Antituberculosis Therapy Research Articles

BIOLOGICAL MODEL OF LUNG CANCER COMBINATION AND TUBERCULOSIS: DEVELOPMENT FOR PRECLINICAL STUDY OF RATIONAL COMBINATIONS OF TARGETED ANTITUMOR AND ANTITUBERCULOSIS THERAPY

Introduction. Lung cancer occupies a leading position in the structure of mortality from cancer. Chronic inflammation characteristic of tuberculosis increases the risk of lung cancer. Currently, more and more information is emerging confirming the cause-and-effect relationship between tuberculosis and cancer. The need to develop recommendations for public health regarding screening and treatment of tuberculosis in the tumor process determines the relevance of experimental studies on biological models of the combination of cancer and tuberculosis.. Aim. Creation а biological model of the combination of lung cancer and tuberculosis for preclinical study of rational combinations of antitumor and antituberculosis therapy. Material and methods: The biological model was implemented on C57BL/6 mice at the age of two months. Lewis epidermoid lung carcinoma was used to reproduce the tumor process. Modeling of tuberculosis was carried out using the reference strain Mycobacterium Tuberculosis H37RV. During the study, the following groups were formed: “intact mice” (healthy, uninfected with the Mycobacterium Tuberculosis (MBT) H37Rv strain without tumor cell transplantation); “control of MBT infection” (animals infected with Mycobacterium Tuberculosis strain H37Rv), “tumor control” (animals that were transplanted with epidermoid Lewis lung carcinoma) and “main group” (animals that were transplanted with epidermoid Lewis lung carcinoma simultaneously with MBT infection). Results. During the experiment, several models for creating the combined pathology of lung cancer and tuberculosis were identified. In the first (simultaneous infection and tumor inoculation), carcinoma developed more slowly in infected animals than in the tumor control group, and lung damage occurred with a predominance of the tuberculous process over the tumor process. The second (staged infection) also showed minimal metastatic manifestations with pronounced secondary changes in the primary tumor node. Analysis of the choice of model showed that the model with simultaneous infection and tumor inoculation most adequately ensures the development of the tumor process and tuberculosis infection, which allows maintaining the viability of the animal, fully developing the tumor process with metastasis to the lungs and obtaining the development of morphologically verified pulmonary tuberculosis.

Tuberculosis miliar en paciente inmunocompetente: Reporte de caso

Milar Tuberculosis (TB) is a presentation with a fatal outcome if it is not diagnosed or treated on time; although certain conditions are required to develop this presentation. In this In this article, the case of a 48-year-old man with no pathological history is studied, who started the disease with a time of six months with an initial diffuse gastrointestinal pain and later one month before admission presented progressive respiratory symptoms; he was admitted for emergencies where bilateral diffuse miliary compromise was evident in the chest computed tomography; upon admission, he was administered oxygen and support measures, an HIV test was obtained which was negative, and positive results were obtained in the sputum smear microscopy. His clinical evolution was stationary until the administration of antituberculosis therapy, observing slight clinical improvement, likewise, low doses of corticosteroids were administered after which a favorable evolution was demonstrated and he was discharged.

The Unusual Adverse Effects of Antituberculosis Therapy in Kidney Patients.

Chronic kidney disease (CKD) patients are at a high risk of tuberculosis (TB), with a relative risk of developing active TB of 10%-25%. Similarly, glomerular disease increases the risk of TB due to diminished glomerular filtration rate, proteinuria, and immunosuppression use. Further, the first-line anti-TB drugs are associated with acute kidney injury (AKI) even in patients with normal kidney functions. We retrospectively identified 10 patients hospitalized with unusual adverse effects of antituberculosis therapy (ATT) from 2013 to 2022. We found three cases of AKI caused by rifampicin: acute interstitial nephritis, crescentic glomerulonephritis, and heme pigment-induced acute tubular necrosis. We observed rifampicin-induced accelerated hypertension and thrombocytopenia in two patients on maintenance hemodialysis. Isoniazid caused pancreatitis and cerebellitis in two CKD patients, respectively. In a CKD patient, we detected acute gout secondary to pyrazinamide-induced reduced uric acid excretion. We also observed cases of drug rash with eosinophilia and systemic symptoms and hypercalcemia due to immune reconstitution inflammatory syndrome in patients with glomerular disease on ATT. Immediate discontinuation of the offending drug, along with specific and supportive management, led to a recovery in all cases. The adverse effects of ATT may be unusually severe and varied in kidney patients due to decreased renal elimination. Early recognition of these adverse effects and timely discontinuation of the offending drug is essential to limit morbidity and mortality.

