Updated: Sep 26, 2019
Author: Mary Beth Graham, MD; Chief Editor: William D James, MD 



In 1970, when smallpox was nearly eradicated, a previously unrecognized orthopoxvirus named monkeypox was identified in humans. The first known human case occurred in the Equateur province of Zaire (now known as the Democratic Republic of Congo [DRC]) when a 9-year-old boy developed a smallpoxlike illness, which was eventually confirmed as human monkeypox by the World Health Organization.[1] Retrospectively, similar cases occurring in 1970-1971 from the Ivory Coast, Liberia, Nigeria, and Sierra Leone were attributed to monkeypox infection.

Monkeypox was limited to the rain forests of central and western Africa until 2003, when the first cases in the Western Hemisphere were reported. In late spring 2003, multiple persons were identified in the midwestern United States who had developed fever, rash, respiratory symptoms, and lymphadenopathy following exposure to ill pet prairie dogs (Cynomys species) infected with the monkeypox virus.[2]

Note the image below.

Vesicular rash on the dorsal aspect of the hand. V Vesicular rash on the dorsal aspect of the hand. Vesicopustules are seen; some have a central umbilication.

Most confirmed cases reported direct contact or exposure to ill prairie dogs showing signs of profuse nasal discharge, ocular discharge, dyspnea, lymphadenopathy, and mucocutaneous lesions. Traceback investigators concluded that all confirmed cases of monkeypox were associated from a common animal distributor where prairie dogs were housed or transported with African rodents from Ghana. Among these rodents were Gambian rats, which are known reservoirs of monkeypox in their native habitat of Africa.

In the 2003 US outbreak, imported asymptomatic animals transmitted a nonindigenous pathogen to an indigenous susceptible animal. After an average incubation period of 12 days, the animal became ill and was capable of transmitting the pathogen to humans when in close proximity. The potential for human-to-human transmission and human-to-animal transmission remains unknown.


The monkeypox virus is a member of the genus orthopox (family Poxviridae); other members include cowpox, vaccinia, and variola (smallpox) viruses.[3] It is a zoonotic virus with primary transmission believed to occur through direct contact with infected animals or possibly by ingestion of their inadequately cooked flesh. Inoculation may be from cutaneous or mucosal lesions on the animal, especially when the skin barrier is compromised secondary to bites, scratches, or other trauma. The infection was first seen in laboratory monkeys in 1958, thus, the name monkeypox, although rodents are believed to be the major reservoir in Africa.[4, 5] A 2010 study reaffirmed that several species of forest-dwelling rodents are at risk for orthopoxvirus (including monkeypox) infection. People living in or near the forested areas may have indirect or low-level exposure, possibly leading to subclinical infection.[6]

Secondary, or human-to-human, disease transmission was found to be another possible route in an outbreak in the DRC in 1996-1997.[5] Studies of this outbreak suggested that within households, monkeypox was secondarily transmitted to 8-15% of human contacts. Prior to this, monkeypox was not identified as an important worldwide health problem because human infection rates were not known to play a significant role in the pathogenesis. Analysis of the 2003 US outbreak implicates animal-to-animal and animal-to-human transmission as the significant route of transmission. However, in the 2003 US outbreak, clear exposure to an infected animal could not be identified in one case, and, therefore, human-to-human transmission could not be excluded.


Outbreaks in western and central Africa have been linked to exposure to rats, rabbits, squirrels, monkeys, porcupines, and gazelles. Inhabitants of remote tropical rain forests may become infected from direct contact while capturing, slaughtering, and/or preparing these animals for food; ingestion has also been linked to infection. Because of the diversity of animals eaten by local inhabitants, conclusions about the relative risk of meat sources are not known with certainty.

In the DRC in 1997, animals caught from the wild were tested for the monkeypox virus. The following animals were found to have neutralizing antibodies against the monkeypox virus, suggesting a role as natural reservoirs: domestic pig (Sus scrofa), Gambian rat (Cricetomys emini), elephant shrew (Petrodromus tetradactylus), Thomas's tree/rope squirrel (Funisciurus anerythrus), Kuhl's tree squirrel (Funisciurus congicus), and sun squirrel (Heliosciurus rufobrachium).[5]

Human-to-human transmission supplanted the prominence of animal-to-human transmission in the 1996-1997 outbreak in the DRC. Crowded living quarters, poor hygiene, discontinuation of the smallpox vaccination, and decreased herd immunity were implicated. Respiratory droplets and direct contact with mucocutaneous lesions or fomites have been postulated as routes of human-to-human transmission.



