LRG1 promotes the apoptosis of pulmonary microvascular endothelial cells through KLK10 in chronic obstructive pulmonary disease.

INTRODUCTION: Cigarette smoking is one of the most important causes of COPD and could induce the apoptosis of pulmonary microvascular endothelial cells (PMVECs). The conditional knockout of LRG1 from endothelial cells reduced emphysema in mice. However, the mechanism of the deletion of LRG1 from endothelial cells rescued by cigarette smoke (CS) induced emphysema remains unclear. This research aimed to demonstrate whether LRG1 promotes the apoptosis of PMVECs through KLK10 in COPD. METHODS: Nineteen patients were divided into three groups: control non-COPD (n=7), smoker non-COPD (n=7), and COPD (n=5). The emphysema mouse model defined as the CS exposure group was induced by CS exposure plus cigarette smoke extract (CSE) intraperitoneal injection for 28 days. Primary PMVECs were isolated from the mouse by magnetic bead sorting method via CD31-Dynabeads. Apoptosis was detected by western blot and flow cytometry. RESULTS: LRG1 was increased in lung tissue of COPD patients and CS exposure mice, and CSE-induced PMVECs apoptosis model. KLK10 was over-expressed in lung tissue of COPD patients and CS exposure mice, and CSE-induced PMVECs apoptosis model. LRG1 promoted apoptosis in PMVECs. LRG1 knockdown reversed CSE-induced apoptosis in PMVECs. The mRNA and protein expression of KLK10 were increased after over-expressed LRG1 in PMVECs isolated from mice. Similarly, both the mRNA and protein levels of KLK10 were decreased after LRG1 knockdown in PMVECs. The result of co-immunoprecipitation revealed a protein-protein interaction between LRG1 and KLK10 in PMVECs. KLK10 promoted apoptosis via the down-regulation of Bcl-2/Bax in PMVECs. KLK10 knockdown could reverse CSE-induced apoptosis in PMVECs. CONCLUSIONS: LRG1 promotes apoptosis via up-regulation of KLK10 in PMVECs isolated from mice. KLK10 promotes apoptosis via the down-regulation of Bcl-2/Bax in PMVECs. There was a direct protein-protein interaction between LRG1 and KLK10 in PMVECs. Our novel findings provide insights into the understanding of LRG1/KLK10 function as a potential molecule in COPD.

Development and validation of a nomogram model for mortality prediction in stable chronic obstructive pulmonary disease patients: A prospective observational study in the RealDTC cohort.

Background: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. There is no nomogram model available for mortality prediction of stable COPD. We intended to develop and validate a nomogram model to predict mortality risk in stable COPD patients for personalised prognostic assessment. Methods: A prospective observational study was made of COPD outpatients registered in the RealDTC study between December 2016 and December 2019. Patients were randomly assigned to the training cohort and validation cohort in a ratio of 7:3. We used Lasso regression to screen predicted variables. Further, we evaluated the prognostic performance using the area under the time-dependent receiver operating characteristic curve (AUC) and calibration curve. We used the AUC, concordance index, and decision curve analysis to evaluate the net benefits and utility of the nomogram compared with three earlier prediction models. Results: Of 2499 patients, the median follow-up was 38 months. The characteristics of the patients between the training cohort (n = 1743) and the validation cohort (n = 756) were similar. ABEODS nomogram model, combining age, body mass index, educational level, airflow obstruction, dyspnoea, and severe exacerbation in the first year, was constructed to predict mortality in stable COPD patients. In the integrative analysis of training and validation cohorts of the nomogram model, the three-year mortality prediction achieved AUC = 0.84; 95% confidence interval (CI) = 0.81, 0.88 and AUC = 0.80; 95% CI = 0.74, 0.86, respectively. The ABEODS nomogram model preserved excellent calibration in both the training cohort and validation cohort. The time-dependent AUC, concordance index, and net benefit of the nomogram model were higher than those of BODEx, updated ADO, and DOSE, respectively. Conclusions: We developed and validated a prognostic nomogram model that accurately predicts mortality across the COPD severity spectrum. The proposed ABEODS nomogram model performed better than earlier models, including BODEx, updated ADO, and DOSE in Chinese patients with COPD. Registration: ChiCTR-POC-17010431.

Prediction of Hospitalization and Mortality in Patients with Chronic Obstructive Pulmonary Disease with the New Global Initiative for Chronic Obstructive Lung Disease 2023 Group Classification: A Prospective Cohort and a Retrospective Analysis.

