Chronic rhinosinusitis (CRS) is a major inflammatory disease of the paranasal sinuses and nasal passages, affecting approximately 5% to 12% of the global population [1]. Characterized by persistent sinonasal symptoms such as nasal obstruction, facial pressure/pain, anterior/posterior rhinorrhea, and olfactory dysfunction lasting longer than 12 weeks, CRS significantly impairs health-related quality of life (HRQoL) and imposes a major economic burden on healthcare systems worldwide [2]. Pathophysiologically, CRS is no longer viewed as a uniform disease process, but rather as an umbrella term encompassing complex, highly heterogeneous inflammatory endotypes [3].

Traditionally, clinical guidelines categorized CRS into two primary clinical phenotypes based on anterior rhinoscopy and nasal endoscopy: Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) and Chronic Rhinosinusitis without Nasal Polyps (CRSsNP) [4]. However, breakthroughs in molecular immunology have demonstrated that phenotypic appearance does not always align with underlying tissue pathophysiology. Instead, disease behavior is dictated by specific endotypes characterized by distinct cytokine profiles (Type 2 vs. non-Type 2 inflammation) and cellular infiltrates [5]. Eosinophilic Chronic Rhinosinusitis (eCRS), dominated by Type 2 helper T-cell (T_H2) cytokines (such as IL-4, IL-5, and IL-13) and tissue eosinophilia, is notoriously prone to mucosal edema, extensive polyp formation, and high rates of postoperative recurrence [6]. In contrast, non-eosinophilic Chronic Rhinosinusitis (neCRS) often involves Type 1 or Type 17 inflammatory pathways with neutrophilic infiltration and dense tissue fibrosis [7].

The management of CRS begins with Maximal Medical Therapy (MMT), which includes prolonged administration of intranasal corticosteroids (INCS), systemic corticosteroids, high-volume nasal saline irrigations, and targeted short-course systemic antibiotics [8]. When MMT fails to yield symptomatic relief or control mucosal inflammation, Functional Endoscopic Sinus Surgery (FESS) is indicated. The primary objective of FESS is to restore physiological paranasal sinus ventilation and mucociliary clearance by resecting diseased mucosa, opening sinus ostia, and facilitating the direct topical delivery of postoperative pharmacotherapy to the sinonasal cavities [9].

Despite the established role of FESS, significant challenges persist in the perioperative pharmacotherapeutic management of CRS. In clinical practice, real-world drug utilization patterns frequently deviate from evidence-based international guidelines, such as the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) [10]. Empirical over-prescription of broad-spectrum systemic antibiotics prior to surgery remains widespread, contributing to antimicrobial resistance without altering underlying mucosal inflammatory drives [11]. Furthermore, post-FESS pharmacotherapy essential for preventing disease recurrence is often prescribed as a one-size-fits-all regimen rather than tailored to the patient’s specific tissue endotype.

While the diagnostic value of routine histopathological examination of FESS specimens is acknowledged, tissue parameters (such as eosinophil counts per high-power field, basement membrane thickness, subepithelial fibrosis, and osteitis) are rarely integrated systematically into postoperative drug stewardship [12]. Examining the relationship between preoperative/postoperative drug consumption and quantitative histopathological profiles offers a vital opportunity to refine treatment strategies.

Therefore, this prospective observational study was designed to systematically analyze drug utilization patterns in patients undergoing FESS, investigate the correlation between clinical drug utilization and specific histopathological endotypes, and identify tissue biomarkers that independently predict post-FESS maintenance drug requirements and disease recurrence.

