Variation on a Theme by Fenner: The Pathogenesis of Chickenpox

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COMMENTARIES 735

Let’s stand up, pediatricians. Let’s consider the

legacy for not only our patients but also the young

people who will follow us in our professional careers.

We may not need an increase in the number of

pediatricians in this country, but we certainly need

an increase in the percentage of pediatricians of the

moment and the future who believe in themselves,

their mission, their training, their capabilities, and their worth.

ACKNOWLEDGMENTS

I appreciate the wisdom, experience and counsel of my colleagues, Drs Bascom Anthony, Milton Arnold, Frank Disney, Delbert Fisher, and Neil Litman, who reviewed these remarks with me and encouraged me to submit them to the scrutiny of our national pediatric community.

JOSEPH W. ST GEME, JR, MD

Department of Pediatrics

UCLA School of Medicine

Harbor-UCLA Medical Center

Torrance, California

Variation

on a Theme

by

Fenner:

The

Pathogenesis

of

Chickenpox

In a study exemplifying both brevity in

experi-mental design and brffliance in execution, Fenner’

delineated the pathogenesis of the acute exanthems.

He lumped together the human diseases of

small-pox, chickenpox, measles, and rubella because of

similarities in clinical presentation after a relatively

long incubation period, even though etiologically

these diseases are caused by a diverse group of

DNA and RNA viruses (poxvirus, herpesvirus,

par-amyxovirus, and togavirus, respectively). The

ani-mal model that he selected was the murine virus

infection called mousepox or infectious ectromelia.

Inasmuch as the natural route of infection is

through minute abrasions in the skin, Fenner

inoc-ulated the test animals in either the foot or pinna

with small doses of mousepox. He killed two mice

at daily intervals up to 24 days postinoculation and

followed the progression of infection by light

mi-croscopy and virus isolation. He observed that

within eight hours, virus passed from the site of

cutaneous inoculation to the regional lymph nodes,

where local replication commenced. After two to

three days, virus was detected in the blood (primary

viremia) and soon thereafter in the phagocytes of

the liver and spleen. Further viral multiplication

occurred in the internal organs, and virus was again

released in the bloodstream (secondary viremia).

Although described as “secondary,” the latter

vi-remic phase was of considerably greater magnitude

than the primary viremia and led to widespread

focal infection of the skin by the sixth day

postin-oculation. The appearance of the exanthem

her-alded the end of the week-long incubation period.

In summary, the murine infection of ectromelia is

characterized by four stages prior to exanthematous

disease: (1) invasion and replication at a local site,

(2) a primary viremia, (3) replication in the internal

organs (“secondary sites”), and (4) a secondary

viremia.

Fenner speculated that the pathogenesis of

chick-enpox also would follow the dual viremic model of

mousepox, but sufficient clinical and experimental

information was not yet available to confirm the

hypothesis. A recent comprehensive summary of

the literature on varicella-zoster virus (VZV)

infec-tions up to 19802 has supplied additional data to

verify Fenner’s hypothesis and construct a logical

schema (Figure). Chickenpox undoubtedly is

ac-quired via droplets onto either the conjunctival or

nasal/oral mucosa. Numerous epidemiologic

obser-vations of single chance encounters between

suscep-tible contacts and presymptomatic but infectious

index cases,3’4 as well as a recent study of primary

VZV infections acquired via airborne transmission,5

leave no alternative explanation. The primary site

of replication may be the regional lymph nodes and

tonsils, where large multinuclear giant cells have

been seen three days prior to the onset of

chicken-pox,6 or possibly the ductal tissue of the salivary

gland, where two other herpes group viruses,

cyto-megalovirus7 and Epstein-Barr virus,8 replicate

dur-ing primary infection.

The duration of viral replication at this local site

is four to six days, a reliable estimate derived from

the observation that the total incubation period for

chickenpox is reduced by a four- to six-day period

when the first phase of viral replication at a local

site is bypassed by direct introduction of virus via

the bloodstream.2 Thereafter, a primary viremia

occurs and seeds the internal organs. This phase is

usually entirely asymptomatic, although the rare

patient may exhibit an occasional vesicular lesion

or a short-lived scarlatiniform rash. The major

in-ternal foci of viral replication are not known but

can be deduced from data collected at autopsy on

patients with acute chickenpox to include the

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Primary viremia DAY 4-6

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Secondary viremia

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736 PEDIATRICS Vol. 68 No. 5 November 1981

Infection of conjunctivae and/or mucosa of upper respiratory tract

Viral replication in regional

lymph nodes

Viral replication in liver, spleen and (?) other organs

Infection of skin and

appearance of vesicular rash DAY 14

Figure. Pathogenesis of chickenpox. Incubation period includes two episodes of viremia:

primary viremia follows virus replication at a local focus and seeds internal organs;

secondary and more prolonged viremia, which leads to widespread cutaneous infection and characteristic exanthem, occurs when virus in high titer is released from internal sites of

multiplication.

dular epithelium of the liver, pancreas, and

adre-nals; the columnar epithelium of the respiratory

tract and gut; the spleen and also Hassall’s

bodies.9’#{176} After replication in some or all of the

above sites, VZV in high titer is released into the

bloodstream (secondary viremia), whence it has

been isolated,”2 and quickly invades the cutaneous

tissues. By histologic examination of newly forming

vesicular lesions, Tyzzer’3 documented long ago

that infection began in the dermis and spread

out-ward to the epidermis, a progression compatible

only with blood-borne transmission. At

approxi-mately the 14th day postinvasion, the infection

manifests itself as the typical vesicular exanthem of

chickenpox.

