Особливості цитокінової регуляції при мультирезистентному туберкульозі залежно від ступеня ендогенної інтоксикації

Optimising medication adherence is one of the essential factors in reversing the tide of a TB-HIV syndemic in sub-Saharan Africa, especially South Africa. Impairment in key neurocognitive domains may impair patients' ability to maintain adherence to treatment, but the level of cognition and its relationship to HIV status has not been examined in individuals with drug-resistant TB. We therefore investigated performance on several key neurocognitive domains in relationship to HIV status in a multidrug-resistant tuberculosis patients (MDR-TB) sample. We enrolled microbiologically confirmed MDR-TB inpatients at a TB-specialist referral hospital in KwaZulu-Natal province, South Africa. We collected cross-sectional data on sociodemographic, clinical and neurocognitive function (e.g. attention, memory, executive functioning, language fluency, visual-spatial, eye-hand coordination). For the primary analysis, we excluded participants with major depressive episode/substance use disorder (MDE/SUD). We fitted adjusted Poisson regression models to explore the association between HIV and neurocognitive function. We enrolled 200 people with MDR-TB; 33 had MDE/SUD, and data of 167 were analysed (151 HIV+, 16 HIV-). The mean age of participants was 34.2years; the majority were female (83%), and 53% had not completed secondary school. There was evidence of impaired neurocognitive functioning across all domains in both HIV+/- study participants. Based on the regression analyses, individuals with co-infection (MDR-TB/HIV+), as well as those who had longer duration of hospital stays experienced significantly lower cognitive performance in several domains. Poor cognitive performance was significantly related to older age and lower educational attainment. The presence of major depression or substance use disorders did not influence the significance of the findings. Adults with MDR-TB have significant neurocognitive impairment, especially if HIV positive. An integrated approach is necessary in the management of MDR-TB as cognitive health influences the ability to adhere to chronic treatment, clinical outcomes and functionality.

Nigeria is one of the countries with a high burden of tuberculosis (TB) in the world. TB associated inflammation is reported to be central to progression from latent TB to active TB or drug sensitive TB (DSTB) to drug resistant TB (DRTB). Inflammatory cytokines, especially interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), act synergistically in the control of TB infection. They activate macrophages to produce effector molecules such as inducible nitric oxide synthase (iNOS), nitric oxide, and ultimately 3-nitrotyrosines(3-NTs), which are involved in the control of TB. This study investigated the potential involvement of TNF-α, IFN-γ, iNOS, and 3-NT in differentiating DRTB and DSTB in Ibadan, Nigeria. One hundred participants above 18 years were recruited into this study and were grouped as follows: 32 DRTB, 34 DSTB, and 34 apparently healthy controls. Plasma from the patients was used for the analyses of inflammatory (TNF α and IFN-γ) and oxidative stress (iNOS and 3-NT) biomarkers using the ELISA. Mann-Whitney test was applied for the statistical test. Mean levels of plasma TNF-α, IFN-γ, iNOS, and 3-NT were higher in DRTB (19.74 ± 3.62 pg/mL, 4.41 ± 0.96 pg/mL, 1791.07 ± 419.42 pg/mL, and 20.27 ± 1.80 ng/mL, respectively) and DSTB (17.02 ± 1.84 pg/mL, 5.59 ± 1.40 pg/mL, 2823.42 ± 685.32 pg/mL, and 25.06 ± 2.15 ng/mL, respectively) compared with controls (12.18 ± 0.92 pg/mL, 1.58 ± 0.21 pg/mL, 1275.86 ± 166.12 pg/mL, and 19.98 ± 1.23 ng/mL, respectively). In addition, higher plasma levels of IFN-γ (P > 0.05), iNOS (P > 0.05), and 3-NT (P < 0.05) were observed in DSTB compared with DRTB patients. The 3-NT may be used as differentiating markers of DSTB from DRTB.

