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Reye’s Syndrome

The Case For a Causal Link with Aspirin

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Abstract

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.

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References

  1. Sullivan-Bolyai JZ, Corey L. Epidemiology of Reye’s syndrome. Epidemiol Rev 1981; 3: 1–26

    PubMed  CAS  Google Scholar 

  2. Glasgow JFT, Hall SM. Reye syndrome and aspirin. In: Rainsford KD, editor. Aspirin and related drugs. London: Taylor and Francis, 2004: 555–585

    Google Scholar 

  3. Glasgow JFT, Middleton B, Moore R, et al. The mechanism of inhibition of P-oxidation by aspirin metabolites in skin fibroblasts from Reye’s syndrome patients and controls. Biochimica et Biophysica Acta 1999; 1454: 115–25

    Article  PubMed  CAS  Google Scholar 

  4. Orlowski JP, Hanhan UA, Fiallos MR. Is aspirin a cause of Reye syndrome? A case against. Drug Saf 2002; 25: 225–31

    Article  PubMed  Google Scholar 

  5. Starko KM, Ray CG, Dominguez LB, et al. Reye’s syndrome and salicylate use. Pediatrics 1980; 66: 859–64

    PubMed  CAS  Google Scholar 

  6. Waldman RJ, Hall WN, McGee H, et al. Aspirin as a risk factor in Reye’s syndrome. JAMA 1982; 247: 3089–94

    Article  PubMed  CAS  Google Scholar 

  7. Halpin TJ, Holtzhauer FJ, Campbell RJ, et al. Reye’s syndrome and medication use. JAMA 1982; 248: 687–91

    Article  PubMed  CAS  Google Scholar 

  8. 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: 849–57

    Article  PubMed  CAS  Google Scholar 

  9. Hurwitz ES, Barrett MJ, Bregman D, et al. Public Health Service study of Reye’s syndrome and medications: report of the main study [published erratum appears in JAMA 1987 Jun 26; 257 (24): 3366]. JAMA 1987; 257: 1905–11

    Article  PubMed  CAS  Google Scholar 

  10. Forsyth BW, Horwitz RI Acampora D, et al. New epidemiologic evidence confirming that bias does not explain the aspirin/Reye’s syndrome association. JAMA 1989; 261: 2517–24

    Article  PubMed  CAS  Google Scholar 

  11. Reye RDK, Morgan G, Baral J. Encephalopathy and fatty degeneration of the viscera. A disease entity in childhood. Lancet 1963; 2: 749–52

    Article  PubMed  CAS  Google Scholar 

  12. National Reyes Syndrome Foundation UK. Workshop on Reye’s syndrome and Reye-like inherited disorders [online]. Available from URL: www.reyessyndrome.co.uk [Accessed 2006 Nov 8]

  13. Glasgow JFT. Clinical features and prognosis of Reye’s syndrome. Arch Dis Child 1984; 59: 230–5

    Article  PubMed  CAS  Google Scholar 

  14. Hall SM, Lynn R. Reye syndrome. In: Lynn R, Nicoll A, Rahi J, et al., editors. British Paediatric Surveillance Unit, 15th Annual Report. RCPCH, London 2002: 27–30

    Google Scholar 

  15. Centers for Disease Control(CDC). Surgeon General’s advisory on the use of salicylates and Reye syndrome. MMWR Morb Mortal Wkly Rep 1982 Jun 11; 31 (22): 289–90.

  16. White JM. Reye’s syndrome and salicylates. N Engl J Med 1986; 314: 920

    Article  Google Scholar 

  17. Hall SM, Plaster PA, Glasgow JFT, et al. Pre-admission antipyretics in Reye’s syndrome. Arch Dis Child 1988; 63: 857–66

    Article  PubMed  CAS  Google Scholar 

  18. CSM update: Reye’s syndrome and aspirin. BMJ 1986; 292: 1590

    Google Scholar 

  19. Aspirin and Reye’s syndrome in children up to and including 15 years of age. Current Problems in Vigilance’s 2002; 28: 4

