Cohort profile: the KDCA-Tuberculosis-NHIS cohort linking tuberculosis surveillance and health insurance data in Korea.

CD4+FoxP3+ T regulatory cells in drug-susceptible and multidrug-resistant tuberculosis

Tuberculosis

Objective To systematically review the efficacy of percutaneous lung cavity injection of medicine for treatment of multi-drug resistant cavernous tuberculosis. Methods The Pubmed、Cochranel Library、CNKI、CMB、VIP、Wanfang database were retrieved to collect the randomized controlled trial (RCT) of the efficacy of percutaneous lung cavity injection of medicine for treatment of multi-drug resistant cavernous tuberculosis, up to April 2016 sincedatabase establishment.Two reviewers in dependently screened studies according to the inclusion and exclusion criteria, extracted data and assessed quality of the included studies.Then Meta-analysis was conducted using RevMan 5.3 software. Results 15 RCT were included, involving 1 546 cases of multi-drug resistant cavernous tuberculosis.In the effectiveness, sputum negative conversion rate、cavity closure rate、lesion absorption rate with Percutaneous lung cavity injection were all higher than those in the multi-drug resistant cavernous tuberculosis control group.Percutaneous lung cavity injection of medicinefor treatment can improve the clinical effectiveness of the multi-drug resistant cavernous tuberculosis significantly. Conclusions It deserves further investigation and spreading in clinical practice. Key words: Percutaneous lung puncture; Multi-drug resistant tuberculosis; Cavity; RCT; Meta-analysis

Tuberculosis (TB) is the seventh leading cause of morbidity and mortality in Bangladesh. Although the National TB control program (NTP) of Bangladesh is implementing its nationwide TB control strategies, more specific and effective single or combination interventions are needed to control drug-susceptible (DS) and multi-drug resistant (MDR) TB. In this study, we developed a two strain TB mathematical model with amplification and fit it to the Bangladesh TB data to understand the transmission dynamics of DS and MDR TB. Sensitivity analysis was used to identify important parameters. We evaluated the cost-effectiveness of varying combinations of four basic control strategies including distancing, latent case finding, case holding and active case finding, all within the optimal control framework. From our fitting, the model with different transmission rates between DS and MDR TB best captured the Bangladesh TB reported case counts. The estimated basic reproduction number for DS TB was 1.14 and for MDR TB was 0.54, with an amplification rate of 0.011 per year. The sensitivity analysis also indicated that the transmission rates for both DS and MDR TB had the largest influence on prevalence. To reduce the burden of TB (both DS and MDR), our finding suggested that a quadruple control strategy that combines distancing control, latent case finding, case holding and active case finding is the most cost-effective. Alternative strategies can be adopted to curb TB depending on availability of resources and policy makers’ decisions.