Background: The revised Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2023 group ABE classification has undergone major modifications, which can simplify clinical assessment and optimize treatment recommendations for Chronic Obstructive Pulmonary Disease (COPD). However, the predictive value of the new grouping classification for prognosis is worth further exploration. We aimed to compare the prediction of hospitalization and mortality between this new GOLD group 2023 ABE classification and the earlier 2017 ABCD classification in a Chinese COPD cohort. Methods: Data from 2,499 outpatients with COPD, who first registered in the RealDTC study of Second Xiangya Hospital from December 2016 to December 2019, were collected prospectively and assessed retrospectively. Patients were followed up on all-cause mortality until October 2022 or death. Results: Of the 2,499 patients with COPD, the risk of hospitalization during the first-year follow-up was higher in group E than in groups A and B. The mortality was higher in group E than in groups A and B, and group B was higher than group A. No differences were seen in the area under the curve (AUC) of 2017 vs 2023 GOLD grouping to predict hospitalization. The time-dependent AUC and concordance index for predicting mortality is slightly higher in the GOLD 2017 ABCD than in the 2023 ABE groups. The new GOLD 12-subgroup (1A-4E) classification combining the GOLD 1-4 staging and grouping performed similarly discriminate predictive power for mortality to the GOLD 2017 16-subgroup (A1-4D) classification. Conclusion: The risk of hospitalization during the first-year follow-up was higher in group E than in groups A and B. The all-cause mortality increased gradually from GOLD group A to E. The GOLD 2023 classification based on ABE groups did not predict mortality better than the earlier 2017 ABCD classifications.

MiR-216a reduces apoptosis of pulmonary microvascular endothelial cells in COPD by targeting DNMT1.

INTRODUCTION: Abnormal apoptosis of pulmonary microvascular endothelial cells (PMVECs) participates in the pathogenesis of COPD. Studies have shown that microRNAs (miRNAs) contribute to the pathogenesis of pulmonary diseases by regulating cell apoptosis. The present study aimed to investigate the effects of miR-216a in cigarette smoke extract (CSE)-induced apoptosis of PMVECs in COPD and explore the potential mechanisms. METHODS: The emphysema model mice were treated with CSE and CS exposure. The expression of miR-216a and DNA methyltransferase 1 (DNMT1) was assessed in emphysema mice and COPD patients. The miR-216a mimic and Lenti-DNMT1 were transfected into PMVECs to identify the underlying mechanisms. The expression levels of miR-216a and DNMT1 were detected by real-time quantitative polymerase chain reaction (RT-qPCR) or Western blot. Moreover, cell apoptosis was examined by flow cytometry assays. RESULTS: The results show that the expression of miR-216a was decreased, whereas the expression of DNMT1 was increased in the lung tissue of emphysema mice and COPD patients. In addition, the expression of miR-216a was significantly reduced in CSE-treated PMVECs, and the overexpression of miR-216a attenuated CSE-induced PMVEC apoptosis. Furthermore, the expression of DNMT1 was increased in the CSE-induced PMVECs and then was reduced after the overexpression of miR-216a in the CSE-stimulated PMVECs. Luciferase reporter assays confirmed the target reaction between miR-216a and DNMT1. Also, the overexpression of DNMT1 was able to reverse the anti-apoptotic effect of miR-216a in CSE-induced PMVECs. CONCLUSIONS: The results indicate that miR-216a may play a crucial role in CSE-induced apoptosis by directly regulating its target gene DNMT1 in COPD. It provides insights into the function of MiR-216a/DNMT1 as a potential molecule in COPD.

Serum Krebs von den Lungen-6 is associated with in-Hospital mortality of patients with severe Community-Acquired Pneumonia: A retrospective cohort study.

BACKGROUND: Currently, no ideal biomarker can accurately stratify the risk of patients with severe community-acquired pneumonia (SCAP). This study aimed to evaluate the role of serum Krebs von den Lungen-6 (sKL-6) in predicting in-hospital mortality in adults with SCAP. METHODS: In this retrospective cohort study, 249 severe pneumonia adult patients were recruited between 6 May 2021 to 30 April 2023 in Xiangya Hospital of Central South University. The sKL-6 level within 48 h of admission was measured, and the primary outcome assessed was in-hospital mortality. Multivariable logistic regression analysis was performed to calculate adjusted odds ratios (OR) with 95% confidence intervals (CI). Survival curves were plotted and subgroup analyses were conducted, stratified by relevant covariates. RESULTS: A total of 249 patients were included in the study,with 124 patients having normal sKL-6 levels, and 125 patients having abnormal sKL-6 levels. The overall in-hospital mortality rate was 28.9% (72 out of 249 patients). Univariate and multivariate logistic regression analysis revealed that the patients with abnormal sKL-6 levels had a higher risk of in-hospital mortality compared to those with normal sKL-6 levels, both in the total SCAP patient population (OR: 5.38, 95%CI: 2.41-12.01, P < 0.001) and the non-COVID-19 SCAP patients subgroup (OR: 8.12, 95%CI: 3.16-20.84, P < 0.001). Subgroup and interaction analyses confirmed the stability of the relationship between sKL-6 levels and in-hospital mortality(P for interaction > 0.05). Kaplan-Meier survival curves showed that patients with abnormal sKL-6 levels had a higher in-hospital mortality rate than those with normal sKL-6 levels (P < 0.05). However, the results of restricted cubic spline plots(RCS) analysis demonstrated a nonlinear association between sKL-6 levels (as a continuous variable) and in-hospital mortality in patients with SCAP. Similar results were observed in non-COVID-19 SCAP patients. Furthermore, the receiver operating characteristic curve (ROC) analysis revealed that sKL-6 had superior predictive performance compared to existing biomarkers (e.g., APACHE-II, SOFA, BUN/Cr, PCT, and D-dimer) for in-hospital mortality in non-COVID-19 SCAP patients. CONCLUSION: sKL-6 is a practical and useful biomarker for predicting in-hospital mortality in patients with SCAP.

