Current recommendations for the pharmacologic therapy in Kawasaki syndrome and management of its cardiovascular complications

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1 European Review for Medical and Pharmacological Sciences 2007; 11: Current recommendations for the pharmacologic therapy in Kawasaki syndrome and management of its cardiovascular complications G. DE ROSA*, M. PARDEO*, D. RIGANTE *Section of Pediatric Cardiology; Department of Pediatric Sciences, Università Cattolica del Sacro Cuore Rome (Italy) Abstract. Kawasaki syndrome is a potentially life-threatening disease of early childhood that untreated holds a risk of severe coronary involvement. Its diagnosis is made via a list of clinical signs because etiology and pathophysiology are still unknown and no specific laboratory tool is available. Appropriate therapy with intravenous immunoglobulins and aspirin reduces the incidence of coronary abnormalities to less than 5%. Immunoglobulins have been shown to be highly effective in reducing disease symptoms or their severity and chiefly in reducing the rate of coronary artery aneurysm development. Aspirin is firstly used in high dose for its anti-inflammatory properties and then in low dose for its anti-thrombotic effects. Timely diagnosis and precociously administered treatment are two crucial points in the definition of prognosis for Kawasaki syndrome. In this review heart complications are discussed and therapeutic options stratified according to both severity of coronary involvement and grading of cardiovascular risk. Key Words: Kawasaki syndrome, Cardiovascular complications. Introduction Kawasaki syndrome (KS) or muco-cutaneouslymph node syndrome is an acute systemic vasculitis of unknown etiology that involves the walls of medium- and small-sized muscular arteries throughout the body in the pediatric age, which was firstly described by Tomisaku Kawasaki in At that time, he reported 50 children from who presented with a distinctive clinical illness characterized by fever and skin rash, which was then thought to be a be- nign childhood disease: several years later, fatalities occurred in Japan among children with KS younger than 2 years when they had apparently recovered. Post-mortem examinations revealed complete thrombotic occlusion of coronary artery aneurysms with myocardial infarction as the immediate cause of death. This syndrome has now surpassed rheumatic fever as the leading cause of acquired heart disease in the developed countries among children younger than 5 years 1. Although its etiology is largely unknown, epidemiological findings suggest that genetic factors play a role in the pathogenesis of KS: although KS has been reported all over the world, it is overexpressed among Asian populations, especially in children of Japanese ancestry. KS results 10 times more prevalent in Japan, if compared with other nations, especially for infants with less than 2 years. The proportions of KS Japanese patients with cardiac sequels (such as dilation or stenosis of coronary arteries, myocardial infarction and valvular lesions) 1 month or more after onset were analyzed using nationwide survey protocols: the prevalence of heart abnormalities was particularly high in males, infants younger than 1 year and children older than 5 years of age 2. In the natural history of the disease three phases occur: we can distinguish an acute phase (in the first 2 weeks of illness), a subacute phase (including the 3 th and 4 th week of illness) and a phase of convalescence (lasting from the 5 th to the 8 th week since the onset). The original guidelines for the diagnosis of KS were created by a committee that was appointed by the Japanese Ministry of Health in In the acute phase KS usually starts with more than 5 days of high fever followed by at least 4 of 5 main clinical features: non-exudative conjunctival injection, polymorphous skin rash, reddening/fissuring of lips and oral mucosa, abnormalities in- Corresponding Author: Donato Rigante, MD; drigante@rm.unicatt.it 301

