CLINICAL REPORT Guidance for the Clinician in Rendering Pediatric Care
Tuberculosis Infection in Children and
Adolescents: Testing and Treatment
Dawn Nolt, MD, MPH, FAAP,a Jeffrey R. Starke, MD, FAAP,b COMMITTEE ON INFECTIOUS DISEASES
Tuberculosis (TB) remains an important problem among children in
the United States and throughout the world. There is no diagnostic
reference standard for latent tuberculosis infection (also referred to
as tuberculosis infection [TBI]). The tuberculin skin test (TST) has
many limitations, including difficulty in administration and
interpretation, the need for a return visit by the patient, and false-
positive results caused by cross-reaction with Mycobacterium
bovis–bacille Calmette-Guerin vaccines and many nontuberculous
mycobacteria. Interferon-gamma release assays (IGRAs) are blood
tests that use antigens specific for M tuberculosis; as a result, IGRAs
yield fewer false-positive results than the TST. Both IGRAs and the
TST have reduced sensitivity in immunocompromised children,
including children with severe TB disease. Both methods have high
positive predictive value when applied to children with risk factors
for TBI, especially recent contact with a person who has TB disease.
The advantages of using IGRAs and diminished experience with the
placement and interpretation of the TST favor expanded use of
IGRAs in children in the United States. There are now several
effective and safe regimens for the treatment of TBI in children. For
improved adherence to therapy, the 3 rifamycin-based regimens are
preferred because of their short duration. Daily isoniazid can be used
if there is intolerance or drug interactions with rifamycins. A TB
specialist should be involved when there are questions regarding
testing interpretation, selection of an appropriate treatment
regimen, or management of adverse effects.
INTRODUCTION
Tuberculosis (TB) remains an important disease in the United States and
throughout the world. Approximately 9000 new cases occur each year in
the United States.1 Of the 5175 children and adolescents younger than 18
years with TB disease reported in the United States from 2010 to 2017,
32% were born in other countries.2 Infants and young children (younger
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abstract
a
Department of Pediatrics, Division of Infectious Diseases, Oregon
Health and Science University, Portland, Oregon; and bDepartment of
Pediatrics, Division of Infectious Diseases, Baylor College of Medicine,
Houston, Texas
The authors have indicated they have contributed equally to the
writing of this article and approved the final manuscript as
submitted.
This document is copyrighted and is property of the American
Academy of Pediatrics and its Board of Directors. All authors have
filed conflict of interest statements with the American Academy of
Pediatrics. Any conflicts have been resolved through a process
approved by the Board of Directors. The American Academy of
Pediatrics has neither solicited nor accepted any commercial
involvement in the development of the content of this publication.
Clinical reports from the American Academy of Pediatrics benefit
from expertise and resources of liaisons and internal (AAP) and
external reviewers. However, clinical reports from the American
Academy of Pediatrics may not reflect the views of the liaisons or
the organizations or government agencies that they represent.
The guidance in this report does not indicate an exclusive course
of treatment or serve as a standard of medical care. Variations,
taking into account individual circumstances, may be appropriate.
All clinical reports from the American Academy of Pediatrics
automatically expire 5 years after publication unless reaffirmed,
revised, or retired at or before that time.
DOI: https://doi.org/10.1542/peds.2021-054663
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2021 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they do not
have a financial relationship relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they
have no potential conflicts of interest to disclose.
To cite: Nolt D, Starke JR; AAP Committee on Infectious
Diseases. Tuberculosis Infection in Children and Adolescents:
Testing and Treatment. Pediatrics. 2021;148(6):e2021054663
FROM THE AMERICAN ACADEMY OF PEDIATRICS
 than 4 years) have the highest rate for
tuberculosis infection (TBI)
progressing to TB disease rapidly after
exposure, within a few weeks to
several months. Children who move to
the United States from countries with
high TB burden (eg, Asia, Middle East,
Africa, Latin America, countries of the
former Soviet Union) often received
no testing for TBI, expanding the pool
of infected children in the United
States. Some of these children
developed TB disease or are evaluated
and treated for TBI after emigrating,
but many have untreated TBI and are
at risk for developing TB disease later
in life. In addition, many US-born
children who have been infected with
Mycobacterium tuberculosis within the
United States or abroad have gone
undetected.
In most children and adolescents,
initial infection with M tuberculosis
is eliminated or contained by host
defenses, and the person remains
asymptomatic. However, residual
bacilli may remain viable and
become active again to cause TB
disease. Treatment of TBI
substantially reduces the risk of
developing TB disease in children
who adhere to therapy by 90% in
both the immediate and distant
future.3 Therefore, the goal of
testing for TBI is to identify
individuals who are at risk for
developing TB disease and will
benefit from treatment.4–6
In the pediatric population, infants
and children (younger than 4 years)
and adolescents are at higher risk of
progressing from TBI to TB disease
than are primary school-aged
children. The risk of progression in
infants younger than 12 months
with untreated TBI is 40% to 50%,
decreases to 25% in children 1 to 2
years of age, drops to 5% to 10% in
school-aged children, and is 10% to
15% in adolescents (Table 1).
Epidemiological factors also define
risk of infection: children who were
born and lived in or have traveled
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to an area of the world with a high
prevalence of TB and those who
have had a household or family
member with TB disease or TBI are
at higher risk for TBI than the
general population. As a result,
selective testing for TBI of children
on the basis of their risk factors has
been adopted as the main strategy
in the United States.7,8
Although the diagnosis of TB disease
is confirmed by the detection of M
tuberculosis in a clinical sample,
there is no diagnostic gold standard
for diagnosis of TBI.3,9,10 Two
available but imperfect methods for
identification of TBI are the
tuberculin skin test (TST) and the
interferon-c release assay (IGRA).
Both methods depend on cell-
mediated immunity and provide
immunologic evidence of host
sensitization to antigens of M
tuberculosis. Neither method can
distinguish between TBI and TB
disease, and both methods display
suboptimal performance in
immunocompromised patients, who
are at greatest risk for progression
of TBI to TB disease.
GENERAL TESTING CONSIDERATIONS
Both the TST and IGRA depend on
the host immune response to
specific antigens found in M
tuberculosis. Determining the
sensitivity and specificity of both
test types for children is difficult.
They were studied and compared
initially in children with culture-
TABLE 1 Age-Associated Risk of Progression
From TBI to TB Disease
Risk of Progression
from TBI to Disease
Age if Untreated, %
<12 mo
1–2 y
School-aged
Adolescents
Adults
Risk of progression is also increased in immunocom-
promised individual and those recently infected with M
tuberculosis.
confirmed TB disease because
microbiologic confirmation is the only
real proof of TB disease. However,
children with culture-proven TB
disease tend to have more severe
manifestations and clinical illness.
Increased severity of disease may
result in immunosuppression and
diminish the sensitivity of tests that
rely on the immune response, such as
both the IGRA and TST. As a result,
the sensitivity of both test types can
be low for TB disease.11,12 Children
with less severe TB disease often do
not have microbiologic confirmation,
lacking the absolute proof of infection
that is needed to accurately assess test
sensitivity and specificity, and many
studies have used less reliable
methods of clinical diagnosis of TB
disease instead. The major difficulty
for interpreting studies of the relative
performance of the TST and IGRA is
that there is no gold standard test, so
it is difficult to determine for
discordant test results whether the
negative test result is more specific or
the positive test result is more
sensitive.
The TST
The TST is the intradermal injection
of 5 TU of purified protein
derivative (PPD) or 2 tuberculin
units (TU) of PPD-RT23, the latter
used predominantly in Europe. PPD
tuberculin solution contains dozens
of TB antigens, with the exact
composition varying among batches
and preparations. Many of these
antigens also are present in
environmental nontuberculous
mycobacteria (NTM) prevalent
throughout the United States and in
the bacille Calmette-Gu
erin (BCG)
vaccines. A patient who mounts a
40–50
25 cell-mediated response to tuberculin
5–10 antigens has a delayed-type
10–15 hypersensitivity response usually
5–10
within 48 to 72 hours, causing
measurable induration at the
injection site.
 TST results can be difficult to
interpret. The test depends on
accurate intradermal injection,
which should be performed by an
experienced individual.
Interpretation requires that the
patient returns in 48 to 72 hours.
Correct interpretation of the
reaction involves careful
measurement of induration that
should be determined by a provider
with experience in this
measurement. The measurement
should be recorded to the nearest
millimeter of the transverse
diameter of the induration (Fig 1).
Reaction size can vary (on average)
within the same individual by 15%,
which has been described when the
test is placed simultaneously on
both arms.13 The variability in
measuring induration among
experienced observers also varies by
about 15% and is much greater
among inexperienced personnel and
untrained people, especially family
members.13 Therefore, family
members should not be allowed to
interpret a TST result. False-
FIGURE 1 Measurement of TST reaction. The
technician is marking the widest
edges of the patient’s induration (a
hard, dense, raised formation) with a
pen for accurate measurement of the
TST reaction. To locate the skin test
site, the arm should be inspected in
good light and on a firm surface. A
light, gentle motion is used to sweep
the fingertips over the surface of the
forearm to locate the margins or
edges of induration. As in this image,
the widest edges of the induration are
marked with a pen, using the finger-
tips as a guide. A millimeter ruler is
then used to measure the diameter of
the induration between the 2 marks.
Image courtesy of CDC/Gabrielle
Benenson.
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negative TST results can be caused
by improper handling of the
tuberculin solution, improper
placement of the test, and incorrect
interpretation of the results.13
Induration at the site of the TST is
caused by migration of mostly
mononuclear cells to the area and
the inflammatory process secondary
to these cells’ response. This
response can be attributable to
infection with M tuberculosis,
exposure to NTM, or receipt of BCG
vaccine. The patient’s history and
the size of the induration help to
determine which of these 3 potential
causes may be likely associated with
TST reaction. People with exposure
to environmental NTM often have
indurations <10 mm, but larger
reactions are not uncommon. Among
populations with a low prevalence
of TB but a high prevalence of
exposure to environmental NTM,
such as in the United States, the
distribution of reactions between
individuals with TBI and those with
NTM exposure overlap to a
considerable degree.7 The most
effective way to minimize false-
positive results is to avoid testing
individuals who lack a risk factor for
TBI (Table 2).
To improve TST performance, the
practice has been to vary the cutoff
for the size of the TST reaction
considered positive to optimize the
sensitivity and specificity of the
result. The cutoff is set at $15 mm
to optimize specificity for people
lacking TBI risk factors but who are
tested for administrative reasons,
$10 mm for people with a risk
factor for TBI, and $5 mm to
optimize sensitivity for people at
high risk of having or developing TB
disease if they have TBI (clinical
evidence of TB disease, recent TB
exposure, or significant immune
compromise).14
BCG vaccines are administered in
countries with high TB burden
because they reduce the risk of
disseminated (miliary) and central
nervous system TB in children.15
Interpretation of TST results in BCG
recipients who are known contacts
of a person with TB disease or at
high risk for TB disease is the same
as for people who have not received
BCG vaccine. For a foreign-born
child, history of BCG vaccination
should be determined by
examination of the vaccination
record and the finding of a typical
BCG scar, usually located on the
deltoid region of either arm. Many
of the antigens in PPD also are
found in M bovis-BCG, the organism
in the BCG vaccines. Some
individuals who are not infected
with M tuberculosis may express
induration in response to the TST
that reflects previous receipt of a
BCG vaccination. The size of the TST
reaction varies with the strain and
dose of vaccine,16 the route of
administration,17 age at
vaccination,18 the time interval since
vaccination,19 and the number of
BCG doses. Approximately half of
infants who received a BCG
vaccination will respond with
significant induration to a TST.
Although most, perhaps as many as
90%, of children 5 years or older
who received a BCG vaccine as an
infant will not have a positive
response to a TST (unless also
infected with M tuberculosis, which
may not be prevented by BCG
vaccination), some will retain this
response, causing a false-positive
result. The induration often
measures <10 mm but can be >15
mm.7,20 Children born in countries
with a high TB burden (Table 2) are
candidates for selective testing for
TBI, but a large number of false-
positive results occur when the TST
is used on children who have
received a BCG vaccine. Children
who have received a BCG
vaccination also may be subject to
“boosting” from the TST, the
immunologic recall of
3
 TABLE 2 Risk Factors for Increased Risk of Acquiring TBI and/or Progressing to TB Disease
Contacts of people with confirmed or suspected contagious TB (contact investigation)
Children with radiographic or clinical findings suggesting TB disease
Children immigrating from countries with endemic infection (eg Asia, Middle East, Africa, Latin America, countries of the former Soviet Union), including
international adoptees
Children with history of significant travela to countries with endemic infection who have substantial contact with the resident population
Children with HIV infection
Children with other medical conditions, including diabetes mellitus, chronic renal failure, malnutrition, or congenital or acquired immunodeficiencies and
children receiving TNF-a antagonists, which may enhance the possibility for progression to severe disease
a
Determination of significant travel should account for the frequency of travel and the duration of time. Testing should be conducted 8–10 wk after completion of travel, to allow
for the known incubation period of M tuberculosis.

