Giant coronary aneurysms in children with Kawasaki disease and major cardiac complications and dynamic follow-up

Abstract

BACKGROUND

Giant coronary artery aneurysms (CAA), entailing thrombosis, myocardial infarction, and sudden death, are the most severe and life-threatening complications of Kawasaki disease (KD). Giant aneurysms rarely regress and can later transform into stenoses. Data on dynamic follow-up are scarce in the literature.

AIM

To evaluate clinical features and long-term outcomes of giant CAA in children with KD.

METHODS

A single-center retrospective study included data from patients with KD and giant CAA in the Irkutsk region (2012-2023). CAA criteria according to the American Heart Association guidelines of 2017 were used: (1) Dilated coronary artery with diameter Z-score > 2 standard deviations (SD) but < 2.5 SD; (2) Small CAA with Z-score > 2.5 SD but < 5 SD; (3) Medium CAA with Z-score > 5 SD but < 10 SD; and (4) Giant CAA with Z-score > 10 SD or ≥ 8 mm.

RESULTS

The mean age of children with coronary dilatation/aneurysms was 2.5 years, and the male-to-female ratio was 3:1. Patients with giant/medium CAA had symptoms of cerebral dysfunction more often compared with children with moderate (Z-score < 5 SD but > 2.0 SD) coronary dilatation (62.0% vs 21.0%, P = 0.019). Major cardiovascular events (myocardial infarction, coronary artery bypass grafting, acute coronary syndrome, ischemic cardiomyopathy, left ventricular aneurysm, and giant extracardiac aneurysm) occurred in 55.5% of patients who had giant CAA. At follow-up the complete regression of giant/medium CAA was observed in 58.0% and partial regression in 42.0% after a mean of 2.3 and 5.5 years, respectively. All thrombi detected by echocardiography, CT, and angiography in giant/medium CAA disappeared between 1 year and 5 years (mean: 15 months). All patients survived.

CONCLUSION

Risk factors for giant CAA were male sex, early age, and cerebral dysfunction. Complete regression of giant coronary aneurysms occurred in 58.0% of patients after follow-up of 2.3 years.

Key Words: Kawasaki disease; Children; Coronary arteries; Giant coronary aneurysms; Coronary artery dilatation; Myocardial infarction; Coronary thrombosis

Core Tip: A study of the evolution of giant and medium-sized coronary aneurysms in children with Kawasaki disease was conducted. Giant coronary aneurysms occurred in 6.5% of patients with Kawasaki disease, and 75.0% of patients with giant/medium coronary aneurysms were male. Only males had giant bilateral coronary aneurysms. Major cardiac events occurred in 38.5% of patients with giant/medium coronary aneurysms. Slow regression of giant/medium-sized coronary aneurysms occurred in all patients, complete regression occurred in 58.0%, and partial regression in 42.0% after an average of 2-4 months (from 1 year to 5 years) of observations with antithrombotic treatment. There were no fatal outcomes.

INTRODUCTION

Giant coronary artery aneurysms (CAA) are the most severe and characteristic manifestation of Kawasaki disease (KD) that lead to life-threatening cardiac complications, including thrombosis of aneurysms, myocardial infarction (MI), coronary stenoses, myocardial ischemic damage, and sudden cardiac death. Giant CAA is defined as its diameter has a Z-score ≥ 10 or ≥ 8 mm in absolute value, and such aneurysms rarely regress[1,2]. The likelihood of the disappearance of giant CAA is low, and within ≥ 30 years of KD onset, they are associated with a 50% risk of thrombotic occlusion and acute coronary syndrome due to progressive stenoses requiring revascularization[3].

There are few publications on the prevalence and clinical course of giant CAA due to KD, and more often they are presented as single cases[4-7]. The most extensive series of giant CAA observations was analyzed in Japan in nationwide epidemiologic studies from 1999 to 2010[2]. The incidence of these aneurysms decreased over these 10 years from 0.52% to 0.18% among the total number of patients due to advances in the recognition and treatment of KD in this country. A total of 209 children with giant CAA were identified from the studies. Almost all (96%) received an initial intravenous immunoglobulin (IVIG) course. However, more than half of the patients (180 out of 209) required a second IVIG course with or without corticosteroids due to the first course of IVIG treatment failure that was administered on an average of 8 days from onset (5-30 days). Even the timely administration of IVIG does not entirely protect against the development of giant CAAs. The mortality rate for giant coronary aneurysms was 5.7% with 83.3% of deaths occurring within the first year after the onset of the KD[2].

A retrospective study (1995-2015) from Mexico found a higher incidence (8%) of giant CAA in patients with KD than in Japan[2,8]. The risk of giant CAA in the studies was associated with delayed diagnostics of KD, very young age (< 1 year), and first course of IVIG failure, requiring additional treatment[8-11]. Giant CAA in children with KD is occasionally combined with giant extracardiac aneurysms, which are usually symmetric[11,12]. Coronary stenoses[1,2] are a late complication of giant CAA[13-16].

