Prevalence of inappropriate tuberculosis treatment regimens: a systematic review.

A potential threat to the success of new tuberculosis (TB) drugs is the development of resistance. Using drugs in appropriate regimens, such as those recommended in the World Health Organization (WHO) treatment guidelines, prevents the development of resistance. We performed a systematic review to assess the prevalence of inappropriate prescription of TB drugs for the treatment of TB. MEDLINE, EMBASE and other databases were searched for relevant articles in January 2011. Observational studies published from 2000 that included TB patients receiving treatment were selected. A treatment regimen was considered inappropriate if the regimen was not a WHO recommended regimen. 37 studies were included. Inappropriate treatment regimens were prescribed in 67% of studies. The percentage of patients receiving inappropriate regimens varied between 0.4% and 100%. In 19 studies the quality of treatment regimen reporting was low. Despite the fact that assessment of inappropriate treatment was hampered by low quality of reporting, our data indicate a reasonable amount of inappropriate prescription of TB treatment regimens. Thus, there is a risk that new drugs will be used in inappropriate treatment regimens, even with WHO guidelines in place, introducing the risk of resistance development. This article highlights the need to improve implementation of the WHO treatment of TB guidelines.

TB and MDR/XDR-TB in European Union and European Economic Area countries: managed or mismanaged?

In spite of the growing awareness of emerging drug-resistant Mycobacterium tuberculosis, the extent of inappropriate tuberculosis (TB) case management may be underestimated, even in Europe. We evaluated TB case management in the European Union/European Economic Area countries, with special focus on multidrug-resistant (MDR) and extensively drug-resistant (XDR)-TB, using a purposely developed, standardised survey tool. National reference centres in five countries representing different geographical, socioeconomic and epidemiological patterns of TB in Europe were surveyed. 40 consecutive, original clinical TB case records (30 MDR/XDR-TB cases) were reviewed in each of the five countries. The findings were recorded and, through the survey tool, compared with previously agreed and identified international standards. Deviations from international standards of TB care were observed in the following areas: surveillance (no information available on patient outcomes); infection control (lack of respiratory isolation rooms/procedures and negative-pressure ventilation rooms); clinical management of TB, MDR-TB and HIV co-infection (inadequate bacteriological diagnosis, regimen selection and treatment duration); laboratory support; and diagnostic/treatment algorithms. Gaps between present international standards of care and the management of MDR/XDR-TB patients were identified. Training, increased awareness, promotion of standards and allocation of appropriate resources are necessary to ensure appropriate care and management as well as to prevent further emergence of drug resistance.

European union standards for tuberculosis care.

The European Centre for Disease Prevention and Control (ECDC) and the European Respiratory Society (ERS) jointly developed European Union Standards for Tuberculosis Care (ESTC) aimed at providing European Union (EU)-tailored standards for the diagnosis, treatment and prevention of tuberculosis (TB). The International Standards for TB Care (ISTC) were developed in the global context and are not always adapted to the EU setting and practices. The majority of EU countries have the resources and capacity to implement higher standards to further secure quality TB diagnosis, treatment and prevention. On this basis, the ESTC were developed as standards specifically tailored to the EU setting. A panel of 30 international experts, led by a writing group and the ERS and ECDC, identified and developed the 21 ESTC in the areas of diagnosis, treatment, HIV and comorbid conditions, and public health and prevention. The ISTCs formed the basis for the 21 standards, upon which additional EU adaptations and supplements were developed. These patient-centred standards are targeted to clinicians and public health workers, providing an easy-to-use resource, guiding through all required activities to ensure optimal diagnosis, treatment and prevention of TB. These will support EU health programmes to identify and develop optimal procedures for TB care, control and elimination.

Interferon-γ release assays for the diagnosis of active tuberculosis: a systematic review and meta-analysis.

