Current Recommendations for the Pharmacologic Therapy in Kawasaki Syndrome and Management of Its Cardiovascular Complications

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European Review for Medical and Pharmacological Sciences 2007; 11: 301-308 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 po- nign childhood disease: several years later, fatali- tentially life-threatening disease of early child- ties occurred in Japan among children with KS hood that untreated holds a risk of severe coronary involvement. Its diagnosis is made via a list younger than 2 years when they had apparently of clinical signs because etiology and patho- recovered. Post-mortem examinations revealed physiology are still unknown and no specific complete thrombotic occlusion of coronary artery laboratory tool is available. Appropriate therapy aneurysms with myocardial infarction as the im- with intravenous immunoglobulins and aspirin mediate cause of death. This syndrome has now reduces the incidence of coronary abnormalities surpassed rheumatic fever as the leading cause of to less than 5%. Immunoglobulins have been acquired heart disease in the developed countries shown to be highly effective in reducing disease 1 symptoms or their severity and chiefly in reduc- among children younger than 5 years . Although ing the rate of coronary artery aneurysm devel- its etiology is largely unknown, epidemiological opment. Aspirin is firstly used in high dose for findings suggest that genetic factors play a role in its anti-inflammatory properties and then in low the pathogenesis of KS: although KS has been re- dose for its anti-thrombotic effects. Timely diag- ported all over the world, it is overexpressed nosis and precociously administered treatment among Asian populations, especially in children are two crucial points in the definition of prognosis for Kawasaki syndrome. In this review of Japanese ancestry. KS results 10 times more heart complications are discussed and thera- prevalent in Japan, if compared with other na- peutic options stratified according to both tions, especially for infants with less than 2 years. severity of coronary involvement and grading of The proportions of KS Japanese patients with car- cardiovascular risk. diac sequels (such as dilation or stenosis of coronary arteries, myocardial infarction and valvular Key Words: lesions) 1 month or more after onset were ana- Kawasaki syndrome, Cardiovascular complications. lyzed 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 age2. In the natural history of the disease three phases occur: we can Introduction distinguish an acute phase (in the first 2 weeks of illness), a subacute phase (including the 3th and 4th Kawasaki syndrome (KS) or muco-cutaneous- week of illness) and a phase of convalescence lymph node syndrome is an acute systemic vas- (lasting from the 5th to the 8th week since the on- culitis of unknown etiology that involves the set). The original guidelines for the diagnosis of walls of medium- and small-sized muscular arter- KS were created by a committee that was appoint- ies throughout the body in the pediatric age, ed by the Japanese Ministry of Health in 1970. In which was firstly described by Tomisaku the acute phase KS usually starts with more than Kawasaki in 1967. At that time, he reported 50 5 days of high fever followed by at least 4 of 5 children from 1961-1967 who presented with a main clinical features: non-exudative conjunctival distinctive clinical illness characterized by fever injection, polymorphous skin rash, reddening/fis- and skin rash, which was then thought to be a be- suring of lips and oral mucosa, abnormalities in-

Corresponding Author: Donato Rigante, MD; e-mail: [email protected] 301 G. De Rosa, M. Pardeo, D. Rigante volving extremities of limbs and perineum and Table I. Criteria for the diagnosis of Kawasaki syndrome. cervical lymphadenitis (Table I). In the absence of specific diagnostic tests, pathognomonic features Fever persisting at least for 5 days (or more) plus at or evidence-based diagnostic algorithms, KS di- least 4 of the following 5 clinical main signs: agnosis remains basically clinical3. Laboratory Bilateral bulbar conjunctival injection without exudate findings are frequently helpful in confirming the Polymorphous skin rash correct diagnostic suggestion: inflammatory Changes in lips (reddened, dry or cracked) and oral markers as erythrocyte sedimentation rate (ESR), cavity (strawberry tongue, diffuse oral and C-reactive protein (CRP), serum amyloid-A pharyngeal hyperemia) (SAA) are markedly elevated; neutrophil leuko- Changes in the extremities and in the perineum (erythema of palms