Anne Detjen

Interferon-gamma release assays and childhood tuberculosis: systematic review and meta-analysis.

BACKGROUND Children infected with Mycobacterium tuberculosis have significant risk of developing tuberculosis (TB) and can therefore benefit from preventive therapy. OBJECTIVE To assess the value of interferon-gamma release assays (IGRAs) and the tuberculin skin test (TST) in the diagnosis of TB infection and disease in children. METHODS Thirty-three studies were included, assessing commercial IGRAs (QuantiFERON®-TB [QFT] and T-SPOT.®TB) and TST. Reference standards for infection were incident TB or TB exposure. Test performance for disease diagnosis was evaluated in studies assessing children with confirmed and/or clinically diagnosed TB, compared to children where TB was excluded. RESULTS Two small studies measured incident TB in children tested with QFT and found weak positive predictive value. Association of test response with exposure-categorized dichotomously or as a gradient-was similar for all tests. The sensitivity and specificity of all tests were similar in diagnosing the disease. Stratified analysis suggested lower sensitivity for all tests in young or human immunodeficiency virus infected children. CONCLUSIONS Available data suggest that TST and IGRAs have similar accuracy for the detection of TB infection or the diagnosis of disease in children. Heterogeneous methodology limited the comparability of studies and the interpretation of results. A rigorous, standardized approach to evaluate TB diagnostic tests in children is needed.BACKGROUND Children infected with Mycobacterium tuberculosis have significant risk of developing tuberculosis(TB) and can therefore benefit from preventive therapy. OBJECTIVE To assess the value of interferon-gamma release assays (IGRAs) and the tuberculin skin test (TST)in the diagnosis of TB infection and disease in children. METHODS Thirty-three studies were included, assessing commercial IGRAs (QuantiFERON®-TB [QFT] andT-SPOT.®TB) and TST. Reference standards for infection were incident TB or TB exposure. Test performance for disease diagnosis was evaluated in studies assessing children with confirmed and/or clinically diagnosed TB,compared to children where TB was excluded. RESULTS Two small studies measured incident TB in children tested with QFT and found weak positive predictive value. Association of test response with exposure-categorized dichotomously or as a gradient-was similar for all tests. The sensitivity and specificity of all tests were similar in diagnosing the disease. Stratified analysis suggested lower sensitivity for all tests in young or human immuno deficiency virus infected children. CONCLUSIONS Available data suggest that TST and IGRAs have similar accuracy for the detection of TB infection or the diagnosis of disease in children. Heterogeneous methodology limited the comparability of studies and the interpretation of results. A rigorous, standardized approach to evaluate TB diagnostic tests in children is needed.

Old ideas to innovate tuberculosis control: preventive treatment to achieve elimination

The introduction of new rapid diagnostic tools for tuberculosis (TB) and the promising TB drugs pipeline together with the development of a new World Health Organization Strategy post 2015 allows new discussions on how to direct TB control. The European Respiratory Society’s European Forum for TB Innovation was created to stimulate discussion on how to best take advantage of old and new opportunities, and advances, to improve TB control and eventually progress towards the elimination of TB. While TB control is aimed at reducing the incidence of TB by early diagnosis and treatment of infectious cases of TB, TB elimination requires focus on sterilising the pool of latently infected individuals, from which future TB cases would be generated. This manuscript describes the three core components that are necessary to implement the elimination strategy fully. 1) Improve diagnosis of latent TB infected individuals. 2) Improve regimens to treat latent TB infection. 3) ensure public health commitment to make both 1) and 2) possible. Old and new evidence is critically described, focusing on the European commitment to reach elimination and on the innovative experiences and best practices available. Diagnosis and treatment of latent TB infection is the core intervention to reach elimination http://ow.ly/mjW0R

Xpert® MTB/RIF for national tuberculosis programmes in low-income countries: when, where and how?

Xpert ® MTB/RIF offers new and important possibilities for the diagnosis of sputum smear-negative tuberculosis (TB) and/or rifampicin (RMP) resistance, and many are encouraging rapid and widespread implementation. This simple test can be implemented almost everywhere, and it provides results within a few hours. In low-income countries (LICs), however, its cost, environmental limitations (stable and regular electricity, adequate room temperature) and difficulties involved in supply and maintenance are major obstacles. While it may be suitable for major reference hospitals, operational research is needed to evaluate the test and its additional yield above high-quality smear microscopy and clinical algorithms before its use at the peripheral level. In the meantime, direct microscopy should remain the initial diagnostic test for TB suspects. In most LICs, the prevalence of RMP resistance among new TB patients is very low; an Xpert MTB/RIF result indicating RMP resistance will thus always need confirmation by another test. In a population at high risk of RMP resistance (> 15%), however, the positive predictive value for RMP resistance by Xpert MTB/RIF is high, and identification of RMP resistance is an excellent proxy for multidrug-resistant TB (MDR-TB). The assay should be widely used for this purpose if, and only if, excellent MDR-TB management is available, both for ethical reasons and to reduce the risk of extensively drug-resistant TB.

