Introduction
Methods
Study population and design
Data collection
Follow-up and outcomes of the study
Fibrosis progression
Statistical analysis
Results
Demographic and clinical characteristics of the whole cohort
Cluster 1, n = 181 | Cluster 2, n = 164 | Cluster 3, n = 134 | Cluster 4, n = 96 | All, n = 575 | P | ||
---|---|---|---|---|---|---|---|
#Age (quartile) | 65 (57,71)† | 59.5 (49,68.5)‡§ | 66 (60,73)§ | 62 (59,69) | 63 (56,70) | < 0.001 | |
#Male, n (%) | 57 (51.5)†‡* | 30 (18.3)‡§ | 119 (88.8) | 87 (90.6) | 293 (51.0) | < 0.001 | |
#BMI (quartile) | 25.9 (24.1,28.4) | 25.7 (23.9,27.5) | 25.8 (23.6,27.5) | 25.9 (24.1,28.2) | 25.9 (23.9,27.9) | 0.351 | |
Smoking status, n (%) | |||||||
Ever smokers | 31 (17.1)‡§ | 18 (11.0)‡§ | 107 (79.9) | 62 (64.6) | 218 (37.9) | < 0.001 | |
#Heavy smokers* | 12 (6.6)‡§ | 6 (3.7)‡§ | 91 (67.9) | 51 (53.1) | 160 (27.8) | < 0.001 | |
Smoking cessation > 1 yr | 24 (13.3)‡ | 16 (9.8) | 77 (57.5) | 40 (41.7) | 157 (27.3) | 0.003 | |
#Exposure history, n (%) | 73 (40.3)§ | 46 (28.0) | 38 (28.4) | 84 (87.5) | 241 (41.9) | < 0.001 | |
Inorganic | 48 (26.5)†‡§ | 12 (7.3)§ | 18 (13.4)§ | 51 (53.1) | 129 (22.4) | ||
Organic | 20 (11.0)§ | 31 (18.9) | 16 (11.9)§ | 25 (26.0) | 92 (16.0) | ||
Mixed | 4 (2.2) | 3 (1.8) | 3 (2.2) | 6 (6.3) | 16 (2.8) | < 0.001 | |
Symptoms, n (%) | |||||||
Dry cough | 127 (90.7)† | 88 (77.2) | 85 (82.5) | 46 (82.1) | 346 (83.8) | 0.032 | |
Productive cough | 44 (24.3)† | 20 (12.2) | 15 (11.2) | 19 (19.8) | 98 (17.0) | 0.004 | |
Shortness of breath | 126 (69.6)†§ | 80 (48.8) | 83 (61.9)§ | 34 (35.4) | 323 (56.2) | < 0.001 | |
Joint discomfort | 37 (20.4) | 39 (23.8)‡§ | 15 (11.2) | 9 (9.4) | 100 (17.4) | 0.003 | |
Signs, n (%) | |||||||
#Clubbing of fingers | 37 (20.4)‡§ | 46 (28.0)‡§ | 74 (55.2)§ | 1 (1.0) | 158 (27.5) | < 0.001 | |
#Velcro crackles | 137 (75.7)‡§ | 124 (75.6)‡§ | 128 (95.5)§ | 28 (29.2) | 417 (72.5) | < 0.001 | |
Pulmonary function | |||||||
#FVC (L) (SD) | 2.1 (0.64) | 2.4 (0.7) | 3.0 (0.7) | 3.1 (0.9) | 2.6 (0.8) | < 0.001 | |
#FVC% pred (quartile) | 79.7(65.7,95.3)†§ | 89.6 (72.3,106.6) | 85.1 (73.9,99.7) | 87.3 (74.4,106.1) | 85.2 (72,100.4) | < 0.001 | |
#DLCO% pred (quartile) | 56.1 (45.2,71.2)§ | 61 (48.8,74)§ | 58 (44.2,70.5)§ | 71.7 (58.4,88) | 60.3 (48.2,74) | < 0.001 | |
HRCT, n (%) | |||||||