Fucoidan coated liposomes loaded with novel antituberculosis agent: preparation, evaluation, and cytotoxicity study

In this article, we described a novel antituberculosis imidazotetrazine derivative designed in fucoidan-coated liposomes to reduce its cytotoxicity and investigate its mucoadhesive properties. Firstly, fucoidan extracted from Ascophyllum nodosum was used for additional stabilization of liposomal suspensions and to give it mucoadhesive properties. PEG-600 and/or Tween-80 were used to increase the shelf life of liposomal suspension. The ratio of the fucoidan: lipids 1:2 was found to be the optimum that produces stable fucoidan-coated liposomes. The particle size of the optimum formulation was 336.3 ± 5.4, the PDI was 0.33, and the zeta potential was −39.6. This size and the practical spherical shape of the particles were confirmed by atomic force microscopy. In addition, the in vitro release profiles from uncoated and fucoidan-coated liposomes revealed significant and faster release compared to free antituberculosis agent. Using the MTT assay test, the fucoidan-coated liposomes exhibited fourteen times lower cytotoxicity (IC50 7.14 ± 0.91 µg/ml) than the free drug (IC50 0.49 ± 0.06). Moreover, the mucoadhesive capabilities of these liposomal formulations were also confirmed using snail mucin, which highlighting their potential use as an effective delivery system for antituberculosis therapy, with notable improvements in dissolution rate and reduced cytotoxicity.

Perspectives on Determinants of Poor Adherence to Anti-Tuberculosis Drugs amongst Patients Attending a Tuberculosis Treatment Center in South East, Nigeria

Background of the study: Tuberculosis is curable and preventable as long as the infected patients take their medication as prescribed without interruption and all preventive measures observed both within the hospital and the community. Adherence to tuberculosis treatment by tuberculosis patients is key to the global control of tuberculosis. Methods: This cross sectional study was carried out at the Mile-4 hospital, a tuberculosis treatment center in Abakaliki, Ebonyi State, Nigeria. A total of 125 tuberculosis patients were recruited for the study and self-administered questionnaires and focus group discussions were used to get responses from the patients. Descriptive and inferential statistics with the aid of SPSS version 20 was used for data analysis. Results: Major reasons given for missing appointment and not following treatment schedule closely were lack of money, long distance from health facility, inadequate health education and non provision of food. Lack of money and long distance from health facility accounted for 60.9% of the reasons for not adhering to the treatment schedule by the tuberculosis patients. Conclusion: Adherence to tuberculosis treatment can be facilitated by extensive health education, minimal financial support and provision of food to tuberculosis patients. Distance from health facilities is also very important in the adherence to anti tuberculosis therapy by tuberculosis patients.

TOLLIP inhibits lipid accumulation and the integrated stress response in alveolar macrophages to control Mycobacterium tuberculosis infection.

A polymorphism causing deficiencies in Toll-interacting protein (TOLLIP), an inhibitory adaptor protein affecting endosomal trafficking, is associated with increased tuberculosis (TB) risk. It is, however, unclear how TOLLIP affects TB pathogenesis. Here we show that TB severity is increased in Tollip-/- mice, characterized by macrophage- and T cell-driven inflammation, foam cell formation and lipid accumulation. Tollip-/- alveolar macrophages (AM) specifically accumulated lipid and underwent necrosis. Transcriptional and protein analyses of Mycobacterium tuberculosis (Mtb)-infected, Tollip-/- AM revealed increased EIF2 signalling and downstream upregulation of the integrated stress response (ISR). These phenotypes were linked, as incubation of the Mtb lipid mycolic acid with Mtb-infected Tollip-/- AM activated the ISR and increased Mtb replication. Correspondingly, the ISR inhibitor, ISRIB, reduced Mtb numbers in AM and improved Mtb control, overcoming the inflammatory phenotype. In conclusion, targeting the ISR offers a promising target for host-directed anti-TB therapy towards improved Mtb control and reduced immunopathology.

Successful resolution of mesenteric tuberculosis and HIV co-infection following 6 months of anti-tuberculosis therapy: a case report

