Kawasaki Disease

Practice Essentials

Kawasaki disease (KD), also known as mucocutaneous lymph node syndrome and Kawasaki syndrome, is an acute febrile illness of early childhood characterized by vasculitis of the medium-sized arteries. Given its predilection for the coronary arteries, there is a potential for the development of coronary artery aneurysms (CAAs) and thus sudden death. CAAs develop in approximately 25% of untreated cases; appropriate treatment decreases this risk to 3-5%.^[1]  Echocardiography is the study of choice to evaluate for CAAs. KD is the leading cause of acquired heart disease in developed nations.^[2]

The incidence of KD in the continental United States is approximately 25/100,000 children under 5 years of age; in Japan, the incidence has been estimated at approximately 250/100,000 children < 5 years of age.^[1]

The etiology of this disorder remains unknown.

Diagnosis of Kawasaki disease

There are two forms of KD: complete and incomplete. Diagnosis of complete KD requires fever of at least 5 days' duration along with 4 or 5 of the principal clinical features. The principal clinical features are as follows:

• Extremity changes
• Polymorphous rash
• Oropharyngeal changes
• Bilateral, nonexudative, limbic sparing, painless bulbar conjunctival injection
• Acute unilateral nonpurulent cervical lymphadenopathy with lymph node diameter greater than 1.5 cm

The acronym "FEBRILE" is used to remember the criteria as follows:

• Fever
• Enanthem (mucous membrane rash)
• Bulbar conjunctivitis
• Rash
• Internal organ involvement (not part of the criteria)
• Lymphadenopathy
• Extremity changes

Incomplete KD is diagnosed when a patient presents with fever for 5 days or longer, 2 or 3 of the principal clinical features, and laboratory findings suggestive of the disease or echocardiographic abnormalities. Suggestive laboratory findings include elevated erythrocyte sedimentation rate (ESR), elevated C-reactive protein (CRP), hypoalbuminemia, anemia, elevated alanine aminotransferase (ALT), thrombocytosis, leukocytosis, and pyuria. The American Heart Association (AHA) suggests an algorithm for the diagnosis of incomplete KD in the most recent guideline.^[2]

Echocardiography is the study of choice to evaluate for CAAs. Serial echocardiograms should be obtained as follows:

• At the time of KD diagnosis
• 1-2 weeks after the onset of the illness
• 5-6 weeks after the onset of the illness

See Clinical Presentation and Workup for more details.

Management of Kawasaki disease

The principal goal of treatment is to prevent coronary artery disease. Intravenous immunoglobulin (IVIG), a purified preparation of gamma globulin, and aspirin are the mainstays of treatment. Patients should be treated with IVIG within 10 days after the onset of fever to prevent the development of cardiac sequelae.^{[3, 4, 5]}

Other medications that are used variably as adjunctive treatments or for IVIG-resistant KD include corticosteroids, infliximab, cyclophosphamide, methotrexate, and ulinastatin. In addition to aspirin, other anticoagulants are sometimes utilized, including clopidogrel, dipyridamole, warfarin, and heparin.^[6]

Guidelines

Clinical guidelines include the following:

• Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association
• Guidelines for diagnosis and management of cardiovascular sequelae in Kawasaki disease from the Japanese Circulation Society

See Treatment for more details.

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See Kawasaki Disease: Do You Know the Signs?, a Critical Images slideshow, for more information on the diagnosis and management of KD.

View Video

Video overview of Kawasaki disease pathophysiology, symptoms, diagnosis, and treatment.

• References

Background

KD is an acute febrile vasculitic syndrome of early childhood. The disorder has also been called mucocutaneous lymph node syndrome and infantile periarteritis nodosa. It was first described in 1967 by Dr Tomisaku Kawasaki, who reported 50 cases of a distinctive illness in children seen at the Tokyo Red Cross Medical Center in Japan.^[7] These children presented with fever, rash, conjunctival injection, cervical lymphadenopathy, inflammation of the lips and oral cavity, and erythema and edema of the hands and feet. In 1976, Melish et al first reported KD in the United States, in a group of 12 children from Honolulu.^[8]  KD is now recognized worldwide, although the greatest number of cases has been in Japan.

The illness was initially thought to be benign and self-limited. However, subsequent reports indicated that nearly 2% of patients with KD later died from the illness. These children died while they were improving or after they had seemingly recovered. Postmortem examinations revealed complete thrombotic occlusion of CAAs, with myocardial infarction (MI) as the immediate cause of death. It is now recognized as the leading cause of acquired heart disease in children in the developed world, surpassing rheumatic fever, and is a risk factor for adult ischemic heart disease.

The photographs below depict various manifestations of KD.

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Kawasaki disease: Patchy generalized macular erythema, which is also typical of some viral exanthems.

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Kawasaki disease: Peeling and erythema of the fingertips.

View Image

Kawasaki disease: Strawberry tongue.

• References

Pathophysiology

Despite the prominent mucocutaneous clinical findings that define the illness, KD is best regarded as a generalized vasculitis that involves medium-sized arteries. Although the vascular inflammation is most pronounced in the coronary vessels, vasculitis can also occur in veins, capillaries, small arterioles, and larger arteries.

In the earliest stages of the disease, the endothelial cells and the vascular media become edematous, but the internal elastic lamina remains intact. Then, approximately 7-9 days after the onset of fever, an influx of neutrophils occurs, which is quickly followed by a proliferation of CD8⁺ (cytotoxic) lymphocytes and immunoglobulin A–producing plasma cells. The inflammatory cells secrete various cytokines (tumor necrosis factor, vascular endothelial growth factor, monocyte chemotactic and activating factor), interleukins (IL-1, IL-4, IL-6), and matrix metalloproteinases (primarily MMP3 and MMP9) that target the endothelial cells and result in a cascade of events that lead to fragmentation of the internal elastic lamina and vascular damage.^[9]  In severely affected vessels, the media develops inflammation with necrosis of smooth muscle cells. The internal and external elastic laminae can split, leading to aneurysms.