or soles, indurative edema of cytosis (with toxic granulations and left shift), hands or feet, desquamation of perineal skin) mild-to-moderate normochromic anemia (with Acute cervical lymph node enlargement (with a haemoglobin levels < 2 SD for age), hypoalbu- diameter superior than 15 mm) minemia (< 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 desqua- thrombosis. High-dose aspirin is administered to mation starting in the subungual regions of the reduce fever and KS inflammatory signs. The ef- fingers and spreading to palms and soles in com- ficacy of intravenous immunoglobulins is dose- bination with the increase of platelet count, some- depending: a randomized-controlled trial has times exceeding 1.000.000/mm3. In some patients demonstrated that a single infusion of 2 g/kg in- arthralgias or arthritides can appear in the suba- fused in a time of 10 hours has a higher efficacy cute phase. Incomplete and atypical forms of KS than a 4-day-infusion of 400 mg/kg/day5. There (with other vasculitic features as abdominal pain, is no evidence that immunoglobulin treatment on pneumonia, seizures, meningitis, urethritis, he- day 4 of fever or earlier has greater efficacy in patitis and gallbladder distention, parotitis, preventing cardiac complications than treatment uveitis, etc.) are more common in young infants on days 5 to 9. The mechanism of action of intra- with less than 1 year of age4. Characteristics sug- venous immunoglobulins is unknown, though it gesting disease other than KS include exudative might include neutralization of hypothetic infec- conjunctivitis, exudative pharyngitis, bullous, tious agents, inhibition of endothelial cell func- vesicular or exfoliating rash and generalized tions, non-specific anti-inflammatory effects by adenopathy. There is a great number of pathologic the down-regulation of proinflammatory cy- conditions mimicking KS which require to be con- tokines as tumour necrosis factor-α (TNF-α) and sidered attentively in the differential diagnosis as interferon-gamma, blockage of Fc-receptors on staphylococcal scalded skin syndrome, toxic shock macrophages, suppression of T and B cells and syndrome, Stevens-Johnson syndrome, scarlet blockage of complement cascade. Aspirin in- fever, measles, Epstein-Barr virus infection, Cyto- hibits prostaglandin synthesis and has been the megalovirus infection, tick-borne diseases, juve- first drug used in children with KS. High doses nile rheumatoid arthritis, reaction to drugs and are used only during the acute inflammatory mercury hypersensitivity (acrodynia). phase and vary across countries: 30-50

Therapeutical Approach in Kawasaki Syndrome A combination of a single dose of intravenous Table II. Standard treatment for Kawasaki syndrome. immunoglobulins (2 grams/kg of body weight infused over a period of 10-12 hours) and aspirin at Intravenous immunoglobulins: 2 g/kg of body weight (infused over a period of 10-12 hours) high doses (30 to 100 mg/kg/day in four divided Aspirin: 30-100 mg/kg orally, daily divided into 4 doses) are recommended when KS diagnosis is doses, until the normalization of inflammatory made during the first 10 days of illness. KS ther- parameters apy is schematized in the Table II. Treatment Subsequent antiplatelet treatment with aspirin: 3-5 with intravenous immunoglobulins is directed at mg/kg orally, once daily for 6-8 weeks (starting in reducing the inflammation in the vessel walls in- the subacute phase of the disease) or continued indefinitely if coronary abnormalities are volved by the disease, mostly in the coronary observed artery walls, and at preventing coronary artery

302 Pharmacologic therapy in Kawasaki syndrome and its cardiovascular complications mg/kg/day in the United Kingdom and 80-100 brachial arteries, with the exception of central mg/kg/day in Japan and in the United States6-8. nervous system arteries. The major sequels of Low-dose aspirin in the subacute phase inhibits KS are related to the cardiovascular district platelet aggregation and is aimed at the reduction which might be interested in all its structures: of the thrombotic risk which is higher in patients pericardium, myocardium, endocardium and showing coronary artery dilations. However, the above all coronary arteries. Myocardial disease occurrence of coronary abnormalities is not in- during the acute phase is commonly reported: fluenced by the association intravenous im- inflammation has been documented in 50-70% munoglobulins-aspirin, if compared with intra- of autoptic descriptions14-16. Its clinical find- venous immunoglobulins alone9. It is not known ings are tachycardia, gallop rhythm and con- the correct timing