Inflammation-mediated tissue damage in pulmonary tuberculosis and host-directed therapeutic strategies.

Treatment of tuberculosis (TB) involves the administration of anti-mycobacterial drugs for several months. The emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb, the causative agent) together with increased disease severity in people with co-morbidities such as diabetes mellitus and HIV have hampered efforts to reduce case fatality. In severe disease, TB pathology is largely attributable to over-exuberant host immune responses targeted at controlling bacterial replication. Non-resolving inflammation driven by host pro-inflammatory mediators in response to high bacterial load leads to pulmonary pathology including cavitation and fibrosis. The need to improve clinical outcomes and reduce treatment times has led to a two-pronged approach involving the development of novel antimicrobials as well as host-directed therapies (HDT) that favourably modulate immune responses to Mtb. HDT strategies incorporate aspects of immune modulation aimed at downregulating non-productive inflammatory responses and augmenting antimicrobial effector mechanisms to minimise pulmonary pathology and accelerate symptom resolution. HDT in combination with existing antimycobacterial agents offers a potentially promising strategy to improve the long-term outcome for TB patients. In this review, we describe components of the host immune response that contribute to inflammation and tissue damage in pulmonary TB, including cytokines, matrix metalloproteinases, lipid mediators, and neutrophil extracellular traps. We then proceed to review HDT directed at these pathways.

Uncovering the Bronchoalveolar Single-Cell Landscape of Patients With Pulmonary Tuberculosis With Human Immunodeficiency Virus Type 1 Coinfection.

BACKGROUND: Coinfection of human immunodeficiency virus type 1 (HIV-1) is the most significant risk factor for tuberculosis (TB). The immune responses of the lung are essential to restrict the growth of Mycobacterium tuberculosis and avoid the emergence of the disease. Nevertheless, there is still limited knowledge about the local immune response in people with HIV-1-TB coinfection. METHODS: We employed single-cell RNA sequencing (scRNA-seq) on bronchoalveolar lavage fluid from 9 individuals with HIV-1-TB coinfection and 10 with pulmonary TB. RESULTS: A total of 19 058 cells were grouped into 4 major cell types: myeloid cells, T/natural killer (NK) cells, B cells, and epithelial cells. The myeloid cells and T/NK cells were further divided into 10 and 11 subsets, respectively. The proportions of dendritic cell subsets, CD4+ T cells, and NK cells were lower in the HIV-1-TB coinfection group compared to the TB group, while the frequency of CD8+ T cells was higher. Additionally, we identified numerous differentially expressed genes between the CD4+ and CD8+ T-cell subsets between the 2 groups. CONCLUSIONS: HIV-1 infection not only affects the abundance of immune cells in the lungs but also alters their functions in patients with pulmonary TB.

Increased tuberculosis case detection in Tanzanian children and adults using African giant pouched rats.

BACKGROUND: African giant pouched rats, trained by Anti-Persoonsmijnen Ontmijnende Product Ontwikkeling (APOPO), have demonstrated their ability to detect tuberculosis (TB) from sputum. We assessed rat-based case detection and compared the mycobacterium bacillary load (MTB-load) in children versus adults. METHODS: From January-December 2022, samples were collected prospectively from 69 Directly Observed Therapy (DOT) facilities' presumed TB patients. Using an average of five rats, APOPO re-evaluated patients with bacteriologically negative (sputum-smear microscopy or Xpert MTB/RIF) results. Rat-positive samples were tested using concentrated smear light-emitting diode microscopy to confirm TB detection before treatment initiation. The rats' identification of pulmonary TB is based on smelling TB-specific volatile organic compounds (VOCs) in sputum. Using STATA, Chi-square for odds ratio and confidence interval was calculated and evaluated: (1) the yield of rat-based TB detection compared to that of the health facilities; (2) rat-based TB detection in children versus adults; and (3) rats' ability to detect TB across MTB-loads and between children and adults. RESULTS: From 35,766 patients, 5.3% (1900/35,766) were smear-positive and 94.7% (33,866/35,766) were smear or Xpert-negatives at DOTS facility. Of those with negative results, 2029 TB cases were detected using rats, contributing to 52% (2029/3929 of total TB identified), which otherwise would have been missed. Compared to DOT facilities, rats were six-fold more likely to detect TB among Acid Fast Bacilli (AFB) 1+/scanty [90% (1829/2029) versus 60% (1139/1900), odds ratio, OR = 6.11, 95% confidence interval, CI: 5.14-7.26]; twice more likely to identify TB cases among children [71% (91/129) versus 51% (1795/3542), OR = 2.3, 95% CI: 1.59-3.42]; and twice more likely to identify TB cases among children with AFB 1+/scanty than adults with the same MTB-load [5% (86/1703) versus 3% (28/1067), OR = 2.0, 95% CI: 1.28-3.03]. CONCLUSIONS: Rats contributed over half of the TB cases identified in program settings, and children, especially those with a lower MTB-load, were more likely to be diagnosed with TB by rats. The chemical signatures, VOCs, were only available for adults, and further research describing the characteristics of VOCs in children versus adults may pave the way to enhance TB diagnosis in children.