Over the next few weeks to months, the active inflammatory cells are replaced by fibroblasts and monocytes, and fibrous connective tissue begins to form within the vessel wall. The intima proliferates and thickens. The vessel wall eventually becomes narrowed or occluded owing to stenosis or a thrombus.^{[10, 11, 12, 13, 14]} Cardiovascular death may occur from a myocardial infarction secondary to thrombosis of a coronary aneurysm or from rupture of a large coronary aneurysm. The period during of the greatest vascular damage is when a concomitant progressive increase in the serum platelet count occurs, and this is the point of the illness when the risk of death is most significant.

• References

Etiology

The etiology of KD remains unknown. There has been a strong suspicion that the etiology of KD is infectious; however, no single infectious agent has been implicated. However, autoimmune reactions and genetic predisposition have been suggested as possible etiologic factors. By 2014, 6 genetic loci were linked to KD through genome-wide studies. However, the etiology of KD is complex, and these genetic factors still need to be fully applied to diagnosis and treatment.^[15]

Infection

Features of KD that raise concern for an infectious etiology include the occurrence of epidemics primarily in late winter and spring, with 3-year intervals, and the wavelike geographic spread of those epidemics. KD is unusual in infants younger than 4 months, suggesting that maternal antibodies may provide passive immunity. Epidemiologic data suggest, however, that person-to-person transmission of the disease is unlikely.

Some authors have proposed a controversial association of KD with recent carpet shampooing, flooding, the use of a humidifier in the room of a child with an antecedent respiratory illness,^[16] and locations near bodies of water.^[17] These data have led to a waterborne vector hypothesis.

The overall clinical presentation of patients with KD is similar to that of patients with a viral or superantigenic disease. However, investigations have shown that the immune response in KD is oligoclonal, which is seen as a response to a conventional antigen, rather than polyclonal, as would be found in a superantigen-driven response.^{[18, 19]}

Over the years, multiple infectious agents have been implicated; however, to date, no single microbial agent has surfaced as the prevailing cause.^{[20, 21]} Suspected pathogens and infections have included the following:

• Parvovirus B19
• Neisseria meningitidis
• Bacterial toxin–mediated superantigens
• Mycoplasma pneumoniae
• Klebsiella pneumoniae
• Adenovirus
• Cytomegalovirus^[22]
• Parainfluenza type 3 virus
• Rotavirus
• Measles
• Epstein-Barr virus
• Human lymphotropic virus
• Mite-associated bacteria
• Tick-borne diseases
• Rickettsia
• Propionibacterium acnes

Using light and electron microscopy, researchers have identified cytoplasmic inclusion bodies containing RNA in 85% of acute- and late-stage KD fatalities and 25% of adult controls. Based on this finding, it is hypothesized that the KD infective agent could be a ubiquitous RNA virus that results in asymptomatic infection in most individuals, but leads to KD in a subset of genetically predisposed individuals. It is also possible that many infectious agents trigger one final common pathway in susceptible hosts, which leads to KD.^[1]

Genetic factors associated with Kawasaki disease

A genetic predilection to KD has long been suspected.^{[23, 24]} Siblings of affected children have a 10-20 times higher probability of developing KD than the general population, and children in Japan whose parents had KD seem to have a more severe form of the disease and to be more susceptible to recurrence.^[25] This risk of 2 family members having KD is greatest in twins, for whom the rate is approximately 13%.^[26]

In 1978, Kato et al discovered that patients with KD are more likely to express HLA-Bw22J2, which is a major histocompatibility complex antigen seen predominantly in Japanese populations. This further implicated a genetic influence to the increased susceptibility to KD in Japanese patients.^{[27, 28]} A genome-wide linkage analysis of affected sibling pairs was performed in Japan, and a multipoint linkage analysis identified evidence of linkage on chromosome 12q24.^[29]

Dergun et al, Newburger et al, and Burns et al described families with multiple members affected with Kawasaki disease.^{[30, 31, 32]} In these families, KD occurred in 2 generations or in multiple siblings. No clear pattern of inheritance could be deduced from these pedigrees. Therefore, multiple polymorphic alleles likely influence KD susceptibility.

A functional polymorphism of the inositol 1,4,5-triphosphate 3-kinase C (ITPKC) gene on band 19q13.2 has been found to be significantly associated with an increased susceptibility to developing KD. In addition, this polymorphism was associated with an increased risk of coronary artery lesions in both Japanese and American children.^[33]

In a Dutch cohort, Breunis et al observed an association of KD with common genetic variants in the chemokine receptor gene-cluster CCR3-CCR2-CCR5.^[34] The association of CCR2-CCR5 haplotypes and CCL3L1 copy number with KD, coronary artery lesions, and responses to IVIG have been reported in Japanese and other children.^[35]

Genetic factors may influence the development of coronary artery lesions in Kawasaki disease.^[36] In one study, genomic DNA was extracted from whole blood collected from 56 patients with Kawasaki disease who received IVIG treatment, and the genotypes for Fcg RIIIb-NA(1,2), Fcg RIIa-H/R131, and Fcg RIIIa-F/V158 were determined. About 23% of patients with the HH allele for the Fcg RIIa polymorphism developed coronary artery lesions, compared with 60% with the HR and RR alleles. HR and RR alleles may be a predictor of the progression of coronary lesions in KD before the start of IVIG.

