Possible ibuprofen anaphylaxis
Question:
7/6/2018
11 year-old Caucasian male with allergic rhinitis (dust mite and cockroach) but no asthma or food allergies, developed coughing, SOB, wheezing neck swelling, breaking in to hives all over body within an hour or two of going to bed, was taken to local ER, treated with breathing treatment and Benadryl but no Epinephrine. Reported to eat hamburger which would be 3-4 hours prior to reaction. Reported to have similar reaction two weeks before this one. After seeing us in the clinic, he ate steak and fried rice with eggs at 1 PM which he had before many times without any issues. At 2 PM he complained of headache, was given Ibuprofen at 2 PM and around 2:45 PM, developed rhinorrhea, neck swelling, throat burning, and only half of his air getting in and hives to his neck, was taken to ER and was treated. Mom reports that in retrospect he has c/o headache with each episode and has received Ibuprofen with each event of reaction. He had tolerated Ibuprofen without any issues several years ago. Denied any other NSAID use except Tylenol. Denied chronic Urticaria. Work up included CBC with Diff, Tryptase, alpha gal, IGE to beef, pork, lamb, IGE to ibuprofen and aspirin, all unremarkable except mild eosinophilia. He has been tolerating red mammalian meat for more than one year without any further allergic reaction. It seems like single NSAID induced anaphylaxis. Although it is more likely to be IGE mediated, my literature search suggested to have oral challenge with chemically nonrelated strong COX-1 inhibitor first (aspirin) and if it is negative to have Ibuprofen challenge later. Is this approach correct? I have found aspirin challenge protocol of two days with placebo on Day1 and aspirin of total of 500 mg on day 2. Do you suggest any different protocol?
Answer:
I think the issue depends on whether the question is for diagnosis or management. If you are concerned that your patient has anaphylaxis to ibuprofen and you are looking for treatment alternatives, then one option would be to challenge with a non-propionic acid NSAID (propionic acid group includes ibuprofen, ketoprofen, naproxen). If the challenge is negative, suggest this NSAID be used for headache or fever and avoid indefinitely ibuprofen or other propionic acid NSAIDs. Typically, anaphylactic NSAID reactions are drug specific in contrast to reactions to all NSAIDS in AERD. If you are concerned that the cause of the reactions is unknown and you are looking to prove a cause, then an ibuprofen graded challenge would be a consideration. I think the challenge has risk but would be reasonably safe if done under controlled conditions and no evidence of active asthma prior to the challenge. I think the cause of your patient’s symptoms are unknown and delayed mammalian meat anaphylaxis (specific-IgE for galactose-α1,3- galactose) remains a concern despite the negative in vitro tests with commercial meat extracts and galactose-α1,3-galactose. Of interest, patients with B or AB blood group may be less likely to develop sensitivity to galactose-α1,3-galactose (1). Other considerations for your patient could be idiopathic anaphylaxis, monosodium glutamate reaction, carcinoid syndrome or mast cell activation due to alternative mechanism.
My suggestion would be to have a shared decision making discussion with the patient and family. I would avoid ibuprofen for the time being and utilize acetaminophen for fever or headache. If the family and patient are comfortable with waiting, I would provide epinephrine autoinjector and see if further episodes occur. If no further episodes occur, then this would support ibuprofen anaphylaxis and effectively eliminate delayed meat anaphylaxis, idiopathic anaphylaxis, or carcinoid syndrome. If subsequent episodes occur and blood pressure is increased during these episodes, I would recommend studies for carcinoid syndrome (urinary 5HIAA and serotonin and blood chromogranin [low specificity]). I would also consider a tryptase during future episodes to see if increase suggests mast cell activation (>1.2X baseline + 2 ng/ml or >1.3 X baseline). You might also want to perform intradermal testing to mammalian meat as described by Commins, Platts-Mills et al, particularly if serum tryptase is increased during events (2).
There is a basophil histamine test for ibuprofen available, but I do not think this would help you as it has limited sensitivity and is likely not covered by insurance (see attached Ask the Expert question from the archives below). There are a variety of NSAID and ASA challenge protocols from which to choose (3). Most start with doses of 15-30 mg and increase dose every 1-2 hours, but most of this experience is based upon AERD rather than anaphylaxis. Anaphylaxis from ASA has not been reported to my knowledge, but there have been reports of anaphylaxis from acetaminophen (4,5).
I hope this information is of some help to you and your practice.
All my best.
