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Aspirin-induced asthma Lee, Jae-Young Department of Internal Medicine Eulji Medical College Hospital What does make it important? • • • • Doctor/Scientist Patient Company Student What is Asthma? “ Asthma is a chronic inflammatory disorder of the airways… recurrent episodes of wheezing, breathlessness, chest tightness, and cough,… which is usually associated with widespread but variable airflow limitation… and an associated increase in airway responsiveness…” Global Strategy for Asthma Management. Publication No. 95-3659, 1995 WHO and NIH Bronchial Asthma Pathology of Asthma ECP Asthma Normal Airway inflammation in asthma Normal Asthmatic P Jeffery, in: Asthma, Academic Press 1998 Basement membrane thickening P Jeffery, in: Asthma, Academic Press 1998 Asthma is is not a homogeneous disease Allergic asthma Non-allergic asthma TDI-induced asthma Aspirin-induced asthma History • Salicylic acid 1874 – Kolbe in Germany • Acetylsalicylic acid – Felix Hoffman in Bayer – New drug ‘Aspirin’ in 1899 • Widal 1922 – ASA sensitivity – Asthma – Nasal polyposis • Samter & Beers 1968 – Aspirin triad Definition Sensitive ? Intolerance ? • Aspirin-induced asthma(AIA) • Aspirin-sensitive asthma Allergy ? • Aspirin-intolerant asthma ; an aggressive mucosal inflammatory disease combined with precipitation of asthma and rhinitis attacks after ingestion of ASA and most nonsteroidal anti-inflammatory drugs(NSAIDs) Szczeklik et al J Allergy Clin Immunol 1999 Drug Reactions • Drug overdose : toxic reactions linked to excess dose or impaired excretion. • Drug side-effect : undesirable pharmacological and unavoidable effect. • Drug interaction : action of a drug on the effectiveness or toxicity of another drug • Drug intolerance : a condition defined by a lowered threshold to the normal pharmacological action of a drug. Another meaning can be given to the drug intolerance syndrome, especially when speaking about aspirin hypersensitivity(sometimes called analgesic idiosyncrasy) Pradal & Vervloet in AB Kay(ed): Allergy and Allergic Diseases. 1998 Drug Reactions • Drug idiosyncrasy : considered to be a genetically determined, qualitatively abnormal reaction to a drug related to metabolic or enzyme deficiency • Drug allergy : involves immunological mechanism and is characterized by specificity to a given agent, transferability by antibodies or lymphocytes and recurrence when there is re-exposure to the culprit drug. • Pseudoallergic reactions : same clinical manifestations as allergic reactions but lacking the specific immune mechanism of drug allergy. Pradal & Vervloet in AB Kay(ed): Allergy and Allergic Diseases. 1998 Definition • Aspirin-induced asthma(AIA) • Aspirin-sensitive asthma • Aspirin-intolerant asthma ; an aggressive mucosal inflammatory disease combined with precipitation of asthma and rhinitis attacks after ingestion of ASA and most nonsteroidal anti-inflammatory drugs(NSAIDs) Szczeklik et al J Allergy Clin Immunol 1999 Clinical presentation(I) • Sequence of symptoms – Rhinitis at an average age of 30 years, related to a flu-like infection in half of patients – Asthma(2 years later) – Aspirin intolerance and nasal polyposis(4 years later) • Women – Outnumber men by 2.3:1 – More progressive and severe • Atopy – one third Szczeklik et al Eur Respir J 2000 Clinical presentation(II) • Most patients with AIA have moderate or severe persistent asthma. – Inhaled corticosteroids; 80% – Oral steroids; 51% Szczeklik et al Eur Respir J 2000 Szczeklik et al Eur Respir J 2000 Szczeklik et al Eur Respir J 2000 Clinical presentation(III) • After ingestion – acute asthma attack occurs within 3 hours, usually accompanied by profuse rhinorrhea, conjunctival injection, periorbital edema, and sometimes a scarlet flushing of head and neck Szczeklik et al J Allergy Clin Immunol 1999 • AIA is a common precipitant of life-threatening attack of asthma(7 out of 92 asthmatics who underwent mechanical ventilation) Picado et al Eur Respir J 1989 • 25% of asthmatic patients requiring emergency