Study Design and Ethical Approval This single-center, prospective observational cohort study was conducted in the Department of Otorhinolaryngology–Head and Neck Surgery in collaboration with the Department of Pathology and Clinical Pharmacology at multiple tertiary academic medical center over a 36-month period (January 2023 to December 2025). The study protocol was approved by the Institutional Ethics Committee, and written informed consent was obtained from all participants prior to enrollment in accordance with the Declaration of Helsinki. Study Population and Eligibility Criteria Adult patients (aged ≥ 18 years) diagnosed with medically refractory CRS with or without nasal polyposis who were scheduled to undergo primary or revision FESS were consecutively screened. Refractory CRS was defined as persistent disease fulfilling EPOS 2020 diagnostic criteria despite an adequate course of MMT (consisting of at least 8 consecutive weeks of compliant INCS use, combined with a trial of systemic corticosteroids and/or targeted short-course systemic antibiotics, and daily high-volume saline irrigations) [10]. Inclusion Criteria: 1. Adult patients (≥ 18 years) with clinical, endoscopic, and computed tomography (CT) evidence of CRS. 2. Failure of compliant Maximal Medical Therapy. 3. Candidate for elective FESS. 4. Willingness to participate in a 12-month post-surgical follow-up protocol. Exclusion Criteria: 1. Presence of sinonasal inverted papilloma, benign or malignant sinonasal neoplasms. 2. Unilateral isolated sinonasal disease suggestive of fungal ball or antrochoanal polyp. 3. Cystic fibrosis, Primary Ciliary Dyskinesia, or severe immunodeficiency disorders. 4. Granulomatous vasculitides (e.g., Granulomatosis with Polyangiitis, Eosinophilic Granulomatosis with Polyangiitis). 5. Pregnancy or lactation. 6. Systemic corticosteroid administration within 3 weeks prior to surgery (to avoid pharmacologically blunting tissue eosinophil counts and mucosal edema during histopathological assessment). Clinical and Radiological Assessment At baseline, demographic information, smoking history, asthma status, and aspirin-exacerbated respiratory disease (AERD) history were recorded. Disease-specific quality of life was measured using the validated 22-item Sino-Nasal Outcome Test (SNOT-22; score range 0–110). Endoscopic severity was evaluated using the Lund-Kennedy endoscopic scoring system (range 0–12). Non-contrast High-Resolution Computed Tomography (HRCT) of the paranasal sinuses was performed within 4 weeks prior to surgery and graded using the Lund-Mackay staging system (range 0–24). Drug Utilization Evaluation Detailed pharmacological histories covering the 12 months preceding surgery and the 12 months following surgery were obtained using patient medical records, electronic prescription databases, and standardized patient questionnaires. Medications were categorized using the World Health Organization (WHO) Anatomical Therapeutic Chemical (ATC) classification system. Drug consumption metrics were standardized using the Defined Daily Dose (DDD) per 1000 inhabitants per day or quantified as the annual number of treatment courses for acute exacerbations. The specific drug classes tracked were: • Intranasal Corticosteroids (INCS; ATC code: R01AD) • Systemic Corticosteroids (ATC code: H02AB) • Systemic Antibiotics (ATC code: J01) • Antihistamines for Systemic Use (ATC code: R06A) • Leukotriene Receptor Antagonists (LTRAs; ATC code: R03DC) • Topical Antiseptics/Nasal Saline Preparations (ATC code: R01AX) • Biologics / Monoclonal Antibodies (e.g., Dupilumab, Omalizumab; ATC code: R03DX) Surgical Procedure and Tissue Processing FESS was performed under general anesthesia using standard full-house or targeted endoscopic techniques (including anterior/posterior ethmoidectomy, maxillary antrostomy, sphenoidotomy, and frontal sinusotomy as dictated by disease distribution). Intraoperatively, representative mucosal tissue specimens were systematically collected from the ethmoid sinuses, maxillary sinus