Does enhanced diabetes management reduce the risk and improve the outcome of tuberculosis?

SETTING: The Bureau of National Health Insurance (NHI) has implemented a pay-for-performance (p4p) programme for diabetes mellitus (DM) in Taiwan. OBJECTIVE: To investigate whether patients with DM enrolled in the p4p programme (DM-p4p) are less likely to develop tuberculosis (TB) and whether they have a better outcome than patients with DM not enrolled in the p4p programme (DM-non-p4p) if they do develop TB. DESIGN: A random sample of 79,471 DM-p4p, 100,000 DM-non-p4p and 100,000 non-diabetic patients (non-DM) was obtained from the 2008-2009 NHI database, and the patients were matched with the National TB Registry to determine whether they had developed TB by the end of 2010. RESULTS: The average annual incidence of TB was respectively 259.9 (95%CI 230.2-293.4), 137.5 (95%CI 116.4-162.5) and 74.1 (95%CI 59.0-93.0) per 100,000 population among DM-non-p4p, DM-p4p and non-DM patients. The relative risk of death over treatment success was 1.79 (95%CI 1.05-3.04) among DM-non-p4p and 1.69 (95%CI 0.84-3.40) among non-DM patients, relative to DM-p4p patients. CONCLUSIONS: Enhanced case management of DM reduced risk and improved outcomes of TB among patients with DM.

Serum concentrations of cycloserine and outcome of multidrug-resistant tuberculosis in Northern Taiwan.

BACKGROUND: Therapeutic drug monitoring (TDM) has been advocated to promote the efficacy of anti-tuberculosis agents. Cycloserine (CS) is a second-line anti-tuberculosis drug whose serum concentrations in tuberculosis (TB) patients are largely unknown. OBJECTIVES: To investigate serum CS concentrations after drug ingestion in TB patients. METHODS: Multidrug-resistant TB patients who were taking CS in a tertiary care centre in northern Taiwan between 1 April 2009 and 31 October 2009 were enrolled in the study. Serum CS concentrations were measured at 2 and 6 h after drug administration. RESULTS: Of 32 patients enrolled, 23 were males and 9 females. The mean CS dose was 8.8 ± 1.3 mg/kg. The mean serum concentrations at 2 and 6 h were respectively 19.7 ± 8.3 and 18.1 ± 8.7 µg/ml. Seven patients (22%) had serum drug concentrations that were higher at 6 h than at 2 h, 12 (38%) had peak serum concentrations within the recommended range of 20-35 µg/ml; 18 patients (56%) had concentrations <20 µg/ml at both 2 h and 6 h; and 2 patients (6%) had at least one measurement >35 µg/ml. CONCLUSION: Lower than recommended serum CS concentrations and delayed absorption were common. It is essential to develop practical TDM to maintain proper serum drug concentrations.

UGT1A1 polymorphisms associated with risk of induced liver disorders by anti-tuberculosis medications.

First-line drug treatment for tuberculosis (TB) is frequently associated with liver toxicity. The goal of this study was to examine the association between UDP-glucuronosyl-transferase 1A1 (UGT1A1) genetic variations and anti-tuberculosis drug-induced hepatotoxicity (ATDH). A total of 98 patients, including 17 patients with ATDH, were enrolled; compound UGT1A1*27 and UGT1A1*28 were associated with an increased risk for developing ATDH after adjusting for age (OR 13.859; 95%CI 1.085-177.056). These findings require confirmation. However, screening for genetic variations prior to TB treatment may reduce the incidence of ATDH and improve treatment adherence.

Inconsistent dosing of anti-tuberculosis drugs in Taipei, Taiwan.

