Shenjie Tang

Efficacy, safety and tolerability of linezolid for the treatment of XDR-TB: a study in China

Heterogeneity amongst cohorts of patients treated for drug-resistant tuberculosis (TB) make assessing the efficacy of new drugs and regimens unreliable without randomisation [1]. We warmly welcome the randomised controlled trial (RCT) “Efficacy, safety and tolerability of linezolid for the treatment of XDR-TB: a study in China” presented by Tang et al. [2]. Linezolid is now included on the WHO list of essential medicines [3] and falling prices will improve access. That Tang et al. [2] report a 35.3% absolute reduction in the risk of a poor outcome by adding linezolid to an optimised background regimen argues in favour of wider use. Linezolid remains a WHO “Group 5” drug, classifying it as an “anti-TB drug with limited data on efficacy and/or long term safety in the treatment of [drug-resistant]-TB” [4]. The limited data on the efficacy of drugs in this class has recently been reviewed [5]. These WHO classifications may shortly be revised and the exciting results from this study have the potential to alter guidance regarding the treatment of extensively drug-resistant (XDR) TB. We note the proposal to re-classify linezolid into Group 3 in an editorial in the October edition of the European Respiratory Journal [6]. It is with this in mind that we seek some clarifications. Response to the interesting RCT on linezolid for XDR-TB and request for information which may impact new guidelines http://ow.ly/Z1dX5Linezolid may be effective in treating multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. We conducted a prospective, multicentre, randomised study to further evaluate the efficacy, safety and tolerability of linezolid in patients with extensively drug-resistant tuberculosis in China. 65 patients who had culture-positive sputum for extensively drug-resistant tuberculosis were randomly assigned to a linezolid therapy group or a control group. Patients in the two groups adopted a 2-year individually based chemotherapy regimen. The linezolid therapy group was given linezolid at a start dose of 1200 mg per day for a period of 4-6 weeks and this was then followed by a dose of 300-600 mg per day. The proportion of sputum culture conversions in the linezolid therapy group was 78.8% by 24 months, significantly higher than that in the control group (37.6%, p<0.001). The treatment success rate in linezolid therapy group was 69.7%, significantly higher than that in the control group (34.4%, p=0.004). 27 (81.8%) patients had clinically significant adverse events in the linezolid group, of whom 25 (93%) patients had events that were possibly or probably related to linezolid. Most adverse events resolved after reducing the dosage of linezolid or temporarily discontinuing linezolid. Linezolid containing chemotherapy for treatment of extensively drug-resistant tuberculosis may significantly promote cavity closure, increase sputum culture-conversion rate and improve treatment success rate.

Risk Factors for Poor Treatment Outcomes in Patients with MDR-TB and XDR-TB in China: Retrospective Multi-Center Investigation

Background The treatment of patients with MDR- and XDR-TB is usually more complex, toxic and costly and less effective than treatment of other forms of TB. However, there is little information available on risk factors for poor outcomes in patients with MDR- and XDR-TB in China. Methodology/Principal Findings We retrospectively analyzed the clinical records of HIV-negative TB Patients with culture-proven MDR- or XDR-TB who were registered from July 2006 to June 2011 at five large-scale Tuberculosis Specialized Hospitals in China. Among 1662 HIV-seronegative TB cases which were culture-positive for M. tuberculosis complex and had positive sputum-smear microscopy results, 965 cases (58.1%) were DR-TB, and 586 cases (35.3%) were classified as having MDR-TB, accounting for 60.7% of DR-TB. 169 cases (10.2%) were XDR-TB, accounting for 17.5% of DR-TB, 28.8% of MDR-TB. The MDR-TB patients were divided into XDR-TB group (n=169) and other MDR-TB group (non-XDR MDR-TB) (n=417). In total, 240 patients (40.95%) had treatment success, and 346 (59.05%) had poor treatment outcomes. The treatment success rate in other MDR-TB group was 52.2%, significantly higher than that in the XDR-TB group (13%, P<0.001). In multivariate logistic regression analysis, poor outcomes were associated with duration of previous anti-TB treatment of more than one year (OR, 0.077; 95% CI, 0.011-0.499, P<0.001), a BMI less than 18.5 kg/m2 (OR, 2.185; 95% CI, 1.372-3.478, P<0.001), XDR (OR, 13.368; 95% CI, 6.745-26.497, P<0.001), retreatment (OR, 0.171; 95% CI, 0.093-0.314, P<0.001), diabetes (OR, 0.305; 95% CI, 0.140-0.663, P=0.003), tumor (OR, 0.095; 95% CI, 0.011-0.795, P=0.03), decreased albumin (OR, 0.181; 95% CI, 0.118-0.295, P<0.001), cavitation (OR, 0.175; 95% CI, 0.108-0.286, P<0.001). Conclusions/Significance The patients with MDR-TB and XDR-TB have poor treatment outcomes in China.The presence of extensive drug resistance, low BMI, hypoalbuminemia, comorbidity, cavitary disease and previous anti-TB treatment are independent prognostic factors for poor outcome in patients with MDR-TB.

