Study participants
Figure 1 shows the patient’s selection process. The baseline characteristics of the final 228 patients included in the study are shown in Table 1, and more details are provided in the Additional File 1.
Table 1. Baseline patient characteristics
Characteristics
|
Overall N=228
|
Fibrosis*<5%, N=89
|
Fibrosis 5–10% N=54
|
Fibrosis ≥10% N=85
|
p value†
|
Number of males (%)
|
205 (89.9)
|
74 (83.1)
|
46 (85.2)
|
85 (100.0)
|
<0.001
|
Median age, years (IQR)
|
69.9 (66.0, 76.3)
|
68.0 (62.0, 73.0)
|
72.0 (67.3, 77.0)
|
73.0 (66.0, 77.0)
|
0.001
|
Median body mass index
|
22.9 (20.9, 25.0)
|
22.8 (20.8, 24.8)
|
23.5 (20.9, 25.9)
|
22.9 (21.0, 24.6)
|
0.578
|
Former/Current smoker (%)
|
155 (68.0)/73(32.0)
|
52 (58.4)/37(41.5)
|
39 (72.2)/15(27.8)
|
64 (75.3)/21(24.7)
|
0.113
|
Pack-years smoking, median (IQR)
|
50 (36, 79)
|
50 (36, 70)
|
47 (34, 74)
|
59 (40, 84)
|
0.188
|
Charlson Comorbidity Index score 1/2/3/4/5≤, %
|
23.2/19.7/25.9/9.6 /21.6
|
27.0/27.0/22.5/15.7 /7.9
|
22.2/14.8/25.9/5.6 /31.5
|
20.0/15.3/29.4/5.9 /29.4
|
0.002
|
Serum KL-6, median U/mL (IQR)
|
554.0 (368.8, 847.5)
|
367.0 (274.0, 542.0)
|
626.0 (509.0, 1020.0)
|
666.0 (452.0, 906.5)
|
<0.001
|
IPF (%)
|
34 (14.9)
|
1 (1.1)
|
10 (18.5)
|
23 (27.1)
|
<0.001
|
Pulmonary hypertension (%)
|
26 (11.4)
|
10 (11.2)
|
5 (9.3)
|
11 (12.9)
|
0.8
|
Lung cancer (%)
|
53 (23.2)
|
11 (12.4)
|
13 (24.1)
|
29 (34.1)
|
0.003
|
Connective tissue disease (%)
|
47 (20.6)
|
24 (27.0)
|
8 (14.8)
|
15 (17.6)
|
0.152
|
Pulmonary Function Test, median (IQR)
|
|
|
|
|
FEV1, L
|
2.2 (1.8, 2.6)
|
2.2 (1.8, 2.7)
|
2.2 (1.8, 2.6)
|
2.2 (1.8, 2.6)
|
0.934
|
FEV1, % predicted
|
96.9 (84.3, 110.3)
|
94.6 (84.4, 109.1)
|
102.4 (90.9, 115.2)
|
96.8 (83.3, 109.4)
|
0.157
|
FVC, L
|
3.13 (2.6, 3.7)
|
3.32 (2.82, 3.89)
|
3.15 (2.69, 3.67)
|
2.94 (2.35, 3.34)
|
<0.001
|
FVC, % predicted
|
101.2 (86.8, 115.2)
|
106.1 (96.5, 120.3)
|
104.1 (91.6, 115.9)
|
89.4 (76.8, 104.2)
|
<0.001
|
FEV1/FVC ratio
|
70.6 (63.3, 78.7)
|
66.2 (58.7, 73.2)
|
70.0 (62.1, 75.0)
|
77.3 (69.4, 85.4)
|
<0.001
|
DLco, ml/min/mmHg
|
10.9 (8.0, 13.6)
|
12.5 (10.3, 16.9)
|
10.6 (8.9, 13.4)
|
8.3 (6.2, 12.0)
|
0.002
|
DLco, % predicted
|
66.7 (50.9, 83.3)
|
82.3 (67.7, 91.3)
|
71.4 (59.5, 79.7)
|
53.1 (44.0, 66.9)
|
<0.001
|
Composite physiologic index‡
|
27.7 (13.7, 41.1)
|
11.3 (5.3, 26.0)
|
27.5 (16.2, 33.6)
|
42.2 (25.1, 54.3)
|
<0.001
|
ILD-GAP model
0-1/2-3/4-5/6-8, %
|
11.8/68.0/15.8/4.4
|
21.3/69.7/9.0/0
|
5.6/83.3/5.6/5.6
|
5.9/56.5/29.4/8.2
|
<0.001
|
Initial CT findings§
|
|
|
|
|
|
Total lung volume, median cm3 (IQR)
|
4417.8 (3849.0, 5184.6)
|
4671.7 (4155.2, 5341.2)
|
4241.7 (3790.6, 5278.9)
|
