The Relevance of Small Airway Dysfunction in Asthma with Nocturnal Symptoms

Figures & data

Table 1 Patients‘ Clinical Characteristics

n	166
Age, years	52 (45–64)
Sex, % male	56
BMI, kg/m^2	26.8 (23.9–30.0)
Current smokers, %	9
Smoking history *, %	22
Maintenance ICS use,%	89
Maintenance ICS use combined with LABA, %	81
ICS dose, µg	500 (250–1000)
LAMA use,%	22
Maintenance OCS use,%	22
Biological therapy, %	6
Blood eosinophils /µL	230 (130–380)
Sputum eosinophils, %	1.7 (0.4–5.9)
FeNo, ppb	23 (15–33)
FEV1, %	84 (67–96)
FEV1/FVC, %	65 (56–72)
FEF50, %	48 (29–71)
FEF25–75, %	47 (27–66)
R20, kPa/L/s	34 (29–42)
R5-20, kPa/L/s	0.11 (0.06–0.19)
X5Hz, kPa/L/s	−0.14 (−0.10 −0.21)
RV, %	128 (111–151)
RV/TLC, %	41 (35–48)
sReff, %	107 (83–169)
LCI	6.7 (5.9–7.60)
N2 Delta/l	2.1 (1.5–3.4)

Note: Values are presented in percentage or median and IQR.

Abbreviations: BMI, body mass index; ICS, inhaled corticosteroids; LABA, long-acting beta-2-agonists; LAMA, long-acting muscarinic receptor antagonists; ICS dose, fluticasone equivalent; OCS, oral corticosteroids; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in first second; FVC, forced vital capacity; FEF50% and FEF25–75, mean forced expiratory flow at 50% and between 25% and 75% of the forced vital capacity; R20, proximal airway resistance at 20 Hz; R5-20, small airway resistance (total lung resistance – large airway resistance); X5, lung reactance at 5 Hz; RV, residual volume; TLC, total lung capacity; sReff, specific effective airway resistance; LCI, lung clearance index from multiple breath washout, delta; N2, the slope of phase III nitrogen single-breath washout. Smoking history ≥ 10 pack years.

Figure 1 Odds ratio of nocturnal symptoms based on the severity of lung function impairment: Odds of having nocturnal asthma in regard to severity of central airflow obstruction (A), spirometric measures of small airway function (B) and non-spirometric measures of small airway function (C). OR with lower and upper borders of 95% CI of each measure are outlined in the Online Supplementary. Cutoff values of FEV1 and FEV/FVC were determined at lower limit of normal, the 50th, 25th, and 10th percentiles. For FEF25-75 and FEF50 cutoff values were 75th, 50th, and 10th percentiles, where the 10th percentile indicates more severe large and mid-expiratory airflow obstruction. Cutoff values for R5-20, X5Hz, RV/TLC, sReff, delta N2 and LCI were at the 50th and 75th percentiles, where the 75th percentile indicates more severe SAD.

Abbreviations: FEV1, forced expiratory volume in first second; FVC, forced vital capacity; FEF50% and FEF25–75, mean forced expiratory flow at 50% and between 25% and 75% of the forced vital capacity; R20, proximal airway resistance at 20 Hz; R5-20, small airway resistance (total lung resistance – large airway resistance); X5, lung reactance at 5 Hz; RV, residual volume; TLC, total lung capacity; sReff, specific effective airway resistance; LCI, lung clearance index from multiple breath washout, delta; N2, the slope of phase III nitrogen single-breath washout.

Table 2 Clinical and Lung Physiology Characteristics of Asthma Patients According to the Frequency of Nocturnal Symptoms

