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\begin{document}

\title{Non-eosinophilic asthma in nonsteroidal anti-inflammatory drug
exacerbated respiratory disease}



\author[1]{Lucyna Mastalerz}%
\author[1]{Natalia Celejewska-Wójcik}%
\author[2]{Adam Ćmiel}%
\author[1]{Krzysztof Wójcik}%
\author[1]{Joanna Szaleniec}%
\author[1]{Karolina Hydzik-Sobocińska}%
\author[1]{Jerzy Tomik}%
\author[1]{Marek Sanak}%
\affil[1]{Uniwersytet Jagiellonski w Krakowie Collegium Medicum}%
\affil[2]{Akademia Gorniczo-Hutnicza im Stanislawa Staszica w Krakowie}%


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  \date{May 24, 2024}


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\begin{abstract}
\textbf{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.
\textbf{Methods}: Induced sputum was collected from 133 patients with
N-ERD. Sixty six patients (49.6\%) 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. \textbf{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 D \textsubscript{2} levels
distinguished cluster \#1 from the remaining clusters with an area under
the curve of 0.94. \textbf{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 PGD \textsubscript{2} levels, asthma severity,
and age of patients. The heterogeneity of non-eosinophilic N-ERD
suggests a need for novel targeted interventions.%
\end{abstract}%



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