PLoS One. 2009 Dec 14;4(12):e8257.

IFNgamma response to Mycobacterium

tuberculosis, risk of infection and disease in
household contacts of tuberculosis patients
in Colombia.
del Corral H, Pars SC, Marn ND, Marn DM, Lpez L, Henao HM, Martnez T, Villa L,
Barrera LF, Ortiz BL, Ramrez ME, Montes CJ, Oquendo MC, Arango LM, Riao F, Aguirre
C, Bustamante A, Belisle JT, Dobos K, Meja GI, Giraldo MR, Brennan PJ, Robledo J,
Arbelez MP, Rojas CA, Garca LF.

Source
Grupo de Epidemiologa, Universidad de Antioquia, Medelln, Colombia.

Abstract
OBJECTIVES:
Household contacts (HHCs) of pulmonary tuberculosis patients are at high risk of
Mycobacterium tuberculosis infection and early disease development. Identification of
individuals at risk of tuberculosis disease is a desirable goal for tuberculosis control.
Interferon-gamma release assays (IGRAs) using specific M. tuberculosis antigens provide an
alternative to tuberculin skin testing (TST) for infection detection. Additionally, the levels of
IFNgamma produced in response to these antigens may have prognostic value. We estimated
the prevalence of M. tuberculosis infection by IGRA and TST in HHCs and their source
population (SP), and assessed whether IFNgamma levels in HHCs correlate with tuberculosis
development.
METHODS:
A cohort of 2060 HHCs was followed for 2-3 years after exposure to a tuberculosis case.
Besides TST, IFNgamma responses to mycobacterial antigens: CFP, CFP-10, HspX and
Ag85A were assessed in 7-days whole blood cultures and compared to 766 individuals from
the SP in Medelln, Colombia. Isoniazid prophylaxis was not offered to child contacts
because Colombian tuberculosis regulations consider it only in children under 5 years, TST
positive without BCG vaccination.
RESULTS:
Using TST 65.9% of HHCs and 42.7% subjects from the SP were positive (OR 2.60,
p<0.0001). IFNgamma response to CFP-10, a biomarker of M. tuberculosis infection, tested
positive in 66.3% HHCs and 24.3% from th e SP (OR = 6.07, p<0.0001). Tuberculosis
incidence rate was 7.0/1000 person years. Children <5 years accounted for 21.6% of incident
cases. No significant difference was found between positive and negative IFNgamma

responders to CFP-10 (HR 1.82 95% CI 0.79-4.20 p = 0.16). However, a significant trend for
tuberculosis development amongst high HHC IFNgamma producers was observed (trend Log
rank p = 0.007).
DISCUSSION:
CFP-10-induced IFNgamma production is useful to establish tuberculosis infection
prevalence amongst HHC and identify those at highest risk of disease. The high tuberculosis
incidence amongst children supports administration of chemoprophylaxis to child contacts
regardless of BCG vaccination.
PMID:
20011589
[PubMed - indexed for MEDLINE]
PMCID: PMC2788133
Free PMC Article

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PLoS One. 2009; 4(12): e8257.
Published online 2009 December 14. doi: 10.1371/journal.pone.0008257
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Figure 1
Study profile.
HHCs = Household contacts, IGRA = IFN Release Assay, TST = Tuberculin Skin Test, SP =
source population, CFP-10 = Culture Filtrate Protein-10.
http://www.ncbi.nlm.nih.gov/pubmed/20011589

Kekkaku. 2006 Nov;81(11):681-6.

[Characteristics of a diagnostic method for

tuberculosis infection based on whole blood
interferon-gamma assay].
[Article in Japanese]
Harada N.

