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- Aspirin -
11/21/05 re: Allergies to corticosteroids; aspirin-induced urticaria I have seen a pt today that needs an intra articular steroid injection and she is also on a beta blocker. In Jan 1993 she received an injection into a muscle with DepoMedral and Marcaine and 10 hrs later had a rash which she said only effected her various joints and she doesn't think the rash was hive like. It took over a week for that rash to resolve. Also no other meds were introduced at that episode.
My sense was that it was the local anesthetic, but I would appreciate your advise in how to approach this case i.e. skin testing to the steroid and is that really accurate and what dosing would I do for the steroid and if negative is a challenge appropriate esp. if she is on a beta blocker???
If I may ask a second case which I just saw, A female who needs to go on ASA 81 mg daily and about 7 yrs ago had hives twice with cataflam (Voltaren) and no NSAIDs since then. If I challenge her or desensitize her could you suggest a protocol. My understanding is that ASA urticaria occurs at about 150- 325 mg, but I would not feel comfortable to tell this pt to just go ahead and use ASA 81 mg. She has not asthma.
It is possible, though very unusual, to see a delayed reaction to a ‘caine-type local anesthetic (LA), assuming no reaction to a preservative or other added agent in the particular LA preparation. To investigate this unusual possibility our group has long used the approach described by Drs Rick DeShazo and Hal Nelson in 1979 (see reference enclosed below). We rarely see any documented allergic reactions to amide LA.
Allergic reactions to systemic corticosteroids are also rare. However, there have been several reports of reactions apparently due to particular corticosteroids while certain other corticosteroid agents are tolerated (see enclosed abstracts). In the case you described one might test with methyl prednisolone solution but Depo-Medrol would not be suitable for testing. It would appear that if this patient truly had a reaction induced by methylprednisolone then betamethasone might be a choice with a reasonable chance of eliciting a negative reaction in testing and would later be tolerated if challenged with increasing doses.
In their extensive experience, Stevenson et al of the Scripps Clinic usually start their aspirin challenges with a 30 mg dose whether the previous aspirin-induced manifestations were respiratory or urticaria. They generally give doubling increasing doses if the lower dose was tolerated. You may need assistance from your hospital pharmacist to prepare these doses. Comments from Dr. Stevenson are enclosed in my response to a recent Ask the Expert question dealing with aspirin sensitivity.
deShazo RD, Nelson HS.
An approach to the patient with a history of local anesthetic hypersensitivity: experience with 90 patients.
J Allergy Clin Immunol. 1979 Jun;63(6):387-94.
Br J Dermatol. 2003 Jan;148(1):139-41. Related Articles, Links
Alternative glucocorticoids for use in cases of adverse reaction to systemic glucocorticoids: a study on 10 patients.
Ventura MT, Calogiuri GF, Matino MG, Dagnello M, Buquicchio R, Foti C, Di Corato R.
Department of Internal Medicine, Immunology and Infectious Diseases, University of Bari, Policlinico, Piazza G. Cesare 11, Italy.BACKGROUND: Reactions to systemically administered corticosteroids are rare, despite their widespread use. OBJECTIVES: To identify alternative glucocorticoids for emergency use in patients with adverse reactions to systemic glucocorticoids. METHODS: Ten patients were identified as having adverse reactions after the use of systemic corticosteroids. Skin prick tests and intradermal tests to hydrocortisone (HC) and methylprednisolone (MP), and intradermal tests to betamethasone and dexamethasone, were performed in all patients, and oral challenge tests to betamethasone (n=10) and deflazacort (n=6). RESULTS: Skin prick tests were negative in all patients, whereas intradermal tests to HC and MP were positive in eight; two patients showed only an isolated cutaneous sensitivity to MP. Intradermal tests to betamethasone and dexamethasone were negative, and oral challenge tests were negative in all patients. CONCLUSIONS: Our results suggest the possibility of an IgE-mediated mechanism for allergic reactions to HC and MP, probably due, at least in part, to a steroid-glyoxal. We suggest that betamethasone and deflazacort could be reserved for emergency use in patients with adverse reactions to other corticosteroids
Dermatology. 2002;204(3):248-50.
A case of cutaneous delayed-type allergy to oral dexamethasone and to betamethasone.
Nucera E, Buonomo A, Pollastrini E, De Pasquale T, Del Ninno M, Roncallo C, Schiavino D, Patriarca G.
