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Abstract Type 2 alveolar epithelial (AT2) cells of the lung are fundamental in regulating alveolar inflammation in response to injury. Impaired mitochondrial long-chain fatty acid β-oxidation (mtLCFAO) in AT2 cells is assumed to aggravate alveolar inflammation in acute lung injury (ALI), yet the importance of mtLCFAO to AT2 cell function needs to be defined. Here we show that expression of carnitine palmitoyltransferase 1a (CPT1a), a mtLCFAO rate limiting enzyme, in AT2 cells is significantly decreased in acute respiratory distress syndrome (ARDS). In mice, Cpt1a deletion in AT2 cells impairs mtLCFAO without reducing ATP production and alters surfactant phospholipid abundance in the alveoli. Impairing mtLCFAO in AT2 cells via deleting either Cpt1a or Acadl (acyl-CoA dehydrogenase long chain) restricts alveolar inflammation in ALI by hindering the production of the neutrophilic chemokine CXCL2 from AT2 cells. This study thus highlights mtLCFAO as immunometabolism to injury in AT2 cells and suggests impaired mtLCFAO in AT2 cells as an anti-inflammatory response in ARDS.

Abstract Background Airflow obstruction is a hallmark of disease severity and prognosis in bronchiectasis. The relationship between lung microbiota, airway inflammation, and outcomes in bronchiectasis with fixed airflow obstruction (FAO) remains unclear. This study explores these interactions in bronchiectasis patients, with and without FAO, and compares them to those diagnosed with chronic obstructive pulmonary disease (COPD). Methods This prospective observational study in Taiwan enrolled patients with either bronchiectasis or COPD. To analyze the lung microbiome and assess inflammatory markers, bronchoalveolar lavage (BAL) samples were collected for 16S rRNA gene sequencing. The study cohort comprised 181 patients: 86 with COPD, 46 with bronchiectasis, and 49 with bronchiectasis and FAO, as confirmed by spirometry. Results Patients with bronchiectasis, with or without FAO, had similar microbiome profiles characterized by reduced alpha diversity and a predominance of Proteobacteria, distinctly different from COPD patients who exhibited more Firmicutes, greater diversity, and more commensal taxa. Furthermore, compared to COPD and bronchiectasis without FAO, bronchiectasis with FAO showed more severe disease and a higher risk of exacerbations. A significant correlation was found between the presence of Pseudomonas aeruginosa and increased airway neutrophilic inflammation such as Interleukin [IL]-1β, IL-8, and tumor necrosis factor-alpha [TNF]-α, as well as with higher bronchiectasis severity, which might contribute to an increased risk of exacerbations. Moreover, in bronchiectasis patients with FAO, the ROSE (Radiology, Obstruction, Symptoms, and Exposure) criteria were employed to classify individuals as either ROSE (+) or ROSE (−), based on smoking history. This classification highlighted differences in clinical features, inflammatory profiles, and slight microbiome variations between ROSE (−) and ROSE (+) patients, suggesting diverse endotypes within the bronchiectasis with FAO group. Conclusion Bronchiectasis patients with FAO may exhibit two distinct endotypes, as defined by ROSE criteria, characterized by greater disease severity and a lung microbiome more similar to bronchiectasis without FAO than to COPD. The significant correlation between Pseudomonas aeruginosa colonization and increased airway neutrophilic inflammation, as well as disease severity, underscores the clinical relevance of microbial patterns. This finding reinforces the potential role of these patterns in the progression and exacerbations of bronchiectasis with FAO.

