Reye Syndrome

Reye syndrome is a rare, acute, non-inflammatory encephalopathy accompanied by fatty degeneration of the liver, affecting mainly children and teenagers, typically during or shortly after a viral illness such as chickenpox (varicella) or influenza.^[1] Aspirin (acetylsalicylic acid, ASA) use during that viral illness has been strongly linked to its development, and current Canadian regulation requires every over-the-counter ASA-containing product to carry an explicit warning against use in anyone under 18 years of age with chicken pox, cold, or flu symptoms.^[1][2] Untreated or unrecognized, Reye syndrome is genuinely dangerous: Health Canada's own figures put case fatality at 20-30%, with permanent brain damage among survivors.^[1]

Because the disease itself is now so rare, a portion of children historically diagnosed with "Reye syndrome" — particularly those under 2 years of age, those with recurrent episodes, or those without a clear preceding viral illness or documented salicylate exposure — are, on more sophisticated modern metabolic testing, ultimately found to have an underlying inborn error of metabolism instead (see Assessment & Diagnosis and Special Populations).^[5][4]

The classic biphasic pattern

Reye syndrome classically follows a biphasic course: a child has an ordinary viral illness — an upper respiratory infection or influenza-like illness, chickenpox, or a gastroenteritis-type illness — and appears to be recovering, then, typically 3-7 days after the viral illness began (StatPearls describes a wider possible window of 12 hours to 3 weeks, most commonly 3-6 days), develops sudden, persistent, forceful vomiting, often without diarrhea, that is frequently the first thing a caregiver notices.^[6][4] Within hours, this is followed by rapidly progressive changes in mental status and behaviour.^[6][4]

What families and frontline staff actually observe

• Persistent, repeated vomiting in a child or teenager who seemed to be getting better.^[6]
• Unusual sleepiness or lack of energy, or the opposite — irritability, agitation, or aggressive/combative behaviour that is out of character.^[6]
• Confusion, disorientation, or slurred speech.^[6]
• Progressing, if unrecognized, to seizures and coma.^[6]
• No jaundice — this is a genuinely important negative finding, not an oversight; despite significant hepatic involvement, the skin and sclerae typically do not turn yellow, because bilirubin handling itself is preserved even though transaminases and ammonia are markedly elevated (see Assessment & Diagnosis).^[7]
• Hepatomegaly is found on examination in roughly 40% of cases, typically non-tender.^[7]
• Focal neurologic findings (weakness on one side, cranial nerve deficits) are typically absent — their presence should prompt reconsideration of the diagnosis (see Assessment & Diagnosis).^[7]

The five-stage clinical scale

Once encephalopathy is recognized, clinical staging both communicates severity and drives the intensity of supportive care (see Choose Initial Treatment).

^[4] Reported mortality tracks this staging closely — under 2% in Stage 1, rising to over 80% in Stages 4-5 — which is the clearest possible illustration of why early recognition, at the vomiting-plus-mental-status-change stage rather than after progression to stupor or coma, is the single highest-value clinical action in this chapter.^[7]

• Age. Reye syndrome affects mainly children and teenagers; StatPearls reports a peak incidence age of 5-14 years, though cases occur in infants and young children as well — a group in which an underlying inborn error of metabolism is a more likely explanation for a similar presentation (see Assessment & Diagnosis and Special Populations).^[1][4]
• A preceding viral illness is present in the great majority of cases. In US surveillance data, influenza A or B preceded roughly 73% of cases, varicella (chickenpox) preceded roughly 21%, and a gastroenteritis-type illness preceded roughly 14%; less common associations include coxsackievirus, Epstein-Barr virus, cytomegalovirus, adenovirus, and certain bacterial infections (Mycoplasma, Bordetella pertussis, Shigella, Chlamydia).^[4]
• Salicylate (aspirin) exposure during that viral illness is the dominant, causally implicated risk factor — more than 80% of children diagnosed with Reye syndrome had taken aspirin in the preceding three weeks.^[4] This is the single fact this chapter's counselling centerpiece exists to act on; see Non-Pharmacologic Treatment.
• Seasonal clustering broadly December through April, tracking influenza and varicella season.^[4]
• A minority of cases occur without any documented salicylate exposure. In the current, post-warning era, an apparent Reye-syndrome-like illness without a clear salicylate history — especially in a young child, or with recurrent episodes — should raise suspicion for an underlying inborn error of metabolism rather than being accepted as idiopathic Reye syndrome (see Assessment & Diagnosis).^[5][4]

