Objective: Disease progression is a strong indicator of treatment for Mycobacterium avium complex lung disease (MAC-LD). The impact of MAC subspecies on the risk of disease progression remains uncertain in MAC-LD patients. Methods: In this cohort study, we included MAC-LD patients from 2013 to 2018 and classified them into M. intracellulare, M. avium, M. chimaera and other subspecies groups by genotype. We observed the disease progression of MAC-LD, indicated by antibiotic initiation and/or radiographic progression. We used Cox regression analysis to assess predictors for disease progression. Results: Of 105 MAC isolates from unique MAC-LD patients, 35 (33%) were M. intracellulare, 41 (39%) M. avium, 16 (15%) M. chimaera and 13 (12%) other subspecies. After a mean follow-up time of 1.3 years, 56 (53%) patients developed disease progression: 71% (25/35), 54% (22/41), 31% (4/13) and 31% (5/16) in patients with M. intracellulare, M. avium, others and M. chimaera, respectively. The independent predictors for disease progression were M. chimaera subspecies (HR 0.356, 95% CI (0.134-0.943)), compared with the reference group of M. intracellulare, body mass index <= 20 kg/m(2) (HR 1.788 (1.022-3.130)) and initial fibrocavitary pattern (HR 2.840 (1.190-6.777)) after adjustment for age, sex and sputum smear positivity. Among patients without fibrocavitary lesions (n = 94), the risk of disease progression significantly decreased in patients with other subspecies (HR 0.217 (0.050-0.945)) and remained low in those with M. chimaera (HR 0.352 (0.131-0.947)). Conclusions: Mycobacterium chimaera was not uncommon in this study; unlike M. intracellulare, it was negatively correlated with disease progression of MAC-LD, suggesting a role of MAC subspecies identification in prioritizing patients. (C) 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Elderly individuals with tuberculosis (TB) are more likely to have a non-specific clinical presentation of TB and high mortality. However, factors associated with mortality in elderly TB patients have not been extensively studied. This retrospective cohort study aimed to identify factors associated with death among elderly Taiwanese with TB. All elderly patients with TB from 2006 to 2014 in Taipei, Taiwan, were included in a study. Multiple logistic regression was used to identify the factors associated with death in elderly TB patients. The mean age of the 5011 patients was 79·7 years; 74·1% were men; 32·7% had mortality during the study follow-up period. After controlling for potential confounders, age ⩾75 years (reference: 65-74 years), male sex, end-stage renal disease (ESRD), malignancy, acid-fast bacilli-smear positivity, TB-culture positivity, pleural effusion on chest radiograph and notification by an ordinary ward or intensive care unit were associated with a higher risk of all-cause death; while high school, and university or higher education, cavity on chest radiograph and directly observed therapy were associated with a lower risk of all-cause death. This study found that the proportion of death among elderly patients with TB in Taipei, Taiwan, was high. To improve TB treatment outcomes, future control programmes should particularly target individuals with comorbidities (e.g. ESRD and malignancy) and those with a lower socio-economic status (e.g. not educated).

The occurrence of osteoporosis in tuberculosis, a chronic infection, has rarely been evaluated. In this study, we found significantly higher incidence rates of osteoporosis (Adjusted hazard ratio (AHR) 1.82) and osteoporotic fracture (AHR 2.33) in tuberculosis patients than matched cohorts, which suggest that osteoporosis screening should be considered in tuberculosis patients’ follow-up program. The aim of this study is to determine the occurrence of incident osteoporosis in patients who completed anti-tuberculosis (TB) treatment.

