Multidrug-resistant tuberculosis in

children: evidence from global

surveillance
Matteo Zignol
1
, Charalambos Sismanidis
1
, Dennis Falzon
1
, Philippe Glaziou
1
,
Masoud Dara
2
and Katherine Floyd
1
Affiliations:
1
STOP TB Dept, World Health Organization, Geneva, Switzerland.
2
TB and M/XDR-TB Programme,
World Health Organization Regional Office for Europe, Copenhagen, Denmark.
Correspondence: M. Zignol, STOP TB Dept, World Health Organization, 20 Avenue Appia, 1211 Geneva 27,
Switzerland. E-mail: [email protected]
ABSTRACT 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 o15 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.
@ERSpublications
Surveillance data from 35 countries suggest that proportions of MDR-TB in children are not lower
than those in adults http://ow.ly/kPgPH
Received: Nov 01 2012
|
Accepted after revision: Dec 24 2012
|
First published online: Dec 06 2012
Support statement: This study was supported by the United States Agency for International Development through a grant
to the World Health Organization (US-2013-0579). The funders had no role in study design, data collection and analysis,
decision to publish, or preparation of the manuscript.
Conflict of interest: None declared.
ERJ Open articles are open access and distributed under the terms of the Creative Commons Attribution Non-
Commercial Licence 3.0.
|
ORIGINAL ARTICLE
TUBERCULOSIS
Eur Respir J 2013; 42: 701707 | DOI: 10.1183/09031936.00175812 701
Introduction
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 worlds 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 [1]. 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). However, very little is known about the magnitude of this problem in children [4]. 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 cannot expectorate sputum [5]. 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 [5].
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 o15 years) to have MDR-TB in each country for which
data are available.
Methods
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 [14]. 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 o15 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 o15 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
TUBERCULOSIS | M. ZIGNOL ET AL.
DOI: 10.1183/09031936.00175812 702
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.
Results
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. No
country reported MDR-TB in children in the period 19941999. 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%). Table 1 summarises the
characteristics of the data reported.
Odds ratios (95% CI) for MDR-TB in children aged ,15 years compared to adults aged o15 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 o15 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 could be established (fig. 2).
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
,5 years and in children aged 514 years. In these countries the odds of harbouring MDR-TB was not
significantly different between these two groups of children.
Discussion
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
No MDR-TB in children aged <15 years
At least one case of MDR-TB in children aged <15 years
No data available
FIGURE 1 Countries that reported drug resistance survey/surveillance data disaggregated by age group, 20002011.
MDR-TB: multidrug-resistant tuberculosis.
TUBERCULOSIS | M. ZIGNOL ET AL.
DOI: 10.1183/09031936.00175812 703
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TUBERCULOSIS | M. ZIGNOL ET AL.
DOI: 10.1183/09031936.00175812 704
testing of all bacteriologically confirmed tuberculosis cases. Continuous surveillance represents the most
appropriate approach to monitoring of drug resistance [15], 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 [21]. 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.
Less MDR-TB in children
Country
Children tested
for MDR-TB n
Children with
MDR-TB n
Children with
MDR-TB % OR (95% CI)
Georgia 20 1 5.0 0.25 (0.023.34)
0.37 (0.052.87)
0.42 (0.044.00)
0.45 (0.121.67)
0.45 (0.131.50)
0.50 (0.211.20)
0.59 (0.142.45)
0.64 (0.094.70)
0.68 (0.162.81)
0.76 (0.105.64)
0.82 (0.312.17)
0.88 (0.116.89)
0.91 (0.253.29)
1.00 (0.721.38)
1.03 (0.711.50)
1.05 (0.138.15)
1.14 (0.158.34)
1.19 (0.207.17)
1.34 (0.296.16)
1.35 (0.1710.50)
1.48 (0.643.42)
1.52 (1.331.74)
1.58 (1.032.44)
1.75 (0.525.91)
1.80 (0.2413.75)
1.82 (0.2413.95)
1.86 (0.983.53)
2.04 (0.498.47)
2.35 (1.433.85)
2.36 (1.603.49)
3.11 (0.3825.56)
3.18 (0.5020.19)
3.44 (1.1310.51)
3.60 (0.3734.71)
5.76 (0.7643.98)
0.7
11.1
10.0
10.0
26.9
2.4
2.3
3.8
1.1
1.6
8.3
1.1
15.4
38.5
7.7
2.2
40.0
7.7
5.9
2.7
16.4
3.4
3.2
1.0
4.5
3.1
2.1
2.9
2.5
9.1
2.3
20.0
75.0
4.5
1
1
1
5
7
2
1
2
1
4
1
2
21
45
1
4
2
2
1
3
257
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3
1
1
3
1
18
24
1
1
4
3
1
135
9
10
50
26
82
43
53
93
254
12
183
136
117
13
185
5
26
17
112
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872
95
103
22
96
47
613
971
11
44
20
4
22
Portugal
Estonia
Armenia
Lithuania
Republic of Moldova
Saudi Arabia
Italy
Turkey
Switzerland
Belgium
Somalia
The Netherlands
Latvia
Kazakhstan
Bangladesh
Austria
Uzbekistan
Bulgaria
Argentina
Sweden
South Africa
Germany
Norway
Denmark
Yemen
Australia
Ireland
USA
UK
Hungary
New Zealand
Namibia
Belarus
More MDR-TB in children
Poland
0.03 1 30

FIGURE 2 Forest plot depicting the association between multidrug-resistant tuberculosis (MDR-TB) in children (aged ,15 years) versus adults (aged o15 years)
in countries reporting at least one MDR-TB case in children. Data among all (new and retreated) cases are presented.
TUBERCULOSIS | M. ZIGNOL ET AL.
DOI: 10.1183/09031936.00175812 705
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 [9], 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 more than
half of children with tuberculosis are ,5 years old [27]. 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%) [1]. 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). Overall,
missing data on age did not affect the interpretation of the results. 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. These limitations should be taken into consideration when interpreting the results
of our study.
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 should be systematically
implemented and should always include children [29, 30]. 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.
Acknowledgements
All authors are staff members of the World Health Organization. The authors alone are responsible for the views
expressed in this publication and they do not necessarily represent the decisions or policies of the World Health
Organization.
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