Kawasaki disease was first described in 1967, by a Japanese paediatrician, Tomisako Kawasaki. 1 He characterised the illness, then termed mucutaneous lymph node syndrome, as including high fever, non-exudative conjunctivitis, inflammation of the oral mucosa, rash, cervical adenopathy, and findings in the limbs, including swollen hands and feet, red palms and soles, and, later, subungual peeling. At the time, the disease was thought to be self-limited, without long-term consequences. Later, Kawasaki disease was shown to cause coronary arterial aneurysms, which may cause complications of angina, myocardial infarction, and sudden death. Although the disease continues to have the highest relative risk in children of Japanese ancestry, it has been described worldwide in children of all races and ethnicities. In the United States of America, where more than 4000 children with Kawasaki disease are hospitalised annually, 2 Kawasaki disease has surpassed rheumatic fever as a cause of acquired cardiac disease in children. In this chapter, I will summarise current knowledge about the aetiology and pathogenesis, diagnosis, treatment in the acute phase, and natural history of Kawasaki disease.
EPIDEMIOLOGY
The incidence of Kawasaki disease differs according to race and ethnicity. In Japan, Kawasaki disease has an incidence of approximately 138 cases for each 100,000 children under the age of 5 years. 3 In the United States of America, Kawasaki disease has been reported to be most common among Asians and Pacific Islanders, with an incidence of 32.5 cases for each 100,000 children under the age of 5 years, intermediate in non-Hispanic African Americans, where the number is 16.9, and Hispanics, at 11.1 cases, and lowest in Caucasians, with 9.1 cases in each 100,000 children under the age of 5 years. 2 Previous smaller state-based studies suggested similar prevalence according to race. 4,5
Kawasaki disease is most common in children younger than age 5 years, but one-quarter of cases in the United States of America occur in older children. 2 Young infants have the highest rate of formation of coronary arterial aneurysms, and often present with incomplete features. Children older than age 8 years also have a higher rate of coronary arterial involvement. 6–9 In contrast to young infants, older children generally present with typical findings, but suffer an increased incidence of coronary arterial aneurysms, in part because of delayed diagnosis by physicians, who mistakenly believe that Kawasaki disease only occurs in very young children. Males are affected more than females by a ratio of approximately 1.5 to 1, and the illness is most common during the winter and early spring months. 2,10 Data linking Kawasaki disease to antecedent exposure to carpet cleaning, or to viral infections of the respiratory tract, have been inconsistent. 4,5,11–14 Other studies have suggested that Kawasaki disease is associated with residence near a standing body of water, 15 antecedent eczema, 16 and use of humidifiers. 14
In Japan, the rate of recurrence of the disease is approximately 3%, 17 and the proportion of cases with a positive family history is approximately 1%. 17,18 Siblings have a relative risk that is 10-fold that of the normal Japanese population, with half developing the disease within 10 days of the first case. 19 The risk of occurrence in twins may be as much as 100-fold higher than in the general population. 19,20 Parents of Japanese children with Kawasaki disease, compared to the general population, have a two-fold higher risk of having had Kawasaki disease themselves in childhood. 19–22 Of note, in the United States, the familial incidence of Kawasaki disease is believed to be far lower than in Japan.
Coronary arterial disease is responsible for almost all deaths in patients with Kawasaki disease. 23 The case fatality rate is 0.08% in Japan. 17 In the United States, reported in-hospital mortality for Kawasaki disease has varied from 0% to 0.17%. 2,24 Although the highest risk of myocardial infarction and death occurs in the first months after illness onset, 25 sudden death from ischaemic heart disease may occur many years later in patients with coronary arterial aneurysms and stenoses. 26
AETIOLOGY AND PATHOGENESIS
The cause of Kawasaki disease remains unknown, despite decades of investigation and spirited controversy. For many reasons, an infectious cause or trigger seems most likely. The illness is self-limited, and usually non-recurring. Its clinical signs and symptoms overlap with those in known toxin-mediated or viral infections. Its predilection for young children, with rare occurrence in neonates and adults, suggest that immunity is acquired. An infectious agent is further suggested by winter-spring seasonality, outbreaks in the community, and occasional epidemics. Person-to-person transmission does not occur, but infection with a common agent could produce asymptomatic disease in most children, and recognisable signs and symptoms of the disease in a tiny subset of susceptible individuals. It has not been linked to exposure to drugs or to environmental pollutants.