Parameter	No NA (n = 79)	Infrequent NA (n = 58)	Frequent NA (n = 29)	P-value
Age, years	51 (43–63)	54 (46–63)	58 (49–67)	0.32
Sex, % male	51	55	72	0.12
BMI (kg/m2)	25.9 (23.8–28.9)	27.8 (24.2–30.9)	26.3 (24.4–29.0)	0.18
Current smokers,%	5	3	10	1.0
Smoking history*, %	22	22	27	0.71
Maintenance ICS use, %	88	90	90	0.34
ICS dose, µg	400 (250–775)	750 (287–1000)	600 (500–1000)	0.004
Maintenance ICS/LABA, %	77	84	88	0.48
LAMA use, %	16	27	24	0.28
Maintenance OCS use, %	16	27	38	0.063
Biological therapy; %	5	8	6	0.71
FeNO, ppb	23 (14–33)	22 (15–31)	29 (17–67)	0.22
Blood eosinophils, /µL	210 (130–365)	220 (120–295)	320 (200–450)	0.14
Sputum eosinophil count %	1.5 (0.5–5.1)	0.9 (0.4–4.2)	4.0 (1.3–9.0)	0.24
FEV1, %	85 (73–104)	81 (64–92)	81 (65–91)	0.071
FEV1/FVC	65 (58–72)	63 (53–73)	62 (52–70)	0.32
R20Hz, KPa/l/s	34 (29–42)	34 (29–41)	39 (30–46)	0.35
FEF25-75,%	53 (30–76)	46 (24–61)	41 (27–56)	0.12
FEF50, %	53 (34–76)	48 (24–69)	41 (23–56)	0.15
RV/TLC, %	39 (33–45)	42 (36–49)	43 (38–58)	0.016
RV, %	120 (109–144)	128 (115–152)	132 (122–158)	0.072
sReff%	100 (79–139)	128 (115–152)	135 (97–211)	0.002
R5Hz, KPa/l/s	0.46 (0.35–0.52)	0.45 (0.36–0.62)	0.55 (0.41–0.69)	0.03
R5-20Hz, KPa/l/s	0.09 (0.06–0.14)	0.13 (0.06–0.22)	0.16 (0.09–0.24)	0.009
X5Hz, kPa/L	−0.12 (−0.16, −0.1)	−0.16 (−0.25, −0.10)	−0.20 (−0.30, −0.13)	0.004
N2 Delta /l	2.0 (1.4 −2.9)	2.5 (1.57–3.87)	2.9 (1.6–4.9)	0.03
LCI	6.4 (5.6 −6.8)	6.9 (6.1–8.0)	7.3 (6.4–8.2)	<0.001
ACT score	22 (19–24)	17 (13–20)	13 (9–16)	<0.001
AQLQ mean score	5.9 (5.2–6.5)	4.7 (4.0–5.6)	3.7 (2.9–4.7)	<0.001
MFI-20	39 (29–50)	43 (35–58)	54 (48–64)	<0.001

Note: Values are presented in percentage or median and IQR.

Abbreviations: NA, nocturnal asthma; BMI, body mass index; ICS, inhaled corticosteroids; LABA, long-acting beta-2-agonists; LAMA, long-acting muscarinic receptor antagonists; ICS dose, fluticasone equivalent; OCS, oral corticosteroids; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in first second; FVC, forced vital capacity; FEF50% and FEF25–75, mean forced expiratory flow at 50% and between 25% and 75% of the forced vital capacity; R20, proximal airway resistance at 20 Hz; R5-20, small airway resistance (total lung resistance – large airway resistance); X5, lung reactance at 5 Hz; RV, residual volume; TLC, total lung capacity; sReff, specific effective airway resistance; LCI, lung clearance index from multiple breath washout; delta N2, the slope of phase III nitrogen single-breath washout; ACT, asthma control test; AQLQ, asthma quality of life questionnaire; MFI-20, multidimensional fatigue inventory, smoking history with ≥ 10 pack years.

Table 3 Principle Component Analysis

Variable	PC1 Variances	PC2 Variances
LCI	−0.32	−0.39
RV%	−0.27	−0.47
sReff%	−0.26	−0.56
FEV1%	0.15	0.15
ACT-question 1	0.37	−0.36
ACT-question 2	0.38	−0.17
ACT-question 3	0.40	−0.12
ACT-question 4	0.37	−0.16
ACT-question 5	0.39	−0.29
Proportion of variance	0.47	−0.17
Cumulative Proportion	0.47	−0.64

Note: The table demonstrates the first two principle components only.

Abbreviations: LCI, lung clearance index from multiple breath washout; RV, residual volume; sReff, specific effective airway resistance; FEV1, forced expiratory volume in first second; PC1, first principle components that demonstrates the highest variance among all components. PC2: principle component 2.

Figure 2 The correlation of nocturnal asthma with air trapping and ventilation heterogeneity in patients without airflow obstruction: A biplot demonstrates a trend of increased air trapping and ventilation heterogeneity in patients with nocturnal asthma, who did not have airflow obstruction based on spirometry.

Abbreviations: LCI, lung clearance index; RV, residual volume.