Original article
Use of Quantiferon-TB-Gold in Tube® test for detecting latent tuberculosis in patients considered as candidates for anti-TNF therapy in routine clinical practicePapel del test Quantiferon-TB-Gold in Tube® en el diagnóstico de infección tuberculosa latente en pacientes candidatos a tratamiento con anti-TNF en la práctica clínica

https://doi.org/10.1016/j.eimc.2012.06.014Get rights and content

Abstract

Background/methods

Quantiferon-TB-Gold in Tube® test (QFT-G-IT) may have advantages if combined with TST when screening for Latent Tuberculosis Infection (LTBI) prior to initiating anti-TNF therapy in an area of intermediate tuberculosis incidence such as Spain. In a small-scale prospective study, we evaluate the use of QFT-G-IT in combination with the screening recommended in Spain (Tuberculin-Skin Test, TST retest, clinical data, and Chest X-Ray (CXR)) for LTBI in patients considered as candidates for anti-TNFα treatment.

Results

From June 2008 to October 2010, 123 patients from a 300-bed hospital in Palma de Mallorca (Spain) were included in the study. The majority of patients were under immunosuppressive therapy. A positive TST and TST booster were found in 22 and 17 patients, respectively. Thus 39 (31.7%) of the 123 patients had a positive TST. QFT-G-IT was positive in 16 patients (13.6%), indeterminate in 4 (3.2%), and negative in 103 (83.7%). One of the two tests was positive and LTBI was diagnosed in 34.1% of patients. The agreement between TST and QFT-G-IT among vaccinated patients was low and not statistically significant (Kappa = 0.15) and was almost perfect among non-BCG vaccinated patients (K = 0.81). TST positive responses were significantly related to BCG-vaccination (p < 0.05) and QFT-G-IT positive response rates were related to older age (p < 0.05).

Conclusion

QFT-G-IT may have advantages when combined with TST in immunosuppressed patients especially in older patients with a negative TST; in BCG vaccinated patients with a positive TST, QFT-G-IT could avoid unnecessary treatments and toxicities related to a false-positive TST result.

Resumen

Introducción/método

Quantiferon-TB-Gold in Tube® (QFT-G-IT) en combinación con la Prueba de la tuberculina (PT) puede ser útil para el diagnóstico de infección tuberculosa latente (ITL) en pacientes candidatos a tratamiento con anti-TNF en un país de incidencia intermedia de tuberculosis como España. Se evalúa en un estudio piloto prospectivo QFT-G-IT en combinación con las pruebas recomendadas en España (PT, PT-booster, datos clínicos y radiografía de tórax) para el diagnóstico de ITL en pacientes con enfermedades inmunológicas candidatos a tratamiento con fármacos anti-TNFα.

Resultados

Se incluyeron 123 pacientes desde junio de 2008 a octubre de 2010 en el hospital Son Llàtzer de Palma de Mallorca. La PT inicial y la PT booster fueron positivas en 22 y 17 pacientes, respectivamente, el 31,6% tuvo una PT positiva, QFT-G-IT fue positivo en 16 (13,6%), indeterminado en 4 (3,2%) y negativo en 103 pacientes (83,7%). En 34,1% al menos uno de los dos tests fue positivo y se diagnosticó ITL. La concordancia entre PT y QFT-G-IT fue baja en pacientes vacunados con BCG (Kappa = 0,15) y excelente en no vacunados con BCG (K = 0,81). La positividad de la PT se relacionó con la vacunación con BCG (p<0.05) y la de QFT-G-IT con una mayor edad (p<0.05).

Conclusión

El uso de QFT-G-IT puede optimizar el diagnóstico de ITL en estos pacientes especialmente en los más añosos con una PT negativa. En pacientes vacunados de BCG con una PT positiva, QFT-G-IT podría evitar tratamientos innecesarios de ITL relacionados con un falso positivo.

