Sinonasal Outcomes Using Oral Corticosteroids in Patients with Chronic Rhinosinusitis with Nasal Polyps and Positive Sinonasal Cultures

Abstract

Introduction Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and positive sinonasal bacterial cultures may be recalcitrant to topical therapy alone due to the additional local inflammatory burden associated with bacterial infection/colonization.

Objective To evaluate sinonasal outcomes in CRSwNP patients with a positive perioperative bacterial culture, who were treated with postoperative intranasal corticosteroids (INCS) alone versus INCS in combination with a short-term course of oral corticosteroids (OCS).

Methods This is a retrospective chart review of CRSwNP patients. A total of 59 patients met inclusion criteria, including positive perioperative bacterial culture and treatment with INCS with or without concomitant use of OCS. Two cohorts were formed based on the chosen postoperative medical treatment; 32 patients underwent postoperative INCS alone, while 27 underwent INCS plus a ≤ 2-week course of OCS. The 22-item sinonasal outcome test (SNOT-22) scores and Lund-Kennedy scores (LKS) were assessed preoperatively, and at 2-week, 4-week, and 4 to 6 months after endoscopic sinus surgery (ESS).

Results There were no statistically significant differences in postoperative sinonasal symptoms or endoscopic scores between the cohorts treated with INCS plus OCS versus those prescribed INCS alone (p > 0.05). Our regression model failed to demonstrate a relationship between the use of OCS and better sinonasal outcomes at 2-week, 4-week, and 4 to 6 months after ESS (p > 0.05).

Conclusion Our study suggests that in a cohort of CRSwNP patients with recent bacterial infections, the postoperative use of combined OCS and INCS did not result in a statistical improvement of endoscopic and symptomatic outcomes over INCS irrigation alone. However, both treatment groups had a clinically significant improvement based on the Minimal Clinically Important Difference.

Keywords

chronic rhinosinusitis with nasal polyps - corticosteroids - culture - 22-item sinonasal outcome test - endoscopic sinus surgery

Introduction

There is evidence suggesting that the local inflammation associated with an active bacterial infection in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) plays a crucial role in the postoperative healing process.[1] [2] For example, multiple studies suggest that persistent bacterial infections, such as those caused by Staphylococcus aureus (S. aureus), affect the innate immune system provoking local inflammation, barrier disruption, and bacterial dysbiosis.[3] [4] [5] [6] [7] [8] This immune response ultimately leads to an increased production of interleukin-4 (IL-4), IL-5, and IL-13, with a subsequent increase in immunoglobulin-E and eosinophilia.[9] Previous studies have found that active infections at the time of endoscopic sinus surgery (ESS) lead to abnormal postoperative mucosal recovery and worse postoperative prognosis.[2] [10] One study looked at patients with purulent drainage noted in the maxillary sinus at the time of their ESS; patient outcomes were analyzed based on culture status, and the group with negative culture results was found to have the best surgical outcome.[2] Another study looked at biofilm potentiating organisms and their effect on postoperative sinus symptoms and endoscopy; they found that both Pseudomonas and S. aureus had high levels of biofilm formation which was associated with poor control of disease symptoms and endoscopy at 1-year after surgery.[11]

Both the innate and adaptive immune responses play a role in controlling bacterial infections, and in the resolution of resultant inflammatory responses. The epithelial barrier mechanism, mucociliary clearance, and an inflammatory cascade of cytokine and chemokine production characterize the innate and adaptive immune barriers that control or respond to bacterial infection. Once the bacterial response is controlled, macrophages cause apoptosis and phagocytosis of these inflammatory cells leading to the resolution of the acute process.[12] It is likely that treatment targeted at the resolution of this post-infectious phenomenon may be beneficial in controlling inflammation, which may lead to or exacerbate chronic rhinosinusitis (CRS).[13] Corticosteroids inhibit the activation and survival of inflammatory cells stimulated by host defense systems. They thereby affect the recruitment, localization, protein synthesis, and survival of inflammatory cells such as eosinophils.[14] It has been shown that systemic corticosteroids have a modulating effect on the nasal mucosa, promoting the epithelial repair, increasing collagen content, and reducing the eosinophil infiltration in the mucosa and the epithelial hyperplasia.[15] While it is reasonable to assume that the mechanism of action of systemic corticosteroids would show benefit in the setting of an acute infection, there is limited data on the use of oral corticosteroids (OCS) in acute exacerbations of CRS.

Therapeutic options for CRSwNP include treatment with topical or systemic agents, surgical intervention, or a combination thereof.[16] [17] The effect of corticosteroid treatment, both topically and orally, on symptomatology and endoscopic scores has already been studied in CRS patients.[18] [19] [20] [21] [22] [23] [24] However, the effectiveness of postoperative combined therapy with OCS and intranasal corticosteroids (INCS) in CRSwNP patients with a positive sinonasal culture remains unexplored, leaving a gap in the literature. We aim to evaluate the postoperative sinonasal outcomes in culture-positive CRSwNP patients who received INCS alone, compared with those who received INCS in combination with a short course of OCS.

