Efficacy of Tezepelumab in Patients with Severe, Uncontrolled Asthma Across Multiple Clinically Relevant Subgroups in the NAVIGATOR Study.

INTRODUCTION: Many patients with severe asthma continue to experience symptoms and exacerbations despite treatment with standard-of-care therapy. In the phase 3 NAVIGATOR study, tezepelumab significantly reduced exacerbations over 52 weeks compared with placebo in patients with severe, uncontrolled asthma. This analysis assessed the efficacy of tezepelumab in reducing asthma exacerbations in various clinically relevant subgroups of patients in NAVIGATOR. METHODS: NAVIGATOR was a phase 3, multicentre, randomized, double-blind, placebo-controlled study. Participants (12-80 years old) with severe, uncontrolled asthma were randomized 1:1 to receive tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. Pre-specified and post hoc analyses were performed to evaluate the annualized asthma exacerbation rate (AAER) over 52 weeks in clinically relevant subgroups of patients defined by baseline patient characteristics, medical history, exacerbation triggers, medication eligibility and medication use before and during the study. RESULTS: Tezepelumab reduced the AAER over 52 weeks compared with placebo across a wide range of patient subgroups assessed. Reductions in exacerbations were similar across subgroups defined by baseline patient characteristics, ranging from 48% (95% confidence interval [CI]: 21, 65) to 60% (95% CI: 44, 71) in subgroups analysed by sex, smoking history and body mass index. Among the asthma-related comorbidity subgroups investigated, patients with aspirin or NSAID sensitivity had the greatest reductions in AAER with tezepelumab compared with placebo (83%; 95% CI: 66, 91). In patients eligible to receive dupilumab, tezepelumab reduced exacerbations compared with placebo by 64% (95% CI: 54, 71). Reductions in the AAER with tezepelumab compared with placebo were also observed irrespective of exacerbation trigger category and the number of asthma controller medications patients were receiving at baseline. CONCLUSION: These findings further support the benefits of tezepelumab in patients with severe, uncontrolled asthma and can help to inform healthcare providers' treatment decisions. CLINICAL TRIAL REGISTRATION: NAVIGATOR (NCT03347279).

MELTEMI and COLUMBA: 5-Year Comparative Safety Analysis of Benralizumab and Mepolizumab.

BACKGROUND: Benralizumab and mepolizumab are interleukin (IL)-5Rα/interleukin-5-targeted monoclonal antibodies indicated as add-on treatments for patients with uncontrolled severe eosinophilic asthma (SEA). OBJECTIVE: To evaluate and compare the safety of benralizumab and mepolizumab among patients with SEA treated in MELTEMI and COLUMBA open-label, long-term extension studies, respectively. METHODS: MELTEMI was an extension study of benralizumab every 4 weeks (q4w) or every 8 weeks (q8w) for adults (aged 18-75 y) with SEA. MELTEMI participants transitioned from the BORA extension, preceded by participation in 1 of 3 placebo-controlled studies (SIROCCO, CALIMA, or ZONDA). COLUMBA was an extension study of mepolizumab for patients (aged ≥ 12 y) with SEA who transitioned from the dose-ranging DREAM study. Safety endpoints were presented as drug exposure patient-years (MELTEMI, q4w 784.28, q8w 797.03; COLUMBA 1,201) for nonserious adverse events, serious adverse events, and infections; malignancies were counted numerically. RESULTS: This analysis included 446 MELTEMI patients (benralizumab q4w 220; benralizumab q8w 226) and 347 COLUMBA patients (mepolizumab q4w). Viral upper respiratory tract infection was the most common nonserious adverse event in both studies (MELTEMI q8w 46.5%; q4w 47.3%; COLUMBA, 48.7%). Asthma-related events were the most common serious adverse events in both studies: MELTEMI 8.0% (q8w) and 8.6% (q4w) and COLUMBA 9.5%. Serious infections included pneumonia (MELTEMI q8w, 2 [0.9%]; COLUMBA, 6 [1.7%]); cellulitis (MELTEMI q8w, 1 [0.4%]; COLUMBA, 2 [0.6%]); and respiratory tract infections (COLUMBA, 2 [0.6%]). COLUMBA reported 6 malignancies and MELTEMI reported 4 malignancies in each group. CONCLUSIONS: This analysis demonstrated generally similar safety events between mepolizumab and benralizumab in patients with SEA.

