Etiology

The cause of KD remains unknown, but certain epidemiologic and clinical features support an infectious origin. These features include the young age group affected, epidemics with wavelike geographic spread of illness, the self-limited nature of the acute febrile illness, and the combination of clinical features fever, rash, enanthem, conjunctival injection, and cervical lymphadenopathy. Further evidence of an infectious trigger includes the infrequent occurrence of the illness in infants younger than 3 mo, likely the result of maternal antibodies, and the virtual absence of cases in adults, likely the result of prior exposures with subsequent immunity. Nonetheless, it is unusual to have multiple cases present at the same time within a family or daycare center. A genetic role in the pathogenesis of KD seems likely, as evidenced by the higher risk of KD in Asian children regardless of country of residence and in siblings and children of individuals with a history of KD. Furthermore, genome-wide association studies, including sibling pair analyses, have identified susceptibility loci.

A KD-associated antigen has been described in cytoplasmic inclusion bodies within ciliated bronchial epithelial cells from acute fatal cases. These inclusions appear consistent with viral protein aggregates and support the hypothesis of a respiratory portal of entry of the KD agent. However, no single infectious etiologic agent has been successfully identified, despite a comprehensive search.

Some of the features of KD, such as fever and diffuse rash, suggest superantigen activity, similar to that seen in toxin-mediated diseases like staphylococcal toxic shock syndrome. Studies of polyclonal activation of T cells, characteristic of superantigen-mediated processes, have yielded conflicting results in patients with KD. Similarly, the role of regulatory T cells, chemokines, and Toll-like receptors in KD has been studied, with inconclusive results. During the subacute phase of illness, levels of all immunoglobulins (Igs) are elevated, suggesting that a vigorous antibody response occurs. As in other forms of vasculitis, it is likely that a common environmental trigger leads to the phenotype of KD in genetically predisposed individuals.

Epidemiology

In 2000, the hospitalization rate for KD in the Kids Inpatient Database was reported to be 17.1/100,000 in children <5 yr of age. Asian and Pacific Islander children are at higher risk for KD; the same database yielded a hospitalization rate for KD of 39/100,000 children of Asian and Pacific Islander background, compared with 19.7/100,000 black, non-Hispanic children, 13.6/100,000 Hispanic children, and 11.4/100,000 white, non-Hispanic children. Between 2001 and 2006, the number of hospitalizations for KD in free-standing children’s hospitals participating in the Pediatric Health Information System increased by more than 30%. In Japan, >200,000 cases of KD have been reported since the 1960s. KD is an illness of early childhood, as the median age of illness is 2-3 yr and 80% of children are <5 yr old. KD may occur in adolescents.

Several risk stratification models have been constructed to determine which patients with KD are at highest risk for coronary artery abnormalities. Predictors of poor outcome include young age, male gender, and laboratory abnormalities including neutrophilia, thrombocytopenia, hepatic transaminase elevation, hyponatremia, hypoalbuminemia, and elevated C-reactive protein levels. Asian and Pacific Islander race and Hispanic ethnicity are also risk factors for coronary artery abnormalities. Prolonged fever is associated with the development of coronary artery disease.

Pathology

KD is a vasculitis that predominantly affects the medium-sized arteries, with a striking predilection for the coronary arteries. Pathologic examination of fatal cases in the acute or subacute stages reveals edema of endothelial and smooth muscle cells with intense inflammatory infiltration of the vascular wall, initially by polymorphonuclear cells but rapidly thereafter by macrophages, lymphocytes (primarily CD8+ T cells), and plasma cells. IgA plasma cells are particularly prominent in the inflammatory infiltrate. In the most severely affected vessels, inflammation involves all three layers of the vascular wall, with destruction of the internal elastic lamina. Loss of structural integrity weakens the vessel wall and results in dilation (ectasia) or saccular or fusiform aneurysm formation. Thrombi may form in the lumen and obstruct blood flow. Over time, the vascular wall can become progressively fibrotic with marked intimal proliferation, producing arterial stenosis or occlusion.

