Hydrogen sulfide dysregulates the immune response by suppressing central carbon metabolism to promote tuberculosis.

The ubiquitous gasotransmitter hydrogen sulfide (H2S) has been recognized to play a crucial role in human health. Using cystathionine γ-lyase (CSE)-deficient mice, we demonstrate an unexpected role of H2S in Mycobacterium tuberculosis (Mtb) pathogenesis. We showed that Mtb-infected CSE-/- mice survive longer than WT mice, and support reduced pathology and lower bacterial burdens in the lung, spleen, and liver. Similarly, in vitro Mtb infection of macrophages resulted in reduced colony forming units in CSE-/- cells. Chemical complementation of infected WT and CSE-/- macrophages using the slow H2S releaser GYY3147 and the CSE inhibitor DL-propargylglycine demonstrated that H2S is the effector molecule regulating Mtb survival in macrophages. Furthermore, we demonstrate that CSE promotes an excessive innate immune response, suppresses the adaptive immune response, and reduces circulating IL-1ß, IL-6, TNF-α, and IFN-γ levels in response to Mtb infection. Notably, Mtb infected CSE-/- macrophages show increased flux through glycolysis and the pentose phosphate pathway, thereby establishing a critical link between H2S and central metabolism. Our data suggest that excessive H2S produced by the infected WT mice reduce HIF-1α levels, thereby suppressing glycolysis and production of IL-1ß, IL-6, and IL-12, and increasing bacterial burden. Clinical relevance was demonstrated by the spatial distribution of H2S-producing enzymes in human necrotic, nonnecrotic, and cavitary pulmonary tuberculosis (TB) lesions. In summary, CSE exacerbates TB pathogenesis by altering immunometabolism in mice and inhibiting CSE or modulating glycolysis are potential targets for host-directed TB control.

Pulmonary tuberculosis associated with immune checkpoint inhibitors: a pharmacovigilance study.

We examined case reports of immune checkpoint inhibitors (ICIs) associated pulmonary tuberculosis (PT) using data from the Food and Drug Administration Adverse Event Reporting System database. Disproportionality analysis was performed by using the reporting OR (ROR) with relevant 95% CI. A total of 74 cases of PT related to ICIs therapy were identified. ICIs were significantly associated with over-reporting frequencies of PT (ROR=3.16, 95% CI: 2.51 to 3.98), while the signal was differed between anti-programmed death-1/ligand-1 and anti-cytotoxic T lymphocyte antigen-4 agents. Most indications were lung cancer (64.9%), the median onset age was 70 years, the median time to onset of PT was 70 days, ICIs were discontinued in most cases (85.2%).

Transmission phenotype of Mycobacterium tuberculosis strains is mechanistically linked to induction of distinct pulmonary pathology.

In a study of household contacts (HHC), households were categorized into High (HT) and Low (LT) transmission groups based on the proportion of HHC with a positive tuberculin skin test. The Mycobacterium tuberculosis (Mtb) strains from HT and LT index cases of the households were designated Mtb-HT and Mtb-LT, respectively. We found that C3HeB/FeJ mice infected with Mtb-LT strains exhibited significantly higher bacterial burden compared to Mtb-HT strains and also developed diffused inflammatory lung pathology. In stark contrast, a significant number of mice infected with Mtb-HT strains developed caseating granulomas, a lesion type with high potential to cavitate. None of the Mtb-HT infected animals developed diffused inflammatory lung pathology. A link was observed between increased in vitro replication of Mtb-LT strains and their ability to induce significantly high lipid droplet formation in macrophages. These results support that distinct early interactions of Mtb-HT and Mtb-LT strains with macrophages and subsequent differential trajectories in pathological disease may be the mechanism underlying their transmission potential.

Phosphorylated STAT3 suppresses microRNA-19b/1281 to aggravate lung injury in mice with type 2 diabetes mellitus-associated pulmonary tuberculosis.