Interferon-γ release assays (IGRAs) are now established for the immunodiagnosis of latent infection with Mycobacterium tuberculosis in many countries. However, the role of IGRAs for the diagnosis of active tuberculosis (TB) remains unclear. Following preferred reporting items for systematic reviews and meta-analyses (PRISMA) and quality assessment of diagnostic accuracy studies (QUADAS) guidelines, we searched PubMed, EMBASE and Cochrane databases to identify studies published in January 2001-November 2009 that evaluated the evidence of using QuantiFERON-TB® Gold in-tube (QFT-G-IT) and T-SPOT.TB® directly on blood or extrasanguinous specimens for the diagnosis of active TB. The literature search yielded 844 studies and 27 met the inclusion criteria. In blood and extrasanguinous fluids, the pooled sensitivity for the diagnosis of active TB was 80% (95% CI 75-84%) and 48% (95% CI 39-58%) for QFT-G-IT, and 81% (95% CI 78-84%) and 88% (confirmed and unconfirmed cases) (95% CI 82-92%) for T-SPOT.TB®, respectively. In blood and extrasanguinous fluids, the pooled specificity was 79% (95% CI 75-82%) and 82% (95% CI 70-91%) for QFT-G-IT, and 59% (95% CI 56-62%) and 82% (95% CI 78-86%) for T-SPOT.TB®, respectively. Although the diagnostic sensitivities of both IGRAs were higher than that of tuberculin skin tests, it was still not high enough to use as a rule out test for TB. Positive evidence for the use of IGRAs in compartments other than blood will require more independent and carefully designed prospective studies.

Tuberculosis and HIV co-infection in European Union and European Economic Area countries.

In order to ensure the availability of resources for tuberculosis (TB) and HIV management and control, it is imperative that countries monitor and plan for co-infection in order to identify, treat and prevent TB-HIV co-infection, thereby reducing TB burden and increasing the years of healthy life of people living with HIV. A systematic review was undertaken to determine the burden of TB-HIV infection in the European Union (EU) and European Economic Area (EEA). Data on the burden of HIV infection in TB patients and risk factors for TB-HIV co-infection in the EU/EEA were extracted from studies that collected information in 1996 and later, regardless of the year of initiation of data collection, and a narrative synthesis presented. The proportion of HIV-co-infected TB patients varied from 0 to 15%. Western and eastern countries had higher levels and increasing trends of infection over time compared with central EU/EEA countries. Groups at higher risk of TB-HIV co-infection were males, young adults, foreign-born persons, the homeless, injecting drug users and prisoners. Further research is needed into the burden and associated risk factors of co-infection in Europe, to help plan effective control measures. Increased HIV testing of TB patients and targeted and informed strategies for control and prevention could help curb the co-infection epidemic.

The burden of TB-HIV in the EU: how much do we know? A survey of surveillance practices and results.

Information on the burden of tuberculosis (TB)-HIV co-infection is critical for the planning and evaluation of TB-HIV control and treatment strategies. This study assessed current practices in countries of the European Union (EU) and European Economic Area (EEA) for monitoring HIV co-infection in TB surveillance systems, countries' current co-infection burden and associated clinical practice. An online survey was distributed to all national TB surveillance nominated European Centre for Disease Prevention and Control contact points in the EU/EEA. We received 25 responses from 30 countries (83% response rate). Patients' HIV status was collected in 18 out of the 25 TB surveillance systems, usually via clinician reporting (16 out of 18 surveillance systems). Although most countries recommended routine testing of TB patients for HIV, the proportion actually tested varied from 5% to 90%. The burden of HIV co-infection was found to be elevated in countries with higher levels of HIV testing and higher prevalence of HIV. We suggest that TB-HIV co-infection be monitored in all EU/EEA countries to facilitate the planning and evaluation of TB-HIV control strategies. Strengthening collaboration between TB and HIV clinicians and surveillance departments, and consideration of patient confidentiality restraints would be advantageous. The level of HIV testing in TB patients is low despite national recommendations and testing should be further promoted and monitored.

Interferon-γ release assays for the diagnosis of latent Mycobacterium tuberculosis infection: a systematic review and meta-analysis.