  20. Hall SM, Lynn R. Reye syndrome [letter]. New Eng J Med 1999; 341: 845

    Article  PubMed  CAS  Google Scholar 

  21. Medicines and Healthcare products Regulatory Agency [online]. Available from URL: http://www.mhra.gov.uk [Accessed 2006 Nov 6]

  22. Department of Health. Emergency planning: pandemic flu [online]. Available from URL: http://www.dh.gov.uk/Policy-AndGuidance/EmergencyPlanning/PandemicFlu/fs/en [Accessed 2006 Nov 8]

  23. Orlowski JP, Gillis J, Kilham A. A catch in the Reye. Pediatrics 1987; 80: 638–42

    PubMed  CAS  Google Scholar 

  24. Orlowski JP, Campbell P, Goldstein S. Reye’s syndrome: a case control study of medication use and associated viruses in Australia. Cleve Clin J Med 1990; 57: 323–9

    PubMed  CAS  Google Scholar 

  25. Committee on Reye’s syndrome research 1983. Japanese Ministry of Health and Welfare Official Report. Unpublished

  26. Baral J. Aspirin and Reye syndrome [letter]. Pediatrics 1988; 82: 135

    PubMed  CAS  Google Scholar 

  27. Hall SM. Reye study criticized [letter]. Pediatrics 1988; 82: 391–4

    PubMed  CAS  Google Scholar 

  28. McGee HB, Sienko DG. A catch in the Reye. Pediatrics 1988; 82: 390–9

    PubMed  CAS  Google Scholar 

  29. Hurwitz ES, Mortimer EA. A catch in the Reye is awry. Cleve Clin J Med 1990; 57: 318–9

    PubMed  CAS  Google Scholar 

  30. Orlowski JP. What happened to Reye’s syndrome? Did it ever really exist? Crit Care Med 1999; 27: 1582–7

    Article  PubMed  CAS  Google Scholar 

  31. Rennebohm RM, Heubi JE, Daugherty CC, et al. Reye syndrome in children receiving salicylate therapy for connective tissue disease. Journal of Pediatrics 1985; 107: 877–80

    Article  PubMed  CAS  Google Scholar 

  32. Belay ED, Bresee JS, Holman RC, et al. Reye’s syndrome in the United States from 1981 through 1997. N Engl J Med 1999; 340: 1377–82

    Article  PubMed  CAS  Google Scholar 

  33. Stumpf DA. Reye syndrome: an international perspective. Brain and Development 1995, 78

    Google Scholar 

  34. Hardie RM, Newton LH, Bruce JC, et al. The changing clinical pattern of Reye’s syndrome 1982-1990. Arch Dis Child 1996; 74: 400–5

    Article  PubMed  CAS  Google Scholar 

  35. Clark J, Nagamori K, Fitzgerald JF. Confirmation of serum salicylate levels in Reye’s syndrome: a comparison between the Natelson colorimetric method and high performance liquid chromatography. Clinica Chimica Acta 1985; 145: 243–7

    Article  CAS  Google Scholar 

  36. Pinsky PF, Hurwitz ES, Schonberger LB, et al. Reye’s syndrome and aspirin: evidence for a dose-response effect. JAMA 1988; 260: 657–61

    Article  PubMed  CAS  Google Scholar 

  37. Casteels-Van Daele M. Reye syndrome or side-effects of antiemetics? European J Pediatr 1991; 150: 456–9

    Article  CAS  Google Scholar 

  38. Casteels-Van Daele M, Van Geet C, Wouters C, et al. Reye syndrome revisited: a descriptive term covering a group of heterogeneous disorders. Eur J Pediatr 2000 Sep; 159(9): 641–8

    Article  PubMed  CAS  Google Scholar 

  39. Hall SM. Reye’s syndrome [letter; comment]. BMJ 1994; 309: 411

    Article  PubMed  CAS  Google Scholar 

  40. Khan AS, Kent J, Schonberger LB. Aspirin and Reye’s syndrome [letter]. Lancet 1993; 341: 968

    Article  PubMed  CAS  Google Scholar 

  41. Barrett MJ, Hurwitz ES, Schonberger LB, et al. Changing epidemiology of Reye syndrome in the United States. Pediatrics 1986; 77: 598–602

