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Pulmonary Emphysema Subtypes on Computed Tomography: The MESA COPD Study

      Abstract

      Background

      Pulmonary emphysema is divided into 3 major subtypes at autopsy: centrilobular, paraseptal, and panlobular emphysema. These subtypes can be defined by visual assessment on computed tomography (CT); however, clinical characteristics of emphysema subtypes on CT are not well defined. We developed a reliable approach to visual assessment of emphysema subtypes on CT and examined if emphysema subtypes have distinct characteristics.

      Methods

      The Multi-Ethnic Study of Atherosclerosis COPD Study recruited smokers with chronic obstructive pulmonary disease (COPD) and controls ages 50-79 years with ≥10 pack-years. Participants underwent CT following a standardized protocol. Definitions of centrilobular, paraseptal, and panlobular emphysema were obtained by literature review. Six-minute walk distance and pulmonary function were performed following guidelines.

      Results

      Twenty-seven percent of 318 smokers had emphysema on CT. Interrater reliability of emphysema subtype was substantial (K: 0.70). Compared with participants without emphysema, individuals with centrilobular or panlobular emphysema had greater dyspnea, reduced walk distance, greater hyperinflation, and lower diffusing capacity. In contrast, individuals with paraseptal emphysema were similar to controls, except for male predominance. Centrilobular, but not panlobular or paraseptal, emphysema was associated with greater smoking history (+21 pack-years P <.001). Panlobular, but not other types of emphysema, was associated with reduced body mass index (−5 kg/m2; P = .01). Other than for dyspnea, these findings were independent of the forced expiratory volume in 1 second. Seventeen percent of smokers without COPD on spirometry had emphysema, which was independently associated with reduced walk distance.

      Conclusions

      Emphysema subtypes on CT are common in smokers with and without COPD. Centrilobular and panlobular emphysema, but not paraseptal emphysema, have considerable symptomatic and physiological consequences.

      Keywords

      • Centrilobular and panlobular emphysema detected visually on computed tomography (CT) were associated with increased symptoms and reduced exercise capacity.
      • Paraseptal emphysema, although common, was of little physiologic significance.
      • Emphysema on CT also was observed among 17% of participants without spirometry-defined chronic obstructive pulmonary disease and was associated with functional impairment.
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      • et al.
      The diagnosis of emphysema. A computed tomographic-pathologic correlation.
      • Miller R.R.
      • Müller N.L.
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      • Morrison N.J.
      • Staples C.A.
      Limitations of computed tomography in the assessment of emphysema.
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      • et al.
      The diagnosis of mild emphysema. Correlation of computed tomography and pathology scores.
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      We therefore developed a reliable approach to visual assessment of emphysema subtypes on CT in order to examine clinical characteristics of emphysema subtypes in a multicenter study of smokers drawn predominantly from the general population.

      Materials and Methods

      The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited cases of COPD and controls predominantly from MESA, a population-based prospective cohort study of subclinical atherosclerosis,
      • Bild D.E.
      • Bluemke D.A.
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      • et al.
      Multi-ethnic study of atherosclerosis: objectives and design.
      and the Emphysema and Cancer Action Project (EMCAP), a separate, nonoverlapping lung cancer screening study,
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      Plasma carbonyls do not correlate with lung function or computed tomography measures of lung density in older smokers.
      and also from the outpatient community at Columbia University Medical Center. Included participants were 50-79 years of age with ≥10 pack-year smoking history. Exclusion criteria were clinical cardiovascular disease, stage IIIb-V chronic kidney disease, asthma before age 45 years, prior lung resection, contraindication to magnetic resonance imaging, and pregnancy.
      Protocols for this study were approved by the institutional review board of participating institutions and by the National Heart, Lung, and Blood Institute. Written informed consent was obtained from all participants.

      Visual Assessment of Emphysema Subtypes (See Supplementary Appendix for Additional Details)

      Reliability of emphysema subtype assessment was assessed first in a training set of 40 CT scans from participants selected randomly in EMCAP
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      • Yeh C.C.
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      Plasma carbonyls do not correlate with lung function or computed tomography measures of lung density in older smokers.
      who were not in the MESA COPD Study and verified in an independent validation set of all 127 participants who were recruited into the MESA COPD Study from EMCAP and the community. Scans for the remaining 192 MESA COPD Study participants were read by a single rater (JHMA).

      CT acquisition

      All thoracic CT scans were acquired at suspended inspiration without intravenous contrast and reconstructed using a high-spatial-contrast algorithm with 0.75-mm-slice thickness. The training set scans were acquired on a Siemens 16 multidetector scanner (Siemens Medical Solutions, Malvern, Pa) and all MESA COPD Study scans were acquired on Siemens and GE 64-slice scanners (GE Healthcare, Waukesha, Wis). All scans were acquired at 120 kVp, 0.5 seconds, with milliamperes (mA) set by body mass index for MESA participants (145 for <20 kg/m2, 180 for 20-30 kg/m2, and 270 for >30 kg/m2) following the MESA Lung/SPIROMICS protocol,
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      and 200 mA for EMCAP participants.

      Raters

      Four chest radiologists from 2 academic medical centers independently assessed emphysema subtypes at CT without clinical information. Measurement of image density was not permitted.

      Visual emphysema subtype assessment

      Radiologists used an electronic score sheet to record the extent of each emphysema subtype assessed visually on CT (Supplementary Table 1). Definitions of emphysema subtypes were based on review of the literature:
      The definition of emphysema. Report of a National Heart, Lung, and Blood Institute, Division of Lung Diseases workshop.
      • Leopold J.G.
      • Gough J.
      The centrilobular form of hypertrophic emphysema and its relation to chronic bronchitis.
      • Fletcher C.M.
      • Gilson J.G.
      • Hugh-Jones P.
      • Scadding J.G.
      Terminology, definitions, and classification of chronic pulmonary emphysema and related conditions: a report of the conclusions of a CIBA guest symposium.
      • Pratt P.C.
      • Kilburn K.H.
      A modern concept of the emphysemas based on correlations of structure and function.
      • Heard B.E.
      • Khatchatourov V.
      • Otto H.
      • Putov N.V.
      • Sobin L.
      The morphology of emphysema, chronic bronchitis, and bronchiectasis: definition, nomenclature, and classification.
      • Hansell D.M.
      • Bankier A.A.
      • MacMahon H.
      • McLoud T.C.
      • Müller N.L.
      • Remy J.
      Fleischner Society: gGlossary of terms tor thoracic imaging.
      Centrilobular emphysema: Focal regions of low attenuation, surrounded by normal lung attenuation, located within the central portion of secondary pulmonary lobules. As severity increases, vessels appear “pruned” and low attenuation regions enlarge.Panlobular emphysema: Diffuse regions of low attenuation involving entire secondary pulmonary lobules. As severity increases, paucity of peripheral vessels increases.Paraseptal emphysema: Regions of low attenuation adjacent to visceral pleura (including fissures).
      Raters assigned separate scores for the upper, mid, and lower zones of the right and left lung. The extent of emphysema was defined as the percentage (0 to 100%) of the lung zone affected by each subtype.
      Upon completion of training set assessment by all raters, reference images were selected based on all 4 raters independently agreeing on the isolated presence of each emphysema subtype (Figure 1).
      Figure thumbnail gr1
      Figure 1Reference images for absence of emphysema and emphysema subtypes. Axial computed tomography images were selected from training set scans in which all 4 raters independently agreed on the absence or isolated presence of each emphysema subtype. (A) Absence of emphysema; (B) Centrilobular emphysema; (C) Paraseptal emphysema; (D) Panlobular emphysema.

