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Background Reye's syndrome is characterized by encephalopathy and fatty degeneration of the liver, usually after influenza or varicella. Beginning in 1980, warnings were issued about the use of salicylates in children with those viral infections because of the risk of Reye's syndrome.
Methods To describe the pattern of Reye's syndrome in the United States, characteristics of the patients, and risk factors for poor outcomes, we analyzed national surveillance data collected from December 1980 through November 1997. The surveillance system is based on voluntary reporting with the use of a standard case-report form.
Results From December 1980 through November 1997 (surveillance years 1981 through 1997), 1207 cases of Reye's syndrome were reported in patients less than 18 years of age. Among those for whom data on race and sex were available, 93 percent were white and 52 percent were girls. The number of reported cases of Reye's syndrome declined sharply after the association of Reye's syndrome with aspirin was reported. After a peak of 555 cases in children reported in 1980, there have been no more than 36 cases per year since 1987. Antecedent illnesses were reported in 93 percent of the children, and detectable blood salicylate levels in 82 percent. The overall case fatality rate was 31 percent. The case fatality rate was highest in children under five years of age (relative risk, 1.8; 95 percent confidence interval, 1.5 to 2.1) and in those with a serum ammonia level above 45 µg per deciliter (26 µmol per liter) (relative risk, 3.4; 95 percent confidence interval, 1.9 to 6.2).
Conclusions Since 1980, when the association between Reye's syndrome and the use of aspirin during varicella or influenza-like illness was first reported, there has been a sharp decline in the number of infants and children reported to have Reye's syndrome. Because Reye's syndrome is now very rare, any infant or child suspected of having this disorder should undergo extensive investigation to rule out the treatable inborn metabolic disorders that can mimic Reye's syndrome.
Various inborn metabolic disorders, which require extensive laboratory testing for diagnosis, can present with manifestations that mimic those of Reye's syndrome, and clinical differentiation is often difficult. The majority of these inherited disorders are specific enzymatic defects that commonly become evident before the age of three years.4,5,6,7 These disorders are characterized by recurrent episodes, the presence of the disorder in siblings, frequent hypoglycemia, cardiac enlargement, and muscle weakness. The most consistent distinguishing features of Reye's syndrome on electron microscopy are ultrastructural changes in liver tissue, specifically the proliferation of smooth endoplasmic reticulum and peroxisomes and the presence of enlarged and pleomorphic mitochondria with loss of dense granules.7,8 In enzymatic defects with Reye's syndrome–like manifestations, in contrast, the mitochondria are normal in size and appearance.
Although the precise cause of Reye's syndrome is unknown, it is often preceded by a viral syndrome, usually varicella, gastroenteritis, or an upper respiratory tract infection such as influenza.9 Studies have demonstrated a strong epidemiologic association between the ingestion of aspirin during antecedent varicella or influenza-like illnesses and the subsequent development of Reye's syndrome.10,11,12,13,14 Beginning in 1980, as a result of these reports, the Centers for Disease Control and Prevention (CDC) cautioned physicians and parents not to use salicylates in children with varicella or influenza-like illnesses.15,16,17 An advisory was also issued by the surgeon general of the United States in June 1982,18 and a warning label was required for all aspirin-containing medications beginning in 1986.19
In this article, we describe the epidemiologic characteristics of patients with Reye's syndrome and the trends in cases reported to the National Reye Syndrome Surveillance System (NRSSS) from December 1, 1980, through November 30, 1997.
Methods
Surveillance for Reye's Syndrome
A system of national surveillance for Reye's syndrome was established during the period from December 15, 1973, through June 30, 1974, to monitor the incidence of Reye's syndrome during an anticipated epidemic of influenza B. The CDC reinstituted national surveillance for Reye's syndrome in December 1976 and has continued it through the NRSSS ever since. The NRSSS is a voluntary passive-surveillance system in which practicing physicians and hospital personnel report cases of Reye's syndrome to local or state health departments or, in a few states, directly to the CDC. A standard case-report form is used to collect information on patients, including demographic characteristics, antecedent illness, diagnostic criteria, levels of consciousness, laboratory data, and the outcome of the illness. The surveillance year for Reye's syndrome begins on December 1 and ends on November 30 in order to reflect the influenza season.
