Incidence of Reye's syndrome in France: A hospital-based survey

doi:10.1016/S0895-4356(00)00366-8

Journal of Clinical Epidemiology

Volume 54, Issue 8, August 2001, Pages 857-862

https://doi.org/10.1016/S0895-4356(00)00366-8 Get rights and content

Abstract

At the time of the study no information was available in France about the incidence of Reye's Syndrome (RS) and no warnings about RS and aspirin. The objective was to evaluate the incidence of RS in France by a hospital-based study. For a period of 1 year from November 1995 to November 1996, all French paediatric departments were required to report any child under 15 years with unexplained noninflammatory encephalopathy (i.e., CDC consciousness level stage I or deeper with normal CSF) and a threefold (or greater) increase in serum aminotransferase and/or ammonia. All suspected cases were classified by a panel of experts as probable RS or excluded RS. In 10% of randomly selected paediatric departments we checked that every suspected case had been reported. Forty-six suspected cases were reported during the year of the survey, of which 14 were classified as RS. Five of these 14 cases had a metabolic disorder. Nine children were definitively diagnosed as having RS (i.e., an estimated incidence of RS of 0.79/1,000,000 children, i.e., below 15/year). Eight children had been exposed to aspirin, four to aspirin alone and four to aspirin and acetaminophen. On the basis of these results the incidence of RS in France in 1996–1997 was not substantially different from that of countries where warning labels were already in use, but it was higher than in the US after 1994. This was probably due to the reduction in aspirin prescription in France because of warnings in Europe and the US and also because many cases of RS are now identified as metabolic disease. On the basis of these results and because the relationship between aspirin and RS has already been proved, public and professional warnings concerning RS on aspirin-containing products in cases of varicella and viral febrile illness have been adopted by the French Drugs Agency.

Introduction

Reye's syndrome (RS) is a severe, acute paediatric disorder characterized by encephalopathy with pronounced cerebral oedema and by diffuse fatty infiltration of the liver. It may occur at any age in childhood [1]. The illness is typically biphasic: there is apparent near-recovery from a viral type prodromal illness followed after a few days by vomiting and altered consciousness. There is a rise in blood ammonia concentrations and transminase levels. Various factors (viral, toxic, drug related and metabolic) appear to have a role in RS, but only aspirin use during the prodrome has been proved to be associated with RS 2, 3, 4. In the United States two different studies 5, 6, conducted with very strict methodology [7] in terms of the selection of controls and drug exposure, confirmed a significant association between RS and aspirin ingestion during the prodrome. As a result, warnings against aspirin administration to children were issued in the United States in 1980. In the United Kingdom, paediatric preparations were withdrawn from sale and public and professional warnings about the use of aspirin in children under 12 years were introduced in 1986. The incidence of RS in the United Kingdom was reduced from 0.3/100,000 children in 1985–1986 8, 9 to 0.1 in 1990–1991 [10]. In the United States, the incidence was reduced from 0.6/100,000 children in 1979 to less than 0.1 in 1989 11, 12, 13, 14. In the United States from 1987 through 1993, no more than 36 cases were reported each year and from 1994 through 1997 no more than two cases were reported each year [15]. In the same period there was no information in France about the incidence of RS and no label warnings about RS on aspirin products currently used for children. However, after the publication of Hurwitz et al.'s [6] findings in 1987, the French Medicines Agency required information about the incidence of RS. The aim of this study was to estimate the incidence of RS in France.

Section snippets

Method

The study was a hospital-based survey conducted over 1 year between November 1, 1995 and November 1, 1996, including all paediatric departments in France. Each paediatric department was asked to report to the coordinating center any child aged more than 8 days and less than 15 years admitted for unexplained acute noninflammatory encephalopathy (i.e., CDC consciousness level stage I or deeper with normal CSF) and a threefold or greater increase in serum levels of alanine aminotransferase (ALT),

Results

All French Departments of Paediatrics—except 11 that were too specialized—took part in the study (i.e., 370 departments with a total of 9126 beds). The coordinating center conducted 3547 telephone interviews, 296 per month and 10.6 for each of the 370 paediatricians in the study.

