Disproportionally Impaired Diffusion Capacity Relative to Airflow Limitation in COPD

Figures & data

Figure 1. Patient flowcharts.

A. The KOCOSS Cohort was cross-sectionally analyzed. B. The Kyoto University Cohort was cross-sectionally and longitudinally analyzed.

Table 1. Demographics of patients in the two cohorts.

	KOCOSS	Kyoto University
N	743	195
Age (years)	68.9 (7.6)	69.9 (8.5)
Male (%)	100%	100%
Smoking pack-years	47.2 (24.2)	67.2 (34.7)
Height (cm)	165.4 (5.6)	164.5 (6.1)
Weight (kg)	62.8 (9.6)	59.8 (9.3)
Body mass index	22.9 (3.1)	22.1 (2.9)
FEV1 (% predicted)	62.4 (19.2)	61.6 (19.7)
FVC (% predicted)	101.9 (19.2)	101.0 (18.4)
FEV1 (z-score)	–2.2 (1.1)	–2.2 (1.1)
FVC (z-score)	0.1 (1.3)	0.0 (1.3)
FEV1/FVC	0.48 (0.11)	0.48 (0.12)
DLCO (% predicted)	58.1 (19.1)	58.0 (21.9)
DLCO (z-score)	–3.0 (1.6)	–3.0 (1.9)
mMRC ≥ 2 (%)	34%	25%

Data are reported as means (SD). FEV₁ = forced expiratory volume in 1 s. FVC = forced vital capacity. D_LCO = diffusion capacity for carbon monoxide. mMRC = modified MRC dyspnea scale.

Figure 2. Distributions of FEV₁ and D_LCO in the two cohorts.

A. KOCOSS Cohort. B. Kyoto University Cohort. Patients were categorized into four groups: (1) FEV₁ z-score > –3 and D_LCO z-score > –3 (reference, red), (2) FEV₁ z-score > –3 and D_LCO z-score ≤ –3 (disproportionally impaired D_LCO, green), (3) FEV₁ z-score ≤ –3 and D_LCO z-score > –3 (disproportionally impaired FEV₁, blue), and (4) FEV₁ z-score ≤ –3 and D_LCO z-score ≤ –3 (mixed-impaired, purple).

Figure 3. Associations of D_LCO, FEV₁, and both impairments with patient-reported outcomes and exercise capacity in a multivariable analysis of the KOCOSS cohort.

Patients (n = 743) were categorized into four groups: (1) FEV₁ z-score > –3 and D_LCO z-score > –3 (reference, n = 351), (2) FEV₁ z-score > –3 and D_LCO z-score ≤ –3 (disproportionally impaired D_LCO, n = 212), (3) FEV₁ z-score ≤ –3 and D_LCO z-score > –3 (disproportionally impaired FEV₁, n = 62), and (4) FEV₁ z-score ≤ –3 and D_LCO z-score ≤ –3 (mixed-impaired, n = 118). A dot with an error bar indicates the least-square mean (LS mean) with the 95% CI. * p<.05 compared to the reference group in the multivariable models. Each model was adjusted for age, pack-years of smoking, height and weight. 6MWD = six-minute walking distance. CAT = COPD assessment test. SGRQ = St. George's Respiratory Questionnaire. 6MWD, CAT, and SGRQ data were available for 641, 717, and 395 patients, respectively.

Table 2. Clinical characteristics of the four groups in the KOCOSS Cohort.

