Definition/Morphology
Tomisaku Kawasaki first reported Kawasaki disease (KD) in 1967. At first, KD was thought to be an acute and self-limiting febrile disorder; however, the first nationwide survey in Japan revealed that 1.7% of patients had died from acute cardiac failure with necropsy showing coronary arteritis accompanied by aneurysms and thrombotic occlusion. KD is an acute febrile multisystem vasculitic syndrome of unknown etiology that occurs predominantly in infants and young children and involves small and medium-sized arteries, particularly the coronary arteries. Although based entirely on clinical features, the diagnosis of KD is easy when characteristic cutaneous and mucosal manifestations are expressed. However, about 2.6% of recent cases are atypical KD and 18.6% are incomplete KD that lack some of the typical symptoms or coronary involvement, and therefore it is possible the diagnosis of KD is sometimes missed. In incomplete KD, the incidence of coronary artery lesions is higher than in other forms of KD, possibly because the diagnosis was delayed.
Genetics, Epidemiology and Etiology
Many fascinating signs of KD were noted initially in Japan and later in many other countries. A total of 331,115 (male: 191,448, female: 139,667) cases have been recognized in Japanese children through the end of 2014. The number of children who develop KD has been increasing since the mid-1990s. The number exceeded 10,000 in 2005, and there are now more than 15,000 new patients per year in Japan. KD affects children primarily in the first 5 years of life, although cases can also occur in older children and, rarely, in adults. The preponderance of males is notable (male-to-female ratio of 1.5:1) and complications, and serious and fatal cases of KD are much more common in males than females. With longer follow-up, eventual recurrence rates reach 3% or more. Secondary sibling cases occur in about 1% of all cases. In Japan, nationwide epidemics of KD were recognized in several different years.
The etiology of KD remains unknown. Many investigators believe that KD has an infectious cause or is the result of an immune response to an infectious agent. A wide variety of microorganisms have been proposed as causative agents with little or no evidence of an etiologic relationship. The hypothesis that KD is related to a bacterial superantigen has been suggested. The agent responsible for KD and the mechanism by which such agents lead to coronary vasculitis in a minority of affected patients remained to be elucidated. Investigations have demonstrated immunologic derangement in the serum of KD patients, including abnormalities in T-cell populations and an increase in circulating cytokine levels. The expanding body of descriptive immunologic data is of interest but does not point to any specific mechanism of immunopathogenesis. The factors leading to coronary vasculitis are still unknown, but there is certainly involvement of activated endothelial cells, monocytes and macrophages, cytotoxic lymphocytes, and immunoglobulin (Ig)A plasma cells.
Early Presentation and Management
Acute systematic vasculitis usually subsides within several weeks or months after onset. KD is normally acute and self-limiting; however, cardiac damage sustained when KD is active and severe may be progressive. The diagnosis rests entirely on clinical grounds, even in adults, and includes a characteristic combination of prolonged high fever, multiform rash, stomatitis, conjunctivitis, erythema of the hands and feet with characteristic late peeling of the digits, and lymphadenopathy ( Table 59.1 ). There are no specific laboratory tests that are diagnostic of the disease, but supportive evidence includes marked thrombocytosis. However, thrombocytopenia is one of the risk factors for future development of coronary artery aneurysm (CAA) and acute myocardial infarction (AMI). Two-dimensional echocardiography (2DE) can accurately demonstrate dilatation and aneurysms of the proximal coronary arteries and specific signs of cardiac inflammation, including abnormal ventricular wall motion, pericardial effusion, mitral regurgitation (MR), and diminished cardiac function. From multiple studies, it is clear that approximately 15% to 30% of patients who do not receive intravenous gammaglobulin (IVG) develop CAA detectable by angiography, 2DE, magnetic resonance imaging (MRI), or multidetector computed tomography (MDCT). These abnormalities may appear between 7 days and as late as 4 weeks after onset. After clinical diagnosis in the acute stage of illness, the treatment of choice is IVG. Efficacy has been demonstrated in several studies. The risk of CAA has been lowered to about 3% when IVG (dose of 2000 mg/kg per day is increasing recently) is given during the first 10 days of illness. However, for infants, even with IVG treatment, the risk of coronary abnormalities at 4 weeks is 8.5%. Coronary complications continued after 1 month in 2.6% of cases in 2013–2014. Pericarditis and pericardial effusion are observed in around 15% of cases and myocarditis in about 40%. However, these complications are usually mild and subside after the acute phase of the illness. Most valvular abnormalities during the acute phase are due to valvulitis leading to regurgitation, and involve especially the mitral and rarely the aortic valve. These abnormalities usually disappear several months after onset. However, MR due to papillary muscle dysfunction is progressive and will become an important late complication.
