Kawasaki Disease : Current Understanding of the Mechanism and Evidence-Based Treatment

Foreword 12 Preface 14 References 15 Contents 16 Part I: Basic Research 21 The History of Kawasaki Disease: A Personal Perspective 22 Introduction 22 The Era of Clinical Description and Pathologic Recognition: 1960-1984 23 Back to the Future: 1871-1984 and Other Riddles of KD 25 The Era of Enhanced Discovery and International Collaboration: 1984-2015 26 References 27 Histopathology of Coronary Arteritis in Acute Kawasaki Disease and Murine Systemic Vasculitis Induced by Candida Albicans Cell... 29 Introduction 29 Histopathological Characteristics of Coronary Arteritis in Acute KD 30 The C. Albicans Cell Wall Polysaccharide-Induced Murine Vasculitis Model 31 Model Development and Description of the Vasculitis-Inducing Agent 31 Histopathological Characteristics of C. Albicans Polysaccharide-Induced Murine Vasculitis 31 Relationship of Mouse Genetic Background to Cytokines and Vasculitis 32 Response of C. Albicans Polysaccharide-Induced Vasculitis to Treatment 33 References 33 Histopathological Characteristics of Noncardiac Organs in Kawasaki Disease 35 Introduction 35 Brief Overview of Systemic Vascular Lesions in KD 35 Histological Changes in Noncardiac Organs in KD 36 References 39 Identification of Novel Kawasaki Disease Susceptibility Genes by Genome-Wide Association Studies 41 Introduction 41 History of the Genetic Study of KD 42 Genomic Studies of KD in the Post-Genomic era 42 ITPKC 42 CASP3 42 FCGR2A 43 BLK 45 CD40 45 HLA class II 45 Current Understandings and Recognition 46 Recent Advances 46 References 46 Immunological Abnormalities and Use of Biomarkers and Cytokines to Predict the Severity of Kawasaki Disease 48 Introduction 48 KD and Hypercytokinemia 49 Which Cytokines/Biomarkers Best Predict KD Severity? 50 Conclusions 52 References 53 Pathophysiology of Kawasaki Disease 55 Introduction 56 History 56 The Three Linked Pathological Processes of KD Vasculopathy 57 Recent Advances in Etiological, Genomic, and Gene Expression Studies 58 Conclusions 59 References 59 Update on Pathogenesis: Lessons Learned from Animal Models of Disease 61 Introduction 61 T-Cell Activation and Survival and the Role of Costimulation 62 Murine Models of KD 63 References 65 The Climate-KD Link 68 References 71 Kawasaki Disease Shock Syndrome 73 Introduction 73 Incidence and Demographics 73 Mechanisms 74 Clinical Course and Treatment 75 Differential Diagnosis 76 Future Perspectives 76 References 77 Future Directions in Kawasaki Disease Research 78 Advances in Treatment 78 Advances in Genetics 79 Advances in Biomarkers and Diagnostic Tests 80 Advances in Understanding Long-Term Outcomes 80 References 81 Part II: Epidemiology 83 Epidemiologic Perspectives 84 Historical Perspective 84 KD Surveillance: Moving Forward 85 KD Surveillance: Prescription for the Future 85 References 87 Update on Nationwide Surveys and Epidemiologic Characteristics of Kawasaki Disease in Japan 89 Introduction 89 Methods of the Nationwide Surveys 89 Results of Nationwide Surveys 90 What We Have Learned from the Descriptive Epidemiology 92 Conclusions 93 References 94 Kawasaki Disease Epidemiology in Europe 95 History 95 Incidence 96 Age 98 Seasonality 98 Cardiac Sequelae 98 Way Ahead 98 References 98 Recent Topics in the Epidemiology of Kawasaki Disease 100 Kawasaki Disease in Japan and Other Countries 100 Epidemiologic Characteristics of Intravenous Immunoglobulin Nonresponders 101 Epidemiology of Adult-Onset KD 102 Forty-Five Years After the First Report of KD 102 References 103 Part III: Medical Treatment 104 Overview of Medical Treatment 105 Introduction 106 Intravenous Immunoglobulin Therapy 106 Corticosteroid Therapy 107 Other Anti-inflammatory Therapies 107 Conclusions 108 References 108 Overview of the New Japanese Guideline2012 for the Medical Treatment of Acute Stage of Kawasaki Disease 110 Introduction 110 Fundamentals of New Guideline 2012 111 Previous Guideline 2003 111 General Principles of the New Guideline 2012 111 What to Do When the Child is Admitted 112 Guidelines for medical treatment of acute Kawasaki disease: Report of the Research Committee of the Japanese Society of Pediat... 113 Immunoglobulin 118 Purpose 118 Mechanism of action 120 Indications 121 Treatment method and dosage 121 Period of treatment 121 Dosage 121 Product types and directions for use 122 IVIG retreatment for IVIG-resistant patients 130 Effectiveness 131 Side-effects 132 Evidence levels 133 Methylprednisolone pulse 134 Purpose 134 Mechanism of action 134 Indications 134 Treatment method and dosage 134 Effectiveness 138 Side-effects 138 Evidence levels 139 Prednisolone 139 Purpose 139 Mechanism of action 139 Indications 139 Treatment method and dosage 139 Effectiveness 140 Side-effects 140 Evidence levels 141 Biologics (infliximab) 141 Purpose 141 Mechanism of action 141 Indications 142 Treatment method and dosage 142 Effectiveness 142 Side-effects 143 Infusion-associated reaction 144 Exacerbation of heart failure 144 Exacerbation of infectious diseases 144 Development of malignant tumors 145 Carriers of hepatitis B and C 145 Other 146 Evidence levels 146 Ulinastatin 146 Purpose 146 Mechanism of action 146 Suppression of TNF-α 146 Blocking of neutrophil elastase 147 Indications 147 Treatment method and dosage 147 Effectiveness 147 Side-effects 148 Evidence level 148 Immunosuppressants 148 Cyclosporin A 148 Purpose 148 Mechanism of action 149 Indications 149 Treatment method and dosage 149 Effectiveness 149 Side-effects 149 Evidence level 150 Methotrexate 150 Purpose 150 Mechanism of action 150 Indications 150 Effectiveness 150 Side-effects 151 Evidence levels 151 Plasma exchange 151 Purpose 151 Mechanism of action 151 Indications 151 Treatment method and dosage 151 Effectiveness 152 Side-effects 152 Evidence level 152 Antiplatelets/anticoagulants 153 Aspirin 153 Purpose 153 Mechanism of action 153 Indications 153 Treatment method and dosage 153 Effectiveness 153 Side-effects 158 Evidence level 158 Other antiplatelet medications 158 Flurbiprofen (Froben) 158 Dipyridamole (Persantin tablets, Anginal) 158 Ticlopidine (Panaldine) 158 Clopidogrel (Plavix) 159 Other cardiovascular agents 159 Anticoagulants 159 Warfarin 159 Mechanism of action 159 Indications 160 Treatment method and dosage 160 Usefulness 160 Side-effects 161 Evidence level 161 Unfractionated heparin 161 Evidence level 161 Low-molecular-weight heparin 161 Evidence level 162 Thrombolytics 162 Purpose 162 Mechanism of action 162 Indications 163 Treatment method and dosage 163 Urokinase 163 Alteplase (Activacin, Grtpa) 163 Monteplase (Cleactor) 163 Effectiveness 164 Side-effects 164 Evidence level 164 Anti-anginals and coronary vasodilators 164 Evidence level 165 Indication 165 Reference 174 Tumor Necrosis Factor-α Blockade for Treatment of Acute Kawasaki Disease 175 Introduction 175 Current Understanding 176 Infliximab 176 Etanercept 176 Safety of TNF-α Inhibitors 178 References 178 Methylprednisolone Pulse Therapy for Nonresponders to Immunoglobulin Therapy 180 Introduction 180 History 181 Current Understanding and Recognition [10-12] 181 Assigned Evidence Class and Recommendation [10-12] 183 References 183 Prednisolone 185 Introduction 185 History 186 Current Understanding and Recognition 187 Assigned Evidence Class and Recommendation 188 References 188 Cyclosporin A for IVIG Nonresponders 190 Introduction 190 Historical Overview 191 Current Understanding and Recognition 192 Pilot Study [12] 192 Patients 192 Protocol 192 Results and Discussion of the Pilot Study 192 Third IVIG as an Effective Option for CsA-Resistant Patients 193 Prevention of CAL Development by CsA 194 Adverse Events 195 Trough CsA Levels 195 Route of CsA Administration 196 Summary and Future Direction 196 References 196 Other Challenging Therapies 198 Introduction 198 Biological Agents 199 Cytotoxic Agents 199 Plasma Exchange 200 References 201 Antiplatelet and Antithrombotic Therapy for Giant Coronary Aneurysm 202 Introduction 202 Historical