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Commentary |

Unraveling the Pathophysiology of the Asthma-COPD Overlap SyndromeAsthma-COPD Overlap Syndrome: Unsuspected Mild Centrilobular Emphysema Is Responsible for Loss of Lung Elastic Recoil in Never Smokers With Asthma With Persistent Expiratory Airflow Limitation FREE TO VIEW

Arthur F. Gelb, MD, FCCP; Alfred Yamamoto, MD; Eric K. Verbeken, MD; Jay A. Nadel, MD
Author and Funding Information

From the Pulmonary Division, Department of Medicine (Dr Gelb) and the Department of Pathology (Dr Yamamoto), Lakewood Regional Medical Center, Lakewood, CA; the Geffen School of Medicine at UCLA Medical Center (Dr Gelb), Los Angeles, CA; the Department of Pathology (Dr Verbeken), Katholieke Univeritair Ziekenhuis Gasthuisberg, Leuven, Belgium; and the Departments of Medicine (Dr Nadel), Physiology (Dr Nadel), and Radiology (Dr Nadel), University of California, San Francisco Medical Center, San Francisco, CA.

CORRESPONDENCE TO: Arthur F. Gelb, MD FCCP, 3650 E South St, Suite 308, Lakewood, CA 90712; e-mail: afgelb@msn.com


FOR EDITORIAL COMMENT SEE PAGE 297

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Chest. 2015;148(2):313-320. doi:10.1378/chest.14-2483
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Investigators believe most patients with asthma have reversible airflow obstruction with treatment, despite airway remodeling and hyperresponsiveness. There are smokers with chronic expiratory airflow obstruction despite treatment who have features of both asthma and COPD. Some investigators refer to this conundrum as the asthma-COPD overlap syndrome (ACOS). Furthermore, a subset of treated nonsmokers with moderate to severe asthma have persistent expiratory airflow limitation, despite partial reversibility. This residuum has been assumed to be due to large and especially small airway remodeling. Alternatively, we and others have described reversible loss of lung elastic recoil in acute and persistent loss in patients with moderate to severe chronic asthma who never smoked and its adverse effect on maximal expiratory airflow. The mechanism(s) responsible for loss of lung elastic recoil and persistent expiratory airflow limitation in nonsmokers with chronic asthma consistent with ACOS remain unknown in the absence of structure-function studies. Recently we reported a new pathophysiologic observation in 10 treated never smokers with asthma with persistent expiratory airflow obstruction, despite partial reversibility: All 10 patients with asthma had a significant decrease in lung elastic recoil, and unsuspected, microscopic mild centrilobular emphysema was noted in all three autopsies obtained although it was not easily identified on lung CT scan. These sentinel pathophysiologic observations need to be confirmed to further unravel the epiphenomenon of ACOS. The proinflammatory and proteolytic mechanism(s) leading to lung tissue breakdown need to be further investigated.

Figures in this Article

There are some former or current smoking patients with chronic expiratory airflow obstruction despite therapeutic intervention who have features of both asthma and COPD.15 This conundrum has been labeled the asthma-COPD overlap syndrome (ACOS).59 In 2014, a document endorsed by both GINA (Global Initiative for Asthma) and GOLD (Global Initiative for Chronic Obstructive Lung Disease) provided in-depth analyses, with diagnostic and therapeutic recommendations for ACOS.10 The clinical course of these patients is often compounded by frequent exacerbations, especially in patients with asthma who continue to smoke. Furthermore, investigators have also identified never smoked asthma phenotypes or subgroups with shared characteristics. This has allowed stratification of patients with moderate to severe asthma using input from multiple sources: clinical data, BAL, large airways pathology, blood inflammatory biomarkers, genetic markers, lung function, demographics, lung CT scan, and medication response.1114 A recent study demonstrated the potential therapeutic limitation using cluster analysis and variable response in Cluster 5, which is best aligned with ACOS.14 And, genetic studies have suggested less than a firm overlap between asthma and COPD.8,9,15 However, these asthma cluster studies have not specifically addressed ACOS and the pathophysiologic mechanism(s) responsible for persistent expiratory airflow limitation.

In patients with asthma who are nonsmokers, we16 and several other investigators1724 have previously reported reversible loss of lung elastic recoil and hyperinflation at total lung capacity during acute attacks of asthma that were either spontaneous1620 or induced by exercise21,22 or by antigen challenge.23,24 Furthermore, loss of lung elastic recoil has been reported in chronic asthma with only partially reversible airway obstruction despite treatment17,18,20,2528 and also in mild asthma.29 The sentinel study by Gold et al16 in 1967 reported the reversible loss of lung elastic recoil in acute asthma. And, the sentinel study by Woolcock and Read17 in 1968 demonstrated the unexpected chronic loss of lung elastic recoil in patients with stable asthma with expiratory airflow limitation and partially reversible, nearly parallel left shift in the pressure-volume curve with exacerbation. This unexpected loss of lung elastic recoil contributes greatly to exaggerate airflow limitation due to intrinsic peripheral airway bronchoconstriction.30 These nonsmokers with asthma with loss of lung elastic recoil and persistent limitation of maximal expiratory airflow have normal diffusing capacity corrected for alveolar volume. They have normal or only mild parenchymal attenuation of lung density using voxel quantification on high-resolution thin-section (1 mm) lung CT scan at full inspiration,2527 with trivial Thurlbeck “emphysema scores” ≤ 15.31,32 However, the limited resolution of lung CT scan may not be capable of discriminating between mild emphysema and hyperinflation.3335 Because well-performed structure-function studies of the lungs in asthma are rarely published, the pathophysiologic mechanism(s) responsible for the loss of lung elastic recoil in acute1624 and chronic asthma17,18,20,2529 remain an enigma. Here, we review our pathologic and physiologic data36 in never smokers with asthma with persistent expiratory airflow limitation consistent with asthma guidelines,37 which we hope will begin to unravel the paradigm of ACOS.510

