Eczema Vaccinatum in a Household Contact • CID 2008:46 (15 May) • 1555
M A J O R A R T I C L E
Severe Eczema Vaccinatum in a Household Contact
of a Smallpox Vaccinee
Surabhi Vora,1Inger Damon,8Vincent Fulginiti,10,11Stephen G. Weber,3,4Madelyn Kahana,2Sarah L. Stein,5
Susan I. Gerber,7Sylvia Garcia-Houchins,3Edith Lederman,8Dennis Hruby,12Limone Collins,13Dorothy Scott,14
Kenneth Thompson,6John V. Barson,9Russell Regnery,8Christine Hughes,8Robert S. Daum,1Yu Li,8Hui Zhao,8
Scott Smith,8Zach Braden,8Kevin Karem,8Victoria Olson,8Whitni Davidson,8Giliane Trindade,8Tove Bolken,12
Robert Jordan,12Debbie Tien,12and John Marcinak1
Centers Network, Department of Defense, and
1Infectious Diseases and
8Poxvirus and Rabies Branch and
10University of Arizona, Tucson;
2Critical Care, Department of Pediatrics, and
6Department of Pathology, University of Chicago Medical Center, and
9Division of Bioterrorism Preparedness and Response, Centers for Disease Control and Prevention,
11University of Colorado, Denver;
14US Food and Drug Administration, Washington, D.C.
3Infection Control Program, and Sections of
7Chicago Department of Public Health, Chicago,
12SIGA Technologies, Corvallis, Oregon;
vaccination since routine vaccination was discontinued in 1972. A 28-month-old child with refractory atopic
dermatitis developed eczema vaccinatum after exposure to his father, a member of the US military who had
recently received smallpox vaccine. The father had a history of inactive eczema but reportedly reacted normally
to the vaccine. The child’s mother also developed contact vaccinia infection.
Treatment of the child included vaccinia immune globulin administered intravenously, used for the
first time in a pediatric patient; cidofovir, never previously used for human vaccinia infection; and ST-246, an
investigational agent being studied for the treatment of orthopoxvirus infection. Serological response to vaccinia
virus and viral DNA levels, correlated with clinical events, were utilized to monitor the course of disease and to
guide therapy. Burn patient–type management was required, including skin grafts.
The child was discharged from the hospital after 48 days and has recovered with no apparent systemic
sequelae or significant scarring.
This case illustrates the need for careful screening prior to administration of smallpox vaccine
and awareness by clinicians of the ongoing vaccination program and the potential risk for severe adverse events
related to vaccinia virus.
We report the first confirmed case of eczema vaccinatum in the United States related to smallpox
Vaccination with vaccinia virus to protectagainstsmall-
pox infection was practiced globally until the World
Health Organization declared that smallpox had been
eradicated in 1980. Recognition of adverse events as-
sociated with vaccinia vaccination and the decreased
risk of smallpox led to the discontinuation of routine
childhood immunization in the United States in 1972
 and for military personnel in 1990.
In December 2002, in response to the possible threat
Received 26 October 2007; accepted 6 January 2008; electronically published
3 April 2008.
Reprints or correspondence: Dr. Surabhi Vora, University of Chicago Medical
Center, Dept. of Pediatrics, Section of Infectious Diseases, 5841 S. Maryland Ave.,
Chicago, IL 60637 (email@example.com).
Clinical Infectious Diseases2008;46:1555–61
? 2008 by the Infectious Diseases Society of America. All rights reserved.
of intentional release of smallpox virus, the US gov-
ernment implemented a program to immunize select
military and public health personnel against smallpox.
As of May 2007, more than 1.2 million vaccinations
had been administered .
Eczema vaccinatum is a potentially life-threatening
illness that occurs in people with atopic dermatitis or
other forms of eczema who are exposed to vaccinia
virus. Exposure may occur through smallpox vacci-
nation or contact with a recent vaccinee. Deaths occur
most often in young children . Since vaccination
programs were reinstituted in 2002, there have been no
confirmed cases of eczema vaccinatum in the United
A 28-month-old boy with a history of refractory atopic
dermatitis and failure to thrive was transferred to the
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1556 • CID 2008:46 (15 May) • Vora et al.
lesions on hospital day 5 (A), hospital day 7 (B), hospital day 13 (C), and
hospital day 28 (D).
