Imbalance of NET and Alpha-1-Antitrypsin in Tuberculosis Patients Is Related With Hyper Inflammation and Severe Lung Tissue Damage

Background: Pulmonary tuberculosis (PTB) can lead to lung tissue damage (LTD) and compromise the pulmonary capacity of TB patients that evolve to severe PTB. The molecular mechanisms involved in LTD during anti-tuberculous treatment (ATT) remain poorly understood.Methods and findings: We evaluated the role of neutrophil extracellular trap (NET) and the occurrence of LTD through chest radiographic images, the microbial load in sputum, and inflammatory serum profile (IL-12p40/p70, IL-8, IL-17A, IL-23, VEGF-A, MMP-1, and -8, galectin-3, citrunillated histone H3—cit-H3, alpha-1-antitrypsin—α1AT, C-reactive protein—CRP and albumin) in a cohort of 82 PTB patients before and after 60 days of ATT. Using univariate analysis, LTD was associated with neutrophilia and increase of several inflammatory proteins involved in the neutrophil-mediated response, being cit-H3 the more related to the event. In the multivariate analysis, neutrophilia and cit-H3 appear as directly related to LTD. The analysis of the ROC curve at day 60 presented AUC of 0.97 (95.0% CI 0.95–1). Interestingly, at day 0 of ATT, these biomarkers demonstrated fine relation with LTD showing an AUC 0.92 (95.0% CI 0.86–0.99). Despite of that, the same molecules have no impact in culture conversion during ATT.Conclusions: Our data revealed that NETs may play a key role in the pathway responsible for non-specific inflammation and tissue destruction in PTB. High level of cit-H3 and low level of α1AT was observed in the serum of severe TB patients, suggesting a breakdown in the intrinsic control of NET-driven tissue damage. These data show a new insight to knowledge TB immunopathogenesis, the role of neutrophil and NET pathway. Likewise, we identified possible biomarkers to screening of PTB patients eligible to adjuvants therapies, as anti-inflammatories and alpha-1-antitrypsin

Clinical Impact of the Line Probe Assay and Xpert® MTB/RIF Assay in the Presumptive Diagnosis of Drug-Resistant Tuberculosis in Brazil: A Pragmatic Clinical Trial

Background: Rapid molecular methods such as the line probe assay (LPA) and Xpert® MTB/RIF assay (Xpert) have been recommended by the World Health Organization for drug-resistant tuberculosis (DR-TB) diagnosis. We conducted an interventional trial in DR-TB reference centers in Brazil to evaluate the impact of the use of LPA and Xpert. Methods: Patients with DR-TB were eligible if their drug susceptibility testing results were available to the treating physician at the time of consultation. The standard reference MGITTM 960 was compared with Xpert (arm 1) and LPA (arm 2). Effectiveness was considered as the start of the appropriate TB regimen that matched drug susceptibility testing (DST) and the proportions of culture conversion and favorable treatment outcomes after 6 months. Results: A higher rate of empirical treatment was observed with MGIT alone than with the Xpert assay (97.0% vs. 45.0%) and LPA (98.2% vs. 67.5%). Patients started appropriate TB treatment more quickly than those in the MGIT group (median 15.0 vs. 40.5 days; p<0.01) in arm 1. Compared to the MGIT group, culture conversion after 6 months was higher for Xpert in arm 1 (90.9% vs. 79.3%, p=0.39) and LPA in arm 2 (80.0% vs. 83.0%, p=0.81). Conclusions: In the Xpert arm, there was a significant reduction in days to the start of appropriate anti-TB treatment and a trend towards greater culture conversion in the sixth month

