Small-Airway Function Variables in Spirometry, Fractional Exhaled Nitric Oxide, and Circulating Eosinophils Predicted Airway Hyperresponsiveness in Patients with Mild Asthma

Figures & data

Table 1 Demographic Data, Spirometric Variables, IOS Variables, and Values for FENO and Peripheral Eosinophils of Patients with Positive or Negative Bronchial Provocation Tests

Variables	CV for All Subjects (%)	Positive Bronchial Provocation Test	CV for BPT^+ (%)	Negative Bronchial Provocation Test	CV for BPT^− (%)	P value
n	-	170	-	522	-	-
Age, years^†	33.79	43.90 (14.56)	33.17	43.80 (14.90)	34.02	0.980
Male, n (%)	-	53 (31.18%)	-	203 (38.89%)	-	0.082
BMI, kg/m^2†	14.88	22.94 (2.99)	13.01	23.51 (3.61)	15.37	0.075
Past smoking history (n/%)	-	31 (18.24)	-	97 (18.58)	-	0.204
FVC, % predicted^†	11.82	101.10 (10.85)	10.73	101.60 (12.36)	12.17	0.993
FEV1, % predicted^†	11.95	99.33 (11.01)	11.08	105.50 (12.49)	11.84	< 0.001
FEV1/FVC, %^†	6.72	82.55 (5.51)	6.67	86.87 (5.45)	6.28	< 0.001
FEV3/FVC, %^†§	1.98	97.65 (2.26)	2.31	98.47 (1.76)	1.79	0.001
PEF, % predicted^†	16.27	90.61 (13.93)	15.38	96.21 (15.65)	16.27	< 0.001
FEF25%, % predicted^†	21.63	90.08 (15.87)	17.61	100.80 (22.10)	21.92	< 0.001
FEF50%, % predicted^†	25.55	77.26 (17.74)	22.96	98.20 (23.24)	23.66	< 0.001
FEF75%, % predicted^†	31.84	74.91 (22.43)	29.94	101.20 (60.72)	29.62	< 0.001
FEF25%-75%, % predicted^†	25.51	75.95 (17.64)	23.23	97.01 (22.76)	23.46	< 0.001
Small-airway dysfunction	-	104	-	132	-	< 0.001
R5-R20, kPa·L^−1·s^†¶	94.65	0.13 (0.11)	88.85	0.10 (0.09)	95.50	< 0.001
X5, kPa·L^−1·s^†¶	97.54	−0.12 (0.10)	107.93	−0.10 (0.08)	87.30	< 0.001
Fres, L^−1·s^†¶	42.52	17.53 (9.02)	51.47	14.24 (5.03)	35.29	< 0.001
FENO, ppb^‡	94.96	59 (28–98)	75.03	24 (15–45)	86.65	< 0.001
EOS in blood, % ^‡	95.46	5.16 (1.70–7.73)	84.47	3.37 (1.20–4.40)	96.58	< 0.001
EOS in blood, cells/μL^‡	106.10	370.6 (120–530)	91.90	237.2 (80–302.5)	108.97	< 0.001
PD20, mg^‡	130.68	0.079 (0.026- 0.369)	130.68	–	–	–

Notes: Small-airway dysfunction was identified if 2 of the variables FEF_50%, FEF_75% and FEF_25%-75% were lower than 80%. ^†Mean (SD) values. ^‡Median (IQR) values. ^§ n = 333, 92 for positive bronchial provocation, 241 for negative bronchial provocation. ^¶ n = 619, 153 for positive bronchial provocation, 466 for negative bronchial provocation. Bold font indicates statistical significance.

Abbreviations: IOS, impulse oscillometry; FENO, fractional exhaled nitric oxide; CV, Coefficient of variance; BPT⁺, positive bronchial provocation test; BPT⁻, negative bronchial provocation test; BMI, body mass index; FVC, forced vital capacity; FEV₁, forced expiratory volume in 1 second; FEV₃, FEV in 3 seconds; PEF, peak expiratory flow; FEF_25%, forced expiratory flow at 25% of FVC; FEF_50%, FEF at 50% of FVC; FEF_75%, FEF at 75% of FVC; FEF_25%-75%, FEF at 25% to 75% of FVC; EOS, eosinophils; ppb, parts per billion; PD₂₀, provocative dose causing a 20% fall in FEV in the first second; R5, total airway resistance at 5 Hz; R20, central airway resistance at 20 Hz; R5-R20, peripheral airway resistance as the difference between 5 and 20 Hz; X5, reactance at 5 Hz; Fres, resonant frequency.

