science

By THERESA A. WALKER

Mysterious Reye's Syndrome: Should the state require all cases be reported?

REYE'S Syndrome is a complex, mysterious, neurologic disease of children which affects many body systems, especially the brain and liver. The disease was first described as a syndrome — a group of distinct and characteristic clinical and pathological features — by an Australian pathologist, R.D.K. Reye, in 1963. That same year, a physician in North Carolina, G. M. Johnson, reported a 1962 outbreak of an unusual encephalitis-like condition that resembled the syndrome described by Dr. Reye. The major pathologic features of Reye's Syndrome are brain swelling and accumulation of fat in the liver.

Almost invariably, Reye's Syndrome is preceded by a viral infection, most commonly influenza or chicken pox. Typically, as symptoms of the viral illness begin to abate, severe vomiting begins. This is the first evidence of neurologic disease, i.e., disease involving the brain or nervous system. Next, the child shows behavior changes and may, for example, become disoriented or combative. If the disease progresses, the

child may become comatose, and could die in a matter of days if no treatment is provided. Prospects for survival are enhanced by early recognition of the disease and appropriate medical treatment. Among survivors, those who reach deeper stages of coma may suffer residual neurologic problems such as seizures, defective speech and learning disabilities.

Cause and treatment of Reye's Syndrome

RESEARCH into the cause of Reye's Syndrome has centered on three elements: the involvement of a virus, the involvement of a toxin, and a metabolic predisposition to the disease.

An almost universal feature of Reye's Syndrome is the preceding viral illness. But even though Reye's Syndrome is inextricably linked with a virus, it is not a viral infection. The pathology seen in Reye's Syndrome is not of the inflammatory type seen in cases of infection and seldom has a virus been isolated from a Reye's Syndrome patient. Nor is there any indication that Reye's Syndrome is communicable.

The major clinical features of Reye's Syndrome and the abrupt nature of both its onset and its resolution in recovery or death suggest that a toxin might be the primary cause. Over the years, studies of case histories disclosed few likely candidates for a toxic agent, but it has often been noted that most patients had received medication, often aspirin, during the preceding viral illness. In Thailand, Reye's Syndrome has been linked to aflatoxin, a substance produced by a fungus that commonly contaminates foods. Studies using animal subjects have implicated an emulsifier in pesticide preparations as a possible causative agent.

In an effort to reconcile, on one hand, the involvement of a virus and, on the other hand, the resemblance of Reye's Syndrome to a toxic response, a synergistic mechanism has been suggested. While a toxin or a virus may by itself be incapable of causing Reye's Syndrome, the toxin and virus may act together to cause the disease. In an experimental animal system, a pesticide emulsifier caused Reye's Syndrome only in combination with a viral infection. Neither the emulsifier alone nor the virus alone caused the disease.

Some researchers have suggested that certain individuals may be somehow metabolically predisposed to get Reye's Syndrome. For example, a person might have a metabolic defect, which is benign and easily compensated for under normal conditions, but may cause disease when stressed by the effects of a toxin or viral infection or both.

Recent research has provided promising leads in the search for the cause(s) of Reye's Syndrome. However, current ideas about the involvement of viruses, toxic substances, and inherited or acquired metabolic deficiencies are still only educated guesses. Refinement of these ideas requires much further study. The cause of Reye's Syndrome remains a medical mystery.

Recent epidemiological studies have suggested an association between Reye's Syndrome and aspirin use during the preceding viral illness. The studies compared the recent medication histories of Reye's Syndrome patients and persons of the same age, sex and race who had had the same preceding illness but did not get Reye's Syndrome. These studies showed that more Reye's Syndrome patients had taken aspirin and Reye's Syndrome patients had used aspirin more often than those who didn't get Reye's Syndrome. The studies also showed that the Reye's Syndrome patients tended to take larger doses of aspirin.

If indeed an association exists between Reye's Syndrome and aspirin use, the nature of this association is unclear. Aspirin toxicity resembles Reye's Syndrome in many respects. In Reye's Syndrome, however, the doses of aspirin that may have been taken generally are not in the toxic range. If the viral illness acts in synergy with aspirin, it may be that an effect of the virus is to alter the body's response to aspirin, so that a normally safe dose becomes a toxic dose.

Some physicians view with skepticism the purported link between aspirin and Reye's Syndrome. Only a statistical relationship has been shown; a cause-effect relationship remains to be established. These physicians fear that the widespread publicity connecting aspirin with Reye's Syndrome will lead to the overuse of acetaminophen (e.g., Tylenol, Datril) in place of aspirin. Although acetaminophen has not been linked with Reye's Syndrome, in high dosages it is a liver toxin. In the view of some, acetaminophen is potentially more toxic than aspirin.

A specific cure for Reye's Syndrome does not exist because the primary cause of the disease is unknown. At best, medical treatment consists of management measures designed to maintain body functions during the course of the disease. Death from Reye's Syndrome and neurologic damage in survivors are almost always the result of brain swelling. So the first goal of treatment is to control the brain swelling by reducing intracranial pressure (pressure within the skull). But intensive supportive measures are also required to counter the many biochemical disturbances that characterize the disease.

Early treatment of mild to moderate cases of Reye's Syndrome is less intense and consists of basic monitoring and supportive measures. But, should the patient's condition worsen, intracranial pressure monitoring would normally be started.

