REYE (RAY'S) SYNDROME: A PROBLEM EVERYONE SHOULD REMEMBER.

Reye syndrome is a rare but a very dangerous emergency that children and teenagers suffer. This threatening condition occurs during the treatment of fever in the clinical course of viral diseases with drugs containing acetylsalicylic acid and other salicylates. The high mortality rate from this disease is associated with the development of a rapidly progressing toxic encephalopathy and hepatic insufficiency. The etiology and pathogenesis of the Reye syndrome, despite the large number of investigations, is not clear enough. Today, special attention is paid to the development of so-called Reye-like syndromes in the context of congenital metabolic defects, although cases of the true Reye syndrome occur quite often. In spite of the long discussion among scientists, the effect of acetylsalicylic acid is an important factor of development of this pathological syndrome. Taking this fact into consideration, the use of acetylsalicylic acid by children, especially in case of colds, should be strictly controlled by a doctor and parents should be informed about possible complications, especially the development of the Reye syndrome. This issue is very urgent in countries with non-prescription antipyretics realization and a high percentage of self-treatment among patients.

Linking drugs to obscure illnesses: lessons from pure red cell aplasia, nephrogenic systemic fibrosis, and Reye's syndrome. a report from the Southern Network on Adverse Reactions (SONAR).

Identification of serious adverse drug reactions (sADRS) associated with commonly used drugs can elude detection for years. Reye's syndrome (RS), nephrogenic systemic fibrosis (NSF), and pure red cell aplasia (PRCA) among chronic kidney disease (CKD) patients were recognized in 1951, 2000, and 1998, respectively. Reports associating these syndromes with aspirin, gadodiamide, and epoetin, were published 29, 6, and 4 years later, respectively. We obtained primary information from clinicians who identified causes of these sADRs and reviewed factors contributing to delayed identification of these toxicities. Overall, 3,500 aspirin-associated RS cases in the United States, 1,605 gadolinium-associated NSF cases, and 181 epoetin-associated PRCA cases were reported. Delays in FDA regulation of over-the- counter medications and administration of aspirin to children contributed to development of RS. For NSF, in 1996, the Danish Medicine Agency approved high-dose gadodiamide administration to chronic kidney disease (CKD) patients undergoing MR scans. Overall, 88 % of Danish NSF cases were from two hospitals and 97 % of United States' NSF cases were from 60 hospitals. These hospitals frequently administered high-doses of gadodiamide to CKD patients. Another factor was the decision to administer linear chelated contrast agents versus lower risk macrocyclic chelated agents. For PRCA, increased use of subcutaneous epoetin formulations to CKD patients, in part due to convenience and cost-savings considerations, and a European regulatory requirement requiring removal of albumin as a stabilizer, led to toxicity. Overall, 81, 13, and 17 years elapsed between drug introduction into practice and identification of a causal relationship for aspirin, erythropoietin, and gadodiamide, respectively. A substantial decline in new cases of these sADRs occurred within two years of identification of the offending drug. Clinicians should be vigilant for sADRs, even for frequently-prescribed pharmaceuticals, particularly in settings where formulation or regulatory changes have occurred, or when over-the-counter, off-label, or pediatric use is common.

Aspirin and Reye syndrome: a review of the evidence.