mucosa, and polypoid tissues. Specimens were immediately fixed in 10% neutral buffered formalin for 24 hours, embedded in paraffin blocks, sectioned at 4-µm thickness, and stained with Hematoxylin and Eosin (H&E). Specialized staining (Masson’s trichrome and Periodic Acid-Schiff [PAS]) was performed to assess tissue fibrosis and basement membrane integrity. Quantitative Histopathological Assessment Histopathological slides were evaluated by two senior gastrointestinal/head-and-neck pathologists who were blinded to patient clinical features and drug utilization profiles. Discrepancies were resolved via consensus conference. The following parameters were quantitatively analyzed: 1. Tissue Eosinophilia: Eosinophils were counted across 10 non-overlapping, high-density High-Power Fields (HPF; 400X magnification, optical area 0.237 mm2). Patients were categorized into: o Eosinophilic CRS (eCRS): Mean count ≥ 10 eosinophils/HPF [13]. o Non-Eosinophilic CRS (neCRS): Mean count < 10 eosinophils/HPF. 2. Inflammatory Infiltrate Composition: Presence of neutrophils, lymphocytes, plasma cells, and histiocytes graded semi-quantitatively (0 = absent, 1 = mild, 2 = moderate, 3 = severe). 3. Basement Membrane (BM) Thickness: Measured using calibrated digital micrometry at 5 distinct points per section, categorized as Normal (≤10µm), Moderate (10.1–15µm), or Severe (>15 µm). 4. Submucosal Edema & Fibrosis: Graded on a scale of 0 to 3 based on interstitial fluid separation and collagen deposition. 5. Goblet Cell Hyperplasia: Graded based on PAS-positive epithelial cell proportion (<25%, 25–50%, >50%). 6. Structural Bone Changes (Osteitis): Evaluated from intraoperative bony fragments when available, noting osteoclastic resorption, osteoid formation, and periosteal thickening. Postoperative Protocol and Follow-up Postoperatively, all patients followed a standardized core care protocol involving daily high-volume nasal saline douching starting on post-op day 1 and resumption of INCS at week 2. Clinical evaluation, diagnostic nasal endoscopy (Lund-Kennedy score), and assessment of SNOT-22 scores were conducted at 1, 3, 6, and 12 months postoperatively. Systemic steroids, systemic antibiotics, or advanced biologic therapies were prescribed postoperatively only upon endoscopic or clinical demonstration of recalcitrant inflammation or infectious exacerbations. Disease recurrence was defined as the endoscopic reappearance of mucosal polyposis or persistent mucopurulent sinus inflammation along with deterioration in SNOT-22 score (≥ 8.9 points change) at 12 months. Statistical Analysis Sample size calculation indicated that a minimum of 290 patients was required to achieve 80% statistical power (\beta = 0.20) at an alpha level of α= 0.05 to detect a 15% difference in postoperative drug utilization between eCRS and neCRS cohorts. Statistical processing was performed using R version 4.3.2 and SPSS version 28.0 (IBM Corp., Armonk, NY). Continuous variables were tested for normality using the Kolmogorov-Smirnov test and expressed as mean ± standard deviation (SD) or median (interquartile range [IQR]). Categorical variables were expressed as absolute frequencies and percentages. Comparisons between eCRS and neCRS cohorts were conducted using Student's t-test or Mann-Whitney U test for continuous data, and Chi-square (\chi^2) or Fisher's exact test for categorical variables. Changes in drug utilization from preoperative to postoperative periods were evaluated using the Wilcoxon signed-rank test or McNemar’s test. To identify independent predictors of high postoperative drug utilization (defined as requiring ≥ 2 courses of systemic corticosteroids or continuous systemic medication maintenance post-FESS) and disease recurrence, multivariable forward stepwise logistic regression models were constructed. Variable entry threshold was set at p < 0.10 and retention at p < 0.05. Adjusted Odds Ratios (aOR) with 95% Confidence Intervals (95% CI) were calculated. Two-tailed p-values < 0.05 were considered statistically significant.