Department of Allergology, Policlinico 'A. Gemelli', Universita Cattolica del Sacro Cuore, Roma, Italia.Corticosteroids are drugs that may cause allergic contact dermatitis, but systemic allergic reactions to these drugs are rare. A 29-year-old man developed a maculopapular rash during an oral therapy with betamethasone. Patch tests demonstrated a delayed-type allergy to dexamethasone, betamethasone and fluocortolone. Oral, intramuscular or topical provocation tests with other corticosteroids - deflazacort, hydrocortisone, methylprednisolone, fluticasone dipropionate, triamcinolone and prednisone - were all negative. This demonstrates that a patient with a systemic allergy to a group of corticosteroids can tolerate those of other groups.
11/7/05 re: Doclofenac challenge I have a 54 year old who, within 15 minutes of taking Micardis/HCT and diclofenac, had anaphylaxis - sudden onset of itching of hands and feet, warmth and tingling in extremities, hypotension, syncope, and erythema over her back and abdomen. She has never had such and episode. She had been using Aleve up to three times each week. She has also tolerated Mobic and aspirin. She last used diclofenac 2 - 3 months ago. Her episode was not associated with food ingestion or exercise. I suspect that diclofenac caused her episode. I have told her to avoid all NSAIDs for now. She may use acetaminophen up to 650 mg for pain. I have heard at a recent board review that it is possible to have anaphylaxis to one particular NSAID while tolerating other NSAIDs. Should I arrange for a graded challenge to other NSAIDs in my office? If so, what doses should I start with (e.g. 1 mg, 30 mg, 100 mg, etc.)?
The Scripps Clinic group in La Jolla, CA (leading investigators in this field) has described situations in which a patient has apparently been sensitive to only one particular NSAID and not other NSAID or aspirin (ASA). There have been occasional reports or adverse reactions limited to diclofenac (see enclosed title of such a report). As pointed out by the Scripps group, certain precautions are suggested in carrying out a challenge with the suspected NSAID or ASA: 1) Obtain written informed consent in advance; 2) challenge carried out in a facility suitably equipped for emergency treatment. The Scripps group carries out their challenges in the Clinical Research Center of their hospital. They also mention Intensive Care Units as a suitable site. This is particularly important if the previous reaction was anaphylactoid; 3) the challenge should be a least single-blind, including a placebo challenge. Many patients may be anxious with "anticipatory symptoms"; 4) If a positive reaction occurs to the challenge, it may be advisable to repeat the challenge at the inciting dose 1 week later (see Stevenson's editorial- Ann Allergy, Asthma. Immunol 1993;71:417-18); 5) If the patient reported respiratory symptoms during the previous episode, get pre-challenge and post-challenge spirometry with flow volume loops.
In their description of aspirin/NDAID sensitivity in the most recent edition of the Middleton Allergy textbook, Stevenson et al comment that only ASA (and not NSAID) is available in the doses appropriate for oral challenge. Therefore, you will likely need help from your pharmacist in preparing the needed doses. The Scripps group generally starts their challenges with 30 mg of ASA. They used a similar starting dose of a COX-2 inhibitor in a recent report (Ann Allergy 2004;93:339-44). Their dosage protocol is shown on pg 1698 of the Middleton text referred to above. However, if your patient truly had an anaphylactoid reaction to diclofenac, it may be prudent to start with a much smaller dose such as 1 mg. The question could be raised whether the information obtained from such challenges is worth the effort and possible risk. If the patient truly tolerated naproxen (Aleve), why not challenge her with that agent? Most patients will get some degree of symptomatic relief from other NSAID if they are benefited by one particular NSAID.
del Pozo MD, Lobera T, Blasco A.
Selective hypersensitivity to diclofenac.
Allergy. 2000 Apr;55(4):412-3.Stevenson DD.
Challenge procedures in detection of reactions to aspirin and nonsteroidal anti-inflammatory drugs.
Ann Allergy. 1993 Nov;71(5):417-8del Pozo MD, Lobera T, Blasco A.
Selective hypersensitivity to diclofenac.
Allergy. 2000 Apr;55(4):412-3.Stevenson DD.
Challenge procedures in detection of reactions to aspirin and nonsteroidal anti-inflammatory drugs.
Ann Allergy. 1993 Nov;71(5):417-87/18/05 re: Aspirin desensitization for nasal polyps I'm an allergist practicing in Toronto, Canada. I wonder if you can tell me, and if possible give me references, as to the utility of ASA desensitization in a patient with severe chronic polypoid rhinosinusitis but no ASA sensitivity (ASA challenge negative), who is refractory to all usual treatments-only transient improvement with IM corticosteroid (80mg DepoMedrol)+Intranasal corticosteroid spray BID+leukotriene inhibitor (Singulair) taken regularly.