Study Design and Selection of Patients With Asthma

We have studied many adult nonsmokers with asthma followed in a tertiary referral asthma clinic for moderate to severe cases37 with persistent maximal expiratory airflow limitation despite treatment and partial reversibilty.2527,36 All patients with asthma were clinically stable at the time of lung function studies and had tapered off oral corticosteroid for ≥ 6 weeks. Most of the patients with asthma studied had nearly lifelong history of asthma and had never smoked. None had chronic bronchitis or history of exposure to potential agents that might cause lung injury, including exposure to secondhand smoke.

In our sentinel pilot pathophysiologic study initiated nearly 10 years ago, only two of 10 patients with asthma had recurrent chronic rhinosinusitis.36 All had normal serum values for α1-antitrypsin. Two of the 10 patients with asthma had experienced acute exacerbations in the past that required hospitalization including endotracheal intubation and short-term mechanical ventilation. Within the previous 2 years of study, all patients with asthma satisfied the spirometric criteria for at least partial reversibility, with an increase in FEV1 > 200 mL and 12% following 270 μg aerosolized albuterol sulfate via spacer chamber when not using any long-acting and short-acting β2-agonist and muscarinic antagonist metered dose inhalers for 24 and 6 h, respectively. Results in the 10 patients in our pilot study36 have not been included in our previous studies.2527

Lung CT Scan, Asthma Control Test, Serum IgE, and Eosinophil Count Results

In 10 adult treated patients with asthma (five women) aged 52 ± 14 years (mean ± SD), the BMI was 27 ± 6, total blood eosinophil values were 206 (131-260) cells/μL (median, 1-3 interquartile range), and IgE level was 280 (31-500) kμ/L.36 The Asthma Control Test38 score was 16 to 19 when both clinical status and spirometry were optimally improved by maximizing therapeutic intervention. This included both short- and long-acting β2 agonist, muscarinic receptor antagonist, inhaled beclomethasone equivalent ≤ 0.4 mg/d, and tapering oral corticosteroid as needed. Thurlbeck lung CT scan emphysema score32 was ≤ 10, consistent with trivial or no emphysema in seven patients with asthma. In the three patients with asthma with loss of lung elastic recoil and persistent expiratory airflow limitation who died, all had mild, diffuse centrilobular emphysema at autopsy, The Thurlbeck lung CT scan emphysema score (0 = none to 100 = very extensive lung tissue breakdown)32 was between 10 and 20, consistent with trivial to mild emphysema as per radiologist Mark J. Schein, MD, by this criterion.36 In one patient with asthma with a Thurlbeck emphysema score32 of 10 who was autopsied, the lung CT scan voxel quantification score for ≤ −950 Hounsfield units (HU) was 6.5% for right lung and 0.9% for left lung. This is consistent with hyperinflation and air trapping but not diagnostic for emphysema (≥ 10% lung voxel ≤ −950 HU).3335

Lung Function Studies

In 10 patients with asthma, the postbronchodilator (270 μg albuterol sulfate metered dose inhaler with spacer) vital capacity was 4.2 ± 1.1 L (90% ± 14% predicted) (mean ± SD), FVC was 4.0 ± 1.0 L (88% ± 13% predicted), FEV1 was 2.5 ± 0.4 L (69% ± 14% predicted), and FEV1/FVC ratio was 63% ± 9% (Table 1). Specific airway conductance was markedly reduced (0.06 [0.05-0.08] lps/cm H2O/L [median, 1-3 interquartile range], 123 [100-142]% predicted. Hyperinflation and air trapping were marked at both functional residual capacity 4.3 (3.5-4.4) L, 123 (109-142)% predicted, and residual volume 3.4 (2.8-3.5) L, 143 (141-176)% predicted This was probably caused by premature “airway closure” as a result of both intrinsic airway obstruction and loss of lung elastic recoil. Total lung capacity (TLC) was mildly elevated at 7.3 (6.8-7.5) L, 112 (110-119)% predicted. Static lung elastic recoil pressure at TLC was 15 (13-18) cm H2O, 63 (50-70)% predicted. Diffusing capacity after correction for alveolar volume was normal or increased (5.5 [4.6-6.0] mL/min/mm Hg/L 130 [112-141]% predicted). This implies integrity of alveolar-capillary surface area when using an underestimated alveolar lung volume compared with plethysmographic derived values. All 10 patients with asthma had measured loss of static lung elastic recoil compared with age-matched control subjects (Fig 136,39). Furthermore, the reduction in both lung elastic recoil and in airway conductance had a similar contribution to the decrease in expiratory maximal expiratory airflow at 90% predicted TLC (78% observed TLC) (Fig 2). Measurement of large airways and peripheral airways/alveolar exhaled nitric oxide was normal.40 The clinical, laboratory, and physiologic studies in these 10 patients with asthma were similar to those we reported previously.2527

Table Graphic Jump Location
TABLE 1 ]  Studies in Four Never Smokers With Asthma With Loss of Lung Elastic Recoil and Persistent Expiratory Airflow Obstruction Who Had Unsuspected Microscopic Mild Centrilobular Emphysema at Autopsy

