INTRODUCTION — Monkeypox is a viral zoonotic infection that results in a rash similar to smallpox. However, the person-to-person spread and the mortality from a monkeypox infection are significantly lower than for smallpox. Clinically, these two viral infections are difficult to distinguish, raising concerns that monkeypox could be used for bioterrorism [1].

This topic will review the virology, epidemiology, clinical manifestations, diagnosis, and treatment of monkeypox. Topic reviews that discuss smallpox are presented separately. (See "Variola virus (smallpox)" and "Identifying and managing casualties of biological terrorism".)

VIROLOGY — Monkeypox, an orthopoxvirus, was first isolated in the late 1950s from a colony of sick monkeys. The virus is in the same genus as variola (causative agent of smallpox) and vaccinia viruses (the virus used in smallpox vaccine). Electron microscopy of cells infected with monkeypox virus shows a brick-like virion, indistinguishable from the virions of variola or vaccinia viruses (picture 1).

Two distinct strains of monkeypox exist in different geographic regions of Africa, as suggested by epidemiologic, animal, and molecular evidence [2]. In comparison to strains isolated from Central Africa, monkeypox from Western Africa is less virulent and lacks a number of genes present in the other viral strain [2,3].

EPIDEMIOLOGY

History — It is believed that monkeypox virus has infected humans for thousands of years in sub-Saharan Africa [1].

Monkeypox was first identified as a cause of disease in humans in the 1970s in the Democratic Republic of the Congo (formerly the Republic of Zaire) [1,4-7]. Following its recognition as a human pathogen, 59 cases of human monkeypox were reported between 1970 and 1980, with a mortality rate of 17 percent. All of these cases occurred in the rain forests of Western and Central Africa among individuals exposed to small forest animals (eg, rodents, squirrels, and monkeys).

The first outbreak of monkeypox in the Western Hemisphere occurred in the United States in 2003 [8-10]. (See 'United States' below and 'Other countries' below.)

Transmission — The virus is typically acquired through contact with an infected animal's bodily fluids or through a bite. Monkeys and humans are incidental hosts; the reservoir remains unknown but is likely to be rodents. Infected rodents from Western Africa were accidentally imported into the United States; this led to the first human monkeypox infections in the Western Hemisphere.

In general, transmissibility from person-to-person is very low [11]. However, when it does occur, it is primarily through large respiratory droplets, and prolonged face-to-face contact is required for transmission (eg, within a 6-foot radius for ≥3 hours in the absence of personal protection equipment [PPE]) [12].

Based on findings during the US outbreak, the route of infection and extent of exposure (eg, bite wound versus touching an infected animal) can influence the severity of clinical manifestations of monkeypox infection. For example, one study categorized exposures to a prairie dog as noninvasive (eg, the person touched an infected animal, cleaned an infected animal's cage) or "complex" (eg, invasive bite or scratch from an ill prairie dog) [13]. Patients with complex exposures were more likely than patients with noninvasive exposures to develop signs of systemic illness.

Geographic distribution — After the eradication of smallpox and the discontinuation of smallpox immunization (ie, vaccinia virus vaccine), the World Health Organization (WHO) monitored subsequent human monkeypox activity. The WHO was concerned that elimination of the vaccinia virus vaccine, which also protects against monkeypox, would lead to increased susceptibility of the population and the possibility of an increased incidence of monkeypox infection.

Since discontinuation of smallpox immunization, most cases have occurred in Central and West Africa. However, sporadic cases in returning travelers have been reported in several countries, and in the United States, there was an outbreak due to importation of exotic animals from Africa, as discussed below. (See 'United States' below.)

Africa — From 1996 to 1998, an outbreak of febrile illness with associated pustular lesions occurred among about 100 persons with reports of secondary attack rates of 80 percent [4,7]. A concurrent chickenpox outbreak may have resulted in misclassification of cases and likely explained the high secondary attack rates. Nevertheless, this outbreak created concern that monkeypox had mutated to become more like smallpox [4,7]. However, sequence analyses of monkeypox from persons with active cases indicated no significant genetic changes [11,14]. The overall low mortality during this outbreak of less than 5 percent was another indication that monkeypox had not mutated into a more lethal human pathogen [7,11].

