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Chronic obstructive pulmonary disease (COPD) is a strong risk factor for lung cancer. Published studies about variations of genes encoding glutathione metabolism, DNA repair, and inflammatory response pathways in susceptibility to COPD were inconclusive. We evaluated 470 single-nucleotide polymorphisms (SNP) from 56 genes of these three pathways in 620 cases and 893 controls to identify susceptibility markers for COPD risk, using existing resources. We assessed SNP- and gene-level effects adjusting for sex, age, and smoking status. Differential genetic effects on disease risk with and without lung cancer were also assessed; cumulative risk models were established. Twenty-one SNPs were found to be significantly associated with risk of COPD (P < 0.01); gene-based analyses confirmed two genes (GCLC and GSS) and identified three additional genes (GSTO2, ERCC1, and RRM1). Carrying 12 high-risk alleles may increase risk by 2.7-fold; eight SNPs altered COPD risk without lung cancer by 3.1-fold and 4 SNPs altered the risk with lung cancer by 2.3-fold. Our findings indicate that multiple genetic variations in the three selected pathways contribute to COPD risk through GCLC, GSS, GSTO2, ERCC1, and RRM1 genes. Functional studies are needed to elucidate the mechanisms of these genes in the development of COPD, lung cancer, or both. Cancer Prev Res; 5(3); 365–73. ©2011 AACR.

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BACKGROUND: Methacholine bronchoprovocation or challenge testing (MCT) is commonly performed to assess airway hyper-responsiveness in the setting of suspected asthma. Nebulization is an aerosol-generating procedure, but little is known about the risks of MCT in the context of the ongoing coronavirus disease 2019 (COVID-19) pandemic. We aimed to quantify and characterize aerosol generation during MCT by using different delivery methods and to assess the impact of adding a viral filter. METHODS: Seven healthy subjects performed simulated MCT in a near particle-free laboratory space with 4 different nebulizers and with a dosimeter. Two devices continuously sampled the ambient air during the procedure, which detected ultrafine particles, from 0.02–1 μm, and particles of sizes 0.3, 0.5, 1.0, 2.0, 5.0, and 10 µm, respectively. Particle generation was compared among all the devices, with and without viral filter placement. RESULTS: Ultrafine-particle generation during simulated MCT was significant across all the devices. Ultrafine-particle (0.02–1 μm) concentrations decreased 77%–91% with the addition of a viral filter and varied significantly between unfiltered (P < .001) and filtered devices (P < .001). Ultrafine-particle generation was lowest when using the dosimeter with filtered Hudson nebulizer (1,258 ± 1,644 particle/mL). Ultrafine-particle concentrations with the filtered nebulizer devices using a compressor were higher than particle concentrations detected when using the dosimeter: Monaghan (3,472 ± 1,794 particles/mL), PARI (4,403 ± 2,948), Hudson (6,320 ± 1,787) and AirLife (9,523 ± 5,098). CONCLUSIONS: The high particle concentrations generated during MCT pose significant infection control concerns during the COVID-19 pandemic. Particle generation during MCT was significantly reduced by using breath-actuated delivery and a viral filter, which offers an effective mitigation strategy.

Methacholine challenge testing (MCT) is a common bronchoprovocation technique used to assess airway hyper-responsiveness. We previously demonstrated that the addition of a viral filter to the nebulizer exhalation limb substantially reduced expelled particles during MCT. Our aim was to evaluate whether this modification affects the delivered dose of methacholine.A mechanical ventilator was connected to a lung simulator with breathing frequency 15 breaths/min, tidal volume 500 mL, inspiratory-expiratory ratio 1:1, with a sinusoidal waveform. We compared methacholine dose delivery using the Hudson Micro Mist or AeroEclipse II BAN nebulizers powered by either a dry gas source or a compressor system. A filter placed in line between the nebulizer and test lung was weighed before and after 1 min of nebulized methacholine delivery. Mean inhaled mass was measured with and without a viral filter on the exhalation limb. Dose delivery was calculated by multiplying the mean inhaled mass by the respirable fraction (particles5 μm) and inhalation time. UnpairedThe addition of a viral filter did not significantly affect methacholine dose delivery across all devices tested. Using a 50-psi dry gas source, dose delivered with or without a viral filter did not differ with the Hudson (422.3 μg vs 282.0 μg,The addition of a viral filter to the nebulizer exhalation limb did not affect methacholine dose during bronchoprovocation testing. Routine use of a viral filter should be considered to improve pulmonary function technician safety and infection control measures during the ongoing COVID-19 pandemic.

BackgroundHepatopulmonary syndrome affects 10–30% of patients with cirrhosis and portal hypertension. We evaluated the serum angiogenic profile of hepatopulmonary syndrome and assessed the clinical impact of hepatopulmonary syndrome in patients evaluated for liver transplantation.MethodsThe Pulmonary Vascular Complications of Liver Disease 2 study was a multicentre, prospective cohort study of adults undergoing their first liver transplantation evaluation. Hepatopulmonary syndrome was defined as an alveolar–arterial oxygen gradient ≥15 mmHg (≥20 mmHg if age >64 years), positive contrast-enhanced transthoracic echocardiography and absence of lung disease.ResultsWe included 85 patients with hepatopulmonary syndrome and 146 patients without hepatopulmonary syndrome. Patients with hepatopulmonary syndrome had more complications of portal hypertension and slightly higher Model for End-Stage Liver Disease-Na score compared to those without hepatopulmonary syndrome (median (interquartile range) 15 (12–19) versus 14 (10–17), p=0.006). Hepatopulmonary syndrome patients had significantly lower 6-min walk distance and worse functional class. Hepatopulmonary syndrome patients had higher circulating angiopoietin 2, Tie2, tenascin C, tyrosine protein kinase Kit (c-Kit), vascular cell adhesion molecule 1 and von Willebrand factor levels, and lower E-selectin levels. Patients with hepatopulmonary syndrome had an increased risk of death (hazard ratio 1.80, 95% CI 1.03–3.16, p=0.04), which persisted despite adjustment for covariates (hazard ratio 1.79, 95% CI 1.02–3.15, p=0.04). This association did not vary based on levels of oxygenation, reflecting the severity of hepatopulmonary syndrome.ConclusionHepatopulmonary syndrome was associated with a profile of abnormal systemic angiogenesis, worse exercise and functional capacity, and an overall increased risk of death.

BACKGROUND: The association between chronic obstructive pulmonary disease (COPD) and sudden cardiac death has not been fully elucidated. OBJECTIVE: Investigate if decreased left ventricular ejection fraction (LVEF) can explain the increased rate of ventricular tachycardias (VT) in COPD. METHODS: In this retrospective study, we included consecutive adult patients who underwent pulmonary function testing (PFT), Holter monitoring, and trans-thoracic echocardiography. COPD was correlated with the frequency of VT in a multivariate analysis which adjusted for known confounders including LVEF. Long term all-cause mortality of patients with COPD and VT was examined. RESULTS: From 6351 patients who were included in this study (age 66±15 years, 48% woman, 92% Caucasian, LVEF 59±12%), 2800 (44%) had PFT indicative of COPD. VT was nearly twice as likely to occur during the Holter monitoring in COPD patients (13%vs.23%;p

One of the frequent reasons patients see their primary care physicians is for the symptom of dyspnea. Among the objective tests to quantify this symptom is the pulmonary function test, which includes several different studies: spirometry with flow-volume loop, lung volumes, and diffusing capacity of lung for carbon monoxide. The results may indicate both respiratory and nonrespiratory disorders, including helping in the diagnosis of cardiac or neuromuscular diseases. This review, intended for the generalist, describes common findings of pulmonary function tests and provides a road map for interpretation.

