1 INTRODUCTION THESIS Necessity of topics Kawasaki disease has many organ involvements, but coronary artery involvement is the most serious problem of the disease, since the coronary artery inflammation is progressing silently for several months, several years leading to intimal thickening, arteriosclerosis, calcification and myocardial infarction even sudden death Thus, long-term follow-up of cardiac lesions, especially of giant aneurysms is necessary At the acute stage, when the children are small, the use of echocardiography is a basic and sufficient for diagnosing the coronary artery involvement However, as children grow up, the use of echocardiography will be limited, especially in assessment of stenosis or in distal segment Therefore additional diagnostic imaging methods are needed Coronary angiography is the gold standard in assessment but is invasive method, so it is not used regularly The introduction of a multiple slice computed tomography 256 (MSCT256) allowed the estimation of adequate and accurate coronary lesions in children However, application of MSCT-256 in the diagnosis of coronary artery disease in children in general and children with Kawasaki in particular has not been applied much, especially in Vietnam Therefore, we conducted the research project "Evaluate progress of coronary artery involvement in Patient with Kawasaki disease” with the following objectives: Evaluate progress of coronary artery involvement and related factors for the regression coronary artery involvement in children with Kawasaki disease Assess the value of diagnostic imaging methods (echocardiography, multiple slice computed tomography 256- MSCT 256) in evaluating and monitoring coronary lesions in Kawasaki disease New contributions of the thesis The study used a MSCT-256 with echocardiography to monitor and evaluate coronary lesions in long-term in children with Kawasaki disease with long- term follow-up MSCT- 256 allows evaluating the entire system of coronary artery from the proximal to distal segment, assessing the aneurysm, stenosis and calcification Image in MSCT256 is honest, objective and accurate Thus, the study provides a comprehensive and accurate assessment of coronary lesions sufficiently, in overview about this progress We hope that, it could provide readers with the information about the role of each imaging method (echocardiography, MSCT-256) in monitoring and evaluation of coronary artery involvement, which defenses on time after onset Therefore, the topic is scientific, practical value, contributing greatly in improving the quality of treatment of coronary artery disease in children, especially children with Kawasaki disease The topic also contributes to the study of Kawasaki disease in Vietnam Thesis layout The thesis consists of 127 pages, apart from the introduction (2 pages), the conclusion (2 pages) and the recommendation (1page) also has four chapters include: Chapter 1: Overview (38 pages); Chapter 2: Materials and Methods (16 pages); Chapter 3: Results (30 pages); Chapter 4: Discussions (38 pages) The thesis consists of 35 tables, 12 pictures, charts, diagrams and 133 references (5 in Vietnamese; 128 in English) and appendix Chapter 1: LITERATURE REVIEW 1.1 Progress of coronary artery involvement Inflammation of the entire vascular wall progresses silently leading to damage of the middle layer of blood vessels, smooth muscle cell necrosis, disrupting normal structure into blood vessel Vessels become weakened and vascular aneurysm appears Endothelial damage and dysfunction of the endothelium cells cause platelet deposition, which is the risk of blood clots forming, narrowing the arteries causing the arteries to become clogged, either by thrombosis, or by narrowing of the arteries (Figure 1.2) Figure 1.2 Progression of coronary artery involvement 1.2 Criteria for cardiac lesions in Kawasaki: Coronary artery