Globally, an estimated one-million new tuberculosis (TB) cases occurred in children in 2014. For a long time, research of TB in children has been neglected. Most research and surveillance of TB is performed in adults, and the resulting lack of evidence in children is a major barrier for implementation of rational control strategies for children, including diagnosis. More research on TB in children is of importance as children are more susceptible to developing severe extrapulmonary TB, children require different approaches to both diagnosis and treatment and paediatric TB reflects the ongoing transmission of TB in the population. This research gap on the epidemiology of tuberculosis in children, especially in high burden countries, should be addressed in order to better understand the dynamics of TB transmission in both adults and children. Accurate data are the basis for establishment of effective control strategies. This thesis aims to assess the diagnostic role of microscopic observation drug susceptibility (MODS) and mycobacterial blood culture for diagnosis of TB in children as well as to present the epidemiological characteristics of paediatric TB in northern Vietnam with regard to drug resistance and genotypes of Mycobacterium tuberculosis (MTB), the causative agent of TB, isolated from them. MODS is a low cost non-commercial liquid culture assay to detect MTB by microscopy. MODS was compared with conventional assays including Ziehl-Neelsen smear (ZN) and Lowenstein-Jensen culture (LJ) in a study conducted from 2009 to 2010 at the National Hospital for Paediatrics, a general paediatric hospital, in Hanoi, Vietnam. In suspected paediatric TB cases, the MODS test was shown to be significantly more sensitive than both smear (46.0% vs. 8.8%) and LJ (46.0% vs. 38.9%), and significantly faster than LJ with a median time difference of 28 days in favour of MODS (7 days vs. 35 days). The findings suggest that MODS is a rapid low-cost diagnostic tool for TB diagnosis in the paediatric population. The additional yield of mycobacterial blood culture was assessed in comparison to routine detection methods for TB diagnosis in children in two hospitals in Vietnam. The findings show that mycobacterial blood culture detected an additional six TB cases of which 5 cases were negative with other tests and in the remaining case no other tests were done. All six cases were susceptible to rifampicin and isoniazid. The overall performance of TB blood culture was poor as compared to routine culture with regard to detection rate (2.9%, 16/554 vs. 16.6%, 92/554) and turnaround time (26 days vs. 14 days). The incremental cost for adding one additional TB case is substantial. Therefore, addition of mycobacterial blood culture into routine diagnostics has limited utility in resource limited settings. To assess the molecular epidemiology of paediatric TB in northern Vietnam, a collection of 125 MTB isolates from children with TB admitted to NHP during 2009 to 2013 was analysed. Drug susceptibility testing results from 121 isolates and genotypes from 120 isolates were generated. The phenotypic drug susceptibility testing showed that 20.7% was resistant to isoniazid (25/121), 3.3% resistant to rifampicin (4/121), 28.1% resistant to streptomycin (34/121) and 2.5% resistant to ethambutol (1/121). There were 4 cases with multidrug resistant TB. The high frequency of resistance to isoniazid and streptomycin are consistent with data from adults in Vietnam, suggesting the ongoing transmission of drug resistant MTB in the community. MIRU typing patterns showed that the Beijing genotype was predominant in this population (63.3%, 76/120), which is in agreement with various prior studies in adults in Vietnam. These findings provide more evidence to support the hypothesis of the epidemic spread of the Beijing genotype in Vietnam. In this study, an association between Beijing genotype and drug resistance to streptomycin and isoniazid was observed. The number of MDR isolates was too small to draw conclusions regarding association of MDR and Beijing genotype. Collectively, these results demonstrate that liquid culture can improve the yield of TB diagnosis in Vietnam and mycobacterial blood culture should not be routinely performed for paediatric cases. The molecular epidemiology study also showed that the Beijing genotype is the predominant lineage among actively transmitted strains in Vietnam and that it is associated with both isoniazid and streptomycin resistance. Paediatric TB remains a significant cause of morbidity and mortality in Vietnamese children and sustained political and social commitment from all stakeholders, including governments, funders, academics and the medical community will be needed to improve diagnosis, treatment and prevention of TB in children globally.

Dealing With Threat of Drug-Resistant Tuberculosis: Background Information for Interpreting the Andrew Speaker and Related Cases

