Kawasaki’s Disease

Kawasaki’s disease is a rare, acute illness of unknown cause that most commonly affects children under two years of age. The disease is characterized by fever lasting one to two weeks; conjunctivitis; dryness and cracking of the lips; swollen lymph nodes in the neck; reddening of the palms and soles; and a generalized rash.

By the end of the second week of illness, the skin at the tips of the fingers and toes peels and other symptoms subside.

The heart muscle and coronary arteries are affected in some cases. High doses of gamma-globulin and aspirin may be given in order to prevent associated heart complications. The majority of children recover completely.

Kawasaki's disease in detail - technical

Topics covered:

  • Essentials
  • Introduction
  • Historical perspective
  • Aetiology, genetics, pathogenesis, and pathology
  • Epidemiology
  • Prevention
  • Clinical and laboratory features
  • Differential diagnosis
  • Clinical investigation
  • Criteria for diagnosis
  • Treatment
  • Prognosis and long-term management
  • Likely future developments
  • Further reading

Essentials

Kawasaki’s disease is an acute, self-limited, inflammatory vasculitis of unknown aetiology, with a peak incidence under 5 years of age.

Clinical features—the diagnosis is made in the presence of persistent fever for 5 days or more and at least four of the following five clinical signs: (1) nonpurulent conjunctivitis, (2) oropharyngeal inflammation, (3) cervical lymphadenopathy, (4) polymorphous exanthem, and (5) erythema of the palms and soles with subsequent desquamation. Incomplete presentations occur in approximately 25% of patients. The primary complications are cardiac, with coronary artery dilation and aneurysms evident in approximately 15 to 25% of untreated patients.

Management and prognosis—primary therapy consists of a single high dose of intravenous gammaglobulin, reducing the prevalence of coronary artery complications to approximately 4% if given within 10 days of the onset of fever. Persistent coronary artery lesions, with an ongoing risk of thrombosis and stenosis, are the predominant long-term morbidity. In adults, new presentations of myocardial ischemia with the associated finding of coronary artery aneurysms may suggest a previous episode of Kawasaki’s disease during childhood.

Introduction

Kawasaki’s disease is an acute, self-limited, inflammatory vasculitis, predominantly occurring in children under 5 years of age, complicated by coronary artery dilatation and aneurysms, with subsequent risk of thrombosis, stenosis, and cardiac ischaemia, and sudden death.

Historical perspective

Kawasaki’s disease was first described in Japan in 1967 by Dr Tomisaku Kawasaki, a paediatrician. In his initial report he described the characteristic clinical features, but concluded that it was a self-limiting illness with no sequelae. Subsequently, it has been recognized that Kawasaki’s disease is a systemic vasculitis with a predilection for the coronary arteries, resulting in dilatation and aneurysms. It has now been described world wide in all races, and has become the leading cause of acquired cardiac disease in children.

Bullet list 1 Epidemiological case definition of Kawasaki’s disease

Classic clinical criteriaa
Fever persisting at least 5 daysb
 
Presence of at least four principal features:
  • Changes in extremities
  • • Acute—erythema of palms, soles; oedema of hands, feet
  • • Subacute—periungual peeling of fingers, toes in weeks 2 and 3
  • Polymorphous exanthem
  • Bilateral bulbar conjunctival injection without exudate
  • Changes in lips and oral cavity—erythema, lips cracking, strawberry tongue, diffuse injection of oral and pharyngeal mucosae
  • Cervical lymphadenopathy (>1.5 cm diameter), usually unilateral
Exclusion of other diseases with similar findingsc
 
