Shared Decision-Making Facilitates Inhaler Choice in Patients with Newly-Diagnosed Chronic Obstructive Pulmonary Disease: A Multicenter Prospective Study.

Purpose: Inadequate inhaler technique and nonadherence to therapy are associated with poorer clinical outcomes in chronic obstructive pulmonary disease (COPD). Shared decision-making (SDM), based on clinical evidence, patient goals and preferences, improves quality of care. This study aims to investigate the initial patients' choices of inhaler devices in patients with newly-diagnosed COPD after an SDM process. Patients and Methods: We conducted a prospective, observational, multi-center study in four hospitals in Taiwan from December 2019 to July 2021. All treatment-naïve patients with newly-diagnosed COPD who were able to use three different inhalers of dual bronchodilators (Respimat®, Ellipta®, and Breezhaler®) in the outpatient setting were enrolled. After an SDM process, every patient was prescribed with one inhaler chosen by him- or herself. Errors of using inhalers were recorded after prescription of the inhaler, and at the follow-up visit a month later. The patients' adherence, satisfaction score, and willingness to keep the initially chosen inhaler were investigated. Results: In 109 enrolled patients, 43, 45, and 21 patients chose Respimat®, Ellipta®, and Breezhaler®, respectively. Patients chose different inhalers had similar rates of critical error on both visits, while the rates greatly decrease on the follow-up visit, no matter which inhaler devices they chose initially. The majority of patients had good adherence (use as the prescription daily, n = 79, 82%), satisfaction (satisfaction score ≥4, n = 70, 73%), and strong willingness to keep the initial inhaler (n = 89, 93%) on the follow-up visit regardless of disease severity and their comorbidities. Conclusion: SDM might facilitate inhaler choosing, reduce inhaler errors (versus baseline) with good adherence, satisfaction and strong willingness to keep the initial inhaler in patients with newly-diagnosed COPD.

Investigation of clinical predictors of survival in idiopathic pulmonary fibrosis patients: A cohort study in Taiwan.

BACKGROUND: Two antifibrotic medications, pirfenidone and nintedanib, have been approved as treatments for idiopathic pulmonary fibrosis (IPF)-a life-threatening interstitial lung disease. However, there are insufficient current data regarding clinical predictors of survival for patients with IPF in the era of antifibrotics. METHODS: We retrospectively analyzed the medical records of patients with IPF treated between April 2017 and May 2020. Univariate and multivariate Cox proportional hazard models were used to identify independent predictors of mortality among these patients with IPF. RESULTS: A total of 40 patients with IPF (average age, 75.58 ± 8.34 years) were included in the study, 27 (67.5%) of whom were treated with antifibrotic drugs. In the entire cohort, 14 (35%) patients died, and the overall survival of the study population was 48.52 ± 5 months (median, not applicable [NA] [29-NA] months). The univariate and multivariate Cox proportional hazard models indicated that chest tightness, finger clubbing, acute exacerbation after medication, decreased percentage forced vital capacity (%FVC), and decreased percentage 1-second forced expiratory volume were clinical factors linked to all-cause mortality among all patients, although without statistical significance at the multivariate level. Meanwhile, only finger clubbing was a significant mortality predictor among patients who received antifibrotic medications. A mortality scoring system was built upon the aforementioned risk factors, with the exclusion of %FVC, whose individual mortality score was nearly zero. CONCLUSION: Chest tightness, finger clubbing, acute exacerbation after medication, and decreased %FVC were clinical factors associated with mortality in patients with IPF, although without statistical significance. A scoring system including these factors can be used to predict all-cause mortality in patients with IPF. The mere intake of antifibrotic medications was not a significant mortality predictor in this study. This might be owed to the retrospective nature of the study, where many patients started the medications after the deterioration of their pulmonary function rather than from the start.

Advanced Lung Adenocarcinoma Patient with ERBB2 Amplification Identified by Comprehensive Genomic Profiling Benefits from Trastuzumab.

