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1. The Association Between Lung Hyperinflation and Coronary Artery Disease in Smokers

Author

Divay Chandra, Aman Gupta, Gregory L. Kinney, Carl R. Fuhrman, Joseph K. Leader, Alejandro A. Diaz, Jessica Bon, R. Graham Barr, George Washko, Matthew Budoff, John Hokanson, Frank C. Sciurba, James D. Crapo, Edwin K. Silverman, Barry J. Make, Elizabeth A. Regan, Terri Beaty, Ferdouse Begum, Adel R. Boueiz, Peter J. Castaldi, Michael Cho, Dawn L. DeMeo, Marilyn G. Foreman, Eitan Halper-Stromberg, Lystra P. Hayden, Craig P. Hersh, Jacqueline Hetmanski, Brian D. Hobbs, John E. Hokanson, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Margaret M. Parker, Dmitry Prokopenko, Dandi Qiao, Phuwanat Sakornsakolpat, Emily S. Wan, Sungho Won, Mustafa Al Qaisi, Harvey O. Coxson, Teresa Gray, MeiLan K. Han, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, David A. Lynch, John D. Newell, James C. Ross, Raul San Jose Estepar, Joyce Schroeder, Jered Sieren, Douglas Stinson, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, Carla G. Wilson, Robert Jensen, Jim Crooks, Douglas Everett, Camille Moore, null Strand, John Hughes, Gregory Kinney, Katherine Pratte, Kendra A. Young, Surya Bhatt, Carlos Martinez, Susan Murray, Xavier Soler, Farnoush Banaei-Kashani, Russell P. Bowler, Katerina Kechris, Jeffrey L. Curtis, Perry G. Pernicano, Nicola Hanania, Mustafa Atik, Aladin Boriek, Kalpatha Guntupalli, Elizabeth Guy, Amit Parulekar, Craig Hersh, John Austin, Belinda D’Souza, Byron Thomashow, Neil MacIntyre, H. Page McAdams, Lacey Washington, Charlene McEvoy, Joseph Tashjian, Robert Wise, Robert Brown, Nadia N. Hansel, Karen Horton, Allison Lambert, Nirupama Putcha, Richard Casaburi, Alessandra Adami, Hans Fischer, Janos Porszasz, Harry Rossiter, William Stringer, Michael E. DeBakey, Amir Sharafkhaneh, Charlie Lan, Christine Wendt, Brian Bell, Ken M. Kunisaki, Eugene Berkowitz, Gloria Westney, Russell Bowler, Richard Rosiello, David Pace, Gerard Criner, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D’Alonzo, Parag Desai, Michael Jacobs, Steven Kelsen, Victor Kim, A. James Mamary, Nathaniel Marchetti, Aditi Satti, Kartik Shenoy, Robert M. Steiner, Alex Swift, Irene Swift, Maria Elena Vega-Sanchez, Mark Dransfield, William Bailey, Surya P. Bhatt, Anand Iyer, Hrudaya Nath, J. Michael Wells, Joe Ramsdell, Paul Friedman, Andrew Yen, Alejandro P. Comellas, Karin F. Hoth, John Newell, Brad Thompson, Ella Kazerooni, Carlos H. Martinez, Joanne Billings, Abbie Begnaud, Tadashi Allen, Frank Sciurba, Carl Fuhrman, Joel Weissfeld, Antonio Anzueto, Sandra Adams, Diego Maselli-Caceres, and Mario E. Ruiz

Subjects
Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Coronary Artery Disease, Critical Care and Intensive Care Medicine, COPD: Original Research, Coronary artery disease, 03 medical and health sciences, FEV1/FVC ratio, 0302 clinical medicine, Functional residual capacity, Risk Factors, Internal medicine, medicine, Humans, Lung volumes, 030212 general & internal medicine, Myocardial infarction, Lung, Subclinical infection, COPD, business.industry, Smoking, Organ Size, Middle Aged, respiratory system, medicine.disease, Coronary Vessels, United States, Respiratory Function Tests, respiratory tract diseases, Airway Obstruction, Plethysmography, Biological Variation, Population, Pulmonary Emphysema, 030228 respiratory system, Asymptomatic Diseases, Cohort, Cardiology, Airway Remodeling, Female, Tomography, X-Ray Computed, Cardiology and Cardiovascular Medicine, business
Abstract

BACKGROUND: Smokers manifest varied phenotypes of pulmonary impairment. RESEARCH QUESTION: Which pulmonary phenotypes are associated with coronary artery disease (CAD) in smokers? STUDY DESIGN AND METHODS: We analyzed data from the University of Pittsburgh COPD Specialized Center for Clinically Oriented Research (SCCOR) cohort (n = 481) and the Genetic Epidemiology of COPD (COPDGene) cohort (n = 2,580). Participants were current and former smokers with > 10 pack-years of tobacco exposure. Data from the two cohorts were analyzed separately because of methodologic differences. Lung hyperinflation was assessed by plethysmography in the SCCOR cohort and by inspiratory and expiratory CT scan lung volumes in the COPDGene cohort. Subclinical CAD was assessed as the coronary artery calcium score, whereas clinical CAD was defined as a self-reported history of CAD or myocardial infarction (MI). Analyses were performed in all smokers and then repeated in those with airflow obstruction (FEV(1) to FVC ratio, < 0.70). RESULTS: Pulmonary phenotypes, including airflow limitation, emphysema, lung hyperinflation, diffusion capacity, and radiographic measures of airway remodeling, showed weak to moderate correlations (r < 0.7) with each other. In multivariate models adjusted for pulmonary phenotypes and CAD risk factors, lung hyperinflation was the only phenotype associated with calcium score, history of clinical CAD, or history of MI (per 0.2 higher expiratory and inspiratory CT scan lung volume; coronary calcium: OR, 1.2; 95% CI, 1.1-1.5; P = .02; clinical CAD: OR, 1.6; 95% CI, 1.1-2.3; P = .01; and MI in COPDGene: OR, 1.7; 95% CI, 1.0-2.8; P = .05). FEV(1) and emphysema were associated with increased risk of CAD (P < .05) in models adjusted for CAD risk factors; however, these associations were attenuated on adjusting for lung hyperinflation. Results were the same in those with airflow obstruction and were present in both cohorts. INTERPRETATION: Lung hyperinflation is associated strongly with clinical and subclinical CAD in smokers, including those with airflow obstruction. After lung hyperinflation was accounted for, FEV(1) and emphysema no longer were associated with CAD. Subsequent studies should consider measuring lung hyperinflation and examining its mechanistic role in CAD in current and former smokers.

Published
2021

2. Alpha-1 Antitrypsin MZ Heterozygosity Is an Endotype of Chronic Obstructive Pulmonary Disease

Author

Auyon J. Ghosh, Brian D. Hobbs, Matthew Moll, Aabida Saferali, Adel Boueiz, Jeong H. Yun, Frank Sciurba, Lucas Barwick, Andrew H. Limper, Kevin Flaherty, Gerard Criner, Kevin K. Brown, Robert Wise, Fernando J. Martinez, David Lomas, Peter J. Castaldi, Vincent J. Carey, Dawn L. DeMeo, Michael H. Cho, Edwin K. Silverman, Craig P. Hersh, James D. Crapo, Barry J. Make, Elizabeth A. Regan, Terri H. Beaty, Adel El-Boueiz, Marilyn G. Foreman, Lystra P. Hayden, Jacqueline Hetmanski, John E. Hokanson, Wonji Kim, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Dmitry Prokopenko, Jarrett Morrow, Dandi Qiao, Phuwanat Sakornsakolpat, Emily S. Wan, Juan Pablo Centeno, Jean-Paul Charbonnier, Harvey O. Coxson, Craig J. Galban, MeiLan K. Han, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, David A. Lynch, Pietro Nardelli, John D. Newell, Aleena Notary, Andrea Oh, James C. Ross, Raul San Jose Estepar, Joyce Schroeder, Jered Sieren, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, Gonzalo Vegas Sanchez-Ferrero, Lucas Veitel, George R. Washko, Carla G. Wilson, Robert Jensen, Douglas Everett, Jim Crooks, Katherine Pratte, Matt Strand, Erin Austin, Gregory Kinney, Kendra A. Young, Surya P. Bhatt, Jessica Bon, Alejandro A. Diaz, Barry Make, Susan Murray, Elizabeth Regan, Xavier Soler, Russell P. Bowler, Katerina Kechris, Farnoush Banaei-Kashani, Jeffrey L. Curtis, Perry G. Pernicano, Nicola Hanania, Mustafa Atik, Aladin Boriek, Kalpatha Guntupalli, Elizabeth Guy, Amit Parulekar, Craig Hersh, George Washko, R. Graham Barr, John Austin, Belinda D’Souza, Byron Thomashow, Neil MacIntyre, H. Page McAdams, Lacey Washington, Charlene McEvoy, Joseph Tashjian, Robert Brown, Nadia N. Hansel, Karen Horton, Allison Lambert, Nirupama Putcha, Richard Casaburi, Alessandra Adami, Matthew Budoff, Hans Fischer, Janos Porszasz, Harry Rossiter, William Stringer, Amir Sharafkhaneh, Charlie Lan, Christine Wendt, Brian Bell, Ken M. Kunisaki, Eric L. Flenaugh, Hirut Gebrekristos, Mario Ponce, Silanath Terpenning, Gloria Westney, Richard Rosiello, David Pace, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D’Alonzo, Parag Desai, Michael Jacobs, Steven Kelsen, Victor Kim, A. James Mamary, Nathaniel Marchetti, Aditi Satti, Kartik Shenoy, Robert M. Steiner, Alex Swift, Irene Swift, Maria Elena Vega-Sanchez, Mark Dransfield, William Bailey, Anand Iyer, Hrudaya Nath, J. Michael Wells, Douglas Conrad, Andrew Yen, Alejandro P. Comellas, Karin F. Hoth, John Newell, Brad Thompson, Ella Kazerooni, Wassim Labaki, Craig Galban, Dharshan Vummidi, Joanne Billings, Abbie Begnaud, Tadashi Allen, Divay Chandra, Joel Weissfeld, Antonio Anzueto, Sandra Adams, Diego Maselli-Caceres, Mario E. Ruiz, and Harjinder Singh