Clinical Manifestations

Fever is characteristically high (≥101°F), unremitting, and unresponsive to antibiotics. The duration of fever without treatment is generally 1-2 wk but may persist for 3-4 wk. In addition to fever, the five principal clinical criteria of KD are: bilateral nonexudative bulbar conjunctival injection with limbal sparing; erythema of the oral and pharyngeal mucosa with strawberry tongue and dry, cracked lips; edema and erythema of the hands and feet; rash of various forms (maculopapular, erythema multiforme, or scarlatiniform) with accentuation in the groin area; and nonsuppurative cervical lymphadenopathy, usually unilateral, with node size >1.5 cm (Table 160-1; Figs. 160-1 to 160-4). Perineal desquamation is common in the acute phase. Periungual desquamation of the fingers and toes begins 1-3 wk after the onset of illness and may progress to involve the entire hand and foot (Fig. 160-5).

Figure 160-1 Clinical symptoms and signs of Kawasaki disease. A summary of the clinical features from 110 cases of Kawasaki disease seen in Kaohsiung, Taiwan. LAP, lymphadenopathy in head and neck area; BCG, reactivation of bacille Calmette-Guérin inoculation site; CAD, coronary artery dilatation, defined by an internal diameter > 3 mm.

(From Wang CL, Wu YT, Liu CA, et al: Kawasaki disease: infection, immunity and genetics, Pediatr Infect Dis J 24:998–1004, 2005.)

Figure 160-2 Strawberry tongue in mucocutaneous lymph node syndrome (Kawasaki disease).

(Courtesy of Tomisaku Kawasaki, MD.) (From Hurwitz S: Clinical pediatric dermatology, ed 2, Philadelphia, 1993, WB Saunders.)

Figure 160-3 Congestion of bulbar conjunctiva in a patient with mucocutaneous lymph node syndrome (Kawasaki disease).

(Courtesy of Tomisaku Kawasaki, MD.) (From Hurwitz S: Clinical pediatric dermatology, ed 2, Philadelphia, 1993, WB Saunders.)

Figure 160-4 Indurative edema of the hands in mucocutaneous lymph node syndrome (Kawasaki disease).

(Courtesy of Tomisaku Kawasaki, MD.) (From Hurwitz S: Clinical pediatric dermatology, ed 2, Philadelphia, 1993, WB Saunders.)

Figure 160-5 Desquamation of the fingers in a patient with mucocutaneous lymph node syndrome (Kawasaki disease).

(Courtesy of Tomisaku Kawasaki, MD.) (From Hurwitz S: Clinical pediatric dermatology, ed 2, Philadelphia, 1993, WB Saunders.)

Associated symptoms other than the clinical criteria are common in the 10 days prior to diagnosis of KD. Gastrointestinal symptoms (vomiting, diarrhea, or abdominal pain) occur in almost 65% of patients, and respiratory symptoms (interstitial infiltrates, effusions) occur in 30%. Other clinical findings include significant irritability that is especially prominent in infants and likely due to aseptic meningitis, mild hepatitis, hydrops of the gallbladder, urethritis and meatitis with sterile pyuria, and arthritis. Arthritis may occur early in the illness or may develop in the second or third week. Small or large joints may be affected, and the arthralgias may persist for several weeks. Clinical features that are less consistent with KD include exudative conjunctivitis, exudative pharyngitis, generalized lymphadenopathy, discrete oral lesions, and bullous, pustular, or vesicular rashes.

Cardiac involvement is the most important manifestation of KD. Myocarditis occurs in most patients with acute KD and manifests as tachycardia out of proportion to fever along with diminished left ventricular systolic function. Occasionally, patients with KD present in shock, with markedly diminished left ventricular function. Pericarditis with a small pericardial effusion can also occur during the acute illness. Mitral regurgitation of at least mild severity is evident on echocardiography in approximately one quarter of patients at presentation but diminishes over time, except among rare patients with coronary aneurysms and ischemic heart disease. Coronary artery aneurysms develop in up to 25% of untreated patients in the second to third week of illness and are best detected by two-dimensional echocardiography. Giant coronary artery aneurysms (≥8 mm internal diameter) pose the greatest risk for rupture, thrombosis or stenosis, and myocardial infarction (Fig. 160-6). Axillary, popliteal, iliac, or other arteries may also be involved by aneurysm, which manifests as a localized pulsating mass.

Figure 160-6 Coronary angiogram demonstrating giant aneurysm of the left anterior descending coronary artery (LAD) with obstruction and giant aneurysm of the right coronary artery (RCA) with an area of severe narrowing in 6 yr old boy.