Any merit in regular ASA (650mg QID)? How long would you give it before judging efficacy? Would you give it indefinitely? Would you use a proton pump inhibitor for gastric protection at the same time?
I am not aware of any published report about the use of aspirin (ASA) desensitization approaches in those with nasal polyps but no evidence of ASA intolerance. Therefore, I obtained input from Dr. Donald Stevenson of the Scripps Clinic. As you likely know, Dr. Stevenson and colleagues are leading investigators of ASA/NSAID intolerance and nasal polyps. His response is enclosed below
Dr. Stevenson's comments:
I am unaware of a published paper on this subject. Three years ago, an abstract from our group at Scripps (Farenholtz Allergy Fellow first author) on 35 patients with neg ASA challenges but rhino sinusitis, nasal polyps and asthma was presented at the AAAAI meeting. Sequential evaluations before and after ASA treatment showed improved symptom scores and decreased steroid use. I have a number of such patients in my clinical practice that are treated with ASA. It takes about a month before improvement occurs and does not work on everyone (particularly those with a co-morbid condition such as GERD or allergic respiratory disease). In our hands, the starting dose of ASA in such approaches is 650 mg BID x first month. If improved drop the dose to 325 mg BID, and then go to once daily if you can.
We do not start a PPI or ranitidine during ASA desensitization until patients have epigastric pain (about 10%), because the expense would be prohibitive if all took PPIs.
9/10/04 re: Aspirin desensitization in patient on beta-blocker Patient is a 52 year old man on toprol and his P.C.P. wants him on daily Aspirin. But several yrs ago, he had throat swelling with alka-seltzer and was advised to avoid NSAIDS, ASA. Can he be desensitized with Aspirin and also can it be done, him being on beta-blocker? I appreciate your response.
You have described a difficult clinical situation. To respond to your questions, I obtained input from Dr. Donald Stevenson of the Scripps Clinic in La Jolla CA. As you likely know, Dr. Stevenson is one of the leading investigators of “aspirin sensitivity” and related syndromes in the world. His prompt response is enclosed below. If the adverse reaction in your patient was due to an IgE reaction specifically against ASA, perhaps a trial of a chemically unrelated anti-platelet drug such as clopidogrel would be worthwhile (see enclosed abstract).
Dr. Stevenson's comments:
A 52 year old male without nasal polyps and asthma or chronic idiopathic urtciara has a low probability of having cross-reacting NSAID- induced angioedema via the COX-1 inhibition pathway. However, your questioner wants him on aspirin, which is the drug often most likely responsible for the probable IgE mediated laryngeal edema in this case. I don't do any drug desensitizations in patients taking beta blockers even if the historical reaction to ASA was just urticaria. I have also not attempted ASA rapid desensitization for aspirin in patients with IgE type sensitivity and a history of anaphylactic shock or laryngeal edema. I have done it in patients with prior history of just an urticarial reaction to aspirin. In this patient, it would seem to be an inordinate risk to attempt desensitization to aspirin.
Ann Pharmacother. 2001 May;35(5):589-617.
New recommendations from the 1999 American College of Cardiology/American Heart Association acute myocardial infarction guidelines.
Spinler SA, Hilleman DE, Cheng JW, Howard PA, Mauro VF, Lopez LM, Munger MA, Gardner SF, Nappi JM.
Department of Pharmacy Practice and Pharmacy Administration, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, PA, USA.Objective: To review literature relating to significant changes in drug therapy recommendations in the 1999 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for treating patients with acute myocardial infarction (AMI). DATA SOURCES: 1999 ACC/AHA AMI guidelines, English-language clinical trials, reviews, and editorials researching the role of drug therapy and primary angioplasty for AMI that were referenced in the guidelines were included. Additional data published in 2000 or unpublished were also included if relevant to interpretation of the guidelines.
Study Selection: The articles selected influence AMI treatment recommendations.
Data Synthesis: Many clinicians and health systems use the ACC/AHA AMI guidelines to develop treatment plans for AMI patients. This review highlights important changes in AMI drug therapy recommendations by reviewing the results of recent clinical trials. Insights into evolving drug therapy strategies that may impact future guideline development are also described.
