Figures
- FIGURE 1
Study workflow. YCAAD: Yale Center for Asthma and Airways Disease; SARP: Severe Asthma Research Programme; NYUBAR: New York University/Bellevue Asthma Registry; T2: type 2.
- FIGURE 2
Serum YKL-40 levels in the four YKL-40 asthma clusters (C1–C4). a) Serum YKL-40 levels in C1–C4 in the Yale Center for Asthma and Airways Disease (YCAAD) cohort. C3 and C4 had elevated serum levels of YKL-40 compared with C1 and C2. b, c) Serum YKL-40 levels were similar among the clusters in the b) Severe Asthma Research Programme and c) New York University/Bellevue Asthma Registry cohorts compared with the YCAAD cohort. d) Combined values for all cohorts. *: p<0.05; **: p<0.01.
- FIGURE 3
Differences in lung function among the YKL-40 clusters (C1–C4) in the three cohorts: a) Yale Center for Asthma and Airways Disease, b) Severe Asthma Research Programme and c) New York University/Bellevue Asthma Registry. Post-bronchodilator forced expiratory volume in 1 s (FEV1) was significantly different among the YKL-40 clusters in all three cohorts. C3 had severely reduced post-bronchodilator FEV1 in all three cohorts. d) Combined values for all cohorts. **: p<0.01.
- FIGURE 4
Rates of near-fatal asthma exacerbations requiring mechanical ventilation in the YKL-40 clusters (C1–C4) among the three cohorts. YCAAD: Yale Center for Asthma and Airways Disease; SARP: Severe Asthma Research Programme; NYUBAR: New York University/Bellevue Asthma Registry. The rate was significantly higher in C3 in all three cohorts.
- FIGURE 5
a) Sputum YKL-40 levels and b) sputum neutrophils in the Yale Center for Asthma and Airways Disease cohort. Both values were increased in clusters C3 and C4 compared with C1 and C2.
- FIGURE 6
Analysis of the type 2 (T2) sputum transcriptome in the YKL-40 clusters and healthy controls in the Yale Center for Asthma and Airways Disease cohort. Mean T2 gene expression levels (interleukin (IL)-4, IL-5 and IL-13) among the YKL-40 clusters demonstrate lower levels of T2 gene expression in C1 and C4.
- FIGURE 7
Analysis of the non-type 2 sputum transcriptome in the YKL-40 clusters and healthy controls in the Yale Center for Asthma and Airways Disease cohort. a) Heatmap of sputum gene expression in C3 compared with healthy controls shows activation of innate immunity pathways and the NETosis pathway. b) Heatmap of sputum gene expression in C4 compared with healthy controls shows activation of the interleukin (IL)-1 and IL-18 pathways in C4. See supplementary tables E10 and E12 for full details of probesets and gene symbols.
Tables
- TABLE 1
Demographic and clinical characteristics of the YKL-40 clusters in the Yale Center for Asthma and Airways Disease (YCAAD), Severe Asthma Research Programme (SARP) and New York University/Bellevue Asthma Registry (NYUBAR) cohorts
