Long COVID symptoms after 8-month recovery: persistent static lung hyperinflation associated with small airway dysfunction.

BACKGROUND: Limited research has investigated the relationship between small airway dysfunction (SAD) and static lung hyperinflation (SLH) in patients with post-acute sequelae of COVID-19 (PASC) especially dyspnea and fatigue. METHODS: 64 patients with PASC were enrolled between July 2020 and December 2022 in a prospective observational cohort. Pulmonary function tests, impulse oscillometry (IOS), and symptom questionnaires were performed two, five and eight months after acute infection. Multivariable logistic regression models were used to test the association between SLH and patient-reported outcomes. RESULTS: SLH prevalence was 53.1% (34/64), irrespective of COVID-19 severity. IOS parameters and circulating CD4/CD8 T-cell ratio were significantly correlated with residual volume to total lung capacity ratio (RV/TLC). Serum CD8 + T cell count was negatively correlated with forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) with statistical significance. Of the patients who had SLH at baseline, 57% continued to have persistent SLH after eight months of recovery, with these patients tending to be older and having dyspnea and fatigue. Post-COVID dyspnea was significantly associated with SLH and IOS parameters R5-R20, and AX with adjusted odds ratios 12.4, 12.8 and 7.6 respectively. SLH was also significantly associated with fatigue. CONCLUSION: SAD and a decreased serum CD4/CD8 ratio were associated with SLH in patients with PASC. SLH may persist after recovery from infection in a substantial proportion of patients. SAD and dysregulated T-cell immune response correlated with SLH may contribute to the development of dyspnea and fatigue in patients with PASC.

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.

Mouth opening/breathing is common in sleep apnea and linked to more nocturnal water loss.

BACKGROUND: Mouth opening/breathing during sleep is common in patients with obstructive sleep apnea (OSA), which is probably associated with more water loss and higher risk for nocturnal ischemic heart attack. This study aimed to evaluate nocturnal changes in hematocrit/hemoglobin levels and estimated plasma volume loss in OSA patients and its relation to their OSA severity and mouth open/breathing. METHODS: Sixty OSA patients and fifteen healthy controls were enrolled and underwent overnight polysomnography. Mouth status was evaluated via an infrared camera and nasal/mouth airflow. Hematocrit and hemoglobin levels in peripheral venous blood were measured before and after sleep to estimate the change of plasma volume. RESULTS: Compared to controls, OSA patients had a greater nocturnal increase in hematocrit (1.35% vs. 1.0%, p = 0.013), hemoglobin (0.50% vs. 0.30%, p = 0.002) and more estimated water loss (5.5% vs 3.7% of plasma volume, p < 0.013). The extent of increase was correlated to apnea-hypopnea index (AHI)_the marker of OSA severity (Spearman's ρ = 0.332, p = 0.004; ρ = 0.367, p = 0.001 for hematocrit, hemoglobin, respectively), which remained significant after serial multivariate adjustment. OSA patients had more sleep time with mouth open (96.7% vs 26.7% of total sleep time, p < 0.001) and time with complete mouth breathing (14.1% vs 2.7%, p < 0.001). The extent of mouth breathing was correlated to AHI (ρ=0.487, p < 0.001), nocturnal increase in hematocrit/hemoglobin levels (ρ = 0.236, p = 0.042; ρ = 0.304, p = 0.008, respectively) and estimated plasma volume loss (ρ = 0.262, p = 0.023). CONCLUSION: OSA patients had a greater increase in hematocrit/hemoglobin levels after sleep, which is probably linked to more water loss and more sleep time with mouth open/breathing.

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.

Obstructive sleep apnea in young Asian adults with sleep-related complaints.

This study aimed to investigate the proportion of young OSA adults with sleep-related complaints in a sleep center, affiliated with a tertiary medical center for over a decade. This study presents a chronicle change in the numbers of young adults receiving polysomnography (PSG) and young patients with OSA from 2000 to 2017. We further analyzed 371 young patients with OSA among 2378 patients receiving PSG in our sleep center from 2016 to 2017 to capture their characteristics. Young adults constituted a substantial and relatively steady portion of examinees of PSG (25.1% ± 2.8%) and confirmed OSA cases (19.8 ± 2.4%) even though the total numbers increased with the years. Young adults with OSA tend to be sleepier, have a greater body mass index, and have a higher percentage of cigarette smoking and alcohol consumption. They also complained more about snoring and daytime sleepiness. They had a higher apnea-hypopnea index on average and experienced more hypoxemia during their sleep, both in terms of duration and the extent of desaturation. Even though the prevalence of comorbidities increased with age, hypertension in young male adults carried higher risks for OSA. Young adults with OSA have constituted a relatively constant portion of all confirmed OSA cases across time. The young adults with OSA were heavier, more symptomatic, and with more severe severity.Clinical trial: The Institutional Review Board of Taipei Veterans General Hospital approved the study (VGHIRB No. 2018-10-002CC). The study is registered with ClinicalTrials.gov, number NCT03885440.