BACKGROUND: Mesenteric tuberculosis (TB), a rare extrapulmonary variant of TB, poses diagnostic and therapeutic challenges in its management. Therefore, discussing a case of mesenteric TB is both intriguing and informative for gaining insights into its clinical presentation and optimal treatment strategies. CASE PRESENTATION: A 50-year-old male presented symptoms of blackish stools three days post-gallstone surgery, accompanied by approximately two months of abdominal discomfort, described as squeezing or stabbing, alleviated temporarily by analgesics, alongside abdominal distension, rigidity, decreased appetite, and afternoon fevers. Physical examination revealed normal vital signs, with pale conjunctiva and asymmetrical chest wall movement, dull percussion, and decreased breath sounds in the lower left hemithorax. Abdominal inspection indicated distension, postsurgical signs, and ascites. Following laboratory investigations, chest and abdominal radiographs, and tissue biopsies, the patient was diagnosed with HIV co-infection along with pulmonary and mesenteric TB. Treatment comprised an intensive phase of four fixed-dose combinations (FDC) of anti-TB drugs, followed by a continuation phase of two FDC tablets, alongside first-line antiretroviral (ARV) therapy and cotrimoxazole prophylaxis. By the sixth month follow-up, clinical improvement was observed, with resolution of symptoms and weight gain to 56 kg. CONCLUSION: This case highlights the effective management of mesenteric TB and HIV co-infection, emphasizing the importance of comprehensive care and collaborative efforts between TB and HIV/AIDS control programs.

IL-10 and TGF-β1 may weaken the efficacy of preoperative anti-tuberculosis therapy in older patients with spinal tuberculosis.

Spinal tuberculosis is a common extrapulmonary type that is often secondary to pulmonary or systemic infections. Mycobacterium tuberculosis infection often leads to the balance of immune control and bacterial persistence. In this study, 64 patients were enrolled and the clinicopathological and immunological characteristics of different age groups were analyzed. Anatomically, spinal tuberculosis in each group mostly occurred in the thoracic and lumbar vertebrae. Imaging before preoperative anti-tuberculosis therapy showed that the proportion of abscesses in the older group was significantly lower than that in the younger and middle-aged groups. However, pathological examination of surgical specimens showed that the proportion of abscesses in the older group was significantly higher than that in the other groups, and there was no difference in the granulomatous inflammation, caseous necrosis, inflammatory necrosis, acute inflammation, exudation, granulation tissue formation, and fibrous tissue hyperplasia. B cell number was significantly lower in the middle-aged and older groups compared to the younger group, while the number of T cells, CD4+ T cells, CD8+ T cells, macrophages, lymphocytes, plasma cells, and NK cells did not differ. Meaningfully, we found that the proportion of IL-10 high expression and TGF-β1 positive in the older group was significantly higher than that in the younger group. TNF-α, CD66b, IFN-γ, and IL-6 expressions were not different among the three groups. In conclusion, there are some differences in imaging, pathological, and immune features of spinal tuberculosis in different age groups. The high expression of IL-10 and TGF-β1 in older patients may weaken their anti-tuberculosis immunity and treatment effectiveness.

The challenges in diagnosing isolated epididymal tuberculosis (TB) in an adolescent male: a case report

BackgroundGenitourinary tuberculosis (GUTB) is a common form of extrapulmonary TB (EPTB) in children. An example of GUTB is epididymal TB, which usually presents unspecific chronic clinical manifestations. Definitive diagnosis can be conducted based on bacteriologic confirmation and histopathologic results, but this is challenging due to the paucibacillary nature of EPTB. Therefore, we reported the challenges in diagnosing isolated epididymal TB in an adolescent male.Case presentationA 16-year-old male presented to respirology clinic with painful swelling of the left scrotum for 3 months before visiting to the hospital. The symptoms were associated with persistent coughing for 2 months, and physical examination of the left scrotum showed swelling accompanied by cardinal signs. A palpable hard mass was found on the left scrotum, with firm borders, measuring 7 × 4 cm. Laboratory examination and tumor markers were within normal limits, although leukocyturia was found, and the urine culture was negative. Genital ultrasound (US) showed epididymitis sinistra with septal hydrocele, while magnetic resonance imaging (MRI) indicated inhomogeneous left epididymitis with bilateral inguinal lymph node enlargement. Although TB evaluation presented a negative purified protein derivative (PPD) test and bacteriologic examination, chest X-ray (CXR) showed perihilar lymphadenopathy. Based on the clinical and radiologic results suggesting TB, the patient was diagnosed with isolated epididymal TB and received quadruple antituberculosis therapy (ATT) for 6 months. After treatment, the left testicle size started to shrink and was equal to the right testicle, also, there were no signs of inflammation, the body weight increased by 5 kg, and cough disappeared. Sperm analysis at the end of treatment indicated teratozoospermia, which was subsequently treated by the urologic surgery department.ConclusionsBiopsy and bacteriologic confirmation for TB epididymitis were challenging to perform in the clinical setting. Epididymal TB should be considered in adolescent males with complaints of chronic scrotal swelling and pain. Clinical judgment based on history taking, physical examination, and radiologic features supporting TB features could be helpful in accurate and fast diagnosis for favorable outcome.