Diagnostic criteria

Reye syndrome is diagnosed clinically, supported by a characteristic laboratory pattern, and is ultimately a diagnosis of exclusion. The commonly used diagnostic criteria require all three of the following: (1) an acute, non-inflammatory encephalopathy — altered consciousness, with cerebrospinal fluid, if sampled, showing 8 leukocytes/mm³ or fewer; (2) hepatopathy, confirmed either by liver biopsy showing the characteristic changes or by at least a threefold elevation in AST/ALT or ammonia; and (3) no better alternative explanation for the encephalopathy or hepatic abnormality.^[4]

The central laboratory pearl: elevated transaminases and ammonia with a normal bilirubin

This is the single most important laboratory teaching point in this chapter. Reye syndrome produces markedly elevated AST and ALT (typically more than three times the upper limit of normal), an elevated blood ammonia level, and a prolonged prothrombin time — together with a normal bilirubin.^[4][7] This pattern — real, significant hepatic dysfunction without jaundice or hyperbilirubinemia — genuinely distinguishes Reye syndrome from viral hepatitis and most other causes of acute hepatic failure, where hyperbilirubinemia is expected, and it explains why the classic presentation described in Recognize the Condition specifically lacks jaundice despite hepatomegaly and abnormal liver enzymes.^[7] Ammonia is often the earliest and most sensitive abnormality, typically rising within 1-2 days of the encephalopathy's onset, and the degree of elevation correlates with clinical severity and prognosis.^[4]

Other supporting laboratory and CSF findings

• Hypoglycemia — a common and directly treatable finding, especially in younger children (see Choose Initial Treatment).^[4]
• Prolonged prothrombin time and other coagulopathy from impaired hepatic synthetic function.^[4]
• Metabolic acidosis and electrolyte disturbance are common, reflecting both the illness itself and the effects of persistent vomiting.^[4]
• Cerebrospinal fluid, when sampled to exclude meningitis/encephalitis, characteristically shows 8 leukocytes/mm³ or fewer and normal protein, with increased opening pressure reflecting cerebral edema rather than infection.^[4]
• Liver biopsy provides the definitive diagnosis when performed — diffuse microvesicular fatty infiltration of hepatocytes, notably without significant necrosis or inflammatory infiltrate, again contrasting with the necroinflammatory picture of viral hepatitis. It is now rarely performed given the syndrome's rarity, its invasiveness, and improved non-invasive recognition, but remains particularly useful in sporadic or atypical cases.^[4]
• Neuroimaging (CT or MRI) may show diffuse cerebral edema; it does not confirm the diagnosis but is used to exclude a mass lesion, hemorrhage, or stroke and to help guide intracranial pressure management.

The differential diagnosis — inborn errors of metabolism are genuinely important, not a footnote

^[4][7] Any child under 2 years of age, any child with a recurrent "Reye-like" episode, and any presentation without a clear preceding viral illness or documented salicylate exposure should prompt an urgent metabolic work-up (plasma amino acids, urine organic acids, acylcarnitine profile, and urine orotic acid if a urea cycle disorder is suspected) in parallel with — not instead of — standard supportive management, together with metabolic genetics involvement.^[4] This is not a theoretical concern: in a UK national surveillance review of 418 cases diagnosed as Reye syndrome, 89 diagnoses were later revised on more sophisticated testing, and 36% of those revisions were to an inborn error of metabolism — a striking, concrete reminder that "presumed Reye syndrome" in the wrong clinical context deserves a genuine metabolic work-up, not just a mention in the differential.^[5]

• Recognize the biphasic pattern — vomiting following apparent recovery from a viral illness, then altered mental status — early enough to escalate before significant neurologic injury occurs.
• Correct and maintain euglycemia throughout the acute illness.
• Prevent and treat cerebral edema and manage elevated intracranial pressure aggressively when present, matched to clinical stage.
• Correct coagulopathy and other metabolic derangements (acidosis, electrolyte disturbance).
• Actively exclude — in parallel, not sequentially — an underlying inborn error of metabolism or another alternative diagnosis, particularly in a young child or a recurrent presentation.
• Provide meticulous, stage-matched supportive/ICU care, since no specific antidote or disease-modifying drug exists.
• Support full neurologic recovery, which is achievable for most patients when recognized and treated promptly.
• Prevent the next case. Given how rare and how severe this condition is, and how directly modifiable the salicylate risk factor is, primary-prevention counselling is, in practical terms, this chapter's single most impactful pharmacist-level intervention — see Non-Pharmacologic Treatment.