United States

No cases occurred in the United States until the late spring 2003 outbreak in the Midwestern states. Between May 16 and June 20, 2003, 71 suspected cases of monkeypox were investigated.[7] A total of 47 individuals were identified with confirmed (n = 37) or probable (n = 10) monkeypox virus infection. Monkeypox cases were confirmed on the basis of virus isolation or detection of the virus by polymerase chain reaction (PCR) from a clinical specimen (eg, skin biopsy or throat culture). Individuals who presented with fever and rash within 21 days of exposure to monkeypox and had serum positive for orthopox immunoglobulin M (IgM), but did not have culture- or PCR-positive clinical specimens, were classified as having a probable case of infection.[8, 9]


This condition is rare and only known to be indigenous to the rain forests of western and central Africa.[10] It was first recognized in humans in 1970 after the eradication of smallpox, possibly because of the subsequent unmasking of the infection. Surveillance reports from 1981-1986 documented 338 cases in the DRC (out of a 1982 estimated population of 5 million). In the 1996-1997 outbreak in the DRC, the attack rate was 22 cases per 1000 population.

Human infection with monkeypox has not been reported in West Africa since 1978. Monkeypox is considered endemic in northern and central DRC. Sporadic occurrences of disease are reported in neighboring countries.[11] In 2003, 11 cases and 1 death were reported from the DRC and 10 cases with no deaths were reported from Sudan in 2005.[12]

In 2009, interethnic violence in northwestern DRC lead to an influx of refugees into the Republic of the Congo (ROC). The United Nations International Children's Emergency Fund (UNICEF) sponsored a program of intensive community education in the refugee settlements that included modules on monkeypox recognition and prevention, which resulted in the indentification of 10 suspected cases of monkeypox. Seven of these 10 cases were tested and 2 were found to be positive by polymerase chain reaction assays.[13]

The results of this outreach campaign suggest that intensive community education can lead to increased capacity for detection of monkeypox in high transmission–risk settings. They also highlight the need to educate physicians in the recognition and treatment of monkeypox.[14]


Poxvirus infections have no racial predilection.


The incidence is equal in males and females.


In the African epidemics, 90% of the patients were children younger than 15 years.[15] In the recent US outbreak, of the confirmed cases in 2003 (n = 35), 11 patients were younger than 18 years and 24 were older. Although the highest age-specific incidences and the greatest number of cases occur among persons younger than 15 years, a trend toward increasing incidence among persons aged 15-30 years has been seen in recent years. It has been hypothesized that cessation of smallpox vaccination may be a factor in the increasing incidence in this age group, but this theory fails to account for why the disease has not reemerged in countries where the disease was seen previously, such as West Africa.[12]


Mortality rates ranging from 1-10% have been reported in Africa, but no fatalities occurred in the United States 2003 outbreak. Death rates are disproportionately high in African children. Health status, comorbidities, vaccination status, and severity of complications influence the prognosis in the United States and Africa.

Uncomplicated cases resolve in 2-4 weeks, with only pock scars remaining.


The disease in the United States was generally self-limited, with resolution in 2-4 weeks, depending on the severity of the illness. However, a small subset of patients, most commonly pediatric patients, had a more severe course, with several patients requiring ICU care.[16]

Complications reported from African outbreaks include pitted scars, deforming scars, secondary bacterial infection, bronchopneumonia, respiratory distress, keratitis, corneal ulceration, blindness, septicemia, and encephalitis.

Data from the African outbreaks suggest that prior smallpox vaccination confers 85% protection from monkeypox; infection may be milder even several years after vaccination, and the incidence of complications may be reduced.[17, 18] With the 2003 US outbreak, the Centers for Disease Control and Prevention (CDC) recommended smallpox vaccination up to 2 weeks, ideally within 4 days, after a significant, unprotected exposure to a diseased animal or a confirmed human case.[19]

African cases have mortality rates of 1-10%, with the highest rates occurring in children and individuals without vaccination. In general, the prognosis is related to the amount of exposure to the virus, host immune response, comorbidities, vaccination status, and severity of complications.

