The impact of inclusion, dose and duration of pyrazinamide (PZA) on efficacy and safety outcomes in tuberculosis: systematic review and meta-analysis protocol.

BACKGROUND: Pyrazinamide (PZA) is a key component of current and future regimens for tuberculosis (TB). Inclusion of PZA at higher doses and for longer durations may improve efficacy outcomes but must be balanced against the potential for worse safety outcomes. METHODS: We will search for randomised and quasi-randomised clinical trials in adult participants with and without the inclusion of PZA in TB treatment regimens in the Cochrane infectious diseases group's trials register, Cochrane central register of controlled trials (CENTRAL), MEDLINE, EMBASE, LILACS, the metaRegister of Controlled Trials (mRCT) and the World Health Organization (WHO) international clinical trials registry platform. One author will screen abstracts and remove ineligible studies (10% of which will be double-screened by a second author). Two authors will review full texts for inclusion. Safety and efficacy data will be extracted to pre-piloted forms by one author (10% of which will be double-extracted by a second author). The Cochrane risk of bias tool will be used to assess study quality. The study has three objectives: the association of (1) inclusion, (2) dose and (3) duration of PZA with efficacy and safety outcomes. Risk ratios as relative measures of effect for direct comparisons within trials (all objectives) and proportions as absolute measures of effect for indirect comparisons across trials (for objectives 2 and 3) will be calculated. If there is insufficient data for direct comparisons within trials for objective 1, indirect comparisons between trials will be performed. Measures of effect will be pooled, with corresponding 95% confidence intervals and p values. Meta-analysis will be performed using the generalised inverse variance method for fixed effects models (FEM) or the DerSimonian-Laird method for random effects models (REM). For indirect comparisons, meta-regression for absolute measures against dose and duration data will be performed. Heterogeneity will be quantified through the I2-statistic for direct comparisons and the τ2 statistic for indirect comparisons using meta-regression. DISCUSSION: The current use of PZA for TB is based on over 60 years of clinical trial data, but this has never been synthesised to guide rationale use in future regimens and clinical trials. Systematic review registration: International Prospective Register of Systematic Reviews (PROSPERO) CRD42019138735.

Towards standardisation: comparison of five whole genome sequencing (WGS) analysis pipelines for detection of epidemiologically linked tuberculosis cases.

BackgroundWhole genome sequencing (WGS) is a reliable tool for studying tuberculosis (TB) transmission. WGS data are usually processed by custom-built analysis pipelines with little standardisation between them.AimTo compare the impact of variability of several WGS analysis pipelines used internationally to detect epidemiologically linked TB cases.MethodsFrom the Netherlands, 535 Mycobacterium tuberculosis complex (MTBC) strains from 2016 were included. Epidemiological information obtained from municipal health services was available for all mycobacterial interspersed repeat unit-variable number of tandem repeat (MIRU-VNTR) clustered cases. WGS data was analysed using five different pipelines: one core genome multilocus sequence typing (cgMLST) approach and four single nucleotide polymorphism (SNP)-based pipelines developed in Oxford, United Kingdom; Borstel, Germany; Bilthoven, the Netherlands and Copenhagen, Denmark. WGS clusters were defined using a maximum pairwise distance of 12 SNPs/alleles.ResultsThe cgMLST approach and Oxford pipeline clustered all epidemiologically linked cases, however, in the other three SNP-based pipelines one epidemiological link was missed due to insufficient coverage. In general, the genetic distances varied between pipelines, reflecting different clustering rates: the cgMLST approach clustered 92 cases, followed by 84, 83, 83 and 82 cases in the SNP-based pipelines from Copenhagen, Oxford, Borstel and Bilthoven respectively.ConclusionConcordance in ruling out epidemiological links was high between pipelines, which is an important step in the international validation of WGS data analysis. To increase accuracy in identifying TB transmission clusters, standardisation of crucial WGS criteria and creation of a reference database of representative MTBC sequences would be advisable.

Mycobacterium tuberculosis Drives Expansion of Low-Density Neutrophils Equipped With Regulatory Activities.