3991.9 (3497.9, 4642.3)
|
<0.001
|
Extent of normal lung, median cm3(IQR), %¶
|
3104.4 (2359.0, 3781.4), 77.1
|
3634.1 (3191.6, 4156.0), 82.0
|
3067.3 (2669.1, 3450.9), 79.9
|
2467.0 (1853.7, 3049.6), 70.2
|
<0.001
|
Extent of emphysema, median cm3 (IQR), %
|
644.3 (301.0, 1292.1), 15.2
|
700.6 (330.9, 1424.1), 15.6
|
630.7 (313.7, 1005.5), 13.1
|
567.4 (270.8, 1308.6), 13.7
|
0.394
|
Extent of fibrosis, median cm3 (IQR), %
|
292.2 (142.0, 528.7), 7.7
|
133.8 (95.3, 159.5), 2.4
|
308.9 (275.4, 366.5), 7.0
|
609.3 (516.4, 780.2), 16.1
|
<0.001
|
|
IQR interquartile range, IPF idiopathic pulmonary fibrosis, FEV 1 forced expiratory volume in one second, FVC forced vital capacity, DLco diffusing capacity for carbon monoxide.
* Extent of fibrosis was defined as the percentage (%) sum of reticular shadowing, grand glass opacity, and honeycombing calculated in CALIPER.
† p values are reported for the differences between the fibrosis proportion groups, using a chi-squared test, Fisher exact test, t test, or Wilcoxon rank-sum test as appropriate.
‡ Composite physiologic index = 91.0 - [0.53 × percent predicted FVC] - [0.65 × percent predicted DLco] + [0.34 × percent predicted FEV1]
§ Calculated results from CALIPER
¶ Calculated the percentage to account for the emphysema volume and total lung volume in each individual.
Representative images of the CALIPER evaluation are shown in Figure 2. The ternary plot in Figure 3 shows the distribution proportion of fibrosis, emphysema, and normal lung for all 228 participants at initial evaluation. Fibrosis was in the range of 30%; however, emphysema was distributed from approximately 0% to 80%. The distribution of the ternary plot from the lower left to the upper right suggests that the percentage of emphysema is negatively correlated to the percentage of fibrosis. Disease progression and death were associated with a higher percentage of fibrosis.
Outcomes
The study outcomes are shown in Table 2. he numbers of all deaths and acute exacerbations were significantly lower in patients with less severe fibrosis. The composite progression was highest in patients with 5 to <10% fibrosis compared to other groups (p<0.001). Regarding per-year change in PFTs and chest CT findings, the mean absolute and relative decline in FVC, decline in total lung volume, and progression of fibrosis were highest and lowest in patients with 5 to <10% fibrosis and <5% fibrosis, respectively (p<0.001). Per-year change in DLco and emphysema severity was not significantly different across the three groups. The study outcomes in subgroups of emphysema extent are shown in Additional File 2 and none of them were significantly different.