For non-small-cell lung cancer (NSCLC) patients without established actionable alterations in genes such as EGFR or ALK, options for targeted therapy remain limited in clinical practice. About 5% of lung adenocarcinoma patients have tumors with ERBB2 genetic alterations, with even fewer patients harboring ERBB2 amplification. Currently, clinical trials mainly use IHC, FISH, or mutation testing to identify potential responders to ERBB2-targeting agents. The use of next-generation sequencing (NGS) to detect ERBB2 alterations, including copy number variants, is rare. In this study, we present an EGFR- and ALK-negative advanced NSCLC case for which we conducted comprehensive tumor genomic profiling to identify potentially actionable alterations. The tumor harbored an ERBB2 amplification, and trastuzumab-based therapy resulted in an excellent response, with a necrotic regression of the patient's lung lesion. Although he developed brain metastasis four months after trastuzumab initiation, he survived for an additional period of eight months without local recurrence or other systemic metastasis. This case report shows that the use of comprehensive genetic testing enables the identification of rare actionable alterations in NSCLC patients without other options for targeted treatment.

Clinical Significance of Bioimpedance Spectroscopy in Critically Ill Patients.

BACKGROUND: Early fluid resuscitation is a key aspect in the successful management of critically ill patients, but the optimal goal for volume control after the acute stage of critical illness remains unclear. This study aimed to evaluate the prognostic value of bioimpedance spectrometry for fluid management in critically ill patients. METHODS: In this prospective observational study, patients who consented to participate were screened within the first 24 hours of admission to a medical intensive care unit (ICU) from February 4, 2015, to January 31, 2016. Information on demographics, comorbidities, primary reasons for admission, baseline laboratory data, and ventilator or inotropic use were documented. Data of fluid intake, fluid output, and body weight were recorded for the first 3 days of ICU admission. Bioimpedance spectrometry was performed on the first and third days after ICU admission. All participants were followed until death or hospital discharge. RESULTS: Of the 140 enrolled patients (median age: 70 years, interquartile range: 60-77 years), 23 (16.4%) patients died during hospitalization. Independent predictors of hospital mortality were Acute Physiology and Chronic Health Evaluation II scores (per 1 point increase, odds ratio [OR]: 1.101) and overhydration (OH) volume on the first day (per 1 L increase, OR: 1.216). Compared to normal OH status (OH volume between -1 and 1 L), hyper OH status (OH volume < -1 L) on the third day after ICU admission was an independent predictor of hospital death (OR: 7.609). Normal OH status on the third day was associated with greater numbers of ICU-free and ventilator-free days. CONCLUSION: Bioimpedance spectrometry can be used to predict outcomes in critically ill patients. Increased OH volume on day 1 and hyper OH volume on day 3 of ICU admission are associated with a greater risk of hospital mortality. Volume status on day 3 is associated with durations of ventilator use and ICU stay.

Glycopyrronium bromide inhibits lung inflammation and small airway remodeling induced by subchronic cigarette smoke exposure in mice.

The effects of long-acting muscarinic receptor antagonists (LAMAs) have not been evaluated in a model with simultaneous lung inflammation and small airway remodeling induced by cigarette smoke (CS). We exposed the mice to CS for four weeks with daily treatment with a LAMA (glycopyrronium bromide, NVA237) or its vehicle. Human bronchial epithelial cells (PBECs) and lung fibroblasts were exposed to CS extract (CSE) or acetylcholine with or without NVA237 treatment. We found that NVA237, but not its vehicle, suppressed elevations in inflammatory score, epithelial thickness, and peribronchial collagen deposition in CS-exposed mice. NVA237 alleviated CS-induced increased levels of chemokines, inflammatory cells, and total protein in the bronchoalveolar lavage fluid. NVA237 suppressed acetylcholine- or CSE-induced elevations in IL-8 production in PBECs and elevations in proliferation and collagen production in lung fibroblasts. These phenomena were also prevented by a p44/42 MAPK inhibitor. In conclusion, NVA237 exerted a potent suppressive effect on lung inflammation and small airway remodeling induced by subchronic CS exposure.

Post-bronchodilator Reversibility of FEV1 and Eosinophilic Airway Inflammation in COPD / Reversibilidad del FEV1 postbroncodilatador e inflamación eosinofílica de la vía aérea en la EPOC

