Obstructive sleep apnea severity, circulating biomarkers, and cancer risk.

STUDY OBJECTIVES: To determine if obstructive sleep apnea (OSA) severity and/or biomarkers of inflammation/angiogenesis are associated with incident cancer in this clinical cohort. METHODS: Consenting adult patients at the University of British Columbia Hospital between 2003-2014 completed a questionnaire about their medical history and sleep habits prior to undergoing a polysomnogram (PSG). Blood samples were collected the morning after PSG and processed for biomarkers of inflammation and angiogenesis. The clinical, PSG, and biomarker data were linked to the British Columbia Cancer Registry to ascertain incident cancer diagnoses. Cox proportional hazard regression were used to assess the association between OSA severity and biomarker concentrations with cancer risk. RESULTS: A total of 1,990 patients were included in the analysis with a mean follow-up time of 12.8 years; 181 of them (9.1%) developed cancer after PSG. OSA severity was significantly associated with cancer risk after controlling for relevant covariates (hazard ratio (HR) = 1.08 per 10 events/h apnea-hypopnea index (AHI) increase, CI = 1.02-1.15, p=0.015). In an exploratory analysis, two biomarkers were significantly associated with an increased cancer risk after controlling for relevant covariates (HR per interquartile range (IQR) pg/mL increase of endostatin = 1.45, CI = 1.12-1.87, p=0.01 and HR for IQR pg/mL increase of VCAM-1 = 1.48, CI = 1.04-2.11, p=0.03, respectively). CONCLUSIONS: OSA severity was an independent risk factor for cancer. Furthermore, two circulating markers were significantly associated with cancer risk. If these preliminary findings can be reproduced in other cohorts, biomarkers could potentially be used to prognosticate OSA patients with respect to cancer risk.

Systemic and Airway Epigenetic Disruptions Are Associated with Health Status in COPD.

Epigenetic modifications are common in chronic obstructive pulmonary disease (COPD); however, their clinical relevance is largely unknown. We hypothesized that epigenetic disruptions are associated with symptoms and health status in COPD. We profiled the blood (n = 57) and airways (n = 62) of COPD patients for DNA methylation (n = 55 paired). The patients' health status was assessed using the St. George's Respiratory Questionnaire (SGRQ). We conducted differential methylation analyses and identified pathways characterized by epigenetic disruptions associated with SGRQ scores and its individual domains. 29,211 and 5044 differentially methylated positions (DMPs) were associated with total SGRQ scores in blood and airway samples, respectively. The activity, impact, and symptom domains were associated with 9161, 25,689 and 17,293 DMPs in blood, respectively; and 4674, 3730 and 5063 DMPs in airways, respectively. There was a substantial overlap of DMPs between airway and blood. DMPs were enriched for pathways related to common co-morbidities of COPD (e.g., ageing, cancer and neurological) in both tissues. Health status in COPD is associated with airway and systemic epigenetic changes especially in pathways related to co-morbidities of COPD. There are more blood DMPs than in the airways suggesting that blood epigenome is a promising source to discover biomarkers for clinical outcomes in COPD.

Airway Eosinophilia on Bronchoalveolar Lavage and the Risk of Exacerbations in COPD.

The associations between airway eosinophilia, measured in sputum or peripheral blood, and acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are inconsistent. We therefore aimed to determine the association between eosinophilia in bronchoalveolar lavage (BAL) fluid and AECOPD in a clinical cohort. We analyzed differential cell counts from baseline BAL fluid in participants in the DISARM clinical trial (Clinicaltrials.gov #NCT02833480) and classified participants by the presence or absence of BAL eosinophilia (>1% of total leukocytes). We determined the association between BAL eosinophilia and AECOPD over 1 year of follow-up using negative binomial regression and Cox proportional hazards test. N = 63 participants were randomized, and N = 57 had BAL differential cell counts available. Participants with BAL eosinophilia (N = 21) had a significantly increased rate of acute exacerbations (unadjusted incidence rate ratio (IRR) 2.0, p = 0.048; adjusted IRR 2.24, p = 0.04) and a trend toward greater probability of acute exacerbation (unadjusted hazard ratio (HR) 1.74, p = 0.13; adjusted HR 2.3, p = 0.1) in the year of follow-up compared to participants without BAL eosinophilia (N = 36). These associations were not observed for BAL neutrophilia (N = 41 participants), BAL lymphocytosis (N = 27 participants) or peripheral blood eosinophilia at various threshold definitions (2%, N = 37; 3%, N = 27; 4%, N = 16). BAL may therefore be a sensitive marker of eosinophilic inflammation in the distal lung and may be of benefit for risk stratification or biomarker-guided therapy in COPD.

