Predictors of the Need for Additional Postoperative Treatment for Eosinophilic Chronic Rhinosinusitis Free

Eosinophilic chronic rhinosinusitis (ECRS) is an intractable type of chronic rhinosinusitis (CRS) that is resistant to standard treatments and is prone to recurrence of nasal polyps [1, 2]. ECRS is classified as diffuse bilateral inflammation due to the main endotype of type 2 inflammation as an immune response to infection and damage in the epithelial mucosae in the respiratory tract [3]. Regarding pathophysiology, epithelial-derived cytokines (thymic stromal lymphopoietin, TSLP; and interleukins – IL-25, IL-33) and activated type 2 innate lymphocytes induce high levels of type 2 cytokines such as IL-4, IL-13, IL-5, and tissue immunoglobulin E (IgE), followed by the development of eosinophilic inflammation [4, 5]. Furthermore, nasal polyps form due to interstitial oedema, albumin leakage with increased vascular permeability, increased coagulation system, and a suppressed fibrinolytic system [6, 7]. Many patients with ECRS experience nasal congestion and severe olfactory dysfunction due to nasal polyps at an early stage, which significantly reduces their quality of life and productivity. The incidence of ECRS has been increasing in Japan and has been designated as an intractable disease by the Japanese Ministry of Health, Labor, and Welfare [2]. Therefore, ECRS has been designated as priority disease for research due to the difficulty in treatment and the high costs incurred along with it. Functional endoscopic sinus surgery (FESS) is recommended as the initial treatment for ECRS to remove and irrigate inflamed sinonasal lesions. For cases of intractable recurrence after FESS, medical treatment with corticosteroids (steroids) and biologics (dupilumab, a fully human monoclonal antibody that inhibits the signalling of the IL-4 and IL-13 pathways) and/or revision FESS were selected depending on the severity of ECRS. While approximately 65% patients with ECRS indicated actual improvement without any additional treatment after FESS, the remaining patients required additional treatment for postoperative recurrence in our previous study [8]. In patients with recurrence, a favourable postoperative course was achieved with steroids alone, and some required dupilumab or revision FESS. The clinical characteristics and treatment strategies for patients with intractable ECRS who are refractory to steroid therapy and require dupilumab or reoperation remain controversial. Thus, preoperative prediction of the need for additional treatment after the initial FESS is important in planning treatment for ECRS.

The purpose of this study was to determine the factors influencing the effectiveness of steroid treatment and to evaluate the outcomes of alternative treatments such as dupilumab or revision FESS in patients with postoperative recurrence of ECRS. Additionally, this study aimed to statistically compare patient profile factors and therapeutic effects between those who improved with steroids alone and those required further treatment.

Between April 2007 and July 2021, 118 adult patients with ECRS who underwent an initial FESS at our department and required additional treatment (steroids, dupilumab, or revision FESS) for postoperative recurrence were enrolled. Median patient age was 50 (range, 22–75) years. This study included 67 males and 51 females. The median postoperative follow-up period was 36 (range, 3–146) months. This study used a retrospective case series design and conformed to the regulations of the Ethics Committee of Hyogo Medical University (approval numbers: 1512 and 3308). The study was conducted in accordance with the principles of the Declaration of Helsinki.

Patients were divided into two groups of responders and non-responders to steroids (shown in Fig. 1). The responders comprised 84 patients who required steroid treatment (local and/or systemic) and non-responders comprised 34 patients who required dupilumab or revision FESS. Patients profile factors, sinonasal manifestations, and examination findings were compared between these two groups.

Patients with CRS who had unfulfilled ECRS diagnostic criteria (described later), a history of sinonasal surgery before the study period, traumatic sinonasal lesions, paranasal cysts, or tumours were excluded from this study. Initial full-house FESS was performed on all patients under general anaesthesia after informed consent was obtained in accordance with the guidelines of the Ethics Committee of Hyogo Medical University.

