Mini-symposium: Childhood TB in 2010

Management of multidrug-resistant tuberculosis in children: a survival guide for

paediatricians
H. Simon Schaaf *, Ben J Marais
Department of Paediatrics and Child Health, Faculty of Health Sciences, Stellenbosch University, and Tygerberg Childrens Hospital, Cape Town, South Africa
HOW COMMON IS TUBERCULOSIS AND MDR-TB IN CHILDREN?
The World Health Organization (WHO) estimated that in 2008,
440,000 (3.6%) of the 9.4 million tuberculosis (TB) cases worldwide
had multidrug-resistant (MDR)-TB (i.e. resistance to isoniazid and
rifampicin).
1
Childhood TB comprise approximately 10-15% of the
global disease burden, with higher rates in developing countries.
2
Little data is available on the occurrence of MDR-TB in children.
3
A
prospective drug resistance surveillance study conducted from
1994-2007 in the Western Cape province, South Africa, demon-
strated a clear upward trend with an increase in any resistance
(isoniazidand/or rifampicin) from6.9%to15.1%andinMDR-TBfrom
2.3% to 6.7%.
4
Since the majority of children (>90%) who develop TB
do so within 12 months of infection, paediatric surveillance studies
provide unique epidemiologic insight into current Mycobacterium
tuberculosis transmission patterns within communities, indicating
which genotypes are successfully transmitted.
5,6
The absence of data on drug-resistant TB among children reects
the fact that cultures for M. tuberculosis and drug susceptibility
testing(DST) are rarely done, since obtaining adequate specimens in
child TB suspects are difcult and mycobacterial culture yields are
low. In addition, careful identication of the likely adult source case
is poorly performed and if child contacts are identied, the
treatment response and/or DST of the adult source case is rarely
considered when treatment or chemoprophylaxis is initiated in
children.
4,7
This overview describes what is known about the
epidemiology, diagnosis andmanagement of childrenwithMDR-TB.
HOW DOES DRUG RESISTANCE DEVELOP AND SPREAD?
There are two underlying concepts; 1) the acquisition of drug
resistance by individual patients, originally infected with drug-
susceptible bacilli (acquired drug resistance), and 2) transmission
of drug-resistant bacilli (transmitted drug resistance).
M. tuberculosis acquires drug resistance through spontaneous
gene mutations; there is no horizontal gene transfer between
Paediatric Respiratory Reviews 12 (2011) 3138
EDUCATIONAL AIMS
To discuss the epidemiology of and mechanisms responsible for the emergence of drug resistant TB in children
To provide clear guidance on how best to diagnose and treat drug-resistant TB in children
To discuss ancillary treatment options and the management of HIV-infected children with drug-resistant TB
A R T I C L E I N F O
Keywords:
multidrug-resistant
tuberculosis
children
XDR-TB
MDR-TB
treatment
S U M M A R Y
WHO estimated that of 9.4 million cases of tuberculosis (TB) worldwide in 2008, 440,000 (3.6%) had
multidrug-resistant (MDR)-TB. Childhood TB is estimated at 10-15% of the total burden, but little is
known about the burden of MDR-TB inchildren. Children in close contact with MDR-TB cases are likely to
become infected with the same resistant strains and are vulnerable to develop disease. Although MDR-
TB is a microbiological diagnosis, children should be treated empirically according to the drug
susceptibility result of the likely source case, as often cultures cannot be obtained from the child. MDR-
TB treatment in children is guided by the same principles, using the same second-line drugs as in adults,
with careful monitoring for adverse effects. Co-infection with HIV poses particular challenges and
requires early initiation of antiretroviral therapy. Preventive therapy for high-risk MDR-TB contacts is
necessary, but no consensus guidance exists on how best to manage these cases. Pragmatic and effective
Infection control measures are essential to limit the spread of MDR-TB.
2010 Elsevier Ltd. All rights reserved.
* Corresponding author. Department of Paediatrics and Child Health, PO Box
19063, Tygerberg, 7505, South Africa. Tel.: +27 21 9389112; Fax: +27 21 9389138.
E-mail address: hss@sun.ac.za (H.S. Schaaf).