mechanical ventilation – AIA(147 asthmatics) Marquette et al Am Rev Respir Dis 1992 Prevalence of aspirin induced asthma according to severity of bronchial hyperresponsiveness 60 P < .01 (%) 40 27.3 20 5.8 0 PC20 > 1 mg/ml PC20 ≤ 1 mg/ml 이재영 등 천식 및 알레르기 2001 Clinical presentation(IV) • At one time AIA was though to not occur in atopic patients, positive skin test response to common aeroallergens are actually similar in patients with AIA and those with other types of asthma Bochenek et al Allergy 1996 Diagnosis • Clinical history • Three provocation test – Oral – Bronchial – Nasal Pathogenesis • IgE mediated immediate hypersensitivity • Cyclooxygenase theory(COX theory) • Leukotriene C4 synthase overexpression theory(LTC4s theory) Cyclooxygenase pathway • COX-1 and COX-2 have molecular weights of 71 kd and 60% homology • COX-1 constitutive form • COX-2 induced during inflammation and enhances synthesis of inflammatory prostanoids • PGE2 – Reduce LT biosynthesis through inhibition of 5-LO – Inhibits cholinergic transmission – Prevents discharge of granular mediators from mast cells – Prevents ASA-precipitated bronchoconstriction and the expected rise in urinary LTE4 • PGE2 administration by inhalation inhibits aspirin induced bronchoconstriction Sestini et al AJRCCM 1996 • Selective COX-2 inhibitor(celecoxib, rofecoxib) – preserve PGE2 and do not cross-react with ASA Stevenson et al J Allergy Clin Immunol 2001 Szczeklik et al Clin Exp Allergy 2001 Fig. 1. Oral aspirin challenge in 12 individual AIA patients Szczeklik et al Clin Exp Allergy 2001 Fig. 2. Individual FEV1 courses following oral rofecoxib challenge in 12 AIA patients Szczeklik et al Clin Exp Allergy 2001 Stevenson et al J Allergy Clin Immunol 2001 바이옥스 정(Tab) 12.5mg VIOXX TAB(Tab) 12.5mg (발매일자 : 2000.06 ) 한국엠에스디 MSD Korea (제조: Merck Sharp & Dohme) 복지부 분류 : 114 / KIMS 분류 : Antirheumatic, Anti-inflammatory Analgesics (4c) 보험코드 : E09060191 [전문] Tab 12.5mg, 25mg. 성분명 : Rofecoxib. 적응증 골관절염의 증상 및 증후 완화, 급성 통증 완화(수술후, 발치후 진통), 원 발성 월경곤란증의 치료. 용법/용량 골관절염의 치료: 초기 1일 1회 12.5mg, 1일 1회 25mg까지 증량 가능. 1일 최대 25mg. 급성 통증 완화 및 원발성 월경곤란증의 치료: 초기량 1 일 1회 50mg, 필요시 1일 1회 25-50mg씩 추가 투여. 1일 최대 50mg. 금기 본제 과민증 환자, 아스피린이나 다른 비스테로이드성 소염제에 대하여 천식, 두드러기, 알러지 반응 기왕력자, 임신 말기. 주의 간기능 부전 환자, 신기능 부전 환자, 기관지 천식 환자, 심부전 환자, 고 혈압 환자, 체액저류 환자, 이뇨제나 ACE저해제 투여 환자, 고령자, 궤양 성 질환이나 위장관 출혈의 기왕력자, 임부. 분류 수입완제품. 포장/가격 Tab 12.5mg×5's, 100's. (보)₩1,409/T. 25mg×5's, 100's. (보)₩1,409/T. Fig. 1. This illustration could represent either a mast cell or eosinophil, the 2 most prominent cells detected in the respiratory mucosa of patients with AIA. Other inflammatory cells could also participate, although PMNs and macrophages predominantly synthesize LTB4 . During inflammatory respiratory disease, Cys-LTs, histamine, and eosinophilic cationic protein (ECP) are formed and released, effecting eosinophil recruitment, vascular permeability, mucus secretion, and bronchial hyperreactivity. When ASA is added, the respiratory reaction begins, COX-1 and COX-2 are both disabled, PGE2 synthesis ceases and its modulating effects on mast cells and 5-LO are removed, and mediators are released or synthesized. If LTC4 synthase is increased, augmented synthesis of Cys-LTs also occurs. During ASA desensitization, COX-1 and COX-2 continue to be disabled, with concomitant blocking of prostanoid formation. Histamine secretion ceases, but Cys-LTs continue to be synthesized at a rate found at baseline. However, Cys-LT bronchial receptors are downregulated. 