Standard Anti-tuberculosis Treatment Research Articles

The Clinical Characteristics, Treatment and Prognosis of Tuberculosis-Associated Chronic Obstructive Pulmonary Disease: A Protocol for a Multicenter Prospective Cohort Study in China.

Tuberculosis and chronic obstructive pulmonary disease (COPD) are significant public health challenges, with pulmonary tuberculosis recognized as a pivotal risk factor for the development of COPD. Tuberculosis-associated COPD is increasingly recognized as a distinct phenotype of COPD that potentially exhibits unique clinical features. A thorough understanding of the precise definition, clinical manifestations, prognosis, and most effective pharmacological strategies for tuberculosis-associated COPD warrants further investigation. This prospective, observational cohort study aims to enroll over 135 patients with tuberculosis-associated COPD and 405 patients with non-tuberculosis-associated COPD, across seven tertiary hospitals in mainland China. The diagnosis of tuberculosis-associated COPD will be established based on the following criteria: (1) history of pulmonary tuberculosis with standard antituberculosis treatment; (2) suspected pulmonary tuberculosis with radiological evidence indicative of tuberculosis sequelae; (3) no definitive history of pulmonary tuberculosis but with positive interferon-gamma release assay results and radiological signs suggestive of tuberculosis. At baseline, demographic information, medical history, respiratory questionnaires, complete blood count, interferon-gamma release assays, medications, spirometry, and chest computed tomography (CT) scans will be recorded. Participants will be followed for one year, with evaluations at six-month intervals to track the longitudinal changes in symptoms, treatment, lung function, and frequencies of COPD exacerbations and hospitalizations. At the final outpatient visit, additional assessments will include chest CT scans and total medical costs incurred. The findings of this study are expected to delineate the specific characteristics of tuberculosis-associated COPD and may propose potential treatment options for this particular phenotype, potentially leading to improved clinical management and patient outcomes.

Estimating optimal therapeutic drug levels of anti-tuberculosis medications based on treatment safety and effectiveness.

Therapeutic drug ranges (TDR) for standard anti-tuberculosis (TB) treatment have been determined based on expected drug levels at least 2 hours after taking the dose. In this study we constructed TDR for TB drug levels based on minimizing drug toxicity and maximizing treatment effectiveness. Participants were followed prospectively in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil observational cohort study. We focused on participants with culture-confirmed drug-susceptible pulmonary TB who underwent standard TB therapy. TDR were estimated for each TB drug separately: isoniazid (INH), rifampin (RIF), ethambutol (EMB), and pyrazinamide (PZA). TDR were defined as drug concentrations that were both safe and effective: safety was defined as the probability of having an ADR of at most 5%, while effectiveness was defined as a probability of at least 95% of not having either TB treatment failure or recurrence. There were 765 plasma samples from 448 patients; 110 (24.6%) were people with HIV, 9 (2.0%) had a grade 3 or higher ADR, and 15 (3.3%) had treatment failure/recurrence. Higher drug concentrations of INH, RIF and EMB were associated with increased odds of having ADR. High concentrations of INH suggested protection against treatment failure/recurrence. Estimated therapeutic drug range for INH (2.3-8.2 µg/ml) and for RIF (0.5-7.5 µg/ml) differed from the currently recommended drug ranges (3-5 µg/ml and 8-24 µg/ml, respectively). Estimates for PZA and EMB were similar to the currently recommended values. Our estimated upper end TDR were higher for INH and lower for RIF compared to currently recommended ranges.

Evaluation of Systemic Inflammation Before and After Standard Anti-tuberculosis Treatment in Patients With Active Pulmonary Tuberculosis and Diabetes Mellitus.

