Reye Syndrome and Juvenile

Rheumatoid Arthritis in Michigan

Patrick L. Remington, MD; Charles L. Shabino, MD; Harry
Ashok P. Sarniak, MBBS; William N. Hall, MD, MPH
\s=b\ Reye

syndrome (RS) is believed to

infrequently among children receiving long-term aspirin therapy. We
reviewed all cases of RS reported to the
Michigan Department of Public Health
during 1982 and 1983. Three of the 36
patients were receiving aspirin for the
treatment of juvenile rheumatoid arthritis. All three patients had clinical
occur

courses characteristic of RS and two

had supportive histologic findings on
liver biopsy. The incidence of RS among
children with juvenile rheumatoid arthritis is significantly greater than the incidence of RS among children who do not
have juvenile rheumatoid arthritis.
These findings support previous studies
that showed that the use of aspirin during the antecedent illness may be a risk
factor for the development of RS. Physicians should be aware of the potential for
the development of RS among children
who are receiving long-term aspirin therapy for the treatment of systemic inflammatory illnesses.

(AJDC 1985;139:870-872)

epidemiologie studies sug

gest that children who use aspirin
during influenza or varicella infections
are at an increased risk for developing

Reye syndrome (RS).13

true, then
a

one

see

If this

867.
were

would expect to

see

greater incidence of RS among

From the Division of Field Services, EpiCenters for Disease

Control, Atlanta (Dr Remington); Michigan Department of Public Health, Lansing (Drs Remington and Hall and Mr McGee); Pediatric Intensive Care Unit, Bronson Methodist Hospital,
Kalamazoo, Mich (Dr Shabino); and Detroit Children's Hospital (Drs Preston and Sarniak). Dr
Remington is currently with Division of Nutrition, Center for Health Promotion and Education, Centers for Disease Control, Atlanta.
Reprint requests to Division of Field Services,
Epidemiology Program Office, Centers for Disease Control, Atlanta, GA 30333 (Dr Reming-

demiology Program Office,

ton).

children who routinely take aspirin

compared with children who do not.
Children with juvenile rheumatoid
arthritis routinely take aspirin for
long periods of time; however, the inci
dence of RS among these children is
unknown. Although it has been sug
gested that it occurs only rarely,4 there
have been recent reports of children
with juvenile rheumatoid arthritis
who developed RS while receiving
long-term aspirin therapy.5 To deter
mine if children with juvenile rheu
matoid arthritis are at an increased
risk for the development of RS, we
conducted a population-based study of
RS cases reported to the Michigan
Department of Public Health during
1982 and 1983.
PATIENTS AND METHODS

Reye syndrome is a legally reportable

Michigan and the Michigan De

disease in

partment of Public Health communicates

"Decent

For editorial comment

McGee, MPH; Greg Preston, MD;

frequently by letter and telephone with 15

RS hospital-reporting centers. For this
study, we reviewed the medical records of
the RS cases reported to the Division of
Diseases Surveillance at the Michigan De
partment of Public Health between Jan 1,
1982 and Dec 31,1983. Thirty-six cases met

following Centers

for Disease Control

definition of RS: (1) Acute noninflam
matory encephalopathy documented by the
clinical picture of an alteration in con
sciousness and, if available, a record of
cerebrospinal fluid containing no more than
eight leukocytes per cubic millimeter, or
histologie sections of the brain demonstrat
ing cerebral edema without perivascular or
meningeal inflammation. (2) Fatty meta
morphosis of the liver diagnosed by either
biopsy or autopsy or a threefold or greater
rise in the levels of either serum glutamicoxaloacetic transaminase, serum glutamicthe

case

pyruvic transaminase,

or serum

ammonia.

