Does eosinophilic inflammation affect the outcome of endoscopic sinus surgery in chronic rhinosinusitis in Koreans? So Young Kim, M.D.,1 Joo Hyun Park, M.D.,1 Chae-Seo Rhee, M.D.,1 Jin-Haeng Chung, M.D.,2 and Jeong-Whun Kim, M.D.1
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ABSTRACT
Background: The implication of eosinophilic inflammation in chronic rhinosinusitis (CRS) has not been sufficiently studied in Asians. The aim of this study was to evaluate the relationship between eosinophilic inflammation in sinonasal tissues and the surgical outcome of functional endoscopic sinus surgery (FESS) in Koreans. Methods: A retrospective review of medical records was performed for 347 patients who had undergone bilateral FESS. During FESS, nasal polyp (NP) or sinonasal pathological mucosa was obtained and histopathological analyses were performed. For analyses of surgical outcomes, 173 patients whose follow-up was ⬎12 months were included. The sinonasal cavity was evaluated by endoscopic examination at the last follow-up using a Lund-Kennedy endoscopic scoring system. Results: Of 347 patients whose tissues were histologically evaluated, 250 (72%) had noneosinophilic CRS. The patients were categorized into four groups according to the presence of NP and eosinophilic inflammation. Of 173 patients, 43 patients (24.9%) had eosinophilic CRS with NP, 15 (8.7%) had eosinophilic CRS without NP, 74 (42.7%) had noneosinophilic CRS with NP, and 41 (23.7%) had noneosinophilic CRS without NP. There were no statistically significant differences in prevalence of allergic rhinitis and asthma and in their preoperative Lund-Mackay scores among four groups. Also, there was no statistically significant difference in the postoperative Lund-Kennedy score between eosinophilic and noneosinophilic CRS groups. Conclusion: The results suggest that eosinophilic inflammation in CRS may not be related to the surgical outcome in Koreans. (Am J Rhinol Allergy 27, e166 –e169, 2013; doi: 10.2500/ajra.2013.27.3959)
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hronic rhinosinusitis (CRS) is a group of disorders characterized by inflammation of the sinonasal tissues for at least 12 weeks.1 Its etiology and pathophysiology are very heterogeneous and intensive investigations have been performed worldwide.1,2 The categorization of CRS into subtypes may have important implications for treatment and prediction of long-term outcomes. Previous studies investigating surgical outcomes for CRS have shown significant improvements in symptom scores and quality of life across all patients with CRS.3,4 It has been shown that various demographic factors, clinical factors, and comorbidities can affect baseline disease severity and outcomes.5,6 Eosinophilic inflammation has been reported to play a major role in the pathophysiology of CRS with nasal polyp (NP).7,8 The clinical importance of eosinophilic inflammation has also been recognized. It was reported that eosinophilic inflammation in the sinonasal tissues was correlated to the advanced severity of CRS9 and the poor outcomes of functional endoscopic sinus surgery (FESS).7,8 However, most of the studies have been performed in the Western countries. Although the eosinophilic type of sinonasal inflammation comprises ⬎80% of NPs in the Western countries, just ⬍50% of NPs is eosinophilic in Koreans.10 Moreover, in our clinical experience, the outcome of FESS in patients with eosinophilic CRS did not seem to be worse than that in ones with noneosinophilic CRS. Thus, we hypothesized that clinical and histopathological features of eosinophilic CRS might be different in Koreans. The purpose of this study was to investigate the relationship between eosinophilic inflammation in the sinonasal tissues and the surgical results of FESS in Koreans.
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From the Departments of 1Otorhinolaryngology and 2Pathology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea The authors have no conflicts of interest to declare pertaining to this article Address correspondence to Jeong-Whun Kim, M.D., Ph.D., Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam, Kyunggi-do 463-707, South Korea E-mail address: [email protected]; alternative: [email protected]; alternative: [email protected] Copyright © 2013, OceanSide Publications, Inc., U.S.A.
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SUBJECTS AND METHODS Study Sample
The medical records of 432 patients who had undergone bilateral FESS by a single surgeon at Seoul National University Bundang Hospital were reviewed. All of the patients had a diagnosis of bilateral CRS based on the Rhinosinusitis Task Force criteria endorsed by the American Academy of Otolaryngology–Head and Neck Surgery.1 Patients who had failed in medical management were indicated for surgery. The medical management included administration of broadspectrum antibiotics, topical nasal corticosteroid spray, and saline irrigation. Oral glucocorticoid was not used at least for 1 month before surgery. Patients who had undergone surgery for mucocele, antrochoanal polyps, or fungal sinusitis were excluded. NPs or sinonasal pathological mucosa was available for histopathological analyses in 347 patients. Among them, 173 patients were followed up for ⬎12 months. Preoperative demographic and medical history were obtained including age, sex, history of prior sinus surgery, NPs, asthma, allergy (confirmed by either skin-prick test or modified radioallergic sorbent test),and diabetes mellitus. The paranasal sinus computed tomography (CT) scan was preoperatively evaluated and scored according to the Lund-Mackay scoring system.11 This study was approved by the Institutional Review Board of Seoul National University Bundang Hospital. S.Y. Kim and J.H. Park contributed equally to this work.
