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It is unclear whether the high burden of COPD in rural areas is related to worse outcomes in patients with COPD or is because the prevalence of COPD is higher in rural areas. We assessed the association of rural living with acute exacerbations of COPD (AECOPDs)-related hospitalization and mortality. We retrospectively analyzed Veterans Affairs (VA) and Medicare data of a nationwide cohort of veterans with COPD aged ≥ 65 years with COPD diagnosis between 2011 and 2014 that had follow-up data until 2017. Patients were categorized based on residential location into urban, rural, and isolated rural. We used generalized linear and Cox proportional hazards models to assess the association of residential location with AECOPD-related hospitalizations and long-term mortality. Of 152,065 patients, 80,162 (52.7%) experienced at least one AECOPD-related hospitalization. After adjusting for demographics and comorbidities, rural living was associated with fewer hospitalizations (relative risk-RR = 0.90; 95% CI: 0.89–0.91; P < 0.001) but isolated rural living was not associated with hospitalizations. Only after accounting for travel time to the closest VA medical center, neighborhood disadvantage, and air quality, isolated rural living was associated with more AECOPD-related hospitalizations (RR = 1.07; 95% CI: 1.05–1.09; P < 0.001). Mortality did not vary between rural and urban living patients. Our findings suggest that other aspects than hospital care may be responsible for the excess of hospitalizations in isolated rural patients like poor access to appropriate outpatient care.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease. Historically, two COPD phenotypes have been described: chronic bronchitis and emphysema. Although these phenotypes may provide additional characterization of the pathophysiology of the disease, they are not extensive enough to reflect the heterogeneity of COPD and do not provide granular categorization that indicates specific treatment, perhaps with the exception of adding inhaled glucocorticoids (ICS) in patients with chronic bronchitis. In this review, we describe COPD phenotypes that provide prognostication and/or indicate specific treatment. We also describe COPD-like phenotypes that do not necessarily meet the current diagnostic criteria for COPD but provide additional prognostication and may be the targets for future clinical trials.

Heated, humidified high-flow air (HHHFA) has been shown to reduce exacerbations in patients with COPD or bronchiectasis with significant sputum production. This pilot study evaluated the short-term effects of nocturnal HHHFA in COPD patients with chronic bronchitis. This was a prospective, single-center, open-label, randomized, placebo-controlled trial. Participants with COPD, chronic bronchitis, and ≥ 2 exacerbations in the prior year were randomized to either nocturnal HHHFA or usual care. Assessments included sleep quality, dyspnea, quality of life, cough, lung function, imaging, and exercise capacity at baseline and 6 weeks. Of 11 eligible participants, seven completed the study (four intervention, three control). Baseline characteristics were generally similar, though the intervention group had a higher BMI and a lower emphysema percentage. No statistically significant differences were observed between groups in primary or secondary outcomes. Nocturnal HHHFA over 6 weeks did not improve clinical or imaging outcomes in this small cohort of COPD patients with chronic bronchitis. The study was likely underpowered due to recruitment challenges. Larger trials are needed to assess the potential of HHHFA in this population. ClinicalTrials.gov identifier: NCT03959982.

Introduction The study objective was to estimate the prevalence of chronic hypercapnic respiratory failure (CHRF) and home noninvasive ventilation (NIV) use in a high‐risk population, individuals with a history of at least one COPD‐related hospitalizations. Methods We retrospectively analyzed electronic medical record data of patients with at least one COPD‐related hospitalization between October 1, 2011, and September 30, 2017, to the Iowa City VA Medical Center. We excluded individuals with no obstructive ventilatory defect. Results Of 186 patients, the overall prevalence of compensated hypercapnic respiratory failure (CompHRF), defined as PaCO2 > 45 mmHg with a pH = 7.35–7.45, was 52.7%, while the overall prevalence of home NIV was 4.3%. The prevalence of CompHRF was 43.6% and home NIV was 1.8% in those with one COPD‐related hospitalization. Among those with ≥4 COPD‐related hospitalizations, the prevalence of CompHRF was 77.8% (14 of 18), and home NIV was 11.1% (2 of 18). Conclusion Approximately half of individuals with at least one COPD‐related hospitalization have CompHRF, but only 8.2% of those use home NIV. Future studies should estimate CHRF rates and the degree of underutilization of home NIV in larger multicenter samples. Approximately half of individuals with at least one COPD‐related hospitalization have hypercapnia, but only 8.2% of those use home noninvasive ventilation. Future studies should estimate chronic hypercapnic respiratory failure rates and the degree of underutilization of home noninvasive ventilation in larger multicenter samples and identify barriers and facilitators for home noninvasive ventilation use in patients with COPD‐related hospitalizations.

