Kawasaki disease (KD) is one of the most common systemic vasculitides in children, second only to Henoch-Schönlein purpura.1 Although described worldwide, it is most commonly seen in Asia, especially Japan. In the Unites States, incidence is highest among children of Asian or Pacific Islander descent living in Hawaii or California, suggesting genetic susceptibility. KD was first reported in 1967 by Tomisaku Kawasaki2 who described 50 cases of children presenting with a self-limited febrile illness associated with coronary arteritis. The former name of KD was mucocutaneous lymph node syndrome, which describes the disease phenotype.2 The majority of cases occur in children younger than age 5 years with an average age of 2 to 3 years; however, there are case reports of this disease occurring in older children and adults.3 It is more common in boys than in girls, with a ratio of 1.5 to 1.3 The etiology of KD is not known. Although seasonal clustering in the winter and spring months suggests an infectious or environmental trigger, none has been identified to date.
Although KD is most often a self-limited illness, a major complication is coronary vasculitis, which is the main cause of morbidity and mortality in KD. The inflammatory injury occurs early in the disease course, during the acute phase of the illness, with evidence of coronary artery aneurysms (CAAs) often evident by echocardiogram within 2 weeks of onset of fever. Recognition of the clinical symptoms and the early diagnosis of KD are essential as timely treatment of this disease has been shown to significantly decrease coronary vessel inflammation and resulting complications.4
A previously healthy 16-month-old girl presented with persistent high fever (>104°F) associated with decreased activity and irritability. She was prescribed oral amoxicillin, and after the first dose (day 3 of illness) she developed a truncal erythematous, nonpruritic, maculopapular rash and lip swelling without mucous membrane changes. She was admitted to the hospital because of persistent high fever and irritability, and she was started on ceftriaxone and vancomycin (at doses suitable for meningitis) immediately after lumber puncture. At day 4 of illness, she developed a nonpurulent conjunctivitis, crackled lips, and mild palmar/plantar erythema. Her rash persisted with perianal accentuation. Her laboratory testing showed a white blood cell count of 17,000 cells/mm3 (left shift, N% 64), normochromic normocytic anemia (9.8 g/dL), platelet count of 265,000 mm3, C-reactive protein (CRP) of 143 mg/L (normal <5 mg/L), erythrocyte sedimentation rate (ESR) of 54 mm/h, albumin of 2.7 g/dL, and normal liver transaminases and urinalysis. She had cerebrospinal fluid (CSF) pleocytosis, normal CSF chemistry, negative CSF virology polymerase chain reaction, and negative blood, CSF, throat, and urine cultures at 24 hours. Her KD diagnosis was confirmed when transthoracic echocardiogram (TTE) showed dilated left main coronary artery (3.2 mm, z score +2.75), irregular left anterior descending artery (2.1 mm, z score +1.63), and mildly reduced left ventricular function (29%). On day 5, intravenous immune globulin (IVIG) (2 g/kg) was given over a period of 10 hours and aspirin (80 mg/kg per day divided every 6 hours) was started as a standard treatment for KD. The antibiotics were discontinued after negative cultures.
The IVIG treatment failed, as the patient's fever persisted and her laboratory results showed continued or increased inflammation (CRP of 257 mg/L) and decreasing hemoglobin (7.6 g/dL). Given her refractory disease, intravenous methylprednisolone (10 mg/kg per day) was given for 3 days. Her fever subsided after the first day of corticosteroids and her laboratory abnormalities significantly improved after 3 days. Her TTE 1 week later was stable to improved, and a repeat TTE 3 weeks later was normal with no structural or functional abnormalities. Her aspirin dosage was decreased to an antithrombotic dose when the fever subsided and was continued for 6 weeks.
