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19.11.12 Kawasaki disease 4590 Brian W. McCrindle

19.11.12 Kawasaki disease 4590 Brian W. McCrindle

section 19  Rheumatological disorders 4590 Ghosh P, Borg FA, Dasgupta B (2010). Current understanding and management of giant cell arteritis and polymyalgia rheumatia. Expert Rev Clin Immunol, 6, 913–​28. Hutchings A, et  al. (2007). Clinical outcomes, quality of life and diagnostic uncertainty in the first twelve months in polymyalgia rheumatica. Arthritis Rheum, 57, 803–​9. Lawrence RC, et al. (2008). Estimates of the prevalence of arthritis and other rheumatic conditions in the United States Part 2. Arthritis Rheum, 58, 26–​35. Ma-​Krupa W, et al. (2004). Activation of arterial wall dendritic cells and breakdown of self-​tolerance in giant cell arteritis. J Exp Med, 199, 173–​83. Matteson EL, et al. (2012). Patient-​reported outcomes in polymyalgia rheumatica. J Rheum, 39, 4. Polymyalgia Rheumatica & Giant Cell Arteritis UK (PMRGCAUK). https://​www.pmrgcauk.com Smeeth L, Cook C, Hall AJ (2006). Incidence of diagnosed polymyalgia rheumatica and temporal arteritis in the United Kingdom 1990–​2001. Ann Rheum Dis, 65, 1093–​8. Walsh LJ, et al. (1996). Use of oral glucocorticoids in the community and the prevention of secondary osteoporosis:  a cross sectional study. BMJ, 313, 344–​6. 19.11.12  Kawasaki disease Brian W. McCrindle ESSENTIALS Kawasaki disease is an acute, self-​limited, inflammatory vasculitis of unknown aetiology, with a peak incidence under five years of age. Coronary complications can present in adults. Clinical features—​diagnosis requires persistent fever for five days or more and at least four of the following five clinical signs: (1) non​purulent conjunctivitis, (2)  oropharyngeal inflammation, (3) cervical lymphadenopathy, (4) polymorphous exanthem, and (5) erythema of the palms and soles with subsequent desquam- ation. Coronary artery dilation and aneurysms occur in 15–​25% of untreated patients. Management and prognosis—​primary therapy is with intravenous γ-globulin. Thrombosis and stenosis in damaged coronary artery segments leading to myocardial ischemia are the predominant long-​term morbidity. In adults, new presentations of myocardial ischaemia with coronary artery aneurysms may suggest a previous episode of Kawasaki disease during childhood. Introduction Kawasaki disease is an acute, self-​limited, inflammatory vascu- litis predominately occurring in children under five years of age, complicated by coronary artery dilation and aneurysms, with sub- sequent risk of thrombosis, stenosis and cardiac ischaemia, and sudden death. Historical perspective Kawasaki disease was first described in Japan by Dr Tomisaku Kawasaki, a paediatrician, in 1967. In his initial report, he described the characteristic clinical features, but concluded that it was a self-​ limited illness with no sequelae. It has since been recognized that Kawasaki disease is a systemic vasculitis with a predilection for the coronary arteries, resulting in dilation and aneurysms. It has now been described worldwide in all races, and has become the leading cause of acquired cardiac disease in children in developed countries. Epidemiology While Kawasaki disease has been reported worldwide, the incidence remains highest in Japan and children of Japanese descent, now more than c.300 cases per 100 000 children less than five years of age. The incidence is lowest in Caucasians at less than one-​tenth of the rate. While most cases occur in children less than five years of age, Kawasaki disease has been reported in older children and adolescents. Males are more commonly affected by a ratio of 1.5:1. Recurrence is rare, with estimates of 3–​7 episodes occurring per 1000 years of pa- tient follow-​up. Recurrence usually occurs within two years of the initial episode. Familial occurrences are rare; the proportion of cases with a positive family history is 1%. Siblings may have a 10-​fold rela- tive risk compared to the general population. Aetiology The aetiology of Kawasaki disease is unknown. The marked racial differences in the incidence, together with familial occurrences, sug- gest