Chronic Rhinosinusitis with Nasal Polyps — Structured Data

AI-optimized single page. All data for Chronic Rhinosinusitis with Nasal Polyps in dense, structured format. Last updated: 2026-03-09.

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Key Statistics

Total reported cases: Unknown
Mean onset age: 42 years
Onset range: 20–70 years
Sex ratio (M:F): 1.5:1
Diagnostic delay: ~3 years
Discovered: 1000 (Ancient Egyptian physicians (earliest surgical descriptions))
Prevalence: <1/1,000,000
Classification: inflammatory, otorhinolaryngologic
Pathophysiology: partially understood
Treatment status: effective options available
Genetic basis: under investigation
Aliases: CRSwNP, Nasal Polyposis, Eosinophilic CRS

Symptoms (12)

Symptom	Frequency	Severity	Category	Description
Nasal obstruction/congestion	95%	cardinal	sinonasal	Bilateral nasal blockage, often progressive and unresponsive to decongestants. Worse on lying down. Most bothersome symptom reported by patients.
Anosmia/hyposmia	85%	cardinal	sinonasal	Loss or reduction of smell is a hallmark feature, often the earliest and most distressing symptom. Strongly correlates with eosinophilic inflammation and polyp burden. May persist after surgery without biologic therapy.
Anterior/posterior rhinorrhea	80%	major	sinonasal	Thick, mucopurulent or clear nasal discharge. Posterior nasal drip causes throat clearing and cough.
Facial pain/pressure	60%	major	sinonasal	Dull pressure over cheeks, forehead, or between eyes. Less prominent in CRSwNP than in CRS without polyps.
Impaired quality of life	90%	major	systemic	SNOT-22 scores significantly elevated. Sleep disturbance, fatigue, and reduced productivity. Impact comparable to COPD and heart failure.
Taste dysfunction	70%	major	sinonasal	Closely linked to anosmia. Reduced flavour perception significantly impacts nutrition and quality of life.
Sleep disturbance	75%	major	systemic	Mouth breathing, snoring, and obstructive sleep apnoea secondary to nasal obstruction.
Blood eosinophilia	70%	major	laboratory	Peripheral blood eosinophils >300 cells/μL in majority of patients. Correlates with disease severity and recurrence risk.
Elevated total IgE	55%	minor	laboratory	Serum total IgE often elevated, reflecting type 2 immune activation. Local polyp IgE may be elevated even with normal serum levels.
Headache	50%	minor	sinonasal	Secondary to sinus obstruction and mucosal congestion. Often worse on bending forward.
Comorbid asthma symptoms	50%	minor	respiratory	Approximately 50% of CRSwNP patients have comorbid asthma. Unified airway concept — upper and lower airway inflammation are linked.
Ear fullness/hearing changes	20%	minor	otologic	Eustachian tube dysfunction from nasopharyngeal inflammation and oedema.

Molecular Pathway (13 molecules)

