Reye's syndrome
Encyclopedia
Reye's syndrome is a potentially fatal disease
that causes numerous detrimental effects to many organs, especially the brain
and liver
, as well as causing a lower than usual level of blood sugar (hypoglycemia
). The classic features are liver damage, aspirin use and a viral infection. The exact cause is unknown, and while it has been associated with aspirin
consumption by children with viral illness, it also occurs in the absence of aspirin use.
The disease causes fatty liver
with minimal inflammation and severe encephalopathy
(with swelling of the brain). The liver may become slightly enlarged and firm, and there is a change in the appearance of the kidney
s. Jaundice
is not usually present.
Early diagnosis is vital; while most children recover with supportive therapy, severe brain injury or death are potential complications.
" rather than a disease
as the clinical features that physicians use to diagnose it are quite broad.
The serious symptoms of Reye's syndrome appear to result from damage to cellular mitochondria, at least in the liver, and there are a number of ways that aspirin could cause or exacerbate mitochondrial damage. A potential increased risk of developing Reye's syndrome is one of the main reasons that aspirin has not been recommended for use in children and teenagers, the age group for which the risk of lasting serious effects is highest.
No research has found a definitive cause of Reye's syndrome, and association with aspirin has only been shown through epidemological studies. The diagnosis of "Reye's Syndrome" greatly decreased in the 1980s, when genetic testing for inborn errors of metabolism was becoming available in developed countries
. A retrospective study of 49 survivors of cases diagnosed as "Reye's Syndrome" showed that the majority of the surviving patients had various metabolic disorders.
In some countries, oral mouthcare product Bonjela
(not the form specifically designed for teething) has labeling cautioning against its use in children, given its salicylate content. There have been no cases of Reye's secondary to its use, and the measure is a precaution. Other medications containing salicylates are often similarly labeled as a precaution.
The Centers for Disease Control and Prevention
(CDC), the U.S. Surgeon General, the American Academy of Pediatrics
(AAP) and the Food and Drug Administration
(FDA) recommend that aspirin and combination products containing aspirin not be given to children under 19 years of age during episodes of fever-causing illnesses. Hence, in the United States
, it is advised that the opinion of a doctor or pharmacist be obtained before anyone under 19 years of age is given any medication containing aspirin (also known on some medicine labels as acetylsalicylate, salicylate, acetylsalicylic acid, ASA or salicylic acid).
Current advice in the United Kingdom
by the Committee on Safety of Medicines is that aspirin should not be given to those under the age of 16 years, unless specifically indicated in Kawasaki disease
or in the prevention of blood clot formation.
In 1980, after CDC began cautioning physicians and parents about the association between Reye’s syndrome and the use of salicylates in children with chickenpox or viruslike illnesses, the incidence of Reye's syndrome in the United States began to decline. In the United States between 1980 and 1997, the number of reported cases of Reye’s syndrome decreased from 555 cases in 1980 to about 2 cases per year since 1994. During this time period 93% of reported cases for which racial data were available occurred in whites and the median age was six years. In 93% of cases a viral illness had occurred in the preceding three week period. For the period 1991-1994, the annual rate of hospitalizations due to Reye’s syndrome in the US was estimated to be between 0.2 and 1.1 per million population less than 18 years of age.
During the 1980s, a case-control study carried out in the United Kingdom also demonstrated an association between Reye’s syndrome and aspirin exposure. In June 1986, the United Kingdom Committee on Safety of Medicines issued warnings against the use of aspirin in children under 12 years of age and warning labels on aspirin-containing medications were introduced. UK surveillance for Reye’s syndrome documented a decline in the incidence of the illness after 1986. The reported incidence rate of Reye’s syndrome decreased from a high of 0.63 per 100,000 population less than 12 years of age in 1983/84 to 0.11 in 1990/91.
From November 1995 to November 1996 in France, a national survey of pediatric departments for children under 15 years of age with unexplained encephalopathy
and a threefold (or greater) increase in serum aminotransferase and/or ammonia led to the identification of nine definite cases of Reye’s syndrome (0.79 cases per million children). Eight of the nine children with Reye’s syndrome were found to have been exposed to aspirin. In part because of this survey result, the French Medicines Agency reinforced the international attention to the relationship between aspirin and Reye’s syndrome by issuing its own public and professional warnings about this relationship.