2 G. De Rosa, M. Pardeo, D. Rigante volving extremities of limbs and perineum and cervical lymphadenitis (Table I). In the absence of specific diagnostic tests, pathognomonic features or evidence-based diagnostic algorithms, KS diagnosis remains basically clinical 3. Laboratory findings are frequently helpful in confirming the correct diagnostic suggestion: inflammatory markers as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum amyloid-a (SAA) are markedly elevated; neutrophil leukocytosis (with toxic granulations and left shift), mild-to-moderate normochromic anemia (with haemoglobin levels < 2 SD for age), hypoalbuminemia (< 3.5 g/dl), hyponatremia (< 135 meq/l), elevated serum transaminases and sterile pyuria are typical of KS. In the subacute phase the vast majority of patients displays skin desquamation starting in the subungual regions of the fingers and spreading to palms and soles in combination with the increase of platelet count, sometimes exceeding /mm 3. In some patients arthralgias or arthritides can appear in the subacute phase. Incomplete and atypical forms of KS (with other vasculitic features as abdominal pain, pneumonia, seizures, meningitis, urethritis, hepatitis and gallbladder distention, parotitis, uveitis, etc.) are more common in young infants with less than 1 year of age 4. Characteristics suggesting disease other than KS include exudative conjunctivitis, exudative pharyngitis, bullous, vesicular or exfoliating rash and generalized adenopathy. There is a great number of pathologic conditions mimicking KS which require to be considered attentively in the differential diagnosis as staphylococcal scalded skin syndrome, toxic shock syndrome, Stevens-Johnson syndrome, scarlet fever, measles, Epstein-Barr virus infection, Cytomegalovirus infection, tick-borne diseases, juvenile rheumatoid arthritis, reaction to drugs and mercury hypersensitivity (acrodynia). Therapeutical Approach in Kawasaki Syndrome A combination of a single dose of intravenous immunoglobulins (2 grams/kg of body weight infused over a period of hours) and aspirin at high doses (30 to 100 mg/kg/day in four divided doses) are recommended when KS diagnosis is made during the first 10 days of illness. KS therapy is schematized in the Table II. Treatment with intravenous immunoglobulins is directed at reducing the inflammation in the vessel walls involved by the disease, mostly in the coronary artery walls, and at preventing coronary artery Table I. Criteria for the diagnosis of Kawasaki syndrome. Fever persisting at least for 5 days (or more) plus at least 4 of the following 5 clinical main signs: Bilateral bulbar conjunctival injection without exudate Polymorphous skin rash Changes in lips (reddened, dry or cracked) and oral cavity (strawberry tongue, diffuse oral and pharyngeal hyperemia) Changes in the extremities and in the perineum (erythema of palms or soles, indurative edema of hands or feet, desquamation of perineal skin) Acute cervical lymph node enlargement (with a diameter superior than 15 mm) thrombosis. High-dose aspirin is administered to reduce fever and KS inflammatory signs. The efficacy of intravenous immunoglobulins is dosedepending: a randomized-controlled trial has demonstrated that a single infusion of 2 g/kg infused in a time of 10 hours has a higher efficacy than a 4-day-infusion of 400 mg/kg/day 5. There is no evidence that immunoglobulin treatment on day 4 of fever or earlier has greater efficacy in preventing cardiac complications than treatment on days 5 to 9. The mechanism of action of intravenous immunoglobulins is unknown, though it might include neutralization of hypothetic infectious agents, inhibition of endothelial cell functions, non-specific anti-inflammatory effects by the down-regulation of proinflammatory cytokines as tumour necrosis factor-α (TNF-α) and interferon-gamma, blockage of Fc-receptors on macrophages, suppression of T and B cells and blockage of complement cascade. Aspirin inhibits prostaglandin synthesis and has been the first drug used in children with KS. High doses are used only during the acute inflammatory phase and vary across countries: Table II. Standard treatment for Kawasaki syndrome. Intravenous immunoglobulins: 2 g/kg of body weight (infused over a period of hours) Aspirin: mg/kg orally, daily divided into 4 doses, until the normalization of inflammatory parameters Subsequent antiplatelet treatment with aspirin: 3-5 mg/kg orally, once daily for 6-8 weeks (starting in the subacute phase of the disease) or continued indefinitely if coronary abnormalities are observed 302