hypersensitivity to antigens in the
PPD that are also present in M
bovis-BCG, which creates a false-
positive TST result.21,22
False-negative TST results can occur
because of limited ability of certain
children with TBI or TB disease to
mount an appropriate delayed-type
sensitivity response, especially those
who are immunosuppressed either
by disease (such as advanced HIV
infection, advanced TB, cancer, or
malnutrition) or who receive
immunosuppressive treatments
(such as corticosteroids, cancer
chemotherapy, and
immunomodulating biological
agents, especially the tumor necrosis
factor-a [TNF-a] inhibitors or live-
virus vaccines). Unfortunately,
children for whom the TST has
diminished sensitivity are those
individuals most likely to progress
to TB disease if infected.3
In summary, there are limitations to
both the sensitivity and the
specificity of the TST. The positive
predictive value of the TST is much
greater when it is applied to
individuals who have a recognized
risk factor for TBI. When the TST is
used for individuals lacking risk
factors, the vast majority of the
positive results may be falsely
positive, and this problem is
accentuated in children who
received a BCG vaccine.7 One large
study using latent class analysis (a
method of analysis that creates a
statistical gold standard when no
such test is available) demonstrated
that the positive predictive value of
the TST for TBI among foreign-born
children younger than 5 years, most
of whom had received a BCG
vaccine, was 10%, meaning that
90% of the positive results were
presumably falsely positive.23 In
addition, the test has poor
sensitivity in immunocompromised
children, who have the greatest risk
of progression to TB disease.
Because of these limitations, some
experts have called for the
“retirement” of the TST in favor of
the IGRA.24
The IGRA
IGRAs are ex vivo blood tests that
detect interferon-c (IFN-c) release
from a patient’s CD41 and CD81 T
lymphocytes after stimulation by
antigens found on M tuberculosis
complex (which includes M
tuberculosis, M bovis, M africanum, M
microti, and M canetti). Two IGRAs
are available commercially: the
QuantiFERON-TB Gold Plus assay
(QFT; Qiagen, Hilden, Germany),
which has largely replaced the
previously used and studied
QuantiFERON-TB Gold In-Tube
assay, and the T-SPOT.TB assay
(T-SPOT; Oxford Immunotec,
Abingdon, United Kingdom).
However, the studies of QFT
published before 2017 used the
QuantiFERON-TB Gold In-Tube assay.
Both the QFT and T-SPOT use early
secreted antigenic target 6 (ESAT-6)
and culture filter protein 10 (CFP-
10) encoded by genes located within
the region of difference 1 (RD1)
locus of the M tuberculosis genome.
The RD1 antigens used in the 2
IGRAs are not encoded in the
genomes of M bovis-BCG strains,
although they are present on wild-
type M bovis, or most species of
NTM, specifically not on the M avium
complex organisms that are the most
ubiquitous pathogenic environmental
NTMs. The RD1 antigens may be
found on other NTM strains that are
rare causes of human disease (M
marinum, M kansasii, M szulgai, and
M flavescens). As a result, because
the antigens in IGRAs are not found
on most clinically relevant NTM and
M bovis-BCG strains, one would
expect that IGRAs will be more
specific than the TST, yielding fewer
false-positive results. Like the TST,
IGRAs do not distinguish between
TBI and TB disease.25
Test Characteristics
Both IGRAs are performed with
positive and negative controls. The
QFT assay is an enzyme-linked
immunosorbent assay (ELISA) whole
blood test. The QFT has 2 TB
antigen tubes: tuberculosis antigen
tube 1 (TB1) and tuberculosis
antigen tube 2 (TB2). TB1 contains
peptides from ESAT-6 and CFP-10,
which are designed to elicit an
immune response from CD41 T-
helper lymphocytes. TB2 contains an
additional set of peptides targeted
for a cell-mediated immune
response from CD81 cytotoxic T
lymphocytes, included to bolster
overall test sensitivity. The test
result is considered positive when
the IFN-c response to the TB
antigens (contained in TB1 and