a genetic component. Genetic susceptibility factors have been identified from family linkage studies and genome-​wide association studies. Polymorphisms identified in six genes or gene regions in- clude FcγR2a, Caspase 3 (CASP3), HLA Class II, B cell lymphoid kinase, inositol 1,4,5-​trisphosphate kinase-​C (ITPKC), and CD40. Some of these, and additional gene polymorphisms, have also been shown to be associated with response to treatment and with vas- cular complications. These genetic and signalling pathway insights are leading to trials of novel and more specific therapies. Epidemiologic features have also suggested an infectious aetiology. However, many candidate pathogens have been proposed and refuted. Examination of rare autopsy material from Kawasaki disease patients has shown the presence of intracyoplasmic inclusion bodies in bron- chial epithelial cells, and the presence of ribonucleic acid virus-​like particles. Epidemic years, particularly in Japan, have been described. The incidence shows important seasonal variation, and is approximately 40% higher during the winter months of January through March in the Northern Hemisphere extratropical latitudes. The incidence is lower in the tropics and the Southern Hemisphere extratropics, with a less pronounced peak during May through June. A novel hypoth- esis for these seasonal peaks has emerged based on an ecologic as- sociation between trophospheric wind patterns and fluctuations in the incidence in Japan. The winds have been hypothesized to carry an infectious or environmental aetiologic agent from northeastern China, and sampling has suggested a Candida species. Of note, extracts from Candida albicans has been one agent that has been used to create a mouse model of Kawasaki disease. Additionally, a

19.11.12  Kawasaki disease 4591 recent focus on environmental factors has suggested support for a ‘hygiene hypothesis’, with environmental factors interacting with a developing immune system to influence susceptibility to the causa- tive infectious or environmental trigger. Pathology Examination of rare autopsy material has suggested three processes in the arterial pathology of Kawasaki disease (Fig. 19.11.12.1). During the acute phase, severe involvement is characterized by necrotizing arteritis, a neutrophilic process which may variably lead to destruction of the intima, media and elastica layers, and sometimes extend to the adventitia. The thin rim of remaining adventitia and perivascular tissue, together with hydrostatic pressures, leads to aneurysm development and the rare risk of rupture. Also beginning in the first two weeks after onset, a subacute/​chronic vasculitis may be evident, with nonsynchronous infiltration of lymphocytes, plasma cells, and eosinophils. This vasculitic process begins in the adventitia and perivascular tissue and results in further inflammation and ar- terial damage. This process can persist for months to years, and is closely linked to a chronic process of luminal myofibroblastic proliferation. The vasculitis induces the transition of surviving smooth muscle cells from the media and adventitia to classic myofibroblasts. This, combined with ongoing inflammation and associated matrix products, leads to a proliferative process that progressively encroaches into the lumen. Resulting circulating factors may induce luminal myofibroblastic proliferation in more remote vascular beds. Reduction of luminal dimensions occurs as a result of these processes, and continued proliferation can lead to stenoses. The development of laminar thrombus with organization also contributes to stenoses and calcification, and occlusive thrombus can recanalize. Both thrombosis and sten- osis can lead to myocardial ischaemia or infarction. Evidence of myocarditis has been reported on autopsy and in biopsy speci- mens during the acute illness and follow-​up, but the long-​term relevance remains unclear. Fig. 19.11.12.1  Pathologic features of coronary artery abnormalities after Kawasaki disease. (a) Necrotizing arteritis of a coronary artery, with a friable fragmenting wall with neutrophils and debris extending from the lumen to the