Human M1 macrophages express unique innate immune response genes after mycobacterial infection to defend against tuberculosis.

Mycobacterium tuberculosis (Mtb) is responsible for approximately 1.5 million deaths each year. Though 10% of patients develop tuberculosis (TB) after infection, 90% of these infections are latent. Further, mice are nearly uniformly susceptible to Mtb but their M1-polarized macrophages (M1-MΦs) can inhibit Mtb in vitro, suggesting that M1-MΦs may be able to regulate anti-TB immunity. We sought to determine whether human MΦ heterogeneity contributes to TB immunity. Here we show that IFN-γ-programmed M1-MΦs degrade Mtb through increased expression of innate immunity regulatory genes (Inregs). In contrast, IL-4-programmed M2-polarized MΦs (M2-MΦs) are permissive for Mtb proliferation and exhibit reduced Inregs expression. M1-MΦs and M2-MΦs express pro- and anti-inflammatory cytokine-chemokines, respectively, and M1-MΦs show nitric oxide and autophagy-dependent degradation of Mtb, leading to increased antigen presentation to T cells through an ATG-RAB7-cathepsin pathway. Despite Mtb infection, M1-MΦs show increased histone acetylation at the ATG5 promoter and pro-autophagy phenotypes, while increased histone deacetylases lead to decreased autophagy in M2-MΦs. Finally, Mtb-infected neonatal macaques express human Inregs in their lymph nodes and macrophages, suggesting that M1 and M2 phenotypes can mediate immunity to TB in both humans and macaques. We conclude that human MФ subsets show unique patterns of gene expression that enable differential control of TB after infection. These genes could serve as targets for diagnosis and immunotherapy of TB.

Behaviors and Attitudes Toward Smoking Among Health Care Workers at Health Facilities in 4 Provinces of Vietnam: A Representative Cross-Sectional Survey.

Tobacco smoking is a leading cause of premature death. Smoking prevalence in Vietnam ranks among the highest in Southeast Asia. Given the important role of health care workers (HCWs) in promoting and supporting smoking cessation, this project aimed to characterize the prevalence of smoking among HCWs in Vietnam, and their attitudes toward smoking cessation interventions. A cross-sectional survey was conducted among care workers in four levels of the health system, within four provinces of Vietnam. Descriptive statistics evaluated participant attitudes, perception, behaviors, and knowledge about smoking. Multivariable logistic regression models evaluated risk factors for smoking. Among 3343 HCWs, 7.5% identified as current smokers, comprising 22.2% males and 0.5% of females. Males had substantially greater odds (adjusted odds ratio = 55.3; 95% confidence interval [29.0, 105.6] of identifying as current smokers compared with females. HCWs in urban settings had higher odds of identifying as smokers compared with rural workers (adjusted odds ratio = 1.72; 95% confidence interval [1.23, 2.24]. Strong support for smoking cessation policies and interventions were identified, even among staff who smoked. HCWs play an integral role in identifying smokers and supporting smoking cessation interventions for their patients. Efforts to support affordable smoking cessation interventions within health facilities are likely to contribute to a reduction in smoking prevalence in Vietnam.

Bedaquiline Drug Resistance Emergence Assessment in Multidrug-Resistant Tuberculosis (MDR-TB): a 5-Year Prospective In Vitro Surveillance Study of Bedaquiline and Other Second-Line Drug Susceptibility Testing in MDR-TB Isolates.