DESENVOLVIMENTO DE COLEÇÕES ESPECIAIS EM BIBLIOTECAS UNIVERSITÁRIAS: O CASO DOS PERIÓDICOS CIENTÍFICOS

Este trabalho tem por objetivo relatar a experiência de avaliação no desenvolvimento de coleções dos periódicos científicos disponibilizados na Biblioteca de Ciências da Saúde (BCS), biblioteca setorial do Sistema de Bibliotecas da Universidade Federal do Ceará (UFC). Apresenta desde o resgate histórico a importância dos periódicos científicos na área da saúde para o público universitário. Descreve a experiência no diagnóstico deste acervo, o desenvolvimento das ações planejadas e executadas na reorganização e acesso dessa importante fonte de pesquisa aos seus usuários. Conclui-se que o resgate histórico e o levantamento real sobre a situação deste acervo resultou em uma nova dinâmica de planejamento na organização dos periódicos da BCS/UFC. Proporciona também uma reflexão acerca da importância sobre a responsabilidade histórica, técnica e social na elaboração do desenvolvimento de coleções de periódicos em Bibliotecas universitárias

Associations between systemic inflammation, mycobacterial loads in sputum and radiological improvement after treatment initiation in pulmonary TB patients from Brazil: a prospective cohort study

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2016-12-01T16:54:14Z No. of bitstreams: 1 Mesquita EDD Associations between....pdf: 2555083 bytes, checksum: 6681311b66abb75aeb0367e0f9f6a915 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2016-12-01T17:15:35Z (GMT) No. of bitstreams: 1 Mesquita EDD Associations between....pdf: 2555083 bytes, checksum: 6681311b66abb75aeb0367e0f9f6a915 (MD5)Made available in DSpace on 2016-12-01T17:15:35Z (GMT). No. of bitstreams: 1 Mesquita EDD Associations between....pdf: 2555083 bytes, checksum: 6681311b66abb75aeb0367e0f9f6a915 (MD5) Previous issue date: 2016-08-05CNPq/INCT 573548/2008-0; Faperj Process: Processo - E-26/110.974/2011.Ary Parreira Institute. State Secretary of Health of Rio de Janeiro. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório Integrado de Microbiologia e Imunorregulação (LIMI). Unidade de Medicina Investigativa. Salvador, BA, Brasil / Fundação José Silveira. Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative. Salvador, BA, Brasil / Faculdade de Tecnologia e Ciências. School of Medicine. Salvador, BA, BrasilFederal University of Rio de Janeiro. School of Medicine. Tuberculosis Academic Program. Rio de Janeiro, RJ, BrasilFederal University of Rio de Janeiro. School of Medicine. Radiology Department. Rio de Janeiro, RJ, BrasilFederal University of Rio de Janeiro. School of Medicine. Tuberculosis Academic Program. Rio de Janeiro, RJ, Brasil / State University of North Fluminense Darcy Ribeiro. Recognize the Biology Laboratory. Center of Bioscience and Biotechnology. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Development Center for Technology on Health. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório Integrado de Microbiologia e Imunorregulação (LIMI). Unidade de Medicina Investigativa. Salvador, BA, Brasil / Fundação José Silveira. Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative. Salvador, BA, Brasil / Faculdade de Tecnologia e Ciências. School of Medicine. Salvador, BA, BrasilFederal University of Rio de Janeiro. School of Medicine. Tuberculosis Academic Program. Rio de Janeiro, RJ, BrasilRede-TB Study groupMycobacterium tuberculosis infection is known to cause inflammation and lung tissue damage in high-risk populations. Nevertheless, direct associations between mycobacterial loads, systemic inflammation and pulmonary lesions upon treatment initiation have not been fully characterized. In the present exploratory study, we prospectively depict the immune profile, microbial clearance and evolution of radiographic lesions in a pulmonary tuberculosis (PTB) patient cohort before and 60 days after anti-tuberculous treatment (ATT) initiation. Methods: Circulating levels of cytokines (IL-2, IL-4, IL-6, IL-10, IFN-γ, TNF-α) and C-reactive protein (CRP), as well as values of erythrocyte sedimentation rate (ESR) were measured in cryopreserved serum samples obtained from 73 PTB patients at pre-ATT and day 60 of treatment. Changes of the immune profile over time were compared with mycobacterial loads in sputum and culture conversion at day 60 of ATT. Additional analyses tested associations between improvement of chest radiographic lesions at day 60 and pre-treatment status of inflammation and mycobacterial loads. Results: Within the inflammatory parameters evaluated, values of CRP, IL-2, IL-4, TNF-α and ESR significantly decreased upon treatment initiation. On the converse, IL-10 levels substantially increased at day 60 of ATT, whereas concentrations of IL-6 and IFN-γ remained unchanged. Multidimensional analyses revealed that ESR, IL-2, IL-4 and CRP were the parameters with the highest power to discriminate individuals before and after treatment initiation. We further demonstrated that higher bacterial loads in sputum at pre-ATT were associated with increased systemic inflammation and higher risk for positive M. tuberculosis sputum cultures at day 60 of treatment. Furthermore, we found that pre-ATT mycobacterial loads in sputum and systemic inflammation synergistically associated with the status of radiographic lesions during treatment (Relative risk for chest X-ray improvement: 10.0, 95 % confidence interval: 2.4–40.0, P = 0.002). Conclusions: M. tuberculosis loads in sputum are directly associated to the status of systemic inflammation and potentially impact the immune profile, culture conversion and evolution of lung lesions upon ATT initiation

