Papular Spongiotic Dermatitis of Smallpox Vaccination: Report of 2 Cases With Review of the Literature

With the recent reintroduction of smallpox vaccinations as a public health and military readiness measure, a variety of cutaneous complications have resurfaced. Given the long time lapse since previous mass smallpox vaccinations, many of these complications are unfamiliar to modern health care professionals. Most historical literature concerning this topic discusses the most serious known complications, including eczema vaccinatum, vaccinia necrosum, and generalized vaccinia.1–3 However, a variety of less grave, but likely more common, skin changes have been described. These changes range from local reactions, such as keloid formation and contact dermatitis, to more generalized exanthemas, such as erythema multiforme, pityriasis rosea, and granuloma annulare.4–6 The association of these relatively common conditions with vaccinia inoculation is not widely known; thus, the reported cases likely reflect only a portion of those affected. As noted in a recent issue of Morbidity and Mortality Weekly Report discussing smallpox vaccination, “nonserious events are reported via passive surveillance and are expected to be underreported.” 7 We discuss 2 cases of generalized nonspecific dermatitis following smallpox vaccination.

A 33-year-old man presented with a generalized pruritic skin exanthema that had been present for 1 day. The patient had received a smallpox vaccination approximately 11 days prior to presentation. The rash consisted of diffusely scattered, erythematous papules. The lesions ranged from 6 to 8 mm in diameter. There was a crusted vaccination site on the left upper arm, which had surrounding erythema and edema. A punch biopsy of a representative lesion from the neck was performed. The patient was treated with topical clobetasol cream and antipruritic agents, and the eruption resolved without sequelae within approximately 7 days after onset.

A 29-year-old woman presented with a 2-week history of diffuse erythematous macules and papules. She had received a smallpox vaccination 7 days prior to onset. The individual lesions were brightly erythematous, nonblanchable, and 3 to 6 mm in diameter (Figure 1). A punch biopsy of a representative thigh lesion was performed. The patient was treated with clobetasol and antipruritic agents, but was lost to follow-up.

The 4-mm punch biopsies of skin were processed in a standard fashion. Two hematoxylin-eosin–stained slides were available for each case. Grocott methenamine silver stain was performed on case 2, per the published protocol.8 Both cases demonstrated a variably prominent spongiotic dermatitis. The biopsy from case 2 showed mild, patchy epidermal spongiosis with an associated mild, superficial dermal perivascular chronic inflammatory infiltrate. Scattered areas of lymphocytic exocytosis and extravasated red blood cells within the superficial dermis and epidermis were also present (Figures 2 and 3). The described features are those of a pityriasis rosea–like histologic reaction pattern. The biopsy from case 1 showed a subacute spongiotic dermatitis with scale crust and evidence of epidermal erosion. The latter change was likely secondary to physical trauma (scratching) from clinical pruritus. A brisk superficial dermal perivascular and interstitial chronic inflammatory infiltrate with eosinophils was present (Figure 4). Areas of viral cytopathic effect were not identified in either case. Grocott methenamine silver stain was negative for fungal organisms in case 2.

A variety of nonspecific cutaneous complications have been reported after smallpox vaccination. These accounts are generally decades old and represent compilations of reported occurrences after mass vaccination. A study performed in 1948, analyzing results from more than 6 million vaccinations given in New York City, identified several of these nonspecific cutaneous sequelae. These included postvaccination erythema multiforme (10 cases), pityriasis rosea (7 cases), toxic erythema (2 cases), granuloma annulare (2 cases), generalized erythema (1 case), and erythema nodosum (1 case).4–6 A 1942 study identified “123 regional or generalized postvaccinial eruptions” after approximately 500 000 vaccinations in Glasgow, United Kingdom.9 These lesions included papular, urticarial, purpuric, pustular, and eczematoid changes, such as papular urticaria (37 cases). No cases were felt to represent generalized or localized vaccinia, or smallpox. When combined, these studies reviewed more than 20 million vaccinated individuals. The most common nonspecific reactions identified were erythema multiforme and urticaria, with approximately 88 and 43 reported cases, respectively. Per 1 multistate survey, 13% of all complications from primary vaccinia inoculation were secondary to erythema multiforme.10 Only a small number of the other described cutaneous conditions were noted. Other rarely reported dermatoses include lichen simplex and impetigo.

As opposed to the more consequential skin lesions directly caused by vaccinia virus, these nonspecific cutaneous reactions were felt to be secondary to generalized vascular changes associated with vaccination, or “secondary products of inflammation absorbed from the vaccine pustule.” 2,9 Previous studies have repeatedly failed to culture active virus from these lesions. Additionally, nonspecific dermatitides have been reported in association with other vaccinations, including hepatitis B.11 Although the possibility exists that the described lesions occurred independently of the vaccination, the cited authors feel there is an etiologic link between these entities. Cited evidence includes frequent origin of these exanthemas in the region of the vaccination site with subsequent dissemination, the same types of dermatoses occurring in conjunction with vaccination in several studies, and the occurrence of some of these lesions in conjunction with generalized vaccinia.5,6 

Clinically, the reported skin changes predominantly occur 7 to 11 days after the immunization and have a self-limited course. However, individual examples have occurred within 2 days after vaccination, and late examples have occurred up to 7 weeks later. Similar reactions have occurred in patients receiving primary vaccination, as in those receiving repeat inoculation, although the timeframe and frequency may be slightly different. Interestingly, a variety of benign and malignant localized skin lesions have occurred within smallpox vaccination scars years after vaccination, including malignant fibrous histiocytoma,12 malignant melanoma,11,13 and discoid lupus erythematosus.14 

The major importance of recognizing these interesting nonspecific vaccinial complications is in the differentiation from localized or generalized vaccinia, or less likely, variola infection. As 1 author noted, distinguishing life-threatening from incidental skin changes can be difficult.9 Clinical features, such as pruritus, coupled with the distribution and appearance of the exanthema, can generally distinguish these conditions. For the practicing pathologist, awareness of the association of these nonserious changes with smallpox vaccination can aid in appropriate case analysis and potentially spare clinicians and patients unnecessary worry and therapeutic intervention.