REVIEW

CURRENT
OPINION Tuberculosis in children: screening, diagnosis
and management
Annaleise R. Howard-Jones a and Ben J. Marais a,b,c

Purpose of review
The present review focuses on recent advances and current challenges in screening, diagnosis and
management of tuberculosis (TB) in children, encompassing TB infection and TB disease, and public health
priorities for screening and family engagement.
Recent findings
Although awareness has improved in recent years that children in TB endemic areas suffer a huge disease
burden, translation into better prevention and care remains challenging. Recent WHO guidelines have
incorporated screening of all household contacts of pulmonary TB cases, but implementation in high
incidence settings remains limited. Improved tests using noninvasive samples, such as the lateral flow
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urinary lipoarabinomannan assay and the new Xpert Ultra assay applied to induced sputum or stool in
young children, are showing promise and further assessment is eagerly awaited. From a treatment
perspective, child-friendly dispersible fixed dose combination tablets are now widely available with
excellent acceptability and tolerance reported in young children.
Summary
High-level government commitment to TB control as a public health priority and feasible strategies to
achieve this are required to contain the global epidemic, whereas strong engagement of local TB clinics
and affected families in TB prevention is essential to limit secondary cases and protect exposed children.
Keywords
children, screening, tuberculosis

INTRODUCTION primary infection [6]. Childhood disease is often

Mycobacterium tuberculosis is one of the world’s old- acquired following close contact with an infectious
est and most formidable human pathogens. With an adult case [7,8], but in high incidence settings the
estimated 10 million new cases of tuberculosis (TB) majority of children may have no discernible source
&&

disease in 2018, the global disease burden is
immense and is largely borne by the most vulnera-
&&
ble populations [1 ,2]. Following TB exposure, the
mycobacterial–host interaction generates a wide
case identified [9 ]. In general, paediatric TB cases
provide a marker of uncontrolled TB transmission at
the household and population level. Studies suggest
that around 10% (range 8–19%) of new TB diagno-
&& &

clinical spectrum from total clearance of the patho-
gen through to active TB disease, with different
degrees of severity (Fig. 1) [3]. TB infection, an
asymptomatic state with a demonstrable host
immune response to TB, sits between these
extremes. Although TB infection is a quiescent
phase, the risk of TB reactivation remains as long
as the infection persists. Given that a quarter of the
world’s population is estimated to have TB infection
[4], this represents an enormous reservoir of poten-
tial future disease [5].
The risk of severe TB disease – including TB
meningitis – is highest in the very young (2 years
of age) and usually occurs within 12 months of
ses occur in children <15 years [1 ,10,11 ],
although this is highly dependent on local trans-
mission dynamics and population composition. It is
a
Department of Infectious Diseases & Microbiology, The Children’s
Hospital at Westmead, Westmead, bDiscipline of Child and Adolescent
Health and cMarie Bashir Institute for Infectious Diseases & Biosecurity,
University of Sydney, Sydney, New South Wales, Australia
Correspondence to Annaleise R. Howard-Jones, The Children’s Hospital
at Westmead, Westmead, New South Wales, Australia.
Tel: +61 2 9845 3489; fax number is þ61 2 9845 3489;
e-mail: annaleise.howard-jones@health.nsw.gov.au
Curr Opin Pediatr 2020, 32:395–404
DOI:10.1097/MOP.0000000000000897

