Comparative Effectiveness and Molecular Profiling of Dupilumab Versus Endoscopic Sinus Surgery in Chronic Rhinosinusitis With Nasal Polyps (CRSWNP)

Abstract

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a prevalent inflammatory disorder of the upper airway that significantly impairs quality of life and imposes a substantial healthcare burden. Once viewed as a mechanical or infectious condition, CRSwNP is now recognized as a disease of dysregulated type 2 inflammation driven by interleukins (IL)-4, IL-5, and IL-13. This paradigm shift has transformed management strategies from surgical intervention to targeted biologic immunomodulation. Endoscopic sinus surgery (ESS) remains a cornerstone therapy for restoring sinus ventilation and topical drug delivery; however, recurrence rates remain high, particularly in patients with asthma or aspirin-exacerbated respiratory disease. Dupilumab, a monoclonal antibody that blocks IL-4/IL-13 signaling through antagonism of the IL-4 receptor alpha subunit, represents the first biologic therapy to directly target the immunologic drivers of CRSwNP. Despite its demonstrated efficacy, no prospective studies have directly compared dupilumab with ESS, limiting evidence-based guidance for individualized treatment selection. This dissertation addressed this gap through three complementary investigations: a systematic review and meta-analysis synthesizing existing evidence, a prospective longitudinal cohort comparing clinical and molecular outcomes between dupilumab and ESS, and a translational study evaluating how these interventions differentially influence bacterial infection risk. The systematic review included seventy-three studies encompassing 4,772 patients and assessed validated outcomes including SNOT-22, nasal polyp score (NPS), and olfactory function. Both ESS and biologic therapy produced significant clinical improvement, though high heterogeneity (I² > 80%) and inconsistent outcome reporting limited the strength of pooled conclusions. While both treatments improved SNOT-22 scores at six and twelve months, biologics achieved superior olfactory gains at six months (129% vs. 31% for ESS; p < 0.001), whereas ESS produced greater polyp reduction at twelve months. The prospective study followed fifty adults with CRSwNP for twelve months after initiating dupilumab or undergoing ESS, with standardized assessments at three, six, nine, and twelve months. ESS provided more rapid symptom relief at three months, but dupilumab achieved superior outcomes at twelve months across multiple domains, including SNOT-22 (8.5 vs. 23.8; p < 0.001), UPSIT-40 (32.8 vs. 24.9; p < 0.001), and ACQ-5 (0.1 vs. 0.5; p < 0.001). Transcriptomic profiling revealed that dupilumab progressively downregulated IL-4/IL-13–mediated inflammation and restored epithelial metabolic homeostasis, while ESS induced transient wound-healing and neutrophil-activation pathways. The bacterial exacerbation analysis provided novel mechanistic insight, demonstrating that dupilumab-treated patients experienced 66% fewer culture-confirmed infections than ESS patients (0.40 vs. 1.17 episodes per patient; p = 0.002), with Staphylococcus aureus isolated in 57% of post-ESS but only 25% of post-dupilumab infections. Collectively, these studies provide the first integrated comparative evidence between ESS and dupilumab in CRSwNP, showing that both are effective but differ fundamentally in mechanism and durability. ESS offers rapid anatomic decompression and early symptom relief, whereas dupilumab provides sustained immunologic recalibration, epithelial restoration, and protection against bacterial exacerbations. These findings support a paradigm shift from traditional stepwise procedural approaches toward precision, endotype-based therapy selection. Dupilumab may be preferred for patients with asthma, high inflammatory burden, or recurrent infections, while ESS remains appropriate for those seeking immediate relief or with minimal systemic inflammation. This research establishes a foundation for biomarker-guided, cost-effective, and personalized CRSwNP management, advancing the field toward durable disease modification rather than symptomatic control.