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Kawasaki Disease

Author: Elizabeth Kline Satter, MD, MPH, Staff Dermatologist and Head of Dermatopathology for Residency Program, Department of Dermatology, Naval Medical Center, San Diego
Contributor Information and Disclosures

Updated: May 8, 2008

Introduction

Background

In 1967, Dr Tomisaku Kawasaki reported 50 cases of a unique self-limited childhood illness. Because the condition had not been previously described, he referred to it as "acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children."¹ Subsequent to this initial report, several fatalities were reported in association with this "benign self-limited" condition that occurred as a result of acute vasculitis and coronary aneurysms.

Case reports of a similar condition had been reported in the European literature in the late 19th century and the 20th century; however, because the primary focus was on the vascular complications, rather than the cutaneous manifestations, the condition was referred to as periarteritis nodosa or infantile polyarteritis nodosa. The current belief is that mucocutaneous lymph node syndrome and infantile polyarteritis nodosa lie within a spectrum of medium-sized vessel vasculitides, and, in recognition of his contributions, this condition is now most commonly referred to as Kawasaki disease (KD) or Kawasaki syndrome.

Although KD has been reported worldwide, the greatest number of cases has been in Japan, with more than 140,000 cases identified since 1967. A genetic predilection has long been suspected based on the fact that siblings of affected children have a 10-20 times increased probability of developing KD compared with the general population, and children born of parents with a history of KD are twice as likely to be affected.²

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 predominately in Japanese populations, thereby further implicating a genetic influence to the increased susceptibility to KD in Japanese patients.^3,4 Most recently a functional polymorphism of the inositol 1,4,5-triphosphate 3-kinase C (ITPKC) gene on band 19q13.2 has been identified to be not only significantly associated with an increased susceptibility to developing KD, but also is associated with an increased risk of coronary artery lesions in both Japanese and US children.²

DD, despite the prominent mucocutaneous clinical findings that define the illness, is best regarded as a generalized vasculitis that involves small- to medium-sized arteries. Although the vascular inflammation is most pronounced in the coronary vessels, the same process can be found in the renal, celiac, mesenteric, iliac, axillary, brachial, and other medium-sized vessels. The extent of the coronary vascular involvement is so significant that KD has now surpassed rheumatic fever as the leading cause of acquired heart disease in children from developed nations.

Pathophysiology

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 (ie, tumor necrosis factor, vascular endothelial growth factor, monocyte chemotaxic and activating factor), interleukins (ILs) (ie, IL-1, IL-4, IL-6), and matrix metalloproteinases (MMPs) (ie, primarily MMP3 and MMP9) that target the endothelial cells and result in a cascade of events that eventuates in fragmentation of the internal elastic lamina and vascular damage.
 
Over the next few weeks to months, the active inflammatory cells are replaced by fibroblasts and monocytes that are involved in tissue repair and remodeling, but the process can also lead to progressive fibrosis and vascular stenosis.^5,6,7,8,9

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.

Frequency

United States

In the United States, approximately 3000-4000 cases of KD are reported annually; however, the exact incidence depends on the patient's ethnic descent. The approximate annual race-specific incidence per 100,000 children younger than 5 years is 32.5 cases for Americans of Asian and Pacific Island descent, 16.9 cases for non-Hispanic African Americans, 11.1 cases for Hispanics, and 9.1 cases for whites.

International

The highest incidence of KD has been reported in Japan, with a 10- to 20-times higher frequency of the disease in that country compared with  that found in Western countries.²
Approximately 5000-6000 cases are reported annually (112 cases per 100,000 population younger than 5 y), with several epidemiclike peaks reported in 1979, 1982, and 1986. Other Asian countries also have an elevated incidence of KD, but none has been reported to be as high as that in Japan.
 
On average, the approximate annual incidence of KD in various Asian populations per 100,000 children younger than 5 years is 90-112 cases for Japan, 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.¹⁰

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.

Mortality/Morbidity

Kawasaki disease has surpassed rheumatic heart disease as the leading cause of acquired heart disease in the US in children under the age of 5.On average, coronary aneurysms have been reported to occur in approximately 25% of untreated patients; however, with early initiation of intravenous immune globulin (IVIG) therapy, this rate has been reduced to 5-10%.