Increased Cytokines Response in Patients with Tuberculosis Complicated with Chronic Obstructive Pulmonary Disease

Objectives To explore the change and its significance of cytokines in patients with pulmonary tuberculosis complicated with COPD. Methods The immune function of 152 cases of pulmonary tuberculosis with COPD was detected to compare with 150 cases of patients with pulmonary tuberculosis, 157 cases of patients with COPD and 50 cases of healthy volunteers who were in the hospital during the same period. T lymphocyte cell population in peripheral blood was detected by flow cytometry. The serum levels of sIL-2R, IL-6, IFN-γ, TNF-α were measured using ELISA. Results The percentage of CD4+ T cells in TB patients with or without COPD and COPD patients without TB was significantly lower than that in control group. The percentage of CD4+ T cells in patients with TB and COPD was significantly lower than that in the non-COPD TB patients. The percentage of CD8+ T cells was higher in the TB patients group than that in control group. The CD4+/CD8+ ratio in the TB patients group was significantly lower than that in control group. The concentrations of sIL-2R, IL-6, TNF-α, IFN-γ in TB patients with or without COPD and COPD patients without TB were significantly higher than those in control group. In addition, sIL-2R, IL-6, TNF-α concentrations in the patients with TB and COPD were higher than those in the non-COPD TB patients. The concentrations of sIL-2R, IL-6, TNF-α, IFN-γ in COPD patients with TB were significantly higher than those in COPD patients without TB. There was a significant negative correlation between serum levels of TNF-α, IL-6 and FEV1 (%, predicted) in COPD without TB group. Conclusions The patients with pulmonary tuberculosis complicated with COPD were impaired in cellular immunity, and its extent of immune impairment is more serious than those of the patients with pulmonary tuberculosis and the patients with COPD.

A Large Cohort Study on the Clinical Value of Simultaneous Amplification and Testing for the Diagnosis of Pulmonary Tuberculosis.

AbstractThe AmpSure simultaneous amplification and testing method for the detection of Mycobacterium tuberculosis (SAT-TB assay) was designed to diagnose rapidly pulmonary tuberculosis (PTB). Unfortunately, the diagnostic advantage is unclear from previous small sample studies. In the current inquiry, a large sample size was used to reevaluate the clinical accuracy of the SAT-TB assay using sputum specimens.A total of 3608 patients with suspected PTB were enrolled prospectively for diagnosis from sputum specimens using the SAT-TB assay. Of these, 2457 had a definite diagnosis of PTB confirmed by positive microbiology, or pathologic findings of TB in the lung, or clinical diagnosis of active PTB following anti-TB treatment with a favorable response. The sensitivity, specificity and accuracy of the SAT-TB assay were 75.8%, 100%, and 80.2%, respectively. The sensitivity of SAT-TB was significantly higher than that of the sputum smear (23.8%) (X2 = 1327.437; P = 0.000), wheresa significantly lower than that of sputum culture (89.0%) (X2 = 148.197; P = 0.000). The specificity of SAT-TB was significantly higher than that of sputum smears (96.3%) (X2 = 20.375, P = 0.000), whereas no significant difference was found compared with sputum cultures (99.6%) (X2 = 2.004, P = 0.500).Positive results in the SAT-TB assay using sputum specimens indicates that active PTB is present and anti-TB treatment is strongly recommended regardless of smear and culture test results. Simultaneous amplification and testing method for detection of Mycobacterium tuberculosis is an accurate, cheap, and rapid method for PTB diagnosis.

Differential Levels of Cytokines and Soluble Fas Ligand between Tuberculous and Malignant Effusions

Tuberculous pleurisy, which is characterized by an extensive inflammatory exudate in the pleural space, is a common manifestation of extrapulmonary tuberculosis caused by Mycobacterium tuberculosis infection but is difficult to diagnose. This study compared concentrations of three cytokines (interferon-γ and interleukin [IL]−2 and −4) and soluble Fas ligand in serum and pleural effusions from 36 patients with tuberculous pleurisy, 30 with malignant pleurisy and 30 healthy volunteers. Interferon-γ concentration was significantly higher in serum and pleural effusions, and the concentration of soluble Fas ligand was significantly higher in pleural effusion, from patients with tuberculous pleurisy than in those with malignant pleurisy. Levels of IL-2 and IL-4 were also raised in serum, but failed to reach statistical significance. Interferon-γ and soluble Fas ligand levels were significantly higher in pleural effusion than in serum. Pleural soluble Fas ligand concentrations correlated linearly with those of interferon-γ in patients with tuberculous pleurisy. These findings suggest a predominant T-helper-1 response to M. tuberculosis infection.