SUMMARYMycobacterial diseases are prevalent in cancer and rheumatoid arthritis (RA) patients, especially those receiving tumor necrosis factor-α inhibitor (TNFi). However, the impact of cancer development on the risk of mycobacterial diseases among RA patients is unknown. Data from the Taiwan National Health Insurance Research Database were used to conduct a retrospective study to assess the occurrence of mycobacterial diseases in RA patients developing cancer (cancer-positive), those using TNFi (TNFi-exposure), those with cancer and using TNFi (cancer-TNFi-comb), and those without cancer and not using TNFi (cancer-TNFi-free). Cancer and TNFi exposure were time-dependent, and independent risk factors of mycobacterial diseases were assessed by Cox regression. Among 1344 RA patients diagnosed during 2000–2013, 68 (5·1%) developed cancer before their end points. The incidence rates of mycobacterial diseases in the cancer-positive (n = 56), TNFi-exposure (n = 290), cancer-TNFi-comb (n = 12), and cancer-TNFi-free (n = 986) subgroups were 6·7, 2·0, 7·6, and 1·3 per 1000 person-years, respectively. As compared with the cancer-TNFi-free group, the risk for mycobacterial diseases increased for the TNFi-exposure group (adjusted HR = 3·6, 95% confidence interval (95% CI) 1·1–11·5, P = 0·032) and remained high for cancer-positive (adjusted HR = 14·6, 95% CI 3·3–63·7, P < 0·001) after adjustment. This study suggested that cancer development increased the risk of mycobacterial diseases in RA patients, and risk assessment for this subgroup should be considered.

BACKGROUND: Previous studies have suggested a close correlation between gastroesophageal reflux disease (GERD) and various respiratory disorders. However, the association between GERD and tuberculosis (TB) remains unexplored.METHODS: Using data retrieved from Taiwan's National Health Insurance Research Database from 2000 to 2009, this longitudinal nationwide cohort study included a total of 63 930 patients with GERD and controls matched by age, sex and comorbidities. Risk factors associated with the development of pulmonary TB (PTB) were investigated.RESULTS: Active PTB was documented in 65 (0.20%) patients with GERD and 41 (0.13%) matched cohorts within 1 year of GERD diagnosis. The incidence rate of PTB in the GERD group and the matched cohort was respectively 24.1 and 15.2 cases per 10 000 person years. In multivariate analysis, GERD was an independent risk factor for PTB (adjusted HR 1.63, 95%CI 1.10-2.40, P = 0.015). Among patients with GERD, independent predictors for PTB included older age, male sex, chronic obstructive pulmonary disease, asthma and exposure to proton pump inhibitors (PPIs).CONCLUSION: Patients with GERD have a significantly increased risk of PTB within 1 year of GERD diagnosis. Exposure to PPIs is an independent predictor for PTB among patients with GERD.

BACKGROUND: Tuberculosis (TB) is a serious problem for patients undergoing haematopoietic stem cell transplantation (HSCT) in TB-endemic areas; however, data on these patients are limited.METHODS: We obtained data on 2040 HSCT recipients from the Registry of Catastrophic Illness in Taiwan from 1997 to 2006. We also obtained data on age-, sex- and enrolment date-matched controls from the Longitudinal Health Insurance Database. The cumulative incidence of active TB in HSCT recipients and controls and risk factors for TB were analysed.RESULTS: Among 2040 HSCT recipients identified, 39 (1.9%) had newly diagnosed TB. The incidence rate was 688 per 100 000 person-years. The 10-year cumulative TB incidence was respectively 3.52% and 0.38% in HSCTrecipients and controls (P < 0.001). HSCTwas an independent risk factor for TB compared with matched controls. Among post-HSCT patients, independent risk factors for TB included age >= 18 years and allogeneic recipients with graft-versus-host disease (GVHD). PostHSCT patients with subsequent TB had a higher mortality rate than those without TB (P < 0.001).CONCLUSION: HSCT is associated with an increased risk of TB in endemic regions. Older age and development of chronic GVHD are independent predictors of late onset active TB in HSCT recipients.