A subsequent population-based surveillance study from 2005 to 2007 confirmed a 20-fold increase in incidence of monkeypox infection compared with that seen in the 1980s in the Democratic Republic of Congo [15]. From 2005 to 2007, 760 laboratory-confirmed human monkeypox cases were identified [15]. The study confirmed prior concerns of increased human cases of monkeypox due to the lack of prior smallpox vaccination; persons with a history of smallpox immunization had a fivefold lower risk of monkeypox infection than unvaccinated persons. Other factors associated with an increased risk of infection included living in forested areas, male sex, and age <15 years.

Since 2017, there has been an increase in monkeypox cases in Nigeria; this occurred after almost 40 years with no reported cases [16]. Some of these cases have occurred among returning travelers. (See 'United States' below and 'Other countries' below.)

United States

●Outbreak in 2003 – Between May 15 and June 2003, an outbreak of 71 cases of human monkeypox in six states was investigated by the Centers for Disease Control and Prevention (CDC); 35 cases were laboratory confirmed [8-10]. Prior to this cluster of cases, monkeypox had not been previously found in the Western hemisphere.

The investigation demonstrated that the onset of a febrile illness, with subsequent appearance of a pustular rash, had developed in patients who had recently purchased pet prairie dogs. The prairie dogs appeared to have acquired the virus from African rodents when the two species were housed at a distribution center in Illinois.

Monkeypox infection was confirmed by DNA sequences obtained from skin lesions from 9 of 10 patients from Illinois, Indiana, and Wisconsin and in lymph node tissue of one pet prairie dog that died [8]. Most of the human cases had direct exposure to animals [17], although person-to-person transmission could not be excluded. Of the cases reported in Wisconsin, the veterinary staff who were exposed to an outbreak-associated prairie dog were at particularly high risk, with an attack rate of 23 percent [18].

During this outbreak, monkeypox appeared to have a very low rate of person-to-person transmission. In one study of 57 healthcare workers who were exposed to patients with monkeypox, none reported signs and symptoms of disease [19]. Only one had laboratory evidence of recent orthopoxvirus infection, which was probably secondary to prior smallpox vaccination. By contrast, secondary attack rates for smallpox can be as high as 70 percent [5,20].

Because of this outbreak, the transportation, sale, or release into the wild of prairie dogs and animals from Africa (including tree squirrels, rope squirrels, dormice, brush-tailed porcupines, and striped mice in addition to Gambian giant rats) was subsequently prohibited by the CDC and the United States Food and Drug Administration (FDA) [10]. There have been no other US outbreaks since the time of this prohibition.

●Subsequent cases – In July 2021, a patient was diagnosed with monkeypox in Dallas, Texas [12]. This patient developed symptoms during his return trip from Nigeria.

Other countries — Two cases of monkeypox were reported in the United Kingdom (UK) in September 2018 [21]. Both patients had recently travelled to the UK from southern Nigeria, where cases of monkeypox had recently been reported. One of these patients spread monkeypox to a health care worker [22]. Other cases related to travel from Nigeria were reported in Israel [23] and Singapore [24].

INCUBATION PERIOD — The US outbreak described above allowed estimation of time from exposure to onset of symptoms. Approximately half of the patients reported a scratch, bite, or petting of an infected animal [25]. For 29 patients, the estimated incubation time from exposure to illness was 12 days. Persons with a history of an animal bite or scratch may have a shorter incubation period than those with tactile exposures (13 versus 9 days, respectively) [13].

CLINICAL MANIFESTATIONS — Based largely on seroepidemiological studies in Africa, the majority of monkeypox infections are asymptomatic. In symptomatic individuals, monkeypox causes a systemic illness including fevers, chills, and myalgias, with a characteristic rash that is important to differentiate from that of smallpox. The clinical illness can also differ by viral strain. (See 'Differential diagnosis' below.)

Outbreaks in Africa — In Africa, the monkeypox rash starts on the trunk and then spreads peripherally to involve the palms and soles of the feet. Lesions can also involve the mucous membranes and usually range from 0.5 to 1 centimeter in size. The rash usually begins as macules and papules; the rash then progresses over a two- to four-week period to vesicles, pustules, followed by umbilication, scabbing, and desquamation. Some patients develop only a localized rash on their hands associated with direct contact with the infected animal.