Subjects
Male, Endotype, Respiratory System, Critical Care and Intensive Care Medicine, Medical and Health Sciences, Gastroenterology, Loss of heterozygosity, Pulmonary Disease, Chronic Obstructive, Genotype, 80 and over, 2.1 Biological and endogenous factors, Medicine, Longitudinal Studies, Aetiology, Lung, Aged, 80 and over, COPD, RNA sequencing, Middle Aged, Respiratory Function Tests, medicine.anatomical_structure, Phenotype, Meta-analysis, Respiratory, Female, alpha-1 antitrypsin, Genetic Markers, Adult, Pulmonary and Respiratory Medicine, Chronic Obstructive, Heterozygote, medicine.medical_specialty, Chronic Obstructive Pulmonary Disease, Pulmonary disease, Pulmonary Disease, Clinical Research, Internal medicine, alpha 1-Antitrypsin Deficiency, Humans, Allele, Aged, Emphysema, COPDGene Investigators, Whole Genome Sequencing, business.industry, Original Articles, medicine.disease, Survival Analysis, respiratory tract diseases, meta-analysis, alpha 1-Antitrypsin, Case-Control Studies, business
Abstract

RATIONALE: Multiple studies have demonstrated an increased risk of chronic obstructive pulmonary disease (COPD) in heterozygous carriers of the AAT (alpha-1 antitrypsin) Z allele. However, it is not known if MZ subjects with COPD are phenotypically different from noncarriers (MM genotype) with COPD. OBJECTIVES: To assess if MZ subjects with COPD have different clinical features compared with MM subjects with COPD. METHODS: Genotypes of SERPINA1 were ascertained by using whole-genome sequencing data in three independent studies. We compared outcomes between MM subjects with COPD and MZ subjects with COPD in each study and combined the results in a meta-analysis. We performed longitudinal and survival analyses to compare outcomes in MM and MZ subjects with COPD over time. MEASUREMENTS AND MAIN RESULTS: We included 290 MZ subjects with COPD and 6,184 MM subjects with COPD across the three studies. MZ subjects had a lower FEV(1)% predicted and greater quantitative emphysema on chest computed tomography scans compared with MM subjects. In a meta-analysis, the FEV(1) was 3.9% lower (95% confidence interval [CI], −6.55% to −1.26%) and emphysema (the percentage of lung attenuation areas

Published
2021

3. Longitudinal Association Between Muscle Loss and Mortality in Ever Smokers

Author

Stefanie E. Mason, Rafael Moreta-Martinez, Wassim W. Labaki, Matthew J. Strand, Elizabeth A. Regan, Jessica Bon, Ruben San Jose Estepar, Richard Casaburi, Merry-Lynn McDonald, Harry B. Rossiter, Barry Make, Mark T. Dransfield, MeiLan K. Han, Kendra Young, Jeffrey L. Curtis, Kathleen Stringer, Greg Kinney, John E. Hokanson, Raul San Jose Estepar, George R. Washko, James D. Crapo, Edwin K. Silverman, Sara Cummings, Kelley Madden, Barry J. Make, Juliet Nabbosa, Emily Port, Serine Rashdi, Lori Stepp, Shandi Watts, Michael Weaver, Terri Beaty, Russell P. Bowler, David A. Lynch, Gary Anderson, Eugene R. Bleecker, Harvey O. Coxson, Ronald G. Crystal, James C. Hogg, Michael A. Province, Stephen I. Rennard, Thomas Croxton, Weiniu Gan, Lisa A. Postow, Lisa M. Viviano, Corinne Costa-Davis, Elisha Malanga, Delia Prieto, Ruth Tal-Singer, Homayoon Farzadegan, Akila Hadji, Leena Sathe, David Baraghoshi, Grace Chen, James Crooks, Ruthie Knowles, Katherine Pratte, Carla Wilson, Pearlanne T. Zelarney, Katerina J. Kechris, Sonia Leach, Erin E. Austin, Annika Czizik, Gregory Kinney, Yisha Li, Sharon M. Lutz, Margaret F. Ragland, Nicole Richmond, Kendra A. Young, Michael Cho, Peter J. Castaldi, Kimberly Glass, Craig Hersh, Wonji Kim, Yang-Yu Liu, Craig P. Hersh, Jacqueline Bidinger, Michael H. Cho, Douglas Conrad, Dawn L. DeMeo, Adel R. El-Boueiz, Marilyn G. Foreman, Auyon Ghosh, Georg Hahn, Nadia N. Hansel, Lystra P. Hayden, Brian Hobbs, Woori Kim, Christoph Lange, Merry- Lynn McDonald, Michael McGeachie, Matthew Moll, Melody Morris, Nikolaos A. Patsopoulos, Dandi Qiao, Ingo Ruczinski, Emily S. Wan, Jennifer G. Dy, Sean B. Fain, Shoshana Ginsburg, Eric A. Hoffman, Stephen Humphries, Philip F. Judy, Alex Kluiber Stefanie Mason, Andrea Oh, Clare Poynton, Joseph M. Reinhardt, James Ross, Joyce D. Schroeder, Arkadiusz Sitek, Robert M. Steiner, Edwin van Beek, Bram van Ginneken, Eva van Rikxoort, Robert Jensen, Co-Chair: John E. Hokanson, Surya P. Bhatt, Victor Kim, Nirupama Putcha, MeiLan Han, Alejandro A. Diaz, Elizabeth Regan, Antonio Anzueto, William C. Bailey, Gerard J. Criner, Kim Sprenger, Takis Benos, Nicola A. Hanania, Karin F. Hoth, Allison Lambert, Katherine Lowe, Gabriela Oates, Trisha Parekh, Gloria Westney, Aparna Balasubramanian, Aladin Boriek, Ashraf Fawzy, Francine Jacobson, David C. LaFon, Neil MacIntyre, Diego Maselli-Caceres, Meredith C. McCormack, Frank Sciurba, Xavier Soler, Vickram Tejwani, Edwin JR. van Beek, Raymond C. Wade, Mike Wells, Chris H. Wendt, Jeong H. Yun, Jingzhou Zhang, Lucas Gillenwater, Katherine E. Lowe, Katherine A. Pratte, Margaret Ragland, Amy Attaway, Stefanie Mason, Punam Kumar Saha, Ava Wilson, Hannatu Amaza, Adrienne Baldomero, A. James Mamary, James O’Brien, Robert A. Wise, Michelle Eakin, Jess G. Fiedorowicz, Ben Henkle, Kristen Holm, Anand Iyer, Ken M. Kunisaki, Charlene McEvoy, Takudzwa Mkorombindo, Gen Shinozaki, Abebaw Yohannes, Brian D. Hobbs, Bruce E. Miller, Tara Retson, Lisa McCloskey, Perry G. Pernicano, Mustafa Atik, Laura Bertrand, Thomas Monaco, Dharani Narendra, Veronica V. Lenge de Rosen, Kwame Badu-Danso, Francine L. Jacobson, Laura Kaufman, Cherie Maguire, Sophie Struble, Seth Wilson, R. Graham Barr, Casandra Almonte, John H.M. Austin, Maria Lorena Gomez Blum, Belinda M. D’Souza, Emilay Florez, Rodney Martinez, Wendy Curry, H. Page McAdams, Charlotte V. Reikofski, Lacey Washington, Robert Brown, Cheryl Clare, Marie Daniel, Karen Horton, Cheng Ting 'Tony' Lin, Tahira Mirza, Meagan Scott, Becky Shade, Matt Budoff, Robert Calmelat, Deborah Cavanaugh, Chris Dailing, Leticia Diaz, Hans Fischer, Renee Love Indelicato, Janos Porszasz, April Soriano, William Stringer, Miriam Urrutia, Arianne Baldomero, Brian Bell, Miranda Deconcini, Linda Loes, Jonathan Phelan, Camille Robichaux, Cheryl Sasse, Joseph H. Tashjian, Eric L. Flenaugh, Kema Abson, Hirut Gebrekristos, Priscilla Johnson, Jessica Jordan, Mario Ponce, Silanath Terpenning, Derrick Wilson, Grace Broadhurst, Debra Dyer, Elena Engel, Jay Finigan, Andrew Hill, Alex Jones, Ryan Jones, Jordan Owen, Richard Rosiello, Nicole Andries, Mary Charpentier, Diane Kirk, David Pace, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D’Alonzo, Valena Davis, Parag Desai, Dee Fehrle, Carla Grabianowski, Michael Jacobs, Laurie Jameson, Gayle M. Jones, Steven Kelsen, Nathaniel Marchetti, Francine McGonagle, Aditi Satti, Kartik Shenoy, Regina Sheridan, Maria Vega-Sanchez, Samantha Wallace, Samuel Akinseye-kolapo, Matthew Baker, Arnissa Goggins, Anny McClain, Hrudaya Nath, Satinder P. Singh, Sushil K. Sonavane, Elizabeth Westfall, Marissa Gil, Tarek El Hajjaoui, Albert Hsiao, Amber Martineau, Jenna Mielke, Karl Perez, Gabriel Querido, Tara Reston, Andrew Yen, Alejandro Comellas, Spyridon Fortis, Mauricio Galizia, Eric Garcia, Janet Keating, Archana Laroia, Changhyun Lee, Amber Meyer, Brian Mullan, Prashant Nagpal, Oloigbe Ofori, and Sierra Suiter

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, Chronic Obstructive, Clinical Sciences, Respiratory System, Critical Care and Intensive Care Medicine, COPD: Original Research, Body Mass Index, Pectoralis Muscles, Pulmonary Disease, sarcopenia, Pulmonary Disease, Chronic Obstructive, Interquartile range, Clinical Research, Internal medicine, medicine, Tobacco Smoking, COPD, 2.1 Biological and endogenous factors, Humans, Longitudinal Studies, Aetiology, Pectoralis Muscle, Lung, Nutrition, Smokers, COPDGene Investigators, Proportional hazards model, business.industry, Prevention, Smoking, muscle wasting, medicine.disease, mortality, Confidence interval, Good Health and Well Being, Sarcopenia, Cardiology, Body Composition, Cardiology and Cardiovascular Medicine, business, Body mass index, Bioelectrical impedance analysis, Biomarkers
Abstract