Identifying the Interaction Between Tuberculosis and SARS-CoV-2 Infections via Bioinformatics Analysis and Machine Learning.

The number of patients with COVID-19 caused by severe acute respiratory syndrome coronavirus 2 is still increasing. In the case of COVID-19 and tuberculosis (TB), the presence of one disease affects the infectious status of the other. Meanwhile, coinfection may result in complications that make treatment more difficult. However, the molecular mechanisms underpinning the interaction between TB and COVID-19 are unclear. Accordingly, transcriptome analysis was used to detect the shared pathways and molecular biomarkers in TB and COVID-19, allowing us to determine the complex relationship between COVID-19 and TB. Two RNA-seq datasets (GSE114192 and GSE163151) from the Gene Expression Omnibus were used to find concerted differentially expressed genes (DEGs) between TB and COVID-19 to identify the common pathogenic mechanisms. A total of 124 common DEGs were detected and used to find shared pathways and drug targets. Several enterprising bioinformatics tools were applied to perform pathway analysis, enrichment analysis and networks analysis. Protein-protein interaction analysis and machine learning was used to identify hub genes (GAS6, OAS3 and PDCD1LG2) and datasets GSE171110, GSE54992 and GSE79362 were used for verification. The mechanism of protein-drug interactions may have reference value in the treatment of coinfection of COVID-19 and TB.

Bacteriomes in lesions of pulmonary tuberculosis and its association with status of Mycobacterium tuberculosis excretion.

BACKGROUND: Bacteria in lung play an important role in sustaining lung health. Understanding the characteristics of bacteriomes in lesions of pulmonary tuberculosis (TB) patients, who excrete Mycobacterium tuberculosis (MTB), is important for TB prevention and effective treatment.  METHODS: In this study, bacteriomes in lesions from TB patients excreting bacteria (TB-E) and those from TB patients not excreting bacteria (TB-NE) with matched normal lung tissues (NT) were compared by 16S rRNA sequencing. Bacterial MetaCyc functions in TB lesions were also predicted by PICRUSt2 tool. RESULTS: Alpha diversity of bacteria, including Chao 1 and Shannon indexes, for TB-E was significantly higher than those in TB-NE and NT; while for TB-NE group, Chao 1 index was higher than that in NT group. Predominant phyla in TB lesions and NT were Proteobacteria, Actinobacteria, Firmicutes, and Bacteroidetes, but analysis of similarity (ANOSIM, p < 0.001) revealed significantly different bacterial compositions among TB-E, TB-NE and NT samples. As for bacteriomes in TB lesions, a strong association (ANOSIM, p < 0.001) was observed with the status of MTB excretion. Indicator genera identified in TB-E and TB-NE demonstrated distinctive micro-ecological environments of TB lesions from patients with different clinical manifestations. Co-occurrence analysis revealed a densely-linked bacterial community in TB-NE compared to that in TB-E. MetaCyc functions responsible for menaquinone synthesis and chorismate metabolism that could potentially impact the persistent-state and nutrient metabolism of MTB were enriched in TB-E samples. While in TB-NE samples, enrichment of bacterial MetaCyc function responsible for heme b synthesis might contribute to TB pathology through ferroptosis. CONCLUSION: Bacteriomes and their MetaCyc functions in TB lesions are elucidated, and they are associated with status of MTB excretion among pulmonary TB patients. These results serve as a basis for designing novel strategies for preventing and treating pulmonary TB disease.

Spatial bacterial subpopulations of a human lung lobe and their potential impact on the progression of pulmonary tuberculosis.

Better understanding the spatial variation in resident pulmonary bacteria can help to link the disease severity of pulmonary tuberculosis (TB) with lung bacteriomes. This study aimed to investigate bacterial compositions in subniches of a lung lobe from pulmonary TB patient with two separate visible lesions. There were no significant differences between the bacterial compositions in normal tissue and TB lesions, but the bacterial compositions of the two TB lesions differed significantly (P = 0.009). Interestingly, 52 OTUs (relative abundance >1%) that specifically inhabiting certain lung niches were observed and they were affiliated with five phyla. Specific OTUs affiliated with Firmicutes mainly inhabited normal tissues. The dominant phylum in the lung subniches was Proteobacteria, with a relative abundance between 67.03% and 99.99%. Ralstonia, Achromobacter, and Pseudomonas were the most abundant genera, collectively accounting for 34.02% of total bacterial species. A total of 667 of the 700 bacterial connections in a co-correlation network of 145 OTUs (Operational Taxonomic Unit) were positive, indicating a cooperative relationship between bacterial members. Using PICRUSt tool, we do predict bacterial MetaCyc functions responsible for lipid synthesis and heme biosynthesis across the lung lobe that are essential for generation of caseous necrosis and TB disease pathology. MetaCyc pathways responsible for the degradation of aromatic biogenic amines, sulfur oxidation, and denitrification were all related to M.tb growth status, and they were significantly enriched in the lesion with necrosis than that with inflammation. These results open a new insight for us to comprehend the spatial profile of bacteriomes in a pulmonary TB human lung lobe, and shed light on the design of future diagnosis and treatment for pulmonary TB disease.

