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Njira Lugogo,1 Bradley E Chipps,2 Reynold A Panettieri Jr,3 Frank Trudo,4 Christopher S Ambrose5 1University of Michigan, Ann Arbor, MI, USA; 2Capital Allergy & Respiratory Disease Center, Sacramento, CA, USA; 3Rutgers, The State University of New Jersey, New Brunswick, NJ, USA; 4AstraZeneca, Wilmington, DE, USA; 5AstraZeneca, Gaithersburg, MD, USACorrespondence: Christopher S Ambrose, BioPharmaceuticals Medical, AstraZeneca, One MedImmune Way, Gaithersburg, MD, 20878, USA, Tel +1 301-398-4454, Email chris.ambrose@astrazeneca.comAbstract: There is growing recognition of the adverse consequences of maintenance systemic corticosteroid (mSCS) therapy in severe asthma (SA). The objective of this study was to describe the prevalence of potential adverse effects of long-term mSCS therapy in adults with specialist-confirmed SA in the United States (US). CHRONICLE is an ongoing, noninterventional, observational study of US adults with SA treated by allergists/immunologists and pulmonologists. Once enrolled, patients’ duration of mSCS therapy was reported by sites based on medical record review. For patients enrolled between February 2018 and February 2021, the prevalence of SCS-associated conditions was evaluated among those with no reported history of mSCS use, or mSCS use with < 2 years or ≥ 2 years cumulative duration. Prevalence and incidence estimates were adjusted for age and smoking history. Of 2793 patients enrolled, 311 and 231 had mSCS use for < 2 and ≥ 2 years, respectively. In adjusted analyses, adrenal insufficiency, pneumonia, type 2 diabetes, osteoporosis/osteopenia, congestive heart failure, coronary artery disease, hypertension, anxiety, and depression were statistically significantly associated with any mSCS use. By duration, mSCS use ≥ 2 years was associated with osteopenia/osteoporosis, coronary artery disease, adrenal insufficiency, and diabetes-related neuropathy; mSCS use < 2 years was associated with depression and osteopenia/osteoporosis, and diagnoses of depression, anxiety, and hypertension during the 12 months prior to enrollment. Overall, among patients with specialist-confirmed SA, mSCS use was associated with a high prevalence of multiple adverse conditions. Healthcare professionals should employ mSCS-sparing treatment strategies to avoid these negative consequences.Keywords: duration, steroids, diabetes, pneumonia, osteoporosis

Rachel Pullen, 1, 2 Marc Miravitlles, 3 Anita Sharma, 4 Dave Singh, 5 Fernando Martinez, 6 John R Hurst, 7 Luis Alves, 8, 9 Mark Dransfield, 10 Rongchang Chen, 11 Shigeo Muro, 12 Tonya Winders, 13 Christopher Blango, 14 Hana Muellerova, 15 Frank Trudo, 16 Paul Dorinsky, 17 Marianna Alacqua, 15, 18 Tamsin Morris, 19 Victoria Carter, 1, 2 Amy Couper, 1, 2 Rupert Jones, 20 Konstantinos Kostikas, 1, 21 Ruth Murray, 1 David B Price 1, 2, 22 1Observational and Pragmatic Research Institute, Singapore, Singapore; 2Optimum Patient Care, Cambridge, UK; 3Pneumology Dept, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain; 4Platinum Medical Centre, Chermside, QLD, Australia; 5Division of Infection, Immunity & Respiratory Medicine, University of Manchester, Manchester University NHS Foundation Trust, Manchester, UK; 6New York-Presbyterian Weill Cornell Medical Center, New York, NY, USA; 7UCL Respiratory, University College London, London, UK; 8EPI Unit, Institute of Public Health, University of Porto, Porto, Portugal; 9Laboratory for Integrative and Translational Research in Population Health (ITR), Porto, Portugal; 10Division of Pulmonary, Allergy, and Critical Care Medicine, Lung Health Center, University of Alabama at Birmingham, Birmingham, AL, USA; 11Key Laboratory of Respiratory Disease of Shenzhen, Shenzhen Institute of Respiratory Disease, Shenzhen People’s Hospital (Second Affiliated Hospital of Jinan University, First Affiliated Hospital of South University of Science and Technology of China), Shenzhen, People’s Republic of China; 12Department of Respiratory Medicine, Nara Medical University, Nara, Japan; 13USA & Global Allergy & Airways Patient Platform, Vienna, Austria; 14Janssen Pharmaceutical Companies of Johnson & Johnson, Philadelphia, PA, USA; 15AstraZeneca, Cambridge, UK; 16AstraZeneca, Wilmington, DE, USA; 17AstraZeneca, Durham, NC, USA; 18CSL Behring SpA, Milan, Italy; 19AstraZeneca, Luton, UK; 20Research and Knowledge Exchange, Plymouth Marjon University, Plymouth, UK; 21Respiratory Medicine Department, University of Ioannina School of Medicine, Ioannina, Greece; 22Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UKCorrespondence: David B PriceCentre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Polwarth Building, Foresterhill, Aberdeen, AB25 2ZD, UKTel +65 3105 1489Email dprice@opri.sgBackground: Chronic obstructive pulmonary disease (COPD) are managed predominantly in primary care. However, key opportunities to optimize treatment are often not realized due to unrecognized disease and delayed implementation of appropriate interventions for both diagnosed and undiagnosed individuals. The COllaboratioN on QUality improvement initiative for achieving Excellence in STandards of COPD care (CONQUEST) is the first-of-its-kind, collaborative, interventional COPD registry. It comprises an integrated quality improvement program focusing on patients (diagnosed and undiagnosed) at a modifiable and higher risk of COPD exacerbations. The first step in CONQUEST was the development of quality standards (QS). The QS will be imbedded in routine primary and secondary care, and are designed to drive patient-centered, targeted, risk-based assessment and management optimization. Our aim is to provide an overview of the CONQUEST QS, including how they were developed, as well as the rationale for, and evidence to support, their inclusion in healthcare systems.Methods: The QS were developed (between November 2019 and December 2020) by the CONQUEST Global Steering Committee, including 11 internationally recognized experts with a specialty and research focus in COPD. The process included an extensive literature review, generation of QS draft wording, three iterative rounds of review, and consensus.Results: Four QS were developed: 1) identification of COPD target population, 2) assessment of disease and quantification of future risk, 3) non-pharmacological and pharmacological intervention, and 4) appropriate follow-up. Each QS is followed by a rationale statement and a summary of current guidelines and research evidence relating to the standard and its components.Conclusion: The CONQUEST QS represent an important step in our aim to improve care for patients with COPD in primary and secondary care. They will help to transform the patient journey, by encouraging early intervention to identify, assess, optimally manage and followup COPD patients with modifiable high risk of future exacerbations.Keywords: identification, assessment, intervention, follow-up

Weily Soong,1 Bradley E Chipps,2 Sean O’Quinn,3 Jennifer Trevor,4 Warner W Carr,5 Laura Belton,6 Frank Trudo,7 Christopher S Ambrose3 1Alabama Allergy & Asthma Center, Birmingham, AL, USA; 2Capital Allergy & Respiratory Disease Center, Sacramento, CA, USA; 3BioPharmaceuticals Medical, AstraZeneca, Gaithersburg, MD, USA; 4University of Alabama at Birmingham, Birmingham, AL, USA; 5Allergy & Asthma Associates of Southern California, Mission Viejo, CA, USA; 6Biostatistics, AstraZeneca, Cambridge, UK; 7BioPharmaceuticals Medical, AstraZeneca, Wilmington, DE, USACorrespondence: Weily SoongAlabama Allergy & Asthma Center, 504 Brookwood Boulevard, Birmingham, AL, 35209, USATel +1 205 871-9661Fax +1 205 870-1621Email wsoong@alabamaallergy.comBackground: Health-related quality of life (HRQoL) and productivity of patients with confirmed severe asthma (SA) have not been well characterized in large, real-world populations.Purpose: To characterize SA impact on HRQoL, work productivity, and activity impairment in a large, real-world cohort in the United States (US).Methods: CHRONICLE is an observational study of specialist-treated adults (≥ 18 years) in the US with SA receiving biologics or maintenance systemic corticosteroids (mSCS), or those persistently uncontrolled by high-dosage inhaled corticosteroids with additional controllers (HD ICS+). At enrollment, patients completed the St. George’s Respiratory Questionnaire (SGRQ) and Work Productivity and Activity Impairment (WPAI) questionnaire. Results were analyzed for those enrolled between February 2018 and February 2020.Results: Among patients who completed enrollment questionnaires (n = 1109), mean age was 54 years and most were women (70%). Among SGRQ respondents (n = 960), mean (SD) total score was 43 (23); 51% reported good/very good health. Among WPAI respondents (n = 1057; 566 employed), mean (SD) overall work impairment was 21% (25). Patients receiving biologics (vs mSCS, HD ICS+ only) had better SGRQ total scores (38 vs 59, 48) and lower work impairment (17% vs 34%, 27%). Patients with better SGRQ activity scores relative to symptom scores had better SGRQ impacts scores, total scores, and reported better overall health.Conclusion: SA significantly affects HRQoL, work productivity, and activity. The SGRQ is a valuable research instrument for evaluating HRQoL in SA. Due to its association with HRQoL and overall health, activity impairment should be a focus when monitoring patients’ disease control.Study Registration: ClinicalTrials.gov Identifier: NCT03373045.Keywords: real-world, St. George’s Respiratory Questionnaire, SGRQ, WPAI, symptoms, activity

