Transcriptional responses of host peripheral blood cells to tuberculosis infection

Host responses following exposure to Mycobacterium tuberculosis (TB) are complex and can significantly affect clinical outcome. These responses, which are largely mediated by complex immune mechanisms involving peripheral blood cells (PBCs) such as T-lymphocytes, NK cells and monocyte-derived macrophages, have not been fully characterized. We hypothesize that different clinical outcome following TB exposure will be uniquely reflected in host gene expression profiles, and expression profiling of PBCs can be used to discriminate between different TB infectious outcomes. In this study, microarray analysis was performed on PBCs from three TB groups (BCG-vaccinated, latent TB infection, and active TB infection) and a control healthy group. Supervised learning algorithms were used to identify signature genomic responses that differentiate among group samples. Gene Set Enrichment Analysis was used to determine sets of genes that were co-regulated. Multivariate permutation analysis (p < 0.01) gave 645 genes differentially expressed among the four groups, with both distinct and common patterns of gene expression observed for each group. A 127-probeset, representing 77 known genes, capable of accurately classifying samples into their respective groups was identified. In addition, 13 insulin-sensitive genes were found to be differentially regulated in all three TB infected groups, underscoring the functional association between insulin signaling pathway and TB infection. Published by Elsevier Ltd.

Histamine Plays an Essential Regulatory Role in Lung Inflammation and Protective Immunity in the Acute Phase of Mycobacterium tuberculosis Infection

The course and outcome of infection with mycobacteria are determined by a complex interplay between the immune system of the host and the survival mechanisms developed by the bacilli. Recent data suggest a regulatory role of histamine not only in the innate but also in the adaptive immune response. We used a model of pulmonary Mycobacterium tuberculosis infection in histamine-deficient mice lacking histidine decarboxylase (HDC(-/-)), the histamine-synthesizing enzyme. To confirm that mycobacterial infection induced histamine production, we exposed mice to M. tuberculosis and compared responses in C57BL/6 (wild-type) and HDC(-/-) mice. Histamine levels increased around fivefold above baseline in infected C57BL/6 mice at day 28 of infection, whereas only small amounts were detected in the lungs of infected HDC(-/-) mice. Blocking histamine production decreased both neutrophil influx into lung tissue and the release of proinflammatory mediators, such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha), in the acute phase of infection. However, the accumulation and activation of CD4(+) T cells were augmented in the lungs of infected HDC(-/-) mice and correlated with a distinct granuloma formation that contained abundant lymphocytic infiltration and reduced numbers of mycobacteria 28 days after infection. Furthermore, the production of IL-12, gamma interferon, and nitric oxide, as well as CD11c(+) cell influx into the lungs of infected HDC(-/-) mice, was increased. These findings indicate that histamine produced after M. tuberculosis infection may play a regulatory role not only by enhancing the pulmonary neutrophilia and production of IL-6 and TNF-alpha but also by impairing the protective Th1 response, which ultimately restricts mycobacterial growth.

TLR2-dependent mast cell activation contributes to the control of Mycobacterium tuberculosis infection

Mast Cells (MCs) express toll-like receptor 2 (TLR2), a receptor known to be triggered by several major mycobacterial ligands and involved in resistance against Mycobacterium tuberculosis (MTB) infection. This study investigated whether adoptive transfer of TLR2 positive MCs (TLR2(+/+)) corrects the increased susceptibility of TLR2(-/-) mice to MTB infection. TLR2(-/-) mice displayed increased mycobacterial burden, diminished myeloid cell recruitment and proinflammatory cytokine production accompanied by defective granuloma formation. The reconstitution of these mice with TLR2(+/+) MCs, but not TLR2(-/-), confers better control of the infection, promotes the normalization of myeloid cell recruitment associated with reestablishment of the granuloma formation. In addition, adoptive transfer of TLR2(+/+) MC to TLR2(-/-) mice resulted in regulation of the pulmonary levels of IL-beta, IL-6, TNF-alpha, enhanced Th1 response and activated CD8(+) T cell homing to the lungs. Our results suggest that activation of MCs via TLR2 is required to compensate the defect in protective immunity and inability of TLR2(-/-) mice to control MTB infection. (C) 2009 Elsevier Masson SAS. All rights reserved.