Reye syndrome is an extremely rare but severe and often fatal disease. Death occurs in about 30-40% of cases from brainstem dysfunction. The disease typically is preceded by a viral infection with an intermediate disease-free interval of 3-5 days. The biochemical explanation for Reye-like symptoms is a generalized disturbance in mitochondrial metabolism, eventually resulting in metabolic failure in the liver and other tissues. The etiology of 'classical' Reye syndrome is unknown. Hypothetically, the syndrome may result from an unusual response to the preceding viral infection, which is determined by host genetic factors but can be modified by a variety of exogenous agents. Thus, several infections and diseases might present clinically with Reye-like symptoms. Exogenous agents involve a number of toxins, drugs (including aspirin [acetylsalicylic acid]), and other chemicals. The 'rise and fall' in the incidence of Reye syndrome is still poorly understood and unexplained. With a few exceptions, there were probably no new Reye-like diseases reported during the last 10 years that could not be explained by an inherited disorder of metabolism or a misdiagnosis. This may reflect scientific progress in the better understanding of cellular and molecular dysfunctions as disease-determining factors. Alternatively, the immune response to and the virulence of a virus might have changed by alteration of its genetic code. The suggestion of a defined cause-effect relationship between aspirin intake and Reye syndrome in children is not supported by sufficient facts. Clearly, no drug treatment is without side effects. Thus, a balanced view of whether treatment with a certain drug is justified in terms of the benefit/risk ratio is always necessary. Aspirin is no exception.

Reye's syndrome: the case for a causal link with aspirin.

Reye's syndrome is a serious, acute encephalopathy that has been linked with aspirin (acetylsalicylic acid) use in children and teenagers <18 years of age. Although others may disagree, it is my belief that any objective analysis of published material in the last 20 years must conclude that there is a close link between the devastating encephalopathy Reye's syndrome and ingestion of aspirin during the febrile prodrome. The drug appears to act as a co-factor in susceptible individuals. Although some of the epidemiological data indicate an association between the two, the burden of evidence suggests actual causality and is both consistent and specific as well as strong and time related. Some of the evidence points to illness severity being dose related although it seems that in the presence of a viral infection, no dose of aspirin can be considered safe. No published work, using methodology that can be critically evaluated, has shown evidence to contradict these conclusions and they have been widely accepted. Since government health warnings were appended to aspirin-containing formulations, the decline in case numbers on both sides of the Atlantic has been nothing short of remarkable. Recent in vitro findings have pinpointed the site of action of the drug on the long chain hydroxyacyl-CoA dehydrogenase enzyme (a component of the mitochondrial trifunctional enzyme) and, even at therapeutic concentrations, oxidation is impaired in cultured fibroblasts from patients who have recovered from the disorder. This is quite unlike that seen in cells from normal controls. Even when major influenza outbreaks occur in the future, Reye's syndrome is preventable provided government health warnings are heeded and the cogent evidence set forth here is acted upon by the parents of feverish children and self-medicating teenagers.

Reye syndrome surveillance--United States, 1989.

Reye syndrome (RS) is an acute illness that occurs almost exclusively in children; it is characterized clinically by profuse vomiting and neurologic dysfunction, sometimes progressing to delirium, coma, and death. Continuous national surveillance for RS was established in December 1976. This report summarizes RS cases for the 1989 surveillance year (December 1, 1988-November 20, 1989).

Reye's syndrome: incidence and time trends in Olmsted County, MN, 1950-1981.

Incidence and time trends of Reye's syndrome have been determined in Olmsted County, MN, using the facilities of the Rochester Epidemiology Program Project at Mayo Clinic. Incidence rates in individuals under 18 years of age were 1.1 per 100,000 person-years in the 1970-75 time interval and 1.7 in the 1976-81 interval. Failure to identify any case in the earliest time interval yields a rate of zero, and an incidence higher than 0.6 per 100,000 can be excluded with 95% probability. This finding is consistent with an increasing incidence over time in this community and does not exclude the possibility that Reye's syndrome did not exist in Olmsted County before 1970.

A nationwide outbreak of Reye's Syndrome. Its epidemiologic relationship of influenza B.

Between December 15 and June 30, 1974, 379 cases of confirmed Reye's syndrome were reported to the Center for Disease Control. Of these, 316 occurred during February and March 1974. A simultaneous surveillance system for influenza B indicated that this clustering of cases of Reye's syndrome correlated both temporally and geographically with influenza B outbreaks. The incidence of Reye's syndrome was higher in rural than in urban centers. Epidemiologically, two groups of cases of Reye's syndrome emerge: those which occur in older children (median age 11 years), cluster in time and geographic region, and are associated with antecedent influenza B infection; and those which occur sporadically thoughout the year, are isolated in occurrence, occur in younger children (median age 6 years), and are associated with a wide variety of antecedent viral illnesses.