	Reference	Disproportionally impaired DLCO	Disproportionally impaired FEV1	Mixed-impaired	P
N	351	212	62	118
Age (years)	69.0 (7.6)	70.4 (7.6)	65.7 (7.1) ^†	67.6 (7.3)	<.01
Smoking PY	44.2 (22.7)	51.3 (25.6)^†	45.3 (20.2)	49.4 (26.9)	<.01
BMI	23.9 (2.8)	22.1 (3.0)^†	23.3 (3.1)	21.2 (3.0)^†	<.01
FEV1 (z-score)	–1.7 (0.8)	–1.9 (1.2)^†	–3.4 (0.4)^†	–3.6 (0.4)^†	<.01
FVC (z-score)	0.4 (1.1)	0.5 (1.1)	–1.0 (1.2)^†	–0.9 (1.2)^†	<.01
DLCO (z-score)	–1.8 (0.8)	–4.3 (1.2)^†	–2.2 (0.7)^†	–4.7 (1.2)^†	<.01
mMRC ≥ 2 (%)	21%	34%^†	55%^†	59%^†	<.01
6MWD* (m)	431 (93)	404 (106)^†	417 (77)	361 (108)^†	<.01
CAT*	12.9 (7.2)	15.6 (8.4)^†	17.8 (7.4)^†	19.6 (8.1)^†	<.01
SGRQ total*	27.2 (17.0)	40.4 (18.5)^†	39.4 (18.5)^†	44.6 (20.1)^†	<.01
Symptom*	35.9 (18.1)	48.3 (20.1)^†	51.6 (19.9)^†	49.7 (20.8)^†	<.01
Activity*	38.3(21.9)	52.9 (21.3)^†	52.1 (22.3)^†	59.3 (23.5)^†	<.01
Impact*	18.4 (17.7)	30.9 (20.9)^†	28.3 (19.8)^†	34.5 (22.1)^†	<.01

Data are presented as means (SD). All subjects were male. Smoking PY = smoking pack-years. BMI = body mass index. FEV₁ = forced expiratory volume in 1 s. FVC = forced vital capacity. RV/TLC = ratio of residual volume to total lung capacity. D_LCO = diffusion capacity for carbon monoxide. 6MWD = six-minute walking distance. CAT = COPD assessment test. SGRQ = St. George's Respiratory Questionnaire. Symptom, Activity, and Impact were the domains of the SGRQ score. *6MWD, CAT, and SGRQ data were available for 641, 717, and 395 patients, respectively. P = p-value. ^†p < .05 compared to the reference group based on Tukey’s multiple comparison or multiple Fisher’s exact tests followed by Bonferroni correction.

Figure 4. Associations of D_LCO, FEV₁, and both impairments with emphysema subtypes and arterial blood gases in a multivariable analysis of the Kyoto University Cohort.

Patients (n = 195) were categorized into four groups: (1) FEV₁ z-score > –3 and D_LCO z-score > –3 (reference, n = 89), (2) FEV₁ z-score > –3 and D_LCO z-score ≤ –3 (disproportionally impaired D_LCO, n = 62), (3) FEV₁ z-score ≤ –3 and D_LCO z-score > –3 (disproportionally impaired FEV₁, n = 10), and (4) FEV₁ z-score ≤ –3 and D_LCO z-score ≤ –3 (mixed-impaired, n = 34). (A) Odds ratio for the presence of paraseptal emphysema and centrilobular emphysema on CT. A dot with an error bar indicates the regression coefficient with the 95% CI. (B) Least-square mean (LS mean) with the 95% CI for the partial pressure of oxygen (PaO₂) and partial pressure of carbon dioxide (PaCO₂). * p<.05 compared to the reference group in the multivariable models. Each model was adjusted for age, pack-years of smoking, height and weight. PaO₂ and PaCO₂ data were available for 184 patients.

Table 3. Clinical characteristics of the four groups in the Kyoto University Cohort.

