Previous Article in Journal
High Dietary Salt Exposure During Sensitization Is Associated with Increased Severity of Allergic Contact Dermatitis in Mice
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Allergies
Volume 6
Issue 2
10.3390/allergies6020014
allergies-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Allergic Chronic Rhinosinusitis: Myth, Misnomer, or Missing Endotype?

by
George N. Konstantinou
1,* and
Konstantinos Petalas
2
1
Department of Allergy and Clinical Immunology, 424 General Military Training Hospital, 56429 Thessaloniki, Greece
2
Department of Allergy and Clinical Immunology, 251 General Air Force Hospital, 11525 Athens, Greece
*
Author to whom correspondence should be addressed.
Allergies 2026, 6(2), 14; https://doi.org/10.3390/allergies6020014
Submission received: 22 February 2026 / Revised: 13 March 2026 / Accepted: 27 March 2026 / Published: 14 April 2026
(This article belongs to the Section Rhinology/Allergic Rhinitis)
Browse Figure
Versions Notes

Abstract

Chronic rhinosinusitis (CRS) is a heterogeneous inflammatory syndrome of the sinonasal mucosa that is imperfectly captured by phenotypes with or without nasal polyps. Since allergic rhinitis (AR) and atopy often occur alongside CRS, the term “allergic CRS” is commonly used. However, it is uncertain whether this term indicates a specific allergen-related, IgE-mediated endotype or merely represents a clinical overlap. We synthesize epidemiologic data, mucosal immunobiology, epithelial barrier dysfunction, and host–microbe interactions that can generate IgE-rich type 2 inflammation in CRS. We propose an operational entity test (objective CRS; clinically relevant allergy; evidence of IgE relevance in target tissue; exposure–response patterns; and differential response to allergy-directed interventions) to guide hypothesis testing rather than diagnosis. Using this framework, allergic fungal rhinosinusitis and central compartment atopic disease emerge as the clearest clinical prototypes where allergen contact patterns and IgE relevance plausibly contribute to disease expression. In contrast, microbial superantigens and other non-allergen stimuli can drive local IgE amplification, limiting the specificity of systemic sensitization as a causal marker. We discuss therapeutic implications, including biologics targeting type 2 pathways and epithelial alarmin blockade, and outline research priorities for endotype-resolved cohorts and mechanism-informed trials to test whether allergic CRS should evolve from a heuristic descriptor into a validated endotype.

1. Introduction

Chronic rhinosinusitis (CRS) is a chronic inflammatory disorder of the nose and paranasal sinuses defined by persistent symptoms for ≥12 weeks together with objective evidence of sinonasal mucosal disease on nasal endoscopy and/or computed tomography (CT) imaging [1,2]. Historically, CRS has been divided into phenotypes with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP), but both categories encompass multiple inflammatory mechanisms and clinical trajectories [1,2,3,4,5,6].
Endotyping efforts have therefore focused on defining biologically coherent disease subsets (e.g., type 2-high, eosinophilic, IgE-rich inflammation) that better predict prognosis and treatment response than anatomy alone [3,4,5,6]. Within this context, the label “allergic CRS” is frequently used in clinical discussion, often as shorthand for ‘type 2-high CRS’ or for CRS coexisting with allergic rhinitis (AR) [7]. However, type 2 inflammation in CRS can be sustained by non-allergen drivers. This challenges the specificity of allergy as a causal explanation for CRS.
In this article, we treat “allergic CRS” as a testable mechanistic hypothesis rather than a diagnosis: a subset of CRS in which environmental allergens drive clinically meaningful sinonasal inflammation through IgE-mediated pathways. For clarity, we use “allergic CRS” to denote a putative allergen-driven endotype, “IgE-rich CRS” to denote CRS with increased local and/or systemic IgE irrespective of antigen specificity, and “type 2 CRS” to denote IL-4/IL-5/IL-13/eosinophil-skewed inflammation that may be allergen-driven, superantigen-amplified, mixed, or non-allergen-driven [3,4,5,6]. We review epidemiologic associations, immunologic and epithelial biology, and host–microbe ecology relevant to this hypothesis, highlighting why association studies alone cannot establish causality. We then propose an operational ‘entity test’ framework to standardize evidence thresholds, identify plausible prototypes [notably allergic fungal rhinosinusitis (AFRS) and central compartment atopic disease (CCAD)], and define a research agenda.
Due to the complexities inherent in allergy assessment, we distinguish between systemic sensitization (positive skin prick testing or serum allergen-specific IgE), clinically relevant allergy, and local allergic rhinitis (LAR), in which patients may exhibit localized nasal IgE responses despite negative systemic testing [8,9]. Clinically, AR usually presents with sneezing, nasal itching, rhinorrhea, and variable nasal obstruction after relevant allergen exposure [8]. Systemic sensitization is also common in the general population [10]. These differences are important when the focus is on inflammation in a particular anatomical area, such as the sinonasal mucosa, rather than on atopy as a host characteristic. In this context, the LAR literature is conceptually relevant because it demonstrates that allergen-driven inflammation may remain compartmentalized to the nasal mucosa despite negative systemic testing [11,12].

2. Materials and Methods

This narrative review was designed as a focused, concept-driven synthesis rather than a systematic review. PubMed was searched for English-language literature published from January 2000 through December 2025 using combinations of terms related to chronic rhinosinusitis, nasal polyps, allergy, atopy, IgE, type 2 inflammation, local allergic rhinitis, allergic fungal rhinosinusitis, central compartment atopic disease, biologics, allergen immunotherapy, epithelial barrier dysfunction, biofilms, microbiome, and Staphylococcus aureus enterotoxins. Eligible sources included clinical studies, translational studies, consensus/guideline documents, and pivotal phase 3 therapeutic trials judged to be directly informative for the question of whether an allergen-driven CRS endotype exists. Studies were selected on the basis of conceptual relevance, methodological informativeness, and their ability to clarify causality, competing mechanisms, or therapeutic implications; primary evidence and major consensus documents were prioritized, and references were restricted to PubMed-indexed sources. The literature was screened and curated by the first author, with the second author reviewing the final study set and structure of the synthesis. In line with recommendations for higher-quality narrative reviews, we therefore aimed to make the search strategy, scope, and interpretive framework explicit, while not claiming the comprehensiveness or formal risk-of-bias workflow of a systematic review [13,14].

