Treatment Outcomes in Global Systematic Review and Patient Meta-Analysis of Children with Extensively Drug-Resistant Tuberculosis.

Extensively drug-resistant tuberculosis (XDR TB) has extremely poor treatment outcomes in adults. Limited data are available for children. We report on clinical manifestations, treatment, and outcomes for 37 children (<15 years of age) with bacteriologically confirmed XDR TB in 11 countries. These patients were managed during 1999-2013. For the 37 children, median age was 11 years, 32 (87%) had pulmonary TB, and 29 had a recorded HIV status; 7 (24%) were infected with HIV. Median treatment duration was 7.0 months for the intensive phase and 12.2 months for the continuation phase. Thirty (81%) children had favorable treatment outcomes. Four (11%) died, 1 (3%) failed treatment, and 2 (5%) did not complete treatment. We found a high proportion of favorable treatment outcomes among children, with mortality rates markedly lower than for adults. Regimens and duration of treatment varied considerably. Evaluation of new regimens in children is required.

Treatment and outcomes in children with multidrug-resistant tuberculosis: A systematic review and individual patient data meta-analysis.

BACKGROUND: An estimated 32,000 children develop multidrug-resistant tuberculosis (MDR-TB; Mycobacterium tuberculosis resistant to isoniazid and rifampin) each year. Little is known about the optimal treatment for these children. METHODS AND FINDINGS: To inform the pediatric aspects of the revised World Health Organization (WHO) MDR-TB treatment guidelines, we performed a systematic review and individual patient data (IPD) meta-analysis, describing treatment outcomes in children treated for MDR-TB. To identify eligible reports we searched PubMed, LILACS, Embase, The Cochrane Library, PsychINFO, and BioMedCentral databases through 1 October 2014. To identify unpublished data, we reviewed conference abstracts, contacted experts in the field, and requested data through other routes, including at national and international conferences and through organizations working in pediatric MDR-TB. A cohort was eligible for inclusion if it included a minimum of three children (aged <15 years) who were treated for bacteriologically confirmed or clinically diagnosed MDR-TB, and if treatment outcomes were reported. The search yielded 2,772 reports; after review, 33 studies were eligible for inclusion, with IPD provided for 28 of these. All data were from published or unpublished observational cohorts. We analyzed demographic, clinical, and treatment factors as predictors of treatment outcome. In order to obtain adjusted estimates, we used a random-effects multivariable logistic regression (random intercept and random slope, unless specified otherwise) adjusted for the following covariates: age, sex, HIV infection, malnutrition, severe extrapulmonary disease, or the presence of severe disease on chest radiograph. We analyzed data from 975 children from 18 countries; 731 (75%) had bacteriologically confirmed and 244 (25%) had clinically diagnosed MDR-TB. The median age was 7.1 years. Of 910 (93%) children with documented HIV status, 359 (39%) were infected with HIV. When compared to clinically diagnosed patients, children with confirmed MDR-TB were more likely to be older, to be infected with HIV, to be malnourished, and to have severe tuberculosis (TB) on chest radiograph (p < 0.001 for all characteristics). Overall, 764 of 975 (78%) had a successful treatment outcome at the conclusion of therapy: 548/731 (75%) of confirmed and 216/244 (89%) of clinically diagnosed children (absolute difference 14%, 95% confidence interval [CI] 8%-19%, p < 0.001). Treatment was successful in only 56% of children with bacteriologically confirmed TB who were infected with HIV who did not receive any antiretroviral treatment (ART) during MDR-TB therapy, compared to 82% in children infected with HIV who received ART during MDR-TB therapy (absolute difference 26%, 95% CI 5%-48%, p = 0.006). In children with confirmed MDR-TB, the use of second-line injectable agents and high-dose isoniazid (15-20 mg/kg/day) were associated with treatment success (adjusted odds ratio [aOR] 2.9, 95% CI 1.0-8.3, p = 0.041 and aOR 5.9, 95% CI 1.7-20.5, p = 0.007, respectively). These findings for high-dose isoniazid may have been affected by site effect, as the majority of patients came from Cape Town. Limitations of this study include the difficulty of estimating the treatment effects of individual drugs within multidrug regimens, only observational cohort studies were available for inclusion, and treatment decisions were based on the clinician's perception of illness, with resulting potential for bias. CONCLUSIONS: This study suggests that children respond favorably to MDR-TB treatment. The low success rate in children infected with HIV who did not receive ART during their MDR-TB treatment highlights the need for ART in these children. Our findings of individual drug effects on treatment outcome should be further evaluated.

