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1.
Zhonghua Jie He He Hu Xi Za Zhi ; 47(7): 638-646, 2024 Jul 12.
Artigo em Chinês | MEDLINE | ID: mdl-38955749

RESUMO

Objective: To explore the characteristics of adverse drug reactions during the 24-week therapy with delamanid-containing regimen for patients with multidrug-resistant and rifampicin-resistant pulmonary tuberculosis (MDR/RR-PTB). Methods: The prospective multicenter study was conducted from June 2020 to June 2023. A total of 608 eligible patients with MDR/RR-PTB were enrolled in 26 tuberculosis medical institutions in China including 364 males and 79 females, aged 39.6(19.0-68.0) years. Patients were treated with chemotherapy regimens containing delamanid. Patients were closely supervised during treatment of medication, and all adverse reactions occurring during treatment were monitored and recorded. The clinical characteristics of adverse reactions were evaluated by descriptive analysis. Chi-square test and multivariate logistic regression were used to analyze the related factors of QTcF interval prolongation (QT corrected with Fridericia's formula). Results: Of the 608 patients enrolled in this study, 325 patients (53.5%) reported 710 adverse events within 24 weeks of treatment. The top 6 most common complications were hematological abnormalities (143 patients, 23.5%), QT prolongation (114 patients, 18.8%), liver toxicity (85 patients, 14.0%), gastrointestinal reaction (41 patients, 6.7%), peripheral neuropathy (25 patients, 4.1%) and mental disorders (21 patients, 3.5%). The prolongation of QT interval mostly occurred in the 12th week after the first dose of medication. Serious adverse reactions occurred in 21 patients (3.5%). There were 7 patients (1.2%) with mental disorders, including 2 patients (0.3%) with severe mental disorders. Conclusions: The safety of dalamanid-based regimen in the staged treatment of MDR/RR-PTB patients was generally good, and the incidence of adverse reactions was similar to that reported in foreign studies. This study found that the incidence of QT interval prolongation in Chinese patients was higher than that reported overseas, suggesting that the monitoring of electrocardiogram should be strengthened when using drugs containing delamanid that may cause QT interval prolongation.


Assuntos
Antituberculosos , Nitroimidazóis , Oxazóis , Rifampina , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose Pulmonar , Humanos , Masculino , Feminino , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adulto , Estudos Prospectivos , Rifampina/efeitos adversos , Pessoa de Meia-Idade , Oxazóis/efeitos adversos , Oxazóis/uso terapêutico , Oxazóis/administração & dosagem , Antituberculosos/efeitos adversos , Tuberculose Pulmonar/tratamento farmacológico , Nitroimidazóis/efeitos adversos , Nitroimidazóis/uso terapêutico , Nitroimidazóis/administração & dosagem , Idoso , China , Adulto Jovem , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia
2.
Clin Lab ; 70(7)2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38965946

RESUMO

BACKGROUND: This study aimed to effectively evaluate the diagnostic performance of the EasyNAT Mycobacterium tuberculosis complex (MTC) assay for tuberculosis (TB) detection from sputum. METHODS: The retrospectively analyzed data was collected from September 1, 2021, to November 1, 2023, in our hospital. RESULTS: Forty EasyNAT-positive sputum specimens were simultaneously detected using the GeneXpert MTB/ rifampicin (RIF) assay. The concordance rate between the EasyNAT and GeneXpert MTB/RIF assays was 100%. CONCLUSIONS: Because of the complexity of detecting RIF resistance data information, the rapid EasyNAT system used in conjunction with GeneXpert might be a better choice for the detection of TB in hospitals.


Assuntos
Mycobacterium tuberculosis , Escarro , Humanos , Mycobacterium tuberculosis/isolamento & purificação , Escarro/microbiologia , Estudos Retrospectivos , Rifampina/farmacologia , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/microbiologia , Tuberculose/diagnóstico , Tuberculose/microbiologia , Masculino , Feminino
3.
Drug Res (Stuttg) ; 74(6): 269-279, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38968950

RESUMO

Every year, the World Health Organization reports 500,000 new cases of drug-resistant tuberculosis (TB), which poses a serious global danger. The increased number of XDR-TB and MDR-TB cases reported worldwide necessitates the use of new therapeutic approaches. The main issues with the antitubercular medications now in use for the treatment of multidrug-resistant tuberculosis are their poor side effect profile, reduced efficacy, and antimicrobial resistance. One possible remedy for these problems is bedaquiline. The need for better treatment strategies is highlighted by the strong minimum inhibitory concentrations that bedaquiline (BDQ), a novel anti-TB medicine, exhibits against both drug-resistant and drug-susceptible TB. Bedaquiline may be able to help with these problems. Bedaquiline is a medication that is first in its class and has a distinct and particular mode of action. Bedaquiline is an ATP synthase inhibitor that is specifically directed against Mycobacterium tuberculosis and some nontuberculous mycobacteria. It is metabolized by CYP3A4. Bedaquiline preclinical investigations revealed intralesional drug biodistribution. The precise intralesional and multi-compartment pharmacokinetics of bedaquiline were obtained using PET bioimaging and high-resolution autoradiography investigations. Reduced CFU counts were observed in another investigation after a 12-week course of therapy. Meta-analyses and systematic reviews of phase II trials on bedaquiline's efficacy in treating drug-resistant tuberculosis in patients reported higher rates of cure, better culture conversion, and lower death rates when taken in conjunction with a background regimen. Here is a thorough medication profile for bedaquiline to aid medical professionals in treating individuals with tuberculosis.


