Cost-Effectiveness Analysis Comparing QuantiFERON-TB Gold Plus Test and Tuberculin Skin Test for the Diagnosis of Latent Tuberculosis Infection in Immunocompetent Subjects in Colombia.

OBJECTIVES: To determine the cost-effectiveness of the QuantiFERON-TB Gold Plus (QFT-Plus) test versus the tuberculin skin test in diagnosing latent tuberculosis infection in immunocompetent subjects in the context of the Colombian healthcare system. METHODS: A hypothetical cohort of 2000 immunocompetent adults vaccinated with Bacillus Calmette-Guérin at birth who are asymptomatic for tuberculosis disease was simulated and included in a decision tree over a horizon of <1 year. The direct healthcare costs related to tests, antituberculosis treatment, and medical care were considered, and diagnostic performance was used as a measure of effectiveness. The incremental cost-effectiveness ratio (ICER) was estimated, and univariate deterministic and probabilistic sensitivity analyses were carried out using 5000 simulations. The currency was the US dollar for the year 2022, with a cost-effectiveness threshold of $6666 USD (1 gross domestic product per capita for 2022). RESULTS: QFT-Plus was cost-effective with an ICER of $5687 USD for each correctly diagnosed case relative to a threshold of $6666 USD. In the deterministic analysis, QFT-Plus was cost-effective in half of the proposed scenarios. The variable that most affected the ICER was the prevalence of latent tuberculosis and test sensitivities. In the probabilistic analysis, QFT-Plus was cost-effective in 54.74% of the simulated scenarios, and tuberculin skin test was dominant in 13.84%. CONCLUSIONS: The study provides evidence of the cost-effectiveness of QFT-Plus compared with the tuberculin skin test in diagnosing latent tuberculosis infection in immunocompetent adults in the Colombian context.

A costing framework to compare tuberculosis infection tests.

OBJECTIVE: To develop a framework to estimate the practical costs incurred from, and programmatic impact related to, tuberculosis (TB) infection testing-tuberculin skin tests (TST) versus interferon gamma release assay (IGRA)-in a densely populated high-burden TB area. METHODS: We developed a seven-step framework that can be tailored to individual TB programmes seeking to compare TB infection (TBI) diagnostics to inform decision-making. We present methodology to estimate (1) the prevalence of TBI, (2) true and false positives and negatives for each test, (3) the cost of test administration, (4) the cost of false negatives, (5) the cost of treating all that test positive, (6) the per-test cost incurred due to treatment and misdiagnosis and (7) the threshold at which laboratory infrastructure investments for IGRA are outweighed by system-wide savings incurred due to IGRA utilisation. We then applied this framework in a densely populated, peri-urban district in Lima, Peru with high rates of Bacillus Calmette-Guérin (BCG) vaccination. FINDINGS: The lower sensitivity of TST compared with IGRA is a major cost driver, leading to health system and societal costs due to misdiagnosis. Additionally, patient and staff productivity costs were greater for TST because it requires two patient visits compared with only one for IGRA testing. When the framework was applied to the Lima setting, we estimate that IGRA-associated benefits outweigh infrastructural costs after performing 672 tests. CONCLUSIONS: Given global shortages of TST and concerns about costs of IGRA testing and laboratory capacity building, this costing framework can provide public health officials and TB programmes guidance for decision-making about TBI testing locally. This framework was designed to be adaptable for use in different settings with available data. Diagnostics that increase accuracy or mitigate time to treatment should be thought of as an investment instead of an expenditure.

Teste de Liberação de Interferon-gama (IGRA) para detecção de infecção latente pelo Mycobacterium tuberculosis em pacientes com doenças inflamatórias imunomediadas ou receptores de transplante de órgãos sólidos / Interferon Gamma Release Test (IGRA) for detection of latent infection by Mycobacterium tuberculosis in patients with immune-mediated inflammatory diseases or solid organ transplant recipients

