Updatesinpediatric Tuberculosisin Internationalsettings: Sadia Shakoor,, Fatima Mir

U p date s i n P ed i at r i c
Tu b e rcu l o s i s i n
In t er n ation al S et t i n g s
Sadia Shakoor, MBBS, FCPS Microbiologya,
Fatima Mir, MBBS, FCPS Pediatrics, MsCRb,*
KEYWORDS
Childhood TB LTBI in children Policy-practice gaps LMICs HBCs
Paucibacillary TB diagnostics DS-TB
KEY POINTS
Poor surveillance in international settings, especially resource-poor high-burden settings,
due largely to health system barriers, variations in case definitions and difficulty in diag-
nosis, and standardization and reporting, lead to an underdetected epidemic of childhood
tuberculosis (TB).
Considerable progress has been made in consolidated guidelines on appropriate dosing
and safe and effective regimens for treating childhood TB. However, gaps in implementing
treatment completion in high-burden countries (HBCs) remain.
New drugs in pipeline have yet to permeate national TB programs in low- and middle-
income countries.
BCG vaccination at birth is implemented in most HBCs. However, efficacy against TB is
higher when coupled with stringent tuberculin skin test screening, which is missing in
most HBCs.
Policy-practice gaps stem from poor integration of TB services for children with other
maternal and children health programs such as reproductive health, integrated manage-
ment of childhood illness, HIV, and nutrition support and immunization, resulting in inad-
equate detection of TB exposures, infections and cases among children.
INTRODUCTION
Over 1 million children are diagnosed with tuberculosis (TB) each year.1 Many more in
high-burden countries (HBCs) are exposed to tuberculous adult contacts and are
never evaluated for exposure or preventive therapy,2 thus maintaining a vulnerable
a
Department of Pathology, Section of Microbiology, Aga Khan University, Supariwala Build-
ing, PO Box 3500, Karachi, Pakistan; b Department of Pediatrics and Child Health, The Aga
Khan University, Faculty Office Building, PO Box 3500, Stadium Road, Karachi 74800, Pakistan
* Corresponding author.
E-mail address: [email protected]
Pediatr Clin N Am 69 (2022) 19–45

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20 Shakoor & Mir
pool of children and weakening any existing control measures. The current vaccine is
not effective enough to prevent TB. The epidemic of pediatric TB in low- and middle-
income countries (LMICs) therefore continues unabated and is complicated by
emerging infectious and noninfectious epidemics, viz, human immunodeficiency virus
(HIV), malnutrition, coronavirus disease 2019 (COVID-19), and diabetes.
Advances in the science, diagnosis, and management of TB in children have
continued, and this review presents the existing situation in international settings and
focuses on recent advances with the potential to improve outcomes of pediatric TB.
EPIDEMIOLOGY OF PEDIATRIC TUBERCULOSIS IN INTERNATIONAL SETTINGS
TB continues to afflict several populations across the globe in different socioeconomic

settings. The highest burden of disease is typically seen in countries with weakened
health systems,3,4 which characteristically also marginalize vulnerable pediatric pop-
ulations. Prevention of spread and control as well as adequate individual management
of TB therefore requires political will and a strategic system approach, with ambitious
targets and rigorous monitoring and evaluation framework.
Programmatic Approach
The World Health Organization (WHO) announced an End TB strategy in 2015, with
overarching targets to reduce TB incidence and mortality by 90% and 95%, respec-
tively, by 2035.1 The goals and performance targets for subpopulations were revised
at the United Nations high-level meeting in September 2018. A new strategy and road-
map were released jointly by the StopTB Partnership and WHO with special emphasis
on prevention and control of pediatric TB.
Global Situation and Gaps

In 2019 children accounted for 12% of the global estimated TB cases and 16.5% of
the total deaths. Children, however, are disproportionate to their estimated share of
incident cases in regard to having poor access to health care, late diagnosis, and
poor management.
Fig. 1 shows target attainment gaps in case detection and treatment of rifampin-
resistant (RR) TB and multidrug-resistant (MDR) TB (ie, resistant to both isoniazid
and rifampin). Of the estimated 1.2 million cases, only half a million were diagnosed
and notified in 2019.1 Less than 10% of the estimated RR TB cases were diagnosed
in children in 2019.1 Although improved from previous years, these fell short of the
required 5-year targets, and the future notifications are expected to fall in 2020 onward
owing to the impact of the ongoing COVID-19 pandemic and interruption in health
services.5
Of note, children comprised less than 5% of total notified cases in 8 of 30 HBCs, a
figure that highlights underdetection and underreporting of pediatric disease and rai-
ses pertinent concerns about health care access and equality.
Regional Incidence of Childhood Tuberculosis: Where are the Gaps?

Driven by the HBCs within regions, the estimated incidence of TB among children 0 to
14 years of age was highest in the WHO Southeast Asia region, followed by Africa,
Western Pacific, and Eastern Mediterranean region (Fig. 2).1 Both the estimated
and reported female to male ratio in children 0 to 14 years of age remained 0.9 in
HBCs.
Fig. 3 is a snapshot of the case detection gaps in children 0 to 14 years of age in the
20 highest burden countries that shared 84% of the overall incident cases in all age
Pediatric Tuberculosis in International Settings 21
Fig. 1. Progress in pediatric TB 2018 to 2022 target achievements; targets were set by WHO.
Achieved targets in 2018 and 2019 for case detection fell short by 10% (1.04 million cases
detected in 2 years vs an estimated 2-year target of 1.4 million), whereas those for
multidrug-resistant (MDR) TB fell short by 32.2% (8986 children treated vs an estimated
requirement of 46,000 in 2 years). Latent TB infection (LTBI) treatment targets for children
aged 0 to 4 years also lagged annually by 10%. (Source of data: Global Tuberculosis Report,
WHO, 2020.)
groups in 2019.1 Greatest gaps exist in low-resource settings with severely reduced
health care budget allocations in Africa and Asia. Although many of these countries
have TB programs supported by the Global Fund to Fight AIDS, TB, and Malaria,
the lack of a coordinated health system and weaknesses of horizontal programs
such as Integrated Management of Childhood Illnesses and lack of integration result
in unmet gaps in access and management.
Age-disaggregated data were not available for MDR and RR TB for all the 20 HBCs
and for none of the WHO member states before 2018. The practice of age-
disaggregated surveillance of TB is recent, and expected to give impetus to pediatric
TB monitoring, evaluation, and service improvement. However, this will only be
possible with removal of existing health system barriers that impact coverage, access,
and affordability of pediatric services in high-burden settings.
Fig. 2. Regional estimates of burden of TB in children 0 to 14 years of age, data from Global
TB report 2020. Regional estimates are driven by data in high-burden countries (HBCs).
(Source of data: Global Tuberculosis Report, WHO, 2020.)
22 Shakoor & Mir
Fig. 3. Map with pediatric TB incidence (number reported in 2019) as per 2020 Global TB
Report in 20 HBCs with 84% of total reported case burden in 2019. Despite a high burden
of TB, childhood cases (0–14 years) only comprise 0% to 5% of total notified cases, high-
lighting gaps in case detection and diagnosis. (Source of data: Global Tuberculosis Report,
WHO, 2020.)
Drug-Resistant Tuberculosis in Children