Assuntos
Antituberculosos , Diarilquinolinas , Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose Pulmonar , Diarilquinolinas/uso terapêutico , Diarilquinolinas/farmacocinética , Humanos , Antituberculosos/uso terapêutico , Antituberculosos/farmacocinética , Antituberculosos/farmacologia , Antituberculosos/administração & dosagem , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia , Mycobacterium tuberculosis/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Animais
4.
J Med Primatol ; 53(4): e12722, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38949157

RESUMO

BACKGROUND: Tuberculosis (TB) kills approximately 1.6 million people yearly despite the fact anti-TB drugs are generally curative. Therefore, TB-case detection and monitoring of therapy, need a comprehensive approach. Automated radiological analysis, combined with clinical, microbiological, and immunological data, by machine learning (ML), can help achieve it. METHODS: Six rhesus macaques were experimentally inoculated with pathogenic Mycobacterium tuberculosis in the lung. Data, including Computed Tomography (CT), were collected at 0, 2, 4, 8, 12, 16, and 20 weeks. RESULTS: Our ML-based CT analysis (TB-Net) efficiently and accurately analyzed disease progression, performing better than standard deep learning model (LLM OpenAI's CLIP Vi4). TB-Net based results were more consistent than, and confirmed independently by, blinded manual disease scoring by two radiologists and exhibited strong correlations with blood biomarkers, TB-lesion volumes, and disease-signs during disease pathogenesis. CONCLUSION: The proposed approach is valuable in early disease detection, monitoring efficacy of therapy, and clinical decision making.


Assuntos
Biomarcadores , Aprendizado Profundo , Macaca mulatta , Mycobacterium tuberculosis , Tomografia Computadorizada por Raios X , Animais , Biomarcadores/sangue , Tomografia Computadorizada por Raios X/veterinária , Tuberculose/veterinária , Tuberculose/diagnóstico por imagem , Modelos Animais de Doenças , Tuberculose Pulmonar/diagnóstico por imagem , Masculino , Feminino , Pulmão/diagnóstico por imagem , Pulmão/patologia , Pulmão/microbiologia , Doenças dos Macacos/diagnóstico por imagem , Doenças dos Macacos/microbiologia
5.
Front Cell Infect Microbiol ; 14: 1410015, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38957797

RESUMO

Background: Tuberculosis (TB) persists as a global health challenge, with its treatment hampered by the side effects of long-term combination drug therapies and the growing issue of drug resistance. Therefore, the development of novel therapeutic strategies is critical. This study focuses on the role of immune checkpoint molecules (ICs) and functions of CD8+ T cells in the search for new potential targets against TB. Methods: We conducted differential expression genes analysis and CD8+ T cell functional gene analysis on 92 TB samples and 61 healthy individual (HI) samples from TB database GSE83456, which contains data on 34,603 genes. The GSE54992 dataset was used to validated the findings. Additionally, a cluster analysis on single-cell data from primates infected with mycobacterium tuberculosis and those vaccinated with BCG was performed. Results: The overexpression of LAG-3 gene was found as a potentially important characteristic of both pulmonary TB (PTB) and extrapulmonary TB (EPTB). Further correlation analysis showed that LAG-3 gene was correlated with GZMB, perforin, IL-2 and IL-12. A significant temporal and spatial variation in LAG-3 expression was observed in T cells and macrophages during TB infection and after BCG vaccination. Conclusion: LAG-3 was overexpressed in TB samples. Targeting LAG-3 may represent a potential therapeutic target for tuberculosis.


Assuntos
Antígenos CD , Linfócitos T CD8-Positivos , Proteína do Gene 3 de Ativação de Linfócitos , Mycobacterium tuberculosis , Tuberculose , Humanos , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/genética , Linfócitos T CD8-Positivos/imunologia , Tuberculose/imunologia , Tuberculose/microbiologia , Animais , Antígenos CD/genética , Vacina BCG/imunologia , Macrófagos/imunologia , Macrófagos/microbiologia , Interleucina-2/metabolismo , Interleucina-2/genética , Perfilação da Expressão Gênica , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Interleucina-12/genética , Interleucina-12/metabolismo , Perforina/genética , Perforina/metabolismo , Masculino
6.
Int J Tuberc Lung Dis ; 28(7): 348-353, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38961546

RESUMO

BACKGROUNDSubnational TB estimates are crucial for making informed decisions to tailor TB control activities to local TB epidemiology.METHODSA cross-sectional survey was conducted among 143,005 individuals in Tamil Nadu, India. Participants were screened for symptoms and underwent chest X-ray (CXR). Participants with symptoms of TB and/or abnormal CXR were tested for TB using Xpert, smear, and liquid culture.RESULTSThe prevalence of microbiologically confirmed pulmonary TB (MCPTB) was 212 (95% CI 184-239) per 100,000 population. The prevalence-to-notification ratio (P:N) in the state was 2.05 (95% CI 1.8-2.29). Low body mass index and diabetes together had a population attributable fraction of 54.15 (95% CI 45.68-61.97). Approximately 39% of the TB cases were asymptomatic and were identified only by CXR screening. In the general population, only 26.9% sought care at a health facility among those with symptoms suggestive of TB.CONCLUSIONThe programme needs to prioritise screening with CXR to potentially detect cases earlier and curtail the transmission and upscale molecular tests in the selected population to increase the yield of case finding. Innovative health education strategies must be devised to address health-seeking behaviour..


