The Department of Health and Human Services is finalizing plans
for a U.S. vaccination program against smallpox. As more vaccinia
virus vaccine has become available, the debate over how manypersons
to vaccinate has centered on two issues: the safetyof the live
vaccine and the transmissibility of vaccinia virusfrom a recently
vaccinated person to a susceptible host.
The issue of safety has received substantial attention, giventhat
a predictable number of adverse events will occur amongvaccine
recipients. Furthermore, an extensive literature hasestablished
credible estimates of the complication rates.1,2,3,4The risk of secondary transmission, however, is discussed much
less, perhaps because relatively little is known. A report on
vaccine-related deaths in the United States during the 1960sfound
that 12 of the 68 deaths occurred in unvaccinated personsexposed to
recently vaccinated family members or friends, afinding that
demonstrates the potential gravity of the problem.5A recent reconsideration of the transmission rates during the
1960s concluded that spread is remarkably infrequent; this findingis
quite reassuring for immunocompetent persons in the general
population.4
However, the finding of infrequent transmission may not applyto
hospitals, where large numbers of workers will be vaccinated,many
for the first time. There is a large concentration of immunocompromisedpatients in hospitals, a situation distinctly unlike that in
1947, the last time a mass vaccination campaign was mountedin the
United States. The prospect that a series of decisionsmight
unwittingly introduce a live, transmissible, and potentiallylethal
virus into hospitals has dampened the enthusiasm of manyfor
widespread vaccination.
In this article, I review the literature on the secondary transmissionof vaccinia virus, including transmission in hospitals, among
families, and in other circumstances. Many of the older articles
would not pass modern peer review. However, the informationthey
contain cannot be obtained elsewhere a fact thatmakes them,
however limited, of real value.
Nosocomial Spread
Nosocomial spread of vaccinia virus has been reported at least12
times, from 1907 through 1975, and has resulted in 85 secondarycases6,7,8,9,10,11,12,13,14,15,16,17
(Table 1). Several additionaloutbreaks of Kaposi's
varicelliform eruption unrelated to vacciniavirus have also been
described. The cause of this diffuse skineruption, whose name is
often incorrectly used interchangeablywith eczema vaccinatum (a
known complication of vaccinia virusvaccination), was debated till
the middle of the 20th century.Experts argued whether herpes simplex
or vaccinia was the morelikely cause; current thinking accepts both
these and otherviruses as etiologic agents. Studies that clearly
demonstratedherpes simplex to be the cause of a patient's Kaposi's
varicelliformeruption are therefore not discussed in this article.18,19,20
The incidence of secondary transmission of vaccinia virus isnot
easily calculated. In Glasgow, Scotland, after a three-year-oldgirl
with eczema vaccinatum was hospitalized, all 11 childrenon her ward
and 4 on an adjoining ward had generalized disease.7Smaller series from Germany,6 Sweden,9
Philadelphia,10 and SãoPaulo, Brazil,15
demonstrated transmission to 16 of 27 susceptiblepatients (59
percent). In a single outbreak involving adultsat a hospital in
Brazil where vaccination was given to severalpatients with pemphigus
foliaceus, 16 unvaccinated persons developedsecondary disease.16
However, because many patients on the wardwere vaccinated
simultaneously, the opportunity for exposureincreased. Furthermore,
the denominator was not clearly definedbut may have included 187
patients whose vaccine history wasunknown, yielding an incidence of
secondary vaccinia of about9 percent.
A single French report examined the contribution of the duration
of exposure to the risk of vaccinia virus transmission. An infant
presented in the daytime with eczema vaccinatum, was hospitalizedon
an eczema ward, and by evening was transferred to isolation.13Despite this, four secondary cases occurred in children on the
eczema ward, though none had close contact with the index case.
The exact route of transmission is also uncertain. In the above
study,13 all of the children were confined to
cribs and weretoo ill to interact. In another, after hospitalization
of theindex patient, several cases of disease occurred in an
adjoiningward.7 Although the affected
children did not mix, they werecared for by the same professional
staff. A sore throat developedin three treating nurses, one of whom
had several "pustularbullae" on the forearms, but none were formally
evaluated.7In a carefully studied case
of transmission from an adult withdisseminated vaccinia to a woman
with active mycosis fungoidesin California, investigators remained
uncertain how the virusmoved from the isolation room to the woman,
whose room was some25 m (75 ft) away.17
They suggested that perhaps health careworkers carried the virus or
that the two patients occupiedthe same hall area for several hours,
resulting in fomite-basedspread. The studies also raise the
possibility of aerosol transmissionof vaccinia virus.7,8,13
Any of these potential methods of spreadhas substantial implications
for infection-control teams thatmay be called on to isolate and care
for a patient with eczemavaccinatum.