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Pulmonology
KEY POINTS
 TB in children carries high morbidity and mortality,
particularly in the very young (2 years) and those
with immunosuppression or comorbidities.
 Given household acquisition is commonplace in young
children with TB disease, reverse contact tracing is
important and susceptibility data from the ‘likely source’
can be used to guide treatment.
 Diagnostic challenges include difficulties in collecting
respiratory specimens and the paucibacillary nature of
childhood TB. Urinary LAM assays afford high
accuracy and the Xpert MTB/RIF and new Xpert Ultra
offer enhanced sensitivity and feasibility (including
application to analysis of stool specimens), but a simple
structured approach using available resources can also
guide treatment.
 New short-course regimes using child-friendly fixed-
dose dispersible formulations show excellent
acceptability for the treatment of TB infection
(prevention) and TB disease.
 Ultimately, TB epidemic containment requires effective
population-based strategies with consideration of local
transmission dynamics and the sociocultural context.
estimated that children contribute 15% of global TB-
&&
related mortality [1 ], and TB disease is recognized
as a top-10 cause of under-5 mortality in TB endemic
&
areas [12 ].
Childhood disease is bimodal in phenotype with
young children (<5 years) manifesting more intra-
thoracic lymph node involvement, disseminated/
miliary disease and TB meningitis, whereas adoles-
cents (>10 years) are more likely to develop adult-
type cavitary lung disease [6]. Children aged 5–10
years have the lowest risk of developing TB disease
and are less likely to develop disseminated disease,
FIGURE 1. Spectrum of TB–host interaction (adapted from Fox et al. [3]). , Recent data suggests that the majority of contacts
(>90%) exposed to TB will clear the infection, although they remain reactive as detected by immune-based testing [62 ]. §,
This state likely represents a ‘tipping point’ above which immune control of the organism is overwhelmed setting up a positive
feedback loop leading to mycobacterial multiplication and disease manifestation.
396 www.co-pediatrics.com
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
which probably reflects an optimal immunological
balance before the onset of puberty [13 ].
&&
Effective screening and case finding strategies,
together with appropriate therapy delivered with
high compliance, provide the backbone of effective
TB management at an individual and population
&&
level [1 ]. However, low-resourced settings are chal-
lenged with limited diagnostic tools and con-
strained public health response mechanisms to
contain disease spread [14].
SCREENING FOR TUBERCULOSIS
INFECTION
The burden of TB disease in children remains poorly
quantified in most TB endemic areas [15 ] and,
&
because children rarely contribute to TB transmis-
sion in the community, their care has been under-
emphasized as a public health priority [16]. Recent
adult studies provide compelling evidence that pas-
sive case finding – only identifying patients who
present to healthcare services with symptoms – is an
inadequate strategy to contain TB at a population
level [17]. Active case finding through screening of
household TB contacts provides an efficient strategy
& &
to identify additional TB cases [18 ,19 ], whereas
community-wide screening strategies have demon-
strated meaningful transmission impact in high
&&
endemic settings [20 ]. In screening for TB, clini-
cians need to be cognizant of variable cultural and
family-based living arrangements, which may
demand screening and engagement beyond the
nuclear family unit.
A detailed exposure history is complemented by
an immune-based test (interferon-gamma release
assay, IGRA, or tuberculin skin test, TST) to measure
TB infection or reactivity [21]. Neither IGRA nor TST
can distinguish TB infection from TB disease and
both rely on a robust delayed type hypersensitivity
&
Volume 32  Number 3  June 2020