of high-dose aspirin adminis- gestive heart failure in cases of disturbed ven- tration and some physicians use low-dose aspirin tricular function. The electrocardiogram may even during the acute phase of illness: there are show arrhythmias, prolongation of PR, de- no clinical-trials to confirm this therapeutic strat- creased QRS voltage and T-wave flattening. egy or the effectiveness of the association of Echocardiography is useful in detecting left high-dose aspirin with intravenous immunoglob- ventricular dilation or reduced systolic func- ulins10. Aspirin dose can be reduced to the single tion. In the acute phase the severity of myocar- daily dose of 3-5 mg/kg after having obtained the dial involvement is unrelated to the develop- complete normalization of the inflammatory ment of coronary artery abnormalities during markers, specifically CRP. This antiaggregating sub-acute or chronic phases17,18. Myocardial dosage is continued for 6 to 8 weeks after the on- mechanics improves rapidly after pharmaco- set of illness, but it should be continued indefi- logical therapy. Intravenous immunoglobulins nitely over time in those children who have de- combined with aspirin have given substantial veloped coronary abnormalities11. Coronary results in the prevention of coronary artery di- thrombosis can be prevented using other an- lation and the reduction of severity of coronary tiplatelet agents, depending on the severity of aneurysms. Perspective controlled clinical tri- coronary involvement, though no perspective da- als have showed that the infusion of intra- ta exist to guide clinicians in choosing the opti- venous immunoglobulins during the first week mal therapy and recommendations are based on to 10 days of illness reduces the incidence of the empirical stratification of the cardiovascular coronary aneurism from 23 to 9% after the risk, published by a committee of the American first month and up to 4% after two months19-21. Heart Association (Table III). A host of retrospective observations has proved the low incidence of coronary abnor- Prognosis in Kawasaki Syndrome malities when KS is promptly diagnosed with Prognosis in KS strictly depends on the car- therapy instituted within the first 10 days of diac involvement and is of lifetime signifi- illness22. Immunoglobulins should be also ad- cance: coronary artery aneurysms develop in ministered to children presenting after the 10th 20-40% of untreated children and may lead to day of illness, either having persistent fever rupture in adulthood, ischemic heart disease without other explanation or significant eleva- and myocardial infarction12,13. Due to the fact tion of ESR, CRP and SAA23,24. Treatment that KS is a generalized systemic vasculitis in- with intravenous immunoglobulins should not volving blood vessels throughout the body, be started in children in whom KS diagnosis aneurysms might be demonstrated in other ex- was missed earlier or if it occurred retrospec- tra-parenchymal muscular arteries such as the tively without evidence of persisting laborato- celiac, mesenteric, femoral, renal, axillary and ry signs of inflammation.

Table III. Anti-thrombotic treatment related to the severity of coronary artery involvement in patients with Kawasaki syndrome.

Mild coronary involvement Low-dose aspirin Mild-to-moderate coronary involvement Combination of aspirin with dipyridamole Coronary aneurysm in rapid expansion Combination of heparin with aspirin Giant aneurysm Combination of aspirin with warfarin

303 G. De Rosa, M. Pardeo, D. Rigante

Management of Unresponding and to not underestimate this possibility, due to the Recurrent Kawasaki Syndrome increased risk of coronary artery involvement Clinical efficacy of intravenous immunoglobu- than in the primary disease36. The recurrence of lins is proved by the deverfescence within 12- skin peeling in patients who have previously 24 hours. Approximately 10% of patients with suffered from KS appears relatively common in KS fail to respond after the first infusion of im- the case of other viral feverish diseases: thus the munoglobulins with an increasing risk of devel- only presence of skin peeling is not a diagnostic oping coronary artery abnormalities: this has feature to confirm the recurrence of KS37. After been observed mostly in infants with incom- using intravenous immunoglobulins, the admin- plete or atypical forms of KS25. In the refractory istration of live viral vaccines (such as the ones cases of KS there are no documented treatment for measles and chickenpox) should be deferred guidelines. Most experts in the field of KS rec- of about 11 months, though there are differ- ommend re-treatment