The challenges of TB surveillance, reporting and diagnosis are even more pronounced
for MDR TB in children. Age-disaggregated data on MDR TB treatment (number of
cases treated as notified by country programs) for WHO member states is only avail-
able after 2018. Data on incidence are sparse and inaccurate.
Dodd and colleagues6 estimated through a modeling approach that in 2014, of
850,000 new infections in children, 25,000 were MDR and 1200 were extensively
drug resistant ([XDR] currently defined as an MDR TB strain that is resistant to fluoro-
quinolones).6 Other modeling estimates have concluded that at least 30,000 MDR TB
infections occur in children every year (3.2% of incident cases in children).7 Children
with bacteriologically confirmed MDR TB are sicker and more likely to have comorbid
conditions such as HIV and malnutrition,8 making TB surveillance a priority in HIV and
undernourished populations.
One of the challenges in determining MDR TB rates is the requirement of bacterio-
logic confirmation. Without the scale-up of culture-independent rapid molecular diag-
nostic tools to diagnose RR and MDR TB in children and the adaptation of
epidemiologic definitions,9 prevalence statistics and incidence estimations based
on modeling with unreliable inputs will remain inadequate.
The impact of underdetection is clearly perceived in the lag in MDR TB treatment
target achievement (see Fig. 1), where only a very small proportion of children are re-
ported as being treated for MDR TB. Owing to incomplete vital registries and incom-
plete mortality reporting especially in HBCs and high MDR burden settings, the
disease outcomes of children with MDR TB are unavailable but are expected to be
dire.
Pulmonary Tuberculosis Versus Extrapulmonary Tuberculosis and Disseminated

Tuberculosis in Children
Extrapulmonary sites of infection are more likely to occur in children than in adults
owing to more efficient lymphatic spread. However, because many children will also
have pulmonary disease, surveillance data may misclassify them as pulmonary TB

cases. Moreover, if clinicians also fail to identify signs of extrapulmonary TB, cases
will be undertreated. The challenges therefore are multifold and exist at both macro-
levels and microlevels.
Of note, for specific forms of extrapulmonary TB, viz, TB meningitis, outcomes are
significantly poorer especially in children younger than 5 years.10 Disaggregated data
reporting for specific types of extrapulmonary TB is therefore critical in estimating its
burden especially in HBCs to divert resources to develop and sustain specific strate-
gies in the detection and management more effectively.
Arguably defined as TB involving the hematopoietic system or 2 or more noncon-
tiguous body sites,11 disseminated TB is common in children. No data on dissemi-
nated TB are reported by TB programs in HBCs. Disseminated TB is estimated to
occur in up to 5% of TB cases in adults12; however, children are at greater risk
because they are disproportionately affected by specific risk factors such as malnu-
trition. In HBCs therefore it is likely that a significant proportion of undetected burden
of both extrapulmonary and disseminated TB exists with proportionately high mor-
tality in children.
Congenital and Neonatal tuberculosis

There are no incidence estimates available for perinatal or neonatal TB. Congenital TB
is a result of exposure in utero or during birth. Exposure to maternal respiratory drop-
lets after birth can lead to neonatal TB. Although TB in pregnancy was estimated to
occur in more than 200,000 women in 2014 alone, the actual incidence of maternal
TB resulting in neonatal TB is likely higher in HBCs owing to increased susceptibility
to TB in late pregnancy.13 Congenital and neonatal TB have high mortality, but data
are not available to inform the true burden in HBCs.
Because little scientific evidence is available for the impact of various strategies for
diagnosis, management, and prevention of congenital and neonatal TB, this is an area
requiring attention and further research. Studies in high-prevalence areas, viz, the 30
high TB and HIV burden settings, in pregnant women and neonates can be highly
informative in the planning of successful diagnostic, treatment, and preventive
strategies.
Tuberculosis Mortality
Owing to limitations in national vital registration data availability in HBCs, TB mor-
tality data reported by HBCs remain inaccurate. Estimates of TB deaths (based on
incidence and case fatality data) for the 0- to 14-year age group for both HIV-
positive and HIV-negative children were 16% of total TB deaths across all regions
and slightly higher for male children.1 Most deaths occurred in Africa and South
East Asia, however, the ratio of under-14 mortality to the overall mortality did not
vary significantly, with the exception of higher mortality estimate among HIV-
infected children in Africa.1 Dodd and colleagues14 performed a global mortality
burden estimate for children aged 0 to 14 years in 2015 and reported an average
case fatality rate of 24%, with higher rates among HIV-infected children in Africa.
Data also suggested that mortality would be reduced by half if case detection rates
were improved in children.
Prevalent and Emerging Risk Factors

To effectively reduce the transmission of TB, it is important to focus on pediatric sub-
populations with predisposing risk factors. Active TB disease in children is at least a 2-
step process: first, an exposure leading to infection, and second, infection progressing
24 Shakoor & Mir
to active disease. Risk factors for initial infection are socioeconomic and lifestyle asso-
ciated. Owing to the impact of socioeconomic factors on initial infection, screening
and treatment of latent TB infection (LTBI) is an effective strategy to reduce the inci-
dence of TB in migrant children. In contrast, progression to disease depends on bio-
logical and host-specific risk factors. Among known host characteristics that are risk
factors for active TB in children are HIV, primary immune deficiency disorders, and un-
dernutrition.1 Undernutrition is prevalent in HBCs, with prevalence ranging from 2.5%
in Brazil and Russia to as high as 40% in Congo and 60% in Central African Republic.1
The prevalence of HIV varies in different settings; 14 of the 20 highest burden countries
also have high HIV prevalence, and additional 16 countries are also included in the
WHO list of high TB and HIV burden countries.1 Of note, data on estimates for children
living with HIV for the period 2015 to 2019 were only available for 10 of these countries,
with a rising trend in 3 countries.15 Only 53% children accessed antiretroviral treat-
ment in 2019,16 which is a mere 5% increase from 2015 reports.17 Rising incidence
and marginalization leading to limited access to antiretroviral treatment increases
the risk of active TB in children.
Contribution of other known risk factors such as childhood diabetes and parental
smoking is less well defined. Exposure to parental smoking is associated with a 2-
fold increased risk of TB infection and 4-fold increased risk for active TB in children.18
Prevalence of TB in one study among type 1 diabetic children was 5-fold higher than in
children without diabetes.19 Other issues such as illicit drug use among children also
seem to be common in HBCs20 but is underdetected among marginalized children in
LMICs.21
Major Issues and Barriers in Delineating Tuberculosis Epidemiology Among