	Reference	Disproportionally impaired DLCO	Disproportionally impaired FEV1	Mixed-impaired	P
N	89	62	10	34
Age (years)	68.8 (9.0)	73.6 (6.4)^†	67.5 (5.1)	66.9 (9.2)	<.01
Smoking PY	65.2 (34.8)	72.6 (35.9)	70.4 (39.4)	61.7 (30.5)	.43
BMI	23.0 (2.7)	21.6 (3.1)^†	21.3 (2.4)	20.8 (2.7)^†	<.01
FEV1 (z-score)	–1.6 (0.9)	–2.0 (0.8)^†	–3.5 (0.4) ^†	–3.7 (0.6) ^†	<.01
FVC (z-score)	0.3 (1.1)	0.4 (1.0)	–0.7 (1.4)^†	–1.2 (1.2)^†	<.01
RV/TLC (%)	39.2 (6.4)	42.3 (7.9)^†	48.0 (11.2)^†	48.8 (6.1)^†	<.01
DLCO (z-score)	–1.6 (0.9)	–4.2 (1.0)^†	–1.7 (0.9)	–5.1 (1.5)^†	<.01
Kco (z-score)	–1.0 (1.2)	–3.5 (1.0)^†	–1.1 (0.9)	–4.0 (1.5)^†	<.01
VA/TLC (%)	81.8 (5.2)	78.4 (7.1)^†	82.7 (7.4)	74.0 (7.4)^†	<.01
mMRC ≥ 2 (%)	15%	32%^†	10%	47%^†	<.01
PaO2* (mmHg)	79.6 ()	74.0 (8.1)^†	72.3 (9.2)	74.6 (7.3)^†	<.01
PaCO2* (mmHg)	39.8 (3.5)	38.0 (3.7)^†	42.4 (2.7)	40.2 (4.4)	<.01
LAV% (%)	24.0 (6.8)	32.4 (6.9)^†	31.4 (6.7)^†	39.5 (8.2)^†	<.01
WA% (%)	59.7 (5.8)	60.3 (6.1)	61.3 (5.1)	59.1 (5.9)	.68
PSE	35%	58%^†	10%	53%	<.01
CLE	29%	92%^†	60%	94%^†	<.01
PA/Ao	0.77 (0.11)	0.76 (0.10)	0.77 (0.06)	0.80 (0.13)	0.51

Data are presented as means (SD). All subjects were male. Smoking PY = smoking pack-years. BMI = body mass index. FEV₁ = forced expiratory volume in 1 s. FVC = forced vital capacity. RV/TLC = ratio of residual volume to total lung capacity. D_LCO = diffusion capacity for carbon monoxide (CO). Kco = CO transfer coefficient. V_A/TLC = ratio of alveolar volume to total lung capacity. PaO₂ = partial pressure of oxygen. PaCO₂ = partial pressure of carbon dioxide. PSE = paraseptal emphysema. CLE = moderate to severe centrilobular emphysema. LAV% = low attenuation volume percentage. WA% = wall area percentage. PA/Ao = diameter ratio of pulmonary artery to aorta. * PaO₂ and PaCO₂ data were available for 184 patients. P = p value. ^†p < 0.05 compared to the reference group based on Tukey’s multiple comparison or multiple Fisher’s exact tests followed by Bonferroni correction.

Figure 5. Long-term survival of patients with COPD in the Kyoto University Cohort.

(A) Kaplan–Meier curves of survival for the four groups: (1) FEV₁ z-score > –3 and D_LCO z-score > –3 (reference, n = 89), (2) FEV₁ z-score > –3 and D_LCO z-score ≤ –3 (disproportionally impaired D_LCO, n = 62), (3) FEV₁ z-score ≤ –3 and D_LCO z-score > –3 (disproportionally impaired FEV₁, n = 10), and (4) FEV₁ z-score ≤ –3 and D_LCO z-score ≤ –3 (mixed-impaired, n = 34). (B) Causes of death. (C) Multivariable Cox proportional hazard models. A dot with an error bar indicates the hazard ratio with 95% CI. * p<.05 compared to the reference group in the multivariable models. The model used for the upper panel included the group, age, pack-years of smoking, height, and weight as independent variables, and the model used for the lower panel included the group, age, pack-years of smoking, height, weight, and LAV% (a CT index of emphysema severity) as independent variables.