Mepolizumab Reduces Systemic Corticosteroid Use in Chronic Rhinosinusitis With Nasal Polyps.

BACKGROUND: Systemic corticosteroids (SCSs) are associated with short- and long-term adverse effects. OBJECTIVE: To assess mepolizumab efficacy according to prior SCS use and characterize mepolizumab's SCS-sparing capabilities, in patients with severe chronic rhinosinusitis with nasal polyps. METHODS: In the randomized, double-blind, phase III SYNAPSE trial (NCT03085797), adults with severe chronic rhinosinusitis with nasal polyps eligible for repeat sinus surgery despite standard of care treatment received mepolizumab (100 mg subcutaneously) or placebo every 4 weeks for 52 weeks. The impact of prior SCS courses (0/1/>1) on mepolizumab versus placebo treatment responses (changes from baseline in total endoscopic nasal polyp [week 52], nasal obstruction visual analog scale [weeks 49-52], and 22-item Sino-Nasal Outcome Test total [week 52] scores) was analyzed post hoc. To characterize mepolizumab's SCS-sparing capabilities, time-to-first SCS course for nasal polyps (prespecified) and total prednisolone-equivalent oral corticosteroid dose by patient baseline characteristics (post hoc, in patients with ≥1 SCS course during SYNAPSE) were assessed up to week 52. RESULTS: Mepolizumab versus placebo improved treatment responses, irrespective of prior SCS use. By week 52, the probability of requiring SCSs for nasal polyps (Kaplan-Meier estimate [95% CI]) was lower with mepolizumab (25.4% [20.0-32.1]) versus placebo (37.5% [31.1-44.6]). In patients requiring 1 or more dose of SCSs, total (mean ± SD mg/y) prednisolone-equivalent oral corticosteroid dose was lower with mepolizumab (438.9 ± 350.40) versus placebo (505.2 ± 455.091), overall and irrespective of prior sinus surgeries, blood eosinophil count, or comorbidities. CONCLUSIONS: Mepolizumab is associated with clinical benefits in patients with severe chronic rhinosinusitis with nasal polyps regardless of prior SCS use and has an SCS-sparing effect.

Evaluating enrollment and outcome criteria in trials of biologics for chronic rhinosinusitis with nasal polyps.

OBJECTIVE: Treatment for chronic rhinosinusitis with nasal polyps (CRSwNP) generally involves intranasal corticosteroids (INCS) and saline irrigation, followed by short courses of systemic corticosteroids (SCS) or surgery with postoperative medical therapy for patients who do not respond to INCS. However, both SCS use and surgery are associated with a range of adverse effects or complications, have a high recurrence rate, and are unsuitable for some patients. Biologics targeting the underlying pathophysiology are promising treatment alternatives for these patients. Dupilumab, omalizumab, and mepolizumab are approved for use in patients with severe, uncontrolled CRSwNP. However, the lack of a consistent definition of severe CRSwNP makes the decision to initiate biologic treatment particularly complex. Furthermore, the position of each biologic in the overall management of CRSwNP remains to be clarified. DATA SOURCES: Publications reporting results of phase III trials of dupilumab, omalizumab, mepolizumab, and benralizumab in the treatment of CRSwNP. STUDY SELECTIONS: Randomized, controlled phase III trials of biologics approved for CRSwNP. RESULTS: These trials all used different enrollment criteria. We discuss the complexities of assessing CRSwNP disease severity and highlight how these impact comparisons of the populations and outcomes of the phase III biologic trials. CONCLUSION: To position biologic agents appropriately within the existing CRSwNP treatment paradigm, future trials will need to include comparable patient populations and standardized outcome measures. Such trials will help to ensure that biologic treatment is targeted appropriately to support optimal clinical outcomes.