Pictures of the patient depicting the progression of skin
University of Chicago Medical Center (Chicago, IL) with fever
and new-onset blistering. He experienced increased itchingand
erythema on his hands and face for 4–5 days, and fever (tem-
perature, up to 39?C) for 2 days. On the morning of admission
to the hospital, his mother noticed blisters on his hands that
had spread to his arms and face. Initial physical examination
was remarkable for erythema over much of the face, with mul-
tiple areas of shallow erosion, small vesicles, and yellow-crusted
papules. The neck, chest, and arms demonstrated lichenified
plaques and scattered vesicles, pustules, anderosions.Thelower
extremities had lichenified plaques consistent with chronic se-
vere atopic dermatitis. The patient weighed 10 kg (less than
the third percentile for his age).
The patient was hospitalized with a presumed diagnosis of
eczema herpeticum with bacterial superinfection and was
placed on contact isolation, and therapy with intravenous clin-
damycin and acyclovir was initiated at weight-appropriatedos-
ages. Results of directfluorescentantibodytestsofsamplesfrom
vesicular lesions were negative for herpes simplex virus and
varicella zoster virus. However, cytopathic effect was noted in
cell culture. Staphylococcus aureus was isolated from initial
blood and skin cultures. Subsequent cultures showed no bac-
terial growth. Over the next 3 days, the patient’s condition
worsened, with increasingly umbilicated vesicles spreading to
the legs and trunk (figure 1A).
Additional history obtained on hospital day 5 revealed that
the patient’s father was in the US Army serving in Iraq. He
had visited his family for 5 days, 2 weeks prior to the patient’s
admission and 21 days after receiving the smallpoxvaccination.
According to the father’s report, his reaction to the smallpox
vaccine was within expected limits, and the resulting scab had
separated prior to his visit home. Also, he kept a bandage over
the vaccination site throughout his visit home. The father en-
gaged in routine activities with the child that included hugging,
bathing, sharing towels, and sleeping. Both the father and pa-
tient’s sibling reported histories of inactive “eczema.”
The US Department of Defense (DoD) and Centers for Dis-
ease Control (CDC) were consulted regarding the diagnosis of
eczema vaccinatum. On hospital day 6, nonvariola orthopox-
virus was detected in vesicular scrapings and viral culture su-
pernatant from the patient’s skin lesions using PCR tests per-
formedat theIllinois Department
(Springfield). This result was confirmed by vaccinia virus–spe-
cific PCR at the CDC. Later that day, vaccinia immune globulin
intravenous (VIGIV) obtained from the CDC was administered
to the patient at a dose of 6000 IU/kg. The patient was trans-
ferred to the Pediatric Intensive Care Unit for aggressivewound
care and fluid and electrolyte management for burn patient–
type physiology. Ophthalmologic monitoring and trifluridine
ocular drop treatment were initiated. Because of recurrence of
fever, the patient’s antimicrobial regimen was broadened.
of Public Health
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Eczema Vaccinatum in a Household Contact • CID 2008:46 (15 May) • 1557
In light of the child’s critical condition and need for pain
control and sedation, the patient underwent intubationonhos-
pital day 7. Skin lesions continued to spread (figure 1B). Two
additional doses of VIGIV were administered to reach a total
cumulative dose of 24,000 IU/kg. Nevertheless, by hospital day
8, his condition had deteriorated, with worsening acidosis, hy-
poalbuminemia, hypothermia, and hypotension. New lesions
appeared on his shoulder and face. Because of the possibility
of ongoing viremia, cidofovir (5 mg/kg) with probenecid and
hydration was administered.
An Emergency Investigational New Drug Application was
issued, and on hospital day 9, ST-246, an investigational agent
with activity against multiple orthopoxvirus species, was ad-
ministered at a dose of 5 mg/kg via nasogastric tube. The pa-
tient’s condition continued to worsen, with increasing edema,
anuria, rising creatinine levels, and increasing hypotension re-
quiring vasopressor therapy. After a peritoneal catheter was
emergently placed to relieve abdominal compartment syn-
drome and 700 mL of sterile transudative fluid were drained,
his clinical condition stabilized. Clindamycin treatment was
restarted on hospital day 10 because of the possible contri-
bution of staphylococcal toxin to the severity of illness. In the
next few days, renal dysfunction improved, acidosis resolved,
and the patient became normotensive.