Conclusions: Several changes in drug therapy recommendations were included in the 1999 AMI ACC/AHA guidelines. There is emphasis on administering fibrin-specific thrombolytics secondary to enhanced efficacy. Selection between fibrin-specific agents is unclear at this time. Low response rates to thrombolytics have been noted in the elderly, women, patients with heart failure, and those showing left bundle-branch block on the electrocardiogram. These patient groups should be targeted for improved utilization programs. The use of glycoprotein (GP) IIb/IIIa receptor inhibitors in non-ST-segment elevation MI was emphasized. Small trials combining reduced doses of thrombolytics with GP IIb/IIIa receptor inhibitors have shown promise by increasing reperfusion rates without increasing bleeding risk, but firm conclusions cannot be made until the results of larger trials are known. Primary percutaneous coronary intervention (PCI) trials suggest lower mortality rates for primary PCI when compared with thrombolysis alone. However, primary PCI, including coronary angioplasty, is only available at approximately 13% of US hospitals, making thrombolysis the preferred strategy for most patients. Clopidogrel has supplanted ticlopidine as the recommended antiplatelet agent for patients with aspirin allergy or intolerance following reports of a better safety profile. The recommended dose of unfractionated heparin is lower than previously recommended, necessitating a separate nomogram for patients with acute coronary syndromes. Routine use of warfarin, either alone or in combination with aspirin, is not supported by clinical trials; however, warfarin remains a choice for antithrombotic therapy in patients intolerant to aspirin. Beta-adrenergic receptor blockers continue to be recommended, and emphasis is placed on improving rates of early administration (during hospitalization), even in patients with moderate left ventricular dysfunction. New recommendations for drug treatment of post-AMI patients with low high-density lipoprotein cholesterol and/or elevated triglycerides are included, with either niacin or gemfibrozil recommended as an option. Supplementary antioxidants are not recommended for either primary or secondary prevention of AMI, with new data demonstrating lack of efficacy vitamin E in primary prevention. Estrogen replacement therapy or hormonal replacement therapy should not be initiated solely for prevention of cardiovascular disease, but can be continued in cardiovascular patients already taking long-term therapy for other reasons. Bupropion has been added as a new treatment option for smoking cessation. As drug therapy continues to evolve in treating AMI, more frequent updates of therapy guidelines will be necessary.
5/12/04 re: Physicians carrying out aspirin desensitization on East Coast (Other than the Scripps/La Jolla group), are there any tertiary care/university hospital sites on the East coast that are willing to perform aspirin desensitization on ASA/NSAID triad patients with severe asthma /nasal polyposis?
To respond to your question, I consulted Dr. Donald Stevenson of the Scripps Clinic group. His response was:
The following are doing ASA desensitization on a fee for service basis:
Johns Hopkins: Bruce Bochner
Univ Virginia, Chaarlottesville-Larry Borish
Cleveland Clinic-David Lang
Univ Rhode Island-Russ Settipane
Univ of S.Florida at Tampa-Dick Lockey
3/15/02 re: Cross-reactivity between ASA and NSAID NOT speaking of aspirin associated wheezing/asthma, is it safe for an "aspirin allergic" individual (who perhaps had hives or some other non-wheezy anaphylactoid symptoms) to take ibuprofen? Your previous questions all dealt with the cross sensitivity of NSAIDs and ASA in asthmatics or wheezers. To answer your question, I consulted Dr. Donald Stevenson of the Scripps Clinic, one of the leading investigators of aspirin-induced "sensitivity" reactions in the world. His response is enclosed below. "With respect to ASA-induced urticaria, there are three syndromes:
(1) ASA - IgE mediated reactions. Only ASA induces urticaria. Can take all other NSAIDs without reactions.
(2) ASA/NSAID cross reacting COX-1 inhibiting urticaria
a. 99% of these patients have chronic idiopathic urticaria
b. 1% are otherwise normal individuals(3) COX-2 inhibiting drugs have been reported to cause urticaria with first dose exposure for reasons unknown (only reports from Mario Sanches-Borges).
I hope this helps."
3/14/02 re: Cross-reacting NSAID in urticaria I am presently consulting upon a 47-year-old man who has had three successive reactions to analgesics. He has no history of asthma or chronic sinusitis or overt allergic rhinitis but lists hayfever as a past illness. In January, after eating in a Chinese restaurant, he noted a mild headache and before boarding a plane bought an OTC analgesic. Thirty minutes later he related some cough, facial edema and wheezing. He took some Benadryl but amazingly made the trip without incident. On February 3 he had another headache and took Motrin and again 30 minutes post had the same symptoms along with some edema of his foreskin. Two weeks later his right knee was swollen and tender for 24 hours but this seems to be a red herring. He is on active duty with the Army and does a lot of running. He had not ingested any medication. Then in early February for another headache again took Motrin and had similar symptoms. He has also had some hives during the reactions. On this occasion he went to the emergency room for the first time. He had taken Benadryl and was stable upon arrival but was treated with prednisone, and given an IV and a Rx for epinephrine. I saw him a week later. Vs and exam not remarkable. He cannot recall if the first medication he took was a NSAID or ASA. There is no way to procure it. He has taken Tylenol since with out any symptoms. He seems to fit the classification of Don Stevenson for urticaria/angioedema or anaphylaxis caused by a specific analgesic. BUT the big question is, was the first analgesic Motrin or ASA? I would bet Motrin or Advil. In one of his papers he recommends a challenge with 3 mgm. of ASA or another NSAID for such cases. I am tempted to challenge with ASA in the ICU with an IV in place. I would be interested in your approach. I still cannot find any new COX inhibitor that is recommended to use in patients with ASA or NSAID reactions. One statement says some are generally safe! This I would not bet upon.
