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C.H. Malcolmson, MD

Reye's Syndrome
SUMMARY
The author defines and discusses Reye's
syndrome and the hypotheses relating to its
causes and associating its incidence with that
of chickenpox and influenza A and B. The
recent decline in the incidence of Reye's
syndrome appears to be related to the
reduced use of Aspirin in children and
adolescents. Although evidence so far is
circumstantial, North American P(a)ediatric
Associations have indicated that Asprinn
should not be used to control fever in children
who have viral infections but especially in
children suspected of having chickenpox or
influenza A or B. (Can Fam Physician 1987;
33:2615-2617.)
Key words: Reye's syndrome, acetylsalicylic acid, Aspirin
M"wm. 5-:.:
RESUME
L'auteur definit le syndrome de Reye et en discute
les hypotheses etiologiques et l'association entre son
incidence et celle de la varicelle et de l'influenza de
type A et B. Le declin recent de l'incidence du
syndrome de Reye semble relie a l'usage restreint de
l'Aspirine chez les enfants et les adolescents. Malgre
l'absence, a ce jour, de preuves directes, les
associations nord-americaines de pediatrie ont
indique que l'Aspirine ne devrait pas etre utilisee
pour controler la fievre dans les cas de varicelle ou
d'influenza de type A et B chez les enfants.
noulon

Dr. Malcolmson is an associate
professor in Pediatrics at McMaster
University, Hamilton. He is also
Director of the Pediatric Intensive
Care Unit and Intermediate Care
Unit of Chedoke-McMaster
Hospitals, Hamilton. Requests for
reprints to: Dr. C.H. Malcolmson,
Box 2000, Station A, 1200 Main St.
W., Hamilton, Ont. L8N 3Z5
EYE'S SYNDROME is tradi-
itionally described as a biphasic
disease characterized by an initial
viral illness, often resolving com-
pletely, with the sudden onset, of
variable severity, of a complex cas-
cade of profuse (intractable) vomit-
ing, alterations in consciousness
(combattiveness), sometimes progres-
sion of the altered neurological state
to delirium, coma, and, on occasion,
CAN. FAM. PHYSICIAN Vol. 33: NOVEMBER 1987
death. 1, 2 At any stage this progression
may resolve, with variable outcome,
for no known predictable reason. The
outcome appears to have little predic-
tability. The severity of the prodromal
illness or the particular associated
viral illness has no predictive value.
The degree or stage of Reye's syn-
drome has predictive value only in
that patients with stage-I Reye's syn-
drome make a complete recovery. In-
deed, it is unlikely that stage I of the
disease will even be recognized. Pa-
tients with stage-II Reye's syndrome
almost always make a complete re-
covery also, but of those who pro-
gress to stage III, it has so far been
accepted that a number will have
neurological impairment ranging from
an almost insignificant degree up-
ward. In the light of newer and more
specific neuropsychological studies,
however, such as those dealing with
children who have experienced head
injuries, this view may well need to
be reconsidered.
It has been postulated that Reye's
syndrome is caused by a disruption in
mitochondrial function, initiated by a
viral infection and aggravated or com-
pounded by a toxin in a possibly gen-
etically susceptible individual.1 The
mitochondria are the major energy
sources in the cell. Without the pro-
duction of energy by the mitochon-
dria, cell function does not occur.
Such things as Na, K, intra- and ex-
tracellular water transport, and the
production of clotting factors, along
with the formation of urea from am-
monia and defects in the urea cycle,
are obvious deficits characteristic of
Reye's syndrome.
The preceding viral infection is typ-
ically influenza A or B, or chicken-
pox. A variety of other viral infec-
tions have at times been associated
with Reye's syndrome. As mentioned
2615
above, the severity of the viral illness
has little to do with outcome.
The two toxins most commonly as-
sociated with Reye's syndrome have
been Aspirin and the emulsifying
agent used with Spruce Budworm
spray.' Again, however, a confusion
of confounding factors enter into the
equation. A significant number of pa-
tients who have had Reye's syndrome
have not been exposed to any toxin.
In the Aspirin study about 10% of
subjects (2 of 27), had not had any
salicylate.3 Many other agents have
been implicated in the case studies
over the years, mostly in an anecdotal
fashion, and certainly in insufficient
numbers to establish any concrete as-
sociation.