. In retrospect, the occurrence of the syndrome may have first been reported in 1929. Also in 1964, Dr. George Johnson and colleagues published an investigation of an outbreak of influenza B that described 16 children who developed neurological problems, four of whom had a profile remarkably similar to Reye’s syndrome. Some investigators refer to this disorder as Reye-Johnson syndrome, although it is more commonly called Reye's syndrome. In 1979, Dr. Karen Starko and colleagues conducted a case-control study in Phoenix, Arizona and found the first statistically significant link between aspirin use and Reye's syndrome. Studies in Ohio and Michigan soon confirmed her findings pointing to the use of aspirin during an upper respiratory tract or chickenpox infection as a possible trigger of the syndrome. Beginning in 1980, the CDC cautioned physicians and parents about the association between Reye’s syndrome and the use of salicylates in children and teenagers with chickenpox or viruslike illnesses. In 1982 the U.S. Surgeon General issued an advisory, and in 1986 the Food and Drug Administration
required a Reye’s syndrome-related warning label for all aspirin-containing medications.
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
that causes numerous detrimental effects to many organs, especially the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
and liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, as well as causing a lower than usual level of blood sugar (hypoglycemia
Hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
). The classic features are liver damage, aspirin use and a viral infection. The exact cause is unknown, and while it has been associated with aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
consumption by children with viral illness, it also occurs in the absence of aspirin use.
The disease causes fatty liver
Fatty liver
Fatty liver, also known as fatty liver disease , is a reversible condition where large vacuoles of triglyceride fat accumulate in liver cells via the process of steatosis...
with minimal inflammation and severe encephalopathy
Encephalopathy
Encephalopathy means disorder or disease of the brain. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of global brain dysfunction; this syndrome can be caused by many different illnesses.-Terminology:...
(with swelling of the brain). The liver may become slightly enlarged and firm, and there is a change in the appearance of the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
s. Jaundice
Jaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
is not usually present.
Early diagnosis is vital; while most children recover with supportive therapy, severe brain injury or death are potential complications.
Symptoms and signs
Reye's syndrome progresses through five stages, explained below:- Stage I
- Rash on palms of hands and feet
- Persistent, heavy vomitingVomitingVomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
that is not relieved by not eating - Generalized lethargy
- ConfusionConFusionConFusion is an annual science fiction convention organized by the Stilyagi Air Corps and its parent organization, the Ann Arbor Science Fiction Association. Commonly, it is held the third weekend of January. It is the oldest science fiction convention in Michigan, a regional, general SF con...
- NightmareNightmareA nightmare is an unpleasant dream that can cause a strong negative emotional response from the mind, typically fear or horror, but also despair, anxiety and great sadness. The dream may contain situations of danger, discomfort, psychological or physical terror...
s - High feverFeverFever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
- Headaches
- Stage II
- StuporStuporStupor is the lack of critical cognitive function and level of consciousness wherein a sufferer is almost entirely unresponsive and only responds to base stimuli such as pain. This is often mistaken for delirium and treated with Haldol and or other anti-psychotic drugs...
caused by encephalitisEncephalitisEncephalitis is an acute inflammation of the brain. Encephalitis with meningitis is known as meningoencephalitis. Symptoms include headache, fever, confusion, drowsiness, and fatigue... - HyperventilationHyperventilationHyperventilation or overbreathing is the state of breathing faster or deeper than normal, causing excessive expulsion of circulating carbon dioxide. It can result from a psychological state such as a panic attack, from a physiological condition such as metabolic acidosis, can be brought about by...
- Fatty liverFatty liverFatty liver, also known as fatty liver disease , is a reversible condition where large vacuoles of triglyceride fat accumulate in liver cells via the process of steatosis...
(found by biopsyBiopsyA biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
) - Hyperactive reflexesHyperreflexiaHyperreflexia is defined as overactive or overresponsive reflexes. Examples of this can include twitching or spastic tendencies, which are indicative of upper motor neuron disease as well as the lessening or loss of control ordinarily exerted by higher brain centers of lower neural pathways...
- Stupor
- Stage III
- Continuation of Stage I and II symptoms
- Possible comaComaIn medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...
- Possible cerebral oedema
- Rarely, respiratory arrestRespiratory arrestRespiratory arrest is the cessation of breathing. It is a medical emergency and it usually is related to or coincides with a cardiac arrest. Causes include opiate overdose, head injury, anaesthesia, tetanus, or drowning...
