Standard Antituberculosis Research Articles

Perplexing paradoxical reactions: navigating the complexity of protracted tuberculosis meningitis—a case report

Tuberculous meningitis (TBM) has considerable mortality and morbidity, and it often presents therapeutic challenges when complicated by paradoxical reactions (PRs). Here, the clinical course of four cases of TBM patients complicated by PRs in a longitudinal TB cohort is described while also providing insights from the larger clinical cohort. Research flow cytometry, biomarker analysis, and drug concentrations were performed on available samples. All participants were initiated on standard antituberculosis therapy (ATT) and enrolled at the onset of PRs (PR group) or 2–4 months after the start of ATT (controls). The four TBM participants highlighted here presented with fevers, headaches, neurological deficits, and fatigue at the initial presentation. Upon diagnosis, all were initiated on rifampin, isoniazid, pyrazinamide, and ethambutol (RHZE) at standard doses and on corticosteroids. The median time to first PR was 37 days with recrudescence of initial TBM signs and symptoms at the time of PR. At the time of referral, all participants had low drug concentrations requiring dose optimization and regimen intensification as well as recrudescent flares upon corticosteroid taper, with one individual developing enlargement of tuberculoma 1 year following completion of ATT. Based on biomarkers and flow cytometry, PRs are characterized by elevated interferon-gamma and ferritin levels in the plasma compared to controls. In the TBM participants, T-cell activation with elevated levels of inflammatory biomarkers in the cerebrospinal fluid (CSF) was seen at the time of PR. These unique and highly detailed TBM cases provide insights into the pathogenesis of PRs, which may assist with future diagnostics and treatment.

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.

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.

Combination Activity of Standard Antituberculosis Drugs and Extracts of Medicinal Plants Commonly Used in Traditional Treatment of Tuberculosis in Uganda

Combination Activity of Standard Antituberculosis Drugs and Extracts of Medicinal Plants Commonly Used in Traditional Treatment of Tuberculosis in Uganda

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.

Standard-dose versus double-dose dolutegravir in HIV-associated tuberculosis in South Africa (RADIANT-TB): a phase 2, non-comparative, randomised controlled trial

The drug-drug interaction between rifampicin and dolutegravir can be overcome by supplemental dolutegravir dosing, which is difficult to implement in high-burden settings. We aimed to test whether virological outcomes with standard-dose dolutegravir-based antiretroviral therapy (ART) are acceptable in people with HIV on rifampicin-based antituberculosis therapy. RADIANT-TB was a phase 2b, randomised, double-blind, non-comparative, placebo-controlled trial at a single site in Khayelitsha, Cape Town, South Africa. Participants were older than 18 years of age, with plasma HIV-1 RNA greater than 1000 copies per mL, CD4 count greater than 100 cells per μL, ART-naive or first-line ART interrupted, and on rifampicin-based antituberculosis therapy for less than 3 months. By use of permuted block (block size of 6) randomisation, participants were assigned (1:1) to receive either tenofovir disoproxil fumarate, lamivudine, and dolutegravir plus supplemental 50 mg dolutegravir 12 h later or tenofovir disoproxil fumarate, lamivudine, and dolutegravir plus matched placebo 12 h later. Participants received standard antituberculosis therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol for the first 2 months followed by isoniazid and rifampicin for 4 months). The primary outcome was the proportion of participants with virological suppression (HIV-1 RNA <50 copies per mL) at week 24 analysed in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03851588. Between Nov 28, 2019, and July 23, 2021, 108 participants (38 female, median age 35 years [IQR 31-40]) were randomly assigned to supplemental dolutegravir (n=53) or placebo (n=55). Median baseline CD4 count was 188 cells per μL (IQR 145-316) and median HIV-1 RNA was 5·2 log10 copies per mL (4·6-5·7). At week 24, 43 (83%, 95% CI 70-92) of 52 participants in the supplemental dolutegravir arm and 44 (83%, 95% CI 70-92) of 53 participants in the placebo arm had virological suppression. No treatment-emergent dolutegravir resistance mutations were detected up to week 48 in the 19 participants with study-defined virological failure. Grade 3 and 4 adverse events were similarly distributed between the study arms. The most frequent grade 3 and 4 adverse events were weight loss (4/108 [4%]), insomnia (3/108 [3%]), and pneumonia (3/108 [3%]). Our findings suggest that twice-daily dolutegravir might be unnecessary in people with HIV-associated tuberculosis. Wellcome Trust.

