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

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

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

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

Prevalence of aspirin sensitivity among patients with asthma

Pre

vale

nce

(%

)

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)

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

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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.

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 !!!

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

Pathogenesis of chronic inflammation in patients with AERD

AAabnormaliti

es

Allergy Infections

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

Atopic sensitization in ASA-sensitive asthmatics

Earlier studies -no reference populations

More recent studies with reference populations

% o

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ents

% o

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ents

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

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

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

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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

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

COX-2COX-1

Arachidonic acid

PGE, PGI2, TXB2 Prostaglandins

CytoprotectionRegulation Inflammation

?

Aspirin

CoxibsCelecoxib

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%

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

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

*

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

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)

Overlapping phenotypes in AERD

ASA-induced reactions

Infections

Chronic Rhinosinusitis Eosinophilia

Arachidonic acid abnormalities Nasal Polyps

Autoimmunity

Severe/non severe asthma