The prevalence of Chronic Sinusitis with Nasal Polyps (CRSwNP) in the United States is estimated at roughly 4%, which equates to over 13 million Americans. Until recently, the only medical treatment options available for patients with CRSwNP were corticosteroids, with surgery reserved for medical failure. The development of biologic medications over the last 5 years has revolutionized the treatment of CRSwNP. Three biologic medications have been FDA approved and available for the treatment of CRSwNP: dupilumab, omalizumab, and mepolizumab. However, data from the clinical trials for these drugs do not show universal improvement across all patients with CRSwNP. In fact, there is a wide range of outcomes for patients in these trials. The result is that clinicians have no way of knowing which specific biologic would be the best option for any given patient, nor do they know whether biomarkers can be used to predict response to biologics. It is hoped that findings from this study will inform whether any one biologic has superior outcomes to another and whether clinicians can identify patients at baseline who are most likely to improve on biologic therapy.

Inclusion Criteria:

• Age > 18 years
• Confirmed diagnosis of chronic rhinosinusitis with nasal polyposis using ICAR-21 (International Consensus Statement 20215) criteria
• Bilateral nasal polyposis visible on sinonasal endoscopy
• Nasal polyp score > 5
• Baseline SNOT-22 total score > 30
• Patient elects biologic therapy for the management of CRSwNP
• Capable of receiving all 3 biologic therapy medications.
• Treatment with intranasal mometasone ≥200 μg. once daily (or equivalent of another intranasal corticosteroid) for 1-month prior to baseline visit.

Exclusion Criteria:

• Inability or unwillingness of a participant to give written informed consent or comply with study protocol
• Endoscopic sinus surgery within 6-months preceding enrollment / randomization.
• Oral corticosteroid use within 30-days preceding enrollment / randomization.
• Serum IgE level outside the dosing range for omalizumab (i.e., <30 IU/ml. or a weight-based dose with insufficient data to determine dose as per FDA dosing chart)
• Comorbid atopic dermatitis, urticaria, or any other condition that would require a specific biologic per the standard of care.
• Currently pregnant or plan to become pregnant within the 6 months after enrollment / randomization.
• Any previous treatment with any of the 3 biologic medications.
• Comorbid cystic fibrosis, CVID, or ciliary dyskinesia.
• Comorbid systemic inflammatory disorders (e.g., GPA, EGPA, Sarcoidosis, SLE)
• Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks for participation in the study, may interfere with the participant's ability to comply with study requirements, or that may impact the quality or interpretation of the data obtained from the study.

The laboratory analyzing the samples will be blinded to the intervention