BackgroundBody composition measures, specifically low weight or reduced muscle mass, are associated with mortality in COPD, but the effect of longitudinal body composition changes is undefined.Research questionIs the longitudinal loss of fat-free mass (FFM) associated with increased mortality, including in those with initially normal or elevated body composition metrics?Study design and methodsParticipants with complete data for at least one visit in the COPDGene study (n= 9,268) and the ECLIPSE study (n= 1,760) were included and monitored for 12 and 8 years, respectively. Pectoralis muscle area (PMA) was derived from thoracic CT scans and used as a proxy for FFM. A longitudinal mixed submodel for PMA and a Cox proportional hazards submodel for survival were fitted on a joint distribution, using a shared random intercept parameter and Markov chain Monte Carlo parameter estimation.ResultsBoth cohorts demonstrated a left-shifted distribution of baseline FFM, not reflected in BMI, and an increase in all-cause mortality risk associated with longitudinal loss of PMA. For each 1-cm2 PMA loss, mortality increased 3.1%(95%CI, 2.4%-3.7%; P< .001) in COPDGene, and 2.4%(95%CI, 0.9%-4.0%; P< .001) in ECLIPSE. Increased mortality risk was independent of enrollment values for BMI and disease severity [BODE (body mass, airflow obstruction, dyspnea, and exercise capacity) index quartiles] and was significant even in participants with initially greater than average PMA.InterpretationLongitudinal loss of PMA is associated with increased all-cause mortality, regardless of BMI or initial muscle mass. Consideration of novel screening tests and further research into mechanisms contributing to muscle decline may improve risk stratification and identify novel therapeutic targets in ever smokers.

Published
2021

4. Emphysema Progression and Lung Function Decline Among Angiotensin Converting Enzyme Inhibitors and Angiotensin-Receptor Blockade Users in the COPDGene Cohort

Author

Vickram Tejwani, Ashraf Fawzy, Nirupama Putcha, Peter J. Castaldi, Michael H. Cho, Katherine A. Pratte, Surya P. Bhatt, David A. Lynch, Stephen M. Humphries, Gregory L. Kinney, Franco R. D’Alessio, Nadia N. Hansel, James D. Crapo, Edwin K. Silverman, Barry J. Make, Elizabeth A. Regan, Terri Beaty, Ferdouse Begum, Michael Cho, Dawn L. DeMeo, Adel R. Boueiz, Marilyn G. Foreman, Eitan Halper-Stromberg, Lystra P. Hayden, Craig P. Hersh, Jacqueline Hetmanski, Brian D. Hobbs, John E. Hokanson, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Margaret M. Parker, Dmitry Prokopenko, Dandi Qiao, Phuwanat Sakornsakolpat, Emily S. Wan, Sungho Won, Juan Pablo Centeno, Jean-Paul Charbonnier, Harvey O. Coxson, Craig J. Galban, MeiLan K. Han, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, Pietro Nardelli, John D. Newell, Aleena Notary, Andrea Oh, James C. Ross, Raul San Jose Estepar, Joyce Schroeder, Jered Sieren, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bramvan Ginneken, Eva van Rikxoort, Gonzalo Vegas Sanchez-Ferrero, Lucas Veitel, George R. Washko, Carla G. Wilson, Robert Jensen, Douglas Everett, Jim Crooks, Katherine Pratte, Matt Strand, Gregory Kinney, Kendra A. Young, Jessica Bon, Alejandro A. Diaz, Barry Make, Susan Murray, Elizabeth Regan, Xavier Soler, Russell P. Bowler, Katerina Kechris, Farnoush Banaei-Kashani, Jeffrey L. Curtis, Perry G. Pernicano, Nicola Hanania, Mustafa Atik, Aladin Boriek, Kalpatha Guntupalli, Elizabeth Guy, Amit Parulekar, Craig Hersh, George Washko, R. Graham Barr, John Austin, Belinda D’Souza, Byron Thomashow, Neil MacIntyre, H. Page McAdams, Lacey Washington, Eric Flenaugh, Silanth Terpenning, Charlene McEvoy, Joseph Tashjian, Robert Wise, Robert Brown, Karen Horton, Allison Lambert, Richard Casaburi, Alessandra Adami, Matthew Budoff, Hans Fischer, Janos Porszasz, Harry Rossiter, William Stringer, Amir Sharafkhaneh, Charlie Lan, Christine Wendt, Brian Bell, KenM. Kunisaki, Russell Bowler, Richard Rosiello, David Pace, Gerard Criner, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D’Alonzo, Parag Desai, Michael Jacobs, Steven Kelsen, Victor Kim, A. James Mamary, Nathaniel Marchetti, Aditi Satti, Kartik Shenoy, Robert M. Steiner, Alex Swift, Irene Swift, Maria Elena Vega-Sanchez, Mark Dransfield, William Bailey, Anand Iyer, Hrudaya Nath, J. Michael Wells, Douglas Conrad, Andrew Yen, Alejandro P. Comellas, Karin F. Hoth, John Newell, Brad Thompson, Ella Kazerooni, Wassim Labaki, Craig Galban, Dharshan Vummidi, Joanne Billings, Abbie Begnaud, Tadashi Allen, Frank Sciurba, Divay Chandra, Carl Fuhrman, and Joel Weissfeld

Subjects
Pulmonary and Respiratory Medicine, Male, Angiotensin receptor, medicine.medical_specialty, Population, Vital Capacity, Angiotensin-Converting Enzyme Inhibitors, Walk Test, Critical Care and Intensive Care Medicine, Cohort Studies, 03 medical and health sciences, Angiotensin Receptor Antagonists, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Internal medicine, Forced Expiratory Volume, Medicine, Humans, cardiovascular diseases, 030212 general & internal medicine, Prospective Studies, education, Aged, COPD, education.field_of_study, Lung, biology, business.industry, Angiotensin-converting enzyme, respiratory system, Middle Aged, Protective Factors, medicine.disease, Angiotensin II, respiratory tract diseases, medicine.anatomical_structure, 030228 respiratory system, Genetic epidemiology, Pulmonary Emphysema, Spirometry, Cohort, biology.protein, Cardiology, Disease Progression, Female, Cardiology and Cardiovascular Medicine, business, Lung Volume Measurements, Tomography, X-Ray Computed
Abstract

Background Attenuation of transforming growth factor β by blocking angiotensin II has been shown to reduce emphysema in a murine model. General population studies have demonstrated that the use of angiotensin converting enzyme inhibitors (ACEis) and angiotensin-receptor blockers (ARBs) is associated with reduction of emphysema progression in former smokers and that the use of ACEis is associated with reduction of FEV1 progression in current smokers. Research Question Is use of ACEi and ARB associated with less progression of emphysema and FEV1 decline among individuals with COPD or baseline emphysema? Methods Former and current smokers from the Genetic Epidemiology of COPD Study who attended baseline and 5-year follow-up visits, did not change smoking status, and underwent chest CT imaging were included. Adjusted linear mixed models were used to evaluate progression of adjusted lung density (ALD), percent emphysema (%total lung volume Results Over 5 years of follow-up, compared with nonusers, ACEi and ARB users with COPD showed slower ALD progression (adjusted mean difference [aMD], 1.6; 95% CI, 0.34-2.9). Slowed lung function decline was not observed based on phase 1 medication (aMD of FEV1 % predicted, 0.83; 95% CI, –0.62 to 2.3), but was when analysis was limited to consistent ACEi and ARB users (aMD of FEV1 % predicted, 1.9; 95% CI, 0.14-3.6). No effect modification by smoking status was found for radiographic outcomes, and the lung function effect was more pronounced in former smokers. Results were similar among participants with baseline emphysema. Interpretation Among participants with spirometry-confirmed COPD or baseline emphysema, ACEi and ARB use was associated with slower progression of emphysema and lung function decline. Trial Registry ClinicalTrials.gov ; No.: NCT00608764; URL: www.clinicaltrials.gov

Published
2020

5. Lobar Emphysema Distribution Is Associated With 5-Year Radiological Disease Progression

Author

Adel Boueiz, Yale Chang, Michael H. Cho, George R. Washko, Raul San José Estépar, Russell P. Bowler, James D. Crapo, Dawn L. DeMeo, Jennifer G. Dy, Edwin K. Silverman, Peter J. Castaldi, James Crapo, Edwin Silverman, Barry Make, Elizabeth Regan, Terri Beaty, Nan Laird, Christoph Lange, Stephanie Santorico, John Hokanson, Dawn DeMeo, Nadia Hansel, Craig Hersh, Peter Castaldi, Merry-Lynn McDonald, Emily Wan, Megan Hardin, Jacqueline Hetmanski, Margaret Parker, Marilyn Foreman, Brian Hobbs, Robert Busch, Dandi Qiao, Eitan Halper-Stromberg, Ferdouse Begum, Sungho Won, Sharon Lutz, David A. Lynch, Harvey O. Coxson, MeiLan K. Han, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, John D. Newell, James C. Ross, Raul José Estépar, Berend C. Stoel, Juerg Tschirren, Eva van Rikxoort, Bram van Ginneken, Carla G. Wilson, Mustafa Al Qaisi, Teresa Gray, Alex Kluiber, Tanya Mann, Jered Sieren, Douglas Stinson, Joyce Schroeder, Edwin Van Beek, Robert Jensen, Douglas Everett, Anna Faino, Matt Strand, Carla Wilson, John E. Hokanson, Gregory Kinney, Kendra Young, Katherine Pratte, Lindsey Duca, Jeffrey L. Curtis, Carlos H. Martinez, Perry G. Pernicano, Nicola Hanania, Philip Alapat, Venkata Bandi, Mustafa Atik, Aladin Boriek, Kalpatha Guntupalli, Elizabeth Guy, Amit Parulekar, Arun Nachiappan, Francine Jacobson, R. Graham Barr, Byron Thomashow, John Austin, Belinda D’Souza, Gregory D.N. Pearson, Anna Rozenshtein, Neil MacIntyre, Lacey Washington, H. Page McAdams, Charlene McEvoy, Joseph Tashjian, Robert Wise, Robert Brown, Karen Horton, Nirupama Putcha, Richard Casaburi, Alessandra Adami, Janos Porszasz, Hans Fischer, Matthew Budoff, Harry Rossiter, Amir Sharafkhaneh, Charlie Lan, Christine Wendt, Brian Bell, Gloria Westney, Eugene Berkowitz, Russell Bowler, David Lynch, Richard Rosiello, David Pace, Gerard Criner, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D’Alonzo, Parag Desai, Michael Jacobs, Steven Kelsen, Victor Kim, A. James Mamary, Nathaniel Marchetti, Aditi Satti, Kartik Shenoy, Robert M. Steiner, Alex Swift, Irene Swift, Maria Elena Vega-Sanchez, Mark Dransfield, William Bailey, J. Michael Wells, Surya Bhatt, Hrudaya Nath, Joe Ramsdell, Paul Friedman, Xavier Soler, Andrew Yen, Alejandro Cornellas, John Newell, Brad Thompson, MeiLan Han, Ella Kazerooni, Carlos Martinez, Joanne Billings, Tadashi Allen, Frank Sciurba, Divay Chandra, Joel Weissfeld, Carl Fuhrman, Jessica Bon, Antonio Anzueto, Sandra Adams, Diego Maselli-Caceres, and Mario E. Ruiz

