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Common Pitfalls in Allergy Prof. Kiat Ruxrungtham, M.D. Head, Division of Allergy and Clinical Immunology Department of Medicine Faculty of Medicine Chulalongkorn University Epidemiology of Allergic Diseases Prevalence (%) in Thai Children 45 40 35 30 25 20 15 10 5 0 1990 1995 40 17.9 13 13 4.2 Atopic Dermatitis Allergic Rhinitis Asthma AllergyChula Epidemiology of Allergic Rhinitis in Thai Adults 25 23 22 Prevalence (%) 20 20 15 10 5 0 1975 Tuchinda 1983 Debhakam 1995 Bunnag AllergyChula Allergic Rhinitis: The General Perception • Common disease • Easy to Diagnose • Easy to treat “This is partially true” Common Pitfalls in Managing Allergic Rhinitis • Underdiagnosis • Undertreatment PAR versus SAR Characteristic Secretion Seasonal +++ (watery) Perennial + /++ Seromucous, Post nasal drip Sneezing +++ + /++ Obstruction + /++ +++ Anosmia 0 /+ +/ ++ Eye symptoms +++ 0/+ Asthma 0/++ ++ Sinusitis + ++ predominant Van Cauwenberge P et al Allergy 2000 AllergyChula Clinical Patterns of PAR Classic Type: Runner/Sneezer Blocker Type Combined Type Under diagnosed Type: <10% 30 % 50 % ~20 % Chronic cough Post-nasal drip, throat clearing symptoms Chronic headache Shortness of breath or mouth breathing Vertigo, Epistaxis Problems in sleep, sleepiness during the day Snoring Hyperventilation syndrome AllergyChula Nasal Blockage Allergy Chula 1999 Symptoms of Unrecognized Chronic Nasal Blockage Chronic Cough Postnasal drip, +/- BHR Chronic Headache Throat clearing S/S Unregnized Nasal Blockage Paranasal sinsuses obstruction Postnasal drip Severe obstruction Difficulty in Breathing Mouth breathing Dry mouth, stomatitis Aggravating asthma Vertigo ET dysfucntion Snoring or problem in sleeping AllergyChula Functions of the Nose FUNCTION Airway: upper airway Olfaction Filtration Mucociliary transport Airconditioning Control of middlle ear pressure DYSFUNCTION • Blockage, mouth breathing • Anosmia • Cough, infection • Cough, infection • Headache, Sinusitis • Eustachian tube dysfunction, vertigo AllergyChula The link : Noses, Eyes, Ears, and Sinuses Common Pitfalls in Diagnosis of Rhinitis Commonly Unrecognised Symptoms Chronic cough (including nocturnal cough) The most common cause is rhinitis, not bronchitis Mechanisms: post-nasal drip (PNDS), rhinitis with BHR Shortness of Breath (requires mouth breathing) “Inadequate air”, relieve by mouthing breathing, some may have “carpo-pedal spasm” due to hyperventilation ~ can be miss-Dx as anxeity neurosis . Mechanism: Severe nasal obstruction Chronic headache (frontal, periorbital, paranasal) Rhinitis +/- sinusitis is also a common cause of headache Mechanisms: severe nasal congestion, sinus congestion, sinusitis Vertigo/dizziness (Eustachian tube dysfunction) Post-nasal drip Throat clearing, hoarseness of voice AllergyChula Infra-orbital Edema and Discoloration Allergic Shiner Ocular pruritus Increased lacrimation Mouth Breathing Will lead to • Dry mouth • Stomatitis • Dental malocclusion Indicating Severe Nasal Obstruction Phenomenon After Allergen Exposure: Immediate, Late Phase Allergic Reactions and Hyperreactivity Nasal Symptoms Immediate phase Late phase Nasal Hyperresponsiveness Antigen minutes 1 2 3 4 5 6 7 8 9 10 -hrs//------days Time after Allergen Challenge Treatment of allergic rhinitis (ARIA) Allergic rhinitis and its impact on asthma >4 days /wk <4 days /wk >4 wk/yr Moderate <4 wk /yr severe Mild intermittent Moderate severe intermittent Mild persistent persistent Impaired QOL Intra-nasal steroid local cromone Antihistamines : oral or local non-sedative H1-blocker Intra-nasal decongestant (<10 days) or oral decongestant Allergen and irritant avoidance immunotherapy Treatment of Allergic Rhinitis in Adults Drug Itch/ sneezing Rhinorrhea Blockage Anosmia Antihistamines Nasal CS +++ +++ ++ +++ + ++/+++ +/++ Oral CS +++ +++ +++ ++/+++ Nasal decongestants - - +++ - Ipratropium bromide - +++ - - Sodium cromoclycate + + + - Van Cauwenberge P et al Allergy 2000 Sites of Action of Corticosteroids Scadding GK. Allergy 2000 Corrigan CJ. 1999 Epithelium ICAM-1 PGE2, PGF2a endothelin, NO Fibroblast Mo, DC TNFa, IL-1 T cell Th2 GM-CSF, G-CSF IL-6, RANTES, Eotaxin, etc SCF Mast cell IL-2 IL-3 Myeloid precursor B Cell IL-5 IL-4 Th2 IL-5 Endothelium VCAM-1 permeability IL-3, 5 Basophil Eosinophil LTC4, histamine AllergyChula Meta-analysis of Intranasal Steroids Favors Steroid AllergyChula Pitfalls in prescribing of the 1st, 2nd and 3rd generation antihistamines First Generation antihistamines and CNS Side Effects Impact of Sedating Antihistamines on Safety and Productivity Kay GG, Quig ME. Allergy Asthma Proc 2001 • Sedating antihistamines remains commonly use • Patients taking these agents frequently don’t feel sleepy, but their brain function impaired • Frequently found to be a causal factor in: – Work-related injuries – fatal traffic accidents – aviation fatalities 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 Common Cold: Antihistamines ? • Only 1st generation but not the 2nd generation antihistamines is effective on treating clinical symptoms and signs of “COMMON COLD” • Confirmed both in the natural or experimental “COLDs” Muether PS Clin Infect Dis 2001 Nov; 33:1483-8 AllergyChula Clinical Uses of H1 Antagonists Clinical Generation of Antihistamines First Second and Third Allergic Rhinitis ++ ++ (better compliance) Urticaria ++ Atopic dermatitis ++/+++ Asthma NS)URI/NAR ++ Itching dermatosis ++/+++ Anti-motion sickness ++ Antiemetic ++ Appetite stimulation ++ Insomnia ++ ++ (better compliance) ++ (better compliance) -/++ (Meta-analysis= ++ - (+ for astemizole) AllergyChula Underdiagnosis and treatment in Rhinosinusitis PAR and Rhinosinusitis Concordance of Allergy and Sinusitis 25-70 % Rachelefsky GS et al JACI 1978 Shapiro GG Ped Infect Dis J 1985 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 The Link Lower Respiratory Tract Structures - Trachea —> alveoli Functions - Inhalation-exhalation - Gas exchange - Acid-base balance How to Avoid • Underdiagnosis of AR – Be aware of non-nasal symptoms or the underrecognized symptoms • Undertreatment of AR – Chronic moderate/severe cases required nasal steroid therapy not antihistamines PAR is easy to diagnose and easy to treat, if we really know about it ASTHMA Common Pitfalls Asthma: Risk Factors 5q: IL4, CD14, B2ADR Environmental Genetic Aeroallergens Pollutants Triggers ~19 genes 6p: DRB1, TNF 11q: FCERB1, CC16 16p: IL4RA Clinical Asthma Thailand ~5 % in Adults 13 % in Children AllergyChula Asthma 2002 Airway Inflammation Smooth Muscle Dysfunction Airway Remodeling Normal Barnes PJ 1999 Asthma Early and Late Phase Allergic Reactions (EPAR and LPAR) FEV1 BHR mins 1 2 3 4 5 6 7 8 9 10 -hrs//------days Antigen Time after