• References

Epidemiology

United States statistics

The incidence of KD in the continental United States is approximately 25 per 100,000 children under 5 years of age. A 2010 article retrospectively examined all hospitalizations of children younger than 18 years who had KD and found that the rate of hospitalization in the United Sates from 1997-2007 remained relatively stable, except for a slight increase in 2005. The hospitalization rate for children younger than 5 years was 20.8 cases per 100,000 children in 2006 and demonstrated a slight male predilection.^[37]

International statistics

KD is most frequently observed in Japan, Taiwan, and Korea. The highest incidence of KD has been reported in Japan, where the frequency of the disease is 10 to 20 times higher than in western countries.^[33]   Although the birth rate has declined, the numbers of patients diagnosed as having KD and the incidence rate in Japan have risen rapidly since the 1990s. The incidence in 2000 was 134.2 cases per 100,000 children younger than 5 years; in 2012, the incidence was 264.8 per 100,000 children younger than 5 years.^[38]  Epidemics occurred in Japan during the years 1979, 1982, and 1986. No epidemics have occurred since that time. Marked spatial and temporal patterns have been noted in both the seasonality and deviations from the average number of KD cases in Japan. Seasonality is bimodal, with peaks in January and June and/or July and a nadir in October. This pattern was consistent throughout Japan during an entire 14-year period which was studied. Very high or low numbers of cases were reported in certain years, but the overall variability was consistent throughout the entire country. Temporal clustering of KD cases was detected with nationwide outbreaks.^[39]

Park et al noted the average annual rate of incidence of KD in South Korea was 105 cases per 100,000 in children younger than 5 years, which was the second highest reported rate in the world.^[40] On average, the approximate annual incidence of KD in various Asian populations per 100,000 children younger than 5 years is 54.9 cases for Taiwan, 25.4 cases for Hong Kong, 16.8-36.8 cases for Shanghai, and 18.2-30.6 cases for Beijing.

The annual incidence reported in white populations outside the United States is similar to that reported in the US population, with 11.3-14.7 cases per 100,000 children younger than 5 years in Canada and 3.6 cases per 100,000 children younger than 5 years in Australia.^{[41, 42]} From 1999-2000, the incidence in the United Kingdom was 8.1 cases per 100,000 children.^[43]

Ontario has the highest rate of KD outside of Asia, with a yearly incidence of 26.2 cases per 100,000 population younger than 5 years. The incidence significantly increased from 1995 to 2006, with more patients diagnosed with incomplete KD. A reduction in coronary abnormalities was also seen during this period and was attributed to better recognition and treatment of the disease.^[44]

Racial and sexual differences in incidence

Although KD has been reported in children of all ethnic origins, it occurs most commonly in Asian children, especially those of Japanese descent. Rates are intermediate among African Americans, Polynesians, and Filipinos, and are lowest among Caucasians.^[45]

KD is slightly more common in males than in females. The male-to-female ratio ranges from 1.3-1.83:1 depending on the country from which the statistics are reported. Arthritis appears to be more common in girls than in boys. Death and serious complications are more common in boys than in girls.^[37]

Age-related differences in incidence

Approximately 85-90% of KD cases occur in children younger than 5 years^[22] ; 90-95% of cases occur in children younger than 10 years. In the United States, the incidence peaks in children aged 18-24 months. In Japan, the incidence peaks in children aged 6-12 months.

KD has rarely been reported in adolescents and adults, most of whom are between ages 18 and 30 years.^[44] Fewer than 60 adult patients have been described in the literature for various geographic locations, including 25 in Europe, 23 in North America, 5 in Asia, 2 in South America, and 2 in Africa.^[46]  Kawasaki-like syndromes have been reported in adults infected with human immunodeficiency virus (HIV). However, it is unclear whether this is a variant of KD or an unrelated entity in the immunocompromised population.^[47]

Children younger than 6 months and those older than 9 years are more likely to have an incomplete presentation, and are also more likely to have a suboptimal outcome.^[48]  

• References

Prognosis

The prognosis relies on the extent and severity of cardiac disease. KD has surpassed rheumatic heart disease as the leading cause of acquired heart disease in the United States in children under the age of 5 years. Cardiovascular complications include the following:

• Diffuse coronary artery ectasia and aneurysm formation, including giant aneurysms
• Clinically significant heart failure or myocardial dysfunction (unlikely to occur once fever is resolved)
• Myocardial infarction
• Myocarditis (common, but rarely causes chronic heart failure)
• Valvulitis, usually mitral (only occurs in 1% of patients and rarely requires valve replacement)
• Pericarditis with small pericardial effusions (occurs in 25% of patients with acute illness)
• Systemic arterial aneurysms
• Rupture of coronary artery aneurysms with hemopericardium

Approximately 20-25% of untreated patients develop cardiac sequelae, including CAAs. Aneurysms develop in 3-5% of patients treated with IVIG before the 10th day of illness.^[49]

Risk factors for CAAs include the following:

• Fever >8 days
• Recurrence of fever after an afebrile period of at least 48 hours
• Male sex
• Cardiomegaly
• Age younger than 1 year
• Asian and Pacific Islander race
• Hispanic ethnicity

The most important predictor is total duration of fever longer than 8 days.^[50] Incomplete Kawasaki disease may also be an independent predictor of CAA development.^[51] Wilder et al reported that delayed diagnosis contributes to the development of these aneurysms.^[52]  Studies have shown that even in children who do not form aneurysms, up to 50% show a decrease in ventricular function and/or mild valvular regurgitation on echocardiograms.

Patients who do not develop CAAs recover fully. In those who develop CAAs, the severity of aneurysms determines the prognosis. More than half of all aneurysms resolve within 2 years. Endovascular ultrasonography has shown that, even when aneurysms resolve, marked intimal thickening is present in some. Vessel flow may be abnormal. These patients may have an increased risk of premature coronary atherosclerotic disease.^[53]

Coronary artery bypass grafting (CABG) has been required in some children with severe perfusion deficits. Follow-up of children and adolescents 20-25 years after CABG has shown a 95% survival rate, though some patients have required repeat CABG or percutaneous coronary intervention.^[54] Transplant has been performed in some children who had large aneurysms in vessels not amenable to bypass.

The greatest risk of cardiac damage occurs in children younger than 1 year and in older children, which may be related to the incomplete presentation often seen in the older age group that leads to delay in diagnosis and, consequently, treatment. Providers must be aware of both the complete and incomplete presentations of this disease to ensure timely diagnosis and treatment. Therapy with IVIG should be started within 10 days, and ideally within 7 days, of fever onset to prevent cardiac complications.^[55]

Recurrence of KD is unusual: the recurrence rate in Japan is 3%, and it is approximately 1% in North America. Most relapses occur within 2 years from the initial episode. The highest incidence is in younger children and those who had cardiac sequelae from the initial episode.

