drug - resistant tuberculosis and multidrug - resistant tuberculosis ( mdr - tb ) in particular represent a major threat to the fight against tuberculosis globally .
mdr - tb is defined as disease caused by strains of mycobacterium tuberculosis resistant to at least isoniazid and rifampicin , the two most powerful first - line antituberculosis drugs . among the world 's 12 million ( range 1113 million )
prevalent cases of tuberculosis estimated by the world health organization ( who ) in 2011 , the best estimate was that 630 000 ( 5.3% ) had mdr - tb . globally ,
most cases of mdr - tb remain undetected and untreated because of limited laboratory capacity to conduct tests for drug resistance and limited access to second - line treatment , which is very long ( 20 months is recommended for most cases according to current who guidelines ) as well as toxic and expensive [ 13 ] . as with other forms of tuberculosis , mdr - tb can affect people of all age groups , including children ( aged 014 years ) .
the diagnosis of mdr - tb is bacteriological by definition , based on the isolation of strains resistant to medicines . while isolating m. tuberculosis in adults with pulmonary tuberculosis is generally an easy procedure ( the exception is patients who are immunocompromised ) , children mainly have paucibacillary disease , which means that specimens for culture and drug susceptibility testing are often difficult to obtain , particularly from the youngest who can not expectorate sputum . in most cases
adults represent the source of infection for children but household contact investigations are rarely performed as part of routine surveillance activities in resource - limited settings with a high burden of tuberculosis and tend to be confined to special research projects [ 6 , 7 ] .
therefore , the results of drug susceptibility testing from adult source cases are not systematically used to investigate drug resistance in children . for these reasons published reports of drug - resistant tuberculosis in children
are largely from hospital settings [ 811 ] where more efforts can be made to obtain respiratory specimens by gastric aspirates , induced sputum and/or nasopharyngeal aspirates , and bronchoalveolar lavage .
the objectives of the analyses presented in this manuscript are to describe all the available data on drug - resistant tuberculosis among children collected by the who global project on anti - tuberculosis drug resistance surveillance between 1994 and 2011 , and to assess the evidence whether children ( aged < 15 years ) are more or less likely than adults ( aged 15 years ) to have mdr - tb in each country for which data are available .
since 1994 aggregated drug resistance surveillance data have been reported on an annual basis to who , which ascertains the quality and representativeness of the data , performs analyses and disseminates the findings on regular basis [ 1 , 12 , 13 ] .
three main principles are used to ensure data quality : 1 ) data should be representative of the patients with tuberculosis in the country / geographical setting under study ; 2 ) patients ' treatment histories should be carefully obtained and available medical records reviewed to clearly determine whether patients have or have not previously received antituberculosis drugs ; and 3 ) laboratory methods for antituberculosis drug susceptibility testing should be selected from among those recommended by who , and all laboratory processes should be quality - assured in cooperation with a partner supranational reference laboratory [ 14 , 15 ] .
drug resistance surveillance data can be collected via special surveys of a representative sample of patients or continuous surveillance based on routine diagnostic drug susceptibility testing . in both cases ,
all consecutive patients with bacteriologically confirmed ( smear and/or culture positive ) pulmonary tuberculosis are included .
those with extrapulmonary disease and those who are already on treatment for tuberculosis are excluded . in special surveys , in order to select a sample of patients representative of all patients in a geographic setting , either of the following sampling techniques is used : 100% sampling of all diagnostic centres or probability - proportional - to - size cluster sampling . in routine surveillance , in order to ensure representativeness of the data , the coverage of culture and drug susceptibility testing should be high . a detailed description of the criteria used by who to ascertain whether survey and continuous surveillance data meet quality and representativeness standards is provided elsewhere [ 1 , 16 ] .
surveillance data used in this analysis were reported to who disaggregated by history of treatment ( new or previously treated ) , sex ( male or female ) and age ( < 15 or 15 years ) .
the full database of the global project on anti - tuberculosis drug resistance surveillance was investigated for this study .
subnational level data that were not representative of the entire country were excluded from the analysis .
data on susceptibility to isoniazid and rifampicin were reviewed and proportions of mdr - tb in children aged < 15 years and adults aged 15 years were compared . to assess the relationship between mdr - tb and age group , odds ratios with 95% confidence intervals were calculated using logistic regression models run separately for each country . for countries with data from multiple years
, robust standard errors were calculated to account for within - country time dependencies and the longitudinal facet of the data .