Other clinical and laboratory findings
  • Cardiovascular findings
    • • Congestive heart failure, myocarditis, pericarditis, valvular regurgitation
  • • Coronary artery abnormalities
    • • Aneurysms of medium-sized noncoronary arteries
    • • Raynaud’s phenomenon
    • • Peripheral gangrene
  • Musculoskeletal system
    • • Arthritis, arthralgia
  • Gastrointestinal tract
    • • Diarrhoea, vomiting, abdominal pain
    • • Hepatic dysfunction
    • • Hydrops of gallbladder
  • Central nervous system
    • • Extreme irritability
    • • Aseptic meningitis
    • • Sensorineural hearing loss
  • Genitourinary system
    • • Urethritis/meatitis
  • Other findings
    • • Erythema, induration at bacille Calmette–Guérin (BCG) inoculation site
    • • Anterior uveitis (mild)
    • • Desquamating rash in groin
  • Laboratory findings in acute Kawasaki disease
    • • Leukocytosis with neutrophilia and immature forms
    • • Elevated erythrocyte sedimentation rate
    • • Elevated C-reactive protein
    • • Anaemia
    • • Abnormal plasma lipids
    • • Hypoalbuminaemia
    • • Hyponatraemia
    • • Thrombocytosis after week 1d
    • • Sterile pyuria
    • • Elevated serum transaminases
    • • Elevated serum gammaglutamyl transpeptidase
    • • Pleocytosis of cerebrospinal fluid
    • • Leukocytosis in synovial fluid​

a Patients with lever at least 5 days and less than four principal criteria can be diagnosed with Kawasaki’s disease when coronary artery abnormalities are detected by two-dimensional echocardiography or angiography.

b In the presence of four or more principal criteria, diagnosis of Kawasaki’s disease can be made on day 4 of illness. Experienced clinicians who have treated many patients with Kawasaki’s disease may establish diagnosis before day 4.

c See text.

d Some infants present with thrombocytopenia and disseminated intravascular coagulation.

From Newburger JW et al; Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease; Council on Cardiovascular Disease in the Young; American Heart Association; American Academy of Pediatrics (2004), 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. Circulation 110, 2747–71.

Aetiology, genetics, pathogenesis, and pathology

The aetiology of Kawasaki’s disease is unknown. Some features suggest an infectious aetiology, including clinical similarities to infectious diseases, with a seasonal increase in incidence in winter to spring months and periodic epidemics, and recurrences being rare. Some features are consistent with a superantigen-mediated illness, whereas others suggest the presence of a conventional infection. Familial cases, although rare, do occur, and, together with marked differences in incidence according to race, suggest that some individuals may have a genetic predisposition.

The illness is characterized by a generalized systemic vasculitis. The coronary arteries are predominantly affected with dilatation and aneurysms, but other small- to medium-sized arteries may also be involved. Active inflammation with swelling and oedema of the endothelium and media is present acutely, with an initial influx of neutrophils followed by lymphocytes, mononuclear cells, and IgA plasma cells. Destruction of the internal elastic lamina leads to aneurysm formation. Resolution of active inflammation is followed by progressive fibrosis and intimal thickening, and stenoses may develop. Rupture occurs rarely in the acute stage. Thrombosis may be related to endothelial activation, thrombocytosis, and a hypercoagulable state in the acute stage, or chronically related to stasis within giant aneurysms.

Epidemiology

Although Kawasaki’s disease has been reported world wide, the incidence remains highest in Japan and children of Japanese descent at about 110 cases per 100 000 children aged less than 5 years of age. The incidence is lowest in white people at less than a tenth of this rate. Although most cases occur in children aged less than 5 years, Kawasaki’s disease has been reported in older children and adolescents. Boys are more commonly affected. Recurrence and familial occurrence are rare. Reported environmental factors have been inconsistent, although a seasonal increase during the winter and early spring months is evident.