Introduction: The relationship between bronchodilator responsiveness and eosinophilic airway inflammation has not been well documented in COPD. It has been investigated in this retrospective study. This issue has grown in importance due to increasing interest in the asthma-COPD overlap syndrome. Methods: 264 stable COPD patients with no past history of asthma were retrospectively analyzed. Correlation analyses between FEV1 reversibility and sputum eosinophil levels were conducted. Sputum eosinophil levels were dichotomized using FEV1 reversibility cut-off points (>0.4 L and >15% vs. >0.2L and >12%) and compared. The effectiveness of FEV1 reversibility to predict sputum eosinophilia (>3%) was analyzed with a logistic regression and a ROC analysis. Results: 82 (31.1%) patients with higher FEV1 reversibility values (0.14 vs. 0.11 L, P = .01) presented sputum eosinophilia. FEV1 reversibility was weakly correlated with the sputum eosinophil level (r = 0.162, P = .008). Patients with FEV1 > 0.4 L and >15% increment had higher sputum eosinophil levels (6.11 vs. 1.02%, P = .049) whereas the level did not differ when dichotomized by FEV1 increment >0.2 L and >12%. Very positive FEV1 reversibility (>0.4L and >15%) predicted sputum eosinophilia after adjustment forage, baseline FEV1 and FVC (OR: 4.262, P = .029). In the ROC analysis, the AUC was 0.58 (P = .034), and FEV1 increment>0.4L and >15% had a positive predictive value of 63.6% and an overall accuracy of 70.1%. Conclusions: FEV1 reversibility was weakly correlated with sputum eosinophil levels in COPD. Positive FEV1 reversibility (> 0.4 L and >15%) is moderately successful in predicting sputum eosinophilia (> 3%)

La relación entre la reactividad al broncodilatador y la inflamación eosinofílica de la vía aérea no está bien documentada en la EPOC y se ha investigado en este estudio retrospectivo. Esta cuestión ha adquirido mayor importancia debido al creciente interés que despierta el fenotipo mixto asma-EPOC. Métodos: Se analizó retrospectivamente a 264 pacientes con EPOC estable y sin antecedentes de asma. Se efectuaron análisis de correlación entre la reversibilidad del FEV1 y las concentraciones de eosinófilos en esputo, que se compararon una vez dicotomizadas en función de diferentes puntos de corte de la reversibilidad del FEV1 (> 0,4 l y > 15% vs. > 0,2 l y > 12%). La utilidad de la reversibilidad del FEV1 para predecir la eosinofilia del esputo (> 3%) se evaluó mediante una regresión logística y un análisis de la curva ROC. Resultados: En los 82 pacientes (31,1%) que presentaban eosinofilia del esputo, la reversibilidad del FEV1 fue mayor (0,14 vs. 0., 1 l, p = 0,01). La reversibilidad del FEV1 se correlacionó débilmente con la concentración de eosinófilos en esputo (r = 0,162, p = 0,008). Los pacientes con incrementos del FEV1 > 0,4 l y > 15% mostraron mayores concentraciones de eosinófilos en el esputo (6,11 vs. 1,02%, p = 0,049), aunque las concentraciones no difirieron tras dicotomizarlas de acuerdo a un incremento del FEV1 > 0,2 l y > 12%. Tras ajustarla en función de la edad, el FEV1 inicial y la FVC, la reversibilidad del FEV1 muy alta (> 0,4 l y > 15%) continuó siendo significativa para predecir la eosinofilia del esputo (OR: 4,262, p=0,029). El análisis de la curva ROC mostró que el valor predictivo positivo de un AUC de 0,58 (p=0,034) y un incremento del FEV1 > 0,4 l y > 15% es del 63,6%, con una precisión total del 70,1%. Conclusiones: En pacientes con EPOC, la reversibilidad del FEV1 se correlacionó débilmente con las concentraciones de eosinófilos en esputo. Una reversibilidad del FEV1 muy alta (> 0,4l y > 15%) puede predecir la eosinofilia del esputo (> 3%), pero su rendimiento es modesto

Measuring (1,3)-ß-D-glucan in tracheal aspirate, bronchoalveolar lavage fluid, and serum for detection of suspected Candida pneumonia in immunocompromised and critically ill patients: a prospective observational study.