Overview 203 Current Understanding and Recognition 203 Assigned Evidence Class and Recommendations 203 Recent Advances and Future Directions 206 References 206 Characteristics of Sudden Cardiac Death Late After Acute Kawasaki Disease 209 Introduction 209 History 210 Current Understanding 211 Evidence Quality and Recommendations 213 Recent Advances 214 References 214 Kawasaki Disease Diagnosis and Complication Rates in the United States and Japan 216 Guidelines for Kawasaki Disease in the United States and Japan 217 Diagnosis 217 Complete KD 217 Incomplete KD 219 Complication: Coronary Artery Aneurysms 219 References 222 Mechanism of Action of Immunoglobulin: Sialylated IgG 224 Introduction 224 Glycosylated IgG 226 Sialylation of IgG Fc 227 General Characteristics of DC-SIGN 228 The Potential DC-SIGN-Mediated IVIG Mechanism 229 Conclusion 230 References 230 Treatment Options for Refractory Kawasaki Disease: Alternative Treatments for Infliximab Nonresponders 232 Introduction 232 IFX Nonresponders 233 IFX Therapy in KD 233 IFX Nonresponse in Inflammatory Disease 233 Definition and Incidence of IFX Nonresponse in KD 234 Treatment of IFX Nonresponders 234 Conclusion 236 References 236 Ulinastatin 239 Introduction 239 Historical Overview 240 Current Understanding 241 Assigned Evidence Class and Recommendation 241 Recent Advances 242 References 243 Part IV: Diagnosis and Examinations 245 Diagnosis and Management of Cardiovascular Risk Factors 246 Introduction 246 Cardiovascular Risk Factors and Vascular Disease 247 Assessment 248 Management 249 Lifestyle Management 249 Drug Therapy 251 Summary 251 References 252 Diagnosis and Characteristics of Typical and Incomplete Kawasaki Disease 254 Introduction 254 Patient Characteristics 256 Age 256 Sex 256 Symptoms and Diagnostic Criteria 256 Principal Symptoms (Table1) 256 Fever 256 Bilateral Bulbar Conjunctival Injection (Fig.2) 258 Changes in the Lips and Oral Cavity (Fig.3) 258 Polymorphous Exanthema (Fig.4) 258 Changes in Extremities (Fig.5) 259 Acute Nonpurulent Cervical Lymphadenopathy (Fig6) 260 Definition of Final Diagnosis 262 Other Significant Symptoms or Findings 262 Gastrointestinal Tract 262 Gall Bladder Swelling 262 Liver Dysfunction 263 Paralytic Ileus 263 Urine Analysis 263 Erythema or Induration at the BCG Inoculation Site: (See Principal Symptom 4, Fig.8) 263 Cardiovascular Symptoms 264 Other Symptoms 264 Incomplete KD 264 Summary 267 References 267 Scoring Systems to Predict Coronary Artery Lesions and Nonresponse to Initial Intravenous Immunoglobulin Therapy 269 Introduction 269 History of Scoring Systems 269 Scoring System to Predict Nonresponse to Initial IVIG 271 References 274 Use of Magnetic Resonance Angiography for Assessment of Coronary Artery Lesions Caused by Kawasaki Disease 276 Introduction 276 Procedure 277 MRCA: Indications in Patients with KD 277 Advantages of MRCA 278 Limitations of MRCA 280 Conclusion 280 References 281 CT Coronary and Myocardial Images in Patients with Coronary Artery Lesions 282 Beyond Cardiac Catheterization 283 Coronary Computed Tomographic Angiography 283 Overview 283 Indications for CCTA 283 Three Drawbacks of CCTA 283 Beta-Blockade 284 Contrast Medium 284 Radioactive Exposure 284 Advantages of CCTA 284 Advantages of CCTA as Compared with Magnetic Resonance Coronary Angiography 284 CCTA Advantages in Patients with Coronary Artery Lesions After KD 285 Cardiac Radionuclide Imaging 286 Category 286 Indications for MPI 286 Planning of Rest and Stress Imaging for MPI 286 One-Day Protocol 286 Two-Day Protocol 286 Outline of Stress Imaging 287 Exercise Stress Imaging 287 Pharmacologic Stress Imaging 287 Comprehensive Plan for Image Acquisition Using Tc-Labeled Agents 288 Control of Body Movement 288 Time Interval in Image Acquisition 288 Monzen Position 288 Soda Water 288 High-Fat Meal 288 Appropriate Administration of Nuclear Agents 289 Future Directions 290 References 291 Long-Term Follow-Up and Education Regarding Daily Life Activities, School Life, and Guidelines After Acute KD 293 Two to 3 Months After Onset 293 Vaccination After KD 294 After 2-3 Months from Onset 294 Evaluation and Management of Patients with CAL 295 Management of School Life in Japan 295 Preparation for Transition to Adult Cardiologists 295 References 296 Assessment of Cardiac Ischemia During Acute and Long-Term Follow-Up and Rheologic Assessment of Coronary Artery Lesions After ... 298 Assessment of Cardiac Ischemia During Short- and Long-Term Follow-Up 298 Exercise Electrocardiography 299 Treadmill Stress and Ergometer Stress ECG 299 Pharmacologic Stress Body Surface Potential Mapping 299 Signal-Averaged ECG 299 Stress Echocardiography 300 Radionuclide Imaging 300 Pharmacologic Stress Myocardial Perfusion Scintigraphy 300 Cardiac Ischemia Assessed by Rheologic Index 301 Rheologic Assessment of CAL After KD 301 Methods and Criteria for Assessment of Coronary Hemodynamics 301 Change in Coronary Hemodynamics Associated with CAL 303 Hemodynamics in Coronary Aneurysms Without Significant Stenosis and in Distal Vessels 303 Hemodynamics in Aneurysms 303 Hemodynamics in Vessels Distal to an Aneurysm 303 Hemodynamics in the Area Distal to a Stenotic Lesion 304 References 304 Promising Biomarkers in Acute Kawasaki Disease and Acute Coronary Ischemia 306 Introduction 307 Predicting Nonresponse to Immunoglobulin Therapy 307 Diagnosis and Evaluation of the Severity and Likelihood of CAL Formation in KD 308 Inflammatory Proteins 308 CRP 308 Pentraxin-3 (PTX3) 308 Serum Amyloid A (SAA) 309 General Laboratory Variables 309 Total Protein and Albumin 309 Serum Transaminase 309 Serum Electrolyte 309 Urinary Beta-2 Microglobulin (u-beta2MG) 309 Brain Natriuretic Peptide (BNP) and N-Terminal proBNP (NT-proBNP) 310 Inflammatory Cytokines 310 Acute Coronary Ischemia 311 Markers in Myocardial Cytoplasm 311 CK and CK-MB 311 Myoglobin 312 H-FABP 312 Myocardial Structural Proteins as Markers 312 TnT and TnI 312 MLC 312 References 313 Coronary Artery Diameter Z Score Calculator 315 Introduction 315 History 315 Recent Advances 316 Coronary Artery Diameter Z Score Calculator 317 Meaning of Coronary Artery Diameter Z Scores 317 References 326 Evidence of Endothelial Damage in Acute KD 328 Introduction 329 The Endothelium and Endothelial Injury and Repair 329 Clinical Assessment of Endothelial Function and KD 329 Circulating Markers of Endothelial Function and KD 330 Recent Advances 332 References 332 Oxidative Stress in Kawasaki Disease 334 What Is Oxidative Stress? 334 Inflammation and Oxidative Stress 335 Oxidative Stress During Acute KD 336 Involvement of Oxidative Stress in Vascular Illnesses After the Acute Phase 338 Real Picture of Oxidative Stress During Late KD 340 Conclusion 343 References 344 Part V: Catheter Intervention and Surgery 346 Antiplatelet and Anticoagulant Therapies for Kawasaki Disease: Theory and Practice 347 Introduction 347 Historical Review 348 The Procoagulant State in KD 348 Vasculitis as the Basis for Hypercoagulability 349 Flow Disturbance and Stagnation Stimulate Coagulation 349 Platelet Activation, Adhesion, and Aggregation in KD 350 Antiplatelet Drugs 351 Aspirin 351 Thienopyridine ADP Receptor Blockers (Ticlopidine and Clopidogrel) 353 Dipyridamole 354 Abciximab (Glycoprotein IIb/IIIa Inhibitor) 355 Anticoagulant Drugs 355 Warfarin 355 Unfractionated Heparin 358 LMWH 359 Thrombolytic Therapy 360 Future Directions in Antiplatelet and Anticoagulant Therapies for KD 361 Initiative Toward Evidence-Based Uses of Antiplatelet Agents 361 Randomized Clinical Trials of New Oral Direct Anticoagulants 362 References 362 Guideline for Catheter Intervention in Coronary Artery Lesion in Kawasaki Disease 365 Research Group of Ministry of Health, Labour and Welfare ``Study of treatment and long-term management in Kawasaki disease´´. 