After hospital day 8, there were no new skin lesions; the
existing lesions began to flatten and became confluent. By day
13, the lesions began to crust; some had hemorrhagic centers.
During this time, areas on his arms, hands, chin, and neck
became increasingly denuded (figure 1C). Silver sulfadiazine
cream and xeroform gauze dressings were applied to these
The patient experienced several hematologic complications,
including neutropenia, anemia, and thrombocytopenia; all
complications resolved while the child continued to receive
both VIGIV and ST-246. A basic immunologic analysis, in-
cluding a complete blood cell count with differential, HIV
ELISA, and quantitative immune globulin measurements, re-
vealed no abnormalities.
Daily teleconferences with the CDC, DoD, US Food and
Drug Administration, and ST-246 manufacturer guided ther-
apeutic decisions. The child received 24,000 IU/kg of VIGIV
daily from hospital day 10 to 14. With stabilization of anti-
orthopoxvirus IgG levels, doses were administered less fre-
quently (figure 2A). Vaccinia virus DNA load, which was mea-
sured daily, showed a decreasing trend from day 7 onward and
was undetectable at day 18 (figure 2B). The patient’s plasma
ST-246 level was monitored daily; and the dosage was adjusted
on the basis of pharmacokinetic data (figure 3). Antibioticther-
apy was discontinued on hospital day 26. Cadaveric allografts
were eventually placed in areas where the skin had completely
denuded (figure 1D), resulting in successful epithelialization.
The child underwent extubation on hospital day 31 and was
discharged home on day 48.
The patient’s mother also reported a rash on hospital day 3.
She described having had a “breakout” of acne on her face that
began prior to the father’s visit. The mother was previously
healthy, with no history of eczema or smallpox vaccination.On
examination, she had several umbilicated vesicles on her face.
These spread to include her neck, eyelid and finger over the
next 5 days, and she developed lymphadenopathy, fatigue, and
myalgias. Vaccinia infection was confirmed by PCR analysis.
After treatment with a single dose of VIGIV (6000 IU/kg), her
lesions began to scab and systemic symptoms resolved.
Vaccinia virus DNA–specific PCR assays were used to confirm
the diagnoses of both the patient and his mother. A second
real-time PCR assay, targeting the orthopoxvirus DNA poly-
merase gene, was used to quantitate viral DNA in tissues(figure
2B). Anti-orthopoxvirus IgM and IgG reactivities were mea-
sured using methods described elsewhere (figure 2A) .
Analysis of the pharmacokinetics of ST-246 therapy (figure
3) was performed at MPI Research. Serum was harvested by
centrifugation and analyzed by liquid chromatography mass
spectrometry using a validated analytical method. Pharmaco-
kinetic parameters were determined using WinNonlin software
Multilocus sequence typing revealed that the patient’s S. au-
reus blood isolate was ST188 from clonal cluster 1. The skin
isolate was ST8 and contained SCCmec IV and the Panton-
Valentine leukocidin genes. Methods are described elsewhere
To our knowledge, this is the first confirmed case of eczema
vaccinatum related to smallpox vaccination in the UnitedStates
since routine vaccination was discontinued in 1972. A case of
eczema vaccinatum in an adult vaccinee was reported from
Israel in 2002 .
Much of our understanding of the frequency of adverse
events associated with smallpox vaccine is based on data from
the 1960s. Despite the high prevalence of atopic dermatitis and
“eczema” in the population, eczema vaccinatum has always
been rare, with an estimated incidence of 10–38.5 cases per
among individuals who acquired vaccinia via contact trans-
mission . Today’s population may be more susceptible to
adverse reactions because of the larger number of nonimmune
individuals, prevalence of HIV infection, increased rates of
atopic dermatitis, and increases in other immunosuppressed
Atopic dermatitis, regardless of severity or current activity,
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1558 • CID 2008:46 (15 May) • Vora et al.
subraction (cut-off value [COV]). Hospital day 1 corresponds with 10–14 days after the patient’s exposure to vaccinia virus. Although, at the time of
the first serological sampling (hospital day 6), the child had no detectable orthopoxvirus-specific IgG response and was gravely ill, he did have a high
IgM antibody level and an elevated serum vaccinia virus-neutralization titer (data not shown). B, Time course of the level of intravascular orthopoxvirus
DNA in EDTA blood specimens determined by quantitative PCR using reference standards.
