Extensively drug-resistant tuberculosis is a burgeoning global health crisis mainly affecting economically active young adults, and has high mortality irrespective of HIV status. In some countries ...such as South Africa, drug-resistant tuberculosis represents less than 3% of all cases but consumes more than a third of the total national budget for tuberculosis, which is unsustainable and threatens to destabilise national tuberculosis programmes. However, concern about drug-resistant tuberculosis has been eclipsed by that of totally and extremely drug-resistant tuberculosis--ie, resistance to all or nearly all conventional first-line and second-line antituberculosis drugs. In this Review, we discuss the epidemiology, pathogenesis, diagnosis, management, implications for health-care workers, and ethical and medicolegal aspects of extensively drug-resistant tuberculosis and other resistant strains. Finally, we discuss the emerging problem of functionally untreatable tuberculosis, and the issues and challenges that it poses to public health and clinical practice. The emergence and growth of highly resistant strains of tuberculosis make the development of new drugs and rapid diagnostics for tuberculosis--and increased funding to strengthen global control efforts, research, and advocacy--even more pressing.
Summary Although progress has been made to reduce global incidence of drug-susceptible tuberculosis, the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis ...during the past decade threatens to undermine these advances. However, countries are responding far too slowly. Of the estimated 440 000 cases of MDR tuberculosis that occurred in 2008, only 7% were identified and reported to WHO. Of these cases, only a fifth were treated according to WHO standards. Although treatment of MDR and XDR tuberculosis is possible with currently available diagnostic techniques and drugs, the treatment course is substantially more costly and laborious than for drug-susceptible tuberculosis, with higher rates of treatment failure and mortality. Nonetheless, a few countries provide examples of how existing technologies can be used to reverse the epidemic of MDR tuberculosis within a decade. Major improvements in laboratory capacity, infection control, performance of tuberculosis control programmes, and treatment regimens for both drug-susceptible and drug-resistant disease will be needed, together with a massive scale-up in diagnosis and treatment of MDR and XDR tuberculosis to prevent drug-resistant strains from becoming the dominant form of tuberculosis. New diagnostic tests and drugs are likely to become available during the next few years and should accelerate control of MDR and XDR tuberculosis. Equally important, especially in the highest-burden countries of India, China, and Russia, will be a commitment to tuberculosis control including improvements in national policies and health systems that remove financial barriers to treatment, encourage rational drug use, and create the infrastructure necessary to manage MDR tuberculosis on a national scale.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
3.
Tuberculosis Infectiousness and Host Susceptibility Turner, Richard D.; Chiu, Christopher; Churchyard, Gavin J. ...
The Journal of infectious diseases,
11/2017, Volume:
216, Issue:
suppl_6
Journal Article
Peer reviewed
Open access
The transmission of tuberculosis is complex. Necessary factors include a source case with respiratory disease that has developed sufficiently for Mycobacterium tuberculosis to be present in the ...airways. Viable bacilli must then be released as an aerosol via the respiratory tract of the source case. This is presumed to occur predominantly by coughing but may also happen by other means. Airborne bacilli must be capable of surviving in the external environment before inhalation into a new potential host—steps influenced by ambient conditions and crowding and by M. tuberculosis itself. Innate and adaptive host defenses will then influence whether new infection results; a process that is difficult to study owing to a paucity of animal models and an inability to measure infection directly. This review offers an overview of these steps and highlights the many gaps in knowledge that remain.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
BACKGROUND:Black, Hispanic, and Indigenous persons in the United States have an increased risk of SARS-CoV-2 infection and death from COVID-19, due to persistent social inequities. However, the ...magnitude of the disparity is unclear because race–ethnicity information is often missing in surveillance data.
METHODS:We quantified the burden of SARS-CoV-2 notification, hospitalization, and case fatality rates in an urban county by racial–ethnic group using combined race−ethnicity imputation and quantitative bias analysis for misclassification.
RESULTS:The ratio of the absolute racial–ethnic disparity in notification rates after bias adjustment, compared with the complete case analysis, increased 1.3-fold for persons classified Black and 1.6-fold for those classified Hispanic, in reference to classified White persons.
CONCLUSIONS:These results highlight that complete case analyses may underestimate absolute disparities in notification rates. Complete reporting of race−ethnicity information is necessary for health equity. When data are missing, quantitative bias analysis methods may improve estimates of racial−ethnic disparities in the COVID-19 burden.
