Matched cohort study of therapeutic strategies to prevent preschool wheezing/asthma attacks

Figures & data

Figure 1 Study schematic.

Notes: The eligibility criterion of two or more OCS prescriptions (at different points in time) could be for any combination of OCS, with or without concomitant SABA, with accompanying code for a lower respiratory complaint. ^aPrescribed therapy could change during the outcome year after the index date.
Abbreviations: ICS, inhaled corticosteroid; LTRA, leukotriene receptor antagonist; OCS, oral corticosteroid; SABA, short-acting β-agonist.

Table 1 Baseline year characteristics of children included in the controller (ICS or LTRA) vs SABA matched cohort comparisons

Characteristics	ICS vs SABA		LTRA vs SABA
	ICS (n=990)	SABA (n=3,960)	LTRA (n=259)	SABA (n=1,036)
Male sex, n (%)a	602 (60.8)	2,408 (60.8)	168 (64.9)	672 (64.9)
Age at index date (years), mean (SD)a	3.2 (1.3)	3.2 (1.3)	2.6 (1.2)	2.6 (1.2)
Comorbidity, n (%)b
Eczemaa	372 (37.6)	1,488 (37.6)	97 (37.5)	388 (37.5)
Rhinitis	36 (3.6)	170 (4.3)	11 (4.3)	35 (3.4)
Total wheezing/asthma attacks, n (%)a
0	635 (64.1)	2,540 (64.1)	134 (51.7)	536 (51.7)
≥1	355 (35.9)	1,420 (35.9)	125 (48.3)	500 (48.3)
OCS courses, n (%)
0	656 (66.3)	2,657 (67.1)	147 (56.8)	582 (56.2)
1	222 (22.4)	884 (22.3)	59 (22.8)	293 (28.3)
2	78 (7.9)	320 (8.1)	30 (11.6)	115 (11.1)
≥3	34 (3.4)	99 (2.5)	10 (3.9)	9 (0.9)
≥1 wheezing/asthma attack and ≥1 acute OCS course	334 (33.7)	1,303 (32.9)	112 (43.2)	454 (43.8)
Acute antibiotic prescriptions, n (%)a
0	510 (51.5)	2,040 (51.5)	105 (40.5)	420 (40.5)
1	235 (23.7)	981 (24.8)	59 (22.8)	293 (28.3)
2	129 (13.0)	539 (13.6)	54 (20.9)	180 (17.4)
≥3	116 (11.7)	400 (10.1)	21 (8.1)	58 (5.6)
Mean (SD) daily no. of SABA doses^a,c	0.65 (0.56)	0.65 (0.47)	0.66 (0.50)	0.66 (0.49)
Median (IQR) daily no. of SABA dosesc	0.55 (0.55–0.82)	0.55 (0.55–0.82)	0.55 (0.55–0.82)	0.55 (0.55–0.82)
Hospital admission, ≥1, n (%)	36 (3.7)	157 (4.0)	21 (8.1)	64 (6.2)e
ED attendance, ≥1, n (%)	13 (1.3)	52 (1.3)	19 (7.3)	20 (2.0)
Acute respiratory event, ≥1, n (%)d	617 (62.3)	2,468 (62.3)	193 (74.5)	772 (74.5)
Risk-domain asthma control, n (%)d	373 (37.7)	1,492 (37.7)	66 (25.5)	264 (25.5)
Oral candidiasis, ≥1, n (%)d	11 (1.1)	55 (1.4)	7 (2.7)	26 (2.5)
Pneumonia, yes, n (%)d	12 (1.2)	43 (1.1)	9 (3.5)	8 (0.8)e

Notes:

a Matching variable. Wheezing/asthma attacks were defined as any of the following: an asthma-related ED attendance, an asthma-related hospital admission, or an OCS prescription coded for asthma or wheeze.

b Comorbidities were defined as follows: eczema as ever-recorded diagnostic Read code + topical corticosteroid; and rhinitis, as ever-recorded diagnosis and/or prescription for nasal corticosteroids.

c The daily SABA dose was calculated as the number of doses in issued prescriptions averaged over the baseline year. One SABA dose was two puffs (100 µg per puff).

d An acute respiratory event was defined as occurrence of 1) an asthma-related hospital admission or ED attendance or 2) an acute course of OCSs coded for asthma or 3) antibiotics prescribed with a lower respiratory consultation. Risk-domain asthma control was defined as follows: 1) no asthma-related hospital admission, ED attendance, or outpatient department attendance; 2) no acute OCS prescription with a lower respiratory consultation; and 3) no antibiotics prescribed with a lower respiratory consultation (Table S1). Oral candidiasis (thrush) was defined as a Read code for oral candidiasis or topical antifungal prescription definitely for treating oral candidiasis. Pneumonia was defined as a diagnostic Read code for pneumonia.

e P≤0.001 for comparison between LTRA and SABA cohorts. There were no significant differences between ICS and SABA cohorts or between LTRA and SABA cohorts for other variables.