KL-6 levels in the connective tissue disease population: typical values and potential confounders-a retrospective, real-world study.

Background: Krebs von den Lungen 6 (KL-6) is a potential biomarker for determining the severity of interstitial lung disease (ILD) in patients with connective tissue disease (CTD). Whether KL-6 levels can be affected by potential confounders such as underlying CTD patterns, patient-associated demographics, and comorbidities needs further investigation. Methods: From the database created by Xiangya Hospital, 524 patients with CTD, with or without ILD, were recruited for this retrospective analysis. Recorded data included demographic information, comorbidities, inflammatory biomarkers, autoimmune antibodies, and the KL-6 level at admission. Results of CT and pulmonary function tests were collected one week before or after KL-6 measurements. The percent of predicted diffusing capacity of the lung for carbon monoxide (DLCO%) and computed tomography (CT) scans were used to determine the severity of ILD. Results: Univariate linear regression analysis showed that BMI, lung cancer, TB, lung infections, underlying CTD type, white blood cell (WBC) counts, neutrophil (Neu) counts, and hemoglobin (Hb) were related to KL-6 levels. Multiple linear regression confirmed that Hb and lung infections could affect KL-6 levels independently; the ß were 9.64 and 315.93, and the P values were 0.015 and 0.039, respectively. CTD-ILD patients had higher levels of KL-6 (864.9 vs 463.9, P < 0.001) than those without ILD. KL-6 levels were closely correlated to the severity of ILD assessed both by CT and DLCO%. Additionally, we found that KL-6 level was an independent predictive factor for the presence of ILD and further constructed a decision tree model to rapidly determine the risk of developing ILD among CTD patients. Conclusion: KL-6 is a potential biomarker for gauging the incidence and severity of ILD in CTD patients. To use this typical value of KL-6, however, doctors should take Hb and the presence of lung infections into account.

The clinical characteristics and treatment response of patients with chronic obstructive pulmonary disease with low body mass index.

Background: This study aimed to analyze the clinical characteristics and treatment response of patients with chronic obstructive pulmonary disease (COPD) with low body mass index (BMI). Methods: In this cross-sectional study, we enrolled patients with stable COPD from the database setup by the Second Xiangya Hospital of Central South University. We classified the patients into three groups based on BMI: low-BMI (<18.5 kg/m2), normal-BMI (≥18.5 and <24.0 kg/m2), and high-BMI (≥24 kg/m2) groups. We defined clinically important deterioration (CID) as a COPD Assessment Test (CAT) score increase of ≥2 and minimum clinically important difference (MCID) as a CAT score decrease of ≥2 during 6 months of follow-up. We recorded the number of exacerbations and mortality during 1 year of follow-up. Results: A total of 910 COPD patients were included with 144 (15.8%) patients in low-BMI, 475 (52.2%) in normal-BMI, and 291 (32.0%) in high-BMI groups. Patients with low BMI had worse pulmonary function, higher symptom scores, and exacerbations in the past year compared with normal- and high-BMI groups (p < 0.05). Logistic regression analysis revealed that age, Global Initiative for Chronic Obstructive Lung Disease grades 3 and 4, and hospitalizations in the past year were independent risk factors for patients with low BMI (p < 0.05). After 1 year of follow-up, patients with low BMI had higher mortality and number of hospitalizations. Patients with low BMI were more likely to attain CID and less likely to attain MCID compared with patients with high BMI (p < 0.05). In addition, patients with low BMI treated with long-acting ß2-agonist (LABA)+long-acting muscarinic antagonist (LAMA) and LABA+LAMA+inhaled corticosteroid (ICS) were more likely to attain MCID than those treated with LABA+ICS and LAMA (p < 0.05). Conclusion: COPD patients with low BMI had worse pulmonary function, higher symptom scores, and higher risk of future hospitalizations and mortality and were less likely to attain MCID and more likely to attain CID. It is worth noting that patients with low BMI treated with LABA+LAMA and LABA+LAMA+ICS were more likely to attain MCID than those treated with LABA+ICS and LAMA.

The impact of impaired sleep quality on symptom change and future exacerbation of chronic obstructive pulmonary disease.