Patient Cohort and Baseline Characteristics

A total of 348 patients were screened, of whom 320 met all eligibility criteria and completed the 12-month postoperative protocol. Based on quantitative histopathological evaluation, 184 patients (57.5%) were classified into the eCRS group (≥10 eosinophils/HPF) and 136 patients (42.5%) into the neCRS group (<10 eosinophils/HPF).

Baseline demographic, clinical, endoscopic, and radiological characteristics stratified by histopathological endotype are presented in Table 1. The mean age of the overall cohort was 46.8  ±  13.2 years, with a slight male predominance (56.3%). Patients in the eCRS group had significantly higher rates of comorbid asthma (46.2% vs. 16.2%; p < 0.001), self-reported AERD (15.8% vs. 2.2%; p < 0.001), and clinical presentation of CRSwNP (81.5% vs. 27.9%; p < 0.001). Baseline objective markers of disease burden, including SNOT-22, Lund-Kennedy, and Lund-Mackay scores, were significantly higher in the eCRS group compared to the neCRS group (p < 0.001).

Table 1. Baseline Demographic, Clinical, and Radiological Characteristics of the Study Cohort (N = 320)

Abbreviations: AERD, Aspirin-Exacerbated Respiratory Disease; CRSwNP, Chronic Rhinosinusitis with Nasal Polyps; CRSsNP, Chronic Rhinosinusitis without Nasal Polyps; eCRS, Eosinophilic Chronic Rhinosinusitis; FESS, Functional Endoscopic Sinus Surgery; HPF, High-Power Field; neCRS, Non-Eosinophilic Chronic Rhinosinusitis; SNOT-22, 22-item Sino-Nasal Outcome Test.

Preoperative vs. Postoperative Drug Utilization Patterns

Evaluation of drug utilization revealed distinct shifts in pharmacological strategies following FESS, as well as clear divergence between histopathological endotypes.

Overall, preoperative drug utilization was marked by a heavy reliance on oral systemic antibiotics. In the 12 months preceding FESS, 270 out of 320 patients (84.4%) received at least one course of oral systemic antibiotics, with an overall mean of 3.2 ± 1.5 courses/patient/year. As shown in Table 2, systemic antibiotic consumption was significantly higher in the neCRS group prior to surgery compared to the eCRS group (3.8 ± 1.4 vs. 2.7 ±1.3 courses/year; p<0.001). Broad-spectrum beta-lactamase inhibitor combinations (e.g., Amoxicillin-Clavulanate) and macrolides (e.g., Azithromycin) were the predominant prescribed classes.

Following FESS, overall antibiotic consumption dropped significantly across the entire cohort to a mean of 0.8  ±  0.9 courses/patient/year (p < 0.001). The proportion of patients requiring systemic antibiotics in the 12 months post-FESS fell from 84.4% to 31.3%.

Conversely, systemic corticosteroid utilization exhibited the opposite distribution. Preoperatively, systemic corticosteroids were consumed by 68.8% of eCRS patients compared to only 23.5% of neCRS patients (p<0.001). Postoperatively, the absolute requirement for systemic corticosteroids dropped markedly in both groups. However, 33.7% of eCRS patients still required at least one post-surgical rescue course of oral steroids for acute inflammatory exacerbations or recurrent polyposis, whereas only 7.4% of neCRS patients required post-surgical systemic steroids (p < 0.001).

Compliance with INCS and high-volume nasal saline irrigations improved substantially postoperatively. At 12-month follow-up, 88.4% of patients maintained regular INCS therapy. The utilization of second-line add-on therapies, such as LTRAs (Montelukast), was almost exclusively confined to the eCRS group both pre- and post-operatively (28.3% vs. 4.4% post-op; p < 0.001). Advanced biologic therapy (Dupilumab) was introduced postoperatively in 14 patients (7.6%) with severe recalcitrant eCRS.

Table 2. Drug Utilization Patterns Before and 12 Months After FESS Stratified by Histopathological Endotype

*Statistically significant reduction from Pre-FESS to Post-FESS in the total cohort (p < 0.001, Wilcoxon signed-rank test).

Histopathological Features and Cellular Profiling

Quantitative histological examination of surgical mucosal specimens demonstrated striking structural and cellular differences between the two clinical endotypes, as summarized in Table 3.

The mean tissue eosinophil count in the eCRS group was 38.4±18.6 per HPF, compared to 3.2±2.4 per HPF in the neCRS group (p<0.001). Conversely, neCRS tissue specimens demonstrated significantly higher neutrophil infiltration, with 54.4% showing moderate-to-severe neutrophilic infiltration, compared to only 12.0% in eCRS (p < 0.001).