Effectiveness of Screening in Patients with Rheumatic Disease on Biological Therapy and Risk of Active Tuberculosis

Background: Treatment with biologic therapy has been associated with a high risk of reactivation of latent tuberculosis (TB). Aims and Objectives: The study aimed to access the effectiveness of TB screening recommendations before the initiation of biological therapy and identify the incidence of active TB among these patients. Materials and Methods: A hospital-based retrospective cohort study among rheumatic disease patients on biological therapy in two centers between January 2005 to December 2019 was performed. Data was collected through review of medical records. Results: A total of 365 patients were included over a period of 14 years. Majority had Rheumatoid arthritis (RA) (80%). The mean age was 47.54 (±14.2), 311 (85%) were females with a mean duration of disease 8.45 years (± 6.58). Hundred forty-nine (42.3%) were on steroids. Anti TNFs were prescribed in 213 (58.4%) patients, Non-Anti-TNFs 124 (36.6%) patients, and Jak inhibitors 18 (5%) patients. TB screening was done to all patients except 3 patients (data missing) before commencing biologics. Forty-four (12.1%) patients had latent TB at baseline and all received chemoprophylaxis with isoniazid before starting biologics. Four patients with active TB were identified (one with Behcet’s disease and three with RA). One patient had a reactivation of latent TB and 3 patients developed de novo TB. Two were on rituximab and one each on infliximab and adalimumab. Two cases had pulmonary TB and two others had extrapulmonary TB (pericarditis and brain abscess each). All four patients with active TB were treated with standard anti TB medications. Three had complete resolution of their TB and one died. Conculsion: Baseline screening has been effectively carried out in our cohort as per recommendations. Physicians should be vigilant for symptoms and signs of active TB as not only reactivation of latent TB can occur with patients on biologics but in addition de novo TB can occur specially in endemic areas. Funding: None

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.

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.

Peritoneal and Pulmonary Tuberculosis in a Postpartum Female with Elevated Cancer Antigen 125 and Ascites

Peritoneal tuberculosis is a rare form of extrapulmonary tuberculosis and presents a challenging diagnosis because of its nonspecific clinical manifestations. Peritoneal TB mimics other pathologies, including abdominal carcinomatosis, especially when the patient presents with ascites and an elevated cancer antigen (CA)-125 levels. Case Presentation. A postpartum 20-year-old Hispanic female recently discharged after transverse cesarean surgery, presented to the ER with fever, chills, edema, abdominal distension, nausea, and vomiting. The patient was febrile, tachycardic, and hypotensive. Chest X-ray demonstrated alveolar and interstitial consolidations; chest CT revealed tree-in-bud opacities in the right lower lobe, suggestive of atypical (TB)/fungal infection. CT of the abdomen and pelvis demonstrated ascites, omental thickening, peritoneal thickening, and mesenteric adenopathy, suggestive of carcinomatosis. She was admitted with a presumed diagnosis of sepsis secondary to pneumonia and started empirically on broad-spectrum antibiotics without clinical improvement. A battery of oncology markers was ordered and revealed a mildly elevated cancer antigen (CA)-125. Diagnostic paracentesis showed lymphocytic predominance with positive mycobacteria PCR, elevated adenosine deaminase (ADA), and no malignant cells. Subsequently, the sputum acid-fast bacilli (AFB) stain returned positive for tuberculosis, confirming the diagnosis of pulmonary tuberculosis. A peritoneal biopsy was obtained and demonstrated caseating granulomas consistent with peritoneal tuberculosis. The patient was started on standard antituberculosis therapy with clinical improvement. This case highlights the need for a high-level of suspicion for peritoneal tuberculosis in a patient with pulmonary tuberculosis who presents with intra-abdominal ascites, omental thickening, peritoneal thickening, and mesenteric lymphadenopathy, despite the presence of an elevated CA-125 level.