BACKGROUND: While Candida pneumonia is life-threatening, biomarker measurements to early detect suspected Candida pneumonia are lacking. This study compared the diagnostic values of measuring levels of (1, 3)-ß-D-glucan in endotracheal aspirate, bronchoalveolar lavage fluid, and serum to detect suspected Candida pneumonia in immunocompromised and critically ill patients. METHODS: This prospective, observational study enrolled immunocompromised, critically ill, and ventilated patients with suspected fungal pneumonia in mixed intensive care units from November 2010 to October 2011. Patients with D-glucan confounding factors or other fungal infection were excluded. Endotracheal aspirate, bronchoalveolar lavage fluid and serum were collected from each patient to perform a fungal smear, culture, and D-glucan assay. RESULTS: After screening 166 patients, 31 patients completed the study and were categorized into non-Candida pneumonia/non-candidemia (n = 18), suspected Candida pneumonia (n = 9), and non-Candida pneumonia/candidemia groups (n = 4). D-glucan levels in endotracheal aspirate or bronchoalveolar lavage were highest in suspected Candida pneumonia, while the serum D-glucan level was highest in non-Candida pneumonia/candidemia. In all patients, the D-glucan value in endotracheal aspirate was positively correlated with that in bronchoalveolar lavage fluid. For the detection of suspected Candida pneumonia, the predictive performance (sensitivity/specificity/D-glucan cutoff [pg/ml]) of D-glucan in endotracheal aspirate and bronchoalveolar lavage fluid was 67%/82%/120 and 89%/86%/130, respectively, accounting for areas under the receiver operating characteristic curve of 0.833 and 0.939 (both P < 0.05), respectively. Measuring serum D-glucan was of no diagnostic value (area under curve =0.510, P = 0.931) for the detection of suspected Candida pneumonia in the absence of concurrent candidemia. CONCLUSIONS: D-glucan levels in both endotracheal aspirate and bronchoalveolar lavage, but not in serum, provide good diagnostic values to detect suspected Candida pneumonia and to serve as potential biomarkers for early detection in this patient population.

Post-bronchodilator Reversibility of FEV1 and Eosinophilic Airway Inflammation in COPD.

INTRODUCTION: The relationship between bronchodilator responsiveness and eosinophilic airway inflammation has not been well documented in COPD. It has been investigated in this retrospective study. This issue has grown in importance due to increasing interest in the asthma-COPD overlap syndrome. METHODS: 264 stable COPD patients with no past history of asthma were retrospectively analyzed. Correlation analyses between FEV1 reversibility and sputum eosinophil levels were conducted. Sputum eosinophil levels were dichotomized using FEV1 reversibility cut-off points (>0.4L and >15% vs. >0.2L and >12%) and compared. The effectiveness of FEV1 reversibility to predict sputum eosinophilia (>3%) was analyzed with a logistic regression and a ROC analysis. RESULTS: 82 (31.1%) patients with higher FEV1 reversibility values (0.14 vs. 0.11L, P=.01) presented sputum eosinophilia. FEV1 reversibility was weakly correlated with the sputum eosinophil level (r=0.162, P=.008). Patients with FEV1>0.4L and >15% increment had higher sputum eosinophil levels (6.11 vs. 1.02%, P=.049) whereas the level did not differ when dichotomized by FEV1 increment >0.2L and >12%. Very positive FEV1 reversibility (>0.4L and >15%) predicted sputum eosinophilia after adjustment forage, baseline FEV1 and FVC (OR: 4.262, P=.029). In the ROC analysis, the AUC was 0.58 (P=.034), and FEV1 increment>0.4L and >15% had a positive predictive value of 63.6% and an overall accuracy of 70.1%. CONCLUSIONS: FEV1 reversibility was weakly correlated with sputum eosinophil levels in COPD. Positive FEV1 reversibility (>0.4L and >15%) is moderately successful in predicting sputum eosinophilia (>3%).

Long-Term Mortality and Major Adverse Cardiovascular Events in Sepsis Survivors. A Nationwide Population-based Study.

RATIONALE: Patients with sepsis who survive to hospital discharge may present with ongoing high morbidity and mortality. However, little is known about the risk of long-term, all-cause mortality and cardiovascular outcomes after sepsis. OBJECTIVES: Our study aimed to investigate the long-term clinical outcomes in sepsis survivors. METHODS: In this nationwide population-based study, data from patients with sepsis were retrieved from Taiwan's National Health Insurance Research Database between 2000 and 2002. Each sepsis survivor was 1:1 propensity-matched to control subjects from two different control populations: subjects who were in the general population and subjects who were hospitalized for a nonsepsis diagnosis. The primary outcomes were all-cause mortality, major adverse cardiovascular events, myocardial infarction, heart failure, stroke, and sudden cardiac death or ventricular arrhythmia. MEASUREMENTS AND MAIN RESULTS: Compared with matched population control subjects, sepsis survivors had higher risks of all-cause mortality (hazard ratio [HR], 2.18; 95% confidence interval [CI], 2.14-2.22), major adverse cardiovascular events (HR, 1.37; 95% CI, 1.34-1.41), ischemic stroke (HR, 1.27; 95% CI, 1.23-1.32), hemorrhagic stroke (HR, 1.36; 95% CI, 1.26-1.46), myocardial infarction (HR, 1.22; 95% CI, 1.14-1.30), heart failure (HR, 1.48; 95% CI, 1.43-1.53), and sudden cardiac death or ventricular arrhythmia (HR, 1.65; 95% CI, 1.57-1.74). Similar results, although slightly attenuated risks, were found when comparisons were made with hospitalized control subjects without sepsis. CONCLUSIONS: These data indicate that sepsis survivors had substantially increased risks of subsequent all-cause mortality and major adverse cardiovascular events at 1 year after discharge, which persisted for up to 5 years after discharge.