Acute mesenteric ischemia (AMI) is a life-threatening condition that can result in multiple organ injury and death. A timely diagnosis and treatment would have a significant impact on the morbidity and mortality in high-risk patient population. The purpose of this study was to investigate if intestinal fatty acid binding protein (I-FABP) and α-defensins can be used as biomarkers for early AMI and resultant lung injury. C57BL/6 mice were subjected to intestinal ischemia by occlusion of the superior mesenteric artery. A time course of intestinal ischemia from 0.5 to 3 h was performed and followed by reperfusion for 2 h. Additional mice were treated with N-acetyl-cysteine (NAC) at 300 mg/kg given intraperitoneally prior to reperfusion. AMI resulted in severe intestinal injury characterized by neutrophil infiltrate, myeloperoxidase (MPO) levels, cytokine/chemokine levels, and tissue histopathology. Pathologic signs of ischemia were evident at 1 h, and by 3 h of ischemia, the full thickness of the intestine mucosa had areas of coagulative necrosis. It was noted that the levels of α-defensins in intestinal tissue peaked at 1 h and I-FABP in plasma peaked at 3 h after AMI. Intestinal ischemia also resulted in lung injury in a time-dependent manner. Pretreatment with NAC decreased the levels of intestinal α-defensins and plasma I-FABP, as well as lung MPO and cytokines. In summary, the concentrations of intestinal α-defensins and plasma I-FABP predicted intestinal ischemia prior to pathological evidence of ischemia and I-FABP directly correlated with resultant lung injury. The antioxidant NAC reduced intestinal and lung injury induced by AMI, suggesting a role for oxidants in the mechanism for distant organ injury. I-FABP and α-defensins are promising biomarkers, and may guide the treatment with antioxidant in early intestinal and distal organ injury.

Spyridon Fortis Department of Medicine, Division of Pulmonary, Critical Care and Occupational Medicine, University of Iowa, Iowa City, IA, USA Airflow obstruction or obstructive ventilatory defect (OVD) is defined as low forced expiratory volume in 1 second (FEV1) to vital capacity (VC) ratio. VC can be measured in various ways, and the definition of “low FEV1/VC” ratio varies. VC can be measured during forced expiration before bronchodilators (forced vital capacity [FVC]) and after bronchodilators (post-FVC), and during slow expiration (slow vital capacity [SVC]) and during inspiration (inspiratory vital capacity [IVC]). Theoretically, in a healthy person, VC values should be the same regardless of the maneuver used. Nevertheless, SVC is usually larger than FVC except in patients with no OVD and body mass index <25 kg/m2.1 In obstructive lung diseases, FVC may be reduced, which may result in an increase of FEV1/FVC ratio and misdiagnosis.2 For that reason, American Thoracic Society–European Respiratory Society recommends using SVC or IVC to calculate the FEV1/VC ratio.2 Approximately, 10% of smokers have FEV1% predicted <80% and FEV1/FVC >70%, a pattern known as preserved ratio impaired spirometry.3 Of all the subjects with FVC below the lower limit of normal (LLN) and FEV1/FVC > LLN, only 64% have restriction in lung volumes. The rest 36% have a nonspecific Pulmonary Function Test pattern.4 Approximately, 15% of patients with this nonspecific PFT pattern develop OVD in follow-up PFTs.4 It is possible that a portion of patients with obstructive lung disease remain underdiagnosed when FVC is used to compute FEV1/FVC ratio. View the original paper by Torén and colleagues.

IntroductionWe compared the predictive value of prebronchodilator and postbronchodilator spirometry for chronic obstructive pulmonary disease (COPD) features and outcomes.MethodsWe analysed COPDGene data of 10 192 subjects with smoking history. We created regressions models with the following dependent variables: clinical, functional and radiographic features, and the following independent variables: prebronchodilator airflow obstruction (PREO) and postbronchodilator airflow obstruction (POSTO), prebronchodilator and postbronchodilator FEV1% predicted. We compared the model performance using the Akaike information criterion (AIC).ResultsThe COPD prevalence was higher using PREO. About 8.5% had PREO but no airflow obstruction in postbronchodilator spirometry (POSTN) (PREO-POSTN) and 3% of all subjects had no aiflow obstruction in prebronchodilator spirometry (PREN) but POSTO (PREN-POSTO). We found no difference in COPD features and outcomes between PREO-POSTN and PREN-POSTO subjects. Although, both prebronchodilator and postbronchodilator spirometries are both associated with chronic bronchitis, dyspnoea, exercise capacity and COPD radiographic findings, models that included postbronchodilator spirometric measures performed better than models with prebronchodilator measures to predict these COPD features. The predictive value of prebronchodilator and postbronchodilator spirometries for respiratory exacerbations, change in forced expiratory volume in 1 s, dyspnoea and exercise capacity during a 5-year period is relatively similar, but postbronchodilator spirometric measures are better predictors of mortality based on AIC.ConclusionsPostbronchodilator spirometry may be a more accurate predictor of COPD features and outcomes.

