a b s t r a c t

Background: Understanding the relationship between contrast agents and Kounis syndrome (KS) is mainly based on case reports. The purpose of this research is to explore the clinical characteristics of contrast media induced KS. Methods: We searched for contrast-induced KS case reports through Chinese and English databases from 1991 to October 31, 2021.

Results: A total of 26 patients (19 men and 7 women,) were included, with a median age of 60 years (range 30-83). The contrast agents that cause KS mainly included gadolinium-based contrast agent (7 cases), iodine- containing contrast media (12 cases). KS mainly occurred within 30 min after administration and mainly manifests as chest pain and Allergic reactions. Electrocardiogram (ECG) mainly showed ST elevation. Echocardi- ography mainly revealed normal. Coronary angiography showed normal, Coronary vasospasm, Stent thrombosis, occlusion and stenosis. After treatment with steroids, antihistamines and anti-ischemic therapy, 24 patients recovered completely and 2 patients died.

Conclusions: KS is a rare adverse reaction of contrast media. Radiologists should recognize this rare but Serious disease to ensure rapid diagnosis and proper management.

(C) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://

creativecommons.org/licenses/by-nc-nd/4.0/).

1. Methods

Kounis syndrome (KS) is an acute coronary syndrome caused by an allergic reaction, first described by Kounis and Zavras in 1991, and is also called “Allergic angina syndrome” or “allergic myocardial infarc- tion” [1]. A variety of reasons can induce KS, including various drugs, en- vironmental exposures and several conditions [2]. KS can occur at any age and is often missed in clinical diagnosis due to Atypical clinical manifestations [3].

Contrast media is a chemical product injected (or taken) into human tissues or organs to enhance the effect of image observation. Adverse re- actions of contrast agents can be divided into renal or non-renal. They can be acute (<1 h after contrast medium injection), late (>1 h to

<1 week after contrast medium injection), or very late (>1 week after contrast medium injection) [4]. KS is a rare adverse reaction of contrast media. However, the incidence and the clinical features of contrast- induced KS are still unclear. The purpose of this study is to explore the clinical characteristics of contrast-induced KS by collecting relevant case report.

* Corresponding author at: No. 138 Tong zipo Road, YueLu District, Changsha, Hunan 410013, China.

E-mail address: [email protected] (Z. Li).

• 1. Search strategy

We searched for contrast-induced KS case reports through Chinese and English databases from 1991 to October 31, 2021. Search using a combination of subject and free words, including Kounis syndrome, contrast media, Iodine contrast media, gadolinium contrast media, coronary artery spasm, angina, myocardial infarction, cardiac arrest, hypersensitivity.

• 1. Inclusion and exclusion criteria

Inclusion criteria: We collected case reports and case analyses of contrast-induced KS for inclusion as preliminary studies. Exclusion criteria: Reviews, repeated cases, animal studies, mechanism studies, and literatures lacking full texts were excluded.

• 1. Data extraction

Two researchers independently conducted a preliminary screening of the literature according to the inclusion and exclusion criteria, and then the group discussed the literature to be included in the analysis. Use a self-designed data extraction table to extract the following

https://doi.org/10.1016/j.ajem.2021.12.036

0735-6757/(C) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

information of the patient: nationality, gender, age, primary disease, co- morbid diseases, dose and type of contrast agent, route of administra- tion, time of onset, clinical manifestations, laboratory examinations, imaging examinations, treatment and prognosis, etc.

1. Results
   1. Basic information

A total of 26 patients were included, including 19 men and 7 women, with a median age of 60 years (range 30-83) (Table 1) [5-29]. These patients were mainly from Asia (12 cases), Europe (8 cases), the United States (4 cases), Chile (1 case), Australia (1 case). Twenty-one patients had medical history, including myocardial infarction (5 cases) [5,7,15,17,19], diabetes (5 cases), [8,9,12,18,27] and hypertension (9 cases) [7,9,11,16,18,22,24,26,27]. Two patients had a history of smoking [5,22]. In eight of these 26 cases, KS was associated with coronary arteriography (CAG).