Preparation and Evaluation of Low-Dose Calcitriol Dry Powder Inhalation as Host-Directed Adjunct Therapy for Tuberculosis.

BackgroundIt is unclear whether Vitamin D is efficacious as a host-directed therapy (HDT) for patients of tuberculosis (TB). We investigated pulmonary delivery of the active metabolite of Vitamin D3, i.e., 1, 25-dihydroxy vitamin D3 (calcitriol) in a mouse model of infection with Mycobacterium tuberculosis (Mtb).MethodsWe optimized a spray drying process to prepare a dry powder inhalation (DPI) of calcitriol using a Quality by Design (QbD) approach. We then compared outcomes when Mtb-infected mice were treated with inhaled calcitriol at 5 ng/kg as a stand-alone intervention versus DPI as adjunct to standard oral anti-tuberculosis therapy (ATT).ResultsThe DPI with or without concomitant ATT markedly improved the morphology of the lungs and mitigated histopathology in both the lungs and the spleens. The number of nodular lesions on the lung surface decreased from 43.7 ± 3.1 to 22.5 ± 3.9 with the DPI alone and to 9.8 ± 2.5 with DPI + ATT. However, no statistically significant induction of host antimicrobial peptide cathelicidin or reduction in bacterial burden was seen with the DPI alone. DPI + ATT did not significantly reduce the bacterial burden in the lungs compared to ATT alone.ConclusionsWe concluded that HDT using the low dose calcitriol DPI contributed markedly to mitigation of pathology, but higher dose may be required to evoke significant induction of bactericidal host response and bactericidal activity in the lung. Supplementary InformationThe online version contains supplementary material available at 10.1007/s11095-022-03360-5.

Sarcoidosis Mimicking Primary Lung Cancer on 99mTc-3PRGD2 Scintigraphy in a PTC Patient.

Sarcoidosis is a multi-system disease of unknown etiology that typically occurs in middle-aged adults, often presenting as the formation of granulomas in various organs, including the lungs. Non-typical pulmonary sarcoidosis is rare, and it isnecessary to distinguish its imaging features from lung cancer and tuberculosis. They may appear as an irregular mass with multiple nodules on thoracic computed tomography (CT). In this case, primary lung cancer was suspected in a 57-year-old papillary thyroid carcinoma patient, as the pulmonary lesions were non-radioiodine avid and progressed shortly afterward. The asymmetrical focal uptake that was demonstrated in integrin receptor imaging (99mTc-PEG4-E[PEG4-c(RGDfK)]2 (99mTc-3PRGD2)) warranted flexible-bronchoscope biopsy. Meanwhile, no evidence of malignancy was found, and pathological manifestations led to the subsequent six months of anti-tuberculosis treatment. Combined with the fact that standard anti-tuberculosis showed no improvement, and the patient’s condition was stabilized by corticosteroid treatment alone, a final diagnosis of sarcoidosis was made by an MDT (multidisciplinary consultation). Reported herein is the first case of a hyper vascularization condition within the non-typical asymmetrical sarcoidosis lesions, which should help to establish that the uptake of 3PRDG2 in sarcoidosis can avoid imaging pitfalls.

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.)

Lactobacillus casei modulates inflammatory cytokines and metabolites during tuberculosis treatment: A post hoc randomized controlled trial.