Inhaled Corticosteroids Selectively Alter the Microbiome and Host Transcriptome in the Small Airways of Patients with Chronic Obstructive Pulmonary Disease.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) are commonly treated with inhaled corticosteroid/long-acting ß2-agonist combination therapy. While previous studies have investigated the host-microbiome interactions in COPD, the effects of specific steroid formulations on this complex cross-talk remain obscure. METHODS: We collected and evaluated data from the Study to Investigate the Differential Effects of Inhaled Symbicort and Advair on Lung Microbiota (DISARM), a randomized controlled trial. Bronchoscopy was performed on COPD patients before and after treatment with salmeterol/fluticasone, formoterol/budesonide or formoterol-only. Bronchial brush samples were processed for microbial 16S rRNA gene sequencing and host mRNA sequencing. Longitudinal changes in the microbiome at a community, phylum and genus level were correlated with changes in host gene expression using a Spearman's rank correlation test. FINDINGS: In COPD patients treated with salmeterol/fluticasone, the expression levels of 676 host genes were significantly correlated to changes in the alpha diversity of the small airways. At a genus level, the expression levels of 122 host genes were significantly related to changes in the relative abundance of Haemophilus. Gene enrichment analyses revealed the enrichment of pathways and biological processes related to innate and adaptive immunity and inflammation. None of these changes were evident in patients treated with formoterol/budesonide or formoterol alone. INTERPRETATION: Changes in the microbiome following salmeterol/fluticasone treatment are related to alterations in the host transcriptome in the small airways of patients with COPD. These data may provide insights into why some COPD patients treated with inhaled corticosteroids may be at an increased risk for airway infection, including pneumonia. FUNDING: The Canadian Institute of Health Research, the British Columbia Lung Association, and an investigator-initiated grant from AstraZeneca.

Altered Polarization and Impaired Phagocytic Activity of Lung Macrophages in People With Human Immunodeficiency Virus and Chronic Obstructive Pulmonary Disease.

BACKGROUND: People with human immunodeficiency virus (PWH) have an increased risk of developing chronic obstructive pulmonary disease (COPD). METHODS: We phenotyped lung macrophages in 4 subgroups-M1 (CD40+CD163-), M2 (CD40-CD163+), double positives (CD40+CD163+), and double negatives and (CD40-CD163-)-and we determined their phagocytic capacity in PWH with and without COPD. RESULTS: People with human immunodeficiency virus with COPD have more double-negative macrophages (84.1%) versus PWH without (54.3%) versus controls (23.9%) (P=.004) and reduced phagocytosis (P=.012). Double-negative macrophages had the worst phagocytic capacity (P<.001). CONCLUSIONS: People with human immunodeficiency virus with COPD have an abundance of nonpolarized macrophages, which have poor phagocytic capacity and therefore predispose PWH to increased risk of disease progression.

Effects of Inhaled Corticosteroid/Long-Acting ß2-Agonist Combination on the Airway Microbiome of Patients with Chronic Obstructive Pulmonary Disease: A Randomized Controlled Clinical Trial (DISARM).