with intravenous im- ences between Japan and United States sugges- munoglobulins (at the same dosage of 2 g/kg of tions related to the interval before vaccination. body weight) which can be repeated for a total In patients who need long-term therapy with as- of three infusions26,27. Corticosteroids have also pirin the annual vaccination against influenza been used to treat patients who have failed to virus is recommended to reduce the risk of Reye respond to the standard therapy: studies of syndrome38. steroids as initial treatment for KS or as treatment of patients with persistent or recrudescent Heart Complications in fever despite treatment with intravenous im- Kawasaki Syndrome munoglobulins have shown that they reduce Coronary artery aneurysms are the major risk fever, although their effects on coronary artery associated with KS and echocardiographic ex- abnormalities are still uncertain28. The most amination, focused on the coronary arteries, in- commonly used steroid regime is intravenous cluding quantitative assessment of the internal pulse methylprednisolone (30 mg/kg of body vessel diameters, remains a critical part of the weight administered once daily in a time of 2-3 diagnostic course of all patients with a suspect- hours for 1 to 3 days)29-33. The use of biological ed KS. Coronary artery abnormalities might de- agents directed against proinflammatory cy- velop in 20-40% of untreated patients or in pa- tokines as TNF-α has recently been suggested tients treated with only aspirin, with differ- by the American Heart Association: infliximab, ences depending on the ultrasound assessment the chimeric monoclonal antibody IgG1, com- of coronary involvement. When a coronary prising 75% human and 25% murine sequences, artery is dilated without a segmental aneurysm acts by blocking the molecular system that dri- and the internal diameter of this segment mea- ves the immune response through TNF-α and sures 1.5 times than an adjacent segment it is has been approved for the treatment of moder- defined as ectasia. The Japanese Ministry of ate-to-severe Crohn’s disease refractory to con- Health criteria classify coronary arteries as “ab- ventional therapy. Infliximab, at a dose of 5 normal” if the internal lumen diameter is mg/kg, can reverse the clinical signs of KS un- greater than 3 mm in children with less than 5 responding to intravenous immunoglobulins and years or greater than 4 mm in children aged methylprednisolone, although its effectiveness more than 5 years. Care must be taken in mak- in reducing the prevalence of coronary artery ing the diagnosis of ectatic coronary arteries aneurysms is still unproven. Further studies because of normal variability in coronary artery seem to be necessary with a major number of distribution and dominance. Aneurysms are cases treated to confirm infliximab efficacy and classified as saccular if axial and lateral diame- safety34. Because controlled data are lacking, ters are nearly equal or as fusiform if symmetric other treatments including plasmapheresis or dilation with gradual proximal and distal taper- cytotoxic agents such as cyclosporine or cy- ing are seen. In the last American Heart Asso- clophosphamide for patients with refractory KS ciation statement coronary aneurysms were remain of doubtful usefulness. The recurrence classified as “small” (when the internal lumen rate of KS is low: 1-3% in the Japanese and 1% diameter of the coronary artery is inferior than in the Caucasian population35. Clinical criteria 5 mm), “medium” (when the internal diameter for diagnosing recurrent KS are the same as in is 5 to 8 mm) or “giant” (when the internal di- the classic form and it is of outstanding priority ameter is superior than 8 mm)39. The echocar-

304 Pharmacologic therapy in Kawasaki syndrome and its cardiovascular complications diographic evaluation of patients with suspect- ence of subclinical abnormalities of the en- ed KS should be focused on visualizing the left dothelial function also in those patients without main coronary artery, the right coronary artery coronary artery dilations at any phase of and the left circumflex coronary artery. This illness45. study should include the quantitative assessment of their internal diameters, should be Management of Coronary aimed at diagnosing the presence of ectasia, the Artery Abnormalities number and the location of eventual aneurysms In patients with coronary artery changes long- and the finding of intraluminal thrombi. In pa- term antiplatelet therapy with aspirin should be tients correctly treated with intravenous im- administered with the aim of reducing the risk of munoglobulins the incidence of