Treatment Duration for Patients with Drug-Resistant Tuberculosis, United States

The article by Kvasnovsky et al1 in this issue of JAIDS: J Acquir Immune Defic Syndr describing the dismal treatment outcomes of patients with extensively drug-resistant tuberculosis (TB) in the Eastern Cape of South Africa—a setting with a high prevalence of HIV and an extremely high TB burden—is a ghastly reminder of the toll exacted by this explosive public health crisis. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB have derailed the relatively few gains made in TB control in areas such as South Africa with high HIV prevalence. It is no surprise that South Africa, with its high incidence of active TB (almost 1% of South Africa's 50 million people were diagnosed with TB in 20092) and its historically high rates of poor treatment outcomes, should also have a large number of individuals with drug-resistant TB. Drug-resistant Mycobacterium tuberculosis does not exist in nature—it is the product of human intervention, selected by inappropriate or inadequate treatment and poor adherence. XDR TB-MDR TB that has acquired resistance to second-line drugs for TB including the fluoroquinolones and at least one so-called injectable agent—is the product of mismanagement of MDR TB. In South Africa, the mistakes of the past are amplified by the large number of people rendered profoundly susceptible to TB by HIV infection, compounded by ongoing weaknesses in TB control. A significant proportion of individuals with MDR and XDR TB have never had exposure to the selective pressure of TB treatment and appear likely to have been initially infected with a resistant strain.3,4 When drug-resistant TB develops, delays in diagnosis and initiation of appropriate treatment exacerbate an already terrible situation by amplification of resistance, ongoing transmission of infection in the community (and health institutions), and rapid progression of disease to death. The article by Kvasnovsky et al1 highlights several important challenges in responding to drug-resistant TB. First, the prognosis of patients with XDR is extremely poor, irrespective of HIV serostatus; one quarter of the XDR TB patients reported in this study died before they received any treatment for XDR, and many of these are likely to have been co-infected with HIV. HIV-seronegative patients comprised a large proportion (45%) of those who survived to receive XDR TB therapy, but over half had died within 2 years of diagnosis. HIV-infected patients treated for XDR TB who did not receive antiretroviral therapy (ART) had extremely poor survival, with only a third surviving to 1 year. As a comparison, Harries et al5 reported that 23% of patients with all forms of TB died during TB treatment in Malawi in 1997. Those fortunate enough to have been started on ART in the current study had a similar survival to HIV-seronegative XDR patients, but this should be viewed as “equally bad” rather than “equally good.” Two landmark trials comparing optimal timing of ART initiation in relation to TB therapy in HIV-infected adults have clearly shown that early initiation of ART reduces mortality—an effect apparent at both high and low CD4 counts.6,7 Differences in prognosis by HIV serostatus and ART reported here are similar to a larger retrospective report from 4 treatment centers in South Africa8 (which seems to include at least some of the patients in the Kvasnovsky article). The survival data reported here—particularly the pre-XDR treatment mortality rate—are better than those in the report which sounded the initial alarm of the potential threat of XDR to HIV-infected adults. Gandhi et al3 described short-term outcomes in patients diagnosed at a general hospital in the KwaZulu Natal, Province—neighboring the Eastern Cape Province—about 2 years before those in this article. The authors reported that 52 of 53 XDR patients in their study died, 70% within a month of the diagnostic specimen being taken and that all who were HIV tested were HIV seropositive. In both settings mortality is unacceptably high, underscoring the urgent need for new approaches to managing MDR and XDR TB. New drugs and new regimens of drug combinations are desperately needed to treat drug-resistant TB. The recent publication of a randomized trial of the novel ATP synthase inhibitor TMC207 in MDR TB patients was an important step forward.9 Testing of this and other novel TB agents should include both HIV-infected individuals and children if these products are to be used in these populations. Successful regimens for drug-resistant TB require a variety of drugs. They will likely include the following: new agents, such as TMC 207, OPC-67683,10 and PA-82411; repurposed drugs, such as respiratory fluoroquinolones; and optimized old drugs, including isoniazid and pyrazinamide. Although the world waits in eager anticipation of the novel agents, existing agents are not being optimally used or may be misused. For example, it is abundantly clear that moxifloxacin is a potent fluoroquinolone12—more so than ofloxacin13—but many programs continue to use ofloxacin because it is less expensive, contributing to treatment failure and the selection of fluoroquinolone-resistant organisms. In addition, there is reason to believe that high-dose isoniazid may be effective in treating organisms with mutations in the inhA gene,14 and this could improve and shorten regimens for MDR and XDR TB. Second, the authors highlight delays in diagnosis of XDR TB; patients in this retrospective cohort had a mean of 15.7 months of TB treatment before XDR diagnosis and cohort entry. Delays in the clinical triggers to suspect and investigate drug-resistant TB, which could be fatal, are compounded by the built-in tardiness of culture-based drug sensitivity testing for first and then second-line TB drugs. The line probe assay (Genotype MTBDRplus) which has been made available in several high through-put laboratories in South Africa offers some hope of overcoming lengthy delays in diagnosis of MDR TB and also rapidly confirms infection with M. tuberculosis.15 Unfortunately, its usefulness is restricted to smear-positive cases, thereby excluding most HIV-infected individuals with TB who are likely to be smear negative. The recently described Xpert MTB/RIF real-time polymerase chain reaction assay has enormous potential to identify both M. tuberculosis infection and genotypic rifampin resistance,16 but expense may limit widespread implementation. A further issue that complicates management of TB treatment is the possibility of re-infection with another M. tuberculosis strain during and after treatment, quite possibly in the clinics or hospitals where patients are receiving their MDR or XDR TB therapy. Although confining patients in sanatoria may prevent spread of resistant TB in the community, the risk of transmission is likely still present, not only between patients but also to health workers who seem to be at higher risk of being admitted to hospital with XDR TB than the populations they serve.17 Finally, reports such as the one in this issue, of programmatic outcomes, are bedeviled by their retrospective and incomplete nature and describe only a subset of patients who not only survive long delays before being diagnosed with MDR or XDR TB but then have to reach specialist public sector treatment programs which are often long distances from their homes. Highlighting this diagnostic gap is a postmortem biopsy study with mycobacterial culture and drug sensitivity testing conducted at a hospital in KwaZulu Natal that showed 17% of cadavers dying from “natural” causes were infected with MDR TB; only 1 was on MDR treatment before death.18 There is clearly a pressing need for much improved surveillance of all forms of TB in high-burden countries, including all diagnosed cases, deaths, and treated patients. Currently, only patients who enroll in directly observed therapy, short course programs are reported in many high-incidence countries, excluding mortality statistics to monitor and assess progress—or the lack thereof. Important public health and epidemiological lessons have been learnt from the XDR TB epidemic. However, research and control efforts must continue to address all forms of TB, including the approximately 93% of patients who do not have drug-resistant TB. Earlier identification of cases of TB by active case finding,19,20 together with rapid routine drug sensitivity testing, coupled with preventive treatment for those without evidence of active TB, efforts to improve treatment adherence, and implementation of infection control measures will reduce incidence of both drug-susceptible and drug-resistant TB. Retrospective studies such as this one provide a critical baseline from which progress can be measured, but prospective and complete epidemiologic surveillance, including molecular epidemiology, is crucially important to monitor, respond to and overcome the TB pandemic.

