Comment
Triage tests: a new priority for tuberculosis diagnostics
Tuberculosis remains a global health concern and
the roll out of new diagnostics in the countries most
affected is key to accelerate control of the disease
and find the up to 3 million cases that are not being
diagnosed or notified.1 In the past decade, substantial
progress has been made with tuberculosis diagnostics,
with many candidates entering the pipeline of
clinical development. WHO has endorsed the Xpert
MTB/RIF assay, a rapid within-cartridge PCR-based
test for the diagnosis of pulmonary tuberculosis
(from sputum specimens) and some forms of
extrapulmonary tuberculosis.2 The higher sensitivity
of the assay for tuberculosis diagnosis compared
with smear microscopy (especially for patients with
tuberculosis and HIV infection) and its ability to
detect resistance to rifampicin, a reliable marker of
multidrug-resistant tuberculosis, have led to the rapid
adoption of Xpert MTB/RIF by countries around the
world3—108 countries by June, 2014.1
Although the Xpert MTB/RIF assay undoubtedly
constitutes a major breakthrough in tuberculosis
diagnosis, it does not fulfill its potential to substantially
increase tuberculosis case finding. Although economic
assessments have shown that the replacement of
traditional smear examination with the Xpert MTB/
RIF assay or similar molecular technologies would
be a cost-effective intervention in high-burden and
low-burden settings,4,5 affordability remains a serious
concern, particularly for the low-income countries
that have the highest disease incidence. Consequently,
many countries restrict use of the Xpert MTB/RIF assay
to patients with HIV infection or suspected multidrug-
resistant tuberculosis, or make it available only at
specialised tuberculosis services. The assay is not truly
designed for point of care and is too expensive for health
systems and patients in many countries with a high
burden of tuberculosis. It thus seems unlikely to become
used universally as a first-line test for all presumptive
tuberculosis cases. Neither will the assay, used in this
way, help to reduce the long delays in the diagnosis
and treatment of tuberculosis, which often result when
patients are unable to access tuberculosis services after
repeated visits at the same health-care level (usually
the most peripheral one).6 Similar molecular assays with
similar costs will face the same issue.
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Therefore, researchers need to develop alternative
diagnostic approaches to improve the use and
affordability of the available tests. A triage strategy
would be one such approach: if an inexpensive point-
of-care test (the triage test) is positive, health-care
workers would then use a more expensive and more
specific molecular test (the confirmatory test); if the
triage test is negative, it would be interpreted as
ruling out tuberculosis. The sensitivity of the triage
test would be maximised at the expense of specificity,
whereas its specificity would be a trade-off with cost.
Such a strategy would improve the diagnostic process
by ruling out tuberculosis for most presumptive
cases tested at a point-of-care level (who do not have
the disease) and by increasing access to diagnosis
because only patients with a high likelihood of having
tuberculosis—testing positive to the triage test—would
be referred (either physically or by transported sputum
specimen) for subsequent, more expensive testing at
specialist tuberculosis services. Thus, this approach
could greatly reduce costs for the health system and
patients.7 On April 28–29, 2014, in Geneva, Switzerland,
an international forum of tuberculosis experts,
researchers, assay developers, and donors identified a
triage test as one of four high-priority target product
profiles to guide the development of new diagnostics
for tuberculosis.8
No established triage tests for tuberculosis exist
at present. However, several candidate tests (both
Mehau Kulyk/Science Photo Library
177
 Comment
existing and novel) should be investigated as possible
triage tests for tuberculosis. These include biomarkers
whose concentrations are increased in patients
with tuberculosis to levels that can be measured
with point-of-care platforms, such as C-reactive
protein,9 procalcitonin,10 neopterin,11 and CXCL10
(IP-10).12 Another candidate triage test is digital
radiography with automated reading, which can be
used to produce a tuberculosis probability score13 and
has very low running costs. Nonetheless, all of the
suggested candidates have potential shortcomings
with respect to attainable specificity for an optimised
sensitivity. Ideally, the desired intrinsic performance
characteristics of a tuberculosis triage assay would
include sensitivity higher than 95% of that of the
molecular assay used subsequently in the event of a
positive result. The desired specificity will depend on
the cost of the triage test and the setting in which
it is used (eg, in clinics vs community-based active
case finding),7 but should generally not be lower
than 80% to justify the process of further diagnostic
investigation. Ideally, the triage test would have
these characteristics for pulmonary tuberculosis in
adults and children.8 Validation studies are needed to
assess these and other candidate triage tests for their
diagnostic performance (in combination with one or
more confirmatory tests) against the gold standard.
In addition to good diagnostic performance and
low price, implementation issues, such as electricity
requirements and temperature robustness, cannot
be overlooked. Moreover, the use of candidate triage
tests will depend on whether they can be made easy
to use (ideally by community health workers) with an
accessible clinical sample and able to provide results in
a short period of time.
Candidate diagnostic tests for tuberculosis are in
various stages of research and development; some are in
proof-of-concept stages, whereas others have entered
validation, evaluation, or demonstration phases of
development. Combinations of different biomarkers
within a unique designed-locked assay would also need
to be explored, particularly if this approach can increase
sensitivity without sacrificing specificity. When triage
tests are developed and their diagnostic performances
are well characterised, they need to be assessed within
the overall tuberculosis diagnostic algorithm, in which
178
other, more specific, tests can confirm the presence of
Mycobacterium tuberculosis. The most cost-effective and
affordable algorithm will depend on the setting and the
characteristics of the population where it is intended
to be applied, such as paediatric versus adult patients,
HIV status, or prevalence of drug resistance (and
multidrug resistance). The development of a triage test
for tuberculosis with the desired characteristics8 poses
substantial research challenges in many directions, but
the potential benefits for health systems and patients
in countries with a high-burden of the disease merit the
necessary investment and the sustained efforts of the
scientific community.
*Alberto L García-Basteiro, Frank Cobelens
Centro de Investigação em Saude de Manhiça, CP 1929 Maputo,
Mozambique (ALG-B); ISGlobal, Barcelona Centre for International
Health Research, University of Barcelona, Barcelona, Spain (ALG-B);
Amsterdam Institute for Global Health and Development,
Academic Medical Centre, Amsterdam, Netherlands (FC); and
KNCV Tuberculosis Foundation, The Hague, Netherlands (FC)
alberto.garcia-basteiro@manhica.net
We declare no competing interests.
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