Determinants of Severe Asthma – A Long-Term Cohort Study in Northern Sweden

Figures & data

Table 1 Demography at Study Entry Among Those with and without Severe Asthma at Follow-Up, According to Two Different definitions of Severe Asthma

		Other Asthma	Severe Asthma
			GINA		ERS/ATS
		n=875	n=131	p-value	n=40	p-value
Mean age (SD) in years		40.0 (11.7)	43.7 (11.1)	0.001	44.1 (9.8)	0.031
Sex	Female	54.4%	61.8%	0.111	62.5%	0.314
Mean BMI (SD)		25.5 (4.0)	26.4 (4.6)	0.021	26.0 (4.7)	0.484
BMI group	Under weight	5.4%	4.8%	0.783	10.5%	0.179
	Normal weight	47.2%	38.4%	0.064	34.2%	0.115
	Over weight	34.2%	36.0%	0.698	34.2%	0.998
	Obese	13.1%	20.8%	0.021	21.1%	0.162
Family history of asthma		40.9%	42.7%	0.691	35.0%	0.456
Family history of ARC		41.6%	43.5%	0.679	35.0%	0.407
Asthma onset ≥30y*		46.7%	63.6%	<0.001	62.5%	0.051
Smoking	Never	44.9%	40.5%	0.338	45.0%	0.991
	Ex	27.0%	36.6%	0.022	35.0%	0.265
	Current	28.1%	22.9%	0.212	20.0%	0.262
Socioeconomic status based on occupation	MWI	18.4%	13.0%	0.129	10.0%	0.177
	MWS	28.7%	30.5%	0.663	37.5%	0.230
	ANME	15.2%	22.1%	0.044	20.0%	0.411
	SNP	3.9%	3.8%	0.970	2.5%	0.655
	INME, PAE	22.9%	22.9%	0.991	20.0%	0.673
	SAH, OTHERS	11.0%	7.6%	0.246	10.0%	0.847

Notes: Presented as column % unless otherwise stated. Study entry = in 1986–2001. Follow-up = in 2012–2014. P-value = comparing severe asthma with the n=875 not having severe asthma according to both of the respective criteria. P-values from Chi-square tests or t-test, as appropriate. Bold font indicates p<0.05. Family history of ARC = family history of allergic rhinoconjunctivitis.

Abbreviations: MWI, Manual workers industry; MWS, Manual workers service; ANME, Assistant Non-manual employees; SNP, Self-employed non-professionals; INME, Intermediate Non-manual employees; PAE, Professionals and Executives; SAH, Students and housewives; OTHERS, Others and non-classifiable.

Table 2 Factors Assessed at Study Entry in Association with Severe Asthma According to GINA and Severe Uncontrolled Asthma at Follow-Up, Among All Participants and Exclusively in Participants That Were ICS Naïve at Study Entry. Analyzed by Poisson Regression, with Results Presented as Risk Ratios (RR) with 95% Confidence Intervals (95% CI), Including Other Asthma as Reference Category

		Among All Participants				In ICS Naïve At Study Entry
		Severe Asthma		Severe Uncontrolled Asthma		Severe Asthma		Severe Uncontrolled Asthma
		RR	(95% CI)	RR	(95% CI)	RR	(95% CI)	RR	(95% CI)
Smoking	Current smoker	0.84	(0.55–1.28)	1.07	(0.65–1.77)	0.93	(0.59–1.48)	1.33	(0.76–2.32)
	Ex-smoker	1.27	(0.89–1.83)	1.41	(0.89–2.25)	1.12	(0.73–1.74)	1.12	(0.63.2.01)
BMI	Overweight	1.25	(0.84–1.87)	1.21	(0.73–1.99)	1.16	(0.73–1.84)	1.13	(0.63–2.05)
	Obese	1.74	(1.12–2.70)	2.18	(1.30–3.65)	1.72	(1.03–2.89)	2.33	(1.27–4.29)
Age at onset	≥30 years	1.52	(1.06–2.17)	1.64	(1.06–2.53)	1.70	(1.09–2.64)	1.91	(1.19–3.28)

Notes: In line with the definitions stated in the methods section, all with severe uncontrolled asthma also have severe asthma according to GINA. None of those with severe asthma according to GINA were underweight at study entry. Bold font indicates p<0.05. All factors are measured at study entry. The following covariates were included in the models: age ≥30 years at asthma onset (onset before age 30 as reference), smoking habits (non-smoker as reference), BMI categories (normal weight as reference), sex (not shown), original cohort (not shown), and the models additionally include follow-up time as offset variable.

Figure 1 Prevalence (%) of severe asthma according to GINA at follow-up, stratified by (A) sex and BMI group at study entry (p from test-for-trend), and (B) sex and age at asthma onset (p from chi-square test). Participants with underweight are excluded due to low numbers.

Table 3 Lung Function at Study Entry Among Those with and without Severe Asthma at Follow-Up

	Other Asthma	Severe Asthma
		GINA		ERS/ATS
	n=875	n=131	p-value	n=40	p-value
Mean FEV1 pre-bd % of predicted	89.3	81.7	<0.001	79.0	<0.001
Mean FVC pre-bd % of predicted	87.6	83.3	<0.001	80.7	<0.001
Mean FEV1 pre-bd Z-score	−1.0	−1.6	<0.001	−1.9	<0.001
Mean FVC pre-bd Z-score	−1.1	−1.4	<0.001	−1.6	0.001
Mean FEV1/FVC pre-bd Z-score	0.3	−0.3	<0.001	−0.4	0.002
FEV1 pre-bd <80%	20.3%	45.7%	<0.001	50.0%	<0.001
FEV1 pre-bd<LLN	24.1%	49.6%	<0.001	60.0%	<0.001
FEV1/FVC pre-bd < LLN	7.0%	17.1%	<0.001	22.5%	<0.001
FEV1/FVC post-bd < 0.7	6.0%	14.7%	<0.001	17.5%	0.004
FEV1 reversibility post-bd* >12% and 200mL	14.7%	32.7%	0.002	33.3%	0.035
FEV1 reversibility post-bd* >20%	3.3%	20.4%	<0.001	22.2%	<0.001
Hyperreactivity**	79.0%	87.7%	0.126	94.7%	0.096