In human tuberculosis (TB) neutrophils represent the most commonly infected phagocyte but their role in protection and pathology is highly contradictory. Moreover, a subset of low-density neutrophils (LDNs) has been identified in TB, but their functions remain unclear. Here, we have analyzed total neutrophils and their low-density and normal-density (NDNs) subsets in patients with active TB disease, in terms of frequency, phenotype, functional features, and gene expression signature. Full-blood counts from Healthy Donors (H.D.), Latent TB infected, active TB, and cured TB patients were performed. Frequency, phenotype, burst activity, and suppressor T cell activity of the two different subsets were assessed by flow cytometry while NETosis and phagocytosis were evaluated by confocal microscopy. Expression analysis was performed by using the semi-quantitative RT-PCR array technology. Elevated numbers of total neutrophils and a high neutrophil/lymphocyte ratio distinguished patients with active TB from all the other groups. PBMCs of patients with active TB disease contained elevated percentages of LDNs compared with those of H.D., with an increased expression of CD66b, CD33, CD15, and CD16 compared to NDNs. Transcriptomic analysis of LDNs and NDNs purified from the peripheral blood of TB patients identified 12 genes differentially expressed: CCL5, CCR5, CD4, IL10, LYZ, and STAT4 were upregulated, while CXCL8, IFNAR1, NFKB1A, STAT1, TICAM1, and TNF were downregulated in LDNs, as compared to NDNs. Differently than NDNs, LDNs failed to phagocyte live Mycobacterium tuberculosis (M. tuberculosis) bacilli, to make oxidative burst and NETosis, but caused significant suppression of antigen-specific and polyclonal T cell proliferation which was partially mediated by IL-10. These insights add a little dowel of knowledge in understanding the pathogenesis of human TB.

CD4+ T Responses Other Than Th1 Type Are Preferentially Induced by Latency-Associated Antigens in the State of Latent Mycobacterium tuberculosis Infection.

Mycobacterium tuberculosis (M. tuberculosis) produces a diverse range of antigenic proteins in its dormant phase. The cytokine profiles of CD4+ T cell responses, especially subsets other than Th1 type (non-Th1 type), against these latency-associated M. tuberculosis antigens such as α-crystallin (Acr), heparin-binding hemagglutinin (HBHA), and mycobacterial DNA-binding protein 1 (MDP-1) remain elusive in relation to the clinical stage of M. tuberculosis infection. In the present study, peripheral blood mononuclear cells (PBMCs) collected from different stages of M. tuberculosis-infected cases and control PBMCs were stimulated with these antigens and ESAT-6/CFP-10. Cytokine profiles of CD4+ T cells were evaluated by intracellular cytokine staining using multicolor flow cytometry. Our results demonstrate that Th1 cytokine responses were predominant after TB onset independent of the type of antigen stimulation. On the contrary, non-Th1 cytokine responses were preferentially induced by latency-associated M. tuberculosis antigens, specifically IL-10 response against Acr in latent M. tuberculosis infection. From these results, we surmise a shift in the CD4+ T cell response from mixed non-Th1 to Th1 dominant type during TB progression.

BCG-Induced Cross-Protection and Development of Trained Immunity: Implication for Vaccine Design.

The Bacillus Calmette-Guérin (BCG) is a live attenuated tuberculosis vaccine that has the ability to induce non-specific cross-protection against pathogens that might be unrelated to the target disease. Vaccination with BCG reduces mortality in newborns and induces an improved innate immune response against microorganisms other than Mycobacterium tuberculosis, such as Candida albicans and Staphylococcus aureus. Innate immune cells, including monocytes and natural killer (NK) cells, contribute to this non-specific immune protection in a way that is independent of memory T or B cells. This phenomenon associated with a memory-like response in innate immune cells is known as "trained immunity." Epigenetic reprogramming through histone modification in the regulatory elements of particular genes has been reported as one of the mechanisms associated with the induction of trained immunity in both, humans and mice. Indeed, it has been shown that BCG vaccination induces changes in the methylation pattern of histones associated with specific genes in circulating monocytes leading to a "trained" state. Importantly, these modifications can lead to the expression and/or repression of genes that are related to increased protection against secondary infections after vaccination, with improved pathogen recognition and faster inflammatory responses. In this review, we discuss BCG-induced cross-protection and acquisition of trained immunity and potential heterologous effects of recombinant BCG vaccines.

HIV-associated morbidity and mortality in a setting of high ART coverage: prospective surveillance results from a district hospital in Botswana.