Although I have my own thoughts about approaching the clinical problem you described, I wanted to be sure that I would be quoting the most recent recommendations of Dr. Donald Stevenson and colleagues. Therefore, I forwarded your message to Don Stevenson, who kindly responded very promptly. His response is enclosed below. I should also mention FYI that the report of Stevenson et al describing the tolerance of a challenge with COX-2 inhibitor in aspirin-intolerant asthmatics, to which Don referred, was published in the JACI in 2001 (see abstract enclosed below) Dr. Stevenson's comments:
For the most part you are correct and in our experience we have not seen urticaria/ angioedema reactions to either Vioxx or Celebrex with first dose exposure to these selective COX-2 inhibitors. After first dose exposure, specific immune sensitization can occur and reports of any type of immune reactions are available during Phase 3 trials and in case reports since drug release in 1999. There is one report by an excellent scientist in Central America, Mario Sanches-Borges, of first dose reactions of urticaria and angioedema to both Celecoxib and Vioxx (Annals Allergy, Sept issue, 2001). All the reports from the European literature have never seen a first dose reaction to Celebrex and Vioxx, which is also our experience. When you think about it logically, how can the selective COX-2 inhibitors (with their sulfonyl side chains) actually fit into the smaller COX-1 channel? The answer is they cannot. Therefore, in the cases presented by Sanches-Borges, what was the mechanism of the urticarial reaction? I cannot believe they were COX-1 inhibition.
With respect to the case report you sent me - what should be done. One simply does not know whether or not the first reaction was to ASA or ibuprofen, which of course is the critical piece of information. The fact that the patient can take Tylenol is not helpful, since doses of 1000 mg or more of acetaminophen can cross-react with the older NSAIDs about a third of the time in Samter's triad (aspirin-intolerant asthma) but in chronic urticaria, acetaminophen rarely cross-reacts, even at these higher doses. What to do in this case? It depends on what they want to accomplish. If they need a drug for arthritis pain, I would bring the patient into my office and give the first dose of Vioxx or Celebrex in my office. No reaction would occur and the patient would be given a prescription for the selective COX-2 inhibitor. For headaches use Tylenol.
For platelet inhibition, particularly with coronary stinting, ASA is required. I would still bring patient into my outpatient office, start an IV and have Benadryl and ranitadine (50 mg of each available and ready for IV infusion). I would start with ASA 40.5 mg (1/2 of a baby ASA) and if no reaction in one hour I would give the other 1/2 tablet. That is all you need for platelet inhibition and they can then purchase a big bottle of St. Joseph's 81 mg for adults. Take one each day. Problem solved."
J Allergy Clin Immunol 2001 Jul;108(1):47-51
Lack of cross-reactivity between rofecoxib and aspirin in aspirin-sensitive patients with asthma.
Stevenson DD, Simon RA.
Division of Allergy, Asthma and Immunology, Department of Medicine, Scripps Clinic and The Scripps Research Institute. La Jolla, CA 92037, USA.Background: Patients with aspirin-sensitive respiratory disease experience cross-reactions to all nonsteroidal anti-inflammatory drugs, which inhibit cyclooxygenase enzymes. With the introduction of antiarthritis drugs, which selectively inhibit cyclooxygenase-2, questions are raised as to whether cross-reactivity occurs between aspirin and these new cyclooxygenase-2 inhibitors.
Objective: The goal of this study was to determine whether rofecoxib cross-reacts in aspirin-sensitive patients with asthma.
Methods: Sixty patients with asthma underwent doubleblinded, placebo-controlled oral challenges with rofecoxib (12.5 mg, 25 mg, and 2 placebos) over 48 hours in our General Clinical Research Center. The next day, aspirin sensitivity was proven in each of the 60 patients through use of single-blinded oral aspirin challenges.