Abbreviations: ED, emergency department; ICS, inhaled corticosteroid; IQR, interquartile range; LTRA, leukotriene receptor antagonist; OCS, oral corticosteroid; SABA, short-acting β-agonist.

Figure 2 Forest plot depicting OR (95% CIs) of wheezing/asthma attack for the four matched cohort comparisons.

Notes: The reference cohort (attack odds =1.0) is listed second. EF: EF particle; fine: fine particle.
Abbreviations: EF, extrafine; ICS, inhaled corticosteroid; LTRA, leukotriene receptor antagonist; SABA, short-acting β-agonist.

Figure 3 Percentage of children with one or more wheezing/asthma attacks during the baseline year (before the first prescription of ICS, LTRA, or repeat SABA) and during the outcome year in the four matched cohort comparisons: (A) ICS ± SABA vs SABA, (B) LTRA ± SABA vs SABA, (C) LTRA vs ICS, and (D) EF-particle ICS vs fine-particle ICS.

Notes: A wheezing/asthma attack was defined as an asthma-related ED attendance, an asthma-related hospital admission, or an OCS prescription coded for asthma or wheeze. EF: EF particle; fine: fine particle.
Abbreviations: ED, emergency department; EF, extrafine; ICS, inhaled corticosteroid; LTRA, leukotriene receptor antagonist; OCS, oral corticosteroid; SABA, short-acting β-agonist.

Table 2 Outcome measures during 1 follow-up year for the controller (ICS or LTRA) vs SABA matched cohort comparisons

Outcome	ICS vs SABA			LTRA vs SABA
	ICS (n=990)	SABA (n=3,960)	P-valuea	LTRA (n=259)	SABA (n=1,036)	P-valuea
Wheezing/asthma attack, n (%)
0	728 (73.5)	2,918 (73.7)	0.92	157 (60.6)	682 (65.8)	0.097
1	161 (16.3)	649 (16.4)		54 (20.9)	216 (20.9)
≥2	101 (10.2)	393 (9.9)		48 (18.5)	138 (13.3)
Hospital admission, n (%)
0	975 (98.5)	3,884 (98.1)	0.40	251 (96.9)	1,002 (96.7)	0.88
1	12 (1.2)	67 (1.7)		6 (2.3)	28 (2.7)
≥2	3 (0.3)	9 (0.2)		2 (0.8)	6 (0.6)
ED visit, n (%)
0	969 (97.9)	3,921 (99.0)	0.004	252 (97.3)	1,022 (98.7)	0.13
1	19 (1.9)	37 (0.9)		5 (1.9)	12 (1.2)
2	0 (0)	2 (0.1)		2 (0.8)	2 (0.2)
3	2 (0.2)	0 (0)		0	0
Acute OCS prescription, n (%)
0	814 (82.2)	3,250 (82.1)	0.91	164 (63.3)	703 (67.9)	0.14
1	128 (12.9)	509 (12.9)		46 (17.8)	206 (19.9)
2	33 (3.3)	144 (3.6)		23 (8.9)	77 (7.4)
3	8 (0.8)	45 (1.1)		0	0
4	6 (0.6)	10 (0.3)		4 (1.5)	9 (0.9)
≥5	1 (0.1)	1 (0.0)		3 (1.2)	0

Note:

a Matched cohorts were compared (for none vs ≥1 outcome) using conditional logistic regression.

Abbreviations: ED, emergency department; ICS, inhaled corticosteroid; LTRA, leukotriene receptor antagonist; OCS, oral corticosteroid; SABA, short-acting β-agonist.

Table 3 Baseline year characteristics of children included in the two controller therapy matched cohort comparisons: LTRA vs ICS and EF-particle ICS vs fine-particle ICS