Type 2 diabetes mellitus (T2DM) is a risk factor for pulmonary tuberculosis (PTB) and increased mortality. This work focused on the functions of phosphorylated STAT3 in lung injury in mouse with T2DM-associated PTB and the molecules involved. A mouse model with T2DM-PTB was induced by administrations of streptozotocin, nicotinamide and mycobacterium tuberculosis (Mtb). A pSTAT3-specific inhibitor AG-490 was given into mice and then the lung injury in mice was observed. The molecules involved in AG-490-mediated events were screened out. Altered expression of miR-19b, miR-1281 and NFAT5 was introduced to identify their involvements and roles in lung injury and PTB severity in the mouse model. Consequently, pSTAT3 expression in mice with T2DM-associated PTB was increased. Down-regulation of pSTAT3 by AG-490 prolonged the lifetime of mice and improved the histopathologic conditions, and inhibited the fibrosis, inflammation, Mtb content and number of apoptotic epithelial cells in mouse lung tissues. pSTAT3 transcriptionally suppressed miR-19b/1281 expression to up-regulate NFAT5. Inhibition of miR-19b/1281 or up-regulation of NFAT5 blocked the protective roles of AG-490 in mouse lung tissues. To conclude, this study evidenced that pSTAT3 promotes NFAT5 expression by suppressing miR-19b/1281 transcription, leading to lung injury aggravation and severity in mice with T2DM-associated PTB.

US Tuberculosis Rates among Persons Born Outside the United States Compared with Rates in Their Countries of Birth, 2012-20161.

The US Centers for Disease Control and Prevention recommends screening populations at increased risk for tuberculosis (TB), including persons born in countries with high TB rates. This approach assumes that TB risk for expatriates living in the United States is representative of TB risk in their countries of birth. We compared US TB rates by country of birth with corresponding country rates by calculating incidence rate ratios (IRRs) (World Health Organization rate/US rate). The median IRR was 5.4. The median IRR was 0.5 for persons who received a TB diagnosis <1 year after US entry, 4.9 at 1 to <10 years, and 10.0 at >10 years. Our analysis suggests that World Health Organization TB rates are not representative of TB risk among expatriates in the United States and that TB testing prioritization in the United States might better be based on US rates by country of birth and years in the United States.

Need for BCG Vaccination to Prevent TB in High-Incidence Countries and Populations.

An estimated one quarter of persons worldwide are infected with Mycobacterium tuberculosis. In 2018, the World Health Organization issued revised guidance on BCG vaccine for high-risk groups. The World Health Organization should consider guiding countries on a case-by-case basis in developing appropriate BCG policies to deliver equitable healthcare and protect public health.

Public Health Response to Tuberculosis Outbreak among Persons Experiencing Homelessness, Minneapolis, Minnesota, USA, 2017-2018.

Tuberculosis (TB) is a greater risk for populations experiencing homelessness. When a TB exposure occurs in a homeless shelter, evaluation of contacts is both urgent and challenging. In 2017, local public health workers initiated a response to a TB outbreak in homeless shelters in Minneapolis, Minnesota, USA. In this contact investigation, we incorporated multiple techniques to identify, evaluate, and manage patients, including the concentric-circle method to characterize amount of contact, identifying the most frequent sites of sporadic medical care, using electronic medical records, and engaging with medical providers treating this population. Of 298 contacts evaluated, 41 (14%) had latent TB infection and 2 had active TB disease. Our analysis indicated a significant relationship between duration of exposure and positive TB test result (p = 0.001). We encourage local public health departments to expand beyond traditional contact tracing techniques by leveraging partnerships and existing systems to reach contacts exposed in shelters.

Mycobacterium tuberculosis Complex Lineage 3 as Causative Agent of Pulmonary Tuberculosis, Eastern Sudan1.

