Pediatric Drugs

, Volume 9, Issue 3, pp 195–204 | Cite as

Aspirin and Reye Syndrome

A Review of the Evidence
  • Karsten SchrörEmail author
Review Article


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.


Influenza Aspirin Acetaminophen Salicylate Kawasaki Disease 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Funding for the preparation of this review was provided by Bayer HealthCare, Leverkusen, Germany. The author would like to thank Ertan Mayatepek (University Clinics Düsseldorf, Department of Pediatrics, Düsseldorf, Germany) for his critical comments and valuable advice as well as Erika Lohmann for her assistance in preparing this manuscript.

The author has not received income from patents, royalties, or stocks, or received any other financial or material gain that are directly related to the subject matter of this review. The author has received research grants from and been involved with the advisory boards of the following companies: Astra-Zeneca GmbH, Bayer HealthCare, Sanofi-Aventis, Schering AG, and Schwarz Pharma GmbH.

The author receives current project support from the following companies: Bayer HealthCare, Schering AG, and Schwarz Pharma GmbH. The author consults for Astra-Zeneca GmbH, Bayer HealthCare, Boehringer Ingelheim Pharma GmbH & Co. KG, BBraun Melsungen AG, Schering AG, and Sanofi-Aventis. The author’s work on the side effects of drugs is supported by grants from BfArM (Bundesinstitut für Arzneimittel und Medizinprodukte).