Gary T Ferguson,1 Tor Skärby,2 Lars H Nordenmark,2 Rosa Lamarca,3 Audrone Aksomaityte,4 Dan Lythgoe,4 Ileen Gilbert,5 Frank Trudo5 1Department of Medicine, Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA; 2BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 3BioPharmaceuticals R&D, AstraZeneca, Barcelona, Spain; 4Statistics Department, Phastar, London, UK; 5BioPharmaceuticals Medical – US, AstraZeneca LP, Wilmington, DE, USACorrespondence: Gary T FergusonMD, Pulmonary Research Institute of Southeast Michigan, 29255 West 10 Mile Road, Suite A, Farmington Hills, MI 48336, USATel +1 248 478 6561Email garytferguson@msn.comPurpose: Moderate and severe COPD exacerbations are a significant health-care burden, but patients also experience “mild” exacerbations, or COPD symptom-related attacks, which often go unreported. We aimed to define and then determine the incidence of COPD symptom-related attacks and their impact on future risk of moderate/severe exacerbations, health-related quality of life (HRQoL), and lung function. The effect of COPD maintenance therapy on the attack definition was then evaluated by comparing budesonide/formoterol with formoterol alone.Patients and Methods: This post hoc analysis of the RISE study defined COPD symptom-related attacks as ≥ 2 consecutive days of both worsening symptoms and increased daily rescue medication use based upon thresholds of > 2 and > 4 short-acting β2-agonist (SABA) inhalations/day above baseline. The impact of these events on subsequent moderate/severe exacerbation risk was estimated using a time-varying Cox proportional hazards model. The effects of COPD symptom-related attacks on St George’s Respiratory Questionnaire (SGRQ) total score and pre-bronchodilator forced expiratory volume in 1 second (FEV1) were evaluated as average changes from baseline to first post-attack measurement. Rates of attacks were compared between treatment groups using negative binomial regression models.Results: COPD symptom-related attacks elevated the risk of subsequent moderate/severe exacerbations at both > 2 and > 4 inhalations/day above baseline (HR 1.86 and 2.21, respectively; p< 0.0001), with a cumulative increase in risk with increasing attacks. HRQoL and lung function were reduced for patients with ≥ 1 versus no COPD symptom-related attacks at both rescue medication thresholds. There were fewer COPD symptom-related attacks with budesonide/formoterol versus formoterol alone, with no increased risk of pneumonia and lower respiratory tract infections.Conclusion: COPD symptom-related attacks are common and typically unreported. Importantly, these attacks can account for considerable morbidity and should not be regarded as “mild”. Detection of such exacerbations may be valuable in identifying patients at greater risk and guiding preventive therapeutic interventions.Keywords: COPD, exacerbation, symptoms, rescue inhaler, mild COPD exacerbations

Matthew J Hegewald,1,2 Benjamin D Horne,3,4 Frank Trudo,5 James L Kreindler,5 Yen Chung,5 Susan Rea,6 Denitza P Blagev1,2 1Pulmonary and Critical Care Medicine Division, Intermountain Medical Center, Murray, UT, USA; 2Pulmonary and Critical Care Medicine, University of Utah, Salt Lake City, UT, USA; 3Intermountain Heart Institute at Intermountain Healthcare, Salt Lake City, UT, USA; 4Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; 5Health Economics Outcomes Research, AstraZeneca, Wilmington, DE, USA; 6Enterprise Analytics, Intermountain Healthcare, Salt Lake City, UT, USACorrespondence: Matthew J HegewaldPulmonary and Critical Care Medicine Division, Intermountain Medical Center, 5121 S Cottonwood Street, Murray, UT 84107, USATel +1-801-507-4870Fax +1-801-507-4792Email matt.hegewald@imail.orgPurpose: This retrospective, observational cohort study investigated the association of blood eosinophil counts within 1 week of hospitalization for acute exacerbation of COPD (AECOPD) with subsequent risk of all-cause and COPD-related readmission from a large integrated health system.Patients and Methods: Electronic medical records were extracted for index hospitalization for AECOPD at all Intermountain Healthcare hospitals. The primary outcome was the relationship of blood eosinophil count to 30-day all-cause readmission; secondary outcomes were 60-day, 90-day, and 12-month all-cause readmission, COPD-related readmission, and empiric derivation of the eosinophil count with the highest area under the curve (AUC) for predicting 30-day all-cause readmission.Results: Of 2445 included patients, 1935 (79%) had a blood eosinophil count < 300 cells/μL and 510 (21%) had a count ≥ 300 cells/μL. Using a 300-cells/μL threshold, there was no significant difference between high and low eosinophil groups in 30-day (odds ratio [OR]=1.05, 95% confidence interval [CI]=0.75– 1.47) or 60-day (OR=1.15, 95% CI=0.88– 1.51) all-cause readmissions. However, patients with greater (versus lesser) eosinophil counts had increased 90-day and 12-month all-cause readmissions (OR=1.35, 95% CI=1.06– 1.72, and OR=1.32, 95% CI=1.07– 1.62). COPD-related readmission rates were significantly greater for patients with greater (versus lesser) eosinophil counts at 30, 60, and 90 days and 12 months (OR range=1.52– 1.97). A total of 70 cells/μL had the most discriminatory power to predict 30-day all-cause readmission (highest AUC).Conclusion: Eosinophil counts in patients with COPD were not associated with a difference in 30-day all-cause readmissions. However, greater eosinophil counts were associated with increased risk of all-cause readmission at 90 days and 12 months and COPD-related readmission at 30, 60, and 90 days and 12 months. Patients with eosinophils < 70 cells/μL had the lowest risk for 30-day all-cause readmission. Blood eosinophils in patients hospitalized with AECOPD may be a useful biomarker for the risk of hospital readmission.Keywords: AECOPD, phenotype, biomarkers, eosinophils, electronic medical records

Frank Trudo,1 Lee Kallenbach,2 Joseph Vasey,2 Yen Chung,1 Alan Wilk,2 Lukas Slipski,2 Dan O’Brien,2 Charlie Strange3 1Respiratory and Inflammation Therapeutic Area, AstraZeneca, Wilmington, DE, USA; 2Life Sciences, Practice Fusion, San Francisco, CA, USA; 3Department of Medicine, Medical University of South Carolina, Charleston, SC, USACorrespondence: Frank TrudoAstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19897, USAEmail Frank.Trudo@astrazeneca.comPurpose: We sought to describe clinical and economic outcomes for COPD patients by blood eosinophil (EOS) count.Methods: This retrospective cohort study of COPD patients used data from the Practice Fusion electronic medical records (EMR) database linked to Symphony Health Solutions transactional pharmacy, medical, outpatient, and inpatient claims data to evaluate COPD-related and all-cause health care resource utilization and cost in the 12-month period following the date of each patient’s greatest recorded blood eosinophil count during the 27-month period from January 2014 to March 2016. A post-index moderate exacerbation was defined as an outpatient or emergency care visit for COPD and a prescription for oral corticosteroid and/or antibiotics within 10 days of the visit. Severe exacerbation was defined as an inpatient hospitalization with COPD as primary diagnosis.Results: Of 48,090 EMR patients, 39,939 (83.1%) had a charge in the claims data both pre- and post-index (mean age 67.2 years, 58.3% female), 17,397 (43.6%) had EOS ≥220 cells/μL. Moderate and severe exacerbations were more frequent for patients with EOS≥220 cells/μL compared with those with EOS Conclusion: COPD patients with EOS counts ≥220 cells/μL were more likely to have had moderate or severe exacerbations and greater cost of care than those with EOS Keywords: clinical phenotypes, electronic medical records, exacerbations, health care resource utilization, eosinophils