Source
Immunology Division, Mycobacterium Reference Center, Research Institute of Tuberculosis,
Japan Anti-Tuberculosis Association (JATA). harada@jata.or.jp

Abstract
It is assumed that about 10% of individuals infected with M. tuberculosis (Mtb) develop
tuberculosis (Tb), and the remaining 90% suppress contain Mtb through their immune
systems, but have a latent tuberculosis infection (LTBI). To effectively control Tb, it is
essential to detect individuals with LTBI in a Tb outbreak and provide chemoprophylaxis for
them. Until recently, the tuberculin skin test (TST) has been the only diagnostic method for
LTBI. However, the specificity of TST is low, because the purified protein derivative (PPD)
used for TST contains numerous Mtb antigens that are almost identical to BCG antigens or
similar to non-tuberculous mycobacterium (NTM) antigens. For this reason, TST may
produce positive results in BCG-vaccinated individuals or NTM-infected individuals without
Mtb infection. Therefore, it is very difficult to diagnose LTBI in Japan, where BCG
vaccination is widely administered. In addition to this, TST has other defects, such as
technical variations for injecting PPD or measuring the TST response, the necessity of a
return visit to the doctor to measure the TST response 2 days after PPD injection, and the
booster effect through reinjection of PPD. More recently, a new diagnostic method that can
overcome these defects in TST, QuantiFERON TB-2G (QFT-2G), has been developed. In
QFT-2G, two Mtb-specific antigens, ESAT-6 and CFP-10, are used to stimulate whole blood,
and based on produced interferon-gamma (IFN-gamma), Mtb infection is diagnosed. Since
ESAT-6 and CFP-10 are absent from all M. bovis BCG substrains and most of NTM
including M. avium, M. intracellulare, but are present in tuberculosis complex (M.
tuberculosis, M. bovis, M. africanum) and only a few strains of NTM, QFT-2G is not affected
by prior BCG vaccination nor most of NTM infections. Moreover, as measurement of IFNgamma can be carried out by machines on the next day following the blood draw, more
objective results are obtained more quickly than with TST. It is not necessary to consider the
booster effect in QFT-2G as PPD is not injected, nor to revisit the doctor. Thus, QFT-2G
overcomes the defects of TST described here. From a clinical trial of QFT-2G in which the
subjects were smear-positive, untreated Tb patients and BCG-vaccinated healthy individuals,
it has been demonstrated that the specificity and sensitivity of QFT-2G are 98.1% and 89.0%,
respectively, and QFT-2G is an excellent diagnostic method. Furthermore, many contact
investigations have shown that QFT-2G detects not only active Tb but also LTBI. Several
data indicate that frequency of contact with Tb patients correlates well with QFT-2G positive
rates in contact investigations. The validity and usefulness of diagnosing LTBI by QFT-2G

have been suggested in other countries. In many contact investigations, it has been shown that
most contacts who had been diagnosed as LTBI based on TST results were QFT-2G negative,
suggesting that as a result, many unnecessary chemoprophylaxes were indicated. On the
contrary, many QFT-2G positives were identified in those who were diagnosed to be
uninfected with Mtb based on TST. Therefore, as the wide spread of QFT-2G testing in
contact investigations would prevent unnecessary chemoprophylaxes and detect true infected
individuals more accurately, we hope that more effective Tb control could be performed.
Although QFT-2G is an excellent diagnostic method, it is still new, and some questions
remain to be answered. For example, the period of converting QFT-2G positive after Mtb
infection, alteration of long-term QFT-2G responses after Mtb infection, and the effects of
treatment for Tb or LTBI are not fully understood. The behavior of QFT-2G in infants or
children is not understood either. Especially in infants, the problem of the blood volume
required for the QFT-2G test is the major issue. We are working on these issues to provide
more appropriate directions for QFT-2G users, and hope that we can contribute to Tb control.
PMID:
17154047
[PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/pubmed/17154047

Kekkaku. 2011 Feb;86(2):101-12.

[The clinical application of quantiferon TB2G: its usefulness and limitations].

[Article in Japanese]
Sato S, Nagai H.

Source
Department of Medical Oncology and Immunology, Graduate School of Medical Sciences,
Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya-shi, Aichi 467-8601
Japan. ssato@med.nagoya-cu.ac.jp