Pathophysiology of KD
KD is a medium-vessel vasculitis that affects coronary vessels as well as noncoronary medium-sized muscular and elastic arteries (eg, axillary, renal, iliac, and mesenteric). Three pathologic processes are described.5 During the first 2 weeks of the illness (acute phase), a necrotizing arteritis characterized by neutrophilic infiltrate leads to injury of the arterial wall, resulting in aneurysm formation. These saccular aneurysms can rarely thrombose or rupture. During this phase, proinflammatory cytokine activation, including interleukin-1 (IL-1), IL-6, tumor necrosis factor (TNF), and others, occurs. A subacute/chronic vasculitis starting about 2 weeks after fever onset and lasting months to years is characterized by the presence of predominantly cytotoxic T-cell lymphocytes in vessel walls injured during the acute necrotizing arteritis. This process starts in the perivascular tissues and vessel adventitia, and progresses to the lumen, injuring the arterial wall along the way. Thrombosis with revascularization or with myocardial infarction (MI) can occur during this time. The third pathologic process, luminal myofibroblastic proliferation, occurs months to years after the acute illness and is associated with progressive stenosis of vessels and sometimes subacute/chronic vasculitis, leading to tissue ischemia and MI.
Diagnostic Criteria and Other Clinical Manifestations of KD
The diagnosis of KD is based on clinical criteria of fever and at least four additional criteria of conjunctivitis, rash, mucous membrane changes, extremity changes, and lymphadenopathy (Table 1). In 2004, a proposed updated criterion considered the presence of fever and fewer than 4 other criteria to be adequate to confirm KD if coronary artery changes are seen by echocardiogram.6 Incomplete KD should be considered in children, especially young infants, with unexplained fever for 5 or more days associated with 2 or 3 of the clinical criteria listed in Table 1. A retrospective study of 221 patients with KD found that those patients younger than age 12 months with incomplete KD were at increased risk for developing CAAs.7
Diagnostic Criteria for Kawasaki Disease
Several additional clinical manifestations can be seen in patients with KD. These children usually are irritable, which sometimes may be related to aseptic meningitis. Other reported manifestations include arthritis, uveitis, dysuria, pneumonitis, gastroenteritis, hydrops of the gallbladder, and febrile seizures.
Although there is no diagnostic test for KD, laboratory evaluation is essential to rule out other etiologies of the fever and to increase suspicion of KD. Most patients present with an elevated CRP, ESR, and WBC (with left shift), as well as a normochromic anemia. Platelets are usually normal initially, and then increase to an average of 700,000/mm3 approximately 2 weeks after illness presentation. Thrombocytopenia may represent disseminated intravascular coagulation and is associated with higher risk for CAAs. Other laboratory findings commonly present are transaminitis, hypoalbuminemia, and sterile pyuria.
An echocardiogram is performed as soon as the diagnosis of KD is made or highly suspected, such as in the infant with an incomplete KD presentation. The echocardiogram is repeated 2 weeks after fever onset, and then 4 to 6 weeks after treatment. The coronary vessels are assessed for aneurysms, which are described as small, medium, or giant based on either internal luminal diameter or z scores (which are used to normalize the internal coronary artery dimensions for body surface area through standard deviation units from the mean).8 A small aneurysm is 4 mm or less (z score ≥2.5 to <5), a medium aneurysm is 4 to 8 mm (z score ≥5 to <10), and a giant aneurysm is larger than 8 mm (z score ≥10). A z score of 2 to 2.5 is considered a coronary dilation, which usually resolves within the first 6 weeks of illness. Patients with aneurysms should have the echocardiogram repeated at least twice weekly until the vessel dimensions stabilize.
Echocardiogram will also identify other complications that may occur during the acute illness, such as pericardial effusion, myocardial dysfunction, valvular (primarily mitral) insufficiency, or aortic root dilatation.
A baseline electrocardiogram should also be performed. This may show arrhythmia, changes suggestive of myocarditis and/or pericarditis, myocardial ischemia, or infarction.