Efficacy and safety of combined isoniazid-rifampicin-pyrazinamide-levofloxacin dry powder inhaler in treatment of pulmonary tuberculosis: A randomized controlled trial.

OBJECTIVE: To determine the efficacy and safety of add-on dry powder for inhalation (DPI) of combined anti-TB agents prepared as a particulate system (study group) compared with placebo DPI (control group) in patients diagnosed with pulmonary TB. METHODS: This study was a randomized, placebo-controlled, double-blinded parallel design. Subjects were pulmonary TB patients, new or re-treatment, aged 18 years or older. The eligible patients were randomly allocated (1:1) to either the study group or the control group using stratified blocked randomization. The add-on DPI of combined anti-TB therapy (each capsule contained isoniazid 5 mg, rifampicin 2 mg, pyrazinamide 16 mg, and levofloxacin 2 mg) was used throughout the course of the standard oral anti-TB treatment. The primary outcome was Mycobacterium tuberculosis (MTB) sputum culture conversion measured after receiving treatment for eight weeks. Secondary outcomes were clinical signs and symptoms of pulmonary TB and adverse drug reactions (ADRs) related to anti-TB agents. The percentages of patients who achieved the primary outcome were compared (95% confidence interval). All analyses were performed using the modified intention-to-treat principle. RESULTS: 91 patients were randomly allocated: 44 to the study group and 47 to the control group. Important baseline data (%peak expiratory flow rate, chest X-ray findings, resistance to anti-TB agents, renal and liver function tests) were similar between the two groups. Although the percentages of patients who achieved the primary outcome were similar in both groups (34/44 [77.3%] in the study group and (34/47 [72.3%] in the control group; relative risk [RR] 1.07, 95% CI 0.84-1.36; p = 0.589), the study group patients seemed to achieve the primary outcome earlier than the control group (22/44 [50.0%] vs 15/47 [31.9%]; RR 1.57, 95% CI 0.94-2.61; p = 0.079) at the end of week 4. Cough was significantly lower in the study group than in the control group (23/44 [52.3%] vs 43/47 [91.5%]; RR 0.57, 95% CI 0.43-0.77; p < 0.001) at week 4 of treatment. Hemoptysis was found in approximately half of each group at baseline. The percentage of patients having hemoptysis was substantially reduced at week 2 of treatment (5 [11.4%] in the study group and 11 [23.0%] in the control group, p = 0.132). Regarding safety outcomes, no dyspnea or severe ADRs were reported. Adverse events (AEs) related to oral anti-TB agents, (e.g. liver function tests) were in normal ranges in most patients in both groups during the treatment. The incidences of common AEs reported (e.g. anorexia, dizziness, numbness, arthralgia, rash, and itching) were similar between the two groups, while the incidences of nausea and vomiting were significantly lower in the study group than the control group (38.6% vs 74.5%, p = 0.001, and 43.2% vs 66.0%, p = 0.029, respectively). CONCLUSIONS: Add-on combined anti-TB DPI therapy to the standard oral anti-TB treatment did not increase MTB sputum culture conversion at two months of treatment. However, the percentage of patients having cough in the study group was significantly lower than in the control group at two months after treatment. A reduction in cough might represent adequate response to treatment, and result in a decreased risk of spread of infection. Combined anti-TB DPI therapy was safe. Further study investigated in a larger sample using higher strengths of DPI therapy is required.

Clinical characteristics and outcome of genitourinary tuberculosis in Sri Lanka: an observational study.