Molecule	Role	Expression change	Evidence level	Targeted by	Explanation
IL-4	Type 2 master cytokine	Elevated	established	Dupilumab (via IL-4Rα blockade)	IL-4 drives B-cell class switching to IgE, promotes Th2 differentiation, and upregulates VCAM-1 for eosinophil recruitment. Signals through IL-4Rα/JAK1/STAT6. Dupilumab blocks IL-4 signalling by targeting IL-4Rα.
IL-13	Effector cytokine / tissue remodeller	Elevated	established	Dupilumab (via IL-4Rα blockade)	IL-13 drives goblet cell hyperplasia, MUC5AC mucus production, epithelial barrier disruption, and subepithelial fibrosis. Shares IL-4Rα receptor with IL-4. Central to polyp tissue remodelling and oedema formation.
IL-5	Eosinophil survival factor	Elevated	established	Mepolizumab, Benralizumab (via IL-5Rα)	IL-5 is the master regulator of eosinophil biology: drives maturation, tissue recruitment, activation, and survival. Elevated IL-5 correlates with polyp recurrence. Targeted by mepolizumab and indirectly by benralizumab.
IgE	Allergic effector immunoglobulin	Elevated (local and systemic)	established	Omalizumab	Polyclonal IgE is produced locally within polyp tissue independent of systemic atopy. IgE activates mast cells and basophils, amplifying type 2 inflammation. S. aureus superantigens drive polyclonal IgE. Targeted by omalizumab.
TSLP	Epithelial alarmin	Elevated	strong	Tezepelumab (investigational)	Released by damaged epithelial cells. Activates dendritic cells and ILC2s, initiating the type 2 cascade. An upstream target being investigated for CRSwNP therapy (tezepelumab).
IL-33	Epithelial alarmin	Elevated	strong	Itepekimab (investigational anti-IL-33)	Released from necrotic epithelial cells. Binds ST2 receptor on ILC2s and Th2 cells, powerfully amplifying IL-5 and IL-13 production. A key upstream driver of type 2 inflammation.
IL-25	Epithelial alarmin	Elevated	moderate	—	Third epithelial alarmin. Activates ILC2s and Th2 cells. Works synergistically with IL-33 and TSLP to sustain type 2 inflammation.
ILC2s	Innate type 2 lymphoid cells	Expanded in polyp tissue	strong	—	ILC2s are the innate counterpart of Th2 cells. They respond to alarmins (IL-33, IL-25, TSLP) by producing large amounts of IL-5 and IL-13 without antigen-specific activation. Critical for initiating and sustaining eosinophilic inflammation.
Eosinophils	Effector granulocytes	Massively infiltrated in tissue	established	Mepolizumab, Benralizumab	Tissue eosinophilia is the hallmark of CRSwNP. Eosinophils release MBP, ECP, EDN, and EPO — cytotoxic proteins that damage epithelium and perpetuate inflammation. Eosinophil counts in polyps correlate with recurrence.
Periostin	Extracellular matrix protein	Elevated	moderate	—	Produced by epithelial cells and fibroblasts under IL-4/IL-13 stimulation. Promotes eosinophil adhesion and tissue remodelling. Potential biomarker for type 2 inflammation severity.
MUC5AC	Gel-forming mucin	Upregulated	strong	—	IL-13 drives MUC5AC overexpression in goblet cells, causing the thick mucus secretion characteristic of CRSwNP. Contributes to sinus obstruction and mucus plug formation.
S. aureus enterotoxins	Superantigen / disease perpetuator	Present in polyp tissue	strong	—	Staphylococcus aureus enterotoxins act as superantigens, driving polyclonal T-cell activation and local IgE production within polyps. Create a self-sustaining inflammatory niche independent of systemic allergy.
Eotaxin-3 (CCL26)	Eosinophil chemoattractant	Elevated	strong	—	IL-4/IL-13 induce eotaxin-3 production by epithelial cells. Eotaxin-3 is the most potent eosinophil chemoattractant and correlates with tissue eosinophilia in polyps.

Genetic Findings (6)

