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Talbot TR, Bredenberg HK, Smith M, LaFleur BJ, Boyd A, Edwards KM. Focal and Generalized Folliculitis Following Smallpox Vaccination Among Vaccinia-Naive Recipients. JAMA. 2003;289(24):3290–3294. doi:10.1001/jama.289.24.3290
Author Affiliations: Departments of Medicine (Drs Talbot, Bredenberg, Smith, and Boyd), Pediatrics (Drs Smith and Edwards), Preventive Medicine (LaFleur), and Pathology (Dr Boyd), Vanderbilt University School of Medicine, Nashville, Tenn.
Context With the reintroduction of smallpox vaccination, detailed contemporary
descriptions of adverse reactions to the vaccine are needed to adequately
inform the public and clinicians. During a multicenter, randomized controlled
trial investigating the efficacy of various dilutions of smallpox vaccine,
we observed the appearance of a papulovesicular eruption (focal and generalized)
in study volunteers.
Objective To characterize the papulovesicular eruptions by clinical, virologic,
and histopathological characteristics.
Design, Setting, and Participants Prospective case series of papulovesicular eruptions following smallpox
vaccination in healthy, vaccinia-naive adult participants compared with noncases
conducted from October 2002 to March 2003. Variables potentially related to
these eruptions were collected retrospectively through chart review. Eruptions
were described based on viral culture, clinical examination, and histopathological
evaluation (1 biopsy specimen from 1 case).
Main Outcome Measure Cases of papulovesicular eruptions following vaccination.
Results During the trial, of 148 volunteers (56% women; mean age 23.6 years),
4 participants (2.7%) developed generalized eruptions and 11 (7.4%) noted
focal eruptions. Viral cultures of sample lesions were negative for vaccinia.
The result of a skin biopsy sample from 1 case of generalized rash revealed
suppurative folliculitis without evidence of viral infection. All lesions
resolved without scarring. In the cohort, cases and noncases did not show
significant differences in terms of sex, in the use of nonsteroidal anti-inflammatory
drugs or oral or depo contraceptives, in medication allergies, in the incidence
of fever or lymphadenopathy after vaccination, or in the dilution of vaccine
Conclusions Folliculitis is a common and benign eruption observed in vaccinia-naive
adult volunteers following smallpox vaccination. This eruption may be seen
in volunteers receiving the vaccine in the newly instituted vaccination programs
and may be met with heightened anxiety, potentially being confused with generalized
vaccinia. This description of folliculitis using clinical, virologic, and
histopathological findings should allay these concerns and provide additional
insight into this eruption.
Adverse dermatologic reactions after smallpox vaccine administration,
including eczema vaccinatum and progressive vaccinia, were well described
when smallpox vaccination was routine practice.1 While
these reactions were rare, they were associated with significant morbidity
and occasional mortality. Other less severe dermatologic reactions to smallpox
vaccine also were reported, including generalized vaccinia2 and
During a clinical trial investigating the efficacy and safety of vaccinia
immunization in healthy, vaccinia-naive adult volunteers, (ie, those not previously
vaccinated) we observed a papulovesicular eruption following vaccination in
several volunteers that mirrored generalized vaccinia on initial inspection.
While cases were initially identified as generalized rashes, with a heightened
awareness to this eruption, cases of focal variants were noted as the trial
progressed. To further define the focal eruption to and contrast it with generalized
vaccinia, we reviewed the cases in our cohort and outlined the clinical, virologic,
and histopathological characteristics of this eruption.
After providing written informed consent, healthy, vaccinia-naive adult
participants aged 18 years to 32 years were enrolled in a multicenter, double-blind,
randomized controlled trial that was investigating the safety and efficacy
of 3 dilutions of smallpox vaccine (Aventis Pasteur Smallpox Vaccine, Swiftwater,
Pa). Exclusion criteria for eligibility to participate in this clinical trial
and to receive smallpox vaccine are noted in the Box. Approval for the trial was granted by the Vanderbilt
University institutional review board.
History of autoimmune diseaseUse of immunosuppressive medicationsHistory
of human immunodeficiency virus infectionHistory of solid organ or
bone marrow transplantationHistory of malignancyHistory of or
current illegal injection drug useEczema (active or quiescent)Current
exfoliative skin disordersPresence of a typical vaccinia scar or history
of smallpox vaccinationPrior vaccination with any vaccinia-vectored
or other pox-vectored experimental vaccinePresence of medical or psychiatric
conditions or occupational responsibilities that precluded subject compliance
with the protocolAcute febrile illness (≥100.5°F [38°C])
on the day of vaccinationAllergies to components of the vaccinePregnant
or lactating womenHousehold or sexual contacts having any of the following
conditions: history of or concurrent eczema, a history of exfoliative skin
disorders, a history of the immunosuppressive conditions noted above, ongoing
pregnancy, or children younger than 12 months of age
Eligible participants were randomized to receive 1 of 3 dilutions of
the vaccine (undiluted, n = 49; 1:5, n = 48; and 1:10, n = 51 dilutions).
