Follow-Up Study of Echocardiography in 38 Children With Kawasaki Disease Complicated by Heart Lesion

Background: The most common and most serious complication of Kawasaki disease (KD)is heart lesion(HL), which is the main cause of childhood acquired HL. Objective: Use echocardiography to study the HL recovery of children with KD complicated by HL, and provide an important theoretical basis for the prognosis of KD complicated by HL. Methods: Using prospective research methods, 38 children with KD complicated by HL were followed up for echocardiographic examination, and the longest examination time was one year. And carry on statistical analysis to the inspection data. Results: In 38 children with KD complicated by HL, 36 cases of coronary artery lesion (CAL), including 29 cases of coronary artery dilation(CAD), 7 cases of coronary artery stenosis(CAS), and 2 cases of simple pericardial effusion without CAL. CAL complicated with valve regurgitation in 4 cases, pericardial effusion in 3 cases, and left ventricular enlargement in 4 cases. In about 3 weeks, most of the pericardial effusion and mild CAD recovered. At 3 months, except for a few severe CAL, heart valve regurgitation and left ventricular enlargement all recovered. The recovery of moderate CAD was slow. One case still failed to return to normal after 1 year, but the coronary artery diameter gradually decreased. Conclusion: Kawasaki disease complicated by heart lesion mainly affects the coronary arteries, and the main manifestation is expansion. The more the expansion, the slower the recovery.

rash; (5)nonpurulent bilateral eye injection; and (6)cervical lymphadenopathy(> 15mm). Those who meet 5 of the above 6 diagnostic criteria are diagnosed as CKD; Those who only meet 3 or more but less than 5 items are diagnosed as IKD after CAL is found in cardiac imaging examination and other diseases are excluded [15]. Therefore, echocardiography has become an important basis for diagnosing KD.
People are not very clear about the etiology and pathogenesis of KD. Rigante D recently explored the potential role of viruses in triggering the in ammation that generates KD in genetically predisposed children [16]. Findings seem to suggest that a dysregulated immune response to various microbial agents, such as viruses, may be the main cause of the onset of KD. Although KD is a self-limiting disease, it will leave sequelae such as CAD. Severe CAD, it is di cult to recover in the short term, therefore, some children need long-term or even life-long follow-up.
This study conductes echocardiographic follow-up examinations of 38 children with KD complicated by HL, and analyzes the examination data in order to understand the recovery of HL in children with KD and provide experimental evidence for clinical research.

Research object
Selected the cases in children with KD complicated by HL who were admitted to the Pediatric Department of Weifang People's Hospital Province, China from January 2015 to January 2020 as the study objects.
All cases underwent routine echocardiographic examinations when they were admitted to the hospital, and performed echocardiographic examinations continuously during the 3 weeks, 6 weeks, 3 months, 6 months, and 1 year after initial onset to observe the prognosis. If the HL had recovered, the echocardiographic examination will not be continued. Recorded medical records and all examination data in detail. The study was approved by the Ethics Committee of Weifang People's Hospital(No: 2020019) and obtained the consent of the child's family or guardian and signed an informed consent form.

Inspection Method
During the examination, the child was lying on the left side, and all were performed in a state of sleep or emotional stability. Used the instrument Philips i E33 ultrasonic diagnostic instrument, seted the probe frequency to 3.5 ~ 8.0MHz, followed the American Echocardiography Association Pediatric Echocardiography Guide for echocardiography examination [17]. Find out the size of the heart chamber, wall motion, heart function and blood ow, observe whether there is pericardial effusion. Focus on the coronary artery scan, measure the left main coronary artery, left anterior descending and proximal right coronary artery inner diameters, store dynamic images play back the measurement, repeat 3 times, and nally take the average value.