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 TB2) is above the test cutoff of 0.35
IU/mL (after subtracting the
negative control value from the test
antigen value). If the test result is
negative but the positive control
also shows a poor response (a
positive control failure from
immunosuppression), or the
background response in the negative
control is too high (a negative
control failure, perhaps from high
baseline IFN-c production
attributable to systemic
inflammation26), the result is
considered indeterminate (neither
negative nor positive). In this
situation, testing on a different
specimen is recommended.27
The T-SPOT assay is an enzyme-
linked immunosorbent spot
(ELISPOT) assay performed on
peripheral blood mononuclear cells
that have been incubated with
peptides from ESAT-6 and CFP-10.
The result is reported as the
number of IFN-c producing T-cells
(spot-forming cells). The test result
is considered positive when the
number of spots in the test sample,
after subtracting the number of
spots in the negative control,
exceeds a specific threshold of
$8 spots; the test result is negative
if there are 4 or fewer spots. Results
with a corrected spot count of 5, 6,
or 7 are considered borderline
(equivocal), and retesting on a
different specimen is recommended
by the manufacturer. If the positive
control shows a poor response (<20
spots), or if the background
response in the negative control is
too high ($10 spots), the result is
termed invalid or indeterminate
(neither negative nor positive).9 In
this situation, testing on a different
specimen is recommended.27
Although there are standard
manufacturer instructions for
performing IGRAs, concerns have
been raised about the
reproducibility of the results on
serial performance. Serial testing of
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health care workers at low risk of
TBI have revealed cases of
unexplained cases of low-level
positive IGRA results reverting to
negative on repeat testing.28
Nkurunungi et al29 performed
T-SPOT tests on 405 Ugandan
children at age 5 years and then
repeated the test 3 weeks later. Of
79 children who had an initial
positive T-SPOT result, only 30
(38%) had a positive result 3 weeks
later, whereas 96% of the children
with an initial negative result had a
negative result on repeat testing. The
test agreement was better among
children who were household
contacts of a person with TB (j 5
0.77) than among noncontacts (j 5
0.29). The majority of the reversions
and conversions occur among low-
level results, usually between 0.35
and 1.0 IU/mL for QFT, although
they can occur at higher levels.30,31
The exact cause(s) of low-level false-
positive results are unknown, but
there appear to be seasonal
variations that might explain
increased nonspecific reactivity in
the assay.32
A further explanation of low-level
positive IGRA results is the concept
of test-retest variability.33 For
example, a test with 80% sensitivity
and 70% specificity and a 5% test-
retest variability would be
associated with a conversion rate of
3.7% in the absence of TBI and a
reversion rate of 7.7%. However, a
test with 80% sensitivity and 95%
specificity but 10% test-retest
variability would be associated with
a conversion rate of 5.5% and a
reversion rate of 57%. T-lymphocyte
assays are susceptible to test-retest
variability by numerous factors,
including manufacturing issues;
sample collection issues, such as
inconsistencies in specimen
collection, inadequate blood volume,
delays in isolation and incubation of
cells, and inadequate shaking
(mixing) of the IGRA collection
tubes; and laboratory issues caused
by systematic or random error.34
Efforts to reduce test variability
through better specimen collection
and handling and laboratory
standardization will minimize low-
level false-positive results.3,33
Published studies have shown a
variety of differences in outcomes
between the 2 basic IGRA
techniques, ELISA (QFT) and
ELISPOT (T-SPOT). However, these
differences have been small and
inconsistent among studies, and the
preponderance of evidence supports
the conclusion that, in terms of
accuracy, neither IGRA is strongly
preferred over the other.
General Aspects of Studies in
Children
The major difficulty for interpreting
studies of TBI is determining, for
discordant test results between the
TST and IGRAs, whether the
negative test result is attributable to
enhanced test specificity or whether
the positive test result is
attributable to enhanced test
sensitivity. Four systematic reviews
and meta-analyses of the available
studies of the use of IGRAs in
children were published in 2011
and 201235–38; analysis of the
studies was hampered by the
heterogeneous methodologies used,
including varying definitions of a
clinical case of TB disease. Some of
the early published studies used
ELISA and ELISPOT techniques that
were different from those that
currently are commercially
available. More recent rigorous
studies using commercially available
assays have clarified some issues.
Studies have been performed in
countries with both low and high TB
burden, which often differ greatly in
the severity of TB disease, rates of
malnutrition in children, availability
of TB diagnostic tools, structures of
households where transmission
often occurs, and the use of various
5
 BCG strains and vaccination
techniques.
Test Specificity in Children
Although there are variable results
among individual published studies,
the strongest and most consistent
result is that IGRAs have a higher
specificity for TBI, especially in
settings of low TB burden and for
BCG-vaccinated children.39–43 This
conclusion is based on comparison
of test results across exposure
gradients of contact investigations in
schools and the community in
otherwise low-burden settings.44,45
In their meta-analysis, Sun et al37
included 7 studies that assessed
IGRA specificity in populations with
rates of BCG vaccination ranging
from 0% to 100%. The specificity of
ELISPOT was 89% for BCG-
vaccinated and 95% for BCG-
unvaccinated children, compared
with a TST specificity of 49% for
BCG-vaccinated and 93% for BCG-
unvaccinated children: agreement
(measured by j scores) between the
TST and IGRA in BCG-unvaccinated
children was higher than in
vaccinated children, probably
because of false-positive TST results
caused by previous BCG vaccination.
Lighter et al44 found that among
207 children in New York, only 23%
of the children with a positive TST
result had a positive QFT, and,
unlike the TST results, positive QFT
results correlated with increased
risk of TB exposure. Chun et al46
also found among 227 BCG-
vaccinated children in South Korea
that QFT results were more closely
associated with exposure to a TB
case than were TST results.
The most convincing evidence of
increased specificity of IGRAs would
be to determine rates of progression
to TB disease among untreated
children who have positive TST
results and negative IGRA results.
Ling et al47 evaluated how clinicians
in Montreal used IGRA results to
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determine management of children.
Among 55 children with positive
TST results and negative QFT results
who were part of TB contact
investigations, the negative QFT
result changed management in only
3 children; 52 children received
isoniazid. However, of 201 children
with positive TST results and
negative QFT results who were
tested in school and immigration
screenings, 145 did not receive
treatment, and none developed TB
disease in 1 year of follow-up.
Researchers in a prospective
multicenter trial in the United
Kingdom studied 431 children who
were recently exposed in their
household to an infectious case of
TB; 18 children with a positive TST
but negative IGRA result went
untreated, and none developed TB
disease.48 A large multicenter trial
in the United States performed a
TST and IGRA on 3593 children at
risk for TBI and/or progression to
TB disease (mostly because of birth
in a country with high burden of
disease). Of 533 children with
positive TST and negative IGRA
results who were not treated for
TBI, including 54 children younger
than 2 years, none progressed to
disease over a 2-year period.10
Lowenthal et al49 reviewed the
results from California of testing for
TBI among children moving to the
United States from 2002 to 2013.
Among 4035 children who had a
positive TST result before entry,
only 23% had a positive IGRA result
after entry, and as expected, the
proportion with a positive IGRA
increased with age, reflecting higher
risk of true infection over time.
Finally, among 762 healthy children
with a preimmigration positive TST
result arriving to Sweden, only 33%
with a BCG scar had a positive QFT
result, compared with 76% without
a BCG scar.50
However, low-level (<1.00 IU/mL
for QFT, <8 spots for T-SPOT) false-
positive IGRA results do occur, not
because of cross-reaction with BCG
vaccination or NTM but caused by
nonspecific reactivity or technical
factors in testing. Low-level IGRA
test conversions (negative to
positive) and reversions (positive to
negative) occur frequently among
low-risk health care workers in
serial testing programs and do not
represent TBI. Although there are
no specific data for children, it is
recommended that if a patient has
an unexpected low-level positive
IGRA result, either the same test
should be repeated or a different
test should be performed, and action
should be taken on the second
result. The best way to minimize
false-positive results with any test of
TBI is to test only children with
legitimate risk factors for TBI.
The sum of all published studies
supports the concept that IGRAs are
more specific than TST in children
of all ages.51 Despite the greater
apparent specificity of IGRAs, the
decision to treat or not in a patient
with a positive TST result and a
negative IGRA result should be
based on clinical judgment that
takes into consideration the risk of
progression to disease and the
degree of exposure. For example,
children who were recently exposed
to a case of contagious TB disease
should be considered to have TBI if
either the TST or IGRA result is
positive, because they have a high
risk of progressing rapidly to TB
disease.
Test Sensitivity in Children
The analysis of studies in children of
the sensitivity of IGRAs compared
with TST is far more difficult, and
the results have been highly
variable. The earliest information
came from the meta-analyses of
studies of children with TB disease,
diagnosed by either culture or
clinical diagnosis.35–38 Sun et al37
found a sensitivity for all TB disease
 in children of 70% for ELISA
(mostly QFT [range, 57% to 96%]),
62% for ELISPOT (mostly T-SPOT
[range, 40% to 100%]), and 71% for
TST (range, 43% to 100%). When
the analysis was divided into cases
of culture-confirmed TB and
clinically diagnosed TB, the
sensitivities were 85% and 64% for
ELISA (mostly QFT), 76% and 58%
for ELISPOT (mostly T-SPOT), and
85% and 66% for the TST,
respectively. All 3 tests had lower
sensitivity in clinically diagnosed
cases; there are many possible
explanations, including misdiagnosis
of TB in the clinically diagnosed
group.52 Another study conducted in
a setting with high TB burden also
found low sensitivity of IGRAs and
the TST for TB disease, which did
not add value to the clinical data
and conventional tests for diagnosis
of TB disease in these children.53 A
systematic review and meta-analysis
(15 studies included) of the
performance of TST and IGRAs in
immunocompetent children with
microbiologically confirmed TB
disease calculated the sensitivities of
the TST, QFT, and T-SPOT to be
88.2%, 89.6%, and 88.5%,
respectively.54 Kay et al55 analyzed
California TB registry data for 778
patients 18 years or younger with
laboratory-confirmed TB. Among
children ages 5 to 18 years, the
sensitivity of the IGRA was 96% vs
83% for the TST; IGRA sensitivity
compared with TST in children ages
2 to 4 years was 91% vs 91% (so
equivalent), and the sensitivity
compared with TST in children
younger than 2 years was 80% vs
87%. A smaller study in Italy of
children with TB disease
demonstrated the sensitivity of QFT
to be 93.3% vs 86.5% for the TST.56
The sum of all published studies
suggests that the sensitivity of
IGRAs in settings of low TB burden
is comparable to the TST, with both
being less sensitive in settings of
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high TB burden and for
extrapulmonary TB disease.11,39
There is some evidence that the
sensitivity is increased when both a
TST and IGRA are performed and
the child is considered infected if
either test result is positive. Hill
et al57 investigated child household
contacts of adult TB cases in the
Gambia. Overall agreement between
the TST and ELISPOT was 83%, with
each test result being positive in
32% of the children, and neither
test was affected by BCG
vaccination. An additional Gambian
study demonstrated a 10%
sensitivity benefit for using both a
TST and IGRA in children at high
risk.58
Indeterminate/Invalid Results in
Children
Indeterminate (preferably called
invalid in relation to the T-SPOT
test) results occur most commonly
when the test sample is negative but
the positive control has insufficient
activity but also occur when the
background activity in the negative
control is too high. Indeterminate/
invalid results often occur because
of technical factors, most frequently
inadequate shaking of the IGRA
tubes after the patient’s sample has
been added.3 Rates of
indeterminate/invalid results among
children varied in early studies
between 0% and 35%,36,59–61 but
the reported rates have been lower
(0% to 8%) with the more recent
versions of the commercially
available tests.32,34,62–64 Rego et al65
reviewed 645 947 T-SPOT assays,
finding 0.6% invalid and 1.8%
borderline results. When 5044
borderline tests were repeated,
59.2% were negative, 20.0% were
positive, and 20.2% remained
borderline; the subject’s age did not
affect the results. Indeterminate/
invalid rates generally are higher
among individuals with
compromised immune systems
whose T lymphocytes cannot mount
an adequate response to the positive
control, especially people living with
HIV infection62,66; these rates also
have been noted to be higher in
children with poorly controlled
inflammatory bowel disease,
hepatitis, malaria, and helminthic
infection.67,68 Some researchers
have found that otherwise healthy
children younger than 3 years are
more likely to have indeterminate/
invalid test results than older
children and adolescents.69–72
However, authors of a recent
systematic review and meta-analysis
of 133 studies using IGRAs to
diagnose TB found a 4% rate of
invalid results and no difference
between children 0 to 7 years of age
and those 8 years or older.73
Test Performance in Immune-
Compromised Children
Data are scarce for determining the
sensitivity and specificity of IGRAs
for immune-compromised children,
who are at increased risk of
developing TB disease if they are
infected with M tuberculosis. There
are scant data for children living
with HIV infection, because IGRAs
are generally not available in areas
with high TB burden where there is
also a high burden of HIV infection.
Systematic reviews of the
performance of IGRAs in people
living with HIV infection, mostly
adults, have concluded that the T-
SPOT test may be slightly more
sensitive than the QFT (72% vs
61%), but neither was more
sensitive than the TST.66,74,75
Several small studies have included
children living with HIV infection
with varied results; in general, the
IGRAs have less concordance with
the TST in children with advanced
HIV infection, especially if they have
concomitant malnutrition.76–78 The