Inhibition of ABCC1 Decreases cAMP Egress and Promotes Human Airway Smooth Muscle Cell Relaxation.

In most living cells, the second-messenger roles for adenosine 3',5'-cyclic monophosphate (cAMP) are short-lived, confined to the intracellular space, and tightly controlled by the binary switch-like actions of Gαs (stimulatory G protein)-activated adenylyl cyclase (cAMP production) and cAMP-specific PDE (cAMP breakdown). Here, by using human airway smooth muscle (HASM) cells in culture as a model, we report that activation of the cell-surface ß2AR (ß2-adrenoceptor), a Gs-coupled GPCR (G protein-coupled receptor), evokes cAMP egress to the extracellular space. Increased extracellular cAMP levels ([cAMP]e) are long-lived in culture and are induced by receptor-dependent and receptor-independent mechanisms in such a way as to define a universal response class of increased intracellular cAMP levels ([cAMP]i). We find that HASM cells express multiple ATP-binding cassette (ABC) membrane transporters, with ABCC1 (ABC subfamily member C 1) being the most highly enriched transcript mapped to MRPs (multidrug resistance-associated proteins). We show that pharmacological inhibition or downregulation of ABCC1 with siRNA markedly reduces ß2AR-evoked cAMP release from HASM cells. Furthermore, inhibition of ABCC1 activity or expression decreases basal tone and increases ß-agonist-induced HASM cellular relaxation. These findings identify a previously unrecognized role for ABCC1 in the homeostatic regulation of [cAMP]i in HASM that may be conserved traits of the Gs-GPCRs (Gs-coupled family of GPCRs). Hence, the general features of this activation mechanism may uncover new disease-modifying targets in the treatment of airflow obstruction in asthma. Surprisingly, we find that serum cAMP levels are elevated in a small cohort of patients with asthma as compared with control subjects, which warrants further investigation.

Safety and Efficacy of Mepolizumab in Hypereosinophilic Syndrome: An Open-Label Extension Study.

BACKGROUND: A double-blind, placebo-controlled, phase III study (200622) showed that mepolizumab reduces disease flares for patients with uncontrolled FIP1-like-1-platelet-derived growth factor receptor α-negative hypereosinophilic syndrome (HES) and two or more flares in the previous year. OBJECTIVE: To further characterize the safety, clinical benefit, and pharmacodynamics of mepolizumab. METHODS: Eligible patients from both treatment arms of the double-blind study could enter an open-label extension study (205203; NCT03306043) to receive 4-weekly mepolizumab (300 mg subcutaneously) plus background therapy for 20 weeks. Primary end points were safety-based; other end points included flare rates and changes from baseline in mean daily oral corticosteroid (OCS) dose and blood eosinophil count. RESULTS: Of 104 patients who completed the double-blind study, 98% (previous placebo, n = 52; previous mepolizumab, n = 50) enrolled in the open-label extension. Overall, 66 of patients reported adverse events (AEs) (65%), 15 reported treatment-related AEs (15%), and nine reported serious AEs (9%). No events were fatal. The annualized flare rate (95% confidence interval) in the previous placebo and previous mepolizumab groups was 0.37 (0.16-0.86) and 0.14 (0.04-0.49) events/y, respectively. Of 72 patients receiving OCS during weeks 0 to 4, 20 (28%; previous placebo, n = 14; previous mepolizumab, n = 6) achieved 50% or greater reductions in mean daily dose during weeks 16 to 20. At week 20, blood eosinophil count was reduced by 89% in patients previously receiving placebo and remained reduced for those previously receiving mepolizumab. CONCLUSIONS: Extended mepolizumab treatment was associated with a positive benefit-risk profile. Continued control of disease flares and blood eosinophil counts, plus reductions in OCS use, were observed with mepolizumab in patients with FIP1-like-1-platelet-derived growth factor receptor α-negative HES.

