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Tuberculosis kills more people than any other infectious disease. Three pivotal trials testing 4-month regimens failed to meet non-inferiority margins; however, approximately four-fifths of participants were cured. Through a pooled analysis of patient-level data with external validation, we identify populations eligible for 4-month treatment, define phenotypes that are hard to treat and evaluate the impact of adherence and dosing strategy on outcomes. In 3,405 participants included in analyses, baseline smear grade of 3+ relative to <2+, HIV seropositivity and adherence of ≤90% were significant risk factors for unfavorable outcome. Four-month regimens were non-inferior in participants with minimal disease defined by <2+ sputum smear grade or non-cavitary disease. A hard-to-treat phenotype, defined by high smear grades and cavitation, may require durations >6 months to cure all. Regimen duration can be selected in order to improve outcomes, providing a stratified medicine approach as an alternative to the ‘one-size-fits-all’ treatment currently used worldwide. Analysis of tuberculosis drug trials identifies features to stratify patients for longer or shorter treatment duration than the standard of care, in order to improve therapeutic outcomes.

Extrapulmonary tuberculosis (EPTB) accounts for a significant proportion of tuberculosis cases worldwide. Nevertheless, the diagnosis is often delayed or even missed due to insidious clinical presentation and poor performance of diagnostic tests. Culture, the classical gold standard for tuberculosis, suffers from increased technical and logistical constraints in EPTB cases. In this review the authors outline current diagnostic options for the main forms of EPTB. The authors also discuss the opportunities and challenges linked in particular to microbiological diagnostics and to the attempts to find a new gold standard test for EPTB. Finally, new biomarkers and tests currently under evaluation are hopefully on the way to introduce significant improvements in EPTB diagnosis, for which clinical suspicion will nevertheless be essential.

DNA methylation is considered to be a relatively stable epigenetic mark. However, a growing body of evidence indicates that DNA methylation levels can change rapidly; for example, in innate immune cells facing an infectious agent. Nevertheless, the causal relationship between changes in DNA methylation and gene expression during infection remains to be elucidated. Here, we generated time-course data on DNA methylation, gene expression, and chromatin accessibility patterns during infection of human dendritic cells with Mycobacterium tuberculosis. We found that the immune response to infection is accompanied by active demethylation of thousands of CpG sites overlapping distal enhancer elements. However, virtually all changes in gene expression in response to infection occur before detectable changes in DNA methylation, indicating that the observed losses in methylation are a downstream consequence of transcriptional activation. Footprinting analysis revealed that immune-related transcription factors (TFs), such as NF-κB/Rel, are recruited to enhancer elements before the observed losses in methylation, suggesting that DNA demethylation is mediated by TF binding to cis-acting elements. Collectively, our results show that DNA demethylation plays a limited role to the establishment of the core regulatory program engaged upon infection.

Background. The risk of progression to active tuberculosis is greatest in the several years following initial infection. The extent to which latent tuberculosis infection reduces the risk of progressive disease following reexposure and reinfection is not known. Indirect estimates from population models have been highly variable. Methods. We reviewed prospective cohort studies of persons exposed to individuals with infectious tuberculosis that were published prior to the widespread treatment of latent tuberculosis to estimate the incidence of tuberculosis among individuals with latent tuberculosis infection (LTBI group) and without latent tuberculosis (uninfected; UI group). We calculated the incidence rate ratio (IRR) of tuberculosis disease following infection between these 2 groups. We then adjusted incidence for expected reactivation, proportion of each group that was infected, and median time of observation following infection during the study. Results. We identified 18 publications reporting tuberculosis incidence among 23 paired cohorts of individuals with and without latent infection (total N = 19 886). The weighted mean adjusted incidence rate of tuberculosis in the LTBI and UI groups attributable to reinfection was 13.5 per 1000 person-years (95% confidence interval [CI]: 5.0—26.2 per 1000 person-years) and that attributable to primary infection was 60.1 per 1000 person-years (95% CI: 38.6—87.4 per 1000 person-years). The adjusted IRR for tuberculosis in the LTBI group compared with the UI group was 0.21 (95% CI: .14—.30). Conclusions. Individuals with latent tuberculosis had 79% lower risk of progressive tuberculosis after reinfection than uninfected individuals. The risk reduction estimated in this study is greater than most previous estimates made through population models.

