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1.
Brasília; CONITEC; out. 2020.
No convencional en Portugués | BRISA/RedTESA | ID: biblio-1141494

RESUMEN

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


Asunto(s)
Humanos , Tuberculosis Latente/diagnóstico , Tuberculosis Latente/inmunología , Ensayos de Liberación de Interferón gamma/métodos , Evaluación de la Tecnología Biomédica , Sistema Único de Salud , Brasil , Análisis Costo-Beneficio/economía
2.
PLoS One ; 15(9): e0239289, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32936814

RESUMEN

Mycobacterium tuberculosis (Mtb) is the causative agent for tuberculosis, the most extended infectious disease around the world. When Mtb enters inside the pulmonary alveolus it is rapidly phagocytosed by the alveolar macrophage. Although this controls the majority of inhaled microorganisms, in this case, Mtb survives inside the macrophage and multiplies. A posterior chemokine and cytokine cascade generated by the irruption of monocytes, neutrophils and posteriorly, by T-cells, does not necessarily stop the growth of the granuloma. Interestingly, the encapsulation process built by fibroblasts is able to surround the lesion and stop its growing. The success of this last process determines if the host enters in an asymptomatic latent state or continues into a life-threatening and infective active tuberculosis disease (TB). Understanding such dichotomic process is challenging, and computational modeling can bring new ideas. Thus, we have modeled the different stages of the infection, first in a single alveolus (a sac with a radius of 0.15 millimeters) and, second, inside a secondary lobule (a compartment of the lungs of around 3 cm3). We have employed stochastic reaction-diffusion equations to model the interactions among the cells and the diffusive transport to neighboring alveolus. The whole set of equations have successfully described the encapsulation process and determine that the size of the lesions depends on its position on the secondary lobule. We conclude that size and shape of the secondary lobule are the relevant variables to control the lesions, and, therefore, to avoid the evolution towards TB development. As lesions appear near to interlobular connective tissue they are easily controlled and their growth is drastically stopped, in this sense secondary lobules with a more flattened shape could control better the lesion.


Asunto(s)
Simulación por Computador , Granuloma/patología , Mycobacterium tuberculosis/patogenicidad , Tuberculosis/inmunología , Quimiocinas/inmunología , Citocinas/inmunología , Citocinas/metabolismo , Difusión , Granuloma/inmunología , Granuloma/microbiología , Humanos , Tuberculosis Latente/inmunología , Tuberculosis Latente/microbiología , Tuberculosis Latente/patología , Pulmón/inmunología , Pulmón/metabolismo , Macrófagos Alveolares/enzimología , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patología , Mycobacterium tuberculosis/inmunología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Fagocitosis/inmunología , Linfocitos T/inmunología , Linfocitos T/patología , Tuberculosis/microbiología , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/microbiología , Tuberculosis Pulmonar/patología
3.
PLoS Pathog ; 16(7): e1008413, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32730321

RESUMEN

Human immunodeficiency virus infection is the most common risk factor for severe forms of tuberculosis (TB), regardless of CD4 T cell count. Using a well-characterized cynomolgus macaque model of human TB, we compared radiographic, immunologic and microbiologic characteristics of early (subclinical) reactivation of latent M. tuberculosis (Mtb) infection among animals subsequently infected with simian immunodeficiency virus (SIV) or who underwent anti-CD4 depletion by a depletion antibody. CD4 depleted animals had significantly fewer CD4 T cells within granulomas compared to Mtb/SIV co-infected and Mtb-only control animals. After 2 months of treatment, subclinical reactivation occurred at similar rates among CD4 depleted (5 of 7 animals) and SIV infected animals (4 of 8 animals). However, SIV-induced reactivation was associated with more dissemination of lung granulomas that were permissive to Mtb growth resulting in greater bacterial burden within granulomas compared to CD4 depleted reactivators. Granulomas from Mtb/SIV animals displayed a more robust T cell activation profile (IFN-α, IFN-γ, TNF, IL-17, IL-2, IL-10, IL-4 and granzyme B) compared to CD4 depleted animals and controls though these effectors did not protect against reactivation or dissemination, but instead may be related to increased viral and/or Mtb antigens. SIV replication within the granuloma was associated with reactivation, greater overall Mtb growth and reduced Mtb killing resulting in greater overall Mtb burden. These data support that SIV disrupts protective immune responses against latent Mtb infection beyond the loss of CD4 T cells, and that synergy between SIV and Mtb occurs within granulomas.


