Summary Tuberculosis (TB) is an airborne disease caused by Mycobacterium tuberculosis (MTB) that usually affects the lungs leading to severe coughing, fever, and chest pains. Although current ...research in the past four years has provided valuable insight into TB transmission, diagnosis, and treatment, much remains to be discovered to effectively decrease the incidence of and eventually eradicate TB. The disease still puts a strain on public health, being only second to HIV/AIDS in causing high mortality rates. This review will highlight the history of TB as well as provide an overview of the current literature on epidemiology, pathogenesis and the immune response, treatment, and control of TB. In this race to combat a disease that knows no boundaries, it is necessary to have a conceptual and clear understanding of TB overall with the hope of providing better treatment through novel and collaborative research and public health efforts.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The tuberculosis (TB) bacillus, Mycobacterium tuberculosis (Mtb), and HIV-1 act synergistically; however, the mechanisms by which Mtb exacerbates HIV-1 pathogenesis are not well known. Using in vitro ...and ex vivo cell culture systems, we show that human M(IL-10) anti-inflammatory macrophages, present in TB-associated microenvironment, produce high levels of HIV-1. In vivo, M(IL-10) macrophages are expanded in lungs of co-infected non-human primates, which correlates with disease severity. Furthermore, HIV-1/Mtb co-infected patients display an accumulation of M(IL-10) macrophage markers (soluble CD163 and MerTK). These M(IL-10) macrophages form direct cell-to-cell bridges, which we identified as tunneling nanotubes (TNTs) involved in viral transfer. TNT formation requires the IL-10/STAT3 signaling pathway, and targeted inhibition of TNTs substantially reduces the enhancement of HIV-1 cell-to-cell transfer and overproduction in M(IL-10) macrophages. Our study reveals that TNTs facilitate viral transfer and amplification, thereby promoting TNT formation as a mechanism to be explored in TB/AIDS potential therapeutics.
Display omitted
•TB-induced anti-inflammatory M(IL-10) macrophages are prone to HIV-1 overproduction•Tunneling nanotubes between TB-induced M(IL-10) macrophages promote HIV-1 spread•The IL-10/STAT3 axis triggers tunneling nanotube induction in the TB microenvironment•M(IL-10) macrophages accumulate in TB/HIV co-infected patients and non-human primates
Tuberculosis is a clear, yet confounding, risk factor for HIV-1-induced morbidity and mortality. In this issue, Souriant et al. reveal that a tuberculosis-associated microenvironment triggers IL-10/STAT3-dependent tunneling nanotube formation in M(IL-10) macrophages, which promotes HIV-1 exacerbation during co-infection. M(IL-10) macrophage accumulation is also observed in vivo in co-infected subjects.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Tuberculosis can be treated, prevented, and cured. Rapid, sustained declines in tuberculosis deaths in many countries during the past 50 years provide compelling evidence that ending the pandemic is ...feasible. Yet this disease—which has plagued humanity since before recorded history and has killed hundreds of millions of people over the past two centuries—remains a relentless scourge. In 2017, 1·6 million people died from tuberculosis, including 300 000 people with HIV, representing more deaths than any other infectious disease. Moreover, in many parts of the world, drugresistant forms of tuberculosis threaten struggling control efforts. The world can no longer ignore the enormous pall cast by the tuberculosis epidemic. Going forward, the global tuberculosis response must be an inclusive, comprehensive response within the broader sustainable development agenda. No one-size-fits-all approach can succeed.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Tens of millions of children are exposed to Mycobacterium tuberculosis globally every year; however, there are no contemporary estimates of the risk of developing tuberculosis in exposed children. ...The effectiveness of contact investigations and preventive therapy remains poorly understood.
