Out of the Dark:
An implementers’ guide to
managing TB in children

msfaccess.org

Out ofthe Dark:
An implementers’ guide to
managing TB in children

MSF TB TREATMENT PROGRAMMESMSF TB programmes
MSF drug-resistant
TB programmes

MSF provided TB treatment to 30,000 people in 29 countries in 2010.
That included 3,300 children under the age of 15 and 1,000 people
receiving treatment for drug-resistant TB.

Front Cover Photo: © Susan Sanders / MSF

2

Médecins Sans Frontières    Out of the Dark: An implementers’ guide to managing TB in children© Bruno De CockThough curable, tuberculosis (TB)
kills at least 130,000 children
each year,1 making it one of the top
ten causes of death in children.
There are also rising numbers ofchildren who are infected withdrug-resistant forms of TB which
require complex treatment.
Paediatric TB is a neglected disease.
Insufficient research and developmentattention has led to a lack of diagnostic
methods adapted for children’s needs anda lack of appropriate drug formulations
for children. This, in turn, has contributed
to a situation in which TB programmes
often under-diagnose, under-treat, oromit altogether children with TB.
Despite the difficulties in diagnosing andtreating children with TB, children can be
cured, and it is imperative to make thebest use of the tools that are available
today to ensure that children with TB do
not remain in the dark. This report will
outline the current state of paediatric TB

care, looking at current practices, newdevelopments and research needs – inpaediatric TB diagnosis, treatment andprevention. It intends to act as a guide totreatment programmes for implementationof the best standard of care currently
available to children with TB, and toraise awareness of the need to continue
to push for improvements in the
management of childhood TB.
Paediatric TB treatment has also been
neglected as a strategic priority. Until
recently, the World Health Organization’s(WHO) Global Tuberculosis Control
strategy has focused on identifying andmanaging the most infective causes ofTB (primarily smear-positive pulmonary
TB). However, children with TB, especiallythose under ten years of age, tend tohave a form of the disease that is difficult
to diagnose, as it reveals very few bacteria
in the lungs (paucibacillary smearnegative disease). Because paediatric TB
is an indicator for the current control of
TB in the general population, and also

acts as a future reservoir for TB disease,any successful TB control programmeshould include a paediatric focus.
Children with TB differ from adults intheir disease progression in ways that haveimportant implications for the prevention,
diagnosis and treatment of TB. Young age,and co-morbidities such as malnutrition
and HIV, all further worsen the mortality
and morbidity in children with TB.
However, when started promptly, theoutcome of TB treatment in children
is generally good, even in those thatare young and immuno-compromised.
Some studies suggest that compared toadults, children appear to experience
fewer adverse events associated withuse of the recommended treatment
regimens.2
While critical gaps in research anddevelopment for paediatric TB remain
and must be filled, there is muchthat can be done today to reduce thenumber of children dying from thedisease each year.

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3Diagnosis“ It’s really difficult
sometimes for one person to
make a decision where thecase is not straightforward.
So you always consult
each other, you share.
You can go to the nextroom, present the case,show the person the x-ray.
Then you can have a small
discussion in relation to
the x-ray and the previous
history. Then you can takea collective decision, it’s
not just one person who
decides who is to start indifficult cases. So I thinkthat has really assistedus, sharing informationand consulting each otherwhen we get stuck.”Hussain Kerrow, MSF
Clinical Officer, Kenya

Outdated tools and enormous
practical challenges make thediagnosis of paediatric TB very
difficult, especially in resource-poor
settings. Poor diagnostic capacity inmany parts of the world means thatmany children die without everbeing diagnosed or treated; others
are diagnosed only long after they
have developed active disease,making treatment more complicatedand less likely to succeed.

they can, sputum-based tests do not detect
paucibacillary or extrapulmonary TB that occurs
more frequently in children. Only 15% of
paediatric TB cases are sputum smear-positive,
and only 30 to 40% yield mycobacteriapositive cultures;3 for children who are coinfected with HIV, the figures are even lower.
Other diagnostic methods, such as chest
x-ray and tuberculin skin testing, do not
involve detecting the presence of TB bacteria
directly, but each of these non-microbiologicalmethods also has major limitations.

While most of these problems also apply to
TB in adults, diagnosing TB in children is far
more problematic.

