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existing and novel) should be investigated as possible other, more specific, tests can confirm the presence of
triage tests for tuberculosis. These include biomarkers Mycobacterium tuberculosis. The most cost-effective and
whose concentrations are increased in patients affordable algorithm will depend on the setting and the
with tuberculosis to levels that can be measured characteristics of the population where it is intended
with point-of-care platforms, such as C-reactive to be applied, such as paediatric versus adult patients,
protein,9 procalcitonin,10 neopterin,11 and CXCL10 HIV status, or prevalence of drug resistance (and
(IP-10).12 Another candidate triage test is digital multidrug resistance). The development of a triage test
radiography with automated reading, which can be for tuberculosis with the desired characteristics8 poses
used to produce a tuberculosis probability score13 and substantial research challenges in many directions, but
has very low running costs. Nonetheless, all of the the potential benefits for health systems and patients
suggested candidates have potential shortcomings in countries with a high-burden of the disease merit the
with respect to attainable specificity for an optimised necessary investment and the sustained efforts of the
sensitivity. Ideally, the desired intrinsic performance scientific community.
characteristics of a tuberculosis triage assay would
include sensitivity higher than 95% of that of the *Alberto L García-Basteiro, Frank Cobelens
molecular assay used subsequently in the event of a Centro de Investigação em Saude de Manhiça, CP 1929 Maputo,
Mozambique (ALG-B); ISGlobal, Barcelona Centre for International
positive result. The desired specificity will depend on
Health Research, University of Barcelona, Barcelona, Spain (ALG-B);
the cost of the triage test and the setting in which Amsterdam Institute for Global Health and Development,
it is used (eg, in clinics vs community-based active Academic Medical Centre, Amsterdam, Netherlands (FC); and
case finding),7 but should generally not be lower KNCV Tuberculosis Foundation, The Hague, Netherlands (FC)
than 80% to justify the process of further diagnostic alberto.garcia-basteiro@manhica.net
investigation. Ideally, the triage test would have We declare no competing interests.
1 WHO. Global Tuberculosis Report 2014. Geneva: World Health
these characteristics for pulmonary tuberculosis in Organization, 2014.
adults and children.8 Validation studies are needed to 2 WHO. Rapid Implementation of the Xpert MTB / RIF diagnostic test.
Technical and operational ‘how-to’ practical considerations. Geneva: World
assess these and other candidate triage tests for their Health Organization, 2011.
diagnostic performance (in combination with one or 3 Lawn SD, Mwaba P, Bates M, et al. Advances in tuberculosis diagnostics: the
Xpert MTB/RIF assay and future prospects for a point-of-care test.
more confirmatory tests) against the gold standard. Lancet Infect Dis 2013; 13: 349–61.
In addition to good diagnostic performance and 4 Vassall A, van Kampen S, Sohn H, et al. Rapid diagnosis of tuberculosis with
the Xpert MTB/RIF assay in high burden countries: a cost-effectiveness
low price, implementation issues, such as electricity analysis. PLoS Med 2011; 8: e1001120.
requirements and temperature robustness, cannot 5 Choi HW, Miele K, Dowdy D, Shah M. Cost-effectiveness of Xpert® MTB/RIF
for diagnosing pulmonary tuberculosis in the United States.
be overlooked. Moreover, the use of candidate triage Int J Tuberc Lung Dis 2013; 17: 1328–35.
6 Storla DG, Yimer S, Bjune GA. A systematic review of delay in the diagnosis
tests will depend on whether they can be made easy and treatment of tuberculosis. BMC Public Health 2008; 8: 15.
to use (ideally by community health workers) with an 7 van’t Hoog AH, Cobelens F, Vassall A, et al. Optimal triage test
characteristics to improve the cost-effectiveness of the Xpert MTB/RIF
accessible clinical sample and able to provide results in assay for TB diagnosis: a decision analysis. PLoS One 2013; 8: e82786.
a short period of time. 8 WHO. High-priority target product profiles for new tuberculosis
diagnostics: report of a consensus meeting. Geneva: World Health
Candidate diagnostic tests for tuberculosis are in Organization, 2014.
various stages of research and development; some are in 9 Drain PK, Mayeza L, Bartman P, et al. Diagnostic accuracy and clinical role of
rapid C-reactive protein testing in HIV-infected individuals with presumed
proof-of-concept stages, whereas others have entered tuberculosis in South Africa. Int J Tuberc Lung Dis 2014; 18: 20–26.
validation, evaluation, or demonstration phases of 10 Huang S-L, Lee H-C, Yu C-W, et al. Value of procalcitonin in differentiating
pulmonary tuberculosis from other pulmonary infections: a meta-analysis.
development. Combinations of different biomarkers Int J Tuberc Lung Dis 2014; 18: 470–77.
11 Agranoff D, Fernandez-Reyes D, Papadopoulos MC, et al. Identification of
within a unique designed-locked assay would also need diagnostic markers for tuberculosis by proteomic fingerprinting of serum.
to be explored, particularly if this approach can increase Lancet 2006; 368: 1012–21.
12 Mihret A, Bekele Y, Bobosha K, et al. Plasma cytokines and chemokines
sensitivity without sacrificing specificity. When triage differentiate between active disease and non-active tuberculosis infection.
tests are developed and their diagnostic performances J Infect 2013; 66: 357–65.
13 Breuninger M, van Ginneken B, Philipsen RHHM, et al. Diagnostic accuracy of
are well characterised, they need to be assessed within computer-aided detection of pulmonary tuberculosis in chest radiographs: a
the overall tuberculosis diagnostic algorithm, in which validation study from sub-Saharan Africa. PLoS One 2014; 9: e106381.