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Chronic obstructive pulmonary disease (COPD) has significant contributions to morbidity and mortality world-wide. Early symptoms of COPD are not readily distinguishable, resulting in a low rate of diagnosis and intervention. Different guidelines and recommendatations for the diagnosis and treatment of COPD exist globally. The first edition of clinical practice guidelines for COPD was published in 2016 by the Ministry of Health and Welfare in Taiwan in collaboration with the Taiwan evidence-based medicine association and Cochrane Taiwan, and was revised in 2019 in order to update recent diagnostic and therapeutic modalities for COPD and its acute exacerbation. This revised guideline covered a range of topics highlighted in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) report, including strategies for the diagnosis, assessment, monitoring, and management of stable COPD and exacerbations, with particular focus on evidence from Taiwan. The recommendations included in the revised guideline were formed based on a comprehensive systematic review or meta-analysis of specific clinical issues identified by an expert panel that surveyed relevant scientific evidence in the literature and guidelines published by the clinical communities and organizations nationally and internationally. The guidelines and recommendations are applicable to the clinical settings in Taiwan. We expect this revised guideline to facilitate the diagnosis, treatment and management of patients with COPD by physicians and health care professionals in Taiwan. Adaptations of the materials included herein for educational and training purposes is encouraged.

Background/purpose: Tuberculosis (TB) in the elderly population remains a major challenge in areas with intermediate disease burden like Taiwan. Despite the increasing burden and high risks of TB in the elderly population, particularly those living in long-term care facilities (LTCFs), diagnostic testing for latent tuberculosis infection (LTBI) has not been carefully evaluated in this group. This study aimed to investigate the prevalence and predictors of LTBI in older adults living in LTCFs. Methods: Older adults living in seven LTCFs in Taiwan were prospectively enrolled between January and July 2017. Interferon-gamma release assay (IGRA) through QuantiFERON-TB Gold In-tube was used to determine presence of LTBI. Predictors for LTBI were analyzed. Results: A total of 258 participants were enrolled, including 240 older residents (mean age, 81.6 years; male, 51.2%) and 18 employees (mean age, 64.8 years; male, 22.2%). The proportion of independent status in ambulation assessments significantly declined with aging (p

Background The differential risk of pneumonia among inhaled corticosteroid (ICS) use in patients with COPD requires more investigation, especially regarding beclomethasone-containing inhalers. The goal of this study was to compare the risk and benefit profile of different ICS/long-acting β2-agonist (LABA) combinations in patients with COPD. Methods This retrospective cohort study was conducted by using national health insurance claims data from the years 2009 to 2015 in Taiwan and included patients with COPD with new ICS/LABA use. Propensity score matching and Cox regression models were used to estimate the hazard ratios of severe pneumonia and acute exacerbation for different ICS/LABA users. Results Both budesonide/formoterol (BUD/FOR) dry-powder inhalers and beclomethasone/formoterol (BEC/FOR) metered-dose inhalers, compared with fluticasone propionate/salmeterol (FLU/SAL) delivered via the same device type, were associated with a lower risk of severe pneumonia (BUD/FOR hazard ratio [HR], 0.83 [95% CI, 0.70-0.98]; BEC/FOR HR, 0.69 [95% CI, 0.58-0.81]) and severe acute exacerbation (BUD/FOR HR, 0.88 [95% CI, 0.78-0.99]; BEC/FOR HR, 0.82 [95% CI, 0.72-0.93]). After additionally adjusting for the average daily ICS dose, BUD/FOR dry-powder inhaler users continued to have a significantly decreased risk of severe pneumonia (18%), although BEC/FOR metered-dose inhaler users did not. The results were consistent in most of the prespecified subgroups and across all the sensitivity analyses. Conclusions This study augments the existing evidence concerning the different safety and effectiveness outcomes of ICS/LABA combinations in patients with COPD, which may be considered when making clinical treatment decisions.

Mycobacterium abscessus complex (MABC) is an emerging non-tuberculous mycobacterium (NTM). Specific MABC clones are reportedly spreading globally in cystic fibrosis (CF) patients, however, associated genomic epidemiology studies are lacking in East Asia. Analysis of whole-genome sequencing data for MABC isolates from 220 pre-treatment, non-CF patients in Japan and Taiwan revealed that 112/220, 105/220, and 3/220 were M. abscessus subsp. abscessus (ABS), M. abscessus subsp. massiliense (MAS), and M. abscessus subsp. bolletii (BOL), respectively. No significant differences in subspecies composition were noted based on location. Moreover, >50% of ABS and >70% of MAS were related to four predominant clones in the region. Known mutations conferring acquired macrolide resistance were rare (1.4%) and not enriched in the predominant clones. Conversely, the macrolide-susceptible erm(41) T28C mutation was significantly enriched in one predominant ABS clone. The most predominant ABS clone was genetically related to the dominant circulating clone (DCC). Hence, we have clarified the relationship between the predominant clones in Japan and Taiwan, and those reported in the international CF patient community. Our results provide insights regarding the genetic characteristics of globally dominant and area-specific strains isolated from patients with or without CF, as well as differences between globally spread and regionally-specific strains.

Background: Timely diagnostic investigation to establish the microbial etiology of pneumonia is essential to ensure the administration of effective antibiotic therapy to individual patients. Methods: We evaluated a multiplex PCR assay panel, the FilmArray® pneumonia panel (FilmArray PP, BioFire Diagnostics), for detection of 35 respiratory pathogens and resistance determinants and compared the performance of the standard-of-care test in intensive care unit patients with lower respiratory tract infections. Results: Among the 59 endotracheal aspirates and bronchoalveolar lavage specimens obtained from 51 adult patients, FilmArray PP was effective in detecting respiratory bacterial pathogens with an overall positive percent agreement of 90% (95% confidence interval [CI], 73.5–97.9%) and negative percent agreement of 97.4% (95% CI, 96.0–98.4%). FilmArray PP semi-quantitative reporting demonstrated a concordance rate of 53.6% for the culture-positive specimens and 86.3% for the culture-negative specimens. FilmArray PP detected 16 viral targets, whereas the conventional viral isolation failed, except influenza A, which showed 100% concordance with PCR. Coinfections were detected in 42.3% of the specimens. Substantial discrepancies were observed in identifying antimicrobial resistance gene targets and in the susceptibility testing. However, FilmArray PP may still be useful at the early stage of pneumonia before culture and susceptibility test reports are available. Consequently, the results of FilmArray PP might alter the antibiotic prescription in 40.7% of the patients. Conclusions: FilmArray PP offers a rapid and sensitive diagnostic method for lower respiratory tract infections. However, clinical correlation is advised to determine its significance in interpreting multiple pathogens and detection of genes involved in antimicrobial resistance. Keywords: FilmArray pneumonia panel, Respiratory failure, Pneumonia, Pathogen detection, Resistant genes, Performance

Objectives: The incidence of Pneumocystis pneumonia (PCP) has been increasing among non-HIV-infected patients. Here, we investigated the clinical characteristics, treatment outcomes, and prognostic factors of PCP in non-HIV-infected patients. Patients and methods: Information on clinical characteristics, treatment outcomes, and prognostic factors of PCP patients who were treated at a medical center in northern Taiwan from October 2015 to October 2016 were retrieved from medical records and evaluated. Results: Among the patients with PCP included in the study, 84 were non-HIV-infected and 25 were HIV-infected. Non-HIV-infected patients with PCP had a longer duration between radiographic findings and treatment (P

