Background
Methods
Subjects
Measurement of serum analyte concentrations
Statistical Analyses
Results
COPD and healthy control cohorts
Parameter | T54 COPDa | BioServe COPDb | Healthy controlsc | p (COPD vs healthy control)d | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Total | Placebo | 3 mg/kg | 5 mg/kg | p-value | Total | p (vs T54) | Ctr1 | Ctr2 | Ctr1 vs T54, BS | Ctr2 vs T54, BS | |
Sample size (n)
| 234e | 68 | 64 | 68 | 160 | 50 | 109 | ||||
Gender(n: male/female)
| 140/94 | 43/25 | 40/24 | 37/31 | 0.51 | 73/87 | 0.37 | 30/20 | 54/42 | (1.0, 0.52) | (0.27, 0.63) |
Age (years)
| 65.2 ± 8.8 | 65.0 ± 8.9 | 64.4 ± 8.2 | 64.9 ± 9.6 | 0.93 | 65.8 ± 11.8 | 0.57 | 38.7 ± 11.8 | 49.9 ± 14.5 | (< 10-4, < 10-4) | (< 10-4, < 10-4) |
BMI (kg/m
2
)
| 27.2 ± 6.1 | 28.2 ± 6.1 | 26.6 ± 5.4 | 27.0 ± 6.6 | 0.32 | 26.5 ± 7.0 | 0.27 | 27.0 ± 6.8 | 27.9 ± 6.9 | (0.82, 0.65) | (0.46, 0.16) |
Race (n)
| 0.46 | 0.036 | (< 10-4, < 10-4) | (< 10-4, < 10-4) | |||||||
Black | 10 | 3 | 1 | 4 | 14 | 25 | 41 | ||||
Caucasian | 223 | 64 | 63 | 64 | 143 | 5 | 22 | ||||
Other | 1 | 1 | 0 | 0 | 3 | 20 | 12 | ||||
Smoking status (n)
| 0.93 | 0.00011 | (< 10-4, < 10-4) | (< 10-4, < 10-4) | |||||||
Current smoker | 104 | 29 | 29 | 31 | 50 | 33 | 36 | ||||
Ex-smoker | 130 | 39 | 35 | 37 | 100 | ||||||
Non-smoker | 9 | 16 | 24 | ||||||||
GOLD stage (n)
| 0.66 | < 10-9 | n/a | n/a | n/a | n/a | |||||
stage I | 3 | 1 | 0 | 2 | 40 | ||||||
stage II | 74 | 23 | 21 | 20 | 40 | ||||||
stage III | 104 | 33 | 31 | 26 | 40 | ||||||
stage IV | 53 | 11 | 16 | 16 | 40 | ||||||
Subtype (n)
| 0.58 | < 10-9 | n/a | n/a | n/a | n/a | |||||
Chronic bronchitis | 54 | 20 | 11 | 15 | 41 | ||||||
Chronic emphysema | 95 | 26 | 28 | 28 | 80 | ||||||
Both | 85 | 22 | 25 | 25 | 3 | ||||||
FEV
1
(% predicted)
| |||||||||||
Baseline | 43.4 ± 16.0 | 45.2 ± 16.2 | 43.9 ± 17.5 | 41.8 ± 14.9 | 0.49 | 52.7 ± 25.1 | 0.000051 | n/a | n/a | n/a | n/a |
Change from baseline | -1.1 ± 6.7 | -1.4 ± 7.5 | 0.3 ± 6.1 | -1.9 ± 7.5 | 0.19 | n/a | n/a | n/a | n/a | n/a | n/a |
CRQ total score
| |||||||||||
Baseline | 80.4 ± 19.1 | 83.8 ± 20.1 | 77.1 ± 17.5 | 80.2 ± 19.3 | 0.11 | n/a | n/a | n/a | n/a | n/a | n/a |
Change from baseline | 10.3 ± 18.6 | 12.3 ± 19.2 | 12.7 ± 22.7 | 15.1 ± 10.0 | 0.70 | n/a | n/a | n/a | n/a | n/a | n/a |
Associations of baseline serum analyte levels and COPD
Analytea | Medianb | Fold (COPD/control)c | FDRd | |||||||
---|---|---|---|---|---|---|---|---|---|---|
BS | T54 | Ctr1 | Ctr2 | BS/Ctr1 | T54/Ctr1 | BS/Ctr2 | T54/Ctr2 | |||
COPD > Control
| ||||||||||
CD40 Ligand | ng/mL | 2.50 | 0.96 | 0.01 | 0.01 | 250 | 95.9 | 250 | 95.9 | < 10-8 |