United States outbreak — Although comprehensive clinical information is limited on monkeypox in Africa, the 2003 US outbreak allowed further characterization of the illness in 34 of 37 subjects for whom medical records were available [25]. The predominant signs and symptoms were:

●Rash (97 percent)

●Fever (85 percent)

●Chills (71 percent)

●Lymphadenopathy (71 percent)

●Headache (65 percent)

●Myalgias (56 percent)

The onset of fever preceded the rash by approximately two days, but the median duration of fever was shorter than the rash (8 and 12 days, respectively). The following clinical pictures of the initial case identified in the United States were taken at the Marshfield Clinic in Wisconsin (picture 2A-D). The rash in this US outbreak was described as maculopapular in nature on initial presentation; the rash subsequently evolved into vesicles, then pustules, which eventually crusted within a two- to three-week period [25].

Nine of the 34 patients were hospitalized for a variety of reasons, including nausea, vomiting, and dysphagia. The discharge diagnoses of two of the most seriously ill patients were encephalopathy and a retropharyngeal abscess. All of the patients in this case series survived with supportive therapy; no antiviral therapy was administered. Multiple nonspecific laboratory findings were also noted including abnormal aminotransferases, leukocytosis, mild thrombocytopenia, and hypoalbuminemia.

DIAGNOSIS — Although clinical features are helpful in making the diagnosis, laboratory confirmation of monkeypox virus is necessary to differentiate this disease from those caused by other potential etiologies. Diagnostic assays include virus isolation (in mammalian cell cultures), electron microscopy, real-time polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA), and immunofluorescent antibody assay [1,26]. Characteristic brick-shaped poxvirus virions are found on electron microscopy. Histopathologic analysis may demonstrate ballooning degeneration of keratinocytes, prominent spongiosis, dermal edema, and acute inflammation; however these findings can also be seen in other viral infections [27].

Using sera from patients obtained during the 2003 United States outbreak, the Centers for Disease Control and Prevention (CDC) developed an immunoglobulin M-capture and an IgG ELISA that demonstrated recent monkeypox virus infection. Serum IgM and IgG antibodies were detected five and eight days after onset of rash, respectively [28]. Other experimental antibody and cellular based assays are under development, which may be useful for the prospective and retrospective diagnosis of monkeypox [20].

If the diagnosis of monkeypox is being considered, local and state public health officials, along with the CDC, should be notified so that the samples are quickly processed. (See 'Differential diagnosis' below.)

DIFFERENTIAL DIAGNOSIS — Two other infections need to be considered in the differential diagnosis of monkeypox: varicella and smallpox.

Given the worldwide eradication of smallpox, the most likely diagnostic consideration is varicella (chickenpox). Unlike varicella where vesicular lesions are characteristically in different stages of development and healing when the patient is examined, monkeypox lesions are all generally at the same stage. (See "Clinical features of varicella-zoster virus infection: Chickenpox".)

Because of concerns regarding bioterrorism, it is also important to consider the possibility of smallpox in the differential diagnosis of a patient who has not been in the rain forests of Africa or exposed to potentially infected animals [6]. Lymphadenopathy, which has been observed in the majority of unvaccinated patients, is a key distinguishing feature of monkeypox [10]. Lymphadenopathy can occur in the submandibular, cervical, or inguinal regions. (See "Identifying and managing casualties of biological terrorism" and "Variola virus (smallpox)".)

Also in the differential diagnosis is tanapox, another African poxvirus that causes a febrile prodrome and skin lesions that resolve over several weeks without sequelae. A case of tanapox infection was diagnosed using electron microscopy and DNA analysis (polymerase chain reaction testing) of a biopsied skin lesion in an American college student who had worked in the Republic of Congo for eight weeks caring for chimpanzees; none of the others working with these animals developed the infection [29].

Orf and bovine stomatitis (also caused by parapoxviruses) can produce localized skin lesions similar to those of monkeypox, but can be differentiated by an experienced microscopist by morphologic features on electron microscopy. Parapoxvirions are slightly smaller than orthopoxvirus virions and have a more regular surface pattern than orthopoxviruses.

PATIENT MANAGEMENT

Supportive care — Most patients have mild disease and recover without medical intervention. Others who have risk factors for dehydration (eg, nausea, vomiting, dysphagia) may require a short hospital stay for intravenous hydration. For the seriously ill patient, supportive care is necessary until the patient recovers from the infection.

