ARIA ( Allergic rhinitis and its Impact on Asthma ), 2001 “ 過敏性鼻炎之治療” ARIA ( Allergic rhinitis and its Impact on Asthma ), 2001 ARIA update, 2008 吳俊良 國立成功大學醫學院附設醫院 耳鼻喉部 座長與各位醫師先進大家午安，今天我要講的題目是「過敏性鼻炎治療」，內容的主軸是參考2001年「過敏性鼻炎的處理及其對氣喘的影響」指引手冊。

ARIA的由來 (1)2001年秋天,WHO正式發表一篇有關過敏性鼻炎和氣喘之關 連性文章，簡稱為ARIA (Allergic Rhinitis and its Impact on Asthma) (2)這篇報告和以往發表之臨床指引最大的不同處,在ARIA係以 實證醫學(Evidence-base medicine)的觀點提出過敏性鼻炎 實證醫學式的診斷及治療模式(階梯式逐步治療方針) (3)ARIA 2008 update：comorbidity of persistent allergic rhinitis and asthma, combination treatment of upper and lower airways

Allergic Rhinitis (AR) Clinically definition: a symptomatic disorder of the nose, allergen exposure, IgE-mediated inflammation Global health problem (2008) (1) > 10-25 % (600 million) of general population (2) 29.3% were persistent AR in the global study Increasing prevalence of allergic rhinitis (1) UK: 12.0 % (1958)  23.1 % (1970) (2) Taiwan (NTUH, Ped.): 7.8 % (1985)  33.5 % (1994) (perennial type: 40%, combined Otitis Media / Paranasal Sinusitis: 33%) (3) Taiwan (北市醫, 北市二萬名小一生): 49.4 % (2008) 台大，謝貴雄教授，台北市區國小同學調查鼻過敏

(Clark et al., 2009)

Changing prevalence of atopic disease in children Percent (%)

Epidemiologic Study of Atopic Disease in Taiwan Asthma >> Allergic rhinitis Hospital-based >> Community-based 1018031, nationwide survey, 1995-1996 國內研究多侷限醫院或小區域研究。 Prevalence of physician-diagnosed AR  M / F = 28.6 % / 19.5% Prevalence of questionnaire-determined AR  M / F = 42.4 % / 34.0% (ISAAC)

Epidemiology of Allergic Rhinitis Age: occurrence mostly before 20 y/o peak in adolescent and young adult  USA: 17 ~ 34 y/o Taiwan (VGH): 42% in 11-20 y/o Sex: M > F in childhood

Epidemiology of Allergic Rhinitis Potential predictive factors  Younger subjects  Males  Level of parental education ( lower allergen exposure at higher socioeconomic levels )  Cigarette consumption in families  Incense burning at home  Regular exercise  Increased temperature (> 30°C) & relative humidity ( mites, especially during colder seasons )

過敏性鼻炎是一個複雜的疾病 (Rasanen et al., 1998) 環境因素 遺傳因子

Uncertainty still exits on the way !!! Ethnic differences Environmental influences Susceptibility to common disorders among different populations arginine, Arg glutamine, Gln Functional polymorphism

Impact of Allergic Rhinitis Symptoms: nasal itching, sneezing, rhinorrhea, nasal stuffiness  quality of life Impact on school / work performance & productivity  the burden of socio-economic cost

“ one airway, one disease ” Predisposing factors Atopic factor  56-74% of asthma associated with A.R.  17-19% of A.R. associated with asthma “ one airway, one disease ” Genetic factor  One parent (+): 29% risk  Two parents(+): 47% risk  Possible genes on chromosoms 5q, 11q Early exposure of aeroallergen  Higher risk if born just before pollen season

Inducing factors Allergens Pollutants Aeroallergens Indoor  mites, domestic animals, insects, plant origin Outdoor  pollens, molds Occupational rhinitis ( less documented than occupational asthma ) Latex allergy ( patients, health professionals ) Pollutants Indoor air pollution: indoor gas pollutants ( tobacco ) urban-type pollution: automobile origin, O₃, NOx, SO₂ Medication (eg. Aspirin, ACE inhibitor)

Pathogenesis Sensitization  allergic symptoms (-)  Formation of specific IgE Provocation  allergic symptoms (+)  Early-phase response (10-15 minutes after exposure) Late-phase response (4-6 hours after exposure)

