ENCEPHALITIS AFTER YELLOW FEVER VACCINATION

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ENCEPHALITIS

AFTER

YELLOW

FEVER VACCINATION

Morris Feitel, M.D., Ernest H. Watson, M.D., and Kenneth W. Cochran, Ph.D.

Department of Pediatrics, University Medical Center (M.F., E.H.W.), and Department of Epidemiology

and Virus Laboratory, School of Public Health, University of Michigan (K.W.C.)

(Accepted November 19, 1959; submitted October 12.)

These studies were aided in part by a grant from the National Foundation.

ADDRESS: (M.F.) Ann Arbor, Michigan.

PEDIATRICS, June 1960

956

T

HE RELATIVELY recent increase in world

travel has led to the necessity of giving immunizations which are not routine in the United States. Immunization against yellow fever is an example. The 17-D vaccine is the one used in this country, and it is an at-tenuated live vaccine. Untoward reactions

to the vaccine are not common but they

seem to be more prevalent in young infants.1

All reported cases of encephalitis after yel-low fever vaccination have occurred in young infants. This excludes the number of

cases which occurred in Brazil, but those were later found to be due to defective vac-cine.2 Stuart et al. refer to other cases of encephalitis after yellow fever vaccination due to the 17-D vaccine. At the Pasteur In-stitute during 1952-1953, 5 cases of meningo-encephalitis occurred among 1,800 vac-cinated children under 1 year of age. Since that time other cases have been reported in young infants in the British literature.49 The vaccine used in all of these cases corn-plied with the Standards for the Manufac-tune and Control of Yellow Fever Vaccine of the United Nations Relief and Rehabilita-tion Administration.

This paper will present what is probably

the first case of encephalitis after yellow

fever vaccination to be reported in the

United

States.

Assistance

from

the

Virus

Laboratory of the Department of

Epidemi-ology, University of Michigan School of

Public Health, made possible a more ex-haustive study as to the etiology of the

ill-ness than has heretofore been attempted.

Evidence will be presented as to the correla-tion of the vaccination with the encephalitis,

and will attempt to show that the

occur-rence of the encephalitis is more than just

coincidental with the administration of the

vaccine.

History

CASE

REPORT

L.S., a 10-week-old white female infant,

was admitted in May, 1959 to the University

of Michigan Medical Center with a chief

corn-plaint of increasing irritability and fever. The

symptoms began 12 hours prior to admission.

The patient was seen by a ph’sician the

morn-ing of the onset of symptoms. A temperature

of 38.9#{176}C and a full anterior fontanelle were

noted. No explanation for the fever could be

found, and a lumbar puncture was performed.

Leukocvtes were seen in the cerebrospinal

fluid and the patient was referred to the

Uni-versity of Michigan Medical Center. Additional

history revealed that the patient had received

an injection of 0.2 ml of 17-D yellow fever

vaccine intramuscularly 12 days prior to the

on-set of symptoms.

Physical Findings

Positive phsical findings at the time of

ad-mission included a temperature of 39.2#{176}C,

irritability, and a full anterior fontanelle. There

were also exaggerated deep tendon reflexes in

the lower extremities, and sustained clonus on

the left.

Laboratory Findings

Hematologic studies revealed a hemoglobin of 9.2 gm/100 ml and a leukocvte count of

14,850/mm3 with 60% granulocytes, 32%

lym-phocytes, and 8% monocytes. An Old

Tubercu-lin skin test, 1 :4000 dilution, was negative as

was the routine urinalysis. A lumbar puncture

was performed and examination of the cerebro-spinal fluid revealed 101 leukocvtes with 65%

granulocytes and 35% lymphocytes.

Quantita-tive sugar was 48 mg/100 ml and protein 260

mg/100 ml. Examination of the smear of the

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ARTICLES

957

TABLE I

ATTK\II’T4 AT \IR1M ISOLATION IN AN INFANT VITH ENcEeIIALITIS AFTEIL YELLOW FEVEIL \ACCINF:

Material from Palie,,1 Method of Study Result

‘too1 Monkey kidney tissue culture Negative

(‘erehrospinal fluid Intracerebral & intraperitoneal injection into

baby mice; homogenates passed to

Baby mice

Adult mice

Homogenate pas.sed to baby mice

Negative

1 (lied on day 5

1(lied 011 (lay It) Negative

Acute serum Intraeerel)ral and intraperitoneal injection into

Monkey Baby mice

1sacrificed on (lay 4; homogenate passed to

Baby mice

A(lUlt mice

Negative All well

Negative

I paralyzed on (lay 21

Vaccine* Intracerebral & intraperitoneal injection into

Baby mice

Adult mice

Monkey

All died 7-9 days**

7 of 8 died 8-1 1 days**

Negative

* Same lot of Vaccine as infant received. The 17-I) yellow fever vaccine is prepared by inoculating eggs with the

17-D strain of virus.

