Poxviridae

Epidemiology

Variola, the virus causing smallpox, is among the most feared viruses and has had a tremendous impact on human civilizations throughout history ( Box 202.1 ). Currently, smallpox is primarily a concern because of its use as a potential biological weapon. Though the virus is only stored in two official laboratories (Centers for Disease Control and Prevention [CDC] in Atlanta, US, and VECTOR in Novosibirsk, Russia), it is possible that additional smallpox virus is present in unsanctioned stockpiles or that it could be created de novo using modern synthetic biology technologies.

Smallpox was a solely human disease. The lack of an animal reservoir and the availability of an effective intervention to prevent transmission of the virus (i.e., smallpox vaccine) were critical factors allowing eradication. Smallpox was spread by respiratory droplets, with transmission typically resulting from close or prolonged contact. In pre-eradication studies, 37%–88% of unvaccinated household members developed smallpox after contact with a known case, compared with 90% for measles and pertussis. ^,

Acquisition of variola virus infection usually occurred through the respiratory tract. Skin and eye inoculation, and transplacental spread also have been documented. The average incubation period was 10–14 days, with a range of 7–19 days. ^{, ,} During incubation, the virus replicated in the upper respiratory tract and reached the reticuloendothelial system through a transient primary viremia. Most virus transmission occurred during the first 7–10 days after lesion onset because the highest amount of viral shedding occurred during this period.

Vaccinia is the virus used for smallpox vaccination. Its origins are unclear; phylogenetic analysis suggests that it was not recently derived from variola or cowpox. Eradication of smallpox using the smallpox vaccine is among the greatest achievements in public health.

Vaccinia has a broader host range than most poxviruses, which has allowed it to be used as a model for smallpox infection in laboratory animals. Certain strains have become enzootic in sylvatic animal reservoirs, resulting in occasional zoonotic transmission in South Asia and South America. These infections usually are localized and self-limited.

Clinical Manifestations

Smallpox began abruptly with a prostrating febrile prodrome characterized by high fever, chills, headache, backache, vomiting, and severe abdominal pain. In ordinary-type smallpox infections, the first lesions appeared in the oropharynx 1–4 days after the onset of fever. Skin lesions developed first on the face or forearms and then spread to the rest of the body. The highest concentration of lesions was on the face and distal extremities. The palms and soles were commonly involved. Lesions developed slowly from macules to papules to vesicles to pustules, with each stage lasting approximately 2 days. Lesions on any one part of the body were characteristically in the same stage of development at any given time. Crusting of lesions was usually complete within 2–3 weeks after the onset of rash.

Variola major produced several distinct clinical syndromes and had an overall mortality rate of about 30%. ^, The mortality rate was higher for very young children. Approximately 90% of cases in the largest series were ordinary smallpox, characterized by round, firm, well-circumscribed pustules 7–10 mm in diameter. The mortality rate was approximately 10% for patients with discrete lesions and 60% for patients with confluent lesions. Less common clinical presentations were characterized by flat or hemorrhagic lesions and were associated with case-fatality rates >90%. Modified smallpox (i.e., 2% of unvaccinated and 25% of vaccinated cases) was similar to ordinary smallpox but had a milder and more accelerated course. Fever and other constitutional symptoms without rash (i.e., variola sine eruptione) occurred in rare instances. ^, Variola minor (alastrim) usually produced milder disease and was rarely fatal.

Laboratory Findings and Diagnosis

To aid those evaluating patients with rash illnesses that are suspected to be smallpox, the CDC and collaborating organizations created an algorithm based on the clinical features of ordinary smallpox. Three major criteria and five minor criteria are combined to assess the risk of smallpox (i.e., low, medium, or high risk) ( Box 202.2 ). Specific diagnostic measures are recommended based on the risk level ( Fig. 202.1 ).

Laboratory testing for variola is not recommended for low- or moderate-risk cases in the absence of known circulating smallpox. The positive predictive value of these tests is extremely low in this scenario, and the public health implications of false-positive results could be considerable. ^, If undertaken, laboratory diagnostic testing for variola virus is available through the Laboratory Response Network with confirmatory testing by the CDC. Polymerase chain reaction (PCR) testing of lesions material (e.g., swabs or crusts) is the preferred method for laboratory confirmation, although electron microscopy, serology, and other methods may be useful for diagnosis. CDC guidelines for laboratory testing of suspected smallpox cases are available at https://www.cdc.gov/smallpox/lab-personnel/index.html .

Illnesses that can be confused with smallpox are listed in Box 202.3 . Chickenpox is the illness most commonly confused with smallpox. Important features useful in distinguishing these two diseases are listed in Table 202.2 . Monkeypox also can be difficult to distinguish from smallpox in the absence of epidemiologic clues, although lymphadenopathy is more prominent with monkeypox.