The mortality from KD is low at less than 0.5%, with the highest risk in the first year after disease onset. Death is typically due to acute MI in the setting of giant aneurysms. Aneurysm rupture is rare and typically occurs within the first few months after the illness began. In the first week, severe myocarditis leading to hemodynamic instability or arrhythmias can occur.^[1]

• References

Patient Education

Patient and family education on KD should include the following key points:

• KD causes swelling and damage to the blood vessels in the body.
• The cause is not known, but it is not believed to spread from person to person.
• KD is treated with an IV medication called IVIG, which is infused over 8-12 hours. It is also treated with aspirin. If the patient still has fevers 36 hours after IVIG, the patient will likely receive a second dose, and may receive other medications as well.
• The patient will need pictures of the heart taken to look for swelling of the blood vessels of the heart and other heart abnormalities, which are dangerous complications of KD. With treatment with IVIG, this occurs in only 3-5 out of 100 patients with KD. Patients with KD who do not receive treatment are at much higher risk for heart problems. If heart problems are not present 6-8 weeks after symptoms began, it is very likely that the patient will have a full recovery with no complications.
• The patient will need to follow up with a primary care doctor and a cardiologist after discharge from the hospital. This is very important so that the patient is appropriately treated and monitored for heart complications.

• References

History

Most children with KD are brought to medical attention because of prolonged fever. There are two forms of KD: complete and incomplete. Diagnosis of complete KD requires fever of at least 5 days' duration along with 4 or 5 of the principal clinical features. The most recent version of the AHA guidelines suggest that if a patient presents with 4 or more of the principal criteria, KD can be diagnosed on day 4 of fever.^[2] Experienced clinicians who have treated many KD patients may establish diagnosis before day 4, and patients who present with coronary artery disease can be diagnosed if they have at least 3 of the 5 major diagnostic criteria.^[56]  The principal clinical features are as follows:

• Extremity changes: 1) Erythema of the palms and soles, sometimes accompanied by firm and painful induration of the hands or feet that can impede ambulation 2) Desquamation of the fingers and toes which begins in the periungual region, within 2-3 weeks after the onset of fever 3) Beau's lines (deep transverse grooves across the nails) may be present 1-2 months after fever onset
• Polymorphous rash: Typically diffuse and maculopapular, but can take on a variety of forms. Bullous, vesicular, and petechial rashes are not consistent with KD. 
• Oropharyngeal changes: 1) Erythema, fissuring, bleeding, and/or crusting of the lips; 2) Strawberry tongue with prominent fungiform papillae; 3) Diffuse erythema of the oropharyngeal mucosa
• Bilateral, nonexudative, limbic sparing, painless bulbar conjunctival injection (>90% of patients)
• Acute unilateral nonpurulent cervical lymphadenopathy with lymph node diameter of at least 1.5 cm (least common criteria present)

Phases of Kawasaki disease

The clinical presentation of KD varies over time, with the clinical course conventionally divided into 3 stages: acute, subacute, and convalescent (see the image below). Some authors add a fourth, chronic, phase.

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Clinical manifestations and time course of Kawasaki disease.

Stage 1: acute febrile stage

The acute stage begins with an abrupt onset of fever and lasts approximately 7-14 days. The fever is typically high-spiking and remittent, with peak temperatures ranging from 102-104°F (39-40°C) or higher. This fever is not responsive to antibiotics and can persist for up to 3-4 weeks if untreated. With appropriate therapy with IVIG, the fever typically remits within 36 hours.

In addition to fever and the principal clinical features listed above, signs and symptoms of this phase may include the following:

• Irritability (often out of proportion to the degree of fever and other symptoms)
• Aseptic meningitis
• Anterior uveitis
• Otitis media
• Myocarditis and pericarditis
• Pneumonitis
• Hepatic, renal, and GI dysfunction
• Orchitis
• Meatitis, vulvitis, urethritis
• Perianal erythema and/or desquamation

Additionally, erythema and induration at the site of bacillus Calmette-Guérin (BCG) inoculation is commonly observed in Japan.

Stage 2: subacute stage

The subacute stage begins when the fevers have abated, and it continues until week 4-6. The hallmarks of this stage are desquamation of the digits, thrombocytosis (the platelet count may exceed 1 million/μL), and the development of CAAs. The risk for sudden death is highest at this stage. 20-40% of patients experience arthralgia or arthritis during this period, both of which tend to favor the large weight-bearing joints. Other characteristics of the subacute stage are persistent irritability, anorexia, and conjunctival injection. 

Persistence of fever beyond 2-3 weeks may be an indication of recrudescent KD. If fever persists, the outcome is less favorable because of a greater risk of cardiac complications.

Stage 3: convalescent phase

The convalescent phase is marked by complete resolution of clinical signs of the illness, usually within 3 months of presentation. This stage begins with the return to baseline of the acute phase reactants and other laboratory abnormalities. Deep transverse grooves across the nails (Beau lines) may become apparent 1-2 months after the onset of fever.

During the convalescent stage, cardiac abnormalities may still be apparent. Smaller CAAs tend to resolve on their own (60% of cases), but larger aneurysms may expand, and MI may occur. In patients whose echocardiograms were previously normal, however, detection of new aneurysms is unusual after week 8 of the illness.

Chronic phase

This stage is of clinical importance only in patients who have developed cardiac complications. Its duration is sometime for a lifetime, because an aneurysm formed in childhood may rupture in adulthood. In some cases of previously undiagnosed aneurysms rupturing in adult life, careful reviews of past medical histories have revealed febrile childhood illnesses of unknown etiology that are suspected to have potentially been unrecognized KD.

