Epidemiology

In the United States, national surveillance for Reye syndrome was conducted first during the 1973 to 1974 nationwide outbreak of influenza B and influenza A (H1N1). Such surveillance led to the recognition of outbreaks of Reye syndrome regionally and nationally that were associated with outbreaks of influenza in these and subsequent years. During the first 5 years of surveillance, 250 to 550 cases were reported nationally—an underestimate because it was based on voluntary reporting. Population-based studies conducted in several geographic locations showed that the average annual incidence of the syndrome was one or two cases per 100,000 children younger than 18 years. Adults rarely were affected. Case-fatality rates reported through national surveillance, initially 40%, declined to 20% to 30% in later years when the syndrome was prevalent, although this rate undoubtedly was an overestimate because of the tendency to report more severe and fatal cases through this system.

Between 1980 and 1982, four case-control studies reported an association between Reye syndrome and the ingestion of aspirin during an antecedent respiratory or chickenpox illness. The results of these studies subsequently were confirmed in the Public Health Service Pilot and Main Studies of Reye Syndrome and Medications. In these studies, more than 90% of patients with Reye syndrome compared with 40% to 70% of controls had received aspirin for the antecedent respiratory or chickenpox illness; reported odds ratios were 11.5 to 40. After these studies were reported, publicity and recommendations from various expert panels, including recommendations issued by the US Food and Drug Administration in 1985, led to a decline in the use of aspirin and a decline in the incidence of Reye syndrome, particularly in the age group that had been affected most—children 5 to 15 years old.

Clinical Manifestations and Laboratory Findings

Reye syndrome is described classically as an illness characterized by the abrupt onset of severe vomiting and progressive encephalopathy in a child who is just recovering from a viral illness, the most common of which are influenza and chickenpox. The onset of these symptoms typically occurs within several days after the onset of the viral illness and commonly during a period when the child seems to be recovering from this illness. In association with severe—often projectile—vomiting, which occurs for a transient period, are progressive encephalopathic changes that may follow stages from delirium through confusion, agitation, and lethargy to coma if untreated.

The definition used by the Centers for Disease Control and Prevention (CDC) and widely adopted for clinical purposes includes (1) evidence of acute encephalopathy manifested by alterations in consciousness and documented, when available, by cerebrospinal fluid with less than 9 × 10 ⁶ /L leukocytes or by biopsy or autopsy evidence of cerebral edema without perivascular or meningeal inflammation in histologic sections of the brain; (2) evidence of liver involvement, including either biopsy or autopsy findings of fatty metamorphosis of the liver if available or, in the absence of such specimens, elevations in liver enzymes (alanine aminotransaminase, aspartate aminotransaminase, or serum ammonia) that typically are more than three times normal levels; and (3) no other more reasonable explanation for the cerebral or hepatic abnormalities. The last requirement emphasizes that Reye syndrome is a diagnosis of exclusion and that every effort should be undertaken to identify other possible causes for the clinical and laboratory abnormalities.

Liver biopsy or autopsy findings are considered characteristic and include panlobular microvesicular fat and mitochondrial abnormalities on electron microscopic examination showing peroxisome swelling and enlarged pleomorphic mitochondria with loss of dense granules. Additional findings include normal bilirubin levels and absence of jaundice. Most patients also have hypoglycemia and a prolonged prothrombin time. The typically elevated cerebrospinal fluid pressure in patients leads to progressive stages of coma.

Staging criteria for Reye syndrome have been used to define the level of encephalopathy. Patients have been reported with liver involvement but without evidence of encephalopathy. These patients have been described as having stage 0 encephalopathy and, although they do not meet the CDC criteria for Reye syndrome, are considered to have mild disease. Patients with stage I encephalopathy are difficult to arouse and lethargic, whereas patients with stage II are delirious and combative, with some movement. Patients with higher stages of encephalopathy (III to V) cannot be aroused and have progressively deeper stages of coma. These patients have a poor prognosis, with a mortality rate approaching 50% for patients admitted at stage III or greater and 90% for patients admitted at stage V.

Exclusion of other diseases that may resemble Reye syndrome, such as salicylate toxicity, is essential in patients with symptoms resembling this entity. Intensive laboratory investigations should be undertaken to exclude such disorders. In young children, particularly children younger than 3 years, inherited metabolic disorders frequently may mimic Reye syndrome and must be excluded. Such metabolic disorders include disorders of fatty acid oxidation, urea cycle disorders, carnitine transport defects, and organic acidemias. Laboratory studies must be performed for the younger age group to exclude these disorders before a diagnosis of Reye syndrome is made, particularly because some of these disorders can be treated effectively. With the declining incidence of Reye syndrome in the typical age group (5 to 15 years) after virtual elimination of the use of aspirin in children, an increasing number of patients with features of Reye syndrome are in this younger age group and ultimately are found, after careful evaluation, to have one of the many metabolic disorders that mimic this syndrome.

An acute encephalopathy mimicking Reye syndrome was noted in 2010. This 11-year-old boy’s illness was due to the Bacillus cereus emetic toxin cereulide. Ikeda and Sonoda noted a 26-year-old woman with Reye-like syndrome associated with suspected Bordetella pertussis infection and aspirin use.