Histopathological Evaluation During ESS under general anesthesia, NP or inflamed ethmoid sinus mucosa was obtained and transferred for histopathological examination. The specimens were reviewed by a board-certified surgical pathologist. A detailed histological review was performed to assess the percentage of eosinophils out of all the inflammatory cells at 400⫻ amplification under a microscope. The pathological finding was reported as “eosinophilic” or “noneosinophilic.” Eosinophilic inflammation was defined when eosinophils account for ⬎20% of the total inflammatory cells. Patients were classified into four groups of CRS based on the presence of polyps and dominance of eosinophils as follows: (1) eosinophilic CRS with NP, (2) eosinophilic CRS without
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Figure 1. Distributions of four groups of chronic rhinosinusitis (CRS). The histopathology of CRS was divided into four groups according to eosinophilic inflammation and the presence of nasal polyps (NPs) in a (A) total of 347 patients whose tissues were histopathologically analyzed and (B) in 173 patients who were followed up for ⬎12 months after functional endoscopic sinus surgery (FESS).
NP, (3) noneosinophilic CRS with NP, and (4) noneosinophilic CRS without NP.
The patients were followed up consecutively after surgery. Postoperatively, a broad spectrum of oral antibiotics was administered for 2 weeks and topical nasal steroid spray was administered for 3 months. Nasal saline irrigation was applied for ⬎3 months. The endoscopic findings at 1 year were scored according to a Lund-Kennedy scoring system, which assesses scarring and/or adhesion, edema, pus discharge, crust, and polyp.12 Each category was scored 0 (absent), 1 (mild), or 2 (severe) according to the presence of abnormal findings.
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Statistical Analysis
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Postoperative Endoscopic Evaluation
A Kruskal-Wallis analysis was used to analyze the differences between the four groups. A comparison between two groups was performed using Mann-Whitney U test. Statistical analyses were performed using SPSS for Windows Version 12.0 (SPSS Inc., Chicago, IL). The criterion for statistical significance was set at p ⬍ 0.5.
RESULTS
Of 347 patients whose tissues were histopathologically analyzed, 97 (28%) had eosinophilic CRS (80 with NP versus 17 without NP) and 250 (72%) had noneosinophilic CRS (185 with NP versus 65 without NP; Fig. 1 A).
Characteristics of Patients with Long-Term Follow-Up A total of 173 patients (85 men and 88 women) were followed up for ⬎12 months. The average age was 43.3 ⫾ 17.8 years (range, 12–81 years). Twenty-six (15.0%) patients had a history of prior sinus surgery. Fifty-two patients (30.1%) had allergic rhinitis and 13 (7.5%) had asthma. Seventy-nine (45.7%) patients showed a Lund-Mackay score of ⱖ7 in their preoperative paranasal sinus CT scans. Of 173 patients, 58 (33.6%) had eosinophilic CRS (43 with NPversus 15 without NP) and 115 (66.4%) had noneosinophilic CRS (74 with NP
versus 41 without NP; Fig. 1 B). There was no significant difference in age; gender; frequency of revision surgeries; and prevalence of asthma, allergic rhinitis, and diabetes mellitus among four groups (Table 1). The proportion of patients with Lund-Mackay score ⱖ7 was highest in the eosinophilic CRS with NP group (60.4%; p ⫽ 0.039).
Postoperative Endoscopic Findings In the eosinophilic CRS with NP group, 41.1% of the patients had at least one positive abnormal finding among five categories of LundKennedy scoring system and 33.3% in the eosinophilic CRS without NP group. In the noneosinophilic CRS with NP group, 45.9% had at least one positive abnormal finding among the five categories and 39.0% in the noneosinophilic CRS without NP group. There was no significant difference in scar and/or adhesion, edema, pus discharge, crust, and polyp among the four groups (Table 2). The average score of five abnormal findings of each group was 0.56 in the eosinophilic CRS with NP, 0.33 in the eosinophilic CRS without NP, 0.46 in the noneosinophilic CRS with NP, and 0.39 in the noneosinophilic CRS without NP, respectively (p ⫽ 0.126). The eosinophilic CRS and noneosinophilic CRS were also compared. In the eosinophilic CRS group, 47.1% had at least one positive abnormal finding among five categories and 34.3% in the noneosinophilic CRS group (p ⫽ 0.217). There was no statistical difference in the average Lund-Kennedy score between eosinophilic and noneosinophilic CRS (p ⫽ 0.686). The postoperative endoscopic findings were also compared according to the preoperative Lund-Mackay score of the CT scan. The postoperative endoscopic findings were likely to be better in patients with a Lund-Mackay score of ⬍7 (average score of 0.29) than in patients with the score ⱖ7 (p ⫽ 0.065).