Abstract The study assessed the impact of procedural errors on the remote dielectric sensing system (ReDS), a non-invasive lung fluid assessment technology, in an Asian cohort. Healthy volunteers underwent ReDS measurements following manufacturer’s instructions, with two consecutive measurements one minute apart. A subset of 20 participants had modified procedure settings. Reliability was measured using intraclass correlation coefficient (ICC). The study included 86 healthy volunteers, and all ReDS measurements fell within the recommended normal range. The intra-rater reliability of ReDS measurements was excellent, with an ICC of 0.968. Among the subset of 20 subjects, deviations in height and weight did not significantly affect ReDS values. However, deviations in chest size by ± 3 cm had a noticeable impact on ReDS measures, and incorrect station selection led to fluctuations in ReDS readings. In conclusion, the ReDS system demonstrated excellent intra-rater reliability and applicability in an Asian cohort. Procedural errors, such as chest size measurement and station selection, significantly influenced ReDS measurements. Adherence to standardized operating procedures is crucial to ensure accurate and consistent results. These findings highlight the importance of adherence to manufacturer instructions when utilizing ReDS for lung fluid assessment, thereby enhancing its reliability and clinical applicability.

Abstract Background Our study aimed to confirm a simplified radiological scoring system, derived from a modified Reiff score, to evaluate its relationship with clinical symptoms and predictive outcomes in Taiwanese patients with noncystic fibrosis bronchiectasis (NCFB). Methods This extensive multicenter retrospective study, performed in Taiwan, concentrated on patients diagnosed with NCFB verified through high-resolution computed tomography (HRCT) scans. We not only compared the clinical features of various types of bronchiectasis (cylindrical, varicose, and cystic). Furthermore, we established relationships between the severity of clinical factors, including symptom scores, pulmonary function, pseudomonas aeruginosa colonization, exacerbation and admission rates, and HRCT parameters using modified Reiff scores. Results Data from 2,753 patients were classified based on HRCT patterns (cylindrical, varicose, and cystic) and severity, assessed by modified Reiff scores (mild, moderate, and severe). With increasing HRCT severity, a significant correlation was found with decreased forced expiratory volume in the first second (FEV1) (p

Background Impact of lung fluid content changing during exercise has not been investigated in chronic obstructive pulmonary disease (COPD). Using a novel point-of-care measurement system (remote dielectric sensing (ReDS) system), we aimed to investigate changes in lung fluid content before and after 6-minute walk test (6MWT); especially, differences between patients with and without comorbid heart failure (HF) were evaluated.Methods From June 2021 to July 2022, patients with COPD referred for 6MWT were prospectively enrolled. Measurements of lung fluid content by ReDS were conducted before and after 6MWT. Data on demographics, exacerbation history, spirometry and 6MWT were collected. Patients were also assessed for comorbid HF by cardiovascular evaluation. The main variables of interest were pre-6MWT ReDS, post-6MWT ReDS and post–pre ∆ReDS.Results In total, 133 patients with COPD were included. Comparisons between patients with COPD with and without HF indicated similar pre-6MWT ReDS (26.9%±5.9% vs 26.5%±4.7%; p=0.751), but a significant difference in post-6MWT ReDS (29.7%±6.3% vs 25.7%±5.3%; p=0.002). Patients with COPD without HF exhibited a significant decrease in post-6MWT ReDS (from 26.5% to 25.7%; paired t-test p=0.001); conversely, those with HF displayed a remarkable increase in post-6MWT ReDS (from 26.9% to 29.7%; paired t-test p

Abstract Background The BODE index, consisting of body mass index (B), airflow obstruction (O), dyspnea score (D), and exercise capacity (E), can predict outcomes in COPD. However, when spirometry was restricted to prevent cross-infection such as COVID-19 pandemic, a modified index would be needed. Because cardiovascular dysfunction is associated with poor clinical outcomes in COPD, we conducted a novel BHDE-index by replacing spirometry with post-exercise heart rate recovery (HRR, H) and evaluated its predictive performance in this observational study. Methods From January 2019 to December 2019, enrolled patients were analyzed as a derivation cohort for the setup of the model. This model was verified in another group of patients generated between January 2020 and December 2020, as the validation cohort. The post exercise HRR was defined as the difference of heart rate immediately after and 1 min after test cessation. Results A total of 447 patients with COPD were enrolled. Patients with abnormal HRR were older, with more severe airway obstruction, severe airway symptoms, faster resting heart rate, shorter 6-min walk distance and higher frequency of severe acute exacerbation in previous one year. The prediction performance of the BHDE-index for one-year severe COPD exacerbation was similar to that of the BODE-index in both the derivation and validation groups [area under the receiver operating characteristic curve (AUROC) 0.76 vs. 0.75, p = 0.369; AUROC 0.74 vs. 0.79, p = 0.05]. The prediction performance for 1 year mortality was also similar between BHDE-index and BODE-index in both cohorts [AUROC 0.80 vs. 0.77, p = 0.564; 0.76 vs. 0.70, p = 0.234]. Univariate and multivariate analyses also showed that the BHDE-index was an independent and important predictor of annual severe COPD exacerbation in the derivation and validation cohorts. Conclusions The BHDE-index is a good and easy-to-perform prediction model for the risk of severe acute exacerbation and 1-year mortality in COPD wherever spirometry results are unavailable.