3 Pharmacologic therapy in Kawasaki syndrome and its cardiovascular complications mg/kg/day in the United Kingdom and mg/kg/day in Japan and in the United States 6-8. Low-dose aspirin in the subacute phase inhibits platelet aggregation and is aimed at the reduction of the thrombotic risk which is higher in patients showing coronary artery dilations. However, the occurrence of coronary abnormalities is not influenced by the association intravenous immunoglobulins-aspirin, if compared with intravenous immunoglobulins alone 9. It is not known the correct timing of high-dose aspirin administration and some physicians use low-dose aspirin even during the acute phase of illness: there are no clinical-trials to confirm this therapeutic strategy or the effectiveness of the association of high-dose aspirin with intravenous immunoglobulins 10. Aspirin dose can be reduced to the single daily dose of 3-5 mg/kg after having obtained the complete normalization of the inflammatory markers, specifically CRP. This antiaggregating dosage is continued for 6 to 8 weeks after the onset of illness, but it should be continued indefinitely over time in those children who have developed coronary abnormalities 11. Coronary thrombosis can be prevented using other antiplatelet agents, depending on the severity of coronary involvement, though no perspective data exist to guide clinicians in choosing the optimal therapy and recommendations are based on the empirical stratification of the cardiovascular risk, published by a committee of the American Heart Association (Table III). Prognosis in Kawasaki Syndrome Prognosis in KS strictly depends on the cardiac involvement and is of lifetime significance: coronary artery aneurysms develop in 20-40% of untreated children and may lead to rupture in adulthood, ischemic heart disease and myocardial infarction 12,13. Due to the fact that KS is a generalized systemic vasculitis involving blood vessels throughout the body, aneurysms might be demonstrated in other extra-parenchymal muscular arteries such as the celiac, mesenteric, femoral, renal, axillary and brachial arteries, with the exception of central nervous system arteries. The major sequels of KS are related to the cardiovascular district which might be interested in all its structures: pericardium, myocardium, endocardium and above all coronary arteries. Myocardial disease during the acute phase is commonly reported: inflammation has been documented in 50-70% of autoptic descriptions Its clinical findings are tachycardia, gallop rhythm and congestive heart failure in cases of disturbed ventricular function. The electrocardiogram may show arrhythmias, prolongation of PR, decreased QRS voltage and T-wave flattening. Echocardiography is useful in detecting left ventricular dilation or reduced systolic function. In the acute phase the severity of myocardial involvement is unrelated to the development of coronary artery abnormalities during sub-acute or chronic phases 17,18. Myocardial mechanics improves rapidly after pharmacological therapy. Intravenous immunoglobulins combined with aspirin have given substantial results in the prevention of coronary artery dilation and the reduction of severity of coronary aneurysms. Perspective controlled clinical trials have showed that the infusion of intravenous immunoglobulins during the first week to 10 days of illness reduces the incidence of coronary aneurism from 23 to 9% after the first month and up to 4% after two months A host of retrospective observations has proved the low incidence of coronary abnormalities when KS is promptly diagnosed with therapy instituted within the first 10 days of illness 22. Immunoglobulins should be also administered to children presenting after the 10 th day of illness, either having persistent fever without other explanation or significant elevation of ESR, CRP and SAA 23,24. Treatment with intravenous immunoglobulins should not be started in children in whom KS diagnosis was missed earlier or if it occurred retrospectively without evidence of persisting laboratory signs of inflammation. Table III. Anti-thrombotic treatment related to the severity of coronary artery involvement in patients with Kawasaki syndrome. Mild coronary involvement Mild-to-moderate coronary involvement Coronary aneurysm in rapid expansion Giant aneurysm Low-dose aspirin Combination of aspirin with dipyridamole Combination of heparin with aspirin Combination of aspirin with warfarin 303

