Angiotensin-(1-7) attenuates SARS-CoV2 spike protein-induced interleukin-6 and interleukin-8 production in alveolar epithelial cells through activation of Mas receptor.

BACKGROUND: SARS-CoV-2 spike proteins (SP) can bind to the human angiotensin-converting enzyme 2 (ACE2) in human pulmonary alveolar epithelial cells (HPAEpiC) and trigger an inflammatory process. Angiotensin-(1-7) may have an anti-inflammatory effect through activation of Mas receptor. This study aims to investigate whether SARS-CoV-2 SP can induce inflammation through ACE2 in the alveolar epithelial cells which can be modulated through angiotensin-(1-7)/Mas receptor axis. METHODS: HPAEpiC were treated with SARS-CoV-2 SP in the presence or absence of ACE2 antagonist-dalbavancin and Mas receptor agonist-angiotensin-(1-7). Proinflammatory cytokine production (IL-6 and IL-8) were measured at mRNA and protein levels. MAP kinase phosphorylation and transcription factor activation was determined by Western Blot. Mas receptor was blocked by either antagonist (A779) or knockdown (specific SiRNA). Experiments were replicated using A549 cells. FINDINGS: SARS-CoV-2 SP (5 µg/mL) significantly induced MAP kinase (ERK1/2) phosphorylation, downstream transcription factor (activator protein-1, AP-1) activation and cytokine production (IL-6 and IL-8) at both mRNA and protein levels. Pretreatment with dalbavancin (10 µg/mL), or angiotensin-(1-7) (10 µM) significantly reduced ERK1/2 phosphorylation, AP-1 activation, and cytokine production. However, these angiotensin-(1-7)-related protective effects were significantly abolished by blocking Mas receptor with either antagonist (A799,10 µM) or SiRNA knockdown. INTERPRETATION: SARS-CoV-2 SP can induce proinflammatory cytokine production, which can be inhibited by either ACE2 antagonist or Mas receptor agonist-angiotensin-(1-7). Angiotensin-(1-7)-related protective effect on cytokine reduction can be abolished by blocking Mas receptor. Our findings suggest that ACE2/angiotensin-(1-7)/Mas axis may serve as a therapeutic target to control inflammatory response triggered by SARS-CoV-2 SP.

The role of transforming growth factor-ß2 in cigarette smoke-induced lung inflammation and injury.

AIMS: Transforming growth factor-ß2 (TGF-ß2) plays an important role in pleiotropic functions and has been reported to be involved in the pathogenesis of chronic obstructive lung disease. The role of TGF-ß2 in regulating cigarette smoke (CS)-induced lung inflammation and injury has not been investigated, and its underlying mechanism remains unclear. MAIN METHODS: Primary bronchial epithelial cells (PBECs) were treated with cigarette smoke extract (CSE), and the signaling pathway of TGF-ß2 regulating lung inflammation was investigated. Mice were exposed to CS and treated with TGF-ß2 i.p. or bovine whey protein extract containing TGF-ß2 p.o., and the role of TGF-ß2 in alleviating lung inflammation/injury was studied. KEY FINDINGS: In vitro, we demonstrated that TGF-ß2 attenuated CSE-induced IL-8 production from PBECs through the TGF-ß receptor I (TGF-ßRI), Smad3, and mitogen-activated protein kinase signaling pathways. Selective TGF-ßRI inhibitor (LY364947) and antagonist of Smad3 (SIS3) abolished the effect of TGF-ß2 on alleviating CSE-induced IL-8 production. In vivo, CS exposure for 4 weeks in mice increased the levels of total protein, inflammatory cell counts, and monocyte chemoattractant protein-1 in bronchoalveolar fluid and induced lung inflammation/injury, as revealed by immunohistochemistry. Administration of TGF-ß2 through intraperitoneal injection or oral feeding with bovine whey protein extract containing TGF-ß2 significantly reduced CS-induced lung inflammation and injury. SIGNIFICANCE: We concluded that TGF-ß2 reduced CSE-induced IL-8 production through the Smad3 signaling pathway in PBECs and alleviated lung inflammation/injury in CS-exposed mice. The anti-inflammatory effect of TGF-ß2 on CS-induced lung inflammation in humans deserves further clinical study.