Abstract
QuantiFERON TB-2G (QFT) is widely used in clinical settings for the identification of
tuberculosis infection because of its high level of utility. It is well known that QFT stimulates
peripheral blood lymphocytes in vitro by means of M. tuberculosis-specific protein, and that
infection is identified by measuring the interferon-gamma released. Interpretation of QFT
results is therefore difficult in immunosuppressed subjects in whom the function of
immunocompetent cells, including lymphocytes, is suppressed, making it difficult for them to
produce interferon-gamma. There is a high incidence of tuberculosis among hemodialysis

patients. It has been conjectured that the use of powerful immunosuppressive agents
following kidney transplantation results in a high risk of tuberculosis. How QFT results
change immediately following kidney transplantation is an extremely interesting question. In
recent years, an increasing number of institutions have been using TNF-alpha inhibitors to
treat rheumatoid arthritis patients. Is QTF useful for identifying whether patients have latent
tuberculosis infection before the administration of anti-TNF antibodies? In particular, many
rheumatoid arthritis patients may have been given methotrexate or glucocorticoids, which
suppress the immune system, prior to the administration of TNF-alpha inhibitors, possibly
making it difficult to interpret the QFT results. We must be aware of this limitation when
performing QFT on immunosuppressed patients. It is also important that we understand the
clinical parameters influencing QFT results (such as lymphocyte counts). The morbidity rate
of tuberculosis is high among healthcare workers, particularly nurses. A number of studies
have reported that QFT is useful in hospital infection control for tuberculosis, but the
effectiveness of QFT for monitoring the health of healthcare workers is still not fully
understood. In this symposium, we will debate how far QFT can be used and the extent of its
usefulness under exceptional circumstances. (1) How do we manage kidney transplant
recipients with latent tuberculosis infection?: Norihiko GOTO (Transplant Surgery, Nagoya
Daini Red Cross Hospital) It is unclear whether QuantiFERON-second generation (QFT-2G)
is useful for diagnostic screening and follow up of latent tuberculosis infection (LTBI) in
immunosuppressed kidney transplant (KTx) recipients. The QFT-2G assay that included
response to mitogen stimulation was performed before and 6 months after KTx. Non
responder was 0 (0%) at baseline, 3 (3%) at 6 months. Response to mitogen stimulation was
9.7 +/- 5.3 IU/mL at baseline vs. 10.4 +/- 5.0 IU/mL at 6 months after KTx (p = 0.29). QFT2G is a useful screening test for LTBI and active tuberculosis (TB) even during maintenance
of immunosuppression of KTx. (2) QuantiFERON-TB Gold in Japanese rheumatoid arthritis
patients for assessing latent tuberculosis infection prior treatment of anti-tumor necrosis
factor antibody: Shogo BANNO (Division of Rheumatology and Nephrology, Department of
Internal Medicine, Aichi Medical School of Medicine) To determine the positive rate of LTBI
in RA patients using the QFT-2G test, we divided RA patients into two groups: with or
without old TB findings by chest CT. With a cutoff level set at 0.35 IU/ml, the positive rate of
QFT-2G in LTBI was detected only 5.8%, when setting cutoff at 0.1 IU/ml (lower cutoff
level), 23.1% was detected in LTBI patients. The positive TST results were significantly
increased in non-LTBI patients compared than in LTBI patients. The QFT-2G test was not
affected by the treatment of MTX, and the incidence of indeterminate result was low. The
QFT-2G was useful compared to TST before administration of TNF inhibitors in RA patients,
because of superior specificity of QFT-2G. (3) Clinical parameters that influence the
sensitivity of T-cell assays: Haruyuki ARIGA (National Hospital Organization Tokyo
National Hospital) The detection of tuberculosis (TB) infection in compromised hosts is
essential for TB control, but T cell assay might be influenced by the degree of cell-mediated
immunosuppression. The relationship between immunocompetence and specific interferon
(IFN)-gamma response in whole blood QuantiFERON-TB Gold (QFT) is uncertain. Immunerelated clinical indicators associated with the degree of antigen-specific IFN-gamma
production were analysed using a large immunologically-unselected population with obvious
TB infection. The absolute number of blood lymphocyte in TB patients was significantly
associated with specific IFN-gamma production in a linear regression model. Sensitivity of 2
IFN-gamma Release Assays, QFT and ELISPOT, partly depends on peripheral lymphocyte
counts. At low lymphocyte count conditions, ELISPOT assay is superior to whole blood QFT
for detecting tuberculosis infection. (4) QuantiFERON TB-2G among staffs in the hospitals
of Nationao Hospital Organization: Susumu OGURI, Chihiro NISHIO, Kensuke SUMI,
Masayoshi MINAGUCHI, Tomomasa TSUBOI, Atuo SATOU, Osamu TOKUNAGA,

