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.

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

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

Spectrum of cancer risk among Taiwanese with chronic obstructive pulmonary disease.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) are liable to develop significant comorbidities, including lung cancer. Whether they are at a higher risk for cancer of other types remains debatable, especially for Asians. We studied the risk of incident cancer in COPD patients using a nationwide representative database, the Taiwan National Health Insurance Research Database. METHODS: From 1995 to 2008, 50,875 COPD patients who were free of antecedent malignancy were identified and followed up to development of malignancy, death or end of 2008, whichever came first. The risk of cancer was determined with the standardized incidence ratio (SIR), which is based on comparison to the national cancer incidence among the general population. RESULTS: During a median follow-up period of 5.61 years, 3623 (7.02 %) patients developed cancer and the SIR was 1.2 [95 % confidence interval (CI) 1.16-1.24, p < 0.001]. The risk remained higher at <1, 1-5, and even ≥5 years after the diagnosis of COPD (SIR 1.83, 1.07, and 1.11, respectively). Furthermore, the risk was significantly higher for some specific types of cancer, including head and neck cancer (SIR 1.23, 95 % CI 1.08-1.39, p = 0.002), esophageal cancer (SIR 1.35, 95 % CI 1.08-1.67, p = 0.010), lung and mediastinal cancer (SIR 1.86, 95 % CI 1.74-1.99, p < 0.001), breast cancer (SIR 1.19, 95 % CI 1.01-1.4, p = 0.041), prostate cancer (SIR 1.20, 95 % CI 1.06-1.35, p < 0.001), cancer of the central nervous system (SIR 1.58, 95 % CI 1.05-2.28, p = 0.030), lymphoma (SIR 1.53, 95 % CI 1.22-1.90, p < 0.001), and multiple myeloma (SIR 1.95, 95 % CI 1.31-2.80, p = 0.001). CONCLUSION: COPD patients had increased risk for incident cancers, including lung cancer and several extrapulmonary cancers.

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

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

Exhaled nitric oxide predicts eosinophilic airway inflammation in COPD.

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

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

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

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

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

The 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.

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.

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

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

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.

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.

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.

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.

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.

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.

The roles of transforming growth factor-ß1 and vascular endothelial growth factor in the tracheal granulation formation.

BACKGROUND: Acquired tracheal stenosis is common in patients with a long-term tracheostomy and granulation is one of the most commonly observed lesions in benign airway stenosis. The aim of this study was to investigate the mechanisms of tracheal granulation formation and find the potential therapeutic targets to prevent the granulation formation. RESULTS: In granulation tissue obtained from patients during interventional bronchoscopy for the relief of airway obstruction, increased expression of transforming growth factor (TGF)-ß1 and vascular endothelial growth factor (VEGF), as well as increased numbers of fibroblasts, was found by immunohistochemical staining. TGF-ß1 expression was detected in both the epithelial and submucosal layers. The highest levels of VEGF and vimentin expression occurred in the submucosal layers. In comparison with the control, significantly increased numbers of small vessels were observed in the submucosal layers of the granulation tissue. In vitro, TGF-ß1 stimulated production of VEGF by cultured fibroblasts at both the mRNA and protein level. VEGF siRNA treatment resulted in a significant decrease of TGF-ß1-induced VEGF production. SIS3, a selective Smad3 inhibitor, and UO126 both inhibited p44/42 MAP kinase phosphorylation and attenuated subsequent VEGF production by fibroblasts. A low concentration of erythromycin (1 µg/ml), but not dexamethasone (100 µM), inhibited TGF-ß1-induced VEGF production. CONCLUSION: This study provides important information that facilitates an understanding, at least in part, of the mechanisms of granulation formation. Targeting these mediators and cells may help to prevent the formation of granulation tissue in long-term tracheostomy or prolonged endotracheal intubation patients.

The minimum period of polysomnography required to confirm a diagnosis of severe obstructive sleep apnoea.

BACKGROUND AND OBJECTIVE: To combine the diagnosis of OSA with titration of positive airway pressure (PAP), current guidelines recommend that split-night polysomnography (PSG) be performed if an AHI of ≥40/h is recorded over 2h. However, the diagnostic validity of partial-night PSG is uncertain. This study aimed to test the validity of partial-night PSG and to determine the optimum AHI cut-off points. METHODS: Patients who visited the sleep centre at a tertiary medical centre between January and December 2008, for symptoms related to sleep disorders (sleepiness, snoring, sleep disturbance), and who completed full-night PSG, were evaluated for this study. Full-night PSG data were processed to obtain partial-night PSG data, from which AHI were computed as a reference for diagnosing severe OSA. Full-night and partial-night PSG data obtained over different recording times (expressed as x-h PSG, where xONL001831140 =1-6) were compared using receiver operating characteristic (ROC) curve analysis. The diagnostic validity of 2-h PSG with different AHI cut-off points (25/h to 45/h) was also calculated. RESULTS: Data from 198 PSG recordings was processed. For 2-h PSG, an AHI cut-off point of 30/h gave the highest accuracy of 90.9%. Comparing areas under the ROC curves (AUC), 2-h PSG (AUC=0.97) was as good as 2.5-h PSG (AUC=0.977, P=0.057) and 3-h PSG (AUC=0.978, P=0.125), but was better than 1.5-h PSG (AUC=0.955, P=0.016). CONCLUSIONS: Partial-night PSG is effective for diagnosing severe OSA. If there is an unabridged PSG recording indicating an AHI of ≥30/h for 2h, severe OSA can be diagnosed and PAP titration initiated.