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William Walter Busse,1 Ian Douglas Pavord,2 Shahid Siddiqui,3 Asif Hameed Khan,4 Amy Praestgaard,5 Scott Nash,3 Juby Anne Jacob-Nara,6 Paul Jonathan Rowe,6 Yamo Deniz3 1Department of Medicine, Division of Allergy, Pulmonary and Critical Care, University of Wisconsin, Madison, WI, USA; 2Oxford Respiratory NIHR BRC, Nuffield Department of Medicine, University of Oxford, Oxford, UK; 3Medical Affairs, Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA; 4Global Medical Affairs, Sanofi, Chilly-Mazarin, France; 5Department of Biostatistics, Sanofi, Cambridge, MA, USA; 6Global Medical Affairs, Sanofi, Bridgewater, NJ, USACorrespondence: William Walter Busse, Department of Medicine, Division of Allergy, Pulmonary and Critical Care, University of Wisconsin, Madison, WI, USA, Tel +1 608 263-6183, Email wwb@medicine.wisc.eduPurpose: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 inflammatory disease frequently coexisting with other type 2 conditions including asthma and non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD). Coexisting asthma leads to increased CRSwNP symptom burden. Dupilumab, a monoclonal antibody that blocks the shared receptor component for interleukin-4 and -13, demonstrated efficacy in adults with severe CRSwNP in the Phase 3 SINUS-24 (NCT02912468) and SINUS-52 (NCT02898454) studies, including in patients with coexisting asthma/NSAID-ERD. However, the impact of different asthma characteristics on dupilumab treatment in this population is unknown. We report CRSwNP and asthma outcomes with dupilumab in patients with CRSwNP and coexisting asthma according to baseline asthma characteristics.Methods: Change from baseline at Week 24 (pooled studies) and Week 52 (SINUS-52) in CRSwNP outcomes (nasal polyp score, nasal congestion, 22-item Sino-Nasal Outcome Test [SNOT-22], loss of smell score, University of Pennsylvania Smell Identification Test) and asthma outcomes (5-item Asthma Control Questionnaire [ACQ-5], pre-bronchodilator forced expiratory volume in 1 second [FEV1]) were analyzed post hoc for placebo and dupilumab 300 mg every 2 weeks according to baseline blood eosinophils ≥ 150/≥ 300 cells/μL, ACQ-5 scores < 1.5/≥ 1.5, and FEV1 < 80%.Results: In the pooled studies, 428/724 patients (59.1%) had coexisting asthma, of which 181/428 (42.3%) had coexisting NSAID-ERD. Dupilumab significantly improved all CRSwNP and asthma outcomes vs placebo at Week 24 (P < 0.001) regardless of baseline eosinophil or ACQ-5 category, or FEV1 < 80%. Similar magnitude of improvement was seen at Week 52 (SINUS-52) and in patients with NSAID-ERD (pooled studies, Week 24). By Week 24, improvements with dupilumab exceeded the minimum clinically important differences for ACQ-5 and SNOT-22 in 35.2% to 74.2% and 72.0% to 78.7% of patients, respectively.Conclusion: Dupilumab improved CRSwNP outcomes in patients with CRSwNP and coexisting asthma, and improved asthma outcomes, regardless of differences in baseline asthma characteristics.Keywords: chronic rhinosinusitis with nasal polyps, dupilumab, asthma

Stephanie Chen,1 Marc Miravitlles,2 Chin Kook Rhee,3 Ian D Pavord,4 Rupert Jones,5 Victoria Carter,6 Benjamin Emmanuel,1 Marianna Alacqua,7 David B Price6,8 1BioPharmaceuticals Medical, Respiratory & Immunology, AstraZeneca, Gaithersburg, MD, USA; 2Pneumology Department, 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; 3College of Medicine, Seoul St Mary’s Hospital, the Catholic University of Korea, Seoul, South Korea; 4Oxford Respiratory NIHR BRC, Nuffield Department of Medicine, University of Oxford, Oxford, UK; 5Faculty of Health, University of Plymouth, Plymouth, UK; 6Observational and Pragmatic Research Institute, Singapore, Singapore; 7BioPharmaceuticals Medical, Respiratory & Immunology, AstraZeneca, Cambridge, UK; 8Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UKCorrespondence: David B Price, Observational and Pragmatic Research Institute, 22 Sin Ming Lane, #06-76, Midview City, Singapore, 573969, Singapore, Tel +65 3105 1489, Email dprice@opri.sgBackground: Some patients with chronic obstructive pulmonary disease (COPD) experience frequent exacerbations despite maximal inhaled therapy (“triple therapy”), possibly leading to high health care resource utilization (HCRU).Aim: Describe characteristics, future HCRU, and mortality of patients with COPD who