Randomization was performed using an Internet-based program with fixed blocks
of 6 assignments per block. Vaccine dilutions were performed by the study
pharmacist, and vaccine doses were delivered to the study clinic in vials
labeled with a dilution group number (G1, G2, or G3). Both volunteers and
study personnel were blinded during the course of the study to the specific
vaccine dilution associated with each group number.
The frozen vaccine was reconstituted with diluent-containing glycerin,
phenol, and sterile water. The vaccine was administered to the deltoid region
via scarification by 15 punctures with a bifurcated needle, and the site was
covered with occlusive dressings, as described previously.4 Volunteers
were examined every 3 to 5 days for scheduled dressing changes, assessment
of response to the vaccine, and evaluation of adverse events. Volunteers were
counseled on routine self-assessment for new dermatologic lesions. Baseline
dermatologic examinations were performed at initial screening, but subsequent
examinations occurred only after volunteer report of a cutaneous eruption.
Bandages were changed until the site was deemed well-scabbed by study investigators,
usually several weeks after vaccination.
Specimens from eruptions were cultured for vaccinia virus using methods
described previously.5 Briefly, specimens were
placed into viral transport media and frozen at −70°C for batch
processing. After thawing, 0.2 mL of each specimen was inoculated onto BSC-40
cells and incubated at 37°C. Uninfected BSC-40 cells were used as controls.
The presence of the distinctive cytopathic effect of vaccinia6 were
assessed every 48 to 72 hours for 10 days. Specimens considered positive for
vaccinia were those that developed cytopathic effect, while those without
cytopathic effect at 10 days were considered negative for vaccinia. Polymerase
chain reaction for vaccinia virus was not available for confirmation of culture
Cases were prospectively defined as volunteers who developed a focal
or generalized papulovesicular rash distant from the vaccination site during
the month following vaccination. Noncases did not develop these findings.
Variables potentially related to a focal or generalized papulovesicular
rash were collected retrospectively for both cases and noncases via chart
review and included concurrent medications (oral or depo contraceptives, nonsteroidal
anti-inflammatory medications), medication allergies, the presence of fever
or lymphadenopathy after vaccination (surrogate markers of systemic and local
immune response), and vaccine dilution group number. Continuous variables
were compared between cases and noncases using the Fisher exact test; age
was compared using the Student t test with unequal
The statistical analysis was performed using STATA version 7.0 (Stata
Corp, College Station, Tex).
At the Vanderbilt site, 148 volunteers underwent smallpox vaccination.
The mean age of the cohort was 23.6 years; 56% of the group were women. All
participants completed follow-up. Four participants (2.7%) developed a generalized
papulovesicular reaction following vaccination with onset between 9 and 11
days postvaccination. The eruption was observed on several body sites, including
the face, torso, and extremities. The lesions began as follicular erythematous
papules that progressed into pustules, which eventually resolved without scarring.
Concurrent lesions were at different stages of development. All 4 participants
were afebrile at the time of the eruption.
In an additional 11 participants (7.4%), focal eruptions that were morphologically
similar to the generalized lesions were noted. These eruptions occurred on
various body sites away from the primary vaccination site, including the face,
neck, back, and extremities. Ten of these cases were afebrile throughout the
postvaccination course. One individual developed fever on day 6 postvaccination,
2 days before rash onset. All rashes resolved without scarring.
A 20-year-old man presented 10 days after vaccination with a 2-day history
of "worsening acne" and "ingrown hairs" on his leg. He noted an acneiform
rash along his beard line as well as several nontender, nonpruritic papules
on his legs. He denied fevers, chills, or other systemic symptoms. He denied
use of any new medications except ibuprofen and naproxen taken after vaccination.
He was afebrile (98.6°F [37°C]) and did not appear ill. His mucous
membranes were without abnormalities. His vaccination site measured 17mm in
diameter with 135 mm of surrounding skin showing erythema and associated induration.
Dermatologic examination revealed numerous follicular papules, macules, and
pustules in different stages of development on his chest, back, legs, face,
and right axilla (Figure 1). The
result of viral culture of 1 sample lesion was negative for vaccinia. Histopathological
findings of a skin biopsy sample taken from a lesion on the back revealed
a suppurative folliculitis with a neutrophil-predominant infiltrate involving
pilosebaceous structures (Figure 2).
The result of Gomori-Methenamine silver stain was negative for fungi. Histopathological
changes associated with viral infection (Guarnieri inclusion bodies, ballooning
keratinocyte degeneration, giant cells, dyskeratotic keratinocytes, ulceration,
and dermal edema) were absent. Treatment was given to ameliorate any symptoms
(eg, pain, itching), and the eruptions resolved during the next week without
Vaccinia virus was not isolated from any of the 17 lesion samples from
7 of the volunteers available for culture (4 cases with generalized rash and
3 cases with focal rash).
Cases and noncases were not significantly different in terms of their
sex, in the use of nonsteroidal anti-inflammatory drug or oral or depo contraceptives,
in medication allergies, in vaccine dilution group, and in incidence of fever
or lymphadenopathy. Cases were significantly younger than noncases (mean age
22.2 years vs 23.7 years, P = .03).