Towards Shorter, Child-Friendly Regimens for Treatment of Tuberculosis Disease and Infection in Children.

The objective: to evaluate main parameters of cellular, humoral immunity and natural resistance in tuberculosis patients with primary and acquired multiple drug resistance; to study the correlation of these parameters with clinical and radiological manifestations.Subjects and Methods. A prospective study was conducted which included 169 patients with pulmonary tuberculosis, 80 of them were new cases of drug susceptible pulmonary tuberculosis and they made the Comparison Group (CG), and 89 patients suffered from multiple drug resistant tuberculosis and they made the Main Group (MG). The Main Group was divided into 2 subgroups: MG-1 – 40 patients with primary multiple drug resistant tuberculosis; MG-2 ‒ 49 patients who acquired drug resistance of Mycobacterium tuberculosis during treatment of tuberculosis.The immune assays included the lymphocyte blast transformation reaction (LBTR) to phytohemagglutinin and tuberculin (PPD), immunophenotyping of CD3+ and CD19+ cells; phagocytic index and phagocytic number were calculated; nitro blue tetrazolium test was used, concentrations of immunoglobulins and antimycobacterial antibodies were determined.Results. The clinical laboratory data demonstrated a more severe course of the disease in patients with multiple drug resistant tuberculosis, especially in those with acquired multiple drug resistant tuberculosis which was confirmed by the severity of immune deficiencies of the cellular immunity and innate resistance as well as by the overactivity of humoral immunity. The levels of CD3+ and LBTR reaction to PPD had a negative correlation with clinical manifestations and radiological features demonstrating the severity of pulmonary tuberculosis in patients with multiple drug resistance, especially in those with acquired multiple drug resistance; and CD19+ and antimycobacterial antibodies positively correlated with clinical manifestations and radiological signs.Conclusions. Parameters of cellular immunity and natural resistance were the lowest in the patients with acquired multiple drug resistance of Mycobacterium tuberculosis versus primary multiple drug resistance and drug susceptible Mycobacterium tuberculosis. Parameters of humoral immunity demonstrated the increased activity to compensate for the insufficiency of cellular immunity regardless of the type of resistance of Mycobacterium tuberculosis.

