The Rate and Predictors of Allergic Fungal Rhinosinusitis Recurrence Post-sinus Surgery: A Retrospective Cohort Study

Objectives Chronic rhinosinusitis (CRS) is the persistent inflammation of the mucosal lining of the paranasal sinuses (PNS). By definition, the inflammatory process persists beyond 12 weeks. One of its subtypes is allergic fungal rhinosinusitis (AFRS), which has a high risk of recurrence, leading to revision surgery. This study aimed to establish the predictive factors for the recurrence of AFRS in post-sinus surgery patients. Methods This single-center retrospective study was conducted in Al-Noor Specialist Hospital, Makkah, Saudi Arabia. The charts of patients with AFRS who underwent surgery in our rhinology clinic between 2000 and 2020 were reviewed. Results Among the 116 patients included in this study, approximately half (53%) were female, with a median age of 24.5 years. Thirty-nine (33.6%) patients had recurrence post-sinus surgery, with 33.3% occurring within six months of follow-up. The results showed that patients with coexisting bronchial asthma were three times more likely to experience recurrence (adjusted odds ratio {AOR}, 3.43; confidence interval {CI}, 1.35-8.71), patients with uncorrected deviated nasal septum (DNS) were three times more likely to experience symptoms again following surgery (AOR, 3.70; CI, 1.14-12.02), and patients who presented with concomitant sinus headaches are 66% less likely to experience recurrence (AOR, 0.34; CI, 0.13-0.86). Conclusion The results showed that 33.62% of patients experienced recurrence following surgery. Bronchial asthma and DNS were strongly associated with recurrence; however, their presence does not always imply the need for additional surgery.


Introduction
Chronic rhinosinusitis (CRS) is the persistent inflammation of the mucosal lining of the paranasal sinuses (PNS) for at least 12 weeks with or without topical or systemic therapeutic measures [1]. It is classified into primary and secondary CRS. Primary CRS is furtherly categorized based on anatomical localization and the dominant endotype [2]. Allergic fungal rhinosinusitis (AFRS) is a type 2 dominant noninvasive disease, characterized by an intensified inflammatory process through immunoglobulin E (IgE)-mediated hypersensitivity against fungal components. The main pathologic feature of AFRS is the partial or complete obstruction of the ostia of the paranasal sinuses, which become packed with thick, heavy, and dense mucinous secretions accompanied by eosinophil degranulation and mast cell [3]. Five major criteria were proposed by Bent and Kuhn for the diagnosis of AFRS: (1) confirmed type 1 hypersensitivity by history, serology, or skin tests; (2) the presence of nasal polyps; (3) radiological findings on computed tomography (CT); (4) eosinophil-containing mucus; and (5) positive fungal stain [4].
The ideal management for AFRS is still under scrutiny. However, both surgical and medical interventions may be required [5]. The medical and surgical component thrust is to eradicate the allergic mucin and debris, establish aeration and permanent sinus drain, and control recurrence. In 2015, Philpott et al. [6] studied the incidence of revision surgery in the United Kingdom and found that patients with AFRS had high risks of both initial and revision surgeries. However, it must be noted that the overall prevalence of AFRS varies according to geographical location. A review of the literature revealed that large numbers of AFRS cases were reported from regions of elevated temperature and humidity [7]. An incidence of 6.95%-7.4% was reported in the Asian population based on a nationwide survey conducted in China and Korea [8]. Meanwhile, the rate was between 2.1% and 4.2% in Western countries [9].
Functional endoscopic sinus surgery (FESS) is commonly required for the management of AFRS. Approximately 54.5% of cases require revision surgery [10]. Surgeons may encounter further challenges while performing revision FESS due to the past removal of critical anatomical landmarks and the presence of adhesions. Lee et al. [11] compared the surgical outcomes of primary and revision endoscopic sinus surgeries and reported similar success rates. Although high recurrence rates have been reported, the risk factors and predictors of the disease have not yet been extensively investigated. The aim of this study is to establish predictive factors for recurrence in patients with AFRS post-sinus surgery.

Study design and selection of patients
This single-center retrospective cohort study was conducted in a tertiary hospital in Makkah, Saudi Arabia. The charts of patients who presented to our rhinology clinic with chronic sinusitis and underwent rhinology surgery from November 2000 to December 2020 were reviewed. Patients who met the following criteria for AFRS were included: the presence of eosinophilic mucin, nasal obstruction, unilateral or bilateral nasal polyp, and computed tomography (CT) results characteristic of AFRS. Patients who are immunocompromised, have uncontrolled diabetes, are histopathologically diagnosed with invasive fungal infection, underwent sinus surgery previously outside our hospital, underwent rhinology surgery other than functional endoscopic sinus surgery (FESS), or are followed up for less than nine months were excluded.

Data collection and assessment criteria
Medical records were screened, and data regarding sociodemographic information, clinical presentation, histopathological findings, past medical history, paranasal sinus (PNS) CT scan, pre-and postoperative medical management, intraoperative notes, and postoperative clinic visit notes were extracted.
Patients received nasal irrigation, antihistamine, intranasal steroid, and/or systematic steroid preoperatively. All the included patients underwent FESS, and turbinectomy or septoplasty was performed whenever indicated. Patients received saline nasal douching and were placed on intranasal steroids postoperatively. A total of 42 patients received systemic steroids with prednisone 0.2-0.5 mg/day for 5-7 days. Subsequently, they were followed up and reassessed at 1-2 weeks, three months, and 6-9 months postoperatively and as needed afterward. Patients were considered to have a recurrence if they developed at follow-up nasal obstruction, nasal discharge, postnasal drip, or loss of smell or if an endoscopic examination showed a nasal polyp or thick secretions. In addition, a PNS CT scan showed the opacification of the sinuses or double density.

Data analysis
The data were extracted, revised, cleaned, coded, and input into the statistical software Statistical Package for Social Sciences (SPSS) version 25 (IBM SPSS Statistics, Armonk, NY). All statistical analyses used twotailed tests. Statistical significance was set at P < 0.05. Descriptive analysis based on frequency and percentage was performed for categorical variables. Since the numerical variables showed abnormal distribution, the median and interquartile ranges (IQR) were calculated. Comparisons between the groups were performed using chi-square test, Fisher's exact test, and Mann-Whitney test whenever appropriate. Univariate regression analysis was performed to explore variables that predict recurrence post-surgery. Factors with P < 0.25 were included for the multivariate logistic regression analysis. In multivariate logistic regression, a backward stepwise approach was performed with a removal criterion of P ≥ 0.10. If the removed variables changed the model's β coefficient by more than 20%, the variables were retained again in the model to adjust other variables in the model.

Results
A total of 585 patients were diagnosed with chronic sinusitis and underwent surgery. Among them, 409 patients were excluded because they were diagnosed with other diseases other than AFRS. In addition, 20 patients were excluded because they did not undergo FESS. Moreover, 40 patients did not meet the diagnostic criteria or were followed up for less than nine months. Thus, 116 patients were finally included in our study as shown in Figure 1.

AFRS: allergic fungal rhinosinusitis
Regarding the characteristics of the patients with AFRS, approximately half of the patients were females, with ages ranging from 18.6 to 34 years and a median age of 24.5 years. The patients reported the following: nasal obstruction (88.8%), headache (70.7%), bilateral nasal polyp (52.6%), unilateral nasal polyp (47.4%), rhinorrhea (25%), and sneezing (19%). In addition, a significant number of patients were found to have a clinically significant deviated nasal septum (DNS) (12.9%). A total of 31 patients (26.7%) had a history of bronchial asthma, while the remaining patients had eczema (12.1%), diabetes mellitus (6.9%), and hypothyroidism (0.9%). FESS was performed on all 116 patients; in addition, 16   Out of 116 patients, 39 had a recurrence. The presence of DNS (P = 0.037) and a history of bronchial asthma (P = 0.049) were significantly associated with the recurrence of symptoms after surgery. A significant association between patients with other clinical findings and recurrence was not observed as shown in Table  1.

Discussion
The clinical features of AFRS and other forms of chronic sinusitis highly overlap [12]. The symptoms are initially similar to CRS; however, as AFRS progresses, a unique set of radiological and pathophysiological findings can be observed. The specific pathogenesis of AFRS has not yet been fully understood. Nevertheless, it is unilateral in 19% of cases; however, there is no clear explanation for why AFRS tends to be unilateral [13].
The main symptoms of patients with AFRS in our study were nasal obstruction and headache. This finding is similar to another study that was conducted from January 2011 to December 2015 at the Liaquat National Hospital, which reported that the common presenting symptoms of AFRS included nasal obstruction, headache, nasal discharge, and proptosis [14].
After nasal obstruction and headache, rhinorrhea was the most common complaint of patients. This result was also supported by a study conducted by the honorary and corresponding members (otorhinolaryngologists) of the Italian Society of Rhinology [15].
Although the recurrence rate of AFRS varies from one study to another, it was reportedly mostly high (e.g., in our study, 33% of patients had a recurrence). These results are almost consistent with the study of Alghonaim et al. [16], which reported that 29% of patients with AFRS had recurrence post-sinus surgery. Moreover, a study by Makary et al. [13] reported a recurrence rate of up to 50% in patients with AFRS. In addition, a previous study published in 2017 by Marglani et al. [17] included 52 patients diagnosed with AFRS. Hence, only 16 patients reported to have unilateral disease involvement had a recurrence rate of 19%, and those with bilateral AFRS involvement had a 61% recurrence. These findings should be taken into consideration in managing these patients.
In the current study, asthma and AFRS were strongly associated. This finding was also supported by a previous study in Karachi, Pakistan, from December 2016 to November 2018, which reported that patients with asthma are more likely to have this disease [18]. In addition, patients with concha bullosa usually develop AFRS, which means that they may be potentially associated [13].
In summary, our study determined the recurrence rate and potential factors that may lead to revision surgery in patients with AFRS. Nevertheless, our study has several limitations. The most significant limitations were the retrospective nature of the study and the inclusion of only a small number of patients. Moreover, the possibility of our patients reporting facial pain and heaviness as headache was also high. Another weak point was the lack of the standardization of the operative technique and postoperative care. In addition, the follow-up period was limited to only nine months. Finally, due to the varying culture protocols of different laboratories, reporting on fungal cultures was challenging.

Conclusions
A total of 116 patients were diagnosed with AFRS, with 39 experiencing a recurrence but only 17 undergoing revision surgery. Bronchial asthma and DNS were strongly associated with recurrence; however, their presence does not always imply the need for additional surgery, as this decision must always depend on the treating surgeon and postoperative care. Nevertheless, further understanding of the establishment of AFRS in poorly aerated nasal passages and the associated poorly aerated sinuses is a factor that must be borne in mind.