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Desensitization in non-steroidal anti-inflammatory drugs (NSAID) hypersensitivity Ricardo Cardona Villa, M.D. MSc in Immunology - Allergist Chief of Clinical Allergology Service IPS Universitaria - Clínica León XIII Medical School Universidad de Antioquia Acetylsalycilic acid (ASA) A model of NSAID The End of Suffering http://goyotovar.lasideas.es/wp-content/imagenes/aspirina.jpg Acetylsalycilic acid is extracted from the tree "Salix alba", called salicin, discovered in 1827 History 1899 The product was registered as Aspirin by Felix Hoffman 1980 Stevenson et al described two patients with previous ASA induced asthmatic reactions The creator of Aspirin, Felix Hoffmann and a package circa 1900. Chemical classification of NSAIDs Chemical group Drugs Alkanones Nabumetone Anthranilic acids (fenamates) Meclofenamic acid, mefenamic acid Arylpropionic acids Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Oxaprozín Enolic acids Oxicams (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 derivatives Aspirin, choline magnesium trisalicylate, diflunisal, Olsalazine, Salicylsalicylic, Salsalate, Salicylate, Sulfasalazine Mario Sánchez-Borges. WAO Journal 2008; 1: 29-33 Terminology Selectivity: agents that inhibit more one enzyme than the other, but can inhibit both of them (Meloxicam, Nimesulide) Specificity: agents that inhibit only one enzyme at doses that produce maximum clinical efficacy (Celecoxib - Etoricoxib - Lumiracoxib) Classification of some NSAIDs Selectivity Weak COX inhibitors Drugs 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 Concept COX Membrane phospholipids (–) glucocorticoids (–) arachidonic acid COX-1 Endotoxins cytokines mitogens (+) (–) (–) Stomach: PGE2/PGI2 Kidney: PGE2/PGI2 Platelets: TxA2 Endothelium: PGI2 Physiological effects (–) COX-2 "Classic NSAIDs" Inflammation: macrophages synoviocytes Inflammatory mediators Selective inhibitors of COX-2 Meloxicam Celecoxib Rofecoxib COX-1 / COX-2 comparison PARAMETER COX-1 COX-2 HOMOLOGY Similar to COX-2 ( 60%*- 75%) Similar to COX-1 ( 60%*- 75%) REGULATION Constitutive Inducible TISSUE EXPRESSION Most tissues, but particularly platelets, stomach and kidney Inflammatory stimuli and mitogens in macrophages/monocytes, synoviocytes, chondrocytes, fibroblasts, endothelial cells. Constitutive in CNS and kidney COX-1 and COX-2 structure COX-1 COX-2 C-terminal active site C-terminal active site Hydrophobic Channel Hydrophobic Channel Isoleucine at 523, closes the hydrophilic pocket N-terminal Valin at 523 allows the access to the hydrophilic pocket Hydrophilic pocket N-terminal Arginin At 120 Kurumbail R G, Stevens A M, Gierse J K, McDonald J J, et al. Nature. 1996;384:644–648 Arginin at 120 Membrane phospholipids Arachidonic acid Lipoxygenase pathway Cyclooxygenase pathway 5-Lipoxygenase (5-LO) Cyclooxygenase Shunt from COX – towards the LO-pathway LT-A4 LTA4 hydrolase LT-B4 COX-1 ASA/ NSAID LTC4 synthase Cys-leucotriene LTC4, LTD4, LTE4 PG-E2 Reduced inhibition COX-2 Change of the COX-2 structure Generation of products of the LO-pathway Claudia Jenneck, Uwe Juergens, Markus Buecheler, and Natalija Novak Ann Allergy Asthma Immunol. 2007;99:13–21. Using the classification proposed by the Committee of the World Allergy Organization, the following types of hypersensitivity reactions should be considered: Allergic hypersensitivity Non-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 Manifestations 1. Allergic hypersensitivity 1.1 Immediate reactions 1.1.1 Urticaria and Angioedema 1.1.2 Allergic Anaphylaxis Sànchez Borges, M. Clinical management of non steroidal antiinflammatory drug hypersensitivity. 2008;1:29-33. WAO Journal. Clinical Manifestations 1. Allergic hypersensitivity 1.1 Immediate reactions 1.1.1 Urticaria and Angioedema 1.1.2 Allergic Anaphylaxis 1.2 Late reactions 1.2.1 Skin diseases 1.2.2 Pneumonitis 1.2.3 Aseptic meningitis 1.2.4 Nephritis 1.2.5 Hepatitis Sànchez Borges, M. Clinical management of non steroidal antiinflammatory drug hypersensitivity. 2008;1:29-33. WAO Journal. Clinical Manifestations 1. Allergic hypersensitivity 1.1 Immediate reactions 1.1.1 Urticaria and Angioedema 1.1.2 Allergic Anaphylaxis 1.2 Late reactions 1.2.1 Skin diseases 1.2.2 Pneumonitis 1.2.3 Aseptic meningitis 1.2.4 Nephritis 1.2.5 Hepatitis 2. Nonallergic hypersensitivity 2.1 Respiratory Hypersensitivity 2.2 Skin Hypersensitivity 2.3 Non-allergic anaphylaxis Sànchez Borges, M. Clinical management of non steroidal antiinflammatory drug hypersensitivity. 