A ILTB é um estado de resposta imune persistente aos antígenos do Mycobacterium tuberculosis, porém, sem sintomas clínicos ou achados radiológicos compatíveis com doença ativa. Estima-se que esta condição possa estar presente em um terço da população mundial. Assim, é importante diagnosticar a ILTB nas populações que requerem terapias imunossupressoras devido ao potencial risco de ativação da doença para sua forma transmissível. O diagnóstico precoce da ILTB permite o tratamento preconizado que impede sua ativação, sendo fundamental esta estratégia sanitária para reduzir e controlar a carga global da tuberculose (TB). O Centre for Disease Control and Prevention (CDC) americano informa que é recomendável o uso do IGRA ou PT para diagnóstico da ILTB na prática de saúde pública, enfatizando as limitações de ambos os testes, e recomenda que a TB deve ser excluída antes de iniciar o tratamento para ILTB. A World Health Organization (WHO) informa que tanto a PT quanto o IGRA podem ser usados para testar a ILTB, embora não haja fortes evidências de que um teste deva ser preferido em relação ao outro em termos de predizer a progressão da infecção para a doença de TB ativa. A WHO ainda recomenda que não sejam usados nem a PT nem os IGRAs em pessoas com baixo risco de infecção e com TB ativa, sendo necessário excluir a possibilidade de a doença estar ativa por meio de avaliação clínica, radiografia de tórax e exame de escarro. PERGUNTA DE PESQUISA: O teste de liberação de interferon-gama (IGRA), quando comparado a prova tuberculínica (PT), é acurado para detecção de infecção latente pelo Mycobacterium tuberculosis (ILTB) e capaz de prever ativação da tuberculose (TB) em pacientes com doença inflamatória imunomediada (DIIM) ou receptores de órgão sólidos candidatos ou em uso de terapia imunossupressora? AVALIAÇÃO ECONÔMICA: Foi realizada análise de custo-efetividade da ampliação de uso do IGRA para o diagnóstico da ILTB, tendo como comparador a PT, sob a perspectiva do SUS. Para tanto, um modelo de árvore de decisão foi elaborado, considerando como desfecho o número de casos de TB ativa evitados. A razão de custo-efetividade incremental (RCEI) para utilização do IGRA foi igual a R$ 8.340,68 por caso adicional de TB evitado em pacientes portadores de DIIM. Para pacientes candidatos a transplante de órgãos sólidos, a RCEI foi igual a R$ 48.905,19 por caso adicional de TB ativa evitado. De acordo com a análise de sensibilidade determinística, a variável mais sensível do modelo, no caso de pacientes portadores de DIIM, foi a especificidade do IGRA. Por outro lado, a sensibilidade do IGRA foi a variável mais sensível no caso de pacientes candidatos a transplantes de órgãos sólidos. Das 1.000 simulações realizadas na análise de sensibilidade probabilística, para a população portadora de DIIM, em 98% o IGRA mostrou ser a alternativa mais efetiva e de maior custo, enquanto este percentual foi cerca de 89% para pacientes candidatos a transplantes de órgão sólidos. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: O impacto orçamentário incremental total em cinco anos da incorporação do IGRA para diagnóstico da ILTB em pacientes portadores de DIIM foi igual a R$ 40.527.273,25. No caso dos pacientes candidatos a transplante de órgãos sólidos, o impacto orçamentário incremental em cinco anos foi igual a R$ 1.131.654,58. Considerando a incorporação do IGRA para ambas as populações, o impacto orçamentário incremental total em cinco anos seria de R$ 41.658.927,83. Em um cenário alternativo, em que o IGRA alcançaria um market share de 90% após cinco anos de sua incorporação, o impacto orçamentário incremental total seria de R$ 103.202.100,74 para ambas as populações. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram encontradas quatro novas tecnologias, sendo uma de produção nacional (Eco F TB Feron ­ IFN-Gamma), dois testes com registros Anvisa, mas sem aprovação FDA (Vidas TB-IGRA, da empresa Biomerieux SA e QIAreach Quantiferon-TB Test, da empresa Qiagen GmbH) e um dispositivo com registro Anvisa e FDA (Família Liaison Quantiferon TB Gold Plus, da empresa Diasorin Ltda). Em relação aos depósitos e patentes concedidas, foi possível evidenciar quatro documentos patentários, sendo um, em fase nacional, com pedido brasileiro. CONSIDERAÇÕES FINAIS: Por não existir padrão ouro para o diagnóstico da ILTB, a implantação da estratégia da identificação dos casos antes do início de uma terapia imunossupressora é um desafio. Foram avaliados desfechos relevantes para o desempenho dos testes com populações heterogêneas com alto risco para o desenvolvimento da tuberculose ativa: pacientes com DIIM e pacientes candidatos a transplante de órgãos sólidos. As evidências incluídas foram provenientes de países com realidades diversas quanto à situação vacinal com BCG e taxas endêmicas de TB. Além disso, os estudos apresentaram grande fragilidade metodológica com variabilidade na métrica e nos resultados de acurácia, como também, heterogeneidade dos tipos de teste IGRA avaliados e no ponto de corte de positividade da PT, impossibilitando a metaanálise dos resultados na maioria dos estudos de síntese. De modo geral, os estudos não foram capazes de aferir o teste mais acurado ou mesmo a taxa de concordância entre eles, assim como não foram esclarecedores quanto ao teste com maior desempenho estratégico para identificar ILTB e evitar progressão da TB ativa. Contudo, os diferentes tipos de teste IGRA demonstraram resultados semelhantes com a PT, com certo direcionamento favorável ao IGRA para prever progressão de TB ativa quando se trata de pacientes com DIIM. Embora na perspectiva econômica os resultados tenham apontado para o IGRA como uma tecnologia com maior custo e maior efetividade, comparado à PT nas duas populações avaliadas, a incorporação do teste IGRA como uma alternativa de teste diagnóstico da ILTB pode se tornar uma decisão estratégica no que se refere a previsão e a provisão da rede quando na análise de possível desabastecimento do teste diagnóstico já disponível no SUS. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros presentes na 110ª Reunião Ordinária, em 06 de julho de 2022, deliberaram, por unanimidade, sem nenhuma declaração de conflito de interesses, encaminhar o tema para consulta pública com recomendação preliminar favorável a ampliação de uso do teste de liberação de interferon-gama (IGRA) para detecção de infecção latente pelo Mycobacterium tuberculosis em pacientes com doenças inflamatórias imunomediadas ou receptores de transplante de órgãos sólidos. Considerou-se a importância do IGRA como alternativa diagnóstica para o controle epidemiológico da tuberculose e para o auxílio na identificação e no prognóstico dos pacientes com maior risco de desenvolver a tuberculose ativa, além das questões organizacionais e logísticas que sugerem a necessidade de mais um teste diagnóstico para ILTB. CONSULTA PÚBLICA: A Consulta Pública nº 64/2022 foi realizada no período de 20/09/2022 a 10/10/2022 recebendo 135 contribuições de experiência ou opinião. A maioria destes respondentes apresentou-se favorável à recomendação inicial da Conitec. Dois profissionais de saúde manifestaram-se desfavoráveis à incorporação do procedimento. Em geral, os participantes que se posicionaram de forma favorável mencionaram a precisão do teste IGRA na detecção de ILTB, a garantia de um tratamento adequado para determinados grupos de pacientes, a garantia do uso com segurança de imunobiológicos e imunossupressores, a necessidade de acesso ao teste pelo SUS, as vantagens do procedimento em relação à prova tuberculínica e a alta prevalência da tuberculose no Brasil. Entre os participantes que possuíram experiência com a tecnologia avaliada, foram mencionados como aspectos positivos o rastreio mais específico e sensível do teste, a comodidade na realização, maior segurança e resultado rápido. Em contraponto, o alto custo do procedimento foi apontado como uma dificuldade de acesso. As contribuições técnico-científicas totalizaram 37, sendo quatro oriundas de pessoa jurídica e 33 de pessoa física, e todas concordaram com a recomendação inicial da Conitec. RECOMENDAÇÃO FINAL DA CONITEC: Os membros presentes na 114ª Reunião Ordinária, em 09 de novembro de 2022, deliberaram, por unanimidade, sem nenhuma declaração de conflito de interesses, recomendar a ampliação de uso do teste de liberação de interferon-gama (IGRA) para detecção de infecção latente pelo Mycobacterium tuberculosis em pacientes com doenças inflamatórias imunomediadas ou receptores de transplante de órgãos sólidos. Considerou-se a importância do IGRA como alternativa diagnóstica e nas questões organizacionais e logísticas no SUS. Foi assinado o Registro de Deliberação nº 778/2022. DECISÃO: : Ampliar o uso, no âmbito do Sistema Único de Saúde - SUS, do Teste de Liberação de Interferon-gama (IGRA) para detecção de infecção latente pelo Mycobacterium tuberculosis em pacientes com doenças inflamatórias imunomediadas ou receptores de transplante de órgãos sólidos, conforme protocolo estabelecido pelo Ministério da Saúde, conforme a Portaria nº 171, publicada no Diário Oficial da União nº 230, seção 1, página 295, em 8 de dezembro de 2022.