A number of investigations, including reports of selective expansion of Vβ 2 and Vβ 8 T-cell receptor families in the acute stage of the disease, have suggested that the illness may be caused by bacterial superantigens. 27–30 The prevalence of toxin-producing strains was similar, nonetheless, in patients with the disease and febrile controls in a prospective, multi-centre study. 31 Other investigations have suggested that the immune response in the disease is evoked by a conventional antigen. 32–34 Recently, a cytoplasmic antigen, bound by a synthetic IgA antibody, has been observed in the proximal bronchial epithelium and coronary arteries of the majority of postmortem specimens from children with the disease, but not in postmortem control patients. The nature of the antigen is as yet undetermined. 35 The data suggests that the disease may be caused by a respiratory infectious agent with tropism for vascular tissue. 35 It is also possible that it may be triggered by more than one microbial agent in a susceptible host.
The importance of genetic factors in susceptibility is supported by the influence of race and family history on its incidence (see Epidemiology above). In addition, an increasing literature has explored the association of genetic polymorphisms to susceptibility to the disease, or to development of aneurysms. 22,36–45
The pathogenesis includes marked immune activation, with release of pro-inflammatory cytokines and growth factors, activation of endothelial cells, and infiltration of coronary arteries and other medium-sized extraparenchymal arteries by CD68+ monocyte/macrophages, CD8+ cytotoxic lymphocytes, and oligoclonal IgA plasma cells. 33,46–55 The integrity of the arterial wall may be disrupted by infiltration of macrophages and release of matrix metalloproteinases. 56
PATHOLOGY
Mortality peaks between 15 and 45 days after onset of fever, when patients are in a hypercoagulable state and have thrombocytosis and disrupted vascular endothelium. 57 Mortality declines significantly beyond the first year after the onset of the illness. Because of progressive coronary arterial stenosis, however, myocardial infarction may occur many years later. An increasing literature has shown that when diagnosis is not made in childhood, the disease can cause myocardial infarction in young adults. 58
Because few patients die in the acute phase of the disease in the current era, much of our knowledge about its pathology derives from early studies in Japan. 23,59 In the first 9 days of illness, findings include acute perivasculitis and vasculitis of the microvessels and small arteries, as well as acute perivasculitis and endarteritis of the three major coronary arteries, with influx of neutrophils. Inflammation in the pericardium, myocardium, atrioventricular conduction system, and endocardium are also present. Deaths in this early period are caused by myocarditis and abnormalities of conduction. In the second through fourth weeks of the disease, the coronary arteries are affected by panvasculitis, and aneurysms form, with coronary arterial thrombosis. The cells infiltrating the arterial wall range from neutrophils to large mononuclear cells, and include lymphocytes and plasma cells. At this stage, the internal elastic lamina shows segmental destruction. Pericarditis, myocarditis, inflammation of the atrioventricular conduction system, and endocarditis with valvitis, continue to be present. Mortality in these weeks is most likely to be secondary to ischaemic heart disease, rupture of aneurysms, and myocarditis, including lesions of the conduction system. After 1 month, active inflammation begins to be replaced by progressive neointimal proliferation, neoangiogenesis, and fibrosis with formation of scars. Late deaths are characterised by severe coronary arterial stenosis.
Aneurysms produced by the disease occur in locations that are similar to those of atherosclerotic lesions, that is, in the proximal segments and branches of the coronary arteries, suggesting a role for shear stress in both types of coronary lesions. In addition, growth factors are prominently expressed at the inlets and outlets of the aneurysms, these also being sites of high shear stress. 60 Aneurysms can occur in medium-sized extraparenchymal arteries other than the coronary arteries. In particular, the coeliac, mesenteric, femoral, iliac, renal, axillary, and brachial arteries can be affected. 59 Peripheral arterial aneurysms, however, never occur in the absence of aneurysms involving the coronary arteries.
CLINICAL DIAGNOSIS
General Aspects of Initial Diagnosis
Diagnostic criterions are summarised in Table 52-1 . 61 The epidemiologic definition for diagnosis includes fever for 4 days with at least four principal clinical criterions, or fever and fewer than four principal criterions in the presence of coronary arterial abnormalities. By convention, the first day of the disease is considered to be the day on which the fever initially occurs. All clinical features are rarely present at the same time, so the diagnosis requires sequential evaluation of the patient. In the absence of treatment, the mean duration of fever is 11 days, and fever rarely persists beyond 4 weeks. The principal clinical findings are not pathognomonic, so other diseases with similar clinical features should be excluded ( Table 52-2 ).