Children in International Settings
Childhood TB epidemiology remains difficult to address. Health system as well as so-
cial and diagnostic issues serve as barriers against pediatric TB case finding in HBCs.
Systematic issues of data capture and reporting are underlined in the global TB report
as major obstacles in detecting children with TB1; inventory studies and capture-
recapture surveys are important to highlight the inadequacy of current notification sys-
tems in HBCs. Box 1 highlights the important barriers to overcome to improve the
detection and management of TB disease among children.
UPDATES IN PEDIATRIC TUBERCULOSIS CASE DETECTION AND DIAGNOSIS
Diagnosis of pediatric TB may be made based on bacteriologic testing, clinical criteria,

or a combination of supportive evidence provided by biomarkers and radiological im-
aging. Despite advances in each of these, diagnosis of pediatric TB remains difficult in
clinical settings.
Clinical Diagnosis
Clinical judgment remains valuable in the diagnosis of pediatric TB. A detailed history
of contact with a known TB case (mostly an adult household) is highly suggestive of
active TB in a sick child. Healthy children in this situation should be evaluated for LTBI.
Initial signs and symptoms of pulmonary and extrapulmonary TB are nonspecific in
younger (<2–3 years) children. However, childhood TB is highly responsive to antitu-
berculous treatment especially if detected early. Early detection in younger children
requires a meticulous history taking for failure to thrive, irritability, reduced playfulness,
poor appetite, vomiting, and abdominal pain. Sleep disturbances may also be
observed.22,23
Box 1
Barriers to childhood tuberculosis control and elimination in high-burden settings
Health system barriers

Incomplete health care access to marginalized populations
Inability of health system infrastructure to support integrated care
Lack of programmatic linkages
Lack of political commitment to new strategies (eg, lack of commitment to LTBI treatment)
Lack of prioritization of children and pregnant women
Disproportionate financing (lack of funds to support programs)
Systematic corruption
High turnover (low retention) of trained health care personnel in programs
Case finding barriers
Difficult diagnosis, difficult sampling in children
Insufficiently sensitive diagnostic tests
Inadequate physician training in clinical diagnosis
Unavailable diagnostic tools (lack of availability or scale-up)
Underreporting (incomplete data)
Overdiagnosis
Socioeconomic barriers
Poverty
Lack of trust in medical care
Poor health literacy
Social stigma
Presence of chronic cough alone in children increases the odds of being diagnosed
with TB (odds ratio, 13.8; 95% confidence interval [CI], 2–83).24 A wide confidence in-
terval, however, indicates a high level of heterogeneity within the pediatric population,
stemming from differences in underlying health, age, and weight; these differences
may be more relevant within pediatric populations in HBCs. A combination of persis-
tent cough, weight loss, and listlessness has a positive predictive value of greater than
80% in children with pulmonary TB.23 However, positive predictive values of various
combinations of symptoms may vary significantly in undernourished or HIV-infected
children, due to masking of symptoms in young, malnourished, or immune-deficient
children.
Studies of clinical diagnostic criteria in HBCs are therefore required, especially using
clinical diagnostic criteria proposed for pulmonary TB in children.25 Owing to the lower
standalone specificity of clinical signs and symptoms and risk of overdiagnosis even in
HBCs, bacteriologic confirmation should be sought.
Bacteriologic Confirmation with Conventional and Advanced Tools

HBCs rely heavily on smear microscopic diagnosis of TB, because laboratory capacity
for culture and molecular testing is limited.1 However, smear microscopy for the diag-
nosis of pediatric TB is insensitive. Culture of Mycobacterium tuberculosis provides re-
sults after a minimum of 10 days (2–4 weeks), which is not ideal for urgent situations in
which TB is considered. Clinical diagnosis therefore takes precedence over a negative
smear and culture result, particularly in situations requiring urgent treatments such as
TB meningitis or disseminated TB in infants or HIV-infected children, especially where
alternative rapid diagnostic tools are not available. Rapid molecular diagnosis is rec-
ommended by WHO using prequalified diagnostic tools.26
Global Fund-supported disbursement of rapid molecular diagnostics has been initi-
ated in some HBCs, but is not available at large scale and remains underutilized.27
26 Shakoor & Mir
Xper Ultra assay is an automated, integrated, cartridge-based molecular assay to

identify TB as well as rifampicin resistance directly from sputum. The development
of such assay with its high sensitivity is ideal for pediatric populations, wherein lower
bacillary load prevents good performance of microscopic smear and culture. Of note,
such rapid tests have been shown to perform well with extrapulmonary specimens,
except urine and pleural fluid.26
A major obstacle that prevents uptake of microbiological diagnostic tools even when
available is the difficulty of obtaining appropriate samples from children. Younger chil-
dren often do not produce sputum and thus require gastric lavage after overnight fasting
in a hospital setting, or where available, bronchoscopy to obtain respiratory samples.
Recently, stool has been evaluated as an alternative specimen for TB diagnosis.26
Use of noninvasive stool specimens for the diagnosis of pulmonary TB in children is
valuable, and the scale-up of stool-based Xpert Ultra assay can increase case detection
rates in HBCs. Bacteriologic confirmation of extrapulmonary TB without coexisting pul-
monary disease often requires invasive sampling techniques such as lumbar puncture,
needle aspirations, needle biopsies, or surgical biopsies. Such sampling may, however,
be made less invasive in selected cases by interventional radiology.
Histopathological diagnosis
Histopathological diagnosis demonstrating caseation and granulomas in biopsy spec-
imens often proves valuable especially in situations with coexisting tumor pathology,
or where a diagnosis is questionable, for instance, in low-prevalence settings. In
HBCs, histopathological diagnosis is less often used because of the unavailability
and inadequacy of pathology and laboratory medicine services.28 Efforts to improve
the pathology and laboratory medicine services in LMICs will improve clinical care
beyond improving TB case detections, by preventing overdiagnosis and misdiagno-
ses in children with illnesses that mimic TB.29
Biomarkers
Accurate biomarker-supported diagnosis has 2 potential advantages over bacterio-
logic diagnosis in children. First, biomarkers are usually evaluated and performed in
relatively easy-to-access specimens as opposed to invasive procedures required
for obtaining samples for culture. Second, biomarkers provide supportive evidence
of TB in children with a high likelihood of the disease but negative bacteriologic tests.
Furthermore, biomarkers can potentially allow disease monitoring and
prognostication.
Urine lipoarabinomannan lateral flow point-of-care test has a sensitivity of 43%
(95% CI, 23%–66%) and specificity of 80% (95% CI, 69%–88%) as an add-on test
for detection of TB in children living with HIV.30 WHO recommends use of this test
among HIV-positive children with CD4 counts less than 100/mm3 in outpatient set-
tings, in combination with clinical diagnosis.30 Use in HBCs with high HIV prevalence
can enhance case detections; however, only 13 of 30 HBCs have adopted this test in
their diagnostic algorithms,1 highlighting policy and implementation gaps.
Candidate biomarkers under development and evaluation include microRNAs, inter-
leukins, and cytokines. Complex methodological issues prevent wider usage, and a
recent systematic review also highlighted the need for further studies in diagnostic
evaluations to avoid overestimates of accuracy.31
Biosignatures comprising several integrated biomarkers may have higher overall ac-
curacy than single biomarkers. Immune cytokine profiles, proteins (proteomic), meta-
bolic end products (metabolomic), and messenger as well as microRNA
(transcriptomic) biosignatures32 hold promise as a point-of-care biomarker of active