Adult narcoleptic patients have increased risk of cancer: A nationwide population-based study.

BACKGROUND: The comorbidity profile, especially cancer risk, of narcoleptic patients has seldom been explored. We used a nationwide database to evaluate the risk of cancer among adult narcoleptic patients. METHODS: We conducted the cohort study using National Health Insurance Research Database from 2000 to 2009. Standardized incidence ratios (SIRs) of cancers were calculated to compare the cancer incidence of the study cohort with that of the general population. RESULTS: 2833 narcoleptic patients were identified after excluding patients with antecedent malignancy and age younger than 18 years old. The study cohort was observed for 15,913 person-years during a 10-year period. The median follow-up interval was 5.6 ± 3.0 years. Seventy-four cancers occurred in during the follow-up. The risk of all cancers was found significantly increased in adult narcoleptic patients (SIR 1.32; 95% CI, 1.04-1.66, p=0.0248). Regarding sex, the overall cancer risk was increased in female patients (SIR 1.52; 95% CI, 1.05-2.13, p=0.026). Furthermore, females were found to have more head and neck cancers (SIR 6.17; 95% CI, 1.66-15.80, p=0.009) and gastric cancers (SIR 4.87; 95% CI, 1.31-12.48, p=0.02). For males, the incidence of overall and specific cancer types was not significantly increased. CONCLUSIONS: Adult narcoleptic patients had a higher risk for cancer. Further research is warranted to elucidate the mechanism underlying its association.

Sleep disorders and increased risk of autoimmune diseases in individuals without sleep apnea.

STUDY OBJECTIVES: To explore the association between the non-apnea sleep disorder (NSD) and autoimmune diseases. DESIGN: Cohort study. SETTING: Nationwide database research. PARTICIPANTS: 84,996 adult patients with NSD diagnoses recorded in the Taiwan National Health Insurance Research Database between 2000 and 2003, after excluding those with antecedent autoimmune diseases. A comparison cohort of 84,996 participants was formed by age-, gender-, income-, and urbanization-matched controls. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: The two cohorts were followed up for occurrence of autoimmune diseases, including rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), and systemic sclerosis (SSc). A Cox proportional hazards regression model was used for muti-variate adjustment. In patients with NSD, the overall risk for incident autoimmune diseases was significantly higher than in controls (adjusted hazard ratio [HR] = 1.47, 95% confidence interval [CI] = 1.41-1.53). With regard to individual diseases, the risks for SLE, RA, AS and SS among NSD patients were also significantly higher than in controls (HR [95% CI] for SLE, RA, AS, and SS were 1.81 [1.50-2.18], 1.45 [1.36-1.54], 1.53 [1.38-1.70], and 1.51 [1.43-1.60], respectively), whereas the increased risk for SSc did not reach statistical significance (HR: 1.36 [0.82-2.26]). CONCLUSION: Patients with non-apnea sleep disorder were associated with a higher risk for developing autoimmune diseases.

Budesonide/formoterol maintenance and reliever therapy in asthma control: acute, dose-related effects and real-life effectiveness.