4 G. De Rosa, M. Pardeo, D. Rigante Management of Unresponding and Recurrent Kawasaki Syndrome Clinical efficacy of intravenous immunoglobulins is proved by the deverfescence within hours. Approximately 10% of patients with KS fail to respond after the first infusion of immunoglobulins with an increasing risk of developing coronary artery abnormalities: this has been observed mostly in infants with incomplete or atypical forms of KS 25. In the refractory cases of KS there are no documented treatment guidelines. Most experts in the field of KS recommend re-treatment with intravenous immunoglobulins (at the same dosage of 2 g/kg of body weight) which can be repeated for a total of three infusions 26,27. Corticosteroids have also been used to treat patients who have failed to respond to the standard therapy: studies of steroids as initial treatment for KS or as treatment of patients with persistent or recrudescent fever despite treatment with intravenous immunoglobulins have shown that they reduce fever, although their effects on coronary artery abnormalities are still uncertain 28. The most commonly used steroid regime is intravenous pulse methylprednisolone (30 mg/kg of body weight administered once daily in a time of 2-3 hours for 1 to 3 days) The use of biological agents directed against proinflammatory cytokines as TNF-α has recently been suggested by the American Heart Association: infliximab, the chimeric monoclonal antibody IgG 1, comprising 75% human and 25% murine sequences, acts by blocking the molecular system that drives the immune response through TNF-α and has been approved for the treatment of moderate-to-severe Crohn s disease refractory to conventional therapy. Infliximab, at a dose of 5 mg/kg, can reverse the clinical signs of KS unresponding to intravenous immunoglobulins and methylprednisolone, although its effectiveness in reducing the prevalence of coronary artery aneurysms is still unproven. Further studies seem to be necessary with a major number of cases treated to confirm infliximab efficacy and safety 34. Because controlled data are lacking, other treatments including plasmapheresis or cytotoxic agents such as cyclosporine or cyclophosphamide for patients with refractory KS remain of doubtful usefulness. The recurrence rate of KS is low: 1-3% in the Japanese and 1% in the Caucasian population 35. Clinical criteria for diagnosing recurrent KS are the same as in the classic form and it is of outstanding priority to not underestimate this possibility, due to the increased risk of coronary artery involvement than in the primary disease 36. The recurrence of skin peeling in patients who have previously suffered from KS appears relatively common in the case of other viral feverish diseases: thus the only presence of skin peeling is not a diagnostic feature to confirm the recurrence of KS 37. After using intravenous immunoglobulins, the administration of live viral vaccines (such as the ones for measles and chickenpox) should be deferred of about 11 months, though there are differences between Japan and United States suggestions related to the interval before vaccination. In patients who need long-term therapy with aspirin the annual vaccination against influenza virus is recommended to reduce the risk of Reye syndrome 38. Heart Complications in Kawasaki Syndrome Coronary artery aneurysms are the major risk associated with KS and echocardiographic examination, focused on the coronary arteries, including quantitative assessment of the internal vessel diameters, remains a critical part of the diagnostic course of all patients with a suspected KS. Coronary artery abnormalities might develop in 20-40% of untreated patients or in patients treated with only aspirin, with differences depending on the ultrasound assessment of coronary involvement. When a coronary artery is dilated without a segmental aneurysm and the internal diameter of this segment measures 1.5 times than an adjacent segment it is defined as ectasia. The Japanese Ministry of Health criteria classify coronary arteries as abnormal if the internal lumen diameter is greater than 3 mm in children with less than 5 years or greater than 4 mm in children aged more than 5 years. Care must be taken in making the diagnosis of ectatic coronary arteries because of normal variability in coronary artery distribution and dominance. Aneurysms are classified as saccular if axial and lateral diameters are nearly equal or as fusiform if symmetric dilation with gradual proximal and distal tapering are seen. In the last American Heart Association statement coronary aneurysms were classified as small (when the internal lumen diameter of the coronary artery is inferior than 5 mm), medium (when the internal diameter is 5 to 8 mm) or giant (when the internal diameter is superior than 8 mm) 39. The echocar- 304