      Emphysema Subtypes and Clinical Characteristics

      Lung function and 6-minute walk test

      Body plethysmography, single-breath diffusing capacity of carbon monoxide (DLCO), postbronchodilator spirometry, and 6-minute walk distance (6MWD) were assessed following American Thoracic Society recommendations.
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      Standardisation of spirometry.
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      Standardisation of the measurement of lung volumes.
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      • et al.
      Standardisation of the single-breath determination of carbon monoxide uptake in the lung.
      Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories
      ATS statement: guidelines for the six-minute walk test.
      Predicted lung function and 6MWD values were calculated using reference equations.
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      Performance of American Thoracic Society-recommended spirometry reference values in a multiethnic sample of adults: the multi-ethnic study of atherosclerosis (MESA) lung study.
      • Crapo R.O.
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      Lung volumes in healthy nonsmoking adults.
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      Standardized single breath normal values for carbon monoxide diffusing capacity.
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      Lung volume reference values for women and men 65 to 85 years of age.
      COPD was defined as postbronchodilator ratio of forced expired volume in 1 second to forced vital capacity (FEV1/FVC) <0.7 and spirometric severity as mild (FEV1 ≥80% predicted), moderate (50% ≤ FEV1 <80% predicted), severe, or very severe (<50% predicted).
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      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.

      Lung density assessment

      Attenuation was assessed using standard reconstruction CT images with APOLLO software (VIDA Diagnostics, Coralville, Iowa).
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      Percent of emphysema-like lung was defined as the percentage of total voxels within the lung field below −950 Hounsfield units (percent emphysema<-950HU).
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      • de Maertelaer V.
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      • Yernault J.C.
      Comparison of computed density and macroscopic morphometry in pulmonary emphysema.

      Anthropometry, demographics, and other covariates

      Height, weight, and white blood cell (WBC) count were measured, and body mass index (BMI) calculated by standardized protocol. Race-ethnicity was self-reported and dyspnea was assessed using the 5-level (0 to 4) modified Medical Research Council (mMRC) dyspnea scale.
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      The significance of respiratory symptoms and the diagnosis of chronic bronchitis in a working population.
      Resting arterial hemoglobin saturation was estimated by pulse oximetry (SpO2, CMS-50F, Contec Medical Systems, Hebei, China). Low SpO2 was defined as a saturation ≤95% while breathing ambient air or long-term use of supplemental oxygen. Smoking history was confirmed with plasma or urine cotinine levels.
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      Statistical Analysis

      Dichotomous variables are presented as proportions and continuous variables as means with standard deviation unless otherwise indicated.
      Primary analysis assessed the reliability of visual assessment of centrilobular, paraseptal, and panlobular emphysema affecting both lungs by summing the percent severity for upper, mid, and lower zones of both lungs and dividing by 6. For dichotomous analyses, the presence of an emphysema subtype was defined as ≥1% of the lung volume affected. Unweighted Cohen's Κ statistic was computed for presence of an emphysema subtype. The level of agreement was interpreted as follows: <0.2: poor, 0.21-0.4: fair, 0.41-0.6: moderate, 0.61-0.80: substantial, and 0.81-1.0: excellent.
      • Landis J.R.
      • Koch G.G.
      The measurement of observer agreement for categorical data.
      Reliability of subtype severity assessment was estimated with intraclass correlation coefficient.
      For associations between clinical characteristics and visually detected emphysema subtypes, emphysema subtype scores were averaged for CT scans with multiple raters. The predominant emphysema subtype was defined as the subtype affecting the greatest percentage of lung. In order to obtain unbiased estimates of emphysema subtype prevalence in the source population, analyses were weighted by the ratio of COPD prevalence in the source study to that in the MESA COPD Study, as previously described.
      • Smith B.M.
      • Kawut S.M.
      • Bluemke D.A.
      • et al.
      Pulmonary hyperinflation and left ventricular mass: the Multi-Ethnic Study of Atherosclerosis COPD study.
      Clinical characteristics of individuals with centrilobular-, paraseptal-, and panlobular-predominant emphysema were compared with individuals without emphysema using bivariate and multivariate regression, adjusting for age, sex, race-ethnicity, and smoking status. Additional adjustment for percent predicted FEV1 and percent emphysema<-950HU was performed in sensitivity analyses. Dunnett's procedure was used to adjust P-values for multiple pairwise comparisons against participants without emphysema.
      All calculations were performed using SAS 9.3 (Cary, NC) with a hypothesis testing alpha level of 0.05.

      Results

      Reliability of Visual Emphysema Subtype Assessment

      Characteristics of participants included in the training and validation sets are summarized in Supplementary Table 2. The mean age was 68 years in both groups and approximately half were male.
      In the training set, intrareader agreement for the presence of centrilobular, paraseptal, and panlobular emphysema was substantial to excellent (Supplementary Table 3). Interreader agreement was moderate to substantial for centrilobular and paraseptal emphysema, but poor for panlobular emphysema. Nonetheless, reliability of severity of emphysema was moderate to excellent for all subtypes for both intrareader and interreader assessment. In the validation set, findings were generally similar (Supplementary Table 4). The interreader agreement for predominant emphysema subtype was substantial (K: 0.70; 95% confidence interval [CI], 0.59-0.80).

      Prevalence of Emphysema Subtypes

      Of 321 MESA COPD Study participants, 3 CT scans had excessive motion artifact preventing assessment of emphysema subtypes. Among the 318 participants included in the analysis, mean age was 68 ± 7 years, 60% were male, and 48% had COPD that was predominantly moderate in severity (39% mild, 47% moderate, and 14% severe).
      The estimated population prevalence of emphysema was 27% (95% CI, 21%-32%), with centrilobular-predominant emphysema being most common (14%; 95% CI, 10%-18%), followed by paraseptal-predominant (9%; 95% CI, 6%-12%) and panlobular-predominant emphysema (4%; 95% CI, 1%-6%). Among participants with any emphysema, multiple subtypes were present in 57%, with co-existent centrilobular and paraseptal emphysema being most frequent (Figure 2).
      Figure thumbnail gr2
      Figure 2Proportions of MESA COPD Study participants with one or multiple subtypes of emphysema. Presence of each emphysema subtype was defined as ≥1% of the lung volume affected. Proportions are weighted to reflect distribution in the source population (see Methods for details). COPD = chronic obstructive pulmonary disease; MESA = Multi-Ethnic Study of Atherosclerosis.