Inhaled corticosteroids (ICSs) combined with bronchodilators have been identified to improve outcomes in COPD but also to be associated with certain adverse effects. We performed a systematic review and meta-analysis to compile and summarize data on the efficacy and safety of dosing levels (high versus medium/low) of ICS alongside ancillary bronchodilators following PRISMA guidelines. Medline and Embase were systematically searched until December 2021. Randomized, clinical trials (RCTs) that met predefined inclusion criteria were included. Risk ratios (RRs) with 95% confidence intervals (CI) were extracted. Any acute exacerbation of COPD (AECOPD) risk was chosen as the primary efficacy outcome, mortality rate as the primary safety outcome, moderate/severe AECOPD risk as the secondary efficacy outcome and pneumonia risk as the secondary safety outcome. Subgroup analyses of individual ICS agents, of patients with baseline moderate/severe/very severe COPD and of patients with recent COPD exacerbation history were also performed. A random-effects model was used. We included 13 RCTs in our study. No data on low doses were included in the analysis. High dose ICS was not associated with a statistically significant difference in any AECOPD risk (RR: 0.98, 95% CI: 0.91-1.05, I : 41.3%), mortality rate (RR: 0.99, 95% CI: 0.75-1.32, I : 0.0%), moderate/severe AECOPD risk (RR: 1.01, 95% CI: 0.96-1.06, I : 0.0%) or pneumonia risk (RR: 1.07, 95% CI: 0.86 -1.33, I : 9.3%) compared to medium dose ICS. The same trend was identified with the several subgroup analyses. Our study collected RCTs investigating the optimal dosing level of ICS prescribed alongside ancillary bronchodilators to patients with COPD. We identified that the high ICS dose neither reduces AECOPD risk and mortality rates nor increases pneumonia risk relative to the medium dose.

Visual assessment of computed tomography (CT) of the lung is routinely employed in the diagnosis of emphysema. Quantitative CT (QCT) can complement visual CT but must be well validated. QCT emphysema is defined as ≥5% of lung volume occupied by low attenuation areas ≤-950 Hounsfield units (LAA-950). Discordant visual and QCT assessments are not uncommon. We examined the association between visual and quantitative chest CT evaluation within a large cohort of subjects to identify variables that may explain discordant visual and QCT findings. Volumetric inspiratory CT scans of 1221 subjects enrolled in phase 1 of the COPDGene study conducted at the University of Iowa were reviewed. Participants included never smokers, smokers with normal spirometry, preserved ratio impaired spirometry, and Global Initiative for Obstructive Lung Disease (GOLD) stages I-IV. CT scans were quantitatively scored and visually interpreted by both the COPDGene Imaging Center and the University of Iowa radiologists. Individual-level visual assessments were compared with QCT measurements. Agreement between the two sets of radiologists was calculated using kappa statistic. We assessed variables associated with discordant results using regression methods. There was a fair agreement for the presence or absence of emphysema between our center's radiologists and QCT (61% concordance, kappa 0.22 [0.17-0.28]). Similar comparisons showed a slight agreement between the COPDGene Imaging Center and QCT (56% concordance, kappa 0.16 [0.11-0.21]), and a moderate agreement between both sets of visual assessments (80% concordance, kappa 0.60 [0.54-0.65]). Current smoking and female gender were significantly associated with QCT-negative but visually detectable emphysema. The slight-to-fair agreement between visual and quantitative CT assessment of emphysema highlights the need to utilize both modalities for a comprehensive radiologic evaluation. Discordant results may be attributable to one or more factors that warrant further exploration in larger studies. ClinicalTrials.gov Identifier NCT000608764.

Purpose Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter through activation of GABA receptors. Volatile anesthetics activate type-A (GABA A ) receptors resulting in inhibition of synaptic transmission. Lung epithelial cells have been recently found to express GABA A receptors that exert anti-inflammatory properties. We hypothesized that the volatile anesthetic sevoflurane (SEVO) attenuates lung inflammation through activation of lung epithelial GABA A receptors. Methods Sprague–Dawley rats were anesthetized with SEVO or ketamine/xylazine (KX). Acute lung inflammation was induced by intratracheal instillation of endotoxin, followed by mechanical ventilation for 4 h at a tidal volume of 15 mL/kg without positive end-expiratory pressure (two-hit lung injury model). To examine the specific effects of GABA, healthy human lung epithelial cells (BEAS-2B) were challenged with endotoxin in the presence and absence of GABA with and without addition of the GABA A receptor antagonist picrotoxin. Results Anesthesia with SEVO improved oxygenation and reduced pulmonary cytokine responses compared to KX. This phenomenon was associated with increased expression of the π subunit of GABA A receptors and glutamic acid decarboxylase (GAD). The endotoxin-induced cytokine release from BEAS-2B cells was attenuated by the treatment with GABA, which was reversed by the administration of picrotoxin. Conclusion Anesthesia with SEVO suppresses pulmonary inflammation and thus protects the lung from the two-hit injury. The anti-inflammatory effect of SEVO is likely due to activation of pulmonary GABA A signaling pathways.