Genomic sequencing of US, western African, and central African monkeypox isolates have confirmed the existence of 2 distinct monkeypox clades.[20] The isolates from the United States were identical to the western African isolates. The disease course for individuals infected with the western African isolates is milder with less human-to-human transmission than for those infected with isolates from central Africa.[21] In 2010, a dosage comparison using a prairie dog animal model reconfirmed that the Congo Basin strain of monkeypox virus is more virulent than the West African strain of monkeypox virus.[22]

Patient Education

After the 2003 outbreak, the CDC implemented an immediate embargo on the importation of all rodents (order Rodentia) from Africa.

In addition, the CDC and the Food and Drug Administration prohibited the transportation or offering for transportation in interstate commerce, or the sale, offering for sale, or offering for any other type of commercial or public distribution, including release into the environment of prairie dogs and the following rodents from Africa: tree squirrels (Heliosciurus species), rope squirrels (Funisciurus species), dormice (Graphiurus species), Gambian giant pouched rats (Cricetomys species), brush-tailed porcupines (Atherurus species), and striped mice (Hybomys species).

Investigation of the exotic pet industry by state and federal authorities was triggered by the 2003 outbreak. The US Food and Drug Administration (FDA) lifted its restrictions on pet prairie dogs in 2008. The FDA consulted with the CDC and determined that the domestic restrictions placed on certain African rodents, prairie dogs, and certain other animals were no longer needed. However, the CDC restriction on the importation of all African rodents remains in effect to prevent any reintroduction of the monkeypox virus into the United States.[23]




Monkeypox can cause a syndrome clinically similar to smallpox but overall is less infectious and less deadly.

Transmission can occur from contact with ill animals or animal reservoirs from Western Africa (eg, prairie dogs, rabbits, rats, mice, squirrels, dormice, monkeys, porcupines, gazelles). Additionally, preparing or ingesting infected animals can transmit monkeypox infection. Finally, direct cutaneous (skin-to-skin) or respiratory contact with an animal or person who is infected can transmit the infection.

The incubation period averages 12 days, ranging from 4-20 days.

In the prodrome or preeruptive stage (lasts 1-10 d), fever is commonly the first symptom (usually 38.5-40.5°C). The febrile illness is often accompanied by chills, drenching sweats, severe headache, backache, myalgia, malaise, anorexia, prostration, pharyngitis, shortness of breath, and cough (with or without sputum). Lymphadenopathy appears within 2-3 days after the fever. In the 2003 outbreak, 47% of patients had nodes measuring several centimeters in diameter in the cervical and submental areas.

In the exanthem (eruptive) stage, most persons develop a rash within 1-10 days after the onset of fever. The rash often starts on the face and then spreads to the rest of the body. It persists for 2-4 weeks until all lesions have shed the crusts. Encephalitis with immunoglobulin M found in the cerebrospinal fluid has been reported.[24]

Physical Examination

The most reliable clinical sign differentiating monkeypox from smallpox and chickenpox is enlarged lymph nodes, especially the submental, submandibular, cervical, and inguinal nodes.[25] Note the image below.

Lymphadenopathy in monkeypox. Large nodes in the m Lymphadenopathy in monkeypox. Large nodes in the mandibular, cervical, or inguinal region are commonly seen in monkeypox. The presence of significant lymphadenopathy helps differentiate monkeypox from smallpox and chickenpox.

With regard to enanthema, nonspecific lesions and inflammation of the pharyngeal, conjunctival, and genital mucosae have been observed.

In the exanthema stage, within a particular body region, lesions evolve synchronously over 14-21 days, similar to the development of lesions with smallpox. However, unlike smallpox, skin lesions may appear in crops. In contrast to smallpox, the lesions do not have a strong centrifugal distribution. Lesions progress from macules to papules to vesicles and pustules; umbilication, crusting, and desquamation follow. Most lesions are 3-15 mm in diameter.

Note the image below.

