title: Global burden of drug-resistant tuberculosis in children: a mathematical modelling study.
abstract: After infection with Mycobacterium tuberculosis, children are at an increased risk of progression to tuberculosis disease; a condition that can be challenging to diagnose. New estimation approaches for children have highlighted the gap between incidence and notifications of M tuberculosis, and suggest there are more cases of isoniazid-resistant and multidrug-resistant (MDR) disease than are identified. No work has yet quantified the burden of drug-resistant infection, or accounted for other types of drug resistance or sampling uncertainty.
  
  
  
  We combined a mathematical model of tuberculosis in children with an analysis of drug-resistance patterns to produce country-level, regional, and global estimates of drug-resistant infection and disease. We determined drug resistance using data from the Global Project on Antituberculosis Drug Resistance Surveillance at WHO, from surveys and surveillance reported between 1988 and 2014. We combined 1000 sampled proportions for each country from a Bayesian approach with 10 000 sampled country estimates of tuberculosis disease incidence and M tuberculosis infection prevalence. We estimated the proportions of tuberculosis cases at a country level with isoniazid monoresistance, rifampicin monoresistance, multidrug resistance (MDR), fluoroquinolone-resistant multidrug resistance, second-line injectable-resistant multidrug resistance, and extensive multidrug resistance with resistance to both a fluoroquinolone and a second-line injectable (XDR).
  
  
  
  We estimated that 850 000 children developed tuberculosis in 2014; 58 000 with isoniazid-monoresistant tuberculosis, 25 000 with MDR tuberculosis, and 1200 with XDR tuberculosis. We estimate 67 million children are infected with M tuberculosis; 5 million with isoniazid monoresistance, 2 million with MDR, and 100 000 with XDR. Africa and southeast Asia have the highest numbers of children with tuberculosis, but the WHO Eastern Mediterranean region, European region, and Western Pacific region also contribute substantially to the burden of drug-resistant tuberculosis because of their much higher proportions of resistance.
  
  
  
  Far more drug-resistant tuberculosis occurs in children than is diagnosed, and there is a large pool of drug-resistant infection. This finding has implications for approaches to empirical treatment and preventive therapy in some regions of the world.
  
  
  
  UNITAID.
authors.affiliation: School of Health and Related Research, University of Sheffield, Sheffield, UK. Electronic address: p.j.dodd@sheffield.ac.uk.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Dodd
authors.affiliation: Global TB Programme, World Health Organization, Geneva, Switzerland.
authors.forename: Charalambos
authors.initials: C
authors.lastname: Sismanidis
authors.affiliation: Department of Paediatric Infectious Diseases, Imperial College London, London, UK.
authors.forename: James A
authors.initials: JA
authors.lastname: Seddon
mesh_terms: D000995:Antitubercular Agents / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D014943:Global Health; D006801:Humans; D015994:Incidence; D007538:Isoniazid / Q000627:therapeutic use; D008962:Models, Theoretical; D009169:Mycobacterium tuberculosis / Q000302:isolation & purification; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000453:epidemiology
chemical_list: D000995:Antitubercular Agents; D007538:Isoniazid