DISCUSSION Consensus guidelines have defined CRS based on the presence of characteristic symptoms combined with objective evidence of mucosal inflammation.13 This definition of CRS, although useful for diagnosis, describes just a generic condition, wherein multiple underlying etiologies, pathophysiologies, and phenotypes exist.14 Phenotyping of CRS
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Table 1 CT findings, medical history, and endoscopic findings according to histopathology Eosinophilic CRS with NPs (n ⫽ 43) General characteristics Sex (M/F) 23:20 Age 45.3 ⫾ 16.7 CT findings and medical history L-M score ⱖ7 26 (60.4%) Revision surgery 7 (16.3%) Asthma 6 (13.9%) Allergic rhinitis 18 (41.9%) Diabetes mellitus 1 (2.3%) Endoscopic findings Scar 8 (18.6%) Edema 5 (11.6%) Pus discharge 6 (13.9%) Crust 2 (4.7%) Polyp 3 (6.9%) L-K score 0.56
Eosinophilic CRS without NPs (n ⫽ 15)
Noneosinophilic CRS with NPs (n ⫽ 74)
Noneosinophilic CRS without NPs (n ⫽ 41)
p Value
7:8 41.2 ⫾ 14.9
40:34 42.2 ⫾ 20.3
15:26 46.4 ⫾ 20.8
5 (33.3%) 1 (6.7%) 1 (6.7%) 3 (20.0%) 1 (6.7%)
36 (48.6%) 12 (16.2%) 4 (5.4%) 22 (29.7%) 3 (4.1%)
12 (29.3%) 6 (14.6%) 2 (4.9%) 9 (21.9%) 2 (4.9%)
0.039* 0.812 0.179 0.312 0.783
1(6.7%) 0 3 (20.0%) 0 1 (6.7%) 0.33
14 (18.9%) 6 (8.1%) 7 (9.5%) 0 7 (9.5%) 0.46
6 (14.6%) 1 (2.4%) 7 (17.1%) 0 2 (4.9%) 0.39
0.734 0.673 0.577 0.108 0.836 0.126
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*The value of p ⬍ 0.05 is statistically significant. CT ⫽ computed tomography; CRS ⫽ chronic rhinosinusitis; NP ⫽ nasal polyp; L-M ⫽ Lund-Mackay; L-K ⫽ Lund-Kennedy.
Table 2 CT findings, medical history, and endoscopic findings according to eosinophilic inflammation
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Eosinophilic CRS (n ⫽ 58) CT findings and medical history L-M score ⱖ7 Revision surgery Asthma Allergic rhinitis Diabetes mellitus Endoscopic findings Scar Edema Pus discharge Crust Polyp L-K score
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31 (53.4%) 8 (13.8%) 7 (12.1%) 21 (36.2%) 2 (3.4%)
O N 9 (15.5%) 5 (8.6%) 9 (15.5%) 2 (3.4%) 4 (6.9%) 0.50
Noneosinophilic CRS (n ⫽ 115)
p Value
48 (41.7%) 18 (15.7%) 6 (5.2%) 31 (26.9%) 5 (4.3%)
0.306 0.747 0.211 0.316 0.517
20 (17.4%) 7 (6.1%) 14 (12.2%) 0 9 (7.8%) 0.43
0.509 0.216 0.662 0.046* 0.793 0.686
CT ⫽ computed tomography; CRS ⫽ chronic rhinosinusitis; NP ⫽ nasal polyp; L-M ⫽ Lund-Mackay; L-K ⫽ Lund-Kennedy.
into subtypes may have important implications for treatment and longterm outcomes. The importance of eosinophilic inflammation has been recognized and it is suggested that patients with eosinophilic CRS represent a unique group that is especially refractory to medical and surgical intervention.15 Histopathologically, eosinophils have been considered to play a central role in the pathogenesis of NP although there are many kinds of other inflammatory cells such as lymphocytes, neutrophils, and plasma cells.16 There was a study suggesting that infiltrating macrophages, IL-17A, and a mucin gene (MUC5AC), as well as eosinophils could have roles in the development of eosinophilic CRS.17 However, in the actual clinical setting of the authors, eosinophilic inflammation was less likely to be correlated with surgical outcomes. There were reports showing differences of the cellular composition of NP between the Koreans and Westerners.18 It was reported that eosinophilic NP comprised only 25.5% of 496 NPs obtained from Koreans, whereas it was ⬃80% in the Westerners.18 Thus, the hypothesis of our study was that there may be no differences in surgical outcomes between eosinophilic and noneosinophilic CRS. Our study showed that eosinophilic CRS was not different from noneosinophilic CRS in Lund-Kennedy endoscopic scores at 1 year after surgery in Koreans.
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There were several studies in the Western countries comparing each subtype of CRS according to eosinophilic inflammation and presence of NPs. It was shown that patients with NPs had more severe symptoms with higher CT scores at presentation, worse improvement after operation, and a significantly higher need for revision surgery.19 Some have emphasized the clinical implication of eosinophilic inflammation for surgical outcome. Patients with a total peripheral blood eosinophil count of ⬎520/L and patients with mucus or mucosal eosinophilia were likely to experience recurrence of CRS within 5 years after surgery.20 In a prospective cohort study for 1 year, CRS patients were also classified based on the presence of NPs and mucosal eosinophilia.21 Eosinophilic inflammation was found in 59.6% of patients with CRS with NPs. Patients with mucosal eosinophilia had a higher polyp recurrence rate than patients without mucosal eosinophilia, whereas the patients with NPs did not have a higher polyp recurrence rate than those without NPs. Presence of mucosal eosinophilia was a more important factor than NPs for determining NP recurrence.21 However, there were significant differences across racial and ethnic categories with regard to the prevalence of CRS and some studies for Koreans showed different outcomes.18,22 The prevalence and clinical
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implications of eosinophilic CRS in Koreans were different from those in the Westerners. The main histological type of NP in Koreans was noneosinophilic.10 The present study also showed that the majority of NPs was noneosinophilic (185 noneosinophilic NPs of 265 NPs; 69.8%). In our study, the patients were also divided into four groups according to the presence of NPs and eosinophilic inflammation. There were no significant differences in the five categories of Lund-Kennedy scoring system among the four groups. Even when the patients were simply divided into eosinophilic and noneosinophilic CRS, there were no significant differences in the postoperative outcomes. It is necessary to understand that no standard method for evaluation of the surgical outcome has been established and various methods have been used.23 Patients can be asked questions about their quality of life, or visual analog scale can be performed to measure subjective outcome of ESS.24 However, these subjective outcomes are not always correlated with objective measures.25 Therefore, we adapted an objective method to evaluate surgical outcome. Because of ethical and radiation issues, all of the study population can not undergo postoperative CT scanning. Postoperative endoscopic examination is an objective and available parameter to measure surgical outcomes. In this background, we applied the Lund-Kennedy scoring system to evaluate surgical outcomes. One of the issues to be solved is definition of eosinophilic inflammation. To date, there is no consensus on it. We defined CRS as eosinophilic when eosinophils accounted for ⬎20% of all of the inflammatory cells. In a study, the absolute number of eosinophils per high power field was counted and the tissues with 120 eosinophils or more were diagnosed as having mucosal eosinophil.21 A recent study suggested that the tissue eosinophil proportion of ⱖ11% be a criterion for eosinophilic polyp because the proportion of eosinophils may be correlated well with asthma and allergy.26,27 Our study also has some limitations. Because of its retrospective nature, the preoperative characteristics were not controlled at the beginning of the study, leading to a selection bias. However, there were no significant differences in the preoperative characteristics among groups such as the prevalence of allergic rhinitis and asthma and their Lund-Mackay scores. Also, during the follow-up period, several confounding factors could affect the results and therefore a causal relationship might not be clear. To exclude these limitations, a prospective cohort study should be designed. The number of patients was not large. In addition, the study sample was recruited from one institute. These factors might cause another selection bias. However, the proportion of eosinophilic CRS was similar to that in the previous studies. In the future, multicenter studies including a larger population need to be performed to verify the difference between Korean and Western populations. It is also necessary to establish a standard surgical protocol in more detail to identify the impact of histopathology per se without the confounding effect of surgical techniques. Finally, given the difference in definition of tissue eosinophilia in previous studies, its international consensus should be made to increase the reliability of interstudy comparison. In conclusion, the present study exhibited that eosinophilic CRS or NPs may not be the major phenotype in the Korean population. We also validated the hypothesis that eosinophilic inflammation is less likely to affect the surgical outcome in Korean patients with CRS in comparison with those in Western countries. Even if the size of study sample was not large, this study suggested that the clinical implication of eosinophilic inflammation would be differently understood and another surgical prognosticators need to be studied in Koreans.
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Benninger MS, Ferguson BJ, Hadley JA, et al. Adult chronic rhinosinusitis: Definitions, diagnosis, epidemiology, and pathophysiology. Otolaryngol Head Neck Surg 129:S1–S32, 2003.
