Ricardo Cardona Villa, M.D. MSc in Immunology - Allergist Chief of Clinical Allergology Service IPS...

Ricardo Cardona Villa, Ricardo Cardona Villa, M.D.M.D.MSc in Immunology - AllergistMSc in Immunology - Allergist

Chief of Clinical Allergology ServiceChief of Clinical Allergology Service

IPS Universitaria - Clínica León XIIIIPS Universitaria - Clínica León XIII

Medical SchoolMedical School

Universidad de AntioquiaUniversidad de Antioquia

Desensitization in non-steroidal Desensitization in non-steroidal anti-inflammatory drugs (NSAID) anti-inflammatory drugs (NSAID)

hypersensitivityhypersensitivity

Acetylsalycilic acid (ASA)Acetylsalycilic acid (ASA) A model of NSAID A model of NSAID

The End of Suffering The End of Suffering

http://goyotovar.lasideas.es/wp-content/imagenes/aspirina.jpg

Acetylsalycilic acid is extracted from the treeAcetylsalycilic acid is extracted from the tree "Salix alba""Salix alba",, called salicin, discovered in 1827called salicin, discovered in 1827

18991899 The product was registered as The product was registered as Aspirin by Aspirin by Felix HoffmanFelix Hoffman

The creator of Aspirin, Felix Hoffmann The creator of Aspirin, Felix Hoffmann and a package circa 1900.and a package circa 1900.

HistoryHistory

1980 1980 StevensonStevenson et al described et al described two patients with previous two patients with previous ASA induced asthmatic ASA induced asthmatic reactionsreactions

Chemical classification of NSAIDsChemical classification of NSAIDs

Mario Sánchez-Borges. WAO Journal 2008; 1: 29-33

Chemical group Drugs

Alkanones Nabumetone

Anthranilic acids (fenamates) Meclofenamic acid, mefenamic acid

Arylpropionic acids Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Oxaprozín

Enolic acidsOxicams (Piroxicam, Tenoxicam, Meloxicam), Pyrazolidinediones (Oxyphenthatrazone, Phenylbutazone)

Heteroaryl acetic acids Diclofenac, Ketorolac, Tolmetin

Indole and indene acetic acids Etodolac, Indomethacin, Sulindac

Para-aminophenol derivatives Acetaminophen (paracetamol)

Pyrazol derivatives Aminopyrine, Antipyrine, Dipyrone

Salicylic acid derivativesAspirin, choline magnesium trisalicylate, diflunisal, Olsalazine, Salicylsalicylic, Salsalate, Salicylate, Sulfasalazine

TerminologyTerminology

Selectivity:Selectivity: agents that inhibit agents that inhibit more onemore one enzyme than enzyme than the other, but can inhibit both of them (Meloxicam, the other, but can inhibit both of them (Meloxicam, Nimesulide)Nimesulide)

Specificity:Specificity: agents that inhibit agents that inhibit only oneonly one enzyme at enzyme at doses that produce maximum doses that produce maximum clinical efficacy clinical efficacy (Celecoxib - Etoricoxib - Lumiracoxib)(Celecoxib - Etoricoxib - Lumiracoxib)

Classification of some NSAIDsClassification of some NSAIDsSelectivity Drugs

Weak COX inhibitors

Acetaminophen, Salsalate, Salicylamide, sodium salicylate, choline-magnesium trisalicylate

COX-1 / COX-2 inhibitors

Piroxicam, Indomethacin, Sulindac, Tolmetin, Ibuprofen, Naproxen, Fenoprofen, Meclofenamate, Mefenamic acid, Diflunisal, Ketoprofen, Diclofenac, Ketorolac, Etodolac, Nabumetone, Oxaprozin, Flurbiprofen

COX-2 preferential inhibitors Nimesulide, Meloxicam

COX-2 selective inhibitors Celecoxib, Rofecoxib, Valdecoxib, Parecoxib, Etoricoxib, Lumiracoxib

Mario Sánchez-Borges. WAO Journal 2008; 1: 29-33

Membrane phospholipidsMembrane phospholipidsglucocorticoidsglucocorticoids EndotoxinsEndotoxins

cytokinescytokinesmitogensmitogens

(–)(–)

(–)(–)(–)(–)

COX-1COX-1

COX-2COX-2

(+)

arachidonic acidarachidonic acid

Stomach: PGE2/PGI2Stomach: PGE2/PGI2

Kidney: PGE2/PGI2Kidney: PGE2/PGI2

Platelets: TxA2Platelets: TxA2

Endothelium: PGI2Endothelium: PGI2

Inflammation: Inflammation: macrophages macrophages synoviocytessynoviocytes

"Classic"ClassicNSAIDs"NSAIDs"

