Residual Dyspnea May Predict Small Airways Dysfunction and Poor Responsiveness to Single-Inhaler Triple Therapy in Asthmatic Patients

Figures & data

Table 1 Characteristics of the Studied Patients and Comparison of Responders and Non-Responders

	All Patients (n = 45)	Responders (n = 34)	Non-Responders (n = 11)	p-value
Age, years	73 (66, 77)	72 (67, 77)	75 (58, 79)	0.55
Age ≥ 65, n (%)	35 (78)	27 (79)	8 (73)	0.69
Sex, F, n (%)	16 (36)	12 (35)	4 (36)	>0.99
BMI, kg/m^2	23.7 (20.6, 25.3)	23 (21.1, 25.2)	24 (19.4, 26.4)	0.41
BMI ≥ 25 kg/m^2, n (%)	14 (31)	11 (32)	3 (27)	>0.99
Comorbid with COPD, n (%)	29 (64)	24 (71)	5 (45)	0.16
Smoking, never/ex or current, n (%)	9 (20) / 36 (80)	5 (15) / 29 (85)	4 (36) / 7 (64)	0.19
History of exacerbation, yes, n (%)	18 (40)	12 (35)	6 (55)	0.30
Duration of disease, years	5.0 (3.0, 9.5)	4.0 (2.8, 10)	6.0 (5.0, 9.0)	0.16
Atopic predisposition, n (%) *^†	19 (53)	15 (56)	4 (44)	0.71
Doses of ICSs, μg/daily*^‡	640 (500, 960)	640 (500, 960)	500 (400, 800)	0.20
Use of LAMAs, UMEC / GLY, n (%)	23 (51) / 22 (49)	18 (53) / 16 (47)	5 (45) / 6 (55)	0.74
Reasons for SITT, adherence/step up/ initial treatment, n (%)	11 (24) / 25 (56) / 9 (20)	8 (24) / 17 (76) / 9 (100)	3 (27) / 8 (73) / 0 (0)	0.15
Treatment steps 2–3/4–5, n (%) *	8 (22) / 28 (78)	6 (24) / 19 (76)	2 (18) / 9 (82)	>0.99
Respiratory symptoms, yes, n (%)
Cough	25 (56)	18 (53)	7 (64)	0.73
Sputum	7 (16)	6 (18)	1 (9)	0.66
Dyspnea	22 (49)	13 (38)	9 (82)	0.02
Blood Eo/μL	138 (80.1, 250.1)	147.4 (81.8, 274.8)	134.6 (69.3, 255.4)	0.77
Blood Eo ≥ 300/μL, n (%)	10 (23)	8 (24)	2 (20)	>0.99
Blood Neut/μL	3700 (2800, 4675)	3800 (2875, 4700)	3200 (2550, 4450)	0.33
Total serum IgE, IU/mL*	107 (30.1, 258.5)	114.5 (25, 405.2)	105 (58, 215)	0.89
FeNO, ppb	24 (14.1, 37.9)	27.2 (12.2, 44.5)	20.7 (14.7, 29.6)	0.39
FeNO ≥ 25 ppb, n (%)	22 (49)	19 (56)	3 (27)	0.17
FEV1, L	2.0 (1.5, 2.7)	2.1 (1.6, 2.7)	1.7 (1.0. 2.7)	0.32
FEV1% predicted	82.3 (63.0, 94.3)	84.3 (67.8, 96.0)	63.6 (48.7, 90.1)	0.10
FEV1% < 80%, n (%)	22 (49)	14 (41)	8 (73)	0.09
FVC, L	3.3 (2.4, 4.2)	3.4 (2.6, 4.2)	2.5 (1.8, 4.5)	0.16
FVC% predicted	107.5 (88.5, 117)	110.5 (93.4, 117.5)	85.5 (72.4, 102.2)	0.02
FVC% < 80%, n (%)	6 (13)	2 (6)	4 (36)	0.02
FEV1/FVC	62.8 (52.0, 72.7)	63 (51.4, 71.6)	62.1 (52.1, 75)	>0.99
FEV1/FVC < 70%, n (%)	33 (73)	25 (74)	8 (73)	>0.99
FEF25–75, L/s	0.83 (0.36, 1.36)	0.86 (0.39, 1.34)	0.66 (0.31, 1.65)	0.69
FEF25–75% predicted	31 (16.8, 55.6)	31.3 (17.0, 58.8)	25.8 (13.5, 53.9)	0.42

Notes: Date are presented as medians (25th percentile, 75th percentile) or numbers (%). *n = 36. ^†Patients were considered atopic if they had at least one serum specific IgE antibody positive (≥0.35 IU/mL). ^‡Equivalent to fluticasone propionate.