risk of TB disease among people
with HIV infection remains higher
than that of the general population,
and the cadence of TB testing in
7
 HIV-infected patients is discussed
elsewhere.79
Researchers in 2 small studies have
examined the performance of IGRAs
and the TST in children with cancer.
Stefan et al found that among 37
children with untreated cancer in
Cape Town, South Africa, a region
with extremely high rates of TB, 7
had positive results with at least 1
test; there was a higher rate of
positive results with the T-SPOT,
poor concordance among the TST
and IGRAs, and a high rate of test
failure because of low lymphocyte
counts in patients.80 During a
contact investigation of 18 children
in a pediatric hematology-oncology
hospital unit after a patient was
found to have pulmonary TB, only 2
patients had a positive T-SPOT
result, and this test had more
invalid/indeterminate results than
the QFT.81
Screening for TB risk factors should
be performed before any
immunosuppressing therapy is
given, but it is especially important
before therapy with
immunomodulating biological
agents, such as monoclonal
antibodies against TNF-a.3 This topic
has been the subject of many small
adult studies.82,83 Most of the adult
patients in these studies also had
been treated with a variety of other
immunosuppressing agents, which
may have affected the results of the
TST or IGRAs. Rates of
indeterminate/invalid results were
higher than usual in the adult
patients because of immune
suppression by both disease and
drugs. Within one small study of 79
children in Greece receiving
antirheumatic treatment (only 18
were tested before treatment with
an anti–TNF-a drug), patients with a
risk factor for TBI were 27.6 times
more likely to have a positive QFT
result, and no child had a positive
TST result.84 For these children, test
sensitivity is more important than
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specificity because of the increased
risk of progression of TBI to TB
disease. The current evidence
does not consistently suggest that
IGRAs are better than the TST in
identifying immunosuppressed
individuals who will benefit from
treatment of TBI. It is commonly
recommended that all patients
who will be receiving an
immunomodulating biological agent,
regardless of specific TB risk factors,
should be tested for TBI before
starting the therapy. Many experts
have suggested that to increase
sensitivity, both the TST and an
IGRA should be performed initially
for patients who also have a risk
factor for TBI, and appropriate
treatment of TBI should be started if
either test result is positive once TB
disease has been ruled out.82–88
Patients whose initial test results for
TBI are negative should be screened
annually for new TBI risk factors,
but annual testing is not generally
recommended in the absence of a
new risk factor while on continued
immunosuppression.
Effect of Age on Test Results
There has been a hesitancy to use
IGRAs in children younger than 5
years because of a lack of data for
this age group and concerns about
inadequate sensitivity of the IGRAs.
Because infants and young children
(younger than 4 years) are more
likely than older children to have
progression from untreated TBI to
TB disease and young children are
more prone to develop serious
forms of TB, failure to accurately
diagnose TBI in this age group can
have dire consequences.14
Resolution of this issue has been
hampered by the lack of a reference
standard for TBI. The earliest
studies suggested that IGRA
sensitivity is diminished in young
children, but the results were
inconsistent.36 However, subsequent
studies have demonstrated better
performance of newer versions of
the commercially available IGRAs in
young children than previously
reported. Debord et al89 found that
among 19 children with TB disease,
6 of 10 children younger than 2
years and 9 of 9 children who were
2 to 5 years of age had a positive
QFT result. Moyo et al90 studied 397
children in South Africa who were
younger than 3 years and were
suspected of having TB disease.
Agreement between the QFT and
TST was 94%, but both tests had
lower sensitivity for TB disease
(38% for QFT and 35% for the TST)
than has been reported in older age
groups.
Although the IGRAs have low
sensitivity for detecting TB disease
in young children whose immune
responses may be blunted by
malnutrition and TB itself, it is not
clear whether they have a higher
sensitivity for detecting TBI in
otherwise healthy young children.
Pavic et al91 studied 142 healthy
BCG-vaccinated children in Croatia
who recently had been exposed to
infectious TB disease. Both the QFT
and TST had proportions of positive
results that were associated with
degree of exposure, and there was
no evidence that age affected QFT
performance. Critselis et al72
performed a TST and QFT in 761
healthy Greek children in 4 age
groups who were referred for
several indications. Among the 198
children younger than 5 years (74
children were younger than 2
years), infants with positive QFT
results produced a greater mean
titer of IFN-c than older children
and adolescents. Agreement
between the TST and QFT results
was not significantly different
between younger and older children.
Velasco-Arnaiz et al92 found that
among 39 children younger than 5
years with confirmed TB disease (15
children were younger than 2
years), the sensitivity of QFT was
93%, and in 79 children with either
 TBI or TB disease, there was no
correlation between age and
antigen-stimulated IFN-c responses.
From 2005 to 2008, the San
Francisco TB program followed 146
untreated TST-positive/QFT-
negative children, including 44
children younger than 2 years, and
none developed TB disease.93
It is clear that the use of the TST in
infants and young children who
received a BCG vaccine will lead to
many false-positive results caused by
cross-reaction with the BCG. Although
some experts currently support the
use of IGRAs to test for TBI in infants
and toddlers, especially those at low
risk of TBI who have received a BCG
vaccine, others do not recommend
their routine use in children younger
than 2 years until additional
supportive data are available. In
summary, if an IGRA is performed in
an infant or young child, a positive
result likely indicates infection with M
tuberculosis, but a negative result does
not rule it out. A negative result for
either a TST or an IGRA should be
considered as especially unreliable in
infants younger than 3 months. The
rates of indeterminate/invalid results
appear to be higher in infants and
toddlers than in older children.
STRATEGIES FOR THE USE OF IGRAs IN
CHILDREN
Some of the major differences
between the TST and IGRAs are
summarized in Table 3. The basis
for deciding which diagnostic test to
use is fundamentally different for a
child than for an adult, and it differs
between the diagnosis of TBI and TB
disease. When testing otherwise
healthy individuals, the purpose of
the TST or an IGRA is to determine
if the person is infected with M
tuberculosis and will benefit from
treatment. The positive predictive
value of both tests for the
development of TB disease is low in
adults and children 5 years or older,
because only 5% to 10% of those
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TABLE 3 Comparison of the TST and IGRAs
Characteristic TST IGRA
Antigens used Many: PPD 3 (QFT) or 2 (T-SPOT)
Sample Intradermal injection Blood draw
Patient visits required 2 1
Distinguish between TBI and disease No No
Cross-reactivity with BCG Yes No
Cross-reactivity with NTM Yes Only rare speciesa
Differing threshold for positive values Yes No
by level of risk for TBI
Causes boosting Yes No
Subject to boosting by previous TST Yes Unknown but possible
Durability over time (stays positive with Yes Unknown but likely
or without treatment)
Difficulties with test reproducibility Yes Yes
Location of need for trained staff “Bedside” Laboratory
Age <2 yb Recommended Acceptable
Estimated specificity in BCG-unvaccinated children, % 95–100 90–95
Estimated specificity in BCG-vaccinated children, % 49–65 89–100
Estimated sensitivity (confirmed TB disease), % 75–85 80–85
Estimated sensitivity (clinical TB disease), % 50–70 60–80
a
Mycobacterium marinum, Mycobacterium kansasii, Mycobacterium szulgai, and Mycobacterium flavescens.
b
Negative result of either the TST or an IGRA should be considered especially unreliable in a child younger than 3 mo.
who test positive and go untreated immunosuppression, or are
will develop TB disease in their suspected of having TB disease
lifetime. In these groups, test should be tested. However, a
specificity is important to avoid negative result from either type of
massive overtreatment of test is not reliable for excluding the
individuals with false-positive presence of TB disease. Deciding
results. However, children younger which test to use involves a
than 2 years with untreated TBI consideration of sensitivity and
have a 25% to 50% risk of specificity. When high specificity is
developing TB disease within 1 year, desired (for example, otherwise low-
so optimizing test sensitivity is risk BCG-vaccinated children), the
important for this age group. In IGRAs are the clearly superior tests.
addition, children tend to tolerate Neither method has a clear
the treatment of TBI much better advantage in sensitivity; when
than adults, so their risk of adverse sensitivity is the main concern, such
events caused by treatment is less. as recent contact with a contagious
However, test specificity is also an case of TB disease, a positive result
issue for the youngest children, with either the TST or IGRA should
especially if they have received a be considered indicative of infection
BCG vaccine or have a likelihood of with M tuberculosis. When
exposure to NTM in their sensitivity is paramount, such as
environment; testing them with only high suspicion of TB disease or
the TST will lead to an appreciable testing a child who has a TB risk
proportion of false-positive results factor and who will soon receive an
when the prevalence of TBI is low, immunomodulating biological agent,
as in the United States. performing both an IGRA and a TST
should be strongly considered, with
Both the TST and IGRAs are a positive result for either test
imperfect methods. As a result, only leading to the child being diagnosed
children who have a risk factor for with TBI. Performing both tests will
TBI or TB disease, have a disease or lower the overall specificity and lead
condition that may require to some false-positive results, but in
significant therapeutic children with a high risk of
9
 progression to TB disease, this is an ^ For exposed contacts with However, neither method can be
acceptable trade-off. impaired immunity (eg, HIV used to rule out TB disease, and a
infection) and all contacts negative result of either the TST
Summary of Recommendations younger than 5 years, or an IGRA should be considered
Regarding Testing treatment of possible TBI especially unreliable in a child
Table 4 shows potential strategies should be initiated, even if the younger than 3 months.
for testing. Some specific points are initial TST or IGRA result is  Indeterminate/invalid IGRA results
as follows: negative, once TB disease is are more common in very young chil-
excluded (often referred to as dren (younger than 2 years) and
 Only children who have a risk “window prophylaxis”). If the immunosuppressed patients. When
factor for TBI or are at risk for TST or IGRA result still is an IGRA result is indeterminate/inva-
progressing to disease, are sus- negative with repeat testing in lid, either a repeat IGRA test using the
pected of having TB disease, or 8 to 10 weeks, treatment can
same or the other IGRA can be per-
who have an immunosuppressive be discontinued. If a TST or
formed, ensuring proper technique of
disease or about to start immu- IGRA result of a contact
specimen collection and processing,
nosuppressive therapy should be becomes positive, the regimen
or a TST can be performed.
tested with a TST or an IGRA. for TBI should be completed.
 For children without TB risk factors
 There is no compelling evidence  For children who have received a
other than foreign birth who have
to support the use of one IGRA BCG vaccine and have no known
(QFT, T-SPOT) over the other. exposure to a contagious TB case an unexpected low-level positive
 If the child of any age has been and no other TB risk factor other IGRA result (QFT <1.00 IU/mL, T-
exposed to an infectious case of than birth in a foreign country, 2 SPOT with 5–7 spots), a second
TB disease, he or she should be strategies can be used9: diagnostic test, either an IGRA or a
evaluated and, if determined not (1) an IGRA can be used and the TST, should be performed; the child
to have TB disease, given a full result acted on; or is considered infected only if results
course of treatment of TBI if  (2) a TST can be performed, and of both tests are positive.9
either a TST or IGRA result is if the result is negative, no fur-  Although IGRAs are more expen-
interpreted to be positive. ther testing is necessary; if the sive than the TST, their use may
 Even with a negative initial test result is positive, an IGRA be more cost-effective than the
result, contacts of a person with should be performed and its TST because of time savings for
known TB disease should be result acted on. the family and the elimination of
retested in 8 to 10 weeks, usually  When evaluating a child of any many false-positive results.94
with the same test, regardless of age for TB disease, both a TST and  A TB specialist should be
whether the initial test used was one or both IGRAs can be per- involved when there is a ques-
a TST or IGRA. formed to maximize sensitivity. tion about testing interpretation.
 Early communication with public
TABLE 4 Suggested Uses of TST and IGRA in Children health authorities during evalua-
TST preferred, IGRA acceptablea tion for a positive test result in
Children younger than 2 yb children is strongly encouraged.
IGRA preferreda
Children 2 y or older, especially those who have received BCG vaccine
Children of any age who are unlikely to return for the TST reading
TREATMENT OF TBI
Bothc the TST and an IGRA should be considered when:
Rationale
The initial and repeat IGRA results are indeterminate or invalid
The initial test (TST or IGRA) result is negative and: The goal of treatment is to prevent
There is clinical suspicion of TB diseasec (to maximize sensitivity) TBI from progressing to TB disease
The child has a risk factor and is at high risk of progression and poor outcome (especially
therapy with an immunomodulating biological agent, such as a TNF-a antagonist)c,d
and to diminish the reservoir for
An initial TST is positive and: future TB cases. All children who
The child has a history of BCG vaccination have TBI should receive a course of
Additional evidence is needed to increase adherence with therapy therapy. The risk of developing TB
a
In situations of testing obligated by law or credentialing bodies in person unlikely to be uninfected with TB, IGRA is
disease is highest during the 6
preferred.9
b
Many experts will use an IGRA in children of any age, especially if the child has received a BCG vaccine but have months after infection and remains
no other significant risk factors other than foreign birth. However, data from children in this age group are few.
c
high for 2 years.95 Not all people
A positive result of either test is considered significant in these groups.
d
The clinician should obtain the complementary test (eg, if a TST was initially performed, then IGRA should be with TBI have the same level of risk
obtained for a complete set). of progression to disease. Three