In this systematic review and meta-analysis, we investigated the development of tuberculosis in children closely exposed to a tuberculosis case and followed for incident disease. We restricted our search to cohort studies published between Jan 1, 1998, and April 6, 2018, in MEDLINE, Web of Science, BIOSIS, and Embase electronic databases. Individual-participant data and a pre-specified list of variables were requested from authors of all eligible studies. These included characteristics of the exposed child, the index case, and environmental characteristics. To be eligible for inclusion in the final analysis, a dataset needed to include: (1) individuals below 19 years of age; (2) follow-up for tuberculosis for a minimum of 6 months; (3) individuals with household or close exposure to an individual with tuberculosis; (4) information on the age and sex of the child; and (5) start and end follow-up dates. Studies assessing incident tuberculosis but without dates or time of follow-up were excluded. Our analysis had two primary aims: (1) estimating the risk of developing tuberculosis by time-period of follow-up, demographics (age, region), and clinical attributes (HIV, tuberculosis infection status, previous tuberculosis); and (2) estimating the effectiveness of preventive therapy and BCG vaccination on the risk of developing tuberculosis. We estimated the odds of prevalent tuberculosis with mixed-effects logistic models and estimated adjusted hazard ratios (HRs) for incident tuberculosis with mixed-effects Poisson regression models. The effectiveness of preventive therapy against incident tuberculosis was estimated through propensity score matching. The study protocol is registered with PROSPERO (CRD42018087022).
In total, study groups from 46 cohort studies in 34 countries—29 (63%) prospective studies and 17 (37%) retrospective—agreed to share their data and were included in the final analysis. 137 647 tuberculosis-exposed children were evaluated at baseline and 130 512 children were followed for 429 538 person-years, during which 1299 prevalent and 999 incident tuberculosis cases were diagnosed. Children not receiving preventive therapy with a positive result for tuberculosis infection had significantly higher 2-year cumulative tuberculosis incidence than children with a negative result for tuberculosis infection, and this incidence was greatest among children below 5 years of age (19·0% 95% CI 8·4–37·4). The effectiveness of preventive therapy was 63% (adjusted HR 0·37 95% CI 0·30–0·47) among all exposed children, and 91% (adjusted HR 0·09 0·05–0·15) among those with a positive result for tuberculosis infection. Among all children <5 years of age who developed tuberculosis, 83% were diagnosed within 90 days of the baseline visit.
The risk of developing tuberculosis among exposed infants and young children is very high. Most cases occurred within weeks of contact investigation initiation and might not be preventable through prophylaxis. This suggests that alternative strategies for prevention are needed, such as earlier initiation of preventive therapy through rapid diagnosis of adult cases or community-wide screening approaches.
National Institutes of Health.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A past history of pulmonary tuberculosis (TB) is a risk factor for long-term respiratory impairment. Post-TB lung dysfunction often goes unrecognised, despite its relatively high prevalence and its ...association with reduced quality of life. Importantly, specific host and pathogen factors causing lung impairment remain unclear. Host immune responses probably play a dominant role in lung damage, as excessive inflammation and elevated expression of lung matrix-degrading proteases are common during TB. Variability in host genes that modulate these immune responses may determine the severity of lung impairment, but this hypothesis remains largely untested. In this review, we provide an overview of the epidemiological literature on post-TB lung impairment and link it to data on the pathogenesis of lung injury from the perspective of dysregulated immune responses and immunogenetics.
Purpose
Covid-19 is a global threat that pushes health care to its limits. Since there is neither a vaccine nor a drug for Covid-19, people with an increased risk for severe and fatal courses of ...disease particularly need protection. Furthermore, factors increasing these risks are of interest in the search of potential treatments. A systematic literature review on the risk factors of severe and fatal Covid-19 courses is presented.
Methods
The review is carried out on PubMed and a publicly available preprint dataset. For analysis, risk factors are categorized and information regarding the study such as study size and location are extracted. The results are compared to risk factors listed by four public authorities from different countries.
