eMedicine Specialties > Emergency Medicine > Pediatric

Pediatrics, Kawasaki Disease

Author: Steven J Parrillo, DO, FACOEP, FACEP, Associate Professor, Emergency Medicine, Jefferson Medical College and Philadelphia College of Osteopathic Medicine; Medical Director, Department of Emergency Medicine, Einstein Elkins Park; Chair, Emergency Management Committee, Albert Einstein Healthcare Network; Medical Director, Disaster Medicine and Management Masters Program, Philadelphia University
Coauthor(s): Catherine V Parrillo, DO, FACOP, FAAP, Clinical Assistant Professor, Department of Pediatrics, Philadelphia College of Osteopathic Medicine
Contributor Information and Disclosures

Updated: Oct 28, 2009

Introduction

Background

Kawasaki disease (KD) (ie, Kawasaki syndrome [KS]) is a febrile illness of childhood. It is a self-limited acute vasculitic syndrome of unknown etiology, first described by Tomisaku Kawasaki in 1967. At that time, he reported 50 children from 1961-1967 who presented with a distinctive clinical illness characterized by fever and rash, which was then thought to be a benign childhood illness.

Several years later, fatalities occurred in Japan among children younger than 2 years. The fatalities occurred when patients were improving or had recovered. Postmortem examinations revealed complete thrombotic occlusion of coronary artery aneurysms with a myocardial infarction (MI) as the immediate cause of death. It soon became evident that, when studied by echocardiography (ECHO), 20-25% of untreated children developed cardiovascular sequelae ranging from asymptomatic coronary artery ectasis or aneurysm formation to giant coronary artery aneurysms with thrombosis, MI, and sudden death. Even today, 15-25% of untreated patients develop coronary artery aneurysms. (The increase from older quotes of 5% is largely based on revised echocardiographic criteria for aneurysmal dilatation).

Although inflammatory infiltrates have been shown in the myocardium, pancreas, kidney, and biliary tract, no significant sequelae persist in those nonvascular tissues. A single report of pulmonary involvement has appeared in the literature. Gallbladder vasculitis (hydrops) is a significant, though uncommon complication.

Kawasaki syndrome has now surpassed rheumatic fever as the leading cause of acquired heart disease in the United States among children younger than 5 years.

In recent years, much attention has been given to incomplete cases of Kawasaki disease.

Pathophysiology

The etiology of Kawasaki disease remains unknown, although many suspect an infectious etiology. Indicators suggesting an infectious etiology include the occurrence of periodic epidemics with geographic spread; the self-limited nature; the winter and summer presentations; and the characteristic fever, adenopathy, and eye signs.

Some now believe that many factors (viruses, staphylococci "super antigens") are capable of triggering a final common pathway that results in immune activation. All effective therapies are directed at this immune activity.¹ Other proposed infectious agents include Parvovirus B19, Yersinia, and cytomegalovirus.¹

The frequency of Kawasaki disease in Asian populations has led several authors to suggest a genetic predisposition to genetic polymorphisms.^2,3

Treadwell et al have suggested that an association exists between Kawasaki disease and the use of a humidifier in the room of a child with an antecedent respiratory illness.⁴ Others have noted association with freshly cleaned carpets and living near a body of water.⁵  

Frequency

United States

Epidemics occur primarily in late winter and spring with 3-year intervals, lending some credence to the possibility of an infectious etiology. Kawasaki disease is most commonly observed in children from the middle and upper-middle classes. The estimated number of children hospitalized annually in the United States is about 3000, though more than 4000 admissions occurred in 2006, some of which were incomplete cases. The highest incidence in the United States is in Hawaii at 17 per 100,000 children younger than 5 years.⁶

International

Outside the United States, the disease is most frequently observed in Japan, Taiwan, and Korea. The prevalence of Kawasaki disease increased from 1967 to the mid 1980s and has leveled out at 5000-6000 cases per year. Several epidemics occurred in Japan during the years 1979, 1982, and 1985. The current Japanese incidence is approximately 112 cases per 100,000 population.