BACKGROUND: Although genitourinary Tuberculosis (GUTB) is the second commonest source of extrapulmonary TB in most countries, the reported rate of GUTB in Sri Lanka remains low. The characteristics of GUTB in Sri Lanka have not been studied and documented so far. We aimed to study the clinical and imaging characteristics, treatment modalities and outcome of GUTB in Sri Lanka. METHODS: Data collected from patients treated by a single urological surgeon in two institutes consecutively over a period of 21 years were analysed. All patients with a microbiological and/or histopathological diagnosis of GUTB were included. Median duration of follow-up was 24 months (range: 6-96). RESULTS: There were 82 patients and 45 (54.9%) were men. The median age was 51 (range: 26-75) years. Most patients (39%, n = 32) had vague non-specific symptoms at presentation. Common specific symptoms at presentation were haematuria (15.8%, n = 13) and scrotal manifestations (15.8%, n = 13). Mantoux test was done in 70 patients and was > 10 mm in 62 (88.5%). Erythrocyte sedimentation rate was available in 69 patients and was > 30 mm in 54 (78.3%) patients. Chest x-ray and x-ray kidney-ureter-bladder (KUB) abnormalities were detected in 9 (11%) and 6 (7.3%) respectively. CT-urography was performed in 72 patients and abnormalities were detected in 57 (79%) patients. Forty-two patients underwent cystoscopy and 73.8% (n = 31) had abnormal findings. Microbiological diagnosis was feasible in 43 (52.4%) and rest were diagnosed histopathologically. Commonest organs involved were kidney (64.6%, n = 53), ureter (51.2%, n = 42), bladder (43.9%, n = 36) and testis/epididymis (15.8%, n = 13). One patient had TB of the prostate. All were treated primarily with anti-TB drugs however, 50 (61%) required ancillary therapeutic interventions. The majority of interventions were reconstructive surgeries (n = 20, 24.4%) followed by excisional surgeries (n = 19, 23.2%) and drainage procedures (n = 11, 13.4%). Seven patients developed serious adverse reactions to anti-TB drugs. Five patients developed a thimble bladder with disabling storage symptoms. Eight patients had deranged renal functions at diagnosis and three patients developed progressive deterioration of renal function and two patients died of end stage renal disease. CONCLUSIONS: The combination of urine for acid-fast bacilli, Mantoux test, CT-Urography, cystoscopy and histopathology is necessary to diagnose GUTB in resource-poor settings. Most ureteric strictures, non-functioning kidneys and epididymal masses need surgical treatment. Long-term follow up is essential to detect progressive deterioration of renal function.

Sputum smear conversion and associated factors among smear-positive pulmonary tuberculosis patients in East Gojjam Zone, Northwest Ethiopia: a longitudinal study.

BACKGROUND: Sputum smear conversion is a key indicator of treatment response and reduced infectivity among bacteriologically confirmed pulmonary tuberculosis (PTB) patients. This study aimed at estimating sputum smear conversion and identifying factors hindering sputum smear conversion among bacteriologically confirmed PTB cases in East Gojjam Zone, Northwest Ethiopia. METHODS: A total of 282 bacteriologically confirmed PTB patients were followed for 22 weeks through weekly sputum smear examination. Due to the absence of sputum culture and rapid diagnostic services, sputum smear conversion evaluation was conducted microscopically using acid-fast-bacilli staining technique of sediments from a 5% sodium hypochlorite concentration technique. Data on socio-demographic, clinical profile and personal behavior variables were collected using a pretested interviewer-administered questionnaire. Various descriptive statistics including mean, median with interquartile range (IQR), and proportions were computed to describe study objectives. Factors of sputum smear conversion were identified by multivariable logistic regression analysis and statistical significance was determined at a p value < 0.05. RESULTS: Over half, 166 (59%) of bacteriologically confirmed PTB patients were males and 147 (52%) were rural dwellers. The mean age of respondents was 35 ± 5 SD years. About 88 (31.2%) of bacteriologically confirmed PTB patients had comorbidities, 102 (36.2%) faced stigma, and 54 (19%) history of cigarette smoking. The median sputum smear conversions during the intensive phase and 5th  months of treatment follow up were 35 dyas (IQR: 21-56 days) and 53 days (IQR: 28-82 days), respectuvely. The majority, 85% (95% CI 76-93%) and 95% (95% CI 85-99%) of bacteriologically confirmed PTB patients underwent sputum smear conversion at the end of 2nd and 5th months of treatment, respectively. Poor knowledge on TB, being HIV positive, higher smear grading, having diabetes mellitus, undernutrition, cigarette smoking, facing societal stigma, and TB service delays were positively associated with the length of sputum smear conversion (p value < 0.05). CONCLUSION: Based on this study, the median sputum smear conversion time was higher compared to TB program expectations and findings from former studies. The study also identified important factors associated with sputum smear conversion time. Improving health literacy of the community by revising the existing community awareness strategies is essential to enhance treatment adherence and lower infectiousness after treatment initiation.

MicroRNA-23a-3p Down-Regulation in Active Pulmonary Tuberculosis Patients with High Bacterial Burden Inhibits Mononuclear Cell Function and Phagocytosis through TLR4/TNF-α/TGF-ß1/IL-10 Signaling via Targeting IRF1/SP1.