Subjects
Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Pathology, Genome-wide association study, Comorbidity, Critical Care and Intensive Care Medicine, Severity of Illness Index, Gastroenterology, 03 medical and health sciences, FEV1/FVC ratio, 0302 clinical medicine, Forced Expiratory Volume, Internal medicine, medicine, Humans, COPD, Distribution (pharmacology), 030212 general & internal medicine, Aged, business.industry, Middle Aged, respiratory system, medicine.disease, respiratory tract diseases, Pulmonary Emphysema, 030228 respiratory system, Genetic epidemiology, Radiological weapon, Cohort, Disease Progression, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Female, Metabolic syndrome, Tomography, X-Ray Computed, Cardiology and Cardiovascular Medicine, business, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Contains fulltext : 194255.pdf (Publisher’s version ) (Open Access) BACKGROUND: Emphysema has considerable variability in its regional distribution. Craniocaudal emphysema distribution is an important predictor of the response to lung volume reduction. However, there is little consensus regarding how to define upper lobe-predominant and lower lobe-predominant emphysema subtypes. Consequently, the clinical and genetic associations with these subtypes are poorly characterized. METHODS: We sought to identify subgroups characterized by upper-lobe or lower-lobe emphysema predominance and comparable amounts of total emphysema by analyzing data from 9,210 smokers without alpha-1-antitrypsin deficiency in the Genetic Epidemiology of COPD (COPDGene) cohort. CT densitometric emphysema was measured in each lung lobe. Random forest clustering was applied to lobar emphysema variables after regressing out the effects of total emphysema. Clusters were tested for association with clinical and imaging outcomes at baseline and at 5-year follow-up. Their associations with genetic variants were also compared. RESULTS: Three clusters were identified: minimal emphysema (n = 1,312), upper lobe-predominant emphysema (n = 905), and lower lobe-predominant emphysema (n = 796). Despite a similar amount of total emphysema, the lower-lobe group had more severe airflow obstruction at baseline and higher rates of metabolic syndrome compared with subjects with upper-lobe predominance. The group with upper-lobe predominance had greater 5-year progression of emphysema, gas trapping, and dyspnea. Differential associations with known COPD genetic risk variants were noted. CONCLUSIONS: Subgroups of smokers defined by upper-lobe or lower-lobe emphysema predominance exhibit different functional and radiological disease progression rates, and the upper-lobe predominant subtype shows evidence of association with known COPD genetic risk variants. These subgroups may be useful in the development of personalized treatments for COPD.

Published
2018

6. Combined Forced Expiratory Volume in 1 Second and Forced Vital Capacity Bronchodilator Response, Exacerbations, and Mortality in Chronic Obstructive Pulmonary Disease

Author

Spyridon Fortis, Alejandro Comellas, Barry J. Make, Craig P. Hersh, Sandeep Bodduluri, Dimitris Georgopoulos, Victor Kim, Gerard J. Criner, Mark T. Dransfield, Surya P. Bhatt, James D. Crapo, Edwin K. Silverman, Elizabeth A. Regan, Terri Beaty, Ferdouse Begum, Robert Busch, Peter J. Castaldi, Michael Cho, Dawn L. DeMeo, Adel R. Boueiz, Marilyn G. Foreman, Eitan Halper-Stromberg, Nadia N. Hansel, Megan E. Hardin, Lystra P. Hayden, Jacqueline Hetmanski, Brian D. Hobbs, John E. Hokanson, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Margaret M. Parker, Dandi Qiao, Stephanie Santorico, Emily S. Wan, Sungho Won, Mustafa Al Qaisi, Harvey O. Coxson, Teresa Gray, MeiLan K. Han, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, David A. Lynch, John D. Newell, James C. Ross, Raul San Jose Estepar, Joyce Schroeder, Jered Sieren, Douglas Stinson, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, George Washko, Carla G. Wilson, Robert Jensen, Douglas Everett, Jim Crooks, Camille Moore, Matt Strand, John Hughes, Gregory Kinney, Katherine Pratte, Kendra A. Young, Jeffrey L. Curtis, Carlos H. Martinez, Perry G. Pernicano, Nicola Hanania, Philip Alapat, Mustafa Atik, Venkata Bandi, Aladin Boriek, Kalpatha Guntupalli, Elizabeth Guy, Arun Nachiappan, Amit Parulekar, Craig Hersh, R. Graham Barr, John Austin, Belinda D’Souza, Gregory D.N. Pearson, Anna Rozenshtein, Byron Thomashow, Neil MacIntyre, H. Page McAdams, Lacey Washington, Charlene McEvoy, Joseph Tashjian, Robert Wise, Robert Brown, Karen Horton, Allison Lambert, Nirupama Putcha, Richard Casaburi, Alessandra Adami, Matthew Budoff, Hans Fischer, Janos Porszasz, Harry Rossiter, William Stringer, Amir Sharafkhaneh, Charlie Lan, Christine Wendt, Brian Bell, Eugene Berkowitz, Gloria Westney, Russell Bowler, Richard Rosiello, David Pace, Gerard Criner, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D’Alonzo, Parag Desai, Michael Jacobs, Steven Kelsen, A. James Mamary, Nathaniel Marchetti, Aditi Satti, Kartik Shenoy, Robert M. Steiner, Alex Swift, Irene Swift, Maria Elena Vega-Sanchez, Mark Dransfield, William Bailey, Surya Bhatt, Anand Iyer, Hrudaya Nath, J. Michael Wells, Joe Ramsdell, Paul Friedman, Xavier Soler, Andrew Yen, Alejandro P. Comellas, John Newell, Brad Thompson, Ella Kazerooni, Joanne Billings, Abbie Begnaud, Tadashi Allen, Frank Sciurba, Jessica Bon, Divay Chandra, Carl Fuhrman, Joel Weissfeld, Antonio Anzueto, Sandra Adams, Diego Maselli-Caceres, and Mario E. Ruiz

Subjects
Pulmonary and Respiratory Medicine, Spirometry, Male, Vital capacity, medicine.medical_specialty, medicine.drug_class, Vital Capacity, Pulmonary disease, Risk Assessment, Severity of Illness Index, Cohort Studies, 03 medical and health sciences, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Internal medicine, Bronchodilator, Forced Expiratory Volume, medicine, Humans, 030212 general & internal medicine, Respiratory system, Asthma, Aged, Proportional Hazards Models, Retrospective Studies, Original Research, medicine.diagnostic_test, business.industry, Middle Aged, medicine.disease, Survival Analysis, respiratory tract diseases, Bronchodilator Agents, Respiratory Function Tests, Logistic Models, Treatment Outcome, 030228 respiratory system, Volume (thermodynamics), Multivariate Analysis, Cardiology, Disease Progression, Female, business, Tomography, X-Ray Computed
Abstract

Rationale: The American Thoracic Society (ATS)/European Respiratory Society defines a positive bronchodilator response (BDR) by a composite of BDR in either forced expiratory volume in 1 second (FEV(1)) and/or forced vital capacity (FVC) greater than or equal to 12% and 200 ml (ATS-BDR). We hypothesized that ATS-BDR components would be differentially associated with important chronic obstructive pulmonary disease (COPD) outcomes. Objectives: To examine whether ATS-BDR components are differentially associated with clinical, functional, and radiographic features in COPD. Methods: We included subjects with COPD enrolled in the COPDGene study. In the main analysis, we excluded subjects with self-reported asthma. We categorized BDR into the following: 1) No-BDR, no BDR in either FEV(1) or FVC; 2) FEV(1)-BDR, BDR in FEV(1) but no BDR in FVC; 3) FVC-BDR, BDR in FVC but no BDR in FEV(1); and 4) Combined-BDR, BDR in both FEV(1) and FVC. We constructed multivariable logistic, linear, zero-inflated negative binomial, and Cox hazards models to examine the association of BDR categories with symptoms, computed tomography findings, change in FEV(1) over time, respiratory exacerbations, and mortality. We also created models using the ATS BDR definition (ATS-BDR) as the main independent variable. Results: Of 3,340 COPD subjects included in the analysis, 1,083 (32.43%) had ATS-BDR, 182 (5.45%) had FEV(1)-BDR, 522 (15.63%) had FVC-BDR, and 379 (11.34%) had Combined-BDR. All BDR categories were associated with FEV(1) decline compared with No-BDR. Compared with No-BDR, both ATS-BDR and Combined-BDR were associated with higher functional residual capacity %predicted, greater internal perimeter of 10 mm, and greater 6-minute-walk distance. In contrast to ATS-BDR, Combined-BDR was independently associated with less emphysema (adjusted beta regression coefficient, −1.67; 95% confidence interval [CI], −2.68 to −0.65; P = 0.001), more frequent respiratory exacerbations (incidence rate ratio, 1.25; 95% CI, 1.03–1.50; P = 0.02) and severe exacerbations (incidence rate ratio, 1.34; 95% CI, 1.05–1.71; P = 0.02), and lower mortality (adjusted hazards ratio, 0.76; 95% CI, 0.58–0.99; P = 0.046). Sensitivity analysis that included subjects with self-reported history of asthma showed similar findings. Conclusions: BDR in both FEV(1) and FVC indicates a COPD phenotype with asthma-like characteristics, and provides clinically more meaningful information than current definitions of BDR.