Serious cutaneous adverse reactions after smallpox vaccination have
been described1 and, while rare, are associated
with significant morbidity and some mortality. Vaccinia necrosum, usually
seen in patients who have immunodeficiencies, begins as a necrotic lesion
that relentlessly progresses to systemic infection and death. Eczema vaccinatum
occurs in individuals with eczema (active or quiescent) and may lead to disseminated
disease with extensive scarring and, rarely, death. Other less-severe, self-limited
cutaneous reactions due to smallpox vaccination also have been described,
including an erythematous urticarial reaction in primary vaccinees,7 mild forms of erythema multiforme,3 and
generalized vaccinia, which appears 6 to 9 days after vaccination and has
lesions similar in appearance to those at the vaccination site.2
We describe folliculitis following smallpox vaccination, another eruption
that should be added to this list of cutaneous complications. While benign
in our cohort, this eruption may be initially confused with generalized vaccinia,
because of morphological characteristics of the lesions and the generalized
distribution in some cases. Folliculitis following smallpox vaccination appears
distinct from earlier descriptions of generalized vaccinia. The lesions of
folliculitis exhibit neutrophil-predominant follicular inflammation without
histopathological evidence of viral infection, develop in different stages
(unlike generalized vaccinia), and do not scar after healing (Table 1). Mild forms of generalized vaccinia1,2 have
been previously described and may represent the folliculitis observed in our
study, although the vaccine type administered in these cases may have differed
from the vaccine used in our study (Aventis Pasteur smallpox vaccine).
In this study, most cases of folliculitis following smallpox vaccination
occurred at the time of maximal viral replication and local inflammatory symptoms,
suggesting that the pathophysiology of this eruption may be explained by the
host response to vaccination and its accompanying inflammatory reaction. Similar
eruptions related to drug- and viral exposures have been reported. Acute generalized
exanthematous pustulosis, a generalized pustular rash associated with fever
and histopathological results showing leukocytosis and suppurative dermal
pustules, has been associated with drug and viral-induced T-cell activation
and an increase in IL-8 production.14,15 Our
study cohort comprised healthy adults who could be expected to mount a robust
immune response to exposed antigens, and the substantial incidence of folliculitis
seen in our study may reflect a vigorous immune response to the vaccine. In
contrast to the children immunized with vaccinia virus when vaccination was
routine practice, the primary vaccinees in the current study are older and
may represent slightly different hosts. For example, prepubertal children
have limited hair follicles, and this might account for the difference in
rates of folliculitis in our cohort when compared with younger historical
controls. While cases were significantly younger than the noncases in this
study, the clinical significance of this finding is unclear given the limited
age range in our population.
The local inflammation around the sebaceous glands seen with folliculitis
following smallpox vaccination is curious. Targeting of the sebaceous glands
was described in natural smallpox disease with deep glandular involvement
leading to scarring.8 With smallpox, scarring
was much more common on the face, which has a greater distribution of sebaceous
glands compared with other body parts.8 Although
vaccinia virus was not isolated from eruptions in our study, it is interesting
to speculate whether the tropism of vaccinia virus for glandular tissue may
relate to the pathogenesis of this folliculitis.
Our characterization of folliculitis following smallpox vaccination
has limitations. Our study population consisted of young adults who could
be expected to have nonspecific dermatologic eruptions, such as acne. Although
this could lead to an overemphasis of routine eruptions, the cases were noted
to have follicular eruptions unlike any prior rashes, especially in severity
and distribution. A further limitation is that only 1 participant underwent
biopsy of the eruption. However, given the similar clinical picture in other
cases of follicular eruptions, they likely reflect the same process. While
we did not have the results of polymerase chain reaction to confirm our negative
viral culture results, culture data has been used as the criterion standard
for vaccinia in the past.5 We also have assumed
that the focal eruptions represent the same clinical and pathological process
as the generalized reaction. However, even if the local reactions are excluded,
4 participants (2.7%) of the vaccinia-naive cohort developed generalized folliculitis
This high rate of presumed folliculitis after smallpox vaccine administration
has clinical importance, especially in the setting of larger-scale vaccination.
Early reports from the current military and civilian vaccination campaigns
have separately highlighted individuals who developed a pustular rash approximately
10 days after vaccination that was classified as "generalized vaccinia."16,17 These eruptions also may represent
folliculitis following smallpox vaccination. While these individuals received
a different formulation of vaccinia (New York City Board of Health strain,
Dryvax, Wyeth Laboratories, Marietta, Pa) than that administered in our trial,
it was derived from the same strain of vaccinia virus and might be expected
to have similar adverse events. In addition, a recent clinical trial investigating
the New York City Board of Health strain of smallpox vaccine noted the development
of a papular rash that appears very similar to folliculitis following smallpox
While folliculitis following vaccination resolved fully in our volunteers,
required no specific interventions, and showed no apparent residual sequelae,
the concern caused by this eruption on the part of the participants and the
clinicians was substantial. The potential for misinformation and concern about
skin eruptions following smallpox vaccination are important issues. It is
hoped that this report will help educate clinicians, reduce anxiety, and provide
reassurance to the medical community.
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