Cardiovascular disease is a common comorbidity in patients with chronic obstructive pulmonary disease. Although β-blockers can be used safely in patients with chronic obstructive pulmonary disease, concerns remain regarding safety and efficacy interactions in patients using concomitant inhaled long-acting β-agonists.To compare the differential effects of long-acting β-agonist or inhaled corticosteroid use on clinical outcomes in patients with heightened cardiovascular risk treated and not treated with β-blockers.We examined data from 16,485 participants in the SUMMIT study (Study to Understand Mortality and Morbidity in COPD) who were randomized to once-daily inhaled fluticasone furoate, vilanterol, fluticasone furoate/vilanterol combination, or placebo and examined the associations between treatment allocation and lung function, chronic obstructive pulmonary disease exacerbations, cardiovascular events, and all-cause mortality, stratified by baseline β-blocker therapy.Baseline β-blocker therapy was used by 31% (n = 5,159) of SUMMIT participants. There was no evidence of an interaction between baseline β-blocker therapy and the association between inhaled treatments and forced expiratory volume in 1 second at 3 months (P = 0.27), 6 months (P = 0.14), or 12 months (P = 0.33). The placebo-adjusted mean differences in post-bronchodilator forced expiratory volume in 1 second at 3 months in the vilanterol-alone group were 58 ml (95% confidence interval, 38-78) in those receiving baseline β-blocker therapy and 51 ml (95% confidence interval, 38-65) in those not receiving baseline β-blocker therapy. The placebo-adjusted mean differences in post-bronchodilator forced expiratory volume in 1 second at 3 months in the combination fluticasone furoate/vilanterol group were 85 ml (95% confidence interval, 65-105) in those receiving baseline β-blocker therapy and 68 ml (95% confidence interval, 54-82) in those not receiving baseline β-blocker therapy. Overall, there was no evidence of interaction by randomized treatment, including vilanterol alone or in combination with fluticasone furoate, for chronic obstructive pulmonary disease exacerbations (P = 0.18), cardiovascular composite events (P = 0.33), and all-cause mortality (P = 0.41).There is no evidence to suggest that baseline β-blocker therapy reduces the respiratory benefits or increases the cardiovascular risk of inhaled long-acting β-agonists in patients with chronic obstructive pulmonary disease and heightened cardiovascular risk. Clinical trial registered with www.clinicaltrials.gov (NCT01313676).

Background Most patients with restriction have a pulmonary function test (PFT) pattern in which total lung capacity (TLC), FVC, and FEV 1 are reduced to a similar degree. This pattern is called "simple restriction" (SR). In contrast, we commonly observe a pattern in which FVC percent predicted ( pp ) is disproportionately reduced relative to TLC pp . This pattern is termed "complex restriction" (CR), and we attempted to characterize its clinical, radiologic, and physiologic features. Methods This study reviewed PFT results of patients tested between November 2009 and June 2013 who had restriction (TLC less than the lower limit of normal). SR was defined as TLC pp -FVC pp ≤ 10%, and CR was stratified into four classes based on TLC pp -FVC pp discrepancy: Class 1 CR, TLC pp -FVC pp > 10% and ≤ 15%; Class 2 CR, TLC pp -FVC pp > 15% and ≤20%; Class 3 CR, TLC pp -FVC pp > 20% and ≤ 25%; and Class 4 CR, TLC pp -FVC pp > 25%. The medical records of 150 randomly selected patients with SR and 50 patients from each CR class were reviewed. Results Of 39,277 PFTs completed, we identified 4,532 patients (11.5%) with restriction: 2,407 (6.1%) with SR, 1,614 (4.1%) with CR, and 511 (1.3%) with a mixed pattern. Patients with CR were younger, were more often women, and had a higher prevalence of neuromuscular disease, BMI > 40 kg/m 2 or 2 , diaphragmatic dysfunction, bronchiectasis, CT mosaic attenuation, and pulmonary hypertension ( P P Conclusions CR is a common PFT pattern with distinct clinical features. The associated clinical entities share impaired lung emptying (eg, neuromuscular disease, occult obstruction, chest wall limitation). Clinicians should be aware of this novel PFT pattern and how it shapes the differential diagnosis.

TOPIC: Respiratory Care TYPE: Original Investigations PURPOSE: Methacholine challenge testing (MCT) is a common bronchoprovocation technique used to assess airway hyperresponsiveness. Current ERS guidelines recommend that measures should be taken to minimize technician exposure to methacholine aerosol, with added infection control concerns in the context of the ongoing COVID-19 pandemic. We previously demonstrated that the addition of a viral filter to the nebulizer exhalation limb reduced expelled particle concentrations by 77-91% during MCT. Our aim was to evaluate whether this modification resulted in a change in the delivered dose of methacholine. METHODS: Following published industry testing standards for MCT, we connected a Hamilton-G5 mechanical ventilator and Michigan lung simulator in series with respiratory rate 15 breaths/min, tidal volume (VT) 500 mL, I:E ratio 1:1 with a sinusoidal waveform. We compared methacholine dose delivery using the Hudson MicroMist and AeroEclipse II BAN nebulizers powered by either a dry gas source at 50 psi and 4.5 L/min or the Ombra compressor system, in addition to our current MCT protocol which utilizes Hudson MicroMist nebulizer with KoKo dosimeter (3 breaths). A filter placed in line between the nebulizer and test lung was weighed before and after 1 minute of nebulized methacholine delivery. Mean inhaled mass was calculated from three trials of each method with and without a viral filter on the exhalation limb. Dose delivery was calculated by multiplying the mean inhaled mass by the respirable fraction (particles < 5 µm) and inhalation time. Unpaired t-test was used to compare methacholine dose delivery with and without viral filter placement. Due to multiple independent comparisons, Bonferroni correction was used and alpha level was set at 0.01. RESULTS: The addition of a viral filter did not significantly affect methacholine dose delivery across all devices tested. Using the 50 psi dry gas source, dose delivered with the Hudson MicroMist did not differ with (461.0 µg) or without (307.8 µg) a viral filter (P=0.11) or with the AeroEclipse II BAN with (580.8 µg) or without (678.4) a viral filter (P=0.59). Using the Ombra compressor, dose delivered with the Hudson MicroMist did not differ with (1063.3 µg) or without (947.5 µg) a viral filter (P=0.026) or with AeroEclipse II BAN with (843.8 µg) or without (648.3) viral filter (P=0.42). Dose delivery did not differ significantly when using the KoKo dosimeter and Hudson MicroMist with or without a viral filter (P=0.20) using a 3-breath protocol. CONCLUSIONS: The addition of a viral filter to the nebulizer expiratory limb did not result in a significant change in the in the delivered dose of methacholine. CLINICAL IMPLICATIONS: Based on these findings, use of a viral filter to limit the concentration of expelled aerosol during MCT should be considered to improve pulmonary function technician safety and potentially reduce the risk of infectious exposure during the ongoing COVID-19 pandemic. DISCLOSURES: No relevant relationships by Kaiser Lim, source=Web Response no disclosure submitted for todd meyer;No relevant relationships by Alexander Niven, source=Web Response No relevant relationships by Paul Scanlon, source=Web Response No relevant relationships by Yosuf Subat, source=Web Response No relevant relationships by Keith Torgerud, source=Web Response

