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Brendan Clark,1 Brian J Wells,2 Amit K Saha,3 Jessica Franchino-Elder,1 Asif Shaikh,4 Bonnie MK Donato,1 Jill A Ohar5 1Health Economics and Outcomes Research, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, USA; 2Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA; 3Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC, USA; 4Clinical Development and Medical Affairs, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, USA; 5Department of Medicine, Section of Pulmonary, Critical Care, Allergy and Immunology, Wake Forest School of Medicine, Winston-Salem, NC, USACorrespondence: Jill A Ohar, Department of Medicine, Section of Pulmonary, Critical Care, Allergy and Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA, Tel +1 336-406-6733, Fax +1 336-716-7277, Email johar@wakehealth.eduBackground: Patients with chronic obstructive pulmonary disease (COPD) can have low peak inspiratory flow (PIF), especially after hospitalization for acute exacerbation of COPD (AECOPD).Purpose: To characterize patients hospitalized for AECOPD, and to assess the prevalence of low PIF, changes in PIF after hospitalization, and the association of low PIF with healthcare resource utilization (HRU) outcomes.Patients and Methods: A retrospective cohort study was conducted using electronic health record data of hospitalized COPD patients in the Wake Forest Baptist Health system (01/01/2017 through 06/30/2020). Patients with a first eligible AECOPD hospitalization (index hospitalization) who were discharged before 05/31/2020 were included. PIF was measured using the In-Check DIAL™ at both medium-low resistance (R-2) and high resistance (R-5) during the index hospitalization. For R-2 and R-5, PIF was divided into low PIF (< 60 L/min; < 30 L/min) and high PIF (≥ 60 L/min; ≥ 30 L/min) groups. The primary outcome was the prevalence of low PIF. The stability of PIF after hospitalization was described. Adjusted regression models evaluated associations between low PIF and subsequent 30-day readmissions, 90-day readmissions, and HRU outcomes, including hospitalizations, emergency department visits, inpatient days, and intensive care unit (ICU) days.Results: In total, 743 patients with PIF measured at R-2 and R-5 during a AECOPD hospitalization were included. The prevalence of low PIF was 56.9% at R-2 and 14.7% at R-5. PIF values were relatively stable after hospitalization. Adjusted analyses showed significant increases in HRU (all-cause hospitalizations [31%], COPD hospitalizations [33%], COPD inpatient days [46%], and COPD ICU days [24%]) during the follow-up period among patients with low PIF (< 60 L/min) at R-2. The 30- and 90-day readmission risks were similar between patients with low PIF and high PIF.Conclusion: Low PIF is common among patients hospitalized for AECOPD, relatively stable after hospital discharge, and associated with increased HRU.Keywords: AECOPD, electronic health records, healthcare utilization, PIF

Dry powder inhalers (DPIs) are breath actuated, and patients using DPIs need to generate an optimal inspiratory flow during the inhalation maneuver for effective drug delivery to the lungs. However, practical and standardized recommendations for measuring peak inspiratory flow (PIF)—a potential indicator for effective DPI use in chronic obstructive pulmonary disease (COPD)—are lacking. To evaluate recommended PIF assessment approaches, we reviewed the Instructions for Use of the In-Check™ DIAL and the prescribing information for eight DPIs approved for use in the treatment of COPD in the United States. To evaluate applied PIF assessment approaches, we conducted a PubMed search from inception to August 31, 2021, for reports of clinical and real-life studies where PIF was measured using the In-Check™ DIAL or through a DPI in patients with COPD. Evaluation of collective sources, including 47 applicable studies, showed that instructions related to the positioning of the patient with their DPI, instructions for exhalation before the inhalation maneuver, the inhalation maneuver itself, and post-inhalation breath-hold times varied, and in many instances, appeared vague and/or incomplete. We observed considerable variation in how PIF was measured in clinical and real-life studies, underscoring the need for a standardized method of PIF measurement. Standardization of technique will facilitate comparisons among studies. Based on these findings and our clinical and research experience, we propose specific recommendations for PIF measurement to standardize the process and better ensure accurate and reliable PIF values in clinical trials and in daily clinical practice.

Background Peak inspiratory flow (PIF) has been proposed as a measure to assess a patient’s ability to use dry powder inhalers (DPIs). However, robust quality criteria to determine a repeatability limit for measuring PIF are lacking. Research Questions What are the repeatability limits for measuring PIF? What is the relationship between PIF measured using the In-Check DIAL device at Diskus (GlaxoSmithKline; PIFD) and HandiHaler (Boehringer Ingelheim; PIFHH) resistances? Study Design and Methods Data from a randomized, controlled, phase 3 trial (study 0149; see Clinical Trial Registration data) were used to define repeatability limits for PIF. In addition, a model to characterize the relationship between PIF measured with the In-Check DIAL device at PIFD and PIFHH was defined using data from two randomized, controlled, phase 3 trials (studies 0128 and 0149). Results In study 0128, the mean values (SD) for PIF at zero resistance and PIFHH were 84.6 (33.4) and 57.3 (26.1) L/min, respectively. In study 0149, the mean values (SD) for PIFD and PIFHH were 42.4 (11.2) and 29.0 (8.3) L/min, respectively. At the mean level, the mean difference between measurement attempts for PIFD and PIFHH was small, Interpretations This analysis demonstrated that the two highest values of PIF using the In-Check DIAL device among three inspiratory efforts, met the repeatability limit. Altogether, these data provide guidance for measuring PIF against the simulated resistance of a specific DPI in clinical practice and research studies. Clinical Trial Registration ClinicalTrials.gov; Nos.: NCT02518139 (study 0128) and NCT03095456 (study 0149); URL: www.clinicaltrials.gov .