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
1526-0542/$ see front matter 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.prrv.2010.09.010
bacilli. Therefore, the risk of acquiring drug resistance is directly
proportional to the number of bacilli present; a bacterial load of
>10
6
bacilli is likely to contain some drug-resistant mutants.
8
Spontaneous resistance mutations occur with variable frequency;
mutations against second-line drugs occur with greater frequency
compared to rst-line drugs. The estimated number of bacilli
present in caseous foci (e.g. intrathoracic lymph node disease in
children), is low(10
4
-10
5
), while large numbers of bacilli (10
7
-10
9
)
are present within pulmonary cavities of adult-type lung disease.
8
Drug-resistant TB is a man-made disease reecting sub-optimal
case management. Treatment with a single drug rapidly selects for
drug-resistant disease. Using a combination of 3-4 drugs kills
different mycobacterial subpopulations and protects against the
development of drug resistance. If single drugs are used in
succession, or a weak combination of drugs with insufcient
protection of companion drugs, then additional drug resistance
accumulates. Acquisition and amplication of drug resistance
result from poor drug regimens (e.g. adding a single drug to a
failing regimen, prescribing a weak combination of drugs,
interruption of drug supply or using drugs with poor bioavail-
ability) and/or non-adherence to treatment. The risk is highest in
adults with lung cavities and relatively low in children with
paucibacillary disease.
Delayed diagnosis and/or poor management of infectious drug-
resistant TB cases allows drug-resistant M. tuberculosis strains to be
transmitted and cause disease, especially in vulnerable groups
such as young children and immunocompromised patients. Early
diagnosis of drug-resistant TB is essential to limit ongoing
transmission, and this is not achieved by sputum smear micro-
scopy which is the only test available in most TB endemic areas.
HOW TRANSMISSIBLE (INFECTIOUS) AND VIRULENT (ABLE TO
CAUSE DISEASE) IS DRUG-RESISTANT TB?
Snider et al
9
showed that isoniazid-resistant strains caused as
much infection as drug-susceptible strains in child contacts.
Successful transmission of MDR-TB strains fromadult source cases
to child contacts with progression to disease was also conrmed by
DNA ngerprint studies.
10
Infection control studies from Peru
showed that MDR-TB strains can be highly infectious and rapidly
transmitted within poorly ventilated hospital wards.
11
The importance of close contact is reected by the concordance
observed between DST results in drug-resistant source cases and
their close contacts who developed disease; varying from 46% in
adults to 80% in children.
7,12,13
Discordant results may result from
poor standardization of second-line DSTs, while contacts could
also have been infected by other, often unidentied, source cases
with drug-susceptible TB. In practice this means that special effort
has to be made to obtain specimens for culture and DST in any child
TB suspect who report recent close contact (within 12 months)
with someone diagnosed with drug-resistant TB. While awaiting

New child TB case
Conrmed DR-TB DST known Conrmed DS-TB
No
Contact with infecous TB case?
Yes Yes or No
Drug-resistant source case Source case DST not done & No source case known or
- child failing 1
st
-line treatment or DST not done, no risk factor
- source retreatment or chronic TB case Drug-suscepble source case
Conrmed or Probable DR-TB Suspected DR-TB Probable or Conrmed DS-TB
Treat as DR-TB according to Do culture/DST on child & sources Do culture/DST on childs
DST result of child or sources isolate specimens. Treat as DS-TB specimens if DS not conrmed
Do culture & DST Close follow-up essenal mainly if poor response to treatment
if DR not conrmed
Check DST results Check DST results
Check response to treatment If DST shows DR treat as DR-TB
If DST shows DR or if failing
adherent therapy, treat as DR-TB
DST = drug suscepbility test; DR = drug-resistant; DS = drug-suscepble
Reference to culture and DST implies that facilies are available
[Adapted from ref 16]
Figure 1. Algorithm for the diagnosis of suspected or conrmed drug-resistant TB in children.
H.S. Schaaf, B.J. Marais / Paediatric Respiratory Reviews 12 (2011) 3138 32
DST results, children should be treated according to the DST result
of the likely source cases isolate.
WHEN TO SUSPECT DRUG-RESISTANT TB IN A CHILD?