We investigated the prevalence of spirometric restriction in liver transplantation (LT) candidates and the clinical impacts of restriction. We performed a cross-sectional study within the Pulmonary Vascular Complications of Liver Disease 2 (PVCLD2) study, a multicenter prospective cohort study of patients being evaluated for LT. Patients with obstructive lung disease or missing spirometry or chest imaging were excluded. Patients with and without restriction, defined as a forced vital capacity (FVC)

BackgroundObservational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease (COPD), but these findings have not been confirmed in randomized trials.MethodsIn this prospective, randomized trial, we assigned patients between the ages of 40 and 85 years who had COPD to receive either a beta-blocker (extended-release metoprolol) or placebo. All the patients had a clinical history of COPD, along with moderate airflow limitation and an increased risk of exacerbations, as evidenced by a history of exacerbations during the previous year or the prescribed use of supplemental oxygen. We excluded patients who were already taking a beta-blocker or who had an established indication for the use of such drugs. The primary end point was the time until the first exacerbation of COPD during the treatment period, which ranged from 336 to 350 days, depending on the adjusted dose of metoprolol.ResultsA total of 532 patients underwent randomization. The mean (±SD) age of the patients was 65.0±7.8 years; the mean forced expiratory volume in 1 second (FEV1) was 41.1±16.3% of the predicted value. The trial was stopped early because of futility with respect to the primary end point and safety concerns. There was no significant between-group difference in the median time until the first exacerbation, which was 202 days in the metoprolol group and 222 days in the placebo group (hazard ratio for metoprolol vs. placebo, 1.05; 95% confidence interval [CI], 0.84 to 1.32; P = 0.66). Metoprolol was associated with a higher risk of exacerbation leading to hospitalization (hazard ratio, 1.91; 95% CI, 1.29 to 2.83). The frequency of side effects that were possibly related to metoprolol was similar in the two groups, as was the overall rate of nonrespiratory serious adverse events. During the treatment period, there were 11 deaths in the metoprolol group and 5 in the placebo group.ConclusionsAmong patients with moderate or severe COPD who did not have an established indication for beta-blocker use, the time until the first COPD exacerbation was similar in the metoprolol group and the placebo group. Hospitalization for exacerbation was more common among the patients treated with metoprolol. (Funded by the Department of Defense; BLOCK COPD ClinicalTrials.gov number, NCT02587351.).

Background: The ATS-ERS have established QA models as components of their PF technical standards (TS), however other than calibration many are not performed. We wanted to ensure high quality PF test results across the >70 facilities which comprize the Mayo Clinic (MC) health system. Objective: Implement a QA program for all lung function testing across the MC enterprise. Establish the individual components and QA metrics if not defined in the TSs. Methods: Basic training was defined as completion of a 2-day spirometry course for all personnel if not already specifically certified in PF testing. Ensure mechanical and biological models were being performed, set the target ranges if not defined by the TS, (Table 1). We developed a method to document the processes. A Sharepoint (figure 2) was created to facilitate communication, provide resources, house forms for documentation including spreadsheets with target limits and CVs. Conclusion: Standardized training and reporting tools, setting the target criteria for QA models, and a single reporting location have been essential elements in implementing the MC PFL QA program.

Screening for hepatopulmonary syndrome (HPS) using pulse oximetry is recommended in liver transplant (LT) candidates because mortality is increased, independently of the severity of the oxygenation defect. LT exception points may be afforded to those with HPS and severe hypoxemia. We assessed the screening characteristics of pulse oximetry for HPS. The Pulmonary Vascular Complications of Liver Disease 2 study is a multicenter, prospective cohort study of adults undergoing their first LT evaluation. Patients underwent protocolized assessment of oxygen saturation by pulse oximetry (SpO2 ), arterial blood gas, spirometry, and contrast-enhanced echocardiography (CE). HPS was defined as an alveolar-arterial gradient ≥15 mm Hg (≥20 mm Hg if age >64 years), intrapulmonary vascular dilatation on CE, and absence of lung disease. The study sample included 363 patients. Of these, 75 (20.7%; 95% confidence interval [CI], 16.6%-25.2%) met the criteria for HPS. The area under the receiver operating characteristic curve (or c-statistic) for SpO2 in discriminating HPS was 0.59 (95% CI, 0.51-0.66). An SpO2

Patients with Chronic Obstructive Pulmonary Disease (COPD) frequently experience unplanned hospital readmissions leading to increased morbidity [1]. The European Union COPD audit found that 35% of patients admitted with acute exacerbation of COPD (AECOPD) were readmitted within 90 days [2]. In the United States, 22% of patients admitted with AECOPD experienced a 30-day readmission, motivating financial policies to incentivize readmission reduction [1]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Krishnan reports grants from NHLBI/NIH, during the conduct of the study. Conflict of interest: Ms. Voelker has nothing to disclose. Conflict of interest: Dr. Connett has nothing to disclose. Conflict of interest: Dr. Niewoehner reports grants from National Institute of Health, during the conduct of the study; personal fees from Boehringer Ingelheim, personal fees from Astrazeneca, personal fees from GlaxoSmithKline, outside the submitted work. Conflict of interest: Dr. Albert has nothing to disclose. Conflict of interest: Dr. Scanlon reports grants from National Heart Lung and Blood Institute, during the conduct of the study; grants from Astra Zeneca, grants from Boehringer Ingelheim, grants from Forest Pharmaceuticals, grants from GlaxoSmithKline, grants from Novartis, grants from Pearl Therapeutics, other from Boehringer Ingelheim, other from GlaxoSmithKline, outside the submitted work. Conflict of interest: Dr. Dransfield reports grants from NHLBI, during the conduct of the study; grants from Department of Defense , personal fees and other from Boehringer Ingeheim, personal fees and other from GlaxoSmithKline, other from Novartis, personal fees and other from AstraZeneca, other from Yungjin, other from PneumRx/BTG, other from Pulmonx, personal fees from Genentech, personal fees and other from Boston Scientific , outside the submitted work. Conflict of interest: Dr. Han reports personal fees from BI, personal fees from GSK, personal fees from AZ, non-financial support from Novartis, non-financial support from Sunovion, outside the submitted work. Conflict of interest: Dr. Martinez reports non-financial support from GlaxoSmithKline, during the conduct of the study; personal fees from Continuing Education, personal fees from Forest Laboratories, other from Janssen, personal fees from GlaxoSmithKline, personal fees from Nycomed/Takeda, personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Bellerophon (formerly Ikaria), personal fees from Genentech, personal fees from Novartis, personal fees from Pearl, personal fees from Roche, personal fees from Sunovion, personal fees from Theravance, personal fees from CME Incite, personal fees from Annenberg Center for Health Sciences at Eisenhower, personal fees from Integritas, personal fees from InThought, personal fees from National Association for Continuing Education, personal fees from Paradigm Medical Communications, LLC, personal fees from PeerVoice, personal fees from UpToDate, personal fees from Haymarket Communications, personal fees from Western Society of Allergy and Immunology, from Proterixbio (formerly Bioscale), personal fees from Unity Biotechnology, personal fees from ConCert Pharmaceuticals, personal fees from Lucid, personal fees from Methodist Hospital, personal fees from Columbia University, personal fees from Prime Healthcare Ltd, personal fees from WebMD, personal fees from PeerView Network, personal fees from California Society of Allergy and Immunology, personal fees from Chiesi, personal fees from Puerto Rico Thoracic Society, outside the submitted work. Conflict of interest: Dr. Criner reports grants from Boehringer- Ingelheim, grants from Novartis, grants from Astra Zeneca, grants from Respironics, grants from MedImmune, grants from Actelion, grants from Forest, grants from Pearl , grants from Ikaria , grants from Aeris , grants from PneumRx, grants from Pulmonx , other from HGE Health Care Solutions, Inc, other from Amirall, other from Boehringer- Ingelheim, other from Holaira, outside the submitted work.