coronary ab- thrombosis or myocardial ischemia: serial stress normalities is inferior than 5%. Ten years ago tests, such as echo stress test – a specific ultra- de Zorzi et al40 showed the importance of coro- sound examination performed during exercise or nary vessel measurements adjusted for body under infusion of drugs – are mandatory in the surface to avoid underestimating the true management of these patients to assess the exis- prevalence of coronary involvement in KS in tence and functional consequences of coronary comparison with normal children: in particular, artery abnormalities in children with KS and de- a z score 2.5 (i.e. a coronary dimension that is termine the need for coronary angiography, tran- 2.5 SDs above the mean for body surface area) scatheter interventions or coronary bypass in proximal right coronary artery or left anterior surgery. In patients with acute coronary occlu- descending coronary artery would be expected sion due to acute thrombosis a thrombolytic to occur in 0.6% of the population without KS. treatment must be promptly started46. Catheter Frequent sites of coronary aneurysms are the interventions should be considered in patients proximal left anterior descending coronary presenting with ischemic symptoms or without artery, the proximal right coronary artery and ischemic symptoms but with reversible ischemia the left main coronary artery. Cardiac ultra- on stress test and patients without ischemia but sound studies need to be performed serially at with stenosis greater than 75% in the descending the time of the diagnosis, at 2 weeks and at 6 to coronary artery47. Stent placement has resulted 8 weeks after the onset of KS and should be su- useful in older children with mild calcifications pervised by an experienced pediatric echocar- and in children with giant aneurysms. Patients diographer. The indication of stricter echocar- who develop large coronary artery aneurisms diographic evaluations should be given by the may benefit from a new pharmacologic agent, pediatric cardiologist41. Because detailed named abciximab, a glycoprotein IIb/IIIa recep- echocardiographic imaging is compromised if tor inhibitor that has been shown to prevent children are overweight, other non-invasive or thrombotic complications and promote vascular invasive cardiac tests can be required for more remodelling. In the Primary Children’s Medical specific evaluations such as heart magnetic res- Center of Salt Lake City standard therapy for KS onance imaging, trans-esophageal echocardiog- in patients with large aneurysms has been com- raphy, coronary angiography and intravascular pared with abciximab in addition to standard ultrasound. In patients without coronary artery therapy. Abciximab was administered intra- changes on echocardiography at any phase of venously at a dose of 0.25 mg/kg, followed by KS no antiplatelet therapy is needed beyond the the infusion of 0.125 µg/kg/minute for 12 hours. initial 6 to 8 weeks after the onset of illness. The resolution of coronary artery aneurysms oc- Periodic assessment of children having passed curred in 68% (13 of 19) of aneurysms in the KS is strongly suggested to control the known group treated with abciximab at a short-term fol- cardiovascular risk factors at least every 2 low-up48. The indication for coronary by-pass years, because these patients seem to be prone should be considered when there are severe oc- to a higher cardiovascular risk profile with high clusions of the main trunk of the left coronary blood pressure and greater adiposity compared artery, of more than one major coronary artery with control children42-44. Coronary artery le- or in the proximal segment of the descending sions resulting from KS tend to diminish over coronary artery49. Cardiac transplantation is only time, although fibrous intimal thickening and indicated for a small number of patients with KS reduced vascular reactivity might persist: vari- presenting with severe myocardial dysfunction ous research articles suggest the constant pres- or severe coronary arterial lesions, for whom in-