TB disease with high accuracy regardless of HIV status.33
Radiological Diagnosis
Plain radiography and ultrasonography are both low cost and widely available in
HBCs. The limitations are low sensitivity in pulmonary and extrapulmonary TB in chil-
dren and the impact of operator variability for ultrasonography.34,35 Advances in
digital-assisted interpretation can overcome operator and reader subjectivity but
cannot account for inherently lower sensitivity. To be able to uncover small lesions
of extrapulmonary TB and lymphadenopathy in children and facilitate diagnostic or
therapeutic drainage, computed tomography or MRI may be required. Given that
such facilities are not widely available in HBCs, facilitated referral of children identified
through clinical diagnosis or scoring (see later) as being high risk for TB can enhance
case detection and management.
Diagnostic Markers of Latent Tuberculosis Infection in Children

Immune response to M tuberculosis antigens is considered a diagnostic surrogate for
TB. Currently available tests (tuberculin skin test and interferon gamma assays) are
methodologically complex and highly variable in children younger than 4 years.36
Testing, however, is not a prerequisite before preventive treatment can be given to
household contacts of patients with infectious TB. However, in a few instances, diag-
nosis of LTBI holds value in children, viz, in refugees or internationally displaced chil-
dren from high-burden settings, in children with immunodeficiencies with uncertain
contact history, and in children who will receive immunosuppressive or myeloablative
therapies in high-burden settings and with uncertain contact histories. Moreover, ev-
idence of LTBI serves as a criterion in clinical scoring systems for active TB in children.
The test result does not have standalone value as a diagnostic element but adds to the
certainty of diagnosis when used in combination with other suggestive criteria.
Clinical Scoring and Nonscoring Diagnostic Systems

Challenges surrounding the difficulty of using a single ideal diagnostic tool for the
detection of TB in children necessitate the development of composite scoring systems
or unscored diagnostic systems. Several scoring systems have been in use in clinical
settings for decades; a systematic review in 2012 found that validity of scoring sys-
tems is not systematically evaluated.37 The relatively recent Brazilian Ministry of
Health scoring system has undergone rigorous evaluation and has been shown to
have 48.3% (95% CI, 35.2%–61.6%) sensitivity and 76.5% (95% CI, 62.5%–87.2%)
specificity in HIV-infected children.38 Nonscoring systems such as the Marais criteria
have greater sensitivity of 84.4% (95% CI, 73.1%–92.2%) but lower specificity of
29.8% (95% CI, 18.4%–43.4%) in the absence of microbiological diagnosis and has
previously been shown to have high sensitivity in HIV-uninfected children.37
However, both the Marais system and the Brazilian Ministry of Health score were
developed for the diagnosis of pulmonary TB. Older scoring systems such as the Ken-
neth Jones and Keith Edwards criteria also focus on extrapulmonary TB and therefore
remain in wide usage for difficult clinical situations to rule in extrapulmonary TB. More-
over, these latter scoring systems also have improved specificity, allowing their use as
rule-out scoring systems.39 Table 1 summarizes the various diagnostic tests and stra-
tegies for the detection of TB in children.
28 Shakoor & Mir
Programmatic Challenges and Implementation Gaps

Gaps in bacteriologic confirmation of pediatric TB and MDR TB are the limited labo-
ratory and diagnostic capacity in HBCs.1 Multiple factors prevent routine bacteriologic
confirmation of TB in children, viz, paucibacillary disease, difficult sampling of clinical
specimens, and unavailability of diagnostic tools (see Box 1). Lack of investment in
diagnostic tools by programs leads to limited rollout of rapid and ultrasensitive molec-
ular diagnostic tools.1 Moreover, human resource, biomedical support, and connec-
tivity are major obstacles in implementation of recommended diagnostic
algorithms.28 Moreover, physician training in algorithms and interpretation of labora-
tory and imaging tools is limited.40 Such gaps, obstacles, and training must be
addressed in the fight against pediatric TB globally.
UPDATES IN TREATMENT IN HIGH-BURDEN COUNTRIES

Treatment of Drug-Susceptible Tuberculosis in Children
TB disease in children has traditionally been treated with the agents used to treat adult
disease. First-line regimens for drug-susceptible TB across the world still contain
isoniazid, rifampin, ethambutol, and pyrazinamide. Dosages have recently been
increased by WHO41,42 with 2 months of rifampicin (R) (10–20 mg/kg, maximum
[max] dose 600 mg/d), pyrazinamide (Z) (30–40 mg/kg), isoniazid (H) (10–15 mg/kg,
max dose 300 mg/d), and sometimes ethambutol (E) (15–25 mg/kg, in areas of high
HIV or isoniazid resistance prevalence) followed by 4 months of rifampicin and isoni-
azid at the aforementioned doses.43,44 There are still remaining concerns over subop-
timal plasma concentrations especially in resource-constrained settings where
therapeutic drug monitoring is nonexistent.45 WHO recommends the fixed drug com-
binations over separate formulations for children based on evidence from trials in
adults.46 A revised isoniazid range of 7 to 15 mg/kg/d was advised to national pro-
grams as adequate even in children younger than 2 years or fast acetylators (sub-
groups at risk of suboptimal serum drug concentrations) based on the impossibility
of meeting recommended isoniazid range (10–15 mg/kg/d) with the existing fixed
drug combination for children (H50R75Z150) without exceeding the therapeutic
dose range of pyrazinamide.42,44,47,48
In rifamycin group (rifampicin, rifabutin, and rifapentine), despite revision in rifampicin
dosage (15 mg/kg/d), there is an increasing focus on higher doses (30–35 mg/kg) with
early reports of acceptable tolerance and higher serum levels.49 For children with HIV-
TB coinfection, rifabutin at the dose of 5 mg/kg (children) and 150 to 300 mg/d (adults)
has been recommended based on lesser HIV-TB drug interactions and side effects.50
A 4-month fluoroquinolone-based regimen (2 months of isoniazid [H], rifampicin [R],
prothionamide [pt], pyrazinamide [Z], and moxifloxacin [Mfx] [2HRptZMfx] followed by
2 months of HRptMfx) has been compared with 6-month standard regimens (2HRZE/
4HR) in adults and have been found to have higher relapse rates.51–53 Only recently in
2021, two 4-month regimens (first regimen, 2 months of isoniazid [H], rifapentine
[RPT], pyrazinamide [Z], and ethambutol [E] followed by 9 weeks of RPT and H, and
second regimen, 2 months of HRPTZMfx followed by 9 weeks of HRPTMfx) were
compared with standard 6-month rifampicin-based regimen (2HRZE/4HR) and
showed noninferiority to the standard of care for drug-susceptible TB in adults54; how-
ever, this has not translated into guidelines yet.
Drug-Susceptible Pulmonary Tuberculosis

A new possible alternative to the classic 6-month rifampicin-based regimen (2HRZE/
4HR) is a 4-month rifapentine-based regimen41 composed of rifapentine, isoniazid,
Table 1
Clinical application and limitations of various diagnostic tools for detection of TB in children with reference to needs of high-burden settings
Diagnostic Element Settings Where Applicablea Clinical Utility Limitations