Epidemiologic Case Definition (Classic Clinical Criterions)
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Other Clinical and Laboratory Findings
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Laboratory Findings in Acute Kawasaki Disease
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A diagnosis of incomplete disease may be made in patients who do not fulfill the classic criterions outlined in Table 52-1 , whereas the term atypical disease refers to patients who have features not generally seen, for example those presenting with haemophagocytic syndrome, or renal failure. Because coronary arterial disease is now well recognised to occur in children with incomplete or atypical features, and treatment with immunoglobulins must be started early to be effective, a new algorithm for evaluation and treatment of the child with suspected disease was recently developed ( Fig. 52-1 ). 62 The diagnosis may be based upon abnormalities of the coronary arteries by echocardiography when the classic epidemiologic definition is not fulfilled. Because young infants are most likely to have incomplete criterions, and also have the highest risk of aneurysms, echocardiography is recommended for infants less than age 6 months with a fever lasting for 7 or more days without other explanation, in whom there is elevation of either C-reactive protein or the rate of erythrocytic sedimentation.
Laboratory features are reflective of an acute inflammatory response. Virtually all patients at presentation have elevation of the rate of erythrocytic sedimentation or C-reactive protein. 63 The average level of haemoglobin at the time of presentation is two standard deviations below the mean for age, with the anaemia being normocytic and normochromic. The number of white blood cells is generally increased, at a median of 15,000/mm 3 , with a leftward shift. The platelet count is usually normal in the first week of the illness, peaking in the third week of the illness to values sometimes higher than 1,000,000/mm 3 . After the seventh day of illness, counts are usually at least 450,000/mm 3 . Plasma gammaglutamyl transpeptidase, transaminases, and bilirubin, are frequently elevated. 64,65 Synthesis of albumin is decreased in the acute phase, and hypoalbuminaemia is common. Microscopic evaluation of the urine may reveal an elevated count of white blood cells with no identified infectious agent, so-called sterile pyuria. Cerebrospinal fluid contains an increased number of white blood cells, predominantly mononuclear cells, with normal levels of glucose and protein. 66 Serum cardiac troponin 67–69 and brain natriuretic factor 70 may also be elevated in the acute phase of the disease.
Cardiac Findings
The acute phase of the disease may be associated with myocarditis, pericarditis, valvitis, and inflammation in the coronary arterial wall. Cardiac auscultation typically reveals a hyperdynamic praecordium, tachycardia, and a gallop rhythm, even in the absence of fever. Almost all children have an innocent flow murmur related to anaemia and fever. In addition, some children with significant mitral regurgitation have a pansystolic regurgitant murmur at the apex. The disease may occasionally present with low cardiac output syndrome or shock. Electrocardiography may show arrhythmia, prolonged PR interval, or nonspecific ST and T wave changes.
At the time of acute presentation, the maximal z scores for the coronary arteries normalised to body surface area are greater than in the general afebrile population. A maximal z score for the proximal segments of the right or anterior interventricular arteries is at least 2.5 in approximately one-quarter of patients. 71 Coronary arterial dimensions then diminish in the majority of patients treated with immunoglobulins within the first 10 days of illness.
Coronary arterial aneurysms are the most serious long-term complications of the disease. Approximately one in five children who are not treated with high doses of immune globulin given intravenously within the first 10 days of illness develops coronary arterial ectasia or aneurysms. The aneurysms may be detected by echocardiography beginning 7 days after the first appearance of fever, with their diameter usually peaking around 4 weeks after onset of the illness. Independent predictors of development have included age less than 1 year, male gender, delayed treatment with immunoglobulins, persistent or recrudescent fever after immunoglobulins, so-called immunoglobulin resistance, and laboratory measures suggesting worse inflammation. 71–77 Asian/Pacific Islander race and Hispanic ethnicity are also risk factors. 78 Sociodemographic factors appear to play an important role in delayed diagnosis. 79
Aneurysms are considered to be saccular when their axial and lateral diameters are nearly equal. Fusiform aneurysms occur when there is symmetric dilation, with gradual proximal and distal tapering. Coronary arteries are considered to be ectatic when the dimension is dilated without a segmental aneurysm. Aneurysms are classified as giant when the internal diameter is at least 8 mm. 61,80
Depression of myocardial function is common in the acute phase of the disease. Endomyocardial biopsies have suggested that myocarditis is a universal feature of Kawasaki disease, and myocardial inflammation is present in from half to three-quarters of patients based upon nuclear imaging. Fortunately, myocardial function usually improves rapidly after administration of intravenous immune globulin, and long-term, clinically significant abnormalities of systolic function are uncommon in the absence of ischaemic heart disease secondary to coronary arterial aneurysms.