Do not give any aspirin- or salicylate-containing product at any point in this presentation or its recovery — this should be self-evident, but confirm no salicylate-containing product (including bismuth subsalicylate, given for the antecedent GI symptoms) remains in the treatment plan; use acetaminophen, dosed cautiously given the hepatic involvement, if antipyresis is separately needed.^[1][6]

Supportive care during the acute episode

• General ICU-level supportive nursing care: positioning, temperature control, seizure precautions, and meticulous neurologic-status monitoring matched to clinical stage.
• Hold enteral feeds during significant encephalopathy given aspiration risk and likely ileus; once stabilized, resume nutrition with an initial, short-term caution around protein and fat intake, transitioning back to normal intake as hepatic function recovers — this caution should be short-term only, not a lasting dietary restriction, unless an underlying inborn error of metabolism specifically requiring long-term dietary management is ultimately confirmed (see Assessment & Diagnosis).
• Assess swallowing safety before resuming oral intake in any child recovering from Stage 3 or higher encephalopathy.

Ordinary post-viral vomiting versus the red-flag pattern

Most vomiting during a routine childhood viral illness is not Reye syndrome. Routine caregiver guidance — small, frequent sips of fluid, oral rehydration solution if needed, and gradual reintroduction of food — remains appropriate for ordinary viral-illness vomiting. What distinguishes the pattern in this chapter is the combination of persistent, forceful vomiting with any accompanying change in mental status or behaviour, particularly following apparent recovery from the initial illness — see Red Flags & Refer.

Infants and children under 2 years

An inborn error of metabolism — particularly a fatty acid oxidation disorder (e.g., MCAD deficiency) or a urea cycle disorder (e.g., OTC deficiency) — is a substantially more likely explanation for a Reye-like presentation at this age than true Reye syndrome. Pursue urgent metabolic work-up (plasma amino acids, urine organic acids, acylcarnitine profile, urine orotic acid) in parallel with standard supportive care rather than sequentially, and involve metabolic genetics early (see Assessment & Diagnosis).^[4][5]

Recurrent "Reye-like" episodes, or no documented salicylate exposure

Treat as presumptive inborn error of metabolism until proven otherwise, and pursue the same urgent metabolic work-up. A family history of unexplained infant or early childhood death is a specific additional prompt to pursue this work-up aggressively.^[4]

Varicella-exposed children

Chickenpox is one of the two classic viral triggers for Reye syndrome and remains a specific, named prompt for aspirin-avoidance counselling in Canadian public health messaging.^[1][2] Reinforce this counselling explicitly at the point a chickenpox diagnosis is made or suspected, and during any local varicella activity, independent of whether the child has been varicella-vaccinated.

Influenza season

Reinforce salicylate-avoidance counselling proactively during flu season — at influenza vaccination visits, and whenever recommending or dispensing any OTC product for a feverish child or teenager.

Children on chronic salicylate therapy for another indication

A small number of children remain on long-term aspirin therapy for a specific, physician-directed indication — the clearest example on this platform is Kawasaki disease, where acute- and maintenance-phase aspirin is a deliberate, guideline-endorsed exception to routine pediatric salicylate avoidance (see the Kawasaki Disease chapter). These children need a temporary switch to an alternative antiplatelet agent (clopidogrel or dipyridamole) if they develop varicella or influenza while on aspirin, and are specifically recommended to receive annual influenza vaccination to reduce exposure to one of the two classic triggers. Counsel these families with the specific nuance intact rather than a blanket "never give aspirin" message.

Households with an adult on chronic low-dose ASA

A grandparent or other household member on cardioprotective low-dose aspirin represents a real, practical inadvertent-exposure risk for a child in the home — counsel on secure, separate storage, and specifically ask about this when taking a medication history for any ill child.

• Track neurologic status and clinical stage trend at frequent, defined intervals; where ICP monitoring is in place, use it to guide osmotic therapy and sedation in real time rather than relying on intermittent clinical exam alone.
• Trend glucose, ammonia, transaminases, bilirubin, and coagulation studies serially — ammonia trajectory in particular correlates with clinical severity and is useful prognostically, distinct from its diagnostic role at presentation.^[4]
• Arrange long-term neurodevelopmental follow-up for survivors, particularly those who experienced seizures or decerebrate/decorticate posturing during the acute illness, since this group carries a meaningfully higher risk of residual neurologic deficit.^[7]
• Where a metabolic work-up was pursued, ensure results are actively followed up and communicated — an identified inborn error of metabolism carries genetic-counselling and family-planning implications well beyond the index episode.
• Document a clear, durable flag in the patient's record for any confirmed Reye syndrome episode: salicylate/ASA avoidance should be considered indefinite going forward, not limited to the acute recovery window, and every future caregiver (including school and daycare staff) should know it.
• At every subsequent pharmacy contact with the family — for this child or any sibling — reinforce the aspirin/salicylate-avoidance counselling framework in Non-Pharmacologic Treatment; household risk factors and habits are shared across siblings.

