Kawasaki Disease

Context

• Kawasaki disease is generally considered a rare disease however it is becoming increasingly common with 1,000 hospital admissions per year in the UK, making it more common than measles and bacterial meningitis.
• Kawasaki disease can be difficult to recognise, because the symptoms overlap with many other more common childhood illnesses.
• Urgent recognition and prompt treatment is required. Delay can lead to permanent heart damage and death.
• Kawasaki disease is the leading cause of acquired heart disease in children in the UK, which may be preventable.
• Kawasaki disease has gained increasing attention since the Covid-19 pandemic, with unhelpful terms such as “Kawasaki-like” causing confusion amongst parents and health professionals alike.

Definition

Kawasaki disease is a systemic inflammatory disease that causes vasculitis of medium and small vessels.

It predominately affects children under 5 years of age, however approximately 20% of cases are reported in older children¹. Peak incidence is in late infancy (9–11 months), with a gradual decrease in incidence with advancing age.  Despite being described by Dr Kawasaki over 50 years ago², this condition is still poorly understood and difficult to recognise.

Learning Bite

If you look to exclude Kawasaki disease, you are less likely to miss it.

The pathogenesis of Kawasaki disease is poorly understood.  The leading theory is that an unknown stimulus triggers an immune-mediated inflammatory cascade in a genetically susceptible child causing damage to the small and medium sized vessels – the most clinically significant of which are the coronary vessels^3-5.

The coronary artery is composed of three layers:

 

1. Tunica intima – single layer of endothelial cells.
2. Tunica media – thicker layer of smooth muscle cells.
3. Tunica adventitia – surrounding layer of loose connective tissue.

In Kawasaki disease, neutrophilic infiltration occurs in the first two weeks causing destruction of the intima, media and adventitia. This leads to aneurysm formation and necrotising arteritis; a common histopathological finding observed in vasculitic disease processes (Figure 1).  Pro-inflammatory mediators also promote thrombosis formation and stenosis of arteries (Figure 2).

 

Figure 1. Inflammatory mediators cause inflammation and destruction of the coronary arteries⁶

 

Figure 2. Epicardial coronary artery (right) and epicardial vein (left) from a 19-month-old child who died 10 months after Kawasaki disease onset. The epicardial vein contains blood and shows mild thickening of the wall, while the coronary artery shows almost complete occlusion by luminal myofibroblastic proliferation with a fine slit-like lumen³.

Genetics

A genetic culprit has not been identified in Kawasaki disease, although the evidence suggests a contributing genetic component is highly likely.  Kawasaki disease does not appear to follow Mendelian inheritance but familial aggregation is well recognised¹.

 

• There is significant geographical variability with the highest case numbers reported in Japan and South Korea (Table 1).
• Relative risk is 10 times higher if an older sibling has been affected.
• Concordance risk in identical twins is approximately 13%.
• There is increased incidence in children who have a positive family history.

Table 1. Incidence of Kawasaki disease in various countries¹

Country	Incidence (Per 100,000)
Japan	308
South Korea	194.7-217.2
USA	19.1
Australia	9.34
Germany	7.2
United Kingdom	4.55

Interestingly, several single-nucleotide polymorphisms in different genes implicated in Kawasaki disease are also associated with other inflammatory conditions (such as rheumatoid arthritis, ulcerative colitis and systemic lupus erythematosus) which may indicate a common pathway in the inflammatory immune response⁵.

Infection

No specific infection has been linked to Kawasaki disease, despite a variety of bacterial, fungal and viral pathogens having been investigated. There are a few soft signs that indicate an infectious aetiology is possible^3,5.

 

• Consistent peak in the number of cases reported in winter months, when childhood infections are at their most prevalent
• Temporal clusters of epidemics reported in Japan, North America and other countries
• Significant overlap of clinical features between Kawasaki disease and other infectious pathologies

There is no evidence that vaccine administration during childhood triggers Kawasaki disease^7-10.

Learning Bite

28% of affected children will develop heart damage and 19% will have lasting coronary artery aneurysms.

Fever

The strongest defining symptom of Kawasaki disease is a persistent fever >38°C for five days.  Without appropriate treatment, fever usually continues for 1 to 3 weeks.

Spontaneous resolution of fever after seven days should not be used to exclude Kawasaki disease.

Eyes

Bilateral non-exudative conjunctival injection usually begins shortly after fever onset and often spares the limbus, an avascular zone around the iris.

 

Exudative conjunctivitis is not consistent with Kawasaki disease and should prompt a search for an alternative diagnosis.

