eMedicine Specialties > Pediatrics: General Medicine > Infectious Disease

Kawasaki Disease

Author: Noah S Scheinfeld, MD, JD, FAAD, Assistant Clinical Professor, Department of Dermatology, Columbia University; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Private Practice
Coauthor(s): Elena L Jones, MD, Clinical Assistant Professor of Dermatology, College of Physicians and Surgeons of Columbia University; Clinic Chief, Department of Dermatology, St Luke's-Roosevelt Hospital Center
Contributor Information and Disclosures

Updated: Jun 25, 2008

Introduction

Background

Kawasaki disease (KD) is an acute febrile vasculitic syndrome of early childhood. While at the Tokyo Red Cross Medical Center in Japan, Tomisaku Kawasaki reported 50 children in 1961-1967 who presented with fever, rash, conjunctival injection, cervical lymphadenitis, inflammation of the lips and oral cavity, and erythema and edema of the hands and feet. Children younger than 2 years died when they were improving or after they had seemingly recovered. Postmortem examinations revealed complete thrombotic occlusion of coronary artery aneurysms (CAAs) with myocardial infarction (MI) as the immediate cause of death. In 1976, Melish et al first reported Kawasaki disease in the United States in a group of 12 children from Honolulu examined from 1971-1973.¹

KD is now recognized worldwide. Cardiac involvement occurs in 20-25% of patients who are not treated, and the mortality rate is 0.1-2%. Early administration of intravenous immunoglobulin (IVIG) reduces the risk of developing cardiac involvement to 5%. KD is the leading cause of acquired heart disease in children in the developed world and may be a risk factor for adult ischemic heart disease. In the United States, KD has now surpassed acute rheumatic fever as the leading cause of acquired heart disease in children.²

Pathophysiology

The etiology of KD is unknown. Increasing evidence supports an infectious etiology for KD; however, whether the inflammatory response results from a conventional antigen or a superantigen continues to be debated. Recent immunohistochemical findings suggest that many vascular growth factors then play a role in the formation of the coronary artery lesions. The activated suppressor/cytotoxic T cells increase, and the CD8⁺ suppressor T cells decrease. Serum levels of interleukin (IL)–1, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and IL-6 are elevated. Involvement of the coronary vessels mimics infantile polyarteritis nodosa, but antibody profiles differ.

Most of the pathology of the disease is induced by a medium vessel arterial vasculitis. Initially, neutrophils are present in great numbers, but the infiltrate rapidly switches to mononuclear cells, T lymphocytes, and immunoglobulin A (IgA)–producing plasma cells. Inflammation involves all 3 layers of vessels. Eosinophils are preferentially accumulated in microvessels.

Dergun et al, Newburger et al, and Burns et al described families with multiple members affected with KD to increase awareness of the familial occurrence of KD among practitioners who care for these patients.^3,2,4 They retrospectively reviewed medical records at 2 medical centers and data collected from remote families with KD who contacted the Kawasaki Syndrome Research Program at the University of California, San Diego.

The researchers studied 18 families with multiple affected members. Nine families had 2 affected siblings. In San Diego, 3 (0.7%) of 424 families with KD had cases involving siblings. Nine families were identified with KD in 2 generations or in multiple affected members, yielding a total of 24 children with KD. No clear pattern of inheritance could be deduced from these pedigrees. Therefore, multiple polymorphic alleles likely influence KD susceptibility. The authors concluded physicians should counsel affected families and make them aware of the potential increased risk of KD among family members.

Frequency

United States

Epidemics primarily occur in the late winter and spring, at 2- to 3-year intervals. Approximately 3000 children with KD are hospitalized annually in the United States. Regional incidence rates are reported to range from 67.2 cases per 100,000 children younger than 5 years in large, urban, multiethnic populations (eg, Los Angeles, Calif) to 9.8 cases per 100,000 children younger than 5 years in populations in states such as Georgia.

International

Approximately 5000-6000 cases are reported each year in Japan. The incidence in 2000 was 134.2 cases per 100,000 children younger than 5 years. Several epidemics have occurred in Japan during the years 1979, 1982, and 1985. No epidemics have occurred since that time.

Marked spatial and temporal patterns were noted in both the seasonality and deviations from the average number of KD cases in Japan. Seasonality was bimodal, with peaks in January and June and/or July and a nadir in October. This pattern was consistent throughout Japan during the entire 14-year period. 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.⁵

Yanagawa et al (2006) reviewed the epidemiology of KD in Japan.⁶ From 1999-2002, 18,604 boys and 13,662 girls with KD were reported. The average annual incidence was 137.7 per 100,000 children younger than 5 years. The male-to-female ratio was 1.3:1. The incidence peaked at age 9-11 months, and the proportion of patients younger than 1 year was 26%. Most cases occurred in January. Acute-stage cardiac lesions and cardiac sequelae occurred more often in children younger than 1 year and older than 4 years. The following symptoms were reported (listed in decreasing incidence):

• Fever that persisted for 5 or more days
• Conjunctival congestion
• Changes in lips and oral cavity
• Polymorphous exanthema
• Changes of extremities
• Cervical lymphadenopathy

Mortality/Morbidity

The mortality rate is reported to be 0.1-2%. Approximately 20-25% of untreated patients develop cardiac problems, including CAAs, acute MI secondary to true coronary artery obstruction, myocarditis, congestive heart failure (CHF), pericarditis with pericardial effusion, mitral or aortic insufficiency, and dysrhythmias. Aneurysms develop in less than 5-10% of patients treated with intravenous gamma globulin before the 10th day of illness. Approximately 5% may have aortic or mitral regurgitation due to valvulitis, transient papillary muscle dysfunction, or MI. Arthritis persists in some children. KD appears to be a rare cause of adult cardiac dysfunction.