David B Price,1,2 Frank Trudo,3 Jaco Voorham,1 Xiao Xu,4 Marjan Kerkhof,1 Joanna Ling Zhi Jie,1 Trung N Tran5 1Observational and Pragmatic Research Institute, Singapore, Singapore; 2Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; 3Medical Affairs, AstraZeneca, Wilmington, DE, USA; 4Global Payer Evidence and Pricing, AstraZeneca, Gaithersburg, MD, USA; 5Medical Evidence and Observational Research, AstraZeneca, Gaithersburg, MD, USA Purpose: Prior work suggests a threshold of four courses/year of systemic corticosteroid (SCS) therapy is associated with adverse consequences. The objective of this study was to investigate the onset of adverse outcomes beginning at SCS initiation in a broad asthma population. Patients and methods: This historical matched cohort study utilized anonymized, longitudinal medical record data (1984–2017) of patients (≥18 years) with active asthma. Matched patients with first SCS prescription (SCS arm) and no SCS exposure (non-SCS arm) were followed until first outcome event. Associations between time-varying exposure measures and onset of 17 SCS-associated adverse outcomes were estimated using Cox proportional hazard regression, adjusting for confounders, in separate models. Results: We matched 24,117 pairs of patients with median record availability before SCS initiation of 9.9 and 8.7 years and median follow-up 7.4 and 6.4 years in SCS and non-SCS arms, respectively. Compared with patients in the non-SCS arm, patients prescribed SCS had significantly increased risk of osteoporosis/osteoporotic fracture (adjusted hazard ratio 3.11; 95% CI 1.87–5.19), pneumonia (2.68; 2.30–3.11), cardio-/cerebrovascular diseases (1.53; 1.36–1.72), cataract (1.50; 1.31–1.73), sleep apnea (1.40; 1.04–1.86), renal impairment (1.36; 1.26–1.47), depression/anxiety (1.31; 1.21–1.41), type 2 diabetes (1.26; 1.15–1.37), and weight gain (1.14; 1.10–1.18). A dose-response relationship for cumulative SCS exposure with most adverse outcomes began at cumulative exposures of 1.0–0–

Frank Trudo,1 David M Kern,2 Jill R Davis,1 Ozgur Tunceli,2 Siting Zhou,2 Emma L Graham,3 Charlie Strange,4 Setareh A Williams1 1AstraZeneca Pharmaceuticals LP, 2HealthCore, Inc., Wilmington, DE, USA; 3AstraZeneca Pharmaceuticals LP, Alderley Park, Cheshire, UK; 4Division of Pulmonary and Critical Care Medicine, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA Background: Inhaled corticosteroid/long-acting β2-agonist combinations and/or long-acting muscarinic antagonists are recommended first-line therapies for preventing chronic obstructive pulmonary disease (COPD) exacerbation. Comparative effectiveness of budesonide/formoterol combination (BFC, an inhaled corticosteroid/long-acting β2-agonist combination) vs tiotropium (long-acting muscarinic antagonist) in the US has not yet been studied.Methods: Using US claims data from the HealthCore Integrated Research Environment, COPD patients (with or without comorbid asthma) ≥40 years old initiating BFC or tiotropium between March 1, 2009 and February 28, 2012 and at risk for exacerbation were identified and followed for 12 months. Patients were propensity score matched on demographics and COPD disease severity indicators. The primary outcome was time to first COPD exacerbation. Secondary outcomes included COPD exacerbation rate, health care resource utilization, and costs.Results: The Cox proportional hazards model for time to first exacerbation yielded a hazard ratio (HR) of 0.78 (95% CI =[0.70, 0.87], P

David M Kern,1 Jill Davis,2 Setareh A Williams,3 Ozgur Tunceli,1 Bingcao Wu,1 Sally Hollis,4 Charlie Strange,5 Frank Trudo2 1HealthCore, Inc., Wilmington, DE, 2AstraZeneca Pharmaceuticals, Wilmington, DE, 3AstraZeneca Pharmaceuticals, Gaithersburg, MD, USA; 4AstraZeneca Pharmaceuticals, Cheshire, UK; 5Department of Medicine, Division of Pulmonary and Critical Care Medicine, Medical University of South Carolina, Charleston, SC, USA Objective: To estimate the accuracy of claims-based pneumonia diagnoses in COPD patients using clinical information in medical records as the reference standard.Methods: Selecting from a repository containing members’ data from 14 regional United States health plans, this validation study identified pneumonia diagnoses within a group of patients initiating treatment for COPD between March 1, 2009 and March 31, 2012. Patients with ≥1 claim for pneumonia (International Classification of Diseases Version 9-CM code 480.xx–486.xx) were identified during the 12 months following treatment initiation. A subset of 800 patients was randomly selected to abstract medical record data (paper based and electronic) for a target sample of 400 patients, to estimate validity within 5% margin of error. Positive predictive value (PPV) was calculated for the claims diagnosis of pneumonia relative to the reference standard, defined as a documented diagnosis in the medical record.Results: A total of 388 records were reviewed; 311 included a documented pneumonia diagnosis, indicating 80.2% (95% confidence interval [CI]: 75.8% to 84.0%) of claims-identified pneumonia diagnoses were validated by the medical charts. Claims-based diagnoses in inpatient or emergency departments (n=185) had greater PPV versus outpatient settings (n=203), 87.6% (95% CI: 81.9%–92.0%) versus 73.4% (95% CI: 66.8%–79.3%), respectively. Claims-diagnoses verified with paper-based charts had similar PPV as the overall study sample, 80.2% (95% CI: 71.1%–87.5%), and higher PPV than those linked to electronic medical records, 73.3% (95% CI: 65.5%–80.2%). Combined paper-based and electronic records had a higher PPV, 87.6% (95% CI: 80.9%–92.6%).Conclusion: Administrative claims data indicating a diagnosis of pneumonia in COPD patients are supported by medical records. The accuracy of a medical record diagnosis of pneumonia remains unknown. With increased use of claims data in medical research, COPD researchers can study pneumonia with confidence that claims data are a valid tool when studying the safety of COPD therapies that could potentially lead to increased pneumonia susceptibility or severity. Keywords: positive predictive value, pneumonia, validation, claims data, medical record review

David M Kern,1 Setareh A Williams,2 Ozgur Tunceli,1 Catrin Wessman,3 Siting Zhou,1 Ned Pethick,2 Hanaa Elhefni,2 Frank Trudo2 1HealthCore Inc., 2AstraZeneca, Wilmington, DE, USA; 3AstraZeneca, Mölndal, Sweden Objective: To compare clinical and demographic characteristics, resource utilization and costs of chronic obstructive pulmonary disease (COPD) patients prior to initiating budesonide–formoterol combination (BFC) or tiotropium-maintenance therapy. Materials and methods: This cross-sectional study used claims-based diagnosis to identify COPD patients in the HealthCore Integrated Research Database who initiated BFC or tiotropium therapy between March 1, 2009 and January 31, 2012 (intake period); the index date was defined as the initial prescription fill for either agent. Patients diagnosed with respiratory tract cancer or receiving inhaled corticosteroids/long-acting β2-adrenergic agonists or tiotropium in 12 months prior to index date were excluded. Categorical variables were evaluated with Χ2 tests; mean cost differences were evaluated using γ-regression. Results: Overall, 6,940 BFC and 10,831 tiotropium patients were identified. The BFC group was younger (mean age 64 versus 67 years), with a greater proportion of females (54% versus 51%). BFC-treated patients had more comorbid respiratory conditions, including asthma (25% versus 13%), but fewer comorbid cardiovascular conditions, including atherosclerosis (7% versus 10%) and myocardial infarction (4% versus 6%). A greater proportion of BFC patients received prior respiratory medication, including oral corticosteroids (46% versus 35%) and short-acting β2-agonists (44% versus 35%). Tiotropium-treated patients had a greater mean number of COPD-related outpatient visits (4.6 versus 4.1). BFC-treated patients had lower total all-cause ($17,259 versus $17,926) and COPD-related ($1,718 versus $1,930) health care costs, driven by lower all-cause and COPD-related inpatient expenditures. Conclusion: Initiators of BFC or tiotropium showed differences in clinical and demographic characteristics and health care utilization and costs prior to starting COPD maintenance therapy. Keywords: observational study, retrospective analysis, chronic respiratory condition, outcome research, health care utilization and costs

Objective: To quantitatively examine changes in the upper airway caliber of normal subjects at graded negative inspiratory pressures generated during nasopharyngoscopy with a Müller maneuver.Study Design: Eighteen normal subjects prospectively underwent nasopharyngoscopy with Müller maneuvers. Subjects performed graded and maximal effort Müller maneuvers while sitting upright, and maximal-effort Müller maneuvers in the supine position. Two regions of the upper airway--the retropalatal and retroglossal--were examined.Methods: Images from the endoscopic examination were objectively analyzed by adjusting manually traced airway contours using full-width, half-maximum edge detection algorithm software. The adjusted tracings' area and dimensions through the airway centroid were measured.Results: Müller maneuvers performed at -40 cm H2O resulted in a 64%+/-17% (P = .0001) reduction in upper airway area that consisted of a 51%+/-20% (P = .0001) reduction in the lateral dimension and a 21%+/-24% (P = .0026) reduction in antero-posterior dimension. Müller maneuvers in the retroglossal region did not significantly reduce airway area (P = .575), but demonstrated an altered airway conformation that consisted of lateral narrowing and an increase in antero-posterior dimension. Changes in body position did not result in significant differences in either airway caliber or airway dimension.Conclusions: Airway caliber during forced inspiration is mediated primarily through changes in the lateral pharyngeal walls. This study has also shown that antero-posterior and lateral airway structures are largely independent in their response to Müller maneuvers. Similarly, the retropalatal and retroglossal regions of the upper airway respond differently to forced negative intraluminal pressure. [ABSTRACT FROM AUTHOR]