3. What Would Make “Allergic CRS” a Valid Endotype?

In endotype research, a label is scientifically useful only if it identifies a subgroup with reproducible biology that is causally linked to disease mechanisms and that meaningfully predicts outcomes or treatment response [3,4,5,6,7]. Applying this standard to “allergic CRS” requires more than demonstrating that patients with CRS are more likely to have positive allergy testing. Because sensitization is prevalent in the general population [10], the core question is whether allergen-specific IgE responses are relevant within the CRS target tissue and whether allergen exposure drives clinically meaningful sinonasal inflammation.
Therapeutic response can be one form of causal evidence, but the literature remains limited. A systematic review found weak, non-randomized evidence that allergen immunotherapy (AIT) may improve CRS outcomes—particularly in postoperative settings—yet robust endotype-stratified trials are lacking [15]. In CCAD, retrospective postoperative data suggest that patients receiving AIT may have less middle turbinate edema and improved endoscopic findings, but confounding cannot be excluded [16]. These data suggest that AIT can be a credible method for investigating mechanisms in specific, well-defined subgroups, rather than serving as definitive evidence that CRS is predominantly caused by allergens.
We therefore propose an operational ‘entity test’ for a putative allergic CRS endotype (Table 1). Table 1 is intended as a concise, practical summary of this framework that separates (i) required elements that define the syndrome and demonstrate clinically relevant allergy from (ii) supportive elements that increase the likelihood of allergen relevance in the sinonasal compartment, while clearly listing alternative explanations that can lead to IgE-rich type 2 inflammation without allergen involvement (e.g., microbial superantigen amplification, barrier dysfunction, and non-IgE type 2 entities). A conceptual schematic summarizing these hypothesized allergy–barrier–microbiome interactions across the atopic sinonasal spectrum is shown in Figure 1.
Two clinical prototypes illustrate how this framework can be applied. AFRS is widely viewed as an allergen-driven CRS subtype defined by eosinophilic mucin, fungal elements, and intense type 2 inflammation with local IgE responses [17,18,19,20]. CCAD is a more recently described CRSwNP phenotype characterized by polypoid edema centered in the middle/superior turbinates and central compartment structures, strongly associated with inhalant allergy and asthma [21,22,23,24,25]. These entities do not prove that a broader ‘allergic CRS’ endotype exists, but they provide test cases where allergen contact patterns, local IgE biology, and clinical phenotype reasonably match.
Table 1. Operational entity test framework for a putative “allergic CRS” endotype.
Table 1. Operational entity test framework for a putative “allergic CRS” endotype.
DomainOperational Criteria/Evidence Threshold
A1. Objective CRS (required)Symptoms for ≥12 weeks plus objective evidence of sinonasal inflammation on endoscopy and/or CT [1,2].
A2. Clinically relevant allergy (required)Sensitization confirmed by SPT or serum allergen-specific IgE with concordant history (seasonality/exposure). Consider LAR when systemic tests are negative but clinical suspicion is high [8,9,11,12].
A3. Type 2/IgE signal in CRS compartment (required)Evidence of type 2 inflammation in sinonasal disease (e.g., tissue eosinophilia, elevated IL-5/IL-13 signatures, local IgE). Note: supports type 2 endotyping but is not specific for allergen causality [3,4,5,6,7,26,27,28,29,30].
B1. Anatomic pattern consistent with allergen contact (supportive)Central compartment–predominant polypoid edema (middle/superior turbinates, posterosuperior septum) and/or central pattern of sinus disease, compatible with CCAD [21,22,23,24,25,31].
B2. AFRS features (supportive)Clinicopathologic features compatible with AFRS (eosinophilic mucin, fungal elements, characteristic imaging) [17,18,19,20].
B3. Evidence of allergen relevance in target tissue (supportive)Allergen-specific IgE detected in sinonasal secretions or tissue and/or markers consistent with local IgE generation (e.g., class-switch/receptor revision signatures). Distinguish from superantigen-amplified, non-allergen IgE (see Section 5) [32,33,34].
B4. Exposure–response coupling (supportive)Objective CRS worsening aligned with allergen exposure (seasonal/occupational) and improvement with validated avoidance strategies.
B5. Differential response to allergy-directed intervention (supportive)Improvement in CRS-specific outcomes with allergy-directed therapy (e.g., AIT in selected phenotypes) beyond expected benefit from standard CRS care; current evidence base is limited and phenotype-specific [15,16].
C. Competing explanations/confoundersFeatures suggesting alternate primary drivers (secondary CRS causes, AERD/N-ERD, superantigen-related IgE amplification, medication effects) that reduce specificity of an allergic endotype hypothesis [1,2,29,30,32,33,35,36].
Allergies 06 00014 g001
Figure 1. Conceptual schematic of hypothesized barrier–immune–microbiome interactions in atopic sinonasal inflammation. External allergens can drive IgE-mediated activation, while local microbiome dysbiosis and Staphylococcus aureus enterotoxins may amplify local IgE responses. Epithelial barrier dysfunction increases permeability and may facilitate antigen access and microbial colonization, while remodeling pathways (e.g., impaired fibrinolysis) can stabilize edema and polypoid change. Arrows indicate bidirectional, hypothesized associations rather than established causality or temporal sequence [32,33,34,37,38,39,40,41,42].
Figure 1. Conceptual schematic of hypothesized barrier–immune–microbiome interactions in atopic sinonasal inflammation. External allergens can drive IgE-mediated activation, while local microbiome dysbiosis and Staphylococcus aureus enterotoxins may amplify local IgE responses. Epithelial barrier dysfunction increases permeability and may facilitate antigen access and microbial colonization, while remodeling pathways (e.g., impaired fibrinolysis) can stabilize edema and polypoid change. Arrows indicate bidirectional, hypothesized associations rather than established causality or temporal sequence [32,33,34,37,38,39,40,41,42].
Allergies 06 00014 g001

4. Epidemiology: Signals, Confounders, and Why “Association” Is Not Enough

Epidemiologic studies evaluating allergy–CRS relationships are limited by heterogeneity in CRS definitions (symptom-based vs. objective criteria), selection bias (population vs. tertiary care cohorts), and confounding by asthma and other comorbidities. Population-based analyses illustrate that radiographic mucosal thickening is common and does not necessarily correlate with patient-reported symptoms, complicating case definitions [26,27]. Accordingly, the discussion below appraises studies not only for whether they report an association, but also for case definition, comparator choice, sample size, control of major comorbidities, and whether the measured signal is relevant to the target sinonasal compartment [1,2,26,27].
Across regions, CRS prevalence estimates vary widely, reflecting both true heterogeneity and methodological differences [26,27,28,29]. Large observational cohorts have consistently shown that asthma is a strong comorbidity of CRSwNP and that atopy/AR are common [29], but evidence that atopy independently predicts CRS severity or recurrence remains inconsistent and generally weak [30,31,35]. For example, one tertiary cohort found no association between atopy status and either disease severity or recurrence in CRSwNP [30], whereas other studies highlight phenotypic and immunologic heterogeneity across CRS subgroups rather than a uniform effect of atopy [31,35].
These data support two non-exclusive interpretations: (i) a true allergen-driven subset exists but is diluted within broad CRS case definitions; and/or (ii) systemic sensitization is a marker of a host milieu with type 2 propensity, rather than directly causing sinonasal inflammation. Both interpretations highlight the importance of endotype-specific study designs, which require objective disease definitions, standardized allergy phenotyping, and measurements of target-tissue biomarkers.

5. Mechanistic Substrate: Type 2 Immunity and IgE in CRS

Type 2 immunity (characterized by IL-4/IL-5/IL-13 signaling, eosinophilia, and IgE production) is a dominant inflammatory program in many CRSwNP cohorts, particularly in Western populations, but with substantial geographic variation [3,4,5,6,35,36]. This biology can arise from classical allergen-driven Th2 responses. However, in CRS it may also reflect epithelial alarmin signaling, innate lymphoid cell activation, and microbial stimuli.
IgE itself is a particularly ambiguous marker. Elevated total and tissue IgE are common in nasal polyps, but their antigen specificity can be polyclonal and may not necessarily be directed against inhalant allergens. Importantly, evidence indicates that B-cell activation occurs locally within polyp tissue, involving receptor revision and class switching to IgE directly in situ. This suggests that IgE responses are generated and diversified locally rather than passively passing from the serum [32].
Microbial superantigens provide a plausible non-allergen pathway for IgE amplification. In nasal polyps, IgE antibodies to Staphylococcus aureus enterotoxins have been associated with higher tissue total IgE, greater eosinophilic inflammation, and asthma comorbidity across European and Asian cohorts [33]. Reviews and experimental studies further support that staphylococcal enterotoxins can act as potent immunologic adjuvants and may promote a ‘type 2/IgE amplification’ loop within inflamed sinonasal mucosa [34].
Taken together, these findings suggest a significant refinement in understanding the allergic CRS hypothesis: demonstrating IgE-rich type 2 inflammation is not equivalent to demonstrating allergen causality. To support an allergen-driven endotype, studies should move beyond systemic sensitization to directly evaluate allergen-specific IgE and exposure–response relationships at the target-tissue level, while concurrently measuring alternative IgE drivers such as enterotoxin-specific IgE. The LAR literature offers a useful parallel for this problem: local allergen-specific reactivity can exist without systemic atopy, but proving this generally requires compartment-specific testing, with nasal allergen challenge/provocation regarded as the reference method and nasal specific IgE or basophil activation testing used as supportive tools rather than standalone routine diagnostics [11,12,43]. Even so, extrapolation from localized nasal mucosal reactivity to diffuse CRS should remain cautious, because nasal allergic reactivity does not by itself establish allergen causality within sinus tissue.