More research is needed for a simple diagnostic

The most commonly used TB test is sputum
smear microscopy to confirm the presence of
TB mycobacteria. A positive culture is howeverconsidered the “gold standard” definitive
result, although the technique can take weeks
or months to give results. But most children,
especially the youngest ones, cannot produce
enough sputum for these tests. And even whenmake a TB diagnosis, based on the cumulative

tool that can give on-the-spot results. Yet
despite these challenges, physicians usually canevidence from several approaches along withclinical findings, with enough confidence
to justify initiating treatment. The following
section describes the main tools available fordiagnosing paediatric TB and summarises
how to optimise their use in deciding onwhether to start treatment.

Current Practices
Current WHO guidelines4 focus on gathering evidence from the following range of approaches:

4

ClinicalCareful history (including TB contact; symptoms consistent with TB)
Physical examination (including growth assessment)
HIV testing (in high HIV prevalence areas)

Non-microbiological

Tuberculin skin testing (TST)Other investigations relevant for pulmonary or extrapulmonary
TB (e.g., x-rays)

Microbiological

Bacteriological confirmation whenever possible

Médecins Sans Frontières    Out of the Dark: An implementers’ guide to managing TB in children

Clinical Approaches
In the absence of a definitive“gold standard” test, clinicalfindings and judgement areespecially important indiagnosing TB.
The key components to consider are:• Clinical examination for symptoms
consistent with suspected pulmonaryor extrapulmonary TB, plus growthassessment. Beyond looking for classicalsymptoms of TB in adults, extra
vigilance is essential since children
are more likely than adults to present
with atypical symptoms. In addition,
symptoms for extrapulmonary TB vary
widely, depending on where in the
body the infection is located.
• HIV testing (in high prevalence areas).
Children with HIV are more susceptible
to TB, at increased risk of diseaseprogression, but are more likely tohave smear-negative disease.

© Susan Sanders / MSF• Careful history, including history of
TB contact and symptoms consistent
with TB. Contact history is particularly
important, especially in very young
children with suspected TB.

Charity Achieng lives with her mother in Mathare, a slum on the edges of
Kenya’s capital, Nairobi. Charity is suspected of having TB but is finding it hard
to cough up the necessary sputum sample from deep inside her chest required toattempt a diagnosis through miscroscopy. To get hold of an adequate sample,
Charity is given a gastric lavage to extract sputum from her stomach.

Non-Microbiological Approaches• A chest x-ray (CXR) can be useful for
diagnosing TB, but presents several
challenges. An x-ray machine is notalways readily available, especially inresource-limited settings. Obtaining
quality films is difficult, and trained
personnel are needed to interpret the
x-ray appropriately and to ensure
maintenance and safety of the machine.
If these difficulties can be addressed,
possibly by using novel techniquessuch as teleradiology for interpretation,then CXR is a helpful addition to
the diagnostic toolkit.
• Tuberculin skin testing (TST). Althougha positive TST has been considered as
evidence supporting a TB diagnosis, theutility of TST in endemic countries isseverely limited by some shortcomings.
Chief among these: an inability to
distinguish between latent and active

TB, high proportions of both false
negative and false positive results, andparticular unreliability in HIV-infected
and malnourished children.
Detection of interferon-y production bysensitised mononuclear cells (T-SPOT) or
whole blood (interferon-y release assayIGRA) on stimulation by specific M.
tuberculosis antigens represents analternative to TST, but has not beenshown to have major advantages over
TST in terms of sensitivity and specificity.5
Thus, while these tests can play a rolein diagnosing latent TB in high-income,non-endemic countries, their utility
in diagnosing active TB in children in
high-burden countries is very limited.
WHO advises against the use of IGRA
in middle- and low-income countries.6• Serological tests. Dozens of serologicaltests for active TB are sold commerciallyin parts of the world. In 2010, a
meta-analysis of published studies onthese tests found that they show poor
diagnostic accuracy for pulmonary
and extrapulmonary TB in adults.7
Based on these findings, WHO issued
a “negative policy guidance”, strongly
recommending against using thesetests for diagnosing active TB.8
• “Score charts” that weigh the findings
from these different diagnostic measures
have long been used in various contexts
as aids in reaching a final diagnosis;
more than 16 such tools have beendeveloped. However, their performancevaries widely across different settingsand is poorest in children withpulmonary TB and those whoare HIV-infected.9

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5Microbiological Confirmation
Although obtaining
mycobacteriological confirmationof TB in children poses significant
challenges, it should neverthelessbe attempted whenever andwherever possible, and especially

One major constraint in obtaining bacterial
confirmation is that most young children
cannot produce adequate sputum –instead, they produce only saliva. Several
procedures are currently being used or

studied to improve the collection of sputum
from children or to test the usefulnessof alternative non-respiratory specimens(see Table 1) so that more paediatric TB
cases can be confirmed microbiologically.

should not be delayed for“ If we are lucky enough to be able to access better facilities, for instance in a
local hospital, there are a few techniques we can use to get hold of a sputum
sample. But access to even these less than perfect procedures is a luxury for mostof our patients who don’t live near a hospital. So most of the time you make adecision based on your clinical observation – should I or should I not treat thischild for TB. And making that decision you’re talking about the life of a child,so it is not something to be taken lightly.”

specimen collection if there is

Dr Bern-Thomas Nyang’wa, MSF TB Implementerin suspected DR-TB cases, toensure that a decision to initiate
DR-TB treatment is correct.
However, initiation of treatment

clinical suspicion of TB.