** The ilijedion of yellow fever vaccine into mice causes the (leath of the mice in a short period of time. This

ifl(lieateS that the Vaccine 15 live and is effective.

fluid were negative for bacteria. Blood cultures

ol)tained from the patient also were negative

for bacteria. Specimens of the patient’s blood,

cerebrospinal fluid, and stools were sent to the

Virus Laboratory for attempted isolation of

Coxsackie, adenoviruses and ECHO viruses.

Therapy and Course

Despite the lack of evidence of bacteriologic

infection, the patient was given antibiotics as

a precautionary measure. The clinical picture,

including fever, irritability, and full anterior fontanelle, remained unchanged for the first

3 days of hospitalization and then showed

gradual improvement until the time of

dis-charge on the tenth hospital day. The

cerebro-spinal fluid also showed gradual decrease in number of cells, and on the ninth hospital day

mary of the viral studies is given in Table

I.

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958 YELLOW FEVER VACCINATION

was isolated. Secondly, no other cases of aseptic meningitis were seen at the time this patient became ill, and the University of Michigan Medical Center is the referral center for this type of illness in the south-eastern part of Michigan, excluding Dc-troit. Thirdly, in a search of the literature, the cases reported of encephalitis after ye1-low fever vaccination occurred during all times of the year, and not only when the known types of aseptic meningitis could be expected. From the epidemiologic point of view, these findings would make a coin-cidental cause for the encephalitis seem un-likely. This, together with the negative re-suits from attempts at virus isolation

sug-gest a direct correlation between the

ad-ministration of yellow fever vaccine and the subsequent occurrence of encephalitis in this infant. It would be pure speculation at this time to consider whether this is a hyper-sensitivity reaction, or a neurotropic affinity of the virus peculiar to young infants. The fact that no yellow fever virus could be iso-lated may be related to the time the

speci-mens were drawn.

Although the vaccine used in the patient reported does contain egg protein, the ence-phalitis exhibited in this patient is not typi-cal of the allergic reactions usually seen due to egg protein and the authors do not be-lieve that this played a role in the patient’s illness.

SUMMARY

A case of encephalitis after yellow fever vaccination in a young infant is reported. The results of efforts to identify a virus and

the probable etiology are discussed. From the negative results of attempts at virus isolation and from epidemiologic criteria, it

is concluded that there is a cause and effect

relationship between the administration of

yellow fever vaccine and the occurrence of

subsequent encephalitis in this infant.

Acknowledgment

The authors wish to express their sincere gratitude to Dr. James L. Wilson and Dr. Gordon Brown for their helpful advice in the preparation of this paper.

REFERENCES

1. Theiler, M. : In Viral and Rickettsial

Infec-tions of Man, 3rd Ed. edited by Rivers,

T. M., and Horsfall, F. L., Jr. Philadel-phia, Lippincott, 1959, p. 357.

2. Fox,

J.

P., Lennette, E. H., Masso, C., and Souza Aguiar,

J.

R. : Encephalitis in man

following vaccination with 17-D yellow

fever virus. Am.

J.

Hyg., 36:117, 1942.

3. Stuart, G., et a!. : Yellow Fever Vaccination. World Health Organization, Monograph

Series No. 30, 1956, pp. 143-189.

4. Smith,

J.

H. : Encephalitis in an infant after

vaccination with 17-D yellow fever virus. Bnit. M.

J.,

2:852, 1954.

5. Swift, S. : Encephalitis after yellow fever

vaccination. Brit. M.

J.,

2:677, 1955.

6. Haas, L.: Encephalitis after yellow fever

J.,

2:992, 1954.

7. Scott, L. C.: Encephalitis after yellow fever

J.,

2:1108, 1954.

8. Beet, E. A.: Encephalitis after yellow fever

J.,

1:226, 1955. 9. Thomson, W. 0.: Encephalitis in infants

fol-lowing vaccination with 17-D yellow fever

virus: report of a further case. Brit. M.

J.,

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1960;25;956

Pediatrics

Morris Feitel, Ernest H. Watson and Kenneth W. Cochran