Mepolizumab improves clinical outcomes in patients with severe asthma and comorbid conditions.

BACKGROUND: Comorbidities can complicate the management of severe asthma; therefore, the presence of comorbid conditions or traits often need to be considered when considering treatment options for patients with severe asthma. The aim of this analysis is to investigate the efficacy of mepolizumab in patients with severe eosinophilic asthma and comorbidities. METHODS: This was a post hoc analysis (GSK ID:209140) of data from the Phase IIb/III studies DREAM, MENSA, SIRIUS, and MUSCA. Patients aged ≥ 12 years with severe eosinophilic asthma were randomized to: mepolizumab 750, 250, or 75 mg intravenously or placebo (DREAM); mepolizumab 75 mg intravenously or 100 mg subcutaneously or placebo (MENSA); or mepolizumab 100 mg subcutaneously or placebo (SIRIUS and MUSCA) every 4 weeks for 24 weeks in SIRIUS and MUSCA, 32 weeks in MENSA or 52 weeks in DREAM. In this analysis the primary endpoint was the annual rate of clinically significant exacerbations; secondary endpoints were Asthma Control Questionnaire-5 score, St George's Respiratory Questionnaire total score, and pre-bronchodilator forced expiratory volume in 1 s at study end. Subgroups were based on comorbidities at baseline. RESULTS: Overall, 1878 patients received placebo (n = 689) or mepolizumab (n = 1189). Across all comorbidity subgroups mepolizumab reduced the rate of clinically significant exacerbations by 44-68% versus placebo, improved Asthma Control Questionnaire-5 score by 0.27-0.59 points, and improved St George's Respiratory Questionnaire total score by 5.0-11.6 points. Pre-bronchodilator forced expiratory volume in 1 s was improved by 27.1-286.9 mL in all but one comorbidity subgroup, the diabetes mellitus subgroup. CONCLUSIONS: Mepolizumab reduces exacerbations, and improves asthma control, health-related quality of life, and lung function in patients with severe eosinophilic asthma despite comorbid conditions, including upper respiratory conditions, psychopathologies, cardiovascular conditions, gastroesophageal reflux disease, diabetes mellitus, and obesity. TRIAL REGISTRATION: https://clinicaltrials.gov/ DREAM, MEA112997/NCT01000506; MENSA, MEA115588/NCT01691521; SIRIUS, MEA115575/NCT01842607; MUSCA, 200862/NCT02281318.

SPLUNC1: a novel marker of cystic fibrosis exacerbations.

BACKGROUND: Acute pulmonary exacerbations (AE) are episodes of clinical worsening in cystic fibrosis (CF), often precipitated by infection. Timely detection is critical to minimise morbidity and lung function declines associated with acute inflammation during AE. Based on our previous observations that airway protein short palate lung nasal epithelium clone 1 (SPLUNC1) is regulated by inflammatory signals, we investigated the use of SPLUNC1 fluctuations to diagnose and predict AE in CF. METHODS: We enrolled CF participants from two independent cohorts to measure AE markers of inflammation in sputum and recorded clinical outcomes for a 1-year follow-up period. RESULTS: SPLUNC1 levels were high in healthy controls (n=9, 10.7 µg·mL-1), and significantly decreased in CF participants without AE (n=30, 5.7 µg·mL-1; p=0.016). SPLUNC1 levels were 71.9% lower during AE (n=14, 1.6 µg·mL-1; p=0.0034) regardless of age, sex, CF-causing mutation or microbiology findings. Cytokines interleukin-1ß and tumour necrosis factor-α were also increased in AE, whereas lung function did not decrease consistently. Stable CF participants with lower SPLUNC1 levels were much more likely to have an AE at 60 days (hazard ratio (HR)±se 11.49±0.83; p=0.0033). Low-SPLUNC1 stable participants remained at higher AE risk even 1 year after sputum collection (HR±se 3.21±0.47; p=0.0125). SPLUNC1 was downregulated by inflammatory cytokines and proteases increased in sputum during AE. CONCLUSION: In acute CF care, low SPLUNC1 levels could support a decision to increase airway clearance or to initiate pharmacological interventions. In asymptomatic, stable patients, low SPLUNC1 levels could inform changes in clinical management to improve long-term disease control and clinical outcomes in CF.