Gene	Variant	Type	Frequency in disease	Significance	Also found in
HLA-DQA1/HLA-DRB1	Multiple alleles (6p21)	germline	Strongest GWAS signal	HLA region shows the most replicated association with CRSwNP. Specific alleles influence antigen presentation and T-cell polarisation toward type 2 responses.	Asthma (Overlapping alleles); Allergic rhinitis (Partial overlap)
ALOX5 / LTC4S / CYSLTR1-2	Promoter and coding variants	germline	Enriched in AERD subtype	Leukotriene pathway gene variants alter cysteinyl leukotriene synthesis and receptor signalling. Strongly associated with aspirin-exacerbated respiratory disease (AERD) — the triad of CRSwNP, asthma, and NSAID intolerance.	AERD/Samter's triad (Defining feature); Severe asthma (Subset)
IL33 / IL1RL1 (ST2)	Regulatory and coding SNPs	germline	GWAS-identified risk loci	IL-33 and its receptor ST2 are central to ILC2 activation and type 2 inflammation initiation. Genetic variants influence IL-33 expression and alarmin signalling.	Asthma (Major GWAS locus); Atopic dermatitis (Associated)
TSLP	Regulatory SNPs	germline	Associated in multiple GWAS	TSLP variants influence epithelial alarmin production. TSLP activates dendritic cells to drive Th2 polarisation and directly activates ILC2s.	Asthma (Well-established); Eosinophilic esophagitis (Associated)
SPINK5 (LEKTI)	Missense and regulatory variants	germline	Candidate gene association	SPINK5 encodes a serine protease inhibitor critical for epithelial barrier integrity. Variants lead to increased protease activity and barrier disruption.	Netherton syndrome (Causative (biallelic)); Atopic dermatitis (Associated)
Epigenetic modifications	DNA methylation changes at IL-13, IL-5, FOXP3 loci	unknown	Broadly observed in polyp tissue	Hypomethylation at type 2 cytokine loci and hypermethylation at regulatory T-cell loci (FOXP3) in polyp tissue. Suggests environmental epigenetic programming may be more important than germline variants.	—

Treatment Evidence Matrix (10 treatments)

Drug	Mechanism	Route	Response rate	Onset	IgM effect	Line	Explanation
Dupilumab	Anti–IL-4Rα monoclonal antibody (blocks IL-4 and IL-13)	SC 300mg every 2 weeks	~75% polyp reduction	4–8 weeks	Reduces polyp score by ~2 points (NPS)	1st-line biologic	Blocks both IL-4 and IL-13 signalling via IL-4Rα. SINUS-24 and SINUS-52 trials demonstrated significant improvements in nasal polyp score (NPS), nasal congestion, Lund-Mackay CT score, SNOT-22, and olfaction (UPSIT). FDA-approved 2019. The most broadly effective biologic with consistent benefit across multiple outcomes.
Omalizumab	Anti-IgE monoclonal antibody	SC every 2–4 weeks (dose by IgE/weight)	Significant NPS reduction	4–8 weeks	Reduces polyp score	1st-line biologic	Binds free IgE, preventing mast cell/basophil activation. POLYP 1 and POLYP 2 trials showed significant NPS improvement, reduced congestion, and improved SNOT-22. FDA-approved 2020 for CRSwNP. May be preferred in patients with high IgE and comorbid allergic asthma.
Mepolizumab	Anti–IL-5 monoclonal antibody	SC 100mg every 4 weeks	Significant NPS reduction	4–8 weeks	Reduces polyp score	1st-line biologic	Neutralises IL-5, reducing eosinophil maturation and survival. SYNAPSE trial demonstrated significant reduction in polyp size and need for surgery. FDA-approved 2021 for CRSwNP. May be preferred in patients with high eosinophil counts and comorbid eosinophilic asthma.
Benralizumab	Anti–IL-5Rα monoclonal antibody (ADCC-mediated eosinophil depletion)	SC 30mg every 4–8 weeks	Near-complete eosinophil depletion	4 weeks	Reduces polyp score	1st-line biologic	Binds IL-5Rα and induces antibody-dependent cellular cytotoxicity (ADCC), depleting eosinophils and basophils. OSTRO trial showed significant NPS and congestion improvement. FDA-approved 2024 for CRSwNP. Unique mechanism achieving near-complete tissue eosinophil depletion.
Intranasal corticosteroids	Topical anti-inflammatory	Intranasal daily (mometasone, fluticasone, budesonide)	Modest polyp reduction	Weeks–months	Modest polyp reduction	1st	First-line medical therapy for all CRSwNP patients. Suppress local inflammation and can modestly reduce polyp size. Most effective as maintenance therapy after surgery or alongside biologics. Budesonide rinses may provide better sinus distribution than sprays.
Oral corticosteroids (short course)	Systemic anti-inflammatory	Oral prednisone 25–50mg, 5–14 day taper	Rapid polyp shrinkage	Days	Rapid temporary reduction	Rescue	Rapid but temporary polyp reduction. EPOS 2020 recommends limiting to 1–2 courses per year due to cumulative toxicity (osteoporosis, diabetes, adrenal suppression, cataracts). Frequent need for oral steroids is an indication for biologic therapy.
Functional endoscopic sinus surgery (FESS)	Surgical polyp removal and sinus drainage	Endoscopic surgery under GA	Immediate symptom relief	Immediate	Complete polyp removal (temporary)	1st (surgical)	Gold standard surgical approach. Removes polyps, opens sinus ostia, and restores drainage. Significant symptom improvement in 80–90% of patients. However, polyp recurrence affects 40–80% of patients, with 25% requiring revision surgery. Best combined with ongoing medical/biologic therapy.
Saline nasal irrigation	Mechanical clearance / mucosal hydration	Nasal irrigation 1–2x daily	Symptom improvement	Days–weeks	No direct effect	Adjunctive	High-volume saline irrigation improves mucociliary clearance and reduces symptom scores. Recommended as adjunctive therapy in all CRSwNP patients by EPOS 2020. Low cost, no side effects.
Leukotriene receptor antagonists	CysLT1 receptor blockade (montelukast)	Oral 10mg daily	Modest in AERD subtype	Weeks	Minimal	Adjunctive	Most effective in AERD subtype where cysteinyl leukotriene overproduction drives disease. Montelukast can reduce polyp size and improve symptoms in this subset. Limited efficacy in non-AERD CRSwNP.
Aspirin desensitisation	COX-1 tolerance induction	Oral escalating doses then daily maintenance	Effective in AERD	Weeks	Slows polyp regrowth	AERD-specific	Specifically for AERD patients. Gradual aspirin dose escalation followed by daily maintenance (325–650mg) reduces polyp recurrence and need for revision surgery. Requires specialist supervision.

