Prognostic Value of a T-Cell–Based, Interferon- Biomarker in Children with Tuberculosis Contact

2 December 2008 | Volume 149 Issue 11 | Pages 777-786

Background: Enzyme-linked immunospot (ELISpot) assay is an increasingly widely used, T-cell–based, interferon-–release assay for diagnosing tuberculosis infection, but whether positive results are prognostic of active tuberculosis is not known.

Objective: To determine whether ELISpot results predict the development of active tuberculosis among persons with recent tuberculosis exposure.

Design: Longitudinal cohort study of children and adolescents with tuberculosis contact recruited from October 2002 to April 2004.

Setting: Community-based contact investigations in Turkey.

Patients: 908 children and adolescents with recent household tuberculosis exposure.

Intervention: Enzyme-linked immunospot assay, incorporating early secretory antigenic target-6 and culture filtrate protein-10, and tuberculin skin test were done at baseline.

Measurements: Incidence rates ratios of progression to active tuberculosis for contacts with positive tuberculin skin test and ELISpot results, and relative incidence rates comparing contacts with positive and negative test results.

Results: Isoniazid preventive therapy was given to 688 (76%) contacts according to local guidelines. Fifteen contacts developed active tuberculosis over 1201 person-years of follow-up. Of 381 contacts with positive ELISpot results, 11 developed active tuberculosis over 536 person-years of follow-up (incidence rate, 21 per 1000 person-years [95% CI, 10.2 to 36.7 per 1000 person-years]), a statistically significant 3- to 4-fold increased risk for progression relative to ELISpot-negative contacts. Of 550 contacts with positive tuberculin skin test results, 12 developed active tuberculosis over 722 person-years of follow-up (incidence rate, 17 per 1000 person-years [CI, 8.6 to 29.0 per 1000 person-years]).

Limitation: Only 3 of the 15 incident cases were confirmed by culture.

Conclusion: Positive ELISpot results predict subsequent development of active tuberculosis in recent tuberculosis contacts. Although tuberculosis contacts with positive ELISpot results have an incidence rate of tuberculosis similar to that of contacts with positive tuberculin skin test results, ELISpot testing could allow more focused targeting of preventive therapy to fewer contacts.

Editors' Notes Context Interferon-–release assays, such as enzyme-linked immunospot (ELISpot), are increasingly used to help diagnose latent tuberculosis infection, but information about the ability of these tests to predict development of tuberculosis among exposed persons is scant. Contribution This longitudinal study followed 908 children and adolescents with recent household exposure to tuberculosis, most of whom received preventive therapy. Of 381 children with positive ELISpot results, 11 subsequently developed active tuberculosis compared with 12 of 550 children with positive tuberculin skin test results. Implication Household contacts with positive ELISpot results have about a 3- to 4-fold increased risk for progression to active tuberculosis compared with contacts with negative ELISpot results. Compared with the tuberculin skin test, ELISpot could allow more focused targeting of preventive therapy to fewer contacts. —The Editors

 

Author and Article Information

From Marmara University School of Medicine, Istanbul, Turkey; Tuberculosis Immunology Group, National Heart and Lung Institute, Imperial College London, London, United Kingdom; and University of Birmingham, Edgbaston, Birmingham, United Kingdom.

Note: Drs. Bakir and Millington contributed equally to this work.

Acknowledgment: The authors thank the children who took part in the study and their parents. They also acknowledge the crucial support of the Istanbul Association for the Fight Against Tuberculosis and the physicians and nurses of the 7 government-run tuberculosis clinics in the Anatolian side of Istanbul.

Grant Support: By the Wellcome Trust and the United Nations (International) Children's Fund/United Nations Development Programme/World Bank/World Health Organization Special Programme for Research and Training in Tropical Diseases, a UK Department of Health Senior Fellowship in Evidence Synthesis (Dr. Deeks), and the Sir Halley Stewart Trust (Dr. Dosanjh's PhD studentship). Dr. Lalvani is a Wellcome Senior Research Fellow in Clinical Science, and Dr. Millington was a Wellcome Trust Prize PhD student. Both are members of the Wellcome Trust-funded Centre for Respiratory Infection, Imperial College London.