Results
The 28 records included, eleven of which are preprints, indicate that conditions and comorbidities connected to a poor state of health such as high age, obesity, diabetes and hypertension are risk factors for severe and fatal disease courses. Furthermore, severe and fatal courses are associated with organ damages mainly affecting the heart, liver and kidneys. Coagulation dysfunctions could play a critical role in the organ damaging. Time to hospital admission, tuberculosis, inflammation disorders and coagulation dysfunctions are identified as risk factors found in the review but not mentioned by the public authorities.
Conclusion
Factors associated with increased risk of severe or fatal disease courses were identified, which include conditions connected with a poor state of health as well as organ damages and coagulation dysfunctions. The results may facilitate upcoming Covid-19 research.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Highlights • Human-adapted MTBC comprises seven phylogenetic lineages. • MTBC strains belonging to separate lineages differ by 1200 single nucleotide polymorphisms on average. • MTBC lineages are ...associated with different geographical regions. • Lineage 2 (includes Beijing) and Lineage 4 are more geographically widespread than other lineages. • Lineages 2 and 4 are more pathogenic and transmissible than geographically restricted lineages.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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.
Abstract Mendelian susceptibility to mycobacterial disease (MSMD) is a rare condition characterized by predisposition to clinical disease caused by weakly virulent mycobacteria, such as BCG vaccines ...and environmental mycobacteria, in otherwise healthy individuals with no overt abnormalities in routine hematological and immunological tests. MSMD designation does not recapitulate all the clinical features, as patients are also prone to salmonellosis, candidiasis and tuberculosis, and more rarely to infections with other intramacrophagic bacteria, fungi, or parasites, and even, perhaps, a few viruses. Since 1996, nine MSMD-causing genes, including seven autosomal ( IFNGR1 , IFNGR2 , STAT1 , IL12B , IL12RB1 , ISG15 , and IRF8 ) and two X-linked ( NEMO , and CYBB ) genes have been discovered. The high level of allelic heterogeneity has already led to the definition of 18 different disorders. The nine gene products are physiologically related, as all are involved in IFN-γ-dependent immunity. These disorders impair the production of ( IL12B , IL12RB1 , IRF8 , ISG15 , NEMO ) or the response to ( IFNGR1 , IFNGR2 , STAT1 , IRF8 , CYBB ) IFN-γ. These defects account for only about half the known MSMD cases. Patients with MSMD-causing genetic defects may display other infectious diseases, or even remain asymptomatic. Most of these inborn errors do not show complete clinical penetrance for the case-definition phenotype of MSMD. We review here the genetic, immunological, and clinical features of patients with inborn errors of IFN-γ-dependent immunity.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis, is a major cause of morbidity and mortality worldwide. Efforts to control it are hampered by difficulties with diagnosis, ...prevention and treatment. Most people infected with M. tuberculosis remain asymptomatic, termed latent TB, with a 10% lifetime risk of developing active TB disease. Current tests, however, cannot identify which individuals will develop disease. The immune response to M. tuberculosis is complex and incompletely characterized, hindering development of new diagnostics, therapies and vaccines. Here we identify a whole-blood 393 transcript signature for active TB in intermediate and high-burden settings, correlating with radiological extent of disease and reverting to that of healthy controls after treatment. A subset of patients with latent TB had signatures similar to those in patients with active TB. We also identify a specific 86-transcript signature that discriminates active TB from other inflammatory and infectious diseases. Modular and pathway analysis revealed that the TB signature was dominated by a neutrophil-driven interferon (IFN)-inducible gene profile, consisting of both IFN- and type I IFN- signalling. Comparison with transcriptional signatures in purified cells and flow cytometric analysis suggest that this TB signature reflects changes in cellular composition and altered gene expression. Although an IFN-inducible signature was also observed in whole blood of patients with systemic lupus erythematosus (SLE), their complete modular signature differed from TB, with increased abundance of plasma cell transcripts. Our studies demonstrate a hitherto underappreciated role of type I IFN- signalling in the pathogenesis of TB, which has implications for vaccine and therapeutic development. Our study also provides a broad range of transcriptional biomarkers with potential as diagnostic and prognostic tools to combat the TB epidemic.
Full text
Available for:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