Umbilicated papule on the lower part of the leg. T Umbilicated papule on the lower part of the leg. This smaller lesion still shows the typical umbilicated morphology.

The face, the trunk, the extremities, and the scalp are involved. Lesions appear in covered and uncovered areas. Lesions may be seen on the palms and the soles. Necrosis, petechiae, and ulceration may be features. Pain is unusual, and, if it occurs, it is often associated with secondary bacterial infection. Pruritus may occur.

In patients who have been previously vaccinated against smallpox, a milder form of disease occurs. In children, the lesions may appear as nonspecific, erythematous papules that are 1-5 mm in diameter and suggestive of arthropod bite reactions. Subtle umbilication may be seen.

In the African outbreaks, 20% of unvaccinated patients developed a confluent, erythematous eruption on the face and the upper part of the trunk, which some authors have termed the septicemic rash of monkeypox.[15]

Hemorrhagic and flat forms, which can be seen with smallpox, have not been reported in patients with monkeypox. Deep pock scars can result as the lesions resolve.


Complications include pitted scars, deforming scars, secondary bacterial infection, bronchopneumonia, respiratory distress, keratitis, corneal ulceration, blindness, septicemia, and encephalitis.



Differential Diagnoses



Diagnostic Criteria

The diagnostic criteria are summarized below; refer to the current criteria established by the CDC at Updated Interim Case Definition for Human Monkeypox, January 2004.

Confirmed case

Meets one or more of the following laboratory criteria:

  • Isolation of the monkeypox virus in culture from a sample obtained from the patient

  • Demonstration of the monkeypox virus on PCR in a specimen obtained from the patient

  • Demonstration of the orthopox virus by electron microscopy in samples obtained from the patient in the absence of exposure to other orthopoxviruses

  • Demonstration of the monkeypox virus by immunohistochemical methods in samples obtained from the patient in the absence of exposure to another orthopoxvirus

Probable case

This is contact that meets current epidemiologic criteria per the CDC. It is the occurrence of fever and vesicular-pustular rash, with the onset of the first sign or symptom at most 21 days after the last exposure, meeting the epidemiologic exposure.

Suspected case

This is contact that meets current epidemiologic criteria per the CDC. It the occurrence of fever or unexplained rash and 2 or more other signs or symptoms, with the onset of the first sign or symptom at most 21 days after exposure, meeting the epidemiologic criteria. Symptoms are as follows:

  • Chills and/or sweats

  • Lymphadenopathy

  • Sore throat

  • Cough

  • Shortness of breath

  • Headache

  • Backache

Laboratory Studies

Information regarding procurement and disposition of specimens for the CDC may be obtained at Laboratory Testing of Human and Animal Specimens.

A viral culture should be obtained from an oropharyngeal or nasopharyngeal swab. A skin biopsy specimen of the vesiculopustular rash or a sample of the roof of an intact vesiculopustule should be analyzed.

Tissue for PCR of DNA sequence-specific for the monkeypox virus may be obtained.[26]

Paired sera for acute and convalescent titers may be analyzed. Serum collected more than 5 days for IgM detection or serum collected more than 8 days after rash onset for IgG detection was most efficient for the detection of the monkeypox virus infection.[8]

A Tzanck smear can help differentiate monkeypox from other nonviral disorders in the differential diagnosis. However, a Tzanck smear does not differentiate a monkeypox infection from smallpox or herpetic infections.

A recent pilot of the Tetracore Orthopox BioThreat Alert provided promising results using lesion specimens from acute Orthopoxvirus infections. This assay correctly identified 5 of 6 clinical specimens tested. Although not specific for monkeypox virus, this assay could be used in monkeypox-endemic areas for Orthopoxvirus confirmation by proxy.[27]

Histologic Findings

Histologically, papular lesions show acanthosis, individual keratinocyte necrosis, and basal vacuolization. This is accompanied by a superficial and deep perivascular, lymphohistiocytic infiltrate in the dermis. Lesions in the vesicular stage demonstrate spongiosis with reticular and ballooning degeneration. Multinucleated epithelial giant cells may be seen. Pustular lesions are characterized by epidermal necrosis with numerous eosinophils and neutrophils, many displaying karyorrhexis. Necrosis may extend through full-thickness epidermis with sharp lateral demarcation from adjacent intact epidermis. The associated perivascular infiltrate includes eosinophils and neutrophils in addition to lymphocytes and histiocytes. Petechial lesions demonstrate secondary vasculitis. Amphophilic intranuclear structures suggestive of viral inclusions may be seen in keratinocytes.