Acetylsalicylic acid, as well as ace-
taminophen and other non-steroidal
anti-inflammatory analgesics, have
been associated with liver toxicity.4' 5
In fact, Prescott states that Aspirin
given in sufficient doses and over suf-
ficient periods of time, will have a he-
patotoxic effect on most patients.4 In
only a small number of instances does
an idiosyncratic reaction occur with
severe hepatotoxicity and with throm-
bocytopenia. Acetaminophen poison-
ing is also characterized by hepatotox-
icity, at times to the point of
irreversible hepatic failure. In both
these instances there is characteristic
hepatocellular damage which includes
mitochondrial damage.5
The incidence of Reye's syndrome
has been said to vary with the re-
ported frequency of cases in a specific
epidemic of influenza or chickenpox,
and the decline in the incidence has
been associated with the declining use
of Aspirin in children under 10 years
of age. 3' 6In the most recent data pub-
lished by the Center for Disease Con-
trol,3 the incidence of Reye's syn-
drome has also declined in the total
population, even the 11- to 19-year
age group.7 Again, this trend has
been correlated with the decline in the
use of Aspirin even in this group of
patients who were more inclined to
self-medicate, and who appeared pre-
viously not to be affected by the
overall decline in the incidence of
Reye's syndrome.
The incidence of Reye's syndrome
has steadily declined during the past
seven years to the point that it is now
difficult to collect data even in a mul-
ticentre trial.7 In 1977, 454 cases
were reported, and in that year the
2616
major influenza strain was the influ-
enza B virus. The incidence of Reye's
syndrome rose to 555 in 1980, when
the major influenza strain identified
was the influenza B virus. In 1984,
when there was a mix of the influenza
A and the influenza B viruses, 204
cases of Reye's syndrome were re-
ported. This number represented a
significant decline in the expected re-
porting of Reye's syndrome. In 1985,
81 cases were reported as of the date
of reporting.7 This figure, too, repre-
sented a significant decrease in re-
ported cases.
In the same period there had been a
major information campaign stressing
to the general public the concern that
there was an association between
Reye's syndrome and the use of
Aspirin. The decline in use of Aspirin
was most noticeable in the 0- 10 age
group which was studied by P.L.
Remmington and his associates.6 On
comparing the use of antipyretics in
the years 1981 and 1983, these re-
searchers found a marked decrease of
at least 50% in the use of Aspirin but
no comparable decrease in the use of
acetaminophen.
Reye's syndrome may well always
have been a much more common dis-
ease than physicians ever considered
it to be. Lichtenstein and his asso-
ciates suggest that the incidence of
Reye's syndrome is much higher than
is generally perceived, and that physi-
cians may have been missing the
diagnosis, or that with today's better
knowledge physicians are considering
this diagnosis and doing the confirma-
tory tests. Whether there is a high as-
sociation between the use of acetylsa-
licylic acid and stage-I Reye's
syndrome awaits a future study and
remains to be proven.
Many articles have been based on
the Public Health Service Study of
Reye's Syndrome and Medications.
A pilot study3 9 looked at 27 patients
with stage-II or higher Reye's syn-
drome as confirmed by a panel of ex-
perts. All these patients had had a
viral illness prior to the onset of the
typical signs of Reye's syndrome. In
only two cases had the patients not
been exposed to Aspirin; 90% had
been exposed to Aspirin during the
antecedent illness and prior to the
onset of Reye's syndrome.
Several articles have been pub-
lished describing the increased inci-
dence of Reye's syndEromze in children)
who had been taking acetylsalicylic
acid for collagen vascular disease,
specifically juvenile rheumatoid ar-
thritis.7
In spite of some arguments about
the design of the study, the research
from this and all similar studies, very
strongly supports the theory that
Aspirin is likely a significantly contri-
buting component to the development
of Reye's syndrome.8 In the editor's
opinion little new information has
been published on the subject over the
past six years, and by now, in his
view, the association should be evi-
dent to everyone. Crocker has sug-
gested' that the chemical contributor
likely acts in a compounding toxic ac-
tion on the mitochondria, causing the
breakdown of mitochondrial function
and therefore of cell-energy produc-
tion and inherent cell function. This
process then leads to a breakdown of
functions that leads to the syndrome
complex called 'Reye's syndrome'.
Why the seemingly exact same set of
circumstances (viral illness and toxin)
causes Reye's syndrome in one child
and brings about no sign of the syn-
drome in another is not known. It has
been suggested that a genetic factor
exists that predisposes particular indi-
viduals to this type of response, al-
though there has so far been no evi-
dence, other than circumstantial, to
support this hypothesis.
Nevertheless both the American Pe-
diatric Association and the Canadian
Paediatric Association have strongly
recommended that Aspirin not be
used to control fevers in the child
with a viral infection, specifically in
epidemics of chickenpox and influ-
enza A and B. Indeed, with few ex-
ceptions, unless a child has a colla-
gen-vascular disease or a disease
requiring the specific anti-inflamma-
tory or anticoagulant effect of salicy-
late, such as Kawasaki's disease,10
there is likely little place in pediatrics
for the use of Aspirin (acetylsalicylic
acid).