Abstract Background Vedolizumab (ENTYVIO) is a humanized α4β7 integrin antagonist approved for the treatment of inflammatory bowel disease, which selectively blocks gut-specific lymphocyte trafficking. We evaluated the risk of opportunistic infections of interest in patients treated with vedolizumab. Methods We determined the frequency of opportunistic infections and tuberculosis in patients receiving vedolizumab in phase 3 clinical trials and post-marketing settings. We also evaluated adverse events reported in the post-marketing setting in patients with a history of or concurrent hepatitis B/C virus infection. Results The incidence of opportunistic infections in patients receiving vedolizumab was 0.7 (GEMINI 1 and 2 clinical trials) and 1.0 (long-term safety study) per 100 patient-years, with 217 events reported in approximately 114,071 patient-years of exposure (post-marketing setting). Most opportunistic infections were nonserious and the majority of patients continued treatment with vedolizumab. Clostridium difficile was the most commonly reported infection, with an incidence rate of 0.5 per 100 patient-years (clinical trials). Tuberculosis was reported at 0.1 per 100 patient-years (clinical trials), with 7 events in the post-marketing setting. No tuberculosis-related deaths were reported in either setting. No cases of progressive multifocal leukoencephalopathy were reported. In 29 patients with a history of or concurrent hepatitis B/C infection in the post-marketing setting, no viral reactivation was observed. Conclusions Clinical trials and post-marketing data showed that the rate of serious opportunistic infections in patients receiving vedolizumab was low and most patients could continue vedolizumab treatment. The frequency of tuberculosis infection was also low and no hepatitis B/C viral reactivation was reported.

Ethiopia reported a high rate of extra-pulmonary tuberculosis (EPTB) and the cases are increasing since the last three decades. However, diagnostic evidence to initiate TB treatment among EPTB cases is not well known. Therefore, we described the epidemiology and assessed how EPTB is diagnosed in a teaching hospital in Ethiopia. We conducted a retrospective review among all adult EPTB cases diagnosed in Yekatit 12 Hospital Medical College from 2015 to 2019. Using a standardized data abstraction sheet, we collected data from patients' medical records on sociodemographic, sites, and laboratory diagnosis of EPTB cases. Of the 965 total TB cases, 49.8%(481) had a recorded diagnosis of EPTB during the study period. The mean age of EPTB patients was 32.9 years (SD±13.9) and 50.7% were males. Tubercular lymphadenitis (40.3%), abdominal (23.4%), and pleural TB(13.5%) were the most common sites of EPTB involvement, followed in descending order by the genitourinary, skeletal, central nervous system, abscess, breast, and laryngeal TB. We found a histopathology finding consistent with EPTB in 59.1% of cases, Acid-fast bacilli positive in 1.5%, and the rest diagnosed on radiological grounds. In the majority of cases, more than one diagnostic method was used to diagnose EPTB cases. Nearly half of TB patients had a recorded diagnosis of EPTB that comprise heterogeneous anatomical sites. All EPTB patients were started anti-TB therapy without definitive microbiology results. This indicates the diagnostic challenge of EPTB faced in our setting and proves to be significant for TB control in Ethiopia.

Tuberculosis (TB) is the leading cause of death from a single infectious agent, requiring at least 6 months of multidrug treatment to achieve cure 1 . However, the lack of reliable data on antimicrobial pharmacokinetics (PK) at infection sites hinders efforts to optimize antimicrobial dosing and shorten TB treatments 2 . In this study, we applied a new tool to perform unbiased, noninvasive and multicompartment measurements of antimicrobial concentration–time profiles in humans 3 . Newly identified patients with rifampin-susceptible pulmonary TB were enrolled in a first-in-human study 4 using dynamic [ 11 C]rifampin (administered as a microdose) positron emission tomography (PET) and computed tomography (CT). [ 11 C]rifampin PET–CT was safe and demonstrated spatially compartmentalized rifampin exposures in pathologically distinct TB lesions within the same patients, with low cavity wall rifampin exposures. Repeat PET–CT measurements demonstrated independent temporal evolution of rifampin exposure trajectories in different lesions within the same patients. Similar findings were recapitulated by PET–CT in experimentally infected rabbits with cavitary TB and confirmed using postmortem mass spectrometry. Integrated modeling of the PET-captured concentration–time profiles in hollow-fiber bacterial kill curve experiments provided estimates on the rifampin dosing required to achieve cure in 4 months. These data, capturing the spatial and temporal heterogeneity of intralesional drug PK, have major implications for antimicrobial drug development. Distinct patterns of exposure to a first-line tuberculosis drug in separate lung lesions within patients are revealed by PET–CT imaging. Use of the technique might help optimize the duration and dosing of antimicrobial drugs.