Observation indicators
Use echocardiography to observe HL changes and coronary artery diameter at each follow-up time point.
The diagnostic criteria of CAD: mild dilation (coronary artery diameter > 3mm, ≤4mm), moderate dilation (coronary artery diameter 4 ~ 7mm) [18]. The coronary artery intima is thickened, blurred, uneven, echo enhanced, and inner diameter narrowed, which is judged as CAS. The standard value for the return of the coronary artery diameter to normal in children is: under 3 years old, coronary artery diameter < 2.5 mm; 3 to 9 years old, coronary artery diameter < 3.0 mm [19].
Statistical analysis SPSS 23.0 (IBM Corp, Armonk, NY, USA) was used for statistical analysis. The measurement data was expressed as a percentage, and the counting data was expressed as a percentage. The statistical method used analysis of variance. P < 0.05 indicates that the difference was statistically signi cant.

Basic characteristics of the study subjects
A total of 332 cases in children with KD diagnosed were admited to the Department of Pediatrics, Weifang People's Hospital, Shandong Province, China from January 2013 to January 2020. Among them, 38 cases (24 males and 14 females) were complicated by HL, accounting for 11.45% of the total number of children with KD. The age of onset in children with HL was 6 months to 5 years, with an average of (27.66 ± 12.82) months. The basic clinical characteristics are shown in Table 1.   The in ammation began to subside in the cases about 3 weeks, and pericardial effusion and most of themild CAD returned to normal. At 6 weeks, the myocardium gradually recovered and the pericardial effusion was completely absorbed. At 3 months, except for a few severe CAL, heart valve regurgitation and left ventricular enlargement all recovered. The recovery of moderate CAD was slow. One case still failed to recover after 1 year. See Table 3 and Fig. 1. Compared with the coronary artery diameter at the initial onset, the coronary artery diameter at each tracking point was reduced, and the coronary artery diameter in the mild dilation group recovered faster.
The coronary artery diameter of children in the moderate dilation group recovered more slowly than that of mild dilation, and there was still one case at 1 year that did not recover, but the coronary artery diameter values was gradually decreasing. See Table 4. .48 ± 0.21*#&( Mild group: *compared with Initial episode P < 0.01,# compared with 3 weeks P < 0.01 & compared with 6 weeks P < 0.05; Moderately group *compared with Initial episode P < 0.01 #compared with 3 weeks P < 0.01 &compared with 6 weeks P < 0.01 ^ compared with 3 months P < 0.05 )