Gender disparities in tuberculosis (TB) cases are reported worldwide, and socio-cultural factors have been proposed as possible causes. To date, gender differences in treatment outcomes of TB patients remain controversial. In this prospective observational study, newly diagnosed, culture-proven TB patients from six hospitals in Taiwan were enrolled for analysis. Gender differences in demographic characteristics and treatment outcomes, including sputum conversion and on-treatment mortality, were analysed accordingly. From January 2007 through to December 2009, a total of 1059 patients were enrolled, including 819 (77.3%) males and 240 (22.7%) females. The ratio of male gender was around 50~60% in TB patients below 35 years and >80% for those older than 65 years. When compared with the female patients, the male patients were older, more likely to have the habit of smoking, chronic obstructive pulmonary disorder, malignancy and liver cirrhosis, and more likely to present with haemoptysis, body weight loss and pleural effusion. Regarding treatment outcomes, male gender is associated with a lower 2-month sputum culture conversion rate (78.8% vs. 89.3%, p 0.002) and higher on-treatment mortality (21.1% vs. 12.1%, p 0.002). Kaplan-Meier survival analysis demonstrated significantly higher mortality in the men (p 0.005). In multivariate analysis, male gender was an independent risk factor for 2-month sputum culture un-conversion (OR, 1.96; 95% CI, 1.12–3.41). Our findings suggest that male gender is associated with older age, more co-morbidities and worse treatment outcomes. Gender-specific strategies, including active case finding in elderly women and smoking cessation in male patients, are warranted to optimize TB management.

Sputum smears and culture conversion are frequently used to evaluate treatment response in pulmonary tuberculosis patients. Limited data are available on the evaluation of the correlation between under-treatment sputum smear results and culture conversion.This prospective study included sputum culture-proven pulmonary tuberculosis patients at six hospitals in Taiwan. At least two sets of sputum were collected at the completion of 8 weeks of TB treatment. The sensitivities and specificities of 2-month sputum smears were estimated based on culture conversion status.A total of 371 patients were enrolled for analysis. Factors associated with culture conversion included having a smear positive before treatment, presence of a cavity on radiography, rifampicin resistance and usage of the DOTS (directly observed therapy, short course) strategy. The sensitivities of 2-month sputum smears for culture conversion among all patients, initially smear-positive patients and initially smear-negative patients were 64.3, 71.4 and 38%, respectively, and the specificities were 81.6, 69.9 and 92.8%, respectively. In patients who were 2-month sputum smear-positive, the 2-month culture conversion rate was 80% if the patients were under DOTS and without cavitary lesions in radiograms.The predictive value of 2-month sputum smears in culture conversion was limited and highly influenced by clinical factors in pulmonary tuberculosis patients.

SETTING:The W-Beijing strain of Mycobacterium tuberculosis is distributed globally, and is associated with high drug resistance rates in some areas. The effect of the W-Beijing strain on radiological features of pulmonary tuberculosis (PTB) remains unclear.OBJECTIVE:To compare the chest radiological presentation of PTB in patients infected with W-Beijing with that of patients infected with non-W-Beijing strains, and to explore factors affecting radiological patterns.DESIGN:Culture-proven PTB patients without previous anti-tuberculosis treatment were enrolled retrospectively. Chest radiographs were independently reviewed by two qualified chest physicians, and radiological presentation was classified into characteristic and unusual patterns.RESULTS:Of 233 patients studied, 123 (52.8%) were infected with the W-Beijing strain. Characteristic radiological patterns (91.1% vs. 76.4%, P = 0.002) and fibronodular lesions without cavity (57.7% vs. 43.6%, P = 0.032) were more common, while miliary lesions (0.0% vs. 3.8%, P = 0.048) were less frequent, in the W-Beijing group. After stepwise logistic regression analysis, the W-Beijing strain (P = 0.006) was found to be an independent factor for the characteristic radiological pattern for PTB.CONCLUSION:The characteristic radiological pattern for PTB was more common in patients infected with the W-Beijing strain. M. tuberculosis genotyping was an independent factor affecting the radiological presentation of pulmonary TB.