Immunohistochemistry staining for orthopox viral antigens can be performed in a reference laboratory. With electron microscopy, intracytoplasmic, round-to-oval inclusions with sausage-shaped structures centrally, measuring 200-300 µm, are observed.[28] Inclusions are consistent with orthopox viruses, permitting differentiation from parapox and herpes viruses.



Medical Care

The disease is usually self-limited; resolution occurs in 2-4 weeks. In the African cases, the mortality rate was 1-10%, and death was related to the patients' health status, and other comorbidities. Most patients died of secondary infections. No fatalities were reported in the recent US outbreak.

Patients often feel poorly during the febrile stage of the illness; therefore, bedrest along with supportive care may be necessary. Hospitalization may be necessary in more severe cases; a negative pressure room is preferable.

To avoid infection of health care workers and close contacts, airborne and contact precautions should be applied. See the current CDC recommendations at Guideline for Isolation Precautions in Hospitals and Updated Interim Infection Control and Exposure Management Guidance in the Health-Care and Community Setting for Patients with Possible Monkeypox Virus Infection.

Isolation must be continued until the last crust is shed.


Importation of exotic animals as domestic pets poses a threat to the health of both people and animals by introducing nonindigenous pathogens. Animals, especially those implicated above (see Causes) or those in contact with them, demonstrating signs of respiratory distress, mucocutaneous lesions, rhinorrhea, ocular discharge, and/or lymphadenopathy should be quarantined immediately. Avoidance of contact, especially bites, scratches, and exposure to fluids/secretions, is essential. Guidance can be obtained from veterinarians, state/local authorities, and the CDC. See the current CDC recommendations at Monkeypox Infections In Animals: Updated Interim Guidance for Veterinarians.

In September 2019, the FDA approved an attenuated, live, nonreplicating smallpox and monkeypox vaccine (Jynneos) for immunization of adults at high risk for smallpox or monkeypox infection. Approval was determined in a clinical study comparing the immune responses in study participants who received either Jynneos or ACAM2000, an FDA-approved vaccine for the prevention of smallpox. The study included approximately 400 healthy adults, aged 18-42 years who had never been vaccinated for smallpox. Half of the study participants received 2 doses of Jynneos administered 28 days apart, and half received 1 dose of ACAM2000. The group vaccinated with Jynneos had an immune response that was not inferior to immune responses to ACAM2000.[29, 30]

A 2010 report describes experimental low-dose intranasal infection in a STAT1-deficient C57BL/6 mouse model that caused 100% mortality. However, vaccination with modified vaccinia virus Ankara, followed by a booster vaccination, was protective against intranasal infection and produced a more vigorous immune response compared with a single vaccination.[31] Other mouse models are being used to investigate monkeypox pathogenesis, disease progression, viral shedding, and virulence, with the possible aim of testing antivirals and next-generation vaccines.[32]

Long-Term Monitoring

Outpatient management is appropriate and cost-effective in most cases of human infection, but care must be taken to follow recommended quarantine procedures at home.

Contact and respiratory isolation precautions should be exercised to prevent the spread of disease. Direct contact with skin lesions or fomites is considered infectious until the crust detaches from the last skin lesion. Patients and unexposed contacts should wear masks until respiratory symptoms resolve.

Health care workers and others who are asymptomatic and in contact with patients who are infected must closely monitor their symptoms and their temperature for 21 days after the last known contact. See the current CDC recommendations at Updated Interim Infection Control and Exposure Management Guidance in the Health-Care and Community Setting for Patients with Possible Monkeypox Virus Infection.



