Mixed Th2 and non-Th2 inflammatory pattern in the asthma–COPD overlap: a network approach

Figures & data

Table 1 Characteristics of patients according to the baseline diagnosis

	Asthma	COPD	ACO	p-value
Number of subjects	94	89	109
Age (years)	61.8 (12.3)	67.9 (8.6)	63.31 (10.6)	<0.001
Gender (% female)	55.3	24.7	34.9	<0.001
BMI (kg/m^2)	28.6 (4.7)	28.4 (4.9)	28.6 (6)	0.96
Pack-years	3.4 (5.8)	48.7 (22.5)	45.1 (24)	<0.001
Positive SPT (%)	46.8	7.9	32.1	<0.001
Rhinitis (%)	53.2	9.3	31.1	<0.001
Pre-BD FEV1 (%)	61.2 (17.7)	51.4 (18.2)	53.8 (16.5)	<0.001
Post-BD FEV1 (%)	69.5 (18.9)	55.1 (18.5)	58.9 (17)	<0.001
PBT (%)	44.6	19.2	37.7	0.001
DLCO (%)	83.4 (18.7)	63.6 (25.9)	66.6 (19.1)	<0.001
Exacerbations in previous year	0.97 (1.37)	1.08 (1.32)	0.97 (1.36)	0.92
Blood eosinophils (cells/µL)	300 (0, 4,350)	100 (0, 200)	300 (0, 1,000)	<0.001
Sputum eosinophils (n=35, %)	4.8 (5.8)	1.8 (2.1)	6.3 (5.8)	0.21
IgE (IU/mL)	123 (4, 2,909)	51 (4, 2,301)	89.8 (4, 2,500)	0.094
FeNO (ppb)	36.0 (24.1)	17.3 (9.6)	22.5 (21)	<0.001
CAT	14.8 (8.8)	13.0 (6.7)	13.3 (7.7)	0.83
ACT	20.2 (4.4)	20.4 (4.3)	19.4 (4.8)	0.54
ICS (%)	100	66.3	75.2	<0.01
LABA (%)	99	93.3	93.6	0.19
LAMA (%)	54.3	87.6	73.4	<0.01

Notes: Data are expressed as mean (SD), median (percentile 25, percentile 75), or n and %. Overall p-values are reported. Exacerbations: number of severe exacerbations during the past 12 months.

Abbreviations: ACO, asthma–COPD overlap; ACT, asthma control test; BMI, body mass index; CAT, COPD assessment test; COPD, chronic obstructive pulmonary disease; DLCO, carbon monoxide diffusing capacity; FeNO, fractioned exhaled nitric oxide levels; FEV₁, forced expiratory volume in the first second; ICS, inhaled corticosteroid; IgE, immunoglobulin E; LABA, long-acting β2-agonists; LAMA, long-acting muscarinic antagonists; PBT, positive bronchodilator test; post-BD, post-bronchodilator; pre-BD, pre-bronchodilator; SPT, skin prick test.

Figure 1 Flowchart diagram of recruitment process.

Abbreviations: ACO, asthma–COPD overlap; COPD, chronic obstructive pulmo nary disease. FEV₁, forced expiratory volume in the first second; FVC, forced vital capacity.

Table 2 Biomarker values according to the baseline diagnosis

	Asthma (n=94)	COPD (n=89)	ACO (n=109)	p-value
IL-6 (pg/mL)	1.77 (0.71–3.66)	1.13 (0.43–2.30)*	1.42 (0.57–2.44)	0.031
IL-8 (pg/mL)	7.03 (4.69–10.44)	9.45 (6.61–13.12)**	9.58 (6.39–13.51)**	<0.001
TNF-α (pg/mL)	3.93 (3.11–5.50)	4.21 (2.57–5.68)	4.17 (3.22–5.43)	0.660
IL-13 (pg/mL)	2.98 (0.23–7.63)	1.25 (0.23–5.31)	1.98 (0.23–9.92)	0.213
IL-5 (pg/mL)	2.09 (0.61–3.57)	1.11 (0.12–2.42)*	1.73 (0.41–2.77)	0.012
Periostin (ng/mL)	37.4 (26.6–49.2)	33.5 (27.7–49.9)	35 (27.9–44)	0.232
IL-17 (pg/mL)	6.94 (3.11–15.90)	5.33 (1.41–11.37)	6.75 (2.64–12.47)	0.075
IL-13/IL-8	0.43 (0.05–0.63)	0.15 (0.04–0.56)	0.14 (0.03–0.53)	0.013
IL-5/IL-8	0.25 (0.08–0.63)	0.12 (0.02–0.25)	0.14 (0.05–0.29)	<0.001
FeNO (ppb)	33 (19.8–41.3)	17.3 (12–18.8)**	19.6 (10–24.6)**	<0.001

Notes: Overall p-values from Kruskal–Wallis ANOVA; pairwise p-values from Mann–Whitney U-test, Bonferroni-corrected:

* p<0.05 vs asthma;

** p<0.001 vs asthma.

Abbreviations: ACO, asthma–COPD overlap; ANOVA, analysis of variance; COPD, chronic obstructive pulmonary disease; FeNO, fractional exhaled nitric oxide; TNF-α, tumor necrosis factor-α.

Figure 2 Cytokine concentrations in asthma, ACO, and COPD.

