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Meeting Summary
Workshop on T-Cell Based Diagnosis of Latent
Tuberculosis Infection in Resource-Limited
Settings
Co-organized by FIND and WHO on Behalf of the
Stop TB Working Group on New Diagnostics
16-17 March 2006, Geneva, Switzerland
Meeting
summary contributed by: Madhukar Pai, MD, PhD,
Keertan Dheda, MB Bch, FCP(SA), PhD, Jane
Cunningham, MD, Fabio Scano, MD, and Richard
O’Brien, MD [Meeting Chair]
An estimated one third of the world’s
population is infected with Mycobacterium
tuberculosis. This enormous pool of
individuals with latent tuberculosis infection (LTBI)
poses a major hurdle for tuberculosis (TB)
elimination. Treatment of persons with LTBI,
including those with HIV coinfection,
effectively reduces the risk of progression from
LTBI to active disease, but there is currently
no accurate tool to predict which latently
infected individuals are at greatest risk of
disease progression. For nearly a century, the
tuberculin skin test (TST) was the only tool
available for the detection of LTBI. Although
the TST has proven to be useful in clinical
practice, it has known limitations in accuracy
and reliability.
A major breakthrough in recent years has been
the development of in vitro assays that
measure T cell release of interferon-γ
(IFN-γ) in
response to stimulation with highly TB-specific
antigens. In contrast, TST is reliant upon
cellular immune response to purified protein
derivative (PPD), a crude mixture of proteins
from heat-killed M. tuberculosis. Within a short
span of time, two IFN-γ release assays (IGRAs)
have become commercially available: the
QuantiFERON-TB Gold® (Cellestis Ltd, Carnegie,
Australia) assay and the TSPOT.TB® test (Oxford
Immunotec, Oxford, UK).
With the availability of standardized IGRAs,
there is great interest in using these assays in
variety of settings. Current evidence suggests
IGRAs have higher specificity than TST, better
correlation with surrogate markers of exposure
to M. tuberculosis in low incidence
settings, and less cross-reactivity due to BCG
vaccination and sensitization by non-tuberculous
mycobacteria (NTM) than the TST. IGRAs also
appear to be at least as sensitive as the TST
for active TB (used as a surrogate for LTBI). In
the absence of a gold standard for LTBI
diagnosis, sensitivity and specificity for LTBI
cannot be directly estimated. Besides high
specificity, other potential advantages of IGRAs
include logistical convenience, need for fewer
patient visits to complete testing, avoidance of
unreliable, and somewhat subjective,
measurements such as skin induration, and the
ability to perform serial testing without
inducing the boosting phenomenon. Overall,
because of its high specificity and other
potential advantages, IGRAs are likely to
replace the TST in low-incidence, high income
settings where crossreactivity due to BCG might
adversely impact the interpretation and utility
of the TST.
The body of literature supporting the use of
IGRAs has rapidly expanded. However, despite a
growing evidence base, several unresolved and
unexplained issues remain. These include
unexplained discordance between the TST and
IGRAs results, ill-defined correlation between
bacterial burden and T cell responses, unknown
predictive value of IGRAs for the development of
active TB, insufficient data on test performance
in high-risk populations such as children and
individuals with HIV infection, inadequate
information on IGRA performance in serial
testing, and lack of evidence on the utility of
IGRAs in epidemiologic studies. Scientific
knowledge gaps are matched by the paucity of
data pertaining to the feasibility,
applicability, cost effectiveness, and potential
utility of these assays in high incidence and
resource limited settings.
An international effort is required to
address knowledge gaps efficiently, and, to this
end, an expert group was assembled in Geneva
(March 2006) by the Stop TB Working Group on New
Diagnostics. The meeting was co-organized by the
Foundation for Innovative New Diagnostics
(FIND), and the World Health Organization (WHO)
for the Working Group. The group was charged
with reviewing the research evidence supporting
the use of IGRAs, their clinical utility, their
limitations, and directions for future research,
with a specific focus on resource-limited
settings. The overarching goal was to move the
field forward by identifying critical areas for
research and implementation.
Based on two days of presentations and
discussions (view
workshop presentations), a comprehensive
research agenda was generated which will propel
the field forward by stimulating focused,
high-impact research, and encourage the
investment of resources needed to tackle
priority research questions especially in
resource-limited settings. The research agenda
included key questions grouped under seven
domains: 1) biologic issues and assay
development; 2) test performance in high risk
populations and poorly studied groups; 3) risk
prediction and modeling; 4) reproducibility and
serial testing; 5) T cell responses during
treatment and role in treatment monitoring; 6)
epidemiologic and field applications; and 7)
health systems, operational and economic
research. Download a slide presentation of the key
research questions pdf 65kb. A comprehensive
report based on the research agenda has been
submitted for publication. Once published, this
document will be widely disseminated.
In summary, the emergence of novel tools,
such as IGRAs, is a welcome development,
because, for the first time, these assays have
expanded the armamentarium of diagnostics
available for LTBI. The expert group that met in
Geneva has made an important contribution by
helping to develop a comprehensive research
agenda which will move the field forward. The
agenda provides a comprehensive compilation of
key research questions that deserve attention to
ensure appropriate and optimal use of LTBI
diagnostics in TB control, especially in the
context of the HIV epidemic. The agenda will
advance the field by stimulating focused,
high-impact research, and by engaging a wider
network of researchers and institutions. It
should also encourage the investment of
resources needed to tackle research questions of
high importance and potential impact, especially
in resource limited settings with high TB and
HIV burden. Ultimately, if adequately financed,
the research findings will inform appropriate
use of novel LTBI diagnostics in global TB
control.
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