Consensus statement
Guidelines for the use of interferon-γ release assays in the diagnosis of tuberculosis infectionGuía de práctica clínica sobre el uso de las pruebas de liberación de interferón-γ para el diagnóstico de infección tuberculosa

https://doi.org/10.1016/j.eimc.2015.11.022Get rights and content

Abstract

Introduction

Interferon-gamma release assays are widely used for the diagnosis of tuberculosis infection in low-prevalence countries. However, there is no consensus on their application. The objective of this study was to develop guidelines for the use of interferon-gamma release assays in specific clinical scenarios in Spain.

Methods

A panel of experts comprising specialists in infectious diseases, respiratory diseases, microbiology, pediatrics and preventive medicine, together with a methodologist, formulated the clinical questions and outcomes of interest. They conducted a systematic literature search, summarized the evidence and rated its quality, and prepared the recommendations following the GRADE (Grading of Recommendations of Assessment Development and Evaluations) methodology.

Results

The panel prepared recommendations on the use of interferon-gamma release assays for the diagnosis of tuberculosis infection in the contact-tracing study (both adults and children), health care workers, immunosuppressed patients (patients infected with human immunodeficiency virus, patients with chronic immunomediated inflammatory diseases due to start biological therapy and patients requiring organ transplant) and for the diagnosis of active tuberculosis. Most recommendations were weak, mainly due to the lack of good quality evidence to balance the clinical benefits and disadvantages of the interferon-gamma release assays as compared with the tuberculin skin test.

Conclusion

This document provides evidence-based guidance on the use of interferon-gamma release assays for the diagnosis of tuberculosis infection in patients at risk of tuberculosis or with suspicion of active disease. The guidelines will be applicable in specialist and primary care and in public health settings.

Resumen

Introducción

Las técnicas de detección in vitro de interferón-gamma (IGRA, del inglés interferon-gamma release assays) están ampliamente implantadas para el diagnóstico de infección tuberculosa en países de baja prevalencia. Sin embargo, no hay consenso sobre su aplicación. El objetivo fue desarrollar una guía de práctica clínica para el uso de los IGRA en los diferentes escenarios clínicos en España.

Métodos

Un grupo de expertos compuesto por especialistas en enfermedades infecciosas, enfermedades respiratorias, microbiología, pediatría y medicina preventiva, junto con un metodólogo formularon las preguntas clínicas y los desenlaces de interés, llevaron a cabo una búsqueda sistemática de la literatura, sintetizaron la evidencia y graduaron su calidad, y formularon las recomendaciones siguiendo la metodología Grading of Recommendations of Assessment Development and Evaluations (GRADE).

Resultados

El grupo de trabajo formuló las recomendaciones sobre el uso de los IGRA para el diagnóstico de infección tuberculosa en el estudio de contactos (adultos y niños), trabajadores sanitarios, pacientes inmunosuprimidos (pacientes infectados por el virus de la inmunodeficiencia humana, pacientes afectos de enfermedades inflamatorias inmunomediadas candidatos a terapias biológicas y pacientes que requieren trasplante de órganos), y en el diagnóstico de enfermedad tuberculosa activa. La mayor parte de las recomendaciones fueron débiles, principalmente debido a la falta de evidencia de calidad para establecer un balance entre beneficios y daños de los IGRA en comparación con la prueba de la tuberculina.

Conclusión

Este documento proporciona una guía basada en la evidencia para el uso de los IGRA en el diagnóstico de infección tuberculosa en pacientes en riesgo de tuberculosis o con sospecha de enfermedad activa. Esta guía es aplicable en la atención especializada y primaria, y salud pública.

Introduction

The diagnosis of tuberculosis (TB) infection relied solely on the tuberculin skin test (TST) until a decade or so ago when in vitro immunodiagnostic tests, known as interferon-gamma release assays (IGRAs), became available. At present, the question of whether IGRAs should be used to complement or substitute the TST is under debate.

The aim of detecting TB infection is to identify and treat people at risk of developing active disease. Close-contacts of patients with TB, people infected with the human immunodeficiency virus (HIV), patients receiving immunosuppressive therapies, and health care workers are all at risk of active TB. Therefore, screening and preventive chemotherapy in cases of infection should be considered in these populations.1 The TST consists of the intradermal injection of PPD-S (Seibert's purified protein derivative), or the PPD-RT23 equivalent in Spain. However, this contains a mixture of more than 200 antigens that are shared by mycobacteria other than Mycobacterium tuberculosis, and includes the vaccine strain of Mycobacterium bovis bacillus Calmette-Guérin (BCG). Therefore, people sensitized by previous exposure to non-tuberculous mycobacteria (NTM) or the BCG vaccine may respond to a TST. Another major limitation is the loss of sensitivity of the test in certain groups, such as immunosuppressed patients and young children.2 It should also be remembered that a negative TST obtained early after the onset of infection with M. tuberculosis does not exclude infection because the test takes up to eight weeks to emerge as positive. This interval is usually referred to as the “window period.”

