Common Allergy Update 2001 Asst. Prof. Kiat Ruxrungtham, M.D. Division of Allergy and Clinical Immunology Department of Medicine Faculty of Medicine Chulalongkorn University.
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Common Allergy Update 2001 Asst. Prof. Kiat Ruxrungtham, M.D. Division of Allergy and Clinical Immunology Department of Medicine Faculty of Medicine Chulalongkorn University โรคภู มแ ิ พ้ทพบบ่ ี่ อย โรคภู มแ ิ พ้ทางจมู ก Allergic Rhinitis โรคหืดจากภู มแ ิ พ้ Allergic Asthma โรคภู มแ ิ พ้ทางผิวหนัง Atopic Dermatitis โรคลมพิษ Urticaria โรคแพ้อาหาร Food Allergy Allergy Chula 1999 Epidemiology of Allergic Diseases in Thai Children 1990 1995 13 Asthma 4.2 40 Allergic Rhinitis 17.9 Atopic Dermatitis 13 0 10 20 30 40 Prevalence (%) พยนต์ บุญญฤทธิพงษ์ และมนตรี ตู ้จินดา 2533; ปกิต วิชยานนท์ และค Mediators of Mast Cells and Basophils Primary Mediators Secondary Mediators Histamine Prostaglandins Leukotrienes PAF Histamine RFs IL-3, 4, 5, 6, 7, 8 GM-CSF, TNFa Chemokines MCP1, MIP1 Oxygen radicals Tryptase Chymotryptase Heparin/Chondroitin Kininogenase Chemotactic Factors Sim TC, Grant JA 1996 AllergyChula Mediators of Mast Cells and Allergy H, PGD2, LTs, PAF bradykinin Blood Vessels Smooth Muscles H, PGD2, LTs, PAF H Mast Cell Basophil LTB4 PAF IL3, IL5 Chemokines Mucus Glands Sensory Nerves Leukocytes Urticaria, Angioedema Laryngeal edema, Shock Bronchospasm Abd. pain, Vomiting Diarrhea, Rhinorhea Bronchial secretion Itching Inflammation - LPAR AllergyChula Pathogenesis of Allergic Disease Adjuvant factors: Genetic Susceptibility Lack of protective factors: Allergic Sensitzation • Tobacco smoke • Air pollutants • Infection ? • Immunization ? • Nutrition ? Allergen Exposure Upper/lower airway or Skin hyperresponsiveness Pollutants Infection Excercise Allergic Diseases Modified from Ulrich Wahn 1998 Vary in spectrum and severity Principle Pathogenesis of Allergic Diseases Durham and Till 1998, Lu 1998, Drazen 1996 Allergen APC CD4+ T-cell IL-12 Th-1 Allergen Th-2 IL-4 IFN-g B-cell CD8+ cell IgG _ Other cells IL-5 IL-3 GM-CSF + Late Phase Reaction AllergyChula IgE B-cell Mast IL-5 cell MBP ECP, LTs Eosonophil Tryptase, LTs The Respiratory Tract Upper Respiratory Tract Structures - Nose —> trachea - Sinuses, eustachian tubes - Ciliated mucosal lining Functions - Conditioning the air - Defense Filtration Inflammatory reaction Immune reaction - Smell - Voice Lower Respiratory Tract Structures - Trachea —> alveoli Functions - Inhalation-exhalation - Gas exchange - Acid-base balance Co-existence of Asthma and AR 23-Years Follow-up Study of Former Brown University Students (N=738) 21 % Asthma 79 % no 306 former students with Allergic Rhinitis no 86 % AR 84 former students with Asthma Greisner WA et al Allergy Asthma Proc 1998; 19:185-8 Ragweed Hay Fever with Seasonal Asthma Upper-Lower Airway Linked Placebo Welsh et al. Mayo Clin Proc 1987;62:125-34 AR in Patients with Mild Asthma Treatment with intranasal corticosteroids : Effect on lower airway responsiveness PC20 Methacholine (mg/mL) Baseline Intranasal BDP Placebo P =0.04 4 3 2 1 0 Baseline Intranasal BDP Placebo At 4 Weeks of Treatment Watson WTA et al J Allergy Clin Immunol 1993; 91:97-101 AllergyChula Mean Changes in FEV1 (Litre) in Treated AR with Mild Asthma Morning (AM) Loratadine/Pseudoephredine 0.25 Placebo * P=0.01 0.2 * 0.15 * *<0.05 * 0.1* 0.05 0 Wk 1 Wk 2 Wk 4 Wk 6 Corren J, et al J Allergy Clin Immuno 1997; 100:781-788 Ideal Antihistamines Pharmacology Safety • Specific H1 receptor blockade No CNS toxicity No cardiotoxicity • Additional potent antiallergic/anti-inflammatory effects • Rapid onset of action • Long-acting • No-tachyphylaxis • No drug interaction • No dose-adjustment required in special-risk groups Simons FE EAACI 1998 AllergyChula PK and PD : Second-Third generation Antihistamines Inhibition of Histamine-wheal/ Drug Metabolism T1/2 (h)* Onset Peak Duration Terfenadine Liver 16-24 1-2 h 3-4 h 8-12 h Astemizole Liver 9.5 days 2 day 9-12d weeks Loratadine Liver 17-24 >1 h Cetirizine no (Kidney) 25 Fexofenadine minimal 14.4 1h 1h 4-8 h 4-8 h 2-3 h Kaliner M. Clin Geriatrics 1997; Simons FE, NEJM 1994 24 h 24 h 24 h AllergyChula H1-Antagonists and Drug Interaction First-generation H1-Antagonists Potentiation of Sedation : Alcohol, sedative agents, hypnotics, antidepressants Potentiation of anticholinergic effect: Antidepressants Second-generation H1-Antagonists (Terfenadine, astemizole, ebastine-animal model , but not loratadine) Decrease hepatic metabolism and increase risk of cardiotoxicity: Drugs that inhibit cytochrome p450 : Ketoconazole, macrolideserythromycin, other azoles- itraconazole Drugs that prolong QT : quinidine Third-generation H1-Antagonists (Cetirizine, Fexofenadine) No clinical significant in drug interaction AllergyChula Antihistamines in Elderly • Drawsiness, fatigue and may increase risk falling or accident • The first-generation H1 antagonist should be avoided in patient with glaucoma • The first-generation H1 antagonist should also be avoided in patient with prostrate hypertrophy • Be aware of cardiotoxic risk; terfenadine, astemizole should be used with caution AllergyChula Treatment of Allergic Rhinitis in Adults Drug Itch/ sneezing Rhinorrhea Blockage Anosmia Antihistamines Topical CS +++ +++ ++ +++ + ++/+++ +/++ Oral CS +++ +++ +++ ++/+++ Topical decongestants - - +++ - Ipratropium bromide - +++ - - Sodium cromoclycate + + + Allergy Immunol Clinic 2000 ่ เยือจมู กบวมใน โรคภู มแ ิ พ้ ทางจมู ก Allergy Chula 1999 Characteristics of Antihistamines Characteristics First Second/Third Generation H1 Antagonist +++ Anticholinergic +++ - (Cetirizine -dry mouth) Sedation ++/+++ - (Cetirizine +/-) Duration of Action +/++ +++ ++/+++ (Astemizole-longest) Antiallergic Antiinflammatory -/+ - -/++ (Azelastine) -/+ (Clinical ?) (Citirizine, Loratadine Fexofenadine) AllergyChula Adverse Effects of H1Antagonists Adverse Effects CPM HZ TF ASZ LD CZ FX Sedation + ++ - - - -/+ - Appetite stim. - -/+ - -/++ - -/+ - Weight gain - -/+ - -/++ - -/+ - Dry mouth ++ + - - - -/+ - Prolong QTc -/ ? -/ ? +* +* - - - Torsade de Points - - +* +* - - - AllergyChula Weiler JM et al. Ann Intern Med 2000 Mar 7;132(5):354-63 Effects of fexofenadine, diphenhydramine, and alcohol on driving performance: in the Iowa driving simulator Overall driving performance • Fexofenadine = placebo • Alcohol >placebo • Diphenhydramine > alcohol • Drowsiness ratings were not a good predictor of impairment • suggesting: drivers cannot use drowsiness to indicate when they should not drive. AllergyChula Mann RD, et al. BMJ 2000 Apr 29;320(7243):1184-1187 Sedation with "non-sedating” antihistamines: four prescriptionevent monitoring studies in general practice N= a total of 43 363 patients: Drowsiness The Odd Ratio (versus Loratadine) Fexofenadine 0.63 (0.36-1.11) Acrivastine 2.79 (1.69-4.58) Cetirizine 3.53 (2.07-5.42) P value 0.1 <0.0001 <0.0001 No increased risk of accident or injury was evident with any of the four drugs. Antihistamines in Elderly • Drawsiness, fatigue and may increase risk falling or accident • The first-generation H1 antagonist should be avoided in patient with glaucoma • The first-generation H1 antagonist should also be avoided in patient with prostrate hypertrophy • Be aware of cardiotoxic risk; terfenadine, astemizole should be used with caution AllergyChula Anti-H1 and Anti-inflammation Antihistamine Evidence-based In Vitro In Vivo (DPCT) (positive results/total) Loratadine yes 1/3 Cetirizine yes 3/5 Terfenadine yes 1/1 Fexofenadine yes nd AllergyChu GINA guidelines 1998 Focus on ICS an ß2-agonists Intermittent Mild persistent Moderate persistent Severe persistent Short-acting ß2 prn Inhaled corticosteroids Long-acting ß2 J Bousquet Berlin 1999 Theophylline: Plasma concentrations Clinical Efficacy in Chronic Asthma as a monotherapy : – 10-20 mg/ml Anti-inflammatory, Immunomodulatory : – >5-10 mg/ml Food and Drug Interaction • Increase clearance: anticonvalsants (phenobarbital, phynytoin,carbamazepine), rifampicin • Decrease clearnace: alcohol, antibiotics (erythromycin, clarithromycin, ciprofloxacin), cimetidine AllergyChula Theophylline as an Add On Regimen (1) Evans DJ, et al N Engl J Med 1997; 13:1412-8 Mean Morning PEF (L/min) Low dose Bud + Theo Low dose 440 420 400 High dose + Placebo *Median serum Theophylline =8.7 mg/ml NS 412 N=31 per group 402 380 360 Week 0 Week 3 Week 6 Week 9 Week 12 Budesonide: Theophylline: Low dose =400, High dose=800 BID** (**Decreased cortisol level) Low dose =250 mg BID (BW<80 kg) or =375 mg BID (BW>80) Theophylline as an Add On Regimen (2) Ukena et al Eur Respir J 1997; 10:2754-60 Mean AM PEF (L/min) Week 0 500 400 300 200 100 0 P<0.01 Beclo 200 bid + Theophylline N= 69 Week 6 P=ns P<0.01 Beclo 400 bid + Placebo N= 64 Pathogenesis of Allergy and Asthma and Potential Novel Therapy B Cells T-Helper Cells Th2 IL-4 Anti--IL-4 Ab IFNg (Th1) IgE Mast cell Leukotrienes PGD2 Histamine Anti--leukotrienes Zileuton Zafirlukast Montelukast IFNg (Th1 switch) IL-5 Anti--IL-5 Ab Eosinophil Recruitment and Production Eosinophil Bronchoconstriction and Mucus