Diagnostic Criteria

EPOS 2020 Criteria (2020)

Major criteria (all required)

≥2 sinonasal symptoms (nasal obstruction, rhinorrhea, facial pain/pressure, anosmia) for ≥12 weeks
Bilateral nasal polyps visible on endoscopy

Minor criteria (0+ required)

Mucosal changes on CT (Lund-Mackay score >0)
Blood eosinophils >250 cells/μL
Total IgE >100 IU/mL
Comorbid asthma
Comorbid NSAID-exacerbated respiratory disease

Diagnosis requires both major criteria. Minor criteria help classify endotype severity and guide biologic eligibility. CT is not required for diagnosis but aids surgical planning. EPOS 2020 introduced the concept of 'uncontrolled CRSwNP' to identify candidates for biologic therapy.

Biologic Eligibility Criteria (EPOS 2020) (2020)

Major criteria (all required)

Bilateral polyps (NPS ≥5 of 8) AND
≥3 criteria: type 2 inflammation (tissue eos ≥10/HPF or blood eos ≥250 or IgE ≥100), need for ≥2 systemic steroid courses/year, significantly impaired QoL (SNOT-22 ≥40), significant smell loss, comorbid asthma

Minor criteria (0+ required)

Prior sinus surgery without adequate control
Lund-Mackay CT score ≥12

Defines 'uncontrolled CRSwNP' for biologic eligibility. All major criteria required. Represents patients failing standard medical and/or surgical therapy.