Profiling cellular heterogeneity in asthma with single cell multiparameter CyTOF.

Asthma is a chronic inflammatory disease of the airways that afflicts over 30 million individuals in the United States and over 300 million individuals worldwide. The inflammatory response in the airways is often characterized by the analysis of sputum, which contains multiple types of cells including neutrophils, macrophages, lymphocytes, and rare bronchial epithelial cells. Subtyping patients using microscopy of the sputum has identified both neutrophilic and eosinophilic infiltrates in airway inflammation. However, with the extensive heterogeneity among these cell types, a higher resolution understanding of the inflammatory cell types present in the sputum is needed to dissect the heterogeneity of disease. Improved recognition of the distinct phenotypes and sources of inflammation in asthmatic granulocytes may identify relevant pathways for clinical management or investigation of novel therapeutic mediators. Here, we employed mass cytometry or cytometry by time-of-flight to quantify frequency and define functional status of sputum derived airway cells in asthmatic patients and healthy controls. This in-depth single cell analysis method identified multiple distinct subtypes of airway immune cells, especially in neutrophils. Significance was discovered by statistical analysis as well as a data-driven unbiased clustering approach. Our multidimensional assessment method identifies differences in cellular function and supports identification of cellular status that may contribute to diverse clinical responses. This technical advance is relevant for studies of pathogenesis and may provide meaningful insights to advance our knowledge of asthmatic inflammation.

Single-Cell Transcriptional Archetypes of Airway Inflammation in Cystic Fibrosis.

Rationale: Cystic fibrosis (CF) is a life-shortening, multisystem hereditary disease caused by abnormal chloride transport. CF lung disease is driven by innate immune dysfunction and exaggerated inflammatory responses that contribute to tissue injury. To define the transcriptional profile of this airway immune dysfunction, we performed the first single-cell transcriptome characterization of CF sputum.Objectives: To define the transcriptional profile of sputum cells and its implication in the pathogenesis of immune function and the development of CF lung disease.Methods: We performed single-cell RNA sequencing of sputum cells from nine subjects with CF and five healthy control subjects. We applied novel computational approaches to define expression-based cell function and maturity profiles, herein called transcriptional archetypes.Measurements and Main Results: The airway immune cell repertoire shifted from alveolar macrophages in healthy control subjects to a predominance of recruited monocytes and neutrophils in CF. Recruited lung mononuclear phagocytes were abundant in CF and were separated into the following three archetypes: activated monocytes, monocyte-derived macrophages, and heat shock-activated monocytes. Neutrophils were the most prevalent in CF, with a dominant immature proinflammatory archetype. Although CF monocytes exhibited proinflammatory features, both monocytes and neutrophils showed transcriptional evidence of abnormal phagocytic and cell-survival programs.Conclusions: Our findings offer an opportunity to understand subject-specific immune dysfunction and its contribution to divergent clinical courses in CF. As we progress toward personalized applications of therapeutic and genomic developments, we hope this inflammation-profiling approach will enable further discoveries that change the natural history of CF lung disease.

Clinical Research Needs for the Management of Chronic Rhinosinusitis with Nasal Polyps in the New Era of Biologics: A National Institute of Allergy and Infectious Diseases Workshop.

The development of biologics targeting various aspects of type 2 inflammation for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) will provide clinicians with powerful tools to help treat these patients. However, other therapies are also available, and positioning of biologics in a management algorithm will require comparative trials. In November 2019, the National Institute of Allergy and Infectious Diseases convened a workshop to consider potential future trial designs. Workshop participants represented a wide spectrum of clinical specialties, including otolaryngology, allergy, and pulmonary medicine, as well as expertise in CRSwNP pathophysiology and in trial methodology and statistics. The workshop discussed the current state of knowledge in CRSwNP and considered the advantages and disadvantages of various clinical trial or observational study designs and various clinical outcomes. The output from this workshop, which is presented in this report, will hopefully provide investigators with adequate information and ideas to design future studies and answer critical clinical questions. It will also help clinicians understand the current state of the management of CRSwNP and its gaps and be more able to interpret the new information to come.