  1. 1.
    Reye RDK, Morgan G, Baral J. Encephalopathy and fatty degeneration of the viscera: a disease entity in childhood. Lancet 1963; II: 749–52CrossRefGoogle Scholar
  2. 2.
    Mowat AP. Reye’s syndrome and aspirin. In: Vane JR, Botting RM, editors. Aspirin and other salicylates. London: Chapman & Hall Medical, 1992: 531–47Google Scholar
  3. 3.
    Orlowski JP, Hanhan UA, Fiallos MR. Is aspirin a cause of Reye’s syndrome? A case against. Drug Saf 2002; 25: 225–31PubMedCrossRefGoogle Scholar
  4. 4.
    Heubi J, Partin E, Partin JC, et al. Reye’s syndrome: current concepts. Hepatology 1987; 7: 155–64PubMedCrossRefGoogle Scholar
  5. 5.
    Visentin M, Salmona M, Tacconi MT. Reye’s and Reye-like syndromes, drug-related diseases? (causative agents, etiology, pathogenesis, and therapeutic approaches). Drug Metab Rev 1995; 27: 517–39PubMedCrossRefGoogle Scholar
  6. 6.
    Casteels-Van Daele M, Wouters C, Van Geet C, et al. Reye-syndrome revisited: a descriptive term covering a group of heterogenous disorders. Eur J Pediatr 2000; 159: 641–8PubMedCrossRefGoogle Scholar
  7. 7.
    Weiner DL. Pediatrics, Reye syndrome, 2001 [online]. Available from URL: [Accessed 2003 Dec 22]
  8. 8.
    Glasgow JFT, Middleton B. Reye-syndrome: insights on causation and prognosis. Arch Dis Child 2001; 85: 351–3PubMedCrossRefGoogle Scholar
  9. 9.
    Green A, Hall S. Investigation of metabolic disorders resembling Reye’s syndrome. Arch Dis Child 1992; 67: 1313–7PubMedCrossRefGoogle Scholar
  10. 10.
    Hardie RM, Newton LH, Bruce JC, et al. The changing clinical pattern of Reye’s syndrome 1982–1990. Arch Dis Child 1996; 74: 400–5PubMedCrossRefGoogle Scholar
  11. 11.
    Schrör K. Acetylsalicylic acid. Frechen, Germany: Dr. Schrör Verlag — Nature & Science. In pressGoogle Scholar
  12. 12.
    Larsen SU. Reye’s syndrome. Med Sci Law 1997; 37: 235–41PubMedGoogle Scholar
  13. 13.
    Glasgow JFT, Middleton B, Moore R, et al. The mechanism of inhibition of β-oxidation by aspirin metabolites in skin fibroblasts from Reye’s syndrome patients and controls. Biochem Biophys Acta 1999; 1454: 115–25PubMedCrossRefGoogle Scholar
  14. 14.
    Cooperstock MS, Tucker RP, Baublis JV. Possible pathogenic role of endotoxin in Reye’s syndrome. Lancet 1975; I: 1272–4CrossRefGoogle Scholar
  15. 15.
    Prandota J. Important role of prodromal viral infections responsible for inhibition of xenobiotic metabolizing enzymes in the pathomechanisms of idiopathic Reye’s syndrome. Am J Ther 2002; 9: 149–56PubMedCrossRefGoogle Scholar
  16. 16.
    Ogawa E, Kanazawa M, Yamamoto S, et al. Expression analysis of two mutations in carnitine palmitoyltransferase IA deficiency. J Hum Genet 2002; 47: 342–7PubMedCrossRefGoogle Scholar
  17. 17.
    Rahbeeni Z, Vaz F-M, Al-Hussein K, et al. Identification of two novel mutations in OCNT2 from two Saudi patients with systemic carnitine deficiency. J Inherit Metab Dis 2002; 25: 363–9PubMedCrossRefGoogle Scholar
  18. 18.
    Tamaoki Y, Kimura M, Hasegawa Y, et al. A survey of Japanese patients with mitochondrial fatty acid beta-oxidation and related disorders as detected from 1985–2000. Brain Dev 2002; 24: 675–80PubMedCrossRefGoogle Scholar
  19. 19.
    Scaglia F, Scheuerle AE, Towbin JA, et al. Neonatal presentation of ventricular tachycardia and a Reye-like syndrome episode associated with disturbed mitochondrial energy metabolism. BMC Pediatr 2002; 2: 12PubMedCrossRefGoogle Scholar
  20. 20.
    Marsden D, Nyhan WL, Barshop BA. Creatine kinase and uric acid: early warning for metabolic imbalance resulting from disorders of fatty acid oxidation. Eur J Pediatr 2001; 160: 599–602PubMedCrossRefGoogle Scholar
  21. 21.
    Schulze A, Lindner M, Kohlmuller D, et al. Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications. Pediatrics 2003; 111: 1399–406PubMedCrossRefGoogle Scholar
  22. 22.
    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: 1377–82PubMedCrossRefGoogle Scholar
  23. 23.
