Latent tuberculosis infection in patients with rheumatic diseases

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ABSTRACT

Most people infected by Mycobacterium tuberculosis (Mtb) do not have any signs or disease symptoms, a condition known as latent tuberculosis infection (LTBI). The introduction of biological agents, mainly tumor necrosis factor (TNF) inhibitors, for the treatment of immune-mediated diseases such as Rheumatoid Arthritis (RA) and other rheumatic diseases, increased the risk of reactivation of LTBI, leading to development of active TB. Thus, this review will approach the aspects related to LTBI in patients with rheumatologic diseases, especially those using iTNF drugs. For this purpose it will be considered the definition and prevalence of LTBI, mechanisms associated with diseases and medications in use, criteria for screening, diagnosis and treatment. Considering that reactivation of LTBI accounts for a large proportion of the incidence of active TB, adequate diagnosis and treatment are crucial, especially in high-risk groups such as patients with rheumatologic diseases.

RESUMO

A maioria das pessoas infectadas por Mycobacterium tuberculosis (Mtb) não possui sinais ou sintomas da doença, quadro conhecido como infecção latente por tuberculose (ILTB). A introdução de agentes biológicos, sobretudo inibidores do fator de necrose tumoral (iTNF), para o tratamento de doenças imunomediadas, como artrite reumatoide (AR) e outras doenças reumatológicas, aumentou o risco de reativação de ILTB, levando ao desenvolvimento de tuberculose (TB) ativa. Assim, esta revisão abordará os aspectos relacionados à ILTB em pacientes com doenças reumatológicas, especialmente naqueles em uso de medicamentos iTNF. Para tanto, serão considerados a definição e a prevalência de ILTB, os mecanismos associados às doenças e às medicações em uso, bem como os critérios para rastreamento, diagnóstico e tratamento da ILTB. Como a reativação da ILTB é responsável pela grande proporção de casos de TB ativa, o diagnóstico e o tratamento adequados são cruciais, principalmente em grupos de alto risco, como os pacientes com doenças reumatológicas.

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Most cited references 50

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Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: an update.

Madhukar Pai, Alice Zwerling, Dick Menzies (2008)

Interferon-gamma-release assays (IGRAs) are alternatives to the tuberculin skin test (TST). A recent meta-analysis showed that IGRAs have high specificity, even among populations that have received bacille Calmette-Guérin (BCG) vaccination. Sensitivity was suboptimal for TST and IGRAs. To incorporate newly reported evidence from 20 studies into an updated meta-analysis on the sensitivity and specificity of IGRAs. PubMed was searched through 31 March 2008, and citations of all original articles, guidelines, and reviews for studies published in English were reviewed. Studies that evaluated QuantiFERON-TB Gold, QuantiFERON-TB Gold In-Tube (both from Cellestis, Victoria, Australia), and T-SPOT.TB (Oxford Immunotec, Oxford, United Kingdom) or its precommercial ELISpot version, when data on the commercial version were lacking. For assessing sensitivity, the study sample had to have microbiologically confirmed active tuberculosis. For assessing specificity, the sample had to comprise healthy, low-risk individuals without known exposure to tuberculosis. Studies with fewer than 10 participants and those that included only immunocompromised participants were excluded. One reviewer abstracted data on participant characteristics, test characteristics, and test performance from 38 studies; these data were double-checked by a second reviewer. The original investigators were contacted for additional information when necessary. A fixed-effects meta-analysis with correction for overdispersion was done to pool data within prespecified subgroups. The pooled sensitivity was 78% (95% CI, 73% to 82%) for QuantiFERON-TB Gold, 70% (CI, 63% to 78%) for QuantiFERON-TB Gold In-Tube, and 90% (CI, 86% to 93%) for T-SPOT.TB. The pooled specificity for both QuantiFERON tests was 99% among non-BCG-vaccinated participants (CI, 98% to 100%) and 96% (CI, 94% to 98%) among BCG-vaccinated participants. The pooled specificity of T-SPOT.TB (including its precommercial ELISpot version) was 93% (CI, 86% to 100%). Tuberculin skin test results were heterogeneous, but specificity in non-BCG-vaccinated participants was consistently high (97% [CI, 95% to 99%]). Most studies were small and had limitations, including no gold standard for diagnosing latent tuberculosis and variable TST methods and cutoff values. Data on the specificity of the commercial T-SPOT.TB assay were limited. The IGRAs, especially QuantiFERON-TB Gold and QuantiFERON-TB Gold In-Tube, have excellent specificity that is unaffected by BCG vaccination. Tuberculin skin test specificity is high in non-BCG-vaccinated populations but low and variable in BCG-vaccinated populations. Sensitivity of IGRAs and TST is not consistent across tests and populations, but T-SPOT.TB appears to be more sensitive than both QuantiFERON tests and TST.

