Clinical trial NCT00707317: T Cell Interferon-gamma Release Assay (TIGRA) in Immunocompromised Individuals
Official title: Prospective Head-to-head Comparison of the Two Commercially Available Approved TIGRA (QuantiFERON-TB Gold In-Tube and T.SPOT.TB) With the Established Mendel-Mantoux Skin-test in Immunocompromized Patients
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Tuberculosis
Monitoring, Immunologic
Keywords: M. tuberculosis
latent tuberculosis infection
Quantiferon assay
ELISPOT assay
tuberculin skin test
immunocompromised patients
Lead sponsor: Tuberculosis Network European Trialsgroup
Sponsor class: NETWORK
First posted: 2008-06-30
Enrollment: 1843
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: immunocompetent and immunocompromised patients

Brief summary: Until recently, the tuberculin skin test (TST) was the only available diagnostic assay for detection of latent infection with M. tuberculosis (LTBI). Despite the low overall incidence of symptomatic tuberculosis infection in low-prevalence countries, the potential mortality and morbidity mandate constant vigilance to identify patients at risk for reactivation. Due to systemic immunosuppression, immunocompromised patients with latent M. tuberculosis infection are at increased risk of progression to active disease. This applies to patients with various causes of immunodeficiency such as HIV-infected patients, allogeneic stem cell and solid organ transplant recipients, patients with rheumatoid arthritis and patients with chronic renal failure. Therefore, current guidelines aimed at preventing tuberculosis infection in immunocompromized individuals recommend a generalized screening for evidence of latent infection to target appropriate preventative prophylaxis. At present, tuberculosis control programs exclusively rely on the tuberculin skin test to identify a latent infection in asymptomatic individuals.

Recently, novel in vitro assays termed T cell interferon-gamma release assay (TIGRA) have become available that are based on the detection of interferon-gamma (IFN-gamma) production in T cells or supernatants after stimulation with highly specific antigens of M. tuberculosis. Two TIGRA are commercially available, the ELISPOT based T.SPOT.TB and the ELISA based QuantiFERON-TB Gold test (now available as an "IN-TUBE" version).

The aim of the study is a prospective comparison of the two commercially available approved TIGRA (QuantiFERON-TB Gold In-Tube and T.SPOT.TB) with the established Mendel-Mantoux skin-test in immunocompromized patients (main focus on sensitivity and specificity).

The study hypotheses are as follows:

1. In immunocompromised patients, the two commercially available approved TIGRA (QuantiFERON-TB Gold In-Tube and T.SPOT.TB) have increased sensitivity and specificity as compared to the established Mendel-Mantoux skin-test.
2. Results from QuantiFERON-TB Gold In-Tube and T.SPOT.TB do not differ in immunocompromised patients.

Detailed description: Until recently, the tuberculin skin test (TST) was the only available diagnostic assay for detection of latent infection with M. tuberculosis (LTBI). Despite the low overall incidence of symptomatic tuberculosis infection in low-prevalence countries, the potential mortality and morbidity mandate constant vigilance to identify patients at risk for reactivation. Due to systemic immunosuppression, immunocompromised patients with latent M. tuberculosis infection are at increased risk of progression to active disease. This applies to patients with various causes of immunodeficiency such as HIV-infected patients, allogeneic stem cell and solid organ transplant recipients, patients with rheumatoid arthritis and patients with chronic renal failure. Therefore, current guidelines aimed at preventing tuberculosis infection in immunocompromized individuals recommend a generalized screening for evidence of latent infection to target appropriate preventative prophylaxis. At present, tuberculosis control programs exclusively rely on the tuberculin skin test to identify a latent infection in asymptomatic individuals.

Recently, novel in vitro assays termed T cell interferon-gamma release assay (TIGRA) have become available that are based on the detection of interferon-gamma (IFN-gamma) production in T cells or supernatants after stimulation with highly specific antigens of M. tuberculosis. Two TIGRA are commercially available, the ELISPOT based T.SPOT.TB and the ELISA based QuantiFERON-TB Gold test (now available as an "IN-TUBE" version). Current evidence suggests that TIGRA based on cocktails containing ESAT-6 and CFP-10 have the potential to become useful diagnostic tools. It has, however, been shown, that rates of indeterminate and positive results may differ between both tests, suggesting that they might provide different results in routine clinical practice. Moreover, there is only inadequate evidence on the value of those TIGRA in the management of immunocompromised individuals. Based on the current literature and most recent meta-analyses, there is an urgent need for head-to-head comparative studies of the two commercially available tests in immunocompromised patients. This study is designed to carry out a head-to-head comparison of the T.SPOT.TB and the ELISA based QuantiFERON-TB Gold In-Tube test with the TST in immunosuppressed populations. In a second step that will be addressed at a later stage, this study may be extended to longitudinally assess the predictive value of a positive blood test for progression to active disease.