The aim of this study is to explore the role of microRNAs (miR)-21/23a/146a/150/155 targeting the toll-like receptor pathway in active tuberculosis (TB) disease and latent TB infection (LTBI). Gene expression levels of the five miRs and predicted target genes were assessed in peripheral blood mononuclear cells from 46 patients with active pulmonary TB, 15 subjects with LTBI, and 17 non-infected healthy subjects (NIHS). THP-1 cell lines were transfected with miR-23a-3p mimics under stimuli with Mycobacterium TB-specific antigens. Both miR-155-5p and miR-150-5p gene expressions were decreased in the active TB group versus the NIHS group. Both miR-23a-3p and miR-146a-5p gene expressions were decreased in active TB patients with high bacterial burden versus those with low bacterial burden or control group (LTBI + NIHS). TLR2, TLR4, and interleukin (IL)10 gene expressions were all increased in active TB versus NIHS group. MiR-23a-3p mimic transfection reversed ESAT6-induced reduction of reactive oxygen species generation, and augmented ESAT6-induced late apoptosis and phagocytosis, in association with down-regulations of the predicted target genes, including tumor necrosis factor (TNF)-α, TLR4, TLR2, IL6, IL10, Notch1, IL6R, BCL2, TGF-ß1, SP1, and IRF1. In conclusion, the down-regulation of miR-23a-3p in active TB patients with high bacterial burden inhibited mononuclear cell function and phagocytosis through TLR4/TNF-α/TGF-ß1/IL-10 signaling via targeting IRF1/SP1.

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.

Tuberculosis in Poland in 2018.

AIM OF THE STUDY: To evaluate the main features of tuberculosis (TB) epidemiology in 2018 in Poland and to compare with the situation in the EU/EEA countries. METHODS: Analysis of case- based data on TB patients from National TB Register, data on anti-TB drug susceptibility testing results in cases notified in 2018, data from National Institute of Public Health- National Institute of Hygiene on HIV-positive subjects for whom TB was an AIDS-defining disease, data from Central Statistical Office on deaths from tuberculosis based on death certificates, data from the report " European Centre for Disease Prevention and Control/WHO Regional Office for Europe. Tuberculosis surveillance and monitoring in Europe 2020- 2018 data. Stockholm: European Centre for Disease Prevention and Control, 2020". RESULTS: In 2018, 5487 TB cases were reported in Poland. The incidence rate was 14.3 cases per 100000, with large variability between voivodeships from 7.3 to 23.4 per 100 000. The mean annual decrease of TB incidence in 2014- 2018 was 3.8%. In 2018, 4852 cases were newly diagnosed with no history of previous treatment i.e. 12.6 per 100 000. 635 cases i.e. 1.7 per 100 000 - 11.6% of all registered subjects were previously treated for tuberculosis. In 2018, the number of all pulmonary tuberculosis cases was 5224 i.e. 13.7 per 100000. Pulmonary cases represented 95.2% of all TB cases. In 2018, 243 extrapulmonary TB cases were found i.e. 0.6 per 100 000. In the whole country there were 52 pediatric cases of tuberculosis. TB in children represented 0.9% of all cases notified in Poland in 2018. The incidence rates of tuberculosis were growing along with the age group from 0.9 per 100 000 among children to 24.7 per 100 000 among subjects in the age group 45-64 years (the highest incidence rate). In 2018, the incidence rate in the age group ≥65 years was 21.3 per 100 000. The TB incidence among men i.e. 21.0 per 100 000 was 2.6 times higher than among women i.e. 8.0 per 100 000. The biggest difference in the TB incidence between the two sex groups occurred in persons aged 55 to 59 years - 44.9 vs. 9.8 and in age group 60- 64 years - 43.7 vs. 10.2. The TB incidence in rural population was lower than in urban, respectively 13.4 per 100 000 and 14.9 per 100 000. The number of all registered culture positive TB cases was 4075. Pulmonary tuberculosis was bacteriologically confirmed in 3935 subjects. Cases confirmed by culture represented 74.3% of all TB cases and 75.3% of all pulmonary TB cases. The number of smear-positive pulmonary TB cases reported in 2018 was 2324 i.e. 6.1 per 100 000 accounting for 44.3% of all pulmonary TB cases and 59.1% of pulmonary TB cases confirmed by culture. In all patients with tuberculosis in Poland in 2018 there were 48 cases with MDR-TB (among them 14 foreigners) and 83 patients with resistance to isoniazid only, representing respectively 1.3% and 2.2% of cases with known DST results (DSTs were available in 90.7% of all culture-confirmed TB cases). In 2018, there were 97 patients of foreign origin among all cases of tuberculosis in Poland. TB was AIDS-indicative disease in 14 subjects with HIV co-infection. There were 490 deaths due to tuberculosis reported in 2017 - 1.3 per 100 000; 468 people died from pulmonary and 22 from extrapulmonary tuberculosis. Mortality among males - 2.1 per 100 000 - was 3.6 X higher than among females - 0.5. 40.2% of all TB deaths were cases 65 years old and older - 3.1 per 100 000. In 2017, there was no death from tuberculosis in children and no deaths in adolescents. In 2017, tuberculosis represented 0.1% of total mortality in Poland and 25.4% of mortality from infectious and parasitic diseases. CONCLUSIONS: In 2018, the incidence of tuberculosis in Poland was lower than in 2017. Despite a continuous decline it is still higher than the average in the EU/EEA countries. The highest incidence rates were observed in older age groups. The participation of pediatric cases is smaller than average in the EU/EEA countries. The incidence in males was more than 2 times higher than in females. The impact of migration on the characteristics of tuberculosis in Poland is not substantial. In Poland, MDR-TB is less common than the average in the EU/EEA countries.