MATERIALS AND METHODS

Design

In this retrospective cohort study, the data were collected from 139 children with KD who were observed at the regional pediatric clinical hospital in Irkutsk in 2012-2023. The diagnosis of KD was made with the presence of fever in the onset ≥ 4 days in combination with 4-5 other diagnostic criteria [rash, cervical lymphadenitis, bilateral conjunctivitis, inflammatory changes of oral mucous membranes, hyperemia/edema/peeling of palms and feet (complete form), in the absence of 2-3 of these-incomplete form][1]. CAA criteria according to the American Heart Association guidelines of 2017 were used: (1) Dilated coronary artery (CA) with diameter Z-score > 2 standard deviations (SD) but < 2.5 SD; (2) Small CAA with Z-score > 2.5 SD but < 5 SD; (3) Medium CAA with Z-score > 5 SD but < 10 SD; and (4) Giant CAA with Z-score > 10 SD or ≥ 8 mm. We compared the patients with different grades of CAA and those without it. The duration of follow-up of children with CAA averaged from 1 month to 14 years (mean: 3 years).

Evaluations

The following clinical data were evaluated: (1) A wide range of clinical symptoms associated with KD including shock, acute respiratory distress syndrome (ARDS), and the presence of neurological injury, including aseptic meningitis and secondary hemophagocytic syndrome; and (2) Major cardiac events (MACE) including coronary thrombosis, acute MI (AMI) or ischemic myocardial damage (clinical symptoms of angina equivalent combined with quorum sensing morphology on electrocardiogram and/or ST-T changes, an increase in troponin level), acute heart failure (HF), left ventricle (LV) aneurysm, and CA bypass grafting.

CA lesions were assessed by echocardiography at KD onset, 1 month, 3 months, 6 months, 12 months, 4 years, and 5 years. Five patients out of 9 with giant CAA underwent coronary angiography, and angiography of branches of the ascending and descending aorta was performed in one.

Statistical analysis

The STATISTICA software package version 12.0 (StatSoft Inc., Tulsa, OK, United States) was used. Numerical measures were represented by the median (25^th and 75^th percentile) and categorical variables in absolute numbers and fractions (%). The Pearson χ² test for comparing independent categorical variables and the Mann-Whitney test for independent numerical variables were applied. Differences were considered statistically significant if the P value was less than 0.05.

RESULTS

Patient characteristics

One hundred thirty-nine children aged 2 months to 13 years were under observation, including 94 children under 5 years (68.0%) and 38 (27.0%) children under 1 year. CA lesions were found in 32 (29.9%) of 139 patients, including moderate coronary dilatation (Z-score < 5 SD but > 2.5 SD) in 19 (13.7%) and giant (n = 9/139; 6.5%)/medium (n = 4/139; 2.9%) CAA in 13 (9.3%) patients.

Children with coronary lesions were younger (2.1 years vs 3.8 years, P < 0.004) with a male predominance (75.0% vs 46.0%, P < 0.003) compared with children without coronary lesions. The male-to-female ratio was 3:1 in children with coronary lesions, whereas the ratio was (0.9:1) in children without coronary lesions. A complete form of KD was diagnosed in 62 (45.0%) children without a significant difference between the groups of children with (41.0%) and without (46.0%) coronary lesions.

Serious clinical events on admission were shock in 49 (35.0%) children with a similar rate between children with (n = 11/32; 34.0%) and without (n = 38/107; 35.5%) CAA (P = 0.906) and neurologic symptoms (hyperirritability or stunned consciousness, aseptic meningitis/meningoencephalitis) in 36/139 (26.0%) patients without a difference between the same studied groups with (n = 12/32; 37.0%) and without (n = 24/107; 22.0%) coronary lesions (P = 0.088). In contrast ARDS was diagnosed significantly more frequently among children with (n = 30; 22.0%) and without (n = 12; 38.0%) coronary lesions (P = 0.012). Acute renal failure and hematologic abnormalities were diagnosed in 7 patients (5.0%) with a similar frequency between the studied groups (Table 1).

Table 1 Overall clinical features of patients with Kawasaki disease.

Parameters	Total group (n = 139)	Without CA lesions (n = 107)	With CA lesions (n = 32)	P value
Onset age (years), median (25%, 75%)	3.0 (1.0, 5.0)	3.0 (1.3, 5.5)	1.0 (0.5, 3.4)	0.004
Number of days of fever (days), median (25%, 75%)	10.0 (5.0, 14.0)	11.0 (7.0, 15.0)	5.5 (3.0, 13.0)	0.068
Male sex	73 (53.0)	49 (46.0)	24 (75.0)	0.003
Complete Kawasaki disease criteria	62 (45.0)	49 (46.0)	13 (41.0)	0.608
Neurological symptoms, including	36 (26.0)	24 (22.0)	12 (37.0)	0.088
Aseptic meningitis	9 (6.5)	5 (5.0)	4 (12.0)	0.116
Shock	49 (35.0)	38 (35.5)	11 (34.0)	0.906
Acute renal failure	7 (5.0)	4 (4.0)	3 (9.0)	0.203
Hematologic abnormalities	7 (5.0)	5 (5.0)	2 (6.0)	0.722
Polyserositis	22 (16.0)	18 (17.0)	4 (12.0)	0.560
Acute respiratory distress syndrome	30 (22.0)	18 (17.0)	12 (38.0)	0.012
Coronary thrombosis	6 (4.3)	0	6 (19.0)
Acute heart failure	9 (6.5)	6 (6.0)	3 (9.0)	0.450

Data are presented as n (%). СA: Coronary artery.

Coronary thromboses were detected by ultrasound, CT, and angiography in 6/139 children (4.3%) and only in children with coronary lesions [6/32 (19.0%)].

Clinical features of KD in children with giant/medium CAA

To evaluate the features of the clinical course, we compared patients with giant (group 1, n = 13) and moderate CAA (group 2, n = 19). There were no differences in sex distribution and onset age between the studied subgroups (1 and 2). The proportion of males was over 70.0% in both groups (Table 2). The mean number of days of fever in children with giant/medium CAA was twice as long as in children with moderate CAA although the difference was insignificant (Table 2).

