Interventions for improving adherence to treatment for latent tuberculosis infection: a systematic review.

BACKGROUND: Latent tuberculosis infection (LTBI) control relies on high initiation and completion rates of preventive treatment to preclude progression to tuberculosis disease. Specific interventions may improve initiation and completion rates. The objective was to systematically review data on determinants of initiation, adherence and completion of LTBI treatment, and on interventions to improve initiation and completion. METHODS: A systematic review of the literature (PubMed, Embase) published up to February 2014 was performed. Relevant prospective intervention studies were assessed using GRADE. RESULTS: Sixty-two articles reporting on determinants of treatment initiation and completion were included and 23 articles on interventions. Determinants of LTBI treatment completion include shorter treatment regimen and directly observed treatment (DOT, positive association), adverse events and alcohol use (negative association), and specific populations with LTBI (both positive and negative associations). A positive effect on completion was noted in intervention studies that used short regimens and social interventions; mixed results were found for intervention studies that used DOT or incentives. CONCLUSION: LTBI treatment completion can be improved by using shorter regimens and social interventions. Specific needs of the different populations with LTBI should be addressed taking into consideration the setting and condition in which the LTBI treatment programme is implemented.

Initiation and completion rates for latent tuberculosis infection treatment: a systematic review.

BACKGROUND: Control of latent tuberculosis infection (LTBI) is an important step towards tuberculosis elimination. Preventive treatment will prevent the development of disease in most cases diagnosed with LTBI. However, low initiation and completion rates affect the effectiveness of preventive treatment. The objective was to systematically review data on initiation rates and completion rates for LTBI treatment regimens in the general population and specific populations with LTBI. METHODS: A systematic review of the literature (PubMed, Embase) published up to February 2014 was performed. RESULTS: Forty-five studies on initiation rates and 83 studies on completion rates of LTBI treatment were found. These studies provided initiation rates (IR) and completion rates (CR) in people with LTBI among the general population (IR 26-99 %, CR 39-96 %), case contacts (IR 40-95 %, CR 48-82 %), healthcare workers (IR 47-98 %, CR 17-79 %), the homeless (IR 34-90 %, CR 23-71 %), people who inject drugs (IR 52-91 %, CR 38-89 %), HIV-infected individuals (IR 67-92 %, CR 55-95 %), inmates (IR 7-90 %, CR 4-100 %), immigrants (IR 23-97 %, CR 7-86 %), and patients with comorbidities (IR 82-93 %, CR 75-92 %). Generally, completion rates were higher for short than for long LTBI treatment regimens. CONCLUSION: Initiation and completion rates for LTBI treatment regimens were frequently suboptimal and varied greatly within and across different populations.

Identifying components for programmatic latent tuberculosis infection control in the European Union.

Individuals with latent tuberculosis infection (LTBI) are the reservoir of Mycobacterium tuberculosis in a population and as long as this reservoir exists, elimination of tuberculosis (TB) will not be feasible. In 2013, the European Centre for Disease Prevention and Control (ECDC) started an assessment of benefits and risks of introducing programmatic LTBI control, with the aim of providing guidance on how to incorporate LTBI control into national TB strategies in European Union/European Economic Area (EU/EEA) Member States and candidate countries. In a first step, experts from the Member States, candidate countries, and international and national organisations were consulted on the components of programmatic LTBI control that should be considered and evaluated in literature reviews, mathematical models and cost-effectiveness studies. This was done through a questionnaire and two interactive discussion rounds. The main components identified were identification and targeting of risk groups, determinants of LTBI and progression to active TB, optimal diagnostic tests for LTBI, effective preventive treatment regimens, and to explore the potential for combining LTBI control with other health programmes. Political commitment, a solid healthcare infrastructure, and favourable economic situation in specific countries were identified as essential to facilitate the implementation of programmatic LTBI control.

Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries.