anomaly is defined at least one of the findings on echocardiography presented: 1.2.1 According to Japanese Ministry of Health (JMH)-1998  Absolute internal lumen diameter ≥ 3mm in children aged younger than years or ≥ 4mm in children aged years or older  A segmental internal diameter of any segment ≥1.5 times greater than that of an adjacent segment  Coronary artery walls are noticeably abnormal Studies on coronary artery involvement in KD mostly follow this standard 1.2.2 According to the American Heart Association (AHA) 2004:  Internal diameter ≥ + 2.5 SD normal value by skin area  The inner diameter of a segment is 1.5 times greater than the adjacent segment  Abnormal coronary artery vessels, bright light around the vessels and coronary arterial diameter losing tapping 1.3 Classification of coronary artery aneurysms (AHA -1994)  Small aneurysms: Lumen diameter < 5mm  Medium aneurysms: Lumen diameter ≥ 5mm < 8mm  Giant aneurysm: Luminal diameter ≥ mm 1.4 Classification of severity: According to JMH 2008  Grade I: No dilated lesions in the acute phase  Grade II: Transient dilatation in the acute phase: Mild, transient dilation that normalizes after 8-10 weeks  Grade III: Regression: Residual aneurysms formation equivalent to or greater than dilation by 8-10 weeks that have completely normalized by year after onset but grade V is not applicable  Grade IV: Residual coronary artery aneurysm is seen more than year later and to whom grade V is not applicable  Grade V: Coronary artery stenosis  Va: No ischemic findings  Vb: Ischemic findings JMH- 2013 revised, shortened the time of grade II and III to 30 days 1.5 Study of coronary artery involvement in patient with Kawasaki 1.5.1 In the world: There have been many studies on coronary artery involvement, evolution of this involvement and many topics about the factor related to the evolution of coronary artery lesion as well as diagnostic methods for monitoring lesions In Japan, there is a Kawasaki Specialized Research Center There are so many specialists in the field of genetics, pathology, and treatment in the world 1.5.2 In Vietnam: Kawasaki disease has been diagnosed for the last two decades There have been a number of studies on the disease, but almost of them has been clinical, subclinical findings, and coronary involvement in acute phase There is less long-term follow-up study on later In 2008, Dang Thi Hai Van's research was also on this subject, but her subjects with follow-up time no longer enough, most of her assessments are in acute and sub-acute phase There were limits on follow-up period, and means for monitoring lesion In particular, there was no published study about the role of MSCT in evaluating coronary artery lesions in Kawasaki KD with large numbers of KD Chapter 2: MATERIALS AND METHODS 2.1 Research subjects: 89 patients with Kawasaki disease (KD) 2.1.1 Standard KD selection: Enough of conditions + Was diagnosed with KD based on the diagnostic criteria of the Japan National Committee for Kawasaki Disease and the American Heart Association, treated at the National Hospital of Pediatrics Include: • 24 KD diagnosed before 2012 • 65 KD diagnosed from January 2012 to June 2016 + Has at least 1coronary artery involvement grade III or higher according to Japanese Ministry of Health (JMH-2008), including: • 24 KD diagnosed before 2012: Coronary artery involvement detected on echocardiography existing after 12 months onset (≥ grade IV) • 65 KD diagnosed from January 2012 to June 2012: Residual coronary artery involvement on echocardiography after months onset (≥ grade III) KD was identified to have coronary lesions in the acute phase, which were followed for at least the first months and subsequent months according to the severity of the lesion + KD were monitored by clinical examination, electrocardiogram, echocardiography and MSCT-256 was done at least once