PURPOSE: Study the impact of impaired sleep quality on symptom change and future exacerbation of chronic obstructive pulmonary disease (COPD) patients. METHODS: This was a prospective study. Patients with COPD were recruited into the study and followed up for one year. Pittsburgh sleep quality index (PSQI) was collected at baseline. Symptom change was assessed with Minimum clinically important difference (MCID) in COPD Assessment Test (CAT) at 6-month visit, which is an indicator to assess symptom improvement. Exacerbation was recorded during the one-year visit. PSQI score > 5 was defined as poor sleep quality, whereas PSQI score ≤ 5 was defined as good sleep quality. MCID was defined as attaining a CAT decrease ≥ 2. RESULTS: A total of 461 patients were enrolled for final analysis. Two hundred twenty-eight (49.4%) patients had poor sleep quality. Overall, 224 (48.6%) patients attained MCID at 6-month visit and the incidence of exacerbation during the one-year visit was 39.3%. Fewer patients with impaired sleep quality achieved MCID than patients with good sleep quality. Good sleepers were significantly more likely to attain MCID (OR: 3.112, p < 0.001) than poor sleepers. Fewer poor sleepers in GOLD A and D groups attained MCID with ICS/LABA, and fewer poor sleepers in the GOLD D group attained MCID with ICS/LABA/LAMA than good sleepers. Poor sleep quality was a greater risk factor of future exacerbation in Cox regression analysis. The ROC curves showed that PSQI score had a predictive capacity for future exacerbation. More patients with poor sleep quality experienced future exacerbation in GOLD B and D group with treatment of ICS/LABA/LAMA compared to good sleepers. CONCLUSIONS: COPD patients with impaired sleep quality were less likely to achieve symptom improvement and were at increased risk of future exacerbation compared to patients with good sleep quality. Besides, sleep disturbance may affect the symptom improvement and future exacerbation of patients with different inhaled medication or in different GOLD groups.

The effects of different inhalation therapies on less symptomatic chronic obstructive pulmonary disease patients in a Chinese population: a real-world study.

BACKGROUND: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) document suggests that patients with chronic obstructive pulmonary disease (COPD) should be divided into a less symptomatic group. Moreover, single-inhaled drugs are recommended as initial inhalation therapy for them. However, many less symptomatic patients are provided double or triple-inhaled drugs as initial therapy in the real world. This study aimed to describe the inhalation prescriptions and compare the effects of different inhalation therapies on less symptomatic COPD patients. PATIENTS AND METHODS: This was an observational study. Stable COPD patients were recruited and divided into a less symptomatic group including Groups A and C based on the GOLD 2019 document. We collected the data of inhalation therapies prescriptions. Then, the patients were classified into long-acting muscarinic antagonist (LAMA), long-acting ß2-agonist (LABA) + inhaled corticosteroid (ICS), LABA + LAMA, and LABA + LAMA + ICS groups. All the patients were followed up for 1 year to collect exacerbation and mortality data. RESULTS: We found that only 45.4% of patients in Group A and 43.6% of patients in Group C received reasonable inhalation therapy in reference to the GOLD document. In addition, the LAMA group had a higher forced expiratory volume in one second (FEV1), FEV1%pred, FEV1/forced vital capacity and peak expiratory flow compared with LABA + ICS, LABA + LAMA and LABA + LAMA + ICS groups. However, we did not find any significant differences of exacerbation, hospitalization and mortality during the follow-up among different inhalation therapies groups on less symptomatic COPD patients. CONCLUSION: Over half of the less symptomatic patients received inhalation therapy that were inconsistent with the GOLD document recommendations in a Chinese population in the real world. In fact, the single inhaled drug of LAMA should be recommended and pulmonary function is not a good indicator for the choice of initial inhalation therapy in less symptomatic COPD patients.KEY MESSAGESOver half of the less symptomatic COPD patients received inhalation therapy that were inconsistent with the GOLD document recommendations in a Chinese population in the real world.The clinicians should offer a single inhaled drug of LAMA to less symptomatic COPD patients and pulmonary function is not a good indicator for the choice of initial inhalation therapy.

Prohibitin Protects Pulmonary Microvascular Endothelial Cells Against Cigarette Smoke Extract-Induced Cell Apoptosis and Inflammation.