A systematic review of cost-utility analyses of screening methods in latent tuberculosis infection in high-risk populations.

BACKGROUND: The World Health Organisation (WHO) recommends that testing and treatment for latent tuberculosis infection (LTBI) should be undertaken in high-risk groups using either interferon gamma release assays (IGRAs) or a tuberculin skin test (TST). As IGRAs are more expensive than TST, an assessment of the cost-effectiveness of IGRAs can guide decision makers on the most appropriate choice of test for different high-risk populations. This current review aimed to provide the most up to date evidence on the cost-effectiveness evidence on LTBI testing in high-risk groups-specifically evidence reporting the costs per QALY of different testing strategies. METHODS: A comprehensive search of databases including MEDLINE, EMBASE and NHS-EED was undertaken from 2011 up to March 2021. Studies were screened and extracted by two independent reviewers. The study quality was assessed using the Bias in Economic Evaluation Checklist (ECOBIAS). A narrative synthesis of the included studies was undertaken. RESULTS: Thirty-two studies reported in thirty-three documents were included in this review. Quality of included studies was generally high, although there was a weakness across all studies referencing sources correctly and/or justifying choices of parameter values chosen or assumptions where parameter values were not available. Inclusions of IGRAs in testing strategies was consistently found across studies to be cost-effective but this result was sensitive to underlying LTBI prevalence rates. CONCLUSION: While some concerns remain about uncertainty in parameter values used across included studies, the evidence base since 2010 has grown with modelling approaches addressing the weakness pointed out in previous reviews but still reaching the same conclusion that IGRAs are likely to be cost-effective in high-income countries for high-risk populations. Evidence is also required on the cost-effectiveness of different strategies in low to middle income countries and countries with high TB burden.

GeneXpert or chest-X-ray or tuberculin skin testing for household contact assessment (GXT): protocol for a cluster-randomized trial.

