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\begin{document}

\title{Aspirin induced urticaria in a recently diagnosed ischemic stroke
patient: A case report and literature review.}



\author[1]{abhinav dahal}%
\author[2]{sushant gautam}%
\author[3]{aliza shakya}%
\author[3]{ashmita pant}%
\author[4]{kriti bhandari}%
\author[5]{Abhigan  Shrestha}%
\affil[1]{Sukraraj Tropical and Infectious Disease Hospital}%
\affil[2]{Nepalgunj Medical College}%
\affil[3]{Manipal College of Medical Sciences}%
\affil[4]{Nepal Medical College}%
\affil[5]{M Abdur Rahim Medical Medical College Hospital}%


\vspace{-1em}



  
  \date{May 21, 2024}


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\textbf{Aspirin induced urticaria in a recently diagnosed ischemic
stroke patient: A case report and literature review.} Abhinav Dahal :
Sukraraj Tropical and Infectious Disease Hospital, Teku, Kathmandu,
Nepal Email: abhinav.dahal333@gmail.com

Sushant gautam: Nepalgunj medical college, banke,Nepal

email: gautamsushant1941@outlook.com

Aliza Shakya : Manipal college of medical sciences, Pokhara, Nepal

email: shakyaaliza@gmail.com

Ashmita pant: Manipal college of medical sciences, Pokhara, Nepal

email: ashmita.pant@gmail.com

Kriti Bhandari , Nepal Medical College, Jorpati, Kathmandu, Nepal
itirkbhandari977@gmail.com

Abhigan Babu Shrestha, M Abdur Rahim Medical College, Dinajpur,
Bangladesh. Abigan17@gmail.com

Corresponding author:

ABS; M Abdur Rahim Medical College, Dinajpur, Bangladesh.
Abigan17@gmail.com

Abstract: Aspirin and urticaria correlation has not been fully
understood. The pharmacological inference is suspected to be the
diversion of arachidonic acid metabolism. Aspirin sensitivity can
aggravate pre-existing chronic urticaria and in some instances causes
acute urticaria. We report a case of a 53-year old male, recently
diagnosed with stroke, who presented with complaints of multiple rash
over trunk and upper extremity with aspirin. NSAIDs induced urticarial
are usually neglected by physicians during diagnosis. Keywords: Aspirin,
urticarial, stroke, hemiplegia\textbf{Introduction:} Aspirin is a drug
which is widely used to reduce the risk of stroke, transient ischemic
attack, and cardiovascular events. This is due to its antithrombotic
properties by irreversibly inhibiting the cyclooxygenase enzyme,
reducing the synthesis of Thromboxane A2 and thus subsequently reducing
platelet aggregation {[}1-- 3{]}. Aspirin and NSAIDs' pharmacological
properties also result in adverse reactions like GI upset, renal
toxicity, and hemorrhagic complications, as well as potentiate
hypersensitivity reactions {[}4{]}. Aspirin Hypersensitivity is reported
by 0.9 to 1.5\% of the general population {[}5{]}. Hypersensitivity
reactions to NSAIDs are classified on the basis of 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{[}6{]}. In this report, we document a case of
aspirin induced urticaria in a patient with a recent history of
Ischaemic stroke and Hypertension.\textbf{Case Description:} A 53 years
old male presented to the emergency department with a chief complaint of
multiple rashes with burning and itching sensation over trunk and
extremities. Figure 1 and 2. The patient was a known case of
hypertension with recent diagnosis of left sided ischemic stroke with
right sided hemiparesis 7 days back for which he was admitted for 3
days. There were no significant reactions to the treatment noticed
during the hospital stay. He was discharged with a daily dose of aspirin
75 mg o.d., enalapril 10 mg o.d., atorvastatin 20 mg o.d., omeprazole 20
mg b.d. He was advised for proper bed rest with two hourly posture
changes \& physiotherapy. He was solely on prescribed medications for
the past 4 days. On the next day, he was admitted following the
appearance of cutaneous manifestations with no other associated symptoms
such as angioedema or shortness of breath. He had no prior history of
allergic reactions. On further enquiry, he denied any changes to diet or
environmental stimuli including no exposure to any pets or animals. He
also gave a negative history of family members having such allergic
manifestations. On examination, multiple, pruritic, erythematous,
blanching macules were present on bilateral upper extremities and
trunk(Figure 1). His vital signs were within normal limits. Leukocytosis
(wbc:12,000 cells/mm3) with higher eosinophil count ( 550 per ml of
blood) was noted while other complete blood count and comprehensive
metabolic panels were unremarkable. Medical history revealed he was
taking enalapril 10 mg o.d. for the past 3 years for hypertension. As
ACE inhibitors are commonly responsible for causing the side effects
such as allergies, drug rash \& even angioedema, it was replaced with
amlodipine 5 mg o.d. He was started on histacin 4 mg b.d for symptomatic
management. However, there was no significant improvement in his
condition. Therefore, we decided to stop the current medication one at a
time to identify the culprit drug. Aspirin was replaced with clopidogrel
75 mg o.d. \& given daily. He was kept under observation \& followed up
the next day with improvement. Patient told that his itching and the
degree of rash spread throught his body were diminished. Three days
later, the rashes almost fully subsided \& he was advised to continue
histacin for 1 more week without stopping clopidogrel intake. Aspirin
was identified as the sole cause for the rashes. He was discharged
following complete recovery of cutaneous symptoms after 3 days with
proper counselling regarding his condition and precaution to be taken
for future aspirin use.\textbf{Discussion:} Aspirin and other NSAID are
known to cause hypersensitivity reactions. One of the manifestation of
such reactions is urticaria. The prevalence of aspirin induced urticaria
is estimated to be around 0.3\% excluding individuals with recurrent
urticaria, hay fever and chronic chest disease {[}7{]}. Aspirin induced
Urticaria(AIU) can be classified into two types as aspirin intolerant
acute urticaria(AIAU) and aspirin intolerant chronic urticaria(AICU).
The symptoms develop within minutes to 24 hour in AIAU and lasts for
less than 6 weeks whereas, in AICU symptoms typically last for more than
6 weeks.{[}8{]} Elevated IgE levels and atopy are suggested as a common
predisposingfactors for AIU according to a genetic study done in Korean
population{[}8{]}. In addition, HLA-DRB1 * 1302 - DQB1*0609 also has
been identified as a genetic marker{[}9{]}. Besides this, various
genetic studies have reported that high affinity IgE receptor{[}10{]} ,
histamine \emph{N}-methyltransferase{[}11{]} and adenosine A3
receptor{[}12{]} are other genetic determinants for AIU. These findings
allude that, causes leading to the release of inflammatory mediators
either by increased histamine release, faulty histamine degradation or
augmented mast cell signalling, contributes to the manifestation of AIU.
NSAIDs and Aspirin are known to be one of the common drugs causing
hypersensitivity drug reactions.(13) Drug Hypersensitivity Reactions
constitute about one third of all adverse drug reactions and affects
10-20\% of hospitalized patients and 7\% of outpatients.{[}14{]}
Depending on the type of hypersensitivity reaction, patient can develop
an array of cutaneous manifestations ranging from urticaria/ angioedema,
fixed drug eruption, maculopapular exanthem to more severe
manifestations such as DRESS or SJS/TEN.{[}15{]} We have previously
encountered a case of Stevens Johnson Syndrome, Type III
Hypersensitivity Reaction due to an antibiotic namely Cefixime.{[}16{]}
In this case, we have encountered a case of Single NSAID Induced
Urticaria/ Angioedema or Anaphylaxis, a Type I Hypersensitivity
Reaction. Figure 3.