In the acute phase, mitral regurgitation may result from valvitis, or from transient dysfunction of the papillary muscles. More than one-quarter of children have mitral regurgitation at the time of presentation. 81 Late mitral regurgitation is usually the result of ischaemic disease. Aortic regurgitation, presumably secondary to valvitis, is infrequently detected by echocardiography in the acute phase. 81 Only rare instances of late mitral regurgitation unrelated to ischaemia or late aortic regurgitation of clinical significance have been reported. 82–84
Echocardiography
Echocardiographic imaging of the coronary arteries is essential in the evaluation of all patients with definite or suspected disease ( Fig. 52-2 ). Its sensitivity and specificity for the detection of dilation of the proximal coronary arterial segments are high when performed with appropriate transducers by experienced sonographers in cooperative or sedated children. Because aneurysms also occur in the absence of the classic criterions, echocardiography has an important role in evaluation of children with protracted fever and some findings consistent with features of Kawasaki disease. Additional echocardiographic features in the acute phase include coronary arterial ectasia, lack of tapering, and perivascular brightness. Left ventricular contractility may also be diminished, and mild valvar regurgitation, particularly mitral regurgitation, is relatively common. 81 Although pericardial effusions may occur, they are infrequently significant in size. 81
Echocardiography should be performed shortly after diagnosis to provide a baseline examination of coronary dimensions, left ventricular function, valvular regurgitation, and pericardial effusion. In children whose fever resolves after initial treatment with intravenous immune globulin, and who remain afebrile, echocardiography should be repeated at 2 weeks, and again at approximately 6 to 8 weeks after onset of the illness. Children at higher risk, that is those with recrudescent fever, baseline coronary arterial abnormalities, diminished left ventricular function, or pericardial effusion, should undergo more frequent echocardiographic evaluation to guide the need for additional therapies.
Cross sectional echocardiographic imaging should be performed with the transducer of the highest frequency available, and recorded in a dynamic video or digital cine format. The imaging planes and transducer positions required for optimal visualisation of the coronary arterial segments are depicted in Table 52-3 . Whenever possible, all major coronary arterial segments should be visualised. The most common site for formation of aneurysms are the proximal segments of the anterior interventricular and right coronary arteries, followed in descending order by the main stem of the left coronary artery, the circumflex artery and the distal part of the right coronary artery, and the junction between the right coronary artery and inferior interventricular artery. Measurements are made from inner edge to inner edge, excluding points of branching.
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Statistics about the prevalence of aneurysms are based upon criterions set forth by the Japanese Ministry of Health in 1984. These classify coronary arteries as abnormal if the internal luminal diameter is greater than 3 mm in children less than 5 years of age, or 4 mm in children at least 5 years of age, if the internal diameter of a segment measures at least 1.5 times that of an adjacent segment, or if the coronary arterial lumen is clearly irregular. 85
Because normal dimensions are related to body size, dimensions may also be expressed as units of standard deviation, or z scores, adjusted for body surface area ( Fig. 52-3 ). 86 Use of such z scores has suggested that the criterions adopted by the Japanese Ministry of Health may result in under-diagnosis and under-estimation of the true prevalence of arterial dilation in the first weeks of the illness. Some limitations should be noted. There is no normative data for febrile patients with other diseases. Z scores are available only for the main stem of the left coronary artery and the proximal segments of the anterior interventricular and right coronary arteries. For this reason, the criterion of size 1.5 times that of the surrounding segment is still useful for diagnosis of aneurysms in peripheral sites. Imaging of the coronary arteries may also reveal lack of normal tapering and perivascular echogenicity or brightness, but these qualities are difficult to quantitate and verify. 87
Stress Testing
Children with aneurysms should undergo periodic stress testing, with assessment of myocardial perfusion or function. Most methods of stress testing used in adult cardiology have been reported in small series of children with Kawasaki disease. 88–98 Because the sensitivity and specificity of tests to provoke myocardial ischaemia have been exhaustively studied in adults with coronary arterial disease, adult guidelines should be followed to choose the best test based upon specific characteristics of the patients. 99 Additional factors in the choice of modality for testing include institutional expertise with particular techniques, and the age and ability of the child to cooperate with exercise. False positive tests are more likely in patients with a low prior probability of coronary arterial disease. I do not recommend performing stress tests in patients without a history of coronary arterial enlargement.
