Development Of Active Pulmonary Tuberculosis Research Articles

Whole Genome DNA Methylation Analysis of Active Pulmonary Tuberculosis Disease Identifies Novel Epigenotypes: PARP9/miR-505/RASGRP4/GNG12 Gene Methylation and Clinical Phenotypes.

We hypothesized that DNA methylation patterns may contribute to the development of active pulmonary tuberculosis (TB). Illumina’s DNA methylation 450 K assay was used to identify differentially methylated loci (DML) in a discovery cohort of 12 active pulmonary TB patients and 6 healthy subjects (HS). DNA methylation levels were validated in an independent cohort of 64 TB patients and 24 HS. Microarray analysis identified 1028 DMLs in TB patients versus HS, and 3747 DMLs in TB patients after versus before anti-TB treatment, while autophagy was the most enriched signaling pathway. In the validation cohort, PARP9 and miR505 genes were hypomethylated in the TB patients versus HS, while RASGRP4 and GNG12 genes were hypermethylated, with the former two further hypomethylated in those with delayed sputum conversion, systemic symptoms, or far advanced lesions. MRPS18B and RPTOR genes were hypomethylated in TB patients with pleural involvement. RASGRP4 gene hypermethylation and RPTOR gene down-regulation were associated with high mycobacterial burden. TB patients with WIPI2/GNG12 hypermethylation or MRPS18B/FOXO3 hypomethylation had lower one-year survival. In vitro ESAT6 and CFP10 stimuli of THP-1 cells resulted in DNA de-methylation changes of the PARP9, RASGRP4, WIPI2, and FOXO3 genes. In conclusions, aberrant DNA methylation over the PARP9/miR505/RASGRP4/GNG12 genes may contribute to the development of active pulmonary TB disease and its clinical phenotypes, while aberrant DNA methylation over the WIPI2/GNG12/MARPS18B/FOXO3 genes may constitute a determinant of long-term outcomes.

Prevalence of invasive aspergillosis in suspected pulmonary tuberculosis at a referral tuberculosis hospital in Shandong, China.

AbstractAlthough the progression of invasive aspergillosis (IA) shares some risk factors in the development of active pulmonary tuberculosis (PTB), however, the prevalence of IA in suspected PTB remains unclear. During a period of 1 year (from January 2016 to December 2016), consecutive patients with suspected PTB were included in a referral TB hospital. Data, including demographic information and underlying diseases, were collected from medical records. PTB were all confirmed by mycobacterial culture (Lowenstein–Jensen medium). IA were diagnosed as proven or probable according to the criteria of the 2008 EORTC/MSG definitions. A descriptive analysis was performed to estimate the corresponding prevalence. During the study year, 1507 patients have a positive mycobacterial culture, with a mean age of 45.6 (s.d.19.9) years old and a female:male ratio of 1:4. Among the 82 patients with non-tuberculous mycobacterial diseases, two patients (2.44%, 95% CI 0.67–8.46%) were diagnosed as IA (one proven and one probable); two probable IA patients (0.15%, 95% CI 0.04–0.55%) were diagnosed in PTB patients (n= 1315), and all were retreatment cases. In addition, all four IA patients (100%) exhibited cavities in both lobes on radiograph. In China, the prevalence of IA is low in active PTB patients. However, when high-risk factors for IA are encountered in PTB patients, further investigations are required and empirically treatment for IA might be warranted.

Ambient Air Pollution and Pulmonary Tuberculosis in Malaysia

Introduction: The possible impact of ambient air pollution exposure on the development of active tuberculosis (TB) remains obscure. This study investigated the potential role of ambient air pollution in activating pulmonary TB (PTB) compared to extrapulmonary TB (EPTB). Materials and Methods: Data on TB cases were obtained from national surveillance data in Malaysia during 2013 and air pollution data were obtained from 52 air-monitoring stations around the country for the 3-year period of 2011-2013. Analyses were performed to estimate the odds of PTB vs. EPTB with changes in the 3-year (2011-2013) average Air Pollutant Index (API) and specific ambient air pollutants. Results: Results showed that the 95th-percentile of API levels during 2011-2013 was moderate and it was not associated with PTB. However, the odds of active PTB compared to EPTB was significantly elevated with the 95th-percentile levels for particulate matter with an aerodynamic diameter of 10 μm or less (aOR = 1.006, 95% CI: 1.002, 1.011), p-value < 0.01, and sulfur dioxide (aOR = 1.012, 95% CI: 1.006, 1.019), p-value < 0.01. Conclusions: These results provide suggestive evidence of the effects of ambient air pollution on development of active pulmonary TB compared to extrapulmonary TB. Additional research on the impacts of ambient air pollution on TB is warranted.

