Clinical Phenotyping of Asthma in the ATLANTIS Cohort: The Role of Sputum Eosinophils in Patients With Low Blood Eosinophils

Abstract Introduction: Asthma is often characterized by eosinophilic airway inflammation, with higher eosinophil levels linked to poorer asthma control and reduced responsiveness to treatments. Therefore, it is important to assess whether eosinophilic inflammation contributes to a clinical asthma phenotype. Eosinophilia is typically identified through blood or sputum analysis; however, due to the complexity of sputum analysis, blood measurements are preferred in clinical practice. Relying solely on blood may overlook patients with isolated sputum eosinophilia, which could impact clinical asthma management given the implications of eosinophilia. Our study investigates the prevalence of sputum eosinophilia in ATLANTIS asthma patients with low blood eosinophil counts and assesses its association with more severe disease and higher risk of exacerbations. Methods: This analysis focused on 425 asthma patients of the ATLANTIS multinational prospective cohort study. Patients with low blood eosinophil levels (<300 cells/μL) and with sputum eosinophilia (≥2%) were compared to those without eosinophilia in blood and sputum, as well as to patients with high blood eosinophil counts (≥300 cells/μL). Lung function, including parameters reflecting small airways disease, asthma control, exacerbations, and asthma severity were assessed. Results: We showed that 20% of the patients with low blood eosinophil counts had elevated sputum eosinophil counts. Patients with isolated sputum eosinophilia had more severe large and small airways disease, as reflected by lower FEV1/FVC ratios (80% vs 87%, p<0.01) and higher SCOND values (0.05 1/L vs 0.03 1/L, p=0.02), and increased median airway wall thickening on CT scans (37 vs 33 mm2, p=0.02) compared to those with low eosinophil counts in both blood and sputum. Isolated sputum eosinophilia was not associated with exacerbations or asthma severity. No significant differences in clinical characteristics were observed between patients with isolated sputum eosinophilia and those with blood eosinophilia. Conclusion: Our findings indicate that assessment of sputum eosinophilia in those with low blood eosinophil counts is important as isolated sputum eosinophilia occurs in a considerable subset of patients and is associated with clinically relevant asthma outcomes, particularly more severe large and small airways disease. In patients with isolated sputum eosinophilia, physicians may consider intensifying treatment with either a higher dose inhaled corticosteroids or a biologic.