A joint cross-border investigation of a cluster of multidrug-resistant tuberculosis in Austria, Romania and Germany in 2014 using classic, genotyping and whole genome sequencing methods: lessons learnt.

Molecular surveillance of multidrug-resistant tuberculosis (MDR-TB) using 24-loci MIRU-VNTR in the European Union suggests the occurrence of international transmission. In early 2014, Austria detected a molecular MDR-TB cluster of five isolates. Links to Romania and Germany prompted the three countries to investigate possible cross-border MDR-TB transmission jointly. We searched genotyping databases, genotyped additional isolates from Romania, used whole genome sequencing (WGS) to infer putative transmission links, and investigated pairwise epidemiological links and patient mobility. Ten isolates from 10 patients shared the same 24-loci MIRU-VNTR pattern. Within this cluster, WGS defined two subgroups of four patients each. The first comprised an MDR-TB patient from Romania who had sought medical care in Austria and two patients from Austria. The second comprised patients, two of them epidemiologically linked, who lived in three different countries but had the same city of provenance in Romania. Our findings strongly suggested that the two cases in Austrian citizens resulted from a newly introduced MDR-TB strain, followed by domestic transmission. For the other cases, transmission probably occurred in the same city of provenance. To prevent further MDR-TB transmission, we need to ensure universal access to early and adequate therapy and collaborate closely in tuberculosis care beyond administrative borders.

Tuberculosis Surveillance in Romania Among Vulnerable Risk Groups Between 2015 and 2017.

Purpose: Romania has the highest tuberculosis (TB) burden in the European Union/European Economic Area (EU/EEA) comprising almost a quarter (23.4%) of the reported patients in 2017, and a TB notification rate six times higher than the EU/EEA average. Although the overall TB notification rate in Romania declined from 154/100.000 individuals to 66/100.000 individuals in the general population between 2002 and 2017, TB notification rates remain high in certain vulnerable populations groups such as prisoners, the homeless population and among drug users. Patients and Methods: We conducted a descriptive study regarding TB monitoring data in Romania, including the aforementioned TB risk groups. Results: Analysis regarding notified TB cases among these risk groups indicates that TB rates are 7 to 18 times higher than in the general population. One of the most alarming aspects regards the exceedingly high proportion of HIV-seropositivity among drug users and the high mortality rates among the homeless population and among drug users with TB. Conclusion: This data underlines the importance of early identification among social risk groups using outreach active case-finding (ACF) activities, possibly combining TB screening with screening for other common, possibly life-threatening, co-morbidities for which an effective treatment is available. ACF could have a decisive role in TB control and eradication in Romania, when aimed at these high-risk groups.

[Aspects of TB endemia in Romania and the response of the National Programme for Prevention, Surveillance and Control of Tuberculosis]. / Aspecte ale endemiei de tuberculoza in România si raspunsul Programului National de Prevenire, Supraveghere si Control al Tuberculozei (PNPSCT).

In Romania, tuberculosis is a major public health problem. Consistent with the remarkable improvement of success rate in bacteriological confirmed cases from 51% in 1995 to 85.8% in 2011, the global incidence of the disease fell from a maximum of 142.2 per hundred thousand in 2002 to 73.3 per hundred thousand in 2013. The endemia attenuation (so far from historically low in 1985) is highlighted also by the incidence in children and mortality rates. In MDR/XDR TB disease, the situation is significantly different. Although, the endemia intensity is low (500 incident cases and 1,500 prevalent cases) the therapeutic impact is minimum, as demonstrated by the analysis of outcomes. The success rate in the range of 20% is unacceptable in a context of significant issues of legislation and procedures deficiency, with an insufficient funding in which a far too large role returns to external programs, unpredictable and limited as objectives and duration.