To improve the effectiveness of case detection and treatment of multi-drug resistant tuberculosis (MDR-TB) by implementing a mechanism of cooperation between hospitals and centers for disease control (CDC). Since 1 March 2010, a new mechanism of cooperation between hospitals and CDCs had been established in 5 cities including Daqing, Quzhou, Puyang, Tianjin and Wanzhou in China. Data of MDR-TB case-detection, treatment and economic burdens before the intervention (January 1, 2006-June 30, 2009) and after the intervention (March 1, 2010-February 29, 2012) were collected. Then all data were analyzed by statistical method. After the intervention, samples from 68.4% (5 287/7 733) of smear-positive TB patients in the study regions underwent TB drug-resistant testing, and the number of the detected MDR-TB cases were 9.8 times that prior to the intervention. 93.1% (108/116) of the patients incorporated into the treatment of MDR-TB received the standardized initial chemotherapy program, and the number was 7 times that before the intervention. The referral rates after hospital discharge raised from 0% before the intervention to 92.8% after (90/97) the intervention; and 85.7% (83/97) of the patients received treatment and management by CDC. When the 6-month injection ended, MDR-TB patients still under treatment after the intervention were 84.5% (82/97), and those whose sputum culture became negative were 56.7% (55/97). The proportion of patients with self-paid and with catastrophic expenditures after the intervention were reduced to 18.0% (1 678/9 324) and 44.7% (17/38) respectively, as compared to 75.4% (7 659/10 158) and 76.7% (23/30) respectively before the intervention. To establish a well-performed Hospital-CDC cooperation mechanism could promote the performance of MDR-TB case detection and treatment.

Tuberculosis (TB) has been and is still an important public health issue in China. According to the most recent report from the World Health Organization, China had an estimation of 1.4 million existing TB and 1 million incident TB in 2011 [1]. Among the new cases, approximately 1.2% combined the existing HIV infection [1]. Since TB is directly related to people’s health status and work capability, therefore, the control of TB prevalence has been of priority both in the public health and in the economic development of China. The progress in controlling TB in China is, however, currently influenced by the following two major factors. First, the migration and health system compounds the prevention from TB. It is known that eighty percent of TB exists in rural areas, particularly in north and northwestern regions with low socioeconomic status in China. In the past three decades, there has been an increasing number of people from these areas that immigrated to the large urban cities; and they could potentially result in the spread of the disease in cities if they were TB-carriers. The urban living style and working conditions promote the transmission of TB in the big cities via crowded conditions and airborne pollution. However, the subsidized management of TB is only available through facilities in the birth place of immigrants and it is sometimes difficult for them to get screened, diagnosed and treated in the big cities. Also, multidrug resistant (MDR) TB has been another pressing public health issue in China. MDR TBs are spread from individual to individual in the same manner as regular TB, but are usually resistant to at least isoniazid and rifampicin, the two most powerful first-line anti-TB medications. Since most TB therapy consists of short-course chemotherapy, the treatment could only cure a small proportion of MDR TBs and the treatment using second-line TB medications is usually very expensive. Therefore, MDR TBs have brought about difficulty in the treatment, especially in developing countries such as China. With an increasing number of patients not being treated, TB would be problematic, and the epidemic of TB would be revived. In 2013, the prevalence of MDR TB in mainland China was 5.3% to 27.4% [2]. Despite these challenges, Chinese government has successfully addressed TB problem in the past few decades, and has great contribution to global TB prevention. Also, Centers for Disease Control in China together with other institutes conducts many preventive interventions of TB funded by The Global Fund to Fight AIDS, Tuberculosis, and Malaria program initiated by the World Health Organization. Chinese health professionals believe that they could fulfill the world-wide goal towards elimination of tuberculosis by 2050 [3].

