Abstract
Objectives: To identify the risk factors for postoperative relapse of chronic rhinosinusitis with nasal polyps (CRSwNP) using multivariate Logistic regression analysis and to explore potential improvements in clinical treatment measures. Methods: We selected 270 CRSwNP patients who underwent surgery at The First People’s Hospital of Jiangxia District between January 2022 and July 2024. The patients were divided into two groups based on the presence or absence of postoperative relapse: 40 cases with relapse were designated as the relapse group, and the other 230 cases without relapse were designated as the non-relapse group. Serum samples were collected from both groups before surgery to measure eosinophilic cationic protein (ECP)/myeloperoxidase (MPO), immunoglobulin E (IgE), and C-C motif chemokine ligand 4 (CCL4). Receiver operating characteristic (ROC) curves were used to analyze the predictive value of these indices for postoperative relapse in CRSwNP patients. The correlation of these indices with postoperative relapse was analyzed using Spearman’s correlation coefficients. Univariate and multivariate analyses were employed to identify factors influencing postoperative relapse of CRSwNP. Results: The relapse group showed markedly higher ECP/MPO, IgE, and CCL4 compared to the non-relapse group. The area under the curve (AUC) for predicting postoperative relapse of CRSwNP by each single indicator approximated 0.800, while the AUC of combined detection was above 0.900. ECP/MPO, IgE, and CCL4 all exhibited a significant positive correlation with postoperative relapse of CRSwNP. Univariate analysis revealed that the postoperative relapse of CRSwNP was significantly linked to the Davos score of nasal polyps, smoking history, postoperative infection, ECP/MPO, IgE, and CCL4. Multivariate analysis confirmed that ECP/MPO, IgE, and CCL4 were independent risk factors for postoperative recurrence of CRSwNP. Conclusions: ECP/MPO, IgE, and CCL4 are reliable predictors of postoperative relapse in CRSwNP patients, and their combined detection can further enhance the predictive accuracy. These biomarkers are closely and positively correlated with postoperative relapse and serve as risk factors for postoperative recurrence. Given the elevated risk of postoperative recurrence in CRSwNP patients with high levels of ECP/MPO, IgE, and CCL4, it is recommended to optimize clinical treatment strategies for these patients to reduce the likelihood of recurrence.
Keywords: Chronic rhinosinusitis, nasal polyps, postoperative relapse, multivariate Logistic regression analysis, improvement in clinical treatment
Introduction
Chronic rhinosinusitis (CRS) is an upper airway inflammatory disorder primarily affecting the nasal cavity and sinus mucosa. It is not only prevalent but also characterized by a complex pathological process and diverse etiology [1,2]. Generally, CRS is classified into two types based on the presence or absence of nasal polyps, namely CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP) [3]. In comparison to the latter, CRSwNP has a higher incidence risk, with patients typically experiencing more severe clinical manifestations, greater impairment to their quality of life, and a heavier personal and socioeconomic burden [4,5]. CRSwNP patients often present with several comorbidities, such as asthma, sleep disorders, allergic rhinitis, gastroesophageal reflux disease, and cognitive dysfunction, which affect their daily lives to varying degrees [6]. Epidemiological data indicate that CRSwNP affects 0.5-4.0% of the global population [7]. Currently, surgical intervention is the main treatment modality for CRSwNP. However, there is a certain risk of postoperative recurrence, which increases the complexity of treatment [8]. To alleviate the disease impact and reduce the economic burden on CRSwNP patients, it is crucial for healthcare providers to explore the risk factors for postoperative relapse and optimize the treatment and management strategies for CRSwNP.
Eosinophilic cationic protein (ECP), a biomarker derived from eosinophil secretory granules, is released in response to stimuli such as immunoglobulins and complements. It exhibits antibacterial and antiviral properties and has been identified as a potential marker of eosinophilic inflammation [9,10]. Myeloperoxidase (MPO), essentially a heme enzyme, can be used for screening infectious rhinitis [11]. ECP/MPO levels can also serve as an indicator for the endotype diagnosis of CRS [12]. Previous research has also indicated that immunoglobulin E (IgE), closely associated with elevated eosinophilic inflammation, plays a significant role in the pathophysiological process of nasal polyposis to some extent [13]. C-C motif chemokine ligand 4 (CCL4), a CC chemokine related to immune cell transport and derived from airway epithelial cells, influences the accumulation and activation of eosinophils at inflammatory sites [14,15]. Despite their potential relevance, limited studies have investigated whether ECP/MPO, IgE, and CCL4 can predict postoperative relapse of CRSwNP and serve as risk factors for recurrence. This study aims to address this gap by analyzing these biomarkers to contribute to the prevention of postoperative recurrence of CRSwNP.
