Arthur F Gelb1, Alfred Yamamoto2, Eric K Verbeken3, Mark J Schein4, Roxanna Moridzadeh5, Diem Tran5, Christine Fraser5, Richard Barbers6, Wafaa Elatre7, Michael N Koss7, Eric F Glassy8, Jay A Nadel9. 1. Pulmonary Division, Department of Medicine, Lakewood Regional Medical Center (LRMC), Lakewood, CA; Geffen School of Medicine at UCLA Medical Center, Los Angeles, CA. Electronic address: afgelb@msn.com. 2. Department of Pathology, LRMC, Leuven, Belgium. 3. Department of Pathology, Katholieke Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium. 4. Department of Radiology, LRMC, Lakewood, CA. 5. Independent Investigators, Los Angeles, CA. 6. Pulmonary Division, Department of Medicine, Keck Hospital at the University of Southern California Medical Center (Keck, USC), Los Angeles, CA. 7. Department of Pathology, Keck, USC, Los Angeles, CA. 8. Affiliated Pathologists Medical Group, Rancho Dominguez, CA. 9. Cardiovascular Research Institute and Departments of Medicine (Pulmonary Division), Physiology, and Radiology, University of California, San Francisco Medical Center, San Francisco, CA.
Abstract
BACKGROUND: Previously, we and other investigators have described reversible loss of lung elastic recoil in patients with acute and persistent, moderate-to-severe, chronic, treated asthma who never smoked, and its adverse effect on maximal expiratory airflow. In four consecutive autopsies, we reported the pathophysiologic mechanism(s) has been unsuspected mild, diffuse, middle and upper lobe centrilobular emphysema. METHODS: We performed prospective studies (5 to 22 years) in 25 patients (12 female) with chronic asthma, age 55 ± 15 years, who never smoked, with persistent moderate-to-severe expiratory obstruction. Studies included measuring blood eosinophils, IgE, total exhaled nitric oxide (NO), central airway NO flux, peripheral airway/alveolar NO concentration, impulse oscillometry, heliox curves, lung elastic recoil, and high-resolution thin-section (1 mm) lung CT imaging at full inspiration with voxel quantification. RESULTS: In 25 patients with stable asthma with varying type 2 phenotype, after 270 μg of aerosolized albuterol sulfate had been administered with a metered dose inhaler with space chamber, FVC was 3.1 ± 1.0 L (83% ± 13% predicted) (mean ± SD), FEV1 was 1.8 ± 0.6 L (59% ± 11%), the FEV1/FVC ratio was 59% ± 10%, and the ratio of single-breath diffusing capacity of the lung for carbon monoxide to alveolar volume was 4.8 ± 1.1 mL/min/mm Hg/L (120% ± 26%). All 25 patients with asthma had loss of static lung elastic recoil pressure, which contributed equally to decreased intrinsic airway conductance in limiting expiratory airflow. Lung CT scanning detected none or mild emphysema. In all four autopsied asthmatic lungs previously reported and one unreported explanted lung, microscopy revealed unsuspected mild, diffuse centrilobular emphysema in the upper and middle lung fields, and asthma-related remodeling in airways. In eight cases, during asthma remission, there were increases in measured static lung elastic recoil pressure-calculated intrinsic airway conductance, and measured maximal expiratory airflow at effort-independent lung volumes. CONCLUSIONS: As documented now in five cases, unsuspected microscopic mild centrilobular emphysema is the sentinel cause of loss of lung elastic recoil. This contributes significantly to expiratory airflow obstruction in never-smoking patients with asthma, with normal diffusing capacity and near-normal lung CT scan results. TRIAL REGISTRY: Protocol No. 20070934 and Study No. 1090472, Western Institutional Review Board, Olympia, WA; ClinicalTrials.gov; No. NCT00576069; URL: www.clinicaltrials.gov.