2008;1:29-33. WAO Journal. Classification: Respiratory pattern Includes respiratory disease exacerbated by ASA, the Tetrad of Samter (nasal polyposis, rhinosinusitis, asthma and intolerance to ASA) and ASA-induced asthma. Andrzej Szczeklik and Marek Sanak European Journal of Pharmacology 533 (2006) 145–155 M. Sánchez-Borges, A. Capriles-Hulett, F. Caballero-Fonseca J Invest Allergol Clin Immunol 2004; Vol. 14(4): 329-334 Skin Pattern Including urticaria and angioedema induced by NSAIDs urticaria and angioedema induced by multiple drugs and urticaria and angioedema induced by a single drug. Mario Sánchez-Borges WAO Journal 2008;1:29Y33 M. Sánchez-Borges, A. Capriles-Hulett, F. Caballero-Fonseca J Invest Allergol Clin Immunol 2004; Vol. 14(4): 329-334 Mixed Pattern It presents with skin and respiratory symptoms including urticaria and angioedema associated with cough, breathlessness, runny nose, wheezing, tearing 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 Systemic Pattern Anaphylactic reactions are type I hypersensitivity, usually observed in simple reactors who tolerate other chemically unrelated NSAIDs IgE antibodies specific for the allergen. 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 Management The management of patients with intolerance to NSAIDs depends on their medical history. The patient should be classified as simple reactor or cross reactor and according to the type of reaction either cutaneous or systemic. 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 When the patient is a simple reactor, oral provocation testing with an NSAID of a different chemical group involved is recommended. If the test is negative, the patient may receive treatment with NSAIDs testing and avoid the suspected medication. If the test is positive, the patient should be handled as a cross reactor. 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 When the patient is classified as a cross reactor, an oral challenge test can be performed with a weak COX-1 inhibitor or preferential COX-2, or with a specific COX-2 inhibitor. If the test is negative, it can be administered to the patient and if positive try oral challenge with another COX-2 specific inhibitor. If the latter (previous) test is positive, avoid all NSAIDs 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 Algorithm for clinical management of skin NSAID-induced reactions Weak COX-1 Inhibitors Acethaminofen Salsalate Another COX-2 Desensitization 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 Oral challenge with unrelated NSAID Alternative medication Negative Avoid COX-1 inhibitors, oral challenge with COX-2 inhibitors Oral challenge With COX-2 inhibitor Weak COX-1 Inhibitors Acethaminofen Salsalate Treatment Single drug anaphylaxis Negative * Positive Negative Treatment Positive Positive Another COX-2 Algorithm for clinical management of skin NSAID-induced reactions Modificated of Mario Sánchez-Borges, Arnaldo Capriles-Hulett and Fernan Caballero-Fonseca Am J Clin Dermatol 2002; 3 (9): 599-607 Treatment * Positive Avoidance NSAID Desensitization NSAID avoidance * Position paper The indications for drug provocation testing can be divided into 4 groups that are intertwined: 1. To exclude hypersensitivity – in history not suggestive of hypersensitivity to the drug and in patients with nonspecific symptoms, 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 Position paper 2. To provide safety – pharmacology and / or structural unrelated drugs as proven hypersensitivity to other antibiotics in patients allergic to beta-lactams. This can also be helpful in anxious people who could reject the drug recommended without tolerance tests W. Aberer, A. Bircher, A. Romano, M. Blanca, P. Campi, J. Fernandez, K. Brockow, W. J. Pichler, P. Demoly Allergy 2003: 58: 854–863 Position paper 3. To exclude cross-reactivity of related drugs in proven hypersensitivity, such as a cephalosporin in a patient allergic to penicillin or an alternative to NSAIDs in asthmatic patients sensitive to ASA W. Aberer, A. Bircher, A. Romano, M. Blanca, P. Campi, J. Fernandez, K. Brockow, W. J. Pichler, P. Demoly Allergy 2003: 58: 854–863 Position paper 4. To establish a firm diagnosis in history suggestive of drug hypersensitivity to allergic tests negative, inconclusive or unavailable, such as a maculopapular rash during treatment with Aminopenicillin with negative allergy tests W. Aberer, A. Bircher, A. Romano, M. Blanca, P. Campi, J. Fernandez, K. Brockow, W. J. Pichler, P. Demoly Allergy 2003: 58: 854–863 A drug provocation test is the controlled administration