Dennis K. Ledford, MD, FAAAAI
1. Brestoff, Jonathan R., et al. "B Antigen Protects Against the Development of α-Gal-mediated Red Meat Allergy." Journal of Allergy and Clinical Immunology 141.2 (2018): AB230.
2. Platts-Mills, Thomas AE, et al. "Anaphylaxis to the carbohydrate side chain alpha-gal." Immunology and Allergy Clinics 35.2 (2015): 247-260.
3. Chaudhry, T., et al. "Oral drug challenges in non‐steroidal anti‐inflammatory drug‐induced urticaria, angioedema and anaphylaxis." Internal medicine journal 42.6 (2012): 665-671.
4. Van Diem L, Grilliat JP. Anaphylactic shock induced by paracetamol. Eur J Clin Pharmacol. 1990;38(4):389.
5. Leung R, Plomley R, Czarny D. Paracetamol anaphylaxis. Clin Exp Allergy. 1992;22(9):831.
5/1/2015
Ibuprofen and basophil histamine release test
Any insight/references regarding predictive value of basophil histamine release assays in the assessment of possible IgE-mediated reaction to ibuprofen (or other drugs/foods for that matter)? Patient with bilateral orbital/eyelid edema, tearing and mild conjunctival injection 20 minutes after ibuprofen, with 3 milder episodes over prior 3 months within 1 hour of ibuprofen, but nearly daily dosing between no symptoms. No urticaria or other concurrent symptoms consistent with IgE mediated reactions, and few other suspicious exposure (food/environmental assessment, complement studies in progress). No other NSAID exposures in the timeline of these reactions or since.
I am not sure if I understood, but I believe your description is that your patient has had 4 episodes of upper respiratory symptoms with ibuprofen. I am not clear if “daily dosing” refers to daily ibuprofen without a reaction. There is a refractory period for up to 3-4 days following a NSAID reaction with respiratory symptoms. This refractory period could explain daily dosing without symptoms but I was not clear as to whether the subsequent reaction occurred despite daily ingestion of ibuprofen.
The basophil histamine release test with ibuprofen is available through Viracor-IBT Laboratories but I could not find the accuracy and specificity of the specific test. In general, histamine release assays suffer from low sensitivity and specificity. The basophil activation test with flow cytometry is probably preferable to measuring histamine release. This assay is available commercially and is used by some clinicians to document autoantibody to the high-affinity IgE receptor. The presence of the antibody is identified by the expression of activation markers on the basophils, CD 69 or 203c, recognized by flow cytometry. The same assay can be used for detection of in vitro basophil activation following exposure to a specific substance. The performance for NSAIDs is reported to have a sensitivity of 15-75% and specificity of 45-95% (Sanz, Leysen). However, the conditions for mixing the ibuprofen with the basophils is not well defined and some of the NSAID reactions are not likely to show a positive basophil activation test.
If your patient is experiencing AERD related to NSAID, a urinary leukotriene level may be increased. If your patient is having a specific reaction to ibuprofen with anaphylactic-like symptoms, then this reaction may be specific for ibuprofen. I am not aware of any test to prove this other than challenge testing.
I have shared your question and my response with Dr. Ron Simon of the Scripps Clinic and an international expert with respect to NSAID sensitivity. Dr. Simon has replied.
“I have no direct experience with the basophil histamine release assays for detection of allergy to any NSAID, including ibuprofen. I agree with you that overall the assays don't have great sensitivity and specificity. I have even greater concern regarding NSAID allergy. First actual (presumed) IgE mediated reactions to individual NSAID's are rare so I don't know how they would get a single patient, let alone, enough such patients for positive controls to establish the sensitivity & specificity for that specific assay. Another problem is that NSAID's are generally not water soluble so difficult to work with in biologic/in vitro assays (even ELISA's).
Finally, in my opinion, if the patient is using the treatment nearly every day in between reactions but not having reactions the patient is a neither allergic nor coming in & out of refractory periods (as he/she should remain in the refractory period with daily dosing of the NSAID as we see with AERD patients treated with aspirin or to use an IgE mediated example, patients on oral peanut immunotherapy).”
Sanz ML,Gamboa PM, De Weck AL. In vitro tests: basophil activation tests. Drug Hypersensitivity. 2007;391-402.
Leysen J et al. The basophil activation test in the diagnosis of immediate drug hypersensitivity. Expert Rev Clin Immunol 2007;7:349-55.
I hope this information is of help to you and your patient.
All my best.
Dennis K. Ledford, MD, FAAAAI