Focal and Generalized Folliculitis Following Smallpox Vaccination Among Vaccinia-Naive Recipients
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ORIGINAL CONTRIBUTION Focal and Generalized Folliculitis Following Smallpox Vaccination Among Vaccinia-Naive Recipients Thomas R. Talbot, MD, MPH Context With the reintroduction of smallpox vaccination, detailed contemporary de- H. Keipp Bredenberg, MD scriptions of adverse reactions to the vaccine are needed to adequately inform the pub- Michael Smith, MD lic and clinicians. During a multicenter, randomized controlled trial investigating the efficacy of various dilutions of smallpox vaccine, we observed the appearance of a papu- Bonnie J. LaFleur, PhD lovesicular eruption (focal and generalized) in study volunteers. Alan Boyd, MD Objective To characterize the papulovesicular eruptions by clinical, virologic, and Kathryn M. Edwards, MD histopathological characteristics. Design, Setting, and Participants Prospective case series of papulovesicular erup- DVERSE DERMATOLOGIC REAC- tions following smallpox vaccination in healthy, vaccinia-naive adult participants com- tions after smallpox vaccine pared with noncases conducted from October 2002 to March 2003. Variables poten- administration, including ec- tially related to these eruptions were collected retrospectively through chart review. zema vaccinatum and pro- Eruptions were described based on viral culture, clinical examination, and histopatho- Agressive vaccinia, were well described logical evaluation (1 biopsy specimen from 1 case). when smallpox vaccination was rou- Main Outcome Measure Cases of papulovesicular eruptions following vaccination. 1 tine practice. While these reactions Results During the trial, of 148 volunteers (56% women; mean age 23.6 years), 4 par- were rare, they were associated with sig- ticipants (2.7%) developed generalized eruptions and 11 (7.4%) noted focal eruptions. nificant morbidity and occasional mor- Viral cultures of sample lesions were negative for vaccinia. The result of a skin biopsy sample tality. Other less severe dermatologic from 1 case of generalized rash revealed suppurative folliculitis without evidence of viral reactions to smallpox vaccine also were infection. All lesions resolved without scarring. In the cohort, cases and noncases did not reported, including generalized vac- show significant differences in terms of sex, in the use of nonsteroidal anti-inflammatory cinia2 and erythema multiforme.3 drugs or oral or depo contraceptives, in medication allergies, in the incidence of fever or During a clinical trial investigating the lymphadenopathy after vaccination, or in the dilution of vaccine received. efficacy and safety of vaccinia immuni- Conclusions Folliculitis is a common and benign eruption observed in vaccinia- zation in healthy, vaccinia-naive adult naive adult volunteers following smallpox vaccination. This eruption may be seen in volunteers, (ie, those not previously vac- volunteers receiving the vaccine in the newly instituted vaccination programs and may be met with heightened anxiety, potentially being confused with generalized vac- cinated) we observed a papulovesicu- cinia. This description of folliculitis using clinical, virologic, and histopathological find- lar eruption following vaccination in ings should allay these concerns and provide additional insight into this eruption. several volunteers that mirrored gener- JAMA. 2003;289:3290-3294 www.jama.com alized vaccinia on initial inspection. While cases were initially identified as cohort and outlined the clinical, viro- blind, randomized controlled trial that generalized rashes, with a heightened logic, and histopathological character- was investigating the safety and efficacy awareness to this eruption, cases of fo- istics of this eruption. of 3 dilutions of smallpox vaccine cal variants were noted as the trial pro- gressed. To further define the focal erup- METHODS Author Affiliations: Departments of Medicine (Drs Tal- bot, Bredenberg, Smith, and Boyd), Pediatrics (Drs tion to and contrast it with generalized Study Participants Smith and Edwards), Preventive Medicine (LaFleur), vaccinia, we reviewed the cases in our and Pathology (Dr Boyd), Vanderbilt University School After providing written informed con- of Medicine, Nashville, Tenn. sent, healthy, vaccinia-naive adult Corresponding Author and Reprints: Thomas R. Talbot, See also pp 3278, 3283, 3295, participants aged 18 years to 32 years MD, MPH, Department of Medicine, A-3310 Medical and 3306. Center North, Vanderbilt University Medical Center, Nash- were enrolled in a multicenter, double- ville, TN 37232 (e-mail: [email protected]). 