748950
research-article2017
CPJXXX10.1177/0009922817748950Clinical PediatricsColeman et al
Commentary
Tuberculosis Testing in Children
Jessica L. Coleman, MS, BS1,2, Barley R. Halton, BA1,2,
and Russell W. Steele, MD1,2,3
Childhood tuberculosis (TB) remains a major concern in
many developing countries, representing a prominent
cause of morbidity and mortality in these regions. The
World Health Organization estimates that at least 500
000 children become infected, and approximately 70
000 die each year with children younger than 2 years
being at greatest risk for disease progression.1,2 This
being said, in the United States, there are only 500 newly
diagnosed cases per year in children making diagnosis
and management of this disease uncommon for the gen-
eral pediatrician and primary care physician in the
United States. Mortality is less than 1% except in chil-
dren with congenital and neonatal TB where the mortal-
ity is approximately 50%.
Latent TB infection (LTBI) treatment is the main
strategy for treating TB, but to achieve this, reliable test-
ing methods are required, especially for groups at high
risk for the disease. Recognition of potential TB disease
and diagnosis in children has been particularly difficult
as early signs and symptoms are subtle. Pneumonia
unresponsive to antibacterial therapy, fever of unknown
origin, scrofula, and abdominal pain are the most fre-
quent presentations.
In adults, the diagnosis of Mycobacterium tuberculo-
sis is based on clinical features, an abnormal chest radio-
graph, sputum containing acid-fast organisms, and most
important, a positive culture. The tuberculin skin test
(TST) was the standard screening test in the past, but
this has been largely replaced by a interferon-gamma
release assay (IGRA) for adults. Major problems with
the TST have been differing strengths and types of puri-
fied protein derivative (PPD) used, variability in admin-
istration and reading of test results and differences in the
interpretation of skin test induration responses. Other
confounding variables include infection with nontuber-
culous mycobacterial organisms and the previous
administration of the bacille Calmette-Guerin (BCG)
vaccine.
Current Guidelines for TB Testing
in Children
Official clinical practice guidelines for the diagnosis
of tuberculosis in adults and children were recently
Clinical Pediatrics
1­–4
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DOI: 10.1177/0009922817748950
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published by the American Thoracic Society, Infectious
Diseases Society of America, and Centers for Disease
Control and Prevention.3 They recommend when testing
is required for adults or children >5 years of age at low
risk for M tuberculosis that performing an IGRA is pre-
ferred over the TST because of its higher sensitivity and
specificity as well as the advantage that patients need
not return for a second visit when the test is negative.
However, the guidelines state,
we suggest performing a TST rather than an IGRA in
healthy children <5 years of age for whom it has been
decided that diagnostic testing for LTBI is warranted. This
is stated as a “conditional recommendation with very low-
quality evidence.”
The reason for this difference in method of testing based
on age is the high incidence of indeterminate IGRA
assays in young children.
IGRA Versus TST to Diagnose TB in
Children
IGRAs have been extensively evaluated for the diagno-
sis of TB infection. In contrast to the TST, IGRAs
require a single visit, are not positive in BCG vaccine
recipients, are not positive for the majority of nontuber-
culous mycobacteria, and do not rely on subjective read-
ing. Several reports have shown in both adults and
children that IGRAs are more sensitive and specific for
diagnosis.3-5 This being said, the cost of IGRAs is highly
prohibitive in endemic regions, where resources are
limited.
Data for IGRA efficacy and utility of diagnosis in
children are limited and reports that do exist are
primarily from low-burden settings.6-10 In a study by
1
University of Queensland School of Medicine, Herston,
Queensland, Australia
2
Ochsner Clinical School, Ochsner Children’s Health Center, New
Orleans, LA, USA
3
Tulane University School of Medicine, New Orleans, LA, USA
Corresponding Author:
Jessica L. Coleman, 1412 Eighth Street, New Orleans, LA, USA.
Email: jcoleman409@gmail.com
2 Clinical Pediatrics 00(0)
Table 1.  Our Institution’s Results for TB IGRA Assays in
Children.
Age % No. Indeterminate/
(Years) Indeterminate No. Tested
0-1 43 6/14
1-2 36 8/22
2-3 32 10/31
3-4 25 4/16
4-5 11 1/9
>5 2 1/47
Abbreviations: IGRA, interferon-gamma release assay; TB,
tuberculosis.
Lodha, et al11 of 362 children between 6 months and 15
years, it was found that in high-burden countries, IGRA
was comparable to TST and offered no added advantage
in the diagnosis of childhood intrathoracic TB. The pro-
portion of indeterminate test results in this group was
found to be just 2%7 in immune-competent children.11
This study did not include any children with HIV and
the study used the commercially available PPD (5 TU),
which varies from the earlier guidelines in India, which
recommended the use of 1 TU PPD.10 More recent
guidelines from that country for pediatric TB recom-
mend the use of 2 TU of PPD RT23 or equivalent.12 This
difference could lead to an increase in TST sensitivity
because reaction to PPD increases with PPD strength.