National patterns of aspirin use and Reye syndrome reporting, United States, 1980 to 1985.

The number of cases of Reye syndrome reported annually to the Centers for Disease Control declined markedly between 1980 and 1985. In this article, we present pharmaceutical marketing research data that suggest sharp decreases in the use and purchase of children's aspirin between 1980 and 1985. These trends appear to correspond to the decrease in reporting of Reye syndrome cases. Additionally, analysis of physician mentions of aspiring and acetaminophen for treating flu and chickenpox showed statistically significant trends toward decreasing recommendations for the use of aspirin and significant trends toward increasing recommendations for use of acetaminophen. Trends in wholesale purchases of aspirin and acetaminophen by drug stores from 1979 through 1985 demonstrated a significant decline for the 81-mg children's aspirin tablet and an increase in purchases of children's acetaminophen products. Many factors may influence physician and parents' choice of analgesic/antipyretic medication, including information about Reye syndrome. Data suggest that a continuing decline in the use of aspirin for children may be accompanied by a continuing decline in the reported number of Reye syndrome cases.

A catch in the Reye.

Twenty-six cases of Reye syndrome from The Children's Hospital, Camperdown, Australia, occurring between 1973 and 1982 were reviewed. Of these, 20 cases met the US Public Health Service Centers for Disease Control criteria for the diagnosis of Reye syndrome. Aspirin or salicylate ingestion had occurred in only one of the 20 cases (5%), and paracetamol (acetaminophen) had been administered in only six of the cases (30%). Pathologic confirmation of the diagnosis of Reye syndrome was accomplished in 90% of the cases. The incidence of Reye syndrome in New South Wales, Australia, is estimated from this study to be approximately nine cases per 1 million children compared with recent US data of ten to 20 cases per 1 million children and three to seven cases per 1 million children in Great Britain. The mortality for these Reye syndrome cases in Australia was 45% as compared with a 32% case-fatality rate in the United States. In Australia, the pediatric usage of aspirin has been extremely low for the past 25 years (less than 1% of total dosage units sold), with paracetamol (acetaminophen) dominating the pediatric analgesic and antipyretic market. Reye syndrome may be disappearing from Australia despite a total lack of association with salicylates or aspirin ingestion, since there were no cases found at The Children's Hospital in 1983, 1984, or 1985.

Decreasing trends in Reye syndrome and aspirin use in Michigan, 1979 to 1984.

The incidence of Reye syndrome has been decreasing in Michigan, perhaps as a result of decreased aspirin use among children. To evaluate possible changes in the frequency of aspirin use, 199 families in Tecumseh, MI, with children younger than 18 years of age were interviewed by telephone in February 1981 and again in February 1983. Based on the reported use of medications for colds or influenza between 1981 and 1983, fewer parents gave aspirin (56% v 25%), but acetaminophen use did not change (59% v 55%). Younger parents and parents who had heard of the association between aspirin and Reye syndrome were more likely to stop giving aspirin. More parents chose to use either no medication or medications containing neither aspirin nor acetaminophen (6% v 32%) for the treatment of colds or influenza. Approximately 90% of parents who chose not to give aspirin for fever also gave medications for colds or influenza that did not contain aspirin. These results suggest that fewer children are receiving aspirin during illnesses that may precede Reye syndrome. The associated decrease in the incidence of Reye syndrome tends to support the hypothesis that the use of aspirin increases the risk for the development of Reye syndrome.

National surveillance for Reye syndrome: a five-year review.