Meltzer EO, Hamilos DL, Hadley JA, et al. Rhinosinusitis: Establishing definitions for clinical research and patient care. J Allergy Clin Immunol 114:155–212, 2004. Smith TL, Mendolia-Loffredo S, Loehrl TA, et al. Predictive factors and outcomes in endoscopic sinus surgery for chronic rhinosinusitis. Laryngoscope 115:2199–2205, 2005. Bhattacharyya N. Symptom outcomes after endoscopic sinus surgery for chronic rhinosinusitis. Arch Otolaryngol Head Neck Surg 130: 329–333, 2004. Mendolia-Loffredo S, Laud PW, Sparapani R, et al. Sex differences in outcomes of sinus surgery. Laryngoscope 116:1199–1203, 2006. Robinson JL, Griest S, James KE, and Smith TL. Impact of aspirin intolerance on outcomes of sinus surgery. Laryngoscope 117:825–830, 2007. Bhattacharyya N, Vyas DK, Fechner FP, et al. Tissue eosinophilia in chronic sinusitis: Quantification techniques. Arch Otolaryngol Head Neck Surg 127:1102–1105, 2001. Zadeh MH, Banthia V, Anand VK, and Huang C. Significance of eosinophilia in chronic rhinosinusitis. Am J Rhinol 16:313–317, 2002. Szucs E, Ravandi S, Goossens A, et al. Eosinophilia in the ethmoid mucosa and its relationship to the severity of inflammation in chronic rhinosinusitis. Am J Rhinol 16:131–134, 2002. Kim JW, Hong SL, Kim YK, et al. Histological and immunological features of non-eosinophilic nasal polyps. Otolaryngol Head Neck Surg 137:925–930, 2007. Lund VJ, and Kennedy DW. Staging for rhinosinusitis. Otolaryngol Head Neck Surg 117:S35–S40, 1997. Lund VJ, and Kennedy DW. Quantification for staging sinusitis. The Staging and Therapy Group. Ann Otol Rhinol Laryngol Suppl 167:17–21, 1995. Rosenfeld RM, Andes D, Bhattacharyya N, et al. Clinical practice guideline: Adult sinusitis. Otolaryngol Head Neck Surg 137:S1–S31, 2007. Kern RC, Conley DB, Walsh W, et al. Perspectives on the etiology of chronic rhinosinusitis: An immune barrier hypothesis. Am J Rhinol 22:549–559, 2008. Ferguson BJ. Categorization of eosinophilic chronic rhinosinusitis. Curr Opin Otolaryngol Head Neck Surg 12:237–242, 2004. Nguyen LH, Fakhri S, Frenkiel S, and Hamid QA. Molecular immunology and immunotherapy for chronic sinusitis. Curr Allergy Asthma Rep 3:505–512, 2003. Ono N, Kusunoki T, and Ikeda K. Relationships between IL-17A and macrophages or MUC5AC in eosinophilic chronic rhinosinusitis and proposed pathological significance. Allergy Rhinol (Providence) 3:e50–e54, 2012. Hellquist HB. Nasal polyps update. Histopathology. Allergy Asthma Proc 17:237–242, 1996. Deal RT, and Kountakis SE. Significance of nasal polyps in chronic rhinosinusitis: Symptoms and surgical outcomes. Laryngoscope 114: 1932–1935, 2004. Matsuwaki Y, Ookushi T, Asaka D, et al. Chronic rhinosinusitis: Risk factors for the recurrence of chronic rhinosinusitis based on 5-year follow-up after endoscopic sinus surgery. Int Arch Allergy Immunol 146(suppl 1):77–81, 2008. Nakayama T, Yoshikawa M, Asaka D, et al. Mucosal eosinophilia and recurrence of nasal polyps - New classification of chronic rhinosinusitis. Rhinology 49:392–396, 2011. Soler ZM, Mace JC, Litvack JR, and Smith TL. Chronic rhinosinusitis, race, and ethnicity. Am J Rhinol Allergy 26:110–116, 2012. Noda N, Takeno S, Fukuiri T, and Hirakawa K. Monitoring of oral and nasal exhaled nitric oxide in eosinophilic chronic rhinosinusitis: A prospective study. Am J Rhinol Allergy 26:255–259, 2012. Kennedy DW. Prognostic factors, outcomes and staging in ethmoid sinus surgery. Laryngoscope 102:1–18, 1992. Bhattacharyya N. Radiographic stage fails to predict symptom outcomes after endoscopic sinus surgery for chronic rhinosinusitis. Laryngoscope 116:18–22, 2006. Jeong WJ, Lee CH, Cho SH, and Rhee CS. Eosinophilic allergic polyp: A clinically oriented concept of nasal polyp. Otolaryngol Head Neck Surg 144:241–246, 2011. Peric´ A, Vojvodic´ D, Vukomanovic´-Ðurevic´ B, and Baletic´ N. Eosinophilic inflammation in allergic rhinitis and nasal polyposis. Arh Hig Rada Toksikol 62:341–348, 2011. e
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ABSTRACT
Background: The implication of eosinophilic inflammation in chronic rhinosinusitis (CRS) has not been sufficiently studied in Asians. The aim of this study was to evaluate the relationship between eosinophilic inflammation in sinonasal tissues and the surgical outcome of functional endoscopic sinus surgery (FESS) in Koreans. Methods: A retrospective review of medical records was performed for 347 patients who had undergone bilateral FESS. During FESS, nasal polyp (NP) or sinonasal pathological mucosa was obtained and histopathological analyses were performed. For analyses of surgical outcomes, 173 patients whose follow-up was ⬎12 months were included. The sinonasal cavity was evaluated by endoscopic examination at the last follow-up using a Lund-Kennedy endoscopic scoring system. Results: Of 347 patients whose tissues were histologically evaluated, 250 (72%) had noneosinophilic CRS. The patients were categorized into four groups according to the presence of NP and eosinophilic inflammation. Of 173 patients, 43 patients (24.9%) had eosinophilic CRS with NP, 15 (8.7%) had eosinophilic CRS without NP, 74 (42.7%) had noneosinophilic CRS with NP, and 41 (23.7%) had noneosinophilic CRS without NP. There were no statistically significant differences in prevalence of allergic rhinitis and asthma and in their preoperative Lund-Mackay scores among four groups. Also, there was no statistically significant difference in the postoperative Lund-Kennedy score between eosinophilic and noneosinophilic CRS groups. Conclusion: The results suggest that eosinophilic inflammation in CRS may not be related to the surgical outcome in Koreans. (Am J Rhinol Allergy 27, e166 –e169, 2013; doi: 10.2500/ajra.2013.27.3959)
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hronic rhinosinusitis (CRS) is a group of disorders characterized by inflammation of the sinonasal tissues for at least 12 weeks.1 Its etiology and pathophysiology are very heterogeneous and intensive investigations have been performed worldwide.1,2 The categorization of CRS into subtypes may have important implications for treatment and prediction of long-term outcomes. Previous studies investigating surgical outcomes for CRS have shown significant improvements in symptom scores and quality of life across all patients with CRS.3,4 It has been shown that various demographic factors, clinical factors, and comorbidities can affect baseline disease severity and outcomes.5,6 Eosinophilic inflammation has been reported to play a major role in the pathophysiology of CRS with nasal polyp (NP).7,8 The clinical importance of eosinophilic inflammation has also been recognized. It was reported that eosinophilic inflammation in the sinonasal tissues was correlated to the advanced severity of CRS9 and the poor outcomes of functional endoscopic sinus surgery (FESS).7,8 However, most of the studies have been performed in the Western countries. Although the eosinophilic type of sinonasal inflammation comprises ⬎80% of NPs in the Western countries, just ⬍50% of NPs is eosinophilic in Koreans.10 Moreover, in our clinical experience, the outcome of FESS in patients with eosinophilic CRS did not seem to be worse than that in ones with noneosinophilic CRS. Thus, we hypothesized that clinical and histopathological features of eosinophilic CRS might be different in Koreans. The purpose of this study was to investigate the relationship between eosinophilic inflammation in the sinonasal tissues and the surgical results of FESS in Koreans.