Table 2 Clinical features of patients with Kawasaki disease and giant/medium coronary artery aneurysms.

Parameters	Giant1 and medium2 CAA (n = 13)	Moderate CAA dilatation3 (n = 19)	P value
Onset age, years, median (25%, 75%)	2.0 (0.8, 5.0)	0.8 (0.4, 1.7)	0.196
Male sex	10 (77.0)	14 (74.0)	0.841
Number of days of fever, median (25%, 75%)	10 (5, 14)	5 (3, 10)	0.073
Complete Kawasaki disease criteria	7 (54.0)	6 (32.0)	0.220
Neurological symptoms	8 (62.0)	4 (21.0)	0.019
Aseptic meningitis	2 (15.0)	2 (11.0)	0.694
Acute kidney failure	1 (8.0)	2 (11.0)	0.795
Polyserositis	2 (15.0)	2 (11.0)	0.694
Hematologic abnormalities	1 (8.0)	1 (5.0)	0.788
Coronary thrombosis	5 (42.0)	1 (5.0)	0.017
Shock	7 (54.0)	4 (21.0)	0.057
Acute heart failure	2 (17.0)	1 (5.0)	0.350
Myocardial dysfunction (heart failure) 1-4 functional class	10 (77.0)	11 (58.0)	0.280
Pericarditis	5 (38.0)	6 (32.0)	0.698
Hemophagocytic syndrome	1 (8.0)	2 (11.0)	0.795
Left ventricle dilatation	1 (8.0)	2 (11.0)	0.795
Right ventricle dilatation	3 (23.0)	3 (16.0)	0.617
Reduced left ventricle ejection fraction	1 (8.0)	0 (0)	-

¹Giant coronary artery aneurysm (CAA) was defined by a Z-score > 10 standard deviations (SD).

²Medium CAA was defined by a Z-score > 5 SD but < 10 SD.

³Moderate CAA dilatation was defined by Z-score < 5 SD but > 2.5 SD.

CAA: Coronary artery aneurysms.

Half of the patients (54.0%) with giant/medium CAA (group 1) developed shock and multiorgan failure. In comparison shock was half as common among patients with moderate coronary dilatation (21.0%, P = 0.057) at the onset of KD. Various symptoms of cerebral dysfunction, such as hyperirritability, stunned consciousness, lethargy and sometimes deeper degrees of cerebral coma and aseptic meningitis/meningoencephalitis were observed three times more frequently among children with giant/medium CAA (62.0%) than in children with moderate coronary dilatation (21.0%, P = 0.019). Acute kidney failure, hematologic abnormalities, and secondary hemophagocytic syndrome were significantly less frequent than neurologic symptoms among patients of both groups without significant differences (Table 2).

Cardiovascular complications in patients with KD with giant/medium coronary aneurysms

Myocardial dysfunction occurred in 21 out of 32 (66.0%) children with coronary dilatation. It was caused by shock with multiorgan failure, myocarditis, and myocardial ischemic damage. Due to the combination of these causes in many patients, separating the main one was not always possible. The proportion of children with HF was slightly higher in children with giant/medium coronary aneurysms (77.0%) than in children with moderate coronary dilatation (58.0%). Acute HF was rare (17.0% vs 5.0%, P = 0.350). Usually, it was caused by AMI in children with giant/medium aneurysms and by myocarditis in children with moderate coronary dilatation (Table 2).

Thromboses (of exclusively coronary localization) were visualized on echocardiography in almost half of patients with giant/medium CAA (n = 5/13; 42.0%) and were eight times less frequent among children with moderate coronary dilatation (n = 1/19; 5.0%; P = 0.017).

Giant aneurysms (diameter Z-score > 10 SD) were found in 9/13 (69.0%) patients (subgroup 1a; giant CAA), and medium aneurysms (diameter Z-score > 5 SD but < 10 SD) in 4/13 (31.0%) patients (subgroup 1b, medium CAA).

Subgroup 1a (9 patients with giant CAAs)

Five patients had only one giant CAA in the left CA (LCA) (Table 3) while the remaining four patients had giant CAAs in both main coronary arteries. One of these 4 patients (patient 3, Table 3) additionally had giant bilateral aneurysms of the axillary and subclavian arteries.

Table 3 Clinical features of patients with Kawasaki disease and giant coronary artery aneurysms (subgroup 1a).