National surveillance for Reye syndrome conducted during five years, including the period 1973-1974 and December 1976 through November 1980, has resulted in the reporting of more than 2,000 cases of Reye syndrome. The highest reported incidence of Reye syndrome occurred during years of primary influenza B and A (H1N1) activity; the reported incidence during one period of influenza A (H3N2) activity was somewhat lower. Regional outbreaks of Reye syndrome have been associated with influenza A (H1N1) and B but now with influenza A (H3N2). Cases of Reye syndrome in whites tend to be distributed throughout all age groups whereas a large percentage of cases in blacks have been reported in infants less than 1 year of age in three of the past four years. Nationally, there has been a decline in the case-fatality ratio in recent years.

A cluster of cases of Reye syndrome associated with chickenpox.

In the spring of 1980, four confirmed, and three possible cases of Reye syndrome, each associated with a chickenpox prodromal illness, were identified in Las Cruces, NM. One patient, a 5-year-old girl, died. Cases tended to occur in one section of the community, among children attending two of the 16 elementary schools. A telephone survey of parents with school-aged children (6 to 9 years old) suggested that a significantly greater attack rate of chickenpox occurred in children attending those two schools. Based upon this survey and the expected distribution of chickenpox among children less than 15 years of age, the incidence of Reye syndrome following chickenpox infection in the county in which Las Cruces is located was estimated to be 2.5/10,000 cases of chickenpox; these data reveal a four- to ninefold greater incidence of Reye syndrome than that following influenza B infections, which was previously estimated based upon a cluster of five cases in a county in Michigan. Additional investigations of Reye syndrome clusters are needed in an effort to identify and study suspected risk factors and to better define the relationship between Reye syndrome and viral infections.

National Reye syndrome surveillance, 1982.

Despite the fact that influenza B was the primary influenza virus strain during the winter of 1981-1982, only 213 cases of Reye syndrome were reported to the Centers for Disease Control (CDC) between Dec 1, 1981 and Nov 30, 1982. This national reported incidence of 0.33 cases per 100,000 children less than 18 years of age is the lowest reported incidence since the Centers for Disease Control began surveillance in 1973. This relatively low incidence probably reflected, at least in part, the fact the influenza B activity was spotty and the illness relatively mild the winter of 1981-1982. The 213 cases were reported from 43 states; and in 56% of the patients, Reye syndrome occurred following a respiratory illness. The mean age of the children was 7.0 years; there were equal numbers of girls and boys; and 93% were white. Of the ten black patients, 80% were less than 1 year of age compared with 9% of the white patients. Of the 208 patients with reported admission stage, 45% were admitted in stage I or 0, a slightly lower proportion than that observed in the previous 2 years. Salicylate levels were obtained in 55% of the patients and were reported as "detectable" in 81% compared with 96% in 1981 (P = .003, chi 2). Of the 200 patients with known outcome, 70 patients died (a case fatality ratio of 35%).

Changing epidemiology of Reye syndrome in the United States.

The average annual incidence of Reye syndrome reported through national surveillance was lower during 1981 to 1984 than during the previous five surveillance years. This is accounted for by a decrease in cases among children younger than 10 years of age; the number of cases in 10- to 19-year-old persons remained relatively stable during this period. The overall decline in incidence and the differing age-specific incidence trends are apparent for both varicella-associated cases and for nonvaricella-associated cases. During 1985, the incidence has been much lower than during any previous year since surveillance was initiated; this most recent decrease includes children 10 to 19 years of age. Independently conducted surveys suggest that the prevalence of salicylate use for viral illnesses has decreased among children in recent years, particularly among children younger than 10 years of age. The changing epidemiology of Reye syndrome may reflect, in part, the declining use of salicylates among children and teenagers in the United States.

Reye's syndrome in Olmsted County, Minnesota: did it exist before 1963?