      Clinical Characteristics of Emphysema Subtypes

      Age and race/ethnicity were similar across predominant emphysema subtypes when compared with participants without emphysema, whereas paraseptal emphysema occurred more frequently in men (Table 1). Current smoking was more common among participants with all emphysema subtypes compared with participants without emphysema.
      Table 1Clinical Characteristics of MESA COPD Study Participants by Predominant Emphysema Subtype
      Clinical CharacteristicMean or Proportion of Clinical Characteristic
      Means and proportions are weighted to reflect distribution in the source population (see Methods for details).


      P-Value Adjusted for Multiple Subtype Comparisons
      P-values comparing emphysema subtypes to a control group (absence of emphysema) are adjusted for multiple comparisons using Dunnett's procedure.
      Global P-Value
      Global P-values are from Kruskal-Wallis, chi-squared, or Fisher exact tests where appropriate.
      Absence of Emphysema

      n = 205 (73%)
      Centrilobular Predominant Emphysema

      n = 65 (14%)
      Paraseptal Predominant Emphysema

      n = 33 (9%)
      Panlobular Predominant Emphysema

      n = 15 (4%)
      Age – years68 ± 7

      Reference
      68 ± 5

      P > 0.99
      68 ± 7

      P > 0.99
      69 ± 5

      P = .97
      .56
      Proportion male – n (%)120 (54)

      Reference
      35 (53)

      P > 0.99
      28 (78)

      P = .02
      8 (58)

      P = .99
      .02
      Race/ethnicity – n (%)
       White101 (51)

      Reference
      43 (56)

      P = .92
      13 (44)

      P = .82
      11 (57)

      P = .97
      .74
       Black50 (22)

      Reference
      18 (33)

      P = .30
      14 (35)

      P = .32
      3 (23)

      P > 0.99
      .25
       Other54 (27)

      Reference
      4 (11)

      P = .08
      6 (21)

      P = .90
      1 (20)

      P = .95
      .10
      Proportion of current smokers – n (%)45 (17)

      Reference
      25 (40)

      P = .003
      15 (45)

      P = .004
      8 (53)

      P = .02
      <.001
      MESA COPD = Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease Study.
      Means and proportions are weighted to reflect distribution in the source population (see Methods for details).
      P-values comparing emphysema subtypes to a control group (absence of emphysema) are adjusted for multiple comparisons using Dunnett's procedure.
      Global P-values are from Kruskal-Wallis, chi-squared, or Fisher exact tests where appropriate.
      Individuals with centrilobular-predominant emphysema had significantly higher numbers of pack-years compared with participants without emphysema (Figure 3A). Individuals with centrilobular-predominant emphysema also were more likely to report grade 2 or higher mMRC dyspnea and have a shorter 6MWD compared with controls, in addition to greater hyperinflation, lower diffusing capacity, higher percent emphysema<-950HU, and higher WBC count after adjustment for age, sex, race-ethnicity, and current smoking status (Table 2). Associations of centrilobular-predominant emphysema with pack-years, 6MWD, hyperinflation, diffusing capacity, lung density, and WBC count remained significant after additional adjustment for percent predicted FEV1 (Table 3). The proportion of individuals with low SpO2 also was greater with centrilobular-predominant emphysema compared with those without emphysema, but this comparison did not achieve statistical significance (Table 2).
      Figure thumbnail gr3
      Figure 3Male sex, body mass index, and pack-years of smoking among MESA COPD Study participants by emphysema subtype. *Indicates P <.05 for bivariate comparison of emphysema subtype versus control group (no emphysema) adjusted for multiple subtype comparisons using Dunnett's procedure. Pack-years, sex prevalence, and body mass are weighted to reflect distribution in the source population (see Methods for details). (A) Pack-years of smoking; (B) Sex; and (C) Body mass index. COPD = chronic obstructive pulmonary disease; MESA = Multi-Ethnic Study of Atherosclerosis.
      Table 2Clinical Characteristics of MESA COPD Study Participants by Predominant Emphysema Subtype
      Clinical CharacteristicPredicted Mean or Proportion of Clinical Characteristic Adjusted for Age, Sex, Race-ethnicity, and Smoking Status
      Predicted means and proportions are weighted to reflect distribution in the source population (see methods for details).


      (95% CI)

      P-Value Adjusted for Multiple Subtype Comparisons
      P-values comparing emphysema subtypes to a control group (absence of emphysema) are adjusted for multiple comparisons using Dunnett's procedure.
      Global P-Value
      Global p-values are from likelihood ratio tests comparing models with and without emphysema subtype term.
      Absence of Emphysema

      n = 205 (73%)
      Centrilobular Predominant Emphysema

      n = 65 (14%)
      Paraseptal Predominant Emphysema

      n = 33 (9%)
      Panlobular Predominant Emphysema

      n = 15 (4%)
      Height – cm166 (165-167)

      Reference
      168 (166-169)

      P = .41
      165 (163-167)

      P = .82
      169 (166-173)

      P = .27
      .13
      Weight – kg78 (75-80)

      Reference
      75 (70-79)

      P = .51
      77 (71-82)

      P = .96
      67 (58-76)

      P = .07
      .11
      Body mass index28 (27-29)

      Reference
      26 (25-28)

      P = .13
      28 (26-30)

      P = .99
      23 (20-27)

      P = .01
      .009
      Pack-years31 (28-34)

      Reference
      52 (46-58)

      P <.001
      35 (27-43)

      P = .70
      33 (21-45)

      P = .99
      <.001
      Proportion with mMRC dyspnea scale ≥2 – %
      6MWD was measured on 263 participants, and mMRC and resting SpO2 measured on 297 participants.
      7.9 (2.2-25)

      Reference
      26 (14-44)

      P <.001
      7.5 (2.0-24)

      P > 0.99
      29 (9.4-62)

      P = .03
      .001
      Proportion

      with COPD – %
      15 (4-47)

      Reference
      54 (32-74)

      P <.001
      29 (12-55)

      P = .08
      48 (16-82)

      P = .04
      <.001
      Percent predicted FEV197 (93-100)

      Reference
      87 (81-93)

      P = .009
      91 (93-98)

      P = .37
      86 (74-98)

      P = .23
      .008
      Percent predicted FVC96 (94-99)

      Reference
      100 (95-105)

      P = .33
      95 (89-101)

      P = .99
      104 (94-114)

      P = .33
      0.20
      FEV1/FVC0.76 (0.75-0.77)

      Reference
      0.64 (0.61-0.67)

      P <.001
      0.73 (0.69-0.76)

      P = .20
      0.62 (0.56-0.68)

      P <.001
      <.001
      Percent predicted RV
      Plethysmography and diffusing capacity were measured on validation participants only.
      82 (74-90)

      Reference
      101 (90-113)

      P = .01
      96 (78-114)

