Longitudinal impact of sputum inflammatory phenotypes on small airway dysfunction and disease outcomes in asthma.

BACKGROUND: Little is known about the relationship between airway inflammatory phenotypes and some important asthma features such as small airway dysfunction (SAD). OBJECTIVE: To describe the longitudinal impact of airway inflammatory phenotypes on SAD and asthma outcomes METHODS: We measured eosinophil and neutrophil counts in induced sputum at baseline and one year later to stratify 197 adult asthma patients into four inflammatory phenotypes. We conducted a comprehensive assessment of lung function using spirometry, body plethysmography, impulse oscillometry, inert gas single and multiple breath washouts. We compared lung function, asthma severity, exacerbation frequency and symptom control between the phenotypes. We studied the longitudinal impact of persistent sputum inflammatory phenotypes and the change of sputum cell counts on lung function. RESULTS: Patients were stratified into eosinophilic (23%, n=45), neutrophilic (33%, n=62), mixed granulocytic (22%, n=43), and paucigranulocytic (24%, n=47) phenotypes. Eosinophilic and mixed granulocytic asthma patients had higher rates of airflow obstruction and severe exacerbation as well as poorer symptom control than paucigranulocytic asthma patients. All SAD measures were worse in eosinophilic and mixed than in paucigranulocytic asthma patients (all p-values <0.05). Eosinophilic asthma also indicated worse distal airflow obstruction, increased ventilation inhomogeneity (all p-values <0.05), and higher tendency for severe exacerbation (p= 0.07) than neutrophilic asthma. Longitudinally, persistent mixed granulocytic asthma was associated with the worst follow-up measures of SAD compared to persistent neutrophilic, persistent paucigranulocytic or non-persistent asthma phenotypes. In patients with stable FEV1, the mean increase in small airway resistance (R5-20) was greater in persistent mixed granulocytic patients (+103%) than in patients with persistent neutrophilic (+26%), p=0.040, or persistent paucigranulocytic asthma (-41%), p=0.028. Multivariate models adjusted for confounders and treatment with inhaled or oral corticosteroids or anti-eosinophilic biologics indicated that the change of sputum eosinophil rather than neutrophil counts is an independent predictor for the longitudinal change in FEV1, FEF25-75, sReff, RV and LCI. CONCLUSION: In asthma, airway eosinophilic inflammation is the main driver of lung function impairment and poor disease outcomes, which might also be aggravated by the coexistence of airway neutrophilia to confer a severe mixed asthma phenotype. Persistent airway eosinophilia might be associated with dynamic SAD even in patients with stable FEV1