5LO and FLAP enzymes are not different from those of normal subjects and are not directly affected by ASA/NSAIDs. Szczeklik et al J Allergy Clin Immunol 1999 • PGE2 vs. PGD2, PGF2, 9,11-PGF2 Szczeklik et al AJRCCM 1996 • Bronchial inhalation of lysine-aspirin reduce BAL fluid PGE2 levels in AIA to the same extent as in ATA Sladek et al AJRCCM 1994 • The expression of COX-1 and COX-2 did not differ between the AIA and ATA Cowburn et al J Clin Invest 1998 Table III Expression of COX-1 and COX-2 in AIA, ATA, and N Biopsies Placebo COX-1 Lys-aspirin COX-2 COX-1 COX-2 30.5±3.0* (10) 19.8± 5.6 (10) AIA 35.8±11.2 (10) 6.2±1.2 (10) ATA 25.5±6.5 (10) 8.7±2.7 (10) N 24.7±4.0 (8) 13.2±4.0 (5) 11.9±2.9 (5) 14.3±4.5 (8) Counts of cells immunostaining for COX-1 and COX-2 in bronchial mucosal biopsies of patients with AIA and ATA taken 20 min after bronchoscopic challenge with placebo or with lys-aspirin (10 mg aspirin equivalents). Counts of cells immunostaining for COX-1 and COX-2 are also shown in bronchial biopsies of unchallenged, N controls. Values are mean±SEM cells/mm2 (n). The expression of COX-1 and COX-2 did not differ between the AIA, ATA, and N biopsies after placebo challenge (Mann-Whitney), and did not change significantly after lysaspirin challenge compared with the placebo challenge of the same group (Wilcoxon). * P = 0.012 vs. ATA. Cowburn et al J Clin Invest 1998 • Why the interruption of PGE2 synthesis by ASA/NSAIDs does not induce respiriatory reaction in all humans, or at least all asthmatic subjects, is the crux of the riddle in understanding of ASA-induced respiratory reactions. The lipoxygenase pathway • Cys-LTs in AIA – Urine, baseline and after stimulation – Nasal secretion after stimulation – BAL fluid after stimulation Fig. 3. Counts of cells immunostaining for 5-LO pathway enzymes in bronchial mucosal biopsies from patients with AIA (n = 10), with ATA (n = 10), and N subjects (n = 9), taken 20 min after bronchoscopic challenge with placebo solution. Enzymes are 5-LO, FLAP, LTA4 hydrolase (LTA4H), and LTC4 synthase (LTC4S). Horizontal bars, mean±SEM. All significant comparisons between subject groups (P < 0.05 Mann-Whitney) are indicated. Cowburn et al J Clin Invest 1998 Fig. 1. This illustration could represent either a mast cell or eosinophil, the 2 most prominent cells detected in the respiratory mucosa of patients with AIA. Other inflammatory cells could also participate, although PMNs and macrophages predominantly synthesize LTB4 . During inflammatory respiratory disease, Cys-LTs, histamine, and eosinophilic cationic protein (ECP) are formed and released, effecting eosinophil recruitment, vascular permeability, mucus secretion, and bronchial hyperreactivity. When ASA is added, the respiratory reaction begins, COX-1 and COX-2 are both disabled, PGE2 synthesis ceases and its modulating effects on mast cells and 5-LO are removed, and mediators are released or synthesized. If LTC4 synthase is increased, augmented synthesis of Cys-LTs also occurs. During ASA desensitization, COX-1 and COX-2 continue to be disabled, with concomitant blocking of prostanoid formation. Histamine secretion ceases, but Cys-LTs continue to be synthesized at a rate found at baseline. However, Cys-LT bronchial receptors are downregulated. 5LO and FLAP enzymes are not different from those of normal subjects and are not directly affected by ASA/NSAIDs. Szczeklik et al J Allergy Clin Immunol 1999 Polymorphism of LTC4 synthase • A to C transversion of nucleotide 444 upstream • The C444 allele is 60% more common in patients with AIA Sanak et al Lancet 1997 • ASA provocation leads to dramatic increases in urinary LTE4 in carriers of the C444 allele Sanak et al Allergy 1998 Chronic inflammation of the airway • Eosinophil infiltration of airway tissue appears to be a central feature of AIA Fig. 1. Immunostain-ing for myeloid cell markers in GMA-embedded bronchial mucosal biopsies from patients with AIA ( ; n = 10), patients with ATA ( ; n = 10), and N subjects ( ; n = 9), taken 20 min after bronchoscopic challenge with placebo solution. Cell markers are total cellular ECP (EG1, total eosinophils), translocated ECP (EG2, "activated" eo- sinophils), mast cell tryptase (AA1), and CD68 (PG-M1, CD68 macrophages). Horizontal bars, mean±SEM. All significant comparisons between subject groups (P < 0.05 Mann-Whitney) are indicated Cowburn et al J Clin Invest 1998 Figure 1. The expression of IL-5 in the submucosal inflammatory cells of aspirin-sensitive asthmatic (ASA) and non-ASA (NASA) subjects. Each point represents an individual patient. Bars represent the mean of each group. Sousa et al