Information and methodology
General information
This retrospective study was approved by the Ethics Committee of The First People’s Hospital of Jiangxia District. This study selected 270 patients with CRSwNP who underwent surgical treatment at The First People’s Hospital of Jiangxia District from January 2022 to July 2024. Of these, 40 cases were assigned to the relapse group and 230 to the non-relapse group. The two cohorts were clinically comparable, with no statistical difference in general information (P>0.05).
Inclusion and exclusion criteria
Inclusion criteria: Patients aged 18 years or older who met the diagnostic criteria for CRSwNP [16] and the Davos scoring criteria for nasal polyps [17]; All patients were treatment-naive, diagnosed at our hospital, and underwent endoscopic sinus surgery; no relevant drug treatment in the four weeks prior to operation; no history of postoperative medication; and intact clinical data and case records.
Exclusion criteria: Those with fungal sinusitis, posterior maxillary sinus nostril polyps, a history of endoscopic sinus surgery, impaired heart, lung, or kidney function, infectious diseases, or immune system disorders; pregnant or lactating women.
Treatment
Preoperative nasal endoscopy and coronal CT scans of the sinuses were carried out. Under general anesthesia, the operation was completed using the Messerklinger technique. The procedure involved the removal of nasal polyps, resection of the uncinate process, and opening of the sphenoid, ethmoid, or frontal sinuses. The maxillary sinus ostium was enlarged, and the diseased tissues in the sinus cavity and ostium were removed. Both groups received routine anti-infection treatment after the operation.
Detection indicators
Fasting venous blood (2 mL) was collected from all patients in the morning, and the serum was separated by centrifugation. Biochemical indexes, including ECP and MPO levels, were detected by enzyme-linked immunosorbent assay (ELISA), and the ECP/MPO ratio was calculated. Serum IgE levels were quantified using radioimmunoassay, and CCL4 levels were detected by liquid-phase chip technology.
Patients’ medical records were retrieved from the hospital’s electronic medical record system. Information such as age, gender, body mass index (BMI), the course of chronic sinusitis, Davos score of nasal polyps, lesion location, smoking history, alcohol consumption history, and postoperative infections was collected. The relationship between the above-mentioned indicators and postoperative relapse was analyzed through univariate and multivariate analyses.
Statistical analysis
SPSS 21.0 was used for data analysis. For continuous data, mean ± standard error of the mean (SEM) was used for statistical description; the independent samples t-test was used for comparison between the two groups, and the paired t-test was used for comparison before and after treatment. For count data, rate (percentage) was used for representation, and the χ2 test was employed for comparison between groups. The estimation of the sample size in this study was based on the empirical rule of multivariate Logistic regression analysis. That is, the sample size should be at least 10 to 15 times the number of covariates. Assuming 10 covariates, the required sample size was calculated to be between 100 and 150 cases. The inclusion of 270 patients in this study far exceeded the minimum requirement, ensuring sufficient statistical power for the analysis. A P-value less than 0.05 indicated a statistically significant difference.
Results
Comparison of serum ECP/MPO, IgE, and CCL4 levels between the relapse and non-relapse groups
The serum levels of ECP/MPO, IgE, and CCL4 in the relapse group were (1.09±0.19), (711.42±114.22) pg/mL, and (62.40±17.12) pg/mL, respectively, compared to (0.80±0.31), (492.05±176.16) pg/mL, and (45.93±19.75) pg/mL in the non-relapse group (all P<0.001; Figure 1; Table 1).
Figure 1.
Comparison of serum ECP/MPO, IgE, and CCL4 levels between the relapse and non-relapse groups. A. Comparison of serum ECP/MPO levels. B. Comparison of serum IgE levels. C. Comparison of serum CCL4 levels. Note: ***P<0.001. ECP, eosinophilic cationic protein; MPO, myeloperoxidase; IgE, immunoglobulin E; CCL4, C-C motif chemokine ligand 4.
Table 1.