Case Definition
The CDC defines a case of Reye's syndrome as one in which there is acute, noninflammatory encephalopathy, manifested clinically by alterations in the level of consciousness and documented, when such results are available, by the measurement of 8 or fewer leukocytes per cubic millimeter of cerebrospinal fluid or by the presence of cerebral edema without perivascular or meningeal inflammation in histologic sections of the brain. The encephalopathy must be associated with either fatty metamorphosis of the liver, diagnosed by biopsy or at autopsy, or a tripling (or a greater increase) in the levels of alanine aminotransferase, aspartate aminotransferase, or ammonia in serum. There must, moreover, be no other more reasonable explanation of the cerebral or hepatic abnormalities.
A clinical staging system is used in the NRSSS (Table 1). Patients with a clinical history and laboratory abnormalities compatible with Reye's syndrome, but without central nervous system symptoms, are classified as at stage 0. Such patients do not fulfill the CDC case definition, because this definition requires symptoms of encephalopathy. Also in the NRSSS, an additional category, made up of patients to whom curare or an equivalent drug had been administered and who were therefore unable to be classified, is used for patients who had been given medications that would interfere with the evaluation of the level of consciousness.
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Only patients under 18 years of age who fulfilled the CDC case definition for Reye's syndrome were included in the statistical analysis. Variations in the number of patients in the denominator are due to nonresponse to questions on the case-report form or to responses of "unknown." The chi-square statistic was used to test for an association between race and the distribution of cases according to age group and for an association between detectable blood salicylate levels and period. We compared the characteristics and laboratory results of patients who died with those of survivors in order to identify associated risk factors; relative risks and 95 percent confidence intervals were calculated. Multiple logistic-regression analysis was used for the further examination of risk factors that were significantly associated with increased case fatality by fitting a series of hierarchical models.20
Results
From December 1, 1980, through November 30, 1997 (surveillance years 1981 through 1997), a total of 1207 cases of Reye's syndrome in patients under 18 years of age were reported to the CDC. A dramatic decline in the number of reported cases of Reye's syndrome was observed during this 17-year period (Figure 1). A peak of 555 cases were reported in surveillance year 1980. In 1985 and 1986, there was an average of just under 100 reported cases per year. From 1987 through 1993, no more than 36 cases were reported each year, and from 1994 through 1997, no more than 2 cases were reported each year.
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Nine hundred fifty-five of 1178 patients with Reye's syndrome (81.1 percent) had a stage 0, 1, or 2 illness at the time of hospital admission. Although a small proportion of patients had disease classified as stage 2 through 5 at admission, 428 of 931 patients (46.0 percent) had stage 3, 4, or 5 illness at some point. Higher stages of illness at admission were associated with a poor prognosis; 16 of 90 patients (17.8 percent) with stage 0 illness at admission died, for example, as compared with 69 of 77 patients (89.6 percent) with stage 5 illness (P<0.01) (Table 2).
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Discussion
There has been a dramatic decline in the number of reported cases of Reye's syndrome since 1980. This decline followed reports of the association of Reye's syndrome with the use of aspirin during antecedent varicella and influenza-like illness,10,11,12,16,17 the issuance of an advisory by the surgeon general,18 and the labeling of aspirin-containing medications with a warning about the risk of Reye's syndrome.19 Studies have documented a decline in the rate of use of aspirin in children after these precautionary measures were taken.21,22,23
The peak in reported cases of Reye's syndrome from December through April correlates with the seasonal occurrence of viral upper respiratory tract infections, particularly influenza, in the United States. This seasonal occurrence of Reye's syndrome has become less obvious since 1990, indicating that respiratory infections alone are not sufficient to cause distinct seasonal peaks in the numbers of cases of Reye's syndrome.