Rationale: Inhaled corticosteroids (ICS) are commonly prescribed with long-acting ß2-agonists (LABA) in chronic obstructive pulmonary disease (COPD). To date, the effects of ICS therapy on the airway microbiome in COPD are unknown. Objectives: To determine the effects of ICS/LABA on the airway microbiome of patients with COPD. Methods: Clinically stable patients with COPD were enrolled into a 4-week run-in period during which ICS was discontinued and all participants were placed on formoterol (Form) 12 µg twice daily (BID). The participants were then randomized to budesonide/formoterol (Bud + Form; 400/12 µg BID), fluticasone/salmeterol (Flu + Salm; 250/50 µg BID), or formoterol only (12 µg BID) for 12 weeks. Participants underwent bronchoscopy before and after the 12-week treatment period. The primary endpoint was the comparison of changes in the airway microbiome over the trial period between the ICS/LABA and LABA-only groups. Measurements and Main Results: Sixty-three participants underwent randomization: Bud + Form (n = 20), Flu + Salm (n = 22), and Form (n = 21) groups; 56 subjects completed all visits. After the treatment period, changes in α-diversity were significantly different across groups, especially between Flu + Salm and Form groups (Δrichness: P = 0.02; ΔShannon index: P = 0.03). Longitudinal differential abundance analyses revealed more pronounced microbial shifts from baseline in the fluticasone (vs. budesonide or formoterol only) group. Conclusions: Fluticasone-based ICS/LABA therapy modifies the airway microbiome in COPD, leading to a relative reduction in α-diversity and a greater number of bacterial taxa changes. These data may have implications in patients who develop pneumonia on ICS. Clinical trial registered with www.clinicaltrials.gov (NCT02833480).

Circulating levels of cell adhesion molecules and risk of cardiovascular events in obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) patients are at increased risk of cardiovascular disease (CVD). Cell adhesion molecules (CAM) are increased in OSA and CAM are also implicated in the development of CVD. RESEARCH QUESTION: Do CAM (ICAM-1, VCAM-1 and E-selectin) have prognostic value in identifying risk of cardiovascular events in OSA? STUDY DESIGN AND METHODS: Patients with suspected OSA referred for a polysomnogram provided a fasting blood sample. Plasma levels of ICAM-1, VCAM-1 and E-selectin were determined by multiplex Luminex Assay (Milliporesigma ON, Canada). Cardiovascular events were determined by deterministic linkage to provincial health databases. RESULTS: 418 patients were included in the analysis. Mostly male (68.2%), mean age of 50.7 yrs, median AHI 16.5 events/hour, and mean BMI of 31.7 kg/m2. 36 cardiovascular events occurred in 8-yrs of follow up. Higher levels of ICAM-1 were associated with developing CVD (HR = 3.65 95% CI 1.40-9.53, 2nd and 3rd tertiles vs. 1st tertile), including in patients with OSA (HR = 3.1 95% CI 1.16-8.25). E-selectin was significantly associated with cardiovascular events in patients with moderate to severe OSA (HR = 3.31 95% CI 0.94-11.72, 2nd and 3rd tertiles vs. 1st tertile) but not in patients without moderate to severe OSA (HR = 0.67 95% CI 0.19-2.38), p-value for interaction = 0.07. INTERPRETATION: In a suspected OSA cohort, patients with higher levels of ICAM-1 (>816 ng/ml) were significantly more likely to experience a cardiovascular event within 8 years after PSG. In moderate to severe OSA patients, a higher E-selectin (>36.4 ng/ml) was significantly associated with cardiovascular events.

Macrophages with reduced expressions of classical M1 and M2 surface markers in human bronchoalveolar lavage fluid exhibit pro-inflammatory gene signatures.

The classical M1/M2 polarity of macrophages may not be applicable to inflammatory lung diseases including chronic obstructive pulmonary disease (COPD) due to the complex microenvironment in lungs and the plasticity of macrophages. We examined macrophage sub-phenotypes in bronchoalveolar lavage (BAL) fluid in 25 participants with CD40 (a M1 marker) and CD163 (a M2 marker). Of these, we performed RNA-sequencing on each subtype in 10 patients using the Illumina NextSeq 500. Approximately 25% of the macrophages did not harbor classical M1 or M2 surface markers (double negative, DN), and these cells were significantly enriched in COPD patients compared with non-COPD patients (46.7% vs. 14.5%, p < 0.001). 1886 genes were differentially expressed in the DN subtype compared with  all other subtypes at a 10% false discovery rate. The 602 up-regulated genes included 15 mitochondrial genes and were enriched in 86 gene ontology (GO) biological processes including inflammatory responses. Modules associated with cellular functions including oxidative phosphorylation were significantly down-regulated in the DN subtype. Macrophages in the human BAL fluid, which were negative for both M1/M2 surface markers, harbored a gene signature that was pro-inflammatory and suggested dysfunction in cellular homeostasis. These macrophages may contribute to the pathogenesis and manifestations of inflammatory lung diseases such as COPD.