SETTING: Taipei City, Taiwan. OBJECTIVES: To evaluate prescribing practices for anti-tuberculosis drugs in the treatment of tuberculosis (TB). METHOD: Medical audit of the medical charts of all patients notified and treated for TB in Taiwan in 2003 to determine the treatment regimens prescribed and to compare these with recommended dosages. RESULTS: A total of 24 different anti-tuberculosis regimens were prescribed. Of 1700 patients notified, 1096 (64.5%) had their body weight recorded. Of 506 patients prescribed a three-drug fixed-dose combination (FDC), the dosage was adequate in 374 (73.9%), too low in 100 (19.8%) and too high in 32 (6.3%). Of 75 patients prescribed a two-drug FDC, the dosage was adequate in 57 (76.0%), too low in 15 (20.0%) and too high in 3 (4.0%). Of 481 patients prescribed rifampicin, the dosage was adequate in 302 (62.8%), too low in 152 (31.6%) and too high in 27 (5.6%). Of 451 patients prescribed isoniazid, the dosage was adequate in 396 (87.8%), too low in 29 (6.4%) and too high in 26 (5.8%). CONCLUSION: The prescribing practices for anti-tuberculosis drugs were substandard and need improvement. These findings imply that the National TB Programme needs strengthening.

Tuberculosis-related deaths without treatment.

Of 536 culture-positive tuberculosis (TB) patients notified in 2003 in Taipei, 507 (94.6%) received anti-tuberculosis treatment in reporting health facilities and 29 (5.4%) did not. Of these 29 patients, 26 (89.7%) died, 2 (6.9%) were re-notified 1 year later and 1 (3.5%) was lost to follow-up. In multivariate analysis, patients aged > or =65 years, patients with negative smear or smear not done, patients with sepsis and/or respiratory failure and patients with liver diseases were significantly less likely to receive anti-tuberculosis treatment. Overall, of the 536 TB patients, 97 (18.1%) died, of whom 26 (26.8%) died without anti-tuberculosis treatment.

Factors associated with a clinician's decision to stop anti-tuberculosis treatment before completion.

OBJECTIVES: To investigate the diagnosis of pulmonary tuberculosis (PTB) and factors associated with a clinician's decision to stop anti-tuberculosis treatment before completion. DESIGN: The medical charts of all citizens of Taipei City, Taiwan, reported to have received treatment for PTB in 2003 were investigated. RESULTS: Of 1126 PTB patients, 512 (45.5%) started treatment immediately based solely on chest X-ray (CXR) findings; treatment for 214 (19.0%) was based on a positive sputum smear for acid-fast bacilli, for 261 (23.2%) it was based on other findings and for 139 (12.3%) it was based on a positive mycobacterial culture. Of the 1126 PTB patients, 156 (13.9%) had their diagnosis of TB changed by a clinician. Multivariate analysis shows that patients whose diagnosis was based on CXR or other findings, female patients, patients who interrupted treatment for 2 months, patients who continued care at other health facilities (transfer) and patients with lung cancer were significantly more likely to have their diagnosis changed than other groups. CONCLUSION: A substantial proportion of patients were prescribed anti-tuberculosis treatment based on CXR findings alone, and a considerable proportion were advised to stop treatment before completing a full course, findings that require the immediate attention of Taiwan's National Tuberculosis Programme.

Outcome of pulmonary multidrug-resistant tuberculosis: a 6-yr follow-up study.

A retrospective study was performed to determine factors associated with the outcome of pulmonary multidrug-resistant tuberculosis (MDR-TB) in Taipei, Taiwan. All patients newly diagnosed with pulmonary MDR-TB in a referral centre from 1992-1996 were enrolled and their outcome over the subsequent 6 yrs was determined. A total of 299 patients were identified, comprising 215 (71.9%) males and 84 (28.1%) females with a mean age of 47.3 yrs. The patients received a mean of 3.7 effective drugs. Out of the 299 patients, 153 (51.2%) were cured, 31 (10.4%) failed, 28 (9.4%) died and 87 (29.1%) defaulted. Of the 125 patients receiving second-line drugs with ofloxacin, 74 (59.2%) were cured. Those who received ofloxacin had a lower risk of relapse than those receiving only first-line drugs (hazard ratio (HR) 0.16, 95% confidence interval (CI) 0.03-0.81) and a lower risk of TB-related death than those receiving second-line drugs but not ofloxacin (adjusted HR 0.50, 95% CI 0.31-0.82). In conclusion, multidrug-resistant tuberculosis patients who received ofloxacin were more likely to be cured, and were less likely to die, fail or relapse. The utility of new-generation fluoroquinolones, such as moxifloxacin, in the treatment of multidrug-resistant tuberculosis needs to be evaluated. Default from treatment is a major challenge in the treatment of multidrug-resistant tuberculosis.