Selective Selective inhibitors of inhibitors of

COX-2COX-2

MeloxicamMeloxicamCelecoxibCelecoxibRofecoxibRofecoxib

Physiological effectsPhysiological effects Inflammatory mediatorsInflammatory mediators

Concept COX Concept COX

COX-1 / COX-2 comparisonCOX-1 / COX-2 comparison

PARAMETER PARAMETER

HOMOLOGYHOMOLOGY

REGULATIONREGULATION

TISSUETISSUEEXPRESSIONEXPRESSION

COX-1COX-1

Similar to COX-2Similar to COX-2( 60%*- 75%)( 60%*- 75%)

ConstitutiveConstitutive

Most tissues, but Most tissues, but particularly platelets, particularly platelets, stomach and kidneystomach and kidney

COX-2COX-2

Similar to COX-1 Similar to COX-1 ( 60%*- 75%)( 60%*- 75%)

InducibleInducible

Inflammatory stimuli and Inflammatory stimuli and mitogens in mitogens in macrophages/monocytes, macrophages/monocytes, synoviocytes, chondrocytes, synoviocytes, chondrocytes, fibroblasts, endothelial cells.fibroblasts, endothelial cells.Constitutive in CNS and Constitutive in CNS and kidneykidney

COX-1 and COX-2 COX-1 and COX-2 structurestructure

COX-1 COX-2COX-2

HydrophilicHydrophilicpocketpocket

HydrophobicHydrophobicChannelChannel

N-terminalN-terminal N-terminalN-terminal

HydrophobicHydrophobicChannelChannel

IsoleucineIsoleucineat 523, at 523, closes thecloses thehydrophilichydrophilicpocketpocket

Valin at Valin at 523 allows523 allows the access the access to theto the hydrophilic hydrophilic pocketpocket

ArgininArgininAt 120At 120

C-terminalC-terminalactive siteactive site

C-terminalC-terminalactive siteactive site

ArgininArgininatat 120120

Kurumbail R G, Stevens A M, Gierse J K, McDonald J J, et al. Nature. 1996;384:644–648

Claudia Jenneck, Uwe Juergens, Markus Buecheler, and Natalija Novak Ann Allergy Asthma Immunol. 2007;99:13–21.

Membrane phospholipids

Arachidonic acid

Lipoxygenase pathway Cyclooxygenase pathway

5-Lipoxygenase (5-LO) Cyclooxygenase

LT-A4

LTA4 hydrolase LTC4 synthase

LT-B4 Cys-leucotrieneLTC4,

LTD4, LTE4

COX-1 COX-2ASA/

NSAID

Generation of products of the LO-pathway

PG-E2

Shunt from COX – Shunt from COX – towards the towards the

LO-pathwayLO-pathway

Reduced Reduced inhibitioninhibition

Change of Change of the COX-2 the COX-2 structurestructure

Using the classification proposed by the Using the classification proposed by the Committee of the World Allergy Organization, Committee of the World Allergy Organization,

the following types of hypersensitivity the following types of hypersensitivity reactions should be considered:reactions should be considered:

Allergic hypersensitivityAllergic hypersensitivity Non-allergic hypersensitivityNon-allergic hypersensitivity

Johansson SGO, Bieber T, Dahl R, et al. Revised nomenclature for allergy for global use: report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol.2004;113:832-836.

Mario Sánchez-Borges WAO Journal 2008;1:29 - 33

Clinical ManifestationsClinical Manifestations1.1. Allergic hypersensitivityAllergic hypersensitivity

1.1 Immediate reactions1.1 Immediate reactions1.1.1 Urticaria and 1.1.1 Urticaria and Angioedema Angioedema1.1.2 Allergic Anaphylaxis1.1.2 Allergic Anaphylaxis

Sànchez Borges, M. Clinical management of non steroidal anti-inflammatory drug hypersensitivity.

2008;1:29-33. WAO Journal.



1.2 Late reactions1.2 Late reactions1.2.1 Skin diseases1.2.1 Skin diseases

1.2.2 Pneumonitis1.2.2 Pneumonitis1.2.3 Aseptic meningitis1.2.3 Aseptic meningitis1.2.4 Nephritis1.2.4 Nephritis1.2.5 Hepatitis1.2.5 Hepatitis


2008;1:29-33. WAO Journal.