EGF | pg/mL | 699.49 | 230.99 | 14.84 | 3.70 | 47.1 | 15.6 | 189 | 62.4 | < 10-8 |
BDNF | ng/mL | 28.50 | 24.80 | 0.52 | 0.56 | 55.0 | 47.9 | 50.5 | 44.0 | < 10-8 |
RANTES | ng/mL | 18.65 | 15.90 | 1.28 | 1.22 | 14.5 | 12.4 | 15.2 | 13.0 | < 10-8 |
Myeloperoxidase | ng/mL | 2144.71 | 686.50 | 119.47 | 87.50 | 18.0 | 5.7 | 24.5 | 7.8 | < 10-8 |
Eotaxin | pg/mL | 232.50 | 162.50 | 20.50 | 20.50 | 11.3 | 7.9 | 11.3 | 7.9 | < 10-8 |
EN-RAGE | ng/mL | 254.97 | 35.60 | 13.40 | 14.50 | 19.0 | 2.7 | 17.6 | 2.5 | < 10-8 |
Ferritin | ng/mL | 166.00 | 113.00 | 18.95 | 28.00 | 8.8 | 6.0 | 5.9 | 4.0 | < 10-8 |
IL-1RA | pg/mL | 360.50 | 111.50 | 31.82 | 38.00 | 11.3 | 3.5 | 9.5 | 2.9 | < 10-8 |
ENA-78 | ng/mL | 2.07 | 1.68 | 0.32 | 0.35 | 6.5 | 5.2 | 5.9 | 4.8 | < 10-8 |
PAI-1 | ng/mL | 199.00 | 183.50 | 26.05 | 54.00 | 7.6 | 7.0 | 3.7 | 3.4 | < 10-8 |
MCP-1 | pg/mL | 558.00 | 483.00 | 170.00 | 100.00 | 3.3 | 2.8 | 5.6 | 4.8 | < 10-8 |
MIP-1beta | pg/mL | 341.49 | 259.50 | 99.00 | 87.50 | 3.4 | 2.6 | 3.9 | 3.0 | < 10-8 |
Thrombopoietin | ng/mL | 4.92 | 4.70 | 1.62 | 1.60 | 3.0 | 2.9 | 3.1 | 2.9 | < 10-8 |
TIMP-1 | ng/mL | 211.00 | 192.00 | 70.44 | 67.00 | 3.0 | 2.7 | 3.1 | 2.9 | < 10-8 |
IL-16 | pg/mL | 1174.99 | 440.50 | 233.49 | 273.50 | 5.0 | 1.9 | 4.3 | 1.6 | < 10-8 |
VEGF | pg/mL | 1275.00 | 933.00 | 447.00 | 383.50 | 2.9 | 2.1 | 3.3 | 2.4 | < 10-8 |
Cancer antigen 19-9 | U/mL | 7.19 | 5.94 | 2.11 | 3.30 | 3.4 | 2.8 | 2.2 | 1.8 | 3.7 × 10-7 - 4.5 × 10-4 |
CD40 | ng/mL | 1.84 | 1.06 | 0.61 | 0.59 | 3.0 | 1.7 | 3.1 | 1.8 | < 10-8 |
Creatine kinase-MB | ng/mL | 0.48 | 0.45 | 0.21 | 0.21 | 2.3 | 2.2 | 2.3 | 2.2 | 6.1 × 10-7 - 8.3 × 10-5 |
C-reactive protein | ug/mL | 4.51 | 3.36 | 2.06 | 1.70 | 2.2 | 1.6 | 2.7 | 2.0 | 4.2 × 10-7 - 0.0074 |
Myoglobin | ng/mL | 16.00 | 16.10 | 7.14 | 9.30 | 2.2 | 2.3 | 1.7 | 1.7 | < 10-8 - 3.0 × 10-8 |
Stem cell factor | pg/mL | 395.00 | 402.00 | 221.00 | 191.00 | 1.8 | 1.8 | 2.1 | 2.1 | < 10-8 |
IL-18 | pg/mL | 302.49 | 253.50 | 148.00 | 154.50 | 2.0 | 1.7 | 2.0 | 1.6 | < 10-8 |
TNF-RII | pg/mL | 5.85 | 5.18 | 3.38 | 3.20 | 1.7 | 1.5 | 1.8 | 1.6 | < 10-8 |
COPD < Control
| ||||||||||
IGF-1 | ng/mL | 45.30 | 29.30 | 188.55 | 203.00 | -4.2 | -6.4 | -4.5 | -6.9 | 3.0 × 10-7 - < 10-8 |
IgE | ng/mL | 22.85 | 23.25 | 60.89 | 60.00 | -2.7 | -2.6 | -2.6 | -2.6 | 0.0043 - 6.0 × 10-6 |
Influence of smoking and age
Analytea | T54 COPD/Ctr1b | BioServe COPD/Ctr1 | T54 COPD/Ctr2 | BioServe COPD/Ctr2 | ||||
---|---|---|---|---|---|---|---|---|
Fold/controlc | FDRc | Fold/control | FDR | Fold/control | FDR | Fold/control | FDR | |
COPD > Control
| ||||||||
CD40 Ligand | 102.5 | < 10-8 | 282.0 | < 10-8 | 102.5 | < 10-8 | 282.0 | < 10-8 |