Methods

This retrospective study was approved by the Mayo Clinic Institutional Review Board (IRB 19–009794). Patients with a diagnosis of CRSwNP that underwent ESS from 2012 to 2020 and had a positive sinonasal culture taken preoperatively or intraoperatively were identified. The diagnosis of CRSwNP was based on criteria from the American Academy of Otolaryngology – Head and Neck Surgery (AAO-HNS) guidelines.[25] All patients were treated with INCS (budesonide respule 0.5 mg/2 ml in 240 ml saline, twice a day). Patients were divided into two groups based on whether they received immediate treatment postoperatively, with a combined therapy of INCS and short-term course of OCS (< 2-weeks), or not. Patients were excluded if there was a diagnosis of cystic fibrosis, primary ciliary dyskinesia, immunodeficiency, sarcoidosis, or vasculitis disorders.

Patient-reported symptom scores were assessed using the 22-item Sinonasal Outcome Test (SNOT-22).[26] Additionally, endoscopy scores were evaluated using the Lund-Kennedy endoscopic score (LKS).[27] Patients filled out the SNOT-22 questionnaire in the preoperative visit and at each postoperative follow-up. Additionally, the LKS was also calculated preoperatively and at each postoperative visit, according to the endoscopic findings. Data from the preoperative, 2-weeks, 4-weeks, and 4–6 months postoperative visits were collected and analyzed for this study. Electronic medical records were also reviewed for the following clinical characteristics: demographics, surgical history, urinary leukotriene E4 (LTE4), and comorbidities. All clinical data, including results of sinonasal cultures and sinonasal outcomes, were collected and placed in the Research Electronic Data Capture (REDCap, Vanderbilt University. Nashville, TN, US) software.

Statistical analysis was performed on the Statistical Package Social Sciences (SPSS, IBM Corp, Armonk, NY, US) software, version 25.0. Standard descriptive statistics were obtained and presented as percentages and mean ± standard deviations (SD). According to data distribution of quantitative variables, a parametric analysis (paired t-test) and non-parametric analysis (Wilcoxon signed-rank and Mann-Whitney U tests) were performed to compare means of sinonasal outcomes over time within and between treatment groups. A square root transformation of the data was completed to correct the skewed distribution of the LKS and perform a regression analysis. A linear regression model was used with preoperative SNOT-22 and LKS scores as fixed factors in the analysis and aimed to evaluate: 1) The effect of postoperative use of OCS on sinonasal outcomes among the overall cohort. 2) The effect of postoperative use of OCS on sinonasal outcomes among patients with aspirin-exacerbated respiratory disease (AERD). 3) The effect of concurrent oral antibiotics during the short oral corticosteroid regimen on both sinonasal outcomes. A p-value < 0.05 was considered statistically significant.

Results

Patient characteristics

We identified an initial cohort of 212 patients, but only a total of 59 patients met the criteria for this study. The mean age of the overall cohort was 53 (± 14) with a 1.2:1 female/male ratio. The median time between the preoperative visit and surgical intervention was 20 days. Thirty-two patients received postoperative INCS only, while twenty-seven received combined therapy with INCS and a short-term course of OCS. Six patients received an oral dose of prednisone ≥30mg, and 21 individuals received a course of < 30 mg/day. The treatment period in both scenarios was between five to fourteen days. No differences were observed between the groups at baseline regarding the gender, age, AERD diagnosis, medical history of asthma, allergic rhinitis, smoking, culture results, and preoperative SNOT-22 or LKS (p > 0.05).

The majority of our patients (97%) had purulent drainage cultured. The most common bacteria identified with S. aureus which was present in 27 patients, (45.7%), while six patients (10.1%) grew Pseudomonas. Other isolated bacteria included: Streptococcus pneumoniae, Haemophilus influenzae, Propionibacterium acnes, Klebsiella, Serratia rubidaea, Enterobacter aerogenes, Stenotrophomonas maltophilia, and coagulase-negative Staphylococci. ([Fig. 1]). When collecting the clinical information, we noted that 10 patients received a culture-directed oral antibiotic regimen for two weeks as part of the postoperative treatment. Prescribed oral antibiotic agents included amoxicillin/clavulanate, levofloxacin, doxycycline, and trimethoprim/sulfamethoxazole. ([Table 1]).

Table 1 Demographic and clinical data of the overall cohort

Characteristics	n = 59
Gender, no. (%), female	33 (55.9)
Mean age, years (SD)	53 (14)
CRS subtypes
AERD, no. (%)	37 (62.7)
All other (non-characterized CRS), no. (%)	22 (37.3)
Disease status at presentation
History of previous ESS, no. (%)	39 (66.1)
Number of previous ESS, mean (range)	2.1 (1 -8)
Comorbidities
Asthma, no. (%)	45 (76.3)
Allergic rhinitis, no. (%)	33 (55.9)
Smoking, no. (%)	23 (39)
Obesity, no. (%)	24 (40.7)
OSA, no. (%)	15 (25.4)

Abbreviations: AERD, aspirin-exacerbated respiratory disease; CRS, chronic rhinosinusitis; ESS, endoscopic sinus surgery; OSA, obstructive sleep apnea.

Fig. 1 Bacteria distribution among different groups of patients. Abbreviations: INCS, intranasal corticosteroids; INCS + OCS, intranasal corticosteroids + oral corticosteroids.