• 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. The greatest risk of cardiac damage occurs in children younger than 1 year and in older children, which may be related to an atypical presentation often seen in this age group that leads to a delay in treatment.
• The peak mortality occurs 15-45 days after the onset of fever, with a mortality rate ranging from 0.08-3.7%. However, the consequences of coronary damage may not become evident until years later, when the patient presents with an acute myocardial infarction.
• Based predominately on Asian literature, 1-3% of patients have a relapse, with the highest incidence occurring within 2 years from the initial episode. The greatest incidence is in younger children and those who had cardiac sequelae from the initial episode. The incidence also appears to be slightly increased in cases within families, with approximately 2.1% of siblings affected within 10 days to 1 year from the first sibling's illness. This risk of 2 family members having KD is greatest in twins, for whom the rate is approximately 13%.¹¹
• To date, no deaths have been reported in adult cases of KD.

Race

As stated previously, a significant increased incidence is reported in Japan, which also exceeds that of other Asian populations; however, cases have been reported worldwide. See Frequency for detailed information.

Sex

A slight male predominance is apparent, ranging from 1.3-1.83:1 depending on the country from which the statistics are reported.

Age

Regardless of nationality, 90% of cases occur in children younger than 5 years.

• A slightly earlier age of occurrence is reported in Japan, with the average child ranging in age from 6-12 months; this is different from the peak incidence of 18-24 months reported from other countries.
• KD is unusual in infants younger than 4 months, suggesting that maternal antibodies may provide passive immunity.
• Although most cases of KD occur in children, it has also been reported in adolescents and adults, most of whom are between ages 18 and 30 years.¹²

Clinical

History

Because no specific test can be performed for KD and because no clinical feature is pathognomonic, the diagnosis of KD is based on the presence of a constellation of clinical findings.^{1,12,13,14,15}

• The diagnostic criteria established by the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease; the Council on Cardiovascular Disease in the Young; and the American Heart Association include fever lasting longer than 5 days and 4 of the 5 main clinical features, after diseases with similar findings have been excluded. The most recent guidelines suggest that if a patient presents with 4 or more of the principal criteria, KD can be diagnosed on day 4 of the fever.^11,16
• The 5 major clinical findings are as follows:
  • Change in the extremities, typically painful erythema and edema
  • Polymorphous exanthem
  • Changes in the lips and oropharyngeal mucosa
  • Bilateral, nonexudative, bulbar conjunctival injection
  • Unilateral nonsuppurative cervical lymphadenopathy
• Patients who present with coronary artery disease can be diagnosed with KD if they have at least 3 of the 5 major diagnostic criteria.
• The clinical presentation of KD varies over time, with the clinical course conventionally divided into 3 stages, as follows (see Media File 1):
  • Stage 1: The acute stage begins with an onset of fever and lasts approximately 7-14 days. It is heralded by an abrupt febrile episode that is typically high-spiking and remittent, with peak temperatures typically ranging from 102-104ºF (39-40ºC). This fever is not responsive to antibiotics and antipyretics and can persist for up to 3-4 weeks if untreated. With appropriate therapy, high-dose aspirin, and IVIG, the fever typically remits within 48 hours. During the acute phase, the mucocutaneous changes and lymphadenopathy are most evident, and the diagnosis should be made in this phase.
  • Stage 2: 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, and the development of coronary aneurysms. This stage is when the patient is at highest risk for sudden death.
  • Stage 3: The convalescent stage begins with the return of the acute phase reactants and other laboratory abnormalities to baseline. During this stage, most of the clinical findings resolve; however, 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, but in patients whose echocardiograms were previously normal, detection of new aneurysms is unusual after week 8 of the illness.

