Correspondence
Reye's Syndrome
N Engl J Med 1999; 341:845-847September 9, 1999
- Article
To the Editor:
Belay and colleagues (May 6 issue)1 caution that a decrease in the sensitivity of the passive scheme for reporting Reye's syndrome in the United States might have contributed to the observed decline in incidence. Initially, the reporting in the United Kingdom was also done on a passive basis. However, in July 1986 the British Paediatric Surveillance Unit was established as an active case-reporting system for uncommon childhood disorders.2 The method of data collection involves monthly mailing of a report card to every consulting pediatrician in the United Kingdom, which must be returned even if no cases of a reportable disorder have been seen. The rate of card return in 1997 was 93 percent.3 All reported deaths are also screened for those attributed to Reye's syndrome, with the same case definition as was used by Belay et al.
Table 1Table 1
Number of Cases of Reye's Syndrome, 1981 to 1996. shows that, in spite of the improved method of identifying cases, after warnings about the effects of aspirin were issued to the public and to health care professionals in June 1986, there was a dramatic decline in the reported incidence of Reye's syndrome in the United Kingdom. Between August 1996 and May 1999, only 17 cases have been reported. Because of the nonspecific nature of the case definition of Reye's syndrome, we follow up all reported cases. Of the total of 597 reports as of August 1998, 155 (26 percent) cases were revised, of which 76 (49 percent) were deemed to be “Reye's-like” inherited metabolic disorders.We remain concerned that reported cases are not always fully investigated as possible inherited metabolic disorders and that the age limit of 12 years included in the warning in the United Kingdom may be too restrictive, since 10 of 17 cases since June 1986 in which exposure to aspirin was reported have involved patients over the age of 12. Belay et al. found that 8 percent of the U.S. cases involved patients who were 15 or older.
In the United Kingdom, as in the United States, parents have had a vital role in this public health success.4 Here in the United Kingdom, the National Reye's Syndrome Foundation has supported our surveillance scheme since 1995. Finally, we acknowledge the British pediatrician who in 1965 published evidence supporting his hypothesis that there was a link between aspirin and Reye's syndrome.5
5 ReferencesSusan M. Hall, F.R.C.P.
Sheffield Children's Hospital, Sheffield S10 2TH, United KingdomRichard Lynn, M.Sc.
Royal College of Paediatrics and Child Health, London W1N 6DE, United Kingdom1
Belay ED ,Bresee JS ,Holman RC ,Khan AS ,Shahriari A ,Schonberger LB . Reye's syndrome in the United States from 1981 through 1997. N Engl J Med 1999;340:1377-1382
Full Text | Web of Science | Medline2
Hall SM ,Nicoll A . The British Paediatric Surveillance Unit -- a pioneering method for investigating the less common disorders of childhood. Child Care Health Dev 1998;24:129-143
CrossRef | Web of Science | Medline3
Surveillance activities in 1997. In: Guy M, Nicoll A, Lynn R, eds. British Paediatric Surveillance Unit 12th annual report. London: Royal College of Paediatrics and Child Health, 1998:8-10.
4
Monto AS . The disappearance of Reye's syndrome -- a public health triumph. N Engl J Med 1999;340:1423-1424
Full Text | Web of Science | Medline5
Giles HM . Encephalopathy and fatty degeneration of the viscera. Lancet 1965;1:1075-1075
CrossRef | Web of Science | Medline
To the Editor:
Did the labeling of aspirin really result in the eradication of Reye's syndrome, as stated by Belay et al.? I have followed this syndrome since 1962, when my colleagues and I made our discovery in North Carolina of 16 school-age children and adolescents who died of encephalopathy and fatty degeneration of the viscera associated with severe influenza B infection.1 Since the early 1980s, before there were widespread warnings about aspirin, influenza B has markedly diminished in severity. Now Reye's syndrome is almost gone.
The initial studies impugning aspirin relied on distant parental recall.2 Subsequent careful studies sponsored by the Centers for Disease Control and Prevention (CDC) linking aspirin were done after widespread national furor. No prospective long-term studies ever solidly linked extended aspirin use (for juvenile rheumatoid arthritis or Kawasaki's disease) with this syndrome.3,4 As Monto pointed out in his accompanying editorial,5 political and commercial interests also became highly involved in the issue.