Although the overall decline in the number of cases of Reye's syndrome reported to the NRSSS is clear, the absolute number of cases should — as in any passive-surveillance system — be interpreted cautiously. A slight decrease in the sensitivity of reporting to the NRSSS, particularly during the 1990s, might have occurred, but not enough to account for the dramatic decline described in this summary. A trend toward a decline in hospitalizations for Reye's syndrome from 1991 through 1994 was shown by a recent review of hospital-discharge data from approximately one third of all nonfederal general acute care hospitals and all specialized children's hospitals in the United States (Sullivan KM: unpublished data). This review indicated a decline in the number of hospitalizations for Reye's syndrome from 30 in 1991 to 15 in 1994. On the basis of this study, the nationwide annual rate of hospitalizations for Reye's syndrome during 1994 was estimated as 0.06 per 100,000 persons under 18 years of age. This is likely to be an overestimate, because the patients included in the hospital-discharge data were not known to fulfill the CDC case definition for Reye's syndrome. In contrast, for the years preceding the reports of the association of Reye's syndrome with aspirin use, population-based studies suggested an average annual incidence of Reye's syndrome of approximately 1 case per 100,000 persons under 18 years of age.24,25 Our data are consistent with those from the British Isles, where a warning issued in June 1986 against the use of aspirin in children resulted in an overall decline in reported cases of Reye's syndrome and a significant reduction in cases that, according to a scoring system, are believed to represent true Reye's syndrome.26
According to NRSSS data, 14 of 361 patients with Reye's syndrome for whom data on aspirin use were available (3.9 percent) had regularly taken salicylate-containing medications for illnesses such as juvenile rheumatoid arthritis and Kawasaki's disease. Several studies have documented a higher attack rate of Reye's syndrome among children taking salicylates for juvenile rheumatoid arthritis.27,28 Similarly, children taking higher doses of aspirin have been shown to be at increased risk for Reye's syndrome.29 These findings underscore the importance of giving special attention to the care of patients with conditions that require the long-term administration of aspirin, such as Kawasaki's disease and juvenile rheumatoid arthritis. Vaccination against influenza and varicella should be offered to these patients in accordance with the recommendations of the Advisory Committee on Immunization Practices.30 Their care givers should also be informed about the risks of long-term aspirin treatment and trained to recognize the early symptoms of Reye's syndrome so that aspirin can be promptly withdrawn if Reye's syndrome is suspected.
Inborn metabolic disorders that mimic Reye's syndrome may lead to misdiagnosis, particularly in children younger than three years of age. As the incidence of Reye's syndrome decreases, manifestations that resemble those of Reye's syndrome are increasingly likely to be due to inborn metabolic disorders. Rigorous testing of patients with such signs and symptoms is indicated, either to confirm the diagnosis of Reye's syndrome or to identify specific enzymatic defects. Histologic examination of a liver-biopsy specimen should be performed and preferably reviewed by a pathologist experienced in recognizing electron-microscopical features of Reye's syndrome. The patient's family history of similar illness and precipitating factors such as changes in diet, prolonged fasting, unusual odor of the urine, or stress-related events, which are more common in persons with inborn metabolic disorders, may provide some clues for clinical decision making. The early detection of potentially treatable inborn metabolic disorders may prevent subsequent serious, life-threatening complications.
The decline in the incidence of Reye's syndrome that began soon after the public reports of the epidemiologic association of Reye's syndrome with aspirin demonstrates the importance of disseminating timely preventive messages to the public. Reye's syndrome, a severe neurologic disease that causes death or long-term neurologic sequelae in about one third of patients, was shown to be epidemiologically associated with the ingestion of aspirin, a widely used analgesic and antipyretic agent. The subsequent publicity about this association was critical to the success in reducing the occurrence of Reye's syndrome and its associated neurologic complications and in preventing the deaths of many children.
We are indebted to Anne Mather and John O'Connor for editorial assistance, Tara Strine and Eric Mandel for technical assistance, and the numerous health care providers and public health workers who submitted Reye's syndrome case-report forms to the CDC.
Source Information
From the Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta.
Address reprint requests to Dr. Belay at Mailstop A-39, Centers for Disease Control and Prevention, 1600 Clifton Rd., N.E., Atlanta, GA 30333, or at ebb8{at}cdc.gov.
References
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Related Letters:
Reye's Syndrome
Hall S. M., Lynn R., Johnson G. M., Belay E. D., Schonberger L. B., Monto A. S.
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Full Text
N Engl J Med 1999;
341:845-847, Sep 9, 1999.
Correspondence
This article has been cited by other articles:
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