Physical

KD is a dynamic illness with various features that are most pronounced at different times. The most characteristic features are usually present at the time of presentation or appear shortly thereafter.^{1,12,13,14,15,17}

• Greater than 95% of patients present with protracted fever, which has a remittent pattern of several temperature spikes each day. The patient is ill and often extremely irritable.
• Greater than 90% of patients present with a polymorphic exanthem within 3-5 days of the onset of fever. See Media File 2.
  • Initially, the child may present with nonspecific erythema of the palms, soles, and perineal regions, which gradually and diffusely involves the trunk and extremities. The eruption is usually pruritic and can be macular, papular, morbilliform, scarlatiniform, urticarial, erythrodermatous, targetoid, or composed of fine micropustules, but it is never vesicular or bullous.
  • Within a few days after the onset of the eruption, a fine desquamation of the perineal region occurs. See Media File 3.
• The extremities show distinctive changes in 94% of patients. After the initial acral erythema, the palms and soles gradually become indurated and painful, which may limit mobility. Then, during the subacute phase of the illness, approximately 14 days after the onset of fever, desquamation occurs in a glovelike fashion first involving the periungual region of the fingers, followed a week later by a similar desquamation of the toes. See Media File 4.
• Mucous membrane and oropharyngeal alterations begin within the first few days after the onset of fever. Changes in the lips are seen in 75-90% of patients and include erythema, dryness, cracking, and bleeding. From 50-77% of patients have an extremely erythematous tongue with protuberance of the fungiform papillae, which has been referred to as strawberry tongue. This feature, while clinically impressive, is indistinguishable from that seen in patients with scarlet fever, a streptococcal infection. See Media File 5.
• Bilateral, nonexudative, bulbar conjunctival injection with relative sparing around the limbus occurs within a few days after the onset of fever and lasts 1-3 weeks in approximately 88% of patients. See Media File 6. Mild iridocyclitis or anterior uveitis may be seen during a slit-lamp examination but is rarely associated with eye pain or photophobia.
• The least common of the 5 major diagnostic criteria is a unilateral, nontender, nonsuppurative anterior cervical lymphadenopathy. This typically involves a single node larger than 1.5 cm in diameter. This finding is only seen in 70% of cases in Japan and in 50-86% of cases in the United States.
• The last feature seen during the acute febrile stage is cardiovascular alterations. Cardiac auscultation may reveal various findings such as a hyperdynamic precordium, tachycardia, a gallop rhythm, or an innocent flow murmur. These findings are nonspecific and may be initially attributed to mild anemia and/or fever.
• In the subacute phase, more serious abnormalities arise, such as congestive heart failure, pericardial effusions, valvular regurgitation, aneurysms, and arrhythmias. These findings, however, may not be appreciated during a physical examination; specific tests, such as an electrocardiogram or echocardiogram, may be required. See Imaging Studies.
• Noncardiac findings can occur in other organ systems during the subacute stage of the illness, including the following:
  • Central nervous system findings are reported. Although nearly all children with KD are extremely irritable, 33% can present with lethargy, with 25-50% having aseptic meningitis. Less frequently (and often a temporary finding), patients develop unilateral facial palsy or high-frequency sensorineural hearing loss.
  • Genitourinary system findings include sterile pyuria in 33-70% of patients, which appears to be urethral in origin.
  • Gastrointestinal system findings include diarrhea, vomiting, and abdominal pain in 33% of patients. In addition, hepatic enlargement, jaundice, and transient elevation in the serum transaminases and gamma-glutamyl-transpeptidases can be seen in 40-67% of patients. Acute distension of the gallbladder can be identified based on abdominal ultrasound findings; this occurs in 15% of patients.
  • Musculoskeletal system findings occur early in the illness, with patients experiencing diffuse arthralgia that involves multiple joints, both large and small. In the subacute phase, 20-40% of patients present with arthralgia or arthritis, both of which tend to favor the large weight bearing joints.

Causes

Despite the fact that 40 years have elapsed since the disease was first reported, a definitive etiology remains unknown. The most common hypothesis is that the disease has an infectious etiology, based on the acute clinical presentation, seasonal variation, clustering of cases in various geographic locations, and the age distribution. Over the years, multiple infectious agents have been implicated; however, to date, no single microbial agent has surfaced as the prevailing cause.^18,19

Another major hypothesis is that a variety of stimuli trigger a superantigen-driven response in genetically predisposed patients, leading to selective expansion of the immune system; however, this theory remains to be substantiated. In fact, recent investigations have shown that the immune response in KD is oligoclonal, as is seen as a response to a conventional antigen, rather than polyclonal, as would be found in a superantigen-driven response.^17,20

Regardless of the etiology, the increased production of various pro-inflammatory cytokines and elevated levels of matrix metalloproteinases appear to mediate the vascular endothelial damage.

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