305 G. De Rosa, M. Pardeo, D. Rigante terventional catheterization or coronary artery mental controls. The risk level for a patient with by-pass procedures are not feasible50. The angio- coronary artery involvement may change over graphic resolution of coronary aneurysms has time because of the changes in the coronary been observed 1 to 2 years after the onset of the artery morphology. disease in 50 to 67% of vessels: factors positive- In conclusion, children without known cardiac ly associated with the possibility of aneurysm sequels during the first month of KS appear to re- regression include initial size, age at onset infe- turn to their previous state of health without signs rior than 1 year, morphology and location51-53. of cardiac impairment, but research studies sug- Coronary abnormalities persist in the long-term gest subclinical abnormalities of endothelial in the remaining 33-50% cases: these patients function and abnormal myocardial flow reserve had probably presented coronary artery many years after the onset of KS. Even patients aneurysms larger than 5 mm or multi-vessel in- with aneurysms regressed over time are managed volvement54. Clinical experience with KS has controversially because structural and functional permitted the stratification of patients according coronary artery abnormalities persist over time. to their relative risk of myocardial ischemia. A host of questions related to KS still remain to There are five risk-categories (Table IV): this be answered: the expanding knowledge about its stratification is useful for the management of pa- pathogenesis will probably permit in the near fu- tient with KS in order to establish the frequency ture to define the best long-term surveillance of clinical follow-up and the timing of instru- 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-year- intervals 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 11-20 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 Pharmacologic therapy in Kawasaki syndrome and its cardiovascular complications

References AW, WILSON W, P ETER G, DURACK DT, RAHIMTOOLA SH, MEMBERS OF THE COMMITTEE ON RHEUMATIC FEVER, EN- DOCARDITIS AND KAWASAKI DISEASE, COUNCIL ON CARDIO- 1) TAUBERT KA, ROWLEY AH, SHULMAN ST. Nationwide VASCULAR DISEASE IN THE YOUNG, AMERICAN HEART AS- survey of Kawasaki disease and acute rheumatic SOCIATION. Diagnosis and therapy of Kawasaki dis- fever. J Pediatr 1991; 119: 279-282. ease in children. Circulation 1993; 87: 1776- 2) NAKAMURA Y, F UJITA Y, N AGAI M, YANAGAWA H, IMADA 1780. Y, O KAWA S, KAWASAKI T, K ATO H. Cardiac sequelae 14) FUJIWARA H, HAMASHIMA Y. Pathology of the heart in of Kawasaki disease in Japan: statistical analysis. Kawasaki disease: Pediatrics 1978; 61: 100-107. Pediatrics 1991; 88: 1144-1147. 15) YUTANI C, OKANO K, KAMIYA T, O GUCHI K, KOZUKA T, 3) STAPP J, MARSHALL GS. Fulfillment of diagnostic cri- OTA M, ONISHI S. Histopathological study on right teria in Kawasaki disease. Southern Med J 2000; endomyocardial biopsy of Kawasaki disease. Br 93: 44-47. Heart J 1980; 43: 589-592. 4) JOFFE A, KABANI A, JADAVJI T. Atypical and compli- 16) MATSUURA H, ISHIKITA T, YAMAMOTO S, UMEZAWA T, I TO cated Kawasaki disease in infants. Do we need R, HASHIGUCHI R, SAJI T, M ATSUO N, TAKANO M. Galli- criteria? West J Med 1995; 162: 322-327. um-67 myocardial imaging for the detection of 5) NEWBURGER JW. Treatment of Kawasaki disease. myocarditis in the acute phase of Kawasaki dis- Lancet 1996; 347: 1128. ease (mucocutaneous lymph node syndrome): the usefulness of single photon emission comput- 6) BROGAN PA, BOSE A, BURGNER D, SHINGADIA D, TUL- ed tomography. Br Heart J 1987; 58: 385-392. LOH R, MICHIE C, KLEIN N, BOOY R, LEVIN M, DILLON MJ. Kawasaki disease: an evidence based ap- 17) ANDERSON TM, MEYER RA, KAPLAN S. Long-term proach to diagnosis, treatment and proposals for echocardiographic evaluation of cardiac size and future research. Arch Dis Child 2002; 86: 286- function in patients with Kawasaki disease. Am 290. Heart J 1985; 110: 107-115. 7) LAUPLAND KB, DELE DAVIES H. Epidemiology, etiolo- 18) HIRAISHI S, YASHIRO K, OGUCHI K, KUSANO S, ISHII K, gy and management of Kawasaki disease: state NAKAZAWA K. Clinical course of cardiovascular in- of the art. Pediatr Cardiol 1999; 20: 177-183. volvement in the mucocutaneous lymph node syndrome. Relation between clinical signs of 8) NAKASHIMA L, EDWARDS DL. Treatment of Kawasaki carditis and development of coronary arterial disease. Clin Pharm 1990; 9: 755-762. aneurysm. Am J Cardiol 1981; 47: 323-330. 9) TERAI M, SHULMAN ST. Prevalence of coronary 19) TSE SM, SILVERMAN ED, MCCRINDLE BW, YEUNG RS. artery abnormalities in Kawasaki disease is highly Early treatment with intravenous immunoglobulin dependent on gamma globulin dose but indepen- in patients with Kawasaki disease. J Pediatr dent of salicylate dose. J Pediatr 1997; 131: 888- 2002; 140: 450-455. 893. 20) NAGASHIMA M, MATSUSHIMA M, MATSUOKA H, OGAWA 10) HSICH KS, WENG KP, LIN CC, HUANG TC, LEE CL, A, OKUMURA N. High-dose gammaglobulin therapy HUANG SM. Treatment of acute Kawasaki disease: for Kawasaki disease. J Pediatr 1987; 110: 710- aspirin’s role in the febrile stage revisited. Pedi- 712. atrics 2004; 114: e689-e693. 