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 postmortem 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 (now the Centers for Disease Control and Prevention), scientists observed that the syndrome occurred in association with outbreaks of the flu, especially influenza B. They also noted that it followed chickenpox, with children aged 5 to 15 most often affected. Less often it was associated with other viruses and acute respiratory and diarrheal illnesses.
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.
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.
The earlier the diagnosis and treatment of Reye syndrome, the better the chance for survival.
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 have stayed between 40 and 53 percent ever since. CDC experts speculate that these higher death rates despite fewer reports each year may reflect decreasing interest in the syndrome--because of its rarity--resulting in the reporting of only the most serious cases.
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 chickenpox.
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 chickenpox 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 chickenpox.
The public was quick to pick up on the association. "A kind of natural study was occurring, because once people heard about the results [of the studies], they started to lower the use of aspirin in their children," says Schonberger. "If aspirin had nothing to do with it [Reye syndrome], then one might anticipate that there would be no clear decrease in the incidence of Reye syndrome."
In most cases, children seem to be recovering from a viral illness when the following symptoms occur:
* vomiting, usually very severe
* stupor or coma, sometimes followed by convulsions
* wild delirium and unusual restlessness noted in about half of patients*
That's not what happened. Aspirin use in children under 10 declined by at least 50 percent from 1981 to 1988, and the number of Reye syndrome cases went down correspondingly. In the opinion of Peter C. Rowe, M.D., assistant professor of pediatrics, Children's Hospital of Eastern Canada, Ottawa, Ontario, the declining use of aspirin and the decreasing incidence of Reye syndrome represent a "natural ecological experiment."
The federal government made other moves. To confirm the preliminary findings of the state studies, in 1985-1986 the government sponsored the "Public Health Service Study of Reye's Syndrome and Medications." Twenty-seven children who developed Reye syndrome after a preceding respiratory illness or chickenpox were matched with 140 children who had had the same illnesses at the same time, but did not develop Reye syndrome. More than 96 percent of the Reye syndrome cases, compared with 38 percent of the controls (the children who did not develop Reye syndrome), had received aspirin (or other salicylates) to treat the preceding illness. The study was prematurely ended because not enough Reye syndrome children who had not been exposed to aspirin could be found to justify the expense of continuing the investigation, in itself an indication of a public health triumph.
In 1986, FDA adopted a preliminary rule requiring aspirin manufacturers to add warnings to product labels about the possible association between aspirin use and the development of Reye syndrome. The permanent rule became final in 1988, and the labeling reads: Children and teenagers should not use this medicine for chicken pox or flu symptoms before a doctor is consulted about Reye syndrome, a rare but serious illness reported to be associated with aspirin.
The number of Reye syndrome cases, which reached a high in 1980 with 555 cases, has steadily decreased, compared with years in which there has been similar types of influenza activity. The decline has been most dramatic among children from 5 to 10 years of age. According to CDC, since 1985, 40 to 65 percent of reported Reye syndrome patients have been older than 10. Because this age group often self-medicates, recent educational efforts have been geared to reach them.
Some questions about the relationship between aspirin and Reye syndrome still remain. Although figures show that 90 to 95 percent of Reye syndrome patients in the United States have taken aspirin during a preceding viral illness, it is estimated that less than 0.1 percent of children having a viral infection and treated with aspirin develop the syndrome. Are other factors involved?
Apparently so. Reye syndrome has always been a puzzling disease. Research on possible causes has been hampered because no one can come up with a simple specific diagnostic test for the syndrome. The waters are further muddied by the existence of at least 19 viruses, including the chickenpox and flu viruses, which cause infectious illnesses that can precede Reye syndrome development. Some experts have proposed that Reye syndrome develops from the interaction of a viral illness, genetic susceptibility to the disease, and exposure to chemicals, such as salicylates, pesticides and aflatoxin. Others speculate that unidentified viruses or other infectious agents are involved.
That some children may be more susceptible to Reye syndrome than others has been shown by cases appearing among children in the same family and by recurrent episodes of the illness in the same child. It is possible that more than one type of Reye syndrome exists, or that some of these cases may not be Reye syndrome at all.
Predominant Influenza Strains and Reported Cases of Reye Syndrome-United States, 1974 and 1977-1992
Predominant Case Influenza Varicella- Total Fatality Year Strains Total Associated Incidence Rate (%) 1974 B 379 - 0.6 41 1977 B 454 73 0.7 42 1978 A(H3N2) 236 69 0.4 29 1979 A(H1N1) 389 113 0.6 32 1980 B 555 103 0.9 23 1981 A(H3N2) 297 77 0.5 30 1982 B 213 45 0.3 35 1983 A(H3N2) 198 28 0.3 31 1984 A(H1N1)+B 204 26 0.3 26 1985 A(H3N2) 93 15 0.2 31 1986 B 101 5 0.2 27 1987 A(H1N1) 36 7 0.1 29 1988 A(H3N2) 25 4 0.0 40 1989 A(H1N1)+B 25 3 0.0 40 1990 A(H3N2) 19 2 0.0 53 1991 B 15 1 0.0 40 1992 A(H3N2) 13 1 0.0 46
Continuous RS surveillance began in December 1976. Reporting year begins Dec. 1 of previous year. Incidence is per 100,000 U.S. population under 18 years of age (U.S. Bureau of the Census data).
(Source: Centers for Disease Control and Prevention)
In the light of what we know now, it is questionable whether all of Dr. Reye's cases were true Reye syndrome. Recent research indicates that some children diagnosed in the past with Reye syndrome, particularly those under 5, may have had underlying metabolic abnormalities that produce similar symptoms.
"There may well be certain cases that come in even today--in the very young--that five years from now we'll find are really some other abnormal congenital problem--where they have a metabolic defect and it expresses itself in a form that looks much like Reye syndrome," says CDC's Schonberger. Because these children require different treatment, proper diagnosis can be a matter of life or death. In children 5 or older, a Reye syndrome diagnosis is more conclusive--especially when symptoms occur during flu and chickenpox epidemics--since few other diseases in this age group mimic common Reye syndrome symptoms.
Metabolic disorders may prove some day to be the chief cause of Reye syndrome. Until then, it's important to remember that aspirin use during flu or chickenpox is asking for trouble.
In Schonberger's words: "The association between aspirin and Reye syndrome is so strong that it has now become literally foolhardy to act as if no etiologic [cause-and-effect] relationship exists." *
Evelyn Zamula is a freelance writer in Potomac, Md.
A REPRINT FROM FDA CONSUMER MAGAZINE
This reprint contains revisions made in May 1994.
This article originally appeared in the November 1990 FDA Consumer.
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