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 high-risk groups bear special
attention for disease progression:
1. Infants and young children
(particularly those younger than
2 years) may progress rapidly to
disease (40% to 50% of infected
children younger than 1 year;
25% of infected children 1–2
years of age) including meningitis
or miliary disease (15% of
infected children younger than 1
year; 5% to 7% of infected
children 1–2 years of age).
2. Postpubertal adolescents (older
than 12 years) who also have the
risk of progression to adult-type
disease.
3. Children and adolescents with
immunocompromising conditions
or receiving certain
immunosuppressing treatments,
including patients with diabetes
mellitus, chronic renal failure,
malnutrition, congenital or
acquired immunodeficiencies;
patients with malignancy;
patients receiving TNF-a
antagonists or blocking agents;
and patients preparing for or
experiencing organ or
hematologic transplant.
There are several barriers to
completion of treatment of TBI.
Children with infection are
asymptomatic, and families do not
readily observe a response to
treatment96 and often do not
appreciate a clear need to continue
medications. Pediatric formulations
of anti-TB medications are not
generally available in the United
States, requiring compounding or
adaptation of adult formulations
such as crushing pills or opening
capsules (see “Administration of
Antituberculosis Medication to
Children”). Medical providers for
children and adolescents should be
familiar with all the regimens
available to treat TBI to select the
best regimen for the individual child
and family. The regimen ultimately
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prescribed for children should be
safe, effective, and relatively
inexpensive, allow easy
administration to young children, and
result in a high completion rate. The
one characteristic that consistently
inversely correlates with completion
of treatment is the length of
treatment: the shorter the duration,
the higher the completion rate.
General Principles
The practitioner should be cognizant
of the following principles and
assumptions when caring for
pediatric patients with TBI:
 Infants and children with TBI
who have been recently infected
have an increased risk of rapid
disease development, and young
age at infection predicts more
years at risk for disease progres-
sion into adulthood.
 Assume that the causative M
tuberculosis is susceptible to mul-
tiple drugs unless specific knowl-
edge of drug resistance is
available. The incidence of isonia-
zid resistance among TB isolates
from US patients is approxi-
mately 9%,97 and the incidence
of rifampin resistance is <1%.98
The assumption is negated if the
source case is known to have a
drug-resistant isolate.
 A thorough physical examination
and high-quality chest radio-
graphs (posterior-anterior and
lateral views) should be per-
formed before starting treatment.
It is crucial to ensure that TB dis-
ease is not inadvertently treated
with an inadequate drug regi-
men; otherwise, the risk of devel-
oping drug-resistant TB while on
therapy is high (particularly with
monotherapy with isoniazid or
rifampin). Chest radiographs rule
out lung parenchymal disease
and any enlarged thoracic aden-
opathy,95 and the physical exami-
nation helps to exclude
extrapulmonary TB (including
adenopathy and hepatosplenome-
galy). If evidence of TB disease is
found, additional diagnostic pro-
cedures should be performed,
and the treatment regimens will
be different from those for TBI.
 Anti-TB treatment regimens that
are efficacious in adults will be
effective in children. Performing
efficacy trials exclusively in chil-
dren to mirror those previously
conducted in study populations
of both adults and children
(which enrolled >100 000
patients on isoniazid) would be
difficult and expensive. Extensive
experience has shown that treat-
ment regimens for both TBI and
TB disease that are effective in
adults also will be effective in
children. Rather than focusing on
efficacy, studies regarding TB
regimens in children are
designed to assess and improve
medication safety, tolerability,
pharmacokinetics, and
adherence.
 Laboratory testing before or dur-
ing treatment is not necessary in
otherwise healthy pediatric
patients. The use of isoniazid
monotherapy for pediatric TBI
causes low rates of hepatotoxic-
ity (<1%). Alternate regimens,
which may include 2 drugs but
for a shorter duration, are even
less hepatotoxic than the 9
months of isoniazid monother-
apy. This reduced toxicity stems,
in part, from the overall
decreased time of drug expo-
sure.99,100 However, increased
risk of hepatotoxicity can be
experienced by children who are
obese and have nonalcoholic
steatohepatitis, are taking other
potentially hepatotoxic medica-
tions (especially anticonvulsants),
are pregnant in the first 12
weeks of gestation, or have
underlying liver disease. These
children should have baseline
hepatic function tests (alanine
transaminase, aspartate
11
 transaminase) and periodic labo- reminders from providers.99,103 radiographs unless a new exposure
ratory monitoring (eg, monthly) A successful program in is documented or the child develops
during therapy. Houston, Texas, has been SAT- a clinical illness consistent with TB,
 Completion of regimens for TBI based, but the health the latter being extremely rare in
in high-risk groups (including department delivers the North America. A TB specialist
children and adolescents) is medications to the patient’s should be involved if questions arise
imperative. Historically, medica- home on a monthly basis and regarding selection of an
tion regimens for TBI have been contacts the family weekly to appropriate treatment regimen or
through self-administered ther- support the treatment.100 management of adverse effects.
apy (SAT). Although completion o Video DOT may be used in lieu
of isoniazid by SAT was >80% of the traditional in-person Specific Drugs
within the context of a research DOT strategy, provided the Isoniazid
study, completion rates decrease patient has a personal device Pediatric experience with isoniazid is
to approximately 60% in the real and that privacy restrictions of extensive and well published.
world because of patient fatigue the Health Insurance Portability Isoniazid can inhibit pyridoxine
or drug intolerance.101 Adher- and Accountability Act are metabolism; however, otherwise
ence may be improved by applied.104,105 Video DOT may healthy children and adolescents in
directly observed therapy (DOT), be synchronous (in real time) the United States given
when medications are adminis- or asynchronous (video clips recommended doses rarely develop
tered directly to the patient by a are recorded and then associated peripheral neuritis or
health care professional or uploaded for later review). seizures and do not need pyridoxine
trained third party (not a relative supplements as a preventive
or friend) who observes and  Children with adequate anti-TB measure. However, isoniazid
documents that the patient treatment need not be retested. overdose, as in a suicide attempt, can
ingests each dose of medication. The test of infection (either TST or lead to generalized seizures that are
There has been success in admin- IGRA) remains positive after ade- difficult to control unless large doses
istering DOT through school- quate treatment and should not be of pyridoxine are administered.
based health centers.102 DOT used as a test of cure or as surveil- Routine pyridoxine supplementation
should be considered for treat- lance for emergence of TB disease. is recommended for exclusively
ment of children and adolescents breastfed infants and for children
with TBI who are at high risk of Treatment Selection
and adolescents on meat- and milk-
rapid progression to disease. Anti-TB drugs kill or inhibit deficient diets; children with
When well conducted, DOT is a multiplication of M tuberculosis, nutritional deficiencies, including all
package of services, including thereby arresting progression of symptomatic children living with HIV
enablers and reinforcements, infection and preventing most infection; and pregnant adolescents
designed to help the patient and complications. Historically, the and women. Bioavailability of
family complete therapy. dominant regimen was 6 to 9 isoniazid is improved with
months of isoniazid monotherapy by administration on an empty stomach,
o DOT provides the highest rates SAT. Other alternatives to treatment although dyspepsia may be alleviated
of medication completion of TBI have emerged, with similar with small amounts of food.
(approximately 80% to 95%).96 rates of efficacy to protect against
It requires both financial and development of disease. Factors to Hepatotoxicity caused by isoniazid is
staff resources, usually from consider in regimen selection rare in otherwise healthy children,
the local health department, include the child’s age and and routine laboratory testing is not
and can be time consuming for requirement for liquid formulations, necessary (Table 5). There can be
the staff and families. The time need for speedy treatment (such as transiently mild elevations of
and resources required often a pending stem cell or solid organ transaminases, with no clinical
make DOT unacceptable to transplant), use of concomitant consequence given that these
patients and providers. hepatotoxic medications, concurrent resolve spontaneously. When testing
o SAT-hybrid models may be HIV infection, and suspected is indicated because of development
alternate methods for infection with drug-resistant M of clinical signs or symptoms (eg,
improving patient compliance. tuberculosis. If therapy is completed abdominal pain, vomiting, jaundice)
One example is self- successfully, there is no need to that could be caused by hepatitis,
administration, with text perform additional tests or chest hepatotoxicity may be defined as