Background: Noninvasive ventilation (NIV) is used for patients with chronic obstructive pulmonary disease (COPD) and chronic hypercapnia. However, evidence for clinical efficacy and optimal management of therapy is limited. Target Audience: Patients with COPD, clinicians who care for them, and policy makers. Methods: We summarized evidence addressing five PICO (patients, intervention, comparator, and outcome) questions. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was used to evaluate the certainty in evidence and generate actionable recommendations. Recommendations were formulated by a panel of pulmonary and sleep physicians, respiratory therapists, and methodologists using the Evidence-to-Decision framework. Recommendations: 1) We suggest the use of nocturnal NIV in addition to usual care for patients with chronic stable hypercapnic COPD (conditional recommendation, moderate certainty); 2) we suggest that patients with chronic stable hypercapnic COPD undergo screening for obstructive sleep apnea before initiation of long-term NIV (conditional recommendation, very low certainty); 3) we suggest not initiating long-term NIV during an admission for acute-on-chronic hypercapnic respiratory failure, favoring instead reassessment for NIV at 2–4 weeks after resolution (conditional recommendation, low certainty); 4) we suggest not using an in-laboratory overnight polysomnogram to titrate NIV in patients with chronic stable hypercapnic COPD who are initiating NIV (conditional recommendation, very low certainty); and 5) we suggest NIV with targeted normalization of PaCO2 in patients with hypercapnic COPD on long-term NIV (conditional recommendation, low certainty). Conclusions: This expert panel provides evidence-based recommendations addressing the use of NIV in patients with COPD and chronic stable hypercapnic respiratory failure.

Purpose The clinical manifestation of COPD can differ by gender, with women experiencing worse lung function and health-related quality of life than men. Additionally, women tend to report more symptoms given the same disease severity. Accordingly, the impact of gender on efficacy and safety in patients with moderate-to-very-severe COPD was examined following 12 weeks of nebulized glycopyrrolate (GLY) 25 µg twice daily (BID) or placebo. Patients and methods GLY and placebo pooled data from the replicate 12-week GOLDEN 3 and 4 studies (n=861) were grouped by gender. Endpoints reported were change from baseline in trough forced expiratory volume in 1 second (FEV1), St George's Respiratory Questionnaire (SGRQ) and EXAcerbations of COPD Tool-Respiratory Symptoms (EXACT-RS) total scores. Safety was evaluated by reviewing the incidence of adverse events (AEs) and serious AEs. Results Men (placebo: 54.7%; GLY: 56.1%) were generally older with a greater proportion of high cardiovascular risk and use of background long-acting β2-agonists or inhaled corticosteroids. GLY treatment resulted in significant, clinically important improvements in trough FEV1, regardless of gender. Patients treated with GLY reported significant improvements in SGRQ total score, irrespective of gender; however, the improvement was numerically higher in women. Although EXACT-RS improved in both genders, only women experienced a significant improvement. Overall, GLY was well tolerated with a numerically lower incidence of AEs in men than women. Conclusion Treatment with nebulized GLY resulted in lung function, SGRQ total score, and EXACT-RS total score improvements regardless of gender. However, only EXACT-RS showed significantly greater improvements in women compared with men. Treatment with GLY was generally well tolerated across genders. These data support the efficacy and safety of GLY 25 µg BID in patients with moderate-to-very-severe COPD, independent of gender. Gender similarities in airflow improvement and differences in symptom-reporting augment the evidence supporting the consideration of individualized treatment plans for COPD patients.

Purpose Adequate peak inspiratory flow rate (PIFR) is required for drug dispersion with dry powder inhalers (DPIs). Prevalence of PIFR discordance (suboptimal PIFR with prescribed inhalers) and factors influencing device-specific PIFR are unclear in COPD. The objective of this study was to determine the prevalence of PIFR discordance and associated clinical factors in a stable COPD population. Patients and methods An observational, single-center, cohort study was conducted including 66 outpatients with COPD. PIFR was measured using the In-Check™ Dial with applied resistance of prescribed inhalers. Participants were defined as discordant if measured PIFR was

Purpose Bronchodilator reversibility has been reported in patients with COPD, although correlations between reversibility and treatment response are unclear. The effect of reversibility on lung function, health status, and dyspnea was assessed in patients with moderate-to-severe COPD receiving glycopyrrolate (GLY) 15.6 µg twice daily vs placebo in the Glycopyrrolate Effect on syMptoms and lung function 1 and 2 (GEM1 and GEM2) replicate, 12-week, placebo-controlled studies. Patients and methods Reversibility was defined as a post-bronchodilator increase of ≥12% and ≥0.200 L in FEV1. FEV1 area under the curve from 0 to 12 hours (AUC0-12 h), trough FEV1, St George's Respiratory Questionnaire (SGRQ) total score, COPD Assessment Test (CAT™) score, Transition Dyspnea Index (TDI) focal score, daily symptom scores, and rescue medication use were assessed by reversibility status. Incidences of adverse events and serious adverse events were also assessed. Results Data from 846 patients enrolled in GEM1 and GEM2 with known reversibility status were pooled for post hoc analysis. GLY significantly improved FEV1 AUC0-12 h, trough FEV1, SGRQ and CAT total scores, and rescue medication use compared with placebo in reversible and nonreversible patients. Significant improvements in TDI focal score and daily symptom scores with GLY over placebo were observed only among reversible patients. Improvements in FEV1 AUC0-12 h (0.165 vs 0.078 L; P