Influence of diabetes mellitus on immunity to human tuberculosis.

Type 2 diabetes mellitus(DM) is a major risk factor for the development of active pulmonary tuberculosis (TB), with development of DM pandemic in countries where TB is also endemic. Understanding the impact of DM on TB and the determinants of co-morbidity is essential in responding to this growing public health problem with improved therapeutic approaches. Despite the clinical and public health significance posed by the dual burden of TB and DM, little is known about the immunological and biochemical mechanisms of susceptibility. One possible mechanism is that an impaired immune response in patients with DM facilitates either primary infection with Mycobacterium tuberculosis or reactivation of latent TB. Diabetes is associated with immune dysfunction and alterations in the components of the immune system, including altered levels of specific cytokines and chemokines. Some effects of DM on adaptive immunity that are potentially relevant to TB defence have been identified in humans. In this review, we summarize current findings regarding the alterations in the innate and adaptive immune responses and immunological mechanisms of susceptibility of patients with DM to M. tuberculosis infection and disease.

Association of high serum vitamin D concentrations with active pulmonary TB in an HIV co-endemic setting, Harare, Zimbabwe

BackgroundThere is paucity data on the association of vitamin D deficiency (VDD) and active tuberculosis (TB) in southern Africa where the human immunodeficiency virus (HIV) is co-endemic. We examined the association of serum vitamin D concentrations with active pulmonary tuberculosis (PTB) in HIV-infected (n = 284) and uninfected (n = 267) Black Zimbabweans, in Harare, Zimbabwe.MethodsWe conducted a cross-sectional study of 551 participants comprising 145 HIV+/PTB +, 139 HIV+/PTB−, 134 HIV−/PTB+ and 133 HIV−/PTB−. PTB status was confirmed using sputum by culture, or smear microscopy, or GeneXpert MTB/RIF. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were measured using a competitive chemiluminescent immunoassay prior to commencement of anti-TB treatment.ResultsIn all four groups, the median vitamin D concentrations were above the 20 ng/ml cut off for VDD. However, the median vitamin D concentrations in all the four groups were below the cut off for vitamin D sufficiency ≥30 ng/ml. The median vitamin D concentrations were significantly higher in PTB+ cases; 24.2 ng/ml (IQR: 18.8–32.0) compared to PTB− controls 20.9 ng/ml (IQR: 17.1–26.9), p < 0.0001 regardless of HIV status. The HIV+/PTB+ group had the highest median vitamin D concentration (25.3 (IQR: 18.0–33.7 ng/ml) whilst the HIV+/PTB− group had the lowest; 20.4 ng/ml (IQR: 14.6–26.9), p = 0.0003. Vitamin D concentration <30 ng/ml was associated with 43% lower odds of being PTB+ OR 0.57 (95% CI 0.35–0.89).ConclusionsOur results are not in agreement with the generally accepted hypothesis that VDD is associated with active PTB. To the contrary our results showed an association of higher vitamin D concentrations with active TB irrespective of HIV status. Although findings from the available pool of case control studies remain inconsistent, the results from the current study provide further rationale for larger-scale, prospectively designed studies to evaluate whether sufficient vitamin D concentrations do indeed precede the development of active PTB in our setting.