Background: Pulmonary rehabilitation (PR) is now considered fundamental when managing patients with chronic respiratory disease. The individual variation in functional exercise capacity (FEC) response to PR within the cohort is unknown. The purpose of this study was to identify FEC patterns in response to PR in patients with chronic respiratory disease using the trajectory modeling method. Methods: The data of 67 patients with the chronic respiratory disease were retrospectively reviewed and analyzed in this study. All patients received once-weekly supervised training for 8 weeks. Six-minute walk distance (6MWD) was used to measure FEC. Muscle strength and 6MWD were assessed at baseline, Week 4, Week 8 and monthly for two months after PR completion. Group-based trajectory modeling (GBTM) was used to identify patterns in 6MWD in response to PR. The generalized estimating equation method was then used to detect the differences within and between the trajectories of identified groups across time. Results: Patients were grouped into low- (n=13), moderate- (n=34) and high- (n=20) FEC group based on GBTM analysis. All groups demonstrated significant improvements in 6MWD and leg muscle strength after 8-week PR. Compared to the high-FEC group, a greater proportion of the patients in the low-FEC group required oxygen supplementation during training and had worse baseline leg muscle strength. Conclusions: Patients showed distinct patterns of 6MWD changes in response to 8-week PR. Distinct characteristics for the low-FEC group included poor lower extremity strength and a greater proportion of required oxygen use at home and during training.

Optimal peak inspiratory flow rate (PIFR) is crucial for inhalation therapy in patients with chronic obstructive pulmonary disease (COPD). However, little is known about the impact of PIFR-guided inhalation therapy on the clinical outcomes among patients with varying severities of COPD. A PIFR-guided inhalation therapy, including PIFR assessment and PIFR-guided inhaler education, was introduced in a pay-for-performance COPD management program in National Taiwan University Hospital. Among 383 COPD patients, there was significant reduction in incidence of severe acute exacerbation in the PIFR-guided inhalation therapy (PIFR group) than conventional inhaler education (control group) (11.9 vs. 21.1%, p = 0.019) during one-year follow-up. A multivariable Cox’s proportional-hazards analysis revealed that the PIFR-guided inhalation therapy was a significant, independent factor associated with the reduced risk of severe exacerbation (adjusted hazard ratio = 0.49, 95% confidence interval, 0.28–0.84, p = 0.011). Subgroup analysis found PIFR-guided inhalation therapy was more beneficial to patients with older age, short body stature, COPD stage 1&2, group C&D (frequent exacerbation phenotype), and using multiple inhalers. This study showed the PIFR-guided inhalation therapy significantly reduced the incidence of severe acute exacerbation than conventional inhaler education in patients with COPD. Careful PIFR-assessment and education would be crucial in the management of COPD.

Background Heterogeneity in acute respiratory distress syndrome (ARDS) has led to many statistically negative clinical trials. Etiology is considered an important source of pathogenesis heterogeneity in ARDS but previous studies have usually adopted a dichotomous classification, such as pulmonary versus extrapulmonary ARDS, to evaluate it. Etiology-associated heterogeneity in ARDS remains poorly described. Methods In this retrospective cohort study, we described etiology-associated heterogeneity in gas exchange abnormality (PaO2/FiO2 [P/F] and ventilatory ratios), hemodynamic instability, non-pulmonary organ dysfunction as measured by the Sequential Organ Failure Assessment (SOFA) score, biomarkers of inflammation and coagulation, and 30-day mortality. Linear regression was used to model the trajectory of P/F ratios over time. Wilcoxon rank-sum tests, Kruskal–Wallis rank tests and Chi-squared tests were used to compare between-etiology differences. Results From 1725 mechanically ventilated patients in the ICU, we identified 258 (15%) with ARDS. Pneumonia (48.4%) and non-pulmonary sepsis (11.6%) were the two leading causes of ARDS. Compared with pneumonia associated ARDS, extra-pulmonary sepsis associated ARDS had a greater P/F ratio recovery rate (difference = 13 mmHg/day, p = 0.01), more shock (48% versus 73%, p = 0.01), higher non-pulmonary SOFA scores (6 versus 9 points, p p = 0.02) and higher mortality (43% versus 67%, p = 0.02). In pneumonia associated ARDS, there was significant difference in proportion of shock (p = 0.005) between bacterial and non-bacterial pneumonia. Conclusion This study showed that there was remarkable etiology-associated heterogeneity in ARDS. Heterogeneity was also observed within pneumonia associated ARDS when bacterial pneumonia was compared with other non-bacterial pneumonia. Future studies on ARDS should consider reporting etiology-specific data and exploring possible effect modification associated with etiology.

Background and objectives The main target of inspiratory muscle training (IMT) is to improve diaphragm function in patients with COPD who have inspiratory muscle weakness. Ventilatory demand is already increased during quiet breathing in patients with COPD, and whether threshold load imposed by IMT would active more accessory muscle remained to be determined. The purpose of this study was to examine diaphragm and sternocleidomastoid (SCM) activation during IMT with intensities of 30% and 50% maximal inspiratory pressure (PImax). Methods Patients with COPD and a PImax lower than 60 cmH2O were recruited for the study. Surface electromyography (EMG) was used to measure diaphragm and SCM activation, and group-based trajectory modeling (GBTM) was used to identify activation patterns during IMT. The generalized estimating equation (GEE) was then used to detect differences of variables between various breathing tasks. Statistical significance was established at p Results A total of 30 patients with COPD participated in this study. All patients demonstrated significant increases in diaphragm and SCM activation during 30% and 50% PImax of IMT than during quiet breathing (all p Conclusion Diaphragm and SCM were substantially activated during IMT in patients with COPD who had inspiratory muscle weakness. Regardless of whether diaphragm activation was high or low, SCM was activated to a greater extent in response to IMT.

Background/purpose This study aimed to investigate the clinical characteristics and outcomes of bacteremia caused by Haemophilus and Aggregatibacter species in patients who were treated at a medical center between 2006 and 2018. Methods Haemophilus and Aggregatibacter isolates were identified up to the species level using Bruker Biotyper MALDI-TOF analysis and ancillary 16S rRNA gene sequencing analysis (in case of ambiguity). Clinical characteristics and outcomes of patients with bacteremia caused by these organisms were evaluated. Results Sixty-five Haemophilus and Aggregatibacter species isolates causing bacteremia were identified from nonduplicated patients, including 51 (78.5%) Haemophilus influenzae, 6 (9.2%) Haemophilus parainfluenzae, 1 (1.5%) Haemophilus haemolyticus, 3 (4.6%) A. aphrophilus, and 4 (6.2%) A. segnis. Hospital mortality was observed in 18 (28.1%) of 64 patients with bacteremia caused by Haemophilus (n = 57) and Aggregatibacter species (n = 7). The majority of patients with bacteremia had community-acquired disease with low severity. The average Sequential Organ Failure Assessment (SOFA) score was low (4.4 ± 4.7). But, a higher SOFA score (adjusted odds ratio 2.5, 95% confidence interval 1.22–5.12; P = 0.01) was an independent factor predicting poor 7-day clinical outcomes in patients with community-acquired H. influenzae bacteremia (n = 39). Conclusions The overall hospital mortality of 28.1% was observed among patients with bacteremia due to Haemophilus and Aggregatibacter species. A higher SOFA score was and independent predictor of poor 7-day clinical outcomes in patients with community-acquired H. influenzae bacteremia.

