INT J TUBERC LUNG DIS 16(4):492495

2012 The Union

http://dx.doi.org/10.5588/ijtld.11.0416
Published online 8 February 2012
SHORT COMMUNICATION
Development of tuberculosis in immunocompromised patients
with a positive tuberculosis-specific IGRA
B. Lange,*

M. Vavra,* W. V. Kern,* D. Wagner*

*

Center for Infectious Diseases and Travel Medicine, and

IFBCenter for Chronic Immunodeficiency, University
Hospital Freiburg, Freiburg, Germany
Correspondence to: B Lange, Hugstetter Str. 55, 79106 Freiburg, Germany. Tel: (+49) 761 270 18190. Fax: (+49) 761 270
18200. e-mail: berit.lange@uniklinik-freiburg.de
Article submitted 16 June 2011. Final version accepted 18 October 2011.
There is a lack of data on the predictive value of tuber-
culosis (TB) specific interferon-gamma release assays
(TIGRAs) for both immunocompetent and immuno-
compromised individuals. We retrospectively followed
up 460 such patients after QuantiFERON

-TB Gold In-

Tube (QFT-GIT) testing (mean follow-up 28 months)
by reviewing patient charts. A total of 1/38 QFT-GIT-
positive and no QFT-GIT-negative patients developed
active TB. The incidence rate of progression to active
TB assessed retrospectively in these patients after posi-
tive TIGRA was therefore low (1.2 events/100 person-
years). The need for careful follow-up and prophylactic
therapy after positive TIGRA in this patient group needs
to be evaluated prospectively.
KEY WORDS: tuberculosis; interferon-gamma release
a ssay; risk of progression
TUBERCULOSIS (TB) specifc interferon-gamma
(IFN-) release assays (TIGRAs) have recently been
established as an alternative to the tuberculin skin
test (TST) for the diagnosis of latent TB.
1,2
Previous
meta-analyses have shown high specifcity for active
TB; however, in a recent meta-analysis, specifcity for
active TB, including studies with suspects of TB, was
actually lower than previously thought, especially for
the TB-specifc ELISPOT assay (T-SPOT

.TB, Oxford
Immunotec, Oxford, UK).
3
There are few data on the
positive and negative predictive value of TIGRAs or
on the incidence of progression to active TB (IPTB) in
immunocompetent patients, and even fewer data on
immunocompromised patients, although these are
most at risk for TB reactivation.
411
We retrospec-
tively analysed patients with different conditions of
immunosuppression known to increase TB risk after
TIGRA testing, and determined TB status to deter-
mine IPTB by patient chart review. The analysis of
risk factors for indeterminate results for these pa-
tients has been presented previously.
12
After obtaining ethical approval from the local
ethics committee, 460 immunocompromised patients
were enrolled from 2006 to 2007 at University Hos-
pital Freiburg, Freiburg, Germany, and tested with
the third generation Quanti FERON

-TB Gold In-

Tube assay (QFT-GIT; Cell estis, Carnegie, VIC, Aus-
tralia) according to the manufacturers instructions.
Patients were followed at regular intervals at the out-
patient clinics of their respective departments.
Demographic data, disease groups, history of TB
and patients lost to follow-up are recorded in Table 1.
Retrospective chart follow-up was performed in Oc-
tober 2010. Retrospective follow-up time was calcu-
lated as the time between QFT-GIT testing and the last
chart entry in any of the university hospital depart-
ments. All charts were screened for diagnosis of TB,
as well as clinical signs suggestive of TB. The IPTBs
were calculated in events/100 person-years (py).
The mean retrospective follow-up time in the 460
patients was 28 months. Of these, 38 (8.3%) had
positive QFT-GIT results that were predicted by older
age on multivariate analysis. One QFT-GIT-positive
patient received anti-tuberculosis treatment for sus-
pected tuberculous sialoadenitis immediately follow-
ing the QFT-GIT. No material was sent for culture,
and symptoms did not resolve with standard anti-
tuberculosis treatment.
One German-born human immunodefciency virus
positive patient (CD4 count 202 cells/l, viral load
>500 000/ml) with a positive QFT-GIT, no indica-
tion of active TB, and who was not given preventive
treatment at the time of QFT-GIT testing, was diag-
nosed with culture-proven lymph-node TB 1 year later.
No QFT-GIT-negative or QFT-GIT-indeterminate pa-
tients were diagnosed with TB during the follow-up
period. The IPTB after positive TIGRA, assessed retro-
spectively (including only the culture-proven case), was
1.2/100 py (95% confdence interval 03.3; Table 1).
Immunocompromised patients are at high risk for
progression from latent to active TB. The present study
presents the frst analysis of IPTB after QFT-GIT
S U MMA R Y
Active TB with a positive IGRA 493
testing in this patient group. In this study, the IPTB
a fter positive TIGRA was low, at 1.2/100 py, and
might be underestimated by the retrospective design.
The IPTB in HIV- and QFT-GIT-positive patients
(mean CD4 count 402 cells/l) followed prospec-
tively in Austria was reported to be 5.1/100 py.
13