The emergence of antimicrobial resistance (AMR) across bacterial pathogens presents a serious threat to global health. This threat is further exacerbated in tuberculosis (TB), mainly due to a protracted treatment regimen involving a combination of drugs. A diversity of factors contributes to the emergence of drug resistance in TB, which is caused by the pathogen Mycobacterium tuberculosis (Mtb). While the traditional genetic mutation-driven drug resistance mechanisms operate in Mtb, there are also several additional unique features of drug resistance in this pathogen. Research in the past decade has enriched our understanding of such unconventional factors as efflux pumps, bacterial heterogeneity, metabolic states, and host microenvironment. Given that the discovery of new antibiotics is outpaced by the emergence of drug resistance patterns displayed by the pathogen, newer strategies for combating drug resistance are desperately needed. In the context of TB, such approaches include targeting the efflux capability of the pathogen, modulating the host environment to prevent bacterial drug tolerance, and activating the host anti-mycobacterial pathways. In this review, we discuss the traditional mechanisms of drug resistance in Mtb, newer understandings and the shaping of a set of unconventional approaches to target both the emergence and treatment of drug resistance in TB.

Tuberculosis (TB) is an airborne infectious disease that causes millions of deaths worldwide each year (1.2 million people died in 2019). Alarmingly, several strains of the causative agent, Mycobacterium tuberculosis (MTB)—including drug-susceptible (DS) and drug-resistant (DR) variants—already circulate throughout most developing and developed countries, particularly in Bangladesh, with totally drug-resistant strains starting to emerge. In this study we develop a two-strain DS and DR TB transmission model and perform an analysis of the system properties and solutions. Both analytical and numerical results show that the prevalence of drug-resistant infection increases with an increasing drug use through amplification. Both analytic results and numerical simulations suggest that if the basic reproduction numbers of both DS ({text{R}}_{{0{text{s}}}}) and DR ({text{R}}_{{0{text{r}}}}) TB are less than one, i.e. max left[ {{text{R}}_{{0{text{s}}}} ,{text{ R}}_{{0{text{r}}}} } right] < 1, the disease-free equilibrium is asymptotically stable, meaning that the disease naturally dies out. Furthermore, if {text{R}}_{{0{text{r}}}} > {text{max}}left[ {{text{R}}_{{0{text{s}}}} ,1} right], then DS TB dies out but DR TB persists in the population, and if {text{R}}_{{0{text{s}}}} > {text{max}}left[ {{text{R}}_{{0{text{r}}}} ,1} right] both DS TB and DR TB persist in the population. Further, sensitivity analysis of the model parameters found that the transmission rate of both strains had the greatest influence on DS and DR TB prevalence. We also investigated the effect of treatment rates and amplification on both DS and DR TB prevalence; results indicate that inadequate or inappropriate treatment makes co-existence more likely and increases the relative abundance of DR TB infections.