• References

Physical Examination

Because no specific test can be performed for KD and no clinical feature is pathognomonic, the diagnosis of KD is based on the presence of a constellation of clinical findings which may or may not be present at the time of physical exam.^{[7, 46, 57, 49, 3]} ​. This is due to the highly variable presence and time course of the signs and symptoms of KD. This is particularly true for incomplete KD.

Representative photographs of some of the principal clinical features are provided below:

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Kawasaki disease: Patchy generalized macular erythema, which is also typical of some viral exanthems.

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Kawasaki disease: Peeling and erythema of the fingertips.

View Image

Kawasaki disease: Strawberry tongue.

For more information on features of this illness, see the Medscape Reference articles Dermatologic Manifestations of Kawasaki Disease and Ophthalmologic Manifestations of Kawasaki Disease.

• References

Approach Considerations

Complete KD is a clinical diagnosis; no laboratory or imaging evaluations are required aside from echocardiography once the diagnosis is made. Pre-diagnosis laboratory and imaging evaluations are of greater utility for cases of incomplete KD, when the diagnosis is suspected but the patient does not meet criteria for complete KD. Normal results on some studies can help narrow the differential diagnosis; however, it should be noted that KD can occur concurrently with other diseases that mimic its findings, including respiratory viruses.

A typical initial laboratory evaluation may include a complete blood count (CBC), electrolyte panel, renal function testing, liver enzymes, albumin, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and urinalysis. Certain laboratory abnormalities coincide with various stages. On complete blood counts, mild-to-moderate normochromic anemia is often observed in the acute stage. During the subacute stage, thrombocytosis is common. The platelet count begins to rise in the second week and continues to rise during the third week. Platelet counts average 700,000/μL, but levels as high as 2 million have been observed. Thrombocytopenia is associated with severe coronary artery disease and MI; rarely, it may be associated with disseminated intravascular coagulation. Hypoalbuminemia may be present and is often associated with more severe and prolonged illness. Acute-phase reactants are almost universally elevated at presentation. Sterile pyuria is also sometimes present due to urethral inflammation. In the convalescent stage, the levels of platelets and other markers begin to return to values within the reference range. Laboratory values may require 6-8 weeks to normalize.

Research is ongoing to attempt to identify specific biomarkers to aid in the diagnosis of KD. Recently, 2 urine proteins have been identified as potential biomarkers of KD: meprin A and filamin C. Meprin A is an immune regulator, and filamin C is associated with endothelial and myocardial cell injury.^{[60, 61]}

Diagnostics for Cardiac Complications

Echocardiography is the study of choice to evaluate for CAAs, in both fully manifested and suspected incomplete cases of KD. Serial echocardiograms should be obtained, preferably at the time of KD diagnosis, at 1-2 weeks, and at 5-6 weeks after the onset of the illness. These may need to be performed more frequently in high-risk patients.^{[56, 62, 4]}

On electrocardiography (ECG), tachycardia, prolonged PR interval, ST-T wave changes, and decreased voltage of R waves may indicate myocarditis. Q waves or ST-T wave changes may indicate MI.

Cardiac enzyme levels (creatine kinase, troponin) are elevated during an MI.

A select group of patients may require cardiac catheterization and angiography. Cardiac angiography provides a more detailed study of the arteries, but it is associated with greater risks of rupture, especially when performed in the acute phase of the illness; it should be limited to select cases. Coronary computed tomography angiography (CTA) and magnetic resonance angiography (MRA) may also prove beneficial in the evaluation and follow-up of the coronary arteries.^{[63, 64]}

Studies for Selected Patients

Abdominal imaging may be indicated depending on the patient's clinic presentation. Liver and gallbladder ultrasonography may be necessary if liver or gallbladder dysfunction is suspected. Acute distention of the gallbladder (hydrops) is identified on abdominal ultrasonography in 15% of patients. Gallbladder hydrops usually resolves without surgical intervention.

Scrotal ultrasound may be indicated if concerning signs or symptoms are present. Although epididymitis is generally an inflammatory process that affects boys aged 9-14 years, it can be observed in younger boys with Henoch-Schönlein purpura and KD.

Arthrocentesis may be indicated in patients with joint involvement to rule out septic arthritis. Joint fluid analysis in patients with KD typically shows numerous white blood cells, ranging from 125,000-300,000/µL, with normal glucose levels and negative culture results.

Lumbar puncture may be indicated in patients with clinical signs suggesting meningitis. In children who undergo lumbar puncture, 50% show evidence of aseptic meningitis with a predominance of mononuclear cells, along with normal glucose and protein levels.

• References

Diagnosis of Incomplete Kawasaki Disease

In some cases, patients have prolonged fever and some of the principal clinical features of KD but not as many as are required to meet standard diagnostic criteria. Hence, the term "incomplete" rather than "atypical" is used to describe these cases. The AHA recommends that when fever for 5 days or longer plus 2 or 3 of the principal clinical features are present without an alternative explanation, a C-reactive protein (CRP) level and erythrocyte sedimentation rate (ESR) should be obtained. If the CRP level is less than 3 mg/dL and the ESR is less than 40 mm/hr, the child is monitored clinically. Re-evaluation of these laboratory markers takes place if fevers persist, and an echocardiogram is performed if skin peeling develops.

If the CRP is 3 mg/dL or higher and/or the ESR is 40 mm/hr or more, the next step is to obtain supplemental laboratory studies. Abnormal limits include the following:

• Albumin 3 g/dL or less
• Anemia for age
• Elevated ALT level
• Platelets >450,000 (after 7 days of fever)
• WBC count 15,000/mm³ or greater
• Urine WBC 10/hpf or greater

If 3 or more supplemental laboratory criteria are positive, a diagnosis of incomplete KD is made. The child should have an echocardiogram and be treated. Alternatively, if a patient has a positive echocardiogram with or without positive supplemental laboratory criteria, the patient should be treated.