Modulation of dendritic cell and monocyte subsets in tuberculosis-diabetes co-morbidity upon standard tuberculosis treatment

Type 2 diabetes mellitus (DM) is a major risk factor for the development of active pulmonary tuberculosis (PTB), with development of DM pandemic in countries where tuberculosis (TB) is also endemic. However, the effect of anti-TB treatment on the changes in dentritic cell (DC) and monocyte subset phenotype in TB-DM co-morbidity is not well understood. In this study, we characterized the frequency of DC and monocyte subsets in individuals with PTB with (PTB-DM) or without coincident diabetes mellitus (PTB-NDM) before, during and after completion of anti-TB treatment. PTB-DM is characterized by diminished frequencies of plasmacytoid and myeloid DCs and classical and intermediate monocytes at baseline and 2 months of anti-TB treatment but not following 6 months of treatment completion in comparison to PTB-NDM. DC and monocyte subsets exhibit significant but borderline correlation with fasting blood glucose and glycated hemoglobin levels. Finally, while minor changes in the DC and monocyte compartment were observed at 2 months of treatment, significantly increased frequencies of plasmacytoid and myeloid DCs and classical and intermediate monocytes were observed at the successful completion of anti-TB treatment. Our data show that coincident diabetes alters the frequencies of innate subset distribution of DC and monocytes in TB-DM co-morbidity and suggests that most of these changes are reversible following anti-TB therapy.

Expansion of Pathogen-Specific T-Helper 1 and T-Helper 17 Cells in Pulmonary Tuberculosis With Coincident Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (DM) is a major risk factor for the development of active pulmonary tuberculosis, although the immunological mechanisms underlying this interaction remain unexplored. The influence of poorly controlled diabetes on pathogen-specific T-helper 1 (Th1) and T-helper 17 (Th17) responses have not been examined. To identify the role of Th1 and Th17 cells in tuberculosis with coincident DM, we examined mycobacteria-specific immune responses in the whole blood of individuals who had tuberculosis with DM and compared them to those in individuals who had tuberculosis without DM. Tuberculosis coincident with DM is characterized by elevated frequencies of monofunctional and dual-functional CD4(+) Th1 cells following Mycobacterium tuberculosis antigen stimulation and elevated frequencies of Th17 subsets at both baseline and following antigen stimulation. This was associated with increased systemic (plasma) levels of both Th1 and Th17 cytokines and decreased baseline frequencies of natural regulatory T cells but not interleukin 10 or transforming growth factor β. Therefore, our data reveal that tuberculosis in persons with DM is characterized by elevated frequencies of Th1 and Th17 cells, indicating that DM is associated with an alteration in the immune response to tuberculosis, leading to a biased induction of Th1- and Th17-mediated cellular responses and likely contributing to increased immune pathology in M. tuberculosis infection.

MCP-1 −2518 A/G functional polymorphism is associated with increased susceptibility to active pulmonary tuberculosis in Tunisian patients

Monocyte chemoattractant protein-1 (MCP-1) plays crucial role in protective immunity against Mycobacterium tuberculosis (MT). In this study, we examined whether single nucleotide polymorphism (SNP) -2518 A/G (rs 1024611) of MCP-1 affect the susceptibility to active tuberculosis (TB) in Tunisian populations. Genomic DNA from patients with active TB (168 cases of pulmonary TB and 55 cases of extrapulmonary TB) and ethnically controls (150 cases) was genotyped for the MCP-1 -2518 A/G SNP by polymerase chain reaction fragment length polymorphism (PCR-RFLP). We observed that -2518 G allele and GG genotype (high MCP-1 producer) frequencies were significantly more elevated in active pulmonary TB group in comparison to control group [34 vs. 22%; P = 0.0007; 15 vs. 5%, P corrected for the number of genotypes (Pc) = 0.015; respectively]. Additionally, they were associated with increased risk development of this clinical form of TB [odds ratio (OR) = 1.83, 95% confidence intervals (CI) = 1.26-2.66; OR = 3.1, 95% CI = 1.28-7.76; respectively]. However, wild type allele -2518 A and AA genotype were over-represented in control group (78 and 62%) and seem to be protective factors against TB. Moreover, -2518 AA genotype was more frequent in control group and was associated with resistance against development of active pulmonary TB (OR = 0.56, 95% CI = 0.35-0.89, Pc = 0.03). Our findings confirm the key role of -2518 A/G SNP of MCP-1 and support its association with resistance/susceptibility to the development of active pulmonary TB in the Tunisian population.