Global Strategy for the Diagnosis, Management, and Prevention of COPD 2018 is a consensus report published periodically since 2001 by an international panel of health professionals from respiratory medicine, socioeconomics, public health, and education comprising the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The GOLD documents endeavor to incorporate latest evidence and expert consensus and are intended for use as "strategy documents" for implementation of effective care for chronic obstructive lung disease (COPD) on a global level. The GOLD 2018 report defines COPD as a "common, preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities, usually caused by significant exposure to noxious particles or gases," with the criteria of "persistent respiratory symptoms" being a new and controversial inclusion since 2017. With the availability of newer pharmacotherapy options, treatment recommendations are made on the basis of a review of the latest literature and directed by symptom burden and health care utilization. Apart from the change in definition, a major shift in the recommendations is the exclusion of severity of airflow limitation as one of the major factors in guiding therapy. We review the salient features of the GOLD 2018 document and provide commentary on features that merit further discussion based on our clinical experience and practice as well as literature review current as of February 2018.

Inhaled corticosteroids are commonly prescribed for patients with severe chronic obstructive pulmonary disease. Although their use improves quality of life and reduces exacerbations, it is associated with increased risk of pneumonia. Curiously, their use has not been associated with increased risk of pneumonia-related or overall mortality. We review pertinent literature to further explore the effects of inhaled corticosteroids on incident pneumonia and mortality in patients with chronic obstructive pulmonary disease. The association of use of inhaled corticosteroids and incident pneumonia is substantial and has been present in the majority of the studies on the topic. This includes both randomized controlled trials and observational studies. However, all of the studies have substantial risk of bias. Most randomized trials are limited by lack of systematic ascertainment of pneumonia; they depended on adverse event reporting. Many observational studies included proper radiographic assessment of pneumonia, but they are limited by their retrospective, observational design. The unadjusted higher risk of pneumonia is associated with longer duration of use, more potent ICS compounds, and higher doses. That implies a dose–effect relationship. Unlike pneumonia, mortality is a precise outcome. Despite the robust association of inhaled corticosteroid use with increased risk of pneumonia, all studies find either no difference or a reduction in pulmonary-related and overall mortality associated with the use of inhaled corticosteroids. These observations suggest a double effect of inhaled corticosteroids (i.e., an adverse effect plus an unexplained mitigating effect).

Background Intrapulmonary vascular dilatations (IPVD) frequently are detected in patients with liver disease by the delayed appearance of microbubbles at contrast-enhanced echocardiography. IPVD with an elevated alveolar-arterial (A-a) gradient define hepatopulmonary syndrome (HPS); however, the importance of IPVD in the absence of abnormal gas exchange is unknown. We aimed to determine the clinical impact of IPVD in patients with liver disease. Methods We performed a cross-sectional study within the Pulmonary Vascular Complications of Liver Disease 2 Study, a multicenter, prospective cohort study of patients being evaluated for liver transplant. We excluded patients with obstructive or restrictive lung disease, HPS, or intracardiac shunting. We compared patients with and those without IPVD. Results Forty-six patients with IPVD and 81 patients without IPVD were included. Patients with IPVD were more likely to have autoimmune hepatitis and less likely to have cryptogenic cirrhosis and hepatocellular carcinoma. Patients with IPVD had higher Child-Pugh scores (6 [interquartile range (IQR), 5-7] vs 5 [IQR, 4-7]; P = .04), possibly higher Model for End-Stage Liver Disease scores (14.5 [IQR, 11.6-15.8] vs 12.2 [IQR, 9.4-15.5]; P = .06), higher PaO2 levels (97.9 [IQR, 92.0-103.0] vs 89.0 [IQR, 82.0-96.9] mm Hg; P Conclusions Autoimmune hepatitis and increased liver disease severity were associated with the presence of IPVD, which was characterized by higher PaO2 levels. Future studies to better characterize IPVD pathogenesis and the relationship of IPVD to HPS are warranted.

Most patients with restriction have a pulmonary function test (PFT) pattern in which total lung capacity (TLC), FVC, and FEVThis study reviewed PFT results of patients tested between November 2009 and June 2013 who had restriction (TLC less than the lower limit of normal). SR was defined as TLCOf 39,277 PFTs completed, we identified 4,532 patients (11.5%) with restriction: 2,407 (6.1%) with SR, 1,614 (4.1%) with CR, and 511 (1.3%) with a mixed pattern. Patients with CR were younger, were more often women, and had a higher prevalence of neuromuscular disease, BMI40 kg/mCR is a common PFT pattern with distinct clinical features. The associated clinical entities share impaired lung emptying (eg, neuromuscular disease, occult obstruction, chest wall limitation). Clinicians should be aware of this novel PFT pattern and how it shapes the differential diagnosis.

BACKGROUND Retrospective studies have shown that statins decrease the rate and severity of exacerbations, the rate of hospitalization, and mortality in chronic obstructive pulmonary disease (COPD). We prospectively studied the efficacy of simvastatin in preventing exacerbations in a large, multicenter, randomized trial. METHODS We designed the Prospective Randomized Placebo-Controlled Trial of Simvastatin in the Prevention of COPD Exacerbations (STATCOPE) as a randomized, controlled trial of simvastatin (at a daily dose of 40 mg) versus placebo, with annual exacerbation rates as the primary outcome. Patients were eligible if they were 40 to 80 years of age, had COPD (defined by a forced expiratory volume in 1 second [FEV1] of less than 80% and a ratio of FEV1 to forced vital capacity of less than 70%), and had a smoking history of 10 or more pack-years, were receiving supplemental oxygen or treatment with glucocorticoids or antibiotic agents, or had had an emergency department visit or hospitalization for COPD within the past year. Patients with diabetes or cardiovascular disease and those who were taking statins or who required statins on the basis of Adult Treatment Panel III criteria were excluded. Participants were treated from 12 to 36 months at 45 centers. RESULTS A total of 885 participants with COPD were enrolled for approximately 641 days; 44% of the patients were women. The patients had a mean (±SD) age of 62.2±8.4 years, an FEV 1 that was 41.6±17.7% of the predicted value, and a smoking history of 50.6±27.4 pack-years. At the time of study closeout, the low-density lipoprotein cholesterol levels were lower in the simvastatin-treated patients than in those who received placebo. The mean number of exacerbations per person-year was similar in the simvastatin and placebo groups: 1.36±1.61 exacerbations and 1.39±1.73 exacerbations, respectively (P = 0.54). The median number of days to the first exacerbation was also similar: 223 days (95% confidence interval [CI], 195 to 275) and 231 days (95% CI, 193 to 303), respectively (P = 0.34). The number of nonfatal serious adverse events per person-year was similar, as well: 0.63 events with simvastatin and 0.62 events with placebo. There were 30 deaths in the placebo group and 28 in the simvastatin group (P = 0.89). CONCLUSIONS Simvastatin at a daily dose of 40 mg did not affect exacerbation rates or the time to a first exacerbation in patients with COPD who were at high risk for exacerbations. (Funded by the National Heart, Lung, and Blood Institute and the Canadian Institutes of Health Research; STATCOPE ClinicalTrials.gov number, NCT01061671.)