Background Diabetes mellitus (DM) is a common comorbidity of active pulmonary tuberculosis (APTB) that increases the risk of treatment failure during anti-tuberculosis chemotherapy. Evaluating systemic inflammatory response could help determine differences in response to treatment between APTB patients and those with APTB and DM. Methodology To explore changes in systemic inflammation, measured by a set of inflammatory mediators in subjects with APTB and TBDM before and after six months of anti-tuberculosis chemotherapy, 30 APTB and nine TBDM subjects underwent cytokine testing, including interleukin (IL)-6, IL-8, IL-10, interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta 1 (TGF-β1) by enzyme-linked immunosorbent assay, C-reactive protein by nephelometry, and sialic acid by colorimetric assay at baseline and following six months of standard anti-tuberculosis treatment. Sputum smear microscopy or molecular biology (Xpert MTB/RIF) was used for diagnosis, and sputum smear microscopy was performed monthly during the treatment of the patient with pulmonary tuberculosis to evaluate his evolution. Principal component analysis examined changes in the inflammatory status. Results Both groups showed negative sputum smear microscopy in the sixth month after starting anti-tuberculosis chemotherapy. TGF-β1 was found to be significantly higher in subjects with TBDM before treatment compared to APTB patients (p<0.001), and systemic inflammation continued only in TBDM subjects after treatment (accumulation and persistence of inflammatory mediators like IL-6, IL-8, IL-10, IFN-γ, TNF-α, TGF-β1, C-reactive protein, and sialic acid in blood). On the other hand, the mediators IFN-γ, C-reactive protein, and total sialic acid were found to be most influential in distinguishing pre- and post-treatment inflammatory response in subjects with APTB without DM. Conclusions Inflammatory mediators analyzed in combination, including IFN-γ, CRP, and total sialic acid, may be useful in evaluating the systemic inflammatory response in subjects with APTB and TBDM before and after anti-tuberculosis treatment. Determining these mediators revealed persistent systemic inflammation in TBDM subjects after six months of standard tuberculosis treatment, despite negative sputum smear microscopy results and good glycemic control. This suggests a need for inflammation-modulating therapies during tuberculosis control. Finally, monitoring sputum smear microscopy results alongside the determination of proposed inflammatory mediators (IFN-γ, CRP, and total sialic acid) are effective in evaluating the response to anti-tuberculosis treatment in APTB subjects without DM, warranting further investigation.

Mesenchymal stem cells-derived extracellular vesicles for therapeutics of renal tuberculosis

Extrapulmonary tuberculosis with a renal involvement can be a manifestation of a disseminated infection that requires therapeutic intervention, particularly with a decrease in efficacy of conventional regimens. In the present study, we investigated the therapeutic potency of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) in the complex anti-tuberculosis treatment (ATT). A rabbit model of renal tuberculosis (rTB) was constructed by injecting of the standard strain Mycobacterium tuberculosis H37Rv into the cortical layer of the kidney parenchyma. Isolated rabbit MSC-EVs were intravenously administered once as an addition to standard ATT (isoniazid, pyrazinamide, and ethambutol). The therapeutic efficacy was assessed by analyzing changes of blood biochemical biomarkers and levels of anti- and pro-inflammatory cytokines as well as by renal computed tomography with subsequent histological and morphometric examination. The therapeutic effect of therapy with MSC-EVs was shown by ELISA method that confirmed a statistically significant increase of the anti-inflammatory and decrease of pro-inflammatory cytokines as compared to conventional treatment. In addition, there is a positive trend in increase of ALP level, animal weigh, and normalization of ADA activity that can indicate an improvement of kidney state. A significant reduction of the area of specific and interstitial inflammation indicated positive affect of MSC-EVs that suggests a shorter duration of ATT. The number of MSC-EVs proteins (as identified by mass-spectometry analysis) with anti-microbial, anti-inflammatory and immunoregulatory functions reduced the level of the inflammatory response and the severity of kidney damage (further proved by morphometric analysis). In conclusion, MSC-EVs can be a promising tool for the complex treatment of various infectious diseases, in particularly rTB.