of a drug in order to diagnose hypersensitivity reactions The challenge test should be done under medical supervision for an alternative drug, structurally or pharmacologically related to the suspect medicine. The provocation test drug is also known as challenge or controlled re-challenge, drug challenge, incremental challenge, re-challenge or test of tolerance. W. Aberer, A. Bircher, A. Romano, M. Blanca, P. Campi, J. Fernandez, K. Brockow, W. J. Pichler, P. Demoly Allergy 2003: 58: 854–863 Regarding the limitations of drug provocation test, consider the "gold standard“ to establish or refute the diagnosis of hypersensitivity to a substance. Although allergic symptoms can be reproduced, so can the adverse reaction by another mechanism W. Aberer, A. Bircher, A. Romano, M. Blanca, P. Campi, J. Fernandez, K. Brockow, W. J. Pichler, P. Demoly Allergy 2003: 58: 854–863 After provocation test, it is desirable to keep the patient under observation for 24 hours, but local restrictions may affect this ideal W. Aberer, A. Bircher, A. Romano, M. Blanca, P. Campi, J. Fernandez, K. Brockow, W. J. Pichler, P. Demoly Allergy 2003: 58: 854–863 Protocol of nasal aspirin challenge Basal nasal symptoms, nasal inspiratory flows and volumes are recorded during the first 30 minutes every 10 minutes. Then for the evaluation of specific nasal hyperreactivity, are challenged with 0.9% NaCl (80 ul) instilled into each nostril with an Eppendorf pipette. E. Nizankowska-Mogilnicka, G. Bochenek, L. Mastalerz, M. S´wierczynska, C. Picado, et al. Allergy 2007: 62: 1111–1118 Protocol of nasal aspirin challenge Nasal symptoms, nasal inspiratory flow and volume are measured within 30 minutes every 10 minutes. If there is a change from 20% in the values recorded upper airway is hyperreactive and therefore the challenge can not be done. Finally, 80 ul of L-ASA are instilled into each nostril (total aspirin dose: 16 mg) 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 choice in the diagnosis of NSAID intolerance Instillation: Syringe MILEWSKI M, MASTALERZ L, NIZANKOWSKA E, SZCZEKLIK A. Nasal provocation 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 nasal response by acoustic rhinometry. horax 2000;55:921–924. Control of peak nasal inspiratory flow is an objective measure of response, which has high specificity Inspiratory flow meter 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 nasal obstruction. 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. In conclusion, a history of previous reaction after ingestion of aspirin is not a reliable guide to the diagnosis of aspirin hypersensitivity (AH). Since there is no other in vitro test of AH, the challenge of 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 Aspirin-Exacerbated Respiratory Disease (AERD) M. Sánchez-Borges, A. Capriles-Hulett, F. Caballero-Fonseca J Invest Allergol Clin Immunol 2004; Vol. 14(4): 329-334 Desensitization is a term used in a broad sense, refers to the elimination of reactions to ASA by repeated exposure and increasing doses of medication M. Pilar Berges-Gimeno and Donald D. Stevenson JOURNAL OF ASTHMA Vol. 41, No. 4, pp. 375–384, 2004 Tips •During the desensitization with ASA, there is a continuous inhibition of COX-1 and of phospholipase A2. This leads to a decrease in the synthesis of LTs and prostanoids. •Recipients (patients) cysLT1 are "down regulated“, then there is a "leveling" of the effects of the LTs. Studies have shown that during acute desensitization there is a slight decrease in TXB2 and LTB4. •During chronic desensitization, the synthesis of LTB4 substantially decreases 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. General requirements for aspirin desensitization ASA desensitization should be performed in a place capable of providing advanced cardiac care, ventilator support and continuous monitoring by qualified personnel. The supervising physician must be available immediately to the bedside of the patient after the drug is first applied, and recognize early warning signs. This is when the most severe and unpredictable reactions almost always occur 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 Force Ann Allergy Asthma Immunol. 