5 Pharmacologic therapy in Kawasaki syndrome and its cardiovascular complications diographic evaluation of patients with suspected KS should be focused on visualizing the left main coronary artery, the right coronary artery and the left circumflex coronary artery. This study should include the quantitative assessment of their internal diameters, should be aimed at diagnosing the presence of ectasia, the number and the location of eventual aneurysms and the finding of intraluminal thrombi. In patients correctly treated with intravenous immunoglobulins the incidence of coronary abnormalities is inferior than 5%. Ten years ago de Zorzi et al 40 showed the importance of coronary vessel measurements adjusted for body surface to avoid underestimating the true prevalence of coronary involvement in KS in comparison with normal children: in particular, a z score 2.5 (i.e. a coronary dimension that is 2.5 SDs above the mean for body surface area) in proximal right coronary artery or left anterior descending coronary artery would be expected to occur in 0.6% of the population without KS. Frequent sites of coronary aneurysms are the proximal left anterior descending coronary artery, the proximal right coronary artery and the left main coronary artery. Cardiac ultrasound studies need to be performed serially at the time of the diagnosis, at 2 weeks and at 6 to 8 weeks after the onset of KS and should be supervised by an experienced pediatric echocardiographer. The indication of stricter echocardiographic evaluations should be given by the pediatric cardiologist 41. Because detailed echocardiographic imaging is compromised if children are overweight, other non-invasive or invasive cardiac tests can be required for more specific evaluations such as heart magnetic resonance imaging, trans-esophageal echocardiography, coronary angiography and intravascular ultrasound. In patients without coronary artery changes on echocardiography at any phase of KS no antiplatelet therapy is needed beyond the initial 6 to 8 weeks after the onset of illness. Periodic assessment of children having passed KS is strongly suggested to control the known cardiovascular risk factors at least every 2 years, because these patients seem to be prone to a higher cardiovascular risk profile with high blood pressure and greater adiposity compared with control children Coronary artery lesions resulting from KS tend to diminish over time, although fibrous intimal thickening and reduced vascular reactivity might persist: various research articles suggest the constant presence of subclinical abnormalities of the endothelial function also in those patients without coronary artery dilations at any phase of illness 45. Management of Coronary Artery Abnormalities In patients with coronary artery changes longterm antiplatelet therapy with aspirin should be administered with the aim of reducing the risk of thrombosis or myocardial ischemia: serial stress tests, such as echo stress test a specific ultrasound examination performed during exercise or under infusion of drugs are mandatory in the management of these patients to assess the existence and functional consequences of coronary artery abnormalities in children with KS and determine the need for coronary angiography, transcatheter interventions or coronary bypass surgery. In patients with acute coronary occlusion due to acute thrombosis a thrombolytic treatment must be promptly started 46. Catheter interventions should be considered in patients presenting with ischemic symptoms or without ischemic symptoms but with reversible ischemia on stress test and patients without ischemia but with stenosis greater than 75% in the descending coronary artery 47. Stent placement has resulted useful in older children with mild calcifications and in children with giant aneurysms. Patients who develop large coronary artery aneurisms may benefit from a new pharmacologic agent, named abciximab, a glycoprotein IIb/IIIa receptor inhibitor that has been shown to prevent thrombotic complications and promote vascular remodelling. In the Primary Children s Medical Center of Salt Lake City standard therapy for KS in patients with large aneurysms has been compared with abciximab in addition to standard therapy. Abciximab was administered intravenously at a dose of 0.25 mg/kg, followed by the infusion of µg/kg/minute for 12 hours. The resolution of coronary artery aneurysms occurred in 68% (13 of 19) of aneurysms in the group treated with abciximab at a short-term follow-up 48. The indication for coronary by-pass should be considered when there are severe occlusions of the main trunk of the left coronary artery, of more than one major coronary artery or in the proximal segment of the descending coronary artery 49. Cardiac transplantation is only indicated for a small number of patients with KS presenting with severe myocardial dysfunction or severe coronary arterial lesions, for whom in- 305

