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"Medical Journeys" is a set of clinical resources reviewed by doctors, meant for physicians and other healthcare professionals as well as the patients they serve. Each episode of this journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

This installment: A noteworthy case study.

What caused a 53-year-old man with hypertension who had recently been treated for a stroke to suddenly develop burning, itchy rashes all over his truck, arms, and legs? That's what Abhigan Babu Shrestha, MBBSc, of M Abdur Rahim Medical College in Dinajpur, Bangladesh, and colleagues had to determine when the patient presented to the emergency department less than a week after being discharged from a 3-day hospital stay.

As the team explained in , the earlier hospital admission had occurred when the patient had weakness and loss of function on his right side. At that time, he was diagnosed with left-sided ischemic stroke with right-sided hemiparesis.

He had no significant reactions to treatment during his initial hospital stay. He was discharged on day 4 with a prescription for aspirin 75 mg o.d. daily, enalapril 10 mg o.d., atorvastatin 20 mg o.d., and omeprazole 20 mg b.d. He was advised to get proper bed rest with two hourly posture changes, and was referred for physiotherapy.

When the patient presented with skin rashes on day 5, he told clinicians that he had taken nothing other than his prescribed medications for the past 4 days. The following day, however, he was readmitted after the rashes appeared; he had no other associated symptoms such as dyspnea or angioedema.

His prior history did not include any allergic reactions. He said he had no changes to his diet or surroundings, and had not been exposed to any pets or animals. There was also no family history of any allergic manifestations.

Physical examination revealed multiple itchy, inflamed, red areas of skin with blanching macules on the chest and back and both arms; vital signs were within normal limits.

Results of blood tests and comprehensive metabolic panels were unremarkable except for an elevated white blood cell count of 12,000 cells/mm³, indicating leukocytosis, and a higher eosinophil count (550/mL of blood).

The patient's medical records showed he had been on enalapril 10 mg o.d. for the past 3 years to manage high blood pressure. In light of the well-known side effects of angiotensin-converting enzyme inhibitors, including allergies, drug rash, and in some cases, angioedema, the medical team switched the patient to amlodipine 5 mg o.d. and prescribed histacin 4 mg b.d to help manage the symptoms.

Because there was still no improvement, the decision was made to discontinue the current medications one at a time to identify the "culprit drug."

The team replaced aspirin with clopidogrel 75 mg o.d. By the following day, the patient reported that his rash was less itchy, and the area of affected skin was becoming smaller. Three days later, the rashes were almost fully resolved. Clinicians advised the patient to continue taking histacin for one more week, without discontinuing clopidogrel treatment.

Shrestha and co-authors concluded that the sole cause of the rashes was aspirin. Three days after the rash and pruritus had completely disappeared, the patient was advised about his condition and future precautions around aspirin use, and discharged.

Discussion

Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to reduce the risk of stroke, transient ischemic attacks, and cardiovascular events. However, these drugs are also associated with various hypersensitivity reactions, including urticaria.

Hypersensitivity to aspirin affects approximately 0.9% to 1.5% of the general population, the case authors noted: "Hypersensitivity reactions to NSAIDs are classified based on their involvement of the skin, like urticaria or angioedema, the airways or other organs, their acute or delayed onset, the presence of underlying diseases, and their cross reactivity."

The link between aspirin and urticaria is not fully understood. "The pharmacological inference is suspected to be the diversion of arachidonic acid metabolism. Aspirin sensitivity can aggravate preexisting chronic urticaria and in some instances causes acute urticaria," Shrestha and co-authors said.

urticaria affects about 0.3% of healthy adults. Depending on the onset of symptoms, the condition is classified as acute or chronic. Symptoms of the acute form develop within minutes to 24 hours and last for less than 6 weeks, whereas symptoms of chronic type generally persist for more than 6 weeks.

Genetic Factors

A genetic study that looked at clinical characteristics predisposing to acute versus chronic aspirin-induced urticaria in the Korean population identified elevated immunoglobulin (Ig) E levels and atopy as common predisposing factors for aspirin-induced urticaria and implicated a genetic marker: HLA-DRB1*1302-DQB1*0609.

Other genetic studies have identified additional genetic markers including high-affinity IgE receptors, histamine N-methyltransferase, and adenosine A3 receptors. There is a suggestion, therefore, that the release of inflammatory mediators either by increased histamine release, faulty histamine degradation, or augmented mast cell signaling, could contribute to the development of aspirin-induced urticaria, Shrestha and co-authors said.

In general, NSAIDs and aspirin are known to be associated with hypersensitivity drug . These account for about one-third of all adverse drug reactions, affecting about 10-20% of hospitalized patients and 7% of outpatients.