CRS was diagnosed when nasal respiratory and olfactory symptoms (including nasal obstruction, anterior rhinorrhoea, postnasal drip, facial pain/headache, cough, sputum, and/or loss of smell) were observed for more than 3 months, based on the guidance provided by the Japan Rhinologic Society and previous reports from Europe [1] and the USA [9] and the International Consensus Statement [10]. Bilateral nasal polyps were observed on nasal endoscopy, and evidence of paranasal sinus lesions was detected on CT. Surgical management in the form of initial FESS was indicated for patients with CRS when nasal symptoms and physical findings did not improve despite intensive medical therapy [9]. Intensive medical therapy was defined as the administration of low-dose macrolides (clarithromycin at a dose of 200 mg/day) for 3 months.

ECRS was diagnosed when the total score of the following four items (i–iv) was 11 points or more: (i) bilateral lesions (3 points), (ii) nasal polyps (2 points), (iii) dominant ethmoid sinus involvement or pansinusitis on CT (2 points), and (iv) percentage of blood eosinophils >2% and ≤5% (4 points), >5% and ≤10% (8 points), or >10% (10 points), based on the criteria reported by Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) study [11]. ECRS severity was determined based on factors I and II (shown in Fig. 2). Factor I consisted of two items: ≥5% eosinophils in peripheral blood and ethmoid-dominant opacification on CT. Factor II included the comorbidity of bronchial asthma, aspirin intolerance, and/or non-steroidal anti-inflammatory drug intolerance. Patients with ECRS were classified into three grades as follows: mild – when one or no factor I items were present, without the presence of any factor II items; moderate – when both factor I items were present, but no factor II item was present, or one or no factor I item and/or one factor II item was present; and severe – when both factor I items were present, with any factor II item.

The nasal symptoms questionnaire (NSQ) is a self-administered questionnaire consisting of 10 items divided into two parts (I and II) [12]. Part I includes eight items related to nasal symptoms: (1) sneezing and/or nasal itching, (2) nasal discharge, (3) nasal obstruction, (4) postnasal drip and/or sputum, (5) olfactory loss, (6) pain (including toothache, buccal pain, facial pain, and/or headache), (7) eye itching and/or epiphora, and (8) cough and/or throat irritation. Part II includes two items related to quality of life: (9) reduced productivity at school/work, limitation of outdoor activities and/or social functioning, and (10) sleep disturbances, general physical issues, and/or emotional problems. Each item in the NSQ is rated on a four-point scale: 0 (no symptoms), 1 (mild), 2 (moderate), and 3 (severe). The total score of the NSQ ranges from 0 to 30 points, and its components are analysed accordingly. In addition, a third part (III) consists of a visual analog scale (VAS) for nasal symptoms, using a 10-cm linear scale with endpoints labelled “normal” (0%) at the left end and “most severe” (100%) at the right end. The VAS is used as a parameter to evaluate the severity of overall nasal symptoms, not limited to olfactory dysfunction.

During the period leading up to FESS, all patients received postoperative basic treatment with nasal spray (mometasone furoate [200 μg/day] or fluticasone furoate [110 μg/day], once a day in each nasal cavity) and oral leukotriene receptor antagonists (montelukast, 10 mg/day) after the initial FESS. Patients received steroid treatment as the first therapeutic choice for relapse after the initial FESS. Biologic treatment (dupilumab) and/or revision FESS was required after steroid treatment failed (shown in Fig. 1).

Sinonasal topical steroid treatment was performed using a bioabsorbable device consisting of oxidized regenerated cellulose (Surgicel Absorbable Haemostat™; Johnson and Johnson, Tokyo, Japan) and triamcinolone acetonide (Kenacort™ 40 mg/mL vial; Bristol Myers Squibb, Tokyo, Japan) based on previous reports [13, 14]. First, cotton swabs impregnated with 4% xylocaine and 5,000-fold diluted adrenaline were bilaterally inserted into the surgically opened ethmoid sinuses and olfactory clefts to shrink the nasal mucosae for 5–10 min. Second, a moderate amount of oxidized regenerated cellulose was bilaterally inserted into the ethmoid sinuses and the olfactory cleft. Third, triamcinolone acetonide in a half-vial (20 mg/0.5 mL) was dripped onto the oxidized regenerated cellulose on each side.

