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\begin{document}

\title{Ondansetron-induced pseudoallergy with non-ischemic myocardial injury: A
rare case report of Kounis Syndrome}



\author[1]{Eden Firew}%
\author[2]{Helen  Huang}%
\author[3]{Ayush Anand}%
\author[4]{Yonathan Asfaw}%
\author[5]{Charmy Parikh}%
\author[6]{Humza  Khan}%
\affil[1]{American Medical Center}%
\affil[2]{Royal College of Surgeons in Ireland Faculty of Medicine and Health Sciences}%
\affil[3]{BP Koirala Institute of Health Sciences}%
\affil[4]{Addis Hiwot Hospital}%
\affil[5]{Pramukhswami Medical College}%
\affil[6]{Bahawal Victoria Hospital}%


\vspace{-1em}



  
  \date{June 18, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Ondansetron is an FDA-approved selective serotonin 5-HT3 receptor
commonly indicated as an anti-emetic agent for nausea and vomiting. It
is rare to observe fatal reactions from ondansetron despite having no
allergies or previous exposure. We report a case of anaphylactoid
reaction with spontaneous coronary vasospasms in response to intravenous
ondansetron.%
\end{abstract}%



\sloppy


\textbf{Ondansetron-induced pseudoallergy with non-ischemic myocardial
injury: A rare case report of Kounis Syndrome}

\textbf{Authors} :

Eden Firew (EF)*

American Medical Center, Addis Ababa, Ethiopia Email id:
edenfirew24@gmail.com ORCID:

Helen Huang (HH)

University of Medicine and Health Sciences, Royal College of Surgeons in
Ireland, Dublin, Ireland Email id: HelenHuang@rcsi.ie ORCID:
https://orcid.org/0000-0002-2809-0154

Ayush Anand (AA)

B. P. Koirala Institute of Health Sciences, Dharan, Nepal Email id:
ayushanandjha@gmail.com
ORCID:\emph{https://orcid.org/0000-0003-0279-4636}

Yonathan Aliye Asfaw (YAA)

Internal medicine, Addis Hiwot Hospital, Addis Ababa, Ethiopia Email id:
dreaminglatee@gmail.com ORCID: https://orcid.org/0000-0002-1541-2257

Charmy Parikh (CP)

Pramukh Swami Medical College, Gujarat, India Email id:
charmyparikhd14@gmail.com

Humza Rafique Khan (HRK)

Bahawal Victoria Hospital, Bahawalpur, Pakistan Email id:
Hrk151@outlook.com

*\textbf{Corresponding Author}

\textbf{Abstract}

Ondansetron is an FDA-approved selective serotonin 5-HT3 receptor
commonly indicated as an anti-emetic agent for nausea and vomiting. It
is rare to observe fatal reactions from ondansetron despite having no
allergies or previous exposure. We report a case of anaphylactoid
reaction with spontaneous coronary vasospasms in response to intravenous
ondansetron.

\textbf{Key Clinical Message}

Ondansetron is one of the most widely used antiemetic with a minimal
side effect profile. It is rare to observe Kounis syndrome (KS) is
multi-factorial in pathology and should be approached with a high index
of clinical suspicion.

\textbf{Introduction}

Ondansetron is an FDA-approved selective serotonin 5-hydroxytryptamine3
(5-HT3) receptor antagonist with several therapeutic applications and is
commonly indicated as an anti-emetic agent for patients with severe
nausea and vomiting\textsuperscript{(1)}. Ondansetron has multiple
mechanisms of actions by blocking serotonin on central sites and
peripheral sites. Central antagonism targets the chemoreceptor trigger
zone located on the fourth ventricle floor, while peripheral action
affects the vagus nerve\textsuperscript{(2,3)}. As a result, the trigger
zone and the vagus nerve play a crucial role in the regulation of
serotonin and are responsible for triggering nausea and emesis
originating from the stomach\textsuperscript{(4,5)}. Typically,
ondansetron is indicated in patients with a history of chemotherapy,
radiotherapy, drug poisoning, antidepressant therapies, head trauma, or
gastrointestinal motility disorders that lead to symptoms of
emesis\textsuperscript{(6)}. A meta-analysis by Piechotta et al.
revealed that ondansetron alone or in combination with other antiemetic
agents effectively controlled the vomiting due to chemotherapy in
adults\textsuperscript{(6)}. However, recent studies have also shown the
efficacy of ondansetron in reducing the number of vomiting episodes in
pediatric patients with acute gastroenteritis\textsuperscript{(7, 8)}.