Unmet Need for Oral Corticosteroids Use and Exacerbations of Asthma in Primary Care in Taiwan.

Patients with asthma are treated in primary healthcare facilities (PHCFs) in Taiwan, where the asthma control status associated with acute exacerbation (AE) and use of oral corticosteroids (OCS) and short-acting ß2-agonist (SABA) inhalers remains unclear. A cross-sectional, close-ended, face-to-face questionnaire survey invited board-certified physicians who treat adult asthma patients in PHCFs. The contents of the questionnaire included three parts: rescue OCS to treat AE, regular OCS for asthma control, and AE-related adverse outcomes. There were 445 out of 500 physicians who completed the questionnaire, with 61% of them being non-pulmonologists. A substantial proportion of asthma patients needed rescue OCS or regular OCS each month, or ≥3 canisters of SABA inhalers per year. Approximately 86% of physicians reported their patients with ≥2 AE-related unscheduled visits to clinics or emergency departments in the past year. A total of 41% of physicians reported their patients receiving intubation or intensive care in the past year. A total of 92% of physicians prescribed rescue OCS ≤ 40 mg/day. A total of 92% of physicians prescribed rescue OCS for a duration of ≤7 days for AEs. A total of 85% of physicians prescribed regular OCS ≤ 10 mg/day for asthma control. This is the first study to present the perceptions of asthma-treating physicians on the use of OCS in PHCFs. In summary, 31% of physicians reported ≥ 6% of their patients needed OCS for asthma control and 41% of physicians reported their patients with adverse outcomes in the past year. Thus, the need to improve asthma control in Taiwan is suggested by our study results.

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.

Fractional Exhaled Nitric Oxide Guided-Therapy in Chronic Obstructive Pulmonary Disease: A Stratified, Randomized, Controlled Trial

Introduction: Chronic obstructive pulmonary disease (COPD) with eosinophilic airway inflammation represents a distinct phenotype that might respond to treatment with inhaled corticosteroids. Fractional exhaled nitric oxide (FENO) might predict eosinophilic inflammation and guide treatment option. We hypothesized that COPD patients with different baseline levels of FENO might have differentiated response to treatment with salmeterol/fluticasone (SFC) or tiotropium (TIO). Methods: This open-label, randomized-controlled trial enrolled treatment-naïve COPD patients who were stratified into high- (≥23.5ppb) and low-FENO group, followed by 12-week treatment with SFC or TIO. A linear mixed model with repeated measures was applied to analyze the changes in FENO (primary outcome), COPD assessment test (CAT) score, FEV1, and parameters in induced sputum and blood after treatment. Results: 134 patients were divided into 4 subgroups: low-FENO/SFC (n=30), low-FENO/TIO (n=29), high-FENO/SFC (n=37), and high-FENO/TIO (n=38). At baseline, FENO 23.5ppb clearly differentiated between eosinophilic and non-eosinophilic inflammation groups based on the eosinophils in induced sputum and blood. FENO significantly correlated with sputum and blood eosinophils at baseline. High-FENO/SFC (vs. high-FENO/TIO) subgroup had significant reduction in FENO and sputum inflammation profiles (including eosinophils, macrophages, matrix metalloproteinase-9, and interlukin-8) after treatment. These differences were not replicated between low-FENO/SFC and low-FENO/TIO subgroups. The improvement in CAT and FEV1 after treatment was indiscriminate between SFC and TIO in the low- and high-FENO groups. Conclusion: High baseline FENO can serve as an indicator of eosinophilic airway inflammation in COPD patients who may respond favorably to treatment with inhaled corticosteroids/long-acting β2-agonists. (AU)

Potentiality of impulse oscillometry to evaluate bronchodilator reversibility in untreated adult patients with newly diagnosed asthma.