Introduction. Mycobacterium tuberculosis (MTB) is continually evolving in order to resist treatment. This has resulted in drug-resistant tuberculosis, which has a greater rate of therapy failure and mortality, as well as the necessity for other ways of disease transmission prevention. Pre-extensively drug-resistant tuberculosis (Pre-XDR TB) is caused by MTB strains that are resistant to isoniazid, rifampicin, and any fluoroquinolone medicines. Case Report. A 19-year-old HIV-negative immunocompetent female presented to our emergency department with dyspnea and severe headache. She also complained of a cough, a low-grade temperature, and weight loss. She has no relevant medical history and has never been exposed to tuberculosis. A chest X-ray revealed infiltrates with cavities and fibrosis in both lungs, while a brain CT suggested meningoencephalitis. We performed a sputum drug sensitivity test and discovered that this patient was resistant to rifampin, isoniazid, levofloxacin, and moxifloxacin. She was later diagnosed with Pre-XDR TB and was given a tailored lengthier regimen that included Bedaquiline, Cycloserin, Linezolide, Clofazimine, and Etambutol. Her symptoms improved significantly as a result of this program. Discussion. Primary pre-XDR TB in an immunocompetent patient is uncommon, and our case is even more unusual due to meningoencephalitis involvement. The treatment of pre-XDR TB requires a personalized regimen that is tailored to the patient's clinical status and comorbidities. The possibility of transmission via a positive contact was raised in this patient, prompting us to conduct a more thorough contact inquiry to prevent future spread. Conclusion. In our region, there is a risk of'silent' drug resistant tuberculosis. Early detection and treatment of such patients are critical to preventing uncontrollable pan-resistant TB. Successful management with cautious contact investigation will minimize the mortality rate and spread rate of drug-resistant TB. Keywords. Drug-Resistant Lung Tuberculosis, Drug-Resistant Meningoencephalitis Tuberculosis

World TB Day, March 24, 2000 – Forging new partnerships to stop TB

Introduction: RNTCP estimates MDR in India as 2-3% in new and 12-17% in treated cases. Mumbai is a hot spot for TB drug resistance in India. A prior study evaluating MDR patients revealed 29.4% MDR, 56.8% pre XDR, 10.6% XDR and 5.6% XXDR in Mumbai. Aims & objectives: To evaluate the patterns of drug resistance in TB patients following up at our hospital. Methods: A retrospective observational study of drug susceptibility testing (DST) results on positive TB MGIT cultures of 53 TB patients from January 2015 to December 2015) was conducted. Patients were classified into 5 categories based on the DST results as drug sensitive TB, MDR TB, pre XDR TB, XDR TB & XXDR TB. Results: 43 patients (81.13%) had pulmonary and 10 patients (18.87%) had extra-pulmonary TB. Of the 43 pulmonary cases, 18(41.86%) had drug sensitive TB and 25(58.13%) had drug resistant TB. In drug resistant pulmonary cases, pre XDR TB was found in 15(60%), MDR TB in 6(24%), XXDR TB in 2(8%), XDR TB in 1(4%) and INH mono resistance in 1(4%). Amongst 10 extra-pulmonary TB cases, 4(40%) had drug sensitive TB and 6(60%) had drug resistant TB of which pre XDR TB was found in 4(66.66%), XXDR in 1(16.66%) and INH mono resistance in 1(16.66%). Overall incidence of pre-XDR TB was 61.9% (19 Patients). Conclusion: Incidence of pre XDR TB is on the rise among drug resistant pulmonary and extra-pulmonary TB patients in Mumbai. This necessitates the need for complete drug susceptibility testing and not relying solely on molecular techniques that will identify MDR only. Individualized drug regimens for these patients based on DST will help in curtailing transmission of resistant strains within the community.