    Orlowski JP. What happened with Reye’s syndrome? Did it ever really exist? Crit Care Med 1999; 27: 1582–7PubMedCrossRefGoogle Scholar
  24. 24.
    Hall SM, Lynn R. Reye syndrome. In: Guy M, Nicoll A, Lynn R, editors. British Paediatric Surveillance Unit, 12th annual report. London: RCPCH, 1998Google Scholar
  25. 25.
    Coates PM, Hale DE, Stanley CA, et al. Genetic deficiency of medium-chain acyl coenzyme A dehydrogenase: studies in cultured skin fibroblasts and peripheral mononuclear leukocytes. Pediatr Res 1985; 19: 671–6PubMedCrossRefGoogle Scholar
  26. 26.
    Fromenty B, Pessayre D. Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity. Pharm Ther 1995; 67: 101–54CrossRefGoogle Scholar
  27. 27.
    Tonsgard JH, Getz GS. Effects of Reye’s syndrome serum on isolated chinchilla liver mitochondria. J Clin Invest 1985; 76: 816–25PubMedCrossRefGoogle Scholar
  28. 28.
    Desschamps 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: 894–904Google Scholar
  29. 29.
    Troll MM, Menten ML. Salicylate poisoning: report of four cases. Am J Dis Child 1945; 69: 37–43Google Scholar
  30. 30.
    Starko KM, Mullick FG. Hepatic and cerebral pathology findings in children with fatal salicylate intoxication: further evidence for a causal relation between salicylate and Reye’s syndrome. Lancet 1983; I: 326–9CrossRefGoogle Scholar
  31. 31.
    Ng KJ, Andresen BD, Hilty MD, et al. Identification of long-chain dicarboxylic acids in the serum of two patients with Reye’s syndrome. J Chromatogr 1983; 276: 1–10PubMedCrossRefGoogle Scholar
  32. 32.
    Tonsgard JH. Serum dicarboxylic acids in Reye’s syndrome. J Pediatr 1986; 109: 440–5PubMedCrossRefGoogle Scholar
  33. 33.
    Rocchiccioli F, Aubourg P, Bougneres PF. Medium and long-chain dicarboxylic aciduria in patients with Zellweger syndrome and neonatal adrenoleukodystrophy. Ped Res 1986; 20: 62–6CrossRefGoogle Scholar
  34. 34.
    Partin JS, Partin JC, Schubert WK, et al. Serum salicylate concentrations in Reye’s disease. Lancet 1982; I: 191–4CrossRefGoogle Scholar
  35. 35.
    Segalman TY, Lee CP. Reye’s syndrome: plasma-induced alterations in mitochondrial structure and function. Arch Biochem Biophys 1982; 214: 522–30PubMedCrossRefGoogle Scholar
  36. 36.
    Daugherty CC, McAdams AJ, Partin JS. Aspirin and Reye’s syndrome. Lancet 1983; 322: 104CrossRefGoogle Scholar
  37. 37.
    Partin JS, Daugherty CC, McAdams AJ, et al. A comparison of liver ultra structure in salicylate intoxication and Reye’s syndrome. Hepatology 1984; 4: 687–90PubMedCrossRefGoogle Scholar
  38. 38.
    Hautekeete ML, Degott C, Benhamou JP. Microvesicular steatosis of the liver. Acta Clin Belg 1990; 45: 311–26PubMedGoogle Scholar
  39. 39.
    Martens ME, Chang CH, Lee CP. Reye’s syndrome: mitochondrial swelling and Ca2+ release induced by Reye’s plasma, allantoin, and salicylate. Arch Biochem Biophys 1986; 244: 773–86PubMedCrossRefGoogle Scholar
  40. 40.
    Trinder P. Rapid determination of salicylate in biological fluids. Biochem J 1954; 57: 301–3PubMedGoogle Scholar
  41. 41.
    Kang ES, Todd TA, Capaci MT, et al. Measurement of true salicylate concentrations in serum from patients with Reye’s syndrome. Clin Chem 1983; 29: 1012–4PubMedGoogle Scholar
  42. 42.
    Andresen BD, Alexander MS, Ng KJ, et al. Aspirin and Reye’s disease: a reinterpretation. Lancet 1982; I: 903CrossRefGoogle Scholar
  43. 43.
    Pinsky PF, Hurwitz ES, Schonberger LB, et al. Reye’s-syndrome and aspirin: evidence for a dose-response effect. JAMA 1988; 260: 657–61PubMedCrossRefGoogle Scholar
  44. 44.
    Clark JH, 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. Clin Chim Acta 1985; 145: 243–7PubMedCrossRefGoogle Scholar
  45. 45.
    Chu AB, Nerurkar LS, Witzel N, et al. Reye’s syndrome: salicylate metabolism, viral antibody levels, and other factors in surviving patients and unaffected family members. Am J Dis Child 1986; 140: 1009–12PubMedGoogle Scholar
  46. 46.
    Daniels SR, Greenberg RS, Ibrahim MA. Scientific uncertainties in the studies of salicylate use and Reye’s syndrome. JAMA 1983; 249: 1311–6PubMedCrossRefGoogle Scholar