Background: Patients with COPD had history of pulmonary tuberculosis (TB) which is a relative contraindication for the use of inhaled corticosteroid, however, the lung microbiome of this population have seldom been evaluated. Aim: We aim to investigate the difference of lung microbiome and airway inflammation in COPD patients with or without history of TB. Methods: Stable COPD patients with or without history of pulmonary TB were prospectively enrolled. The pellet of bronchoalveolar lavage (BAL) were collected for lung microbiome analysis via 16S rRNA sequencing. Neutrophil extracellular traps (NETs) and Inflammatory cytokines of BAL were examined. The associated clinical information and blood samples of the patients were collected for further analysis. Results: A total of 25 patients were enrolled for analysis, including 10 patients with COPD, 9 COPD patients with history of TB infection and 6 non-COPD patients. Lung microbiome analysis showed COPD patients with history of TB had predominant Proteobacteria spp. (Pseudomonas. aeruginosa) colonization and the lower shannon diversity compared to COPD and non-COPD groups. Moreover, beta diversity revealed that COPD with history of TB had significantly change of lung microbiome composition compared to COPD and non-COPD groups. Nevertheless, the NET level and inflammatory cytokines were only relatively higher in COPD with history of TB group, which do not reach statistical significance. Conclusions: Our study demonstrated that the composition of lung microbiome is different in COPD patients after TB infection compared to COPD and non-COPD patients, but without significantly change of airway inflammation

Patients with nontuberculous mycobacterial lung disease (NTM-LD) often have significant exercise intolerance and poorer health-related quality of life (HRQL). The goals of treatment for NTM-LD should include reducing the severity of symptoms, improving HRQL, and reducing acute exacerbations. Nonpharmacological treatment, including pulmonary rehabilitation program and optimal nutritional strategy, should be one part of treatment for NTM-LD. A pulmonary rehabilitation (PR) program can comprise education, airway clearance techniques instruction, exercise training program, and inspiratory muscle training (IMT). Airway clearance techniques can improve the volume of sputum expectorated, cough symptom, breathlessness, and HRQL. Exercise training can improve exercise capacity and HRQL, and reduce acute exacerbations and dyspnea. Clinical benefits of IMT remain controversial but high-intensity IMT has been shown to be effective in increasing respiratory muscle strength with concurrent improvement of HRQL and exercise capacity. Body weight and muscle mass loss are common in patients with NTM-LD. An adequate protein and caloric diet combined with antioxidant nutrients might be the most appropriate dietary strategy. Comprehensive treatment for NTM-LD should include the combination of both pharmacological and nonpharmacological treatments. The management programs should be tailored to the individual's condition.

Optimal peak inspiratory flow rate (PIFR) is crucial for optimizing dry powder inhaler (DPI) effectiveness for chronic obstructive pulmonary disease (COPD). This study provide an insight that there was a substantial proportion of improper PIFRs (not only insufficient but also excessive) among COPD patients using DPIs. We enrolled 138 COPD patients from a medical center in Taiwan and measured PIFRs against different internal resistances of DPIs. Proportion of excessive, optimal, suboptimal, and insufficient PIFRs were 2%, 54%, 41%, 3%, respectively, against medium-high resistance; 2%, 77%, 20%, 1%, respectively, against medium resistance; 27%, 63%, 9%, 1%, respectively, against medium-low resistance; and 42%, 57%, 1%, 0%, respectively, against low resistance (p

Background Pneumocystis pneumonia (PCP) is a fatal complication in patients with rheumatic diseases, and prognostic factors are not well recognized.1 Adjunctive glucocorticoid therapy is beneficial for PCP in patients with acquired immunodeficiency syndrome, but the role in patients with rheumatic diseases is debated.2 Objectives To investigate the prognostic factors of PCP in patients with rheumatic diseases. Methods Retrospective data was collected for all subjects with rheumatic diseases and PCP between October 2015 and October 2018 in a tertiary referral center. PCP was diagnosed via a positive sputum Pneumocystis jirovecii PCR in the presence of a compatible clinical presentation. The clinical characteristic, underlying rheumatic diseases, comorbidity, immunosuppressants, adjunctive glucocorticoid dose, and outcome were evaluated. Chest X-ray (CXR) was evaluated as a radiographic score (0-18), and a higher score suggested a more severe lung involvement. The prognostic factors of mortality were analyzed by multivariate logistic regression analysis. Results 40 patients with PCP and rheumatic diseases were included. The mean age of the patients was 55.7 years, and twenty (50%) were female. The underlying rheumatic diseases were systemic lupus erythematosus (30%), rheumatoid arthritis (22.5%), Sjogren’s syndrome (12.5%), systemic vasculitis (12.5%), antiphospholipid syndrome (10%), idiopathic inflammatory myopathies (10%), undifferentiated connective tissue disease (7.5%), and psoriatic arthritis (2.5%). All subjects were separated into survivors (n=17) and non-survivors (n=23) groups. The overall in-hospital mortality rate was 57.5%. The group of non-survivors had a higher adjunctive glucocorticoid dose (p=0.016), an older age (p=0.017), and a higher CXR radiographic score (p=0.029). In multivariate analysis, independent predictors of mortality were increased glucocorticoid dose (>10mg/day) as adjunctive therapy (odds ratio, OR=5.58, 95% confidence interval, C.I.=1.09-28.62; p=0.039), age (OR=1.06, 95% C.I.=1.00-1.11; p=0.037), and CXR radiographic score (OR=1.21, 95% C.I.=1.00-1.47, p=0.048). Conclusion Increased glucocorticoid dose (>10mg/day) as adjunctive therapy, older age, and CXR radiographic score were independently prognostic factors of mortality in PCP patients with rheumatic diseases. Disclosure of Interest None declared References [1] Teichtahl AJ, Morrisroe K, Ciciriello S, et al. Pneumocystis jirovecii pneumonia in connective tissue diseases: Comparison with other immunocompromised patients. Semin Arthritis Rheum 2015;45:86–90. [2] Ando T, Abe Y, Endo Y, et al. Rapid glucocorticoid tapering therapy to reduce mortality from pneumocystis pneumonia in patients with rheumatic disease. Mod Rheumatol 2018;13:1–6. Disclosure of Interests None declared

Background/purpose: Early recognition of causative pathogens is critical for the appropriate management of central nervous system infection and improved outcomes. The BioFire® FilmArray® Meningitis/Encephalitis Panel (BioFire® ME Panel, BioFire Diagnostics) is the first U.S. Food and Drug Administration (FDA)-approved multiplex PCR assay that allows the rapid detection of 14 pathogens, including bacteria (n = 6), viruses (n = 7), and fungi (n = 1), from cerebrospinal fluid (CSF). The performance of the panel is expected to be dependent on the epidemiology of M/E in different geographical regions. Methods: In this preliminary study, we used the BioFire® ME Panel in 42 subjects who presented to the emergency department with symptoms of M/E in our hospital. The results were compared to conventional culture, antigen detection, PCR, and various laboratory findings. Results: The panel detected six positive samples, of which five were viral and one bacterial. We observed an overall agreement rate of 88% between the BioFire® ME Panel results and the conventional methods. There were no false-positive findings, but five discordant results were observed for enterovirus, herpes simplex virus type 1, Escherichia coli, and Cryptococcus species. Conclusions: The BioFire® ME Panel performed equivalently to the traditional PCR methods for virus detection, and better than bacterial cultures. This revolutionary system represents a paradigm shift in the diagnosis of M/E and may aid in the rapid identification of community-acquired M/E. However, the usefulness of this tool is limited in regions with a high prevalence of infectious M/E caused by microorganisms not included in the panel. Keywords: BioFire® ME panel, Encephalitis, Emergency department, Meningitis, Multiplex PCR assay

