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.

Using Machine Learning with Impulse Oscillometry Data to Develop a Predictive Model for Chronic Obstructive Pulmonary Disease and Asthma.

We aimed to develop and validate a machine learning model using impulse oscillometry system (IOS) profiles for accurately classifying patients into three assessment-based categories: no airflow obstruction, asthma, and chronic obstructive pulmonary disease (COPD). Our research questions were as follows: (1) Can machine learning methods accurately classify obstructive disease states based solely on multidimensional IOS data? (2) Which IOS parameters and modeling algorithms provide the best discrimination? We used data for 480 patients (240 with COPD and 240 with asthma) and 84 healthy individuals for training. Physiological and IOS parameters were combined into six feature combinations. The classification algorithms tested were logistic regression, random forest, neural network, k-nearest neighbor, and support vector machine. The optimal feature combination for identifying individuals without pulmonary obstruction, with asthma, or with COPD included 15 IOS and physiological features. The neural network classifier achieved the highest accuracy (0.786). For discriminating between healthy and unhealthy individuals, two combinations of twenty-three features performed best in the neural network algorithm (accuracy of 0.929). When distinguishing COPD from asthma, the best combination included 15 features and the neural network algorithm achieved an accuracy of 0.854. This study provides compelling technical evidence and clinical justifications for advancing IOS data-driven models to aid in COPD and asthma management.

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.

Pulse corticosteroid therapy in the treatment of steroid-refractory immune checkpoint inhibitor-related pneumonitis: Case report and review.

Immune checkpoint inhibitors (ICIs) have demonstrated promising therapeutic outcomes in treating a variety of malignancies, but immune-related adverse events (irAE) may develop. Among all the irAE, immune-related pneumonitis was relatively common and life-threatening. High-dose corticosteroid was recommended for the initial management, but a part of patients developed steroid-refractory pneumonitis. Other immunosuppressants were recommended, but the optimal treatment is still controversial. Here, we report two cases of steroid-refractory immune-related pneumonitis who were successfully treated with pulse corticosteroid therapy. Case 1 was hepatocellular carcinoma treated with nivolumab for 5 months. She developed acute respiratory distress syndrome due to grade 4 immune-related pneumonitis that was refractory to intravenous methylprednisolone 2 mg/kg/day treatment. Methylprednisolone 500 mg for 3 days followed by 2 mg/kg/day steroid as maintenance therapy was given. Subsequently, her pneumonitis was regressed, and the endotracheal tube was successfully removed on day 9 after the start of pulse therapy. Case 2 presented with grade 4 immune-related pneumonitis in spite the use of methylprednisolone 1 mg/kg for his skin rash. Pulse corticosteroid therapy was prescribed, then his pneumonitis was completely regressed on day 12. In this report, we demonstrated the potential role of pulse corticosteroid therapy for steroid-refractory pneumonitis.

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.

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.

The clinical manifestations and interval changes of reverse-transcriptase quantitative polymerase chain reactions among different specimens of coronavirus disease 2019 patients.

BACKGROUND: Since December 2019, a number of cases and deaths due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic have been reported worldwide. In spite of clinical manifestations similar to the SARS-CoV epidemic in 2003, affected organs and severity are yet to be defined. Moreover, viral load alterations and viral shielding among different specimens remained scarce. Therefore, clarifying clinical presentations and correlations among viral loads, disease severity, and viral shielding of SARS-CoV-2 infection is crucial in the disease prevention. METHODS: The clinical courses of SARS-CoV-2 cases were presented through Gantt charts. Laboratory examinations and reverse-transcriptase quantitative polymerase chain reactions (RT-qPCR) among different specimens were tested periodically. Cycle thresholds (CT) were recorded and presented as viral loads. RESULTS: From March 2020 to April 2020, 4 SARS-CoV-2 cases were presented, of which, cases 1 and 2 manifested the symptoms severer than cases 3 and 4, along with higher serum lactate dehydrogenase levels and graded for lymphocytopenia. Case 4 initially exhibited anosmia but recovered within a short period. Curves of the CT of all the cases, except case 2, concaved upward after prescribing hydroxychloroquine (HCQ) and azithromycin. Except for case 4, the CT in most stool specimens remained undetectable; however, none of the cases presented gastrointestinal symptoms. Surprisingly, the CT values of the saliva specimens were inconsistent with those of the nasopharyngeal swabs and sputum. CONCLUSION: SARS-CoV-2 manifests various symptoms. Sudden onset of central nervous system symptoms should be considered. The timing of HCQ and azithromycin administration might be a key factor in the viral load reduction. Positive prediction values of RT-qPCR of different specimens should be tested carefully to prevent false-negative results.

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.

Using lung ultrasound changes to evaluate the response of recruitment maneuver in a patient recovering from coronavirus disease 2019 with acute respiratory distress syndrome.