Latent tuberculosis infection (LTBI) is characterised by the presence of immune responses to previously acquired Mycobacterium tuberculosis infection without clinical evidence of active tuberculosis (TB). Here we report evidence-based guidelines from the World Health Organization for a public health approach to the management of LTBI in high risk individuals in countries with high or middle upper income and TB incidence of <100 per 100 000 per year. The guidelines strongly recommend systematic testing and treatment of LTBI in people living with HIV, adult and child contacts of pulmonary TB cases, patients initiating anti-tumour necrosis factor treatment, patients receiving dialysis, patients preparing for organ or haematological transplantation, and patients with silicosis. In prisoners, healthcare workers, immigrants from high TB burden countries, homeless persons and illicit drug users, systematic testing and treatment of LTBI is conditionally recommended, according to TB epidemiology and resource availability. Either commercial interferon-gamma release assays or Mantoux tuberculin skin testing could be used to test for LTBI. Chest radiography should be performed before LTBI treatment to rule out active TB disease. Recommended treatment regimens for LTBI include: 6 or 9 month isoniazid; 12 week rifapentine plus isoniazid; 3-4 month isoniazid plus rifampicin; or 3-4 month rifampicin alone.

Tuberculosis control and economic recession: longitudinal study of data from 21 European countries, 1991-2012.

OBJECTIVE: To investigate whether the economic recession affected the control of tuberculosis in the European Union. METHODS: Multivariate regression models were used to quantify the association between gross domestic product, public health expenditure and tuberculosis case detection rates, using data from 21 European Union member states (1991-2012). The estimated changes in case detection attributable to the recession were combined with mathematical models of tuberculosis transmission, to project the potential influence of the recession on tuberculosis epidemiology until 2030. FINDINGS: Between 1991 and 2007, detection rates for sputum-smear-positive tuberculosis in the European Union were stable at approximately 85%. During the economic recession (2008-2011) detection rates declined by a mean of 5.22% (95% confidence interval, CI: 2.54-7.90) but treatment success rates showed no significant change (P = 0.62). A fall in economic output of 100 United States dollars per capita was associated with a 0.22% (95% CI: 0.05-0.39) mean reduction in the tuberculosis case detection rate. An equivalent fall in spending on public health services was associated with a 2.74% (95% CI: 0.31-5.16) mean reduction in the detection rate. Mathematical models suggest that the recession and consequent austerity policies will lead to increases in tuberculosis prevalence and tuberculosis-attributable mortality that are projected to persist for over a decade. CONCLUSION: Across the European Union, reductions in spending on public health services appear to have reduced tuberculosis case detection and to have increased the long-term risk of a resurgence in the disease.

Tuberculosis among migrant populations in the European Union and the European Economic Area.

BACKGROUND: Although tuberculosis (TB) incidence has been decreasing in the European Union/European Economic Area (EU/EEA) in the last decades, specific subgroups of the population, such as migrants, remain at high risk of TB. This study is based on the report 'Key Infectious Diseases in Migrant Populations in the EU/EEA' commissioned by The European Centre for Disease Prevention and Control. METHODS: We collected, critically appraised and summarized the available evidence on the TB burden in migrants in the EU/EEA. Data were collected through: (i) a comprehensive literature review; (ii) analysis of data from The European Surveillance System (TESSy) and (iii) evidence provided by TB experts during an infectious disease workshop in 2012. RESULTS: In 2010, of the 73,996 TB cases notified in the EU/EEA, 25% were of foreign origin. The overall decrease of TB cases observed in recent years has not been reflected in migrant populations. Foreign-born people with TB exhibit different socioeconomic and clinical characteristics than native sufferers. CONCLUSION: This is one of the first studies to use multiple data sources, including the largest available European database on infectious disease notifications, to assess the burden and provide a comprehensive description and analysis of specific TB features in migrants in the EU/EEA. Strengthened information about health determinants and factors for migrants' vulnerability is needed to plan, implement and evaluate targeted TB care and control interventions for migrants in the EU/EEA.

Emergence of hypervirulent mutants resistant to early clearance during systemic serotype 1 pneumococcal infection in mice and humans.

BACKGROUND: Streptococcus pneumoniae serotype 1 has a high likelihood of causing invasive disease. Serotype 1 isolates belonging to CC228 are associated with low mortality, while CC217 isolates exhibit high mortality in patients. METHODS: Clinical pneumococcal isolates and mutants were evaluated in wild-type C57BL/6 mice, macrophage-depleted mice, neutrophil-depleted mice, and SIGN-R1 knockout mice. In vitro models included binding and phagocytosis by THP-1 cells, capsule measurements, hydrogen peroxide production, and viability assays. RESULTS: During early systemic infection in mice with serotype 1, large-colony variants appeared in blood. Similar large colonies were found in blood specimens from patients with invasive disease. Large morphotypes contained higher numbers of viable bacteria, grew faster, produced no or little hydrogen peroxide, and contained mutations in the spxB gene. spxB mutants were considerably more virulent in wild-type mice, less susceptible to early host clearance than wild-type strains after intravenous infection, but impaired in colonization. spxB mutants were less efficiently phagocytosed by macrophages than wild-type bacteria, which, in contrast to spxB mutants, caused more-severe disease when macrophages or SIGN-R1 were depleted. CONCLUSIONS: Hypervirulent spxB mutants are selected in both mice and patients and are resistant to early macrophage-mediated clearance.

