TABLE 1

The main characteristics and outcomes for the three high-risk C and D subgroups

	C1	C2	C3	p-value			D1	D2	D3	p-value
				*C1 versus* C2**	*C1 versus* C3**	*C2 versus* C3**				*D1 versus* D2**	*D1 versus* D3**	*D2 versus* D3**
Patients	336 (70%)	62 (13%)	85 (18%)				522 (63%)	72 (9%)	236 (28%)
Demographics
Age years	63.2±7.2	61.8 ±7.7	62.3 ±6.9	0.228	0.215	0.866	63.7±7.0	63.5±7.1	63.5±6.6	0.963	0.577	0.72
Female	95 (28%)	27 (44%)	27 (32%)	0.017	0.527	0.145	147 (28%)	41 (57%)	92 (39%)	<0.001	0.003	0.007
BMI kg·m⁻²	25.1±5.0	25.9±4.7	25.2±5.0	0.299	0.961	0.444	26.3±6.0	29.0±7.3	26.3±5.7	0.003	0.826	0.007
FFMI kg·m⁻²	16.7±2.5	17.1±2.6	16.6±2.4	0.365	0.895	0.416	17.0±2.8	17.9±3.3	17.0±2.9	0.027	0.74	0.028
Smoking pack-years	45.3±22.7	46.1±24.1	44.2±24.6	0.948	0.439	0.552	51.5±26.7	50.3±33.8	50.6±27.9	0.201	0.696	0.356
Period smoking years	39.7±10.4	39.9±10.0	39.4±7.7	0.769	0.413	0.347	40.2±9.6	40.8±8.3	40.8±10.0	0.878	0.305	0.65
Current smoker	143 (43%)	32 (52%)	32 (38%)	0.188	0.412	0.093	167 (32%)	26 (36%)	74 (31%)	0.485	0.862	0.451
Symptoms
mMRC dyspnoea score	0.8±0.4	0.8±0.4	0.8±0.4	0.911	0.46	0.519	2.5±0.7	2.5±0.7	2.7±0.8	0.932	0.026	0.245
SGRQ-C total score	43.2±17.0	41.8±14.9	51.9±15.2	0.597	<0.001	<0.001	60.2±15.8	65.3±15.3	65.5±14.4	0.009	<0.001	0.933
Moderate-to-severe ECOPD^#	0.3±0.5	2.5±1.0	2.8±1.5	<0.001	<0.001	0.133	0.4±0.5	2.8±1.1	2.9±1.2	<0.001	<0.001	0.423
CESD total score	9.2±8.2	10.1±7.4	10.0±8.9	0.166	0.558	0.552	12.5±9.2	15.3±10.5	15.3±10.0	0.033	<0.001	0.863
Chronic bronchitis	126 (38%)	28 (45%)	28 (33%)	0.256	0.436	0.133	195 (37%)	28 (39%)	95 (40%)	0.801	0.447	0.836
Physiology^¶
FEV₁⁺ % pred	39.7±7.6	63.7±8.7	36.3±8.5	<0.001	<0.001	<0.001	35.1±8.7	60.2±9.3	35.1±8.5	<0.001	0.969	<0.001
FEV₁ % reversibility	10.1±13.5	8.7±9.7	12.1±15.7	0.517	0.491	0.259	10.3±14.7	9.6±10.9	10.4±15.2	0.835	0.97	0.852
FVC⁺ % pred	81.4±17.4	99.5±16.5	81.3±18.9	<0.001	0.938	<0.001	74.8±17.0	96.0±15.5	78.1±19.1	<0.001	0.025	<0.001
RV % pred	175.1±48.8	147.0±36.1	184.1±50.5	0.038	0.271	0.023	180.9±47.4	122.6±29.3	189.7±56.3	<0.001	0.589	<0.001
TLC % pred	121.4±16.5	118.2±14.7	122.8±18.9	0.612	0.532	0.351	121.1±18.4	110.2±15.3	123.8±19.4	0.025	0.726	0.014
FRC % pred	157.0±29.3	137.8±27.3	162.2±34.1	0.017	0.381	0.011	160.9±35.1	124.2±26.0	161.7±36.7	<0.001	0.935	<0.001
S_aO₂ %	94.4±3.0	95.6±2.2	93.7±4.4	<0.001	0.188	<0.001	93.6±3.2	95.1±2.0	93.7±3.3	<0.001	0.5	<0.001
6MWD m	405±108	446±97	394±97	0.016	0.515	0.011	313±117	320±92	289±111	0.633	0.007	0.033
BODE index	2.8±1.0	0.8±0.8	3.0±1.0	<0.001	0.192	<0.001	5.1±1.5	3.3±1.2	5.5±1.6	<0.001	0.014	<0.001
Imaging
% LAA −950 HU	19.9±11.1	10.7±8.2	21.3±13.0	<0.001	0.429	<0.001	22.9±13.2	15.2±9.8	24.0±11.9	<0.001	0.178	<0.001
Systemic inflammation
WBC 10⁹·L^-1	7.6 (2.5)	7.6 (2.3)	7.4 (2.6)	0.584	0.312	0.749	7.8 (2.6)	7.7 (2.7)	8.0 (2.6)	0.779	0.106	0.264