Table 1 Risk stratification and long-term management
Risk level Pharmacological therapy Physical activity Follow-up and diagnostic testing Invasive testing
I (no coronary artery changes at any stage of illness) None beyond first 6–8 weeks No restrictions beyond first 6–8 weeks Cardiovascular risk assessment, counselling at 5-year intervals None recommended
II (transient coronary artery ectasia disappears within first 6–8 weeks) None beyond first 6–8 weeks No restrictions beyond first 6–8 weeks Cardiovascular risk assessment, counselling at 3- to 5-year intervals None recommended
III (1 small–medium coronary artery aneurysm/major coronary artery) Low-dose aspirin (3–5 mg/kg aspirin per day), at least until aneurysm regression documented
  • For patients <11 years old, no restriction beyond first 6–8 weeks;
  • For patients 11–20 years old, physical activity guided by biennial stress lest, evaluation of myocardial perfusion scan; contact or high-impact sports discouraged for patients taking antiplatelet agents
Annual cardiology folllow-up with echocardiogram + ECG. combined with cardiovascular risk assessment, counselling; biennial stress test/evaluation of myocardial perfusion scan Angiography, if noninvasive test suggests ischaemia
IV (≥1 large or giant coronary artery aneurysm, or multiple or complex aneurysms in same coronary artery, without obstruction) Long-term antiplatelet therapy and warfarin (target INR 20–25) or LMWH (target: antifactor Xa level 05–1.0 U/mL) should be combined in giant aneurysms Contact or high-impact sports should be avoided because of risk of bleeding; other physical activity recommendations guided by stress test/evaluation of myocardial perfusion scan outcome Biannual follow-up with echocardiogram + ECG; annual stress test/evaluation of myocardial perfusion scan First angiography at 6–12 months or sooner if clinically indicated: repeated angiography if noninvasive test, clinical, or laboratory findings suggest ischaemia: elective repeat angiography under some circumstances (see text)
V (coronary artery obstruction) Long-term low-dose aspirin: warfarin or LMWH if giant aneurysm persists: consider use of β-blockers to reduce myocardial oxygen consumption Contact or high-impact sports should be avoided because of risk of bleeding; other physical activity recommendations guided by stress test/myocardial perfusion scan outcome Biannual follow-up with echocardiogram + ECG; annual stress test/evaluation of myocardial perfusion scan Angiography recommended to address therapeutic options

LMWH, low-molecular-weight heparin.

From Newburger JW et al; Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease; Council on Cardiovascular Disease in the Young; American Heart Association; American Academy of Pediatrics (2004), 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. Circulation 110, 2747–71. Table 1 p2764.

Prevention

Given that the aetiology remains unknown, prevention strategies are not available.

Clinical and laboratory features

Clinical and laboratory features are consistent with a generalized inflammatory process and are largely nonspecific (Bullet list 1). The timely diagnosis therefore requires a high index of suspicion, but some features are more strongly suggestive of Kawasaki’s disease and the doctor should be alert to these. The desquamation following the acute illness generally follows a characteristic pattern, beginning first in the periungual regions. Hydrops of the gallbladder occurs in about 15% of patients, with Henoch–Schonlein purpura usually easily excluded as the only other common cause. Thrombocytosis may become profound after the first week.

In addition to vasculitis, particularly coronary arteritis, cardiovascular involvement may be evident as a pancarditis, with valvulitis, myocarditis, and pericarditis with effusion. Rarely, patients may develop cardiovascular collapse or ventricular arrhythmias in the acute stage. Coronary artery changes are often evident by echocardiography at the time of diagnosis and are virtually diagnostic of Kawasaki’s disease.

With the exception of arterial involvement, all abnormalities resolve without sequelae, although there have been rare reports of persistent sensorineural hearing loss.

Differential diagnosis

One of the challenges regarding the diagnosis of Kawasaki’s disease rests in its similarities to a number of other childhood illnesses that are much more common. Viral infections, e.g. adenovirus, enterovirus, Epstein–Barr virus, and measles, and bacterial infections, e.g. scarlet fever, can have many clinical similarities to Kawasaki’s disease. Toxin-mediated illness, e.g. staphylococcal scalded skin syndrome and toxic shock syndrome, also share similar clinical features. Although traditionally the presence of infection was presumed to exclude the diagnosis of Kawasaki’s disease, many patients do indeed have concomitant infection.

Drug hypersensitivity reactions and Stevens–Johnson syndrome may be difficult to differentiate from Kawasaki’s disease, given that many children are presumptively treated with antibiotics before the diagnosis of Kawasaki’s disease is made. Other rarer conditions to be considered include Rocky Mountain spotted fever, leptospirosis, juvenile rheumatoid arthritis, and acrodynia.

Patients—particularly those who are younger or older than typical—may not manifest all of the clinical criteria simultaneously, so continued observation and repeated consideration of the diagnosis is required.

Clinical investigation

There is no single ‘diagnostic test’ for Kawasaki’s disease. Laboratory assessment is used to detect associated abnormalities (see Table 1) and exclude similar illnesses, as well as to provide additional evidence to support the diagnosis, particularly for patients with insufficient clinical criteria.

