Davide Manissero

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-&ggr; 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.

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

Interferon-&ggr; 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.

Delamanid improves outcomes and reduces mortality in multidrug-resistant tuberculosis

Multidrug-resistant and extensively drug-resistant tuberculosis (TB) are associated with worse treatment outcomes for patients, including higher mortality, than for drug-sensitive tuberculosis. Delamanid (OPC-67683) is a novel anti-TB medication with demonstrated activity against multidrug-resistant disease. Patients who participated in the previously reported randomised, placebo-controlled trial of delamanid and the subsequent open-label extension trial were eligible to participate in a 24-month observational study designed to capture treatment outcomes. Treatment outcomes, as assessed by clinicians and defined by the World Health Organization, were categorised as favourable and unfavourable. Delamanid treatment groups were combined for analysis, based on their duration of treatment. In total, for 421 (87.5%) out of 481 patients from the original randomised controlled trial, consent was granted for follow-up assessments. Favourable outcomes were observed in 143 (74.5%) out of 192 patients who received delamanid for ≥6 months, compared to 126 (55%) out of 229 patients who received delamanid for ≤2 months. Mortality was reduced to 1.0% among those receiving long-term delamanid versus short-term/no delamanid (8.3%; p<0.001). Treatment benefit was also seen among patients with extensively drug-resistant TB. This analysis suggests that treatment with delamanid for 6 months in combination with an optimised background regimen can improve outcomes and reduce mortality among patients with both multidrug-resistant and extensively drug-resistant TB.

Multidrug resistance after inappropriate tuberculosis treatment: A meta-analysis

We conducted a systematic review and meta-analysis to assess the evidence for the postulation that inappropriate tuberculosis (TB) regimens are a risk for development of multidrug-resistant (MDR)-TB. MEDLINE, EMBASE and other databases were searched for relevant articles in January 2011. Cohort studies including TB patients who received treatment were selected and data on treatment regimen, drug susceptibility testing results and genotyping results before treatment and at failure or relapse were abstracted from the articles. Four studies were included in the systematic review and two were included in the meta-analysis. In these two studies the risk of developing MDR-TB in patients who failed treatment and used an inappropriate treatment regimen was increased 27-fold (RR 26.7, 95% CI 5.0–141.7) when compared with individuals who received an appropriate treatment regimen. This review provides evidence that supports the general opinion that the development of MDR-TB can be caused by inadequate treatment, given the drug susceptibility pattern of the Mycobacterium tuberculosis bacilli. It should be noted that only two studies provided data for the meta-analysis. The information can be used to advocate for adequate treatment for patients based on drug resistance profiles.

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.

TB and M/XDR-TB infection control in European TB reference centres: the Achilles’ heel?

To the Editors: The emergence of multidrug-resistant (MDR) tuberculosis (TB), defined as in vitro resistance to isoniazid and rifampicin, and extensively drug-resistant (XDR)-TB, defined as in vitro drug resistance to isoniazid and rifampicin plus any fluoroquinolone and at least one of the injectable drugs (amikacin, capreomycin or kanamycin), represents a major threat to TB control at the global level [1–5]. XDR-TB is a manmade product, resulting, in essence, from clinical mismanagement of newly diagnosed susceptible and resistant TB cases [2–5]. Moreover, existing MDR/XDR-TB cases must be promptly detected and treated, and the transmission from infectious source cases has to be prevented, particularly in nosocomial settings [2–6]. The World Health Organization (WHO), in its Stop TB Strategy [7] and its recent Policy on Infection Control [8], clearly underlines the importance of implementing effective measures of infection control in clinical facilities managing TB and MDR-TB patients. At present, no international study is available to investigate how infection control measures are implemented in healthcare facilities managing TB patients. The aim of the present study was to document how infection control measures are implemented in selected settings in the European Union, focusing on national MDR/XDR-TB reference centres. A standardised and comprehensive survey tool was developed, as discussed previously [9, 10]. In summary, the tool consisted of items covering the key areas that a panel of experts considered adequate to evaluate TB infection control in the selected countries. A Delphi process was used to identify the key elements belonging to infection control, and …

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 nations 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.

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. TB in foreign-born cases does not have a significant influence on TB in the native population in EU/EEA http://ow.ly/pTTXv

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.