1.2 Late reactions1.2 Late reactions1.2.1 Skin diseases1.2.1 Skin diseases

1.2.2 Pneumonitis1.2.2 Pneumonitis1.2.3 Aseptic meningitis1.2.3 Aseptic meningitis1.2.4 Nephritis1.2.4 Nephritis1.2.5 Hepatitis1.2.5 Hepatitis

2. Nonallergic hypersensitivity2. Nonallergic hypersensitivity2.1 Respiratory 2.1 Respiratory HypersensitivityHypersensitivity

2.2 Skin Hypersensitivity2.2 Skin Hypersensitivity

2.3 Non-allergic anaphylaxis2.3 Non-allergic anaphylaxis


2008;1:29-33. WAO Journal.

Classification:Classification:

Respiratory patternRespiratory patternIncludes respiratory disease exacerbated by ASA,

the Tetrad of Samter (nasal polyposis, rhinosinusitis, asthmaand intolerance to ASA) and ASA-induced asthma.

Andrzej Szczeklik and Marek SanakEuropean Journal of Pharmacology 533 (2006) 145–155

M. Sánchez-Borges, A. Capriles-Hulett, F. Caballero-FonsecaJ Invest Allergol Clin Immunol 2004; Vol. 14(4): 329-334

Skin PatternSkin Pattern

Mario Sánchez-BorgesWAO Journal 2008;1:29Y33

M. Sánchez-Borges, A. Capriles-Hulett, F. Caballero-FonsecaJ Invest Allergol Clin Immunol 2004; Vol. 14(4): 329-334

Including urticaria and angioedema Including urticaria and angioedema induced by NSAIDsinduced by NSAIDs

urticaria and angioedema induced urticaria and angioedema induced by multiple drugs andby multiple drugs and

urticaria and angioedema induced urticaria and angioedema induced by a single drug.by a single drug.

It presents with skin and respiratory symptoms It presents with skin and respiratory symptoms including urticaria and angioedema associated with including urticaria and angioedema associated with

cough, breathlessness, runny nose, wheezing, cough, breathlessness, runny nose, wheezing, tearing or conjunctival irritationtearing or conjunctival irritation

M. Sánchez-Borges, A. Capriles-Hulett, F. Caballero-Fonseca J Invest Allergol Clin Immunol 2004; Vol. 14(4): 329-334

Mario Sánchez-Borges

WAO Journal 2008;1:29-33

Mixed PatternMixed Pattern

Anaphylactic reactions are type I hypersensitivity, Anaphylactic reactions are type I hypersensitivity, usually observed in usually observed in simple reactorssimple reactors who tolerate other who tolerate other

chemically unrelated NSAIDs IgE antibodies specific chemically unrelated NSAIDs IgE antibodies specific for the allergen.for the allergen.

Systemic PatternSystemic Pattern




The management of patients with intolerance to The management of patients with intolerance to NSAIDs NSAIDs depends on their medical history.depends on their medical history.

ManagementManagement




The patient should be classified asThe patient should be classified as simple reactor simple reactor or or cross reactor cross reactor and according to the type of and according to the type of

reaction eitherreaction either cutaneous or systemiccutaneous or systemic..

When the patient is aWhen the patient is a simple reactorsimple reactor,, oral provocation oral provocation testing with an NSAID of a different chemical group testing with an NSAID of a different chemical group

involved is recommended.involved is recommended.




If the test isIf the test is negativenegative, , the patient may receive the patient may receive treatment with NSAIDs testing and avoid the treatment with NSAIDs testing and avoid the

suspected medication.suspected medication.

If the test isIf the test is positivepositive,, the patient should be handled as the patient should be handled as a cross reactor.a cross reactor.

When the patient is classified as aWhen the patient is classified as a cross reactorcross reactor, , an oral an oral challenge test can be performed with a weak COX-1 challenge test can be performed with a weak COX-1

inhibitor or preferential COX-2, orinhibitor or preferential COX-2, orwith a specific COX-2 inhibitor.with a specific COX-2 inhibitor.




If the test isIf the test is negativenegative,, it can be administered to the it can be administered to the patient and ifpatient and if positivepositive try oral challenge with another try oral challenge with another

COX-2 specific inhibitor.COX-2 specific inhibitor.

