Outcome correlation of smear-positivity but culture-negativity during standard anti-tuberculosis treatment in Taiwan.

BACKGROUND: The appearance of smear-positivity but culture-negativity (SPCN) for acid-fast bacilli among sputum specimen is frequently found in pulmonary tuberculosis (TB) patients during treatment. This study aimed to investigate clinical risk factors, impacts on treatment course, and relapse pattern associated with sputum SPCN. METHODS: We retrospectively enrolled 800 patients with culture-proven pulmonary TB who were receiving standard treatment and follow-up at six TB-referral hospitals in Taiwan between January 2006 and December 2007. Relevant patient characteristics and chemotherapy data were analyzed for associations with incidence of SPCN. Data from patients who relapsed within 3 years after completing treatment were analyzed for associations with SPCN during treatment. RESULTS: Of the 800 subjects, 111 (13.8%) had sputum SPCN during treatment. Three factors were found to predict the development of SPCN; namely, high initial acid-fast staining grading (OR, 3.407; 95% CI, 2.090-5.553), cavitation on chest-X ray films (OR, 2.217; 95% CI, 1.359-3.615), and smoking (OR, 1.609; 95% CI, 1.006-2.841). Patients with SPCN had longer treatment duration (rifampicin: 284 ± 91 vs. 235 ± 69 days, P <0.001; isoniazid: 289 ± 90 vs. 234 ± 69 days, P < 0.001) than those without SPCN. Finally, the rate of relapse within 3 years of completing treatment was similar for groups with/without SPCN (2.7%, 3/111 vs. 1.0%, 7/689, respectively; P = 0.15). CONCLUSIONS: In conclusion, severity of infection was a major risk factor for SPCN during treatment; however, the relapse rate within 3 years of completing treatment was not affected by the appearance of SPCN.

Factors associated with misdiagnosis of smear-negative tuberculosis: an experience in Taiwan.

BACKGROUND: A negative sputum smear from a patient with history, physical examination, and chest x-ray findings suggestive of tuberculosis (TB) presents a diagnostic dilemma. We investigated the possible factors associated with a misdiagnosis and inappropriate treatment of TB among such patients. METHODS: We reviewed the records of 193 patients whose diagnoses with TB included conflicting test results and were reported to the Taiwan Centers for Disease Control in 2004. When other conditions were found to underlie the initial abnormal chest x-ray finding, the diagnosis was revised. RESULTS: Mycobacterium tuberculosis was isolated from sputum samples in 72 of 193 patients (37%), nontuberculous mycobacteria from 4 (2%), and no bacteriologic evidence of M. tuberculosis from 117 (61%). The initial diagnosis of TB was revised for 26 (13.5%) patients. Patients with positive M. tuberculosis culture had a lower incidence of revised diagnoses (4.2%, P < .001) than those negative for mycobacterial culture (17.1%) and those with nontuberculous mycobacteria (75%). Chest cavitations in this study were not a significant predictor of revised diagnosis (odds ratio 0.30, P = .08). CONCLUSIONS: An incorrect diagnosis of TB despite a negative sputum smear result is more likely to be made for patients positive for nontuberculous mycobacteria culture and less likely for patients with positive M. tuberculosis culture.

Six-channel ECG-based pulse wave velocity for assessing whole-body arterial stiffness.

BACKGROUND: Despite the proposal of different means of non-invasive arterial stiffness assessment, none offers simultaneous information on whole-body peripheral arterial condition. We investigated the validity of applying a six-channel electrocardiogram-based pulse wave velocity (ECG-PWV) measurement system for this purpose. METHODS: The study consisted of two parts. Part One enrolled hypertensive (Group 1, n = 32) and normal (Group 2, n = 32) subjects, whereas Part Two recruited diabetic (Group 3, n = 50) and normal (Group 4, n = 50) subjects. To validate the application of ECG-PWV in assessing peripheral arterial stiffness in different parts of body, ECG-PWV data were compared with three other parameters including the cardio-ankle vascular index (CAVI), pulse wave velocity-digital volume pulse (PWV-DVP) and intima-media thickness (IMT). RESULTS: ECG-PWV in healthy subjects in Part One correlated significantly with CAVI and PWV-DVP (p < 0.05), whereas ECG-PWV and CAVI were significantly different between the hypertensive and normal subjects. Moreover, comparison of IMT and ECG-PWV from different sites showed significant correlation only between IMT and ECG-PWV from earlobe (r = 0.495, p = 0.004). No significant association, however, was noted between IMT and CAVI. For Part Two, significant differences existed between diabetic and normal subjects in body weight, waist circumference, level of HbA1c, fasting blood sugar, serum creatinine and ECG-PWV from the foot. However, no significant difference was noted in PWV-DVP between two groups. CONCLUSIONS: Six-channel ECG-PWV measurement system showed remarkable correlation with IMT in hypertensive subjects and with key anthropometric and biochemical parameters in diabetic patients, suggesting its validity in assessing whole-body arterial stiffness in subjects with peripheral arterial diseases within 10 min.