Intraclonal variations among Streptococcus pneumoniae isolates influence the likelihood of invasive disease in children.

BACKGROUND: Pneumococcal serotypes are represented by a varying number of clonal lineages with different genetic contents, potentially affecting invasiveness. However, genetic variation within the same genetic lineage may be larger than anticipated. METHODS: A total of 715 invasive and carriage isolates from children in the same region and during the same period were compared using pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing. Bacterial genome sequencing, functional assays, and in vivo virulence mice studies were performed. RESULTS: Clonal types of the same serotype but also intraclonal variants within clonal complexes (CCs) showed differences in invasive-disease potential. CC138, a common CC, was divided into several PFGE patterns, partly explained by number, location, and type of temperate bacteriophages. Whole-genome sequencing of 4 CC138 isolates representing PFGE clones with different invasive-disease potentials revealed intraclonal sequence variations of the virulence-associated proteins pneumococcal surface protein A (PspA) and pneumococcal choline-binding protein C (PspC). A carrier isolate lacking PcpA exhibited decreased virulence in mice, and there was a differential binding of human factor H, depending on invasiveness. CONCLUSIONS: Pneumococcal clonal types but also intraclonal variants exhibited different invasive-disease potentials in children. Intraclonal variants, reflecting different prophage contents, showed differences in major surface antigens. This suggests ongoing immune selection, such as that due to PspC-mediated complement resistance through varied human factor H binding, that may affect invasiveness in children.

Tuberculosis transmission between foreign- and native-born populations in the EU/EEA: a systematic review.

Tuberculosis (TB) control programmes of many low TB incidence countries of the European Union/European Economic Area (EU/EEA) perceive challenges in controlling TB due to high numbers of TB in migrants from high-incidence countries. To assess the extent of TB transmission from the foreign-born to the native-born population, we quantitatively investigated the dynamics of TB transmission between these populations in the EU/EEA, using published molecular epidemiological studies. We searched PubMed and EMBASE databases from 1990 to August 2012. We identified 15 studies performed during 1992-2007 covering 12,366 cases, of which median (range) 49.2% (17.7%-86.4%) were foreign-born. The proportion of clustered isolates ranged between 8.5% and 49.1% of the total number of TB cases genotyped and among these, foreign-born cases were equally or more likely to have unique isolates compared to native-born cases. One third of the clusters were "mixed", i.e. composed of foreign- and native-born cases, involving 0-34.2% of all genotyped cases. Cross-transmission among foreign and native populations was bidirectional, with wide differences across studies. This systematic review provides evidence that TB in a foreign-born population does not have a significant influence on TB in the native population in EU/EEA.

Management of patients with multidrug-resistant/extensively drug-resistant tuberculosis in Europe: a TBNET consensus statement.

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) substantially challenges TB control, especially in the European Region of the World Health Organization, where the highest prevalence of MDR/XDR cases is reported. The current management of patients with MDR/XDR-TB is extremely complex for medical, social and public health systems. The treatment with currently available anti-TB therapies to achieve relapse-free cure is long and undermined by a high frequency of adverse drug events, suboptimal treatment adherence, high costs and low treatment success rates. Availability of optimal management for patients with MDR/XDR-TB is limited even in the European Region. In the absence of a preventive vaccine, more effective diagnostic tools and novel therapeutic interventions the control of MDR/XDR-TB will be extremely difficult. Despite recent scientific advances in MDR/XDR-TB care, decisions for the management of patients with MDR/XDR-TB and their contacts often rely on expert opinions, rather than on clinical evidence. This document summarises the current knowledge on the prevention, diagnosis and treatment of adults and children with MDR/XDR-TB and their contacts, and provides expert consensus recommendations on questions where scientific evidence is still lacking.

Polymorphisms in the gene that encodes the iron transport protein ferroportin 1 influence susceptibility to tuberculosis.

