Causative agent
Monkeypox is an infectious disease of animals and humans caused by an orthopoxvirus, a genus of the Chordopoxviridae subfamily of the Poxviridae family of viruses. Other members of the orthopoxviridae subfamily include human smallpox (variola), vaccinia, camelpox, and cowpox. Poxviruses are large, enveloped, double-stranded DNA viruses.

Natural distribution
Monkeypox exists in nature as a disease of nonhuman primates, rabbits, and some wild rodents (e.g., prairie dogs, ground squirrels, Gambian rats, and mice). The extent of animal susceptibility is unknown; caution therefore dictates that all mammals be considered susceptible.

The virus was first recognized in 1958 in captive cynomolgus monkeys. The first human monkeypox infections were reported in 1970 in the Democratic Republic of Congo (DRC, formerly Zaire).

Geographically, monkeypox occurs primarily in the rainforest countries of Central and West Africa. The virus is established (endemic) in the Congo Basin. Animal antibody surveys in the DRC provide some evidence that rope squirrels may play a major role as a reservoir of the virus and that humans are sporadically infected. Monkeypox was reported in southern Sudan in 2005; prior to 2005, the disease had not been reported in that region.

On June 7, 2003, the CDC announced the first evidence of community-acquired monkeypox infection in the United States and the Western Hemisphere. Seventy-two suspected cases of human monkeypox infection were identified during the outbreak; cases were reported in Illinois, Indiana, Kansas, Missouri, Ohio, and Wisconsin. Laboratory confirmation of monkeypox was made in 37 cases, and 10 other cases showed symptoms but could not be confirmed with laboratory testing. Most affected persons in the US outbreak had direct contact with recently purchased ill prairie dogs (including bites, handling, household contact, or handling of cages and bedding). These prairie dogs were exposed to the virus through contact with animals imported from Africa that were intended to be sold as pets. The imported animals included Gambian rats, rope squirrels, dormice, and other small mammals. The infected prairie dogs were sold to an animal distributor, who sold them to two pet shops and at a pet swap meet in northern Wisconsin.

Transmission
Transmission generally occurs as a result of close contact with infected animals, most often through an animal bite or exposure to an infected animal's sores, blood, or other body fluids. In Africa, transmission is often associated with the use of wild animals for food. Viral entry most often occurs through small lesions in the skin or oral mucous membranes, although human-to-human transmission via respiratory droplets during direct and prolonged face-to-face contact is possible. Limited human-to-human spread of infection has been reported as occurring in disease-endemic areas in Africa; however, a 1997 outbreak in the DRC initially appeared to have a higher rate of human-to-human infection and longer chains of transmission than had previously been reported. All confirmed human cases of monkeypox during the 2003 outbreak in the U.S. resulted from direct contact with infected animals.

Experts have suggested that changes in the epidemiology of the disease may be expected as a result of ending smallpox vaccination programs in the late 1970s (vaccination against smallpox also provides protection against monkeypox). Transmission via virus-contaminated objects, such as bedding or clothing, is also possible. The incubation period for African monkeypox cases is approximately 12 days but can range from 4 to 20 days. Cases in the U.S. exhibited incubation periods that were slightly longer; the average was 14.5 days with a range of 4 to 24 days. Analysis of the DNA of the U.S. virus revealed that it was part of the West African group of the virus, which is a less virulent (less likely to infect) group than the virus group found in the Congo Basin.

Types and clinical signs of monkeypox in animals and humans
Rabbits and rodents (including prairie dogs)—The first signs of illness may include blepharoconjunctivitis (swelling of the eyelids and the membranes around the eyes), discharge from the eyes and nose, sneezing, fever, coughing, lymphadenopathy (swollen lymph nodes), loss of appetite, and lethargy. These signs may be followed by development of a nodular rash, with patches of alopecia (hair loss), and pneumonia. In the outbreak in the United States, some animals have died whereas others recovered.

Monkeys—Lesions in captive monkeys consist of discrete and multiple papules (raised bumps on the skin) with diameters that vary from 1 to 4 mm. The palms of the hands are most often affected, but lesions may also be found on the trunk and tail. Papules contain pus-like material, and umbilication (a depression in the center that resembles a belly button) is common. Ulcers may also appear in the mouth.

Humans—More than 80% of human monkeypox cases in Africa occur in children less than 10 years old. The symptoms are similar to human smallpox, although the disease is typically much less serious. One important factor in differentiating monkeypox from smallpox is that marked lymphadenopathy is found in the majority of monkeypox cases, but is not observed in smallpox.

Individuals affected most often first experience a prodromal phase that consists of flu-like symptoms, including fatigue, fever, headache, chills, drenching sweats, muscular and back pain, lymphadenopathy (especially in the neck and groin), and a nonproductive cough. In more severe cases, patients may experience difficulty breathing. Humans infected with monkeypox during the 2003 U.S. outbreak also developed nausea, vomiting, nasal congestion, mouth sores, swollen eyelids, conjunctivitis (reddening of the membranes around the eyes), and other abdominal problems. The prodromal phase is followed in 1 to 10 days by eruption of a rash that evolves from maculas (blotchy spots) to papules, vesicles (blisters), pustules (pimples), and scabs. In some patients, early lesions become ulcerated and most patients will have multiple lesions in various stages of development. Lesions are usually more numerous on the extremities (legs and arms), although they may also be present on the head and trunk. Illness typically lasts for 2 to 4 weeks. In Africa, associated fatalities have ranged from 1 to 22%, with the highest death rate occurring in young children. No fatalities were reported in the 2003 U.S. outbreak.