Table 2 Spearman Correlation Between PD₂₀ and Other Variables in BPT⁺ Subjects

	N	r	P	95% CI
FENO	170	–0.266	0.0005	–0.404 ~ –0.116
EOS	170	–0.054	0.481	–0.208 ~ 0.101
EOS%	170	–0.039	0.609	–0.193 ~ 0.116
FEF25%	170	0.272	0.0003	0.122 ~ 0.409
FEF50%	170	0.213	0.005	0.060 ~ 0.356
FEF75%	170	0.173	0.024	0.018 ~ 0.319
FEF25%-75%	170	0.229	0.003	0.077 ~ 0.371
FEV3/FVC	92	–0.016	0.881	–0.225~ 0.196
R5-R20	153	–0.026	0.754	–0.188 ~ 0.138
X5	153	0.115	0.158	–0.050 ~ 0.273
Fres	153	–0.064	0.433	–0.226 ~ 0.101

Note: Bold font indicates statistical significance.

Abbreviations: PD₂₀, provocative dose causing a 20% fall in FEV in the first second; BPT⁺, positive bronchial provocation test; CI, confidence interval; FENO, fractional exhaled nitric oxide; EOS, eosinophils; FEF_25%, forced expiratory flow at 25% of FVC; FEF_50%, FEF at 50% of FVC; FEF_75%, FEF at 75% of FVC; FEF_25%-75%, FEF at 25% to 75% of FVC; FEV₃, FEV in 3 seconds; FVC, forced vital capacity; R5-R20, peripheral airway resistance as the difference between 5 and 20 Hz; X5, reactance at 5 Hz; Fres, resonant frequency.

Table 3 Optimal Cut-Off Values and Other Measures of Usefulness for Predicting Airway Hyperresponsiveness

Characteristic Variables	AUC	Cut-Off Values^†	Sensitivity %	Specificity %	PPV %	NPV %	PCC %	Odds Ratio	95% CI	P value
FEV1, % predicted	0.649	95.8	47.65	75.86	39.13	81.65	68.93	0.955	(0.939, 0.971)	< 0.001
FEV1/FVC, %	0.713	84.67	66.47	67.62	40.07	86.10	67.34	0.867	(0.837, 0.898)	< 0.001
FEV3/FVC, %	0.616	99.06	67.39	51.87	34.83	80.65	56.16	0.817	(0.726, 0.920)	< 0.001
FEF25%, % predicted	0.656	103.8	84.12	41.38	31.85	88.89	51.88	0.973	(0.963, 0.982)	< 0.001
FEF50%, % predicted	0.762	76.8	58.82	80.46	49.50	85.71	75.14	0.950	(0.939, 0.960)	< 0.001
FEF75%, % predicted	0.745	81.4	66.47	69.92	41.85	86.49	69.08	0.963	(0.955, 0.971)	< 0.001
FEF25%-75%, % predicted	0.763	84.4	70.00	68.97	42.35	87.59	69.22	0.950	(0.940, 0.960)	< 0.001
R5-R20, kPa·L^−1·s	0.604	0.88	0.65	100.00	100.00	75.40	75.44	18.961	(3.119, 115.3)	0.001
X5, kPa·L^−1·s	0.607	−0.14	43.79	78.76	40.36	81.02	70.11	0.025	(0.003, 0.223)	0.001
Fres, L^−1·s	0.634	15.71	56.95	68.32	36.91	82.98	65.53	1.081	(1.046, 1.117)	< 0.001
FENO, ppb	0.748	41	65.29	78.16	49.33	87.37	75.00	1.024	(1.019, 1.030)	< 0.001
EOS in blood, %	0.630	3.4	55.88	66.28	35.06	82.19	63.73	1.130	(1.079,1.182)	< 0.001
EOS in blood, cell/μL	0.638	360	41.76	80.65	41.28	80.96	71.10	4.367	(2.413,7.903)	< 0.001
Platelets, ×10^^9/L	0.491	269	80.00	24.71	25.71	79.14	38.30	0.995	(0.995,0.996)	< 0.001