Cidofovir — Cidofovir has in vitro activity against monkeypox and has been shown to be effective against lethal challenge in animal models [30-32]. However, there are no clinical data regarding its efficacy against monkeypox infection in humans and its use can be associated with significant adverse events, including nephrotoxicity.

Clinical consultation for guidance regarding the management of life-threatening cases of monkeypox is available from the Centers for Disease Control and Prevention (CDC) (1-800-232-4636). CDC guidelines for management of monkeypox during an outbreak can be found at www.cdc.gov/ncidod/monkeypox/clinicians.htm. (See "Cidofovir: An overview".)

Tecovirimat — In July 2018, tecovirimat was approved for use in the United States for treatment of smallpox [33]. This drug protects nonhuman primates from lethal monkeypox virus infections [33-35] and will likely be efficacious against this infection in humans as well. Tecovirimat is a potent inhibitor of an orthopoxvirus protein required for the formation of an infectious virus particle that is essential for dissemination within an infected host. A more detailed discussion of this agent is found elsewhere. (See "Variola virus (smallpox)", section on 'Treatment'.)

Brincidofovir — In June 2021, brincidofovir was approved for use in the United States for treatment of smallpox [36]. Brincidofovir is an analog of cidofovir that can be given orally. (See "Variola virus (smallpox)", section on 'Treatment'.)

There are only limited published data with the use of brincidofovir for treatment of monkeypox in an animal model [37], but other animal models show that it is likely an effective treatment of orthopoxvirus infections [38,39].

MORTALITY — In Central Africa, the fatality rate is approximately 10 percent and deaths generally occur in the second week of illness [1,40]. In contrast, there were no deaths in the outbreak in the United States. These more favorable outcomes in the United States may be related to a healthier patient population, greater availability of supportive medical care, and a less virulent strain of monkeypox, which was imported from the West African nation of Ghana [25].

PREVENTION — Data suggest that prior immunization with smallpox vaccine prevents infection and ameliorates symptoms. The role of postexposure prophylaxis with smallpox vaccine or vaccinia immunoglobulin is unclear, as discussed below.

Smallpox immunization — Prior smallpox vaccination with vaccinia virus has a significant protective effect against acquisition of monkeypox virus and may ameliorate the clinical manifestations of this infection [5,20]. In September 2019, a modified vaccinia Ankara (MVA) vaccine (sold under the trade names Imvamune and Jynneos) was approved for prevention of smallpox and monkeypox [41]. (See "Vaccinia virus as the smallpox vaccine", section on 'Modified vaccinia Ankara vaccine'.)

In Africa, secondary attacks rates varied greatly among 2278 household contacts depending on their prior smallpox vaccination status (7.5 compared with 1.3 percent in vaccinated and unvaccinated subjects) [19]. In the study that showed an increasing incidence of human monkeypox cases in Africa [15], vaccinated people had a fivefold lower risk of monkeypox as compared with unvaccinated persons (0.78 versus 4.05 per 10,000). In that study, vaccine efficacy was estimated to be approximately 81 percent in those with a distant history of smallpox vaccination.

In the US outbreak, further investigation using experimental techniques identified three additional monkeypox exposures in individuals who had previously received smallpox vaccination 13, 29, and 48 years prior to exposure to monkeypox [20]. These individuals were unaware that they had been infected because they did not have any recognizable disease symptoms. These findings suggested that the US monkeypox outbreak was larger than previously realized. Furthermore, cross-protective antiviral immunity against West African monkeypox can potentially be maintained for decades after smallpox vaccination.

Postexposure prophylaxis

Postexposure vaccination — In addition to monitoring and isolating close contacts, postexposure vaccination with MVA vaccine may be considered for certain patients after exposure to monkeypox (eg, direct contact with patient or materials from patient’s room without personal protection equipment (PPE) [22]). This decision must be made in conjunction with public health authorities.