response, affected by immune maturity and com-
promise [22]. The TST is the most widely used
immune based test. False positive results after Bacil-
lus Calmette-Guérin (BCG) vaccination is a concern,
but the effect wanes over time with less than 1%
false positivity 10 years after at-birth vaccination;
reactivity persists longer in children who receive
BCG later in life [23]. The TST may have slightly
superior sensitivity compared to IGRA (which is
more specific) in children under the age of 2–5 years
(87% compared to 80%), but this is not observed in
&
older age groups [24 ]. Indeterminate IGRA results
occur in about 4% of children, most frequently in
those with underlying immunodeficiency such as
&
HIV coinfection [25 ]. Given the 6- to 8-week delay
in immune-based test conversion following TB
infection, exposure of very young and vulnerable
children necessitates consideration of so-called
‘window prophylaxis’. The possibility of a false-neg-
ative result must also be considered in a child with
suggestive clinical features, and immune-based tests
can never be used as a ‘rule-out’ test for TB disease.
DIAGNOSIS OF TUBERCULOSIS DISEASE
Young children are susceptible to rapid disease pro-
gression [6], with severe and extrapulmonary man-
ifestations of TB occurring at a higher frequency
than in adults. In the pre-BCG era, 50% of infants
with TB infection progressed to TB disease, with 10–
20% developing disseminated disease [26]. BCG
vaccination protects against disseminated disease
during the first 1–2 years of life [27], before the
infant’s T-cell immunity is fully mature [22].
Distinguishing TB infection from active disease
requires careful clinical and radiological assessment
to guide management (Fig. 2). Considered step-wise
assessment differs in those presenting with concern-
ing symptoms for TB (Fig. 2A) compared with those
identified via screening approaches (Fig. 2B). Micro-
biological confirmation is challenging in young
children because of their paucibacillary disease
and inability to expectorate sputum [28,29]. Sub-
acute onset is typical, although acute illness may
occur in young children with primary infection. In
children older than 3 years, the combined presence
of three symptoms – unremitting cough of more
than 2 weeks duration, documented failure to thrive
(over preceding 3 months) and fatigue – has dem-
onstrated reasonable diagnostic accuracy in TB
endemic settings (sensitivity 82%, specificity 90%)
[16]. Careful clinical examination is advised, but
rarely helpful, since most children with pulmonary
TB have minimal clinical signs despite having typi-
cal symptoms. In children who have been exposed
to TB, use of a more sensitive symptom-based
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Tuberculosis in children Howard-Jones and Marais
screening approach that distinguishes completely
asymptomatic children can be used in low-resource
settings to identify children who may benefit from
preventive therapy without further evaluation.
Chest X-ray interpretation can be challenging
and this is compounded in a child with a low pre-
test probability of TB disease. Viral and bacterial
infections can complicate chest X-ray interpreta-
tion, given that most radiological signs are fairly
nonspecific. Radiological assessment requires care-
ful consideration of the likely stage of disease and
age of the child (Fig. 3) [30,31]. The primary Ghon
focus may be distinguished by enlarged lymph
nodes and localized parenchymal consolidation.
Bronchial disease with partial or complete airway
obstruction may present with either lobar collapse
or air-trapping. Adult-type cavitatory lung disease is
fairly pathognomonic, but mostly only seen in post-
pubertal adolescent patients. Repeat imaging
together with serial clinical review may be required
to exclude alternative causes and reach a firm diag-
nosis. It is important to remember that a TB diagno-
sis is rarely urgent; only TB meningitis and miliary
TB represent medical emergencies where rapid treat-
ment initiation is imperative.
Microbiological specimens remain the corner-
stone of TB diagnosis, although more elusive in
young children who cannot expectorate [32]. Alter-
native collection methods include induced sputum
or early-morning gastric aspirates, usually requiring
inpatient admission, although studies have demon-
strated success in out-patient settings [33]. Trials are
ongoing to optimize the yield from stool, because
this represents a more readily accessible respiratory
specimen in young children who reflexively swal-
&& &&
low their sputum [34 ,35 ].
The advent of nucleic acid amplification tests
(NAATs) such as the Xpert MTB/RIF and the new
Xpert Ultra assays has greatly reduced diagnostic
turnaround times with reasonable sensitivity
(70%) and high specificity (98%) on sputum speci-
& &
mens compared to culture [36,37 ,38 ]. Recent stud-
ies suggest good sensitivity (63%) and specificity
(99%) of Xpert MTB/RIF on stool specimens, with
even higher sensitivity (80%) in severely immuno-
&
suppressed children with HIV [39 ]. Because Xpert
MTB/RIF and Xpert Ultra include rpoB gene amplifi-
cation, this also provides rapid information on likely
rifampicin susceptibility.
In well resourced settings, routine whole
genome sequencing provides comprehensive infor-
mation on genotypic drug resistance and allows
accurate reconstruction of likely transmission net-
&&
works [40,41,42 ]. At present, its broader applica-
bility is hampered by high cost and requirement for
advanced bioinformatics expertise.
www.co-pediatrics.com 397
Pulmonology