Assessment of antitubercular treatment induced adverse drug reactions data at a tertiary care hospital

Background: Standard anti-tuberculosis (TB) treatment is highly effective, but managing adverse drug responses is a major challenge that can negatively affect treatment compliance and outcomes of an anti-tubercular treatment (ATT) regimen. Hence, monitoring of these adverse drug reactions (ADRs) is very essential wherein the drug-causing ADR can be detected and an appropriate therapeutic regimen can be given to the patient. Aims and Objectives: To assess the ATT-induced ADRs in Individual Case Safety Reports (ICSRs), to find the incidence and prevalence of ADRs due to ATT, and to analyze the causality assessment of the ADRs due to ATT. Materials and Methods: A retrospective observational study was carried out using spontaneous ICSRs data from the ADR monitoring centre at Madras Medical College, Chennai. A suspected adverse drug reaction reporting form (sADR reporting form) provided by the Pharmacovigilance Programme of India was used to collect the data of an ICSR. Results: A total of 93 ICSRs were assessed during the study period. The majority of the ADRs occurred in males (n = 55), and the maximum number of ADRs were found in the age group of 18–44 years (n = 46). The majority of the ICSRs were categorized as “serious” (n = 60), of which the maximum number of ADRs belonged to the “hospitalization/prolonged hospital stay” category (n = 45). Most of the suspected ATT drugs involved in implicating ADRs were found to be fixed-dose combination pills of Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol (n = 71). Most of the ADRs were “skin and subcutaneous disorders” (n = 51) of the system organ class. The outcome of the ADRs was assessed and found that the majority of them were in the “recovering” (n = 54) category, and the majority of the ICSRs were found to be “probable” (n = 67). Conclusion: An effective implementation of a Pharmacovigilance system with early detection and management of ADRs is needed to overcome the nonadherence to TB therapy.

General non-specific adaptation reactions and levels of organism reactivity in patients with pulmonary tuberculosis and associated with the human immunodeficiency virus at the stages of medication

The data of 165 patients were analyzed, of which 121 with pulmonary tuberculosis, new cases, who were treated according to the modified DOTS schemes with retrosternal instillation of the 10%-5ml isoniazid solution and 44 patients with pulmonary tuberculosis associated with human immunodeficiency virus, who received standard antituberculosis and antiretroviral treatment. The patients were assessed the reactions of general nonspecific adaptation, the reactivity levels of the organization and the sum of the score accumulated by the patient according to the method of L.H.Garcavi and coaut., 1979. It was found that in the quotas of patients from both groups up to treatment prevailed low levels of reactivity of the organism, which after the intensive phase DOTS (and corresponding – antiretroviral treatment) in patients only with pulmonary tuberculosis or more maintained at 50%, and in the group and with HIV Association low levels remained the same. Pathological adaptation reactions at that time in the first group persisted in every third patient, while in the other group they remained without changes. These data are useful in assessing the risk of activation of the process, the prognosis of further evolution of the disease and the correction of curative measures.

Pathophysiological features of reparative processes in adjuvant therapy of renal tuberculosis with extracellular vesicles in an experiment