New Therapies for Emerging Endotypes of Asthma.

The presentation, pathobiology, and prognosis of asthma are highly heterogeneous and challenging for clinicians to diagnose and treat. In addition to the adaptive immune response that underlies allergic inflammation, innate immune mechanisms are increasingly recognized to be critical mediators of the eosinophilic airway inflammation present in most patients with asthma. Efforts to classify patients by severity and immune response have identified a number of different clinical and immune phenotypes, indicating that the innate and adaptive immune responses are differentially active among patients with the disease. Advances in the detection of these subgroups using clinical characteristics and biomarkers have led to the successful development of targeted biologics. This has moved us to a more personalized approach to managing asthma. Here we review the emerging endotypes of asthma and the biologics that have been developed to treat them.

Pulmonary artery pseudoaneurysm causing massive hemoptysis in hyperimmunoglobulin E syndrome: a case report.

BACKGROUND: Hyperimmunoglobulin E syndrome (HIES) is a rare primary immunodeficiency disorder defined by high serum immunoglobulin E titers that is associated with recurrent respiratory infections, formation of pneumoatoceles, recurrent skin abscesses, and characteristic dental and skeletal abnormalities. CASE PRESENTATION: We report a case of a 56-year-old male with a history of HIES, cavitary mycetomas, and allergic bronchopulmonary aspergillosis who presented with recurrent massive hemoptysis. Bronchial artery angiography and bronchoscopy failed to identify active hemorrhage, and two embolizations of the bronchial artery did not resolve the bleeding. Subsequently, selective pulmonary artery angiography was conducted that demonstrated a subsegmental pulmonary artery branch pseudoaneurysm with extravasation into an adjacent lung cavity. This was treated successfully with transcatheter embolization. CONCLUSIONS: To our knowledge, this is the first case reported of pulmonary artery pseudoaneurysm in HIES in the medical literature. Pulmonary artery pseudoaneurysm should be considered in the differential diagnosis in patients with HIES and massive hemoptysis.

Practice Patterns and Perceptions of Chest Health Care Providers on Electronic Cigarette Use: An In-Depth Discussion and Report of Survey Results.

INTRODUCTION: The emergence of electronic cigarettes (ECs) has become a growing phenomenon that has sharply split opinion among the public health community, physicians, and lawmakers. AIMS: We sought to determine chest physician perceptions regarding ECs. METHODS: We conducted a web-based survey of 18,000 American College of Chest Physician (CHEST) members to determine healthcare provider experiences with EC users and to characterize provider perceptions regarding ECs. RESULTS/FINDINGS: There were 994 respondents. 88% reported that patients had asked their opinion of ECs, and 31% reported EC use among at least 10% of their patients. More disagreed than agreed (41% vs. 21%) that patients could improve their health by switching from tobacco smoking to daily EC use. Respondents were split on whether ECs promote tobacco cessation (32% agree vs. 33% disagree). CONCLUSIONS: Current perceptions of ECs are variable among providers. More than 1/3 of respondents felt that EC's could be used for smoking cessation for smokers who failed prior quit attempts with approved therapies. However, many respondents were not convinced that ECs will reduce harms from tobacco use. There is an urgent need to generate additional high quality scientific data regarding ECs to inform chest physicians, health professionals and the general public.

Electronic cigarettes for adults with tobacco dependence enrolled in a tobacco treatment program: A pilot study.