Discussion
Echocardiography is an important method to assess the degree of vascular damage in KD complicated by HL. For children 5 years old and below, the chest wall is thin, echocardiography has good sound permeability, and can be repeated, non-radiation, non-invasive. The high-frequency ultrasound probe can clearly display the inner diameter, intima thickness and course of the coronary artery, and can quantitatively measure the degree of lesions. It has high sensitivity and speci city and is the rst choice for early diagnosis and follow-up of coronary artery [20]. In addition, echocardiography can clearly detect valvular regurgitation, pericardial effusion, segmental myocardial movement abnormalities, heart enlargement and other pathologies. It has become the rst choice for children's cardiovascular system disease examination.
The incidence of HL in KD varies from country to country. The Pediatric Department of Weifang People's Hospital admitted 332 cases in children with KD in 5 years, of which 38 cases were complicated by HL, accounting for 11.45% of the total number of children with KD. The incidence of CAL is 10.84%, which is slightly higher than the latest Japanese report [21]. In recent years, with the increase in the incidence of IKD, the incidence of CAL has also increased [7,8,22]. The occurrence of HL in KD is related to its pathophysiology. Systemic vasculitis is one of the characteristic lesions of KD, which is caused by excessive activation of the immune system. Continuous fever causes the release of in ammatory transmitters, leading to dysfunction of vascular endothelial cells, thereby enhancing the adhesion of leukocytes and participating in the formation of vasculitis [20,23]. Such as Interleukin-6 (IL-6), etc. are signi cantly increased, especially in patients with IKD [24,25]. The cardiovascular system in the acute stage of KD has obvious manifestations, including the pericardium, myocardium, endocardium, various valves and coronary arteries, which can cause arrhythmia, ventricular enlargement, valve regurgitation, and myocardial ischemia. KD most often invades the coronary arteries, causing them to dilate, stenosis, or harden. Especially IKD has a higher incidence of CAL than CKD [26-28]. Severe KD can lead to macrophage activation syndrome, causing multiple organ failure [29]. Therefore, for clinically suspected KD patients, cardiac imaging examinations should be performed in time to con rm the diagnosis, so as not to miss the opportunity for diagnosis and treatment.
There are three interrelated vascular pathological processes in KD, acute self-limiting necrotizing arteritis (NA), subacute or chronic vasculitis (SA/C) and luminal myo broblastic proliferation (LMP) [30]. NA is the neutrophil in ammation of the vascular endothelium synchronized with KD. It is a self-limiting process that starts and ends within 2 weeks of fever. SA/C vasculitis is asynchronous with the onset of KD. It is an in ammatory process dominated by small lymphocytes. It can begin within 2 weeks of onset and last for months to years, and is closely related to LMP lesions. SA/C vasculitis damages the blood vessel wall to varying degrees from the adventitia or surrounding tissues of the blood vessel, causing the blood vessel wall to form tumor-like expansion. LMP mainly causes stenosis of the lumen. Consistent with SA/C vasculitis, LMP can start within 2 weeks of onset and last for months to years [18].
The recovery of CAL is related to the degree of injury. The pathological basis of mild dilation is mainly NA, which is relatively easy to recover. The main pathological change of moderate to severe dilatation is SA/C, the disease has a slow recovery, and the recovery rate is low, which is consistent with our research.
According to literature reports, the incidence of huge CAA (severe expansion) is 0.13-0.70% [3], and the possibility of recovery is very small [31]. We have not found a huge CAA in our research. Since KD is a self-limiting disease, the coronary arteries with transient or mild dilation during the acute phase will usually return to normal within 3 months as the in ammation disappears in the late acute phase. With the application of gamma globulin and aspirin, myocarditis, pericarditis and other pathologies returned to normal in more than 6 weeks. Consistent with our research. Numerical changes of cardiac and coronary echocardiograms are closely related to clinical pathological changes and become an important clinical reference.
The y in the ointment was in all HL cases, the cardiac ultrasound data parameters are not available when normal, such as the size of the left ventricular diameter, the physiological regurgitation of the valve. There are individual differences in these data, so it is impossible to compare before and after the individuals themselves, which may have a certain impact on the prognostic evaluation of these disease parameters. In addition, the case of coronary artery dilation does not have the data before the onset, so when the dilated coronary artery diameter returns to the normal range, whether the data is different from the coronary artery diameter when it is normal is not known, because the inner diameter of the coronary artery itself has individual differences. On the other hand, for the HL that recovered, the follow-up could not be continued for one year, so that the later heart changes could not be observed.

Conclusion
In summary, KD can cause pericarditis, myocarditis, endocarditis, and invade various valves and coronary arteries. It has become the main cause of childhood acquired heart disease. The main manifestation is CAD. The heavier the dilation, the slower the recovery. Echocardiography plays an important role in cardiac examination and is the rst choice for children's cardiovascular disease examination. The use of echocardiography to continuously track and check children with HL can accurately and conveniently grasp the prognosis of HL. In addition, KD has a certain recurrence rate [32][33][34][35], and long-term follow-up has important clinical value for studying the recurrence of KD.
Abbreviations CAL coronary artery lesion CAD coronary artery dilation CAS coronary artery stenosis CAA coronary artery aneurysm; CKD: Complete Kawasaki disease; HL heart lesion IKD: incomplete Kawasaki disease; KD Kawasaki disease LMP: luminal myo broblastic proliferation; NA: necrotizing arteritis; SA/C: subacute or chronic vasculitis. Figure 1 HL recovery curve in childrens