adventitia. (b) Subacute/​chronic inflammation in a coronary artery aneurysm, with the adventitia and media rich in inflammatory cells. The myofibroblasts of luminal myofibroblastic proliferation, extending from the lumen through the internal elastic lamina and into the media are mostly obscured by inflammatory cells. (c) Subacute/​chronic inflammation and luminal myofibroblastic proliferation causing and eccentric narrowing of a coronary artery, with disruption of the media and internal elastic lamina at the top, with inflammation extending into the adventitia. From Orenstein JM et al. (2012). Three linked vasculopathic processes characterize Kawasaki disease: a light and transmission electron microscopic study. PLoS One, 7, e38998. Fig. 19.11.12.1  Continued

section 19  Rheumatological disorders 4592 Clinical features Clinical and laboratory features are consistent with a generalized in- flammatory process, and are largely nonspecific, hence timely diag- nosis requires a high index of suspicion. Diagnosis requires persistent fever for five days or more and at least four of the following five clinical signs: (1) non​purulent con- junctivitis, (2)  oropharyngeal inflammation, (3)  cervical lymph- adenopathy, (4) polymorphous exanthem, and (5) erythema of the palms and soles with subsequent desquamation (Fig. 19.11.12.2). (a) (b) (d) (e) (f) (g) (c) Fig. 19.11.12.2  Typical appearance of the diagnostic physical features of Kawasaki’s disease. (a) Bilateral, non​exudative conjunctival injection with perilimbal sparing. (b) Strawberry tongue with loss of filiform papillae and persistence of fungiform papillae (‘seeds’ of strawberry). (c) Erythematous, fissured lips. (d) Unilateral enlarged left jugulodigastric nodes. (e) Erythematous rash. (f) Erythema of soles, swelling of dorsa of feet. (g) Periungual desquamation of toes in convalescent phase. With acknowledgement to Dr T Kawasaki.

19.11.12  Kawasaki disease 4593 The desquamation following the acute illness generally follows a characteristic pattern, beginning first in the periungual regions, and may also occur in the diaper area in infants. Hydrops of the gallbladder occurs in c.15% of patients, with IgA vasculitis (Henoch- Schonlein purpura) usually easily excluded as the only other major cause. Thrombocytosis may become profound after the first week. Rarely, patients may have features of macrophage activation syn- drome. With the exception of arterial involvement, all abnormalities resolve without sequelae, although there have been rare reports of persistent sensorineural hearing loss. In addition to vasculitis, particularly coronary arteritis, cardio- vascular involvement may be evident as a pancarditis, with valvul- itis, myocarditis, and pericarditis with effusion. Rarely, patients may develop cardiovascular collapse (Kawasaki disease shock syndrome) or ventricular arrhythmias during the acute illness. Coronary ar- tery changes are often evident by echocardiography at the time of diagnosis, and are virtually diagnostic of Kawasaki disease. Rarely, patients may die suddenly before the diagnosis is recognized from rupture or thrombosis of a coronary artery aneurysm. Risk factors for the development of coronary artery abnormalities. These may include male gender, age less than one year (more so if less than 6 months), higher C-​reactive protein level, higher white blood cell, or neutrophil count, thrombocytopenia, anaemia, low serum albumin level, and treatment delays, or persistent or recurrent fever. Differential diagnosis Kawasaki disease has similarities with several other commoner childhood illnesses. Viral infections, such as adenovirus, entero- virus, Ebstein-​Barr virus and measles, and bacterial infections, such as scarlet fever, can be very similar. While traditionally the presence of infection was presumed to exclude the diagnosis, many patients do indeed have a concomitant infection. Possible infectious disease symptoms are common, with gastrointestinal symptoms present in 60% and respiratory symptoms in 35% of patients during the acute illness. Toxin-​mediated illness, such as Staphylococcal scalded skin syndrome and toxic shock syndrome, also