ID, sex, age	Affected coronary arteries	KD form	Cardiovascular events	Other KD manifestation	Treatment
1, M, 5 months	Bilateral multiple LCA d = 0.60 cm (Z-score = 13.7), RCA d = 0.45 cm (Z-score = 10.79)	Complete	Acute HF: HF 4 FC. Subtotal thrombosis of AIVA, acute anterolateral myocardial infarction, ischemic DCM, apical aneurysm of LV	CNS injury-aseptic meningitis, seizures	IVIG 2 courses, AA + clopidogrel, heparin, and LMWH, therapy of chronic HF, Mammarocoronary AIVA bypass grafting
2, M, 9 months	Bilateral multiple LCA d = 0.51 cm (Z-score = 10.25); RCA d = 0.50-0.51 cm (Z-score = 10.79)	Complete	Acute coronary syndrome, ischemic myocardial damage	CNS injury (stunned consciousness) hemophagocytic syndrome	IVIG + GCS + AA + clopidogrel, heparin/LMWH
3, M, 3 months	Bilateral multiple LCA d = 0.50 cm (Z-score = 10.8); RCA d = 0.35 cm (Z-score = 6.8)	Complete	Acute HF giant extracardiac aneurysms	CNS injury-aseptic meningitis hemophagocytic syndrome	IVIG + GCS + AA + clopidogrel, heparin/LMWH
4, M, 8 years	Bilateral multiple AIVA d = 0.626 cm (Z-score = 11.29), circumflex 0.372 cm (Z-score = 4.25); RCA trunk 0.428 cm (Z-score = 4.77), mid. RCA 0.531 cm (Z-score = 7.83)	Complete	Ischemic DCM, HF 4 FC	CNS injury–stunned consciousness	IVIG + АА + LMWH
5, M, 3 years	LCA aneurysm d = 0.7 cm (Z-score = 11.28)	Incomplete	LCA aneurysm, thrombosis, LV dilatation	KD recurrence after 12 months	IVIG + AA + LMWH
6, M, 3 months	RCA aneurysm d = 1.5 cm (Z-score = 37)	Complete	NA	NA	IVIG + AA
7, F, 5 years	LCA aneurysm d = 0.874 cm (Z-score = 18.00	Complete	Ischemic DCM, aortic valve valvulitis with transient, transvalvular flow, acceleration (blood flow rate = 1.78 m/second, pressure gradient 1733 kPa)	CNS injury-stunned consciousness arthritis with rapid reversal	IVIG + AA
8, F, 8 months	Dilatation of the LCA and descending branch, aneurysm of the circumflex artery d = 0.74 cm (Z-score = 17.66)	Incomplete	NA	CNS injury-cerebral vasculitis	IVIG + AA
9, F, 2 years	LCA aneurysm d = 0.715 cm (Z-score = 14.39)	Incomplete	Near-wall thrombus in LCA aneurysm	NA	IVIG + AA

АА: Acetylsalicylic acid; AIVA: Anterior interventricular artery; CNS: Central nervous system; d: Diameter; DCM: Dilated cardiomyopathy; F: Female; FC: Functional class; GCS: Glucocorticosteroids; HF: Heart failure; IVIG: Intravenous immunoglobulin; KD: Kawasaki disease; LCA: Left coronary artery; LMWH: Low molecular weight heparin; LV: Left ventricle; M: Male; NA: Not available; RCA: Right coronary artery.

Echocardiography visualized the thrombosis of CAA in three children in this subgroup [in two of them, near-wall thrombosis, and in another (patient 1; Table 3), a subocclusive thrombosis of a giant aneurysm of the anterior interventricular artery (AIVA), which led to the development of AMI]. Ventricular dilatation was recorded on echocardiography in 3 (33.0%) patients with giant CAA (Table 3). After admission to the hospital, right ventricular dilatation was more common than left and was associated with ARDS, shock, and multiorgan failure. Both ventricles were dilated in three children. One patient had significant enlargement of the LV with a low left ventricular ejection fraction (LVEF) (37.0%) at the time of admission due to acute anterolateral MI.

A variety of neurologic symptoms, ranging from hyperirritability to stunned consciousness and aseptic meningitis, were also noted in 6 of 9 patients (67.0%) with giant CAA. All neurologic manifestations regressed by the termination of the acute episode of KD without residual symptomatology.

Ischemic cardiomyopathy was detected in 2 patients at the onset of the disease, one after an MI that has persisted for the last 13 years. He is constantly receiving therapy for HF. Another patient developed ischemic cardiomyopathy on a background of a giant aneurysm of the left internal carotid artery, which disappeared 4 years later along with the regression of the aneurysm. Throughout the time that LV dilation was observed, she was constantly receiving therapy for HF. Another patient with giant aneurysms of the LCA and right CA (RCA) developed ischemic CMP at a late stage, and he was also prescribed ongoing supportive treatment for HF.

Subgroup 1b (4 patients with medium CAAs)

In children with medium-sized CAAs, no bilateral coronary lesions, central nervous system involvement, secondary hemophagocytic syndrome, or extracardiac aneurysms were detected. Echocardiography visualized the coronary thrombus in the RCA aneurysm in only 1 out of 4 patients (patient 11; Table 4). Ventricular dilatation, decreased myocardial contractility, MI, or secondary ischemic dilated cardiomyopathy (DCM) development did not occur in any of the patients in this subgroup.

Table 4 Clinical features of patients with Kawasaki disease and medium coronary artery aneurysms (subgroup 1b).

ID, sex, age	Affected coronary arteries	KD form	Cardiovascular events	Other KD manifestations	Therapy
10, M, 6 years	LCA aneurysm d = 0.55 cm (Z-score = 8.24)	Complete	NA	NA	IVIG + AA
11, M, 6 years	RCA aneurysm d = 0.65 cm (Z-score = 9.84)	Incomplete	Near-wall thrombus in RCA aneurysm coronary-right atrial fistula	NA	IVIG + AA + heparin and low molecular weight heparin surgical closure of the coronary fistula
12, M, 1.5 years	LCA aneurysm along d = 0.53 cm (Z-score = 9.57)	Complete	NA	NA	IVIG + AA
13, M, 3 years	LCA aneurysm d = 4.6 mm	Complete	NA	NA	IVIG + AA

Numbering continued from Table 3. АА: Acetylsalicylic acid; d: Diameter; IVIG: Intravenous immunoglobulin; KD: Kawasaki disease; LCA: Left coronary artery; M: Male; NA: Not available; RCA: Right coronary artery.