BACKGROUND: Identifying positive bronchodilator reversibility (BDR) helps the diagnosis of asthma. However, not all patients can adequately perform the forced expiration during the spirometry test. An alternative test is required. Impulse oscillometry (IOS) is an effort-independent technique that enables the measurement of lung mechanics during quiet tidal breathing. We investigated the potentiality of IOS to evaluate BDR in untreated adult patients with newly diagnosed asthma (UAPNDS). METHODS: All UAPNDS (aged 20-80 years) who never smoke and underwent IOS and spirometry before and after salbutamol inhalation at their initial visit to the hospital from March 22, 2017, to December 31, 2019, were identified. A total of 323 patients were enrolled. Data from the medical record, including demographic characteristics, laboratory examination, spirometric data, and IOS parameters, were retrospectively reviewed. The associations of parameters with the positive BDR and the performance of parameters in predicting the positive BDR were evaluated by statistical methods. RESULTS: Patients (n = 323) had a median age of 64 years and were mostly female (67.5%). Several variables, including serum total immunoglobulin level, blood eosinophil counts, blood eosinophil percentage (%), and two IOS parameters, were found to be different between the positive (n = 93) and negative BDR (n = 230) groups. Multivariate logistic regression analyses after adjustment by cofactors revealed that the percentage change of the area under the reactance curve between 5 Hz and resonant frequency [ΔAx (%)] after salbutamol inhalation was the only independent factor for the positive BDR. The area under the receiver operating characteristic curve of ΔAx (%) in predicting the positive BDR was 0.614 ( p = 0.0013), and its optimal cutoff value was -53.8% (sensitivity, 39.78% and specificity, 80.43%). CONCLUSION: In addition to spirometry, ΔAx (%), an IOS parameter, may serve as a novel indicator to evaluate BDR in UAPNDS.

High-flow nasal cannula improves respiratory impedance evaluated by impulse oscillometry in chronic obstructive pulmonary disease patients: a randomised controlled trial.

Non-pharmacological treatment with high-flow nasal cannula (HFNC) may play a vital role in treatment of patients with chronic obstructive pulmonary disease (COPD). To evaluate the efficacy of HFNC, impulse oscillation system (IOS) is a new noninvasive technique in measuring the impedance of different portions of lungs. It shows higher sensitivity in contrast to conventional pulmonary function tests (PFT). However, whether IOS is an appropriate technique to evaluate the efficacy of HFNC in improving the impedance of small airways or peripheral lung in patients with COPD is still unclear. We enrolled 26 stable COPD participants randomised into two groups receiving HFNC or nasal cannula (NC) for 10 min followed by a 4-week washout period and crossover alternatively. IOS was used to detect the difference of respiratory impedance after HFNC or NC interventions. IOS parameters, PFT results, transcutaneous partial pressure of carbon dioxide, peripheral oxygen saturation, body temperature, respiratory rate, pulse rate, and blood pressure at the time of pre-HFNC, post-HFNC, pre-NC, and post-NC, were collected and analysed using SPSS (version 25.0, IBM, Armonk, NY, USA). The IOS measurement indicated that HFNC significantly improved R5, R5% predicted, R5-R20, X5-predicted, and Fres compared with NC, whereas no significant difference was observed through the PFT measurement. The beneficial effect of HFNC in improving small airway resistance and peripheral lung reactance compared with that of NC in patients with stable COPD was confirmed through IOS measurement.Trial registration: ClinicalTrials.gov NCT05130112 22/11/2021.