Background The World Health Organization has projected that by 2030, chronic obstructive pulmonary disease (COPD) will be the third-leading cause of mortality and the seventh-leading cause of morbidity worldwide. Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are associated with an accelerated decline in lung function, diminished quality of life, and higher mortality. Accurate early detection of acute exacerbations will enable early management and reduce mortality. Objective The aim of this study was to develop a prediction system using lifestyle data, environmental factors, and patient symptoms for the early detection of AECOPD in the upcoming 7 days. Methods This prospective study was performed at National Taiwan University Hospital. Patients with COPD that did not have a pacemaker and were not pregnant were invited for enrollment. Data on lifestyle, temperature, humidity, and fine particulate matter were collected using wearable devices (Fitbit Versa), a home air quality–sensing device (EDIMAX Airbox), and a smartphone app. AECOPD episodes were evaluated via standardized questionnaires. With these input features, we evaluated the prediction performance of machine learning models, including random forest, decision trees, k-nearest neighbor, linear discriminant analysis, and adaptive boosting, and a deep neural network model. Results The continuous real-time monitoring of lifestyle and indoor environment factors was implemented by integrating home air quality–sensing devices, a smartphone app, and wearable devices. All data from 67 COPD patients were collected prospectively during a mean 4-month follow-up period, resulting in the detection of 25 AECOPD episodes. For 7-day AECOPD prediction, the proposed AECOPD predictive model achieved an accuracy of 92.1%, sensitivity of 94%, and specificity of 90.4%. Receiver operating characteristic curve analysis showed that the area under the curve of the model in predicting AECOPD was greater than 0.9. The most important variables in the model were daily steps walked, stairs climbed, and daily distance moved. Conclusions Using wearable devices, home air quality–sensing devices, a smartphone app, and supervised prediction algorithms, we achieved excellent power to predict whether a patient would experience AECOPD within the upcoming 7 days. The AECOPD prediction system provided an effective way to collect lifestyle and environmental data, and yielded reliable predictions of future AECOPD events. Compared with previous studies, we have comprehensively improved the performance of the AECOPD prediction model by adding objective lifestyle and environmental data. This model could yield more accurate prediction results for COPD patients than using only questionnaire data.

Fluoroquinolones (FQs) are effective second-line drugs for treating antibiotic-resistant tuberculosis (TB) and are being considered for use as first-line agents. Because FQs are used to treat a range of infections, in a setting of undiagnosed TB, there is potential to select for drug-resistant Mycobacterium tuberculosis mutants during FQ-based treatment of other infections, including pneumonia. Here we present a detailed characterization of ofloxacin-resistant M. tuberculosis samples isolated directly from patients in Taiwan, which demonstrates that selection for FQ resistance can occur within patients who have not received FQs for the treatment of TB. Several of these samples showed no mutations in gyrA or gyrB based on PCR-based molecular assays, but genome-wide next-generation sequencing (NGS) revealed minority populations of gyrA and/or gyrB mutants. In other samples with PCR-detectable gyrA mutations, NGS revealed subpopulations containing alternative resistance-associated genotypes. Isolation of individual clones from these apparently heterogeneous samples confirmed the presence of the minority drug-resistant variants suggested by the NGS data. Further NGS of these purified clones established evolutionary links between FQ-sensitive and -resistant clones derived from the same patient, suggesting de novo emergence of FQ-resistant TB. Importantly, most of these samples were isolated from patients without a history of FQ treatment for TB. Thus, selective pressure applied by FQ monotherapy in the setting of undiagnosed TB infection appears to be able to drive the full or partial emergence of FQ-resistant M. tuberculosis , which has the potential to confound diagnostic tests for antibiotic susceptibility and limit the effectiveness of FQs in TB treatment.

It is unclear whether the use of moxifloxacin (MFX), a newer synthetic fluoroquinolone, results in better outcomes in patients with ofloxacin (OFX)-resistant multidrug-resistant tuberculosis (MDR-TB). During the period from April 2006 to December 2013, a total of 2,511 patients with culture-confirmed tuberculosis (TB) were treated at a TB referral hospital in southern Taiwan. Of the 2,511 patients, 325 (12.9%) had MDR-TB, and of those 325 patients, 81 (24.9%) had OFX-resistant MDR-TB and were included in the study. Among the 81 patients with OFX-resistant MDR-TB, 50 (61.7%) were successfully treated and 31 (38.3%) had unfavorable outcomes, including treatment failure ( n = 25; 30.9%), loss to follow-up ( n = 2; 2.5%), and death ( n = 4; 4.9%). Patients treated with MFX had a significantly higher rate of treatment success (77.3% versus 43.2%; odds ratio [OR] = 4.46, 95% confidence interval [CI] = 1.710 to 11.646, P = 0.002) than patients not treated with MFX, especially among those infected with MFX-susceptible isolates (40.7%) or isolates with low-level resistance to MFX (28.4%). Multivariate logistic regression analysis showed that treatment with MFX (adjusted odds ratio = 6.54, 95% CI = 1.44 to 29.59, P = 0.015) was the only independent factor associated with treatment success. Mutation at codon 94 in the gyrA gene was the most frequent mutation (68.0%) associated with high-level MFX resistance. Multivariate Cox proportional hazards regression analysis showed that treatment with MFX was also an independent factor associated with early culture conversion (hazard ratio = 3.12, 95% CI = 1.48 to 6.54, P = 0.003). Our results show that a significant proportion of OFX-resistant MDR-TB isolates were susceptible or had low-level resistance to MFX, indicating that patients with OFX-resistant MDR-TB benefit from treatment with MFX.

Organ dysfunction is common in patients with major burns and associated with poor outcomes. The risk factors for early onset multiple organ dysfunction syndrome (MODS) in major burn patients with invasive ventilator support has rarely been evaluated before. In this study, major burn patients with invasive ventilator support from 499 victims suffered in a mass casualty color dust explosion were retrospectively enrolled. The development of early MODS that occurred within 5 days after burn injury was determined and the risk factors associated with early MODS were analyzed. A total of 88 patients from five medical centers were included. Their mean total body surface area (TBSA) was 60.9 ± 15.8%, and 45 (51.1%) patients had early MODS. Hematologic failure was the most common organ failure (68.6%), followed by respiratory failure (48.9%). Independent clinical factors associated with early MODS included TBSA ≥55% (OR: 3.83; 95% CI: 1.29–11.37) and serum albumin level