#UIP-like pattern | 21 (11.6)†‡§ | 15 (9.1)‡ | 99 (73.9)§ | 2 (2.1) | 137 (23.8) | < 0.001 | |
#Emphysema | 2 (1.1)‡§ | 0 (0)‡§ | 22 (16.4) | 11 (11.5) | 35 (6.1) | < 0.001 | |
#Hypoxemia at rest, n (%) | 120 (66.3)†‡§ | 0 (0)‡§ | 44 (32.8)§ | 11 (11.5) | 175 (30.4) | < 0.001 | |
#ANA, n (%) | 97 (53.6)‡§ | 89 (54.3) | 44 (32.8)§ | 12 (12.5) | 242 (42.1) | < 0.001 | |
Comorbidities, n (%) | |||||||
#Pulmonary hypertension | 45 (24.9)†‡§ | 5 (3.0) | 13 (9.7) | 4 (4.2) | 67 (11.7) | < 0.001 | |
#Diabetes | 91 (50.3)†‡§ | 0 (0)‡§ | 41 (30.6)§ | 11 (11.5) | 143 (24.9) | < 0.001 | |
#Coronary heart disease | 55 (30.4)†‡ | 5 (3.0)‡§ | 17 (12.7) | 19 (19.8) | 96 (16.7) | < 0.001 | |
Hypertension | 88 (48.6)†‡ | 45 (27.4) | 39 (29.1) | 46 (47.9) | 218 (37.9) | < 0.001 | |
Hypothyroidism | 7 (3.9) | 9 (5.5)‡ | 0 (0) | 0 (0) | 16 (2.8) | 0.008 | |
GERD | 43 (32.7)§ | 32 (29.7) | 20 (24.2) | 9 (17.4) | 104 (18.1) | 0.019 | |
GAP-index | |||||||
Score | 3 (2,4)† | 2 (1,3)‡§ | 3 (2,4) | 3 (2,4) | 3 (1,3) | < 0.001 | |
Stage I | 134 (74.0) | 152 (92.7) | 93 (69.4) | 68 (70.8) | 447 (77.7) | ||
Stage II | 43 (23.7) | 12 (7.3) | 35 (26.1) | 28 (29.2) | 118 (20.5) | ||
Stage III | 4 (2.2) | 0 | 6 (4.5) | 0 | 10 (1.7) | < 0.001 | |
Treatment, n (%) | |||||||
Corticosteroid | 133 (73.5)‡§ | 128 (78.0)‡§ | 56 (41.8) | 41 (42.7) | 358 (62.3) | < 0.001 | |
Immunosuppressive agents | 97 (53.6)‡§ | 101 (61.6)‡§ | 33 (24.6) | 20 (20.8) | 251 (43.7) | < 0.001 | |
Anti-fibrotic treatment | 38 (21.0)†‡§ | 25 (15.2)‡ | 51 (38.1)§ | 8 (8.3) | 122 (21.2) | < 0.001 | |
Long-term oxygen therapy | 34 (18.8)†§ | 12 (7.3) | 21 (15.7)§ | 4 (4.2) | 71 (12.3) | 0.015 |
Cluster 1, n = 181 | Cluster 2, n = 164 | Cluster 3, n = 134 | Cluster 4, n = 96 | All, n = 575 | |
---|---|---|---|---|---|
IPF | 8 (4.4) | 3 (1.8) | 76 (56.7) | 7 (7.3) | 94 (16.3) |
CTD-ILD | 120 (66.3) | 119 (72.6) | 42 (31.3) | 18 (18.8) | 299 (52.0) |
iNSIP | 1 (0.6) | 1 (0.6) | 0 (0) | 0 (0) | 2 (0.3) |
FHP | 7 (3.9) | 20 (12.2) | 6 (4.5) | 15 (15.6) | 48 (8.3) |
uIIP | 7 (3.9) | 12 (7.3) | 6 (4.5) | 11 (11.5) | 36 (6.3) |
Occupational related ILDs | 38 (21.0) | 6 (3.7) | 4 (3.0) | 45 (46.9) | 93 (16.2) |
Chronic silicosis | 4 (2.2) | 1 (0.7) | 0 | 12 (12.5) | 17 (3.0) |
Asbestos | 34 (18.8) | 5 (3.0) | 4 (3.0) | 33 (34.4) | 76 (13.2) |
Sarcoidosis | 0 (0) | 3 (1.8) | 0 (0) | 0 (0) | 3 (1.8) |
Clinical characteristics of the clusters