There is irrefutable evidence that germline BRCA1-associated protein 1 gene (BAP1) mutations contribute to malignant mesothelioma (MM) susceptibility. However, BAP1 mutations are not found in all cases with evidence of familial MM or in other high-risk cancer families affected by various cancers, including MM. The goal of this study was to use whole genome sequencing (WGS) to determine the frequency and types of germline gene variants occurring in 12 MM patients who were selected from a series of 141 asbestos-exposed MM patients with a family history of cancer but without a germline BAP1 mutation. WGS was also performed on two MM cases, a proband and sibling, from a previously reported family with multiple cases of MM without the inheritance of a predisposing BAP1 mutation. Altogether, germline DNA sequencing variants were identified in 21 cancer-related genes in 10 of the 13 probands. Germline indel, splice site and missense mutations and two large deletions were identified. Among the 13 MM index cases, 6 (46%) exhibited one or more predicted pathogenic mutations. Affected genes encode proteins involved in DNA repair (ATM, ATR, BRCA2, BRIP1, CHEK2, MLH3, MUTYH, POLE, POLE4, POLQ and XRCC1), chromatin modification (ARID1B, DNMT3A, JARID2 and SETD1B) or other cellular pathways: leucine-rich repeat kinase 2 gene (LRRK2) (two cases) and MSH4. Notably, somatic truncating mutation or deletions of LRRK2 were occasionally found in MMs in The Cancer Genome Atlas, and the expression of LRRK2 was undetectable or downregulated in a majority of primary MMs and MM cell lines we examined, implying that loss of LRRK2 expression is a newly recognized tumor suppressor alteration in MM.

Both asthma and chronic obstructive pulmonary disease (COPD) are inflammatory chronic respiratory conditions with high rates of morbidity and mortality worldwide. The objectives of this review are to briefly describe the pathophysiology and epidemiology of asthma and COPD, discuss guideline recommendations for uncontrolled disease, and review a new generic option for the treatment of asthma and COPD. Although mild forms of these diseases may be controlled with as-needed pharmacotherapy, uncontrolled or persistent asthma and moderate or severe COPD uncontrolled by bronchodilators with elevated eosinophilia or frequent exacerbations may require intervention with combination therapy with inhaled corticosteroids (ICS) and long-acting beta agonists (LABAs), according to international guidelines. Fixed-dose combinations of ICS/LABA are commonly prescribed for both conditions, with fluticasone propionate (FP) and salmeterol forming a cornerstone of many treatment plans. An oral inhalation powder containing the combination of FP and salmeterol has been available as Advair Diskus® in the United States for almost 20 years, and the first and only substitutable generic version of this product has recently been approved for use: Wixela™ Inhub™. Bioequivalence of Wixela Inhub and Advair Diskus has been established. Furthermore, the Inhub inhaler was shown to be robust and easy to use, suggesting that Wixela Inhub may provide an alternative option to Advair Diskus for patients with asthma or COPD requiring intervention with an ICS/LABA.

UNLABELLED Chronic obstructive pulmonary disease is the third leading cause of death and disease burden worldwide. It includes a spectrum of diseases including chronic bronchitis which is characterized by overproduction, hypersecretion and decreased elimination of mucus. Chronic bronchitis has numerous clinical consequences, including predisposition to lower respiratory tract infections, accelerated decline in lung function, increased exacerbation rate and decreased health-related quality of life. UNLABELLED Although the inflammatory mechanisms responsible for mucus cell metaplasia in chronic obstructive pulmonary disease and stable chronic bronchitis are poorly understood, the main goals of therapy are to decrease mucus hypersecretion by controlling inflammation and to increase mucus clearance. Non-pharmacological measures include smoking cessation and chest physiotherapy. Pharmacological interventions include expectorants and mucolytics together with long-acting beta2-adrenergic receptor agonists, anticholinergics, glucocorticoids, phosphodiesterase-4 inhibitors, antioxidants, and antibiotics. UNLABELLED Guaifenesin is an expectorant that is thought to increase hydration and decrease viscosity of mucus leading to improved clearance of accumulated secretions from the upper and lower airway. Although guaifenesin has a Food and Drug Administration Over-the-Counter (OFC) Monograph indication to "help loosen phlegm (mucus) and thin bronchial secretions in patients with stable chronic bronchitis," there is limited published evidence of either mechanism of action or clinical efficacy in this disease state. Here we review the pathophysiology and consequences of chronic mucus hypersecretion and examine the evidence for the use of guaifenesin in patients with stable chronic bronchitis.

Background: Patients with chronic obstructive pulmonary disease (COPD) and suboptimal peak inspiratory flow rate (sPIFR) may not benefit optimally from dry powder inhalers (DPI) because of inadequate inspiratory flow. Nebulized bronchodilators may provide a better alternative. We compared bronchodilation with the long-acting muscarinic antagonist (LAMA) revefenacin for nebulization versus the DPI LAMA tiotropium, in patients with COPD and sPIFR (< 60 L/min against the resistance of Diskus(®)). Methods: This was a randomized, double-blind, double-dummy, 28-day Phase 3b study in patients with COPD enrolled based on sPIFR. The primary endpoint was trough forced expiratory volume in 1 second (FEV(1)) on Day 29 for revefenacin for nebulization versus tiotropium HandiHaler(® )DPI. Results: We enrolled 206 patients with mean (standard deviation) age, 65 (8) years; percent predicted FEV(1), 37 (16)%; PIFR, 45 (12) L/min. In the intent-to-treat (ITT) population, revefenacin improved trough FEV(1) from baseline; however, the difference versus tiotropium was not significant (least squares [LS] mean difference [standard error], 17.0 [22.4] mL, P=0.4461). In a prespecified analysis of patients with FEV(1) < 50% predicted, revefenacin produced an LS mean difference (95% confidence interval [CI]), 49.1 (6.3—91.9) mL in trough FEV(1) and 103.5 (7.7—199.3) mL in forced vital capacity versus tiotropium. Revefenacin produced >100 mL increase in FEV(1) in 41.6% versus 34.4% of patients with tiotropium in ITT and 41.4% versus 25.7% of patients in FEV(1) < 50% predicted populations. Conclusions: Revefenacin did not produce significant improvements in FEV(1) versus tiotropium in the ITT population, but increased trough FEV(1) in patients with FEV(1) < 50% predicted and sPIFR. Clinical Trial Registration (www.Clinicaltrials.gov): Study 0149 (NCT03095456)