The care of Reye's Syndrome patients is one of the most intensive in medicine, requiring sophisticated intensive-care facilities and skills of experienced medical specialists — pediatricians, neurosurgeons and intensive-care nurses. One Reye's Syndrome specialist has estimated that the nationwide cost of this acute care for Reye's Syndrome is between $25 million and $37 million per year. In contrast, in 1979 the National Institutes of Health, the nation's major source of support for medical research, spent less than $1 million on research projects directly related to Reye's Syndrome. Basic research to understand the mechanism of the disease holds the only hope for finding a cure.

The true incidence of Reye's Syndrome is difficult to determine. The U.S. Public Health Service's Center for Disease Control (CDC) maintains a nationwide Reye's Syndrome surveillance program, but only 16 states require that Reye's Syndrome cases be reported to health departments, and participation by states in the CDC surveillance program is voluntary. Illinois does not yet have legislation that requires a report of all identified cases of Reye's Syndrome.

Not only do some diagnosed cases of Reye's Syndrome go unreported, but personnel at the National Reye's Syndrome Foundation suspect that many cases of the disease go undiagnosed. Foundation personnel estimate that the true incidence of Reye's Syndrome may be three to five times the reported incidence, and specialists in the disease generally agree that the harder one looks for Reye's Syndrome the more cases one finds. The confusion in Reye's Syndrome reporting is illustrated by the fact that the National Center for Health Statistics (also part of the Public Health Service) estimated 2,650 deaths from Reye's Syndrome in 1977, while only 418 cases of the disease were reported to the CDC that year. There were 506 cases of Reye's Syndrome reported to the CDC in 1980.

Reye's Syndrome reporting in Illinois is purely voluntary. When a case of Reye's Syndrome is reported to the Illinois Department of Public Health (IDPH), further information is solicited so that the diagnosis of Reye's Syndrome can be confirmed. (The department makes this data available to the CDC.) The table lists the number of verified Reye's Syndrome cases and the number of deaths from the disease reported to the IDPH from 1974 to 1979.

Because of the obvious limitations in the available data on the incidence of Reye's Syndrome, any interpretations of the data are subject to qualification.

Of 83 Reye's Syndrome cases reported in the United States before 1967, 69 (83 percent) ended in death. The high mortality was largely due to the fact that no rational treatment for the disease was known; but it is possible that the apparent death rate was artificially elevated because of lack of reporting of less severe cases of the disease. Prospects for survival have greatly improved over the past decade. In 1980, death occurred in 22 percent of reported Reye's Syndrome cases. Certain institutions and regions have more favorable statistics. For example, in Ohio only 4 percent of Reye's Syndrome patients died in 1980. This low death rate can be attributed in part to the fact that Ohio has six pediatric centers equipped and staffed for Reye's Syndrome treatment. In addition, the medical community and the general population tend to be more vigilant; thus, Reye's Syndrome is recognized in the early treatable stages, and the data base of reported cases includes the less severe cases.

In contrast, IDPH statistics suggest a higher mortality in Illinois. Over the last seven years, about 63 percent of reported Reye's Syndrome cases have ended in death, and the annual rate has ranged from 44 to 88 percent. It is possible that this apparent higher mortality represents a bias in Reye's Syndrome reporting in Illinois, with more fatal than nonfatal cases being reported to the IDPH. The data on Reye's Syndrome in Illinois are so scanty that any conclusions one may draw are very tenuous.

A bill (H. B. 31) creating a Reye's Syndrome Reporting Act has been introduced in the 82nd General Assembly. This reporting act would require reporting of Reye's Syndrome cases to the IDPH. Representatives of the National Reye's Syndrome Foundation believe that making Reye's Syndrome a reportable disease will have several important results. First, it will provide accurate information about the incidence of the disease and the circumstances surrounding its occurrence. Accurate and complete case histories provide the necessary data base for research into the cause of Reye's Syndrome. Foundation personnel also believe that if the true incidence of Reye's Syndrome were known, more money would be earmarked for research on the disease. Finally, making a disease reportable increases awareness of the disease in both the medical community and the general population. And since Reye's Syndrome is a rapidly progressive disease, and survival depends on early recognition and appropriate medical intervention, that awareness may be a key to survival for many victims.

The IDPH, while granting the usefulness of a Reye's Syndrome Reporting Act, opposes H.B. 31 solely on fiscal grounds. The department estimates that the annual cost of implementing the act would be $29,760. Proponents of the bill maintain that the fiscal argument is invalid. They point out that since mechanisms are already in place for the reporting of other diseases, the burden imposed by making Reye's Syndrome reportable would be minimal. Reporting act proponents suggest that the act could be largely implemented simply by making one person at each medical institution in the state responsible for reporting cases of Reye's Syndrome. Since the disease is rare, the additional work load for each person would be quite small.

Making Reye's Syndrome a reportable disease in all states is a major goal of the National Reye's Syndrome Foundation, a nonprofit, tax exempt, volunteer organization headquartered in Bryan, Ohio. The Foundation also provides nominal support for Reye's Syndrome research from its limited financial resources and conducts public awareness programs through the use of brochures, bulletins, television and radio public service announcements, films, and a speakers bureau. The foundation is represented in Illinois by a Chicago Chapter in Glencoe and a Southwest Illinois Chapter in Edwardsville.

Support for this column, which reports policy developments concerning science and technology, is provided in part by a National Science Foundation grant to the Illinois Legislative Council Science Unit, where Theresa A. Walker is a science intern.

April 1981/Illinois Issues/27