Asunto(s)
Coinfección/inmunología , Tuberculosis Latente/inmunología , Tuberculosis Latente/virología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Activación Viral/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Granuloma/virología , Huésped Inmunocomprometido/inmunología , Macaca fascicularis , Mycobacterium tuberculosis/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología
4.
Sci Rep ; 10(1): 7472, 2020 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-32366931

RESUMEN

Tuberculin skin test (TST) and IFN-γ release assays are currently used to detect Mycobacterium tuberculosis (Mtb) infection but none of them differentiate active from latent infection (LTBI). Since improved tests to diagnose Mtb infection are required, we studied the immune response to Mtb latency antigen Rv2626c in individuals exposed to the bacteria during different periods. Tuberculosis patients (TB), TB close contacts (CC: subjects exposed to Mtb for less than three months) and healthcare workers (HW: individuals exposed to Mtb at least two years) were recruited and QuantiFERON (QFT) assay, TST and IFN-γ secretion to Rv2626c were analyzed. Twenty-two percent of the individuals assessed had discordant results between QFT and TST tests. Furthermore, QFT negative and QFT positive individuals produced differential levels of IFN-γ against Rv2626c, in direct association with their exposure period to Mtb. Actually, 91% of CC QFT negative subjects secreted low levels of IFN-γ to Rv2626c, whereas 43% of HW QFT negative people produced elevated IFN-γ amounts against Rv2626c. Conversely, 69% of CC QFT positive subjects didn´t produce IFN-γ to Rv2626c. Interestingly, a similar pattern of IgG anti-Rv2626c plasma levels was observed. Therefore, determination of IFN-γ and IgG levels against the dormancy antigen Rv2626c allows to identify established LTBI.


Asunto(s)
Anticuerpos Antibacterianos , Antígenos Bacterianos , Inmunoglobulina G , Interferón gamma , Tuberculosis Latente , Mycobacterium tuberculosis , Adolescente , Adulto , Anciano , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Antígenos Bacterianos/sangre , Antígenos Bacterianos/inmunología , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Interferón gamma/sangre , Interferón gamma/inmunología , Tuberculosis Latente/sangre , Tuberculosis Latente/diagnóstico , Tuberculosis Latente/inmunología , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/metabolismo
6.
Mol Immunol ; 120: 187-195, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32179338

RESUMEN

BACKGROUND: To facilitate better discrimination between patients with active tuberculosis (TB) and latent TB infection (LTBI), whole blood transcriptomic studies have been performed to identify novel candidate host biomarkers. SERPING1, which encodes C1-inhibitor (C1-INH), the natural inhibitor of the C1-complex has emerged as candidate biomarker. Here we collated and analysed SERPING1 expression data and subsequently determined C1-INH protein levels in four cohorts of patients with TB. METHODS: SERPING1 expression data were extracted from online deposited datasets. C1-INH protein levels were determined by ELISA in sera from individuals with active TB, LTBI as well as other disease controls in geographically diverse cohorts. FINDINGS: SERPING1 expression was increased in patients with active TB compared to healthy controls (8/11 cohorts), LTBI (13/14 cohorts) and patients with other (non-TB) lung-diseases (7/7 cohorts). Serum levels of C1-INH were significantly increased in The Gambia and Italy in patients with active TB relative to the endemic controls but not in South Africa or Korea. In the largest cohort (n = 50), with samples collected longitudinally, normalization of C1-INH levels following successful TB treatment was observed. This cohort, also showed the most abundant increase in C1-INH, and a positive correlation between C1q and C1-INH levels. Combined presence of increased levels of both C1q and C1-INH had high specificity for active TB (96 %) but only very modest sensitivity 38 % compared to the endemic controls. INTERPRETATION: SERPING1 transcript expression is increased in TB patients, while serum protein levels of C1-INH were increased in half of the cohorts analysed.


Asunto(s)
Proteína Inhibidora del Complemento C1/biosíntesis , Proteína Inhibidora del Complemento C1/genética , Tuberculosis Latente/genética , Tuberculosis Latente/inmunología , Tuberculosis Pulmonar/genética , Tuberculosis Pulmonar/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Estudios de Casos y Controles , Estudios de Cohortes , Proteína Inhibidora del Complemento C1/metabolismo , Complemento C1q/metabolismo , Femenino , Expresión Génica , Humanos , Tuberculosis Latente/sangre , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Tuberculosis Pulmonar/sangre , Adulto Joven
7.
PLoS One ; 15(3): e0230376, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32182274