Cellular and mechanism in Rhinitis Platelet activating factor Immediate rhinitis symptoms Itch sneezing watery discharge nasal congestion Histamine, Leukotrienes Prostaglandins, bradykinin Mast cells Ig-E B lymphocytes IL- 4 T lymphocytes (Th2) Allergen Chronic ongoing rhinitis nasal blockage loss of smell nasal hyper-reactivity Eosinophil VCAM-1 IL-3,IL-5 GM-CSF

Effect of Histamine H1 receptor Upregulated in allergic rhinitis On Endothelium   Vascular permeability  Vasodilatation On Nociceptive nerve  Itch  Systemic reflex: sneezing  Parasympathetic reflex: glandular exocytosis

Co-morbidities Asthma Other co-morbidities Epidemiological studies: co-exist in the same patients Pathophysiological studies: a common inflammatory process, amplified by interconnected mechanisms Allergic inflammation does not limit itself to the nasal airway Other co-morbidities Sinusitis,,Conjunctivitis Nasal polyposis, Otitis media ( ? )

Classification of Allergic Rhinitis Traditional ( based on time of exposure ) seasonal, perennial, occupational Current ( based on duration, symptoms and quality of life ) Intermittent symptoms < 4 days / week or < 4 weeks Persistent symptoms > 4 days / week and > 4 weeks Mild normal sleep normal daily activities, leisure normal work and school no troublesome symptoms Moderate-Severe abnormal sleep impairment of daily activities, leisure problems caused at work or school troublesome symptoms

Diagnosis of Allergic Rhinitis Typical history of allergic symptoms  Symptoms: frequency,severity, trigger, duration, onset of age, seasonality  Atopic diathesis  Family history Physical examination Laboratory tests

Physical Examination Grimace Allergic salute Supranasal crease Open-mouth breathing Adenoid face

Nasal endoscopy: more useful Normal Inferior Turbinate Nasal Examination Local examination is necessary  Anterior rhinoscopy with speculum: limited information Nasal endoscopy: more useful Normal Inferior Turbinate Allergic Rhinitis

Nasal Endoscopy

 Laboratory Test Specific IgE  In vivo: skin test  In vitro: serum specific IgE test Total IgE: elevated ( Normal in 20% allergic patients ) Nasal smear ( eosinophils >10% ) Nasal provocation test ( occupational rhinitis )

Immediate Hypersensitivity Skin Test Widely used A major diagnostic tool in the field of allergy Prick test  Preferred method  Lower risk of anaphylaxis The most severe type of anaphylaxis - anaphylactic shock Intradermal test  Higher sensitivity  Higher risk of anaphylaxis

Serum specific IgE test Radioallergosorbent test (RAST): MAST <<< CAP Correlated well with skin test

Serum specific IgE test Advantage  Safe  Not affected by drugs Disadvantage  Expensive  Result not immediately available  Less sensitive than skin test

Management of Allergic Rhinitis Allergen avoidance (very important, but insufficient to control symptoms ) Medications (safety, effectiveness, easy administration ) Specific immunotherapy (alter nature course, anaphylaxis ) Education Surgery (1) Treatment of both upper and lower airway disease (2) “ Follow-up ” for persistent & severe intermittent rhinitis

How to Select Medications Medications have no long-lasting effect  maintenance treatment required for persistent disease Intranasal corticosteroids are the first-line therapy for moderate-severe disease; effective against ocular symptoms Alternative therapy (e.g. herbalism, acupuncture) for the treatment of rhinitis Intramuscular / Intranasal injection of steroids is not usually recommended (systemic, blindness)

Effect of Therapies on Rhinitis symptoms ( anti- cholinergics ) ( disodium cromoglycate ) ( Allergy, 2000 )