Assuntos
Programas de Rastreamento , Tuberculose Pulmonar , Humanos , Índia/epidemiologia , Estudos Transversais , Prevalência , Adulto , Masculino , Feminino , Tuberculose Pulmonar/epidemiologia , Tuberculose Pulmonar/diagnóstico , Pessoa de Meia-Idade , Programas de Rastreamento/métodos , Adulto Jovem , Adolescente , Radiografia Torácica , Criança , Idoso , Pré-Escolar
7.
Int J Tuberc Lung Dis ; 28(7): 317-321, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38961554

RESUMO

Despite its historical decline, TB remains a significant cause of infectious disease-related global deaths. The lack of reliable diagnostic tests for vulnerable groups, such as children and immunocompromised patients, remains a challenge for TB control. For decades, it has been recognised that exhaled breath has great potential as a non-invasive and universally accessible clinical alternative to sputum and invasive sampling methods. Although translation into clinical practice has not yet occurred, there has been significant progress with promising results in various applications, including diagnosis, estimation of infectiousness, and monitoring of treatment response. More recently, the COVID-19 pandemic reignited global interest in this field and technological advances have further accelerated its development. In the coming decade, breath sampling will enhance our understanding of respiratory infectious diseases and host-immune responses, which may lead to clinical applications. Here we discuss the diagnostic landscape of TB and the current state of the art of breath sampling.


Assuntos
Testes Respiratórios , COVID-19 , Tuberculose Pulmonar , Humanos , Testes Respiratórios/métodos , Tuberculose Pulmonar/diagnóstico , COVID-19/diagnóstico , Expiração , SARS-CoV-2
8.
BMJ Open Respir Res ; 11(1)2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38991950

RESUMO

INTRODUCTION: Pakistan has significantly strengthened its capacity for active case finding (ACF) for tuberculosis (TB) that is being implemented at scale in the country. However, yields of ACF have been lower than expected, raising concerns on its effectiveness in the programmatic setting. Distribution of TB in communities is likely to be spatially heterogeneous and targeting of ACF in areas with higher TB prevalence may help improve yields. The primary aim of SPOT-TB is to investigate whether a policy change to use a geographically targeted approach towards ACF supported by an artificial intelligence (AI) software, MATCH-AI, can improve yields in Pakistan. METHODS AND ANALYSIS: SPOT-TB will use a pragmatic, stepped wedge cluster randomised design. A total of 30 mobile X-ray units and their field teams will be randomised to receive the intervention. Site selection for ACF in the intervention areas will be guided primarily through the use of MATCH-AI software that models subdistrict TB prevalence and identifies potential disease hotspots. Control areas will use existing approaches towards site selection that are based on staff knowledge, experience and analysis of historical data. The primary outcome measure is the difference in bacteriologically confirmed incident TB detected in the intervention relative to control areas. All remaining ACF-related procedures and algorithms will remain unaffected by this trial. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Health Services Academy, Islamabad, Pakistan (7-82/IERC-HSA/2022-52) and from the Common Management Unit for TB, HIV and Malaria, Ministry of Health Services, Regulation and Coordination, Islamabad, Pakistan (26-IRB-CMU-2023). Findings from this study will be disseminated through publications in peer-reviewed journals and stakeholder meetings in Pakistan with the implementing partners and public-sector officials. Findings will also be presented at local and international medical and public health conferences. TRIAL REGISTRATION NUMBER: NCT06017843.


Assuntos
Inteligência Artificial , Tuberculose , Humanos , Paquistão/epidemiologia , Tuberculose/epidemiologia , Software , Prevalência , Ensaios Clínicos Pragmáticos como Assunto , Programas de Rastreamento/métodos , Tuberculose Pulmonar/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos
9.
BMC Infect Dis ; 24(1): 690, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38992607