Potential drug resistance should be considered in any child
diagnosed with TB. The diagnosis of TB in children often relies on a
constellation of; a history of contact with an infectious TB source
case; symptoms and signs suggestive of TB (e.g. chronic cough,
weight loss/failure to thrive or signs of pulmonary or extra-
pulmonary TB); and special investigations (e.g. tuberculin skin test
(TST) and/or chest radiography). In most cases smear microscopy
for acid-fast bacilli (AFB), culture and DST are not done, as
adequate specimens are difcult to obtain and often negative.
Although drug-resistant TB is primarily a microbiological diag-
nosis, a history of previous TB treatment or contact with adult
drug-resistant TB cases is extremely important.
The following practice points should guide the diagnosis of
drug-resistant TB in children (see also Figure 1):
1416
WHAT SPECIMENS TO COLLECT?
When MDR-TB is suspected, every effort should be made to
conrm the diagnosis by obtaining specimens for culture and DST.
Respiratory specimens may be obtained by gastric aspirates,
induced sputum and/or nasopharyngeal aspirates. Bronchoalveo-
lar lavage offers no advantage over less invasive methods. Older
children (>6-8 years) can often expectorate sputum.
17
More
invasive methods for obtaining specimens may be justied in
children with extrapulmonary TB, for example ne needle
aspiration biopsy or formal biopsy from peripheral lymphadenitis,
or pus swab if a draining sinus has formed. Other specimens that
should be obtained are cerebrospinal uid in TB meningitis, pleural
or pericardial uid if effusions are present, ascitic uid, ear swabs
in chronic otorrhoea, bone marrowaspiration if disseminated TB is
suspected and biopsies/swabs from other areas such as abscesses
or osteoarticular TB.
WHAT DIAGNOSTIC METHODS ARE AVAILABLE?
Many developing countries either have no culture and DST
facilities (although there is a strong drive to improve laboratory
capacity) or use solid culture media (Lo wenstein-Jensen or agar
plates) and the indirect proportion method for DST. Culture yields
are poor with solid media, and culture and DST results could take
from 6 weeks to 4 months. Automated liquid broth media, such as
the Mycobacterial Growth Indicator Tube (MGIT) 960 system
(Becton-Dickinson, Sparks, MD) improved culture yields and
reduced time to culture and DST results (10-14 days in specimens
with high organism loads). However, in children with paucibacil-
lary TB, culture and DST results can still be delayed for 6-8 weeks.
These systems are expensive and need well equipped laboratories
and technical expertise.
The risk posed by ongoing transmission of drug-resistant
strains and the risk of amplication of resistance if patients are
treated with incorrect regimens call for rapid and reliable
diagnosis. More rapid culture and DST methods, such as the
microscopic observed drug-susceptibility (MODS) assay, in which
culture and DST is performed at the same time and results are
known within 7-14 days shows benet, but have not been
implemented widely.
18
Since many of the genes encoding
resistance have been determined, nucleic acid amplication tests
(NAATs) offer great promise for rapid and accurate diagnosis.
NAATs that have shown promise include the GenoType MTBDRplus
(Hain Lifescience, Nehren, Germany) and INNO-LiPA.Rif.TB (Inno-
genetics, Zwijndrecht, Belgium).
3
The GenoType MTBDRplus
identies the majority of rifampicin and isoniazid resistance while
the INNO-LiPA Rif.TB only identies rifampicin resistance.
Correlation with conventional culture and DST methods is high
(95% for rifampicin resistance).
19
The INNO-LiPA.Rif.TB does not
identify isoniazid resistance, while the GenoType MTBDRplus assay
only identies isoniazid resistance associated with the inhA
promoter region or katG gene mutations, which may cause
over-diagnosis of rifampicin mono-resistance since a proportion
of isoniazid-resistant strains will not be detected. Rifampicin-
monoresistant TB cases diagnosed by these assays only should be
managed as MDR-TB cases.
Between 5-10% of all MDR-TB patients have extensively drug-
resistant (XDR)-TB (i.e. MDR-TB plus resistance to the uoroqui-
nolones and one of the second-line injectable agents). DST for rst-
line drugs other than isoniazid and rifampicin and second-line
drugs are still done by conventional culture and DST methods,
which remain time consuming and poorly standardized. New
genetic tests, such as the GenoType MTBDRsl (Hain Lifescience for
second-line drugs, Nehren, Germany) are being developed to
improve time-to-detection and reliability of DSTs for these drugs,
especially the uoroquinolones and injectable agents.
