What is the cause of Kawasaki disease in children under 5 years old?

Cause of Kawasaki Disease

The cause of Kawasaki disease remains unknown, but the American Heart Association states it is most likely triggered by an unidentified infectious agent—possibly a novel RNA virus entering through the respiratory tract—that produces disease only in genetically susceptible children, particularly those of Asian descent. 1, 2

The Infectious Trigger Hypothesis

The clinical and epidemiological features strongly support an infectious etiology, though no specific pathogen has been identified despite decades of investigation 3:

• The self-limited nature of the illness with fever, rash, conjunctivitis, oral changes, and cervical adenopathy fits the pattern of an infectious disease 3
• Winter-spring seasonality, community outbreaks with wave-like geographic spread, and apparent epidemic cycles suggest a transmissible childhood disease 3, 2
• The prominence of IgA plasma cells in the respiratory tract—similar to findings in fatal viral respiratory infections—suggests a respiratory portal of entry 3
• Conventional bacterial and viral cultures, serological methods, and animal inoculation studies have all failed to identify a causative infectious agent 3

Genetic Susceptibility as a Critical Factor

Genetic predisposition plays a crucial role, with specific susceptibility genes identified including HLA class II, ITPKC, CD40, BLK, and Fcγ receptors. 1

The striking ethnic variation in incidence demonstrates the genetic component 1, 2:

• Japanese children: 243-265 per 100,000 children under 5 years old
• Asian/Pacific Islander Americans: 32.5 per 100,000
• African Americans: 16.9 per 100,000
• Hispanic Americans: 11.1 per 100,000
• White Americans: 9.1 per 100,000

The Leading Pathogenic Model

The most widely accepted hypothesis is that Kawasaki disease results from a ubiquitous infectious agent that triggers an immune-mediated inflammatory cascade only in genetically predisposed individuals 3, 1:

• The rarity in the first few months of life suggests protection by passive maternal antibodies 3
• The rarity in adults suggests acquired immunity to the causative agent 3, 2
• Little evidence of person-to-person transmission suggests most infected children experience asymptomatic infection, with only a small fraction developing overt clinical disease 3

Immunopathogenesis

Once triggered, the disease involves both innate and adaptive immune activation 1:

• Early innate immune activation with cytokine storm
• Endothelial cell activation with involvement of CD68 monocyte/macrophages, CD8 cytotoxic lymphocytes, and oligoclonal IgA plasma cells 3
• Marked cytokine cascade stimulation including VEGF, MCP-1, TNF-α, and various interleukins 3
• Matrix metalloproteinases capable of damaging arterial wall integrity contribute to aneurysmal dilatation 3

Clinical Implications

The unknown etiology means no specific diagnostic test exists—diagnosis relies entirely on clinical criteria, making early recognition paramount. 2

• Boys are affected 1.5 to 1.7 times more often than girls 3
• 76% of cases occur in children under 5 years old 3
• Treatment with IVIG within 10 days reduces coronary artery abnormality risk from 25% to approximately 5% 2
• Infants under 6 months have the highest risk of coronary complications and require particularly high clinical suspicion 2