6. Barrier Dysfunction and Remodeling: A Gateway to Persistent Inflammation

Epithelial barrier dysfunction is increasingly recognized as a central feature across type 2 inflammatory diseases. In CRS, altered tight junction expression, mucus abnormalities, and impaired epithelial repair can increase permeability and antigen access, potentially lowering the threshold for both allergen and microbial stimulation [37,38]. Importantly, barrier dysfunction can be both a cause and a consequence of inflammation, creating circular causality challenges for endotyping.
Cytokine networks further shape barrier integrity. For example, oncostatin M has been implicated in epithelial barrier disruption in CRS, providing one mechanistic link between inflammatory signaling and increased epithelial permeability [38]. In parallel, emerging concepts such as ‘inflammatory memory’ suggest that epithelial cells may retain primed transcriptional states after allergen or pathogen exposures, potentially contributing to chronicity and relapse [39].
Tissue remodeling stabilizes disease expression once inflammation is established. Impaired fibrinolysis (e.g., reduced tissue plasminogen activator activity) and increased fibrin deposition have been linked to edema and polyp formation, offering a mechanism by which CRSwNP can become self-sustaining even if the initiating trigger attenuates [40,41]. Within an allergic CRS framework, remodeling is therefore best viewed as a downstream amplifier and stabilizer rather than as specific proof of allergen causation.

7. Host–Microbe Ecology: Dysbiosis, Biofilms, and Viral Modulation

The sinonasal microbiome is altered in CRS, but whether dysbiosis is a driver, a consequence, or both remains unresolved. This section focuses specifically on host–microbe ecology, including microbial community structure, biofilms, and superantigen-related amplification pathways that may perpetuate inflammation independently of classical inhalant allergy [42,44,45,46,47,48,49].
Several studies report reduced microbial diversity and depletion of presumed commensals in CRS, with enrichment of potential pathobionts, although patterns are not uniform across populations [44,45,46,47,48,49]. In CRSwNP, dysbacteriosis and biofilm formation may contribute to persistent inflammation by providing chronic antigenic stimulation and by shaping epithelial and immune responses. Importantly, ‘microbiome signals’ can also be confounded by disease severity and prior interventions, underscoring the need for longitudinal designs.
Interactions between atopy and the microbiome further complicate interpretation. Atopy has been associated with distinct nasal microbiome profiles in some cohorts [50], and eosinophilic CRS may show characteristic microbial shifts [51]. Related microbiome differences have also been described in N-ERD, another type 2-skewed CRS-associated entity that can confound interpretation of “allergic” signals [52]. Viral infections are also increasingly recognized as potential modulators of CRS biology, through effects on barrier integrity and innate immunity, although causal evidence remains limited [53].
For allergic CRS, the microbiome is relevant in at least two ways: (i) microbial products can amplify type 2/IgE inflammation (e.g., enterotoxin-specific IgE), and (ii) dysbiosis and biofilms may perpetuate epithelial stress and barrier dysfunction, increasing susceptibility to both allergen and microbial triggers. These pathways predict that ‘allergic CRS’—if it exists—will not be exclusively allergen-driven but will instead involve barrier–immune–microbiome interactions.

8. Prototypes and Constraints: Where an Allergic Mechanism Is Most (and Least) Plausible

Key prototypes across the proposed spectrum of atopic sinonasal disease, along with their supporting evidence, are summarized in Table 2.

8.1. Allergic Fungal Rhinosinusitis (AFRS): A Strong Prototype

AFRS is the most widely accepted example of an allergy-linked CRS subtype and is commonly defined by nasal polyposis, allergic mucin with eosinophilic debris, evidence of fungal elements, and characteristic radiographic findings [17,18,19,20]. Although there is ongoing debate about whether fungi are causative allergens or merely colonizers, AFRS remains a useful prototype because it exemplifies a clear set of clinicopathologic features aligned with intense type 2 inflammation and local IgE responses.
Recent microbiome profiling has highlighted a complex sinonasal microenvironment in AFRS, including bacterial and fungal community features within this allergic mucin-rich disease [54]. For allergic CRS generally, AFRS offers a methodological model: identify target-tissue characteristics, specify antigen exposure, and quantify local immune responses that likely link exposure to inflammation.

8.2. Central Compartment Atopic Disease (CCAD): Allergen Contact Pattern as Phenotype

CCAD describes a pattern of polypoid edema and remodeling predominantly involving the middle turbinate, superior turbinate, and posterosuperior nasal septum, often with a central (rather than peripheral) pattern of sinus opacification [21,22,23,24,25]. This phenotype is strongly associated with inhalant allergy and asthma, and its anatomic distribution is biologically appealing because it overlaps with regions of high airflow turbulence and likely allergen deposition.
However, CCAD remains an evolving concept with heterogeneity across studies. A recent comprehensive review suggested diagnostic criteria that highlight the importance of endoscopic confirmation of central compartment polypoid changes along with a history of allergies, noting that radiology alone is inadequate for diagnosis [54]. This reinforces an important point for allergic CRS endotyping: anatomic pattern can increase plausibility, but it cannot substitute for direct mechanistic evidence (e.g., allergen-specific IgE and exposure–response data).

8.3. Anatomic and Physical Constraints: Do Inhaled Allergens Reach the Sinuses?

A frequently overlooked constraint is physical access. Experimental work suggests that inhaled pollen may have limited penetration into the paranasal sinuses under typical conditions, raising questions about whether allergen exposure in the sinus cavity is sufficient to drive diffuse sinus inflammation [55]. This does not diminish the importance of allergy in nasal cavity inflammation or central compartment structures, but it warns against presuming that systemic atopy always means allergen exposure in the sinus compartments.

8.4. Non-IgE Type 2 Entities: Preventing Diagnostic Oversimplification

Several CRS-related entities can present with severe type 2 inflammation yet are not primarily allergen-driven. Aspirin-exacerbated respiratory disease (AERD; also termed NSAID-exacerbated respiratory disease (N-ERD)) is characterized by CRSwNP, asthma, and respiratory reactions to COX-1 inhibitors, with prominent eosinophilic inflammation and dysregulated eicosanoid pathways [57,58,59,60].
Because AERD/N-ERD can occur alongside atopy and show elevated IgE levels, it serves as a key example of why systemic sensitization and type 2 biomarkers alone are inadequate to identify an allergic endotype. In suspected allergic CRS, it is essential to explicitly exclude or stratify AERD/N-ERD and other non-allergic type 2 disorders to clarify the underlying mechanisms.