The occurrence rate in the United Kingdom doubled in the last decade.⁶

Mortality/Morbidity

• The development of coronary artery aneurysms (CAA) with consequences such as thrombosis or rupture determines the degree of disability. Acute MI has been reported secondary to true coronary artery obstruction. These aneurysms tend to develop approximately 1-2 weeks after onset of symptoms. 
• Myocarditis, congestive heart failure, pericarditis with pericardial effusion, mitral or aortic insufficiency, and dysrhythmias may be observed early in the disease. Decreased left ventricular function is present in approximately 50% of all patients with Kawasaki syndrome. Additionally, arthritis persists in some children.
• The risk of aneurysm is increased in patients who have fever for more than 16 days, who have recurrence of fever after an afebrile period of at least 48 hours, are male, who have cardiomegaly, and especially who are younger than 1 year. Some laboratory values at presentation may also predict a greater likelihood of aneurysm development including hematocrit <35%, thrombocytopenia (<350,000), elevated C-reactive protein (CRP), albumin <3.5g/dL, and WBC >12,000. Incomplete Kawasaki may also be an independent predictor of CAA development.⁷ The most important predictor is total duration of fever longer than 8 days.⁸
• Researchers are beginning to look at the possibility that patients with aneurysms may have an increased risk of premature coronary atherosclerotic disease.
• Until recently, the long-term outcome of pediatric coronary artery bypass performed in these children was unknown. Kitamura et al followed 114 children and adolescents for as long as 25 years after bypass. Survival rates were 95%, though some had either percutaneous coronary intervention or repeat CABG. Only 5 deaths occurred in the group.⁹

Race

Kawasaki disease is more common in the Japanese-American population. Worldwide, it is most common in all Asian populations.

Sex

Kawasaki disease is more common in males than in females, with a male-to-female ratio of 1.5:1.

Age

Eighty-five percent of children with Kawasaki disease are younger than 5 years.¹

In the United States, the peak prevalence is in children aged 18-24 months. The Japanese patient population is younger than the patient population in the United States; Kawasaki disease is most frequently observed in infants aged 6-12 months, with equal numbers in the first and second year of life.

Pannaraj et al noted that Kawasaki disease may occur at the extremes of age range, meaning infants younger than 6 months or children older than 5 years and that pediatricians and infectious diseases specialists frequently fail to consider the diagnosis.¹⁰

Infants aged 6 months or younger may have maternal antibody protection, but incomplete cases — and some of the poorest outcomes — have been reported in that age group.⁸

Manlhiot et al suggest that children at the extremes of the age spectrum, those younger than 6 months and those older than 9 years, are more likely to have a suboptimal outcome.¹¹

Clinical

History

Most children present because of concern of a prolonged fever. Diagnosis requires fever of at least 5 days duration (though many believe that the diagnosis can be made earlier in otherwise classic presentations). Parents may note that the fever began abruptly. Antibiotic therapy may have been initiated for other diagnoses, but fever persists. The affected child is usually more irritable than would be expected by the degree of fever.

Key historical clues include the following:

• Fever
  • At least 5 days in duration
  • Often abrupt in onset
  • Unresponsive to antibiotic therapy, if given
• Irritability - Out of proportion to the degree of fever or other signs (Note that a lumbar puncture to rule out meningitis may demonstrate a pleocytosis).

Physical

Diagnosis and clinical features of Kawasaki disease

• The diagnosis of classic Kawasaki disease requires fever (>39°C) of at least 5 days' duration and the presence of 4 of the following:
  • Changes in extremities including erythema, edema, and desquamation. This may limit movement and cause the child to refuse to bear weight. Desquamation of the fingers and toes begins in the periungual region, may involve the palms and soles, and is usually observed 1-2 weeks after the onset of fever. (Occurrence is approximately 75%.)

• Bulbar conjunctivitis (not associated with exudates) is almost always bilateral. (Occurrence is approximately 85%.)
• Polymorphous rash (not vesicular) is usually generalized but may be limited to the groin or lower extremities. (Occurrence is approximately 80%.)
• Cervical lymphadenopathy is usually greater than 1.5 cm and unilateral; it is the least common of all clinical features in US cases, though it is more common in Asia. (US occurrence is approximately 40%.)
• Changes in the lips and oral cavity include pharyngeal erythema, dry/fissured or swollen lips, and strawberry tongue. (Occurrence is approximately 90%.)

• Clinical features
  • The onset is usually abrupt with a high sustained fever that is unresponsive to antibiotic therapy and lasts for 1 week or longer. In addition, other typical features may be present.
  • Lips become erythematous and fissured. Bleeding may be noted.
  • The tongue is described as a strawberry tongue because of the diffuse erythema and prominent papillae.

• The neck may be stiff enough to consider meningitis, especially since many such patients are very irritable. Aseptic meningitis (pleocytosis) may be present in one half of all patients.
• The primary cardiac involvement is the development of coronary artery aneurysms. Myocarditis and pericarditis with or without effusion may also occur in the acute stage.
• Other clinical features of the disease may include urethritis, orchitis, arthritis/arthralgia, abdominal pain, vomiting/diarrhea (one third of patients), sterile pyuria (one third of patients), hepatitis, and gallbladder distention.
• Although rare in the United States, reactions of erythema, induration, and ulcerations may occur at the inoculation site of children who have received the BCG vaccine.