Differential Diagnoses (7)

Condition	Key distinction	Shared features
CRS without Nasal Polyps (CRSsNP)	No visible polyps on endoscopy. Predominantly neutrophilic/Th1 inflammation. Less eosinophilic. Different treatment approach.	Nasal obstruction, Rhinorrhea, Facial pain, CT opacification
Allergic Fungal Rhinosinusitis (AFRS)	Eosinophilic mucin with fungal hyphae. Unilateral or asymmetric. Markedly elevated specific fungal IgE. Bone erosion possible.	Nasal polyps, Eosinophilia, Elevated IgE, CT opacification
Antrochoanal polyp	Unilateral large polyp arising from maxillary sinus extending to nasopharynx. Non-eosinophilic. Typically young patients.	Nasal obstruction, Visible polyp
Inverted papilloma	Unilateral. Benign but locally aggressive neoplasm. Malignant transformation risk (5–15%). Requires complete surgical excision.	Unilateral nasal mass, Nasal obstruction
Eosinophilic Granulomatosis with Polyangiitis (EGPA)	Systemic vasculitis with marked eosinophilia, asthma, and nasal polyps. ANCA may be positive. Multi-organ involvement (neuropathy, cardiac, renal).	Nasal polyps, Asthma, Eosinophilia
Cystic fibrosis	Bilateral polyps in children/young adults. Thick mucus. Sweat chloride test positive. CFTR mutations.	Bilateral nasal polyps, Chronic sinusitis, Nasal obstruction
Sinonasal malignancy	Unilateral obstruction, epistaxis, pain. Mass on imaging with bone destruction. Biopsy diagnostic.	Nasal obstruction, Sinonasal mass

Hypotheses (6)

Hypothesis	Domain	Status	Evidence score	Studies	Evidence for	Evidence against
Epithelial barrier dysfunction is the primary initiating event, with alarmin release driving type 2 polarisation	pathogenesis	leading	70/100	120	Epithelial tight junction defects precede polyp formation Alarmins (IL-33, TSLP, IL-25) are elevated in early-stage disease Barrier function genes (SPINK5, CDHR3) are genetic risk loci Environmental triggers (pollution, microbes) damage epithelium first	Some patients have normal epithelial function Barrier defects may be consequence rather than cause Does not explain why only some people with barrier defects develop polyps
CRSwNP is a unified airway disease — upper and lower airway inflammation share common type 2 mechanisms	pathogenesis	leading	65/100	150	50% comorbid asthma prevalence Shared type 2 biomarkers (eosinophils, IgE, IL-5) Biologics simultaneously improve both nasal and asthma outcomes Common genetic risk loci (IL33, TSLP, IL13)	Not all CRSwNP patients have asthma Sinonasal-only inflammation exists Some treatments work differently in upper vs lower airways
Eosinophil-mediated tissue damage creates a self-perpetuating inflammatory cycle	pathogenesis	competing	60/100	90	Tissue eosinophilia is the strongest predictor of recurrence Eosinophil granule proteins (MBP, ECP) damage epithelium Anti-IL-5 therapies reduce polyps by depleting eosinophils Eosinophil extracellular traps found in polyp tissue	Eosinophil depletion alone does not resolve all inflammation Non-eosinophilic CRSwNP exists (especially in East Asia) Eosinophils may have tissue-repair roles
Endotype classification (type 2 vs non-type 2) should guide treatment selection	treatment	leading	60/100	100	Biologic responders are enriched in type 2 biomarker-high patients East Asian CRSwNP has higher proportion of non-type 2 disease EPOS 2020 recommends endotype-based treatment approach Composite biomarker scores predict biologic response	No validated algorithm for biologic selection yet Overlap between endotypes is substantial Biomarker cutoffs remain debated
Staphylococcus aureus superantigens drive local immune activation and disease persistence	pathogenesis	competing	55/100	80	S. aureus colonisation rates >60% in CRSwNP Enterotoxin-specific IgE found in polyp tissue Superantigens drive polyclonal T-cell and B-cell activation Local IgE production occurs independent of systemic atopy	Not all CRSwNP patients are S. aureus colonised Anti-staphylococcal therapies have not shown consistent benefit May be consequence of barrier defect rather than primary cause
Epigenetic reprogramming by environmental exposures shapes disease susceptibility	genetics	emerging	30/100	25	DNA methylation changes at IL-13, IL-5, FOXP3 loci in polyp tissue Air pollution exposure correlates with CRSwNP incidence Smoking alters sinonasal epigenome Microbiome composition influences local epigenetic landscape	Cause vs consequence unclear Limited longitudinal studies Epigenetic changes are tissue-specific and may not be generalisable