Of the 59 included patients, 37 had a diagnosis of AERD based on clinical history and confirmed by elevated levels of LTE4 on liquid chromatography-mass spectrometry (> 166 pg/mg Cr). Among the AERD patients, 20 received combined therapy with OCS and INCS, while seventeen were treated with INCS alone. No statistically significant difference was found when comparing the distribution of AERD patients between groups (p-value = 0.10).

Sinonasal outcomes

As outlined in [Fig. 2], sinonasal outcomes were collected and compared over time and between treatment groups. The SNOT-22 scores significantly improved from the preoperative visit to 4-weeks postoperation, and from the preoperative visit to 4 to 6 months after ESS, in both the INCS only and combined OCS and INCS groups (p < 0.05). However, there was no statistically significant difference in mean change in the SNOT-22 scores detected between the INCS group and combined OCS and INCS group at the 2-weeks, 4-weeks, or 4 to 6 months postoperative visits. ([Table 2]).

Table 2 Changes over time on SNOT-22 among the overall cohort (mean, SD)

	SNOT-22
	INCS group	INCS + OCS group	Comparison between groups (p-value)
Preoperative	54 ± 20	53 ± 22	0.82
2-weeks postoperative	32 ± 22 a	30 ± 14 b	0.80
4-weeks postoperative	19 ± 16 c	24 ± 10 d	0.32
4–6 months postoperative	17 ± 15 e	23 ± 12 f	0.23

Abbreviations: INCS, intranasal corticosteroids; LKS, Lund-Kennedy endoscopic score; OCS, oral corticosteroids; SNOT-22, 22-item sinonasal outcome test. Notes: ^a p-value between preoperative and 2-weeks postoperative in the INCS group= 0.074. ^b p-value between preoperative and 2-weeks postoperative in the INCS + OCS group= 0.24. ^c p-value between preoperative and 4-weeks postoperative in the INCS group = 0.0001. ^d p-value between preoperative and 4-weeks postoperative in the INCS + OCS group = 0.003. ^e p-value between preoperative and 4 to 6 months postoperative in the INCS group = 0.0001. ^f p-value between preoperative and 4 to 6 months postoperative in the INCS + OCS group = 0.002.

Fig. 2 (A) Change over time in 22-item sinonasal outcome test (SNOT-22) among the overall cohort. (B) Change over time in Lund-Kennedy endoscopic score (LKS) among the overall cohort. (C) Change over time in SNOT-22 among aspirin-exacerbated respiratory disease (AERD) patients. (D) Change over time in LKS among AERD patients.

A sequential improvement in the mean LKS was found at 2-weeks, 4-weeks, and 4 to 6 months after surgery in both the OCS and INCS group and the INCS only group. However, the overall change in mean LKS between groups did not reach statistical significance (p > 0.05). In the INCS only group, there was a statistically significant change in the mean LKS from preoperative to 2-weeks, 4-weeks, and 4 to 6 months postoperative scores (p < 0.05). A statistically significant change in the mean LKS was also noted among the combined therapy group from the preoperative visit to 4-weeks and 4 to 6 months after surgery (p = 0.003, p = 0.001). However, no significant difference was noted when comparing the mean preoperative LKS to 2-weeks after ESS (p = 0.22) ([Table 3]).

Table 3 Changes over time on LKS among the overall cohort (mean, SD)

	LKS
	INCS group	INCS + OCS group	Comparison between groups (p-value)
Preoperative	7 ± 3	6 ± 3	0.39
2-weeks postoperative	5 ± 2 g	5 ± 2 h	0.44
4-weeks postoperative	5 ± 2 i	5 ± 3 j	0.71
4–6 months postoperative	2 ± 3 k	3 ± 3 l	0.14

Abbreviations: INCS, intranasal corticosteroids; LKS, Lund-Kennedy endoscopic score; OCS, oral corticosteroids; SNOT-22, 22-item sinonasal outcome test. Notes: ^g p-value between preoperative and 2-weeks postoperative in the INCS group= 0.004. ^h p-value between preoperative and 2-weeks postoperative in the INCS + OCS group= 0.22. ⁱ p-value between preoperative and 4-weeks postoperative in the INCS group = 0.001. ^j p-value between preoperative and 4-weeks postoperative in the INCS + OCS group = 0.003. ^k p-value between preoperative and 4 to 6 months postoperative in the INCS group = 0.001. ^l p-value between preoperative and 4 to 6 months postoperative in the INCS + OCS group = 0.001.

Similar results were found among the sub-cohort of AERD patients. The SNOT-22 had a progressive and statistically significant improvement over time between the preoperative and the 4-weeks and 4 to 6 months postoperative assessments in both the INCS only group and the combined OCS and INCS group (p < 0.05). There was no significant difference in the mean change of SNOT-22 between the AERD patients who had received OCS compared with those who did not. ([Table 4]). The LKS had a significant long-term improvement in both groups, but no difference was found between treatment groups (p > 0.05). ([Tables 4] and [5]).

