Kawasaki Disease Kawasaki disease (KD), formerly known as mucocutaneous lymph node syndrome and infantile polyarteritis nodosa,

is an acute febrile vasculitis of childhood first described by Dr. Tomisaku Kawasaki in Japan in 1967. The disorder occurs worldwide, with Asians at highest risk. Approximately 20% of untreated patients develop coronary artery abnormalities including aneurysms, with the potential for severely affected patients to develop coronary artery thrombosis or stenosis, myocardial infarction, aneurysm rupture, and sudden death. Kawasaki disease is the leading cause of acquired heart disease in children in the United States and Japan. ETIOLOGY. The cause of the illness remains unknown, but epidemiologic and clinical features strongly 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 of fever, rash, enanthem, conjunctival injection, and cervical lymphadenopathy. Nonetheless, it is unusual to have multiple cases present at the same time from a family or day care center. One hypothesis is that a ubiquitous childhood infectious agent causes Kawasaki disease and that symptomatic illness occurs only in genetically predisposed persons. The infrequent occurrence of the illness in infants <3 mo may be the result of maternal antibody, and the virtual absence of cases in adults may be due to widespread immunity. A KDassociated antigen may be present in cytoplasmic inclusion bodies within ciliated bronchial epithelial cells of 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. Kawasaki disease has recurred in families when previously affected parents have children who develop the disease. Genetic variation of CCR5, which encodes a high-affinity receptor for the chemokines CCL3 and CCL3L1, suggests an influential role of gene-gene interactions for susceptibility to Kawasaki disease. EPIDEMIOLOGY. An estimated 3,000 cases are diagnosed annually in the United States. The incidence of Kawasaki disease in Asian children is substantially higher than in other racial groups, but the illness occurs worldwide in all ethnic groups. Most cases in the United States occur in white and black children, reflecting the racial composition of the population. In Japan, almost 200,000 cases have been reported since the 1960s. Kawasaki disease is not a new illness; infantile periarteritis nodosa was an autopsy diagnosis before the 1960s that appears in retrospect to have represented fatal Kawasaki disease. The disorder bears marked clinical similarities to measles and may have been particularly difficult to identify clinically before widespread immunization with measles vaccine. The illness occurs predominantly in young children; 80% of patients are <5 yr, and, only occasionally, are teenagers or, more rarely, adults affected. More often, affected adolescents or adults may actually meet the criteria for toxic shock syndrome, which has some similar features to Kawasaki disease. PATHOGENESIS. Kawasaki disease causes severe vasculitis of all blood vessels but 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 followed 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. The vessel loses its structural integrity and weakens, resulting in dilatation, or saccular or fusiform aneurysm formation. Thrombi may form in the lumen and obstruct blood flow. In the healing phase, the vascular wall can become progressively fibrotic with marked intimal proliferation, which may lead to stenotic occlusion of the vessel over time. In acute Kawasaki disease, an inflammatory infiltrate, including IgA plasma cells, is present in certain nonvascular tissues including myocardium, upper respiratory tract, pancreas, kidney, and biliary tract, suggesting that the infectious agent may cause a host immune response in a variety of tissues. No significant sequelae appear to occur in any of these nonvascular tissues after resolution of the acute illness. Elevated serum levels of all immunoglobulins develop during the subacute phase of illness, suggesting that a vigorous antibody response occurs. It is unclear whether the etiologic agent, the host immune response, or both are the major causal factors leading to coronary artery disease. CLINICAL MANIFESTATIONS. Fever is characteristically high (104F or higher), remittent, and unresponsive to antibiotics. The duration of fever without treatment is generally 12 wk, but it may persist for 34 wk.