Cough and phlegm are common in COPD. Previous studies have shown conflicting evidence regarding their association with mortality and lung function. We sought to better understand how cough and phlegm impact mortality and lung function in COPD. We analyzed data from the Lung Health Study, consisting of 5,887 smokers with mild to moderate airflow obstruction followed longitudinally. We assessed the association between baseline symptoms of cough alone, phlegm alone, and cough and phlegm with 12.5-year mortality and annual lung function decline. Average age at entry was 48.5 years (± 6.8) with 63% males and 4% African Americans. Cough alone was present in 17%, phlegm alone in 12%, while 31% had both. Neither symptom alone was associated with death, but the combination was associated with increased risk of death after adjustment for age, gender, race, smoking status at year 5, pack-years smoked, randomization group, baseline FEV1 percent predicted (HR 1.27, 95% CI 1.02-1.59). Individuals with cough and phlegm together more commonly died of respiratory causes than those without. Cough with phlegm was associated with 48 mL lower baseline FEV1 (95% CI -90, -6), while neither symptom alone was associated with baseline FEV1. No symptom was associated with FEV1 longitudinally. Cough and phlegm together are associated with mortality and lung function decrement in mild-to-moderate COPD, independent of lung function and smoking status. Respiratory causes of death are common among those with cough and phlegm. Such information can help to identify subsets of individuals with COPD having higher risk for adverse outcomes.

Aims: The follow-up of the ECLIPSE study, a prospective longitudinal study to identify and define parameters that predict disease progression over 3 years in chronic obstructive pulmonary disease (COPD), allows the examination of the effect of body composition changes on COPD-related outcomes. Methods: Body composition and health status were established in 2,115 COPD patients, 327 smoking and 239 nonsmoking controls at baseline and 3 years, while mortality was recorded in year 2 and 3 in the COPD patients. Associations between fat free mass index (FFMI) and fat mass index (FMI) changes to deterioration in health status and mortality were determined. Results: Change in FFMI and FMI over 3 years was small and comparable between the groups. Underweight and obese patients had the worst health status. Worsening health status was associated with FFMI decrease in underweight patients and FMI increase in overweight/obese patients. While overweight patients had the lowest mortality, FFMI or FMI decrease was associated with a higher mortality. Conclusion: Changes in body composition over 3 years were small and comparable in COPD patients and control subjects. Nevertheless, muscle mass decline in underweight and fat mass increase in overweight/obese patients is associated with worsening health status. Overweight is associated with decreased mortality, but muscle mass and fat mass decline are detrimental for mortality.

The sawtooth sign in spirometry is associated with redundant upper airway tissue and snoring, but its predictive value for identifying obstructive sleep apnea (OSA) is disputed. We retrospectively assessed the predictive value of the spirometric sawtooth sign in terms of the odds ratio (OR) of association with a diagnosis of OSA compared to those without the sign. Consecutive spirometry reports showing a sawtooth sign were identified from our laboratory. We identified 50 subjects with sawtooth sign and 100 control subjects without sawtooth sign, matched for age, BMI, and gender. The electronic medical record of each patient was queried for a diagnosis of OSA based on physician-reported diagnoses. Of the 50 subjects with sawtooth sign, 22 were found to have a current diagnosis of OSA (44%). Twenty-seven of the 100 controls (27%) also had OSA. From logistic regression analysis, sawtooth sign was associated with an increased likelihood of OSA (OR = 2.12, 95% C.I. 1.04 to 4.35). Similar results were obtained after adjustment for age, gender, pack years, and BMI (OR = 2.61, 95% C.I. 1.13 to 6.21). Patients with the sawtooth sign have greater odds of having a diagnosis of OSA compared with those without the sign. If prospectively evaluated, as a result of improved identification, we hypothesize that the sawtooth sign may show an even stronger association with OSA. This relatively common finding, which adds no cost to routine spirometry, may serve as an indicator for OSA workup for some individuals not already identified as having OSA.

Pulmonary function testing (PFTs) is necessary for the diagnosis and optimal management of many common lung diseases. PFTs are underutilized, particularly in the elderly and underprivileged, who face multiple barriers to receiving good medical care, including lack of access to high-quality pulmonary function testing. Language barriers can adversely affect accuracy of PFTs. Many factors including socioeconomic status, air quality, and education all influence lung function. Differences in lung function have been observed by race. Some, but not all, of these observed differences in lung function are attributable to environmental factors. PFT results are interpreted in comparison with reference values derived from large, healthy, mostly white populations. They are calculated using age, gender, height, and race. The use of “race correction” factors to adjust predicted values from reference equations is an imperfect tool that has generated controversy, but is currently the best available methodology. More precise adjustment based on genetic testing may be feasible in the future but is not yet developed for practical use.

Background. Although the 23-valent pneumococcal polysaccharide vaccine (PPSV23) protects against invasive disease in young healthy persons, randomized controlled trials in chronic obstructive pulmonary disease (COPD) have demonstrated no benefit in the intention-to-treat population. We previously reported that the 7-valent diphtheria-conjugated pneumococcal polysaccharide vaccine (PCV7) is safe and induced greater serotype-specific immunoglobulin G (IgG) and functional antibody than did PPSV23 1 month after vaccination. We hypothesized that these advantages would persist at 1 and 2 years. Methods. One hundred eighty-one patients with moderate to severe COPD were randomized to receive PPSV23 (n = 90) or PCV7 (1.0 mL; n = 91). We measured IgG by enzyme-linked immunosorbent assay and assessed functional antibody activity by a standardized opsonophagocytosis assay, reported as a killing index (OPK). We determined differences in IgG and OPK between vaccine groups at 1 and 2 years. Results. Relative to PPSV23, PCV7 induced greater OPK at both 1 and 2 years for 6 of 7 serotypes (not 19F). This response was statistically greater for 5 of 7 serotypes at 1 year and 4 of 7 at 2 years. Comparable differences in IgG were observed but were less often statistically significant. Despite meeting Centers for Disease Control and Prevention criteria for PPSV23 administration, almost 50% of individuals had never been vaccinated. No differences in the frequency of acute exacerbations, pneumonia, or hospitalization were observed. Conclusions. PCV7 induces a greater functional antibody response than PPSV23 in patients with COPD that persists for 2 years after vaccination. This superior functional response supports testing of conjugate vaccination in studies examining clinical end points. Clinical Trials Registration: {"type":"clinical-trial","attrs":{"text":"NCT00457977","term_id":"NCT00457977"}}NCT00457977.