      P = .36
      110 (90-130)

      P = .02
      <.001
      Percent predicted FRC
      Plethysmography and diffusing capacity were measured on validation participants only.
      91 (86-96)

      Reference
      108 (101-116)

      P <.001
      95 (82-107)

      P = .89
      125 (111-138)

      P <.001
      <.001
      Percent predicted TLC
      Plethysmography and diffusing capacity were measured on validation participants only.
      92 (88-95)

      Reference
      102 (97-107)

      P = .002
      98 (89-106)

      P = .41
      104 (95-113)

      P = .03
      <.001
      Percent predicted DLCO/VA
      Plethysmography and diffusing capacity were measured on validation participants only.
      79 (74-83)

      Reference
      64 (59-70)

      P <.001
      81 (72-90)

      P = .96
      65 (56-75)

      P = .03
      <.001
      Percent predicted 6MWD
      6MWD was measured on 263 participants, and mMRC and resting SpO2 measured on 297 participants.
      92 (88-95)

      Reference
      80 (74-87)

      P = .005
      89 (81-98)

      P = .91
      73 (59-87)

      P = .03
      <.001
      Percent emphysema<-950HU1.0 (0.8-1.2)

      Reference
      2.7 (1.9-3.8)

      P <.001
      1.1 (0.7-1.7)

      P = .96
      2.6 (1.4-5.1)

      P = .02
      <.001
      Proportion with SpO2 ≤95% – %
      6MWD was measured on 263 participants, and mMRC and resting SpO2 measured on 297 participants.
      17 (5.2-42)

      Reference
      30 (15-50)

      P = .11
      18 (5.5-44)

      P > 0.99
      32 (9.1-70)

      P = .44
      .07
      White blood cell count – ·109/L6.3 (6.0-6.6)

      Reference
      7.1 (6.6-7.7)

      P = .02
      7.0 (6.3-7.7)

      P = .15
      6.7 (5.6-7.7)

      P = .89
      .02
      6MWD = 6-minute walk distance; CI = confidence interval; DLCO/VA = diffusing capacity of the lung for carbon monoxide divided by alveolar volume; FEV1 = forced expired volume in the first second; FRC = functional residual capacity; FVC = forced vital capacity; HU = Hounsfield units; MESA COPD = Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease Study; mMRC = modified Medical Research Council; RV = residual volume; SpO2 = pulse-oximeter estimated arterial oxygen-hemoglobin saturation; TLC = total lung capacity.
      Predicted means and proportions are weighted to reflect distribution in the source population (see methods for details).
      P-values comparing emphysema subtypes to a control group (absence of emphysema) are adjusted for multiple comparisons using Dunnett's procedure.
      Global p-values are from likelihood ratio tests comparing models with and without emphysema subtype term.
      § 6MWD was measured on 263 participants, and mMRC and resting SpO2 measured on 297 participants.
      Plethysmography and diffusing capacity were measured on validation participants only.
      Table 3Clinical Characteristics of MESA COPD Study Participants by Predominant Emphysema Subtype with Additional Adjustment for Percent Predicted FEV1
      Clinical CharacteristicPredicted Mean or Proportion of Clinical Characteristic Adjusted for Age, Sex, Race-ethnicity, Smoking Status, and Percent Predicted FEV1
      Predicted means and proportions are weighted to reflect distribution in the source population (see Methods for details).


      (95% CI)

      Adjusted P-Value for Multiple Comparisons of Subtypes to Control Group
      P-values comparing emphysema subtypes to a control group (absence of emphysema) are adjusted for multiple comparisons using Dunnett's procedure.
      Global P-Value
      Global P-values are from likelihood ratio tests comparing models with and without emphysema subtype term.
      Absence of Emphysema

      n = 205 (73%)
      Centrilobular Predominant Emphysema

      n = 65 (14%)
      Paraseptal Predominant Emphysema

      n = 33 (9%)
      Panlobular Predominant Emphysema

      n = 15 (4%)
      Body mass index28 (27-29)

      Reference
      26 (25-28)

      P = .08
      28 (26-30)

      P = .97
      23 (20-26)

      P = .008
      .006
      Pack-years31 (28-35)

      Reference
      51 (45-57)

      P <.001
      35 (27-42)

      P = .81
      32 (20-44)

      P > 0.99
      <.001
      Proportion with

      mMRC dyspnea scale ≥2 – %
      6MWD was measured on 263 participants, and mMRC and resting SpO2 measured on 297 participants.
      5.7 (1.2-23)

      Reference
      9.5 (4.1-21)

      P = .23
      3.8 (0.9-15)

      P = .92
      7.5 (1.7-28)

      P = .72
      .53
      Percent predicted RV
      Plethysmography and diffusing capacity were measured on validation participants only.
      83 (75-90)

      Reference
      99 (88-110)

      P = .02
      93 (76-111)

      P = .56
      107 (88-126)

      P = .05
      .01
      Percent predicted FRC
      Plethysmography and diffusing capacity were measured on validation participants only.
      91 (86-96)

      Reference
      109 (101-116)

      P <.001
      96 (84-108)

      P = .80
      126 (112-139)

      P <.001
      <.001
      Percent predicted TLC
      Plethysmography and diffusing capacity were measured on validation participants only.
      91 (88-95)

      Reference
      103 (98-108)

      P <.001
      99 (91-107)

      P = .14
      106 (97-114)

      P = .004
      <.001
      Percent predicted DLCO/VA
      Plethysmography and diffusing capacity were measured on validation participants only.
      81 (77-85)

      Reference
      64 (58-70)

      P <.001
      81 (72-91)

      P > 0.99
      65 (55-75)

      P <.001
      <.001
      Percent predicted 6MWD
      6MWD was measured on 263 participants, and mMRC and resting SpO2 measured on 297 participants.
      92 (88-95)

      Reference
      81 (74-87)

      P = .009
      89 (81-97)

      P = .93
      74 (60-88)

      P = .04
      .002
      Percent emphysema-950 HU1.0 (0.8-1.2)

      Reference
      2.5 (1.8-3.6)

      P <.001
      1.1 (0.7-1.6)

      P = .99
      2.5 (1.3-4.8)

      P = .03
      <.001
      White blood cell count – ·109/L6.3 (6.1-6.6)

      Reference
      7.1 (6.5-7.6)

      P = .05
      7.0 (6.3-7.7)

      P = .21
      6.6 (5.5-7.6)