Clinical features and cardiovascular complications in patients with KD and moderate coronary dilatation

Among the 19 patients (group 2) in whom the CA dilatation Z-score did not exceed 5, males were also predominant (74.0%), similar to patients with giant/medium aneurysms (Table 1). The number of days of fever was half that of children with giant CAAs (statistically insignificant). However, neurologic symptoms in general, including hyperirritability, stunned consciousness, or any other neurologic symptoms, were significantly less frequent in this group than in patients with giant/medium CAA (P = 0.019). Aseptic meningitis, acute kidney failure, secondary hemophagocytic syndrome, and polyserositis occurred equally in 11.0% of patients with no difference from children with giant/medium CAA (Table 2). Pericarditis (with small effusion) was detected on echocardiography in 6 (32.0%) patients (Table 2), similar to children with giant/medium CAA (n = 5; 38.0%).

Treatment at the onset of KD

Treatment with IVIG was administered in 131 (94.0%) children with KD, including all 13 patients with giant/medium CAA and 17 (89.0%) children with moderate coronary dilatation. The first IVIG administration failure, realized in persistent fever > 36 h and persistently high levels of inflammatory biomarkers, required repeated IVIG courses in two children. Refractory fever after two IVIG courses persisted in only one child with a giant LCA aneurysm and required additional immunomodulatory therapy with the tumor necrosis factor alpha inhibitor etanercept 0.8 mg/kg/week. After the third etanercept injection, the fever and high levels of inflammatory blood biomarkers disappeared, followed by etanercept withdrawal.

Glucocorticosteroids and cyclosporine A were administered to treat secondary hemophagocytic syndrome in three children (one from group 1 and two from group 2) and ranged from 5 days to 3 weeks with a corticosteroid tapering with the subsequent withdrawal.

All patients with giant/moderate CAA and 18 (95.0%) children with moderate coronary dilatation received acetylsalicylic acid (ASA) at a dosage from 30 mg/kg/day to 50 mg/kg/day before IVIG administration with a reduction to 5 mg/kg/day after the end of immunoglobulin administration. Overall, ASA was administered to 97.0% of the entire group of patients with KD. Anticoagulant therapy with heparin/Low-molecular-weight heparins was prescribed in 7 (54.0%) patients with giant CAA when coronary thrombosis was detected (Table 5).

Table 5 Treatment at the onset of Kawasaki disease.

Therapy at onset	Children with coronary dilatation (n = 32)	Group 1 (with giant/medium coronary artery aneurysms) (n = 13)	Group 2 (with moderate coronary dilatation) (n = 19)
Intravenous immunoglobulin	30 (94.0)	13 (100)	17 (89.0)
Glucocorticosteroids	3 (9.0)	2 (15.0)	1 (5.0)
Etanercept	1 (3.0)	1 (8.0)	0 (0)
Cyclosporine	2 (6.0)	1 (8.0)	1 (5.0)
Acetylsalicylic acid	31 (97.0)	13 (100)	18 (95.0)
Anticoagulants: LMWH or heparin (intravenous) with subsequent LMWH	12 (38.0)	7 (54.0)	5 (26.0)
Heart failure therapy at the Kawasaki disease onset
Carditonics	2 (6.0)	1 (8.0)	1 (5.0)
Diuretics	22 (69.0)	11 (85.0)	11 (58.0)
Beta-blockers	14 (44.0)	5 (38.0)	9 (47.0)
Angiotensin-converting enzyme inhibitors	7 (22.0)	5 (38.0)	2 (11.0)
Outcomes
Regression of thrombosis	6/6 (100)	6/6 (100)	0 (0)
Ischemic dilated cardiomyopathy	3 (9.4)	3 (23.0)	0 (0)

Data are presented as n (%). LMWH: Low molecular weight heparin.

Cardiotonic drugs (dopamine, dobutamine, adrenaline) and furosemide were administered by intravenous infusion to 1 patient with bilateral giant CAA who developed AMI, and another child with moderate coronary dilatation and myocarditis at the time of admission to the clinic at the onset of KD due to acute HF. Symptoms of chronic two to four functional classes of HF occurred in the majority of patients with giant/medium CAA and half of the children with moderate coronary dilatation. Diuretics, carvedilol, and angiotensin-converting enzyme (ACE) inhibitors were used for HF treatment (Table 5).

Surgical treatment in the early stage of KD (5 weeks from the onset of the disease) was performed in one case (mammary-coronary bypass grafting on a beating heart) in a male aged 4.5 months with bilateral giant CAA and subocclusive thrombosis of the AIVA due to rapidly progressive HF despite the full scope of urgent conservative therapy.

Follow-up in a chronic (late) stage of KD

Evolution of giant aneurysms of the LCA: Giant aneurysms of the LCA were observed in 9 children, and in 6 children the giant aneurysms of the LCA regressed completely (n = 2) or partially (n = 4) in 12 months. In the remaining 3 patients, one did not have changes in giant CAA diameter, another patient had an increase in giant CAA diameter, and another patient had moderate dilatation of the LCA at the onset of KD but developed a giant LCA aneurysm in a recurrent KD episode by the end of the first year.