Race

The prevalence of KD is highest among Japanese. Rates are intermediate among blacks, Polynesians, and Filipinos and are lowest among whites.

Sex

KD is more common in males than in females, with a male-to-female ratio of 1.3-1.6:1. Arthritis appears more common in girls than in boys.

Age

Approximately 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. The earliest reported case in Japan occurred in a 20-day-old newborn. KD in adults is rare. Kawasakilike syndromes have been reported in adults infected with human immunodeficiency virus (HIV).

Clinical

History

Kawasaki disease (KD) has 3 stages, as follows:

• Acute stage (1-11 d)
  • High fever (temperature >104°F)
  • Irritability
  • Nonexudative bilateral conjunctivitis (90%)
  • Anterior uveitis (70%)
  • Perianal erythema (70%)
  • Acral erythema and edema that impede ambulation
  • Strawberry tongue and lip fissures
  • Hepatic, renal, and GI dysfunction
  • Myocarditis and pericarditis
  • Lymphadenopathy (75%), generally a single, enlarged, nonsuppurative cervical node measuring approximately 1.5 cm
• Subacute stage (11-30 d)
  • Persistent irritability, anorexia, and conjunctival injection
  • Decreased temperature
  • Thrombocytosis
  • Acral desquamation
  • Aneurysm forms
• Convalescent or chronic phase (>30 d)
  • Expansion of aneurysm
  • Possible MI
  • A tendency for smaller aneurysms to resolve on their own (60% of cases)

Physical

• Patients with classic KD must have 5 of the following symptoms (fever is an absolute criterion):
  • Fever, lasting more than 5 days and refractory to appropriate antibiotic therapy
  • Polymorphous erythematous rash
  • Nonpurulent bilateral conjunctival injection
  • Oropharyngeal changes, including diffuse hyperemia, strawberry tongue, and lip changes (eg, swelling, fissuring, erythema, bleeding)
  • Peripheral extremity changes, including erythema, edema, induration, and desquamation
  • Nonpurulent cervical lymphadenopathy
• Other findings may include the following:
  • General - Irritability
  • Cardiac - Coronary aneurysms, pericardial effusion, myocarditis, CHF
  • Neurologic - Stiff neck secondary to aseptic meningitis, facial palsy, cerebral infarction
  • Renal - Sterile pyuria, proteinuria, nephritis, acute renal failure
  • Musculoskeletal - Joint involvement (arthralgias or arthritis)
  • Pulmonary -Pleural effusion, infiltrates
  • GI - Abdominal pain, diarrhea, hepatitis, obstructive jaundice, hydrops, pancreatitis, gall bladder distention
  • Tissues - Meatitis, vulvitis, urethritis
  • Ophthalmologic - Conjunctivitis, uveitis
  • Dermatologic - Peripheral extremity gangrene, pustules, erythema multiforme–like lesions, perianal desquamation, macules, papules, measleslike rash, scarlet fever–like erythema, and induration at the site of bacille Calmette-Guérin (BCG) inoculation (commonly observed in Japan); pustulovesicular skin eruption in a child with probable KD; Beau lines associated with KD after the disease resolves; pustular rash¹¹
• As many as 10-45% of published cases have incomplete or atypical clinical presentations. The 2 most commonly missing findings include cervical lymphadenopathy and polymorphous rash.
• Mucous-membrane changes are the most common manifestations of KD, occurring in more than 90% of patients with either typical or atypical forms of the disease.

Causes

The etiology of KD remains unknown. At present, most of the epidemiologic and immunologic evidence indicates that the causative agent is probably infectious. This idea of an infectious etiology is supported by the age of the patients affected, the periodic epidemics, the wavelike and geographic spread of illness during the epidemic, and the self-limited nature of the illness. Furthermore, 1.4% of cases in Japan involve siblings. The overall clinical presentation of patients with KD is similar to that of patients with a viral or superantigenic disease.

The failure to isolate one pathogen highlights the likelihood that the cause of KD is multifactorial and that genetic and immunologic factors, and possibly a vector, influence the disease. Superantigens and cytotoxic T cells appear to be involved. Passive maternal immunity might account for the failure of most cases to develop before the patient is aged 4 months.

KD has been linked to various infections, including the following:

• Parvovirus B19
• Meningococcal septicemia
• Coxiella burnetii
• Bacterial toxin–mediated superantigens
• HIV
• Mycoplasma pneumoniae
• Adenovirus
• Klebsiella pneumoniae bacteremia
• Parainfluenza type 3 virus
• Rotavirus infection
• Measles
• Human lymphotropic virus infection

A case of KD with CAAs and Yersinia pseudotuberculosis infection has been reported. KD does not appear to be linked to Rickettsia conorii, Rickettsia typhi, C burnetii, or Ehrlichia phagocytophila group allergens, such as anionic detergents and house dust mites, and some chemicals (including heavy metals). KD is not associated with human herpesvirus 8, transfusion transmitted virus (TTV), GB virus C/hepatitis G virus, or Chlamydia pneumoniae infections.

Hypercoagulability does not occur during the acute stage of KD.

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