Clinical Characteristics of Rapid Eye Movement-Related Obstructive Sleep Apnea: An Experience in a Tertiary Medical Center of Taiwan.

Purpose: Obstructive sleep apnea (OSA) is characterized by intermittent hypoxemia and sleep fragmentation. While apnea is pronounced with severe desaturation during rapid eye movement (REM) sleep, REM-related OSA is a distinct phenotype of OSA associated with respiratory disturbances predominantly during REM sleep. In this study, we investigated the clinical features of REM-related OSA in Taiwan. Patients and Methods: All patients diagnosed with OSA in the Taipei Veterans General Hospital from 2015 to 2017 were analyzed retrospectively and classified into REM-related OSA (REM-OSA) group, non-REM related OSA (NREM-OSA) group, and non-stage specific-OSA group. The clinical demographics, OSA-related symptoms, polysomnography results, and medical comorbidities of the three groups were analyzed. Results: Among 1331 patients with OSA, 414 (31.1%) were classified as REM-OSA, 808 (60.7%) as NREM-OSA, and 109 (8.2%) as non-stage specific-OSA. After being adjusted for OSA severity, the REM-OSA group was associated with less portion of males, longer desaturation duration, and lower nadir oxygen saturation (SpO2) compared with the NREM-OSA group in mild and moderate OSA. In moderate OSA, the non-stage specific-OSA group featured more OSA severity and more desaturation compared with the other groups. The Epworth Sleepiness Scale scores and the prevalence of comorbidities did not vary among the REM-OSA, NREM-OSA, and non-stage specific-OSA groups. High REM-AHI/NREM-AHI ratio was associated with young age, female gender, high BMI, and low AHI. Conclusion: OSA patients with high REM-AHI/NREM-AHI ratio are related to young age, female gender, high BMI, and low AHI. Patients with REM-related OSA presented with longer desaturation duration and lower nadir SpO2 after being adjusted for OSA severity.

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.

Acute-on-chronic pancreatitis complicated with mediastinal pseudocysts and cardiac tamponade: A case report and literature review.

The clinical course and severity of pancreatitis might vary largely. Pancreatitis-related thoracic complications might be life-threatening but frequently ignored. We report an alcoholic patient who initially presented to the emergency department with community-acquired pneumonia, acute respiratory failure and acute-on-chronic pancreatitis with massive pancreatic pleural effusion. Subsequently, he developed insidiously pancreatitis-related intra-abdominal, mediastinal pseudocysts, and unexpectedly sudden onset of cardiac tamponade. Although tamponade-related haemodynamic instability improved soon after timely diagnosis and emergent pericardial drainage, his recovery period was prolonged. His serum amylase and lipase were persistently elevated until definitive treatment with endoscopic retrograde cholangiopancreatography-assisted removal of pancreatic duct stones. Pancreatitis-related cardiac tamponade is rare but lethal without prompt diagnosis and management. We reviewed pancreatitis-related thoracic complications, particularly for cardiac tamponade, and discussed about the pathophysiology and management options.

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.

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.

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.

Independent risk factors for death in patients admitted for asthma exacerbation in Taiwan.