Bilateral Endoscopic Debridement Combined with Local Antituberculosis Drugs for Thoracic Tuberculosis with Large Paravertebral Abscess: A Multicenter Study with 4-year Follow-Up

BackgroundParavertebral abscess represents a prevalent manifestation of thoracic tuberculosis, often necessitating surgical intervention. In this study, we introduced a novel approach by employing bilateral endoscopic debridement to address large Paravertebral abscesses associated with thoracic tuberculosis, a method not previously proposed in the literature. The clinical efficacy was examined through a comprehensive 4-year follow-up. MethodsWe conducted a retrospective analysis on patients diagnosed with thoracic tuberculosis and paravertebral abscess (TB-PA) who underwent bilateral endoscopic debridement combined with local antituberculosis drugs (BED+LAD) between February 2015 and February 2019. A total of 29 eligible patients (12 males and 17 females) with a median (interquartile ranges, IQR) of 59.0(16.5) years were included in the study. All patients received the BED+LAD treatment. After the surgery, the patients were treated with a 4-drug antituberculosis therapy (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol). All relevant indicators were meticulously recorded and analyzed. ResultsThe surgical procedures were successfully completed for all subjects, with an average intraoperative bleeding volume of (25.2 ± 8.9) ml, an average surgical time of (68.4 ± 14.0) minutes, an average fluoroscopy frequency of (21.7 ± 8.2) times, an average hospital stay of (14.2 ± 4.3) days, and an average medication period of (42.1 ± 9.6) weeks. All subjects completed at least a 4-year follow-up period. At the final follow-up, ESR and CRP levels returned to normal, and there was no significant increase in the Cobb angle (P>0.05). ConclusionThe application of BED+LAD in the treatment of TB-PA proved to be a safe, effective, and feasible approach.

Management of anti-tuberculosis drug induced xerostomia in completely edentulous patient-A case report

Tuberculosis (TB) is one of the major systemic conditions which is a preventable and curable infection but remains a significant cause of death and reduced quality of life of patients.Weight loss, tiredness and loss of appetite are common symptoms that are even more aggravated in geriatric patients affecting the quality of life of the patient.Edentulism, hyposalivation and dryness of the mouth further contribute to the discomfort in patients wearing dentures that leads to the weight reduction, indigestion and loss of appetite in such patients. Compromised esthetics and speech of the patient just multiply the social trauma and isolation the patient is already facing due to TB.This paper describes a novel method of managing a patient with active TB on Anti Tuberculosis therapy (ATT) reporting symptoms of xerostomia.Completely Edentulous Maxillary and Mandibular Residual Alveolar Ridges: PDI Class II with associated ATT-induced Xerostomia.Split denture with a salivary reservoir in the mandibular denture.Improved aesthetics & speech, improved mastication and reduced weight loss due to denture wearing.Split dentures with artificial saliva can increase the patient's comfort in wearing dentures which overturns the impact of infection significantly and leads to increased quality of life in edentulous patients on ATT.

Genetic mechanisms of co-emergence of INH-resistant Mycobacterium tuberculosis strains during the standard course of antituberculosis therapy.

The incidence of isoniazid (INH) resistant Mycobacterium tuberculosis is increasing globally. This study aimed to identify the molecular mechanisms behind the development of INH resistance in M. tuberculosis strains collected from the same patients during the standard course of treatment. Three M. tuberculosis strains were collected from a patient before and during antituberculosis (anti-TB) therapy. The strains were characterized using phenotypic drug susceptibility tests, Mycobacterial Interspersed Repeated Unit-Variable-Number Tandem Repeats (MIRU-VNTR), and whole-genome sequencing (WGS) to identify mutations associated with INH resistance. To validate the role of the novel mutations in INH resistance, the mutated katG genes were electroporated into a KatG-deleted M. tuberculosis strain (GA03). Three-dimensional structures of mutated KatG were modeled to predict their impact on INH binding. The pre-treatment strain was susceptible to INH. However, two INH-resistant strains were isolated from the patient after anti-TB therapy. MIRU-VNTR and WGS revealed that the three strains were clonally identical. A missense mutation (P232L) and a nonsense mutation (Q461Stop) were identified in the katG of the two post-treatment strains, respectively. Transformation experiments showed that katG of the pre-treatment strain restored INH susceptibility in GA03, whereas the mutated katG genes from the post-treatment strains rendered negative catalase activity and INH resistance. The protein model indicated that P232L reduced INH-KatG binding affinity while Q461Stop truncated gene transcription. Our results showed that the two katG mutations, P232L and Q461Stop, accounted for the co-emergence of INH-resistant clones during anti-TB therapy. The inclusion of these mutations in the design of molecular assays could increase the diagnostic performance.IMPORTANCEThe evolution of drug-resistant strains of Mycobacterium tuberculosis within the lung lesions of a patient has a detrimental impact on treatment outcomes. This is particularly concerning for isoniazid (INH), which is the most potent first-line antimycobacterial drug. However, the precise genetic factors responsible for drug resistance in patients have not been fully elucidated, with approximately 15% of INH-resistant strains harboring unknown genetic factors. This raises concerns about the emergence of drug-resistant clones within patients, further contributing to the global epidemic of resistance. In this study, we revealed the presence of two novel katG mutations, which emerged independently due to the stress exerted by antituberculosis (anti-TB) treatment on a parental strain. Importantly, we experimentally demonstrated the functional significance of both mutations in conferring resistance to INH. Overall, this research sheds light on the genetic mechanisms underlying the evolution of INH resistance within patients and provides valuable insights for improving diagnostic performance by targeting specific mutations.