BACKGROUND AND OBJECTIVE: The efficacy of budesonide/formoterol maintenance and reliever therapy (BFMRT) in asthma control is well documented in large randomized controlled trials. However, the acute reliever effects and real-life effectiveness are seldom reported. METHODS: This multicenter trial enrolled steroid-naïve, symptomatic asthmatics with baseline exhaled nitric oxide (eNO) of ≥ 40 ppb. There were 120 eligible patients who were randomized and received a dose of inhaled budesonide/formoterol 320/9 µg (lower dose budesonide/formoterol), 640/18 µg (higher dose budesonide/formoterol (HDBF)), or terbutaline (TERB) 1 mg. Inflammatory cells and mediators in induced sputum, eNO and lung function were measured at baseline and 6 h (acute phase). Subsequently, all patients used BFMRT as real-life practice for 24 weeks (maintenance phase). RESULTS: In the acute phase, the degree of post-treatment reduction in total eosinophil counts, interleukin-8 and matrix metalloproteinase-9 in induced sputum were significantly greater in group HDBF (vs TERB, P < 0.05). The increase in forced expiratory volume in first second (FEV1 ) in group HDBF was significantly higher (vs LDBF and TERB, P < 0.05) 3 h after dosing. In the maintenance phase, significant improvement of asthma control (presented by eNO, FEV1 and a five-item asthma control questionnaire) in real-life settings was observed at 4 weeks and sustained to the end of study. The rate of patients who followed scheduled visits declined over time (87% at week 4 and 42% at week 24). CONCLUSIONS: Budesonide/formoterol as reliever exerts acute, dose-related anti-inflammatory effects and FEV1 improvement in symptomatic asthmatics. BFMRT is effective in asthma control. However, the decrease in long-term follow-up rate remains an issue to overcome in real-life settings.

Association of postdischarge rehabilitation with mortality in intensive care unit survivors of sepsis.

RATIONALE: Intensive care unit (ICU)-acquired weakness is a common issue for sepsis survivors that is characterized by impaired muscle strength and causes functional disability. Although inpatient rehabilitation has not been found to reduce in-hospital mortality, the impact of postdischarge rehabilitation on sepsis survivors is uncertain. OBJECTIVES: To investigate the benefit of postdischarge rehabilitation to long-term mortality in sepsis survivors. METHODS: We conducted a nationwide, population-based, high-dimensional propensity score-matched cohort study using Taiwan's National Health Insurance Research Database. The rehabilitation cohort comprised 15,535 ICU patients who survived sepsis and received rehabilitation within 3 months after discharge between 2000 and 2010. The control cohort consisted of 15,535 high-dimensional propensity score-matched subjects who did not receive rehabilitation within 3 months after discharge. The endpoint was mortality during the 10-year follow-up period. MEASUREMENTS AND MAIN RESULTS: Compared with the control cohort, the rehabilitation cohort had a significantly lower risk of 10-year mortality (adjusted hazard ratio, 0.94; 95% confidence interval, 0.92-0.97; P < 0.001), with an absolute risk reduction of 1.4 per 100 person-years. The frequency of rehabilitation was inversely associated with 10-year mortality (≥3 vs. 1 course: adjusted hazard ratio, 0.82; P < 0.001). Compared with the control cohort, improved survival was observed in the rehabilitation cohort among ill patients who had more comorbidities, required more prolonged mechanical ventilation, and had longer ICU or hospital stays, but not among those with the opposite conditions (i.e., less ill patients). CONCLUSIONS: Postdischarge rehabilitation may be associated with a reduced risk of 10-year mortality in the subset of patients with particularly long ICU courses.

Exhaled nitric oxide predicts eosinophilic airway inflammation in COPD.

PURPOSE: Chronic obstructive pulmonary disease (COPD) with eosinophilic airway inflammation may represent a unique phenotype, possibly with shared features of COPD and asthma. The role of exhaled nitric oxide (eNO) in identifying COPD patients with sputum eosinophilia was examined in this study. METHODS: Ninety COPD patients without past medical history of asthma or allergic diseases were prospectively enrolled, and their eNO, lung function, and cellular profile of induced sputum were measured. Eosinophil cationic protein and IgE in sputum and venous blood also were determined. Subjects with and without sputum eosinophilia (>3 %) were compared. The role of eNO in the prediction of sputum eosinophilia was assessed in a logistic regression model. RESULTS: Patients with sputum eosinophilia had significantly higher levels of eNO (29 vs. 18 ppb, p = 0.01) than those without. The difference in serum total IgE (168 vs. 84.9 IU/ml, p = 0.057) and percentages of positive allergen test results (48.3 vs. 29.5 %, p = 0.082) showed a trend toward significance. The sputum eosinophil level was significantly correlated to the eNO level (r = 0.485, p < 0.001). The eNO level at the cutoff of 23.5 ppb had the maximum sum of sensitivity (62.1 %) and specificity (70.5 %). The unadjusted and adjusted odds ratios of a higher eNO level (>23.5 ppb) in the prediction of sputum eosinophilia were 3.909 (confidence interval (CI) 1.542-9.91, p = 0.004) and 4.329 (CI 1.306-14.356, p = 0.017), respectively. CONCLUSIONS: eNO is a good marker to identify COPD patients with eosinophilic airway inflammation.