Summary Multidrug-resistant (MDR) tuberculosis is a growing clinical and public-health concern. To evaluate existing evidence regarding treatment regimens for MDR tuberculosis, we used a Bayesian ...random-effects meta-analysis of the available therapeutic studies to assess how the reported proportion of patients treated successfully is influenced by differences in treatment regimen design, study methodology, and patient population. Successful treatment outcome was defined as cure or treatment completion. 34 clinical reports with a mean of 250 patients per report met the inclusion criteria. Our analysis shows that the proportion of patients treated successfully improved when treatment duration was at least 18 months, and if patients received directly observed therapy throughout treatment. Studies that combined both factors had significantly higher pooled success proportions (69%, 95% credible interval CI 64–73%) than other studies of treatment outcomes (58%, 95% CI 52–64%). Individualised treatment regimens had higher treatment success (64%, 95% CI 59–68%) than standardised regimens (54%, 95% CI 43–68%), although the difference was not significant. Treatment approaches and study methodologies were heterogeneous across studies. Many important variables, including patients' HIV status, were inconsistently reported between studies. These results underscore the importance of strong patient support and treatment follow-up systems to develop successful MDR tuberculosis treatment programmes.
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The Eastern European country of Georgia initiated a nationwide hepatitis C virus (HCV) elimination program in 2015 to address a high burden of infection. Screening for HCV infection through antibody ...testing was integrated into multiple existing programs, including the National Tuberculosis Program (NTP). We sought to compare the hepatitis C care cascade among patients with and without tuberculosis (TB) diagnosis in Georgia between 2015 and 2019 and to identify factors associated with loss to follow-up (LTFU) in hepatitis C care among patients with TB.
Using national ID numbers, we merged databases of the HCV elimination program, NTP, and national death registry from January 1, 2015 to September 30, 2020. The study population included 11,985 adults (aged ≥18 years) diagnosed with active TB from January 1, 2015 through December 31, 2019, and 1,849,820 adults tested for HCV antibodies between January 1, 2015 and September 30, 2020, who were not diagnosed with TB during that time. We estimated the proportion of patients with and without TB who were LTFU at each step of the HCV care cascade and explored temporal changes. Among 11,985 patients with active TB, 9,065 (76%) patients without prior hepatitis C treatment were tested for HCV antibodies, of which 1,665 (18%) had a positive result; LTFU from hepatitis C care was common, with 316 of 1,557 (20%) patients with a positive antibody test not undergoing viremia testing and 443 of 1,025 (43%) patients with viremia not starting treatment for hepatitis C. Overall, among persons with confirmed viremic HCV infection, due to LTFU at various stages of the care cascade only 28% of patients with TB had a documented cure from HCV infection, compared to 55% among patients without TB. LTFU after positive antibody testing substantially decreased in the last 3 years, from 32% among patients diagnosed with TB in 2017 to 12% among those diagnosed in 2019. After a positive HCV antibody test, patients without TB had viremia testing sooner than patients with TB (hazards ratio HR = 1.46, 95% confidence intervals CI 1.39, 1.54, p < 0.001). After a positive viremia test, patients without TB started hepatitis C treatment sooner than patients with TB (HR = 2.05, 95% CI 1.87, 2.25, p < 0.001). In the risk factor analysis adjusted for age, sex, and case definition (new versus previously treated), multidrug-resistant (MDR) TB was associated with an increased risk of LTFU after a positive HCV antibody test (adjusted risk ratio aRR = 1.41, 95% CI 1.12, 1.76, p = 0.003). The main limitation of this study was that due to the reliance on existing electronic databases, we were unable to account for the impact of all confounding factors in some of the analyses.
LTFU from hepatitis C care after a positive antibody or viremia test was high and more common among patients with TB than in those without TB. Better integration of TB and hepatitis C care systems can potentially reduce LTFU and improve patient outcomes both in Georgia and other countries that are initiating or scaling up their nationwide hepatitis C control efforts and striving to provide personalized TB treatment.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The metabolic signaling pathways that drive pathologic tissue inflammation and damage in humans with pulmonary tuberculosis (TB) are not well understood. Using combined methods in plasma ...high-resolution metabolomics, lipidomics and cytokine profiling from a multicohort study of humans with pulmonary TB disease, we discovered that IL-1β-mediated inflammatory signaling was closely associated with TCA cycle remodeling, characterized by accumulation of the proinflammatory metabolite succinate and decreased concentrations of the anti-inflammatory metabolite itaconate. This inflammatory metabolic response was particularly active in persons with multidrug-resistant (MDR)-TB that received at least 2 months of ineffective treatment and was only reversed after 1 year of appropriate anti-TB chemotherapy. Both succinate and IL-1β were significantly associated with proinflammatory lipid signaling, including increases in the products of phospholipase A2, increased arachidonic acid formation, and metabolism of arachidonic acid to proinflammatory eicosanoids. Together, these results indicate that decreased itaconate and accumulation of succinate and other TCA cycle intermediates is associated with IL-1β-mediated proinflammatory eicosanoid signaling in pulmonary TB disease. These findings support host metabolic remodeling as a key driver of pathologic inflammation in human TB disease.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives:
The objectives of our study were (1) to determine risk factors associated with tuberculosis (TB)–specific and non–TB-specific mortality among patients with TB and (2) to examine whether ...risk factors for TB-specific mortality differed from those for non–TB-specific mortality.
