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Ventilation Heterogeneity in Never-smokers and COPD

Posted Mar 31, 2016 Updated Apr 10, 2023
By Christopher Davis MD , Khadija Sheikh BSc , Damien Pike BSc , Sarah Svenningsen PhD , David G. McCormack MD , Denis O'Donnell MD , J. Alberto Neder MD , Grace Parraga PhD
12 min read

Rationale and Objectives

Pulmonary functional magnetic resonance imaging provides a way to quantify ventilation and its heterogeneity—a hallmark finding in chronic obstructive pulmonary disease (COPD). Unfortunately, the etiology and physiological meaning of ventilation defects and their relationship to pulmonary function and symptoms in COPD are not well understood. Another biomarker of ventilation heterogeneity is provided by the “poorly communicating fraction” (PCF), and is calculated as the ratio of total lung capacity to alveolar volume made using whole-body plethysmography. Our objective was to compare ventilation heterogeneity using hyperpolarized 3 He magnetic resonance imaging (MRI) and PCF measurements in elderly never-smokers and in ex-smokers with COPD.

Materials and Methods

One hundred forty-six participants (71 ± 8 years, range = 48–87 years) provided written informed consent including 45 elderly never-smokers (71 ± 6 years, range = 61–84 years) and 101 ex-smokers with COPD (71 ± 8 years, range = 48–87 years). During a single 2-hour visit, spirometry, plethysmography, and hyperpolarized 3 He MRI were acquired. The MRI-derived ventilation defect percent (VDP) and plethysmography measurements were acquired and PCF values were calculated. Linear regression, Pearson correlations, and Bland-Altman analysis were used to evaluate the relationships for PCF and MRI VDP.

Results

PCF ( P < 0.001) and VDP ( P < 0.001) were significantly increased with increasing COPD severity. There was a significant relationship for VDP and PCF (r = 0.68, P < 0.001) in all subjects and COPD subjects alone (r = 0.61, P < 0.001). Bland-Altman analysis showed that PCF and VDP were significantly different (mean bias = 9.7, upper limit = 32, lower limit = −13, P < 0.001), and in severe-grade COPD, PCF overestimates of VDP were significantly greater.

Conclusions

In elderly never-smokers and in ex-smokers with COPD, PCF and VDP are moderately correlated estimates of COPD ventilation heterogeneity that may be reflecting similar pathophysiology.

Introduction

Chronic obstructive pulmonary disease (COPD) is a major cause of long-term disability and mortality . COPD is recognized as physiologically heterogeneous among patients as well as regionally heterogeneous within individual patients. Patchy ventilation, ventilation heterogeneity, and ventilation defects are hallmark findings in COPD and are believed to represent the abnormally long time constants for lung filling and emptying due to both airways disease and emphysematous bullae . Noninvasive techniques that measure ventilation heterogeneity in COPD patients include multiple-breath nitrogen washout , dual tracer gas single-breath washout to measure the “lung clearance index” , as well as imaging methods that provide visual and quantitative evidence of ventilation and its spatial distribution. Such pulmonary imaging methods include high-resolution X-ray computed tomography , single positron emission tomography , positron emission tomography , and inhaled noble gas magnetic resonance imaging (MRI) .

Recently, a novel physiological biomarker of ventilation heterogeneity, the “poorly communicating fraction” (PCF) , was reported and evaluated in COPD patients. As shown in the schematic in Figure 1 , the PCF is generated as the ratio of total lung capacity (TLC) to alveolar volume (V A ) . V A is the volume of gas that ventilates alveoli in each breath and is generated as the ratio of inhaled to exhaled inert tracer gas (He, Ne, CH 4 ) multiplied by the difference of the total inspiratory and dead space volume . Importantly, the PCF was recently shown to predict exercise intolerance in COPD patients , but this measurement has not been directly compared to other measurements of ventilation heterogeneity, including those quantified using imaging.

Figure 1, Schematic for magnetic resonance imaging (MRI) and poorly communicating fraction (PCF) measurements of ventilation heterogeneity. PCF was determined using a single-inhalation breath of 10 Ne gas from functional residual capacity (FRC), whereas ventilation defect percent (VDP) was generated using a single-inhalation breath-hold of 3 He gas. The gas diffusion spatial characteristics of 10 Ne are indicated with “?” because their spatial distribution cannot be quantified. Regions of interest with focal 3 He MRI ventilation defects are indicated in black shadow. F A,Tr , concentration alveolar/expired tracer; F I,Tr , concentration inspired tracer; TCV, thoracic cavity volume; VDV, ventilation defect volume; VI, ventilatory volume; VT, total inspiratory volume.