(3) No obvious alternative explanation for

the cerebral or hepatic abnormalities.6

In the

analysis,

the number of children

persons younger than 18 years
of age) with juvenile rheumatoid arthritis
in Michigan was calculated using the range
of prevalence estimates for juvenile rheu
matoid arthritis in the United States (from
a low of 0.1 to a high of 1.1 cases per 1,000
children)7 and a 1982 population estimate of
children in Michigan (2,654,000).8 The inci
dence of RS among these children was
compared with the reported incidence of
RS among children without juvenile rheu
matoid arthritis in Michigan in 1982 and
1983. The standardized morbidity ratio and
95% exact confidence limits were deter
mined using Rothman and Boice's program
for a programmable calculator.9

(defined

as

PATIENT REPORTS
Three of the 36 patients with RS were
identified as having received long-term as
pirin therapy for juvenile rheumatoid ar
thritis before the onset of RS.
Patient 1.On Feb 15,1982, an 8-yearold girl was admitted to the Bronson Meth
odist Hospital, Kalamazoo, Mich, with
vomiting and lethargy. Four days before
her admission, she developed a respiratory
illness with cough, runny nose, and fever
(temperature, 38 C). On the day of admis
sion, the patient had the sudden onset of
persistent vomiting and became lethargic.
Her medical history included a diagnosis of
juvenile rheumatoid arthritis at the age of
4_ years. At that time, she had a swollen,
asymptomatic right knee with bilateral
iridocyclitis, an erythrocyte sedimentation
rate of 40 mm/hr (normal, <22 mm/hr),
normal total complement values, negative
rheumatoid factors in serum and synovial
fluid, and a negative antinuclear antibody
titer. The patient was treated with aspirin
and was receiving 100 mg/kg/day at the
time of the onset of illness. Three months
before admission, her serum salicylate level
was 16 mg/dL.
At the time of admission, the patient was
lethargic, but fully responsive with normal
vital signs. Laboratory study results are
listed in Table 1. The results of hepatitis

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Table 1.Admission Laboratory Examination

Results in Patients With Reye Syndrome, Michigan, 1982 to 1983*
Patient No.

Serum

Laboratory Test
glutamic-oxaloacetic

transaminase, IU
Serum ammonia, mg/dL
Serum glucose, mg/dL
Total bilirubin, mg/dL
Prothrombin time, s
Partial thromboplastin time,
Serum salicylate, mg/dL
*Data in

(10-30)
115(20-40)

(10-30)
180(20-40)

740

185

43

93

0.2
13
30

0.3

(-11)
(-23)

150
0.4

(-11)
33 (-23)

36

37.0

17.5

13

13.3

342 (0-30)
408(17-61)

14

(-11.5)
(_33.5)

parentheses are the normal value ranges.

Table 2.SMR for RS

Among Children With JRA in Michigan,

1982 to 1983*

JRA Prevalence Estimate

Estimated prevalence rates of JRA/1,000

children7
No. of children with JRA in Michigan based on
above prevalence estimates
Observed 2-yr incidence of RS/100,000
children with JRA
Expected 2-yr incidence of RS/100,000,
based on 33 cases of RS among children
without JRA

SMR, observed/expected ratio

95% confidence interval of the SMR9

High

Low

1.1

0.1

2,919

265

102.8

1,132.1

1.2

1.2

86

943

22-233

254-2,721

*SMR indicates standardized morbidity ratio; RS, Reye syndrome; and JRA, juvenile rheumatoid
arthritis.

surface antigen and antibody studies and

mononucleosis and toxicology screens were
negative. The patient was treated accord
ing to a RS protocol, which included fluid
restriction, phytonadione, and sufficient
intravenous hypertonic glucose solution to
maintain a blood glucose concentration
above 100 mg/dL. She recovered, and five
days later was discharged from the hospi
tal. Her pediatrician elected to treat her
with naproxen and she remained asympto
matic.
Patient 2.On Feb 7,1983, a 5-year-old
girl was admitted to Bronson Methodist
Hospital with confusion and combativeness. Seven days before her admission, she
developed a respiratory illness with sore
throat, cough, and fever (temperature, 38.9
C). Three days before her admission, she
began vomiting. On the day of admission,
the patient developed progressive confu
sion and became combative. Her medical
history included a diagnosis of juvenile
rhematoid arthritis when she was 3 years
old. At that time, the patient had a left
knee effusion with synovial thickening,
an erythrocyte sedimentation rate of