If the latter (previous) test isIf the latter (previous) test is positivepositive,, avoid all NSAIDsavoid all NSAIDs

Algorithm for clinical managementAlgorithm for clinical managementof skin NSAID-induced reactions of skin NSAID-induced reactions

Mario Sánchez-Borges, Arnaldo Capriles-Hulett and Fernan Caballero-Fonseca

Am J Clin Dermatol 2002; 3 (9): 599-607

Weak COX-1 Inhibitors AcethaminofenSalsalate

Another COX-2

Desensitization

Modificated of Mario Sánchez-Borges, Arnaldo Capriles-Hulett and Fernan Caballero-Fonseca

Am J Clin Dermatol 2002; 3 (9): 599-607

Medical history

Cutaneous single-reactor

Cutaneous cross reactor

Single drug anaphylaxis

Alternative medication

Oral challengeWith COX-2 inhibitor

Negative Weak COX-1 Inhibitors

AcethaminofenSalsalate

Treatment

Positive

Another COX-2

Positive

NSAID avoidance

Avoid COX-1 inhibitors, oral challenge

with COX-2 inhibitors

Negative

Treatment

Positive

Avoidance NSAID

Desensitization

Algorithm for clinical managementAlgorithm for clinical managementof skin NSAID-induced reactionsof skin NSAID-induced reactions

Oral challenge with unrelated NSAID

Negative

Treatment

Positive

*

*

*

Position paperPosition paper

The indications for drug provocation testing can be The indications for drug provocation testing can be divided into 4 groups that are intertwined:divided into 4 groups that are intertwined:

1.1. To exclude hypersensitivityTo exclude hypersensitivity – – in history not suggestive of in history not suggestive of hypersensitivity to the drug and in patients with nonspecific hypersensitivity to the drug and in patients with nonspecific symptoms, such as vagal symptoms by local anesthesiasymptoms, such as vagal symptoms by local anesthesia

W. Aberer, A. Bircher, A. Romano, M. Blanca, P. Campi, J. Fernandez,K. Brockow, W. J. Pichler, P. Demoly

Allergy 2003: 58: 854–863


2.2. To provide safetyTo provide safety – – pharmacology and / or structural unrelated pharmacology and / or structural unrelated drugs as proven hypersensitivity to other antibiotics in drugs as proven hypersensitivity to other antibiotics in patients allergic to beta-lactams. This can also be helpful in patients allergic to beta-lactams. This can also be helpful in anxious people who could reject the drug recommended anxious people who could reject the drug recommended without tolerance testswithout tolerance tests


Allergy 2003: 58: 854–863


3.3. To exclude cross-reactivityTo exclude cross-reactivity of related drugs in proven of related drugs in proven hypersensitivity, such as a cephalosporin in a patient allergic hypersensitivity, such as a cephalosporin in a patient allergic to penicillin or an alternative to NSAIDs in asthmatic patients to penicillin or an alternative to NSAIDs in asthmatic patients sensitive to ASAsensitive to ASA


Allergy 2003: 58: 854–863


4.4. To establish a firm diagnosisTo establish a firm diagnosis in history suggestive of drug in history suggestive of drug hypersensitivity to allergic tests negative, inconclusive or hypersensitivity to allergic tests negative, inconclusive or unavailable, such as a maculopapular rash during treatment unavailable, such as a maculopapular rash during treatment with Aminopenicillin with negative allergy testswith Aminopenicillin with negative allergy tests


Allergy 2003: 58: 854–863

A drug provocation test is the controlled A drug provocation test is the controlled administration of a drug in order to administration of a drug in order to diagnose hypersensitivity reactionsdiagnose hypersensitivity reactions

The challenge test The challenge test should be doneshould be done under medical supervision under medical supervision for an alternative drug, structurally or pharmacologically for an alternative drug, structurally or pharmacologically

related to the suspect medicinerelated to the suspect medicine..


Allergy 2003: 58: 854–863

The provocation test drug is also known as challenge or The provocation test drug is also known as challenge or controlled re-challenge, drug challenge, incremental controlled re-challenge, drug challenge, incremental

challenge, re-challenge or test of tolerance.challenge, re-challenge or test of tolerance.

