Potencial do teste IGRA (Interferon Gama Release Assay) para o diagnóstico de tuberculose ocular. Revisão e análise comparativa com o teste tuberculínico cutâneo (PPD) / The potential of the IGRA (Interferon Gamma Release Assay) test for the diagnosis of ocular tuberculosis. Review and comparative analysis with the tuberculosis skin test

Resumo A detecção precisa da infecção latente por tuberculose está se tornando cada vez mais importante devido ao aumento do uso de medicamentos imunossupressores e da epidemia do vírus da imunodeficiência humana, o que aumentou o risco de reativação à tuberculose ativa (TB). O Teste IGRA QuantiFERON® TB Gold apresenta vantagens frente ao teste de PPD como por exemplo, requer somente uma coleta de amostra sanguínea ; não há necessidade que o paciente retorne ao laboratório para leitura e interpretação dos resultados; Os resultados são objetivos, não requerem interpretação do leitor ou interferência de critérios subjetivos; trata-se de um teste in vitro, portanto não há "efeito booster" (potenciação da reação tuberculínica); o teste não é afetado por vacinação prévia por BCG ou infecção por outras espécies de micobactérias. Limitações são descritas, apesar de raras, como reações cruzadas deste método com infecções por algumas espécies de micobactérias não-tuberculosis (incluindo Mycobacterium kansasii, Mycobacterium szulgai e Mycobacterium marinum). Ainda há poucos dados sobre o teste IGRA em certas populações, como por exemplo, em crianças, pacientes imunocomprometidos e mulheres grávidas. Nestes grupos, a interpretação do teste pode ser difícil e mais estudos se fazem necessários.

Abstract Precise detection of latent tuberculosis infection is becoming increasingly important due to increased use of immunosuppressive drugs and the human immunodeficiency virus epidemic , which increased the risk of reactivation to active tuberculosis (TB).The QuantiFERON® TB Gold IGRA Test has advantages over the skin test for TB, otherwise known as a Mantoux tuberculin test, for example, requires only a blood sample collection; there is no need for the patient to return to the laboratory for reading and interpretation of the results; The results are objective, do not require interpretation of the reader or interference of subjective criteria; it is an in vitro test, so there is no "booster effect" (potentiation of the tuberculin reaction); the test is not affected by prior BCG vaccination or infection with other species of mycobacteria. Limitations are described, although rare, as cross-reactions of this method with infections by some species of non-tuberculosis mycobacteria (including Mycobacterium kansasii, Mycobacterium szulgai and Mycobacterium marinum). There is still little data on the IGRA test in certain populations, such as in children, immunocompromised patients and pregnant women. In these groups, the interpretation of the test can be difficult and more studies are needed.

Interferon-gamma release assay performance in northeastern Brazil: influence of the IFNG+874 A>T polymorphism

ABSTRACT Introduction Latent tuberculosis infection diagnosis based on the release of interferon-gamma in cultures of peripheral blood cells stimulated with Mycobacterium tuberculosis antigens has replaced the tuberculin skin test in many countries with low tuberculosis prevalence. The IFN-γ production can be influenced by genetic polymorphisms, of which the IFNG + 874 (rs62559044) locus is the most studied. We investigated the possible influence of the IFNG + 874 A/T polymorphism on interferon-gamma test performance. Methods Patients diagnosed with pulmonary tuberculosis (75), volunteers with positive tuberculin skin test (70) and healthy volunteers with negative tuberculin skin test and no history of contact with tuberculosis (57) were evaluated regarding the IFNG + 874 genotype and the IFN-γ levels in whole blood cultures performed using an interferon-gamma commercial kit (QuantiFERON-TB® Gold In-Tube). Results IFN-γ production was not influenced by the IFNG + 874 genotype, regardless of antigen or mitogen-based stimulation, which suggests that other genes may influence IFN-γ production in response to mycobacteria. The IFNG + 874 polymorphism was found to exert no influence over QFT-IT test sensitivity in our study. Conclusions The IFNG + 874 polymorphism was not shown to influence QuantiFERON-TB® Gold In-Tube test performance in an admixed population from northeastern Brazil.