Pathogen-based factors associated with tuberculosis (TB) in eastern Sudan are not well defined. We investigated genetic diversity, drug resistance, and possible transmission clusters of Mycobacterium tuberculosis complex (MTBC) strains by using a genomic epidemiology approach. We collected 383 sputum specimens at 3 hospitals in 2014 and 2016 from patients with symptoms suggestive of TB; of these, 171 grew MTBC strains. Whole-genome sequencing could be performed on 166 MTBC strains; phylogenetic classification revealed that most (73.4%; n = 122) belonged to lineage 3 (L3). Genome-based cluster analysis showed that 76 strains (45.9%) were grouped into 29 molecular clusters, comprising 2-8 strains/patients. Of the strains investigated, 9.0% (15/166) were multidrug resistant (MDR); 10 MDR MTBC strains were linked to 1 large MDR transmission network. Our findings indicate that L3 strains are the main causative agent of TB in eastern Sudan; MDR TB is caused mainly by transmission of MDR L3 strains.

Multidrug- and Extensively Drug-Resistant Mycobacterium tuberculosis Beijing Clades, Ukraine, 2015.

Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) is an emerging threat to TB control in Ukraine, a country with the third highest XDR TB burden globally. We used whole-genome sequencing of a convenience sample to identify bacterial genetic and patient-related factors associated with MDR/XDR TB in this country. MDR/XDR TB was associated with 3 distinct Mycobacterium tuberculosis complex lineage 2 (Beijing) clades, Europe/Russia W148 outbreak, Central Asia outbreak, and Ukraine outbreak, which comprised 68.9% of all MDR/XDR TB strains from southern Ukraine. MDR/XDR TB was also associated with previous treatment for TB and urban residence. The circulation of Beijing outbreak strains harboring broad drug resistance, coupled with constraints in drug supply and limited availability of phenotypic drug susceptibility testing, needs to be considered when new TB management strategies are implemented in Ukraine.

Tuberculosis associated with Triplet therapy for lung cancer.

We report the first case of TB associated with triplet therapy (chemotherapy and immunotherapy concurrently) for lung cancer, developing just 44 days after treatment initiation. We feel that several important learning points arise from the discussion that are likely to be very relevant to the broad readership of Thorax, and have important clinical and scientific implications. In the three discussion paragraphs, we highlight that: 1) Triplet therapy is now standard first-line treatment for inoperable lung cancer. 2) TB reactivation is increasingly recognised as an adverse effect of immune checkpoint inhibition, but sending diagnostic samples is critical to avoid a missed diagnosis. 3) These insights from novel cancer immunotherapies are challenging the traditional views of the host-pathogen interaction in TB, with wide implications for future control strategies. We propose that the cases reported in the literature are likely to be the tip of the iceberg as most people with lung cancer managed with antiprogrammed death-1 agents who develop new lung lesions will be treated with standard antibiotics and then palliated when they do not respond.

Determinants associated with areas with higher tuberculosis mortality rates: an ecological study.

OBJECTIVE: To characterise tuberculosis deaths in a region of northeast Brazil during the period from 2006 to 2017 and to identify determinants associated with areas with higher tuberculosis mortality rates. METHODS: Ecological descriptive study of deaths from tuberculosis with multivariate mapping and logistic regression, carried out from 2006 to 2017 in the 75 municipalities of Sergipe, Brazil. The focus of the analysis was the mean mortality rate from tuberculosis, dichotomised according to the median. The independent variables were selected based on the conceptual model of the social determinants of health. RESULTS: Mortality due to tuberculosis in Sergipe, Brazil, was most prevalent among males, mixed-race people, and people over 40 years old and with a low level of education. Multivariate logistic regression identified the mean incidence rate for tuberculosis (aOR: 1.06), the proportion of HIV testing (aOR: 7.10), people without primary education and with informal occupation (aOR: 1.26) and people living in urban households without waste collection service (aOR: 0.10) as determinants associated to municipalities with higher tuberculosis mortality rates, with area under the ROC curve of 84% (P-value 0.000). Mapping revealed evident spatial variability. CONCLUSIONS: The tuberculosis epidemic in Brazil is determined by access to health services, especially the provision of HIV testing among those diagnosed with tuberculosis, accelerated urbanisation with large pockets of poverty and unsanitary housing conditions, corroborating global trends.