share similar clinical fea- tures. Drug hypersensitivity reactions and Stevens–​Johnson syn- drome may be difficult to differentiate from Kawasaki disease, given that many children are presumptively treated with antibiotics before the diagnosis of Kawasaki disease is made. Other rarer conditions to be considered include Rocky Mountain spotted fever, leptospirosis, juvenile rheumatoid arthritis, and acrodynia. Clinical investigation Ongoing clinical assessment may be necessary as patients may not manifest all of the clinical criteria simultaneously, particularly younger and older patients. Laboratory assessment is used to detect associated abnormalities, exclude similar illnesses, as well as to pro- vide additional evidence to support the diagnosis, particularly for pa- tients with insufficient clinical criteria. Routine laboratory assessment performed at presentation should include full blood cell count with differential, erythrocyte sedimentation rate (ESR) and C-​reactive protein (CRP), serum sodium, albumen, hepatic transaminases, and urinalysis with microscopic examination of sediment. N-​terminal pro-​brain natriuretic peptide has been proposed as a biomarker to differentiate Kawasaki disease from other febrile conditions. Echocardiography to detect early coronary artery abnormalities may provide further evidence to support the diagnosis, as well as to identify patients who may be developing severe involvement. It should be performed at the time of diagnosis (but not delay treat- ment), after 1–​2 weeks, and at 4–​8 weeks for uncomplicated patients. If severe coronary artery complications are evident, echocardiog- raphy may be performed more frequently. In addition to coronary artery abnormalities, echocardiography may reveal pericardial ef- fusions, valvular regurgitation, and abnormalities of both systolic and diastolic ventricular function. Quantitative measurements of coronary artery diameters are best related to available body surface area specific nomograms for the definition of abnormalities. Several sources of normative equations allow conversion to Z scores, and classification of abnormalities should incorporate maximal Z scores, absolute dimensions, and qualitative aspects. Echocardiography op- timally images the proximal segments of the coronary arteries, with distal segments less well assessed. However, it is very rare for pa- tients to have distal involvement without some evidence of proximal abnormalities. For selected patients with severe coronary artery ab- normalities, additional imaging may be required to determine the presence and extent of more distal coronary artery involvement or involvement in other systemic arteries (such as the axillary, iliac, femoral, and splanchnic arteries). This may include magnetic reson- ance angiography, computed tomographic angiography or conven- tional coronary angiography (Fig. 19.11.12.3). Criteria for diagnosis The diagnosis of Kawasaki disease rests on meeting the classical clinical criteria, which includes fever of at least five days duration and the pres- ence of at least four of the five principal clinical signs. The diagnosis can be made earlier by experienced clinicians. Early in the illness course, patients with features of Kawasaki disease are often mistakenly given alternative diagnoses, particularly viral or bacterial infection, and may have been treated empirically with antibiotics. In addition, a detailed clinical history may note some features that may have resolved by the time of presentation. However, for patients early in their presentation or for those who do not have sufficient principal clinical signs, add- itional surveillance, and laboratory testing may provide supportive evidence and identify patients who require treatment, as per the algo- rithm for suspected incomplete Kawasaki disease in Fig. 19.11.12.4. About 25% of patients have incomplete Kawasaki disease. This occurs more commonly in infants and older children or adoles- cents, may contribute to delayed diagnosis, and carries a similar risk of coronary artery complications as those who meet full cri- teria for diagnosis. The presence of elevated erythrocyte sedi- mentation