Smallpox vaccination has been associated with a number of rare, but clinically significant, complications including a wide variety of exanthems. Among these is vaccinia folliculitis, which typically coincides with the peak of viral replication at the vaccination site. Viable vaccinia virus has not been isolated from these lesions, which heal without scarring. We report a case of vaccinia folliculitis in a vaccinia-naive laboratory worker who subsequently developed swelling and violet discoloration of his hands and feet. Although vaccinia folliculitis is a benign complication of vaccinia vaccination, it can lead to diagnostic confusion with more severe complications such as generalized vaccinia.
Division of Infectious Diseases, Massachusetts General Hospital, Boston and Division of Immunology, New England Primate Research Center, Harvard Medical School, One Pine Hill Drive, Southborough, MA.
S.W. is supported by a career development grant from the New England Regional Center of Excellence for Biodefense and Emerging Infectious Diseases (AI057159-03). P.J. is supported by National Institutes of Health grant RR 00168 and AI62412.
Address correspondence and reprint requests to R. Paul Johnson, MD, Infectious Disease Unit, Massachusetts General Hospital, 149 13th Street, 5th Floor, Charlestown, MA 02129. E-mail: email@example.com.
A 32-year-old vaccinia-naive researcher who worked with vaccinia virus and recombinant vaccinia strains elected to receive Dryvax (Wyeth, Pearl River, NY) vaccination as recommended by the Centers for Disease Control and Prevention.1 His medical history was notable for mild intermittent asthma and allergic rhinitis for which he took over-the-counter antihistamines. He received Dryvax via 3 punctures with a bifurcated needle on his left lateral deltoid region and noted the development of a papule 4 days later. By day 10, the lesion had progressed to a large pustule. On day 14, he noted the appearance of multiple 2- to 8-mm papules with blanching, erythematous bases, mostly centered at follicles (Fig. 1). The papules were present largely on the upper arms, left more than right, with some scattered papules on the forearms. The papules all seemed to be at the same stage of development. No significant vesicular lesions were seen. Rare lesions had a tiny punctate follicular head at the center. There was no mucous membrane involvement, and no rash elsewhere on the body. The patient had no systemic complaints, and noted that the papules were neither painful nor pruritic. The primary vaccination site had a typical Jennerian ulcer measuring about 15 mm in diameter, with granulation tissue and mild surrounding erythema. There was confluence of the macular and papular lesions at site of the adhesive dressing, suggesting Koebnerization (Fig. 1B).
Public health authorities were consulted because the differential diagnosis included disseminated vaccinia. Based on the appearance of the lesions and the patient's lack of systemic symptoms, it was felt that disseminated vaccinia was unlikely. The patient declined biopsy of the lesions, and viral cultures from the lesions were not obtained.
No new lesions appeared over the next day and by day 16, the papules seemed to be receding. However, he developed tense, nonpitting edema of both hands, particularly at his fingers, and a blanching, violet-colored palmar rash (Fig. 2). The patient continued to have no systemic symptoms; the hand swelling resolved over the next 2 days, and the follicular-based papules faded over the subsequent 5 days. The primary vaccination site healed by day 26, leaving a typical scar. There was no evidence of contact vaccinia in his household contacts. The generalized eruption healed without scarring.
Recent events have renewed interest in smallpox vaccination and led to a limited civilian vaccination program for "first responders" and a larger military vaccination program. Although the overall frequency of significant side effects seemed to be quite low,2,3 there were rare adverse events,4 some of which had not been generally recognized in historical studies.5 Dermatologic complications after smallpox vaccination have long been recognized and include potentially life-threatening reactions, such as progressive vaccinia or vaccinia necrosum, eczema vaccinatum, and disseminated vaccinia.6,7 More commonly seen, however, are less serious reactions, such as satellite lesions, viral cellulitis, and a variety of rashes which have been estimated to occur at a frequency of about 1:3700 vaccinees.8
Vaccinia folliculitis was first reported in a trial of a formerly licensed smallpox vaccine.9 In that report, 2.7% of recipients experienced a generalized eruption, and an additional 7.4% had a focal exanthem. The generalized eruptions appeared 9 to 11 days after vaccination and were observed on the face, torso, and extremities. Cultures of lesions from 7 affected individuals did not grow vaccinia virus, whereas a biopsy from 1 case of generalized folliculitis revealed a suppurative folliculitis with a neutrophilic infiltrate around the pilosebaceous structures.9 Talbot et al9 also noted retrospectively that generalized pustular and vesicular exanthems had occurred frequently in a trial of diluted Dryvax,10 and speculated that many of these may have been vaccinia folliculitis.
