Supplementary Material for: Endotyping Difficult-to-Treat Chronic Rhinosinusitis with Nasal Polyps by Structured Histopathology

<b><i>Introduction:</i></b> This study aimed to identify the histopathologic characteristics associated with difficult-to-treat chronic rhinosinusitis with nasal polyps (CRSwNPs), enabling physicians to predict the risk of poor outcome after endoscopic sinus surgery (ESS). <b><i>Methods:</i></b> A prospective cohort study performed at the First Affiliated Hospital of Sun Yat-sen University between January 2015 and December 2018 with CRSwNP patients who underwent ESS. Polyp specimens were collected during surgery and were subjected to structured histopathological evaluation. Difficult-to-treat CRSwNPs were determined at 12–15 months post-operation according to the European Position Paper. Multiple logistic regression model was used to assess the association between histopathological parameters and the difficult-to-treat CRSwNP. <b><i>Results:</i></b> Among 174 subjects included in the analysis, 49 (28.2%) were classified with difficult-to-treat CRSwNP, which had higher numbers of total inflammatory cells, tissue eosinophils, and percentages of eosinophil aggregates and Charcot-Leyden crystals (CLC) formation but a lower number of interstitial glands than the nondifficult-to-treat CRSwNP. Inflammatory cell infiltration (adjusted OR: 1.017), tissue eosinophilia (adjusted OR: 1.005), eosinophil aggregation (adjusted OR: 3.536), and CLC formation (adjusted OR: 6.972) were independently associated with the difficult-to-treat outcome. Furthermore, patients with tissue eosinophil aggregation and CLC formation had an increasingly higher likelihood of uncontrolled disease versus those with tissue eosinophilia. <b><i>Conclusion:</i></b> The difficult-to-treat CRSwNP appears to be characterized by increased total inflammatory infiltrates, tissue eosinophilia, eosinophil aggregation, and CLC formation in structured histopathology.