INTRODUCTION: Antiretroviral therapy (ART) has significantly improved survival in Africa in recent years. In Botswana, where adult HIV prevalence is 21.9%, AIDS-related mortality is estimated to have declined by 58% between 2005 and 2013 following the initial wide-spread introduction of ART, and ART coverage has steadily increased reaching 84% in 2016. However, there remains little data about the burden of HIV and its impact on mortality in the hospital setting where most deaths occur. We aimed to describe the burden of HIV and related morbidity and mortality among hospitalized medical patients in a district hospital in southern Botswana in the era of widespread ART coverage. METHODS: We prospectively reviewed medical admissions to Scottish Livingstone Hospital from December 2015 to November 2017 and recorded HIV status, demographics, clinical characteristics and final diagnoses at discharge, death or transfer. We ascertained outcomes and determined factors associated with mortality. Results were compared with similar surveillance data collected at the same facility in 2011 to 2012. RESULTS: A total of 2316 admissions occurred involving 1969 patients; 42.4% were of HIV-positive patients, 46.9% of HIV-negative patients and 10.7% of patients with unknown HIV status. Compared to HIV-negative patients, HIV-positive patients had younger age (mean 42 vs. 64 years, p < 0.0001) and higher mortality (22.2% vs. 18.0%, p = 0.03). Tuberculosis was the leading diagnosis among mortality cases in both groups but accounted for a higher proportion of deaths among HIV-positive admissions (44.5%) compared with HIV-negative admissions (19.4%, p < 0.0001). Compared with similar surveillance in 2011 to 2012, HIV prevalence was lower (42.4% vs. 47.6%, p < 0.01), and among HIV-positive admissions: ART coverage was higher (72.2% vs. 56.2%, p < 0.0001), viral load suppression was similar (78.6% vs. 80.3%, p = 0.77), CD4 counts were higher (55.0% vs. 44.6% with CD4 ≥200 cells/mm3 , p < 0.001), mortality was similar (22.2 vs. 22.7%, p = 0.93), tuberculosis diagnoses increased (27.5% vs. 20.1%, p < 0.01) and tuberculosis-associated mortality was higher (35.9% vs. 24.7%, p = 0.05). CONCLUSIONS: Despite high ART-coverage in Botswana, HIV-positive patients continue to be disproportionately represented among hospital admissions and deaths. Deaths from tuberculosis may be contributing to lack of reduction in inpatient mortality. Our findings suggest that control of HIV and tuberculosis remain top priorities for reducing inpatient mortality in Botswana.

Presentation of pulmonary tuberculosis and actinomyces co-infection as a lung mass: a literature review and unique case report.

Parenchymal lung infections occasionally present with clinical symptoms and radiological findings similar to lung malignancy. Pulmonary actinomycosis is a rare condition of its own right, let alone in coexistence with tuberculosis. We report a case of a man presenting with hemoptysis alongside a chest computed tomography compatible with lung cancer. The diagnosis, after removal of a large endobronchial mass with flexible bronchoscopy and cryon, was a concomitant infection with Mycobacterium tuberculosis and Actinomyces odontoliticus. In the literature, there are few reported cases with concomitant tuberculosis and actinomycosis. To our knowledge, such radical treatment without surgical intervention has not been reported in the past.

Malignant bronchial ulcer with coexistent pulmonary tuberculosis.

Ulceration in the bronchial mucosa is noted rarely in bronchoscopy. In the past, it was frequently encountered in endobronchial tuberculosis. Deep necrotic bronchial ulcers are seen very rarely in clinical practice. Here we are reporting a first-ever case report of malignant bronchial ulcer presenting as necrotic deep bronchial ulcer, in a 70-year-old male, chronic smoker, who complained of breathlessness for 3 months, cough for 3 months, loss of weight and of appetite for 1 month. Bronchoscopy showed a large necrotic ulcer with dense anthracotic pigmentation which bleeds in touch with forceps. Bronchial washings, brushings, endobronchial biopsy were taken from the ulcer which was suggestive of poorly differentiated bronchogenic carcinoma. TBNA from the mediastinal nodes showed the features of caseous necrosis with granulomatous inflammation. Consequently, with the diagnosis of poorly differentiated carcinoma with pulmonary tuberculosis and COPD, the patient was started on anti-tuberculosis drugs, inhaled bronchodilators and referred to an oncologist for chemotherapy.

Eosinophil Polymorphonuclear Leukocytes in TB: What We Know so Far.