Table 1: Overview of specimen collection methods10
SPECIMENCOLLECTION METHOD*DESCRIPTION & CHARACTERISTICS

Gastric aspiration 42

Pipe inserted down throat into stomach to extract sputum• Difficult, invasive procedure• Requires hospitalisation or repeated visits on three consecutive days
• Must be performed by trained nurses• Highly uncomfortable for children; poorly accepted

Lymph node fine needle
aspiration• Minimally invasive• Can be safely performed on outpatient basis 43• Yields specimens suitable for smear microscopy, culture and drug-sensitivity testing• Yield for bacteriological culture (to confirm TB diagnosis) might be higher than with sputum• Potentially under-utilised diagnostic option

Sputum induction44

Child breathes into nebulizer containing gases which irritate lungs & induce coughing• Can be performed on most children. Requires some basic equipment and infection control measures• Requires trained nurses. Highly operator dependent• One sputum induction provides same yield of bacteriological confirmation as three gastricaspirations45 in hospitalised children; incremental yield with a second sputum induction• Useful in hospital settings; limited data currently available on the use of this method in primary
healthcare facilities

String test

Child swallows gelatin capsule containing coiled nylon string, capsule recovered later by pulling string• Most appropriate for older children, who tolerate procedure well46• Yield of bacteriological confirmation similar to sputum induction in HIV-infected adult population47• Limited by cost, lack of widespread availability• Younger children have difficulty swallowing the capsule• Not yet widely used; additional studies needed48

Nasopharyngeal aspiration• Relatively non-invasive• Variable performance, but some studies suggest similar yield to culture of sputum induction49,50• Not yet widely used; more data needed51,52 to assess usefulness of samples obtained

Stool• Easily obtained; can be done at primary health facilities• Contains TB bacteria from swallowed secretions•S pecimen requires stringent decontamination procedures, thus culture from stool specimens
has proven insensitive so far• More studies needed to assess usefulness, feasibility* Most published data and most widely used test listed first.

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Médecins Sans Frontières    Out of the Dark: An implementers’ guide to managing TB in children© David Levene

New Developments
The most significant recent
advance in TB diagnosis is Xpert
MTB/RIF, an automated systemthat identifies TB bacteria (bydetecting its DNA) from sputum
samples in less than two hours
and also detects mutations
which confer resistance torifampicin, a key TB drug.
Although it uses expensive
machinery and requires alaboratory infrastructure withtrained personnel, Xpert MTB/
RIF could potentially mean
major increases in diagnostic
capacity where implemented.
A first evaluation of this technology for
diagnosing paediatric pulmonary TB wasrecently published.11 It found that Xpert
MTB/RIF has a higher detection rate thansmear microscopy; however, sensitivity
for smear-negative TB was lower onsamples from children compared withthose from adults.
Furthermore, Xpert MTB/RIF was lesssensitive than standard culture methods
in diagnosing childhood TB, althoughmuch faster (one day vs 12 days).
While this shows that Xpert MTB/RIF can
support much more rapid diagnosis of
paediatric TB, it also reveals diagnostic
challenges and limitations that still need
to be overcome – not least a reliance on
sputum samples, which limit its utility
to a minority of paediatric cases.
In general though, emerging methods
and technologies for diagnosing TB are
rarely evaluated in samples from children,
leading to a paucity of information on theperformance of new tests in paediatricpatient populations. For example, of fivepromising new methods – microscopicobservation drug-susceptibility assay(MODS), nitrate reductase assay (NRA),
colorimetric redox indicator assay (CRI),
line-probe assay (LPA) and loop-mediatedisothermal amplification (LAMP) – studies
are either limited or completely lacking
in children. Evidence for the performanceof these methods on extra- pulmonary
samples is even weaker.12
The ideal TB diagnostic test would be
one that works with specimens otherthan sputum, so that microbiologicalconfirmation of paediatric TB would