rate and C-​reactive protein together with three or more supplemental laboratory criteria should prompt treatment. These criteria include anaemia for age, elevated white cell count over 15 000/​mm3, thrombocytosis with platelet count more than 450 000 after seven days of fever, low albumen under 3.0 g/​dl, ele- vated alanine aminotransaminase, and sterile pyuria (white cells on urine microscopy of >10 per high powered field). The presence of a positive echocardiogram performed at any time should also prompt treatment, regardless of laboratory features. A positive echocardiogram is defined as a Z score of over 2.5 in the right coronary artery or left anterior descending branch; or the presence of a coronary artery aneurysm; or the presence of three or more other features, including ventricular dysfunction, pericardial

section 19  Rheumatological disorders 4594 effusion, mitral valve regurgitation, or coronary artery Z scores be- tween 2 and 2.5. For patients with suspected incomplete Kawasaki disease with a positive echocardiogram who present after the tenth day of fever, treatment should be given if there are laboratory and clinical signs of persistent inflammation. Treatment In addition to supportive management, the mainstay of therapy is a single high dose infusion of 2 grams per kilogram of intravenous γ-globulin (IVIG), infused over c.10 hours. Pretreatment with an antihistamine is often used. IVIG is ideally given within the first 10 days from the onset of fever, and as soon as possible after the diagnosis is made. Timely treatment with intravenous γ-globulin reduces the risk of coronary artery complications to less than 4%. Patients presenting after 10 days should be given intravenous γ-globulin if they have current fever, evidence of ongoing inflam- mation, or evolving coronary artery abnormalities. Patients are usually concomitantly given moderate (30–​50 mg/​kg/​day) or high dose (80–​100  mg/​kg/​day) acetylsalycilic acid (ASA) as an anti-​ inflammatory agent, at least until they are afebrile. The dose is then lowered (3–​5 mg/​kg/​day) for antiplatelet effects for a period of 4–​8 weeks, then discontinued if there are no coronary artery abnormal- ities. Primary adjunctive treatment with other anti-​inflammatory agents, such as corticosteroids or infliximab, is not indicated. Approximately 25% of patients will continue to have fever or initially defervesce and then have a recurrence of fever within 36 hours of conclusion of their intravenous γ-globulin infusion. Such patients are said to be intravenous γ-globulin resistant and may have residual clinical signs and elevated C-​reactive protein (erythrocyte sedimentation rate may be falsely elevated after initial intravenous γ-globulin treatment). These patients are at increased risk for coronary artery abnormalities. An additional dose of intra- venous γ-globulin is recommended, although pulse corticosteroid and possibly infliximab are reasonable alternatives. For patients with refractory disease, use of a longer course of corticosteroids, infliximab, cyclosporine, plasma exchange, or cytotoxic agents may be warranted. A trial in Japan of a longer course of corticosteroids in addition to intravenous γ-globulin for initial treatment for pa- tients predicted to be intravenous γ-globulin resistant noted some reduction in coronary artery abnormalities. However, existing risk scoring systems have been shown to have poor predictive capabil- ities in non-​Asian populations. (a) (b) (d) (e) (c) Fig. 19.11.12.3  Imaging of severe arterial involvement complicating Kawasaki disease. (a) Multiple fusiform aneurysms along the length of the proximal right coronary artery. (b) A large fusiform and small saccular aneurysm of the proximal left anterior descending coronary artery branch. (c) Magnetic resonance angiogram showing aneurysmal arterial involvement in other small to medium-​sized arteries. (d) Fusiform and saccular aneurysms of the right coronary artery with complete occlusion (arrow) of the distal exit of the aneurysm. (e) Successful reperfusion of the distal right coronary artery with placement of a right internal mammary artery bypass graft.