The independent risk factors for death in patients admitted for asthma exacerbation have not been thoroughly investigated. This study aimed to investigate these independent risk factors and the relationship between mortality and the prescription patterns of anti-asthmatic medications in patients admitted for asthma exacerbation. Using a nested case-control design, we identified 267 cases (death after asthma admission) and 1035 controls (survival after asthma admission) from the Taiwan National Health Insurance Research Database (NHIRD) from 2001 to 2010. Conditional logistic regressions were used to estimate the odds ratios (ORs) with 95% confidence intervals (CIs). We identified the independent risk factors for death as the comorbidities of pneumonia (aOR 3.82, 95% CI 2.41-6.05), genitourinary disease (aOR 1.75, 95% CI 1.17-2.62), septicemia (aOR 4.26, 95% CI 2.61-6.94), diabetes mellitus (aOR 2.10, 95% CI 1.30-3.38), arrhythmia (aOR 2.00, 95% CI 1.14-3.50), and a history of asthmatic hospitalization (aOR 4.48, 95% CI 2.77-7.25). Moreover, the use of short-acting ß2-agonist (SABA) and the dosage of oral corticosteroids (OCSs) >70 mg prednisolone during previous hospitalization (all p < 0.05) and the dosage of OCSs ≥110 mg prednisolone/month (aOR 2.21, 95% CI 1.08-4.50) during outpatient treatment independently increased the risk of death. The inhaled corticosteroids (ICSs) ≥4 canisters/year (aOR 0.39, 95% CI 0.19-0.78) independently reduced the risk of death. Specific comorbidities, asthma severity, and prescription patterns of SABA, OCSs, and ICSs were independently associated with mortality in patients admitted for asthma exacerbation. These results can be utilized to help physicians identify asthmatic patients who are at a higher mortality risk and to refine the management of the condition.

Small Airway Dysfunction by Impulse Oscillometry in Symptomatic Patients with Preserved Pulmonary Function.

BACKGROUND: Asthma and chronic obstructive pulmonary disease are characterized by persistent airway inflammation and airflow limitation. Early detection of these diseases in patients with respiratory symptoms and preserved pulmonary function (PPF) defined by spirometry is difficult. Impulse oscillometry (IOS) may have better sensitivity than effort-dependent forced expiratory flow between 25% and 75% (FEF25%-75%) to detect small airway dysfunction (SAD). OBJECTIVE: To identify SAD in patients with respiratory symptoms and PPF using IOS. METHODS: Medical records of symptomatic patients without acute or known structural lung diseases were evaluated. Patients had bronchodilator testing and IOS in the outpatient clinic between March 1 and July 31, 2017. Correlations between respiratory symptoms, spirometry, and IOS parameters were determined. RESULTS: Among 349 patients enrolled to the study, 255 (73.1%) patients met the criteria of PPF. The IOS parameters-difference in resistance at 5 Hz and resistance at 20 Hz , reactance at 5 Hz, resonant frequency (Fres), and area under reactance curve between 5 Hz and resonant frequency-were significantly correlated with FEF25%-75%. The cutoffs for SAD were difference in resistance at 5 Hz and resistance at 20 Hz greater than 0.07 kPa/(L/s), reactance at 5 Hz less than -0.12 kPa/(L/s), Fres greater than 14.14 Hz, and area under reactance curve between 5 Hz and resonant frequency greater than 0.44 kPa/L. Of the IOS parameters, Fres and reactance at 5 Hz had the highest sensitivity and specificity. When compared with FEF25%-75%, Fres had greater sensitivity to detect SAD in patients with PPF. Patients with IOS-defined SAD had a significantly higher incidence of wheeze or sputum production than did those defined by FEF25%-75%. CONCLUSIONS: Patients with respiratory symptoms and PPF may have SAD, which can be identified with the aid of IOS in addition to spirometry.

Independent factors associate with hospital mortality in patients with acute exacerbation of chronic obstructive pulmonary disease requiring intensive care unit admission: Focusing on the eosinophil-to-neutrophil ratio.

