Epidemiology

The highest annual incidence is thought to occur in Japan at ~120-180 cases per 100,000 children aged under 5 years. The incidence appears to be rising year on year in Japan.^[4]

In Europe, recent surveys have demonstrated a peak annual incidence among children of Asian descent of 90 cases per 100,000 children aged under 5 years.^[5]

Analysis of hospital statistics in England has shown an incidence of 8 per 100,000 of children aged under 5 years. The higher incidence in North East Asians persists after migration to countries with low incidence.^[6]

The incidence does appear to be variable, with local epidemic outbreaks occurring in winter and spring on a three-year cycle, suggesting an infective aetiology.^[1]

In the USA, the approximate annual race-specific incidence per 100,000 children younger than 5 years ranges from 9.1 for children of white descent to 32.5 for children of Asian and Pacific island descent.^[7] The Caucasian incidence is thought to be roughly about a tenth of the Pacific Asian incidence, overall.

Risk factors

• It is much more common in Asian populations (see above).
• It is more common in boys, with a M:F ratio of 1.5:1.^[8]
• In the USA/Europe, peak incidence is in children aged 18-24 months.
• Japanese peak incidence is 6-12 months.
• 80% of cases occur in children aged <5 years.
• The condition occurs only rarely in children aged <6 months or >5 years (although cases have, rarely, been observed in adolescents and adults).

Aetiology and pathophysiology

These remain a mystery, although a combination of an infective trigger and genetic susceptibility seems likely (research is focusing on the role of the expression of HLA-Bw22J2 antigen, a component of the major histocompatibility complex, found predominantly in Japanese populations).^[7] The condition is caused by an autoimmune-mediated systemic vasculitis that affects small- and medium-sized arteries.

Presentation

Consider the diagnosis of Kawasaki disease in a child who is irritable with a persistent fever. The classic clinical features of Kawasaki disease may not all be present. The rash may mimic common infections (eg, measles, rubella, parvovirus and scarlet fever) and may also resemble erythema multiforme.^[6] 

Symptoms

The usual presenting feature is a fever of abrupt onset. The child tends to be very irritable and unwell when febrile, often out of proportion to the severity of the fever. Most consider that the fever must have been present for at least five days for Kawasaki disease to be diagnosed; however, experienced clinicians may make the diagnosis earlier in its course, if there are other classical features. As well as fever, there must be at least four of the following to fit the diagnostic criteria (or echocardiographic evidence of coronary artery aneurysms):

• Inflammation and irritation of the lips, mouth and/or tongue.
• Erythema, oedema and/or desquamation of the extremities.
• Bilateral dry conjunctivitis.
• Widespread non-vesicular rash.
• Cervical lymphadenopathy >1.5 cm in size.

Other possible features include lethargy, symptoms of urethritis, diarrhoea, vomiting, abdominal pain, myalgia, arthralgia and arthritis. A Chinese survey found that there appears to be an appreciable incidence of atypical or 'incomplete' Kawasaki disease and that such cases appear to have a high prevalence of coronary artery lesions. The presence of perianal desquamation may be a useful indicator of the likelihood of such 'incomplete' cases.^[9]

Signs

• The lips typically become erythematous or fissured, along with inflamed oral mucosa and the presence of a 'strawberry tongue' - so-called because it is extremely erythematous with prominent papillae.
• The rash is described as a polymorphic exanthem and comes on within 3-5 days of the onset of fever. It usually begins with nonspecific erythema of the soles, palms, and perineum, spreading to involve the trunk and the rest of the extremities. It is often itchy and variable in appearance, but is never vesiculo-bullous. It is usually markedly red and may appear macular, morbilliform, papular, scarlatiniform, urticarial, akin to erythema multiforme or be made up of very many tiny micropustules.
• Desquamation may affect the perineal area, moving to the fingers and then the toes. In the extremities, it usually begins in the periungual region.
• The hands and feet often become red and swollen and tender before desquamation begins.
• The conjunctivitis is never associated with exudate, is bilateral and tends to spare the perilimbal area.
• Cervical lymphadenopathy is usually unilateral, non-tender and affects the anterior cervical chain.
• Cardiovascular signs are usually nonspecific. Tachycardia, a hyperdynamic precordium, a gallop rhythm or a flow murmur may be present; however, these signs are not unusual in febrile patients without Kawasaki disease. There are occasionally signs of valvular incompetence.
• Other possible signs include:
  • Neck stiffness due to aseptic meningitis.
  • Hepatomegaly and jaundice.

Phases of the illness

The disease typically follows three phases, as outlined in the table below:

Subsidiary features of the disease

• Cardiovascular - pancarditis, aortic or mitral incompetence.
• Gastrointestinal - hydrops of gallbladder, jaundice, diarrhoea.
• Blood - mild anaemia.
• Renal - sterile pyuria, mild proteinuria.
• CNS - aseptic meningitis.
• Musculoskeletal - arthritis, arthralgia.
• Others - anterior uveitis, BCG-site inflammation.^[10]

Differential diagnosis

• Measles.
• Rubella.
• Infectious mononucleosis.
• Enteroviruses.
• Parvovirus B19 infection.
• Any bacterial infection - especially staphylococcal and streptococcal infections causing staphylococcal scalded skin syndrome, toxic shock syndrome and scarlet fever.
• Toxic epidermal necrolysis.
• Other drug reactions, particularly erythema multiforme and Stevens-Johnson syndrome.
• Meningitis or encephalitis.
• Tick-borne disease such as Rocky Mountain spotted fever and relapsing fever.
• Mercury toxicity (acrodynia).
• Toxoplasmosis.

