Patient is a 62 year-old male with h/o mild persistent asthma (controlled with Q var inhaler) and allergic rhinitis (not on medicines) who gives h/o anaphylactic reaction with hypotension to Aleve in 2009. Patent presented to allergy clinic recently and would like to know if he could be tested so that he will know whether he can take aspirin or NSAID.

Patient states that one morning, after walking his dog, he took 2 tablets of Aleve (naproxyn) and then walked to the restaurant for breakfast with his wife. Before ingestion of any food, within half hour to one hour of taking Aleve, while in the restaurant, he felt flushed with itching and nausea and then had sycopal episode. Paramedic was called. He was noted to have bp of 56/palpable. Benadryl and IV bolus given. He was then taken to ED. He was further treated with IV hydration, solumedrol and pepcid and zofran. His bp recovered and symptoms improved. Serial troponins were measured in ED. First was normal, second and third ones were elevated. Subsequent stress treadmill test was negative. No tryptase drawn.

No previous h/o nasal polyps, chronic urticaria or reaction to aspirin or NSAID prior to that episode. Since that episode, patient was told to avoid all aspirin and NSAID products. His FEV1 is 95%.

Given this history, what are your thoughts on the risk of an aspirin oral challenge? Would you do aspirin desensitization instead and advise patient to be on aspirin for life?

Thank you for your response.


Thank you for your inquiry.

We have responded to similar inquiries submitted to our website in the past, and two of these responses may be helpful to you. I have copied them below.

Basically, anaphylactic/urticarial reactions to nonsteroidal antiinflammatory drugs are most often drug-specific rather than class-specific. Therefore, on a statistical basis, your patient would likely be able to take aspirin without problem. However, there is no way to predict whether cross-reactivity would occur other than an oral challenge.

As mentioned, an oral challenge would more than likely be safe, but usually we do not perform oral challenges to nonsteroidal antiinflammatory drugs in this type of situation unless there is an imminent need for the drug. Your patient has an alternative for pain and fever (acetaminophen), and if there is no imminent need for aspirin, I personally would not proceed with a challenge at this time.

However, that strategy is simply a matter of opinion, and if you personally feel that the risk/benefit ratio favors a challenge, then I would perform one in a graded dosage fashion starting with a dose of 30 mg and progressing with doses every 30 to 45 minutes until a full therapeutic dose is reached or a reaction occurs. This type of desensitization protocol can be done more rapidly than one done to desensitize to aspirin in a patient having aspirin-exacerbated respiratory tract disease.

If you choose not to do the oral challenge because you have analyzed the risk/benefit ratio in favor of continued avoidance, I do not feel you need to tell the patient that he must avoid aspirin his entire life. It may be, in the future, that he will have the need for this drug, and I would therefore tell him that an oral challenge could probably be done safely if this is the case, but since he does not need the drug at this time, you would prefer not putting him through the risk.

Thank you again for your inquiry and we hope this response is helpful to you.

Ask The Expert inquiry dated 4/21/2009: Allergic reaction to Daypro: Possible cross-reactivity with other NSAIDs

I recently have seen a 48-year-old female who experienced an allergic reaction to what we believe was Daypro. She started Daypro for arthritic complaints with complaints of pruritis developing approximately 24 hours after taking and hives developing approximately 2 to 3 days after starting the medication. She also experienced facial swelling and lip swelling and her throat felt full with some difficulty swallowing starting 2 to 3 days after starting. She did not experience wheezing and is not an asthmatic. She has taken Advil, aspirin and ibuprofen without any allergic reaction in the past. She has never taken Celebrex.

As Daypro is a propionic acid derivative, as is ibuprofen, would we be safe in assuming that an allergic reaction to Daypro would predict a similar reaction toibuprofen or is there a reason to consider a challenge?

Naproxen is an arylacetic acid derivative, is there reason to think there might be cross reactivity with Daypro or ibuprofen, and thus is an in-office challenge reasonable to do?

Lastly, given the reaction to Daypro, would we avoid ASA as well, or is it unlikely she would have a reaction to ASA?

What would you see as the best approach in evaluating this patients allergic reaction and future recommendations in taking other NSAIDs, ASA or Celebrex given there is no history of asthma, polyps, or recurrent sinusitis or history of chronic urticaria?

Thank you for your recent inquiry regarding urticaria to Daypro.

Unfortunately, I am not going to be able to give you a definitive answer to your question. The reason for this is, as you know, the only way to determine whether or not your patient will react to a given NSAID is to administer the drug. The only way to decide whether or not to do so is a personal assessment of the risk/benefit ratio.

Unfortunately, I am not aware of anything in the literature that gives set parameters for the assessment of risk/benefit ratio in these situations. The background material for these comments is found in the references noted below (1-4).