BACKGROUND: The World Health Organization recommends tuberculosis (TB) preventive treatment (TPT) for all people living with HIV (PLH) and household contacts (HHC) of index TB patients. Tests for TB infection (TBI) or to rule out TB disease (TBD) are preferred, but if not available, this should not be a barrier if access to these tests is limited for high-risk people, such as PLH and HHC under 5 years old. There is equipoise on the need for these tests in different risk populations, especially HHC aged over 5. METHODS: This superiority cluster-randomized multicenter trial with three arms of equal size compares, in Benin and Brazil, three strategies for HHC investigation aged 0-50: (i) tuberculin skin testing (TST) or interferon gamma release assay (IGRA) for TBI and if positive, chest X-Ray (CXR) to rule out TBD in persons with positive TST or IGRA; (ii) same as (i) but GeneXpert (GX) replaces CXR; and (iii) no TBI testing. CXR for all; if CXR is normal, TPT is recommended. All strategies start with symptom screening. Clusters are defined as HHC members of the same index patients with newly diagnosed pulmonary TBD. The main outcome is the proportion of HHC that are TPT eligible who start TPT within 3 months of the index TB patient starting TBD treatment. Societal costs, incidence of severe adverse events, and prevalence of TBD are among secondary outcomes. Stratified analyses by age (under versus over 5) and by index patient microbiological status will be conducted. All participants provide signed informed consent. The study was approved by the Research Ethic Board of the Research Institute of the McGill University Health Centre, the Brazilian National Ethical Board CONEP, and the "Comité Local d'Éthique Pour la Recherche Biomédicale (CLERB) de l'Université de Parakou," Benin. Findings will be submitted for publication in major medical journals and presented in conferences, to WHO and National and municipal TB programs of the involved countries. DISCUSSION: This randomized trial is meant to provide high-quality evidence to inform WHO recommendations on investigation of household contacts, as currently these are based on very low-quality evidence. TRIAL REGISTRATION: ClinicalTrials.gov NCT04528823.

Predicting Airborne Infection Risk: Association Between Personal Ambient Carbon Dioxide Level Monitoring and Incidence of Tuberculosis Infection in South African Health Workers.

BACKGROUND: High rates of tuberculosis (TB) transmission occur in hospitals in high-incidence countries, yet there is no validated way to evaluate the impact of hospital design and function on airborne infection risk. We hypothesized that personal ambient carbon dioxide (CO2) monitoring could serve as a surrogate measure of rebreathed air exposure associated with TB infection risk in health workers (HWs). METHODS: We analyzed baseline and repeat (12-month) interferon-γ release assay (IGRA) results in 138 HWs in Cape Town, South Africa. A random subset of HWs with a baseline negative QuantiFERON Plus (QFT-Plus) underwent personal ambient CO2 monitoring. RESULTS: Annual incidence of TB infection (IGRA conversion) was high (34%). Junior doctors were less likely to have a positive baseline IGRA than other HWs (OR, 0.26; P = .005) but had similar IGRA conversion risk. IGRA converters experienced higher median CO2 levels compared to IGRA nonconverters using quantitative QFT-Plus thresholds of ≥0.35 IU/mL (P < .02) or ≥1 IU/mL (P < .01). Median CO2 levels were predictive of IGRA conversion (odds ratio [OR], 2.04; P = .04, ≥1 IU/mL threshold). Ordinal logistic regression demonstrated that the odds of a higher repeat quantitative IGRA result increased by almost 2-fold (OR, 1.81; P = .01) per 100 ppm unit increase in median CO2 levels, suggesting a dose-dependent response. CONCLUSIONS: HWs face high occupational TB risk. Increasing median CO2 levels (indicative of poor ventilation and/or high occupancy) were associated with higher likelihood of HW TB infection. Personal ambient CO2 monitoring may help target interventions to decrease TB transmission in healthcare facilities and help HWs self-monitor occupational risk, with implications for other airborne infections including coronavirus disease 2019.

Prevalence of Latent Tuberculosis Infection Among Healthy Young Children and Adolescents and a Two-step Approach for the Diagnosis of Tuberculosis Infection in Chengdu, China.

BACKGROUND: China has a high burden of tuberculosis and latent tuberculosis infection (LTBI). The aim of this study was to estimate the prevalence of LTBI among healthy young children and adolescents and test a 2-step approach to explore the threshold for the diagnosis of tuberculosis infection in Chengdu, China. METHODS: Healthy preschool children and school-going children in Chengdu, Sichuan Province, were screened for LTBI using the tuberculin skin test (TST). Preschool children with TST ≥ 5 mm also underwent interferon-γ release assay (IGRA) to explore the threshold of this 2-step approach. RESULTS: In total, 5667 healthy young children and adolescents completed TST test between July 2020 and January 2021 and were included in the present analysis. The age of the participants ranged from 2.4 to 18 years (median 7.25 ± 4.514 years), of which 2093 (36.9%) were younger than 5 years. The overall prevalence of LTBI was 6.37% and 6.64% in children younger than 5 years old. Fourteen of the 341 preschool children with TST ≥5 mm were interferon-γ release assay positive, of which 4 showed a TST result of 5-10 mm, and 6 preschool children received preventive treatment for LTBI. CONCLUSIONS: Healthy young children and adolescents should also be considered as important target populations for LTBI screening. TST can be recommended for first-line screening as part of a 2-step approach for LTBI screening using a positive threshold of 5 mm.

Latent Tuberculosis Infection Screening and Treatment in Congregate Settings (TB FREE COREA): Demographic Profiles of Interferon-Gamma Release Assay Cohort.