All patients with giant CAA were continuously treated with ASA 5 mg/kg/day, and one received a combination of ASA with clopidogrel during the first 6 months after hospital discharge. All patients who developed CAA thrombosis received anticoagulants (intravenous continuous heparin infusion switched to low-molecular-weight heparins, calcium nadroparin/enoxaparin sodium or warfarin) from several weeks to 12 months. Anticoagulants were discontinued after the disappearance of thrombus visualization in giant CAA. Children with ischemic myocardial damage or myocarditis at the beginning of KD were more likely to develop HF and receive ACE inhibitors, carvedilol, and diuretics. Two patients (patient 3 and patient 5) received atorvastatin due to progressive CAA dilation at 4 months and 12 months, respectively, with the following gradual regression of aneurysms. In a male with mammary coronary bypass surgery (patient 1), 11 months later a thrombus in the AIVA recanalized and coincided with the closure of the mammary coronary bypass.

The complete regression of giant LCA aneurysms occurred in 6 patients up to 4 years and partial regression (size reduction) in 2 patients. One patient never returned for follow-up.

Evolution of giant aneurysms of the RCA: Giant RCA aneurysms in three children gradually regressed by the end of the first year of follow-up. Complete regression of aneurysms occurred in two children after 3 years and 4 years, and another child had partial regression. Complete regression did not occur during the follow-up period up to 5 years. It should be noted that the decrease in the size of the aneurysms of the RCA occurred evenly and gradually unlike in patients with aneurysms in the LCA (Table 6).

Table 6 Follow-up of patients with Kawasaki disease and giant coronary aneurysms (9 patients, subgroup 1a).

ID, sex, age at KD onset	CA	CA, Z-score, SD				Clinical events
		At onset	After 3 months	After 6 months	After 1 year
1, M, 5 months	LCA	12.80 multiple aneurysms	9.80	NA	4.80	Giant CA of AIVA and RCA, subtotal thrombosis of AIVA, acute myocardial infarction, coronary bypass grafting. After 1-year complete recanalization of thrombosis. Regression of LCA aneurysm to ectasia, recanalization of AIVA, and shunt thrombosis. After 15 years normal LCA and RCA diameter
	RCA	13.70 multiple aneurysms	4.20	NA	2.90	Regression to ectasia, normal diameter after 15 years
2, M, 9 months	LCA	11.08	8.80	8.51	6.74	Partial regression, complete regression after 3 years
	RCA	10.44	8.39	6.83	5.93	Partial regression, normal diameter after 3 years
3, M, 3 months	LCA	10.80	5.41	6.69	3.56	Slow wave-like regression to ectasia after 5 years
	RCA	6.80	5.73	7.26	4.71	Slow wave-like regression to ectasia after 5 years
4, M, 8 years	LCA	11.20	NA	NA	-0.44	Complete regression after 1 year
	RCA	8.43	NA	NA	3.07	Slow regression to ectasia in 1-year, complete regression after 4 years
5, M, 3 years	LCA	2.12	0.91	0.24	11.59	Moderate dilatation in the first episode of KD with regression and formation of giant CA in the recurrence of KD. Complete regression after 4 years
	RCA	2.22	0.81	0.65	1.29	In the first episode of KD, moderate coronary dilatation with further complete regression
6, M, 3 months	LCA	1.74	NA	6.8	3.59	Coronary dilatation after 6 months with progression to CA and partial regression to ectasia after 1 year
	RCA	26.50	NA	1.70	4.88	Complete regression did not occur after 1 year of partial regression of giant CA to ectasia; complete regression did not occur
7, F, 5 years	LCA	10.90	18.00	NA	0.11	Giant CA with diameter increased after 3 months and complete regression after 1 year from the onset of KD
	RCA	1.37	1.06	NA	0.06	Not involved
8, F, 8 months	LCA	12.90	NA	12.70	12.21	Giant aneurysm after 1 year without change, complete regression after 5 years
	RCA	-0.51	NA	-0.58	-0.36	Not involved
9, F, 2 years	LCA	14.30	NA	NA	16.36	Giant CA with diameter increased after 1-year, partial regression to large aneurysm (Z-score < 10) after 4 years
	RCA	0.50	NA	NA	0.72	Not involved

Numbering corresponds to Table 3. AIVA: Anterior interventricular artery; СA: Coronary artery; F: Female; KD: Kawasaki disease; LCA: Left coronary artery; M: Male; NA: Not available; RCA: Right coronary artery; SD: Standard deviation.

Evolution of medium-sized coronary aneurysms: In the children with medium-diameter CAA (subgroup 1b), 1 patient had complete regression of the LCA aneurysm in 1 year. In another patient the LCA aneurysm decreased in size to a dilatation in 1 year (not observed further). In another patient with RCA near-wall giant aneurysm thrombosis, a right coronary arterial fistula was detected by echocardiography, followed by coronary angiography 4 months after KD onset. It had not been found on previous echocardiography. The fistula was successfully closed using ligation. After 1 month, the thrombus was no longer visualized on coronary angiography, and after 6 months the aneurysm of the RCA disappeared, according to echocardiography data.

These 3 patients with medium-sized aneurysms received low-dose ASA (5 mg/kg/day) continuously and spironolactone; the patient with RCA thrombosis additionally received calcium nadroparin for 1 month, 120 units/kg/day, and a beta-blocker, carvedilol at a dose of 0.05 mg/kg/day. The fourth patient in this group did not come for follow-up.

MACE

All 4 patients with bilateral giant CAA (size Z-score > 10) had MACE: (1) Acute coronary syndrome (n = 1); (2) MI/coronary bypass/Left ventricular apex aneurysm (n = 1); (3) Ischemic DCM (n = 3); and (4) Giant extracardiac aneurysms of axillary and brachial arteries (n = 1). MACE occurred in 5/13 (38.5%) patients with giant/medium CAA and 5/9 (55.5%) patients with giant CAA.