Results: None of the 60 patients experienced any symptoms, changes in nasal examination findings, or declines in FEV(1) values during their challenges with rofecoxib. All 60 patients experienced typical naso-ocular and asthmatic reactions to aspirin with a mean provoking dose of 61 mg. The exact 1-sided CI for the probability of rofecoxib inducing crossreactions in aspirin-sensitive patients with asthma is calculated to be between 0% and 0.05%.
Conclusion: Given that none of the 60 patients reacted to rofecoxib and given the statistical power of this large sample size, we conclude that cross-reactivity between aspirin and rofecoxib does not occur in patients with aspirin-sensitive respiratory disease. This does not exclude rofecoxib from participating in other types of reactions, including immune recognition after prior treatment with the drug. From the standpoint of the mechanisms involved in aspirin-induced respiratory reactions, this study strongly supports inhibition of cyclooxygenase-1 as the essential initiator of these types of reactions.
5/1/01 re: nutritional problems in patient with nasal polyps I have a patient with asthma and nasal polyps. She was recently started on a salicylate avoidance diet by her ENT avoiding many fruits including oranges, etc. Her potassium has fallen to 3.3. I am not familiar with this protocol and question whether she should follow "this" diet and, if so, what is advised to keep her potassium intake sufficient to avoid adding potassium Rx.
Your patient is taking a limited diet based on an outdated, flawed concept. When it was found years ago that some patients with nasal polyps and associated asthma were consistently worse after ingestion of aspirin (acetyl salicylate acid, ASA), a few clinicians reported that ingestion of other salicylates naturally present in some nuts and fruits would also trigger respiratory symptoms. It was later found that: 1) The deleterious effects of ASA in these "aspirin triad" patients are really related to their capacity to inhibit the COX-1 enzyme system resulting in less prostaglandin E formation. There is also increased formation of and sensitivity to leukotrienes, with resultant pro-inflammatory and bronchoconstrictive effects. This effect is also induced by varying degrees by different NSAID agents (e.g. ibuprofen, indomethacin, naproxen);. 2) However, non-acetylated salicylates such as sodium salicylate, choline salicylate and the salicylates present naturally in some foods have weak, if any, inhibitory effects on the COX-1 enzymes. As a result, they do not trigger respiratory symptoms in aspirin triad patients. Therefore, there is no reason for your patient to avoid fruits because of concerns about their salicylate content. Presumably, eliminating this dietary restriction would correct the problem of low serum potassium levels.
FYI, I have enclosed abstracts of some recent review articles in this area of study.
Aspirin and asthma
Babu KS, Salvi SS
Department of Respiratory Cell and Molecular Biology, University of Southampton, Southampton General Hospital, Southampton, UKAspirin is not only one of the best-documented medicines in the world, but also one of the most frequently used drugs of all times. In addition to its role as an analgesic, aspirin is being increasingly used in the prophylaxis of ischemic heart disease and strokes. The prevalence of aspirin intolerance is around 5 to 6%. Up to 20% of the asthmatic population is sensitive to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) and present with a triad of rhinitis, sinusitis, and asthma when exposed to the offending drugs. This syndrome is referred to as aspirin-induced asthma (AIA). The pathogenesis of AIA has implicated both the lipoxygenase (LO) and the cyclooxygenase (COX) pathways.
By inhibiting the COX pathway, aspirin diverts arachidonic acid metabolites to the LO pathway. This also leads to a decrease in the levels of prostaglandin (PG) E(2), the anti-inflammatory PG, along with an increase in the synthesis of cysteinyl leukotrienes (LTs). Evidence suggests that patients with AIA have increased activity of LTC(4) synthase, the rate-limiting enzyme in the cysteinyl LT synthesis, in their bronchial biopsy specimens, thereby tilting the balance in favor of inflammation. LT-modifying drugs are effective in blocking the bronchoconstriction provoked by aspirin and are used in the treatment of this condition. Aspirin desensitization has a role in the management of AIA, especially in patients who need prophylaxis from thromboembolic diseases, myocardial infarction, and stroke. This review covers the latest understanding of pathogenesis, clinical features, and management of AIA.