Fractional Exhaled Nitric Oxide Guided-Therapy in Chronic Obstructive Pulmonary Disease: A Stratified, Randomized, Controlled Trial.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) with eosinophilic airway inflammation represents a distinct phenotype that might respond to treatment with inhaled corticosteroids. Fractional exhaled nitric oxide (FENO) might predict eosinophilic inflammation and guide treatment option. We hypothesized that COPD patients with different baseline levels of FENO might have differentiated response to treatment with salmeterol/fluticasone (SFC) or tiotropium (TIO). METHODS: This open-label, randomized-controlled trial enrolled treatment-naïve COPD patients who were stratified into high- (≥23.5ppb) and low-FENO group, followed by 12-week treatment with SFC or TIO. A linear mixed model with repeated measures was applied to analyze the changes in FENO (primary outcome), COPD assessment test (CAT) score, FEV1, and parameters in induced sputum and blood after treatment. RESULTS: 134 patients were divided into 4 subgroups: low-FENO/SFC (n=30), low-FENO/TIO (n=29), high-FENO/SFC (n=37), and high-FENO/TIO (n=38). At baseline, FENO 23.5ppb clearly differentiated between eosinophilic and non-eosinophilic inflammation groups based on the eosinophils in induced sputum and blood. FENO significantly correlated with sputum and blood eosinophils at baseline. High-FENO/SFC (vs. high-FENO/TIO) subgroup had significant reduction in FENO and sputum inflammation profiles (including eosinophils, macrophages, matrix metalloproteinase-9, and interlukin-8) after treatment. These differences were not replicated between low-FENO/SFC and low-FENO/TIO subgroups. The improvement in CAT and FEV1 after treatment was indiscriminate between SFC and TIO in the low- and high-FENO groups. CONCLUSION: High baseline FENO can serve as an indicator of eosinophilic airway inflammation in COPD patients who may respond favorably to treatment with inhaled corticosteroids/long-acting ß2-agonists. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT02546349.

Global Variability in Administrative Approval Prescription Criteria for Biologic Therapy in Severe Asthma.

BACKGROUND: Regulatory bodies have approved five biologics for severe asthma. However, regional differences in accessibility may limit the global potential for personalized medicine. OBJECTIVE: To compare global differences in ease of access to biologics. METHODS: In April 2021, national prescription criteria for omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab were reviewed by severe asthma experts collaborating in the International Severe Asthma Registry. Outcomes (per country, per biologic) were (1) country-specific prescription criteria and (2) development of the Biologic Accessibility Score (BACS). The BACS composite score incorporates 10 prescription criteria, each with a maximum score of 10 points. Referenced to European Medicines Agency marketing authorization specifications, a higher score reflects easier access. RESULTS: Biologic prescription criteria differed substantially across 28 countries from five continents. Blood eosinophil count thresholds (usually ≥300 cells/µL) and exacerbations were key requirements for anti-IgE/anti-IL-5/5R prescriptions in around 80% of licensed countries. Most countries (40% for dupilumab to 54% for mepolizumab) require two or more moderate or severe exacerbations, whereas numbers ranged from none to four. Moreover, 0% (for reslizumab) to 21% (for omalizumab) of countries required long-term oral corticosteroid use. The BACS highlighted marked between-country differences in ease of access. For omalizumab, mepolizumab, benralizumab, and dupilumab, only two, one, four, and seven countries, respectively, scored equal or higher than the European Medicines Agency reference BACS. For reslizumab, all countries scored lower. CONCLUSIONS: Although some differences were expected in country-specific biologic prescription criteria and ease of access, the substantial differences found in the current study present a challenge to implementing precision medicine across the world.

Consensus statement and recommendations on the treatment of COVID-19: 2021 update.

Many treatments including antiviral and non-antiviral drugs, and critical care are considered for the management of coronavirus disease 2019 (COVID-19). Practice recommendations need to be updated and graded according to the critical evaluation of rapidly emerging literature. In June 2020, Research Center for Epidemic Prevention-National Yang Ming Chiao Tung University formed a task group comprising infectious disease clinicians, pulmonologists, and intensivists with varied areas of expertise. The steering committee prioritized questions and outcomes. The keywords for the searches were COVID-19 and prone position, extracorporeal membrane oxygenation (ECMO), noninvasive positive pressure ventilation (NIPPV), remdesivir, lopinavir, hydroxychloroquine/chloroquine (HCQ/CQ), azithromycin, corticosteroid, tocilizumab, convalescent plasma therapy, and intravenous immunoglobin (IVIG). A systematic review of peer-reviewed literature was performed by the consensus panel. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used in assessing the certainty of evidence and making recommendations. The effects of COVID-19 treatments on mortality and clinical improvement were summarized in 11 tables, and GRADE was presented to define the strength and quality of evidence for recommendation. The consensus recommended that prone position implanted in COVID-19 patients with hypoxic respiratory failure (IIC), careful selection for the support of ECMO (IIB), NIPPV being feasible but a risk of staff contamination (IIC), remdesivir generally administered in mild-to-moderate COVID-19 patients (IA), the use of dexamethasone in critically ill COVID-19 patients (IA), and the use of tociliziumab in hospitalized severe/critical COVID-19 patient with elevated markers of systemic inflammation (IA). The consensus recommended against the use of lopinavir/ritonavir (IB), HCQ/CQ (IA), azithromycin (IA), convalescent plasma therapy (IA), and IVIG (IA). The inception of the consensus and task group has provided much-needed evidence of the efficacy and safety of various therapies for the management of COVID-19 patients, and make a description about the benefits and harms for most treatments.