Ohar JA, Ozol-Godfrey A, Goodin T, Sanjar S. Int J ChronObstruct Pulmon Dis. 2020;15:995–1004. The authors have advised there is an error in Figure 4B onpage 1000. For EXACT-RS responder rates, the OR forboth genders are shown to be significant at p

Dry powder inhalers (DPIs) are prescribed after hospitalization for acute exacerbation of COPD (AECOPD). Peak inspiratory flow (PIF) affects DPI delivery.To study the impact of PIF on readmission after hospitalization for AECOPD.A retrospective analysis of hospitalized patients, enrolled in an AECOPD care plan, was performed. Data analyzed included PIF, age, sex, length of stay, Charlson Comorbidity Index, COPD Assessment Test score, modified Medical Research Council score, percent predicted FEVOf the 123 subjects, 52% (n = 64) had sPIF. They had greater COPD Assessment Test scores (29.1 ± 5.9 vs. 25.3 ± 8.7; P = 0.0073), rates of 90-day COPD readmissions (28.1 vs. 13.6%; P = 0.048), fewer median days to COPD (63.5 [interquartile range (IQR), 21-89.8] vs. 144 [IQR, 66-218]; P = 0.002) and all-cause readmissions (65.5 [IQR, 24.3-107.3] vs. 101 [IQR, 54.5-205.5]; P = 0.009). PIF was the only variable (P = 0.041) that predicted days to COPD readmission in a multivariate model incorporating age, sex, percent predicted FEVsPIF is common during AECOPD and predicts all-cause and COPD readmissions. Patients with sPIF may benefit from nebulized therapies. We recommend checking PIF in patients hospitalized for AECOPD for selection of delivery devices.

Peak inspiratory flow (PIF) has been proposed as a measure to assess a patient's ability to use dry powder inhalers (DPIs). However, robust quality criteria to determine a repeatability limit for measuring PIF are lacking.What are the repeatability limits for measuring PIF? What is the relationship between PIF measured using the In-Check DIAL device at Diskus (GlaxoSmithKline; PIFData from a randomized, controlled, phase 3 trial (study 0149; see Clinical Trial Registration data) were used to define repeatability limits for PIF. In addition, a model to characterize the relationship between PIF measured with the In-Check DIAL device at PIFIn study 0128, the mean values (SD) for PIF at zero resistance and PIFThis analysis demonstrated that the two highest values of PIF using the In-Check DIAL device among three inspiratory efforts, met the repeatability limit. Altogether, these data provide guidance for measuring PIF against the simulated resistance of a specific DPI in clinical practice and research studies.ClinicalTrials.gov; Nos.: NCT02518139 (study 0128) and NCT03095456 (study 0149); URL: www.clinicaltrials.gov.

Bronchodilator reversibility occurs in patients with COPD. Pooled analysis of two 12-week, placebo-controlled randomised studies (FLIGHT1 [NCT01727141]; FLIGHT2 [NCT01712516]) assessed the effect of bronchodilator reversibility on lung function, patient-reported outcomes, and safety in 2,043 patients with moderate-to-severe COPD treated with indacaterol/glycopyrrolate (IND/GLY) 27.5/15.6 µg twice daily. Reversibility was defined as post-bronchodilator increase in forced expiratory volume in one second (FEV1) of ≥12% and ≥0.200 L. Overall, mean reversibility (mean post-bronchodilator FEV1 increase) was 22.8%, and 54.5% of patients met reversibility criteria. IND/GLY resulted in significant (p < 0.05) placebo-adjusted improvements from baseline at Week 12 in reversible and non-reversible patients in FEV1 area under the curve from 0 to 12 hours (0.308 L and 0.170 L, respectively), trough FEV1 (0.260 L and 0.174 L), St. George's Respiratory Questionnaire total score (-6.3 and -3.5), COPD Assessment Test total score (-2.3 and -1.2), daily rescue medication use (-1.52 and -0.79), and daily total symptom score (-0.86 and -0.63); Transition Dyspnoea Index focal score also showed improvements (1.93 and 1.29) at Week 12, irrespective of reversibility status. Improvements in lung function and rescue medication use were significantly (p < 0.05) greater in IND/GLY patients in the reversible subgroup compared with the non-reversible subgroup. The safety profile was similar across treatment groups and reversibility subgroups. Overall, treatment with IND/GLY led to significant improvements in lung function and PROs in patients with moderate-to-severe COPD, regardless of reversibility status, with greater improvements in the reversible subgroup. Safety profile was not affected by reversibility status.

Purpose Bronchodilator reversibility has been reported in patients with COPD, although correlations between reversibility and treatment response are unclear. The effect of reversibility on lung function, health status, and dyspnea was assessed in patients with moderate-to-severe COPD receiving glycopyrrolate (GLY) 15.6 µg twice daily vs placebo in the Glycopyrrolate Effect on syMptoms and lung function 1 and 2 (GEM1 and GEM2) replicate, 12-week, placebo-controlled studies. Patients and methods Reversibility was defined as a post-bronchodilator increase of ≥12% and ≥0.200 L in FEV1. FEV1 area under the curve from 0 to 12 hours (AUC0–12 h), trough FEV1, St George’s Respiratory Questionnaire (SGRQ) total score, COPD Assessment Test (CAT™) score, Transition Dyspnea Index (TDI) focal score, daily symptom scores, and rescue medication use were assessed by reversibility status. Incidences of adverse events and serious adverse events were also assessed. Results Data from 846 patients enrolled in GEM1 and GEM2 with known reversibility status were pooled for post hoc analysis. GLY significantly improved FEV1 AUC0–12 h, trough FEV1, SGRQ and CAT total scores, and rescue medication use compared with placebo in reversible and nonreversible patients. Significant improvements in TDI focal score and daily symptom scores with GLY over placebo were observed only among reversible patients. Improvements in FEV1 AUC0−12 h (0.165 vs 0.078 L; P

