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National Surveillance for Reye Syndrome, 1981: Update, Reye Syndrome and Salicylate Usage

For the period December 1, 1980-October 31, 1981,* CDC received written reports of 221 cases of Reye syndrome that met the CDC case definition (1). These cases were reported from 39 states and the District of Columbia. The sex, age, and racial distribution of patients was similar to that reported in previous years. Of patients for whom sex was known, 51% were female. Of patients of known age, 35% (73) were less than or equal to 4 years of age, 59% (124) were 5-14 years, and 6% (12) were greater than or equal to 15 years. Among 211 patients of known race, 94% were white, 4% black, and 2% of Asian extraction. Of the patients with a reported antecedent illness, 60% (121) had respiratory symptoms, 30% (60) had varicella, and 10% (22) had diarrhea.

Seventy-seven percent of the patients with Reye syndrome were hospitalized in the period December 5-March 27, coincident with reports of increased influenza A(H3N2/H1N1) virus activity in the United States. Numbers of hospitalizations rose in direct proportion to increases in numbers of reports of influenza A(H3N2) virus activity (Figure 1). The number of Reye syndrome cases peaked approximately 1 week after the peak number of reported influenza A (H3N2) isolates, presumably reflecting the 5-7 day interval between antecedent illness and hospitalization of patients with Reye syndrome (2). The number of cases of Reye syndrome remained elevated during the peak period of H1N1 activity.

The incidence of Reye syndrome reported in 1980-1981 was similar to that reported in a previous year (1977-1978) of influenza A (H3N2/H1N1) activity and was approximately half that reported in years when influenza B or influenza A (H1N1) was prevalent (Table 1).

In 1981, of 208 reported cases for which the outcome was reported, there were 58 deaths, for a case fatality ratio (CFR) of 28%. This ratio is approximately equal to the average CFR for the preceding 3 years and one-third lower than that reported during the first 2 surveillance periods (1973-1974, 1976-1977) (Table 1). CFRs reported to CDC probably represent overestimates, because of a tendency for physicians and health departments to report severe illness or death more consistently than mild illness. Although the lower CFRs in recent years may have resulted in part from more complete reporting of mild cases, it is noteworthy that a larger percentage of all patients reported in recent years were admitted to the hospital in an early stage of the syndrome (suggesting earlier recognition). Furthermore, there has been a decrease in mortality rates among patients admitted in each stage of encephalopathy (suggesting improvements in therapy).

In addition to 3 previously reported case-control studies conducted in Arizona, Michigan and Ohio (3,4), a fourth study, reported to CDC by the Michigan Department of Public Health, demonstrated a relationship between Reye syndrome and the ingestion of salicylates during the antecedent illness. The goal of this study was to test the reproducibility of findings of the earlier study conducted by the Michigan Department of Public Health during the 1979-1980 influenza season. The recent study concentrated on all medications, including dosage and frequency of administration, taken during the illness preceding Reye syndrome. Patients and controls (1-3 controls for each patient) matched for year in school (plus or minus 1), race, febrile response (100 F, 100 F-102.9 F, and greater than or equal to 103 F) and nature of prodromal illness (i.e., chickenpox or respiratory or gastrointestinal illness) were selected. Interviews were conducted as soon as possible after each case was reported (mean 5.5 days).

All 12 patients with Reye syndrome versus 12 of 29 (41.4%) controls reported using medications containing salicylates during the prodromal illness (p 0.001). None of the 12 patients versus 16 of 29 (55.2%) controls received a product containing acetaminophen (p 0.005). Analysis of factors that might confound the usage of salicylates, including mean duration of viral illness, mean age of parents, mean number of medications received during the viral illness, and mean peak temperature reported, revealed that patient and control groups were similar. The total amount of salicylates received by children with Reye syndrome during their prodromal illness ranged from 19.4 mg/kg body weight to 324 mg/kg (mean 121.6 mg/kg), and the maximum daily dosage received ranged from 10.8 to 78.6 mg/kg (mean 41.7 mg/kg). Reported by W Hall, MD, Michigan Dept of Public Health; Viral Diseases Div, Center for Infectious Diseases, CDC.