Open Questions (6)

Why do only some CRS patients develop nasal polyps?
CRS without polyps (CRSsNP) and CRSwNP share the same sinuses but have fundamentally different inflammatory profiles. What tips the balance toward polyp formation?
How should biologics be selected and sequenced for individual patients?
Four approved biologics target different molecules. No head-to-head trials exist. Biomarker-driven selection is theoretically attractive but unvalidated prospectively.
Can biologics achieve disease remission or only suppression?
Most trials show polyp regrowth upon biologic discontinuation. Whether long-term treatment can fundamentally reset the immune environment is unknown.
What drives the geographic variation in CRSwNP endotypes?
Western CRSwNP is predominantly eosinophilic/type 2, while East Asian CRSwNP historically had more neutrophilic/non-type 2 disease — though this is shifting toward Western patterns with urbanisation.
What is the role of the sinonasal microbiome in disease initiation and persistence?
S. aureus colonisation is associated with severe disease, but whether dysbiosis is cause or consequence remains debated. Microbiome-targeted therapies are unexplored.
Can upstream alarmin blockade (anti-TSLP, anti-IL-33) prevent disease rather than just suppress it?
Current biologics target downstream effectors. Blocking epithelial alarmins might intervene earlier in the cascade and potentially modify disease course.

Complications (6)

Complication	Risk	Timeframe	Description	Monitoring
Polyp recurrence after surgery	40–80%	18 months post-FESS	The central challenge in CRSwNP management. Eosinophilic polyps recur in 40–80% of patients. Higher blood eosinophils, comorbid asthma, and AERD predict faster recurrence.	Regular nasal endoscopy every 3–6 months post-surgery
Obstructive sleep apnoea	20–30%	—	Chronic nasal obstruction leads to obligate mouth breathing and increased upper airway collapsibility during sleep.	Sleep quality assessment; polysomnography if symptomatic
Asthma exacerbation	50% have comorbid asthma	Ongoing	CRSwNP and asthma worsen in parallel. Polyp burden correlates with asthma control. Biologics improve both simultaneously.	Regular asthma control assessment (ACQ/ACT); spirometry
Orbital complications (rare)	<1%	—	Acute sinusitis superimposed on CRSwNP can cause orbital cellulitis, subperiosteal abscess. Requires urgent intervention.	Urgent ophthalmology referral if periorbital swelling, diplopia, or proptosis
Anosmia-related depression	Variable	—	Persistent smell loss significantly impacts quality of life, nutrition, and safety (inability to detect gas leaks, fire). Associated with depression and social isolation.	SNOT-22; olfactory testing (UPSIT); mental health screening
Systemic corticosteroid toxicity	Dose-dependent	Cumulative over years	Repeated oral steroid courses cause osteoporosis, diabetes, cataracts, adrenal suppression, weight gain. A major driver of the shift toward biologic therapy.	Bone density; HbA1c; adrenal function; ophthalmology review

Sources (28)