1. Persistent or worsening mental status, or new posturing, despite initial supportive measures — reassess and intensify the intracranial-pressure protocol, consider invasive ICP monitoring if not already in place, and obtain neurosurgical consultation.^[4]
2. Ammonia continuing to rise, or crossing a markedly elevated threshold, despite supportive care — escalate to ammonia-scavenging pharmacotherapy (sodium benzoate/sodium phenylacetate) or hemodialysis/continuous renal replacement therapy, specialist-directed.^[4]
3. Uncontrolled coagulopathy or active bleeding — escalate vitamin K, fresh frozen plasma, and/or cryoprecipitate, and involve hematology.
4. Presentation does not fit cleanly (age under 2 years, recurrent episodes, no clear preceding viral illness, or no documented salicylate exposure) — pursue urgent metabolic work-up and genetics consultation in parallel with ongoing supportive care rather than continuing to treat empirically as classic Reye syndrome (see Assessment & Diagnosis).^[5][4]
5. Ongoing seizures despite standard first-line measures — escalate per the institution's pediatric status-epilepticus protocol (see this platform's Febrile Seizure chapter for the equivalent benzodiazepine escalation ladder used more broadly in pediatric seizure management).
6. Following recovery — regardless of how the acute episode resolved, treat any future salicylate/ASA exposure risk as a standing, lifelong counselling point for this child, and document it clearly (see Monitoring & Follow-Up).

• Treating persistent vomiting plus a mental status or behaviour change following a viral illness as routine dehydration or "just the flu" without specifically asking what OTC products the child received during the preceding illness.
• Waiting overnight, or for symptoms to "prove themselves," before seeking emergency care — progression can occur within hours.^[4]
• Relying on jaundice or an elevated bilirubin to confirm hepatic involvement — a normal bilirubin alongside elevated transaminases and ammonia is the expected, classic pattern, not a reason to lower suspicion for Reye syndrome.^[7][4]
• Accepting an apparent Reye syndrome diagnosis at face value in a child under 2 years of age, with recurrent episodes, or without a clear preceding viral illness or documented salicylate exposure, instead of pursuing an urgent metabolic work-up — historical data show a genuinely substantial share of such cases are ultimately inborn errors of metabolism.^[5]
• Asking only "did you give aspirin?" instead of asking specifically about all products given, including bismuth subsalicylate ("stomach medicine"), combination analgesics, and any borrowed adult medication — a caregiver can correctly and honestly say "no" to the direct question while having given a salicylate-containing product without recognizing it.^[6]
• Delivering a blanket "never give your child aspirin" message without the Kawasaki disease exception nuance for a family already correctly following a physician-directed chronic-ASA regimen — see Special Populations and the Kawasaki Disease chapter.
• Continuing protein/fat dietary restriction beyond the acute recovery phase without a confirmed inborn error of metabolism specifically requiring it — the correct approach is short-term caution during active encephalopathy, not a lasting dietary restriction.
• Recommending or dispensing any ASA- or salicylate-containing product (including bismuth subsalicylate) for anyone under 18 with a current fever, cold/flu-type illness, or chickenpox without first checking the active-ingredient panel — brand recognition and marketed use category are not reliable enough on their own.^[2]

How to use this table: Doses are adult doses and require patient-specific confirmation (renal/hepatic function, weight, allergy history). Pediatric dosing is weight-based per the current product monograph unless stated. Drug pricing is intentionally omitted. Select any drug name to open its complete Pharmasist Drug Database page.

Salicylates — Avoid in Anyone Under 18 During a Current Viral Illness

Both entries below are salicylates, strongly linked to Reye syndrome. Canadian regulation requires an explicit Reye syndrome warning on every OTC ASA-containing product and prohibits marketing ASA products for use by children or teenagers.

Safe Antipyretic/Analgesic Alternatives

Preferred, effective substitutes for any fever, pain, or discomfort in a child or teenager under 18, with no Reye syndrome association.

Acute Supportive/ICU Therapy for Confirmed or Presumed Reye Syndrome

No agent here is disease-modifying — all are supportive, targeting a specific complication of the encephalopathy/hepatopathy. Specialist/ICU-directed dosing throughout.

Symptomatic Adjuncts

Supportive only — never a substitute for recognizing and escalating the red-flag vomiting-plus-altered-mental-status pattern itself.