9. Clinical Implications: A Mechanism-Informed Approach Without Overdiagnosis

9.1. A Pragmatic Diagnostic Workflow: From Syndrome to Mechanism

Step 1: Confirm objective CRS using guideline-based criteria and avoid symptom-only case definitions [1,2]. Because incidental radiographic mucosal thickening is common, objective evidence should be interpreted in the context of symptoms and endoscopy [26,27].
Step 2: Phenotype the patient’s allergic disease with attention to clinical relevance. Document AR symptoms (especially sneezing, itching, rhinorrhea, and obstruction), seasonality, and exposure triggers, confirm sensitization with skin testing or serum specific IgE, and consider LAR when suspicion remains high despite negative systemic testing [8,9]. A positive skin test or serum allergen-specific IgE result should be interpreted as evidence of sensitization, not as proof that allergy is the dominant driver of CRS itself [8,10]. In specialized settings, nasal allergen challenge/provocation may be informative when LAR is suspected, whereas nasal specific IgE and basophil activation testing should be interpreted as adjunctive evidence [11,12,43].
Step 3: Identify prototypes and competing explanations. Evaluate for AFRS and CCAD patterns when present [17,18,19,20,21,22,23,24,25], and concurrently screen for non-allergic type 2 entities such as AERD/N-ERD [57,58,59,60] and for secondary causes of CRS (e.g., immunodeficiency, cystic fibrosis, ciliary disorders) as recommended by consensus guidance [1,2].
Step 4: Characterize target-tissue inflammation when feasible. Endoscopic appearance, tissue eosinophilia, and local IgE measurements can support a type 2/IgE-rich state, but clinicians should recognize that tissue IgE may be polyclonal or superantigen-amplified [32,33,34]. No single biomarker currently establishes “allergic CRS”; blood eosinophils, total IgE, tissue eosinophilia, and local IgE are better viewed as markers of a type 2/IgE-rich milieu that must be interpreted alongside phenotype, anatomy, and exposure–response data [61,62]. When research infrastructure permits, measuring allergen-specific IgE in sinonasal tissue or secretions is more directly aligned with an allergic endotype hypothesis.
Step 5: Link mechanism to treatment decisions. In CRSwNP, biologic eligibility and response assessment are increasingly guided by severity, comorbid asthma, prior surgery, and type 2 biomarkers, as reflected in consensus updates for biologic evaluation [61]. Accordingly, biologic selection in routine practice should continue to follow validated severe CRSwNP/type 2 pathways rather than a presumed “allergic CRS” label alone [61,62]. In contrast, a putative allergic CRS endotype would additionally prioritize exposure–response patterns and allergen-directed interventions as mechanistic probes.

9.2. Therapeutic Implications: What Changes if Allergy Is Mechanistically Relevant?

Foundational CRS therapy remains suitable regardless of suspected endotype, including saline irrigations and intranasal corticosteroids, with escalation to short courses of systemic corticosteroids, endoscopic sinus surgery, and adjuvant therapies as clinically indicated [1,2]. Endotyping should not delay these evidence-based interventions.
When clinically relevant inhalant allergy is present, standard AR management (environmental control, antihistamines, intranasal corticosteroids) is indicated primarily to treat AR symptoms and may secondarily improve overlapping nasal symptoms [8]. Whether AIT improves CRS-specific outcomes remains uncertain. Existing evidence is limited and largely non-randomized, with the strongest signal in postoperative settings and in selected phenotypes such as AFRS and CCAD [15,16]. In practice, AIT is likely most justified when used to treat clear AR or asthma comorbidities, while also being investigated as a mechanistic modifier in carefully phenotyped CRS cohorts.
Biologics offer an alternative way to investigate the underlying mechanism. In CRSwNP with severe type 2 inflammation, randomized trials have demonstrated clinically meaningful benefit from dupilumab (anti–IL-4Rα), omalizumab (anti–IgE), and mepolizumab (anti–IL-5) [63,64,65]. More recently, epithelial alarmin blockade has entered the therapeutic landscape: tezepelumab (anti–TSLP) improved nasal polyp outcomes and symptoms in a phase 3 trial, supporting the concept that upstream epithelial pathways can sustain type 2 inflammation in CRSwNP [66]. These data strengthen the rationale for integrating barrier/alarmin biology into allergic CRS hypotheses, while again emphasizing that type 2 response to biologics does not by itself prove allergen causality.
Microbiome-directed therapies remain investigational but may be particularly relevant if dysbiosis and superantigen pathways are central drivers of IgE amplification. Early-phase studies suggest feasibility of intranasal bacteriotherapy and bacteriophage approaches in CRS [67,68], and conceptual work has proposed nasal microbiota transplantation as a potential future strategy [69]. For an allergic CRS endotype, these methods should ideally be tested together with allergen-specific treatments to distinguish whether IgE amplification is caused by allergens or microbes.
A summary of therapeutic classes and the strength of supporting evidence in CRS/CRSwNP is provided in Table 3.

9.3. Monitoring and Outcomes: What to Track in “Possible Allergic CRS”

If allergic CRS is being evaluated as a hypothesis, monitoring should capture both CRS outcomes (e.g., symptom scores, endoscopic polyp burden, CT opacification, need for systemic steroids or revision surgery) and allergy metrics (validated rhinitis symptom scores, allergen exposure logs, and, in selected specialized settings, nasal allergen provocation testing; where feasible, biomarkers such as allergen-specific IgE in secretions or tissue may provide supportive information) [12,43]. Demonstrating exposure–response coupling and target-tissue immunologic change is more persuasive than changes in systemic testing alone.

10. Research Agenda: Converting a Heuristic Label into a Testable Endotype

Several principles of study design emerge from the mechanistic ambiguities discussed earlier.
First, cohorts must use objective CRS definitions and report endoscopic and radiographic phenotypes with standardized outcome measures. Second, allergy phenotyping should distinguish sensitization from clinically relevant allergy and should incorporate LAR assessment where feasible, ideally with standardized nasal allergen challenge in appropriate specialized settings rather than reliance on systemic testing alone [11,12,43]. Third, target-tissue readouts are essential: studies should quantify tissue eosinophils, cytokine profiles, and IgE specificity (aeroallergen-specific vs. enterotoxin-specific vs. polyclonal).
Fourth, exposure–response designs are needed. Seasonality, occupational exposures, and natural experiments (relocation, high/low pollen years) can be utilized, but they must be paired with objective outcome measures and biomarker tracking. Finally, intervention trials should be endotype-stratified: AIT, allergen avoidance, and anti–IgE strategies are informative only when the subgroup is defined by evidence of allergen relevance in the sinonasal compartment.
If these principles are met, the field can determine whether “allergic CRS” represents: (i) a distinct allergen-driven endotype, (ii) a set of prototypes (AFRS, CCAD) rather than a generalizable category, or (iii) a misnomer for IgE-rich type 2 inflammation sustained primarily by non-allergen drivers.

11. Conclusions

“Allergic CRS” is widely used as a clinical shorthand, but its scientific validity depends on demonstrating allergen causality within the sinonasal compartment rather than merely documenting systemic sensitization or type 2 biomarkers. Evidence for local IgE generation, superantigen-driven IgE amplification, and barrier–immune–microbiome feedback loops explains why IgE-rich inflammation is not synonymous with allergen-driven disease.
AFRS and CCAD offer the most advanced prototypes where phenotype, anatomical contact patterns, and IgE biology likely correlate with an allergic mechanism, although further refinement of diagnostic criteria and mechanistic validation are still needed. Emerging therapeutics, including upstream epithelial alarmin blockade, underscore that multiple non-allergen pathways can converge on type 2 inflammation in CRSwNP.
A standardized entity-testing framework can help the field move from imprecise labels to hypotheses that can be rigorously tested. Future research should focus on endotype-specific, target-tissue-guided studies to identify when allergy plays a mechanistic role in CRS and when it is merely an epiphenomenon.