In 2017, the Korean government launched an unprecedentedly large-scaled latent tuberculosis infection (LTBI) screening project which covered more than a million individuals in congregate settings. A total of 1,047,689 participants of source population (n = 2,336,157) underwent LTBI testing from 2017 to 2018. The overall LTBI test uptake rate during this project was 44.8%. Workers in daycare centers (83.5%) and kindergartens (78.9%) showed high participation rate. A total of 1,012,206 individuals with valid results of interferon-gamma release assay (IGRA) were selected to constitute the IGRA cohort. Most of the enrolled participants in the IGRA cohort were in their working age. Approximately, three-quarters of total enrolled population were female. Investigating the LTBI prevalence, stages of LTBI care cascade, natural history of LTBI, efficacy of LTBI treatment and cost-effectiveness of LTBI screening are feasible within this IGRA cohort.

Comparing the cost-effectiveness of two screening strategies for latent tuberculosis infection in Portugal.

INTRODUCTION AND OBJECTIVES: Screening for latent tuberculosis infection (LTBI) in close contacts of infectious TB cases might include Tuberculin Skin Test (TST) and Interferon-Gamma Release Assays (IGRA), in combination or as single-tests. In Portugal, the screening strategy changed from TST followed by IGRA to IGRA-only testing in 2016. Our objective was to compare the cost-effectiveness of two-step TST/IGRA with the current IGRA-only screening strategy in immunocompetent individuals exposed to individuals with respiratory TB. MATERIALS AND METHODS: We reviewed clinical records of individuals exposed to infectious TB cases diagnosed in 2015 and 2016, in two TB outpatient centers in the district of Porto. We estimated medical, non-medical and indirect costs for each screening strategy, taking into account costs of tests and health care personnel, travel distance from place of residence to screening site and employment status. We calculated the incremental cost-effectiveness ratio (ICER) as the cost difference between the two screening strategies with the difference number of LTBI diagnosis as a measure of cost-effectiveness, assuming that treating LTBI is a cost-effective intervention. We also calculated adjusted odds-ratios to test the association between diagnosis of LTBI and screening strategy and estimated the total cost for averting a potential TB case. RESULTS: We compared 499 contacts TST/IGRA screened with 547 IGRA-only. IGRA-only strategy yielded a higher screening effectiveness for diagnosing latent tuberculosis infection (aOR 2.12, 95%CI: 1.53 - 2.94). ICER was €106 per LTBI diagnosis, representing increased effectiveness with a slightly increased cost of IGRA-only screening strategy. CONCLUSIONS: Our data suggests that in Portugal LTBI screening with IGRA-only is more cost-effective than the two-step TST/IGRA testing strategy, preventing a higher number of cases of TB cases.

A cross-sectional study of latent tuberculosis infection, insurance coverage, and usual sources of health care among non-US-born persons in the United States.

ABSTRACT: More than 70% of tuberculosis (TB) cases diagnosed in the United States (US) occur in non-US-born persons, and this population has experienced less than half the recent incidence rate declines of US-born persons (1.5% vs 4.2%, respectively). The great majority of TB cases in non-US-born persons are attributable to reactivation of latent tuberculosis infection (LTBI). Strategies to expand LTBI-focused TB prevention may depend on LTBI positive non-US-born persons' access to, and ability to pay for, health care.To examine patterns of health insurance coverage and usual sources of health care among non-US-born persons with LTBI, and to estimate LTBI prevalence by insurance status and usual sources of health care.Self-reported health insurance and usual sources of care for non-US-born persons were analyzed in combination with markers for LTBI using 2011-2012 National Health and Nutrition Examination Survey (NHANES) data for 1793 sampled persons. A positive result on an interferon gamma release assay (IGRA), a blood test which measures immunological reactivity to Mycobacterium tuberculosis infection, was used as a proxy for LTBI. We calculated demographic category percentages by IGRA status, IGRA percentages by demographic category, and 95% confidence intervals for each percentage.Overall, 15.9% [95% confidence interval (CI) = 13.5, 18.7] of non-US-born persons were IGRA-positive. Of IGRA-positive non-US-born persons, 63.0% (95% CI = 55.4, 69.9) had insurance and 74.1% (95% CI = 69.2, 78.5) had a usual source of care. IGRA positivity was highest in persons with Medicare (29.1%; 95% CI: 20.9, 38.9).Our results suggest that targeted LTBI testing and treatment within the US private healthcare sector could reach a large majority of non-US-born individuals with LTBI. With non-US-born Medicare beneficiaries' high prevalence of LTBI and the high proportion of LTBI-positive non-US-born persons with private insurance, future TB prevention initiatives focused on these payer types are warranted.

Teste de liberação interferon-gama (interferon gamma release assay - IGRA) para detecção de tuberculose latente em pacientes imunocomprometidos / Gamma interferon release test (interferon gamma release assay - IGRA) for tuberculosis detection latent in immunocompromised patients

INTRODUÇÃO: A ILTB é definida como um estado de resposta imune persistente à estimulação por antígenos de Mycobacterium tuberculosis sem evidência, sintomas clínicos ou achados radiológicos de doença ativa. Estima-se que um terço da população mundial possua ILTB. A importância de diagnosticar a ILTB reside no potencial de reativação para a doença ativa e transmissível quando o indivíduo estiver imunossuprimido com comorbidades ou em terapia biológica. Quando identificado o potencial de desenvolvimento de doença ativa em um indivíduo com ILTB é recomendada a realização do tratamento preconizado, de forma a impedir que ocorra a reativação. A identificação e tratamento da ILTB constituem estratégias fundamentais para reduzir a carga global de tuberculose, especialmente em países em desenvolvimento. TECNOLOGIA: Teste de liberação de interferon-gama (do inglês interferon gamma release assay - IGRA). PERGUNTAS DE PESQUISA: O uso de IGRA apresenta maior acurácia na detecção de ILTB e capacidade para prever o desenvolvimento de tuberculose ativa, em comparação ao PPD, em pacientes imunocomprometidos? EVIDÊNCIAS CLÍNICAS: Foram analisadas dez revisões sistemáticas que avaliaram o desempenho do IGRA

Assessment of Interferon-Gamma Release Assay in Patients with Non-Tuberculous Mycobacteria Pulmonary Disease.