In the last decade, in vitro immunodiagnostic tests have been developed to overcome the deficiencies of the TST. Based on the in vitro quantification of the cellular immune response, IGRAs detect interferon-gamma (IFN-γ) release by sensitized T cells after stimulation with specific M. tuberculosis antigens.3 The two main antigens used are the 6-kD M. tuberculosis early-secreted antigenic target protein (ESAT-6) and the 10-kD culture filtrate protein (CFP-10), encoded in the region of difference 1 (RD1), which is present in M. tuberculosis but not in BCG nor in most NTM.4 Currently there are two commercially available assays: the QuantiFERON®-TB Gold assay (QFT-G) (Qiagen, Hilden, Germany) and the T-SPOT®.TB assay (Oxford Immunotec, Oxford, UK). The QFT-G tests are whole-blood assays that use enzyme-linked immunosorbent assays to detect IFN-γ produced in supernatants by stimulated T cells. The QFT-G in-tube version (QFT-GIT) includes a third antigen, TB7.7, which is encoded in RD11 and is missing from BCG strains and most of the common environmental mycobacteria.5 The T-SPOT.TB detects the number of IFN-γ-producing T cells after stimulation of a definite number of isolated peripheral blood mononuclear cells with ESAT-6 and CFP-10, separately, using an enzyme-linked immunospot assay. Both tests include a positive control that detects the capacity of T cells to produce IFN-γ upon stimulation with a mitogen. Like the TST, IGRAs have a window period of conversion after exposure to M. tuberculosis, but the duration of this window has not been clearly determined.

Section snippets

Scope and objectives

Currently there is no consensus on the use of IGRAs in different clinical scenarios and settings. Despite the abundance of literature about IGRAs, there is a scarcity of good quality evidence evaluating important patient outcomes in given populations. This, in turn, is reflected in the inconsistency of the recommendations of official organizations and scientific societies, which largely rely on expert opinion.6, 7 Moreover, recommendations that are suitable for one area or country may not be

The panel

These guidelines were developed by a panel of experts comprising in infectious diseases, respiratory diseases, microbiology, pediatrics and preventive medicine specialists, together with a methodology expert with experience in the development of clinical guidelines. All panel members were assigned to a specific subgroup (contact tracing, health care workers, children, HIV-infected people, patients with chronic inflammatory diseases, transplant candidates, and patients suspected of having active

Recommendations

A summary of the recommendations is provided in Table 1.

Further considerations

The panel noted the following additional considerations:

  • 1.

    The resources needed for IGRAs to be implemented are low. However, implementation in non-urban settings, where a close laboratory for rapid handling of samples is required, may be difficult. This was acknowledged to be particularly important when using the T-SPOT.TB, which should be performed within the first 24 h, or in the case of the T-SPOT.TB® Extend, within 48 h after incubation.87 Furthermore, the need for venous punctures in large

Appliability of the guidelines

The panel does not expect major limitations to the applicability of these guidelines in Spain because IGRAs are widely available, particularly the QTF-GIT, and because the cost burden would be easily assumed by the public health system. However, the panel anticipates more difficulty when implementing community contact studies (e.g., in schools, workplaces, and other settings). In such settings, the need for multiple venous punctures and sample collections may be regarded as added inconveniences

Updating of the guidelines

The panel considers that these guidelines should be updated within five years of their publication, or earlier if relevant information becomes available.

Funding and editorial independence

The panel received no funding from any for-profit companies or organizations. The Spanish Society of Respiratory Diseases and Thoracic Surgery (SEPAR) hosted the in-person meetings, while SEPAR and the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) funded the travel and housing costs for members to attend the meetings. Neither the SEIMC nor SEPAR have direct or indirect influence on the elaboration of the guidelines.

Conflict of interest statement

All the authors provided a conflict of interest statement. M.S. declared the following conflicts of interest: he received a fee for speaking at two conferences sponsored by Inverness Medical Iberica, S.A.U., supplier of the QuantiFERON®-TB Gold In-tube in Spain, and he is the PI of a Clinical Trial assessing QuantiFERON®-TB Gold In-tube in contact-tracing, which was supplied with blood collection tubes by Cellestis, Inc. (Carnegie, Australia). Any declared conflicts of interest were not deemed

Acknowledgements

External reviewers: Fernando Alcaide (Service of Microbiology, Bellvitge University Hospital, University of Barcelona, L’Hospitalet de Llobregat, Barcelona), Ángel Domínguez (Service of Infectious Diseases, Hospital Virgen Macarena, Sevilla), Jordi Dorca (Service of Pneumology, Bellvitge University Hospital, University of Barcelona, L’Hospitalet de Llobregat, Barcelona), María J. Mellado Peña (Service of General Pediatrics and Infectious and Tropical Diseases, Hospital Universitario Infantil La

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