19.11.12  Kawasaki disease 4595 Despite recommended treatment, c.20% of patients will develop coronary artery dilation, c.4% aneuryms and c.1% giant aneur- ysms. For those with aneurysms, close follow-​up and more fre- quent echocardiograms are required during the acute illness while involvement is progressing. In addition to low dose acetylsalycilic acid, systemic anticoagulation with warfarin or fractioned heparin is needed to prevent thrombotic occlusions during this high-​risk period. If the patient with aneurysms requires a non​steroidal anti-​ inflammatory agent, usually to manage arthritis, the acetylsalycilic acid should be switched to an alternative antiplatelet agent. For patients with multiple giant aneurysms or recent thrombosis, the addition of a second antiplatelet agent may be considered. Thrombolytic agents may be necessary for patients who develop acute thromboses. Prognosis and long-​term management Most patients who have had Kawasaki disease will have no or min- imal coronary artery involvement, have an excellent long-​term prognosis, and do not require cardiology assessments beyond 4–​ 8 weeks after resolution of the acute illness. However, all patients should have screening and management for cardiovascular disease risk factors. The pathological sequence of coronary artery abnor- malities is shown in Fig. 19.11.12.5. Aneurysms may show reduc- tions in dimensions over the long-​term, primarily resulting from luminal myofibroblastic proliferation and organization of laminar thrombus. These reductions may result in normalization of the lu- minal dimension and reduction in thrombotic risk, but may also progress to stenoses and obstructions, most common at entry and exit points of aneurysms. Thrombosed aneurysms may show or- ganization and recanalization, and the effect on myocardial perfu- sion of stenoses and occlusions may be mitigated by the presence of collateralization from other branches. The risk of myocardial ischaemia and infarction is determined by both the degree of max- imal involvement, and the nature and cumulative effect of these pathologic processes. Long-​term management is focused on surveillance for myocar- dial ischaemia and calibration of thromboprophylaxis. The greater the degree of coronary artery involvement, the greater is the need for assessment and medical management to be individualized. For all patients, participation in daily physical activity should be pro- moted, with the types of activities and the intensity level calibrated to the risk of bleeding related to thromboprophylaxis and the risk of myocardial ischaemia. Risk stratification guiding manage- ment is based on both maximal coronary artery involvement and changes over time. For patients with small aneurysms (maximal Z score 3–5), reduction to a normal luminal dimension is likely over a relatively short period of time. The risk of thrombosis is low, and acetylsalicylic acid alone is sufficient for thromboprophylaxis. The risk of ischemia is also low, although periodic lifelong follow-up is reasonable, with infrequent testing for inducible myocardial is- chemia (stress echocardiography, MRI or nuclear medicine stress perfusion imaging) every 3–5 years. Echocardiography may be omitted once the luminal dimensions are normal. For patients with medium aneurysms (maximal Z score 5–10 with an abso- lute dimension <8 mm), changes occur more slowly and less com- pletely. The risk of thrombosis is also low, and acetylsalicylic acid alone is recommended, although patients with multiple or distal aneurysms may also be considered for an additional antiplatelet agent. Cardiology assessment is initially frequent, and can be re- duced to every 1–2 years as the luminal dimension approaches normal. The risk of ischemia is low, and stress perfusion testing is recommended every 2–3 years. For patients with large or giant aneurysms (maximal Z score >10 or absolute dimension >8 mm), the prognosis is less certain and reduction to a normal luminal dimension is rare. The risk of thrombosis is initially high, and systemic anticoagulation with warfarin or low molecular weight Children with fever ≥5 days and 2 or 3 compatible clinical criteria OR Infants with fever for ≥7 days without other explanation Evaluation of Suspected Incomplete Kawasaki Disease Assess Laboratory Tests CRP ≥3.0 mg/dl and/or ESR ≥40 mm/hr CRP <3.0 mg/dl and ESR <40 mm/hr 3 or more Laboratory Findings:

  1. Anemia for age
  2. Platelet count of ≥450000 after the 7th day of fever
  3. Albumin ≤3.0 g/dl
  4. Elevated ALT level
  5. WBC count of ≥15000/mm3
  6. Urine ≥10 WBC/hpf OR Positive echocardiogram Serial clinical and laboratory re-evaluation if fevers persist Echocardiogram if typical peeling develops Treat NO YES Fig. 19.11.12.4  Evaluation of suspected incomplete Kawasaki disease. Reproduced from McCrindle BW et al. (2017). Diagnosis, treatment, and management of Kawasaki disease. Circulation 135:e927–e999. Copyright 2017, American Heart Association with permission from Wolters Kluwer Health, Inc.

