Fractional Exhaled Nitric Oxide is Associated with the Severity of Stable COPD

Figures & data

Figure 1. Distribution of FeNO with respect to blood eosinophils.

Notes: The coordinate axes are expressed as logarithms of the corresponding data. Although a significant association between FeNO and blood eosinophils was seen (Pearson correlation coefficient r = 0.192, P < 0.001), use of the cutoff of 200 cells/μL or more blood eosinophils (horizontal line) to predict FeNO of at least 25 ppb (vertical line) will mistakenly identify many patients with lower FeNO (upper left quadrant) and miss many patients with actual FeNO of 25 ppb or more (lower right quadrant).

Table 1. Demographics for patients stratified by the mean FeNO or blood eosinophil counts at baseline.

	FeNO < 25 ppb (N = 223)	FeNO ≥ 25 ppb (N = 167)	P-value*	Blood eosinophils < 200 cells/µL (N = 252)	Blood eosinophils ≥ 200 cells/µL (N = 138)	P-value*
Age, year	64.1 ± 7.1	65.2 ± 6.5	0.104	64.5 ± 7.0	64.7 ± 6.6	0.746
Men	212 (95.1%)	164 (98.2%)	0.099	242 (96.0%)	134 (97.1%)	0.587
Current smoker^#	100 (44.8%)	43 (25.7%)	<0.001	92 (36.5%)	51 (37.0%)	0.930
Smoking pack-years	40.5 (30.0–51.0)	41.0 (28.0–54.0)	0.997	41.0 (30.8–52.4)	40.0 (26.9–51.5)	0.162
BMI	24.7 (22.1–27.0)	24.5 (22.1–26.5)	0.994	24.7 (22.1–26.8)	24.5 (22.2–27.1)	0.791
Inhaled treatment
ICS + LABA	79 (35.4%)	61 (36.5%)	0.823	83 (32.9%)	57 (41.3%)	0.100
LAMA	13 (5.8%)	13 (7.8%)	0.444	20 (7.9%)	6 (4.3%)	0.174
ICS + LABA + LAMA	52 (23.3%)	38 (22.8%)	0.896	60 (23.8%)	30 (21.7%)	0.643
tIgE, kU/mL	58.7 (28.3–185.0)	108.0 (41.0–222.5)	0.019	67.0 (30.7–171.8)	88.4 (37.5–293.0)	0.064
sIgE, kU/mL	0.07 (0.04–0.19)	0.11 (0.06–0.40)	0.004	0.07 (0.04–0.22)	0.10 (0.06–0.33)	0.020
sIgE positive rate^†, %	35 (15.7%)	45 (26.9%)	0.006	48 (19.0%)	32 (23.2%)	0.333
Blood eosinophils, cells/µL	140.0 (90.0–220.0)	160.0 (100.0–280.0)	0.028	–	–	–
FeNO, ppb	–	–	–	21.0 (14.0–31.0)	25.0 (16.8–36.0)	0.004

Data are mean ± SD or median (interquartile range) or n (%);

* Continuous variables were tested by parametric tests (Student’s t-test) or non-parametric tests (Mann-Whitney U test), and categorical variables with the chi-squared or Fisher’s exact tests;

^# Current smoker was defined as having smoked 100 cigarettes in one’s lifetime and currently smoking cigarettes;

^† sIgE positive was defined as sIgE ≥ 0.35 kU/mL.

BMI, body mass index; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LAMA, long-acting muscarinic antagonist; tIgE, total immunoglobulin E; sIgE, specific immunoglobulin E; FeNO, Fractional exhaled Nitric Oxide.

Table 2. Clinical characteristics for patients stratified by the mean FeNO or blood eosinophil counts.

	FeNO < 25 ppb (N = 223)	FeNO ≥ 25 ppb (N = 167)	P-value*	Blood eosinophils < 200 cells/µL (N = 252)	Blood eosinophils ≥ 200 cells/µL (N = 138)	P-value*
GOLD stage			0.063			0.560
I(FEV1≥80% predicted)	37 (16.6%)	19 (11.4%)		39 (15.5%)	17 (12.3%)
II(50% ≤ FEV1 < 80% predicted)	90 (40.4%)	90 (53.9%)		111 (44.1%)	69 (50.0%)
III(30% ≤ FEV1 < 50% predicted)	75 (33.6%)	46 (27.5%)		82 (32.5%)	39 (28.3%)
IV(FEV1 < 30% predicted)	21 (9.4%)	12 (7.2%)		20 (7.9%)	13 (9.4%)
COPD score(CAT)	14.0 (8.0–22.0)	13.0 (7.3–18.8)	0.059	14.0 (8.0–22.0)	13.0 (8.0–20.0)	0.623
SGRQ
SGRQ (total)	31.0 (20.1–45.1)	27.0 (15.0–41.6)	0.014	30.4 (17.9–44.3)	28.7 (16.7–42.8)	0.379
SGRQ (symptoms)	38.3 (23.3–57.0)	31.8 (18.3–52.4)	0.025	37.6 (19.0–57.2)	34.2 (23.4–51.9)	0.991
SGRQ (impact)	24.2 (10.8–40.2)	19.3 (7.6–38.4)	0.050	22.9 (10.3–38.5)	20.5 (8.6–41.6)	0.424
SGRQ (activity)	41.4 (29.3–59.5)	35.5 (17.3–54.2)	0.042	41.3 (24.1–54.4)	35.5 (23.3–59.5)	0.637
Moderate or severe exacerbation in preceding 12 months^#, n	65 (29.1%)	31 (18.6%)	0.016	56 (22.2%)	40 (28.9%)	0.138

Data are median (interquartile range) or n (%);

* Continuous variables were tested by parametric tests (Student’s t-test) or non-parametric tests (Mann-Whitney U test), and categorical variables with the chi-squared or Fisher’s exact tests;

^# Moderate or severe exacerbation was defined as exacerbation required treated with antibiotics and/or oral corticosteroids, or required hospitalization or visited emergency room.