6 G. De Rosa, M. Pardeo, D. Rigante terventional catheterization or coronary artery by-pass procedures are not feasible 50. The angiographic resolution of coronary aneurysms has been observed 1 to 2 years after the onset of the disease in 50 to 67% of vessels: factors positively associated with the possibility of aneurysm regression include initial size, age at onset inferior than 1 year, morphology and location Coronary abnormalities persist in the long-term in the remaining 33-50% cases: these patients had probably presented coronary artery aneurysms larger than 5 mm or multi-vessel involvement 54. Clinical experience with KS has permitted the stratification of patients according to their relative risk of myocardial ischemia. There are five risk-categories (Table IV): this stratification is useful for the management of patient with KS in order to establish the frequency of clinical follow-up and the timing of instrumental controls. The risk level for a patient with coronary artery involvement may change over time because of the changes in the coronary artery morphology. In conclusion, children without known cardiac sequels during the first month of KS appear to return to their previous state of health without signs of cardiac impairment, but research studies suggest subclinical abnormalities of endothelial function and abnormal myocardial flow reserve many years after the onset of KS. Even patients with aneurysms regressed over time are managed controversially because structural and functional coronary artery abnormalities persist over time. A host of questions related to KS still remain to be answered: the expanding knowledge about its pathogenesis will probably permit in the near future to define the best long-term surveillance modalities in all patients with a history of KS. Table IV. Cardiovascular risk stratification for patients with Kawasaki syndrome. Risk level Therapy Physical activity Follow-up Invasive testing I (No coronary None beyond No restrictions beyond Counseling at None artery changes) first 6-8 weeks first 6-8 weeks 5-year-intervals II (Transient coronary None beyond No restrictions beyond Counseling at None artery ectasia) first 6-8 weeks first 6-8 weeks 3- to 5-yearintervals III (One small-medium Low-dose aspirin For patients < 11 years: Annual Angiography, coronary artery at least until no restriction; echocardiogramm if non invasive aneurysm) aneurysm for patients of years: + ECG; biannual tests suggest regression is physical activity must be stress test and ischemia documented guided by stress test and myocardial myocardial perfusion scan; perfusion scan discouraged contact or high-impact sports IV ( 1 large or giant Long term Contact or high-impact Biannual Angiography coronary artery antiplatelet therapy sports should be avoided echocardiogramm at 6-12 months aneurysm or multiple and warfarin or because of risk of + ECG; annual after the aneurysms without low-molecular- bleeding; other physical stress test and disease obstruction) weigh heparin activity recommendations myocardial must be guided by stress perfusion scan test and myocardial perfusion scan V (coronary artery Long term low- Contact or high-impact Biannual Angiography is obstruction) dose aspirin, sports should be avoided echocardiogramm recommended warfarin or low- because of risk of bleeding; + ECG; annual to address molecular-weight other physical activity stres stest and the best heparin if giant recommendations must be myocardial personalized aneurysms persist guided by stress test and perfusion scan therapeutic myocardial perfusion scan options 306

