Byproducts released by processes in cholesterol biosynthesis also serve as biologically active inflammatory mediators involved in innate and adaptive immunity. Airway inflammation is regulated by these mediators, and statins have also been reported to induce anti-inflammatory effects in human airway epithelial inflammation, as takes place in asthma or chronic rhinosinusitis (CRS) [3]. In addition, a lower prevalence of CRS and a reduced risk of acute exacerbations of asthma were reported in patients taking statins [4-6]. Thus, we investigated the effect of statins on postoperative outcomes in patients with CRS who underwent endoscopic sinus surgery (ESS).

We retrospectively reviewed the electronic medical records of 380 patients (82 patients taking statins and 298 patients without statin use) diagnosed with CRS with and without nasal polyps who underwent unilateral/bilateral functional ESS at single center between 2017 and 2021. All CRS patients satisfied the clinical criteria of the European Position Paper on Rhinosinusitis and Nasal Polyps [7]. Patients who were diagnosed with sinonasal tumors (e.g., inverted papilloma, angiofibroma, Natural killer (NK)/T cell lymphoma, odontogenic cyst, mucocele, postoperative cheek cyst, etc.) or fungal rhinosinusitis on a histological examination or had a history of head and neck malignancy or radiation therapy were excluded. The statin-taking group was defined as those who were already taking statins, such as atorvastatin, rosuvastatin, simvastatin, pravastatin, or pitavastatin, at their first visit to the outpatient clinic, regardless of whether the statin prescriptions were from our hospital or other hospitals. Revision surgery was defined as cases where one or more operations were performed other than the operation at the time of investigation by patients’ reports or medical records. In addition, uncontrolled CRS was defined as the presence of symptoms suggesting CRS and the prescription of rescue medication (antibiotics and/or oral steroids) and/or the performance of an additional operation at least 3 months after surgery. All data were analyzed using IBM SPSS ver. 20.0 statistical software (IBM Corp.). This study was conducted in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was approved by the Human Investigation Committee of Kyung Hee University (No. 2021-11-011), and informed consent was waived due to retrospective nature of this study.

First, we sought to identify the factors associated with the need for revision surgery. In the univariate analysis, statin use tended to be inversely correlated with the necessity of revision surgery (odds ratio [OR], 0.430; P=0.068) (Table 1). Interestingly, the multivariate analysis showed that statin use was significantly associated with a lower rate of revision surgery (adjusted OR, 0.412; P=0.038) (Table 1).

The preoperative eosinophil count, eosinophil cationic protein (ECP), and total immunoglobulin (Ig)E in serum were significantly higher in the statin-free group than in the statin-taking group (P<0.05 for all) (Table 2), although there was no significant difference in comorbid allergic diseases, including asthma and allergies, between the two groups (P>0.05 for all) (Table 2). Notably, we found a significantly lower rate of uncontrolled disease in statin-taking CRS patients than in CRS patients without statins (31.71% vs. 44.97%, P=0.031, respectively) (Table 2).

In terms of subjective and objective measurements such as the Lund-Mackay score, Sinonasal Outcome Test, the total nasal symptom score, the Lund-Kennedy endoscopic scores (L-K scores), and olfactory function test (Korean version of the Sniffin’ Sticks test II), no significant differences were found between the statin-taking and statin-free groups preoperatively. Regarding postoperative outcomes, we found that the statin-taking group showed significantly lower mean L-K scores for discharge than the statinfree group at 6 months (0.15±0.50 vs. 0.40±0.78, P=0.033) and 12 months (0.16±0.52 vs. 0.46±0.79, P=0.049) after surgery.

In this study, we found that statin use might have a beneficial effect on reducing the recurrence rate of CRS and improving the L-K score for discharge after ESS. The prevalence of CRS was reported to be 0.719–0.79 times lower in patients taking statins than in those not taking statins in previous studies conducted in the United States [4,5].

Anti-inflammatory and immunomodulatory effects of statins in the airway epithelium have recently been shown. In an in vitro study with human sinus tissues from CRS patients, the expression of inflammatory mediators such as CCL5, CCL11, and IL13RA was suppressed in patients taking statins [3]. Statins also regulated small G proteins/MAP kinases/nuclear factor kappa B (NF-κB) acting on various allergic responses in a mouse allergic asthma model [8]. Given these results, we hypothesized that statin use might modulate inflammatory responses in the nasal epithelium, resulting in protective effects on recurrence after surgery in patients with CRS. Interestingly, we demonstrated that the eosinophil count, ECP, and total IgE in serum were significantly higher in the statin-free group. Supporting our results, in a mouse model, both pravastatin and atorvastatin inhibited Th1- and Th2-mediated antibody responses, thereby reducing serum-specific IgE, IgG, IgG1, and IgG2a levels, which effectively regulated airway hypersensitivity [9].

Regardless of statin use, no significant between-group differences were found in either preoperative subjective symptoms or objective findings, suggesting that statin use alone did not modify CRS severity. Unlike the preoperative findings, the L-K score for discharge was significantly lower in the statin-taking group than in the statin-free group 6 and 12 months after surgery. It has been reported that statins suppress airway mucus secretion via inhibition of interleukin-13, which may be responsible for goblet cell hyperplasia and MUC5AC mRNA expression [10]. Although statins do not show a strong effect on the severity of CRS, they are expected to play an auxiliary role in maintaining improvements in CRS patients after surgery. Nevertheless, this was a retrospective study, and we could not analyze the effect of the administration duration or the type of statin. Moreover, we did not establish a direct mechanism through which statins exert beneficial effects on postoperative outcomes. Future studies are required to elucidate these mechanisms.

In conclusion, our results demonstrated that statin use was associated with a lower rate of revision surgery and uncontrolled disease in patients with CRS. Furthermore, statins showed additive beneficial effects on the L-K score for discharge after ESS, suggesting that statins might be of potential therapeutic value to enhance the postoperative outcomes of ESS in patients with CRS.