366 I. Background 367 II. Natural history of coronary artery lesion in Kawasaki disease 368 III. Catheter intervention for patients with Kawasaki disease 368 1) Indication of catheter intervention 368 a. Consideration of indication in patient´s conditions 368 b. Consideration of indication in lesion sites 369 2) Types of procedures, and their indications and precautions 369 (1) Percutaneous transluminal coronary revascularization (PTCR) 369 (2) Percutaneous transluminal coronary balloon angioplasty (PTCA) 370 (3) Stent implantation 370 (4) Rotational ablation (Rotablator) 370 (5) Intravascular ultrasound imaging 371 3) Institute and backup system 371 IV. The management of post-procedure and evaluation, and follow-up 371 V. Prospects: especially relation to bypass surgery 371 Long-Term Clinical Follow-Up After Rotational Atherectomy for Coronary Arterial Stenosis in Kawasaki Disease 375 Clinical Outcomes for Rotablation for Kawasaki Disease Coronary Artery Lesions 375 Patients, Lesions, and Information on the Procedures 375 Acute Outcomes 376 Late Restenosis 377 New Coronary Aneurysms in the Late Period 377 Long-Term Prognosis for Patients Undergoing PCI on KD Coronary Artery Lesions 378 Summary 379 References 379 Long-Term Outcomes of Pediatric Coronary Artery Bypass Grafting and Down-Sizing Operation for Giant Coronary Aneurysms 380 Long-Term Outcomes of Pediatric CABG 381 Introduction 381 Choice of Conduit 381 CABG Timing and Indications 382 CABG at Our Center 385 Patients and Methods 385 Operative Procedure 386 Results 387 Case Presentations 388 Case 1 (Fig.3) 388 Case 2 (Fig.4) 389 Down-Sizing Operation for Giant Coronary Aneurysms 389 Introduction 389 Surgical Procedure of Down-Sizing Operation 390 Down-Sizing Operation at Our Center 392 Case Presentation 393 Case 3 (Fig.6) 393 Case 4 (Fig.7) 394 References 394 Long-Term Graft Patency and Surgical Outcomes of Coronary Artery Bypass Surgery in Children with Kawasaki Disease 398 Introduction 398 Historical Overview 399 Operation 399 Growth Response of Grafts in Children 400 Disadvantages of the ITA Graft 400 Long-Term Graft Patency and Morphology in Growing Children 401 Survival of KD Children Treated by Pediatric CABG 401 Event Incidence After Pediatric Bypass Surgery for KD 403 PCI for Coronary Obstructive Lesions Due to KD 405 Current Status of Pediatric Coronary Bypass Surgery in the World 405 References 406 Part VI: Follow-Up Concerns 409 Functional and Structural Alterations of Coronary Arteries Late After Kawasaki Disease and the Risk of Acute Coronary Syndrome... 410 Introduction 410 Reports of ACS in Adults with a History of Confirmed or Presumed KD 411 Vascular Endothelial Function, Chronic Inflammation, and Oxidative Stress in KD 412 Intravascular Ultrasound Findings in Patients Long After KD 412 Coronary Sequelae in Adults Long After KD and the Risk of ACS 413 References 413 Psychosocial Effects of Kawasaki Disease and Transition to Adult Care 415 Psychosocial Issues 415 Introduction 415 Impact of KD on Families 416 Current Understanding of Psychosocial Issues 416 Psychosocial Issues: Recommendations for Clinicians 417 Transition to Adult Care 418 Historical Overview 418 Transition to Adult Care: Current Practices 419 Principles of Transition 420 Dealing with Grown-Up Issues in KD and CAA 421 Preventive Cardiology 421 Risk Behaviors 421 Pregnancy 422 Transition to Adult Care: Summary and Recommendations (Tables1 and 2) 422 References 424 Kawasaki Disease: Road Map for the Future 426 References 429 Appendix: Guidelines for diagnosis and management of cardiovascular sequelae in Kawasaki disease (JCS 2013) 431 Guidelines for Diagnosis and Treatment of Cardiovascular Diseases (2012 Joint Working Groups Report) 431 [Digest Version] 431 Guidelines for diagnosis and management of cardiovascular sequelae in Kawasaki disease (JCS 2013) 431 Introduction of the Revised Guidelines 433 I. Epidemiology of Kawasaki Disease, Current Acute-Phase Treatment, and Pathophysiology of Acute-Phase Disease 436 1. Current Epidemiology 436 1.1 Number of Patients and Diagnosis (Figure1) 436 1.2 Cardiovascular Complications (Figure2) 437 1.3 Treatment4) 439 1.4 Non-Cardiovascular Complications4) 440 1.5 International Comparison 440 2. Genetic Background of Kawasaki Disease 440 3. Severity Classification 441 4. Diagnosis and Treatment of Incomplete Kawasaki Disease 443 II. Genetic Background and Pathology of Cardiovascular Sequelae and Coronary Hemodynamics 444 1. Genetic Background of Cardiovascular Sequelae 444 2. Pathology of Cardiovascular Sequelae 444 2.1 Coronary Artery Lesions 444 2.1.1 Natural Course of Acute-Phase Coronary Arteritis 445 2.1.2 Coronary Sequelae 445 a. Reduction and Regression of Coronary Aneurysms 445 b. Arteries with Remaining Aneurysms 445 c. Coronary Arteries without Aneurysm Formation 446 2.2 Myocardial Disorders 446 2.3 Non-Coronary Arterial Disorders 446 3. Coronary Hemodynamics in Patients with Coronary Sequelae 446 3.1. Methods and Criteria for Assessment of Coronary Hemodynamics 446 3.2 Change in Coronary Hemodynamics Associated with Coronary Artery Lesions 447 3.2.1 Hemodynamics in Coronary Aneurysms without Significant Stenosis and in the Distal Vessels 447 a. Hemodynamics in Aneurysms 447 b. Hemodynamics in Vessels Distal to an Aneurysm 448 3.2.2 Hemodynamics in the Area Distal to a Stenotic Lesion 448 III. Examinations and Diagnosis of Cardiovascular Sequelae 448 1. Blood Test, Biomarkers and Arteriosclerosis 448 1.1 Blood Test 448 1.1.1 Myocardial Ischemia, Myocardial Infarction (Table6) 448 a. Markers of Myocardial Cytoplasm 448 i. CK, CK-MB 448 ii. Myoglobin 450 iii. Heart-Type Fatty Acid-Binding Protein 450 b. Markers of Myocardial Structural Proteins 450 i. Myocardial Troponin T and I 450 ii. Myosin Light Chain 450 c. Inflammatory Proteins 451 i. High-Sensitive CRP 451 ii. Serum Amyloid A Protein 451 1.1.2 Arteriosclerosis 451 a. Dyslipidemia (Table7)69) 451 i. Total Cholesterol 451 ii. Serum Low Density Lipoprotein Cholesterol 452 iii. Serum High Density Lipoprotein Cholesterol 452 iv. Serum Triglycerides 452 b. Homocysteine 452 c. Criteria for Diagnosis of Metabolic Syndrome in Children 452 d. Children in the Remote Phase of Kawasaki Disease 452 e. Adults in the Remote Phase of Kawasaki Disease 452 2. Physiological Examinations 453 2.1 Electrocardiography at Rest 453 2.2 Holter ECG 454 2.3 Stress ECG 454 2.3.1 Exercise ECG 454 a. Double or Triple Master´s Two-Step Test 454 b. Treadmill Test and Ergometer Stress Test 454 2.3.2 Pharmacological Stress Test and Body Surface Potential Mapping 454 2.3.3 Electrophysiological Tests 455 2.4 Signal-Averaged ECG 455 2.5 Summary of Physiological Examinations 455 3. Diagnostic Imaging 456 3.1 Chest X-Ray 456 3.1.1 X-Ray Finding of Calcified Coronary Aneurysms 456 3.1.2 Cardiac Dysfunction Due to Previous Myocardial Infarction and Enlarged Heart Shadow Due to Valvular Diseases 456 3.2 Echocardiography 457 3.2.1 Echocardiography at Rest 457 3.2.2 Stress Echocardiography 457 3.2.3 Myocardial Contrast Echocardiography 457 3.3 Radionuclide Imaging 457 3.3.1 Tc-Labeled Myocardial Perfusion Scintigraphy 458 3.3.2 Pharmacological Stress Myocardial Perfusion Scintigraphy 458 3.3.3 Appropriate Doses of Nuclear Medicine Agents 458 3.4 Coronary CT and MRCA 459 3.4.1 Contrast Coronary CT Angiography (MDCT) 459 3.4.2 MRCA 460 3.4.3 Magnetic Resonance Myocardial Imaging 460 4. Cardiac Catheterization 461 4.1 CAG 461 4.1.1 Indications 461 a. Evaluation of Severity of Coronary Artery Lesions and Patient Follow-Up 461 b. CAG before and after PCI 461 c. Intracoronary Thrombolysis 461 4.1.2 Coronary Artery Lesions Indicated for CAG 461 a. Dilatation Lesions 461 b. Localized Stenosis 462 c. Occlusion 462 4.2 Cardiac Function Test 462 4.3 Intravascular Ultrasound 463 4.3.1 Morphological Evaluation of Coronary Artery Lesions 463 4.3.2 Coronary Arterial Vasodilator Function 463 5. Summary of Examinations and Diagnosis (Table 11) 463 IV. Treatment of Cardiovascular Sequelae 465 1. Pharmacotherapy 465 1.1 Treatment Policy 465 1.2 Pharmacotherapy of Vascular Disorders 466 1.3 Antiplatelet Drugs and Anticoagulant Drugs 466 1.3.1 Antiplatelet Drugs (Table 13) 466 a. Dosage and Administration 466 b. Adverse Drug Reactions 