Published
2019

7. Long-term safety and efficacy of benralizumab in patients with severe, uncontrolled asthma: 1-year results from the BORA phase 3 extension trial

Author

William W Busse, Eugene R Bleecker, J Mark FitzGerald, Gary T Ferguson, Peter Barker, Stephanie Sproule, Richard F Olsson, Ubaldo J Martin, Mitchell Goldman, Anahí Yañez, Marcelo Fernández, Alberto Tolcachier, Juan Belloni, Jorge Taborda, Maria De Salvo, Jorge Maspero, Carlos Victorio, Miguel Chirino Navarta, Monica Grilli, Pablo Rodríguez, María Otaola, Víctor Cambursano, Patricia Malamud, Ana Stok, German Arce, Osiris Roza, Fernando Scherbovsky, Pedro Elias, Maria Salazan Saez, Matthew Peters, Martin Phillips, John Upham, Peter Gibson, Francis Thien, Jo Douglass, Paul Thomas, Philip Bardin, Dimitar Sajkov, Mark Hew, David Langton, Andreia Pez, Carlos Fritscher, Jorge Hetzel, Waldo Mattos, Rafael Stelmach, Martti Antila, Ana Luisa Fernandes, Hristo Metev, Yavor Ivanov, Aneliya Bogdanova, Ana Dancheva Markova, Marinka Peneva, Rumyana Veselinova, Tatyana Petkova, Vanushka Petrova, Elena Shopova, Yuliya Ivanova, Rumyana Yotsova, Ginka Kirkova, Galina Petrova, Svetoslav Dachev, Kostadinka Sotirova, Mariyana Stoyanova, Oleg Yakov, Vanya Ilieva-Fartunova, Catherine Lemiere, Michel Laviolette, William Yang, Bonavuth Pek, William Patrick Killorn, Claude Poirier, Guy Chouinard, Lyle Melenka, Richard Leigh, Parameswaran Nair, Delbert Dorscheid, James Martin, Juana Pavie, Andres Rosenblut, Claudia Cartagena, Carlos Quilodran, Silvia Muñoz, Ivana Malkusova, Josef Veverka, Stanislav Holub, Jaroslav Mares, Radovan Kozel, Daniela Kopecka, Vladimir Zindr, Pavel Cerva, Pascal Chanez, Arnaud Bourdin, Gilles Devouassoux, Camille Taille, Frédéric De Blay, Francois Goupil, Christophe Leroyer, Delphine Gourcerol, Toufik Didi, Alain Didier, Gilles Garcia, Philippe Bonniaud, Riazate Rossanaly Vasram, Marek Lommatzsch, Ulf Harnest, Anneliese Linnhoff, Claus Keller, Gerhard Hoheisel, Karin Förster, Thomas Schultz, Isabelle Schenkenberger, Joachim Kirschner, Tibor Schmoller, Stefan Zielen, Marc Kornmann, Ekkehard Beck, Lutz Volgmann, Rolf Dichmann, Axel Overlack, Jörg Winkler, Petra Mikloweit, Sabine Ballenberger, Mathias Rolke, Stephanie Korn, Helmut Pabel, Martin Hoffmann, Jan Feimer, Klaus Rabe, Regina Deckelmann, Tobias Welte, Hiroyuki Ohbayashi, Soichiro Hozawa, Terufumi Shimoda, Makoto Yoshida, Toshikazu Nagakura, Tadashi Kamei, Yasuyuki Sano, Shinichiro Kagami, Hisaho Takahashi, Michiko Haida, Goro Kimura, Hiroyuki Nakamura, Yasuo To, Masaharu Shinkai, Tadasuke Shimokawaji, Makoto Kudo, Noriharu Shijyubo, Takao Tochigi, Motokazu Kato, Akihiko Tanaka, Yasuhiro Gon, Norihisa Sasaki, Tetsuro Ohdaira, Chiharu Omori, Toshiki Takahashi, Satomi Takeuchi, Kiyotaka Nakajima, Hironi Makita, Masahiro Kaneko, Kenjiro Furuta, Masami Taniguchi, Yoshito Inobe, Hiroshi Miki, Yoichi Nakamura, Naoki Miyazawa, Shuichi Yano, Masayuki Iijima, Tsuyoshi Yamato, Javier Diaz, Alberto Matsuno, Efrain Felix, Alfredo Guerreros, Alejandro Daly, Fernando Rodriguez Chariarse, Danilo Salazar, Socorro Castro, William Chavez, Rolando Estrella, Teresita Aquino, Tito Atienza, Ronnie Samoro, Marie Grace Dawn Isidro, Piotr Kuna, Adam Antczak, Michał Bednarek, Danuta Mądra-Rogacka, Teresa Hofman, Marek Jutel, Ewa Pisarczyk-Bogacka, Agata Kot, Robert Mróz, Małgorzata Czupryńska-Borkowska, Małgorzata Żurowska-Gębala, Andrzej Dyczek, Grażyna Jasieniak-Pinis, Piotr Wojnowski, Ewa Trębas-Pietraś, Małgorzata Dobryniewska, Marcin Stobiecki, Marzenna Tarnowska-Matusiak, Alina Magner, Andrzej Kolczyński, Tomasz Kachel, Zbigniew Bartuzi, Bernadetta Majorek-Olechowska, Paweł Śliwiński, Violetta Balicka, Elżbieta Hajoł, Jacek Stachera, Marta Rachel, Marek Michnar, Jarosław Tałałaj, Ewa Springer, Piotr Napora, Tomasz Grzelewski, Renata Bijata-Bronisz, Anna Świderska, Grzegorz Mincewicz, Zbigniew Sankowski, Tomasz Fijołek, Artur Kwaśniewski, Joanna Jerzyńska, Jerzy Cygler, Ryszard Olesiejuk, Iwona Von Steiner, Wojciech Machowiak, Krzysztof Filipek, Piotr Piskorz, Ewa Uhryn, Marita Nittner-Marszalska, Elżbieta Rybicka-Liszewska, Anna Bodzenta-Łukaszyk, Marta Chełmińska, Izabella Krupa-Borek, Wojciech Skucha, Anna Płoszczuk, Traian Mihaescu, Ioan Dorin Petrui, Angelica Savu, Ghiulten Apti, Claudia Toma, Ana Trailescu, Sergei Sokurenko, Vasiliy Trofimov, Igor Leshchenko, Natalia Shaporova, Inna Ilyashevich, Irina Stitsenko, Alexander Vizel, Yulia Ilkovich, Dmitrii Tikhanov, Svetlana Goncharova, Andrey Ezhov, Galina Ignatova, Nadezhda Izmozherova, Nadezhda Berdnikova, Ludmila Goryachkina, Veronika Popova, Laura Bolieva, Andrey Rebrov, Vladimir Nosov, Olga Magnitskaya, Sergey Nedogoda, Vladimir Abrosimov, Artem Molotkov, Galina Reshedko, Mikhail Smirnov, Marina Osipenko, Elena Pavlysh, Svetlana Myasoedova, Liudmila Lenskaya, Valery Chistyakov, Elena Vishneva, Liliya Uon, Anna Zateyschikova, Svetlana Laleko, Tatiana Pak, Axel Bruning, Visvakuren Naidoo, Jeevren Reddy, Richard Van Zyl Smit, Hae-Sim Park, Young Joo Cho, Sang-Heon Cho, Sang Haak Lee, Byung Jae Lee, Ju Sang Kim, You Sook Cho, Choon-Sik Park, Mi-Kyeong Kim, Young-Il Koh, Joo-Hee Kim, Sook Young Lee, Sang Pyo Lee, Jung Won Park, Kwang Ha Yoo, Hyoungkyu Yoon, Jaechun Lee, Gyu-Young Hur, Soo Keol Lee, HeeKyoo Kim, David Ramos Barbón, Elena Laffond Yges, Eva Martínez Moragón, Miguel Arias Guillen, Alberto Saura Vinuesa, Fernando Sánchez-Toril López, José Luis Velasco Garrido, Borja García-Cosio Piqueras, Luis Pérez de Llano, Antonio Luis Valero Santiago, Myriam Calle Rubio, Leif Bjermer, Bo Lundbäck, Bilun Gemicioglu, Sevim Bavbek, Dane Ediger, Munevver Erdinc, Ismail Hanta, Sibel Nayci, Sibel Arinc, Liudmyla Iashyna, Yuriy Mostovoy, Mykola Ostrovskyy, Lesia Kuryk, Ivan Lemko, Tetyana Ospanova, Liubov Moskalenko, Oleksii Korzh, Viktor Blazhko, Olena Krakhmalova, Liliia Romaniuk, Yevgeniya Dytyatkovs'ka, Oleh Yakovenko, Volodymyr Gavrysyuk, Hassan Burhan, Dinesh Saralaya, Stephen Scott, Alyn Morice, Ewart Jackson-Voyzey, Thida Win, Shuab Nasser, Richard Harrison, Rekha Chaudhuri, Monica Nordstrom, Pradip De, Matthew Masoli, Adel Mansur, Anthony Gunstone, Robert Niven, Timothy Harrison, Suresh Babu, Subodh Bhuchar, Shahrukh Kureishy, John Zwetchkenbaum, Lawrence Kaplan, Eugene Bleecker, Santiago Reyes, Faisal Fakih, Marvin Heuer, Ryan Klein, Michael Marcus, Iftikhar Hussain, Tonny Tanus, Hengameh Raissy, Sady Alpizar, Hector Rodriguez, Gerald Gleich, Tracy Bridges, Joe Pouzar, Gary Steven, Jonathan Matz, Shana Krstevska, Dama Ziworitin, Adolfo Kaplan, James Sublett, James DeAngelo, Amy Darter, John Agaiby, John Hagan, Enrique Davis, Dareen Siri, Charlene Mcevoy, Chrisette Dharma, Najmuddin Karimjee, Steven Kelsen, Manuel Frade, Amy Silverthorn, Joel Kline, Francis Averill, Jose Ruiz, Emory Robinette, Zeeshan Shaikh, Carlos Aguilar, William Nish, German Alvarez, Younus Ismail, Purvi Parikh, Mila Leong, Dennis Murphy, Francisco Garcia, Alan Goldsobel, Antonio Blanco, Edward Campbell, Guido Perez, Geoffrey Chupp, Toby Bates, Vandely Perez, Sally Wenzel, Kartik Shenoy, Rohit Katial, David Bernstein, Neil Parikh, William Sims, Gary Ferguson, David Pham, Anu George, Richard Beasley, Gilberto Perez, Robert Garver, Miriam Garcia-Portela, Stephen Wong, Weily Soong, Richard Guillot, Golda Hudes, Ahmed Arif, Josefa Binker, Manuel Villareal, Ulrike Ziegner, Joseph Ojile, Sanjeev Goswami, Carlos Piniella, Ilia Segal, Heidi Zafra, Mitchell Lee, Martha Tarpay, John Panuto, Rajan Merchant, Peter Springsteen, Timothy Scialla, Paul Shapero, Karen Allen, Mark Moss, Humberto Cruz, Jeffrey Rumbyrt, Amy Boyd, Robert Nathan, Jonathan Bernstein, Joshua Jacobs, Elliot Ginchansky, Janice Johnston, Barbara Baxter, Thomas Johnson II, Stephen Apaliski, Clinton Corder, David Fuentes, Joseph Diaz, Chau Ngo, Lan Le, Department of Medicine, University of Wisconsin-Madison-School of Medicine and Public Health, Fundación Cidea Allergy and Respiratory Research Unit, University of Oxford [Oxford], University of Newcastle, Newcastle, NSW Australia., Defence Science and Technology Laboratory (Dstl), Ministry of Defence (UK) (MOD), Organização Multinacional de Formação, Agence Universitaire de la Francophonie (AUF), University of Calgary, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), laboratoire du sommeil, CHU Grenoble, Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Strasbourg, Centre Hospitalier du Mans, Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), CIC Brest, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche, Service de pneumologie, Centre hospitalier de la région d'Annecy, Cytokines, chimiokines et immunopathologie, Université Paris-Sud - Paris 11 (UP11)-IFR13-Institut National de la Santé et de la Recherche Médicale (INSERM), J.W. Goethe Universität, Institut für Geowissenschaften, Altenhöferallee 1, D-60438 Frankfurt am Main, Germany, Department of Pulmonary Medicine, Leiden University Medical Center (LUMC), Hannover Medical School [Hannover] (MHH), Japan Energy Corporation, Medical University of Łódź (MUL), Wroclaw Medical University, Saint-Petersburg State University, Physical Department, Petrodvoretz, 194508 St.-Petersburg, Russia, Physical Department (PD), St Petersburg State University (SPbU)-St Petersburg State University (SPbU), Ankara University, Oak Ridge National Laboratory [Oak Ridge] (ORNL), UT-Battelle, LLC, Department of Earth Sciences, University of Cambridge, University of Cambridge [UK] (CAM), Center for Genomics and Personalized Medicine, Wake Forest University, Mayo Clinic [Rochester], Department of Wildlife Management, Pir Mehr Ali Shah Arid Agriculture University, Lab Biotecnol Bacteriana, Inst Ciencia & Tecnol Alimentos & Nutr ICTAN, Universidade da Coruña, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO), Centre recherche en CardioVasculaire et Nutrition (C2VN), Université de Brest (UBO), University of Oxford, University of Newcastle [Callaghan, Australia] (UoN), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Universiteit Leiden-Universiteit Leiden, Wrocław Medical University, Department of Earth Sciences [University of Cambridge], and Pir Mehr Ali Shah Arid Agriculture University = PMAS-Arid Agriculture University Rawalpindi (AAUR)