OBJECTIF: Caractériser les décès dus à la tuberculose dans une région du nord-est du Brésil au cours de la période de 2006 à 2017 et identifier les déterminants associés aux zones où les taux de mortalité par tuberculose sont plus élevés. MÉTHODES: Etude descriptive écologique des décès par tuberculose avec une cartographie multivariée et une régression logistique, réalisée de 2006 à 2017 dans les 75 municipalités de Sergipe, au Brésil. L'analyse était axée sur le taux moyen de mortalité par tuberculose, dichotomisé selon la médiane. Les variables indépendantes ont été sélectionnées sur la base du modèle conceptuel des déterminants sociaux de la santé. RÉSULTATS: La mortalité due à la tuberculose à Sergipe, au Brésil, était plus fréquente chez les hommes, les personnes métissées, les personnes de plus de 40 ans et avec un faible niveau d'éducation. La régression logistique multivariée a identifié le taux moyen d'incidence de la tuberculose (aOR: 1,06), la proportion des tests de dépistage du VIH (aOR: 7,10), les personnes sans éducation primaire et occupant une fonction informelle (aOR: 1,26) et les personnes vivant dans des ménages en milieu urbain sans service de collecte des déchets (aOR: 0,10) comme étant des déterminants associés aux municipalités avec des taux de mortalité par tuberculose plus élevés, avec une aire sous la courbe ROC de 84 % (p=0,000). La cartographie a révélé une variabilité spatiale évidente. CONCLUSIONS: L'épidémie de tuberculose au Brésil est déterminée par l'accès aux services de santé, en particulier la fourniture des tests de dépistage du VIH chez les personnes diagnostiquées avec la tuberculose, l'urbanisation accélérée avec de grandes poches de pauvreté et les conditions de logement insalubres, corroborant les tendances mondiales.

Association between polymorphisms in mannose-binding lectin 2 gene with pulmonary tuberculosis susceptibility.

BACKGROUND: Mannose-binding lectin (MBL2) is considered to play a role in the human innate immune response to tuberculosis (TB) infections, and 4 common single nucleotide polymorphisms (SNPs) may be associated with pulmonary tuberculosis (PTB) risk. To examine these potential associations, we performed a comprehensive analysis to assess the relationships between MBL2 polymorphisms and PTB. METHODS: The PubMed, Embase, and SinoMed databases were searched for articles published prior to June 13, 2019. Odds ratios with 95% confidence intervals were calculated to evaluate the strength of the relationships. RESULTS: There were 37 case-control studies examining the effects of the four SNPs in MBL2 on PTB. A positive association between rs11003125 and PTB risk was observed in the hospital-based subgroup. Moreover, for the combined polymorphism and PTB risk, positive associations were detected not only in the total population but also in those with Asian origins across all source of control subgroups. No associations were found for rs7096206 or rs7095891. CONCLUSIONS: Our current study indicated that several SNPs in MBL2 may be associated with susceptibility to PTB.

A Unique Spectrum of Tuberculosis Flare Up Related to Cardiothoracic Surgery.

Three cases of tuberculosis (TB) related to or complicating cardiothoracic surgery are presented in this paper. The aim of this article is to alert cardiothoracic surgeons about the presence or rebound of TB, which can complicate cardiothoracic surgeries even in the immediate postoperative course.

Active Pulmonary Tuberculosis Triggered by Interferon Beta-1b Therapy of Multiple Sclerosis: Four Case Reports and a Literature Review.

In this paper, we reported on four cases of severe pulmonary active tuberculosis in patients with multiple sclerosis (MS) undergoing interferon beta-1b (IFNß-1b) therapy. Disease-modifying therapies (DMTs) in MS may increase the risk of developing active tuberculosis (TB) due to their impact on cellular immunity. Screening for latent infection with Mycobacterium tuberculosis (LTBI) should be performed, not only for the newer DMTs (alemtuzumab, ocrelizumab) but also for IFNß-1b, alongside better supervision of these patients.