34 mm/hr, a positive antinuclear antibody

titer of 1:40 with a homogeneous pattern,
and negative rheumatoid factors and HLAB27. She had no evidence of iridocyclitis.
She was treated initially with aspirin and
was receiving 55 mg/kg/day, at the time of
onset of illness. Six months before her
admission, the patient's serum salicylate
level was 18 mg/dL.

On admission, she was combative but

responsive to stimuli. The cerebrospinal
fluid was normal, and a computed to
mographic scan showed bifrontal cerebral
edema. A percutaneous liver biopsy was
performed, and oil red 0 stain disclosed
numerous intracytoplasmic vacuolizations
and microvesicular fatty infiltration with
out periportal inflammation. The patient
was treated with fluid restriction, in
travenous glucose solution, and phytona

dione. She made an uneventful and com

recovery. Aspirin therapy was not
resumed and she remained asymptomatic.
Patient 3.On Sept 28, 1983, a 3-yearold boy was admitted to Children's Hospital
of Michigan, Detroit, with delirium and
combativeness. Seven days before his ad-

plete

mission he developed a respiratory illness

with fever, coryza, sore throat, and a
cough. On the day before his admission he
developed persistent vomiting and became
confused and combative. The patient's med
ical history disclosed the diagnosis of juve
nile rheumatoid arthritis one month before
his admission, following a history of gener
alized joint pain and right hip, right wrist,
and left ankle swelling. He was receiving
82.5 mg/kg/day of aspirin at the time of the
onset of illness.
Soon after admission, he developed per
sistent decerebrate rigidity and deep, rapid
respirations. The cerebrospinal fluid was
normal. A percutaneous liver biopsy was
performed and oil red O stain disclosed
microvesicular fatty infiltration without
necrosis. Electron microscopy demon
strated generalized mitochondrial ma
tricular swelling and rarefaction. The
patient was treated with intracranial
pressure monitoring, mechanical hyper
ventilation, mannitol osmotherapy, and

pentobarbital-induced coma. The hospital

course was complicated by frequent
intracranial pressure spikes (peak,
40 mm Hg), and episodes of flaccidity,
areflexia, and dilated unreactive pupils.
After five days, the pentobarbital-induced
coma was discontinued, and two days later
the patient regained consciousness. During
the first week of recovery he had tremors,
unsteady gait, and marked motor incoor
dination. Over the next three months there

gradual improvement and, ultimately,

complete resolution of symptoms.
was

RESULTS
Since RS surveillance in Michigan is
population-based, a comparison of the
RS rate among children with juvenile
rheumatoid arthritis (three RS cases)
with the RS rate among children with
out juvenile rheumatoid arthritis (33
RS cases) is possible. Because of the
uncertainty of the population of chil
dren with juvenile rheumatoid arthri
tis in Michigan, both a high and low
prevalence estimate are used.7 Both of
these estimates result in a signifi
cantly elevated standardized mor
bidity ratio, ranging from 86 (95% con
fidence interval, 22 to 233) to 943 (95%
confidence interval, 254 to 2,721), for
the occurrence of RS among children
with juvenile rheumatoid arthritis
compared with children without juve
nile rheumatoid arthritis (Table 2).