Secretion Chemotaxis Tryptase PAF Inflammation Airway Hyperreactivity Tryptase inhibitor Anti-PAF Eotaxin RANTES MCP4 Future Options Phosphodiesterase 4 (PDE-4) inhibitors • Theophylline is a non-selective PDE-4 inhibitor • Selective inhibitors: CDP840, KF 19514, CP80, 633 – Increase intracellular c-AMP – Decreased eosinophil survival (IL-5 induced) – Decreeased IL-4, IL-13 production Momose T 1998, Faissier L 1996, Shichijo M 1997 ่ สิงแวดล้อม ก ับ โรคภู มแ ิ พ ่ ฝุ่ นบีนอน เกสร ฝุ่ นบ้าน ตัวไร่ฝุ่น ้ เชือรา ่ ักฝุ่ น ทีก สัตว ์ ้ เลียง อาหาร สงิ่ เหล่านีม ้ อ ี ยูร่ อบตัวเรา มีทงั ้ ในบ ้านและนอกบ ้าน แต่มห ี ลายอย่างทีเ่ ราหลีกเลีย ่ งได ้ หากเรารู ้วิธท ี การจัดห้องนอนให้ปลอดไรฝ เฟอร ์นิ เจอร ์ มีเฟอร์นเิ จอร์เท่าที่ จาเป็ น ควรใชวั้ สดุทท ี่ าความสะอาดง่าย ่ ไม ้ เชน บุหนังแท ้หรือเทียม ไม่ควรบุผ ้า ้ อง ไม่ควรปูพรม พืนห้ ม่าน ไม่ควรใชผ้ ้าม่านเพราะกักฝุ่ น ควรใชมู้ ล ่ แ ี่ ทน เพราะทาความ ้ งั เคราะห์ และหุ ้มด ้วยผ ้าไวนิลหรือ ผ ้าใย หมอน สะอาดง่ายควรใชใยส สงั เคราะห์พเิ ศษ ั ดาห์ และไม่ใชนุ้ ่น หรือขนนก ตากแดดทุก 1-2 สป ่ ทีนอน ควรหุ ้มด ้วยผ ้าสงั เคราะห์ทป ี่ ้ องกันไรฝุ่ นได ้ ตากแดด ั ดาห์ ทุก 1-2 สป ผ้าห่ม ควรทาจากใยสงั เคราะห์หรือผ ้าแพร การทาความสะอาด ซกั เครือ่ งนอนต่างๆด ้วย 0 ่ ควันบุหรี ควันธู ป Principles of Allergen Immunotherapy Induction Maintenance Phase AllergyChula Allergen IT: Literature Searched by Tittle Words in IGM (31 Oct 1998) Food 1 1 Cock 3 Mold Dog 16 Cat 21 4 HDM 64 Ragweed 143 Pollen 407 Venom 0 100 200 300 400 AllergyChula Efficacy of Venom Immunotherapy (VIT) (Protection from systemic reaction to the insect stings) Muller 1992(wasp) Muller 1992(Bee) Mosbach 1986 Reisman 1986 Golden 1981 Gillman1980 Hunt 1978 0 25 50 75 100 % Efficcacy AllergyChula Clinical Efficacy of AIT in Allergic Rhinitis (41 DBPC trials as by October 1998) No. of study 20 17 Yes No 15 12 10 5 2 2 3 3 1 1 0 Grass Pollen Ragweed Tree HDM AllergyChul Indications of Allergen Immunotherapy • Insect sting allergy Systemic reaction (absolute indication) • Allergic rhinitis* • Allergic asthma* (PFT >70% pred. value) *Dissatisfactory with avoidance + pharmacotherapy AllergyChul Allergen Immunotherapy not proven effective in: • Atopic Dermatitis • Food Allergy • Chronic Urticaria AllergyChula Pathogenesis of Allergy and Asthma and Potential Novel Therapy B Cells T-Helper Cells Th2 IL-4 Anti--IL-4 Ab IFNg (Th1) IgE Mast cell Leukotrienes PGD2 Histamine Anti--leukotrienes Zileuton Zafirlukast Montelukast IFNg (Th1 switch) IL-5 Anti--IL-5 Ab Eosinophil Recruitment and Production Eosinophil Bronchoconstriction and Mucus Secretion Chemotaxis Tryptase PAF Inflammation Airway Hyperreactivity Tryptase inhibitor Anti-PAF Eotaxin RANTES MCP4 Factors Affecting Clinical Outcomes of Allergic Diseases Treatment Enivronmental • Allergens • Irritants • Westernization Genetic Degree of atopy • Anti-inflammatory • Anti-allergic • Relievers Compliance • Avoidance Infection • Medication uses • Viral • Bacterial Allergen Immunotherapy Allergic Diseases Remission Mild Future Therapy Moderate Severe AllergyCh