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BackgroundAdult asthma is phenotypically heterogeneous with unclear aetiology. We aimed to evaluate the potential contribution of environmental exposure and its ensuing response to asthma and its heterogeneity.MethodsEnvironmental risk was evaluated by assessing the records of National Health Insurance Research Database (NHIRD) and residence-based air pollution (particulate matter with diameter less than 2.5 micrometers (PM2.5) and PM2.5-bound polycyclic aromatic hydrocarbons (PAHs)), integrating biomonitoring analysis of environmental pollutants, inflammatory markers and sphingolipid metabolites in case–control populations with mass spectrometry and ELISA. Phenotypic clustering was evaluated by t-distributed stochastic neighbor embedding (t-SNE) integrating 18 clinical and demographic variables.FindingsIn the NHIRD dataset, modest increase in the relative risk with time-lag effect for emergency (N=209 837) and outpatient visits (N=638 538) was observed with increasing levels of PM2.5and PAHs. Biomonitoring analysis revealed a panel of metals and organic pollutants, particularly metal Ni and PAH, posing a significant risk for current asthma (ORs=1.28–3.48) and its severity, correlating with the level of oxidative stress markers, notably Nε-(hexanoyl)-lysine (r=0.108–0.311, p2.5exposure. Further, levels of circulating sphingosine-1-phosphate and ceramide-1-phosphate were found to discriminate asthma (pInterpretationThese results suggest the potential contribution of environmental factors from multiple sources, their ensuing oxidative stress and sphingolipid remodeling to adult asthma and its phenotypic heterogeneity.

Idiopathic pulmonary fibrosis (IPF) is a rare and chronic fibrosing interstitial lung disease. However, the clinical features and outcomes of IPF in Taiwan have not been well studied. In addition, the survival difference between patients with IPF alone and combined pulmonary fibrosis and emphysema (CPFE) remains controversial.Patients diagnosed with IPF between 2006 and 2016 were retrospectively enrolled in this study. IPF was defined according to the 2011 American Thoracic Society/European Respiratory Society guideline. The clinical features, comorbidities, and outcomes of CPFE group and IPF-alone group were compared. The extents of emphysema and fibrosis were evaluated.In total, 114 patients with IPF were enrolled, and 86.8% of them were men with a mean age of 77.8 years. The median survival was 3.33 years in all patients with IPF. Moreover, 30 patients (26.3%) met the CPFE criteria. The CPFE group had a higher percentage of smokers (90% vs 50%, p0.001), higher forced vital capacity (82% vs 59%, p0.001), and lower fibrosis scores (8.5 ± 2.9 vs 10 ± 3.2, p = 0.022) than did the IPF-alone group. The baseline room air saturation and percentage of pulmonary hypertension were similar between the two groups. The survival time was not significantly different between the CPFE and IPF-alone groups (median survival, 3.58 vs 2.39 years, p = 0.163). In the multivariate analysis, higher fibrosis score, room air saturation90%, and lung cancer were significant factors associated with mortality.Our study showed that emphysema had no significant effect on the survival of patients with IPF. The outcome of IPF was mainly determined by the baseline disease severity and other comorbidities.