Potential Financial Conflicts of Interest: Consultancies: A. Lalvani (Oxford Immunotec Ltd. [nonexecutive director from 2003 to 2007]). Stock ownership or options (other than mutual funds): A. Lalvani (Oxford Immunotec Ltd.), University of Oxford (Oxford Immunotec Ltd.). Patents received: A. Lalvani (T-cell–based diagnosis of tuberculosis infection.) Patents pending: K.A. Millington (T-cell–based diagnosis of tuberculosis infection.), D.P.S. Dosanjh (T-cell–based diagnosis of tuberculosis infection.), A. Lalvani (T-cell–based diagnosis of tuberculosis infection.)

Reproducible Research Statement: Study protocol: Not available. Statistical code and data set: Available to academic investigators from Dr. Lalvani (e-mail, a.lalvani{at}imperial.ac.uk) after agreement is made by written request.

Requests for Single Reprints: Ajit Lalvani, DM, Tuberculosis Immunology Group, Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, Norfolk Place, London W2 1PG, United Kingdom; e-mail, a.lalvani{at}imperial.ac.uk.

Current Author Addresses: Drs. Bakir and Soysal, Ms. Efee, and Ms. Aslan: Department of Paediatrics, Marmara University School of Medicine, Tophanelioglu Caad. No. 13-15, Altunizade, Istanbul, Turkey.

Drs. Millington, Dosanjh, and Lalvani: Tuberculosis Immunology Group, Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, Norfolk Place, London W2 1PG, United Kingdom.

Dr. Deeks: Unit of Public Health, Epidemiology and Biostatistics, School of Population Health and Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.

Author Contributions: Conception and design: M. Bakir, A. Lalvani.

Analysis and interpretation of the data: M. Bakir, K.A. Millington, A. Soysal, J.J. Deeks, D.P.S. Dosanjh, A. Lalvani.

Drafting of the article: K.A. Millington, A. Lalvani.

Critical revision of the article for important intellectual content: K.A. Millington, J.J. Deeks, A. Lalvani.

Final approval of the article: M. Bakir, K.A. Millington, A. Soysal, J.J. Deeks, S. Efee, Y. Aslan, D.P.S. Dosanjh, A. Lalvani.

Provision of study materials or patients: M. Bakir, A. Soysal, S. Efee, Y. Aslan.

Statistical expertise: K.A. Millington, J.J. Deeks, A. Lalvani.

Obtaining of funding: M. Bakir, A. Lalvani.

Administrative, technical, or logistic support: M. Bakir, A. Soysal, S. Efee, Y. Aslan, A. Lalvani.

Collection and assembly of data: M. Bakir, K.A. Millington, A. Soysal, S. Efee, Y. Aslan, D.P.S. Dosanjh, A. Lalvani.

Read all Rapid Responses

Prognostic Value of a T-Cell–Based, Interferon- Biomarker in Turkish Children

Eduardo Hernández-Garduño

Annals Online, 30 Oct 2008 [Full text]

Prognostic Value of a T-Cell–Based, Interferon- Biomarker in Turkish Children – authors’ response

Ajit Lalvani, et al.

Annals Online, 7 Nov 2008 [Full text]

DIAGNOSTIC COHORT STUDIES FOR PEDIATRIC TUBERCULOSIS: WHAT DOES THE FUTURE HOLD?

Anneke C. Hesseling, et al.

Annals Online, 18 Nov 2008 [Full text]

Diagnostic Cohort Studies for Pediatric Tuberculosis: What does the future hold? – authors’ response

Ajit Lalvani, et al.

Annals Online, 19 Nov 2008 [Full text]