[Tuberculosis in children in Romania]. / Tuberculoza la copii în Romania.

According to the World Health Organization and Stop TB Partnership, tuberculosis among children often remains undiagnosed, the main reported causes being lack of access to health services or because health professionals unrecognizing the signs and symptoms of tuberculosis in this age group. In Romania, consistent with TB endemic levels, the overall incidence progressively decreased from 142.2%ooo in 2002 to 82.8%ooo in 2011, incidence of TB in children 0-14 years dropped steadily from 47.2 %ooo (1784 cases) in the same "peak year"2002 to 23.6% ooo (766 cases) in 2011. The distribution of TB disease in children by counties shows variations between these, the explanations may be related both to differences in offer of the bacilli between different areas (prevalence of pulmonary patients smear and/or culture positive) and by deficiencies in the detection of cases and lack of rigor in diagnosis (variation in the incidence of TB in 0-14 years from 2.S%ooo in Salaj county up to 53.2%ooo in Maramures county in 2011). The number of serious cases of TB in children (meningoencephalitis, miliary, cavitary) still maintains a constant high annual rate (65 cases in 2011), which demonstrates the severity of endemic TB in our country. Prompt assurance of TB diagnostic and also the accurate management of TB treatment constitute the guarantee of the decrease of this disease, goal applies to all age groups.

[Prudent optimism and the evolution of the main indicators of endemic tuberculosis in Romania in 2012]. / Optimismul prudent si evolutia principalilor indicatori ai endemiei tuberculoase în anul 2012, în România.

The implementation of programmes for Tuberculosis Control (NPTC) in the medium term, starting in 1997, who under the auspices and the coordination of the Ministry of Health, was the guarantor of the achievements in these years in TB control, therapeutic success rate of cases being a constant source of 80%. The global incidence of TB (IG) (new cases and relapses) has decreased in the past 10 years with 42%, from a maximum of 142.2per 100 thousand in 2002, to 79.2 per 100 thousand in 2012. The incidence of TB in children between 0 and 14 years of age has dropped significantly, from 48.2 per 100 thousand in 2002 (1843) a t28.3per 100 thousand in 2011 (770). Mortality declined from 10.8% in 2002 to 6% in 2011. To increase the control of TB, and in accordance with the envisaged country strategy for the period 2013-2017, the anti-TB Programme will give priority to the following measures: gradual introduction of rapid molecular techniques able to identify in the shortest time TB and chemoresistancies; centralized procurement anti-TB drugs; better integration ofpractices of diagnosis and treatment of TB in children with standard practices for tuberculosis control; for a proper diagnosis and treatment to all people suffering from MDR-TB (until 2015).

[Tuberculosis in Romania between 2006-2008]. / Tuberculoza in România intre anii 2006-2008.

The high level of TB incidence places Romania among first places in Europe and on the first place in European Union; in the last years a slowly, but hopefully descending trend can be observed (from 114.2 per hundred thousand in 2006 to 109.8 per hundred thousand in 2007 and 108 per hundred thousand in 2008). TB incidence in children has also decreased from 31.6 per hundred thousand in 2006 to 30.8 per hundred thousand in 2007 and 28.5 per hundred thousand in 2008. TB mortality decreased to 7.8 per hundred thousand in 2006 and 7.4 per hundred thousand in 2007. Every year, 800 cases with MDR TB are notified in Romania. The results obtained in the cohort of new patients with pulmonary SS(+) tuberculosis: the success rate reached in 2003 was 79.5% and 83.9% in 2006. The success rate was greater in pulmonary patients confirmed by culture: 82% in 2003 and 85.5% in 2006. In conclusion, the results of NTP implementation in Romania, reflected by the evolution of the principal epidemio-metrical indicators (decrease of the global incidence, TB incidence at children, TB mortality and increase of therapeutical successes) confirms the TB control activities efficacy.