Structural remodeling features also diverged sharply:

• Basement Membrane Thickness: Severe basement membrane thickening (>15 µm) was present in 48.9% of eCRS cases, compared to only 14.7% of neCRS cases (p<0.001).
• Submucosal Edema: Moderate-to-severe stromal edema was observed in 82.6% of eCRS specimens, reflecting intense vascular permeability, whereas neCRS specimens were characterized predominantly by dense subepithelial collagenous fibrosis (61.8% vs. 23.9%; p<0.001).
• Goblet Cell Hyperplasia: Extensive goblet cell hyperplasia (>50% of mucosal surface) was significantly more common in eCRS (58.2% vs. 22.1%; p<0.001).
• Osteitis: Histological evidence of bone remodeling and osteitis in surgical fragments was present in 35.3% of the total cohort, with a higher prevalence in revision FESS cases and eCRS patients (42.4% vs. 25.7%; p = 0.002).

Table 3. Detailed Histopathological and Remodeling Parameters Stratified by Endotype

Correlation Between Drug Utilization and Histopathological Profiles

Bivariate correlation analysis revealed strong relationships between specific tissue markers and pharmacological consumption:

1. Systemic Corticosteroid Consumption vs. Eosinophilia: Annual preoperative systemic corticosteroid courses correlated strongly with tissue eosinophil counts per HPF (r = 0.68, p < 0.001). Furthermore, patients with tissue eosinophilia ≥ 30/HPF had a 4.2-fold higher likelihood of requiring postoperative rescue oral steroids compared to those with counts between 10–29/HPF (p < 0.001).
2. Systemic Antibiotic Consumption vs. Neutrophilia: Preoperative systemic antibiotic courses correlated directly with the degree of tissue neutrophilic infiltration (r = 0.59, p < 0.001) and subepithelial fibrosis (r = 0.44, p < 0.001).
3. Basement Membrane Thickening vs. INCS Maintenance: Patients with severe basement membrane thickening (>15 µm) demonstrated significantly higher rates of disease breakthrough despite continuous INCS compliance, showing an inverse correlation with post-FESS SNOT-22 score improvement (r = -0.52, p < 0.001).

Multivariate Analysis: Predictors of High

Postoperative Drug Utilization and Recurrence

To evaluate independent risk factors for recalcitrant post-FESS disease defined as requiring multiple rescue courses of systemic steroids/antibiotics or exhibiting endoscopic polyp recurrence at 12 months a multivariate binary logistic regression model was constructed (Table 4).

After adjusting for age, sex, smoking, baseline SNOT-22, and Lund-Mackay scores, the analysis established that:

• Tissue Eosinophilia (≥ 10/HPF) was the primary independent predictor of recalcitrant disease requiring high post-FESS corticosteroid maintenance (aOR: 3.42, 95% CI: 1.88–6.22, p < 0.001). Extreme eosinophilia (≥ 30/HPF) further elevated this risk (aOR: 5.12, 95% CI: 2.64–9.95, p < 0.001).
• Severe Basement Membrane Thickening (>15 µm) independently doubled the risk of disease recurrence and pharmacotherapeutic escalation (aOR: 2.15, 95% CI: 1.14–4.05, p = 0.018).
• Histopathological Osteitis was an independent predictor of revision surgical need and post-FESS antibiotic reliance (aOR: 1.98, 95% CI: 1.08–3.62, p = 0.027).
• Comorbid Asthma remained an independent clinical predictor (aOR: 2.04, 95% CI: 1.12–3.71, p = 0.019).

Table 4. Multivariate Logistic Regression Model for Independent Predictors of Recalcitrant Post-FESS Disease and Elevated Maintenance Pharmacotherapy at 12 Months

 *Adjusted for age, sex, smoking status, baseline SNOT-22, Lund-Mackay CT score, and prior FESS status.