Perhaps the most salient one, for your purposes, is the Stevenson, et al., article appearing in Allergy: Principles and Practice, Volume 2, 6th edition, 2003; pages 1695-1710. This article discusses the classification of patients with “pseudoallergic” reactions to NSAIDs.

Using this classification, two types of urticarial reactions occur to NSAIDs in otherwise normal individuals. In one type, patients react to more than one NSAID. It is unclear as to whether this is dependent on the biochemical class of the NSAID, and certainly, there have been reactions in patients to NSAIDs of different classes. There are, however, other studies which imply that it is more likely, for some of these patients, to react only to a given biochemical class (see Quiralte, Reference Number 1, below). This observation would make it more reasonable, should you perform a challenge, to use a compound from a different class than that of Daypro.

There are, as noted above, three possibilities regarding urticarial reactions to NSAIDs (see Sezceklik, Reference Number 3, below).

• Patients that react to a single NSAID only.
• Patients that react to NSAIDs only of a certain chemical class.
• Patients that react to any NSAID.

In all probability, your patient would be reactive only to Daypro, but, as noted, unfortunately, there is no way to predict this with any accuracy. A challenge remains the only alternative in this regard. The fact, however, that she has taken a number of other NSAIDs gives some comfort in this regard.

Taking this information as a whole, if your patient does require the further administration of an NSAID, you will have to consider the risk/benefit ratio of a challenge.

It seems most reasonable, based upon the above observations, that should a challenge be done, you should use an NSAID that is not a propionic acid derivative. You mentioned Naproxen. This would be a reasonable candidate. We do perform such challenges in-office pending the severity of the nature of the initial event. With urticaria, we usually proceed in the office.

The comments noted above for Naproxen and other NSAIDs also would apply to aspirin as well. Again, the only way to tell whether she would react to aspirin is to perform a challenge.

Since these reactions seem to have no relationship to the drugs ability to inhibit prostaglandin synthesis, there should be no increased concern regarding asthma, nasal polyps or recurrent sinusitis.

In summary, your only option is to make a judgment as to the risk/benefit ratio of performing a challenge to the selected NSAID. It would seem most reasonable, should a challenge be done, to utilize a drug of a different class than Daypro. A challenge would also be necessary to decide whether aspirin could be given. On the other hand, your patient is at no increased risk for the development of asthma, nasal polyps or sinusitis by virtue of the fact that urticarial reactions are not related to the drug’s capacity to inhibit prostaglandin synthesis.

If you decide to do a challenge, you should utilize a graded dosage provocation test. There are no definitive studies that determine the starting dose or the interval of time between oral dosing. Arbitrarily, we use 1/10th of the desired dose in cases of urticaria, and dose at approximate 2-hour intervals. Doing this, we double the dose for the first two administrations, giving a total of 7/10th (0.1 followed by 0.2, followed by 0.4) at the end of 4 hours. We then give a dose of 3/10th two hours later and observe the following two hours. This would allow you to do this within an 8-hour period.

This protocol is arbitrary, of course, and there are many variations which you could employ.

1. Quiralte J, et al. Anaphylactoid reactions due to nonsteroidal antiinflammatory drugs: Clinical and cross reactivity studies. Annals of Allergy, Asthma, and Immunology 1997; 78:293-296.
2. Stevenson DD, et al. Classification of allergic and pseudoallergic reactions to drugs that inhibit the cyclooxygenase enzymes. Annals of Allergy, Asthma, and Immunology 2001; 87:1-4.
3. Sezceklik A, et al. Hypersensitivity to aspirin and nonsteroidal antiinflammatory drugs. Middleton's Allergy: Principles and Practice, 7th edition, Volume 2, 2009; pages 1227-1243.
4. Stevenson DD, et al. Sensitivity to aspirin and nonsteroidal antiinflammatory drugs. Middleton’s Allergy: Principles and Practice, 6th edition, Volume 2, 2003; pages 1695-1710

Ask The Expert inquiry dated 1/30/2009: Cross-reactivity of anaphylactic/urticarial reactions to nonsteroidal antiinflammatory drugs

I am an allergist who saw today a patient who had been given Naproxen for the first time about a month ago, which he took for 3 days without problems. About 2 weeks later, he took another dose and within 30- 45 minutes, he developed eyelid swelling, redness and itching all over, and felt he was panting. In the couple of minutes it took to get his physician's office on the line, his breathing was back to normal, and when he took Benedryl as instructed, the itching resolved within an hour, although the redness and swelling took about 12 hours to disappear. He takes one baby aspirin daily and has continued to do so without problems. He has no h/o asthma or sinus disease, so my assumption is that this is a reaction to Naprosyn as opposed to a COX-I reaction. However, I gathered from a previous answer in this valuable resource, that the only way to be sure of this diagnosis is if the patient has tolerated another NSAID.