All values are post 270 μg albuterol metered dose inhaler, with normal prediction values previously noted.2527,39 Results demonstrate moderate to severe expiratory airflow limitation on spirometry, with marked reduction in specific airway conductance. There is hyperinflation (trapped gas) at static lung volumes including FRC, RV, and TLC. The hyperinflation at TLC is presumably due to loss of lung elastic recoil. The increase in RV and evidence of airway narrowing suggests early airway closure during expiration (“trapped gas”). Expiratory airflow limitation and hyperinflation at FRC and RV are interpreted as due to a combination of loss of lung elastic recoil and decreased intrinsic airway conductance. The latter is due to intrinsic airway remodeling, including mucous plugging and bronchoconstriction, with resultant premature airway closure. The normal Dlco/Va suggests the presence of an alveolar-capillary surface area within normal limits. The Thurlbeck scores32 on lung CT scan suggest trivial/mild emphysema. However, microscopic sections of formalin-inflated lung demonstrated mild diffuse breakdown of lung tissue (emphysema in Figure 3). Dlco/Va = diffusing capacity corrected for alveolar volume; FRC = functional residual capacity; HU = Hounsfield units; L = left; R = right; RV = residual volume; SGaw = specific airway conductance; TLC = total lung capacity; VC = vital capacity; VQ = voxel quantification for % lung < −950 HU. Cases 4, 9, and 10 were previously reported; case 11 has not been reported previously. Case numbers refer to dashed lines in Figure 1. (Adapted with permission from Gelb et al.36)

Figure Jump LinkFigure 1 –  Static lung elastic recoil pressure (Pst[l]) was measured in a subgroup of 10 (five women) treated never smokers with asthma aged 52 ± 14 y (mean ± SD) with persistent expiratory airflow limitation.36 All had significant loss of lung elastic recoil compared with normal values. The dashed lines represent four cases which all had autopsy-proven mild diffuse emphysema; three cases (4, 9, 10) were previously reported, and case 11 was not previously reported.36 The individual curves are clearly shifted to the left of lower limit of age-matched normal subjects39 with mild increase in compliance. TLC was mildly elevated at 7.3 (6.8-7.5) L, 112 (110-119)% predicted (median, 1-3 interquartile range). Pst(l) at TLC was 15 (13-18) cm H2O, 63 (50-70)% predicted. TLC = total lung capacity. (Adapted with permission from Gelb et al.36)Grahic Jump Location
Figure Jump LinkFigure 2 –  At any effort independent lung volume, VmaxE = Pst(l) × Gus (conductance of upstream airways).30 At 90% predicted TLC (78% observed TLC) the loss of lung elastic recoil contributes to airflow limitation to a similar extent as the reduction in peripheral airway conductance. Cases 1 to 10 were recently reported, as noted in Figure 1.36 Results in case 11 are similar. Gus = conductance of upstream airways; VmaxE = maximal expiratory flow. See Figure 1 legend for expansion of other abbreviations. (Reprinted with permission from Gelb et al.36)Grahic Jump Location
Autopsy Findings

In three autopsied cases, as previously reported,36 all had significant maximal expiratory airflow limitation with hyperinflation and air trapping, normal diffusing capacity, and trivial to mild Thurlbeck lung CT scan emphysema score32 of 10, 15, and 20. Transaxial macroscopic section of autopsy obtained of formalin-fixed and inflated lungs to 15 cm H2O revealed trivial to mild emphysema by Thurlbeck emphysema scores32 of 10 (case 10), 15 (case 4), and 20 (case 9). However, microscopic examination revealed mild, diffuse, centrilobular emphysema in all three cases. Intraalveolar chord diameter in areas of normal lung parenchyma was ≤ 300 μm, whereas it was much greater in emphysematous parenchyma in cases 9 and 10 (Figs 3A‐D). In case 10, there were also areas of alveolar ductal ectasia and nearly homogeneous alveolar hyperinflation consistent with “senile lung” alterations as described by Verbeken et al.41,42 In all three patients with asthma, there were also concurrent microscopic findings of typical asthma in large and small airways, including mucosal goblet cell metaplasia and thickening of both the basement membrane and airway smooth muscle layers. Mucin deposition (identified by Alcian blue/Periodic acid-Schiff stain) and mucous plugs were noted in lumens of conducting airways and extending to terminal bronchioles and were laden predominantly with recruited neutrophils (CD15 stain), especially in cases 9 and 10. The typical asthma airway remodeling changes were consistent with previous studies,4347 including decrease in airway remodeling in older patients with fatal asthma when compared with age-matched control subjects.48 In a control case with asthma (Fig 3E), an 80-year-old woman with reversible airway obstruction on treatment, there was no evidence for lung parenchymal tissue breakdown, but typical airway remodeling and senile hyperinflation and ductal ectasia changes were noted.41,42Figure 3F demonstrates normal lung parenchyma in a healthy elderly man. Since publication of the initial study,36 a fourth never smoker with lifelong asthma with microscopic mild emphysema (case 11), and senile lung alterations41,42 on autopsy has been confirmed and is included in Table 1. Case numbers refer to Figure 1.