Clinical diagnosis
History, symptoms, and signs All Can be applied in all settings, Do not perform well as standalone
indispensable in informing criteria; sensitivity and PPV vary
physicians’ “clinical judgment” with underlying conditions in
History of exposure essential for children and are low in HIV-
both active infection and infected children
screening for latent infection Potential for overdiagnosis due to
low specificity
Scoring/diagnostic systems All; some scoring systems perform Increase certainty of diagnosis and Higher sensitivity than clinical
better in referral settings sensitivity by using multiple signs and symptoms alone
composite criteria Issue of overdiagnosis may remain
Useful in both HIV-infected and when bacteriologic diagnosis
Pediatric Tuberculosis in International Settings

uninfected children not used
Systems with better performance Need to train health care workers
are BMOH (clinical in use and interpretation
manifestations, radiograph, Systems with high sensitivity for
contact history, nutritional PTB do not perform well for
status, tuberculin skin test) and children with EPTB
Marais criteria (in addition to
BMOH, includes other risk
factors, viz, HIV, extrapulmonary
signs and symptoms, and
microbiological evaluation)
In vitro diagnosis
Smear and culture Need small laboratory for direct When positive have high PPV for Direct smear is highly insensitive
smear and advanced biosafety TB in children in HBCs Concentrated smear and culture
level for concentrated smear Culture allows further limited by need for laboratories
and culture susceptibility testing and whole- with advanced biosafety levels;
genome sequencing where culture results are not rapid
(continued on next page)
29
30
Shakoor & Mir

Table 1
(continued )
Diagnostic Element Settings Where Applicablea Clinical Utility Limitations
advanced service linkages Positive smear may be found in
available, to delineate NTM infections, especially in
molecular epidemiology low-burden settings
Rapid molecular All (new point-of-care platforms 1–2 h to results in most settings Require connectivity for rapid
diagnosis with expected to be available in allows use in all settings in result communication if not
capability to detect 2021) which equipment can be placed placed in clinic settings
rifampin resistance New tests with sensitivity Biomedical maintenance is
comparable to concentrated required, which may be
culture are recommended for unavailable in HBCs
use in children
Allow rapid detection of rifampin
resistance and exclude NTM
infection
Biomarkers of Inpatient and outpatient settings Available for use as point-of-care Not recommended for use in HIV-
active infection serving HIV-infected children, all lateral flow devices uninfected children
levels; point-of-care, no need for Allow culture-independent testing Performance limited in children
laboratory in easy-to-access specimens without symptoms or in children
(urine) in children with HIV with CD4 counts greater than
where bacteriologic 200/mm3
confirmation may not be
possible
Biomarkers of Laboratory setting, referral Allow diagnosis of “infection” as Do not diagnose active TB in
latent infection centers surrogate for exposure as part of children
some diagnostic systems IGRAs limited by methodological
issues and interlaboratory
variability of results
Radiological
diagnosis
Radiography Secondary care and with annexed Wider availability and Interobserver agreement and
and ultrasonography services in some primary care acceptability as diagnostic tools interpretation issues
settings May allow diagnostic and Have limited sensitivity and
therapeutic aspiration in EPTB specificity with potential for
overdiagnosis when used
without bacteriologic
confirmation
Advanced: CT, MRI, Referral centers Advanced-level diagnostic tools Limited availability and expertise
or fluoroscopic for use in referral centers, allow in HBCs
imaging detection as well as diagnostic
and therapeutic drainage in
EPTB
Abbreviations: BMOH, Brazilian Ministry of Health; CT, computed tomography; EPTB, extrapulmonary tuberculosis; NTM, nontuberculous mycobacteria; PPV, pos-
itive predictive value; PTB, pulmonary tuberculosis.

a
Primary and/or secondary versus referral center or laboratory versus point of care.
31
32 Shakoor & Mir
pyrazinamide, and moxifloxacin.54,55 The noninferiority trial enrolled participants aged

12 years and older with newly diagnosed pulmonary TB confirmed by a WHO-
recommended diagnostic test and who were susceptible to isoniazid, rifampicin,
and fluoroquinolones. Preliminary results from the multicenter SHINE trial comparing
a 4-month rifampicin-based regimen (2HRZE/2HR) with the standard 6-month
regimen (2HRZE/4HR) in participants aged less than 16 years (median age 3.5 years)
has shown noninferiority in treatment failure and relapse rates56; this may eventually
influence future recommendations on duration of treatment of nonsevere TB in
children.57
Drug-Susceptible Extrapulmonary Tuberculosis
Recommended regimens for extrapulmonary TB by WHO guidance to national pro-
grams are in Table 2. Classic regimens are 6 months long except for meningeal and
osteoarticular TB, which should be 12 months. Adjuvant corticosteroid therapy with
dexamethasone or prednisolone is recommended for meningeal and pericardial TB.
Dosing Frequency for Treatment of Tuberculosis Disease in Children
Directly Observed Treatment, Short Course (DOTS) strategy has largely targeted
adults leading to less evidence on intermittent dosing in children.58–60 There is no
change in the recommendation of daily dosing for children with TB disease.61 Data
on trials comparing intermittent with daily dosing are insufficient to support intermit-
tent regimens over daily treatment in children with TB.43,62 However, recognizing prac-
tical limitations, WHO guidance to national programs is flexible in stating that thrice
weekly dosing can be considered in continuation phase for new patients with pulmo-
nary TB provided they do not have HIV and they are directly observed.
Treatment of Latent Tuberculosis Infection in Children
Chances of progression of latent disease to active inflates from 10% in healthy adults
to as high as 50% in children younger than 5 years.63,64 Risk of TB is particularly high in
children younger than 3 years of age. Children older 2 years of age can be treated for
LTBI with once-weekly isoniazid-rifapentine (3HP) for 3 months (see Table 2). Higher
weight-adjusted doses may be required for efficacy in treating children with LTBI.65
Four months of rifampicin (4R) or 3 months of daily isoniazid plus rifampicin (3HR) is
now preferred over 6 to 9 months of isoniazid (6H/9H) monotherapy.66,67 Even though
these regimens are equally acceptable, patients may be more likely to complete
shorter treatment regimens. Table 2 shows LTBI regimens recommended for children.
Treatment of Drug-Resistant Tuberculosis in Children
Oxazolidinones (cycloserine and linezolid) are core drugs in drug-resistant TB regi-
mens. There are scarce data available about the use in children for drug-resistant
TB, but data from adults point toward utility.68
Imipenem-cilastatin and meropenem are enlisted in WHO Group C for treatment of
drug-resistant TB.69
New Drugs for Drug-Resistant Tuberculosis
Initially WHO recommended bedaquiline as part of second-line therapy in patients
older than 18 years. Now it can be used conditionally in treatment of patients with
MDR and RR TB aged 3 years or more. Delamanid (nitroimidazole) has been studied
more extensively than pretomanid. WHO recommends delamanid for 6 months of
intensive phase in patients with MDR TB and XDR TB with high baseline risk for
poor outcomes.70 Delamanid has been associated with increased sputum culture
Table 2
Recommended regimens for children with tuberculosis infection and DS disease in international settings modified from WHO guidelines41,42,64
Number of
Tablets by
Weight
Number of Tablets by Weight Band Once Daily Band
Recommended Less Strength of
Regimen/DT Than 2– Adult Tablet
Drug Strength (mg) 2 kg 2.9 kg 3–3.9 kg 4–7.9 kg 8–11.9 kg 12–15.9 kg 16–24.9 kg (mg) 25–39.9 kg 40–54.9 kg >55 kg
TB treatment regimens for children (low HIV prevalence [and HIV-negative children] and low-isoniazid-resistance settings)
Smear-negative 2HRZ/4HR 0.25/0.25 0.5/0.5 0.75/0.75 1/1 2/2 3/3 4/4 2HRZE/4HR 2/2 3/3 4/4
pulmonary TB (50/75/150)/ (75/150/400/
Intrathoracic (50/75) 245)/(75/150)
lymph node TB
Tuberculous
peripheral
lymphadenitis
Extensive 2HRZ 1 E/4HR 0.75 1 1 1 1/1 2 1 2/2 3 1 3/3 4 1 4/4 2HRZE/4HR 2/2 3/3 4/4