BACKGROUND: Previously, we and other investigators have described reversible loss of lung elastic recoil in patients with acute and persistent, moderate-to-severe, chronic, treated asthma who never smoked, and its adverse effect on maximal expiratory airflow. In four consecutive autopsies, we reported the pathophysiologic mechanism(s) has been unsuspected mild, diffuse, middle and upper lobe centrilobular emphysema. METHODS: We performed prospective studies (5 to 22 years) in 25 patients (12 female) with chronic asthma, age 55 ± 15 years, who never smoked, with persistent moderate-to-severe expiratory obstruction. Studies included measuring blood eosinophils, IgE, total exhaled nitric oxide (NO), central airway NO flux, peripheral airway/alveolar NO concentration, impulse oscillometry, heliox curves, lung elastic recoil, and high-resolution thin-section (1 mm) lung CT imaging at full inspiration with voxel quantification. RESULTS: In 25 patients with stable asthma with varying type 2 phenotype, after 270 μg of aerosolized albuterol sulfate had been administered with a metered dose inhaler with space chamber, FVC was 3.1 ± 1.0 L (83% ± 13% predicted) (mean ± SD), FEV1 was 1.8 ± 0.6 L (59% ± 11%), the FEV1/FVC ratio was 59% ± 10%, and the ratio of single-breath diffusing capacity of the lung for carbon monoxide to alveolar volume was 4.8 ± 1.1 mL/min/mm Hg/L (120% ± 26%). All 25 patients with asthma had loss of static lung elastic recoil pressure, which contributed equally to decreased intrinsic airway conductance in limiting expiratory airflow. Lung CT scanning detected none or mild emphysema. In all four autopsied asthmatic lungs previously reported and one unreported explanted lung, microscopy revealed unsuspected mild, diffuse centrilobular emphysema in the upper and middle lung fields, and asthma-related remodeling in airways. In eight cases, during asthma remission, there were increases in measured static lung elastic recoil pressure-calculated intrinsic airway conductance, and measured maximal expiratory airflow at effort-independent lung volumes. CONCLUSIONS: As documented now in five cases, unsuspected microscopic mild centrilobular emphysema is the sentinel cause of loss of lung elastic recoil. This contributes significantly to expiratory airflow obstruction in never-smoking patients with asthma, with normal diffusing capacity and near-normal lung CT scan results. TRIAL REGISTRY: Protocol No. 20070934 and Study No. 1090472, Western Institutional Review Board, Olympia, WA; ClinicalTrials.gov; No. NCT00576069; URL: www.clinicaltrials.gov.
Authors: Alfred D Doyle; Manali Mukherjee; William E LeSuer; Tyler B Bittner; Saif M Pasha; Justin J Frere; Joseph L Neely; Jake A Kloeber; Kelly P Shim; Sergei I Ochkur; Terence Ho; Sarah Svenningsen; Benjamin L Wright; Matthew A Rank; James J Lee; Parameswaran Nair; Elizabeth A Jacobsen Journal: Eur Respir J Date: 2019-05-30 Impact factor: 16.671
Authors: Arthur F Gelb; Alfred Yamamoto; Eric K Verbeken; James C Hogg; Donald P Tashkin; Diem N T Tran; Roxanna M Moridzadeh; Christine Fraser; Mark J Schein; Marc Decramer; Eric F Glassy; Jay A Nadel Journal: Chronic Obstr Pulm Dis Date: 2021-01
Authors: Loren C Denlinger; Brenda R Phillips; Ronald L Sorkness; Eugene R Bleecker; Mario Castro; Mark D DeBoer; Anne M Fitzpatrick; Annette T Hastie; Jonathan M Gaffin; Wendy C Moore; Michael C Peters; Stephen P Peters; Wanda Phipatanakul; Juan Carlos Cardet; Serpil C Erzurum; John V Fahy; Merritt L Fajt; Benjamin Gaston; Bruce D Levy; Deborah A Meyers; Kristie Ross; W Gerald Teague; Sally E Wenzel; Prescott G Woodruff; Joe Zein; Nizar N Jarjour; David T Mauger; Elliot Israel Journal: Am J Respir Crit Care Med Date: 2021-04-01 Impact factor: 21.405