US Pharm. 2012;37(3):HS6-HS8.
Reye’s syndrome is a rare and potentially fatal condition
affecting children and adolescents, initially described by Australian
pathologist R.D. Reye in 1963.1 It is a metabolic noninflammatory encephalopathy associated with fatty degeneration of the liver.2
Reye’s syndrome is typically preceded by a viral illness, and generally
presents with severe protracted vomiting, followed by encephalopathy
that may progress to coma or death, or may spontaneously resolve.3 Residual neurocognitive effects may remain after recovery from Reye’s syndrome, although some children recover completely.
The initial report by R.D. Reye described 21 children who
presented with severe vomiting, tachypnea, hypoglycemia, and elevated
liver enzymes.1 They also experienced mental status changes
and varying degrees of reduced consciousness, some progressing to coma.
Of these 21 children, 17 died within the first 3 days of admission.
Prior to this syndrome, each of the patients had experienced malaise,
usually associated with an upper respiratory infection. In this report,
Reye notes that the etiology may not be identical in all of these 21
In the mid 1960s, after the publication of Reye’s report,
physicians and researchers around the world worked to identify a cause
for Reye’s syndrome. As early as 1965, it was suggested that the
syndrome could be caused by hypersensitivity to salicylates.4 This view was generally accepted by the late 1980s.5 In 1986, the FDA placed a warning on all OTC aspirin-containing products, and a warning remains on aspirin products today.3
It reads: “Children and teenagers who have or are recovering from
chicken pox or flu-like symptoms should not use this product. When using
this product, if changes in behavior with nausea and vomiting occur,
consult a doctor because these symptoms could be an early sign of Reye’s
syndrome, a rare but serious illness.” However, the link between
aspirin and Reye’s syndrome has not been proven, and this link is still
challenged and debated today.
In 1977, 454 cases of Reye’s syndrome were reported in the
United States. Of the 373 cases with follow-up, 42% of these patients
died, and 11% survived with residual neurologic damage.6
Incidence was increased with viral epidemics, especially influenza B and
varicella. Reye’s syndrome cases in the U.S. numbered 555 in 1980, but
they have fallen drastically. From 1994 until 1997, identified cases in
the U.S. were fewer than two per year.7 The mean mortality rate of Reye’s syndrome is approximately 40% and appears to be higher in males than in females.8
There are several proposed causes for the drastically
reduced rate of Reye’s syndrome cases. Because of efforts to educate the
public regarding the potential danger of using aspirin in children and
adolescents, aspirin use in this population has been largely abandoned,
except for several clinical scenarios in which aspirin is significantly
beneficial, such as Kawasaki disease. Another reason may be improvement
in the recognition and diagnosis of various metabolic diseases and
inborn errors of metabolism, which may present with symptoms similar to
Reye’s syndrome. In fact, some of the cases originally diagnosed as
Reye’s syndrome were later found to be patients with metabolic
disorders. In 2008, a report by Gosalakkal and Kamoji describes a
14-year-old girl presenting with symptoms very similar to Reye’s
syndrome.9 It was determined that the patient actually had
long-chain acyl-coenzyme A (CoA) dehydrogenase deficiency, a metabolic
disorder. An additional explanation that has been proposed to explain
the changing rates is viral mutation over time.10
Although the incidence of Reye’s syndrome is certainly
dropping, there are still reports in the literature. McGovern et al
report two cases of Reye’s syndrome occurring in 1999 in a 12-year-old
boy and a 9-month-old boy.11 Both children were given
aspirin, and metabolic disorders were ruled out. Bhutta et al reported
on a 3-year-old boy in 1999 with recent history of fever and upper
respiratory infection who presented with vomiting and mental status
changes.12 This patient had been given aspirin during his
febrile illness and also promethazine for his vomiting. Liver biopsy was
consistent with Reye’s syndrome, and severe cerebral edema resulted in
herniation. Autopsy results supported the diagnosis of Reye’s syndrome.
Chow and Cherry report a 10-year-old girl presenting in 2002 with a
recent history of sore throat and upper respiratory infection, for which
she had taken aspirin.6 Three days following her aspirin
therapy, she experienced progressive vomiting and dehydration, followed
by confusion and combativeness. Once admitted, she became obtunded and
apneic and was therefore intubated. Symptoms and biopsies were
consistent with Reye’s syndrome. After a few days, the patient was
declared brain dead.
A case of Reye’s syndrome associated with H3N2 influenza and salicylate intake was reported by Ninove et al.13
The patient was a 12-year-old boy who presented in early 2009 with a
recent history of upper respiratory tract infection, later found to be
influenza A (H3N2), and fever. He had been treated with aspirin for this
illness. Two days later, he was admitted with neurologic distress and
gastrointestinal (GI) disease and hematemesis. He also had hypoglycemia
and liver dysfunction. Soon after, he experienced confusion and
drowsiness, and later cerebral edema. This patient died 2 days after
Pathophysiology and Risk Factors
The pathophysiology of Reye’s syndrome is thought to
involve mitochondrial injury, which inhibits oxidative phosphorylation
and fatty-acid beta-oxidation. High concentrations of ammonia may
accumulate due to the decrease in the activity of the mitochondria. On
biopsy, the liver will appear fatty, and changes to the appearance of
the mitochondria are often evident. A brain biopsy will show similar
findings, along with edema. The proposed mechanism for aspirin
contributing to the development of Reye’s syndrome is related to
mitochondrial damage that can be caused by salicylates, which may be
intensified during viral illness by endotoxins and cytokines.14
Causation of Reye’s syndrome remains unclear and is a topic of debate.14
There are many published case-control studies that support a strong
association between aspirin and Reye’s syndrome. One study found a
dose-response effect as well.15 A total dose of less than 45
mg/kg of aspirin was found to increase the risk of Reye’s syndrome
20-fold, and the authors concluded that any amount of aspirin is unsafe
in a child with a viral infection, regardless of the dose. Many authors
point to the radically decreasing rates of Reye’s syndrome that occurred
with the cessation of aspirin use in children as evidence of a
causative link as well. Since it is now recognized that several
metabolic disorders can cause symptoms that are very similar to Reye’s
syndrome, many hypothesize that reported Reye’s syndrome cases
represented a variety of disorders. These disorders likely include
metabolic disorders that were not diagnosed at the time, and may also
include idiopathic Reye’s syndrome in which aspirin was, in fact, a
Others, however, claim that the association between
aspirin and Reye’s syndrome does not necessarily prove a causal
relationship. Reye’s syndrome was first described in 1963, but aspirin
was used in children long before the 1960s. In addition, aspirin was not
universally used in all children who developed Reye’s syndrome, and
there were some control patients without the syndrome who had taken
aspirin. Skeptics of this link further highlight that these case studies
are retrospective, and recall bias can be an issue with this type of
study design. They also point out that at the time most of these case
studies were done, parents may not have distinguished between
acetaminophen and aspirin.10 Salicylate serum concentrations
were usually not measured in the patients studied, and biopsy
confirmation of the Reye’s syndrome diagnosis was also frequently not
obtained.10 As such, some authors have questioned whether aspirin does, in fact, need to be avoided by children.17
Several infectious agents have been correlated with Reye’s
syndrome and Reye-like syndrome. Viral agents include influenza A and
B, varicella, parainfluenza, measles, adenoviruses, coxsackie viruses,
cytomegalovirus, Epstein–Barr virus, HIV, hepatitis A and B, and
rotavirus.18 Some bacterial agents may play a role as well, including Mycoplasma, Chlamydia, Shigella, and Salmonella.18
Of note, an association has also been observed between
Reye’s syndrome and several other medications and toxins, including
hypoglycin from the ackee fruit, aflatoxin, paint-thinner,
acetaminophen, valproic acid, outdated tetracycline, zidovudine, and
didanosine.19 The relationship of these agents to Reye’s
syndrome is not as strong of an association as that of aspirin and the
syndrome. A possible role of antiemetics was suggested in the 1970s
because at that time, as many as 71% of Reye’s syndrome cases were
associated with phenothiazine use early in the course of the disease.19
This hypothesis was discarded based on the results of epidemiologic
studies in the 1980s, but some authors and practitioners argue that this
relationship may, in fact, be significant.19
Because no test is specific for Reye’s syndrome, it is a
diagnosis of exclusion. A high index of suspicion must be present in a
patient with vomiting and mental status changes. Diagnostic criteria
from the CDC are listed in TABLE 1.20
Diseases and conditions that resemble Reye’s syndrome must
be ruled out. These conditions include metabolic disorders such as
defects in fatty acid oxidation (including acyl-CoA dehydrogenase
deficiencies), disorders of oxidative phosphorylation, urea-cycle
defects, disorders of carbohydrate metabolism, other metabolic disorders
and errors of inborn metabolism, CNS infection or meningitis, and drug
or toxic ingestion. Disorders causing presentation with acute liver
failure should also be ruled out.
Reye’s syndrome is a biphasic condition that typically
occurs in a child who is otherwise healthy. It begins as a prodromal
febrile illness that is likely viral in nature, such as an upper
respiratory infection or varicella, or possibly rotavirus.21 After this illness resolves, the child will recover for 3 to 5 days.18
Following this period is sudden onset of protracted vomiting along with
a degree of mental status changes that will vary with severity of
disease. Patients will often present with some degree of hepatomegaly
and hepatic dysfunction due to fatty degeneration of the liver, but they
will not be icteric. There also may be an elevation of intracranial
The severity of Reye’s syndrome can be classified with the clinical staging system (TABLE 2).22
Stages 1 through 3 are considered to represent mild-to-moderate
disease, while stages 4 and 5 of the illness represent severe Reye’s
There is no specific treatment for Reye’s syndrome, and
therefore the appropriate treatment strategy is to provide supportive
care. Early diagnosis is important, and other diseases causing similar
symptoms must be ruled out. Hypoglycemia can be treated by administering
fluids such as 10% dextrose, thus providing glucose to the patient.
Coagulopathies may be managed with blood transfusions, and intubation
may be necessary to provide adequate oxygenation. Intracranial pressure
must be monitored and controlled in patients with cerebral edema.
Management of cerebral edema may involve fluid restriction, diuresis,
and corticosteroids. Pentobarbital has been given to patients to
decrease cerebral metabolic demands.23 Therapies to reduce
hyperammonemia may also be indicated. In patients who develop seizures,
antiepileptic medications may be necessary.
Reye’s syndrome is a serious condition of children and
adolescents that is rarely seen today. Aspirin is considered to be the
most significant causative agent, although this association is often
challenged. Pharmacists can play a role in ensuring the appropriate use
of aspirin in the pediatric population. Despite the controversy
regarding the relationship of aspirin to Reye’s syndrome, this is a
condition with significant morbidity and mortality and therefore it is
prudent to continue to limit the use of aspirin in children. A
risk-benefit assessment must be done on a patient-by-patient basis.
While the benefit likely outweighs the risk in patients with disorders
such as Kawasaki disease, the pharmacist can play a role in ensuring
that these patients receive their influenza vaccination to decrease
their chance of viral illness during their aspirin therapy. In otherwise
healthy children, the use of aspirin as an antipyretic or
anti-inflammatory agent is not recommended because the benefit likely
does not outweigh the risk. In this circumstance, the pharmacist can
play an important role in recommending an alternative agent, such as
ibuprofen or acetaminophen.
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2. Schrör K. Aspirin and Reye syndrome: a review of the evidence. Paediatr Drugs. 2007;9:195-204.
3. Fitzgerald DA. Aspirin and Reye syndrome. Paediatr Drugs. 2007;9:205-206.
4. Giles HM. Encephalopathy and fatty degeneration of the liver. Lancet. 1965;1:1075.
5. Clark I, Whitten R, Molyneux M, et al. Salicylates, nitric oxide, malaria, and Reye’s syndrome. Lancet. 2001;357:625-627.
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13. Ninove L, Daniel L, Gallou J, et al. Fatal case of
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17. Langford NJ. Aspirin and Reye’s syndrome: is the response appropriate? J Clin Pharm Ther. 2002;27:157-160.
18. Pugliese A, Beltramo T, Torre D. Reye’s and Reye’s-like syndromes. Cell Biochem Funct. 2008;26:741-746.
19. Casteels-Van Daele M, Van Geet C, Wouters C, et al.
Reye syndrome revisited: a descriptive term covering a group of
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20. CDC. National Reye syndrome surveillance—United States, 1982 and 1983. MMWR Morb Mortal Wkly Rep. 1984;33:41-42.
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22. Lovejoy FH, Smith AL, Bresnan MJ, et al. Clinical staging in Reye syndrome. Am J Dis Child. 1974;128:36-41.
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