Xpert MTB/RIF assay for the diagnosis of pulmonary tuberculosis in children: a systematic review and meta-analysis.

BACKGROUND Microbiological confirmation of childhood tuberculosis is rare because of the difficulty of collection of specimens, low sensitivity of smear microscopy, and poor access to culture. We aimed to establish summary estimates for sensitivity and specificity of of the Xpert MTB/RIF assay compared with microscopy in the diagnosis of pulmonary tuberculosis in children. METHODS We searched for studies published up to Jan 6, 2015, that used Xpert in any setting in children with and without HIV infection. We systematically reviewed studies that compared the diagnostic accuracy of Xpert MTB/RIF (Xpert) with microscopy for detection of pulmonary tuberculosis and rifampicin resistance in children younger than 16 years against two reference standards-culture results and culture-negative children who were started on anti-tuberculosis therapy. We did meta-analyses using a bivariate random-effects model. FINDINGS We identified 15 studies including 4768 respiratory specimens in 3640 children investigated for pulmonary tuberculosis. Culture tests were positive for tuberculosis in 12% (420 of 3640) of all children assessed and Xpert was positive in 11% (406 of 3640). Compared with culture, the pooled sensitivities and specificities of Xpert for tuberculosis detection were 62% (95% credible interval 51-73) and 98% (97-99), respectively, with use of expectorated or induced sputum samples and 66% (51-81) and 98% (96-99), respectively, with use of samples from gastric lavage. Xpert sensitivity was 36-44% higher than was sensitivity for microscopy. Xpert sensitivity in culture-negative children started on antituberculosis therapy was 2% (1-3) for expectorated or induced sputum. Xperts pooled sensitivity and specificity to detect rifampicin resistance was 86% (95% credible interval 53-98) and 98% (94-100), respectively. INTERPRETATION Compared with microscopy, Xpert offers better sensitivity for the diagnosis of pulmonary tuberculosis in children and its scale-up will improve access to tuberculosis diagnostics for children. Although Xpert helps to provide rapid confirmation of disease, its sensitivity remains suboptimum compared with culture tests. A negative Xpert result does not rule out tuberculosis. Good clinical acumen is still needed to decide when to start antituberculosis therapy and continued research for better diagnostics is crucial. FUNDING WHO, Global TB Program of Texas Childrens Hospital.

Neue Empfehlungen für die Umgebungsuntersuchungen bei Tuberkulose

In 2007, the German Central Committee against Tuberculosis (DZK) published recommendations for contact tracing that introduced the new interferon gamma release assays (IGRAs). Meanwhile, substantial progress has been made in documenting the utility of IGRAs. Because IGRAs are usually superior to the tuberculin skin test (TST) in detecting latent TB infection (LTBI) with respect to sensitivity and specificity in adult contact populations that are at least partially BCG vaccinated, it is now recommended that instead of two-step testing only IGRAs be used.[nl]As the literature does not yet provide sufficient data on the accuracy of IGRAs in children younger than 5 years, the TST remains the method of choice in that age group. To date, also, no clear body of data exists to substantiate better performance for IGRAs than for the TST in older children, thus in this age group using of either test is recommended. The new recommendations also underscore the importance of a diligent preselection of close contacts in order to achieve a high probability that positive test results represent recent infection and to thus increase the benefit of chemopreventive treatment for those identified as requiring it. In a third point of update, it is noted that re-testing of contacts individuals found positive for LTBI may produce a considerable number of false-negative results and should thus be avoided in case of documented exposure.