FIGURE 2. Diagnostic approach for TB in children including (a) passive case finding algorithm; and (b) active case finding
algorithm. , Young children may present with acute symptoms. §, Positive result for acid-fast bacilli (AFB) on smear may be
used as a positive finding but only if performed on sputum; smear analysis of gastric aspirates is not recommended due to
poor yield and potentially low specificity. ¥, Children in high incidence settings may have no documented exposure; TST/
IGRA may be negative in children with severe disease, and is not sufficiently sensitive to serve as a ‘rule out’ test. #, Or
relevant signs for extrapulmonary disease.  TB is rarely an emergency, with the exception of TB meningitis or miliary /
disseminated TB, and serial assessment may be warranted.

Extrapulmonary TB requires a high index of
suspicion and appropriately targeted investiga-
tions. As in intra-thoracic disease [6,43], radiolog-
ical, microbiological, and/or tissue-specific
investigations are required to establish a disease
diagnosis. Cerebrospinal fluid (CSF) testing –
including Xpert MTB/RIF or Xpert Ultra where
available – is imperative in children with possible
TB meningitis, given the need for rapid diagnosis
of TB and for exclusion of alternative diagnoses.
Analysis of urine specimens via lateral flow lip-
oarabinomannan assays (LAMs) has been added to
WHO recommendations for point-of-care assess-
ment of suspected TB disease in adults and chil-
dren with HIV; efficacy has been demonstrated in
extrapulmonary disease and pulmonary TB
&&
[44 ,45]. In line with adult data, paediatric studies
suggest enhanced sensitivity in HIV positive chil-
dren (60%) compared to those without HIV
&
(43%).[39 ]

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 Tuberculosis in children Howard-Jones and Marais

FIGURE 2. (Continued).

TREATMENT OF TUBERCULOSIS DISEASE of drug-susceptible pulmonary TB comprises

It has long been understood that treatment of TB
disease requires multiagent therapy to reduce the
risk of rapid resistance acquisition with single drug
use [46]. Drug-susceptible TB is treated in adults
with a four-drug regime – isoniazid (INH), rifampi-
cin (RIF), pyrazinamide (PZA) and ethambutol
(EMB) [47]. Because of the risk of optic neuritis with
EMB and difficulties in detecting its early signs in
young children, this drug is typically avoided in
paediatrics unless high rates of INH resistance have
been documented. Standard short-course treatment
6 months of therapy, with a three drug (INH/RIF/
PZA) intensive phase given over the first 2 months,
followed by a 4-month dual agent (INH/RIF) con-
tinuation phase (Table 1) [48]. Supplemental pyri-
doxine (vitamin B6) is usually added to reduce
adverse effects related to INH [48]. The initial inten-
sive phase aims to rapidly reduce the mycobacterial
burden whilst minimizing the risk of developing
resistance; the continuation phase aims to sterilize
the site of disease and reduce the risk of relapse. New
dispersible formulations of fixed-dose combinations
provide more palatable, child-friendly treatment

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Pulmonology

FIGURE 3. Schematic of TB disease phenotype in children. (a) Pictorial representation of the spectrum of intrathoracic TB in
children (used with permission, from Perez-Valez et al. [43]). (b) Schematic of TB disease phenotype by age in children
demonstrating (a) TB lobar pneumonia, (b) disseminated / miliary disease, (c) mediastinal lymph node disease and (d) adult-
type cavitatory disease. Further representative chest X-ray images are outlined separately [30].