Table 4 Changes over time on SNOT-22 among AERD patients (mean, SD)

	SNOT-22
	INCS group	INCS + OCS group	Comparison between groups (p-value)
Preoperative	61 ± 23	55 ± 22	0.52
2-weeks postoperative	27 ± 20 a	29 ± 13 b	0.80
4-weeks postoperative	21 ± 18 c	21 ± 10 d	0.99
4–6 months postoperative	19 ± 16 e	23 ± 12 f	0.57

Abbreviations: AERD, aspirin-exacerbated respiratory disease; INCS, intranasal corticosteroids; LKS, Lund-Kennedy endoscopic score; OCS, oral corticosteroids; SNOT-22: 22-item sinonasal outcome test. Notes: p-values were calculated within groups and results are as follows: ^a p-value between preoperative and 2-weeks postoperative in the INCS group= 0.096. ^b p-value between preoperative and 2-weeks postoperative in the INCS + OCS group= 0.24. ^c p-value between preoperative and 4-weeks postoperative in the INCS group = 0.01. ^d p-value between preoperative and 4-weeks postoperative in the INCS + OCS group = 0.007. ^e p-value between preoperative and 4–6 months postoperative in the INCS group = 0.015. ^f p-value between preoperative and 4–6 months postoperative in the INCS + OCS group = 0.008.

Table 5 Changes over time on LKS among AERD patients (mean, SD)

	LKS
	INCS group	INCS + OCS group	Comparison between groups (p-value)
Preoperative	8 ± 3	6 ± 3	0.28
2-weeks postoperative	5 ± 2 g	5 ± 2 h	0.94
4-weeks postoperative	5 ± 3 i	4 ± 2 j	0.79
4–6 months postoperative	4 ± 3 k	3 ± 2 l	0.48

Abbreviations: AERD, aspirin-exacerbated respiratory disease; INCS, intranasal corticosteroids; LKS, Lund-Kennedy endoscopic score; OCS, oral corticosteroids; SNOT-22: 22-item sinonasal outcome test. Notes: p-values were calculated within groups and results are as follows: ^g p-value between preoperative and 2-weeks postoperative in the INCS group= 0.008. ^h p-value between preoperative and 2-weeks postoperative in the INCS + OCS group= 0.22. ⁱ p-value between preoperative and 4-weeks postoperative in the INCS group = 0.008. ^j p-value between preoperative and 4-weeks postoperative in the INCS + OCS group = 0.06. ^k p-value between preoperative and 4–6 months postoperative in the INCS group = 0.003. ^l p-value between preoperative and 4–6 months postoperative in the INCS + OCS group = 0.01.

Linear regression

When analyzing the impact of the postoperative use of a short-term course of OCS on sinonasal outcomes among the overall cohort, our linear regression model failed to demonstrate a detectable effect on the 2-weeks, 4-weeks, or 4 to 6 months postoperative SNOT-22 (p = 0.29, p = 0.35, and p = 0.18), and on the 2-weeks, 4-weeks or 4 to 6 months postoperative LKS (p = 0.74, p = 0.18, and p = 0.06, respectively). ([Table 6]) Our linear regression model for concurrent therapy with OCS on sinonasal outcomes among AERD patients did not show any effect on the postoperative SNOT-22 at 2-weeks, 4-weeks, or 4–6 months after treatment (p = 0.47, p = 0.84, and p = 0.57, respectively). Additionally, no statistically significant effect on the 2-weeks, 4-weeks, or 4–6 months postoperative LKS was found (p = 0.56, p = 0.40, and p = 0.82, respectively). ([Table 7]).

Table 6 Linear regression analysis of the effect of postoperative short-term use of oral corticosteroids on sinonasal outcomes over time among overall cohort

	β value	Standard Error	(95% CI)	p-value
2-weeks after treatment
SNOT-22
Postoperative oral corticosteroids	-9.25	8.5	(-27.1–8.6)	0.29
LKS*
Postoperative oral corticosteroids	0.28	0.87	(-1.5–2)	0.74
4-weeks after treatment
SNOT-22
Postoperative oral corticosteroids	5	5.3	(-5.9–15.9)	0.35
LKS*
Postoperative oral corticosteroids	-0.07	0.18	(-0.4–0.25)	0.68
4–6 months after treatment
SNOT-22
Postoperative oral corticosteroids	8.7	6.2	(-4.3–21.7)	0.18
LKS*
Postoperative oral corticosteroids	0.56	0.29	(-0.02–1.1)	0.06*

Abbreviations: LKS, Lund-Kennedy endoscopic score; SNOT-22, 22-item sinonasal outcome test. Notes: * This analysis was calculated based on square-root transformed data.

Table 7 Linear regression analysis of the effect of postoperative short-term use of oral corticosteroids on sinonasal outcomes over time among AERD patients

	β value	Standard Error	(95% CI)	p-value
2-weeks after treatment
SNOT-22
Postoperative oral corticosteroids	-9.1	12.1	(-36 to 18.2)	0.47
LKS*
Postoperative oral corticosteroids	-0.67	1.1	(-3.1 to 1.7)	0.56
4-weeks after treatment
SNOT-22
Postoperative oral corticosteroids	1.6	8.3	(-16.7 to 20)	0.84
LKS
Postoperative oral corticosteroids	-0.22	0.26	(-0.7 to 0.3)	0.40
4–6 months after treatment
SNOT-22
Postoperative oral corticosteroids	6.2	10.7	(-18.1 to 30.5)	0.57
LKS
Postoperative oral corticosteroids	0.08	0.38	(-0.7 to 0.8)	0.82

Abbreviations: LKS, Lund-Kennedy endoscopic score; SNOT-22, 22-item sinonasal outcome test. Notes: * This analysis was calculated based on square-root transformed data.