Table 2. Study outcomes
|
Overall, N=228
|
Fibrosis*<5%, N=89
|
Fibrosis 5-10%, N=54
|
Fibrosis ≥10%, N=85
|
p value †
|
Composite progression (%)
|
127 (55.7)
|
16 (18.0)
|
42 (77.8)
|
69 (81.2)
|
<0.001
|
All deaths (%)
|
75 (32.9%)
|
4 (4.5)
|
22 (40.7)
|
49 (57.6)
|
<0.001
|
Respiratory-related deaths (%)
|
47 (20.6)
|
2 (2.2)
|
14 (25.9)
|
31 (36.5)
|
<0.001
|
Acute exacerbation (%)
|
35 (15.4)
|
0 (0.0)
|
10 (18.5)
|
25 (29.4)
|
<0.001
|
Progression in pulmonary function tests (%)
|
67 (29.4%)
|
12 (13.5)
|
31 (57.4)
|
24 (28.2)
|
<0.001
|
Change in median body mass index/year (IQR)
|
-0.02 (-0.34, 0.26)
|
0.00 (-0.15, 0.17)
|
-0.10 (-0.28, 0.17)
|
-0.04 (-0.30, 0.12)
|
0.103
|
Smoking cessation during the follow-up period (%)
|
40 (17.5)
|
18 (50.0)
|
9 (60.0)
|
13 (59.1)
|
0.718
|
Changes in forced vital capacity‡
|
|
|
|
|
|
Median absolute change/year, L (IQR)
|
-0.06 (-0.15, 0.02)
|
-0.02 (-0.07, 0.04)
|
-0.12 (-0.23, -0.08)
|
-0.07 (-0.16, 0.06)
|
<0.001
|
Median relative change/year, % (IQR)
|
-1.67 (-4.57, 0.66)
|
-2.88 (-8.41, 3.08)
|
-13.66 (-22.01, -5.56)
|
-4.30 (-15.27, 7.87)
|
<0.001
|
Changes in DLco
|
|
|
|
|
|
Median absolute change/year, ml/min/mmHg (IQR)
|
-0.25 (-0.49, 0.11)
|
-0.05 (-0.24, 0.64)
|
-0.93 (-2.46, -0.08)
|
-0.31 (-0.46, 0.00)
|
0.057
|
Median relative change/year, % (IQR)
|
3.03 (1.72, 5.60)
|
1.46 (-0.91, 3.90)
|
-3.90 (-21.74, -0.09)
|
-1.36 (-2.02, 1.36)
|
0.05
|
Changes in composite physiologic index§
|
|
|
|
|
|
median absolute change/year (IQR)
|
0.93 (-5.54, 10.11)
|
0.55 (-5.08, 5.43)
|
1.33 (-5.73, 12.48)
|
0.28 (-4.98, 7.58)
|
0.86
|
Changes in computed tomography findings, median, %/year (IQR)
|
|
|
|
|
|
Total lung volume
|
-6.97 (-16.91, -0.15)
|
-3.69 (-10.11, 1.32)
|
-12.87 (-24.13, -2.95)
|
-11.46 (-21.46, -2.64)
|
<0.001
|
Extent of normal lung
|
-1.69 (-4.08, 0.53)
|
-1.21 (-2.57, -0.47)
|
-2.21 (-4.09, -1.35)
|
-2.11 (-5.48, -0.50)
|
0.083
|
Extent of emphysema
|
0.68 (-0.01, 1.92)
|
0.49 (-0.01, 1.77)
|
0.70 (0.01, 1.50)
|
0.96 (-0.02, 2.43)
|
0.505
|
Extent of fibrosis
|
1.57 (0.10, 3.85)
|
0.21 (-0.03, 0.91)
|
1.64 (0.33, 4.05)
|
0.89 (0.11, 4.14)
|
0.001
|
|
IQR interquartile range, FVC forced vital capacity, DLco diffusing capacity for carbon monoxide.