(From Newburger JW, Takahashi M, Gerber MA, et al: Diagnosis, treatment, and long-term management of Kawasaki disease, Pediatrics 114:1708–1733, 2004.)

In the absence of treatment, KD can be divided into 3 clinical phases. The acute febrile phase is characterized by fever and the other acute signs of illness and usually lasts 1-2 wk. The subacute phase is associated with desquamation, thrombocytosis, the development of coronary aneurysms, and the highest risk of sudden death in patients in whom aneurysms have developed, and generally lasts about 2 wk. The convalescent phase begins when all clinical signs of illness have disappeared and continues until the erythrocyte sedimentation rate (ESR) returns to normal, typically about 6-8 wk after the onset of illness.

Laboratory Findings

There is no diagnostic test for KD, but patients usually have characteristic laboratory findings. The leukocyte count is normal to elevated, with a predominance of neutrophils and immature forms. Normocytic, normochromic anemia is common. The platelet count is generally normal in the first week of illness and rapidly increases by the second to third week of illness, sometimes exceeding 1,000,000/mm³. An elevated sedimentation rate and/or C-reactive protein value is universally present in the acute phase of illness. The ESR may remain elevated for weeks. Sterile pyuria, mild elevations of the hepatic transaminases, hyperbilirubinemia, and cerebrospinal fluid pleocytosis may also be present.

Two-dimensional echocardiography is the most useful test to monitor for development of coronary artery abnormalities and should be performed by a pediatric cardiologist. Although frank aneurysms are rarely detected early in the illness, brightness of the arterial walls and lack of normal tapering of the vessels are typical. Moreover, coronary artery dimensions, adjusted for body surface area (BSA), are significantly increased in the first 5 wk after presentation. BSA-adjusted coronary artery dimensions on baseline echocardiography in the first 10 days of illness appear to be good predictors of involvement during early follow-up. Aneurysms have been defined with use of absolute dimensions by the Japanese Ministry of Health and are classified as small (<5 mm internal diameter), medium (5-8 mm internal diameter), or giant (>8 mm internal diameter).

Echocardiography should be performed at diagnosis and again after 2-3 wk of illness. If the results are normal, a repeat study should be performed 6-8 wk after onset of illness. If results of either of the initial studies are abnormal or the patient has recurrent symptoms, more frequent echocardiography or other studies may be necessary. In patients without coronary abnormalities at any time during the illness, performance of echocardiography and a lipid profile is recommended 1 year later. After this time, periodic evaluation for preventive cardiology counseling is warranted, and some experts recommend cardiologic follow-up every 5 yr. For patients with coronary abnormalities, the type of testing and the frequency of cardiology follow-up visits are tailored to the patients’ coronary status.

Diagnosis

The diagnosis of KD is based on the presence of characteristic clinical signs. For classic KD, the diagnostic criteria require the presence of fever for at least 4 days and at least four of five of the other principal characteristics of the illness (see Table 160-1). In atypical or incomplete KD, patients have persistent fever but fewer than four of the five characteristics. In these patients, laboratory and echocardiographic data can assist in the diagnosis (Fig. 160-7). Incomplete cases are most frequent in infants, who, unfortunately, also have the highest likelihood of development of coronary artery abnormalities. Ambiguous cases should be referred to a center with experience in the diagnosis of KD. Establishing the diagnosis with prompt institution of treatment is essential to prevent potentially devastating coronary artery disease.