Allergen Challenge AllergyChula Pitfalls in Asthma Diagnosis • Over diagnosis – Shortness of breath is not always caused by asthma – diagnose COPD as asthma • Under diagnosis –mild asthma –nocturnal asthma Classification of Severity CLASSIFY SEVERITY Clinical Features Before Treatment Symptoms Nocturnal Symptoms STEP 4 Severe Persistent Continuous Limited physical activity Frequent STEP 3 Moderate Persistent Daily Attacks affect activity > 1 time week STEP 2 Mild Persistent > 1 time a week but < 1 time a day STEP 1 Intermittent < 60% predicted Variability > 30% 60 - 80% predicted > 2 times a month Variability > 30% > 80% predicted Variability 20 - 30% < 1 time a week Asymptomatic and normal PEF between attacks FEV1 or PEF > 2 times a month > 80% predicted Variability < 20% The presence of one feature of severity is sufficient to place patient in that category. Part 4: Long-term Asthma Management : GINA 2002 Stepwise Approach to Asthma Therapy - Adults Outcome: Best Possible Results Outcome: Asthma Control Controller: Controller: Controller: None Controller: Daily inhaled corticosteroid Daily inhaled corticosteroid Daily longacting inhaled β2-agonist Daily inhaled corticosteroid Daily long – acting inhaled β2-agonist plus (if needed) -Theophylline-SR -Leukotriene -Long-acting inhaled β2- agonist -Oral corticosteroid Reliever: Rapid-acting inhaled β2-agonist prn STEP 2: STEP 3: STEP 4: STEP 1: Moderate Severe Mild Intermittent Persistent Persistent Persistent When asthma is controlled, reduce therapy Monitor STEP Down Alternative controller and reliever medications may be considered (see text). The Guidelines : not well implemented 48 yo female, with chronic persistent asthma for 3 years • Recently, she has asthmatic attack everyday including at night for 6 months. • She has been seeking treatment from at least 2 hospitals. The main prescriptions included slow-released theophylline and inhaled b-2 agonist as needed. • The severity of her asthma became more and so severe that she had to miss several working days a week. • She was eventually forced to leave the job. A Case Study (2) • Baseline PEFR=150 and 180 L/min, pre and post b-2 agonist, respectively. • After 2 weeks of a short course prednisolone followed by inhaled corticosteroids plus inhaled long-acting b-2 agonist PEFR = 360 L/min. • Her QOL has returned to normal. • Unfortunately, however, she has lost her job. AllergyChula Asthma: A Highly Variable Disease Infection AR Avoidance Sinusitis Allergens Treatment Airway Inflammation Pollutants Adherence AHR Variable Asthmatic Symptoms Genetics Smooth Muscle Dysfunction Airway Remodeling Reversible Airway Obstruction Drugs Psychological ASA/NSAIDS • Intermittent • Persistent • Mild • Moderate • Severe • Irreversibility Cold air Excercise Treating Asthma: Individualized and Dynamics Approach Peak Flow Meter Male : >500 L/min Female : >400 L/min Case Study 1: PM, age 44(cont’d) Variation of Clinical symptoms and PEF Peak flow rate (L/min) 500 LABA/ICS 400 300 200 100 LABA/ICS 410 400 410 250 250 Lost FU 230 PEF 240 120 Sinusitis Sinusitis Sinusitis 0 Mar- Jun- July- Aug- Nov- Jan- May- Jun97 00 00 00 00 01 01 01 Case Study 2: VN, Male age 60 Known of Asthma for 30 years, non-smoker Variation of Clinical symptoms and PEF LABA/ICS 400 200 100 PEF LABA/ICS 370 370 390 300 300 250 290 280 230 360 320 240 300 300 230 230 Lost FU Lost FU