experience frequent exacerbations despite triple therapy; characterize individuals who may be candidates for biologic therapies.Methods: This descriptive observational study used primary care data of patients aged ≥ 40 years in the United Kingdom receiving maintenance therapy for COPD who had ≥ 1 year of data prior to index date and ≥ 1 year of follow-up data. We described these patients’ clinical and demographic characteristics, including blood eosinophil counts (BEC), pattern of exacerbations, hospitalizations, and corticosteroid exposure, as well as future exacerbations, hospitalizations, and death.Results: Of 43,753 patients with maintenance-treated COPD, 6480 experienced exacerbations despite ≥ 3 months of triple therapy. Of these, 5669 had available BEC: 1287 (22.7%) had BEC ≥ 250 cells/μL and ≥ 3 exacerbations in the year prior to the index date; 471 (36.6%) received ≥ 4 acute courses of oral corticosteroids. Patients with a pattern of high disease burden continued to have high disease burden: 51.1% experienced ≥ 3 exacerbations and 2.6% experienced ≥ 3 hospitalizations. Patients who experienced exacerbations despite triple therapy had a significantly higher risk of COPD-related death than other maintenance-treated patients (5.8% vs 2.1%).Conclusion: Nearly one-quarter of patients receiving triple therapy for COPD who experienced frequent exacerbations had elevated BEC and ≥ 3 exacerbations, suggesting a potential mechanism of persistent eosinophilic inflammation that could be a target for eosinophil-depleting biologic therapy.Keywords: chronic obstructive pulmonary disease, disease burden, eosinophils, exacerbations, health care resource utilization

Ian D Pavord,1 Salman Siddiqui,2 Alberto Papi,3 Jonathan Corren,4 Lawrence D Sher,5 Philip Bardin,6 David Langton,7 Hae-Sim Park,8 Megan S Rice,9 Yamo Deniz,10 Paul Rowe,11 Heribert W Staudinger,11 Naimish Patel,11 Marcella Ruddy,10 Neil MH Graham,10 Ariel Teper11 1Respiratory Medicine Unit and Oxford Respiratory National Institute for Health Research Biomedical Research Centre, University of Oxford, Oxford, UK; 2University of Leicester and Leicester National Institute for Health Research Biomedical Research Centre (Respiratory Theme), Leicester, UK; 3Department of Respiratory Medicine, University of Ferrara, Ferrara, Italy; 4David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 5Peninsula Research Associates, Rolling Hills Estate, CA, USA; 6Department of Lung and Sleep Medicine, Monash University and Medical Centre, Clayton, Melbourne, VIC, Australia; 7Department of Thoracic Medicine, Frankston Hospital, Frankston, Melbourne, VIC, Australia; 8Ajou University Hospital, Suwon, South Korea; 9Sanofi, Cambridge, MA, USA; 10Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 11Sanofi, Bridgewater, NJ, USACorrespondence: Ian D PavordNDM Research Building, Nuffield Department of Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7FZ, UKTel +44 (0)1865 612897Email ian.pavord@ndm.ox.ac.ukPurpose: The Phase 3 LIBERTY ASTHMA QUEST study in patients aged ≥ 12 years with uncontrolled, moderate-to-severe asthma demonstrated the efficacy and safety of dupilumab 200 mg and 300 mg every 2 weeks (q2w) vs matched placebo in the overall population. This post hoc analysis assessed dupilumab efficacy by disease severity as evidenced by baseline % predicted forced expiratory volume in 1 second (FEV1) and dose of inhaled corticosteroids (ICS).Patients and Methods: Severe asthma exacerbation rates, change from baseline in FEV1, asthma control, quality of life, and fractional exhaled nitric oxide (FeNO) levels over the 52-week treatment period were assessed in patients with elevated type 2 inflammation biomarkers stratified by ICS dose and FEV1% predicted at baseline.Results: In patients with elevated baseline eosinophils, dupilumab 200 mg and 300 mg q2w vs placebo reduced severe exacerbation rates by 50% (P=0.06) and 67% (P=0.001), respectively, in those with medium-dose ICS/FEV1% predicted 60– 90%, and by 59% (P< 0.001) and 47% (P=0.006) in those with high-dose ICS/FEV1% predicted < 60%, improved pre-bronchodilator FEV1 at Week 12 by 0.16L (P=0.005) and 0.08L (P=0.13), and by 0.20L (P=0.003) and 0.21L (P< 0.001), respectively, in the same subgroups. Dupilumab vs placebo also improved asthma control and quality of life and suppressed FeNO levels in all patient subgroups with similar results observed irrespective of baseline biomarker status or disease severity.Conclusion: Dupilumab reduced severe exacerbations and improved lung function, asthma control and quality of life in patients with elevated baseline eosinophils irrespective of baseline ICS dose or FEV1% predicted.Keywords: asthma, biomarkers, dupilumab, exacerbation, FEV1