options which should increase compliance and
&
completion rates (Table 2) [49 ]; early qualitative
&
data suggest good community acceptance [50 ].
Treatment of TB meningitis is more complex,
largely because of variable central nervous system
(CNS) penetration of the TB drugs. Corticosteroids
at initiation reduce adverse inflammatory responses
and are usually tapered after the first month of
treatment, although these can be restarted or con-
tinued for longer if adverse inflammatory responses
redevelop or persist [51]. A recent meta-analysis
suggests that a 6-month course of intensive therapy
gives equivalent outcomes to longer courses in non-
HIV infected children and adults [52].
Anti-tuberculous agents are not without side
effects (Table 1) and monitoring for adverse effects
&
is important [53 ,54]. Elevation of transaminases to
two or three times the upper limit of normal is
commonplace during the initiation phase and is
generally well tolerated, with subsequent normali-
zation [54]. When discontinuation of all agents is
indicated due to marked elevation of transaminases

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 Tuberculosis in children Howard-Jones and Marais

FIGURE 3. (Continued).

(>5x the upper limit of normal) or clinical jaundice,
their step-wise re-introduction is frequently toler-
&
ated if this is carefully monitored [53 ,54].
Paradoxical reactions, manifesting as apparent
disease deterioration, may occur because of exces-
sive inflammation at disease site(s), including
unmasking of occult sites of disease. This
immune-reconstitution inflammatory syndrome
(IRIS) has been most carefully described in children
with HIV who commence antiretroviral therapy
(ART) and usually manifests within the first 2–3
months of ART [55]. It is important to recognize

Table 1. Pediatric dosing and adverse effects of first-line TB medications

Medication Recommended dosea Adverse effects Additional notes

Rifampicin (R) 10–20 mg/kg/dayb Hepatitis, rash, Induction of cytochrome

(maximum 900 mg/day) discoloration of P450s with multiple
secretions drug–drug interactions
Isoniazid (H) 7–15 mg/kg/day Hepatitis, peri pheral Give pyridoxine (5–25
neonates 5–10 mg/kg/day; neuropathy, rash mg/day) concurrently to
high dose 15–20 mg/kg/day reduce risk of peripheral
(max 600 mg/day) neuropathy
Pyrazinamide (Z) 30–40 mg/kg/day Arthritis/arthralgia, Most common cause of
(max 2000 mg) hepatitis, rash hepatotoxicity
Ethambutol (E) 15–25 mg/kg/day Optic neuritis Vision/colour vision review
(max 1200 mg/day) if available; avoid if
possible in young
children
Rifapentine (Rpt) Once weekly dosing: Hepatitis, discoloration of Only approved in children
10–14kg: 300 mg secretions, 2 years
>14–25 kg: 450 mg gastrointestinal
>25–32 kg: 600 mg disturbance
>32–50 kg: 750 mg
>50 kg: 900 mg
Rifabutin (Rfb) 5 mg/kg daily or 3/week Uveitis, myelosuppression Dosing in children not
(max 300 mg) established

&&
Note: Adapted from Khatami et al. [57 ].
a
Children over 25–30 kg can be dosed as per adult regimens.
b & &
Recent reports suggest that rifampicin is not optimally dosed and that doses of up to 40 mg/kg/day are safe with likely increased efficacy [63 ,64 ].

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Pulmonology

Table 2. Available water-dispersible fixed-dose combination (FDC) tablets in children

Dispersible tablet Dosing (according to

FDC products rifampicin component)a Adverse effects Additional notes

Rifampicin 75 mg þ
isoniazid 50 mg
per tablet
Rifampicin 75 mg þ
isoniazid 50 mg þ
pyrazinamide 150 mg
per tablet
10–20 mg/kg/day of rifampicin Hepatitis, rash, Give pyridoxine (5-25 mg/
(maximum 900 mg/day rifampicin) discoloration of day) concurrently to
Round to nearest whole tablet increment. secretions, peripheral reduce risk of peripheral
Weight banded dosing: neuropathy neuropathy
4–7 kg: 1 tablet
8–11 kg: 2 tablets
12–15 kg: 3 tablets
16–24 kg: 4 tablets
10–20 mg/kg/day of rifampicin Hepatitis, rash, Give pyridoxine (5–25
(maximum 900mg/day rifampicin) discoloration of mg/day) concurrently to
Round to nearest whole tablet increment. secretions, peripheral reduce risk of peripheral
Weight banded dosing: neuropathy arthritis/ neuropathy
4–7 kg: 1 tablet arthralgia
8–11 kg: 2 tablets
12–15 kg: 3 tablets
16–24 kg: 4 tablets