Currently, various studies are focusing on the potential of stem cells as adjuvant therapy for tuberculosis. In addi-tion, there is significant interest in the use of extracellular vesicles (EVs), since compared with whole-cell therapy, EVs derived from mesenchymal stromal cells (MSCs) have many advantages such as good tolerability, low immuno-genicity, no risk of malignancy, more stable membrane structure than MSCs, etc. These advantages open up broad prospects for the treatment of a large number of diseases. In the present study, we investigated the protein composition of extracellular vesicles and assessed their therapeutic potential in a rabbit model of renal tuber-culosis in combination with standard anti-TB treatment. Materials and methods. The study involved 20 rabbits with renal tuberculosis, which were intravenously injec-ted with extracellular vesicles isolated from mesenchymal stem cells. Therapeutic efficacy was assessed by analyzing changes in the level of anti- and pro-inflammatory cyto-kines, as well as by computed tomography of the kidneys with subsequent histological and morphometric examina-tion. The protein composition of extracellular vesicles was determined using liquid chromatography and mass spec-trometry. Results. The addition of extracellular vesicles to standard anti-tuberculosis treatment resulted in a statis-tically significant increase in anti-inflammatory cytokines and a decrease in pro-inflammatory cytokines, as well as a significant decrease in the area of specific inflammation compared to groups with standard treatment, which was largely due to the proteins included in the extracellular vesicles. Conclusion. The use of extracellular vesicles as a component of complex anti-tuberculosis therapy in-creases the effectiveness of renal tuberculosis treatment by accelerating reparative processes in the area of specific inflammation

Effect of Metformin on Plasma Exposure of Rifampicin, Isoniazid, and Pyrazinamide in Patients on Treatment for Pulmonary Tuberculosis.

To evaluate the effect of metformin on the plasma levels of rifampicin, isoniazid, and pyrazinamide in patients with drug-sensitive pulmonary tuberculosis being treated with first-line antituberculosis treatment (ATT) and to assess the influence of gene polymorphisms on the metabolic pathway of metformin and plasma levels of antitubercular drugs. Nondiabetic adults aged 18-60 years with pulmonary tuberculosis were randomized to either the standard ATT (ATT group) or ATT plus metformin (METRIF group) groups in a phase IIB clinical trial. An intensive pharmacokinetic study with blood collection at 0 hour (predosing), followed by 1, 2, 4, 6, 8, and 12 hours after dosing was conducted during the first month of treatment in a subset of 60 study participants after a minimum of 14 doses. Plasma concentrations of rifampicin, isoniazid, pyrazinamide, and metformin were measured by high-performance liquid chromatography using validated methods, and pharmacokinetic parameters and OCT1 and MATE1 gene polymorphisms were compared between the groups. Significant increases in the clearance of rifampicin, isoniazid, and pyrazinamide were observed in patients in the METRIF group (n = 29) compared with those in the ATT group (n = 31). The AA genotypes of the single-nucleotide polymorphism of rs2289669 ( MATE1 ) in the METRIF group showed a significantly decreased area under the concentration-time curve to the last observation point and increased clearance of rifampicin. Metformin altered rifampicin and isoniazid plasma concentrations in patients receiving antituberculosis treatment for pulmonary tuberculosis with little effect on sputum conversion at the end of treatment. Studies with larger sample sizes are needed to understand host drug-drug interactions.

Assessment of peripheral lymph node tuberculosis: a prospective study of 24 cases

Abstract Introduction: Tubercular lymphadenitis which comes under Extra-pulmonary Tuberculosis (EPTB) has been affecting mankind since ancient times. Peripheral lymph node involvement is the commonest form of EPTB among which cervical lymph nodes are most frequently affected. Objectives: The aim of this study was to evaluate the demographic, clinical characteristics and treatment outcomes of peripheral lymph node Tuberculosis cases in a rural tertiary health care centre. Methods: The study was conducted prospectively at Prathima Institute of Medical Sciences, Nagunur, Karimnagar between January 2021 to August 2022. Pathologically confirmed cases of lymph node Tuberculosis were assessed and followed up. Results: 24 cases of lymph node TB were included with 83.3% females and 16.6% males (p=0.02) with a mean age of 32.6 ± 15.24 years. The mean age among males was 37 ± 15.59 years and among females was 31.75 ± 15.24 years. 58.3% were from rural areas. All of them presented with a history of swelling, 37.5% had a fever, 50% had a loss of appetite and 54.1% had a loss of weight. 8% had a past history of tuberculosis. 79.1% had cervical swelling and 20.8% had axillary swelling. 83.3% had multiple lymph nodes and 33.3% had lymph node matting. Three cases were lost to follow-up, 79% improved with standard anti-Tuberculosis treatment (ATT) and one case died during treatment. Conclusion: Lymph node TB is still prevalent in TB endemic countries and has to be considered first in the differential diagnosis of peripheral lymph node swellings.