Comparison of serum ECP/MPO, IgE, and CCL4 levels between the relapse and non-relapse groups
| Indicators | Relapse group (n=40) | Non-relapse group (n=230) | χ2/t | P |
|---|---|---|---|---|
| ECP/MPO | 1.09±0.19 | 0.80±0.31 | 5.727 | <0.001 |
| IgE (pg/mL) | 711.42±114.22 | 492.05±176.16 | 7.597 | <0.001 |
| CCL4 (pg/mL) | 62.40±17.12 | 45.93±19.75 | 4.958 | <0.001 |
Note: ECP, eosinophilic cationic protein; MPO, myeloperoxidase; IgE, immunoglobulin E; CCL4, C-C motif chemokine ligand 4.
Prediction of postoperative relapse of CRSwNP
ROC analysis was conducted to evaluate the predictive value of serum ECP/MPO, IgE, and CCL4 for postoperative relapse of CRSwNP. The analysis results indicated that the area under the curve (AUC) for ECP/MPO predicting postoperative relapse of CRSwNP was 0.843, with specificity and sensitivity being 85.00% and 75.22%, respectively, and the optimal cut-off value being 0.90. The AUC of IgE for predicting postoperative recurrence of CRSwNP was 0.853, with the specificity, sensitivity, and optimal cut-off value being 87.50%, 73.04%, and 592.00 pg/mL, respectively. The AUC of CCL4 for predicting postoperative relapse of CRSwNP was 0.741, the specificity was 87.50%, the sensitivity was 53.91%, and the best cut-off value was 47.50 pg/mL. Furthermore, the combined AUC for predicting postoperative relapse using all three indicators was 0.933, with 100.00% specificity, 76.96% sensitivity, and an optimal cut-off value of 0.91 (Figure 2 and Table 2).
Figure 2.
ROC analysis of the predictive value of ECP/MPO, IgE, and CCL4 for postoperative relapse of CRSwNP. ROC, receiver operating characteristic; ECP, eosinophilic cationic protein; MPO, myeloperoxidase; IgE, immunoglobulin E; CCL4, C-C motif chemokine ligand 4; CRSwNP, chronic rhinosinusitis with nasal polyps.
Table 2.
Predictive performances of ECP/MPO, IgE, and CCL4 for postoperative relapse of CRSwNP analyzed by ROC curve analysis
| Indicators | AUC | SE | P value | Specificity | Sensitivity | Optimal cutoff |
|---|---|---|---|---|---|---|
| ECP/MPO | 0.843 | 0.025 | <0.001 | 85.00% | 75.22% | 0.90 |
| IgE | 0.853 | 0.026 | <0.001 | 87.50% | 73.04% | 592.00 pg/mL |
| CCL4 | 0.741 | 0.038 | <0.001 | 87.50% | 53.91% | 47.50 pg/mL |
| Combined detection | 0.933 | 0.015 | <0.001 | 100.00% | 76.96% | 0.91 |
Note: ECP, eosinophilic cationic protein; MPO, myeloperoxidase; IgE, immunoglobulin E; CCL4, C-C motif chemokine ligand 4; CRSwNP, chronic rhinosinusitis with nasal polyps; ROC, receiver operation characteristics.
Univariate analysis of factors influencing postoperative relapse of CRSwNP
Univariate analysis (Table 3) revealed significant associations between postoperative relapse of CRSwNP and the following factors: Davos score for nasal polyps, smoking history, and postoperative infection (all P<0.05). No significant associations were found with age, gender, BMI, course of chronic sinusitis, lesion location, or alcohol consumption history (all P>0.05).
Table 3.
Univariate analysis of factors influencing postoperative relapse of CRSwNP
| Variable | Relapse group (n=40) | Non-relapse group (n=230) | χ2/t | P |
|---|---|---|---|---|
| Age (years old) | 40.70±9.41 | 41.83±12.03 | 0.565 | 0.573 |
| Gender | 0.316 | 0.574 | ||
| Male | 24 (60.00) | 127 (55.22) | ||
| Female | 16 (40.00) | 103 (44.78) | ||
| Body mass index (kg/m2) | 23.32±2.48 | 23.50±2.44 | 0.430 | 0.668 |
| Course of Chronic Sinusitis (Year) | 5.78±2.06 | 5.57±2.14 | 0.576 | 0.565 |
| Davos score of nasal polyps (points) | 2.15±0.70 | 1.46±0.57 | 6.819 | <0.001 |
| Lesion location | 2.020 | 0.155 | ||
| Olfactory cleft polyp | 12 (30.00) | 46 (20.00) | ||
| Nasal septum deviation | 28 (70.00) | 184 (80.00) | ||
| Smoking history | 6.251 | 0.012 | ||
| Without | 27 (67.50) | 106 (46.09) | ||
| With | 13 (32.50) | 124 (53.91) | ||
| Alcoholism history | 0.702 | 0.402 | ||
| Without | 18 (45.00) | 120 (52.17) | ||
| With | 22 (55.00) | 110 (47.83) | ||
| Postoperative infection | 9.150 | 0.003 | ||
| Without | 16 (40.00) | 150 (65.22) | ||
| With | 24 (60.00) | 80 (34.78) |
Note: CRSwNP, chronic rhinosinusitis with nasal polyps.