* Extent of fibrosis was defined the extent (%) of combined reticular shadow, grand glass opacity, and honeycombing resulted in CALIPER. Twenty-nine CT series were unavailable for CALIPER analysis because of CT condition.
† P values are reported for the difference between groups between fibrosis proportions, using a x 2 test, Fisher exact test, t test, or Wilcoxon rank-sum test as appropriate.
‡ Change in FVC was calculated as the relative change (FVC baseline−FVC timepoint 2/FVC baseline, using either FVC in litres or % predicted FVC) and absolute change (FVC baseline−FVC timepoint 2, using % predicted FVC).
§ Composite physiologic index = 91.0 - [0.53 × percent predicted FVC] - [0.65 × percent predicted DLco] + [0.34 × percent predicted FEV1].
Kaplan–Meier curves for overall survival and progression-free survival are shown in Figure 4. Overall survival and progression-free survival significantly differed across the fibrosis groups. Overall survival and progression-free survival were 7.3 years (interquartile range [IQR]: 4.8 years–not applicable) and 3.7 years (IQR: 2.7–6.4 years), respectively, in the 5 to <10% fibrosis group; and 5.7 years (IQR: 3.5–7.6 years) and 3.5 years (IQR: 2.4–4.2 years), respectively, in the ≥10% group. For the <5% fibrosis group, overall survival could not be statistically calculated because the events were below 50%. In contrast, Kaplan–Meier curves for PFT progression showed the 5 to <10% fibrosis group and the <5% fibrosis group were most and least affected, respectively. Cox proportional hazard model for CPFE progression was used to assess fibrosis proportion (Table 3). In hazard models, fibrosis proportion was a risk factor independent of age, sex, smoking pack-years, CCI, lung cancer, connective tissue disease, and IPF.
Table 3. Cox regression model for progression (vs. fibrosis <5%)
|
Fibrosis 5–10%
|
Fibrosis ≥10%
|
HR (95% CI)
|
p value
|
HR (95% CI)
|
p value
|
Fibrosis proportion only
|
7.42
(3.31, 16.65)
|
<0.001
|
5.61
(2.47, 12.74)
|
<0.001
|
Adjusted for age and sex
|
7.42
(3.28, 16.79)
|
<0.001
|
5.76
(2.49, 13.35)
|
<0.001
|
Adjusted for age, sex, pack-years smoking, and CCI
|
7.58
(3.34, 17.24)
|
<0.001
|
6.24
(2.65, 14.71)
|
<0.001
|
Adjusted for age, sex, pack-years smoking, CCI,
lung cancer, and CTD
|
7.49
(3.27, 17.16)
|
<0.001
|
6.17
(2.60, 14.63)
|
<0.001
|
Adjusted for age, sex, pack-years smoking, CCI,
lung cancer, CTD, and IPF
|
6.85
(2.95, 15.89)
|
<0.001
|
5.78
(2.42, 13.85)
|
<0.001
|
Hazard ratios are shown (with 95% confidence intervals in parentheses).
CCI Charlson Comorbidity Index, CTD connective tissue disease, IPF idiopathic pulmonary fibrosis, CI confidence interva
Comparison of patients with and without connective tissue disease
Since 20.6% of the study population had connective tissue diseases (CTDs), we performed subgroup analysis to compare characteristics and outcomes in patients with CTD versus those without CTD. The CTD group comprised significantly more female patients, of younger age, with fewer smoking pack-years, and lower lung cancer prevalence; CT findings and fibrosis quantity did not differ significantly (Additional File 3). Most patients with CTD (~60%) had rheumatoid arthritis. Among those without CTD, nearly 25% manifested positive autoantibody, consistent with the concept of interstitial pneumonia with autoimmune features formulated in 2015 [21]. Kaplan–Meier curves for overall survival showed no significant difference between the subgroups (Additional File 4). Multivariate analysis (Additional File 6) revealed mortality was not influenced by CTD or sex; instead, it was affected by the presence of IPF, lung cancer, and age.