Editorial Note

Editorial Note: Previous statements on the possible association of medications and Reye syndrome have been issued by an NIH consensus conference (5) the FDA (6) and CDC (1). These earlier statements were made before the availability of the study results presented above.

All 4 studies reported from Arizona, Michigan (2 studies), and Ohio, showed a relationship between Reye syndrome and salicylates. As in all epidemiologic studies, a number of issues must be considered in interpreting results and reaching conclusions. To evaluate the data, CDC recently solicited assistance from 8 outside consultants* who were asked to review the 4 reported studies and assess the strength of the association between salicylate use and Reye syndrome.

Issues cited and discussed by CDC in its report on the Ohio and first Michigan studies included 1) recall bias, i.e., difficulties in obtaining comparable and accurate medication histories for patients following a significant event (Reye syndrome) when compared with controls with a relatively mild illness, and the difficulty of accurate recall of events several weeks later; 2) severity of illness, i.e., the possibility that patients with Reye syndrome had more severe antecedent illness and thus may have been predisposed to take more medications, including salicylates, than did matched controls; and 3) the comparability of viral infections in case and control groups; serologic studies were not done as part of these investigations.

Some additional areas of concern noted by the consultants, industry representatives and others included : 1) interviewer bias, i.e., the knowledge of the interviewer of the case-control status of the subject; 2) interview techniques that were not comparable, i.e., medication histories were more often verified (including checking of medication labels) for controls (whose parents were interviewed at home) than for patients (whose parents were usually interviewed in the hospital), which may have resulted in a tendency for parents of patients more often than for parents of controls to misclassify the generic drug used by their children; 3) possibile misclassification of Reye syndrome, i.e., since biopsies were not routinely performed, it was possible that some persons with mild illness might be included in the group of patients diagnosed as having Reye syndrome.

After reviewing the data from all 4 studies and discussing the various epidemiologic and analytic methods and results, the CDC consultants concluded that it was unlikely for the limitations of the studies, either singly or in combination, to explain totally the strength and consistency of the observed association between Reye syndrome and salicylates. The consultants felt there was "...sufficient evidence to support the cautionary statements on salicylate usage that had been published previously by the Centers for Disease Control (4) and the NIH Consensus Development Conference (5)." Furthermore, it was the consensus of the consultants that "...until the nature of the association between salicylates and Reye syndrome is clarified, the use of salicylates should be avoided, when possible, for children with varicella infections and during presumed influenza outbreaks." In addition, these consultants suggested that it would be prudent to reserve the use of all antipyretic agents for persons who have an illness of such a nature that the need to reduce elevated temperatures outweighs other considerations (7).

In summary, these studies indicate to CDC that salicylates may be a factor in the pathogenesis of Reye syndrome, although the observed epidemiologic association does not prove causality. The exact pathogenesis of this disease and the possible role of salicylates in its pathogenesis remain to be determined. Additional well-controlled studies are also needed. Until definitive information is available, CDC advises physicians and parents of the possible increased risk of Reye syndrome associated with the use of salicylates for children with chickenpox or influenza-like illness.

References

  1. CDC. Follow-up on Reye syndrome--United States. MMWR 1980;30:321-2.

  2. Corey L, Rubin RJ, Hattwick MA, Noble GR, Cassidy E. A national outbreak of Reye's syndrome; its epidemiologic relationship to influenza B. Am J Med 1976;61:615-25.

  3. Starko KM, Ray CG, Dominguez LB, Stromberg WL, Woodall DF. Reye's syndrome and salicylate use. Pediatrics 1980;66:859-64.

  4. CDC. Reye syndrome--Ohio, Michigan. MMWR 1980;29:532, 537-9.

  5. Consensus Conference: Diagnosis and treatment of Reye's syndrome. JAMA 1981; 26:2441-4.

  6. FDA Drug Bulletin, Vol. 6, No. 5, Nov-Dec 1976.



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