Comment

www.thelancet.com/respiratory Published online March 24, 2014 http://dx.doi.org/10.1016/S2213-2600(14)70009-8 1

Child health and tuberculosis
Historically, children were excluded from programmes
for tuberculosis control that focused exclusively on the
identication and treatment of infectious adult cases.
Tuberculosis was included in the sixth Millennium
Development Goal (MDG). This goal focused on major
global epidemics, which reinforced the emphasis on
epidemic control with little appreciation of the im port-
ance of tuberculosis in the context of child survival. This
situation is changing. World Tuberculosis Day 2012 was
devoted to childhood tuberculosis and there is growing
awareness that tuberculosis is a major cause of illness
and death in young children in tuberculosis-endemic
areas.
A recent Save the Children report about preventable
deaths in childhood celebrated some impressive
achievements, but emphasised that rising inequities
will jeopardise the gains.
1
Globally, the deaths in children
are increasingly concentrated in the poorest and
most disadvantaged groups in society.
1
Tuberculosis
is strongly associated with social deprivation, and
poverty stricken areas are often pockets of frequent and
sustained transmission of Mycobacterium tuberculosis.
The contribution of tuberculosis to child mortality
requires careful scrutiny in these areas, but accurate
data are hard to obtain because of di culties in
conrmation of the diagnosis and frequent overlap
of clinical presentation with other common causes
of child mortality in these settings. Pooled analysis of
autopsy studies identied tuberculosis in about 10% of
811 children (with and without HIV infection) who died
from respiratory disease in ve African countries.
2
Of
the estimated 13 million deaths in children attributed
to pneumonia in 2011, most occurred in young children
living in tuberculosis-endemic areas, almost half in
Africa.
3
Apart from its contribution to pneumonia
deaths, tuberculosis can also be the underlying cause
in children dying from meningitis, presumed sepsis,
HIV/AIDS, or severe malnutrition.
4
The WHO Global Tuberculosis Report 2013 estimates
that 530 000 children developed tuberculosis during
2012, resulting in 74 000 deaths in HIV-uninfected
children.
5
Estimates are limited by poor case ascertain-
ment and incomplete recording and reporting practices.
Increasing the visibility of the tuberculosis burden
in children requires improved diagnostic methods
combined with enhanced surveillance and reporting
systems. Until then, mathematical modelling with
setting-specic epi demio logical and demographic data
and known age-related risks of infection and disease
might improve the estimation of disease burden. The
table summarises recent progress and key challenges in
childhood tuberculosis.
Lancet Respir Med 2014
Published Online
March 24, 2014
http://dx.doi.org/10.1016/
S2213-2600(14)70009-8
See Editorial Lancet Respir Med
2013: 1: 755
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Progress Challenges
Disease burden Updated estimates included in 2013 global tuberculosis report
5
Disease estimates are conservative, and deaths only include children without HIV infection;
no information on drug-resistant tuberculosis in children
Diagnosis Roll out of Xpert MTB/RIF assay Cartridge cost; restricted availability; no information about isoniazid susceptibility; poor
sensitivity in children; no point-of-care test; restricted availability of chest radiography
Treatment
Drug-susceptible
tuberculosis
Optimal dose guidance; short-course regimens to be assessed in limited
disease
Awaiting quality-assured, child-friendly, xed-dose combination preparations
Drug-resistant
tuberculosis
Excellent treatment outcomes in children with drug-resistant tuberculosis;
new drugs available; regulatory encouragement to develop child-friendly
formulations; and assess safety, tolerability, and pharmacokinetics
Few children are treated in existing programmes for the treatment of drug-resistant
tuberculosis; many side-eects to consider, especially ototoxicity with injectable drugs
Prevention
Infection control Greater risk awareness and improved guidelines Poor implementation in most tuberculosis-endemic areas; little awareness of the risk posed
to susceptible young children
Vaccines Several new candidate vaccines, and well established trial sites No correlate of protection; no protective eect from rst new vaccine tested; di cult to
dene clinically relevant trial endpoints
Drug-susceptible
tuberculosis
Pragmatic guidance using simple symptom-based screening; new
short-course preventive therapy options
Policy-practice gaps remain; safety and tolerability of new short-course options to be
established in children
Drug-resistant
tuberculosis
Benet of preventive therapy in susceptible young children after contact
with someone who is infectious for multidrug resistance tuberculosis
Universal applicability of study ndings is uncertain; di cult to generate high-quality
evidence with few children exposed to multidrug-resistance tuberculosis and with variable
drug resistance proles
Table: Progress and challenges in childhood tuberculosis (updated from Marais and colleagues
6
)
Comment
2 www.thelancet.com/respiratory Published online March 24, 2014 http://dx.doi.org/10.1016/S2213-2600(14)70009-8
Vertical national tuberculosis control programmes
(NTPs) can provide improved focus and oversight,
but the entry point to diagnosis and care for young
children with tuberculosis is usually in the child health-
care sector. There is a need for stronger links and
collaboration between the child health-care sector
and NTPs to provide improved case-detection and
management (including at the primary and secondary
levels of care), to provide more robust national data
of child tuberculosis cases and outcomes, and to
undertake gap analysis and operational research to
address the wide policy-practice gaps. The need for a
more integrated approach to care within the maternal
and child health sector is a major theme of the recently
launched roadmap for tuberculosis in children.
4