Regarding the limitations of drug provocation test, Regarding the limitations of drug provocation test, consider the consider the "gold standard“"gold standard“ to establish or refute to establish or refute the diagnosis of hypersensitivity to a substance. the diagnosis of hypersensitivity to a substance. Although allergic symptoms can be reproduced, so Although allergic symptoms can be reproduced, so can the adverse reaction by another mechanismcan the adverse reaction by another mechanism

W. Aberer, A. Bircher, A. Romano, W. Aberer, A. Bircher, A. Romano, M. Blanca, P. Campi, J. Fernandez,M. Blanca, P. Campi, J. Fernandez,K. Brockow, W. J. Pichler, K. Brockow, W. J. Pichler, P. DemolyP. Demoly

Allergy 2003: 58: 854–863Allergy 2003: 58: 854–863

After provocation test,After provocation test, it is desirable to keep the it is desirable to keep the patient under observation for 24 hours,patient under observation for 24 hours, but local but local restrictions may affect this idealrestrictions may affect this ideal


Allergy 2003: 58: 854–863

Protocol of nasal aspirin Protocol of nasal aspirin challengechallenge

Basal nasal symptoms, nasal inspiratory flows and volumes Basal nasal symptoms, nasal inspiratory flows and volumes are recorded during the first 30 minutes every 10 minutes. are recorded during the first 30 minutes every 10 minutes. Then for the evaluation ofThen for the evaluation of specific nasal hyperreactivityspecific nasal hyperreactivity,, are are challenged with 0.9% NaCl (80 ul) instilled into each nostril challenged with 0.9% NaCl (80 ul) instilled into each nostril with an Eppendorf pipette.with an Eppendorf pipette.

E. Nizankowska-Mogilnicka, G. Bochenek, L. Mastalerz, M. S´wierczynska, C. Picado, et al. Allergy 2007: 62: 1111–1118

Nasal symptoms, nasal inspiratory flow and volume are Nasal symptoms, nasal inspiratory flow and volume are measured within 30 minutes every 10 minutes. If there is a measured within 30 minutes every 10 minutes. If there is a change fromchange from 20% 20% in the values recorded upper airway is in the values recorded upper airway is hyperreactive and therefore the challenge can not be done. hyperreactive and therefore the challenge can not be done. Finally, 80 ul of L-ASA are instilled into each nostril (total Finally, 80 ul of L-ASA are instilled into each nostril (total aspirin dose: 16 mg)aspirin dose: 16 mg)

Protocol of nasal aspirin Protocol of nasal aspirin challengechallenge

E. Nizankowska-Mogilnicka, G. Bochenek, L. Mastalerz, M. S´wierczynska, C. Picado, et al. Allergy 2007: 62: 1111–1118

Nasal provocation tests may be the first Nasal provocation tests may be the first choice in the diagnosis of NSAID choice in the diagnosis of NSAID

intoleranceintolerance

MILEWSKI M, MASTALERZ L, NIZANKOWSKA E, SZCZEKLIK A. Nasalprovocation test with lysine-aspirin for diagnosis of aspirin-sensitive asthma.

J Allergy Clin Immunol 1998;101:581–586.CASADEVALL J, VENTURA PJ, MULLOL J, PICADO C. Intranasal challenge with

aspirin in the diagnosis of aspirin intolerance asthma: evaluation of nasalresponse by acoustic rhinometry. horax 2000;55:921–924.

Instillation: SyringeInstillation: Syringe

Control of peak nasal inspiratory flow is an Control of peak nasal inspiratory flow is an objective measure of response, which has objective measure of response, which has

high specificityhigh specificity

S. JIMENEZ-TIMON J., VIGARA Y.M., CIMARRA C., MARTINEZ CERA. Nasal challenge in patients allergic to Alternaria. Allergy 1997, 52. 37, 208–209.

HOLMSTROM M., SCADDING G.K., LUND V.J., DARBY Y.C., . Assessment of nasalobstruction. A comparison between rhinomanometry and nasal inspiratory

peak flow. Rhinology 1990;28:191–196.KRAYENBUHL M.C., HUDSPITH B.N. SCADDING G.K., BROSTOFF J. Nasal response to allergen and hyper-osmolar

challenge. Clin Allergy 1988;18:157–164.

Inspiratory flow meterInspiratory flow meter

In conclusion, a history of previous reaction after In conclusion, a history of previous reaction after ingestion of aspirin is not a reliable guide to the ingestion of aspirin is not a reliable guide to the diagnosis of aspirin hypersensitivity (AH). Since diagnosis of aspirin hypersensitivity (AH). Since

there is no other there is no other in vitro in vitro test of AH,test of AH, the challenge the challenge of aspirin is the only diagnostic tool availableof aspirin is the only diagnostic tool available

L. J. Cormican, S. Farooque, D. R. Altmannw and T. H. Lee

Clin Exp Allergy 2005; 35:717–722


Management of patients with Management of patients with Aspirin-Exacerbated Respiratory Aspirin-Exacerbated Respiratory