stata ( version 12 ; statacorp , college sta , tx , usa ) was used for all analyses .
since 1994 data on susceptibility to isoniazid and rifampicin disaggregated by age group have been reported to who from continuous surveillance or special surveys from a total of 85 countries . among them , 35 countries reported at least one case of mdr - tb in children < 15 years old during the period 20002011 .
figure 1 shows the 85 countries that reported drug resistance surveillance data by age group as well as the 35 countries that had at least one case of mdr - tb in children .
a total of 323 046 patients with tuberculosis who received drug susceptibility testing for isoniazid and rifampicin in these 35 countries , including 6070 children aged < 15 years ( 2% of all those tested ) , were included in the analysis .
for most countries ( 28 ( 80% ) out of 35 ) , data were generated from continuous surveillance systems and for two - thirds ( 23 ( 66% ) out of 35 ) , data were available for more than 1 year .
coverage of drug susceptibility testing in culture - positive cases was 86100% in all age groups except for bulgaria , georgia , hungary and south africa ( range 3672% ) .
countries that reported drug resistance survey / surveillance data disaggregated by age group , 20002011 .
mdr - tb : multidrug - resistant tuberculosis ; tb : tuberculosis ; na : not available . :
new and previously treated tb cases ; : estimates refer to the year of reporting , where multiple years are shown , estimates refer to the latest year of reporting . data from .
odds ratios ( 95% ci ) for mdr - tb in children aged < 15 years compared to adults aged 15 years varied widely among countries , from 0.25 ( 0.023.34 ) to 5.76 ( 0.7643.98 ) . in five countries children
aged < 15 years with tuberculosis had significantly higher odds of harbouring mdr - tb strains compared to adult patients aged 15 years ( germany : 1.58 ( 1.032.44 ) ; namibia : 3.44 ( 1.1310.51 ) ; south africa : 1.52 ( 1.331.74 ) ; uk : 2.36 ( 1.603.49 ) ; usa : 2.35 ( 1.433.85 ) . in australia ,
a weak positive association between mdr - tb and age < 15 years was documented ( 1.86 ( 0.983.53 ) ) . in the remaining 29 countries , no association between mdr - tb and age
forest plot depicting the association between multidrug - resistant tuberculosis ( mdr - tb ) in children ( aged < 15 years ) versus adults ( aged 15 years ) in countries reporting at least one mdr - tb case in children .
data among all ( new and retreated ) cases are presented . among the 36 countries included in our analysis , 10 ( austria , belgium , germany , latvia , namibia , norway , republic of moldova , sweden , uk and usa ) reported at least one case of mdr - tb in children aged
the odds of harbouring mdr - tb was not significantly different between these two groups of children .
this study is the first analysis of levels of mdr - tb among children using a very large dataset that has been developed over 10 years by the who global project on anti - tuberculosis drug resistance surveillance .
the results suggest that , in a given setting , the proportion of mdr - tb in children and adults with bacteriologically confirmed tuberculosis is broadly similar , a finding consistent with reports from a few small - scale surveys conducted in the central african republic , india , south africa and the usa [ 11 , 1820 ] . in none of the countries in our study was the risk of mdr - tb in children significantly lower than in adults . at the same time , levels of mdr - tb in children are highly variable among countries , but insufficient data on potential risk factors mean that further research is needed to understand this heterogeneity .
the global dataset that we analysed illustrates that drug resistance in children is reported mainly by high - income countries with continuous surveillance systems based on routine diagnostic drug susceptibility testing of all bacteriologically confirmed tuberculosis cases .
continuous surveillance represents the most appropriate approach to monitoring of drug resistance , but it requires good laboratory infrastructure that is generally not available in resource - limited settings . since the countries included in our analysis are a convenient sample and not representative of global regions , pooled estimates of the burden of mdr - tb in children have not been calculated .
only seven countries were able to identify mdr - tb in children through special surveys conducted among representative samples of patients with tuberculosis .
surveys are generally not designed to accurately measure mdr - tb in a selected group of patients , such as children , as this would require very large sample sizes . in addition , obtaining ethical clearance for surveys involving children is very complex in some settings and this is sometimes used as a justification for excluding children from enrolment in surveys .
novel survey approaches in screening , sampling and diagnosis that would allow the measurement of drug resistance in children in countries with limited laboratory capacity need to be explored .
a new molecular technology has been recently introduced for the rapid diagnosis of tuberculosis and tuberculosis resistant to rifampicin .