A study in Thailand concluded that a TST is preferred
over IGRAs in diagnosing latent and active TB in
healthy Thai children because of cost constraints and
lack of difference in test performances. In a healthy pop-
ulation of 158 Thai pediatric patients, no indeterminate
results were found. This study with the mean age at 7.2
years, however, did not focus on the younger pediatric
population.13
A 2016 publication compared the TST to IGRA QFT
in immigrants in the United States with US citizens. The
findings found discordances between the 2 tests in 3% in
US natives but differences ranging up to 19% in nonciti-
zens across all ages.14 This questions the efficacy of
many results with our current testing.
Indeterminate IGRA Assays in
Children
Studies that have employed IGRA assays have reported
a wide range of indeterminate assays, ranging from 0%
to 31%. These findings are most likely dependent on the
age and illness of the child examined. Few studies have
broken down results by age. Some studies have reported
a very low incidence of indeterminate results, as low as
0.2% to 4%.15,16 It is clear that patients with impaired
immunity have a very high incidence of indeterminate
results, which are most attributable to their inability to
No. release interferon gamma in response to the control phy-
Positive tohemagglutinin (PHA) mitogen which makes the nega-
tive response to tuberculin uninterpretable.7,17
0 We present our own data in children who had IGRA
1 determinations (Table 1). None of these children were
0
immune deficient, but more than half had been ill and
0
were undergoing early evaluation for solid organ
0
transplant.
2
A French study of pediatric patients tested because of
signs and symptoms suggestive of tuberculosis had
indeterminate results in 14%, with no laboratory or clin-
ical explanation.18 Altet-Gomez et al19 suggested that it
was more likely that indeterminate results in young chil-
dren younger than 5 years were not from a responding
impairment to specific antigens and PHA but to an inad-
equate separation of mononuclear cells or from insuffi-
cient blood taken. This was the documented source of
the indeterminate results in their study for 3 children
who failed the IGRA (T-SPOT.TB) test; a problem they
felt is inherent in all the IGRA tests.19-22
A study by Bui et al23 found a much higher number of
indeterminate results in that fifty-six of 182 (31%) of
children had indeterminate IGRA (QuantiFERON-TB
Gold) assays, which was associated with inpatient sta-
tus, suggesting more severe illness, but not age, gender,
or medical comorbidities. It was suggested this could be
due to improperly handled specimens.23 A French study
of just 19 inpatient immunocompetent children aged
between 0.29 and 5.36 years with active tuberculosis
found that the rates of indeterminate test results were 0
with rates of positivity for children <2 years of age at
6/10 and for those >2 years was 9/9.24
TST, but not IGRAs, were significantly inhibited by
prior BCG vaccination in a cohort of HIV infected adults
from a low prevalence TB country. Therefore, IGRA
should preferentially be used for LTBI-testing in these
patients. More studies are needed to determine if this
should also be the approach for testing in the pediatric
HIV population.25
In a meta-analysis in 2010 by Diel et al,26 the pooled
rate of indeterminate results were low: 2.1% and 3.8%
for 2 different IGRA assays, increasing to 4.4% and
6.1% in immunosuppressed hosts.
The various IGRA assays have been compared with
conflicting results. One large study demonstrated that in
children with no documented contact but increasing TB
exposure, TST and the QuantiFERON-TB Gold positiv-
ity was higher than T-SPOT.TB, a type of ELISPOT
assay. In this study, there was no difference between
young and old children in either test. Overall, this study
determined that IGRAs could improve LTBI detection,
Coleman et al 3
guide targeted therapy, and improve TB control in chil-
dren but due to financial constraints these investigators
did not recommend its routine use in low- and middle-
income countries. However, the study does support
using IGRA assays in children who are young, recently
exposed, and infected with HIV.27
Conclusion
Current guidelines for testing children younger than 5
years recognize the limitations of our current diagnostic
methodology. IGRAs assays are both more sensitive and
specific, but have the disadvantage of a large number of
indeterminate results in young children.
For children who require testing for illnesses where
tuberculosis is in the differential or for children who
require screening prior to transplantation we recom-
mend doing both an IGRA and TST so that the more
sensitive test is included and a result is available when
the IGRA assay is indeterminate. With discordant
results, the IGRA assay is preferred for making a treat-
ment decision. For children screened for adoption or
emigration, we suggest the TST alone.
Author Contributions
JLC researched the records and the literature, and wrote the
initial draft. BRH was responsible for reviewing and modifica-
tion of the article and additional research. RWS was responsi-
ble for identifying the need for the research as well as the
reviewing and modification of the article.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
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