Reye Syndrome:  The Decline of a Disease
by Evelyn Zamula

  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.
  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." 
  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." 

Other Government Actions
  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 chicken pox 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. In 1989, a heavy influenza B year,
27 cases of Reye syndrome were reported to CDC, almost half of them fatal.
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.

Other Factors:
  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 chicken pox
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.

Reye-Like Disorders 
  In the light of what we know now, it is even questionable whether all 
pathologist 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 very 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, the 
diagnosis of Reye syndrome is more conclusive--especially when symptoms 
occur during flu and chicken pox epidemics--since few other diseases in this
age group mimic common Reye syndrome symptoms.
  It's possible that metabolic disorders will prove some day to be the chief
cause of Reye syndrome. However, until then, it's important to remember that
aspirin use during flu or chicken pox 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." n

Evelyn Zamula is a freelance writer in Potomac, Md. 

Reye Syndrome Symptoms

  In most cases, children seem to be recovering from a viral illness when 
the following symptoms occur: 
* nausea
* vomiting, usually very severe 
* fever 
* lethargy
* stupor or coma, sometimes followed by convulsions 
* wild delirium and unusual restlessness noted in about half of patients n