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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.