If fewer than 3 supplemental laboratory criteria are positive, the child is monitored clinically. Re-evaluation of these laboratory studies takes place if fevers persist, and an echocardiogram is performed if skin peeling develops.^[56]

As alluded to above, some patients have been found to not meet the laboratory criteria but developed coronary artery abnormalities seen on echocardiography that were consistent with KD.^[65]  Clinical judgment is required to determine if and when supplemental laboratory criteria should be strictly followed versus when an echocardiogram should be obtained regardless of laboratory results.

It is critical to note that certain patient populations may present with prolonged fever but with very few to none of the principal clinical features or laboratory findings. This includes infants < 6 months old and adolescents. Unfortunately, while the diagnosis is exceedingly difficult to make in these scenarios, these patients are at high risk for cardiac complications. Therefore, the diagnosis of KD and treatment with IVIG should also be considered for patients with isolated prolonged fever of unclear etiology, or prolonged fever with any of the following clinical findings:

• Irritability
• Aseptic meningitis
• Unexplained or culture-negative shock
• Isolated cervical lymphadenitis unresponsive to antibiotics
• Retropharyngeal/parapharyngeal phlegmon unresponsive to antibiotics

Case reports have also highlighed exceedingly rare and unusual presentations of KD. Hinze et al reported a case of KD in a 3-month-old boy manifested by typical signs and CAAs but without fever.^[66]  Other unusual presentations (GI bleeding, lupus-like illness in a recurrent case, rhabdomyolysis) have been published as well.^[22]

• References

Echocardiography

Echocardiography should be performed to evaluate for CAAs during the acute stage. In order of highest to lowest frequency, the involvement of the coronary arteries is as follows:

1. Proximal left anterior descending and right coronary arteries
2. Left main coronary artery
3. Left circumflex artery
4. Distal right coronary artery
5. Posterior descending artery

In addition to evaluating the coronary arteries for dilation and thrombosis, the baseline echocardiogram is also performed to evaluate for other signs of cardiac involvement. This includes aortic root dilation, depressed contractility, ventricular and valvular dysfunction, and pericardial effusion.

Diffuse dilatation of coronary lumina can be observed in 50% of patients by the 10th day of illness. In children, pediatric cardiologists should ideally perform this study, because they are familiar with coronary artery diameter normal values. Coronary artery dimensions must be adjusted for body surface area to accurately identify dilation. A basic rule is that if the internal diameter of a segment is greater than 1.5 times that of an adjacent segment, then dilation probably exists.

The echocardiogram should be repeated at 1-2 weeks and then 5-6 weeks after disease onset; echocardiograms may need to be performed more frequently in high-risk patients.^{[56, 62, 4]} Frequency of subsequent echocardiography and/or additional cardiac imaging is dependent on the disease severity and the expert opinion of pediatric cardiologists.

In a study that examined echocardiograms obtained at diagnosis and 1 and 5 weeks after diagnosis from 198 patients, Printz et al concluded that non-coronary cardiac abnormalities were associated with coronary artery dilation and laboratory evidence of inflammation within the first 5 weeks after the diagnosis of KD. Left ventricular systolic dysfunction was noted in 20% of patients and coronary artery dilation in 29%. Mitral regurgitation was present in 27% of patients and aortic root dilation in 8%.^[67]

• References

MRA and CT

While echocardiography is the preferred initial imaging modality for KD, CTA, MRA, and/or cardiac catheterization are often later utilized in cases of children with significant coronary artery aneurysms. This is at the discretion of pediatric cardiologists.^{[63, 64]}

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Histologic Findings

Biopsy is rarely performed or necessary to make the diagnosis; therefore, most specimens are obtained from autopsies or from patients who have had diseased arterial segments removed during bypass operations. Early findings show acute destruction of the media of the vessels by neutrophils, with loss of elastic fibers. Later, the infiltrate is replaced by lymphocytes, monocytes, and fibroblasts involved in arterial remodeling. Chronic lesions show intimal proliferation, neoangiogenesis, and vascular occlusion.

Weedon summarized the reported findings of KD as follows:

• Lymphocytes and mononuclear cells manifest in a perivascular fashion
• Edema of the papillary dermis may be present
• Pustules with small intraepidermal and subcorneal abscesses unrelated to eccrine ducts may be present
• One report noted subtle vascular alterations, subendothelial edema, focal endothelial cell necrosis, and vascular deposition of minute quantities of fibrinoid material

Upon ultrastructural examination, myocardial changes reveal hypertrophy, various degrees of degeneration, proliferation and abnormality of mitochondria, infiltration of a small number of lymphocytes, and fibrosis. Coronary microvascular lesions are characterized by the following:

• Microvascular dilatation
• Endothelial cell injury
• Platelet aggregation with thrombosis
• Stenotic lumen with thickened walls in the small arterioles^[68]

• References

Approach Considerations

The principal goal of treatment for KD is to prevent coronary artery aneurysms and other cardiac complications. The mainstays of treatment for KD are IVIG and aspirin.^{[3, 4, 5]}  All patients with KD should be admitted to the hospital for administration of IVIG, echocardiography, initiation of aspirin, and for observation until fevers have resolved.

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Intravenous Immunoglobulin

IVIG relieves acute inflammation and has been shown to reduce the rate of CAAs from approximately 25% in untreated patients to 3-5% in treated patients.^[2]  Maximal benefits are seen when IVIG is given within the first 10 days after the onset of fever. Some controversy exists about the ideal time to begin IVIG, but it is given most often from days 5-7.

In the past, IVIG was given as a lower dose over 4 days (400 mg/kg/day), but newer studies have shown that single high doses are more effective. In current practice, the dose is 2 g/kg intravenously over 10-12 hours.^[9]

10-15% of patients will fail initial treatment with IVIG; treatment failure is defined as a fever occurring 36 hours or longer after IVIG is administered. In many of these cases, a second treatment with IVIG at the original dose is recommended.^[69] A small subgroup of patients fails to respond to a second dose of IVIG (see Treatment/Treatment of IVIG-Resistant Disease).