      P = .97
      .02
      6MWD = 6-minute walk distance; CI = confidence interval; DLCO = diffusing capacity of the lung for carbon monoxide; FEV1 = forced expired volume in the first second; FRC = functional residual capacity; HU = Hounsfield units; MESA COPD = Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease Study; mMRC = modified Medical Research Council; RV = residual volume; SpO2 = pulse-oximeter estimated arterial oxygen-hemoglobin saturation; TLC = total lung capacity.
      Predicted means and proportions are weighted to reflect distribution in the source population (see Methods for details).
      P-values comparing emphysema subtypes to a control group (absence of emphysema) are adjusted for multiple comparisons using Dunnett's procedure.
      Global P-values are from likelihood ratio tests comparing models with and without emphysema subtype term.
      § 6MWD was measured on 263 participants, and mMRC and resting SpO2 measured on 297 participants.
      Plethysmography and diffusing capacity were measured on validation participants only.
      Paraseptal-predominant emphysema was significantly more common among men compared with women, unlike other forms of emphysema (Figure 3B). Participants with paraseptal-predominant emphysema were otherwise similar to those without emphysema, having no increased symptoms or physiologic abnormalities (Tables 2, 3).
      Individuals with panlobular-predominant emphysema had a similar history of smoking to participants without emphysema (Figure 3A), but a significantly lower BMI (Figure 3C). Similar to individuals with centrilobular-predominant emphysema, they were more likely to have dyspnea, shorter 6MWD, hyperinflation, lower diffusing capacity, and higher percent emphysema<-950HU compared with those without emphysema (Table 2). Associations of panlobular-predominant emphysema with BMI, percent predicted 6MWD, hyperinflation, lung density, and diffusing capacity remained significant after additional adjustment for percent predicted FEV1 (Table 3).
      Adjustment for percent emphysema<-950HU was performed to determine if functional and systemic characteristics significantly associated with predominant subtypes were due to differences in emphysema severity. Subtype-specific associations with BMI, pack-years of smoking, 6MWD, and WBC count remained statistically significant (Supplementary Table 5).

      Emphysema Subtypes and COPD

      Emphysema prevalence was higher among those with COPD on spirometry (51%) and increased with COPD severity (Figure 4). This increase was due to differences across categories of COPD severity in prevalence of centrilobular (P <.001) and panlobular emphysema (P = .007), whereas paraseptal emphysema was similar across stages of COPD (P = .50).
      Figure thumbnail gr4
      Figure 4Prevalence of predominant emphysema subtypes among MESA COPD Study participants by COPD severity. Predominant emphysema subtype was defined as the subtype affecting the greatest percentage of lung in each participant and severity of COPD was defined by GOLD spirometric criteria. Proportions are weighted to reflect distribution in the source population (see Methods for details). COPD = chronic obstructive pulmonary disease; GOLD = global initiative for chronic obstructive lung disease; MESA = Multi-Ethnic Study of Atherosclerosis.
      Emphysema was detected in 17% of participants without COPD on spirometry, in whom paraseptal- and centrilobular-predominant emphysema subtypes were most common (46% and 43%, respectively). Among participants without COPD, those with emphysema were more likely to be current and heavier smokers, have shorter 6MWD and higher WBC count compared with those without emphysema, and DLCO did not differ (Supplementary Table 6). Similar associations were observed adjusting for age, sex, race/ethnicity, and smoking status, however, the higher WBC was no longer statistically significant (Table 4).
      Table 4Clinical Characteristics of Participants without COPD by Spirometric Criteria by Presence of Emphysema on CT
      Clinical CharacteristicMean or Proportion of Clinical Characteristics among

      MESA COPD Study Participants without COPD

      Adjusted for Age, Sex, Race-ethnicity, and Smoking Status

      (95% CI)
      P-Value
      P-values represent bivariate comparison of mean or proportion using chi-squared, Fisher’s exact, or Student’s t test where appropriate.
      Emphysema Absent

      n = 138
      Emphysema Present

      n = 28
      Body mass index28 (26-30)27 (26-29).41
      Pack-years31 (27-35)40 (33-47).03
      Proportion with mMRC dyspnea scale ≥2 – %
      6MWD and mMRC dyspnea scale were measured in a subset of participants (n = 145 and n = 156 participants, respectively).
      7.0 (2.9-11)0.0 (0.0-9).36
      Percent predicted FEV199 (95-102)101 (95-107).51
      Percent predicted FVC96 (93-99)100 (94-106).20
      FEV1/FVC0.78 (0.77-0.79)0.77 (0.75-0.79).16
      Percent predicted RV
      Plethysmography and diffusing capacity were measured on validation participants only.
      74 (61-87)86 (69-103).17
      Percent predicted FRC
      Plethysmography and diffusing capacity were measured on validation participants only.
      90 (80-101)104 (90-118).11
      Percent predicted TLC
      Plethysmography and diffusing capacity were measured on validation participants only.
      89 (82-96)98 (88-107).07
      Percent predicted DLCO/VA
      Plethysmography and diffusing capacity were measured on validation participants only.
      79 (72-86)73 (64-82).20
      Percent predicted 6MWD
      6MWD and mMRC dyspnea scale were measured in a subset of participants (n = 145 and n = 156 participants, respectively).
      94 (90-99)83 (75-91).01
      Percent emphysema<-950HU1.0 (0.8-1.3)0.9 (0.6-1.4).63
      Proportion with SpO2 ≤ 95% - %3.3 (0.1-15)12(2.5-40).10
      White blood cell count – ·109/L6.2 (5.8-6.5)6.9 (6.2-7.5).06
      6MWD = 6-minute walk distance; CI = confidence interval; DLCO/VA = diffusing capacity of the lung for carbon monoxide divided by alveolar volume; FEV1 = forced expired volume in the first second; FRC = functional residual capacity; FVC = forced vital capacity; HU = Hounsfield units; MESA COPD = Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease Study; mMRC = modified Medical Research Council; RV = residual volume; SpO2 = pulse-oximeter estimated arterial oxygen-hemoglobin saturation; TLC = total lung capacity.
      P-values represent bivariate comparison of mean or proportion using chi-squared, Fisher’s exact, or Student’s t test where appropriate.
      6MWD and mMRC dyspnea scale were measured in a subset of participants (n = 145 and n = 156 participants, respectively).
      Plethysmography and diffusing capacity were measured on validation participants only.

      Regional Distribution of Emphysema Subtypes

      Centrilobular and paraseptal emphysema severity were greater in the right lung compared with the left lung (P <.001 for both), whereas panlobular emphysema severity did not differ by side (P = .10). Centrilobular and paraseptal emphysema severity also were greater in higher lung zones than lower lung zones (P <.001 for both), whereas severity of panlobular emphysema did not vary by lung zone (P = .84).