468 1.3.2 Anticoagulant Drugs (Table 13) 468 a. Dosage and Administration 468 b. Adverse Drug Reactions and Drug Interactions 469 1.4 Coronary Vasodilators and Antianginal Drugs (Table 14) 469 1.4.1 Calcium Channel Blockers 469 1.4.2 beta-Blockers 469 1.4.3 Nitrates 469 References 471 1.5 Thrombolytic Therapy and Reperfusion Therapy (Table 15)126) 472 1.5.1 Thrombolytic Therapy 472 a. Intravenous Thrombolysis 474 i. UK 474 ii. t-PAs 474 b. ICT 474 1.5.2 Antithrombotic Therapy during PCI 474 1.6 Initial (Medical) Treatment for AMI 474 1.6.1 General Treatment Policy 474 1.6.2 Initial Treatment 475 a. General Treatment 475 i. Oxygen Therapy 475 ii. Establishment of Vascular Access 475 iii. Pain Control 475 iv. Nitrates 475 v. Intravenous Heparin Therapy 475 vi. Treatment of Complications 475 b. Reperfusion Therapy 475 i. Intravenous Thrombolytic Therapy 475 c. Anticoagulant Therapy and Antiplatelet Therapy to Prevent Recurrence of AMI 476 i. Heparin 476 ii. Warfarin 476 iii. Aspirin 476 2. Non-Pharmacotherapy 476 2.1 Catheter-Based Therapy 476 2.1.1 Indications for Catheter-Based Therapy 476 2.1.2 Types of PCI Techniques, Indications, and Precautions 477 a. PCI 477 i. Reperfusion Therapy 477 ii. Plain Old Balloon Angioplasty 477 b. Stenting 477 c. Rotablator (Percutaneous Transluminal Coronary Rotational Atherectomy, PTCRA) 478 d. IVUS 478 2.1.3 Institutions and Backup System Requirements 478 2.1.4 Postoperative Management, Assessment, and Follow-Up 478 2.2 Surgical Treatment (Table 16) 479 2.2.1 Indications for Surgical Treatment of Kawasaki Disease 479 2.2.2 Age at Surgical Treatment 479 2.2.3 Surgical Techniques 481 2.2.4 Outcome of Surgery 481 a. Graft Patency 481 b. Activities of Daily Life and Problems after Surgery 481 2.2.5 Other Surgery 481 a. Downsizing Operation of Giant Coronary Aneurysms 481 b. Surgical Treatment of Mitral Valve Insufficiency 482 c. Surgical Treatment of Aortic Aneurysms and Peripheral Aneurysms 482 d. Heart Transplantation 482 3. Summary of Treatment Options (Table 17) 482 V. Management and Follow-up during Childhood 483 1. Guidance on Activities of Daily Life and Exercise (Including the School Activity Management Table) 483 1.1 Children without Evidence of Coronary Artery Lesions during the Acute Phase 488 1.2 Patients not Evaluated for Coronary Artery Lesions during the Acute Phase 488 1.2.1 Patients in Whom Examination after the Acute Phase Revealed no Coronary Artery Lesions 488 1.2.2 Patients in Whom Examination after the Acute Phase Revealed Persistent Coronary Artery Lesions According to the Criteria... 488 a. Patients in Whom Examination after the Acute Phase Revealed no Coronary Artery Lesions (or Revealed Regression of Coronary ... 488 b. Patients not Evaluated with CAG 488 c. Patients in Whom CAG Revealed Persistent Coronary Artery Lesions 489 1.3 Patients Who Have Been Evaluated for Coronary Artery Lesions during and after the Acute Phase 489 1.3.1 Patients in Whom Transient Coronary Dilatation Disappeared after the Acute Phase 489 1.3.2 Patients with Remaining Small Aneurysms or Dilatation 489 1.3.3 Patients with Remaining Medium or Giant Aneurysms 489 a. Patients with no Findings of Stenosis or Myocardial Ischemia 490 b. Patients with Findings of Stenosis or Myocardial Ischemia 490 c. Patients with a History of Myocardial Infarction 490 1.4 Lesions other than Coronary Artery Lesions 490 1.4.1 Valvular Disease 490 1.4.2 Arrhythmia 490 1.4.3 Aneurysms other than Coronary Aneurysms 491 1.5 Management after Heart Surgery 491 1.6 Vaccinations 491 1.7 Lifestyle Changes to Prevent Arteriosclerosis 491 1.8 Cooperation with Cardiologists 491 2. Follow-up Evaluation 492 2.1 Severity Classification of Coronary Artery Lesions Based on Echocardiographic Findings 492 2.2 Relationship between Echocardiography-Based Severity Classification and the Severity Classification of Cardiovascular Lesi... 493 2.3 Follow-up Evaluation According to the Echocardiography-Based Severity Classification 493 2.3.1. Patients in Category A-1 493 2.3.2 Patients in Category A-2 493 2.3.3 Patients in Category A-3 494 2.3.4 Patients in Category A-4 494 a. Patients in Category A-4-1 494 b. Patients in Category A-4-2 495 2.3.5 Patients in Category A-5 495 2.4 Acute Phase Kawasaki Disease in Summary 496 3. Problems in Shifting from Childhood to Adulthood 496 3.1 Is a History of Kawasaki Disease a Risk Factor for Arteriosclerosis? 496 3.2 Collaboration with Cardiologists Providing Healthcare Services to Adult Patients 496 3.3 How to Avoid Dropouts 497 VI. Problems during Adulthood 497 1. Progression of Arteriosclerosis: Pathological Features 497 2. Progression of Arteriosclerosis: Clinical Features 498 VII. Management of Adults with a History of Kawasaki Disease 499 1. Diagnosis 500 1.1 Patients without Coronary Aneurysms during Childhood 500 1.2 Asymptomatic Patients with Coronary Aneurysms Persisting from Childhood 500 1.3 Patients with Angina, Myocardial Infarction, Heart Failure, or Severe Arrhythmia in Adulthood 500 1.4 Adult Patients with Coronary Aneurysms with Unknown History of Kawasaki Disease 500 2. Treatment 501 2.1 Pharmacotherapy 501 2.1.1 Patients without Coronary Aneurysms during Childhood 501 2.1.2 Asymptomatic Patients with Coronary Aneurysms Persisting from Childhood 501 2.1.3 Patients with Angina, Myocardial Infarction, Heart Failure, or Severe Arrhythmia in Adulthood 501 2.1.4 Adult Patients with Coronary Aneurysms with Unknown History of Kawasaki Disease 501 2.2 Non-Pharmacotherapy 502 3. Guidance on Lifestyle and Exercise 503 4. Pregnancy, Labor and Childbirth 503 4.1 Pregnancy and Labor 503 4.2 Childbirth 503 4.3 Drugs during Pregnancy and Perinatal Period 504 4.3.1 Anticoagulant Drugs and Antiplatelet Drugs 504 a. Aspirin 504 b. Warfarin 504 4.3.2 Other Drugs 504 4.4 Cardiac Accidents 504 4.4.1 AMI 505 4.4.2 Arrhythmias 505 5. Healthcare System for Adult Patients 505 5.1 Understanding of Kawasaki Foreword 12 Preface 14 References 15 Contents 16 Part I: Basic Research 21 The History of Kawasaki Disease: A Personal Perspective 22 Introduction 22 The Era of Clinical Description and Pathologic Recognition: 1960-1984 23 Back to the Future: 1871-1984 and Other Riddles of KD 25 The Era of Enhanced Discovery and International Collaboration: 1984-2015 26 References 27 Histopathology of Coronary Arteritis in Acute Kawasaki Disease and Murine Systemic Vasculitis Induced by Candida Albicans Cell... 29 Introduction 29 Histopathological Characteristics of Coronary Arteritis in Acute KD 30 The C. Albicans Cell Wall Polysaccharide-Induced Murine Vasculitis Model 31 Model Development and Description of the Vasculitis-Inducing Agent 31 Histopathological Characteristics of C. Albicans Polysaccharide-Induced Murine Vasculitis 31 Relationship of Mouse Genetic Background to Cytokines and Vasculitis 32 Response of C. Albicans Polysaccharide-Induced Vasculitis to Treatment 33 References 33 Histopathological Characteristics of Noncardiac Organs in Kawasaki Disease 35 Introduction 35 Brief Overview of Systemic Vascular Lesions in KD 35 Histological Changes in Noncardiac Organs in KD 36 References 39 Identification of Novel Kawasaki Disease Susceptibility Genes by Genome-Wide Association Studies 41 Introduction 41 History of the Genetic Study of KD 42 Genomic Studies of KD in the Post-Genomic era 42 ITPKC 42 CASP3 42 FCGR2A 43 BLK 45 CD40 45 HLA class II 45 Current Understandings and Recognition 46 Recent Advances 46 References 46 Immunological Abnormalities and Use of Biomarkers and Cytokines to Predict the Severity of Kawasaki Disease 48 Introduction 48 KD and Hypercytokinemia 49 Which Cytokines/Biomarkers Best Predict KD Severity? 