Recurrent cardiac arrests caused by Kounis syndrome without typical allergic symptoms

Abstract

Kounis syndrome is a rare disease in which coronary spasm or acute coronary syndrome is induced by type I allergy. Concurrence of allergic reaction and chest pain are important clues to establish diagnosis. We report a rare case of Kounis syndrome without obvious signs of allergy.

A 52-year-old woman experienced abdominal pain followed by ventricular fibrillation (VF) storm. Ten months earlier, the patient underwent subcutaneous implantable cardioverter-defibrillator implantation based on the previous diagnosis of idiopathic VF. In both episodes, the patient was given dental treatment and administered loxoprofen before VF onset. After we performed loxoprofen provocation test, electrocardiogram revealed ST-segment elevation in leads II, III, and aVF. Moreover, the patient developed VF again. An emergency coronary angiography after recovery showed no significant findings. However, myocardial scintigraphy presented a perfusion-metabolism mismatch in the inferior wall. Furthermore, laboratory test results after provocation revealed increased histamine level. Based on these findings, we diagnosed the patient with Kounis syndrome.

Kounis syndrome without typical allergic symptoms is challenging to diagnose. Therefore, suspecting the possibility of allergic reactions and detailed history taking are important, particularly when confronted with recurrent coronary spasm, acute coronary syndrome, and inexplicable cardiac arrest.

Learning objective

Kounis syndrome is a rare coronary disease with vasospasm or plaque rupture, induced by type I allergy. Since Kounis syndrome without typical allergic symptoms is challenging to diagnose, a high index of suspicion is necessary. Detailed history taking can provide important clues to establish diagnosis, particularly when confronted with recurrent coronary spasm, acute coronary syndrome, and inexplicable cardiac arrest.

Introduction

Kounis syndrome is a rare disease in which coronary spasm or acute coronary syndrome are induced by type I allergy. However, its etiology has not been fully clarified. Concurrence of allergic reaction, such as wheeze, urticaria, and chest pain are important clues for making diagnosis. Thus, Kounis syndrome without obvious allergic syndrome complicates diagnosis. We report a rare case of Kounis syndrome without obvious signs of allergy.

Case report

A 52-year-old woman experienced abdominal pain followed by ventricular fibrillation (VF) storm, after dental treatment at which she took some medications (such as lidocaine hydrochloride supplemented with epinephrine, cefteram pivoxil, and loxoprofen sodium hydrate). During transportation, subcutaneous implantable cardioverter defibrillator (S-ICD) therapy led to return of spontaneous circulation (ROSC) (Fig. 1a). Ten months earlier, the patient had developed VF after dental treatment and received the same medications. Electrocardiogram (ECG), echocardiography, and cardiovascular magnetic resonance imaging findings were normal. Moreover, coronary angiography (CAG) showed no coronary artery disease. The patient had no remarkable medical history, allergies, or a family history of sudden cardiac death. An S-ICD was implanted for secondary prevention based on a previous diagnosis of idiopathic VF in another hospital. After S-ICD implantation, the patient was free from arrhythmic events.

Fig. 1.

(a) Analysis of subcutaneous implantable cardioverter defibrillator (S-ICD) data. Analysis of S-ICD data shows that six consecutive shock deliveries cannot terminate ventricular fibrillation. However the final shock delivered provides termination. (b) Electrocardiogram on admission shows normal sinus rhythm, and ST-segment depression in leads V₃-V_6.

Vital signs in the emergency department were: heart rate, 100 beats per minute; blood pressure, 169/96 mmHg; respiratory rate, 20 breaths per minute; and oxygen saturation, 99 % (on room air). Physical examination indicated no remarkable findings, rales, or skin lesions. Laboratory test results showed increased troponin levels to 2.5512 ng/mL (Table 1). ECG revealed regular rate rhythm, along with normal axis and intervals. ST-segment depression was noted in leads V3-V6 (Fig. 1b), which was recovered immediately. Echocardiography revealed normal cardiac function.

Table 1.

Laboratory findings on admission.

Laboratory test	Patient's values	Reference ranges
White blood cell count	11.6	3.3–8.6 × 103/μL
Hemoglobin	13.3	11.6–14.8 g/dL
Sodium	137	138–145 mmol/L
Potassium	2.9	3.6–4.8 mmol/L
Chloride	101	101–108 mmol/L
Blood urea nitrogen	10.6	8–20 mg/dL
Creatinine	1.2	0.46–0.79 mg/dL
Total bilirubin	0.4	0.4–1.5 mg/dL
CK	108	41–153 U/L
CK-MB	4.2	≤5.0 U/L
Troponin-I	2.6	<0.0296 ng/mL
BNP	22	<18.4 pg/mL

CK, creatine kinase; CK-MB, creatine kinase-myocardial band; BNP, brain natriuretic peptide.

