The Lancet Respiratory Medicine Commission on drug-resistant tuberculosis was published in 2017, which comprehensively reviewed and provided recommendations on various aspects of the disease. Several ...key new developments regarding drug-resistant tuberculosis are outlined in this Commission Update. The WHO guidelines on treating drug-resistant tuberculosis were updated in 2019 with a reclassification of second line anti-tuberculosis drugs. An injection-free MDR tuberculosis treatment regimen is now recommended. Over the past 3 years, advances in treatment include the recognition of the safety and mortality benefit of bedaquiline, the finding that the 9-11 month injectable-based 'Bangladesh' regimen was non-inferior to longer regimens, and promising interim results of a novel 6 month 3-drug regimen (bedaquiline, pretomanid, and linezolid). Studies of explanted lungs from patients with drug-resistant tuberculosis have shown substantial drug-specific gradients across pulmonary cavities, suggesting that alternative dosing and drug delivery strategies are needed to reduce functional monotherapy at the site of disease. Several controversies are discussed including the optimal route of drug administration, optimal number of drugs constituting a regimen, selection of individual drugs for a regimen, duration of the regimen, and minimal desirable standards of antibiotic stewardship. Newer rapid nucleic acid amplification test platforms, including point-of-care systems that facilitate active case-finding, are discussed. The rapid diagnosis of resistance to other drugs, (notably fluoroquinolones), and detection of resistance by targeted or whole genome sequencing will probably change the diagnostic landscape in the near future.
Much remains unknown about
transmission. Seminal experimental studies from the 1950s demonstrated that airborne expulsion of droplet nuclei from an infectious tuberculosis (TB) patient is the primary ...route of transmission. However, these findings did not rule out other routes of
is transmission. We reviewed historical scientific evidence from the late 19th/early 20th century and contemporary studies investigating the presence, persistence and infectiousness of environmental
We found both experimental and epidemiological evidence supporting the presence and viability of
in multiple natural and built environments for months to years, presumably following contamination by a human source. Furthermore, several studies confirm
viability and virulence in the environment using guinea pig and mouse models. Most of this evidence was historical; however, several recent studies have reported consistent findings of
detection and viability in the environment using modern methods. Whether
in environments represents an infectious threat to humans requires further investigation; this may represent an untapped source of data with which to further understand
transmission. We discuss potential opportunities for harnessing these data to generate new insights into TB transmission in congregate settings.
Tuberculosis is a global health challenge and one of the leading causes of death worldwide. In the last decade, the tuberculosis treatment landscape has dramatically changed. After long years of ...stagnation, new compounds entered the market (bedaquiline, delamanid and pretomanid) and phase III clinical trials have shown promising results towards shortening duration of treatment for both drug-susceptible (Study 31/A5349, TRUNCATE-TB, SHINE) and drug-resistant tuberculosis (STREAM, NiX-TB, ZeNix, TB-PRACTECAL). Dose optimization of rifamycins and repurposed drugs have also brought hopes of further development of safe and effective regimens. Consequently, international and World Health Organization clinical guidelines have been updated multiple times in the last years to keep pace with these advances.
This narrative review aims to summarize the state-of-the-art on treatment of drug-susceptible and drug-resistant tuberculosis, as well as recent trials results and an overview of ongoing clinical trials.
A non-systematic literature review was conducted in PubMed and MEDLINE, focusing on the treatment of tuberculosis. Ongoing clinical trials were listed according to the authors’ knowledge, and completed consulting clinicaltrials.gov and other publicly available websites (www.resisttb.org/clinical-trials-progress-report, www.newtbdrugs.org/pipeline/trials).
This review summarizes the recent, major changes in the landscape for drug-susceptible and drug-resistant treatment, with a specific focus on their potential impact on patient outcomes and programmatic TB management. Moreover, insights in host-directed therapies, and advances in pharmacokinetic and pharmacogenomics are discussed. A thorough outline of ongoing therapeutic clinical trials is presented, highlighting different approaches and goals in current TB clinical research.
Future research should be directed to individualize regimens and protect these recent breakthroughs by preventing and identifying the selection of drug resistance and providing widespread, affordable, patient-centered access to new treatment options for all people affected by tuberculosis.
Several studies have identified blood transcriptomic signatures that can distinguish active from latent Tuberculosis (TB). The purpose of this study was to assess how well these existing gene ...profiles classify TB disease in a South Indian population. RNA sequencing was performed on whole blood PAXgene samples collected from 28 TB patients and 16 latently TB infected (LTBI) subjects enrolled as part of an ongoing household contact study. Differential gene expression and clustering analyses were performed and compared with explicit predictive testing of TB and LTBI individuals based on established gene signatures. We observed strong predictive performance of TB disease states based on expression of known gene sets (ROC AUC 0.9007–0.9879). Together, our findings indicate that previously reported classifiers generated from different ethnic populations can accurately discriminate active TB from LTBI in South Indian patients. Future work should focus on converting existing gene signatures into a universal TB gene signature for diagnosis, monitoring TB treatment, and evaluating new drug regimens.
...in Japan, where about 60% of the adult population were screened by chest radiography annually in the 1950s,2 the annual risk of tuberculosis infection declined by 11% per year between the 1950s ...and the 1970s, with corresponding declines in disease incidence and mortality.3 Similarly, there were rapid declines in mortality in Australia during the post-war National Tuberculosis Campaign, which included widespread chest radiography screening for tuberculosis.4,5 Hence, the high burden of tuberculosis in some countries today is not an immutable feature of the epidemiology, but rather represents a stage in disease control strategies. ...in Viet Nam during the period of our study11 and in Australia, there were no major changes in socioeconomic conditions. Since most cases of tuberculosis in high-burden settings are attributable to recently transmitted infection from people with infectious tuberculosis, it follows that people with remotely acquired tuberculosis infection only contribute a small proportion of the incidence of tuberculosis in these settings. ...targeted preventive therapy and a post-infection vaccine—although important with beneficial effects for some high-risk individuals, such as people living with HIV12 and children13—are unlikely to be effective in changing the trajectory of tuberculosis in high-burden settings. CRH is Vice-President of the International Union Against Tuberculosis and Lung Disease and has received research grant funding from the US National Institutes of Health and US Centers for Disease Control and Prevention.
Modeling studies have concluded that 60-80% of tuberculosis (TB) infections result from reinfection of previously infected persons. The annual rate of infection (ARI), a standard measure of the risk ...of TB infection in a community, may not accurately reflect the true risk of infection among previously infected persons. We constructed a model of infection and reinfection with Mycobacterium tuberculosis to explore the predictive accuracy of ARI and its effect on disease incidence.
We created a deterministic simulation of the progression from TB infection to disease and simulated the prevalence of TB infection at the beginning and end of a theoretical year of infection. We considered 10 disease prevalence scenarios ranging from 100/100 000 to 1000/100 000 in simulations where TB exposure probability was homogeneous across the whole simulated population or heterogeneously stratified into high-risk and low-risk groups. ARI values, rates of progression from infection to disease, and the effect of multiple reinfections were obtained from published studies.
With homogeneous exposure risk, observed ARI values produced expected numbers of infections. However, when heterogeneous risk was introduced, observed ARI was seen to underestimate true ARI by 25-58%. Of the cases of TB disease that occurred, 36% were among previously infected persons when prevalence was 100/100 000, increasing to 79% of cases when prevalence was 1000/100 000.
Measured ARI underestimates true ARI as a result of heterogeneous population mixing. The true force of infection in a community may be greater than previously appreciated. Hyperendemic communities likely contribute disproportionally to the global TB disease burden.
Comorbidities such as undernutrition and parasitic infections are widespread in India and other tuberculosis (TB)-endemic countries. This study examines how these conditions as well as food ...supplementation and parasite treatment might alter immune responses to Mycobacterium tuberculosis (Mtb) infection and risk of progression to TB disease.
This is a 5-year prospective clinical trial at Jawaharlal Institute of Post Graduate Medical Education and Research in Puducherry, Tamil Nadu, India. We aim to enroll 760 household contacts (HHC) of adults with active TB in order to identify 120 who are followed prospectively for 2 years: Thirty QuantiFERON-TB Gold Plus (QFT-Plus) positive HHCs ≥ 18 years of age in four proposed groups: (1) undernourished (body mass index BMI < 18.5 kg/m
); (2) participants with a BMI ≥ 18.5 kg/m
who have a parasitic infection (3) undernourished participants with a parasitic infection and (4) controls-participants with BMI ≥ 18.5 kg/m
and without parasitic infection. We assess immune response at baseline and after food supplementation (for participants with BMI < 18.5 kg/m
) and parasite treatment (for participants with parasites). Detailed nutritional assessments, anthropometry, and parasite testing through polymerase chain reaction (PCR) and microscopy are performed. In addition, at serial time points, these samples will be further analyzed using flow cytometry and whole blood transcriptomics to elucidate the immune mechanisms involved in disease progression.
This study will help determine whether undernutrition and parasite infection are associated with gene signatures that predict risk of TB and whether providing nutritional supplementation and/or treating parasitic infections improves immune response towards this infection. This study transcends individual level care and presents the opportunity to benefit the population at large by analyzing factors that affect disease progression potentially reducing the overall burden of people who progress to TB disease. Trial registration ClinicalTrials.gov; NCT03598842; Registered on July 26, 2018; https://clinicaltrials.gov/ct2/show/NCT03598842.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Older age is a risk factor for tuberculosis (TB) in low incidence settings. Using data from the US National TB Surveillance System and American Community Survey, we estimated ...trends and racial/ethnic differences in TB incidence among US-born cohorts aged ≥50 years.
Methods
In total, 42 000 TB cases among US-born persons ≥50 years were reported during 2001–2019. We used generalized additive regression models to decompose the effects of birth cohort and age on TB incidence rates, stratified by sex and race/ethnicity. Using genotype-based estimates of recent transmission (available 2011–2019), we implemented additional models to decompose incidence trends by estimated recent versus remote infection.
Results
Estimated incidence rates declined with age, for the overall cohort and most sex and race/ethnicity strata. Average annual percentage declines flattened for older individuals, from 8.80% (95% confidence interval CI 8.34–9.23) in 51-year-olds to 4.51% (95% CI 3.87–5.14) in 90-year-olds. Controlling for age, incidence rates were lower for more recent birth cohorts, dropping 8.79% (95% CI 6.13–11.26) on average between successive cohort years. Incidence rates were substantially higher for racial/ethnic minorities, and these inequalities persisted across all birth cohorts. Rates from recent infection declined at approximately 10% per year as individuals aged. Rates from remote infection declined more slowly with age, and this annual percentage decline approached zero for the oldest individuals.
Conclusions
TB rates were highest for racial/ethnic minorities and for the earliest birth cohorts and declined with age. For the oldest individuals, annual percentage declines were low, and most cases were attributed to remote infection.
Among US-born individuals aged 50 and over, estimated tuberculosis incidence rates are highest for racial/ethnic minorities and for the earliest birth cohorts. Within birth cohorts, incidence rates decline with age for almost all groups.
OBJECTIVE: To examine the association between diabetes, glycemic control, and risk of tuberculosis (TB). RESEARCH DESIGN AND METHODS: We conducted a population-based case-control study in Northern ...Denmark. Cases of active TB were all individuals with a first-time principal hospital diagnosis of TB between 1980 and 2008. Each case subject was matched with up to five population control subjects with similar age, sex, place and length of residence in Denmark, and country of emigration. We computed odds ratios (ORs) for a first-time TB diagnosis among people with and without diabetes using regression to control for other comorbidities, alcoholism, immunosuppressive medications, and socioeconomic markers. RESULTS: We identified 2,950 patients, including 156 diabetic individuals (5.3%), with active TB, and 14,274 population control subjects, of which 539 had diabetes (3.8%). The adjusted OR for active TB among subjects with diabetes was 1.18 (95% CI 0.96–1.45) compared with nondiabetic individuals. We found a similar risk increase from diabetes in the 843 (29%) TB case subjects who were immigrants; adjusted OR = 1.23 (95% CI 0.78–1.93). In a subset with laboratory data, diabetic individuals with an HbA1c <7.0, 7–7.9, and ≥8.0% had ORs of 0.91 (0.51–1.63), 1.05 (0.41–2.66), and 1.19 (CI 0.61–2.30), respectively, compared with individuals without diabetes. CONCLUSIONS: In the low TB–burden country of Denmark, the TB risk increase associated with diabetes is substantially lower than previously suggested. We found no evidence for any association between TB and dysglycemia.
PDF