Ref	Authors	Title	Journal	Year	Category	Type	Grade	Link
E1	Min JY, et al.	Global incidence and prevalence of chronic rhinosinusitis: a systematic review	Clin Exp Allergy	2025	epidemiology	systematic review	A	DOI
P5	Takeda K, et al.	Eosinophil contribution to tissue remodelling in CRSwNP	Front Immunol	2024	pathophysiology	narrative review	B	DOI
T4	Bachert C, Han JK, Wagenmann M, et al.	Efficacy and safety of benralizumab in CRSwNP (OSTRO): randomised, placebo-controlled, phase 3 trial	Lancet	2024	treatment	RCT	A	DOI
R3	Zhu Y, et al.	IL-4/IL-13 pathway in nasal type 2 inflammation: the central role and targeted therapy	Eye ENT Res	2024	pathophysiology	narrative review	B	DOI
T3	Han JK, Bachert C, Fokkens W, et al.	Mepolizumab for CRSwNP (SYNAPSE): a randomised, double-blind, placebo-controlled, phase 3 trial	Lancet Respir Med	2021	treatment	RCT	A	DOI
P1	Bachert C, et al.	EPOS 2020: endotype-based severity and treatment of CRSwNP	Rhinology	2020	pathophysiology	expert opinion	B	DOI
G1	Oakley GM, et al.	HLA associations in chronic rhinosinusitis	Int Forum Allergy Rhinol	2020	genetics	GWAS	B	DOI
G2	Portelli MA, et al.	Genetic risk factors for CRSwNP: IL-33/ST2 and TSLP pathway variants	J Allergy Clin Immunol	2020	genetics	GWAS	B	DOI
D2	Fokkens WJ, et al.	European Position Paper on Rhinosinusitis and Nasal Polyps 2020 (EPOS 2020)	Rhinology	2020	diagnostics	clinical guideline	A	DOI
D1	Fokkens WJ, Lund VJ, Hopkins C	EPOS 2020: clinical symptoms, endoscopic findings, and CT scoring	Rhinology	2020	diagnostics	clinical guideline	A	DOI
T2	Gevaert P, Omachi TA, Corren J, et al.	Efficacy and safety of omalizumab in nasal polyposis: POLYP 1 and POLYP 2 trials	J Allergy Clin Immunol	2020	treatment	RCT	A	DOI
T5	Fokkens WJ, et al.	EPOS/EUFOREA 2020 treatment algorithm for CRSwNP	Rhinology	2020	treatment	clinical guideline	A	DOI
T6	Hopkins C, et al.	Long-term outcomes of endoscopic sinus surgery for CRSwNP	Laryngoscope	2020	treatment	cohort	B	DOI
R1	Bachert C, et al.	Biologics for chronic rhinosinusitis with nasal polyps	J Allergy Clin Immunol	2020	reviews	narrative review	B	DOI
G4	Kowalski ML, et al.	Epithelial barrier genes SPINK5 and PCDH1 in CRSwNP susceptibility	Allergy	2019	genetics	candidate gene	C	—
G5	Cardenas A, et al.	Epigenomic profiling of nasal polyp tissue reveals type 2 inflammation signatures	J Allergy Clin Immunol	2019	genetics	cohort	C	DOI
T1	Bachert C, Han JK, Desrosiers M, et al.	Efficacy and safety of dupilumab in patients with severe CRSwNP (LIBERTY NP SINUS-24 and SINUS-52)	Lancet	2019	treatment	RCT	A	DOI
T7	Laidlaw TM, et al.	Aspirin desensitisation in AERD: outcomes and protocols	J Allergy Clin Immunol Pract	2019	treatment	cohort	B	DOI
R2	Khan A, et al.	The GALEN/GA2LEN survey: global CRSwNP burden and unmet need	Allergy	2019	reviews	narrative review	B	DOI
G3	Laidlaw TM, Boyce JA	Aspirin-exacerbated respiratory disease — genetic and molecular mechanisms	N Engl J Med	2016	genetics	narrative review	B	DOI
E3	Stevens WW, et al.	Clinical characteristics of CRSwNP in the United States	J Allergy Clin Immunol Pract	2016	epidemiology	cohort	B	DOI
P2	Bachert C, Zhang N, Hellings PW, Bousquet J	Endotype-driven care pathways in patients with chronic rhinosinusitis	J Allergy Clin Immunol	2015	pathophysiology	narrative review	B	DOI
D3	Rudmik L, et al.	Quality of life burden in CRSwNP: SNOT-22 and disease impact	Rhinology	2015	diagnostics	cohort	B	PubMed
P4	Nagarkar DR, et al.	Airway epithelial alarmins in CRSwNP: IL-33, IL-25, and TSLP	J Allergy Clin Immunol	2013	pathophysiology	cohort	B	DOI
P3	Bachert C, et al.	Staphylococcus aureus enterotoxins as immune stimulants in CRSwNP	Allergy	2012	pathophysiology	cohort	B	DOI
P6	Bachert C, et al.	Superantigen-driven polyclonal immune activation in CRSwNP	Am J Respir Crit Care Med	2005	pathophysiology	cohort	B	DOI
D4	Togias A	Rhinitis and asthma: evidence for respiratory system integration	J Allergy Clin Immunol	2003	epidemiology	narrative review	B	DOI
E2	Settipane GA, Chafee FH	Nasal polyps in asthma and rhinitis: prevalence study	J Allergy Clin Immunol	1977	epidemiology	cohort	B	PubMed