Regarding the impact of concurrent therapy with oral antibiotic regimens in a portion of our patients, our linear regression model did not show any effect on the 2-week postoperative SNOT-22 score (β = -8.5 [95% CI: -23–6.3] p = 0.25), 4-weeks postoperative SNOT-22 score (β = -2.6 [95% CI: -13–7.8] p = 0.61), and 4 to 6 months postoperative SNOT-22 score (β = 9.2 [95% CI:-1.7–20] p = 0.09). Additionally, we found no statistically significant effect on the 2-weeks LKS (β = -0.03 [95% CI: -1.2–1.2] p = 0.95), 4-weeks postoperative LKS (β = 0.53 [95% CI: -1.0–2.1] p = 0.50), nor on the 4 to 6 months postoperative LKS (β = 0.2 [95% CI: -1.3–1.8] p = 0.74).

Discussion

The purpose of this study was to determine if the addition of OCS had an impact on sinonasal outcomes by modulating the post-infectious inflammatory response in CRSwNP patients who underwent ESS and had a positive preoperative or intraoperative bacterial sinonasal culture. To our knowledge, this is the first study to focus on the effect of combined OCS and INCS treatment on patients with CRSwNP and positive sinus cultures. The results of this study noted that all groups met the Minimal Clinically Important Difference (MCID) threshold for SNOT-22 after treatment but failed to show a statistically significant difference in the postoperative sinonasal symptoms score when compared. Additionally, our results showed that OCS did not have a statistically significant effect on the LKS at 4 to 6 months in the overall cohort. When we analyzed these results in the subgroup of patients with AERD, the combined therapy had no impact on patients with positive sinonasal cultures.

The pathogenesis of CRSwNP is not completely understood due to its heterogeneous pattern of histologic inflammation, clinical presentation, and responses to medical therapy. Although we could not find a statistical difference in the sinonasal outcomes, our findings demonstrated that all groups of patients met the previously established MCID threshold for SNOT-22 after treatment with the combined therapy.[28] [29] While some previous studies have also reported that the use of OCS had no statistical improvement in SNOT-22 scores,[30] [31] [32] there has not been significant discussion on the potential reasons this medication does not have a clinical effect. The possibility of glucocorticoid insensitivity has been described in both asthma and rhinology literature. Chense et al. looked at the role of IL-17 in patients with severe asthma; based on their literature review, they suggest that the presence of TH17 cells may be responsible for the steroid insensitivity seen in patients with low TH2 phenotype.[33] From a rhinologic perspective, dysregulation in glucocorticoid receptors and S. aureus exotoxin have been associated with steroid insensitivity.[34] The likelihood that a portion of our patients had S. aureus exotoxin is significant, as it has previously been reported that close to 70% of patients with positive S. aureus cultures also had S. aureus exotoxin present.[34]

Another possible explanation for the lack of improvement with the addition of OCS is that these patients had a type 3 inflammatory response, which could have led to glucocorticoid insensitivity. Our traditional understanding of CRS has categorized this disease into type 1 or type 2 endotype. Recently, more information has been published about a third type of inflammatory response, which is described as occurring in both CRS with and without nasal polyps, and is associated with TH-17, neutrophils, and protection against extracellular bacteria and fungi.[35] [36] Stevens et al. found that a portion of the study's patients had a mixed inflammatory response; in their study from 2019, they found that patients with CRSwNP identified as having type-2 and type-3 endotypes were more likely to have purulent drainage.[37] The presence of nasal polyps and positive cultures in our patient population may represent this previously described mixed endotype, which could potentially explain the lack of improvement with corticosteroid treatments.

Several studies have looked at the use of OCS as a monotherapy for acute rhinosinusitis. A Cochrane review found that this treatment regimen had no statistically significant effect on clinical response rates compared with placebo.[38] Additionally, the included studies focused on the resolution of individual symptoms instead of overall effect on quality of life or endoscopic exams, and did not identify if an underlying CRS condition was present.[20] [39] A recent study by Ho et al. showed that patients with eosinophilic CRSwNP and aspirin sensitivity tend to require systemic therapy with OCS and/or biologic agents after ESS because of acute exacerbation of the disease in the postoperative setting.[40] However, no study has reviewed INCS in addition to OCS in the immediate postoperative setting for CRSwNP patients with positive bacterial cultures.

The most recent International Consensus Statement on Allergy and Rhinology (ICAR) on rhinosinusitis recommended the use of short-term therapy with OCS as a part of adequate medical management in CRSwNP but did not address the use of OCS in the setting of an acute exacerbation triggered by bacterial infection.[41] Most of the studies looking at OCS and acute rhinosinusitis did not use SNOT-22 and had a mean follow-up period of 2 to 8 weeks.[30] [42] [43] [44] Our data showed no differences in the endoscopic and symptomatic outcomes between the two postoperative medical treatment protocols at 2-weeks, 4-weeks, and 4 to 6 months after ESS.