The majority of 5-HT3 receptor antagonists have been associated with
electrocardiogram changes that are insidious and asymptomatic in
onset\textsuperscript{(9)}. Common side effects of ondansetron include
headaches, dizziness, and diarrhea or
constipation\textsuperscript{(10)}. However, it is a rare entity to
observe potentially fatal reactions such as coronary vasospasms and
hypersensitivity skin reactions from ondansetron despite having no
allergies to the drug. In this paper, we present a rare case of an
anaphylactoid reaction with spontaneous coronary vasospasms in response
to intravenous ondansetron.

\textbf{Case Report}

A 45-year-old man presented to the emergency department with four
episodes of vomiting of ingested food. It is non bilious, non-projectile
and does not contain blood. He has periumbilical non-radiating abdominal
pain with gradual onset of 3 days duration. He was previously diagnosed
with mild duodenitis via endoscopy, for which he had initiated treatment
with oral Esomeprazole 40mg per day for a month. The patient's medical
history was otherwise not noteworthy. His family history was
noncontributory. He occasionally drinks 2 units of alcohol but has no
history of drug use or smoking.

On admission, he had a body temperature 36.4 \selectlanguage{ngerman}°C, a blood pressure of
120/80 mmHg, a respiratory rate of 16 breaths/min, a heart rate of72
beats/min, and an oxygen saturation of 95\% of room air. On physical
examination, we noticed the patient had dry mucosa and mild epigastric
tenderness. His cardiovascular and respiratory examinations were normal.
Results of his abdominal examination was normal and he had no
lower-extremity edema. A summary of his laboratory investigations are
reported in Table 1. A baseline ECG was obtained, which showed a normal
sinus rhythm with non-ischemic changes. His cardiac troponin T levels
was initially 2.8ng/dL.\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
Investigations & Report & Reference Values*\tabularnewline
White Blood Cell Count/milimeter\selectlanguage{ngerman}³ & 7040 & 4,000-10,000\tabularnewline
Hemoglobin (grams/deciliter) & 15.8 & 14-17\tabularnewline
Hematocrit (\%) & 47.4 & 41-51\tabularnewline
Platelet Count/milimeter\selectlanguage{ngerman}³ & 196,000 & 150,000-350,000\tabularnewline
Serum Sodium(millimoles/Liter) & 140 & 136-145\tabularnewline
Serum Potassium (millimoles/Liter) & 4.2 & 3.5-5.0\tabularnewline
Serum Calcium (milligrams/deciliter) & 10.2 & 9-10.5\tabularnewline
Aspartate Aminotransferase (units/Liter) & 28 & 0-35\tabularnewline
Alanine Aminotransferase (units/Liter) & 65 & 0-35\tabularnewline
Serum Creatinine (milligrams/deciliter) & 0.9 & 0.7-1.3\tabularnewline
Serum Urea (milligrams/deciliter) & 22 & 8-20\tabularnewline
Cardiac troponin T (nanogram/deciliter) & 2.8 & 0-0.10\tabularnewline
\bottomrule
\end{longtable}

Table 1: A summary of laboratory values obtained from the patient in
comparison to the normal values reported by the American College of
Physicians\textsuperscript{(11)}

\textbf{Figure 1: Normal ECG with no ischemic changes}

He was diagnosed with acute exacerbation of dyspepsia and treated with a
single 8mg dose of ondansetron intravenously. Within a few seconds after
taking around 0.5ml (2mg) of ondansetron, the patient developed chest
tightness, redness and burning sensation around the injection site along
with urticaria, hypotension and bronchospasm. He was immediately treated
with hydrocortisone 100 mg intravenously, and the reaction resolved
within a few minutes. His vital signs were as follows: body temperature,
36.2\selectlanguage{ngerman}°C; blood pressure, 90/60 mmHg; respiratory rate,20 breaths/min;
heart rate, 94 beats/min; and oxygen saturation, 88\% on room air.