Knowledge on the cellular immune responses to infection with Mycobacterium tuberculosis has improved drastically in recent years. Though eosinophils and hypereosinophilia are linked with the disease process of tuberculosis, there is paucity of information to prove the actual role played by these polymorphonuclear leukocytes. The aim of this review is to provide an overview of the existing literature on what is known so far about eosinophils and tuberculosis.

The relationship between HbA1c control levels and antituberculosis treatment effects: a meta-analysis.

BACKGROUND: Multiple studies of tuberculosis (TB) treatment have indicated that patients with diabetes mellitus (DM) may experience poor outcomes. We performed a meta-analysis to summarize evidence for the relationship between HbA1c control levels and anti-TB treatment effects in patients afflicted with both TB and DM. METHODS: Both English and Chinese databases were searched. Chinese databases included CNKI, WanFang, SinoMed, and VIP. PubMed, Ovid MEDLINE, Embase, Cochrane Library, and Web of Science were searched for English articles. We included studies that were restricted to the relationship between HbA1c levels and anti-TB treatment effects (sputum conversion rate [SCR] and TB focus absorption) in diabetic patients receiving treatment for TB. We used RevMan 5.3 software to analyze the data. RESULTS: We included 12 studies, of which five reported SCR at 2 months, seven reported the conversion at 3 months, and seven reported TB focus absorption. According to the five studies which reported 2 months-SCR, patients with diabetes and TB had an odds ratio (OR) of 2.14 (95% CI: 0.84-5.43) for the 2 months-SCR between controlled (HbA1c <7.0) and uncontrolled diabetes (HbA1c ≥7.0). However, additional seven studies reporting 3 months-SCR showed that controlled diabetics had higher SCR than uncontrolled (OR 3.39, 95% CI: 2.12-5.43). Moreover, seven of the 12 studies demonstrated that there were differences in TB focus absorption between controlled and uncontrolled diabetes (OR 2.69, 95% CI: 1.91-3.79). CONCLUSION: HbA1c control levels influence the SCR at 3 months and the TB focus absorption at the end of the anti-TB intensive treatment phase. This study highlights a need for increased attention to HbA1c or glucose control in patients afflicted with both TB and DM.

[Use of database linkage and scripting rules to upgrade variables in the Sinan-TB database]. / Uso de linkage entre diferentes bases de dados para qualificação de variáveis do Sinan-TB e a partir de regras de scripting.

Brazil's Information System on Diseases of Notification (Sinan) is the main tool used by tuberculosis (TB) control programs to assess control measures and TB incidence. This requires data from the system that are reliable and accurate, among other features. The study thus aimed to upgrade the entry variables, condition at closure, HIV testing, AIDS-related illness, and diabetes. Linkage was performed between the Sinan-TB database, the Mortality Information System (SIM), and the single AIDS database for the city of Rio de Janeiro, Brazil. Criteria for upgrading the variables were based on technical materials on TB and the Sinan database and were implemented in a script in Structured Query Language (SQL). There was a 115% increase in treatment dropout due to the decrease in transfers, records without closure, and patients closed due to cure in less than 150 days. There was a 2.4% increase in records with diseases associated with diabetes in the affirmative category after using data from the SIM. For the variables HIV testing and AIDS-associated illness, the increases were 5.3% and 8.7%, respectively, when the information in the AIDS database was considered. In conclusion, upgrading the Sinan-TB database through integration with other information systems improved the data's quality for decision-making on TB control.

O Sistema de Informação de Agravos de Notificação (Sinan) é a principal ferramenta utilizada pelos programas de controle da tuberculose (TB), para avaliar as ações de controle e a taxa de incidência da doença. Para tal, faz-se necessário que os dados provenientes desse sistema sejam, dentre outros, confiáveis e acurados. Dessa forma, o objetivo deste estudo foi qualificar as variáveis tipo de entrada, situação de encerramento, teste para HIV, agravo associado aids e diabetes. Foi realizado um linkage entre a base de dados do Sinan-TB, do Sistema de Informações sobre Mortalidade (SIM) e a base única da aids do Município do Rio de Janeiro, Brasil. Os critérios para qualificação das variáveis estão fundamentados em materiais técnicos sobre a TB e sobre o Sinan, e foram implementados em um script em Structured Query Language (SQL). Observou-se um aumento de 115% do abandono de tratamento decorrente da diminuição das transferências, dos registros sem encerramento e de pacientes encerrados por cura com menos de 150 dias. Houve acréscimo de 2,4% de registros com agravo associado diabetes na categoria sim, após utilizada a informação contida no SIM. Para as variáveis teste para HIV e agravo associado à aids o acréscimo foi de 5,3% e 8,7%, respectivamente, com a consideração da informação contida na base da aids. Concluiu-se que a qualificação da base de dados do Sinan-TB, valendo-se da integração com outros sistemas de informação, aprimorou a qualidade da informação para a tomada de decisão para o controle da TB.