Author Contributions

Conceptualization, G.N.K.; methodology, G.N.K.; writing—original draft preparation, G.N.K. and K.P.; writing—review and editing, G.N.K. and K.P.; visualization, G.N.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
AERDaspirin-exacerbated respiratory disease
AFRSallergic fungal rhinosinusitis
ARallergic rhinitis
CCADcentral compartment atopic disease
CRSchronic rhinosinusitis
CRSwNPchronic rhinosinusitis with nasal polyps
CRSsNPchronic rhinosinusitis without nasal polyps
CTcomputed tomography
LARlocal allergic rhinitis
N-ERDNSAID-exacerbated respiratory disease
SEStaphylococcus aureus enterotoxin
SEBStaphylococcus aureus enterotoxin B
SPTskin prick test
TSLPthymic stromal lymphopoietin

References

  1. Fokkens, W.J.; Lund, V.J.; Hopkins, C.; Hellings, P.W.; Kern, R.; Reitsma, S.; Toppila-Salmi, S.; Bernal-Sprekelsen, M.; Mullol, J.; Alobid, I.; et al. European Position Paper on Rhinosinusitis and Nasal Polyps 2020. Rhinology 2020, 58, 1–464. [Google Scholar] [CrossRef] [PubMed]
  2. Orlandi, R.R.; Kingdom, T.T.; Smith, T.L.; Bleier, B.; DeConde, A.; Luong, A.U.; Poetker, D.M.; Soler, Z.M.; Welch, K.C.; Wise, S.K.; et al. International consensus statement on allergy and rhinology: Rhinosinusitis 2021. Int. Forum Allergy Rhinol. 2021, 11, 213–739. [Google Scholar] [CrossRef] [PubMed]
  3. Akdis, C.A.; Bachert, C.; Cingi, C.; Dykewicz, M.S.; Hellings, P.W.; Naclerio, R.M.; Schleimer, R.P.; Ledford, D. Endotypes and phenotypes of chronic rhinosinusitis: A PRACTALL document of the EAACI and the AAAAI. J. Allergy Clin. Immunol. 2013, 131, 1479–1490. [Google Scholar] [CrossRef] [PubMed]
  4. Tomassen, P.; Vandeplas, G.; Van Zele, T.; Cardell, L.-O.; Arebro, J.; Olze, H.; Förster-Ruhrmann, U.; Kowalski, M.L.; Olszewska-Ziąber, A.; Holtappels, G.; et al. Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers. J. Allergy Clin. Immunol. 2016, 137, 1449–1456.e4. [Google Scholar] [CrossRef] [PubMed]
  5. Schleimer, R.P. Immunopathogenesis of Chronic Rhinosinusitis and Nasal Polyposis. Annu. Rev. Pathol. 2017, 12, 331–357. [Google Scholar] [CrossRef] [PubMed]
  6. Kato, A. Immunopathology of chronic rhinosinusitis. Allergol. Int. 2015, 64, 121–130. [Google Scholar] [CrossRef] [PubMed]
  7. Wilson, K.F.; McMains, K.C.; Orlandi, R.R. The association between allergy and chronic rhinosinusitis with and without nasal polyps: An evidence-based review with recommendations. Int. Forum Allergy Rhinol. 2014, 4, 93–103. [Google Scholar] [CrossRef] [PubMed]
  8. Dykewicz, M.S.; Wallace, D.V.; Amrol, D.J.; Baroody, F.M.; Bernstein, J.A.; Craig, T.J.; Dinakar, C.; Ellis, A.K.; Finegold, I.; Golden, D.B.; et al. Rhinitis 2020: A practice parameter update. J. Allergy Clin. Immunol. 2020, 146, 721–767. [Google Scholar] [CrossRef] [PubMed]
  9. Rondón, C.; Campo, P.; Eguiluz-Gracia, I.; Plaza, C.; Bogas, G.; Galindo, P.; Mayorga, C.; Torres, M.J. Local allergic rhinitis is an independent rhinitis phenotype: The results of a 10-year follow-up study. Allergy 2018, 73, 470–478. [Google Scholar] [CrossRef] [PubMed]
  10. Arbes, S.J., Jr.; Gergen, P.J.; Elliott, L.; Zeldin, D.C. Prevalences of positive skin test responses to 10 common allergens in the US population: Results from NHANES III. J. Allergy Clin. Immunol. 2005, 116, 377–383. [Google Scholar] [CrossRef] [PubMed]
  11. Vardouniotis, A.; Doulaptsi, M.; Aoi, N.; Karatzanis, A.; Kawauchi, H.; Prokopakis, E. Local Allergic Rhinitis Revisited. Curr. Allergy Asthma Rep. 2020, 20, 22. [Google Scholar] [CrossRef] [PubMed]
  12. Augé, J.; Vent, J.; Agache, I.; Airaksinen, L.; Campo Mozo, P.; Chaker, A.; Cingi, C.; Durham, S.; Fokkens, W.; Gevaert, P.; et al. EAACI Position Paper on the Standardization of Nasal Allergen Challenges. Allergy 2018, 73, 1597–1608. [Google Scholar] [CrossRef] [PubMed]
  13. Baethge, C.; Goldbeck-Wood, S.; Mertens, S. SANRA-a scale for the quality assessment of narrative review articles. Res. Integr. Peer Rev. 2019, 4, 5. [Google Scholar] [CrossRef] [PubMed]
  14. Sukhera, J. Narrative Reviews: Flexible, Rigorous, and Practical. J. Grad. Med. Educ. 2022, 14, 414–417. [Google Scholar] [CrossRef] [PubMed]
  15. Young, K.; Wentzel, J.L.; Schlosser, R.J.; Nguyen, S.A.; Soler, Z.M. Systematic review of immunotherapy for chronic rhinosinusitis. Am. J. Rhinol. Allergy 2014, 28, 145–150. [Google Scholar] [CrossRef] [PubMed]
  16. Meerwein, C.M.; Sacks, P.-L.; Ho, J.; Choy, C.; Kalish, L.; Campbell, R.G.; Sacks, R.R.; Harvey, R.J. The effect of allergen immunotherapy in patients with central compartment atopic disease post-surgery. Int. Forum Allergy Rhinol. 2025, 15, 128–134. [Google Scholar] [CrossRef] [PubMed]
  17. Chakrabarti, A.; Denning, D.W.; Ferguson, B.J.; Ponikau, J.; Buzina, W.; Kita, H.; Marple, B.; Panda, N.; Vlaminck, S.; Kauffmann-Lacroix, C.; et al. Fungal rhinosinusitis: A categorization and definitional schema addressing current controversies. Laryngoscope 2009, 119, 1809–1818. [Google Scholar] [CrossRef] [PubMed]
  18. Bent, J.P., 3rd; Kuhn, F.A. Diagnosis of allergic fungal sinusitis. Otolaryngol. Head Neck Surg. 1994, 111, 580–588. [Google Scholar] [CrossRef] [PubMed]
  19. Dykewicz, M.S.; Rodrigues, J.M.; Slavin, R.G. Allergic fungal rhinosinusitis. J. Allergy Clin. Immunol. 2018, 142, 341–351. [Google Scholar] [CrossRef] [PubMed]
  20. Collins, M.; Nair, S.; Smith, W.; Kette, F.; Gillis, D.; Wormald, P.J. Role of local immunoglobulin E production in the pathophysiology of noninvasive fungal sinusitis. Laryngoscope 2004, 114, 1242–1246. [Google Scholar] [CrossRef] [PubMed]
  21. DelGaudio, J.M.; Loftus, P.A.; Hamizan, A.W.; Harvey, R.J.; Wise, S.K. Central compartment atopic disease. Am. J. Rhinol. Allergy 2017, 31, 228–234. [Google Scholar] [CrossRef] [PubMed]
  22. Hamizan, A.W.; Loftus, P.A.; Alvarado, R.; Ho, J.; Kalish, L.; Sacks, R.; DelGaudio, J.M.; Harvey, R.J. Allergic phenotype of chronic rhinosinusitis based on radiologic pattern of disease. Laryngoscope 2018, 128, 2015–2021. [Google Scholar] [CrossRef] [PubMed]
  23. Marcus, S.; Schertzer, J.; Roland, L.T.; Wise, S.K.; Levy, J.M.; DelGaudio, J.M. Central compartment atopic disease: Prevalence of allergy and asthma compared with other subtypes of chronic rhinosinusitis with nasal polyps. Int. Forum Allergy Rhinol. 2020, 10, 183–189. [Google Scholar] [CrossRef] [PubMed]
