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EXPERIENCE AND REASON 631

Subclinical

Hepatic

Changes

in Varicella

Infection

Varicella is a common viral disease of children

which frequently occurs in epidemics. The diagnosis

is generally obvious from clinical criteria. The

dis-ease is usually self-limited and benign, but the

complications of pneumonia and encephalitis are

well recognized.’ Recently, chicken pox has been

implicated in 10% to 18% of cases of Reye’s

syn-drome, and varicella hepatitis is being increasingly

recognized.24 However, the incidence of subclinical

liver involvement in children or adults with

van-cella is not known.4’5

In this study we have obtained historical,

physi-cal, and biochemical data on patients with varicella

infections during the active phase of their disease.

Patients were questioned about previous hepatic

disease, the use of salicylates or phenothiazine class

drugs, the onset and sequence of their symptoms,

and signs of neurologic or hepatic involvement.

Physical examination was keyed to the clinical

di-agnosis of chicken pox according to the criteria of

Krugman and Ward’ and to any evidence of hepatic,

pneumonic, or neurologic involvement. The

bio-chemical measurements selected were those rou-tinely required for the diagnosis of varicella

hepa-titis or Reye’s syndrome-determinations of SGOT,

serum ammonia, and glucose levels and of

pro-thrombin activity. When possible, creatine

phos-phokinase (CPK) levels were determined to

evalu-ate myocardial or skeletal muscular involvement.

In addition, a salicylate level was obtained if there

was a history of ingestion within the previous 24

hours.

MATERIALS AND METHODS

Thirty-nine patients with overt varicella

infec-tions, aged 8 months to 25 years, were studied

between January and April 1978. In addition, data

were obtained on 1 1 afebrile noninfected children

seen concurrently in the outpatient department. AU

patients but one were outpatients. Patients were

seen after presenting to the emergency room or

outpatient department, or after referral by a local

pediatrician or the Providence School Department.

Patients were studied and examined by one of the

investigators while they evidenced active cutaneous lesions, with no attempt made to select the duration

Publication of this article was unavoidably delayed by adminis-trative problems.

Reprint requests to (P.A.P.) Department of Pediatrics, Rhode

Island Hospital, 593 Eddy St, Providence, RI 02902.

PEDIATRICS (ISSN 0031 4005). Copyright © 1980 by the

American Academy of Pediatrics.

of disease for entry to the study. When possible, 10

ml of nonfasting blood was obtained from an

ante-cubital or another free-flowing vein. Samples for

ammonia and glucose determinations were

trans-ported on ice; hemolyzed specimens were discarded.

All ammonia determinations were performed within

one hour of drawing, and all determinations were

complete within 24 hours.

SGOT level was determined by a kinetic

spectro-photometric procedure utilizing Spin Chem reagent

(Smith Kline Instruments, mc, Sunnyvale, CA).

With one exception blood studies were performed

using standard laboratory techniques: in

determi-nations of ammonia concentration, in which the

isothermal distillation occurred at pH 10, a

modifi-cation of the method of Seligson and Hirahara6 was

used. Normal values from this laboratory for

chil-dren are reported in the text.

The study was approved by the Human

Investi-gation Committee, and patients were examined only

after informed consent was obtained.

RESULTS

Thirty-nine patients with chicken pox and

with-out clinical evidence of Reye’s syndrome were

stud-ied. Determinations of all ammonias (normal <100

mg/100 ml), CPK (normal <135 lU/liter), glucose

(>40 mg%), and prothrombin activity (>50% of

control) were within normal limits. SGOT (normal

<31 lU/liter) elevations were noted in 77% of

pa-tients (Table). SGOT levels were arbitrarily divided

into three classes: normal (0-31 lU/liter), mildly

elevated (32-50 lU/liter), and markedly elevated

(>50 lU/liter). Twenty-three percent were normal,

49% mildly elevated, and 28% markedly elevated.

x2

and regression analyses disclosed no correlation

between SGOT levels and duration of rash, physical

findings, age of patient, or history of vomiting or

salicylate ingestion. The eight salicylate levels

ranged from 0%-7.7 mg/100 ml which is far below

accepted toxic levels. No patient had received a

phenothiazine class drug.

SGOT level determinations were obtained from

11 afebrile, noninfected children, all of whom had

values within normal limits (mean = 22.6 lU/liter,

SD = 4.0).

