Appropriate Medical Therapy and Selective Modulation of Inflammatory Endotypes in Chronic Rhinosinusitis

To the Editor: We read with interest the study by Park et al. examining the impact of appropriate medical therapy (AMT) on inflammatory biomarkers and clinical outcomes in chronic rhinosinusitis (CRS) [1]. By integrating principal component analysis (PCA) of sinonasal mucus biomarkers with patient-reported and objective disease measures, the authors provide important insight into the differential responsiveness of CRS inflammatory axes to medical therapy. In this prospective cohort, AMT was associated with significant improvements in symptom burden, endoscopic findings, radiographic severity, and olfaction, accompanied by marked reductions in Type 2 (T2) biomarkers (IL-5, IL-13) and eosinophil-associated severity markers (ECP, MIP-1α). In contrast, Type 1/3 (T1/3) biomarkers (IFN-γ, IL-1β) remained largely unchanged. These findings reinforce the concept that T2-driven inflammation represents the most steroid-responsive and clinically tractable endotype in CRS, consistent with prior endotype-based studies [2, 3]. One aspect that merits further consideration is the interpretation of the PCA-derived “severity” axis. Eosinophil cationic protein (ECP), while used here as a marker of inflammatory burden, is biologically downstream of T2 cytokine signaling. Its heavy loading on the severity component suggests that inflammatory severity and T2 biology may not be fully independent dimensions, but rather partially overlapping constructs. This overlap may partly explain why reductions in “severity” biomarkers closely paralleled reductions in T2 cytokines following AMT. Inclusion of non-eosinophilic severity markers, such as neutrophil-associated mediators, could help clarify whether an endotype-independent severity axis exists. Additionally, the lack of measurable change in T1/3 biomarkers despite clear clinical improvement is notable. This observation supports emerging evidence that T1/T3-skewed CRS may represent a relatively corticosteroid-resistant inflammatory phenotype [4]. Persistent T1/3 activity may therefore contribute to incomplete disease control in some patients treated with optimized medical therapy and underscores the need for alternative or adjunctive therapeutic strategies targeting non-T2 pathways. Finally, while AMT regimens were heterogeneous and adherence was not formally monitored, the association between oral or extended-delivery topical steroids and reductions in ECP highlights the importance of drug delivery and tissue penetration in CRS management. This finding has practical implications for optimizing medical therapy prior to escalation to surgical or biologic interventions. In summary, Park et al. provide compelling evidence that AMT preferentially modulates T2-driven and eosinophil-associated inflammation in CRS, with meaningful correlations to clinical improvement. Future longitudinal studies incorporating broader biomarker panels and baseline endotype stratification may further refine precision-based treatment algorithms for CRS. Sincerely SNK: methodology, writing – original draft, writing – review & editing. VV: writing – original draft, writing – review & editing. SK: conceptualization, validation, writing – review & editing. SV: writing – original draft, writing – review & editing. JRP: validation, writing – review & editing. The authors have nothing to report. The authors have nothing to report. The authors have nothing to report. The authors have nothing to report. The authors have nothing to report. The authors declare no conflicts of interest. The authors have nothing to report.