Polymorphisms in TLR4 and TNFA and Risk of Mycobacterium tuberculosis Infection and Development of Active Disease in Contacts of Tuberculosis Cases in Brazil: A Prospective Cohort Study.

BACKGROUND: The role of genetic polymorphisms in latent tuberculosis (TB) infection and progression to active TB is not fully understood. METHODS: We tested the single-nucleotide polymorphisms (SNPs) rs5743708 (TLR2), rs4986791 (TLR4), rs361525 (TNFA), rs2430561 (IFNG) rs1143627 (IL1B) as risk factors for tuberculin skin test (TST) conversion or development of active TB in contacts of active TB cases. Contacts of microbiologically confirmed pulmonary TB cases were initially screened for longitudinal evaluation up to 24 months, with clinical examination and serial TST, between 1998 and 2004 at a referral center in Brazil. Data and biospecimens were collected from 526 individuals who were contacts of 177 active TB index cases. TST conversion was defined as induration ≥5 mm after a negative TST result (0 mm) at baseline or month 4 visit. Independent associations were tested using logistic regression models. RESULTS: Among the 526 contacts, 60 had TST conversion and 44 developed active TB during follow-up. Multivariable regression analysis demonstrated that male sex (odds ratio [OR]: 2.3, 95% confidence interval [CI]: 1.1-4.6), as well as SNPs in TLR4 genes (OR: 62.8, 95% CI: 7.5-525.3) and TNFA (OR: 4.2, 95% CI: 1.9-9.5) were independently associated with TST conversion. Moreover, a positive TST at baseline (OR: 4.7, 95% CI: 2.3-9.7) and SNPs in TLR4 (OR: 6.5, 95% CI: 1.1-36.7) and TNFA (OR: 12.4, 95% CI:5.1-30.1) were independently associated with incident TB. CONCLUSIONS: SNPs in TLR4 and TNFA predicted both TST conversion and active TB among contacts of TB cases in Brazil.

Prevalence of Tuberculosis in Children After Natural Disasters, Bohol, Philippines.

In 2013, a severe earthquake and typhoon affected Bohol, Philippines. To assess the postdisaster risk for emergence of Mycobacterium tuberculosis infection in children, we conducted a cross-sectional multistage cluster study to estimate the prevalence of tuberculin skin test (TST) positivity and tuberculosis (TB) in children from 200 villages in heavily affected and less affected disaster areas. Of the 5,476 children we enrolled, 355 were TST-positive (weighted prevalence 6.4%); 16 children had active TB. Fourteen (7%) villages had >20% TST-positive prevalence. Although prevalence did not differ significantly between heavily affected and less affected areas, living in a shelter with >25 persons approached significance. TST positivity was independently associated with older age, prior TB treatment, known contact with a person with TB, and living on a geographically isolated island. We found a high TST-positive prevalence, suggesting that national programs should consider the differential vulnerability of children and the role of geographically isolated communities in TB emergence.

Mycobacterium Avium Complex Presenting as Pulmonary Nodules in a Child With Sickle Cell Disease.

The case of a 10-year-old child with sickle cell disease with pulmonary nodules and prolonged fevers is reported here. The child was first diagnosed with sarcoidosis based on lung biopsy, but unresponsiveness to therapy led to a second lung biopsy, which revealed the true diagnosis of mycobacterium avium complex disease. Multiple possible explanations for why the patient became infected exist. The patient was baseline immunocompromised due to her sickle cell disease, was exposed to invasive procedures, was taking medications that may predispose to this type of infection, and was found to have a congenital immunodeficiency.

Association of social deprivation and outdoor air pollution with pulmonary tuberculosis in spatiotemporal analysis.