References
1. Crocker JF, Bagnell PC. Reye's syn-
drome: a clinical review. Can Med Assoc
J 1981; 124:375-82.
2. Lichtenstein P, Heubi JE, Daugherty
CC, et al. Grade 1 Reye's syndrome. N
Engl J Med 1983; 309(3):133-8.
3. Hurwitz ES, Barrett MF, Bergman D,
et al. Public Health Service study of
Reye's Syndrome and medications; Report
CAN. FAM. PHYSICIAN Vol. 33: NOVEMBER 1987
of the main study. JAMA 1987;
257(4): 1905- 11.
4. Starko KM, Ray CG, Dominquez LB,
et al. Reyes Syndrome and salicylate use.
Pediatrics 1980; 66(6):859-64.
5. Prescott LF. Effects of non-narcotic an-
algesics on the liver. Drugs 1986;
32(Suppl): 129- 47.
6. Remington PL, Rowley D, McGee H,
et al. Decreasing trends in Reye Syndrome
and aspirin use in Michigan, 1979 to
1984. Pediatrics 1986; 77(1):93 - 8.
7. Barrett MJ, Hurwitz ES, Schonberger
LB, et al. Changing epidemiology of Reye
syndrome in the United Sates. Pediatrics
1986; 77(4):598- 602.
8. Stockman JA. (Editorial comments).
In: Yearbook ofpediatrics. Chicago: Year-
book Medical Publishers, Inc., 1987;
552-4.
9. Hurwitz ES, Barrett MJ, Bergman D,
et al. Public Health Service study on
Reye's Syndrome and medications. Report
of the pilot study. N Engl J Med 1985;
313(14):849- 57.
10. The Reye Syndrome/Aspirin contro-
versy 1986. Kauffman RE. Contemporary
Pediatrics, Nov. Dec. 1986. pgs. 17-24.
For Further Reading
1. Brunner RL, O'grady DJ, Partin JC, et
al. Neurologic consequences of Reye syn-
drome. J Ped 1979; 95(5):706- 11.
2. DeVivo D. How common is Reye's syn-
drome? N Engl J Med 1983; 124:
3. Hurwitz ES, Nelson DB, Davis C, et
al. National surveillance for Reye syn-
drome: a five year review. Pediatrics
1982; 70(6):
4. Rennebohm RM, Heubi JE, Daugherty
CC, et al. Reye syndrome in children re-
ceiving salicylate therapy for connective
tissue disease. J Ped 1985; 107(6):
877- 80.
5. Shaywitz SE, Cohen PM, Cohen DJ, et
al. Long-term consequences of Reye syn-
drome: a sibling-matched controlled study
of neurologic, cognitive, academic, and
psychiatric function. J Ped 1982; 100(1):
41-6.
6. Zimmerman HJ. Effects of aspirin and
acetaminophen on the liver. Arch Int Med
1981; 141:333-42.
7. Surgeon general's advisory on the use
of salicylates on Reye's Syndrome.
MMWR 1982; 31(32):289.
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E4naprox
Indications. (naproxen sodium)
Relief of mild to moderately severe
pain, accompanied by inflammation such
as musculoskeletal trauma, post-dental
extraction, relief of post-partum cramp-
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Contraindications.
Patients who have hypersensitivity to
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steroidal drugs induce asthma, rhinitis
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Not recommended in children under
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Precautions.
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with caution in patients with impaired
renal function, compromised cardiac
function and patients whose overall
intake of sodium is markedly restricted.
(Each tablet contains approximately
25 mg of sodium.)*
*Probenecid increases Anaprox plasma
levels and half-life.
Adverse Reactions.
G.I.: nausea, heartburn, abdominal
discomfort, vomiting, constipation, dys-
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trointestinal bleeding (occasionally
severe) and hematemesis.
C.N.S.: dizziness, headache, drowsi-
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vertigo, inability to concentrate and
depression.
Special Senses: tinnitus, visual distur-
bances, and hearing disturbances.
Skin: itching (pruritus), skin erup-
tions, sweating, ecchymoses, skin rashes,
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Cardiovascular: edema, palpitations,
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renal disease, hematuria, jaundice, angio-
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Maximum daily dose: 5 tablets.
References.
1. Dingfelder J. Primara di'smenorrhea
treatment with prostaglandin inhibitors:
A review. Am J Obstet Gvnecol 1981:
140:874-879.
2 Smith L. Naproxen sodium in di's-
menorrhea: A Canadian clinical trial.
Proceedings: Telemedical SI'mposium
Prostaglandins and Di'smenorrhea.
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