My first question arises from not knowing whether 81 mg of aspirin is sufficient NSAID to make this assumption as I also understand that it can take as much as 325 mg of aspirin to make some patients react.

My second question is if I think it is a specific allergy to naproxen, does the patient need to be concerned about the other NSAIDs within the proprionic acid derivatives, I would appreciate your opinion.

Patients exhibiting urticaria/angioedema or anaphylactic reactions to a nonsteroidal antiinflammatory drug are not in general, like those who experience respiratory symptoms to these drugs, intolerant of non selective COX-1,2 inhibitors in general. There appears to be a different mechanism involved in the urticaria/anaphylactic reactions to these drugs. Such patients characteristically react only to a single nonsteroidal antiinflammatory drug (NSAID) alone (1).

I copied below an abstract which illustrates this principle. However, "cross-reactivity" does rarely occur. When it does occur it is usually to NSAIDs with a similar molecular structure.(eg, propionic NSAIDs such as ibuprofen, naproxen, and ketoprofen) (2).

Thus, from a statistical standpoint it is likely that your patient would be reactive specifically to naproxen. Evidence for this is of course the fact that he continues to take a small dose of aspirin without difficulty. However, unfortunately, this dose of aspirin would not be sufficient to establish this without question, and unfortunately, the only way to tell if he would have a reaction to another NSAID would be to do an oral challenge since there is no in vivo or in vitro tests that would settle this issue reliably.

Thus, in summary, and in specific answer to your questions:

1. I do not think we can make the assumption that no reaction to 81 mg of aspirin would ensure that the patient would not have a reaction to a larger dose or another NSAID.

2. Although, statistically speaking, it is unlikely that your patient would react to any other nonsteroidal, we cannot determine that conclusively without an oral challenge. It would, however, as you mentioned, be more likely that he would react to a propionic acid derivative than to another class.

From a practical standpoint, however, at least in my practice, I suggest complete avoidance of NSAIDs unless one is absolutely needed, and no other drug will suffice. In those cases, in my opinion, a very carefully performed graded oral challenge would be the only way to see if the patient could tolerate another NSAID.

Thank you once again for your inquiry and I hope this response has been helpful to you.

1. Stevenson D, Simon R, Zuraw B. Sensitivity to aspirin and nonsteroidal antiinflammatory drugs. In: Allergy: Principles and Practice, 6th edition, 2003; page 1705.
2. Stevenson DD. Aspirin and nonsteroidal antiinflammatory drugs. Immunol Allergy Clin North Am 1995; 15:529.

Annals of Allergy, Asthma and Immunology
1997, vol. 78, no. 3, pp. 293 - 296
Anaphylactoid Reactions due to Nonsteroidal Antiinflammatory Drugs: Clinical and Cross-Reactivity Studies
J Quiralte MD; C Blanco MD; R Castillo MD; Nancy Ortega MD; Teresa Carrillo MD, PhD
Publisher: American College of Allergy, Asthma and Immunology
Background: Anaphylactoid reactions due to nonsteroidal antiinflammatory drugs have been described.
Objective: To study the clinical characteristics of 21 patients with anaphylactoid reactions due to nonsteroidal antiinflammatory drugs and to determine the cross-reactivity to nonsteroidal antiinflammatory drugs not involved in the previous reactions nor structurally related by means of single-blind, placebo-controlled drug challenges.
Patients and methods: Twenty-one patients who exhibited clinical evidence of anaphylactoid reactions after nonsteroidal antiinflammatory drugs were recruited for the study at the time of admission in Emergency Unit of our hospital. Single-blind, placebo controlled oral challenges with nonsteroidal antiinflammatory drugs (except those reported by the patient as being responsible for the previous reaction), were performed in all patients.
Results: Fifteen patients were women and six men, with a mean age of 35.7 years (range 18 to 62 years). Thirteen patients (60%) were normal subjects without concomitant diseases. No increase in frequency of atopy in comparison to the general population was observed. Pyrazole derivatives were the most common nonsteroidal antiinflammatory drugs involved (71.3%). A tolerance to drugs included in drug challenge protocol was noted in all patients.
Conclusion: In our population, pyrazole derivatives were the most common nonsteroidal antiinflammatory drugs involved in anaphylactoid reactions. Most patients appeared to be otherwise normal subjects without concomitant disease and no cross-reactivity with other nonsteroidal antiinflammatory drugs not involved in the anaphylactoid reaction nor structurally related was found.

Phil Lieberman, M.D.

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