Non-adherence worsening AR n9 Ja 9 n9 M 9 ar -9 M 9 ay A 99 ug -9 D 9 ec -9 Fe 9 b0 A 0 pr -0 M 0 ay -0 O 0 ct -0 No 0 v0 D 0 ec -0 Ja 0 n0 A 1 pr -0 Ju 1 nJu 01 ly -0 1 0 Ja Peak flow rate (L/min) 500 320 Case Study 3: PK, male age 35 Peak flow rate (L/min) Known of Mild Persistent Asthma and AR since 17 y-o Variation of Clinical symptoms and PEF 800 600 400 200 PEF 730 Treated Asthma ICS 450 350 620 690 710 650 720 690 680 Started Treating AR only 0 7 8 0 1 5 6 7 8 9 0 1 8 8 9 9 9 9 9 9 9 0 0 19 19 19 19 19 19 19 19 19 20 20 650 Pitfalls in Asthma management Undertreatment with inhaled corticosteroids even in developed countries Comparable Asthma Severity in the Study Populations Europe AIRE US AIA Mild 22% Mild 19% Moderate 19% Moderate 19% Intermittent 43% Intermittent Severe 19% 40% Severe 19% Severity classified by NIH Symptom Severity Index AllergyChula AIRE : Anti-inflammatory uses N=2803 in 7 European Countries % of Patients 100 Anti-inflammatory Reliever 81 76 80 75 63 60 40 23 26 26 30 20 0 AIRE Total Severe Persistent Moderate Persistent Mild Persistent AllergyChula American: AIA Study Patients and Inhaled Corticosteroids Medicines Used to Treat Asthma by NIH Severity Index: Inhaled Corticosteroids vs Quick-Relief Medications % of Patients Inhaled CS 80 70 60 50 40 30 20 10 0 Reliever 80 78 70 61 40 20 15 18 16 10 Total Severe Persistent Base: All patients (unweighted N=2509). Moderate Persistent Mild Persistent Mild Intermittent AllergyChula Asian-Pacifc: AIRIAP 2001 Prevention treatment vs. Quick Relief Bronchodilators Preventative Treatment 60% 50% Quick Relief Bronchodilators 51% 41% 45% 39% 40% 38% 30% 20% 13% 15% 18% 11% 11% 10% 0% AIRIAP Total Severe Persistent Moderate Persistent Mild Persistent Mild Intermittent AllergyChula Comparison of AIRE, AIA and AIRIAP AIRE : N=2803 in 7 European Countries AIA : N= 2509 in USA AIRIAP: N=3206 in 8 Asian-Pacific countries 19 Emergency room visit 1-2 in 10 23 AIRIAP 10 AIA 15 Hospitalized 1 in 10 9 AIRE 7 30 29 25 Emergent visit 0 20 3 in 10 40 60 80 100 Survey Findings (%) AllergyChula Comparison of AIRE, AIA and AIRIAP AIRE : AIA : AIRIAP: N=2803 in 7 European Countries N= 2509 in USA N=3206 in 8 Asian-Pacific countries 36 Missed school AIRIAP 49 43 AIA 26 25 Missed work AIRE 17 52 Activity limited 64 63 0 20 40 60 80 100 Survey Findings (%) AllergyChula Chronic asthmatics and long term outcomes in lung function Poorly controlled will lead to irreversible air way obstruction Height-adjusted FEV1 (litres) Increased loss of FEV1 in asthma Male non-smokers P <0.001 No asthma (n= 5480) Asthma (n= 314) Age (years) Lange P et al, NEJM 1998 Airway Remodeling in Asthma Cells proliferation: smooth muscle cells, mucous glands Increase matrix protein deposition Reticular basement membrane thickening Angiogenesis AllergyChula Pathology of Asthma Asthma Normal Mild Asthma Heavy smoker metaplasia Busse W, NEJM 2001 Jeffery , Chest 2000 Ignorance the link of upper and lower airway The United Airway Diseases ARIA Guidelines recommendations • Patients with persistent allergic rhinitis should be evaluated for asthma by history, chest examination and, if possible and when necessary, assessment of airflow obstruction before and after bronchodilator • History and examination of the upper respiratory tract for allergic rhinitis should be performed in patients with asthma • A strategy should combine