Prolonged fever is prognostic for the development of coronary artery disease. In addition to fever, the five characteristic features of Kawasaki disease are: bilateral bulbar conjunctival injection, usually without exudate; erythema of the oral and pharyngeal mucosa with strawberry tongue and dry, cracked lips, and without ulceration; 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 of 1.5 cm ( Table 165-1 , Figs. 165-1, 165-2, 165-3, and 165-4 [1] [2] [3] [4]). Perineal desquamation is common in the acute phase. Periungual desquamation of the fingers and toes begins 13 wk after the onset of illness and may progress to involve the entire hand and foot ( Fig. 165-5 ). TABLE 165-1 -- Clinical and Laboratory Features of Kawasaki Disease EPIDEMIOLOGIC CASE DEFINITION (CLASSIC CLINICAL CRITERIA)[*] Fever persisting at least 5 days[] Presence of at least 4 principal features: Changes in extremities Acute: Erythema of palms, soles; edema of hands, feet Subacute: Periungual peeling of fingers, toes in weeks 2 and 3 Polymorphous exanthem Bilateral bulbar conjunctival injection without exudate Changes in lips and oral cavity: Erythema, lips cracking, strawberry tongue, diffuse injection of oral and pharyngeal

mucosae Cervical lymphadenopathy (>1.5 cm diameter), usually unilateral Exclusion of other diseases with similar findings[] OTHER CLINICAL AND LABORATORY FINDINGS Cardiovascular findings Congestive heart failure, myocarditis, pericarditis, valvular regurgitation Coronary artery abnormalities Aneurysms of medium-size noncoronary arteries Raynaud phenomenon Peripheral gangrene Musculoskeletal system Arthritis, arthralgia Gastrointestinal tract Diarrhea, vomiting, abdominal pain Hepatic dysfunction Hydrops of gallbladder Central nervous system Extreme irritability Aseptic meningitis Sensorineural hearing loss Genitourinary system Urethritis/meatitis Other findings

Erythema, induration at BCG inoculation site Anterior uveitis (mild) Desquamating rash in groin LABORATORY FINDINGS IN ACUTE KAWASAKI DISEASE Leukocytosis with neutrophilia and immature forms Elevated erythrocyte sedimentation rate (ESR) Elevated C-reactive protein (CRP) Anemia Abnormal plasma lipids Hypoalbuminemia Hyponatremia Thrombocytosis after week 1[] Sterile pyuria Elevated serum transaminases Elevated serum gamma glutamyl transpeptidase Pleocytosis of cerebrospinal fluid From Newburger JW, Takahashi M, Gerber MA, et al: Diagnosis, treatment, and long-term management of Kawasaki disease. Pediatrics 2004;114:17081733. * Patients with fever at least 5 days and <4 principal criteria can be diagnosed with Kawasaki disease when coronary artery abnormalities are detected by 2DE or angiography. In the presence of e4 principal criteria, Kawasaki disease diagnosis can be made on day 4 of illness. Experienced clinicians who have treated many Kawasaki disease patients may establish diagnosis before day 4. See differential diagnosis.

Some infants present with thrombocytopenia disseminated intravascular coagulation.

and

Figure 165-1 Clinical symptoms and signs of Kawasaki disease. A summary of the clinical features from 110 cases of Kawasaki disease seen in Kaohsiung, Taiwan. LAP indicates lymphadenopathy in head and neck area; BCG, reactivation of BCG site; CAD, coronary artery dilatation defined by an internal diameter of >3 mm. (From Wang CL, Wu YT, Liu CA, et al: Kawasaki disease: Infection, immunity and genetics. Pediatr Infect Dis J 2005;24:9981004.)

Figure 165-2 Strawberry tongue in mucocutaneous lymph node syndrome (Kawasaki disease). (Courtesy of Tomisaku Kawasaki, MD.) (From Hurwitz S: Clinical Pediatric Dermatology, 2nd ed. Philadelphia, WB Saunders, 1993, p 545.)

Figure 165-3 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, 2nd ed. Philadelphia, WB Saunders, 1993, p 545.)