J Allergy Clin Immunol 1999 Jul;104(1):5-13
Aspirin-induced asthma: advances in pathogenesis and management
Szczeklik A, Stevenson DD
Department of Medicine, Jagellonian University School of Medicine, Krakow, PolandIn some patients with asthma, aspirin (ASA) and all nonsteroidal anti-inflammatory drugs that inhibit cyclooxygenase enzymes (cyclooxygenase-1 and -2) precipitate asthmatic attacks and naso-ocular reactions. This distinct clinical syndrome, called aspirin-induced asthma (AIA), is characterized by a typical sequence of symptoms, intense eosinophilic inflammation of nasal and bronchial tissues, combined with overproduction of cysteinyl-leukotrienes (Cys-LTs). At baseline, cys-LT urinary excretion is augmented, and ASA administration leads to its further temporary increase. After ASA challenge, cys-LTs are released into nasal and bronchial secretions and can be collected in the urine. LTC4 synthase, the terminal enzyme for cys-LT production, is markedly overexpressed in eosinophils and mast cells from bronchial biopsy specimens of most patients with AIA. An allelic variant of LTC4 synthase that enhances enzyme transcription is associated with AIA. Avoiding ASA and nonsteroidal anti-inflammatory drugs does not prevent progression of the inflammatory disease. Corticosteroids continue to be the mainstay of therapy, and anti-LT drugs are also indicated for treatment of the underlying disease. After ASA desensitization, daily ingestion of high doses of ASA reduces inflammatory mucosal disease symptoms, particularly in the nasal passages, in most patients with AIA.
12/12/00 re: Role of anti-leukotrienes in aspirin-triad asthma What is the current status of the use of leukotriene inhibitors in the asa triad? As you likely know, there has been evidence for some time of prominently increased urinary leukotriene E4 levels in most cases of aspirin-triad asthma. Therefore, this patient group was one of the first sub-groups of asthmatics for which leukotriene antagonists (LTA) were tried. Most investigators and reviews have concluded that LTA are particularly helpful in triad asthma. Some uncontrolled studies have suggested that LTA are beneficial in the sinus disease of these patients as well. Japanese investigators have found that bronchial hyper-reactivity, as well as symptoms, is improved by LTA therapy in triad asthma. However, the picture may not be as clear-cut as originally reported. Some clinicians have found lack of clinical benefit of LTA therapy in some patients with typical triad asthma. The situation is confused by findings of at least one group that LTA therapy of asthma is particularly helpful in asthmatics with low ratios of LTE4 to prostaglandin levels in the urine.
This somewhat unsettled state of affairs may reflect the pathogenic heterogeneity of triad asthma, and of asthma in general. Nevertheless, I believe that a therapeutic trial of LTA in triad asthma is worth undertaking, particularly if the patient's asthma is steroid-dependent with the aim of achieving a steroid-sparing effect. Please see the below abstracts (at www.medline.com) of several relevant articles for your interest in obtaining more details.
- Ear Nose Throat J 1999 Aug;78(8):604-6, 608, 613, passim
- Clin Exp Allergy 2000 Jan;30(1):64-70
- Biomed Pharmacother 1999 Aug;53(7):312-4
- Allergy 1999 May;54(5):489-94
- Thorax 1993 Dec;48(12):1205-10
2/8/00 re: COX-2 inhibitors and aspirin-induced urticaria Can Patients who have urticaria and/or angioedema to aspirin or NSAID be given cox-2 inhibitors? If yes, are there any challenge protocols available? The frequency of adverse reactions to COX-2 inhibitors in those reacting to NSAID/COX-1 inhibitors is still unsettled based on small published series. I am enclosing abstracts of 2 reports in this area as well as part of my response in March 1999 to a question about COX-2 inhibitor used in asthmatics. Also, Dr. Donald Stevenson, an expert in this area has told me that their challenges of ASA-intolerant asthmatics with COX-2 inhibitors have generally induced no reaction. I should stress that although urticarial and respiratory adverse reactions are sometimes lumped together in discussions of ASA/NSAID intolerance, the mechanisms underlying the urticarial reactions are not defined. Evidence suggesting that the mechanisms may differ for urticaria and asthma includes the clinical observation that it is very unusual to see both types of adverse reactions in the same individual. For more details, I suggest that you read the review of aspirin-intolerant asthma by Stevenson (reviewed in the Current Literature Section of this website).
Drug Saf 1996 Feb;14(2):94-103
Nimesulide in the treatment of patients intolerant of aspirin and other NSAIDs.
Senna GE, Passalacqua G, Andri G, Dama AR, Albano M, Fregonese L, Andri L
Allergy Unit, Verona General Hospital, Italy.