Accuracy of the tuberculosis molecular bacterial load assay to diagnose and monitor response to anti-tuberculosis therapy: a longitudinal comparative study with standard-of-care smear microscopy, Xpert MTB/RIF Ultra, and culture in Uganda

In 2018, the tuberculosis molecular bacterial load assay (TB-MBLA), a ribosomal RNA-based test, was acknowledged by WHO as a molecular assay that could replace smear microscopy and culture for monitoring tuberculosis treatment response. In this study, we evaluated the accuracy of TB-MBLA for diagnosis and monitoring of treatment response in comparison with standard-of-care tests. For this longitudinal prospective study, patients aged 18 years or older with presumptive tuberculosis (coughing for at least 2 weeks, night sweats, and weight loss) were enrolled at China-Uganda Friendship Hospital Naguru (Kampala, Uganda). Participants were evaluated for tuberculosis by TB-MBLA in comparison with Xpert MTB/RIF Ultra (Xpert-Ultra) and smear microscopy, with Mycobacteria Growth Indicator Tube (MGIT) culture as a reference test. Participants who were positive on Xpert-Ultra were enrolled on a standard 6-month anti-tuberculosis regimen, and monitored for treatment response at weeks 2, 8, 17, and 26 after initiation of treatment and then 3 months after treatment. Between Nov 15, 2019, and June 15, 2022, 210 participants (median age 35 years [IQR 27-44]) were enrolled. 135 (64%) participants were male and 72 (34%) were HIV positive. The pretreatment diagnostic sensitivities of TB-MBLA and Xpert-Ultra were similar (both 99% [95% CI 95-100]) but the specificity was higher for TB-MBLA (90%[83-96]) than for Xpert-Ultra (78% [68-86]). Ten participants were Xpert-Ultra trace positive, eight (80%) of whom were negative by TB-MBLA and MGIT culture. Smear microscopy had lower diagnostic sensitivity (75%[65-83]) but higher specificity (98% [93-100]) than TB-MBLA and Xpert-Ultra. Among participants who were smear microscopy negative, the sensitivity of TB-MBLA was 96% (95 CI 80-100) and was 100% (95% CI 86-100) in those who were HIV positive. 129 (61%) participants were identified as tuberculosis positive by Xpert-Ultra and these individuals were enrolled in the treatment group and monitored for treatment response. According to TB-MBLA, 19 of these patients cleared bacillary load to zero by week 2 of treatment and remained negative throughout the 6-month treatment follow-up. Positivity for tuberculosis decreased with treatment as measured by all tests, but therate was slower with Xpert-Ultra. Consequently, 31 (33%) of 95 participants were still Xpert-Ultra positive at the end of treatment but were clinically well and negative on TB-MBLA and culture at 6 months of treatment. Two patients were still Xpert-Ultra positive with a further 3 months of post-treatment follow-up. The rate of conversion to negative of the DNA-based Xpert-Ultra was 3·3-times slower than that of the rRNA-based TB-MBLA. Consequently for the same patient, it would take 13 weeks and 52 weeks to reach complete tuberculosis negativity by TB-MBLA and Xpert-Ultra, respectively. Participants who were positive on smear microscopy at 8weeks, who received an extra month of intensive treatment, had a similar TB-MBLA-measured bacillary load at 8weeks to those who were smear microscopy negative. TB-MBLA has a similar performance to Xpert-Ultra for pretreatment diagnosis of tuberculosis, but is more accurate at detecting and characterising the response to treatment than Xpert-Ultra and standard-of-care smear microscopy. European and Developing Countries Clinical Trials Partnership, Makerere University Research and Innovation Fund, US National Institutes of Health.