  24. Steehler, A.J.; Vuncannon, J.R.; Wise, S.K.; DelGaudio, J.M. Central compartment atopic disease: Outcomes compared with other subtypes of chronic rhinosinusitis with nasal polyps. Int. Forum Allergy Rhinol. 2021, 11, 1549–1556. [Google Scholar] [CrossRef] [PubMed]
  25. Hamizan, A.W.; Christensen, J.M.; Ebenzer, J.; Oakley, G.; Tattersall, J.; Sacks, R.; Harvey, R.J. Middle turbinate edema as a diagnostic marker of inhalant allergy. Int. Forum Allergy Rhinol. 2017, 7, 37–42. [Google Scholar] [CrossRef] [PubMed]
  26. Dietz de Loos, D.; Lourijsen, E.S.; Wildeman, M.A.M.; Freling, N.J.M.; Wolvers, M.D.J.; Reitsma, S.; Fokkens, W.J. Prevalence of chronic rhinosinusitis in the general population based on sinus radiology and symptomatology. J. Allergy Clin. Immunol. 2019, 143, 1207–1214. [Google Scholar] [CrossRef] [PubMed]
  27. Hirsch, A.G.; Nordberg, C.; Bandeen-Roche, K.; Tan, B.K.; Schleimer, R.P.; Kern, R.C.; Sundaresan, A.; Pinto, J.M.; Kennedy, T.L.; Greene, J.S.; et al. Radiologic sinus inflammation and symptoms of chronic rhinosinusitis in a population-based sample. Allergy 2020, 75, 911–920. [Google Scholar] [PubMed]
  28. Shi, J.-B.; Fu, Q.-L.; Zhang, H.; Cheng, L.; Wang, Y.-J.; Zhu, D.-D.; Lv, W.; Liu, S.-X.; Li, P.-Z.; Ou, C.-Q.; et al. Epidemiology of chronic rhinosinusitis: Results from a cross-sectional survey in seven Chinese cities. Allergy 2015, 70, 533–539. [Google Scholar] [CrossRef] [PubMed]
  29. Philpott, C.M.; Erskine, S.; Hopkins, C.; Kumar, N.; Anari, S.; Kara, N.; Sunkaraneni, S.; Ray, J.; Clark, A.; Wilson, A.; et al. Prevalence of asthma, aspirin sensitivity and allergy in chronic rhinosinusitis: Data from the UK National Chronic Rhinosinusitis Epidemiology Study. Respir. Res. 2018, 19, 129. [Google Scholar] [CrossRef] [PubMed]
  30. Li, Q.-C.; Cheng, K.-J.; Wang, F.; Zhou, S.-H. Role of atopy in chronic rhinosinusitis with nasal polyps: Does an atopic condition affect the severity and recurrence of disease? J. Laryngol. Otol. 2016, 130, 640–644. [Google Scholar] [CrossRef] [PubMed]
  31. Benjamin, M.R.; Stevens, W.W.; Li, N.; Bose, S.; Grammer, L.C.; Kern, R.C.; Tan, B.K.; Conley, D.B.; Smith, S.S.; Welch, K.C.; et al. Clinical Characteristics of Patients with Chronic Rhinosinusitis without Nasal Polyps in an Academic Setting. J. Allergy Clin. Immunol. Pract. 2019, 7, 1010–1016. [Google Scholar] [CrossRef] [PubMed]
  32. Gevaert, P.; Nouri-Aria, K.T.; Wu, H.; Harper, C.E.; Takhar, P.; Fear, D.J.; Acke, F.; De Ruyck, N.; Banfield, G.; Kariyawasam, H.H.; et al. Local receptor revision and class switching to IgE in chronic rhinosinusitis with nasal polyps. Allergy 2013, 68, 55–63. [Google Scholar] [CrossRef] [PubMed]
  33. Bachert, C.; Zhang, N.; Holtappels, G.; De Lobel, L.; van Cauwenberge, P.; Liu, S.; Lin, P.; Bousquet, J.; Van Steen, K. Presence of IL-5 protein and IgE antibodies to staphylococcal enterotoxins in nasal polyps is associated with comorbid asthma. J. Allergy Clin. Immunol. 2010, 126, 962–968.e6. [Google Scholar] [CrossRef] [PubMed]
  34. Chegini, Z.; Didehdar, M.; Khoshbayan, A.; Karami, J.; Yousefimashouf, M.; Shariati, A. The role of Staphylococcus aureus enterotoxin B in chronic rhinosinusitis with nasal polyposis. Cell Commun. Signal. 2022, 20, 29. [Google Scholar] [CrossRef] [PubMed]
  35. Wang, X.; Zhang, N.; Bo, M.; Holtappels, G.; Zheng, M.; Lou, H.; Wang, H.; Zhang, L.; Bachert, C. Diversity of TH cytokine profiles in patients with chronic rhinosinusitis: A multicenter study in Europe, Asia, and Oceania. J. Allergy Clin. Immunol. 2016, 138, 1344–1353. [Google Scholar] [CrossRef] [PubMed]
  36. Hulse, K.E.; Stevens, W.W.; Tan, B.K.; Schleimer, R.P. Pathogenesis of nasal polyposis. Clin. Exp. Allergy 2015, 45, 328–346. [Google Scholar] [CrossRef] [PubMed]
  37. Schleimer, R.P.; Berdnikovs, S. Etiology of epithelial barrier dysfunction in patients with type 2 inflammatory diseases. J. Allergy Clin. Immunol. 2017, 139, 1752–1761. [Google Scholar] [CrossRef] [PubMed]
  38. Pothoven, K.L.; Norton, J.E.; Hulse, K.E.; Suh, L.A.; Carter, R.G.; Rocci, E.; Harris, K.E.; Shintani-Smith, S.; Conley, D.B.; Chandra, R.K.; et al. Oncostatin M promotes mucosal epithelial barrier dysfunction, and its expression is increased in patients with eosinophilic mucosal disease. J. Allergy Clin. Immunol. 2015, 136, 737–746.e4. [Google Scholar] [CrossRef] [PubMed]
  39. Ordovas-Montanes, J.; Dwyer, D.F.; Nyquist, S.K.; Buchheit, K.M.; Vukovic, M.; Deb, C.; Wadsworth, M.H., 2nd; Hughes, T.K.; Kazer, S.W.; Yoshimoto, E.; et al. Allergic inflammatory memory in human respiratory epithelial progenitor cells. Nature 2018, 560, 649–654. [Google Scholar] [CrossRef] [PubMed]
  40. Takabayashi, T.; Kato, A.; Peters, A.T.; Hulse, K.E.; Suh, L.A.; Carter, R.; Norton, J.; Grammer, L.C.; Cho, S.H.; Tan, B.K.; et al. Excessive fibrin deposition in nasal polyps caused by fibrinolytic impairment through reduction of tissue plasminogen activator expression. Am. J. Respir. Crit. Care Med. 2013, 187, 49–57. [Google Scholar] [CrossRef] [PubMed]
  41. Chen, C.-L.; Yao, Y.; Pan, L.; Hu, S.-T.; Ma, J.; Wang, Z.-C.; Kern, R.C.; Schleimer, R.P.; Liu, Z. Common fibrin deposition and tissue plasminogen activator downregulation in nasal polyps with distinct inflammatory endotypes. J. Allergy Clin. Immunol. 2020, 146, 677–681. [Google Scholar] [CrossRef] [PubMed]
  42. Psaltis, A.J.; Mackenzie, B.W.; Cope, E.K.; Ramakrishnan, V.R. Unraveling the role of the microbiome in chronic rhinosinusitis. J. Allergy Clin. Immunol. 2022, 149, 1513–1521. [Google Scholar] [CrossRef] [PubMed]
  43. Campo, P.; Canonica, G.W. Local Allergic Rhinitis. J. Allergy Clin. Immunol. Pract. 2024, 12, 1430–1433. [Google Scholar] [CrossRef] [PubMed]
  44. Abreu, N.A.; Nagalingam, N.A.; Song, Y.; Roediger, F.C.; Pletcher, S.D.; Goldberg, A.N.; Lynch, S.V. Sinus microbiome diversity depletion and Corynebacterium tuberculostearicum enrichment mediates rhinosinusitis. Sci. Transl. Med. 2012, 4, 151ra124. [Google Scholar] [CrossRef] [PubMed]