3290 JAMA, June 25, 2003—Vol 289, No. 24 (Reprinted) ©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 FOCAL AND GENERALIZED FOLLICULITIS FOLLOWING SMALLPOX VACCINATION (Aventis Pasteur Smallpox Vaccine, Swiftwater, Pa). Exclusion criteria for eli- Box. Exclusion Criteria for Eligibility to Participate in the gibility to participate in this clinical trial Vaccine Dilution Trial and Receive Smallpox Vaccination and to receive smallpox vaccine are noted History of autoimmune disease in the BOX. Approval for the trial was Use of immunosuppressive medications granted by the Vanderbilt University in- History of human immunodeficiency virus infection stitutional review board. History of solid organ or bone marrow transplantation History of malignancy History of or current illegal injection drug use Vaccination Methods Eczema (active or quiescent) and Follow-up Current exfoliative skin disorders Eligible participants were randomized to Presence of a typical vaccinia scar or history of smallpox vaccination receive 1 of 3 dilutions of the vaccine Prior vaccination with any vaccinia-vectored or other pox-vectored experimental (undiluted, n=49; 1:5, n=48; and 1:10, vaccine n=51 dilutions). Randomization was Presence of medical or psychiatric conditions or occupational responsibilities that performed using an Internet-based pro- precluded subject compliance with the protocol Acute febrile illness (Ն100.5°F [38°C]) on the day of vaccination gram with fixed blocks of 6 assign- Allergies to components of the vaccine ments per block. Vaccine dilutions were Pregnant or lactating women performed by the study pharmacist, and Household or sexual contacts having any of the following conditions: history of vaccine doses were delivered to the study or concurrent eczema, a history of exfoliative skin disorders, a history of the clinic in vials labeled with a dilution immunosuppressive conditions noted above, ongoing pregnancy, or children group number (G1, G2, or G3). Both younger than 12 months of age volunteers and study personnel were blinded during the course of the study to the specific vaccine dilution associ- processing. After thawing, 0.2 mL of inflammatory medications), medica- ated with each group number. each specimen was inoculated onto tion allergies, the presence of fever or The frozen vaccine was reconsti- BSC-40 cells and incubated at 37°C. Un- lymphadenopathy after vaccination (sur- tuted with diluent-containing glyc- infected BSC-40 cells were used as con- rogate markers of systemic and local im- erin, phenol, and sterile water. The vac- trols. The presence of the distinctive cy- mune response), and vaccine dilution cine was administered to the deltoid topathic effect of vaccinia6 were assessed group number. Continuous variables region via scarification by 15 punc- every 48 to 72 hours for 10 days. Speci- were compared between cases and non- tures with a bifurcated needle, and the mens considered positive for vaccinia cases using the Fisher exact test; age was site was covered with occlusive dress- were those that developed cytopathic compared using the Student t test with ings, as described previously.4 Volun- effect, while those without cytopathic unequal variances. teers were examined every 3 to 5 days effect at 10 days were considered nega- The statistical analysis was per- for scheduled dressing changes, assess- tive for vaccinia. Polymerase chain re- formed using STATA version 7.0 (Stata ment of response to the vaccine, and action for vaccinia virus was not avail- Corp, College Station, Tex). evaluation of adverse events. Volun- able for confirmation of culture data. teers were counseled on routine self- RESULTS assessment for new dermatologic Case Ascertainment At the Vanderbilt site, 148 volunteers lesions. Baseline dermatologic exami- Cases were prospectively defined as vol- underwent smallpox vaccination. The nations were performed at initial screen- unteers who developed a focal or gen- mean age of the cohort was 23.6 years; ing, but subsequent examinations oc- eralized papulovesicular rash distant 56% of the group were women. All par- curred only after volunteer report of a from the vaccination site during the ticipants completed follow-up. Four cutaneous eruption. Bandages were month following vaccination. Non- participants (2.7%) developed a gen- changed until the site was deemed well- cases did not develop these findings. eralized papulovesicular reaction fol- scabbed by study investigators, usu- lowing vaccination with onset be- ally several weeks after vaccination. Risk Factor Assessment tween 9 and 11 days postvaccination. and Analysis The eruption was observed on several Culture Collection and Methods Variables potentially related to a focal or body sites, including the face, torso, Specimens from eruptions were cul- generalized papulovesicular rash were and extremities. The lesions began as tured for vaccinia virus using meth- collected retrospectively for both cases follicular erythematous