Oral prednisolone at a dose of 5 mg/day or more was administered when the patients’ symptoms and multiple nasal polyps persisted, even after sinonasal topical steroid treatment to avoid side effects of steroids. The dose was determined by the attending physician based on the degree of inflammation and was administered for a period ranging from 5 to 14 days, with a total dose of 25–140 mg. Out of 84 responders, 47 required systemic steroid treatment, which was used in 1–2 cycles per year.

Dupilumab (Dupixent™ 300 mg per syringe or pen; Sanofi, Tokyo, Japan), a biologic comprising a fully human monoclonal anti-IL-4Rα antibody, was indicated for patients with bilateral CRS with nasal polyps (CRSwNP) who fulfilled all of the following three criteria (i–iii): (i) a definite diagnosis of CRS; (ii) either one of a history of treatment with systemic steroids for CRSwNP within the past 2 years, a history of sinonasal surgical treatment for CRSwNP, or contraindications or intolerance to systemic steroids, and (iii) bilateral total polyps score ≥5 points (score ≥2 in each nasal cavity) [15, 16]; or persistence of severe symptoms of nasal obstruction, olfactory disorders, and nasal discharge for >8 weeks despite existing treatment, according to the guidelines for the promotion of optimal use by the Pharmaceuticals and Medical Devices Agency in the Ministry of Health, Labour and Welfare in Japan. All postoperative ECRS patients who were treated with dupilumab in this study met these conditions. Dupilumab was injected subcutaneously every 2 weeks.

Revision FESS is particularly indicated for patients with ECRS with nasal obstruction, multiple polyposis in the sinonasal area on endoscopy, and residual cells on CT. Initial full-house FESS (or only FESS in some patients who underwent treatment in another hospital) was performed on all patients under general anaesthesia using a navigation system (Fusion^® ENT Navigation System; Medtronic, FL, USA).

The postoperative endoscopic appearance of the operated sinuses and olfactory clefts was scored as follows: 0 (normal), 1 (partially observable due to the presence of polyps, oedematous mucosa, or discharge), and 2 points (unobservable due to the sinuses being completely filled with swollen mucosa, polyps, or discharge) [17]. When the polyps occupied and prevented observation of the posterior part of the sinuses, a score of 2 was assigned to the part of the sinuses that had undergone surgery. For example, if polyps filled the drainage pathway of the frontal sinus and the interior of the frontal sinus could not be observed, a score of 2 points was assigned. When a bilateral full-house FESS was performed, the maximum possible worst score would be a total of 24 points. The percentage of the total score relative to the maximum possible worst score for the operated sinuses and olfactory clefts was rated as the postoperative endoscopic appearance score. Higher scores indicated a worse status. Recurrence was defined as the reappearance of nasal polyps with the postoperative endoscopic score exceeding 30%, according to our previous study [8]. The postoperative endoscopic appearance score indicated the endoscopic relapse ratio of the inflamed lesions in the sinonasal area. The score was repeatedly measured at each time point: before and after steroid treatment, dupilumab, or revision FESS, to determine the therapeutic effects.

To evaluate the severity of CRS, the sinonasal CT findings were scored using the Lund and Mackay [18] scoring system, which is one of the most widely accepted methods in otorhinolaryngology. The frontal, maxillary, anterior/posterior ethmoid, and sphenoid sinuses were scored as 0 (no opacification), 1 (partial opacification), or 2 points (complete opacification). The ostiomeatal complex was scored as 0 (without opacification) or 2 (with opacification) points. The CT score was calculated as the sum of the scores for each site. The CT scores ranged from 0 to 12 points per side (bilateral range, 0–24 points).

