Madhukar Pai⁎

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EBioMedicine 2 (2015) 182–183
Contents lists available at ScienceDirect
EBioMedicine
j ourna l homepage: www.eb iomed ic ine.comIn FocusInnovations in Tuberculosis Diagnostics: Progress and
Translational ChallengesMadhukar Pai⁎
McGill Global Health Programs, McGill International TB Centre, McGill University, Montreal, Quebec, CanadaDespite the long and hard battle against tuberculosis (TB), WHO es- analysis of the TB R&D funding landscape by Treatment Action Group
timated that 9million people developed the disease in 2013, and nearly
1.5 million people died of TB (World Health Organization, 2014). To
make matters worse, drug-resistance is a growing threat, and 3 out of
9 million TB cases are either not diagnosed, or not notified to TB control
programs.
But there is some good news from the perspective of new tool intro-
duction. Slowly but surely, the landscape of TB technologies is changing
(Pai and Schito, 2015).We nowhave a variety of new TBdiagnostics, in-
cluding rapidmolecular tests (e.g. XpertMTB/RIF, Cepheid Inc., USA) for
detection as well as drug susceptibility testing (DST) (UNITAID, 2014).
We also have new TB drugs (e.g. bedaquiline and delamanid) on the
market, and new TB drug regimens are expected within the next
2–3 years. These are major, exciting developments in the fight against
a very ancient scourge.
This article reviews the current best diagnostic tools available for TB
diagnosis and monitoring, and describes the most important gaps, and
translational challenges for developing innovative products that can
meet the needs (Table 1).
As shown in the Table, there are critical unmet needs that range from
a simple, triage test for use in the community, to DST tools that can de-
tect a range of mutations for several important drugs that will make up
future drug regimens (Denkinger et al., 2015a,b). For the next-
generation DST tools, a big translational challenge is the paucity of
good data on the correlation of mutations with phenotypic DST results
and clinical outcomes and the association with cross-resistance
(Solomon et al., 2015). This is particularly important to make sure that
we have companion diagnostics for emerging TB drug regimens
(Denkinger et al., 2015b). The translational challenges associated with
DST are reviewed elsewhere (Solomon et al., 2015).
For the development of rapid triage tests, non-sputum based tests
for active TB, highly predictive LTBI tests, and an accurate test for cure,
we need validated biomarkers. Although considerable efforts are being
made to identify biomarkers that can meet some of these needs, prog-
ress has been slow, and the translational challenges have been reviewed
elsewhere (Wallis et al., 2010).
Increased investments are necessary to support biomarker discov-
ery, validation, and translation into clinical tools. Unfortunately, a recent⁎ Dept of Epidemiology & Biostatistics, 1020 Pine Ave West, Montreal, QC H3A 1A2,
Canada.
E-mail address: madhukar.pai@mcgill.ca.
http://dx.doi.org/10.1016/j.ebiom.2015.01.018
2352-3964/© 2015 The Author. Published by Elsevier B.V. This is an open access article undershowed a big gap between investment needed and actual expenditure
on R&D. Donors, governments, andmembers of the Stop TB Partnership
will need to device creative strategies to plug this gap.
While the TB diagnostics R&D space has managed to attract over 50
companies and product developers, they will require technical and
funding support to overcome the translational challenges shown in
Table 1. Organizations such as Foundation for Innovative New Diagnos-
tics (FIND), Geneva, Bill and Melinda Gates Foundation, World Health
Organization, UNITAID, Global Laboratory Initiative, Stop TB
Partnership's New Diagnostics Working Group, Critical Path Institute,
PATH, McGill International TB Centre, and several academic partners
have worked together to produce several reports that are of great rele-
vance, including a technology and market landscape report, a needs as-
sessment study, a consensus report on target product profiles of highest
priority, a series of market analyses, and a series of articles which out-
line the characteristics of the next-generation assays, and translational
challenges for product development. All of these are available on a
website (www.tbfaqs.org) created to provide answers to the most fre-
quently asked questions by TB product developers. Hopefully, these col-
lective efforts will result in a more robust pipeline of tools that can
overcome the translational challenges, and push the agenda towards
the goal of TB elimination.
Disclosures
The author has no financial or industry conflicts to disclose. He
serves as a consultant to the Bill and Melinda Gates Foundation, and
on the scientific advisory committee of the Foundation for Innovative
New Diagnostics (FIND), Geneva.
References
Barry III, C.E., Boshoff, H.I., Dartois, V., et al., 2009. The spectrum of latent tuberculosis: re-
thinking the biology and intervention strategies. Nat. Rev. Microbiol. 7 (12), 845–855.
Denkinger, C.M., Kik, S.V., Cirillo, D., et al., 2015a. Defining the needs for next generation
assays for tuberculosis. J. Infect. Dis. 211 (S2), S29–S38.
Denkinger, C.M., Dolinger, D., Schito, M., et al., 2015b. Molecular drug susceptibility test-
ing — defining assay characteristics for the use at the level of the microscopy center.
J. Infect. Dis. 211 (S2), S39–S49.
Foundation for Innovative New Diagnostics, 2014. Strategy for Tuberculosis (and lower