Abstract Background To investigate the clinical outcomes and risk factors associated with progressive fibrosing interstitial lung disease (PF-ILD) in patients with primary Sjögren’s syndrome-associated interstitial lung disease (pSjS-ILD). Methods During 2015–2021, pSjS patients with ILD were retrospectively identified. Patients were grouped into non-PF-ILD and PF-ILD. Demographics, laboratory data, pulmonary function tests (PFTs), images, survival outcomes were compared between groups. Results 153 patients with SjS-ILD were reviewed, of whom 68 having primary SjS-ILD (pSjS-ILD) were classified into non-PF-ILD (n = 34) and PF-ILD groups (n = 34). PF-ILD group had persistently lower albumin levels and a smaller decline in immunoglobulin G (IgG) levels at the 3rd month of follow-up. The multivariate logistic regression analysis revealed that persistently low albumin levels were associated with PF-ILD. At the 12th month, the PF-ILD group experienced a smaller increase in FVC and a greater decline in the diffusion capacity of carbon monoxide (DLCO) than at baseline. The 3-year overall survival rate was 91.2%, and PF-ILD group had significantly poorer 3-year overall survival rate than non-PF-ILD group (82.4% vs. 100%, p = 0.011). Poor survival was also observed among female patients with PF-ILD. Conclusions Among patients with pSjS-ILD, the PF-ILD group had poorer 3-year survival outcomes. Persistent lower albumin level might be the risk factor of PF-ILD. Early lung function tests could be helpful for the early detection of PF-ILD.

Immunosuppression increases the risk of nosocomial infection in patients with chronic critical illness. This exploratory study aimed to determine the immunometabolic signature associated with nosocomial infection during chronic critical illness. We prospectively recruited patients who were admitted to the respiratory care center and who had received mechanical ventilator support for more than 10 days in the intensive care unit. The study subjects were followed for the occurrence of nosocomial infection until 6 weeks after admission, hospital discharge, or death. The cytokine levels in the plasma samples were measured. Single-cell immunometabolic regulome profiling by mass cytometry, which analyzed 16 metabolic regulators in 21 immune subsets, was performed to identify immunometabolic features associated with the risk of nosocomial infection. During the study period, 37 patients were enrolled, and 16 patients (43.2%) developed nosocomial infection. Unsupervised immunologic clustering using multidimensional scaling and logistic regression analyses revealed that expression of nuclear respiratory factor 1 (NRF1) and carnitine palmitoyltransferase 1a (CPT1a), key regulators of mitochondrial biogenesis and fatty acid transport, respectively, in natural killer (NK) cells was significantly associated with nosocomial infection. Downregulated NRF1 and upregulated CPT1a were found in all subsets of NK cells from patients who developed a nosocomial infection. The risk of nosocomial infection is significantly correlated with the predictive score developed by selecting NK cell-specific features using an elastic net algorithm. Findings were further examined in an independent cohort of COVID-19-infected patients, and the results confirm that COVID-19-related mortality is significantly associated with mitochondria biogenesis and fatty acid oxidation pathways in NK cells. In conclusion, this study uncovers that NK cell-specific immunometabolic features are significantly associated with the occurrence and fatal outcomes of infection in critically ill population, and provides mechanistic insights into NK cell-specific immunity against microbial invasion in critical illness.

