Focal and Generalized Folliculitis Following Smallpox Vaccination Among Vaccinia-Naive Recipients

ORIGINAL CONTRIBUTION

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- gressiveA 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 progressed. 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]).

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(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 papules that ods described previously.5 Briefly, speci- and noncases via chart review and in- progressed into pustules, which even- mens were placed into viral transport cluded concurrent medications (oral or tually resolved without scarring. Con- media and frozen at −70°C for batch depo contraceptives, nonsteroidal anti- current lesions were at different stages

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of development. All 4 participants were vaccination, 2 days before rash onset. All use of any new medications except afebrile at the time of the eruption. rashes resolved without scarring. ibuprofen and naproxen taken after In an additional 11 participants vaccination. He was afebrile (98.6°F (7.4%), focal eruptions that were mor- Report of a Case [37°C]) and did not appear ill. His phologically similar to the generalized A 20-year-old man presented 10 days mucous membranes were without lesions were noted. These eruptions oc- after vaccination with a 2-day history abnormalities. His vaccination site mea- curred on various body sites away from of “worsening acne” and “ingrown sured 17mm in diameter with 135 mm the primary vaccination site, including hairs” on his leg. He noted an acne- of surrounding skin showing ery- the face, neck, back, and extremities. Ten iform rash along his beard line as well thema and associated induration. Der- of these cases were afebrile throughout as several nontender, nonpruritic pap- matologic examination revealed numer- the postvaccination course. One indi- ules on his legs. He denied fevers, chills, ous follicular papules, macules, and vidual developed fever on day 6 post- or other systemic symptoms. He denied pustules in different stages of develop-

Figure 1. Examples of Acneiform Eruption From Reported Case of Generalized Rash

A B

A, Lesions along beard line. B, Follicular lesion on left thigh.

Figure 2. Histopathological Sections of a Skin Biopsy Sample of a Lesion Taken From the Back of Reported Case With Generalized Rash

A B

A, Within the dermis is an inflammatory infiltrate intimately involving a pilosebaceous structure. Note the sparing of the epidermis and adjacent dermis (original magnification ϫ40, hematoxylin-eosin stain). B, Enlargement of boxed area from panel A showing inflammatory infiltrate consisting of lymphocytes and neutrophils surrounding a sebaceous gland (original magnification ϫ100, hematoxylin-eosin stain).

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ment on his chest, back, legs, face, and Table. Comparison of Classic Generalized Vaccinia and Folliculitis Following Smallpox right axilla (FIGURE 1). The result of Vaccination viral culture of 1 sample lesion was Generalized Vaccinia2,3,8-13 Folliculitis negative for vaccinia. Histopathologi- Time of onset 5-10 d after vaccination, usually 8-10 d after vaccination cal findings of a skin biopsy sample in primary vaccinees taken from a lesion on the back revealed Location Anywhere on the body Greater in areas with larger numbers of (including palms and soles) hair follicles (eg, extremities, face) or a suppurative folliculitis with a neu- sebaceous glands (eg, back) trophil-predominant infiltrate involv- Multiphase or Monotonous Multiphase ing pilosebaceous structures (FIGURE 2). monotonous The result of Gomori-Methenamine sil- Duration Days and, rarely, months 3-5 d ver stain was negative for fungi. Histo- Presence of fever Rare Rare pathological changes associated with and/or chills Presence of regional Rare None viral infection (Guarnieri inclusion bod- lymphadenopathy ies, ballooning keratinocyte degenera- Malaise Rare Rare tion, giant cells, dyskeratotic keratino- Local pruritus Not reported Occasional cytes, ulceration, and dermal edema) Isolation of vaccinia Yes with severe disease No were absent. Treatment was given to Histopathological Guarnieri inclusion bodies, Suppurative folliculitis ameliorate any symptoms (eg, pain, results of lesions keratinocyte degeneration, itching), and the eruptions resolved dur- acanthosis Progression Self-limited in immunocompetent Complete resolution ing the next week without scarring. hosts; systemic illness in some compromised hosts Culture Analysis Residual scarring With severe disease None Vaccinia virus was not isolated from any of the 17 lesion samples from 7 of the taneous reactions due to smallpox vac- fered from the vaccine used in our study volunteers available for culture (4 cases cination also have been described, in- (Aventis Pasteur smallpox vaccine). with generalized rash and 3 cases with cluding an erythematous urticarial In this study, most cases of folliculitis focal rash). reaction in primary vaccinees,7 mild following smallpox vaccination forms of erythema multiforme,3 and occurred at the time of maximal viral Risk-Factor Analysis generalized vaccinia, which appears 6 replication and local inflammatory Cases and noncases were not signifi- to 9 days after vaccination and has le- symptoms, suggesting that the patho- cantly different in terms of their sex, in sions similar in appearance to those at physiology of this eruption may be the use of nonsteroidal anti-inflamma- the vaccination site.2 explained by the host response to vac- tory drug or oral or depo contracep- We describe folliculitis following cination and its accompanying inflam- tives, in medication allergies, in vac- smallpox vaccination, another erup- matory reaction. Similar eruptions related cine dilution group, and in incidence tion that should be added to this list of to drug- and viral exposures have been of fever or lymphadenopathy. Cases cutaneous complications. While be- reported. Acute generalized exanthe were significantly younger than non- nign in our cohort, this eruption may matous pustulosis, a generalized pustu- cases (mean age 22.2 years vs 23.7 be initially confused with generalized lar rash associated with fever and years, P=.03). vaccinia, because of morphological histopathological results showing leu- characteristics of the lesions and the kocytosis and suppurative dermal pus- COMMENT generalized distribution in some cases. tules, has been associated with drug and Serious cutaneous adverse reactions af- Folliculitis following smallpox vacci- viral-induced T-cell activation and an ter smallpox vaccination have been de- nation appears distinct from earlier de- increase in IL-8 production.14,15 Our study scribed1 and, while rare, are associ- scriptions of generalized vaccinia. The cohort comprised healthy adults who ated with significant morbidity and lesions of folliculitis exhibit neutrophil- could be expected to mount a robust some mortality. Vaccinia necrosum, predominant follicular inflammation immune response to exposed antigens, usually seen in patients who have im- without histopathological evidence of and the substantial incidence of follicu- munodeficiencies, begins as a ne- viral infection, develop in different litis seen in our study may reflect a vig- crotic lesion that relentlessly progresses stages (unlike generalized vaccinia), and orous immune response to the vaccine. to systemic infection and death. Ec- do not scar after healing (TABLE). Mild In contrast to the children immunized zema vaccinatum occurs in individu- forms of generalized vaccinia1,2 have with vaccinia virus when vaccination was als with eczema (active or quiescent) been previously described and may rep- routine practice, the primary vaccinees and may lead to disseminated disease resent the folliculitis observed in our in the current study are older and may with extensive scarring and, rarely, study, although the vaccine type ad- represent slightly different hosts. For death. Other less-severe, self-limited cu- ministered in these cases may have dif- example, prepubertal children have lim-