| Characteristic combination of: |
| Prolonged high fever |
| Multiform rash |
| Stomatitis, conjunctivitis |
| Erhythema of the hands and feet with characteristic late peeling |
| Lymphadenopathy |
Salicylates (aspirin, acetylsalicylic acid [ASA]) are used as adjunctive therapy during the early acute phase because coagulation activation has been shown to occur in the first 3 weeks of the illness. Corticosteroids can be used and effective in some cases (combined with IVG: 11.7% in 2014) ; however, corticosteroids are not currently established as initial treatment. Once symptoms of acute inflammation have subsided, single doses of aspirin 3 to 5 mg/kg daily are used until 2DE and/or coronary angiography (CAG) confirm the absence of dilated or aneurysmal coronary arteries approximately 4 to 8 weeks after the onset of illness. In the presence of persistent coronary abnormalities, low-dose aspirin is continued indefinitely. Giant aneurysms, defined as lesions exceeding 8 mm in diameter, are associated more frequently with myocardial ischemia, infarction, and/or death. Although more aggressive therapy might seem indicated (warfarin, dipyridamole, etc.), no single approach has been accepted universally.
Adult Onset Kawasaki Disease
KD is seen almost exclusively in children. Reports of adult cases are viewed with skepticism, although nearly 90 adult cases have been reported in the English literature using the accepted diagnostic criteria. In adults with KD, the incidence of specific diagnostic criteria is similar to children. Sterile pyuria is more common in children than adults, whereas arthralgia, gastrointestinal complications, and liver function abnormalities are more common among adults. ECG abnormalities occur in about the same percentage of adults as children, as does the reported incidence of heart failure. The incidence of CAA in adults is reported to be lower than in children with 5 in 57 reported adult cases. The other reason for a lower incidence of CAA in adults may reflect the difficulty in visualizing the adult coronary arteries with transthoracic echocardiography; this may underestimate the true incidence. There are no published guidelines from consensus panels on the treatment of KD in the adult. The majority of adults have been treated with aspirin therapy in the manner recommended for children. There are more than 5 reported adult cases of treatment with IVG; these patients demonstrated a clinical response and shortened recovery time without coronary involvement, similar to the experience in many children. Although case reports describe the benefit of IVG therapy in adults with acute KD, there are no controlled studies regarding the optimal dose, timing, and clinical benefit of IVG therapy in adults. Internists treating adults with infectious conditions must be aware of this disease.
Late Outcome, Long-Term Management
The important late cardiovascular complications in KD are CAA, ischemic heart disease, AMI, sudden death, arrhythmia, congestive heart failure (CHF), systemic artery aneurysm, valvulopathy, and early-onset atherosclerosis ( Table 59.2 ).
| Coronary artery aneurysm |
| Ischemic heart disease |
| Acute myocardial infarction |
| Sudden cardiac death |
| Arrhythmia |
| Congestive heart failure |
| Systemic artery aneurysm |
| Valvulopathy (mitral regurgitation) |
| Early-onset atherosclerosis |
Although a mortality rate for KD of approximately 2% was reported in the mid-1970s, this has dropped to approximately 0.03% (2013–2014 in Japan) recently. This improvement coincides with the widespread use of IVG in the acute phase, ASA, increased recognition of KD, and greater awareness of cardiac complications, leading to more intensive follow-up and better supportive care. Ten- to 20-year follow-up studies of KD are now being conducted. These demonstrate that large and medium aneurysms may progress to stenosis, leading to the risk of MI, sudden death, and myocardial ischemia.
It is reasonable to divide late outcomes into three groups depending on coronary abnormalities observed in the acute phase:
- 1.
Patients with no evidence of coronary artery abnormalities
- 2.
Patients with transient or small (<5 mm diameter) or medium (5 to 8 mm) CAAs
- 3.
Patients with large and giant (>8 mm) CAAs
Because there are no criteria for CAA size in adults with KD, the definitions of small, medium, and large are taken from the pediatric guidelines.
Patients With No Evidence of Coronary Artery Abnormalities
For patients without CAA, there is no need for ASA or other antiplatelet medication 6 to 8 weeks after onset or for restriction of physical activities beyond the first 6 to 8 weeks. Cardiovascular risk assessment counseling will be performed until 5 years after onset.