Tuberculosis in maintenance dialysis patients.

In this investigation, we tried to find the incidence and characteristics of tuberculosis (TB) in dialysis patients previously found only in a small number of cases. We collected the cases of newly diagnosed TB patients in Taiwan during 1997. Simultaneously, all dialysis patients were collected and matched with the TB cases to identify the dialysis patients who had also contracted TB. The annual incidence of the dialysis population was 493.4/100,000, 6.9 times that of the general population (71.1/100,000). The annual incidence for the male dialysis population was 573.3, the incidence was 479.2 for the female dialysis population. The incidence for the general population was 97.1 and 43.7/100,000, respectively. Although the 1-year mortality rate due to TB (1.7 vs. 1.9%, p > 0.05) was similar in both populations, the non-TB mortality was much higher in the dialysis population than that in the general population (25.6 vs. 11.1%, p < 0.05). Finally, the 1-year mortality rate of dialysis patients with TB is 3.3 times higher than that in dialysis patients without TB (27.3 vs. 8.3%, p < 0.05). The findings suggest that uremia modifies the behavior of TB, jeopardizes female and younger dialysis patients, poses a higher risk of extrapulmonary dissemination, and predicts a higher overall mortality.

Pulmonary resection in the treatment of patients with pulmonary multidrug-resistant tuberculosis in Taiwan.

SETTING: Chronic Disease Control Bureau, Department of Health, Taiwan. OBJECTIVE: To evaluate the role of pulmonary resection in the treatment of pulmonary tuberculosis resistant to isoniazid and rifampin (MDR-TB). DESIGN: In a retrospective cohort study, 27 MDR-TB patients who underwent pulmonary resection between December 1990 and March 1999 were reviewed. Individually-tailored treatment regimens were selected at a once-weekly staff conference following review of the patient's case history and drug susceptibility results. Surgery was performed for selected patients, essentially those: 1) whose medical treatment had failed, or for whom treatment failure seemed highly likely, or for whom post-treatment relapse seemed likely, 2) with predominantly localised disease, 3) with adequate cardiopulmonary reserve, and 4) whose treatment regimen had been composed of at least two effective drugs to diminish the mycobacterial burden. RESULTS: There was no surgical mortality apart from one peri-operative death (4%). Three patients (11%) developed complications, and 24 (92%) patients demonstrated sputum conversion and/or remained negative after surgery. Twenty-three patients have already completed treatment, and during a mean of 42 +/- 18 follow-up months (range 15-80 months), one patient relapsed. This patient was disease-free after another course of treatment. CONCLUSION: For selected patients, pulmonary resection may improve the outcome of pulmonary MDR-TB.

Inflammatory pseudotumor of the lung in a coal miner with pneumoconiosis.

Inflammatory pseudotumors of the lung are uncommon and etiologically diverse lesions that often present as solitary masses in the lung. It may be difficult to distinguish these lesions from more commonly encountered lung neoplasms. Inflammatory pseudotumors can also occur in other organs, but the lung is most commonly involved. We describe a 63-year-old male coal miner with a 40-year history of dust exposure, who had a large right middle lobe mass on chest roentgenograms, with slow growth over the 7 years prior to admission. Repeated transthoracic echo-guided biopsies of the mass were indicative of an inflammatory and reactive process. The radiographic, histologic, and clinical findings indicated a diagnosis of inflammatory pseudotumor. The patient refused surgical intervention and was regularly followed at our outpatient clinic. Follow-up chest roentgenograms for 1 year revealed that the tumor size was stable. This case suggested that inflammatory pseudotumor, although uncommon, should be included in the differential diagnosis in a patient with pneumoconiosis and a solitary mass in the lung.