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From the Departments of 1Otorhinolaryngology and 2Pathology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea The authors have no conflicts of interest to declare pertaining to this article Address correspondence to Jeong-Whun Kim, M.D., Ph.D., Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam, Kyunggi-do 463-707, South Korea E-mail address: [email protected]; alternative: [email protected]; alternative: [email protected] Copyright © 2013, OceanSide Publications, Inc., U.S.A.
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SUBJECTS AND METHODS Study Sample
The medical records of 432 patients who had undergone bilateral FESS by a single surgeon at Seoul National University Bundang Hospital were reviewed. All of the patients had a diagnosis of bilateral CRS based on the Rhinosinusitis Task Force criteria endorsed by the American Academy of Otolaryngology–Head and Neck Surgery.1 Patients who had failed in medical management were indicated for surgery. The medical management included administration of broadspectrum antibiotics, topical nasal corticosteroid spray, and saline irrigation. Oral glucocorticoid was not used at least for 1 month before surgery. Patients who had undergone surgery for mucocele, antrochoanal polyps, or fungal sinusitis were excluded. NPs or sinonasal pathological mucosa was available for histopathological analyses in 347 patients. Among them, 173 patients were followed up for ⬎12 months. Preoperative demographic and medical history were obtained including age, sex, history of prior sinus surgery, NPs, asthma, allergy (confirmed by either skin-prick test or modified radioallergic sorbent test),and diabetes mellitus. The paranasal sinus computed tomography (CT) scan was preoperatively evaluated and scored according to the Lund-Mackay scoring system.11 This study was approved by the Institutional Review Board of Seoul National University Bundang Hospital. S.Y. Kim and J.H. Park contributed equally to this work.
Histopathological Evaluation During ESS under general anesthesia, NP or inflamed ethmoid sinus mucosa was obtained and transferred for histopathological examination. The specimens were reviewed by a board-certified surgical pathologist. A detailed histological review was performed to assess the percentage of eosinophils out of all the inflammatory cells at 400⫻ amplification under a microscope. The pathological finding was reported as “eosinophilic” or “noneosinophilic.” Eosinophilic inflammation was defined when eosinophils account for ⬎20% of the total inflammatory cells. Patients were classified into four groups of CRS based on the presence of polyps and dominance of eosinophils as follows: (1) eosinophilic CRS with NP, (2) eosinophilic CRS without
November–December 2013, Vol. 27, No. 6
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Figure 1. Distributions of four groups of chronic rhinosinusitis (CRS). The histopathology of CRS was divided into four groups according to eosinophilic inflammation and the presence of nasal polyps (NPs) in a (A) total of 347 patients whose tissues were histopathologically analyzed and (B) in 173 patients who were followed up for ⬎12 months after functional endoscopic sinus surgery (FESS).
NP, (3) noneosinophilic CRS with NP, and (4) noneosinophilic CRS without NP.
The patients were followed up consecutively after surgery. Postoperatively, a broad spectrum of oral antibiotics was administered for 2 weeks and topical nasal steroid spray was administered for 3 months. Nasal saline irrigation was applied for ⬎3 months. The endoscopic findings at 1 year were scored according to a Lund-Kennedy scoring system, which assesses scarring and/or adhesion, edema, pus discharge, crust, and polyp.12 Each category was scored 0 (absent), 1 (mild), or 2 (severe) according to the presence of abnormal findings.
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Statistical Analysis
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Postoperative Endoscopic Evaluation
A Kruskal-Wallis analysis was used to analyze the differences between the four groups. A comparison between two groups was performed using Mann-Whitney U test. Statistical analyses were performed using SPSS for Windows Version 12.0 (SPSS Inc., Chicago, IL). The criterion for statistical significance was set at p ⬍ 0.5.
RESULTS
Of 347 patients whose tissues were histopathologically analyzed, 97 (28%) had eosinophilic CRS (80 with NP versus 17 without NP) and 250 (72%) had noneosinophilic CRS (185 with NP versus 65 without NP; Fig. 1 A).
Characteristics of Patients with Long-Term Follow-Up A total of 173 patients (85 men and 88 women) were followed up for ⬎12 months. The average age was 43.3 ⫾ 17.8 years (range, 12–81 years). Twenty-six (15.0%) patients had a history of prior sinus surgery. Fifty-two patients (30.1%) had allergic rhinitis and 13 (7.5%) had asthma. Seventy-nine (45.7%) patients showed a Lund-Mackay score of ⱖ7 in their preoperative paranasal sinus CT scans. Of 173 patients, 58 (33.6%) had eosinophilic CRS (43 with NPversus 15 without NP) and 115 (66.4%) had noneosinophilic CRS (74 with NP
versus 41 without NP; Fig. 1 B). There was no significant difference in age; gender; frequency of revision surgeries; and prevalence of asthma, allergic rhinitis, and diabetes mellitus among four groups (Table 1). The proportion of patients with Lund-Mackay score ⱖ7 was highest in the eosinophilic CRS with NP group (60.4%; p ⫽ 0.039).