  47. 47.
    Linnemann Jr CC, Shea L, Partin JC, et al. Reye’s syndrome: epidemiologic and viral studies, 1963–1974. Am J Epidemiol 1975; 101: 517–26PubMedGoogle Scholar
  48. 48.
    Smith TC. Reye’s syndrome and the use of aspirin. Scott Med J 1996; 41: 4–9PubMedGoogle Scholar
  49. 49.
    McGovern MC, Glasgow JFT, Stewart MC. Lesson of the week: Reye’s syndrome and aspirin: lest we forget. BMJ 2001; 322: 1591–2PubMedCrossRefGoogle Scholar
  50. 50.
    Yu ECL. Reye’s syndrome in Hong Kong. Aust Paediatr J 1988; 24: 61PubMedGoogle Scholar
  51. 51.
    Daugbjerg P, Ranek L. Reye’s syndrome in Denmark. Acta Pediatr Scand 1986; 75: 313–5CrossRefGoogle Scholar
  52. 52.
    Casteels-Van Daele M, Wouters C, van Geet C. Reye’s syndrome revisited: outdated concept of Reye’s syndrome was used [comment on BMJ 2001; 322: 1591–2]. BMJ 2002; 324: 546PubMedCrossRefGoogle Scholar
  53. 53.
    Christo GG, Venkatesh A. Reye syndrome: the Indian experience. Indian J Pediatr 1987; 54: 903–8PubMedCrossRefGoogle Scholar
  54. 54.
    Yamashita F, Eiichiro O, Kimura A, et al. Reye’s syndrome in Asian countries. In: Pollack JD, editor. Reye’s syndrome. 4th ed. Bryon (OH): National Reye’s Syndrome Foundation, 1985: 47–60Google Scholar
  55. 55.
    Weiss KB, Gergen PJ, Wagener DK. Breathing better or wheezing worse? The changing epidemiology of asthma morbidity and mortality. Annu Rev Public Health 1993; 14: 491–513PubMedCrossRefGoogle Scholar
  56. 56.
    Hofman KJ, Rosen EU. Reye’s syndrome in Johannesburg: epidemiology and clinical presentation. S Afr Med J 1982; 61: 281–2PubMedGoogle Scholar
  57. 57.
    Mowat AP. Commentary to the paper of Hall et al. Arch Dis Child 1988; 63: 857CrossRefGoogle Scholar
  58. 58.
    Sengupta CH, Steffen R, Schar M. Das Reye-Syndrom in der Schweiz. Schweiz Rundsch Med 1987; 76: 1114–6Google Scholar
  59. 59.
    Autret-Lecat E, Jonville-Bera AP, Llau ME, et al. Incidence of Reye’s syndrome in France: a hospital-based survey. J Clin Epidemiol 2001; 54: 857–62CrossRefGoogle Scholar
  60. 60.
    Casteels-Van Daele M. Reye syndrome or side-effects of anti-emetics? Eur J Pediatr 1991; 150: 456–9PubMedCrossRefGoogle Scholar
  61. 61.
    Starko KM, Ray CG, Dominguez LB, et al. Reye’s syndrome and salicylate use. Pediatrics 1980; 66: 854–64Google Scholar
  62. 62.
    Waldman RJ, Hall WN, van Amburg G. Aspirin as a risk factor in Reye’s syndrome. JAMA 1982; 247: 3089–94PubMedCrossRefGoogle Scholar
  63. 63.
    Halpin TJ, Holtzhauer FJ, Campbell RJ, et al. Reye’s syndrome and medication use. JAMA 1982; 248: 687–91PubMedCrossRefGoogle Scholar
  64. 64.
    Hurwitz ES, Barrett MJ, Bregman D, et al. Public Health Service study of Reye’s syndrome and medications: report of the main study. JAMA 1987; 257: 1905–11PubMedCrossRefGoogle Scholar
  65. 65.
    Brown AK, Fikrig S, Findberg L. Aspirin and Reye’s syndrome. J Pediatr 1983; 102: 157–78PubMedCrossRefGoogle Scholar
  66. 66.
    Hall SM. Reye’s syndrome and aspirin: areview. J Royal Soc Med 1986; 79: 596–8Google Scholar
  67. 67.
    Consensus conference: diagnosis and treatment of Reye’s syndrome. JAMA 1981; 246: 2441–4Google Scholar
  68. 68.
    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: 849–57PubMedCrossRefGoogle Scholar
  69. 69.
    Kang AS, Crocker JFS, Johnson GM. Reye’s syndrome and salicylates. N Engl J Med 1986; 314: 920–1CrossRefGoogle Scholar
  70. 70.
    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: 2517–24PubMedCrossRefGoogle Scholar
  71. 71.
    Hall SM, Plaster PA, Glasgow JFT, et al. Preadmission antipyretics in Reye’s syndrome. Arch Dis Child 1988; 63: 857–66PubMedCrossRefGoogle Scholar
  72. 72.
    Forsyth BW, Shapiro ED, Horwitz RI, et al. Misdiagnosis of Reye’s-like illness. Am J Dis Child 1991; 145: 964–6PubMedGoogle Scholar
  73. 73.
    Gauthier M, Guay J, Lacroix J, et al. Reye’s syndrome: a reappraisal of diagnosis in 49 presumptive cases. Am J Dis Child 1989; 143: 1181–5PubMedGoogle Scholar