An ECG was obtained 15 minutes after administration of ondansetron which
showed no change from the baseline ECG. However, the patient's cardiac
troponin T levels had elevated to 812ng/L, a 42x increase from his
previous levels. The patient was followed-up 15 minute later following
the reaction, where he complained of severe headache, dizziness and
fatigue. It was noted that the other symptoms had subsided. He was given
once-off aspirin loading dose of 312 mg orally. A subsequent ECG and
cardiac troponin was repeated every 6 hours and showed normal ECG and
serial drop in troponin levels of 231ng/L,178ng/L,128ng/L and 78ng/L\}.
On follow-up, we inquired about his previous usage of ondansetron and
reported no history of drug or food allergies and no previous exposure
to ondansetron. Additionally, he does not have a history of surgery or
chemotherapy.

He was then referred to the cardiac center for complete cardiac
evaluation.~An echocardiogram demonstrated mild left ventricular
hypertrophy with normal ejection fraction with no ischemic changes. He
also underwent a cardiac stress test and had no chest pain or ECG
changes. There was no indication for cardiac catheterization and the
patient was discharged. It was concluded that the sudden cardiac event
was most likely ondansetron-induced coronary spasm that resolved
spontaneously. Based on the allergic reaction that ensued prior to these
presentations, Kounis syndrome was suspected as a probable cause.

\textbf{Discussion}

Ondansetron is considered as a first-line agent in the ED to manage
nausea and vomiting, with a relatively low risk of side effects compared
to other antiemetics\textsuperscript{(12, 13)}. Despite the high safety
profile of ondansetron, emerging literature on ondansetron toxicity has
reported hypersensitivity reactions leading to skin rashes and
urticaria\textsuperscript{(14)} . It is entirely possible that with a
combination of bronchospasms, hypotension, and urticaria-like rash at
the site of injection, this patient had an allergic reaction to
ondansetron prompting hydrocortisone administration. Allergic reactions
to drug administration can be classified into two categories:
Anaphylaxis (IgE-immune mediated) or Anaphylactoid reactions
(non-IgE-immune mediated)\textsuperscript{(15)}. Anaphylaxis is often
caused by a hypersensitivity reaction to drugs in hospital
settings\textsuperscript{(16)}. Pre-sensitized individuals exposed to an
allergen prompt an immunological response involving IgE antibodies
initially binding to mast cells and basophils, and later cross-linking
with other IgE antibodies to initiate the signal transduction cascade of
preformed mediators \textsuperscript{(17)}. On the other hand,
anaphylactoid reaction is independent of antigen-specific immune
responses and mimics symptoms of anaphylaxis. Also known as a pseudo
allergy, this phenomenon often occurs from the first dose of medication
and can attribute to around two-thirds of hypersensitivity
reactions\textsuperscript{(18)}. Typically, they are induced by opioid
(i.e. codeine), complement activation-related drugs, non-steroidal
anti-inflammatory drugs (i.e. aspirin), or traditional Chinese medicine
injections\textsuperscript{(19)}. However, pseudo allergies are well
underreported in the literature and can come with lethal complications
due to its unpredictability. Though IgE levels were not determined, the
absence of prior exposure to ondansetron nor any history of adverse
allergic reaction to drugs makes it likely that this patient experienced
an anaphylactoid reaction to ondansetron. Mehra et. al reported a
similar case of hypersensitivity to intravenous ondansetron which was
concluded to be an anaphylactoid reaction due to the absence of prior
administration in the patient's history\textsuperscript{(14)}.

