Type-2 inflammation and lung function decline in chronic airway disease in the general population

Abstract

Background: It is unclear if type-2 inflammation is associated with accelerated lung function decline in individuals with asthma and chronic obstructive pulmonary disease (COPD). We tested the hypothesis that type-2 inflammation indicated by elevated blood eosinophils (BE) and fraction of exhaled nitric oxide (FeNO) is associated with accelerated lung function decline in the general population.

Methods: We included adults from the Copenhagen General Population Study with measurements of BE (N=15 605) and FeNO (N=2583) from a follow-up examination and assessed forced expiratory volume in 1 s (FEV₁) decline in the preceding 10 years. Based on pre- and post-bronchodilator lung function, smoking history and asthma at follow-up examination, participants were assigned as not having airway disease, asthma with full reversibility (AR), asthma with persistent obstruction (APO), COPD, and not classifiable airflow limitation (NAL).

Results: FEV₁ decline in mL/year increased with 1.0 (95% CI 0.6 to 1.4, p<0.0001) per 100 cells/µL higher BE and with 3.2 (95% CI 2.0 to 4.5, p<0.0001) per 10 ppb higher FeNO. Adjusted FEV₁ decline in mL/year was 18 (95% CI 17 to 20) in those with BE<300 cells/µL and FeNO<20 ppb, 22 (19-25) in BE≥300 cells/µL or FeNO≥20 ppb, and 27 (21-33) in those with BE≥300 cells/µL and FeNO≥20 ppb (p for trend<0.0001). Corresponding FEV₁ declines were 24 (19-29), 33 (25-40) and 44 (31-56) in AR (0.002), 26 (14-37), 36 (12-60) and 56 (24-89) in APO (0.07), 32 (27-36), 31 (24-38) and 44 (24-65) in COPD (0.46), and 27 (21-33), 35 (26-45), and 37 (25-49) in NAL (0.10), respectively.

Conclusions: Type-2 inflammation indicated by elevated BE and FeNO is associated with accelerated FEV₁ decline in individuals with chronic airway disease in the general population, and this association was most pronounced in an asthma-like phenotype.

Keywords: Asthma Epidemiology; Asthma Mechanisms; COPD Pathology; COPD epidemiology; Clinical Epidemiology.

Figure 1

Flow chart. Number of individuals depicted represent those with information on blood eosinophils, while those with information on FeNO in parentheses. AL, airflow limitation; COPD, chronic obstructive pulmonary disease; FeNO, fraction of nitric oxide; FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity.

Figure 2

Blood eosinophils and lung function decline according to chronic airway disease. All analyses were multivariable adjusted for covariates obtained at follow-up examination, including age, age-squared, sex, height, smoking status, tobacco consumption (pack-years) and airway medication. Individuals beyond 1000 cells/µL were included in analyses but not in graphs for visual purposes. Shaded areas indicate 95% CIs. Dashed lines indicate cut-points for blood eosinophils that are used for treatment indication with monoclonal antibodies specifically targeting IL-5, IL-4 and IL-13 signalling, as this may suggest presence of type-2 inflammation and potential treatment response. AL, airflow limitation; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 s.

Figure 3

FeNO and lung function decline according to chronic airway disease. All analyses were multivariable adjusted for covariates obtained at follow-up examination, including age, age-squared, sex, height, smoking status, tobacco consumption (pack-years) and airway medication. Individuals beyond 100 ppb were included in analyses but not in graphs for visual purposes. Shaded areas indicate 95% CIs. Dashed line indicates cut-point for FeNO that is used for treatment indication with monoclonal antibodies specifically targeting IL-5, IL-4 and IL-13 signalling, as this may suggest presence of type-2 inflammation and potential treatment response. AL, airflow limitation; COPD, chronic obstructive pulmonary disease; FeNO, fraction of nitric oxide; FEV₁, forced expiratory volume in 1 s.

Figure 4

Lung function decline according to elevated blood eosinophils and FeNO. All analyses were multivariable adjusted for covariates obtained at follow-up examination, including age, age-squared, sex, height, smoking status, tobacco consumption (pack-years) and airway medication. FeNO, fraction of nitric oxide; FEV₁, forced expiratory volume in 1 s.

Figure 5

Lung function decline according to elevated blood eosinophils and FeNO in chronic airway disease. All analyses were multivariable adjusted for covariates obtained at follow-up examination, including age, age-squared, sex, height, smoking status, tobacco consumption (pack-years) and airway medication. AL, airflow limitation; COPD, chronic obstructive pulmonary disease; FeNO, fraction of nitric oxide; FEV₁, forced expiratory volume in 1 s.