Polymorphisms of the NRAMP1 gene: Distribution and susceptibility to the development of pulmonary tuberculosis in the Greek population

SummaryBackgroundAmple evidence suggests that host genetic factors affect human susceptibility to tuberculosis. The natural resistance–associated macrophage protein 1 (NRAMP1) gene seems to play a role in the pathophysiology of a number of intracellular infections, including mycobacteria. A case-control study was conducted in the Greek population to determine whether NRAMP1 polymorphisms affect the susceptibility to development of overt pulmonary tuberculosis.Material/MethodsNRAMP1 polymorphisms (3′UTR, D543N, INT4) were evaluated among 142 patients with culture-positive pulmonary tuberculosis and 144 ethnically matched healthy controls having latent M. tuberculosis infection. Patients with human immunodeficiency virus infection were excluded.ResultsOut of the 3 NRAMP1 polymorphisms, a trend of increased incidence of INT4 polymorphism was found in the patients’ group compared to the control group. A lack of association was observed between the 2 groups as far as the other 2 polymorphisms (D543N, 3′UTR) are concerned. INT4-CC homozygotes were found to have a higher risk to develop pulmonary tuberculosis compared to GG homozygotes (p=0.022). An increased incidence G/TGTG/C genotype combination was found in the patients’ group as compared to controls. G/TGTG/C genotype combination was associated with a 36% higher risk of developing pulmonary tuberculosis (p=0.004) compared to the baseline expression of G/TGTG/G combination.ConclusionsINT4-NRAMP1 polymorphism may have a role in the development of culture-positive pulmonary tuberculosis after an initial M. tuberculosis latent infection. The possible role of INT4-NRAMP1 polymorphism in the development of active pulmonary tuberculosis needs further investigation.

Use of High-Dose Inhaled Corticosteroids is Associated With Pulmonary Tuberculosis in Patients With Chronic Obstructive Pulmonary Disease

The use of high-dose inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease (COPD) has recently been shown to increase the incidence of pneumonia. However, to our knowledge, the impact of high-dose ICS on pulmonary tuberculosis (TB) has never been investigated. To study that impact, we conducted a retrospective study including patients aged more than 40 years old with irreversible airflow limitation between August 2000 and July 2008 in a medical center in Taiwan. Of the 36,684 patients who underwent pulmonary function testing, we included 554 patients. Among them, patients using high-dose ICS (equivalent to >500 microg/d of fluticasone) were more likely to have more severe COPD and receive oral corticosteroids than those using medium-dose, low-dose, or no ICS. Sixteen (3%) patients developed active pulmonary TB within a follow-up of 25,544 person-months. Multivariate Cox regression analysis revealed that the use of high-dose ICS, the use of 10 mg or more of prednisolone per day, and prior pulmonary TB were independent risk factors for the development of active pulmonary TB. Chest radiography and sputum smear/culture for Mycobacterium tuberculosis should be performed before initiating high-dose ICS and regularly thereafter.

Passive smoking and risk of pulmonary tuberculosis in children immediately following infection. A case-control study

Setting: Passive smoking-related respiratory disorders in children. Objectives: To assess the effect of passive smoking on the development of active pulmonary tuberculosis (PTB) in children immediately following infection by Mycobacterium tuberculosis within the family. Design: An unmatched case-control study in which 93 contacts who became cases (active PTB diagnosed) and 95 contacts who did not became cases (tuberculin-positive children without evidence of active disease) were included. All were household contacts of a new case of pulmonary bacillary tuberculosis. Smoking habits were investigated by a questionnaire. Urinary cotinine was analysed. Odds Ratio (OR) was adjusted for age and socio-economic status using multiple logistic regression analysis. Results: Passive smoking was a risk factor for PTB (OR: 5.29; 95% confidence interval (CI): 2.33–12.82; P < 0.00005). The adjusted OR was 5.39 (95% CI: 2.44–11.91; P < 0.00001). The risk increased when contacts were passive smokers both at home and outside the home within the family (OR: 6.35; 95% CI: 3.20, 12.72; P < 0.00001). Contacts 0–4 and 5–9 years old showed a significantly higher risk than those aged ≥ 10. There was a dose-response relationship between the risk of developing active PTB immediately following infection and the number of cigarettes smoked daily by the household adults ( P < 0.001). Mean (SD) urinary continine detectable concentrations (ng/ml) were different between disease contacts (119.46 [68.61]) and non diseased contacts (91.87 [73.10]). The difference was statistically significant ( P < 0.001). Conclusions: Passive exposure to tobacco smoke in children was associated with an increased risk of developing pulmonary tuberculosis immediately following infection. This is an association of great concern requiring health education programmes and antitobacco medical advice.

