Kawasaki disease

From Ganfyd

An acute febrile illness associated with multiorgan small/medium vessel vasculitis of unknown aetiology that primarily affects infants and children under 6. The most distinctive feature is coronary aneurysms. Diagnosis is based on a cluster of features rather than a specific test, hence atypical presentations common.

In 1967 Tomisaku Kawasaki described an illness characterised by rash, cervical lymphadenopathy, fever, stomatitis and conjunctival congestion. He called it mucocutaneous lymph node syndrome^[1].

In this condition there is a vasculitis affecting capillaries, arterioles and medium sized arteries. There is inflammation of the vascular media with necrosis of the internal and external elastic laminae, as well as damage to smooth muscle fibres. Subsequently the vascular intima thickens and there is stenosis and aneurysm formation, with the risk of thrombosis and infarction. This process typically affects the coronary arteries, and Kawasaki disease is now the leading cause of acquired childhood heart disease. However there is increasing evidence that other medium sized arteries are affected beside the coronaries, with descriptions in the literature of peripheral gangrene and cerebral infarction.

The disease is more common in males, with a male:female ratio of 1.5:1 and a peak age of onset of 18-24 months. It is more common in Japanese children: 95 cases per 100,000 under 5 years of age, cf 10 cases per 100,000 in non-Asian children under 5 years. There is evidence of it being a superantigen mediated disease, indeed coronary aneurysms have been described in other superantigen diseases eg toxic shock syndrome. However, no specific superantigen or infective agent has been identified and it would appear to be an idiosyncratic reaction.

Tumour necrosis factor alpha appears to be important in the pathophysiology - in a mouse model, use of TNF alpha antagonists or knock out mice prevents aneurysm development^[2]. As well, in man adiponectin levels are low in the acute phase and IL-6 raised. ^[3]

Presentation

The typical presentation is with:

• Prolonged fever
• Non-purulent conjunctivitis
• Mucosal changes eg a strawberry tongue.

The child has often been treated empirically with antibiotics without improvement, and is invariably miserable. The established case definition is:

• Fever of 5 days duration or more

• plus 4 of the following:

1. Conjunctivitis: Bilateral, bulbar, non-suppurative
2. Lymphadenopathy: Cervical, >1.5 cm
3. Rash: Polymorphous, no vesicles or crusts
4. Changes of lips or oral mucosa: Red cracked lips; "strawberry" tongue; or diffuse erythema of oropharynx
5. Changes of extremities:
   1. Initial stage, erythema and oedema of palms and soles
   2. Convalescent stage (about two weeks) periungual desquamation of fingers and toes

Kawasaki disease may be diagnosed with fever and only 3 of these features if coronary artery aneurysms are detected. Lymphadenopathy is the least common feature.

It can of course present at any age.

There may be co-existing abdominal pain, diarrhoea, arthralgia and arthritis, and headache. Aseptic meningitis, pneumonitis (with or without pulmonary nodules) have also been described. There may be a murmur of mitral incompetence and cardiac failure may occur due to myocarditis. Induration of the BCG scar, if present, is characteristic. Interestingly, many of these clinical features are outbreak dependent with a different spectrum of clinical findings in one outbreak compared with another, and with cases having similar clinical phenotypes clustering temporally.

Atypical/Incomplete disease

The term atypical or incomplete Kawasaki disease is used for cases without the required number of features. Whether this is the same disease or not is unclear; there will undoubtedly be some cases that overlap with other systemic vasculitides eg polyarteritis nodosa (PAN). In PAN, mucocutaneous changes are uncommon, whereas renal disease is common. On the other hand, having a rigid case definition is perhaps unhelpful since incomplete cases are often seen, particularly in infants, and are associated with a delay in diagnosis and worse prognosis. Under the age of 3 months, the majority of cases with coronary aneurysms have atypical presentations. ^[4]It seems sensible to consider the diagnosis in any young child with a persistent fever, and early echocardiography may assist.

Differential diagnosis

• Scarlet fever
• Toxic shock syndrome
• Scalded skin syndrome
• Measles
• Drug reaction
• Systemic onset juvenile idiopathic arthritis
• Steven-Johnson syndrome

Investigations

These mainly help exclude alternative diagnoses. Typically with the disease itself they simply indicate systemic inflammation and can be useful for monitoring response to treatment. Hence there are usually elevated white cells, [platelet]s, ESR and CRP. Liver function tests are often mildly deranged. Low sodium and albumin suggest vascular leak. The ECG may have PR interval changes, and ST segment or T wave changes. Echocardiography may reveal dilated, ectatic coronary arteries or frank aneurysms.

Treatment

Treatment is with intravenous immunoglobulin (IVIG) 2gm/kg over 8-12 hours, ideally within the first 7-10 days of the illness, and with aspirin 80-100 mg/kg/day orally during the acute phase. This combination reduces the risk of aneurysm formation from 25% to 9%. A recent New England Journal of Medicine RCT showed no significant benefit from adding steroids (although fever settled slightly more quickly).^[5] Most will respond to a single dose, but about 20% will require a second dose. Of these, about half will then defervesce.

Once defervescence has occurred, the aspirin dose can be reduced to an anti-platelet dose of 3-5mg/kg/day.

Outcome

Duration of fever is the most powerful predictor of poor coronary outcome (one additional day of fever increasing the odds of aneurysm development by 3-5x). Outcome also relates to level of inflammation eg platelet count, high % neutrophils, high CRP (a rise in platelet count by 100/fL increasing the odds 8x). In Japan, the Harada score was developed - in addition to the clinical factors already described it includes male sex and age under 12 months. Age over 7yrs, abnormally low platelet count, failure to respond to IVIG, markers of vascular leak (eg low serum sodium, albumin) would also appear to be related to a worse outcome.

Most aneurysms will resolve over time, unless they are giant (>8mm). Serial echocardiography should be done to monitor resolution. Warfarin should be considered for giant aneurysms, although its potential for complications in young children is significant. Stress testing and angiography may be appropriate. Aspirin can be discontinued if aneurysms resolve, but it is likely that the atherosclerosis risk remains high and life long follow up to address other risk factors is sensible.

Mortality in the UK has been as high as 3.7%, but is much lower in Japan.

Refractory disease

In refractory cases where defervescence does not occur after 2 doses of IVIG, treatment becomes more complicated and evidence of effective strategies becomes more scarce.

Firstly, the diagnosis must be reviewed. Consider other forms of systemic vasculitis.

Pulsed methylprednisolone 30mg/kg (max 1g) once daily for 3 days is effective in achieving defervescence in at least 75% of patients, but historically has not prevented progression to aneurysms. A wide range of other immunosuppressant agents has been used including cyclophosphamide, ciclosporin, and methotrexate. Case reports and small case series have reported success with all of these agents. Plasmapheresis has also been used. As described above, there is a good theoretical basis for the use of a TNF alpha antagonist eg infliximab, and in a series from the US it was effective in 13 of 16 patients.^[6]

External links

Evidence based UK guideline by Brogan PA ^[7] American Heart Association statement by Newburger^[8]

References