  45. Ramakrishnan, V.R.; Hauser, L.J.; Feazel, L.M.; Ir, D.; Robertson, C.E.; Frank, D.N. Sinus microbiota varies among chronic rhinosinusitis phenotypes and predicts surgical outcome. J. Allergy Clin. Immunol. 2015, 136, 334–342.e1. [Google Scholar] [CrossRef] [PubMed]
  46. Cope, E.K.; Goldberg, A.N.; Pletcher, S.D.; Lynch, S.V. Compositionally and functionally distinct sinus microbiota in chronic rhinosinusitis patients have immunological and clinically divergent consequences. Microbiome 2017, 5, 53. [Google Scholar] [CrossRef] [PubMed]
  47. Anderson, M.; Stokken, J.; Sanford, T.; Aurora, R.; Sindwani, R. A systematic review of the sinonasal microbiome in chronic rhinosinusitis. Am. J. Rhinol. Allergy 2016, 30, 161–166. [Google Scholar] [CrossRef] [PubMed]
  48. Wagner Mackenzie, B.; Waite, D.W.; Hoggard, M.; Douglas, R.G.; Taylor, M.W.; Biswas, K. Bacterial community collapse: A meta-analysis of the sinonasal microbiota in chronic rhinosinusitis. Environ. Microbiol. 2017, 19, 381–392. [Google Scholar] [CrossRef] [PubMed]
  49. Chalermwatanachai, T.; Vilchez-Vargas, R.; Holtappels, G.; Lacoere, T.; Jauregui, R.; Kerckhof, F.-M.; Pieper, D.H.; Van de Wiele, T.; Vaneechoutte, M.; Van Zele, T.; et al. Chronic rhinosinusitis with nasal polyps is characterized by dysbacteriosis of the nasal microbiota. Sci. Rep. 2018, 8, 7926. [Google Scholar] [CrossRef] [PubMed]
  50. Mahdavinia, M.; Engen, P.A.; LoSavio, P.S.; Naqib, A.; Khan, R.J.; Tobin, M.C.; Mehta, A.; Kota, R.; Preite, N.Z.; Codispoti, C.D.; et al. The nasal microbiome in patients with chronic rhinosinusitis: Analyzing the effects of atopy and bacterial functional pathways in 111 patients. J. Allergy Clin. Immunol. 2018, 142, 287–290.e4. [Google Scholar] [CrossRef] [PubMed]
  51. Liang, Y.; Xie, R.; Xiong, X.; Hu, Z.; Mao, X.; Wang, X.; Zhang, J.; Sun, P.; Yue, Z.; Wang, W.; et al. Alterations of nasal microbiome in eosinophilic chronic rhinosinusitis. J. Allergy Clin. Immunol. 2023, 151, 1286–1295.e2. [Google Scholar] [CrossRef] [PubMed]
  52. Bartosik, T.J.; Campion, N.J.; Freisl, K.; Liu, D.T.; Gangl, K.; Stanek, V.; Tu, A.; Pjevac, P.; Hausmann, B.; Eckl-Dorna, J.; et al. The nasal microbiome in patients suffering from non-steroidal anti-inflammatory drugs-exacerbated respiratory disease in absence of corticosteroids. Front. Immunol. 2023, 14, 1112345. [Google Scholar] [CrossRef] [PubMed]
  53. Kumar, N.; Brar, T.; Kita, H.; Marks, L.A.; Miglani, A.; Marino, M.J.; Lal, D. Viruses in chronic rhinosinusitis: A systematic review. Front. Allergy 2023, 4, 1237068. [Google Scholar] [CrossRef] [PubMed]
  54. Barrow, E.M.; Wise, S.K.; Botros, A.; Harvey, R.J.; Edwards, T.S.; DelGaudio, J.M. Central Compartment Atopic Disease: Analysis of Current Literature and Proposal of Diagnostic Criteria. Int. Forum Allergy Rhinol. 2025, 15, 1113–1135. [Google Scholar] [CrossRef] [PubMed]
  55. Adkins, T.N.; Goodgold, H.M.; Hendershott, L.; Slavin, R.G. Does inhaled pollen enter the sinus cavities? Ann. Allergy Asthma Immunol. 1998, 81, 181–184. [Google Scholar] [CrossRef] [PubMed]
  56. Connell, J.T.; Bouras, G.; Yeo, K.; Fenix, K.; Cooksley, C.; Bassiouni, A.; Vreugde, S.; Wormald, P.J.; Psaltis, A.J. Characterising the allergic fungal rhinosinusitis microenvironment using full-length 16S rRNA gene amplicon sequencing and fungal ITS sequencing. Allergy 2024, 79, 3082–3094. [Google Scholar] [CrossRef] [PubMed]
  57. White, A.A.; Stevenson, D.D. Aspirin-exacerbated respiratory disease. N. Engl. J. Med. 2018, 379, 1060–1070. [Google Scholar] [CrossRef] [PubMed]
  58. Kowalski, M.L.; Agache, I.; Bavbek, S.; Bakirtas, A.; Blanca, M.; Bochenek, G.; Bonini, M.; Heffler, E.; Klimek, L.; Laidlaw, T.M.; et al. Diagnosis and management of NSAID-exacerbated respiratory disease (N-ERD)—A EAACI position paper. Allergy 2019, 74, 28–39. [Google Scholar] [CrossRef] [PubMed]
  59. Rajan, J.P.; Wineinger, N.E.; Stevenson, D.D.; White, A.A. Prevalence of aspirin-exacerbated respiratory disease among asthmatic patients: A meta-analysis of the literature. J. Allergy Clin. Immunol. 2015, 135, 676–681.e1. [Google Scholar] [CrossRef] [PubMed]
  60. Stevens, W.W.; Peters, A.T.; Hirsch, A.G.; Nordberg, C.M.; Schwartz, B.S.; Mercer, D.G.; Mahdavinia, M.; Grammer, L.C.; Hulse, K.E.; Kern, R.C.; et al. Clinical Characteristics of Patients with Chronic Rhinosinusitis with Nasal Polyps, Asthma, and Aspirin-Exacerbated Respiratory Disease. J. Allergy Clin. Immunol. Pract. 2017, 5, 1061–1070.e3. [Google Scholar] [CrossRef] [PubMed]
  61. Fokkens, W.J.; Viskens, A.-S.; Backer, V.; Conti, D.; De Corso, E.; Gevaert, P.; Scadding, G.K.; Wagemann, M.; Bernal-Sprekelsen, M.; Chaker, A.; et al. EPOS/EUFOREA update on indication and evaluation of Biologics in Chronic Rhinosinusitis with Nasal Polyps 2023. Rhinology 2023, 61, 194–202. [Google Scholar] [CrossRef] [PubMed]
  62. Nakayama, T.; Haruna, S.-I. A review of current biomarkers in chronic rhinosinusitis with or without nasal polyps. Expert Rev. Clin. Immunol. 2023, 19, 883–892. [Google Scholar] [CrossRef] [PubMed]
  63. Bachert, C.; Han, J.K.; Desrosiers, M.; Hellings, P.W.; Amin, N.; Lee, S.E.; Mullol, J.; Greos, L.S.; Bosso, J.V.; Laidlaw, T.M.; et al. Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): Results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials. Lancet 2019, 394, 1638–1650. [Google Scholar] [CrossRef] [PubMed]
  64. Gevaert, P.; Omachi, T.A.; Corren, J.; Mullol, J.; Han, J.; Lee, S.E.; Kaufman, D.; Ligueros-Saylan, M.; Howard, M.; Zhu, R.; et al. Efficacy and safety of omalizumab in nasal polyposis: Two randomized phase 3 trials. J. Allergy Clin. Immunol. 2020, 146, 595–605. [Google Scholar] [CrossRef] [PubMed]
  65. Han, J.K.; Bachert, C.; Fokkens, W.; Desrosiers, M.; Wagenmann, M.; Lee, S.E.; Smith, S.G.; Martin, N.; Aboubakri, A.; Amin, N.; et al. Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir. Med. 2021, 9, 1141–1153. [Google Scholar] [CrossRef] [PubMed]
  66. Lipworth, B.J.; Han, J.K.; Desrosiers, M.; Hopkins, C.; Lee, S.E.; Mullol, J.; Pfaar, O.; Li, T.; Chen, C.; Almqvist, G.; et al. Tezepelumab in Adults with Severe Chronic Rhinosinusitis with Nasal Polyps. N. Engl. J. Med. 2025, 392, 1178–1188. [Google Scholar] [CrossRef] [PubMed]