The suppression effects of thalidomide on human lung fibroblasts: cell proliferation, vascular endothelial growth factor release, and collagen production.

BACKGROUND: Expression of transforming growth factor (TGF)-ß1 and increases in angiogenesis and deposition of extracellular matrix are the key features of tracheal granulation formation. The aim of this study was to investigate the potential role of thalidomide in preventing granulation tissue formation from the aspect of cellular effects in vitro, including fibroblast proliferation, vascular endothelial growth factor (VEGF) release, and collagen production. METHODS: Human lung fibroblasts were obtained from bronchus and cultured. The effects of thalidomide on cell proliferation, migration, TGF-ß1-induced VEGF, and signal pathway were investigated. RESULTS: Thalidomide (20 µM) not only inhibited cell proliferation after 24 h [fold increase of cell number, 0.85 ± 0.09 vs. 1.47 ± 0.14 (treatment vs. control group); P < 0.01] and 48 h of incubation (0.85 ± 0.10 vs. 1.97 ± 0.12; P < 0.001), it also inhibited cell migration and slowed wound closure at 24 h (P < 0.001). Thalidomide significantly attenuated TGF-ß1-induced VEGF expression at both the mRNA and protein levels. Incubation of thalidomide with cells stimulated with TGF-ß1 significantly inhibited their production of collagen. Thalidomide inhibited Smad3, STAT3, and subsequent p44/42 kinase phosphorylation. CONCLUSION: Thalidomide may inhibit human fibroblast proliferation and it is worthy of further in vivo investigation.

The effect of cold temperature on increased exacerbation of chronic obstructive pulmonary disease: a nationwide study.

BACKGROUND: Seasonal variations in the acute exacerbation of chronic obstructive pulmonary disease (COPD) have been reported. However, the influence of air temperature and other meteorological factors on COPD exacerbation remains unclear. METHODS: National Health Insurance registry data from January 1, 1999 to December 1, 2009 and meteorological variables from the Taiwan Central Weather Bureau for the same period were analyzed. A case-crossover study design was used to investigate the association between COPD exacerbation and meteorological variables. RESULTS: A total of 16,254 cases who suffered from COPD exacerbation were enrolled. We found that a 1°C decrease in air temperature was associated with a 0.8% increase in the exacerbation rate on event-days (95% confidence interval (CI), 1.015-1.138, p = 0.015). With a 5°C decrease in mean temperature, the cold temperature (28-day average temperature) had a long-term effect on the exacerbation of COPD (odds ratio (OR), 1.106, 95% CI 1.063-1.152, p<0.001). In addition, elderly patients and those who did not receive inhaled medication tended to suffer an exacerbation when the mean temperature dropped 5°C. Higher barometric pressure, more hours of sunshine, and lower humidity were associated with an increase in COPD exacerbation. CONCLUSIONS: This study demonstrated the effect of cold temperatures on the COPD exacerbation rate. Elderly patients and those without inhaled medicine before the exacerbation event were affected significantly by lower mean temperatures. A more comprehensive program to prevent cold stress in COPD patients may lead to a reduction in the exacerbations rate of COPD.

Bile acids increase alveolar epithelial permeability via mitogen-activated protein kinase, cytosolic phospholipase A2 , cyclooxygenase-2, prostaglandin E2 and junctional proteins.

BACKGROUND AND OBJECTIVE: Bile acid (BA) aspiration is associated with various lung diseases. It was hypothesized that BA may induce changes in alveolar epithelium permeability and contribute to the pathogenesis of lung injury. METHODS: Human alveolar epithelial cells were grown in monolayer and stimulated with a major component of BA, chenodeoxycholic acid (CDCA). Transepithelial electrical resistance (TER) and paracellular fluxes were measured to assess permeability alteration. Prostaglandin E2 ( PGE2 ) production was measured, and its effect on TER and junctional proteins (JP) was also examined. Reverse transcription polymerase chain reaction and Western blots were used to investigate the expression of messenger RNA and JP. RESULTS: CDCA induced significant p38 and c-Jun N-terminal kinase (JNK) phosphorylation, cytosolic phospholipase A2 (cPLA2 ) and cyclooxygenase-2 (COX-2) messenger RNA expression, PGE2 production, TER reduction and decay of JP (including occludin, zonula occludens-1 (ZO-1) and E-cadherin, in which ZO-1 had maximal change). CDCA also increased paracellular fluxes, which was abolished by dexamethasone. Both CDCA and PGE2 contributed to TER reduction in an identical trend and a dose-response manner. PGE2 also reduced ZO-1 expression, which was similar to that observed by CDCA stimulation. Pretreatment with inhibitors of p38 (SB203580), JNK (SP600125), cPLA2 (mepacrine) and COX-2 (NS398) as well as dexamethasone reversed the CDCA-induced PGE2 production, TER reduction and decay of ZO-1. CONCLUSIONS: The increase in alveolar permeability was associated with decay of JP. BA may induce permeability alteration through the upregulation of mitogen-activated protein kinase, cPLA2 , COX-2, PGE2 and JP, which may contribute to the pathogenesis of BA-associated lung injury.