      Discussion

      Characteristics of emphysema subtypes on CT were clinically important and varied substantially by predominant emphysema subtype. Centrilobular and panlobular emphysema were associated with increased dyspnea and lower functional capacity on the 6MWD; however, only centrilobular emphysema was associated with smoking history, and only panlobular emphysema was associated with markedly reduced BMI. In contrast, paraseptal emphysema was associated with no increased symptoms or reduced function, and differed from controls only with respect to a male predominance. In addition, emphysema was observed in a substantial minority of smokers without spirometrically defined COPD, and these individuals had a significantly lower 6MWD.
      To our knowledge, this is the largest study to date of the reliability and clinical characteristics of visually assessed emphysema subtypes, and has additional strengths of a multicenter and largely population-based design. The metrics of interrater reliability observed for total emphysema in the present study are as good, if not better, than prior studies.
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      Furthermore, we observed greater proportion of current smokers, higher number of pack-years, shorter 6MWD, and higher WBC count among non-COPD participants with emphysema. While inflammatory responses to cigarette smoke may contribute to the pathogenesis of this underrecognized clinical entity, further mechanistic studies are needed.
      Interrater reliability of panlobular emphysema detection was not as good as centrilobular or paraseptal emphysema, which may reflect the uniform destruction of alveolar walls within the pulmonary lobule in panlobular emphysema.
      The definition of emphysema. Report of a National Heart, Lung, and Blood Institute, Division of Lung Diseases workshop.
      The lack of visual contrast between normal lung density and emphysematous low attenuation within pulmonary lobules, as is seen in centrilobular emphysema, may make visual assessment of panlobular emphysema difficult unless it is advanced.
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      CT densitometry may be better capable of detecting the diffuse low attenuation of panlobular emphysema, particularly at early stages of disease.
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      CT scan appearance, densitometry, and health status in protease inhibitor SZ alpha1-antitrypsin deficiency.
      In support of this hypothesis, greater severity of panlobular emphysema in the present study was independently associated with percent emphysema<-950HU despite poor reliability of visual detection.
      A limitation of the present study is that we did not assess the validity of our emphysema subtype detection method against pathologic specimens. Gold-standard quantification of multiple emphysema subtypes would require microscopic examination of whole lung specimens and was not performed in this population-based sample. We did, however, observe subtype-specific associations with smoking, zonal distributions that were consistent with autopsy descriptions.
      • Anderson Jr., A.E.
      • Foraker A.G.
      Centrilobular emphysema and panlobular emphysema: two different diseases.
      • Anderson Jr., A.E.
      • Hernandez J.A.
      • Eckert P.
      • Foraker A.G.
      Emphysema in lung macrosections correlated with smoking habits.
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      Pulmonary tuberculosis and centrilobular emphysema. The “upright theory” of apical localization.
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      Pulmonary emphysema. Prevalence, severity, and anatomical patterns in macrosections, with respect to smoking habits.
      Differences in disease severity assessed by lung function and percent emphysema, in addition to differences in current smoking, across predominant subtypes may have contributed in part to the observed clinical associations; however, associations generally remained significant, with additional adjustment for the FEV1, percent emphysema<-950HU, and current smoking, the latter being confirmed with cotinine. These findings support a distinct pathobiology and clinical significance of emphysema subtypes, as well as emphysema in the absence of COPD.
      Measures of reliability can be influenced by the spectrum of disease severity. We reported multiple metrics of reliability. In contrast to prior studies of reliability that included patients undergoing lung resection or autopsy,
      • Bergin C.
      • Müller N.
      • Nichols D.M.
      • et al.
      The diagnosis of emphysema. A computed tomographic-pathologic correlation.
      • Miller R.R.
      • Müller N.L.
      • Vedal S.
      • Morrison N.J.
      • Staples C.A.
      Limitations of computed tomography in the assessment of emphysema.
      • Kuwano K.
      • Matsuba K.
      • Ikeda T.
      • et al.
      The diagnosis of mild emphysema. Correlation of computed tomography and pathology scores.
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      • Keyzer C.
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      Pulmonary emphysema: subjective visual grading versus objective quantification with macroscopic morphometry and thin-section CT densitometry.
      our study enrolled a population-based sample of current and former smokers, which increases the applicability of our findings and the importance of studying emphysema subtypes early in the course of disease.
      In summary, a reliable method for detecting emphysema subtypes at CT identified both novel and classically described clinical characteristics that suggest distinct pathophysiology and clinical significance. Centrilobular and panlobular emphysema were associated with increased symptoms, as well as reduced exercise capacity independent of airflow obstruction; whereas paraseptal emphysema, although common, was of little physiologic significance. Emphysema also was observed in a substantial minority of individuals without COPD and was associated with functional impairment.