Figure 165-4 Indurative edema of the hands in mucocutaneous lymph node syndrome (Kawasaki disease). (Courtesy of Tomisaku Kawasaki, MD.) (From Hurwitz S: Clinical Pediatric Dermatology, 2nd ed. Philadelphia, WB Saunders, 1993, p 545.)

Figure 165-5 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, 2nd ed. Philadelphia, WB Saunders, 1993, p 549.)

Other features include extreme irritability that is especially prominent in infants, aseptic meningitis, diarrhea, mild hepatitis, hydrops of the gallbladder, urethritis and meatitis with sterile pyuria, otitis media, and arthritis. Arthritis may occur early in the illness or may develop in the 2nd3rd week, generally affecting hands, knees, ankles, or hips. It is self-limited but may persist for several weeks.

Cardiac involvement is the most important manifestation of Kawasaki disease. Myocarditis, manifested as tachycardia out of proportion to fever occurs in at least 50% of patients; decreased ventricular function occurs in a smaller number of patients. Pericarditis with a small pericardial effusion is common during the acute illness. Coronary artery aneurysms develop in up to 25% of untreated patients in the 2nd3rd wk of illness and are best detected by twodimensional echocardiography. Giant coronary artery aneurysms (8 mm internal diameter) pose the greatest risk for rupture, thrombosis or stenosis, and myocardial infarction ( Fig. 165-6 ). Significant valvular regurgitation and systemic artery aneurysms may occur but are uncommon. Axillary, popliteal, or other arteries may also be involved and manifest as a localized pulsating mass.

Figure 165-6 Coronary angiogram demonstrating giant aneurysm of the LAD with obstruction and giant aneurysm of the RCA with 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 2004; 114:17081733.)

Kawasaki disease is generally divided into three clinical phases. The acute febrile phase, which usually lasts 12 wk, is characterized by fever and the other acute signs of illness. The dominant cardiac manifestation is myocarditis. In addition, a macrophage activation syndrome may rarely be evident (see Chapter 154 ). The subacute phase begins when fever and other acute signs have abated, but irritability, anorexia, and conjunctival injection may persist. The subacute phase is associated with desquamation, thrombocytosis, the development of coronary aneurysms, and the highest risk of sudden death in those who have developed aneurysms. This phase generally lasts until about the 4th wk. The convalescent phase begins when all clinical signs of illness have disappeared and continues until the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) return to normal, 68 wk after the onset of illness. Certain clinical and laboratory findings may predict a more severe outcome. These include male gender, age <1 yr, prolonged fever, recrudescence of fever after an afebrile period, and the following laboratory values at presentation: low hemoglobin or platelet levels, high neutrophil and band counts, hyponatremia, and low albumin and age-adjusted serum IgG levels. Scoring systems based on these factors,

however, have not proven sufficiently sensitive for selective treatment of patients based on risk. DIAGNOSIS. The diagnosis of Kawasaki disease is based on the presence of characteristic clinical signs. For classic Kawasaki disease, the diagnostic criteria require the presence of fever for at least 5 days and at least four of five of the other characteristic clinical features of illness (see Table 165-1 ). In atypical or incomplete Kawasaki disease, the patient has persistent fever but with fewer than four other features of the illness. Accurate identification of incomplete cases is a major clinical challenge ( Fig. 165-7 ). Incomplete cases are most frequent in infants, who, unfortunately, also have the highest likelihood of developing coronary artery disease.