These results differ from a randomized, double-blind, placebo-controlled study from 2007, which evaluated the impact of perioperative OCS on the Sinus Symptom Questionnaire (SSQ) and LKS during the first 6 months after ESS. This study included patients with recalcitrant CRSwNP that were deemed appropriate candidates for ESS based on failure or refusal of maximal medical therapy. Maximal medical therapy in this study included 3 months of INCS and culture-directed antibiotics for 4 to 6 weeks, if indicated. However, the timing and number of patients who received oral antibiotics was not described. In the perioperative period all participants received saline sprays and INCS. Patients were further randomized to receive medical treatment with OCS or placebo. Similar to our study, they found that OCS had no effect on the postoperative symptoms score and showed a progressive improvement in the LKS. They did note a statistically significant improvement in the postoperative endoscopic score at 2-weeks, which differs from our study.[45] This difference in the LKS suggests that the presence of bacteria at the time of surgery may hinder positive response to OCS. Previous publications looking at bacterial exotoxins and steroid insensitivity support this hypothesis.[34] This information is valuable to clinicians when considering the risk and benefits of postoperative oral steroids.

Known to be a particularly challenging phenotype of CRS, AERD is a severe form of CRSwNP associated with adult-onset asthma and aspirin intolerance.[46] [47] Almost 50% of AERD patients require a mean equivalent of 8 mg of oral prednisone, and up to 25% require intravenous corticosteroids every year to stabilize the disease.[48] Appropriate additional medical treatments, such as ESS, are needed to maintain control of the disease and decrease the recurrence of nasal polyps.[49] [50] The use of INCS in AERD patients has already been shown to have a beneficial effect on endoscopic score.[19] Given the challenge in managing these patients post-operatively, we chose to look at this subgroup separately to determine the impact of combined therapy in the presence of a positive bacterial culture. Our results did not find a significant impact of postoperative combined therapy on either SNOT-22 or LKS in the AERD group when compared with CRSwNP patients without AERD.

As a retrospective study focused on the results of medical intervention, there are several intrinsic limitations to consider. For example, because of the retrospective nature of our study, a large number of patients without complete SNOT-22 and LKS data had to be excluded. Consequently, our small sample size limits the statistical power and may have obscured a difference in the SNOT-22 and LKS scores. However, our findings are consistent with other studies looking at both combined therapy and oral steroid treatment alone. The patients in our study had ESS at the onset of the study, which makes separating the surgery's effect from the medical therapy impossible. We noted that INCS irrigations provided a clinically meaningful benefit in patients with CRSwNP.[19] A future randomized study that focuses on this patient population and compares sinonasal outcomes in those treated with and without OCS would eliminate confounders and potentially identify a benefit of OCS therapy alone. The length of OCS use was not standardized in our study. A future study with standardized length and dosage of therapy may detect a difference between the two groups. The average number of patients with positive cultures at the time of surgery has not been reported to our knowledge, but this patient population is essential to understand because of the potential worsening postoperative course and long-term outcomes. Also, there is limited information on the risk of combining oral and topical corticosteroids. However, a recent meta-analysis looking at the adverse effects of INCS in the adult population found that the use of these medications is safe, with minimal risk of increased ocular pressure, hypothalamic-pituitary-axis dysfunction, or headache when compared with placebo.[51] Finally, future studies investigating the effect of different medical therapy based on endotype are important to prevent recalcitrant and recurrent disease.

Conclusion

Our study suggests that in a cohort of CRSwNP patients with recent bacterial infections, the postoperative use of combined OCS and INCS did not result in a statistical improvement of endoscopic and symptomatic outcomes, when compared with INCS irrigation alone. However, the change in the mean SNOT-22 score for both treatment groups was associated with a clinically significant difference based on the MCID.

Conflict of Interests

The authors have no conflicts of interest to declare.

^# First author co-authorship. Both authors have contributed equally and are listed in increasing order of seniority.