OBJECTIVE To define the clinical characteristics and clinical course of hospital-acquired severe acute respiratory syndrome (SARS). PATIENTS AND METHODS This 8-month prospective study of 14 patients with hospital-acquired SARS in Taipei, Taiwan, was conducted from April through December 2003. RESULTS The most common presenting symptoms in our 14 patients with hospital-acquired SARS were fever, dyspnea, dizziness, malaise, diarrhea, dry cough, muscle pain, and chills. Lymphopenia and elevated serum levels of lactate dehydrogenase (LDH) and C-reactive protein (CRP) were the most common initial laboratory findings. Initial chest radiographs revealed various pattern abnormalities and normal results. Five of the 14 patients required mechanical ventilation. The need for mechanical ventilation was associated with bilateral lung involvement on the initial chest radiograph and higher peak levels of LDH and CRP. Clinical severity of disease varied from mild to severe. At 8 months after disease onset, patients with mild or moderate SARS had normal findings or only focal fibrosis on chest high-resolution computed tomography. However, bilateral fibrotic changes remained in the 4 patients who had recovered from severe SARS, 1 of whom had mild restrictive ventilatory impairment. One patient with severe SARS died; she was elderly and had other comorbidities. Five additional patients had reduced diffusing capacity. CONCLUSION The clinical picture of our patients presenting with hospital-acquired SARS revealed atypical pneumonia associated with lymphopenia, elevated serum levels of LDH, rapid clinical deterioration, and lack of response to empirical antibiotic therapy. Substantially elevated levels of LDH and CRP correlated with severe illness requiring mechanical ventilatory support. In those receiving mechanical ventilation, pulmonary function was only mildly reduced at 6 to 8 months after acute illness, consistent with the natural history of acute respiratory distress syndrome due to other causes.

Most cases with antituberculosis drug-induced hepatitis have been attributed to isoniazid. Isoniazid is metabolized by hepatic N-acetyltransferase (NAT) and cytochrome P450 2E1 (CYP2E1) to form hepatotoxins. However, the role of CYP2E1 in this hepatotoxicity has not yet been reported. The aim of this study was to evaluate whether the polymorphism of the CYP2E1 gene is associated with antituberculosis drug-induced hepatitis. A total of 318 tuberculosis patients who received antituberculosis treatment were followed prospectively. Their CYP2E1 and NAT2 genotypes were determined using a polymerase chain reaction with restriction fragment length polymorphism method. Twenty-one healthy volunteers were recruited for CYP2E1 phenotype study using a chlorzoxazone test. Forty-nine (15.4%) patients were diagnosed to have drug-induced hepatotoxicity. Patients with homozygous wild genotype CYP2E1 c1/c1 had a higher risk of hepatotoxicity (20.0%; odds ratio [OR], 2.52) than those with mutant allele c2 (CYP2E1 c1/c2 or c2/c2, 9.0%, P =.009). If CYP2E1 c1/c2 or c2/c2 genotype combined with rapid acetylator status was regarded as the reference group, the risk of hepatotoxicity increased from 3.94 for CYP2E1 c1/c1 with rapid acetylator status to 7.43 for CYP2E1 c1/c1 with slow acetylator status. After adjustment for acetylator status and age, the CYP2E1 c1/c1 genotype remained an independent risk factor for hepatotoxicity (OR, 2.38; P =.017). Furthermore, under the administration of isoniazid, the volunteers with CYP2E1 c1/c1 genotype had higher CYP2E1 activity than those with other genotypes had and, hence, might produce more hepatotoxins. In conclusion, CYP 2E1 genetic polymorphism may be associated with susceptibility to antituberculosis drug-induced hepatitis.