Notes: Pre-bd: value before bronchodilation; post-bd: value after bronchodilation; LLN: lower limit of normal; p-value=comparing severe asthma with the n=875 not having severe asthma (ie other asthma) according to both of the respective criteria, from Chi-square tests or t-tests as appropriate. Bold font indicates p<0.05. OLIN ref values are used to calculate percent of predicted and Z-scores. *Regarding reversibility testing: In total, n=322 out of n=1006 participated in reversibility testing at study entry, calculations in the table are based on those participating. whereof n=49 out of n=131 with GINA severe asthma and n=18 out of n=40 with ERS/ATS severe asthma. In original cohort 1, subjects with FEV₁ < 85% were invited for reversibility testing; in original cohorts 2 and 3, subjects with either of FEV₁ < 90% or FEV₁/ vital capacity (VC) < 0.7 were invited for reversibility testing; in original cohort 4, one subsample was invited to methacholine challenge and these were not invited to reversibility testing. The majority of those participating in reversibility testing had either of FEV₁ < 90% or FEV₁/ vital capacity (VC) < 0.7. in cohort 5, the few not participating in methacholine challenge were invited to reversibility testing. **Regarding methacholine challenge: In total, n=390 out of n=1006 participated in methacholine challenge at study entry, calculations in the table are based on those participating, whereof n=57 out of n=131 with GINA severe asthma and n=19 out of n=40 with ERS/ATS severe asthma.

Figure 2 Association between (A) lung function measures, and (B) triggers for respiratory symptoms at study entry and severe asthma according to GINA at follow-up. Results expressed as risk ratios with 95% CI adjusted for age, sex, smoking and BMI categories.

Table 4 Clinical Characteristics (%) at Study Entry Among Those with and without Severe Asthma at Follow-Up, According to Two Different Definitions of Severe Asthma

	Other Asthma	Severe Asthma
		GINA		ERS/ATS
	n=875	n=131	p-value	n=40	p-value
Recognized by health care as asthma	57.9%	77.1%	<0.001	80.0%	0.006
Recognized by health care as any OAD	63.7%	81.7%	<0.001	90.0%	0.001
Any asthma medication use	34.1%	53.4%	<0.001	55.0%	0.007
ICS use
No	90.2%	75.6%	<0.001	85.0%	0.288
Periodically	3.7%	2.3%	0.426	0.0%	0.218
Most days	6.2%	22.1%	<0.001	15.0%	0.027
Rhinitis	52.2%	61.8%	0.040	65.0%	0.114
Ever hayfever	44.1%	38.2%	0.200	25.0%	0.017
Ever eczema	36.2%	30.5%	0.204	27.5%	0.260
Ischemic heart disease	3.7%	3.1%	0.729	5.0%	0.661
Nasal polyps	10.9%	15.3%	0.139	12.5%	0.745
Longstanding cough	44.0%	51.9%	0.090	40.0%	0.618
Sputum production	65.3%	69.5%	0.344	72.5%	0.346
Chronic productive cough	24.8%	26.0%	0.776	22.5%	0.742
Attacks of SOB	70.7%	81.7%	0.009	82.5%	0.108
Asthmatic wheeze (wheeze with breathlessness without having a cold)	74.9%	86.3%	0.004	92.5%	0.011
Persistent wheeze (wheeze most days/week)	21.1%	42.0%	<0.001	52.5%	<0.001
mMRC≥1	49.1%	64.1%	0.001	65.0%	0.050
mMRC≥2	22.4%	39.7%	<0.001	42.5%	0.003
Nighttime sleep disturbance due to breathing problems last 12m	38.1%	54.2%	<0.001	65.0%	0.001

Notes: P-value from Chi-square test=comparing severe asthma with the n=875 not having severe asthma (ie other asthma) according to both of the respective criteria. Bold font indicates p<0.05.

Abbreviations: OAD, Obstructive airway disease (asthma, chronic bronchitis or emphyzema); SOB, Shortness of breath; mMRC, modified Medical Research Council dyspnea scale (range 0–4).

Table 5 Factors That Triggered Respiratory Symptoms at Study Entry Among Those with and without Severe Asthma at Follow-Up

Factors Triggering Respiratory Symptoms	Other Asthma	Severe Asthma
		GINA		ERS/ATS
	n=875	n=131	p-value	n=40	p-value
Allergy related triggers
Furred animals	38.2%	47.3%	0.045	42.5%	0.582
Pollen	33.3%	33.6%	0.940	20.0%	0.080
Moulds	22.4%	30.5%	0.040	27.5%	0.451
Non-allergy related triggers
Tobacco smoke	44.9%	62.6%	<0.001	75.0%	<0.001
Dust	53.3%	64.9%	0.013	65.0%	0.145
Strong scents	53.0%	70.2%	<0.001	67.5%	0.073
Traffic exhaust	31.9%	52.7%	<0.001	50.0%	0.017
Respiratory infections	68.6%	81.7%	0.002	82.5%	0.062
Cold air	66.5%	74.0%	0.086	70.0%	0.647
Physical activity	67.8%	81.7%	0.001	87.5%	0.009

Notes: P-value=P-value from Chi-square test comparing severe asthma with other asthma (ie, the n=875 not having severe asthma). Bold font indicates p<0.05.