Disease (AERD)Disease (AERD)

M. Pilar Berges-Gimeno and Donald D. Stevenson

JOURNAL OF ASTHMA Vol. 41, No. 4, pp. 375–384, 2004

Desensitization is a Desensitization is a term used in a broad term used in a broad sense, refers to the sense, refers to the

elimination of reactions elimination of reactions to ASA byto ASA by repeated repeated

exposure exposure and and increasing doses of increasing doses of

medicationmedication

•During the During the desensitizationdesensitization with ASA, with ASA, there is a continuous there is a continuous inhibition of COX-1inhibition of COX-1 and and of phospholipase A2of phospholipase A2. This leads to a . This leads to a decrease in the synthesis of LTs and prostanoids. decrease in the synthesis of LTs and prostanoids.

TipsTips

Ferreri NR, Howland WC, Stevenson DD, Spiegelberg HL. Release of leukotrienes, prostaglandins, and histamine into nasal secretions of aspirin-sensitive asthmatics during reactions to aspirin. Am Rev Respir Dis 1988;137:847–854.

Juergens UR, Christiansen SC, Stevenson DD, Zuraw BL. Inhibition of monocyte leukotriene B4 production after aspirin desensitization. J Allergy Clin Immunol 1995;96:148–156.

•Recipients (patients) cysLT1 are "down regulated“, then there is Recipients (patients) cysLT1 are "down regulated“, then there is a "leveling" of the effects of the LTs. Studies have shown that a "leveling" of the effects of the LTs. Studies have shown that during acute desensitization during acute desensitization there is a slight decrease in TXB2 there is a slight decrease in TXB2 and LTB4. and LTB4.

•During chronic desensitization, During chronic desensitization, the synthesis of LTB4 the synthesis of LTB4 substantially decreasessubstantially decreases

General requirements for aspirin General requirements for aspirin desensitizationdesensitization

ASA desensitization should be performed inASA desensitization should be performed in a place capable of a place capable of providing advancedproviding advanced cardiac care, ventilator support and cardiac care, ventilator support and continuous monitoring by qualified personnel.continuous monitoring by qualified personnel.

Eric Macy, MD Jonathan A. Bernstein, MD; Mariana C. Castells, MD, Ph; Sandra M. Gawchik, DO; Tak H. Lee, MD, ScD, FRCPath, FRCP; Russell A. Settipane, MD¶; Ronald A. Simon, MD; Jeffrey Wald, MD; and Katharine M. Woessner, MD;

for the Aspirin Desensitization Joint Task ForceAnn Allergy Asthma Immunol. 2007;98:172–174.

TheThe supervising physician supervising physician must be available immediately to the must be available immediately to the bedside of the patient after the drug is first applied, and bedside of the patient after the drug is first applied, and recognize early warning signs. This is whenrecognize early warning signs. This is when the most severe and the most severe and unpredictable reactionsunpredictable reactions almost always occuralmost always occur

1. 1. AERD* patients who haveAERD* patients who have no no concomitant concomitant respiratory disease butrespiratory disease but who have moderate or severe who have moderate or severe asthma, nasal congestion intractableasthma, nasal congestion intractable or both on the or both on the basis of REIA. These patients should be considered for basis of REIA. These patients should be considered for aspirin desensitization after treatment failure with aspirin desensitization after treatment failure with topical corticosteroids, LTR1A, and 5-LO INH.topical corticosteroids, LTR1A, and 5-LO INH.

Donald D. Stevenson and Ronald A. Simon

J Allergy Clin Immunol 2006;118:801-4.

Candidates for ASA Candidates for ASA desensitizationdesensitization

* AERD: Aspirin-Exacerbated Respiratory Disease* AERD: Aspirin-Exacerbated Respiratory Disease

2.2. AERD patients with concomitant respiratory diseases AERD patients with concomitant respiratory diseases which are under aggressive therapywhich are under aggressive therapy but have not but have not responded to treatmentresponded to treatment,, including topical including topical corticosteroids, LTR1A and 5-LO INH.corticosteroids, LTR1A and 5-LO INH.




3.3. AERD patientsAERD patients with a history of multiple polypswith a history of multiple polyps..

4.4. Patients requiringPatients requiring systemic corticosteroidssystemic corticosteroids to to control AERD.control AERD.