Statistical contrast media include gadolinium-based contrast agent (7 cases), iodine-containing contrast media (12 cases), perflutren lipid microsphere (1 case) and sulphur hexafluoride (1 case), and other un- reported contrast agents (5 cases). Iodine-containing contrast agents in- clude iopromide (5 cases), iohexol (3 cases), iodixanol (2 cases) and iopamidol (1 case). Gadolinium -based contrast agent mainly include gadoterate meglumine (3 cases), gadobenate dimeglumine (2 cases), gadopentetate dimeglumine (1 case). The route of administration was mainly intraarterial injection (9 cases) and intravenous injection (17

cases). Five patients had ever used iodine contrast agent and all had al- lergic reactions [6,12,14,19,24], 1 patient received gadolinium-based contrast agent administration without any allergic reactions [29].

According to the current KS classification, 26 cases of contrast- induced KS were mainly divided into type I (8 cases), type II (11 cases), and type III (4 cases).

• 1. Clinical manifestations

The clinical manifestations of these patients mainly included chest pain (10 cases), sweating (8 cases), and dyspnea (4 cases); uncon- sciousness (9 cases), shock (2 cases), allergic reactions (18 cases), gas- trointestinal reactions (4 cases) Chest tightness and shortness of breath (6 cases) (Table 2). Allergic reactions mainly manifested as itching (5 cases), urticaria (7 cases), rash (6 cases), erythema (4 cases), flushing (4 cases). Hypotension appeared in 16 patients.

Twenty-five patients developed KS within 30 min, including imme-

diately after the infusion (7 cases), during the infusion (3 cases), within minutes (4 cases), within 10 min after the infusion (6 cases), 15-30 min (5 cases). One patient developed signs of anaphylaxis in an hour after using iodinated contrast media [11]. Sixteen patients experienced hypo- tension, and six patients experienced cardiac arrest [6,10,14,16,21,23].

• 1. Laboratory examination

The detection of myocardial injury markers was performed in 13 pa- tients, including normal (2 cases), elevated troponin I (8 cases),

Table 1

Basic information of 26 included patients.

Reference	Region	Sex/age	Medical history	Contrast agent	Dosage	Route of administration	Delay	Blood pressure (mmHg)	KS type
5	Greece	48/M	MI	iopromide	50 mL	intravenous	10 min	110/80	III
6 7	USA Chile	57/M 79/M	gout, depression, prostatic hyperplasia, allergic rhinitis hypertension, angina pectoris	gadobenate dimeglumine Iodixanol	nr nr	intravenous intraarterial	2 min Immediately	nr hypotension	nr II
8	Korea	54/M	DM, CAOD	nr	nr	intraarterial	10 min	40/30	II
9	Turkey	51/M	DM, hypertension	iopromide	30 mL	intraarterial	10 min	nr	II
10	Japan	62/M	pancreatic cancer	iohexol	100 mL	intravenous	During	72/nr	I
11	China	7 l/M	hypertension	iodinated contrast	400 U	intraarterial	infusion 1 h	50/40	I
12	Croatia	46/F	hypophyseal prolactinoma, DM	media gadoterate	15 mL	intravenous	10 min	120/80	II
				meglumine
13	Netherlands	83/F	hip replacement, TAVR	nr	nr	intravenous	During	50/20	I
14	Korea	74/M	no	iopromide	nr	intravenous	infusion Immediately	nr	I
15	Spain	72/F	MI	sulphur hexafluoride	5 mg	intravenous	Immediately	hypotension	III
16	France	81/M	HC, hypertension, arrhythmia	gadoterate	20 mL	intravenous	Several min	85/60	II
17	Australia	83/M	MI	meglumine iohexol	nr	intraarterial	Immediately	hypotension	II
18	Italy	47/M	hypertension, DM, hyperlipidemia	nr	nr	intraarterial	30 min	80/60	III
19	Japan	60/M	HC, MI	iopamidol	80 mL	intravenous	Immediately	70/nr	II
20	usa	53/F	Renal cell carcinoma	GBCA	nr	intravenous	Several min	nr	I
21	Taiwan	81/F	breast cancer	nr	nr	intravenous	15 min	nr	nr
22	China Poland	59/F	hypertension, hyperlipidemia	iopromide	nr	intraarterial	Within min	80/40	I
23	usa	76/M	no	perflutren lipid	nr	intravenous	Within min	hypotension	II
24	Kuwait	60/M	hypertension	microsphere nr	nr	intraarterial	20 min	nr	III
25	usa	30/M	no	gadobenate	nr	intravenous	Immediately	nr	I
26	Japan	78/M	hypertension	dimeglumine gadopentetate	5199.6 mg	intravenous	Immediately	72/48	II
27	China	59/M	hypertension, DM, AF	dimeglumine iodixanol	nr	intraarterial	During	70/40	II
28	China	78/M	no	iohexol	80 mL	intravenous	infusion 20 min	60/32	II
28	China	72/F	renal cell carcinoma	iopromide	80 mL	intravenous	20 min	60/38	nr
29	Italy	45/M	no	gadoterate meglumine	0.2 mL/kg	intravenous	2 min	no	I