Antigenic shift or drift occurs with influenza A and B viruses on a yearly basis. Such drift also occurs with varicella–zoster virus, which has also been connected to Reye's syndrome.6
Many “disease comets” have appeared and disappeared during this century (e.g., swine influenza). It is worth noting that there has been a return of encephalopathy and fatty degeneration of the viscera associated with respiratory illness in Japanese children who did not take aspirin. As Monto points out, “few young parents . . . recognize the name Reye's syndrome or react strongly to it.” Despite the decrease in sales of aspirin it is hard to believe that older children, especially adolescents, have not taken aspirin, despite the presence of warning labels, during recent outbreaks of influenza.
Could it be that aspirin was falsely accused? Could it be that the disease comet will return with a recrudescence of severe influenza B?
6 ReferencesGeorge Magnus Johnson, M.D.
University of North Dakota, Fargo, ND 581021
Johnson GM ,Scurletis TD ,Carroll NB . A study of sixteen fatal cases of encephalitis-like disease in North Carolina children. N C Med J 1963;24:464-473
Medline2
Halpin TJ ,Holtzhauer FJ ,Campbell RJ , et al. Reye's syndrome and medication use. JAMA 1982;248:687-691
CrossRef | Web of Science | Medline3
Remington PL ,Shabino CL ,McGee H ,Preston G ,Sarniak AP ,Hall WN . Reye syndrome and juvenile rheumatoid arthritis in Michigan. Am J Dis Child 1985;139:870-872
Web of Science | Medline4
Rennebohm RM ,Heubi JE ,Daugherty CC ,Daniels SR . Reye syndrome in children receiving salicylate therapy for connective tissue disease. J Pediatr 1985;107:877-880
CrossRef | Web of Science | Medline5
Monto AS . The disappearance of Reye's syndrome -- a public health triumph. N Engl J Med 1999;340:1423-1424
Full Text | Web of Science | Medline6
Grose C . Varicella-zoster virus: less immutable than once thought. Pediatrics 1999;103:1027-1028
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: The similar declines in the incidence of Reye's syndrome in the United Kingdom after 1986, as described by Hall and Lynn, and in the United States after 1980, as we reported, provide further confirmation of a causative role of aspirin in this potentially fatal childhood illness. In both countries, the declines were temporally associated with public health warnings about the risk of Reye's syndrome after the use of aspirin in children with varicella and influenza-like illnesses. This relation between aspirin treatment and Reye's syndrome had been shown in several case–control studies reported in the United States in the early 1980s.1-3
Data from the CDC show a slightly greater effect of influenza B on excess hospitalizations for pneumonia and influenza among persons younger than 65 years of age during the influenza B season of 1985–1986 as compared with that of 1973–1974 (unpublished data). However, 73 percent fewer cases of Reye's syndrome were reported in 1985–1986. These data do not support Johnson's hypothesis that the diminished severity of influenza B since 1980 accounts for the decline in Reye's syndrome in the United States. During outbreaks of influenza B, there have been clusters of cases involving encephalopathy that do not meet the criteria of the CDC for Reye's syndrome.4 In fact, many of the 16 cases of encephalitis-like disease initially reported by Johnson and colleagues as occurring at the same time as increased influenza B activity in North Carolina in 1962 do not fulfill the case definition of Reye's syndrome.5 Given such occurrences and the consistent evidence of a strong relation between treatment with aspirin and cases of Reye's syndrome, more clinical and epidemiologic data are needed before one should accept the anecdotal report of an outbreak of Reye's syndrome among Japanese children who did not take aspirin. Giv-en the data we have, one cannot seriously question that in the United States and United Kingdom the declines in the incidence of Reye's syndrome were related to the documented decreases in the treatment of children with aspirin.
Rare but preventable cases of Reye's syndrome still occur in the United States. For every case related to aspirin, undoubtedly many other children have received aspirin for influenza-like illnesses or varicella. We continue to encourage pediatricians and other health care personnel to specifically advise against the use of aspirin in children with these viral illnesses.