EGF | 16.3 | < 10-8 | 48.3 | < 10-8 | 71.5 | < 10-8 | 211.5 | < 10-8 |
BDNF | 54.0 | < 10-8 | 63.9 | < 10-8 | 58.5 | < 10-8 | 69.3 | < 10-8 |
RANTES | 12.0 | < 10-8 | 16.9 | < 10-8 | 14.1 | < 10-8 | 19.8 | < 10-8 |
Myeloperoxidase | 6.8 | < 10-8 | 24.2 | < 10-8 | 6.5 | < 10-8 | 23.1 | < 10-8 |
Eotaxin | 8.9 | < 10-8 | 10.8 | < 10-8 | 8.9 | < 10-8 | 10.8 | < 10-8 |
EN-RAGE | 3.1 | < 10-8 | 25.5 | < 10-8 | 2.3 | 1.5 × 10-5 | 19.4 | < 10-8 |
Ferritin | 5.6 | < 10-8 | 8.7 | < 10-8 | 2.9 | < 10-8 | 4.5 | < 10-8 |
IL-1RA | 5.6 | < 10-8 | 28.4 | < 10-8 | 3.5 | < 10-8 | 17.6 | < 10-8 |
ENA-78 | 5.9 | < 10-8 | 8.1 | < 10-8 | 7.8 | < 10-8 | 10.8 | < 10-8 |
PAI-1 | 7.5 | < 10-8 | 8.1 | < 10-8 | 5.3 | < 10-8 | 5.7 | < 10-8 |
MCP-1 | 2.8 | < 10-8 | 2.8 | < 10-8 | 4.5 | < 10-8 | 4.5 | < 10-8 |
MIP-1beta | 2.5 | < 10-8 | 3.4 | < 10-8 | 2.6 | < 10-8 | 3.5 | < 10-8 |
Thrombopoietin | 2.9 | < 10-8 | 3.1 | < 10-8 | 2.9 | < 10-8 | 3.1 | < 10-8 |
TIMP-1 | 2.7 | < 10-8 | 3.0 | < 10-8 | 3.1 | < 10-8 | 3.3 | < 10-8 |
IL-16 | 1.8 | < 10-8 | 5.7 | < 10-8 | 1.7 | < 10-8 | 5.4 | < 10-8 |
VEGF | 2.1 | < 10-8 | 2.9 | < 10-8 | 2.6 | < 10-8 | 3.6 | < 10-8 |
Cancer antigen 19-9 | 2.0 | 0.0026 | 2.2 | 0.0084 | 1.6 |
0.18
| 1.8 |
0.25
|
CD40 | 1.7 | < 10-8 | 3.1 | < 10-8 | 1.7 | < 10-8 | 3.2 | < 10-8 |
Creatine kinase-MB | 2.1 | 0.0023 | 2.3 | 0.0006 | 2.1 | 0.044 | 2.3 | 0.0063 |
C-reactive protein | 1.7 | 0.019 | 2.0 | 0.0076 | 1.7 |
0.077
| 2.0 | 0.036 |
Myoglobin | 2.1 | 9.2 × 10-6 | 1.8 | 0.0011 | 1.4 | 0.0023 | 1.2 |
0.074
|
Stem cell factor | 1.7 | < 10-8 | 1.8 | < 10-8 | 1.9 | < 10-8 | 2.1 | < 10-8 |
IL-18 | 1.7 | < 10-8 | 2.4 | < 10-8 | 1.4 | 4.5 × 10-6 | 2.0 | < 10-8 |
TNF-RII | 1.4 | < 10-8 | 1.7 | < 10-8 | 1.5 | < 10-8 | 1.8 | < 10-8 |
COPD < Control
| ||||||||
IGF-1 | -6.0 | 0.00018 | -3.8 | 6.5 × 10-6 | -6.6 | 8.6 × 10-6 | -4.2 | < 10-8 |
IgE | -4.1 | 0.025 | -3.2 | 0.019 | -3.4 | 0.0050 | -2.6 | 0.0068 |
Correlation of inflammatory markers and disease phenotypes
Impact of infliximab
Change from baselinea | Median (IQR) | p-valueb | |
---|---|---|---|
Infliximab | Placebo | ||
TNF-alpha high subset
b
| |||
FEV1 | 0.0 (-4.0, 4.0) | -2.3 (-6.0, 1.0) | 0.11 |
CRQ | 8.0 (0.0, 21.5) | 4.0 (-1.5, 19.0) | 0.34 |
6MWD | 0.0 (-39.0, 41.0) | 21.2 (-49.4, 41.7) | 0.93 |
Dyspnea | 0.0 (0.0, 2.0) | 0.0 (0.0, 2.8) | 0.98 |
log2(CRP) | 0.1 (-1.1, 0.9) | -0.7 (-1.5, 0.2) | 0.10 |
CRP high subset
c
| |||
FEV1 | -1.8 (-4.0, 4.0) | -2.1 (-6.0, 2.0) | 0.51 |
CRQ | 17.0 (0.0, 28.5) | 4.0 (0.0, 24.0) | 0.38 |
6MWD | 3.4 (-55.6, 66.0) | 0.0 (-47.7, 35.0) | 0.67 |
Dyspnea | 0.0 (-3.0, 2.0) | 0.0 (0.0, 2.0) | 0.40 |
log2(CRP) | -1.1 (-1.9, -0.2) | -0.4 (-1.0, 0.4) | 0.075 |