Figure Jump LinkFigure 3 –  A-D, Note emphysema (A, B, case 9; and C, D, case 10 from Table 1), including not only disorganization and unevenly distributed enlarged airspaces but also disrupted alveolar septa even visible at this magnification, as previously reported.36 In these cases, Alcian blue/Periodic acid-Schiff (PAS stain) showed mucin in terminal bronchioles with plugging, especially in cases 9 and 10, and the plugs contained 70% recruited neutrophils. E, Control asthma case was an 80-y-old woman with asthma with reversible expiratory airflow limitation with treatment. Microscopic morphometry was consistent with “senile lung,” with nearly homogenous acinar hyperinflation and alveolar ductal ectasia but without unevenly distributed airspace enlargement or septal disruption and with no free septal fragments detached from the surrounding structures.41,42 F, Sample from a 71-y-old man with normal lung function. AD = alveolar duct; BV = blood vessel; RB = respiratory bronchiole; TB = terminal bronchiole. (Hematoxylin and eosin stain.)Grahic Jump Location

Loss of lung elastic recoil has been reported in chronic asthma with only partially reversible airway obstruction despite treatment17,18,20,2528 and also in mild asthma.29 However, no pathologic data have been obtained. Originally, we studied 18 nonsmokers with asthma aged 59 ± 15 years (mean ± SD) with persistent expiratory airflow limitation.25 Despite normal diffusing capacity corrected for alveolar volume and lung CT scan, there was a significant fixed loss of lung elastic recoil in three of four patients with asthma aged 30 to 49 years, in all five patients with asthma aged 51 to 60 years, and in seven of nine patients with asthma aged 61 to 82 years. The fixed loss of lung elastic recoil was responsible for 35% reduction in maximal expiratory airflow at 80% TLC and 55% reduction at 70% of TLC.25 In another study, we noted fixed loss of lung elastic recoil in all 11 patients with asthma aged 64 ± 11 years with persistent post 270 μg albuterol FEV1 of 60% to 79% predicted, and in five patients with asthma aged 55 ± 16 years with persistent FEV1 of < 60% predicted, but no loss in five patients with asthma aged 51 ± 17 years with FEV1 > 80% predicted.26 The fixed loss of lung elastic recoil was responsible for an average of 34% of decreased maximal expiratory airflow at 80% TLC and 50% decrease at 70% TLC.26 In a study of 43 patients with chronic asthma, we reported that fixed loss of lung elastic recoil was associated with increasing age, duration of disease, and progressive expiratory airflow limitation and was a risk factor for near-fatal asthma.27

Busacker et al33 and Biernacki et al34 noted significant lung attenuation in nonsmokers with severe asthma using quantitative lung CT scan density voxels < −850 HU. This is more consistent with hyperinflation as opposed to lung tissue breakdown (emphysema). Alternatively, > 10% lung parenchyma with quantitative lung CT scan density voxels < −950 HU is more consistent with emphysema.33 Moreover, Madani et al35 have reported good correlation between surgically obtained lung specimens scored for emphysema with voxel scored lung attenuation < −950 HU. However, no correlative physiologic studies including measurements of static lung elastic recoil pressures were obtained, and only one study showed a correlation with lung parenchymal structure.35 From the historical perspective, the editorial by Paganin et al49 traces the significance of lung CT scan diagnosis of emphysema in patients with asthma with lung pathology. Unfortunately, many of the patients with asthma studied were chronic smokers with comorbidities.

One previous sentinel autopsy study by Mauad et al44 in nonsmokers with fatal asthma has reported lung tissue breakdown and localized emphysema, and no study measured lung function including lung elastic recoil.4350 In fatal asthma, Mauad et al44 noted cleavage of bronchiolar-alveolar tethering attachments with fragmented and decreased adventitial elastic fibers, and localized periterminal bronchiolar parenchymal emphysema. Dolhnikoff et al45 and de Magalhães Simões et al50 emphasized the surrounding inflammatory response, including fibronectin, matrix metalloproteases, mast cells, eosinophils, and neutrophils. Baines et al51 reported increased neutrophil elastase was detected in the plasma of patients with asthma with neutrophilic airway inflammation, suggesting systemic neutrophil activation. Andersson et al52 also emphasized mast cell-associated alveolar inflammation in uncontrolled asthma.

The original description of emphysema by Leopold and Gough53 included inflammatory mucous plugs in the terminal bronchioles and suggested that this was the nascent site of lung tissue breakdown that led to centrilobular emphysema. We suggest that recurrent asthma attacks may produce bronchiolar inflammation with activation of a proinflammatory pathway. This may be mediated by an autocrine epidermal growth factor receptor signaling cascade stimulated by inhaled invaders in epithelial cells as we previously suggested.54 Subsequently, specific protective mucociliary responses occur in the airway epithelium via IL-17 and IL-18, which activate IL-8 to induce mucin production and neutrophil recruitment, especially in mild to moderate asthma.54 Moreover, proteases such as neutrophil elastase and cathepsin G, activated eosinophils, macrophages, and mast cells may all induce mucin production via activation of the epidermal growth factor receptor ligand-initiated signaling cascade. Furthermore, neutrophil elastase and cathepsin G are potent secretagogues for submucosal gland epithelial cells. Together with activated matrix metalloproteases, this proteolytic cascade has the potential to cleave and disrupt the normal connective tissue integrity of lung parenchymal-terminal bronchiole attachments, leading to potential loss of anatomic and physiologic interdependence. Bronchiolar instability can lead to air trapping and hyperinflation and negative effort dependence during forced exhalation. We suggest that the epiphenomenon of asthma-related lung tissue breakdown leading to mild emphysema can be explained by a proinflammatory proteolytic cascade. This is similar to terminal bronchiolar-lung parenchymal uncoupling in smokers with loss of lung elastic recoil in early emphysema as described by Saetta et al55 and by Gelb et al.56,57 In normal aging lungs compared with younger lungs, the loss of lung elastic recoil39 may be related to nearly homogeneous acinar hyperinflation and alveolar ductal ectasia without alveolar breakdown and/or fracture.41,42 Similar lung CT scan densitometry studies in an aging population by Bellia et al58 have also confirmed these findings, and the lower limit of normal was −901 HU. Additional voxel quantitative lung CT scan studies, including measurements of distal airway wall thickness as identified by Rutten et al59 in COPD and by Gupta et al60 in asthma subphenotypes, may also be helpful. Furthermore, as in COPD, loss of small airways and terminal bronchioles in asthma can further magnify expiratory airflow limitation.36,61