Incomplete cases also occur. (Clinical features are typical, just not present in the numbers required for fully manifested cases. For that reason, the term "incomplete KD" is used rather than "atypical KD"). In this setting, usually in children younger than 6 months of age, fever plus only 3 features establishes the diagnosis. The rationale is that treatment is safe and effective and that failure to diagnose Kawasaki disease may have a significant negative impact on outcome. The American Academy of Pediatrics (AAP)/American Heart Association (AHA) published criteria for the diagnosis in incomplete Kawasaki disease in 2004 in both Pediatrics and Circulation.¹² Those articles include a helpful algorithm summarized as follows:

• When fever plus 2 or 3 of the typical features are present for 5 days or more, and patient characteristics suggest possible Kawasaki disease, a C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) should be obtained.
  • If CRP level is less than 3 mg/dL and ESR is more than 40 mm/h, the child is monitored and actions taken as appropriate.
  • If CRP is greater than or equal to 3 mg/dL and ESR is greater than or equal to 40 mm/h, supplemental laboratory studies should be performed. Those studies include albumin, alanine aminotransferase (ALT), platelets, WBC count, and urine (for pyuria). Abnormal limits include the following:
    • Albumin <3 g
    • Anemia for age
    • Elevated ALT level
    • Platelets >450,000 (after 7 d)
    • WBC count >12,000
    • Presence of pyuria
  • If 3 or more supplemental laboratory criteria are positive, a diagnosis of Kawasaki disease is made. The child should have an echocardiogram and be treated.
  • If fewer than 3 supplemental laboratory criteria are positive, cardiac echocardiogram should be performed. If negative but fever persists, a repeat echocardiogram may be performed. If the echocardiogram is negative and the fever abates, Kawasaki disease is unlikely. If the echocardiogram is positive, the child is treated for Kawasaki disease.

Newberger questioned the suitability of laboratory findings as evidence of inflammation, noting that in some cases, the clinical criteria are not all present on any given day. Conversely, some patients with an inflammatory disorder did not meet the clinical case definition but developed coronary artery abnormalities consistent with Kawasaki disease.⁶

Hinze et al reported a case of Kawasaki disease in a 3-month-old boy manifested by typical signs and coronary artery aneurysms but without fever. He commented on the difficulty in making the diagnosis in young infants.¹³

Case reports of other unusual presentations have been published including GI bleeding, lupuslike illness in a recurrent case, arthritis, and rhabdomyolysis. Such presentations appear to be very uncommon.¹

Three phases occur, as follows. Some authors add a fourth "chronic" phase.

• Acute febrile phase - 1-2 weeks
  • The temperature is elevated (>104°F).
  • The child is irritable.
  • Bilateral conjunctivitis and rash are present.
  • The hands and feet develop the erythema and edema that cause the child to refuse to walk. Note that this finding may be the last to develop. Lack of extremity findings may cause consideration of incomplete Kawasaki disease.
  • The tongue and oral mucosa become red and cracked.
  • Hepatic dysfunction may develop.
  • Cardiac complications noted in the first stage include myocarditis and pericarditis.
• Subacute phase - Begins when fever and other signs have abated. This phase should end by the 4th week.
  • This is characterized by persistent irritability, anorexia, and conjunctival injection.
  • Fever resolution begins this stage. However, persistent fever beyond 2-3 weeks may be an indication of recrudescent Kawasaki disease. (See Recrudescent Kawasaki disease below).
  • If fever persists, the outcome is less favorable because of a greater risk of cardiac complications.
  • Thrombocytosis develops, and the platelet count may exceed 1 million/mm³.
  • Desquamation of the fingertips and toes begins at this time.
  • Aneurysm formation may occur during this stage.
  • Children are at greatest risk of sudden death during this phase.
• Convalescent phase - Approximately 4-6 weeks
  • This phase begins when all signs of illness have disappeared and continues until acute-phase reactants (ESR, CRP level) have returned to normal.
  • The most significant clinical finding that persists through this phase is the presence of coronary artery aneurysms.
• Chronic phase
  • This stage is only of clinical importance in patients who have developed cardiac complications.
  • Its duration is of lifetime significance because the aneurysm formed in childhood may rupture in adulthood.
  • In some cases of aneurysms rupturing in adult life, careful reviews of past medical histories have revealed febrile childhood illnesses of unknown etiology.

Causes

The etiology of Kawasaki disease remains unknown. Multiple theories exist, including an infectious etiology, an immunological abnormality, and even the possibility of a link with carpet shampoo. Clinical and epidemiologic features support an infectious etiology, but many authorities believe that an autoimmune component also exists. As noted above, many believe there is a predisposition in the Asian population.

One group of authors has suggested a link with tumor necrosis factor-alpha (TNF-alpha).

The US Food and Drug Administration (FDA) required the makers of RotaTeq rotavirus vaccine to report in the package insert that a total of 9 cases of Kawasaki disease had occurred in children who had received the vaccine. However, most believe that there is no connection between the vaccine and the disease and that the incidence of Kawasaki disease is no greater that in the nonimmunized population.¹⁵

One case report in the literature documents a 35-day-old infant who developed Kawasaki disease after his second hepatitis B vaccination.¹⁶

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