What is the pathophysiology of Kawasaki's (Kawasaki disease)?

Pathophysiology of Kawasaki Disease

Kawasaki disease is a systemic vasculitis triggered by an unknown infectious agent (likely a novel RNA virus) in genetically susceptible children, resulting in three distinct pathological processes that damage medium-sized arteries, particularly the coronary arteries, through immune-mediated inflammation. 1, 2

Etiology and Triggering Mechanism

The causative agent remains unidentified despite decades of investigation, but current evidence points to:

• An infectious trigger, most likely a novel RNA virus that enters through the upper respiratory tract in genetically susceptible children 1, 3
• Intracytoplasmic inclusion bodies containing RNA have been identified in bronchial epithelial cells and multiple cell types throughout the body, potentially linked to the causative agent 1
• Seasonality patterns correlate with tropospheric wind patterns, suggesting airborne transport of an inhaled agent 1
• Genetic susceptibility plays a crucial role, with identified genes including HLA class II, ITPKC, CD40, BLK, Fcγ receptors, and caspase 3 3, 4

Immunopathogenesis

The immune cascade involves both innate and adaptive immune activation:

• Early innate immune activation with aberrant activation of monocytes/macrophages, which accumulate markedly in arterial lesions 5
• Cytokine storm with elevated IL-1, IL-2, IL-4, IL-6, IL-10, IFN-gamma, and TNF-alpha driving systemic inflammation 2, 4
• Polyclonal B-cell activation occurs, making serological studies challenging 1
• T- and B-cell memory development emerges, explaining the self-limited nature and low recurrence rate 1
• Regulatory T-cell expansion after IVIG treatment correlates with fever cessation and clinical improvement 3

Three Pathological Processes of Arteriopathy

The American Heart Association's model identifies three distinct, linked pathological processes that define KD vasculopathy: 1

1. Necrotizing Arteritis (Acute Phase)

• Synchronized neutrophilic process that is complete within 2 weeks after fever onset 1
• The only self-limited process among the three pathological mechanisms 1
• Progressively destroys the arterial wall from intima through media into the adventitia 1
• Directly causes aneurysm formation by destroying structural components of the vessel wall 1, 5
• Coronary arteritis begins 6-8 days after disease onset, with inflammation rapidly involving all arterial layers 5

2. Subacute/Chronic Vasculitis

• Asynchronous infiltration of lymphocytes, plasma cells, and eosinophils with fewer macrophages 1
• Begins in the first 2 weeks after fever onset 1
• Can persist for months to years in a small subset of patients, distinguishing it from the self-limited necrotizing phase 1
• Closely linked to the third pathological process (luminal myofibroblastic proliferation) 1
• Inflammatory cell infiltration persists until approximately day 25, then gradually decreases 5

3. Luminal Myofibroblastic Proliferation (LMP)

• Unique medial smooth muscle cell-derived myofibroblastic process that is a key component of KD arteritis 1
• Begins in the first 2 weeks and persists for months to years 1
• Active proliferative process, not scar tissue, as demonstrated by electron microscopy 1
• Causes progressive arterial stenosis in patients with coronary artery abnormalities 1
• Composed of myofibroblasts and their matrix products accompanied by subacute/chronic inflammatory cells 1

Systemic Inflammation and Multi-Organ Involvement

Although coronary artery inflammation produces the most critical clinical outcomes, KD causes systemic inflammation in all medium-sized arteries and multiple organs during the acute febrile phase: 1, 2

• Cardiac involvement: myocarditis, pericarditis, valvulitis 1, 2
• Gastrointestinal tract: abdominal pain, vomiting, diarrhea, gallbladder hydrops 1, 2
• Hepatic: hepatitis 1, 2
• Pulmonary: interstitial pneumonitis 1, 2
• Meningeal: aseptic meningitis, irritability 1, 2
• Urinary tract: pyuria 1, 2
• Pancreatic: pancreatitis 1, 2
• Lymph nodes: lymphadenopathy (though pathology is nonspecific and nondiagnostic) 1

Pathological Outcomes and Long-Term Sequelae

The severity of initial arterial damage determines long-term outcomes:

• Very mildly dilated and inflamed arteries may return to normal 1
• Large saccular aneurysms have lost intima, media, and elastica, which cannot be regenerated; only a rim of adventitia remains 1
• Giant aneurysms (≥8 mm diameter or Z score ≥10) do not truly "resolve," "regress," or "remodel" 1
• Fusiform aneurysms with partially preserved media can thrombose or develop progressive stenosis from LMP 1
• Myocardial infarction can occur from acute or progressive thrombosis or from stenosis caused by LMP 1
• Aneurysm rupture can occur in the first 2-3 weeks after fever onset but rarely thereafter 1
• Thrombotic occlusion can lead to recanalization with continued vascular remodeling, sometimes including reocclusion, even in the remote stage 5

Critical Clinical Implications

Lesions in all arteries are relatively synchronous, evolving from acute to chronic injury in a predictable temporal pattern 5. This synchronous evolution explains why treatment timing is critical—IVIG must be initiated within 10 days of fever onset to reduce coronary artery aneurysm risk from 15-25% in untreated children to approximately 4.7% with treatment 3, 6.