Clinical characteristics and outcome of genitourinary tuberculosis in Balochistan: An observational study.

Objective: To make aware that the healthcare professionals should diagnose GUTB as early as possible to avoid the grave side effects of untreated cases as it can lead to the gross structural abnormalities in the Genito urinary system. Study Design: Single Center Observational study. Setting: Tertiary Care Medicine Unit in Baluchistan, in BMCH Teaching Hospital. Period: 1st January 2012 to 31st Dec 2022. Material & Methods: Total 118 patients were enrolled in the research and patients were taken a detailed history, they went through physical examination, then they went they underwent through different diagnostic modalities as per the availability in indications. The diagnosed cases were treated and the follow up was done the mean duration for the follow up was around two years. Results: All individuals received interventions primarily involving anti-tuberculosis medications. Three patients had bilateral fallopian tubes obstruction who went under laparoscopy and later on 1 couple opted for IVF, for infertility. Anti-TB drug therapy resulted in severe adverse reactions in 8 individuals. Among them, two female patients experienced the formation of a thimble bladder accompanied by incapacitating storage symptoms. Additionally, at the time of diagnosis, 4 patients exhibited impaired renal functions, which, fortunately, remained unaltered following the completion of the prescribed treatment. None of our patients went into ESRD, and no death during study was reported due to GUTB. Conclusion: It was concluded in our study that Genito urinary tuberculosis being the second commonest type of extrapulmonary tuberculosis is also common in Baluchistan and it needs to be treated and diagnosed and treated as soon as possible, we also suggest that if the expert diagnostic modalities for the diagnosis of GUTB are not available even the clinical suspicion can be used to diagnose the case and start the treatment.

Exploring the Therapeutic Benefits of Silymarin Herbal Extract as a Supplement to Pulmonary Tuberculosis Treatment: A Comprehensive Review from Laboratory to Clinical Trials

Abstract: Indonesia is ranked second in the number of tuberculosis (TB) cases with an incidence rate of 300 per 1000 population. A combination of antibiotics with a minimum six-month-administration regimen is an effective first line of TB treatment. Silymarin (Sm) is a plant extract which is known to have hepatoprotective and anti-microbial effects. This literature review aimed to discuss the potential of Sm in pulmonary TB treatment, starting from laboratory studies to clinical trials in humans. Studies on the use of Sm in tuberculosis literatures were obtained from a rapid systematic search in Pubmed and ScienceDirect databases. Supporting articles were searched based on specific keywords with inclusion criteria. The in vitro test showed immunomodulatory and bactericidal capacities of Sm against Mycobacterium tuberculosis. The in vivo test of Sm administration showed that Sm was able to increase the percentage of macrophage cells expressing the cytokines NF-κB and IFN-β. Sm had a bactericidal effect at levels >50 μM. The hepatoprotective character of Sm could prevent the increase in liver enzymes in mice receiving anti-TB drugs. Clinical trials showed that administration of Sm could prevent anti-tuberculosis drug hepatoxicity. In conclusion, silymarin has the potential to be an adjuvant therapy for the treatment of anti-TB drug-sensitive or resistant tuberculosis, as well as protection against the hepatotoxic properties of anti-TB drugs. Keywords: tuberculosis; silymarin; supplementation therapy; antituberculosis therapy

Contact investigation in multidrug-resistant tuberculosis:ethical challenges.

Contact investigation is an evidence-based intervention of multidrug-resistant tuberculosis (MDR-TB) to protect public health by interrupting the chain of transmission. In pursuit of contact investigation, patients' MDR-TB status has to be disclosed to third parties (to the minimum necessary) for tracing the contacts. Nevertheless, disclosure to third parties often unintentionally leads the MDR-TB patients suffered from social discrimination and stigma. For this reason, patients are less inclined to reveal their MDR-TB status and becomes a significant issue in contact investigation. This issue certainly turns into a negative impact on the public interest. Tension between keeping MDR-TB status confidential and safeguarding public health arises in relation to this issue. Regarding MDR-TB management, patient compliance with treatment and contact investigation are equally important. Patients might fail to comply with anti-TB therapy and be reluctant to seek healthcare due to disclosure concerns. In order to have treatment adherence, MDRTB patients should not live through social discrimination and stigma arising from disclosure and TB team has a duty to support them as a mean of reciprocity. However, implementation of contact investigation as a public health policy can still be challenging even with promising reciprocal support to the patients because MDR-TB patients are living in different contexts and situations. There can be no straight forward settlement but an appropriate justification for each distinct context is needed to strike a balance between individual confidentiality and public interest.