Antituberculosis drug-induced hepatitis is one of the most prevalent drug-induced liver injuries. Isoniazid is the major drug incriminated in this hepatotoxicity. Isoniazid is mainly metabolized to hepatotoxic intermediates by N-acetyltransferase (NAT). However, the association of polymorphic NAT acetylator status and antituberculosis drug-induced hepatitis is debatable. To determine whether acetylator status is a risk factor for antituberculosis drug-induced hepatitis, we genotyped NAT2 in 224 incident tuberculosis patients who received antituberculosis treatment. Antituberculosis drug-induced hepatitis was diagnosed based on a positive isoniazid rechallenge test and exclusion of viral hepatitis. Acetylator status was determined by genotyping NAT2 in patients using a polymerase chain reaction with restriction fragment length polymorphism. Univariate analysis and logistic regression analysis were used to evaluate the risk factors of isoniazid-induced hepatitis. Thirty-three patients (14.7%) were diagnosed with antituberculosis drug-induced hepatitis. Slow acetylators had a higher risk of hepatotoxicity than rapid acetylators (26.4% vs. 11.1%, P =.013). Among patients with hepatotoxicity, slow acetylators had significantly higher serum aminotransferase levels than rapid acetylators. Logistic regression showed that slow-acetylator status (odds ratio [OR], 3.66; 95% CI, 1.58-8.49; P =.003) and age (OR, 1.09; 95% CI, 1.04-1.14; P <.001) were the only 2 independent risk factors for antituberculosis drug-induced hepatitis. In conclusion, slow-acetylator status of NAT2 is a significant susceptibility risk factor for antituberculosis drug-induced hepatitis. Additionally, slow acetylators are prone to develop more severe hepatotoxicity than rapid acetylators. Regular monitoring of serum aminotransferase levels is mandatory in patients receiving antituberculosis treatment, especially in slow acetylators.

SETTING:Veterans General Hospital-Taipei, Taiwan.OBJECTIVE:To assess the efficacy and safety of a fixed-dose combination (FDC) of Rifater (RFT)/Rifinah (RFN) in the treatment of newly diagnosed smear-positive pulmonary tuberculosis.DESIGN:Patients were randomly assigned to two 6-month short-course chemotherapy regimens. One group of patients was treated with FDCs and another was given the four component drugs (INH, RMP, EMB and PZA) as separate formulations.RESULTS:The 105 patients enrolled in the study were divided into two treatment groups. Fifty-one patients who had completed treatment without interruption, 26 in the FDC group and 25 in the separate regimen, were eligible for analysis at the end of 2 years. Among the patients with a drug susceptibility test result available, four in the FDC group had bacilli resistant to pyrazinamide. In the separate regimen group, two patients had bacilli resistant to ethambutol and six had bacilli resistant to pyrazinamide. The two regimens were of similar effectiveness with regard to sputum conversion, compliance and radiological improvement. No patient with FDC treatment developed gastointestinal symptoms, visual disturbance or peripheral neuropathy (P < 0.05). However, FDC treatment resulted in drug-induced fever in one patient. One patient (3.8%) in the FDC group relapsed 5 months after completing treatment.CONCLUSION:This study suggests that the two regimens had similar effectiveness in the treatment of smear-positive pulmonary tuberculosis. However, the fewer adverse drug events among those patients treated with the FDC regimen suggests that it has a better safety profile.

We report Mycobacterium bovis BCG infection in two children vaccinated with BCG (Tokyo strain) on the first day of life. Their diagnoses were made by biopsy of skin lesions and pus from an anterior chest wall abscess, respectively, yielding a positive culture of mycobacteria fully susceptible to rifampicin, isoniazid and ethambutol, but resistant to pyrazinamide. M. bovis BCG was identified by a negative niacin test, absence of nitrate reductase and resistance to pyrazinamide and cycloserine. The diagnoses were further confirmed by a combination of an allele-specific polymerase chain reaction ated strain of Mycobacterium bovis, is the only available vaccine for the prevention of tuberculosis. Although complications are rare after BCG vaccination and the outcome is usually favourable, serious BCG infections can occur. We report two cases of M. bovis BCG infection in children, a 4-year-old immunocompetent girl and an 8-month-old immunodeficient boy. To our knowledge, this is the first report of BCG complications in children in which two recently developed polymerase chain reaction (PCR) based methods were used for rapid identification of M. bovis BCG infection. (PCR) and a multiplex PCR method. Based on the drug susceptibility results, treatment with rifampicin, isoniazid and ethambutol was instituted. One patient (Case 1) improved clinically and is well after treatment. However, the other patient with severe combined immunodeficiency died of disseminated BCG infection in spite of intensive anti-tuberculosis therapy. Although BCG is considered to be a safe vaccine, it should be kept in mind that complications related to BCG do occur.