RESUMO

BACKGROUND: Growing evidence suggests that chronic inflammation caused by tuberculosis (TB) may increase the incidence of diabetes. However, the relationship between post-TB pulmonary abnormalities and diabetes has not been well characterized. METHODS: We analyzed data from a cross-sectional study in KwaZulu-Natal, South Africa, of people 15 years and older who underwent chest X-ray and diabetes screening with hemoglobin A1c testing. The analytic sample was restricted to persons with prior TB, defined by either (1) a self-reported history of TB treatment, (2) radiologist-confirmed prior TB on chest radiography, and (3) a negative sputum culture and GeneXpert. Chest X-rays of all participants were evaluated by the study radiologist to determine the presence of TB lung abnormalities. To assess the relationships between our outcome of interest, prevalent diabetes (HBA1c ≥6.5%), and our exposure of interest, chest X-ray abnormalities, we fitted logistic regression models adjusted for potential clinical and demographic confounders. In secondary analyses, we used the computer-aided detection system CAD4TB, which scores X-rays from 10 to 100 for detection of TB disease, as our exposure interest, and repeated analyses with a comparator group that had no history of TB disease. RESULTS: In the analytic cohort of people with prior TB (n = 3,276), approximately two-thirds (64.9%) were women, and the average age was 50.8 years (SD 17.4). The prevalence of diabetes was 10.9%, and 53.0% of people were living with HIV. In univariate analyses, there was no association between diabetes prevalence and radiologist chest X-ray abnormalities (OR 1.23, 95%CI 0.95-1.58). In multivariate analyses, the presence of pulmonary abnormalities was associated with an 29% reduction in the odds of prevalent diabetes (aOR 0.71, 95%CI 0.53-0.97, p = 0.030). A similar inverse relationship was observed for diabetes with each 10-unit increase in the CAD4TB chest X-ray scores among people with prior TB (aOR 0.92, 95%CI 0.87-0.97; p = 0.002), but this relationship was less pronounced in the no TB comparator group (aOR 0.96, 95%CI 0.94-0.99). CONCLUSIONS: Among people with prior TB, pulmonary abnormalities on digital chest X-ray are inversely associated with prevalent diabetes. The severity of radiographic post-TB lung disease does not appear to be a determinant of diabetes in this South African population.


Assuntos
Diabetes Mellitus , População Rural , Humanos , África do Sul/epidemiologia , Feminino , Masculino , Adulto , Estudos Transversais , Pessoa de Meia-Idade , Diabetes Mellitus/epidemiologia , População Rural/estatística & dados numéricos , Prevalência , Adulto Jovem , Radiografia Torácica , Adolescente , Tuberculose Pulmonar/epidemiologia , Tuberculose Pulmonar/diagnóstico por imagem , Tuberculose Pulmonar/complicações , Pulmão/diagnóstico por imagem , Radiografia , Idoso , Tuberculose/epidemiologia , Tuberculose/diagnóstico por imagem
10.
Front Immunol ; 15: 1357360, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38994357

RESUMO

Background: The impact of previous SARS-CoV-2 infection on the systemic immune response during tuberculosis (TB) disease has not been explored. Methods: An observational, cross-sectional cohort was established to evaluate the systemic immune response in persons with pulmonary tuberculosis with or without previous SARS-CoV-2 infection. Those participants were recruited in an outpatient referral clinic in Rio de Janeiro, Brazil. TB was defined as a positive Xpert-MTB/RIF Ultra and/or a positive culture of Mycobacterium tuberculosis from sputum. Stored plasma was used to perform specific serology to identify previous SARS-CoV-2 infection (TB/Prex-SCoV-2 group) and confirm the non- infection of the tuberculosis group (TB group). Plasmatic cytokine/chemokine/growth factor profiling was performed using Luminex technology. Tuberculosis severity was assessed by clinical and laboratory parameters. Participants from TB group (4.55%) and TB/Prex-SCoV-2 (0.00%) received the complete COVID-19 vaccination. Results: Among 35 participants with pulmonary TB, 22 were classified as TB/Prex-SCoV-2. The parameters associated with TB severity, together with hematologic and biochemical data were similar between the TB and TB/Prex-SCoV-2 groups. Among the signs and symptoms, fever and dyspnea were significantly more frequent in the TB group than the TB/Prex-SCoV-2 group (p < 0,05). A signature based on lower amount of plasma EGF, G-CSF, GM-CSF, IFN-α2, IL-12(p70), IL-13, IL-15, IL-17, IL-1ß, IL-5, IL-7, and TNF-ß was observed in the TB/Prex-SCoV-2 group. In contrast, MIP-1ß was significantly higher in the TB/Prex-SCoV-2 group than the TB group. Conclusion: TB patients previously infected with SARS-CoV-2 had an immunomodulation that was associated with lower plasma concentrations of soluble factors associated with systemic inflammation. This signature was associated with a lower frequency of symptoms such as fever and dyspnea but did not reflect significant differences in TB severity parameters observed at baseline.