section 19  Rheumatological disorders 4596 heparin is recommended in addition to antiplatelet therapy. As di- mensions reduce, the risk of thrombosis lessens, anticoagulation can be discontinued and dual antiplatelet therapy or acetylsali- cylic acid alone may be considered. β-blockers and statins may be considered particularly for those with persistent aneurysms. These patients require lifelong cardiology assessment for the de- velopment of stenosis and ischemia, initially frequently but may be decreased to every 2 to 5 years if normal luminal dimensions are achieved. For patients who have had aneurysms, advanced cardiac imaging may be performed periodically, including com- puted tomography (angiography, coronary artery calcium) and MRI (angiography, myocardial function, perfusion, and fibrosis/ scar). The use and frequency is calibrated to the severity and com- plexity of coronary artery involvement, and most applicable for those with large and giant aneurysms, even if there have been important reductions in luminal dimensions. Conventional angi- ography is performed less frequently, although it does afford the opportunity for characterization of the arterial wall with intravas- cular ultrasound or optical coherence tomography. This is useful if a coronary artery intervention is being planned. For patients who develop important stenoses and occlu- sions associated with myocardial ischaemia or infarction, revascularization should be considered. Interventional catheter procedures have been effective, but they are often not feasible in small patients and are associated with a high risk of recurrence. Bypass grafting, particularly with arterial grafts, have been par- ticularly effective and show good longevity in growing patients. Rare patients who develop ischaemic cardiomyopathy or in- tractable ventricular arrhythmias may undergo cardiac trans- plantation. Previously healthy adult patients who present with myocardial ischaemia and a new diagnosis of coronary artery aneurysms may have had a forgotten or missed diagnosis of Kawasaki disease during childhood. FURTHER READING Japanese Circulation Society Joint Working Group (2014). Guidelines for diagnosis and management of cardiovascular sequelae in Kawasaki disease (JCS 2013). Digest version. Circ J, 78, 2521–​62. McCrindle BW, et al. (2017). American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young. Diagnosis, treatment, and long-term management of Kawasaki disease. Circulation, 135, e927–e999. No coronary artery changes Mild, transient dilatation (resolves within 4–6 weeks) Necrotizing arteritis Aneurysm formation Myocardial infarction Complex stenosis Occlusive thrombus formation

  1. Subacute/chronic vasculitis
  2. Luminal myofibroblastic proliferation
  3. Laminar nonocclusive thrombosis Organization of thrombus and recanalization Possible progression to a normal luminal dimension Ischemic heart disease Further progression and ? possible interaction with atherosclerosis risk factors
    Calcification Destruction of intima, elastica interna, media and, variably, adventitia Adventitia Elastica interna Intima Media Fig. 19.11.12.5  Pathological sequences of coronary artery abnormalities. Reproduced from McCrindle BW et al. (2017). Diagnosis, treatment, and management of Kawasaki disease. Circulation 135:e927–e999. Copyright 2017, American Heart Association with permission from Wolters Kluwer Health, Inc.

19.11.12  Kawasaki disease 4597 Newburger JW, et al. (1991). A single intravenous infusion of γ-globulin as compared with four infusions in the treatment of acute Kawasaki syndrome. N Engl J Med, 324, 1633–​9. Orenstein JM, et al. (2012). Three linked vasculopathic processes char- acterize Kawasaki disease: a light and transmission electron micro- scopic study. PLoS One, 7, e38998. Research Committee of the Japanese Society of Pediatric Cardiology; Cardiac Surgery Committee for the Development of Guidelines for Medical Treatment of Acute Kawasaki Disease (2014). Guidelines for medical treatment of acute Kawasaki dis- ease: report of the Research Committee of the Japanese Society of Pediatric Cardiology and Cardiac Surgery (2012 revised version). Pediatr Int, 56, 135–​58. Z score calculator of coronary artery diameter (incorporates multiple sources of normative formulas). http://www.parameterz.com/sites/ coronary-arteries

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