Allergic and "pseudoallergic" reactions to NSAIDs

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D, Allergist/Immunologist and Assistant Professor at LSU-Shreveport

NSAIDs can cause several allergic and "pseudoallergic" reactions. Allergic reactions are immunologic reactions to NSAIDs that are presumed IgE-mediated. Pseudoallergic reactions are non-immunologic.

Pseudoallergic reactions are non-immunologic abd are related to the COX-1 inhibition. They can be elicited by any NSAID that inhibits COX-1, including aspirin. Precise mechanism has not been established.

Allergic NSAID reactions are presumed to be IgE-mediated. They are elicited by a single NSAID in a susceptible individual.


Allergic and "pseudoallergic" reactions to NSAIDs

Pseudoallergic NSAID reactions

Pseudoallergic reactions can be caused by any COX-1 inhibiting NSAID, and the likelihood of these reactions is related to the degree of COX-1 inhibition. Pseudoallergic reactions are usually seen in patients with one of the following comorbidities: the combination of asthma and chronic rhinosinusitis with nasal polyposis; or chronic urticaria.

Pseudoallergic reactions are divided into 4 types:

- Type 1: NSAID-induced asthma and rhinosinusitis
- Type 2: NSAID-induced urticaria/angioedema in patients with chronic urticaria
- Type 3: NSAID-induced urticaria/angioedema in otherwise asymptomatic individuals
- Type 4: Blended reactions in otherwise asymptomatic individuals

Type 3: NSAID-induced urticaria/angioedema in otherwise asymptomatic individuals

There is a small subsets of patients without chronic urticaria who develop acute urticaria and/or angioedema with COX-1 inhibiting NSAIDs/ASA. Isolated angioedema following NSAID ingestion typically involves the face, particularly the periorbital skin, lips, and mouth. This condition is uncommon. These patients may develop urticaria and/or angioedema only after NSAID ingestion or may have intermittent episodes of unexplained urticaria unrelated to NSAID ingestion, but they do not have chronic urticaria.

The probable mechanism is related to COX-1 inhibition, as patients with type 3 pseudoallergy can react to their very first dose of a COX-1 inhibitor and to structurally different COX-1 inhibiting NSAIDs. They are able to tolerate highly selective COX-2 inhibiting NSAIDs (eg, celecoxib).

Allergic NSAID reactions (presumed IgE-mediated)

Allergic reactions to NSAIDs range from urticaria/angioedema to life-threatening anaphylaxis. In contrast to pseudoallergic reactions, these reactions are elicited by a single NSAID, or rarely by more than one agent with similar molecular structures.

These reactions are believed to be IgE-mediated via a drug hapten/carrier protein phenomena. While most of these reactions have been associated with ibuprofen, the first NSAID to become available over the counter in the United States, they can happen with any COX-1 inhibitor. There are no practical available tests to detect IgE to NSAIDs (such as skin testing or drug-specific serum IgE tests).

Allergic reactions may be divided into two types, based on the severity of the symptoms:

- Type 5: Urticaria/angioedema to a single NSAID - urticaria and/or angioedema within minutes to one hour of taking a particular NSAID or ASA. These patients generally do not have underlying chronic urticaria.

- Type 6: Anaphylaxis to a single NSAID (not ASA) - Type 6 reactions are distinguished from type 5 reactions based only upon severity. Typical symptoms of anaphylaxis include shortness of breath/wheezing due to bronchospasm or laryngeal edema and hypotension due to vascular collapse.

It is notable that there are no confirmed cases of anaphylaxis to aspirin itself.

Diagnosis

There are no in vitro or skin testing methods available. Definitive diagnosis requires a challenge procedure, although this is only indicated if the patient has a specific need for regular NSAID therapy (ie, usually NSAIDs for rheumatologic disease or aspirin for cardiovascular disease).

Management of pseudoallergic reactions

Challenge procedures

If a definitive diagnosis is required, then a provocative challenge procedure must be performed.

Without additional information, the clinician must advise the patient to avoid all NSAIDs. However, a challenge procedure with aspirin would clarify whether the patient reacts to all COX-1 inhibitors (pseudoallergic), or only to ibuprofen (allergic).

Alternative to the challenge

An alternative to the challenge is to administer a highly selective COX-2 inhibitor. Highly selective COX-2 inhibitors (eg, celecoxib) are tolerated by patients with pseudoallergic reactions. These agents demonstrate at least a 200 to 300-fold selectivity for inhibition of COX-2 over COX-1 at the defined therapeutic doses.

It is generally safe for patient with a pseudoallergic NSAID reaction to take a highly selective COX-2 inhibitor, such as celecoxib. Some allergists prefer to give an initial dose in a medically supervised setting (eg, a clinic), although there are no reported cases of pseudoallergic reactions who subsequently reacted to celecoxib.

Management of allergic reactions

Type 5 and 6 reactions are presumed IgE-mediated reactions to single NSAIDs. Patients with these types of reactions should avoid the causative agent.

Patients with types 5 and 6 reactions may require diagnostic challenge with aspirin to confirm that they are not sensitive to all COX-1 inhibitors (ie, exclude pseudoallergy), if the history is not sufficient to determine this. Confirmed cases of anaphylaxis to aspirin have not been reported.

Patients with types 5 or 6 reactions may safely take NSAIDS that are structurally dissimilar to the drug that caused the initial reaction.

However, selective COX-2 inhibitors may be unsafe in subjects with urticaria and/or angioedema caused by hypersensitivity reactions to NSAIDs with cross-intolerance if they are intolerant to paracetamol. Allergy, 2011.

References

Patient with Arthritis and Hypersensitivity to Nonsteroidal Antiinflammatory Drugs (NSAIDs)
UpToDate, 2010.

The Kounis-Zavras syndrome with the Samter-Beer triad http://goo.gl/g7qGh

NSAIDs are responsible for 21-25% of reported adverse drug events http://goo.gl/m6vMK

Selective COX-2 inhibitors may be unsafe in subjects with urticaria and/or angioedema caused by hypersensitivity reactions to NSAIDs with cross-intolerance if they are intolerant to paracetamol. Allergy, 2011.

Published: 07/27/2010
Updated: 07/27/2011