We conducted a systematic review and meta-analysis to compare the accuracy of the QuantiFERON-TB® Gold In-Tube (QFT-G-IT) and the T-SPOT®.TB assays with the tuberculin skin test (TST) for the diagnosis of latent Mycobacterium tuberculosis infection (LTBI). The Medline, Embase and Cochrane databases were explored for relevant articles in November 2009. Specificities, and negative (NPV) and positive (PPV) predictive values of interferon-γ release assays (IGRAs) and the TST, and the exposure gradient influences on test results among bacille Calmette-Guérin (BCG) vaccinees were evaluated. Specificity of IGRAs varied 98-100%. In immunocompetent adults, NPV for progression to tuberculosis within 2 yrs were 97.8% for T-SPOT®.TB and 99.8% for QFT-G-IT. When test performance of an immunodiagnostic test was not restricted to prior positivity of another test, progression rates to tuberculosis among IGRA-positive individuals followed for 19-24 months varied 8-15%, exceeding those reported for the TST (2-3%). In multivariate analyses, the odd ratios for TST positivity following BCG vaccination varied 3-25, whereas IGRA results remained uninfluenced and IGRA positivity was clearly associated with exposure to contagious tuberculosis cases. IGRAs may have a relative advantage over the TST in detecting LTBI and allow the exclusion of M. tuberculosis infection with higher reliability.

Childhood tuberculosis in the European Union/European Economic Area, 2000 to 2009.

Childhood tuberculosis (TB) has been neglected for decades as a key component of TB control. However, ensuring proper monitoring of childhood TB has recently been given renewed emphasis. A descriptive analysis of surveillance data was performed to assess burden and trends of paediatric TB in the European Union/European Economic Area (EU/EEA) between 2000 and 2009. From 2000 to 2009, 39,695 notified paediatric (defined as 0­14 years of age) TB cases were reported by the 27 EU countries plus Norway, Iceland and Liechtenstein. These paediatric cases accounted for 4.3% of all notified cases. However, across the EU/EEA Member States, paediatric case notification rates ranged from 29.6 per 100,000 to 0.3 per 100,000 for the latest reporting year, 2009. Overall,though, these rates dropped from 5.5 per 100,000 in 2000 to 4.2 per 100,000 in 2009. The EU/EEA average annual percent changes (AAPC) in paediatric notification rates decreased between 2000 and 2004 by 1.3%and between 2005 and 2009 by 2.4%, with an overall decrease between 2000 and 2009 of 2.8%. Of all paediatric cases reported from 2000 to 2009, only 16.9%were culture-confirmed, amongst which the overall treatment success was 80.5% for all culture-confirmed pulmonary paediatric TB cases. Childhood TB in the EU/EEA remains a public health issue. Due attention should be paid to assessing paediatric trends as they could provide an insight in recent transmission. Whilst the primary aim of further reducing TB rates among children is paramount, better rates of appropriate diagnosis should also be achieved, along with a further improvement of therapeutic success rates.

Evaluation of a lateral-flow nanoparticle fluorescence assay for TB infection diagnosis.

BACKGROUND: Programmatic management of TB infection is a critical component of the WHO End TB Strategy. Interferon-gamma release assays (IGRAs) overcome some limitations of the tuberculin skin test, but implementation of IGRA testing in low-resource settings is challenging.METHODS: In this feasibility study, we evaluated performance of a novel digital lateral-flow assay, the QIAreach® QuantiFERON® TB (QIAreach-QFT) test, against the QuantiFERON®-TB Gold Plus (QFT-Plus) assay. A population with a mix of risk factors for TB infection (111 donors) were sampled over multiple days. A total of 207 individual blood samples were tested according to the manufacturer´s instructions.RESULTS: The overall percentage agreement was 95.6% (two-sided 95% CI 91.8-98), with a positive percentage agreement (i.e., sensitivity) of 100% (95% CI 94.7-100) and a negative percentage agreement (i.e., specificity) of 95.6% (95% CI 90.6-98.4). All QFT-Plus positive specimens with TB1-Nil and TB2-Nil values less than 1 IU/ml tested positive on QIAreach-QFT.CONCLUSIONS: QIAreach QFT is a deployable, accurate testing solution for decentralised testing. It has the potential to overcome key hurdles for TB infection screening in high-burden settings thus helping to achieve the WHO End TB programme goals.