Subjects
Adult, Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Adolescent, [SDV]Life Sciences [q-bio], Antibodies, Monoclonal, Humanized, Placebo, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Time, law.invention, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, law, Internal medicine, Clinical endpoint, Humans, Medicine, Anti-Asthmatic Agents, 030212 general & internal medicine, Child, Adverse effect, ComputingMilieux_MISCELLANEOUS, Aged, Asthma, business.industry, Middle Aged, medicine.disease, Benralizumab, 3. Good health, Clinical trial, Treatment Outcome, 030228 respiratory system, Tolerability, chemistry, Female, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract

Benralizumab is an interleukin-5 receptor α-directed cytolytic monoclonal antibody that has been shown to safely reduce exacerbations and improve lung function for patients with asthma. We assessed the long-term safety and efficacy of benralizumab for patients with severe, uncontrolled eosinophilic asthma.We conducted a randomised, double-blind, parallel-group, phase 3 extension study at 447 sites in 24 countries. Eligible patients had to have completed the SIROCCO or CALIMA trials and remained on subcutaneous benralizumab 30 mg every 4 weeks (Q4W) or every 8 weeks (Q8W). Patients who had received placebo in those trials were re-randomised in a 1:1 ratio, using an interactive web-based system, to benralizumab 30 mg either Q4W or Q8W (first three doses 4 weeks apart). Treatment lasted for 56 weeks for adult patients (age ≥18 years) and 108 weeks for adolescent patients (age 12-17 years). The primary endpoint was the safety and tolerability of the two dosing regimens of benralizumab up to 68 weeks for adult patients (including the follow-up visit post-treatment) and up to 56 weeks for adolescent patients. This endpoint was assessed in the full analysis set, which included all patients from the SIROCCO and CALIMA predecessor studies who received at least one dose of study treatment in BORA and did not continue into another trial. This study is registered with ClinicalTrials.gov (NCT02258542).Between Nov 19, 2014, and July 6, 2016, we enrolled 1926 patients, of whom 633 had received benralizumab Q4W and 639 had received benralizumab Q8W in SIROCCO or CALIMA. The remaining 654 patients had received placebo in those trials and were randomly re-assigned in this trial to receive benralizumab Q4W (n=320) or Q8W (n=334). 1576 patients, including 783 who received benralizumab Q4W (265 newly assigned) and 793 who received benralizumab Q8W (281 newly assigned), were included in the full analysis set. The most common adverse events in all groups were viral upper respiratory tract infection (14-16%) and worsening asthma (7-10%). The most common serious adverse events were worsening asthma (3-4%), pneumonia (1% to 1%), and pneumonia caused by bacterial infection (0-1%). The percentages of patients who had any on-treatment adverse event, any serious adverse event, or any adverse event leading to treatment discontinuation during BORA were similar between patients originally assigned benralizumab and those originally assigned placebo and between benralizumab treatment regimens. The percentage of patients who had any adverse event was similar between SIROCCO or CALIMA (71-75%; benralizumab group only) and BORA (65-71%), as was the percentage of patients who had an adverse event that led to treatment discontinuation (2% in SIROCCO and CALIMA vs 2-3% in BORA).The 2 years of safety results validate that observations observed in the first year of benralizumab continued through a second year of treatment. No new consequences of long-term eosinophil depletion occurred, and the incidence of other adverse events, including opportunistic infections, were similar during the second year.AstraZeneca and Kyowa Hakko Kirin.

Published
2019

8. The St. George's Respiratory Questionnaire Definition of Chronic Bronchitis May Be a Better Predictor of COPD Exacerbations Compared With the Classic Definition

Author

Victor Kim, Huaqing Zhao, Elizabeth Regan, MeiLan K. Han, Barry J. Make, James D. Crapo, Paul W. Jones, Jeffrey L. Curtis, Edwin K. Silverman, Gerard J. Criner, Elizabeth A. Regan, Terri Beaty, Ferdouse Begum, Robert Busch, Peter J. Castaldi, Michael Cho, Dawn L. DeMeo, Adel R. Boueiz, Marilyn G. Foreman, Eitan Halper-Stromberg, Nadia N. Hansel, Megan E. Hardin, Lystra P. Hayden, Craig P. Hersh, Jacqueline Hetmanski, Brian D. Hobbs, John E. Hokanson, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Margaret M. Parker, Dandi Qiao, Stephanie Santorico, Emily S. Wan, Sungho Won, Jean-Paul Charbonnier, Harvey O. Coxson, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, David A. Lynch, John D. Newell, James C. Ross, Raul San Jose Estepar, Jered Sieren, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, George Washko, Carla G. Wilson, Robert Jensen, Douglas Everett, Jim Crooks, Camille Moore, Matt Strand, John Hughes, Gregory Kinney, Katherine Pratte, Kendra A. Young, Carlos H. Martinez, Perry G. Pernicano, Nicola Hanania, Philip Alapat, Mustafa Atik, Venkata Bandi, Aladin Boriek, Kalpatha Guntupalli, Elizabeth Guy, Arun Nachiappan, Amit Parulekar, Craig Hersh, R. Graham Barr, John Austin, Belinda D’Souza, Gregory D.N. Pearson, Anna Rozenshtein, Byron Thomashow, Neil MacIntyre, H. Page McAdams, Lacey Washington, Charlene McEvoy, Joseph Tashjian, Robert Wise, Robert Brown, Karen Horton, Allison Lambert, Nirupama Putcha, Richard Casaburi, Alessandra Adami, Matthew Budoff, Hans Fischer, Janos Porszasz, Harry Rossiter, William Stringer, Amir Sharafkhaneh, Charlie Lan, Christine Wendt, Brian Bell, Eugene Berkowitz, Eric L. Flenaugh, Gloria Westney, Russell Bowler, Richard Rosiello, David Pace, Gerard Criner, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D’Alonzo, Parag Desai, Michael Jacobs, Steven Kelsen, A. James Mamary, Nathaniel Marchetti, Aditi Satti, Kartik Shenoy, Robert M. Steiner, Maria Elena Vega-Sanchez, Mark Dransfield, William Bailey, Surya Bhatt, Anand Iyer, Hrudaya Nath, Gabriela Oates, Sushil Sonavane, J. Michael Wells, Joe Ramsdell, Paul Friedman, Xavier Soler, Andrew Yen, Alejandro P. Comellas, John Newell, Brad Thompson, Ella Kazerooni, Joanne Billings, Abbie Begnaud, Tadashi Allen, Frank Sciurba, Jessica Bon, Divay Chandra, Carl Fuhrman, Joel Weissfeld, Antonio Anzueto, Sandra Adams, Diego Maselli-Caceres, and Mario E. Ruiz