50 Conclusions 52 References 53 Pathophysiology of Kawasaki Disease 55 Introduction 56 History 56 The Three Linked Pathological Processes of KD Vasculopathy 57 Recent Advances in Etiological, Genomic, and Gene Expression Studies 58 Conclusions 59 References 59 Update on Pathogenesis: Lessons Learned from Animal Models of Disease 61 Introduction 61 T-Cell Activation and Survival and the Role of Costimulation 62 Murine Models of KD 63 References 65 The Climate-KD Link 68 References 71 Kawasaki Disease Shock Syndrome 73 Introduction 73 Incidence and Demographics 73 Mechanisms 74 Clinical Course and Treatment 75 Differential Diagnosis 76 Future Perspectives 76 References 77 Future Directions in Kawasaki Disease Research 78 Advances in Treatment 78 Advances in Genetics 79 Advances in Biomarkers and Diagnostic Tests 80 Advances in Understanding Long-Term Outcomes 80 References 81 Part II: Epidemiology 83 Epidemiologic Perspectives 84 Historical Perspective 84 KD Surveillance: Moving Forward 85 KD Surveillance: Prescription for the Future 85 References 87 Update on Nationwide Surveys and Epidemiologic Characteristics of Kawasaki Disease in Japan 89 Introduction 89 Methods of the Nationwide Surveys 89 Results of Nationwide Surveys 90 What We Have Learned from the Descriptive Epidemiology 92 Conclusions 93 References 94 Kawasaki Disease Epidemiology in Europe 95 History 95 Incidence 96 Age 98 Seasonality 98 Cardiac Sequelae 98 Way Ahead 98 References 98 Recent Topics in the Epidemiology of Kawasaki Disease 100 Kawasaki Disease in Japan and Other Countries 100 Epidemiologic Characteristics of Intravenous Immunoglobulin Nonresponders 101 Epidemiology of Adult-Onset KD 102 Forty-Five Years After the First Report of KD 102 References 103 Part III: Medical Treatment 104 Overview of Medical Treatment 105 Introduction 106 Intravenous Immunoglobulin Therapy 106 Corticosteroid Therapy 107 Other Anti-inflammatory Therapies 107 Conclusions 108 References 108 Overview of the New Japanese Guideline2012 for the Medical Treatment of Acute Stage of Kawasaki Disease 110 Introduction 110 Fundamentals of New Guideline 2012 111 Previous Guideline 2003 111 General Principles of the New Guideline 2012 111 What to Do When the Child is Admitted 112 Guidelines for medical treatment of acute Kawasaki disease: Report of the Research Committee of the Japanese Society of Pediat... 113 Immunoglobulin 118 Purpose 118 Mechanism of action 120 Indications 121 Treatment method and dosage 121 Period of treatment 121 Dosage 121 Product types and directions for use 122 IVIG retreatment for IVIG-resistant patients 130 Effectiveness 131 Side-effects 132 Evidence levels 133 Methylprednisolone pulse 134 Purpose 134 Mechanism of action 134 Indications 134 Treatment method and dosage 134 Effectiveness 138 Side-effects 138 Evidence levels 139 Prednisolone 139 Purpose 139 Mechanism of action 139 Indications 139 Treatment method and dosage 139 Effectiveness 140 Side-effects 140 Evidence levels 141 Biologics (infliximab) 141 Purpose 141 Mechanism of action 141 Indications 142 Treatment method and dosage 142 Effectiveness 142 Side-effects 143 Infusion-associated reaction 144 Exacerbation of heart failure 144 Exacerbation of infectious diseases 144 Development of malignant tumors 145 Carriers of hepatitis B and C 145 Other 146 Evidence levels 146 Ulinastatin 146 Purpose 146 Mechanism of action 146 Suppression of TNF-α 146 Blocking of neutrophil elastase 147 Indications 147 Treatment method and dosage 147 Effectiveness 147 Side-effects 148 Evidence level 148 Immunosuppressants 148 Cyclosporin A 148 Purpose 148 Mechanism of action 149 Indications 149 Treatment method and dosage 149 Effectiveness 149 Side-effects 149 Evidence level 150 Methotrexate 150 Purpose 150 Mechanism of action 150 Indications 150 Effectiveness 150 Side-effects 151 Evidence levels 151 Plasma exchange 151 Purpose 151 Mechanism of action 151 Indications 151 Treatment method and dosage 151 Effectiveness 152 Side-effects 152 Evidence level 152 Antiplatelets/anticoagulants 153 Aspirin 153 Purpose 153 Mechanism of action 153 Indications 153 Treatment method and dosage 153 Effectiveness 153 Side-effects 158 Evidence level 158 Other antiplatelet medications 158 Flurbiprofen (Froben) 158 Dipyridamole (Persantin tablets, Anginal) 158 Ticlopidine (Panaldine) 158 Clopidogrel (Plavix) 159 Other cardiovascular agents 159 Anticoagulants 159 Warfarin 159 Mechanism of action 159 Indications 160 Treatment method and dosage 160 Usefulness 160 Side-effects 161 Evidence level 161 Unfractionated heparin 161 Evidence level 161 Low-molecular-weight heparin 161 Evidence level 162 Thrombolytics 162 Purpose 162 Mechanism of action 162 Indications 163 Treatment method and dosage 163 Urokinase 163 Alteplase (Activacin, Grtpa) 163 Monteplase (Cleactor) 163 Effectiveness 164 Side-effects 164 Evidence level 164 Anti-anginals and coronary vasodilators 164 Evidence level 165 Indication 165 Reference 174 Tumor Necrosis Factor-α Blockade for Treatment of Acute Kawasaki Disease 175 Introduction 175 Current Understanding 176 Infliximab 176 Etanercept 176 Safety of TNF-α Inhibitors 178 References 178 Methylprednisolone Pulse Therapy for Nonresponders to Immunoglobulin Therapy 180 Introduction 180 History 181 Current Understanding and Recognition [10-12] 181 Assigned Evidence Class and Recommendation [10-12] 183 References 183 Prednisolone 185 Introduction 185 History 186 Current Understanding and Recognition 187 Assigned Evidence Class and Recommendation 188 References 188 Cyclosporin A for IVIG Nonresponders 190 Introduction 190 Historical Overview 191 Current Understanding and Recognition 192 Pilot Study [12] 192 Patients 192 Protocol 192 Results and Discussion of the Pilot Study 192 Third IVIG as an Effective Option for CsA-Resistant Patients 193 Prevention of CAL Development by CsA 194 Adverse Events 195 Trough CsA Levels 195 Route of CsA Administration 196 Summary and Future Direction 196 References 196 Other Challenging Therapies 198 Introduction 198 Biological Agents 199 Cytotoxic Agents 199 Plasma Exchange 200 References 201 Antiplatelet and Antithrombotic Therapy for Giant Coronary Aneurysm 202 Introduction 202 Historical Overview 203 Current Understanding and Recognition 203 Assigned Evidence Class and Recommendations 203 Recent Advances and Future Directions 206 References 206 Characteristics of Sudden Cardiac Death Late After Acute Kawasaki Disease 209 Introduction 209 History 210 Current Understanding 211 Evidence Quality and Recommendations 213 Recent Advances 214 References 214 Kawasaki Disease Diagnosis and Complication Rates in the United States and Japan 216 Guidelines for Kawasaki Disease in the United States and Japan 217 Diagnosis 217 Complete KD 217 Incomplete KD 219 Complication: Coronary Artery Aneurysms 219 References 222 Mechanism of Action of Immunoglobulin: Sialylated IgG 224 Introduction 224 Glycosylated IgG 226 Sialylation of IgG Fc 227 General Characteristics of DC-SIGN 228 The Potential DC-SIGN-Mediated IVIG Mechanism 229 Conclusion 230 References 230 Treatment Options for Refractory Kawasaki Disease: Alternative Treatments for Infliximab Nonresponders 232 Introduction 232 IFX Nonresponders 233 IFX Therapy in KD 233 IFX Nonresponse in Inflammatory Disease 233 Definition and Incidence of IFX Nonresponse in KD 234 Treatment of IFX Nonresponders 234 Conclusion 236 References 236 Ulinastatin 239 Introduction 239 Historical Overview 240 Current Understanding 241 Assigned Evidence Class and Recommendation 241 Recent Advances 242 References 243 Part IV: Diagnosis and Examinations 245 Diagnosis and Management of Cardiovascular Risk Factors 246 Introduction 246 Cardiovascular Risk Factors and Vascular Disease 247 Assessment 248 Management 249 Lifestyle Management 249 Drug Therapy 251 Summary 251 References 252 Diagnosis and Characteristics of Typical and Incomplete Kawasaki Disease 254 Introduction 254 Patient Characteristics 256 Age 256 Sex 256 Symptoms and Diagnostic Criteria 256 Principal Symptoms (Table1) 256 Fever 256 Bilateral Bulbar Conjunctival Injection (Fig.2) 258 Changes in the Lips and Oral Cavity (Fig.3) 258 Polymorphous Exanthema (Fig.4) 258 Changes in Extremities (Fig.5) 259 Acute Nonpurulent Cervical Lymphadenopathy (Fig6) 260 Definition of Final Diagnosis 262 Other Significant Symptoms or Findings 262 Gastrointestinal Tract 262 Gall Bladder Swelling 262 