no longer be limited by a child’s inability
to cough up sputum. One exciting
approach involves attempts to diagnose
TB in urine, by detecting the presence ofa fatty molecule (lipoarabinomannan, or
LAM) found in the cell wall of TB bacteria
and secreted into the urine by active TB.
Current work is focused on evaluating
this urinary test for diagnosing TB in HIVinfected adults.13 Such a test is potentiallyalso ideal for children, since urine is aplentiful, easily collectable sample.
However, to our knowledge there are
no studies assessing the performance of
this test in paediatric populations.
Several obstacles have hindered suchstudies. One is the lack of a gold standard
test to use in evaluating the performanceof new tests in children; another is the lackof standardisation in study design. However,consensus on the methodologicalapproaches to follow for evaluating new
diagnostic tests in children has recently
been reached,14 eliminating a criticalbarrier in paediatric TB diagnostics
research and development. These new
approaches should be implemented
rapidly so that the rate of progress canbe accelerated.

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TREATMENT© Bruno De Cock

Treatment
Children diagnosed with TB in
a timely manner and started on
appropriate treatment usually
have successful treatment
outcomes – anti-TB drugs are
generally better tolerated inchildren than in adults.2
But achieving treatment success in children
relies not only on prompt diagnosis andtreatment initiation, but also on theadministering of appropriate treatment
regimens, accurate dosing of the child basedon its weight, and support for treatment
adherence. Making sure children’s caregivers
receive appropriate education, counsellingand support is therefore critical. Securing acontinuous supply of quality-assured drugs
is an additional prerequisite for successful
paediatric TB treatment.

in first-line TB treatment. While it is welcomethat the guidelines have been changed
to reflect optimal doses for children, theformulations available on the market today
are not tailored to deliver the new dosages.
And a slow response on the part of WHO
to release recommended drug strengths
and the composition of new fixed-dose
combination drugs (FDC) has meant that,
despite two years having passed since newdosage guidelines were issued, no new FDC
drugs for children have been developed
to correspond to the new doses. Until that
happens, treatment providers are struggling
to provide children the new doses throughcomplex interim dosing recommendations(see Box on page 11).

Despite common practice in a number ofcountries, there is no evidence that routine
hospitalisation of children with TB results inbetter outcomes and it should be required forspecific circumstances only. Policies of routine,
prolonged hospitalisation that persist in many
countries need to be urgently reviewed inlight not only of their potentially negative
psychosocial impact on individual children
and their families, but also in considerationof the risk of hospital-acquired transmission.

Children co-infected with HIV, or withdrug-resistant TB are additionallyproblematic in relation to treatment, withlimited adapted paediatric formulations
available to facilitate simple management.
There are several guidelines available which
provide dosages for children to treat
DR-TB, however for several drugs, conflicting
dosages are published. The majority of drugs
used for treatment of DR-TB are old, and no
pharmacokinetic data is available for use inchildren. Therefore, dosages available today
are based on extrapolation of adult dosages,
expert opinion, and experience.

An important development for paediatric
TB treatment has been the review of anti-TB
drug dosages for children with drugsusceptible TB. In 2009, the World HealthOrganization released revised dosage
guidelines for TB in children that increased
the dosages of each of the four drugs used

And while there are several promising new
drugs for TB under development, only one
drug in the pipeline is being studied inchildren. Children should systematicallybe included in new drug trials, so they
can also benefit from advances in researchand development.

While there are several
promising new drugs for
TB under development,
only one drug in thepipeline is being
studied in children.

“ TB medication in general is safe. It’s difficult to take so many many tablets, but ingeneral the side effects are quite few… However we have to be careful, particularly inchildren to make sure that we dose them correctly and that we monitor them very closely
for side effects. Because obviously children can’t tell us, like an adult can tell us,
what’s wrong with them or if they’re in pain or if they’re not feeling well.”
Dr Marianne Gale, MSF Medical Advisor for Paediatric TB & HIV

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9Current Practices
Treatment regimens
The treatment of drug-sensitive TB inchildren follows the same principles asthat of adults. Four drugs – isoniazid,rifampicin, pyrazinamide and ethambutol– are taken for a two-month intensive
phase, followed by a four-monthcontinuation phase of rifampicin
and isoniazid.
At the end of 2010, WHO released
new guidelines for the management ofchildhood TB. These guidelines clarified
the role of ethambutol in childhood
TB which for several years had beenquestioned due to its toxicity profile,and also advised against the use of
streptomycin in children.