BACKGROUND: We studied the association between iron intake and polymorphisms in the iron transporter gene SLC40A1 and the risk of tuberculosis. METHODS: We compared iron intake, the frequency of SLC40A1 mutations, and interactions among these variables among 98 tuberculosis patients and 125 controls in Kwazulu-Natal, South Africa. RESULTS: Four SLC40A1 single-nucleotide polymorphisms (SNPs) were associated with an increased risk of tuberculosis and 1 SNP with reduced risk. We also found a gene-environment interaction for 4 nonexonic SNPs and iron intake. CONCLUSIONS: This pilot study demonstrated an association between polymorphisms in SLC40A1 and tuberculosis and provided evidence of an interaction between dietary iron and SLC40A1.

Social determinants of tuberculosis in Europe: a prospective ecological study.

Tuberculosis (TB) is considered to be a disease of poverty, since its incidence is exacerbated by socioeconomic factors, inconsistent or partial treatment practices, and immigration from endemic countries. A prospective country level study, using a comprehensive dataset of TB incidence and prevalence taken from countries within the World Health Organization (WHO) European region, was conducted. We employed quintile regression to investigate the prospective association between baseline (measured in 2000) and a nation's wealth, level of egalitarianism, migration rate, health-related lifestyle and social capital with TB incidence and prevalence over a 10-yr period (2000-2009). We found that ∼50% of TB variation is accounted for by a nation's wealth and level of egalitarianism. We observed a negative prospective association between logged gross domestic product and TB rates, and a positive prospective association between income inequality and TB. National income levels per capita and income inequality are important predictors for TB incidence and prevalence in the WHO European region. They account for 50% of country-level variation, indicating the importance of a combined absolute and relative socioeconomic disadvantage in the development of TB. These findings also provide a tool for forecasting potential fluctuations in the level of TB epidemics in the WHO European region, with respect to socioeconomic changes.

Childhood tuberculosis: progress requires an advocacy strategy now.

Childhood tuberculosis (TB) is a preventable and curable infectious disease that remains overlooked by public health authorities, health policy makers and TB control programmes. Childhood TB contributes significantly to the burden of disease and represents the failure to control transmission in the community. Furthermore, the pool of infected children constitutes a reservoir of infection for the future burden of TB. It is time to prioritise childhood TB, advocate for addressing the challenges and grasp the opportunities in its prevention and control. Herein, we propose a scientifically informed advocacy agenda developed at the International Childhood TB meeting held in Stockholm, Sweden, from March 17 to 18, 2011, which calls for a renewed effort to improve the situation for children affected by Mycobacterium tuberculosis exposure, infection or disease. The challenges and needs in childhood TB are universal and apply to all settings and must be addressed more effectively by all stakeholders.

Minimum package for cross-border TB control and care in the WHO European region: a Wolfheze consensus statement.

The World Health Organization (WHO) European region estimates that more than 400,000 tuberculosis (TB) cases occur in Europe, a large proportion of them among migrants. A coordinated public health mechanism to guarantee TB prevention, diagnosis, treatment and care across borders is not in place. A consensus paper describing the minimum package of cross-border TB control and care was prepared by a task force following a literature review, and with input from the national TB control programme managers of the WHO European region and the Wolfheze 2011 conference. A literature review focused on the subject of TB in migrants was carried out, selecting documents published during the 11-yr period 2001-2011. Several issues were identified in cross-border TB control and care, varying from the limited access to early TB diagnosis, to the lack of continuity of care and information during migration, and the availability of, and access to, health services in the new country. The recommended minimum package addresses the current shortcomings and intends to improve the situation by covering several areas: political commitment (including the implementation of a legal framework for TB cross-border collaboration), financial mechanisms and adequate health service delivery (prevention, infection control, contact management, diagnosis and treatment, and psychosocial support).

Role of ferroportin in macrophage-mediated immunity.