Yet another route of transmission was demonstrated by a unique
outbreak in Italy, where vaccinia was spread by a contaminated
urinary catheter.14 After her older brother
received vaccine,a 13-month-old girl had initially undiagnosed
genital lesionsand dysuria resulting from vaccinia infection. At the
hospital,she was catheterized, and the catheter was then placed in apan of Citrosil solution for sterilization. Several other urinarycatheters were soaking in the same pan. Within a five-week period,there were 23 secondary cases with vulvarurethral vaccinia;
each of the patients had been catheterized with one of the contaminatedcatheters. About half had high fevers, and some had gross hematuria.Virus was cultured from the urine of several children.
Two reports have clearly defined the epidemic curve of vaccinia
virus infection. In the 1935 outbreak in Glasgow, all secondarycases
occurred between 8 and 18 days after exposure.7
Examinationof patients treated at an infectious-disease hospital in
Brooklyn,New York, after the 1947 mass vaccination in New York City
foundan average incubation period of 10.6 days (range, 5 to 19).11
Nine of the 85 reported patients (11 percent) died. Worsening
severity of disease with each generation of transmission wasseen in
one outbreak in Germany.8 In another report, from
Scotland,those in whom disease developed later tended to have mildersymptoms.7 Death was typically due to
encephalitis or the developmentof secondary bacterial pneumonia.
Treatment included antibacterialagents and, for several, vaccinia
immune globulin.
Spread within Families
Numerous reports have described the spread of vaccinia virus
within families. The majority are instances of single transmission,
usually from a recently vaccinated child to an unvaccinatedyounger
sibling.22,23,24,25
However, two or more secondary caseshave been reported in at least
eight reports of family outbreakspublished from 1931 to 198126,27,28,29,30,31,32,33
(Table 2).Many of the reports describe severe,
sometimes fatal eczemavaccinatum in the first family member with
secondary diseaseand substantially milder local inoculation disease
in the restof the family. These latter infections might have been
overlookedhad medical attention not been sought for the severe case.
Table 2. Reports Describing Spread
of Vaccinia to Two or More Members of a Household.
These eight reports describe transmission to 27 family members.Only
five (19 percent) had previously received vaccine; thesepersons
invariably had milder disease. Of 19 whose skin examinationresults
were noted, 6 had current or previous eczema, includingthe 3 (11
percent) with fatal disease, none of whom had previouslyreceived
vaccinia virus vaccine. Death was invariably from fulminantdisease,
occurring before vaccinia immune globulin could beadministered.
In many of the family outbreaks,27,28,29,30
sharing close quarterswas a significant factor, suggesting the need
for sustained,intimate contact to transmit vaccinia between intact
hosts.In one outbreak, a bed was shared by three persons in whom
diseasedeveloped, further supporting this notion.27
An unusual aspectof the family outbreaks of vaccinia was the
apparent tendencyfor lesions to be present in similar anatomical
areas in allsecondary cases, including the mouth32
and the face.33
Other Transmission
Scattered reports detail other cases of secondary transmissionsof
vaccinia, exclusively by inadvertent inoculation.34,35,36,37,38,39,40Eyelids, lips, nose, and vulva were most commonly reported.32Humphrey found 70 cases of vulvar vaccinia in the literature,37including the 24 catheter-related cases described above,14
manydue to auto-inoculation and several from sexual transmission.31,34The mucosa may be involved because vaccinia can penetrate more
easily into this tissue than into skin. Alternatively, vacciniamay
have a tropism for mucosal surfaces. This phenomenon maybe
important, since many currently hospitalized patients, suchas those
receiving chemotherapy, have substantial mucosal abnormalitiesand
therefore may be at higher risk for acquisition of secondaryvaccinia
virus infection.
Occupational spread to the hands of those working with vaccinia
virus vaccine has been described, and many workers have repeated
local infection despite previous vaccination.41 A
sustainedoutbreak occurred among 22 farm workers and 450 cows on a
dairyfarm in El Salvador.42 One of the
workers had received vaccineand resumed milking cows before his
lesions had resolved, therebyspreading the virus to cows and thence
to coworkers, includingthe woman who washed the towels used by the
milkers. In all22 affected workers, lesions were confined to the
hands andgenitals.
