The NSAIDs hypersensitivity reactions are categorized into 5 groups based on symptoms, mechanisms, and cross-reactivity: NSAIDs-exacerbated respiratory disease (NERD), NSAIDs-exacerbated cutaneous disease (NECD), NSAIDs-induced urticaria/angioedema (NIUA), single NSAID-induced urticaria/angioedema and anaphylaxis (SNIUAA), and single NSAID-induced delayed hypersensitivity reactions (SNIDHR). [2, 4].

The first three phenotypes are cross intolerance reactions whereby symptoms can be triggered by multiple structurally unrelated NSAIDs across more than one subclass. [1] (Table 1). These reactions are mediated by cyclooxygenase 1 (COX-1) inhibition blocking prostaglandin synthesis from arachidonic acid and promoting leukotriene production. [4, 5].

Table 1 Classification of NSAIDs by chemical structure [1, 7, 11] 1.

NERD manifests as respiratory involvement (dyspnea, cough, wheeze, nasal congestion, rhinorrhea) in patients with underlying airways disease including asthma, nasal polyps, and rhinosinusitis. [2].

2.

NECD manifests as wheals/urticaria and/or angioedema in patients with a history of chronic spontaneous urticaria (CSU). [2] Up to 30% of CSU patients experience exacerbation of their underlying cutaneous disease with NSAIDs use. [6, 7].

3.

NIUA manifests as wheals/urticaria and/or angioedema in otherwise healthy patients without an underlying history of CSU. [2, 4].

The final two groups are selective reactor reactions whereby clinical symptoms are caused by a single NSAID or single NSAIDs subclass, with tolerability of structurally different subclasses. [1] These reactions are immune mediated and not related to degree of COX-1 inhibition. [5].

4.

SNIUAA is characterized by an immediate hypersensitivity reaction, likely mediated by a specific IgE antibody. [1, 4] Patients may develop urticaria, angioedema, or anaphylaxis. [2].

5.

SNIDHR typically occurs 24–48 h after drug administration and involves cutaneous symptoms such as exanthems, fixed drug eruptions, or severe cutaneous adverse reactions. [2] Reactions are presumed mediated by specific T-cell responses. [1].

However, not all clinical reactions fit perfectly into the above traditional categories. Patients can also experience blended reactions, which are estimated to represent up to 28% of NSAIDs hypersensitivity reactions. [5] Symptoms range from isolated gastrointestinal involvement, to multisystemic reactions, to anaphylaxis. [5] These blended reactions have been further divided into 4 subclasses: [5].

I: development of cutaneous symptoms and rhinitis/asthma.

II: development of cutaneous symptoms and glottis edema.

III: development of cutaneous symptoms, rhinitis/asthma, and glottis edema.

IV: development of a combination of gastrointestinal symptoms with cutaneous symptoms, and/or rhinitis/asthma.

Patients who develop multisystemic involvement, including glottis edema and throat tightness, can be clinically indistinguishable from anaphylaxis. [5].

When assessing patients with possible NSAIDs hypersensitivity it is important to clarify and classify the type of reaction as this will have significant clinical and treatment implications. Available skin testing and laboratory testing have limited diagnostic or predictive value. [1, 4] DPTs remain the gold standard for evaluation and diagnosis, and can determine cross-reactivity and safe alternative medications. [1, 4] Acute reactions during challenges are managed similarly to other hypersensitivity reactions including discontinuation of the inciting medication, administration of epinephrine in cases of anaphylaxis, and consideration of supportive therapies including H1-antihistamines or steroids. [4] NERD reactions are typically treated with bronchodilators or leukotriene receptor antagonists. [4].

In the US, ibuprofen and naproxen are the most common NSAIDs associated with SNIUAA. [4] DPT to ASA may be considered as a first step as successful oral challenge to ASA confirms tolerance of structurally unrelated NSAIDs without requiring repeat exposure to the inciting medication. [4] Patients with SNIDHR should also continue to avoid the culprit agent but will tolerate other NSAIDs. [4] For cross-reactive reactions including NERD, NECD, and NIUA, patients should avoid both the triggering as well as cross-reacting COX-1 inhibitors. [2] NSAIDs avoidance remains the mainstay of treatment. [4] Several DPTs may be required to establish the diagnosis and to determine cross-reactivity and safe medication alternatives in order to expand patients’ available therapeutic options. [4].

Alternative therapies for treatment of fever, inflammation, and pain should be identified. [1] Weak COX-1 inhibitors, acetaminophen, and COX-2 inhibitors can be considered. (Table 2). However, weak COX-1 inhibitors may induce symptoms in up to 25% of patients with NIUA, especially when higher doses are used. [2, 8, 9] Cyclooxygenase 2 (COX-2) inhibitors such as celecoxib are typically well tolerated. [4, 10] Formal DPTs to these alternative medications can be considered prior to prescription particularly in patients with a history of severe reaction. [2, 4] In the case of our patient she passed DPTs to treatment doses of acetaminophen and celecoxib.

Table 2 Classification of NSAIDs by degree of COX inhibition [11, 13]

The prevalence of ASA hypersensitivity has been estimated to be 0.5–1.9%.11 Although rare, anaphylactic type reactions to ASA have also been reported. [3] This adds additional clinical complications in treating patients with cardiovascular or cerebrovascular disease where no suitable alternative agent can be used. [3, 12] Fortunately, ASA desensitization can be performed. [12].