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 transaminase elevations of 2 to 3
times the upper limit of normal
if the patient is symptomatic, or
>5 times the upper limit of normal
if the patient is asymptomatic.106
Rifampin
Rifampin is a rifamycin that, because
of its short half-life, must be
administered daily. Rifampin is
readily available by prescription,
including a standard compounded
liquid formulation for young
children. Bioavailability of rifampin
is improved with administration on
an empty stomach, although
dyspepsia may be alleviated with
small amounts of food (Table 5).
A major concern with using any
rifamycin-containing regimen is
drug–drug interactions. These
interactions should be appreciated
as the number of pediatric
immunocompromised patients (such
as those undergoing treatment of
HIV infection, with oncologic
diseases, or who are transplant
recipients) increases. The rifamycins
are potent inducers of the hepatic
CYP 450 enzyme. This increased
enzymatic activity will heighten
metabolism of classes of
antiretroviral drugs such as the
protease inhibitors. Conversely, the
rifamycins may increase the
exposure to specific
immunosuppressive drugs,
necessitating a dose reduction of
agents such as tacrolimus and
cyclosporine.
An additional drug interaction
concern with rifampin is that it can
lower the effectiveness of oral
contraceptives. Female adolescents
taking rifampin must be counseled
that they should rely on other forms
of birth control while taking this
medication. Also, patients should be
warned that rifampin will cause
urine, sweat, saliva, and tears to
turn a red-brown color and can
cause staining of contact lenses.
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Rifapentine
Rifapentine is a rifamycin with a
long half-life allowing for weekly
administration, versus the daily
dosing of rifampin. The
bioavailability of rifapentine is
enhanced by food (particularly
products containing fat, such as milk
or egg), and this medication should
be given as possible with fatty food.
The dosing of the 2 components
(isoniazid, rifapentine) varies by
weight and age of the patient
(Table 6). The drug-drug
interactions with rifapentine appear
less when compared with those of
rifampin.
Treatment Regimens for TBI
Once-Weekly Dosing of Isoniazid and
Rifapentine (3HP) (12 Doses)
This regimen includes the use of
isoniazid and rifapentine, given once
weekly, for 12 doses. The regimen is
commonly referred to as once-
weekly dosing of isoniazid and
rifapentine (3HP): the H is the
international symbol for isoniazid,
the P is the symbol for rifapentine,
and the 3 refers to a treatment
length of 3 months. The 3HP
regimen is considered complete if at
least 11 doses have been taken over
16 weeks. This regimen has similar
efficacy to 9 months of isoniazid
(see below) but is associated with
higher completion rates in adults,99
children, and adolescents.100,107
When first introduced, 3HP was
prescribed under DOT, and
rifapentine was available only
through local health departments.
However, an open-label, phase 4
clinical trial of adult patients (18
years or older) demonstrated
noninferiority for completion rates
and safety of 3HP given by SAT
compared with DOT.103 As a result,
the Centers for Disease Control and
Prevention (CDC) has recommended
that 3HP may be given via SAT
when DOT is not available or
feasible.108,109 Because the study did
not include children or adolescents,
it is not known whether the
similarity of completion rates
observed in adults given 3HP by
SAT or DOT would be seen in
children and adolescents. Use of
DOT may be preferred for patients
at increased risk of rapid
progression to TB disease (recent
contacts of infectious cases,
immune-compromised patients, age
younger than 5 years, some
adolescents).
The 3HP regimen, despite the use of
2 agents, appears to be equally or
less hepatotoxic than 9 months of
isoniazid monotherapy.100 Providers
should be cognizant that the pill
burden of this regimen may be high;
a child weighing 25 kg would need
to take 6 tablets (4 of rifapentine, 2
of isoniazid) simultaneously.
This regimen is recommended for
children 2 years or older (there is a
paucity of data on rifapentine
pharmacokinetics in very young
children). 3HP can be used in HIV-
infected individuals barring drug-
drug interactions with antiretroviral
medications.
4 Months of Daily Rifampin (4R) (120
Doses)
The 4-month regimen of daily
rifampin (4R) is usually taken by
SAT (15–20 mg/kg per dose,
maximum 600 mg per dose).
Rifampin is bactericidal against M
tuberculosis. Therapy is deemed
completed if 120 doses have been
administered within 6 months.
Efficacy is similar to 9 months of
isoniazid, but the shorter period
allows for a significantly higher rate
of completion.110–112
Drug–drug interactions preclude it
as a regimen for HIV-infected
individuals. Because HIV-infected
individuals with low CD41 T-
lymphocyte counts may have
subclinical TB disease, using
13
 rifampin monotherapy may
needed. If symptomatic on treatment, obtain

