Advances in the Diagnosis of Pulmonary Tuberculosis in HIV-Infected and HIV-Uninfected Children
Tom G. Connell
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Heather J. Zar
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Mark P. Nicol
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of Clinical Laboratory Sciences, Institute for Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, National Health Laboratory Service of South Africa IIDMM, University of Cape Town
, Anzio Rd, Observatory, Cape Town, 7925,
South Africa
The identification of improved diagnostic tests for tuberculosis has been identified as a global research priority. Over the past decade, there has been renewed interest in the development and validation of novel diagnostic tools for pulmonary tuberculosis that are applicable to resource-poor settings. These techniques are aimed primarily at improving detection of the organism or a specific host immune response. Although most studies have focused on determining the accuracy of novel tests in adults, it is likely they will also have the capacity to significantly improve the diagnosis of childhood tuberculosis. Improving the quality of clinical samples obtained from children with suspected tuberculosis remains an important research priority while awaiting validation of novel diagnostic tests. This review will focus on a number of recent developments for the diagnosis of tuberculosis, with a specific emphasis on the application of these new tests to children in settings where tuberculosis is endemic.
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achieved. First, it is difficult to obtain representative
samples because young children are usually unable to
expectorate, and extrapulmonary sites may be less
accessible for sample obtainment. Second, because
cavitary disease is unusual in younger children, results of
smear microscopy are often negative, and mycobacterial
culture is required.
In routine practice, in high-burden settings, clinicians
seldom wait for the results of culture to be available
before starting tuberculosis therapy in a child for whom
the diagnosis is suspected [3]. This is because of a
reluctance to delay therapy in children who may have
rapidly progressive illness and also because the
sensitivity of culture for diagnosis of tuberculosis in children
is thought to be poor; thus, a negative culture result
cannot be used as a rule-out test.
In this context, there is an urgent need for improved
diagnostic algorithms and rapid and sensitive
laboratory tests for tuberculosis in children. This review
will focus on a number of advances in diagnosis of
pediatric pulmonary tuberculosis in recent years that
have resulted in incremental progress and will also
highlight recent advances in the diagnosis of adult
tuberculosis that are currently undergoing evaluation in
children.
CLINICAL AND RADIOLOGICAL DIAGNOSIS OF
CHILDHOOD TUBERCULOSIS IS FREQUENTLY
UNRELIABLE
The clinical presentation of pulmonary tuberculosis in
childhood is often nonspecific, and the history of illness may be acute
[2]. There is considerable subjectivity in the interpretation of
radiological findings, particularly hilar lymphadenopathy [4].
These challenges are particularly acute in children infected with
human immunodeficiency virus (HIV) [2] in the context of
which other opportunistic infections may present with
overlapping clinical and radiological findings.
Because childhood tuberculosis typically occurs in
resourcepoor settings, where access to highly trained health professionals
is restricted, scoring systems have been developed to improve
diagnostic accuracy. Such systems usually combine clinical and
radiological evidence of disease, with a history of tuberculosis
exposure or a positive tuberculin skin test (TST) result. There is
considerable literature describing the performance of such
systems; however, many systems are poorly validated, may not be
generalizable to different epidemiological settings, and are not
adapted for use in HIV-infected children [5]. A recent
evaluation of 9 structured scoring systems clearly reveals the problem
[6]. The proportion of 1445 children with suspected tuberculosis
who were assigned a tuberculosis diagnosis by the 9 different
systems varied from 6.9% to 89.2%. Agreement between these
systems was slight, with a median pairwise j statistic of 0.18.
Although such systems may be useful when designed for and
validated in particular epidemiological settings [2], caution
should be exercised when generalizing the validity of a particular
system.
MICROBIOLOGIC CONFIRMATION OF DISEASE
IS CHALLENGING
Microbiologic confirmation of tuberculosis in children by
culture has not been part of routine care in high-burden settings
because of the unavailability of facilities, the difficulty in
obtaining samples, the poor performance of smear microscopy,
and the perception that microbiologic yield is low. However,
several studies have now confirmed that microbiologic
confirmation is feasible and useful to exclude drug-resistant
tuberculosis [3]. In areas with high HIV and tuberculosis coinfection,
confirmation is particularly valuable, because treatment of both
infections is associated with pill burden and complex drug
interactions. For examp (...truncated)