Importance of tuberculosis control to address child survival

Tuberculosis commonly aff ects young children (<5 years) in countries that have high rates of child mortality. The global public health focus to control tuberculosis has traditionally aimed to reduce transmission through early case-fi nding and eff ective treatment of the most infectious cases. Young children have historically been excluded from this focus, since their contribution to tuberculosis transmission is believed to be small. In the past decade, national tuberculosis programmes in highburden settings have given increased attention to the challenges of childhood tuberculosis. In 2012, World TB Day focused on children for the fi rst time. This attention is likely to increase further as the WHO Global Tuberculosis Programme’s ambitious post-2015 tuberculosis control strategy seeks to engage the entire health sector, including maternal and child health. Within the Millennium Developmental Goal (MDG) framework, tuberculosis control and its related targets are framed within MDG 6, and yet are also relevant to MDGs 4 and 5 (child and maternal mortality) and MDG 1 (undernutrition). Improvement of child survival is a major global health priority but tuberculosis is not regarded as important in that context. However, we believe that the relevance of tuberculosis to child survival will become increasingly apparent over the next decade, especially in countries where tuberculosis control remains diffi cult and high rates of Mycobacterium tuberculosis transmission are sustained. Recognition of the relevance and challenges of tuberculosis to child survival is growing. The 2012 WHO Global Tuberculosis Report was the fi rst edition of this report to provide global estimates of the burden of childhood tuberculosis. The diffi culties in provision of accurate estimates of childhood tuberculosis are widely acknowledged and include challenges of case detection, diagnostic accuracy, and poor recording and reporting practices. Vital registration data, in which causes of death are coded according to the two latest revisions of the International Classifi cation of Diseases (ICD; underlying cause of death: ICD-10 A15–A19, equivalent to ICD-9: 010–018), were used to produce a global estimate of childhood mortality attributed to tuberculosis in children not infected with HIV, with the most recent estimate of 74 000 deaths in 2012. Because these deaths represent only about 1% of the estimated total deaths in children globally in 2012, tuberculosis is not regarded as a major contributor to child mortality. However, there are important limitations to the estimate of 74 000 child deaths from tuberculosis. First, tuberculosis is also an important cause of death in children living with HIV, but for these deaths HIV is registered as the underlying cause and tuberculosis as a contributory cause. Since a third of countries with vital registration systems report only the underlying causes of death and not contributory causes to WHO, vital registration data cannot be used to estimate the number of tuberculosis deaths in people living with HIV. Further, vital registration data are available for only 3% of global child deaths and are not available in most tuberculosisendemic countries. The risk of death due to tuberculosis in children is highest for those younger than 5 years. However, accurate characterisation of tuberculosis-related deaths in young children can be challenging because the clinical features of tuberculosis are not specifi c. Tuberculosis in young children is usually a clinical diagnosis that is not confi rmed microbiologically, especially in tuberculosisendemic areas with scarce resources. Therefore, estimation of the contribution of tuberculosis to deaths in young children that have been attributed to pneumonia or malnutrition, either as the direct cause or as comorbidity, is a challenge. Findings from clinical studies show that tuberculosis is common in African children with severe pneumonia. Investigators of a study from Uganda of 270 children with WHO-defi ned severe pneumonia reported that 19% had a clinical diagnosis of tuberculosis and 6% had culture-confi rmed tuberculosis. Pooled analysis of autopsy studies from fi ve African countries of children who died with respiratory disease showed that 11% of 473 children with HIV and 8% of 338 children not infected with HIV had tuberculosis. The fi ndings need to be interpreted with caution because of possible sample bias. These clinical and autopsy studies were mainly from tertiary urban centres representing the most critically ill children, and the direct cause of death in these children is diffi cult to ascertain. However, the fi ndings suggest that tuberculosis could be a more common cause of morbidity and mortality in children with pneumonia than is recognised. 1·3 million children were estimated to have died from pneumonia in 2011, and almost half of these deaths were children in Africa. If then, for example, around 10% of child pneumoniarelated deaths were due to tuberculosis, the present estimates of deaths in children due to tuberculosis would more than double. Tuberculosis can cause substantial weight loss, but data to quantify its contribution to childhood malnutrition are scarce. Investigators of studies from Bangladesh and South Africa report very similar results, despite representing low and high HIV-endemic settings. Tuberculosis was microbiologically confi rmed in 4–6% of children with severe malnutrition and clinically diagnosed in an additional 16–17%. In 2011, an estimated 500 000 deaths in children were associated with severe wasting, and infectious diseases, such as pneumonia, were the immediate causes of these deaths. Lancet 2014; 383: 1605–07

Clinical Case Definitions for Classification of Intrathoracic Tuberculosis in Children: An Update

Consensus case definitions for childhood tuberculosis have been proposed by an international expert panel, aiming to standardize the reporting of cases in research focusing on the diagnosis of intrathoracic tuberculosis in children. These definitions are intended for tuberculosis diagnostic evaluation studies of symptomatic children with clinical suspicion of intrathoracic tuberculosis, and were not intended to predefine inclusion criteria into such studies. Feedback from researchers suggested that further clarification was required and that these case definitions could be further improved. Particular concerns were the perceived complexity and overlap of some case definitions, as well as the potential exclusion of children with acute onset of symptoms or less severe disease. The updated case definitions proposed here incorporate a number of key changes that aim to reduce complexity and improve research performance, while maintaining the original focus on symptomatic children suspected of having intrathoracic tuberculosis. The changes proposed should enhance harmonized classification for intrathoracic tuberculosis disease in children across studies, resulting in greater comparability and the much-needed ability to pool study results.