Obstructive Sleep Apnea Severity, Body Mass Index, and Circulating Levels of Cellular Adhesion Molecules.

PURPOSE: To investigate the relationship between obstructive sleep apnea (OSA) severity, body mass index (BMI), and circulating levels of inflammatory adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin). METHODS: A cross-sectional clinical cohort study on all consecutive adults referred to the University of British Columbia (UBC) Sleep Laboratory for a polysomnogram (PSG) for suspected OSA provided a morning blood sample. Samples were analyzed with multiplex immune assay (MilliporeSigma, CA) to assess the levels of adhesion molecules. RESULTS: 488 patients were studied; the majority were male (68%) with a mean age of 50 yrs, mean AHI of 23 events/hour, and mean BMI of 32 kg/m2. In multivariable linear regression models, all three adhesion molecules were significantly associated with BMI (E-selectin p < 0.0001; ICAM-1 p = 0.0007; VCAM-1 p = 0.0003). However, only E-selectin was independently associated with AHI (p = 0.02); there was no significant interaction between AHI and BMI for E-selectin (p = 0.33). CONCLUSIONS: Although all three adhesion molecules were associated with BMI, only E-selectin was independently associated with OSA severity. Future studies are needed to determine the clinical significance of the relationship between E-selectin and OSA.

Abundance of Non-Polarized Lung Macrophages with Poor Phagocytic Function in Chronic Obstructive Pulmonary Disease (COPD).

Lung macrophages are the key immune effector cells in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Several studies have shown an increase in their numbers in bronchoalveolar lavage fluid (BAL) of subjects with COPD compared to controls, suggesting a pathogenic role in disease initiation and progression. Although reduced lung macrophage phagocytic ability has been previously shown in COPD, the relationship between lung macrophages' phenotypic characteristics and functional properties in COPD is still unclear. (1) Methods: Macrophages harvested from bronchoalveolar lavage (BAL) fluid of subjects with and without COPD (GOLD grades, I-III) were immuno-phenotyped, and their function and gene expression profiles were assessed using targeted assays. (2) Results: BAL macrophages from 18 COPD and 10 (non-COPD) control subjects were evaluated. The majority of macrophages from COPD subjects were non-polarized (negative for both M1 and M2 markers; 77.9%) in contrast to controls (23.9%; p < 0.001). The percentages of these non-polarized macrophages strongly correlated with the severity of COPD (p = 0.006) and current smoking status (p = 0.008). Non-polarized macrophages demonstrated poor phagocytic function in both the control (p = 0.02) and COPD (p < 0.001) subjects. Non-polarized macrophages demonstrated impaired ability to phagocytose Staphylococcus aureus (p < 0.001). They also demonstrated reduced gene expression for CD163, CD40, CCL13 and C1QA&B, which are involved in pathogen recognition and processing and showed an increased gene expression for CXCR4, RAF1, amphiregulin and MAP3K5, which are all involved in promoting the inflammatory response. (3) Conclusions: COPD is associated with an abundance of non-polarized airway macrophages that is related to the severity of COPD. These non-polarized macrophages are predominantly responsible for the poor phagocytic capacity of lung macrophages in COPD, having reduced capacity for pathogen recognition and processing. This could be a key risk factor for COPD exacerbation and could contribute to disease progression.

Macrophages-the immune effector guardians of the lung: impact of corticosteroids on their functional responses.

Lung macrophages (LMs) are key immune effector cells that protect the lung from inhaled particulate matter, noxious gases and pathogens. In Chronic Obstructive Pulmonary Disease (COPD), there is an abundance of macrophages in airspaces and lung tissues suggesting that they play an important role in the pathogenesis of the disease. Furthermore, macrophage phenotype and functional properties are altered in COPD toward a more pro-inflammatory state, characterized by reduced pathogen recognition and processing ability and dysfunctional tissue repair qualities. Inhaled corticosteroids (ICSs), used in the management of COPD, has been shown to reduce acute exacerbations of COPD but is also associated with increased occurrence of pneumonia. Corticosteroids treatment altered LM phenotypic characteristics and their functional properties, and this commentary discusses current knowledge and also the gaps in our understanding of the impact of ICS on LMs phenotype and function. A better understanding of how ICSs impact the immune-inflammatory responses in the lung, in particular ICSs' effects on LMs, could allow more selective personalized tailoring of the use of ICSs in COPD to improve disease progression, morbidity and mortality.

