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Tuberculosis Research Unit, Department of Respiratory Medicine, National Heart and Lung
Institute, Imperial College London, London, UK, and Department of Infectious Disease
Epidemiology, Imperial College London, London, UK
Areas of agreement: IGRAs are more specific than TST for diagnosis of LTBI as
they are not confounded by previous bacille Calmette-Guerin (BCG) vaccination.
Assessing IGRA sensitivity in the absence of a gold standard for LTBI is
challenging. Studies have therefore used surrogate markers such as active TB
and correlation with degree of TB exposure in contact investigations. These
studies suggest that sensitivity of ELISpot is higher than TST while whole-blood
ELISA has similar sensitivity to TST. Recent longitudinal studies demonstrating
the prognostic power of these tests for development of active TB provide
definitive evidence that positive IGRA results reflect infection with dormant yet
viable bacilli.
Areas of controversy: Is the prognostic power of IGRAs greater than the TST?
What are the false-negative rates in immunocompromised individuals with LTBI
at high risk of progressing to active TB?
Accepted: October 7,
2009
*Correspondence to: Ajit
Lalvani, Tuberculosis
Research Unit,
Department of
Respiratory Medicine,
National Heart and Lung
Institute, Imperial College
London, London, UK.
E-mail: a.lalvani@imperial.
ac.uk
& The Author 2009. Published by Oxford University Press. All rights reserved.
For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Introduction
Globally, tuberculosis (TB) continues to be one of the leading infectious causes of morbidity and mortality accounting for an estimated
9 million cases and 2 million deaths per year.1 This failure to adequately control the global epidemic may partly reflect the slow progress
that has been made, over the last century, in developing innovative
diagnostic tools for TB.2 However, the potential to significantly
advance TB control now exists with the development of novel diagnostic modalities for latent TB infection (LTBI).
71
72
HIV-seropositive individuals
73
of the ELISpot was higher than that for the TST and unaffected by
HIV infection, malnutrition and age under 3 years. Overall sensitivity
of ELISpot in children with culture confirmed, or highly probable, TB
was 83%, rising to 91% when combined with the TST.27 Conversely,
the TST alone had a sensitivity of only 36% in those with HIV infection. In a study looking at HIV-positive Zambian adults coinfected
with sputum smear-positive TB, ELISpot sensitivity was maintained at
92%.26 Subsequent studies with ELISpot have shown that the results
remain robust in HIV infection and independent of CD4 cell
count.27,29 31 Independent work by Clark et al.32 and Dheda et al.31
has found that CD4 cell counts do not affect the ELISpot performance
in HIV-positive individualsboth in terms of positivity and the frequency of indeterminate results.
However, the experience gained from using the ELISA in HIV-positive
individuals seems to be more inconsistent. Raby et al. 33 recently evaluated the ELISA in a cross-sectional study of Zambian adults with smearpositive TB, and found that the sensitivity of the ELISA in HIV-positive
individuals was 63%, which was significantly lower than the 84% sensitivity seen in HIV-negative individuals. In a South African study of
HIV-positive individuals comparing the IGRAs and TST in the diagnosis
of TB infection, the sensitivity of the ELISA (28%) was lower than that
for the ELISpot (61%) and the TST (41%).28 On the other hand,
Balcells et al.34 found that in HIV-positive adults the ELISA had a
higher positivity rate than the TST and correlated with TB exposure
whilst the TST did not. In addition, CD4 cell counts did not have an
adverse effect on ELISA results. However, other authors have found that
in advanced HIV where there are low CD4 cell counts, the performance
of the ELISA is compromised. Brock et al. 35 conducted a large crosssectional study of HIV-positive individuals in Denmark and found a significant association between low CD4 cell count and indeterminate
ELISA results. Subsequent studies have also confirmed that with declining CD4 count, false negative and indeterminate results become increasingly common, which may affect the diagnostic utility of the ELISA in
HIV-positive individuals.28,33,35,36
Specificity of IGRAs
75
the TST and IGRAs is, at best, fair in individuals with IMID and that
discordant TST-positive, IGRA-negative results are associated with prior
BCG vaccination.37 39 Conversely, recent work from Italy by Bartalesi
et al. 40 where individuals with IMID were screened for LTBI using the
ELISA and TST found a relatively higher concordance (k 0.55) and
less TST-positive, IGRA-negative discordancy, which possibly reflects
the low proportion of BCG-vaccinated individuals in their population.