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ited hair follicles, and this might account in the setting of larger-scale vaccina- NIH Vaccine Trials and Evaluation group, and col- leagues at the NIAID, particularly Steve Heyse, Walla for the difference in rates of folliculitis tion. Early reports from the current mili- Dempsey, Mamodikoe Makhene, and Holli Hamilton, in our cohort when compared with tary and civilian vaccination cam- for their support of and guidance with this project; Jen- nifer Doersam, Sharon Tollefson, and Peter Wright for younger historical controls. While cases paigns have separately highlighted their assistance with the virological cultures; and Kather- were significantly younger than the non- individuals who developed a pustular ine Hamilton for her assistance with photography. cases in this study, the clinical signifi- rash approximately 10 days after vacci- cance of this finding is unclear given the nation that was classified as “general- REFERENCES limited age range in our population. ized vaccinia.”16,17 These eruptions also 1. Neff JM. Vaccinia virus (cowpox). In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Ben- The local inflammation around the may represent folliculitis following nett’s Principles and Practice of Infectious Diseases. sebaceous glands seen with folliculitis smallpox vaccination. While these indi- 5th ed. Philadelphia, Pa: Churchill Livingstone; 2000: 1553-1554. following smallpox vaccination is cu- viduals received a different formula- 2. Centers for Disease Control and Prevention. Small- rious. Targeting of the sebaceous glands tion of vaccinia (New York City Board pox vaccination and adverse reactions: guidance for clinicians. MMWR Morb Mortal Wkly Rep. 2003;52: was described in natural smallpox dis- of Health strain, Dryvax, Wyeth Labo- 1-29. ease with deep glandular involvement ratories, Marietta, Pa) than that admin- 3. Lane JM, Ruben FL, Neff JM, Millar JD. Compli- 8 cation of smallpox vaccination, 1968: results of ten leading to scarring. With smallpox, istered in our trial, it was derived from statewide surveys. J Infect Dis. 1970;122:303-309. scarring was much more common on the same strain of vaccinia virus and 4. Henderson DA, Ingelsby TV, Bartlett JG, et al. Small- the face, which has a greater distribu- might be expected to have similar adverse pox as a biological weapon: medical and public health management. JAMA. 1999;281:2127-2137. tion of sebaceous glands compared with events. In addition, a recent clinical trial 5. Graham BS, Belshe RB, Clements ML, et al. Vac- other body parts.8 Although vaccinia vi- investigating the New York City Board cination of vaccinia-naı¨ve adults with a human immunodeficiency virus type 1 gp160 recombinant vac- rus was not isolated from eruptions in of Health strain of smallpox vaccine cinia virus in a blinded, controlled, randomized clinical our study, it is interesting to speculate noted the development of a papular rash trial. J Infect Dis. 1992;166:244-252. 6. Hsiung GD. Diagnostic Virology. New Haven, Conn: whether the tropism of vaccinia virus that appears very similar to folliculitis Yale University Press; 1982. for glandular tissue may relate to the following smallpox vaccination.18 7. Neff JM, Drachman RH. Complications of small- pathogenesis of this folliculitis. While folliculitis following vaccina- pox vaccination, 1968: surveillance in a comprehen- sive care clinic. Pediatrics. 1972;50:481-483. Our characterization of folliculitis tion resolved fully in our volunteers, 8. Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi following smallpox vaccination has required no specific interventions, and ID. Smallpox and its eradication. Geneva, Switzer- land: World Health Organization; 1988. Available at: limitations. Our study population con- showed no apparent residual se- http://www.who.int/emc/diseases/smallpox/ sisted of young adults who could be ex- quelae, the concern caused by this erup- Smallpoxeradication.html. Accessed May 29, 2003. 