Liver Dysfunction 263 Paralytic Ileus 263 Urine Analysis 263 Erythema or Induration at the BCG Inoculation Site: (See Principal Symptom 4, Fig.8) 263 Cardiovascular Symptoms 264 Other Symptoms 264 Incomplete KD 264 Summary 267 References 267 Scoring Systems to Predict Coronary Artery Lesions and Nonresponse to Initial Intravenous Immunoglobulin Therapy 269 Introduction 269 History of Scoring Systems 269 Scoring System to Predict Nonresponse to Initial IVIG 271 References 274 Use of Magnetic Resonance Angiography for Assessment of Coronary Artery Lesions Caused by Kawasaki Disease 276 Introduction 276 Procedure 277 MRCA: Indications in Patients with KD 277 Advantages of MRCA 278 Limitations of MRCA 280 Conclusion 280 References 281 CT Coronary and Myocardial Images in Patients with Coronary Artery Lesions 282 Beyond Cardiac Catheterization 283 Coronary Computed Tomographic Angiography 283 Overview 283 Indications for CCTA 283 Three Drawbacks of CCTA 283 Beta-Blockade 284 Contrast Medium 284 Radioactive Exposure 284 Advantages of CCTA 284 Advantages of CCTA as Compared with Magnetic Resonance Coronary Angiography 284 CCTA Advantages in Patients with Coronary Artery Lesions After KD 285 Cardiac Radionuclide Imaging 286 Category 286 Indications for MPI 286 Planning of Rest and Stress Imaging for MPI 286 One-Day Protocol 286 Two-Day Protocol 286 Outline of Stress Imaging 287 Exercise Stress Imaging 287 Pharmacologic Stress Imaging 287 Comprehensive Plan for Image Acquisition Using Tc-Labeled Agents 288 Control of Body Movement 288 Time Interval in Image Acquisition 288 Monzen Position 288 Soda Water 288 High-Fat Meal 288 Appropriate Administration of Nuclear Agents 289 Future Directions 290 References 291 Long-Term Follow-Up and Education Regarding Daily Life Activities, School Life, and Guidelines After Acute KD 293 Two to 3 Months After Onset 293 Vaccination After KD 294 After 2-3 Months from Onset 294 Evaluation and Management of Patients with CAL 295 Management of School Life in Japan 295 Preparation for Transition to Adult Cardiologists 295 References 296 Assessment of Cardiac Ischemia During Acute and Long-Term Follow-Up and Rheologic Assessment of Coronary Artery Lesions After ... 298 Assessment of Cardiac Ischemia During Short- and Long-Term Follow-Up 298 Exercise Electrocardiography 299 Treadmill Stress and Ergometer Stress ECG 299 Pharmacologic Stress Body Surface Potential Mapping 299 Signal-Averaged ECG 299 Stress Echocardiography 300 Radionuclide Imaging 300 Pharmacologic Stress Myocardial Perfusion Scintigraphy 300 Cardiac Ischemia Assessed by Rheologic Index 301 Rheologic Assessment of CAL After KD 301 Methods and Criteria for Assessment of Coronary Hemodynamics 301 Change in Coronary Hemodynamics Associated with CAL 303 Hemodynamics in Coronary Aneurysms Without Significant Stenosis and in Distal Vessels 303 Hemodynamics in Aneurysms 303 Hemodynamics in Vessels Distal to an Aneurysm 303 Hemodynamics in the Area Distal to a Stenotic Lesion 304 References 304 Promising Biomarkers in Acute Kawasaki Disease and Acute Coronary Ischemia 306 Introduction 307 Predicting Nonresponse to Immunoglobulin Therapy 307 Diagnosis and Evaluation of the Severity and Likelihood of CAL Formation in KD 308 Inflammatory Proteins 308 CRP 308 Pentraxin-3 (PTX3) 308 Serum Amyloid A (SAA) 309 General Laboratory Variables 309 Total Protein and Albumin 309 Serum Transaminase 309 Serum Electrolyte 309 Urinary Beta-2 Microglobulin (u-beta2MG) 309 Brain Natriuretic Peptide (BNP) and N-Terminal proBNP (NT-proBNP) 310 Inflammatory Cytokines 310 Acute Coronary Ischemia 311 Markers in Myocardial Cytoplasm 311 CK and CK-MB 311 Myoglobin 312 H-FABP 312 Myocardial Structural Proteins as Markers 312 TnT and TnI 312 MLC 312 References 313 Coronary Artery Diameter Z Score Calculator 315 Introduction 315 History 315 Recent Advances 316 Coronary Artery Diameter Z Score Calculator 317 Meaning of Coronary Artery Diameter Z Scores 317 References 326 Evidence of Endothelial Damage in Acute KD 328 Introduction 329 The Endothelium and Endothelial Injury and Repair 329 Clinical Assessment of Endothelial Function and KD 329 Circulating Markers of Endothelial Function and KD 330 Recent Advances 332 References 332 Oxidative Stress in Kawasaki Disease 334 What Is Oxidative Stress? 334 Inflammation and Oxidative Stress 335 Oxidative Stress During Acute KD 336 Involvement of Oxidative Stress in Vascular Illnesses After the Acute Phase 338 Real Picture of Oxidative Stress During Late KD 340 Conclusion 343 References 344 Part V: Catheter Intervention and Surgery 346 Antiplatelet and Anticoagulant Therapies for Kawasaki Disease: Theory and Practice 347 Introduction 347 Historical Review 348 The Procoagulant State in KD 348 Vasculitis as the Basis for Hypercoagulability 349 Flow Disturbance and Stagnation Stimulate Coagulation 349 Platelet Activation, Adhesion, and Aggregation in KD 350 Antiplatelet Drugs 351 Aspirin 351 Thienopyridine ADP Receptor Blockers (Ticlopidine and Clopidogrel) 353 Dipyridamole 354 Abciximab (Glycoprotein IIb/IIIa Inhibitor) 355 Anticoagulant Drugs 355 Warfarin 355 Unfractionated Heparin 358 LMWH 359 Thrombolytic Therapy 360 Future Directions in Antiplatelet and Anticoagulant Therapies for KD 361 Initiative Toward Evidence-Based Uses of Antiplatelet Agents 361 Randomized Clinical Trials of New Oral Direct Anticoagulants 362 References 362 Guideline for Catheter Intervention in Coronary Artery Lesion in Kawasaki Disease 365 Research Group of Ministry of Health, Labour and Welfare ``Study of treatment and long-term management in Kawasaki disease ́ ́. 366 I. Background 367 II. Natural history of coronary artery lesion in Kawasaki disease 368 III. Catheter intervention for patients with Kawasaki disease 368 1) Indication of catheter intervention 368 a. Consideration of indication in patient ́s conditions 368 b. Consideration of indication in lesion sites 369 2) Types of procedures, and their indications and precautions 369 (1) Percutaneous transluminal coronary revascularization (PTCR) 369 (2) Percutaneous transluminal coronary balloon angioplasty (PTCA) 370 (3) Stent implantation 370 (4) Rotational ablation (Rotablator) 370 (5) Intravascular ultrasound imaging 371 3) Institute and backup system 371 IV. The management of post-procedure and evaluation, and follow-up 371 V. Prospects: especially relation to bypass surgery 371 Long-Term Clinical Follow-Up After Rotational Atherectomy for Coronary Arterial Stenosis in Kawasaki Disease 375 Clinical Outcomes for Rotablation for Kawasaki Disease Coronary Artery Lesions 375 Patients, Lesions, and Information on the Procedures 375 Acute Outcomes 376 Late Restenosis 377 New Coronary Aneurysms in the Late Period 377 Long-Term Prognosis for Patients Undergoing PCI on KD Coronary Artery Lesions 378 Summary 379 References 379 Long-Term Outcomes of Pediatric Coronary Artery Bypass Grafting and Down-Sizing Operation for Giant Coronary Aneurysms 380 Long-Term Outcomes of Pediatric CABG 381 Introduction 381 Choice of Conduit 381 CABG Timing and Indications 382 CABG at Our Center 385 Patients and Methods 385 Operative Procedure 386 Results 387 Case Presentations 388 Case 1 (Fig.3) 388 Case 2 (Fig.4) 389 Down-Sizing Operation for Giant Coronary Aneurysms 389 Introduction 389 Surgical Procedure of Down-Sizing Operation 390 Down-Sizing Operation at Our Center 392 Case Presentation 393 Case 3 (Fig.6) 393 Case 4 (Fig.7) 394 References 394 Long-Term Graft Patency and Surgical Outcomes of Coronary Artery Bypass Surgery in Children with Kawasaki Disease 398 Introduction 398 Historical Overview 399 Operation 399 Growth Response of Grafts in Children 400 Disadvantages of the ITA Graft 400 Long-Term Graft Patency and Morphology in Growing Children 401 Survival of KD Children Treated by Pediatric CABG 401 Event Incidence After Pediatric Bypass Surgery for KD 403 PCI for Coronary Obstructive Lesions Due to KD 405 Current Status of Pediatric Coronary Bypass Surgery in the World 405 References 406 Part VI: Follow-Up Concerns 409 Functional and Structural Alterations of Coronary Arteries Late After Kawasaki Disease and the Risk of Acute Coronary Syndrome... 