To date, there is no evidence of significant cardiovascular sequelae in patients without any evidence of coronary artery abnormalities in the first month after onset. A limited number of postmortem studies of adults with a history of KD or compatible clinical illness have been performed. Fatty deposits and advanced changes similar to atherosclerotic disease have been found, raising the important issue of whether patients with KD are at an increased risk of earlier or more severe atherosclerosis. There may be long-lasting changes in endothelial function in the vessels, even in those with no evidence of coronary artery abnormalities in the acute and subacute phase. Imaging methods such as tissue Doppler imaging, intravascular ultrasound (IVUS), and MRI have demonstrated coronary intimal changes in patients with no history of abnormalities in the acute phase. The long-term significance of these persistent, pervasive, vascular abnormalities is unclear in those thought to have escaped coronary abnormalities in the acute phase. The prevalence of the disease and its uncertain long-term effects suggest that ongoing follow-up may be necessary. The question of whether childhood KD increases the long-term risk for coronary atherosclerosis can be answered only by long-term prospective cohort studies.
Patients With Transient or Small (<5 mm Diameter) or Medium (5 to 8 mm) Coronary Artery Aneurysm
Patients with CAAs that do not include large or giant aneurysms should be started on long-term therapy with ASA 3 to 5 mg/kg daily, at least until resolution of abnormalities, and preferably indefinitely. Regression of small aneurysms appears to be common. Such patients should be followed with yearly cardiac evaluations. There is no need for restriction of physical activities, and such decisions can be guided by stress test and/or CT angiography. Angiography is recommended if noninvasive testing suggests ischemia.
Patients With Large and Giant (>8 mm) Coronary Artery Aneurysm or Post Coronary Artery Occlusion
The risk of giant aneurysms, estimated at 3% to 7% of untreated patients, has been lowered dramatically (0.02% in 2013–2014 survey in Japan) by the administration of IVG. For those with acute coronary artery abnormalities, the greatest risk is in children with large aneurysms, who are at risk of myocardial ischemia, infarction, and sudden death, particularly in the first year after onset. In the first 2 years after onset, regression of aneurysm with restoration of a normal lumen size occurs in one-third to one-half of such cases. Regression of the internal lumen of the aneurysm to normal diameter may occur by intimal proliferation or by thrombus organization and recanalization. These patients have persistent functional and structural abnormalities but appear to have a good short- to midterm prognosis without evidence of ischemia. Aneurysmal segments are known to have an abnormal functional response with decreased ability to dilate in response to exercise or pharmacologic agents. Most patients with regressed aneurysms do not progress to stenosis, but tortuosity and coronary thrombosis still may occur. IVUS shows thickened arteries and coronary calcification present in areas of regressed aneurysms. These changes resemble those of atherosclerosis. There is no need for restriction of physical activities in patients without stress test abnormalities. Angiography is indicated if electrocardiographic or stress test abnormalities develop.
Those with persistent large or giant CAAs are known to be at risk of ultimately developing hemodynamically significant stenosis with resultant myocardial ischemia and the need for medical and catheter or surgical intervention. The risk of developing significant stenosis in the area of a large CAA shows a steady rise over 15 to 20 years of observation. These markedly abnormal vessels are subject to calcification and thrombosis and may cause myocardial ischemia or infarction. Therapy with ASA 3 to 5 mg/kg daily, with or without dipyridamole 2 to 5 mg/kg daily, is indicated and should be continued indefinitely. All such patients should be under the care of a cardiologist with extensive experience in managing patients with KD. Anticoagulant therapy with warfarin can be added, especially during the first 2 years after disease onset. Biannual follow-up with echocardiography and ECG is recommended, and an annual stress test and evaluation of myocardial perfusion scan are necessary. Angiography should be performed initially to define the extent of disease and whenever symptoms or stress tests indicate myocardial ischemia. Physical activity should be regulated on the basis of stress test results and the severity of the coronary artery stenosis by angiography.
Patients with obstructive lesions or signs of ischemia may need to be evaluated for possible catheter or surgical intervention. Balloon angioplasty, rotablator angioplasty, stent implantation ( Fig. 59.1 ), coronary artery bypass graft (CABG), and cardiac transplantation have all been used for patients with serious coronary artery pathology. MR due to coronary ischemia and papillary muscle dysfunction may persist, and occasionally requires mitral valve replacement. In adults with KD after MI, angiotensin-converting enzyme inhibitors and/or beta-adrenergic receptor blockers can be useful to protect against further progression of myocardial damage or MR, but there is no evidence of the efficacy of these medications at present.