Inflammatory cytokines and metabolic abnormalities are common in patients with tuberculosis. Observational studies have indicated that probiotics modulate inflammatory cytokines and metabolites; however, clinical evidence of the effect of probiotics on patients with tuberculosis is lacking. This study investigated the effects of Lactobacillus casei on inflammatory cytokines and metabolites during tuberculosis treatment. A randomized controlled trial was conducted. A total of 47 inpatients were included and randomly assigned to receive standard antituberculosis therapy only (control group) or that treatment together with 1 × 1010 colony-forming units per day of Lactobacillus casei (low-dose group) or 2 × 1010 colony-forming units per day of Lactobacillus casei (high-dose group) for 4 weeks of intensive treatment during hospitalization. Plasma samples were analyzed for inflammatory cytokines and metabolomics with ELISA kits and ultrahigh performance liquid chromatography quadrupole time-of-flight mass spectrometry. Daily Lactobacillus casei supplementation of up to 2 × 1010 colony-forming units significantly lowered the concentrations of tumor necrosis factor-α, interleukin-6, interleukin-10, and interleukin-12 (p=0.007, p=0.042, p=0.002, p<0.001, respectively) in patients with tuberculosis. Compared with the control and low-dose groups, the plasma metabolites of phosphatidylserine, maresin 1, phosphatidylcholine, L-saccharopine, and pyridoxamine were significantly upregulated, and N-acetylmethionine, L-tryptophan, phosphatidylethanolamine, and phenylalanine were downregulated in the high-dose group. Strong correlations were observed between metabolites and inflammatory cytokines. Lactobacillus casei supplementation during the intensive phase of tuberculosis treatment can significantly modulate inflammatory cytokines and metabolites. Decreased inflammatory cytokines may be related to metabolite changes.

Dzherelo (Immunoxel) as adjunctive therapy to standard antituberculosis treatment in patients with pulmonary tuberculosis: a systematic review and meta-analysis of clinical trials

BackgroundDzherelo (Immunoxel) is one of the few approved immunomodulators that has been shown to produce positive treatment outcomes in patients with tuberculosis (TB). The aim of this review was to assess the effectiveness of Immunoxel used as adjunct therapy with conventional anti-TB therapy for the treatment of pulmonary TB.MethodsComprehensive search was conducted in different major databases: PubMed (MEDLINE), EMBASE (OVID), Cochrane Central Register of Controlled Trials (CENTRAL), Scopus (Elsevier). We also searched Google Scholar along with trial registries and hand-searched the reference list of identified original research as well as review articles. Conference proceedings of relevant TB and lung disease annual conferences were also screened. Two independent authors extracted outcome data using a standardised extraction form. Relative risk (RR), mean difference (MD) and standardised mean difference (SMD) with a 95% confidence interval (CI) were used as measures of effect. We assessed certainty of evidence using GRADE.ResultsSix clinical trials, which met the criteria for the review, were identified, and these provided data for the review. Overall results from the six trials that compared antituberculosis treatment (ATT) alone versus ATT and Immunoxel, and ATT and placebo versus ATT and Immunoxel showed an increased number of patients becoming sputum-negative in the Immunoxel group (RR 3.19; 95% CI 2.44 to 4.17; 488 participants). There was also reduction in body temperature among patients receiving Immunoxel compared to ATT alone (MD −0.20, 95% CI −0.22 to −0.18, 345 participants). However, there were no differences in body weight changes across all the studies (MD 5.65; 95% CI −0.80 to 12.11; 382 participants).ConclusionCurrent evidence indicates that the use of Immunoxel as an adjunctive treatment in patients with pulmonary tuberculosis has the potential to enhance the efficacy of antituberculosis treatment. However, well-designed, conducted and adequately powered clinical trials are needed to establish the effectiveness of this adjunctive treatment.Systematic review registrationPROSPERO registration number: CRD42019127823