A study in an ethnically diverse population in San Diego, California, found that patients with IVIG resistance tended to have higher percent bands, CRP, alanine aminotransferase, and gamma-glutamyl transferase, as well as lower platelet counts and age-adjusted hemoglobin concentrations. They were also more likely to have CAAs. However, a proposed scoring system to predict IVIG resistance proved insufficiently accurate to be clinically useful.^[70]

In a review from Singapore by Sittiwangkul et al, initial treatment with IVIG (2 g/kg) failed to elicit a response in 13% of patients.^[71] The diagnosis in 2 patients with IVIG-resistant KD was delayed, and giant aneurysms developed. Patients with a high ESR were at an increased risk of IVIG-resistant Kawasaki disease. Patients with IVIG-resistant KD had a higher prevalence of coronary artery lesions at the acute phase and 2 months after onset.^[71]

It is important to note that the American Academy of Pediatrics Red Book states that live vaccinations are contraindicated for 11 months after administration of IVIG for KD.

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Treatment of IVIG-Resistant Disease

Treatment of patients in which IVIG fails after the first and/or second dose remains controversial and is variable across institutions and providers. Guidelines from the AHA recommend a second dose of IVIG, methylprednisolone, a longer tapering course of prednisolone or prednisone plus IVIG, or infliximab be considered for patients resistant to IVIG.^[2]  Infliximab (Remicade) is a chimeric mouse-human monoclonal antibody directed against soluble and membrane bound tumor necrosis factor-alpha.^[9] Several studies have found infliximab at a dose of 5 mg/kg to be useful in treating KD that is refractory to IVIG.^{[72, 73]} Burns et al reported that infliximab was as effective as a second dose of IVIG in patients who did not respond to a first dose of IVIG.^[74]  In another study, 43 patients with KD who were initially resistant to IVIG were randomized to receive either a first does infliximab (n=11) or second dose of IVIG (n=32). IVIG retreatment gave 65.6% of patients a response while infliximab gave 90.9% of patients a response. Infliximab provided less days of hospitalization and a shorter duration of fever. Adverse events and coronary artery outcomes resembled each other in the two groups.^[75]

The AHA recommends that cyclosporine and other cytotoxic agents, immunomodulatory monoclonal antibody therapy, and plasma exchange be reserved for exceptional patients with particularly refractory KD.

In the future, by identifying a genetic signature for this group, more aggressive and targeted therapies may be used to reduce the risk of coronary complications.^{[33, 22]}

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Aspirin

Aspirin has long been a standard part of therapy for KD. However, its use has been called into question, as it does not impact the development of CAAs.^[1]  Although some authors have suggested that aspirin is no longer needed, most experts use medium- to high-dose aspirin for a variable period, followed by lower-dose aspirin.

Medium- (30-50 mg/kg/day) to high- (80-100 mg/kg/day) dose aspirin divided four times daily is typically given in the acute phase for its anti-inflammatory effects. It is continued until day 14 of the illness or until the patient has been afebrile for 48-72 hours.

Once the patient has remained afebrile for 48-72 hours, low-dose aspirin is often initiated for its antiplatelet activity. The dose is 3-5 mg/kg/day for a total of 6-8 weeks as long as the patient shows no evidence of coronary abnormalities. For patients who have aneurysms, aspirin is commonly continued until the aneurysm resolves or is continued indefinitely.

Randomized controlled trial outcomes are insufficient to indicate whether children with this disorder should continue to receive aspirin as part of the treatment regimen.^[76] Baumer et al concluded that no randomized clinical trials of adequate quality have been performed and that current evidence is insufficient to support or refute the use of aspirin in children with KD as part of their treatment regimen.^[77]

Patients who remain on long-term, low-dose aspirin should receive an annual influenza vaccine and be vaccinated against varicella. Additionally, the risks of developing Reye syndrome during an active infection with influenza or varicella should be addressed. Clopidogrel (Plavix) may be briefly substituted for aspirin in patients who develop influenza or varicella. This agent can also be used in patients allergic to aspirin.^[9]  Patients on prolonged aspirin therapy must also be instructed that concomitant use of ibuprofen antagonizes the irreversible effect of platelet inhibition by aspirin and should be avoided during therapy.

The pediatrician or cardiologist who provides the long-term care should monitor aspirin therapy and decide whether to use additional anticoagulative medications, including warfarin or heparin.

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Other Adjunctive Agents

In addition to their use in treatment of IVIG-resistant KD, corticosteroids have been proposed as part of primary therapy. This indication is controversial, however. Research results have been inconsistent, as follows:

• In a multicenter prospective randomized trial in Japan, the combination of corticosteroids and IVIG significantly decreased coronary artery abnormalities, duration of fever, CRP levels, and initial treatment failure.^[78]  The RAISE trial, conducted in Japan, also had similar findings.^[79]
• A randomized trial in the United States in which a single pulsed dose of methylprednisolone (30 mg/kg) was added to conventional therapy saw a reduction in the ESR at 1 week, but no difference in coronary artery abnormalities^[80]
• In a meta-analysis of 4 studies and 447 patients, Athappan et al concluded that the addition of steroids to standard therapy with IVIG and aspirin decreased the rate of re-treatment but did not decrease the incidence of coronary aneurysms or adverse events.^[81]
• Chen et al reviewed 16 studies that included 2746 patients and found that the rate of coronary artery abnormalities was significantly lower in the corticosteroids plus IVIG group than in the IVIG therapy alone group. The benefit was only found in the group using corticosteroids plus IVIG for the prevention of coronary artery abnormality, and not in the group using the treatment as rescue therapy. The greatest benefit was also seen in patients predicted to be at high risk of IVIG resistance.^{[82, 83]}

Statins are another class of medications that have been used variably in the setting of KD, due to their cholesterol-lowering and immunomodulatory properties. Further research is necessary to determine the impact of statins in the early phase of KD as well as the potential to lower the risk for atherosclerosis in the long term.