A landmark prospective, randomized controlled study in 1986 by Newburger et al.4 demonstrated that treatment with IVIG administered within 10 days of fever onset resulted in a decrease of CAA from 23% in the control group to 8% in the IVIG-treated group. Since then, IVIG has been the accepted primary treatment of KD. It is given as a single dose of 2 g/kg over a period of 10 to 12 hours.9 Although documented to be most effective when administered within 10 days of fever onset, IVIG likely should be given to patients diagnosed after this time frame, especially if fever and elevated CRP persist and/or if coronary vessel changes are present. Recent studies suggest that high-risk patients (age <6 months or coronary artery z score ≥3) should receive parenteral corticosteroids in addition to IVIG as part of their initial treatment, as this may reduce CAA progression.10,11 Aspirin is usually given at anti-inflammatory doses, up to 80 mg/kg per day, until the patient is afebrile, then decreased to antiplatelet doses of 3 to 5 mg/kg per day and continued for at least 6 weeks, with prolonged treatment in those with CAA.
Despite an excellent clinical response by most patients to standard treatment with IVIG and aspirin, some patients do not respond at all or relapse with fevers within 36 hours. These children have a higher risk of CAA and require further medical therapy. Treatment options include a second dose of IVIG (with or without corticosteroids), high-dose pulse parenteral methylprednisolone, one dose of a TNF blocker (infliximab) or cyclosporine.12 KD shock syndrome (KDSS) and macrophage activation syndrome (MAS) are rare but potentially lethal complications of KD that also increase the risk of CAA and require aggressive medical management.
Complications of KD
Complications during the acute phase of the illness include KD that is refractory to treatment, KDSS, and the occurrence of MAS. Cardiac complications secondary to coronary artery vasculitis can occur during the acute illness or months to years later.
Persistent fever or fever recurring within 36 hours after the initial IVIG dose is considered refractory (rKD) and is reported in 10% to 20% of KD patients.13 Children at higher risk for rKD are young (<12 months) and have higher CRP levels, neutrophilia, platelets >300,000, and hyponatremia.9,13 Patients with rKD are at a higher risk for cardiovascular complications so further treatment is warranted.
Management of rKD is controversial, and more prospective studies are needed to propose optimal guidelines. A second dose of IVIG is given to the majority of patients with rKD and has been shown to be successful in two-thirds of refractory patients.12 Several authors have reported the benefit of corticosteroids in rKD, with doses as high as 30 mg/kg per day (maximum of 1 g/d) for 1 to 3 days followed by a gradual taper regimen.14 TNF-alpha and other inflammatory cytokines were found to be elevated in the acute phase of KD, and were the most elevated among patients with CAA.15 As a result, the monoclonal anti-TNF antibody, infliximab, has been used as a treatment for rKD. A multicenter, randomized, controlled trial showed that infliximab is as safe and tolerable as IVIG in rKD.16 It was found to be more effective in inducing defervescence; however, the benefit in CAA is unclear to date.17 Anti–IL-1 biologics or cyclosporine have also been given to patients with rKD. Corticosteroids are often given in combination with the above medications.
