Mycobacteriology
The role of a whole blood interferon-γ assay for the detection of latent tuberculosis infection in Bacille Calmette–Guérin vaccinated children

https://doi.org/10.1016/j.diagmicrobio.2008.08.022Get rights and content

Abstract

The tuberculin skin test (TST) has limitations in children who are under the Bacille Calmette–Guérin (BCG) effect. Our aim was to evaluate the QuantiFERON®-TB Gold In-Tube (QFT-G IT) blood test for Mycobacterium tuberculosis infection in children and to compare results with those of the TST. QFT-G IT and TST data were collected from 227 children between 0 and 15 years of age, split into 4 risk groups. Forty-two children were close contacts, 29 were casual contacts, and 65 were controls. The QFT-G IT positivity rates were 19% (8/42), 6.9% (2/29), and 1.5% (1/65), with a significantly higher rate for the close contacts over the controls (P < 0.05). The high specificity of the QFT-G IT assay and the association of positive results with increasing risk of infection in our study suggest it has major benefits over the TST as a screening test for latent infection with M. tuberculosis in BCG-vaccinated children.

Introduction

Diagnosing latent infection with Mycobacterium tuberculosis (LTBI) in children is problematic and largely based on the tuberculin skin test (TST), developed more than 100 years ago. However, the TST suffers from a number of limitations including the possibility of false-positive results in Bacille Calmette–Guérin (BCG)-vaccinated people and those with exposure to environmental atypical mycobacteria, and operator errors and subjectivity in placement and reading (Connell et al., 2006). Clinicians who are aware of the TST's limitations might therefore hesitate to prescribe isoniazid based only on a positive TST result. In contrast, clinicians who are aware that up to 50% of untreated infants and 15% of older children with LTBI develop disease within 2 years of being infected (Shingadia and Novelli, 2003) might offer tuberculosis medicine to any child younger than 5 years who has known exposure to tuberculosis (TB) patients. To date, the most reliable strategies for detecting LTBI in children are based on thorough and proper contact investigations rather than non-selective skin testing of large populations (American Academy of Pediatrics, 2006). There is an evident need for accurate new diagnostic tests for LTBI in children.

Recent developments in proteomic and genetic technologies have assisted the identification of M. tuberculosis (TB)-specific antigens, which do not exist in BCG strains or most of the common non-tuberculous environmental mycobacteria. Early secreted antigenic target 6-kDa protein (ESAT-6), culture filtrate protein-10 (CFP-10), and TB 7.7 (p.4) are 3 such TB-specific antigens that have been demonstrated to stimulate the production of interferon-γ (IFN-γ) by T cells from M. tuberculosis-infected individuals (Rothel and Andersen, 2005). Two in vitro IFN-γ assays using these TB-specific antigens are now available as commercial kits: QuantiFERON®-TB Gold In-Tube (QFT-G IT; Cellestis Limited, Carnegie, Australia) and T-SPOT.TB® test (Oxford Immunotec, Oxford, UK). An earlier version of the QuantiFERON-TB Gold test was approved by US Food and Drug Administration in 2005 and the QFT-G IT format in 2007. However, there are only a few published studies that describe the performance of the test in children and adolescents. We therefore undertook the present study of QFT-G IT to further evaluate its usefulness for diagnosing LTBI in children.

Section snippets

Subjects

For 13 months, between October 2006 and November 2007, patients younger than 15 years visiting Severance Children's Hospital, Seoul, South Korea, were recruited into the study. Patients were divided into 4 groups. The close contact group was composed of children who resided in the same house with their active tuberculosis index case, the casual contact group was those with exposure outside the household, the control group were TST-positive healthy children with no contact history, and the 4th

Results

Data were collected from 227 pediatric patients (median age, 3.2 years; range, 0–15.8 years). Demographic characteristics are shown in Table 1, and comparative results for the TST and QFT-G, stratified by study group, are displayed in Table 2.

Discussion

Diagnosis of LTBI is hampered by the lack of a gold standard (Mirtskhulava et al., 2008, Pathan et al., 2001, Porsa et al., 2006). In those BCG vaccinated, the TST has poor specificity and the TST is also reported to have only moderate sensitivity in children and the immunosuppressed (Kunst, 2006, Pai et al., 2006, Shingadia and Novelli, 2003, Tufariello et al., 2003). The lack of a definitive test for LTBI has led clinicians to rely heavily on contact histories, and, especially in children,

Conclusion

In conclusion, diagnosis of LTBI in children who are recent contacts should continue to be based on careful epidemiologic tracing of their exposure to active tuberculosis as well as immunologic analysis of their infection status. Our data suggest that the QFT-G IT assay performs better than the TST in screening children for infection, and its high specificity might be helpful in targeting TB treatment to those truly infected, thereby reducing wastage of TB medication and medical workups.

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    These data were presented as poster presentation in the 26th Annual Meeting of the European Society for Paediatric Infectious Diseases, Graz, Austria, May 13 to 17, 2008.

    Preliminary data (collected from October 1, 2006, to April 30, 2007) are to be published at the Korean Journal of Pediatrics as an original article in Korean language.

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