Figure 165-7 Evaluation of suspected incomplete Kawasaki disease (KD). (1) In the absence of 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 months old on day 7 of fever without other explanation should undergo laboratory testing and, if evidence of

systemic inflammation is found, an echocardiogram, even if the infants have no clinical criteria. (3) Patient characteristics suggesting Kawasaki disease are listed in Table 165-1 . Characteristics suggesting disease other than Kawasaki disease include exudative conjunctivitis, exudative pharyngitis, discrete intraoral lesions, bullous or vesicular rash, or generalized adenopathy. Consider alternative diagnoses. (4) Supplemental laboratory criteria include albumin 3.0 g/dL, anemia for age, elevation of alanine aminotransferase, platelets after 7 days 450,000/mm3, white blood cell count 15,000/mm3, and urine 10 white blood cells/high-power field. (5) Can treat before performing echocardiogram. (6) Echocardiogram is considered positive for purposes of this algorithm if any of 3 conditions are met: z score of LAD or RCA 2.5, coronary arteries meet Japanese Ministry of Health criteria for aneurysms, or 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 22.5. (7) If the echocardiogram is positive, treatment should be given to children within 10 days of fever onset and to those beyond day 10 with clinical and laboratory signs (CRP, ESR) of ongoing inflammation. (8) Typical peeling begins under nail bed of fingers and then toes. (From Newburger JW, Takahashi M, Gerber MA, et al: Diagnosis, treatment, and long-term management of Kawasaki disease. Pediatrics 2004;114:17081733.)

Recognition depends on a high index of suspicion and knowledge of the characteristic clinical features. Unfortunately, if the diagnosis is not established and

treatment is not instituted, rare patients may death secondary to myocardial infarction aneurysm rupture, or may develop serious coronary disease that is unrecognized until myocardial ischemia develop later in life. DIFFERENTIAL DIAGNOSIS.

suffer sudden or coronary asymptomatic symptoms of

The differential diagnosis of Kawasaki disease includes scarlet fever, toxic shock syndrome, measles, adenovirus infection, drug hypersensitivity reactions including StevensJohnson syndrome, juvenile rheumatoid arthritis, and, more rarely, Rocky Mountain spotted fever and leptospirosis. Some features of measles that distinguish it from Kawasaki disease include exudative conjunctivitis, Koplik spots, rash that begins on the face and behind the ears, leukopenia, and a normal ESR and/or CRP. Adenovirus infection is associated with exudative pharyngitis and exudative conjunctivitis, unlike Kawasaki disease. Some features of drug reactions, such as the presence of periorbital edema, oral ulcerations, and a normal or minimally elevaled ESR may help to distinguish these reactions from Kawasaki disease. Toxic shock syndrome is distinguished by the presence of hypotension, renal and hepatic dysfunction, elevated creatine phosphokinase level, and focal Staphylococcus aureus infection. A common clinical problem is the differentiation of scarlet fever from Kawasaki disease in a child who is a group A streptococcal carrier. Because patients with scarlet fever have a rapid clinical response to appropriate antibiotic therapy, such treatment for 2448 hr with clinical reassessment at that time generally clarifies the diagnosis. The presence of lymphadenopathy, hepatosplenomegaly, and an evanescent, salmon-colored rash suggests a diagnosis of juvenile rheumatoid arthritis. Accurate diagnosis of incomplete Kawasaki disease remains

a significant challenge for clinicians. Unusual cases should be referred to a center with experience in the diagnosis of Kawasaki disease. LABORATORY FINDINGS. There is no diagnostic test for Kawasaki disease, but certain laboratory findings are characteristic. The leukocyte count is normal to elevated with a predominance of neutrophils and immature forms. Elevated ESR, CRP, and other acute phase reactants are almost universally present in the acute phase of illness and may persist for 46 wk. Normocytic, normochromic anemia is common. The platelet count is generally normal in the 1st week of illness and rapidly increases by the 2nd3rd wk of illness, sometimes exceeding 1,000,000/mm3. Tests for antinuclear antibody and rheumatoid factor are negative. Sterile pyuria, mild elevations of the hepatic transaminases, and cerebrospinal fluid pleocytosis may be present. Two-dimensional echocardiography, which should be performed by a pediatric cardiologist, is the most useful test to monitor potential development of coronary artery abnormalities. Echocardiography should be performed at diagnosis and again after 23 wk of illness. If both are normal, a repeat study should be performed 68 wk after onset of illness. If coronary abnormalities are not detected by 68 wk after onset of illness, and after the ESR has normalized, additional follow-up studies are optional. Some centers routinely perform echocardiography again 6 or 12 mo after onset of illness. Kawasaki disease is an acute vasculitis; there is no convincing evidence of long-term cardiovascular sequelae in children who do not develop coronary abnormalities within 2 mo after the onset of illness.