Lung ultrasound (LUS) is widely used in intensive care units because it provides timely information noninvasively. The use of LUS is recommended to minimize transfers in critically ill patients with coronavirus disease 2019 (COVID-19) during the pandemic. The clinical efficacies of bedside chest X-ray (CXR) and LUS have not been compared in these patients. Herein, we demonstrated serial LUS changes in a 75-year-old woman recovering from COVID-19 with acute respiratory distress syndrome (ARDS) in need of veno-venous extracorporeal membrane oxygenation support. LUS initially revealed extensive consolidation in the bilateral lower lung (BLL) fields with coalescent B-lines. While the patient recovered from ARDS, the findings gradually changed to discrete B-lines and small pleural consolidations. The LUS findings were more sensitive than those of the CXR in detecting re-expansion of the lungs by showing B-lines instead of consolidations in the BLL fields immediately after recruitment maneuver (RM). Compared with physiological parameters, LUS findings provided more precise information about the parts of the lungs that had been recruited by RM. Therefore, we encourage intensivists to extend their use of LUS in critically ill patients with COVID-19 and ARDS to acquire real-time information for a quick response and minimize the risk of viral transmission.

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.

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.

An accurate prediction model to identify undiagnosed at-risk patients with COPD: a cross-sectional case-finding study.

Underuse or unavailability of spirometry is one of the most important factors causing underdiagnosis of COPD. We reported the development of a COPD prediction model to identify at-risk, undiagnosed COPD patients when spirometry was unavailable. This cross-sectional study enrolled subjects aged ≥40 years with respiratory symptoms and a smoking history (≥20 pack-years) in a medical center in two separate periods (development and validation cohorts). All subjects completed COPD assessment test (CAT), peak expiratory flow rate (PEFR) measurement, and confirmatory spirometry. A binary logistic model with calibration (Hosmer-Lemeshow test) and discrimination (area under receiver operating characteristic curve [AUROC]) was implemented. Three hundred and one subjects (development cohort) completed the study, including non-COPD (154, 51.2%) and COPD cases (147; stage I, 27.2%; II, 55.8%; III-IV, 17%). Compared with non-COPD and GOLD I cases, GOLD II-IV patients exhibited significantly higher CAT scores and lower lung function, and were considered clinically significant for COPD. Four independent variables (age, smoking pack-years, CAT score, and percent predicted PEFR) were incorporated developing the prediction model, which estimated the COPD probability (PCOPD). This model demonstrated favorable discrimination (AUROC: 0.866/0.828; 95% CI 0.825-0.906/0.751-0.904) and calibration (Hosmer-Lemeshow P = 0.332/0.668) for the development and validation cohorts, respectively. Bootstrap validation with 1000 replicates yielded an AUROC of 0.866 (95% CI 0.821-0.905). A PCOPD of ≥0.65 identified COPD patients with high specificity (90%) and a large proportion (91.4%) of patients with clinically significant COPD (development cohort). Our prediction model can help physicians effectively identify at-risk, undiagnosed COPD patients for further diagnostic evaluation and timely treatment when spirometry is unavailable.

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

Sleep disorders and an increased risk of Parkinson's disease in individuals with non-apnea sleep disorders: a population-based cohort study.

Sleep disorders are common non-motor symptoms in patients with Parkinson's disease. Our study aims to explore the relationship between non-apnea sleep disorders and future Parkinson's disease. This is a cohort study using a nationwide database. The participants were recruited from the Taiwan National Health Insurance Research Database between 2000 and 2003. A total of 91 273 adult patients who had non-apnea sleep disorders without pre-existing Parkinson's disease were enrolled. An age-, gender-, income-, urbanization- and Charlson comorbidity index score-matched control cohort consisting of 91 273 participants was selected for comparison. The two cohorts were followed for the occurrence of Parkinson's disease, death or until the end of 2010, whichever came first. The Kaplan-Meier analyses revealed patients with non-apnea sleep disorders tended to develop Parkinson's disease (log-rank test, P < 0.001). After a multivariate adjustment in a Cox regression model, non-apnea sleep disorders was an independent risk factor for the development of Parkinson's disease [crude hazard ratio: 1.63, 95% confidence interval (CI): 1.54-1.73, P < 0.001; adjusted hazard ratio: 1.18, 95% CI: 1.11-1.26, P < 0.001]. In the subgroup analysis, patients with chronic insomnia (lasting more than 3 months) had the greatest risk (crude hazard ratio: 2.91, 95% CI: 2.59-3.26, P < 0.001; adjusted hazard ratio: 1.37, 95% CI: 1.21-1.55, P < 0.001). In conclusion, this study revealed that non-apnea sleep disorders, especially chronic insomnia, are associated with a higher risk for future Parkinson's disease.