AJRCCM 1997 Prevalence of aspirin induced asthma according to sputum eosinophil count 100 (%) 80 P < .05 60 38.9 40 20 0 0 Eos < 3 % Eos > 3% 이재영 등 천식 및 알레르기 2001 Fig. 7. Proportion of LTC4 synthase+ cells colocalizing to immunostaining for EG2 (eosinophils), AA1 (mast cells), and CD68 (macrophages) in the 8 of 10 AIA biopsies with a density of LTC4 synthase+ cells sufficient for colocalization on adjacent sections by the camera lucida technique. Horizontal bars, mean±SEM. Cowburn et al J Clin Invest 1998 Chronic inflammation of the airway • Eosinophil infiltration of airway tissue appears to be a central feature of AIA • Persistent airway inflammation in AIA ? Non-IgE-mediated reaction to an endogenous or exogenous antigen or virus ? Prevention and Treatment(I) • The general rules concerning treatment of AIA do not differ from the published guidelines on the management of asthma. Prevention and Treatment(II) • Avoid ASA/COX inhibitor • Acetaminophen(not exceed 1000mg) • Nimesulide, meloxicam – induced mild bronchial obstruction only at high doses • Selective COX-2 inhibitor(celecoxib, rofecoxib) – preserve PGE2 and do not cross-react with ASA TABLE III. Frequency of bronchospastic reactions to acetaminophen in 34 patients with aspirin sensitivity (bronchospastic type) Acetaminophen challenge doses Bronchospasm type 1000 mg 1500 mg Partial bronchospasm 0/34 (0%) 1/34 (3%) Bronchospasm 6/34 (18%) 8/34 (24%) Bronchospasm + NOR 2/34 (6%) 2/34 (6%) Total bronchospasm* 8/34 (26%) 11/34 (32%) NOR, Naso-ocular reaction. *Total bronchospasm = partial bronchospasm + bronchospasm + bronchospasm linked to naso-ocular reaction Settipane et al J Allergy Clin Immunol 1995 Figure 1 Activity in modified whole blood assay of various NSAIDs on COX-1 at a dose that gives an 80% inhibition of COX-2. Those below the line have selectivity towards COX-1 and these are grouped with others that have a less than fivefold selectivity towards COX-2. The next group contains meloxicam, etodolac, celecoxib, and nimesulide which have 5-50 fold selectivity towards COX-2. Only rofecoxib has a greater than 50-fold selectivity for COX-2. Modified from Warner et al.69 Vane Thorax 2000 Prevention and Treatment(III) • Desensitization(Rheumatic & Vascular diseases) – Small incremental oral doses of ASA are ingested over the course of 2 to 3 days until 400 to 650 mg of ASA is tolerated. Prevention and Treatment(IV) • Anti-LT drugs – Pretreatment with LT-modifying drugs attenuate ASA-provoked nasal and bronchial reactions in most patients – Bronchodilation has been observed after treatment with anti-LT drugs in AIA Figure 2. (A) Percent change in FEV1 (treatment mean ± SE) after a single dose of zileuton (600 mg) or matching placebo. The increase in FEV1 was significant compared with placebo at 1, 3, and 4 h (p < 0.05, p < 0.01, and p < 0.01, respectively). The maximum increase in FEV1 during the first 0-4 h was 12.7% for zileuton and 6.8% for placebo; the difference between the two treatments was 5.9% (95% CI 1.9-9.9; p < 0.01). Likewise, at 4 h postdose an increase in FEV1 was seen only on zileuton treated days, the treatment difference being 7.5% (95% CI 3-12; p < 0.01). (B) Improvement in lung function over baseline after 2, 4, and 6 wk of zileuton treatment (600 mg, four times daily) corresponding to, respectively, 9, 3, and 7% differences from placebo in FEV1 (p < 0.001, p = 0.16, and p < 0.01). DAHLÉN et al AJRCCM 1998 Figure 4. Nasal symptom scores showed a significant reduction in loss of smell and rhinorrhea (p < 0.01 and 0.05, respectively) whereas nasal congestion was unaffected (p = 0.63). DAHLÉN et al AJRCCM 1998 Prevention and Treatment(V) • 2-adrenergic agonist – Protect against ASA-induced attacks of asthma through a mechanism that seems unrelated to its bronchodilator properties Prevention and Treatment(VI) • Treatment of chronic eosinophilic rhinosinusitis – Intranasal steroids – LT modifiers – Sinus/polyp operation – ASA desensitization 천식 및 알레르기크리닉 (병원 홈페이지) http://www.emc.ac.kr/center_clinic/clinic/ pmc/default.asp?dep=pmc