Tuberculosis (TB) remains a global emergency and continues to kill 1.7 million people globally each year. Drug-resistant TB is now well established throughout the world and most TB patients are not being screened for drug resistance due to lack of laboratory resources and rapid accurate point-of-care tests. Accurate and rapid diagnosis of TB and drug-resistant TB is of paramount importance in establishing appropriate clinical management and infection control measures. During the past decade, there have been significant advances in diagnostic technologies for TB and drug-resistant TB. The purpose of this article is to review the current data, recommendations and evidence base for these tests. Second-line drug susceptibility testing (DST) is complex and expensive. Automated liquid culture systems and molecular line probe assays are recommended by the WHO as the current 'gold standard' for first-line DST. Liquid culture DST for aminoglycosides, polypeptides and fluoroquinolones has been shown to have relatively good reliability and reproducibility for diagnosis of extensively drug-resistant TB; however, DST for other second-line drugs (ethionamide, prothionamide, cycloserine, terizidone, para-aminosalicylic acid, clofazimine, amoxicillin-clavulanate, clarithromycin, linezolid) is not recommended. Automated liquid culture systems are currently recommended by the WHO as the 'gold standard' for second-line DST. In this review, we describe the phenotypic and genotypic methods currently available for the diagnosis of TB and drug-resistant forms of Mycobacterium tuberculosis and discuss future prospects for TB diagnostics. Current technologies for the detection of drug resistant M. tuberculosis vary greatly in terms of turnaround time, cost and complexity. Ultimately, the 'holy grail' diagnostic for TB must fulfil all technical specifications for a good point-of-care test, screen for drug resistance concurrently and be adaptable to the various health system levels and to countries with diverse economic status and TB burden.

Tuberculosis (TB) continues to be a public health problem globally. The burden is further exacerbated in developing countries like Nigeria, by poor diagnosis, management and treatment, as well as rapid emergence of drug-resistant TB. This study was conducted to evaluate the prevalence of drug-resistant TB, determine the rpoB gene mutation patterns of Mycobacterium tuberculosis (MTB) and model the dynamics of multidrug resistant TB (MDR-TB) in Enugu, Nigeria. A total of 868 samples, from patients accessing DOTS services in designated centres within the zone, were screened by sputum-smear microscopy, while 207 samples were screened by Nucleic Acid Amplification (Xpert® MTB/Rif) Test (NAAT). A deterministic model was formulated to study the transmission dynamics of TB and MDR-TB, using live data generated through epidemiological study. The results showed TB prevalence values of 22.1% and 21.3% by sputum-smear and NAAT assays, respectively. Analysis of the rifampicin resistance patterns showed the highest occurrence of mutations (50%) along codons 523 - 527. Factors such as combination therapy, multiple therapy and compliance to treatment had influence on both prevalence and development of TB drug resistance in the population. This first documentation of Rifampicin resistance patterns in MTB from Nigeria shows that a majority of rpoB gene mutations occurred along codons 523 to 527, contrary to the widely reported codon 531 mutation and that multiple interventions such as combination therapy, with good compliance to treatment are needed to reduce both prevalence and development of TB drug resistance in the population.

SUMMARY The prison setting has been often cited as a possible reservoir of tuberculosis (TB) including multidrug-resistant (MDR)-TB. This is particularly true in low-income, high TB prevalence countries in Sub-Saharan Africa. A systemic literature review was done to assess the prevalence, drug resistance and risk factors for acquiring TB in the prison population. Our review indicated a high prevalence of TB in prisons which is reported to be 3- to 1000-fold higher than that found in the civilian population, indicating evidence and the need for public health policy formulation. In addition, high levels of MDR and extensively drug-resistant (XDR)-TB have been reported from prisons, which is a warning call to review prison TB control strategy. Multiple risk factors such as overcrowding, poor ventilation, malnutrition, human immunodeficiency virus (HIV), and others have fuelled the spread of TB in prisons. Furthermore, the impact extends beyond the prison walls; it affects the civilian population, because family visits, prison staff, and members of the judiciary system could be potential portals of exit for TB transmission. The health of prisoners is a neglected political and scientific issue. Within these background conditions, it is suggested that political leaders and scientific communities should work together and give special attention to the control of TB and MDR-TB in prisons. If not, TB in prisons will remain a neglected global problem and threatens national and international TB control programmes. Further researches are required on the prevalence and drug resistance of smear-negative TB in prisons. In addition, evidence of the circulating strains and transmission dynamics inside prisons is also warranted.