pulmonary (50/75/150) 1 0.75/0.75 t (75/150/400/
disease 100/(50/75) 245)/(75/150)
Smear-positive
pulmonary TB
Severe forms of
extrapulmonary
TB (other than
tuberculous
meningitis/
osteoarticular TB)
TB treatment regimens for children (high HIV prevalence, high isoniazid resistance, or both)
Smear-positive TB 2HRZ D E/4HR 0.25/0.25 0.5/0.5 0.75 1 1 1 1/1 2 1 2/2 3 1 3/3 4 1 4/4 2HRZE/4HR 2/2 3/3 4/4
Smear-positive (50/75/150) 1 0.75/0.75 (75/150/400/
PTB extensive 100/(50/75) 245)/(75/150)
parenchymal
disease
All forms of
EPTB except
(continued on next page)
33
34
Shakoor & Mir

Table 2
(continued )
Number of
Tablets by
Weight
Number of Tablets by Weight Band Once Daily Band
Recommended Less Strength of
Regimen/DT Than 2– Adult Tablet
Drug Strength (mg) 2 kg 2.9 kg 3–3.9 kg 4–7.9 kg 8–11.9 kg 12–15.9 kg 16–24.9 kg (mg) 25–39.9 kg 40–54.9 kg >55 kg
meningeal/
osteoarticular TB
All regions
Meningeal/ 2HRZ D E/10HR 0.25/0.25 0.5/0.5 0.75 t1 1 1 1/1 2 1 2/2 3 1 3/3 4 1 4/4 2HRZE/10HR 2/2 3/3 4/4
osteoarticular TB (50/75/150) 1 0.75 (75/150/400/
100/(50/75) t/0.75 t 245)/(75/150)
TB prophylaxis regimens for children (LTBI)
<5 kg 5.1–9.9 kg 10–13.9 kg 14–19.9 kg 20–24.9 kg 25–34.9 kg 40–54.9 kg >55 kg
B6 50 mg - 0.5 EOD 0.5 EOD 1 OD 1 OD 50 1 OD 1 OD 1 OD
6H 100 mg 0.5 1 1.5 2 2.5 100 mg 3
<5 kg 5.1–9.9 kg 10–14 kg 14.1–20 kg 20.1–25 kg 25.1–32 kg 32.1–50 kg >50 kg
3RH 75/50 0.75 1 2 3 4 150/75 2 3 4
3HP Isoniazid (25 mg/kg (25 mg/kg (25 mg/kg Isoniazid (15 mg/kg (15 mg/kg (15 mg/kg
(100 mg) rounded) rounded) 1 rounded) 1 (100 mg) rounded) rounded) rounded)
1rifapentene 1 (300 mg) (450 mg) (450 mg) 1rifapentene 1 (600 mg) 1 (750 mg) 1 (900 mg)
(150 mg) 2 tab per wk 3 tablets per 3 tab per wk (150 mg) 4 tab per 5 tab per 6 tab per wk
for 12 wk wk for 12 wk for 12 wk wk for wk for for 12 wk
12 wk 12 wk
Abbreviations: B6, vitamin B6 (PYRIDOXINE); 3HP, once-weekly isoniazid-rifapentine for 3 months; 6H, 6 months of isoniazid; DS, drug susceptibility to first line
anti-TB therapy; DT, dispersible tablet; EPTB, extrapulmonary tuberculosis; PTB, pulmonary tuberculosis; 3RH, 3 months of rifampicin isoniazid as prophylaxis; EOD,
every other day or 3 days a week; OD, once daily.
Note: Treatment regimens for MDR TB are not shown in this table and can be accessed through WHO treatment guidelines for MDR TB.73,79,80
conversion and lower mortality in patients with drug-resistant TB.71 This drug can now
be used conditionally in treatment of patients with MDR and RR TB aged 3 years or
more. Pretomanid has also shown encouraging bactericidal activity in murine
models.72 In 2016, WHO recommended use of delamanid in children and adolescents
with MDR TB (resistance to fluoroquinolones or second-line injectables or both). In
children, this drug is a useful adjunct during the initial intensive phase (6 months) in
longer (18–24 months) rather than shorter MDR TB regimens.73 A shorter (9–
12 months) regimen has recently been approved for patients with uncomplicated
MDR TB (Bangladeshi regimen) containing 4 to 6 months of intensive phase (kana-
mycin, moxifloxacin, prothionamide, clofazimine, high-dose isoniazid, pyrazinamide,
and ethambutol) and 5 months of continuation phase (moxifloxacin, clofazimine, pyr-
azinamide, and ethambutol).74
Recommendations on Treatment and Care for Isoniazid-Resistant Tuberculosis

WHO treatment guidelines for children with confirmed isoniazid-resistant TB are
extrapolated from adult data. Only 2% of patients with isoniazid-resistant TB in
WHO Individual Patient Data review were children. Recommended treatment includes
rifampicin, ethambutol, pyrazinamide, and levofloxacin for 6 months ((H)REZ-
Lfx).42,75,76 Adding streptomycin and other injectable agents is not recommended.
Customization is required if additional resistance (especially to pyrazinamide) is sus-
pected or confirmed. Surveillance of isoniazid resistance mutations (katG or inhA)
and host acetylator status at country or regional levels can be useful in guiding national
treatment policy.12
Recommendations on Treatment and Care for Multidrug/Rifampicin-Resistant