The value of multimodal ultrasonography in evaluating therapeutic response of cervical tuberculous lymphadenitis to anti-tuberculosis drugs.

In order to research the value of multimodal ultrasonography in evaluating therapeutic response of cervical tuberculous lymphadenitis to anti-tuberculosis drugs. Sixty-one patients with cervical tuberculous lymphadenitis were enrolled in this study. Ultrasound examination was performed before systemic standard anti-tuberculosis treatment and within 1-2 months after treatment, and the patients were divided into effective group and ineffective group according to the follow-up at the sixth month. The multimodal ultrasound signs of the two groups were compared and analyzed. In the effective group, there were significant differences in the maximum diameter of lymph nodes, the echo of the surrounding tissue and the enlargement of the contrast area before and after treatment (p < 0.05). At 1-2 months after treatment, there were significant differences in the maximum diameter, pus changes, CDFI, elasticity scores, echo of surrounding tissues, changes in enlarged and non-enhanced areas after contrast enhancement between the effective group and the ineffective group (p < 0.05). The multimodal ultrasound signs of the appearance of internal pus or non-enhancement area enlargement, enhanced echo of the surrounding tissue and enlargement after CEUS are related to poor prognosis, and may be used to evaluate the response of anti-tuberculosis chemotherapy when the size change of lymph node is not obvious in individual treatment.

Simultaneous Determination of Rifamycin Antibiotics and Their Active Metabolites in Human Plasma Using UHPLC-MS/MS to Evaluate Their Impact on Target Peak Concentrations: A Short Communication.

Standard and proper antituberculosis (anti-TB) treatment is essential for patients with TB, and rifamycin antibiotics are key components of anti-TB therapy. Therapeutic drug monitoring (TDM) of rifamycin antibiotics can shorten the time to response and complete treatment of TB. Notably, antimicrobial activities of the major active metabolites of rifamycin are similar to those of their parent compounds. Thus, a rapid and simple assay was developed for simultaneous determination of rifamycin antibiotics and their major active metabolites in plasma to evaluate their impact on target peak concentrations. Here, the authors have developed and validated a method for simultaneous determination of rifamycin antibiotics and their active metabolites in human plasma using ultrahigh-performance liquid chromatography tandem mass spectrometry. Analytical validation of the assay was performed in accordance with the bioanalytical method validation guidance for industry described by the US Food and Drug Administration and the guidelines for bioanalytical method validation described by the European Medicines Agency. The drug concentration quantification method for rifamycin antibiotics, including rifampicin, rifabutin, and rifapentine, and their major active metabolites was validated. Significant differences in the proportions of active metabolites in rifamycin antibiotics may affect the redefinition of their effective concentration ranges in the plasma. The method developed herein is expected to redefine the ranges of "true" effective concentrations of rifamycin antibiotics (including parent compounds and their active metabolites). The validated method can be successfully applied for high-throughput analysis of rifamycin antibiotics and their active metabolites for TDM in patients receiving anti-TB treatment regimens containing these antibiotics. Proportions of active metabolites in rifamycin antibiotics markedly varied among individuals. Depending on the clinical indications of patients, the therapeutic ranges for rifamycin antibiotics may be redefined.