KD Shock Syndrome
KDSS is described in the literature as a rare complication of KD characterized by a sustained decrease in systolic blood pressure to ≥20% below baseline or clinical signs of poor perfusion that are not related to adverse events of IVIG infusion.18 It generally occurs during the first week of illness. The mechanism of KDSS is unclear; however, observation data show that shock most commonly occurs in patients with worse systemic inflammation and vasculitis that lead to more severe myocardial involvement. KDSS is associated with a higher risk of CAA, mitral regurgitation, and prolonged myocardial dysfunction. Multiple organ dysfunction syndrome, nonspecific encephalopathy, and acute kidney injury were reported in the majority of children with KDSS in a multicenter retrospective analysis of pediatric intensive care unit admissions.19 KDSS patients are resistant to the first-line treatment of IVIG and thus always require additional treatments, primarily corticosteroids, in addition to supportive intensive care management with fluid resuscitation, vasoactive agents, and respiratory support.20 Early diagnosis is essential as prompt treatment of KDSS is correlated with better outcome in retrospective analysis.18
Macrophage Activation Syndrome in KD
Hemophagocytic lymphohistiocytosis (HLH) can be primary (familial) due to genetic abnormalities or secondary to an underlying infection, malignancy, or inflammatory or rheumatologic disease.21 MAS (the secondary form of HLH) is a potentially lethal hyperinflammatory condition caused by defective cytotoxicity that results in overactive macrophage and T-cell proliferation. Impaired natural killer T-cell activity is the hallmark of defective cytotoxic cell activity and subsequent uncontrolled immune response. MAS presents with the sudden onset of a systemic inflammatory response syndrome in the form of fever, malaise, nonspecific morbilliform rash, hepatosplenomegaly, jaundice, generalized lymphadenopathy, and cytopenia. Delayed diagnosis is associated with severe neurologic symptoms, liver failure, and disseminated intravascular coagulopathy.22 A highly elevated serum ferritin level (>10,000 mcg/L) is 90% sensitive and 96% specific for MAS.23 Other frequent laboratory findings are elevated triglycerides, low fibrinogen, low ESR, low natural killer cell activity, and elevated soluble interleukin-2 receptor levels (sCD25).
MAS is a rare complication of KD and usually diagnosed after KD presentation, although in some cases MAS diagnosis precedes the KD diagnosis.24 It may be challenging to diagnose MAS in the presence of underlying KD given similar clinical manifestations and laboratory findings in the initial testing. Findings more common in MAS than uncomplicated KD include splenomegaly, low ESR, thrombocytopenia, and markedly elevated ferritin. Therefore, the presence of splenomegaly and these laboratory values in the setting of active KD should trigger a high index of suspicion for the complication of MAS.
In a recent systematic review of treatment of MAS secondary to KD, patients received multiple medications: two doses of IVIG (90%), corticosteroids (87%), cyclosporine (49%), etoposide (39%), monoclonal anti-TNF (5.7%), and interleukin-1 receptor antagonist (4.3%).24 Although there is no standard treatment for MAS-KD, corticosteroids are the most common first-line treatment. Corticosteroids are often used in combination with IVIG, cyclosporine, IL-1 receptor antagonist, or anti-TNF biologic therapy. Of note, cyclosporine has been used effectively in rKD and also in MAS that is secondary to systemic juvenile idiopathic arthritis. It is, therefore, a reasonable medication to give to those patients with MAS-KD who do not respond adequately to corticosteroid treatment.
Cardiac Complications of KD
The development of CAAs is the most common cardiac problem seen in KD and may lead to serious, and potentially fatal, short- and long-term complications. CAAs are characterized as small, medium, or large/giant by echocardiogram assessment. The incidence of cardiac sequelae is greatest in the 1% to 2% of patients who develop giant aneurysms (internal luminal diameter >8 mm or z score ≥10). Children at the highest risk for giant aneurysms are those who have rKD, incomplete KD, are younger (age <12 months), or had late diagnosis and treatment. CAAs are documented to regress in 75% to 90% of patients within 2 years; however, regression is much less frequent (<20%) in those with giant aneurysms).10
Cardiac events can occur during the acute illness, subacute phase, or years later. Complications during the acute and subacute phases include pericarditis/pericardial effusion, thrombosis with myocardial infarction, myocarditis, cardiogenic shock, mitral regurgitation, and aortic root dilation. Mortality is highest during the subacute phase. Given the risk of thrombosis in the inflamed and injured coronary vessel, antiplatelet treatment with long-term aspirin is recommended for all patients with CAAs. In those with medium-sized CAAs, a thienopyridine (eg, clopidogrel) may be added to the medical regimen. Those with giant aneurysms are also often treated with anticoagulation therapy (either warfarin or low-molecular weight heparin).11
Long-term sequelae are related to progressive stenosis and thrombosis in injured coronary arteries, and they occur almost exclusively in those with a history of giant CAAs. Tsuda et al.25 evaluated the more than 20-year outcome in patients with KD with giant CAAs. Coronary artery bypass surgery was performed in 37% of patients, myocardial infarction occurred in 23%, and 6% of patients died. Patients with giant CAAs will need to be closely followed for life by a cardiology team to monitor for and manage potential complications, as well as for guidance on ways to decrease other risk factors that may contribute to cardiovascular disease.