Tuberculous pleurisy with effusion.

To assess the clinical features of Taiwanese patients with tuberculous pleurisy and their response to treatment, we analyzed the records of patients treated for this condition from December 1990 through November 1995, at a regional 100-bed referral center for tuberculosis care. Diagnosis of tuberculous pleurisy was based on histologic evidence of caseating granulomatous inflammation in the pleural biopsy specimen, or evidence of mycobacteria in pleural fluid. Patients were also stratified on the basis of parenchymal involvement. Ninety-seven patients (79 men, 18 women) with a mean age of 47.5 (range, 15-90) years were included in the analysis. The two major symptoms were cough (69%) and shortness of breath (57%). Chest roentgenographs showed that the pleural effusion was unilateral in 88 (91%) patients, and small to moderate in amount in 74 (76%). Laboratory analysis of the pleural fluid showed moderate levels of glucose (4.6 mmol/L), with no significant difference between patients with and without parenchymal involvement. The levels of lactate dehydrogenase and triglycerides were significantly higher in patients with parenchymal involvement (172 vs 240.5 IU and 0.36 vs 0.45 mmol/L, respectively). In 85 of 93 patients (91%) with available data, lymphocytes were predominant in the differential count. All patients had received short-course chemotherapy for at least 6 months. After excluding the defaulters and patients receiving subsequent management in other hospitals, the overall rate of successful treatment was 97% (72/74). There was no significant difference in the treatment outcome between patients with parenchymal involvement and those without. None of the successfully treated patients had a relapse within a mean follow-up period of 31.7 +/- 18.4 months. We conclude that current patients with tuberculous pleurisy in Taiwan are not young, and short-course chemotherapy with isoniazid, ethambutol, rifampicin, and pyrazinamide is an effective treatment. The presence of parenchymal tuberculous lesions does not appear to influence the treatment outcome.

Annual risk of tuberculous infection in Taiwan, 1996-1998.

Tuberculosis is still an important public health issue in Taiwan, and monitoring the trend of annual risk of infection (ARI) with Mycobacterium tuberculosis is essential. In this study, we conducted tuberculin skin tests to estimate the prevalence and annual risk of M. tuberculosis infection in first-grade schoolchildren in Taiwan Province. Because mass bacille Calmette-Guérin (BCG) vaccination programs have been carried out here, only non-BCG-vaccinated students were tested. From September 1996 through June 1998, there were 520,866 registered first-grade elementary school students in Taiwan Province. Of them, 15,147 (2.9%) were non-BCG-vaccinated, as determined by the absence of a BCG scar. All of them were tested for M. tuberculosis infection with 1 tuberculin unit (0.1 mL injection) of purified protein derivative RT23, by means of the Mantoux technique. Among the tested schoolchildren, 430 (2.8%) had a positive tuberculin reaction. Thus, the calculated ARI was 0.44%. The ARI varied in different areas of Taiwan, being highest (1.04%) in Nantou County and lowest (0.14%) in Miaoli and Tainan Counties. The ARI in aboriginal areas (1.16%) was 2.7 times that in nonaboriginal areas (0.42%). Our results indicate that the M. tuberculosis ARI is still high in Taiwan. To achieve the World Health Organization target of less than 0.1% for industrialized countries, we must intensify tuberculosis control programs in Taiwan.

Drug resistance patterns of tuberculosis in Taiwan.