Esophageal anthracosis occurred after treatment of esophageal tuberculosis secondary to mediastinal tuberculous lymphadenitis: a rare case report

BackgroundAnthracosis is a disease generally considered to be in the lungs resulting from exposure to industrial dust in the workplace. Esophageal anthracosis is a fairly rare phenomenon and shows a strong correlation with tuberculosis. Moreover, esophageal involvement in tuberculosis is also rare. We here present an extremely rare case in which follow-up gastroesophageal endoscopy revealed a mass with a sunken, black area in the center and raised ring-like pattern in the surrounding mucosa resembling malignant melanoma. Uncovering the patient’s tuberculosis history finally avoided a misdiagnosis or overtreatment.Case presentationA 67-year-old male patient was admitted to the hospital due to “repeated chest pain for 1 month”. Endoscopic ultrasonography and contrast-enhanced CT scans revealed a mass adjacent to the esophageal wall with unclear boundaries. Aspiration biopsy confirmed that esophageal tuberculosis was caused by nearby mediastinal tuberculous lymphadenitis. After a standard anti-tuberculosis treatment regimen, the patient achieved a favorable prognosis. The follow-up gastroesophageal endoscopy showed a sunken black lesion with elevated peripheral mucosa replacing the original tuberculous mass, which was thought to be anthracosis, a disease that rarely occurs in the esophagus.ConclusionThe diagnosis of tuberculosis should be taken into consideration when a submucosal mass appears in the middle part of the esophagus. Endoscopic ultrasonography can effectively contribute to a definite diagnosis. Moreover, this is the first case of esophageal anthracosis observed only 1 year after the treatment of tuberculosis, indicating esophageal anthracosis can be a short-term disease. The traction of the reduction of tubercular mediastinal lymph nodes after anti-tuberculosis treatment may create a circumstance for pigmentation or dust deposition.

Wegener\'s Granulomatosis: Are We Still Missing It?

We report the case of an 18-year-old female who was mis-diagnosed as a smear-negative pulmonary tuberculosis and advised standard antituberculosis treatment. She later presented with clinio-radiological worsening and thrombosis of superficial veins of the lower extremity. Cytoplasmic anti-neutrophil cytoplasmic antibody and computed tomography-guided lung biopsy confirmed the diagnosis of Wegener's granulomatosis. The rare association of superficial vein thrombosis with lung manifestation is highlighted here as also the need for a high index of clinical suspicion to avoid a missed or delayed diagnosis.

Case Report: A case report of multiple co-infections (melioidosis, paragonimiasis, Covid-19 and tuberculosis) in a patient with diabetes mellitus and thalassemia-trait in Myanmar

Burkholderia pseudomallei is a soil-dwelling aerobic bacterium prevalent in tropical and subtropical regions, particularly in Southeast Asia and Northern Australia. It is the causal organism of melioidosis, a severe infection that can manifest as chronic debilitating pneumonia resembling pulmonary tuberculosis. Here, we report a case of melioidosis, pulmonary tuberculosis, covid-19, and paragonimus co-infection in a 50-year-old male with poorly controlled diabetes mellitus and β-thalassemia trait. The patient recovered with intravenous antibiotics and standard anti-tuberculosis treatment.

Case Report: A case report of multiple co-infections (melioidosis, paragonimiasis, Covid-19 and tuberculosis) in a patient with diabetes mellitus and thalassemia-trait in Myanmar

Burkholderia pseudomallei is a soil-dwelling aerobic bacterium prevalent in tropical and subtropical regions, particularly in Southeast Asia and Northern Australia. It is the causal organism of melioidosis, a severe infection that can manifest as chronic debilitating pneumonia resembling pulmonary tuberculosis. Here, we report a case of melioidosis, pulmonary tuberculosis, covid-19, and paragonimus co-infection in a 50-year-old male with poorly controlled diabetes mellitus and β-thalassemia trait. The patient recovered with intravenous antibiotics and standard anti-tuberculosis treatment.

