Version July 2025
INTRODUCTION —
Prior to 2022, mpox (previously referred to as monkeypox) was a viral zoonotic infection that is caused by monkeypox virus (MPXV) and results in a rash similar to that of smallpox. However, historically, person-to-person spread outside the household and mortality from mpox are significantly less than for smallpox. The rash of mpox can also be similar in appearance to more common infectious rashes, such as those observed in secondary syphilis, herpes simplex infection, and varicella-zoster virus infection.
This topic will review the virology, epidemiology, clinical manifestations, and diagnosis of mpox. Topic reviews that discuss the treatment and prevention of mpox are presented separately. (See "Treatment and prevention of mpox (formerly monkeypox)" and "Vaccines to prevent smallpox, mpox (monkeypox), and other orthopoxviruses".)
TERMINOLOGY —
In November 2022, the World Health Organization, who is responsible for naming and renaming of diseases under the International Classification of Diseases (ICD), changed the name of the disease referred to as “monkeypox” to “mpox” [1]. This change was made to follow current best practices of not naming diseases after animals or geographic locations and to reduce any stigma that could be associated with the original name.
The virus that causes mpox will continue to be referred to as monkeypox virus (MPXV) until the International Committee on the Taxonomy of Viruses (ICTV) officially decides what the name of the virus should be. However, the former Congo Basin (Central African) clade was renamed as Clade one (1) and the former West African clade was renamed as Clade two (2). Clade 1 and clade 2 each consists of two subclades. (See 'Virology' below.)
VIROLOGY —
Monkeypox virus (MPXV) is an orthopoxvirus that is in the same genus as variola (the causative agent of smallpox) and vaccinia viruses (the virus used in the smallpox vaccine). Electron microscopy of cells infected with MPXV shows a brick-like virion, indistinguishable from the virions of variola or vaccinia viruses (picture 1).
Two distinct strains of MPXV have existed in different geographic regions of Africa, as suggested by epidemiologic, animal, and molecular evidence [2]. Clade 1 has been responsible for disease in the Congo basin whereas clade 2 has been isolated in West Africa [3]. The strain isolated from West Africa is less virulent and lacks several genes present in the strain from Central Africa [2,4]. More recently, each clade was found to have subclades (clades 1a and 1b, and clades 2a and 2b). The clade 1b virus may be less virulent than the clade 1a virus.
The existence of the two clade 2 subtypes was recognized during the 2022 global outbreak [3,5]. Early analyses of viruses from this multi-country outbreak revealed that the vast majority of outbreak virus was clade 2b, which were similar to sequences of strains circulating in Nigeria from the 2018 to 2019 outbreak. Initial sequence data from 15 isolates indicated that there were more mutations than expected in the DNA genome during the 2022 outbreak, raising the possibility that the circulating virus was undergoing accelerated human adaptation [5], and additional studies have confirmed this finding [6].
The existence of subclades of clade 1 was detected during the outbreak in the Democratic Republic of the Congo (DRC) that started in 2023. Genetic sequencing data suggest that multiple clade 1a monkeypox virus strains are co-circulating in the human population, and genetic diversity suggests multiple independent zoonotic introductions into human populations [7,8]. A distinct subtype, Clade 1b, was found with genomic analysis of MPXV strains isolated from the Kamituga Health Zone in DRC [9]. More detailed information about the outbreak in the DRC is found below. (See 'Africa' below.)
The vaccines and antiviral therapies used to prevent and treat mpox should be effective against both strains [10]. This is based on the antigenic similarities and therapeutic targets shared by all viruses in the orthopoxvirus genus. (See "Treatment and prevention of mpox (formerly monkeypox)".)
EPIDEMIOLOGY —
Monkeypox virus (MPXV) was first isolated in Denmark in the late 1950s from a colony of laboratory monkeys from Singapore that were going to be used for polio virus research [11]. During the following decade, additional outbreaks of mpox were seen in laboratory animals in the United States as well as zoo animals in Rotterdam [12]. MPXV was first identified as a cause of disease in humans in the 1970s in what is now the Democratic Republic of the Congo (DRC).
Geographic distribution — Since the discontinuation of smallpox immunization, which also protects against mpox, cases of mpox have generally occurred in Central and West Africa. The first outbreak of mpox in the Western hemisphere occurred in the United States in 2003 [13-15]. After that, sporadic cases were reported in several previously nonendemic countries, mostly related to travel from Africa. However, in May 2022 a global multi-country outbreak was recognized; this outbreak was associated with person-to-person transmission and involved thousands of individuals in dozens of countries [16,17]. The geographic distribution of mpox outbreaks will be discussed here. Transmission of MPXV is discussed below. (See 'Transmission' below.)