Similarly to our study, during a 19-month follow-up
period, no TIGRA-indeterminate or TIGRA-negative
patients de veloped TB, indicating a high negative
predictive value of TIGRAs in immunocompromised
patients in low-incidence countries.
13

IPTB is dependent on the setting of the study (Ta-
ble 2). Diel et al. followed a cohort of 147 contacts in
a low-incidence country who were QFT-GIT-positive
but refused chemotherapy. Of these, 19 developed ac-
tive TB, translating to an IPTB of 3.7/100 py. In par-
ticular, patients with high IFN- secretion after stim-
ulation were at risk of progression to active TB.
4
This
fnding is supported by a study from Colombia using
an in-house assay, which showed that patients who
responded to stimulation with culture fltrate protein
10 (CFP-10) with very high levels of IFN- (far ex-
ceeding the commercial test cut-offs) were at the
highest risk of developing TB.
15
This suggests that the
IPTB after a positive TIGRA could depend on the cut-
offs used for IFN- secretion. Two studies in adult
contacts in high-incidence countries found IPTBs of
respectively 1.4 and 0.9/100 py in patients with a
positive T-SPOT result. The fact that in these studies
6/380 and 10/1084 contacts with a negative T-SPOT
test also developed TB (IPTB 0.7 and 0.4/100 py) in-
dicates a true negative prediction rate of well below
100%.
5,6
Similarly, isoniazid prophylaxis given to
children after close TB contact did not prevent the
development of TB in T-SPOT-negative contacts in
Turkey.
11
Compared to the available studies on IPTB
after positive TIGRA testing, we did not fnd an in-
creased IPTB in our immunocompromised patient
group (Table 2). The HIV-positive patient who devel-
oped TB had a high CD4 count and a suppressed
HIV load. The HIV-positive patients with a positive
T-SPOT test in Aichelburg et al.s study who devel-
oped TB also had relatively high CD4 counts.
13
The
current approach, advising HIV- and TIGRA-positive
patients, irrespective of their actual CD4 count, to
take prophylactic TB medication,
16
may be supported
by these data. Nevertheless, data for such a recom-
mendation are insuffcent, and future studies will
have to prospectively test this in different immuno-
compromised patient groups. However, the predictive
value of positive TIGRAs for the development of TB
seems to be low in immunocompromised patients
who are not recent contacts, similar to the TST. In a
recent meta-analysis pooling 15 studies (with 448
cases of TB/1000 py after positive TIGRA), Rangaka
et al. calculated an incidence rate ratio of 2.1 (95%CI
1.43.1) for active TB after a positive TIGRA in im-
munocompetent patients.
17