the tool , named xpert mtb / rif assay ( cepheid , sunnyvale , ca , usa ) , has the potential to facilitate the diagnosis of drug resistance in smear - negative patients , including in children .
two studies have suggested that the xpert mtb / rif assay can facilitate the diagnosis of drug resistance in children [ 22 , 23 ] , but more work should be done to improve the sensitivity of the test in patients with paucibacillary disease . among the countries included in our analysis , a particular concern is the elevated risk of mdr - tb in children documented in namibia and south africa , two southern african countries with a high prevalence of hiv .
if confirmed by further data , this finding has important implications for tuberculosis and mdr - tb control . as it is rare for children to develop drug resistance during their treatment , detection of mdr - tb in this age group
is usually a sensitive indicator of recent transmission of drug - resistant strains from contacts present in the environment in which they live .
the fact that in germany , the uk and usa children appear to have a significantly higher risk of mdr - tb compared to adults also requires further evaluation .
contact investigations that are routinely performed in these countries could have played a role in this finding . in these countries
the epidemic of tuberculosis is largely driven by migration [ 2427 ] and foreign - born patients with tuberculosis are known to have higher levels of drug resistance compared to those born in the country . in western european countries
this is a strong indication of household transmission and highlights the need for better prevention and diagnosis of tuberculosis and mdr - tb in children and in particular among the youngest .
research on effective chemoprophylaxis regimens for children exposed to patients with mdr - tb is important .
the fact that in our analysis children aged < 15 years represented 2% of all cases who received drug susceptibility testing is in line with the proportion of children among all cases notified with tuberculosis in 2011 ( 2% ) .
our analysis has two main limitations that are intrinsic to the use of programmatic surveillance data .
first , in a few countries , data on the age of tuberculosis patients were missing ( 8% of patients who were tested for drug susceptibility in south africa and 23% in namibia and italy ) .
second , the inherent challenges involved in diagnosing tuberculosis and mdr - tb in children , described above , are likely to affect the validity of surveillance data . although survey and surveillance data used for this analysis met the representativeness and quality criteria defined by who , it is not possible to completely rule out selection bias introduced by the difficulties in diagnosing tuberculosis in children and by contact investigations in countries where those are routinely performed .
our analysis from a subset of 10 countries showed no significant difference in levels of resistance between children aged < 5 years and children aged 514 years .
this reinforces the hypothesis that , although obtaining specimens for culture from the youngest children is often difficult and drug - resistant tuberculosis is more likely to be underdiagnosed , younger children have a similar likelihood of harbouring drug resistant strains than older children . given the limited availability of data for this analysis this finding should be confirmed by larger studies . in conclusion , this analysis suggests that while the problem of mdr - tb in children is largely unknown and often unreported [ 4 , 5 , 11 , 28 ] , a child with tuberculosis is as likely as an adult with tuberculosis to have mdr - tb . to improve the identification of mdr - tb in children for treatment and for surveillance purposes , household contact investigation of all patients with mdr - tb
in addition , children should be systematically included in all surveillance activities , including drug resistance surveys when routine surveillance is not in place .
more broadly , the data illustrate the need for intensified efforts to develop better tests for the diagnosis of tuberculosis and mdr - tb in children and to improve the availability of paediatric drug formulations for the treatment of children with tuberculosis and mdr - tb .
 multidrug - resistant tuberculosis ( mdr - tb ) can affect persons of any age , but it remains unknown whether children are more or less likely than adults to have mdr-tb.representative drug resistance surveillance data reported to the world health organization between 1994 and 2011 were analysed to test the association between mdr - tb and age group ( children aged < 15 years versus adults aged 15 years ) , using odds ratios derived by logistic regression with robust standard errors.of 85 countries with data from nationwide surveys or surveillance systems , 35 reported at least one paediatric mdr - tb case . 
 aggregated data on age and drug susceptibility testing for 323 046 tuberculosis cases notified in these 35 countries were analysed . 
 odds ratios for mdr - tb in children compared to adults varied widely between countries . in germany , namibia , south africa , the uk and the usa , mdr - tb was positively associated with age < 15 years . in the remaining countries no association was established.despite the limitations intrinsic to the use of surveillance data and to the challenges of diagnosing childhood tuberculosis , our analysis suggests that proportions of mdr - tb in children and adults are similar in many settings . 
 of particular concern is the association found between age < 15 years and mdr - tb in southern african countries with high hiv prevalence . 
Introduction
Methods
Results
Discussion