The operating score was based on the operative findings in the sinuses (sinus score) and olfactory clefts (olfactory cleft score) on both sides [19]. The sinus score was determined based on mucosal scores (mucosal score: normal [0 points], oedema [1 point], and polyps [2 points]; range = 0–20 points) and retained secretion scores (contents score: none [0], mucous [1], and viscous [2]; range = 0–20 points) in the maxillary, anterior, and posterior ethmoid, frontal, and sphenoid sinuses. The olfactory cleft score was based on the aforementioned mucosal scores at the nasal septum, middle turbinate, superior turbinate, superior nasal meatus, and ostium of the sphenoid sinus (sphenoethmoidal recess). The operating score was the sum of the sinus and olfactory cleft scores (range = 0–60 points). Based on the operating score, the severity of the operative findings was classified in terms of three grades: mild (0–20 points), moderate (21–40 points), and severe (41–60 points).

The self-administered odour questionnaire (SAOQ) comprised 20 items (steamed rice, miso, seaweed, soy sauce, baked bread, butter, curry, garlic, orange, strawberry, green tea, coffee, chocolate, household gas, garbage, timber, stercus, sweat, flowers, and perfume), as suggested by the Japan Rhinologic Society [20]. Patients answered 20 items using the following responses: (i) I can understand the smell (2 points); (ii) I can sometimes understand the smell (1 point); (iii) I cannot understand the smell at all (0 points); and (iv) I have not smelled it recently or before (unevaluable). The SAOQ score was calculated by dividing the total score of the evaluable items (i–iii) by the number of evaluable items, multiplying by two, and then converting the result into a percentage. Lower percentages indicated a worse status. Patients who answered 11 or more items with response (iv) (unevaluable items) were considered “invalid” cases.

A standard olfactory test using Takagi and Toyota (T&T) olfactometers, which are covered by health insurance in Japan, was used to evaluate olfactory acuity [21]. The T&T olfactometer test consists of five odorants: (A) β-phenyl ethyl alcohol, which smells like a rose; (B) methyl cyclopentenolone, which has a burnt smell; (C) isovaleric acid, which smells like sweat; (D) γ-undecalactone, which smells like fruit; and (E) skatole, which smells like garbage (Daiichi Yakuhin Sangyo, Co., Ltd., Tokyo, Japan). Reagents A, C, D, and E have eight concentration levels (from −2 to 5), whereas B has seven concentration levels (from −2 to 4). The maximum concentrations of A5, B4, C5, D5, and E5 are 631, 25.1, 100, 795, and 79.5 (mg/mL), respectively. Each reagent was serially diluted ten-fold up to the most diluted stage (−2). The patients were given a paper filter (width, 7 mm; length, 140 mm), one tip of which was dipped into an odorous reagent. The patients sniffed the filter paper at a distance of 10–20 mm from the nostrils. A test kit was used to determine the recognition threshold for each odorant at increasing concentrations. The recognition threshold was defined as the lowest concentration at which each odour could be identified. Subsequently, the recognition thresholds for the five odorants were averaged, and the mean values were used to evaluate the olfactory acuity.

Intravenous olfaction testing was performed using prosultiamine, which smells like garlic or onions (Alinamin™; Takeda Pharmaceutical Company, Osaka, Japan). A dose of 10 mg (2 mL) of Alinamin™ was injected into the antecubital vein at a constant rate of 20 s. Whether patients perceived a smell resembling garlic/onion was then examined after injection. The latency interval and duration of the smell sensation were measured. Patients were divided into positive (response to prosultiamine) and negative (no response to prosultiamine) groups, as described in our previous report [21].