410 Introduction 410 Reports of ACS in Adults with a History of Confirmed or Presumed KD 411 Vascular Endothelial Function, Chronic Inflammation, and Oxidative Stress in KD 412 Intravascular Ultrasound Findings in Patients Long After KD 412 Coronary Sequelae in Adults Long After KD and the Risk of ACS 413 References 413 Psychosocial Effects of Kawasaki Disease and Transition to Adult Care 415 Psychosocial Issues 415 Introduction 415 Impact of KD on Families 416 Current Understanding of Psychosocial Issues 416 Psychosocial Issues: Recommendations for Clinicians 417 Transition to Adult Care 418 Historical Overview 418 Transition to Adult Care: Current Practices 419 Principles of Transition 420 Dealing with Grown-Up Issues in KD and CAA 421 Preventive Cardiology 421 Risk Behaviors 421 Pregnancy 422 Transition to Adult Care: Summary and Recommendations (Tables1 and 2) 422 References 424 Kawasaki Disease: Road Map for the Future 426 References 429 Appendix: Guidelines for diagnosis and management of cardiovascular sequelae in Kawasaki disease (JCS 2013) 431 Guidelines for Diagnosis and Treatment of Cardiovascular Diseases (2012 Joint Working Groups Report) 431 [Digest Version] 431 Guidelines for diagnosis and management of cardiovascular sequelae in Kawasaki disease (JCS 2013) 431 Introduction of the Revised Guidelines 433 I. Epidemiology of Kawasaki Disease, Current Acute-Phase Treatment, and Pathophysiology of Acute-Phase Disease 436 1. Current Epidemiology 436 1.1 Number of Patients and Diagnosis (Figure1) 436 1.2 Cardiovascular Complications (Figure2) 437 1.3 Treatment4) 439 1.4 Non-Cardiovascular Complications4) 440 1.5 International Comparison 440 2. Genetic Background of Kawasaki Disease 440 3. Severity Classification 441 4. Diagnosis and Treatment of Incomplete Kawasaki Disease 443 II. Genetic Background and Pathology of Cardiovascular Sequelae and Coronary Hemodynamics 444 1. Genetic Background of Cardiovascular Sequelae 444 2. Pathology of Cardiovascular Sequelae 444 2.1 Coronary Artery Lesions 444 2.1.1 Natural Course of Acute-Phase Coronary Arteritis 445 2.1.2 Coronary Sequelae 445 a. Reduction and Regression of Coronary Aneurysms 445 b. Arteries with Remaining Aneurysms 445 c. Coronary Arteries without Aneurysm Formation 446 2.2 Myocardial Disorders 446 2.3 Non-Coronary Arterial Disorders 446 3. Coronary Hemodynamics in Patients with Coronary Sequelae 446 3.1. Methods and Criteria for Assessment of Coronary Hemodynamics 446 3.2 Change in Coronary Hemodynamics Associated with Coronary Artery Lesions 447 3.2.1 Hemodynamics in Coronary Aneurysms without Significant Stenosis and in the Distal Vessels 447 a. Hemodynamics in Aneurysms 447 b. Hemodynamics in Vessels Distal to an Aneurysm 448 3.2.2 Hemodynamics in the Area Distal to a Stenotic Lesion 448 III. Examinations and Diagnosis of Cardiovascular Sequelae 448 1. Blood Test, Biomarkers and Arteriosclerosis 448 1.1 Blood Test 448 1.1.1 Myocardial Ischemia, Myocardial Infarction (Table6) 448 a. Markers of Myocardial Cytoplasm 448 i. CK, CK-MB 448 ii. Myoglobin 450 iii. Heart-Type Fatty Acid-Binding Protein 450 b. Markers of Myocardial Structural Proteins 450 i. Myocardial Troponin T and I 450 ii. Myosin Light Chain 450 c. Inflammatory Proteins 451 i. High-Sensitive CRP 451 ii. Serum Amyloid A Protein 451 1.1.2 Arteriosclerosis 451 a. Dyslipidemia (Table7)69) 451 i. Total Cholesterol 451 ii. Serum Low Density Lipoprotein Cholesterol 452 iii. Serum High Density Lipoprotein Cholesterol 452 iv. Serum Triglycerides 452 b. Homocysteine 452 c. Criteria for Diagnosis of Metabolic Syndrome in Children 452 d. Children in the Remote Phase of Kawasaki Disease 452 e. Adults in the Remote Phase of Kawasaki Disease 452 2. Physiological Examinations 453 2.1 Electrocardiography at Rest 453 2.2 Holter ECG 454 2.3 Stress ECG 454 2.3.1 Exercise ECG 454 a. Double or Triple Master ́s Two-Step Test 454 b. Treadmill Test and Ergometer Stress Test 454 2.3.2 Pharmacological Stress Test and Body Surface Potential Mapping 454 2.3.3 Electrophysiological Tests 455 2.4 Signal-Averaged ECG 455 2.5 Summary of Physiological Examinations 455 3. Diagnostic Imaging 456 3.1 Chest X-Ray 456 3.1.1 X-Ray Finding of Calcified Coronary Aneurysms 456 3.1.2 Cardiac Dysfunction Due to Previous Myocardial Infarction and Enlarged Heart Shadow Due to Valvular Diseases 456 3.2 Echocardiography 457 3.2.1 Echocardiography at Rest 457 3.2.2 Stress Echocardiography 457 3.2.3 Myocardial Contrast Echocardiography 457 3.3 Radionuclide Imaging 457 3.3.1 Tc-Labeled Myocardial Perfusion Scintigraphy 458 3.3.2 Pharmacological Stress Myocardial Perfusion Scintigraphy 458 3.3.3 Appropriate Doses of Nuclear Medicine Agents 458 3.4 Coronary CT and MRCA 459 3.4.1 Contrast Coronary CT Angiography (MDCT) 459 3.4.2 MRCA 460 3.4.3 Magnetic Resonance Myocardial Imaging 460 4. Cardiac Catheterization 461 4.1 CAG 461 4.1.1 Indications 461 a. Evaluation of Severity of Coronary Artery Lesions and Patient Follow-Up 461 b. CAG before and after PCI 461 c. Intracoronary Thrombolysis 461 4.1.2 Coronary Artery Lesions Indicated for CAG 461 a. Dilatation Lesions 461 b. Localized Stenosis 462 c. Occlusion 462 4.2 Cardiac Function Test 462 4.3 Intravascular Ultrasound 463 4.3.1 Morphological Evaluation of Coronary Artery Lesions 463 4.3.2 Coronary Arterial Vasodilator Function 463 5. Summary of Examinations and Diagnosis (Table 11) 463 IV. Treatment of Cardiovascular Sequelae 465 1. Pharmacotherapy 465 1.1 Treatment Policy 465 1.2 Pharmacotherapy of Vascular Disorders 466 1.3 Antiplatelet Drugs and Anticoagulant Drugs 466 1.3.1 Antiplatelet Drugs (Table 13) 466 a. Dosage and Administration 466 b. Adverse Drug Reactions 468 1.3.2 Anticoagulant Drugs (Table 13) 468 a. Dosage and Administration 468 b. Adverse Drug Reactions and Drug Interactions 469 1.4 Coronary Vasodilators and Antianginal Drugs (Table 14) 469 1.4.1 Calcium Channel Blockers 469 1.4.2 beta-Blockers 469 1.4.3 Nitrates 469 References 471 1.5 Thrombolytic Therapy and Reperfusion Therapy (Table 15)126) 472 1.5.1 Thrombolytic Therapy 472 a. Intravenous Thrombolysis 474 i. UK 474 ii. t-PAs 474 b. ICT 474 1.5.2 Antithrombotic Therapy during PCI 474 1.6 Initial (Medical) Treatment for AMI 474 1.6.1 General Treatment Policy 474 1.6.2 Initial Treatment 475 a. General Treatment 475 i. Oxygen Therapy 475 ii. Establishment of Vascular Access 475 iii. Pain Control 475 iv. Nitrates 475 v. Intravenous Heparin Therapy 475 vi. Treatment of Complications 475 b. Reperfusion Therapy 475 i. Intravenous Thrombolytic Therapy 475 c. Anticoagulant Therapy and Antiplatelet Therapy to Prevent Recurrence of AMI 476 i. Heparin 476 ii. Warfarin 476 iii. Aspirin 476 2. Non-Pharmacotherapy 476 2.1 Catheter-Based Therapy 476 2.1.1 Indications for Catheter-Based Therapy 476 2.1.2 Types of PCI Techniques, Indications, and Precautions 477 a. PCI 477 i. Reperfusion Therapy 477 ii. Plain Old Balloon Angioplasty 477 b. Stenting 477 c. Rotablator (Percutaneous Transluminal Coronary Rotational Atherectomy, PTCRA) 478 d. IVUS 478 2.1.3 Institutions and Backup System Requirements 478 2.1.4 Postoperative Management, Assessment, and Follow-Up 478 2.2 Surgical Treatment (Table 16) 479 2.2.1 Indications for Surgical Treatment of Kawasaki Disease 479 2.2.2 Age at Surgical Treatment 479 2.2.3 Surgical Techniques 481 2.2.4 Outcome of Surgery 481 a. Graft Patency 481 b. Activities of Daily Life and Problems after Surgery 481 2.2.5 Other Surgery 481 a. Downsizing Operation of Giant Coronary Aneurysms 481 b. Surgical Treatment of Mitral Valve Insufficiency 482 c. Surgical Treatment of Aortic Aneurysms and Peripheral Aneurysms 482 d. Heart Transplantation 482 3. Summary of Treatment Options (Table 17) 482 V. Management and Follow-up during Childhood 483 1. Guidance on Activities of Daily Life and Exercise (Including the School Activity Management Table) 483 1.1 Children without Evidence of Coronary Artery Lesions during the Acute Phase 488 1.2 Patients not Evaluated for Coronary Artery Lesions during the Acute Phase 488 1.2.1 Patients in Whom Examination after the Acute Phase Revealed no Coronary Artery Lesions 488 1.2.2 Patients in Whom Examination after the Acute Phase Revealed Persistent Coronary Artery Lesions According to the Criteria... 