2007;98:172–174. Candidates for ASA desensitization 1. AERD* patients who have no concomitant respiratory disease but who have moderate or severe asthma, nasal congestion intractable or both on the basis of REIA. These patients should be considered for aspirin desensitization after treatment failure with topical corticosteroids, LTR1A, and 5-LO INH. * AERD: Aspirin-Exacerbated Respiratory Disease Donald D. Stevenson and Ronald A. Simon J Allergy Clin Immunol 2006;118:801-4. Candidates for ASA desensitization 2. AERD patients with concomitant respiratory diseases which are under aggressive therapy but have not responded to treatment, including topical corticosteroids, LTR1A and 5-LO INH. 3. AERD patients with a history of multiple polyps. Donald D. Stevenson and Ronald A. Simon J Allergy Clin Immunol 2006;118:801-4. Candidates for ASA desensitization 4. Patients requiring systemic corticosteroids to control AERD. 5. AERD patients who require aspirin for other diseases. Donald D. Stevenson and Ronald A. Simon J Allergy Clin Immunol 2006;118:801-4. Candidates for ASA desensitization 6. Others…... In a long-term study of 65 patients with ASA intolerance who underwent desensitization, there was a significant decrease in the number of infectious sinusitis and the use of prednisone with improvement in smell and symptoms of asthma and rhinitis. The need for sinus surgery decreased from one every 3 years to once every 9 years. This study demonstrated the beneficial effect of long-term desensitization 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. A subsequent study by Berges-Gimeno and colleagues with 172 patients demonstrated a percentage improvement of 67% patients at 6 months of treatment, which persisted for 1 to 5 years with reduction in the occurrence of purulent sinusitis 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 administered for 3 days, increasing doses of the drug until the patient tolerated 650 mg without adverse effects. The patient should continue receiving a daily dose of 650 mg every 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 Scripps Clinic ASA Oral challenge Protocol 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. Jennifer Altamura Namaz y and Ronald A. Simon Ann Allergy Asthma Immunol 2002;89:542–550. Protocol One to 7 days before challenge, determine airway stability. 1. 2. 3. 4. 5. FEV1 >60% of predicted value (>1.5 L absolute). FEV1 every hour x 3 hours – <10% variability. Start or continue montelukast, 10 mg every day. Start or continue ICSs/LABs. Start SCS burst for low FEV1 or any bronchial instability. 6. Discontinue antihistamines 48 hours before challenge. Donald D. Stevenson and Ronald A. Simon J Allergy Clin Immunol 2006;118:801-4. Rapid desensitization There is a rapid desensitization protocol in 7 hours based on the controlled administration of increasing doses of ASA 90minute intervals until the patient can tolerate a dose of 650 mg, measuring lung function using FEV1 and considering 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. Desensitization to aspirin in a 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. Mariana Castells Curr 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. A clinical case • 37 year old female patient • Cronic sinusitis • Serious Asthma • 5 nasal polyps operations • NSAIDs intolerance (Anaphilaxis by ASA) A clinical case • Stable condition • FEV1 - 71% • Progressive doses: up to 81 mgs • Adverse symptoms occur • Systolic blood pressure fell by 20% • FEV1 - 40% drop • …stopped and postponed! A clinical case • Next day… • FEV1 - 73% • Beginning at 81 mg until 650 mg. • Acumulated doses: 1343 mg • One year with a 650 mg dose every 12 hours of ASA. • Today: patient discontinued treatment due to severe stomach problems P 1 Age 46 G Diagnosis Outcome F AERD 1343 650 bid 1262 650 bid Good tolerance 1343 650 bid Good tolerance Oral challenge (875 mg). Next day single dose 650 mg 650 bid Sinus and nasal symptoms improvement 100 100 daily Good tolerance 1343 650 bid Good tolerance 2* 51 F 3* 37 F -AERD - Anaphylaxis with ASA 35 Maintenance dose (mg) Good tolerance, no polyps in the follow up - AERD -ASA induced angioedema - Anaphylaxis with ibuprofen and diclofenac 4 Cumulated Dose (mg) F AERD Cardiologist prescription of ASA. Patient with history of ASA induced urticaria and angioedema 5* 63 F 6 35 M AERD *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 Others…... ASA desensitization can be considered as a therapeutic alternative with good clinical efficacy and very cost-effective in patients who: • Remain intolerant of NSAIDs and chronic pain • Require ASA for prophylaxis cardiovascular and thromboembolic disease • In patients with asthma and recurrent polyposis which can not be controlled with polypectomies or sinus surgery • In women with antiphospholipid syndrome during pregnancy 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. Thanks !!