Clinical prediction rule for stratifying risk of pulmonary multidrug-resistant tuberculosis.
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ABSTRACT:
SUBMITTER: Martinez D
PROVIDER: S-EPMC2920322 | biostudies-other | 2010 Aug
REPOSITORIES: biostudies-other
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Project description:The clinical profile of 28 cases of multidrug resistant pulmonary tuberculosis was studied. All cases were sputum culture proved, with individual patterns of drug resistance. All were exhibited appropriate second-line antitubercular treatment. Seven (25%) patients defaulted, 2 (7.1%) had second line drug failure, but one of these was salvaged and cured after surgery, 3 (10.7%) were cured after drug therapy and 16 (57%) patients were still under treatment, 8 (28.5%) have converted at 6 months.
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Project description:Tuberculosis imposes high human and economic tolls, including in Europe. This study was conducted to develop a severity assessment tool for stratifying mortality risk in pulmonary tuberculosis (PTB) patients. A derivation cohort of 681 PTB cases was retrospectively reviewed to generate a model based on multiple logistic regression analysis of prognostic variables with 6-month mortality as the outcome measure. A clinical scoring system was developed and tested against a validation cohort of 103 patients. Five risk features were selected for the prediction model: hypoxemic respiratory failure (OR 4.7, 95% CI 2.8-7.9), age ?50 years (OR 2.9, 95% CI 1.7-4.8), bilateral lung involvement (OR 2.5, 95% CI 1.4-4.4), ?1 significant comorbidity-HIV infection, diabetes mellitus, liver failure or cirrhosis, congestive heart failure and chronic respiratory disease-(OR 2.3, 95% CI 1.3-3.8), and hemoglobin <12 g/dL (OR 1.8, 95% CI 1.1-3.1). A tuberculosis risk assessment tool (TReAT) was developed, stratifying patients with low (score ?2), moderate (score 3-5) and high (score ?6) mortality risk. The mortality associated with each group was 2.9%, 22.9% and 53.9%, respectively. The model performed equally well in the validation cohort. We provide a new, easy-to-use clinical scoring system to identify PTB patients with high-mortality risk in settings with good healthcare access, helping clinicians to decide which patients are in need of closer medical care during treatment.
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Project description:[This corrects the article DOI: 10.1371/journal.pone.0162797.].
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Project description:BACKGROUND:MDR-TB is a major threat to global TB control. In 2015, 580,000 were treated for MDR-TB worldwide. The worldwide roll-out of GeneXpert MTB/RIF® has improved diagnosis of MDR-TB; however, in many countries laboratories are unable to assess drug resistance and clinical predictors of MDR-TB could help target suspected patients. In this study, we aimed to determine the clinical factors associated with MDR-TB in Bamako, Mali. METHODS:We performed a cross-sectional study of 214 patients with presumed MDR-TB admitted to University of Bamako Teaching Hospital, Point-G between 2007 and 2016. We calculated crude and adjusted odds ratios for MDR-TB disease diagnosis using SPSS. RESULTS:We found that age ?40years (OR=2.56. 95% CI: 1.44-4.55), two courses of prior TB treatment (OR=3.25, 95% CI: 1.44-7.30), TB treatment failure (OR=3.82, 95% CI 1.82-7.79), sputum microscopy with 3+ bacilli load (OR=1.98, 95% CI: 1.13-3.48) and a history of contact with a TB patient (OR=2.48, 95% CI: 1.11-5.50) were significantly associated with confirmation of MDR-TB disease. HIV was not a risk factor for MDR-TB (aOR=0.88, 95% CI: 0.34-1.94). CONCLUSION:We identified several risk factors that could be used to identify MDR-TB suspects and prioritize them for laboratory confirmation. Prospective studies are needed to understand factors associated with TB incidence and clinical outcomes of TB treatment and disease.
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Project description:BACKGROUND:Macrophages play a key role in the infection process, and alternatively activated macrophages (M2 polarization) play important roles in persistent infection via the immune escape of pathogens. This suggests that immune escape of pathogens from host immunity is an important factor to consider in treatment failure and multidrug-resistant tuberculosis (MDR-TB)/extensively drug-resistant tuberculosis (XDR-TB). In this study, we investigated the association between macrophage polarization and MDR-TB/XDR-TB and the association between macrophage polarization and the anti-TB drugs used. METHODS:iNOS and arginase-1, a surface marker of polarized macrophages, were quantified by immunohistochemical staining and imaging analysis of lung tissues of patients who underwent surgical treatment for pulmonary TB. Drug susceptibility/resistance and the type and timing of anti-tuberculosis drugs used were investigated. RESULTS:The M2-like polarization rate and the ratio of the M2-like polarization rate to the M1-like polarization rate were significantly higher in the MDR-TB/XDR-TB group than in the DS-TB group. The association between a high M2-like polarization rate and MDR-TB/XDR-TB was more pronounced in patients with a low M1-like polarization rate. Younger age and a higher M2-like polarization rate were independent associated factors for MDR-TB/XDR-TB. The M2-like polarization rate was significantly higher in patients who received anti-TB drugs containing pyrazinamide continuously for 4 or 6?weeks than in those who received anti-TB drugs not containing pyrazinamide. CONCLUSIONS:The M2-like polarization of macrophages is associated with MDR-TB/XDR-TB and anti-TB drug regimens including pyrazinamide or a combination of pyrazinamide, prothionamide and cycloserine.