ABSTRACT The treatment responses and outcomes in patients with Mycobacterium avium-intracellulare complex pulmonary disease (MAC-PD) remain uncertain. This retrospective study was conducted in Taiwan between 2011 and 2020. A microbiological cure was defined as the requirement for a minimum of three consecutive negative cultures following culture conversion that continued until the completion of anti-MAC treatment. A total of 97 patients with MAC-PD were enrolled in this study. The sputum smear-negative conversion rate was 40% (19/47). Thirty (31%) patients achieved sputum culture-negative conversion rates within 3 years after treatment initiation. All patients with negative sputum culture conversion rates achieved microbiological cure. Patients treated with a macrolide + rifamycin + ethambutol (M + R + EMB)-based regimen had a higher microbiological cure rate than the other patients (39% vs 17%, P = 0.023). Patients with persistently positive sputum smears after 6 months of treatment had a lower microbiological cure rate than those with negative sputum smears (6% vs 44%, P < 0.001). Among 30 patients with microbiological cure, the median time from sputum culture conversion to treatment completion was 221.5 (0–483) days, and the 1-year relapse rate was 17%. Treatment with the M + R + EMB-based regimen was associated with a higher microbiological cure rate, and patients with persistently positive sputum smears after 6 months of treatment had a lower microbiological cure rate. IMPORTANCE The treatment responses and outcomes in patients with Mycobacterium avium-intracellulare complex pulmonary disease (MAC-PD) remain uncertain. In this study, patients with MAC-PD treated with a macrolide + rifamycin + ethambutol (M + R + EMB)-based regimen had a higher microbiological cure rate than those treated with other regimens. After 6 months of treatment, patients with persistently positive sputum smears had a lower microbiological cure rate than those with negative sputum smears. Among patients with microbiological cure, the median time from sputum culture conversion to treatment completion was 221.5 days (range, 0–483), and the 1-year relapse rate was 17%.

ABSTRACT: Objectives: To investigate the clinical outcomes and risk factors of mortality in patients with rheumatic diseases complicated by Pneumocystis pneumonia (PCP). Methods: Between November 2015 and April 2021, patients with rheumatic diseases with PCP in a tertiary referral hospital were retrospectively enrolled. The diagnosis of PCP requires the fulfillment of clinical, radiographic, and microbiological criteria. Factors associated with in-hospital, 30-day, and 90-day mortality were evaluated. Results: A total of 128 patients with rheumatic diseases who had a positive quantitative polymerase chain reaction assay for Pneumocystis jirovecii were screened, and 72 patients were included in the final analysis. The median (interquartile range [IQR]) pneumonia severity index (PSI) was 101.5 (77.0-132.0). The median (IQR) adjunctive corticosteroid dosage was 0.6 (0.4-0.9) mg/kg/day prednisolone equivalent. The receiver operating characteristic curve analysis showed that the optimal cutoff point of median adjunctive corticosteroid dosage was 0.6 mg/kg/day to predict in-hospital, 30-day, and 90-day mortality. In the multivariable logistic regression analysis, median adjunctive corticosteroid dosage ≥0.6 mg/kg/day and PSI >90 were independent factors of in-hospital, 30-day, and 90-day mortality. Conclusion: A median adjunctive corticosteroid dosage of ≥0.6 mg/kg/day might be associated with mortality in patients with rheumatic diseases complicated by PCP.