Outcomes

During the 8.5-year follow-up period, giant CAA was found in 6.5% of children with KD. The main outcomes of the dynamic follow-up of giant/medium CAA were the absence of deaths and new cases of coronary thrombosis and the regression of aneurysms in the majority of patients. Complete regression was achieved in 7/12 (58.0%) and partial regression in 5 (42.0%) patients after 4-5 years. In all 5 patients the complete disappearance of thrombus in giant/medium CAA was recorded from 1 month to 5 years (mean: 15 months).

Coronary angiography in 2 patients with giant CAA (patients 1 and 3; Table 6) revealed residual dilatation along the involved coronary arteries (ectasia). In patient 1 echocardiography visualized ectasia and irregularity of the internal outline of the LCA and its branch-AIVA. The medium AIVA segment was partially occluded, and the circulation of its apical segment was by the RCA collaterals. The non-functioning bypass between AIVA and internal thoracic artery was visualized too. In patient 3 ectasia of the LCA and RCA as well as brachial and axillary arteries on the left and right were observed. No segmental coronary stenoses were detected.

Among three children with ischemic DCM, the LV diameter and LVEF restoration occurred in 2 patients. In the remaining patient LV dilatation persisted with normalization of LVEF during HF treatment (spironolactone, ACE inhibitors, carvedilol, digoxin, dapagliflozin).

In late-stage KD MI has not been documented in any patients. No mortality occurred. Surgical treatment was required in two males (15.4%): (1) One in the early stage of the disease; and (2) The second within 4 months of the onset of KD. We did not observe new MACE in the late stage. No segmental stenoses were found in three of four children (males) who underwent selective coronary angiography 1-14 years after the onset of the disease (Table 7).

Table 7 Follow-up of patients with Kawasaki disease and medium coronary aneurysms.

ID, sex, age	Affected CA	Z-score				Clinical events
		At onset	After 3 months	After 6 months	After 12 months
10, M, 6 years	LCA	8.24	4.10	4.42	3.28	Regression to ectasia, normal diameter after 1 year
	RCA	1.46	1.27	0.04	-0.46	Not involved
11, M, 6 years	LCA	0.86	NA	-0.24	0.65	Not involved
	RCA	8.68	NA	1.57	1.05	Near-wall thrombosis of CA, formation of coronary fistula, ligation of fistula, complete regression of CA
12, M, 1.5 years	LCA	9.57	NA	NA	0.38	Complete regression of CA after 1 year
	RCA	1.56	NA	NA	0.01	Not involved
13, M, 3 years	LCA	6.13	NA	NA	NA	Not seen in follow-up
	RCA	-0.14	NA	NA	NA	Not involved

Numbering of patients corresponds to Table 4 (4 patients, subgroup 1b). СA: Coronary artery; LCA: Left coronary artery; M: Male; NA: Not available; RCA: Right coronary artery.

DISCUSSION

Giant CAA is a rare but extremely severe complication of KD, determining the prognosis of major cardiac life-threatening events, such as coronary thrombosis, CA stenosis, MI, ventricular tachycardia, and sudden cardiac death[5,16-19]. The development of CAA is associated with necrotizing arteritis and dilatation of the inflamed walls. Myofibroblastic proliferation allows restoration of the normal lumen of the vascular wall, but its ability to dilate and contract is impaired. Coronary stenoses are formed in other cases and may progress significantly due to myofibroblastic proliferation.

The frequency of giant CAA in our study was 6.5%, which is close to the data from Mexico (8%)[8] and the Netherlands (6.9%)[20] but significantly higher than in Japan (0.18%)[21,22] and the United States, possible related to different genetic background (2.6%)[1,23,24].

No association of giant CAA with the completeness of KD diagnostic criteria, levels of laboratory inflammatory biomarkers, or any other clinical manifestations has been found. The risk of coronary aneurysms in KD is associated with male sex[25,26] and the early onset age of patients, which is consistent with our data in which the mean age of children with coronary dilatation was 2.5 years vs 3.8 years in children with normal size of coronary arteries (P = 0.004). No significant age differences existed between patients with giant/medium CAA and those with moderate coronary dilatation (Z-score < 5.0). However, Dietz et al[20] indicated that giant CAAs usually occur in infants younger than 1 year. Among our 9 patients with giant CAAs, only 4 patients were under 1 year of age, but interestingly in 3 of these 4 patients, giant CAA was found in both main coronary arteries. Male sex is the highest risk factor for the development of giant CAA[8,20]. In our study 75.0% of patients with giant/medium CAA were males, and only males had giant bilateral CAA, corresponding to data provided by Dietz et al[20].

The duration of fever over 10 days was another risk factor for giant CAA development[25,26]. In our patients with giant CAA, the median fever duration was 12.5 days, which was twice as long. The incidence of neurologic symptoms was three times higher than in children with moderate coronary dilatation (P = 0.019). Warm vasoplegic shock with impaired consciousness, usually in the form of stunning, was reported twice as often as in children with moderate coronary dilatation. No differences in the incidence of secondary hemophagocytic syndrome, polyserositis, hematologic abnormalities, acute kidney failure, and even myocardial dysfunction and acute HF between children with giant CAAs and patients with moderate CA dilation to values Z-score < 5 SD were found.

