慢性鼻竇炎之免疫分型與進階手術治療

The Inflammatory Endotyping of Chronic Rhinosinusitis and Advanced Surgical Managements

林怡岑(Yi-Tsen Lin)

指導教授 ： 江伯倫 ； 葉德輝

國立臺灣大學/醫學院/臨床醫學研究所/博士(2021年)

https://doi.org/10.6342/NTU202102390

摘要

背景：
慢性鼻竇炎為一慢性發炎性疾病，致病機轉甚為複雜，個體差異性大。根據其表現型(phenotypes)可以將慢性鼻竇炎區分成廣泛型(diffuse type)或是局部型(localized type)，其治療方式將有不同。針對廣泛型慢性鼻竇炎，其免疫內分型(immune endotype)分析對於治療與疾病預後相當重要；亞洲地區之慢性鼻竇炎患者之免疫分型分佈與西方國家有所不同，目前國內尚未有相關資料庫之建立，此外，免疫內分型與表現型的關聯性也需要進一步研究分析。針對局部型慢性鼻竇炎，包含單一上頜竇(maxillary sinus)與單一蝶竇(sphenoid sinus)之鼻竇炎，臨床上之處理方式與廣泛型慢性鼻竇炎不同，是否需要手術與手術方式選擇都是重要的課題。
研究目的：
利用慢性鼻竇炎接受內視鏡鼻竇手術患者之世代研究，分析慢性鼻竇炎之表現型與免疫內分型，並探究進階內視鏡鼻竇手術之適應症與功效。
研究方法：
本研究為觀察性研究，在台大醫院耳鼻喉部收集個案，主要對象為20歲至65 歲接受內視鏡鼻竇手術之慢性鼻竇炎患者。於手術前收集其臨床表現、香菸或二手菸暴露、居住環境、過去病史、手術史、過敏史、常規血液檢驗結果、血液過敏原檢測、電腦斷層攝影等資訊，也請受試者填寫鼻及鼻竇疾病評估量表(台灣版22-item Sino-Nasal Outcome Test )，並進行嗅覺檢測。收集手術之病理切片影像，計算其嗜酸性球細胞(eosinophil)之個數，術中多餘的剩餘檢體，進行real time qPCR與酵素結合免疫吸附分析法(ELISA)檢測組織中細胞激素與其他相關免疫分子表現。同時，將於術後一個月、三個月、六個月、一年記錄其術後疾病表現與請受試者填寫鼻及鼻竇疾病評估量表。
研究結果：
關於廣泛型慢性鼻竇炎，分別針對過敏疾病與中央型(central-compartment-type)慢性鼻竇炎等變因，進行臨床表徵與免疫內分型的研究。第一階段，探討過敏對於慢性鼻竇炎的影響，收集於台大醫院耳鼻喉部之雙側慢性鼻竇炎接受內視鏡鼻竇手術138位病人，其中檢測後具有過敏為71位(51%)，過敏組群年紀較輕(p=0.008)且血液中之嗜酸性球細胞比例較高(p=0.008)，兩組的內視鏡分數與鼻及鼻竇疾病評估量表之分數沒有差異，過敏疾病造成慢性鼻竇炎疾病進展較快至需要手術治療。第二階段，探討在中央型慢性鼻竇炎的表現型與內分型之關係，共67位初次接受手術之慢性鼻竇炎案例納入分析，其中16位(23.9%)為電腦斷層影像上表現出中央區為主的病變狀態。透過組間統計檢定，中央型(N=16)與非中央型(N=51)的族群相比，有更嚴重的嗅覺問題(37.5% versus 13.7%, p=0.036)；週邊血液血球檢測發現中央型有較高的嗜酸性球細胞個數(7.39 ± 5.41 versus 3.50 ± 2.46, p=0.001)，鼻竇組織檢體也有較高的嗜酸性球細胞表現(81.3% versus 41.2%, p=0.005)。免疫檢測分析發現，中央型族群鼻內組織呈現出更多的Type 2 cytokine(IL-5, IL-13, p<0.05)。在西方中央型族群觀察到的中央型皆具有過敏疾病之特性，於本次研究族群中並無發現中央型與過敏性疾病的相關性(31.3% versus 45.1%, p=0.327)。在局部型慢性鼻竇炎中，針對單側上頜竇疾病接受內視鏡鼻竇手術個案進行回溯性病例分析，收集於本院耳鼻喉部之因單側上頜竇疾病接受內視鏡鼻竇手術200例，其中經上頜竇開口進行手術共185例，根據病理報告鼻竇腫瘤14例、黴菌感染38例、慢性發炎133例，經淚前隱窩路徑(prelacrimal recess approach)手術15例，病理報告發現腫瘤11例（倒生性乳突瘤10例）、慢性發炎4例；接受追蹤6個月至2年，經淚前隱窩路徑手術之個案並無腫瘤復發之報告，亦無相關合併症發生。針對單一蝶竇疾病(isolated sphenoid sinus disease)接受內視鏡鼻竇手術個案進行回溯性病例分析，收集37例個案，其中包含慢性發炎性疾病29例(78.4%)、腫瘤5例(13.5%)與腦脊髓液漏3例(8.1%)，懷疑有蝶竇腫瘤或腦脊髓液漏可安排核磁造影檢查，可見有較高比例的海綿竇(cavernous sinus)侵犯與顱內侵犯。
結論：
廣泛型慢性鼻竇炎可以針對手術檢體進行病理切片判讀與免疫分型分析，過敏疾病與嗜酸性球細胞增加相關，中央型慢性鼻竇炎與type 2免疫分型相關，不同臨床表徵有其相關的免疫分型，本研究結果有助於術後藥物治療的選擇。針對局部型慢性鼻竇炎，上頜竇炎可以藉由經淚前隱窩路徑手術方式進行內視鏡鼻竇手術，而單一蝶竇疾病容易有顱內合併症，建議儘早手術切片或治療。