Introduction

The use of biological agents interfering with TNF α is an established tool in the treatment of an increasing number of immune-mediated inflammatory chronic diseases (IMIDs). However anti-TNFs cause immunosuppression and have been associated with the reactivation of latent tuberculosis infections (LTBI).1 The Food and Drug Administration2 and the European Medicines Agency3 recommend screening for LTBI prior to the use of anti-TNF agents. Patients with IMIDs are already at high risk of progression to active tuberculosis disease (TB) as a result of their treatments with glucocorticoids and other immunosuppressive therapies,4 and because of the inflammatory disease itself.5 Treatment with anti-TNF-α agents notably intensifies this threat.6

Spain, where the World Health Organization estimates the occurrence of 30 TB cases/100,000 population/year, is one of the Western European countries with the highest incidence of TB.7 An early report from the FDA in 2001 described 70 cases of TB among 147,000 patients treated with infliximab, of which 10 were reported in Spain.1

Interferon-γ Release Assays (IGRAs) have been introduced as important diagnostic tests, complementing or replacing the Tuberculin Skin-Test (TST) for the diagnosis of LTBI. Two ex vivo assay formats, ELISA and ELISpot, are used to detect the interferon-gamma (IFN-γ) response to specific-Mycobacterium tuberculosis (MTB) secreted proteins such as ESAT6, CFP-10, and TB7.7 (this additional antigen is only present in the last generation ELISA test). Both formats have commercially available tests: Quantiferon-TB-Gold in Tube® (QFT-G-IT)8 (Cellestis Ltd., Carnegie, Australia) and T-SPOT.TB® (Oxford Immunotec, UK).9 Both have shown a higher specificity compared with TST especially in BCG-vaccinated populations and a higher sensitivity in immunodepressed patients, and positive IGRA responses are closely associated with risk factors for MTB infection.10 In some countries, IGRAs are already recommended for clinical use in immunodepressed patients who are candidates for anti-TNF α treatment.11, 12 In Spain, guidelines recommend their use in clinical studies, always in combination with TST.13, 14 For patients undergoing immunosuppressive treatment and considered as candidates for anti-TNFα treatment, the recommendations of the Spanish Health Authorities regarding LTBI screening include: obtaining a history of previous exposure, performing a positive initial TST or positive retest (booster), or a CXR finding suggestive of old TB. There are no specific recommendations regarding IGRAs in this setting.15, 16, 17

The aim of this study was to evaluate the usefulness of QFT-G-IT in combination with TST, booster TST, and CXR for the diagnosis of LTBI in patients considered as candidates for anti-TNFα treatment for different IMIDs in routine clinical practice in a hospital in Palma de Mallorca from 2008 to 2010.

Section snippets

Design

This is an observational, small-scale pilot study.

Patients

All consecutive patients considered as candidates for anti-TNFα treatment were evaluated at the Tuberculosis Unit of Hospital Son Llàtzer, a 300-bed hospital in Palma de Mallorca (Spain), from June 2008 to October 2010. All patients provided informed consent before enrolment and the study protocol was approved by the local Ethics Committee. Patients who had previously been under any anti-TNF treatment in other hospitals and who were referred to

Results

One hundred and twenty-three patients were recruited and all consented to the study. There were two withdrawals during follow-up, both due to unexpected deaths which were unrelated to any infectious disease.

Median age was 45 years [range 18–79 years]. There were 105 (84.7%) patients born in Spain, 9 (7.32%) patients born in Western Europe, and 9 patients born in high TB-incidence countries (8 South America, 1 India). There were no patients with known HIV infection. Seventeen patients had at

Discussion

In the current study, LTBI was diagnosed in 34.1% of patients considered as candidates for anti-TNFα treatment. This rate is higher than previously reported in studies conducted in Southern Europe which have found rates ranging from 12 to 22%.17, 20 TST positive rates were higher among BCG-vaccinated patients than in non BCG-vaccinated patients and this difference with regard to BCG vaccination was not seen in QFT-G-IT results. Furthermore, QFT-G-IT positive response rates were related to older

Funding

The study was supported by a grant from the Ministerio de Sanidad y Consumo Instituto de Salud Carlos III, Madrid, Spain, FIS 06/801.

Conflict of interest

The authors declare that they have no conflict of interest.

Acknowledgements

We would like to thank Claire Graham for translation assistance and Dr. Antonio Pareja for statistical assistance.

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