Comparing Patient Characteristics, Clinical Outcomes, and Biomarkers of Severe Asthma Patients in Taiwan.

PURPOSE: To understand the association between biomarkers and exacerbations of severe asthma in adult patients in Taiwan. MATERIALS AND METHODS: Demographic, clinical characteristics and biomarkers were retrospectively collected from the medical charts of severe asthma patients in six hospitals in Taiwan. Exacerbations were defined as those requiring asthma-specific emergency department visits/hospitalizations, or systemic steroids. Enrolled patients were divided into: (1) those with no exacerbations (non-exacerbators) and (2) those with one or more exacerbations (exacerbators). Receiver operating characteristic curves were used to determine the optimal cut-off value for biomarkers. Generalized linear models evaluated the association between exacerbation and biomarkers. RESULTS: 132 patients were enrolled in the study with 80 non-exacerbators and 52 exacerbators. There was no significant difference in demographic and clinical characteristics between the two groups. Exacerbators had significantly higher eosinophils (EOS) counts (367.8 ± 357.18 vs. 210.05 ± 175.24, p = 0.0043) compared to non-exacerbators. The optimal cut-off values were 292 for EOS counts and 19 for the Fractional exhaled Nitric Oxide (FeNO) measure. Patients with an EOS count ≥ 300 (RR = 1.88; 95% CI, 1.26-2.81; p = 0.002) or FeNO measure ≥ 20 (RR = 2.10; 95% CI, 1.05-4.18; p = 0.0356) had a significantly higher risk of exacerbation. Moreover, patients with both an EOS count ≥ 300 and FeNO measure ≥ 20 had a significantly higher risk of exacerbation than those with lower EOS count or lower FeNO measure (RR = 2.16; 95% CI, 1.47-3.18; p = < 0.0001). CONCLUSIONS: Higher EOS counts and FeNO measures were associated with increased risk of exacerbation. These biomarkers may help physicians identify patients at risk of exacerbations and personalize treatment for asthma patients.

Update on guidelines for the treatment of COPD in Taiwan using evidence and GRADE system-based recommendations.

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.

Degree of convexity calculated from expiratory flow-volume curves for identifying airway obstruction in nonsedated and nonparalyzed ventilated patients.

The predictive performance of applying the degree of convexity in expiratory flow-volume (EFV) curves to detect airway obstruction in ventilated patients has yet to be investigated. We enrolled 33 nonsedated and nonparalyzed mechanically ventilated patients and found that the degree of convexity had a significant negative correlation with FEV1% predicted. The mean degree of convexity in EFV curves in the chronic obstructive pulmonary disease (COPD) group (n = 18) was significantly higher than that in the non-COPD group (n = 15; 26.37 % ± 11.94 % vs. 17.24 % ± 10.98 %, p = 0.030) at a tidal volume of 12 mL/kg IBW. A degree of convexity in the EFV curve > 16.75 at a tidal volume of 12 mL/kg IBW effectively differentiated COPD from non-COPD (AUC = 0.700, sensitivity = 77.8 %, specificity = 53.3 %, p = 0.051). The degree of convexity calculated from EFV curves may help physicians to identify ventilated patients with airway obstruction.

Update on guidelines for the treatment of COPD in Taiwan using evidence and GRADE system-based recommendations

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.

Blood tryptase and thymic stromal lymphopoietin levels predict the risk of exacerbation in severe asthma.

