Smallpox, Monkeypox, and Other Poxvirus Infections

Smallpox

The epidemiology of smallpox, caused by Orthopoxvirus variola , is understood through detailed studies conducted during the end of the eradication campaign. Interhuman transmission of variola virus generally occurred through the inhalation of large airborne respiratory droplets of infectious virus. Transmission usually required prolonged face-to-face or other close contact, although airborne transmission over longer distances had been reported. Transmission by fomites or contact with infectious material from the rash also occurred. Aggregate data, collected during the smallpox eradication campaign, suggest a secondary attack rate of about 60% in unvaccinated close or household contacts and a secondary attack rate of about 4% in previously vaccinated close or household contacts. Severity of disease correlated with burden of rash and was also more severe in children and pregnant women. Variola alastrim minor, a variant of variola, had similar human-to-human disease transmission characteristics.

The majority of smallpox infections were initiated by inhalation of respiratory droplets and implantation of virus on the oropharyngeal and respiratory mucosa. No primary localized site of infection was evident if the route of exposure was by inhalation. Disease could also be introduced through suspensions of virus obtained from scabs of infected patients. Transmission by fomites, such as soiled clothing or bed linens, was infrequently reported.

After entry, the virus moves to local lymph nodes and then disseminates to the reticuloendothelial system to replicate further. At this time, the individual is asymptomatic. In 10 to 14 days, secondary viremia occurs and heralds the prodrome of symptomatic illness. During this time, the virus seeds the oropharynx and epidermis. The absence of a keratinized structure in the mucosa of the oropharynx leads to ulceration and release of virus in saliva; the virus replicates in the epidermis to cause the characteristic macular, papular, vesicular, and pustular eruptions of smallpox.

In humans, the viral lesions characteristic of illness primarily develop in the epidermis, where the cells of the Malpighian layer swell and vacuolate to undergo ballooning degeneration. The cytoplasm continues to enlarge, nuclear material is lost, and the coalescence of vacuoles through cell rupture creates reticulating degeneration of the middle and upper layers of the stratum spinosum. In the next stages, the vesicle is formed. High titers of virus are found within the lesions. In mucosal surfaces, the absence of a horny layer allows the necrosis caused by proliferation of virus within the epithelium to create ulcers and leads to liberation of large quantities of virus into the oropharynx. Mild pathologic changes are seen in the lungs.

Vaccinia

Vaccinia is the live virus contained in preparations of the smallpox vaccines used to eradicate smallpox. In the United States, the vaccine is recommended for laboratory personnel who use replication-competent orthopoxviruses and for selected military personnel. Contacts of vaccinees occasionally develop vaccinia infections. Vaccinia viruses may have descended from horsepox virus. Vaccinia variants include buffalopox from contact with infected animals in India and vaccinia viruses in dairy cattle workers in Brazil and Colombia.

Monkeypox

Monkeypox has a more complex epidemiology. The virus is zoonotic, and two genetically discrete virus clades have been described, each with apparent distinct clinical and epidemiologic parameters. In central and western Africa, the seroprevalence of anti-orthopoxvirus antibodies in unvaccinated individuals is about 20 to 25%.

In the original outbreak in the Democratic Republic of Congo, the secondary attack rate in unvaccinated contacts of monkeypox cases was calculated to be about 9%. Previous smallpox vaccination (administered 3 to 19 years prior) appeared to be 85% protective against acquisition of the disease among contacts and also ameliorated the severity of disease. Overall, most identified cases acquire disease from presumed animal exposure, and about 30% of cases were ascribed to person-to-person transmission. In more recent outbreaks, however, data suggest that 50 to 90% of infections may be transmitted from human to human, with these higher rates thought to be related to the cessation of smallpox vaccination programs after that disease was eliminated.

Among primary cases, recent close zoonotic contact—through hunting, skinning, killing, cooking, or playing with carcasses—was identified with Cercopithecus, Colobus , and Cercocebus (primate); Cricetomys (terrestrial rodent); and Funisciurus and Heliosciurus (squirrels). The prevailing hypothesis is that one or more squirrel or rodent species is the probable reservoir of disease.

Monkeypox virus was introduced to the United States in 2003 through a consignment of animals from the West African country of Ghana. The U.S. cases had a less pronounced rash and a less severe illness, with no mortality or human-to-human transmission. These clinical data plus genomic data suggest at least two populations or clades of monkeypox virus. The apparent decreased pathogenicity and transmissibility of West African clade monkeypox virus infection led, in part, to its declassification as a U.S. select agent in 2013. An increasing number of human monkeypox cases were identified in West Africa in 2017, and human monkeypox cases subsequently were identified in the United States, United Kingdom, Israel, and Singapore among returning travelers from Nigeria. More recently, monkeypox spread widely in the United States and throughout the world, initially in men who have sex with men but subsequently in heterosexual contacts, nonsexual contacts, and children. This human to human transmission was facilitated by mutations mostly in APOBEC3 deaminase editing. In the United States, cases peaked in August 2022 and eventually exceeded 30,000 cases, with about 40 deaths. Worldwide, about 90,000 cases have been reported.

Cowpox

Cowpox virus is a zoonosis that is found in Europe and Asia and is maintained in rodents; in Britain, the reservoirs are bank voles and wood mice. The domestic cat is a common source of human infection. Most cases occur between July and October, with only occasional cases between January and June. In Europe, outbreaks in pet rats or feeder rats have been a source of transmission to humans. Cowpox virus also is prevalent in European zoos, where cheetahs, lions, anteaters, rhinoceros, elephants, and okapi have occasionally transmitted infection to animal handlers. No case of bovine cowpox has been detected since 1976, but two cases of a novel orthopoxvirus infection, the Akhmeta virus, were reported in 2013 in the country of Georgia in men who were exposed to ill cows. Alaskapox virus, which is a novel orthopoxvirus infection with a clinical presentation similar to cowpox, has been identified in four patients in Alaska, with wild small mammals living in peri-domestic areas as the likely source.