http://bmj.com/cgi/content/full/322/7302/1591
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BMJ 2001;322:1591-1592 ( 30 June )
Clinical review
Lesson of the week
Reye's syndrome and aspirin: lest we forget
Aspirin is an avoidable risk factor for Reye's syndrome: heightened vigilance can prevent an increasing incidence
M C McGovern, specialist registrar a, J
F T Glasgow, reader in child health b, M
C Stewart, senior lecturer b.
a Royal Belfast Hospital for Sick Children, Belfast BT12 6BE, b Department
of Child Health, Queen's University of Belfast, Belfast BT12 6BE
Correspondence to: J Glasgow, Accident and Emergency Department, Royal Belfast Hospital for Sick Children, Belfast BT12 6BE j.glasgow@qub.ac.uk
Reye's syndrome represents an abrupt, profound failure of mitochondria, the
cause of which is uncertain. It is a biphasic illness, occurring
mainly in childhood, which consists of an acute viral prodrome followed
several days later by an acute encephalopathy associated with
selective hepatic abnormality and metabolic decompensation. A
consistent association has been shown between Reye's syndrome and
the use of aspirin during the prodromal illness.1 Of the
56 children with Reye's syndrome treated at this centre between
January 1979 and December 1986, 46 (82%) had been given
aspirin. During the past 13 years just five cases have been
seen
two
occurred in February 1999, and in both cases the child had been
given aspirin.
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Case
1 |
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A boy aged 12.5 years had flu-like symptoms of mild fever, headache, and generalised aches for five days. He was given aspirin (300 mg every four hours for 24 hours) after which his symptoms seemed to resolve. However, 12 hours later he began vomiting, and this continued almost hourly for 24 hours, at which time his parents sought medical help.
There was no relevant medical history. The boy was admitted to hospital and managed with intravenous fluids. Twelve hours later he became agitated and uncontrollable; no lateralising neurological features were present and fundoscopy findings were normal. No abnormalities were noted in cerebrospinal fluid or on urine toxicology screening or on a computed tomogram of the brain. The boy's liver transaminase activities and blood ammonia concentration were noticeably high (table). He was admitted to the paediatric intensive care unit for neurological observation and was given intravenous glucose and electrolytes. The confusion resolved within 48 hours, and over the next few days his liver test results became normal. However, the boy remained tired and lethargic and it was three months before he had recovered sufficiently to return to school full time.
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Case
2 |
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A 9 month old boy was seen four weeks after case 1. He had had a low
grade fever for about 24 hours, and his mother had given him
150 mg aspirin on one occasion. Twelve hours later he began to
vomit and this persisted for 24 hours. When the general practitioner examined
him the boy was limp and lifeless, and hypoglycaemia was confirmed
(table). The boy improved rapidly after intravenous infusion of a
10% glucose and electrolyte solution, but as he was still drowsy he
was transferred to a paediatric intensive care unit. No other
neurological features developed. His liver transaminase activities
and blood ammonia concentration were raised and the prothrombin time
was prolonged (table). Twelve hours after admission to hospital he
had a brief generalised seizure; it was not associated with
hypoglycaemia, and his cerebrospinal fluid was normal. The seizure
responded to intravenous diazepam, and treatment with phenobarbitone
was continued for several days. After 24 hours the boy was
fully conscious and he subsequently made a full recovery.
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Discussion |
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The diagnostic criteria of Reye's syndrome were fulfilled in each of these
cases. In addition, we excluded inherited metabolic disorders, the
group most likely to mimic Reye's syndrome (
oxidation
defects, urea cycle disorders, and other organic acidurias2), and
other plausible diagnoses.
Reye's syndrome occurred fairly frequently in the late 1970s and early 1980s. In the 24 months between January 1983 and December 1984, there were 26 cases in Northern Ireland. Throughout the 1980s, there was increasing awareness of Reye's syndrome in published reports and the media,3 and of the possible link with aspirin usage.1-4 Use of aspirin in children under 12 years of age fell sharply after the Committee on Safety of Medicines gave advice to doctors in 1986.5 This fall in usage was documented in Northern Ireland. An audit of febrile children being admitted to hospital in 1988-9 showed a 17-fold reduction in the use of over the counter aspirin when compared with the results of a similar audit carried out in 1985-6.6 On both sides of the Atlantic the number of cases of Reye's syndrome has paralleled this decline in aspirin use. A recent editorial in the New England Journal of Medicine described the trend as "a public health triumph."7 In 1994-7, only two cases were reported annually in the United Sates,7 and in the United Kingdom and Ireland in 1996-7 there were only five cases.2
We wish to make three points. Firstly, between the end of 1986 and
January 1999, only three cases of Reye's syndrome were seen in
Northern Ireland in spite of a continuing research interest. In
contrast to these three cases, the clinicopathological features collated
as the Reye score (table) showed that both cases described here
conformed to the characteristics of "classic" (North American) Reye's
syndromethe
subgroup of cases shown to be associated with aspirin use.9 In our
opinion, cases of this type will continue to occur when the
1986 warning by the Committee on Safety in Medicine is
overlooked or disregarded.5
As most parents and many professionals have no direct experience of
the severity and possible long term complications of Reye's
syndrome, all medicines containing aspirin have, since April
1998, contained an information leaflet stating: "there is
a possible association between aspirin and Reye's syndrome when
given to children with a fever." The importance of this advice needs
to be more widely appreciated.