Frequency of indeterminate results from an interferon-gamma release assay among HIV-infected individuals / Taxa de resultados indeterminados de ensaio de liberação de interferon-gama entre pessoas infectadas pelo HIV

ABSTRACT Objective: To evaluate the frequency of and factors associated with indeterminate interferon-gamma release assay (IGRA) results in people living with HIV/AIDS (PLWHA). Methods: We tested 81 PLWHA in the central-west region of Brazil, using the tuberculin skin test and an IGRA. Information on sociodemographic and clinical variables was gathered through the use of questionnaires and from medical records. The association of those variables with indeterminate results was analyzed by calculating the adjusted ORs in a multivariate logistic regression model. Concordance was evaluated by determining the kappa statistic. Results: Among the 81 patients evaluated, the tuberculin skin test results were positive in 18 (22.2%) of the patients, and the IGRA results were positive in 10 (12.3%), with a kappa of 0.62. The IGRA results were indeterminate in 22 (27.1%) of the patients (95% CI: 17.8-38.1%). The odds of obtaining indeterminate results were significantly higher in smokers (adjusted OR = 6.0; 95% CI: 1.4-26.7) and in samples stored for less than 35 days (adjusted OR = 14.0; 95% CI: 3.1-64.2). Patients with advanced immunosuppression (CD4+ T-cell count < 200 cells/mm3) were at a higher risk for indeterminate results (OR adjusted for smoking and inadequate duration of sample storage = 4.7; 95% CI: 0.91-24.0), although the difference was not significant. Conclusions: The high prevalence of indeterminate results can be a major limitation for the routine use of IGRAs in PLWHA. The need to repeat the test increases its costs and should be taken into account in cost-effectiveness studies. The processing of samples can significantly alter the results.

RESUMO Objetivo: Avaliar a frequência de resultados indeterminados de um interferon-gamma release assay (IGRA, ensaio de liberação de interferon-gama) e os fatores relacionados com esses resultados em pessoas vivendo com HIV/AIDS (PVHA). Métodos: Foram avaliadas 81 PVHA na região Centro-Oeste do Brasil, por meio do teste tuberculínico e de um IGRA. Informações a respeito de variáveis sociodemográficas e clínicas foram obtidas por meio de questionários e prontuários médicos. A relação entre essas variáveis e os resultados indeterminados foi avaliada por meio do cálculo da OR ajustada em um modelo de regressão logística multivariada. A concordância foi avaliada por meio do coeficiente kappa. Resultados: Os resultados do teste tuberculínico e do IGRA foram positivos em 18 (22,2%) e 10 (12,3%), respectivamente, dos 81 pacientes avaliados (κ = 0,62). O resultado do IGRA foi indeterminado em 22 (27,1%) dos pacientes (IC95%: 17,8-38,1%). A chance de resultados indeterminados foi significativamente maior em fumantes (OR ajustada = 6,0; IC95%: 1,4-26,7) e em amostras armazenadas durante menos de 35 dias (OR ajustada = 14,0; IC95%: 3,1-64,2). Pacientes com imunossupressão avançada (contagem de células T CD4+ < 200 células/mm3) apresentaram maior risco de resultados indeterminados (OR ajustada para tabagismo e tempo inadequado de armazenamento das amostras = 4,7; IC95%: 0,91-24,0), embora a diferença não tenha sido significativa. Conclusões: A alta prevalência de resultados indeterminados pode ser um grande obstáculo ao uso rotineiro de IGRAs em PVHA. A necessidade de repetir o teste aumenta seu custo e deve ser levada em conta em estudos da relação entre custo e eficácia. O processamento das amostras pode alterar significativamente os resultados.

Isolated posterior scleritis associated with tuberculosis / Esclerite posterior isolada associada à tuberculose

ABSTRACT Ocular tuberculosis (TB) is considered to be rare, although its incidence has varied widely over time and in different populations. Latent TB is diagnosed when a person is infected with Mycobacterium tuberculosis but does not have active TB. During the last decade, interferon-gamma release assay tests have been developed that allow identification of patients with latent TB infection with better specificity than the tuberculin skin test and can differentiate between infection and prior vaccination. Although rare, tuberculous scleritis should be considered in the differential diagnosis of posterior scleritis. Here we describe a patient with posterior scleritis and severe visual loss associated with latent TB without uveitis, anterior scleritis, keratitis, or any other previous ocular disease history. The patient responded well to a combined treatment of antitubercular therapy and oral corticosteroids.

RESUMO A tuberculose (TB) ocular foi considerada rara, embora a sua incidência tenha variado significativamente ao longo do tempo e nas diferentes populações. A TB latente é diagnosticada quando alguém é infetado com Mycobacterium tuberculosis sem possuir doença ativa. Durante a última década, testes tendo por base interferon gamma release assay foram desenvolvidos, permitindo a identificação de pacientes com infeção por tuberculose latente com maior especificidade que o teste tuberculínico e diferenciar infeção e vacinação prévia. Embora rara, a esclerite tuberculosa deve ser tida em consideração no diagnóstico diferencial de esclerite posterior. Reportamos um paciente com esclerite posterior e baixa grave de acuidade visual associada a TB latente, sem uveíte, esclerite anterior, ceratite ou história de doença ocular prévia. O paciente respondeu favoravelmente a um tratamento combinado de fármacos antituberculose e corticoides orais.