This prospective observational study provides a detailed examination of the relationship between clinical drug utilization and tissue-level histopathology in patients undergoing Functional Endoscopic Sinus Surgery for chronic rhinosinusitis. Our findings highlight a sharp divergence in pharmacological trajectories driven by underlying cellular endotypes and structural tissue remodeling. Specifically, we demonstrate that while FESS successfully reduces overall antibiotic consumption across all cohorts, patients with eosinophilic CRS (≥ 10 eosinophils/HPF) and severe basement membrane thickening experience significantly higher rates of persistent post-surgical corticosteroid dependency and disease recurrence. Drug Utilization Trends and the Problem of Antibiotic Overuse A central finding of this study is the marked discordance between preoperative drug utilization and guideline-recommended management. In the 12 months prior to surgical intervention, over 84% of patients received repeated courses of systemic antibiotics, averaging over 3 courses per year. This heavy reliance on antibiotics was particularly pronounced in the non-eosinophilic CRS group (3.8 ± 1.4 courses/year). This real-world pattern reflects a common clinical pitfall: empirical antibiotic over-prescription for chronic inflammatory sinonasal symptoms that are misdiagnosed as recurrent bacterial infections [14]. Guidelines such as EPOS 2020 and the International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR-R) emphasize that long-term or repeated short-course systemic antibiotics offer minimal therapeutic benefit in non-infectious, neutrophilic, or eosinophilic inflammatory CRS unless clear purulent exacerbation is radiologically or endoscopically confirmed [10,15]. The drastic reduction in systemic antibiotic requirements observed post-FESS (dropping from 84.4% to 31.3%) underscores the mechanical therapeutic efficacy of surgery. By opening obstructed sinus ostia, removing diseased mucosal hardware, and restoring mucociliary clearance, FESS mitigates stagnant secretions that predispose patients to secondary bacterial superinfections [16]. Consequently, surgical intervention serves as an effective antimicrobial stewardship mechanism, reducing inappropriate systemic antibiotic exposure. Histopathological Endotyping as a Driver of Post-FESS Pharmacotherapy While FESS restores physical sinus patency, it does not alter the underlying systemic immunologic predisposition of the patient [17]. Our data demonstrate that post-FESS medical requirements are overwhelmingly dictated by the tissue endotype. In our cohort, 57.5% of patients exhibited eosinophilic CRS (≥ 10 eosinophils/HPF). This group presented with significantly higher baseline subjective symptom burdens (SNOT-22) and objective radiological disease (Lund-Mackay), as well as elevated rates of comorbid asthma (46.2%) and AERD (15.8%). Postoperatively, despite mechanical clearance of polyps, over one-third of eCRS patients required rescue systemic corticosteroids within 12 months to manage breakthrough mucosal inflammation. Pathophysiologically, eCRS is driven by TH2-mediated inflammation characterized by dense infiltration of eosinophils, mast cells, and type 2 innate lymphoid cells (ILC2s) [18]. Interleukin-5 (IL-5) promotes eosinophil maturation and survival, while IL-4 and IL-13 drive epithelial barrier disruption, mucus hypersecretion, and tissue edema [19]. When activated, eosinophils release cytotoxic granule proteins—including Major Basic Protein (MBP), Eosinophil Peroxidase (EPO), and Eosinophil-Derived Neurotoxin (EDN) which induce extensive mucosal epithelial stripping and persistent basement membrane damage [20]. Our multivariate analysis established that tissue eosinophilia (≥ 10/HPF) increases the odds of recalcitrant disease requiring high post-FESS maintenance therapy by 3.42-fold, escalating to 5.12-fold in severe tissue eosinophilia (≥ 30/HPF). This aligns with findings from international cohorts (such as the JESREC study in Japan), which identified mucosal eosinophilia as the single most critical determinant of post-FESS polyp recurrence [13,21]. Tissue Remodeling: Basement Membrane Thickening and Osteitis In addition to cellular infiltrates, structural tissue remodeling parameters emerged as key prognostic indicators. Basement membrane thickening a consequence of persistent subepithelial extracellular matrix deposition driven by Transforming Growth Factor-beta (TGF-\beta)—was identified in over two-thirds of eCRS patients and served as an independent predictor of post-FESS treatment failure (aOR: 2.15). Thickening of the basement membrane impairs the passive diffusion of topical intranasal corticosteroids into the deeper submucosal stromal layers [22]. This explains