Funding: World Health Organization and Canadian Institutes of Health Research. Background: Isoniazid-resistant, rifampicin-susceptible (INH-R) tuberculosis is the most common form of drug resistance, and is associated with failure, relapse, and acquired rifampicin resistance if treated with first-line anti-tuberculosis drugs. The aim of the study was to compare success, mortality, and acquired rifampicin resistance in patients with INH-R pulmonary tuberculosis given different durations of rifampicin, ethambutol, and pyrazinamide (REZ); a fluoroquinolone plus 6 months or more of REZ; and streptomycin plus a core regimen of REZ. Methods: Studies with regimens and outcomes known for individual patients with INH-R tuberculosis were eligible, irrespective of the number of patients if randomised trials, or with at least 20 participants if a cohort study. Studies were identified from two relevant systematic reviews, an updated search of one of the systematic reviews (for papers published between April 1, 2015, and Feb 10, 2016), and personal communications. Individual patient data were obtained from authors of eligible studies. The individual patient data meta-analysis was performed with propensity score matched logistic regression to estimate adjusted odds ratios (aOR) and risk differences of treatment success (cure or treatment completion), death during treatment, and acquired rifampicin resistance. Outcomes were measured across different treatment regimens to assess the effects of: different durations of REZ (≤6 months vs >6 months); addition of a fluoroquinolone to REZ (fluoroquinolone plus 6 months or more of REZ vs 6 months or more of REZ); and addition of streptomycin to REZ (streptomycin plus 6 months of rifampicin and ethambutol and 1–3 months of pyrazinamide vs 6 months or more of REZ). The overall quality of the evidence was assessed using GRADE methodology. Findings: Individual patient data were requested for 57 cohort studies and 17 randomised trials including 8089 patients with INH-R tuberculosis. We received 33 datasets with 6424 patients, of which 3923 patients in 23 studies received regimens related to the study objectives. Compared with a daily regimen of 6 months of (H)REZ (REZ with or without isoniazid), extending the duration to 8–9 months had similar outcomes; as such, 6 months or more of (H)REZ was used for subsequent comparisons. Addition of a fluoroquinolone to 6 months or more of (H)REZ was associated with significantly greater treatment success (aOR 2·8, 95% CI 1·1–7·3), but no significant effect on mortality (aOR 0·7, 0·4–1·1) or acquired rifampicin resistance (aOR 0·1, 0·0–1·2). Compared with 6 months or more of (H)REZ, the standardised retreatment regimen (2 months of streptomycin, 3 months of pyrazinamide, and 8 months of isoniazid, rifampicin, and ethambutol) was associated with significantly worse treatment success (aOR 0·4, 0·2–0·7). The quality of the evidence was very low for all outcomes and treatment regimens assessed, owing to the observational nature of most of the data, the diverse settings, and the imprecision of estimates. Interpretation: In patients with INH-R tuberculosis, compared with treatment with at least 6 months of daily REZ, addition of a fluoroquinolone was associated with better treatment success, whereas addition of streptomycin was associated with less treatment success; however, the quality of the evidence was very low. These results support the conduct of randomised trials to identify the optimum regimen for this important and common form of drug-resistant tuberculosis. Funding World Health Organization and Canadian Institutes of Health Research. Postprint

We investigated the prevalence of latent tuberculosis infection (LTBI) among the residents in seven long-term care facilities (LTCFs) located in different regions of Taiwan and compared the performance of two interferon gamma release assays, i.e., QuantiFERON-TB Gold In-Tube (QFT-GIT) and QuantiFERON-TB Gold Plus (QFT-Plus) for screening LTBI. We also assessed the diagnostic performance against a composite reference standard (subjects with persistent-positive, transient-positive, and negative results from QFTs during reproducibility analysis were classified as definite, possible, and not LTBI, respectively). Two hundred forty-four residents were enrolled, and 229 subjects were included in the analysis. The median age was 80 years (range, 60 to 102 years old), and 117 (51.1%) were male. Among them, 66 (28.8%) and 74 (32.3%) subjects had positive results from QFT-GIT and QFT-Plus, respectively, and the results for 215 (93.9%) subjects showed agreement. Using the composite reference standard, 66 (28.8%), 11 (4.8%), and 152 (66.4%) were classified as definite, possible, and not LTBI, respectively. For definite LTBI, the sensitivity, specificity, positive predictive value, and negative predictive value of QFT-GIT were 89.4%, 95.7%, 89.4%, and 95.7%, respectively, and those for QFT-Plus were 100.0%, 95.1%, 89.2%, and 100.0%, respectively. The sensitivity of QFT-GIT decreased gradually with patient age. Compared to QFT-GIT, QFT-Plus displayed significantly higher sensitivity (100.0% versus 89.4%, P = 0.013) and similar specificity (95.1% versus 95.7%). In conclusion, a high prevalence of LTBI was found among elders in LTCFs in Taiwan. The new QFT-Plus test demonstrated a higher sensitivity than QFT-GIT in the older adults in LTCFs.

Background Although bisphosphonate-related osteonecrosis of the jaw (ONJ) develops mainly after tooth extractions (TEs), the strength of the association between them and how the existence of the disease among bisphosphonate (BP)-treated osteoporotic patients exposed to TE remain uncertain. Methods A nationwide retrospective cohort study investigated the influence of alendronate and TE on the development of ONJ. Results Incidence of ONJ following long-term alendronate therapy was 262/100,000 person-years, while no event developed in the control group on raloxifene. Overall prevalence of ONJ in osteoporotic subjects receiving alendronate was estimated at 0.34% which rose to 2.16% after TE. Multiple logistic regression analysis, adjusted for the potential confounders, showed TE (adjusted odds ratio, 9.60 [4.33–21.29]), drug duration exceeding 3 years (3.00 [1.33–6.76]), and concomitant rheumatoid arthritis (4.94 [1.64–14.90]) were independent predictors of ONJ. Conclusions This article strengthens the relationship between ONJ and BPs. Among osteoporotic patients exposed to alendronate, TE confers a 9.6-fold increased risk for ONJ and it should be performed with caution irrespective of drug duration.

Isoniazid mono-resistance is the most common first-line drug resistance in tuberculosis (TB), but its treatment outcome remains unclear. From January 2004 to October 2011, 425 (5.1%) of 8414 patients with culture-confirmed pulmonary TB from four hospitals in Taiwan were identified as having isoniazid mono-resistant TB. Among them, 395 (92.9%) were included and followed up for 2 years after complete treatment. Although 328 (83.0%) patients were successfully treated, 67 (17.0%) had unfavourable outcomes, including death in 56 (14.2%) and treatment failure in 11 (2.8%). The treatment success rate was similar in patients with high-level and low-level isoniazid-resistant TB (82.2% versus 83.4%, p 0.785) and among those taking anti-TB treatment with and without isoniazid (83.1% versus 83.0%, p 1.000). Patients without rifampicin interruption had lower risk of unfavourable outcome (14.3% versus 37.0%, p 12 months had less relapse than 6-month treatment (3.2%, 0%, 3.7% and 25.0%, respectively, p 0.037). Multivariate Cox proportional hazards analysis revealed that co-morbidity with cancer (hazard ratio, 2.43) and rifampicin interruption (hazard ratio 1.91) were independent factors associated with unfavourable outcomes. Treatment throughout with rifampicin and extended treatment for cavitary disease are crucial for improving outcomes in patients with isoniazid mono-resistant TB.

Background: This study aimed to explore the possible association between osteonecrosis of the jaws (ONJ) and oral alendronate or raloxifene used for osteoporosis and to estimate its absolute and attributable risks in the Taiwanese population. Methods: Using an electronic medical records system and manual confirmation of ONJ, we identified patients who began taking alendronate or raloxifene for osteoporosis and developed ONJ between January 2000 and April 2012. Results: The incidence of ONJ associated with oral alendronate for the management of osteoporosis began after 1 year of drug exposure and progressively increased with longer durations of therapy, specifically from 0.23% to 0.92% as the duration of treatment went from 2 years to 10 years. The overall frequency of ONJ related to oral alendronate over a 12-year period was 0.55%. The incidence rate of ONJ attributed to alendronate exposure was 283 per 100 000 persons per year. On multivariate Cox proportional analysis, adjusting for the potential confounders, alendronate remains an independent predictor for ONJ occurrence [hazard ratio 7.42 (1.02–54.09)] compared with raloxifene. Advanced age, drug duration, and coexisting diabetes and rheumatoid arthritis are contributing factors to the development of oral alendronate-related ONJ. Conclusion: We provided the evidence to support the association of ONJ with oral alendronate used in the treatment or prevention of osteoporosis.

