Hot but not twitchy – Eosinophilic airway inflammation dissociates from variable airflow obstruction with increasing asthma severity

<bold>Introduction:</bold> Variable airflow obstruction(VAO) in asthma is generally correlated to the level of T2 airway inflammation but the association between these core pathophysiological disease features across asthma severity is poorly described. <bold>Methods:</bold> Patients with asthma from the BREATHE-cohort were grouped according to severity, defined by budesonide equivalent ICS dose (none; >0 and <1600; ≥1600 or maintenance OCS), and assessed for the presence of airway T2 inflammation(aT2) (sputum eosinophils(S-EOS) ≥3% and/or Fractional exhaled nitric oxide(FeNO) ≥25 ppb) and VAO (B2-reversibility of 200mL and 12% and/or positive mannitol challenge test). <bold>Results:</bold> In the 361 patients, VAO and aT2 were only significantly associated in ICS-free patients (n=103) (p=0.04, chi square; FeNO and PD15 to mannitol (p=0.002); and S-EOS and B2-reversibility (p=0.02)) with a trend towards a numerical decrease in rho with increasing ICS-dose. The prevalence of VAO decreased with severity (65%, 52%, 49%) whereas aT2 (59%, 43%, 63%) was most prevalent in patients with severe asthma (n=72). In patients with aT2 and/or VAO, the rate of concomitant VAO and aT2 decreased with ICS treatment (51%, 31%, 34%) whereas coherence - either the presence or the absence of both - decreased with increasing ICS-dose (60%, 52%, 49%). In severe asthma patients with aT2, absence of VAO was significantly associated with a lower FEV1- and FVC percent predicted (p=0.05 and p=0.04). <bold>Conclusion:</bold> Markers of variable airflow obstruction and T2 inflammation are increasingly discordant with asthma severity, indicating a switch towards an inflammatory process more dissociated from the tendency to cause airway constriction.