- Stage IV
- Deepening coma
- Dilated pupils with minimal response to light
- Minimal but still present hepatic dysfunction
- Stage V
- Very rapid onset following stage IV
- Deep coma
- Seizures
- Multiple organ failure
- FlaccidityFlaccid paralysisFlaccid paralysis is a clinical manifestation characterized by weakness or paralysis and reduced muscle tone without other obvious cause .-Polio:...
- HyperammonemiaHyperammonemiaHyperammonemia is a metabolic disturbance characterised by an excess of ammonia in the blood. It is a dangerous condition that may lead to encephalopathy and death. It may be primary or secondary....
(above 300 mg/dL of blood) - Death
Causes
The precise mechanism by which Reye's syndrome occurs remains unknown. This serious condition is described as a "syndromeSyndrome
In medicine and psychology, a syndrome is the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one or more features alerts the physician to the possible presence of the others...
" rather than a disease
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
as the clinical features that physicians use to diagnose it are quite broad.
Aspirin
Some studies have demonstrated an association between aspirin taken for viral illnesses and the development of Reye’s syndrome. One small study presented findings that acetaminophen (paracetamol) is a greater risk, but this claim is disputed.The serious symptoms of Reye's syndrome appear to result from damage to cellular mitochondria, at least in the liver, and there are a number of ways that aspirin could cause or exacerbate mitochondrial damage. A potential increased risk of developing Reye's syndrome is one of the main reasons that aspirin has not been recommended for use in children and teenagers, the age group for which the risk of lasting serious effects is highest.
No research has found a definitive cause of Reye's syndrome, and association with aspirin has only been shown through epidemological studies. The diagnosis of "Reye's Syndrome" greatly decreased in the 1980s, when genetic testing for inborn errors of metabolism was becoming available in developed countries
Developed country
A developed country is a country that has a high level of development according to some criteria. Which criteria, and which countries are classified as being developed, is a contentious issue...
. A retrospective study of 49 survivors of cases diagnosed as "Reye's Syndrome" showed that the majority of the surviving patients had various metabolic disorders.
In some countries, oral mouthcare product Bonjela
Bonjela
Bonjela Original and Bonjela Cool are oral gels, aimed to relieve the pain of mouth ulcers and denture sores. Bonjela gel contains keratolytic and mildly antiseptic salicylic acid in the form of its salt choline salicylate, the antiseptic cetalkonium chloride, and antiseptic ethanol as active...
(not the form specifically designed for teething) has labeling cautioning against its use in children, given its salicylate content. There have been no cases of Reye's secondary to its use, and the measure is a precaution. Other medications containing salicylates are often similarly labeled as a precaution.
The Centers for Disease Control and Prevention
Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention are a United States federal agency under the Department of Health and Human Services headquartered in Druid Hills, unincorporated DeKalb County, Georgia, in Greater Atlanta...
(CDC), the U.S. Surgeon General, the American Academy of Pediatrics
American Academy of Pediatrics
The American Academy of Pediatrics is the major professional association of pediatricians in the United States. The AAP was founded in 1930 by 35 pediatricians to address pediatric healthcare standards. It currently has 60,000 members in primary care and sub-specialist areas...
(AAP) and the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) recommend that aspirin and combination products containing aspirin not be given to children under 19 years of age during episodes of fever-causing illnesses. Hence, in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
, it is advised that the opinion of a doctor or pharmacist be obtained before anyone under 19 years of age is given any medication containing aspirin (also known on some medicine labels as acetylsalicylate, salicylate, acetylsalicylic acid, ASA or salicylic acid).
Current advice in the United Kingdom
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
by the Committee on Safety of Medicines is that aspirin should not be given to those under the age of 16 years, unless specifically indicated in Kawasaki disease
Kawasaki disease
Kawasaki disease , also known as Kawasaki syndrome, lymph node syndrome and mucocutaneous lymph node syndrome, is an autoimmune disease in which the medium-sized blood vessels throughout the body become inflamed. It is largely seen in children under five years of age...
or in the prevention of blood clot formation.