7 Pharmacologic therapy in Kawasaki syndrome and its cardiovascular complications References 1) TAUBERT KA, ROWLEY AH, SHULMAN ST. Nationwide survey of Kawasaki disease and acute rheumatic fever. J Pediatr 1991; 119: ) NAKAMURA Y, FUJITA Y, NAGAI M, YANAGAWA H, IMADA Y, OKAWA S, KAWASAKI T, KATO H. Cardiac sequelae of Kawasaki disease in Japan: statistical analysis. Pediatrics 1991; 88: ) STAPP J, MARSHALL GS. Fulfillment of diagnostic criteria in Kawasaki disease. Southern Med J 2000; 93: ) JOFFE A, KABANI A, JADAVJI T. Atypical and complicated Kawasaki disease in infants. Do we need criteria? West J Med 1995; 162: ) NEWBURGER JW. Treatment of Kawasaki disease. Lancet 1996; 347: ) BROGAN PA, BOSE A, BURGNER D, SHINGADIA D, TUL- LOH R, MICHIE C, KLEIN N, BOOY R, LEVIN M, DILLON MJ. Kawasaki disease: an evidence based approach to diagnosis, treatment and proposals for future research. Arch Dis Child 2002; 86: ) LAUPLAND KB, DELE DAVIES H. Epidemiology, etiology and management of Kawasaki disease: state of the art. Pediatr Cardiol 1999; 20: ) NAKASHIMA L, EDWARDS DL. Treatment of Kawasaki disease. Clin Pharm 1990; 9: ) TERAI M, SHULMAN ST. Prevalence of coronary artery abnormalities in Kawasaki disease is highly dependent on gamma globulin dose but independent of salicylate dose. J Pediatr 1997; 131: ) HSICH KS, WENG KP, LIN CC, HUANG TC, LEE CL, HUANG SM. Treatment of acute Kawasaki disease: aspirin s role in the febrile stage revisited. Pediatrics 2004; 114: e689-e ) NEWBURGER JW, TAKAHASHI M, GERBER MA, GEWITZ MH, TANI LY, BURNS JC, SHULMAN ST, BOLGER AF, FER- RIERI P, BALTIMORE RS, WILSON WR, BADDOUR LM, LEVI- SON ME, PALLASCH TJ, FALACE DA, TAUBERT KA; COM- MITTEE ON RHEUMATIC FEVER, ENDOCARDITIS AND KAWASAKI DISEASE; COUNCIL ON CARDIOVASCULAR DIS- EASE IN THE YOUNG; AMERICAN HEART ASSOCIATION; AMERICAN ACADEMY OF PEDIATRICS. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004; 110: ) KATO H, SUGIMURA T, AKAGI T, SATO N, HASHINO K, MAENO Y, KAZUE T, ETO G, YAMAKAWA R. Long-term consequences of Kawasaki disease. A 10 to 21 year follow-up study of 594 patients. Circulation 1996; 94: ) DAJANI AS, TAUBERT KA, GERBER MA, SHULMAN ST, FER- RIERI P, FREED M, TAKAHASHI M, BIERMAN FZ, KARCHMER AW, WILSON W, PETER G, DURACK DT, RAHIMTOOLA SH, MEMBERS OF THE COMMITTEE ON RHEUMATIC FEVER, EN- DOCARDITIS AND KAWASAKI DISEASE, COUNCIL ON CARDIO- VASCULAR DISEASE IN THE YOUNG, AMERICAN HEART AS- SOCIATION. Diagnosis and therapy of Kawasaki disease in children. Circulation 1993; 87: ) FUJIWARA H, HAMASHIMA Y. Pathology of the heart in Kawasaki disease: Pediatrics 1978; 61: ) YUTANI C, OKANO K, KAMIYA T, OGUCHI K, KOZUKA T, OTA M, ONISHI S. Histopathological study on right endomyocardial biopsy of Kawasaki disease. Br Heart J 1980; 43: ) MATSUURA H, ISHIKITA T, YAMAMOTO S, UMEZAWA T, ITO R, HASHIGUCHI R, SAJI T, MATSUO N, TAKANO M. Gallium-67 myocardial imaging for the detection of myocarditis in the acute phase of Kawasaki disease (mucocutaneous lymph node syndrome): the usefulness of single photon emission computed tomography. Br Heart J 1987; 58: ) ANDERSON TM, MEYER RA, KAPLAN S. Long-term echocardiographic evaluation of cardiac size and function in patients with Kawasaki disease. Am Heart J 1985; 110: ) HIRAISHI S, YASHIRO K, OGUCHI K, KUSANO S, ISHII K, NAKAZAWA K. Clinical course of cardiovascular involvement in the mucocutaneous lymph node syndrome. Relation between clinical signs of carditis and development of coronary arterial aneurysm. Am J Cardiol 1981; 47: ) TSE SM, SILVERMAN ED, MCCRINDLE BW, YEUNG RS. Early treatment with intravenous immunoglobulin in patients with Kawasaki disease. J Pediatr 2002; 140: ) NAGASHIMA M, MATSUSHIMA M, MATSUOKA H, OGAWA A, OKUMURA N. High-dose gammaglobulin therapy for Kawasaki disease. J Pediatr 1987; 110: ) DURONGPISITKUL K, GURURAJ VJ, PARK JM, MARTIN CF. The prevention of coronary artery aneurysm in Kawasaki disease: a meta-analysis on the efficacy of aspirin and immunoglobulin treatment. Pediatrics 1995; 96: ) WILDER MS, PALINKAS LA, KAO AS, BASTIAN JF, TURNER CL, BURNS JC. Delayed diagnosis by physicians contributes to the development of coronary artery aneurysms in children with Kawasaki syndrome. Pediatr Infect Dis J 2007; 26: ) SHACKELFORD PG, STRAUSS AW. Kawasaki syndrome. N Engl J Med 1991; 324: ) CURTIS N. Kawasaki disease. Br Med J 1997; 315: ) SUNDEL RP, BURNS JC, BAKER A, BEISER AS, NEWBURGER JW. Gamma globulin re-treatment in Kawasaki disease. J Pediatr 1993; 123: ) FREEMAN AF, SHULMAN ST. Refractory Kawasaki disease. Pediatr Infect Dis J 2004; 23: ) HAN RK, SILVERMAN ED, NEWMAN A, MCCRINDLE BW. Management and outcome of persistent or recur- 307