21) DURONGPISITKUL K, GURURAJ VJ, PARK JM, MARTIN CF. 11) NEWBURGER JW, TAKAHASHI M, GERBER MA, GEWITZ The prevention of coronary artery aneurysm in MH, TANI LY, BURNS JC, SHULMAN ST, BOLGER AF, FER- Kawasaki disease: a meta-analysis on the effica- RIERI P, B ALTIMORE RS, WILSON WR, BADDOUR LM, LEVI- cy of aspirin and immunoglobulin treatment. Pedi- SON ME, PALLASCH TJ, FALACE DA, TAUBERT KA; COM- atrics 1995; 96: 1057-1061. MITTEE ON RHEUMATIC FEVER, ENDOCARDITIS AND KAWASAKI DISEASE; COUNCIL ON CARDIOVASCULAR DIS- 22) WILDER MS, PALINKAS LA, KAO AS, BASTIAN JF, TURNER EASE IN THE YOUNG; AMERICAN HEART ASSOCIATION; CL, BURNS JC. Delayed diagnosis by physicians AMERICAN ACADEMY OF PEDIATRICS. Diagnosis, treat- contributes to the development of coronary artery ment, and long-term management of Kawasaki aneurysms in children with Kawasaki syndrome. disease: a statement for health professionals Pediatr Infect Dis J 2007; 26: 256-260. from the Committee on Rheumatic Fever, Endo- 23) SHACKELFORD PG, STRAUSS AW. Kawasaki syndrome. carditis and Kawasaki Disease, Council on Car- N Engl J Med 1991; 324: 1664-1666. diovascular Disease in the Young, American Heart Association. Circulation. 2004; 110: 2747- 24) CURTIS N. Kawasaki disease. Br Med J 1997; 315: 2771. 322-323. 25) SUNDEL RP, BURNS JC, BAKER A, BEISER AS, NEWBURGER 12) KATO H, SUGIMURA T, A KAGI T, S ATO N, HASHINO K, JW. Gamma globulin re-treatment in Kawasaki MAENO Y, K AZUE T, E TO G, YAMAKAWA R. Long-term consequences of Kawasaki disease. A 10 to 21 disease. J Pediatr 1993; 123: 657-659. year follow-up study of 594 patients. Circulation 26) FREEMAN AF, SHULMAN ST. Refractory Kawasaki dis- 1996; 94: 1379-1385. ease. Pediatr Infect Dis J 2004; 23: 463-464. 13) DAJANI AS, TAUBERT KA, GERBER MA, SHULMAN ST, FER- 27) HAN RK, SILVERMAN ED, NEWMAN A, MCCRINDLE BW. RIERI P, F REED M, TAKAHASHI M, BIERMAN FZ, KARCHMER Management and outcome of persistent or recur-

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rent fever after initial intravenous gamma globulin are necessary for follow-up evaluation of patients therapy in Kawasaki disease. Arch Pediatr Ado- with Kawasaki disease ? Am J Cardiol 2001; 88: lesc Med 2000; 154: 694-699. 328-330. 28) KATO H, KOIKE S, YOKOYAMA T. Kawasaki disease: 42) SCOTT JS, ETTEDGUI JA, NECHES WH. Cost-effective effect of treatment on coronary artery involve- use of echocardiography in children with Kawasa- ment. Pediatrics 1979; 63: 175-179. ki disease. Pediatrics 1999; 104: e57. 29) WRIGHT DA, NEWBURGER JW, BAKER A, SUNDEL RP. 43) CHEUNG YF, YUNG TC, TAM SC, HO MH, CHAU AK. Treatment of immune globulin-resistant Kawasaki Novel and traditional cardiovascular risk factors in disease with pulsed doses of corticosteroids. J children after Kawasaki disease: implication for Pediatr 1996; 128: 146-149. premature atherosclerosis. J Am Coll Cardiol 2004; 43: 120-124. 30) NEWBURGER JW. Treatment of Kawasaki disease: corticosteroids revisited. J Pediatr 1999; 135: 44) NEWBURGER JW, BURNS JC, BEISER AS, LO SSCALZO J. 411-413. Altered lipid profile after Kawasaki syndrome. Cir- culation 1991; 84: 625-631. 31) AL-MAYOUF SM. The use of corticosteroid therapy in refractory Kawasaki patients. Clin Rheumatol 45) DHILLON R, CLARKSON P, D ONALD AE, POWE AJ, NASH 2004; 23: 11-13. M, NOVELLI V, D ILLON MJ, DEANFIELD JE. Endothelial dysfunction late after Kawasaki disease. Circula- 32) SHULMAN ST. Is there a role for corticosteroids in Kawasaki disease? J Pediatr 2003; 142: 601-603. tion 1996; 94: 2103-2106. 46) WANG-CLOW F, F OX NI, CANNON CP, GIBSON CM, BERI- 33) SUNDEL RP, BAKER AL, FULTON DR, Newburger JW. Corticosteroids in the initial treatment of Kawasa- OLI S, BLUHMKI E, DANAYS T, B RAUNWALD E, VAN DER ki disease: report of a randomized trial. J Pediatr WERF F, S TUMP DC. Determination of a weight-ad- 2003; 142: 611-616. justed dose of TNK-tissue plasminogen activator. Am Heart J 2001; 141: 33-40. 34) BURAS JC, MASON WH, HAUGER SB, JANAI H, BASTIAN SHII ENO KAGI ABA ARADA AMAO JF, WOHRLEY JD, BALFOUR I, SHEN CA, MICHEL ED, 47) I M, U T, A T, B K, H K, H - KA ATO SUDA EMURA AJI GAWA SHULMAN ST, MELISH ME. Infliximab treatment for re- K, K H, T E, U S, S T, O S, fractory Kawasaki syndrome. J Pediatr 2005; ECHIGO S, YAMAGUCHI T, K ATO H; RESEARCH COMMITTEE 146: 662-667. OF MINISTRY OF HEALTH, LABOUR AND WELFARE. “Study of treatment and long-term management in 35) BURNS JC, KUSHNER HI, BASTIAN JF, SHIKE H, SHIMIZU Kawasaki disease”. Guidelines for catheter inter- C, MATSUBARA T, T URNER CL. Kawasaki disease: a vention in coronary artery lesion in Kawasaki dis- brief history. Pediatrics 2000; 106: e27. ease. Pediatr Int 2001; 43: 558-562.