We analyzed samples from 13,652 patients who had respiratory cultures positive for mycobacteria in Taiwan during 2000–2012 and found that 56.9% were positive for nontuberculous mycobacteria (NTM). Whereas annual prevalence of tuberculosis decreased during the study period, prevalence of NTM disease and colonization increased, particularly among older patients and male patients.

The safety of rifabutin replacing rifampicin among adults having rifampicin-related adverse reactions (ARs) during the treatment of tuberculosis remains unknown.From June 2006 to June 2010, a total of 2868 newly treated tuberculosis patients without HIV infection in a referral hospital were screened in this retrospective cohort study.Among the screened patients, a total of 221 (8%) patients who received rifabutin replacing rifampicin were included. Of these patients, 158 (72%) tolerated rifabutin during treatment, but 47 (21%) and 16 (7%) experienced mild and severe rifabutin-related ARs (including neutropenia, severe hepatitis and uveitis), respectively, and needed to discontinue rifabutin. Those having previous rifampicin-related arthralgia, dermatological events and cholestasis had a higher AR recurrence rate (60%, 23% and 9%, respectively) than others (5% for hepatitis and gastrointestinal intolerance and 0% for flu-like syndrome, neutropenia and others; P0.01). Multivariate logistic regression analysis showed that females (OR 3.35; 95% CI 1.06-10.56; P = 0.04) and patients with hepatitis virus B (HBV) or hepatitis C virus (HCV) coinfection (OR 3.72; 95% CI 1.19-11.67; P = 0.02) were at a higher risk of rifabutin-related severe ARs. No development of new drug resistance and no relapse of tuberculosis were found during 2 years of follow-up.Rifabutin replacing rifampicin was well tolerated in most adults who had rifampicin-related ARs. Females and those with HCV or HBV coinfection were more prone to rifabutin-related severe ARs and required more cautious monitoring.

Background Sputum samples from patients with non-multidrug-resistant (non-MDR) pulmonary TB may remain smear-positive for acid-fast bacilli (AFB) at the fifth month of anti-TB treatment. However, its significance remains unknown. Methods From January 2004 to April 2009, there were 5,403 patients with culture-confirmed pulmonary TB from four hospitals in Taiwan. Among them, 116 patients (2.2%) with non-MDR TB whose sputum samples were smear-positive by concentration smear method at the fifth month of treatment were evaluated. Results Sputum culture yielded Mycobacterium tuberculosis in 10 patients (8.6%, MTB group), nontuberculous mycobacteria in 23 (19.8%, NTM group), and no growth in the remaining 83 (71.6%, no-growth group). The relapse rate (22%) was higher in the MTB group ( P = .01). Four predictors, smear grading ≥ 3+ at the fifth month (“S”) (OR, 10.73; 95% CI, 2.67-43.17), no sputum culture conversion on the second month (“C”) (OR, 7.16; 95% CI, 1.45-35.44), lack of directly observed therapy (“O”) (OR, 6.40; 95% CI, 1.54-26.56), and no radiographic improvement at the fifth month (“R”) (OR, 4.18; 95% CI, 1.02-17.10), were associated with viable M tuberculosis (MTB group). An integrated “SCOR” index of 1 point for each positive factor had the best discriminatory power for predicting culture results at the fifth month. If the SCOR index was 0, all smear-positive sputum was culture-negative for M tuberculosis . Conclusions Positive sputum smears by a concentrated smear method at the fifth month of treatment in patients with non-MDR TB, especially those with a low SCOR index, may be due to nonviable bacilli and NTM. Careful review of the quality of patient supervision, bacteriologic data, and chest radiography is crucial.

BACKGROUND: Abnormal thoraco-abdominal motion may contribute to exercise limitation in patients with COPD. The current study aimed to assess how the thoraco-abdominal asynchrony in COPD patients correlates with exercise performance during the 6-minute walk test (6MWT). METHODS: Eighty-eight COPD subjects (40 moderate and 48 severe) and 14 healthy controls were evaluated at rest and during the 6MWT for the magnitude of rib cage and abdominal motion and asynchrony between the two (phase angle) with respiratory inductive plethysmography. RESULTS: Compared to healthy control subjects, subjects with COPD had similar magnitude of rib cage and abdominal motion, but greater asynchrony at rest. During the 6MWT, subjects with COPD showed decreased rib cage motion and increased asynchrony. Rib cage excursion at 3 min after the beginning of the 6MWT was an independent predictor for the 6MWT distance ( P < .001), in addition to age, percent of predicted FEV1, and residual volume/total lung capacity. There was no correlation between rib cage excursion at 3 min and St George's Respiratory Questionnaire score. CONCLUSIONS: Thoraco-abdominal asynchrony worsens early during 6MWT in subjects with moderate and severe COPD, and rib cage excursion at 3 min predicts poor walking capability. A pulmonary rehabilitation strategy devised to improve rib cage excursion may help improve exercise tolerance.

Background Tuberculous pleurisy is traditionally indicated by extreme lymphocytosis in pleural fluid and low yield of effusion culture. However, there is considerable inconsistency among previous study results. In addition, these data should be updated due to early effusion studies and advances in culture methods. Methods From January 2004 to June 2009, patients with tuberculous pleurisy were retrospectively identified from the mycobacteriology laboratories and the pathology and tuberculosis registration databases of two hospitals in Taiwan where tuberculosis is endemic. Pleural fluid characteristics and yields of mycobacterial cultures using liquid media were evaluated. Results A total of 382 patients with tuberculous pleurisy were identified. The median lymphocyte percentage of total cells in pleural fluids was 84% (IQR 64–95%) and 17% of cases had a lymphocyte percentage of

Lin-Yu Liao,1,2 Kuei-Min Chen,2 Wei-Sheng Chung,3 Jung-Yien Chien4 1Department of Nursing, Chest Hospital, Ministry of Health and Welfare, Rende District, Tainan, 2College of Nursing, Kaohsiung Medical University, Sanmin District, Kaohsiung, 3Department of Internal Medicine, Taichung Hospital, Ministry of Health and Welfare, Taichung, 4Department of Medicine, Chest Hospital, Ministry of Health and Welfare, Rende District, Tainan, Taiwan Clinical trials identifier: NCT02329873 Background: Acute exacerbation (AE) of COPD is characterized by a sudden worsening of COPD symptoms. Previous studies have explored the effectiveness of respiratory rehabilitation for patients with COPD; however, no training program specific to acute exacerbation in elderly patients or unstable periods during hospitalization has been developed.Objective: To evaluate the effects of a respiratory rehabilitation exercise training package on dyspnea, cough, exercise tolerance, and sputum expectoration among hospitalized elderly patients with AECOPD.Methods: A randomized control trial was conducted. Pretest and posttest evaluations of 61 elderly inpatients with AECOPD (experimental group n=30; control group n=31) were performed. The experimental group received respiratory rehabilitation exercise training twice a day, 10–30minutes per session for 4days. The clinical parameters (dyspnea, cough, exercise tolerance, and sputum expectoration) were assessed at the baseline and at the end of the fourth day.Results: All participants (median age =70years, male =60.70%, and peak expiratory flow 140L) completed the study. In the patients of the experimental group, dyspnea and cough decreased and exercise tolerance and sputum expectoration increased significantly compared with those of the patients in the control group (all P