Tuberculin skin test and interferon-gamma release assay values are associated with antimicrobial peptides expression in polymorphonuclear cells during latent tuberculous infection

It has been reported that patients with progressive tuberculosis (TB) express abundant amounts of the antimicrobial peptides (AMPs) cathelicidin (LL-37) and human neutrophil peptide-1 (HNP-1) in circulating cells, whereas latent TB infected donors showed no differences when compared with purified protein derivative (PPD) and QuantiFERON®-TB Gold (QFT)-healthy individuals. The aim of this study was to determine whether LL-37 and HNP-1 production correlates with higher tuberculin skin test (TST) and QFT values in TB household contacts. Twenty-six TB household contact individuals between 26-58 years old TST and QFT positive with at last two years of latent TB infection were recruited. AMPs production by polymorphonuclear cells was determined by flow cytometry and correlation between TST and QFT values was analysed. Our results showed that there is a positive correlation between levels of HNP-1 and LL-37 production with reactivity to TST and/or QFT levels. This preliminary study suggests the potential use of the expression levels of these peptides as biomarkers for progression in latent infected individuals.

Whole Blood Interferon-gamma Release Assay Is Insufficient for the Diagnosis of Sputum Smear Negative Pulmonary Tuberculosis

PURPOSE: We investigated the value of an interferon-gamma release assay (IGRA) for the diagnosis of active pulmonary tuberculosis (PTB) among sputum smear negative PTB suspects in an environment with intermediate burden of PTB and high Bacillus Calmette-Guerin (BCG) vaccination rate. MATERIALS AND METHODS: We retrospectively reviewed IGRA, medical records, chest PA and CT scan of PTB suspects seen at Gangnam Severance Hospital, Seoul, Korea from Oct. 2007 to Apr. 2013. "Active PTB" was diagnosed when 1) M. tuberculosis culture positive, 2) confirmation by pathologic examination; or 3) clinical findings compatible with TB. RESULTS: Of 224 sputum smear negative PTB suspects, 94 were confirmed as having active PTB. There were no statistically significant differences in the diagnostic yield of IGRA between immunocompromised and immunocompetent sputum smear negative PTB suspects. IGRA did show superior sensitivity [81.9%, 95% confidence interval (CI); 74.13-89.70%] in the diagnosis of sputum smear negative PTB when compared with chest high-resolution computed tomography (HRCT), tuberculin skin test (TST), and chest X-ray (p<0.001). Also, IGRA showed highest negative predictive value (82.7%, 95% CI; 75.16-90.15%) when compared with HRCT, TST and chest X-ray (p=0.023). However, combining the results of IGRA with those of HRCT, TST, or both did not increase any diagnostic parameters. CONCLUSION: Failure to increase diagnostic yields by combination with other diagnostic modalities suggests that additional enforcement with IGRA may be insufficient to exclude other diagnoses in sputum smear negative PTB suspects and to screen active PTB in an environment with intermediate TB prevalence and a high BCG vaccination rate.

The Usefulness of Interferon-gamma Release Assay for Diagnosis of Tuberculosis-related Uveitis in Korea

PURPOSE: To evaluate the usefulness of the interferon-gamma release assay (IGRA) for diagnosing tuberculosis (TB)-related uveitis (TRU). METHODS: Records from 181 patients with ocular signs and symptoms suggestive of TRU and intraocular inflammation of unknown etiology were reviewed. All subjects underwent clinical and laboratory testing, including IGRA, to rule out presence of underlying disease. A diagnosis of presumed TRU was made based on an internist's TB diagnosis and a patient's response to anti-TB therapy. Sensitivity, specificity, and positive predictive values of IGRA for TRU diagnosis were calculated. Clinical characteristics were compared between patients with positive and negative IGRA results. RESULTS: The sensitivity and specificity of IGRA for TRU were 100% and 72.0%, respectively. Mean age, percentage of patients with retinal vasculitis, and the anatomic type of uveitis were significantly different between patients with positive and negative IGRA results (all p < or = 0.001). Positive IGRA rates and false-positive rates were significantly different between age and anatomic type groups (both p = 0.001). The positive predictive value of the IGRA among patients with intraocular inflammation was high (70%) when all of younger age (< or =40 years), posterior uveitis, and retinal vasculitis were present. CONCLUSIONS: The IGRA is useful for diagnosing TRU in the Korean population, especially when it is used as a screening test. Clinical characteristics, including younger age (< or =40 years), posterior uveitis, and retinal vasculitis in IGRA-positive patients, increase the likelihood of the patient having TRU.