The information included in this chapter was current as of August 2022. See the most recent information regarding mpox and the 2022 mpox outbreak.

Author(s): Agam Rao, Andrea McCollum

Smallpox

Cowpox, Vaccinia & Similar Orthopoxviruses

Mpox

Infectious Agent

Smallpox is caused by variola virus, genus Orthopoxvirus. Other members of this genus that can infect humans include cowpox virus, vaccinia virus, and mpox virus.

Transmission

Smallpox & Vaccinia

In 1980, the World Health Organization (WHO) officially declared smallpox eradicated; however, the threat of reemergence by intentional introduction (e.g., bioterrorism) persists. Before smallpox was eradicated, it spread from person to person principally through respiratory droplets. Contact with infectious skin lesions or scabs was a less common mode of transmission but sometimes occurred (e.g., when caregivers cared for patients or washed contaminated clothing). Rarely, smallpox spread through air in enclosed settings (airborne transmission).

Vaccinia virus is the live virus component of contemporary smallpox vaccines. One of these vaccines, ACAM2000, is a replication competent vaccinia virus; occasionally, infection occurs from touching the fluid or crust material from the inoculation lesion of someone recently vaccinated against smallpox, or from touching contaminated materials like sheets and towels. Human infections with vaccinia virus have occurred in Brazil, Colombia, and India after contact with agricultural animals, often bovids, infected with sylvatic vaccinia-like viruses.

Cowpox

Contrary to the disease name, wild rodents are considered the reservoirs for cowpox virus. Mammals (e.g., cats, cows, humans) are incidental hosts. Cowpox virus infection occurs after direct contact with infected animals including incidental hosts. Person-to-person transmission has not been observed.

Mpox

Small mammals, not monkeys, are the suspected reservoir for mpox virus. Historically, people at increased risk for transmission have had contact with infected wildlife or wildlife products, infected humans, or the bodily fluids or respiratory droplets from infected wildlife or people. Person-to-person spread of mpox virus can occur through exposure to respiratory secretions and through direct skin-to-skin contact with a lesion or lesions (including scabs). Contact with infectious materials (e.g., shared towels, bedding) is another, albeit less common, means of interpersonal spread. In 2022, a global, multinational mpox outbreak began; through August 2022, most cases had occurred among men who have sex with men and were predominately due to close skin-to-skin contact (including that which occurs during sex).

Epidemiology

Smallpox & Vaccinia

The last documented case of naturally occurring (endemic) smallpox was in 1977. A single confirmed case of smallpox today could be the result of an intentional act (bioterrorism) and would be considered a global public health emergency.

Infections with wild vaccinia-like viruses have been reported among cattle and buffalo herders in India and among dairy workers in southern Brazil and Colombia. Travelers touching affected bovines might acquire a localized, cutaneous infection. Immunosuppressed people or people with certain skin conditions are at an increased risk for developing systemic illness.

Cowpox

Human infections with cowpox virus and cowpox- like viruses have been reported in Europe and the Caucasus (e.g., cowpox and Akhmeta viruses in Georgia). Travelers having direct contact with infected bovines, felines, rodents (including pet rats), or captive exotic animals (e.g., zoo animals) can be at risk for cutaneous infection.

Mpox

Mpox is endemic to the tropical forested regions of West and Central Africa, notably the Congo Basin. Most cases are reported from the Democratic Republic of the Congo (DRC), where mpox was first recognized as a human disease in 1970. Travelers (including immigrants and refugees) leaving the DRC could be infected with mpox virus, but reports of disease imported from the DRC are rare.

In 2003, small mammals imported from Africa were the source of a human mpox outbreak in the United States. The infected, imported animals were housed with domestic prairie dogs being sold as pets. At least 37 people were infected.

Increases in human mpox cases across multiple African countries have occurred over the last few years in Cameroon, Central African Republic, Côte d’Ivoire, Gabon, Liberia, Nigeria, Republic of the Congo, and Sierra Leone. In many of these countries, decades had passed before new cases were detected. During 2018–2021, Nigeria was implicated as the country of origin for 8 cases of exported mpox in humans: 4 cases were diagnosed in people who traveled to the United Kingdom; 2 others traveled to the United States; 1 to Singapore; and 1 to Israel. In the United Kingdom, secondary cases occurred among family members of one of the patients and in a health care provider.

Most recently, a global mpox outbreak began in May 2022. On July 23, the WHO declared the outbreak a Public Health Emergency of International Concern, and on August 4, the United States declared the ongoing spread of the virus to be a public health emergency. As of August 2022, the outbreak had caused tens of thousands of cases in >90 countries, predominately among men who have sex with men; as previously noted, transmission has been associated with close skin-to-skin contact.

Clinical Presentation

Table 5-20 summarizes key clinical characteristics of orthopoxvirus infections in humans. Immunocompromised patients or people with exfoliative skin conditions (e.g., atopic dermatitis or eczema) are at greater risk for severe illness or death. Ocular infections, although rare, have caused permanent corneal scarring. Poor pregnancy outcomes, including fetal death, have been observed when pregnant people have had variola or mpox virus infections.

Smallpox

Clinical signs and symptoms include acute onset of fever >101°F (38.3°C), head and body aches, malaise, and sometimes vomiting, then a characteristic, disseminated rash of firm, deep-seated vesicles or pustules in the same stage of development on each affected body site. Clinically, varicella is the most common rash illness likely to be confused with smallpox (see Sec. 5, Part 2, Ch. 24, Varicella / Chickenpox). Lesions on the palms or soles and a centrifugal distribution of lesions on the body, which are characteristic of smallpox, can sometimes help distinguish orthopoxvirus infection from varicella.

Cowpox & Vaccinia

Human infections with cowpox, cowpox-like viruses, vaccinia, and wild vaccinia-like viruses are most often self-limited, characterized by localized vesicular-pustular lesions, which in cowpox occasionally are ulcerative. Fever and other constitutional symptoms might occur briefly after lesions first appear. Lesions can be painful and persist for weeks.

Mpox

As with smallpox, a person infected with mpox virus classically experiences a febrile prodrome (characterized by high fever, malaise, headache, or back pain) followed by a widespread, characteristic, vesiculopustular rash that sometimes involves the palms and soles. Marked lymphadenopathy is common in classic presentations of mpox, distinguishing it from smallpox.

Cases associated with the worldwide outbreak that began in 2022 have exhibited a different clinical presentation than classic mpox. During the outbreak, rash lesions have been reported as being smaller and less diffusely spread; multiple lesions locally scattered over specific parts of the body or only a single lesion have been observed. In many cases, lesions have involved the anogenital area and caused pain and proctitis. The illness has been self-limited and most patients have not required hospitalization; some deaths have been reported, however.

Diagnosis

PCR testing or virus isolation can confirm an orthopoxvirus infection. Do not send laboratory specimens to CDC without a prior consultation. For guidance on preparation and collection of specimens and other clinically relevant issues, see  Mpox: Information for Healthcare Professionals and Smallpox: For Clinicians.

Mpox

During the 2022 mpox outbreak, public health laboratories and multiple commercial laboratories in the United States tested specimens prior to sending samples to CDC for additional characterization or specialized tests. CDC provides laboratory testing and consultation with mpox subject matter experts when requested.

Particularly during the 2022 outbreak, clinicians have confused mpox (in part due to its atypical presentation) with infections that can present similarly. Evaluate patients for these other infections as well as mpox. Moreover, co-infections with a sexually transmitted infection (e.g., syphilis) or with varicella have been known to occur. CDC is frequently updating its clinical guidance and management recommendations during the global mpox outbreak.

Treatment

Treatment of orthopoxvirus infections is mainly supportive care through hydration, nutritional supplementation, and prevention of secondary infections. To diminish the chances of spreading virus to other parts of the body or to other people, keep all pox lesions covered until the scab detaches; advise patients to avoid touching their eyes before proper hand washing. Managing orthopoxvirus infections in patients at high risk for severe outcomes (e.g., immunocompromised people, those with underlying skin conditions, those with eye involvement) can be challenging. Topical antivirals (e.g., trifluridine drops) have been used to treat ocular involvement. Tecovirimat (TPOXX), brincidofovir (Tembexa), and vaccinia immune globulin have been licensed by the US Food and Drug Administration to treat smallpox or vaccinia complications and are stocked in the US government’s Strategic National Stockpile (SNS).

Mpox

During the 2022 global outbreak, health care providers have used Tecovirimat to treat patients with mpox. Anecdotally, use of this drug has been associated with shorter illness courses, although more evaluations are needed to better understand its role in treatment. Tecovirimat is available through a CDC–sponsored Investigational New Drug protocol for the treatment of mpox.

Prevention

To reduce the chances of contracting mpox and other orthopoxvirus infections, travelers should avoid contact with sick or dead animals, including wild animals, pets, and domestic ruminants (e.g., buffalo, cattle). They should also avoid direct contact with ill humans.

Two vaccines are licensed for the prevention of smallpox in the United States. People at occupational risk for orthopoxvirus infection (e.g., laboratorians who work with variola, mpox, or vaccinia viruses; military personnel who travel to regions in the world where variola virus could be encountered) are vaccinated for preexposure prophylaxis. The Advisory Committee on Immunization Practices only recommends preexposure prophylaxis for people at occupational risk for orthopoxvirus infection (e.g., because of health care delivery to a patient or laboratory work involving orthopoxviruses). Members of the US military might be required to receive the vaccine.

Mpox

In May 2022, a multinational outbreak of monkeypox (mpox) began; 3 months later (by the end of August) it involved people from >90 countries. During the outbreak, the causative agent, monkeypox virus (see Sec. 5, Part 2, Ch. 22, Smallpox & Other Orthopoxvirus-Associated Infections), spread person-to-person primarily through close skin-to-skin (including sexual) contact. Most cases occurred among gay, bisexual, and other men who have sex with men; international travel played a role in introducing the virus to new countries. Remind all travelers that sex with new partners can increase their risk of contracting infections, including mpox.

People at risk of mpox exposure and infection during travel should complete mpox vaccination series at least two weeks prior to departure.  Refer susceptible travelers who have been exposed to mpox for vaccination, as soon as possible (ideally within 4 days of exposure) to help prevent the disease or make it less severe.

CDC websites: Poxvirus; Smallpox