• References

• 1 Jervis-Bardy J, Foreman A, Field J, Wormald PJ. Impaired mucosal healing and infection associated with Staphylococcus aureus after endoscopic sinus surgery. Am J Rhinol Allergy 2009; 23 (05) 549-552
• 2 Lee CW, Lee BJ, Yoo SH, Yi JS. Relationship between positive bacterial culture in maxillary sinus and surgical outcomes in chronic rhinosinusitis with nasal polyps. Auris Nasus Larynx 2014; 41 (05) 446-449
• 3 Schlosser RJ, Soler ZM. Evidence-based treatment of chronic rhinosinusitis with nasal polyps. Am J Rhinol Allergy 2013; 27 (06) 461-466
• 4 De Corso E, Baroni S, Lucidi D. et al. Nasal lavage levels of granulocyte-macrophage colony-stimulating factor and chronic nasal hypereosinophilia. Int Forum Allergy Rhinol 2015; 5 (06) 557-562
• 5 Takeda K, Sakakibara S, Yamashita K. et al. Allergic conversion of protective mucosal immunity against nasal bacteria in patients with chronic rhinosinusitis with nasal polyposis. J Allergy Clin Immunol 2019; 143 (03) 1163-1175.e15
• 6 Cheng KJ, Zhou ML, Xu YY, Zhou SH. The role of local allergy in the nasal inflammation. Eur Arch Otorhinolaryngol 2017; 274 (09) 3275-3281
• 7 Cheng KJ, Wang SQ, Xu YY. Different roles of Staphylococcus aureus enterotoxin in different subtypes of nasal polyps. Exp Ther Med 2017; 13 (01) 321-326
• 8 Kennedy JL, Borish L. Chronic sinusitis pathophysiology: the role of allergy. Am J Rhinol Allergy 2013; 27 (05) 367-371
• 9 Vickery TW, Ramakrishnan VR, Suh JD. The Role of Staphylococcus aureus in Patients with Chronic Sinusitis and Nasal Polyposis. Curr Allergy Asthma Rep 2019; 19 (04) 1-8
• 10 Jervis-Bardy J, Boase S, Psaltis A, Foreman A, Wormald PJ. A randomized trial of mupirocin sinonasal rinses versus saline in surgically recalcitrant staphylococcal chronic rhinosinusitis. Laryngoscope 2012; 122 (10) 2148-2153
• 11 Bendouah Z, Barbeau J, Hamad WA, Desrosiers M. Biofilm formation by Staphylococcus aureus and Pseudomonas aeruginosa is associated with an unfavorable evolution after surgery for chronic sinusitis and nasal polyposis. Otolaryngol Head Neck Surg 2006; 134 (06) 991-996
• 12 London Jr NR, Lane AP. Innate immunity and chronic rhinosinusitis: What we have learned from animal models. Laryngoscope Investig Otolaryngol 2016; 1 (03) 49-56
• 13 Staudacher AG, Stevens WW. Sinus Infections, Inflammation, and Asthma. Immunol Allergy Clin North Am 2019; 39 (03) 403-415
• 14 Hox V, Lourijsen E, Jordens A. et al. Benefits and harm of systemic steroids for short- and long-term use in rhinitis and rhinosinusitis: an EAACI position paper. Clin Transl Allergy 2020; 10: 1-27
• 15 de Borja Callejas F, Martínez-Antón A, Picado C. et al. Corticosteroid treatment regulates mucosal remodeling in chronic rhinosinusitis with nasal polyps. Laryngoscope 2015; 125 (05) E158-E167
• 16 Howard BE, Lal D. Oral steroid therapy in chronic rhinosinusitis with and without nasal polyposis. Curr Allergy Asthma Rep 2013; 13 (02) 236-243
• 17 Miyake MM, Bleier BS. Future topical medications in chronic rhinosinusitis. Int Forum Allergy Rhinol 2019; 9 (S1): S32-S46
• 18 Donaldson AM, Choby G, Kim DH, Marks LA, Lal D. Intranasal Corticosteroid Therapy: Systematic Review and Meta-analysis of Reported Safety and Adverse Effects in Adults. Otolaryngol Head Neck Surg 2020; 163 (06) 1097-1108
• 19 Fandiño M, Macdonald KI, Lee J, Witterick IJ. The use of postoperative topical corticosteroids in chronic rhinosinusitis with nasal polyps: a systematic review and meta-analysis. Am J Rhinol Allergy 2013; 27 (05) e146-e157
• 20 Banglawala SM, Oyer SL, Lohia S, Psaltis AJ, Soler ZM, Schlosser RJ. Olfactory outcomes in chronic rhinosinusitis with nasal polyposis after medical treatments: a systematic review and meta-analysis. Int Forum Allergy Rhinol 2014; 4 (12) 986-994
• 21 Xu Z, Luo X, Xu L. et al. Effect of short-course glucocorticoid application on patients with chronic rhinosinusitis with nasal polyps. World Allergy Organ J 2020; 13 (06) 100131
• 22 Poetker DM, Jakubowski LA, Lal D, Hwang PH, Wright ED, Smith TL. Oral corticosteroids in the management of adult chronic rhinosinusitis with and without nasal polyps: an evidence-based review with recommendations. Int Forum Allergy Rhinol 2013; 3 (02) 104-120
• 23 Alobid I, Benitez P, Pujols L. et al. Severe nasal polyposis and its impact on quality of life. The effect of a short course of oral steroids followed by long-term intranasal steroid treatment. Rhinology 2006; 44 (01) 8-13
• 24 Vaidyanathan S, Barnes M, Williamson P, Hopkinson P, Donnan PT, Lipworth B. Treatment of chronic rhinosinusitis with nasal polyposis with oral steroids followed by topical steroids: a randomized trial. Ann Intern Med 2011; 154 (05) 293-302
• 25 Rosenfeld RM, Piccirillo JF, Chandrasekhar SS. et al. Clinical practice guideline (update): adult sinusitis. Otolaryngol Head Neck Surg 2015; 152 (02, Suppl) S1-S39
• 26 Hopkins C, Gillett S, Slack R, Lund VJ, Browne JP. Psychometric validity of the 22-item Sinonasal Outcome Test. Clin Otolaryngol 2009; 34 (05) 447-454
• 27 Lund VJ, Kennedy DW. Staging for rhinosinusitis. Otolaryngol Head Neck Surg 1997; 117 (3 Pt 2, Supplement) S35-S40
• 28 Chowdhury NI, Mace JC, Bodner TE. et al. Investigating the minimal clinically important difference for SNOT-22 symptom domains in surgically managed chronic rhinosinusitis. Int Forum Allergy Rhinol 2017; 7 (12) 1149-1155
• 29 Sedaghat AR. Understanding the Minimal Clinically Important Difference (MCID) of Patient-Reported Outcome Measures. Otolaryngol Head Neck Surg 2019; 161 (04) 551-560
• 30 Venekamp RP, Bonten MJM, Rovers MM, Verheij TJM, Sachs APE. Systemic corticosteroid monotherapy for clinically diagnosed acute rhinosinusitis: a randomized controlled trial. CMAJ 2012; 184 (14) E751-E757
• 31 Wang M, Shi P, Chen B, Shi G, Li H, Wang H. Superantigen-induced glucocorticoid insensitivity in the recurrence of chronic rhinosinusitis with nasal polyps. Otolaryngol Head Neck Surg 2011; 145 (05) 717-722
• 32 Van Zele T, Gevaert P, Holtappels G. et al. Oral steroids and doxycycline: two different approaches to treat nasal polyps. J Allergy Clin Immunol 2010; 125 (05) 1069-1076.e4
• 33 Chesné J, Braza F, Mahay G, Brouard S, Aronica M, Magnan A. IL-17 in severe asthma. Where do we stand?. Am J Respir Crit Care Med 2014; 190 (10) 1094-1101
• 34 Wang JJ, Chen CY, Liang KL, Jiang RS. Predictors of nasal bacterial culture rates in patients with chronic rhinosinusitis. Eur J Clin Microbiol Infect Dis 2020; 39 (04) 711-716
• 35 Staudacher AG, Peters AT, Kato A, Stevens WW. Use of endotypes, phenotypes, and inflammatory markers to guide treatment decisions in chronic rhinosinusitis. Ann Allergy Asthma Immunol 2020; 124 (04) 318-325
• 36 Tan BK, Min JY, Hulse KE. Acquired Immunity in Chronic Rhinosinusitis. Curr Allergy Asthma Rep 2017; 17 (07) 1-10
• 37 Stevens WW, Peters AT, Tan BK. et al. Associations Between Inflammatory Endotypes and Clinical Presentations in Chronic Rhinosinusitis. J Allergy Clin Immunol Pract 2019; 7 (08) 2812-2820.e3
• 38 Head K, Chong LY, Hopkins C, Philpott C, Burton MJ, Schilder AG. Short-course oral steroids alone for chronic rhinosinusitis. Cochrane Database Syst Rev 2016; 4: CD011991
• 39 Bülbül T, Bülbül ÖG, Güçlü O, Bilsel AS, Gürsan SÖ. Effect of glucocorticoids on nasal polyposis, with detection of inflammatory response by measurement of nitric oxide levels in nasal polyp tissue. J Laryngol Otol 2013; 127 (06) 584-589
• 40 Ho J, Li W, Grayson JW. et al. Systemic medication requirement in post-surgical patients with eosinophilic chronic rhinosinusitis. Rhinology 2021; 59 (01) 59-65
• 41 Orlandi RR, Kingdom TT, Hwang PH. et al. International Consensus Statement on Allergy and Rhinology: Rhinosinusitis. Int Forum Allergy Rhinol 2016; 6 (Suppl 1) S22-S209
• 42 Venekamp RP, Thompson MJ, Hayward G. et al. Systemic corticosteroids for acute sinusitis. Cochrane Database Syst Rev 2014; (03) CD008115
• 43 Ratau NP, Snyman JR, Swanepoel C. Short-course, low-dose oral betamethasone as an adjunct in the treatment of acute infective sinusitis : a comparative study with placebo. Clin Drug Investig 2004; 24 (10) 577-582
• 44 Gehanno P, Beauvillain C, Bobin S. et al. Short therapy with amoxicillin-clavulanate and corticosteroids in acute sinusitis: results of a multicentre study in adults. Scand J Infect Dis 2000; 32 (06) 679-684
• 45 Wright ED, Agrawal S. Impact of perioperative systemic steroids on surgical outcomes in patients with chronic rhinosinusitis with polyposis: evaluation with the novel Perioperative Sinus Endoscopy (POSE) scoring system. Laryngoscope 2007; 117 (11 Pt 2, Suppl 115) 1-28
• 46 Samter M, Beers Jr RF. Concerning the nature of intolerance to aspirin. J Allergy 1967; 40 (05) 281-293
• 47 Samter M, Beers Jr RF. Intolerance to aspirin. Clinical studies and consideration of its pathogenesis. Ann Intern Med 1968; 68 (05) 975-983
• 48 Szczeklik A, Nizankowska E, Duplaga M. AIANE Investigators. European Network on Aspirin-Induced Asthma. Natural history of aspirin-induced asthma. Eur Respir J 2000; 16 (03) 432-436
• 49 Mendelsohn D, Jeremic G, Wright ED, Rotenberg BW. Revision rates after endoscopic sinus surgery: a recurrence analysis. Ann Otol Rhinol Laryngol 2011; 120 (03) 162-166
• 50 Pfaar O, Klimek L. Aspirin desensitization in aspirin intolerance: update on current standards and recent improvements. Curr Opin Allergy Clin Immunol 2006; 6 (03) 161-166
• 51 Yoon HY, Lee HS, Kim IH, Hwang SH. Post-operative corticosteroid irrigation for chronic rhinosinusitis after endoscopic sinus surgery: A meta-analysis. Clin Otolaryngol 2018; 43 (02) 525-532

Publication History

Received: 14 May 2021

Accepted: 21 December 2021

Article published online:
19 December 2022