What is the etiology of Kawasaki disease?

Etiology of Kawasaki Disease

The cause of Kawasaki disease remains unknown, but the American Heart Association and other major guideline bodies strongly suspect it results from an unidentified infectious agent—likely a novel RNA virus entering through the respiratory tract—that triggers an abnormal immune-mediated inflammatory cascade in genetically predisposed children, particularly those of Asian descent. 1, 2, 3

The Infectious Agent Hypothesis

The clinical and epidemiological features of Kawasaki disease overwhelmingly point toward an infectious trigger, though decades of research have failed to identify a specific pathogen 1:

• Clinical presentation mimics infection: The self-limited illness with fever, rash, enanthem, conjunctival injection, and cervical adenopathy fits the pattern of a childhood infectious disease 1, 3
• Epidemiological patterns support transmissibility: Winter-spring seasonality, community outbreaks with wave-like geographic spread, and apparent epidemic cycles all suggest an infectious etiology 1, 3
• Respiratory portal of entry: The prominence of IgA plasma cells in the respiratory tract, similar to findings in fatal viral respiratory infections, suggests the causative agent enters through the respiratory system 1

Critical caveat: Despite extensive investigation using conventional bacterial and viral cultures, serological methods, and animal inoculation, no infectious agent has been definitively identified 1. The disease does not transmit person-to-person and does not cluster within households or schools 4.

Genetic Susceptibility: The Essential Co-Factor

Genetic predisposition is not merely contributory—it appears essential for disease development 2, 3:

• Striking ethnic variation in incidence: Japanese children have the highest rates (112-265 per 100,000 children <5 years), followed by Asian/Pacific Islander Americans (32.5 per 100,000), African Americans (16.9 per 100,000), Hispanic Americans (11.1 per 100,000), and White Americans (9.1 per 100,000) 2, 3
• Specific susceptibility genes identified: HLA class II, ITPKC, CD40, BLK, and Fcγ receptors have been implicated, though the complete genetic basis remains incompletely understood 2

The Current Working Model

The American Heart Association proposes that Kawasaki disease occurs when a ubiquitous infectious agent produces clinically apparent disease only in genetically susceptible individuals 1, 3:

• Age distribution provides clues: The rarity in the first few months of life suggests protection by passive maternal antibodies, while rarity in adults suggests acquired immunity 1, 3
• Most infections are asymptomatic: The lack of person-to-person transmission suggests that most infected children experience asymptomatic infection, with only a small fraction developing overt Kawasaki disease 1

Immunopathogenesis: How the Disease Develops

Once triggered, the disease involves a complex immune cascade 2, 4:

• Innate immune activation predominates: The inflammasome plays an essential role, with evidence suggesting this is primarily an innate immune disorder rather than a typical infectious disease 4
• Pyroptosis and cellular damage: Rapid cell-damaging processes release proinflammatory cellular components from damaged endothelial and innate immune cells 5
• Cytokine storm: Activation of IL-1, IL-6, and TNF signaling pathways drives systemic inflammation 2
• Vascular injury mechanism: Endothelial cell activation, CD68 monocyte/macrophages, CD8 cytotoxic lymphocytes, and oligoclonal IgA plasma cells converge to cause coronary arteritis 1

Clinical Implications for Practice

Understanding the unknown etiology has direct clinical consequences 3:

• No diagnostic test exists: Diagnosis relies entirely on clinical criteria because the causative agent remains unidentified 3
• High suspicion required in specific populations: Children of Asian descent and infants <6 months have the highest risk and warrant heightened clinical vigilance 3
• Time-sensitive treatment window: IVIG must be administered within 10 days of fever onset to reduce coronary artery abnormality risk from 25% to approximately 5%, making early recognition paramount despite diagnostic uncertainty 2, 3

Common Pitfalls

• Waiting for all diagnostic criteria: Do not delay treatment while waiting for complete clinical criteria to manifest, as features may not appear simultaneously 6
• Dismissing incomplete presentations: Atypical or incomplete Kawasaki disease carries at least as high a risk of coronary complications as classic disease 1
• Overlooking environmental associations: While not consistently confirmed, reported associations include antecedent respiratory illness, preexisting eczema, humidifier use, and living near standing water 1