Other Noninvasive Methods for Imaging the Coronary Arteries
In selected patients, noninvasive imaging methods other than echocardiography may be needed for assessment of the coronary arterial anatomy. In particular, ultrafast computerised tomography, and magnetic resonance imaging and angiography, may provide valuable noninvasive imaging data in patients whose coronary arteries cannot adequately be imaged by echocardiography ( Fig. 52-4 ). 100–104 In addition to imaging, cardiac resonance tests can be performed together with pharmacologic stress, and may allow assessment of myocardial infarction using delayed enhancement ( Fig. 52-5 ).
Ultrafast computerised tomography has been shown to have excellent sensitivity for detection of coronary arterial stenoses in patients with the disease. 105 Because the technique is associated with relatively high doses of ionising radiation, 106,107 this test should be reserved for use in circumstances when other non-invasive tests are inadequate for imaging.
Coronary Angiography
Cardiac catheterisation and coronary angiography provide the gold standard for imaging, against which other methods are assessed ( Fig. 52-6 ). Indeed, almost all reports on the natural history of the disease are based upon angiographic studies. In addition to providing better delineation of the distal coronary vasculature than noninvasive tests, angiography is the most reliable method by which to assess coronary arterial stenosis or thrombotic occlusion and the presence of collateral vessels.
Because selective coronary angiography has greater risks than noninvasive imaging, its use should be restricted to selected patients with coronary arterial aneurysms, clinical signs, noninvasive studies indicating myocardial ischaemia, or those in whom noninvasive methods fail to provide adequate images. Angiography is usually performed 6 to 12 months after the onset of the illness in patients with significant aneurysms who have no signs or symptoms of ischaemic heart disease. Angiography can be helpful in guiding anti-thrombotic therapy when proximal aneurysms have regressed, but the distal parts of the coronary arteries cannot be imaged by noninvasive means. Some cardiologists follow patients who have undergone surgical revascularisation or catheter intervention by cardiac catheterisation to evaluate the efficacy of their treatment. To evaluate whether peripheral arterial aneurysms are present, 108 abdominal aortography and subclavian arteriography should be performed in patients undergoing coronary arteriography for the first time.
NATURAL HISTORY
Patients with Kawasaki disease have had careful follow-up only for the past three decades. It is clear, however, that long-term outcomes are related to the extent of dilation of the coronary arteries in the first month of the illness. Aneurysms reach their peak diameter in the first 4 to 6 weeks after onset of the illness. After this time, a myointimal proliferation results in regression of approximately half to two-thirds of aneurysmal segments. 83,109 The likelihood of regression is primarily determined by the peak luminal diameter, with larger aneurysms being less likely to regress. 110,111 Other factors that predict greater likelihood of regression are younger age, distal location, and fusiform shape. 109 Aneurysms that persist may develop significant stenoses secondary to myointimal proliferation at either end of the aneurysm, calcification, tortuosity, or thrombotic occlusion. Rupture of an aneurysm is rare, and generally occurs early after onset rather than as a late complication.
In patients with persistent aneurysms, the prevalence of coronary arterial stenosis increases over time, 83,108,112 with the highest incidence occurring in patients with giant aneurysms. 112 The principal cause of death is myocardial infarction produced by thrombotic occlusion in a coronary arterial segment with an aneurysm and/or stenosis. 25 The highest risk of myocardial infarction occurs in patients with giant aneurysms, related to sluggish flow in a huge vascular space, often in combination with stenosis at its distal end. Although myocardial infarction occurs most frequently in the first year after onset, patients with aneurysms and/or stenoses have a life-long increased risk for ischaemic events. Indeed, previously undiagnosed Kawasaki disease may become apparent in adulthood at the time of presentation with myocardial infarction. 113,114 Fatalities from myocardial infarction are most likely with obstruction in the main stem of the left coronary artery, or in the proximal segments of both the right and anterior interventricular arteries. 25 Thrombosis of the right, compared to the left, coronary artery is more likely to be silent and to recanalise.
Patients with aneurysms have been found to have stiff and thickened carotid arteries 6 to 20 years after onset, and these changes occur independent of dyslipidaemia. 115 The presence of carotid atherosclerosis suggests that the coronary arteries may be similarly affected. Patients with persistent aneurysms also have been found to have higher levels of high sensitivity C-reactive protein than those without aneurysms or normal children. 116,117 Low-grade ongoing inflammation thus appears to be a late effect in patients with coronary arterial aneurysms.