Rationale: The asthma–chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) occurs in patients with fixed airway obstruction that defines COPD and with symptoms more typical of asthma. ACOS prevalence and the comorbidities associated with this syndrome have been inadequately characterized.Objectives: Because this population is prone to more frequent exacerbations, we hypothesized that comorbidities associated with ACOS are higher than those with COPD, asthma, and control populations in the United States.Methods: We examined the self-reported demographics, smoking status, comorbidities, and hospitalization or emergency department (ED) visitation experience among study respondents older than 35 years of age (n = 90,851) in the Behavioral Risk Factor Surveillance System survey and compared participants with ACOS to COPD, asthma, and control groups. We used logistic regression to compare ACOS and COPD populations to model the impact of comorbid conditions and hospitalization/ED visits after adj...

IntroductionCardiovascular collapse is a common complication during tracheal intubation of critically ill adults. Whether administration of an intravenous fluid bolus prevents cardiovascular collapse during tracheal intubation remains uncertain. A prior randomised trial found fluid bolus administration to be ineffective overall but suggested potential benefit for patients receiving positive pressure ventilation during tracheal intubation.Methods and analysisThe PREventing cardiovascular collaPse with Administration of fluid REsuscitation during Induction and Intubation (PREPARE II) trial is a prospective, multi-centre, non-blinded randomised trial being conducted in 13 academic intensive care units in the USA. The trial will randomise 1065 critically ill adults undergoing tracheal intubation with planned use of positive pressure ventilation (non-invasive ventilation or bag-mask ventilation) between induction and laryngoscopy to receive 500 mL of intravenous crystalloid or no intravenous fluid bolus. The primary outcome is cardiovascular collapse, defined as any of: systolic blood pressure 2 test. The sole secondary outcome is 28-day in-hospital mortality. Enrolment began on 1 February 2019 and is expected to conclude in June 2020.Ethics and disseminationThe trial was approved by either the central institutional review board at Vanderbilt University Medical Center or the local institutional review board at each trial site. Results will be submitted for publication in a peer-reviewed journal and presented at scientific conferences.Trial registration numberNCT03787732.

Rationale/Objective: The Behavioral Risk Factor Surveillance System (BRFSS) health survey has been used to describe the epidemiology of chronic obstructive pulmonary disease (COPD) in the US. Through addressing respiratory symptoms and tobacco use, it could also be used to characterize COPD risk. Methods: Four US states added questions to the 2015 BRFSS regarding productive cough, shortness of breath, dyspnea on exertion, and tobacco duration. We determined COPD risk categories: provider-diagnosed COPD as self-report, high-risk for COPD as &ge, 10 years tobacco smoking and at least one significant respiratory symptom, and low risk was neither diagnosed COPD nor high risk. Disease burden was defined by respiratory symptoms and health impairments. Data were analyzed using multiple logistic regression models with age as a covariate. Results: Among 35,722 adults &ge, 18 years, the overall prevalence of COPD and high-risk for COPD were 6.6% and 5.1%. Differences among COPD risk groups were evident based on gender, race, age, geography, tobacco use, health impairments, and respiratory symptoms. Risk for disease was seen early where 3.75% of 25&ndash, 34 years-old met high-risk criteria. Longer tobacco duration was associated with an increased prevalence of COPD, particularly &gt, 20 years. Seventy-nine percent of persons &ge, 45 years-old with frequent shortness of breath (SOB) reported having or being at risk of COPD, reflecting disease burden. Conclusion: These data, representing nearly 18% of US adults, indicates those at high risk for COPD share many, but not all of the characteristics of persons diagnosed with the disease and demonstrates the value of the BRFSS as a tool to define lung health at a population level.

Jill Ohar,1 Robert Tosiello,2 Thomas Goodin,2 Shahin Sanjar2 1Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA; 2Sunovion Pharmaceuticals Inc., Marlborough, MA, USA Background: The efficacy and safety of nebulized glycopyrrolate inhalation solution (GLY), administered twice daily (BID) via the innovative eFlow® Closed System nebulizer (PARI Pharma GmbH, Starnberg, Germany), were demonstrated in two replicate, placebo-controlled, 12-week Phase III studies (GOLDEN 3 and GOLDEN 4). This report evaluates the efficacy and safety of GLY by baseline disease severity and age in the pooled GOLDEN 3 and GOLDEN 4 patient population (N=1,294). Methods: Patients were grouped by baseline predicted post-bronchodilator FEV1 (

Purpose: Objective documentation of airflow obstruction is often lacking inhospitalized patients treated for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). The utility of spirometry performed in hospitalized patients to identify airflow obstruction, and thus a diagnosis of COPD, is unclear. Our aim was to compare inpatient spirometry, performed during an AECOPD, with outpatient spirometry. Methods: A retrospective analysis of data from patients enrolled in an AECOPD care plan was performed. As part of the plan, patients underwent inpatient spirometry to establish a COPD diagnosis and outpatient clinic spirometry within 4 weeks of hospital discharge to confirm it. Data analyzed included forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), slow vital capacity (SVC) and FEV1/ vital capacity (VC). Obstruction was defined by FEV1/VC

