Download Aspirin-induced asthma

Aspirin-induced asthma
Lee, Jae-Young
Department of Internal Medicine
Eulji Medical College Hospital
What does make it important?
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Patient
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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
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