In order to correlate the mutations inside the entire gyrA and gyrB genes with the level of resistance to ofloxacin (OFX) and moxifloxacin (MFX) in isolates of multidrug-resistant Mycobacterium tuberculosis (MDR-TB), a total of 111 isolates were categorized into OFX-susceptible (MIC, ≤2 μg/ml) and low-level (MIC, 4 to 8 μg/ml) and high-level (MIC, ≥16 μg/ml) OFX-resistant isolates and MFX-susceptible (MIC, ≤0.5 μg/ml) and low-level (MIC, 1 to 2 μg/ml) and high-level (MIC, ≥4 μg/ml) MFX-resistant isolates. Resistance-associated mutations inside the gyrA gene were found in 30.2% of OFX-susceptible and 72.5% and 72.2% of low-level and high-level OFX-resistant isolates and in 28.6% of MFX-susceptible and 58.1% and 83.9% of low-level and high-level MFX-resistant isolates. Compared with OFX-susceptible isolates, low-level and high-level OFX-resistant isolates had a significantly higher prevalence of mutations at gyrA codons 88 to 94 (17.0%, 65.0%, and 72.2%, respectively; P < 0.001) and a higher prevalence of the gyrB G512R mutation (0.0%, 2.5%, and 16.7%, respectively; P = 0.006). Similarly, compared with MFX-susceptible isolates, low-level and high-level MFX-resistant isolates had a significantly higher prevalence of mutations at gyrA codons 88 to 94 (14.3%, 51.6%, and 80.6%, respectively; P < 0.001) as well as a higher prevalence of the gyrB G512R mutation (0.0%, 0.0%, and 12.9%, respectively; P = 0.011). D94G and D94N mutations in gyrA and the G512R mutation in gyrB were correlated with high-level MFX resistance, while the D94A mutation was associated with low-level MFX resistance. The prevalence of mutations at gyrA codons 88 to 94 and the gyrB G512R mutation were higher among fluoroquinolone (FQ)-susceptible East Asian (Beijing) and Indo-Oceanic strains than they were among Euro-American strains, implying that molecular techniques to detect FQ resistance may be less specific in areas with a high prevalence of East Asian (Beijing) and Indo-Oceanic strains.

The performance of the BluePoint MycoID plus kit (Bio Concept Corporation, Taichung, Taiwan), which was designed to simultaneously detect Mycobacterium tuberculosis (MTB), rifampin- and isoniazid-resistant MTB, and nontuberculous mycobacteria (NTM) was first evaluated with 950 consecutive positive cultures in Mycobacterium Growth Indicator Tube (MGIT) system (BACTEC, MGIT 960 system, Becton-Dickinson, Sparks) from clinical respiratory specimens. The discrepant results between kit and culture-based identification were finally assessed by 16S rRNA gene sequencing and clinical diagnosis. The accuracy rate of this kit for identification of all Mycobacterium species was 96.3% (905/940). For MTB identification, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the kit were 99.7%, 99.3%, 99.0% and 99.8%, respectively. For rifampicin-resistant MTB identification, the sensitivity, specificity, PPV, and NPV of the kit were 100.0%, 99.4%, 91.3%, and 100.0%, respectively, while the corresponding values of isoniazid-resistant MTB identification were 82.6%, 99.4%, 95.0%, and 97.6%, respectively. In identifying specific NTM species, the kit correctly identified 99.3% of M. abscessus (147/148) complex, 100% of M. fortuitum (32/32), M. gordonae (38/38), M. avium (39/39), M. intracellulare (90/90), M. kansasii (36/36), and M. avium complex species other than M. avium and M. intracellulare (94/94). In conclusions, the diagnostic value of the BluePoint MycoID plus kit was superior to culture method for recoveries and identification of NTM to species level. In addition, the diagnostic accuracy of BluePoint MycoID plus kit in MTB identification was similar to conventional culture method with high accuracy rate of rifampicin-resistant M. tuberculosis identification.

Background The contribution of human immunodeficiency virus (HIV) co-infection to tuberculosis (TB) recurrence is well established worldwide. We conducted this study to investigate associated factors for recurrent TB in Taiwan, which has a relatively low prevalence of HIV. Methods A case-control study nested within a nationwide population-based cohort was performed using the Taiwan National Health Insurance (NHI) database from 1998 to 2010. Patients with notified TB were identified according to diagnosis codes and prescriptions of anti-TB drugs for more than 60 days. Recurrent TB was defined as cases being retreated for more than 60 days and 6 months after the end of previous TB episode. Four controls were randomly selected from cohort and matched to each case by observational period within a calendar year. Socio-demographic variables and comorbidities were evaluated as factors associated with TB recurrence. Results There were totally 760 patients being investigated (608 controls and 152 cases). During an average 5.12 years of follow-up, 3.76% of all developed recurrent TB and the incidence of TB recurrence was 734 per 100,000 person-years. About half of recurrence (55%) was notified within three years of follow-up, and most (86%) recurrences were intrapulmonary. Independent associated factors for TB recurrence included: male (odds ratio, OR: 2.23, 95% confidence interval, CI: 1.40–3.53), diabetes mellitus (DM) (OR: 1.51, 95% CI: 1.02–2.13), chronic obstructive pulmonary disease (COPD) (OR: 1.59, 95% CI: 1.08–2.36) and lower socio-economic status (p=0.001 between groups). Conclusions Despite low prevalence of HIV in the Taiwanese population, the incidence of recurrent TB among Taiwanese was not less than that of other countries. Identification of subgroups such as male gender, low economic status, DM and COPD should be a high priority in TB control programs.

The resistance of Mycobacterium tuberculosis (MTB) to second-line drugs (SLDs) is growing worldwide; however, associations between the appropriateness of treatment for tuberculosis (TB) and whether the directly observed treatment, short course (DOTS)/DOTS-plus programs had an impact on the prevalence of SLD-resistant MTB are still uncertain. We performed a retrospective analysis of resistance profiles among MTB isolates obtained from 6,035 consecutive patients from 2004 to 2011 at two TB referral hospitals in Taiwan. There was a significant decrease (all p-values

OBJECTIVES To investigate the impact of the directly observed therapy, short course (DOTS) and DOTS-Plus strategies on changes in resistance profiles among Mycobacterium tuberculosis (MTB). METHODS We performed a retrospective analysis of resistance profiles among isolates of MTB obtained from 2160 consecutive patients with culture-confirmed pulmonary tuberculosis (TB) between 2005 and 2011 at a referral centre in southern Taiwan. RESULTS Of the 2160 patients, 70 (3.2%) had primary multidrug-resistant (MDR)-TB, 178 (8.2%) had acquired MDR-TB, 10 (0.5%) had primary extensively drug-resistant (XDR)-TB, 23 (1.1%) had acquired XDR-TB and 5 (0.2%) had totally drug-resistant (TDR)-TB. Trend analysis revealed that the rates of acquired MDR-TB were significantly lower after implementation of the DOTS and DOTS-Plus programmes (P