A subunit vaccine based on biodegradable microspheres carrying rHsp65 protein and KLK protects BALB/c mice against tuberculosis infection

Of the hundreds of new tuberculosis ( TB) vaccine candidates some have therapeutic value in addition to their prophylactic properties. This is the case for the DNA vaccine encoding heat-shock protein 65 (DNAhsp65) from Mycobacterium leprae. However, there are concerns about the use of DNA vaccines in certain populations such as newborns and pregnant women. Thus, the optimization of vaccination strategies that circumvent this limitation is a priority. This study evaluated the efficacy of a single dose subunit vaccine based on recombinant Hsp65 protein against infection with M. tuberculosis H37Rv. The Hsp65 protein in this study was either associated or not with immunostimulants, and was encapsulated in biodegradable PLGA microspheres. Our results demonstrate that the protein was entrapped in microspheres of adequate diameter to be engulfed by phagocytes. Mice vaccinated with a single dose of Hsp65-microspheres or Hsp65 + CpG-microspheres developed both humoral and cellular-specific immune responses. However, they did not protect mice against challenge with M. tuberculosis. By contrast, Hsp65+KLK-microspheres induced specific immune responses that reduced bacilli loads and minimized lung parenchyma damage. These data suggest that a subunit vaccine based on recombinant protein Hsp65 is feasible.

TUBERCULOSIS INFECTION MIGHT INCREASE THE RISK OF INVASIVE CANDIDIASIS IN AN IMMUNOCOMPETENT PATIENT

Deep Candida infections commonly occur in immunosuppressed patients. A rare case of a multiple deep organ infection with Candida albicansand spinal tuberculosis was reported in a healthy young man. The 19-year-old man complained of month-long fever and lower back pain. He also had a history of scalded mouth syndrome. Coinfection with Mycobacterium tuberculosis and Candida albicans was diagnosed using the culture of aspirates from different regions. Symptoms improved considerably after antifungal and antituberculous therapy. This case illustrates that infection with tuberculosis might impair the host's immune system and increase the risk of invasive candidiasis in an immunocompetent patient.

Prevalence and incidence of Mycobacterium tuberculosis infection in nursing students in Vitória, Espírito Santo

This prospective study evaluated the incidence of Mycobacterium tuberculosis infection among nursing students at the Federal University of Espírito Santo, using the purified protein derivative test. In parallel, we evaluated whether knowledge on tuberculosis transmission mechanisms had any impact on nursing students' attitudes in relation to the risk of tuberculosis infection. The incidence of tuberculin conversion was 10.5% per year (p=0.035, 95% CI = 3.63-17.43), whereas the expected conversion rate in the overall population in Brazil is 0.5% per year. These results indicate nursing students as a group at risk for TB infection. Among the risk factors studied only the use of NIOSH95 masks was associated with protection against infection (RR=0.2). Furthermore there was no statistical difference among students that PPD converted and those who remained negative regarding disease knowledge and the existence of adequate facilities for patient hospitalization. Our data reinforces the need for implementing special biosafety programs targeting this professional group.

Prevalence and evolution of Mycobacterium tuberculosis infection in tuberculosis case contacts

INTRODUCTION : The tuberculin test is a diagnostic method for detecting latent tuberculosis (TB) infection, especially among disease contact cases. The objective of this study was to analyze the prevalence and evolution of Mycobacterium tuberculosis infection among TB contact cases. METHODS : A retrospective cohort study was performed in a reference center for TB. The study population consisted of 2,425 patients who underwent a tuberculin test from 2003 to 2010 and whose results indicated contact with individuals with TB. The data were collected from the registry book of the tuberculin tests, patient files and the Information System Records of Notification Grievance. To verify the evolution of TB, case records through September 2014 were consulted. Data were analyzed using the Statistical Package for the Social Sciences (SPSS). In all hypothesis tests, a significance level of 0.05 was used. RESULTS : From the studied sample, 435 (17.9%) contacts did not return for reading. Among the 1,990 contacts that completed the test, the prevalence of latent TB infection was 35.4%. Of these positive cases, 50.6% were referred to treatment; the dropout rate was 42.5%. Among all of the contacts, the TB prevalence was 1.8%, from which 13.2% abandoned treatment. CONCLUSIONS : The collected data indicate the need for more effective public policies to improve TB control, including administering tests that do not require a return visit for reading, enhancing contact tracing and encouraging actions that reinforce full treatment adherence.