INTRODUCTION: Electronic cigarettes (ECs) have emerged as a potential harm-reducing alternative for tobacco smokers. However, the role ECs might play in treatment settings is unclear. We conducted an exploratory study of treatment-seeking smokers enrolling in a standard tobacco treatment program who were provided with either a nicotine or non-nicotine EC to use as needed to cease tobacco smoking. METHODS: Treatment-seeking smokers received standard tobacco treatment for 8weeks and were given nicotine transdermal patch therapy, behavioral counseling, and either a nicotine or non-nicotine EC to use as needed. Smoking and EC use patterns were tracked longitudinally to week 24. RESULTS: 40 subjects were enrolled into the study. At week 24, 6 subjects (15%) were abstinent, and the mean reduction in reported cigarettes smoked per day was 6.8±12. There were no significant differences in smoking outcomes between those who received a nicotine or non-nicotine EC (proportion abstinent at 24weeks: nicotine EC=4/20 (20%); non-nicotine EC=2/20 (10%); p=0.66). Among subjects assessed at follow-up, 62.5% were EC non-users. CONCLUSIONS: The addition of a 2nd generation EC to outpatient tobacco treatment among tobacco smokers is feasible. Among those who quit smoking, half were still using the EC at 6-month follow-up. Appeal of the EC among smokers was variable, and those who had quit smoking tended to switch to lower strength nicotine solutions. Further research is needed to determine whether ECs can reduce harm and be an effective adjunct to existing tobacco treatment interventions.

Inhaled Steroids and Active Smoking Drive Chronic Obstructive Pulmonary Disease Symptoms and Biomarkers to a Greater Degree Than Airflow Limitation.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease, and development of novel therapeutics requires an understanding of pathophysiologic phenotypes. OBJECTIVES: The purpose of the Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study was to correlate clinical features and biomarkers with molecular characteristics in a well-profiled COPD cohort. METHODS: A total of 67 COPD subjects (forced expiratory volume in the first second of expiration [FEV1]: 45%-80% predicted) and 63 healthy smoking and nonsmoking controls underwent multiple assessments including patient questionnaires, lung function, and clinical biomarkers including fractional exhaled nitric oxide (FENO), induced sputum, and blood. MEASUREMENTS AND MAIN RESULTS: The impact of inhaled corticosteroids (ICSs), and to a lesser extent current smoking, was more associated with symptom control, exacerbation rates, and clinical biomarkers, than severity by FEV1. The ICS-treated smoking subjects were most symptomatic, with significantly elevated scores on patient-reported outcomes and more annual exacerbations (P < .05). Inhaled corticosteroid users had greater airflow obstruction and air trapping compared with non-ICS users, regardless of smoking status. Smoking, regardless of ICS use, was associated with significantly lower FENO (P < .05). Smoking, in non-ICS users, was associated with an elevated proportion of sputum neutrophils and reduced sputum macrophages. Increased serum C-reactive protein was observed in smokers but not in ICS and nonsmoking ICS users (P < .05). In contrast, only air trapping and neutrophilic inflammation increased with severity, defined by postbronchodilator FEV1. CONCLUSIONS: Compared with COPD severity by FEV1, ICS use and current smoking were better determinants of clinical characteristics and biomarkers. Use of the ADEPT COPD data promises to prove useful in defining biological phenotypes to facilitate personalized therapeutic approaches.

Multiparameter Single Cell Profiling of Airway Inflammatory Cells.

Airway diseases affect over 7% of the U.S. population and millions of patients worldwide. Asthmatic patients have wide variation in clinical severity with different clinical and physiologic manifestations of disease that may be driven by distinct biologic mechanisms. Further, the immunologic underpinnings of this complex trait disease are heterogeneous and treatment success depends on defining subgroups of asthmatics. Because of the limited availability and number of cells from the lung, the active site, in-depth investigation has been challenging. Recent advances in technology support transcriptional analysis of cells from induced sputum. Flow cytometry studies have described cells present in the sputum but a detailed analysis of these subsets is lacking. Mass cytometry or CyTOF (Cytometry by Time-Of-Flight) offers tremendous opportunities for multiparameter single cell analysis. Experiments can now allow detection of up to ∼40 markers to facilitate unprecedented multidimensional cellular analyses. Here we demonstrate the use of CyTOF on primary airway samples obtained from well-characterized patients with asthma and cystic fibrosis. Using this technology, we quantify cellular frequency and functional status of defined cell subsets. Our studies provide a blueprint to define the heterogeneity among subjects and underscore the power of this single cell method to characterize airway immune status. © 2016 International Clinical Cytometry Society.