For patients who develop coronary artery abnormalities, more frequent echocardiographic studies and, potentially, angiography may be indicated. Treatment of such patients should be determined in consultation with a pediatric cardiologist. TREATMENT. Patients with acute Kawasaki disease should be treated with intravenous immunoglobulin (IVIG) and high-dose aspirin as soon as possible after diagnosis and, ideally, within 10 days of disease onset ( Table 165-2 ). The mechanism of action of IVIG in Kawasaki disease is unknown, but treatment should result in rapid defervescence and resolution of clinical signs of illness in 8590% of patients. With therapy, the CRP normalizes much more quickly than the ESR, which will often increase immediately after IVIG therapy. IVIG reduces the prevalence of coronary disease from 2025% in children treated with aspirin alone to 24% in those treated with IVIG and aspirin within the 1st 10 days of illness. Consideration should even be given to treatment of patients diagnosed after the 10th illness day if fever has persisted, because the anti-inflammatory effect may be helpful, although the effect of such therapy on the risk of developing coronary aneurysms is unknown. The dose of aspirin is decreased from anti-inflammatory to antithrombotic doses (35 mg/kg/day as a single dose) on the 14th illness day or after the patient has been afebrile for at least 34 days. Aspirin is continued for its antithrombotic effect until 68 wk after onset, when the ESR has normalized in patients that have not developed abnormalities detected by echocardiography. TABLE 165-2 -- Treatment of Kawasaki Disease ACUTE STAGE

Intravenous immunoglobulin 2 g/kg over 1012 hr with aspirin 80100 mg/kg/day divided every 6 hr orally until 14th illness day CONVALESCENT STAGE Aspirin 35 mg/kg once daily orally until 68 wk after illness onset LONG-TERM THERAPY FOR THOSE WITH CORONARY ABNORMALITIES Aspirin 35 mg/kg once daily orally clopidogrel 1 mg/kg/day (max 75 mg/day) (most experts add warfarin for those patients at particularly high risk of thrombosis) ACUTE CORONARY THROMBOSIS Prompt fibrinolytic therapy with tissue plasminogen activator, streptokinase, or urokinase under supervision of a pediatric cardiologist

Occasional patients have refractory Kawasaki disease that does not respond to an initial IVIG infusion, or exhibits only a partial or transient response. Strong consideration should be given to retreatment of these patients with an additional infusion of IVIG (2 g/kg). Optimal therapy for patients who do not respond to two infusions of IVIG is uncertain. If there is a poor response to the second dose of IVIG, some patients have responded to IV methylprednisolone at a dose of 30 mg/kg/day for 3 days. The value of infliximab (which binds TNF-), other immunomodulators (cyclophosphamide, methotrexate), and plasmapheresis in Kawasaki disease is yet to be determined.

Acute thrombosis may occasionally occur in an aneurysmal or stenotic coronary artery. Thrombolytic therapy may be lifesaving in this circumstance ( Table 165-3 ). Abciximab, a glycoprotein IIb/IIIa inhibitor, has been used in some patients with Kawasaki disease who develop giant coronary aneurysms with possible thrombosis. Few data regarding efficacy are available, but the drug may reduce thrombotic complications. TABLE 165-3 -- Antiplatelet, Anticoagulant, Thrombolytic Medications MEDICATION ROUTE DOSAGE Aspirin Clopidogrel Dipyridamole Oral Oral Oral and