A schema for the pathogenesis provides

consid-erable useful clinical information, e.g., recent

de-scriptions of mild hepatitis during acute chickenpox

in children (without Reye’s syndrome)’4”5 can be

placed in proper perspective as an anticipated

se-quela rather than an unexpected complication of

the systemic viral infection. (For many years

in-ternists have observed that subclinical hepatitis

often accompanies viral pneumonitis in young

adults with primary VZV infection.)’6”7 Two other

aspects of VZV infection fit neatly into the temporal

sequence of events outlined in the Figure. The

neurologic manifestations of chickenpox can be

di-vided into three groups according to their dates of

onset, which in turn correlate precisely with viral

invasion of the CNS following local replication,

primary viremia, or secondary viremia.2 Likewise,

infection of the late gestational fetus during acute

chickenpox in the pregnant woman can occur after

either the maternal primary or secondary viremia.2

In the former situation, the rash in the newborn

infant occurs just one day after the appearance of

the exanthem in the mother.’8

The observed discrepancy in incubation period

following immunization with a high-dose rather

than a low-dose inoculum is also explicable using

the schema. Injection of a large number of

infec-tious particles (eg, from vesicular fluid) increases

the likelihood of transient viremia, which mimics

the primary viremia of a naturally acquired

infec-tion, and shortens the incubation period by

bypass-ing the stage of replication at a local site.2 In

con-tradistinction, immunization with a relatively small

dose of vaccine virus (--500 units) decreases the

chance of immediate blood-borne dissemination

and thereby promotes one or more cycles of

multi-plication at a local site (eg, axifiary lymph nodes)

before viremia occurs. Thus, the incubation period

usually becomes 14 days or longer.’9 Finally, this

conceptual outline provides a reasonable

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COMMENTARIES 737

administered to a susceptible contact within 72 to

96 hours of exposure to chickenpox, zoster-immune

globulin neutralizes virus at sites of invasion and

local replication and thereby aborts the infection

before the primary viremic phase can occur on days

4 to 6.

Fenner was right!

ACKNOWLEDGMENTS

This research was supported by Young Investigator Research Grant 14604 from the National Institute of Allergy and Infectious Diseases, National Institutes of

Health, and by awards from the ELsa U. Pardee

Foun-dation (Midland, MI) and the Thrasher Research Fund

(Salt Lake City, UT).

I

thank Dr Ralph D. Feigin for helpful consultation.

CHARLES GROSE,

MD

Department of Pediatrics

University of Texas Health Science Center

San Antonio

REFERENCES

1. Fenner F: The pathogenesis of the acute exanthems: An interpretation based on experimental investigations with mousepox (infectious ectromelia of mice). Lancet 2:915, 1948 2. Grose C: Varicella-zoster virus infections: Chickenpox (var-icella) and zoster (shingles), in Glaser R, Stematsky T (eds): Human Herpes Virus Infections. New York, Marcel Dekker,

1982, pp 85-150

3. Gordon JE, Meader FM: The period of infectivity and serum prevention of chickenpox. JAMA 93:2013, 1929

4. Evans P: An epidemic of chickenpox. Lancet 2:339, 1940 5. Leclair JM, Zaia JA, Levin MJ, et al.: Airborne transmission

of chickenpox in a hospital. N EngI J Med 302:450, 1980 6. Tomlinson TH: Giant cell formation in the tonsils in the

prodromal stage of chickenpox. Am J Pathol 15:523, 1939 7. Smith MG: Propagation in tissue cultures of a cytopatho-genic virus from human salivary gland (SGV) disease. Proc Soc Exp Biol Med 92:424, 1956

8. Morgan DG, Niederman JC, Miller G, et al.: Site of Epstein-Barr virus replication in the oropharynx. Lancet 1:1154, 1979 9. Oppenheimer EH: Congenital chickenpox with disseminated

visceral lesions. Bull Johns Hopkins Hosp 74:240, 1944 10. Ehrlich RM, Turner JAP, Clarke M: Neonatal varicella: A

case report with isolation of the virus. J Perliatr 53:139, 1958 11. Feldman 5, Epp E: Isolation of varicella-zoster virus from

blood. J Pediatr 88:265, 1976

12. Myers MG: Viremia caused by varicella-zoster virus: Asso-ciation with malignant progressive varicella. J Infect Dis

140:229, 1979

13. Tyzzer EE: The histology of the skin lesions in varicella.

Philippine J Sci 1:349, 1906

14. Hochberger R, Tokarski P, Koranyi K, et al.: Varicella hepatitis in children, in Crocker JFS (ed): Reye’s Syndrome

II. New York, Grune & Stratton, 1979, pp 69-75

15. Ey JL, Smith SM, Fulginiti VA: Varicella hepatitis without neurologic symptoms or findings. Pediatrics 67:285, 1981 16. Krugman 5, Goodrich CH, Ward R: Primary varicella

pneu-monitis. N EngI J Med 257:843, 1957

17. Triebwasser JH, Harris RE, Bryant RE, et al: Varicella pneumonitis in adults. Medicine 46:409, 1967

18. Middlekamp JN: Varicella in newborn twins. J Pediatr 43: 575, 1953

19. Neff BJ, Weibel RE, Villarejos VM, et al.: Clinical and laboratory studies of KMcC strain live attenuated varicella virus (41071). Proc Soc Exp Biol Med 166:339, 1981

PIMPLE VS HICKEY

Re: “Pimple Sign” (Pediatrics 68:105, 1981). Your editor does not realize that

a hickey is not a pimple in current usage. A hickey is an ecchymosis on (usually)

the neck or chest caused by prolonged high vacuum kissing. This occurs during

what used to be heavy necking or petting, but is now more likely to be foreplay.

This is the reason Dr. Butler is pointing out that contraception is needed.

Acne has no relationship to arousal.

Submitted by David Estroff

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1981;68;735

Pediatrics

Charles Grose