Some patients with severe asthma experience exacerbations despite receiving multiple therapy. The risk of exacerbation and heterogeneous response to treatment may be associated with specific inflammatory molecules that are responsive or resistant to corticosteroids. We aimed to identify the independent factors predictive for the future risk of exacerbation in patients with severe asthma. In this multi-center prospective observational study, 132 patients with severe asthma were enrolled and divided into exacerbation (n = 52) and non-exacerbation (n = 80) groups on the basis of exacerbation rate after a 1-year follow-up period. We found that previous history of severe-to-serious exacerbation, baseline blood eosinophil counts (≥ 291cells/µL), and serum tryptase (≤ 1448 pg/mL) and thrymic stromal lymphopoietin (TSLP) levels (≥ 25 pg/mL) independently predicted the future development of exacerbation with adjusted odds ratios (AOR) of 3.27, 6.04, 2.53 and 8.67, respectively. Notably, the patients with high blood eosinophil counts and low tryptase levels were likely to have more exacerbations than those with low blood eosinophil counts and high tryptase levels (AOR 16.9). TSLP potentially played the pathogenic role across different asthma phenotypes. TSLP and tryptase levels may be implicated in steroid resistance and responsiveness in the asthma inflammatory process. High blood eosinophil counts and low serum tryptase levels predict a high probability of future asthma exacerbation.

Predictors of delayed extubation following lung resection: Focusing on preoperative pulmonary function and incentive spirometry.

BACKGROUND: Delayed extubation is one of postoperative pulmonary complications (PPCs). Preoperative pulmonary function test (PFT) is an important assessment for patients undergoing lung resection. Volume-oriented incentive spirometry (IS) is one of physiotherapies to prevent PPCs. Preoperative PFT and IS volume (IS-v) can reflect the physiologic conditions of respiratory system in patients planning to undergo lung resection. However, the relationship between preoperative PFT/IS-v and delayed extubation in patients undergoing lung resection remains unclear. The study investigated the risk factors and impact of delayed extubation after lung resection. We aimed to achieve early recognition of patients being at a higher risk for developing postoperative delayed extubation after lung resection. METHODS: This retrospective observational 4-year cohort study was conducted in a medical center, Taiwan. A total of 353 enrolled patients receiving thoracic surgery for lung resection were further categorized into the delayed extubation (n = 142, 40%) and non-delayed extubation (n = 211, 60%) groups. RESULTS: In multivariate logistic regression analyses, age >65 years (adjusted odds ratio [AOR]: 2.60; 95% confidence interval [CI], 1.52-4.45), American Society of Anesthesiologists score >2 (AOR: 1.72; 95% CI, 1.05-2.82), anesthesia time >6hrs (AOR: 1.80; 95% CI, 1.13-2.88), pneumonectomy (AOR: 5.58; 95% CI, 1.62-19.19), and IS-v/inspiratory capacity (IC) ratio (AOR: 2.07; 95% CI, 1.16-3.68) were associated with delayed extubation after lung resection (all p < 0.05). Patients with delayed extubation were significantly associated with a higher proportion of other pulmonary complications, reintubation, mortality, and prolonged intensive care unit and hospital stays. CONCLUSION: Older age, poor general health status, longer anesthesia time, pneumonectomy, and IS-v/IC ratio could be the independent factors predictive for delayed extubation after lung resection, which was in turn associated with worse outcomes. Preoperative PFT and IS-v were valuable for early recognition of patients being at a higher risk for developing postoperative delayed extubation after lung resection.

Epidemiologic Analysis of Taiwanese Patients with Idiopathic Pulmonary Fibrosis.

Several databases of epidemiologic studies in patients with idiopathic pulmonary fibrosis (IPF) have been analyzed in the Western community. However, few studies have been reported in Asia. The objective of this study was to investigate the epidemiology of IPF in Taiwan. We collected and analyzed patients with IPF from the Taiwan National Health Insurance Research Database from 2001 to 2011. We estimated the annual incidence and cumulative prevalence of IPF and mean survival time of patients and determined the causes of death. The annual incidence rates of IPF remained stable after 2005, ranging from 0.7 to 1.3 cases per 100,000 people per year, whereas the cumulative prevalence rates increased steadily from 3.1 to 6.4 cases per 100,000 people per year during 2006-2011 based on a narrow case definition. Men older than 75 years had higher incidence compared with other age groups. The mean survival after diagnosis was 6.9 years. Old age, male sex, and respiratory hospitalization were associated with shorter survival time after diagnosis. Both the incidence and prevalence rates of IPF were lower in Taiwanese patients than Western ones. Moreover, the survival time was higher in the Asian population compared with the Western population. These results may suggest the heterogeneity of the IPF definition in different study populations and geographic locations.