Diagnosis
Serologic testing of patient specimens aids in diagnosis, but a definitive diagnosis requires demonstrating the existence of specific antibodies against monkeypox virus or isolation of the virus. Monkeypox virus may be isolated from skin lesions, including scabs. Standard techniques, including electron microscopy, polymerase chain reaction, and immunohistochemistry are used in identification. An ELISA test is available.

Prevention
Contact with infected or exposed animals should be avoided, especially prairie dogs or other small mammals already identified as being potentially affected. Hands should be meticulously washed after contact with any animal suspected to be exposed or infected. In the United States, the CDC has recommended vaccinia (smallpox) vaccination for veterinarians and other laboratory workers who directly and regularly handle cultures or animals infected with monkeypox virus. Individuals caring for anyone infected with monkeypox should also consider vaccination. Previous vaccination against smallpox may lessen the severity of the disease. Vaccination is not recommended for individuals with weakened immune systems (due to caner treatment, organ transplant, HIV infection/AIDS, etc.) or for those with life-threatening allergies to latex or any ingredient of the smallpox vaccine.

In March 2004, the National Institute of Allergy and Infectious Disease announced that the modified vaccinia Ankara (MVA) vaccine is nearly as effective as the standard smallpox vaccine, and may be safer for use in higher-risk patients. There have also been encouraging results in the development of a subunit smallpox vaccine.

Treatment
Animals—Due to risks associated with human exposure, euthanasia of ill animal patients is recommended. Owners should not abandon animals at shelters or release them into the wild; both options present opportunities for disease spread and most animals released into the wild will not survive.

Infection control
Because of public health concerns, some state health departments recommend that animals with suspected monkeypox not be transported to veterinary clinics for treatment. Veterinarians should contact their local or state health officials for information. If animals suspected to be ill are brought to a veterinary clinic, they should not be admitted through the public waiting area. Animals should be transported to the clinic in chew-proof, closed containers with air holes provided. After transport, the crate and the area in the vehicle where the animal was confined should be cleaned and disinfected. When ill rodents, rabbits, and exotic pets (especially prairie dogs and Gambian giant rats) are examined, veterinarians should wear personal protective clothing (e.g., gown, gloves, and eye protection). A NIOSH-certified N95 disposable respirator should be used, if available; otherwise, a surgical mask should be worn. When suspect animal cases are identified, they should be housed in isolation, preferably in a negative airflow room, and veterinarians should limit the number of staff having contact with the animal. The physical examination, diagnostics, and any treatment should be conducted in the isolation room. Practicing veterinarians should not perform biopsies for sample collection. Veterinarians should wear personal protective equipment when obtaining serum or conjunctival swab samples for diagnosis.

Suspect human patients should be isolated from others in the reception area as soon as possible, preferably in a private room (negative air flow advised). A surgical mask should be placed over the patient's nose and mouth, and skin lesions should be covered with a sheet or gown to prevent contact with infectious material.

Meticulous hand hygiene should be practiced after each contact with patients or contaminated surfaces. Care should be taken when handling bedding, towels, and other items touching the patient to avoid contact with lesion exudates. Soiled material should not be shaken or otherwise handled in a manner that might aerosolize the infectious agent. Any equipment used in patient care should be disinfected or disposed of in accordance with guidelines for treatment of infectious waste. Environmental surfaces in the patient's environment should be disinfected using an EPA-registered hospital detergent/disinfectant in accordance with the manufacturer's recommendations. Animal carcasses should be incinerated and not disposed of in landfills or backyards. If an ill animal is associated with a human case of monkeypox, it should be tested for the virus. Veterinarians should not perform necropsies on animals with suspected monkeypox; instead, they should double bag and freeze the carcass and contact their state epidemiologist and state health laboratory for instructions.

Persons coming into direct contact with infected patients should be alert for signs of illness for 30 days following the date of exposure. Any mammal that has come in contact with an animal known to have monkeypox is considered exposed and should be placed under quarantine (placed in a room with a closed door and kept away from all other animals and people other than a single caretaker) for 6 weeks from the date of exposure or purchase. Immunocompromised individuals should not care for animals that are ill or quarantined.

In households, standard household detergents can be used to clean all surfaces in areas where ill animals have been housed. Afterward, the use of dilute bleach solution (1/4 cup bleach to 1 gallon of water) is recommended to disinfect the area. Washable toys, cages, food containers, or similar items should be cleaned and disinfected by hand or in a dishwasher. Washable materials, such as bedding or pillows, should be laundered or discarded after disinfection.

In response to the 2003 outbreak in the Midwestern United States, the CDC mandated bans on the importation of African rodents as well as the distribution, sale, and transport of prairie dogs, tree squirrels, rope squirrels, dormice, Gambian giant rats, brush-tailed porcupines, and striped mice.

Reporting
Monkeypox is included in the list of "select agents" published by the US Department of Health and Human Services. Veterinarians, healthcare providers, and public health personnel should report suspect cases of monkeypox in animals and humans to their public health department immediately.

Use of monkeypox as a biological weapon
Although the close relationship of monkeypox virus to smallpox virus has raised concerns about its potential use as a biological weapon, monkeypox virus is not easily transmitted between people. In addition, the disease in most patients is relatively mild and the overall case fatality rate is generally low. A mathematical model to assess the potential for monkeypox to spread in susceptible populations indicated that human-to-human transmission would not sustain monkeypox in humans without repeated reintroduction of the virus.

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