  67. Endam, L.M.; Alromaih, S.; Gonzalez, E.; Madrenas, J.; Cousineau, B.; Renteria, A.E.; Desrosiers, M. Intranasal Application of Lactococcus lactis W136 Is Safe in Chronic Rhinosinusitis Patients with Previous Sinus Surgery. Front. Cell. Infect. Microbiol. 2020, 10, 440. [Google Scholar] [CrossRef] [PubMed]
  68. Ooi, M.L.; Drilling, A.J.; Morales, S.; Fong, S.; Moraitis, S.; Macias-Valle, L.; Vreugde, S.; Psaltis, A.J.; Wormald, P.J. Safety and Tolerability of Bacteriophage Therapy for Chronic Rhinosinusitis Due to Staphylococcus aureus. JAMA Otolaryngol. Head Neck Surg. 2019, 145, 723–729. [Google Scholar] [CrossRef] [PubMed]
  69. Shekhar, S.; Schwarzer, M.; Dhariwal, A.; Petersen, F.C. Nasal microbiota transplantation: A gateway to novel treatments. Trends Microbiol. 2025, 33, 264–267. [Google Scholar] [CrossRef] [PubMed]
Table 2. Prototypes across the proposed spectrum of atopic sinonasal disease and their evidentiary support.
Table 2. Prototypes across the proposed spectrum of atopic sinonasal disease and their evidentiary support.
PrototypeCore Clinical/
Anatomic Features		Putative Exposure
Pattern		Mechanistic
Plausibility		Strength of Evidence for Allergen Causality
Allergic rhinitis
(AR)		Sneezing/itching, rhinorrhea, nasal obstruction; endoscopy without persistent sinus mucosal disease.Direct nasal allergen exposure; often seasonal or exposure-triggered.Allergen-specific IgE with mast cell activation and downstream type 2 inflammation [8,9].High (well-established IgE-mediated disease).
Central compartment
atopic disease
(CCAD)		Polypoid edema centered on middle/superior turbinates and posterosuperior septum; central pattern of sinus disease; often coexists with asthma/AR [21,22,23,24,25,54].Inhalant allergens plausibly deposit in central compartment regions with high airflow turbulence.Anatomic contact pattern plus strong association with inhalant allergy suggest allergen relevance, but direct target-tissue allergen-specific IgE and exposure–response data are limited.Moderate (consistent association; emerging criteria; limited mechanistic validation).
“Allergic CRS”
(hypothesized diffuse endotype)		Diffuse objective CRS (often CRSwNP) with prominent rhinitis symptoms and strong exposure–response pattern.Systemic and/or local allergen-specific IgE; sinus-compartment exposure often unmeasured and may be limited [55].Would require evidence that allergen-specific IgE is present and functional in sinonasal target tissue and is not better explained by local polyclonal/superantigen-amplified IgE [32,33,34].Low (conceptual; requires prospective validation).
Allergic fungal
rhinosinusitis
(AFRS)		CRSwNP with allergic mucin, eosinophilic inflammation, fungal elements, and characteristic imaging [17,18,19,20].Fungal antigens within sinonasal mucus/mucin; exposure may be chronic and compartmentalized.Strong type 2 inflammation with local IgE responses; recent AFRS profiling supports biological complexity beyond simple fungal colonization [17,18,19,20,56].High (strongest current prototype, although mechanistic details remain debated).
Table 3. Therapy landscape relevant to type 2/IgE-rich CRS and the proposed allergic CRS hypothesis.
Table 3. Therapy landscape relevant to type 2/IgE-rich CRS and the proposed allergic CRS hypothesis.
Therapy ClassAxis Targeted/RationaleEvidence Strength in CRS/CRSwNPKey Notes for an “Allergic CRS” Hypothesis
Standard CRS care (saline, intranasal corticosteroids, short systemic steroids, endoscopic sinus surgery)Reduces mucosal inflammation and improves drainage/ventilation; cornerstone of CRS care.High (guideline-based standard of care) [1,2].Necessary regardless of endotype; endotyping should not delay evidence-based escalation.
Allergy-directed therapy (environmental control, antihistamines, AIT)Targets allergen–IgE pathway and AR comorbidity; AIT tests allergen causality over time.Low–moderate (limited and heterogeneous CRS-specific evidence; strongest signal in selected phenotypes and postoperative settings) [15,16].Most defensible when treating clear AR/asthma; potentially informative as a mechanistic modifier in AFRS/CCAD or exposure-linked disease.
Type 2 biologics (anti–IL-4Rα, anti–IgE, anti–IL-5, anti–TSLP)Downstream (IL-4/IL-13, IL-5, IgE) and upstream (TSLP) type 2 pathways in CRSwNP.High for dupilumab, omalizumab, mepolizumab; high for tezepelumab based on phase 3 evidence [63,64,65,66].Clinical response supports type 2 relevance but does not prove allergen causality; anti–IgE response may be more suggestive but can also reflect non-allergen IgE drivers.
Bacteriotherapy (e.g., Lactococcus lactis W136)Modulates local microbiome and host responses; aims to restore colonization resistance.Low (early-phase safety/feasibility data) [67].Mechanistically relevant if dysbiosis and biofilms sustain inflammation or amplify IgE via microbial pathways.
Bacteriophage therapyTargets pathogenic bacteria and biofilms.Low (early-phase safety/tolerability data) [68].May complement endotype-directed therapy if bacterial pathobionts contribute to disease persistence.
Nasal microbiota transplantation (concept)Whole-community microbiome restoration.Very low (conceptual/early translational discussion) [69].Hypothesis-generating; would require careful safety frameworks and mechanistic endpoints.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Konstantinou, G.N.; Petalas, K. Allergic Chronic Rhinosinusitis: Myth, Misnomer, or Missing Endotype? Allergies 2026, 6, 14. https://doi.org/10.3390/allergies6020014

AMA Style

Konstantinou GN, Petalas K. Allergic Chronic Rhinosinusitis: Myth, Misnomer, or Missing Endotype? Allergies. 2026; 6(2):14. https://doi.org/10.3390/allergies6020014

Chicago/Turabian Style

Konstantinou, George N., and Konstantinos Petalas. 2026. "Allergic Chronic Rhinosinusitis: Myth, Misnomer, or Missing Endotype?" Allergies 6, no. 2: 14. https://doi.org/10.3390/allergies6020014

APA Style

Konstantinou, G. N., & Petalas, K. (2026). Allergic Chronic Rhinosinusitis: Myth, Misnomer, or Missing Endotype? Allergies, 6(2), 14. https://doi.org/10.3390/allergies6020014

Article Metrics

Back to TopTop