Regression of the aneurysms restores the internal luminal diameter to normal. The arterial wall, however, shows fibrous intimal thickening on histopathologic examination. Intravascular ultrasound in coronary arteries with regressed aneurysms is characterised by marked symmetric or asymmetric myo-intimal thickening. 118–120 In patients with regressed coronary aneurysms studied by intravascular ultrasound at least 10 years after onset, greater thickening of the intimal and medial layers was significantly associated with larger initial diameter of the coronary arteries. 119
Regressed aneurysms also have abnormalities of function. Pharmacologic testing with intracoronary arterial administration of isosorbide dinitrate has shown that vascular reactivity is reduced in arterial segments with regressed aneurysms when compared to normal vessels. Vasodilation is progressively impaired as the interval from onset lengthens. In addition, endothelial dysfunction in regressed aneurysms is indicated by constriction of the arteries subsequent to administration of acetylcholine. 120–123 Despite abnormalities of structure and function, children with regressed aneurysms rarely have clinical symptoms or events within the first two decades of follow-up.
Children in whom aneurysms were never detected have normal cardiopulmonary fitness, and careful follow-up in Japan over the past three decades shows that they have no greater likelihood of cardiac or other diseases. Research studies suggest, however, that they should be monitored as an at-risk population. Vascular inflammation is diffuse during the acute disease, and lipid metabolism after the disease is altered for years after resolution of acute symptoms, with a pattern similar to that seen in other vasculitides. 124–126 Increased arterial stiffness in children who never had coronary arterial dilation is suggested by higher mean pulsed wave Doppler velocity in the brachial and radial arteries. 126,127 Coronary physiology may also be disturbed, with lower myocardial flow reserve and higher total coronary arterial resistance found in children with a history of Kawasaki disease in whom coronary dilation was never detected compared to normal controls. 128 Endothelium-dependent brachial arterial reactivity, which often mirrors coronary arterial reactivity, has been reported to be abnormal among children without a history of aneurysms. 129 Reports on endothelial function in the epicardial coronary arteries, as assessed by infusion of acetylcholine, have varied in their findings. 130,131
TREATMENT
Treatment of the disease in the first weeks after onset is aimed at lowering fever for comfort, reducing inflammation and shear stress in the arterial wall, and preventing thrombosis. To reduce shear stress, children in whom coronary aneurysms are developing should undergo transfusion of red blood cells if they are profoundly anaemic, ideally to achieve a haematocrit of at least 30%, and β-blockers should be administered to reduce myocardial consumption of oxygen. Among patients with aneurysms, prevention and, if needed, treatment of coronary thrombosis are key components of therapy. Patients with coronary arterial stenosis or occlusion and evidence of reversible ischaemia are candidates for interventional catheterisation and surgical procedures. Specific therapies are detailed below.
Anti-inflammatory Therapies in the Acute Phase of Illness
Aspirin
Although aspirin does not affect the prevalence of coronary arterial aneurysms, 132 it has been a cornerstone of therapy because of its anti-pyretic and anti-platelet effects. The agent is given in high doses, 80 mg/kg/day, divided into four daily doses, and this regime is used until the child has been afebrile for at least 48 hours, after which the dose is lowered to 3 to 5 mg/kg/day for its anti-platelet effects. Aspirin in low doses is continued for approximately 6 weeks, and then discontinued in patients without coronary arterial aneurysms. In children with coronary arterial abnormalities, aspirin is continued indefinitely at low doses, and may be used together with other anti-thrombotic therapies, such as clopidogrel or warfarin, in children with coronary arterial lesions placing them at high risk.
Reye syndrome has been reported in children with the disease who are taking aspirin in high doses. Although this syndrome has not been associated with use of aspirin in low doses, annual vaccination against influenza is recommended for all children on chronic treatment with aspirin. When a child medicated on a chronic basis with aspirin develops a flu-like illness, aspirin should be withheld transiently and, if necessary, another anti-platelet medication, such as clopidogrel, should be substituted until resolution of the illness. Because ibuprofen antagonises the inhibitory effect of aspirin on platelets, sustained therapy with ibuprofen should be avoided in children who are taking aspirin in low doses for prophylaxis of coronary arterial thrombosis. 133
Intravenous Immunoglobulin
Control of inflammation decreases the likelihood of aneurysmal formation, and is the most important aim of therapy in the acute phase of illness. Among the armamentarium of anti-inflammatory agents that have been used, only intravenous immunoglobulin in high doses has been demonstrated to be effective in multiple randomised, multi-centre trials with blinded echo interpretation. 62 When administered in the first 10 days, and ideally within the first 7 days, of illness, intravenous immunoglobulin reduces the prevalence of aneurysms approximately fivefold, to less than 5%. Treatment with intravenous immunoglobulin is also beneficial for children beyond the tenth day of illness in whom fever persists, or who have coronary arterial abnormalities together with persistent clinical and laboratory evidence of inflammation. 134 The standard dosage is 2 g/kg, administered over 8 to 12 hours. In patients who present with diminished left ventricular function, the agent should be administered more slowly, because it provides a considerable volume load. Meta-analyses have demonstrated a dose-response effect, 132 with this data underscoring the current practice of administering a second infusion to the 15% of children who have persistent or recrudescent fever at least 36 hours after completion of the first infusion. For children who defervesce with a second infusion, but in whom fever recurs, a third infusion may be administered. Some children have persistent fever, and develop coronary arterial aneurysms despite treatment, indicating resistance to intravenous gamma globulin. These children should receive alternative anti-inflammatory therapy.