concomitant hepatotoxic drugs: baseline and

periodic (often monthly) LFTs recommended
 Otherwise healthy patient: no baseline LFTs
inadvertently increase TB resistance

 Patient with existing liver disease or with

Drug-Safety Monitoring for All Agents

in those people.

There is no age restriction for the

use of 4R. The adverse effect profile
of 4R is excellent, with similar
transaminase elevations as with 9
months of isoniazid (see
below).110–112 Hence, 4R is
preferred in children without HIV
LFTs

infection of all ages who are not

able to undergo DOT, or if there is a
concern of an isoniazid-resistant
Adapted from Cruz AT, Ahmed A, Mandalakas AM, Starke JR. Treatment of latent tuberculosis infection in children. J Pediatr Infect Dis. 2013;2(3):248–258. LFT, liver function test.
isolate as judged from the exposure
history.

3 Months of Daily Therapy With Isoniazid

and Rifampin (3HR) (90 Doses)
amounts of food may alleviate dyspepsia

amounts of food may alleviate dyspepsia

Should be given with fatty food to enhance

Best if on empty stomach, although small

Best if on empty stomach, although small

This regimen consists of 3 months

of daily isoniazid and rifampin
(3HR), using the same doses as
Bioavailability

when each drug is used alone. There

is no age restriction for the use of
3HR. In combining isoniazid and
rifampin, this regimen is similar in
absorption

principle to 3HP; however, the

medications are given daily because
of the relatively short half-life of
rifampin compared with rifapentine.
Efficacy and rates of completion of
3HR are comparable or better when
compared with isoniazid
TABLE 5 Characteristics of Medications Used in Pediatric Patients With TBI

monotherapy.113
Gastrointestinal upset (common, particularly

Gastrointestinal upset (common, particularly

Hypersensitivity response (rare in children)

if isoniazid is taken on empty stomach)

if these are taken on empty stomach)

6 or 9 Months of Isoniazid (6H) (9H)

Orange discoloration of body fluids
Common Adverse Effects

Isoniazid monotherapy has been the

most widely recommended and used
treatment of pediatric TBI. Isoniazid
is bactericidal against M tuberculosis.
Peripheral neuropathy

(urine, sweat, tears)

Isoniazid may be given daily by SAT

Thrombocytopenia

(10–15 mg/kg per dose, maximum

Hepatotoxicity

Hepatotoxicity

300 mg per dose) or twice weekly

Diarrhea

via DOT (20–30 mg/kg per dose,

Rash

Rash

maximum 900 mg per dose).96

Therapy with 6 months of isoniazid
(6H) is complete if the child has
received 180 doses (if given daily via
SAT) or 52 doses (if given twice
weekly under DOT) within 9 months.
Rifapentine
Rifampin
Isoniazid

If using a 9-month regimen, therapy

Drug

is complete if the child has received

270 doses (if given daily via SAT) or

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 TABLE 6 Regimens Used in Pediatric Patients With TBI
No. Doses
Duration, Needed for Rates of Age
Regimen Agent(s) Dose and Age Group Administration mo Completion Completion, % Restriction Comments
3HP Isoniazid 1 Rifapentine Age $12 y Weekly (SAT or DOT) 3 12 63–97 Not for children Take with food, containing fat if

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<2 y possible; pyridoxine for selected
patientsa
Isoniazid: 15 mg/kg rounded up:
nearest 50 or 100 mg (max
900 mg)
Rifapentine (by wt):
10–14 kg: 300 mg
14.1–25 kg: 450 mg
25.1–32 kg: 600 mg
32.1–49.9 kg: 750 mg
$50.0 kg: 900 mg

PEDIATRICS Volume 148, number 6, December 2021

Age 2–11 y
Isoniazid: 25 mg/kg rounded up:
nearest 50 or 100 mg (max
900 mg)
Rifapentine: see above
4R Rifampin Adult: 10 mg/kg (max 600 mg) Daily (SAT) 4 120 72–96 None Drug–drug interactions
Child: 15–20 mg/kg (max 600 mg)
3HR Isoniazid 1 rifampin Same doses as when drugs are used Daily (SAT) 3 90 82 None Not considered unless 3HP or 4R are
individually not feasible
6H Isoniazid Adult: 5 mg/kg (max dose 300 mg) Daily (SAT) 6 180 20–93 None Seizures with overdose; pyridoxine for

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selected patientsa
Child: 10–15 mg/kg (max 300 mg)
Adult: 15 mg/kg (max dose 900 mg) Twice weekly (DOT) 52
Child: 20–30 mg/kg (max 900 mg)
9H Isoniazid Adult: 5 mg/kg (max dose 300 mg) Daily (SAT) 9a 270 20–93 None Seizures with overdose; pyridoxine for
selected patientsa
Child: 10–15 mg/kg (max 300 mg)
Adult: 15 mg/kg (max dose 900 mg) Twice weekly (DOT) 76
Child: 20–30 mg/kg (max 900 mg)
Table adapted from Cruz AT, Ahmed A, Mandalakas AM, Starke JR. Treatment of latent tuberculosis infection in children. J Pediatr Infect Dis. 2013;2(3):248–258. 6H, 6 months of isoniazid; 9H, 9 months of isoniazid; —, not applicable.
a
Exclusively breastfed infants and for children and adolescents on meat- and milk-deficient diets; children with nutritional deficiencies, including all symptomatic children living with HIV; pregnant adolescents and women.

