Reye Syndrome

by Food and Drug Administration (FDA)

Each year between March 1951 and March 1962, the Royal Alexandra Hospital for Children in New South Wales, Australia, admitted one or two children in such a critical state that most of them could not be saved, despite the most advanced medical care.

The cases had a number of unusual features in common. When admitted, all but two of the 21 children were in a coma or stupor, although their illness had started out a few days or weeks earlier with only common childhood upper respiratory symptoms — usually cough, sore throat, runny nose, or earache. Some children had even appeared to be recovering before the more serious phase of the illness began, with fever, relentless vomiting, convulsions, wild delirium, screaming, intense irritability, and violent movements.

Seventeen of the children died within an average of 27 hours after admission. At autopsy, all were found to have brain swelling, a slightly enlarged, firm and uniformly bright yellow liver, and a change in the appearance of the kidneys. Douglas Reye, M.D., the hospital's director of pathology, and his colleagues believed this set of symptoms represented a distinct disease, which they called fatty degeneration of the viscera (internal organs) of unknown cause. Though they suspected that ingestion of drugs or poisons may have been responsible for the condition, an investigation into the children's homes revealed they had no access to these substances.

In 1963, George Johnson, M.D., and his co-workers reported an epidemic of 16 fatal cases of an encephalitis-like disease occurring within a four-month period during an outbreak of influenza B in a small North Carolina community. Although children in this group were older than those studied by Reye, and their preceding illness was flu, it was subsequently theorized from Johnson's description of the symptoms and post-mortem findings that several of the children who died may have also had the syndrome described by Reye. It became known as Reye-Johnson syndrome, though it's usually referred to as Reye (pronounced rye) syndrome.

After the Reye-Johnson reports were published, numerous reports came in from the United States and other parts of the world showing that the syndrome was both more widespread and more common than was thought. Though this was not a new disease — it had been reported as early as 1929 — for the first time it had been identified and characterized as a distinct entity.

During the 1960s and 70s, when regional and then national surveillance of Reye syndrome was established by the Atlanta-based Centers for Disease Control, scientists observed that the syndrome occurred in association with outbreaks of the flu, especially influenza B. They also noted that it followed chicken pox, with children aged 5 to 15 most often affected. Less often it was associated with other viruses and acute respiratory and diarrheal illnesses.

When Is It Reye?

Many toxic substances (such as carbon tetrachloride, phosphorus and alcohol) and other diseases (such as acute hepatitis and viral encephalitis) can produce symptoms like Reye syndrome. Since most physicians were completely unfamiliar with the syndrome at the time, they needed to know what constituted a positive diagnosis.

CDC established case definitions for regional surveillance and outbreak investigations in the late 1960s. Criteria for a case included mental status changes, such as delirium or coma, and a liver biopsy (tissue sample) showing fat accumulation in the liver (or high levels of liver enzymes and ammonia in the blood). There also needed to be no other more reasonable explanation for the brain or liver abnormalities.

Records show that Reye syndrome has affected an infant as young as 4 days old and has occurred in a 59-year-old man; however, more than 90 percent of reported cases are in children under 15. About 2 percent are in adults over 20.

How the Illness Progresses

The course of the illness is variable. Reye syndrome can be mild and self-limiting, or it can progress rapidly, causing death within hours of onset, usually from brain swelling. But the progression may also stop at any stage, with complete recovery in 5 to 10 days and the quick return of normal liver function.

Doctors classify stages of Reye syndrome based on the level of the patient's consciousness and corresponding physical signs: Stages 0 to 2 are pre-comatose, with lethargy or delirium, and sometimes combativeness, but with the child still responding to stimuli. Coma progressively deepens in stages 3 to 5; the child is unresponsive to stimuli, and heart and lung function begin to shut down.

The earlier the diagnosis and treatment, the better the chance for survival. Intense supportive care in a hospital experienced in dealing with Reye syndrome also improves odds. Children who survive but experience the most severe stages of the illness — especially infants — are sometimes left with neurological abnormalities, often mental retardation or disorders of voice and speech.

Fatality rates when national surveillance began on a regular basis in 1976 were as high as 40 percent, declined to between 20 and 30 percent from 1978 to 1987, but rose in 1988 and 1989. CDC experts speculate that this higher death rate may reflect decreasing interest in the syndrome — because of its rarity — resulting in the reporting of only the most serious cases.

The Aspirin Connection

Just as Reye suspected that a drug or poison may have triggered the disease's development, investigators in the United States looked for some common factor among children who developed the syndrome. They found it in aspirin taken during flu or chicken pox.

In 1980, results of studies conducted in Ohio, Michigan and Arizona demonstrated an association between Reye syndrome and aspirin use during a preceding respiratory tract or chicken pox infection.

"It was those initial studies that we reviewed in 1980 that first led CDC to report in its Morbidity and Mortality Weekly Report [MMWR] that there was an association," states Lawrence B. Schonberger, M.D., an epidemiologist with the agency. In 1981, CDC reported in MMWR results of a fourth study that revealed the same association. In 1982, the Surgeon General of the U.S. Public Health Service issued a warning against giving aspirin to children with flu or chicken pox.

About the Author

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