REYE (RAY'S) SYNDROME: A PROBLEM EVERYONE SHOULD REMEMBER.

Reye syndrome is a rare but a very dangerous emergency that children and teenagers suffer. This threatening condition occurs during the treatment of fever in the clinical course of viral diseases with drugs containing acetylsalicylic acid and other salicylates. The high mortality rate from this disease is associated with the development of a rapidly progressing toxic encephalopathy and hepatic insufficiency. The etiology and pathogenesis of the Reye syndrome, despite the large number of investigations, is not clear enough. Today, special attention is paid to the development of so-called Reye-like syndromes in the context of congenital metabolic defects, although cases of the true Reye syndrome occur quite often. In spite of the long discussion among scientists, the effect of acetylsalicylic acid is an important factor of development of this pathological syndrome. Taking this fact into consideration, the use of acetylsalicylic acid by children, especially in case of colds, should be strictly controlled by a doctor and parents should be informed about possible complications, especially the development of the Reye syndrome. This issue is very urgent in countries with non-prescription antipyretics realization and a high percentage of self-treatment among patients.

Linking drugs to obscure illnesses: lessons from pure red cell aplasia, nephrogenic systemic fibrosis, and Reye's syndrome. a report from the Southern Network on Adverse Reactions (SONAR).

Identification of serious adverse drug reactions (sADRS) associated with commonly used drugs can elude detection for years. Reye's syndrome (RS), nephrogenic systemic fibrosis (NSF), and pure red cell aplasia (PRCA) among chronic kidney disease (CKD) patients were recognized in 1951, 2000, and 1998, respectively. Reports associating these syndromes with aspirin, gadodiamide, and epoetin, were published 29, 6, and 4 years later, respectively. We obtained primary information from clinicians who identified causes of these sADRs and reviewed factors contributing to delayed identification of these toxicities. Overall, 3,500 aspirin-associated RS cases in the United States, 1,605 gadolinium-associated NSF cases, and 181 epoetin-associated PRCA cases were reported. Delays in FDA regulation of over-the- counter medications and administration of aspirin to children contributed to development of RS. For NSF, in 1996, the Danish Medicine Agency approved high-dose gadodiamide administration to chronic kidney disease (CKD) patients undergoing MR scans. Overall, 88 % of Danish NSF cases were from two hospitals and 97 % of United States' NSF cases were from 60 hospitals. These hospitals frequently administered high-doses of gadodiamide to CKD patients. Another factor was the decision to administer linear chelated contrast agents versus lower risk macrocyclic chelated agents. For PRCA, increased use of subcutaneous epoetin formulations to CKD patients, in part due to convenience and cost-savings considerations, and a European regulatory requirement requiring removal of albumin as a stabilizer, led to toxicity. Overall, 81, 13, and 17 years elapsed between drug introduction into practice and identification of a causal relationship for aspirin, erythropoietin, and gadodiamide, respectively. A substantial decline in new cases of these sADRs occurred within two years of identification of the offending drug. Clinicians should be vigilant for sADRs, even for frequently-prescribed pharmaceuticals, particularly in settings where formulation or regulatory changes have occurred, or when over-the-counter, off-label, or pediatric use is common.

Aspirin and Reye syndrome: a review of the evidence.

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.

Reye's syndrome: the case for a causal link with aspirin.

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.