time during follow-up MSCT screening is only conducted after an acute phase of at least months The patients having sequela in the first MSCT, regression markedly aneurysm or suspect of stenosis on echocardiography during follow-up and the agreement for the second time MSCT will be done the second MSCT 2.1.2 Exclusion criteria: Kawasaki KD with ≥1 condition: + Coronary artery involvement grade I, grade II or + Unsubscribe or + MSCT- 256 wasn’t done 2.2 Research Methods 2.2.1 Study design: Descriptive research 2.2.2 Sample size * Objective 1: Descriptive research Sample size is calculated by the formula: p.q d2 Where: Z = 1.96 (α-5%): 95% confidence; d = 0.1: Adjustment factor; p: number of previous experience; q = 1- p The sample size for objective was: p = 0.75: The regression rate for Kevin's G study q = 1- 0.75 = 0.25: Residual Involvement Rate Thus: n = 1.962 (0.75 * 0.25) /0.12=72.04 So the number of KD needs to roll in: 73 KD 89 KD admitted to the study were eligible for sample size Objective 2: 89 KD, each MSCT- 256 could assess at least principal coronary arteries: Left main coronary artery (LMCA); Left anterior descending (LAD); Left Circumflex (LCx); RCA (right coronary artery) These coronary arteries are also evaluated on echocardiography at each time Thus, the number of coronary arteries is evaluated at least: 89 * = 356 With this number of coronary arteries evaluated, it is satisfactory for the statistical evaluation algorithms, for assessment the role of these two imaging methods 2.2.3 Research material: Echocardiography was done on the Hewlett-Packard SONO 5500 and EnVosor with the leading detect 7.5/5.5 MHz and 5.0/ 3.5 MHz at National Hospital Pediatric by Pediatric Cardiologist MSCT-256 was done on Siemens Sensation machine, Somatom definition flash 256 at Bach mai Hospital 2.2.4 Analysis data: On SPSS 16.0 n = Z21-α /2 Chapter 3: RESULTS We used MSCT -256 instead of a coronary angiography combining echocardiography in order to evaluate the progress of coronary arteries involved in 89 KD who have at least coronary artery injury ≥ grade III according to the JMH 3.1 Patient characteristics 3.1.1 Clinical characteristics (table 3.1): 89 KD included 64 male; 56 children with aged onset ≤12 months; 71 typical KD; 83 children received IVIG; 44 infants using gamma globulin (IVIG) before 10 days and 21 infants with IVIG resistance, only KD recurred 3.1.2 Coronary artery involvement at base line: Coronary involvement is confirmed at months after onset: 89 KD with a total of 265 coronary arteries involved, including LMCA (85; 32.1%); LAD (77; 29.0%); LCx (23; 8.7%); RCA (80; 30.2%) Of these, 94 were aneurysm (94/265; 35.5%) The number of coronary arteries involved in each patient was: 1coronary artery involved (6; 6.7%); coronary arteries involved (12; 13.5%); coronary arteries involved (49; 55.1%) and coronary arteries involved (22; 24.7%) 42 (47.2%) KD with small aneurysm; with medium aneurysm (36; 40.4%) KD and giant aneurysm (11; 12.4%) KD (table 3.2 table 3.4) 3.1.3 Coronary artery involvement on echocardiography when taking MSCT for the first time Table 3.7 Coronary injuries on echocardiography at taking MSCT for the first time Coronary artery involvement on echocardiography ∑ Dilatation, stenosis (n**) Aneurysm (n**) ≤12 months 15 23 38 12- ≤24 months 20 21 24-≤72 months 18 20 > 72 months 10 ∑ 59 30 89 * Time after onset MSCT done; ** n: number patient Remarks: The majority of KD underwent MSCT for the first time within a year after onset (38/89) KD Almost all of aneurysm has been seen on echocardiography in one year after onset (23/38 KD) The years later, at the time of MSCT, on cardiography, aneurysm is rarely seen Age of disease * 3.1.4 General information about KD before taking MSCT MSCT were done at least once time for all patients, among the 89 KD, 63 KD with MSCT done once time and 26 KD with MSCT done