Secondly, several effective, alternative treatments (paracetamol, ibuprofen) for symptoms in children with intercurrent infections are not implicated in Reye's syndrome. Children taking aspirin for long term management of connective tissue disorders also run a greater risk of developing Reye's syndrome.10 This was seen in about 4% of 1207 recently reviewed cases in the United States.8 In these circumstances, if a child develops flu-like symptoms or fever, aspirin should be stopped immediately. Although the inherent risks may be greater, similar action might be considered in those requiring aspirin as antiplatelet therapy. In Kawasaki disease, for instance, especially when it is complicated by coronary artery lesions, stopping aspirin prematurely may heighten considerably the chance of thrombosis or even death; specialist advice should be sought and the relative risks carefully balanced. The point is clearly stated in the paediatric formulary, Medicines for Children: "aspirin use should be limited to conditions where a therapeutic advantage is present."11
Thirdly, the carers of case 1 believed that since his 12th birthday had
passed, it was safe to use aspirin for relief of symptoms. Health
professionals need to appreciate that this case is not unique. Among
17 cases reported in the United Kingdom since June 1986, 10 were
in children aged more than 12 years of age who were given
aspirin,12
and in Belay's recent survey of 1207 cases with ages up to
17 years in the United States, 98 (8%) of patients were
aged 15 or older.8
The Medicines Control Agency recently decidedincorrectly,
we believenot
to extend existing advice on aspirin use to include children aged
12 years and above. If this potentially devastating
encephalopathy is not to reappear, there must be heightened
vigilance on the part of the public, parents, and health
professionals, and continued close monitoring by the Medicines
Control Agency.
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Acknowledgments |
We thank Professor K Bartlett and Dr M Pourfarzam for carrying out tandem mass spectrometry.
Contributors: All authors were involved in the management of at least one of the patients described; MCMcG collated the clinical details; JFTG initiated the discussion, and MCS and MCMcG contributed to it.
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Footnotes |
Funding: JFTG received a research grant (1992-8) from the National Reye's Syndrome Foundation of the United Kingdom.
Competing interests: None declared.
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References |
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1. |
Forsyth BW, Horwitz RI, Acampora D, Shapiro ED, Viscoli CM, Feinstein AR, et al. New epidemiologic evidence confirming that bias does not explain the aspirin/Reye's syndrome association. JAMA 1989; 261: 2517-2524[Medline]. |
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2. |
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. |
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3. |
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. Milbank Q 1992; 70: 155-182[Medline]. |
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4. |
Hall SM, Plaster PA, Glasgow JFT, Hancock P. Pre-admission antipyretics in Reye's syndrome. Arch Dis Child 1988; 63: 857-866[Abstract]. |
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5. |
CSM Update: Reye's syndrome and aspirin. BMJ 1986; 292: 1590. |
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6. |
Porter JD, Robinson PH, Glasgow JFT, Banks JH, Hall SM. Trends in the incidence of Reye's syndrome and the use of aspirin. Arch Dis Child 1990; 65: 826-829[Abstract]. |
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7. |
Monto AS. The disappearance of Reye's syndrome |
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8. |
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[Abstract/Full Text]. |
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9. |
Hardie RM, Newton LH, Bruce JC, Glasgow JFT, Mowat AP, Stephenson JPB, et al. The changing clinical pattern of Reye's syndrome 1982-1990. Arch Dis Child 1996; 74: 400-405[Abstract]. |
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10. |
Rennebohm RM, Heubi JE, Daugherty CC, Daniels SR. Reye syndrome in children receiving salicylate therapy for connective tissue disease. J Pediatrics 1985; 107: 877-880[Medline]. |
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11. |
Royal College of Paediatrics and Child Health. Medicines for children. London: Royal College of Paediatrics and Child Health, 1999. |
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12. |
Hall SM, Lynn R. Reye's syndrome |
(Accepted 30 August 2000)
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