The roles of other adjunctive therapies, including pentoxifylline and abciximab, have not yet been definitively determined. Pentoxifylline acts as an anti-inflammatory agent by inhibiting tumor necrosis factor-alpha and may reduce the incidence of aneurysms. Abciximab is a platelet glycoprotein IIb/IIIa receptor inhibitor and has been used in conjunction with standard therapies in patients with KD and giant aneurysms.

Clinical Trials

A selection of ongoing, recruiting, and completed clinical trials is as follows:

• Infliximab Plus Intravenous Immunoglobulin for the Primary Treatment of Kawasaki Disease
• A Study to Evaluate the Use and Safety of CARDIOLITE® in Pediatric Patients With Kawasaki Disease
• Etanercept in Kawasaki Disease
• Etiology Study of Kawasaki Disease
• Infliximab (Remicade) for Patients With Acute Kawasaki Disease

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Consultations

A cardiologist should be consulted for the following:

• Assistance with determining the appropriate timing of initial and/or subsequent echocardiographic studies
• Management of patients with electrocardiogram or echocardiogram abnormalities
• Anticoagulation management
• To determine whether other studies to assess cardiac function (including coronary artery angiography) are required
• Long term follow up and monitoring of patient with confirmed or suspected KD

Other consulting services may be of value depending on the patient's clinical presentations and the differential diagnosis. These may include infectious disease specialists, rheumatologists, and dermatologists.

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Long-Term Monitoring

Long-term management begins at the end of the acute illness, typically 5-6 weeks after fever onset. This is typically when coronary artery involvement has reached its maximal extent and luminal dimensions. Thromboprophylaxis and careful echocardiographic surveillance for coronary artery stenoses and obstructions, as well as myocardial ischemia, are the pillars of management. Patients with severe cardiac complications may require catheterization, coronary artery bypass surgery, or even cardiac transplantation. Successful long-term management requires effective and collaborative programs between pediatric and adult cardiologists.^[2]

Frequency of follow up, medication use, and imaging evaluations are highly dependent on the disease severity. For patients with no evidence of cardiac involvement during the acute phase, they are often discharged from cardiology care at 4-6 weeks after the onset of symptoms without any chronic follow up required. Patients with cardiac disease are treated and monitored regularly by cardiologists with the exact medications used and follow up frequency determined by their provider.^[2]

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Guidelines Summary

The following clinical guidelines are relevant for management of Kawasaki disease:

• Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association
• Guidelines for diagnosis and management of cardiovascular sequelae in Kawasaki disease from the Japanese Circulation Society

• References

Immune globulin, intravenous (Carimune, Gammagard, Gamunex-C, Octagam)

• Dosing, Interactions, etc.

Clinical Context:  IVIG is generally recommended as first-line therapy. It neutralizes circulating myelin antibodies by means of anti-idiotypic antibodies; downregulates proinflammatory cytokines, including interferon-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade; and promotes remyelination. It may increase cerebrospinal fluid IgG levels (10%).

IVIG reduces the prevalence of coronary abnormalities. It leads to rapid defervescence and more rapid normalization of acute-phase reactants.

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Class Summary

IVIG is a purified preparation of gamma globulin. It is derived from large pools of human plasma comprising 4 subclasses of antibodies, approximating the distribution of human serum.

These agents are used to improve clinical and immunologic aspects of Kawasaki disease. They may decrease autoantibody production and increase solubilization and removal of immune complexes.

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Aspirin (Ascriptin, Bayer Aspirin, Bayer Buffered Aspirin, Ecotrin)

• Dosing, Interactions, etc.

Clinical Context:  Aspirin is used to decrease inflammation, inhibit platelet aggregation, and improve complications of venous stasis and thrombosis. It irreversibly inactivates cyclooxygenase, ultimately preventing thromboxane A2 production in platelets. Platelet function does not fully recover until new platelets are made (in 7-10 days). It is first-line therapy, along with IVIG.

Oral absorption may decrease in Kawasaki disease to < 50% (vs typical bioavailability of 85-90%). Altered bioavailability may explain why higher doses are required to achieve a salicylate serum concentration >20 mg/dL.

• References

Class Summary

These agents inhibit prostaglandin synthesis, which prevents formation of platelet-aggregating thromboxane A2. Adequate anti-inflammatory therapy requires that aspirin be combined with gamma globulin. Children with coronary artery disease have received aspirin for prolonged periods.

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Dipyridamole (Persantine)

• Dosing, Interactions, etc.

Clinical Context:  Dipyridamole is a platelet-adhesion inhibitor that possibly inhibits red blood cell uptake of adenosine, itself an inhibitor of platelet reactivity. It may inhibit phosphodiesterase activity, leading to increased cyclic adenosine monophosphate (cAMP) levels in platelets and formation of potent platelet activator thromboxane A2.

• References

Class Summary

Besides aspirin, dipyridamole may be used to prevent microthrombus formation.

• References

Prednisolone acetate (Prelone, Flo-Pred, Millipred)

• Dosing, Interactions, etc.

Clinical Context:  Prednisolone is indicated for the treatment of steroid-responsive inflammation of the palpebral and bulbar conjunctiva, cornea, and anterior segment. It decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

• References

Methylprednisolone (A-Methapred, Medrol, Solu-Medrol)

• Dosing, Interactions, etc.

Clinical Context:  Methylprednisolone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

• References

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

• References

Infliximab (Remicade)

• Dosing, Interactions, etc.

Clinical Context:  Infliximab may be added to treatment if steroids and other immunosuppressant drugs are ineffective in achieving or maintaining remission. Infliximab is a chimeric IgG1k monoclonal antibody that neutralizes cytokine TNF-α and inhibits its binding to the TNF-α receptor. It reduces the infiltration of inflammatory cells and TNF-α production in inflamed areas.

• References

Class Summary

These agents inhibit key factors that mediate immune reactions.

• References

Clopidogrel (Plavix)

• Dosing, Interactions, etc.

Clinical Context: 

• References