Heping Xiao

Evaluation of Cerebrospinal Fluid Adenosine Deaminase Activity for the Differential Diagnosis of Tuberculous and Nontuberculous Meningitis

Introduction: The diagnosis value of adenosine deaminase (ADA) activity in cerebrospinal fluid (CSF) of tuberculous meningitis (TBM) has been well documented. However, the cutoff point of CSF ADA has not been fully assessed. In the current study, the authors set to calculate the cutoff points of ADA and monitor the changes of CSF ADA activities in patients with TBM after antitubercular therapy. Methods: CSF ADA activity in patients with different types of meningitis was measured by Trinder enzyme-coupled assay. Results: The mean CSF ADA values in the patients with TBM, bacterial meningitis, viral meningitis, cryptococcal meningitis and noninfectious neurologic disorders were 14.1 ± 5.4, 9.6 ± 5.5, 4.3 ± 2.5, 7.8 ± 3.4 and 2.6 ± 1.3 U/L, respectively. CSF ADA activity was significantly higher in TBM compared with patients with non-TBM (P < 0.05). Moreover, the best cutoff point for differentiating between TBM and non-TBM was 9.5 U/L. In addition, CSF ADA activity was decreased in patients with TBM after antitubercular therapy in a time-dependent manner. Conclusions: The determination of ADA with a cutoff value of 9.5 U/L in CSF is a useful aid for the differential diagnosis of TBM and non-TBM. Moreover, dynamic monitoring of CSF ADA activity may be an indicator for evaluating antitubercular therapy in TBM.

Prevalence, risk factors, management, and treatment outcomes of first-line antituberculous drug-induced liver injury: a prospective cohort study

Antituberculosis drug‐induced liver injury (ATDILI) is one of the most deleterious side effects associated with chemotherapy against tuberculosis (TB). In this study, our objective was to determine the incidence, risk factors, and management of ATDILI and analyze its impact on the treatment outcome in patients receiving standard anti‐TB chemotherapy.

Drug-induced lymphocyte stimulation test in the prediction of drug-induced hypersensitivity to antituberculosis drugs

Antituberculosis (TB) chemotherapeutic drugs may cause a variety of adverse drug reactions (ADRs). To assess the potential of drug-induced lymphocyte stimulation test (DLST) in screening ADRs in patients treated with anti-TB drugs, we performed DLST in 272 TB patients (176 cases with ADRs and 96 controls without ADRs) treated with anti-TB drugs isoniazid (INH), rifampicin (RFP), ethambutol (EMB), and pyrazinamide (PZA). The ADRs were diagnosed by drug provocation test based on clinical and laboratory examinations. The sensitivities of DLST in the diagnosis of INH-, RFP-, EMB-, or PZA-induced ADRs were 57.8%, 37.1%, 42.4%, and 23.1%, respectively, with the corresponding specificities being 93.4%, 94.0%, 97.5%, and 98.8%. DLST has high specificity and limited sensitivity in the diagnosis of anti-TB drug-induced ADRs. In combination with clinical observation and drug use history, DLST could have a predictive validity of ADRs, especially when a positive result is obtained.

Clinical features and treatment of drug fever caused by anti-tuberculosis drugs

Tuberculosis is a major global health problem. However, anti‐tuberculosis drug treatment has many adverse effects, such as drug‐caused fever. The aim of this study was to investigate the clinical features and treatments of anti‐tuberculosis drugs‐induced fever.

Genetic Polymorphisms of SLCO1B1, CYP2E1 and UGT1A1 and Susceptibility to Anti-Tuberculosis Drug-Induced Hepatotoxicity: A Chinese Population-Based Prospective Case–Control Study

BackgroundDrug transporters and drug-metabolizing enzymes have been linked to drug-induced hepatotoxicity. Solute carrier organic anion transporter family member 1B1 (SLCO1B1), cytochrome P450 2E1 (CYP2E1), and UDP glucuronosyltransferase 1A1 (UGT1A1) were selected as candidate genes to explore their association with susceptibility to anti-tuberculosis drug-induced hepatotoxicity (ATDH).MethodsThirty-four tag single nucleotide polymorphisms (tagSNPs) in SLCO1B1, CYP2E1, and UGT1A1 with 10-kb expansion up- and down-stream were genotyped in 461 patients with ATDH and 466 patients without ATDH in a prospective 1:1 matched case–control study. The frequencies and distributions of genotypes and haplotypes were compared between the groups using three genetic models (dominant, recessive, and additive) to identify associations with susceptibility to ATDH.ResultsPatients with the rs4149034 G/A, rs1564370 G/C, and rs2900478 T/A genotypes of SLCO1B1 had a significantly lower risk of ATDH, while those carrying the rs2417957 T/T and rs4149063 T/T genotypes had an increased risk. The rs4148323 A/A genotype of UGT1A1 was found to significantly reduce the risk of ATDH. Haplotype analysis showed the TGTG, TTTC, and GTTC haplotypes of SLCO1B1 were associated with an increased ATDH risk, whereas the GACC haplotype was related to a reduced risk. The ATG haplotype of UGT1A1 reduced the risk of ATDH. Moreover, treatment outcomes in tuberculosis patients were further affected by genetic variants of SLCO1B1.ConclusionsGenetic polymorphisms of SLCO1B1 and UGT1A1 were found to be associated with susceptibility to ATDH. Molecular identification of susceptibility genes provides a theoretical foundation for predicting the likelihood of ATDH and predicting treatment outcomes in tuberculosis patients.