5.5. AERD patients who require aspirinAERD patients who require aspirin for other for other diseases.diseases.


6.6. Others…...Others…...

In a long-term study ofIn a long-term study of 65 patients 65 patients with ASAwith ASA intolerance intolerance who underwent desensitization, there waswho underwent desensitization, there was a significant a significant

decrease in decrease in the number of infectious sinusitis and the use the number of infectious sinusitis and the use of prednisone with improvement in smell and symptoms of of prednisone with improvement in smell and symptoms of asthma and rhinitis. The need for sinus surgery decreased asthma and rhinitis. The need for sinus surgery decreased from one every 3 years to once every 9 years. This study from one every 3 years to once every 9 years. This study

demonstrated the beneficial effect of long-term demonstrated the beneficial effect of long-term desensitization to ASA over a period of 6 yearsdesensitization to ASA over a period of 6 years

Stevenson DD, Hankammer MA, Mathison DA. Aspirin desensitization treatment of aspirin sensitive patients with rhinosinusitis asthma: long term outcomes. J Allergy Clin Immunol. 1996;98:751-758.

AA subsequent study by Berges-Gimeno and colleagues withsubsequent study by Berges-Gimeno and colleagues with 172 patients 172 patients demonstrated a percentage improvement of demonstrated a percentage improvement of

67% patients at 6 months of treatment, which persisted for 67% patients at 6 months of treatment, which persisted for 1 to 5 years1 to 5 years with reduction in the occurrence with reduction in the occurrence of purulent of purulent

sinusitis about 5 episodes per year to less than halfsinusitis about 5 episodes per year to less than half

Berges-Gimeno, P, Simon RA, Stevenson DD. Long term treatment with aspirin desensitization in asthmatic patients with

aspirin exacerbated respiratory disease. J Allergy Clin Immunol 2003;111:180-186.

The traditional model of desensitization to ASA have been The traditional model of desensitization to ASA have been administered foradministered for 3 days3 days,, increasing doses of the drug until increasing doses of the drug until the patient tolerated 650 mg without adverse effects. The the patient tolerated 650 mg without adverse effects. The patient should continue receiving a daily dose of 650 mg patient should continue receiving a daily dose of 650 mg

every 12 hoursevery 12 hours

Oliver P. and Ludger K. Aspirin desensitization in aspirin intolerance: update on current standars and recent improvements. Current Opinion in Allergy and Clinical

immunology. 2006;6:161-166

Jennifer Altamura Namaz y and Ronald A. Simon

Ann Allergy Asthma Immunol 2002;89:542–550.

Scripps Clinic ASA Oral challenge Scripps Clinic ASA Oral challenge ProtocolProtocol

TIME DAY 1 DAY 2 DAY 3

8 AM Placebo 15-30 mg 150 mg

11 AM Placebo 45-60 mg 325 mg

2 PM Placebo 100 mg 650 mg

FEV1 every hour for 3 hours after each dose.Placebo day: FEV1 baseline or first AM value >70% predicted.

First, AM FEV1 value should be within ±5% from placebo.FEV1 values should not change (i.e. <15%) during 9-hour placebo

challenges.

FEV1 every hour for 3 hours after each dose.Placebo day: FEV1 baseline or first AM value >70% predicted.

First, AM FEV1 value should be within ±5% from placebo.FEV1 values should not change (i.e. <15%) during 9-hour placebo

challenges.



ProtocolOne to 7 days before challenge, determine airway stability.

1. FEV1 >60% of predicted value (>1.5 L absolute).2. FEV1 every hour x 3 hours – <10% variability.3. Start or continue montelukast, 10 mg every day.4. Start or continue ICSs/LABs.5. Start SCS burst for low FEV1 or any bronchial

instability.6. Discontinue antihistamines 48 hours before

challenge.

ProtocolOne to 7 days before challenge, determine airway stability.

1. FEV1 >60% of predicted value (>1.5 L absolute).2. FEV1 every hour x 3 hours – <10% variability.3. Start or continue montelukast, 10 mg every day.4. Start or continue ICSs/LABs.5. Start SCS burst for low FEV1 or any bronchial

instability.6. Discontinue antihistamines 48 hours before

challenge.

Rapid desensitizationRapid desensitization

There is a rapid desensitization protocol inThere is a rapid desensitization protocol in 7 hours 7 hours based on based on the controlled administration of increasing doses of ASA 90-the controlled administration of increasing doses of ASA 90-minute intervals until the patient can tolerate a dose of 650 minute intervals until the patient can tolerate a dose of 650 mg, measuring lung function using FEV1 and considering mg, measuring lung function using FEV1 and considering significant a decrease of over 20 % from the baseline.significant a decrease of over 20 % from the baseline.