Figure 160-7 Algorithm for evaluation of suspected incomplete Kawasaki disease (KD). 1, In the absence of a gold standard for diagnosis, this algorithm cannot be evidence based but rather represents the informed opinion of the expert committee. Consultation with an expert should be sought anytime assistance is needed. 2, Infants ≤6 mo old on day ≥7 of fever or later without other explanation should undergo laboratory testing and, if evidence of systemic inflammation is found, an echocardiogram (Echo), even if they have no clinical criteria. 3, Patient characteristics suggesting KD are listed in Table 160-1. Characteristics suggesting disease other than KD include exudative conjunctivitis, exudative pharyngitis, discrete intraoral lesions, bullous or vesicular rash, and generalized adenopathy. Consider alternative diagnoses (see Table 160-2). 4, Supplemental laboratory criteria include albumin ≤3.0 g/dL, anemia for age, elevation of alanine aminotransferase, platelet count after 7 days ≥450,000/mm³, white blood cell count ≥15,000/mm³, and urine white blood cell count ≥10 /high-power field. 5, Can treat before performing echocardiogram. 6, Echocardiogram findings are considered positive (Echo +) for purposes of this algorithm if any of 3 conditions are met: z score of left anterior descending coronary artery (LAD) or right coronary artery (RCA) ≥2.5; coronary arteries meet Japanese Ministry of Health criteria for aneurysms; ≥3 other suggestive features exist, including perivascular brightness, lack of tapering, decreased left ventricle (LV) function, mitral regurgitation, pericardial effusion, or z scores in LAD or RCA of 2-2.5. 7, If echocardiogram findings are positive, treatment should be given to children within 10 days of fever onset and to those beyond day 10 with clinical and laboratory signs (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR]) of ongoing inflammation. 8, Typical peeling begins under nail beds of fingers and then toes. Echo −, negative echocardiogram findings; f/u, follow-up.

(From Newburger JW, Takahashi M, Gerber MA, et al: Diagnosis, treatment, and long-term management of Kawasaki disease, Pediatrics 114:1708–1733, 2004.)

Differential Diagnosis

Adenovirus, measles, and scarlet fever lead the list of common childhood infections that mimic KD (Table 160-2). Children with adenovirus typically have exudative pharyngitis and exudative conjunctivitis, allowing differentiation from KD. A common clinical problem is the differentiation of scarlet fever from KD in a child who is a group A streptococcal carrier. Patients with scarlet fever typically have a rapid clinical response to appropriate antibiotic therapy. Such treatment for 24-48 hr with clinical reassessment generally clarifies the diagnosis. Furthermore, ocular findings are quite rare in group A streptococcal pharyngitis and may assist in the diagnosis of KD. Streptococcal and staphylococcal toxin–mediated illnesses must also be considered, especially the toxic shock syndromes.

Measles must also be considered; features of measles that distinguish it from KD include exudative conjunctivitis, Koplik spots, rash that begins on the face and hairline and behind the ears, as well as leukopenia. Cervical lymphadenitis can be the initial diagnosis in children who are ultimately recognized to have KD. Less common infections such as Rocky Mountain spotted fever and leptospirosis are occasionally confused with KD. Rocky Mountain spotted fever is a potentially lethal bacterial infection. Its distinguishing features include pronounced myalgias and headache at onset, centripedal rash, and petechiae on the palms and soles. Leptospirosis can also be an illness of considerable severity. Risk factors include exposure to water contaminated with urine from infected animals. The classic description of leptospirosis is of a biphasic illness with a few asymptomatic days between an initial period of fever and headache and a late phase with renal and hepatic failure. In contrast, patients with KD have consecutive days of fever at diagnosis and rarely have renal or hepatic failure.

Children with KD and pronounced myocarditis may demonstrate hypotension with a clinical picture similar to that of toxic shock syndrome. Features of toxic shock syndrome that are not commonly seen in KD include renal insufficiency, coagulopathy, pancytopenia, and myositis. Drug hypersensitivity reactions, including Stevens-Johnson syndrome, share some characteristics with KD. Drug reaction features such as the presence of periorbital edema, oral ulcerations, and a normal or minimally elevated ESR are not seen in KD. Systemic-onset juvenile idiopathic arthritis (systemic juvenile rheumatoid arthritis) is also characterized by fever and rash, but physical findings include diffuse lymphadenopathy and hepatosplenomegaly. Additionally, arthritis develops at some point in the disease course. Laboratory findings may include coagulopathy, elevated fibrin degradation product values, and hyperferritinemia. Interestingly, there are reports of children with systemic-onset juvenile idiopathic arthritis who have echocardiographic evidence of abnormal coronary arteries.