Abbreviations: AUC, area under the curve; PPV, positive predictive values; NPV, negative predictive values; PCC: percentages correctly classified; Odds ratio, odds ratio of characteristic variables for predicting AHR; 95% CI, 95% confidence interval of odds ratio; P value, the p value of the logistic regression test. FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; FEF_25%, forced expiratory flow at 25% of FVC; FEF_50%, FEF at 50% of FVC; FEF_75%, FEF at 75% of FVC; FEF_25%-75%, FEF at 25% to 75% of FVC; R5-R20, peripheral airway resistance as the difference between 5 and 20 Hz; X5, reactance at 5 Hz; Fres, resonant frequency; FENO, fractional exhaled nitric oxide; EOS, eosinophils.

Notes:^†The cut-off points were selected by maximizing the sum of sensitivity and specificity. Bold font indicates AUC higher than 0.7.

Table 4 Predictive Values of the Combination of Different Variables with FENO in Predicting Airway Hyperresponsiveness

Characteristic Variables	AUC	95% CI of AUC	Sensitivity %	Specificity %	PPV %	NPV %	PCC %	Contrast	95% CI of Contrast	P value
FENO + FEF50%	0.845	(0.812,0.878)	83.53	71.65	48.97	93.03	74.57	0.097^†	(0.060,0.135)	< 0.001
FENO + FEF75%	0.824	(0.788,0.859)	72.94	77.01	50.82	89.73	76.01	0.076^‡	(0.038,0.114)	< 0.001
FENO + FEF25%-75%	0.844	(0.811,0.876)	80.59	74.14	50.37	92.14	75.72	0.096^†	(0.058,0.134)	< 0.001
FENO + FEV1/FVC	0.807	(0.769,0.844)	85.88	61.69	42.20	93.06	67.63	0.059^‡	(0.026,0.092)	0.001

Notes: We used the larger of the 2 univariate AUCs to make the comparison; ^†Contrast, the difference between AUC of FENO and AUC of bivariate model; ^‡Contrast, the difference between AUC of FEFs and AUC of bivariate model; P value, contrast’s chi-square test for the significance of the contrast.

Abbreviations: FENO, fractional exhaled nitric oxide; AUC, area under the curve; 95% CI, 95% confidence interval of odds ratio; PPV, positive predictive values; NPV, negative predictive values; PCC, percentages correctly classified; FEF_25%, forced expiratory flow at 25% of FVC; FEF_50%, FEF at 50% of FVC; FEF_75%, FEF at 75% of FVC; FEF_25%-75%, FEF at 25% to 75% of FVC; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity.

Figure 1 ROC curves for the models of FEFs combined with FENO for predicting positive bronchial provocation tests (n = 692). (A) FEF_50% combined with FENO. AUC_Model = 0.845 (95% CI, 0.812–0.878); AUC_FENO = 0.748 (95% CI, 0.702–0.793; P < 0.001, compared with the model); AUC_FEF50% = 0.762 (95% CI, 0.721–0.803; P < 0.001, compared with the model). (B) FEF_75% combined with FENO. AUC_Model = 0.824 (95% CI, 0.788–0.859); AUC_FENO =0.748 (95% CI, 0.702–0.793; P < 0.001, compared with the model); AUC_FEF75% = 0.745 (95% CI, 0.703–0.786; P < 0.001, compared with the model). (C) FEF_25%-75% combined with FENO. AUC_Model = 0.844 (95% CI, 0.811–0.876); AUC_FENO =0.748 (95% CI, 0.702–0.793; P < 0.001, compared with the model); AUC_FEF25%-75% = 0.763 (95% CI, 0.723–0.802; P < 0.001, compared with the model). (D) FEV₁/FVC combined with FENO. AUC_Model = 0.807 (95% CI, 0.769–0.844); AUC_FENO = 0.748 (95% CI, 0.702–0.793; P = 0.001, compared with the model); AUC_FEV1/FVC = 0.713 (95% CI, 0.669–0.758).

Abbreviations: ROC, receiver operating characteristic; FEF, forced expiratory flow; FENO, fractional exhaled nitric oxide; AUC, area under the curve; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; FEF_50%, FEF at 50% of FVC; FEF_75%, FEF at 75% of FVC; FEF_25%-75%, FEF at 25% to 75% of FVC.