Background: Severe eosinophilic asthma (SEA) is characterised by elevated blood/sputum eosinophil counts and airway inflammation, which can lead to mucus plug-mediated airway obstruction, increased exacerbation frequency, declines in lung function, and death. Benralizumab targets the alpha-subunit of the interleukin-5 receptor found on eosinophils, leading to rapid and near complete eosinophil depletion. This is expected to result in reduced eosinophilic inflammation, reduced mucus plugging and improved airway patency and airflow distribution., Methods: BURAN is an interventional, single-arm, open-label, uncontrolled, prospective, multicentre study during which participants will receive three 30 mg subcutaneous doses of benralizumab at 4-week intervals. This study will use functional respiratory imaging (FRI), a novel, quantitative method of assessing patients' lung structure and function based on detailed, three-dimensional models of the airways, with direct comparison of images taken at Weeks 0 and 13. Patients aged ≥ 18 years with established SEA who may be receiving oral corticosteroids and/or other asthma controller medications, who are inadequately controlled on inhaled corticosteroid-long-acting β 2 -agonist therapies and who have had ≥ 2 asthma exacerbations in the previous 12 months will be included. The objectives of BURAN are to describe changes in airway geometry and dynamics, measured by specific image-based airway volume and other FRI endpoints, following benralizumab therapy. Outcomes will be evaluated using descriptive statistics. Changes in FRI parameters, mucus plugging scores and central/peripheral ratio will be quantified as mean percent change from baseline (Week 0) to Week 13 (± 5 days) and statistical significance will be evaluated using paired t-tests. Relationships between FRI parameters/mucus plugging scores and conventional lung function measurements at baseline will be assessed with linear regression analyses for associations between outcomes, scatterplots to visualise the relationship, and correlation coefficients (Spearman's rank and Pearson's) to quantify the strength of these associations., Conclusions: The BURAN study will represent one of the first applications of FRI-a novel, non-invasive, highly sensitive method of assessing lung structure, function and health-in the field of biologic respiratory therapies. Findings from this study will increase understanding of cellular-level eosinophil depletion mechanisms and improvements in lung function and asthma control following benralizumab treatment. Trial registration EudraCT: 2022-000152-11 and NCT05552508., (© 2023. The Author(s).)

Objective: To describe clinical outcomes in patients with severe asthma (SA) by common sociodemographic determinants of health: sex, race, ethnicity, and age., Methods: CHRONICLE is an observational study of subspecialist-treated, United States adults with SA receiving biologic therapy, maintenance systemic corticosteroids, or uncontrolled by high-dosage inhaled corticosteroids with additional controllers. For patients enrolled between February 2018 and February 2020, clinical characteristics and asthma outcomes were assessed by sex, race, ethnicity, age at enrollment, and age at diagnosis. Treating subspecialists reported exacerbations, exacerbation-related emergency department visits, and asthma hospitalizations from 12 months before enrollment through the latest data collection. Patients completed the St. George's Respiratory Questionnaire and the Asthma Control Test at enrollment., Results: Among 1884 enrolled patients, the majority were female (69%), reported White race (75%), non-Hispanic ethnicity (69%), and were diagnosed with asthma as adults (60%). Female, Black, Hispanic, and younger patients experienced higher annualized rates of exacerbations that were statistically significant compared with male, White, non-Hispanic, and older patients, respectively. Black, Hispanic, and younger patients also experienced higher rates of asthma hospitalizations. Female and Black patients exhibited poorer symptom control and poorer health-related quality of life., Conclusions: In this contemporary, real-world cohort of subspecialist-treated adults with SA, female sex, Black race, Hispanic ethnicity, and younger age were important determinants of health, potentially attributable to physiologic and social factors. Knowledge of these disparities in SA disease burden among subspecialist-treated patients may help optimize care for all patients., Supplemental data for this article is available online at at www.tandfonline.com/ijas .

Background: Multiple biologics are now available for severe asthma (SA) treatment and can improve outcomes for patients. However, few available data describe the real-world use and effectiveness of multiple approved biologics, including biologic switching, among subspecialists in the United States., Objective: To evaluate biologic use and associated exacerbation outcomes in a large cohort of subspecialist-treated US adults with SA., Methods: CHRONICLE is an ongoing, noninterventional study of subspecialist-treated US adults with SA receiving biologics, maintenance systemic corticosteroids, or those persistently uncontrolled by high-dose inhaled corticosteroids with additional controllers. For enrolled patients, sites report asthma exacerbations and medication use starting 12 months before enrollment. For patients enrolled between February 2018 and February 2021, biologic use and exacerbation outcomes before and after biologic initiation are described., Results: Among 2793 enrolled patients, 66% (n = 1832) were receiving biologics. The most used biologic (&gt; 1 biologic use per patient allowed) was omalizumab (47%), followed by benralizumab (27%), mepolizumab (26%), dupilumab (18%), and reslizumab (3%). Overall, 16% of patients had biologic switches, 13% had stops, and 89% had ongoing biologic use. Patients starting and switching biologics experienced a 58% (1.80 vs 0.76 per patient-year) and 49% (1.47 vs 0.75 per patient-year) reduction in exacerbations, respectively (both P &lt; .001), with a numerically greater reduction observed among those starting non-anti-immunoglobulin E biologics compared with anti-immunoglobulin E., Conclusion: Real-world starting and switching of biologic therapies for SA were associated with meaningful reductions in exacerbations. With increasing biologic options available, individualized approaches to therapy may improve patient outcomes., Clinical Trial Registration: ClinicalTrials.gov identifier: NCT03373045., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: For patients with severe asthma (SA), overestimation of asthma control may lead to poorer outcomes. The objective of this study was to assess concurrent patient and specialist assessments of asthma control and treatment effectiveness among a large US cohort of SA patients., Methods: CHRONICLE is an ongoing observational study of patients with SA treated by US subspecialists. Asthma control was assessed using the patient-completed Asthma Control Test™ (ACT™) and specialist clinical assessment of control. Treatment effectiveness was measured using the Global Evaluation of Treatment Effectiveness (GETE) completed by patients and specialists., Results: 1109 patients who completed online surveys at enrollment were included. 14%, 28%, 25%, and 33% of patients had ACT™ scores of 5-9, 10-15, 16-19, and 20-25, respectively. Compared with 67% of patients with uncontrolled asthma by ACT™, 44% were uncontrolled by specialist assessment. 54% of patients who were uncontrolled according to the ACT™ were rated as controlled by specialists, demonstrating overestimation of asthma control. Based on ACT™ score, asthma control was more frequent among patients treated with biologics compared to other treatments. Using the GETE, 90% of patients reported treatment effectiveness compared with 71% of specialists. Patient and specialist treatment effectiveness categorizations agreed 73% of the time., Conclusion: Specialists commonly overestimated asthma control relative to ACT™ scores. Patients reported treatment effectiveness more frequently than specialists. These findings emphasize the importance of validated instruments to assess asthma control and reduce potential treatment gaps associated with patient-specialist discordance., Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT03373045.