In 2 other recent cases, folliculitis-like papules were found on the trunk 9 days after smallpox vaccination. In contrast to our case, these 2 patients had also recently received anthrax vaccination,11 which has also been associated with a postvaccination exanthem.12 In a phase I trial of a tissue culture-based smallpox vaccine, Greenberg et al13 reported that 3.6% of the vaccinees who received the experimental vaccine developed benign, self-limited rashes. Whereas most of these rashes were described as urticarial, 1 case was described as a generalized, diffusely pruritic eruption with perifollicular papules that began on day 15 after vaccination with the experimental vaccine and lasted nearly 2 weeks.13 In addition, another trial of a tissue culture-derived smallpox vaccine reported 2 cases of vaccinia folliculitis in vaccinia-naive subjects, one after the experimental ACAM2000 vaccine, and one after Dryvax from a total of 50 subjects in each group.14
The pathophysiology of vaccinia-associated folliculitis is not well understood. Vaccinia has not been isolated from the follicular-based eruption.9 We suspect that this phenomenon is an immune-mediated reaction. The rashes have typically been reported near the time of the onset of host immune responses and the waning of viral replication in young, vaccinia-naive subjects. The dermal inoculation and subsequent intradermal replication of vaccinia may lead to preferential selection of vaccinia-specific T cells which express skin-specific lymphocyte homing molecules.15 These dermatotropic, vaccinia-specific T cells may therefore play a role in the development of postvaccinial folliculitis. In addition, our patient developed swelling of his hands and a violet-colored rash on his palms, reminiscent of an immune-complex deposition rash, while the follicular-based lesions were beginning to resolve. This second reaction seems somewhat different to a case reported by Greenberg et al,13 as our patient did not have perioral swelling, and his rash was restricted to his palms.
The differential diagnosis of our patient's rash included generalized vaccinia, a serious complication of vaccination caused by viremic spread of vaccinia.6,7 The lesions of generalized vaccinia usually appear about 7 days after vaccination and resemble the primary Jennerian pustule, but tend to be smaller and resolve faster.7 Unlike vaccinia folliculitis, the lesions of generalized vaccinia contain live virus and are contagious16 and leave residual scars. The reported cases of vaccinia folliculitis seem to have later onset (10-14 days) than generalized vaccinia, and seem to be only mildly symptomatic.9 The papulopustular appearance, follicular localization, slightly later onset, and absence of systemic symptoms seem to be the key distinguishing features for vaccinia folliculitis.
Because smallpox vaccination is likely to remain a topic of interest for quite some time, clinicians should be aware of the wide range of exanthems that can occur after vaccination, particularly primary vaccination in young adults. Many of these are benign and self limited, but can be disconcerting to the patient and clinician. It is critical to obtain expert consultation to differentiate benign rashes, such as vaccinia folliculitis, from life-threatening eruptions, such as generalized vaccinia or eczema vaccinatum.
The authors thank Kristen Toohey for expert assistance with the photographs.
1. Rotz LD, Dotson DA, Damon IK, et al. Vaccinia (smallpox) vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2001. MMWR
2. Grabenstein JD, Winkenwerder W. US military smallpox vaccination program experience. JAMA
3. Poland GA, Grabenstein JD, Neff JM. The US smallpox vaccination program: a review of a large modern era smallpox vaccination implementation program. Vaccine
4. Anonymous. Update: adverse events following civilian smallpox vaccination-United States, 2003. MMWR
5. Halsell JS, Riddle JR, Atwood JE, et al. Myopericarditis following smallpox vaccination among vaccinia-naive US military personnel. JAMA
6. Vellozzi C, Lane JM, Averhoff F, et al. Generalized vaccinia, progressive vaccinia, and eczema vaccinatum are rare following smallpox (vaccinia) vaccination: United States surveillance, 2003. Clin Infect Dis
7. Fulginiti VA, Papier A, Lane JM, et al. Smallpox vaccination: a review, part II. Adverse events. Clin Infect Dis
9. Talbot TR, Bredenberg HK, Smith M, et al. Focal and generalized folliculitis following smallpox vaccination among vaccinia-naive recipients. JAMA
10. Frey S, Couch RB, Tacket CO, et al. Clinical responses to undiluted and diluted smallpox vaccine. N Engl J Med
11. Oh RC. Folliculitis after smallpox vaccination: a report of two cases. Mil Med
12. Sever JL, Brenner AI, Gale AD, et al. Safety of anthrax vaccine: a review by the Anthrax Vaccine Expert Committee (AVEC) of adverse events reported to the Vaccine Adverse Event Reporting System (VAERS). Pharmacoepidemiol Drug Saf
13. Greenberg RN, Kennedy JS, Clanton DJ, et al. Safety and immunogenicity of new cell-cultured smallpox vaccine compared with calf-lymph derived vaccine: a blind, single-centre, randomised controlled trial. Lancet
14. Artenstein AW, Johnson C, Marbury TC, et al. A novel, cell culture-derived smallpox vaccine in vaccinia-naive adults. Vaccine
15. Santamaria-Babi LF. CLA+ T cells in cutaneous diseases. Eur J Dermatol
16. Sepkowitz KA. How contagious is vaccinia? N Engl J Med