Kawasaki Disease

Original article by Ammar Ahmed | Last updated on 27/5/2014
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Introduction

Kawasaki’s Disease (KD) is an acute febrile vasculitic syndrome of early childhood. The disorder has also been called mucocutaneous lymph node syndrome and infantile periarteritis nodosa.

The illness was initially thought to be benign and self-limiting. However, subsequent reports indicated that nearly 2% of patients with KD later died from the illness. Fatalities occurred among children younger than 2 years. These children died while they were improving or after they had seemingly recovered. Post-mortem examinations revealed complete thrombotic occlusion of coronary artery aneurysms (CAAs), with myocardial infarction (MI) as immediate cause of death. Electrocardiogram (ECG) studies show that 20-25% of the untreated children develop cardiovascular sequelae ranging from asymptomatic coronary artery ectasis or aneurysm formation to giant CAAs with thrombosis, MI and sudden death.

 

Pathophysiology

KD is best defined as a generalized vasculitis that involves small to medium sized arteries, despite there being prominent mucocutaneous clinical findings that define the illness. The vascular inflammation is most pronounced in the coronary vessels.
In the earliest stages of the disease, the endothelial cells and the vascular media become oedematous, but the internal elastic lamina remains intact. Then approximately 7-9 days after the onset of fever, an influc of neutrophils occurs, which is quickly followed by a proliferation of CD8+ (cytotoxic) lymphocytes and Ig-A producing plasma cells.
The inflammatory cells secrete various cytokines (i.e. TNF, VEGF, Monocyte Chemotactic and Activating Factor), interleukins (i.e. IL1, 4, and 6) and matrix metalloproteinases (MMP3 and MMP9) that target the endothelial cells and result in a cascade of events that eventuates in fragmentation of the internal elastic lamina and vascular damage. In severly-affected vessels, the media develops inflammation with necrosis of smooth muscle cells. The internal and external elastic laminae can split, leading to aneurysms.
In the forth-coming weeks to months, the active inflammatory cells are replaced by fibroblasts and monocytes and fibrous tissue begins to form with in the vessel wall. The intima wall thickens and proliferates eventually becoming occluded or narrowed owing to stenosis or thrombus. Cardiovascular death may occur from a MI secondary to thrombosis of a coronary aneurysm or from rupture of a large coronary aneurysm.
Most of the pathology of the disease is induced by a medium vessel arterial vasculitis. Initially, neutrophils are present in great numbers, but the infiltrate rapidly changes to mononuclear cells, T cells, and Ig-A producing plasma cells. Inflammation involves all 3 layers of vessels. Eosinophils are preferentially accumulated in microvessels.
The period during the greatest vascular damage is when concomitant progressive increases in the serum platelets count occurs, and this is the point of the illness when the risk of death is most significant.

 

Aetiology

  • Most likely the disease is due to an infection caused by ubiquitous RNA virus that causes asymptomatic infection in most individuals but in genetically predisposed individuals it causes KD.
  • Genetic predisposition is greatly observed, especially if the disease affects siblings, parents, and 1st degree relatives.

 

Epidemiology

  • Rate of incidence in the Japanese population 120-180/100 000
  • Rate of incidence in England 8/100 000

 

Presentation

Most children are brought to medical attention because of prolonged fever (of usually an abrupt origin and unaffected by medication). Non-specific symptoms commonly precede the onset of fever by several days, such as:

  • Irritability
  • Vomiting
  • Decreased oral intake
  • Cough
  • Diarrhea
  • Rhinorrhea
  • Weakness
  • Abdominal pain
  • Joint pain

KD can be divided into 4 stages:

  1. Acute febrile stage – The acute stage begins with an abrupt onset of fever and lasts approximately 7-14 days. The fever is often high spiking and remittent, with peak temperatures ranging from 39-40°C (102-104F) or higher. The fever is unresponsive to antibiotics or antipyretics and can persist for up to 3-4 weeks if untreated. Common accompanying signs include irritability, non-exudative bilateral conjunctivitis (90%), anterior uveitis (70%), perianal erythema (70%), erythema on hands and feet, strawberry tongue, lip fissures and lymphadenopathy (75%).
  2. Sub-acute stage: The sub-acute stage begins when the fevers have abated, and continues until 4-6 weeks. The hallmarks of this stage are desquamation of the digits, thrombocytosis (>1million/μL), and development of CAAs. The risk of sudden death is highest at this stage.
  3. Convalescent phase: The convalescent phase is marked by complete resolution of clinical signs of the illness, usually within 3 months of presentation. This stage begins with the return to baseline of the acute phase reactants (e.g. ESR, CRP) and other laboratory abnormalities. Beau lines may become apparent in this phase. Small CAAs tend to resolve on their own, but larger ones may expand and MI may occur.
  4. Chronic Stage: this stage is of clinical importance only in patients who have developed cardiac complications and requires lifetime surveillance.

Diagnostic Criteria

Diagnostic criteria established by American Heart Association (AHA) are fever lasting longer than 5 days and 4/5 following main clinical features:

  1. Changes in peripheral extremities: Initial reddening or oedema of the palms and soles, followed by membranous desquamation of the finger and toe tips or transverse grooves across the fingernails and toenails (Beau Lines).
  2. Polymorphous rash (not vesicular): Usually generalized but may be limited to the groin or lower extremities.
  3. Oropharyngeal changes: Erythema, fissuring, and crusting of the lips; strawberry tongue; diffuse mucosal injection of the oropharynx.
  4. Bilateral, non-exudative, painless bulbar conjunctival injection.
  5. Acute purulent cervical lymphadenopathy with lymph node diameter >1.5cm, usually present unilaterally.

Treatment

The principal goal of treatment for KD is to prevent CAAs.

  • Intravenous immunoglobulin
  • High-dose Aspirin (small CAAs), Dipyridamole (large CAAs)
  • I.V. Corticosteroids should be avoided
  • Note that this is one of the only instances when you should give aspirin to a child