Background: Patients with severe asthma (SA) have a heightened risk of exacerbations including hospitalization. The real-world, specialist-verified incidence and characteristics of exacerbations among patients with SA in the United States have not been described., Objective: To describe the real-world incidence, characteristics, and predictors of exacerbations among patients with SA in the United States., Methods: The CHRONICLE study is an ongoing observational study of specialist-treated adults with SA in the United States receiving biologic treatment or maintenance systemic corticosteroids or uncontrolled by high-dosage inhaled corticosteroids with additional controllers. For patients enrolled from February 2018 to February 2020, annualized rates and characteristics of exacerbation-related events were summarized by treatment category for 12 months before enrollment and after enrollment through the latest data collection. Results were further analyzed for subgroups of interest., Results: Among 1884 enrolled patients, 53.5% and 12.3% experienced an exacerbation and asthma hospitalization, respectively (0.81 and 0.14 per person-year). Of all exacerbations, 36%, 9%, and 15% required an unscheduled health care provider visit, emergency department visit without hospitalization, and hospitalization, respectively. Among patients not receiving biologics or systemic corticosteroids, higher blood eosinophil count, higher fractional exhaled nitric oxide, and lower total immunoglobulin E level were associated with higher exacerbation rates. Exacerbation rates decreased after starting or switching biologics (n = 1299). Multivariate analyses of enrolled patients revealed previous-year exacerbations or hospitalizations, lack of asthma control, and the geographic region also predicted event risk., Conclusion: In this real-world cohort of specialist-treated adults with SA in the United States, there was a substantial burden of exacerbations and associated health care resource utilization. Patients receiving biologics had a lower exacerbation burden., Trial Registration: ClinicalTrials.gov Identifier: NCT03373045., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Severe asthma (SA) often requires subspecialist management and treatment with biologic therapies or maintenance systemic corticosteroids (mSCS)., Objective: To describe contemporary, real-world biologic and mSCS use among US subspecialist-treated patients with SA., Methods: CHRONICLE is an ongoing, noninterventional study of US adults with SA treated by allergists/immunologists or pulmonologists. Eligible patients are receiving biologics or mSCS or are uncontrolled on high-dosage inhaled corticosteroids with additional controllers. Biologic and mSCS use patterns and patient characteristics were summarized for patients enrolled between February 2018 and February 2019., Results: Among protocol-eligible patients, 58% and 12% were receiving biologics and mSCS, respectively, with 7% receiving both. Among 796 enrolled, most were women (67%), non-Hispanic white (71%), of suburban residence (50%), and had elevated body mass index (median: 31). Respiratory and nonrespiratory comorbidities were highly prevalent. With biologics (n = 557), 51% were anti-immunoglobulin E and 48% were anti-interleukin (IL)-5/IL-5Rα; from May 2018, 76% of initiations were anti-IL-5/IL-5Rα. In patients receiving mSCS, median prednisone-equivalent daily dose was 10 mg. Multivariate logistic regression found that patients of hospital clinics, sites with fewer nonphysician staff, and with a recorded concurrent chronic obstructive pulmonary disease diagnosis were less likely to receive biologics and more likely to receive mSCS., Conclusion: In this real-world sample of US subspecialist-treated patients with SA not controlled by high-dosage inhaled corticosteroids with additional controllers, mSCS use was infrequent and biologic use was common, with similar prevalence of anti-immunoglobulin E and anti-IL-5/IL-5Rα biologics. Treatment differences associated with patient and site characteristics should be investigated to ensure equitable access to biologics and minimize mSCS use., Trial Registration: ClinicalTrials.gov Identifier: NCT03373045., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Approximately 5-10% of patients with asthma have severe disease. High-quality real-world studies are needed to identify areas for improved management., Objective: Aligned with the International Severe Asthma Registry, the CHRONICLE study (ClinicalTrials.gov: NCT03373045) was developed to address this need in the US., Study Design: Learnings from prior studies were applied to develop a real-world, prospective, noninterventional study of US patients with confirmed severe asthma who are treated by subspecialist physicians and require biologic or maintenance systemic immunosuppressant therapy or who are uncontrolled by high-dosage inhaled corticosteroids and additional controllers. Target enrollment is 4000 patients, with patient observation for ≥3 years. A geographically diverse sample of allergist/immunologist and pulmonologist sites approach all eligible patients under their care and report patient characteristics, treatment, and health outcomes every 6 months. Patients complete online surveys every 1-6 months., Initial Results: From February 2018 to February 2019, 102 sites screened 1428 eligible patients; 936 patients enrolled. Study sites (40% allergist/immunologist, 42% pulmonologist, 18% both) were similar to other US asthma subspecialist samples. Enrolled patients were 67% female with median ages at enrollment and diagnosis of 55 (range: 18-89) and 26 (0-80) years, respectively. Median body mass index was 31 kg/m 2 ; 3% and 29% were current or former smokers, respectively, and >60% reported ≥1 exacerbation in the prior year and suboptimal symptom control., Conclusion: CHRONICLE will provide high-quality provider- and patient-reported data from a large, real-world cohort of US adults with subspecialist-treated severe asthma., Competing Interests: Christopher S. Ambrose, Frank Trudo, and Trung N. Tran are employees of AstraZeneca. Bradley E. Chipps is an advisor for, received consultancy fees from, and is on the speakers’ bureau for AstraZeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Novartis, Regeneron, and Sanofi Genzyme. Wendy C. Moore is on advisory boards for and reports grant and personal fees from AstraZeneca, Sanofi Regeneron, Genentech, and GlaxoSmithKline. She is also a member of the writing and steering committee for the CHRONICLE study as well as a PI of the clinical trial at Wake Forest. Weily Soong is a consultant for and reports grants from AstraZeneca, Genentech, GlaxoSmithKline, Mandala, Novartis, Regeneron, Sanofi, and Teva; and is a speaker for AstraZeneca, GlaxoSmithKline, Regeneron, Sanofi, and Optinose. Jennifer Trevor is a consultant for AstraZeneca; and is on advisory boards for AstraZeneca, GlaxoSmithKline, and Boehringer Ingelheim. Dennis K. Ledford reports research support (paid to University) from Genentech/Roche, Novartis, and AstraZeneca. He reports royalties from Wolters Kluwer Health and Taylor and Francis. He is an Editor for the American Academy of Allergy, Asthma & Immunology (AAAAI). He is also a consultant/speaker for and reports personal fees from ALK, AstraZeneca, Boehringer Ingelheim, Genentech/Roche, GlaxoSmithKline, Meda, Novartis, Sanofi/Regeneron, and Teva, and fees received for legal opinions on drug allergy, metal allergy, radiocontrast reaction, and asthma death. Warner W. Carr is a speaker for AstraZeneca, Teva, Boehringer Ingelheim, Regeneron, and Sanofi; and a consultant for AstraZeneca, Teva, Boehringer Ingelheim, Regeneron, Sanofi, Circassia, CSL Behring, Genentech, GlaxoSmithKline, Horizon Pharma, Kaleo, Mylan, Pfizer, Shire, Meda, Baxalta, Novartis, Greer Laboratories, Alcon Laboratories, Valeant Pharmaceuticals, Grifols, Optinose, and Aerocrine. Njira Lugogo is on advisory boards for AstraZeneca, Sanofi, Genentech, Novartis, Teva, and GlaxoSmithKline. She also reports clinical trial funding to her institution from AstraZeneca, GlaxoSmithKline, and Sanofi. Reynold A. Panettieri Jr is on advisory boards for and reports grant support/personal fees from AstraZeneca, Sanofi, Genentech, Regeneron, MedImmune, RIFM, Equillium, Theravance, Avillion, OncoArendi, Meresa, NIH, and Novartis. The authors report no other conflicts of interest in this work., (© 2020 Ambrose et al.)