Assuntos
COVID-19 , Citocinas , SARS-CoV-2 , Tuberculose Pulmonar , Humanos , COVID-19/imunologia , COVID-19/sangue , Masculino , Feminino , Estudos Transversais , Adulto , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/sangue , Citocinas/sangue , Citocinas/imunologia , Brasil/epidemiologia
11.
Saudi Med J ; 45(7): 658-666, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38955446

RESUMO

OBJECTIVES: To evaluate cytokine profiles and interferon-gamma release assay (IGRA) for their diagnostic capabilities in the differentiation of tuberculosis (TB) from non-TB conditions, as well as smear-negative pulmonary tuberculosis (SNPT) from smear-positive pulmonary tuberculosis (SPPT). METHODS: A total of 125 participants were included, 77 of whom had TB and 48 who didn't, and demographic, clinical, and laboratory data were collected, including cytokine levels and IGRA results. The TB patients were further divided into 2 subgroups: SNPT (n=42) and SPPT (n=35). RESULTS: Compared to non-TB, the TB group had lower BMI, higher WBC, neutrophils, monocytes, ESR and CRP (p<0.05). TB patients showed higher IL-2, IL-6, IFN-γ, IL-8 (p<0.001) and higher IGRA positivity (88.3% versus [vs.] 29.2%, p<0.001). Between SNPT and SPPT, moderate effect sizes were observed for IFN-α, IL-2, IL-10, IL-8 (Cohen's d 0.59-0.76), with lower IGRA positivity in SNPT (81.0% vs. 97.1%, p=0.015). ROC analysis indicated IFN-α, IL-2, IL-10, IL-8 had moderate accuracy for SNPT diagnosis (AUCs 0.668-0.734), and combining these improved accuracy (AUC 0.759, 80% sensitivity, 64.2% specificity). CONCLUSION: A multi-biomarker approach combining these cytokines demonstrates enhanced diagnostic accuracy for tuberculosis.


Assuntos
Citocinas , Tuberculose Pulmonar , Humanos , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/sangue , Masculino , Feminino , Citocinas/sangue , Adulto , Pessoa de Meia-Idade , Estudos Retrospectivos , Testes de Liberação de Interferon-gama , Interleucina-2/sangue , Interleucina-8/sangue , Curva ROC , Interleucina-6/sangue , Interleucina-10/sangue
12.
Sci Rep ; 14(1): 16437, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39013991

RESUMO

Inhalable microparticle-based anti TB drug delivery systems are being investigated extensively for Tuberculosis [TB] treatment as they offer efficient and deep lung deposition with several advantages over conventional routes. It can reduce the drug dose, treatment duration and toxic effects and optimize the drug bioavailability. Yeast derived ß-glucan is a ß-[1-3/1-6] linked biocompatible polymer and used as carrier for various biomolecules. Due to presence of glucan chains, particulate glucans act as PAMP and thereby gets internalized via receptor mediated phagocytosis by the macrophages. In this study, ß-glucan microparticles were prepared by adding l-leucine as excipient, and exhibited 70% drug [Rifabutin] loading efficiency. Further, the sizing and SEM data of particles revealed a size of 2-4 µm with spherical dimensions. The FTIR and HPLC data confirmed the ß-glucan composition and drug encapsulations efficiency of the particles. The mass median aerodynamic diameter [MMAD] and geometric standard deviation [GSD] data indicated that these particles are inhalable in nature and have better thermal stability as per DSC thermogram. These particles were found to be non-toxic upto a concentration of 80 µg/ml and were found to be readily phagocytosed by human macrophage cells in-vitro as well as in-vivo by lung alveolar macrophage. This study provides a framework for future design of inhalable ß-glucan particle based host-directed drug delivery system against pulmonary TB.


Assuntos
Sistemas de Liberação de Medicamentos , Rifabutina , beta-Glucanas , Rifabutina/administração & dosagem , Rifabutina/farmacocinética , Rifabutina/química , beta-Glucanas/química , Humanos , Administração por Inalação , Tuberculose Pulmonar/tratamento farmacológico , Tamanho da Partícula , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Portadores de Fármacos/química , Antituberculosos/administração & dosagem , Antituberculosos/farmacocinética , Antituberculosos/química
13.
Medicine (Baltimore) ; 103(29): e39011, 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-39029059

RESUMO

RATIONALE: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening systemic inflammatory syndrome characterized by an overactive immune response. This hyperactivation can arise from genetic mutations, infections, malignancies, or autoimmune disorders. Medication-induced HLH is extremely rare and requires special attention. PATIENT CONCERNS: A 53-year-old female diagnosed with pulmonary and urinary tract tuberculosis. She underwent quadruple therapy, including isoniazid, rifampin, ethambutol, and pyrazinamide. Subsequently, she developed fever, hepatosplenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, increased soluble CD25 levels, decreased natural killer cell activity, and hemophagocytosis, notably without eosinophilia. Her clinical symptoms were exacerbated by rifampin intake. DIAGNOSES: Pulmonary and left kidney tuberculosis, multiple organ failure, and rifampin-induced HLH. INTERVENTIONS: Anti-tuberculosis regimen (isoniazid, pyrazinamide, ethambutol, and levofloxacin, excluding rifampin) combined with glucocorticoid therapy. OUTCOMES: Satisfactory recovery with improved clinical symptoms, laboratory tests, and chest imaging studies. LESSONS: Early correct diagnosis and appropriate management of HLH are essential to save the lives of affected patients. The potential severe side effects of rifampin should not be ignored.