Abbreviation: MI, myocardial infarction; TAVR, transfemoral transcatheter aorticvalve replacement; CAOD, coronary artery obstructive disease; DM, diabetes mellitus; AF, atrial fibrilla- tion; GBCA, Gadolinium-based contrast agent; HC, Hepatocellular carcinoma.

Table 2

Clinical manifestations, laboratory tests, treatment and prognosis of the 26 included patients.

Reference Clinical manifestations ECG Cardiac

Arrest

Revascularization Troponin

I(ng/ml)

Echocardiography Coronarography Treatment Outcome (hospital day)

• • 1. unwell, pale, weak,dizzy, sweating, retrosternal

discomfort, pain, numbness, itching

ST elevation no PTCA 11.39 nr CCA intrastent

stenosis

steroids, diphenyldramine, ranitidine, nitroglycerin

recovery

• • 1. shortness of breath, warm, erythematous with urticarial lesions, shock
    2. rash, papular erythema, chest pain

nr yes no nr normal nr steroids, epinephrine,

atropine

ST elevation no no nr nr cramps steroids,

chlorpheniramine, salbutamol, verapamil, CCB, nitrates, aspirin, statins, loratadine

recovery (35d)

Recovery (3d)

• • 1. flushing, shortness of breath, chest pain, dyspnea, diaphoresis, facial swelling, pruritic rash

ST elevation no PTCA 0.04^a normal subtotal

occlusion of proximal LAD

steroids, chlorpheniramine, cimetidine, morphine, heparin

recovery (4d)

• • 1. chest pain, urticaria, itching, chilling

AMI no no nr nr mid-LAD occlusion

steroids, antihistaminic recovery

(5d)

• • 1. nausea, unconsciousness, chest pain
    2. hyperspasmia, unconsciousness, flushes, sweating, urticaria

ST elevation yes no normal hyperkinetic no steroids, adrenalin,

dopamine

ST elevation no no nr nr nr steroids, dopamine,

promethazine, glycerin trinitrate, lidocaine

recovery (5d)

recovery

• • 1. urticaria, angioedema, shock

ST

depression

no no 0.311^a normal normal steroids, epinephrine,

chlorpheniramine

recovery (10d)

• • 1. rash ST elevation no no nr nr subocclusive

spasm

steroids, antihistamine, adrenaline, nitrates

recovery

• • 1. unconsciousness, deep coma

ST elevation yes no normal nr normal steroids, epinephrine,

chlorpheniramine

recovery (5d)

• • 1. sweating, dyspnea, rash, chest pain

ST elevation no PTCA nr nr stent thrombosis of RCA

steroids recovery

• • 1. erythema ST elevation yes CAS 1557 normal coronary

vasospasm of LAD

Epinephrine, nitroglycerin died

• • 1. urticaria ST elevation no CAS nr nr Mid-to-distal

RCA vasospasm

steroids, metaraminol, adrenaline

recovery

• • 1. nausea, sweating, chest pain, itch, erythema

ST elevation no PTCA nr nr stent thrombosis

steroids, chlorpheniramine, eptifibatide, DAT, statin, beta blocker, ACEI

recovery (3d)

• • 1. numbness of upper limbs, dyspnea, unconsciousness

ST elevation no no elevated normal nr steroids, adrenaline,

heparin, nicorandil

recovery

• • 1. chest pain, shortness of breath, unresponsive

ST elevation no no 1.12 nr mild disease of

middle RCA

steroids, atropine recovery

• • 1. unconsciousness, rash ST elevation yes no nr normal nr steroids, atropine, CPR,

dopamine

recovery

• • 1. back pain, unconsciousness

ST elevation no no elevated LVOT obstruction normal steroids,norepinephrine recovery