BACKGROUND: COPD guidelines advise on inhaled medication use, yet no advice is offered on when to use and which type of patient could benefit from a specific delivery device. We investigated pulmonologists9 perception of their knowledge and practices with delivery devices for COPD management. METHODS: An online survey was designed by a steering committee of American Thoracic Society clinicians and scientists and conducted by a national market research firm between January 7 and 29, 2016. RESULTS: Two hundred and five respondents completed the survey. Nearly 80% of the respondents believed that they were very knowledgeable in COPD management and the use of medications; 68% believed that they were knowledgeable about preventing exacerbations. Ninety-eight percent of the respondents stated that they were at least somewhat knowledgeable about devices. Many respondents (70%) stated that small-volume nebulizers were more effective than dry powder inhalers and pressurized metered-dose inhalers in the management of COPD exacerbations, and 63% believed that these were more effective in severe COPD (modified Medical Research Council dyspnea scale grade 4). Only 54% of the respondents discussed device options with their patients. Physician screening for physical or cognitive impairments that could impact device choices was 53% and 16%, respectively. Seventy percent of the respondents discussed device use, whereas 9% discussed cleaning and storage during a patient9s first visit. Few respondents were very knowledgeable in teaching patients how to use devices (43%) and, specifically, how to use (32%) or clean and/or maintain (20%) small-volume nebulizers. CONCLUSIONS: Most respondents were confident in their knowledge about treating COPD. Fewer respondents were confident about the use and maintenance of inhalation devices, and most respondents desired to learn more about inhalation devices.

Background: Inhaled medications form the foundation of pharmacologic treatment for chronic obstructive pulmonary disease (COPD).The Delivery Makes a Difference (DMaD) project was conducted to better understand health care provider (HCP) and patient perspectives about the role of inhalation delivery devices in COPD, and to examine the nature of educational efforts between HCPs and patients on proper device technique. Methods: Data were derived from 2 original quantitative, web-based, descriptive, cross-sectional surveys distributed to HCPs who manage COPD (n=513) and patients with COPD (n=499) in the United States. Descriptive statistics were used to assess data across important demographic variables. Inferential statistics were used to assess differences in attitudinal, descriptive, and behavioral measures that were cross-tabulated with demographic data. Results: When prescribing medication for newly diagnosed patients with stable or unstable COPD, only 37% of HCPs considered type of device to be highly important, with only 45% of HCPs assessing device technique in every newly diagnosed patient. Patients with COPD were also relatively unconcerned with proper device technique (64% never concerned), regardless of their COPD severity. Although patients did not identify education as a significant impediment to proper device use, they reported inconsistent educational experiences. Conclusions: We found that HCPs and patients prioritize medication over device when selecting treatments, showing limited concerns about proper device use. These results highlight the need to coordinate professional education with patient-directed educational efforts to further promote proper device selection and use in COPD management.

BACKGROUND: Successful inhalation therapy depends on the ability of patients with COPD to properly use devices. We explored subjects9 COPD knowledge, including education they receive from health care providers, treatment experiences, and practices with inhalation devices. METHODS: A multiple-choice online survey, developed by a steering committee of American Thoracic Society clinicians and scientists, was administered to subjects with COPD who were sourced from the Harris Poll Online panel. RESULTS: Of the 254 respondents (mean age 61.8 y; 49% males), most subjects (82%) claimed to understand their disease and available treatments, yet COPD symptoms and causes were well known to only 45% and 44% of subjects, respectively. Forty-three percent of subjects had ever used a pressurized metered-dose inhaler or dry-powder inhaler. Of the 54% of subjects who had ever used a small-volume nebulizer (SVN), 63% considered this device to be easy to use, 55% considered it to be fast-acting, 53% considered it to be convenient, and 38% considered it to be essential for treatment. Among subjects who had ever used them, SVNs were preferred by 54% over other devices. One third of subjects desired more extensive education during office visits; 25% felt the time was insufficient to cover questions, and 15% felt their concerns about COPD treatment(s) were ignored. Subjects believed physicians (32%), nurses (26%), and no single provider (28%) were primarily responsible for training and assessing proper inhalation technique. CONCLUSION: The survey showed differences between patients9 beliefs and knowledge of COPD; the need for continuous education from health care providers, particularly on inhalation devices; and extensive use of pressurized metered-dose inhalers and dry-powder inhalers despite positive perceptions of SVNs.

This study aims to assess the relationship of body mass index (BMI) status with respiratory conditions, asthma, and chronic obstructive pulmonary disease (COPD) in a state population.Self-reported data from 11,868 adults aged ≥18 years in the 2012 South Carolina Behavioral Risk Factor Surveillance System telephone survey were analyzed using multivariable logistic regression that accounted for the complex sampling design and adjusted for sex, age, race/ethnicity, education, smoking status, physical inactivity, and cancer history.The distribution of BMI (kg/m(2)) was 1.5% for underweight (18.5), 32.3% for normal weight (18.5-24.9), 34.6% for overweight (25.0-29.9), 26.5% for obese (30.0-39.9), and 5.1% for morbidly obese (≥40.0). Among respondents, 10.0% had frequent productive cough, 4.3% had frequent shortness of breath (SOB), 7.3% strongly agreed that SOB affected physical activity, 8.4% had current asthma, and 7.4% had COPD. Adults at extremes of body weight were more likely to report having asthma or COPD, and to report respiratory conditions. Age-adjusted U-shaped relationships of BMI categories with current asthma and strongly agreeing that SOB affected physical activity, but not U-shaped relationship with COPD, persisted after controlling for the covariates (p 0.001). Morbidly obese but not underweight or obese respondents were significantly more likely to have frequent productive cough and frequent SOB than normal weight adults after adjustment.Our data confirm that both underweight and obesity are associated with current asthma and obesity with COPD. Increased emphasis on exercise and nutrition may improve respiratory conditions.