關鍵字

慢性鼻竇炎 ； 免疫內分型 ； 鼻過敏 ； 中央型慢性鼻竇炎 ； 上頜竇 ； 蝶竇 ； 內視鏡鼻竇手術

並列摘要

Background: Chronic rhinosinusitis (CRS) is a common disease caused by the interaction of multiple factors. CRS can be divided into diffuse CRS and localized CRS based on radiological findings. For diffuse CRS, whether presenting with polyps or not dose not adequately reflect the pathophysiologic diversity. The identification of the inflammatory patterns of CRS would improve understanding of the pathophysiological mechanism and aid in selecting treatment strategies. For localized CRS, advanced endoscopic sinus surgery may play an important role.
Objective: The aim of this study was to characterize the immune endotypes of CRS, to clarify the relationship between phenotypes and endotypes, and to determine the indication and feasibility of advanced endoscopic sinus surgery in the treatment of localized CRS.
Methods: The study is an observational study. We enrolled subjects aged 20 to 65 years with CRS who undergoing endoscopic sinus surgery. Pre-operatively, the brief history of rhinosinusitis symptoms and previous treatment, past medical history, past surgical history, allergy to medication history, smoking status, and household allergen exposure were recorded. We collected lab data (including blood eosinophil count and blood specific allergen tests), rhinoscopic findings and CT scan findings. The Taiwanese version of 22-Item Sino-Nasal Outcome Test (SNOT-22) questionnaire was filled by CRS patients. During the operation, we collected part of tissue specimens from patients during endoscopic sinus surgery. The sinonasal tissues were collected for ELISA to examine the expression levels of important inflammatory mediators. We also collected the data about the prognosis of disease and SNOT-22 data one month, 3 months, 6 months, and 1 year post-operatively.
Results: For the diffuse CRS, the impacts of allergy and central-compartment phenotype on the clinical characteristics and immune endotypes were examined. The ImmunoCAP test was positive in 71(51%) patients and negative in 67(49%) patients. The mean age of those who received endoscopic sinus surgery was 7-year younger in the allergic group (p=0.008). The recurrence rate of nasal polyps in the allergic group was higher but had no significant difference. In the study of central-compartment-type CRS, adult patients diagnosed with bilateral CRS with no prior surgery were recruited. Central-compartment-type CRS was found in 16 (23.9%) patients, and noncentral-compartment-type CRS was found in 51 (76.1%) patients. Hyposmia or anosmia as the major symptom was more common in the central-compartment-type CRS group. Central-compartment-type CRS represents an eosinophilic/type 2 inflammation endotype, and its presence was not necessarily correlated with atopic disease in our patients. For the localized CRS, unilateral maxillary sinus disease and isolated sphenoid sinus disease (ISSD) were examined. We reviewed 192 cases of unilateral maxillary sinus diseases; 15 cases underwent endoscopic surgery via the prelacrimal recess approach. Most chronic inflammation and fungal infections of the unilateral maxillary sinuses can be managed through a middle meatal antrostomy. Among 15 patients undergoing surgery via the prelacrimal recess approach, 9 cases were inverted papilloma. The mean follow-up period was 16.5 months (range, 6-28 months). No post-operative complications occurred after the prelacrimal recess approach. The endoscopic prelacrimal recess approach is a reliable and effective method used to approach maxillary sinus diseases. Between 2013 and 2019, a total of 37 patients with ISSD were recruited. Untreated ISSD can result in serious complications due to the proximity of critical structures. Endoscopic transethmoidal sphenoidotomy is a safe and effective approach in the management of ISSD, with a 97.1% success rate and a 5.4% major complication rate. We recommend early surgical intervention for all patients with ISSD.
Conclusions: For the diffuse CRS, the study of immune endotypes is indispensable for the post-operative treatment. CRS with allergy is related to eosinophilic type inflammation, and we observed elevated type 2 inflammation cytokines in central-compartment-type CRS. For the localized CRS, surgery is the mainstay of treatment.

並列關鍵字

chronic rhinosinusitis ； allergy ； endotype ； central-compartment-type ； maxillary sinus ； sphenoid sinus ； endoscopic sinus surgery

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