Inflammatory and immunogenetic markers in correlation with pulmonary tuberculosis

OBJECTIVE: To describe serum levels of the cytokines IL-10, TNF-&#945;, and IFN-&#947;, as well as polymorphisms in the genes involved in their transcription, and their association with markers of the acute inflammatory response in patients with pulmonary tuberculosis.METHODS: This was a descriptive, longitudinal study involving 81 patients with pulmonary tuberculosis treated at two referral hospitals. We collected data on sociodemographic variables and evaluated bacteriological conversion at the eighth week of antituberculosis treatment, gene polymorphisms related to the cytokines studied, and serum levels of those cytokines, as well as those of C-reactive protein (CRP). We also determined the ESR and CD4+ counts.RESULTS: The median age of the patients was 43 years; 67 patients (82.7%) were male; and 8 patients (9.9%) were infected with HIV. The ESR was highest in the patients with high IFN-&#947; levels and low IL-10 levels. IFN-&#947; and TNF-&#945; gene polymorphisms at positions +874 and &#8722;238, respectively, showed no correlations with the corresponding cytokine serum levels. Low IL-10 levels were associated with IL-10 gene polymorphisms at positions &#8722;592 and &#8722;819 (but not &#8722;1082). There was a negative association between bacteriological conversion at the eighth week of treatment and CRP levels.CONCLUSIONS: Our results suggest that genetic markers and markers of acute inflammatory response are useful in predicting the response to antituberculosis treatment

Additional file 1: Table S1. of Associations between systemic inflammation, mycobacterial loads in sputum and radiological improvement after treatment initiation in pulmonary TB patients from Brazil: a prospective cohort study

Spearman correlation values of the network analyses. (DOCX 17 kb

Sustained elevated levels of C-reactive protein and ferritin in pulmonary tuberculosis patients remaining culture positive upon treatment initiation