Added Value of Comprehensive Program to Provide Universal Access to Care for Sputum Smear-Negative Drug-Resistant Tuberculosis, China.

The increase in drug-resistant tuberculosis in China calls for scaling up rapid diagnosis. We evaluated introduction of rapid resistance testing by line-probe assay for all patients with a diagnosis of pulmonary tuberculosis in 2 prefectures in middle and eastern China. We analyzed sputum samples for smear-positive patients and cultures for smear-negative patients. We used a before-after comparison of baseline and intervention periods (12 months each) and analyzed data for 5,222 baseline period patients and 4,364 intervention period patients. The number of patients with rifampin resistance increased from 30 in the baseline period to 97 in the intervention period for smear-positive patients and from 0 to 13 for smear-negative patients, reflecting a low proportion of positive cultures (410/2,844, 14.4%). Expanding rapid testing for drug resistance for smear-positive patients resulted in a 3-fold increase in patients with diagnoses of rifampin-resistant tuberculosis. However, testing smear-negative patients had limited added value because of a low culture-positive rate.

Treatment outcomes and risk factors of extra-pulmonary tuberculosis in patients with co-morbidities.

BACKGROUND: Extra-pulmonary tuberculosis (EPTB) represents about 14% of all cases of tuberculosis (TB) in Malaysia. The aims of the study include evaluation of socio-demographic factors, clinical manifestations, co-morbidities among patients with EPTB and their treatment outcomes. METHODS: A retrospective study was conducted to recognize the epidemiology facts of EPTB. Individual data for EPTB patients were collected from TB registers, laboratory TB registers, treatment cards and TB medical personal files into a standardized study questionnaire. Crude (COR) and adjusted odds ratios (AOR) and 95% confidence intervals (CI) were determined to assess the risk factors for EPTB and unsuccessful treatment outcomes. RESULTS: There were 1222 EPTB patients presenting 13.1% of all TB cases during 2006-2008. Pleural effusion and lymph node TB were the most frequent types and accounted for 45.1% of all EPTB cases among study participants. Treatment success rate was 67.6%. The best treatment completion rates were found in children ≤15 years (0.478 [0.231-1.028]; p = 0.05). On multivariate analysis, age group 56-65 years (1.658 [1.157-2.376]; p = 0.006), relapse cases (7.078 [1.585-31.613]; p = 0.010), EPTB-DM (1.773 [1.165-2.698]; p = 0.008), patients with no formal (2.266 [1.254-4.095]; p = 0.001) and secondary level of education (1.889 [1.085-3.288]; p = 0.025) were recorded as statistically positive significant risk factors for unsuccessful treatment outcomes. Patients at the risk of EPTB were more likely to be females (1.524 [1.311-1.746]; p <  0.001), Malays (1.251 [1.056-1.482]; p = 0.010) and Indians (1.450 [1.142-1.842]; p = 0.002), TB-HIV (3.215 [2.347-4.405]; p <  0.001), EPDM-HIV (4.361 [1.657-11.474]; p = 0.003), EPTB-HIV-HEP (4.083 [2.785-5.987]; p <  0.001), those living in urban areas (1.272 [1.109-1.459]; p = 0.001) and no formal education (1.361 [1.018-1.820]; p = 0.037). CONCLUSION: The findings of this study extend the knowledge of EPTB epidemiology and highlight the need for improved EPTB detection in Malaysia, especially in subpopulations with high risk for EPTB and unsuccessful treatment outcomes.

A prospective study of socio-demographic, clinical characteristics and treatment outcomes of children with tuberculosis in Sindh, Pakistan.

