What are the causes and current treatment ideologies for Kawasaki disease?

Kawasaki Disease: Current Understanding of Etiology and Pathogenesis

The cause of Kawasaki disease remains unknown, but the leading current ideology is that an unidentified infectious agent (likely a novel RNA virus entering through the respiratory tract) triggers an immune-mediated inflammatory cascade in genetically susceptible children, particularly those of Asian descent. 1

Etiological Theories

Infectious Trigger Hypothesis

The most compelling current theory posits that Kawasaki disease results from exposure to a ubiquitous infectious agent that produces clinically apparent disease only in genetically predisposed individuals 1. The clinical and epidemiological features strongly support this infectious etiology:

• Self-limited illness with fever, rash, conjunctival injection, and cervical adenopathy consistent with infectious disease patterns 1
• Winter-spring seasonality and community outbreaks with wave-like geographic spread suggest transmissible disease 1
• Age distribution (rarity in first months of life and adults) suggests an agent to which adults are immune and from which young infants are protected by maternal antibodies 1

Novel RNA Virus Theory

The most recent evidence points toward a novel RNA virus as the causative agent 1:

• Intracytoplasmic inclusion bodies containing RNA have been identified in bronchial epithelial cells and multiple cell types throughout the body 1
• Upper respiratory tract entry is the proposed route of infection 1
• Tropospheric wind patterns correlate with disease seasonality, suggesting airborne transport of an infectious agent that triggers disease when inhaled by genetically susceptible children 1

Critical caveat: Despite four decades of investigation using conventional bacterial and viral cultures, serological methods, and animal inoculation, no infectious agent has been definitively identified 1.

Genetic Susceptibility Factors

Racial and Ethnic Predisposition

Genetic factors play a crucial role in disease susceptibility 1:

• Japanese ancestry shows highest incidence: 243-265 per 100,000 children <5 years in Japan (2011-2012) 1
• Asian/Pacific Islander Americans: 32.5 per 100,000 children <5 years 1
• African Americans: 16.9 per 100,000 1
• Hispanic Americans: 11.1 per 100,000 1
• White Americans: 9.1 per 100,000 (lowest incidence) 1

Specific Genetic Variants

Recent genome-wide association studies have identified specific susceptibility genes 1:

• HLA class II (6p21.3): Involved in antigen presentation and immune cell activation 1
• ITPKC (19q13.2): Negative regulator of calcineurin-NFAT signaling; risk allele increases signaling 1
• CD40 (20q12-13.2): Risk alleles associated with increased translation 1
• BLK (8p23-22): Involved in B-cell receptor signal transduction 1
• Fcγ receptors: Variations affect immunoglobulin handling and immune complex processing 1, 2

Immunopathogenesis

Immune Response Cascade

The disease involves both innate and adaptive immune activation 1:

• Early innate activation with high numbers of activated circulating neutrophils 1
• Cytokine storm involving IL-1, IL-6, and TNF signaling pathways 1
• Adaptive immune response with both proinflammatory and regulatory T cells in circulation during first week 1
• Regulatory T-cell expansion after IVIG administration correlates with fever cessation and clinical improvement 1

Immune Complex Role

Recent evidence has revived interest in immune complexes as key mediators 2:

• Immune complexes were consistently detected in serum of children with Kawasaki disease in multiple studies 2
• Fcγ receptor genetic variants linked to disease susceptibility suggest immune complex handling is critical 2
• Immunoglobulin production genes show variation associated with Kawasaki disease 2

Response to Conventional Antigen

Current understanding favors response to a conventional antigen rather than superantigen 1:

• T- and B-cell memory emerges that is protective against future encounters with the causative agent 1
• Low recurrence rate (self-limited nature) supports development of protective immunity 1
• Polyclonal B-cell activation complicates serological studies 1

Contributing Environmental Factors

Inconsistently Confirmed Associations

Several environmental factors have been reported but not consistently validated 1:

• Antecedent respiratory illness 1
• Carpet-cleaning fluid exposure 1
• Preexisting eczema 1
• Humidifier use 1
• Living near standing water 1

Demographic Risk Factors

Established demographic patterns include 1:

• Male predominance: Boys outnumber girls 1.5-1.7:1 1
• Peak age: 76% of cases occur in children <5 years old 1
• Median age: 2 years at presentation 1

Systemic Pathology

Multi-Organ Inflammation

Kawasaki disease causes systemic vasculitis affecting medium-sized arteries and multiple organs during the acute phase 1:

• Coronary arteries: Most clinically significant with risk of aneurysms and thrombosis 1
• Liver: Hepatitis 1
• Lungs: Interstitial pneumonitis 1
• Gastrointestinal tract: Abdominal pain, vomiting, diarrhea, gallbladder hydrops 1
• Meninges: Aseptic meningitis, irritability 1
• Heart: Myocarditis, pericarditis, valvulitis 1
• Urinary tract: Pyuria 1
• Pancreas: Pancreatitis 1

Important pitfall: Lymph node pathology is nonspecific and nondiagnostic, despite prominent cervical lymphadenopathy being a clinical feature 1.

Current Treatment Ideology

Primary Therapy

Intravenous immunoglobulin (IVIG) 2 g/kg as a single infusion plus aspirin remains the standard initial treatment and must be initiated within 10 days of fever onset to reduce coronary artery aneurysm risk from 25% to approximately 4% 1, 3.

IVIG-Resistant Disease

Approximately 10-20% of patients fail to respond to initial IVIG (persistent fever ≥36 hours after infusion completion) 1:

• Second IVIG dose (2 g/kg) is commonly used as first-line rescue therapy 1
• Corticosteroids (intravenous methylprednisolone 30 mg/kg/day for 3 days or prednisolone with oral taper) show efficacy in Japanese populations 1, 3
• Infliximab, cyclosporine, or methotrexate may be considered for patients failing multiple IVIG doses and steroids 3

Critical limitation: Risk prediction models developed in Asian populations are insufficiently accurate for North American patients, making early identification of high-risk patients challenging 1, 3.