[Multidrug resistant tuberculosis in Romania in the last years (2004-2007)--an extremely important social phenomenon]. / Tuberculoza multidrog rezistenta în România în ultimii ani (2004-2007)--un fenomen social de maxima importanta.

The emergence of resistance to drugs used to treat tuberculosis (TB), and particularly multidrug resistant (MDR-TB) strains, has become a significant public health problem in a number of countries and an obstacle to effective global TB control. In many other countries, the extent of drug resistance is unknown and the management of the patients with MDR-TB is inadequate. In countries where drug resistance has been identified, specific measures need to be taken within TB control programmes to address the problem through appropriate management of patients and adoption of strategies to prevent the propagation and dissemination of drug resistant TB, including MDR-TB. In Romania there are two centers for the management of MDR-TB cases: one in Bucharest at The National Pneumology Institute "Marius Nasta" and the other at Bisericani (Neamt district). The comparative analysis of MDR-TB cases and under treatment evolution was done, in the two excellence centers Bucharest and Bisericani from 2004 to 2007. This is a retrospective study of MDR-TB patients enrolled in Romania between 2004-2007. All patients evaluated were managed under The National Tuberculosis Programme approved protocols and had the opportunity to receive more than 24 months of treatment. In addition, follow-up data on successfully treated patients were collected at the beginning of 2007. This study is based on an MDR register, and a software collecting information on MDR-TB cases. In order to be accepted in one of the two MDR centers, patients need to fulfill certain criteria to improve the treatment results. A total number of 305 MDR-TB patients were registered at the beginning of 2007 in Bucharest MDR center; this study used a number of 170 MDR-TB patients from Bucharest who fulfilled the study's criteria in oppose to the 294 MDR-TB patients from Bisericani. 184 patients from the first cohort of DOTS-Plus project were evaluated until the end of the study: 55 were completed treatment and 54 cured, which means 59,23% succes rate. The conversion rate of culture at 4 months (for the first cohort) in MDR excellence centers was: Bucharest--72,5% and Bisericani--64%.

Romanian anti-TB drugs resistance surveillance 2003-2004.

UNLABELLED: Romania decided and initiated a DRS for anti-TB drugs at national level using the standardized methodology proposed by WHO and IUATLD. The DRS protocol was designed with technical assistance from WHO; the surveillance started in June 2003 and ended in June 2004. It was tested the susceptibility to the 4 first line anti-TB drugs: Isoniazide (H), Rifampicin (R), Streptomycin (S), Ethambutol (E). Drug susceptibility testing used: indirect absolute concentration method. There were included in the survey 1251 TB patients from the 60 clusters: 869 new cases and 382 previously treated. From the penitentiary system were included 85 TB patients, 47 new cases and 38 previously treated. RESULTS: [table: see text]. Estimations of the trend of anti-TB drug resistance in Romania for the next period was proposed.

[National Program for TB Control (NPTC): report of 2005 activities, evolution of endemic disease, challenges, priorities]. / Programul national de control al tuberculozei (PNCT): raportul activitatilor desfasurate în anul 2005, evolutia endemiei, probleme, prioritati.

The authors analyze the current status of anti-TB activity in Romania, in which several factors are involved: the pneumo-phthisiology network, the central unit (M. Nasta Institute of Pneumology), the Health Insurance, Health Ministry as well as international funding and technical assistance units (Global Fund, World Health Organisation). Current TB incidence data are reviewed, as well as the events in NPTC during 2005: training of the personnel involved in TB care (pneumologists and general practitioners, nurses, laboratory staff), improving TB care in risk groups (children, inmates, HIV positives, gypsies), improving the functionality of bK laboratory network, improving access of multidrug resistant TB patients to good quality services, improving the system for acquiring and distributing medication, developing a functional system for monitoring the NPTC, integrating TB in the national system for transmissible diseases survey, elaborating guidelines on different aspects of TB care. In 2005, WHO performed an evaluation mission in Romania, finally proposing solutions for current issues: the Government Decision of the NPTC actions, establishing the status of the county NPTC managers, using incentives for patients, improving drug management by application to international organisms, increasing the personnel numbers in national reference laboratories, improving the informational circuits between factors involved in NPTC.