title: Incidence of multidrug-resistant tuberculosis disease in children: systematic review and global estimates.
abstract: BACKGROUND
  Multidrug-resistant tuberculosis threatens to reverse recent reductions in global tuberculosis incidence. Although children younger than 15 years constitute more than 25% of the worldwide population, the global incidence of multidrug-resistant tuberculosis disease in children has never been quantified. We aimed to estimate the regional and global annual incidence of multidrug-resistant tuberculosis in children.
  
  
  METHODS
  We developed two models: one to estimate the setting-specific risk of multidrug-resistant tuberculosis among child cases of tuberculosis, and a second to estimate the setting-specific incidence of tuberculosis disease in children. The model for risk of multidrug-resistant tuberculosis among children with tuberculosis needed a systematic literature review. We multiplied the setting-specific estimates of multidrug-resistant tuberculosis risk and tuberculosis incidence to estimate regional and global incidence of multidrug-resistant tuberculosis disease in children in 2010.
  
  
  RESULTS
  We identified 3403 papers, of which 97 studies met inclusion criteria for the systematic review of risk of multidrug-resistant tuberculosis. 31 studies reported the risk of multidrug-resistant tuberculosis in both children and treatment-naive adults with tuberculosis and were used for evaluation of the linear association between multidrug-resistant disease risk in these two patient groups. We identified that the setting-specific risk of multidrug-resistant tuberculosis was nearly identical in children and treatment-naive adults with tuberculosis, consistent with the assertion that multidrug-resistant disease in both groups reflects the local risk of transmitted multidrug-resistant tuberculosis. After application of these calculated risks, we estimated that around 999,792 (95% CI 937,877-1,055,414) children developed tuberculosis disease in 2010, of whom 31,948 (25,594-38,663) had multidrug-resistant disease.
  
  
  CONCLUSIONS
  Our estimates underscore that many cases of tuberculosis and multidrug-resistant tuberculosis disease are not being detected in children. Future estimates can be refined as more and better tuberculosis data and new diagnostic instruments become available.
  
  
  BACKGROUND
  US National Institutes of Health, the Helmut Wolfgang Schumann Fellowship in Preventive Medicine at Harvard Medical School, the Norman E Zinberg Fellowship at Harvard Medical School, and the Doris and Howard Hiatt Residency in Global Health Equity and Internal Medicine at the Brigham and Women's Hospital.
authors.affiliation: Division of Global Health Equity, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Jenkins
authors.affiliation: Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Arielle W
authors.initials: AW
authors.lastname: Tolman
authors.affiliation: Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Courtney M
authors.initials: CM
authors.lastname: Yuen
authors.affiliation: Division of Global Health Equity, Brigham and Women's Hospital, Boston, MA, USA; Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA; Partners In Health, Boston, MA, USA.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Parr
authors.affiliation: Division of Global Health Equity, Brigham and Women's Hospital, Boston, MA, USA; Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA; Partners In Health, Boston, MA, USA.
authors.forename: Salmaan
authors.initials: S
authors.lastname: Keshavjee
authors.affiliation: Partners In Health, Boston, MA, USA; Banner Good Samaritan Medical Center, The University of Arizona College of Medicine, Phoenix, AZ, USA.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Pérez-Vélez
authors.affiliation: Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA.
authors.forename: Marcello
authors.initials: M
authors.lastname: Pagano
authors.affiliation: Division of Global Health Equity, Brigham and Women's Hospital, Boston, MA, USA; Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA; Partners In Health, Boston, MA, USA. Electronic address: mbecerra@post.harvard.edu.
authors.forename: Mercedes C
authors.initials: MC
authors.lastname: Becerra
authors.affiliation: Division of Global Health Equity, Brigham and Women's Hospital, Boston, MA, USA; Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
authors.forename: Ted
authors.initials: T
authors.lastname: Cohen
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D014943:Global Health / Q000706:statistics & numerical data*; D006801:Humans; D015994:Incidence; D007223:Infant; D018570:Risk Assessment; D018088:Tuberculosis, Multidrug-Resistant / Q000453:epidemiology*