Objective To investigate the impact of isoniazid (INH)-resistant Mycobacterium tuberculosis (Mtb) on the prevalence and dissemination of multi-drug resistant tuberculosis (MDR-TB). Methods A total of 251 patients diagnosed with tuberculosis in designated hospitals of Guanyun, Jiangsu and Deqing, Zhejiang from 2010 to 2011 were included in the study. The drug susceptibility tests (DST) were performed on all the Mtb isolates available from the sputum cultures. Mycobacteral interspersed repetitive units-variable number tandem repeats (MIRU-VNTR) was conducted for genotyping for all available Mtb isolates. Chi-square test, Fisher exact test, ANOVA and non-conditional Logistic regression modelling were applied for data analysis. Results Among 251 patients with Mtb isolates and DST results available, 72(28.7%) were resistant to INH, including 13 were INH mono-drug resistant. Of the remaining 59 INH-resistant Mtb, 34(13.5%) were resistant to rifampin TB and 25 were resistant to streptomycin and/or ethambutol. The clustering analysis based on MIRU-VNTR genotyping revealed 29 clustered genotypes (including 105 isolates) and 146 unique genotypes (including 119 isolates). Twenty-five clusters contained drug resistant Mtb and 16 clusters of them comprised by 37 INH-resistant isolates and 20 MDR-TB isolates, which accounted for 51.4% of the INH-resistant isolates and 58.8% of the MDR-TB isolates. Single factor analysis showed that sex, age, previous tuberculosis treatment history and sputum smear results were all related to INH-resistant tuberculosis and MDR-TB (all P<0.05). Multiple factors analysis showed that previous tuberculosis treatment history was risk factor of MDR-TB (OR=8.40, 95%CI: 3.342-21.105), while the risk factors of INH-resistant tuberculosis were previous tuberculosis treatment history (OR=3.52, 95%CI: 1.570-7.910), pulmonary caviry (OR=2.27, 95%CI: 1.075-4.799) and sputum smear results (OR=0.50, 95%CI: 0.275-0.892). Conclusions That INH-resistant strain may evolve to the MDR-TB after recent transmission is a possible trend. Patients with previous treatment history and advanced age are at high risk of INH-resistant tuberculosis and MDR-TB. Key words: Mycobacterium tuberculosis; Isoniazid; Tuberculosis, multidrug-resistant

The number of children globally who develop drug-resistant tuberculosis is unclear, in part due to diagnostic challenges and limited resistance testing, and in part because recording and reporting is not comprehensive. Large numbers of children, however, are exposed to drug resistant bacilli each year and it is clear that the very young and those immune-compromised are vulnerable to developing disease. Few studies have looked at the progression from exposure to infection or from infection to disease in the child contacts of adults with drug-resistant tuberculosis. It is uncertain which factors influence this progression and also whether any interventions can prevent it. Finally, few studies have analysed the presentation, treatment and outcome of children with disease. This thesis starts by reviewing what is published regarding drug-resistant tuberculosis in children. This includes systematic reviews of the management of children exposed to drug resistant tuberculosis as well as the management of those with multi drug-resistant tuberculosis disease. It reviews what is known regarding the second-line tuberculosis drugs in children and then clarifies the definitions that are used throughout the rest of the work. The thesis then systematically examines each of the stages from infection to disease with a series of inter-related studies. The first study attempts to quantify the burden of drug resistance in the context that the work is carried out. The following study investigates the risk factors for infection and prevalent disease in children exposed to a multi drug-resistant tuberculosis source case. This is followed by two studies which explore the transmission of drug-resistant bacilli from adults to children. The identification and referral patterns and obstacles to referral for exposed children are examined through operational studies that include qualitative and quantitative components. A descriptive cohort study assesses the toxicity and efficacy of a standardised preventive treatment regimen given to child contacts. The final part of the thesis includes a series of studies to investigate the treatment of drug resistant tuberculosis disease in children and the adverse effects of the second-line medications.

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.

Emergence of additional drug resistance during treatment of multidrug-resistant tuberculosis in China: a prospective cohort study

Multidrug-resistant tuberculosis in children: Are the same therapy options available worldwide?