      Appendix

      Pulmonary Emphysema Subtypes on Computed Tomography in Smokers

      Supplementary Materials and Methods
      Visual Assessment of Emphysema Subtypes
      Reliability of emphysema subtype assessment was assessed using training and validation sets of thoracic computed tomography (CT) scans.
      Training Set: Forty thoracic CT scans were randomly selected from 40 participants in the Emphysema and Cancer Action Project (EMCAP)
      • Mesia-Vela S.
      • Yeh C.C.
      • Austin J.H.
      • et al.
      Plasma carbonyls do not correlate with lung function or computed tomography measures of lung density in older smokers.
      who were not enrolled in the Multi-Ethnic Study of Atherosclerosis chronic obstructive pulmonary disease (MESA COPD) Study. EMCAP participants were 60 years and over with at least 10 pack-years of smoking history. Individuals with a history of cancer (other than nonmelanoma skin cancer) were excluded. All scans included in the training set were acquired at Columbia University Medical Center (CUMC). Duplicates of 10 randomly selected scans were added to the set in random sequence to assess intrareader reliability.
      Validation Set: All thoracic CT scans from MESA COPD Study participants undergoing plethysmography at CUMC were included in the validation set (n = 127).
      CT Acquisition: All thoracic CT scans were acquired at suspended inspiration without intravenous contrast and reconstructed using a high-spatial-contrast algorithm with 0.75-mm-slice thickness. The training set scans were acquired on a Siemens 16 multidetector scanner and MESA COPD Study scans were acquired on a GE 64-slice scanner. All scans were acquired at 120 kVp, 0.5 seconds, with milliamperes (mA) set by body mass index for MESA participants (145 for <20 kg/m2, 180 for 20-30 kg/m2 and 270 for >30 kg/m2) following the MESA Lung/SPIROMICS protocol,
      • Sieren J.P.
      • Hoffman E.A.
      • Baumhauer H.
      • Barr R.G.
      • Goldin J.G.
      • Rennard S.
      CT Imaging Protocol Standardization for Use in a Multicenter Study: Spiromics.
      and 200 mA for EMCAP participants.
      Raters: Four chest radiologists (JHMA with 44 years of experience, JDN Jr. with 34 years of experience, BMD with 10 years of experience, and AR with 18 years of experience) from 2 academic medical centers independently assessed emphysema subtypes at CT without clinical information. The entire training set was evaluated by each of the 4 raters. The validation set was evaluated entirely by 2 raters and in part by the other 2 raters. Raters were instructed to assess thoracic CT scans in a quiet room without overhead lighting using high-resolution displays designed for clinical viewing. Measurement of image density was not permitted.
      Visual Emphysema Subtype Assessment: Raters used an electronic score sheet to record the extent of each emphysema subtype assessed visually at CT (Supplementary Table 1). Definitions of emphysema subtypes were based on review of the literature
      • Leopold J.G.
      • Gough J.
      The centrilobular form of hypertrophic emphysema and its relation to chronic bronchitis.
      • Fletcher C.M.
      • Gilson J.G.
      • Hugh-Jones P.
      • Scadding J.G.
      Terminology, definitions, and classification of chronic pulmonary emphysema and related conditions: a report of the conclusions of a CIBA guest symposium.
      • Pratt P.C.
      • Kilburn K.H.
      A modern concept of the emphysemas based on correlations of structure and function.
      The definition of emphysema. Report of a National Heart, Lung, and Blood Institute, Division of Lung Diseases workshop.
      • Heard B.E.
      • Khatchatourov V.
      • Otto H.
      • Putov N.V.
      • Sobin L.
      The morphology of emphysema, chronic bronchitis, and bronchiectasis: definition, nomenclature, and classification.
      • Hansell D.M.
      • Bankier A.A.
      • MacMahon H.
      • McLoud T.C.
      • Müller N.L.
      • Remy J.
      Fleischner Society: glossary of terms tor thoracic imaging.
      • Foster Jr., W.L.
      • Gimenez E.I.
      • Roubidoux M.A.
      • et al.
      The emphysemas: radiologic-pathologic correlations.
      • Thurlbeck W.M.
      • Muller N.L.
      Emphysema: definition, imaging, and quantification.
      and agreed upon by consensus before initiation of the study. Definitions of the predominant emphysema subtypes used in the validation set are listed below:
      Centrilobular emphysema: Focal regions of low attenuation, surrounded by normal lung attenuation, located within the central portion of secondary pulmonary lobules. As severity increases, vessels appear “pruned” and low attenuation regions enlarge.
      Panlobular emphysema: Diffuse regions of low attenuation involving entire secondary pulmonary lobules. As severity increases, paucity of peripheral vessels increases.
      Paraseptal emphysema: Regions of low attenuation adjacent to visceral pleura (including fissures).
      Raters assigned separate scores for the upper, mid, and lower zones of the right and left lung (Supplementary Table 1). The extent of emphysema was defined as the percentage (0.0 to 100%) of the lung zone affected by each subtype. Extent of paraseptal emphysema also was relative to the entire lung zone and not just the peripheral lung zone.
      Upon completion of training set assessment by all raters, reference images were selected based on all 4 raters independently agreeing on the isolated presence of each emphysema subtype (Figure 1). These images were viewed by raters before initiation of the validation set assessment and were available as reference.
      Supplementary Table 1Sample of Emphysema Score Sheet
      Study ID: XXXXXXXX
      Emphysema/Low Attenuation SubtypeSeverity (0%-100%)
      Upper ZoneMid ZoneLower Zone
      RightLeftRightLeftRightLeft
      Centrilobular8.0%6.0%3.0%2.0%1.0%0.0%
      Panlobular0.0%0.0%0.0%0.0%0.0%0.0%
      Paraseptal2.0%2.0%1.0%0.0%0.0%1.0%
      Ambiguous
      Ambiguous subtype: Use this category if you are certain emphysema is present but uncertain of the subtype. Be as specific as possible (eg, if you are confident that paraseptal emphysema is present but unsure if remainder of emphysema is centrilobular or panlobular, use the paraseptal and ambiguous categories).
      0.0%0.0%0.0%0.0%0.0%0.0%
      Total (auto sum column, maximum 100):10.0%8.0%4.0%2.0%1.0%1.0%
      Other causes of low attenuation: (e.g., paracicatricial emphysema, cyst, non-paraseptal bullae, pneumatocele, cavity, honeycomb, bronchomalacia)Free text
      Zones: Upper zone is defined from apex to mid-aortic arch; mid zone from mid-aortic arch to mid-entry level of the most inferior pulmonary vein; and lower zone from mid-entry level of the most inferior pulmonary vein to the diaphragm. See methods for emphysema subtype and severity definitions.
      Ambiguous subtype: Use this category if you are certain emphysema is present but uncertain of the subtype. Be as specific as possible (eg, if you are confident that paraseptal emphysema is present but unsure if remainder of emphysema is centrilobular or panlobular, use the paraseptal and ambiguous categories).
      Supplementary Table 2Characteristics of Participants Included in the Training and Validation Sets
      Training SetValidation Set
      Thoracic CT scans – no.40127
      Age – years68 ± 568 ± 7
      Male – no. (%)18 (45)69 (54)
      Race-ethnicity – no. (%)
      P <.05 for pairwise comparison between training and validation set.
       White30 (75)91 (72)
       Black3 (8)27 (21)
       Other7 (18)9 (7)
      Height – cm168 ± 11169 ± 10
      Weight – kg77 ± 1878 ± 18
      Body mass index27 ± 527 ± 6
      Smoking status
       Current16 (40)38 (30)
       Former24 (60)89 (70)
      Pack-years – median (1st, 3rd quartile)47 (25, 70)39 (25, 55)
      COPD – no. (%)
      Spirometry was not available for 4 participants in the training set.
       None14 (39)41 (32)
       Mild4 (11)30 (24)
       Moderate14 (39)38 (30)
       Severe / very severe3 (11)18 (14)
      Percent predicted FEV1 – %
      Spirometry was not available for 4 participants in the training set.
      77 ± 2281 ± 25
      Plus-minus values are mean ± standard deviation unless otherwise indicated.
      COPD = chronic obstructive pulmonary disease; CT = computed tomography; FEV1 = forced expired volume in the first second.
      P <.05 for pairwise comparison between training and validation set.
      Spirometry was not available for 4 participants in the training set.
      Supplementary Table 3Reliability of Visually Detected Subtypes of Pulmonary Emphysema at CT in the Training Set
      Presence of EmphysemaExtent of Emphysema
      Unweighted Cohen's Κ (95% CI)ICC Coefficient (95% CI)
      Training set intrareader reliability (n = 10 participants × 4 readers)
       Centrilobular emphysema0.84 (0.67 to 1.00)0.82 (0.73-0.88)
       Paraseptal emphysema0.89 (0.74-1.00)0.81 (0.71-0.88)
       Panlobular emphysema0.79 (0.58-1.00)0.64 (0.48-0.76)
       Any emphysema0.94 (0.82-1.00)0.84 (0.76-0.90)
      Training set interreader reliability (n = 40 participants × 4 readers)
       Centrilobular emphysema0.80 (0.62-0.99)0.74 (0.56-0.85)
       Paraseptal emphysema0.58 (0.34-0.83)0.67 (0.46-0.81)
       Panlobular emphysema0.11 (−0.18-0.40)0.59 (0.35-0.76)
       Any emphysema0.78 (0.58-0.98)0.76 (0.59-0.86)
      CI = confidence interval; CT = computed tomography; ICC intraclass correlation.
      Supplementary Table 4Reliability of Visually Detected Subtypes of Pulmonary Emphysema at CT in the Validation Set
      Presence of EmphysemaExtent of Emphysema
      Unweighted Cohen's Κ (95% CI)ICC Coefficient (95% CI)
      Validation set inter-reader reliability (n = 127 participants × 3 readers)
       Centrilobular emphysema0.78 (0.67-0.89)0.72 (0.64-0.80)
       Paraseptal emphysema0.54 (0.39-0.70)0.93 (0.90-0.95)
       Panlobular emphysema0.16 (0.00-0.36)0.42 (0.31-0.55)
       Any emphysema0.76 (0.65-0.87)0.77 (0.69-0.83)
      CI = confidence interval; CT = computed tomography; ICC intraclass correlation.
      Supplementary Table 5Clinical Characteristics of MESA COPD Study Participants by Predominant Emphysema Subtype with Additional Adjustment for Percent Predicted FEV1 and Percent Emphysema<-950HU
      Clinical CharacteristicPredicted Mean or Proportion of Clinical Characteristic Adjusted for Age, Sex, Race-ethnicity, Smoking Status, Percent Predicted FEV1 and Percent Emphysema<-950HU
      Predicted means and proportions are weighted to reflect distribution in the source population (see Methods for details).
      (95% CI)

