Are You Confident of the Diagnosis?
Characteristic findings on physical examination
During the early stage of the infection, there appears to be an acute, nonspecific worsening in the patient’s baseline eczema (erythema, increased pruritus and weeping: Figure 1). Obtaining additional historical information (contact with a known smallpox vaccinee or any military member) is key to making an early clinical diagnosis. Eczema herpeticum, a much more common infectious complication, can look identical during the first few days. Development of deep-set vesicles which are all at the same stage of development is a key distinction. These lesions progress in a similar fashion to the smallpox vaccine site (papule, vesicle, pustule, eschar) except that the lesions are extensive, preferentially occur on eczematous skin but can occur in any distribution (Figure 2, Figure 3).
Expected results of laboratory studies
Obtaining diagnostics rapidly is critical to receipt of an institution of life-saving therapy. Swabs may be submitted to any state or local public health laboratory participating in the Laboratory Response Network (LRN); polymerase chain reaction (PCR) to confirm an orthopoxvirus infection can be performed at LRN participating centers the same day in most cases. Specimens (swabs, lesion biopsy tissue, and/or sera) can also be sent to the Centers for Disease Control (CDC) Poxvirus and Rabies Branch for vaccinia species confirmation, culture and serologic response (which are important in heralding patient recovery).
Although unlikely to be necessary to confirm the diagnosis, a skin biopsy with standard histopathology preparation/staining will reveal: immunohistochemical staining (CDC, Infectious Disease Pathology Branch) can be used to confirm the diagnosis if necessary. Serology may be useful in management as the use of immunoglobulin is a mainstay of treatment and the decision of whether to give additional doses may be guided by IgG levels.
Who is at Risk for Developing this Disease?
Eczema vaccinatum (EV) is a life-threatening and rare condition that occurs in those with eczema and other related chronic skin diseases (eg, Dariers) who receive the smallpox vaccination or who have close contact with smallpox vaccinees. Having eczema (regardless of current activity) or a household member with eczema is a contraindication to receiving the smallpox vaccination.
What is the Cause of the Disease?
The vaccinia virus cannot penetrate intact skin but can infect through any small breach in the integumen. T cell dysfunction in the skin of patients with eczema leads to a poorly controlled infection and spread of the virus. Pruritus/excoriation and application of topical corticosteroids can contribute to the spread of infection. Viremia and/or bacterial superinfection leading to bacteremia can lead to septic shock and even death. Patients who are primary vaccinees (never received the smallpox vaccination before) are more likely to develop EV than secondary vaccinees.
Systemic Implications and Complications
In patients with extensive skin involvement significant insensible loss of fluid and superinfection may occur, just as in a burn patient. The use of silver sulfadiazine, petroleum gauze, and cadaveric grafts may be needed when large surface areas are involved.
Deaths occur most often among children. The mortality rate is estimated at 7% with the use of vaccinia immune globulin (VIG).
As these patients are shedding millions of virions, infections controls practices (contact precautions) are essential to preventing secondary cases at home and in the health care setting.
Treatment options are summarized in Table I.
|FDA approved: VIG-IV cidofovir (5 mg/kg intravenous)||Cadaveric grafts for temporary coverage||n/a|
|ST-246® (oral; compassionate use)|
|CMX-001® (oral;compassionate use)|
|Antibiotics if clinically indicated – see next section|
Optimal Therapeutic Approach for this Disease
Vaccinia Immune Globulin intravenous (VIG-IV) and cidofovir are the only two FDA-approved treatments for eczema vaccinatum. VIG-IV may be given at 6,000 IU/kg, however, some evidence supports the use of higher doses in critically ill patients (24,000 IU/kg). ST-246® (5 mg/kg) has been used in conjunction with VIG-IV in a toddler with severe EV. CMX-001® should also be efficacious although as of the present time it has not been used specifically for EV.
Bacterial superinfection may occur and culture of skin lesions and blood will be helpful to guide therapy; empiric therapy should cover skin flora including methicillin-resistant Staphylococcus aureus. Choices include vancomycin (12 to 15 mg/kg and adjusted for patient’s creatinine clearance) or daptomycin (4mg/kg iv q24)
EV lesions will progress in the same fashion as innumerable smallpox vaccination lesions – they will all eventually form ecshars and heal. Since eczematous skin is innately poor at clearing viral infections it may take longer than the usual 21 days, but once the lesions have formed scabs and begun to slough specific antiviral treatment can cease. They will potentially remain infectious until all eschars have been shed.
In addition, personal affects/clothing, etc may harbor viable vaccinia virus for weeks after patients have been in contact with them, so careful attention to sanitizing these items should occur. Bleach, lysol and hot washing/steam cleaning should inactivate vaccinia virus and at least one method should be employed for objects/surfaces they have been in contact with while infected. While in the hospital patients should remain under strict contact precautions and their health care workers and visitors (1) should not be pregnant, immunocompromised, or have eczema, Darier’s disease etc, and (2) ideally have received the smallpox vaccination at some point in their life (health care workers) .
Unusual Clinical Scenarios to Consider in Patient Management
The limited use of ST-246® (see Optimal Therapeutic Approach above) in critically ill patients seems to indicate that using higher doses than those studied in healthy individuals is necessary to achieve efficacious plasma concentrations.
What is the Evidence?
Cono, J, Casey, CG, Bell, DM. “Centers for Disease Control and Prevention. Smallpox vaccination and adverse events: guidance for clinicians”. MMWR. vol. 52. 2003. pp. 1-28. (This compendium of adverse events related to the smallpox vaccination is an essential reference for all clinicians who evaluate these vaccine recipients.)
Vora, S, Damon, I, Fulginiti, V. “Severe eczema vaccinatum in a household contact of a smallpox vaccinee”. Clin Infect Dis. vol. 46. 2008. pp. 1555-61. (This case report describes the management of a 2 year old hospitalized with critical illness due to eczema vaccinatum (first case since post-9/11 smallpox vaccination campaign resumed among the military). VIG-IV, cidofovir (single dose) and ST-246 ® were used to manage his care.)
Lederman, E, Miramontes, R, Openshaw. “Eczema vaccinatum resulting from the transmission of vaccinia virus from a smallpox vaccinee: an investigation of potential fomites in the home environment”. Vaccine. vol. 27. 2009. pp. 375-7. (This investigation provides evidence that patients with eczema vaccinatum contaminate fomites in their surroundings with viable vaccinia virus which can survive for at least 2 weeks on household surfaces (clothing, laminates) and provides support for strict contact precaution during hospitalization of these patients.)
Boyd, DA, Sperling, LC, Norton, SA. “Eczema Herpeticum and clinical criteria for investigating smallpox”. Emerg Infect Dis. vol. 15. 2009. pp. 1102-04. Eczema herpeticum is one of the most important clinical entities to distinguish from EV. In this case report authors explain their algorithm to distinguish this patient's exanthem (EH) from a disseminated orthopoxvirus like smallpox or EV).
Grigoryev, DN, Howell, MD, Watkins, TN. “Vaccinia virus-specific molecular signature in atopic dermatitis skin”. J Allergy Clin Immunol. vol. 125. 2010. pp. 153-9. (This paper compares the immune response against vaccinia virus in skin from healthy patients, those with atopic dermatitis and those with psoriasis. AD patients had the weakest responses against vaccinia virus, even in skin that was seemingly unaffected by AD.)
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