• • 1. flushing, diaphoresis, chest pain

ST elevation yes PTCA nr hypokinesis coronary

vasospasm

steroids, diphenhydramine, DAT, anticoagulation, epinephrine, nitroglycerin

died

• • 1. chest pain ST elevation no CAS nr hypokinesis stent

thrombosis of proximal LAD

steroids, antihistamine, DAT, bisoprolol, atorvastatin

ICD (a

few days)

• • 1. urticaria, chest tightness, laryngospasm
    2. tingling sensation, throat discomfort, chest discomfort, dry cough, shortness of breath

normal no no 6.65 normal normal steroids, epinephrine,

antihistamines, heparin, aspirin, nitrates

ST elevation no no nr normal nr steroids, itroglycerine,

isosorbide dinitrate, atropine

recovery (3d)

recovery (9d)

• • 1. rash, itching, chest tightness, nausea
    2. chest pain, sweating, unconsciousness

AF no no 0.372 nr coronary vasospasm

ST elevation no no 0.00832^a nr 30% stenosis of

distal RCA and middle ADA

steroids, adrenaline, dopamine

steroids, dopamine, epinephrine, promethazine, norepinephrine

recovery

recovery (4d)

1. sweating, flushing, abdominal pain, unconsciousness

ST elevation no no no nr nr steroids, dopamine,

epinephrine

recovery (4d)

(continued on next page)

Table 2 (continued)

Reference Clinical manifestations ECG Cardiac

Arrest

Revascularization Troponin

I(ng/ml)

Echocardiography Coronarography Treatment Outcome (hospital day)

1. cough, dyspnea, nausea, desaturation, unconsciousness, urticaria

low progression of R wave

yes no elevated low cardiac output

normal steroids, adrenaline, salbutamol, antihistamines

recovery (4d)

Abbreviation: ECG,Electrocardiogram; CCA, circumflex coronary artery intrastent stenosis; LAD, Left anterior descending; LVOT, left ventricular outflow tract; AMI anterior myocardial in- farction; CCB, calcium channel blocker; ACEI, angiotensin-converting enzyme inhibitor; PTCA, Percutaneous transluminal coronary angioplasty; CPR,Cardiopulmonary resuscitation; CAS, coronary artery stenting; DAT, Dual antiplatelet therapy.

^a Troponin T.

elevated troponin T (3 cases) (Table 2). Serum tryptase level was mark- edly elevated in 2 patients [5,17], and creatine kinase-MB(CK-MB) was elevated in 2 patients [26,28].

• 1. Image examination

The imaging examination results were summarized in the Table 2. Electrocardiogram (ECG) mainly showed ST elevation (20 cases), ST de- pression (1 case), low progression of R wave (1 case), atrial fibrillation (1 case), normal (1 case) and acute myocardial infarction (1 case). Echo- cardiography in 13 patients revealed normal (8 cases), hyperkinetic wall motion (3 cases), low cardiac output (1 case), left ventricular out- flow tract obstruction (1 case). CAG in 19 patients showed normal (5 cases), coronary vasospasm (6 cases), right coronary artery stent thrombosis (3 cases), occlusion (2 cases), stenosis (2 cases), mild disease (1 case).

• 1. Treatment

Treatment of these patients included steroids (25 cases), antihista- mines (14), nitrates (5 cases), epinephrine (15 cases), dopamine (6 cases), antiplatelet drugs (5 cases), and anticoagulant drugs (5 cases) (Table 2). Eight patients underwent revascularization, including percu- taneous transluminal coronary angioplasty (5 cases) [5,8,15,18,23] and coronary artery stenting (3 cases) [16,17,24]. One patient undergoing cardiopulmonary resuscitation [21]. After Symptomatic treatment [23], patients recovered completely, two patients died [16,23] and one pa- tient was implanted with an Implantable cardioverter defibrillator (ICD) to prevent sudden cardiac death [24].