We hope this commentary may help begin to explain the clinical conundrum of ACOS in a subset of nonsmokers with chronic asthma,110 often but not necessarily beginning in childhood, with persistent expiratory airflow obstruction despite treatment, and most often noneosinophilic.62 These patients with asthma are at risk for COPD due to a proinflammatory and proteolytic cascade. This may lead to lung tissue breakdown and unsuspected diffuse, mild centrilobular emphysema that is not easily detected clinically, physiologically, or with lung CT scan.36 We need more structure-function studies that include physiologic measurements of static lung elastic recoil pressure with maximal expiratory flow-static lung elastic recoil pressure curves and correlation with formalin-inflated whole-lung specimens as well as analyses of small and large airway pathology. These also need to be correlated with high-resolution thin-section lung CT scan with voxel quantification and other cogent parameters as identified by phenotype cluster analyses. Furthermore, the proinflammatory and proteolytic mechanism(s) leading to lung tissue breakdown need to be further investigated and inhibited.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: We thank Ranna Patel, BS, HT, ASCP, for pathology technical assistance; Colleen Flynn Taylor, MA, and Randy Newsom, RCP, CPFT, for initial lung function testing; Jennifer Klotchman, PhD, Bob Ward, MSEE, professor at California State University, Long Beach (Computer Science), and Stuart Green, MD, professor at University of California, Irvine Medical Center (Orthopedic Surgery), for graphics; Ouided Rouabhi, BS, and Susan Wood, PhD, of Vida Diagnostics, Inc, Cupertino, California and Coralville, Iowa (vidadiagnostics.com) for lung CT scan voxel quantification; Tracy Dyer, MD, who performed the autopsy in case 1 at Dallas County Southwestern Institute of Forensic Sciences, Dallas, TX; Noe Zamel, MD, professor of medicine, University of Toronto Faculty of Medicine, for collaborative physiologic studies25-27,31,56,57; Christine Fraser, RCP, CPFT, Roxanna Moridzadeh, BS, of UCLA, Dallas Beaird, BS, of UC Santa Barbara, Diem Tran, BA, of UC Berkeley, and Capt Lisa Maginot, of West Point, for additional lung function studies; and Michelle Bolling, RN, for patient care.

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Biernacki W, Redpath AT, Best JJK, MacNee W. Measurement of CT lung density in patients with chronic asthma. Eur Respir J. 1997;10(11):2455-2459. [CrossRef] [PubMed]
 
Madani A, De Maertelaer V, Zanen J, Gevenois PA. Pulmonary emphysema: radiation dose and section thickness at multidetector CT quantification—comparison with macroscopic and microscopic morphometry. Radiology. 2007;243(1):250-257. [CrossRef] [PubMed]
 
Gelb AF, Yamamoto A, Mauad T, Kollin J, Schein MJ, Nadel JA. Unsuspected mild emphysema in nonsmoking patients with chronic asthma with persistent airway obstruction. J Allergy Clin Immunol. 2014;133(1):263-265. [CrossRef] [PubMed]
 
Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma [published correction appears inEur Respir J. 2014;43(4):1216]. Eur Respir J. 2014;43(2):343-373. [CrossRef] [PubMed]
 
Nathan RA, Sorkness CA, Kosinski M, et al. Development of the asthma control test: a survey for assessing asthma control. J Allergy Clin Immunol. 2004;113(1):59-65. [CrossRef] [PubMed]
 
Gelb AF, Zamel N. Effect of aging on lung mechanics in healthy nonsmokers. Chest. 1975;68(4):538-541. [CrossRef] [PubMed]
 
Gelb AF, Moridzadeh R, Singh DH, Fraser C, George SC. In moderate-to-severe asthma patients monitoring exhaled nitric oxide during exacerbation is not a good predictor of spirometric response to oral corticosteroid. J Allergy Clin Immunol. 2012;129(6):1491-1498. [CrossRef] [PubMed]
 
Verbeken EK, Cauberghs M, Mertens I, Clement J, Lauweryns JM, Van de Woestijne KP. The senile lung. Comparison with normal and emphysematous lungs. 1. Structural aspects. Chest. 1992;101(3):793-799. [CrossRef] [PubMed]
 
Verbeken EK, Cauberghs M, Mertens I, Clement J, Lauweryns JM, Van de Woestijne KP. The senile lung. Comparison with normal and emphysematous lungs. 2. Functional aspects. Chest. 1992;101(3):800-809. [CrossRef] [PubMed]
 
Bai TR, Cooper J, Koelmeyer T, Paré PD, Weir TD. The effect of age and duration of disease on airway structure in fatal asthma. Am J Respir Crit Care Med. 2000;162(2 pt 1):663-669. [CrossRef] [PubMed]
 
Mauad T, Silva LF, Santos MA, et al. Abnormal alveolar attachments with decreased elastic fiber content in distal lung in fatal asthma. Am J Respir Crit Care Med. 2004;170(8):857-862. [CrossRef] [PubMed]
 
