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Marek L. Kowalski , M.D., Ph.D.Department of Immunology, Rheumatology and Allergy ,,
Medical University of Łódź, Poland
Aspirin Exacerbated Respiratory Disease
World Allergy Forum2010 AAAAI Annual Meeting
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Asprin-induced asthma – the oldest known asthma phenotype
• „Patient J.M. , 40 years old• The disease began 11 years ago (in 1912) with symptoms of
rhinitis related to polypoid mucosal hypertrophy and associated with frequent „colds” and coughing, but without fever .
• He had several polypectomies which relieved symptoms temporarily …
• Few years later he experienced an acute asthma attack at night after ingesting a tablet of aspirin …
• He suffers a severe asthma with several attacks during day and night …
• Diagnosis : Asthma bronchiale. Rhinitide chronica hyperplastica polyposa (asthma reflectorium). Anaphylaxia ex usu aspirini „
M. Wierzuchowski Pol. Arch. Med. Wewn. 1925 ,2,25-75
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The milestones in the history of aspirin sensitivity
• 1975 - A. Szczeklik
• “ prostglandin inhibition” theory of AIA
• 1902 – R. Hirschberg the first case of ASA- sensitivity reported
• 1922 - F. Widal “ASA-triad”
• 1967 - M.SamterASA-sensitivity as a clinical entity
Poznań, Poland
Chicago,USA
Paris, France
Kraków, Poland
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Aspirin Exacerbated Respiratory Disease
80
% o
f pa
tien
ts
NSAIDs - induced symptoms Clinical phenotype
Hyperplastic CRS with nasal polyps
Moderate to severe asthma
Aspirin triad; Widal’s Syndrome, Samter’s Syndrome; Aspirin-Induced Asthma
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Prevalence of aspirin sensitivity among patients with asthma
Pre
vale
nce
(%
)
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AERD as a severe asthma phenotype
Od
ds R
ati
o
BMIAIA
Wheezing in childhood
OR =2.6
ML Kowalski et al. Allergy 2010 ,in press
Risk factors for severe asthma• Higher medication requirements,
including dependence on oral GCS (Szczeklik A. et al. 2000)
• Irreversible airway obstruction• More likely to have been
intubated and to have a steroid burst in the previous three months ( Mascia K et al . 2005)
• Frequent exacerbations( Koga T. Et al. 2006)
• Association with near fatal asthma ( Plaza W. et al. 2002)
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Severity of CRS in ASA-tolerant and ASA-sensitive patients
CT staging of chronic rhinosinusitis in ASA-sensitive and ASA-tolerant patients
CT
sco
re
% o
f pa
tien
ts
Recurrence of nasal polyps after polypectomy ( follow-up period of 4 years)
Jantti-Alanko S. et al. Rhinology 1989,8.59
Kowalski ML et al. WAJ 2003
ASA-sensitive
ASA-tolerant
• Patients with AERD had history of 10 times as many previous FESS procedures as had the patients without Samter's triad
• ASA triad mean: 5.2• ASA (- ) mean 0.53; (p < 0.001)
30
20
10
*
* * **
*
Kim JE Ear Nose Throat J. 2007 Jul;86(7):396-9.
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Pathomechanisms of Aspirin Exacerbated Respiratory Disease
BronchialNasalOccularsymptoms
ASA /NSAID’s
COX
Mast cell
EOSLeukotrienesTryptaseHistamineECP15-HETE
I. Acute symptoms precipitated by ASA and NSAIDsI. Acute symptoms precipitated by ASA and NSAIDs
I I. Chronic symptoms and underlying airway inflammation
Unrelated to ASA or other NSAIDs intake !!!
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Arachidonic acid
LTA4
LTC 4
LTD4
LTE 4
PGG2
PGH2
5-LOX
PGE2
COX-2COX-1
Cell membrane phospholipids
PLA
LTC4s
EP -REP -R
EOS Mast cell
PGE2
EP -REP -R
ASA
AsthmaRhinorrhea
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Pathogenesis of chronic inflammation in patients with AERD
AAabnormaliti
es
Allergy Infections
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Arachidonic acid
LTA4
PGG2
PGH2
PGE2 TXB2PGI2
Cell membrane phospholipids
15-HETE
PGF2
PGD2
Lipoxins LTC4
LTD4
LTE4
15-LOCOX-1 COX-2
PLA-2
FLAP
LTC4s
5-LO
5-LO
LTB4
LTA4 h
12-HETE12-LO
• Decreased production of PGE2
• Downregulation of Cyclooxygenase-2Cyclooxygenase-1(?)