Over 12 months (November 1995 to November 1996), 46 suspected cases of RS were reported to the coordinating center. Ten were quickly excluded as RS because they did not meet all the inclusion criteria [i.e., serum

Discussion

The annual incidence of RS in France in 1995–1996 (i.e., 0.797/1,000,000 children) is close to the incidence in the United States and in the United Kingdom where use of aspirin is restricted in children 10, 13. The risks of underreporting were limited in our study because of the active surveillance of all the Departments of Paediatrics, confirmed by the absence of unreported cases of RS in the 10% of departments checked. Moreover, because only three biopsies were performed within the first 4

Conclusion

Although aspirin-containing medications in France have no warnings about RS, the incidence of RS in France in 1996–1997 was not substantially different from countries where warning labels have been in existence for some time. Because the relationship between aspirin and RS has already been proved, the low incidence of RS in France in 1996 is probably explained by a decrease in aspirin exposure due to international attention to the relationship, as happened in the US before the warnings were

Acknowledgements

We thank all French hospital paediatricians, regional pharmacovigilance centers and medical emergency services for their collaboration, Dr J. Goujard, Dr C. Kreft-Jais, Dr C. Soubrié, Mr G. Ducharme and Mr B. Giraudeau for their advice. Mme K. Fouquet for secretarial assistance and Professor Kamoun for the metabolic explorations. This study was funded by a grant from the French Medicines Agency.

Reye's Syndrome in France: A National Register

Committee: E. Autret (Tours); A.P. Jonville-Béra

References (25)

R.D.K. Reye et al.
Encephalopathy and faty degeneration of the visceraa disease entity in childhood
Lancet
(1963)
T.J. Halpin et al.
Reye's syndrome and medication use
JAMA
(1982)
K.M. Starko et al.
Reye's syndrome and salicylate use
Pediatrics
(1980)
R.J. Waldman et al.
Aspirine as a risk factor in Reye's syndrome
JAMA
(1982)
E.S. Hurwitz et al.
Public Health Service study on Reye's syndrome and medications. Report of the pilot phase
N Engl J Med
(1985)
E.S. Hurwitz et al.
Public Health Service study of Reye's syndrome and medications. Report of the main study
JAMA
(1987)
B.W. Forsyth et al.
New epidemiologic evidence confirming that bias does not explain the aspirin/Reye's syndrome association
JAMA
(1989)
S. Hall et al.
The British Paediatric Surveillance Unit
Arch Dis Child
(1988)
S. Hall et al.
Reye's syndrome in the British islesfirst annual report of the joint British Paediatric Association and Communicable Disease Surveillance Center surveillance scheme
BMJ
(1984)
L. Newton et al.
Reye's syndrome in the British Islesreport for 1990/91 and the first decade of surveillance
Communiable Dis Rep
(1993)

E.S. Hurwitz

The changing epidemiology of Reye's Syndrome in the United Statesfurther evidence for a public health success

JAMA

(1988)

J.B. Arrowsmith et al.

National patterns of aspirin use and Reye syndrome reporting, United States, 1980 to 1985

Pediatrics

(1987)

Cited by (24)