To evaluate the patterns of drug resistance of Mycobacterium tuberculosis in Taiwan, a total of 1,091 isolates collected from patients from January 1996 through December 1996 were tested for drug susceptibility using the absolute concentration method at the Taiwan Provincial Chronic Disease Control Bureau. The overall drug rate of resistance to at least one drug was 35.5%. Among the 249 isolates from patients who had never been treated for tuberculosis, 16.1% were resistant to one or more drugs; 1.6% were resistant to at least isoniazid and rifampin. Of 200 patients with prior antituberculosis treatment, 67.0% had isolates resistant to one or more drugs and 46.0% had isolates resistant to at least isoniazid and rifampin. We conclude that drug-resistant M. tuberculosis is an important issue in tuberculosis treatment in Taiwan, especially when dealing with patients with a prior history of antituberculosis treatment. More aggressive interventions, such as directly observed therapy, short-course, are needed to improve the cure rate of pulmonary tuberculosis and to decrease resistance rates.

Short-course chemotherapy for isoniazid-resistant pulmonary tuberculosis.

Standard short-course chemotherapy including isoniazid, rifampicin, pyrazinamide, and ethambutol has been the recommended treatment for tuberculosis in Taiwan since November 1990. The effectiveness of this treatment was evaluated retrospectively in 108 patients with isolates resistant to isoniazid alone and 115 patients with drug-susceptible pulmonary tuberculosis diagnosed and treated at the Taiwan Provincial Chronic Disease Control Bureau from November 1990 through December 1995. The success rate of treatment was 94.4% in patients with isoniazid-resistant Mycobacterium tuberculosis strains, which was not significantly different from the 97.4% rate in patients with susceptible strains. Of the patients treated successfully, no bacteriologic relapse was found in 97 patients with isoniazid-resistant strains or 103 patients with drug-susceptible strains 12 months after the end of chemotherapy. No significant advantage in treatment outcome was found in patients infected with isoniazid-resistant strains who received chemotherapy for more than 6 months (successful treatment rate, 95.0% vs 92.8%), but the failure rate was higher in patients with a previous history of antituberculosis therapy (17.6% vs 3.3%). We conclude that short-course chemotherapy is effective for isoniazid-resistant pulmonary tuberculosis and that there is no significant difference in treatment outcome between patients with or without isoniazid-resistant disease.

Screening of human immunodeficiency virus infection in pulmonary tuberculosis patients in Taiwan.

To disclose the impact of human immunodeficiency virus (HIV) infection on the tuberculosis epidemic in Taiwan, we prospectively screened for HIV infection in patients with active pulmonary tuberculosis. A total of 378 patients who were admitted to the Taiwan Provincial Chronic Disease Control Bureau from January through December 1996 were enrolled. HIV serologic testing was performed by enzyme-linked immunosorbent assay (ELISA). A positive ELISA test was confirmed by Western blot analysis. One patient was infected with HIV. We conclude that the impact of HIV infection on the epidemic of tuberculosis in Taiwan is not significant at present.

PIP: The impact of HIV infection on Taiwan's tuberculosis epidemic was investigated in a prospective study of all 378 pulmonary tuberculosis patients (mean age, 53.5 years) admitted to the Taiwan Provincial Chronic Disease Control Bureau in 1996. Bacteriologic or pathologic evidence of pulmonary tuberculosis was obtained in 306 cases (81%); the remaining 72 patients had chest radiographs and clinical courses consistent with a tuberculosis diagnosis. In the former group, the sputum smear yielded acid-fast bacilli in 279 patients (73.8%) and sputum cultures grew Mycobacterium tuberculosis in 263 (69.6%). Only 1 patient, an overseas Chinese man with a history of encounters with prostitutes, was HIV-positive. His symptoms included cough, weight loss, and malaise of 4 months' duration. His sputum culture was positive for M. tuberculosis and the chest radiograph revealed diffuse non-cavity infiltration lesions over the bilateral lung parenchyma and mediastinum lymphadenopathy. These findings suggest that the impact of HIV infection on Taiwan's tuberculosis epidemic is not significant at present, in part because HIV remains uncommon. However, continued monitoring of dual infection is essential to guide tuberculosis control efforts.