A, Time course of anti-orthopoxvirus IgM and IgG levels depicted as anti-orthopoxvirus ELISA optical density (OD) levels, minus background
is a risk factor for eczema vaccinatum among vaccinees and
their contacts and is a contraindication to vaccination. In a
1964 study, two-thirds of those who developed eczema vaccin-
atum had only a history of atopic dermatitis. Contact exposure
to vaccinia accounted for 65% of cases. One-half of the eczema
vaccinatum cases and 73% of associateddeathsoccurredamong
children aged !5 years . An immune modulation defect,
which is specifically related to T cell dysfunction, and a virtual
absence of antimicrobial peptides (cathelicidins) normally pre-
sent in skin  appear to play critical roles in the predispo-
sition of individuals with atopic dermatitis to the initiationand
rapid spread of vaccinia infection, even in intactskin.Prior
to the advent of immunoglobulin therapy,Kempereported
an overall mortality of 30%–40% among patients with eczema
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Eczema Vaccinatum in a Household Contact • CID 2008:46 (15 May) • 1559
ment. Levels of ST-246 in plasma samples acquired 3 h after each dose
are shown. The plasma sample from hospital day 16 was not available
for analysis. Doses were incrementally increased on the basis of a target
peak level of 1000 ng/mL, determined by efficacy studies in nonhuman
primates. The reason for the decrease in plasma levels after hospital day
15 is not known, but because of the improvement in the patient’s clinical
situation no additional increases in ST-246 dose were implemented.
Plasma concentrations of ST-246 in the patient during treat-
vaccinatum, but it was only 7% among those who received
vaccinia immune globulin intramuscularly (VIGIM). This ben-
efit has not been examined in a controlled trial.
This patient’s case emphasizes the need to exclude individ-
uals with a history of remote or active atopic dermatitis from
smallpox vaccination or contact with vaccinees. Vaccinia in-
fections can occur in individuals with other forms of eczema
as well, and clear guidelines need to be established . It is
postulated that two-thirds of the vaccine complications that
occurred during the smallpox vaccination era in the United
States could have been avoided with improved prevaccination
screening . The current systematic training and screening
program employed by the DoD considers both atopic der-
matitis and eczema and may explain the low rates of adverse
events seen since 2002 . However, screening cannot elim-
inate all risk. Vaccine recipients or contacts may have unrec-
ognized risk factors or report an inaccurate history of skin
disease [18, 19].
According to report from the DoD, our patient’s father was
“unsure” about household contacts with “eczema,” but con-
veyed his own personal history and should not have been vac-
cinated. Although his vaccine reaction was reportedly normal
in size, severity, and time to resolution, viral transmission to
his son occurred 21–25 days after vaccination; this was beyond
the generally accepted period of infectivity (3–21 days) .
The father’s history of eczema may have contributed to pro-
longed viral shedding. Findings in the child also indicate ex-
tended viral shedding; swabs fromskinwherescabshadrecently
separated resulted in positive virus culture results even on hos-
pital day 29. The mother’s vaccinia infection likely occurred
via tertiary transmission, and the presence of acne may have
contributed to the extent and distribution of her rash .
Several novel therapies were used for the treatment of this
child, including VIGIV, cidofovir, and ST-246. Vaccinia im-
mune globulin is a sterile solution of purified g-globulin iso-
lated from plasma containing high titers of anti-vaccinia an-
tibody. In the 1960s, VIGIM was routinely administered for
treatment and prophylaxis of complications related tosmallpox
vaccination . The intravenous formulation has recently
been developed to improve tolerability and pharmacokinetic
profiles. Prior to this case, VIGIV treatment had not been given
to a child. The initial dose of 6000 IU/kg was based on a phase
I study that found that dose resulted in neutralizing antibody
activity comparable with that achieved with VIGIM . Sub-
sequent doses of 24,000 IU/kg were based on its demonstrated
safety as the largest dose tested in healthy adults, as well as a
study that indicated that the higher dose more effectively di-
minished the size of a smallpox vaccination lesion (Cangene
Corporation, unpublished data). VIGIV treatment was admin-
istered until anti-orthopoxvirus IgG levels stabilized (figure
2A). Our patient received a total of 3.96 g/kg of vaccinia IgG
in 11 doses. This is equivalent to more than double the max-
imum dose that was administered in severe cases of progressive
vaccinia or eczema vaccinatum in the era of smallpox vacci-
nation (maximum dose, 10 mL/kg or 1.66 g/kg) .