Skin vary depending on the type of hypersensitivity reaction, which can range from urticaria/angioedema, fixed drug eruption, and maculopapular exanthem to more serious problems such as drug reaction with eosinophilia and systemic symptom (DRESS) or Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). The team cited a previous of SJS, a Type III hypersensitivity reaction due to the antibiotic cefixime.

To date, the literature has few case reports about an aspirin-urticaria association, perhaps because of the confounding effect of cross-reaction with NSAIDs, Shrestha and co-authors noted. They did, however, cite of urticaria in three patients caused by aspirin where "pharmaceutical excipients" present in the formulation of the drug were found to be the sole cause for the hypersensitivity reaction in two of the patients.

However, as Shrestha and co-authors noted, acute urticaria is relatively common, such that clinicians do not consider NSAIDs as the cause of an urticarial reaction, since the reaction occurs in the context of different triggers and is thus difficult to establish.

Other potential causes of acute drug-induced urticaria to consider, the team said, include the following:

• Urticaria attributed to infections

• Foodstuffs

• Contact dermatitis

• Solar urticaria

• Cholinergic urticaria

• Arthropod bite reactions

• Autoimmune disorders

• Small vessel vasculitis

In addition, beyond patient history, the diagnostic workup for many of these etiologies requires laboratory parameters and histology findings, the authors emphasized.

Initial lab tests in their patient showed leukocytosis marked by elevated eosinophils. Unfortunately, though, the patient declined further testing when he presented for care, so no blood investigations or skin biopsy were obtained.

NSAID-induced urticaria is managed with strict avoidance of the culprit NSAID and symptomatic management of acute urticaria. Antihistamines are the first-line treatment for management of acute urticaria, with added corticosteroids for severe symptoms, Shrestha and co-authors noted.

Because some types of NSAID hypersensitivity exhibit cross-reactivity, NSAIDs should be avoided until the potential of cross-intolerance is ruled out. When the patient history raises suspicion of selective NSAID-induced urticaria, clinicians can challenge with a chemically unrelated strong COX-1 inhibitor to rule out cross-reactive hypersensitivity.

Once a diagnosis of single NSAID-induced urticaria/angioedema or anaphylaxis is established, a drug allergy passport and patient education can be used to inform care providers and the patient of the NSAID hypersensitivity status, the case authors said.

This informs both avoidance of the culprit and the safe use of chemically unrelated NSAIDs. The patient in the case report requires an alternative to aspirin, the team noted, highlighting the importance of a detailed patient history, physical examination, and clinical course.

"Our patient did not have any history of multisystem involvement, recent infection, past medical history of atopy, inducible urticaria due to heat, cold, or stress, or recent contact with common irritants or insect bites," the case authors wrote.

In the time since the diagnosis of ischemic stroke and hemiparesis, the patient had been taking aspirin, enalapril, and atorvastatin. Enalapril is unlikely to have triggered the skin symptoms, given his 3-year history of tolerating the drug and the fact that the itchy rash actually worsened after he stopped taking the drug.

That his urticaria developed when he started taking aspirin and resolved when it was discontinued suggests the possibility of aspirin-induced urticaria, Shrestha and co-authors said. When they assessed the causality of the adverse drug reaction (ADR) using the ,which estimates the probability of ADRs, the result was "probable" (+6) for an association with aspirin. Notably, the patient's history did not include chronic urticaria. "While the drug provocation test for cross intolerance was not done, the patient's history reveals previous tolerance to other NSAIDs like ibuprofen and paracetamol," the team said.

Conclusion

This case highlights the importance of considering aspirin hypersensitivity as a potential cause of cutaneous symptoms in patients with underlying medical conditions, particularly stroke, the authors stated. Appropriate diagnosis, management, and patient education can help prevent adverse reactions in the future. Aspirin-induced urticaria is managed by discontinuing aspirin and use of prescribed alternatives such as clopidogrel, along with over-the-counter medications such as corticosteroids, antihistamines, and in severe cases, immunomodulators.

Read previous installments in this series:

Part 1: Urticaria/Hives: The Search Continues for Causes

Part 2: Keys to Diagnosis of Urticaria

Part 3: Chronic Spontaneous Urticaria and Autoimmunity

Part 4: Case Study: Terrible Recurrent Itchy Wheals All Over This Woman's Body

Part 5: Managing Comorbidities in Chronic Urticaria

Part 6: What's New in the Treatment of Chronic Urticaria

Part 7: Special Considerations in Treating Urticaria in Pregnant or Lactating Patients