15
 76 doses (if given twice weekly under
DOT) within 12 months.
The efficacy of isoniazid
monotherapy reaches 98% against
development of TB disease.106 The
World Health Organization
recommends a treatment duration
of 6 months114 to provide high
coverage of the population in
countries with a high disease
burden. A 9-month regimen gives an
additional 20% to 30% increase in
efficacy.97 The CDC and National TB
Controllers Association recommends
6-month or 9-month durations of
isoniazid monotherapy, if shorter-
course rifamycin-based regimens
cannot be used.108
Although isoniazid is readily
available, the long duration of
isoniazid monotherapy results in
poor adherence and low completion
rates. This option may be
unattractive to patients and families.
Many TB care providers and clinics
use this regimen only when a
rifamycin-containing regimen cannot
be used because of drug
interactions.
Administration of Antituberculosis
Medication to Children
Given the common inability of young
children to swallow pills and to
mitigate the common adverse effect
of gastrointestinal tract upset right
after taking the medication,
guidance for administering
medication (particularly isoniazid) is
warranted. Commercially available
isoniazid suspension contains large
amounts of sorbitol and often causes
nausea and diarrhea if the volume
exceeds 5 mL and/or if it is taken
when the child has fasted. If the
child is unable to swallow pills, the
pills can be crushed and mixed into
syrup or other palatable liquid to
appeal to the young child, and in the
smallest volume possible to ensure
the entire dose is taken (ie, not in a
full bottle of milk). Rifampin should
be given on an empty stomach or
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with a small amount of food.
Rifapentine should be administered
with food, particularly with a high
fat content, to enhance absorption.
For mothers receiving treatment for
TBI or TB disease who are also
breastfeeding, their infants may be
indirectly receiving TB medications.
The amount being received is
miniscule and is the basis for
recommendations for mothers to
continue breastfeeding even while
receiving TB treatment with first-
line agents.115
Evaluation and Management of
Adverse Reactions
Regardless of the treatment regimen
selected, all children should be
clinically monitored on a regular
basis. This allows the medical
provider to assess for medication
adverse effects, determine if there
is advancement of the TBI to
disease, and continue to educate
patients and families on the
importance of treatment and
adherence. Monthly clinical
evaluation (at a minimum) to
observe for signs or symptoms of
hepatitis and other adverse effects
of drug therapy is appropriate and
can be done without routine
laboratory monitoring of serum
transaminase concentrations.
Children receiving other known
potentially hepatotoxic medications
or who have known or suspected
liver dysfunction (including obese
children at risk for nonalcoholic
steatohepatitis) should have
baseline transaminase levels
determined and followed closely for
clinical signs or symptoms of
hepatitis. The increasing use of
telehealth visits in ambulatory care
settings may allow increased access
for monitoring but has the
disadvantage of not allowing a
thorough physical examination in a
child who is taking hepatotoxic
drugs.
End-of-Therapy Assessment
Families should be advised that
either test of infection (TST or IGRA)
will remain positive after treatment
completion because of immunologic
memory and is not a sign of
treatment failure. Patients and their
parents also should be aware that
the child should not receive a TST in
the future, because there may be an
accelerated reaction that can result
in a blister or even a scar at the site
of the injection. Repeat chest
radiography after treatment
completion is not necessary. If there
is a clinical change or a new risk
factor has emerged, then a complete
physical examination and chest
radiography should be performed for
assessment of TB disease.
Common Drug-Related Adverse
Reactions
Hepatotoxicity
I f any patient, while on treatment,
exhibits clinical signs and symptoms
concerning for a significant adverse
reaction from the medication
(including but not limited to
abdominal pain, anorexia, jaundice,
dark-colored urine, pale stools), the
medication should be stopped
immediately while the clinician is
contacted and directs evaluation.
Many patients who eventually suffer
severe hepatotoxicity had continued
to take the medications even after
clinical signs or symptoms became
apparent. Transaminases should be
assessed and, if elevated, measured
weekly until either resolution or
concern prompting gastroenterology
consultation. Resolution of clinical
symptoms and/or laboratory
abnormalities may allow rechallenge
with the same regimen. In situations
in which resolution does not occur
after medication discontinuation, or
previously resolved abnormalities
resurface at the time of rechallenge,
a different regimen not containing
the suspected offending drug should
be started. This decision to use
drugs other than isoniazid or a
FROM THE AMERICAN ACADEMY OF PEDIATRICS
 rifamycin should be made in
consultation with an expert in
treatment of pediatric TB.
Respiratory Issues
It is exceedingly rare to develop
pulmonary TB disease while on
therapy for TBI, unless adherence is
poor. The anti-TB medications have
a low rate of adverse respiratory
effects, and respiratory illnesses
occurring while on therapy are
usually intercurrent infections or
asthma exacerbations. Evaluation
and management usually should
target acute community-acquired
viral or bacterial pathogens, rather
than emergent TB disease, and
transmission-based precautions
should be followed (ie, droplet and/
or contact precautions with eye
protection) when examining patients
with respiratory symptoms.
Gastrointestinal Tract Upset
Gastrointestinal tract upset (nausea,
vomiting, anorexia, abdominal pain)
may occur, particularly in the first
few weeks of therapy. Symptoms
occurring shortly after
administration of the drugs are
rarely a sign of hepatitis but, more
often, are attributable to irritation of
the stomach mucosa. Having a small
amount of food or milk in the
stomach may alleviate these
symptoms. However, isoniazid and
rifampin should not be taken with
large amounts of food, because this
will affect absorption. If treatment is
by SAT, dyspepsia may be
minimized by taking medications at
bedtime. If medications are not able
to be taken at night, taking antacids
concurrently may alleviate
symptoms without compromising
absorption,116 although
pharmacokinetic studies regarding
this issue did not include children.
By contrast, rifapentine always
should be taken with food,
preferably with an appreciable fat
content, to enhance absorption. It is
incumbent on the clinician to ensure
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that gastrointestinal tract upset, if
not easily relieved with above
measures, is not secondary to
medication-induced hepatotoxicity.
Interruptions in Therapy
Questions may arise regarding how
to manage patients who experience
interruptions in therapy because of
poor adherence, assessment of
possible drug-related toxicity, or
temporary lack of available
medications. No formal trials of
interrupted treatment courses and
efficacy have been conducted.
Published guidance and medical
expert opinion have put forth
acceptable options for completion of
certain regimens (see specifics in
drug regimens above).
Interruptions in treatment regimens
with already short duration of the
rifamycin-based regimens likely
have more detrimental impact on
effectiveness. The clinician needs to
determine if to restart the regimen
or extend the date of completion. If
the interruption occurred early or
over an extended time (over a
month), it may be prudent to restart
courses of rifamycin-based
regimens.
Special Considerations
Treatment of Multidrug-Resistant TBI
Multidrug-resistant TB is defined as
infection or disease caused by a
strain of M tuberculosis that is
resistant to at least isoniazid and
rifampin, the 2 first-line drugs with
greatest efficacy. Optimal therapy
for multidrug-resistant TBI has not
been established and needs to be
individualized on the basis of the
exact drug resistance pattern of the
isolate. Although there have been no
randomized controlled trials, many
experts recommend that a
fluoroquinolone antibiotic, either
levofloxacin or moxifloxacin, alone
or in combination with a second
drug to which the isolate is
susceptible, is the best currently
available regimen.117 The optimal
length of therapy is unknown, with
most experts recommending
treatment duration between 6 and
12 months. These cases should be
managed in consultation with a
specialist with expertise in
managing pediatric TB.
Children Living With HIV Infection
The CDC and National TB
Controllers Association prefer short-
course rifamycin-based regimens for
TBI if there are no prohibitive drug-
drug interactions with antiretroviral
medications.108 Specifically, 3HP is
recommended for children 2 years
and older in this situation, followed
by 3HR in children of all ages. The
combination of isoniazid and
rifapentine has been given
successfully to adults living with HIV
infection,118,119 and some data are
available for children.107,109
Treatment of coinfected individuals
should be guided by clinicians
experienced in the management of
both conditions.
SUMMARY OF RECOMMENDATIONS
REGARDING TREATMENT REGIMENS
 The risk of a child progressing
from having TBI to TB disease
depends on the child’s age and
immune status. Young children
(younger than 4 years), adoles-
cents, and immunocompromised
individuals are at higher relative
risk to progress from infection to
disease.
 Short-course rifamycin-based
regimens are preferred for treat-
ment of TBI. On the basis of
safety, adherence and comple-
tion, and effectiveness, many
experts prefer 3HP, by DOT, in
patients 2 years or older. When
DOT is not available or the child
cannot handle the pill burden of
3HP, 4R or 3HR may be the best
regimen.
 Patient monitoring for adherence
(DOT or SAT-hybrid) should be
17
 strongly considered for patients EX OFFICIO Neil S. Silverman, MD – American
at high risk for progression to TB College of Obstetricians and
disease. David W. Kimberlin, MD, FAAP – Red Gynecologists
 Routine laboratory monitoring is Book Editor Jeffrey R. Starke, MD, FAAP –
not needed for healthy patients Elizabeth D. Barnett MD, FAAP– Red American Thoracic Society
but should be considered for Book Associate Editor Kay M. Tomashek, MD, MPH, DTM –
patients with immune compro- Mark H. Sawyer, MD, FAAP – Red National Institutes of Health
mise, those with existing liver Book Associate Editor STAFF
disease, or those who are taking Henry H. Bernstein, DO, MHCM,
other potentially hepatotoxic FAAP – Red Book Online Associate
medications. Editor Jennifer M. Frantz, MPH
 Respiratory illnesses are rarely a H. Cody Meissner, MD, FAAP – Visual
harbinger of progression to dis- Red Book Associate Editor
ease but likely represent inter- ABBREVIATIONS
CONTRIBUTORS
current community-acquired
3HP: once-weekly dosing of
infections. isoniazid and rifapentine
Juan D. Chaparro, MD, FAAP –
3HR: 3 months of daily isoniazid
LEAD AUTHORS Partnership for Policy
and rifampin
Implementation
4R: 4-month regimen of daily
Stuart T. Weinberg, MD, FAAP,
Dawn Nolt, MD, MPH, FAAP rifampin
FAMIA – Partnership for Policy
Jeffrey R. Starke, MD, FAAP BCG: bacille Calmette-Gu
erin
Implementation
CDC: Centers for Disease Control
COMMITTEE ON INFECTIOUS LIAISONS and Prevention
DISEASES, 2020–2021 CFP-10: culture filter protein 10
DOT: directly observed therapy
Amanda C. Cohn, MD, FAAP –
Yvonne A. Maldonado, MD, FAAP, ELISA: enzyme-linked
Centers for Disease Control and
Chairperson immunosorbent assay
Prevention
Sean T. O’Leary, MD, MPH, FAAP, ELISPOT: enzyme-linked
Karen M. Farizo, MD – US Food and
Vice Chairperson immunosorbent spot
Drug Administration
Ritu Banerjee, MD, PhD, FAAP ESAT-6: early secreted antigenic
Natasha B. Halasa, MD, MPH, FAAP –
James D. Campbell, MD, MS, FAAP target 6
Pediatric Infectious Diseases Society
Mary T. Caserta, MD, FAAP IFN-c: interferon-c
David Kim, MD – HHS Office of
Jeffrey S. Gerber, MD, PhD, FAAP IGRA: interferon-c release assay
Infectious Disease and HIV/AIDS
Athena P. Kourtis, MD, PhD, MPH, NTM: nontuberculous
Policy
FAAP Mycobacterium
Eduardo L
opez Medina, MD, MSc –
Ruth Lynfield, MD, FAAP PPD: purified protein derivative
Sociedad Latinoamericana de
Flor M. Munoz, MD, MSc, FAAP QFT: QuantiFERON-TB Gold In-
Infectologia Pediatrica
Dawn Nolt, MD, MPH, FAAP Tube assay
Denee Moore, MD, FAAFP –
Adam J. Ratner, MD, MPH, FAAP RD1: region of difference 1
American Academy of Family
Samir S. Shah, MD, MSCE, FAAP SAT: self-administered therapy
Physicians
William J. Steinbach, MD, FAAP TB: tuberculosis
Scot B. Moore, MD, FAAP –
Kenneth M. Zangwill, MD, FAAP TB1: tuberculosis antigen tube 1
Committee on Practice Ambulatory
Theoklis E. Zaoutis, MD, MSCE, FAAP TB2: tuberculosis antigen tube 2
Medicine TBI: tuberculosis infection
Lakshmi Panagiotakopoulos, MD, TNF-a: tumor necrosis factor-a
FORMER COMMITTEE MEMBER MPH, FAAP – Centers for Disease T-SPOT: T-SPOT.TB assay
Control and Prevention TST: tuberculin skin test
Ann-Christine Nyquist, MD, MSPH, Laura Sauv
e, MD, MPH, FAAP,
FAAP FCPS – Canadian Pediatric Society

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