Effect of type 2 diabetes mellitus on the clinical severity and treatment outcome in patients with pulmonary tuberculosis: a potential role in the emergence of multidrug-resistance.

BACKGROUND/PURPOSE: A globally increasing trend of type 2 diabetes mellitus (DM), the rising prevalence of tuberculosis (TB) in many countries, and the emergence of multidrug-resistant TB (MDR-TB) in recent years pose a serious challenge for TB control. METHODS: We investigated pulmonary tuberculosis patients with and without type 2 DM (DMTB and TB, respectively) treated at the Chest Hospital, Taiwan, between November 2004 and October 2005. RESULTS: One hundred and ninety-two new patients (60 DMTB, 132 TB) were regularly treated for a full course (≥ 6 months) and prospectively followed for more than 1 year. The DMTB patients had more severe infections (far-advanced: 45.0%vs. 22.7%, p < 0.01), higher mycobacterial loads (sputum smear: 2.9 ± 1.3(+)vs. 1.9 ± 1.7(+), p < 0.01), higher treatment failure rates (17%vs. 2%, p < 0.01), and longer delayed clearance of mycobacteria than did the TB patients (2.5 ± 3.0 months vs. 1.6 ± 1.4 months, p < 0.01). After one year, three DMTB patients and one TB patient had MDR-TB (5.0%vs. 0.8%, p = 0.056). Bacterial genotyping revealed that the proportion of mycobacterial strains was not significantly different in DMTB and TB patients (Beijing strain: 46.7%vs. 40.6%, Non-Beijing strain: 53.3%vs. 59.4%, p = 0.632). CONCLUSION: DMTB patients have more severe TB infections, which require longer treatment and are more likely to develop MDR-TB than are patients with TB alone.

Hyperosmolarity enhanced susceptibility to renal tubular fibrosis by modulating catabolism of type I transforming growth factor-beta receptors.

Hyperosmolarity plays an essential role in the pathogenesis of diabetic tubular fibrosis. However, the mechanism of the involvement of hyperosmolarity remains unclear. In this study, mannitol was used to evaluate the effects of hyperosmolarity on a renal distal tubule cell line (MDCK). We investigated transforming growth factor-beta receptors and their downstream fibrogenic signal proteins. We show that hyperosmolarity significantly enhances the susceptibility to exogenous transforming growth factor (TGF)-beta1, as mannitol (27.5 mM) significantly enhanced the TGF-beta1-induced increase in fibronectin levels compared with control experiments (5.5 mM). Specifically, hyperosmolarity induced tyrosine phosphorylation on TGF-beta RII at 336 residues in a time (0-24 h) and dose (5.5-38.5 mM) dependent manner. In addition, hyperosmolarity increased the level of TGF-beta RI in a dose- and time-course dependent manner. These observations may be closely related to decreased catabolism of TGF-beta RI. Hyperosmolarity significantly downregulated the expression of an inhibitory Smad (Smad7), decreased the level of Smurf 1, and reduced ubiquitination of TGF-beta RI. In addition, through the use of cycloheximide and the proteasome inhibitor MG132, we showed that hyperosmolarity significantly increased the half-life and inhibited the protein level of TGF-beta RI by polyubiquitination and proteasomal degradation. Taken together, our data suggest that hyperosmolarity enhances cellular susceptibility to renal tubular fibrosis by activating the Smad7 pathway and increasing the stability of type I TGF-beta receptors by retarding proteasomal degradation of TGF-beta RI. This study clarifies the mechanism underlying hyperosmotic-induced renal fibrosis in renal distal tubule cells.

Compatibility of pulse-pulse intervals with R-R intervals in assessing cardiac autonomic function and its relation to risks of atherosclerosis.