Discovering novel biomarkers for diagnosis and treatment monitoring of active pulmonary tuberculosis by ion metabolism analysis

Tuberculosis (TB) is a highly lethal infectious disease that poses a global threat. Timely and accurate biomarker for TB diagnosis and treatment monitoring remains a pressing need. Ions, the crucial trace element for humans, may be potential targets for TB diagnosis and the forecasting of TB development. To explore the potential of ions as biomarkers, we measured and compared the levels of various ions in whole blood and plasma samples from healthy control (HC), pulmonary TB patients (TB), cured pulmonary TB patients (RxTB), and other non-TB pneumonia patients (PN) by using ultra-high performance liquid chromatography-tandem mass spectrometry. Our study demonstrated that Cu (AUC = 0.670), Pb (AUC = 0.660), and Zn (AUC = 0.701) in whole blood exhibited promising diagnostic performance for TB. Then we used a neural network (NNET) for TB prediction, the AUC values used to differentiate definite TB from HC or PN in plasma were 0.867 and 0.864, respectively. The AUC values used to differentiate definite TB from HC or PN in whole blood were 0.818 and 0.660, respectively. Our correlation analysis showed that Zn (r= 0.356, p=0.001) and Cu (r= 0.361, p=0.0004) in plasma are most closely related to disease severity. Additionally, six ions (Cu, Sb, V, Mn, Fe, Sr) in plasma and whole blood were altered following anti-TB therapy. These results showed that ions could be diagnostic biomarkers for TB. Furthermore, the level of particular ions can forecast the degree of lung damage and the success of the TB treatment. In conclusion, this study highlights the possibility of using ions from blood samples to enable rapid tuberculosis diagnosis.

Socio-demographic factors & adherence of newly diagnosed pulmonary tuberculosis patients to the newly introduced daily regimen: A hospital survey based follow up study

IntroductionPoor adherence to anti-tuberculosis medication is a major barrier to its global control. Patient adherence to the standard anti-TB therapy (ATT) in developing countries has been estimated to be as low as 40%. Multiple factors influencing adherence to treatment are:Economic and structural factors such as homelessness, unemployment and poverty; patient related factors like ethnicity, gender, age, knowledge about TB, cultural belief systems, mental state etc. Aims & objectivesThis study was planned with the aim to study the association between various socio-demographic factors with level of adherence to the daily regimen amongst newly diagnosed pulmonary TB patients at a tertiary care hospital in metropolitan city of Maharashtra. Additionally, we tried to determine the type of non-adherence along with reasons for it. Methodology: An interview based pre-tested and validated questionnaire was developed & used as data collection tool. Total 181 newly diagnosed, FDC naïve, drug sensitive pulmonary TB patients from DOT center of a tertiary care hospital were enrolled & interviewed for sociodemographic, treatment & adherence details. They were followed up at 2nd & 6th month of their treatment, i.e., IP & CP follow up. Their Nikshay portal data & TB treatment cards were accessed for information on treatment adherence. ResultsOut of 181 patients, 110 (60.8%) were found to be adherent whereas 71 (39.2%) were found to be non-adherent. Among those non-adherent, 64 (90.9%) had treatment gaps (intermittent missed doses) & 7 (9.9%) showed discontinuation of treatment. Majority of these patients reported personal obligations & starting to feel better as the main reason for non-adherence (p < 0.0001). The sociodemographic factors that had significant impact on level of adherence were patients’ age (p = 0.013); level of education (p = 0.035); family size (p = 0.018); family history of TB (p = 0.0001) & current smoking habit (p = 0.025). ConclusionIt is evident from the study that socio-demographic factors do have a major impact on patients’ levels of adherence to treatment. Family history of TB as well as sputum conversion at end of treatment/CP have been identified as independent risk factors among pulmonary TB patients who are non-adherent to treatment. Thus, ensuring robust availability of DBT & intensive tobacco cessation sessions for all diagnosed patients as well as strengthening system for making prophylaxis available for household & close contacts of patients can help in reducing impact of socio-demographic factors & improving adherence levels. RecommendationsIn-patient care option specifically during IP; regular dietary counseling to improve nutrition & help reduce drug side effects & use of alternate adherence technologies like facility-based DOT or Video Observed Therapy (VOT) wherever feasible can help to improve adherence levels for TB patients from all walks of life.