Antiplatelet dose: 35 mg/kg every day 1 mg/kg per day[*] to max (adult dose) of 75 mg/day 26 mg/kg per day in 3 divided doses[] Load: 50 U/kg Infusion: 20 U/kg/h Adjust dosage to achieve desired therapeutic level, usually plasma heparin level = 0.350.7 in antifactor Xa activity or aPTT 6085 s

Unfractionated Intravenous heparin

Low molecular Subcutaneous Infants <12 months weight heparin Treatment: 3 mg/kg per day, divided 12 h

MEDICATION

ROUTE

DOSAGE Prophylaxis: 1.5 mg/kg per day, divided every 12 h Children/adolescents Treatment: 2 mg/kg per day, divided every 12 h Prophylaxis: 1 mg/kg per day, divided every 12 h Adjust dose to achieve desired therapeutic level, usually antifactor Xa = 0.5 1.0 U/mL

Abciximab

Intravenous

Bolus: 0.25 mg/kg Infusion: 0.125 g/kg per min for 12 h

Streptokinase

Intravenous

Bolus: 10004000 U/kg over 30 min Infusion: 10001500 U/kg per h

tPA

Intravenous

Bolus: 1.25 mg/kg Infusion: 0.10.5 mg/kg per h for 6 h, then reassess

Urokinase Warfarin

Intravenous Oral

Bolus: 4400 U/kg over 10 min Infusion: 4400 U/kg per h 0.1 mg/kg per day, given every day (0.050.34 mg/kg per day; adjust dose to achieve desired INR, usually 2.02.5)

From Newburger JW, Takahashi M, Gerber MA, et al: Diagnosis, treatment, and long-term management of Kawasaki disease. Pediatrics 2004;114:17081733. * No published studies in children. Clopidogrel is preferred to dipyridamole, based on adult studies.

Patients with a small solitary aneurysm should continue aspirin indefinitely. Patients with larger or numerous aneurysms may require the addition of clopidogrel, warfarin, or low molecular weight heparin therapy; such decisions should be made in consultation with a pediatric cardiologist. Long-term follow-up of patients with coronary artery aneurysms should include periodic echocardiography with stress testing, and possibly angiography for those with larger aneurysms. Catheter intervention with percutaneous transluminal coronary rotational ablation, directional coronary atherectomy, and stent implantation have all been used for the management of coronary stenosis caused by Kawasaki disease, with some patients requiring coronary artery bypass grafting. Patients receiving long-term aspirin therapy are candidates for annual influenza vaccination to reduce the risk of Reye syndrome. Varicella vaccination should be strongly considered, since the risk of Reye syndrome in children who take salicylates and who receive varicella vaccine is likely to be lower than with wild-type varicella. Patients treated with 2 g/kg IVIG should have measles-mumps-rubella and varicella vaccinations delayed for 11 mo because the specific antiviral antibody in IVIG may interfere with the immune response to live-virus vaccines. Other vaccinations do not need to be delayed.

COMPLICATIONS AND PROGNOSIS. Recovery is complete and without apparent long-term effects for patients who do not develop coronary disease. Recurrent acute illness occurs in only 13% of cases. The prognosis for patients with coronary abnormalities depends on the severity of coronary disease. In Japan, fatality rates are very low, about 0.01%. Overall, 50% of coronary artery aneurysms resolve as assessed by echocardiogram 12 yr after the illness. Intravascular ultrasonography has demonstrated, however, that resolved 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, and it is best accomplished with the use of arterial grafts, which grow with the child and are more likely to remain patent long-term than are venous grafts. Heart transplantation has been required in rare cases in which revascularization is not feasible because of distal coronary stenoses, distal aneurysms, or severe myocardial dysfunction. Whether the presence of coronary artery abnormalities resulting from Kawasaki disease predisposes to the development of atherosclerotic heart disease in young adulthood is unknown, although long-term followup studies in Japan, to date, provide little if any evidence of this.