Inhaled corticosteroids are commonly prescribed for patients with severe COPD. They have been associated with increased risk of pneumonia but not with increased pneumonia-associated or overall mortality.To further examine the effects of inhaled corticosteroids on pneumonia incidence, and mortality in COPD patients, we searched for potentially relevant articles in PubMed, Medline, CENTRAL, EMBASE, Scopus, Web of Science and manufacturers' web clinical trial registries from 1994 to February 4, 2014. Additionally, we checked the included and excluded studies' bibliographies. We subsequently performed systematic review and meta-analysis of included randomized controlled trials and observational studies on the topic.We identified 38 studies: 29 randomized controlled trials and nine observational studies. The estimated unadjusted risk of pneumonia was increased in randomized trials: RR 1.61; 95% CI 1.35-1.93, p0.001; as well as in observational studies: OR 1.89; 95% CI 1.39-2.58, p0·001. Six randomized trials and seven observational studies were useful in estimating unadjusted risk of pneumonia -case-fatality: RR 0.91; 95% CI 0.52-1.59, p = 0.74; and OR 0.72; 95% CI 0.59-0.88, p = 0.001, respectively. Twenty-nine randomized trials and six observational studies allowed estimation of unadjusted risk of overall mortality: RR 0.95; 95% CI 0.85-1.05, p = 0.31; and OR 0.79; 95% CI 0.65-0.97, p = 0.02, respectively.Despite a substantial and significant increase in unadjusted risk of pneumonia associated with inhaled corticosteroid use, pneumonia fatality and overall mortality were found not to be increased in randomized controlled trials and were decreased in observational studies.

Acute exacerbations adversely affect patients with chronic obstructive pulmonary disease (COPD). Macrolide antibiotics benefit patients with a variety of inflammatory airway diseases.We performed a randomized trial to determine whether azithromycin decreased the frequency of exacerbations in participants with COPD who had an increased risk of exacerbations but no hearing impairment, resting tachycardia, or apparent risk of prolongation of the corrected QT interval.A total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. The rate of 1-year follow-up was 89% in the azithromycin group and 90% in the placebo group. The median time to the first exacerbation was 266 days (95% confidence interval [CI], 227 to 313) among participants receiving azithromycin, as compared with 174 days (95% CI, 143 to 215) among participants receiving placebo (P0.001). The frequency of exacerbations was 1.48 exacerbations per patient-year in the azithromycin group, as compared with 1.83 per patient-year in the placebo group (P=0.01), and the hazard ratio for having an acute exacerbation of COPD per patient-year in the azithromycin group was 0.73 (95% CI, 0.63 to 0.84; P0.001). The scores on the St. George's Respiratory Questionnaire (on a scale of 0 to 100, with lower scores indicating better functioning) improved more in the azithromycin group than in the placebo group (a mean [±SD] decrease of 2.8±12.8 vs. 0.6±11.4, P=0.004); the percentage of participants with more than the minimal clinically important difference of -4 units was 43% in the azithromycin group, as compared with 36% in the placebo group (P=0.03). Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P=0.04).Among selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects. Although this intervention could change microbial resistance patterns, the effect of this change is not known. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00325897.).

Background The nonspecific (NS) pulmonary function (PF) pattern refers to a PF test with a normal total lung capacity (TLC), normal FEV1/FVC ratio, and a low FEV1, a low FVC, or both. Currently, no information is available regarding the long-term stability of the NS pattern or variables that predict changes in subjects with an initial NS PF pattern. Methods From 1990 to 2005 we identified 1,284 subjects with an NS pattern on initial PF testing with one or more follow-up PF tests 6 months or more after the initial NS test result. Lung volumes, diffusing capacity, and spirometry data were analyzed. A multivariate, multinomial logistic regression model was used to study the association between different variables and the final PF pattern. Results Overall, 3,674 PF tests were performed in 1,284 subjects over a median follow-up period of 3 years. At last follow-up, 818/1,284 (64%) subjects continued to show the NS pattern, whereas 208/1,284 (16%) showed a restrictive pattern, 191/1,284 (15%) an obstructive pattern, 42/1,284 (3%) a normal pattern, and 25/1,284 (2%) a mixed pattern. The multinomial logistic regression analysis showed that increasing values for specific airway resistance and the difference between TLC and alveolar volume were predictors of a change to an obstructive pattern on follow-up. Conclusions The NS pattern is a distinct and stable PF test pattern with roughly two-thirds of patients continuing to show this pattern on follow-up testing. Current interpretation guidelines erroneously label the NS pattern as representing obstruction and need to be changed to reflect these data.

A medical student's ability to present a case history is a critical skill that is difficult to teach. Case histories presented without theatrical engagement may fail to catch the attention of their intended recipients. More engaging presentations incorporate 'stage presence', eye contact, vocal inflection, interesting detail and succinct, well organised performances. They convey stories effectively without wasting time. To address the didactic challenge for instructing future doctors in how to 'act', the Mayo Medical School and The Mayo Clinic Center for Humanities in Medicine partnered with the Guthrie Theater to pilot the programme 'Telling the Patient's Story'. Guthrie teaching artists taught storytelling skills to medical students through improvisation, writing, movement and acting exercises. Mayo Clinic doctors participated and provided students with feedback on presentations and stories from their own experiences in patient care. The course's primary objective was to build students' confidence and expertise in storytelling. These skills were then applied to presenting cases and communicating with patients in a fresher, more engaging way. This paper outlines the instructional activities as aligned with course objectives. Progress was tracked by comparing pre-course and post-course surveys from the seven participating students. All agreed that the theatrical techniques were effective teaching methods. Moreover, this project can serve as an innovative model for how arts and humanities professionals can be incorporated for teaching and professional development initiatives at all levels of medical education.