Shorter Treatment for Nonsevere Tuberculosis in African and Indian Children

BackgroundTwo thirds of children with tuberculosis have nonsevere disease, which may be treatable with a shorter regimen than the current 6-month regimen.MethodsWe conducted an open-label, treatment-shortening, noninferiority trial involving children with nonsevere, symptomatic, presumably drug-susceptible, smear-negative tuberculosis in Uganda, Zambia, South Africa, and India. Children younger than 16 years of age were randomly assigned to 4 months (16 weeks) or 6 months (24 weeks) of standard first-line antituberculosis treatment with pediatric fixed-dose combinations as recommended by the World Health Organization. The primary efficacy outcome was unfavorable status (composite of treatment failure [extension, change, or restart of treatment or tuberculosis recurrence], loss to follow-up during treatment, or death) by 72 weeks, with the exclusion of participants who did not complete 4 months of treatment (modified intention-to-treat population). A noninferiority margin of 6 percentage points was used. The primary safety outcome was an adverse event of grade 3 or higher during treatment and up to 30 days after treatment.ResultsFrom July 2016 through July 2018, a total of 1204 children underwent randomization (602 in each group). The median age of the participants was 3.5 years (range, 2 months to 15 years), 52% were male, 11% had human immunodeficiency virus infection, and 14% had bacteriologically confirmed tuberculosis. Retention by 72 weeks was 95%, and adherence to the assigned treatment was 94%. A total of 16 participants (3%) in the 4-month group had a primary-outcome event, as compared with 18 (3%) in the 6-month group (adjusted difference, −0.4 percentage points; 95% confidence interval, −2.2 to 1.5). The noninferiority of 4 months of treatment was consistent across the intention-to-treat, per-protocol, and key secondary analyses, including when the analysis was restricted to the 958 participants (80%) independently adjudicated to have tuberculosis at baseline. A total of 95 participants (8%) had an adverse event of grade 3 or higher, including 15 adverse drug reactions (11 hepatic events, all but 2 of which occurred within the first 8 weeks, when the treatments were the same in the two groups).ConclusionsFour months of antituberculosis treatment was noninferior to 6 months of treatment in children with drug-susceptible, nonsevere, smear-negative tuberculosis. (Funded by the U.K. Medical Research Council and others; SHINE ISRCTN number, ISRCTN63579542.)

Adverse Drug Reactions Related to Treatment of Drug-Susceptible Tuberculosis in Brazil: A Prospective Cohort Study

Standard anti-tuberculosis treatment is highly effective, but a great challenge is the management of adverse drug reactions (ADR). Our study aimed to characterize ADR according to type, severity and time of occurrence. A prospective tuberculosis (TB) cohort has been followed, from 2010 to 2016, at a reference center in Rio de Janeiro, Brazil. Clinical and laboratory tests information were collected in all visits. ADR were described according to the affected organ/system, classified as clinical and/or laboratory, early (first 2 months) or late. ADR’s causality and intensity were assessed. In our study 552 patients were included, 78.8% presented at least one ADR, 34% were people living with HIV (PLHIV). Most ADR were clinical (53%), early (82.5%), mild/moderate (88.7%) events and of “metabolic annutritional disorders” category. There were no significant differences in type, severity or causality between “early” and “late” groups. However, “early” group presented a higher frequency of “metabolic and nutritional disorders” (27.8%) and “gastrointestinal system disorders” (23.5%), while “skin and appendages disorders” were more frequent in the “late” group. ADR are frequent and occur at any time during treatment, although the majority are early and grade and not severe.

Plasma adipocytokines distinguish tuberculous lymphadenitis from pulmonary tuberculosis