REK Russell,1,2 S Beer,3 ID Pavord,1,2 R Pullinger,3 M Bafadhel11Respiratory Medicine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; 2NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK; 3Department of Emergency Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UKIntroduction: There has been an increase in interest in the peripheral blood eosinophil count as a biomarker in COPD. Few studies have examined the eosinophil count in patients attending the emergency department (ED) with acute exacerbations of COPD (AECOPD). We investigated the relationship between the blood eosinophil and other variables collected routinely at ED presentation and outcomes.Methods: Retrospective case note review of patients attending the ED with an AECOPD over 18 months. Demographic, clinical and pharmacological data were analyzed at the time of presentation, and clinical outcomes relating to hospital admission, length of hospital stay and mortality were investigated.Results: There were 743 AECOPD index events in 537 patients. Over half (57%) of all attendees were admitted to hospital. They were older, reported an increased number of exacerbations and higher levels of total leukocytes and neutrophils. Length of stay was shorter in patients with a blood eosinophil count ≥2% compared to

Salman H Siddiqui,1,2 Ian D Pavord,3,4 Neil C Barnes,5,6 Alessandro Guasconi,7 Sally Lettis,8 Steven Pascoe,9 Stefano Petruzzelli7 1University of Leicester, Leicester, UK; 2National Institute for Health Research Leicester Biomedical Research Centre, Leicester, UK; 3Respiratory Theme, National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, University of Oxford, Oxford, UK; 4Respiratory Medicine Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK; 5Glaxo Smith Kline, Brentford, London, UK; 6Barts and The London School of Medicine and Dentistry, London, UK; 7Chiesi Farmaceutici SpA, Parma, Italy; 8GSK, Uxbridge, London, UK; 9GSK, King of Prussia, PA, USA Background: Growing evidence suggests that blood eosinophil count is associated with patient responsiveness to inhaled corticosteroids (ICS). We performed post hoc predictive modeling on data from the FORWARD study and two replicate studies by Dransfield, to evaluate the relationships between baseline eosinophil count and the effect of ICS on exacerbations and lung function in patients with COPD. Methods: The studies assessed ICS/long-acting β2 agonist (LABA) combinations vs LABA alone. Using data from each study, we modeled COPD exacerbation rates, predose FEV1, and St George’s Respiratory Questionnaire score ([FORWARD only]) over a continuous range of eosinophils (0–1,000 eosinophils/µL in FORWARD, 0–993 eosinophils/µL in Dransfield). Results: In all studies, ICS/LABA reduced exacerbations versus LABA alone across all eosinophil levels, with progressively greater reductions at increasing baseline blood eosinophil counts. In FORWARD, annual exacerbation rates ranged from 0.78 to 0.83 per year between 0 and 1,000 eosinophils/µL in the ICS/LABA arm, and from 0.81 to 1.54 per year in the LABA-only arm. In the Dransfield studies, exacerbation rates ranged from 0.54 to 1.02 per year in the ICS/LABA arm between 0 and 993 eosinophils/µL, and from 0.56 to 1.75 per year in the LABA-only arm. Change in FEV1 was not associated with eosinophil count in ICS-treated patients in FORWARD, whereas an increased treatment benefit in terms of FEV1 was observed at higher eosinophil levels in the Dransfield studies. ICS/LABA led to greater improvements in St George’s Respiratory Questionnaire total scores compared to LABA alone in patients in FORWARD with ≥67 eosinophils/µL. Conclusion: Higher blood eosinophil count in patients with COPD is associated with an increased beneficial effect from ICS in terms of exacerbation reduction. Further prospective data are required to assess the role of blood eosinophils as a biomarker for therapeutic recommendations. Keywords: lung function, FEV1, COPD, ICS