El Sistema de Información de Enfermedades de Notificación obligatoria (Sinan) es la principal herramienta utilizada por los programas de control de la tuberculosis (TB), para evaluar las acciones de control y la tasa de incidencia de la enfermedad. Para tal fin, es necesario que los datos provenientes de este sistema sean, entre otros aspectos, fiables y precisos. De esta forma, el objetivo de este estudio fue cualificar las variables: tipo de entrada, situación de cierre, test para VIH, enfermedad asociada al SIDA y diabetes. Se realizó una vinculación entre la base de datos del Sinan-TB, del Sistema de Información sobre Mortalidad (SIM) y la base única del SIDA del municipio de Río de Janeiro, Brasil. Los criterios para la cualificación de las variables están fundamentados en materiales técnicos sobre la TB y sobre el Sinan, y fueron implementados en un script con Structured Query Language (SQL). Se observó un aumento de un 115% en el abandono del tratamiento, a consecuencia de la disminución de transferencias, de los registros sin cierre y de pacientes internados por tratamiento menos de 150 días. Hubo un incremento de un 2,4% de los registros con enfermedad asociada a la diabetes en la categoría SIM, tras utilizar la información contenida en el SIM. Para las variables test del VIH y enfermedad asociada al SIDA el incremento fue de un 5,3% y un 8,7%, respectivamente, considerando la información contenida en la base de datos del SIDA. Se concluyó que la cualificación de la base de datos del Sinan-TB, valiéndose de la integración con otros sistemas de información, perfeccionó la calidad de la información en la toma de decisiones para el control de la TB.

Ascaris lumbricoides coinfection reduces tissue damage by decreasing IL-6 levels without altering clinical evolution of pulmonary tuberculosis or Th1/Th2/Th17 cytokine profile.

INTRODUCTION: Immunological control of Mycobacterium tuberculosis infection is dependent on the cellular immune response, mediated predominantly by Th1 type CD4+ T cells. Polarization of the immune response to Th2 can inhibit the host immune protection against pathogens. Patients with tuberculosis coinfected with helminths demonstrate more severe pulmonary symptoms, a deficiency in the immune response against tuberculosis, and an impaired response to anti-tuberculosis therapy. METHODS: We evaluated the cellular immune response and the impact of the presence of Ascaris lumbricoides on the immune and clinical response in pulmonary tuberculosis patients. Ninety-one individuals were included in the study: 38 tuberculosis patients, 11 tuberculosis patients coinfected with Ascaris lumbricoides and other helminths, 10 Ascaris lumbricoides patients, and 34 non-infected control individuals. Clinical evolution of pulmonary tuberculosis was studied on 0, 30, 60, and 90 days post-diagnosis of Mycobacterium tuberculosis and Ascaris lumbricoides. Furthermore, immune cells and plasma cytokine profiles were examined in mono/coinfection by Mycobacterium tuberculosis and Ascaris lumbricoides using flow cytometry. RESULTS: There were no statistical differences in any of the evaluated parameters and the results indicated that Ascaris lumbricoides infection does not lead to significant clinical repercussions in the presentation and evolution of pulmonary tuberculosis. CONCLUSIONS: The association with Ascaris lumbricoides did not influence the Th1, Th2, and Th17 type responses, or the proportions of T lymphocyte subpopulations. However, higher serum levels of IL-6 in tuberculosis patients may explain the pulmonary parenchymal damage.

Tuberculosis treatment outcomes among people living with HIV diagnosed using Xpert MTB/RIF versus sputum-smear microscopy in Botswana: a stepped-wedge cluster randomised trial.