20
WHAT ARE THE PRINCIPLES OF CASE MANAGEMENT?
Children with MDR-TB are managed in much the same way as
adults, but there are some differences. Conrmation of MDR-TB
may not be possible and child TB cases in recent close contact with
an adult MDR-TB case or failing to respond to adherent rst-line
treatment should be empirically treated as MDR-TB cases. Because
of the paucibacillary nature of early primary disease (contained
primary lung lesion or uncomplicated hilar/mediastinal lymph
node enlargement), these children may need fewer drugs and
shorter duration of treatment,
7,21
although there are no rando-
mized control studies to conrm this. Important principles in the
management of MDR-TB are summarized as follows:
14,15
PRACTICE POINTS: MAKING THE DIAGNOSIS OF DRUG-
RESISTANT TB IN CHILDREN
Isolating M. tuberculosis and demonstrating drug resis-
tance on DST remains the only way to conrm drug-
resistant TB
Probable drug-resistant TB can be diagnosed when a child
with TB reports recent close contact with an adult with
drug-resistant TB
Drug resistance should be suspected in any child who fails
to improve while adherent to rst-line anti-TB therapy or
if the adult source case is a treatment failure, a retreatment
case or recently died from TB
Although children usually develop transmitted drug-
resistant TB, some children develop lung cavities with
high bacillary loads and may acquire drug resistance if the
treatment regimen is inadequate, supply of drugs is
irregular or treatment adherence is poor.
PRACTICE POINTS: PRINCIPLES OF MDR/XDR-TB CASE
MANAGEMENT
Never add a single drug to a failing regimen; this may lead
to amplication of resistance
All treatment should be given daily and under direct
observation
H.S. Schaaf, B.J. Marais / Paediatric Respiratory Reviews 12 (2011) 3138 33
WHICH DRUGS TO USE IN THE TREATMENT OF CHILDREN WITH
MDR-TB AND XDR-TB?
WHO identies standardized, empirical and individualized
treatment regimens.
15
The choice of treatment regimen will differ
according to the availability of DST and drug resistance surveil-
lance data in a particular setting. With standardized treatment all
patients in certain categories (e.g. treatment failure) are started on
the same xed regimen. This may be the most pragmatic option,
but is accompanied by a risk of amplifying drug resistance if not
tailored according to ongoing drug resistance surveillance data.
22
Children are best managed with empirical or individualized
treatment regimens, which utilize the same rationale. Empirical
treatment is designed on the basis of previous treatment history
and DST results of the child (or likely source case), while
individualized treatment is based on the patients own current
DST result and previous treatment history.
With extensive pulmonary or disseminated extrapulmonary
disease, a minimum of 4 active drugs should be included in the
regimen.
3
When building a regimen, start with rst-line (Group 1
Table 1) drugs to which DST results show susceptibility. Previous
treatment (i.e. treatment for >1 month) with any specic drug in a
failing regimen should indicate possible resistance to that drug. DST
results for pyrazinamide are difcult to obtain and for ethambutol
notoriously unreliable.
23,24,25
Therefore, if either the child or the
source case had previously been treated with pyrazinamide and/or
ethambutol, thenthese drugs couldstill beusedempiricallyor if DST
shows susceptibility, but only as additional drugs.
25,26
Add one drug from group 2 (injectable agents). There is much
debate about which injectable agent should be used in MDR-TB,
because of cross-resistance between these drugs. We currently use
amikacin in children because of fewer adverse effects and
convenience of smaller ampoules appropriate for dosaging in
children. The majority of MDR-TB patients are resistant to
streptomycin, therefore this drug is not considered in MDR-TB
therapy. However, in XDR-TB DST for streptomycin is worthwhile
doing, since cross-resistance with second-line injectable agents
may not be complete and if susceptible streptomycin could be
added to an XDR-TB regimen.
Thereafter add a uoroquinolone (Group 3 Table 1).
Levooxacin and moxioxacin are superior to ooxacin and if
resistance to ooxacin is found, resistance to the newer generation
uoroquinolones such as moxioxacin, may not be complete
(important for management of XDR-TB).
27,28
Use of ciprooxacin
in anti-TB treatment is no longer recommended.