Total cohort Cluster 1 Cluster 2 Cluster 3 Cluster 4 p-value Discovery cohort: YCAAD Subjects 156 76 (49) 30 (19) 20 (13) 30 (19) Age years 49 (37–58) 42 (17–52) 49 (37–56) 52 (44–57) 60 (52–65) <0.01 Female 117 (75) 70 (92) 7 (23) 13 (65) 27 (90) <0.01 Ethnicity White 114 (73) 60 (79) 24 (80) 11 (55) 19 (63) 0.2 African-American 29 (19) 10 (13) 6 (20) 5 (25) 8 (27) Other 13 (8) 6 (8) 4 (20) 3 (10) Hispanic 18 (12) 6 (8) 3 (10) 3 (15) 6 (20) 0.36 BMI kg·m−2 28.9 (23.8–35.7) 25.1 (22.2–32.0) 30.0 (25.7–32.4) 31.2 (27.1–37.1) 32.9 (29.0–39.7) <0.01 Age of onset years 21 (5–39) 16 (5–31) 30 (10–40) 5 (3–14) 42 (25–54) <0.01 Asthma duration years 21 (10–33) 18 (12–32) 20 (6–29) 40 (32–50) 16 (7–30) <0.01 Severe by EPR-3 63 (40) 16 (21) 13 (43) 16 (80) 18 (60) <0.01 Lifetime hospitalisations for asthma 65 (42) 22 (29) 12 (40) 15 (75) 16 (53) <0.01 Hospitalisations for asthma in the past year 35 (22) 11 (15) 6 (20) 7 (35) 11 (37) 0.04 ACT score 17 (11–21) 20 (17–23) 13 (10–19) 15 (9–20) 10 (9–17) <0.01 Pre-bronchodilator FEV1 % pred 82 (60–94) 91 (85–103) 72 (62–85) 43 (34–53) 72 (53–81) <0.01 Post-bronchodilator FEV1 % pred 86 (71–98) 96 (86–108) 86 (76–98) 51 (39–56) 75 (61–86) <0.01 Post-bronchodilator FEV1/FVC 74 (65–81) 79 (73–85) 70 (64–75) 53 (41–66) 71 (64–83) <0.01 Bronchodilator response % pred 5 (2–9) 4 (2–7) 12 (4–20) 6 (4–8) 5 (1–10) <0.01 Inhaled corticosteroid use 127 (81) 55 (72) 25 (83) 20 (100) 27 (90) 0.02 Inhaled corticosteroid dose μg·day–1 500 (0–675) 320 (0–640) 410 (0–830) 640 (500–1000) 640 (500–1000) <0.01 Oral or systemic corticosteroids 18 (12) 3 (4) 3 (10) 3 (15) 9 (30) <0.01 LABA use 103 (66) 40 (53) 18 (60) 19 (95) 26 (87) <0.01 Serum YKL-40 ng·mL−1 63 (35–108) 48 (32–71) 50 (33–88) 74 (46–108) 206 (110–311) <0.01 Validation cohort 1: SARP Subjects 167 84 (50) 57 (34) 14 (8) 12 (7) Age years 36 (26–47) 33 (25–44) 35 (25–43) 51 (38–59) 48 (46–54) <0.01 Female 115 (68) 84 (100) 19 (33) 6 (43) 4 (33) <0.01 Ethnicity White 119 (71) 60 (71) 41 (72) 11 (79) 7 (58) 0.56 African-American 41 (25) 19 (23) 15 (26) 2 (14) 5 (42) Other 7 (4) 5 (6) 1 (2) 1 (7) BMI kg·m−2 26.8 (23.5–32.4) 26.1 (23.0–29.8) 27.0 (24.0–32.8) 28.6 (24.4–32.4) 31.1 (27.1–33.3) 0.17 Age of onset years 10 (4–26) 11 (4–22) 6 (2–22) 5 (1–28) 40 (38–46) <0.01 Asthma duration years 19 (9–32) 17 (9–29) 20 (15–33) 33 (29–45) 7 (4–11) <0.01 Lifetime hospitalisations for asthma 71 (43) 30 (36) 24 (42) 12 (86) 5 (42) 0.01 Pre-bronchodilator FEV1 % pred 80 (62–92) 88 (80–98) 73 (59–88) 32 (28–41) 58 (49–70) <0.01 Post-bronchodilator FEV1 % pred 92 (79–102) 96 (88–106) 89 (79–100) 44 (40–49) 79 (71–98) <0.01 Bronchodilator response % pred 10 (5–16) 7 (4–10) 15 (12–22) 10 (6–14) 12 (10–22) <0.01 Inhaled corticosteroid use 73 (44) 35 (42) 22 (39) 7 (50) 9 (75) <0.01 Oral or systemic corticosteroids 19 (12) 5 (6) 5 (9) 5 (36) 3 (25) <0.01 LABA use 83 (50) 37 (44) 25 (44) 10 (71) 11 (92) <0.01 Serum YKL-40 ng·mL−1 49 (34–68) 43 (33–61) 54 (28–69) 70 (42–101) 67 (50–165) <0.01 Validation cohort 2: NYUBAR Subjects 341 205 (60) 97 (28) 15 (4) 24 (7) Age years 37 (25–50) 34 (24–49) 34 (26–43) 46 (42–62) 54 (48–62) <0.01 Female 242 (71) 205 (100) 11 (11) 9 (60) 17 (71) <0.01 Ethnicity White 75 (255) 76 (159) 68 (66) 67 (10) 83 (20) 0.06 African-American 19 (66) 20 (40) 19 (19) 27 (4) 13 (3) Other 6 (21) 3 (6) 13 (13) 6 (1) 4 (1) Hispanic 188 (55) 119 (58) 47 (49) 9 (60) 13 (54) 0.46 