Analysis of tuberculosis treatment outcomes in the European Union and European Economic Area: efforts needed towards optimal case management and control.

An analysis of surveillance data was performed to assess treatment outcomes of patients belonging to selected calendar year cohorts. Twenty-two countries in the European Union (EU) and European Economic Area (EEA) reported treatment outcome monitoring data for culture-confirmed pulmonary tuberculosis (TB) cases reported in 2007. The overall treatment success rate was 73.8% for all culture-confirmed pulmonary cases and 79.5% for new culture-confirmed pulmonary cases. For the cohort of new culture-confirmed TB cases, only three countries achieved the target of 85% success rate. This underachievement appears to be a result of relative high defaulting and unknown outcome information. Case fatality remains high particularly among cases of national origin. This factor appears attributable to advanced age of the national cohort. Treatment outcomes for multidrug-resistant tuberculosis were reported by 15 countries, with a range of 19.8% to 100% treatment success at 24 months. The data underline the urgent need for strengthening treatment outcome monitoring in the EU and EEA in order to ensure an effective programme implementation and case management that will ultimately contribute to TB elimination.

Surveillance of extensively drug-resistant tuberculosis in Europe, 2003-2007.

This paper describes the results of second-line drug (SLD) susceptibility tests among multidrug-resistant tuberculosis (MDR TB) cases reported in 20 European countries aiming to identify extensively drug-resistant tuberculosis (XDR TB) cases. A project on molecular surveillance of MDR TB cases was conducted by EuroTB and the National Institute for Public Health and the Environment (RIVM) from 2005 to 2007. Information on drug susceptibility testing (DST) was provided to this project and case-based data on MDR TB cases were reported on a quarterly basis by 20 countries of the World Health Organization s European Region, including 15 European Union Member States. Data included SLD susceptibility test results, enabling a retrospective description of XDR TB cases notified between 2003 and 2007 .In 18 countries DST was performed for two or more of the SLD included in the XDR TB definition. The proportion of MDR TB isolates tested for SLD varied widely between countries (range 20 to 100 percent). In the 18 countries, 149 (10%) XDR TB cases were reported among MDR TB cases with available DST results for SLD. Sixteen additional MDR TB cases were reported by the MDR TB surveillance system when compared with the number of routinely reported MDR TB cases to EuroTB in ten countries with representative data reported during three consecutive years (2003-2005). To counter the threat of XDR TB in Europe, a standardised approach to XDR TB surveillance and DST for SLD is needed, as well as increased laboratory capacity across European countries.

Multidrug- and extensively drug-resistant tuberculosis: a persistent problem in the European Union European Union and European Economic Area.

Since 2008, the European Centre for Disease Prevention and Control has been collecting data from the European Union (EU) and European Economic Area (EEA) on resistance to first- and second-line drugs against tuberculosis (TB). In 2008, the proportion of multidrug-resistant tuberculosis (MDR TB) was 6.0% of the total case load for 25 countries reporting data. Extensively drug-resistant (XDR TB) reporting has increased since 2007 and was observed in 7.3% of the MDR TB cases in 13 reporting countries. MDR TB remains a threat and XDR TB is now established within the EU/EEA borders.

[Berlin Declaration on Tuberculosis: High Level Follow-Up of High Priority Countries for TB Control in the WHO-EURO Region 'Double Trouble or Double Success? Bringing Together Diseases and Programs' - a symposium report]. / Berlin Declaration on Tuberculosis: High Level Follow-Up of High Priority Countries for TB Control in the WHO-EURO Region 'Double Trouble or Double Success? Bringing Together Diseases and Programs' - ein Symposiumsbericht.

