Brief Reports

The Disappearance of Reye’s Syndrome

Sources: Belay ED, et al. Reye’s syndrome in the United States from 1981 through 1997. N Engl J Med 1999; 340:1377-1382; Monto AS. The disappearance of Reye’s syndrome—A public health triumph. N Engl J Med 1999; 340:1423-1424.

Reye’s syndrome is an acute illness characterized clinically by encephalopathy and hepatic dysfunction and hepatomegaly, resulting from fatty infiltration, often occurring in association with influenza or varicella. Sporadic cases of what is now called Reye’s syndrome were probably seen previously in the United States, but it was not until after Reye’s report from Australia in 19631 that increasingly larger numbers of cases were recognized in the United States in the 1970s, with as many as 400-600 cases per year. It was also recognized early that Reye’s syndrome occurred in the wake of infection—respiratory infections, especially influenza2 and varicella—in almost all cases. However, the disease was somewhat difficult to diagnose. The gold standard for diagnosis, namely, the finding of specific mitochondrial changes in liver biopsy specimens, was infrequently performed, so the diagnosis was usually based on clinical and historical criteria.

It was not until 1980 that an association between Reye’s syndrome and the use of aspirin during children’s respiratory infections and varicella was first formally suggested by Starko et al.3 This paper, published in Pediatrics, was followed by larger studies that strongly supported a causal association.4 However, the association was rather reluctantly accepted by the public and medical profession because aspirin, a drug that was in wide use for many years, was considered safe and also because there appeared to be no relation between the amount of aspirin taken by a patient and the subsequent development of Reye’s syndrome. In 1982, the surgeon general issued an advisory concerning the use of salicylates and Reye’s syndrome.5 Beginning in 1980, the numbers of cases of Reye’s syndrome began to fall sharply. This was due to the heightened public and professional awareness of possible dangers as well as an increasing use of acetaminophen as an antipyretic in the United States. In 1986, the FDA mandated labeling of salicylate-containing medications.

In 1980, 550 cases of Reye’s syndrome were reported; between 1985 and 1986, fewer than 100 cases were reported annually; from 1987 through 1993 there were no more than 36 cases per year; and from 1994 through 1997, no more than two cases were reported annually. Thus, Reye’s syndrome has virtually disappeared from the United States. There is now a generation of physicians who have never seen or treated children with Reye’s syndrome.

There are at least two important points to be emphasized concerning Reye’s syndrome. First, because it is unusual today, children presenting with symptoms that mimic Reye’s syndrome are more likely to have certain inherited rare inborn errors of metabolism that may result in encephalopathy and hyperammonemia. Differentiating these from Reye’s syndrome may require a liver biopsy.6 However, despite its current rarity, Reye’s syndrome must remain in the differential diagnosis of children with acute encephalopathy and hepatic dysfunction. A history of a preceding illness and the use of medications—especially salicylates—must be carefully explored. Second, U.S. children may ingest salicylates, either inadvertently or as treatment for conditions such as juvenile rheumatoid arthritis and Kawasaki’s disease. As many as 5% of children who developed Reye’s syndrome in the past were receiving chronic aspirin therapy. Children who must receive salicylate therapy should receive influenza and varicella immunizations. —hap


1. Reye RDK, et al. Encephalopathy and fatty degeneration of the viscera: A disease entity in childhood. Lancet 1963;2:749-752.

2. Corey L, et al. A nationwide outbreak of Reye’s Syndrome. Its epidemiologic relationship to influenza B. Am J Med 1976;61:615-625.

3. Starko KM, et al. Reye’s syndrome and salicylate use. Pediatrics 1980;66:859-864.

4. Hurwitz ES, et al. Public Health Service study of Reye’s syndrome and medications. Report of the main study. JAMA 1987;257:1905-1911.

5. Surgeon General’s advisory on the use of salicylates and Reye syndrome. MMWR Morb Mortal Wkly Rep 1982;31(22):289-290.

6. Forsyth BW, et al. Misdiagnosis of Reye’s-like illness. Am J Dis Child 1991;145:964-966.

Reye’s syndrome:

a. can be easily differentiated from inherited metabolic disorders with encephalopathy and hepatic dysfunction on the basis of clinical features.

b. is less common today in the United States than inherited disorders of metabolism characterized by encephalopathy and hepatic dysfunction.

c. can be related to the dose of salicylate that a child has received.

d. does not occur in children receiving chronic aspirin therapy for rheumatoid arthritis.