We statistically analysed the operating scores in relation to the preoperative olfactory recognition threshold, sinonasal CT imaging score (CT score), and postoperative endoscopic appearance (endoscopic score). To clarify the risk factors for relapse, we retrospectively investigated the patient backgrounds (age, sex, bronchial asthma, aspirin in tolerance, and period from onset to initial FESS), questionnaires (NSQ, VAS and SAOQ), mean olfactory recognition thresholds, and preoperative CT scores among the groups. Comparisons of results between groups were performed using the Mann-Whitney U test. Fisher’s exact test was used to compare sex differences, presence or absence of asthma and aspirin intolerance, and reactivity to the intravenous olfactory test. Data are presented as median values (range) unless otherwise indicated. All p values were two-sided, and values of p < 0.05 were considered significant. All statistical analyses were performed using the Stat Flex version 7.0 software (Osaka, Japan).

Among the cases of recurrence after the initial FESS (n = 118) in ECRS, 84 (71.2%) improved with steroids and 34 (28.8%) did not respond to steroids and required dupilumab and/or revision FESS. The period of illness from onset to initial FESS was significantly longer in non-responders (median: 68 months, 3–182 months) than in responders (median: 20 months, 1–312 months) (U = 558.0, p < 0.001) (shown in Table 1). Other characteristics (age, sex, bronchial asthma and aspirin intolerance), questionnaires (SAOQ, NSQ and VAS), results of examinations (JESREC score, peripheral blood eosinophils, non-specific IgE level, mean olfactory detection and recognition thresholds, intravenous olfactory test and CT score) in the preoperative stage, and operating scores were not significantly different between the two groups.

In responders, comparisons were made between the time points of recurrence and after steroid treatment, whereas in non-responders, comparisons were made between the time points of non-responsiveness to steroid treatment and after dupilumab administration or revision surgery. Regarding the therapeutic effect, both groups showed significant improvements in the questionnaires and detection and recognition olfactory thresholds (p < 0.05) (shown in Table 2). In the comparison between the two groups after treatment, no significant differences were observed in questionnaires and examination findings (shown in Table 3). Therefore, the therapeutic effects of steroids alone in patients with shorter period of illness (responders) and dupilumab or reoperation in patients with longer period of illness (non-responders) for the postoperative recurrence of ECRS were equivalent.

This study demonstrated the background and therapeutic effects of ECRS in a group of patients who improved with steroid treatment alone (responders) and in a group in which steroids were ineffective and required dupilumab or revision FESS (non-responders) for postoperative recurrence of ECRS. Patients with rhinosinusitis for less than 12 months showed a high treatment effect after FESS [22]. Over time, the improvement in quality of life after FESS decreased [23]. In this study, the period of illness from onset to the initial FESS in patients showing improvement after treatment with steroids alone (responders) was significantly shorter than that in patients requiring more advanced treatment with biological agents such as dupilumab or reoperation (non-responders). These results suggest that long-term disease duration may influence the need for additional treatment for postoperative recurrence of ECRS. Delayed disease duration is reportedly affected by steroid resistance [24]. Previous studies have reported that viral and bacterial infections and airway exposure to endotoxins contribute to glucocorticoid insensitivity and the limited efficacy of glucocorticoid treatment [25‒29]. Patients with asthma and allergies are more likely to undergo delayed surgical intervention than other patients. As delayed surgical intervention may worsen long-term clinical outcomes, prompt treatment with early surgery for CRSwNP is recommended, even for chronic inflammation with a comorbid status [30]. Therefore, early therapeutic intervention is important. In mild persistent asthma, early intervention with inhaled budesonide has been associated with improved asthma control and reduced use of additional asthma medication [31]. Dupilumab also exhibited greater improvements in patients with a shorter duration since the last surgery [32].

Steroids and dupilumab are effective agents for CRSwNP [1]. In this study, both groups treated with steroids and dupilumab had favourable outcomes, and no significant difference was observed in the treatment results between the two groups. Even in cases of resistance to postoperative steroid treatment, dupilumab provided treatment outcomes equivalent to those in patients treated with steroids alone. As shown in this study, early intervention can reduce treatment costs by considering disease duration and drug costs.

We evaluated whether the two groups – responders at the time of recurrence and non-responders after failure of steroid treatment – had similar characteristics in terms of demographics, questionnaire responses, and examination results and found no significant differences between the groups. Furthermore, we compared endoscopic scores at various time points, including at the time of recurrence for both groups, after steroid treatment for both groups, and after dupilumab administration for non-responders. No significant differences were observed at any of these time points.

