Reye Syndrome

Updated: Dec 08, 2022
  • Author: Debra L Weiner, MD, PhD; Chief Editor: Kirsten A Bechtel, MD  more...
  • Print
Overview

Practice Essentials

Reye syndrome is characterized by acute noninflammatory encephalopathy and fatty degenerative liver failure. The syndrome was first described in 1963 in Australia by RDK Reye and described a few months later in the United States by GM Johnson. [1, 2] Cases with identical manifestations were described as early as 1929. In the United States, Reye syndrome became a reportable disease in 1973. Peak incidence was reported in 1979-80. [3, 4, 5]

Reye syndrome typically occurs after a viral illness, particularly an upper respiratory tract infection, influenza, varicella, or gastroenteritis, and is associated with the use of aspirin during the illness. A dramatic decrease in the use of aspirin among children, in combination with the identification of medication reactions, toxins, and inborn errors of metabolism (IEMs) that present with Reye syndrome–like manifestations, have made the diagnosis of Reye syndrome exceedingly rare.

With the recognition that Reye syndrome is rare, this condition should be considered in the differential diagnosis in any child with vomiting and altered mental status and classic laboratory findings. A high index of suspicion is essential. Given that manifestations of Reye syndrome are not unique to Reye syndrome but also are seen in a growing list of conditions, and given that no test is specific for Reye syndrome, the diagnosis must be one of exclusion.

All children with manifestations suggestive of Reye syndrome should be tested for IEM. Early recognition and treatment of Reye and Reye-like syndromes, including presumptive treatment for possible IEM (See Inborn Errors of Metabolism) is essential to prevent death and optimize the likelihood of recovery without neurologic impairment.

Some have suggested the term Reye syndrome or Reye-like syndrome should be used to describe clinical manifestations of diseases states regardless of etiology, while causes still without a known etiology after diagnostic workup should be referred to as Reye disease.

Next:

Pathophysiology

The pathogenesis of Reye syndrome, while not precisely elucidated, appears to involve mitochondrial injury resulting in dysfunction that disrupts oxidative phosphorylation and fatty-acid beta-oxidation in a virus-infected, sensitized host potentially with an underlying occult inborn error of fatty acid oxidation, urea cycle or mitochondrial disorder. [6, 7] The host has usually been exposed to mitochondrial toxins, most commonly salicylates (>80% of cases).

Histologic changes include cytoplasmic fatty vacuolization in hepatocytes, astrocyte edema and loss of neurons in the brain, and edema and fatty degeneration of the proximal lobules in the kidneys. All cells have pleomorphic, swollen mitochondria that are reduced in number, along with glycogen depletion and minimal tissue inflammation. Hepatic mitochondrial dysfunction results in hyperammonemia, which is thought to induce astrocyte edema, resulting in cerebral edema and increased intracranial pressure (ICP).

Previous
Next:

Etiology

Pathogens

Influenza virus types A and B and varicella-zoster virus are the pathogens most commonly associated with Reye syndrome. Other pathogens include parainfluenza virus, adenovirus, coxsackievirus, measles, cytomegalovirus, Epstein-Barr virus, HIV, retrovirus, hepatitis virus types A and B, mycoplasma, chlamydia, pertussis, shigella, salmonella, and polio. Reye has occurred after immunization with live viral vaccines. Pessoa et al reported the case of a 7-year-old child with multisystemic inflammatory syndrome associated with COVID-19, who was treated with intravenous immunoglobulin and acetylsalicylic acid and subsequently developed Reye syndrome. [8]

Salicylates

The association of Reye syndrome with salicylates, particularly aspirin, was demonstrated in several epidemiologic studies around the world. Less than 0.1% of children who took aspirin developed Reye syndrome, but more than 80% of patients diagnosed with Reye syndrome had taken aspirin in the past 3 weeks. A causal relation between Reye syndrome and salicylates has not been definitively established and has been questioned on the basis of biases and limitations in the studies, [9] but recommendations by government health agencies that children not be treated with salicylates led to an immediate and dramatic decrease in the incidence of Reye syndrome.