Africa
Outbreak in Central and East Africa starting in 2023 — On August 14, 2024, the World Health Organization (WHO) declared for a second time that mpox was a global public health emergency [18]. From January 1, 2024 to August 18, 2024, a total of 21,786 laboratory-confirmed mpox cases leading to 607 deaths were reported from 12 African countries, with approximately 90 percent of the cases occurring in the DRC [19]. Travel-associated cases outside of Africa have also been linked to this outbreak [20]. (See 'Cases related to travel from endemic countries' below.)
This outbreak started in the DRC in early 2023 and then spread to neighboring countries including the Republic of the Congo and the Central African Republic [21]. Although clade 1 mpox is endemic in these countries, the epidemiologic pattern suggested a link to the DRC. In July 2024, cases linked to the DRC were also reported in the previously nonendemic countries of Burundi, Rwanda, and Uganda.
The ongoing outbreak in Central and East Africa is complex because there appear to be two types of outbreaks happening [22,23]:
●One is an outbreak from clade 1a virus that mostly involves children and is likely from multiple zoonotic introductions. This outbreak has occurred primarily in previously endemic rural areas of the northwestern provinces of the DRC through zoonotic spillover, and person-to-person transmission has occurred through household contact and within the health care setting.
●A second outbreak in previously unaffected and more populated regions of eastern DRC has also been noted. This outbreak mostly involves adults. In a report of 108 polymerase chain reaction (PCR)-confirmed mpox cases in a densely populated mining area, the median age of patients was 22 years, 52 percent were female, and 29 percent were sex workers, suggesting a role for sexual transmission [9]. This outbreak is due to a novel clade 1 lineage, clade 1b, which is linked to sustained human-to-human transmission. (See 'Virology' above.)
Other outbreaks — MPXV was first identified as a cause of disease in humans in the 1970s in the DRC (formerly the Republic of Zaire) [24-28]. Following its recognition as a human pathogen, 59 cases of human mpox were reported between 1970 and 1980 in West Africa and Central Africa, with a mortality rate of 17 percent in children under 10 years of age [29,30]. All of these cases occurred in the rain forests of West and Central Africa among individuals exposed to small forest animals (eg, rodents, squirrels, and monkeys).
After the eradication of naturally occurring smallpox in 1977 and the discontinuation of routine smallpox immunization (ie, vaccinia virus vaccine) in 1980 [31], the World Health Organization (WHO) monitored subsequent human mpox cases [32]. The WHO was concerned that discontinuation of the vaccinia virus vaccine, which also protects against mpox, would lead to increased susceptibility of the population and the possibility of an increased incidence of mpox.
A population-based surveillance study from 2005 to 2007 reported a 20-fold increase in incidence of mpox compared with that seen in the 1980s in the DRC [33]. From 2005 to 2007, 760 laboratory-confirmed human mpox cases were identified. This study supported concerns of increased human cases of mpox due to the lack of prior smallpox vaccination as persons with a history of smallpox immunization had a fivefold lower risk of mpox compared with unvaccinated persons. Other factors associated with an increased risk of infection included living in forested areas, male sex, and age <15 years. Between Jan 1, 2010, and Dec 31, 2023, a total of 60,967 suspected cases and 1798 suspected deaths from mpox were reported in the DRC, with an increase in the annual incidence from approximately 3 per 100 000 in 2010 to 11 per 100 000 in 2023 [34].
Since 2017, there has been an increase in mpox cases in Nigeria; this occurred after almost 40 years with no reported cases [35,36]. Some cases from this outbreak in Nigeria have occurred in travelers returning to nonendemic countries. (See 'Cases related to travel from endemic countries' below.)
In 2022, the WHO reported that mpox was endemic in several African countries including Benin, Cameroon, the Central African Republic, the DRC, Gabon, Ghana (identified in animals only), Ivory Coast, Liberia, Nigeria, the Republic of the Congo, Sierra Leone, and South Sudan. From January to May 2022, most suspected cases of mpox occurred in the DRC, with 1284 cases and 58 deaths reported [16,37].
Global multi-country outbreak — A global multi-country outbreak of mpox was first recognized in Europe in May 2022 [38]. Cases related to this outbreak were reported in previously nonendemic countries worldwide, providing evidence of community spread. On July 23, 2022, the WHO declared this outbreak of mpox a public health emergency of international concern [39]. The public health emergency was declared over on May 11, 2023, but mpox cases have continued to occur since the emergency ended [17].