Streptomycin has long been used to treat
TB re-treatment cases in children, as well
as TB meningitis. However, there is little
evidence of its added value in treatment
regimens, while its adverse effects on
hearing (which can be catastrophic,
especially for children) and the distressresulting from giving children a daily
injection are well known. WHO no
longer advises the use of streptomycin
in any first-line treatment regimen forchildren.17 Children with TB meningitis,
as well as children with osteo-articular
TB (TB of the joints and bones), should
now be treated with a twelve-month
regimen (a two-month intensive phaseof isoniazid, rifampicin, pyrazinamide
and ethambutol, followed by aten-month continuation phase ofrifampicin and isoniazid).

Cases of apparent treatment failurein children in settings of low DR-TB
prevalence are most often due either
to poor adherence, incorrect dosing, or
simply a wrong diagnosis of TB. In suchcases, these factors should be looked
for and corrected if found.
If genuine treatment failure is suspected,
every attempt must be made to obtainappropriate specimens for culture anddrug-sensitivity testing (DST), or where
this is not possible, a decision about what
treatment to give can be made on thebasis of treatment regimen of the source
case, and the likelihood of the casebeing DR-TB.

© Sophie Scott / MSF

Ethambutol is a drug which has beenshown to be safe in children of all ages
when dosed within the recommended
range (15-25 mg per kg). The risk of
optic neuritis (inflammation of the optic
nerve) with this dosage is extremely
low.15 WHO recommends the inclusionof ethambutol in the intensive phaseof treatment in children, in any region

where there is high HIV prevalence orisoniazid resistance. Furthermore, it
should be given to children who haveextensive or severe disease, including
smear-positive TB.16

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Médecins Sans Frontières    Out of the Dark: An implementers’ guide to managing TB in children

New TB drug dosages for children
In 2009, the WHO released revised
dosages for children of the first-line
drugs isoniazid (H), rifampicin (R),pyrazinamide (Z) and ethambutol (E).18
Unlike the old dosages, the current
recommendations take into accountthe physiological differences between
adults and children, with larger doses
required to achieve optimal serum
concentrations.
This is a welcome advance.
However, the change in the guidelines
means that the currently available
FDCs are not tailored to deliver the
new doses. In parallel to the releaseof the new doses, WHO issued
interim guidance to help treatment
providers to prescribe the existing
drug formulations to attain the
new doses.

19

The Hardest Cases
Children who are co-infected with HIV
or are infected with drug-resistant strains
of TB have additional challenges inrelation to treatment. There are limited
formulations adapted for children.
Nevertheless, successful treatment inthese groups is possible.

Children with TB/HIV
co-infection
TB is a major cause of illness and deathin children living with HIV – almost halfof all paediatric TB cases are in children
who are co-infected with HIV.20 Due
to particular difficulties in diagnosing
TB in HIV-positive children, many die
undiagnosed and untreated. Even
when these children are diagnosed,
they are still at great risk of death,particularly during the first two monthsof treatment.21 Immune suppression,

Unfortunately, this is complex andpresents many operational challenges.
It has complicated the prescribing of
TB treatment in children, with several
different combinations of multiple
tablets needed to deliver the newtarget doses (using the current FDC in
addition to single drug formulations).
This situation is not ideal, andvigilance is required in prescribing
and dispensing to minimise the riskof drug errors. The use of multiple
formulations adds additional pressure
to the drug supply channel to ensure
all formulations are available at the
point of dispensing.

supervision, and every effort should be

The complexity of the interim dosing
guidelines has delayed the implementationof new dosing guidelines in paediatric TB
programmes. While complex, this canbe overcome with adequate training andassured FDC to be available, and thisother co-morbidities, poor adherence
that may result from the highpill burden, and risk of immune
reconstitution inflammatory syndrome
can all contribute to poorer TB treatment
outcomes in HIV-positive children.
Intermittent TB regimens are no longer
recommended for the treatment ofchildren in HIV-endemic settings.22

are particularly vulnerable to poor TB

Randomised controlled trials conductedin adults infected with both TB and HIVshow a clear benefit in early antiretroviraltreatment (ART) initiation, within eightweeks of the start of TB treatment,
compared with delayed initiation.23, 24, 25
Current WHO guidance therefore
extrapolates adult evidence to children,
recommending ART initiation between
two to eight weeks after the start of
TB treatment.26

For children on second-line antiretroviralChildren under three years old whoare co-infected with both TB and HIV

explanations to the caregiver

made to ensure the new guidelines
are implemented so that children aretreated in line with current evidence.
Meanwhile, over two years since thepaediatric TB dosages were revised,
WHO has still not clearly indicatedto drug manufacturers what thecomposition of a new FDC – that
corresponds to the new dosages –should be. Drug manufacturers havetherefore understandably been unwillingto invest in the development of a new
FDC for children. It is estimated to takethree to five years for a new qualitytimeline will only begin with clear
advice from WHO about the definitive
composition of the required FDC.
Urgent action is needed.