The study will be performed within the tuberculosis network european trialsgroup (TBNET). It will be performed in a multicenter setting involving 23 participating centers from a total of 14 european countries. The study aims to include a total of 1800 study subjects distributed as follows: 200 HIV infected individuals with high and low CD4 T cells/µl (above and below 250 CD4 T cell/µl), respectively, 200 patients with chronic renal failure, 200 stem cell transplant recipients, 200 solid organ transplantation (lung, liver, kidney, kidney-pancreas) patients, 200 patients with rheumatoid arthritis. In addition, 200 immunocompromised patients with confirmed tuberculosis, 200 immunocompetent individuals with similar risk factors as patients, and 200 immunocompetent controls with no known risk of exposure or tuberculosis will serve as control groups.

Eligibility criteria: Inclusion Criteria:

* Individual as specified for the study population
* Written informed consent
* Indication to perform tuberculin skin test(suspect latent infection, according to standard guidelines, differential diagnosis)

Exclusion Criteria:

* \<18 years of age

Primary outcomes:
measure: IGRA performance
timeFrame: at the time of analysis
Secondary outcomes:
measure: active tuberculosis on follow-up
timeFrame: variable follow-up on all patients
Other outcomes:
Locations:
city: Carnegie
country: Australia
facility: Cellestis Limited
city: Sofia
country: Bulgaria
facility: National Center of Infectious and Parasitic Diseases
city: Herlev
country: Denmark
facility: Herlev Hospital
city: Borstel
country: Germany
facility: Research Center Borstel
city: Frankfurt
country: Germany
facility: HIV Treatment and Clinical Research Unit
city: Freiburg
country: Germany
facility: Department of Infectious Diseases, Univ. of Freiburg
city: Homburg
country: Germany
facility: University of the Saarland
city: Mezourlo-Larissa
country: Greece
facility: Respiratory Medicine, University of Thessaly
city: Milan
country: Italy
facility: Emerging Bacterial Pathogens Unit
city: Roma
country: Italy
facility: National Institute for Infectious Diseases L. Spallanzani
city: Tradate
country: Italy
facility: WHO Collaborating Center for TB and Lung Diseases
city: The Hague
country: Netherlands
facility: KNCV Tuberculosis Foundation
city: Lisbon
country: Portugal
facility: Centro de Diagnóstico Pneumológico
city: Bucharest
country: Romania
facility: Clinica de Pneumologie, Marius Nasta Institute of Pneumology
city: Barcelona
country: Spain
facility: Servei de Microbiologia
city: Stockholm
country: Sweden
facility: Karolinska Institute
city: Geneva
country: Switzerland
facility: Centre Antituberculeux, Hôpital Cantonal Universitarie
city: Ankara
country: Turkey
facility: Baþkent Üniversitesi Týp Fakültesi
city: Ankara
country: Turkey
facility: Department of Chest Diseases and Tuberculosis
city: London
country: United Kingdom
facility: Chest Clinic
city: London
country: United Kingdom
facility: Imperial College London
Study officials:
affiliation: Department of Transplant and Infection Immunology, University of the Saarland, 66421 Homburg
name: Martina Sester, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Div. of Clinical Infectious Diseases, Medical Clinic, Research Center Borstel, Germany
name: Christoph Lange, MD, PhD
role: STUDY_CHAIR
References:
citation: Sester M, van Leth F, Bruchfeld J, Bumbacea D, Cirillo DM, Dilektasli AG, Dominguez J, Duarte R, Ernst M, Eyuboglu FO, Gerogianni I, Girardi E, Goletti D, Janssens JP, Julander I, Lange B, Latorre I, Losi M, Markova R, Matteelli A, Milburn H, Ravn P, Scholman T, Soccal PM, Straub M, Wagner D, Wolf T, Yalcin A, Lange C; TBNET. Risk assessment of tuberculosis in immunocompromised patients. A TBNET study. Am J Respir Crit Care Med. 2014 Nov 15;190(10):1168-76. doi: 10.1164/rccm.201405-0967OC.
citation: Lange C, van Leth F, Sester M; TBnet. Viral Load and Risk of Tuberculosis in HIV Infection. J Acquir Immune Defic Syndr. 2016 Feb 1;71(2):e51-3. doi: 10.1097/QAI.0000000000000834. No abstract available.