    PubMed  CAS  Google Scholar 

  42. Remington PL, Rowley D, McGee H, et al. Decreasing trends in Reye syndrome and aspirin use in Michigan, 1979 to 1984. Pediatrics 1986; 77: 93–8

    PubMed  CAS  Google Scholar 

  43. Soumerai SB, Ross-Degnan D, Kahn JS. Effects of professional and media warnings about the association between aspirin use in children and Reye’s syndrome [review]. Milbank Quarterly 1992; 70: 155–82

    Article  PubMed  CAS  Google Scholar 

  44. Porter JD, Robinson PH, Glasgow JFT, et al. Trends in the incidence of Reye’s syndrome and the use of aspirin. Arch Dis Child 1990; 65: 826–9

    Article  PubMed  CAS  Google Scholar 

  45. Casteels-Van Daele M, Eggermont E. Reye’s syndrome. BMJ 1994; 308: 919–20

    Article  PubMed  CAS  Google Scholar 

  46. Roe CR. Metabolic disorders producing a Reye-like syndrome. In: Wood C, editor. Reye’s syndrome. London: Royal Society of Medicine Services Round Table Series No 8, 1986: 85–107

    Google Scholar 

  47. Sarnaik AP. Reye’s syndrome: hold the obituary. Crit Care Med 1999; 27: 1674–6176

    Article  PubMed  CAS  Google Scholar 

  48. Orlowski JP. Discussion at International Workshop: Reye’s syndrome revisited. Leuven, 1996

    Google Scholar 

  49. Yoshida Y, Fujii M, Brown FR, et al. Effect of salicylic acid on mitochondrial-peroxisomal fatty acid catabolism. Pediatric Research 1988; 23: 338–41

    Article  PubMed  CAS  Google Scholar 

  50. Deschamps D, Fisch C, Fromenty B, et al. Inhibition by salicylic acid of the activation and thus oxidation of long chain fatty acids: possible role in the development of Reye’s syndrome. J Pharmacol Exp Ther 1991; 259: 894–904

    PubMed  CAS  Google Scholar 

  51. Maddaiah VT, Miller PS. Effects of ammonium chloride, salicylate, and carnitine on palmitic acid oxidation in rat liver slices. Pediatr Res 1989; 25: 119–23

    Article  PubMed  CAS  Google Scholar 

  52. Rognstad R. Effects of salicylate on hepatocyte lactate metabolism. Biomedica Biochimica Acta 1991; 50: 921–30

    PubMed  CAS  Google Scholar 

  53. Partin JS, Partin JC, Schubert WK, et al. Serum salicylate concentrations in Reye’s syndrome: a study of 130 biopsyproven cases. Lancet 1982; 1: 191–4

    Article  PubMed  CAS  Google Scholar 

  54. Meert KL, Kauffman RE, Deshmukh DR, et al. Impaired oxidative metabolism of salicylate in Reye’s syndrome. Dev Pharmacol Ther 1990; 15: 57–60

    PubMed  CAS  Google Scholar 

  55. Insel PA. Analgesic-antipyretic and antiinflammatory agents. In: Hardman JG, Limbird LE, editors. Goodman and Gilman’s the pharmacological basis of therapeutics, 9th Ed. New York: McGraw-Hill, 1996; 631–7

    Google Scholar 

  56. Glasgow JFT, Middleton B. Reye syndrome -insights on causation and prognosis. Arch Dis Child 2001; 85: 351–3

    Article  PubMed  CAS  Google Scholar 

  57. Monto AS. The disappearance of Reye’s syndrome: a public health triumph. N Engl J Med 1999; 340: 1423–4

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

For many years, my research was generously supported by The National Reye’s Syndrome Foundation of the UK.[12] I have no conflicts of interest that are directly relevant to the content of this review. I am grateful to Dr Sue Hall for allowing me to draw upon her expertise and several co-authored publications.

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Glasgow, J.F. Reye’s Syndrome. Drug-Safety 29, 1111–1121 (2006). https://doi.org/10.2165/00002018-200629120-00003

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