Background: Prohibitin has been identified to play roles in cell survival and apoptosis. Here, this study aimed to clarify the role of prohibitin in cigarette smoke extract (CSE)-induced endothelial cell apoptosis. Methods: The protein level of prohibitin was assessed by Western blot in lung tissues from emphysema and control mice. CSE-induced human pulmonary microvascular endothelial cells (hPMECs) were applied to mimic smoke-related cell apoptosis in vitro. Prohibitin was overexpressed in hPMECs with or without CSE. Mitochondrial function was analyzed by JC-1 staining and ATP assay kits. Oxidative stress was assessed by flow cytometry, fluorescence staining and immunocytochemistry. Apoptosis was analyzed by flow cytometry, Western blot and caspase-3 activity assays. In addition, the expression of inflammatory markers was assessed by Western blot and real-time polymerase chain reaction (PCR). The secretion of inflammatory cytokines was measured by ELISA. Results: Prohibitin was downregulated in emphysema mouse tissues compared with control experiments. Consistently, CSE inhibited both the protein and RNA levels of prohibitin in hPMECs in a dose-dependent manner. Gain-of-function experiments indicated that CSE induced collapse of mitochondrial membrane potential (MMP) and loss of ATP, while prohibitin improved mitochondrial function. CSE induced robust ROS production and oxidative DNA damage, while prohibitin decreased this damage. Upregulation of prohibitin protected the apoptosis of hPMECs from CSE. Overexpression of prohibitin significantly reduced the levels of the main proinflammatory cytokines. Finally, prohibitin inhibited nuclear factor-kappa B (NF-κB) p65 accumulation and IκBα degradation induced by CSE. Conclusion: The current findings suggest that CSE-mediated mitochondrial dysfunction, oxidative stress, cell apoptosis and inflammation in hPMECs were reduced by overexpression of prohibitin. We identified prohibitin as a novel regulator of endothelial cell apoptosis and survival in the context of CSE exposure.

Symptoms at disease onset predict prognosis in COVID-19 disease.

The main clinical manifestations of coronavirus disease 2019 (COVID-19) onset are respiratory symptoms, including cough, sputum, and dyspnea. However, a significant proportion of patients initially manifested non-respiratory symptoms, such as fever, myalgia, and diarrhea. Here, we compared the different characteristics and outcomes between the patients with respiratory symptoms and non-respiratory symptoms at illness onset. The patients admitted to the respiratory departments from eight hospitals in Hunan and Guangxi Province with nucleic acid-positive severe acute respiratory syndrome coronavirus (SARS-CoV-2) were recruited. Epidemiological information, clinical manifestations, laboratory findings, and radiological characteristics, treatment regimens, and outcomes data were recorded and analyzed. The median age of the recruited 541 subjects was 43 years (IQR, 33-55). Of the 541 subjects, 404 (74.5%) subjects had initial symptom that were respiratory, while 137 (25.5%) subjects had non-respiratory symptoms. Respiratory COVID-19 subjects had more secondary bacterial infections (8.7% vs 0.0%, P < 0.001), needed the intensive care unit more (9.7% vs 2.2%, P = 0.005), non-invasive ventilation more (7.2% vs 1.5%, P = 0.004), developed ARDS more (11.4% vs 2.2%, P = 0.001) and needed longer time to recover (18.5 vs 16.7 days, P = 0.003) compared to predominately non-respiratory COVID-19 subjects. The multivariate model showed that age (OR = 1.04, P = 0.01), dyspnea (OR = 4.91, P < 0.001) and secondary bacterial infection (OR = 19.8, P < 0.001) were independently associated with development of ARDS among COVID-19 patients. We identify COVID-19 subjects with dyspnea at disease onset who have a worse prognosis. We also demonstrate age and secondary bacterial infections to be independently associated with ARDS development in subjects with COVID-19.ABBREVIATIONS: COVID-19: Coronavirus disease 2019; ARDS: acute respiratory distress syndrome; IQR: interquartile range; ICU: intensive care unit; CDC: Chinese Center for Disease Control and Prevention.

Comparative clinical characteristics among different age group of adult COVID-19 patients: A multicenter study.

BACKGROUND: Coronavirus disease (COVID-19) is a global infectious disease with a large burden of illness and high health care costs. This study aimed to compare clinical features among adult COVID-19 patients in different age groups. METHODS: Laboratory-confirmed adult COVID-19 infection cases between December 31, 2019 to March 8, 2020 obtained from Neighboring Cities. Patients were divided into five age groups. Clinical characteristics were compared among different age groups. RESULTS: Of 299 cases, median age was 44 and 158 (53%) were male. A total of 53.3% of 30-40 years, 50% of 40-50 years, 36.6% of <30 years and 36.2% of 50-60 years were primary case, none of the elderly were primary case. Among all the observed symptoms, only symptom of dyspnea was significantly different between the elderly group and other groups (p < .001). Proportion of severe or critical type was 2.4%, 5.3%, 9.5%, 14.5%, and 35% in patients with age <30, 30-40, 40-50, 50-65, ≥65, respectively. A total of 285 patients (95.3%) were cured and discharged, 12 patients (4.0%) were still on medical treatment in hospital. There were 2 (0.7%) deaths which occurred among persons ≥65 years. Patients with a history of chronic heart disease had a more than a 56 times higher risk for severe or critical type of COVID-19 than those without a history of chronic heart disease (odds ratio [OR]: 56.038, 95% confidence interval [CI]: 2.764-1136.053, p = .009). Old age (OR: 1.055, 95% CI: 1.016-1.095, p = .006), high heart rate in admission (OR: 1.085, 95% CI: 1.03-1.144, p = .002), high respiratory rate in admission (OR: 1.635, 95% CI: 1.093-2.431, p = .017) were independently associated with severe or critical type in COVID-19. CONCLUSIONS: Proportion of severe or critical type increased with old age groups. Adults with old age and high heart rate, respiratory rate in admission and history of chronic heart disease were associated with severe or critical type in COVID-19.