Fewer studies have correlated IGRA and TST results in individuals
with IMID with risk factors for LTBI. In a study of 142 patients with
IMID, the ELISA was significantly more closely associated with the
presence of risk factors for LTBI than TST. In addition, a positive TST,
but not IGRA, was significantly associated with previous BCG vaccination.37 Martin et al.41 evaluated both IGRAs in individuals with
inflammatory arthritides and found that both the ELISpot and the
ELISA correlated with risk factors for LTBI. Data from a large Italian
study revealed that individuals who had been in close contact with
smear-positive TB patients were significantly more likely to have a
positive ELISA and TST result.40
On the basis of the current evidence, one can conclude that although
false-negative IGRA results may occur, the diagnostic sensitivity of
IGRAs is more robustly maintained than that of the TST in individuals
with IMID on immunosuppressive treatment.
their reliability. Indeterminate results occur for both IGRAs2 and can
arise for many reasons but the most significant cause is a failed positive
control that usually reflects underlying cellular immune suppression.
Studies suggest that indeterminate results are relatively common with
the ELISA occurring in 5240% of cases with the second-generation
ELISA but less frequently with the newer in tube ELISA.42 44
Indeterminate ELISA results seem to be associated with extremes of
age (under 5 and over 80) and immunosuppression, especially HIV
infection.35 In contrast, indeterminate results are rarer with the
ELISpot occurring in 0 5.4% of tests undertaken.45
Table 1: Currently published studies that have evaluated the prognostic value of the IGRAs.
Study population
Aichelburg
HIV adults
Country
Austria
Number
Progression
Progression
Progression
IGRA
follow up
of
to ATB of
to ATB of
to ATB of
prognostic
(years)
incident
cases
IGRA
contacts
TST
(5 mm)
TST
(10 mm)
contacts
contacts
3/36 (8)
Not
Not done
Yes
Period of
1.6
IGRA used
QFT-G in-tube
IGRA positive
44/783
TST (5 mm)
31/42 (74)
Not done
et al.50
reported
Household contacts:
adults
Germany
QFT-G in-tube
66/601 (11)
243/601 (40)
110/601 (18)
6/41 (15)
5/219 (2)
5/90 (6)
Yes
Bakir
Household contacts:
Turkey
1.3
ELISpot
381/908 (42)
550/908 (61)
462/908 (51)
15
11/381 (3)
12/550 (2)
6/462 (1)
Yes
et al.47
children
Hill et al.48
Household contacts:
children & adults
Gambia
ELISpot
649/1736 (37)
Not done
843/2230 (38)
26
11/649
(1.7%)
Not done
14/843 (1.7)
No
Doherty
Household contacts:
Ethiopia
ELISA (ESAT6
9/24 (38)
Not done
Not done
6/9 (67)
Not done
Not done
Yes
et al.49
adults
only)
77
Diel et al.46
As the evidence base for the performance of IGRAs expands, one can
conclude that both IGRAs are not confounded by BCG vaccination
and are therefore more specific than the TST in the diagnosis of LTBI.
In LTBI, both tests are more sensitive than the TST, with the ELISpot
having a higher sensitivity than the ELISA.24 In children, the ELISpot
seems to be superior to the TST whilst the sensitivity of the ELISA
appears to be comparable to the TST although the data are inconsistent. Whilst both tests are relatively robust in HIV infection, the
ELISpot seems to perform better than the ELISA with a higher sensitivity and a lower proportion of indeterminate results, particularly
when CD4 counts are low. In individuals with IMID undergoing
immunosuppressive therapy, the performance of the ELISpot and
ELISA seem to be equivalent.
are more expensive than the TST, health economic analyses have found
that they are cost-effective as they reduce the number of individuals
needing unnecessary chemoprophylaxis and monitoring whilst on drug
therapy.54,55 The United Kingdom National Institute of Health and
Clinical Excellence (NICE) economic analysis concluded that the
two-step TST and confirmatory IGRA approach would be the most
cost-effective model and this was the basis of the recommendations
made for the UK and most other European countries.52
One consequence of the European/Canadian recommendations is that
immunocompetent individuals who are TST negative but who may
have been IGRA positive may not be identified as having LTBI and
hence left untreated. In contrast, the US/Japanese guidelines may result
British Medical Bulletin 2010;93
79
Fig. 1 Algorithm of all possible outcomes resulting from parallel IGRA and TST testing.
Conclusions
IGRAs represent a new paradigm with the potential to supersede the
century old TST and, in the process, revolutionize the diagnosis, and
thereby targeted chemoprophylaxis, of LTBI. The evidence base supporting their use has expanded dramatically over the last few years
which has resulted in them becoming an important diagnostic tool in
low prevalence settings. However, guidelines vary between countries,
which is likely to reflect some underlying uncertainty about the prognostic value of a positive IGRA result. As a consequence there is an
urgent need for further large, longitudinal studies to explicitly define
the prognostic value of positive IGRA results for the development of
active TB disease, particularly in high-risk groups and subgroups with
discordant IGRA and TST results. Data of this type would provide
80
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