BACKGROUND: Factors associated with hospital mortality are unclear in patients with acute exacerbation of COPD (AECOPD) requiring intensive care unit (ICU) admission. We aimed to characterize these patients and identify factors associated with hospital mortality. PATIENTS AND METHODS: We used a retrospective observational case-control design and recruited patients between January 2015 and March 2017. Of 146 patients enrolled, 24 (16.4%) died during their hospital stay, while 122 survived. RESULTS: Multivariate logistic regression analyses revealed factors associated with hospital mortality: age (adjusted odds ratio [AOR] 1.12, 95% CI: 1.03-1.23), C-reactive protein (CRP) level >7.5 mg/dL at the emergency room (AOR 4.52, 95% CI: 1.27-16.04), peak eosinophil-to-neutrophil ratio (ENR)×102 on days 8-14 of treatment (AOR 0.22, 95% CI: 0.08-0.63), and in-hospital complications (AOR 4.23, 95% CI: 1.12-15.98) (all P<0.05). After receiver operating characteristic curve analyses, cutoff level for peak ENR×102 was 0.224. To examine the synergistic effects of CRP level and peak ENR, we divided patients into four groups: (G0, reference group) Peak ENR×102 >0.224 on days 8-14 and initial CRP <7.5 mg/dL; (G1) Peak ENR×102 >0.224 on days 8-14 and initial CRP >7.5 mg/dL; (G2) Peak ENR×102 <0.224 on days 8-14 and initial CRP <7.5 mg/dL; and (G3) Peak ENR×102 <0.224 on days 8-14 and initial CRP >7.5 mg/dL. For G2 and G3 patients, the AOR of mortality was significantly different from that of the reference group (G2: AOR 10.00, P = 0.020; G3: AOR 61.79, P<0.001). The relationship between 28-day mortality and the four groups was statistically significant (log-rank test, P<0.001). CONCLUSION: Older age, initial CRP >7.5 mg/dL, peak ENR on days 8-14, and in-hospital complications were associated with hospital mortality in patients with AECOPD requiring ICU admission. Patients with both biomarkers, initial CRP >7.5 mg/dL, and peak ENR×102 <0.224 on days 8-14 of treatment, had an increased risk of hospital mortality.

Real-world effectiveness of medications on survival in patients with COPD-heart failure overlap.

The appropriate treatment for patients with coexistent chronic obstructive pulmonary disease (COPD) and heart failure (HF) remains unclear. Data from the Taiwan National Health Insurance Research Database was used for this retrospective cohort study. Patients diagnosed with both diseases between 1997 and 2012 were enrolled as the COPD-heart failure overlap cohort. Patients were categorized as non-users and users of specific COPD and HF medications. Medication prescriptions in each 3-month and 1-year period served as time-dependent covariates. The primary endpoint was cumulative survival. The validation study confirmed the accuracy of definitions of COPD (94.0% sensitivity) and HF (96.3% sensitivity).The study included 275,436 patients with COPD-heart failure overlap, with a mean follow-up period of 9.32 years. The COPD-heart failure overlap cohort had more medical service use and higher mortality than did the COPD alone cohort. Use of inhaled corticosteroid (ICS)/long-acting ß2 agonist (LABA) combinations, long-acting muscarinic antagonist (LAMA), angiotensin receptor blockers (ARBs), ß blockers, aldosterone antagonists, and statins reduced mortality risk compared with non-use. Sensitivity and subgroup analyses confirmed the consistency and robustness of results.ICS/LABA combinations, LAMA, ARBs, ß blockers, aldosterone antagonists, and statins use was associated with a lower mortality risk in patients with COPD-heart failure overlap.

Long-acting muscarinic antagonist versus long-acting ß2 agonist/corticosteroid for moderate to severe chronic obstructive pulmonary disease patients: Exacerbation risk assessment.

BACKGROUND: Whether the beneficial effects of long-acting muscarinic antagonists (LAMA) are better than those of long-acting ß2 agonist/corticosteroids (LABA/ICS) in preventing exacerbations in chronic obstructive pulmonary disease (COPD) remains unclear. This study aimed to assess the risk of exacerbations in moderate to severe COPD patients receiving LAMA versus LABA/ICS. METHODS: We retrospectively reviewed the medical records of patients diagnosed with COPD (2008-2010). The inclusion criteria were age ≥ 40 years, forced expiratory volume in 1 second (FEV1) 30% to 80% of predicted value and at least three prescriptions for COPD medication, including LAMA or LABA/ICS. RESULTS: Of the 557 COPD patients screened, 90 patients were enrolled in the analysis. The demographic characteristics of patients receiving LABA/ICS or LAMA were similar. The all exacerbation rates was significantly higher in patients with global initiative for chronic obstructive lung disease stage II COPD treated with LABA/ICS than in those treated with LAMA (p = 0.001), regardless of previous exacerbation history. Patients with previous exacerbation history showed an independent increase in the risk of moderate or severe exacerbation compared with those without exacerbation history (hazard ratio 3.86, 95% CI 1.75-8.53, p = 0.001). CONCLUSION: In comparison with LABA/ICS, LAMA is beneficial in reducing exacerbation risk for moderate COPD. Previous exacerbation history independently predicts the future risk of exacerbation regardless of treatment.