36) NAKAMURA Y, Y ANAGAWA H. A case-control study of 48) WILLIAMS RV, WILKE VM, TANI LY, MINICH LL. Does recurrent Kawasaki disease using the database abciximab enhance regression of coronary of the nationwide surveys in Japan. Eur J Pediatr aneurysms resulting from Kawasaki disease? Pe- 1996; 155: 303-307. diatrics 2002; 109; e4. 37) MICHIE C, KINSLER V, T ULLOH R, DAVIDSON S. Recur- 49) SUBCOMMITTEE OF CARDIOVASCULAR SEQUELAE, SUBCOM- rent skin peeling following Kawasaki disease. MITTEE OF SURGICAL TREATMENT, KAWASAKI DISEASE RE- Arch Dis Child 2000; 83: 353-355. SEARCH COMMITTEE. Guidelines for treatment and 38) MIURA M, KATADA Y, I SHIHARA J. Time interval of management of cardiovascular sequelae in measles vaccination in patients with Kawasaki Kawasaki disease. Heart Vessels 1987; 3: 50-54. disease treated with additional intravenous im- 50) CHECCHIA PA, PAHL E, SHADDY RE, SHULMAN ST. Car- mune globulin. Eur J Pediatr 2004; 163: 25-29. diac transplantation for Kawasaki disease. Pedi- 39) DAJANI AS, TAUBERT KA, TAKAHASHI M, BIERMAN FZ, atrics 1997; 100: 695-699. FREED MD, FERRIERI P, G ERBER M, SHULMAN ST, KARCH- 51) TAKAHASHI M, MASON W, L EWIS AB. Regression of MER AW, WILSON W, P ETER G, DURACK DT, RAHIM- coronary aneurysms in patients with Kawasaki TOOLA SH. Guidelines for long-term management syndrome. Circulation 1987; 75: 387-394. of patients with Kawasaki disease. Report from the Committee on Rheumatic Fever, Endocardi- 52) FUJIWARA T, F UJIWARA H, HAMASHIMA Y. Size of coro- tis, and Kawasaki Disease, Council on Cardio- nary aneurysm as a determinant factor of the vascular Disease in the Young, American Heart prognosis in Kawasaki disease: clinico-pathologic Association. Circulation 1994; 89: 916-922. study of coronary aneurysms. Prog Clin Biol Res 1987; 250: 519-520. 40) DE ZORZI A, COLAN SD, GAUVREAU K, BAKER AL, SUN- DEL RP, NEWBURGER JW. Coronary artery dimen- 53) NAKANO H, UEDA K, SAITO A, NOJIMA K. Repeated sions may be misclassified as normal in Kawasa- quantitative angiograms in coronary arterial ki disease. J Pediatr 1998; 133: 254-258. aneurysm in Kawasaki disease. Am J Cardiol 1985; 56: 846-851. 41) MCMORROW TUOHY AM, TANI LY, CETTA F, L EWIN MB, EIDEM BW, VAN BUREN P, W ILLIAMS RV, SHADDY RE, 54) NEWBURGER JW, BURNS JC. Kawasaki disease. Vasc TUOHY RP, MINICH LL. How many echocardiograms Med 1999; 4: 187-202.

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