26
More than one drug from group 4 (Table 1), taking into account
similar drugs and adverse effects, should be included in the
Table 1
Drug groups for MDR and XDR-TB treatment regimens [Adapted from reference 26]
Drug Group Drug name Daily dosage in mg/kg Maximum dose (mg)
a
Group 1: Oral rst-line drugs Ethambutol 20-25 2000
Pyrazinamide 30-40 2000
b
Group 2: Injectable agents.
Aminoglycosides
Streptomycin (1
st
-line) 15-20 1000
Amikacin 15-20 1000
Kanamycin 15-20 1000
Cyclic polypeptide Capreomycin 15-20 1000
b
Group 3: Fluoroquinolones Ooxacin 15-20 800
Levooxacin 7.5-10 750
Moxioxacin 7.5-10 400
c
Group 4: Second-line oral drugs Ethionamide (or prothionamide) 15-20 1000
Cycloserine (or terizidone) 10-20 1000
e
Para-aminosalisylic acid (PAS; 4gr sachets) 150 12g
d
Group 5: Drugs of uncertain value High-dose INH 15-20 400
f
Linezolid 10-12 twice daily 300 once/twice daily
Amoxicillin/clavulanate 15 amoxicillin 3 x daily
Clarithromycin 7.5-15 twice daily 500 twice daily
g
Thioacetazone 3-4 150
Imipenem/cilastatin (only IV)
Clofazimine 3-5 300
a. DST could be unreliable use as additional drug if DST result susceptible or not done
25
b. Choose one drug in each of these groups; amikacin preferred to kanamycin in children
c. Choose one or more of these drugs to make up total of 4 new drugs
d. Consider use of these drugs if insufcient drugs to build an acceptable regimen with previous groups. Each drug only considered as half a drug, therefore 2 drugs in this
group counts as one additional drug.
e. PAS is administered in acidic base (e.g. yoghurt or orange juice) for improved absorption
f. Linezolid dosage for TB is uncertain, but lower doses (300mg twice daily or even 300mg daily in adults) cause less adverse effects and still seem effective.
33
g. Thioacetazone should NOT be used in HIV-infected patients
Treat the child according to the DST results from the likely
source case, unless M. tuberculosis culture and DST is
available from the child
Do second-line DST in all MDR-TB cases to exclude
resistance to the uoroquinolones and/or second-line
injectables, as this may call for additional drugs early in
therapy
Give at least 3 (only in early primary disease) or preferably
4 drugs to which the patient or adult source case is na ve or
their isolates susceptible
A regimen should be build from different drug groups (see
table 1) taking into account drug resistance, possible
cross-resistance, adverse effects and previous use of drugs
Caregivers need counseling and support regarding adverse
effects, treatment duration and importance of adherence
at every follow-up visit.
Clinical, radiological and culture response to treatment
should be monitored. Monthly smear microscopy and/or
cultures should be done until conrmed negative on 3
consecutive occasions, thereafter 2-3 monthly follow-up
cultures can be done
Clinical monitoring for adverse effects should be done at
every visit. Special investigations should be guided by the
adverse effect prole of the drugs used
H.S. Schaaf, B.J. Marais / Paediatric Respiratory Reviews 12 (2011) 3138 34
regimen according to DST or non-exposure to these drugs to a total
of 4 active drugs.
If these groups are not sufcient to build an acceptable regimen
of 4 active drugs (excluding drugs with doubtful activity), drugs
fromgroup 5 could be added. WHO recommends that two drugs in
group 5 should be added to make up one active drug.
26
Isoniazid at
high-dose (15-20 mg/kg daily) may be benecial especially when
given with ethionamide where minimal inhibitory concentrations
(MIC) for isoniazid and ethionamide DST are not available.
Depending on which mutation causes resistance, either ethiona-
mide or high-dose isoniazid is likely to retain some activity.
29
A
randomized control trial in India showed that the addition of
high-dose isoniazid to a standard MDR-TB treatment regimen,
compared with normal dose (5 mg/kg) or no isoniazid, resulted in
earlier sputum conversion and improvement in chest radio-
graphs.
30
Linezolid, another group 5 drug, has been used with good
clinical effect in MDR/XDR-TB cases, but cost and severe adverse
effects are restricting its use.
31,32
Some reports have shown lower
dosages (300 mg/day in adults) to be effective and to have fewer
adverse effects.
33
Treatment of tuberculous meningitis requires drugs that
effectively penetrate the blood-brain barrier such as isoniazid,
pyrazinamide, the thioamides, cycloserine/terizidone and the
uoroquinolones. The second-line injectable drugs only penetrate
the blood-brain barrier during acute inammation.
WHAT IS THE OPTIMAL TREATMENT DURATION?
The optimal duration of MDR-TB treatment in children and
adults remains unknown; current recommendations are based on
personal experience and expected efcacy of the various second-
line drugs. WHO guidelines
15,26
recommend treatment until 18
months after the rst negative culture (24 months in XDR-TB).
Because children often have paucibacillary disease shorter
duration of treatment (12 months) may be sufcient for early,
non-extensive disease.
7,21
In case of children with extensive lung
involvement, severe forms of extrapulmonary disease or dissemi-
nated (meningitis or miliary TB) disease, the same duration as in
adults apply.
HOW TO ENSURE TREATMENT ADHERENCE?
It is essential to ensure adequate adherence to treatment, since
treatment options are limited. Treatment of MDR/XDR-TB should
only be given as directly observed therapy by health care workers
or treatment supporters. Hospitalization for the rst 4-6 months of
treatment is often required to administer second-line injectable
agents, monitor for adverse effects and ensure adequate treatment
response.
Comprehensive and continuous counseling of the child and/or
parent/caregiver is essential to ensure that they understand the
seriousness of the situation and the justication of prolonged and
complicated treatment regimens. Socioeconomic evaluation and
support of the family is important. Teenagers need special
attention and in our own experience, adherence should be checked
with the person responsible for direct observation of treatment.
Adverse effects of second-line drugs are more frequent than in
rst-line drug treatment; fortunately, these adverse effects can
usually be managed without stopping drugs (see Table 2).
34
Non-
availability of child-friendly drugs and dosages complicates
administration of drugs to children.
Hospital/clinic-based and community-based treatment models
provide comparable outcomes.
7,35
Some children require initial
admission because of their clinical condition or social circum-
stances. In our experience hospitalization in a specialized unit
duringthe intensive phaseallows for dailyinjections byexperienced
nursing staff and better monitoring of adverse effects and repeat
cultures. The remainder of the treatment is usually given at primary
health care level. Community home-based directly observed
treatment of HIV-uninfected MDR-TB patients in Peru was shown
to be very effective.
35
In both models expert health care teams
should be involved in the continued care of the children.
Table 2
Adverse effects of rst and second-line drugs used in the treatment of children with multidrug-and extensively drug-resistant tuberculosis
Drug Adverse effects How to monitor
Isoniazid Hepatotoxicity Jaundice, liver enzymes
Rash Clinical observation for
Peripheral neuropathy (rare) other adverse effects
Psychosis
Pyrazinamide Hepatotoxicity Jaundice, liver enzymes
Arthralgia Clinical observation for
Rash other adverse effects
Ethambutol Optic neuritis (rare) Vision screening if possible
Second-line injectable drugs Ototoxicity (starts with high frequency hearing
loss and may continue after stopping culprit drug)
Hearing test (audiology)
Amikacin Nephrotoxicity (Renal failure and severe hypokalaemia)
Kanamycin
Capreomycin Serum creatinine and potassium levels
Fluoroquinolones Gastro-intestinal disturbance Clinical observation and caregivers report
Ooxacin Insomnia
Levooxacin Arthralgia Serum uric acid if used with pyrazinamide
Moxioxacin
Thioamides Gastro-intestinal disturbance (nausea, vomiting,
abdominal pain and anorexia)
Clinical observation
Ethionamide Hepatotoxicity Jaundice serum alanine transferase and billirubin
Prothionamide Hypothyroidism Thyroid stimulating hormone and free T4 levels
Cycloserine Psychosis, convulsions, parasthesia, depression Clinical observation
Terizidone
Para-aminosalisylic acid (PAS) Gastro-intestinal disturbance (mainly diarrhoea) Clinical observation
Hypothyroidism Thyroid stimulating hormone levels and free T4
Linezolid Myelosuppression Full blood counts
Lactic acidosis Serum lactate level
Peripheral neuropathy Clinical observation
Pancreatitis Clinical observation
H.S. Schaaf, B.J. Marais / Paediatric Respiratory Reviews 12 (2011) 3138 35
HOW SHOULD ADVERSE EFFECTS BE MANAGED?
Children should continue on effective MDR-TB treatment
regimens, therefore, adverse effects should be managed rather
than drugs stopped. Isoniazid, pyrazinamide and the thioamides
should be stopped immediately if jaundice develops. Once liver
enzymes return to normal these drugs could be reintroduced one
by one, with careful monitoring for an increase in alanine
transferase. The gastrointestinal disturbances caused by the
thioamides and para-aminosalisylic acid (PAS) can be mostly
overcome by splitting the dose or starting with a lower dose
increasing to full dose in 1-2 weeks. Hypothyroidism (thioamides
and PAS) may need addition of low-dose thyroxine supplementa-
tion until completion of MDR-TB treatment.
Ethambutol may cause optic neuritis, which is difcult to
monitor in children less than 5 years of age. Although the risk
seems low at recommended dosages (15-25 mg/kg/day),
36
older
children should be screened by testing visual acuity and colour
vision. Vision disturbance is reversible if stopped early.
All children on injectable agents should be evaluated at 1-2
monthly intervals for hearing loss. If hearing loss develops in a child
responding well to treatment it may be considered to stop the
injectable agent earlier (at four rather than six months). However, if
the child has extensive disease and feweffective drugs are available
the risk versus benet of continuing the injectable agent should be
considered. Nephrotoxicity, renal failure and hypokalaemia in
children is rare, although it has been described in adults.
27,37
Joint or musculoskeletal adverse effects from the uoroquino-
lones in children seems mild and are rare.
7,35
Psychosis is rarely
seen in children, but could be caused by isoniazid or cycloserine/
terizidone. Discontinuing isoniazid and/or lowering the dose of
cycloserine/terizidone may be sufcient.
ADJUNCTIVE THERAPIES
Surgery
Some conditions, such as severe airway obstruction by
mediastinal lymph nodes, pericardial or pleural effusion, or non-
communicating hydrocephalus may require surgery. In adults,
resectional lung surgery has been reported as an adjunct in the
treatment of MDR/XDR-TB, especially those patients resistant to
most drugs.
38,39
Patients for lung surgery need careful selection
and experienced surgeons as these procedures are not without
complications.
38,39
Nutritional support
Malnutrition increases the risk of developing disease after M.
tuberculosis infection, and optimal nutrition is an important part of
treatment. Because the diagnosis and treatment of MDR-TB is often
delayed,
7
nutritional status in these children may have deterio-
rated. Additionally TB is known to be a disease associated with
poor socioeconomical circumstances, and second-line drugs such
as ethionamide and PAS may have gastrointestinal adverse effects
including nausea and anorexia. For these reasons children with
MDR-TB usually require nutritional support.
Several anti-TB and antiretroviral drugs may cause adverse
neurological effects which could be associated with low levels of
pyridoxine (vitamin B6). Low levels of pyridoxine was found in a
large proportion of children hospitalized for TB and levels
remained low in many HIV-infected children despite receiving
daily recommended doses of pyridoxine.
40
Therefore pyridoxine is
recommended in TB/HIV-co-infected children but also for MDR-TB
patients receiving high-dose isoniazid and/or cycloserine/terizi-
done.
15,40
Recommended dosage is 1-2 mg/kg daily.
41
Corticosteroids
Corticosteroids are often used in TB meningitis, large airway
obstruction by mediastinal lymph nodes or pericardial TB. Most
commonly oral prednisone at 2 mg/kg daily (maximum 60 mg) for
4 weeks (reduced over 1-2 weeks) is used.
42
The use of
corticosteroids in children with undiagnosed MDR-TB may cause
further progression of disease.
16
MANAGEMENT OF HIV-INFECTED CHILDREN WITH MDR-TB
All child TB suspects should be screened for HIV infection if
either living in a high prevalence HIV area (prevalence >1%) or
considered to be at risk for HIV infection.
17
HIV-infected children
with TB, especially MDR-TB, are at increased risk of severe disease
and death, which emphasizes the need for early diagnosis and
optimal treatment. Concomitant antiretroviral therapy (ART)
markedly improves TB outcome in children and adults.
43,44
A
prospective trial showed clear benet for starting ART early in TB
treatment despite the stage of HIV disease with no increase in
adverse effects.
44
XDR-TB patients co-infected with HIV also had
improved outcome if started early on ART.
3
WHO recommends
starting ART within 2-8 weeks after starting anti-TB treatment in
HIV-infected children with MDR-TB.
41
Drug interactions are usually not a problem with regimens not
containing rifampicin. Reasons for postponing ART initiation
include possible confusion of overlapping drug adverse effects
and the risk for immune reconstitution inammatory syndrome
(IRIS), a paradoxical worsening of symptoms and signs with
improvement in the bodys immune response.
41
IRIS, if severe,
could be managed by corticosteroids. In addition to early ART
initiation, all co-infected child TB cases should receive cotrimox-
azole prophylaxis and pyridoxine supplementation.
41
MANAGING CHILD CONTACTS OF INFECTIOUS MDR-TB CASES
Preventive therapy for MDR-TB remains controversial. Current
WHO guidelines do not recommend preventive therapy for
contacts of MDR-TB patients.
15
Failure of isoniazid or isoniazid/
rifampicin preventive therapy in MDR-TB contacts has been
documented.
12,45
No randomized controlled trials have been done
on preventive therapy in MDR-exposed or infected individuals.
There is general agreement that preventive therapy is warranted,
especially for high-risk contacts such as immune compromised
individuals or very young children, but there is no consensus on
what regimen(s) should be used.
46
TB guidelines from the United States recommend a two-drug
regimen for people with latent TB infection exposed to MDR-
TB.
47,48
In a prospective observational study where child contacts
of adult MDR-TB cases were offered individually tailored
preventive therapy, with two drugs to which the source cases
isolates were susceptible or na ve for a period of six months, was
found to be effective.
21
Immune immature children (<3 years) and
immunocompromised children, irrespective of their age are highly
vulnerable.
In TB endemic areas, exposure to multiple source cases, both
drug-susceptible and drug-resistant TB, is not uncommon. We
currently use a 3-drug combination of high-dose (15-20 mg/kg)
isoniazid and two drugs to which the source cases isolate is
susceptible or na ve, usually a uoroquinolone (ooxacin) and
ethambutol (or ethionamide). Single-drug preventive therapy with
the new generation uoroquinolones (levooxacin) is currently
explored. Further studies are urgently needed to evaluate regimens
and duration of preventive therapy in high-risk children in close
contact with infectious MDR-TB cases.
H.S. Schaaf, B.J. Marais / Paediatric Respiratory Reviews 12 (2011) 3138 36
Preventive therapy for XDR-TB contacts is not recommended,
but in the light of possible low-level isoniazid resistance, which
could be conrmed by isoniazid MIC or presence of inhA promoter
region mutation on line probe assay, high-dose isoniazid (15-
20 mg/kg) may provide some protection to high-risk child
contacts.
Most important is that child contacts of infectious MDR/XDR-TB
source cases, especially those less than 5 years of age or those HIV-
infected irrespective of age, should be closely followed up for a
minimum of two years and appropriate treatment started as soon
as TB is diagnosed.
15
INFECTION CONTROL
Although childhood TB is generally not infectious, children with
progressive lung disease or cavitary TB (often smear-positive) are
infectious and should be isolated.
49,50
Isolation in hospital should
last until they are sputumsmear-negative on at least two occasions
2-4 weeks apart and preferably culture-negative as well. Also,
accompanying or visiting adults may have infectious pulmonary
TB and pose a transmission risk.
51
CONCLUSION
Despite the lack of epidemiologic data on drug-resistant TB in
children, it is evident that they are as much affected by the growing
MDR/XDR-TB epidemic as adults, especially in settings where
ongoing transmission is poorly controlled. Most children with
MDR-TB have been infected by an infectious adult MDR/XDR-TB
source case. Failing to identify such contact may delay diagnosis of
MDR/XDR-TB, with unnecessary progression of disease and/or
death. Since microbiological conrmation of drug-resistant TB in
children is difcult, empiric treatment is reasonable and should be
guided by the DST pattern of the likely source case. Children
tolerate second-line anti-TB drugs well and, if diagnosed timeously
their outcome is generally good.
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