Smallpox—or a Mimic?

Smallpox, which is caused by infection with poxvirus variola, may follow various courses. An erythematous eruption can precede the appearance of tense, deep-seated papules that rapidly transform into vesicles. The lesions may be sparse or so numerous that they become confluent. Typically, the incubation period of variola major is 12 to 14 days, with a range of 7 to 17 days. Approximately 30% of infected patients die of the disease.¹Routine immunization against smallpox was halted in the United States in 1972 and is not now recommended. Immunity for persons who have received the vaccine is thought to be 3 to 5 years; the duration of residual partial immunity is not known. Vaccine given to a patient within 4 days of exposure can prevent smallpox or significantly lessen the severity of the disease. Persons who have had smallpox cannot contract the disease again.¹PRESENTATIONProdromal symptoms include the acute onset of malaise, fever, rigors, vomiting, headache, and backache. Delirium develops in about 15% of patients; 10% of light-skinned patients have an erythematous rash. Two or 3 days after the prodrome, just as the fever peaks, a discrete, maculopapular rash appears on the face, hands, forearms, and mucous membranes of the mouth and pharynx. Commonly, the palms and soles also are involved. Initially, the lesions are peripheral (A); they move centrally within a few days. During week 2, the rash spreads to the legs and the trunk. The lesions quickly progress from macules and papules to vesicles, then to umbilicated, pustular vesicles, which become crusty scabs between 8 and 14 days after onset. These crusts leave depressions and depigmented scars that are more prominent on the face (B). The resultant facial lesions have been attributed to the destruction of sebaceous glands with subsequent granulation tissue shrinkage and fibrosis.²Flat, or malignant, smallpox.This variant occurs in 2% to 5% of patients and is attributable to the lack of an adequate cell-mediated immune response. The infection is characterized by severe systemic toxicity and the slow evolution of flat, soft, focal skin lesions that coalesce but do not become pustular. The skin takes on a fine-grained reddish color that resembles crepe rubber. Mortality among unvaccinated persons is 95%.Hemorrhagic smallpox. Fewer than 3% of patients have this variant. Extensive petechiae; mucosal hemorrhage; and intense toxemia, including high fever, headache, backache, and abdominal pain, are present. Hemorrhagic smallpox occurs more commonly in pregnant women. Generally, patients die before the typical pox lesions can develop.DIAGNOSISThe CDC Interim Smallpox Response Plan and Guidelines gives specific instructions for reporting suspected cases of the disease and for collecting, processing, and shipping specimens to an appropriate laboratory for evaluation.³ State and local public health authorities need to be contacted as well. The following is a concise overview of the detailed guidelines. Obtain vesicular fluid by opening lesions with the blunt edge of a sterile scalpel. Harvest a droplet of fluid and place on a clean slide for microscopic examination; allow the sample to air dry in a safe location. Scabs may be removed with forceps and placed in a sterile tube. Label all materials carefully. Safely secure all specimens for shipping. The CDC laboratory prefers at least 3 separate slides or a sterile tube with 3 or 4 scabs for each patient tested. The CDC’s Biosafety Level 4 reference laboratory tests specimens with viral cultures that require isolation of the virus and characterization of its growth on chorioallantoic membrane or cell culture.Differential diagnosis. The diagnosis of smallpox requires astute clinical evaluation. Most commonly, the clinical diagnosis can be confused with chickenpox; Cases 1 through 4 illustrate manifestations of chickenpox and its sequelae in adults and children. Also consider erythema multiforme with bullae (Case 5) and allergic contact dermatitis in the differential.Chickenpox, which is caused by the varicella-zoster virus, presents with a mild viral prodrome and crops of papulovesicular lesions. Several clinical clues can help distinguish smallpox from chickenpox (Table).Meningococcemia (Case 6) andacute leukemia (Case 7) need to be included in the differential for hemorrhagic smallpox.TREATMENTSupportive care—intravenous fluids and fever and pain control medication— is the mainstay of therapy. Antibiotics are used to treat secondary bacterial infections. Currently, no antiviral agents have proved effective for the treatment of smallpox. Adefovir dipivoxil(, cidofovir(, and ribavirin( have shown significant in vitro antiviral activity against poxviruses; however, their efficacy as therapy for this disease is uncertain. Cidofovir shows the most promise in animal models.⁴