5 ReferencesErmias D. Belay, M.D.
Lawrence B. Schonberger, M.D., M.P.H.
Centers for Disease Control and Prevention, Atlanta, GA 303331
Reye syndrome -- Ohio, MichiganMMWR Morb Mortal Wkly Rep 1980;29:532, 537-532, 539
2
Starko KM ,Ray CG ,Dominguez LB ,Stromberg WL ,Woodall DF . Reye's syndrome and salicylate use. Pediatrics 1980;66:859-864
Web of Science | Medline3
Waldman RJ ,Hall WN ,McGee H ,Van Amburg G . Aspirin as a risk factor in Reye's syndrome. JAMA 1982;247:3089-3094
CrossRef | Web of Science | Medline4
Hochberg FH ,Nelson K ,Janzen W . Influenza type B-related encephalopathy -- the 1971 outbreak of Reye syndrome in Chicago. JAMA 1975;231:817-821
CrossRef | Web of Science | Medline5
Johnson GM ,Scurletis TD ,Carroll NB . A study of sixteen fatal cases of encephalitis-like disease in North Carolina children. N C Med J 1963;24:464-473
Medline
Author/Editor Response
In my editorial on the disappearance of Reye's syndrome, I pointed out that the relation of the syndrome to aspirin ingestion was identified in a series of case–control studies.1 These studies provided strong evidence that the association was truly causal. However, the report by Belay et al. further confirmed the relation, since it showed that the reduction in aspirin use in the United States was accompanied by a reduction in this disease. Concern remained that the reduction in the incidence of the syndrome might have been exaggerated because of a passive reporting system during a period of decreased attention to the syndrome. Hall and Lynn report important data on the situation in the United Kingdom. The reporting there was active, and a similar reduction in the incidence of the disease was observed. The theory that this reduction was due to aspirin use and not other unrecognized changes was strengthened by the observations that the reduction was less pronounced in children over the age of 12 years and that the aspirin warning was restricted to those 12 or under. It is also remarkable that in the United Kingdom, as in the United States, parents, the biomedical community, and the government all worked together to produce this dramatic improvement.
It is hard to believe that changes in the circulating influenzavirus produced this change, as Johnson et al. suggest.2 Reye's syndrome was mainly associated with type B influenza, which has slower antigenic drift and was more frequently reported in association with the syndrome than influenza A.3 There was no evidence of reduced severity in influenza B infections during this period. Indeed, even during the period of high incidence, Reye's syndrome was a very unusual complication of common illness and not particularly related to the severity of that illness. These facts led to the search for an additional trigger, and the current and past observations amply demonstrate that the trigger is aspirin.
3 ReferencesArnold S. Monto, M.D.
University of Michigan School of Public Health, Ann Arbor, MI 481091
Hurwitz ES ,Barrett MJ ,Bregman D , et al. Public Health Service study on Reye's syndrome and medications: report of the pilot phase. N Engl J Med 1985;313:849-857
Full Text | Web of Science | Medline2
Johnson GM ,Scurletis TD ,Carroll NB . A study of sixteen fatal cases of encephalitis-like disease in North Carolina children. N C Med J 1963;24:464-473
Medline3
Corey L ,Rubin RJ ,Hattwick MA ,Noble GR ,Cassidy E . A nationwide outbreak of Reye's syndrome: its epidemiologic relationship to influenza B. Am J Med 1976;61:615-625
CrossRef | Web of Science | Medline
- Citing Articles (4)
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Bernard C. Portmann, Eve A. Roberts. 2012. Developmental abnormalities and liver disease in childhood. , 101-156.
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Veena Kalra. (2008) Reyes Syndrome. Apollo Medicine 5:2, 106-110
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John F T Glasgow. (2006) Reye???s Syndrome. Drug Safety 29:12, 1111-1121
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Catherine Litalien, Evelyne Jacqz-Aigrain. (2001) Risks and Benefits of Nonsteroidal Anti-Inflammatory Drugs in Children. Paediatric Drugs 3:11, 817-858
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