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2018-03-20T13:19:09Z No. of bitstreams: 1 Miranda P Sustained elevated levels of C-reactive protein....pdf: 3993663 bytes, checksum: 946647b9fe2f4b7304efcdab10931c48 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2018-03-20T13:53:35Z (GMT) No. of bitstreams: 1 Miranda P Sustained elevated levels of C-reactive protein....pdf: 3993663 bytes, checksum: 946647b9fe2f4b7304efcdab10931c48 (MD5)Made available in DSpace on 2018-03-20T13:53:35Z (GMT). No. of bitstreams: 1 Miranda P Sustained elevated levels of C-reactive protein....pdf: 3993663 bytes, checksum: 946647b9fe2f4b7304efcdab10931c48 (MD5) Previous issue date: 2017CNPq (produtividade em pesquisa) and FAPERJ (Cientistas do Nosso Estado). LG-S received scientific initiation fellowship from Fundacão de Amparo à Pesquisa da Bahia (FAPESB) and Fundacão Oswaldo Cruz (FIOCRUZ).Federal University of Rio de Janeiro. Medical School. Tuberculosis Academic Program. Rio de Janeiro, RJ, Brazil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Fundação Jose Silveira. Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brazil / Faculdade de Tecnologia e Ciências. Curso de Medicina. Salvador, BA, Brazil.Federal University of Rio de Janeiro. Medical School. Tuberculosis Academic Program. Rio de Janeiro, RJ, Brazil.Ary Parreira Institute. State Secretary of Health of Rio de Janeiro. Rio de Janeiro, RJ, Brazil.State University of North Fluminense Darcy Ribeiro. Recognize the Biology Laboratory, Center of Bioscience and Biotechnology. Rio de Janeiro, RJ, Brazil / Rede Brasileira de Pesquisas em Tuberculose. Rio de Janeiro, RJ, Brazil.Amsterdam Institute for Global Health and Development. Academic Medical Centre. Amsterdam, The Netherlands.Amsterdam Institute for Global Health and Development. Academic Medical Centre. Amsterdam, The Netherlands.Rede Brasileira de Pesquisas em Tuberculose. Rio de Janeiro, RJ, Brazil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brazil / Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. Rio de Janeiro, RJ, Brazil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Fundação Jose Silveira. Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brasil / Faculdade de Tecnologia e Ciências. Curso de Medicina. Salvador, BA, Brasil / Rede Brasileira de Pesquisas em Tuberculose. Rio de Janeiro, RJ, Brazil / Escola Bahiana de Medicina e Saúde Pública. Salvador, BA, Brasil / Universidade Salvador. Laureate International Universities. Salvador, BA, Brazil.Federal University of Rio de Janeiro. Medical School. Tuberculosis Academic Program. Rio de Janeiro, RJ, Brazil / Rede Brasileira de Pesquisas em Tuberculose. Rio de Janeiro, RJ, Brazil.Clinical trials that evaluate new anti-tubercular drugs and treatment regimens take years to complete due to the slow clearance of Mycobacterium tuberculosis infection and the lack of early biomarkers that predict treatment outcomes. Host Inflammation markers have been associated with tuberculosis (TB) pathogenesis. In the present study, we tested if circulating levels of C-reactive protein (CRP) and ferritin reflect mycobacterial loads and inflammation in pulmonary TB (PTB) patients undergoing anti-tuberculous therapy (ATT). Methods Prospective measurements of CRP and ferritin, used as readouts of systemic inflammation, were performed in cryopreserved serum samples from 165 Brazilian patients with active PTB initiating ATT. Associations between levels of these laboratory parameters with mycobacterial loads in sputum as well as with sputum conversion at day 60 of ATT were tested. Results: Circulating levels of both ferritin and CRP gradually decreased over time on ATT. At pretreatment, concentrations of these parameters were unable to distinguish patients with positive from those with negative acid-fast bacilli (AFB) in sputum cultures. However, patients who remained with positive cultures at day 60 of ATT exhibited heightened levels of these inflammatory markers compared to those with negative cultures at that time point. Conclusions: CRP and Ferritin levels in serum may be useful to identify patients with positive cultures at day 60 of ATT

Delayed culture conversion due to cigarette smoking in active pulmonary tuberculosis patients

Although many studies have assessed factors affecting culture conversion during tuberculosis treatment, few have looked into the effect of tobacco smoking. This study included 89 active pulmonary tuberculosis patients with positive sputum culture upon presentation and collected information regarding smoking history and culture conversion after 60 days of therapy. Current smokers had a higher risk (OR 5.6; 95%CI 1.7-18.7) of non-conversion after two months of therapy when compared to never and ex-smokers. Cavities on chest X-ray and alcohol abuse were shown to confound this association. After adjustment for cavities on the chest X-ray and alcohol abuse current smoking compared to current non-smoking remained significantly associated with culture non-conversion at 60 days of treatment (adjusted OR 6.9; 95%CI 1.8-26.7, p = 0.002) with a significant (p = 0.004) trend in adjusted OR with the number of cigarettes smoked daily to 11.6 (1.8-73.4) among those smoking more than 20 cigarettes per day. In conclusion tobacco smoking was found to delay culture conversion during treatment for pulmonary tuberculosis in a dose-dependent manner. More research is needed to elucidate the effects of smoking on tuberculosis treatment response, and of smoking cessation during tuberculosis treatmen