Umeclidinium bromide (UM) with vilanterol (VI) is the first once-daily long-acting muscarinic antagonist/long-acting β2 agonist (LAMA/LABA) combination approved for use in the treatment of chronic obstructive pulmonary disease (COPD) in the USA. Prior to this, only combinations of short-acting bronchodilators and short-acting muscarinic antagonists were available in the USA as a single inhaler and they required frequent dosing. LAMA or LABA therapy is the recommended first choice for moderate-to-very severe COPD with combination therapy added if monotherapy fails to control patients' symptoms. This allows lower dosing of individual medications, which may limit adverse effects. It could also have the additional benefit of improving patient compliance by making medication regimens less laboring.A comprehensive literature search of journal articles and abstracts looking for trials that evaluated both the efficacy and the safety of UM/VI revealed that UM/VI improves patients' lung function and overall health status, while maintaining excellent safety and tolerability profiles compared to placebo and other bronchodilators.Given the clinical efficacy, favorable safety profile and ease of use, clinicians may recommend UM/VI to patients with moderate-to-very severe COPD - a shift that could have significant impact on the management of COPD.

The global initiative for chronic obstructive lung disease guidelines recommend maintenance therapy using long-acting bronchodilators for patients with chronic obstructive pulmonary disease (COPD) who have daily symptoms. Arformoterol is the (R, R) - enantiomer of the racemic formoterol and is more potent than (R, R/ S, S) - formoterol.Currently, arformoterol is one of two nebulized long-acting β-agonists on the market. It has a low incidence of cardiovascular side effects with incidence of arrhythmia and ischemia similar to placebo. β-adrenergic adverse effects are infrequent, numerically lower than formoterol, but have a quicker onset of action than salmeterol. There was no observed clinical tolerance over 12 months. arformoterol is safe in combination therapy with inhaled corticosteroids, tiotropium and rescue inhalers. A 12-month Phase IV trial found no increased risk of respiratory death or COPD exacerbation-related hospitalizations. arformoterol can potentially benefit patients with hyperinflation and low inspiratory flow rates.The introduction of the centers for medicare and medicaid services penalization for COPD readmissions may boost the appeal of long-acting bronchodilators as new discharge medications. With the advent of ultra long-acting bronchodilators, its potential as a once daily agent in isolation or combination with these new therapies needs further study.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States with a significant economic burden related to hospital admissions for exacerbations. One of the primary treatment modalities for COPD is medications delivered through breath-actuated dry powdered inhalers (DPIs). For users to successfully receive inhaled medication, they must inhale with enough flow to overcome the internal resistance of the device, leading to deaggregation of the medication powder. Peak inspiratory flow rate (PIFR) is the maximal flow rate obtained during an inspiratory maneuver. PIFR measurement can be impacted by the internal resistance of the device, which varies with device design. Many devices require a PIFR >60 L/min for adequate medication dispersal, while others appear to have adequate drug deaggregation with a PIFR >30 L/min. Studies have shown PIFRs are reduced among females and decrease with age, without a clear correlation between forced expiratory volume in 1 second and PIFR. PIFR can be reduced at the time of COPD exacerbation. Recent data suggest that reduced PIFR may be associated with worse COPD-related symptom burden, increased odds of COPD-related hospital readmissions, and improved responsiveness to nebulized therapy. This review article aims to examine the physiology and clinical correlations of PIFR, as well as review published studies related to PIFR with DPIs used to treat COPD.

Aims and objectives: To help define lung health in US adults, we used the 2015 Behavioral Risk Factor Surveillance System telephone survey to assess respiratory symptoms and health characteristics. Methods: A 4 state (Florida, Kentucky, South Carolina, Texas) survey with >70 questions regarding frequency of productive cough, shortness of breath (SOB), SOB affecting physical activities as well as sociodemographics, chronic diseases, and health behaviors was done. Data were analyzed using several multiple logistic regression models with age as a covariate to assess relationships of respiratory symptoms with other factors. Results: Among 37,898 adults >35 yrs (51.3% never smokers, 60.5% female) 9.9%(8.2-10.7) had a productive cough most or every day, 4.7%(4.2-5.3) had SOB most or all the time, 17.9%(16.8-19.0) strongly agreed that SOB affected physical activities. After adjusting for age, sex, race, and education, respondents were at greater risk of frequent SOB with the following-current or former smoker, physician diagnosis of COPD, current asthma, coronary disease, depression, stroke, renal disease, and mental health impairment. Except for stroke and renal disease, these same measures were associated with a frequent productive cough. Being diagnosed with diabetes, having cancer, and higher education were associated with a lower risk of all 3 respiratory symptoms. The only gender difference was more cough in males. Conclusion: Our population-based data provides insight into relationships among frequent respiratory symptoms, chronic diseases, and sociodemographics.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and often deadly syndrome characterized by severe inflammation and cytokine dysregulation. The disease is defined by the HLH-2004 criteria, requiring five of eight findings, and is further differentiated into either primary or secondary causes. Primary HLH tends to be of genetic etiology, while secondary HLH results from other insults such as infection. Secondary HLH is most commonly associated with viral infections in immunocompromised patients. Acute cytomegalovirus (CMV) associated HLH in the immunocompetent host is exceedingly rare and only documented in four case reports to date. We describe the fifth documented case of CMV-associated HLH in an immunocompetent patient, and furthermore, we demonstrate that this patient is the first published case of its type to satisfy all eight of HLH-2004 criteria.