Now, approximately 506,154 persons in the United States areknown
to be living with HIV43; 1.2 million new non-skin
cancersare diagnosed annually44; 2.1
million persons have rheumatoidarthritis and receive therapy with
corticosteroids or otherimmunosuppressive agents45;
and more than 14 million have asthma,many of whom require
intermittent steroid use.46 Thousands ofsolid-organ and bone marrow transplantations are performed each
year and tens of thousands of transplant recipients are aliveand
still receiving immunosuppressive therapy. Atopic dermatitisis also
more common, with prevalence among children rangingfrom 6.8 percent
to 17.2 percent.47 Finally, there are tensof thousands of patients in intensive care units and newborn
nurseries. Current expert opinion recommends that vaccinationof such
persons should be avoided.48 Vaccination can be
avoided,but contact with a recent vaccinee probably cannot.
Of equal importance are the differences in the modern population
of health care workers, some of whom are themselves immunocompromised.Previously, hospitals were staffed with workers who had receivedat least one vaccinia virus vaccine. Such persons were thereforeunlikely to initiate or propagate an outbreak. In contrast,
most current health care workers are susceptible to smallpoxand
vaccinia and so might play a dangerous supporting or evenlead part
in any nosocomial outbreak.
Other than those with underlying skin conditions, it is notknown
which patients are at high risk for secondary disease.Dozens of
reports have described progressive vaccinia (alsoreferred to as
vaccinia necrosum and vaccinia gangrenosa) inimmunocompromised
patients, particularly those with hematologicneoplasms (especially
chronic lymphocytic leukemia), hypogammaglobulinemia,or defects in
cellular immunity.50,51,52,53,54,55
These infections,which are often fatal, may last for months and may
respond poorlyto frequent doses of vaccinia immune globulin.50
Progressivevaccinia in a newly vaccinated soldier with advanced,
previouslyundiagnosed HIV infection has also been described.56
These studiesdemonstrate that vaccinia may be easily transmitted to
hostswith severe dermatologic disorders, with substantial mortalityin the absence of appropriate infection-control measures.
Because of the risk of secondary transmission of vaccinia, many
hospitals remain uncomfortable with the recent recommendationagainst
the provision of administrative leave for newly vaccinatedhealth
care workers.56 Also, the advisability of
immunocompromisedworkers' remaining on the job while colleagues
receive vaccinehas not been determined. Until these controversies
are settled,hospitals must be certain that the rush to vaccinate
healthcare workers does not result in a self-inflicted epidemic not of smallpox, but of infection with the live, potentially
lethal virus, vaccinia.
Supported in part by a grant (K24 AI052239-01) from the
NationalInstitutes of Health.
I am indebted to Linda Han and Sara Tuttle for research assistance,and to Johan Herrlin, Roman Tuma, Gregoire Lauvau, Matthias
Frank, and Svetolik Djurkovic for help in translating the articles
cited.
Source Information
From the Infectious Disease Service, Memorial Sloan-Kettering
Cancer Center, New York.
This article was published at www.nejm.org on December 19, 2002.
Address reprint requests to Dr. Sepkowitz at the Infectious
Disease Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New
York, NY 10021, or at sepkowik@mskcc.org.
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ALL INFORMATION, DATA, AND
MATERIAL CONTAINED, PRESENTED, OR PROVIDED HERE IS FOR GENERAL INFORMATION
PURPOSES ONLY AND IS NOT TO BE CONSTRUED AS REFLECTING THE KNOWLEDGE OR OPINIONS
OF THE PUBLISHER, AND IS NOT TO BE CONSTRUED OR INTENDED AS PROVIDING MEDICAL OR
LEGAL ADVICE. THE DECISION WHETHER OR NOT TO VACCINATE IS AN IMPORTANT AND
COMPLEX ISSUE AND SHOULD BE MADE BY YOU, AND YOU ALONE, IN CONSULTATION WITH
YOUR HEALTH CARE PROVIDER.
"A foolish faith in authority is the worst enemy of truth."
-- Albert Einstein, letter to a friend, 1901
"I know of no safe depository of the ultimate powers of the society but the people themselves, and if we think them not enlightened enough to exercise control with a wholesome discretion, the remedy is not to take it from them, but to inform their discretion by education."
-- Thomas Jefferson, letter to William C. Jarvis, September 28, 1820
"What's the point of vaccination if it doesn't protect you from the unvaccinated?"
-- Sandy Gottstein
"Who gets to decide what the greater good is and how many will be sacrificed to it?"