Clinical study of movable external fixation for elbow tuberculosis

To compare clinical effect of movable external fixation and fusion fixation for the treatment of elbow tuberculosis. From October 2013 to June 2019, 52 patients with elbow tuberculosis treated with standard antituberculosis therapy were divided into movable external fixation group and fusion fixation group according to treatment methods. In group A, there were 25 patients, including 11 males and 14 females, aged from 24 to 75 years old with an average of (42.81± 9.01) years old; the courses of diseases ranged from 2 to 9 months with an average of (3.96±1.45) months. In group B, there were 27 patients, including 15 males and 12 females, aged from 23 to 77 years old with an averageof (44.08±7.44) years old; the courses of diseases ranged from 2 to 7 months with an average of (3.88±1.67) months. All patients were performed focus debridement. Intraoperative blood loss, operative time were compared between two groups. VAS score before operation, 2 weeks and 12 months after operation were applied to evaluate pain relieve;Mayo elbow performance score (MEPS) before operation, 1 and 12 months after operation were used to evaluate clinical effect;changes of erythrocyte sedimentation rate (ESR) and Creactive protein, CRP) before operation, 3 weeks after antituberculosis therapy, 1 week and 6 months after operation were compared between two groups. All patients were followed up from 12 to 20 months with an average of (13.50±4.85) months. No mixed infection and recurrence of tuberculosis occurred. There were no statistical differences in intraoperative blood loss and operative time(P>0.05). There was difference in postoperative VAS score at 2 weeks between movable external fixation group (5.15±0.95) and fusion fixation group (4.04±0.84)(P<0.01);while no difference in postoperative VAS score at 12 months between two groups (P>0.05). No difference in ESR and CRP level between two groups before and after operation (P>0.05). Postoperative Mayo score at 1 and 12 months in movable external fixation group were (78.15±7.83) and (90.19±7.13);in fusion fixation group were (70.40±7.61) and (82.60±8.38);there were differences in Mayo score at different time points between two groups(P<0.01). For elbow tuberculosis, movable external fixation and fusion fixation have equal effect in operative time, amount of bleeding and control of tuberculosis infection indicator. Movable external fixation need earlier functional exercise, not conducive to pain relief at early stage, which may be better than fusion fixation, it is worth clinical promoting.

Differentially culturable tubercle bacteria dynamics during standard anti-tuberculosis treatment: A prospective cohort study

This study aimed to evaluate the dynamics of culture filtrate dependent subpopulations of Mycobacterium tuberculosis in a prospective cohort study following 17 patients through a standard 6-month anti-tuberculosis regimen, performing monthly sputum collection. We performed the limiting dilution method with culture filtrate supplementation of liquid media in pre- and post-treatment sputum samples to assess the bacillary load and to evaluate the Mycobacterium tuberculosis subpopulation dynamics within the 6-months standard anti-tuberculosis regimen. We found that supplementation increased the bacillary load by 30% in pre-treatment samples (p = 0.0005) and 35% in samples after one month of treatment (p = 0.0977). We found a weak linear correlation between the decrease of Mycobacterium tuberculosis growth in liquid media with and without culture filtrate supplementation (ρ = 0.54; p = 0.026). None of the patients had bacilli recovery after two months of treatment. Our study constitutes the first follow-up regarding Mycobacterium tuberculosis subpopulation dynamics throughout a standard 6-month anti-tuberculosis treatment and also supports the use of culture filtrate to increase bacillary load in liquid media. Moreover, it highlights that any new treatment regimens should test the efficacy of the drugs in all Mycobacterium tuberculosis subpopulations.

Debridement and bone grafting with internal fixation via anterior approach for the treatment of tuberculosis of lower cervical vertebrae

To evaluate the clinical effects of debridement and bone grafting with internal fixation via anterior approach in treatment of tuberculosis of lower cervical vertebrae. The clinical data of 15 patients with tuberculosis of lower cervical vertebrae who accepted the treatment of one-stage debridement and bone grafting with internal fixation from June 2010 to December 2018 were retrospectively analyzed. There were 9 males and 6 females, aged from 39 to 72 years with an average of (54.67±10.75) years. The lesion segment was C4 to C6. Pre- and post-operative neurologic functions were evaluated by ASIA grade. All the patients underwent the X-ray films of positive and lateral of cervical spine before and after the operation and accepted the periodic review of CT to evaluate the bone grafting. All the 15 operations were successful, no neurological or vascular injury occurred during the operation, and all patients were followed up for 18 to 52 months. The clinical symptoms improved significantly during the follow-up period and CT showed good bone grafting fusion. One patient suffered a relapse of the illness 3 years later, but was healed during the follow-up visit by strengthening the anti tuberculosis therapy. For the patients with vertebral destruction and loss of cervical stability, one-stage debridement and bone grafting with internal fixation via anterior approach has definite curative effects. On the basis of standard anti tuberculosis treatment before operation, the long-term standard anti-tuberculosis treatment after operation is the key to healing the tuberculosis of lower cervical vertebrae.