The global tuberculosis (TB) situation has deteriorated dramatically since the beginning of the 1990s. In 2007, the WHO identified 18 countries of the WHO European Region as 'high priority countries' and introduced a plan for these countries to improve the situation. To further promote solutions a WHO European Ministerial Forum 'All against Tuberculosis' took place in Berlin in 2007 and resulted in the 'Berlin Declaration' which was commonly endorsed. In October 2009 a meeting was organized by the German Ministry of Health under the title "Berlin Declaration on Tuberculosis: High Level Follow-Up of High Priority Countries for TB Control in the WHO-EURO Region 'Double Trouble or Double Success? Bringing together Diseases and Programs'". This article summarizes the symposium. Besides reporting on the recent epidemiological situation of the WHO-EURO Region (with partly dramatically developments) presentations on psychosocial issues, the role of the EU and the 'Global Fund to Fight AIDS, Tuberculosis and Malaria', the importance of new tools for the fight against tuberculosis and the need for further political commitment were given.

Migrant tuberculosis screening in the EU/EEA: yield, coverage and limitations.

A systematic literature review was performed with the objective of assessing the effectiveness of tuberculosis (TB) screening methods and strategies in migrants in European Union/European Economic Area (including Switzerland) countries. Extracted data on yield and coverage were used as indicators of effectiveness. Reported yields varied considerably between studies and countries. Considering only the 14 studies representative of national screening programmes, a median yield of TB disease of 0.18% (interquartile range 0.10-0.35%) was reported. The data did not indicate differences in effectiveness between the three main strategies: 1) screening at port of entry; 2) screening just after arrival in reception/holding centres; and 3) screening in the community following arrival in European Union countries. The variation seen probably reflects variation in risk factors for TB, in particular the composition of the migrants entering the country. Recommendations include the need for improved data for guiding the optimal frequency and duration of screening; assessment and improvement of cost-effectiveness; access to healthcare for migrants, including illegal migrants; ensuring a continuum of care for those screened; and consideration of screening for latent TB infection with caution. Finally, screening should be a component of a wider approach, rather than a stand-alone intervention.

Effectiveness of tuberculosis contact tracing among migrants and the foreign-born population.

A literature review was performed to assess the effectiveness of tuberculosis (TB) contact tracing among migrants and the foreign-born population with emphasis on the European Union. Effectiveness of contact tracing was assessed using the following indicators: coverage, proportion of contacts with TB (TB yield), proportion of contacts with latent tuberculosis infection (LTBI yield) and number of investigated contacts per index case (contacts/index case ratio). The key findings from the literature review were: Among foreign-born contacts, a higher median LTBI yield was found compared with contacts born in the country, when exposed to the same foreign-born index cases. No clear differences were observed between TB and LTBI yield among contacts of foreign-born index cases compared with contacts of index cases from the general population (including the foreign-born) due to the large variation seen between the studies. The included non-European studies screened more contacts per foreign-born index case, used lower cut-off values to define a positive tuberculosis skin test and found higher LTBI yields among contacts. Although the high heterogeneity across the studies made the comparison challenging, several conclusions are made regarding contact tracing among migrants.

Tuberculosis in the EU and EEA/EFTA countries: what is the latest data telling us?

Since 1 January 2008, the European Centre for Disease Prevention and Control (ECDC) and the World Health Organization Regional Office for Europe (WHO/Europe) jointly coordinate the tuberculosis (TB) surveillance activities in Europe. The data collected provides an opportunity for a comprehensive analysis of the TB situation. We aimed at analysing the EU and EEA/EFTA data to identify general TB trends and to provoke some discussion regarding the challenges and needs for monitoring the epidemic.

Measuring tuberculosis burden, trends, and the impact of control programmes.

The targets for tuberculosis control, framed within the United Nations' Millennium Development Goals, are to ensure that the incidence per head of tuberculosis is falling by 2015, and that the 1990 prevalence and mortality per head are halved by 2015. In monitoring progress in tuberculosis control, the ultimate aim for all countries is to count tuberculosis cases (incidence) accurately through routine surveillance. Disease prevalence surveys are costly and laborious, but give unbiased measures of tuberculosis burden and trends, and are justified in high-burden countries where many cases and deaths are missed by surveillance systems. Most countries in which tuberculosis is highly endemic do not yet have reliable death registration systems. Verbal autopsy, used in cause-of-death surveys, is an alternative, interim method of assessing tuberculosis mortality, but needs further validation. Although several new assays for Mycobacterium tuberculosis infection have recently been devised, the tuberculin skin test remains the only practical method of measuring infection in populations. However, this test typically has low specificity and is therefore best used comparatively to assess geographical and temporal variation in risk of infection. By 2015, every country should be able to assess progress in tuberculosis control by estimating the time trend in incidence, and the magnitude of reductions in either prevalence or deaths.