With novel therapies in development, there is an opportunity to consider asthma remission as a treatment goal. In this Rostrum, we present a generalized framework for clinical and complete remission in asthma, on and off treatment, developed on the basis of medical literature and expert consensus. A modified Delphi survey approach was used to ascertain expert consensus on core components of asthma remission as a treatment target. Phase 1 identified other chronic inflammatory diseases with remission definitions. Phase 2 evaluated components of those definitions as well as published definitions of spontaneous asthma remission. Phase 3 evaluated a remission framework created using consensus findings. Clinical remission comprised 12 or more months with (1) absence of significant symptoms by validated instrument, (2) lung function optimization/stabilization, (3) patient/provider agreement regarding remission, and (4) no use of systemic corticosteroids. Complete remission was defined as clinical remission plus objective resolution of asthma-related inflammation and, if appropriate, negative bronchial hyperresponsiveness. Remission off treatment required no asthma treatment for 12 or more months. The proposed framework is a first step toward developing asthma remission as a treatment target and should be refined through future research, patient input, and clinical study., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Fixed airflow obstruction (FAO) is associated with severe eosinophilic asthma. Benralizumab is an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody for patients with severe, uncontrolled eosinophilic asthma., Objective: We evaluated FAO influence on benralizumab treatment response., Methods: We performed a post hoc analysis of pooled phase III SIROCCO (NCT01928771) and CALIMA (NCT01914757) data for patients with severe, uncontrolled asthma with baseline blood eosinophil counts of 300 or more cells/μL who received benralizumab 30 mg every 8 weeks or placebo. Demographics, baseline clinical characteristics, and treatment responses were evaluated by FAO status. FAO+ and FAO- were defined as ratios of postbronchodilator forced expiratory volume in 1 second (FEV 1 ) to forced vital capacity of less than 70% and 70% or more, respectively, at baseline., Results: FAO+ prevalence was 63% (935/1493). With benralizumab, similar annual asthma exacerbation rate (AER) reductions vs placebo were achieved for FAO+ and FAO- patients (rate ratio [95% confidence interval (CI)] = 0.56 [0.44-0.71] and 0.58 [0.41-0.83], respectively), whereas annual AER reductions associated with emergency department visits or hospitalizations were greater for FAO+ vs FAO- patients (rate ratio [95% CI] = 0.55 [0.33-0.91] and 0.70 [0.33-1.48], respectively). Prebronchodilator FEV 1 (95% CI) increase from baseline to end of treatment was greater for FAO+ vs FAO- patients receiving benralizumab compared with placebo (0.159 L [0.082-0.236] vs 0.103 L [-0.008 to 0.215]). Other lung function measures, patient-reported outcomes, and symptom improvements were also numerically greater for FAO+ vs FAO- patients., Conclusion: Benralizumab improved asthma control across several measures for patients with severe, uncontrolled eosinophilic asthma and FAO., Trial Registration: SIROCCO trial: NCT01928771 (URL: https://clinicaltrials.gov/ct2/show/NCT01928771) CALIMA trial: NCT01914757 (URL: https://clinicaltrials.gov/ct2/show/NCT01914757)., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Benralizumab is a unique eosinophil-depleting monoclonal antibody that significantly reduces asthma exacerbations, improves lung function and asthma symptoms, and permits the reduction of maintenance oral corticosteroid dosage for patients with severe, uncontrolled eosinophilic asthma., Objective: To assess benralizumab's onset of action and efficacy by examining change in morning peak expiratory flow (PEF) after initiation of treatment in the phase 3 clinical trials SIROCCO, CALIMA, and ZONDA., Methods: Mixed-model repeated-measures analysis was used to calculate PEF using daily least squares mean changes from baseline in morning PEF as well as differences between the benralizumab every 8 weeks (first 3 doses every 4 weeks) and placebo groups. A Bayesian nonlinear mixed-effects approach with an exponential relationship was used to model trial data to determine time to clinically meaningful improvement in morning PEF (defined as ≥25 L/min)., Results: Least squares mean morning PEF improvement from baseline was numerically greater by Day 2 after initiation of benralizumab therapy in all 3 trials. The Bayesian nonlinear mixed-effects model indicated that PEF improvement reached the clinically meaningful threshold within 3 weeks in SIROCCO and CALIMA and 2 weeks in ZONDA., Conclusion: In 3 phase 3 randomized clinical trials, benralizumab provided notable improvement in morning PEF 2 days after initiation and clinically meaningful improvements within 3 weeks for patients with severe, uncontrolled eosinophilic asthma. The rapid improvement in PEF demonstrated in these trials suggests that benralizumab's unique mechanism of action rapidly improves lung function for patients with severe, eosinophilic asthma., Trial Registration: ClinicalTrials.gov Identifiers: NCT01928771 (SIROCCO), NCT01914757 (CALIMA), and NCT02075255 (ZONDA)., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Asthma is a chronic respiratory condition with a U.S. prevalence of 7.4%. Despite numerous treatment options, asthma remains poorly controlled in some patients. Uncontrolled asthma is associated with high healthcare resource utilization (HCRU) and reduced productivity. This study assessed symptoms, productivity, and HCRU of patients adherent to medium/high-dosage inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) treatment, and the relationship of asthma control with these parameters., Methods: Data were collected in the U.S. in 2013-2016 in the Adelphi Respiratory Disease Specific Programme, a cross-sectional survey. Participating physicians (n = 258) each completed a record form for eligible patients, who were receiving medium/high-dosage ICS/LABA treatment with self-reported moderate/high adherence, completed the Asthma Control Test (ACT) and the Work Productivity and Activity Impairment (WPAI) questionnaire, and were included in the analyses., Results: Patients (n = 428) had a mean of 59% symptom-free days in the past month. Wheezing was the most troublesome symptom for 25% of patients. In the previous 12 months, the mean number of exacerbations was 1.3; 15% of exacerbations required emergency room treatment and/or hospitalization. Mean physician visits for asthma was 5.7. Asthma impacted leisure/personal time frequently/constantly for 11% of patients, with 20% overall work impairment. Asthma was poorly controlled (ACT score ≤15) in 18% of patients; poorer asthma control was associated with higher rates of exacerbations, work impairment, and HCRU., Conclusion: Given the substantial burden described, greater attention to asthma monitoring and management is necessary. Identification of novel treatments may be important for patients not responding to medium/high-dosage ICS/LABA treatment.

Background: Benralizumab is a humanized, afucosylated, monoclonal antibody that targets interleukin-5 receptor alpha and induces direct, rapid, and nearly complete depletion of eosinophils via enhanced antibody-dependent cell-mediated cytotoxicity. In the United States, benralizumab is indicated for add-on maintenance treatment of patients ≥12 years old with severe asthma and an eosinophilic phenotype., Objective: This study evaluated the effect of benralizumab treatment on seasonal asthma exacerbation rates for patients with severe, uncontrolled asthma., Methods: This was a post hoc analysis of pooled data from the phase III SIROCCO (ClinicalTrials.gov identifier: NCT01928771) and CALIMA (NCT01914757) trials. The primary analysis population was patients ages 12-75 years treated with high-dosage inhaled corticosteroids and long-acting beta-2 agonists who had baseline blood eosinophil counts of ≥300 cells/μL. Patients received benralizumab 30 mg subcutaneously every 4 weeks or every 8 weeks (the first three doses every 4 weeks) or placebo every 4 weeks. Crude exacerbation rates (asthma exacerbations per patient-year) were determined for each month and season. Marginal asthma exacerbation rates and exacerbation rate ratios were estimated by season or month by using a negative binomial model that included covariates for study code, treatment, region, use of maintenance oral corticosteroids, and number of exacerbations in the previous year. Hemispheric seasons were accounted for by normalizing the study site locations., Results: Observed crude exacerbation rates were higher in the fall and winter than in the spring and summer for all the patients. For the patients who received placebo, benralizumab every 4 weeks, and benralizumab every 8 weeks, crude exacerbation rates were the following: fall, 1.52, 0.86, and 0.81, respectively; winter, 1.44, 0.91, and 0.82, respectively; spring, 1.11, 0.66, and 0.52, respectively; and summer, 1.02, 0.55, and 0.51, respectively. Rate reductions in seasonal marginal annual exacerbation rates were 37-50% versus placebo at each season (p < 0.001)., Conclusion: Benralizumab significantly and consistently reduced asthma exacerbations across all seasons versus placebo for patients with severe, uncontrolled eosinophilic asthma.

Background: Patients with severe asthma can have eosinophilic inflammation and/or allergen sensitization. Benralizumab is an anti-eosinophilic monoclonal antibody indicated for add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype., Objective: To investigate the efficacy of benralizumab by atopic status and serum immunoglobulin E (IgE) concentrations., Methods: We analyzed pooled results from the SIROCCO (NCT01928771) and CALIMA (NCT01914757) phase III studies. Patients 12 to 75 years old with severe, uncontrolled asthma on high-dosage inhaled corticosteroids plus long-acting β 2 -agonists received 30 mg of subcutaneous benralizumab every 4 weeks or every 8 weeks (first 3 doses every 4 weeks) or placebo every 4 weeks. The analysis stratified patients who did and did not meet similar omalizumab-qualifying criteria of atopy and serum IgE levels 30 to 700 kU/L. Patients also categorized as having high serum IgE (≥150 kU/L) or low serum IgE (<150 kU/L) and as having atopy or no atopy. Efficacy outcomes were for all patients and by blood eosinophil counts and included annual exacerbation rate ratio and pre-bronchodilator forced expiratory volume in 1 second change at treatment end vs placebo., Results: Benralizumab every 8 weeks decreased exacerbations by 46% (95% confidence interval 26-61, P = .0002) and increased forced expiratory volume in 1 second by 0.125 L (95% confidence interval 0.018-0.232, P = .0218) vs placebo for patients with at least 300 eosinophils/μL who met the atopy and IgE criteria. For patients with eosinophilia and high or low IgE, treatment with benralizumab every 8 weeks resulted in 42% and 43% decreases in exacerbation rate (P ≤ .0004) and 0.123- and 0.138-L increases in forced expiratory volume in 1 second (P ≤ .0041) vs placebo, respectively., Conclusion: Benralizumab treatment decreased exacerbations and improved lung function for patients with severe, uncontrolled eosinophilic asthma regardless of serum IgE concentrations and atopy status., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Severe asthma is recognized in the European Respiratory Society/American Thoracic Society guidelines as a major unmet need in the management of asthma., Objective: The study objective was to describe the clinical burden of Global Initiative for Asthma (GINA) steps 4-5 asthma for patients treated by specialists in the U.S. community setting., Methods: Patients, ages ≥12 years, with asthma who received GINA step 4 or 5 treatment and were treated at a large U.S. allergy practice network between January 1, 2010, and April 30, 2016, were retrospectively identified by using electronic health records. Clinical outcomes included lung function (forced expiratory volume in one second of expiration [FEV1] and FEV1% predicted), symptom control (Asthma Control Test [ACT]), the fractional exhaled nitric oxide (FeNO) value (FeNO ≥25 ppb indicates airway inflammation), and asthma medication use. The change in outcomes from baseline to 12 and 24 months after the index date was calculated., Results: Of 120,116 patients with asthma, 12,922 (10.8%) had severe asthma, 68% (n = 8751) while on step 4 therapy. The mean baseline prebronchodilation FEV1% predicted was 79.7%, and the mean baseline ACT score was 17.0. With uncontrolled asthma defined as an ACT score of ≤19 and/or an FEV1 value of <80% predicted and/or oral corticosteroid use of ≥2 bursts, 52.5% and 57.7% of patients on step 4 and step 5 therapy, respectively, had uncontrolled asthma at baseline. Of a subset of patients, 40.9% had an eosinophil count of ≥300 cells/mm3 and 44% had an FeNO concentration of ≥25 ppb. Small increases in the FEV1 value were observed from baseline to 12 months (n = 4022) and 24 months (n = 2326) postindex (0.07 and 0.04 L, respectively)., Conclusion: A considerable proportion of patients had uncontrolled asthma while on current GINA steps 4-5 treatment, which indicated that additional therapies may be required to reduce the clinical burden of severe asthma.