DISCUSSION

Vancella involvement of the liver has rarely been

described. Four cases of clinical hepatitis with liver

tenderness, jaundice, and abnormal liver function

were observed in 20 adults with varicella

pneu-1 Specific pathologic changes have been

noted at autopsy in fatal cases, and the virus has

been cultured from the liver.7’8 These facts, along

with well-described instances of hepatitis by other

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TABLE. SGOT Level vs Laboratory and Clinical Findings

632 PEDIATRICS Vol. 65 No. 3 March 1980

SGOT* (lU/liter) NH.t (g/100 ml) Glucose (mg/100 ml) PTA (% control) CPKt (lU/li-ter)

Age (yr) Sex History

of Vomit-ing (%) History of Salicylate Ingestion (%) Dura-tion of Rash (days) SGOT (0-31)

n 9 3 5 6 4 9

Mean 28.0 39.3 101.6 62.0 8.8 7 2 2.2

SD 3.7 4.5 27.3 17.5 6.8 2 22% 67% 1.1

SEM 1.3 2.6 12.2 8.7 2.3 0.4

Range 19-31 35-44 75-147 67-100 40-77 3-23 0-4

SGOT (32-50)

n 19 9 15 11 5 19

Mean 40.3 50.6 82.9 54.4 8.1 8 9 2.8

SD 4.6 20.4 9.7 16.5 5.8 11 d 5% 47% 1.4

SEM 1.1 6.8 2.5 7.4 1.4 0.3

Range 33-49 21-85 70-101 84-100 31-67 8mo-25yr 0-7

SGOT (> 50)

n 11 3 7 7 3 11

Mean 156.3 45.0 83.3 54.0 8.5 3 9 3.8

SD 216.6 2.6 8.0 29.0 4.9 8 27% 55% 1.0

SEM 65.3 1.5 3.0 16.8 1.5 0.3

Range 55-794 43-48 76-97 62-100 26-84 2-17 0-7

* Normal SGOT level is 0-31 lU/liter.

t Normal ammonia level is <100 &g/100 ml.

:1:

Normal CPK level is <135 lU/liter.

viruses of the herpes family, would suggest the

potential for subclinical hepatic involvement.

Re-cently, two patients with varicella hepatitis and persistent vomiting were reported.4

Stanton and Joos9 found the SGOT levels to be

normal in children with various infections and

re-solving rheumatic fever. This suggests that our

patients’ elevations with varicella infection are not

simply a response to a nonspecific febrile ifiness.

However, further studies of a large population of

febrile patients are warranted.

We were unable to obtain sufficient follow-up

data to delineate the time course for normalization

of transaminase levels. However, it obviously does

occur since the prior occurrence of chicken pox does

not appear to be associated with any future liver

disorder.

The assignment of the elevated SGOT level as

being hepatic in origin appears warranted. The level

of CPK, which should be elevated if the enzyme

source were cardiac or ‘#{176}was normal in all

12 children studied, eight of whom had elevated

SGOT levels. No patient had clinical evidence of

myositis, carditis, or hemolysis.

We conclude that mild transient hepatic enzyme

elevation, as measured by SGOT levels in

conjunc-tion with normal prothrombin time and ammonia

and glucose levels, appears to be common in

chil-dren with routine cases of chicken pox. Of the six

patients who reported vomiting, in five it occurred

only once at about the time of the onset of the rash.

One patient, however, developed nearly intractable

vomiting on the third day of her illness, with no

change in sensorium. She was admitted for

obser-vation, had an SGOT level of 794 lU/liter and a

normal blood ammonia reading. The vomiting

ceased shortly after admission, and she was

dis-charged on the second day. Her SGOT level was

normal six weeks after discharge. Finally, no

con-stellation of findings on physical examination or

single historical finding correlated with SGOT levels except, as noted above with a single patient,

persistent vomiting.

Our data, when combined with other reports,

suggest that post-vaicella Reye’s syndrome is prob.

ably not merely severe varicella hepatitis. Reye’s

syndrome occurs with SGOT levels no higher than

those in four of our patients (>2#{189}times normal),

none of whom had neurologic changes or changes

in prothrombin activity or in level of glucose or

ammonia. This argues in favor of the view that the

degree of hepatocyte damage is not the only factor.

In addition, autopsy findings in patients dying from

disseminated varicella infection are entirely

differ-ent from those found in Reye’s syndrome.9 It

ap-pears that elevated levels of transaminase with

varicella are common and that marked elevations

of SGOT are probably not rare, whereas Reye’s

syndrome depends on a separate pathogenic

mech-anism.

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EXPERIENCE AND REASON 633 ACKNOWLEDGMENTS

We wish to thank James Driscoll, PhD, Department of

Biochemistry, Rhode Island Hospital, for technical

as-sistance and Ms Donna Perry for secretarial assistance.