Since prior vaccination with vaccinia virus protects against monkeypox infection, the Centers for Disease Control and Prevention (CDC) recommended vaccination with vaccinia virus for the limited number of individuals exposed to monkeypox in the 2003 United States outbreak, including children and pregnant women. The CDC also recommended pre-exposure vaccination for those involved in the investigation of the outbreak and for healthcare workers caring for patients with monkeypox [8,10]. Twenty-eight adults and two children received the smallpox vaccine for this purpose and no cases of monkeypox were identified among these recipients [10]. Furthermore, no cases of monkeypox were identified during pregnancy during the 2003 outbreak; it is not known if the infection carries a different prognosis in pregnant women [42]. In the United Kingdom, where two cases of monkeypox were diagnosed in returning travelers [21], Public Health England developed risk assessment and public health recommendations for persons potentially exposed that are summarized in the table (table 1) [22].

Based on historical data on postexposure vaccination for smallpox with vaccinia vaccine, the optimal time for monkeypox postexposure vaccination is within four days; however, vaccination can be considered for up to 14 days of a close contact exposure, according to the CDC [43]. Close contact is defined as direct exposure within six feet of a probable or confirmed monkeypox case in an animal with respiratory symptoms such as nasal discharge, cough, or conjunctivitis in a setting where the animal has been manipulated (eg, an exam room) [43]. (See "Vaccinia virus as the smallpox vaccine" and "Immunizations during pregnancy", section on 'Smallpox'.)

Vaccinia immune globulin — The use of vaccinia immune globulin may be considered in immunosuppressed patients with an exposure history, since immunization with vaccinia virus vaccine is contraindicated [1].

Infection control precautions — Use of both contact and airborne precautions are recommended for any generalized vesicular rash of unknown etiology in which monkeypox and smallpox are included in the differential diagnosis [19].

During the first week of the rash, persons with suspected monkeypox should be considered infectious and be isolated until all scabs separate and results of throat swab polymerase chain reaction (PCR) are negative [1].

SUMMARY AND RECOMMENDATIONS

●Monkeypox is a viral zoonotic infection that results in a rash similar to smallpox. However, the person-to-person spread and the mortality from a monkeypox infection are significantly lower than for smallpox. Clinically, these two viral infections are difficult to distinguish, raising concerns that monkeypox could be used for bioterrorism. (See 'Introduction' above.)

●Monkeypox, an orthopoxvirus, was first isolated in the late 1950s from a colony of sick monkeys. The virus is in the same genus as variola (causative agent of smallpox) and vaccinia viruses (the virus used in smallpox vaccine). (See 'Virology' above.)

●The virus is acquired through contact with the infected animal's bodily fluids or through a bite. Monkeys and humans are incidental hosts; the reservoir remains unknown but is likely to be rodents. (See 'Transmission' above.)

●Since discontinuation of smallpox immunization, most cases have occurred in Central and West Africa. However, sporadic cases in returning travelers have been reported in several countries, and in the United States, an outbreak due to infected prairie dogs exposed to imported animals from Africa occurred in 2003. (See 'Geographic distribution' above.)

●The incubation period from exposure to clinical illness is less than two weeks. (See 'Incubation period' above.)

●Predominant symptoms of monkeypox include fever, rash, lymphadenopathy, myalgias, and chills. Most patients with monkeypox have a mild illness; those with nausea, vomiting, or dysphagia may need hospitalization for intravenous hydration. (See 'Clinical manifestations' above.)

●Although clinical features are helpful in making the diagnosis, laboratory confirmation of monkeypox virus is necessary to differentiate this disease from those caused by other potential etiologies. Diagnostic assays include virus isolation (in mammalian cell cultures), electron microscopy, real-time polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA), and immunofluorescent antibody assay. If the diagnosis of monkeypox is being considered, local and state public health officials, along with the Centers for Disease Control and Prevention (CDC), should be notified. (See 'Diagnosis' above.)

●Varicella and smallpox should be included in the differential diagnosis of monkeypox. (See 'Differential diagnosis' above.)

●Most patients have mild disease and recover without medical intervention. For the seriously ill patient, supportive care is necessary until the patient recovers from the infection. The antiviral agent, tecovirimat, which was approved for treatment of smallpox in the United States, also has activity against monkeypox in animal models and is likely to be efficacious against this infection in humans as well. (See 'Patient management' above.)

●Both contact and airborne precautions should be initiated in any hospitalized patients with generalized vesicular rash of unknown etiology in which monkeypox and smallpox are included in the differential diagnosis. Close contacts should be isolated and monitored. Postexposure smallpox vaccination should be considered in consultation with public health authorities. (See 'Prevention' above.)