Background: Prevention of exacerbations is a primary goal for chronic obstructive pulmonary disease (COPD) therapy. This randomized, double-blind, double-dummy, parallel-group, multicenter study evaluated the effect of budesonide/formoterol pressurized metered-dose inhaler (pMDI) versus formoterol dry powder inhaler (DPI) on reducing COPD exacerbations., Methods: 1219 patients aged ≥40 years with moderate-to-very-severe COPD (per lung function) and a history of ≥1 COPD exacerbation received budesonide/formoterol pMDI 320/9 μg twice daily (BID) during a 4-week run-in. Patients were then randomized 1:1 to receive budesonide/formoterol pMDI 320/9 μg BID (n = 606) or formoterol DPI 9 μg BID (n = 613) for 26 weeks. Exacerbations were identified using predefined criteria for symptom worsening and treatment with systemic corticosteroids and/or antibiotics and/or hospitalization. The primary endpoint was annual rate of exacerbations., Results: Budesonide/formoterol pMDI resulted in a 24% reduction in annual rate of exacerbations (0.85 vs 1.12; rate ratio: 0.76 [95% CI: 0.62, 0.92]; P = 0.006), and a significant risk reduction for time to first exacerbation (hazard ratio: 0.78 [95% CI: 0.64, 0.96]; P = 0.016) versus formoterol DPI. The most commonly reported adverse events (AEs; ≥3%) in budesonide/formoterol and formoterol groups were COPD (4.5% vs 8.6%) and nasopharyngitis (5.0% vs 5.2%). Pneumonia AEs were reported in 0.5% and 1.0% of budesonide/formoterol-treated and formoterol-treated patients, respectively., Conclusions: Budesonide/formoterol pMDI is an effective treatment option for reducing exacerbation rates in COPD patients with moderate-to-very-severe airflow limitation and history of exacerbations. No increase in pneumonia was observed with budesonide/formoterol; safety data were consistent with its established profile., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Evidence of poor patient adherence to medications for chronic obstructive pulmonary disease (COPD) is well-documented, but its impact on disease exacerbation rates and associated healthcare costs remains unclear., Objective: To assess the association between adherence levels to different inhaled corticosteroid/long-acting ß 2 -adrenergic agonist (LABA) and COPD exacerbation rates and costs in a commercially insured population., Methods: In this observational cohort study, patients with COPD (aged ≥40 years) who were treatment-naïve to inhaled corticosteroid/LABA and were initiating budesonide plus formoterol or fluticasone plus salmeterol between March 1, 2009, and January 31, 2014, were identified in a national representative claims database and were followed for up to 12 months. The date of the first prescription fill for either drug was defined as the index date. Patients were divided into 4 cohorts based on adherence to the index therapy, which was measured by proportion of days covered (PDC); the cohorts were classified as adherent (PDC ≥0.8), mildly nonadherent (0.5 ≤ PDC <0.8), moderately nonadherent (0.3 ≤ PDC <0.5), and highly nonadherent (PDC <0.3). Each nonadherent group was matched in a 1:1 ratio to the adherent group independently, based on prognostically important variables, using propensity score analyses. Exacerbation rates and healthcare costs were analyzed for 1 year after treatment initiation., Results: During the study period, 13,657 eligible patients with COPD initiated inhaled corticosteroid/LABA; of these, only 1898 (13.9%) patients were adherent during follow-up. Group matching resulted in 1572 patients per group for comparison 1 (adherent vs mildly nonadherent), 1604 patients for comparison 2 (adherent vs moderately nonadherent), and 1755 patients for comparison 3 (adherent vs highly nonadherent). The moderately and highly nonadherent cohorts had higher exacerbation rates than the adherent patients (comparison 2: rate ratio [RR], 1.11; 95% confidence interval [CI], 1.01-1.21; P = .03; comparison 3: RR, 1.11; 95% CI, 1.01-1.21; P = .02). Adherent patients incurred significantly lower healthcare costs than all the nonadherent groups (comparison 1, $22,671 vs $25,545; P <.01; comparison 2, $22,508 vs $24,303; P <.01; comparison 3, $22,460 vs $25,148; P <.01)., Conclusions: Patients adhered to their inhaled corticosteroid/LABA treatments had lower COPD exacerbation rates and lower healthcare costs compared with the moderately and highly nonadherent patients. Better adherence to maintenance therapies may help to reduce the clinical and economic burdens of COPD.

Background: The consistency of fixed airflow limitation status during treatment in patients with asthma is unknown., Objective: The objective of this study was to determine the consistency of fixed airflow obstruction (FAO) status during treatment and effects on treatment response., Methods: This post hoc analysis from a 12-week study (NCT00652002) assessed patients aged 12 years or more with moderate-to-severe asthma randomized to twice-daily budesonide/formoterol (BUD/FM) via pressurized metered-dose inhaler (pMDI) 320/9 μg, BUD pMDI 320 μg, FM 9 μg via dry-powder inhaler, or placebo. FAO status was assessed postbronchodilator at screening and after study drug administration at weeks 2, 6, and 12 via the forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) ratio < lower limit of normal (LLN) (FAO+) or ≥ LLN (FAO-). Patients with persistent FAO- and FAO+ retained their screening FAO status at all visits. Patients with inconsistent FAO changed categories at least once during the study. Assessments included early withdrawal due to predefined worsening asthma events (PAEs), lung function, and symptoms., Results: Of 386 patients, 29% had persistent FAO+, 31% inconsistent FAO, and 40% persistent FAO-. PAEs were lowest in the FAO- group overall and with BUD/FM treatment in patients with FAO+ and inconsistent FAO. Baseline demographics and treatment responses of the inconsistent FAO group were most similar to the FAO+ group. The greatest improvements in asthma control days and use of rescue medications were seen with BUD/FM treatment, regardless of FAO status., Conclusions: Approximately one third of patients with moderate-to-severe asthma in this study had inconsistent FAO, and their treatment responses were most similar to patients with FAO+. Regardless of FAO status, patients treated with BUD/FM experienced the most improved treatment responses and fewest withdrawals due to PAEs., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Chronic obstructive pulmonary disease (COPD) affects approximately 15 million people in the United States and accounts for approximately $36 billion in economic burden, primarily due to medical costs. To address the increasing clinical and economic burden, the Global Initiative for Chronic Obstructive Lung Disease emphasizes the use of therapies that help prevent COPD exacerbations, including inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA)., Objective: To evaluate health care costs and utilization among COPD patients newly initiating ICS/LABA combination therapy with budesonide/formoterol (BFC) or fluticasone/salmeterol (FSC) in a managed care system., Methods: COPD patients aged 40 years and older who initiated BFC (160/4.5 μg) or FSC (250/50 μg) treatment between March 1, 2009, and March 31, 2012, were identified using claims data from major U.S. health plans. BFC and FSC patients were propensity score matched (1:1) on age, sex, prior asthma diagnosis, prior COPD-related health care utilization, and respiratory medication use. COPD-related, pneumonia-related, and all-cause costs and utilization were analyzed during the 12-month follow-up period. Post-index costs were assessed with generalized linear models (GLMs) with gamma distribution. Health care utilization data were analyzed via logistic regression (any event vs. none) and GLMs with negative binomial distribution (number of visits) and were adjusted for the analogous pre-index variable as well as pre-index characteristics that remained imbalanced after matching., Results: After matching, each cohort had 3,697 patients balanced on age (mean 64 years), sex (female 52% BFC and 54% FSC), asthma and other comorbid conditions, prior COPD-related health care utilization, and respiratory medication use. During the 12-month follow-up, COPD-related costs averaged $316 less for BFC versus FSC patients ($4,326 vs. $4,846; P = 0.003), reflecting lower inpatient ($966 vs. $1,202; P < 0.001), pharmacy ($1,482 vs. $1,609; P = 0.002), and outpatient/office ($1,378 vs. $1,436; P = 0.048) costs, but higher emergency department ($257 vs. $252; P = 0.033) costs. Pneumonia-related health care costs were also lower on average for BFC patients ($2,855 vs. $3,605; P < 0.001). Similarly, initiating BFC was associated with lower all-use health care costs versus initiating FSC ($21,580 vs. $24,483; P < 0.001, respectively). No differences in health care utilization were found between the 2 groups., Conclusions: In this study, although no difference was observed in rates of health care utilization, COPD patients initiating BFC treatment incurred lower average COPD-related, pneumonia-related, and all-cause costs versus FSC initiators, which was driven by cumulative differences in inpatient, outpatient, and pharmacy costs.