 

Oral Changes

Changes of the lips and oral cavity include:

 

1. Erythema, dryness, fissuring, peeling, cracking, and bleeding of the lips
2. A “strawberry tongue,” with erythema and prominent fungiform papillae
3. Diffuse erythema of the oropharyngeal mucosa.

 

 

 

Oral ulcers and pharyngeal exudates are not consistent with Kawasaki disease and should prompt the consideration of an alternative diagnosis.

Swollen Glands

Cervical lymphadenopathy is the least common of the principal clinical features.  Lymph node swelling is usually unilateral, ≥1.5 cm in diameter, and confined to the anterior cervical triangle.

 

 

Rash

A diffuse maculopapular erythematous rash, primarily involving the trunk and extremities, usually appears within five days of fever onset. Accentuation in the groin with early desquamation is a characteristic feature.

 

 

 

Bullous, vesicular, and petechial rashes are not consistent with Kawasaki disease and should prompt a search for an alternative diagnosis.

Extremities

Erythema, and sometimes painful brawny oedema of the palms and soles, often occurs in the acute phase.  Desquamation of the fingers and toes usually begins in the periungual region between 10-21 days after the onset of fever and may extend to involve the palms and soles.

 

 

 

The absence of skin peeling does not exclude Kawasaki disease.

Kawasaki disease is a clinical diagnosis. It is important to realise that the principle clinical features can appear and disappear by the time of assessment. A careful history may reveal that principal clinical features were present during the early phase of the illness but have resolved by the time of presentation. It is also important to note that the characteristic features of Kawasaki disease are less common in children under 1 year.

The 2013 NICE guideline “Fever in under 5’s” recommended Kawasaki disease be considered when a child has a fever lasting five days or more, and 4 of the 5 principal features of Kawasaki disease specified by the American Heart Association diagnostic criteria³.

Strict adherence to these criteria identified less than half of the patients with Kawasaki disease, which lead to new recommendations on Kawasaki disease in the updated 2019 NICE guideline. NG143 promotes the recognition of “incomplete” Kawasaki Disease i.e. persistent fever associated with fewer than 4 of the 5 principal clinical features.

The emergency department clinician must consider Kawasaki disease in all children with a persistent fever for five days or longer, and actively inquire about the presence of the other principal clinical features which may increase the diagnostic likelihood of Kawasaki disease.

Learning Bite

Clinical features may have disappeared by the time of assessment.

In the Emergency Department

Kawasaki disease is a clinical diagnosis but as many children have “incomplete” Kawasaki disease, some investigations, although nonspecific, are useful in supporting a diagnosis.

Investigation	Result	Comment
FBC	WCC >15 Hb Mild to moderate anaemia Platelets >450 (peaks at 3rd week)	Kawasaki disease is an inflammatory process with elevation of WCC, CRP and ESR. The absence of significant inflammation makes the diagnosis of Kawasaki disease unlikely.
CRP	Raised
ESR	>40
LFTs	Albumin <30 ALT Elevated Bilirubin Raised in 10%	Hepatitis can develop with 40% of patients having raised aminotransferases
Urinalysis	Sterile pyuria	Abnormal urinalysis should prompt culture of sample to exclude UTI
Chest X-ray	Cardiomegaly or evidence of heart failure
ECG	Conduction abnormalities, myocardial ischaemia

Future Investigations

The most important complication of Kawasaki disease is the development of coronary artery abnormalities. Echocardiography is the investigation of choice to evaluate for aneurysms, myocarditis, valvulitis, thrombus or pericardial effusion. Coronary artery dilation can be observed in up to 50% of untreated patients by the tenth day of illness. Echocardiography can also be useful in diagnosing atypical cases but a normal echo does not exclude Kawasaki disease.

Treatment should not be delayed whilst awaiting imaging, as early intervention gives better outcomes.

Early recognition and treatment of Kawasaki disease with aspirin and intravenous immunoglobulin (IVIG) has been shown in meta-analyses to unequivocally reduce the occurrence of coronary artery aneurysms.

IVIG

IVIG is most effective at reducing coronary artery aneurysms when administered within ten days of the onset of fever. The current recommendation is for a single dose of IVIG at 2g/kg over 12 hours.  A single dose vs split dosing has been investigated; a meta-analysis concluded that a single dose has the greatest therapeutic effect in the prevention of coronary artery aneurysms^3,15.