RESUMEN

INTRODUCTION: Household contacts of patients with active pulmonary tuberculosis (TB) often have latent TB infection, and are at risk of progression to disease. We set out to investigate whether index TB case HIV status was linked to a higher probability of latent TB infection among household contacts. MATERIALS AND METHODS: Data were collected prospectively from participants in the intervention arm of a household cluster-randomised trial in two South Africa provinces (Mangaung, Free State, and Capricorn, Limpopo). In intervention group households, TB contacts underwent HIV testing and tuberculin skin testing (TST). TST induration was estimated at two cut-offs (≥5mm, ≥10mm). Multilevel Bayesian regression models estimated posterior distributions of the percentage of household contacts with TST induration ≥5mm and ≥10mm by age group, and compared the odds of latent TB infection by key risk factors including HIV status index case age and study province. RESULTS: A total of 2,985 household contacts of 924 index cases were assessed, with most 2,725 (91.3%) undergoing TST. HIV prevalence in household contacts was 14% and 10% in Mangaung and Capricorn respectively. Overall, 16.8% (458/2,725) had TST induration of ≥5mm and 13.1% (359/2,725) ≥10mm. In Mangaung, children aged 0-4 years had a high TST positivity prevalence compared to their peers in Capricorn (22.0% vs. 7.6%, and 20.5% vs. 2.3%, using TST thresholds of ≥5mm and ≥10mm respectively). Compared to contacts from Capricorn, household contacts living in Mangaung were more likely to have TST induration ≥5mm (odds ratio [OR]: 3.08, 95% credibility interval [CI]: 2.13-4.58) and ≥10mm (OR: 4.52, 95% CI: 3.03-6.97). There was a 90% and 92% posterior probability that the odds of TST induration ≥5mm (OR: 0.79, 95% CI: 0.56-1.14) and ≥10mm (OR: 0.77, 95% CI: 0.53-1.10) respectively were lower in household contacts of HIV-positive compared to HIV-negative index cases. CONCLUSIONS: High TST induration positivity, especially among young children and people living in Mangaung indicates considerable TB transmission despite high antiretroviral therapy coverage. Household contact of HIV-positive index TB cases were less likely to have evidence of latent TB infection than contacts of HIV-negative index cases.


Asunto(s)
Trazado de Contacto/estadística & datos numéricos , Infecciones por VIH/epidemiología , Tuberculosis Latente/epidemiología , Mycobacterium tuberculosis/aislamiento & purificación , Tuberculosis Pulmonar/transmisión , Adulto , Composición Familiar , Femenino , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Tuberculosis Latente/diagnóstico , Tuberculosis Latente/inmunología , Tuberculosis Latente/microbiología , Masculino , Mycobacterium tuberculosis/inmunología , Prevalencia , Factores de Riesgo , Sudáfrica/epidemiología , Prueba de Tuberculina , Tuberculosis Pulmonar/epidemiología , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/microbiología
8.
PLoS One ; 15(1): e0228359, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32004357

RESUMEN

Changes in expression of membrane antigens may accompany the transition of Mycobacterium tuberculosis (Mtb) from 'dormant' to 'active' states. We have determined whether antibody and T cell responses to Mtb membrane (MtM)-associated antigens, especially the latency-induced protein alpha crystallin (Acr), can discriminate between latent tuberculosis infection (LTBI) and active TB (ATB) disease. Study subjects comprised a previously described cohort of healthcare workers (HCWs, n = 43) and smear-positive ATB patients (n = 10). HCWs were further categorized as occupational contacts (OC, n = 30), household contacts of TB (HC, n = 8) and cured TB (CTB, n = 5). Levels (ΔOD) of serum antibody isotypes (IgG, IgA and IgM) were determined by ELISA and blood T cell proliferative responses were determined by flow cytometry using Ki67 protein as marker for DNA synthesis. Antibodies to MtM and Acr were predominantly IgG and their levels in HCWs and ATB did not differ significantly. However, HCWs showed a significantly higher level of anti-MtM IgM and a significantly lower level of anti-Acr IgA antibodies than the ATB patients. Also, a larger proportion of HCWs showed a high (>1) ΔODAcr/ΔODMtM ratio for IgG. HCWs also showed a higher, though not significantly different from ATB, avidity of anti-MtM (IgG) antibodies. A higher proportion of HCWs (35% of OC, 62.5% of HC and 20% of CTB), compared with ATB (10%) showed a positive T cell response to Acr along with significant difference (P <0.05) between HC and ATB. A significant correlation (r = 0.60, P <0.0001) was noted between T cell responses of HCWs towards Acr and MtM (reported earlier by us) and both responses tended to decline with rising exposure to the infection. Even so, positive responses to Acr (38.5%) were significantly lower than to MtM (92%). Neither antibody nor T cell responses to either antigen appeared affected by BCG vaccination or reactivity to tuberculin. Results of the study suggest that the levels of IgM antibodies to MtM, IgA antibodies to Acr and proliferative T cell responses to both the antigens can potentially discriminate between LTBI and active TB disease. They also underscore the necessity of SOPs for antibody assays.


Asunto(s)
Anticuerpos Antibacterianos/metabolismo , Antígenos Bacterianos/inmunología , Tuberculosis Latente/diagnóstico , Mycobacterium tuberculosis/inmunología , Tuberculosis/diagnóstico , Proliferación Celular , Diagnóstico Diferencial , Personal de Salud , Humanos , Tuberculosis Latente/inmunología , Linfocitos T/metabolismo , Tuberculosis/inmunología , alfa-Cristalinas/inmunología
9.
PLoS Pathog ; 16(2): e1008312, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-32069329

RESUMEN

TNF-α- as well as non-TNF-α-targeting biologics are prescribed to treat a variety of immune-mediated inflammatory disorders. The well-documented risk of tuberculosis progression associated with anti-TNF-α treatment highlighted the central role of TNF-α for the maintenance of protective immunity, although the rate of tuberculosis detected among patients varies with the nature of the drug. Using a human, in-vitro granuloma model, we reproduce the increased reactivation rate of tuberculosis following exposure to Adalimumab compared to Etanercept, two TNF-α-neutralizing biologics. We show that Adalimumab, because of its bivalence, specifically induces TGF-ß1-dependent Mycobacterium tuberculosis (Mtb) resuscitation which can be prevented by concomitant TGF-ß1 neutralization. Moreover, our data suggest an additional role of lymphotoxin-α-neutralized by Etanercept but not Adalimumab-in the control of latent tuberculosis infection. Furthermore, we show that, while Secukinumab, an anti-IL-17A antibody, does not revert Mtb dormancy, the anti-IL-12-p40 antibody Ustekinumab and the recombinant IL-1RA Anakinra promote Mtb resuscitation, in line with the importance of these pathways in tuberculosis immunity.


Asunto(s)
Mycobacterium tuberculosis/metabolismo , Tuberculosis/inmunología , Inhibidores del factor de Necrosis Tumorales/farmacología , Adalimumab/farmacología , Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Monoclonales Humanizados/metabolismo , Anticuerpos Monoclonales Humanizados/farmacología , Etanercept/farmacología , Granuloma/tratamiento farmacológico , Granuloma/metabolismo , Humanos , Factores Inmunológicos/metabolismo , Tuberculosis Latente/inmunología , Modelos Biológicos , Mycobacterium tuberculosis/inmunología , Factor de Crecimiento Transformador beta1/metabolismo , Inhibidores del factor de Necrosis Tumorales/metabolismo , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo
10.
J Immunol ; 204(5): 1274-1286, 2020 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-31953351

RESUMEN

Helminth infections are known to influence T and B cell responses in latent tuberculosis infection (LTBI). Whether helminth infections also modulate monocyte responses in helminth-LTBI coinfection has not been fully explored. To this end, we examined the activation, polarization, and function of human monocytes isolated from individuals with LTBI with (n = 25) or without (n = 25) coincident Strongyloides stercoralis infection (S. stercoralis-positive and S. stercoralis-negative respectively). Our data reveal that the presence of S. stercoralis infection is associated with lower frequencies of monocytes expressing CD54, CD80, CD86 at baseline (absence of stimulation) and in response to mycobacterial-Ag stimulation than monocytes from S. stercoralis-negative individuals. In contrast, S. stercoralis infection was associated with higher frequencies of M2-like monocytes, as determined by expression of CD206 and CD163. Monocytes from S. stercoralis-positive individuals had a reduced capacity to phagocytose or exhibit respiratory burst activity following mycobacterial-Ag or LPS stimulation and were less capable of expression of IL-1ß, TNF-α, IL-6, and IL-12 at baseline and/or following Ag stimulation compared with those without S. stercoralis infection. In addition, definitive treatment of S. stercoralis infection resulted in a significant reversal of the altered monocyte function 6 mo after anthelmintic therapy. Finally, T cells from S. stercoralis-positive individuals exhibited significantly lower activation at baseline or following mycobacterial-Ag stimulation. Therefore, our data highlight the induction of dampened monocyte activation, enhanced M2 polarization, and impaired monocyte function in helminth-LTBI coinfection. Our data also reveal a different mechanism by which helminth infection modulates immune function in LTBI.


Asunto(s)
Coinfección , Monocitos , Mycobacterium tuberculosis/inmunología , Strongyloides stercoralis/inmunología , Estrongiloidiasis , Adulto , Animales , Antígenos CD/inmunología , Coinfección/inmunología , Coinfección/microbiología , Coinfección/parasitología , Coinfección/patología , Citocinas/inmunología , Femenino , Humanos , Tuberculosis Latente/inmunología , Tuberculosis Latente/parasitología , Tuberculosis Latente/patología , Masculino , Monocitos/inmunología , Monocitos/patología , Estrongiloidiasis/inmunología , Estrongiloidiasis/microbiología , Estrongiloidiasis/patología
11.
APMIS ; 128(4): 343-349, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31976577

RESUMEN

The purpose of this study was to compare the Quantiferon-TB Gold Plus test analysed with chemiluminescence immunoassay (CLIA) to immunoassay (EIA). One hundred and twenty-five clinical specimens submitted to Karolinska University Hospital for Quantiferon-TB Gold Plus analysis were used to analyse agreement of the CLIA and EIA assays. The imprecision on CLIA was determined by analysis of pooled clinical samples of antigen tubes (TB1 and TB2), a reference material from National Institute for Biological Standards and Control (NIBSC 82/587) and two controls of the test. Recovery on CLIA was determined by analysis of the TB1 and TB2 samples and NIBSC 82/587. Concordant results were obtained for 110 (88.0%) of 125 samples with cut-off including a borderline range. With no borderline range, 121 of 125 samples (96.8%) showed concordant results. Repeatability had a coefficient of variation (CV) of 14.9%. Reproducibility for pooled clinical samples TB1 and TB2 had a CV of 10.5% and 11.0%, respectively, and for the NIBSC 82/587 7.45%, and kit controls 31.0% respective 12.2%. Overall recovery had a mean of 94.1% (SD 12%). We concluded that Quantiferon-TB Gold Plus analysed with the CLIA assay shows good concordance with EIA and acceptable imprecision.


Asunto(s)
Inmunoensayo/métodos , Tuberculosis Latente/inmunología , Mediciones Luminiscentes/métodos , Antígenos Bacterianos/inmunología , Humanos , Mycobacterium tuberculosis/inmunología , Reproducibilidad de los Resultados
12.
J Infect Dis ; 221(1): 162-167, 2020 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-31419285

RESUMEN

The reconstitution of Mycobacterium tuberculosis antigen-specific CD4 T cells in a cohort of HIV-infected persons starting antiretroviral treatment (ART) in a high tuberculosis endemic area is described. Restoration of the antigen-specific CD4 T-cell subsets mirrored the overall CD4 T-cell compartment. Activation (assessed by HLA-DR expression) decreased during ART but remained elevated compared to HIV-uninfected persons. Despite known M. tuberculosis sensitization determined by interferon-γ release assay, 12/23 participants had no M. tuberculosis-specific CD4 T cells detectable by flow cytometry, combined with overall elevated T-cell activation and memory differentiation, suggesting heightened turnover. Our data suggest early ART initiation to maintain polyfunctional immune memory responses.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Tuberculosis Latente/inmunología , Mycobacterium tuberculosis/inmunología , Adulto , Antígenos Bacterianos/inmunología , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/metabolismo , Femenino , Citometría de Flujo , Infecciones por VIH/complicaciones , Antígenos HLA-DR/metabolismo , Humanos , Memoria Inmunológica , Ensayos de Liberación de Interferón gamma , Tuberculosis Latente/diagnóstico , Activación de Linfocitos , Masculino
13.
Ann Rheum Dis ; 79(2): 292-299, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31791950

RESUMEN

OBJECTIVES: To evaluate the rate of tuberculosis (TB) in biologic users for rheumatic diseases in South Africa, the effectiveness of our latent TB infection (LTBI) programme, risk factors and outcome. METHODS: TB cases were collected from the South African Biologics Registry (SABIO), rheumatologists and pharmaceutical companies. Demographics, LTBI screening and treatment, biological and disease modifying antirheumatic drug (DMARD) therapies, TB diagnosis and outcomes were recorded. RESULTS: 96 TB cases were collected from 1999 to June 2017: rheumatoid arthritis 55, ankylosing spondylitis 27, psoriatic arthritis 4, and juvenile inflammatory arthritis 10. The TB rate was 1240/100 000 person years for biologic users (n=96) versus the biologic naive cohort of 0/100 000 years with an incidence rate difference of 0.0124 (p<0.0001). 60/96 had pulmonary and 36/96 had extra-pulmonary TB. Reactivation TB occurred in 45/96 cases. TB occurred in all biologics licenced in South Africa, the majority in monoclonal inhibitors (1683/100 000 person years) compared with etanercept (861/100 000 person years) and non-tumour necrosis factor (TNF) inhibitors (681/100 000 person years). The incidence rate ratio for monoclonal inhibitors compared with etanercept was 1.96 (p=0.005) and 2.47 (p=0.002) compared with non-TNF inhibitors with no significant difference between non-TNF inhibitors and etanercept (p=0.336). From those (12.9%) who screened LTBI positive, 14 developed TB, while the majority (77) screened LTBI negative. Black race, male sex, younger age and residence in the Western Cape were statistical risk factors. Two drug resistant TB cases and six deaths occurred. CONCLUSION: Reactivation and new onset TB is a significant risk for all biologics users in SA. Screening for LTBI is an imperative preventative strategy.


Asunto(s)
Antirreumáticos/efectos adversos , Productos Biológicos/efectos adversos , Tuberculosis Latente/epidemiología , Enfermedades Reumáticas/tratamiento farmacológico , Tuberculosis Pulmonar/epidemiología , Adulto , Antirreumáticos/inmunología , Productos Biológicos/inmunología , Femenino , Humanos , Incidencia , Tuberculosis Latente/inducido químicamente , Tuberculosis Latente/inmunología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sistema de Registros , Enfermedades Reumáticas/inmunología , Sudáfrica/epidemiología , Tuberculosis Pulmonar/inducido químicamente , Tuberculosis Pulmonar/inmunología
14.
Int J Infect Dis ; 91: 177-181, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31877486

RESUMEN

OBJECTIVES: High accuracy diagnostic screening tests for tuberculosis (TB) are required to improve the diagnosis of both active TB and latent Mycobacterium tuberculosis (MTB) infection (LTBI). The novel IGRA LIOFeron®TB/LTBI assay was tested and its accuracy was compared to the QuantiFERON®-TB Gold Plus assay. METHODS: A total of 389 subjects were enrolled in two cohorts and classified as healthy, active TB or LTBI persons. The blood of all the patients was tested with LIOFeron®TB/LTBI assay, containing MTB alanine dehydrogenase, able to differentiate active TB from LTBI diagnosis. The results obtained with both IGRAs, performed on the same 250 samples, were finally compared. RESULTS: The two assays demonstrated an excellent concordance of their results with patients' diagnosis of MTB infection. ROC analysis for QuantiFERON®-TB Gold Plus showed sensitivity and specificity respectively of 98% and 97% in diagnosing active TB patients and 85% and 94% in diagnosing LTBI subjects. LIOFeron®TB/LTBI assay showed sensitivity and specificity respectively of 90% and 98% in diagnosing active TB patients and 94% and 97% in diagnosing LTBI subjects. CONCLUSIONS: The two IGRAs displayed the same high accuracy in diagnosing MTB infection/TB disease, and LIOFeron®TB/LTBI assay demonstrated higher sensitivity than QuantiFERON®-TB Gold Plus test in LTBI detection.


Asunto(s)
Pruebas Diagnósticas de Rutina/métodos , Tuberculosis Latente/diagnóstico , Adulto , Anciano , Estudios de Cohortes , Femenino , Humanos , Tuberculosis Latente/inmunología , Tuberculosis Latente/microbiología , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/aislamiento & purificación , Mycobacterium tuberculosis/fisiología , Curva ROC , Sensibilidad y Especificidad , Linfocitos T/inmunología
16.
Infect Immun ; 88(3)2020 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-31871103

RESUMEN

Tuberculosis (TB) is an infectious disease of extremely high epidemiological burden worldwide that is easily acquired through the inhalation of infected respiratory droplets. The complex pathogenesis of this infection spans from subjects never developing this disease despite intense exposure, to others in which immune containment fails catastrophically and severe or disseminated forms of disease ensue. In recent decades, microRNAs (miRNAs) have gained increasing attention due to their role as gene silencers and because of their altered expression in diverse human diseases, including some infections. Recent research regarding miRNAs and TB has revealed that the expression profile for particular miRNAs clearly changes upon Mycobacterium tuberculosis infection and also varies in the different stages of this disease. However, despite the growing number of studies-some of which have even proposed some miRNAs as potential biomarkers-methodological variations and key differences in relevant factors, such as sex and age, cell type analyzed, M. tuberculosis strain, and antimicrobial therapy status, strongly hinder the comparison of data. In this review, we summarize and discuss the literature and highlight the role of selected miRNAs that have specifically and more consistently been associated with M. tuberculosis infection, together with a discussion of the possible gene and immune regulation pathways involved.