Background: Adult asthma is phenotypically heterogeneous with unclear etiology. We aimed to evaluate the potential contribution of environmental exposure and its ensuing response to asthma and its heterogeneity. Methods: Environmental risk was evaluated by assessing the records of National Health Insurance Research database (NHIRD) and residence-based air pollution [PM2.5 and PM2.5-bound polycyclic aromatic hydrocarbons (PAHs)], integrating biomonitoring analysis of environmental pollutants, inflammatory markers and sphingolipid metabolites in case-control populations with mass spectrometry and ELISA. Phenotypic clustering was evaluated by t-SNE integrating 18 clinical and demographic variables. Findings: In the NHIRD dataset, a modest increase in the relative risk with time-lag effect for emergency (N=209,837) and outpatient visits (N=638,538) was observed with increasing levels of PM2.5 and PAHs. Biomonitoring analysis revealed a panel of metals and organic pollutants, particularly metal Ni and PAH originated from multiple sources, posing a significant risk for current asthma and its severity, correlating with the level of oxidative stress markers, notably Ne-(hexanoyl)-lysine (HEL) as a marker of response in both cases and controls. Further, levels of circulating sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) were found to discriminate asthma, correlating with the levels of exposure to PAH and metals, respectively, and both correlating with a panel of circulating inflammatory markers. Stratification of the combined datasets by 6 phenotypic clusters among 1,163 asthmatic subjects and those with comorbid T2DM revealed cluster-selective environmental risks and biosignatures. Interpretation: These results suggest the potential contribution of environmental factors, their ensuing oxidative stress and sphingolipid remodeling to adult asthma and its phenotypic heterogeneity. Funding Information: This work was supported, in part, by grants from National Health Research Institutes, Taiwan (EOPP10-014, EOSP07-014 and NHRI-102A1-PDCO-03010201) and Ministry of Health, Taiwan (EODOH01), National Science Council (NSC 102-2314-B-037-052), Ministry of Health (EODOH01), Ministry of Science and Technology (MOST 103-2320-B-110-001), and Academic Sinica (BM-102021170), Taiwan. Declaration of Interests: We declare no competing interests. Ethics Approval Statement: All eligible subjects were enrolled in the study after signing the informed consent approved by the respective recruitment hospitals.

We proposed a modification of the ACR Lung Imaging Reporting and Data System (Lung-RADS) to clarify the characteristics of subsolid nodules with categories 1-11, and to compare the diagnostic accuracy with Lung-RADS and National Lung Screening Trial criteria in an Asian population with high prevalence of adenocarcinoma.We analyzed a retrospective cohort of 1978 consecutive healthy subjects (72.8% nonsmoker) who underwent low-dose computed tomography from August 2013 to October 2014 (1084 men, 894 women). Lung-RADS categories 2 and 3 were modified to include subcategories of 2A/2B/2C and 3A/3B/3C, respectively. Clinical information and nodule characteristics were recorded. Receiver operating characteristic curves were used to compare diagnostic accuracy at different cutoffs.Thirty-two subjects (30 nonsmokers) had pathology-proven adenocarcinoma spectrum lesions in the follow-up period (1.6 ± 0.5 years). Modified Lung-RADS, using modified Lung-RADS category 2C as cutoff, had an area under the curve (AUC) of 0.973 in predicting adenocarcinoma spectrum lesions (sensitivity of 100%, specificity of 89.3%), which was significantly higher than that of Lung-RADS (AUC = 0.815, P .001) and National Lung Screening Trial (AUC = 0.906, P .001). Furthermore, modified Lung-RADS showed an AUC of 0.992 in predicting invasive adenocarcinoma (sensitivity of 95%, specificity of 97.8%) when category 3B was used as cutoff.Modified Lung-RADS may substantially improve sensitivity while maintaining specificity for detection of adenocarcinoma spectrum lesions in an Asian population. Compared to Lung-RADS, it has enhanced ability to differentiate invasive from indolent adenocarcinoma by more refined subclassification of subsolid nodules using two cutoff values of category 2C and 3B. The effect of using modified Lung-RADS in clinical practice must be carefully studied in prospective large cohort studies.

Cardiac radiotherapy is rarely used in clinical practice because of concern of adverse effects on the heart. We present a case of a 64-year-old man with advanced small cell lung cancer (SCLC) treated with chemo-radiotherapy who attained partial remission initially but had disease progression to bulky cardiac metastasis and significant pericardial effusion. Severe heart failure with hepatic failure was found. Chemotherapy and pericardiocentesis were contraindicated because of the associated high risk and bleeding tendency. Emergent palliative cardiac radiotherapy resulted in rapid improvements of dyspnea, liver function, and urine output. Pericardiocentesis was performed 5 days later and effusion cytology confirmed metastatic SCLC. To our knowledge, this is the first case of effective cardiac radiotherapy for SCLC with life-threatening cardiac metastasis. Palliative cardiac radiotherapy may be an effective alternative treatment for radiosensitive malignancy with cardiac metastasis in cases of multiple organ dysfunction and unsuitability for chemotherapy and pericardiocentesis.