REFERENCES

PAUL A. PITEL, MD

KENNETH L. MCCORMICK, MD

EILEEN FITZGERALD, MD

JAY M. OisoN, MD

Rhode Island Hospital and

Brown University

Providence, Rhode Island

1. Krugman 5, Ward R (eds): Infectious Diseases of Children,

ed 4. St Louis, CV Mosby Co, 1973, p 412

2. Huttenlocker PR: Reye’s syndrome: Relation of outcome to therapy. J Pediatr 80:845, 1972

3. Vaughan VC, McKay JR (eds): Nelson Textbook of Pedi-atrics, ed 10. Philadelphia, WB Saunders Co, 1975, p 671

4. Landay SG: Varicella hepatitis and Reye’s syndrome: An

interrelationship? Pediatrics 60:746, 1977

5. Hoeprich PD (ed): Infectious Diseases. New York, Harper

and Row Publishers, Inc, 1977, p 750

6. Seligson D, Hirahara K: The measurement of ammonia in

whole blood, erythrocytes, and plasma. J Lab Clin Med 49:

962, 1957

7. Eschar J, Teit L, Waron M, et al: Hepatic lesion in chicken

pox. Gastroenterology 64:462, 1973

8. Cheatham WJ, Weller TH, Dolan TF, et al: Varicella: Report

of two fatal cases with necropsy, virus isolation and serologic studies. Am J Pathol 32:1015, 1956

9. Stanton RE, J005 HA: Glutamic-oxalocete transaminase of

serum in infancy and childhood. Pediatrics 24:352, 1959

10. Seaman WE, Ishak KG, Plotz PH: Aspirin-induced

hepato-toxicity in patients with systemic lupus erythematosis. Ann Intern Med 80:1, 1974

Familial

Asplenia,

Other

Malformations,

and

Sudden

Death

Sometimes the sudden, unexpected death of an

infant is shown by necropsy to be associated with

a clinical entity more clearly defined than sudden

infant death syndrome. This is a report of two

unrelated families, each with two affected members.

In one, asplenia occurred with and without

gastroin-testinal malformations. In the other, cardiovascular

malformations occurred in one member and

lye-mark syndrome’ in the other. Each asplenic infant

died suddenly.

CASE REPORTS

Case 1

I. H., a 7-month-old girl was in good health until fever,

cough, and irritability appeared three days before death.

On postmortem examination, no spleen was detected.

There were no other malformations. The respiratory sys-tern showed congestion of the entire airway. The pulmo-nary arteries were filled with large mononuclear cells and

fibrin that appeared as compact thrombi propagating

from congested larger arteries into small branches. The septa were widened, and their cellularity was increased.

There were a few air spaces with amorphous eosinophiic

material. The brain also showed multiple microthrombi

composed of large mononuclear cells and fibrin.

Postmor-tern bacteriologic culture showed only a rare colony of

Enterobacter. Studies for virus infection showed no

growth.

Case 2

A 1-year-old girl, C. K., died after 24 hours of fever.

Four months previously, she had been treated for a

serious sickness involving shock and hematologic

evi-dence of disseminated intravascular clotting, but with no

growth in a blood culture. At 2 weeks of age, surgery had

been performed on this infant to correct a herniation of

the stomach through the foramen of Bochdalek into the

right hemithorax.

Postmortem examination showed the large intestine to

be imperfectly rotated with the sigmoid largely toward

the midline but stifi on the left. The stomach was in the

right upper quadrant. The liver lay across the upper

abdomen with the right and left lobes approximately the

same size. The gallbladder arose from the right lobe. A

spleen could not be identified. The left diaphragm was

intact. The heart, great vessels, and coronary arteries were entirely unremarkable.

There was no consanguinity in this family, but the

greatgrandmothers of the two cases were sisters.

Case 3

Publication of this article was unavoidably delayed by adminis-trative problems.

Reprint requests to (A.L.K.) Hunterdon Medical Center,

Fle-mington, NJ 08822.

PEDIATRICS (ISSN 0031 4005). Copyright © 1980 by the American Academy of Pediatrics.

The first child in the family was a girl, N. G., who

became cyanotic shortly after birth. Catheterization and

angiographic studies showed transposition of the great

arteries plus the presence of subpulmonary stenosis of a

mild degree. A normal spleen and splenic artery were

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1980;65;631

Pediatrics

Paul A. Pitel, Kenneth L. McCormick, Eileen Fitzgerald and Jay M. Orson

Subclinical Hepatic Changes in Varicella Infection

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1980;65;631

Pediatrics

Paul A. Pitel, Kenneth L. McCormick, Eileen Fitzgerald and Jay M. Orson

Subclinical Hepatic Changes in Varicella Infection

http://pediatrics.aappublications.org/content/65/3/631

the World Wide Web at:

The online version of this article, along with updated information and services, is located on

American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 1980 by the

been published continuously since 1948. Pediatrics is owned, published, and trademarked by the

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has

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