常見鼻炎藥物 口服H1型抗組織胺 口服去充血劑 通稱 商品名 作用機轉 阻隔H1受體 不會發生藥物減效現象 新一代的藥可一天使用一次 第二代 Cetirizine, Ebastine, Fexofenadine, Loratadine, Mizolastine, Acrivastine, Azelastine, Desloratadine, Levocetrizine 第一代 Chlorpheniramine, Clemastine, Hydroxyzine, Ketotifen, Mequitazine, Oxatomide *Terfenadine, Astemizole: QT prolong Ephedrine Phenylephrine Pseudoephedrine 作用機轉 阻隔H1受體 不會發生藥物減效現象 新一代的藥可一天使用一次 擬交感神經興奮劑 緩解鼻腔充血的症狀 副作用 大部分沒有鎮定作用 無抗膽鹼反應 無心臟毒性 常見鎮定作用，抗膽鹼作用 高血壓 心悸 坐立不安 失眠 頭痛 尿液滯留 黏膜乾躁 激動 顫抖 青光眼或甲狀腺毒症加劇 建議 新一代的抗組織胺有較好的藥物效用/安全性比值 新一代的抗組織胺，針對鼻子和眼睛的症狀，更快速有 效 ( < 1小時 ) 對於鼻充血較無效果 心臟病的人使用口服去充血劑應該小心 口服H1型抗組織胺與去充血劑的混合劑 型，可能比各自單獨使用有效，只是其 副作用也是相加乘的

常見鼻炎藥物 類固醇鼻噴劑 口服 / 肌注類固醇 通稱 商品名 作用機轉 降低鼻腔敏感性 有效減低鼻腔炎性反應 Beclomethasone (Beclomet) Budesonide (Pulmicort) Flunisolide Fluticasone (Flixonase) Mometasone (Nasonex) Triamcinolone (Nasacort) Dexamethasone Hydrocortisone Methyprednisolone Prednisolone Prednisone Triamcinolone Betamethasone Deflazacort 作用機轉 降低鼻腔敏感性 有效減低鼻腔炎性反應 (↓Th2 cell, dendritic cell, mucosal mast cell & eosinophil ) 副作用 些許的局部副作用：刺激感、鼻乾躁 全身性副作用很少 少數類固醇鼻噴劑可能影響兒童骨骼生長 (mometasone, fluticasone除外) 全身性副作用常見，尤其是肌注藥物 注射處的藥物沉積，可至局部組織萎縮 建議 最有效的藥物治療方式 對鼻充血有效 會影響嗅覺 在6 ~ 12小時後可見效果 最大效果是在數天之後 如果可能的話，應使用類固醇鼻噴劑取 代口服或肌注類藥物 然而，短期內的口服類固醇有助於嚴重 症狀的改善 (Prednisolone 5-25 mg/ day within 2 wk)

第二代口服H1型抗組織胺的藥物動力學 <1 8-12 24 24-48 Renal Renal / Feces Azelastine Cetirizine Fexofenadine Loratadine Time to peak concentration (hr) 4-6 1 2.6 1.3 Onset of action (hr) 0.5-3.5 <1 1-3 Time to peak effect (hr) 4 4-8 2-3 8-12 Half-life (hr) 22-36 7-10 14.4 8.4 Duration-single dose (hr) 10-12 24 12-24 24-48 Elimination pathway Hepatic Renal Renal / Feces Active metabolites Yes No Drowsiness & somnolence (drug / placebo) 11.5% / 5% 13.7% / 6.3% 1.3% / 0.9% 8% / 6%

鼻內類固醇鼻噴劑的藥物動力學比較 11 1 <2 0.5 <0.1 化學名 商品名 17 230 3 84 20-50 58 Systemic bioavailability (%) Systemic clearance (1/hr) Onset of action (day) Beclomethasone dipropionate Beclomet 17 230 3 Budesonide Pulmicort 11 84 1 Flunisolide Nasarel 20-50 58 4-7 Fluticasone prpionate Flixonase <2 69 0.5 Mometasone Furoate Nasonex <0.1 - Triamcinolone acetonide Nasacort 23 37

Leukotrienes receptor antagonist Cysteinyl leukotrienes ↑vascular permeability ↑vasodilatation ↑mucosal swelling ↑nasal secretion Montelukast (Singulair), Zafirlukast (Accolate)  Monotherapy: less effective  Additive efficacy with antihistamine  Particularly important for “rhinitis + asthma” * Montelukast : Singulair®, Montair® * Zafirlukast : Accolate, Accoleit, Vanticon

Anti-IgE treatment Omalizumab  A humanized kappa IgG1 antibody Effect  Binds to free IgE at the FcεRI binding site  Prevent interaction with FcεRI receptors (mast cell, basophil) Effect  Rapid decrease of free IgE  Down-regulation of FcεRI receptors

