Kawasaki Disease

Introduction

Kawasaki disease is an acute febrile vasculitis of childhood, first described by Tomisaku Kawasaki in 1967. It is self-limiting - the fever will eventually settle whatever you do - but the vasculitis can permanently damage the coronary arteries in the process, and that damage is largely preventable if treatment is given in time.

This is what makes it an important and frequently examined diagnosis. There is no diagnostic test, the individual features are all shared with commoner illnesses, and the therapeutic window closes at around 10 days. A child with 6 days of fever who has been treated for tonsillitis, then for a presumed viral exanthem, and is now on their third antibiotic, is the classic missed case.

Incidence in the UK is roughly 8-9 per 100,000 children under 5. In Japan it is more than thirty times higher, and children of Japanese and Korean ancestry living outside Asia retain an elevated risk - which points to genetic susceptibility rather than environmental exposure alone.¹

Aetiology and pathophysiology

The cause remains unknown. The epidemiology - seasonal peaks, geographical clustering, an age distribution that spares young infants with maternal antibody and older children who are presumably already immune - strongly suggests a widespread infectious trigger that causes disease only in genetically susceptible children. Polymorphisms in ITPKC, a negative regulator of T-cell activation, and in CASP3 are the best-established susceptibility loci. Kawasaki disease is not contagious, and siblings do not need isolating.

Pathologically the arteritis proceeds in three overlapping stages:

1. Necrotising arteritis in the first 2 weeks - neutrophilic destruction of the arterial wall from lumen outwards, which is what produces saccular aneurysms
2. Subacute and chronic vasculitis - a lymphocytic, plasma cell and eosinophilic infiltrate that may persist for months or years and produces fusiform aneurysms
3. Luminal myofibroblastic proliferation - progressive intimal thickening that can cause late stenosis and ischaemia even after an aneurysm appears to have regressed

Two consequences follow. First, aneurysms form during a defined window in the first fortnight, which is why treatment timing matters so much. Second, the arterial wall never truly returns to normal, so a child with significant coronary involvement needs lifelong cardiology follow-up even if the vessel calibre looks normal on later imaging.

Clinical features and diagnostic criteria

Diagnosis requires fever for 5 days or more, plus at least 4 of the 5 principal clinical features.^1,2 The fever is typically high, remittent, and conspicuously unresponsive to antipyretics and antibiotics.

Other features that support the diagnosis

• Extreme irritability - disproportionate, inconsolable and very characteristic; possibly related to an aseptic meningitis
• Erythema and induration at the site of a previous BCG scar - highly suggestive where present, and specific enough to be worth looking for deliberately
• Arthralgia or arthritis, typically of large joints
• Sterile pyuria from urethritis - a common source of confusion with urinary tract infection
• Gastrointestinal upset: vomiting, diarrhoea, abdominal pain, and occasionally hydrops of the gallbladder
• Anterior uveitis on slit lamp examination
• Cardiac involvement: myocarditis, pericardial effusion, tachycardia out of proportion to fever, and a gallop rhythm

The three phases

Differential diagnosis

Investigations

No test confirms or excludes Kawasaki disease. Investigations serve three purposes: to support the diagnosis in incomplete cases, to exclude mimics, and to assess the coronary arteries.

Blood and urine

• FBC - normocytic normochromic anaemia and neutrophilia in the acute phase; a marked thrombocytosis after day 7 is characteristic, with platelet counts often above 450 and sometimes above 1,000 x10^9/L
• CRP and ESR - markedly raised, and their absence should make you question the diagnosis
• LFTs - raised transaminases and a low albumin, which correlates with severity
• U&Es - hyponatraemia is common
• Urinalysis - sterile pyuria with no organisms on culture
• Troponin and BNP where myocarditis is suspected
• Exclusion tests: throat swab and ASO titre, blood cultures, and viral PCR for measles, adenovirus and EBV

Cardiac assessment

• Echocardiography at diagnosis, repeated at 1-2 weeks and again at 6-8 weeks. Coronary dimensions are reported as Z-scores corrected for body surface area, since absolute diameters are meaningless in a growing child.
• ECG - may show a prolonged PR interval, non-specific ST and T wave changes, or arrhythmia in myocarditis
• More frequent imaging, and cardiac CT or MR angiography, where aneurysms are identified or the child is unwell
• A normal early echocardiogram does not exclude the diagnosis or remove the need for treatment - aneurysms typically appear in the second or third week