Multivariate analysis of factors affecting postoperative relapse of CRSwNP
Variables with significant differences in the univariate analysis, as well as serum indicators such as ECP/MPO, IgE, and CCL4 with significant differences between groups, were taken as independent variables, and postoperative relapse was taken as the dependent variable (Table 4).
Table 4.
Assignment table
| Indicators | Variable | Quantization assignment |
|---|---|---|
| Davos score of nasal polyps | X1 | <1.50 points =0, ≥1.50 points =1 |
| Smoking history | X2 | Without =0, with =1 |
| Postoperative infection | X3 | Without =0, with =1 |
| ECP/MPO | X4 | <0.90 =0, ≥0.90=1 |
| IgE | X5 | <592.00 pg/mL =0, ≥592.00 pg/mL =1 |
| CCL4 | X6 | <47.50 pg/mL =0, ≥47.50 pg/mL =1 |
| Postoperative relapse | Y | Non-relapse =0, relapse =1 |
Note: ECP, eosinophilic cationic protein; MPO, myeloperoxidase; IgE, immunoglobulin E; CCL4, C-C motif chemokine ligand 4.
Multivariate binary Logistic regression analysis demonstrated that the Davos score for nasal polyps, postoperative infection, ECP/MPO, IgE, and CCL4 were all significant risk factors for postoperative relapse of CRSwNP (all P<0.05). However, smoking history was not found to be a significant risk factor (P>0.05; Table 5). Subsequently, a nomogram for predicting the postoperative relapse risk of CRSwNP was constructed based on the binary Logistic regression analysis. The total score ranged from 0 to 550 points, allowing prediction of the postoperative recurrence risk of CRSwNP within a range of 10.00%-90.00% (Figure 3).
Table 5.
Multivariate analysis of factors influencing postoperative relapse of CRSwNP
| Variable | β | S.E. | Wald | P | OR | 95% CI |
|---|---|---|---|---|---|---|
| Davos score of nasal polyps | 1.849 | 0.552 | 11.197 | 0.001 | 6.352 | 2.151-18.756 |
| Smoking history | -0.838 | 0.503 | 2.777 | 0.096 | 0.433 | 0.161-1.159 |
| Postoperative infection | 1.144 | 0.497 | 5.294 | 0.021 | 3.139 | 1.185-8.317 |
| ECP/MPO | 1.987 | 0.536 | 13.749 | <0.001 | 7.293 | 2.551-20.847 |
| IgE | 1.761 | 0.576 | 9.355 | 0.002 | 5.821 | 1.883-17.997 |
| CCL4 | 1.994 | 0.598 | 11.139 | 0.001 | 7.346 | 2.277-23.697 |
Note: ECP, eosinophilic cationic protein; MPO, myeloperoxidase; IgE, immunoglobulin E; CCL4, C-C motif chemokine ligand 4; CRSwNP, chronic rhinosinusitis with nasal polyps.
Figure 3.
Nomogram for postoperative relapse risk of CRSwNP. ECP, eosinophilic cationic protein; MPO, myeloperoxidase; IgE, immunoglobulin E; CCL4, C-C motif chemokine ligand 4; CRSwNP, chronic rhinosinusitis with nasal polyps.
Discussion
CRSsNP is an inflammatory infectious disease that can affect the frontal, sphenoid, ethmoid, and maxillary sinuses, causing symptoms such as facial pressure, a sense of fullness, dryness, dry cough, nasal congestion, and obstruction; in more severe cases, it may even lead to olfactory dysfunction and nasal mucosal congestion [18]. The development of this disease is influenced by multiple factors, including mucosal inflammation, environmental factors, and asthma history [19]. This study primarily focuses on analyzing the predictive value of ECP/MPO, IgE, and CCL4 in postoperative relapse of CRSwNP, identifying risk factors for postoperative recurrence, and proposing strategies to optimize clinical treatment.