Hospital readmission after pulmonary lobectomy is not affected by surgical approach.

BACKGROUND: The aim of this study is to identify the predictors of hospital readmission or early unplanned return to clinic within 30 days of discharge after pulmonary lobectomy. METHODS: The medical records of patients undergoing lobectomy by the thoracic surgery service between January 2009 and July 2012 were reviewed. All lobectomies were included irrespective of the etiology of disease. Multivariate logistic regression methods were used to identify predictors of readmission and or early unplanned return to clinic. RESULTS: Two hundred thirteen patients underwent a pulmonary lobectomy during the study period (median age, 67 years). Pathologic diagnosis was malignant in 94% of the patients and benign in 6%. Minimally invasive approaches were used in 69% of the patients, whereas open thoracotomy was used in 31%. Median hospital length of stay was 4 days, and postoperative mortality occurred in 1 patient (0.5%). The Charlson comorbidity index was 1 ± 1. Predicted postoperative forced expiratory volume in 1 second and diffusing capacity of the lung for carbon monoxide were 68% ± 18% and 64% ± 17%, respectively. Postoperative complications occurred in 31% of patients; 13% required readmission to the hospital within 30 days of discharge or early unplanned return to clinic. Predictors of readmission or early unplanned return to clinic were unplanned transfer to the intensive care unit (odds ratio, 10.4; 95% confidence interval, 1.1 to 103.5; p = 0.04) and Charlson comorbidity index greater than 0 (odds ratio, 1.5; 95% confidence interval, 1.04 to 2.03; p = 0.03). Readmission or early unplanned return to clinic was independent of surgical approach (p = 0.32). CONCLUSIONS: Patients who require a postoperative transfer to the intensive care unit or with higher Charlson comorbidity index are at higher risk for hospital readmission after pulmonary lobectomy. Readmission was not affected by the surgical approach. Whether a different strategy to follow-up for these high-risk patients can prevent readmission remains to be determined.

Role of growth arrest-specific gene 6 in the development of fungal allergic airway disease in mice.

Growth arrest-specific gene (Gas)6 is a secreted vitamin K-dependent protein with pleiotropic effects via activation of receptor tyrosine kinase Tyro3, Axl, and Mertk receptors, but little is known about its role in allergic airway disease. We investigated the role of Gas6 in the development of fungal allergic airway disease in mice. The immune response was evaluated in Gas6-deficient (Gas6-/-) and wild-type (WT) mice and in recombinant Gas6-treated WT mice during Aspergillus fumigatus-induced allergic airway disease. Gas6 plasma levels were significantly elevated in adult clinical asthma of all severities compared with subjects without asthma. In a murine model of fungal allergic airway disease, increased protein expression of Axl and Mertk were observed in the lung. Airway hyperresponsiveness (AHR), whole lung Th2 cytokine levels, goblet cell metaplasia, and peribronchial fibrosis were ameliorated in Gas6-/- mice compared with WT mice with fungal allergic airway disease. Intranasal Gas6 administration into WT mice had a divergent effect on airway inflammation and AHR. Specifically, a total dose of 2 µg of exogenous Gas6 (i.e., low dose) significantly increased whole lung Th2 cytokine levels and subsequent AHR, whereas a total dose of 7 µg of exogenous Gas6 (i.e., high dose) significantly suppressed Th1 and Th2 cytokines and AHR compared with appropriate control groups. Mechanistically, Gas6 promoted Th2 activation via its highest affinity receptor Axl expressed by myeloid DCs. Intranasal administration of Gas6 consistently exacerbated airway remodeling compared with control WT groups. These results demonstrate that Gas6 enhances several features of fungal allergic airway disease.