Annual risk of tuberculosis infection in West Sumatra Province, Indonesia.

OBJECTIVE: To estimate the annual risk of tuberculosis infection (ARTI) among children attending elementary school Classes I-III in West Sumatra Province, Indonesia. METHODS: The survey was designed to estimate ARTI among children, irrespective of BCG scar status. Fieldwork was carried out in 72 schools selected by two-stage sampling. Children were administered 2 TU of purified protein derivative RT23 with Tween 80 intradermally on the mid-anterior aspect of the left forearm. The maximum transverse diameter of induration was measured at about 72 h. Analysis was carried out among 5653 satisfactorily test-read children aged 6-9 years. RESULTS: The estimation by mirror-image method among all children (without and with BCG scar) revealed an ARTI of between 1% and 1.3%. The estimated ARTIs among children without and with BCG scar varied between 0.8-1.3% and 0.9-1.4%, respectively, using the mirror-image method, anti-mode method and mixture model. CONCLUSION: Tuberculosis control efforts need to be intensified to reduce the risk of transmission of infection.

The added value of a European Union tuberculosis reference laboratory network--analysis of the national reference laboratory activities.

National reference laboratories (NRL) and other laboratories are the cornerstones of well-functioning tuberculosis programmes and surveillance activities. However, the scope and activity of NRL services for mycobacterial identification and drug susceptibility testing (DST) has not been examined in detail across the European Union (EU), nor has the added value of cooperation and networking at the European level been explored with regard to strengthening laboratory services. Therefore, the European Centre for Disease Prevention and Control (ECDC) has commissioned a survey to explore these issues and to identify areas of work that could bring added value by supporting networking activities of tuberculosis (TB) reference laboratories in the EU. Structured questionnaires were sent to TB reference laboratory experts in the EU and European Economic Area (EEA) countries, and in three additional countries selected on the basis of their networking activities with EU projects and other initiatives (Switzerland, Croatia and Israel). The compiled results describe the activities and structure of 32 NRLs (29 countries replied, a response rate of 91%). The analysis of the survey led to the following recommendations for strengthening TB laboratory services: (1) implementing of the published European standards for TB laboratory services with respect to infrastructure, national reference functions, biosafety, human resources, quality assurance, operational research (including evaluation of new medical diagnostics), accuracy and speed, appropriately trained staff; (2) ensuring that laboratories only perform activities for which they have demonstrated proficiency; (3) implement validated and standardised second-line drug susceptibility testing (DST), including drugs used to define extensively drug-resistant tuberculosis (XDR TB); (4) aiming to identify Mycobacterium tuberculosis complex (MTBC) and rifampicin (RIF) resistance in over 90% of cultures and cases from smear-positive sputum directly within one to two working days. To realise some of the above recommendations and to strengthen links of TB surveillance and microbiology activities in the EU, a list of suggested generic areas of activities for an EU network of reference laboratories is presented. Such a network would build on and link to existing networks and initiatives at the European and global level.

Managing latent tuberculosis infection and tuberculosis in children.

Tuberculosis (TB) is a major cause of childhood morbidity and mortality worldwide. The aim of this review is to describe the management of the child with TB and latent tuberculosis infection (LTBI). To develop this article, a working group reviewed relevant epidemiological and other scientific studies and established practices in conducting LBTI and TB in children. The article describes how to manage the child with LTBI, considering transmission and infectiousness of tuberculosis, contact screening and prioritization of contacts and recommendations on treatment of children with LTBI and how to manage the child with TB considering the susceptibility of children to developing tuberculosis, epidemiology and classification of tuberculosis in children, diagnosis and treatment.