Dolhnikoff M, da Silva LF, de Araujo BB, et al. The outer wall of small airways is a major site of remodeling in fatal asthma. J Allergy Clin Immunol. 2009;123(5):1090-1097. [CrossRef] [PubMed]
 
Mauad T, Bel EH, Sterk PJ. Asthma therapy and airway remodeling. J Allergy Clin Immunol. 2007;120(5):997-1009. [CrossRef] [PubMed]
 
James AL, Elliot JG, Jones RL, et al. Airway smooth muscle hypertrophy and hyperplasia in asthma. Am J Respir Crit Care Med. 2012;185(10):1058-1064. [CrossRef] [PubMed]
 
Senhorini A, Ferreira DS, Shiang C, et al. Airway dimensions in fatal asthma and fatal COPD: overlap in older patients. COPD. 2013;10(3):348-356. [CrossRef] [PubMed]
 
Paganin F, Jaffuel D, Bousquet J. Significance of emphysema observed on computed tomography scan in asthma. Eur Respir J. 1997;10(11):2446-2448. [CrossRef] [PubMed]
 
de Magalhães Simões S, dos Santos MA, da Silva Oliveira M, et al. Inflammatory cell mapping of the respiratory tract in fatal asthma. Clin Exp Allergy. 2005;35(5):602-611. [CrossRef] [PubMed]
 
Baines KJ, Simpson JL, Wood LG, Scott RJ, Gibson PG. Systemic upregulation of neutrophil α-defensins and serine proteases in neutrophilic asthma. Thorax. 2011;66(11):942-947. [CrossRef] [PubMed]
 
Andersson CK, Bergqvist A, Mori M, Mauad T, Bjermer L, Erjefält JS. Mast cell-associated alveolar inflammation in patients with atopic uncontrolled asthma. J Allergy Clin Immunol. 2011;127(4):905-912. [CrossRef] [PubMed]
 
Leopold JG, Gough J. The centrilobular form of hypertrophic emphysema and its relation to chronic bronchitis. Thorax. 1957;12(3):219-235. [CrossRef] [PubMed]
 
Burgel PR, Nadel JA. Epidermal growth factor receptor-mediated innate immune responses and their roles in airway diseases. Eur Respir J. 2008;32(4):1068-1081. [CrossRef] [PubMed]
 
Saetta M, Ghezzo H, Kim WD, et al. Loss of alveolar attachments in smokers. A morphometric correlate of lung function impairment. Am Rev Respir Dis. 1985;132(4):894-900. [PubMed]
 
Gelb AF, Gold WM, Wright RR, Bruch HR, Nadel JA. Physiologic diagnosis of subclinical emphysema. Am Rev Respir Dis. 1973;107(1):50-63. [PubMed]
 
Gelb AF, Zamel N, Hogg JC, Müller NL, Schein MJ. Pseudophysiologic emphysema resulting from severe small-airways disease. Am J Respir Crit Care Med. 1998;158(3):815-819. [CrossRef] [PubMed]
 
Bellia M, Benfante A, Menozzii M, et al. Validation of lung densitometry threshold at CT for the distinction between senile lung and emphysema in elderly subjects. Monaldi Arch Chest Dis. 2011;75(3):162-166. [PubMed]
 
Rutten EPA, Grydeland TB, Pillai SG, et al. Quantitative CT: associations between emphysema, airway wall thickness and body composition in COPD. Pulm Med. 2011;2011(2011):419328. [PubMed]
 
Gupta S, Siddiqui S, Haldar P, et al. Quantitative analysis of high-resolution computed tomography scans in severe asthma subphenotypes. Thorax. 2010;65(9):775-781. [CrossRef] [PubMed]
 
McDonough JE, Yuan R, Suzuki M, et al. Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. N Engl J Med. 2011;365(17):1567-1575. [CrossRef] [PubMed]
 
McGrath KW, Icitovic N, Boushey HA, et al; Asthma Clinical Research Network of the National Heart, Lung, and Blood Institute. A large subgroup of mild-to-moderate asthma is persistently noneosinophilic. Am J Respir Crit Care Med. 2012;185(6):612-619. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Static lung elastic recoil pressure (Pst[l]) was measured in a subgroup of 10 (five women) treated never smokers with asthma aged 52 ± 14 y (mean ± SD) with persistent expiratory airflow limitation.36 All had significant loss of lung elastic recoil compared with normal values. The dashed lines represent four cases which all had autopsy-proven mild diffuse emphysema; three cases (4, 9, 10) were previously reported, and case 11 was not previously reported.36 The individual curves are clearly shifted to the left of lower limit of age-matched normal subjects39 with mild increase in compliance. TLC was mildly elevated at 7.3 (6.8-7.5) L, 112 (110-119)% predicted (median, 1-3 interquartile range). Pst(l) at TLC was 15 (13-18) cm H2O, 63 (50-70)% predicted. TLC = total lung capacity. (Adapted with permission from Gelb et al.36)Grahic Jump Location
Figure Jump LinkFigure 2 –  At any effort independent lung volume, VmaxE = Pst(l) × Gus (conductance of upstream airways).30 At 90% predicted TLC (78% observed TLC) the loss of lung elastic recoil contributes to airflow limitation to a similar extent as the reduction in peripheral airway conductance. Cases 1 to 10 were recently reported, as noted in Figure 1.36 Results in case 11 are similar. Gus = conductance of upstream airways; VmaxE = maximal expiratory flow. See Figure 1 legend for expansion of other abbreviations. (Reprinted with permission from Gelb et al.36)Grahic Jump Location
Figure Jump LinkFigure 3 –  A-D, Note emphysema (A, B, case 9; and C, D, case 10 from Table 1), including not only disorganization and unevenly distributed enlarged airspaces but also disrupted alveolar septa even visible at this magnification, as previously reported.36 In these cases, Alcian blue/Periodic acid-Schiff (PAS stain) showed mucin in terminal bronchioles with plugging, especially in cases 9 and 10, and the plugs contained 70% recruited neutrophils. E, Control asthma case was an 80-y-old woman with asthma with reversible expiratory airflow limitation with treatment. Microscopic morphometry was consistent with “senile lung,” with nearly homogenous acinar hyperinflation and alveolar ductal ectasia but without unevenly distributed airspace enlargement or septal disruption and with no free septal fragments detached from the surrounding structures.41,42 F, Sample from a 71-y-old man with normal lung function. AD = alveolar duct; BV = blood vessel; RB = respiratory bronchiole; TB = terminal bronchiole. (Hematoxylin and eosin stain.)Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Studies in Four Never Smokers With Asthma With Loss of Lung Elastic Recoil and Persistent Expiratory Airflow Obstruction Who Had Unsuspected Microscopic Mild Centrilobular Emphysema at Autopsy

