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

Abstract

BackgroundAn 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 findingsTo 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 To identify unpublished data, we reviewed conference abstracts, contacted experts in the field, and requested data through other routes, including at national and international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 All data were from published or unpublished observational cohorts.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). ...

Pediatric Multidrug-resistant Tuberculosis in Kyiv City, Ukraine

“…Compared with adults with MDR-TB in Ukraine, the children in our cohort had much better treatment outcomes [11,12]. This finding is consistent with those conducted in other settings that have reported higher rates of MDR-TB treatment success in children compared with adults [3]. Most of the children in our cohort were identified through contact tracing, just less than half had intrathoracic lymphadenopathy as their only radiographic abnormalities, and 10% were asymptomatic at the time of diagnosis.…”

“…This rate is far lower than the global treatment success rate of 54% among adults [7]. According to the pediatric MDR-TB meta-analysis mentioned earlier, 78% of children with MDR-TB achieve treatment success [3]; but children from the former Soviet republics were underrepresented in this sample.…”

“…Relatively few cases of pediatric MDR-TB have been reported in the literature. A recent systematic review and meta-analysis reported only 975 cases [3], of which more than two-thirds were from South Africa. Few reports have described pediatric MDR-TB in the former Soviet republics [4][5][6]-despite the fact that this part of the world has the highest proportion of TB cases that are MDR [7].…”

Improving Quality of Patient Data for Treatment of Multidrug- or Rifampin-Resistant Tuberculosis

“…Despite those problems, various studies have collected and pooled observational data, enabling individual patient meta-analyses (IPD-MAs). Since 2010, when WHO and other organizations started using GRADE for drug-resistant TB treatment guidelines (20), WHO recommendations on the type, composition, and duration of second-line TB regimens have been based largely on evidence from observational studies of patients treated under field conditions (21)(22)(23)(24)(25). Ahead of the WHO MDR/RR TB guideline update in 2018, a public call was made for contributors to report IPD conforming to certain criteria and a specific data dictionary (26).…”

Tuberculosis and HIV—An Update on the “Cursed Duet” in Children

“…However, poor nutritional status and severity of disease contribute significantly to mortality and treatment failure (103). As with drug sensitive TB, ART is essential for MDR TB in HIV+ children (104). A standardized, shorter duration of treatment is successful for MDR TB in adults (105,106), and the 9-12 month regimen is now recommended for those without prior exposure to second-line treatment agents or resistance to fluoroquinolones or second line injectables (107).…”