Drug resistant tuberculosis (TB), especially multidrug (MDR) and extensively drug-resistant (XDR) TB, is still a serious problem in global TB control. Slovenia and North Macedonia are low-incidence countries with TB incidence rates of 5.4 and 10.4 in 2017, respectively. In both countries, the percentage of drug resistant TB is very low with sporadic cases of MDR-TB. However, global burden of drug-resistant TB continues to increase imposing huge impact on public health systems and strongly stimulating the detection of gene variants related with drug resistance in TB. Next-generation sequencing (NGS) can provide comprehensive analysis of gene variants linked to drug resistance in Mycobacterium tuberculosis. Therefore, the aim of our study was to examine the feasibility of a full-length gene analysis for the drug resistance related genes (inhA, katG, rpoB, embB) using Ion Torrent technology and to compare the NGS results with those obtained from conventional phenotypic drug susceptibility testing (DST) in TB isolates. Between 1996 and 2017, we retrospectively selected 56 TB strains from our National mycobacterial culture collection. Of those, 33 TB isolates from Slovenian patients were isolated from various clinical samples and subjected to phenotypic DST testing in Laboratory for Mycobacteria (University Clinic Golnik, Slovenia). The remaining 23 TB isolates were isolated from Macedonian patients and sent to our laboratory for assistance in phenotypic DST testing. TB strains included were either mono-, poly- or multidrug resistant. For control purposes, we also randomly selected five TB strains susceptible to first-line anti-TB drugs. High concordance between genetic (Ion Torrent technology) and standard phenotypic DST testing for isoniazid, rifampicin and ethambutol was observed, with percent of agreement of 77%, 93.4% and 93.3%, sensitivities of 68.2%, 100% and 100%, and specificities of 100%, 80% and 88.2%, respectively. In conclusion, the genotypic DST using Ion Torrent semiconductor NGS successfully predicted drug resistance with significant shortening of time needed to obtain the resistance profiles from several weeks to just a few days.

We characterized the spatial distribution of drug-susceptible (DS) and multidrug-resistant (MDR) tuberculosis (TB) cases in Ho Chi Minh City, Vietnam, a major metropolis in southeastern Asia, and explored demographic and socioeconomic factors associated with local TB burden. Hot spots of DS and MDR TB incidence were observed in the central parts of Ho Chi Minh City, and substantial heterogeneity was observed across wards. Positive spatial autocorrelation was observed for both DS TB and MDR TB. Ward-level TB incidence was associated with HIV prevalence and the male proportion of the population. No ward-level demographic and socioeconomic indicators were associated with MDR TB case count relative to total TB case count. Our findings might inform spatially targeted TB control strategies and provide insights for generating hypotheses about the nature of the relationship between DS and MDR TB in Ho Chi Minh City and the wider southeastern region of Asia.

To study the cross-resistance between rifampin and rifabutin in multidrug resistant Mycobacterium tuberculosis complex strains, and therefore to provide laboratory data for using rifabutin in the treatment of multidrug resistant tuberculosis. The MIC(90) of rifabutin and rifampin against 99 multidrug resistant Mycobacterium tuberculosis clinical strains were determined by microplate assays. Statistical analysis was performed by using the χ(2) test and the t test. The cross-resistance rate between rifampicin and rifabutin was 85.9% (85/99), but the MIC(90) of rifabutin (≤ 16 mg/L, median 2 mg/L) was significantly lower than that of rifampicin (≥ 2 mg/L, median > 32 mg/L). The cross-resistance rate increased with the resistance level of rifampicin. The cross-resistance strains in the lower and the medium groups were 0/9 and 5/9 respectively, while the strains of the high rifampicin-resistant group were almost all cross-resistant (98.8%, 80/81). Rifabutin had activities against rifampin resistant Mycobacterium tuberculosis complex strains in vitro, and therefore may be used as an alternative for the treatment of multidrug resistant tuberculosis.