treatment outcomes, and clinical vigilanceis very important. This is due to theirhigh risk of severe TB disease, combinedwith compromised treatment options
resulting from key antiretroviral drugs not
being approved for this young age group,and significant drug interactions with
antiretrovirals and rifampicin.
regimens who develop TB, the treatment
regime is complicated further bydrug interactions which require more
medications, which can be difficult to
procure as well as unpalatable to take.
Significant pill burdens play an importantrole not only in poor adherence, butalso make potentially serious drug errors
more likely to occur. Careful attention
when dispensing drugs and clear
are essential.

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11Children with drug-resistant TB

Observational data suggest that eventhough second-line anti-TB drugs are
known to be more toxic, they are
generally well-tolerated in children.
Given the serious nature of DR-TB,
no drug is absolutely contraindicated.
Some of the major side effects ofconcern in children include hearing loss
and renal impairment from long-term
use of the injectable drugs (kanamycin,
amikacin and capreomycin) andhypothyroidism, which is associatedwith the use of ethionamide and/or
para-aminosalicylic acid (PAS). Educationof caregivers on these side effects, aswell as regular and careful monitoringof children on treatment, is essential.
The management of HIV-positive
children on second-line regimens whodevelop TB is further complicated bydrug interactions and unpalatableregimens.

© Bruno De Cock

There is a paucity of evidence to support
current treatment recommendations
for DR-TB in children. Guidance isbased on extrapolations from adultrecommendations and expert opinions
drawing on data from case series andsmall cohort studies. The generalprinciples of DR-TB treatment are
the same as for adults.27

Among the commonly-used second-line
TB drugs, paediatric formulations exist for
only one of the oral drugs (levofloxacin),which is not widely available. The
manipulation of adult formulations forthe treatment of children with DR-TB is
therefore necessary, but this is a complex
process that is far from ideal, requiring
careful attention, as there are considerable
risks of over- and under-dosing.
Unlike the recent review by WHOof the drug dosages for treatment ofdrug-sensitive TB, the dosages ofsecond-line drugs to treat DR-TB
in children are extrapolated fromadults and based on experience andexpert opinion in light of the limited
pharmacokinetic (PK) data available.
There are some researchers currently
looking into PK studies for drugs for
DR-TB in children.28 This is welcome,and once available, there will be a needto develop age-appropriate formulations
to support treatment of these children.

New Developments© Bruno De Cock

There have been recent
developments in TB treatment
for adults, with several new
drugs currently in the final
stages of development.

12

There is a clear need for these new drugs
to undergo trials in children, or have apaediatric component incorporated inongoing trials, so that when they become
available to the adult population, children
do not have to wait before they can

Médecins Sans Frontières    Out of the Dark: An implementers’ guide to managing TB in children

benefit from them. There also needs tobe research conducted into where thesenew drugs could fit in current regimens,
or indeed whether they might allow
shortening of the TB regimen in the
future. Of the new drugs in the pipeline,
only TMC 207 (bedaquiline) currently hasa paediatric implementation plan in place.
The paediatric population should not beleft without access to these new drugs
once they become available for adults.

© MSFPREVENTION

Prevention
Active screening andproper managementof child contacts of TB
cases has the potential
to greatly reduce theburden of TB in children.

Whereas adults can carry TB for years or decades without developing disease,
TB disease in children is mostly the result of recent disease transmission.
Therefore, the starting point of TB prevention in children is the scale upof prompt diagnosis and treatment of TB cases in the general community.
At the same time, active screening and proper management of child contacts of TB
cases has the potential to greatly reduce the burden of TB in children and is an activity
that must be reinforced.
Ultimately, an effective vaccine is the critical tool needed for prevention, but as yet,no breakthroughs are on the horizon.

Current Practices
Contact Tracing, Screening and Prophylaxis
Despite the fact that tracing, screening andisoniazid preventive therapy (IPT) for eligible
child contacts of drug-sensitive patients haslong been recommended,29 they have not beensystematically or effectively performed, as many
TB programmes have not considered thempriority activities. A recent study of children
with culture confirmed TB in South Africa foundthat opportunities for preventive therapy were
missed in 71% of cases.30 Furthermore, IPT
is frequently perceived to be unfeasible, withthe potential to create drug-resistance if given
to a child with active TB. These myths must
be overcome to address the needs of childcontacts that can benefit hugely not only fromprophylaxis but from intensified case finding
through the tracing and screening process.
To improve contact tracing:• All patients with TB (especially if smearpositive) must be routinely asked aboutclose contact with any child under five years
old or any HIV-infected child regardless ofage. The reason and importance of bringing
these individuals for TB screening must be
explained to the patient.
• Staff should be trained on the importanceof contact tracing, and perhaps a focal
person nominated.
• Simple, systematic data collection shouldbe performed to monitor the volume andquality of contract tracing activity as well as
enable measurable outcomes to be reported.