OBJECTIVE: Heart rate variability (HRV) analysis using electrocardiographic R-R intervals (RRIs) in either a time or a frequency domain is a useful tool for assessing cardiac autonomic dysfunction in clinical research. For convenience, pulse-pulse intervals (PPIs) acquired by photoplethysmography have been used to assess HRV. However, the compatibility of PPI with RRI is controversial. MATERIALS AND METHODS: In this study, we investigated the compatibility of PPI with RRI in five groups of participants, including nonoverweight young individuals with a body mass index (BMI) <24 kg/m2 (Group 1, n = 20, aged 18-40 years), overweight young individuals with a BMI ≥24 kg/m2 (Group 2, n = 13, aged 21-38 years), nonoverweight upper middle-aged individuals with a BMI <24 kg/m2 (Group 3, n = 21, aged 45-89 years), overweight upper middle-aged individuals with a BMI ≥24 kg/m2 (Group 4, n = 14, aged 43-74 years), and diabetic patients with a BMI ≥24 kg/m2 (Group 5, n = 19, aged 35-74 years). We then used cross-approximate entropy (CAE) to assess the compatibility between RRI and PPI and analyzed HRV in the time and frequency domains derived from PPR and RRI with traditional methods. RESULTS: The CAE values in Group 1 were significantly lower than those in Group 2 (1.68 ± 0.16 vs. 1.78 ± 0.15, P = 0.041), Group 3 (1.68 ± 0.16 vs. 2.05 ± 0.27, P < 0.001), Group 4 (1.68 ± 0.16 vs. 1.87 ± 0.23, P = 0.023), and Group 5 (1.68 ± 0.16 vs. 2.09 ± 0.23, P < 0.001). There were no significant differences in HRV acquired by PPI and RRI, except for proportion of pairs of adjacent NN intervals differing by more than 50 ms in the entire recording in Group 1. All HRVs derived from PPI were different from those acquired from RRI in the other groups. CONCLUSION: PPI may be an alternative parameter for effectively assessing cardiac autonomic function in nonoverweight healthy individuals. It should be used carefully in overweight, elderly, or diabetic individuals.

Transmission of Mycobacterium tuberculosis in a family proved by genotyping.

BACKGROUND/PURPOSE: Molecular genetic methods have been applied in various epidemiologic studies including investigations of disease acquisition by contact. This report describes the use of various molecular genetic methods in tracing possible household transmission of tuberculosis by contact. METHODS: Four Mycobacterium tuberculosis strains, each from four members of a family, were first isolated and identified in the clinical laboratory of the Chest Hospital and were submitted to the National Reference Laboratory of Mycobacteriology for further confirmation and genotyping. In this study, IS6110 restriction fragment length polymorphism (RFLP), spacer oligonucleotide typing (spoligotyping) and mycobacterial interspersed repetitive units-variable number tandem repeats (MIRU-VNTR), and rpoB gene sequencing were used for genotyping. RESULTS: All four strains were found to have identical spoligotypes, MIRU-VNTR patterns, and similar IS6110 RFLP profiles. The results of the drug susceptibility test and of rpoB sequencing showed that all four strains were rifampicin resistant. CONCLUSION: Household transmission through close contact was thus proved by genotyping. We conclude that all four family members were infected with the same lineage of M. tuberculosis.

Antituberculosis drug resistance among retreatment tuberculosis patients in a referral center in Taipei.

BACKGROUND AND PURPOSE: To determine the prevalence of antituberculosis drug resistance among retreatment tuberculosis patients in a referral center in Taipei. METHODS: We reviewed the register of susceptibility testing of the mycobacteriology laboratory of the Chronic Disease Control Bureau to identify patients with positive culture for Mycobacterium tuberculosis in the year 2000-2001. Medical charts were reviewed to determine patients' tuberculosis treatment histories. Patients who had multidrug-resistant (MDR) tuberculosis, defined as documentation of isolates resistant to at least isoniazid and rifampin, were identified. Retreatment tuberculosis patients without prior evidence of MDR tuberculosis were classified into 3 categories, i.e., relapse, treatment after default and treatment after failure, and the frequency and patterns of antituberculosis drug resistance were determined. RESULTS: A total of 317 patients who had received antituberculosis treatment for more than 1 month were identified. Among them, 183 were retreatment cases without prior evidence of MDR tuberculosis, including 93 with relapse, 57 with treatment after default, and 33 with treatment after failure. Among the 183 patients, the prevalence of resistance to any drug was 42.6%; 14.2% were resistant to 1 drug, 13.7% to 2 drugs, 7.1% to 3 drugs, 7.7% to 4 drugs or more, and 24.6% had MDR tuberculosis. The prevalence of any drug resistance among patients with relapse, treatment after default and treatment after failure was 33.3%, 42.1%, and 69.7%, respectively, while the prevalence of MDR tuberculosis in these groups was 12.9%, 19.3% and 66.7%, respectively. CONCLUSIONS: If susceptibility results are unavailable, the World Health Organization-recommended retreatment regimen may be used in retreatment tuberculosis patients. However, the high proportion of MDR tuberculosis among patients with treatment after failure poses a challenge to the efficacy of the retreatment regimen.

