Smallpox (variola) infection is the most likely diagnosis in this patient. Smallpox was once a significant worldwide cause of morbidity and mortality but was declared eradicated by the World Health Organization in 1980. Routine active vaccination against this viral illness ended more than 35 years ago. However, owing to its highly contagious nature, ability to cause illness and death, and a population largely nonimmune to infection, smallpox has gained a position on the category A list of potential bioterrorism agents. Because natural infection no longer occurs and most physicians are unfamiliar with the clinical presentation of smallpox, a high level of suspicion must be maintained for the possibility of infection in persons at potential risk, such as this patient with recent travel to an area where bioterrorism agents might be used. An incubation period of 10 to 14 days precedes clinical infection; patients are not contagious during that time. Most infected persons present with a prodromal phase characterized by fever, back pain, headache, vomiting, and pharyngitis. The rash begins as small red dots on the pharyngeal and buccal mucosa, at which time patients become contagious. The lesions then spread in centripetal fashion to the hands and face, followed by the arms, legs, and feet. Classically, the rash of smallpox progresses in synchronous fashion, from macules to papules to vesicles and pustules before crusting over. Patients remain contagious until all crusts are shed.

Measles, or rubeola, is characterized by fever, malaise, and prominent upper respiratory infection manifestations consisting of the classic triad of conjunctivitis, cough, and coryza. Generally, the exanthem begins 2 to 4 days later, often with small, whitish spots on the buccal mucosa (Koplik spots), followed by a morbilliform rash on the face and neck, which eventually spreads to the extremities. Unlike the rash of smallpox, these lesions typically blanch and do not become vesicular. Additionally, universal measles vaccination has resulted in almost complete elimination of this childhood disease; therefore, if this patient had been immunized, it would make measles infection much less likely.

Rickettsial pox, caused by Rickettsia akari, occurs following the bite of a mite found on a reservoir mouse. A papular lesion initially forms at the site of inoculation, later becoming vesicular before eventually forming an eschar and then healing. Occasionally, the rash may become more generalized but can be differentiated from that seen with smallpox by its asynchronous mode of development. Fever and muscle aches accompany the skin lesion.

Chickenpox (varicella) is the viral infection most resembling smallpox, but clearly differs by fact that the rash is mostly localized to the trunk and spreads centrifugally to the periphery of the body. Additionally, varicella lesions can be found in various stages on the same body area at any one time and rarely involve the palms and soles.