The rising number of cases of drug-resistant
tuberculosis threatens traditional control eorts.
7

Descriptions of child contacts with identical resistance
proles to adult source cases
8
provide evidence that
clinical drug-resistant strains are highly transmissible.
True epidemic spread is conrmed with the ndings of
molecular epidemiology studies showing high rates
of strain clustering of several clones.
9
WHO estimated
450 000 (range 300 000600 000) cases of multidrug-
resistant (MDR) tuberculosis in 2012, and less than
20% (77 000) of these received appropriate treatment.
5

Accurate paediatric data are not available, but since
children contribute about 10% of the tuberculosis
disease burden globally
6
and MDR strains are readily
transmitted, about 45 000 paediatric cases might be
expected. Surveillance data suggest that the percentages
of MDR tuberculosis are similar in children and adults
(especially in new adult cases), with high rates of MDR
tuberculosis found in children from settings with high
HIV prevalence.
10
Unlike adults, treatment outcomes for children with
MDR tuberculosis are excellent, with clinical cure rates
in excess of 80%.
11
This outcome has been achieved
in the absence of child-friendly formulations and
pharmacokinetic data to guide dosing in the youngest
age groups. For this reason regulatory authorities are
now encouraging the testing of tuberculosis drugs in
children, to at least ensure the gathering of adequate
safety and pharmacokinetic data.
12
Despite routine
recommendations to use preventive therapy in young
children after exposure to an individual with infectious
drug-susceptible tuberculosis, preventive therapy with
second-line antituberculosis drugs in child contacts of
drug-resistant tuberculosis cases is less well accepted
because there are no randomised controlled trials
to conrm their eectiveness.
13
With evidence from
a pragmatic cohort study in South Africa showing
benet,
14
tailored preventive therapy is becoming
popular but universal applicability remains a concern.
The rise of drug-resistant tuberculosis confronts
traditional control eorts with the uncomfortable
dilemma of personalised (contextualised) versus
programmatic (one size ts all) management, and the
involvement of children emphasises the need for greater
cooperation and integration of tuberculosis and child
health services. Improved integration and optimal-care-
delivery models pose a public health challenge globally,
15

but urgent progress is needed to benet children in
tuberculosis-endemic areas.
*Ben J Marais, H Simon Schaaf, Stephen M Graham
Marie Bashir Institute for Infectious Diseases and Biosecurity and
Childrens Hospital at Westmead, Sydney Medical School,
University of Sydney, Locked Bag 4001, Sydney, NSW 2145,
Australia (BJM); Desmond Tutu Tuberculosis Centre, Department
of Paediatrics and Child Health, Faculty of Medicine and Health
Sciences, Stellenbosch University, Cape Town, South Africa (HSS);
and Centre for International Child Health, University of Melbourne
Department of Paediatrics and Murdoch Childrens Research
Institute, Royal Childrens Hospital, Melbourne, VIC, Australia
(SMG)
ben.marais@health.nsw.gov.au
We declare that we have no conicts of interest.
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