Cigarette smoking as a risk factor for tuberculosis in young adults: A casecontrol study

Setting: The association between smoking and pulmonary tuberculosis has not often been studied. Objective: To assess the influence of cigarette smoking on the development of active pulmonary tuberculosis in young people who were close contacts of new cases of smear-positive pulmonary tuberculosis. Design: A case-control study in which 46 ‘cases’ (patients with active pulmonary tuberculosis: isolation of Mycobacterium tuberculosis or clinical and/or radiographic evidence of current pulmonary tuberculosis, with a positive tuberculin skin test) and 46 ‘controls’ (persons with positive tuberculin reaction, negative bacteriological test and without clinical and/or radiological evidence of pulmonary tuberculosis) were included. Smoking habits were investigated by questionnaire. Univariate and multivariate analysis was performed, and odds ratio (OR) was adjusted for age, gender and socio-economic status. Results: Statistically significant differences were found in active smokers (occasional and daily smokers) (OR: 3.65; 95% CI, 1.46 and 9.21; P < 0.01), daily smokers (OR: 3.53; 95% CI, 1.34 and 9.26; P < 0.05), and individuals who were both passive and active smokers (OR: 5.10; 95 % CI, 1.97 and 13.22; P < 0.01) and passive and daily smokers (OR: 5.59; 95% CI, 2.07 and 15.10; P < 0.001). There was a dose-response relationship between the number of cigarettes smoked daily and the risk of active pulmonary tuberculosis. Conclusions: The data studied show that cigarette smoking is a risk factor for pulmonary tuberculosis in young people, with a dose-response relationship with the number of cigarettes consumed daily.

Active pulmonary tuberculosis after upper gastrointestinal surgery.

The development of active pulmonary tuberculosis after upper gastrointestinal surgery is a well recognized clinical situation (1-7). In 1953 Warthin (8) reported the first series of patients in the U.S. literature. He collected 7 such cases among 142 patients with pulmonary tuberculosis seen at the West Roxbury Veterans Administration Hospital. Since then several wnters have reported similar series (9-15). The present study reviews this association m a group of patients hospitalized for active pulmonary tuberculosis in the Veterans Admmistration Hospital, Cleveland, Ohio, and in patients recently discharged from this hospital with the same diagnosis. The purpose of this study is to try to determine the magnitude of this problem m a Veterans hospital population and to explore Its possible prevention.

THE ICEBERG OF MEDICINE: TUBERCULOSIS

Evidence is presented to show that the most common mechanism for the development of active pulmonary tuberculosis among older persons is the reactivation of dormant tuberculous foci, and not reinfection. The large number of older persons with scars of tuberculosis is likened to an iceberg, of which the greater portion lies hidden beneath the surface but is of great potential danger. Old age, alcoholism, diabetes mellitus, silicosis, steroid therapy, malnutrition and smoldering malignancy may produce reactivation of long dormant foci. It is important that radiologists recognize the continuing danger of apical pulmonary scars even when they show no change year after year.

The interrelationships between Addison's disease and active tuberculosis: a review of 125 cases of Addison's disease.

Excerpt The difficulties of evaluating the effect of adrenal function on the course of an infection are well illustrated in the clinical problem presented by the spontaneous occurrence of active tu...

The use of cortisone and hydrocortisone in allergy.

Excerpt INTRODUCTION During the last few years compound E (cortisone) and compound F (hydrocortisone) have been used with considerable success to suppress the symptoms of allergic and related disor...

Treatment of a patient with lupus erythematosus and pulmonary tuberculosis with ACTH, streptomycin and para-aminosalicylic acid.

Excerpt INTRODUCTION Corticotropin (ACTH) and cortisone are regarded as contraindicated in the presence of tuberculosis because of their suppressive effect on inflammation, granulation tissue forma...

APPEARANCE OF MILIARY TUBERCULOSIS FOLLOWING THERAPY WITH ACTH AND CORTISONE IN A CASE OF ACUTE DISSEMINATED LUPUS ERYTHEMATOSUS

Excerpt Although a great deal of experimental work has been done on animals demonstrating the enhancing effect of ACTH and/or cortisone upon the evolution and development of tuberculous lesions,1-1...