Characteristics	LTRA vs ICS		EF-particle ICS vs fine-particle ICS
	LTRA (n=104)	ICS (n=104)	EF-particle ICS (n=275)	Fine-particle ICS (n=1,100)
Male sex, n (%)a	63 (60.6)	63 (60.6)	186 (67.6)	744 (67.6)
Age at index date (years), mean (SD)a	2.6 (1.1)	2.6 (1.1)	3.2 (1.2)	3.2 (1.2)
Comorbidity, n (%)b
Eczemaa	39 (37.5)	39 (37.5)	113 (41.1)	452 (41.1)
Rhinitis	6 (5.8)	7 (6.7)	10 (3.6)	41 (3.7)
Total wheezing/asthma attacks, n (%)a
0	29 (27.9)	29 (27.9)	133 (48.4)	532 (48.4)
≥1	75 (72.1)	75 (72.1)	142 (51.6)	568 (51.6)
OCS courses, n (%)
0	35 (33.7)	32 (30.8)	140 (50.9)	565 (51.4)
1	41 (39.4)	41 (39.4)	86 (31.3)	340 (30.9)
2	20 (19.2)	20 (19.2)	36 (13.1)	128 (11.6)
≥3	8 (7.7)	11 (10.6)	13 (4.7)	67 (6.1)
≥1 wheezing/asthma attack and ≥1 acute OCS course	69 (66.3)	72 (69.2)	135 (49.1)	535 (48.6)
Acute antibiotic prescriptions, n (%)a
0	30 (28.9)	30 (28.9)	123 (44.7)	492 (44.7)
1	33 (31.7)	29 (27.9)	72 (26.2)	280 (25.5)
2	20 (19.2)	16 (15.4)	49 (17.8)	183 (16.6)
≥3	21 (20.2)	29 (27.9)	31 (11.3)	145 (13.2)
Mean (SD) daily no. of SABA doses^a,c	0.47 (0.27)	0.47 (0.27)	0.63 (0.4)	0.63 (0.4)
Median (IQR) daily no. of SABA dosesc	0.55 (0.27–0.55)	0.55 (0.27–0.55)	0.55 (0.27–0.82)	0.55 (0.27–0.82)
Hospital admission, ≥1, n (%)	12 (11.5)	7 (6.7)	14 (5.1)	47 (4.3)
ED attendance, ≥1, n (%)	9 (8.7)	2 (1.9)e	5 (1.8)	25 (2.2)
Acute respiratory event, ≥1, n (%)d	89 (85.6)	89 (85.6)	142 (51.6)	568 (51.6)
Risk-domain asthma control, n (%)d	15 (14.4)	15 (14.4)	68 (24.5)	272 (24.7)
Oral candidiasis, ≥1, n (%)d	3 (2.9)	0	2 (0.7)	14 (1.3)
Pneumonia, yes, n (%)d	4 (3.8)	1 (1.0)	2 (0.7)	8 (0.7)

Notes:

a Matching variable.

b Comorbidities were defined as follows: eczema as ever-recorded diagnostic Read code + topical steroid; and rhinitis as ever-recorded diagnosis and/or prescription for nasal steroids.

c The daily SABA dose was calculated as the number of doses in issued prescriptions averaged over the baseline year. One SABA dose was two puffs (100 µg per puff).

d An acute respiratory event was defined as occurrence of 1) an asthma-related hospital admission or ED attendance or 2) an acute course of OCSs coded for asthma or 3) antibiotics prescribed with a lower respiratory consultation. Risk-domain asthma control was defined as follows: 1) no asthma-related hospital admission, ED attendance, or outpatient department attendance; 2) no acute OCS prescription with a lower respiratory consultation; and 3) no antibiotics prescribed with a lower respiratory consultation. Oral candidiasis (thrush) was defined as a Read code for oral candidiasis or topical antifungal prescription definitely for treating oral candidiasis. Pneumonia was defined as a diagnostic Read code for pneumonia.

e P=0.03 for comparison between LTRA and ICS cohorts. There were no significant differences between EF-particle ICS and fine-particle ICS cohorts or between LTRA and ICS cohorts for other variables.

Abbreviations: ED, emergency department; EF, extrafine; ICS, inhaled corticosteroid; IQR, interquartile range; LTRA, leukotriene receptor antagonist; OCS, oral corticosteroid; SABA, short-acting β-agonist.

Table 4 Outcome measures during 1 follow-up year for the controller therapy matched cohort comparisons: LTRA vs ICS and EF-particle ICS vs fine-particle ICS

Outcome	LTRA vs ICS			EF-particle ICS vs fine-particle ICS
	LTRA (n=104)	ICS (n=104)	P-valuea	EF-particle ICS (n=275)	Fine-particle ICS (n=1,100)	P-valuea
Wheezing/asthma attack, n (%)
0	57 (54.8)	63 (60.6)	0.38	176 (64.0)	734 (66.7)	0.36
1	25 (24.0)	23 (22.1)		59 (21.5)	249 (22.6)
≥2	22 (21.2)	18 (17.3)		40 (14.5)	117 (10.6)
Hospital admission, n (%)
0	101 (97.1)	102 (98.1)	0.66	268 (97.5)	1,075 (97.7)	0.79
1	2 (1.9)	1 (1.0)		7 (2.5)	22 (2.0)
2	1 (1.0)	1 (1.0)		0	3 (0.3)
ED visit, n (%)
0	100 (96.2)	103 (99.0)	0.22	271 (98.6)	1,087 (98.8)	0.71
1	4 (3.8)	1 (1.0)		4 (1.4)	14 (1.0)
2	0	0		0	0
3	0	0		0	2 (0.2)
Acute OCS prescription, n (%)
0	60 (57.7)	64 (61.5)	0.78	204 (74.2)	846 (76.9)	0.32
1	21 (20.2)	20 (19.2)		48 (17.5)	182 (16.6)
2	11 (10.6)	15 (14.4)		19 (6.9)	51 (4.6)
3	11 (10.6)	4 (3.9)		4 (1.5)	12 (1.1)
4	1 (1.0)	1 (1.0)		0	8 (0.7)
5	0	0		0	1 (0.1)

Note:

a Matched cohorts were compared (for none vs ≥1 outcome) using conditional logistic regression.

Abbreviations: ED, emergency department; EF, extrafine; ICS, inhaled corticosteroid; LTRA, leukotriene receptor antagonist; OCS, oral corticosteroid.