Rifapentine for latent tuberculosis infection treatment in the general population and human immunodeficiency virus-positive patients: summary of evidence

AbstractLatent tuberculosis infection (LTBI) and human immunodeficiency virus (HIV)-coinfection are challenges in the control of tuberculosis transmission. We aimed to assess and summarize evidence available in the literature regarding the treatment of LTBI in both the general and HIV-positive population, in order to support decision making by the Brazilian Tuberculosis Control Program for LTBI chemoprophylaxis. We searched MEDLINE, Cochrane Library, Centre for Reviews and Dissemination, Embase, LILACS, SciELO, Trip database, National Guideline Clearinghouse, and the Brazilian Theses Repository to identify systematic reviews, randomized clinical trials, clinical guidelines, evidence-based synopses, reports of health technology assessment agencies, and theses that investigated rifapentine and isoniazid combination compared to isoniazid monotherapy. We assessed the quality of evidence from randomized clinical trials using the Jadad Scale and recommendations from other evidence sources using the Grading of Recommendations, Assessment, Development, and Evaluations approach. The available evidence suggests that there are no differences between rifapentine + isoniazid short-course treatment and the standard 6-month isoniazid therapy in reducing active tuberculosis incidence or death. Adherence was better with directly observed rifapentine therapy compared to self-administered isoniazid. The quality of evidence obtained was moderate, and on the basis of this evidence, rifapentine is recommended by one guideline. Available evidence assessment considering the perspective of higher adherence rates, lower costs, and local peculiarity context might support rifapentine use for LTBI in the general or HIV-positive populations. Since novel trials are ongoing, further studies should include patients on antiretroviral therapy.

Diagnosis of latent Mycobacterium tuberculosis infection: tuberculin test versus interferon-gamma release

Abstract: INTRODUCTION: The treatment of individuals with active tuberculosis (TB) and the identification and treatment of latent tuberculosis infection (LTBI) contacts are the two most important strategies for the control of TB. The objective of this study was compare the performance of tuberculin skin testing (TST) with QuantiFERON-TB Gold In TUBE(r) in the diagnosis of LTBI in contacts of patients with active TB. METHODS: Cross-sectional analytical study with 60 contacts of patients with active pulmonary TB. A blood sample of each contact was taken for interferon-gamma release assay (IGRA) and subsequently performed the TST. A receiver operating characteristic curve was generated to assess the cutoff points and the sensitivity, predictive values, and accuracy were calculated. The agreement between IGRA and TST results was evaluated by Kappa coefficient. RESULTS: Here, 67.9% sensitivity, 84.4% specificity, 79.1% PPV, 75% NPV, and 76.7% accuracy were observed for the 5mm cutoff point. The prevalence of LTBI determined by TST and IGRA was 40% and 46.7%, respectively. CONCLUSIONS: Both QuantiFERON-TB Gold In TUBE(r) and TST showed good performance in LTBI diagnosis. The creation of specific diagnostic methods is necessary for the diagnosis of LTBI with higher sensitivity and specificity, preferably with low cost and not require a return visit for reading because with early treatment of latent forms can prevent active TB.

Comparison of quantiferon-TB gold with tuberculin skin test for detecting latent tuberculosis infection prior to liver transplantation.

Screening for latent tuberculosis infection (LTBI) is recommended prior to organ transplantation. The Quantiferon-TB Gold assay (QFT-G) may be more accurate than the tuberculin skin test (TST) in the detection of LTBI. We prospectively compared the results of QFT-G to TST in patients with chronic liver disease awaiting transplantation. Patients were screened for LTBI with both the QFT-G test and a TST. Concordance between test results and predictors of a discordant result were determined. Of the 153 evaluable patients, 37 (24.2%) had a positive TST and 34 (22.2%) had a positive QFT-G. Overall agreement between tests was 85.1% (kappa= 0.60, p < 0.0001). Discordant test results were seen in 12 TST positive/QFT-G negative patients and in 9 TST negative/QFT-G positive patients. Prior BCG vaccination was not associated with discordant test results. Twelve patients (7.8%), all with a negative TST, had an indeterminate result of the QFT-G and this was more likely in patients with a low lymphocyte count (p = 0.01) and a high MELD score (p = 0.001). In patients awaiting liver transplantation, both the TST and QFT-G were comparable for the diagnosis of LTBI with reasonable concordance between tests. Indeterminate QFT-G result was more likely in those with more advanced liver disease.

Infection latente a M. tuberculosis, mise a jour 2011 [Latent M. tuberculosis infection, update 2011].

It is estimated that one third of the world population is latently infected by Mycobacterium tuberculosis and thus at risk of reactivation. Latent tuberculosis (TB) impact in Switzerland is often overlooked. Diagnosis and prophylaxis are insufficiently undertaken, especially for people at higher risk of reactivation due to immunosuppression. Interferon-gamma release assays replace tuberculosis skin tests for diagnosis of latent infection in adults. It is still recommended to treat prophylactically a case of latent TB infection with 9 months of isoniazid; however therapy with rifampicin for 4 months, currently an alternative option, is linked to improved adherence and favorable cost-benefit ratio.

