risk of transmission, transmission across jurisdictions, transmission chains, reinfected and relapsing cases, and laboratory cross-contamination. However, several technical problems currently hinder their integration into national tuberculosis programmes, including the absence of a gold standard to effectively assess their discriminatory power. The ECDC recommends monitoring and assessment of transmission of drug-susceptible and drug-resistant mycobacterial strains by adoption of sensitive and specific molecular methods. Molecular fingerprinting, alongside classic epidemiological studies, will be helpful to discriminate real clusters of tuberculosis cases (ie, individuals infected by the same genotypes) and to (indirectly) assess the efficacy of a tuberculosis control programme implemented at a national or regional level. If we are to make tuberculosis elimination a reality, this UK experience needs to be followed up in other European Union countries. The implementation of molecular methods with increased sensitivity allows the bypassing of low discriminatory power associated with traditional contact tracing procedures, scaling up part of the European Union's tuberculosis elimination package.