BACKGROUND: Interferon-gamma release assay (T-SPOT.TB) has the theoretical possibility of discriminating TB from most non-tuberculous mycobacteria (NTM) infections, but there are limited reports on the use of T-SPOT.TB for diseases due to NTM in high TB burden country. The aim of the present study was to assess the utility of T-SPOT.TB in patients with NTM pulmonary disease. METHODS: Clinical parameters and laboratory characteristics of patients with NTM pulmonary disease between July 2011 and Jan 2017 were investigated retrospectively and comprehensively reviewed. RESULTS: A total of 127 patients with NTM pulmonary disease were retrospectively reviewed. Seven NTM species were isolated from 115 patients, and the most common species were M. intracellulare (48.7%, 56/115) and M. abscessus (34.8%, 40/115). NTM isolates were mainly prevalent in people aged 50 years or older (73.0%). The overall positive rate of T-SPOT.TB test was 29.6% (24/81). In patients infected with NTM sharing the RD1 region of Mycobacterium tuberculosis (M. TB), 50% (3/6) were positive in the T-SPOT.TB test, whereas 28.0% (21/75) was positive in the group with NTM not sharing the RD1 region of M. TB. No significant difference was detected in the positive rate of T-SPOT.TB between definite (28.3%, 15/53) and probable disease (32.1%, 9/28). CONCLUSIONS: Our data indicated a relatively high positive rate of T-SPOT.TB test in patients infected with NTM not sharing the RD1 region of M. TB. Thus, T-SPOT.TB test displays a limited ability in differentiating TB infection from NTM disease in a high TB burden country.

Latent Tuberculosis Infection Testing Strategies for HIV-Positive Individuals in Hong Kong.

Importance: With immune recovery following early initiation of antiretroviral therapy (ART), the risk of tuberculosis (TB) reactivation among individuals with HIV could be reduced. The current strategy of annual latent TB infection (LTBI) testing should be revisited to increase cost-effectiveness and reduce the intensity of testing for individuals. Objective: To analyze the cost-effectiveness of LTBI testing strategies for individuals in Hong Kong with HIV who had negative LTBI test results at baseline. Design, Setting, and Participants: This decision analytical model study using a cost-effectiveness analysis included 3130 individuals with HIV in Hong Kong, China, which has an intermediate TB burden and a low incidence of HIV-TB coinfection. A system dynamics model of individuals with HIV attending a major HIV specialist clinic in Hong Kong was developed and parameterized by longitudinal clinical and LTBI testing records of patients during a 15-year period. The study population was stratified by age group, CD4 lymphocyte level, ART status, and right of abode. Alternative strategies for LTBI testing after a baseline test were compared with annual testing under different coverages of ART, LTBI testing, and LTBI treatment scenarios in the model. An annual discounting rate of 3.5% was used in cost-effectiveness analysis. Main Outcomes and Measures: Proportion of new TB cases averted above base case scenario, discounted quality-adjusted life-years gained (QALYG), incremental cost, and incremental cost-effectiveness ratios in 2017 to 2023. Results: A total of 3130 patients with HIV (2740 [87.5%] male and 2800 [89.5%] younger than 50 years at HIV diagnosis) with 16 630 person-years of follow-up data from 2002 to 2017 were analyzed. Of these, 94 patients (0.67 [95% CI, 0.51-0.91] per 100 person-years) developed TB. Model estimates of cumulative number of TB cases would reach 146 by 2023, with the annual number of new TB diagnoses ranging from 6 to 8. For patients who had negative LTBI test results at baseline, subsequent LTBI testing strategies were ranked by ascending effectiveness as follows: (1) no testing, (2) test by risk factors, (3) biennial testing for all, (4) up to 3 tests for all, and (5) annual testing for all. Applying a willingness-to-pay threshold of $50 000 per QALYG, none of the subsequent testing strategies were cost-effective. Test by risk factors and up to 3 tests for all were cost-effective only if the willingness-to-pay threshold was increased to $100 000 per QALYG and $200 000 per QALYG, respectively. More new TB cases would be averted by expanding LTBI testing and/or treatment coverage. Conclusions and Relevance: Changing the current testing strategy to less intense testing strategies is likely to be cost-effective in the presence of an increased coverage of baseline LTBI testing and/or treatment.

Two interferon gamma release assays for predicting active tuberculosis: the UK PREDICT TB prognostic test study.

