www.thelancet.com/infection Published online February 27, 2012 DOI:10.1016/S1473-3099(12)70033-6 1 Articles Treatment outcomes for children with multidrug-resistant tuberculosis: a systematic review and meta-analysis Dena Ettehad, H Simon Schaaf, James A Seddon, Graham S Cooke*, Nathan Ford* Summary Background Paediatric multidrug-resistant (MDR) tuberculosis is a public health challenge of growing concern, accounting for an estimated 15% of all global cases of MDR tuberculosis. Clinical management is especially challenging, and recommendations are based on restricted evidence. We aimed to assess existing evidence for the treatment of MDR tuberculosis in children. Methods We did a systematic review and meta-analysis of published and unpublished studies reporting treatment outcomes for children with MDR tuberculosis. We searched PubMed, Ovid, Embase, Cochrane Library, PsychINFO, and BioMedCentral databases up to Oct 31, 2011. Eligible studies included five or more children (aged ≤16 years) with MDR tuberculosis within a defined treatment cohort. The primary outcome was treatment success, defined as a composite of cure and treatment completion. Results We identified eight studies, which reported treatment outcomes for a total of 315 patients. We recorded much variation in the characteristics of patients and programmes. Time to appropriate treatment varied from 2 days to 46 months. Average duration of treatment ranged from 6 months to 34 months, and duration of follow-up ranged from 12 months to 37 months. The pooled estimate for treatment success was 81·67% (95% CI 72·54–90·80). Across all studies, 5·9% (95% CI 1·3–10·5) died, 6·2% (2·3–10·2) defaulted, and 39·1% (28·7–49·4) had an adverse event. The most common drug-related adverse events were nausea and vomiting. Other serious adverse events were hearing loss, psychiatric effects, and hypothyroidism. Interpretation The treatment of paediatric MDR tuberculosis has been neglected, but when children are treated outcomes can be achieved that are at least as good as those reported for adults. Programmes should be encouraged to report outcomes in children to improve the knowledge base for care, especially as new drugs become available. Funding None. Introduction An estimated 12 million people worldwide have tuber- culosis, of whom about 650 000 have multidrug-resistant (MDR) disease. 1 Childhood tuberculosis is estimated to account for 10–15% of the global tuberculosis burden, 2 and probably accounts for a similar proportion when considering only drug-resistant disease. The highest rates of paediatric MDR tuberculosis are reported in low- income countries, 2 and in some regions the incidence of MDR tuberculosis has risen sharply in the past two decades—eg, in the Western Cape, South Africa, the proportion of culture-confirmed cases of tuberculosis with multidrug-resistance has tripled in the past 15 years from 2·3% to 7·3%. 3 MDR tuberculosis is underdetected in children. Diagnosis of drug resistance needs mycobacterial culture and drug susceptibility testing (DST), 4 but the difficulty in obtaining respiratory secretions, such as sputum or gastric aspirates, or specimens of extrapulmonary tuberculosis from young children, 5 along with the fact that up to half of all children with a clinical diagnosis of tuberculosis disease are smear- negative and culture-negative, makes microbiological confirmation challenging. 6 Strict programmatic requirements for microbiological confirmation of drug resistance combined with insufficient recognition of the importance of taking into account DST patterns from adult source cases can lead to substantial delays in diagnosis and initiation of appropriate treatment. 7 These delays could lead to progression of disease, increased risk of infectiousness of children, greater risk of disease complications such as tuberculous meningitis, and higher rates of morbidity and mortality. 8,9 Paediatric drug-resistant tuberculosis is a neglected concern, with few children being treated relative to the estimated disease burden. 10 WHO guidelines for the treatment of drug-resistant tuberculosis in adults are based on evidence from meta-analyses of individual patients’ data. 11 However, recommendations for children are based on expert opinion, drawing on data from case series and cohort studies, 12,13 often with small sample sizes. Consequently, variation exists in programmatic choices of treatment regimens, with the choice of drugs informed by previous drug exposure and DST results. 14 Because of uncertainties about diagnosis and the best treatment regimens, and concerns about the toxic effects associated with MDR tuberculosis treatment, health-care providers are cautious about treating paediatric MDR tuberculosis. We did a systematic review and meta-analysis of the available evidence for treatment outcomes in children Published Online February 27, 2012 DOI:10.1016/S1473- 3099(12)70033-6 See Online/Comment DOI:10.1016/S1473- 3099(12)70038-5 *These authors share last authorship Faculty of Medicine, Imperial College London, UK (D Ettehad BSc, G S Cooke DPhil); Desmond Tutu Tuberculosis Centre, Faculty of Health Sciences, Stellenbosch University, South Africa (H S Schaaf MD, J Seddon MBBS); Tygerberg Children’s Hospital, South Africa (H Simon Schaaf); Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, UK (J A Seddon); Africa Centre for Health and Population Studies, University of KwaZulu-Natal, South Africa (G S Cooke); Médecins Sans Frontières, Geneva, Switzerland (N Ford PhD); and Centre for Infectious Disease Epidemiology and Research, University of Cape Town, South Africa (N Ford) Correspondence to: Dr Nathan Ford, Médecins Sans Frontières, 78 rue de Lausanne, 1211 Geneva, Switzerland nathan.ford@msf.org