Aspirin

Aspirin reduces the chance of blood clot formation. Aspirin at a dose of 30–50 mg/kg/day in four divided doses is recommended during the acute phase of the illness.  The dose should be reduced to 3–5 mg/kg for 6-8 weeks once fever and inflammation have subsided.  Higher initial doses have been trialled, however, these doses were less well tolerated and did not reduce the incidence of coronary artery aneurysm^3,15.

It is considered the benefits of aspirin in the management of Kawasaki disease outweigh the risks of Reye’s syndrome, which usually contraindicates the use of aspirin in children.

Learning Bite

Delayed treatment is related to poorer outcomes.

• Kawasaki disease is generally considered a rare disease however it is increasingly common with more hospital admissions than measles or bacterial meningitis.
• A high index of suspicion is warranted in all children with prolonged fever.
• The clinical principal features may have appeared and disappeared at the time of assessment.
• A concurrent infection does not exclude Kawasaki disease.  Respiratory viruses such as respiratory syncytial virus, metapneumovirus, coronaviruses, parainfluenza viruses, or influenza viruses have been shown to co-exist with Kawasaki disease
• Desquamation of the fingers and toes is a late sign and its absence does not exclude the diagnosis.
• Normal echocardiography does not exclude Kawasaki disease.
• Delayed treatment due to delayed diagnosis increases the risk of cardiac complications.

Paediatric multisystem inflammatory syndrome temporally associated with Covid-19 (PIMS-TS) is often described as being similar to Kawasaki disease as both are systemic inflammatory conditions and both can present with prolonged fever and mucocutaneous signs. However Kawasaki disease is a distinct entity, particularly in relation to presentation, treatment and frequency of coronary artery complications.

Table 2. A comparison of Kawasaki disease and PIMS-TS

	Kawasaki disease	PIMS-TS
Respiratory symptoms/cough	Rare	Common
GI Disturbance	Uncommon	Common
Clotting abnormalities	Not usually seen	PE possible
Shock Heart failure	Not usually seen	Present
Age	<5	Older children
Coronary aneurysms	Common	Rare

 

Learning Bite

Kawasaki disease is a distinct entity from PIMS-TS.

1. Kim GB. Reality of Kawasaki disease epidemiology. Korean J Pediatr. 2019 Aug;62(8):292-296.
2. Kawasaki T. [Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children]. Arerugi. 1967;16(3):178-222.
3. McCrindle BW, Rowley AH, Newburger JW, Burns JC, et al. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association. Circulation. 2017;135(17):e927-e99.
4. Modesti A, Plewa M. Kawasaki Disease StatPearls [Internet]: Treasure Island (FL); 2021 [Image courtesy S Bhimji MD].
5. Rife E, Gedalia A. Kawasaki Disease: an Update. Curr Rheumatol Rep. 2020;22(10):75.
6. Noval Rivas M, Arditi M. Kawasaki disease: pathophysiology and insights from mouse models. Nat Rev Rheumatol. 2020;16(7):391-405.
7. Abrams JY, Weintraub ES, Baggs JM, McCarthy NL, et al. Childhood vaccines and Kawasaki disease, Vaccine Safety Datalink, 1996-2006. Vaccine. 2015;33(2):382-7.
8. Baker MA, Baer B, Kulldorff M, Zichittella L, et al. Kawasaki disease and 13-valent pneumococcal conjugate vaccination among young children: A self-controlled risk interval and cohort study with null results. PLoS Med. 2019;16(7):e1002844.
9. Hall GC, Tulloh RM, Tulloh LE. The incidence of Kawasaki disease after vaccination within the UK pre-school National Immunisation Programme: an observational THIN database study. Pharmacoepidemiol Drug Saf. 2016;25(11):1331-6.
10. Yung CF, Ma X, Cheung YB, Oh BK, Soh S, Thoon KC. Kawasaki Disease following administration of 13-valent pneumococcal conjugate vaccine in young children. Sci Rep. 2019;9(1):14705.
11. Trager JD. Images in clinical medicine. Kawasaki’s disease. N Engl J Med. 1995;333(21):1391.
12. Association AH. Kawasaki Disease: Signs, Symptoms and Diagnosis.2020 [Photos courtesy of Kawasaki Disease Foundation].
13. Cadogan M, Laud R. Kawasaki disease. Life In The Fast Lane. 2020
14. Eleftheriou D, Levin M, Shingadia D, et al. Management of Kawasaki disease. Arch Dis Child. 2014;99(1):74-83.

Additional Resources

• Kawasaki Disease Foundation
• Societi – The UK Kawasaki Disease Foundation