Note: Available through the global drug facility (GDF).

a
Children over 25 kg can be dosed as per adult regimens.

this entity, which should not be confused for treat-
ment failure, as anti-tuberculous agents should be
continued throughout this period. Adjunct cortico-
steroids or other anti-inflammatory agents may be
indicated to modulate the immune response.
The treatment of drug-resistant TB is setting
dependant. Most high incidence countries use pro-
grammatic approaches, but in low incidence coun-
tries each patient’s regimen is tailored to their drug
susceptibility test (DST) pattern. In children without
microbiological confirmation, the DST pattern is
often inferred from the likely adult source case.
Treatment of multidrug-resistant tuberculosis
(MDR-TB) requires careful consideration of geno-
typic and phenotypic DST, pharmacokinetics and
&&
adverse effect profiles [56 ].
In general, treatment outcomes are excellent in
children once an accurate diagnosis is reached
&&
[57 ]. A recent retrospective cohort study in Uganda
reported 93% success rates in children with TB
&&
disease [58 ]. Outcomes for MDR-TB and exten-
sively drug resistant TB (XDR-TB) in children are
also better than in adults. One recent individual
patient data meta-analysis reported a survival rate
of 89% in XDR-TB, significantly higher than
&&
reported rates in adults [59 ].
specialized input from infectious diseases physicians
familiar with TB in children. Because of the high risk
of disease progression in young children, treatment
of TB infection (so-called preventive therapy or
prophylaxis) has long been recommended for all
children under 5 years and those with immunocom-
promise. WHO recommendations recently changed
to recommend treatment of all infected household
&&
contacts of a pulmonary TB case [1 ], but imple-
mentation will require a major shift in commitment
and resource allocation because less than 25% of
eligible young children received preventive therapy
&&
in 2017 [1 ]. Because household transmission of
drug-resistant strains poses a real risk as well, the
use of appropriate preventive therapy in MDR-TB
&
contacts requires careful consideration [60 ]. Use of
6–9 months of INH has demonstrated efficacy in
adults and children, but shorter course regimes –
including single-agent RIF for 4 months, or a 3-
month course of daily INH/RIF (or weekly INH/
rifapentine in children over 2 years) – have shown
equivalence in recent trials with improved comple-
&
tion rates and similar adverse event profiles [61 ]. A
3-month course of water-dispersible INH/RIF is now
widely available and offers a pragmatic child-
friendly option.

TREATMENT OF TUBERCULOSIS CONCLUSION

INFECTION
A key clinical priority in initiating treatment for TB
infection is reaching a high level of confidence in
the exclusion of active TB disease. Where there is
uncertainty, serial assessment is required and
The global paediatric TB burden has long been
underappreciated, with substantial limitations in
diagnosis and management of children, especially
&
in high incidence settings [15 ]. Because the risk of
disease progression and dissemination is high in

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young children, accurate and timely assessment and
treatment are critical. A systematic approach to TB
diagnosis is imperative to inform treatment deci-
sions, and can deliver a presumptive diagnosis
with reasonable accuracy. Molecular methodolo-
gies, and testing of less-invasive urine and stool
specimens using novel methods, shows much
promise but further validation is required. TB
treatment outcomes are generally excellent and
benefit from a multidisciplinary team approach
including child, family, public health and medical
teams, where this is available. Children present
unique challenges, but also opportunities to mon-
itor progress of TB control. Major advances in TB
control, which will be required to meet ambitious
global TB elimination targets, will require optimal
prevention and management of TB disease in chil-
dren and adults.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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Volume 32  Number 3  June 2020