Figure 2 ROC curves of dichotomous state variables of the models of FEFs combined with FENO in predicting positive bronchial provocation tests (n = 692). (A) FEF_50% combined with FENO. AUC_Model = 0.809 (95% CI, 0.786–0.878); (B) FEF_75% combined with FENO. AUC_Model = 0.797 (95% CI, 0.768–0.866); (C) FEF_25%–75% combined with FENO. AUC_Model = 0.802 (95% CI, 0.780–0.874).

Abbreviations: ROC, receiver operating characteristic; FEF, forced expiratory flow; FENO, fractional exhaled nitric oxide; AUC, area under the curve; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; FEF_50%, FEF at 50% of FVC; FEF_75%, FEF at 75% of FVC; FEF_25%-75%, FEF at 25% to 75% of FVC.

Table 5 Stratified Analysis of Patients with Chest-Tightness: Predictive Values of Combinations of Different Variables with FENO in Predicting Airway Hyperresponsiveness

Characteristic Variables	AUC	95% CI of AUC	Sensitivity %	Specificity %	PPV %	NPV %	PCC %	Contrast	95% CI of Contrast	P value
FENO + FEF50%	0.880	(0.806,0.954)	100.00	60.42	58.70	100.00	74.67	0.129^†	(0.022, 0.236)	0.019
FENO + FEF75%	0.892	(0.812,0.972)	70.37	95.83	90.48	85.19	86.67	0.080^‡	(–0.001, 0.161)	0.053
FENO + FEF25%-75%	0.884	(0.805,0.964)	88.89	75.00	66.67	92.31	80.00	0.121^†	(0.018, 0.224)	0.021
EOS + FEF50%	0.815	(0.716,0.913)	74.07	79.17	66.67	84.44	77.33	0.064^‡	(–0.016, 0.144)	0.115
EOS + FEF75%	0.845	(0.750,0.940)	74.07	89.58	80.00	86.00	84.00	0.033	(–0.017, 0.083)	0.197
EOS + FEF25%-75%	0.816	(0.715,0.917)	70.37	85.42	73.08	83.67	80.00	0.053^‡	(–0.015, 0.120)	0.125

Notes: We used the larger of the 2 univariate AUCs to make the comparison; ^†Contrast, the difference between AUC of FENO and AUC of bivariate model; ^‡Contrast, the difference between AUC of FEFs and AUC of bivariate model; P value, significance of the contrast by chi-square test. Bold font indicates statistical significance.

Abbreviations: FENO, fractional exhaled nitric oxide; AUC, area under the curve; 95% CI, 95% confidence interval of odds ratio; PPV, positive predictive values; NPV, negative predictive values; PCC, percentages correctly classified; FEF25%, forced expiratory flow at 25% of FVC; FEF50%, FEF at 50% of FVC; FEF75%, FEF at 75% of FVC; FEF25%-75%, FEF at 25% to 75% of FVC; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; EOS, eosinophils.

Table 6 Predictive Value of the Combination of Different Variables with EOS in Predicting Airway Hyperresponsiveness

Characteristic Variables	AUC	95% CI of AUC	Sensitivity %	Specificity %	PPV %	NPV %	PCC %	Contrast	95% CI of Contrast	P value
EOS + FEF50%	0.786	(0.748,0.825)	67.06	76.63	48.31	87.72	74.28	0.148	(0.097,0.200)	< 0.001
EOS + FEF25%-75%	0.785	(0.747,0.823)	67.65	75.29	47.13	87.72	73.41	0.147	(0.096,0.199)	< 0.001
EOS + FEV1/FVC	0.734	(0.691,0.777)	56.47	80.84	48.98	85.08	74.86	0.096	(0.045,0.146)	< 0.001

Notes: Contrast, the difference between the AUC of each FEF and the AUC of the bivariate model; we used the larger of the 2 univariate AUCs to make the comparison. P value, significance of the contrast by chi-square test.

Abbreviations: EOS, eosinophils; AUC, area under the curve; 95% CI, 95% confidence interval of odds ratio; PPV, positive predictive values; NPV, negative predictive values; PCC, percentages correctly classified; FEF_50%, FEF at 50% of FVC; FEF_25%-75%, FEF at 25% to 75% of FVC; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity.