How Does Mild Asthma Differ Phenotypically from Difficult-to-Treat Asthma?

Figures & data

Table 1 Comparison of Clinical Characteristics Between Difficult and Mild Asthma Cohorts

Clinical Characteristics	Difficult Asthma Cohort	Mild Asthma Cohort	P-value
Demographics
Number of subjects, (N)	498	67
Sex, % (n)
Female	65.3 (325)	62.7 (44)	>0.9999
Male	34.7 (173)	37.3 (23)
Ethnicity, % (n/N)
Caucasian	92.6 (460/497)	98.6 (66)	0.0711
Non-Caucasian	7.4 (37/497)	1.4 (1)
Age at enrolment, years	50.8 (15.7)	38.3 (11.9)	<0.0001
Body mass index, kg/m^2	30.9 (7.3)	27.8 (5.9)	0.0002
Smoking Status, % (n)
Never	52.3 (260)	47.8 (32)	<0.5165^#
Ever	47.7 (237)	52.2 (35)
Asthma History
Age of asthma onset, years	23.7 (20.4)	17.7 (16.0)	0.1587
Asthma duration, years	26.4 (17.4)	20.7 (12.3)	0.0288

Notes: Categorical variables are represented as percentages (%) and frequencies (n/N); continuous variables as mean (SD). Fisher’s exact test and ^#Chi-squared test were applied for categorical variables, Mann Whitney U-test for non-parametric data. P-values <0.05 are statistically significant (in bold).

Table 2 Comparison of Asthma Morbidity Between Difficult and Mild Asthma Cohorts

Clinical Characteristics	Difficult Asthma Cohort N=498	Mild Asthma Cohort N=67	P-value
Healthcare Utilisation
Hospitalisations in past 12-months	0.7 (1.7)	0 (0)	<0.0001
OCS courses in past 12-months	3.5 (3.5)	0.1 (0.4)	<0.0001
Asthma-related ICU visits ever	0.8 (1.9)	0 (0.3)	<0.0001
Days lost from work in past 12-months	23.4 (48.9)	0.56 (2.5)	<0.0001

Notes: Categorical variables are represented as percentages (%) and frequencies (n/N); continuous variables as mean (SD). Fisher’s exact test was applied for categorical variables, Mann Whitney U-test for non-parametric data. P-values <0.05 are statistically significant (in bold).

Abbreviations: OCS, oral corticosteroids; ICU, intensive care unit.

Figure 1 Lung function characteristics between the difficult and mild asthma cohorts. Post-BD spirometry values shown for difficult asthma and pre-BD spirometry values shown for mild asthma. (A) Clinic FEV₁% predicted., (B) Clinic FVC % predicted, (C) Clinic FEV₁/FVC ratio %, (D) Clinic FEF_25-75% % predicted. Data presented as median ± interquartile range. ****P <0.0001. A full breakdown of the results and statistics is available in Table S4.

Abbreviations: FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; FEF 25–75%, forced expiratory flow between 25% and 75% exhalation.

Table 3 Comparison of T2 Biomarkers and Inflammometry Between Difficult and Mild Asthma Cohorts

Clinical Characteristics	Difficult Asthma Cohort N=498	Mild Asthma Cohort N=67	P-value
Blood Inflammometry
Blood eosinophil count, x 10^9/L	0.26 (0.33)	0.22 (0.14)	0.5185
Blood neutrophil count, x 10^9/L	6.27 (2.85)	3.85 (1.83)	<0.0001
Total IgE, IU/L	298.2 (595.4)	267.1 (448.9)	0.5475
A.fumigatus-specific IgE, IU/L	1.46 (7.40)	0.18 (0.58)	0.0041
Airway Inflammometry
FeNO, ppb	30.6 (34.0)	35.0 (27.3)	0.0053
Sputum eosinophils, % N	8.5 (14.1) 140	6.0 (8.0) 7	0.7636
Sputum neutrophils, % N	43.1 (25.0) 140	24.1 (23.8) 7	0.0450
T2-high Inflammation
GINA T2-high status, % (n/N)	93.5 (435/465)	88.1 (59)	0.1238
Atopy status
Number of positive SPT	2.9 (3.0)	3.4 (2.9)	0.1352
Subjects with ≥ 1 positive SPT, % (n/N)	68.3 (265/388)	73.8 (48/65)	0.4684

Notes: Categorical variables are represented as percentages (%) and frequencies (n/N); continuous variables as mean (SD). Fisher’s exact test was applied for categorical variables, and Mann Whitney U-test for non-parametric data. P-values <0.05 are statistically significant (in bold).

Abbreviations: IgE, immunoglobulin E; A.fumigatus, Aspergillus fumigatus; FeNO, fractional exhaled nitric oxide; ppb, parts per billion; T2, type 2; GINA, Global Initiative for Asthma; SPT, skin prick test.

Figure 2 Comparison of physician and/or clinically diagnosed comorbidity characteristics between the difficult and mild asthma cohorts. Comorbidities are represented as percentages (%). Fisher’s exact test was applied for categorical variables. *P <0.05, **P <0.01, ***P <0.001, ****P <0.0001. A full breakdown of the results and statistics is available in Table S7.

Abbreviations: GORD, gastro-oesophageal reflux disease; ABPA/SAFS, allergic bronchopulmonary aspergillosis/severe asthma with fungal sensitisation; CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease.

Table 4 Comparison of Asthma and Comorbidity-Related Questionnaire Characteristics Between Difficult and Mild Asthma Cohorts

	Difficult Asthma Cohort N=498	Mild Asthma Cohort N=67	P-value
Asthma Control & Health-related QoL
ACQ-6 score	2.50 (1.35)	0.72 (0.70)	<0.0001
ACQ-6 score ≥ 1.50, % (n/N)	76.9 (357/464)	16.7 (11/66)	<0.0001
EQ5D-5L Health Today VAS, %	63.1 (20.3)	84.2 (14.7)	<0.0001
SGRQ total score	50.7 (21.0)	17.7 (13.2)	<0.0001
Comorbidity-related Questionnaires
SNOT22 score	35.1 (21.4)	21.3 (17.9)	<0.0001
Hull Cough Hypersensitivity score	26.2 (15.6)	11.6 (10.2)	<0.0001
Nijmegen score	22.1 (12.4)	15.1 (10.0)	<0.0001
HADS-D score	5.4 (4.4)	2.7 (2.6)	<0.0001
HADS-A score	7.0 (4.7)	7.3 (4.2)	0.4392

Notes: Disease-related questionnaire scores are represented as mean (SD). Fisher’s exact test was applied for categorical variables and Mann Whitney U-test for non-parametric data. P-values <0.05 are statistically significant (in bold).

Abbreviations: QoL, quality of life; ACQ-6, asthma control questionnaire-6; EQ5D-5L, EuroQoL5D-5L; VAS, visual analogue scale; SGRQ, St George’s respiratory questionnaire; SNOT22, sino-nasal outcome test-22; HADS-D, hospital anxiety and depression scale-depression component; HADS-A, hospital anxiety and depression scale-anxiety component.

Figure 3 Summary of mild and difficult asthma phenotypes. Early-onset <18 years, Adult onset ≥18 years.

Abbreviations: BMI, Body mass index; ICS, inhaled corticosteroid; FeNO, fractional exhaled nitric oxide; T2, type 2; HRQoL, health-related quality of life; OCS, oral corticosteroid; mOCS, maintenance oral corticosteroids; A. fumigatus, Aspergillus fumigatus; IgE; Immunoglobulin E.