Consensus Statement on Research Definitions for Drug-Resistant Tuberculosis in Children

Few children with drug-resistant (DR) tuberculosis (TB) are identified, diagnosed, and given an appropriate treatment. The few studies that have described this vulnerable population have used inconsistent definitions. The World Health Organization (WHO) definitions used for adults with DR-TB and for children with drug-susceptible TB are not always appropriate for children with DR-TB. The Sentinel Project on Pediatric Drug-Resistant Tuberculosis was formed in 2011 as a network of experts and stakeholders in childhood DR-TB. An early priority was to establish standardized definitions for key parameters in order to facilitate study comparisons and the development of an evidence base to guide future clinical management. This consensus statement proposes standardized definitions to be used in research. In particular, it suggests consistent terminology, as well as definitions for measures of exposure, drug resistance testing, previous episodes and treatment, certainty of diagnosis, site and severity of disease, adverse events, and treatment outcome.

A Blueprint to Address Research Gaps in the Development of Biomarkers for Pediatric Tuberculosis

Childhood tuberculosis contributes significantly to the global tuberculosis disease burden but remains challenging to diagnose due to inadequate methods of pathogen detection in paucibacillary pediatric samples and lack of a child-specific host biomarker to identify disease. Accurately diagnosing tuberculosis in children is required to improve case detection, surveillance, healthcare delivery, and effective advocacy. In May 2014, the National Institutes of Health convened a workshop including researchers in the field to delineate priorities to address this research gap. This blueprint describes the consensus from the workshop, identifies critical research steps to advance this field, and aims to catalyze efforts toward harmonization and collaboration in this area.

The Impact of a Line Probe Assay Based Diagnostic Algorithm on Time to Treatment Initiation and Treatment Outcomes for Multidrug Resistant TB Patients in Arkhangelsk Region, Russia

Background In the Arkhangelsk region of Northern Russia, multidrug-resistant (MDR) tuberculosis (TB) rates in new cases are amongst the highest in the world. In 2014, MDR-TB rates reached 31.7% among new cases and 56.9% among retreatment cases. The development of new diagnostic tools allows for faster detection of both TB and MDR-TB and should lead to reduced transmission by earlier initiation of anti-TB therapy. Study Aim The PROVE-IT (Policy Relevant Outcomes from Validating Evidence on Impact) Russia study aimed to assess the impact of the implementation of line probe assay (LPA) as part of an LPA-based diagnostic algorithm for patients with presumptive MDR-TB focusing on time to treatment initiation with time from first-care seeking visit to the initiation of MDR-TB treatment rather than diagnostic accuracy as the primary outcome, and to assess treatment outcomes. We hypothesized that the implementation of LPA would result in faster time to treatment initiation and better treatment outcomes. Methods A culture-based diagnostic algorithm used prior to LPA implementation was compared to an LPA-based algorithm that replaced BacTAlert and Löwenstein Jensen (LJ) for drug sensitivity testing. A total of 295 MDR-TB patients were included in the study, 163 diagnosed with the culture-based algorithm, 132 with the LPA-based algorithm. Results Among smear positive patients, the implementation of the LPA-based algorithm was associated with a median decrease in time to MDR-TB treatment initiation of 50 and 66 days compared to the culture-based algorithm (BacTAlert and LJ respectively, p<0.001). In smear negative patients, the LPA-based algorithm was associated with a median decrease in time to MDR-TB treatment initiation of 78 days when compared to the culture-based algorithm (LJ, p<0.001). However, several weeks were still needed for treatment initiation in LPA-based algorithm, 24 days in smear positive, and 62 days in smear negative patients. Overall treatment outcomes were better in LPA-based algorithm compared to culture-based algorithm (p = 0.003). Treatment success rates at 20 months of treatment were higher in patients diagnosed with the LPA-based algorithm (65.2%) as compared to those diagnosed with the culture-based algorithm (44.8%). Mortality was also lower in the LPA-based algorithm group (7.6%) compared to the culture-based algorithm group (15.9%). There was no statistically significant difference in smear and culture conversion rates between the two algorithms. Conclusion The results of the study suggest that the introduction of LPA leads to faster time to MDR diagnosis and earlier treatment initiation as well as better treatment outcomes for patients with MDR-TB. These findings also highlight the need for further improvements within the health system to reduce both patient and diagnostic delays to truly optimize the impact of new, rapid diagnostics.