GOLD, Global Initiative for Chronic Obstructive Lung Disease; CAT, COPD Assessment Test; SGRQ, St George Respiratory Questionnaire; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity.

Figure 2. Receiver operating characteristic analysis for blood eosinophil prediction of FeNO.

Notes: A: Correct prediction of FeNO less than 25 ppb or more. AUC = 0.565 (95% CI 0.506–0.623, P = 0.028); B: Correct prediction of FeNO less than 30 ppb or more AUC = 0.560 (95% CI 0.495–0.625, P = 0.060).

Abbreviations: AUC, area under the curve.

Table 3. Lung function and exacerbations for patients in groups stratified by FeNO and blood eosinophil counts.

	FeNO < 25 ppb and Blood eosinophils < 200 cells/µL (N = 155)	FeNO < 25 ppb and Blood eosinophils ≥ 200 cells/µL (N = 68)	FeNO ≥ 25 ppb and Blood eosinophils < 200 cells/µL (N = 97)	FeNO ≥ 25 ppb and Blood eosinophils ≥ 200 cells/µL (N = 70)	P-value*
Lung function before bronchodilator
FEV1 percentage predicted	48.6 (35.6–64.5)	46.6 (34.1––62.9)	50.6 (37.3–69.5)	53.7 (36.7–64.7)	0.637
FVC percentage predicted	76.4 (66.1–95.8)	75.1 (64.3–90.8)	81.0 (68.7–89.9)	79.5 (67.0–91.0)	0.825
FEV1: FVC	0.49 (0.42–0.58)	0.49 (0.38–0.58)	0.49 (0.41–0.60)	0.52 (0.43–0.61)	0.741
Lung function after bronchodilator
FEV1 percentage predicted	55.2 (40.0–72.0)	54.5 (38.9–69.9)	56.0 (41.4–73.6)	60.3 (41.5–70.7)	0.807
FVC percentage predicted	83.6 (74.0–102.4)	85.7 (74.2–98.9)	89.0 (74.3–96.1)	88.9 (75.2–97.3)	0.948
FEV1: FVC	0.50 (0.42–0.61)	0.48 (0.40–0.61)	0.52 (0.42–0.62)	0.52 (0.44–0.61)	0.819
Moderate or severeexacerbation in preceding 12 months^#	41 (26.5%)	24 (35.3%)	15 (15.5%)	16 (22.9%)	0.030

Data are median (interquartile range) or n (%);

* Kruskal-Wallis was applied between multiple groups of data, and categorical variables with the chi-squared or Fisher’s exact tests;

# Moderate or severe exacerbation was defined as exacerbation required treated with antibiotics and/or oral corticosteroids, or required hospitalization or visited emergency room.

FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity.

Table 4. Adjusted relative impact of groups stratified by FeNO on moderate or severe exacerbation in preceding 12 months.

			Relative risk (95%CI)		P-value
High FeNO level*			0.541 (0.319, 0.917)		0.023
Age			1.025 (0.986, 1.065)		0.206
Men			0.530 (0.153, 1.829)		0.315
Current smoker^#			0.738 (0.421, 1.292)		0.287
Smoking pack-years			1.009 (0.999, 1.019)		0.091
ICS			1.773 (1.039, 3.026)		0.036
GOLD stage
		II cf. I	0.986 (0.425, 2.286)		0.974
		III cf. I	2.170 (0.935, 5.036)		0.071
		IV cf. I	5.649 (2.000, 15.952)		0.001

* FeNO ≥ 25 ppb;

^# Current smoker was defined as having smoked 100 cigarettes in one’s lifetime and currently smoking cigarettes;

FeNO, Fractional exhaled Nitric Oxide; ICS, inhaled corticosteroid.

Table

tIgE, kU/mL	58.7 (28.3–185.0)	108.0 (41.0–222.5)	0.019	67.0 (30.7–171.8)	88.4 (37.5–293.0)	0.064
sIgE, kU/mL	0.07 (0.04–0.19)	0.11 (0.06–0.40)	0.004	0.07 (0.04–0.22)	0.10 (0.06–0.33)	0.020
sIgE positive rate^†, %	35 (15.7%)	45 (26.9%)	0.006	48 (19.0%)	32 (23.2%)	0.333
Blood eosinophils, cells/µL	140.0 (90.0–220.0)	160.0 (100.0–280.0)	0.028	–	–	–
FeNO, ppb	–	–	–	21.0 (14.0–31.0)	25.0 (16.8–36.0)	0.004

Data are mean ± SD or median (interquartile range) or n (%);

* Continuous variables were tested by parametric tests (Student’s t-test) or non-parametric tests (Mann-Whitney U test), and categorical variables with the chi-squared or Fisher’s exact tests;

# Current smoker was defined as having smoked 100 cigarettes in one’s lifetime and currently smoking cigarettes;

† sIgE positive was defined as sIgE ≥ 0.35 kU/mL.

BMI, body mass index; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LAMA, long-acting muscarinic antagonist; tIgE, total immunoglobulin E; sIgE, specific immunoglobulin E; FeNO, Fractional exhaled Nitric Oxide.