Acute coronary syndrome was first reported in 1992 as an adverse effect
of ondansetron\textsuperscript{(20)}. Since then, there have been 9
documented cases of coronary vasospasms and dysrhythmia after
ondansetron administration to date\textsuperscript{(21)}. When the
occurrence of cardiac symptoms arise in the context of anaphylactoid
reactions to drugs, the condition can be coined as ``Kounis Syndrome
(KS)''. Despite KS being underreported, its pathophysiology is well
discerned and can be attributed by an immune response generated from an
anaphylactoid reaction, causing myocardial injury. Mast cell activation
caused by an allergic reaction to a drug can cause the release of
interrelated inflammatory cells such as T-lymphocytes through mast cell
activation\textsuperscript{(22)}. The heart is a target of these
chemical mediators during anaphylactoid reactions and can cause
localized effects on the myocardium, leading to acute myocardial injury
(non-ischaemic changes), ACS such as myocardial infarctions, and
vasoconstriction of coronary vasculature\textsuperscript{(22)}. The
investigations that would support KS include troponin levels, ECG, and
ECHO. The only other case study reporting KS after ondansetron
administration described a pregnant women experiencing a possible
allergic reaction to ondansetron, leading to acute coronary syndrome. In
the aforementioned case, a coronary angiography was indicated in to
confirm the hypothesis of a coronary vasospasm and an ECG exhibited
ST-segment elevations\textsuperscript{(23)}. In our study, though there
was an absence of ischaemic changes and non-abnormal ECG changes, there
were very high elevations of cardiac troponin levels. In a previously
reported clinical study, 31 patients with anaphylaxis and urticaria was
found with significantly increased cardiac troponin I levels compared to
healthy controls\textsuperscript{(24)}. This was further confirmed by
Cha et. al, where myocardial injury and elevated troponin levels was
observed in 300 anaphylaxis cases\textsuperscript{(25)}. Given the
patient's medical history, an angiography was not ordered since his
symptoms subsided after immediate administration of aspirin. On the
echocardiogram, left ventricular hypertrophy was noted, an occurrence
that has been reported once in a case series on KS by Forlani et.
al\textsuperscript{(26)}. Due to the variety of cardiac manifestations
and presentations, it can be difficult to interpret the exact
pathophysiology. However, it is reasonable to suggest that the
non-ischaemic nature of the patient's cardiac symptoms were attributed
by the acute nature of injury inflicted by anaphylactoid reactions,
causing a rise in troponin and leading to hypertrophy as compensation.
In accordance with the results of previous investigations, cardiac
troponin levels may serve as an important marker in patients with acute
allergic reactions\textsuperscript{(25)}.

To our best knowledge, this was one of the first cases of KS
characterized by non-ischaemic myocardial injury and elevated troponin
due to an anaphylactoid reaction to ondansetron. As a result, we bring
awareness to the multi-faceted nature of KS and the importance of taking
detailed history. If left untreated or misdiagnosed, the consequences
can be detrimental to the patient's health\textsuperscript{(22)}. A high
index of clinical suspicion must be exercised when a patient is
suspected to have a combination of allergic reactions and cardiac
symptoms. However, the timing of hypersensitivity symptoms superimposed
with non-ischaemic cardiac changes in our case made it difficult to
diagnose KS. Future studies are warranted to further study how
anaphylactoid reactions play a role in non-ischaemic changes as opposed
to ACS and whether the time of presentation is important in the
diagnosis. Moreover, further investigations should ascertain the
association of pseudo allergies or anaphylactoid reactions with an
increase in cardiac troponin levels. This case prompts a need to better
distinguish anaphylactoid reaction from anaphylaxis when administering
ondansetron and brings to light the multi-factorial presentation of
Kounis syndrome.

There were several limitations to the case report. We did not obtain an
angiogram, which would definitively diagnose a spontaneous coronary
vasospasm that ensued after ondansetron administration. However, the
results from the investigations raised our suspicions of spontaneous and
acute myocardial injury that could have been caused by vasospasms given
the lack of previous cardiovascular co-morbidities. Additionally, we did
not determine the IgE levels of the patient, which would have
strengthened our confidence that the patient has a pseudo allergy to
ondansetron.

\textbf{Conclusion}

Ondansetron, an anti-emetic with a relatively high safety profile, is
prescribed globally for the symptom of vomiting. This was one of the
first cases of KS characterized by non-ischaemic myocardial injury and
elevated troponin due to an anaphylactoid reaction to ondansetron. KS
have potential effects on biochemical parameters such as cardiac
troponin along with an anaphylactoid phenomenon after an intravenous
administration of the recommended dose. Thus, this case warrants more
research for establishing the pathophysiology of KS, the association of
cardiac troponin with anaphylactoid reactions, and ensure the judicial
use of ondansetron.

\textbf{Data Availability Statement}

This manuscript has all the data relevant to this case report included.

\textbf{Author Contribution}

EF, YAA performed data curation, original draft preparation, and
reviewed and edited the manuscript. HH, AA, YAA, CP, HRK performed
original draft preparation, and reviewed and edited the manuscript.~EF,
HH, AA~reviewed and edited the manuscript.

\textbf{Ethical Approval}

Ethical approval was not required.

\textbf{Consent}

Written informed consent was obtained from the patient to publish this
report in accordance with the journal's patient consent policy.

\textbf{Guarantor}

EF is the Guarantor.

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