Notes: *p<0.05 vs asthma; **p<0.001 vs asthma.
Abbreviations: ACO, asthma–COPD overlap; COPD, chronic obstructive pulmonary disease; TNF-α, tumor necrosis factor-α.

Figure 3 Scatterplot of the combination of values from discriminant scores 1 and 2 as compared to each patient’s COAD category.

Abbreviations: COAD, chronic obstructive airway disease; COPD, chronic obstructive pulmonary disease; COPD-e, COPD with eosinophilia; NSA, nonsmoking asthmatics; SA, smoking asthmatics.

Figure 4 Network layout of inflammome in asthma, COPD, and ACO.

Abbreviations: ACO, asthma–COPD overlap; COPD, chronic obstructive pulmonary disease; FeNO, fractional exhaled nitric oxide; TNF-α, tumor necrosis factor-α.

Table 3 Blood biomarkers in Th2-high and Th2-low patients

	Th2-high pattern (n=94)	Th2-low pattern (n=197)	p-value
IL-6 (pg/mL)	1.75 (0.58–2.67)	1.31 (0.50–2.63)	0.174
IL-8 (pg/mL)	8.34 (5.37–12.77)	8.40 (5.88–12.77)	0.856
TNF-α (pg/mL)	4.32 (3.20–6.16)	3.95 (2.91–5.32)	0.055
IL-13 (pg/mL)	2.92 (0.26–5.59)	1.65 (0.23–5.58)	0.150
IL-5 (pg/mL)	1.96 (0.87–3.34)	1.51 (0.29–2.88)	0.025
Periostin (ng/mL)	39.73 (28.05–54.40)	34.20 (26.94–41.43)	0.005
IL-13/IL-8	0.26 (0.06–0.66)	0.15 (0.03–0.78)	0.182
IL-5/IL-8	0.23 (0.08–0.40)	0.13 (0.03–0.33)	0.019
IL-17 (pg/mL)	7.37 (3.46–13.76)	5.73 (2.10–12.12)	0.125

Notes: Data are expressed as medians and interquartile ranges; p-values from the Mann–Whitney U-test.

Abbreviation: TNF-α, tumor necrosis factor-α.

Table 4 Biomarker ROC and best cutoff point to predict Th2-high or Th2-low patterns

Biomarker	ROC	Value
IL-6	AUC (95% CI)	0.550 (0.479–0.620)
	Best cutoff (pg/mL)	NA
IL-8	AUC (95% CI)	0.507 (0.434–0.579)
	Best cutoff (pg/mL)	NA
TNF-α	AUC (95% CI)	0.570 (0.499–0.641)
	Best cutoff (pg/mL)	4.04
IL-13	AUC (95% CI)	0.552 (0.482–0.623)
	Best cutoff (pg/mL)	NA
IL-5	AUC (95% CI)	0.582 (0.512–0.652)
	Best cutoff (pg/mL)	1.79
Periostin	AUC (95% CI)	0.602 (0.528–0.677)
	Best cutoff (IU/mL)	35.2
IL-5 + IL-13	AUC (95% CI)	0.579 (0.508–0.650)
IL-5 + IL-13 + IL-8	AUC (95% CI)	0.593 (0.523–0.662)
IL-13/IL-8	AUC (95% CI)	0.549 (0.479–0.619)
IL-5/IL-8	AUC (95% CI)	0.586 (0.517–0.654)
	Best cutoff	0.15
IL-17	AUC (95% CI)	0.556 (0.486–0.626)
	Best cutoff (pg/mL)	NA

Abbreviations: AUC, area under the ROC; CI, confidence interval; NA, not applicable; ROC, receiver operating curve; TNF-α, tumor necrosis factor-α.

Table S1 Biomarker AUC in the ROC for the diagnosis of the different COAD categories, alone and in combination

Biomarker	Asthma	COPD	ACO
IL-13 (pg/mL)	0.564 (0.490–0.637)	0.532 (0.458–0.605)	0.531 (0.463–0.599)
IL-5 (pg/mL)	0.587 (0.515–0.659)	0.600 (0.528–0.672)	0.508 (0.440–0.577)
IL-17 (pg/mL)	0.563 (0.492–0.635)	0.578 (0.503–0.653)	0.511 (0.444–0.579)
IL-6 (pg/mL)	0.587 (0.514–0.659)	0.578 (0.506–0.650)	0.489 (0.422–0.557)
IL-8 (pg/mL)	0.652 (0.583–0.720)	0.567 (0.497–0.637)	0.581 (0.513–0.649)
TNF-α (pg/mL)	0.506 (0.435–0.577)	0.527 (0.450–0.604)	0.530 (0.462–0.597)
IL-13/IL-8	0.608 (0.564–0.706)	0.551 (0.479–0.623)	0.555 (0.486–0.624)
IL-5/IL-8	0.635 (0.564–0.706)	0.605 (0.533–0.677)	0.531 (0.464–0.599)
Periostin (ng/mL)	0.558 (0.483–0.632)	0.549 (0.480–0.618)	0.573 (0.505–0.641)

Note: Data shown as area under the curve (confidence interval 95%).

Abbreviations: ACO, asthma–COPD overlap; AUC, area under the ROC; COAD, chronic obstructive airway disease; COPD, chronic obstructive pulmonary disease; ROC, receiver operating curve; TNF-α, tumor necrosis factor-α.