  74. 74.
    Gladtke E, Schauseil-Zipf U. Reye’s syndrome. Monatsschr Kinderheilk 1987; 135: 699–704Google Scholar
  75. 75.
    Ziebold C, von Kries R, Lang R, et al. Severe complications of varicella in previously healthy children in Germany: a 1-year survey. Pediatrics 2001; 108: E79PubMedCrossRefGoogle Scholar
  76. 76.
    Palomeque A, Domenech P, Martinez-Gutierrez A, et al. Sindrome de Reye in Espana, 1980–1984 (Estudio cooperativo, Seccion de CIP de la AEP). An Esp Pediatr 1986; 24: 285–9PubMedGoogle Scholar
  77. 77.
    Orlowski JP, Campbell P, Goldstein S. Reye’s syndrome: a case control study of medication use and associated viruses in Australia. Cleve Clin Med 1990; 57: 323–9Google Scholar
  78. 78.
    Hurwitz ES. Reye’s syndrome. Epidemiol Rev 1989; 11: 249–53PubMedGoogle Scholar
  79. 79.
    Arrowsmith JB, Kennedy DL, Kuritsky JN, et al. National patterns of aspirin use and Reye syndrome reporting, United States, 1980 to 1985. Pediatrics 1987; 79: 858–63PubMedGoogle Scholar
  80. 80.
    Langford NJ. Aspirin and Reye’s syndrome: is the response appropriate? J Clin Pharm Ther 2002; 27: 157–60PubMedCrossRefGoogle Scholar
  81. 81.
    Zimmerman HJ. Effects of aspirin and acetaminophen on the liver. Arch Int Med 1981; 141: 333–42CrossRefGoogle Scholar
  82. 82.
    Lee WM. Drug-induced hepatotoxicity. N Engl J Med 2003; 349: 474–85PubMedCrossRefGoogle Scholar
  83. 83.
    Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005; 42: 1364–72PubMedCrossRefGoogle Scholar
  84. 84.
    Rivera-Penera T, Gugig R, Davis J, et al. Outcome of acetaminophen overdose in pediatric patients and factors contributing to hepatotoxicity. J Pediatr 1997; 130: 300–4PubMedCrossRefGoogle Scholar
  85. 85.
    Heubi JE, Bien JP. Acetaminophen use in children: more is not better. J Pediatr 1997; 130: 175–7PubMedGoogle Scholar
  86. 86.
    Maison P, Guillemot D, Vauzelle-Kervroedan F, et al. Trends in aspirin, paracetamol and non-steroidal anti-inflammatory drug use in children between 1981 and 1992 in France. Eur J Clin Pharmacol 1998; 54: 659–64PubMedCrossRefGoogle Scholar
  87. 87.
    Broken PA, Bose A, Burgner D, et al. Kawasaki disease: an evidence-based approach to diagnosis, treatment and proposals for future research. Arch Dis Child 2002; 86: 286–90CrossRefGoogle Scholar
  88. 88.
    van Bever HP, Quek SC, Lim T. Aspirin, Reye syndrome, Kawasaki disease, and allergies; a reconsideration of the links [letter]. Arch Dis Child 2004; 89: 1178PubMedCrossRefGoogle Scholar
  89. 89.
    Lindsley CB. Uses of nonsteroidal anti-inflammatory drugs in pediatrics. Am J Dis Child 1993; 147: 229–36PubMedGoogle Scholar
  90. 90.
    Varner AE, Busse WW, Lemasnke Jr RF. Hypothesis: decreased use of pediatric aspirin has contributed to the increasing prevalence of childhood asthma. Ann Aller Asthma Immunol 1998; 81: 347–51CrossRefGoogle Scholar
  91. 91.
    Morwood K, Gillis D, Smith W, et al. Aspirin-sensitive asthma. Intern Med J 2005; 35: 240–6PubMedCrossRefGoogle Scholar
  92. 92.
    Shaheen SO, Sterne AC, Songhurst CE, et al. Frequent paracetamol use and asthma in adults. Thorax 2000; 55: 266–70PubMedCrossRefGoogle Scholar
  93. 93.
    Robertson CF, Heycock E, Bishop J, et al. Prevalence of asthma in Melbourne schoolchildren; changes over 26 years. BMJ 1991; 302: 1116–8PubMedCrossRefGoogle Scholar
  94. 94.
    Ninan TK, Russell G. Respiratory symptoms and atopy in Aberdeen schoolchildren: evidence from two surveys 25 years apart. BMJ 1992; 304: 873–5PubMedCrossRefGoogle Scholar
  95. 95.
    ISAAC. Worldwide variation in prevalence of symptoms of asthma, allergic rhino conjunctivitis and atopic eczema: ISAAC. The International Study of Asthma and Allergy in Childhood (ISAAC) steering committee. Lancet 1998; 351: 1225–32CrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  1. 1.Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum DüsseldorfHeinrich-Heine-UniversitätDüsseldorfGermany

Personalised recommendations