Bedaquiline Drug Resistance Emergence Assessment in Multidrug-resistant tuberculosis (MDR-TB) (DREAM) was a 5-year (2015 to 2019) phenotypic drug resistance surveillance study across 11 countries. DREAM assessed the susceptibility of 5,036 MDR-TB isolates of bedaquiline treatment-naive patients to bedaquiline and other antituberculosis drugs by the 7H9 broth microdilution (BMD) and 7H10/7H11 agar dilution (AD) MIC methods. Bedaquiline AD MIC quality control (QC) range for the H37Rv reference strain was unchanged, but the BMD MIC QC range (0.015 to 0.12 µg/ml) was adjusted compared with ranges from a multilaboratory, multicountry reproducibility study conforming to Clinical and Laboratory Standards Institute Tier-2 criteria. Epidemiological cutoff values of 0.12 µg/ml by BMD and 0.25 µg/ml by AD were consistent with previous bedaquiline breakpoints. An area of technical uncertainty or intermediate category was set at 0.25 µg/ml and 0.5 µg/ml for BMD and AD, respectively. When applied to the 5,036 MDR-TB isolates, bedaquiline-susceptible, -intermediate, and -resistant rates were 97.9%, 1.5%, and 0.6%, respectively, for BMD and 98.8%, 0.8%, and 0.4% for AD. Resistance rates were the following: 35.1% ofloxacin, 34.2% levofloxacin, 33.3% moxifloxacin, 1.5% linezolid, and 2% clofazimine. Phenotypic cross-resistance between bedaquiline and clofazimine was 0.4% in MDR-TB and 1% in pre-extensively drug-resistant (pre-XDR-TB)/XDR-TB populations. Coresistance to bedaquiline and linezolid and clofazimine and linezolid were 0.1% and 0.3%, respectively, in MDR-TB and 0.2% and 0.4%, respectively, in pre-XDR-TB/XDR-TB populations. Resistance rates to bedaquiline appear to be low in the bedaquiline-treatment-naive population. No treatment-limiting patterns for cross-resistance and coresistance have been identified with key TB drugs to date.

An Innovative Public-Private Mix Model for Improving Tuberculosis Care in Vietnam: How Well are We Doing?

To improve tuberculosis (TB) care among individuals attending a private tertiary care hospital in Vietnam, an innovative private sector engagement model was implemented from June to December 2018. This included: (i) Active facility-based screening of all adults for TB symptoms (and chest x-ray (CXR) for those with symptoms) by trained and incentivized providers, with on-site diagnostic testing or transport of sputum samples, (ii) a mobile application to reduce dropout in the care cascade and (iii) enhanced follow-up care by community health workers. We conducted a cohort study using project and routine surveillance data for evaluation. Among 52,078 attendees, 368 (0.7%) had symptoms suggestive of TB and abnormalities on CXR. Among them, 299 (81%) were tested and 103 (34.4%) were diagnosed with TB. In addition, 195 individuals with normal CXR were indicated for TB testing by attending clinicians, of whom, seven were diagnosed with TB. Of the 110 TB patients diagnosed, 104 (95%) were initiated on treatment and 97 (93%) had a successful treatment outcome. Given the success of this model, the National TB Programme is considering to scale it up nationwide after undertaking a detailed cost-effectiveness analysis.

A household survey on screening practices of household contacts of smear positive tuberculosis patients in Vietnam.

BACKGROUND: Close contacts of tuberculosis (TB) patients are at increased risk of developing tuberculosis. Although passive contact screening guidelines are incorporated in the national TB control program, currently it is unknown how frequent close contacts are screened for TB in Vietnam. This study assesses current contact screening practices in Vietnam and determines the proportion of household contacts screened of newly registered TB patients. METHOD: Survey of household contacts of smear-positive TB patients (index patients) registered for treatment in 2008 in three Vietnamese cities. Households were interviewed in 2010 about screening for TB since treatment registration date of the index patient. RESULTS: We interviewed 4,118 household contacts of 1,091 identified index cases. Contact screening mainly relied on self-referral by household contacts. Of the 4,118 household contacts, 474 (11.5%) self-referred for TB screening, while this screening proportion was only 5.5% among contacts under 5 years old (16/293). Sputum examinations were performed in 374 (78.9%) of the screened contacts. Contact screening identified 27 cases of pulmonary TB (0.7%; or 656 cases/100,000 contacts), of which 20 were detected by sputum smear. CONCLUSIONS: The low proportion of household TB contacts screened for TB illustrates the limitations of passive contact screening as currently practiced in Vietnam. Children under 5 years of age are particularly neglected with this approach. Active contact screening with fixed follow-up times of close contacts of newly diagnosed TB patients should be considered in Vietnam, particularly in case of young children and drug-resistant TB.