Air Pollution and Systemic Inflammation in Patients With Suspected OSA Living in an Urban Residential Area.

BACKGROUND: Air pollution and OSA are independently associated with systemic inflammation, but it is unknown if these exposures interact to influence systemic inflammation. RESEARCH QUESTION: The study objective was to determine the relative importance of these factors and their combined potential to influence systemic inflammation in patients under assessment for sleep ailments. STUDY DESIGN AND METHODS: A total of 315 patients contributed data, including a questionnaire, polysomnogram, and morning serum IL-6 and IL-10 concentrations. For each patient, residential annual average air pollution exposure (nitrogen dioxide [NO2], black carbon [BC], and particulate matter with an aerodynamic diameter ≤ 2.5 µm [PM2.5]) was estimated with a land use regression model. Linear regression modeling was used adjusting for age, sex, apnea-hypopnea index, BMI, smoking, socioeconomic status, and comorbidities. RESULTS: In adjusted models, quartile 4 PM2.5 exposure (compared with quartiles 1-3) was associated with increased IL-6 and IL-10 concentrations (estimated adjusted, 7.1 pg/mL [95% CI, 2.5-11.7; P < .01] and 71.4 pg/mL [95% CI, 38.2-103.7; P < .0001], respectively). OSA, BC, and NO2 were not associated with IL-6 or IL-10 in similar analyses; however, moderate to severe OSA influenced the effect of BC on IL-6 (interaction term, P = .01), with no significant interaction terms observed for NO2 or PM2.5. Subsequent stratified analysis showed that in the 173 patients with moderate to severe OSA, quartile 4 BC exposure (compared with quartiles 1-3) was associated with an increased IL-6 concentration (estimated adjusted, 8.9 pg/mL; 95% CI, 1.7-16.1; P = .02). INTERPRETATION: Long-term residential PM2.5 exposure was associated with increased IL-6 and IL-10 concentrations in patients evaluated for suspected OSA. BC exposure was also associated with increased IL-6 but only in the subgroup of patients with moderate to severe OSA. These data suggest the potential for joint effects of moderate to severe OSA and air pollution on systemic inflammation.

Lung Macrophage Functional Properties in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is caused by the chronic exposure of the lungs to toxic particles and gases. These exposures initiate a persistent innate and adaptive immune inflammatory response in the airways and lung tissues. Lung macrophages (LMs) are key innate immune effector cells that identify, engulf, and destroy pathogens and process inhaled particles, including cigarette smoke and particulate matter (PM), the main environmental triggers for COPD. The number of LMs in lung tissues and airspaces is increased in COPD, suggesting a potential key role for LMs in initiating and perpetuating the chronic inflammatory response that underpins the progressive nature of COPD. The purpose of this brief review is to discuss the origins of LMs, their functional properties (chemotaxis, recruitment, mediator production, phagocytosis and apoptosis) and changes in these properties due to exposure to cigarette smoke, ambient particulate and pathogens, as well as their persistent altered functional properties in subjects with established COPD. We also explore the potential to therapeutically modulate and restore LMs functional properties, to improve impaired immune system, prevent the progression of lung tissue destruction, and improve both morbidity and mortality related to COPD.

Immune-Modulation in Chronic Obstructive Pulmonary Disease: Current Concepts and Future Strategies.

Chronic obstructive pulmonary disease (COPD) is caused by the chronic inhalation of toxic particles and gases that are primarily but not exclusively derived from cigarette smoke that may be either actively or passively inhaled, which initiates a persistent innate and adaptive immune response in the lung. This immune response is associated with an aberrant tissue repair and remodeling process that results in varying degrees of chronic inflammation with excess production of mucus in the central airways and permanent destruction of the smaller conducting airways and gas exchanging surface in the peripheral lung. Currently, the primary aims of treatment in COPD are bronchodilation (inhaled short- and long-acting ß-agonist and antimuscarinic therapies), to control symptoms and nonspecific broad-acting anti-inflammatory agents (inhaled and oral corticosteroids, phosphor-di-esterase inhibitors, and macrolides). That provide symptomatic relief but have little or no impact on either disease progression or mortality. As our understanding of the immune pathogenesis of the COPD improves, available immune modulation therapies have the potential to alter or interfere with damaging immune pathways, thereby slowing relentless progression of lung tissue destruction. The purpose of this brief review is to discuss our current understanding of the immune pathogenesis of both the airways and parenchymal injury as well as the dysfunctional tissue repair process to propose immune modulating interventions in an attempt to stabilize or return these pathological changes to their normal state. The ultimate goal of the immune modulation therapy is to improve both morbidity and mortality associated with COPD.