BACKGROUND: Xpert® MTB/RIF (Xpert) has high sensitivity for diagnosing tuberculosis (TB) compared to sputum-smear microscopy (smear) and can reduce time-to-diagnosis, time-to-treatment and potentially unfavorable patient-level treatment outcome. METHODS: People living with HIV (PLHIV) initiating antiretroviral therapy at 22 HIV clinics were enrolled and underwent systematic screening for TB (August 2012-November 2014). GeneXpert instruments were deployed following a stepped-wedge design at 13 centers from October 2012-June 2013. Treatment outcomes classified as an unfavorable outcome (died, treatment failure or loss-to-follow-up) or favorable outcome (cured and treatment completed). To determine outcome, smear was performed at month 5 or 6. Empiric treatment was defined as initiating treatment without/before receiving TB-positive results. Adjusting for intra-facility correlation, we compared patient-level treatment outcomes between patients screened using smear (smear arm)- and Xpert-based algorithms (Xpert arm). RESULTS: Among 6041 patients enrolled (smear arm, 1816; Xpert arm, 4225), 256 (199 per 2985 and 57 per 1582 person-years of follow-up in Xpert and smear arms, respectively; adjusted incidence rate ratio, 9.07; 95% confidence interval [CI]: 4.70-17.48; p < 0.001) received TB diagnosis and were treated. TB treatment outcomes were available for 203 patients (79.3%; Xpert, 157; smear, 46). Unfavorable outcomes were reported for 21.7% (10/46) in the smear and 13.4% (21/157) in Xpert arm (adjusted hazard ratio, 1.40; 95% CI: 0.75-2.26; p = 0.268). Compared to smear, in Xpert arm median days from sputum collection to TB treatment was 6 days (interquartile range [IQR] 2-17 versus 22 days [IQR] 3-51), p = 0.005; patients with available sputum test result had microbiologically confirmed TB in 59.0% (102/173) versus 41.9% (18/43), adjusted Odds Ratio [aOR], 2.00, 95% CI: 1.01-3.96, p = 0.048). In smear arm empiric treatment was 68.4% (39/57) versus 48.7% (97/199), aOR, 2.28, 95% CI: 1.24-4.20, p = 0.011), compared to Xpert arm. CONCLUSIONS: TB treatment outcomes were similar between the smear and Xpert arms. However, compared to the smear arm, more patients in the Xpert arm received a TB diagnosis, had a microbiologically confirmed TB, and had a shorter time-to-treatment, and had a lower empiric treatment. Further research is recommended to identify potential gaps in the Botswana health system and similar settings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02538952. Retrospectively registered on 2 September 2015.

The clinical impact of drug-induced hepatotoxicity on anti-tuberculosis therapy: a case control study.

BACKGROUND: There are limited data available on whether drug-induced hepatotoxicity (DIH) affects the clinical outcomes of tuberculosis (TB) treatment. We explored the effects of DIH on the clinical course and outcomes of pulmonary TB. METHODS: In this retrospective cohort study, we included patients with culture-proven pulmonary TB treated in a tertiary hospital from 2013 to 2016. DIH was defined as proposed by the official American Thoracic Society statement. We compared the clinical outcomes of DIH and non-DIH patients. RESULTS: Between January 1, 2013 and December 31, 2016, a total of 168 TB patients were included, and 20 (11.9%) were diagnosed with DIH. These patients were significantly older, had a higher Charlson Comorbidity Index score, exhibited more chronic liver disease, included more chronic alcoholics, and had a lower body mass index than non-DIH patients. We found no significant differences between DIH and non-DIH patients in the 2-month sputum culture conversion rate, the time to sputum culture conversion, treatment outcomes, or total treatment duration. However, the ratio of treatment interruption time to total treatment duration and the proportion of hepatotonic users were significantly higher among DIH patients. CONCLUSION: DIH development during TB treatment does not significantly affect the clinical outcomes of pulmonary TB. However, treatment interruption caused by DIH may increase the risks of future relapse and acquired resistance. Further study is needed.

Rare case of a proximal descending thoracic aorta mycotic aneurysm following intravesical BCG injections for the treatment of bladder cancer.

