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.

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 ± 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.

Association of serum levels of iron, copper, and zinc, and inflammatory markers with bacteriological sputum conversion during tuberculosis treatment.

Iron, copper, and zinc are key micronutrients that play an important role in the immune response to Mycobacterium tuberculosis. The present study aimed to evaluate the association between serum levels of those micronutrients, inflammatory markers, and the smear and culture conversion of M. tuberculosis during 60 days of tuberculosis treatment. Seventy-five male patients with pulmonary tuberculosis (mean age, 40.0 ± 10.7 years) were evaluated at baseline and again at 30 and 60 days of tuberculosis treatment. Serum levels of iron, copper, zinc, albumin, globulin, C-reactive protein, and hemoglobin, and smear and cultures for M. tuberculosis in sputum samples were analyzed. Compared to healthy subjects, at baseline, patients with PTB had lower serum iron levels, higher copper levels and copper/zinc ratio, and similar zinc levels. During the tuberculosis treatment, no significant changes in the serum levels of iron, zinc, and copper/zinc were observed. Lower serum copper levels were associated with bacteriological conversion in tuberculosis treatment (tuberculosis-negative) at 30 days but not at 60 days (tuberculosis-positive). C-reactive protein levels and the C-reactive protein/albumin ratio were lower in tuberculosis-negative patients than in tuberculosis-positive patients at 30 and 60 days after treatment. Albumin and hemoglobin levels and the albumin/globulin ratio in patients with pulmonary tuberculosis increased during the study period, regardless of the bacteriological results. High serum globulin levels did not change among pulmonary tuberculosis patients during the study. Serum copper levels and the C-reactive protein/albumin ratio may be important parameters to evaluate the persistence of non-conversion after 60 days of tuberculosis treatment, and they may serve as predictors for relapse after successful treatment.

Association between serum selenium level and conversion of bacteriological tests during antituberculosis treatment / Associações entre níveis de selênio sérico e conversão de testes bacteriológicos durante o tratamento antituberculose

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 ± 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. .

Objetivo: Determinar se os níveis séricos de selênio estão associados à conversão dos testes bacteriológicos em pacientes diagnosticados com tuberculose pulmonar ativa após oito semanas de tratamento-padrão. Métodos: No início do estudo, avaliamos 35 controles saudáveis, do sexo masculino, e 35 pacientes do sexo masculino com tuberculose pulmonar. Estes foram também avaliados após 30 e 60 dias de tratamento antituberculose. Todos os participantes submeteram-se a medições antropométricas e quantificação dos níveis séricos de albumina, proteína C reativa (PCR) e selênio. Como não há valores de referência para a população brasileira, usamos a mediana dos resultados de selênio sérico dos controles como ponto de corte. Aos 30 e 60 dias do tratamento antituberculose, todos os testes bioquímicos foram repetidos, e foram coletadas amostras de escarro para baciloscopia e cultura. Resultados: A média de idade dos pacientes foi de 38,4 ± 11.4 anos. Dos 35 pacientes, 25 (71,0%) referiram alcoolismo, 20 (57,0%) eram fumantes, e 21 (60,0%) e 32 (91,4%) apresentavam depleção muscular pela medição da dobra cutânea tricipital e da área muscular do braço, respectivamente. De 24 pacientes, 12 (39,2%) foram classificados em moderadamente ou gravemente magros, e 15 (62,5%) apresentaram perda de peso > 10% em até seis meses antes do diagnóstico. No início do estudo, o grupo com tuberculose apresentou menores níveis de selênio sérico que os controles. A conversão dos testes bacteriológicos associou-se à relação PCR/albumina e aos níveis de selênio sérico 60 dias após o início do tratamento. Conclusões: Níveis maiores de selênio sérico após 60 ...

Inflammatory and immunogenetic markers in correlation with pulmonary tuberculosis / Marcadores inflamatorios e imunogeneticos e sua relacao com tuberculose pulmonar

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. .

OBJETIVO: Descrever os níveis séricos das citocinas IL-10, TNF-α e IFN-γ, assim como polimorfismos presentes em genes envolvidos na sua transcrição, e sua associação com marcadores de resposta inflamatória aguda em pacientes com tuberculose. MÉTODOS: Estudo descritivo e longitudinal realizado em 81 pacientes com tuberculose pulmonar atendidos em dois hospitais de referência. Foram coletadas informações sociodemográficas, conversão bacteriológica na oitava semana de tratamento antituberculose, polimorfismos relacionados às citocinas estudadas, níveis séricos dessas citocinas, assim como de proteína C reativa (PCR). Também foram avaliados VHS e contagem de CD4+. RESULTADOS: A mediana de idade dos pacientes era de 43 anos, sendo 67 (82,7%) do sexo masculino e 8 (9,9%) infectados por HIV. Os pacientes com níveis elevados de IFN-γ e baixos níveis de IL-10 apresentaram valores mais elevados de VHS. Não houve associação dos polimorfismos do gene IFN-γ na posição +874 e do gene TNF-α na posição −238 com os níveis das citocinas correspondentes. Houve uma associação entre polimorfismos do gene IL-10 nas posições −592 e −819 (mas não −1082) e baixos níveis de IL-10. Houve uma associação negativa entre a taxa de conversão bacteriológica na oitava semana de tratamento e níveis de PCR. CONCLUSÕES: Nossos resultados sugerem que marcadores genéticos e de resposta inflamatória aguda podem ser úteis na predição da resposta ao tratamento antituberculose. .

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.