Management

Intravenous immunoglobulin

IVIG 2 g/kg as a single infusion over 10-12 hours is the definitive treatment. Given within 10 days of the onset of fever - and ideally within 7 - it reduces the incidence of coronary artery aneurysms from around 25% to under 5%.^1,3

• Treat on clinical suspicion. Do not delay waiting for an echocardiogram or for further criteria to appear.
• IVIG is still given after day 10 if the child remains febrile or has persistently raised inflammatory markers or coronary abnormalities, though the benefit is smaller
• About 10-20% of children have IVIG-resistant disease, defined as persistent or recrudescent fever more than 36 hours after the infusion. These children are given a second dose of IVIG, usually with corticosteroids.
• Corticosteroids are added to first-line treatment in children assessed as high risk, and are used in refractory disease. Infliximab, ciclosporin and anakinra are third-line options managed in specialist centres.

Aspirin

• High dose (anti-inflammatory): 7.5-12.5 mg/kg four times daily, continued until the child has been afebrile for 48 hours⁵
• Low dose (antiplatelet): 2-5 mg/kg once daily thereafter, continued for 6-8 weeks and stopped if the 6-8 week echocardiogram is normal
• Indefinite low-dose aspirin if coronary abnormalities persist, with the addition of warfarin or low molecular weight heparin for giant aneurysms, where the thrombotic risk is high
• Kawasaki disease is one of the few situations in which aspirin is deliberately prescribed to a child under 16, accepting a small Reye's syndrome risk because the cardiac benefit is far greater

Supportive care and follow-up

• Admit for observation, fluids and analgesia; these children are miserable and often not drinking
• Daily clinical review for recrudescent fever in the 48 hours after IVIG
• Cardiology follow-up determined by the maximum coronary Z-score, ranging from discharge after a normal 6-8 week echocardiogram to lifelong surveillance with imaging and functional testing for those with giant aneurysms
• Long-term cardiovascular risk factor advice for children with persistent coronary abnormalities - no smoking, activity, lipid monitoring
• Advise parents that recurrence occurs in around 2-3% and that they should seek review early for any prolonged fever in the future

Complications

• Coronary artery aneurysms - the defining complication. Giant aneurysms, 8 mm or more in diameter or with a Z-score of 10 or above, carry the worst prognosis.
• Coronary thrombosis and myocardial infarction - the leading cause of death, occurring most often in the subacute phase or years later in a giant aneurysm. Infarction in a child may present only as pallor, vomiting, abdominal pain or shock rather than chest pain.
• Coronary stenosis from late myointimal proliferation, causing ischaemia in adolescence or adulthood
• Myocarditis, pericardial effusion and mitral regurgitation in the acute phase
• Arrhythmia and sudden cardiac death
• Kawasaki disease shock syndrome - hypotension with myocardial dysfunction and capillary leak, more often IVIG-resistant
• Macrophage activation syndrome - suspect if the child deteriorates with falling platelets, falling ESR, very high ferritin and hypofibrinogenaemia
• Peripheral arterial aneurysms - axillary, iliac or renal, which is why a systemic vasculitis rather than a cardiac disease is the right way to think about it

Red flags

Prognosis

With timely IVIG, mortality in the UK is well under 0.5%, and the great majority of children make a complete recovery with no cardiac sequelae. Around half to two-thirds of small and medium aneurysms regress angiographically within 1-2 years, though the vessel wall remains abnormal histologically.

Giant aneurysms behave differently. They rarely regress, they thrombose, and they require lifelong anticoagulation, surveillance and sometimes coronary intervention or bypass grafting in adolescence or adult life. Whether children who had Kawasaki disease without aneurysms carry any excess long-term cardiovascular risk remains an open question, and current guidance is to manage conventional risk factors attentively.¹

The single determinant of outcome that a clinician controls is time to treatment. That is why the practical message of this topic is not really about vasculitis at all: it is that a young child with fever lasting 5 days or more and no explanation should have Kawasaki disease actively considered and inflammatory markers checked, rather than another course of antibiotics.