Lung Epithelial TRPA1 Mediates Lipopolysaccharide-Induced Lung Inflammation in Bronchial Epithelial Cells and Mice.

Toll-like receptor (TLR) 4 was originally thought to be the sole pattern recognition receptor for lipopolysaccharide (LPS). Transient receptor potential ankyrin 1 (TRPA1), a Ca2+-permeant channel, has been suggested as a non-TLR receptor membrane-bound sensor of LPS. We recently reported that TRPA1 is expressed in lung epithelial cells (LECs) and mediates lung inflammation induced by cigarette smoke. However, the role of TRPA1 in LPS-induced lung inflammation has not been conclusively defined, and its underlying cellular mechanisms remain unclear. In this study, our in vitro results showed that LPS sequentially produced a cascade of events, including the elevation of intracellular Ca2+, the activation of NADPH oxidase, increase in intracellular reactive oxygen species (ROS), the activation of mitogen-activated protein kinase (MAPK)/nuclear factor-kB (NF-κB) signaling, and the induction of IL-8. The increase in intracellular Ca2+ was inhibited by HC030031 (a TRPA1 antagonist) but was unaffected by TAK-242 (a TLR-4 inhibitor). The activation of NADPH oxidase was prevented by its inhibitor apocynin, EGTA (an extracellular Ca2+ chelator), and HC030031. The increase in intracellular ROS was attenuated by apocynin, N-acetyl-cysteine (NAC, a ROS scavenger), EGTA, and HC030031. The activation of the MAPK/NF-κB signaling was halted by NAC, EGTA, and HC030031. IL-8 induction was suppressed by HC030031 and TRPA1 siRNA, and further reduced by the combination of HC030031 and TAK-242. Our in vivo studies showed that trpa1-/- mice exhibited a reduced level of LPS-induced lung inflammation compared with wild-type mice as evidenced by the alleviations of increases in vascular permeability, inflammatory cell infiltration, inflammatory cytokine levels, oxidative stress, and MAPK signaling activation. Thus, in LECs, LPS may activate TRPA1 resulting in an increase in Ca2+ influx. The increased intracellular Ca2+ leads to NADPH oxidase activation, which causes an increase in intracellular ROS. The intracellular ROS activates the MAPK/NF-κB signaling resulting in IL-8 induction. This mechanism may possibly be at work to induce lung inflammation in mice.

Functional parameters of small airways can guide bronchodilator use in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) may present comorbid obstructive lung diseases with small airway dysfunction (SAD). Existing guidelines suggest that inhaled bronchodilators should be used if the ratio of forced expiratory volume in the 1st second and forced vital capacity (FEV1/FVC) < 0.7 in IPF. However, most IPF patients have FEV1/FVC > 0.7 even with coexisting emphysema. We retrospectively enrolled IPF patients who were registered at our outpatient clinic. At baseline, 63 patients completed computed tomography (CT) scans, lung function measurements, and symptom questionnaires. Among these patients, 54 (85.71%) underwent antifibrotic treatment and 38 (60.32%) underwent long-acting bronchodilator treatment. The median FEV1/FVC was 0.86. Not all patients treated with bronchodilators showed significant changes in lung function. IPF patients with SAD, determined by IOS parameters, showed significant improvement in FEV1, FEF25-75%, and symptom scores after bronchodilator treatment. Bronchodilator efficacy was not observed in patients without SAD. CT-confirmed emphysema was seen in 34.92% of patients. There were no changes in lung function or symptom scores after bronchodilator treatment in patients with emphysema. In conclusion, FEV1/FVC cannot reflect the airflow limitation in IPF. Emphysema in IPF is not a deciding factor in whether patients should receive bronchodilator treatment. IOS parameters may be useful to guide bronchodilator therapy in patients with IPF coexisting with SAD.