Risk factors of latent tuberculosis infection among asylum-seekers recently arrived in Switzerland : A pilot study in Vaud county

Background: Asylum seekers may have a higher rate of latenttuberculosis infection (LTBI) than resident populations in Westerncountries. LTBI can be detected by an Interferon Gamma ReleaseAssay (IGRA). Screening asylum seekers at highest risk for LTBI orfuture tuberculosis by IGRA could be considered. The aims of this pilotstudy were to assess the prevalence and the risk factors of LTBI amonga group of asylum seekers recently arrived in Switzerland.Methods: A prospective cross-sectional study was performed amongadult asylum seekers, staying in two migrant centers of the Vaud county,Switzerland, after a first screening for active tuberculosis at the border.The participants were offered IGRA screening using T-SPOT.TB andwere questioned about risk factors associated with LTBI. Migrants with apositive test had a chest radiograph and a medical examination. Thosewith active tuberculosis were excluded and were treated. The migrantswith LTBI received a preventive treatment, if indicated. The risk factorswere analyzed by univariate and multivariate logistical regression.Results: Among 788 migrants recently arrived, 639 were adults, 393agreed to be screened (61.50%) and 98 of them had a positive T-SPOT.TB (24.93%) of which 5 (5.1%) had an active tuberculosis (previouslynot detected at the border), and 2 had already been treated for activetuberculosis. In univariate analysis, the major risk factors associatedwith LTBI were country of origin and travel conditions. Compared withmigrants from Balkanic countries, migrants from Africa had an OR forLTBI of 3.68, migrants from Asia an OR of 4.3 and migrants fromFormer Soviet Union an OR of 4.5. Migrants who crossed severalborders before arriving in Switzerland had an OR of LTBI of 2.49compared with migrants who came directly from the home country.Age, cough and prior exposure to tuberculosis had a non-significantinfluence on the rate of test positivity. In multivariate analysis, thecombination of country of origin, travel conditions, age, cough andexposure to tuberculosis resulted in a score with optimal predictivevalue (Roc = 81%).Conclusions: Asylum seekers recently arrived in Vaud county had ahigh prevalence of LTBI and active tuberculosis. The major risk factorswere country of origin and travel conditions. Selecting for screening byIGRA the asylum seekers with the highest risk factors seems possible.

Eligibility for and outcome of treatment of latent tuberculosis infection in a cohort of HIV-infected people in Spain

BACKGROUND Previous studies have demonstrated the efficacy of treatment for latent tuberculosis infection (TLTBI) in persons infected with the human immunodeficiency virus, but few studies have investigated the operational aspects of implementing TLTBI in the co-infected population.The study objectives were to describe eligibility for TLTBI as well as treatment prescription, initiation and completion in an HIV-infected Spanish cohort and to investigate factors associated with treatment completion. METHODS Subjects were prospectively identified between 2000 and 2003 at ten HIV hospital-based clinics in Spain. Data were obtained from clinical records. Associations were measured using the odds ratio (OR) and its 95% confidence interval (95% CI). RESULTS A total of 1242 subjects were recruited and 846 (68.1%) were evaluated for TLTBI. Of these, 181 (21.4%) were eligible for TLTBI either because they were tuberculin skin test (TST) positive (121) or because their TST was negative/unknown but they were known contacts of a TB case or had impaired immunity (60). Of the patients eligible for TLTBI, 122 (67.4%) initiated TLTBI: 99 (81.1%) were treated with isoniazid for 6, 9 or 12 months; and 23 (18.9%) with short-course regimens including rifampin plus isoniazid and/or pyrazinamide. In total, 70 patients (57.4%) completed treatment, 39 (32.0%) defaulted, 7 (5.7%) interrupted treatment due to adverse effects, 2 developed TB, 2 died, and 2 moved away. Treatment completion was associated with having acquired HIV infection through heterosexual sex as compared to intravenous drug use (OR:4.6; 95% CI:1.4-14.7) and with having taken rifampin and pyrazinamide for 2 months as compared to isoniazid for 9 months (OR:8.3; 95% CI:2.7-24.9). CONCLUSIONS A minority of HIV-infected patients eligible for TLTBI actually starts and completes a course of treatment. Obstacles to successful implementation of this intervention need to be addressed.