488 a. Patients in Whom Examination after the Acute Phase Revealed no Coronary Artery Lesions (or Revealed Regression of Coronary ... 488 b. Patients not Evaluated with CAG 488 c. Patients in Whom CAG Revealed Persistent Coronary Artery Lesions 489 1.3 Patients Who Have Been Evaluated for Coronary Artery Lesions during and after the Acute Phase 489 1.3.1 Patients in Whom Transient Coronary Dilatation Disappeared after the Acute Phase 489 1.3.2 Patients with Remaining Small Aneurysms or Dilatation 489 1.3.3 Patients with Remaining Medium or Giant Aneurysms 489 a. Patients with no Findings of Stenosis or Myocardial Ischemia 490 b. Patients with Findings of Stenosis or Myocardial Ischemia 490 c. Patients with a History of Myocardial Infarction 490 1.4 Lesions other than Coronary Artery Lesions 490 1.4.1 Valvular Disease 490 1.4.2 Arrhythmia 490 1.4.3 Aneurysms other than Coronary Aneurysms 491 1.5 Management after Heart Surgery 491 1.6 Vaccinations 491 1.7 Lifestyle Changes to Prevent Arteriosclerosis 491 1.8 Cooperation with Cardiologists 491 2. Follow-up Evaluation 492 2.1 Severity Classification of Coronary Artery Lesions Based on Echocardiographic Findings 492 2.2 Relationship between Echocardiography-Based Severity Classification and the Severity Classification of Cardiovascular Lesi... 493 2.3 Follow-up Evaluation According to the Echocardiography-Based Severity Classification 493 2.3.1. Patients in Category A-1 493 2.3.2 Patients in Category A-2 493 2.3.3 Patients in Category A-3 494 2.3.4 Patients in Category A-4 494 a. Patients in Category A-4-1 494 b. Patients in Category A-4-2 495 2.3.5 Patients in Category A-5 495 2.4 Acute Phase Kawasaki Disease in Summary 496 3. Problems in Shifting from Childhood to Adulthood 496 3.1 Is a History of Kawasaki Disease a Risk Factor for Arteriosclerosis? 496 3.2 Collaboration with Cardiologists Providing Healthcare Services to Adult Patients 496 3.3 How to Avoid Dropouts 497 VI. Problems during Adulthood 497 1. Progression of Arteriosclerosis: Pathological Features 497 2. Progression of Arteriosclerosis: Clinical Features 498 VII. Management of Adults with a History of Kawasaki Disease 499 1. Diagnosis 500 1.1 Patients without Coronary Aneurysms during Childhood 500 1.2 Asymptomatic Patients with Coronary Aneurysms Persisting from Childhood 500 1.3 Patients with Angina, Myocardial Infarction, Heart Failure, or Severe Arrhythmia in Adulthood 500 1.4 Adult Patients with Coronary Aneurysms with Unknown History of Kawasaki Disease 500 2. Treatment 501 2.1 Pharmacotherapy 501 2.1.1 Patients without Coronary Aneurysms during Childhood 501 2.1.2 Asymptomatic Patients with Coronary Aneurysms Persisting from Childhood 501 2.1.3 Patients with Angina, Myocardial Infarction, Heart Failure, or Severe Arrhythmia in Adulthood 501 2.1.4 Adult Patients with Coronary Aneurysms with Unknown History of Kawasaki Disease 501 2.2 Non-Pharmacotherapy 502 3. Guidance on Lifestyle and Exercise 503 4. Pregnancy, Labor and Childbirth 503 4.1 Pregnancy and Labor 503 4.2 Childbirth 503 4.3 Drugs during Pregnancy and Perinatal Period 504 4.3.1 Anticoagulant Drugs and Antiplatelet Drugs 504 a. Aspirin 504 b. Warfarin 504 4.3.2 Other Drugs 504 4.4 Cardiac Accidents 504 4.4.1 AMI 505 4.4.2 Arrhythmias 505 5. Healthcare System for Adult Patients 505 5.1 Understanding of Kawas Front Matter....Pages i-xix Front Matter....Pages 1-1 The History of Kawasaki Disease: A Personal Perspective....Pages 3-9 Histopathology of Coronary Arteritis in Acute Kawasaki Disease and Murine Systemic Vasculitis Induced by Candida Albicans Cell Wall Polysaccharide....Pages 11-16 Histopathological Characteristics of Noncardiac Organs in Kawasaki Disease....Pages 17-22 Identification of Novel Kawasaki Disease Susceptibility Genes by Genome-Wide Association Studies....Pages 23-29 Immunological Abnormalities and Use of Biomarkers and Cytokines to Predict the Severity of Kawasaki Disease....Pages 31-37 Pathophysiology of Kawasaki Disease....Pages 39-44 Update on Pathogenesis: Lessons Learned from Animal Models of Disease....Pages 45-51 The Climate–KD Link....Pages 53-57 Kawasaki Disease Shock Syndrome....Pages 59-63 Future Directions in Kawasaki Disease Research....Pages 65-69 Front Matter....Pages 71-71 Epidemiologic Perspectives....Pages 73-77 Update on Nationwide Surveys and Epidemiologic Characteristics of Kawasaki Disease in Japan....Pages 79-84 Kawasaki Disease Epidemiology in Europe....Pages 85-89 Recent Topics in the Epidemiology of Kawasaki Disease....Pages 91-94 Front Matter....Pages 95-95 Overview of Medical Treatment....Pages 97-101 Overview of the New Japanese Guideline2012 for the Medical Treatment of Acute Stage of Kawasaki Disease....Pages 103-167 Tumor Necrosis Factor-α Blockade for Treatment of Acute Kawasaki Disease....Pages 169-173 Methylprednisolone Pulse Therapy for Nonresponders to Immunoglobulin Therapy....Pages 175-179 Prednisolone....Pages 181-185 Cyclosporin A for IVIG Nonresponders....Pages 187-194 Front Matter....Pages 95-95 Other Challenging Therapies....Pages 195-198 Antiplatelet and Antithrombotic Therapy for Giant Coronary Aneurysm....Pages 199-205 Characteristics of Sudden Cardiac Death Late After Acute Kawasaki Disease....Pages 207-213 Kawasaki Disease Diagnosis and Complication Rates in the United States and Japan....Pages 215-222 Mechanism of Action of Immunoglobulin: Sialylated IgG....Pages 223-230 Treatment Options for Refractory Kawasaki Disease: Alternative Treatments for Infliximab Nonresponders....Pages 231-237 Ulinastatin....Pages 239-244 Front Matter....Pages 245-245 Diagnosis and Management of Cardiovascular Risk Factors....Pages 247-254 Diagnosis and Characteristics of Typical and Incomplete Kawasaki Disease....Pages 255-269 Scoring Systems to Predict Coronary Artery Lesions and Nonresponse to Initial Intravenous Immunoglobulin Therapy....Pages 271-277 Use of Magnetic Resonance Angiography for Assessment of Coronary Artery Lesions Caused by Kawasaki Disease....Pages 279-284 CT Coronary and Myocardial Images in Patients with Coronary Artery Lesions....Pages 285-295 Long-Term Follow-Up and Education Regarding Daily Life Activities, School Life, and Guidelines After Acute KD....Pages 297-301 Assessment of Cardiac Ischemia During Acute and Long-Term Follow-Up and Rheologic Assessment of Coronary Artery Lesions After Kawasaki Disease....Pages 303-310 Promising Biomarkers in Acute Kawasaki Disease and Acute Coronary Ischemia....Pages 311-319 Coronary Artery Diameter Z Score Calculator....Pages 321-333 Evidence of Endothelial Damage in Acute KD....Pages 335-340 Oxidative Stress in Kawasaki Disease....Pages 341-352 Front Matter....Pages 353-353 Antiplatelet and Anticoagulant Therapies for Kawasaki Disease: Theory and Practice....Pages 355-372 Guideline for Catheter Intervention in Coronary Artery Lesion in Kawasaki Disease....Pages 373-382 Front Matter....Pages 353-353 Long-Term Clinical Follow-Up After Rotational Atherectomy for Coronary Arterial Stenosis in Kawasaki Disease....Pages 383-387 Long-Term Outcomes of Pediatric Coronary Artery Bypass Grafting and Down-Sizing Operation for Giant Coronary Aneurysms....Pages 389-406 Long-Term Graft Patency and Surgical Outcomes of Coronary Artery Bypass Surgery in Children with Kawasaki Disease....Pages 407-417 Front Matter....Pages 419-419 Functional and Structural Alterations of Coronary Arteries Late After Kawasaki Disease and the Risk of Acute Coronary Syndrome in Adults....Pages 421-425 Psychosocial Effects of Kawasaki Disease and Transition to Adult Care....Pages 427-437 Kawasaki Disease: Road Map for the Future....Pages 439-443 Back Matter....Pages 445-552