KD is a common systemic vasculitic illness and the leading cause of acquired cardiac disease in childhood. Treatment with IVIG significantly decreases the risk for CAAs and is the standard initial therapy. Incomplete KD is associated with an increased incidence of resistance to IVIG treatment and subsequently higher risk for CAA. Corticosteroids or infliximab are often effective in patients who are refractory to the IVIG treatment; however, prospective studies are needed to more fully assess their efficacy. Shock and MAS are rare but potentially lethal complications of KD that require aggressive medical management. Children with coronary vessel injury need to be observed by a cardiology team into and during adulthood because of concern for long-term cardiac complications.
- Gardner-Medwin JM, Dolezalova P, Cummins C, Southwood TR. Incidence of Henoch-Schönlein purpura, Kawasaki disease, and rare vasculitides in children of different ethnic origins. Lancet. 2002;360(9341):1197–1202. https://doi.org/10.1016/S0140-6736(02)11279-7 PMID: doi:10.1016/S0140-6736(02)11279-7 [CrossRef]12401245
- Kawasaki T. Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children [Japanese]. Arerugi. 1967;16(3):178–222.6062087
- Holman RC, Belay ED, Christensen KY, Folkema AM, Steiner CA, Schonberger LB. Hospitalizations for Kawasaki syndrome among children in the United States, 1997–2007. Pediatr Infect Dis J. 2010;29(6):483–488. https://doi.org/10.1097/01.inf.0000069765.43405.3b PMID:20104198
- Newburger JW, Takahashi M, Burns JC, et al. The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med. 1986;315(6):341–347. https://doi.org/10.1056/NEJM198608073150601 PMID: doi:10.1056/NEJM198608073150601 [CrossRef]2426590
- Orenstein JM, Shulman ST, Fox LM, et al. Three linked vasculopathic processes characterize Kawasaki disease: a light and transmission electron microscopic study. PLoS One. 2012;7(6):e38998. https://doi.org/10.1371/journal.pone.0038998 PMID: doi:10.1371/journal.pone.0038998 [CrossRef]22723916
- Ozen S, Ruperto N, Dillon MJ, et al. EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides. Ann Rheum Dis. 2006;65(7):936–941. https://doi.org/10.1136/ard.2005.046300 PMID: doi:10.1136/ard.2005.046300 [CrossRef]
- Song D, Yeo Y, Ha K, et al. Risk factors for Kawasaki disease-associated coronary abnormalities differ depending on age. Eur J Pediatr.2009;168(11):1315–1321. https://doi.org/10.1007/s00431-009-0925-0 PMID: doi:10.1007/s00431-009-0925-0 [CrossRef]19159953
- Manlhiot C, Millar K, Golding F, McCrindle BW. Improved classification of coronary artery abnormalities based only on coronary artery z-scores after Kawasaki disease. Pediatr Cardiol. 2010;31(2):242–249. https://doi.org/10.1007/s00246-009-9599-7 PMID: doi:10.1007/s00246-009-9599-7 [CrossRef]
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Diagnostic Criteria for Kawasaki Disease
|Fever ≥5 days and at least four of the following clinical findings:
Fever ≥5 days, fewer than four of the above criteria, and presence of coronary artery aneurysm(s)
Nonexudative bilateral conjunctivitis
Oropharyngeal mucous membrane changes, such as red cracked lips, strawberry tongue, and/or injected pharynx
Extremity changes: erythema of palms/soles, swelling of hands/feet, or periungual desquamation (occurring 10–14 days after presentation)
Cervical adenopathy (≥1.5 cm)