Clinical outcomes among the clusters
Cluster 1, n = 181 | Cluster 2, n = 164 | Cluster 3, n = 134 | Cluster 4, n = 96 | All, n = 575 | P | |
---|---|---|---|---|---|---|
Fibrosis progression, n (%) | ||||||
Criteria A (1 year), n (%) | 54 (29.8) | 32 (19.5)‡ | 48 (35.8)§ | 16 (16.7) | 150 (26.1) | 0.001 |
1 | 33 (18.2) | 27 (16.5) | 25 (18.7) | 12 (12.5) | 97 (16.9) | 0.600 |
2 | 23 (12.7) | 18 (11.0) | 28 (20.9) | 14 (14.6) | 83 (14.4) | 0.087 |
3 | 56 (30.9) | 45 (27.4) | 47 (35.1)§ | 18 (18.8) | 166 (28.9) | 0.049 |
4 | 79 (43.6)† | 48 (29.3) | 57 (42.5) | 28 (29.2) | 212 (36.9) | 0.008 |
Criteria B (2 years), n (%) | 85 (47.0)§ | 62 (37.8) | 66 (49.3)§ | 26 (27.1) | 239 (41.6) | 0.002 |
a | 23 (12.7) | 21 (12.8)‡ | 16 (11.9) | 7 (7.3) | 67 (11.7) | 0.534 |
b | 29 (16.0) | 14 (8.5) | 27 (20.1)§ | 10 (10.4) | 80 (13.9) | 0.019 |
c | 49 (27.1)§ | 39 (23.8) | 42 (31.3)§ | 11 (11.5) | 141 (24.5) | 0.005 |
Acute exacerbation, n (%) | 67 (37.0)†‡§ | 28 (17.1)‡ | 37 (27.6)§ | 14 (14.6) | 146 (25.4) | < 0.001 |
Death, n (%) | 45 (24.9)†§ | 11 (6.7)‡ | 45 (33.6)§ | 12 (12.5) | 113 (19.7) | < 0.001 |
Characteristic | Acute exacerbation | Survival | ||||
---|---|---|---|---|---|---|
HR | 95% CI | P | HR | 95% CI | P | |
Univariate Cox regression | ||||||
Phenotypic clustera | < 0.001 | |||||
Cluster 1 | 2.38 | 1.53–3.70 | < 0.001 | 4.06 | 2.10–7.86 | < 0.001 |
Cluster 3 | 1.80 | 1.10–2.95 | 0.019 | 5.78 | 2.99–11.18 | < 0.001 |
Cluster 4 | 0.76 | 0.40–1.45 | 0.405 | 1.61 | 0.71–3.67 | 0.255 |
Diagnosis categoryb | < 0.001 | |||||
CTD-ILD | 0.93 | 0.61–1.43 | 0.743 | 0.41 | 0.27–0.62 | < 0.001 |
iNSIP | 8.45 | 2.00-35.66 | 0.004 | 2.75 | 0.38–20.11 | 0.319 |
FHP | 0.38 | 0.15–0.98 | 0.045 | 0.28 | 0.11–0.7 | 0.007 |
uIIP | 0.89 | 0.43–1.84 | 0.756 | 0.29 | 0.12–0.74 | 0.010 |
Occupational related ILDs | 0.43 | 0.23–0.78 | 0.006 | 0.15 | 0.08–0.32 | < 0.001 |
Sarcoidosis | 0.00 | 0 | 0.957 | 0.00 | 0 | 0.950 |
GAP score | 1.33 | 1.18–1.50 | < 0.001 | 1.47 | 1.29–1.69 | < 0.001 |
Multivariable Cox regressionc | ||||||
Phenotypic clustera | < 0.001 | |||||
Cluster 1 | 2.29 | 1.43–3.68 | 0.001 | 3.99 | 1.98–8.05 | < 0.001 |
Cluster 3 | 1.21 | 0.65–2.27 | 0.546 | 2.90 | 1.31–6.41 | 0.008 |
Cluster 4 | 0.89 | 0.44–1.79 | 0.741 | 2.03 | 0.84–4.92 | 0.116 |
GAP score | 1.31 | 1.16–1.48 | < 0.001 | 1.34 | 1.17–1.54 | < 0.001 |