The objective of this study was to identify the association between social deprivation, outdoor air pollution, and tuberculosis (TB) incidence rate or mortality rate. The study sample comprised 25 districts in Seoul, Korea. We used two public data derived from the Community Health Survey and Seoul Statistics. The geographic information system analysis and random effects Poisson regression were applied to explore the association of social deprivation and air pollution with TB incidence and mortality. An 1 ppb increase in sulfur dioxide (SO2) concentration was significantly associated with the risk of TB incidence (risk ratio [RR] = 1.046, 95% confidence interval [CI]: 1.028, 1.065). An 1 unit increase in the deprivation index was significantly related to a6% increase in the mortality of TB (RR = 1.063, 95% CI: 1.031, 1.097). : Our results imply that social deprivation and air pollution may affect the different TB outcomes. Effective policy-making for TB control should reflect the differing outcomes between TB incidence and mortality.

THE ROLE OF CIGARETTE SMOKING AND ALCOHOL CONSUMPTION IN PULMONARY TUBERCULOSIS DEVELOPMENT AND RECURRENCE.

During a two-year period (2001-2003), 464 patients were treated for tuberculosis at Jordanovac Department for Lung Diseases in Croatia. Besides pulmonary tuberculosis in 97.7% of patients, patients were also treated for tuberculous pleurisy (0.9%), tuberculous laryngitis (0.6%), tuberculous meningitis (0.2%), tuberculous pericarditis (0.2%) and urogenital tuberculosis (0.4%). Out of the total number of patients, 57.3% declared themselves to be active smokers (men were predominant and made up to 80.8%) and 20.9% to be active alcohol consumers. Both risk factors, i.e. smoking and alcohol consumption, were present in 15.1% of all patients. The most common comorbidities were diabetes mellitus (30.4%), cardiac diseases (11.2%) and chronic obstructive pulmonary disease (8.0%). Lung carcinoma was the most common malignant disease (n=51), with Mycobacterium tuberculosis isolated in 33% of them. Seventy-two of 464 (15.5%) patients had recurrences of tuberculosis. Of these, 30.5% had one of the risk factors (20.8% were smokers and 9.7% consumed alcohol), while 32.5% of patients had both risk factors. In conclusion, cigarette smoking was proved to be the most significant risk factor for development of pulmonary tuberculosis and its recurrence.

Drivers of Seasonal Variation in Tuberculosis Incidence: Insights from a Systematic Review and Mathematical Model.

BACKGROUND: Seasonality in tuberculosis incidence has been widely observed across countries and populations; however, its drivers are poorly understood. We conducted a systematic review of studies reporting seasonal patterns in tuberculosis to identify demographic and ecologic factors associated with timing and magnitude of seasonal variation. METHODS: We identified studies reporting seasonal variation in tuberculosis incidence through PubMed and EMBASE and extracted incidence data and population metadata. We described key factors relating to seasonality and, when data permitted, quantified seasonal variation and its association with metadata. We developed a dynamic tuberculosis natural history and transmission model incorporating seasonal differences in disease progression and/or transmission rates to examine magnitude of variation required to produce observed seasonality in incidence. RESULTS: Fifty-seven studies met inclusion criteria. In the majority of studies (n=49), tuberculosis incidence peaked in spring or summer and reached a trough in late fall or winter. A standardized seasonal amplitude was calculated for 34 of the studies, resulting in a mean of 17.1% (range: 2.7-85.5%) after weighting by sample size. Across multiple studies, stronger seasonality was associated with younger patients, extrapulmonary disease, and latitudes farther from the Equator. The mathematical model was generally able to reproduce observed levels of seasonal case variation; however, substantial variation in transmission or disease progression risk was required to replicate several extreme values. CONCLUSIONS: We observed seasonal variation in tuberculosis, with consistent peaks occurring in spring, across countries with varying tuberculosis burden. Future research is needed to explore and quantify potential gains from strategically conducting mass screening interventions in the spring.