BACKGROUND: Understanding the explanations behind unsuccessful treatment outcomes in tuberculosis (TB) patients is important to improve treatment success. Treatment completion for TB is the mainstay of TB prevention and control. The study was aimed to assess the treatment outcomes and predictors for unsuccessful outcomes among children with TB. METHODS: This was a prospective multicenter study conducted in Sindh. Children aged ≤14 years enrolled from June to November 2016 were included. A structured data collection tool was used to gather information with respect to patients' socio-demographic, clinical and microbiological data. Additionally, to collect the information related to socio-economic and education level of caregivers, validated questionnaire was administered to the caregivers. Treatment outcomes were assessed according to the World Health Organization (WHO) guidelines. The relationship of unsuccessful treatment outcome with socio-demographic and clinical attributes of TB patients was analyzed using logistic regression model. RESULTS: Childhood TB represented 19.3% (508/2634) of all TB cases in selected hospitals. Of these, 268/508 (52.8%) were females and one third of the children were aged ≤2 years (34.3%). In multivariate analysis, pulmonary smear positive TB (PTB+) (AOR = 5.910, 95%CI = 1.64-21.29), those with adverse drug reactions (AOR = 11.601, 95%CI = 4.06-33.12) and those who had known TB contacts (AOR = 3.128, 95%CI = 1.21-8.06) showed statistically significant association with unsuccessful treatment outcomes. CONCLUSIONS: The high proportion of childhood TB cases (19.3%) demonstrates the continuation of TB transmission in the study setting. Furthermore, an increased focus on PTB+ patients, those with adverse drug reactions and household contact with TB is warranted.

Sub-national prevalence survey of tuberculosis in rural communities of Ethiopia.

BACKGROUND: Tuberculosis is a major public health problem with varying prevalence in different settings. National prevalence surveys provide evidence for planning and decision making. However, they lack the capacity to estimate subnational magnitude that affected the capacity to make selected intervention based on the prevalence. Ethiopia is among high TB burden countries with estimated prevalence of 108 per 100,000 population varying by regions. We aimed to study sub national prevalence of smear-positive TB in rural communities of southern Ethiopia. METHODS: This cross-sectional study, enrolled community members aged over 14 years who had cough of at least two weeks duration. Two sputum samples were collected and examined by using smear microscopy. RESULTS: 38,304 eligible people were enumerated (10,779 from Hadiya, 10,059 from Gurage and 17,466 from Sidama) and indentified 960 presumptive cases. 16, 14 and 14 smear-positive pulmonary TB cases were identified respectively. The point prevalence of smear-positive TB were 148 per 100,000 population (95% CI: 91-241) in Hadiya, 139 per 100,000 population (95% CI: 83-234) in Gurage and 80/100,000 population (95%CI: 48-135) in Sidama zone. Gurage zone had the highest prevalent to notified cases of seven to one. CONCLUSIONS: The prevalence of smear positive TB varies by districts and is high in rural southern Ethiopia compared to the estimated national prevalence. More TB patients remain missed and unreached, impacting negatively on health outcomes. TB case finding approaches should be revisited and innovative approaches and tools to identify missing people with TB should be scaled up.

Bacteriologically confirmed extra pulmonary tuberculosis and treatment outcome of patients consulted and treated under program conditions in the littoral region of Cameroon.

BACKGROUND: Extra-pulmonary tuberculosis (EPTB) is defined as any bacteriologically confirmed or clinically diagnosed case of TB involving organs other than the lungs. It is frequently a diagnostic and therapeutic challenge with paucity of data available. The aim of this study was to assess the prevalence of bacteriologically confirmed EPTB; to determine the most affected organs and to evaluate the therapeutic outcome of EPTB patients treated under program conditions in the littoral region of Cameroon. METHODS: A descriptive cross-sectional laboratory-based epidemiological survey was conducted from January 2016 to December 2017 and 109 specimens from 15 of the 39 diagnosis and treatment centers in the littoral region were obtained. Two diagnostic methods (Gene Xpert MTB and culture (LJ and MGIT) were used for EPTB diagnosis. Determine HIV1/2 and SD Biolinewere used for HIV diagnosis. Confirmed EPTB cases were treated following the national tuberculosis guide. RESULTS: The prevalence of bacteriologically confirmed EPTB was 41.3% (45). All 45 cases were sensitive to rifampicin. Males were predominately more infected [26 (57.8%)] likewise the age group 31-45 years with 15 (33.3%) cases. The overall prevalence for HIV was 33.6% (36). HIV infection was present in 28.9% (13) of patients with EPTB. The most affected sites with EPTB were: Lymph nodes (66.5%), pleural cavity (15.6%), abdominal organs (11.1%), neuromeningeal (2.2%), joints (2.2%) and heart (2.2%). Overall, 84.4% of the study participants had a therapeutic success with males responding better 57.9% (p = 0.442). Therapeutic success was better (71.7%) in HIV negative EPTB patients (p = 0.787). CONCLUSION: The prevalence of bacteriologically confirmed EPTB patients treated under program conditions in the littoral region of Cameroon is high with a therapeutic success of 84.4% and the lymph nodes is the most affected site.

Renal Tuberculosis: The Masquerader.

