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Background: The progression from mild-to-moderate to severe asthma remains unclear. This study aimed to assess the risk of progression following the first asthma exacerbation in mild-to-moderate asthma and to identify risk factors and high-risk patient profiles.

Methods: This was an observational cohort study based on Danish data from the Nordic Dataset for Asthma Research collaboration platform. Adult patients with mild-to-moderate asthma experiencing their first asthma exacerbation were identified between 2000 and 2018 and followed prospectively for 5 years for the development of severe asthma according to European Respiratory Society (ERS) / American Thoracic Society (ATS) guidelines. Baseline risk factors for progression to severe asthma were assessed using multivariable logistic regression models, and risk of progression was evaluated across specific patient profiles.

Results: Among 99 748 patients with mild-to-moderate asthma experiencing the first asthma exacerbation, 4.1% progressed to severe asthma within 5 years. Risk factors included baseline age 40-49 years (odds ratio [OR] = 1.62; 95% CI, 1.49-1.77), experiencing an exacerbation despite medium-dose inhaled corticosteroid (ICS) use (OR = 3.72; 95% CI, 3.39-4.09), high use of short-acting beta agonist (OR = 1.76; 95% CI, 1.64-1.90), ≥2 respiratory infections (OR = 1.61; 95% CI, 1.49-1.73), and blood eosinophil counts ≥ 0.6 × 109/L (OR = 1.97; 95% CI, 1.47-2.61). A patient aged 40-49 years with late-onset eosinophilic asthma, treated with medium-dose ICS and with recurrent respiratory infections, had a 30.4% 5-year risk of progressing to severe asthma.

Conclusion: In patients with mild-to-moderate asthma experiencing their first asthma exacerbation, few (4.1%) patients overall progressed to severe asthma within 5 years, but specific high-risk patient profiles faced risks of up to 30%. Whether early recognition can modify this risk warrants further investigation.