Tuberculosis
Longer MDR TB regimens with effective agents are associated with higher cure and
lower mortality rates in adults and children.77 Recommendations on composition of
longer regimens (18–20 months with 15–17 months after culture conversion) include
a minimum of 3 group A agents (levofloxacin/moxifloxacin, bedaquiline, linezolid)
and one group B agent (clofazimine, cycloserine/terizidone) to ensure that the regimen
contains at least 4 effective agents. If the regimen cannot be composed with agents
from groups A and B alone, group C agents (ethambutol, delamanid, pyrazinamide,
imipenem-cilastatin, meropenem, amikacin [streptomycin], ethionamide/prothiona-
mide, p-aminosalicylic acid) are added to complete it.
Longer regimens containing aminoglycosides should have an intensive phase of 6 to
7 months (amikacin/kanamycin, levofloxacin, ethambutol, pyrazinamide, ethionamide,
and cycloserine) and 18 months of continuation phase with levofloxacin, ethambutol,
ethionamide and cycloserine.78 Bedaquiline can be used in younger children (6–
17 years) based on available pharmacokinetic data.79 Delamanid can now be used
conditionally in treatment of patients with MDR/RR TB aged 3 years or more on longer
regimens.80
There is interest in shorter-duration regimens for MDR TB. Clinical effectiveness of
shorter regimens (9–12 months) under programmatic and trial conditions has been re-
ported.81–85 However, the diligent monitoring of treatment response required for shorter
regimens (ie, monthly sputum smear and culture during therapy) is resource intensive
and difficult to implement in most HBCs, making this option potentially unsafe.
Need for Supportive Surgery

Since the advent of antituberculous drugs, surgery has receded to a less important
but, nevertheless, viable treatment option.86 Pulmonary resection combined with
36 Shakoor & Mir
antituberculous drugs has shown success and reduced all-cause mortality in 88% to
92% of adult MDR TB cases.87–89 Even with these encouraging outcomes, surgery re-
mains controversial, at least in children. It has potential utility in complications such as
massive hemoptysis, bronchiectasis, bronchopleural fistula, and aspergilloma and,
mostly, in treatment failures.89
Adverse Effects of First-Line Agents

Even though children have a more sensitive therapeutic index,90–92 side effects to
common first-line drugs including isoniazid (neuropathy and hepatotoxicity), rifam-
picin (drug interactions, hepatotoxicity), pyrazinamide (hepatotoxicity, nongouty
arthralgia and gout-induced arthritis), and ethambutol (optic neuritis) have been rarely
reported.
Isoniazid-associated hepatitis is rare in children. Slow acetylators experience more
toxicity than intermediate or fast acetylators.93 There is limited evidence of hepatic
adverse events when rifampicin is administered alone in children; however, it has po-
tential for interactions with other drugs with hepatic metabolism.94 Pyrazinamide-
related hepatotoxicity is dose and duration dependent in adults,95 and it has been
rarely reported in children.96 Nongouty polyarthralgia and gout-induced arthritis
seen in adults has not been reported in children. Ocular toxicity with ethambutol is
dose and duration dependent and is difficult to detect in younger children who cannot
self-report changes in vision.97
Adverse Effects of Second-Line Agents

Second-line regimens have higher adverse event frequency with toxicity occurring in
up to 40%.98 Aminoglycoside association with nephrotoxicity and ototoxicity needs
further study in TB regimens.91,99 Traditional restriction of long-term fluoroquinolone
use in children due to fear of arthropathy has not been substantiated by evidence.
Nevertheless, side effects in children on prolonged fluoroquinolones need to be moni-
tored. Monitoring for QT interval prolongation in children on bedaquiline and delama-
nid is also essential.
VULNERABLE POPULATIONS
Human Immunodeficiency Virus and Tuberculosis
HIV-infected children are at high risk of acquiring and developing TB after exposure.
These children require immediate preventive therapy after exclusion of active disease,
irrespective of age and immune status. Although preventive therapy should be pro-
vided at each TB exposure, continuous isoniazid prophylaxis is not recommended.
For all patients with HIV and drug-susceptible TB, antiretrovirals should be started
regardless of their CD4 cell count; however, TB treatment should be initiated first, fol-
lowed by antiretrovirals as soon as possible within the first 8 weeks of TB treatment.
Those with severe immune suppression should receive antiretrovirals within the first
2 weeks of TB treatment initiation.
Tuberculosis and Migrant/Refugee Children

TB in migrants may vary based on incidence of TB in the countries of origin (17 new
cases per 100,000 population in the Syrian Arab Republic to 338 per 100,000 in
Nigeria). In high-income countries with stringent entry screening, it can be contained
and appropriately addressed.100 In LMICs with less-stringent criteria on entry and
limited resources for detection and treatment of displaced and refugee populations,
there is imminent risk of outbreaks.101
Primary Immune Deficiency and Tuberculosis

Natural immunity to TB relies on functional interleukin-12/23-interferon-gamma axis in
macrophages.102 In contrast to children with severe primary immune deficiency disor-
ders who present with various infections, children with interleukin-12/23-interferon-
gamma pathway errors (Mendelian susceptibility to the mycobacterial disease
phenotype) are particularly susceptible to mycobacterial infections and nontyphoidal Sal-
monella infections. Although these children usually present with BCG-induced disease
and nontuberculous Mycobacterium infections, they are exceedingly vulnerable to the
more virulent TB especially in high-prevalence countries.103–105
Newborns and Tuberculosis

Worldwide the burden of TB in pregnant women is the greatest in Africa and Southeast
Asia. Most of these countries also have poor implementation of Integrated Manage-
ment of Pregnancy and Childbirth and even poorer linkage to existing TB programs.106
Valuable opportunities are therefore lost to screen pregnant women for TB to prevent
vertical transmission in utero and/or droplet transmission after giving birth. Very little is
known about the burden of congenital TB in HBCs. Even China with relatively higher
case finding and notification rates in pregnant women and a better health system re-
ports very high mortality in sporadic cases.107 Most HBCs also have concurrent high
neonatal mortality and poor antenatal and newborn health service utilization rates
thereby discouraging early identification of congenital TB and screening of newborns
and infants whose mothers or household contacts have TB. Low preventive therapy
coverage in infants is an important surrogate for TB program performance in 2 high-
risk populations, namely, pregnant women and infants.
PREVENTING AND CONTROLLING THE EPIDEMIC

Preventive Therapy
Contact investigation is not routinely implemented in most HBCs. Case finding is pas-
sive at best with very little community engagement or empowerment of first-line health
professionals108; this leads indirectly to poor coverage rates of preventive treatment to
children. In 2017, preventive therapy was not accessed by more than 75% of 1.3
million eligible household contacts younger than 5 years of age. There is a need to
address persistent policy-practice gaps in screening children for TB exposure and
early implementation of preventive therapy109 with focus on health system strength-
ening91 and health literacy.
BCG Vaccination
In HBCs, all healthy newborns should be vaccinated with a single dose of BCG vac-
cine.110,111 This vaccination is also safe in healthy preterm infants born at 32 to
36 weeks of gestation.112,113 However, safety data in very preterm infants less than
32 weeks’ gestation is lacking.
Vaccine efficacy and effectiveness against TB has been extensively studied. BCG
vaccination has the potential to prevent primary infection (19% less infection in
BCG-vaccinated children than unvaccinated children). Among those vaccinated as
neonates, protection against pulmonary TB was 59% (risk ratio, 0.41; 95% CI,
0.29–0.58).114 In studies in which BCG was given in childhood and with stringent tu-
berculin skin test screening, protection against pulmonary TB was 74% (risk ratio,
0.26; 95% CI, 0.18–0.37). BCG efficacy and effectiveness in reducing meningeal
and miliary TB is 85% (risk ratio, 0.15; 95% CI, 0.08–0.31). The combined strategy
38 Shakoor & Mir
of vaccination with BCG early in life during neonatal period and stringent tuberculin
skin testing is associated with the highest protection against severe TB disease.
Patient-Centered Care and Prevention