8 G. De Rosa, M. Pardeo, D. Rigante rent fever after initial intravenous gamma globulin therapy in Kawasaki disease. Arch Pediatr Adolesc Med 2000; 154: ) KATO H, KOIKE S, YOKOYAMA T. Kawasaki disease: effect of treatment on coronary artery involvement. Pediatrics 1979; 63: ) WRIGHT DA, NEWBURGER JW, BAKER A, SUNDEL RP. Treatment of immune globulin-resistant Kawasaki disease with pulsed doses of corticosteroids. J Pediatr 1996; 128: ) NEWBURGER JW. Treatment of Kawasaki disease: corticosteroids revisited. J Pediatr 1999; 135: ) AL-MAYOUF SM. The use of corticosteroid therapy in refractory Kawasaki patients. Clin Rheumatol 2004; 23: ) SHULMAN ST. Is there a role for corticosteroids in Kawasaki disease? J Pediatr 2003; 142: ) SUNDEL RP, BAKER AL, FULTON DR, Newburger JW. Corticosteroids in the initial treatment of Kawasaki disease: report of a randomized trial. J Pediatr 2003; 142: ) BURAS JC, MASON WH, HAUGER SB, JANAI H, BASTIAN JF, WOHRLEY JD, BALFOUR I, SHEN CA, MICHEL ED, SHULMAN ST, MELISH ME. Infliximab treatment for refractory Kawasaki syndrome. J Pediatr 2005; 146: ) BURNS JC, KUSHNER HI, BASTIAN JF, SHIKE H, SHIMIZU C, MATSUBARA T, TURNER CL. Kawasaki disease: a brief history. Pediatrics 2000; 106: e27. 36) NAKAMURA Y, YANAGAWA H. A case-control study of recurrent Kawasaki disease using the database of the nationwide surveys in Japan. Eur J Pediatr 1996; 155: ) MICHIE C, KINSLER V, TULLOH R, DAVIDSON S. Recurrent skin peeling following Kawasaki disease. Arch Dis Child 2000; 83: ) MIURA M, KATADA Y, ISHIHARA J. Time interval of measles vaccination in patients with Kawasaki disease treated with additional intravenous immune globulin. Eur J Pediatr 2004; 163: ) DAJANI AS, TAUBERT KA, TAKAHASHI M, BIERMAN FZ, FREED MD, FERRIERI P, GERBER M, SHULMAN ST, KARCH- MER AW, WILSON W, PETER G, DURACK DT, RAHIM- TOOLA SH. Guidelines for long-term management of patients with Kawasaki disease. Report from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation 1994; 89: ) DE ZORZI A, COLAN SD, GAUVREAU K, BAKER AL, SUN- DEL RP, NEWBURGER JW. Coronary artery dimensions may be misclassified as normal in Kawasaki disease. J Pediatr 1998; 133: ) MCMORROW TUOHY AM, TANI LY, CETTA F, L EWIN MB, EIDEM BW, VAN BUREN P, W ILLIAMS RV, SHADDY RE, TUOHY RP, MINICH LL. How many echocardiograms are necessary for follow-up evaluation of patients with Kawasaki disease? Am J Cardiol 2001; 88: ) SCOTT JS, ETTEDGUI JA, NECHES WH. Cost-effective use of echocardiography in children with Kawasaki disease. Pediatrics 1999; 104: e57. 43) CHEUNG YF, YUNG TC, TAM SC, HO MH, CHAU AK. Novel and traditional cardiovascular risk factors in children after Kawasaki disease: implication for premature atherosclerosis. J Am Coll Cardiol 2004; 43: ) NEWBURGER JW, BURNS JC, BEISER AS, LO SSCALZO J. Altered lipid profile after Kawasaki syndrome. Circulation 1991; 84: ) DHILLON R, CLARKSON P, D ONALD AE, POWE AJ, NASH M, NOVELLI V, DILLON MJ, DEANFIELD JE. Endothelial dysfunction late after Kawasaki disease. Circulation 1996; 94: ) WANG-CLOW F, FOX NI, CANNON CP, GIBSON CM, BERI- OLI S, BLUHMKI E, DANAYS T, BRAUNWALD E, VAN DER WERF F, S TUMP DC. Determination of a weight-adjusted dose of TNK-tissue plasminogen activator. Am Heart J 2001; 141: ) ISHII M, UENO T, AKAGI T, BABA K, HARADA K, HAMAO- KA K, KATO H, TSUDA E, UEMURA S, SAJI T, OGAWA S, ECHIGO S, YAMAGUCHI T, KATO H; RESEARCH COMMITTEE OF MINISTRY OF HEALTH, LABOUR AND WELFARE. Study of treatment and long-term management in Kawasaki disease. Guidelines for catheter intervention in coronary artery lesion in Kawasaki disease. Pediatr Int 2001; 43: ) WILLIAMS RV, WILKE VM, TANI LY, MINICH LL. Does abciximab enhance regression of coronary aneurysms resulting from Kawasaki disease? Pediatrics 2002; 109; e4. 49) SUBCOMMITTEE OF CARDIOVASCULAR SEQUELAE, SUBCOM- MITTEE OF SURGICAL TREATMENT, KAWASAKI DISEASE RE- SEARCH COMMITTEE. Guidelines for treatment and management of cardiovascular sequelae in Kawasaki disease. Heart Vessels 1987; 3: ) CHECCHIA PA, PAHL E, SHADDY RE, SHULMAN ST. Cardiac transplantation for Kawasaki disease. Pediatrics 1997; 100: ) TAKAHASHI M, MASON W, LEWIS AB. Regression of coronary aneurysms in patients with Kawasaki syndrome. Circulation 1987; 75: ) FUJIWARA T, FUJIWARA H, HAMASHIMA Y. Size of coronary aneurysm as a determinant factor of the prognosis in Kawasaki disease: clinico-pathologic study of coronary aneurysms. Prog Clin Biol Res 1987; 250: ) NAKANO H, UEDA K, SAITO A, NOJIMA K. Repeated quantitative angiograms in coronary arterial aneurysm in Kawasaki disease. Am J Cardiol 1985; 56: ) NEWBURGER JW, BURNS JC. Kawasaki disease. Vasc Med 1999; 4: