EV presents with lesions distant from the inoculation site and may comprise umbilicated pustules, papules, vesicles, or erosions with a predilection for sites of previous AD lesions.24 Following vaccination, characteristic lesions may appear concurrently with, or shortly after, lesions of the vaccination site (Figure 8).
A typical major reaction in a primary vaccine is marked by the formation of a papule, vesicle, ulcer, or crusted lesion surrounded by an area of induration on day 6 to 8 postvaccination. Most commonly, the vaccination site progresses through papular, vesicular, pustular, and crusted stages, followed by separation of the crust and resultant scarring. The lesions of EV follow a similar clinical course. In cases of secondary transmission of vaccinia from a vaccinated individual to another person, the eruption of lesions typically occurs 5 to 19 days after exposure.25 Confluent lesions are common in areas previously affected by AD and may cover the entire face or the antecubital and popliteal fossae. Patients often are systemically ill with fever, generalized lymphadenopathy, and malaise.24
EV should be suspected in any patient with a history of AD who exhibits the typical clinical presentation and either has been vaccinated against smallpox or has had contact with an individual who has been vaccinated 5 to 20 days prior to presentation. The diagnosis primarily is clinical and is based on the characteristic clinical presentation in combination with a history of exposure to vaccinia. Histopathologic findings are characteristic and include reticular degeneration of the epidermis with intranuclear and intracytoplasmic inclusion bodies (Figure 9). Although a presumptive diagnosis is sufficient to warrant treatment, the CDC can perform confirmatory tests. The presence of an Orthopoxvirus can be confirmed by electron microscopy of vesicular or pustular fluid, polymerase chain reaction, and restriction fragment length polymorphism testing.26 The CDC recommends that immunologic studies for T-cell function and IgE levels be performed in cases of EV in an effort to identify particular laboratory markers characteristic of those patients at increased risk of development of EV so that the morbidity and mortality attributable to this complication may be lessened.23
Treatment for established cases of EV consists of vaccinia immune globulin, hemodynamic support, wound care, and careful monitoring for the presence of superimposed infections. Vaccinia immune globulin is produced from the plasma of vaccinated individuals and contains a high titer of vaccinia-neutralizing antibody. Historically, the initial dose of vaccinia immune globulin used for patients with EV was 0.6 to 1.0 mL/kg administered by intramuscular injection.26 For patients with severe extensive lesions, 5 to 10 mL/kg was administered intramuscularly in divided doses. The necessity for use of an intramuscular preparation stemmed from the high level of aggregated protein it contained. An intravenous preparation with a lower level of aggregated protein is now available through the CDC, with dosing guided by the investigational new drug protocol under which it is being used. Guidelines for hemodynamic support are similar to those used for patients with sepsis. Electrolytes should be monitored closely with prompt correction of any abnormalities. Meticulous skin care is imperative in patients diagnosed with EV and is similar to that used for burn patients. Patients with EV also are at risk for the development of secondary skin infections and may require appropriate antibacterial and antifungal treatment as guided by results of skin and blood cultures.24
The prevention of EV is dependent on a thorough medical history and appropriate screening. In a pre-exposure setting, smallpox vaccination is contraindicated in any person with a current or past history of eczema or AD, regardless of disease severity. Individuals with close contact to anyone with a history of these conditions also should not receive the vaccine. The CDC recommends that smallpox vaccination also be deferred for those with active acute, chronic, or exfoliative skin conditions that disrupt the epidermis. The guidelines specifically mention Darier disease in a potential vaccine candidate or in a household contact with active disease.27 In the event of a smallpox outbreak, the CDC will distribute specific modifications regarding populations to be vaccinated.26
EV is one of the most severe adverse events that may occur following smallpox vaccination. As the current smallpox vaccination program accelerates, it is important for healthcare workers to screen potential vaccine candidates for a current or past history of skin disease. With uncertainties regarding the most effective indicators for detection of patients at highest risk, many questions surround vaccination protocols in a pre-exposure setting. The development of immunologic studies capable of accurately identifying those at increased risk for EV following smallpox vaccination could have a significant impact on the incidence of this devastating complication.23 A better understanding of subtle underlying immunologic differences that increase susceptibility in particular individuals could lead to new, more specific recommendations concerning individuals who should not receive the vaccine.