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.

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.

Migration, TB control and elimination: Whom to screen and treat.

Tuberculosis (TB) in migrants represents an important clinical and public health threat, particularly in low TB incidence countries. The current review is aimed to assess issues related to screening and treatment of migrants with latent TB infection or TB disease.

Lack of evidence to support policy development for management of contacts of multidrug-resistant tuberculosis patients: two systematic reviews.

BACKGROUND: Existing international guidelines provide different recommendations for the management of contacts of multidrug-resistant tuberculosis (MDR-TB) patients. OBJECTIVE: To conduct two systematic reviews with the aim of identifying chemoprophylactic approaches that are effective in contacts of MDR-TB patients to assist in policy making. DESIGN: We systematically searched the Medline, Embase, Central, LILACS, TRIP and BIOSIS Preview databases for studies on the effectiveness of anti-tuberculosis drugs in preventing active TB in persons at risk of developing MDR-TB. This was done as an update of a systematic review from 2006 using the same methodology. In addition, we searched for studies including persons at risk of developing TB after exposure to non-MDR-TB patients who were treated with anti-tuberculosis drugs other than isoniazid or rifampicin. RESULTS: Of 1195 references assessed in the update, one additional study could be included. As the initial review included two studies, the total number of included studies equals three. One study reported no contacts who developed TB, whether or not they received prophylaxis. The other two studies showed non-significant risk differences of 4% (95%CI -3 to 12), and 5% (95%CI -2 to 11), both in favour of chemoprophylaxis. For the additional review, 2480 references were assessed, but none could be included. CONCLUSION: The attention given to MDR-TB in recent years has not resulted in publications on preventive treatment for contacts of MDR-TB patients. The available evidence is not sufficient to support or reject preventive treatment. Furthermore, the combined available evidence is of very low quality.

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.

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.

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.

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.

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.

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.

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.

[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.

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.