CD14+ monocytes contain precursors for macrophages and fibrocytes, known to be involved in regulating airway remodeling in human asthma and distinguishable by the PM-2K marker. We sought to identify circulating subsets of PM-2K+ macrophage-like cells and evaluate their relationships to lung function, severity and control status. Circulating PM-2K+ macrophage-like cells and fibrocytes could be identified and distinguished between normal individuals (N = 152) and asthmatic subjects (N = 133) using multi-parametric flow cytometry. PM-2K+ macrophage-like cells were found to be significantly lower in asthmatic subjects, particularly noted for the CD14−PM-2K+ subset and PM-2K+CCR7−CD86+ cells in subjects with poor lung function (FEV%/FVC% −CD86+ subset distribution was significantly different in subjects with varying severity. Moreover, exogenous transforming growth factor beta 1 (TGF-β1) was found to inhibit the generation of PM-2K+ macrophage-like cells, but promote the growth of fibrocytes, from CD14+ monocytes, and monocyte-derived TGF-β1 was found to correlate with the lung function, severity and control status in asthmatic patients. Collectively, aberrant differentiation of monocytes into PM-2K+ macrophage-like cell subsets and fibrocytes, together with increased monocyte-derived TGF-β1, characterized patients with severe asthma.

Background: Among respiratory predictors, rapid shallow breathing index (RSBI) has been a commonly used respiratory parameter to predict extubation outcomes. However, the outcome of prediction remains inconsistent. Regarding nonrespiratory predictors, serum albumin, hemoglobin, bicarbonate, and patients’ alertness have been reported to be associated with successful weaning or extubation. We aimed to develop an integrative index combining commonly used predictors in the adult medical intensive care units (MICUs) and to compare the predictability of the index with RSBI. Methods: This prospective observational study with retrospective data collection of planned extubations was conducted in a 14-bed adult MICU. We enrolled patients who received mechanical ventilation via an endotracheal tube in the adult MICU for >24 hours and passed a 2-hour spontaneous breathing trial and underwent extubation. Extubation failure was defined as reinstitution of invasive mechanical ventilation within 48 hours of extubation. Respiratory parameters and Glasgow Coma Scale (GCS) scores of patients were recorded prospectively. Nonrespiratory parameters were recorded retrospectively. Logistic regression was used to determine significant predictors of extubation outcomes. Results: Fifty-nine patients comprising 70 extubations were enrolled. Extubation failure was significantly and positively associated with lower serum albumin (albumin < 2.6 g/dL, odds ratio [OR] = 5.1; 95% confidence interval [CI], 1.04-24.66), lower hemoglobin (hemoglobin < 10.0 g/dL, OR = 10.8; 95% CI, 2.00-58.04), and lower GCS scores (GCS score ≤ 8, OR = 6.1; 95% CI = 1.15-32.34). By using an integrative index combining the 3 parameters together, the sensitivity and specificity to predict extubation outcomes were 78.6% and 75.9%, respectively. The area under the receiver operating characteristic curve of the index was significantly higher than RSBI (0.84 vs 0.61, P = .026). Conclusion: The integrative index combining serum albumin, hemoglobin, and GCS scores could predict extubation outcomes better than RSBI in an adult MICU.

Exposure to polycyclic aromatic hydrocarbons (PAHs) associated with ambient air particulate matter (PM) poses significant health concerns. Several modeling approaches have been developed for simulating ambient PAHs, but no hourly intra-urban spatial data are currently available. The aim of this study is to develop a new modeling strategy in simulating, on an hourly basis, grid-scale PM2.5-PAH levels. PM and PAHs were collected over a one-year time frame through an established air quality monitoring network within a metropolitan area of Taiwan. Multivariate linear regression models, in combination with correlation analysis and PAH source identification by principal component analysis (PCA), were performed to simulate hourly grid-scale PM2.5-PAH concentrations, taking criteria pollutants and meteorological variables selected as possible predictors. The simulated levels of 72-h personal exposure were found to be significantly (R=0.729**, p