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Médecins Sans Frontières    Out of the Dark: An implementers’ guide to managing TB in children

To improve contact screening:• Symptom-based screening must be
adopted. This has been shown to be asafe and feasible alternative to the use ofchest x-rays and tuberculin skin testing
to rule out active TB31 and has long been
recommended. Chest x-rays and tuberculin
skin testing are neither readily available
nor easily performed in many TB-endemic
settings and constitute a barrier
to preventive therapy.
• Children who have a ‘positive’ symptom
screen should go on to be investigated for TB.
• Children who have a ‘negative’ symptom
screen should be prescribed prophylaxis
with six months of isoniazid – a regimen
with proven efficacy following TB exposure/infection. The risk of generating drugresistance in children by inadvertently
giving isoniazid to a child with active TB is
minimal given the generally paucibacillarynature of childhood TB (in contrast to adulttype TB disease).
Interferon Gamma Release Assays (IGRAs)
do not have a place in the screening ofcontacts of TB in resource-limited TB
endemic settings.32
For children in contact with DR-TB, thestrategy for prophylaxis is far less evident,
making this subject a critical area for research.
WHO currently recommends close follow-up
for a period of at least two years.33, 34

Prevention of TB in children with HIV

Vaccination

Children living with HIV should undergo
routine symptom-based screening for
TB at each contact with health services.
All who are contacts of a TB case, butwith no evidence of active TB disease,are eligible for IPT regardless of age(in other words, not only if they are
under five years old).

In contrast, children less than 12 monthsof age who are unlikely to have active
TB and have had no known contact
with a TB case should not receive IPT.
This recommendation is based onevidence that where there is earlyART initiation for infants and vigilance
for TB exposure, IPT has no benefit.37

Furthermore, WHO recommends
that HIV-infected children older than
12 months of age who are unlikely tohave active TB (on symptom-based
screening), and have no known contact
with a TB case should receive six monthsof IPT as part of a comprehensive
package of HIV care.35, 36

Lastly, WHO makes a conditional
recommendation (on the basis ofadult evidence) that all children withHIV who have successfully completed
treatment for TB disease should
receive isoniazid for an additional
six months.

BCG is the only currently licensed
vaccine for TB and is usually standard
for children at birth or shortly after inhigh-burden countries. Studies place
its efficacy between 0-80% with its
main protective effect being against
disseminated forms of TB in young
children. It offers little, if any, protection
against pulmonary forms of TB.38
The BCG vaccine is not recommended
for children with HIV due to the welldescribed risk of disseminated BCG
disease (a form of mycobacterial diseasecaused by the modified mycobacterium
used in the BCG vaccine).39 However,given that children’s HIV status is usually
unknown at birth when BCG is given, thecurrent advice is to continue to give BCG
at birth to all infants in settings where
TB and HIV are highly endemic until it isfeasible to implement policies of delayed,
selective vaccination.40

Infection Control
Good infection control is an importantpart of preventing TB in children.
This encompasses a wide range ofinterventions, some of which are costly
and complex. However there are some
simple practical measures to protect
children that are often not taken.
These include:• Educating TB patients regarding coughhygiene in the home as well as in theclinic environment.
• Advising patients to avoid sleeping inthe same bed or room as children atleast until they become smear-negative.
• Minimising the presence of relatives on
TB wards and in particular not permitting
children on the ward. Well-ventilated
outdoor spaces should be available forvisitors and patients to meet.
• Ensuring well-ventilated clinic
waiting areas, especially wherechildren are present.

© Sifiso Sibandze

For further infection control
practices and advice see:
http://whqlibdoc.who.int/
publications/2009/97892
41598323_eng.pdf

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15

The Way
Forward© Sifiso Sibandze

The way forward
The prevention, diagnosis and treatment of paediatric TB havebeen neglected for many years. However, the recent rise inawareness of paediatric TB combined with new advances in adult
TB care mean that there is now the potential to change this.
Although many gaps remain with regard to the existing tools and treatment forchildren with TB, there are existing recommendations that can be adopted, toolsthat should be implemented and research questions that are waiting to beanswered. These can all be addressed today.
This booklet has highlighted what can be done to improve the services available
for children with TB. However, the work must continue, not only for the paediatricworld to catch up with adult TB services, but also to ensure that children are
included from the outset in all advances in TB care.