Prognosis
Documented cases of Reye’s syndrome in adults are rare. The recovery of adults with the syndrome is generally complete, with liver and brain function returning to normal within two weeks of the illness. In children, however, mild to severe permanent brain damage is possible, especially in infants. Over thirty percent of the cases reported in the United States from 1981 through 1997 resulted in fatality.Differential diagnosis
Causes for similar symptoms include- Various inborn metabolic disorders
- Viral encephalitisViral encephalitisViral encephalitis refers to a type of Encephalitis caused by a virus.Encephalitis may be caused by a variety of afflictions.Types include:*Arbovirus encephalitis**La Crosse encephalitis**California encephalitis virus**Japanese Encephalitis**St...
- Drug overdoseDrug overdoseThe term drug overdose describes the ingestion or application of a drug or other substance in quantities greater than are recommended or generally practiced...
or poisonPoisonIn the context of biology, poisons are substances that can cause disturbances to organisms, usually by chemical reaction or other activity on the molecular scale, when a sufficient quantity is absorbed by an organism....
ing - Head trauma
- Hepatic failure due to other causes
- MeningitisMeningitisMeningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...
- Renal failureRenal failureRenal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
Epidemiology
Reye’s syndrome occurs almost exclusively in children. While a few adult cases have been reported over the years, these cases do not typically show permanent neural or liver damage. Unlike in the UK, the surveillance for Reye’s syndrome in the US is focused on patients under 18 years of age.In 1980, after CDC began cautioning physicians and parents about the association between Reye’s syndrome and the use of salicylates in children with chickenpox or viruslike illnesses, the incidence of Reye's syndrome in the United States began to decline. In the United States between 1980 and 1997, the number of reported cases of Reye’s syndrome decreased from 555 cases in 1980 to about 2 cases per year since 1994. During this time period 93% of reported cases for which racial data were available occurred in whites and the median age was six years. In 93% of cases a viral illness had occurred in the preceding three week period. For the period 1991-1994, the annual rate of hospitalizations due to Reye’s syndrome in the US was estimated to be between 0.2 and 1.1 per million population less than 18 years of age.
During the 1980s, a case-control study carried out in the United Kingdom also demonstrated an association between Reye’s syndrome and aspirin exposure. In June 1986, the United Kingdom Committee on Safety of Medicines issued warnings against the use of aspirin in children under 12 years of age and warning labels on aspirin-containing medications were introduced. UK surveillance for Reye’s syndrome documented a decline in the incidence of the illness after 1986. The reported incidence rate of Reye’s syndrome decreased from a high of 0.63 per 100,000 population less than 12 years of age in 1983/84 to 0.11 in 1990/91.
From November 1995 to November 1996 in France, a national survey of pediatric departments for children under 15 years of age with unexplained encephalopathy
Encephalopathy
Encephalopathy means disorder or disease of the brain. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of global brain dysfunction; this syndrome can be caused by many different illnesses.-Terminology:...
and a threefold (or greater) increase in serum aminotransferase and/or ammonia led to the identification of nine definite cases of Reye’s syndrome (0.79 cases per million children). Eight of the nine children with Reye’s syndrome were found to have been exposed to aspirin. In part because of this survey result, the French Medicines Agency reinforced the international attention to the relationship between aspirin and Reye’s syndrome by issuing its own public and professional warnings about this relationship.
History
The syndrome is named after Dr. R. Douglas Reye, who, along with fellow physicians Dr. Graeme Morgan and Dr. Jim Baral, published the first study of the syndrome in 1963 in The LancetThe Lancet
The Lancet is a weekly peer-reviewed general medical journal. It is one of the world's best known, oldest, and most respected general medical journals...
. In retrospect, the occurrence of the syndrome may have first been reported in 1929. Also in 1964, Dr. George Johnson and colleagues published an investigation of an outbreak of influenza B that described 16 children who developed neurological problems, four of whom had a profile remarkably similar to Reye’s syndrome. Some investigators refer to this disorder as Reye-Johnson syndrome, although it is more commonly called Reye's syndrome. In 1979, Dr. Karen Starko and colleagues conducted a case-control study in Phoenix, Arizona and found the first statistically significant link between aspirin use and Reye's syndrome. Studies in Ohio and Michigan soon confirmed her findings pointing to the use of aspirin during an upper respiratory tract or chickenpox infection as a possible trigger of the syndrome. Beginning in 1980, the CDC cautioned physicians and parents about the association between Reye’s syndrome and the use of salicylates in children and teenagers with chickenpox or viruslike illnesses. In 1982 the U.S. Surgeon General issued an advisory, and in 1986 the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
required a Reye’s syndrome-related warning label for all aspirin-containing medications.