Chronic exposure to ambient polycyclic aromatic hydrocarbons (PAHs) is associated with asthma, but its regulatory mechanisms remain incompletely defined. We report herein that elevated levels of urinary 1-hydroxypyrene, a biomarker of PAH exposure, were found in asthmatic subjects (n = 39) as compared to those in healthy subjects (n = 43) living in an industrial city of Taiwan, where indeno[1,2,3-cd]pyrene (IP) was found to be a prominent PAH associated with ambient PM2.5. In a mouse model, intranasal exposure of mice with varying doses of IP significantly enhanced antigen-induced allergic inflammation, including increased airway eosinophilia, Th2 cytokines, including IL-4 and IL-5, as well as antigen-specific IgE level, which was absent in dendritic cell (DC)-specific aryl hydrocarbon receptor (AhR)-null mice. Mechanistically, IP treatment significantly altered DC’s function, including increased level of pro-inflammatory IL-6 and decreased generation of anti-inflammatory IL-10. The IP’s effect was lost in DCs from mice carrying an AhR-mutant allele. Taken together, these results suggest that chronic exposure to environmental PAHs may pose a significant risk for asthma, in which IP, a prominent ambient PAH in Taiwan, was shown to enhance the severity of allergic lung inflammation in mice through, at least in part, its ability in modulating DC’s function in an AhR-dependent manner.

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the standard therapy for advanced lung adenocarcinomas with common EGFR mutations. Preclinical studies have suggested that uncommon G719X, L861Q, and S768I mutations are also sensitive to EGFR-TKIs. However, the efficacy of EGFR-TKIs in patients with these uncommon mutations remains unclear.A nationwide survey was performed to collect data from gefitinib and erlotinib treatment outcomes of patients with stage IIIB/IV lung adenocarcinoma bearing EGFR G719X/L861Q/S768I mutations. The results were compared with those regarding patients with exon 19 deletions or L858R mutations.One hundred and sixty-one patients with uncommon EGFR mutations were enrolled from 18 institutes throughout Taiwan. Mutations of G719X, L861Q, S768I, G719X + L861Q, and G719X + S768I were observed in 78, 57, 7, 9, and 10 patients, respectively. After receiving EGFR-TKI treatment, patients with uncommon mutations exhibited a significantly inferior tumor response rate (41.6% vs. 66.5%; p0.001) and progression-free survival (median, 7.7 vs. 11.4 months; p0.001) than patients with common mutations. Among the patients who used EGFR-TKIs as first-line treatment, there was a significant difference in overall survival between these two groups of patients (median, 24.0 vs. 29.7 months; p = 0.005).Gefitinib and erlotinib are active in patients with G719X/L861Q/S768I mutations; however, less effective than in those with common mutations.

Rationale: IgG4-related disease is a rare and novel disease entity that tends to involve multiple organs. The pulmonary manifestation of this disease is highly variable and may mimic lung cancer, pneumonia, interstitial lung disease (ILD), sarcoidosis, and so forth. Small airway disease is rarely reported in IgG4-related lung disease (IgG4-RLD). In the current study, we describe a rare case of IgG4-RLD with patterns of ILD and bronchiolitis. Patient concern: A 43-year-old man had chronic cough and dyspnea on exertion for 4 years. Initial chest radiography showed diffuse interstitial infiltration. Follow-up chest computed tomography 4 years later revealed bilateral diffuse centrilobular nodules with tree-in-bud pattern, bronchial wall thickening, and mediastinal lymph nodes. Bilateral diffuse multifocal ground-glass opacities and mosaic attenuation were also observed. Pulmonary function test revealed mixed restrictive and obstructive ventilatory impairment. Diagnoses: Video-assisted thoracoscopic surgery (VATS) lung biopsy showed interstitial fibrosis with lymphoplasmacytic infiltration rich in IgG4-positive plasma cells. Serum IgG4 level also showed remarkable elevation. Therefore, IgG4-RLD is confirmed. Intervention: VATS wedge resection of right upper lobe and mediastinal lymph node. Outcomes: The patient responded well to steroid and immunosuppression therapy, and was regular followed-up in outpatient clinic. Lessons: IgG4-RLD should be considered not only in ILD, but also in small airway disease. Serum IgG4 level may be a useful tool for screening.