There are existing
recommendations that can be
adopted, tools that should be
implemented and researchquestions that are waiting to
be answered. These can all
be addressed today.

Diagnosis – What can be done?
…at the clinical level• Train health staff on the diagnosisof childhood TB.
• Include paediatric-specific diagnostic
advice in clinical guidelines adapted
to the resources of the context.
• Improve the availability, quality andinterpretation of chest radiography
in children.
• Encourage health staff to treat basedon careful clinical assessment, even
if TB is difficult to confirm.
• Encourage taking detailed contact
history, especially in areas of high
DR-TB prevalence.
• Maximise the use of existing tools for
obtaining appropriate specimens inchildren, such as sputum induction
and lymph node biopsies, especiallyin contexts of high DR-TB prevalence,or for children in contact with a caseof DR-TB.

…by the research and diagnostic
development community...by national and international
policy makers• Ensure timely evaluation of diagnostic
methods and technologies inpaediatric populations.

• Raise awareness in the community
about childhood TB.

• Ensure wide endorsement andimplementation of the consensus on
standardised methodological approaches
for evaluation of new diagnostics inpaediatric populations).41• Make childhood TB a publichealth priority.
• Ensure that children have access tofaster diagnosis provided by newtechnologies such as Xpert MTB/RIF.

• Ensure there is a specific focus onchildhood TB in the search for TB
diagnostic biomarkers that could leadto the development of a point-of-care
test for TB in children.
• Prioritise R&D efforts on diagnostics
that use samples other than sputum(i.e. urine or capillary blood).

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17

Treatment – What can be done?
…at the clinical level• Implement new WHO-recommended
treatment strategies for children
with careful attention to correct drug
dispensing and dose adjustment
according to weight.
• Ensure that children with TB/HIV receive
integrated care and are initiated on
ART between two to eight weeks after
TB treatment has commenced.
• Treat children with confirmed orsuspected DR-TB with careful dosing andclose monitoring. Record and reporttreatment outcomes and adverse events.
• Give education, counselling andsupport to the caregiver, as well as tochildren old enough to understandtheir disease.

…by the research and drug
development community...by national and international
policy makers• Develop new fixed-dose combinations
for drug-sensitive TB based on new
WHO recommendations.

• WHO to provide clear guidance todrug developers on needed fixed-dose
combinations of first-line drugs to
support implementation of the new
WHO-recommended dosages.
Donors to support developmentof such formulations.

• Continue to explore existing and new
drugs to optimise a therapeutic strategy
for HIV/TB co-infected children under
three years old.
• Study the pharmacokinetics and safetyof second-line TB drugs in children.
• Optimise treatment strategies forchildren with DR-TB.
• Include children early in clinical trialsof new anti-TB drugs.

• Include up-to-date recommendations
on treatment and monitoring ofchildren in national TB guidelines.
• E nsure that quality-assured, paediatricformulations of anti-TB drugs arecontinuously available.
• Review existing policies on routine
hospitalisation of children with TB andsupport outpatient-based treatment
strategies.

Prevention – What can be done?
…by the research and productdevelopment community...by national and international
policy makers• Identify and initiate studies on potential
prophylactic strategies for child contacts
of DR-TB that are safe and effective,
including with new TB drugs.

•M ake the management of TB contacts apriority component of TB programmes
and require the reporting of
measurable outcomes.

• Use symptom-based screening to ruleout active TB and start eligible children
on INH prophylaxis.

• Study the operational barriers to contact
tracing, screening and prophylaxis inroutine settings.

• Include up to date recommendations
on the management of contacts innational guidelines.

• Use simple data collection to document,
monitor and report activity related tocontact management.

• Continue to investigate optimal strategies
for prophylaxis especially for HIV infectedchildren: including the possibility for ashortened regimen by the use of new
drugs or combination therapy.

• Continue to invest in the developmentof an effective TB vaccine that is safefor HIV infected infants.

…at the clinical level• Undertake child contact tracing in
TB programmes.
• Ensure all HIV infected children arescreened for TB at every visit.

• Ensure good infection control practises
are initiated and maintained throughout
TB services.

• Continue research into new TB vaccines.

• Ensure all pregnant women, especiallythose with HIV, are screened for TB,
as a measure for both the health ofthe mother and infant.

18

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