Abstract Background Prone positioning enables the redistribution of lung weight, leading to the improvement of gas exchange and respiratory mechanics. We aimed to evaluate whether the initial findings of acute respiratory distress syndrome (ARDS) on computed tomography (CT) are associated with the subsequent response to prone positioning in terms of oxygenation and 60-day mortality. Methods We retrospectively included patients who underwent prone positioning for moderate to severe ARDS from October 2014 to November 2020 at a medical center in Taiwan. A semiquantitative CT rating scale was used to quantify the extent of consolidation and ground-glass opacification (GGO) in the sternal, central and vertebral regions at three levels (apex, hilum and base) of the lungs. A prone responder was identified by a 20% increase in the ratio of arterial oxygen pressure (PaO2) to the fraction of oxygen (FiO2) or a 20 mmHg increase in PaO2. Results Ninety-six patients were included, of whom 68 (70.8%) were responders. Compared with nonresponders, responders had a significantly greater median dorsal–ventral difference in CT-consolidation scores (10 vs. 7, p = 0.046) but not in CT-GGO scores (− 1 vs. − 1, p = 0.974). Although dorsal–ventral differences in neither CT-consolidation scores nor CT-GGO scores were associated with 60-day mortality, high total CT-GGO scores (≥ 15) were an independent factor associated with 60-day mortality (odds ratio = 4.07, 95% confidence interval, 1.39–11.89, p = 0.010). Conclusions In patients with moderate to severe ARDS, a greater difference in the extent of consolidation along the dependent-independent axis on CT scan is associated with subsequent prone positioning oxygenation response, but not clinical outcome regarding survival. High total CT-GGO scores were independently associated with 60-day mortality.

This paper presents an integrated and scalable precision health service for health promotion and chronic disease prevention. Continuous real-time monitoring of lifestyle and environmental factors is implemented by integrating wearable devices, open environmental data, indoor air quality sensing devices, a location-based smartphone app, and an AI-assisted telecare platform. The AI-assisted telecare platform provided comprehensive insight into patients’ clinical, lifestyle, and environmental data, and generated reliable predictions of future acute exacerbation events. All data from 1,667 patients were collected prospectively during a 24-month follow-up period, resulting in the detection of 386 abnormal episodes. Machine learning algorithms and deep learning algorithms were used to train modular chronic disease models. The modular chronic disease prediction models that have passed external validation include obesity, panic disorder, and chronic obstructive pulmonary disease, with an average accuracy of 88.46%, a sensitivity of 75.6%, a specificity of 93.0%, and an F1 score of 79.8%. Compared with previous studies, we establish an effective way to collect lifestyle, life trajectory, and symptom records, as well as environmental factors, and improve the performance of the prediction model by adding objective comprehensive data and feature selection. Our results also demonstrate that lifestyle and environmental factors are highly correlated with patient health and have the potential to predict future abnormal events better than using only questionnaire data. Furthermore, we have constructed a cost-effective model that needs only a few features to support the prediction task, which is helpful for deploying real-world modular prediction models.

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.

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 Patients with influenza-associated acute respiratory distress syndrome (ARDS) requiring venovenous extracorporeal membrane oxygenation (vv-ECMO) support have a high mortality rate. Ventilator settings have been known to have a substantial impact on outcomes. However, the optimal settings of mechanical ventilation during vv-ECMO are still unknown. Methods This multicenter retrospective cohort study was conducted in the intensive care units (ICUs) of three tertiary referral hospitals in Taiwan between July 2009 and December 2019. It aims to describe the effect of ventilator settings during vv-ECMO on patient outcomes. Results A total of 93 patients with influenza receiving ECMO were screened. Patients were excluded if they: were receiving venoarterial ECMO, died within three days of vv-ECMO initiation, or were transferred to the tertiary referral hospital >24 hours after vv-ECMO initiation. A total of 62 patients were included in the study, and 24 (39%) died within six months. During the first three days of ECMO, there were no differences in tidal volume (5.1 vs. 5.2 mL/kg, p = 0.833), dynamic driving pressure (15 vs. 14 cmH2O, p = 0.146), and mechanical power (11.3 vs. 11.8 J/min, p = 0.352) between survivors and non-survivors. However, respiratory rates were significantly higher in non-survivors compared with survivors (15 vs. 12 breaths/min, p = 0.013). After adjustment for important confounders, a higher mean respiratory rate of >12 breaths/min was still associated with higher mortality (adjusted hazard ratio = 3.31, 95% confidence interval = 1.10–9.97, p = 0.034). Conclusions In patients with influenza-associated ARDS receiving vv-ECMO support, we found that a higher respiratory rate was associated with higher mortality. Respiratory rate might be a modifiable factor to improve outcomes in this patient population.