why patients with severe basement membrane thickening (>15 µm) frequently exhibit clinical resistance to standard INCS sprays, presenting with rapid disease breakthrough despite high reported medication compliance. Furthermore, histopathological osteitis characterized by neo-osteogenesis, bone resorption, and Haversian canal enlargement within the underlying ethmoid trabeculae was present in 35.3% of surgical specimens. Osteitis acts as a persistent inflammatory reservoir, harboring inflammatory cytokines that continuously stimulate the overlying mucosa long after surface soft tissue has been resected [23]. In our model, osteitis independently doubled the risk of post-FESS treatment escalation (aOR: 1.98), highlighting the need for thorough surgical clearance of hyperostotic bony partitions during primary FESS. Clinical Implications: Transitioning to Precision Pharmacotherapy The clinical findings of this study argue against a uniform, empirical approach to post-FESS care. Currently, routine post-FESS pathology reports in many centers provide only non-specific diagnoses (e.g., "inflammatory sinonasal polyp" or "chronic active sinusitis"). Our findings demonstrate that routine quantitation of mucosal eosinophils per HPF and assessment of basement membrane status should be mandatory standard components of surgical pathology reporting in rhinology. Knowing the specific endotype allows for immediate post-operative stratification: 1. Low-Risk (neCRS): Patients can be managed postoperatively with high-volume saline irrigations and standard INCS, with a focus on avoiding unnecessary systemic antibiotics. 2. High-Risk (eCRS with severe eosinophilia/BM thickening): Patients require intensive topical anti-inflammatory strategies from the early postoperative period. This includes high-volume topical steroid rinses (e.g., Budesonide respules off-label irrigation) or exhalation delivery systems to maximize deep sinonasal distribution [24]. 3. Biologic Integration: For patients exhibiting severe tissue eosinophilia (≥ 30/HPF) combined with comorbid asthma or AERD who fail standard postoperative steroid maintenance, early introduction of targeted TH2 biologics (e.g., Dupilumab, Mepolizumab, Omalizumab) should be prioritized [25]. In our study, the subset of 14 patients initiated on post-FESS Dupilumab achieved complete stabilization of endoscopic disease without requiring further systemic steroids. Strengths and Limitations Strengths of this study include its prospective design, standardized protocol for both drug utilization metrics (WHO ATC/DDD) and surgical techniques, precise quantitative histopathological evaluation by blinded pathologists, and high 12-month patient retention. Several limitations warrant consideration. First, as a single-center study conducted at a tertiary referral institution, the cohort may reflect a higher baseline disease severity than seen in primary care settings, introducing potential referral bias. Second, while we controlled for systemic steroid use within 3 weeks of surgery, prior long-term steroid exposure could have partially blunted tissue inflammatory markers in some patients. Third, tissue cytokine profiles (e.g., direct tissue concentrations of IL-5, IL-13, Periostin) were not directly quantified using ELISA or immunohistochemistry due to cost constraints, relying instead on structural and cellular histopathological surrogates. Finally, a 12-month follow-up period, while adequate for evaluating short-to-medium term recurrence, may understate long-term polyp recurrence rates, which can manifest up to 3 to 5 years postoperatively.

This prospective study demonstrates a clear correlation between sinonasal histopathological endotypes and drug utilization patterns in patients undergoing Functional Endoscopic Sinus Surgery. While FESS effectively reduces inappropriate systemic antibiotic consumption across all patient groups, post-surgical outcomes and maintenance medication requirements are strongly governed by tissue pathology. High tissue eosinophilia (≥ 10/HPF), severe basement membrane thickening (>15 µm), and histopathological osteitis serve as powerful independent predictors of persistent corticosteroid dependency and recalcitrant disease.

Incorporating routine quantitative histopathological endotyping into post-FESS management enables clinicians to move away from empirical, reactive prescribing toward personalized, proactive therapeutic regimens. Tailoring postoperative anti-inflammatory and biologic therapies to specific tissue endotypes holds immense promise for improving long-term surgical success, reducing global antibiotic over-prescription, and enhancing quality of life for patients with chronic rhinosinusitis.

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