Investigations

• There is no diagnostic test for the condition.
• Urinalysis may show sterile pyuria ± proteinuria.
• FBC during the acute phase may show a mild normochromic, normocytic anaemia and variable elevation in the white cell count with a left shift.
• Platelets are elevated and there may be a marked thrombocythaemia that develops throughout the second and third weeks of the illness.
• Acute-phase reactant markers such as ESR and CRP are often elevated.
• LFTs may show elevation of the transaminases and bilirubin.
• Abdominal ultrasound can show evidence of gallbladder distension.
• ECG may show a range of conduction abnormalities due to carditis.
• Echocardiography can reveal dilatation and aneurysms of the coronary arteries, as well as allowing assessment of the pericardium and left ventricular/valvular function; serial echocardiography is often needed to detect occult coronary artery disease as the illness evolves.
• CT angiography has been used successfully to demonstrate coronary artery aneurysms and is less invasive than coronary angiography.^[11]
• Coronary angiography may be carried out in difficult-to-diagnose or extreme cases.

Management

• Children suffering from the condition are usually cared for as inpatients on paediatric or paediatric-cardiology units and put on bed rest, due to the risk of myocardial events.
• The mainstays of management are the use of aspirin and intravenous immunoglobulin (IVIg) to reduce fever, and myocardial inflammation and to prevent or ameliorate cardiac sequelae (the main cause of morbidity and mortality associated with the condition).
• Follow-up echocardiography is useful in determining whether or not there have been any coronary artery complications.
• Percutaneous coronary intervention and coronary artery bypass grafting are usually avoided, particularly in the very young, as they are associated with relatively poor outcomes in the long term, in terms of maintenance of coronary artery perfusion; results in children aged >12 years are more encouraging.^[12]

Aspirin

However, in Kawasaki disease, the antiplatelet and antipyretic effect of the drug provides the rationale for its use. The drug is used widely in a variety of high-dose and low-dose regimens, both in the acute and subsequent phases, and as long-term prophylaxis against coronary events in those who have coronary artery aneurysms. There is a scant evidence base to support its use and little useful research to decide on the optimal regimen. The use of aspirin in Kawasaki disease does seem to be gaining favour.^[13] Aspirin is firstly used in high dose for its anti-inflammatory properties and then in low dose for its anti-thrombotic effects.^[3]

One study has suggested that its use in the acute phase had no effect on preventing the failure of IVIg therapy, the formation of coronary artery aneurysms or in shortening the duration of fever.^[14] A Cochrane review concludes that until good-quality randomised controlled trials are carried out, there is insufficient evidence to indicate whether children with Kawasaki disease should continue to receive aspirin as part of their treatment regimen.^[15]

IVIg

IVIg has been shown to reduce the incidence of coronary artery aneurysms from about 25% in the untreated to about 1-10% in treated patients in some series.^[7][8] However, recent re-evaluations indicate that, although it remains an effective therapy, its potency may have been overstated, and that the timing of the infusion is critical in determining its efficacy.^[16] There is no firm consensus on the optimal treatment regimen with some advocating high-dose therapy, and others suggesting that low-dose 1 g/kg regimens given as a single dose are just as effective. A recent randomised trial supports the view that a low-dose IVIg regimen has equal efficacy to a high-dose regimen in preventing coronary artery aneurysms.^[17]

Adjunctive therapy in refractory cases

The following agents have all been used in refractory cases:

• Pentoxifylline.
• Corticosteroids (avoided routinely as thought to increase complication rate).
• Ulinastatin (human trypsin inhibitor derived from urine).
• Abciximab (platelet glycoprotein IIb/IIIa receptor inhibitor).
• Infliximab (monoclonal antibody acting as tumour necrosis factor-alpha antagonist).^[13][18][19]
• Low-dose methotrexate (further trials called for).^[20][21]
• On occasion, clopidogrel, dipyridamole and low-molecular weight heparins and/or warfarin are used to treat children who develop large coronary artery aneurysms as prophylaxis against coronary events.

Complications

• Sudden cardiac death.
• Myocardial infarction.
• Coronary artery aneurysms leading to stenosis/thrombosis and subsequent ischaemic heart disease.
• Coronary artery aneurysm rupture.
• Pericarditis.
• Cardiac valvular disease.
• Cardiac dysrhythmia.
• Cardiac failure.
• Acute arthritis.
• Dehydration in the acute phase of the illness.
• Recurrence of the condition (estimated to affect 1-3%).

Prognosis

• Although the majority of patients do well and do not suffer major complications, around 50% show echocardiographic evidence of cardiac impairment and mild mitral regurgitation.
• Approximately 25% of untreated patients will suffer coronary artery aneurysms, but this figure is much lower if early diagnosis and therapy are achieved (~1-10%).
• The vast majority of coronary artery aneurysms regress after a period of ~2 years.
• Coronary artery aneurysms are more likely in males aged under 1 year, older than 8 years, or in those who suffer prolonged fever of >14 days' duration.
• Mortality varies between populations and treating centres but is in the range 0.08-3.7%.^[7]
• Follow-up in later life is recommended.^[2]