Human-Beta-Defensin-1, Ferritin, Interleukin-6 and their Relationship with Clinical and Laboratory Parameters of the Severity of the Tuberculosis Process

Establishing relationships between clinical and laboratory parameters, such as general patient’s state, parameters of complete blood count and blood biochemistry and markers of the course of tuberculosis in the future can be used to predict the severity of dysfunction of various organs and tissues in patients with tuberculosis and in particular in patients who receive anti-tuberculosis treatment. Objective — to investigate the relationship between biochemical markers, namely Human-beta-defensin-1, ferritin and interleukin-6, and clinical and laboratory indicators of the severity of the tuberculosis process. Materials and methods. 100 patients diagnosed with pulmonary tuberculosis were included in the study. After receiving 60 doses of anti-tuberculosis treatment, the patients were retrospectively divided into 2 groups. Group 1 (n = 77) consisted of patients in whom sputum conversion was observed after 60 doses of treatment, determined by sputum microscopy. Group 2 (n = 23) comprised patients in whom bacterial secretion was maintained after 60 doses of treatment, as detected by microscopy. In addition to the routine studies provided for the monitoring of patients with tuberculosis by the current orders of the Ministry of Health of Ukraine, the levels of Human-beta-defensin-1, ferritin and interleukin-6 (IL-6) in the fasting blood were additionally measured by ELISA at the beginning of treatment and after 60 days. Statistical data processing was carried out using the Statistica 8.0 software environment. Results. A comparison of the investigated parameters between groups at the beginning of treatment showed significantly higher values of Human-beta-defensin-1 (Group 1 — (18.97 ± 2.42) pg/ml, Group 2 — (55.02 ± ± 15.69) pg/ml), ferritin (Group 1 — (94.86 ± 6.02) ng/ml, Group 2 — (141.61 ± 24.66) ng/ml) and IL-6 (Group 1 — (80.33 ± 5.03) pg/ml, Group 2 — (110.13 ± 10.35) pg/ml) in patients with positive sputum micros­copy after 60 doses of treatment, p &lt; 0.05. All studied markers demonstrated a reliable positive relationship with the massiveness of bacterial excretion, a conditional indicator of the severity of clinical symptoms and signs, ESR and urea level, as well as reliable negative correlations with creatinine level. In addition, patients with a lower body mass index were found to have higher levels of Human-beta-defensin-1 and ferritin. Higher levels of Human-beta-defensin-1 and ferritin are associated with lower hemoglobin levels (Human-beta-defensin-1 was also negatively correlated with erythrocyte count). An increase in the leukocytes level is accompanied by a significant increase in the level of Human-beta-defensin-1 and IL-6. Additionally, a significant negative correlation was found between the level of glucose and ferritin, as well as between the level of bilirubin and ferritin and IL-6. Conclusions. The determined significantly higher levels of Human-beta-defensin-1, ferritin and interleukin-6 in patients in whom sputum microscopy was positive after 60 doses of treatment allow considering the investigated biochemical parameters as markers of the ineffectiveness of anti-tuberculosis therapy. The identified positive relationships with the severity of clinical symptoms indicate the possibility of using the studied parameters as markers of the severity of the tuberculosis course. The possibility of using Human-beta-defensin-1 and ferritin as markers of anemia was also found. Correlations with parameters of blood biochemistry allow us to talk about increased levels of Human-beta-defensin-1, ferritin and interleukin-6 against the background of kidney damage.

Research of Russian physicians' opinions on tuberculosis pharmacogenetics.

There is currently no widespread implementation of pharmacogenetic testing (PGx) methods in the practice of phthisiology service. The aim of this study is to determine how informed and prepared phthisiologists, residents, and postgraduate students of the Russian Medical Academy of Continuing Professional Education (RMACPE, Moscow) use PGx techniques in their work to improve treatment safety, predict the occurrence of adverse reactions (ADRs), and personalize therapy. A survey was conducted among phthisiologists (n =314) living in different regions of the Russian Federation and studying at RMACPE, such as residents and post-graduate students (n =185). The survey was developed on the Testograf.ru web platform and had 25 questions for physicians and 22 for residents and post-graduate students. More than 50% of respondents are ready to use PGx in clinical practice and thus are aware of the method's possibilities. At the same time only a small part of participants were aware of the pharmgkb.org resource. The absence of PGx in clinical guidelines and treatment standards, according to 50.95% of phthisiologists and 55.13% of students of RMACPE, the absence of large-scale randomized clinical trials, according to 37.26% of phthisiologists and 43.33% of students, and the lack of physician knowledge on PGx, according to 41.08% of phthisiologists and 57.83% of students, are all factors that prevent the implementation of PGx in Russia. According to the survey, the overwhelming majority of participants recognize the importance of PGx and are willing to use the method in practice. However, there is a low level of awareness among all respondents about the possibilities of PGx and the pharmgkb.org resource. The implementation of this service could significantly increase patient compliance, lower ADRs, and enhance anti-tuberculosis (TB) therapy quality.