A 79-year-old man presented with an enlarging thoracic aneurysm on the background of superficial bladder cancer treated with intravesical bacillus Calmette-Guérin (BCG) injections. Following the injections, he developed deranged liver function tests and hepatomegaly. Liver biopsy revealed granulomatous hepatitis compatible with disseminated mycobacterial infection (BCG-osis) and was treated with anti-tuberculosis agents for 12 months. A surveillance CT scan performed as a follow-up for his bladder cancer in 2018 revealed a saccular thoracic aneurysm at the ligamentum arteriosum, which was metabolically active on positron emission tomography (PET) scan. Given the timeframe from intravesical instillation of BCG and the metabolic activity on PET scan, the lesion was consistent with a mycotic aneurysm secondary to disseminated mycobacterial infection. Following multidisciplinary team discussion, a thoracic endovascular aneurysm repair was performed. The stent grafts were placed distal to the left subclavian artery with good angiographic results and no immediate postoperative complications. He was initiated on long-term antibiotics to cover potential bacterial pathogens including mycobacterium.

Impact of multidrug-resistant tuberculosis and its medications on adverse maternal and perinatal outcomes: protocol for a systematic review and meta-analysis.

INTRODUCTION: Multidrug-resistant tuberculosis (MDR-TB) is a common public health problem affecting pregnant women. However, the impact of MDR-TB and its medication on pregnancy and perinatal outcomes has been poorly understood and inconsistently reported. Therefore, using the available literature, we aim to determine whether MDR-TB and its medications during pregnancy impact maternal and perinatal outcomes. METHODS AND ANALYSIS: This systematic review and meta-analysis will adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Systematic searches will be conducted in PubMed, Scopus and Web of Science on 10 February 2020 for studies that reported adverse maternal and perinatal outcomes due to MDR-TB and/or its medication. The search will be performed without language and time restrictions. Adverse birth outcomes include miscarriage or abortion, stillbirth, preterm birth, low birth weight, small and large for gestational age, and neonatal death. Two independent reviewers will screen search records, extract data and assess the quality of the studies. The Newcastle-Ottawa Quality Assessment Scale will be used to assess the methodological quality of the included studies. In addition to a narrative synthesis, a random-effects meta-analysis will be conducted when sufficient data are available. I2 statistics will be used to assess the heterogeneity between studies. ETHICS AND DISSEMINATION: As it will be a systematic review and meta-analysis based on previously published evidence, there will be no requirement for ethical approval. Findings will be published in a peer-reviewed journal and will be presented at various conferences.

The risk of active tuberculosis among individuals living in tuberculosis-affected households in the Republic of Korea, 2015.

BACKGROUND: In the Republic of Korea (ROK), compared to other high-income countries, tuberculosis (TB) prevalence is relatively high. Active TB and latent TB infection (LTBI) surveillance of individuals living in TB-affected households has been conducted for several years. Although active case finding is an important strategy in low-prevalence, high-income countries, its effectiveness in a high prevalence setting is unclear. This study evaluated the risk of TB in household contact by calculating the incidence of TB among household contacts and comparing it with the general population of the ROK. METHODS: A retrospective cohort study, including 36,133 household-contacts of 17,958 TB patients reported in 2015, was conducted. The data was extracted from the Korean National TB Surveillance System (web-based TB cases notification system, KNTSS). The Cox proportional hazard regression model was used to evaluate risk factors for incidence of TB. A P-value < .05 was considered statistically significant. RESULTS: In this study, 319 (0.9%) of 36,133 household-contacts were reported as having TB within 1 year, which is a higher rate than the rate for the general population in the ROK. The rate of TB reported for contacts that had completed LTBI treatment (0.6%) was lower than for the LTBI group without treatment (4.6%). In multivariate analysis, age older than 65 (p < .001), being a spouse of a TB patient (p = .007), and LTBI without treatment (p = .013) were each a risk factor for TB incidence among contacts. Younger age (p < .001), presence of a cough (p < .001), testing positive for acid-fast bacilli (AFB; p < .001), and cavity on radiograph (p < .001) of the index patient were also statistically significant risk factors. CONCLUSIONS: Individuals living in TB-affected households are at high risk of developing TB in the ROK and active case finding among them is a strategy effective in the early detection and prevention of TB.

Effectiveness of vitamin D supplementation on the outcome of pulmonary tuberculosis treatment in adults: a meta-analysis of randomized controlled trials.