The Effect of Noninvasive Ventilation Support on COVID-19 Patients and Risk Factors for Invasive Ventilation - A Retrospective and Multicenter Study.

BACKGROUND: Oxygen therapy (OT) is the most widely used supportive regime in patients with hypoxemic acute respiratory failure (ARF) due to severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection. The aim of this study was to identify the effect of noninvasive ventilation support on coronavirus disease 2019 (COVID-19) patients and risk factors for invasive mechanical ventilation (IMV). METHODS: We retrospectively analyzed confirmed COVID-19 subjects from nine hospitals outside Wuhan. All hospitalized patients who tested positive for COVID-19 by real-time polymerase chain reaction between January 1st and March 31st, 2020, were recruited. The patients were divided into four groups based on the most advanced OT regime, including no OT, nasal oxygen therapy, high-flow nasal oxygen therapy (HFNOT) or noninvasive ventilation (NIV), and IMV. Multiple logistic regression models were performed to determine risk factors for IMV. RESULTS: Of the 683 recruited subjects, 315 (46.1%) subjects did not need OT, 300 (43.9%) received nasal oxygen therapy, 51 (7.5%) received HFNOT or NIV, while 17 (2.5%) subjects had to be intubated. The lactate in the OT group was higher than in the no OT group (2.7 vs 1.6, P = 0.02). In addition, HFNOT or NIV patients had a higher respiratory rate, but a lower PaO2 (P < 0.001). HFNOT and NIV had an obvious beneficial effect on ARF with 75% of COVID-19 patients recovering from respiratory failure. Patients with IMV were older (P < 0.001), had a higher rate of hypertension (P < 0.001) and more secondary bacterial infections (P < 0.001) compared to those without intubation. The multivariate model showed that secondary bacterial infection (OR = 6.87, P = 0.009) was independently associated with IMV failure among COVID-19 patients. CONCLUSION: We identified that HFNOT and NIV had an obvious beneficial effect on ARF among COVID-19 patients. We also demonstrated that secondary bacterial infection was an independent risk factor for NIV failure in patients infected by SARS-COV2.

Real-World Effectiveness of Inhalation Therapy Among Patients With Symptomatic COPD in China: A Multicenter Prospective Study.

Purpose: This real-world study evaluated the effectiveness of different inhalation therapies in patients with symptomatic chronic obstructive pulmonary disease (COPD) in China and also explored the relevant factors that influence the effectiveness of inhalation therapy. Patients and Methods: We conducted a multicenter prospective longitudinal study that was carried out in 12 hospitals in China from December 2016 to June 2021. A face-to-face interview was conducted to collect data. Baseline data were collected at the first visit. Minimum clinically important difference (MCID) was defined as attaining a COPD assessment test (CAT) decrease ≥2. We mainly assessed the MCID and the incidence of exacerbations at the 6 months follow-up. Results: In 695 patients, the mean age was 62.5 ± 8.2 years, with a mean CAT score of 15.1 ± 6.0. Overall, 341 (49.1%) patients attained the MCID of CAT and the incidence of exacerbation during follow-up was 22.3%. Females were significantly more likely to attain MCID than male in COPD patients (adjusted odd ratio (aOR) = 1.93, adjusted 95% confidence interval (a95%CI) = 1.09-3.42, p = 0.024). Patients treated with LABA/LAMA or ICS/LABA/LAMA (ICS, inhaled corticosteroid; LABA, long-acting ß2-agonist; LAMA, long-acting muscarinic antagonist) were more likely to attain MCID than patients treated with LAMA (aOR = 3.97, a95%CI = 2.48-6.35, p < 0.001; aOR = 3.17, a95%CI = 2.09-4.80, p < 0.001, respectively). Patients treated with LABA/LAMA had a higher incidence of severe exacerbation than patients treated with ICS/LABA/LAMA (aOR = 1.95, a95%CI = 1.04-3.66, p = 0.038). Conclusion: The incidence of MCID in symptomatic COPD patients treated with inhalation therapy was nearly 50%. Patients treated with LABA/LAMA or ICS/LABA/LAMA were more likely to attain MCID than patients treated with LAMA. Patients treated with LABA/LAMA had a higher incidence of severe exacerbations than with ICS/LABA/LAMA.

Reversal of emphysema by restoration of pulmonary endothelial cells.