Aspirin (acetylsalicylic acid) and other NSAIDs are responsible for many
adverse effects. Among them, pseudo-allergic reactions (urticaria/angioedema, asthma, anaphylaxis) affect up to 9% of the population and up to 30% of asthmatic patients. The mechanisms provoking these reactions have not been fully elucidated, but it appears that inhibition of cyclo-oxygenase (COX) plays a central role. The anti-inflammatory action of nimesulide differs from that of other NSAIDs, possibly because of its chemical structure. In particular, nimesulide is selective for COX-2 and displays additional properties in terms of its effects on inflammatory mediator synthesis and release. For these reasons, nimesulide is generally well tolerated by NSAID-intolerant patients and patients with NSAID-induced asthma. The good tolerability of nimesulide as an alternative drug for use in patients with NSAID intolerance has been demonstrated in a large number of clinical studies.
J Asthma 1999 Dec;36(8):657-63
The use of nimesulide in patients with acetylsalicylic acid and nonsteroidal anti-inflammatory drug intolerance.
Bavbek S, Celik G, Ediger D, Mungan D, Demirel YS, Misirligil Z
Ankara University Faculty of Medicine, Department of Allergy, Turkey
mbavbek@ato.org.tr
Intolerance or idiosyncrasy to acetylsalicylic acid (ASA) and other nonsteroidal anti-inflammatory drugs (NSAIDs) is a crucial problem because these drugs are frequently used in medical treatment. In this study, we tested whether nimesulide, a selective cyclooxygenase-2 (COX-2) inhibitor, might be a valid alternative for patients with histories of adverse reaction to ASA or NSAIDs. A single-blind, placebo-controlled oral challenge procedure was applied to 60 adult patients (19 male, 41 female; with a mean age of 40.31 +/- 10.44 years, range 20-68 years) with a reliable history of ASA/NSAIDs-intolerance. According to history, the clinical presentations of intolerance were urticaria/angioedema in 32 patients, anaphylactoid reaction in 2 patients, respiratory reaction in 19 patients, and respiratory and cutaneous reaction in 7 patients. Atopy was confirmed by means of skin prick test with inhalant allergens. Oral challenge protocol was started with 25 mg of
nimesulide and the remaining 75 mg was given 1 hr later. During the challenge procedure, blood pressure, pulse, nasoocular, pulmonary, and cutaneous symptoms were monitored. Of the 60 patients tested, 55 (91.7%) tolerated the drug with no adverse reaction. Only five (8.3%) patients demonstrated a positive response to oral challenge. The clinical presentations of intolerance to nimesulide were urticaria/angioedema in three patients, mild rhinitis in one patient, and mild dyspnea in one patient. The atopy prevalence was higher, with a ratio of 41.7%, in patients with ASA/NSAIDs intolerance than that of the healthy adult population in Turkey (p < 0.05). We believe that nimesulide can be used as an alternative drug for patients with ASA/NSAIDs intolerance.Response to previously asked Ask the Expert question
However, one must be careful about using COX-2 inhibitors in all asthmatics,
some of whom may be aspirin (ASA)-reactive. As you may know, a varying
percentage of ASA-reactive asthmatics will also experience asthma worsening after ingesting traditional NSAID (COX-1 inhibitors). A report by Vaghi et al (in abstract form) described worsening of asthma in some of such individuals by ingestion of the COX-2 inhibitor meloxicam. However, Di Fonso et al from Italy subsequently described (in abstract form) tolerance of meloxicam by NSAID-reactive individuals (most of whom had cutaneous adverse reactions to NSAID). So the matter is still unsettled.5/23/97 re: aspirin allergy (urticaria) & wheezing Are there any safe NSAIDS for this patient who also has arthritis? All NSAID can potentially induce wheezing in a patient with aspirin (ASA)-induced wheezing, though the incidence of such reactions to NSAID is not 100%. It has been reported that sodium salicylate, choline salicylate and the recently released imidazole salicylate compounds are generally tolerated by ASA-reactive patients although these agents may have less anti-inflammatory effects. The group at the Scripps Clinic in La Jolla has reported successful cautious aspirin "desensitization" of some "triad asthma" patients ( J Allergy Clin Immunol 98:751-8, 1996). 4/7/97 re: ASA allergies What foods (salicylate containing) should a person avoid if they have a documented reaction to ASA? Although older studies suggested that individuals with "triad asthma" sensitive to aspirin would also react adversely to other salicylates contained in certain foods such as nuts and berries, more recent studies have not found this to be the case. The capacity of a chemical to induce adverse reactions in such individuals appears to be linked to its capacity to inhibit the cyclo-oxygenase enzyme. Thus, up to 50% of triad asthma patients have similar adverse reactions to indomethacin, a drug chemically dissimilar to salicylates. In contrast, most triad asthma patients tolerate certain salicylates (e.g. - sodium salicylates even when they cannot tolerate aspirin (acetyl salicylic acid).