All values are post 270 μg albuterol metered dose inhaler, with normal prediction values previously noted.2527,39 Results demonstrate moderate to severe expiratory airflow limitation on spirometry, with marked reduction in specific airway conductance. There is hyperinflation (trapped gas) at static lung volumes including FRC, RV, and TLC. The hyperinflation at TLC is presumably due to loss of lung elastic recoil. The increase in RV and evidence of airway narrowing suggests early airway closure during expiration (“trapped gas”). Expiratory airflow limitation and hyperinflation at FRC and RV are interpreted as due to a combination of loss of lung elastic recoil and decreased intrinsic airway conductance. The latter is due to intrinsic airway remodeling, including mucous plugging and bronchoconstriction, with resultant premature airway closure. The normal Dlco/Va suggests the presence of an alveolar-capillary surface area within normal limits. The Thurlbeck scores32 on lung CT scan suggest trivial/mild emphysema. However, microscopic sections of formalin-inflated lung demonstrated mild diffuse breakdown of lung tissue (emphysema in Figure 3). Dlco/Va = diffusing capacity corrected for alveolar volume; FRC = functional residual capacity; HU = Hounsfield units; L = left; R = right; RV = residual volume; SGaw = specific airway conductance; TLC = total lung capacity; VC = vital capacity; VQ = voxel quantification for % lung < −950 HU. Cases 4, 9, and 10 were previously reported; case 11 has not been reported previously. Case numbers refer to dashed lines in Figure 1. (Adapted with permission from Gelb et al.36)

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Gelb AF, Licuanan J, Shinar CM, Zamel N. Unsuspected loss of lung elastic recoil in chronic persistent asthma. Chest. 2002;121(3):715-721. [CrossRef] [PubMed]
 
Gelb AF, Schein A, Nussbaum E, et al. Risk factors for near-fatal asthma. Chest. 2004;126(4):1138-1146. [PubMed]
 
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Kraft M, Cairns CB, Ellison MC, Pak J, Irvin C, Wenzel S. Improvements in distal lung function correlate with asthma symptoms after treatment with oral montelukast. Chest. 2006;130(6):1726-1732. [CrossRef] [PubMed]
 
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Gelb AF, Hogg JC, Müller NL, et al. Contribution of emphysema and small airways in COPD. Chest. 1996;109(2):353-359. [CrossRef] [PubMed]
 
Thurlbeck WM, Dunnill MS, Hartung W, Heard BE, Heppleston AG, Ryder RC. A comparison of three methods of measuring emphysema. Hum Pathol. 1970;1(2):215-226. [CrossRef] [PubMed]
 
Busacker A, Newell JD Jr, Keefe T, et al. A multivariate analysis of risk factors for the air-trapping asthmatic phenotype as measured by quantitative CT analysis. Chest. 2009;135(1):48-56. [CrossRef] [PubMed]
 
Biernacki W, Redpath AT, Best JJK, MacNee W. Measurement of CT lung density in patients with chronic asthma. Eur Respir J. 1997;10(11):2455-2459. [CrossRef] [PubMed]
 
Madani A, De Maertelaer V, Zanen J, Gevenois PA. Pulmonary emphysema: radiation dose and section thickness at multidetector CT quantification—comparison with macroscopic and microscopic morphometry. Radiology. 2007;243(1):250-257. [CrossRef] [PubMed]
 
Gelb AF, Yamamoto A, Mauad T, Kollin J, Schein MJ, Nadel JA. Unsuspected mild emphysema in nonsmoking patients with chronic asthma with persistent airway obstruction. J Allergy Clin Immunol. 2014;133(1):263-265. [CrossRef] [PubMed]
 
Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma [published correction appears inEur Respir J. 2014;43(4):1216]. Eur Respir J. 2014;43(2):343-373. [CrossRef] [PubMed]
 
Nathan RA, Sorkness CA, Kosinski M, et al. Development of the asthma control test: a survey for assessing asthma control. J Allergy Clin Immunol. 2004;113(1):59-65. [CrossRef] [PubMed]
 
Gelb AF, Zamel N. Effect of aging on lung mechanics in healthy nonsmokers. Chest. 1975;68(4):538-541. [CrossRef] [PubMed]
 