Background: The study was designed to compare the efficacy and tolerability of a fixed combination of extra-fine beclomethasone and formoterol, with the fixed combination fluticasone and salmeterol in Taiwanese asthmatic patients. Methods: This was a phase III, multicentre, randomized, two-arm parallel groups, controlled study. Patients with moderate to severe asthma were randomized to a 12-week treatment with either beclomethasone 100 mcg plus formoterol 6 mcg (BDP/F) or fluticasone 125 mcg plus salmeterol 25 mcg (FP/S), both delivered 2 inhalations twice daily. The efficacy and tolerability of these two combinations were compared. Results: Among the 253 randomized subjects, 244 patients were evaluable (119 in the BDP/F group and 125 in the FP/S group). A significant improvement from baseline to the end of treatment period was observed in both BDP/F and FP/S groups in forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), morning and evening peak expiratory flow (PEF), Asthma Control Test (ACT) score and the use of rescue medication. FVC increase from pre-dose was significant after 5 min post inhalation in the BDP/F group only, while statistically significant within group improvement was not achieved until 30 min post inhalation in the FP/S group. Conclusion: The BDP/F combination is comparable in efficacy and tolerability to FP/S combination in Taiwanese asthmatic patients, with the advantage of rapid onset of improvement of FVC, consistent with the faster improvement of pulmonary hyperinflation with BDP/F. Keywords: Asthma, Combination therapy, Inhaled corticosteroid, Long acting beta2-agonist, Pulmonary hyperinflation

Unplanned extubation (UE) may cause considerable adverse effects in patients receiving mechanical ventilation (MV). Previous literature showed inconsistent prognosis in patients with UE. This study aimed to evaluate the clinical implications and outcomes of UE.The intubated adult patients with MV support in our hospital were enrolled, and they were divided into the UE and non-UE groups. Demographic data, admission unit, MV duration, overall weaning rate, and mortality rates were compared. The outcomes of UE in ordinary ward and intensive care unit (ICU) were also assessed.Totally 9245 intubated adult patients were included. UE occurred in 303 (3.5%) patients, and the UE events were 0.27 times/100 MV days. Old age, nonoperation related MV cause, and admission out of the ICU were significant factors associated with UE events. UE patients showed a trend of better overall weaning rate (71.9% vs 66.7%, P = .054) than non-UE. However, the in-hospital mortality rate (25.7% vs 24.8%, P = .713) were similar between the UE and non-UE patients. The reintubation rate of UE patients was 44.1% (142/322). Successful UEs were associated with patients in weaning process (52.8% vs 38.7%, P = .012), and patients received non-invasive positive pressure ventilation (NIPPV) support after UE (19.4% vs 3.5%, P < .001). Patients with successful UE had significantly shorter MV days, higher overall weaning rate, and lower mortality than those with unsuccessful UE. Outcomes of UE in ordinary ward and in ICU had similar MV duration, reintubation rate, overall weaning rate, and in-hospital mortality rate.The overall weaning rate and in-hospital mortality rates of the UE and non-UE patients were similar. UE occurred in ordinary ward had similar outcomes to those in ICU. Patients receiving MV should be assessed daily for weaning indications to reduce delayed extubation, and therefore, may decrease UE occurrence. Once the UE happened, NIPPV support may reduce the reintubation rate.

A 77-year-old man with a progressively dry cough (two months duration) was admitted with hemoptysis. Chest computed tomography (CT) revealed left lingular lobe consolidation and one thick-walled cavity lesion over the left lower lobe, which was accompanied by satellite micro-nodules in a tree-in-bud pattern. CT-guided biopsy confirmed mycobacterial infection, and subsequent culture yielded Mycobacterium avium complex (MAC). Unremitting hemoptysis was present despite treatment (14 days) with ethambutol, rifampin, clarithromycin, and streptomycin. Initial CT angiography (CTA) to determine the source of the hemoptysis revealed a suspected aneurysm in the consolidated left lingular lobe; however, this could not be localized via catheter angiography during the pulmonary and bronchial arterial phases. Two weeks later, a massive hemoptysis episode led to haemodynamic instability and serious consequences. Follow-up CTA confirmed the previously detected aneurysm, and glue embolization was performed successfully. This case report highlights a rare but catastrophic MAC-associated pseudoaneurysm and relevant treatment options.