In this study, our goals were to determine whether Reye's syndrome existed before the first published report of this entity in 1963 and to describe the long-term incidence and trend of this syndrome. Medical and pathologic records and pathologic specimens for Mayo Clinic patients, including those who were residents of Olmsted County, Minnesota, were reviewed through the facilities of the Rochester Epidemiology Project. On review, 12 cases were identified for the period 1920 through 1962; 2 of these cases were in Olmsted County residents. Of the 12 cases identified before 1963, 10 were in patients younger than 5 years of age. In addition to the aforementioned two cases, five others in Olmsted County were diagnosed between 1963 and 1989. Incidence rates were computed for the Olmsted County population. The number of cases and rates per 100,000 persons younger than 18 years of age in that population were 2 cases (0.3) for 1920 through 1962, 4 cases (0.7) for 1963 through 1980, and 1 case (0.4) for 1981 through 1989. Although cases found during the earlier periods may have included disorders that mimic Reye's syndrome, the recommended criteria from the Centers for Disease Control were applied to review of medical records and supported by pathologic findings in the liver. The data showed an age distribution tending toward young patients and no seasonality of occurrence. The incidence rates in Olmsted County, Minnesota, showed an increase for 1963 through 1980 over previous decades, followed by a decrease. The small numbers preclude any conclusion about trends in the incidence rates.

Incidence of Reye's syndrome in France: a hospital-based survey.

At the time of the study no information was available in France about the incidence of Reye's Syndrome (RS) and no warnings about RS and aspirin. The objective was to evaluate the incidence of RS in France by a hospital-based study. For a period of 1 year from November 1995 to November 1996, all French paediatric departments were required to report any child under 15 years with unexplained noninflammatory encephalopathy (i.e., CDC consciousness level stage I or deeper with normal CSF) and a threefold (or greater) increase in serum aminotransferase and/or ammonia. All suspected cases were classified by a panel of experts as probable RS or excluded RS. In 10% of randomly selected paediatric departments we checked that every suspected case had been reported. Forty-six suspected cases were reported during the year of the survey, of which 14 were classified as RS. Five of these 14 cases had a metabolic disorder. Nine children were definitively diagnosed as having RS (i.e., an estimated incidence of RS of 0.79/1,000,000 children, i.e., below 15/year). Eight children had been exposed to aspirin, four to aspirin alone and four to aspirin and acetaminophen. On the basis of these results the incidence of RS in France in 1996-1997 was not substantially different from that of countries where warning labels were already in use, but it was higher than in the US after 1994. This was probably due to the reduction in aspirin prescription in France because of warnings in Europe and the US and also because many cases of RS are now identified as metabolic disease. On the basis of these results and because the relationship between aspirin and RS has already been proved, public and professional warnings concerning RS on aspirin-containing products in cases of varicella and viral febrile illness have been adopted by the French Drugs Agency.

Is aspirin a cause of Reye's syndrome? A case against.

Reye's syndrome was a rare disease which appeared suddenly in the early 1950s and disappeared just as suddenly in the late 1980s. An association between Reye's syndrome and the ingestion of aspirin (acetylsalicylic acid) was claimed, although no proof of causation was ever established. The presence of salicylates in the blood or urine of Reye's syndrome patients has not been demonstrated, and no animal model of Reye's syndrome has been developed where aspirin causes the disease. It is clear from epidemiological data that the incidence of Reye's syndrome was decreasing well before warning labels were placed on aspirin products. Reye's syndrome disappeared from countries where aspirin was not used in children as well as from countries which continued to use aspirin in children. Reye's syndrome was probably either a viral mutation which spontaneously disappeared, or a conglomeration of metabolic disorders that had not been recognized or described at that time.

Reye syndrome: an international perspective.

An international perspective of Reye syndrome provides insights not noticeable with a parochial perspective. Sources of variation in Reye syndrome include geographic factors. The disappearance of Reye syndrome occurred globally, raising doubts about the importance of regional efforts to eliminate specific putative causes.