BACKGROUNDNatural resistance to Mycobacterium tuberculosis (Mtb) infection in some people with HIV (PWH) is unexplained.METHODSWe performed single cell RNA-sequencing of bronchoalveolar lavage cells, unstimulated or ex vivo stimulated with Mtb, for 7 PWH who were tuberculin skin test (TST) and IFN-γ release assay (IGRA) positive (called LTBI) and 6 who were persistently TST and IGRA negative (called resisters).RESULTSAlveolar macrophages (AM) from resisters displayed a baseline M1 macrophage phenotype while AM from LTBI did not. Resisters displayed alveolar lymphocytosis, with enrichment of all T cell subpopulations including IFNG-expressing cells. In both groups, mycobactericidal granulysin was expressed almost exclusively by a T cell subtype that coexpressed granzyme B, perforin and NK cell receptors. These poly-cytotoxic T lymphocytes (poly-CTL) overexpressed activating NK cell receptors and were increased in resister BAL. Following challenge with Mtb, only intraepithelial lymphocyte-like cells from LTBI participants responded with increased transcription of IFNG. AM from resisters responded with a stronger TNF signature at 6 hours after infection while at 24 hours after infection, AM from LTBI displayed a stronger IFN-γ signature. Conversely, at 24 hours after infection, only AM from resisters displayed an upregulation of MHC class I polypeptide-related sequence A (MICA) transcripts, which encode an activating ligand for poly-CTL.CONCLUSIONThese results suggest that poly-CTL and M1-like pre-activated AM mediate the resister phenotype in PWH.FUNDINGNational Institutes of Health. Canadian Institutes of Health Research. Digital Research Alliance of Canada. French National Research Agency. French National Agency for Research on AIDS and Viral Hepatitis. St. Giles Foundation. General Atlantic Foundation. South African Medical Research Council Centre for Tuberculosis Research.

Development of novel vaccines and treatment approaches against tuberculosis are hampered by limited knowledge of what constitutes a protective immune response against Mycobacterium tuberculosis ( Mtb ). Granulomas are organized immune aggregates that form in the lung in response to mycobacterial infection and are an important site of pathogen-host interaction. The composition and cellular microenvironment within the granuloma impacts the bacterial control capacity. To identify protective responses in granulomas, imaging mass cytometry was used to study archived lung tissue from low dose Mtb -infected non-human primates presenting with various levels of disease. This approach revealed that granuloma composition is correlated with the severity of lung pathology. Granulomas of animals with limited lung pathology were enriched for NK cells showing increased interactions with tissue macrophages. This work improves our understanding of local immune interactions in the lung and how these correlate with severity of tuberculosis disease.

Background Monocytes are the predominant innate immune cells at the early stage of Mycobacterium tuberculosis ( M. tb ) infection as the host defense against intracellular pathogens. Understanding the profile of different monocyte subpopulations and the dynamics of monocyte-related biomarkers may be useful for the diagnosis and prognosis of tuberculosis. Methods We enrolled 129 individuals comprising patients with pulmonary tuberculosis (PTB) ( n  = 39), tuberculous pleurisy (TBP) ( n  = 28), malignant pleural effusion (MPE) ( n  = 21), latent tuberculosis infection (LTBI) ( n  = 20), and healthy controls (HC) ( n  = 21). Surface expression of CD14, CD16, and CD163 on monocytes was detected using flow cytometry. In addition, soluble CD163 (sCD163) was determined by enzyme linked immunosorbent assay. Results Higher frequency of CD14 + CD16 + (15.7% vs 7.8%, P  < 0.0001) and CD14 − CD16 + (5.3% vs 2.5%, P  = 0.0011) monocytes and a decreased percentage of CD14 + CD16 − (51.0% vs 70.4%, P  = 0.0110) cells was observed in PTB patients than in HCs. Moreover, PTB patients displayed a higher frequency of CD163 + cells in CD16 + monocytes than those in the HC group (40.4% vs 11.3%, P  < 0.0001). The level of sCD163 was elevated in TBP patients and was higher in pleural effusion than in plasma (2116.0 ng/ml vs 1236.0 ng/ml, P  < 0.0001). sCD163 levels in pleural effusion and plasma could be used to distinguish TBP from MPE patients (cut-off values: 1950.0 and 934.7 ng/ml, respectively; AUCs: 0.8418 and 0.8136, respectively). Importantly, plasma sCD163 levels in TBP patients decreased significantly after anti-TB treatment. Conclusions Higher expression of membrane and soluble CD163 in active tuberculosis patients might provide insights regarding the pathogenesis of tuberculosis, and sCD163 may be a novel biomarker to distinguish TBP from MPE and to predict disease severity.