BACKGROUND: Despite a recent decline in the annual incidence of tuberculosis (TB) in the UK, rates remain higher than in most Western European countries. The detection and treatment of latent TB infection (LTBI) is an essential component of the UK TB control programme. OBJECTIVES: To assess the prognostic value and cost-effectiveness of the current two interferon gamma release assays (IGRAs) compared with the standard tuberculin skin test (TST) for predicting active TB among untreated individuals at increased risk of TB: (1) contacts of active TB cases and (2) new entrants to the UK from high-TB-burden countries. DESIGN: A prospective cohort study and economic analysis. PARTICIPANTS AND SETTING: Participants were recruited in TB clinics, general practices and community settings. Contacts of active TB cases and migrants who were born in high-TB-burden countries arriving in the UK were eligible to take part if they were aged ≥ 16 years. MAIN OUTCOME MEASURES: Outcomes include incidence rate ratios comparing the incidence of active TB in those participants with a positive test result and those with a negative test result for each assay, and combination of tests and the cost per quality-adjusted life-year (QALY) for each screening strategy. RESULTS: A total of 10,045 participants were recruited between May 2010 and July 2015. Among 9610 evaluable participants, 97 (1.0%) developed active TB. For the primary analysis, all test data were available for 6380 participants, with 77 participants developing active TB. A positive result for TSTa (positive if induration is ≥ 5 mm) was a significantly poorer predictor of progression to active TB than a positive result for any of the other tests. Compared with TSTb [positive if induration is ≥ 6 mm without prior bacillus Calmette-Guérin (BCG) alone, T-SPOT®.TB (Oxford Immunotec Ltd, Oxford, UK), TSTa + T-SPOT.TB, TSTa + IGRA and the three combination strategies including TSTb were significantly superior predictors of progression. Compared with the T-SPOT.TB test alone, TSTa + T-SPOT.TB, TSTb + QuantiFERON® TB Gold In-Tube (QFT-GIT; QIAGEN GmbH, Hilden, Germany) and TSTb + IGRA were significantly superior predictors of progression and, compared with QFT-GIT alone, T-SPOT.TB, TSTa + T-SPOT.TB, TSTa + QFT-GIT, TSTa + IGRA, TSTb + T-SPOT.TB, TSTb + QFT-GIT and TSTb + IGRA were significantly superior predictors of progression. When evaluating the negative predictive performance of tests and strategies, negative results for TSTa + QFT-GIT were significantly poorer predictors of non-progression than negative results for TSTa, T-SPOT.TB and TSTa + IGRA. The most cost-effective LTBI testing strategies are the dual-testing strategies. The cost and QALY differences between the LTBI testing strategies were small; in particular, QFT-GIT, TSTb + T-SPOT.TB and TSTb + QFT-GIT had very similar incremental net benefit estimates. CONCLUSION: This study found modest differences between tests, or combinations of tests, in identifying individuals who would go on to develop active TB. However, a two-step approach that combined TSTb with an IGRA was the most cost-effective testing option. IMPLICATIONS FOR PRACTICE AND FUTURE RESEARCH: The two-step TSTb strategy, which stratified the TST by prior BCG vaccination followed by an IGRA, was the most cost-effective approach. The limited ability of current tests to predict who will progress limits the clinical utility of tests. The implications of these results for the NHS England/Public Health England national TB screening programme for migrants should be investigated. STUDY REGISTRATION: This study is registered as NCT01162265. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

First assessment of interferon gamma release assay results among healthcare workers at a general hospital in China.

INTRODUCTION: China has a very high tuberculosis (TB) burden. The interferon-gamma release assay (IGRA) is more specific for the diagnosis of latent tuberculosis infection (LTBI) than the tuberculin skin test, especially among populations with a high degree of coverage by the BCG vaccine. OBJECTIVES: To evaluate the first screening of healthcare workers (HCW) for LTBI using the IGRA at a general hospital in Beijing. METHODS: A pilot screening program for LTBI was triggered by accidental contact between HCW and two patients with active TB in the emergency department (ED). Given the necessity of estimating the overall LTBI prevalence in the institution, a sample of 518 HCW was enrolled in our cross-sectional study. The second IGRA was repeated with 43 of the 121 HCW in the ED after exposure to index TB cases. Data on putative risk factors were collected with a self-administered questionnaire. RESULTS: The prevalence of LTBI in the targeted population was 21.8%. Differences in the prevalence of LTBI were significantly related to age, employment duration, and history of occupational exposure. A lack of childhood BCG vaccination was independently associated with the prevalence of LTBI (adjusted OR: 1.686, 95% CI: 1.045-2.723, P = .0325). No new LTBI was diagnosed 12 weeks postexposure. No HCW adopted the preventive treatment for LTBI. CONCLUSIONS: Considering the high morbidity of LTBI among HCW even in general hospitals, it is essential to formulate government policies and institutional operation protocols for the systematic screening, registration, and administration of prophylaxes for the control of LTBI.

Validation and comparison of ELISA kits to measure interferon gamma responses in QuantiFERON cultural supernatants for diagnosis of tuberculosis.

Much effort has been made to reduce the cost of LTBI diagnosis with equivalent efficacy and efficiency of interferon-γ release assay (IGRA). This study showed that repeatability, intermediate precision, and accuracy of the Bionote-ELISA were comparable to QFT-ELISA. The Bionote-ELISA could provide the alternative method.

Assessment of the T-SPOT.CMV interferon-γ release assay in renal transplant recipients: A single center cohort study.