| S-EPMC6988333 | biostudies-literature
Project description:Defining the precise relationship between resistance mutations and quantitative phenotypic drug susceptibility testing will increase the value of whole-genome sequencing (WGS) for predicting tuberculosis drug resistance. However, a large number of WGS data sets currently lack corresponding quantitative phenotypic data-the MICs. Using MYCOTBI plates, we determined the MICs to nine antituberculosis drugs for 154 clinical multidrug-resistant tuberculosis isolates from the Shenzhen Center for Chronic Disease Control in Shenzhen, China. Comparing MICs with predicted drug-resistance profiles inferred by WGS showed that WGS could predict the levels of resistance to isoniazid, rifampicin, streptomycin, fluoroquinolones, and aminoglycosides. We also found some mutations that may not be associated with drug resistance, such as EmbB D328G, mutations in the gid gene, and C-12T in the eis promoter. However, some strains carrying the same mutations showed different levels of resistance to the corresponding drugs. The MICs of different strains with the RpsL K88R, fabG1 C-15T mutations and some with mutations in embB and rpoB, had MICs to the corresponding drugs that varied by 8-fold or more. This variation is unexplained but could be influenced by the bacterial genetic background. Additionally, we found that 32.3% of rifampicin-resistant isolates were rifabutin-susceptible, particularly those with rpoB mutations H445D, H445L, H445S, D435V, D435F, L452P, S441Q, and S441V. Studying the influence of bacterial genetic background on the MIC and the relationship between rifampicin-resistant mutations and rifabutin resistance levels should improve the ability of WGS to guide the selection of medical treatment regimens. IMPORTANCE Whole-genome sequencing (WGS) has excellent potential in drug-resistance prediction. The MICs are essential indications of adding a particular antituberculosis drug dosage or changing the entire treatment regimen. However, the relationship between many known drug-resistant mutations and MICs is unclear, especially for rarer ones. The results showed that WGS could predict resistance levels to isoniazid, rifampicin, streptomycin, fluoroquinolones, and aminoglycosides. However, some mutations may not be associated with drug resistance, and some others may confer various MICs to strains carrying them. Also, 32.3% of rifampicin (RIF)-resistant strains were classified as sensitive to rifabutin (RFB), and some mutations in the rpoB gene may be associated with this phenotype. Our data on the MIC distribution of strains with some rarer mutations add to the accumulated data on the resistance level associated with such mutations to help guide further research and draw meaningful conclusions.
| S-EPMC9241708 | biostudies-literature
Project description:Background: Multidrug-resistant pulmonary tuberculosis (MDR-PTB) has become a major cause of high morbidity and mortality related to TB. Conventional drug regimens are ineffective for the treatment of MDR-PTB patients with cavities. This study aimed to evaluate the clinical efficacy and safety of one-way endobronchial valves (EBVs) for the treatment of cavities in MDR-PTB patients. Methods: MDR-PTB patients with positive sputum cultures, sputum smears, and cavities were treated with EBVs in the drainage bronchus of the pulmonary cavity between November 2013 and March 2018. The participants comprised those who had failed previous anti-tuberculosis therapy, as determined by drug susceptibility testing. Results: Thirty-five MDR-PTB patients were included, three of whom were lost during follow-up. The size of the lung cavity was reduced in all of the patients after EBV implantation, including the three lost to follow-up. In the remaining 32 patients, the sputum culture conversion (SCC) rate reached 100%, and the cavity closure rate was 68.8%. There were no significant differences in the cavity closure rate between patients aged ≤40 and >40 years, between the upper and lower lobes, or between the use and non-use of linezolid groups (p > 0.05). Interestingly, the cavity closure rate was higher in women than in men (p = 0.005). Moreover, the cavity closure rate correlated with the time to SCC (correlation coefficient, 0.8933; p < 0.0001). There were no severe adverse events in the patients treated with EBV implantation. Conclusion: EBV installation is effective and safe for the treatment of cavities in MDR-PTB patients. The efficacy of EBV treatment may not be affected by age, disease course, or the location of the lung lobe in the cavity.