ABSTRACT The performance of metagenomic next-generation sequencing (mNGS) was evaluated and compared with that of conventional culture testing in patients with sepsis. Prospective blood and bronchoalveolar lavage fluid (BALF) samples from 50 patients with sepsis were tested using cultures (bacterial, fungal, and viral) and mNGS of microbial DNA (blood and BALF) and RNA (BALF). mNGS had higher detection rates than blood culture (88.0% versus 26.0%, P < 0.001) and BALF culture (92.0% versus 76.0%, P = 0.054). RNA-based mNGS has increased the detection rate of several bacteria, fungi, and viruses, but not mycobacteria and Toxoplasma gondii. The number of multiple detections per specimen was higher in BALF (92.0%) than in blood (78.0%) samples, and the highest number of pathogens detected in a single specimen was 32. Among blood samples, compared to cultures, mNGS detected significantly more bacteria (P < 0.001), fungi (P = 0.012), and viruses (P < 0.001), whereas BALF mNGS had a higher detection rate for bacteria (P < 0.001) and viruses (P < 0.001). The percentage of mNGS-positive samples was significantly higher than that of culture-positive samples for several Gram-negative bacteria, some Gram-positive bacteria, and viruses, but not fungi. Mycobacteria had a higher detection rate by culture than by mNGS, but the difference was not significant due to the small sample size. The positive and negative agreements with 95% confidence intervals of mNGS and culture were 62.0% (50.4 to 72.7) and 96.8% (96.5 to 97.1), respectively. mNGS offers a sensitive diagnostic method for patients with sepsis and is promising for the detection of multipathogen infections. Clinical correlation is advised to interpret mNGS data due to the lack of unified diagnostic criteria. IMPORTANCE Delays in effective antimicrobial therapy have resulted in decreased survival rates among patients with sepsis. However, current culture-based diagnostic methods have low sensitivity because of concurrent antibiotic exposure and fastidious and atypical causative organisms. Among patients with sepsis, we showed that mNGS methods had higher positive rates than culture methods, especially for bacteria, viruses, and multipathogen infections, which are difficult to culture and detect in patients treated with antibiotics. RNA-based mNGS has increased the detection rate of several bacteria, fungi, and viruses, but not mycobacteria and Toxoplasma gondii. mNGS also showed a high negative percent agreement with cultures. However, the interpretation of mNGS data should be combined with clinical data and conventional methods considering the lack of unified diagnostic criteria.

ABSTRACT Mycobacterium abscessus complex (MABC) is a group of emerging, highly antimicrobial-resistant non-tuberculous mycobacteria. Specific MABC clones are spreading globally in patients with cystic fibrosis (CF); however, associated genomic epidemiology is lacking in East Asia, with very few patients with CF. Here, we investigated MABC populations derived from non-CF patients in Japan and Taiwan. Analysis of whole-genome sequencing data of 220 MABC isolates revealed that 112, 105, and 3 were M. abscessus subsp. abscessus (ABS), M. abscessus subsp. massiliense (MAS), and M. abscessus subsp. bolletii (BOL), respectively. Moreover, >50% of ABS and >70% of MAS were related to four predominant clones in the region. Known mutations conferring macrolide resistance were rare (1.4%) and were 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 previously described dominant circulating clone (DCC)1 in patients with CF, whereas no isolates were related to DCC2; isolates related to DCC3 were not necessarily predominant in our sample set. We found that the erm(41) T28C mutants spread globally, and some of them reacquired the functional erm(41) gene through both point mutation and recombination. This study revealed predominant MABC clones in Japan and Taiwan and their relationship with the globally superadding clones in the patient community with CF. Our study provides insights into the genetic characteristics of globally dominant and area-specific strains isolated from patients with or without CF and differences between globally spread and regionally specific strains. IMPORTANCE Members of Mycobacterium abscessus complex (MABC) are frequently isolated from patients. Studies have reported that predominant clones of MABC (known as dominant circulating clones; DCCs) are distributed worldwide and transmitted from humans to humans in patients with cystic fibrosis (CF). However, associated genomic epidemiology has not yet been conducted in East Asia, including Japan and Taiwan, where there are only a few patients with CF. Using whole-genome sequencing data derived from non-CF patients in Japan and Taiwan, we revealed prevalent clones and the incidence of macrolide resistance-associated mutations in the MABC population in this region. We also clarified the associations between these predominant clones and DCCs in the global CF patient community. Our results would assist further studies in elucidating the genetic characteristics of strains isolated from patients with or without CF, the differences between globally spread and regionally specific strains, and the adaptive evolution of MABC within the host.

