International Journal of Mycobacteriology x x x ( 2 0 1 6 ) x x x –x x x

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journal homepage: www.elsevier.com/locate/IJMYCO

Benefits and challenges of molecular diagnostics

for childhood tuberculosis

Cristina Gutierrez 1
Molecular Diagnostics for Childhood Tuberculosis, Avenida Hispanidad 85-5E 36203 Vigo, Spain

A R T I C L E I N F O A B S T R A C T

Article history: Expanding tuberculosis (TB)-diagnostic services, including access to rapid tests, is a World
Received 24 August 2016 Health Organization (WHO) strategy to accelerate progress toward ending TB. Faster and
Accepted 27 August 2016 more sensitive molecular tests capable of diagnosing TB and drug-resistant TB have the
Available online xxxx technical capacity to address limitations associated with smears and cultures by increasing
accuracy and shortening turnaround times as compared with those of these conventional
Keywords: laboratory methods. Nucleic acid amplification assays used to detect and analyze Mycobac-
Tuberculosis terium tuberculosis (MTB)-complex nucleic acids can be used directly on specimens from
Childhood patients suspected of having TB. Recently, several commercial molecular tests were devel-
Diagnosis oped to detect MTB and determine the drug resistance (DR) based on detection of specific
genetic mutations conferring resistance. The first to be endorsed by the WHO was molec-
ular line-probe assay technology. This test uses polymerase chain reaction (PCR) and
reverse-hybridization methods to rapidly identify MTB and DR-related mutations simulta-
neously. More recently, the WHO endorsed Xpert MTB/RIF, Cepheid Inc, CA, USA, a fully
automated assay used for TB diagnosis that relies upon PCR techniques for detection of
TB and rifampicin resistance-related mutations. Other promising molecular TB assays
for simplifying PCR-based testing protocols and increasing their accuracy are under devel-
opment and evaluation.
Although we lack a practical gold standard for the diagnosis of childhood TB, its bacteri-
ological confirmation is always recommended to be sought whenever possible prior to a
diagnostic decision being made. Conventional diagnostic laboratory TB tests are less effi-
cient for children as compared with adults, because sufficient sputum samples are more
difficult to collect from infants and young children, and their disease is often paucibacil-
lary, resulting in smear-negative disease. These inherent challenges associated with child-
hood TB are due to immunological- and pathophysiological-response differences relative to
those observed in adults. Several recent meta-analyses showed low sensitivity estimates of
PCR-based TB assays for paucibacillary forms of TB (extrapulmonary TB and smear-
negative pulmonary disease), which represent the vast majority of childhood TB cases.
Despite the lack of evidence regarding use of the rapid molecular assays to identify TB
and detect DR in children, and due to the clinical nature of childhood TB, TB-expert groups
recommend including rapid methods for TB identification and DR detection in diagnostic
algorithms for children suspected of both smear-positive and -negative pulmonary or
extrapulmonary TB, both with or without human immunodeficiency virus (HIV)-
coinfection, when combined with standard methods (including clinical, microbiological,

1
Tel.: +34 664 381 246.
E-mail address: crisgupe1@gmail.com
Peer review under responsibility of Asian African Society for Mycobacteriology.
http://dx.doi.org/10.1016/j.ijmyco.2016.08.011

Please cite this article in press as: C Gutierrez. Benefits and challenges of molecular diagnostics for childhood tuberculosis. Int. J. Mycobacteriol.
(2016), http://dx.doi.org/10.1016/j.ijmyco.2016.08.011
2 International Journal of Mycobacteriology x x x ( 2 0 1 6 ) x x x –x x x

and radiological assessment) for diagnosing active TB and conventional DR. Since 2011, the
WHO has specifically recommended use of the Xpert MTB/RIF test as an initial diagnostic
tool for children with suspected HIV-associated TB or multidrug-resistant TB based on
successful treatment data related to adults.
Implementation of the rapid molecular assays for rapid detection of TB and DR should
occur in laboratories with proven capability to run molecular tests and where quality
control systems are implemented. Molecular approaches should be more largely tested
in children, given their status as the group in whom the diagnostic dilemma is most
pronounced. These tests should also be included in specific childhood TB diagnostic
algorithms adapted to the local/national context in combination with other strategies for
improving diagnostics, including more effective specimen collection.

Conflicts of interest

None.

Please cite this article in press as: C Gutierrez. Benefits and challenges of molecular diagnostics for childhood tuberculosis. Int. J. Mycobacteriol.
(2016), http://dx.doi.org/10.1016/j.ijmyco.2016.08.011