Two antiviral treatments, each with different mechanisms of
action, were used. When the appearance of new lesions on
hospital day 8 indicated potentially ongoing viremia, 5 mg/kg
of cidofovir was administered on the basis of standard induc-
tion dosing for patients with AIDS who have CMV retinitis.
Because of clinical improvementoverthenextweek,ourpatient
did not require another dose of cidofovir. Although no human
anti-orthopoxvirus trials with this agent have been published,
the CDC currently considers cidofovir a second-line therapy
for severe vaccinia infection , because extensive in vitro
and animal data demonstrate that it has activity against or-
thopoxviruses [25–28]. Renal toxicity is the major toxicity as-
sociated with cidofovir in humans; thus, this treatment could
have contributed to the patient’s transient renal dysfunction.
Because of the child’s critical condition, treatment with ST-
246, an investigational agent under development to prevent
and treat orthopoxvirus infection, was initiated on the basis of
its unique mechanism of action, current safety profile, and
promising efficacy, even when administered at later stages of
illness . The drug targets an envelope protein required for
viral maturation . ST-246 has shown in vitroactivityagainst
multiple species of orthopoxviruses, as well as efficacyinanimal
models, including both monkeypox and variola challenges in
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1560 • CID 2008:46 (15 May) • Vora et al.
pilot studies of nonhuman primates. Thus far, the drug has
shown no toxicity in animal toxicology experiments, and has
been associated with no severe adverse events in Phase I studies
in healthy adult volunteers [28–30] (SIGA Technologies, un-
published data). On the basis of the decreasing viral load, the
improvement of the patient’s clinical and immune status, and
data from non-human primate studies, ST-246 treatment was
discontinued after 14 days.
It is difficult to precisely define the potential contributions
of each agent to the patient’s recovery because of the close
timing of administration. Vaccinia virus DNA levels in blood
samples decreased from pretreatment levels following VIGIV
and cidofovir treatment, then continued to decrease with the
administration of ST-246, especially with achievement of target
peak and trough ST-246 plasma concentration levels (figures
2B and 3). It appears that the patient mounted his own anti-
orthopoxvirus IgG response between days 9 and 10; maximum
IgG levels wereachievedbetweenhospitaldays12and18(figure
2A). Additionally complicating interpretation of the impact of
individual interventions, we cannot yet differentiate between
the patient’s own IgG and that contributed by the VIGIV treat-
ment. Although it is difficult to assess and differentiate the
effects of specific therapeutic interventions, the child’s immune
response almost certainly played a role in the eventual control
of his infection .
This case illustrates the need for meticulous prevaccination
screening and the potential hazards of widespread smallpox
vaccination. It provides an important modelofthecoordinated,
multidisciplinary effort required for the management of such
a complication. This case also exemplifies the utility of novel
treatments, as well as the role of new techniques in laboratory
diagnosis and monitoring of infection, in guiding this therapy.
The need for additional research in the areas of therapeutics
and safer vaccines is clear as long as the perceived threat of
We thank Kenneth Alexander, Arthur Frank, Donald Leung,DanielGlik-
man, and Kirk Chan-Tack, for their critical review of the manuscript; Sue
Boonlanyagoor, for coordinating specimen transport to the CDC; Em-
manuel Semmes, for facilitating the receipt and administrationoftherapies;
Barrett Fromme, Dana Aronson, PICU nursing staff, and many others, for
their assistance with clinical care of the patient; Lori Ferguson,forinfection
control support; William Bower, for coordinating numerous conference
calls; Chris Sinclair (Cangene Corporation), for providing VIGIV data;
Wayne Staggs and Charlene Graves, for assistance with Indiana public
health aspects of the case; Mary Reynolds, Nikki Pesik, Yvonne Stifel, Joel
Price, John Nawrocki, George Dizikes, Kimberly King, and Jie Peng, for
logistics and laboratory assistance; and the Vaccine Healthcare Centers
Network and the Military Vaccine Agency staff, for their help addressing
issues regarding the service member.
Potential conflicts of interest.
D.H., T.B., R.J., and D.T. own equity in
SIGA Technologies. All other authors: no conflicts.
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