Assuntos
Linfo-Histiocitose Hemofagocítica , Rifampina , Humanos , Linfo-Histiocitose Hemofagocítica/induzido quimicamente , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Feminino , Pessoa de Meia-Idade , Rifampina/efeitos adversos , Rifampina/uso terapêutico , Tuberculose Pulmonar/tratamento farmacológico , Antituberculosos/efeitos adversos , Antituberculosos/uso terapêutico
14.
Clin Toxicol (Phila) ; 62(7): 425-431, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38946481

RESUMO

INTRODUCTION: Carbon monoxide poisoning is associated with severe damage to various organs. In this study, we aimed to determine if previous carbon monoxide poisoning was associated with an increased risk of lung diseases. METHODS: The study population was derived from the National Health Insurance Service database of Korea between 1 January 2002 and 31 December 2021. Adults with carbon monoxide poisoning, with at least one visit to medical facilities between 2002 and 2021, were included. For comparison, an equal number of matched controls with the same index date were selected from the database. RESULTS: A total of 28,618 patients with carbon monoxide poisoning and 28,618 matched controls were included in this study. Approximately 42.8 per cent of the patient and control groups were female, with a mean age of 51.3 years. In patients with carbon monoxide poisoning, there was a significant increase in the risk of lung cancer (adjusted hazard ratio, 1.84; 95 per cent confidence interval, 1.42-2.39; P < 0.001), chronic obstructive pulmonary disease (adjusted hazard ratio, 1.60; 95 per cent confidence interval, 1.36-1.89; P < 0.001), pulmonary tuberculosis (adjusted hazard ratio, 1.46; 95 per cent confidence interval, 1.13-1.88; P = 0.003), and non-tuberculous mycobacterial infection (adjusted hazard ratio, 1.54; 95 per cent confidence interval, 1.01-2.36; P = 0.047). DISCUSSION: In this retrospective cohort study, previous carbon monoxide poisoning was associated with an increased risk of lung cancer, chronic obstructive pulmonary disease, pulmonary tuberculosis, and non-tuberculous mycobacterial infection. Further studies are needed to confirm such an association in other populations and the risk of lung diseases due to the toxic effect of carbon monoxide from different sources. CONCLUSIONS: Previous carbon monoxide poisoning was associated with an increased risk of lung diseases, but the relative importance of the causes and sources of exposure was not known. The long-term management of survivors of acute carbon monoxide poisoning should include monitoring for lung cancer, chronic obstructive pulmonary disease, pulmonary tuberculosis, and non-tuberculous mycobacterial infection.


Assuntos
Intoxicação por Monóxido de Carbono , Humanos , Intoxicação por Monóxido de Carbono/epidemiologia , Feminino , República da Coreia/epidemiologia , Masculino , Pessoa de Meia-Idade , Adulto , Fatores de Risco , Idoso , Neoplasias Pulmonares/epidemiologia , Estudos de Coortes , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Estudos Retrospectivos , Pneumopatias/epidemiologia , Tuberculose Pulmonar/epidemiologia , Bases de Dados Factuais , Estudos de Casos e Controles
15.
Nat Commun ; 15(1): 5710, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38977711

RESUMO

Following Mycobacterium tuberculosis infection, alveolar macrophages are initially infected but ineffectively restrict bacterial replication. The distribution of M. tuberculosis among different cell types in the lung changes with the onset of T cell immunity when the dominant infected cellular niche shifts from alveolar to monocyte-derived macrophages (MDM). We hypothesize that changes in bacterial distribution among different cell types is driven by differences in T cell recognition of infected cells and their subsequent activation of antimicrobial effector mechanisms. We show that CD4 and CD8 T cells efficiently eliminate M. tuberculosis infection in alveolar macrophages, but they have less impact on suppressing infection in MDM, which may be a bacterial niche. Importantly, CD4 T cell responses enhance MDM recruitment to the lung. Thus, the outcome of infection depends on the interaction between the T cell subset and the infected cell; both contribute to the resolution and persistence of the infection.


Assuntos
Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Pulmão , Macrófagos Alveolares , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/fisiologia , Animais , Pulmão/microbiologia , Pulmão/imunologia , Pulmão/patologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/microbiologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD4-Positivos/imunologia , Camundongos , Feminino , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia , Macrófagos/imunologia , Macrófagos/microbiologia , Humanos
16.
Immun Inflamm Dis ; 12(7): e1350, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39023413