Echocardiography to detect early coronary abnormalities may provide strong evidence to support the diagnosis, as well as to identify those who may be evolving severe disease. It should be performed at the time of diagnosis, after 2 weeks, and at 6 to 8 weeks for patients with uncomplicated disease, but more frequently if severe coronary artery complications are evident. Quantitative measurements of coronary artery diameters are best related to body surface area-specific normal values for the definition of abnormalities. Echocardiography optimally images the proximal segments of the coronary arteries, with distal segments less well assessed. However, it is very rare for patients to have distal involvement without evidence of proximal abnormalities. For selected patients with severe coronary artery abnormalities, additional imaging may be required to determine the presence and extent of more distal involvement or involvement in other systemic arteries, either with magnetic resonance angiography or conventional coronary arteriography.

Criteria for diagnosis

The diagnosis of Kawasaki’s disease rests on meeting the classic clinical criteria. However, for patients early in their presentation or for those who do not have sufficient criteria, additional surveillance and laboratory testing may provide supportive evidence and identify those who require treatment.

Treatment

In addition to supportive management, the mainstay of therapy is a single dose of 2 g/kg of intravenous gammaglobulin (IVIG), preferably given within the first 10 days from the onset of fever, ideally within 7 days. Timely treatment with IVIG reduces the risk of coronary artery complications to less than 4%. Patients presenting after 10 days should be given IVIG if they have persistent fever, evidence of ongoing inflammation, or evolving aneurysms. Patients are also usually given high-dose (anti-inflammatory) aspirin, at least until they are afebrile, and then low-dose (anti-platelet) aspirin for a period of 6 to 8 weeks.

Patients with persistent or recurrent fever after being given IVIG may benefit from an additional dose or treatment with pulse corticosteroids. Longer-term systemic anticoagulation is usually indicated for patients with multiple or large coronary artery aneurysms. Fibrinolytic agents may be necessary for patients who develop acute thromboses. Patients who develop coronary artery stenoses or occlusions may require catheter-based interventions or surgical revascularization. Rarely, cardiac transplantation has been performed for those with ischaemic cardiomyopathy or ventricular arrhythmias.

Prognosis and long-term management

Several studies have defined risk factors that identify patients at higher risk of developing coronary artery abnormalities. These may include male gender, age less than 1 year (more so if less than 6 months), higher C-reactive protein level, higher white blood cell or neutrophil count, thrombocytopenia, anaemia, low serum albumin level, and treatment delays or persistent or recurrent fever. However, the great majority of patients who have had Kawasaki’s disease will have no or minimal coronary artery involvement, and are felt to have an excellent long-term prognosis. Screening and counselling about risk factors for atherosclerotic cardiovascular disease have been recommended, given the uncertainties concerning the ultra-long-term prognosis. In general, coronary artery involvement may show important regression over time, with a lesser degree of maximal abnormality predicting the earliest and more complete resolution. Persistent abnormalities and risk of stenoses tend to be isolated to those patients with multiple or large aneurysms. For patients who have had important coronary artery complications, long-term surveillance, management, and prognosis are dependent on the ongoing risk of thrombosis and stenoses (Table 1). Rarely, previously healthy adult patients may present with myocardial ischaemia and a new diagnosis of coronary artery aneurysms, which may suggest a prior episode of undiagnosed Kawasaki disease during childhood.

Likely future developments

It is to be hoped that aetiological and pathophysiological mechanisms will be discovered, enabling preventive strategies, and also the development of alternative or additional therapies for preventing coronary artery abnormalities. Studies may also provide information relating to areas where prognosis or best treatment remains uncertain, e.g. the ultra-long-term prognosis for patients with no or minor coronary artery involvement, the best management of patients with persistent or recurrent fever, and the optimal anticoagulation regimen for patients with persistent coronary artery involvement.

Further reading

 
 
McCrindle BW, ed. (2004). Advances in Kawasaki disease. Progr Pediatr Cardiol, 19, 91–206.
 
Newburger JW, et al. (1991). A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome. N Engl J Med, 324, 1633–9. 
 
Newburger JW, et al. (2004). 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. Circulation, 110, 2747–71.
 
Parisi Q, et al. (2004). Clinical manifestations of coronary aneurysms in the adult as possible sequelae of Kawasaki disease during infancy. Acta Cardiol, 59, 5–9.