In line with these fndings, our results show that
the IPTB after a positive TIGRA is low, even in im-
munocompromised patients. However, our results
should be interpreted with caution due to the retro-
spective nature of the study, the heterogeneous study
group and the low patient number per group. Fur-
thermore, the results cannot be translated to regions
with higher TB prevalence. Although the fnding that
few TIGRA-positive immunocompromised patients
progress to active TB needs to be confrmed in larger
prospective studies, these data suggest that new diag-
nostic tests that better predict who will beneft from
preventive therapy are also needed for immunocom-
promised patient groups.
Acknowledgements
This study was supported by the German Federal Ministry of Edu-
cation and Research, Bonn, Germany (BMBF 01 EO 0803). The
authors are responsible for the contents of this publication.
Disclosure: D Wagner has received a speaker fee from Cellestis.
Table 1 TIGRA result and incidence rate of progression to active TB in events /100 py (IPTB) among patient groups
n (%)
Age,
years,
mean
Lost to
follow-up
Positive
n (%)
Negative
n (%)
Indeterminate
n (%)
Events
(progression
to TB)
IPTB after
positive IGRA
(95%CI)
IPTB
overall
(95%CI)
Disease group
Organ transplant 233 (50.6) 54.5 7 25 (10.7) 191 (82) 17 (7.3) 0 0 0
Autoimmune 76 (16.5) 52 7 6 (7.9) 54 (71.1) 16 (21.1) 0 0 0
HIV 51 (11) 45.5 0 4 (7.8) 45 (88.2) 2 (3.9) 1 15 (040) 1.2 (04.4)
Primary immunodeficiency 45 (9.8) 44.8 1 1 (2.2) 40 (88.9) 4 (8.9) 0 0 0
Stem cell transplant 43 (9.3) 58.8 0 1 (2.3) 23 (53.5) 19 (44.2) 0 0 0
Other immunocompromising
condition 12 (2.6) 69 0 1 (8.3) 7 (58.3) 4 (33) 0 0 0
Demographic
Immigrants 17 (3.7) 52.5 1 7 (41.2) 9 (52.9) 1 (5.9) 0 0 0
Female 198 (43) 52.5 9 11 (5.6) 152 (76) 35 (17) 0 0 0
TB
Previous TB 10 (2.2) 62.3 0 4 (40) 5 (50) 1 (10) 0 0 0
Total 460 (100) 52.9 16 38 (8.3) 360 (78.3) 62 (13.5) 1 1.2 (03.3) 0.1 (04)
TIGRA = tuberculosis-specific interferon-gamma release assays; TB = tuberculosis; py = person-years; IGRA = i nterferon-gamma release assay; CI = confidence
interval; HIV = human immunodeficiency virus.
494 The International Journal of Tuberculosis and Lung Disease
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Active TB with a positive IGRA 495
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Active TB with a positive IGRA i
Des donnes font dfaut sur la valeur prdictive des tests
de libration dinterfron-gamma spcifiques pour la tu-
berculose (TB, TIGRA), tant chez les individus immuno-
comptents que chez les individus en tat dimmuno-
dpression. Nous avons suivi rtrospectivement, par une
rvision des dossiers de patients, 460 de tels patients qui
avaient subi le test QuantiFERON

-TB Gold In-Tube

(QFT-GIT ; dure moyenne du suivi 28 mois). Une TB
active sest dveloppe chez 1/38 des QFT-GIT-positifs
et chez aucun sujet QFT-GIT-ngatif. Ds lors, le taux
dincidence de la progression vers la TB active, valu
rtrospectivement chez ces patients aprs un TIGRA posi-
tif, a t faible (1,2 vnements sur 100 annes/personne).
La ncessit dun suivi soigneux et dun traitement pro-
phylactique aprs un TIGRA positif dans ce groupe de
patients doit tre value de manire prospective.
No se cuenta con datos sobre el valor pronstico de las
pruebas de liberacin de interfern gama especficas de
tuberculosis (TB, TIGRAs) en personas inmunocompe-
tentes y en personas con inmunodepresin. Se llev a
cabo un estudio retrospectivo de las historias clnicas de
460 pacientes normocompetentes en quienes se practic
una prueba de QuantiFERON

-TB Gold en Tubo (QFT-

GIT; con seguimiento promedio de 28 meses). Uno de
los 38 pacientes con resultado positivo en la prueba
QFT-GIT contrajo TB activa, pero ninguno de los paci-
entes con resultado negativo. Por lo tanto, segn esta
evaluacin retrospectiva, la tasa de incidencia de la pro-
gresin hacia TB activa despus de un resultado positivo
en este tipo de pruebas fue baja (1,2 casos en 100 aos-
persona). Es necesario evaluar en forma prospectiva la
necesidad de seguimiento y tratamiento profilctico en
este grupo de pacientes que obtienen un resultado TIGRA
positivo.
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