9. Lane JM, Rubin FL, Neff JM, Millar JD. Complica- pected to have nonspecific dermato- tion on the part of the participants and tions of smallpox vaccination, 1968—national surveil- logic eruptions, such as acne. Although the clinicians was substantial. The po- lance in the United States. N Engl J Med. 1969;281: 1201-1208. this could lead to an overemphasis of tential for misinformation and con- 10. Neff JM, Levine RH, Lane JM, et al. Complica- routine eruptions, the cases were noted cern about skin eruptions following tions of smallpox vaccination, United States, 1963— to have follicular eruptions unlike any smallpox vaccination are important is- results obtained by four statewide surveys. Pediat- rics. 1967;39:916-923. prior rashes, especially in severity and sues. It is hoped that this report will 11. Neff JM, Lane JM, Pert JH, Moore R, Millar JD, distribution. A further limitation is that help educate clinicians, reduce anxi- Henderson DA. Complications of smallpox vaccination—national survey in the United States, 1963. only 1 participant underwent biopsy of ety, and provide reassurance to the N Engl J Med. 1967;276:125-132. the eruption. However, given the simi- medical community. 12. Ratner LH, Lane JM, Vicens CN. Complications of smallpox vaccination: surveillance during an island- lar clinical picture in other cases of fol- wide program in Puerto Rico, 1967-1968. Am J Epi- licular eruptions, they likely reflect the Author Contributions: Study concept and design: demiol. 1970;91:278-285. same process. While we did not have Talbot, Edwards. 13. Goldstein JA, Neff JM, Lane JM, Koplan JP. Small- Acquisition of data: Talbot, Bredenberg, Edwards. pox vaccination reactions, prophylaxis, and therapy the results of polymerase chain reac- Analysis and interpretation of data: Talbot, Smith, of complications. Pediatrics. 1975;55:342-347. tion to confirm our negative viral cul- LaFleur, Boyd, Edwards. 14. Sidoroff A, Halevy S, Bavinck JNB, Vaillant L, Rou- Drafting of the manuscript: Talbot, LaFleur, Edwards. jeau J. Acute generalized exanthematous pustulosis ture results, culture data has been used Critical revision of the manuscript for important in- (AGEP)—a clinical reaction pattern. J Cutan Pathol. as the criterion standard for vaccinia in tellectual content: Talbot, Bredenberg, Smith, LaFleur, 2001;28:113-119. 5 Boyd, Edwards. 15. Schmid S, Kuechler PC, Britschgi M, et al. Acute the past. We also have assumed that Statistical expertise: LaFleur generalized exanthematous pustulosis: role of cyto- the focal eruptions represent the same Obtained funding: Edwards. toxic T cells in pustule formation. Am J Pathol. 2002; Administrative, technical, or material support: Talbot, 161:2079-2086. clinical and pathological process as the Boyd, Edwards. 16. Winkenwerder W. Department of Defense Small- generalized reaction. However, even if Study supervision: Edwards. pox Vaccination Program Safety Summary, as of Feb- the local reactions are excluded, 4 par- Funding/Support: Funding for the primary vaccine ruary 12, 2003. Availiable at: http://www.smallpox study was provided by the National Institute of Al- .army.mil/media/pages/SPSafetySum.asp. Accessed ticipants (2.7%) of the vaccinia-naive lergy and Infectious Diseases (NIAID), Division of Mi- May 27, 2003. cohort developed generalized follicu- crobiology and Infectious Diseases (DMID) (grant 17. Centers for Disease Control and Prevention. Small- 02-054). Salary support for Dr Talbot was provided pox vaccine adverse events among civilians—United litis following vaccination. by a grant from the Emerging Infectious Diseases Co- States, February 18-24, 2003. MMWR Morb Mortal This high rate of presumed folliculi- operative Agreement. Wkly Rep. 2003;52:156-157. Acknowledgment: We thank all of the members of the 18. Frey SE, Couch RB, Tacket CO, et al. Clinical re- tis after smallpox vaccine administra- Vanderbilt Pediatric Clinical Research Office, the Vander- sponses to undiluted and diluted smallpox vaccine. tion has clinical importance, especially bilt General Clinical Research Center, members of the N Engl J Med. 2002;346:1265-1274.

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