Pathophysiology Narrative

CRSwNP is driven by type 2 inflammation — a self-amplifying immune cascade centred on eosinophils, Th2 cells, and type 2 innate lymphoid cells (ILC2s).

The process begins at the epithelial barrier. Damaged or dysfunctional epithelial cells release alarmins — IL-25, IL-33, and TSLP — in response to allergens, microbes, pollutants, or Staphylococcus aureus superantigens. These alarmins activate ILC2s, which produce large quantities of IL-5 and IL-13 without requiring antigen-specific priming.

IL-5 is the master regulator of eosinophils: it drives eosinophil maturation in bone marrow, recruits them to tissue, and prolongs their survival. Tissue eosinophils release cytotoxic granule proteins (MBP, ECP, EDN) that damage the epithelium, perpetuating alarmin release in a vicious cycle.

IL-4 and IL-13 activate the IL-4Rα/JAK1/STAT6 signalling axis, inducing B-cell class switching to IgE, goblet cell hyperplasia, mucus hypersecretion (via MUC5AC upregulation), and epithelial barrier disruption. Local IgE production within polyp tissue — often polyclonal and independent of systemic atopy — activates mast cells and further amplifies inflammation.

IL-13 also drives tissue remodelling: fibrin deposition, oedema formation, and pseudocyst development that characterise polyp architecture. Together with TGF-β, it promotes subepithelial fibrosis.

Staphylococcus aureus enterotoxins act as superantigens, driving polyclonal T-cell and B-cell activation within polyp tissue. This creates a 'local immune factory' with self-sustaining IgE production, contributing to disease persistence even after surgical removal.

The epithelial barrier defect is both cause and consequence: tight junction disruption (reduced occludin, claudins) allows pathogen penetration, while eosinophil-mediated damage prevents repair — establishing the chronicity that defines CRSwNP.

Genetic Basis Narrative

CRSwNP is a complex polygenic disease with no single causative gene. Genome-wide association studies (GWAS) and candidate gene studies have identified multiple susceptibility loci, but the genetic architecture is characterised by many variants of small effect.

The HLA region on chromosome 6p21 shows the strongest and most replicated association. Specific HLA-DQA1 and HLA-DRB1 alleles are associated with increased risk, particularly in patients with comorbid asthma and aspirin-exacerbated respiratory disease (AERD).

Leukotriene pathway genes are implicated in AERD: variants in ALOX5 (5-lipoxygenase), LTC4S (leukotriene C4 synthase), and CYSLTR1/2 (cysteinyl leukotriene receptors) alter leukotriene synthesis and signalling, contributing to the aspirin-intolerant phenotype.

Barrier function genes including SPINK5 (encoding LEKTI, a serine protease inhibitor), PCDH1 (protocadherin-1), and CDHR3 contribute to epithelial barrier susceptibility.

Cytokine and immune regulatory variants in IL33, IL1RL1 (encoding IL-33 receptor ST2), TSLP, IL13, and IL4R have been associated with CRSwNP risk, linking genetic susceptibility directly to the type 2 inflammatory axis.

Recent whole-exome and epigenomic studies have revealed that DNA methylation changes at type 2 inflammation loci may be more important than sequence variants, suggesting that epigenetic dysregulation — potentially driven by environmental exposures — plays a major role.