Chronic obstructive pulmonary disease (COPD) is marked by airway inflammation and airspace enlargement (emphysema) leading to airflow obstruction and eventual respiratory failure. Microvasculature dysfunction is associated with COPD/emphysema. However, it is not known if abnormal endothelium drives COPD/emphysema pathology and/or if correcting endothelial dysfunction has therapeutic potential. Here, we show the centrality of endothelial cells to the pathogenesis of COPD/emphysema in human tissue and using an elastase-induced murine model of emphysema. Airspace disease showed significant endothelial cell loss, and transcriptional profiling suggested an apoptotic, angiogenic, and inflammatory state. This alveolar destruction was rescued by intravenous delivery of healthy lung endothelial cells. Leucine-rich α-2-glycoprotein-1 (LRG1) was a driver of emphysema, and deletion of Lrg1 from endothelial cells rescued vascular rarefaction and alveolar regression. Hence, targeting endothelial cell biology through regenerative methods and/or inhibition of the LRG1 pathway may represent strategies of immense potential for the treatment of COPD/emphysema.

Modified and simplified clinically important deterioration: multidimensional indices of short-term disease trajectory to predict future exacerbations in patients with chronic obstructive pulmonary disease.

BACKGROUND AND AIMS: Various prediction indices based on the single time point observation have been proposed in chronic obstructive pulmonary disease (COPD), but little was known about disease trajectory as a predictor of future exacerbations. Our study explored the association between disease trajectory and future exacerbations, and validated the predictive value of the modified and simplified short-term clinically important deterioration (CID). METHODS: This study was a multicenter, prospective observational study. Patients with COPD were recruited into our study and followed up for 18 months. The modified CID (CID-C) was defined as a decrease of 100 mL in forced expiratory volume in 1 second (FEV1), or suffering exacerbations, or increase of 2 units in COPD Assessment Test (CAT) during the first 6 months follow-up. Simplified CID was defined when excluding CAT from the CID-C model. RESULTS: A total of 127 patients were enrolled in our final analysis. Compared with patients without exacerbations during the period of the 6th to the 18th month, patients with exacerbations were more likely to have frequent short-term exacerbations in the first 6 months (2.14 versus 0.21, p < 0.001). The short-term exacerbations were the best predictor for future exacerbations [odds ratio (OR): 13.25; 95% confidence interval: 5.62-34.67; p < 0.001], followed by the history of exacerbation before study entry, short-term changes in FEV1 and CAT. CID-C and Simplified CID were both significantly associated with exacerbations (OR: 7.14 and 9.74, both p < 0.001). The receiver operating characteristic curves showed that the Simplified CID had slightly better predictive capacity for future exacerbation than CID-C (0.754 versus 0.695, p = 0.02). CONCLUSION: Disease trajectory, including both the CID-C and the Simplified CID had significant predictive value for future exacerbations.The reviews of this paper are available via the supplemental material section.

Microarray Analysis of Long Non-Coding RNAs in Lung Tissues of Patients with COPD and HOXA-AS2 Promotes HPMECs Proliferation via Notch1.

Background and Objectives: Long non-coding RNAs (lncRNAs) play an important role in the pathogenesis of many diseases, including cancer, pulmonary fibrosis and chronic obstructive pulmonary disease (COPD). In this study, we intended to identify the differentially expressed lncRNAs and the role of HOXA cluster antisense RNA 2 (HOXA-AS2) in patients with COPD. Methods: We analyzed lncRNA profiles of three non-COPD and seven COPD patients' lungs via microarray and then validated the expression of the top differentially expressed lncRNAs by using real-time polymerase chain reaction (PCR). To identify the mechanism of HOXA-AS2 during COPD pathogenesis and endothelial cell proliferation, we knocked down and overexpressed HOXA-AS2 with siRNA and lentivirus transfection approach in human pulmonary microvascular endothelial cells (HPMECs). Results: Among 29,150 distinct lncRNA transcripts, 353 lncRNAs were significantly (≥2-fold change and P<0.05) upregulated and 552 were downregulated in COPD patients. The fold change of HOXA-AS2 is 9.32; real-time PCR confirmed that HOXA-AS2 was downregulated in COPD patients. In in vitro experiments, cigarette smoke extract (CSE) treatment reduced the expression of HOXA-AS2 and cell proliferation of HPMECs. Knocking down HOXA-AS2 inhibited HPMECs proliferation and the expression of Notch1 in HPMECs. Overexpressing Notch1 could partly rescue the inhibition of cell viability induced by the silence of HOXA-AS2. Conclusion: Our results demonstrated that differentially expressed lncRNAs may act as potential molecular biomarkers for the diagnosis of COPD, and HOXA-AS2 was involved in the pathogenesis of COPD by regulating HPMECs proliferation via Notch1, which may provide a new approach for COPD treatment.