Castells, M. Desensitization for drug allergy. Current Opinion in Allergy and Clinical Immunology.2006;6:476-481.

White AA, Stevenson DD, Simon RA. The blocking effect of essential controller medications during aspirin challenges in patients with aspirine xacerbated respiratory disease. Ann Allergy Asthma Immunol 2005; 95:330–335.

Mariana CastellsCurr Opin Allergy Clin Immunol 6:476–481. 2006

White AA, Stevenson DD, Simon RA. The blocking effect of essential controller medications during aspirin challenges in patients with aspirinexacerbated respiratory disease. Ann Allergy Asthma Immunol 2005; 95:330–335.

Desensitization to aspirin in a Desensitization to aspirin in a patient with asthma patient with asthma

TIME DOSE (mg)

0 4

90 40

180 81

240 162

330 325

420 650

Aspirin to be continued at 650 mg orally, twice a day. Aspirin to be continued at 650 mg orally, twice a day.

• 37 year old female patient37 year old female patient• Cronic sinusitis Cronic sinusitis • Serious AsthmaSerious Asthma• 5 nasal polyps operations5 nasal polyps operations• NSAIDs intolerance NSAIDs intolerance (Anaphilaxis by ASA)(Anaphilaxis by ASA)

A clinical caseA clinical case


• Stable condition Stable condition • FEV1 - 71%FEV1 - 71%• Progressive doses: up to 81 mgsProgressive doses: up to 81 mgs• Adverse symptoms occurAdverse symptoms occur• Systolic blood pressure fell by 20% Systolic blood pressure fell by 20% • FEV1 - 40% dropFEV1 - 40% drop• … …stopped and postponed!stopped and postponed!


• Next day…Next day…• FEV1 - 73%FEV1 - 73%• Beginning at 81 mg until 650 mg.Beginning at 81 mg until 650 mg.• Acumulated doses: 1343 mg Acumulated doses: 1343 mg • One year with a 650 mg doseOne year with a 650 mg dose every 12 hours of ASA.every 12 hours of ASA.• Today: patient discontinued treatment Today: patient discontinued treatment

due to severe stomach problems due to severe stomach problems

P Age G Diagnosis Cumulated Dose (mg)

Maintenance dose (mg) Outcome

1 46 F AERD 1343 650 bidGood tolerance, no polyps in the follow up

2* 51 F

- AERD-ASA induced angioedema- Anaphylaxis with ibuprofen and diclofenac

1262 650 bid Good tolerance

3* 37 F-AERD- Anaphylaxis with ASA 1343 650 bid Good tolerance

4 35 F AERD

Oral challenge (875 mg). Next day single dose

650 mg

650 bidSinus and nasal symptoms improvement

5* 63 FCardiologist prescription of ASA. Patient with history of ASA induced urticaria and angioedema

100 100 daily Good tolerance

6 35 M AERD 1343 650 bid Good tolerance

*Cardona R., Ramírez R.R., Reina Z., Escobar M.F., Morales E. Alergia e intolerancia a antiinflamatorios no esteroideos: desensibilización exitosa en tres casos y revisión de literatura. Biomédica. 2009. 29(2) 181-190

ASA desensitization can be considered asASA desensitization can be considered as a therapeutic a therapeutic alternativealternative with good clinical efficacy and very cost-effective with good clinical efficacy and very cost-effective in patients who: in patients who:

• Remain Remain intolerant of NSAIDs and chronic painintolerant of NSAIDs and chronic pain • Require ASA for Require ASA for prophylaxis cardiovascular and prophylaxis cardiovascular and

thromboembolic diseasethromboembolic disease• In patients with In patients with asthma and recurrent polyposis which asthma and recurrent polyposis which

can not be controlled with polypectomies or sinus can not be controlled with polypectomies or sinus surgery surgery

• In women withIn women with antiphospholipid syndrome during antiphospholipid syndrome during pregnancypregnancy

Gollapudi RR, Teirstein PS, Stevenson DD, Simon RA. Aspirin sensitivity: implications for patients with coronary artery disease. JAMA.2004;292:3017-3023.

Castells, M. Desensitization for drug allergy. Current Opinion in Allergy and Clinical Immunology.2006;6:476-481.

Others…...Others…...

Thanks !!Thanks !!

Ricardo Cardona Villa, M.D. MSc in Immunology - Allergist Chief of Clinical Allergology Service IPS...

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