Treatment

Patients with acute KD should be treated with 2 g/kg of intravenous gammaglobulin (IVIG) and high-dose aspirin (80-100 mg/kg/day divided q6h) as soon as possible after diagnosis and, ideally, within 10 days of disease onset (Table 160-3). The mechanism of action of IVIG in KD is unknown, but treatment results in rapid defervescence and resolution of clinical signs of illness in 85-90% of patients. The prevalence of coronary disease, which is 20-25% in children treated with aspirin alone, is only 2-4% in those treated with IVIG and aspirin within the first 10 days of illness. Strong consideration should be given to treating patients with persistent fever who are diagnosed after the 10th day of fever. The dose of aspirin is usually decreased from anti-inflammatory to antithrombotic doses (3-5 mg/kg/day as a single dose) after the patient has been afebrile for 48 hr, although some experts prescribe high-dose aspirin until the 14th day of illness. Aspirin is continued for its antithrombotic effect until 6 to 8 wk after illness onset and is then discontinued in patients who have had normal echocardiography findings throughout the course of their illness. Patients with coronary artery abnormalities continue with aspirin therapy and may require anticoagulation, depending on the degree of coronary dilation (see later).

IVIG-resistant KD occurs in approximately 15% of patients and is defined by persistent or recrudescent fever 36 hr after completion of the initial IVIG infusion. Patients with IVIG resistance are at increased risk for coronary artery abnormalities. Typically, another dose of IVIG at 2 g/kg is administered to patients with IVIG resistance. Other therapies that have been used to date include intravenous methylprednisolone and, less often, cyclophosphamide and plasmapheresis. A tumor necrosis factor inhibitor, infliximab, has also been given for the treatment of IVIG-resistant disease, usually if a second dose of IVIG or corticosteroids are ineffective.

Complications

The patient with KD who has had a small solitary aneurysm should continue aspirin indefinitely. Patients with larger or numerous aneurysms may require the addition of other antiplatelet agents or anticoagulation; such decisions should be made in consultation with a pediatric cardiologist. Acute thrombosis may occasionally occur in an aneurysmal or stenotic coronary artery; thrombolytic therapy may be lifesaving in this circumstance.

Long-term follow-up of patients with coronary artery aneurysms should include periodic echocardiography with stress testing and possibly angiography if large aneurysms are present. Catheter intervention with percutaneous transluminal coronary rotational ablation, directional coronary atherectomy, and stent implantation have been used for the management of coronary stenosis due to KD, with some patients requiring coronary artery bypass grafting.

Patients undergoing long-term aspirin therapy should receive annual influenza vaccination to reduce the risk of Reye syndrome. Continuation of aspirin therapy after varicella vaccination can be considered, because the risk of Reye syndrome in children who take salicylates and receive the varicella vaccine is likely to be lower than in those exposed to wild-type varicella without previous vaccination. Alternatively, a different antiplatelet agent can be substituted for aspirin during the 6 wk after varicella vaccination. Because IVIG may interfere with the immune response to live virus vaccines because of specific antiviral antibody, the measles-mumps-rubella and varicella vaccinations should generally be deferred until 11 months after IVIG administration. Other vaccinations do not need to be delayed.

Prognosis

The vast majority of patients with KD return to normal health, as timely treatment reduces the risk of coronary aneurysms to less than 5%. Acute KD recurs in 1-3% of cases. The prognosis for patients with coronary abnormalities depends on the severity of coronary disease; therefore, recommendations for follow-up and management are stratified according to coronary artery status. Published fatality rates are very low, generally <1.0%. Overall, 50% of coronary artery aneurysms regress to normal lumen diameter by 1 to 2 yr after the illness, with smaller aneurysms being more likely to regress. Intravascular ultrasonography has demonstrated that regressed aneurysms are associated with marked myointimal thickening and abnormal functional behavior of the vessel wall. Giant aneurysms are unlikely to resolve and are most likely to lead to thrombosis or stenosis. Coronary artery bypass grafting may be required if myocardial perfusion is significantly impaired; it is best accomplished with the use of arterial grafts, which grow with the child and are more likely than venous grafts to remain patent over the long term. Heart transplantation has been required in rare cases in which revascularization is not feasible because of distal coronary stenoses, distal aneurysms, or severe ischemic cardiomyopathy.

Whether children who have had KD and normal echocardiography findings are at higher risk for the development of atherosclerotic heart disease in adulthood is unclear. Studies of endothelial dysfunction in children with a history of KD and normal coronary dimensions have produced conflicting results. Practical advice in regards to a heart-healthy diet, adequate amounts of exercise, tobacco avoidance, and intermittent lipid monitoring is appropriate for all children with a history of KD.