BACKGROUND: The measurement of CMV specific cellular immunity in organ transplant recipients could contribute additional acuity to serology based, CMV infection risk stratification, facilitating optimisation of immunosuppression and anti-viral prophylaxis. METHODS: A pilot study of renal transplant recipient (RTR's) responses in the T-SPOT.CMV ELISPOT based assay. 108 RTR's were recruited 3 months post-transplantation, immediately prior to the cessation of stratified anti-viral prophylaxis, used in recipients from seropositive donors. RTR's were monitored for CMV viremia and disease. Cellular responses to peptides derived from CMV IE1 and pp65 were measured, using the T-SPOT.CMV assay. RESULTS: At recruitment, no CMV specific cellular immunity was detected by T-SPOT.CMV in CMV seronegative recipients (IE1 ≤ 1spot / 2.5x105 PBMC's; pp65 ≤ 3 spots / 2.5x105 PBMC's). At recruitment, CMV sero-positive recipients who made a robust response to both IE1 (>25 spots / 2.5x105 PBMC's) and pp65 (>50 spots / 2.5x105 PBMC's), were less likely to develop high level viremia than those who responded to one or neither antigen (0/28 vs 5/25; p<0.02). CONCLUSIONS: In CMV seronegative RTR's, CMV specific cellular immunity measured by T-SPOT.CMV was not detected prior to cessation of anti-viral prophylaxis. This differs from recent reports of CMV specific cellular immunity in a proportion of CMV seronegative RTR's, associated with protection from CMV infection. In seropositive RTR's, a dual response to IE1 and pp65 at recruitment, was associated with protection from subsequent viremia. This suggests that assessing the diversity of response to CMV antigens, may enhance risk stratification in this group.

Assessment of an ultra-sensitive IFNγ immunoassay prototype for latent tuberculosis diagnosis.

Worldwide there are about 1.7 billion individuals with latent tuberculosis infection (LTBI) and only 5% to 15% will develop active tuberculosis (TB). It is recommended to treat only those most at risk of developing active TB to avoid problems of drug resistance. LTBI diagnosis involves reviewing the individual's medical history, physical examination, and biological tests. Interferon gamma release assays (IGRA) can yield "undeterminate" or "uncertain" results, which makes clinical management decisions difficult. We assessed an ultra-sensitive immunoassay prototype based on single molecule array (SiMoA) technology to evaluate its overall performance, and in particular, its performance for indeterminate and uncertain positive or negative samples, as classified by the results from the current ELISA technique used for IFNγ quantification. We analyzed samples from hospitalized or consulting patients and healthcare workers from three hospitals in Paris, previously classified as negative (n = 30), positive (n = 35), uncertain negative (n = 25), uncertain positive (n = 31), or indeterminate (n = 30). We observed that with the SiMoA assay 83.3% of the indeterminate samples became interpretable and could be classified as negative, whereas 74% of uncertain positive samples were classified as positive. Most uncertain negative samples (72%) were reclassified as uncertain positive (68%) or positive (4%). The results suggest that the ultra-sensitive SiMoA IFNγ assay could represent a useful tool for the identification of true positive and negative samples among those giving indeterminate or uncertain results with the TB IGRA assay currently used.

Assessment of the influence of direct tobacco smoke on infection and active TB management.

BACKGROUND: Smoking is a risk factor for tuberculosis (TB) infection and disease progression. Tobacco smoking increases susceptibility to TB in a variety of ways, one of which is due to a reduction of the IFN-γ response. Consequently, an impaired immune response could affect performance of IFN-γ Release Assays (IGRAs). OBJECTIVE: In the present study, we assess the impact of direct tobacco smoking on radiological manifestations, sputum conversion and immune response to Mycobacterium tuberculosis, analyzing IFN-γ secretion by IGRAs. METHODS: A total of 525 participants were studied: (i) 175 active pulmonary TB patients and (ii) 350 individuals coming from contact tracing studies, 41 of whom were secondary TB cases. Clinical, radiological and microbiological data were collected. T-SPOT.TB and QFN-G-IT were processed according manufacturer's instructions. RESULTS: In smoking patients with active TB, QFN-G-IT (34.4%) and T-SPOT.TB (19.5%) had high frequencies of negative results. In addition, by means of an unconditional logistic regression, smoking was a main factor associated with IGRAs' false-negative results (aOR: 3.35; 95%CI:1.47-7.61; p<0.05). Smoking patients with active TB presented a high probability of having cavitary lesions (aOR: 1.88; 95%CI:1.02-3.46;p<0.05). Mean culture negativization (months) ± standard deviation (SD) was higher in smokers than in non-smokers (2.47±1.3 versus 1.69±1.4). Latent TB infection (LTBI) was favored in smoking contacts, being a risk factor associated with infection (aOR: 11.57; 95%CI:5.97-22.41; p<0.00005). The IFN-γ response was significantly higher in non-smokers than in smokers. Smoking quantity and IFN-γ response analyzed by IGRAs were dose-dependent related. CONCLUSIONS: Smoking had a negative effect on radiological manifestations, delaying time of sputum conversion. Our data establish a link between tobacco smoking and TB due to a weakened IFN-γ response caused by direct tobacco smoke.