Neutrophils 10⁹·L^-1	4.9 (2.3)	4.4 (1.8)	4.9 (2.1)	0.105	0.467	0.376	5.2 (2.2)	4.8 (2.5)	5.2 (2.4)	0.263	0.198	0.075
Neutrophils %	65.5 (11.2)	62.1 (11.4)	66.3 (11.2)	<0.001	0.922	0.006	66.9 (11.3)	65.1 (12.7)	67.0 (10.5)	0.05	0.865	0.047
Eosinophils 10⁹·L^-1	0.2 (0.2)	0.2 (0.2)	0.2 (0.2)	0.481	0.253	0.164	0.2 (0.2)	0.2 (0.1)	0.2 (0.2)	0.994	0.056	0.217
Eosinophils %	2.6 (2.3)	3.1 (2.7)	2.3 (2.9)	0.342	0.446	0.256	2.3 (1.9)	2.1 (1.4)	2.4 (2.6)	0.943	0.187	0.486
hsCRP mg·L⁻¹	2.5 (4.2)	2.7 (5.7)	4.0 (5.9)	0.478	0.024	0.031	3.7 (7.5)	3.9 (6.3)	4.5 (7.8)	0.615	0.028	0.381
IL-6 pg·mL⁻¹	1.4 (2.1)	1.2 (1.7)	1.4 (2.1)	0.096	0.993	0.184	1.8 (2.7)	2.1 (2.4)	1.8 (2.9)	0.545	0.67	0.507
IL-8 pg·mL⁻¹	6.4 (9.5)	6.6 (9.3)	6.7 (8.6)	0.641	0.812	0.888	7.0 (10.6)	8.8 (10.4)	7.5 (9.1)	0.315	0.381	0.54
Fibrinogen mg·dL⁻¹	442.0 (125.0)	436.5 (152.5)	466.0 (132.0)	0.528	0.04	0.071	470.0 (147.5)	457.3 (106.0)	483.0 (134.0)	0.522	0.029	0.032
TNF-α ng·mL⁻¹	2.4 (0.0)	2.4 (51.4)	2.4 (4.8)	0.001	0.486	0.036	2.4 (2.7)	2.4 (7.4)	2.4 (0.0)	0.681	0.335	0.313
CC-16 ng·mL⁻¹	5.1 (3.0)	4.6 (3.5)	5.4 (4.2)	0.116	0.788	0.154	4.8 (3.4)	4.7 (3.4)	4.9 (3.4)	0.168	0.906	0.191
CCL-18 ng·mL⁻¹	100.0 (48.8)	103.1 (48.2)	98.9 (49.6)	0.24	0.318	0.702	107.1 (59.0)	109.9 (56.9)	114.0 (54.7)	0.408	0.112	0.838
SPD ng·mL⁻¹	118.4 (91.2)	120.4 (58.9)	133.1 (95.0)	0.663	0.108	0.113	121.3 (85.0)	122.8 (99.2)	115.8 (87.0)	0.763	0.167	0.665
Concomitant medications
Medications containing ICS	241 (72%)	44 (71%)	79 (93%)	0.903	<0.001	<0.001	421 (81%)	63 (88%)	218 (92%)	0.161	<0.001	0.201
Tiotropium	146 (43%)	23 (37%)	50 (59%)	0.353	0.011	0.01	271 (52%)	43 (60%)	135 (57%)	0.214	0.177	0.705
Statins	69 (21%)	12 (19%)	15 (18%)	0.832	0.552	0.792	126 (24%)	17 (24%)	44 (19%)	0.922	0.093	0.355
Comorbidities^§
Heart trouble	64 (19%)	10 (16%)	15 (18%)	0.561	0.839	0.735	151 (30%)	20 (28%)	63 (28%)	0.796	0.551	0.914
Hypertension	113 (35%)	17 (30%)	23 (29%)	0.477	0.316	0.892	203 (41%)	28 (42%)	93 (41%)	0.797	0.922	0.854
Angina	25 (8%)	5 (8%)	8 (10%)	0.936	0.536	0.71	47 (10%)	11 (16%)	32 (14%)	0.099	0.09	0.637
Heart attack	16 (5%)	0	6 (7%)	0.076	0.381	0.03	46 (9%)	10 (15%)	24 (10%)	0.138	0.548	0.331
Stroke	9 (3%)	4 (7%)	3 (4%)	0.124	0.678	0.409	17 (3%)	5 (7%)	7 (3%)	0.107	0.843	0.117
Heart failure	13 (4%)	1 (2%)	5 (6%)	0.364	0.396	0.184	48 (10%)	5 (8%)	15 (7%)	0.609	0.217	0.812
Arrhythmia	33 (10%)	5 (8%)	10 (12%)	0.671	0.617	0.481	61 (12%)	12 (19%)	30 (14%)	0.163	0.701	0.298
Osteoporosis	38 (12%)	9 (16%)	13 (16%)	0.4	0.305	0.967	57 (12%)	12 (17%)	49 (23%)	0.18	<0.001	0.351
Osteoarthritis	29 (9%)	12 (22%)	13 (17%)	0.005	0.049	0.456	53 (11%)	25 (36%)	34 (16%)	<0.001	0.056	<0.001
Rheumatoid arthritis	11 (3%)	2 (4%)	4 (5%)	0.902	0.498	0.729	12 (2%)	3 (5%)	7 (3%)	0.304	0.588	0.563
Inflammatory bowel disorder	10 (3%)	2 (3%)	5 (6%)	0.878	0.185	0.47	24 (5%)	8 (12%)	10 (4%)	0.019	0.868	0.031