Patients with obstructive sleep apnea (OSA) have increased postoperative complications that are important for patient safety and healthcare utilization. Questionnaires help identify patients at risk for OSA; however, among older adults who preoperatively self-administered OSA questionnaires, the frequency of postoperative Medical Emergency Team Activation (META), rapid response, code blue, code stroke, is unknown.Identify whether having OSA questionnaires completed by patients is feasible in the preoperative clinic. Determine the frequency of META among older patients at risk for OSA.Cohort of prospective patients independently completed 2 OSA questionnaires in a preoperative clinic, STOP-Bang (SB) and ISNORED (IS). Observers blinded to questionnaire responses recorded incidence of META.Of the 898 consecutive patients approached in the preoperative assessment clinic and surgical navigation center, 575 (64%) consented and completed the questionnaires in5 minutes and were included in the analysis.Sleep questionnaire responses and frequency of inpatient postoperative META.With an affirmative response to ≥3 questions on either questionnaire, 65% of patients enrolled were at risk for OSA. Of these, 3.1% sustained an META. In patients at risk for OSA, META occurred in 7.6% (SB+) and 7.2% (IS+) vs 2.5% (SB+) and 1.7% (IS+) for low risk. METAs were disproportionately higher among patients aged ≥65 years (6.3% vs 1.7%; P .018), American Society of Anesthesiologists (ASA) physical status class ≥3, and IS+. All patients with META positively answered ≥3 of 15 components of the 2 questionnaires.Preoperative, self-administration of SB and IS questionnaires is feasible. Overall, 65% of those with affirmative responses to ≥3 questions were at risk for OSA and associated with a disproportionate number of postoperative META in older patients. Additionally, risk of OSA identified by preoperative sleep questionnaires was associated with postoperative META among older adults. Use of clinical tools and OSA questionnaires may improve preoperative identification of META in this population.

Determining which patients with COPD may benefit from a nebulized long-acting beta2-agonist (LABA) is a challenge in current practice. In the absence of strong clinical guidelines addressing this issue, an expert panel convened to develop guiding principles for the use of nebulized LABA therapy in patients with COPD. This article summarizes these guiding principles and other practical issues discussed during a roundtable meeting.

Introduction: > 20% of patients hospitalized for acute exacerbation of COPD (AECOPD) will be readmitted within 30 days. Studies evaluating the effect of interventions on readmissions rely on CPT codes (CPTC) assigned after hospital discharge. Aims and Objectives: We evaluated an intervention implemented during hospitalization to reduce readmits requiring patient identification by clinical criteria (CC). We compared the effect of the intervention on readmits in patients identified by both CPTC and CC. Methods: CC included age > 40 yrs, > 20 pack yrs and AECOPD symptoms. The intervention was bedside spirometry, inhaled corticosteroids, bronchodilators, and patient education. Respiratory therapists (RTs) measured peak inspiratory flow & recommended inhaler devices. Use of supplemental oxygen, pulmonary rehabilitation, palliative care, roflumilast and thrice weekly azithromycin was recommended by pulmonologist consulted by the RTs. Results: 2230 AECOPD admissions were identified by CPTC from 10/2011 – 8/2015. Readmit rate didn9t differ before (18.46%, CI16.11-20.29) vs after (19.17%, CI15.95-20.45) the initiation of RT protocol. Data trended toward decreased expected length of stay (LOS)/observed LOS after, compared with before initiation of the intervention (0.84, CI 0.80-0.88 vs. 0.91, CI 0.85-0.97; p=0.06). The RT protocol CC identified 1607 patients from 5/2014 – 12/2015. CPTC patients overlapped 60% with CC patients. The 16.25% (CI 13.94-18.56) readmit rate for patients on the RT protocol was significantly lower than patients identified by CPTC (19.17% CI 15.95-20.45) over the same time frame. Conclusions: An RT protocol for AECOPD reduces readmits. CPTC identification of AECOPD is imprecise possibly hiding the intervention effect.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and health care expenditure worldwide. Relaxation of airway smooth muscle with inhaled bronchodilators is the cornerstone of treatment for stable COPD, with inhaled corticosteroids reserved for those with a history of exacerbations. Tiotropium has occupied center stage in COPD treatment for over 10 years and improves lung function, quality of life, exercise endurance, and reduces the risk of COPD exacerbation. Long-acting β2-agonists (LABAs) improve lung function, reduce dynamic hyperinflation, increase exercise tolerance, health-related quality of life, and reduce acute exacerbation of COPD. The combination of long-acting muscarinic antagonists (LAMAs) and LABAs is thought to leverage different pathways to induce bronchodilation using submaximal drug doses, increasing the benefits and minimizing receptor-specific side effects. Umeclidinium/vilanterol is the first combination of LAMA/LABA to be approved for use in stable COPD in USA and Europe. Additionally, indacaterol/glycopyrronium and aclidinium/formoterol have been approved in Europe and in numerous locations outside USA. Several other agents are in the late stages of development, most of which offer once-daily dosing. The benefits of new LAMA/LABA combinations include improved pulmonary function, dyspnea, and health-related quality of life, and in some cases, reduced exacerbations. These evolving treatments will provide new opportunities and challenges in the management of COPD.

To assess relationships between obstructive lung diseases, respiratory symptoms, and comorbidities by gender.Data from 12 594 adult respondents to the 2012 South Carolina Behavioral Risk Factor Surveillance System telephone survey were used. Five categories of chronic obstructive airway disease (OAD) were defined: former asthma only, current asthma only, chronic obstructive pulmonary disease (COPD) only, asthma-COPD overlap syndrome (ACOS), and none. Associations of these categories with respiratory symptoms (frequent productive cough, shortness of breath, and impaired physical activities due to breathing problems), overall health, and comorbidities were assessed using multivariable logistic regression for men and women.Overall, 16.2% of men and 18.7% of women reported a physician diagnosis of COPD and/or asthma. Former asthma only was higher among men than women (4.9% vs. 3.2%, t-test p = 0.008). Current asthma only was more prevalent among women than men (7.2% vs. 4.7%, p0.001), as was ACOS (4.0% vs. 2.2%, p0.001). Having COPD only did not differ between women (4.3%) and men (4.4%). Adults with ACOS were most likely to report the 3 respiratory symptoms. COPD only and ACOS were associated with higher likelihoods of poor health and most comorbidities for men and women. Current asthma only was also associated with these outcomes among women, but not among men.In this large population-based sample, women were more likely than men to report ACOS and current asthma, but not COPD alone. Gender differences were evident between the OAD groups in sociodemographic characteristics, respiratory symptoms, and comorbidities, as well as overall health.