Asunto(s)
MicroARNs/metabolismo , Mycobacterium tuberculosis/fisiología , Tuberculosis/genética , Animales , Biomarcadores/metabolismo , Expresión Génica , Humanos , Tuberculosis Latente/genética , Tuberculosis Latente/inmunología , Macrófagos/inmunología , MicroARNs/genética , Viabilidad Microbiana , Mycobacterium tuberculosis/patogenicidad , Transducción de Señal/inmunología , Tuberculosis/inmunología
17.
PLoS One ; 14(12): e0225611, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31821327

RESUMEN

Undernutrition, as described by low body mass index (BMI), is a foremost risk factor for the progression of active Tuberculosis (TB). Undernutrition is also known to impact the baseline frequencies of innate and adaptive immune cells in animal models. To verify whether undernutrition has any influence on the baseline frequencies of immune cells in latent Mycobacterium tuberculosis infection (LTBI), we examined the frequencies of T cell-, B cell, monocyte- and dendritic cell (DC)- subsets in individuals with LTBI and low BMI (LBMI) and contrasted them with LTBI and normal BMI (NBMI) groups. LBMI was characterized by decreased frequencies and absolute cell counts of T cells, B cells and NK cells in comparison with NBMI. LBMI individuals demonstrated significantly enhanced frequencies of naïve and effector CD4+ and CD8+ T cells and significantly decreased frequencies of central memory, effector memory CD4+ and CD8+ T cells and regulatory T cells. Among B cell subsets, LBMI individuals demonstrated significantly diminished frequencies of naïve, immature, classical memory, activated memory, atypical memory and plasma cells. In addition, LBMI individuals showed significantly decreased frequencies of classical monocytes, myeloid DCs and plasmacytoid DCs and significantly increased frequencies of intermediate and non-classical monocytes and myeloid derived suppressor cells. BMI exhibited a positive correlation with B cell and NK cell counts. Our data, therefore, demonstrates that coexistent undernutrition in LTBI is characterized by the occurrence of a significant modulation in the frequency of innate and adaptive immune cell subsets.


Asunto(s)
Inmunidad Celular , Inmunidad Innata , Tuberculosis Latente/inmunología , Desnutrición/inmunología , Tuberculosis Pulmonar/epidemiología , Adolescente , Adulto , Anciano , Linfocitos B/inmunología , Índice de Masa Corporal , Células Dendríticas/inmunología , Progresión de la Enfermedad , Susceptibilidad a Enfermedades/epidemiología , Susceptibilidad a Enfermedades/inmunología , Femenino , Humanos , India/epidemiología , Tuberculosis Latente/sangre , Tuberculosis Latente/microbiología , Masculino , Desnutrición/sangre , Desnutrición/epidemiología , Persona de Mediana Edad , Monocitos/inmunología , Mycobacterium tuberculosis/inmunología , Factores de Riesgo , Población Rural/estadística & datos numéricos , Linfocitos T/inmunología , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/microbiología , Adulto Joven
18.
PLoS One ; 14(12): e0225556, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31821340

RESUMEN

BACKGROUND: Currently, there are serious limitations in the direct diagnosis of active tuberculosis (ATB). We evaluated the levels of the IL-18/IL-37/IP-10 signalling complex proteins in Mycobacterium tuberculosis (M.tb)-specific antigen-stimulated QuantiFERON® Gold In-Tube (QFT) cultures and in serum samples from ATB patients, healthy individuals with latent M.tb infection (LTBI) and healthy controls (HC) to examine whether combined analyses of these proteins were useful in the differentiation of M.tb states. METHODS: The concentrations of IL-18, IL-18BP, IFN-γ, IL-37 and IP-10 in the serum and QFT supernatants were measured using specific enzyme-linked immunosorbent assay (ELISA) kits. Free IL-18 levels were calculated using the law of mass action. RESULTS: Increased concentrations of total and free IL-18, IL-18BP, IFN-γ and IP-10 in the sera of ATB patients were detected. These increases were not counterbalanced by the overproduction of IL-37. Complex co-expression of serum IL-18BP and IL-37, IP-10 and IFN-γ was identified as the highest discriminative biomarker set for the diagnosis of ATB. CONCLUSIONS: Our results suggest that the IL-18 signalling complex might be exploited by M. tuberculosis to expand the clinical manifestations of pulmonary TB. Therefore, direct analysis of the serum components of the IL-18/IL-37 signalling complex and IP-10 may be applicable in designing novel diagnostic tests for ATB.