COMMENT
All three children were

receiving
long-term aspirin therapy at the time

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of the

onset of encephalopathy.
Hepatic dysfunction, as demonstrated
by elevated serum transaminase lev
els, is not uncommon during long-term
aspirin therapy. One investigation has

shown that 59% of the children with

juvenile rheumatoid arthritis had ele

vated serum glutamic-oxaloacetic

transaminase levels at some time dur

ing the course of aspirin therapy,10 and
a recent review article11 cited almost
200 cases of "hepatic injury" among
patients with juvenile rheumatoid ar
were receiving long-term
aspirin therapy. In general, this hepatotoxicity seems to be dose-related,
reversible, recurrent on challenge
with aspirin, and manifested by an
asymptomatic elevation of trans

thritis who

aminase levels.12
Less commonly, severe hepatotoxicity with encephalopathy has been
reported among children undergoing
long-term aspirin therapy.4512'13 Some
of these cases were not believed to
represent RS because of atypical
clinical presentations, liver biopsy
specimens uncharacteristic of RS, or
the recurrence of abnormalities upon
resumption of aspirin therapy.1213 Re
cently, two cases of RS were reported
and nine other cases of RS were re
viewed among children who were re
ceiving long-term aspirin therapy for
the treatment of various inflammatory
conditions.6 These were differentiated
from aspirin-induced hepatotoxicity
because these cases had typical pro
dromal illnesses, met the clinical crite-

ria for RS,14 or had characteristic find

ings on liver biopsy.
The differentiation between RS and
chronic salicylism is difficult.15 Never
theless, it is likely that the three chil
dren reported herein had RS. All had a
prodromal upper respiratory tract ill
nesstwo of these illnesses (patients 1
and 2) occurred during communitywide outbreaks of influenza. All of
these patients developed mental
status changes and persistent vomit
ing four to seven days later, and all
subsequently developed noninflam
matory encephalopathy that met the
clinical criteria of stages I, II, and III
RS (patients 1, 2, and 3, respec
tively).16 Both children who had liver
biopsies performed had microvesicular
fatty infiltration and one of these chil
dren (patient 3) had mitochondrial
changes demonstrable by electron mi
croscopy, which are considered to be
the hallmark of RS and distinct from
pathologic findings in aspirin-induced

hepatotoxicity.15
Alternative anti-inflammatory med
ications for the treatment of juvenile

rheumatoid arthritis have been pro

moted for many years,17 but all have
potentially serious side effects. If
long-term aspirin therapy is used,
then careful observation of these chil
dren for the development of persistent
vomiting or mental status changes is
prudent, especially during viral ill
nesses such as varicella or influenza.18
It is unknown, however, whether the
cessation of aspirin therapy at the time

of onset of one of these illnesses would

be effective in reducing the risk for the
development of RS.
Three cases of RS are more than one
would expect to see among children
with juvenile rheumatoid arthritis in
the state of Michigan in two years.
Looked at in another way, the RS
incidence and juvenile rheumatoid ar
thritis prevalence estimates can be
used to determine how often a case of
RS would be expected to occur in a
child with juvenile rheumatoid arthri
tis, if he or she were at no increased
risk for the development of RS. Using
the greater prevalence estimate of 1.1
cases of juvenile rheumatoid arthritis
per 1,000 children and a high estimate
of RS incidence of four cases per
100,000 children,19,20 one would expect
to see only one case of RS in a child
with juvenile rheumatoid arthritis ev
ery nine years in Michigan or every
eight months in the United States. The
occurrence of RS among these three
children, therefore, supports the pre
vious case-control studies that deter
mined that the use of aspirin during
the antecedent illness may increase
the risk for the development of RS.

We would like to thank Donald F. Johnson, MD,

and S. A. Daniel, MD, for allowing us to work
with their patients, Mary C. White and Richard
C. Dicker, MD, for statistical support, Loraine S.
Good for editorial assistance, and Jeffrey J.
Sacks, MD, MPH, Martha F. Rogers, MD, Rob
ert A. Gunn, MD, John M. Horan, MD, and
Phillip Nieburg, MD, for reviewing the manu

script.

References
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Corey

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B\p=n-\associated Reye's

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