Longer Asthma Duration Is Associated With Elevated Non-T2 Sputum Biomarkers and Reduced T2 Inflammation in Severe Asthma.

BACKGROUND

Longer asthma duration predicts non-remission in Type-2 (T2) biologic-treated severe asthma, but underlying mechanisms remain unclear. We investigated associations between asthma duration and inflammatory biomarkers that may explain differential biologic response.

METHODS

We analysed cross-sectional data from adults with severe asthma in U-BIOPRED. Asthma duration was defined as years from diagnosis to study entry. T2 and non-T2 biomarkers were measured in blood and sputum. Identical assays were performed in PRISM, a validation cohort of biologic-initiators. Multivariable regression models adjusted for age, sex, ethnicity, BMI, smoking and oral corticosteroid dose. Associations between duration-related biomarkers and 12-month biologic remission were explored in PRISM.

RESULTS

In U-BIOPRED (n = 411), median asthma duration was 23 years (IQR 12-38). Longer duration was associated with higher non-T2 biomarkers including sputum CXCL9 (β = 0.024, 95% CI 0.011-0.038), sputum IL-6 (β = 0.024, 95% CI 0.011-0.037) and sputum neutrophils (β = 0.009, 95% CI 0.001-0.017), but lower T2 biomarkers including plasma periostin (β = -0.006, 95% CI -0.009 to -0.003), eosinophils (blood: β = -0.002, 95% CI -0.003 to -0.001; sputum: β = -0.023, 95% CI -0.035 to -0.011), sputum EDN (β = -0.032, 95% CI -0.049 to -0.014) and FeNO (β = -0.006, 95% CI -0.010 to -0.001). PRISM (n = 474) confirmed these associations. Higher sputum CXCL9 was associated with reduced remission in anti-IL-4Rα-treated patients with asthma duration ≥ 20 years (β = -1.73, 95% CI -3.180 to -0.276).

CONCLUSION

Longer asthma duration was associated with elevated airway non-T2 inflammation and reduced systemic and airway T2 inflammation. This highlights the importance of airway biomarker sampling and suggests combined T2 and non-T2 therapeutic strategies may be needed to achieve remission in long-standing asthma.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05164939.