We suspected drug-induced arrhythmia including long QT, due to the close temporal association between drug treatment and VF onset. We at first performed a loxoprofen provocation test in the ward, paying sufficient attention to the patient's circulatory hemodynamics. Before starting the test, the patient had a blood pressure of 138/85 mmHg and heart rate of 78 beats per min. Additionally, ECG showed normal sinus rhythm. After initiating the test, we performed ECG and measured vital signs every 5 min. However, there were no remarkable findings, including ST segment changes or QT prolongation. After 30 min of loading, the patient suddenly reported chest and abdominal pain. In addition, the patient's blood pressure decreased to 71/53 mmHg. Moreover, ECG revealed ST-segment elevation in leads II, III, and aVF (Fig. 2a) without QT prolongation. Transthoracic echocardiogram revealed inferior wall akinesis. At that time, there were no generalized rashes. In spite of taking sublingual nitroglycerin, the patient developed another VF. Since VF persisted despite repeated defibrillation, we placed the patient on extracorporeal membrane oxygenation and achieved ROSC. After hemodynamic stabilization, we performed CAG that showed no coronary spasm or coronary artery disease (Fig. 2b). However, myocardial thallium-201 (201Tl) and iodine-123 beta-methyl 15-para-iodophenyl 3(R, S)-methylpentadecanoic acid (¹²³I-BMIPP) dual scintigraphy showed perfusion-metabolism mismatch in the inferior wall—this indicated the occurrence of an ischemic event (Fig. 2c). In addition, laboratory test results even 6 h after VF onset showed increased histamine levels to 1.72 ng/mL (normal range, ≤0.50 ng/mL, half-life, 20 min), suggesting the involvement of allergic reaction. Eventually, we diagnosed the patient with Kounis syndrome. After provocation tests, the patient's clinical course was uneventful. Therefore, the patient was discharged on day 21. At the time of discharge, the patient was prescribed isosorbide dinitrate and benidipine hydrochloride. After discharge, no recurrence occurred following loxoprofen avoidance.

Fig. 2.

(a) Electrocardiogram after 30 min of loading loxoprofen shows ST-segment elevation in lead II, III, and aV_F. (b) Emergent coronary angiography after loxoprofen test shows neither coronary spasm nor coronary artery disease. ST level recovers at time of imaging. (c) Myocardial 201Tl and ¹²³I-BMIPP dual scintigraphy show perfusion-metabolism mismatch in the inferior wall.

Discussion

Kounis syndrome is defined as the concurrence of acute coronary syndromes and coronary spasm with allergic reactions [1]. Due to its rarity, widespread awareness is limited. Although the pathogenesis appears to be coronary spasm caused by various inflammatory mediators through mast cells and basophil degranulation, its pathophysiology remains unclear.

Four variants of Kounis syndrome have been described [2]: Type I variant that includes coronary spasm induced by allergic reaction in normal or nearly normal coronary arteries. Type II variant includes acute coronary syndrome with plaque erosion or rupture caused by spasm, in pre-existing atheromatous disease. Type III variant comprises inside stent restenosis and obstruction caused by allergic reaction. Type IV variant includes a coronary artery bypass graft thrombosis. In general, Type I is considered the most common. Renda et al. also reported that type I accounted for about 70 % of total cases [3]. Nevertheless, we have not reached a consensus in terms of that classification yet.

The main clinical symptoms and signs of Kounis syndrome are allergic reactions that could be subclinical, clinical, acute, or chronic, accompanied by cardiac symptoms [4]. Therefore, the concurrence of allergic reaction and chest pain are important clues for making diagnosis. On the other hand, similar to this case, a few studies have reported Kounis syndrome without typical and obvious allergic syndromes, such as urticaria and wheeze. In a Turkish study, 76.2 % patients had Kounis syndrome with urticaria [5]. Kounis syndrome without rash is uncommon and complicates accurate diagnosis. Therefore, there are some potentially undiagnosed and overlooked cases. In the present case, in which no obvious allergic symptoms were observed, when we identified drug-induced VF, we determined that it was important to consider Kounis syndrome, in addition to drug-induced QT prolongation, as a differential diagnosis. In such atypical allergic cases of challenging diagnosis, detailed history taking provides us with important clues for suspecting allergic reactions. Although provocation tests of suspected allergens strongly support diagnosis, they are dangerous to routinely perform. However, in this present case, identifying the causative allergens by the provocation test could lead to preventing recurrence and yield a better prognosis. Therefore, provocation tests could be an option, considering the risks and benefits.

Previous studies have revealed that type I allergy could induce Kounis syndrome. However, the exact pathogenesis remains unclear. Among the many mediators, histamine plays a key role in pathogenesis. Histamine acts through four different receptors, all of which modulate allergic reactions in different ways. In particular, the H1-histamine receptor has dual effects on the coronary artery [6], [7]: vasodilation by the release of nitric oxide from the endothelium and vasoconstriction by smooth muscle stimulation. Histamine-induced coronary spasm occurs when vasodilation is impaired or when vasoconstriction is in a hyperactive state mediated via the H1 receptor, respectively: vasoconstriction cancels out vasodilation. Moreover, endothelium-dependent vasodilation of the H1 receptor appears to be impaired in coronary arteries with endothelial dysfunction [8]. Hence, histamine acts as a vasodilator in normal and nearly normal coronary arteries [9], whereas vasoconstriction occurs excessively in patients with impaired endothelium. Furthermore, histamine action via the H1 receptor is concentration dependent [7]. Vasodilation occurs when a low dose of histamine stimulates the H1 receptor, whereas under stimulation of a high dose of histamine, vasoconstriction predominates. These findings raise the possibility that patients with damaged coronary arteries and allergic diathesis, which leads to high levels of histamine release, have a potential risk of developing Kounis syndrome.

In this case, 6 h after loxoprofen provocation test, the patient's histamine level was still high. Thus, we estimated that her coronary arteries were exposed to high levels of histamine during VF, considering the half-life of histamine (about 20 min). This finding implied that the allergic reaction might have influenced disease onset. Hence, loxoprofen triggered a high level of histamine through an allergic reaction, which might have led to Kounis syndrome via the induction of coronary spasm.

Kounis syndrome without typical allergic symptoms is rare and challenging to diagnose. Hence, when confronted with recurrent coronary spasm, acute coronary syndrome, and inexplicable cardiac arrest, it is important to suspect the possibility of allergic reactions and perform detailed history taking.

Declaration of competing interest

None declared.