Diabetes	22 (7%)	0	5 (6%)	0.042	0.847	0.056	60 (12%)	11 (15%)	21 (9%)	0.356	0.287	0.123
Peptic ulcer	36 (11%)	9 (16%)	5 (6%)	0.285	0.191	0.061	47 (9%)	8 (11%)	28 (12%)	0.587	0.21	0.821
Reflux/heartburn	65 (20%)	19 (32%)	17 (20%)	0.032	0.912	0.106	114 (23%)	34 (49%)	67 (30%)	<0.001	0.036	0.003
Depression requiring treatment	46 (14%)	9 (15%)	13 (15%)	0.814	0.734	0.961	84 (16%)	19 (27%)	51 (22%)	0.033	0.051	0.457
Anxiety/panic attacks	37 (11%)	8 (14%)	11 (13%)	0.566	0.598	0.927	97 (19%)	23 (32%)	58 (26%)	0.01	0.049	0.267
3-year follow-up
Mortality rate	29 (9%)	0	12 (14%)	0.016	0.128	0.002	72 (14%)	8 (11%)	34 (14%)	0.532	0.822	0.476
Moderate-to-severe ECOPD rate per person-year	1.1 (1.2%)	1.6 (1.2%)	2.1 (1.8%)	<0.001	<0.001	0.451	1.2 (1.4%)	2.1 (1.7%)	2.6 (1.8%)	<0.001	<0.001	0.018
Rate of FEV₁ decline mL·year⁻¹	−28.0±47.6	−38.1±44.3	−33.5±36.8	0.15	0.426	0.559	−32.8±34.5	−31.0±42.6	−30.1±32.2	0.363	0.861	0.426
CV events	20 (6%)	4 (6%)	6 (7%)	0.88	0.705	0.886	29 (6%)	2 (3%)	19 (8%)	0.321	0.192	0.121
Lung cancer	3 (<1%)	1 (2%)	0	0.602	0.383	0.242	3 (<1%)	1 (1%)	1 (<1%)	0.429	0.791	0.373

Data are presented as n (%), mean±sd and median (interquartile range), unless otherwise stated. C1/D1: patients with forced expiratory volume in 1 s (FEV₁) <50% reference, <2 exacerbations·year⁻¹ and low (C1) or high (D1) symptoms; C2/D2 patients with FEV₁ ≥50% ref., ≥2 exacerbations·year⁻¹ and low (C2) or high (D2) symptoms; C3/D3: patients with both FEV₁ <50% ref., ≥2 exacerbations·year⁻¹ and low (C3) or high (D3) symptoms. Lung volumes were only assessed in a subset of the ECLIPSE cohort at select sites, therefore, ∼30% of group C patients and 21% of group D patients had lung volume data. BMI: body mass index; FFMI: fat-free mass index; mMRC: modified Medical Research Council; SGRQ-C: St George's Respiratory Questionnaire for chronic obstructive pulmonary disease patients (COPD); ECOPD: exacerbation of COPD. CESD: Center for Epidemiological Studies Depression Scale; FVC: forced vital capacity; RV: residual volume; TLC: total lung capacity; FRC: functional residual capacity; S_aO₂: arterial oxygen saturation; 6MWD: 6-min walking distance: BODE: BMI, airflow obstruction, dyspnoea, exercise capacity; % LAA: percentage of low attenuation areas (i.e. emphysema) in the computed tomography; WBC: white blood cells; hsCRP: high-sensitivity C-reactive protein; IL: interleukin; TNF-α: tumour necrosis factor-α; CC-16: serum club cell secretory protein; CCL-18: chemokine C-C ligand 18; SPD: surfactant protein D; ICS: inhaled corticosteroids. ^#: 12 months prior to baseline; ^¶: lung volumes were only assessed in a subset of the ECLIPSE cohort at select sites, therefore, ∼30% of group C patients and 21% of group D patients had lung volume data; ⁺: post-bronchodilator; ^§: based on patient self-report.