Abstract 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

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

Objectives: Characteristics of the Mycobacterium avium–intracellulare complex pulmonary disease (MAC-PD) caused by distinct subspecies remain uncertain. Methods: This study was conducted from 2013–2015 in three hospitals in Taiwan. Results: Among the 144 patients with MAC-PD, 57 (39.6%), 37 (25.7%), 37 (25.7%), and 13 (9.0%) were infected with Mycobacterium intracellulare subspecies intracellulare (MIsI), Mycobacterium avium subspecies hominissuis (MAsH), Mycobacterium intracellulare subspecies chimaera (MIsC), and others, respectively. Patients with MAsH-PD were younger (p = 0.010) with higher human immunodeficiency virus infection rates (27.0%, 0.0%, 0.0%, and 7.7% for MAsH-PD, MIsC-PD, MIsI-PD, and others, respectively; p

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

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/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 clinical impact of infection with Mycobacterium (M.) abscessus complex (MABC), a group of emerging non-tuberculosis mycobacteria (NTM), is increasing. M. abscessus subsp. abscessus/bolletii frequently shows natural resistance to macrolide antibiotics, whereas M. abscessus subsp. massiliense is generally susceptible. Therefore, rapid and accurate discrimination of macrolide-susceptible MABC subgroups is required for effective clinical decisions about macrolide treatments for MABC infection. We aimed to develop a simple and rapid diagnostic that can identify MABC isolates showing macrolide susceptibility. Methods: Whole genome sequencing (WGS) was performed for 148 clinical or environmental MABC isolates from Japan to identify genetic markers that can discriminate three MABC subspecies and the macrolide-susceptible erm(41) T28C sequevar. Using the identified genetic markers, we established PCR based- or DNA chromatography-based assays. Validation testing was performed using MABC isolates from Taiwan. Finding: We identified unique sequence regions that could be used to differentiate the three subspecies. Our WGS-based phylogenetic analysis indicated that M. abscessus carrying the macrolide-susceptible erm(41) T28C sequevar were tightly clustered, and identified 11 genes that were significantly associated with the lineage for use as genetic markers. To detect these genetic markers and the erm(41) locus, we developed a DNA chromatography method that identified three subspecies, the erm(41) T28C sequevar and intact erm(41) for MABC in a single assay within one hour. The agreement rate between the DNA chromatography-based and WGS-based identification was 99·7%. Interpretation: We developed a novel, rapid and simple DNA chromatography method for identification of MABC macrolide susceptibility with high accuracy. Funding: AMED, JSPS KAKENHI

Background Mycobacterium abscessus (MAB) has emerged as the predominant pulmonary non-tuberculous mycobacterial pathogen in parts of Asia, including Taiwan. The reasons for the significant increase in MAB infections in the non-cystic fibrosis (CF) populations are poorly understood. The study aimed to elucidate whether this increase is related to the spread of the globally successful clone of MAB. Methods We performed multilocus sequence typing of 371 nonduplicated MAB pulmonary isolates from 371 patients sampled between 2010–2017 at seven hospitals across Taiwan. Results In total, 183 (49.3%) isolates were M. abscessus subsp. abscessus (MAB-a), 187 (50.4%) were M. abscessus subsp. massiliense (MAB-m), and 1 (0.3%) was M. abscessus subsp. bolletii (MAB-b). MAB-a sequence type (ST)1 (23.7%) and ST127 (3.8%), followed by MAB-m ST48 (16.2%), ST117 (15.1%), ST23 (8.6%) were most common overall. Of MAB-a strains, 50 (27.3%) belonged to novel STs and 38 (10.2%) were singleton strains, while of MAB-m strains, only 10 (5.3%) were novel and 8 (2.2%) were singletons. From 2010 to 2017, the frequency of the historically dominant ST1 declined from 28.6% to 22.5%, whereas the recently emerged globally successful clonal cluster 3, ST23 and ST48, increased from 14.3% to 40.0%. Conclusions The dominance of ST1 particularly in the last 2 years of this study appears to be declining, while ST23, reported in outbreaks among CF and post-surgical cohorts across the Americas and Europe, alongside the closely related ST48, is present among non-CF populations in Taiwan. These trends need to be confirmed with further ongoing studies to track the molecular epidemiology of clinical MAB isolates worldwide.