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Methods

Study Subjects

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Data Acquisition

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VA=FI,Tr/FA,Tr(VT−Vdeadspace) VA

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F

I

,

Tr

/

F

A

,

Tr

(

VT

−

Vdeadspace

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PCF=1−(VA/TLC) PCF

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1

−

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Statistical Analysis

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Results

Participant Characteristics

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Table 1

Demographic and Ventilation Heterogeneity Data

Mean (SD) Never-smokers ( n = 45) Ex-smokers with COPD ( n = 101) Sig. Diff. P Age years [Range] 71 (6) [61–84] 71 (8) [48–87] 1.00 Men n [%] 18 [40] 65 [65] <0.05 BMI [Range] 27 (4) [20–34] 27 (5) [16–37] 0.70 FEV 1 L 2.7 (0.7) 1.7 (0.7) <0.001 FEV 1 % 107 (20) 62 (23) <0.001 FEV 1 /FVC 77 (6) 50 (12) <0.001 DL CO % 87 (18) 54 (20) <0.001 RV % 104 (29) 156 (47) <0.001 FRC % 107 (20) 140 (37) <0.001 TLC % 107 (14) 118 (18) <0.001 V a L 5.4 (1.3) 5.1 (1.3) 0.17 V a % 93 (13) 85 (16) 0.001 PCF % 12 (10) 28 (16) <0.001 VDP % 4 (3) 18 (10) <0.001

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Ventilation Heterogeneity and COPD Severity

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Figure 2, 3 He magnetic resonance imaging (MRI) ventilation heterogeneity never-smokers and ex-smokers. Single-inhalation breath-hold 3 He MRI ( cyan ) co-registered with 1 H anatomical MRI ( gray scale ).

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Figure 3, Chronic obstructive pulmonary disease (COPD) severity and ventilation heterogeneity. (a) Boxplot (median, interquartiles, and range) for ventilation defect percent (PCF) ( shaded ) and VDP ( white ) in never-smokers and in ex-smokers with COPD by Global initiative for Obstructive Lung Disease (GOLD) grade. Outliers greater than 1.5× the interquartile range are indicated with solid dots. Mean ventilation defect percent (VDP) for never-smoker (NS) = 4% ± 3%, GI = 9% ± 5%, GII = 16% ± 8%, GIII/IV = 25 ± 8; mean PCF for NS = 12 ± 10, GI = 15 ± 14, GII = 25 ± 12, GIII/IV = 39 ± 13. (b) Cumulative percent distribution of PCF by tertiles and VDP by GOLD grade. For NS and GI, VDP = 100% mild, PCF = 91%/86% mild; for GI VDP = 79% mild, PCF = 53% mild; for GIII/VI VDP = 44% mild, PCF = 9% mild.

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Relationships for PCF and MRI Ventilation Heterogeneity

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Figure 4, Relationship and agreement for poorly communicating fraction (PCF) and ventilation defect percent (VDP). (a) Relationship of PCF and VDP for all subjects (y = 9.67 + x, r = 0.68, P < 0.001), (b) Bland-Altman analysis of agreement showing that PCF and VDP are significantly different ( P < 0.001) with a bias toward PCF overestimating percent ventilation defect in higher chronic obstructive pulmonary disease (COPD) Global initiative for Obstructive Lung Disease (GOLD) grade. Upper limit = 32, lower limit = −13, mean bias = 9.7. GI, GOLD grade I; GII, GOLD grade II; GIII, GOLD grade III; GIV, GOLD grade IV; NS, never-smokers.

Figure 5, Differences in ventilation defect percent (VDP) and poorly communicating fraction (PCF) by chronic obstructive pulmonary disease (COPD) severity. Percent differences (PCF-VDP) for healthy never-smokers and Global initiative for Obstructive Lung Disease (GOLD) grade I–IV patients displayed as cumulative percent of subgroup. GI, GOLD grade I; GII, GOLD grade II; GIII, GOLD grade III; GIV, GOLD grade IV; NS, never-smokers.

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Discussion

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PCF and VDP Worsen with Increasing COPD Severity

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PCF and VDP Are Correlated

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VDP Underestimates PCF in Severe COPD

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Limitations

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Conclusions

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Acknowledgments

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Academic Radiology, Volume 23, Issue 4
Journals General Radiology
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