A 76-year-old man with a history of large-territory ischemic stroke has been bed-bound and fed through a nasogastric tube for 12 years. He was brought to the hospital because of fever and worsening dyspnea. Shortly after presentation, he was intubated uneventfully for hypoxemic respiratory failure. A chest radiograph (Figure 1A) showed patchy consolidation in …

Background During the past 2 decades, invasive trichosporonosis has emerged as an opportunistic infectious disease in immunocompromised patients. However, no case series have been reported recently. Methods All patients with a culture that was positive for Trichosporon species from May 2000 through May 2008 at a medical center were evaluated. The identity of all Trichosporon species was confirmed by analysis of the intergenic spacer 1 region of the fungal ribosomal RNA gene. In vitro susceptibility testing was performed using the reference broth microdilution method. Results Forty-three patients were found to have a culture that was positive for Trichosporon species. T. asahii was the most frequently isolated species (32 isolates; 74%), followed by T. dermatis (5; 12%), T. montevideense (2; 5%), and T. asteroides (1; 2%), T. cutaneum (1; 2%), T. faecale (1; 2%), and T. ovoides (1; 2%). Nineteen patients had invasive infections; 16 (84%) were caused by T. asahii, and 1 (5%) each was caused by T. dermatis, T. montevideense, and T. asteroides. Of the 19 episodes of invasive trichosporonosis, 14 (74%) were fungemia, 3 (16%) were pulmonary infection, and 1 (5%) each was soft-tissue infection and meningitis. Most invasive infections were associated with prior antibiotic therapy (95%), use of a central catheter (90%), malignancy (58%), and intensive care unit admission (47%). Azoles had good in vitro activity, whereas amphotericin B and echinocandins were not active against Trichosporon isolates. The 30-day all-cause mortality rate was 42% and was higher among patients with a malignancy (55%) than among those without an underlying malignancy (25%). Conclusions Invasive trichosporonosis tended to develop in patients with an underlying malignancy and to be associated with higher mortality. T. asahii and other unusual Trichosporon species may cause invasive trichosporonosis.

SummaryCandida intermedia is rarely reported as a human pathogen. We report two cases of catheter-related fungemia caused by C. intermedia which were treated successfully with intravenous fluconazole and catheter removal. The isolates were identified by commercial biochemical methods, oligonucleotide array, and partial sequencing analysis of rRNA genes.

Nosocomial meningitis is rare, and routine cerebrospinal fluid study is seldom recommended for hospitalized patients with fever and acute delirium. We present a case of Enterobacter cloacae meningitis complicated with a nontraumatic pneumocephalus. Maintaining a high index of suspicion of nosocomial meningitis is crucial in patients with acute delirium and multiple underlying comorbid conditions.

Objective and background: Pathological changes in severe acute respiratory syndrome (SARS) suggest that SARS sequelae are associated with dysregulation of cytokine and chemokine production. To improve understanding of the immuno-pathological processes involved in lung injury associated with SARS, the temporal changes in cytokine/chemokine profiles in the sera of SARS patients were compared with those of patients with community-acquired pneumonia (CAP), according to the degree of lung involvement. Methods: Serum levels of 11 cytokines and chemokines, in 14 patients with SARS and 24 patients with CAP, were serially checked using a bead-based multiassay system. Sera from 12 healthy subjects were used as normal controls. Results: The serum levels of interferon-γ-inducible protein-10 (IP-10), IL-2 and IL-6 were significantly elevated during SARS infection. In patients with CAP, but not in those with SARS, the levels of interferon-γ, IL-10, IL-8 and monokine induced by interferon-γ (MIG) were significantly elevated compared with the levels in healthy controls. Among the chemokines/cytokines, IL-6 levels correlated most strongly with radiographic scores (r = 0.62). The elevation of IP-10 and IL-2 antedated the development of chest involvement and reached peak levels earlier than the radiographic scores. In contrast, the dynamic changes in IL-6, C-reactive protein and neutrophils occurred synchronously with the changes in radiographic scores. The mean ratio of IL-6 to IL-10 in SARS patients (4.84; range 0.41–21) was significantly higher than that in CAP patients (2.95; range 0.02–10.57) (P = 0.04). Conclusions: The early induction of IP-10 and IL-2, as well as the subsequent over-production of IL-6 and lack of IL-10 production, probably contribute to the main immuno-pathological processes involved in lung injury in SARS. These changes in cytokine/chemokine profile are remarkably different from those observed in CAP patients.

Objectives The aim of this study was to define the effect of statin on 30-day mortality in an oriental population with sepsis. Design We conducted a retrospective study on patients with sepsis at National Taiwan University Hospital from 2001 to 2002. The effects of statins on 30-day mortality were evaluated based on clinical settings. Log-rank test and Cox regression analysis were performed using the proportional hazards assumption. Results A total of 763 episodes of sepsis were reviewed; 454 consecutive patients were considered eligible. Among them, 104 (22.9%) took a statin at least 30 days before admission and during sepsis course, whereas the other 350 control (77.1%) did not. There was no significant difference of 30-day sepsis-related mortality between groups (19.2% vs 18.9%, P = .952). Statin treatment was not associated with decreased mortality at 30 days ( P = .853; risk ratio, 0.95; 95% confidence interval, 0.53-1.68). Conclusion Short-term, sepsis-related mortality in a septic Taiwanese population was not reduced with statin treatment in our study. We concluded that statin therapy may have little effect on the survival of sepsis in oriental people, particularly in Taiwanese.

To assess the initial serum levels of lipids and lipoproteins and their correlations with the clinical outcome for patients with severe sepsis. The ability of high-density lipoprotein (HDL) to attenuate lipopolysaccharide (LPS)-induced cytokine production was also examined in vitro.Prospective, observational cohort study.Medical intensive care unit (ICU) of a tertiary-level university hospital.Sixty-three consecutive patients with severe sepsis.Blood samples were drawn within the first day of severe sepsis and the subsequent 14 days. Clinical outcome, including length of ICU stay, infection subsequent to hospital stay, and death, were monitored prospectively.Compared with the survivors, patients who died within 30 days had significantly lower levels of HDL cholesterol and apolipoprotein A-I during the first 4 days of severe sepsis. On day 1, HDL cholesterol levels correlated inversely with interleukin-6 (r = -0.72; p.01) and tumor necrosis factor (TNF)-alpha (r = -0.70; p.01) concentrations. Not only the overall and sepsis-attributable 30-day mortality rates but also the risk of prolonged ICU stay (7 days) and the hospital-acquired infection rate were increased among patients with day 1 levels of HDL cholesterol of20 mg/dL and apolipoprotein A-I of100 mg/dL. Multivariate analysis identified an HDL cholesterol level of20 mg/dL on day 1 (odds ratio, 12.92; 95% confidence interval, 2.73-61.29) and Acute Physiology and Chronic Health Evaluation II score (odds ratio, 1.15; 95% confidence interval, 1.04-1.26) as independent predictors of the overall 30-day mortality rate. In human macrophages, LPS-induced TNF-alpha release was attenuated by incremental doses of HDL cholesterol added simultaneously (p.01). However, HDL failed to suppress LPS-induced TNF-alpha production when administered after macrophages were exposed to LPS.A low HDL cholesterol level on day 1 of severe sepsis is significantly associated with an increase in mortality and adverse clinical outcomes. In cultured macrophages, HDL can attenuate LPS-induced TNF-alpha production only if added concomitantly with, but not after, LPS exposure.

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