Takeshi MIYAMOMAE, Takuya KURASAWA (National Hospital Organization MinamiKyoto National Hospital)
PURPOSE:
To investigate the infection rate of tuberculosis among staffs working in the hospitals of
NHO.
METHOD:
Questionnaires were sent to the hospitals and the responses were analyzed.
RESULT:
Among the staffs working in the hospitals with tuberculosis wards, positive rate of
QuantiFERON TB-2G was 6.9%, probable positive rate was 5.6%. On the other hand, among
the staffs working in the hospitals without tuberculosis wards, positive rate was 4.4%,
probable positive rate was 3.9%.
CONCLUSION:
It is necessary to monitor the infection rate among hospital staffs

Research

Persistently elevated T cell interferon-

responses after treatment for latent
tuberculosis infection among health care
workers in India: a preliminary report
Madhukar Pai3,1,2*, Rajnish Joshi1,2, Sandeep Dogra2, Deepak K Mendiratta2, Pratibha
Narang2, Keertan Dheda4 and Shriprakash Kalantri2

* Corresponding author: Madhukar Pai madhupai@berkeley.edu

Author Affiliations
1

Division of Epidemiology, School of Public Health, University of California, Berkeley,

USA
2

Departments of Medicine & Microbiology, Mahatma Gandhi Institute of Medical Sciences,

Sevagram, India
3

Division of Pulmonary & Critical Care Medicine, San Francisco General Hospital,
University of California, San Francisco, USA
4

Centre for Infectious Diseases and International Health The Royal Free and University
College Medical School, London, UK
For all author emails, please log on.
Journal of Occupational Medicine and Toxicology 2006, 1:7 doi:10.1186/1745-6673-1-7

The electronic version of this article is the complete one and can be found online at:
http://www.occup-med.com/content/1/1/7
Received:
Accepted:
Published:

10 February 2006
23 May 2006
23 May 2006

2006 Pai et al; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted
use, distribution, and reproduction in any medium, provided the original work is properly
cited.

Abstract
Background
T cell-based interferon- (IFN-) release assays (IGRAs) are novel tests for latent
tuberculosis infection (LTBI). It has been suggested that T cell responses may be correlated
with bacterial burden and, therefore, IGRAs may have a role in monitoring treatment
response. We investigated IFN- responses to specific TB antigens among Indian health care
workers (HCWs) before, and after LTBI preventive therapy.
Methods
In 2004, we established a cohort of HCWs who underwent tuberculin skin testing (TST) and
a whole-blood IGRA (QuantiFERON-TB-Gold In-Tube [QFT-G], Cellestis Ltd, Victoria,
Australia) at a rural hospital in India. HCWs positive by either test were offered 6 months of
isoniazid (INH) preventive therapy. Among the HCWs who underwent therapy, we
prospectively followed-up 10 nursing students who were positive by both tests at baseline.
The QFT-G assay was repeated 4 and 10 months after INH treatment completion (i.e.
approximately 12 months and 18 months after the initial testing). IFN- responses to ESAT-6,
CFP-10 and TB7.7 peptides were measured using ELISA, and IFN- 0.35 IU/mL was used
to define a positive QFT-G test result.
Results
All participants (N = 10) reported direct contact with smear-positive TB patients at baseline,
during and after LTBI treatment. All participants except one started treatment with high
baseline IFN- responses (median 10.0 IU/mL). The second QFT-G was positive in 9 of 10
participants, but IFN- responses had declined (median 5.0 IU/mL); however, this difference
was not significant (P = 0.10). The third QFT-G assay continued to be positive in 9 of 10
participants, with persistently elevated IFN- responses (median 7.9 IU/mL; P = 0.32 for
difference against baseline average).
Conclusion
In an environment with ongoing, intensive nosocomial exposure, HCWs had strong IFN-
responses at baseline, and continued to have persistently elevated responses, despite LTBI
treatment. It is plausible that persistence of infection and/or re-infection might account for
this phenomenon. Our preliminary findings need confirmation in larger studies in high
transmission settings. Specifically, research is needed to study T cell kinetics during LTBI
treatment, and determine the effect of recurrent exposures on host cellular immune responses.