BACKGROUND: Tuberculosis (TB) is one of the most debilitating diseases worldwide. Current studies have shown that vitamin D plays a significant role in host immune defense against Mycobacterium tuberculosis, but clinical trials reported inconsistent results. Therefore, we systematically reviewed the literature to investigate whether vitamin D supplementation could improve the effect of anti-TB therapy. METHODS: We systematically searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials from their inception to February 8th, 2019 for randomized controlled trials on vitamin D supplementation in patients with pulmonary TB receiving anti-TB therapy. The primary outcomes were time to sputum culture and smear conversion and proportion of participants with negative sputum culture. The secondary outcomes were clinical response to treatment and adverse events. A random-effects model was used to pool studies. Data were analyzed using RevMan 5.3 software. RESULTS: Five studies with a total of 1126 participants were included in our meta-analysis. Vitamin D supplementation did not shorten the time to sputum culture and smear conversion (hazard ratio [HR] 1.04, 95% confidence interval [CI] 0.89-1.23, P = 0.60; HR 1.15, 95% CI 0.93-1.41, P = 0.20, respectively) and did not lead to an increase in the proportion of participants with negative sputum culture (relative risk [RR] 1.04, 95% CI 0.97-1.11, P = 0.32). However, it reduced the time to sputum culture conversion in the sub-group of participants with TaqI tt genotype (HR 8.09, 95% CI 1.39-47.09, P = 0.02) and improved the multidrug-resistant (MDR) TB sputum culture conversion rate (RR 2.40, 95% CI 1.11-5.18, P = 0.03). There was no influence on secondary outcomes. CONCLUSIONS: Vitamin D supplementation had no beneficial effect on anti-TB treatment, but it reduced the time to sputum culture conversion in participants with tt genotype of the TaqI vitamin D receptor gene polymorphism and improved the MDR TB sputum culture conversion rate.

Caring for Tuberculosis Patients: Understanding the Plight of Nurses at a Regional Hospital in Limpopo Province, South Africa.

Tuberculosis (TB) is a disease which is caused by a relatively large, non-motile, rod-shaped pathogen called Mycobacterium tuberculosis. TB is a major cause of illness and death worldwide, especially in Asia and Africa. Despite the fact that TB is a curable illness, the tragedy is that TB remains the biggest killer in the world as a single pathogen. The aim of this study was to determine the experiences of nurses caring for TB patients at a regional hospital in Limpopo Province, South Africa. Qualitative, exploratory, and descriptive designs were used. A non-probability purposive sampling method was used to select the participants. The personal experiences of six nurses with more than five years' experience caring for TB patients at a regional hospital were explored, and it was guided by data saturation. Data were collected through in-depth individual interviews. Data were analyzed using Colaizzi's method. Trustworthiness was ensured and ethical considerations were observed in this study. The research findings revealed six major themes from the raw data: challenges of the working environment, problems impacting on the quality of nursing care, fear, anxiety, stress and risk of contracting infection, nurses' perceptions towards patients, support structure available in the hospital, and support needs for the nurses. Therefore, there is an urgent need to address the challenges experienced by nurses caring for communicable diseases through provision of a positive practice work environment.

Systemic RAGE ligands are upregulated in tuberculosis individuals with diabetes co-morbidity and modulated by anti-tuberculosis treatment and metformin therapy.

BACKGROUND: Ligands of the receptor for advanced glycation end products (RAGE) are key signalling molecules in the innate immune system but their role in tuberculosis-diabetes comorbidity (TB-DM) has not been investigated. METHODS: We examined the systemic levels of soluble RAGE (sRAGE), advanced glycation end products (AGE), S100A12 and high mobility group box 1 (HMGB1) in participants with either TB-DM, TB, DM or healthy controls (HC). RESULTS: Systemic levels of AGE, sRAGE and S100A12 were significantly elevated in TB-DM and DM in comparison to TB and HC. During follow up, AGE, sRAGE and S100A12 remained significantly elevated in TB-DM compared to TB at 2nd month and 6th month of anti-TB treatment (ATT). RAGE ligands were increased in TB-DM individuals with bilateral and cavitary disease. sRAGE and S100A12 correlated with glycated hemoglobin levels. Within the TB-DM group, those with known diabetes (KDM) revealed significantly increased levels of AGE and sRAGE compared to newly diagnosed DM (NDM). KDM participants on metformin treatment exhibited significantly diminished levels of AGE and sRAGE in comparison to those on non-metformin regimens. CONCLUSIONS: Our data demonstrate that RAGE ligand levels reflect disease severity and extent in TB-DM, distinguish KDM from NDM and are modulated by metformin therapy.