Ian D Pavord,1 Paul W Jones,2 Pierre-Régis Burgel,3 Klaus F Rabe4,5 1Respiratory Medicine Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK; 2Division of Clinical Science, St George’s, University of London, London, UK; 3Department of Respiratory Medicine, Cochin Hospital, University Paris Descartes, Sorbonne Paris Cité, Paris, France; 4Department of Medicine, Christian Albrecht University, Kiel, Germany; 5LungenClinic, Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany Abstract: Exacerbations of chronic obstructive pulmonary disease (COPD) are defined as sustained worsening of a patient’s condition beyond normal day-to-day variations that is acute in onset, and that may also require a change in medication and/or hospitalization. Exacerbations have a significant and prolonged impact on health status and outcomes, and negative effects on pulmonary function. A significant proportion of exacerbations are unreported and therefore left untreated, leading to a poorer prognosis than those treated. COPD exacerbations are heterogeneous, and various phenotypes have been proposed which differ in biologic basis, prognosis, and response to therapy. Identification of biomarkers could enable phenotype-driven approaches for the management and prevention of exacerbations. For example, several biomarkers of inflammation can help to identify exacerbations most likely to respond to oral corticosteroids and antibiotics, and patients with a frequent exacerbator phenotype, for whom preventative treatment is appropriate. Reducing the frequency of exacerbations would have a beneficial impact on patient outcomes and prognosis. Preventative strategies include modification of risk factors, treatment of comorbid conditions, the use of bronchodilator therapy with long-acting β2-agonists or long-acting muscarinic antagonists, and inhaled corticosteroids. A better understanding of the mechanisms underlying COPD exacerbations will help to optimize use of the currently available and new interventions for preventing and treating exacerbations. Keywords: COPD, exacerbation, phenotype, biomarker, bronchodilator

Mona Bafadhel,1 Koirobi Haldar,2 Bethan Barker,2,3 Hemu Patel,4 Vijay Mistry,2,3 Michael R Barer,2–4 Ian D Pavord,1 Christopher E Brightling2,3 1Respiratory Medicine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; 2Department of Infection, Immunity and Inflammation, University of Leicester, 3Institute for Lung Health, National Institute for Health Research Respiratory Biomedical Research Unit, Glenfield Hospital, University of Leicester, 4Department of Clinical Microbiology, University Hospitals of Leicester NHS Trust, Leicester, UK Background: Potentially pathogenic microorganisms can be detected by quantitative real-time polymerase chain reaction (qPCR) in sputum from patients with COPD, although how this technique relates to culture and clinical measures of disease is unclear. We used cross-sectional and longitudinal data to test the hypotheses that qPCR is a more sensitive measure of bacterial presence and is associated with neutrophilic airway inflammation and adverse clinical outcomes.Methods: Sputum was collected from 174 stable COPD subjects longitudinally over 12 months. Microbial sampling using culture and qPCR was performed. Spirometry and sputum measures of airway inflammation were assessed.Findings: Sputum was qPCR-positive (>106 copies/mL) in 77/152 samples (Haemophilus influenzae [n=52], Moraxella catarrhalis [n=24], Streptococcus pneumoniae [n=19], and Staphylococcus aureus [n=7]). Sputum was culture-positive in 50/174 samples, with 49 out of 50 culture-positive samples having pathogen-specific qPCR bacterial loads >106 copies/mL. Samples that had qPCR copy numbers >106/mL, whether culture-positive or not, had increased sputum neutrophil counts. H. influenzae qPCR copy numbers correlated with sputum neutrophil counts (r=0.37, P106/mL three or more times in 19 patients, eight of whom were repeatedly sputum culture-positive. Persistence, whether defined by culture, qPCR, or both, was associated with a higher sputum neutrophil count, lower forced expiratory volume in 1 second (FEV1), and worsened quality of life.Interpretation: qPCR identifies a significant number of patients with potentially bacteria-associated neutrophilic airway inflammation and disease that are not identified by traditional culture-based methods. Keywords: H. influenzae, qPCR, sputum