Gelb AF, Moridzadeh R, Singh DH, Fraser C, George SC. In moderate-to-severe asthma patients monitoring exhaled nitric oxide during exacerbation is not a good predictor of spirometric response to oral corticosteroid. J Allergy Clin Immunol. 2012;129(6):1491-1498. [CrossRef] [PubMed]
 
Verbeken EK, Cauberghs M, Mertens I, Clement J, Lauweryns JM, Van de Woestijne KP. The senile lung. Comparison with normal and emphysematous lungs. 1. Structural aspects. Chest. 1992;101(3):793-799. [CrossRef] [PubMed]
 
Verbeken EK, Cauberghs M, Mertens I, Clement J, Lauweryns JM, Van de Woestijne KP. The senile lung. Comparison with normal and emphysematous lungs. 2. Functional aspects. Chest. 1992;101(3):800-809. [CrossRef] [PubMed]
 
Bai TR, Cooper J, Koelmeyer T, Paré PD, Weir TD. The effect of age and duration of disease on airway structure in fatal asthma. Am J Respir Crit Care Med. 2000;162(2 pt 1):663-669. [CrossRef] [PubMed]
 
Mauad T, Silva LF, Santos MA, et al. Abnormal alveolar attachments with decreased elastic fiber content in distal lung in fatal asthma. Am J Respir Crit Care Med. 2004;170(8):857-862. [CrossRef] [PubMed]
 
Dolhnikoff M, da Silva LF, de Araujo BB, et al. The outer wall of small airways is a major site of remodeling in fatal asthma. J Allergy Clin Immunol. 2009;123(5):1090-1097. [CrossRef] [PubMed]
 
Mauad T, Bel EH, Sterk PJ. Asthma therapy and airway remodeling. J Allergy Clin Immunol. 2007;120(5):997-1009. [CrossRef] [PubMed]
 
James AL, Elliot JG, Jones RL, et al. Airway smooth muscle hypertrophy and hyperplasia in asthma. Am J Respir Crit Care Med. 2012;185(10):1058-1064. [CrossRef] [PubMed]
 
Senhorini A, Ferreira DS, Shiang C, et al. Airway dimensions in fatal asthma and fatal COPD: overlap in older patients. COPD. 2013;10(3):348-356. [CrossRef] [PubMed]
 
Paganin F, Jaffuel D, Bousquet J. Significance of emphysema observed on computed tomography scan in asthma. Eur Respir J. 1997;10(11):2446-2448. [CrossRef] [PubMed]
 
de Magalhães Simões S, dos Santos MA, da Silva Oliveira M, et al. Inflammatory cell mapping of the respiratory tract in fatal asthma. Clin Exp Allergy. 2005;35(5):602-611. [CrossRef] [PubMed]
 
Baines KJ, Simpson JL, Wood LG, Scott RJ, Gibson PG. Systemic upregulation of neutrophil α-defensins and serine proteases in neutrophilic asthma. Thorax. 2011;66(11):942-947. [CrossRef] [PubMed]
 
Andersson CK, Bergqvist A, Mori M, Mauad T, Bjermer L, Erjefält JS. Mast cell-associated alveolar inflammation in patients with atopic uncontrolled asthma. J Allergy Clin Immunol. 2011;127(4):905-912. [CrossRef] [PubMed]
 
Leopold JG, Gough J. The centrilobular form of hypertrophic emphysema and its relation to chronic bronchitis. Thorax. 1957;12(3):219-235. [CrossRef] [PubMed]
 
Burgel PR, Nadel JA. Epidermal growth factor receptor-mediated innate immune responses and their roles in airway diseases. Eur Respir J. 2008;32(4):1068-1081. [CrossRef] [PubMed]
 
Saetta M, Ghezzo H, Kim WD, et al. Loss of alveolar attachments in smokers. A morphometric correlate of lung function impairment. Am Rev Respir Dis. 1985;132(4):894-900. [PubMed]
 
Gelb AF, Gold WM, Wright RR, Bruch HR, Nadel JA. Physiologic diagnosis of subclinical emphysema. Am Rev Respir Dis. 1973;107(1):50-63. [PubMed]
 
Gelb AF, Zamel N, Hogg JC, Müller NL, Schein MJ. Pseudophysiologic emphysema resulting from severe small-airways disease. Am J Respir Crit Care Med. 1998;158(3):815-819. [CrossRef] [PubMed]
 
Bellia M, Benfante A, Menozzii M, et al. Validation of lung densitometry threshold at CT for the distinction between senile lung and emphysema in elderly subjects. Monaldi Arch Chest Dis. 2011;75(3):162-166. [PubMed]
 
Rutten EPA, Grydeland TB, Pillai SG, et al. Quantitative CT: associations between emphysema, airway wall thickness and body composition in COPD. Pulm Med. 2011;2011(2011):419328. [PubMed]
 
Gupta S, Siddiqui S, Haldar P, et al. Quantitative analysis of high-resolution computed tomography scans in severe asthma subphenotypes. Thorax. 2010;65(9):775-781. [CrossRef] [PubMed]
 
McDonough JE, Yuan R, Suzuki M, et al. Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. N Engl J Med. 2011;365(17):1567-1575. [CrossRef] [PubMed]
 
McGrath KW, Icitovic N, Boushey HA, et al; Asthma Clinical Research Network of the National Heart, Lung, and Blood Institute. A large subgroup of mild-to-moderate asthma is persistently noneosinophilic. Am J Respir Crit Care Med. 2012;185(6):612-619. [CrossRef] [PubMed]
 
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