Postoperative Endoscopic Findings In the eosinophilic CRS with NP group, 41.1% of the patients had at least one positive abnormal finding among five categories of LundKennedy scoring system and 33.3% in the eosinophilic CRS without NP group. In the noneosinophilic CRS with NP group, 45.9% had at least one positive abnormal finding among the five categories and 39.0% in the noneosinophilic CRS without NP group. There was no significant difference in scar and/or adhesion, edema, pus discharge, crust, and polyp among the four groups (Table 2). The average score of five abnormal findings of each group was 0.56 in the eosinophilic CRS with NP, 0.33 in the eosinophilic CRS without NP, 0.46 in the noneosinophilic CRS with NP, and 0.39 in the noneosinophilic CRS without NP, respectively (p ⫽ 0.126). The eosinophilic CRS and noneosinophilic CRS were also compared. In the eosinophilic CRS group, 47.1% had at least one positive abnormal finding among five categories and 34.3% in the noneosinophilic CRS group (p ⫽ 0.217). There was no statistical difference in the average Lund-Kennedy score between eosinophilic and noneosinophilic CRS (p ⫽ 0.686). The postoperative endoscopic findings were also compared according to the preoperative Lund-Mackay score of the CT scan. The postoperative endoscopic findings were likely to be better in patients with a Lund-Mackay score of ⬍7 (average score of 0.29) than in patients with the score ⱖ7 (p ⫽ 0.065).
DISCUSSION Consensus guidelines have defined CRS based on the presence of characteristic symptoms combined with objective evidence of mucosal inflammation.13 This definition of CRS, although useful for diagnosis, describes just a generic condition, wherein multiple underlying etiologies, pathophysiologies, and phenotypes exist.14 Phenotyping of CRS
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Table 1 CT findings, medical history, and endoscopic findings according to histopathology Eosinophilic CRS with NPs (n ⫽ 43) General characteristics Sex (M/F) 23:20 Age 45.3 ⫾ 16.7 CT findings and medical history L-M score ⱖ7 26 (60.4%) Revision surgery 7 (16.3%) Asthma 6 (13.9%) Allergic rhinitis 18 (41.9%) Diabetes mellitus 1 (2.3%) Endoscopic findings Scar 8 (18.6%) Edema 5 (11.6%) Pus discharge 6 (13.9%) Crust 2 (4.7%) Polyp 3 (6.9%) L-K score 0.56
Eosinophilic CRS without NPs (n ⫽ 15)
Noneosinophilic CRS with NPs (n ⫽ 74)
Noneosinophilic CRS without NPs (n ⫽ 41)
p Value
7:8 41.2 ⫾ 14.9
40:34 42.2 ⫾ 20.3
15:26 46.4 ⫾ 20.8
5 (33.3%) 1 (6.7%) 1 (6.7%) 3 (20.0%) 1 (6.7%)
36 (48.6%) 12 (16.2%) 4 (5.4%) 22 (29.7%) 3 (4.1%)
12 (29.3%) 6 (14.6%) 2 (4.9%) 9 (21.9%) 2 (4.9%)
0.039* 0.812 0.179 0.312 0.783
1(6.7%) 0 3 (20.0%) 0 1 (6.7%) 0.33
14 (18.9%) 6 (8.1%) 7 (9.5%) 0 7 (9.5%) 0.46
6 (14.6%) 1 (2.4%) 7 (17.1%) 0 2 (4.9%) 0.39
0.734 0.673 0.577 0.108 0.836 0.126
Y P
O C
*The value of p ⬍ 0.05 is statistically significant. CT ⫽ computed tomography; CRS ⫽ chronic rhinosinusitis; NP ⫽ nasal polyp; L-M ⫽ Lund-Mackay; L-K ⫽ Lund-Kennedy.
Table 2 CT findings, medical history, and endoscopic findings according to eosinophilic inflammation
T
Eosinophilic CRS (n ⫽ 58) CT findings and medical history L-M score ⱖ7 Revision surgery Asthma Allergic rhinitis Diabetes mellitus Endoscopic findings Scar Edema Pus discharge Crust Polyp L-K score
O D
31 (53.4%) 8 (13.8%) 7 (12.1%) 21 (36.2%) 2 (3.4%)
O N 9 (15.5%) 5 (8.6%) 9 (15.5%) 2 (3.4%) 4 (6.9%) 0.50
Noneosinophilic CRS (n ⫽ 115)
p Value
48 (41.7%) 18 (15.7%) 6 (5.2%) 31 (26.9%) 5 (4.3%)
0.306 0.747 0.211 0.316 0.517
20 (17.4%) 7 (6.1%) 14 (12.2%) 0 9 (7.8%) 0.43
0.509 0.216 0.662 0.046* 0.793 0.686
CT ⫽ computed tomography; CRS ⫽ chronic rhinosinusitis; NP ⫽ nasal polyp; L-M ⫽ Lund-Mackay; L-K ⫽ Lund-Kennedy.