Tuberculous empyema.

The clinical courses of 35 tuberculous empyema patients were investigated retrospectively from November 1990 through November 1995. Most patients had nonspecific symptoms and signs but with far-advanced pulmonary parenchymal lesions in their chest roentgenographs. The effusions showed neutrophilic leukocytosis with a 60% positive culture rate for Mycobacterium tuberculosis. Multidrug resistant strains were found in 7 out of 18 cultures. All patients received chemotherapy and eight of them underwent additional surgical management. Twenty-two (62.9%) patients had been treated successfully and one patient is still under treatment. The remaining 12 patients either died during treatment or defaulted; and four (11.4%) of them had died of tuberculosis. We conclude that the treatment outcome of tuberculous empyema is less satisfactory than that of pulmonary tuberculosis, however, modern multidrug chemotherapy with repeated drainage and opportune surgical interventions could be in prospect of successful treatment of tuberculous empyema.

Initial drug resistance of Mycobacterium tuberculosis in Taiwan.

The prevalence and mortality rate of pulmonary tuberculosis in adults are high in Taiwan. Because the emergence of drug-resistant tuberculosis is one of the major causes of this sustained high tuberculosis mortality, surveillance of initial drug resistance is important. We tested Mycobacterium tuberculosis isolates from 1,935 newly diagnosed tuberculosis patients from January 1990 through December 1995 at the Taiwan Provincial Chronic Disease Control Bureau. The overall initial drug resistance rate was 12.3%; 8.7% of isolates were resistant to only one drug, 2.6% to two drugs, 0.7% to three drugs, and 0.3% to four drugs. The resistance rates to individual drugs were: streptomycin, 5.7%; isoniazid, 9.2%; ethambutol, 0.7%; and rifampin, 1.5%. The frequency of multidrug-resistant M. tuberculosis (resistant to at least isoniazid and rifampin) was 1.2%. In view of the high initial isoniazid resistance rate and low initial ethambutol resistance rate, ethambutol should be added to the regimen for the initial treatment of tuberculosis in Taiwan. The emergence of multidrug-resistant M. tuberculosis is ominous and should be considered when treating patients in Taiwan.

Serodiagnosis of tuberculosis. A study comparing three specific mycobacterial antigens.

To compare the efficacy of different mycobacterial specific antigens and to assess the applicability of the combination of several different antigens in the diagnosis of tuberculosis, three ELISA tests derived by Antigen 60, 38kda, and Kp90 were evaluated in 594 Chinese patients (312 patients with active pulmonary tuberculosis and 282 control subjects). Quantified levels of sensitivity and specificity were compared with those in the nontuberculous control groups. Antigen 60 IgG (sensitivity and specificity, 80.77 and 88.4%) was more antigenic and more effective in its determination than was 38kda IgG (sensitivity and specificity, 64.21 and 80.74%) and Kp90 IgA (sensitivity and specificity, 62.58 and 66.3%). The clinical significance of the difference, however, was not striking: negative predictive value of Antigen 60, 38kda, and Kp90 was 93, 86 and 83%, respectively; positive predictive value of Antigen 60, 38kda, and Kp90 was 71, 54, and 39%, respectively. Combination of different antigens could improve the sensitivity and specificity by no more than 10%, with the sacrifice of the opposite parameter by no less than 20%. The same improvement in sensitivity could be easily achieved by adjusting the cutoff values in the ELISA test by a single antigen. We conclude that the sensitivity and specificity of presently available antigens for serodiagnosis of tuberculosis still remains limited at around 80%, which makes it a poor diagnostic tool for disease confirmation. In low incidence areas, its clinical value may be useful in disease exclusion. A combination of several different antigens provides no more improved diagnostic yield than what can be provided by cutoff value adjustment in a single antigen serologic test.