the treatment of both the upper and lower airway disease in terms of efficacy and safety 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 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 Ignorance in Environmental Factors Environment and Allergy ฝุ่ นบ้ าน ฝุ่ นบี่นอน เกสร ตัวไร่ ฝุ่น สั ตว์ เลีย้ ง เชื้อรา ทีก่ กั ฝุ่ น อาหาร สิ่ งเหล่านี้มีอยูร่ อบตัวเรา มีท้ งั ในบ้านและนอกบ้าน แต่มีหลายอย่างที่เราหลีกเลี่ยงได้ หากเรารู ้วิธีที่ถูกต้อง Indoor Irritants Patient Education for Environmental Control Pitfalls in Drug Allergy and Drug Sensitivity Highlight on 3 issues • Penicillin Skin Testing • Aspirin and NSAIDs sensitivity • Cross sensitivity with paracetamol Penicillin Skin testing • Gold standard testing: (sensitivity >90%) – Major determinant: Pre-Pen (Penicilloyl polylysine) – Minor determinant (MDM) – Penicillin G • In Thailand: only penicillin G being used for testing (sensitivity <50%) Aspirin/NSAIDs sensitivity Underestimated and management Case study: Diagnosis Aspirin Triad Rhinosinusitis with nasal polyps Chronic asthma ASA sensitivity More specific diagnosis: Aspirin Disease AllergyChula Clinical Features of NSAIDs/Analgesic Sensitivity A Thai Cohort (N=31) Angioedema 3% 3% Nasoocular+ angioedema 10% Asthma+ Anaphylactoid Angioedema 44% 13% 10% Urticaria+ angioedema 17% Anaphylactoid 2 Aspirin disease (ASA Triad) Ruxrungtham K. 2001 Urticaria/angioedema Asthma with others Naso-ocular with angioedema Urticaria Rash AllergyChula NSAIDs/Analgesic Sensitivity A Thai Cohort Type of Agents N=31 Mixed 32% Paracetamol 21% ASA 26% NSAIDs 14% Dipyrone 7% ASA NSAIDs Dipyrone Paracetamol Mixed Ruxrungtham K. 2001 AllergyChula NSAIDs/Analgesic Sensitivity A Thai Cohort Cross-reaction with paracetamol N=25 Yes 4% No 56% Ruxrungtham K. 2001 Yes 40% No Not known AllergyChula A Thai Cohort of NSAIDs/Analgesic Sensitivity Hospitalization 6/27 (22 %) Ruxrungtham K. 2001 AllergyChula A Thai Cohort of NSAIDs/Analgesic Sensitivity Onset and Duration of Reactions Median (Range) Onset: 20 min (5-360 min) Duration: 48 hrs (0.5-168 hrs) Episodes of event: 3 (1-17 times) Ruxrungtham K. 2001 AllergyChula Responses to Standard Treatment (Adrenaline, antihistamines, steroids) in patients with angioedema or anaphylactoid reaction Total N=14 <30 min : 7 % (n=1) 30-60 min : 21 % (n=3) Not response : 71 % (n=10) Ruxrungtham K. 2001 AllergyChula Pitfalls in Urticaria Over treat chronic urticaria with systemic corticosteroids • Problem of rebound • Systemic side effects of CS AllergyChula CHRONIC IDIOPATHIC URTICARIA TREATMENT • Antihistamines for Chronic Idiopathic urticaria - Non-sedating - Sedating CHRONIC IDIOPATHIC URTICARIA TREATMENT Options: If single drug therapy ineffective Combinations - First + second-generation antihistamines - H1 antihistamine + H2-blocking agent Pitfalls in Anaphylaxis Mediators of Mast Cells and Basophils Primary Mediators Histamine Tryptase Chymotryptase Heparin/Chondroitin Kininogenase Chemotactic Factors Sim TC, Grant JA 1996 Secondary Mediators Prostaglandins Leukotrienes PAF Histamine RFs IL-3, 4, 5, 6, 7, 8 GM-CSF, TNFa Chemokines MCP1, MIP1 Oxygen radicals AllergyChula Improper treatment • Use antihistamines and/or dexmethasone as first choice but not adrenaline • Standard of care: – Adrenaline, Adrenaline, Adrenaline IM !!!! Plus: – Antihistamines – Dexamethasone – H2 blocker, etc AllergyChula Thank You