BMI kg·m−2 28.0 (24.0–33.0) 28.0 (23.0–33.0) 27.0 (24.0–32.0) 32.0 (27.5–40.0) 28.5 (24.0–33.5) 0.09 Age of onset years 16 (8–28) 18 (10–27) 12 (6–22) 9 (5–21) 45 (39–53) <0.01 Asthma duration years 16 (7–28) 15 (6–25) 18 (12–29) 36 (32–42) 8 (3–16) <0.01 Severe by EPR-3 209 (61) 121 (59) 50 (52) 15 (100) 23 (96) 0.01 Hospitalisations for asthma in the past year 36 (11) 14 (7) 11 (11) 7 (47) 4 (17) <0.01 Pre-bronchodilator FEV1 % pred 82 (71–93) 86 (76–95) 79 (68–89) 40 (33–48) 67 (55–72) <0.01 Post-bronchodilator FEV1 % pred 87 (76–96) 89 (80–99) 86 (77–95) 48 (45–51) 73 (60–76) <0.01 Bronchodilator response % pred 4 (1–7) 3 (1–6) 5 (2–10) 4 (1–9) 6 (2–8) <0.01 Inhaled corticosteroid use 191 (56) 109 (53) 45 (46) 15 (100) 22 (92) <0.01 Oral or systemic corticosteroids 199 (58) 115 (56) 51 (53) 15 (100) 18 (75) <0.01 LABA use 141 (41) 85 (42) 29 (30) 12 (80) 15 (63) <0.01 Serum YKL-40 ng·mL−1 56 (42–87) 52 (40–80) 57 (39–86) 99 (60–177) 103 (61–156) <0.01 Data are presented as n, n (%) or median (interquartile range). BMI: body mass index; EPR-3: Expert Panel Report-3; ACT: Asthma Control Test; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; LABA: long-acting β-agonist.
- TABLE 2
Biomarkers in the Yale Center for Asthma and Airways Disease (YCAAD), Severe Asthma Research Programme (SARP) and New York University/Bellevue Asthma Registry (NYUBAR) cohorts by YKL-40 asthma cluster
Total cohort Cluster 1 Cluster 2 Cluster 3 Cluster 4 p-value YCAAD Subjects 156 76 (49) 30 (19) 20 (13) 30 (19) Sputum YKL-40 ng·mL−1# 15 (0–40) 10 (0–37) 10 (0–26) 28 (5–58) 32 (8–43) 0.16 Serum IgE IU·mL−1 91 (25–277) 77 (23–220) 85 (17–328) 163 (48–341) 72 (30–351) 0.40 FENO ppb 28 (19–53) 25 (18–55) 43 (23–60) 20 (15–35) 32 (21–50) 0.02 Absolute blood eosinophil count cells·μL−1 165 (86–335) 136 (84–276) 170 (101–322) 192 (86–399) 170 (91–338) 0.69 Eosinophils in sputum %# 3 (1–7) 2 (1–5) 4 (2–8) 2 (1–4) 5 (2–12) 0.08 Neutrophils in sputum %# 37 (27–48) 34 (27–44) 37 (24–45) 46 (34–55) 43 (29–50) 0.15 Macrophages in sputum % 55 (42–65) 60 (51–67) 51 (42–67) 47 (35–55) 44 (35–58) <0.01 SARP Subjects 167 84 (50) 57 (34) 14 (8) 12 (7) Serum IgE IU·mL−1 116 (34–301) 73 (24–191) 177 (60–354) 162 (18–262) 270 (200–333) 0.03 FENO ppb 25 (16–50) 21 (11–52) 29 (23–63) 27 (16–40) 52 (16–111) 0.04 Blood eosinophils % 3 (2–5) 2.5 (1.8–4.0) 4.0 (2.0–6.0) 5.1 (4.0–7.5) 4.5 (2.3–9.8) <0.01 NYUBAR Subjects 341 205 (60) 97 (28) 15 (4) 24 (7) Serum IgE IU·mL−1 129 (41–345) 119 (31–328) 197 (74–443) 130 (52–278) 94 (46–173) 0.02 Data are expressed as n, n (%) or median (interquartile range). FENO: exhaled nitric oxide fraction. #: data available for n=113 (C1, n=54; C2, n=17; C3, n=18; C4, n=24).
Supplementary Material
Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Supplementary material ERJ-00800-2017_Supplement
Supplementary figures ERJ-00800-2017_Supplementary_figures
Supplementary Material
G.L. Chupp ERJ-00800-2017_Chupp
L. Cohn ERJ-00800-2017_Cohn
G.M. Crisafi ERJ-00800-2017_Crisafi
J.L. Gomez ERJ-00800-2017_Gomez
N.N. Jarjour ERJ-00800-2017_Jarjour
J. Reibman ERJ-00800-2017_Reibman