RESUMO

BACKGROUND: Differentially expressed genes/proteins (DEGs/DEPs) play critical roles in pulmonary tuberculosis (PTB) diagnosis and treatment. However, there is a scarcity of reports on DEGs/DEPs in lung tissues and blood samples in PTB patients. OBJECTIVE: We aim to identify the DEGs/DEPs in lung tissues and blood samples of PTB patients and investigate their roles in PTB. MATERIALS AND METHODS: The lung granulomas and normal tissues were collected from PTB patients for proteomic and transcriptomic analyses. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses annotated the functions of DEGs/DEPs. The GSE107994 data set was downloaded to identify the DEGs/DEPs in peripheral blood. The common DEGs and DEPs were identified. A nomogram was established. Pearson correlation analysis was conducted. RESULTS: Eighty-three DEGs/DEPs were identified. These DEGs/DEPs were mainly enriched in the movement of cell or subcellular components, regulation of cellular component biogenesis, and actin filament-based process as well as in the pathways of inositol phosphate metabolism, adherens junction, phosphatidylinositol signaling system, leukocyte transendothelial migration, regulation of actin cytoskeleton, and tight junction. There were eight common DEGs/DEPs (TYMP, LAP3, ADGRL2, SIL1, LMO7, SULF 1, ANXA3, and PACSIN3) between the lung tissues and blood samples. They were effective in predicting tuberculosis. Moreover, the activated dendritic cells, macrophages, monocytes, neutrophils, and regulatory T cells were significantly positively correlated with TYMP (r > .50), LAP3 (r > .50), SIL1 (r > .50), ANXA3 (r > .5), and PACSIN3 (r < .50), while negatively correlated with LMO7 (r < -0.50) (p < .05). ADGRL2 and SULF1 did not have a significant correlation (p > .05). LIMITATIONS: The sample size was small. CONCLUSIONS: Eight common DEGs/DEPs of lung tissues and blood samples were identified. They were correlated with immune cells and demonstrated predictive value for PTB. Our data may facilitate the diagnosis and treatment of PTB.


Assuntos
Perfilação da Expressão Gênica , Pulmão , Tuberculose Pulmonar , Humanos , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/genética , Pulmão/metabolismo , Pulmão/patologia , Pulmão/imunologia , Proteômica/métodos , Feminino , Masculino , Ontologia Genética , Transcriptoma , Biologia Computacional/métodos , Regulação da Expressão Gênica
17.
PLoS One ; 19(7): e0307307, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39024223

RESUMO

Tuberculosis (TB) is an infectious, chronic, and progressive disease occurring globally. Human TB is caused mainly by Mycobacterium tuberculosis (M. tuberculosis), while the main causative agent of bovine TB is Mycobacterium bovis (M. bovis). The latter is one of the most important cattle pathogens and is considered the main cause of zoonotic TB worldwide. The mechanisms responsible for tissue damage (necrosis) during post-primary TB remain elusive. Recently, IL-17A was reported to be important for protection against M. tuberculosis infection, but it is also related to the production of an intense inflammatory response associated with necrosis. We used two M. bovis isolates with different levels of virulence and high IL-17A production to study this important cytokine's contrasting functions in a BALB/c mouse model of pulmonary TB. In the first part of the study, the gene expression kinetics and cellular sources of IL-17A were determined by real time PCR and immunohistochemistry respectively. Non-infected lungs showed low production of IL-17A, particularly by the bronchial epithelium, while lungs infected with the low-virulence 534 strain showed high IL-17A expression on Day 3 post-infection, followed by a decrease in expression in the early stage of the infection and another increase during late infection, on Day 60, when very low bacillary burdens were found. In contrast, infection with the highly virulent strain 04-303 induced a peak of IL-17A expression on Day 14 of infection, 1 week before extensive pulmonary necrosis was seen, being lymphocytes and macrophages the most important sources. In the second part of the study, the contribution of IL-17A to immune protection and pulmonary necrosis was evaluated by suppressing IL-17A via the administration of specific blocking antibodies. Infection with M. bovis strain 534 and treatment with IL-17A neutralizing antibodies did not affect mouse survival but produced a significant increase in bacillary load and a non-significant decrease in inflammatory infiltrate and granuloma area. In contrast, mice infected with the highly virulent 04-303 strain and treated with IL-17A blocking antibodies showed a significant decrease in survival, an increase in bacillary loads on Day 24 post-infection, and significantly more and earlier necrosis. Our results suggest that high expression of IL-17A is more related to protection than necrosis in a mouse model of pulmonary TB induced by M. bovis strains.


Assuntos
Interleucina-17 , Camundongos Endogâmicos BALB C , Mycobacterium bovis , Tuberculose Pulmonar , Interleucina-17/metabolismo , Interleucina-17/imunologia , Animais , Mycobacterium bovis/patogenicidade , Mycobacterium bovis/imunologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia , Camundongos , Virulência , Pulmão/microbiologia , Pulmão/patologia , Pulmão/imunologia , Feminino , Bovinos
18.
Int J Mol Sci ; 25(13)2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38999932

RESUMO

The World Health Organization (WHO) highlights a greater susceptibility of males to tuberculosis (TB), a vulnerability attributed to sex-specific variations in body fat and dietary factors. Our study delves into the unexplored terrain of how alterations in body fat influence Mycobacterium tuberculosis (Mtb) burden, lung pathology, immune responses, and gene expression, with a focus on sex-specific dynamics. Utilizing a low-dose Mtb-HN878 clinical strain infection model, we employ transgenic FAT-ATTAC mice with modulable body fat to explore the impact of fat loss (via fat ablation) and fat gain (via a medium-fat diet, MFD). Firstly, our investigation unveils that Mtb infection triggers severe pulmonary pathology in males, marked by shifts in metabolic signaling involving heightened lipid hydrolysis and proinflammatory signaling driven by IL-6 and localized pro-inflammatory CD8+ cells. This stands in stark contrast to females on a control regular diet (RD). Secondly, our findings indicate that both fat loss and fat gain in males lead to significantly elevated (1.6-fold (p ≤ 0.01) and 1.7-fold (p ≤ 0.001), respectively) Mtb burden in the lungs compared to females during Mtb infection (where fat loss and gain did not alter Mtb load in the lungs). This upsurge is associated with impaired lung lipid metabolism and intensified mitochondrial oxidative phosphorylation-regulated activity in lung CD8+ cells during Mtb infection. Additionally, our research brings to light that females exhibit a more robust systemic IFNγ (p ≤ 0.001) response than males during Mtb infection. This heightened response may either prevent active disease or contribute to latency in females during Mtb infection. In summary, our comprehensive analysis of the interplay between body fat changes and sex bias in Mtb infection reveals that alterations in body fat critically impact pulmonary pathology in males. Specifically, these changes significantly reduce the levels of pulmonary CD8+ T-cells and increase the Mtb burden in the lungs compared to females. The reduction in CD8+ cells in males is linked to an increase in mitochondrial oxidative phosphorylation and a decrease in TNFα, which are essential for CD8+ cell activation.