Immunotherapy Specific immunotherapy is an alternative method Trained personnel, patients monitored for 20 minutes after injection, anaphylaxis Indication for subcutaneous specific immunotherapy Insufficiently controlled by conventional pharmacotherapy Pharmacotherapy produces undesirable side effects Refuse to receive long-term pharmacotherapy  In children, specific immunotherapy can be considered Contraidication for children < 5 y/o Sublingual immunotherapy: a safe & effective treatment

Surgical intervention (only for nasal obstruction) Indication  Drug-resistant inferior turbinate hypertrophy  Nasal septal deviation with functional relevance  Secondary chronic sinusitis Modality  Turbinate surgery: cautery, laser, radiofrequency  Septomeatoplasty  Functional Endoscope Sinus Surgery

階梯式逐步治療方針 (青少年與成人) (ARIA, 2001, 2008) 過敏性鼻炎之診斷 (病史皮膚試驗或血清特異性IgE) 檢查有無氣喘 (特別是持續性或重度鼻炎的患者) 間歇性症狀 持續性症狀 口服H1型抗組織胺 H1型抗組織胺鼻噴劑 和 / 或去充血鼻噴劑 或白三烯受體拮抗劑 輕度 口服H1型抗組織胺 H1型抗組織胺鼻噴劑 和 / 或去充血鼻噴劑 類固醇鼻噴劑 (Beclomethasone) 如果症狀未改善，則予以升階治療 如果症狀改善，持續現階治療一個月 若為持續性鼻炎，2~4週後重新評估 輕度 中度 / 重度 中度 / 重度 類固醇鼻噴劑 (Beclomethasone) H1型抗組織胺或白三烯受體拮抗劑 2~4週後重新評估 症狀改善 症狀未改善 降階治療且持續治療一個月 增加類固醇鼻噴劑劑量 鼻癢/打噴嚏：加H1型抗組織胺 流鼻水：加抗膽鹼藥物 鼻塞：加去充血鼻噴劑或口服類固醇 未改善 外科處置 重新評估診斷，順從性。考慮感染或其他原因 避免過敏原或刺激原可能是有助益的 如果有結膜炎，請眼科醫師協助診治 (H1型抗組織胺:口服藥、眼部外用藥) 考慮特異性減敏治療

Treatment of Concomitant Rhinitis and Asthma Glucocorticosteroids & Antileukotrienes Effective for both diseases H1-antihistamines: Important for “Rhinitis” “Asthma” Optimal management of rhinitis may improve coexisting asthma

Pediatric Aspects Intermittent allergic rhinitis is unusual before 2 y/o Allergic rhinitis is most prevalent during school age years Symptoms can impair cognitive functioning and school performance (sedating oral H1-antihistamines) Oral & intra-muscular steroids should be avoided

Special Considerations Pregnancy Nasal obstruction aggravated by the pregnancy itself Caution for any medication during pregnancy Ageing Allergy is less common Atrophic rhinitis is common and difficult to control Phentolamine, Methyldopa, ACEI can cause rhinitis Decongestants & Anti-cholinergics & some Anti-histamine may cause urinary retention in BPH patients Sedative drugs may have greater side effects *Phentolamine: α-adrenergic antagonist *Methyldopa: adrenergic anti-HTN medication *ACEI: for HTN, CHF

過敏性鼻炎治療藥物的FDA懷孕危險分級 A B C D X 分級 分級描述 說明 過敏性鼻炎治療藥物 動物實驗及完整的人類研究無致畸胎性 無危險性 - B 動物實驗無致畸胎性，但無完整的人類 研究；動物實驗有致畸胎性，但完整的 人類研究排除致畸胎性 無危險證據 Budesonide, Cetirizine, Cromoglycate, Dexchlorpheniramine, Diphenhydramine, Ipratropium, Loratadine, Nedocromil, Pseudoephedrine C 動物實驗有致畸胎性或無動物實驗資 料，亦無無完整的人類研究；但藥物 的好處超過其可能的危險性 不能排除危 險性 其他的corticosteroids, Azelastine, Brompheniramine, Fexofenadine, Hydroxyzine,.其他的充血解除劑 D 完整的人類研究具致畸胎性，但於某些 狀況下，藥物的好處超過其危險性 有危險證據 X 完整的人類研究顯示增加致畸胎性， 且危險性遠超過藥物的好處 使用禁忌

知易行難 (ARIA update, 2008)

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