Perturbations in iron metabolism have been shown to dramatically impact host response to infection. The most common inherited iron overload disorder results from defects in the HFE gene product, a major histocompatibility complex class I-like protein that interacts with transferrin receptors. HFE-associated hemochromatosis is characterized by abnormally high levels of the iron efflux protein ferroportin. In this study, J774 murine macrophages overexpressing ferroportin were used to investigate the influence of iron metabolism on the release of nitric oxide (NO) in response to infection. Overexpression of ferroportin significantly impaired intracellular Mycobacterium tuberculosis growth during early stages of infection. When challenged with lipopolysaccharide (LPS) or M. tuberculosis infection, control macrophages increased NO synthesis, but macrophages overexpressing ferroportin had significantly impaired NO production in response to LPS or M. tuberculosis. Increased NO synthesis in control cells was accompanied by increased iNOS mRNA and protein, while upregulation of iNOS protein was markedly reduced when J744 cells overexpressing ferroportin were challenged with LPS or M. tuberculosis, thus limiting the bactericidal activity of these macrophages. The proinflammatory cytokine gamma interferon reversed the inhibitory effect of ferroportin overexpression on NO production. These results suggest a novel role for ferroportin in attenuating macrophage-mediated immune responses.

Effectiveness of service models and organisational structures supporting tuberculosis identification and management in hard-to-reach populations in countries of low and medium tuberculosis incidence: a systematic review.

OBJECTIVE: To determine which service models and organisational structures are effective and cost-effective for delivering tuberculosis (TB) services to hard-to-reach populations. DESIGN: Embase and MEDLINE (1990-2017) were searched in order to update and extend the 2011 systematic review commissioned by National Institute for Health and Care Excellence (NICE), discussing interventions targeting service models and organisational structures for the identification and management of TB in hard-to-reach populations. The NICE and Cochrane Collaboration standards were followed. SETTING: European Union, European Economic Area, European Union candidate countries and Organisation for Economic Co-operation and Development countries. PARTICIPANTS: Hard-to-reach populations, including migrants, homeless people, drug users, prisoners, sex workers, people living with HIV and children within vulnerable and hard-to-reach populations. PRIMARY AND SECONDARY OUTCOME MEASURES: Effectiveness and cost-effectiveness of the interventions. RESULTS: From the 19 720 citations found, five new studies were identified, in addition to the six discussed in the NICE review. Community health workers from the same migrant community, street teams and peers improved TB screening uptake by providing health education, promoting TB screening and organising contact tracing. Mobile TB clinics, specialised TB clinics and improved cooperation between healthcare services can be effective at identifying and treating active TB cases and are likely to be cost-effective. No difference in treatment outcome was detected when directly observed therapy was delivered at a health clinic or at a convenient location in the community. CONCLUSIONS: Although evidence is limited due to the lack of high-quality studies, interventions using peers and community health workers, mobile TB services, specialised TB clinics and improved cooperation between health services can be effective to control TB in hard-to-reach populations. Future studies should evaluate the (cost-)effectiveness of interventions on TB identification and management in hard-to-reach populations and countries should be urged to publish the outcomes of their TB control systems. PROSPERO REGISTRATION NUMBER: CRD42015017865.

Molecular and clinical characteristics of invasive group A streptococcal infection in Sweden.

BACKGROUND: The incidence and severity of invasive group A streptococcal infection demonstrate great variability over time, which at least, in part, seems to be related to group A streptococcal type distribution among the human population. METHODS: An enhanced surveillance study of invasive group A streptococcal infection (746 isolates) was performed in Sweden from April 2002 through December 2004. Noninvasive isolates from either the throat or skin (773 isolates) were collected in parallel for comparison. Clinical and epidemiological data were obtained from 88% of patients with invasive disease and were related to isolate characteristics, including T type, emm sequence type, and the presence of 9 superantigen genes, as well as pulsed-field gel electrophoresis pattern comparisons of selected isolates. RESULTS: The annual incidence was 3.0 cases per 100,000 population. Among the patients with invasive disease, 11% developed streptococcal toxic shock syndrome, and 9.5% developed necrotizing fasciitis. The overall case-fatality rate was 14.5%, and 39% of the patients with streptococcal toxic shock syndrome died (P<.001). The T3/13/B3264 cluster accounted for 33% of invasive and 25% of noninvasive isolates. Among this most prevalent type cluster, emm types 89 and 81 dominated. Combined results from pulsed-field gel electrophoresis, emm typing, and superantigen gene profiling identified subgroups within specific emm types that are significantly more prone to cause invasive disease than were other isolates of the same type. CONCLUSIONS: This study revealed a changing epidemiology of invasive group A streptococcal infection in Sweden, with emergence of new emm types that were previously not described. The results also suggest that some clones may be particularly prone to cause invasive disease.