Assuntos
Tecido Adiposo , Pulmão , Mycobacterium tuberculosis , Animais , Feminino , Masculino , Camundongos , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Pulmão/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/imunologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/patologia , Tuberculose Pulmonar/microbiologia , Camundongos Transgênicos , Fatores Sexuais , Modelos Animais de Doenças , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Caracteres Sexuais , Camundongos Endogâmicos C57BL
19.
Bull Exp Biol Med ; 177(1): 140-146, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38960962

RESUMO

The dynamics of lung microbiota in tuberculosis remains poorly understood. Sequencing of variable regions of the 16S rRNA gene from surgically excised tuberculosis foci and biopsy specimens of normal lung tissue allowed characterization of the diversity and predictive potential of bacterial communities. Taxonomic diversity indices attested to differences in the structure of microbial communities between "healthy" lungs and tuberculomas. The microbial composition of "healthy" lungs varied in taxonomic diversity and was presented by both gram-positive and gram-negative bacteria with sufficiently similar metabolic potential. The microbiota of the examined tuberculomas consisted of Mycobacterium tuberculosis in 99.9% of cases. A significant part of the metabolic pathways predicted by PICRUSt2 included cholesterol catabolism, sulfate assimilation, and various pathways for the biosynthesis of cell wall components.


Assuntos
Pulmão , Mycobacterium tuberculosis , RNA Ribossômico 16S , Tuberculoma , Humanos , RNA Ribossômico 16S/genética , Mycobacterium tuberculosis/genética , Tuberculoma/microbiologia , Tuberculoma/patologia , Tuberculoma/genética , Pulmão/microbiologia , Pulmão/patologia , Pulmão/metabolismo , Microbiota/genética , Microbiota/fisiologia , Masculino , Adulto , Tuberculose Pulmonar/microbiologia , Feminino , Pessoa de Meia-Idade , Bactérias Gram-Negativas/genética , Bactérias Gram-Positivas/genética , Bactérias Gram-Positivas/metabolismo , Bactérias Gram-Positivas/classificação
20.
PLoS One ; 19(7): e0305855, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39012889

RESUMO

BACKGROUND: By encouraging treatment adherence and lowering mortality, dietary supplements can serve as adjuvant therapy for the success of medical interventions. We determined the effect of locally accessible food supplements on treatment outcomes, and health-related quality of life in patients with pulmonary tuberculosis initiating anti-tuberculosis treatment (ATT) in Odisha, India. METHOD: Between September 2017 and December 2018, implementation research in patients with newly diagnosed sputum smear-positive pulmonary tuberculosis initiating ATT in five districts of the tribal belt of Odisha, offered food supplements along with ATT in a phased manner. Clinical symptoms, anthropometry, sputum for M. tuberculosis (M. tb), health-related quality of life and return to normal function were assessed periodically, and favourable treatment outcome (cure or treatment completed) was measured at the end of treatment. The effect of the food supplement on unfavorable outcomes (treatment failure, death, or lost-to-follow-up) was modelled using mixed-effects Poisson regression to determine the risk factors. RESULTS: Among the 761 participants enrolled, 614 participants received the food supplement and 147 did not receive the food supplement. Among the 614 participants in the supplement group, 537 (87%) had a favorable outcome and among the 147 participants in the no-supplement group, 113 (77%) had a favorable outcome (p = 0.0017). Higher age (>55 years) [aRR = 2.1(95% CI: 1.1-3.8)], male gender [aRR = 1.7(95% CI: 1.2-2.9)], and smear grading ≥2+ [aRR = 1.5 (95% CI: 1.1-2.2)] were associated with unfavorable treatment outcomes. Nutritional status, quality of life and lung health showed significant improvement from baseline in the supplement group. CONCLUSION: Improvement in the nutritional status of the patient can be considered a predictor of treatment success rates. Early food supplementation has a positive impact on the nutritional status.


Assuntos
Antituberculosos , Suplementos Nutricionais , Qualidade de Vida , Tuberculose Pulmonar , Humanos , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/psicologia , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Antituberculosos/uso terapêutico , Resultado do Tratamento , Índia , Adulto Jovem
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