twice Of the 26 KD undergoing MSCT twice, there were KD, the first of which was done before 2012 Clinical examine, echocardiography realized before taking each MSCT: 1-7 days Table 3.8 General information about KD before taking MSCT Age of disease* ≤ 12 months 12-72 months > 72 months Average age of disease (month) Average real age (month) MSCT for the first time (n=89) 38 41 10 26.3±29.3 (2-125) Median: 15 43.6±37.1 (6-191) Median: 31 MSCT done once time (n=63) 26 33 22.4±23.0 (3-120) Median: 15 37.1±28.7 (8-163) Median: 28 Average distance between two MSCT done MSCT done times ∑** First time Second time (n=26) (n=26) 12 39 13 54 12 22 35.9±40.0 67.2±50.1 (2-125) (12-204) Median: Median: 20 49 35.9±40.0 67.2±50.1 (2-125) (12-204) Median: Median: 20 49 31.4±26.9 months (6-141) Median: 25 months *: Time after onset MSCT done; **: Number MSCT done Remarks: Minimum age of disease, the minimum real age of KD taking MSCT is months and months, respectively 3.2 Progress of coronary arteries followed by diagnostic imaging 89 KD with coronary artery involvement in grade III or more severe, duration of follow-up ranged from 3-204 months; median: 20 months We saw: 3.2.1 Regression: The regression rate was 50.6% (45/89) KD and the regression rate was 73.2% (194/265) coronary arteries involved Table 3.11 Rate of regression of coronary arteries involved according to the time after onset Regression No-regression Total Time after onset n % n % n % ≤ 12 months 12 - 72 months >72 months Total *p0,05 Coronary artery Total n 85 77 23 80 265 % 100 100 100 100 100 Remarks: In general, the regression rate of the left coronary artery system is higher than right coronary artery LMCA regression rate was higher than LAD and RCA (p 0.05) Table 3.10 Progress of coronary artery involvement according to their classification of size NoClassificaRegression regression Total tion of se95%CI OR verity n % n % n % Small an- 137 84.6 25 15.4 162 100 eurysm 1.8-6.0 Medium 54 62.8 32 37.2 86 100 3.2 aneurysm Giant an- 17.6 14 82.4 17 100 25.6 6.6-95.5 eurysm Total 194 73.2 71 26.8 265 100 p0.05) In medium aneurysms, the rate of regression of the LMCA was higher than that of LAD and the RCA (p80%) and all had RCA stenosis (5/5), only 2/5 KD with LAD stenosis (table 3.17) 3.3 Value of echocardiography, MSCT- 256 in the assessment, monitoring of coronary artery involved in patients with Kawasaki 3.3.1 Role of echocardiography Table 3.21 Value of echocardiography versus MSCT in detecting coronary aneurysm Examine on MSCT Aneurysm No∑ aneurysm Aneurysm 55 13 68 Examine on No77 315 392 Echocardiography aneurysm Total 132 328 460 Remarks: Sensitivity: 41.7% Specificity: 96.0% Positive Predictive Value: 80.9% Negative Predictive Value: 80.4% 13 Table 22 Value of echocardiography versus MSCT in detecting coronary aneurysm in case of age of disease ≤ 12 months Examine on MSCT Aneurysm No∑ aneurysm Aneurysm 39 44 Examine on No21 91 112 Echocardiography aneurysm ∑ 60 96 156 Remarks: Sensitivity: 65% Specificity: 94% Positive Predictive Value: 88.6% Negative Predictive Value: 81.3% Table 23 Value of echocardiography versus MSCT in detecting coronary aneurysm in case of age of disease > 12 months Examine on MSCT Aneurysm No∑ aneurysm Aneurysm 16 24 Examine on No56 224 280 Echocardiography aneurysm ∑ 72 232 304 Remarks: Sensitivity: 22.2% Specificity: 96.6% Positive Predictive Value: 66.7% Negative Predictive Value: 80.0% Table 3.26 Progress of coronary aneurysms follow-up on Echocardiography Initial coronary Results after follow-up on p2 aneurysm echocardiography Coronary n Average n Average Rate of artery lumen lumen regresdiameter diameter sion (SD) (SD) (%) LMAC 26 13.3±5.5 7.5±4.7 69.2 0.05) Reduced size of aneurysms was noted for significant differences in all three coronary arteries: LMCA; LAD and RCA (p 0.05 LAD 15 14.5±6.1 9.9±6.2 0.05 RCA 25* 18.3±8.4 15 12.1±9.5