Abbreviations: SITT, single-inhaler triple therapy; BMI, body mass index; ICSs, inhaled corticosteroids; UMEC, umeclidinium; GLY, glycopyrrolate; Blood Eo, blood eosinophil count; Blood Neut, blood neutrophil count; FeNO, fractional exhaled nitric oxide; IU, international unit; FVC, forced vital capacity; FEF_25–75, forced expiratory flow between 25% and 75% of FVC.

Table 2 Predictors of Responsiveness to SITT: Univariate and Multivariate Analyses

Variables	Univariate Analysis			Multivariate Analysis
	OR	95% CI	p-value	OR	95% CI	p-value*
Age ≥ 65	1.44	0.30–6.92	0.64	ー	ー	ー
Sex, Female	0.95	0.23–3.93	0.95	ー	ー	ー
BMI ≥ 25 kg/m^2	1.28	0.28–5.77	0.75	ー	ー	ー
Smoking, ex or current	3.31	0.70–15.7	0.13	ー	ー	ー
History of exacerbation, yes	0.45	0.11–1.81	0.26	ー	ー	ー
Duration of disease, years	1.01	0.94–1.09	0.75	ー	ー	ー
Atopic predisposition^†	1.56	0.34–7.13	0.56	ー	ー	ー
Use of UMEC	1.35	0.34–5.28	0.67	ー	ー	ー
Treatment steps 4–5	0.70	0.12–4.20	0.70	ー	ー	ー
Respiratory symptoms, yes
Cough	0.64	0.16–2.61	0.54	ー	ー	ー
Sputum	2.14	0.23–20.1	0.50	ー	ー	ー
Dyspnea	0.14	0.03–0.74	0.02	0.14	0.02–0.85	0.02
Blood Eo/μL	1.72	0.30–9.74	0.54	ー	ー	ー
Blood Eo ≥ 300/μL	1.38	0.25–7.77	0.71	ー	ー	ー
Blood Neut/μL	1.00	1.00–1.00	0.60	ー	ー	ー
Total serum IgE, IU/mL	1.14	0.40–3.29	0.80	ー	ー	ー
FeNO, ppb	1.21	0.17–8.41	0.85	ー	ー	ー
FeNO ≥ 25 ppb	3.38	0.76–15.0	0.11	ー	ー	ー
FEV1, L	1.48	0.59–3.69	0.40	ー	ー	ー
FEV1% predicted	1.03	1.00–1.07	0.09	ー	ー	ー
FEV1% < 80%	0.26	0.06–1.17	0.08	0.46	0.08–2.69	0.39
FVC, L	1.69	0.83–3.44	0.15	ー	ー	ー
FVC% predicted	1.05	1.01–1.10	0.01	ー	ー	ー
FVC% < 80%	0.11	0.02–0.72	0.02	0.16	0.02–1.57	0.12
FEV1/FVC	1.00	0.95–1.05	0.92	ー	ー	ー
FEV1/FVC < 70%	1.04	0.23–4.81	0.96	ー	ー	ー
FEF25–75, L/s	1.00	1.00–1.00	0.66	ー	ー	ー
FEF25–75% predicted	1.01	0.98–1.04	0.59	ー	ー	ー

Notes: *Other indices with p > 0.10 were not used for the multivariate selections. ^†Patients were considered atopic if they had at least one serum specific IgE antibody positive (≥0.35 IU/mL).

Abbreviations: OR, odds ratio; CI, confidence interval; BMI, body mass index; UMEC, umeclidinium; Blood Eo, blood eosinophil count; Blood Neut, blood neutrophil count; FeNO, fractional exhaled nitric oxide; IU, international unit; FVC, forced vital capacity; FEF_25–75, forced expiratory flow between 25% and 75% of FVC.