Methods:
We obtained data from the National Tuberculosis Surveillance System and included all patients who had TB between 2009 and 2013 in the United States and its territories. We used multinomial logistic regression analysis to determine the adjusted odds ratio (aOR) of each risk factor for TB-specific and non–TB-specific mortality.
Results:
Of 52 175 eligible patients with TB, 1404 died from TB, and 2413 died from other causes. Some of the risk factors associated with the highest odds of TB-specific mortality were multidrug-resistant TB diagnosis (aOR = 3.42; 95% CI, 1.95-5.99), end-stage renal disease (aOR = 3.02; 95% CI, 2.23-4.08), human immunodeficiency virus infection (aOR = 2.63; 95% CI, 2.02-3.42), age 45-64 years (aOR = 2.57; 95% CI, 2.01-3.30) or age ≥65 years (aOR = 5.76; 95% CI, 4.37-7.61), and immunosuppression (aOR = 2.20; 95% CI, 1.71-2.83). All of these risk factors except multidrug-resistant TB were also associated with increased odds of non–TB-specific mortality.
Conclusion:
TB patients with certain risk factors have an elevated risk of TB-specific mortality and should be monitored before, during, and after treatment. Identifying the predictors of TB-specific mortality may help public health authorities determine which subpopulations to target and where to allocate resources.
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BFBNIB, INZLJ, NMLJ, NUK, OILJ, PNG, SAZU, UKNU, UL, UM, UPUK, VSZLJ, ZRSKP
Abstract
The degree to which individual heterogeneity in the production of secondary cases (“superspreading”) affects tuberculosis (TB) transmission has not been systematically studied. We searched ...for population-based or surveillance studies in which whole genome sequencing was used to estimate TB transmission and in which the size distributions of putative TB transmission clusters were enumerated. We fitted cluster-size–distribution data to a negative binomial branching process model to jointly infer the transmission parameters $R$ (the reproduction number) and the dispersion parameter, $k$, which quantifies the propensity of superspreading in a population (generally, lower values of $k$ ($<1.0$) suggest increased heterogeneity). Of 4,796 citations identified in our initial search, 9 studies from 8 global settings met the inclusion criteria (n = 5 studies of all TB; n = 4 studies of drug-resistant TB). Estimated $R$ values (range, 0.10–0.73) were below 1.0, consistent with declining epidemics in the included settings; estimated $k$ values were well below 1.0 (range, 0.02–0.48), indicating the presence of substantial individual-level heterogeneity in transmission across all settings. We estimated that a minority of cases (range, 2%–31%) drive the majority (80%) of ongoing TB transmission at the population level. Identifying sources of heterogeneity and accounting for them in TB control may have a considerable impact on mitigating TB transmission.
The epidemics of HIV-1 and tuberculosis in South Africa are closely related. High mortality rates in co-infected patients have improved with antiretroviral therapy, but drug-resistant tuberculosis ...has emerged as a major cause of death. We assessed the prevalence and consequences of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis in a rural area in KwaZulu Natal, South Africa.
We undertook enhanced surveillance for drug-resistant tuberculosis with sputum culture and drug susceptibility testing in patients with known or suspected tuberculosis. Genotyping was done for isolates resistant to first-line and second-line drugs.
From January, 2005, to March, 2006, sputum was obtained from 1539 patients. We detected MDR tuberculosis in 221 patients, of whom 53 had XDR tuberculosis. Prevalence among 475 patients with culture-confirmed tuberculosis was 39% (185 patients) for MDR and 6% (30) for XDR tuberculosis. Only 55% (26 of 47) of patients with XDR tuberculosis had never been previously treated for tuberculosis; 67% (28 of 42) had a recent hospital admission. All 44 patients with XDR tuberculosis who were tested for HIV were co-infected. 52 of 53 patients with XDR tuberculosis died, with median survival of 16 days from time of diagnosis (IQR 6–37) among the 42 patients with confirmed dates of death. Genotyping of isolates showed that 39 of 46 (85%, 95% CI 74–95) patients with XDR tuberculosis had similar strains.
MDR tuberculosis is more prevalent than previously realised in this setting. XDR tuberculosis has been transmitted to HIV co-infected patients and is associated with high mortality. These observations warrant urgent intervention and threaten the success of treatment programmes for tuberculosis and HIV.
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