Paucigranulocytic Asthma in Aspirin-Hypersensitive Patients: Pleiotropic Regulation of Type 2 Biomarkers

Up to 50% of patients with nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) exhibit a noneosinophilic airway inflammatory phenotype, with paucigranulocytic asthma being the most prevalent. The aim was to identify clusters within N-ERD and aspirin-tolerant asthma (ATA) controls with a paucigranulocytic asthma phenotype.

Two separate hierarchical cluster analyses were performed using 23 variables in 36 N-ERD patients and 19 ATA controls. Variables included demographic, clinical, treatment-related, and hematologic parameters; sputum cytology; sinus computed tomography findings; and eicosanoid levels in induced sputum supernatant (ISS) and urine.

Two clusters were identified in each group: 1_N-ERD, 2_N-ERD, 1_ATA, and 2_ATA. Cluster 1_N-ERD patients had less severe asthma and required lower doses of inhaled corticosteroids (ICS) but showed higher blood eosinophil counts, Lund-Mackay (LM) scores, and ISS leukotriene E₄ (LTE₄) levels than those in cluster 2_N-ERD. Cut-off values defining a T2-high paucigranulocytic asthma profile in N-ERD included LM score ≥ 18, blood eosinophils ≥ 300 cells/mm³, and ISS LTE₄ ≥ 30 pg/mL, with the LM score demonstrating the highest AUC at 0.8. Among ATA controls, cluster 1_ATA had more severe asthma, higher ICS doses, more severe sinonasal disease, and increased ISS leukotriene D₄ and LTE₄ levels compared with cluster 2_ATA.

Two clusters were identified among N-ERD patients with a paucigranulocytic asthma phenotype. Cluster 1_N-ERD was characterized by milder asthma, more severe sinonasal disease, elevated blood eosinophil counts, and elevated ISS LTE₄. This T2-high-like cluster may represent a subgroup requiring further evaluation for anti-T2 biologic therapy targeting chronic rhinosinusitis with nasal polyps, although further validation is required.