Tuberculosis (TB) remains a worldwide scourge and the most common cause of mortality from infectious disease. Around 95% of cases occur in developing country. Renal TB is a rare cases that complicates 3-4% of pulmonary TB patients and commonly overlooked in clinical practice due to its symptoms may mimic other diseases.A-39-year-old man was admitted to our institution due to flank pain. He had history of low grade fever and oligouria since 5 months prior. He had no complaint of cough, dyspnea, or night sweat. He was a non smoker and had no past medical history of tuberculosis. Previous 4 months abdominal ultrasound showed left pelvocaliectasis and ureteral dilatation with suspicion of left ureteral stenosis. Ureterolithiasis could not be excluded. No prostate enlargement or vesicolithiasis was seen. Intravenous pyelography (IVP) examination demonstrated similar finding. Initial laboratory blood examination showed anemia (10.7 g/dl), leukocytosis (14,080/ul), increased in serum creatinin (4.2 mg/dl), ureum (227 mg/dl), and calcium (6.78 mg/dl). Serology examinations were negative for HIV, HBsAg, anti HCV and blood culture had no growth. Urinary examination revealed severe leucocyturia, hematuria, and negative for bacteria, nitrite and cast. Urine culture was positive for Candida glabrata. Pulmonary X-ray suggested right pleural fibrotic. He was initially diagnosed as multiple myeloma with fungal infection. Nevertheless, additional peripheral blood smear showed neither rouleaux formation nor blast. He underwent percutaneous nephrostomy and got micafungin intravenously. Instead of improving, the patient deteriorated and transferred to intensive room. We then explored the possibility of TB infection. Further examination revealed positive for Mycobacterium tuberculosis in urinary polymerase chain reaction (PCR) test. Tracheal sputum examination was positive for acid fast bacilli staining. There was low level of serum vitamin D2 (5.8 ng/ml). He got TB treatment with rifampicin, isoniazid, pyrazinamide, and ethambutol. Unfortunately, the patient eventually succumbed.

Phenotypic and functional heterogeneity of peripheral γδ T cells in pulmonary TB and HIV patients in Addis Ababa, Ethiopia.

BACKGROUND: Previous studies reported HIV infection alters the distribution and function of γδ T cells and their subsets. γδ T phenotypes in healthy and diseased individuals has received little attention in Ethiopia. We conducted this study to analyze the distribution of γδ T cells, the subsets and levels of expression of activation (CD38), exhaustion or anergy (CD95, PD1), adhesion (N-CAM/CD56 and CD103), among HIV and TB infected patients. METHOD: The distributions of total γδ T cells, Vδ1 and Vδ2 T cells subsets were analyzed in clinical samples collected from asymptomatic HIV, pulmonary TB patients and apparently healthy controls. Multicolor flow cytometry and IFN-γ ELISA were used to assess surface markers and functional responses of Vδ2 T cells to isopentenyl pyrophosphate stimulation, respectively. RESULT: A total of 52 study participants were enrolled in this study, 22 HIV + TB-, 10 HIV-TB+ and 20 healthy controls. No significant differences were observed in the distribution of total γδ T cells and in the proportion of Vδ1 subsets in all study groups, though slightly higher proportions were observed in HIV + TB- patients for the latter, of borderline statistical significance (p = 0.07). However, the proportion of Vδ2 T cells, as well as the IFN-γ response to IPP stimulation, was significantly reduced in HIV + TB- patients compared to healthy controls (p < 0.002). Expression of the activation marker CD38 (p < 0.001) and adhesion marker CD103 (αEß7) were significantly higher in the Vδ1 T cell subset among both HIV + TB- (p = 0.013) and HIV-TB+ (p = 0.006) patients compared to healthy controls. Similarly, exhaustion markers, CD95 and PD1, were significantly higher in these two T cell subsets among both HIV + TB- and HIV-TB+ patients (p < 0.01). Interestingly, we also observed an increased proportion of effector memory (CD45RA-CD27-) and effector cytotoxic (CD45RA + CD27-) Vδ2 T cell subsets in HIV negative pulmonary TB patients. CONCLUSION: In sum, HIV infection was associated with an increase in Vδ1 and a decrease in the function and frequencies of Vδ2 T cells. Moreover, increased effector Vδ2 T cells were observed among HIV negative pulmonary TB patients suggesting a potential role of these T cells in the host response to TB.

A case study of a patient with multidrug-resistant tuberculosis.

In this case study, a nurse presents her reflections on the challenges of supporting a patient through his treatment journey for multidrug-resistant tuberculosis. The patient has significant comorbidities and social issues, such as diabetes and homelessness. There was also a language barrier. All these aspects made the management of his treatment challenging. The medication side effects and his lifestyle were also a barrier to full engagement. The same multidisciplinary team was involved with the patient and, despite the obstacles, he seemed willing to engage with treatment and the team.