Subjects
Pulmonary and Respiratory Medicine, Male, medicine.medical_specialty, Chronic bronchitis, Exacerbation, Critical Care and Intensive Care Medicine, Severity of Illness Index, 03 medical and health sciences, Diagnostic Self Evaluation, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Internal medicine, Medicine, Humans, Per patient per year, 030212 general & internal medicine, Respiratory system, Aged, COPD, Normal spirometry, business.industry, Severe exacerbation, Middle Aged, medicine.disease, Prognosis, humanities, Obstructive lung disease, respiratory tract diseases, Bronchitis, Chronic, 030228 respiratory system, Disease Progression, Female, Cardiology and Cardiovascular Medicine, business, human activities
Abstract

Background Chronic bronchitis (CB) increases risk of COPD exacerbations. We have shown that the St. George's Respiratory Questionnaire (SGRQ) CB definition identifies patients with a similar clinical phenotype as classically defined CB. Whether the SGRQ CB definition is a predictor of future COPD exacerbations is unknown. Methods We analyzed 7,557 smokers with normal spirometry and Global Initiative for Chronic Obstructive Lung Disease stage 1-4 COPD in the Genetic Epidemiology of COPD study with longitudinal follow-up data on exacerbations. Subjects were divided into classic CB+ or classic CB–, using the classic definition. In addition, subjects were divided into SGRQ CB+ or SGRQ CB–. Exacerbation frequency and severe exacerbation frequency were determined in each group. Multivariable linear regressions were performed for exacerbation frequency with either classic CB or SGRQ CB and relevant covariates. Results There were 1,434 classic CB+ subjects and 2,290 SGRQ CB+ subjects. The classic CB+ group had a greater exacerbation frequency compared with the classic CB– group (0.69 ± 1.26 vs 0.36 ± 0.90 exacerbations per patient per year; P Conclusions The SGRQ CB definition identified more subjects at risk for future exacerbations than the classic CB definition. SGRQ CB was at least a similar if not better predictor of future exacerbations than classic CB.

Published
2018

9. Blood eosinophil count thresholds and exacerbations in patients with chronic obstructive pulmonary disease

Author

Jeong H. Yun, Andrew Lamb, Robert Chase, Dave Singh, Margaret M. Parker, Aabida Saferali, Jørgen Vestbo, Ruth Tal-Singer, Peter J. Castaldi, Edwin K. Silverman, Craig P. Hersh, James D. Crapo, Barry J. Make, Elizabeth A. Regan, Terri Beaty, Ferdouse Begum, Robert Busch, Michael Cho, Dawn L. DeMeo, Adel R. Boueiz, Marilyn G. Foreman, Eitan Halper-Stromberg, Nadia N. Hansel, Megan E. Hardin, Lystra P. Hayden, Jacqueline Hetmanski, Brian D. Hobbs, John E. Hokanson, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Dandi Qiao, Stephanie Santorico, Emily S. Wan, Sungho Won, Mustafa Al Qaisi, Harvey O. Coxson, Teresa Gray, MeiLan K. Han, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, David A. Lynch, John D. Newell, James C. Ross, Raul San Jose Estepar, Joyce Schroeder, Jered Sieren, Douglas Stinson, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, George Washko, Carla G. Wilson, Robert Jensen, Douglas Everett, Jim Crooks, Camille Moore, Matt Strand, John Hughes, Gregory Kinney, Katherine Pratte, Kendra A. Young, Jeffrey L. Curtis, Carlos H. Martinez, Perry G. Pernicano, Nicola Hanania, Philip Alapat, Mustafa Atik, Venkata Bandi, Aladin Boriek, Kalpatha Guntupalli, Elizabeth Guy, Arun Nachiappan, Amit Parulekar, Craig Hersh, R. Graham Barr, John Austin, Belinda D'Souza, Gregory D.N. Pearson, Anna Rozenshtein, Byron Thomashow, Neil MacIntyre, H. Page McAdams, Lacey Washington, Charlene McEvoy, Joseph Tashjian, Robert Wise, Robert Brown, Karen Horton, Allison Lambert, Nirupama Putcha, Richard Casaburi, Alessandra Adami, Matthew Budoff, Hans Fischer, Janos Porszasz, Harry Rossiter, William Stringer, Amir Sharafkhaneh, Charlie Lan, Christine Wendt, Brian Bell, Eugene Berkowitz, Gloria Westney, Russell Bowler, Richard Rosiello, David Pace, Gerard Criner, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D'Alonzo, Parag Desai, Michael Jacobs, Steven Kelsen, Victor Kim, A. James Mamary, Nathaniel Marchetti, Aditi Satti, Kartik Shenoy, Robert M. Steiner, Alex Swift, Irene Swift, Maria Elena Vega-Sanchez, Mark Dransfield, William Bailey, Surya Bhatt, Anand Iyer, Hrudaya Nath, J. Michael Wells, Joe Ramsdell, Paul Friedman, Xavier Soler, Andrew Yen, Alejandro P. Comellas, John Newell, Brad Thompson, Ella Kazerooni, Joanne Billings, Abbie Begnaud, Tadashi Allen, Frank Sciurba, Jessica Bon, Divay Chandra, Carl Fuhrman, Joel Weissfeld, Antonio Anzueto, Sandra Adams, Diego Maselli-Caceres, Mario E. Ruiz, Y. Ivanov, K. Kostov, J. Bourbeau, M. Fitzgerald, P. Hernandez, K. Killian, R. Levy, F. Maltais, D. O'Donnell, J. Krepelka, J. Vestbo, E. Wouters, D. Quinn, P. Bakke, M. Kosnik, A. Agusti, J. Sauleda, P. de Mallorca, Y. Feschenko, V. Gavrisyuk, L. Yashina Kiev, N. Monogarova, P. Calverley, D. Lomas, W. MacNee, D. Singh, J. Wedzicha, A. Anzueto, S. Braman, R. Casaburi, B. Celli, G. Giessel, M. Gotfried, G. Greenwald, N. Hanania, D. Mahler, B. Make, S. Rennard, C. Rochester, P. Scanlon, D. Schuller, F. Sciurba, A. Sharafkhaneh, T. Siler, E. Silverman, A. Wanner, R. Wise, R. ZuWallack, H. Coxson, C. Crim, L. Edwards, R. Tal Singer, J. Yates, B. Miller, R. Tal-Singer, RS: NUTRIM - R3 - Respiratory & Age-related Health, Pulmonologie, and MUMC+: MA Longziekten (3)

Subjects
Male, Exacerbation, Allergy, AIRWAY INFLAMMATION, INHALED CORTICOSTEROIDS, Rate ratio, Leukocyte Count, 0302 clinical medicine, exacerbation, CLINICAL CHARACTERISTICS, Immunology and Allergy, 030212 general & internal medicine, Longitudinal Studies, Lung, COPD, medicine.diagnostic_test, Chronic obstructive pulmonary disease, Complete blood count, Middle Aged, RANDOMIZED CONTROLLED-TRIAL, Observational Studies as Topic, medicine.anatomical_structure, Disease Progression, Respiratory, Female, SHORT-TERM RESPONSE, medicine.medical_specialty, Chronic Obstructive, Chronic Obstructive Pulmonary Disease, Immunology, Pulmonary Disease, 03 medical and health sciences, FEV1/FVC ratio, Clinical Research, Internal medicine, White blood cell, medicine, Humans, eosinophil, Asthma, Aged, business.industry, COPDGene and ECLIPSE Investigators, Eosinophil, asthma, medicine.disease, Eosinophils, 030228 respiratory system, SPUTUM-EOSINOPHILIA, OVERLAP SYNDROME, business, COPENHAGEN GENERAL-POPULATION
Abstract

BACKGROUND:Eosinophilic airway inflammation in patients with chronic obstructive pulmonary disease (COPD) is associated with exacerbations and responsivity to steroids, suggesting potential shared mechanisms with eosinophilic asthma. However, there is no consistent blood eosinophil count that has been used to define the increased exacerbation risk. OBJECTIVE:We sought to investigate blood eosinophil counts associated with exacerbation risk in patients with COPD. METHODS:Blood eosinophil counts and exacerbation risk were analyzed in patients with moderate-to-severe COPD by using 2 independent studies of former and current smokers with longitudinal data. The Genetic Epidemiology of COPD (COPDGene) study was analyzed for discovery (n=1,553), and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study was analyzed for validation (n=1,895). Asubset of the ECLIPSE study subjects were used to assess the stability of blood eosinophil counts over time. RESULTS:COPD exacerbation risk increased with higher eosinophil counts. An eosinophil count threshold of 300cells/μL or greater showed adjusted incidence rate ratios for exacerbations of 1.32 in the COPDGene study (95% CI, 1.10-1.63). The cutoff of 300cells/μL or greater was validated for prospective risk of exacerbation in the ECLIPSE study, with adjusted incidence rate ratios of 1.22 (95% CI, 1.06-1.41) using 3-year follow-up data. Stratified analysis confirmed that the increased exacerbation risk associated with an eosinophil count of 300cells/μL or greater was driven by subjects with a history of frequent exacerbations in both the COPDGene and ECLIPSE studies. CONCLUSIONS:Patients with moderate-to-severe COPD and blood eosinophil counts of 300cells/μL or greater had an increased risk exacerbations in the COPDGene study, which was prospectively validated in the ECLIPSE study.