BACKGROUND: A key feature of chronic obstructive pulmonary disease (COPD) is an accelerated rate of decline in forced expiratory volume in 1 second (FEV1), but data on the variability and determinants of this change in patients who have established disease are scarce. METHODS: We analyzed the changes in FEV1 after administration of a bronchodilator over a 3-year period in 2163 patients. A random-coefficient model was used to evaluate possible predictors of both FEV1 levels and their changes over time. RESULTS: The mean (±SE) rate of change in FEV1 was a decline of 33±2 ml per year, with significant variation among the patients studied. The between-patient standard deviation for the rate of decline was 59 ml per year. Over the 3-year study period, 38% of patients had an estimated decline in FEV1 of more than 40 ml per year, 31% had a decline of 21 to 40 ml per year, 23% had a change in FEV1 that ranged from a decrease of 20 ml per year to an increase of 20 ml per year, and 8% had an increase of more than 20 ml per year. The mean rate of decline in FEV 1 was 21±4 ml per year greater in current smokers than in current nonsmokers, 13±4 ml per year greater in patients with emphysema than in those without emphysema, and 17±4 ml per year greater in patients with bronchodilator reversibility than in those without reversibility. CONCLUSIONS: The rate of change in FEV1 among patients with COPD is highly variable, with increased rates of decline among current smokers, patients with bronchodilator reversibility, and patients with emphysema. (Funded by GlaxoSmithKline; ECLIPSE ClinicalTrials.gov number, NCT00292552.) Copyright © 2011 Massachusetts Medical Society. BACKGROUND: A key feature of chronic obstructive pulmonary disease (COPD) is an accelerated rate of decline in forced expiratory volume in 1 second (FEV1), but data on the variability and determinants of this change in patients who have established disease are scarce. METHODS: We analyzed the changes in FEV1 after administration of a bronchodilator over a 3-year period in 2163 patients. A random-coefficient model was used to evaluate possible predictors of both FEV1 levels and their changes over time. RESULTS: The mean (±SE) rate of change in FEV1 was a decline of 33±2 ml per year, with significant variation among the patients studied. The between-patient standard deviation for the rate of decline was 59 ml per year. Over the 3-year study period, 38% of patients had an estimated decline in FEV1 of more than 40 ml per year, 31% had a decline of 21 to 40 ml per year, 23% had a change in FEV1 that ranged from a decrease of 20 ml per year to an increase of 20 ml per year, and 8% had an increase of more than 20 ml per year. The mean rate of decline in FEV 1 was 21±4 ml per year greater in current smokers than in current nonsmokers, 13±4 ml per year greater in patients with emphysema than in those without emphysema, and 17±4 ml per year greater in patients with bronchodilator reversibility than in those without reversibility. CONCLUSIONS: The rate of change in FEV1 among patients with COPD is highly variable, with increased rates of decline among current smokers, patients with bronchodilator reversibility, and patients with emphysema. (Funded by GlaxoSmithKline; ECLIPSE ClinicalTrials.gov number, NCT00292552.) Copyright © 2011 Massachusetts Medical Society.

Treatment of cancer-related symptoms represents a major challenge for physicians. The purpose of this pilot study was to determine whether a brief bedside visual art intervention (BVAI) facilitated by art educators improves mood, reduces pain and anxiety in patients with haematological malignancies. Thirty-one patients (21 women and 10 men) were invited to participate in a BVAI where the goal of the session was to teach art technique for ~30 min. Primary outcome measures included the change in visual analog scale, the State-Trait Anxiety Inventory and the Positive and Negative Affect Schedule scale, from baseline prior to and immediately post-BVAI. Total of 21 patients (19 women and two men) participated. A significant improvement in positive mood and pain scores (p = .003 and p = .017 respectively) as well as a decrease in negative mood and anxiety (p = .016 and p = .001 respectively) was observed. Patients perceived BVAI as overall positive (95%) and wished to participate in future art-based interventions (85%). This accessible experience, provided by artists within the community, may be considered as an adjunct to conventional treatments in patients with cancer-related mood symptoms and pain, and future studies with balanced gender participation may support the generalisability of these findings.

Debate exists about the immunogenicity and protective efficacy of antibodies produced by the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in chronic obstructive pulmonary disease (COPD). The 7-valent diphtheria-conjugated pneumococcal polysaccharide vaccine (PCV7) induces a more robust immune response than PPSV23 in healthy elderly adults.We hypothesized that serotype-specific IgG antibody concentration and functional antibody activity would be superior after PCV7 vaccination compared with PPSV23 in moderate to severe COPD. We also posited that older age and prior PPSV23 vaccination would be associated with reduced vaccine responsiveness.One hundred twenty patients with COPD were randomized to PPSV23 (63 subjects) or PCV7 (57 subjects). IgG concentrations were determined by ELISA; functional antibody activity was assayed with a standardized opsonophagocytosis assay and reported as an opsonization killing index (OPK). Increases in serotype-specific IgG and OPK at 1 month post vaccination were compared within and between vaccine groups.Both vaccines were well tolerated. Within each study group, postvaccination IgG and OPK were higher than baseline (P0.01) for all serotypes. Adjusted for baseline levels, postvaccination IgG was higher in the PCV7 group than the PPSV23 group for all seven serotypes, reaching statistical significance for five (P0.05). PCV7 resulted in a higher OPK for six of seven serotypes (statistically greater for four) compared with PPSV23. In multivariate analyses, younger age, vaccine naivety, and receipt of PCV7 were associated with increased OPK responses.PCV7 induces a superior immune response at 1 month post vaccination compared with PPSV23 in COPD. Older age and prior PPSV23 reduce vaccine responsiveness. Clinical trial registered with www.clinicaltrials.gov (NCT00457977).

Background Little is known about a fairly frequent abnormal pattern of pulmonary function test results: reduced FEV1 and FVC with a normal FEV1/FVC and normal total lung capacity. We term this a nonspecific pattern (NSP). We sought to identify medical conditions having this pattern and to explore mechanisms producing it. Methods From a database of 80,929 test results, the NSP was found in 7,702 subjects from whom was drawn a random sample of 100 subjects. Medical records and all available tests were examined. Results Airway hyperresponsiveness (AHR) and obesity were common. Two groups of subjects were identified. Group A consisted of 68 subjects with evidence of airway disease, including AHR and chronic lung disease. A volume derecruitment model was proposed to explain their NSP. Group B consisted of 32 subjects with no evidence of airway disease. Restricted expansion of the thorax or lung may explain the NSP in most of these subjects. Forty subjects had repeated tests, and in only 17 were the test results consistently nonspecific. Conclusions In a random sample of 100 subjects with the NSP, the probable underlying cause of the pattern in 68 subjects was airway disease. In most of the remaining 32 subjects, restricted expansion of the thorax or lung may be implicated.

Rationale: Computed tomography (CT) scanning of the lung may reduce phenotypic heterogeneity in defining subjects with chronic obstructive pulmonary disease (COPD), and allow identification of genetic determinants of emphysema severity and distribution. Objectives: We sought to identify genes associated with CT scan distribution of emphysema in individuals without α1-antitrypsin deficiency but with severe COPD. Methods: We evaluated baseline CT densitometry phenotypes in 282 individuals with emphysema enrolled in the Genetics Ancillary Study of the National Emphysema Treatment Trial, and used regression models to identify genetic variants associated with emphysema distribution. Measurements and Main Results: Emphysema distribution was assessed by two methods—assessment by radiologists and by computerized density mask quantitation, using a threshold of −950 Hounsfield units. A total of 77 polymorphisms in 20 candidate genes were analyzed for association with distribution of emphysema. GSTP1, EPHX1, and MMP1 polymorphisms were associated with the densitometric, apical-predominant distribution of emphysema (p value range = 0.001–0.050). When an apical-predominant phenotype was defined by the radiologist scoring method, GSTP1 and EPHX1 single-nucleotide polymorphisms were found to be significantly associated. In a case–control analysis of COPD susceptibility limited to cases with densitometric upper-lobe–predominant cases, the EPHX1 His139Arg single-nucleotide polymorphism was associated with COPD (p = 0.005). Conclusions: Apical and basal emphysematous destruction appears to be influenced by different genes. Polymorphisms in the xenobiotic enzymes, GSTP1 and EPHX1, are associated with apical-predominant emphysema. Altered detoxification of cigarette smoke metabolites may contribute to emphysema distribution, and these findings may lead to further insight into genetic determinants of emphysema.