• Increased generation of cysLTs (urine , BAL, EAC)
• Overexpression of LT receptors
• Specific release of 15-HETE upon ASA challenge
• Abnormal lipoxins generation
Several polymorphisms in AA related genes have been associated with AERD
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Atopic sensitization in ASA-sensitive asthmatics
Earlier studies -no reference populations
More recent studies with reference populations
% o
f pati
ents
% o
f pati
ents
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Role of infections in the pathogenesis of AERD
• Viral hypothesis (A. Szczeklik;1988)
– Flu-like symptoms precede the development of aspirin-sensitivity
– Chronic viral respiratory tract infection may both initiate and perpetuate chronic airway inflammation in AERD
• Enterotoxin hypothesis (C. Bachert; 2005)– (Staphylococcus aureus enterotoxins (SAE) are potent
superantigens and inflammatory cell activators – Specific IgE to SAE have been found in nasal polyp
tissue – sIgE to SAE are associated with eosinophilic
inflammation in rhinosinusitis
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sIgE to SAEs in ASA-sensitive and ASA-tolerant polyps
C. Perez-Novo et al. Int. Archs All& Imm. 2004
kU
a/l
m
ed
ian
Correlation of SEA-sIgE with ECP and IL-5 in nasal polyps
Y.J.Suh et al. Clin Exp Allergy 2004
Concentration of SAE-specific IgE in nasal polyps
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0
0,2
0,4
0,6
0,8
1
1,2
ASA (-) ASA (+)
sIgE to Staphylococcus aureus enterotoxins in serum and asthma severity - LODZ Study
SA
E c
on
cen
trati
on
kU
a/l
N= 52
M.LKowalski ,C.Bachert et al . Allergy 2010 in press
N= 145
7670
0
0,2
0,4
0,6
0,8
1
1,2
1,4
1,6
HC NS SevereN= 29 N= 97 N= 100
**
Severe and non-severe asthmatics
ASA- tolerant and ASA-sensitive asthmatics
SA
E c
on
cen
trati
on
kU
a/l
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Diagnosis of respiratory type of hypersensitivity to NSAIDs
• History
• Aspirin challenge– Oral– Inhaled– Intranasal
• In vitro testing– Cellular activation tests
• BAT• ASPITest (15-HETE)
– Urinary LTE4
• Genetic testing
Aspirin-Sensitive PatientsIdentification Test (ASPITest)
Sensitivity 82% PPV 79%Specificity 83% NPV 86%
M.L.Kowalski et al. Allergy 2005,60,1139-45
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Management of ASA-sensitive rhinosinusitis/asthma
Avoidance of NSAIDs • Recommendations for selective
COX-2 inhibitors
Pharmacologic treatment• Intranasal /inhaled
glucocorticosteroids • Leukotriene antagonists – as effective
as in ASA-tolerant patients
Sinus surgery / polypectomy• Less effective in ASA-sensitive
Aspirin desensitization• Clinical use: risks / benefits
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COX-2COX-1
Arachidonic acid
PGE, PGI2, TXB2 Prostaglandins
CytoprotectionRegulation Inflammation
?
Aspirin
CoxibsCelecoxib
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Cox-2 inhibitors and in AERD
• Aspirin-induced asthma is a COX-1 dependent phenomenon
• Preferential COX-2 inhibitors are tolerated by 80-90% of ASA-sensitive asthmatics
• Selective COX-2 inhibitors are generally well tolerated
• COX-2 selective NSAIDs can be used by ASA-sensitive asthmatics, but tolerance test is recommended before an alternative drug is prescribed
• Single reports of COX-2 inhibitor-induced asthmatics reactions were published– Celcoxib -3– Rofecoxib -1– Etoricoxib -1
R. Munoz-Cano et al. J Investig Allergol Clin Immunol 2009,19,64
FEV1%
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Clinical efficacy of leukotriene receptor inhibitors in ASA hypersensitive and ASA-tolerant patients
Add on therapy study : 3 monthstreatment with montelukast 10 mg
Ragab S. et al , C E A 2001,31,1385 Kowalski ML et al , 2008
Change in s
ym
pto
ms
(%)
Change in s
ym
pto
ms
(%)
* **** **
*
Add on therapy study : 2 monthstreatment with zafirlukast 20 mg
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Endoscopic Sinus Surgery and CRS outcomes in ASA-sensitive and ASA-tolerant patients
Patients• 19 ASA-sensitive and
104 ASA-tolerant patients with CRS were recruited to prospective study
• Patients were subjected to ESS and followed for a mean of 17,7 months after surgery
Results• Similar proportions of ASA
sensitive and ASA-tolerant patients had improved:
– Endoscopic score
– Quality of Life scores
• Larger proportion of ASA-sensitive patients reported increased medication use
). Robinson JL et al.. The Laryngoscope 2007 ,117,830
Endoscopy scores before and after ESS
Increase in medication use
*
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Aspirin desensitization in patients with AERD
• Daily oral ASA after desensitization (300-2400mg) in some patients may lead to:– Improvement in asthma symptoms– Improvement in rhinosinusitis symptoms– Decreased need for sinus surgery/polypectomy
• 1923 F. Vidal reported „desensitization” to aspirin
• 1976 C. R. Zeiss & R.F. Lockey described refractory period to aspirin
• 1981 D.D. Stevenson reported clinical benefits of prolonged treatment with aspirin after desensitization
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Indications for ASA- desensitization
• Aspirin sensitive asthma/rhinosinusitis – Patients with aggressive polypoid CRS– Patients do not responding to pharmacological
treatment– Corticosteroid-induced side effects
• ASA-sensitive patients with– Coronary heart disease– Antiphospholytic syndrome– Chronic inflammatory diseases (AR; OA)
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Overlapping phenotypes in AERD
ASA-induced reactions
Infections
Chronic Rhinosinusitis Eosinophilia
Arachidonic acid abnormalities Nasal Polyps
Autoimmunity
Severe/non severe asthma