Asunto(s)
Quimiocina CXCL10/sangre , Interleucina-18/sangre , Interleucina-1/sangre , Tuberculosis Latente/diagnóstico , Tuberculosis Pulmonar/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Quimiocina CXCL10/inmunología , Estudios de Cohortes , Diagnóstico Diferencial , Femenino , Humanos , Péptidos y Proteínas de Señalización Intercelular/sangre , Péptidos y Proteínas de Señalización Intercelular/inmunología , Interferón gamma/sangre , Interferón gamma/inmunología , Tuberculosis Latente/sangre , Tuberculosis Latente/inmunología , Masculino , Persona de Mediana Edad , Polonia , Tuberculosis Pulmonar/sangre , Tuberculosis Pulmonar/inmunología , Adulto Joven
19.
Front Immunol ; 10: 2807, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31849981

RESUMEN

Mycobacterium tuberculosis (M. tuberculosis) produces a diverse range of antigenic proteins in its dormant phase. The cytokine profiles of CD4+ T cell responses, especially subsets other than Th1 type (non-Th1 type), against these latency-associated M. tuberculosis antigens such as α-crystallin (Acr), heparin-binding hemagglutinin (HBHA), and mycobacterial DNA-binding protein 1 (MDP-1) remain elusive in relation to the clinical stage of M. tuberculosis infection. In the present study, peripheral blood mononuclear cells (PBMCs) collected from different stages of M. tuberculosis-infected cases and control PBMCs were stimulated with these antigens and ESAT-6/CFP-10. Cytokine profiles of CD4+ T cells were evaluated by intracellular cytokine staining using multicolor flow cytometry. Our results demonstrate that Th1 cytokine responses were predominant after TB onset independent of the type of antigen stimulation. On the contrary, non-Th1 cytokine responses were preferentially induced by latency-associated M. tuberculosis antigens, specifically IL-10 response against Acr in latent M. tuberculosis infection. From these results, we surmise a shift in the CD4+ T cell response from mixed non-Th1 to Th1 dominant type during TB progression.


Asunto(s)
Antígenos Bacterianos/inmunología , Linfocitos T CD4-Positivos/inmunología , Tuberculosis Latente/inmunología , Mycobacterium tuberculosis/inmunología , Células TH1/inmunología , Adulto , Linfocitos T CD4-Positivos/metabolismo , Estudios de Casos y Controles , Citocinas/metabolismo , Femenino , Humanos , Tuberculosis Latente/metabolismo , Tuberculosis Latente/microbiología , Masculino , Persona de Mediana Edad , Células TH1/metabolismo , Adulto Joven
20.
Cell Rep ; 29(11): 3564-3579.e5, 2019 12 10.
Artículo en Inglés | MEDLINE | ID: mdl-31825836

RESUMEN

The immunometabolic mechanisms underlying suboptimal T cell immunity in tuberculosis remain undefined. Here, we examine how chronic Mycobacterium tuberculosis (Mtb) and M. bovis BCG infections rewire metabolic circuits and alter effector functions in lung CD8+ T cells. As Mtb infection progresses, mitochondrial metabolism deteriorates in CD8+ T cells, resulting in an increased dependency on glycolysis that potentiates inflammatory cytokine production. Over time, these cells develop bioenergetic deficiencies that reflect metabolic "quiescence." This bioenergetic signature coincides with increased mitochondrial dysfunction and inhibitory receptor expression and was not observed in BCG infection. Remarkably, the Mtb-triggered decline in T cell bioenergetics can be reinvigorated by metformin, giving rise to an Mtb-specific CD8+ T cell population with improved metabolism. These findings provide insights into Mtb pathogenesis whereby glycolytic reprogramming and compromised mitochondrial function contribute to the breakdown of CD8+ T cell immunity during chronic disease, highlighting opportunities to reinvigorate immunity with metabolically targeted pharmacologic agents.


Asunto(s)
Linfocitos T CD8-positivos/metabolismo , Citocinas/metabolismo , Glucólisis , Tuberculosis Latente/inmunología , Mitocondrias/metabolismo , Animales , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Células Cultivadas , Femenino , Hipoglucemiantes/farmacología , Tuberculosis Latente/microbiología , Metformina/farmacología , Ratones , Ratones Endogámicos C57BL , Mycobacterium bovis/patogenicidad , Mycobacterium tuberculosis/patogenicidad
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