Most progress in care and support of children with TB has been the inclusion of chil-
dren and adolescents in clinical practice guidelines, the development of training and
reference materials on childhood TB, the collection of better age- and sex-
disaggregated data from programs, and the availability of pediatric drug formulations.
Poor integration of national TB program with other services accessed by women
and children such as reproductive health, HIV, nutrition and immunization results in
missed opportunities for identification of TB exposure, infection, and disease in
women and children.115 Achieving continuum of care requires a high level of multisec-
toral collaboration and political commitment, which is lacking in most HBCs. Interven-
tions such as transportation vouchers, convenient clinic hours and location, reminder
systems for missed appointments, social support schemes (housing, food stamps, sti-
pends), and outreach workers to implement adherence have all shown positive
impact116 on detection and notification rates.117,118
New Developments
Research and innovation is essential for meeting the Sustainable Development Goals and
End TB Strategy targets set for 2030.1 Priorities include progress in exposure and infec-
tion prevention (new vaccines, better tests for LTBI, clinical trials evaluating short-course
preventive therapy for children exposed to drug-susceptible and drug-resistant TB),
diagnosis (collection of pediatric specimens and monitoring of drug resistance in children
in HBCs), and treatment (pharmacokinetic and pharmacodynamic studies of antitubercu-
lous drugs in children; optimal regimens for children, pregnant women, and HIV-infected
children; and complications of disease and therapy in children).119
The diagnostic pipeline seems robust so far in terms of the number of tests, prod-
ucts, or methods in development. Examples include several cartridge-based technol-
ogies for the detection of drug resistance, next-generation sequencing assays for
detecting drug-resistant TB directly from sputum specimens, and newer skin tests
and interferon-gamma release assays.
The crusade to control TB by permeating and implementing known and tested
knowledge and interventions at all levels (community, patients, health care providers,
laboratory personnel, policy makers, governance) is an ongoing step toward universal
health especially in HBCs and in keeping with the Global Strategy for TB Research and
Innovation adopted by WHO member states through a World Health Assembly Reso-
lution in August 2020.
CLINICS CARE POINTS
When biopsying tissue for histopathological diagnosis of suspected exptrapulmonary TB

(EPTB) in LMICs, it should be ensured that tissue (lymph node, bone marrow, skin lesions
refractory to standard treatment, lumps/masses) is sent for Xpert and/or AFB culture to avoid
missing nontuberculous mycobacterial infections, fungal infection, and lymphoma (TB
mimics).
TB should be part of most chronic presentations by default because it can have atypical
presentations in endemic HBCs such as isolated psoas abscess (without vertebral
involvement), dactylitis, and ossicular osteomyelitis (chronically draining ear).
Establishing radiological resolution at end of therapy may be helpful even in children with
good clinical response if they have disseminated disease because it may unmask treatment
failure and lead to considering risk factors such as fast acetylator status or immune
deficiency.
Signs of clinical improvement should be observed (appetite, weight gain, defervescence,
work of breathing [pulmonary TB]) and improvement in presenting signs and symptoms
(EPTB) as intensive phase progresses because lack of improvement by end of intensive phase
should lead to suspicion of alternate diagnosis (including MDR TB).
Patients should only get their anti-tuberculous therapy (ATT) from certified sources like
National TB Programs (over-the-counter counterfeit medicine is a potential risk in
countries with poor health systems monitoring and evaluation).
Preparing parents for drug-related effects like reddish urine, nausea after early morning
medication, and repetition of dosage if vomiting within half hour of intake will keep
them committed to adherence.
DISCLOSURE
The authors have nothing to disclose.
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Pediatr Clin N Am 69 (2022) 19–45

EPIDEMIOLOGY OF PEDIATRIC TUBERCULOSIS IN INTERNATIONAL SETTINGS

TB continues to afflict several populations across the globe in different socioeconomic

Global Situation and Gaps

Regional Incidence of Childhood Tuberculosis: Where are the Gaps?

Drug-Resistant Tuberculosis in Children

Pulmonary Tuberculosis Versus Extrapulmonary Tuberculosis and Disseminated

have pulmonary disease, surveillance data may misclassify them as pulmonary TB

Congenital and Neonatal tuberculosis

Prevalent and Emerging Risk Factors

Major Issues and Barriers in Delineating Tuberculosis Epidemiology Among

UPDATES IN PEDIATRIC TUBERCULOSIS CASE DETECTION AND DIAGNOSIS

Diagnosis of pediatric TB may be made based on bacteriologic testing, clinical criteria,

Health system barriers

Bacteriologic Confirmation with Conventional and Advanced Tools

Xper Ultra assay is an automated, integrated, cartridge-based molecular assay to

(transcriptomic) biosignatures32 hold promise as a point-of-care biomarker of active

Diagnostic Markers of Latent Tuberculosis Infection in Children

Clinical Scoring and Nonscoring Diagnostic Systems

Programmatic Challenges and Implementation Gaps

UPDATES IN TREATMENT IN HIGH-BURDEN COUNTRIES

Drug-Susceptible Pulmonary Tuberculosis

Diagnostic Element Settings Where Applicablea Clinical Utility Limitations

Pediatric Tuberculosis in International Settings

(continued on next page)

Shakoor & Mir

Pediatric Tuberculosis in International Settings

pyrazinamide, and moxifloxacin.54,55 The noninferiority trial enrolled participants aged

Pediatric Tuberculosis in International Settings

(continued on next page)

Shakoor & Mir

Recommendations on Treatment and Care for Isoniazid-Resistant Tuberculosis

Recommendations on Treatment and Care for Multidrug/Rifampicin-Resistant

Need for Supportive Surgery

Adverse Effects of First-Line Agents

Adverse Effects of Second-Line Agents

Tuberculosis and Migrant/Refugee Children

Primary Immune Deficiency and Tuberculosis

Newborns and Tuberculosis

PREVENTING AND CONTROLLING THE EPIDEMIC

Patient-Centered Care and Prevention

CLINICS CARE POINTS

 When biopsying tissue for histopathological diagnosis of suspected exptrapulmonary TB

The authors have nothing to disclose.

1. Organization WH. Global tuberculosis report 2020. Geneva (Switzerland): WHO;

50. Moultrie H, McIlleron H, Sawry S, et al. Pharmacokinetics and safety of rifabutin

meropenem and amoxicillin/clavulanate. J Antimicrob Chemother 2013;68(2):

87. Marrone M, Venkataramanan V, Goodman M, et al. Surgical interventions for

108. Organization WH. Roadmap towards ending TB in children and adolescents.

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