Association of Mycobacterium tuberculosis genotypes and clinical and epidemiological features - a multi-center study in Taiwan.

Genotypes of Mycobacterium tuberculosis (MTB) are related to the geographic origin of the patients and population migration. The relationship between genotypes of MTB and clinical presentations has mainly focused on transmission of multi-drug resistant MTB strain in population. This study aimed to investigate the molecular epidemiology and dynamic change of MTB genotypes in Taiwan, and their association with clinical presentation among patients with pulmonary tuberculosis. A multi-center, two-year study which enrolled 516 patients with 516 MTB isolates was conducted, including: (1) 254 isolates from northern Taiwan; (2) 38 isolates from mid-western Taiwan; (3) 211 isolates from southern Taiwan; and (4) 13 isolates from the east coast of Taiwan. The isolates were genotyped with spoligotyping and standardized 12-loci-MIRU-VNTR method. The results showed Beijing/Beijing-like family was the major genotype of MTB in the northern (58%), eastern (53%), and southern (33%) regions. The second most widely spread lineage were the EAI-Manila (20% in the west and south) and Haarlem family (13-27% in the south, west, and east). According to the cluster analysis of 12-MIRU-VNTR genotypes, there were differences in distribution of MTB genotype between the northern and southern regions, and a temporal relationship between isolation year and 12-MIRU-VNTR genotype especially in loci 26 and 39 might exist. Furthermore, some patients with cavity lesions on chest films were associated with a cluster of Beijing family MTB strains, which can be defined by cluster analysis of 12-MIRU-VNTR genotype. However, the results of 12-loci-MIRU-VNTR genotyping in a longitudinal study should be interpreted with caution due to its short term instability. Further investigations of different molecular methodologies are necessary.

Initial presentations predict mortality in pulmonary tuberculosis patients--a prospective observational study.

BACKGROUND: Despite effective anti-TB treatments, tuberculosis remains a serious threat to public health and is associated with high mortality. Old age and multiple co-morbidities are known risk factors for death. The association of clinical presentations with mortality in pulmonary tuberculosis patients remains an issue of controversy. METHODS: This prospective observational study enrolled newly diagnosed, culture-proven pulmonary tuberculosis patients from five medical centers and one regional hospital, which were referral hospitals of TB patients. Radiographic findings and clinical symptoms were determined at the time of diagnosis. Patients who died for any reason during the course of anti-TB treatment were defined as mortality cases and death that occurred within 30 days of initiating treatment was defined as early mortality. Clinical factors associated with overall mortality and early mortality were investigated. RESULTS: A total of 992 patients were enrolled and 195 (19.7%) died. Nearly one-third (62/195, 31.8%) of the deaths occurred before or within 30 days of treatment initiation. Older age (RR = 1.04, 95%CI: 1.03-1.05), malignancy (RR = 2.42, 95%CI: 1.77-3.31), renal insufficiency (RR = 1.77, 95%CI: 1.12-2.80), presence of chronic cough (RR = 0.63, 95%CI: 0.47-0.84), fever (RR = 1.45, 95%CI: 1.09-1.94), and anorexia (RR = 1.49, 95%CI: 1.07-2.06) were independently associated with overall mortality. Kaplan-Meier survival analysis demonstrated significantly higher mortality in patients present with fever (p<0.001), anorexia (p = 0.005), and without chronic cough (p<0.001). Among patients of mortality, those with respiratory symptoms of chronic cough (RR = 0.56, 95%CI: 0.33-0.98) and dyspnea (HR = 0.51, 95%CI: 0.27-0.98) were less likely to experience early mortality. The radiological features were comparable between survivors and non-survivors. CONCLUSIONS: In addition to demographic characteristics, clinical presentations including the presence of fever, anorexia, and the absence of chronic cough, were also independent predictors for on-treatment mortality in pulmonary tuberculosis patients.