into subtypes may have important implications for treatment and longterm outcomes. The importance of eosinophilic inflammation has been recognized and it is suggested that patients with eosinophilic CRS represent a unique group that is especially refractory to medical and surgical intervention.15 Histopathologically, eosinophils have been considered to play a central role in the pathogenesis of NP although there are many kinds of other inflammatory cells such as lymphocytes, neutrophils, and plasma cells.16 There was a study suggesting that infiltrating macrophages, IL-17A, and a mucin gene (MUC5AC), as well as eosinophils could have roles in the development of eosinophilic CRS.17 However, in the actual clinical setting of the authors, eosinophilic inflammation was less likely to be correlated with surgical outcomes. There were reports showing differences of the cellular composition of NP between the Koreans and Westerners.18 It was reported that eosinophilic NP comprised only 25.5% of 496 NPs obtained from Koreans, whereas it was ⬃80% in the Westerners.18 Thus, the hypothesis of our study was that there may be no differences in surgical outcomes between eosinophilic and noneosinophilic CRS. Our study showed that eosinophilic CRS was not different from noneosinophilic CRS in Lund-Kennedy endoscopic scores at 1 year after surgery in Koreans.
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There were several studies in the Western countries comparing each subtype of CRS according to eosinophilic inflammation and presence of NPs. It was shown that patients with NPs had more severe symptoms with higher CT scores at presentation, worse improvement after operation, and a significantly higher need for revision surgery.19 Some have emphasized the clinical implication of eosinophilic inflammation for surgical outcome. Patients with a total peripheral blood eosinophil count of ⬎520/L and patients with mucus or mucosal eosinophilia were likely to experience recurrence of CRS within 5 years after surgery.20 In a prospective cohort study for 1 year, CRS patients were also classified based on the presence of NPs and mucosal eosinophilia.21 Eosinophilic inflammation was found in 59.6% of patients with CRS with NPs. Patients with mucosal eosinophilia had a higher polyp recurrence rate than patients without mucosal eosinophilia, whereas the patients with NPs did not have a higher polyp recurrence rate than those without NPs. Presence of mucosal eosinophilia was a more important factor than NPs for determining NP recurrence.21 However, there were significant differences across racial and ethnic categories with regard to the prevalence of CRS and some studies for Koreans showed different outcomes.18,22 The prevalence and clinical
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implications of eosinophilic CRS in Koreans were different from those in the Westerners. The main histological type of NP in Koreans was noneosinophilic.10 The present study also showed that the majority of NPs was noneosinophilic (185 noneosinophilic NPs of 265 NPs; 69.8%). In our study, the patients were also divided into four groups according to the presence of NPs and eosinophilic inflammation. There were no significant differences in the five categories of Lund-Kennedy scoring system among the four groups. Even when the patients were simply divided into eosinophilic and noneosinophilic CRS, there were no significant differences in the postoperative outcomes. It is necessary to understand that no standard method for evaluation of the surgical outcome has been established and various methods have been used.23 Patients can be asked questions about their quality of life, or visual analog scale can be performed to measure subjective outcome of ESS.24 However, these subjective outcomes are not always correlated with objective measures.25 Therefore, we adapted an objective method to evaluate surgical outcome. Because of ethical and radiation issues, all of the study population can not undergo postoperative CT scanning. Postoperative endoscopic examination is an objective and available parameter to measure surgical outcomes. In this background, we applied the Lund-Kennedy scoring system to evaluate surgical outcomes. One of the issues to be solved is definition of eosinophilic inflammation. To date, there is no consensus on it. We defined CRS as eosinophilic when eosinophils accounted for ⬎20% of all of the inflammatory cells. In a study, the absolute number of eosinophils per high power field was counted and the tissues with 120 eosinophils or more were diagnosed as having mucosal eosinophil.21 A recent study suggested that the tissue eosinophil proportion of ⱖ11% be a criterion for eosinophilic polyp because the proportion of eosinophils may be correlated well with asthma and allergy.26,27 Our study also has some limitations. Because of its retrospective nature, the preoperative characteristics were not controlled at the beginning of the study, leading to a selection bias. However, there were no significant differences in the preoperative characteristics among groups such as the prevalence of allergic rhinitis and asthma and their Lund-Mackay scores. Also, during the follow-up period, several confounding factors could affect the results and therefore a causal relationship might not be clear. To exclude these limitations, a prospective cohort study should be designed. The number of patients was not large. In addition, the study sample was recruited from one institute. These factors might cause another selection bias. However, the proportion of eosinophilic CRS was similar to that in the previous studies. In the future, multicenter studies including a larger population need to be performed to verify the difference between Korean and Western populations. It is also necessary to establish a standard surgical protocol in more detail to identify the impact of histopathology per se without the confounding effect of surgical techniques. Finally, given the difference in definition of tissue eosinophilia in previous studies, its international consensus should be made to increase the reliability of interstudy comparison. In conclusion, the present study exhibited that eosinophilic CRS or NPs may not be the major phenotype in the Korean population. We also validated the hypothesis that eosinophilic inflammation is less likely to affect the surgical outcome in Korean patients with CRS in comparison with those in Western countries. Even if the size of study sample was not large, this study suggested that the clinical implication of eosinophilic inflammation would be differently understood and another surgical prognosticators need to be studied in Koreans.
O D
2.
3.
4.
5. 6. 7.
8. 9.
10.
11. 12. 13.
O N
T 14.
15. 16.
17.
18. 19.
20.
21.
22. 23.
24. 25.
26.
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