Non-eosinophilic asthma in nonsteroidal anti-inflammatory drug exacerbated respiratory disease

Abstract

Background: The cellular inflammatory pattern of nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) is heterogeneous. However, data on the heterogeneity of non-eosinophilic asthma (NEA) with aspirin hypersensitivity are scanty. By examination of N-ERD patients based on clinical data and eicosanoid biomarkers we aimed to identify NEA endotypes potentially guiding clinical management.

Methods: Induced sputum was collected from patients with N-ERD. Sixty six patients (49.6% of 133 N-ERD) with NEA were included in the hierarchical cluster analysis based on clinical and laboratory data. The quality of clustering was evaluated using internal cluster validation with different indices and a practical decision tree was proposed to simplify stratification of patients.

Results: The most frequent NEA pattern was paucigranulocytic (PGA; 75.8%), remaining was neutrophilic asthma (NA; 24.2%). Four clusters were identified. Cluster #3 included the highest number of NEA patients (37.9%) with severe asthma and PGA pattern (96.0%). Cluster #1 (24.2%) included severe only asthma, with a higher prevalence of NA (50%). Cluster #2 (25.8%) comprised well-controlled mild or severe asthma (PGA; 76.5%). Cluster #4 contained only 12.1% patients with well-controlled moderate asthma (PGA; 62.5%). Sputum prostaglandin D₂ levels distinguished cluster #1 from the remaining clusters with an area under the curve of 0.94.

Conclusions: Among identified four NEA subtypes, clusters #3 and #1 represented N-ERD patients with severe asthma but a different inflammatory signatures. All the clusters were discriminated by sputum PGD₂ levels, asthma severity, and age of patients. The heterogeneity of non-eosinophilic N-ERD suggests a need for novel targeted interventions.

Keywords: aspirin hypersensitivity; cluster analysis; inflammatory phenotypes; non-eosinophilic asthma.

FIGURE 1

(A) Distribution of patients with nonsteroidal anti‐inflammatory drug–exacerbated respiratory disease (N‐ERD) (n = 133) according to the cellular inflammatory pattern of the induced sputum. Paucigranulocytic (38%) and neutrophilic (18%) phenotype was considered as non‐eosinophilic asthma (NEA), and these patients (n = 66) were included in the study. (B) Distribution of patients with paucigranulocytic or neutrophilic asthma phenotype among NEA patients with N‐ERD. eos, eosinophilic; mix, mixed; neu, neutrophilic; pauci, paucigranulocytic.

FIGURE 2

A receiver operating characteristic analysis of non‐eosinophilic asthma clusters using sputum prostaglandin D₂ to distinguish between cluster #1 and clusters #2, #3, and #4. AUC, area under the curve; CI, confidence interval.

FIGURE 3

A simplified decision tree for assignment of the study subjects into subtypes of N‐ERD with non‐eosinophilic asthma using only 3 variables (sputum PGD₂ level, severity of asthma, and age of the patient). An available biological therapy is proposed on the premises of tentative pathomechanism underlying the clusters.