Dihydrolipoamide dehydrogenase deficiency: A still overlooked cause of recurrent acute liver failure and Reye-like syndrome
2013, Molecular Genetics and Metabolism
Citation Excerpt :
This acute condition may be reversible; however it is life-threatening because of the cerebral involvement, leading to a 30 to 40% mortality rate. None of the symptoms are specific, as they may be observed in some drug intoxications [2–4] or in several inborn errors of metabolism, primarily urea cycle disorders and fatty acid beta oxidation (FAO) defects [5–7]. DLD deficiency (MIM ID: 238331) caused by recessively-inherited mutations in the DLD gene, leads to a range of presentations, mostly characterized by severe neurological impairment in early childhood with encephalopathy and seizures [8,9].
The causes of Reye-like syndrome are not completely understood. Dihydrolipoamide dehydrogenase (DLD or E3) deficiency is a rare metabolic disorder causing neurological or liver impairment. Specific changes in the levels of urinary and plasma metabolites are the hallmark of the classical form of the disease. Here, we report a consanguineous family of Algerian origin with DLD deficiency presenting without suggestive clinical laboratory and anatomopathological findings. Two children died at birth from hepatic failure and three currently adult siblings had recurrent episodes of hepatic cytolysis associated with liver failure or Reye-like syndrome from infancy. Biochemical investigation (lactate, pyruvate, aminoacids in plasma, organic acids in urine) was normal. Histologic examination of liver and muscle showed mild lipid inclusions that were only visible by electron microscopy. The diagnosis of DLD deficiency was possible only after genome-wide linkage analysis, confirmed by a homozygous mutation (p.G229C) in the DLD gene, previously reported in patients with the same geographic origin. DLD and pyruvate dehydrogenase activities were respectively reduced to 25% and 70% in skin fibroblasts of patients and were unresponsive to riboflavin supplementation. In conclusion, this observation clearly supports the view that DLD deficiency should be considered in patients with Reye-like syndrome or liver failure even in the absence of suggestive biochemical findings, with the p.G229C mutation screening as a valuable test in the Arab patients because of its high frequency. It also highlights the usefulness of genome-wide linkage analysis for decisive diagnosis advance in inherited metabolic disorders.
Liver pathology in Malawian children with fatal encephalopathy
2011, Human Pathology
Citation Excerpt :
None of our possible patients with Reye syndrome had evidence of malarial retinopathy, which is an established clinical marker for CM [30-34]. Our finding of several deaths due to possible Reye syndrome contrasts with the reports of the disappearance of this disease in nontropical areas in parallel with the diminishing use of salicylates among children in such populations [20,35,36]. We found salicylate in the plasma of 41 (21%) of 198 other children admitted during the same period to the same research ward (data not shown), suggesting that there is still considerable use of salicylate-containing medications in Malawi, as there is in rural Kenya [22,37].
A common clinical presentation of Plasmodium falciparum is parasitemia, complicated by an encephalopathy for which other explanations cannot be found, termed cerebral malaria—an important cause of death in young children in endemic areas. Our objective was to study hepatic histopathology in Malawian children with fatal encephalopathy, with and without P falciparum parasitemia, to assess the contributions of severe malaria. We report autopsy results from a series of 87 Malawian children who died between 1996 and 2008. Among 75 cases with P falciparum parasitemia, 51 had intracerebral sequestered parasites, whereas 24 without sequestered parasites had other causes of death revealed by autopsy including 4 patients with clinicopathologic findings which may represent Reye syndrome. Hepatic histology in parasitemic cases revealed very limited sequestration of parasites in hepatic sinusoids, even in cases with extensive sequestration elsewhere, but increased numbers of hemozoin-laden Kupffer cells were invariably present with a strong association with histologic evidence of cerebral malaria by quantitative analysis. Of 12 patients who were consistently aparasitemic during their fatal illness, 5 had clinicopathologic findings which may represent Reye syndrome. Hepatic sequestration of parasitized erythrocytes is not a feature of fatal malaria in Malawian children, and there is no structural damage in the liver. Reye syndrome may be an important cause of fatal encephalopathy in children in Malawi with and without peripheral parasitemia and warrants close scrutiny of aspirin use in malaria-endemic areas.
Fatal case of Reye's syndrome associated with H3N2 influenza virus infection and salicylate intake in a 12-year-old patient
2011, Clinical Microbiology and Infection
Ultrasound guidance for nerve blocks: Principles and practical implementation
2009, British Journal of Anaesthesia
Is the outcome for central neuraxial blockade really reassuring?
2009, British Journal of Anaesthesia
Drug-Induced Hepatic Injury (Prevention)
2006, Therapy of Digestive Disorders

View all citing articles on Scopus

View full text

Original articleIncidence of Reye's syndrome in France: A hospital-based survey

Abstract

Introduction

Section snippets

Method

Results

Discussion

Conclusion

Acknowledgements

Lancet

Reye's syndrome and medication use

JAMA

Reye's syndrome and salicylate use

Pediatrics

Aspirine as a risk factor in Reye's syndrome

JAMA

Public Health Service study on Reye's syndrome and medications. Report of the pilot phase

N Engl J Med

Public Health Service study of Reye's syndrome and medications. Report of the main study

JAMA

New epidemiologic evidence confirming that bias does not explain the aspirin/Reye's syndrome association

JAMA

The British Paediatric Surveillance Unit

Arch Dis Child

Reye's syndrome in the British islesfirst annual report of the joint British Paediatric Association and Communicable Disease Surveillance Center surveillance scheme

BMJ

Reye's syndrome in the British Islesreport for 1990/91 and the first decade of surveillance

Communiable Dis Rep

The changing epidemiology of Reye's Syndrome in the United Statesfurther evidence for a public health success

JAMA

National patterns of aspirin use and Reye syndrome reporting, United States, 1980 to 1985

Pediatrics

Original article
Incidence of Reye's syndrome in France: A hospital-based survey