Adipocytokines are the major secretory products of adipose tissue and potential markers of metabolism and inflammation. However, their association in host immune response against tuberculous lymphadenitis (TBL) disease is not known. Thus, we measured the systemic levels of adipocytokines in TBL (n = 44) and compared to pulmonary tuberculosis (PTB, n = 44) and healthy control (HC, n = 44) individuals. We also examined the pre and post-treatment adipocytokine levels in TBL individuals upon completion of standard anti-tuberculosis treatment (ATT). The receiver operating characteristics (ROC) were performed between TBL, PTB and HCs to find the potential discriminatory markers. Finally, principal component (PCA) analysis was performed to reveal the expression patterns of adipocytokines among study groups. Our results demonstrate that TBL is associated with significantly higher systemic levels of adipocytokines (except resistin) when compared with PTB and significantly lower levels when compared with HC (except adiponectin) individuals. Upon completion of ATT, the systemic levels of adiponectin and resistin were significantly decreased when compared to pre-treatment levels. Upon ROC analysis, all the three adipocytokines discriminated TBL from PTB but not with HCs, respectively. Similarly, adipocytokines were differentially clustered in TBL in comparison to PTB in PCA analysis. Therefore, adipocytokines are a distinguishing feature in TBL compared to PTB individuals.

Randomized Trial of Metformin With Anti-Tuberculosis Drugs for Early Sputum Conversion in Adults With Pulmonary Tuberculosis

BackgroundMetformin, by reducing intracellular Mycobacterium tuberculosis growth, can be considered an adjunctive therapy to anti-tuberculosis treatment (ATT). We determined whether metformin with standard ATT reduces time to sputum culture conversion and tissue inflammation in adults with pulmonary tuberculosis (PTB).MethodsIn a randomized, 8-week, clinical trial, newly diagnosed, culture-positive PTB patients were randomized to standard ATT (HREZ = control arm) or standard ATT plus daily 1000 mg metformin (MET-HREZ = Metformin with Rifampicin [METRIF] arm) for 8 weeks during 2018–2020 at 5 sites in India. The primary end point was time to sputum culture conversion by liquid culture during 8 weeks of ATT. Plasma inflammatory markers were estimated in a subset. A Cox proportional hazard model was used to estimate time and predictors of culture conversion.ResultsOf the 322 patients randomized, 239 (74%) were male, and 212 (66%) had bilateral disease on chest radiograph with 54 (18%) showing cavitation. The median time to sputum culture conversion by liquid culture was 42 days in the METRIF arm and 41 days in the control arm (hazard ratio, 0.8; 95% confidence interval [CI], .624–1.019). After 8 weeks of ATT, cavitary lesions on X-ray (7, 5.3% vs 18, 12.9%; relative risk, 0.42; 95% CI, .18–.96; P = .041) and inflammatory markers were significantly lower in the METRIF arm. Higher body mass index and lower sputum smear grading were associated with faster sputum culture conversion.ConclusionsThe addition of metformin to standard ATT did not hasten sputum culture conversion but diminished excess inflammation, thus reducing lung tissue damage as seen by faster clearance on X-ray and reduced inflammatory markers.Clinical Trials RegistrationClinical Trial Registry of India (CTRI/2018/01/011176)

Acute Phase Proteins Are Baseline Predictors of Tuberculosis Treatment Failure.

Systemic inflammation is a characteristic feature of pulmonary tuberculosis (PTB). Whether systemic inflammation is associated with treatment failure in PTB is not known. Participants, who were newly diagnosed, sputum smear and culture positive individuals with drug-sensitive PTB, were treated with standard anti-tuberculosis treatment and classified as having treatment failure or microbiological cure. The plasma levels of acute phase proteins were assessed at baseline (pre-treatment). Baseline levels of C-reactive protein (CRP), alpha-2 macroglobulin (a2M), Haptoglobin and serum amyloid P (SAP) were significantly higher in treatment failure compared to cured individuals. ROC curve analysis demonstrated the utility of these individual markers in discriminating treatment failure from cure. Finally, combined ROC analysis revealed high sensitivity and specificity of 3 marker signatures comprising of CRP, a2M and SAP in distinguishing treatment failure from cured individuals with a sensitivity of 100%, specificity of 100% and area under the curve of 1. Therefore, acute phase proteins are very accurate baseline predictors of PTB treatment failure. If validated in larger cohorts, these markers hold promise for a rapid prognostic testing for adverse treatment outcomes in PTB.