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

Inflammatory and immunogenetic markers in correlation with pulmonary tuberculosis

OBJECTIVE: To describe serum levels of the cytokines IL-10, TNF-α, and IFN-γ, 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-γ levels and low IL-10 levels. IFN-γ and TNF-α gene polymorphisms at positions +874 and −238, respectively, showed no correlations with the corresponding cytokine serum levels. Low IL-10 levels were associated with IL-10 gene polymorphisms at positions −592 and −819 (but not −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

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

Tuberculosis-associated anemia is linked to a distinct inflammatory profile that persists after initiation of antitubercular therapy

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2019-03-19T12:30:50Z No. of bitstreams: 1 Gil- Santana L Tuberculosis-associated anemia...2019.pdf: 2138735 bytes, checksum: fa23c714d2df26221664e23e61cfeee9 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2019-03-19T12:55:49Z (GMT) No. of bitstreams: 1 Gil- Santana L Tuberculosis-associated anemia...2019.pdf: 2138735 bytes, checksum: fa23c714d2df26221664e23e61cfeee9 (MD5)Made available in DSpace on 2019-03-19T12:55:49Z (GMT). No. of bitstreams: 1 Gil- Santana L Tuberculosis-associated anemia...2019.pdf: 2138735 bytes, checksum: fa23c714d2df26221664e23e61cfeee9 (MD5) Previous issue date: 2019-01-04Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)/Instituto Nacional de Ciência e Tecnologia (INCT, grant number: 573548/2008–0) and Fundação de Amparo à Pesquisa do Rio de Janeiro (FAPERJ, grant number: E-26/110.974/2011). This study was also financed in part by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) (Finance Code 001). A.K. is the recipient of a career award from CNPq (produtividade em pesquisa) and FAPERJ (Cientistas do Nosso Estado). L.G.-S. was a scientific initiation fellow and M.B.A. received PhD fellowship from Fundação de Amparo à Pesquisa da Bahia (FAPESB) and Fundação Oswaldo Cruz (FIOCRUZ). L.A.B.C. is a research fellow from CNPq. The work from B.B.A. was supported by intramural research program from FIOCRUZ and from the National Institutes of Health (U01AI115940).Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Fundação José Silveira. Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brasil / Faculdade de Tecnologia e Ciências. Curso de Medicina. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Fundação José Silveira. Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brasil / Faculdade de Tecnologia e Ciências. Curso de Medicina. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Fundação José Silveira. Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brasil.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 José Silveira. Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brasil / Universidade Salvador. Laureate Universities. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Fundação José Silveira. Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brasil.Federal University of Rio de Janeiro. Medical School. Tuberculosis Academic Program. Rio de Janeiro, RJ, Brazil / State University of North Fluminense Darcy Ribeiro. Center of Bioscience and Biotechnology. Recognize the Biology Laboratory. Rio de Janeiro, RJ, Brazil.Federal University of Rio de Janeiro. Medical School. Tuberculosis Academic Program. Rio de Janeiro, RJ, Brazil.State Secretary of Health of Rio de Janeiro. Ary Parreira Institute. Rio de Janeiro, RJ, Brazil.Amsterdam University Academic Medical Centre. Amsterdam Institute for Global Health and Development. Amsterdam, The Netherlands.Amsterdam University Academic Medical Centre. Amsterdam Institute for Global Health and Development. Amsterdam, The Netherlands.Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. Rio de Janeiro, RJ, Brasil.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 José Silveira. Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brasil / Faculdade de Tecnologia e Ciências. Curso de Medicina. Salvador, BA, Brasil / Universidade de Salvador. Laureate Universities. Salvador, BA, Brasil / Escola Bahiana de Medicina e Saúde Pública. Salvador, BA, Brasil.Pulmonary tuberculosis (PTB) is associated with chronic inflammation and anemia. How anemia impacts systemic inflammation in PTB patients undergoing antitubercular therapy (ATT) is not fully understood. In the present study, data on several blood biochemical parameters were retrospectively analyzed from 118 PTB patients during the first 60 days of ATT. Multidimensional statistical analyses were employed to perform detailed inflammatory profiling of patients stratified by anemia status prior to treatment. Anemia was defined as hemoglobin levels <12.5 g/dL for female and <13.5 g/dL for male individuals. The findings revealed that most of anemia cases were likely caused by chronic inflammation. A distinct biosignature related to anemia was detected, defined by increased values of uric acid, C-reactive protein, and erythrocyte sedimentation rate. Importantly, anemic patients sustained increased levels of several biochemical markers at day 60 of therapy. Preliminary analysis failed to demonstrate association between persistent inflammation during ATT with frequency of positive sputum cultures at day 60. Thus, TB patients with anemia exhibit a distinct inflammatory profile, which is only partially reverted at day 60 of ATT

Association between serum selenium level and conversion of bacteriological tests during antituberculosis treatment

Objective: To determine whether serum selenium levels are associated with the conversion of bacteriological tests in patients diagnosed with active pulmonary tuberculosis after eight weeks of standard treatment. Methods: We evaluated 35 healthy male controls and 35 male patients with pulmonary tuberculosis, the latter being evaluated at baseline, as well as at 30 and 60 days of antituberculosis treatment. For all participants, we measured anthropometric indices, as well as determining serum levels of albumin, C-reactive protein (CRP) and selenium. Because there are no reference values for the Brazilian population, we used the median of the serum selenium level of the controls as the cut-off point. At 30 and 60 days of antituberculosis treatment, we repeated the biochemical tests, as well as collecting sputum for smear microscopy and culture from the patients. Results: The mean age of the patients was 38.4 &#177; 11.4 years. Of the 35 patients, 25 (71%) described themselves as alcoholic; 20 (57.0%) were smokers; and 21 (60.0%) and 32 (91.4%) presented with muscle mass depletion as determined by measuring the triceps skinfold thickness and arm muscle area, respectively. Of 24 patients, 12 (39.2%) were classified as moderately or severely emaciated, and 15 (62.5%) had lost > 10% of their body weight by six months before diagnosis. At baseline, the tuberculosis group had lower serum selenium levels than did the control group. The conversion of bacteriological tests was associated with the CRP/albumin ratio and serum selenium levels 60 days after treatment initiation. Conclusions: Higher serum selenium levels after 60 days of treatment were associated with the conversion of bacteriological tests in pulmonary tuberculosis patients