The largest aneurysm diameter at the time of diagnosis was the most significant factor for serious cardiac complications in patients with giant CAA[23,24]. Our study was consistent with these findings in which coronary thrombi were visualized on echocardiography in 42.0% of children with giant/medium CAA and 5.0% with moderate coronary dilatation (P = 0.017). Only patients with giant LCA aneurysms with a Z-score diameter > 10 SD had such life-threatening complications as MI, acute coronary syndrome, secondary ischemic cardiomyopathy, and left ventricular aneurysm. Bilateral localization of giant CAAs is also among the high-risk factors for MACE[23,27]. Our data confirmed that; among 13 patients with giant/medium CAA, 4 patients had bilateral CAA, and 3 of these 4 patients had combined MACE (acute HF in 3 patients, AMI/bypass grafting/LV apex aneurysm in 1 patient, acute coronary syndrome in 1 patient, secondary ischemic DCM in 3 patients, and giant extracardiac aneurysms in 1 patient).

Refractory response to treatment with IVIG is considered another high-risk factor for the development of giant CAA[27,28]. The refractory response is a persistent fever 36 h an IVIG dose of 1.8-2.0 g/kg/course. Immunoglobulin at a single dose of 1.8-2.0 g/kg/course was given to all children with giant CAA observed by us. Refractory response to one course of IVIG was observed in two children, and they received a second course of IVIG. In contrast the refractory response to two courses of IVIG was observed in only 1 patient out of 13 with giant/medium CAA who received a tumor necrosis factor alpha blocker (etanercept).

Although the risk of giant CAAs increases with delayed diagnosis, timely IVIG administration cannot entirely prevent giant CAA formation. Sometimes, these aneurysms occur even in children with early diagnosis and administration of immunoglobulin in due time, noting a genetic predisposition to their development[29].

Giant CAA usually persists or regresses over time, progressing to segmental stenosis in adulthood due to CA remodeling caused by neointimal proliferation with wall thickening and calcification[30-32]. Stenosis or occlusion localized mainly in areas adjacent to aneurysms, resulting in MI or secondary ischemic cardiomyopathy late in the course of the disease. Analysis of observational studies of giant CAA in KD in Japan from 1980-2010 showed uncommon MACE: (1) 16% of patients experienced MI; and (2) 10.5% had an unfavorable outcome or heart transplantation[3]. Survival rates at 10 years, 20 years, and 30 years were 95%, 88%, and 88%, respectively.

However, some data reflected that some patients were treated with ASA alone at the onset of KD under the then-existing treatment protocols. In a study of giant CAA from southwest China from 2002-2018, the incidence of MI was 21%, and the mortality rate (solely from MI) was 4.2%[33]. MACE occurred in 5/13 our children (38.5%) with giant/medium CAA, but in 5 children out of 9 (55.5%) with giant CAAs. They occurred within the first year from the onset of KD, predominantly during the onset[13,14]. Among all our patients with KD during the analyzed period, the rate of MACE was 3.5%, which is significantly lower than the incidence of MACE (10%) in KD patients according to Santimahakullert et al[34].

Complete regression of giant CAAs with normalization of their diameter occurred in 26.7% of patients during a mean follow-up period of 3.6 years (0.6-12.0 years)[23]. In our study complete regression was achieved in 7/12 (58.0%) children who remained under follow-up, and partial regression in 5 (42.0%) after an average of 2 years 4 months (1-5 years) of follow-up with supportive treatment.

There was no MI or death in late-stage KD in our patients during the available observation period. All children discharged from the hospital were active, mobile, and had a good quality of life. They were subject to therapy for HF, antithrombotic therapy, and limited sports activities. Surgical treatment was performed in 15.4% of children with giant/medium CAA in the first 6 months from disease onset, and there were no new acute ischemic events at dynamic follow-up in late-stage KD. However, longer follow-up (up to 30 years) indicates a high long-term risk of coronary stenoses and the need for different types of surgical revascularization in more than half of patients with giant CAAs[3]. These data suggest the necessity of prolonged follow-up of patients with giant coronary aneurysms with close collaboration between pediatric and adult cardiologists.

Limitations

The retrospective nature of the study may introduce biases, and the exclusion of specific patient groups and the small number of the cohort may also lead to bias. With a sample size of only 19 patients with giant CAA, our findings may lack statistical power and may not be generalizable to broader populations. A small sample size increases the risk of type II errors in which actual effects may not be detected. The missing data and heterogeneous population (specific types of disease and different ages) could influence the study results. Our study did not evaluate the confounding variables that could affect outcomes, such as comorbidities, variations in treatment protocols over time, or differences in healthcare access. These factors could skew the results and interpretations. A more comprehensive analysis that accounts for these confounders would provide more robust and reliable findings.

CONCLUSION

Giant and medium coronary aneurysms occur in 9.3% of children with KD (including giant aneurysms in 6.5%) and are more often accompanied by neurologic symptoms compared with moderate coronary dilatation. High-risk factors for the development of giant aneurysms are male sex, early age, and prolonged fever at the onset of KD. Bilateral localization of giant aneurysms was detected only in males, mainly under the age of 1 year. The occurrence of MACE was recorded in 55.5% of children with giant aneurysms. The disappearance of blood clots on imaging in giant/medium CAA after an average of 15 months and complete regression of aneurysms in 58.0% of patients occurred on average 2.3 years after the onset of the disease during the prolonged antithrombotic therapy and in some cases with the use of atorvastatin. The high incidence of giant CAs and major cardiovascular events in KD requires early detection and continuity of follow-up between pediatricians and pediatric and adult cardiologists.