Smallpox Vaccine Complications: The Dermatologist’s Role in Diagnosis and Management

Eczema Vaccinatum

A national survey estimated the prevalence of eczema in the United States at 31.6 million individuals,¹⁰ with 2- to 3-fold increases in incidence since the 1970s.¹¹ Due to the risk for developing EV, the Advisory Committee on Immunization Practices considers personal history of eczema or contact with a family member who has eczema (either currently or in the past) contraindications to nonemergency administration of the vaccine.^12,13 However, atopic conditions in general are underrecognized, with only approximately one-third of patients carrying an official diagnosis from a physician.¹⁰ Despite a large atopic and vaccinated population, EV remains relatively uncommon at 10 to 39 cases per million vaccines.⁶

The EV rash classically involves the midface, neck, and antecubital and popliteal fossae but can present in any location. The lesions start as papules that quickly progress to vesicles and pustules with crusting on an erythematous base. Given the extent of denudation of the epidermis, impetiginization can occur. Death rates as high as 30% have been reported¹⁴ but have only occurred in instances of secondary contact transmission with no deaths occurring in the primary vaccinees.¹⁵ In a case published in 2008, a 2-year-old boy developed the first documented EV case under the new program after exposure to his father’s predeployment vaccine.¹⁶ A similar rash is shown in Figure 1 with notable vesicles and pustules. The child required burn patient–type management, VIGIV, and treatment with cidofovir and an investigational antiorthopox agent. He was discharged from the hospital after 48 days without sequelae or considerable scarring.¹⁶ If a family member has a contraindication barring secondary contact with the vaccine, the US Department of Defense’s policy defers vaccination in active-duty members until they reach their deployment destination, at which point the inoculation is administered.

Image appears with permission from VisualDx.

Progressive Vaccinia

Progressive vaccinia is also known as vaccinia necrosum or vaccinia gangrenosum. It is a dreaded but uncommon complication, occurring once in every 1 million vaccinations. It carries an overall case fatality rate of 15%,¹⁷ but it nearly always is fatal in patients with severe T-cell defects.¹⁸ Progressive vaccinia occurs exclusively in patients with cell-mediated immunodeficiency, with the severity of the acute illness correlating with the severity of immunodeficiency. In patients with cell-mediated immunodeficiency but intact humoral immunity, progression can be limited to expansion of the lesion, as it is thought that antibody production restricts viremia.¹⁸ Progressive vaccinia should be suspected in a patient if the vaccine site shows no signs of improvement by 14 days.¹⁹ The PV lesions do not heal and may progress or recur in patients with signs of prior healing. The leading edge has confluent vesicles, and the center of the lesion develops necrosis with thick black eschar formation. Most specifically, there is no surrounding inflammation; however, inflammation can develop later as a response to treatment or secondary infection. Figure 2 shows a PV lesion with black eschar and a transition to intact dermis without inflammation.

Image appears with permission from VisualDx.

The first known case of PV since the 1960s vaccination campaign occurred in an active-duty Marine vaccinated with vaccinia before a diagnosis of acute myelogenous leukemia was recognized 2 weeks later.¹⁹ The vaccine site was stable in size and crusted when he received neutropenia-inducing chemotherapy 6.5 weeks after vaccination. The site then progressed in a manner typical for PV with central necrosis and a lack of inflammation at the expanding painless wound edge.¹⁹ This classic appearance with progression of satellite lesions prompted the treatment team to obtain wound and serum samples, which yielded the orthopox virus from polymerase chain reaction and viral culture. He required 2 months of care in an intensive care unit and received treatment with topical imiquimod, VIGIV, a topical and intravenous antiorthopox agent, and a second investigational antiorthopox agent; the patient ultimately survived.^17,20

Generalized Vaccinia

Generalized vaccinia (GV) typically is a benign vaccine complication resulting from viremic spread from the initial inoculation site and is most commonly seen in healthy patients. Generalized vaccinia is only life threatening in immunocompromised patients. The incidence of GV is 23.4 to 241.5 patients per million vaccines.⁶ The majority of GV cases occur 5 to 12 days after vaccination when small distant pustules or vesicles appear on any part of the body, including the palms and soles. The lesions usually are smaller than the primary vaccination site and resolve more quickly. Generalized vaccinia can have a few to several hundred pocks, though the rash is rarely as diffuse as EV presentations.³ Given that EV can present diffusely on skin unaffected by atopic dermatitis, GV can be difficult to distinguish from EV. Features more common to EV include more systemically ill patients, increased numbers of lesions, and lesions that become confluent in an atopic distribution. It has been suggested that GV can be differentiated from vesicular or vesiculopapular EM because GV does not develop flaccid bullae and EM typically has targetoid lesions.¹⁸ Mild GV disease requires no treatment, but VIGIV can be used in more extensive cases.