Background: Inhaled corticosteroid/long-acting β2-agonist combinations (ICS/LABA) have emerged as first line therapies for chronic obstructive pulmonary disease (COPD) patients with exacerbation history. No randomized clinical trial has compared exacerbation rates among COPD patients receiving budesonide/formoterol combination (BFC) and fluticasone/salmeterol combination (FSC) to date, and only limited comparative data are available. This study compared the real-world effectiveness of approved BFC and FSC treatments among matched cohorts of COPD patients in a large US managed care setting., Methods: COPD patients (≥40 years) naive to ICS/LABA who initiated BFC or FSC treatments between 03/01/2009-03/31/2012 were identified in a geographically diverse US managed care database and followed for 12 months; index date was defined as first prescription fill date. Patients with a cancer diagnosis or chronic (≥180 days) oral corticosteroid (OCS) use within 12 months prior to index were excluded. Patients were matched 1-to-1 on demographic and pre-initiation clinical characteristics using propensity scores from a random forest model. The primary efficacy outcome was COPD exacerbation rate, and secondary efficacy outcomes included exacerbation rates by event type and healthcare resource utilization. Pneumonia objectives included rates of any diagnosis of pneumonia and pneumonia-related healthcare resource utilization., Results: Matching of the identified 3,788 BFC and 6,439 FSC patients resulted in 3,697 patients in each group. Matched patients were well balanced on age (mean=64 years), gender (BFC: 52% female; FSC: 54%), prior COPD-related medication use, healthcare utilization, and comorbid conditions. During follow-up, no significant difference was seen between BFC and FSC patients for number of COPD-related exacerbations overall (rate ratio [RR]=1.02, 95% CI=[0.96,1.09], p=0.56) or by event type: COPD-related hospitalizations (RR=0.96), COPD-related ED visits (RR=1.11), and COPD-related office/outpatient visits with OCS and/or antibiotic use (RR=1.01). The proportion of patients diagnosed with pneumonia during the post-index period was similar for patients in each group (BFC =17.3%, FSC =19.0%, odds ratio=0.92 [0.81,1.04], p=0.19), and no difference was detected for pneumonia-related healthcare utilization by place of service., Conclusion: This study demonstrated no difference in COPD-related exacerbations or pneumonia events between BFC and FSC treatment groups for patients new to ICS/LABA treatment in a real-world setting., Trial Registration: ClinicalTrials.gov identifier NCT01921127 .

Rationale: To assess equivalence of twice daily (bid) budesonide/formoterol (BUD/FM) 160/4.5 μg via breath-actuated metered-dose inhaler (BAI) versus pressurized metered-dose inhaler (pMDI)., Methods: This 12-week, double-blind, multicenter, parallel-group study, randomized adolescents and adults (aged ≥12 years) with asthma (and ≥3 months daily use of inhaled corticosteroids) to BUD/FM BAI 2 × 160/4.5 μg bid, BUD/FM pMDI 2 × 160/4.5 μg bid, or BUD pMDI 2 × 160 μg bid. Inclusion required prebronchodilator forced expiratory volume in one second (FEV1) ≥45 to ≤85% predicted, and reversibility of ≥12% in FEV1 (ages 12 to <18 years) or ≥12% and 200 mL (ages ≥18 years). Confirmation that 60-min postdose FEV1 response to BUD/FM pMDI was superior to BUD pMDI was required before equivalence testing. Therapeutic equivalence was shown by treatment effect ratio of BUD/FM BAI vs BUD/FM pMDI on 60-min postdose FEV1 and predose FEV1 within confidence intervals (CIs) of 80-125%., Results: Mean age of 214 randomized patients was 42.7 years. BUD/FM pMDI was superior to BUD pMDI (60-min postdose FEV1 treatment effect ratio, 1.10; 95% CI, 1.06-1.14; p < 0.001). Treatment effect ratios for BUD/FM BAI versus pMDI for 60-min postdose FEV1 (1.01; 95% CI, 0.97-1.05) and predose FEV1 (1.03; 95% CI, 0.99-1.08) were within predetermined CIs for therapeutic equivalence. Adverse event profiles, tolerability, and patient-reported ease of use were similar., Conclusions: BUD/FM 2 × 160/4.5 μg bid BAI is therapeutically equivalent to BUD/FM conventional pMDI. The introduction of BUD/FM BAI would expand options for delivering inhaled corticosteroid/long-acting β2-agonist combination therapy to patients with moderate-to-severe asthma. ClinicalTrials.gov NCT01360021., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Comparative effectiveness of the budesonide-formoterol fumarate dihydrate combination (BFC) and the fluticasone propionate-salmeterol combination (FSC) therapy on asthma exacerbation has not been assessed in real-world settings in the United States., Objective: To compare exacerbation rates and health care utilization for patients with asthma who initiate BFC versus FSC therapy., Methods: This retrospective cohort comparative effectiveness study queried medical and pharmacy data for patients with asthma from a large managed care data repository that covers major US population centers. The patients were 12 to 64 years old, with ≥12 months of pre- and postindex enrollment and ≥1 pharmacy claim(s) for BFC or FSC initiated during June 1, 2007, and September 30, 2010; the first prescription fill date was defined as the index date. Patients with other respiratory diseases and/or cancer were excluded. Exacerbation was defined as asthma-related hospitalization, emergency department visit, and/or oral corticosteroid prescription fill. Cohorts were matched by using propensity scores., Results: A total of 3043 patients per cohort were matched and balanced. During the 12 months following the initiation the BFC cohort had lower adjusted exacerbations per person year versus the FSC cohort (0.85 vs 0.93; RR 0.92, 95% CI [0.85-0.99]), lower oral corticosteroid fill rates, and fewer asthma-related emergency department visits but comparable asthma-related hospitalization., Conclusions: Asthma exacerbation was lower for BFC versus FSC initiators due to lower rates of oral corticosteroid use and asthma-related emergency department visits, which indicate better treatment effectiveness of those patients initiated with BFC compared with FSC., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The role of fixed airflow obstruction (FAO) in asthma is unclear., Objective: To assess the relationship between FAO and clinical features of asthma and the effect of FAO on treatment response., Methods: Post hoc descriptive analysis of data stratified by FAO category (screening post-albuterol FEV1/FVC

State-dependent changes in upper airway caliber were studied with magnetic resonance imaging (MRI) techniques. We hypothesized that changes in airway caliber during sleep in normal subjects would result from positional and dimensional changes in upper airway soft-tissue structures, including the lateral pharyngeal walls, tongue, and soft palate. We used MRI to study 15 normal subjects during wakefulness and sleep. Sleep was facilitated by one night of sleep deprivation prior to MRI. During sleep, the volume of the retropalatal (RP) airway was reduced by 19% (p = 0.03). The volume of the retroglossal (RG) airway was not significantly reduced during sleep, suggesting that the RP region may be more likely to collapse. The mean minimal cross-sectional airway area was reduced by 228% (p = 0.004) in the RP and by 22% (p = 0.02) in the RG region during sleep as compared with values in anatomically matched axial images during wakefulness. Airway anteroposterior (AP) and lateral dimensions were also significantly reduced in the RP region. Airway narrowing in the RP region was associated with a 7% increase in thickness of the lateral pharyngeal walls (p = 0.04). In nine subjects, sagittal data showed significant posterior displacement of the soft palate during sleep as compared with wakefulness. Multiple linear regression analyses indicated that reduction in the RP airway area during sleep resulted from posterior movement of the soft palate, thickening of the lateral pharyngeal walls, and an increase in tongue oblique distance. We conclude that the lateral pharyngeal walls play an important role in upper airway narrowing during sleep in normal subjects.