Tolerabilidad de Aspirina / Aspirin tolerability

El ácido acetilsalicílico (AAS) es un fármaco profusamente utilizado en todo el mundo, presente tanto en preparados que requieren prescripción médica como en productos de libre dispensación, sea en formulaciones que lo contienen como único principio activo, sea como parte de asociaciones a dosis fija. Se emplea tanto de forma puntual, en indicaciones agudas, sintomáticas, como de forma continuada en los regímenes profilácticos anti-trombóticos. Así pues, es muy importante disponer de una sustancia bien tolerada y segura, por su perfil de reacciones adversas y capacidad para interaccionar con otros fármacos. Ambos rasgos son particularmente importantes cuando la población expuesta al fármaco es de cierta edad, debido a sus particulares características que aumentan la susceptibilidad ante reacciones adversas y sus complicaciones. Aspirina comparte el perfil general de reacciones adversas de los AINE, de los que se considera el fármaco prototipo. Administrada de forma aguda, la incidencia de reacciones adversas, por lo general leves, parece similar a la de otros analgésicos. Destacan por su frecuencia los efectos sobre el tracto gastrointestinal, habiéndose detectado una serie de factores de riesgo para el desarrollo de complicaciones graves de las lesiones digestivas. La consideración de estos factores de riesgo junto con la toma de medidas profilácticas, puede disminuir su morbimortalidad. En los últimos años se ha prestado especial atención a las reacciones de hipersensiblidad, destacando el asma inducido por Aspirina, que puede ser cruzado con otros AINE de uso, asimismo, frecuente. El sector de la población más susceptible a presentar reacciones de tipo asmático, presenta unos rasgos bien definidos. Las propiedades antiagregantes de Aspirina pueden complicar ciertas situaciones en que la hemostasia está comprometida, no obstante, se ha demostrado su beneficio en la prevención de accidentes vasculares de carácter atero-trombótico. El síndrome de Reye es un cuadro de rara presentación, pero de graves consecuencias, que contraindica el uso de Aspirina en niños o adolescentes con fiebre o ciertas infecciones virales. Dada la extensa utilización de Aspirina, puede ser considerado un fármaco bien tolerado en general, cuyas reacciones adversas más graves deben ser objeto de una especial farmacovigilancia, prestando especial atención a la población de mayor riesgo. Esta situación aconseja, asimismo, la puesta en marcha de programas de educación sanitaria sobre el uso de los analgésicos. En todo caso, Aspirina sigue siendo un fármaco de referencia con una importante potencialidad terapéutica derivada de los beneficios inherentes a su uso (AU)

The acetylsalicylic acid (ASA) is a widely used drug worldwide, both as prescription and over-the-counter products, and both as the only active drug or associated to other drugs in fixed doses. It is used either occasionally for the management of acute symptomatic conditions, or continuously in prophylactic anti-thrombotic regimes. Its profile of adverse reactions and potential interactions with other drugs makes it very important to have a well-tolerated and safe substance. Both things are particularly relevant when the population exposed to this drug has reached a certain age, since its specific features may increase its susceptibility to side effects and complications. Aspirin shares the general profile of adverse reactions of the NSAIs and it is considered as its prototype. When acutely administered, the incidence of side effects, most of them light, are the same as with other analgesics. Gastrointestinal effects are the most frequent of all and several risk factors have been identify for the development of severe gastrointestinal complications. These risk factors must be considered along with the need to take prophylactic measures in order to reduce the morbi-mortality. In recent years, special attention has been devoted to hypersensitivity reactions, in particular Aspirin-induced asthma, and potential cross-reactions with other frequently used NSAIs. The most susceptible sub-population for asthmatic reactions has well-defined features. The anti-aggregation effects of Aspirin can complicate some conditions associated to hemostasis disorders; however, its benefit has been shown for the prevention of athero-thrombotic vascular accidents. The Reye´s Syndrome is a rare but severe condition in which the use of Aspirin is contraindicated in children or adolescents with fever or certain viral infections. Given the extensive use of Aspirin, it can generally be considered a well-tolerated drug whose most severe adverse reactions require special pharmacovigilance, as well as special attention to high risk populations. This also suggests the need to implement health education programs about the use of analgesics. In any case, Aspirin is still a reference drug with a high therapeutic potential derived from the benefits provided by its use (AU)

Is aspirin a cause of Reye's syndrome? A case against.

Reye's syndrome was a rare disease which appeared suddenly in the early 1950s and disappeared just as suddenly in the late 1980s. An association between Reye's syndrome and the ingestion of aspirin (acetylsalicylic acid) was claimed, although no proof of causation was ever established. The presence of salicylates in the blood or urine of Reye's syndrome patients has not been demonstrated, and no animal model of Reye's syndrome has been developed where aspirin causes the disease. It is clear from epidemiological data that the incidence of Reye's syndrome was decreasing well before warning labels were placed on aspirin products. Reye's syndrome disappeared from countries where aspirin was not used in children as well as from countries which continued to use aspirin in children. Reye's syndrome was probably either a viral mutation which spontaneously disappeared, or a conglomeration of metabolic disorders that had not been recognized or described at that time.

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

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.