Results of in vitro studies are contradictory on impact of aspirin on beta-oxidation metabolism. One study demonstrated that salicylates decrease beta-oxidation of the long-chain fatty acid palmitate by cultured fibroblasts from children who recovered from Reye syndrome as compared with control subjects. [6] Another study showed that in two different cell lines, aspirin increased mitochondrial long-chain fatty acid oxidation, did not change oxidation of medium chain fatty acids, and inhibited peroxisomal fatty acid oxidation, which suggest that aspirin impairs long-chain fatty acid transport into mitochondria. [10] Some have postulated that salicylates stimulate the expression of inducible nitric oxide synthase (iNOS) because of the findings of iNOS stimulation in African children with fatal malaria, a disease that causes symptoms similar to those of Reye syndrome and is often treated with aspirin.

Recognition of the structural similarity between aspirin metabolites and enzyme substrates for the mitochondrial trifunctional enzyme important in beta-oxidation led to identification of the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) component of the enzyme as the target of salicylate inhibition. [11] Absence of inhibition of beta-oxidation by salicylates in fibroblasts from patients with LCHAD deficiency substantiated the finding.

Other agents

Other medications

Acetaminophen, outdated tetracycline, valproic acid, warfarin, zidovudine didanosine, and some neoplastic drugs have been associated with Reye syndrome or Reye-like syndrome. Nonsteroidal anti-inflammatory drugs, including sodium diclofenac and mefenamic acid, are thought to produce or worsen Reye syndrome. An association with antiemetics, such as phenothiazines, has been postulated but not substantiated. An association with acetaminophen was reported but has been refuted, although there may be a synergistic effect of acetaminophen and salicylates. [12]

Toxins

Reye syndrome or Reye-like syndrome may also be associated with insecticides; herbicides; aflatoxins; isopropyl alcohol; paint; paint thinner; margosa (neem) oil; hepatotoxic mushrooms; hypoglycin in ackee fruit (Jamaican vomiting sickness); and herbal medications with atractyloside, a diterpenoid glycoside found in the extracts of the tuber of Callilepis laureola (impila poisoning). Bacillus cereus cereulide toxin has also been reported as producing Reye syndrome.

Inborn errors of metabolism

IEMs that produce Reye-like syndromes include fatty-acid oxidation defects, particularly medium-chain acyl dehydrogenase (MCAD) and long-chain acyl dehydrogenase deficiency (LCAD) inherited and acquired forms, urea-cycle defects, amino and organic acidopathies, primary carnitine deficiency, and disorders of carbohydrate metabolism. Undoubtedly, other IEMs that cause Reye-like syndrome will be identified.

The percentage of patients with a previous diagnosis of Reye syndrome is 0.4%. The percentage of patients who have a sibling with a Reye syndrome history is 2.9%. It is likely that at least of some of these patients had an IEM rather than Reye syndrome.

IEMs may account for the heterogeneity of disease manifestations in patients younger than 5 years who have received a diagnosis of Reye syndrome, especially those younger than 1 year. The possibility that IEMs are more likely than true Reye syndrome in patients younger than 5 years may also explain why decreases in salicylate use and decreases in the incidence of Reye syndrome have been greatest in patients older than 5 years.

IEM is suggested by recurrence of symptoms, precipitating factors, including prolonged fasting, changes in diet, decompensation out of proportion to intercurrent illnesses, failure to thrive, neurologic abnormalities, neurologic dysfunction, and family members with similar symptoms and/or unexplained infant deaths.

A retrospective study by Goetz et al included 58 children who were hospitalized with Reye syndrome. Of these patients, 41 (71%) had a confirmed inherited metabolic disorder (IMD). The IMDs included urea cycle disorders (51%), fatty-acid oxidation disorders (24%), ketogenesis defects (5%), other mitochondrial energy metabolism defects (10%), NBAS mutation (7%), and glycosylation disorders (2%). [13]

Previous
Next:

Epidemiology

United States statistics

In the United States, national surveillance for Reye syndrome began in 1973. It is believed that before the 1970s, most of the cases that met the criteria for Reye syndrome were diagnosed as encephalitis or drug intoxication.

The peak annual incidence of 555 cases reported to the Centers for Disease Control and Prevention (CDC) was in 1979-1980. Between December 1, 1980, and November 30, 1997, 1207 cases of Reye syndrome in patients younger than 18 years were reported. [14] During that period, the incidence was 0.15-0.88 cases per 100,000 children per year and as high as 6 cases per 100,000 during regional outbreaks of influenza.

Cases of Reye syndrome declined in number after 1980, when the government began issuing warnings about the association between this syndrome and aspirin. Whereas an average of 100 cases per year were reported in 1985 and 1986, the maximum number of cases reported annually between 1987 and 1993 was 36, with a range of 0.03-0.06 cases per 100,000 per year. Since 1994, 2 or fewer cases have been reported every year. While Reye syndrome reporting to CDC is no longer mandated, many local/state health boards continue to require reporting.

The dramatic decrease in the frequency of Reye syndrome since the 1980s is largely attributable to reduced aspirin use in children, as well as to discoveries of and advances in the diagnosis of inborn errors of metabolism (IEMs) and identification of toxins and drugs capable of producing symptoms that mimic Reye syndrome. The decrease may also be partially attributable to overreporting of cases during the peak years that did not fully meet criteria and underreporting of cases in subsequent years by physicians who did not consider the diagnosis.

Seasonal occurrence initially peaked from December to April, which correlated with the peak occurrence of viral respiratory infections, particularly influenza. Since 1990, the seasonal variation has been less pronounced than was suggested by this initial observation.

International statistics

In the United Kingdom, 597 cases were reported between 1981 and 1996. After warnings of the association between Reye syndrome and aspirin were issued in 1986, the incidence of Reye syndrome decreased substantially, from a high of 0.63 per 100,000 children younger than 12 years in 1983-1984 to 0.11 cases per 100,000 in 1990-1991. Of the 597 cases, 155 were later reclassified, 76 of them as involving an IEM. [15] Similar rates have been reported from other countries.

Age-, sex-, and race-related demographics

Based on US CDC surveillance statistics for 1980-1997 for patients younger than 18 years, 1207 cases were reported in the United States. [14] Incidence peaks between age 5 and 14 years (median, 6 years; mean, 7 years); 13.5% were younger than 1 year. Reye syndrome rarely occurs in newborns or in children older than 18 years. Reye syndrome is equally distributed between the sexes. The racial distribution of Reye syndrome is 93% white and 5% African American, with the remaining percentage Asian, American Indian, and Native Alaskan. Of those younger than 1 year, 67% were African American and 12% were white.

Previous
Next:

Prognosis

The mortality rate has decreased from 50% to less than 20% as a result of early diagnosis, recognition of mild cases, and aggressive therapy. The 1980-1997 case review reports a mortality rate of 31.3%, 42.8% in those younger than 5 years and 24.2% in those older than 5 years, with a relative risk of 1.8% (95% confidence interval [CI], 1.5-2.1%). Decreased mortality also likely reflects an increase in diagnosis of inborn errors of metabolism (IEMs), which is critical for life-saving treatment of disease-specific metabolic derangements. Death is usually due to cerebral edema or increased intracranial pressure (ICP), but it may be due to myocardial dysfunction, cardiovascular collapse, respiratory failure, renal failure, gastrointestinal (GI) bleeding, status epilepticus, or sepsis.

Increased risk of mortality is associated with the following:

  • Age younger than 5 years, with a relative risk of 1.8 (95% CI, 1.5-2.1)

  • Rapid progression from stage 1 to stage 3 and/or presentation with stage 4 or 5 (See Physical Examination) - The death rate by stage at the time of admission is 18% for patients in stage 0 and 90% for those in stage 5; meaningful survival beyond stage 3 is unlikely; full recovery is possible for patients in stages 0-2

  • Central venous pressure (CVP) less than 6 mm H2 0

  • Ammonia level greater than 45 µg/dL (26 µmol/L), with a relative risk of 3.4 (95% CI, 1.9-6.2) [14]

  • Glucose value less than 60 mg/dL

  • Hypoproteinemia unresponsive to fresh frozen vitamin K and fresh frozen plasma (FFP)

  • Muscle involvement

  • Antecedent diarrheal illness

Patients who survive may recover completely. The 1980-1997 US data indicate full recovery in 62% of the 1134 patients with known outcomes. Survivors are at increased risk for long-term neurologic sequelae if ammonia levels exceed 45 µg/dL, if they have stage 2-5 disease, or if they are younger than 5 years. Approximately 3% of patients have neurologic sequelae if ammonia levels are below 45 µg/dL, whereas nearly 11% have sequelae if levels are above 45 µg/dL, with a relative risk of 4.1 (95% CI, 1.2-14).

Complications

Complications of Reye syndrome include the following:

  • Status epilepticus

  • Brain herniation

  • Aspiration pneumonia

  • Acute respiratory failure

  • Cardiac arrhythmias

  • Myocardial infarction

  • Cardiovascular collapse

  • Gastrointestinal bleeding

  • Pancreatitis
  • Diabetes insipidus

  • Acute renal failure

  • Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)

  • Sepsis

  • Death

Previous