Medication Summary

The CDC recommends a smallpox vaccination within 2 weeks of exposure, ideally within 4 days, for exposed health care workers and household contacts of confirmed cases. Cidofovir has been suggested as a possible treatment option in severe, life-threatening cases only.[33, 34] Vaccinia immune globulin (VIG) has not demonstrated efficacy in either treatment or prophylaxis. Smallpox preparedness research has led to the development of new antiviral agents for the treatment of orthopoxvirus infections. One such agent, ST-246, has been studied in an animal model of monkeypox virus infection with demonstrated efficacy for prophylactic, postexposure, and therapeutic treatment.[35]

In September 2019, the FDA approved an attenuated, live, nonreplicating smallpox and monkeypox vaccine (Jynneos) for immunization of adults at high risk for smallpox or monkeypox infection.[29, 30]

Antiviral Agent

Cidofovir (Vistide)

Cidofovir is a nucleotide analog that selectively inhibits viral DNA production in CMV and other herpes viruses.

Vaccine, Live Virus

Class Summary

Vaccinia vaccine promotes active immunity against the smallpox virus by inducing specific antibodies. Currently available stocks of vaccinia vaccine were derived from the vaccinia strain maintained at the New York Board of Health. Wyeth Laboratories manufactured the last batches of the vaccine (Dryvax) in the early 1980s. These batches were made by using the calf lymph method, and they were lyophilized but are no longer available.

Several attenuated vaccinia vaccine candidates are undergoing investigation, with ACAM2000 receiving FDA approval as a replacement for Dryvax. Another vaccine (smallpox [vaccinia] and monkeypox vaccine, live, nonreplicating [Jynneos]) has also been approved by the FDA for immunization of adults at high risk for smallpox or monkeypox infection.

New, cell-derived lots of vaccinia appear to have adverse effect profiles similar to the older, calf lymph–derived lots.

Primary immunization as soon as possible after exposure or at the first sign of infection is indicated for the prevention and management of smallpox. Currently, US military personnel, US Department of Defense civilian employees, and health care professionals are recommended candidates to receive the vaccination because they will likely be at highest risk in case of a biologic attack (eg, bioterrorism).

Smallpox vaccine (ACAM2000)

This agent is made from vaccinia, which is related to, but different from, the virus that causes smallpox. It contains live vaccinia virus and works by causing a mild infection that stimulates an immune response that effectively protects against smallpox without actually causing disease.

The vaccine contains live vaccinia virus but does not contain variola virus, the virus that causes smallpox. Vaccinia is a member of the Orthopoxvirus genus, which includes smallpox (variola), cowpox, monkeypox, gerbilpox, camelpox, and others. Following inoculation, the vaccine induces an immune reaction that serves to protect against smallpox.

ACAM2000 is derived from Dryvax, which is the only other smallpox vaccine licensed by the FDA. Dryvax, which was approved in 1931, is now in limited supply because it is no longer being manufactured. The US military resumed vaccination of at-risk personnel in 1999 after concluding that the disease posed a potential bioterrorism threat.

ACAM2000 was studied in 2 populations: (1) persons who had never been vaccinated for smallpox and (2) those who had received smallpox vaccination many years earlier. The percentage of unvaccinated persons who developed a successful immunization reaction was similar to that of Dryvax. ACAM2000 was also found to be acceptable as a booster in persons previously vaccinated for smallpox.

Because ACAM2000 contains live vaccinia virus, care must be taken to prevent the virus from spreading from the inoculation site to other parts of the body and to other individuals. To minimize known risks, vaccine licensing is subject to a Risk Minimization Action Plan (RiskMAP), which requires providers of the vaccine and patients to be educated about vaccination risks.

The medication guide explains proper care of the vaccination site and provides information about serious adverse effects associated with ACAM2000.

In studies, about 1 in 175 healthy adults who received smallpox vaccine for the first time developed myocarditis and/or pericarditis. Of the 10 affected adults, 4 had no symptoms at the end of the study, and symptoms resolved in all but 1 patient.

Smallpox (vaccinia) and monkeypox vaccine, live, nonreplicating (Jynneos)

This vaccine is derived from a vaccinia virus, a virus that is closely related to, but less harmful than, variola and monkeypox viruses and can protect against both of these diseases. It is indicated for prevention of smallpox and monkeypox disease in adults who are at high risk for smallpox or monkeypox infection. It is administered as a 2-dose series administered 4 weeks apart.