| S-EPMC9414730 | biostudies-literature
Project description:BACKGROUND:Treatment outcomes among patients treated for multidrug-resistant tuberculosis (MDR-TB) are often sub-optimal. Therefore, the early prediction of poor treatment outcomes may be useful in patient care, especially for clinicians when they have the ability to make treatment decisions or offer counselling or additional support to patients. The aim of this study was to develop a simple clinical risk score to predict poor treatment outcomes in patients with MDR-TB, using routinely collected data from two large countries in geographically distinct regions. METHODS:We used MDR-TB data collected from Hunan Chest Hospital, China and Gondar University Hospital, Ethiopia. The data were divided into derivation (n = 343; 60%) and validation groups (n = 227; 40%). A poor treatment outcome was defined as treatment failure, lost to follow up or death. A risk score for poor treatment outcomes was derived using a Cox proportional hazard model in the derivation group. The model was then validated in the validation group. RESULTS:The overall rate of poor treatment outcome was 39.5% (n = 225); 37.9% (n = 86) in the derivation group and 40.5% (n = 139) in the validation group. Three variables were identified as predictors of poor treatment outcomes, and each was assigned a number of points proportional to its regression coefficient. These predictors and their points were: 1) history of taking second-line TB treatment (2 points), 2) resistance to any fluoroquinolones (3 points), and 3) smear did not convert from positive to negative at two months (4 points). We summed these points to calculate the risk score for each patient; three risk groups were defined: low risk (0 to 2 points), medium risk (3 to 5 points), and high risk (6 to 9 points). In the derivation group, poor treatment outcomes were reported for these three groups as 14%, 27%, and 71%, respectively. The area under the receiver operating characteristic curve for the point system in the derivation group was 0.69 (95% CI 0.60 to 0.77) and was similar to that in the validation group (0.67; 95% CI 0.56 to 0.78; p = 0.82). CONCLUSION:History of second-line TB treatment, resistance to any fluoroquinolones, and smear non-conversion at two months can be used to estimate the risk of poor treatment outcome in patients with MDR-TB with a moderate degree of accuracy (AUROC = 0.69).
| S-EPMC6941813 | biostudies-literature
Project description:A population pharmacokinetic (PopPK) model of delamanid in patients with pulmonary multidrug-resistant tuberculosis (MDR-TB) was developed using data from four delamanid clinical trials. The final PopPK data set contained 20,483 plasma samples from 744 patients with MDR-TB receiving an optimized background regimen (OBR). Delamanid PK was adequately described for all observed dosing regimens and subpopulations by a two-compartment model with first-order elimination and absorption, an absorption lag time, and decreased relative bioavailability with increasing dose. Relative bioavailabilities of 200-mg and higher doses (250 and 300 mg) were 76% and 58% of a 100-mg dose, respectively. Relative bioavailability was 26% higher after evening doses than morning doses and 9% higher in outpatient settings than inpatient settings. The rate of absorption was higher, and lag time was shorter, following a morning dose than an evening dose. Relative bioavailabilities in patients in Northeast Asian and Southeast Asian regions were 53% and 40% higher, respectively, than in patients in non-Asian regions. Apparent clearance was higher (to the power of -0.892) in patients with hypoalbuminemia (albumin levels of <3.4 g/dl). Coadministration of efavirenz in patients with HIV increased delamanid clearance by 35%. Delamanid exposure was not affected by age (18 to 64 years), mild or moderate renal impairment, anti-TB antibiotic resistance status, HIV status, or markers of hepatic dysfunction or by concomitant administration of OBR, lamivudine, tenofovir, pyridoxine, CYP3A4 inhibitors and inducers, or antacids. Model evaluation suggested reasonable model fit and predictive power, indicating that the model should prove reliable to derive PK metrics for subsequent PK/PD analyses.
| S-EPMC7927850 | biostudies-literature
Project description:Rationale: There is poor understanding about protective immunity and the pathogenesis of cavitation in patients with tuberculosis.Objectives: To map pathophysiological pathways at anatomically distinct positions within the human tuberculosis cavity.Methods: Biopsies were obtained from eight predetermined locations within lung cavities of patients with multidrug-resistant tuberculosis undergoing therapeutic surgical resection (n = 14) and healthy lung tissue from control subjects without tuberculosis (n = 10). RNA sequencing, immunohistochemistry, and bacterial load determination were performed at each cavity position. Differentially expressed genes were normalized to control subjects without tuberculosis, and ontologically mapped to identify a spatially compartmentalized pathophysiological map of the cavity. In silico perturbation using a novel distance-dependent dynamical sink model was used to investigate interactions between immune networks and bacterial burden, and to integrate these identified pathways.Measurements and Main Results: The median (range) lung cavity volume on positron emission tomography/computed tomography scans was 50 cm3 (15-389 cm3). RNA sequence reads (31% splice variants) mapped to 19,049 annotated human genes. Multiple proinflammatory pathways were upregulated in the cavity wall, whereas a downregulation "sink" in the central caseum-fluid interface characterized 53% of pathways including neuroendocrine signaling, calcium signaling, triggering receptor expressed on myeloid cells-1, reactive oxygen and nitrogen species production, retinoic acid-mediated apoptosis, and RIG-I-like receptor signaling. The mathematical model demonstrated that neuroendocrine, protein kinase C-θ, and triggering receptor expressed on myeloid cells-1 pathways, and macrophage and neutrophil numbers, had the highest correlation with bacterial burden (r > 0.6), whereas T-helper effector systems did not.Conclusions: These data provide novel insights into host immunity to Mycobacterium tuberculosis-related cavitation. The pathways defined may serve as useful targets for the design of host-directed therapies, and transmission prevention interventions.
| S-EPMC6680310 | biostudies-literature