To date, there are only few case reports published in pubmed
highlighting the association of aspirin with urticaria. This may be due
to the fact that aspirin sensitivity is often neglected because of the
cross reaction with NSAIDs. One case report has documented urticaria in
three patients caused by aspirin where pharmaceutical excipients present
in the formulation of drug was found to be the sole cause for the
hypersensitivity reaction in two of those patients.{[}17{]}However,
acute urticaria is not uncommon and when patients present with an
urticarial reaction clinicians do not consider NSAIDs as the cause, as
the reaction occurs in context of different triggers and is thus
difficult to establish.

Beyond drug induced urticaria, differential diagnosis of acute urticaria
includes urticaria attributed to infections, foodstuffs, contact
dermatitis, solar urticaria, cholinergic urticaria, arthropod bite
reactions, autoimmune disorders, small vessel vasculitis. Diagnostic
workup for many of these etiologies rely on laboratory parameters and
histological evidence in addition to history. Initial laboratory
investigations revealed lekocytosis with a predominance of eosinophils.
However, access to further testing was limited due to patient's refusal
and unfortunately no blood investigations or skin biopsy was taken at
presentation. Management of NSAID induced urticaria includes strict
culprit NSAID avoidance along with symptomatic management of acute
urticaria.{[}18{]} Antihistamines are the first line treatment for
management of acute urticaria. In severe cases, corticosteroids can be
added to control symptoms.{[}19,20{]} Some types of NSAID
hypersensitivity are known to exhibit cross reactivity thus strict NSAID
avoidance should be done until potential of cross-intolerance is ruled
out. If patient has history suggesting selective NSAID induced
urticaria, challenge to chemically unrelated strong COX-1 inhibitor may
be done to rule out crossreactivity type hypersensitivity.{[}21{]} Once
diagnosis of SNIUAA is established, use of drug allergy passport and
patient education help both the medical provider and the patient know
about the NSAID hypersensitivity status, avoidance of the culprit NSAID
as well as use of chemically unrelated NSAIDs as safe alternatives. In
this entity, alternative drug to aspirin must be sought.{[}18,21{]}
Therefore our clinical reasoning is composed from detailed patient's
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, recent contact with common irritants or insect bite. The patient
had been taking Aspirin, Enalapril and Atorvastatin following the
diagnosis of Ischemic Stroke with Right Sided Hemiparesis. The urticaria
and pruritus should not be caused by Enalapril, since the patient was
tolerating the medication well for the past 3 years and the patient's
symptoms worsened even after withdrawing of the drug. The temporal
correlation between the appearance of urticarial rash and aspirin
intake, and the resolution of urticarial rash and pruritus following
aspirin discontinuation suggests the possibility of Aspirin Induced
Urticaria. The causality assessment of the adverse drug reaction (ADR)
was carried out using the Naranjo Scale, a method for estimating the
probability of adverse drug reactions. The assessment revealed the ADR
to be `Probable'(+6) to be associated with Aspirin.{[}22{]}The patient's
history notably lacked presence of 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.

\textbf{Conclusion}

In conclusion, our case highlights the importance of considering aspirin
hypersensitivity as a potential cause of cutaneous symptoms in patients
with underlying medical conditions particularly stroke. Although aspirin
is generally well-tolerated, it can cause adverse reactions such as
urticaria. Clinicians should be aware of this possibility and
appropriately diagnose, manage, and counsel patients to prevent future
adverse reactions. The treatment for aspirin-induced urticaria involves
discontinuing aspirin and prescribing alternative medications such as
clopidogrel, along with countermedications like corticosteroids,
antihistamines and immunomodulators in severe cases.

Declaration of patient consent

Written informed consent was obtained from the patient for publication
of this case report and

accompanying images. A copy of the written consent is available for
review by

the Editor-in-Chief of this journal on request.

Sources of funding

None

Ethical approval

N/A

Conflicts of Interest

There are no conflicts of interest.

Provenance and peer review

Not commissioned, externally

peer-reviewed

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\textbf{Figure legend:}

Figure 1. Multiple pruritic erythematous macules over lower part of
trunk Figure 2. Multiple pruritic erythematous macules over upper limb.

Figure 3. Mechanism of inflammation caused by aspirin (NSAIDs).

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