Adhesion molecule gene variants and plasma protein levels in patients with suspected obstructive sleep apnea.

STUDY OBJECTIVES: Untreated obstructive sleep apnea (OSA) patients have an increased risk of cardiovascular disease (CVD). Adhesion molecules, including soluble E-selectin (sE-selectin), intercellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1), are associated with incident CVD. We hypothesized that specific genetic variants will be associated with plasma levels of adhesion molecules in suspected OSA patients. We also hypothesized that there may be an interaction between these variants and OSA. METHODS: We measured levels of sE-selectin, sICAM-1 and sVCAM-1 in 491 patients with suspected OSA and genotyped them for 20 polymorphisms. RESULTS: The most significant association was between the ABO rs579459 polymorphism and sE-selectin levels (P = 7×10-21), with the major allele T associated with higher levels. The direction of effect and proportion of the variance in sE-selectin levels accounted for by rs579459 (16%) was consistent with estimates from non-OSA cohorts. In a multivariate regression analysis, addition of rs579459 improved the model performance in predicting sE-selectin levels. Three polymorphisms were nominally associated with sICAM-1 levels but none with sVCAM-1 levels. The combination of severe OSA and two rs579459 T alleles identified a group of patients with high sE-selectin levels; however, the increase in sE-selectin levels associated with severe OSA was greater in patients without two T alleles (P = 0.05 test for interaction). CONCLUSIONS: These genetic polymorphisms may help to identify patients at greatest risk of incident CVD and may help in developing a more precision-based approach to OSA care.

Emergency department management of acute exacerbations of chronic obstructive pulmonary disease: factors predicting readmission.

Rationale: Readmissions are common following acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and are partially responsible for increased morbidity and mortality in COPD. Numerous factors have been shown to predict readmission of patients previously admitted to hospital for AECOPD; however, factors related to readmission in patients who are triaged in emergency departments (EDs) and sent directly home are poorly understood. We postulate that patients seen in the ED for AECOPD and directly sent home have a high readmission rate, and we suspect that inadequate management and follow-up contribute to this high readmission rate. Methods: We conducted a 1-year retrospective study of all patients seen in the ED for AECOPD at an inner-city tertiary care hospital; 30- and 90-day readmission rates for COPD and all-cause admissions to the ED and hospital were determined. Patients discharged directly home from the ED were compared with those admitted to hospital for management. Patient, treatment, and system variables that could potentially impact readmission were documented. Multivariate Poisson regression models were used to determine which factors predicted readmissions. Results: The readmission rates in the ED group (n=240) were significantly higher than that in the hospitalized group (n=271): 1) the 90-day ED readmissions (1.29 vs 0.51, p<0.0001) and 30-day ED readmissions (0.54 vs 0.20, p<0.0001) (ED vs hospitalized groups) were significantly higher in the ED group; 2) the time to first readmission was significantly shorter in the ED group than in the hospitalized group (24.1±22 vs 31.8±27.8 days; p<0.05). Cardiovascular comorbidities (p<0.00001), substance abuse disorder (p<0.001), and mental illness (p<0.001) were the strongest predictors of readmission in the ED group. Age (p<0.01), forced expiratory volume in 1 second (p<0.001), and cardiovascular comorbidities (p<0.05) were the best predictors for both 30- and 90-day COPD readmission rates in the ED group. Only 50% of the ED group patients received bronchodilators, oral steroids, and antibiotics inclusively, and only 68% were referred for community follow-up. The need for oral steroids to treat AECOPD predicted future 90-day COPD readmissions in the ED group (p<0.003). Conclusion: Patients discharged directly home from EDs have a significantly higher risk of readmission to EDs than those who are hospitalized. One possible reason for this is that COPD management is variable in EDs with <50% receiving appropriate therapy.