a. Clinical Syndrome.

(1) Characteristics. Smallpox virus, an orthopoxvirus with a narrow host range confined to humans, was an important cause of morbidity and mortality in the developing world until recent times. Eradication of the natural disease was completed in 1977 and the last human cases (laboratory infections) occurred in 1978. The virus exists today in only 2 laboratory repositories in the U.S. and Russia. Appearance of human cases outside the laboratory would signal use of the virus as a biological weapon. Under natural conditions, the virus is transmitted by direct (face-to face) contact with an infected case, by fomites, and occasionally by aerosols. Smallpox virus is highly stable and retains infectivity for long periods outside of the host. A related virus, monkeypox, clinically resembles smallpox and causes sporadic human disease in West and Central Africa.

(2) Clinical Features. The incubation period is typically 12 days (range, 10-17 days). The illness begins with a prodrome lasting 2-3 days, with generalized malaise, fever, rigors, headache, and backache. This is followed by defervescence and the appearance of a typical skin eruption characterized by progression over 7-10 days of lesions through successive stages, from macules to papules to vesicles to pustules. The latter finally form crusts and, upon healing, leave depressed depigmented scars. The distribution of lesions is centrifugal (more numerous on face and extremities than on the trunk). Lesions are in the same stage of development at any point in time. Fever may reappear around the 7th day after onset of rash. The case fatality rate is approximately 35% in unvaccinated individuals. A subset of patients develop a hemorrhagic diathesis with disseminated intravascular coagulopathy and have a poor prognosis. Other complications include arthritis, pneumonia, bacterial superinfection of skin lesions, osteomyelitis, and keratitis. Permanent joint deformities and blindness may follow recovery. Vaccine immunity may prevent or modify illness. Fully immune individuals exposed to the virus by the respiratory route may develop fever, sore throat, and conjunctivitis (“contact fever”) lasting several days.

b. Diagnosis.

(1) Routine Laboratory Findings. Leukopenia is frequently present in severe cases of smallpox. The differential count shows granulocytopenia and a relative increase in lymphocytes. In the early hemorrhagic form, with onset of bleeding before the eruption, severe thrombocytopenia, global reduction in clotting factors, and circulating antithrombin are present, as well as a marked increase in immature lymphoid cells in the peripheral blood, sometimes mistaken for acute leukemia.

(2) Differential Diagnosis. The eruption of chickenpox (varicella) is typically centripetal in distribution (worse on trunk than face and extremities) and characterized by crops of lesions in different stages on development. Chickenpox papules are soft and superticial, compared to the firm, shotty, and deep papules of smallpox. Chickenpox crusts fall off rapidly and usually leave no scar. Monkeypox cannot be easily distinguished from smallpox clinically, although generalized lymphadenopathy is a more common feature of the disease. Monkeypox occurs only in forested areas of West and Central Africa as a sporadic, zoonotic infection transmitted to humans from wild squirrels. Person-to-person spread is rare and ceases after 1-2 generations. Mortality is 15%. Other diseases that are sometimes confused with smallpox include typhus, secondary syphilis, and malignant measles.

(3) Specific Laboratory Diagnosis. Skin samples (scrapings from papules, vesicular fluid, pus, or scabs) may provide a rapid identification of smallpox by direct electron microscopy, agar gel immunoprecipitation, or immunofluorescence. Virus may be recovered from these samples or blood by inoculation of eggs or cell cultures, but culture techniques require several days. Serological tests may be useful for confirmation, or early presumptive diagnosis.

c. Therapy. There is no specific treatment available although some evidence suggests that vaccinia-immune globulin may be of some value in treatment if given early in the course of the illness. The antiviral drug, n-methylisatin ß-thiosemicarbazone (Marboran ®) is not thought to be of any therapeutic value.

d. Prophylaxis.

(1) Vaccines.

(a) Vaccinia virus is a live poxvirus vaccine that induces strong crossprotection against smallpox for at least 5 years and partial protection for 10 years or more. The vaccine is administered by dermal scarification or intradermal jet injection; appearance of a vesicle or pustule within several days is indication of a “take.” Contraindications to vaccination are pregnancy, clinical immunosuppression, eczema, or leukemia/lymphoma. Complications are infrequent, but include: 1) progressive vaccinia in immunosuppressed individuals (case-fatality >75%); 2) eczema vaccinatum in persons with eczema or a history of eczema, or in contacts with eczema (case-fatality 10-15%); 3) postvaccinal encephalitis, almost exclusively seen after primary vaccination, occurring at an incidence of about 1/500,000, with a case-fatality rate of 25%; 4) generalized vaccinia, seen in immunocompetent individuals and having a good prognosis; and 5) autoinnoculation of the eye or genital area, with a secondary lesion.(b) Vaccinia-immune human globulin at a dose of 0.3 mg/kg body weight provides >70% protection against naturally occurring smallpox if given during the early incubation period. Administration immediately after or within the first 24 hours of exposure would provide the highest level of protection, especially in unvaccinated persons.

(c) If vaccinia-immune globulin is unavailable, vaccination or revaccination should be performed as early as possible after (and within 24 hours of) exposure, with careful surveillance for signs of illness.

(2) Antiviral Drug. The antiviral drug, n-methylisatin ß-thiosemicarbazone (Marboran®) afforded protection in some early trials, but not others, possibly because of noncompliance due to unpleasant gastrointestinal side effects. Critical review of the published literature suggests a possible protective effect among unvaccinated contacts of naturally infected individuals.

(3) Quarantine, Disinfection. Patients with smallpox should be treated by vaccinated personnel using universal precautions. Objects in contact with the patient, including bed linens, clothing, ambulance, etc.; require disinfection by fire, steam, or sodium hypochlorite solution.

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