Other Therapies
Corticosteroids are the mainstay of therapy for many childhood vasculitides, and they have been administered to children with Kawasaki disease, both as primary and rescue therapies. Uncontrolled case series, and one open and unblinded multi-centre randomised trial, have suggested that primary treatment may be beneficial. 135–141 In a recent randomised, multi-centre placebo-controlled and blinded trial, primary therapy with pulsed-dose intravenous methylprednisolone did not improve outcomes with regard to coronary arterial lesions in patients who also received standard therapy with immunoglobulins and aspirin. 81
More often, corticosteroid therapy is administered to the patient resistant to intravenous immune globulin, in whom at least two courses of immunoglobulins are unsuccessful in controlling fever. Once again, retrospective studies and case series suggest that treatment with steroids improves fever and the inflammatory response. 142–146 In a randomised trial in patients with persistent fever after two treatments with immunoglobulins, patients randomised to pulse steroids, compared to those treated with immunoglobulins given at 1 g/kg, had fevers of shorter duration, and reduced length of stay in hospital, but no difference in the incidence of coronary arterial aneurysms. 146 Based upon the currently available literature, treatment with pulse steroids should be reserved for children who have persistent or recrudescent fever despite at least two courses of intravenous gamma globulin given at 2 g/kg.
Abciximab, a murine monoclonal antibody to the platelet glycoprotein IIbIIIa receptor, has been reported in a single-center case series with historical controls to promote regression in the maximal diameter of the aneurysms. 147 This salutary effect is presumed to be secondary to promotion of vascular remodeling through the anti-inflammatory effects of abciximab.
Infliximab, a chimeric monoclonal antibody to TNF-α, is being used increasingly as rescue therapy in those patients who are resistant to immunoglobulins. 148,149 Its efficacy in reducing the prevalence and severity of coronary arterial aneurysms is unknown.
Plasma exchange has been reported to lower the incidence of aneurysms in uncontrolled studies. 150–152 Because this therapy is technically complex to administer, it should be used only when other methods have failed. Rarely, cytotoxic agents have been used to treat refractory patients with acute disease, 145,153 but the risks of such therapies exceed their benefits for the majority of patients.
Prevention of Coronary Arterial Thrombosis
The risk of thrombosis depends upon the size of the coronary arterial aneurysm, as well as the presence of coronary arterial stenosis. Thus, the types of agents used for prophylaxis of thrombosis are tailored to the extent and severity of arterial involvement. 62 Because randomised trials of anti-thrombotic regimes have not been performed, the choice of agents is derived primarily from experience in adults with atherosclerotic disease, including aneurysms, as well as case series and consensus of experts. Patients with small aneurysms are treated with aspirin in doses sufficient to produce an anti-platelet effect (see above). At the other end of the spectrum, giant aneurysms, with a diameter of greater than 8 mm, are characterised by stagnant flow, so anticoagulation with warfarin or low-molecular weight heparin is added to aspirin therapy. For most patients, the international normalised ratio is maintained between 2.0 and 2.5. Patients with giant aneurysms and a history of coronary arterial thrombosis may benefit from treatment similar to that used in patients after replacement of the mitral valve, using, for example, warfarin to maintain the international normalised ratio between 2.5 and 3.5 along with aspirin. The optimal anti-thrombotic regimen for patients with aneurysms intermediate in size between small and giant is controversial. Clopidogrel 154 or anti-coagulation may be added to treatment with aspirin, depending upon the individual situation. For example, treatment of a 3-month-old infant with an aneurysm of 6 mm, with characteristics of flow similar to a giant aneurysm, usually includes anticoagulation together with aspirin. The same-sized aneurysm in an adolescent weighing 80 kg might warrant only anti-platelet therapy. Thus, it is important to consider the z scores, although guidelines for their use in choice of an anti-coagulation regimen have not been developed.