respiratory tract infections) 2015–2020. in: FIND Geneva, ed. FIND, Geneva.
Pai, M., Schito, M., 2015. Tuberculosis diagnostics in 2015: landscape, priorities, needs,
and prospects. J. Infect. Dis. 211 (S2), S21–S28.the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Table 1
Unmet needs in TB diagnosis and monitoring.
Indication for testing Currently used tools Limitations of existing tools Desirable new tools (key
references)
Translational challenges for
new tool development (key
references)
Triage test to identify
individuals with
presumed TB who need
confirmatory testing
1. TB symptoms (e.g. 2 weeks
of cough)
2. Chest x-rays
1. Symptoms lack sensitivity and
specificity, especially in HIV-infected
populations and children
2. Chest x-rays are sensitive, but not
specific for TB
A simple, low cost triage test
for use by first-contact care
healthcare providers as a
rule-out test, ideally suitable
for use by community health
workers (Denkinger et al.,
2015a)
Lack of validated biomarkers
(Foundation for Innovative
New Diagnostics, 2014).
Diagnosis of active
pulmonary TB
1. Sputum smear microscopy
2. Nucleic acid amplification
tests (NAAT)
3. Cultures
1. Smear microscopy lacks sensitivity
and cannot detect drug resistance.
2. NAAT are expensive and not easily
deployable at the peripheral level.
3. Cultures are expensive and require
BSL3 labs, and results take time.
A sputum-based replacement
test for smear-microscopy; A
non-sputum-based biomarker
test for all forms of TB, ideally
suitable for use at levels below
microscopy centers
(Denkinger et al., 2015a)
While several NAATs are being
developed for microscopy
centers, they will need to be
evaluated in field conditions
for policy. For the non-sputum
TB test, the biggest challenge is
the lack of validated
biomarkers (UNITAID, 2014;
Denkinger et al., 2015a;
Foundation for Innovative
New Diagnostics, 2014).
Diagnosis of
extrapulmonary (EPTB)
and childhood TB
1. Smear microscopy
2. Nucleic acid amplification
tests
3. Cultures
1. Children and patients with EPTB often
do not produce sputum. Invasive
samples are usually necessary. Smear
microscopy lacks sensitivity and can-
not detect drug resistance.
2. NAAT are expensive and not easily
deployable at the peripheral level.
Sensitivity in EPTB samples is lower
than sputum.
3. Cultures are expensive and require
BSL3 labs, and results take time.
A non-sputum-based
biomarker test for all forms of
TB, ideally suitable for use at
levels below microscopy
centers (Denkinger et al.,
2015a)
For the non-sputum TB test,
the biggest challenge is the
lack of validated biomarkers
(Foundation for Innovative
New Diagnostics, 2014).
Drug susceptibility testing 1. Nucleic acid amplification
tests
2. Cultures
1. Current NAATs cannot reliably detect
all mutations and sensitivity for drugs
other than rifampicin is poor.
2. Cultures are expensive and require
BSL3 labs, and results take time.
A newmolecular DST for use at
a microscopy center level,
which can evaluate for
resistance to rifampin,
fluoroquinolones, isoniazid
and pyrazinamide and enable
the selection of the best drug
regimen (Denkinger et al.,
2015b).
Lack of good data on the
correlation of mutations with
phenotypic results and clinical
outcomes and the association
with cross-resistance
(Denkinger et al., 2015b;
Solomon et al., 2015). There is
also a need to align emerging
TB drug regimens with
companion diagnostics
(Denkinger et al., 2015b).
Diagnosis of latent TB
infection (LTBI)
1. Tuberculin skin test (TST)
2. Interferon-gamma release
assays (IGRA)
Neither TST nor IGRA can separate latent
infection from active disease. Neither test
can accurately identify those at highest
risk of progression to active disease.
A test that can resolve the
spectrum of TB, and identify
the subset of latently infected
individuals who are at highest
risk of progressing to active
disease, and will benefit from
preventive therapy (Pai et al.,
2014; Barry et al., 2009).
Lack of validated biomarkers
(Pai et al., 2014; Barry et al.,
2009).
Test of cure (treatment
monitoring)
1. Serial smear microscopy
2. Serial cultures
1. Smears lack sensitivity, and cannot
distinguish between live and dead
bacilli.
2. Serial cultures are expensive and
time-consuming.
An accurate test for cure that
can be used to make changes
in management (e.g. changes
in regimens, or DST) (Wallis
et al., 2010).
Lack of validated biomarkers
(Wallis et al., 2010).
183M. Pai / EBioMedicine 2 (2015) 182–183Pai, M., Denkinger, C.M., Kik, S.V., et al., 2014. Gamma interferon release assays for detec-
tion of Mycobacterium tuberculosis infection. Clin. Microbiol. Rev. 27, 3–20.
Solomon, H., Yamaguchi, K.D., Cirillo, D., et al., 2015. Integration of published information
into a resistance-associated mutation database for mycobacterium tuberculosis.
J. Infect. Dis. 211 (S2), S50–S57.
UNITAID, 2014. Tuberculosis: Diagnostics Technology and Market Landscape, 3rd edition,
in: Secretariat U., ed., WHO, Geneva, pp. 1–42.Wallis, R.S., Pai, M., Menzies, D., et al., 2010. Biomarkers and diagnostics for tuberculosis:
progress, needs, and translation into practice. Lancet 375, 1920–1937.
World Health Organization, 2014. Global Tuberculosis Report 2014. WHO, Geneva,
pp. 1–289.


In Focus Innovations in Tuberculosis Diagnostics: Progress and Translational Challenges

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In Focus Innovations in Tuberculosis Diagnostics: Progress and Translational Challenges

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