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Compromised Function of Regulatory T Cells in Rheumatoid Arthritis and Reversal by Anti-TNFα Therapy

Michael Ehrenstein, Jamie G. Evans, Animesh Singh … (2004)

Regulatory T cells have been clearly implicated in the control of disease in murine models of autoimmunity. The paucity of data regarding the role of these lymphocytes in human autoimmune disease has prompted us to examine their function in patients with rheumatoid arthritis (RA). Regulatory (CD4+CD25+) T cells isolated from patients with active RA displayed an anergic phenotype upon stimulation with anti-CD3 and anti-CD28 antibodies, and suppressed the proliferation of effector T cells in vitro. However, they were unable to suppress proinflammatory cytokine secretion from activated T cells and monocytes, or to convey a suppressive phenotype to effector CD4+CD25− T cells. Treatment with antitumor necrosis factor α (TNFα; Infliximab) restored the capacity of regulatory T cells to inhibit cytokine production and to convey a suppressive phenotype to “conventional” T cells. Furthermore, anti-TNFα treatment led to a significant rise in the number of peripheral blood regulatory T cells in RA patients responding to this treatment, which correlated with a reduction in C reactive protein. These data are the first to demonstrate that regulatory T cells are functionally compromised in RA, and indicate that modulation of regulatory T cells by anti-TNFα therapy may be a further mechanism by which this disease is ameliorated.

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LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement.

G Bothamley, L N V S Arend, P Ravn … (2009)

Tuberculosis control relies on the identification and preventive treatment of individuals who are latently infected with Mycobacterium tuberculosis. However, direct identification of latent tuberculosis infection is not possible. The diagnostic tests used to identify individuals latently infected with M. tuberculosis, the in vivo tuberculin skin test and the ex vivo interferon-gamma release assays (IGRAs), are designed to identify an adaptive immune response against, but not necessarily a latent infection with, M. tuberculosis. The proportion of individuals who truly remain infected with M. tuberculosis after tuberculin skin test or IGRA conversion is unknown. It is also uncertain how long adaptive immune responses towards mycobacterial antigens persist in the absence of live mycobacteria. Clinical management and public healthcare policies for preventive chemotherapy against tuberculosis could be improved, if we were to gain a better understanding on M. tuberculosis latency and reactivation. This statement by the TBNET summarises knowledge and limitations of the currently available tests used in adults and children for the diagnosis of latent tuberculosis infection. In summary, the main issue regarding testing is to restrict it to those who are known to be at higher risk of developing tuberculosis and who are willing to accept preventive chemotherapy.

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Author and article information

Journal

Journal ID (nlm-ta): J Bras Pneumol

Journal ID (iso-abbrev): J Bras Pneumol

Journal ID (publisher-id): jbpneu

Title: Jornal Brasileiro de Pneumologia

Publisher: Sociedade Brasileira de Pneumologia e Tisiologia

ISSN (Print): 1806-3713

ISSN (Electronic): 1806-3756

Publication date (Print and electronic): Mar-Apr 2019

Publication date (Print): Mar-Apr 2019

Volume: 45

Issue: 2

Electronic Location Identifier: e20190023

Affiliations

[1 ]. Programa de Pós-Graduação em Ciências Pneumológicas, Universidade Federal do Rio Grande do Sul, Porto Alegre (RS), Brasil.

[2 ]. Serviço de Pneumologia, Hospital de Clínicas de Porto Alegre, Porto Alegre (RS), Brasil.

[3 ]. Serviço de Reumatologia, Hospital de Clínicas de Porto Alegre, Porto Alegre (RS), Brasil.

[4 ]. Instituto de Doenças do Tórax, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro (RJ), Brasil.

Author notes

[Correspondence to: ] Denise Rossato Silva. Rua Ramiro Barcelos, 2350, Sala 2050, Bairro Santa Cecília, CEP: 900035-903, Porto Alegre, RS, Brasil. Tel.: 51 3359-8000. E-mail: denise.rossato@ 123456terra.com.br