1. Discussion

The diagnosis of KS is based on clinical symptoms and signs, as well as laboratory, electrocardiogram, echocardiography, and angiography. Three variants of KS have been described [30]. The type I variant refers to patients with Normal coronary arteries without any Cardiovascular risk factors. The type II variant occurs in patients with existing coronary artery disease. The type III variant occurs in patients with stent throm- bosis. Previous allergy, hypertension, smoking, diabetes, and hyperlip- idemia are risk factors for the development of KS [31]. Our research showed that 19.2% of patients had a known history of allergies. A careful review of the clinical history of allergic reactions is important for the prevention and treatment of KS.

KS induced by contrast agents was mostly type I and II, which often oc- curred in elderly male patients. Most modern iodinated contrast media are classified as low-osmolality contrast media (LOCM) and isoosmolar con- trast media (IOCM) [32]. Most KS cases were related to LOCM, such as iopromide, iohexol, and iopamidol. Only a few cases were related to IOCM, iodixanol. Gadolinium was divided into two groups based on their chemical structure - linear and macrocyclic. In particular, licences for the linear agents gadodiamide and gadopentetate dimeglumine were suspended due to the risk of nephrogenic systemic fibrosis (NSF) and re- tention in the brain and other tissues. And macrocyclic chelates are of

lowest risk [33]. Our research found that KS was related to macrocyclic gadolinium-containing contrast agents (GdCAs). In addition, intracoronary injections and intravenous injections of contrast agents can cause any type of KS. Despite its rare incidence, as doctors’ awareness of KS increased, it may lead to a further increase in KS-related case reports. Therefore, in our opinion, diagnostic radiologists who routinely use any type of contrast agent should understand KS. Further research is needed to prove whether the risks of KS induced by different contrast agents are the same.

The exact pathophysiological mechanism of KS is still unclear. mast cells play a central role in the underlying mechanism of KS. Mast cells are abundant in the heart and blood vessels. The degranulation of mast cells leads to the release of allergic Inflammatory mediators, in- cluding histamine, proteases, leukotrienes, traxane, and platelet activat- ing factor [30]. Serum tryptase levels can provide more information about allergic reactions [34]. Tryptase level as a specific indicator of Mast cell degranulation [35].

Currently, there are no standards and guidelines for the treatment of KS. The treatment of KS is challenging because it requires simultaneous resolution of allergic reactions and cardiac symptoms [3]. The prognos- tic factors that affect KS mainly include the type of KS, complications, al- lergens, etc. Generally, type I variant had the best prognosis, and type III variant had the worst prognosis. Our research showed that contrast- induced KS can cause serious complications, with a cardiac arrest rate of 23.1% and a mortality rate of 7.7%. In patients with the type I variant, the symptoms can be eliminated by treating allergies alone, such as glu- cocorticoids, H₁ and H₂ receptor blockers. In patients with the type II variant, treatment should be initiated with an acute coronary event pro- tocol together with corticosteroids and antihistamines. In patients with type III variant the current acute myocardial infarction protocol to- gether with urgent aspiration of intrastent thrombus followed by histo- logical examination of aspirated material. Calcium blockers and nitrates can eliminate coronary artery spasm caused by allergies. Beta-blockers can aggravate coronary artery spasm and should be avoided. Although epinephrine is the drug of choice for the treatment of conventional allergic reactions, it can aggravate myocardial ischemia and cause coro- nary artery spasm in KS patients [36]. Most patients receive intravenous corticosteroids, diphenhydramine, and epinephrine to abolish allergic symptoms in our study. Coronary arteries have achieved almost com- plete Blood flow restoration by nitrate injections and interventional treatments. Two patients still died of multiple organ failure and recur- rent cardiac arrest.

The effective prevention method of KS is unclear. It is still challeng-

ing to switch to another type of contrast medium. In particular, CAG/ percutaneous coronary intervention (PCI) should be considered for pa- tients with coronary artery spasm/thrombosis progressing to acute myocardial infarction.

1. Conclusion

In summary, contrast-induced KS is a rare adverse reaction. Radiolo- gists should recognize this rare but serious disease to ensure rapid diag- nosis and proper management.

Funding

This study was funded by the Natural Science Foundation of Hunan Province (No. 2021JJ80083).

Declaration of Competing Interest

All authors declare that they have no conflict of financial interest.

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