MicroRNA-27a controls the intracellular survival of Mycobacterium tuberculosis by regulating calcium-associated autophagy

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) kills millions every year, and there is urgent need to develop novel anti-TB agents due to the fast-growing of drug-resistant TB. Although autophagy regulates the intracellular survival of Mtb, the role of calcium (Ca2+) signaling in modulating autophagy during Mtb infection remains largely unknown. Here, we show that microRNA miR-27a is abundantly expressed in active TB patients, Mtb-infected mice and macrophages. The target of miR-27a is the ER-located Ca2+ transporter CACNA2D3. Targeting of this transporter leads to the downregulation of Ca2+ signaling, thus inhibiting autophagosome formation and promoting the intracellular survival of Mtb. Mice lacking of miR-27a and mice treated with an antagomir to miR-27a are more resistant to Mtb infection. Our findings reveal a strategy for Mtb to increase intracellular survival by manipulating the Ca2+-associated autophagy, and may also support the development of host-directed anti-TB therapeutic approaches.How Mycobacterium tuberculosis (Mtb) escapes autophagy-mediated clearance is poorly understood. Here, Liu et al. show that Mtb-induced MicroRNA-27a targets the ER-associated calcium transporter CACNA2D3, leading to suppression of antimicrobial autophagy and to enhanced intracellular survival of Mtb.

Comparison of closed-chest drainage with rib resection closed drainage for treatment of chronic tuberculous empyema

Background This study aimed to compare the efficacy of closed-chest drainage with rib resection closed drainage of chronic tuberculous empyema. Methods This retrospective study reviewed 86 patients with tuberculous empyema in Shanghai Pulmonary Hospital from August 2010 to November 2015. Among these included patients, 22 patients received closed-chest drainage, and 64 patients received rib resection closed drainage. Results The results showed that after intercostal chest closed drain treatment, 2 (9.09%) patients were recovery, 13 (59.09%) patients had significantly curative effect, 6 (27.27%) patients had partly curative effect, and 1 (4.55%) patient had negative effect. After treatment of rib resection closed drainage, 9 (14.06%) patients were successfully recovery, 31 (48.44%) patients had significantly curative effect, 19 (29.69%) patients had partly curative effect, and 5 (7.81%) patients had negative effect. There was no significant difference in the curative effect (P>0.05), while the average catheterization time of rib resection closed drainage (130.05±13.12 days) was significant longer than that (126.14±36.84 days) in course of intercostal chest closed drain (P<0.05). Conclusions This study had demonstrated that closed-chest drainage was an effective procedure for treating empyema in young patients. It was less invasive than rib resection closed drainage and was associated with less severe pain. We advocated closed-chest drainage for the majority of young patients with empyema, except for those with other diseases.

Short-course Regimen for Subsequent Treatment of Pulmonary Tuberculosis: A Prospective, Randomized, Controlled Multicenter Clinical Trial in China

PURPOSE We designed a prospective, multicenter, randomized, controlled study to assess a 5-month regimen compared with the standard regimen on previously treated patients with pulmonary tuberculosis (TB). METHODS We enrolled 917 sputum smear-positive patients undergoing additional treatment in 27 major tuberculosis hospitals in China. Patients were randomly assigned to a test group (n = 626)treated with a 5-month regimen of moxifloxacin, pasiniazid, rifabutin, ethambutol, and pyrazinamide or a reference group (n = 291) treated with an 8-month regimen of isoniazid, rifampicin, and streptomycin. All patients with a favorable response were followed up for 5 years after the end of treatment. FINDINGS Of the study patients, 61 in the test group and 19 in the reference group had multidrug-resistant (MDR) TB. The treatment success rate in the study group was 74.12%, which was significantly higher than the 67.70% in the reference group (P = 0.04), whereas the treatment success rate of patients with MDR-TB was not significantly different between the test and reference groups (70.5% vs 63.1%, P =0.79). The adverse effects rates in the test and reference groups were 7.4% and 3.1%, respectively (P = .01). The difference in the TB recurrence rates between the group arm (9.6%) and the reference group (21.8%) was statistically significant (P < 0.001). IMPLICATIONS The moxifloxacin, pasiniazid, rifabutin, ethambutol, and pyrazinamide test regimen yielded higher success and lower recurrence rates than the currently recommended isoniazid, rifampicin, and streptomycin regimen, but the rate of adverse effects was higher. ClinicalTrials.gov identifier: NCT02331823.

Drug-Resistant TB

The situation of drug-resistant tuberculosis (TB) worldwide remains very serious, especially for multidrug-resistant and extensively drug-resistant TB epidemics. These diseases have much longer infectious periods than drug-sensitive TB, making them much more harmful to both patients and public health. The measures required to treat drug-resistant TB successfully include early detection of drug-resistant patients with proper techniques and methods, an effective chemotherapy regimen, and management with Directly Observed Therapy (DOT) and the World Health Organization’s “Stop TB Strategy.”