This study evaluated the performance of the Xpert MTB/RIF Ultra assay (Xpert Ultra) to detect smear-negative pulmonary tuberculosis (PTB). Xpert Ultra assay was prospectively performed using bronchial washing fluid (BWF) in comparison to COBAS TaqMan MTB (COBAS) assay and mycobacterial culture. Of the 165 enrolled participants, 27 (16.4%) had PTB based on composite reference standard and 16 (9.7%) had culture-confirmed PTB. By the composite reference standard of PTB, the sensitivity of Xpert Ultra (63.0, 95% confidence interval, CI, 42.4–80.6%) was higher than the COBAS assay (25.9%, P = 0.006), BWF-culture (33.3%, P = 0.029) and sputum-culture (37.0%, P = 0.057). Meanwhile, the specificity of Xpert Ultra was 99.3% which was slightly lower than the 100.0% specificity of the COBAS assay (P = 1.000) and cultures (P = 1.000). Against the reference standard of culture-confirmed PTB, Xpert Ultra also had a higher sensitivity (62.5, 95% CI, 35.4–84.8%) than the COBAS assay (31.3%, P = 0.077) and was similar to BWF-culture (56.3%, P = 0.719) and sputum-culture (62.5%, P = 1.000). However, one subject with previously treated old PTB had a false-positive result on the Xpert Ultra assay. This prospective study showed Xpert Ultra assay using BWF had better sensitivity than COBAS assay and mycobacterial cultures but could represent a false positive in patients with inactive old PTB.

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.

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.A nationwide retrospective cohort study investigated the influence of alendronate and TE on the development of ONJ.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.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.

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.

We used an in-house saponin-based extraction method to evaluate the performance of the Bruker Biotyper matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS) system for the identification of bacteria and fungi in 405 positively flagged blood culture bottles. Results obtained from MALDI-TOF/MS were compared with those obtained using conventional phenotypic identification methods. Of the 405 positively flagged blood culture bottles, 365 showed monomicrobal growth and were correctly identified to the species (72.1%) or genus (89.6%) level using the Bruker Biotyper system. The remaining 40 positively flagged blood culture bottles showed polymicrobial growth. Of them, 82.5% (n=33) of the isolates were correctly identified to the species level and 92.5% (n=37) to the genus level using the Bruker Biotyper system. The overall accuracy of identification to the genus level in flagged blood cultures was 89.5% for Gram-positive organisms, 93.5% for Gram-negative pathogens and 71.9% for fungi. Confidence scores were 1.500 for 307 (75.8%) bottles, 1.700 for 249 (61.5%) bottles and 2.000 for 142 (35.1%) bottles. None of the yeast cultures yielded scores 1.700. Using an identification-score cutoff of 1.500, the MALDI Biotyper correctly identified 99.2% of Gram-positive bacteria, 97.6% of Gram-negative bacteria and 100% of yeast isolates to the genus level and 77.6% of Gram-positive bacteria, 87.1% of Gram-negative bacteria and 100.0% of yeast isolates to the species level. The overall rate of identification using our protocol was 89.9% (364/405) for genus level identification and 73.1% (296/405) for species level identification. Yeast isolates yielded the lowest confidence scores, which compromised the accuracy of identification. Further optimization of the protein extraction procedure in positive blood cultures is needed to improve the rate of identification.

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.

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.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.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).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.