Published
2018

10. Genetic Association and Risk Scores in a Chronic Obstructive Pulmonary Disease Meta-analysis of 16,707 Subjects

Author

Robert Busch, Brian D. Hobbs, Jin Zhou, Peter J. Castaldi, Michael J. McGeachie, Megan E. Hardin, Iwona Hawrylkiewicz, Pawel Sliwinski, Jae-Joon Yim, Woo Jin Kim, Deog K. Kim, Alvar Agusti, Barry J. Make, James D. Crapo, Peter M. Calverley, Claudio F. Donner, David A. Lomas, Emiel F. Wouters, Jørgen Vestbo, Ruth Tal-Singer, Per Bakke, Amund Gulsvik, Augusto A. Litonjua, David Sparrow, Peter D. Paré, Robert D. Levy, Stephen I. Rennard, Terri H. Beaty, John Hokanson, Edwin K. Silverman, Michael H. Cho, James Crapo, Edwin Silverman, Barry Make, Elizabeth Regan, Terri Beaty, Nan Laird, Christoph Lange, Michael Cho, Stephanie Santorico, Dawn DeMeo, Nadia Hansel, Craig Hersh, Peter Castaldi, Merry-Lynn McDonald, Emily Wan, Megan Hardin, Jacqueline Hetmanski, Margaret Parker, Marilyn Foreman, Brian Hobbs, Adel El-Bouiez, Dandi Qiao, Eitan Halper-Stromberg, Ferdouse Begum, Sungho Won, Sharon Lutz, David A. Lynch, Harvey O. Coxson, MeiLan K. Han, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, John D. Newell, James C. Ross, Raul San Jose Estepar, Berend C. Stoel, Juerg Tschirren, Eva van Rikxoort, Bram van Ginneken, George Washko, Carla G. Wilson, Mustafa Al Qaisi, Teresa Gray, Alex Kluiber, Tanya Mann, Jered Sieren, Douglas Stinson, Joyce Schroeder, Edwin Van Beek, Robert Jensen, Douglas Everett, Anna Faino, Matt Strand, Carla Wilson, John E. Hokanson, Gregory Kinney, Kendra Young, Katherine Pratte, Lindsey Duca, Jeffrey L. Curtis, Carlos H. Martinez, Perry G. Pernicano, Nicola Hanania, Philip Alapat, Venkata Bandi, Mustafa Atik, Aladin Boriek, Kalpatha Guntupalli, Elizabeth Guy, Amit Parulekar, Arun Nachiappan, Francine Jacobson, R. Graham Barr, Byron Thomashow, John Austin, Belinda D'Souza, Gregory D. N. Pearson, Anna Rozenshtein, Neil MacIntyre, Lacey Washington, H. Page McAdams, Charlene McEvoy, Joseph Tashjian, Robert Wise, Robert Brown, Karen Horton, Nirupama Putcha, Richard Casaburi, Alessandra Adami, Janos Porszasz, Hans Fischer, Matthew Budoff, Harry Rossiter, Amir Sharafkhaneh, Charlie Lan, Christine Wendt, Brian Bell, Gloria Westney, Eugene Berkowitz, Russell Bowler, David Lynch, Richard Rosiello, David Pace, Gerard Criner, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D'Alonzo, Parag Desai, Michael Jacobs, Steven Kelsen, Victor Kim, A. James Mamary, Nathaniel Marchetti, Aditi Satti, Kartik Shenoy, Robert M. Steiner, Alex Swift, Irene Swift, Maria Elena Vega-Sanchez, Mark Dransfield, William Bailey, J. Michael Wells, Surya Bhatt, Hrudaya Nath, Joe Ramsdell, Paul Friedman, Xavier Soler, Andrew Yen, Alejandro Comellas, John Newell, Brad Thompson, MeiLan Han, Ella Kazerooni, Carlos Martinez, Joanne Billings, Tadashi Allen, Frank Sciurba, Divay Chandra, Joel Weissfeld, Carl Fuhrman, Jessica Bon, Antonio Anzueto, Sandra Adams, Diego Maselli-Caceres, Mario E. Ruiz, Jaume Sauleda, Peter M. A. Calverley, Stephen Rennard, Y. Ivanov, K. Kostov, J. Bourbeau, M. Fitzgerald, P. Hernandez, K. Killian, R. Levy, F. Maltais, D. O'Donnell, J. Krepelka, J. Vestbo, E. Wouters, D. Quinn, P. Bakke, M. Kosnik, A. Agusti, J. Sauleda, Y. Feschenko, V. Gavrisyuk, L. Yashina, N. Monogarova, P. Calverley, D. Lomas, W. MacNee, D. Singh, J. Wedzicha, A. Anzueto, S. Braman, R. Casaburi, B. Celli, G. Giessel, M. Gotfried, G. Greenwald, N. Hanania, D. Mahler, B. Make, S. Rennard, C. Rochester, P. Scanlon, D. Schuller, F. Sciurba, A. Sharafkhaneh, T. Siler, E. Silverman, A. Wanner, R. Wise, R. ZuWallack, H. Coxson, C. Crim, L. Edwards, R. Tal Singer, J. Yates, B. Miller, R. Tal-Singer, J. Benditt, G. Criner, M. DeCamp, P. Diaz, M. Ginsburg, L. Kaiser, M. Katz, M. Krasna, N. MacIntyre, R. McKenna, F. Martinez, Z. Mosenifar, J. Reilly, A. Ries, J. Utz, RS: NUTRIM - R3 - Respiratory & Age-related Health, Pulmonologie, MUMC+: MA Longziekten (3), and RS: NUTRIM - R3 - Chronic inflammatory disease and wasting

Subjects
0301 basic medicine, Male, Clinical Biochemistry, EMPHYSEMA, SUSCEPTIBILITY, AIR-FLOW OBSTRUCTION, Pulmonary Disease, Chronic Obstructive, Risk Factors, Medicine, EPIDEMIOLOGY, Genetic epidemiology, Original Research, COPD, COMPLEX DISEASE, RECLASSIFICATION, Chronic obstructive pulmonary disease, Middle Aged, Genetic risk score, Respiratory Function Tests, LUNG-FUNCTION, Genetic risk factors, alpha-1 antitrypsin, Meta-analysis, Female, SMOKING, Pulmonary and Respiratory Medicine, medicine.medical_specialty, genetic epidemiology, Pulmonary disease, Single-nucleotide polymorphism, genetic risk score, chronic obstructive pulmonary disease, 03 medical and health sciences, Internal medicine, Genetic variation, genetic risk factors, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Molecular Biology, Genotyping, Genetic association, Aged, business.industry, Cell Biology, Heritability, medicine.disease, respiratory tract diseases, 030104 developmental biology, Physical therapy, business, Genome-Wide Association Study
Abstract

The heritability of chronic obstructive pulmonary disease (COPD) cannot be fully explained by recognized genetic risk factors identified as achieving genome-wide significance. In addition, the combined contribution of genetic variation to COPD risk has not been fully explored. We sought to determine: (1) whether studies of variants from previous studies of COPD or lung function in a larger sample could identify additional associated variants, particularly for severe COPD; and (2) the impact of genetic risk scores on COPD. We genotyped 3,346 single-nucleotide polymorphisms (SNPs) in 2,588 cases (1,803 severe COPD) and 1,782 control subjects from four cohorts, and performed association testing with COPD, combining these results with existing genotyping data from 6,633 cases (3,497 severe COPD) and 5,704 control subjects. In addition, we developed genetic risk scores from SNPs associated with lung function and COPD and tested their discriminatory power for COPD-related measures. We identified significant associations between SNPs near PPIC (P = 1.28 X 10(-8)) and PPP4R4/SERPINA1 (P = 1.01 X 10(-8)) and severe COPD; the latter association may be driven by recognized variants in SERPINA1. Genetic risk scores based on SNPs previously associated with COPD and lung function had a modest ability to discriminate COPD (area under the curve, similar to 0.6), and accounted for a mean 0.9-1.9% lower forced expiratory volume in 1 second percent predicted for each additional risk allele. In a large genetic association analysis, we identified associations with severe COPD near PPIC and SERPINA1. A risk score based on combining genetic variants had modest, but significant, effects on risk of COPD and lung function.

Published
2017

11. Mucosal eosinophilia: prevalence and racial/ethnic differences in symptoms and endoscopic findings in adults over 10 years in an urban hospital

Author

Rebecca Thomas, Joel E. Richter, Zubair Malik, Steven Kelsen, Matthew Bohm, Christopher Sebastiano, and John P. Gaughan

Subjects
Adult, Male, medicine.medical_specialty, Black People, Disease, Gastroenterology, White People, Hospitals, Urban, Internal medicine, Biopsy, Eosinophilia, medicine, Prevalence, Esophagitis, Humans, Esophagus, Age of Onset, Mid-Atlantic Region, Eosinophilic esophagitis, medicine.diagnostic_test, business.industry, Hispanic or Latino, Eosinophil, Middle Aged, medicine.disease, Dysphagia, Radiography, Connecticut, medicine.anatomical_structure, Female, Racial/ethnic difference, Esophagoscopy, medicine.symptom, Age of onset, business
Abstract

Background Eosinophilic esophagitis is a chronic inflammatory disease with mucosal accumulation of eosinophils. There is a paucity of data among racial/ethnic groups other than white patients. Aim To determine if racial/ethnic differences exist in clinical presentation, endoscopic appearance, and biopsy results in adult patients (age ≥18 y) with mucosal eosinophilia and examine the prevalence of mucosal eosinophilia at an urban hospital over a 10-year period. Methods Pathology reports searched at Temple University Hospital 2000 to 2009; key words: "eosinophils", "esophagus", and "biopsy". Clinical and endoscopic records reviewed on patients with ≥15 eosinophils/high power field. Results A total of 64 adults (average age, 41 y; 62% male patients; 81% white, 12% black, and 6% Hispanic). White patients were significantly younger (P=0.03). Adult mucosal eosinophilia diagnosis increased by 833% (3 in 2000 to 25 in 2009); black/Hispanic diagnosis increased by 500% (1 in 2000 to 5 in 2009). Solid food dysphagia was more common among white patients (72% vs. 0.33%, P=0.02). Reflux symptoms were more common in black/Hispanic patients (42% vs. 22%, P=0.16). Normal endoscopy (42% vs. 13%, P=0.04) and reflux changes (41% vs. 21%, P=0.16) were more common in black/Hispanic patients. Furrows (42% vs. 8%, P=0.04) and rings (46% vs. 0%, P=0.002) were more common in white patients. Average eosinophil counts did not vary between groups. Conclusions Mucosal eosinophilia presents with significant differences between racial/ethnic groups in age at onset, symptoms at presentation, and endoscopic features. Differences may reflect different phenotypes of the same disease or separate disease entities.

Published
2011

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