      Adjusted P-Value for Multiple Comparisons of Subtypes to Control Group
      P-values comparing emphysema subtypes to a control group (absence of emphysema) are adjusted for multiple comparisons using Dunnett's procedure.
      Global P-value
      Global P-values are from likelihood ratio tests comparing models with and without emphysema subtype term.
      Absence of Emphysema n = 205 (73%)Centrilobular Predominant Emphysema n = 65 (14%)Paraseptal Predominant Emphysema n = 33 (9%)Panlobular Predominant Emphysema n = 15 (4%)
      Body mass index28 (27-29)

      Reference
      27 (25-28)

      P = .48
      28 (26-30)

      P = .98
      24 (21-27)

      P = .03
      .008
      Pack-years31 (28-35)

      Reference
      51 (45-57)

      P <.001
      35 (27-43)

      P = .81
      32 (20-43)

      P > 0.99
      <.001
      Proportion with mMRC dyspnea scale ≥2 – %
      6MWD was measured on 263 participants, and mMRC and resting SpO2 measured on 297 participants.
      5.5 (1.1-24)

      Reference
      9.0 (2.9-25)

      P = .29
      3.6 (0.6-19)

      P = .56
      7.0 (1.0-36)

      P = .76
      .59
      Percent predicted 6MWD
      6MWD was measured on 263 participants, and mMRC and resting SpO2 measured on 297 participants.
      92 (88-96)

      Reference
      80 (74-87)

      P = .005
      90 (81-98)

      P = .93
      73 (58-87)

      P = .03
      .002
      White blood cell count – ·109/L6.3 (6.0-6.6)

      Reference
      7.1 (6.6-7.7)

      P = .03
      7.0 (6.3-7.7)

      P = .20
      6.6 (5.6-7.7)

      P = .92
      .02
      6MWD = 6-minute walk distance; CI = confidence interval; DLCO/VA = diffusing capacity of the lung for carbon monoxide divided by alveolar volume; FEV1 = forced expired volume in the first second; FRC = functional residual capacity; FVC = forced vital capacity; HU = Hounsfield units; MESA COPD = Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease Study; mMRC = modified Medical Research Council; RV = residual volume; SpO2 = pulse-oximeter estimated arterial oxygen-hemoglobin saturation; TLC = total lung capacity.
      Predicted means and proportions are weighted to reflect distribution in the source population (see Methods for details).
      P-values comparing emphysema subtypes to a control group (absence of emphysema) are adjusted for multiple comparisons using Dunnett's procedure.
      Global P-values are from likelihood ratio tests comparing models with and without emphysema subtype term.
      6MWD was measured on 263 participants, and mMRC and resting SpO2 measured on 297 participants.
      Supplementary Table 6Clinical Characteristics of MESA COPD Study Participants without COPD by Presence of Emphysema on CT
      Clinical CharacteristicMean or Proportion of Clinical Characteristics among MESA COPD Study Participants without COPD

      (95% CI)
      P-Value
      P-values represent bivariate comparison of mean or proportion using Chi-square, Fisher's exact or Student's t test where appropriate.
      Emphysema Absent n = 138Emphysema Present n = 28
      Age – years68 (67-69)67 (65-70).84
      Proportion male – %53 (44-61)57 (38-77).68
      Race/ethnicity – %
       White46 (37-54)36 (17-55).33
       Black22 (15-30)39 (20-59).06
       Other16 (24-40)25 (7.9-42).47
      Proportion of current smokers – %16 (9.8-22)50 (30-70)<.001
      Height – cm167 (165-168)168 (164-171).51
      Weight – kg81 (78-84)79 (72-85).58
      Body mass index29 (28-30)28 (26-30).24
      Pack-years30 (27-34)41 (33-48).01
      Proportion with mMRC dyspnea scale ≥2 – %
      6MWD and mMRC dyspnea scale were measured in a subset of participants (n = 145 and n = 156 participants, respectively).
      7.0 (2.9-11)0 (0-9).36
      Percent predicted FEV1100 (97-103)100 (95-106).91
      Percent predicted FVC97 (94-99)100 (94-105).37
      FEV1/FVC0.78 (0.78-0.79)0.77 (0.75-0.79).11
      Percent predicted RV
      Plethysmography and diffusing capacity were measured on validation participants only.
      84 (75-93)92 (76-108).37
      Percent predicted FRC
      Plethysmography and diffusing capacity were measured on validation participants only.
      94 (86-101)106 (93-119).11
      Percent predicted TLC
      Plethysmography and diffusing capacity were measured on validation participants only.
      97 (91-102)102 (92-112).34
      Percent predicted DLCO/VA
      Plethysmography and diffusing capacity were measured on validation participants only.
      80 (76-85)76 (65-88).44
      Percent predicted 6MWD
      6MWD and mMRC dyspnea scale were measured in a subset of participants (n = 145 and n = 156 participants, respectively).
      95 (91-98)82 (74-90).003
      Percent emphysema<-950HU1.0 (0.7-1.4)1.2 (1.0-1.4).36
      Proportion with SpO2 ≤ 95% - %13 (7.4-19)19 (2.9-34).54
      White blood cell count – ·109/L6.1 (5.8-6.4)6.9 (6.2-7.5).03
      6MWD = 6-minute walk distance; CI = confidence interval; DLCO/VA = diffusing capacity of the lung for carbon monoxide divided by alveolar volume; FEV1 = forced expired volume in the first second; FRC = functional residual capacity; FVC = forced vital capacity; HU = Hounsfield units; MESA COPD = Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease Study; mMRC = modified Medical Research Council; RV = residual volume; SpO2 = pulse-oximeter estimated arterial oxygen-hemoglobin saturation; TLC = total lung capacity.
      P-values represent bivariate comparison of mean or proportion using Chi-square, Fisher's exact or Student's t test where appropriate.
      6MWD and mMRC dyspnea scale were measured in a subset of participants (n = 145 and n = 156 participants, respectively).
      Plethysmography and diffusing capacity were measured on validation participants only.

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