Treatment of Coronary Arterial Thrombosis
Thrombolytic therapy in children with coronary arterial thrombosis is primarily guided by studies in adults with acute coronary syndromes. The most common agent used in children is tissue plasminogen activator, at doses of 0.1 to 0.5 mg/kg/hr for 6 hours, administered together with aspirin and heparin or low-molecular-weight heparin. 62 The burden of thrombus in a giant aneurysm is large, and some children have rebound of thrombosis after cessation of thrombolytic therapy. For this reason, treatment may occasionally involve a combination of tissue plasminogen activator and abciximab, given as a bolus of 0.25 mg/kg over 30 minutes, followed by an infusion of 0.125 μg/kg/minute for 12 hours. Mechanical restoration of myocardial perfusion by means of interventional cardiology may be used in patients whose vessels are large enough to accommodate adult-sized catheters.
Interventional Catheterisation Procedures
The indications for interventional catheterisation procedures have not been assessed in randomised trials in children and adults with coronary arterial stenoses secondary to Kawasaki disease. Most of the techniques used in adults with atherosclerotic coronary arterial disease have been applied to the population of children with Kawasaki disease. These include percutaneous transluminal coronary angioplasty, rotational atherectomy, and placement of stents. 155 To provide practical interim suggestions for clinicians until evidence-based guidelines are available, the Research Committee of the Japanese Ministry of Health, Labor and Welfare published recommendations for conditions under which catheter intervention should be considered in such patients. 155 These include presentation with ischaemic symptoms, presence of reversible ischaemia on stress testing, or presence of at least 75% stenosis of the anterior interventricular coronary artery. Contraindications to catheter intervention include severe left ventricular dysfunction, and coronary arteries with multiple, ostial, or long-segment stenoses.
Longer-term results for catheter interventions have now been published with a median follow-up of 3.6 years. 156 For vessels in which angioplasty was used, the early success rate was 86%. For rotational atherectomy, the figure was 96%, and for placement of stents, 90%. At the latest follow-up, stenoses had recurred in 29% of arterial segments in which angioplasty had been performed: in 28% of segments following rotational atherectomy, and in 8% of segments following placement of a stent. Neoaneurysms were noted in 7% of segments treated with angioplasty and rotational ablation, likely related to the high pressure of inflation needed to relieve stenoses in stiff coronary arteries. Procedures are best performed by a multi-disciplinary team that takes advantage of the technical expertise and knowledge of adult cardiologists, working together with paediatric cardiologists, anaesthesiologists, and nurses.
Surgery
As with interventional catheterisation procedures, the indications for bypass grafting in children with Kawasaki disease are based upon experience in adult patients and consensus of experts. Coronary arterial bypass surgery is performed with the goal of improving symptoms of angina, enhancing myocardial perfusion, and lowering the future risk of myocardial infarction or sudden death. 157,158 Children with reversible ischaemia on stress-imaging tests are generally considered for intervention, be it transcatheter or surgical. In addition, high-grade obstructions in at least two major coronary arteries, or in the main stem of the left coronary artery, are indications for surgery because these findings predict a high risk of myocardial infarction. Some experts also consider high-grade stenosis in the anterior interventricular artery to be an indication for intervention. Bypass grafting is contraindicated when there is arterial disease distal to the planned anastomosis, or nonviable myocardium in regions supplied by the affected vessel. 159 Competing flow into arteries supplied by a graft causes a string sign, and may result in occlusion.
Although saphenous venous grafts were used in the earliest surgical series, they are rarely used today because of poor long-term patency in children. 160 Instead, arterial grafts, such as those provided using the internal mammary, radial, and gastroepiploic arteries, have better long-term patency, enlarge in length and diameter as the child grows, and improve myocardial perfusion. 158
Coronary arterial bypass procedures in children have low morbidity and mortality. 157 In a national survey of such grafting in Japan, 157 long-term rates of patency were shown to be affected by the age of the patient at the time of the graft. Specifically, when performed in children at least 12 years of age, internal mammary arterial grafts had patency rates of 95%, 91%, and 91% at 1, 5, and 15 years after surgery. Lower patency was seen in those who underwent surgery at ages younger than 12 years, at 93%, 73%, and 65%, respectively. Left ventricular ejection fraction of less than 40% was a risk factor for mortality. A recent small series suggests that the use of percutaneous transluminal balloon angioplasty for anastomotic stenosis after bypass grafting improves the long-term patency in small children to rates similar to those in older children. 161
Cardiac transplantation can be performed in children with Kawasaki disease who have end-stage ischaemic cardiomyopathy in whom severe coronary arterial lesions cannot be treated further with interventional catheterisation or coronary arterial bypass procedures. 162
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