This study has several limitations. Follow-up was not possible for all patients as they did not return for postoperative treatment unless regular follow-up was strongly recommended after their initial FESS. Patients with more severe disease and a worse disease course were more likely to return for follow-up. Especially in patients with intractable ECRS, it is necessary to educate them about the need for continuous follow-up to maintain favourable conditions and further improve treatment results. As a potential limitation, we could not have local studies demonstrating comparable outcomes with the lower preoperative steroid dose used in our department. Further studies are required to assess its efficacy and potential risks. This study has a possible bias due to the background of evolution of surgery since 2007 and the fact that attending surgeons have changed. Comparing 2007 of beginning of this study period with the recent year, there have been advances due to improved performance of endoscopic monitors for surgical fields, navigation systems, and powered devices such as microdebriders and burrs. Although the attending surgeons certainly changed due to personnel changes, the last author, K.T., has attendingly performed and supervised all surgeries for the patients during the period in this study. Therefore, there have been no major changes in the surgical system and procedures at our facility. This study was based on data from a single institution and was not multicenter. Moreover, this was a retrospective study, but we plan to conduct a prospective cohort study in the future.

Another important consideration is the potential variability in patients’ adherence to postoperative treatment protocols, including the use of steroids and biologics. Patient education and adherence play crucial roles in the management of ECRS, and further studies should assess the impact of patient adherence on treatment success. Furthermore, while our study focused on the need for additional postoperative treatments, the quality of life and long-term patient satisfaction were not thoroughly evaluated. These aspects are critical in understanding the full scope of ECRS management and should be incorporated into future research.

Our findings also highlight the need for personalized treatment strategies based on disease duration and individual patient characteristics. The significant difference in the duration from onset to initial FESS between responders and non-responders suggests that early surgical intervention could prevent the progression of steroid-resistant disease, thereby reducing the need for biologics or revision surgeries. In clinical practice, a tailored approach that considers patient-specific factors, such as the presence of comorbidities and previous responses to treatment, may improve overall outcomes and reduce healthcare costs associated with prolonged and recurrent disease management.

Early intervention is crucial, as prolonged disease duration diminishes the therapeutic effect of steroids on inflamed sinonasal lesions in ECRS. Precision medicine, including dupilumab or reoperation for steroid-resistant cases, can achieve comparable therapeutic outcomes. Further research is needed to establish standardized guidelines that incorporate these findings and optimize patient care.

The authors acknowledge the help of the technical assistant, Ms. Yumi Kida.

The authors assert that all procedures contributing to this work complied with the ethical standards of the relevant National and Institutional guidelines on human experimentation (Nuremberg Code) and the Declaration of Helsinki of 1975, as revised in 2008. This study employed a retrospective case series design and conformed to the regulations of the Ethics Committee of Hyogo Medical University (Approval No.: 1512 and 3308). Written informed consent was obtained from all patients to participate in this study.

The authors have no conflicts of interest to declare.

This work was supported by Grants-in-Aid for Scientific Research (Grant No.: 20K09700 and 24K12687) from the Japan Society for the Promotion of Science (JSPS KAKENHI) and a Health Labor Sciences Research Grant (21FC1013). The funder had no role in the design, data collection, data analysis, and reporting of this study.

Takahiro Saito: conceptualization, methodology, data curation, formal analysis, and writing – original draft. Katsuya Fushimi: data curation, formal analysis, and writing – original draft. Tomoki Hirose and Takenori Haruna: data curation and formal analysis. Kenzo Tsuzuki: surgical supervisor, conceptualization, methodology, data curation, formal analysis, and writing – original draft. All the authors approved the final version of the manuscript.

The data that support the findings of this study are not publicly available due to containing information that could compromise the privacy of research participants but are available from the corresponding author, T.S., upon reasonable request.