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Editor—The paper by McGovern et al is based on a non-specific definition and an outdated concept of Reye's syndrome in spite of recent convincing data relating to this issue.1 Reye's syndrome is no longer a specific clinicopathological entity but a descriptive term covering a group of heterogeneous disorders of infectious, metabolic, or toxic aetiology.2
All symptoms in the first case, including the neurological complications, can be explained by the influenza A infection.2 Moreover, the confusion lasting for only 48 hours might have been the result of using antiemetics in a patient who had been vomiting almost hourly for 24 hours.2 Urine toxicology screening does not exclude this additional complication.
In the second case, exhaustive virological investigations and liver biopsy were not performed, and the metabolic screening is incomplete. In both patients the diagnosis of Reye's syndrome is therefore put forward—in the best case—by default.
We are surprised that McGovern et al ignore the misleading biases in the epidemiological studies suggesting a link between Reye's syndrome and aspirin.2,3 The studies were performed on series of children with heterogeneous disorders, which already invalidates their results. In the studies that recorded correctly all drugs given before admission, the use of not one but two drugs was significant—namely, aspirin and antiemetics.2 Neither is the decline of Reye's syndrome an argument for a link with aspirin; evidence shows that this decline is the result of medical progress leading to more correct diagnosis of infectious, metabolic, or toxic disease.2,4
When promoting paracetamol and ibuprofen it would be wise not to conceal their side effects—for example, the hepatotoxicity of paracetamol, which can occur even at minor overdoses given during a few days. This was documented by Rivera-Penera et al and discussed in an accompanying editorial by Heubi and Bien, who assumed that the estimates of the occurrence of paracetamol toxicity are the tip of the iceberg of the total number of cases seen in the United States.5
We end with a question about the five cases seen over 13 years mentioned by McGovern et al in their introduction. Two cases occurred in February 1999, and in both the child had been given aspirin. What had been given to the other children?
Footnotes
Competing interests: The authors have no ongoing affiliation or financial involvement with any pharmaceutical company or with any other entity with a financial interest in the subject matter.
References
1.McGovern MC, Glasgow JFT, Stewart MC. Reye's syndrome and aspirin: lest we forget. BMJ. 2001;322:1591–1592. doi: 10.1136/bmj.322.7302.1591. . (30 June.) [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Casteels-Van Daele M, Van Geet C, Wouters C, Eggermont E. Reye's syndrome revisited: a descriptive term covering a group of heterogenous disorders. Eur J Pediatrics. 2000;159:641–648. doi: 10.1007/pl00008399. [DOI] [PubMed] [Google Scholar]
3.Hall SM. Reye's syndrome and aspirin: a review. J R Soc Med. 1986;79:596–598. doi: 10.1177/014107688607901014. [DOI] [PMC free article] [PubMed] [Google Scholar]
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5.Rivera-Penera T, Gugig R, Davis J, McDiarmid S, Vargas J, Rosenthal P, et al. Outcome of acetaminophen overdose in pediatric patients and factors contributing to hepatotoxicity. J Pediatr. 1997;130:300–304. doi: 10.1016/s0022-3476(97)70359-7. [DOI] [PubMed] [Google Scholar]
Editor—Neither nosology nor nomenclature should be regarded as static but as dynamic disciplines that evolve as understanding of causation and pathogenesis bear on clinical experience and its reporting. But Casteels-Van Daele et al go too far in saying that Reye's syndrome is no longer a clinicopathological entity but a term embracing heterogeneous, disparate disorders. On the contrary, increased understanding has come about by the adoption of a standardised definition that enables case ascertainment—epidemiology as a springboard for biological research.1-1 In Northern Ireland children with encephalopathic illnesses are referred for investigation and management to a single tertiary unit, and paediatricians maintain a high degree of vigilance so that inherited metabolic disorders are unlikely to masquerade as Reye's syndrome or vice versa.
Remarkably few patients have been seen since 1986 (when the Committee on Safety of Medicines warned professionals against use of aspirin in children), by contrast with previous numbers. In 1979-80 there were nine; in 1981-82, 10; in 1983-84, 25; and in 1985-86,11. This action and continuing case surveillance has been rightly regarded as a triumph in primary prevention of a devastating childhood illness.
We appreciate that Reye's syndrome is not a single entity, but broad consensus remains that a major identifiable variant is associated with aspirin taken for the symptoms of febrile illness, of which our cases are examples.1-2 Our primary concerns are in relation to warnings on sales over the counter, and the age limit above which aspirin is—erroneously, in our opinion—regarded as safe. Another concern is case surveillance, especially in the event of further influenza outbreaks. With reference to the specific cases described, the first patient had not received any medicine except aspirin; antiemetics are not usually given in Northern Ireland for brief gastrointestinal upsets in children. Even if the patients had received alternative treatments, evidence linking drugs other than aspirin with Reye's syndrome has never been accepted or sustained. The other three patients seen between 1986 and 1998 were each atypical, had low Reye scores, and were not linked to use of either drug.
Clear thinking is crucial to understanding this spectrum of encephalopathy—Reye's-like syndromes associated with an inherited metabolic disorder, Reye's syndrome that meets the non-specific, diagnostic criteria, and “classic” (aspirin associated) Reye's syndrome that we must try to prevent.1-1,1-2
We have demonstrated biological plausibility using cultured fibroblasts from recovered patients with Reye's syndrome. Salicylate within the therapeutic range and its metabolites reversibly inhibit activity of β-oxidation at 3-hydroxyacyl-CoA dehydrogenase of the mitochondrial trifunctional enzyme—quite the opposite response to that found in control cells.1-3
References
1-1.Royal College of Paediatrics and Child Health. British Paediatric Surveillance Unit – annual report 2000-2001. London: RCPCH; 2001. [Google Scholar]
1-2.Hardie RM, Newton LH, Bruce JC, Glasgow JFT, Mowat AP, Stephenson JBP, et al. The changing clinical pattern of Reye's syndrome 1982-1990. Arch Dis Child. 1996;74:400–405. doi: 10.1136/adc.74.5.400. [DOI] [PMC free article] [PubMed] [Google Scholar]
1-3.Glasgow JFT, Middleton B, Moore R, Gray A, Hill J. The mechanism of inhibition of β-oxidation by salicylate in skin fibroblasts from Reye's syndrome patients and controls. Biochem Biophys Acta. 1999;1454:115–125. doi: 10.1016/s0925-4439(99)00025-3. [DOI] [PubMed] [Google Scholar]