Bethan L Barker,1 Susan McKenna,1 Vijay Mistry,1 Mitesh Pancholi,1 Hemu Patel,2 Koirobi Haldar,3 Michael R Barer,3 Ian D Pavord,4 Michael C Steiner,1 Christopher E Brightling,1 Mona Bafadhel4 1Institute for Lung Health, NIHR Respiratory Biomedical Research Unit, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom; 2Department of Clinical Microbiology, University Hospitals of Leicester NHS Trust, Leicester, United Kingdom; 3Department of Infection, Immunity, and Inflammation, University of Leicester, Leicester, United Kingdom; 4Respiratory Medicine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus, Oxford, United Kingdom Background: Nutritional depletion is an important manifestation of chronic obstructive pulmonary disease (COPD), which has been related to systemic inflammation. It remains unclear to what degree airway inflammation contributes to the presence or progression of nutritional depletion. Objectives: To determine whether airway inflammation and lung bacterial colonization are related to nutritional status or predict progressive weight loss and muscle atrophy in patients with COPD. Methods: Body composition using dual energy X-ray absorptiometry, indices of airway inflammation, and bacterial colonization were measured in 234 COPD patients. Systemic inflammation was assessed from serum C reactive protein (CRP) and circulating total and differential leukocyte counts. Nutritional depletion was defined as a body mass index (BMI) less than 21 kg/m2 and/or fat-free mass index (FFMI) less than 15 or 17 kg/m2 in women and men, respectively. FFMI was calculated as the fat-free mass (FFM) corrected for body surface area. Measurements were repeated in 94 patients after a median 16-month follow-up. Regression analysis was used to assess the relationships of weight change and FFM change with indices of bacterial colonization and airway and systemic inflammation. Results: Nutritional depletion occurred in 37% of patients. Lung function was worsened in patients with nutritional depletion compared to those without (forced expiratory volume in 1 second 1.17 L versus 1.41 L, mean difference 0.24, 95% confidence interval 0.10 to 0.38, P

Roshan Siva,1 Mona Bafadhel,2 William Monteiro,3 Christopher E Brightling,3 Ian D Pavord2 1Department of Respiratory Medicine, Croydon University Hospital, Croydon Health Services NHS Trust, London, 2Department of Respiratory Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus, Oxford, 3Institute for Lung Health, NIHR Respiratory Biomedical Research Unit, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK Rationale: Airway inflammation persists after smoking cessation in established chronic obstructive pulmonary disease (COPD), suggesting that other factors drive the airway inflammatory response. Objectives: We tested the hypothesis that high levels of bacterial colonization are associated with increased levels of neutrophilic airway inflammation in stable COPD by examining the cross-sectional relationship between these measurements and by conducting a randomized, double-blind, placebo-controlled study of the effect of levofloxacin in patients with stable COPD. Methods: Patients were randomized to receive either levofloxacin 500 mg daily or placebo for 7 days and underwent sputum induction for a differential cell count and quantitative bacterial analysis at baseline and at days 7, 14, and 28. Results: Sputum percentage neutrophil count correlated with airway bacterial load at baseline (r=0.56; P=0.003). Levofloxacin reduced bacterial load compared with placebo by 4.9-fold (95% confidence interval, 1.4–25.7; P=0.02) at day 7 but had no effect at any point on any marker of neutrophilic airway inflammation. In patients with a baseline bacterial load of more than 106 cfu/mL, levofloxacin treatment was associated with a 26.5% (95% confidence interval, 1.8%–51.3%; P=0.04) greater reduction in the percentage neutrophil count compared with placebo at day 7. Change in percentage neutrophil count correlated significantly with baseline airway bacterial load and change in airway bacterial load. Conclusion: In stable COPD, levofloxacin treatment causes a short-term reduction in bacterial load. This is associated with a reduction in neutrophilic airway inflammation in patients with high bacterial loads. Further studies are required to investigate whether this effect is clinically advantageous. Keywords: bacteria, antibiotics, sputum