Pathophysiology of Reye's Syndrome in Aspirin-Treated Kawasaki Disease
Mitochondrial Dysfunction as the Central Mechanism
Reye's syndrome represents an acute metabolic encephalopathy caused by severe mitochondrial dysfunction, particularly affecting the liver and brain, with aspirin acting as a critical co-factor that impairs mitochondrial fatty acid oxidation in susceptible individuals. 1
The pathophysiologic sequence involves:
- Mitochondrial injury is the hallmark finding, though the exact mechanism linking viral illness to mitochondrial damage remains incompletely understood 2
- Aspirin specifically impairs the long-chain hydroxyacyl-CoA dehydrogenase enzyme (a component of the mitochondrial trifunctional enzyme), blocking fatty acid oxidation even at therapeutic concentrations 1
- This enzymatic blockade occurs in susceptible individuals, with cultured fibroblasts from recovered patients showing persistent oxidation impairment unlike normal controls 1
Metabolic Cascade and Organ Dysfunction
The mitochondrial injury triggers a devastating metabolic cascade:
- Insufficient substrate availability to the brain results from impaired fatty acid oxidation and energy production 2
- Massive cytotoxic cerebral edema develops as the primary cerebral insult 2
- Hepatic dysfunction manifests with elevated transaminases, coagulopathy, and hyperammonemia 3
- Hypoglycemia and hypoketonemia occur due to failed gluconeogenesis and ketogenesis 4
Aspirin's Role as Co-Factor in Kawasaki Disease Context
In the specific context of Kawasaki disease treatment:
- Aspirin acts as a co-factor in susceptible individuals during the febrile viral prodrome, not as a sole causative agent 1
- The drug appears to be dose-related in illness severity, though no dose can be considered completely safe in the presence of viral infection 1
- High-dose aspirin therapy (80-100 mg/kg/day) used in acute Kawasaki disease creates particular risk during the inflammatory phase 5
- The case report of a 10-month-old infant developing Reye's syndrome just 3 days after initiating high-dose aspirin for Kawasaki disease demonstrates this vulnerability in the target age group 3
Age-Specific Vulnerability in Infants
Infants under 8 months face compounded risk:
- Metabolic immaturity may increase susceptibility to mitochondrial toxins 4
- Reye-like syndromes from undiagnosed inborn errors of metabolism (particularly medium-chain and long-chain acyl-CoA dehydrogenase deficiencies) can present identically and may be unmasked by aspirin exposure 4, 3
- The end result of mitochondrial dysfunction appears similar whether from true Reye's syndrome or underlying metabolic defects 4
Critical Clinical Pitfall
The most dangerous aspect is that Reye's syndrome can develop even during appropriate therapeutic use of aspirin for Kawasaki disease, as documented in the 10-month-old case where symptoms emerged during standard high-dose therapy without concurrent influenza or varicella infection 3. This challenges the traditional teaching that risk exists only with concurrent viral infections like influenza or varicella 5, 6.