Hospital outcomes for patients with stage III and IV lung cancer admitted to the intensive care unit for sepsis-related acute respiratory failure.

BACKGROUND: In recent years, intensive care for cancer patients has improved and treatment of critically ill cancer patients has become increasingly aggressive over time. However, not all cancer patients would benefit from aggressive care, especially those with late-stage cancer. OBJECTIVE: We aimed to investigate the outcome of late-stage lung cancer patients with sepsis-related respiratory failure and identify predictors of mortality. METHODS: From 2007 to 2008, consecutive stage III and IV lung cancer patients admitted to an intensive care unit (ICU) of a teritiary medical center in Taiwan for sepsis-related respiratory failure were retrospectively enrolled. Data at baseline and upon ICU admission were collected. In-hospital survival was analyzed. Variables of the survivors to hospital discharge and patients who died were compared by uni- and multivariate analyses. RESULTS: Seventy patients were enrolled. During a mean follow-up period of 30.10 days, 29 (41.4%) patients survived to hospital discharge and 41(58.6%) died. Compared with the survivors, the patients who died had poor performance status, lower serum albumin level, higher percentage of disseminated intravascular coagulation, and more severe organ dysfunction as disclosed by higher Sequential Organ Failure Assessment (SOFA) scores. Multivariate analyses revealed that SOFA score (p=0.026) was the only independent predictor of mortality; 44.8 % (13/29) of survivors were weaned from ventilator during hospitalization. CONCLUSION: Among late-stage lung cancer patients with sepsis-related respiratory failure, those with lower SOFA scores seemed to have better survival rate and may benefit from intensive care in the ICU. Early palliative care should be considered for all patients with advanced lung cancer, and hospice care is suggested for those with sepsis-respiratory failure and high SOFA scores.

Long-acting ß2 agonists and corticosteroids restore the reduction of histone deacetylase activity and inhibit H2O2-induced mediator release from alveolar macrophages.

BACKGROUND: Treatment of COPD with a combination of long-acting ß(2) agonists and corticosteroids is currently used worldwide. The mechanisms of the anti-inflammatory effects and their associations with histone deacetylase (HDAC) activity remain unclear. METHODS: Human alveolar macrophages were isolated and stimulated with H(2)O(2) in the presence of varying concentrations of long-acting ß(2) agonists and corticosteroids. Supernatants were collected for IL-8 and MMP-9 measurements. Cell lysates were analyzed for HDAC (mainly HDAC1/HDAC2) activity. Quantitative real-time PCR was performed to determine the levels of IL-8 and MMP-9 mRNA. RESULTS: Both long-acting ß(2) agonists, salmeterol and formoterol, and corticosteroids, fluticasone and budesonide, showed anti-inflammatory effects to a certain extent on H(2)O(2)-induced IL-8 and MMP-9 release in alveolar macrophages. Combinations of long-acting ß(2) agonists and corticosteroids exerted greater effects to suppress mediator release, and both transcription and translation of IL-8 and MMP-9 were inhibited. It seemed that the levels of IL-8 and MMP-9 after H(2)O(2) stimulation were inversely associated with the activity of HDAC. H(2)O(2) stimulation resulted in a significant decrease in HDAC activity and was associated with an increase in mediator release. In contrast, treatment with long-acting ß(2) agonists, corticosteroids or theophylline restored the H(2)O(2)-induced decrease in HDAC activity and inhibited mediator release. CONCLUSION: Combinations of long-acting ß(2) agonists and corticosteroids exerted greater effects on the suppression of mediator release in relation to the enhancement of HDAC activity. This supports at least in part the likely contribution of anti-inflammatory effects of long-acting ß(2) agonists and corticosteroids to the clinical benefits seen in COPD patients.