Background Aclidinium/formoterol fixed-dose combination (FDC) is in development for the management of COPD. The ACLIFORM and AUGMENT studies assessed the effects of twice-daily FDC on health status in patients with moderate to severe COPD. Method ACLIFORM and AUGMENT were multinational, double-blind, placebo- and active-controlled, parallel-group studies. Patients were randomized to receive placebo, aclidinium 400 µg, formoterol 12 µg, FDC 400/6 µg or FDC 400/12 µg. Change from baseline in SGRQ total score at Week 24 and the percentage of patients achieving or exceeding the MCID (≥4 units) were assessed. Results In total, 1726 (mean age 63.2 years; 67.6% male; moderate COPD 60.1%; mean baseline SGRQ score 46.2) and 1668 (mean age 63.9 years; 53.2% male; moderate COPD 57.0%; mean baseline SGRQ score 46.0) patients were included in the ITT population in ACLIFORM and AUGMENT, respectively. In both studies, both FDC doses improved SGRQ total score by ≥MCID at Week 24 and >50% of patients receiving FDC achieved or exceeded the MCID (Table). In ACLIFORM, improvements in SGRQ total score with FDC did not reach significance versus placebo, possibly due to a very large placebo response (>MCID). Conclusion These studies indicate that aclidinium/formoterol FDC improves health status in patients with moderate to severe COPD, notwithstanding the large placebo effect that may have masked the treatment effect in ACLIFORM. ![Figure][1] [1]: pending:yes

Study objectives: Inhaled corticosteroids (ICS) are widely used in the treatment of COPD. One of the potential adverse effects of their use is the development of adrenal suppression. Our study aimed to determine the effects of ICS on adrenal function over 3 years of use in patients with COPD. Methods: Two hundred twenty-one subjects were recruited from the 1,116 patients already enrolled in Lung Health Study II and were randomized to receive either triamcinolone, 1,200 g, or placebo daily. Basal cortisol levels and cortisol levels at 30 min and 60 min following cosyntropin injection were measured at study entry and after 1 year and 3 years of participation. Results: Basal cortisol levels in the placebo group were higher than in those receiving active drug at all time points and rose through the study period. There was no suppression of cortisol levels after cosyntropin stimulation at any study point in any subgroup. Conclusion: Use of inhaled triamcinolone, 1,200 g/d, over 3 years does not suppress baseline adrenal function or diminish adrenal responsiveness to cosyntropin stimulation. (CHEST 2003; 124:57– 62)

Background Undertreatment of asthma is associated with significant potentially preventable morbidity, including frequent school absences. Guideline dissemination and clinician education have met with variable success. School-based identification of children with potentially undertreated asthma may provide an alternative strategy for improving asthma management in children. Objective To evaluate the effectiveness of school-based identification of potentially undertreated asthma. Methods A controlled trial of school-based identification of children with known but symptomatic asthma using mailed parent surveys, letters recommending medical follow-up, and medical record review to evaluate changes in asthma treatment after referral. Results Most parents (79.9%, n=5,116 respondents) responded to the survey and 19.4% (n = 994) of children were reported to have a physician diagnosis of asthma or reactive airway disease. Letters of referral were sent to 489 children with parent-reported asthma who were identified as having potentially undertreated asthma. Approximately one-third (31.2%, n=153) of these children had physician visits, and 92 (18.8% of all referred) had documented medication changes. In addition, there were 20 new physician diagnoses in this group of children. In the control group of 604 children with asthma, there were significantly fewer children with asthma-related visits (131, 21.7%, P = 0.0004) and children with medication changes (74, 12.3%, P = 0.002) in a comparable 6-month window. Conclusions School-based screening or case identification increased the number of physician asthma-related visits and changes in asthma therapy.

RationaleDaily azithromycin decreases acute exacerbations of chronic obstructive pulmonary disease (AECOPD), but long-term side effects are unknown.ObjectivesTo identify the types of exacerbations most likely to be reduced and clinical subgroups most likely to benefit from azithromycin, 250 mg daily, added to usual care.MethodsEnrollment criteria included irreversible airflow limitation and AECOPD requiring corticosteroids, emergency department visit, or hospitalization in the prior year or use of supplemental oxygen. Recurrent events and cumulative incidence analyses compared treatment received for AECOPD by randomization group, stratified by subgroups of interest. Cox proportional hazards models estimated treatment effects in subgroups adjusted for age, sex, smoking status, FEV1% predicted, concomitant COPD medications, and oxygen use.Measurements and main resultsAzithromycin was most effective in reducing AECOPD requiring both antibiotic and steroid treatment (n = 1,113; cumulative incidence analysis, P = 0.0002; recurrent events analysis, P = 0.002). No difference in treatment response by sex (P = 0.75), presence of chronic bronchitis (P = 0.19), concomitant inhaled therapy (P = 0.29), or supplemental oxygen use (P = 0.23) was observed. Older age and milder Global Initiative for Chronic Obstructive Lung Disease stage were associated with better treatment response (P = 0.02 and 0.04, respectively). A significant interaction between treatment and current smoking was seen (P = 0.03) and azithromycin did not reduce exacerbations in current smokers (hazard ratio, 0.99; 95% confidence interval, 0.71-1.38; P = 0.95).ConclusionsAzithromycin is most effective in preventing AECOPD requiring both antibiotic and steroid treatment. Adjusting for confounders, we saw no difference in efficacy by sex, history of chronic bronchitis, oxygen use, or concomitant COPD therapy. Greater efficacy was seen in older patients and milder Global Initiative for Chronic Obstructive Lung Disease stages. We found little evidence of treatment effect among current smokers. Clinical trial registered with www.clinicaltrials.gov (NCT0011986 and NCT00325897).

Chronic obstructive pulmonary disease (COPD) is associated with increased cardiovascular morbidity and mortality, yet the exact pathophysiological links remain unclear. Whether the presence and severity of COPD are associated with atrial or ventricular arrhythmias recorded on continuous electrocardiographic monitoring is unknown. We identified consecutive adult patients who underwent clinically indicated pulmonary function testing as well as 24-hour Holter monitoring at the Mayo Clinic, Rochester, from 2000 to 2009. Demographic data and relevant co-morbidities were gathered from the electronic medical record; severity of COPD was classified according to the GOLD classification, and arrhythmias were classified in concordance with the current clinical guidelines. From 7,441 patients who were included (age 64±16 years, 49% woman, 92% Caucasian), COPD was diagnosed in 3,121 (41.9%). Compared with those without COPD, the presence and severity of COPD were associated with increased likelihood of atrial fibrillation/atrial flutter (AF/AFL; 23.3% vs 11.0%, respectively, p0.0001), nonsustained ventricular tachycardia (NSVT; 13.0% vs 5.9%, respectively, p0.0001), and sustained ventricular tachycardia (0.9% vs 1.6%, respectively, p0.0001). COPD remained a significant predictor of AF/AFL and NSVT (p0.0001 and p0.0001, respectively) after adjusting for age, gender, tobacco use, obesity, hypertension, coronary artery disease, heart failure, diabetes, anemia, cancer, chronic kidney disease, and rate/rhythm control medications. In conclusion, the independent association between the presence and severity of COPD and arrhythmias (AF/AFL and NSVT) provides further insight into the markedly increased cardiovascular mortality of patients with COPD. Further studies should explore which anti-arrhythmic strategies would best apply to the patients with COPD.