The Value of FENO Measurement for Predicting Treatment Response in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

Background: Fractional exhaled nitric oxide (FENO) has been shown to be a marker of airway inflammation in various pulmonary diseases, including chronic obstructive pulmonary disease (COPD). In this study, we assessed the FENO level in patients with acute exacerbations of COPD (AECOPD) and analyzed the predictive value of the FENO level for treatment response. Methods: Demographic data were collected at admission. FENO, lung function, blood gases, COPD Assessment Test (CAT), and modified Medical Research Council (mMRC) scores were measured at admission and on day 7. At the second visit, the patients were asked to report their health status; scores ranged from 1 to 5, representing "much better", "slightly better", "no change", "slightly worse", and "much worse", respectively. The treatment response was evaluated based on the patient's reported health status (responders were those who reported much better and slightly better) and lung function (responders were those who presented an increase in FEV1 over 200 mL). Results: A total of 182 patients were recruited into the analysis. The FENO level positively correlated with an increase in FEV1 and FEV1% (r = 0.291, p < 0.001 and r = 0.205, p = 0.005, respectively), but negatively correlated with a decrease in the COPD Assessment Test (CAT) score (r = -0.197, p = 0.008) and patient-reported health status (rho = -0.408, p<0.001). An inverse correlation was observed between FENO concentrations at admission and the length of hospital stay. The cut-off point for differentiating responders, identified by health status, was 18 ppb, with the sensitivity being 89.7% and specificity 88.9%. Conclusion: FENO levels, determined at hospital admission, are potential to predict the overall treatment response in AECOPD patients, including remission in subjective patient-reported health statuses and, also, improvements in lung function. Registry Number: ChiCTR-ROC-16,009,087 (http://www.chictr.org.cn/).

Determinants of Clinical COPD Questionnaire in Patients with COPD: A Cross-Sectional Observational Study.

BACKGROUND: The Clinical COPD Questionnaire (CCQ) has been suggested by the Global Initiative of Chronic Obstructive Lung Disease (GOLD) as a comprehensive symptom measurement tool, which helps to classify patients in order to direct pharmacological treatment. Therefore, it is essential to understand its determinants. OBJECTIVES: To identify the determinants of the overall CCQ score and scores of its 3 subdomains among chronic obstructive pulmonary disease (COPD) patients from China. METHODS: A total of 1,241 COPD patients in the outpatient department of the Second Xiangya Hospital in China were recruited. Basic information and clinical data were collected. Differences in the GOLD categories based on Modified Medical Research Council Dyspnea Scale (mMRC), COPD Assessment Test (CAT), and CCQ were compared. Multiple linear regression analyses were performed to evaluate determinant factors of the total CCQ and subdomain scores. RESULTS: The total CCQ and/or separate domain scores significantly differed with sex, age, BMI, smoking status, biomass fuel exposure, exacerbation frequency, mMRC, CAT, and GOLD grades and groups. Subjects with asthma-COPD overlap (ACO) had worse health status based on CCQ than those with COPD alone. As for the 16 subgroups based on GOLD 2017, statistical differences in the total CCQ and functional domain scores were found among subgroups 1A-4A, 1B-4B, and 1D-4D. The mMRC classified much more patients into more symptom groups than CAT and CCQ. No significant difference was observed in the GOLD categories between the CAT and CCQ (cut point = 1.5). Multiple linear regression analysis showed that smoking status, underweight, ACO, post-bronchodilator FEV1% predicted <50%, exacerbation history, and mMRC were independently associated with the total CCQ score. Only 3 variables were significantly associated with the symptom domain: ACO, exacerbations, and mMRC; for the functional domain, age ≥75 years, ACO, post-bronchodilator FEV1% predicted <50%, exacerbation history, and mMRC were significant; female sex, underweight, frequent exacerbations (≥2), and mMRC were significantly associated with higher scores in the mental domain. CONCLUSIONS: The classification of COPD produced by mMRC, CAT, and CCQ was not identical. Smoking status, underweight, ACO, post-bronchodilator FEV1% predicted <50%, exacerbation history, and mMRC were associated with lower health-related quality of life assessed by the total CCQ score, while different subdomains of CCQ had different determinant factors.

Whole transcriptome analyis of human lung tissue to identify COPD-associated genes.

Identification of the dysfunctional genes in human lung from patients with Chronic obstructive pulmonary disease (COPD) will help understand the pathology of this disease. Here, using transcriptomic data of lung tissue for 91 COPD cases and 182 matched healthy controls from the Genotype-Tissue Expression (GTEx) database. we identified 1359 significant differentially expressed genes (DEG) with 707 upregulated and 602 downregulated respectively. We evaluated the identified DEGs in an independent microarray cohort of 219 COPD and 108 controls, demonstrating the robustness of our result. Functional annotation of COPD-associated genes highlighted the activation of complement cascade, dysregulation of inflammatory response and extracellular matrix organization in the COPD patients. In addition, we identified several novel key-hub genes involved in the COPD pathogenesis using a network analysis method. To our knowledge, our analysis is currently the largest RNA-seq based COPD transcriptomic analyses, providing great resource for the molecular research in the COPD community.