Our study found that serum ECP/MPO, IgE, and CCL4 levels were abnormally elevated in the relapse group compared to the non-relapse group, suggesting that these markers may play a role in the pathological progression of CRSwNP and contribute to the postoperative recurrence of CRSwNP. This aligns with the findings of Van Zele T et al. [20], who observed higher levels of IgE and ECP in patients with recurrent CRSwNP.
ROC analysis revealed that the AUCs of serum ECP/MPO, IgE, and CCL4 for predicting postoperative relapse of CRSwNP were 0.843, 0.853, and 0.741, respectively. Among them, IgE exhibited the best predictive performance, followed by ECP/MPO and CCL4. Furthermore, the combined detection of these three factors for predicting the postoperative recurrence of CRSwNP showed an increased AUC to 0.933, with 100.00% specificity and 76.96% sensitivity. In the report by Zheng M et al. [21], the relapse group showed notably higher levels of ECP/MPO, IgE, and CCL4 than the non-relapse group; moreover, IgE demonstrated the highest sensitivity (82.4%) in predicting CRSwNP recurrence, and ECP/MPO presented the highest specificity (83.7%), which were similar to the findings of this study.
Univariate analysis identified several factors potentially linked to postoperative relapse, including Davos score of nasal polyps, smoking history, and postoperative infection. The Davos score, which reflects the severity of nasal polyps, was associated with an increased risk of recurrence. A higher Davos score may imply more severe nasal polyps, which could increase the risk of relapse after surgery [22]. Smoking, which harms the nasal mucosal defense mechanisms, exacerbates the inflammatory response and increases the risk of recurrence [23]. Postoperative infections, by triggering excessive inflammation and increased secretion in the nasal mucosa, can also contribute to higher relapse rates [24,25]. Similarly, Fageeh YA et al. [26] indicated that smoking history, bilateral polyps, and asthma were significantly associated with postoperative recurrence, while Rosati D et al. [27] pointed out that the long-term postoperative recurrence of CRSwNP was closely correlated with high-level eosinophil infiltration and high interleukin (IL)-5 expression.
Multivariate analysis confirmed that the Davos score of nasal polyps, postoperative infection, ECP/MPO, IgE, and CCL4 were prominent risk factors for the postoperative recurrence of CRSwNP. In a prospective study by Brescia G et al. [28], it was also noted that eosinophilic CRSwNP was independently associated with postoperative recurrence in CRSwNP patients. Meanwhile, considering the influences of IgE and CCL4 on the potential pathological process of CRSwNP, we hypothesize that these two factors may, to some extent, mediate pre-existing and postoperative infections in CRSwNP patients. Further in-depth exploration and verification through relevant research in the future are thus warranted. Finally, a nomogram was developed based on these variables to predict the risk of postoperative recurrence. Clinically, for CRSwNP patients with a high Davos score of nasal polyps, presence of postoperative infection, and high levels of ECP/MPO, IgE, and CCL4, the adjustment of treatment strategies or the enhancement of targeted preventive care for postoperative infection should be considered to further reduce the postoperative relapse risk of CRSwNP patients.
This study has several limitations that warrant attention in future research. First, the duration of postoperative infections was not quantified, which limits our understanding of its precise relationship with CRSwNP recurrence. A more detailed analysis of infection duration would help clarify this link. Second, while ECP/MPO has been suggested as a potential nasal secretion indicator for CRS endotype diagnosis, further investigation into pre- and post-surgical levels of ECP/MPO in CRSwNP patients could help elucidate its clinical advantages and potential applications. Third, the time interval between surgery and relapse was not incorporated into our analysis, but this data would provide additional insights into the timing of postoperative recurrence. Finally, research into the molecular mechanisms linking IgE and CCL4 to pre- and postoperative infections in CRSwNP patients is needed to clarify their role in the recurrence process.
In summary, ECP/MPO, IgE, and CCL4 appear to play a significant role in mediating the postoperative recurrence mechanism in CRSwNP patients. When used in combination, these three biomarkers demonstrate strong diagnostic performance in predicting postoperative relapse. Additionally, they are identified as key risk factors for postoperative recurrence, alongside the Davos score of nasal polyps and postoperative infection. Our study offers valuable insights and reliable evidence for predicting the postoperative relapse of CRSwNP in patients and presents a quantitative tool for predicting the risk of postoperative recurrence in such patients.
Disclosure of conflict of interest
None.
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