The first cases of mpox in this outbreak were identified in the United Kingdom in mid-May 2022. These were not associated with recent travel to an endemic area or close contact with a person known to have mpox. Although mpox was identified in the UK in a person with recent travel to Nigeria on May 7, 2022, the cases did not appear to be related [40].
Nontravel-related cases of mpox were subsequently reported in other parts of Europe [41]. As an example, in Portugal, five confirmed cases and more than 20 suspected cases of mpox were reported in May 2022. All were in young men in Lisbon and the Tagus Valley. Spain also reported several suspected cases around this time [42].
In the United States, the first mpox case was also reported in May 2022 [43,44]. Genome sequencing results from virus recovered from this patient displayed similarities to other published genomes in this outbreak from Europe and are related to the mpox outbreak in Nigeria that occurred from 2017 to 2018. (See 'Africa' above and 'Virology' above.)
Thousands of confirmed mpox/orthopoxvirus cases in dozens of countries were subsequently reported. At the outbreak peak in the second week of August 2022, there were 1000 cases per day worldwide. By contrast, in 2024, 646 new laboratory-confirmed cases of mpox were reported during the entire month of May [45]. An updated list of case counts and countries can be found on the Centers for Disease Control and Prevention (CDC) website, the European Centers for Disease Control website, and the WHO website.
Additional details of this outbreak include:
●Burden of disease – During the multi-country outbreak that started in 2022, most cases have been identified in men who have sex with men (MSM), leading to the hypothesis that there may be spread as a result of close contact during sexual activity. In a report of 528 cases of confirmed human mpox infection from 16 countries between April and June of 2022, 98 percent of the persons were MSM [46]. Although the number of mpox cases have decreased since 2023, most cases continue to be reported in MSM [47].
Mpox has been reported in small numbers of other patient groups as well. In the United States, 769 cisgender women aged ≥15 years were identified, representing 2.7 percent of all reported mpox cases; the majority reported sexual activity or close intimate contact as the likely route of exposure [48]. One report of 74 cisgender women and 62 transgender women found that transgender women were exposed to mpox by sexual contact to a greater extent than cisgender women, and the infection coexisted more frequently with HIV infection [49]. Other modes of transmission in women have included exposure linked to a tattoo studio [50] and occupational exposures. More detailed discussions on specific types of exposures are found below. (See 'Risk of transmission in different settings' below.)
Household transmission to young children has also been reported [51,52]. However, the incidence of such transmissions is rare. In the United States, children under age 15 represent only 0.21 percent of cases [53].
●Association with sexual activity – In the multi-country outbreak that started in 2022, most patients diagnosed with mpox reported high-risk sexual behavior (eg, sex with multiple partners) as a potential risk factor. Many early cases occurred in people who had attended an international pride event held on the Spanish island of Gran Canaria that was linked to transmission chains in several European countries [42,54-56].
However, by the end of May 2022, locally acquired infections and community transmission became predominant in all affected countries [54]. Some of the patients diagnosed with mpox have reported having multiple or anonymous sexual partners in the previous two weeks, attending 'sex-on-premises' venues (eg, gay bathhouses, backrooms, clubs) or 'group sex' sessions, and using recreational drugs during sex. About 40 percent of patients infected with MPXV are people taking pre-exposure prophylaxis to prevent acquiring HIV [46,57]. (See "HIV pre-exposure prophylaxis".)
Although most of the initial cases during this outbreak were associated with close contact in the context of sexual activity, anyone who has direct skin-to-skin contact or live in a home with someone who has mpox is at risk, and there have been cases of mpox in household contacts. (See 'Human-to-human transmission' below.)
Concomitant sexually transmitted infections were reported in a range of 17 to 32 percent of individuals tested in the published cohorts of the 2022 outbreak with gonorrhea, chlamydia, and syphilis being the most common infections [46,58,59].
●Association with HIV – In the published cohorts of the outbreak that began in 2022, the percentage of people living with human immunodeficiency virus (HIV) is high, ranging from 36 to 42 percent among cases diagnosed with mpox infection [46,58,59]. It is not yet known whether HIV infection affects a person's risk for acquiring mpox; however, the risk of progressing to severe disease is higher in those with CD4 counts below 200 cells/microL [60,61]. (See 'Other complications' below and 'Prognosis and risk for severe disease' below.)
●Role of prior smallpox vaccination – Previous smallpox vaccination provides some protection against severe disease, but it does not provide lifelong protection from getting infected and infecting someone else. During the outbreak that began in 2022, several people who were infected with MPXV had previously been vaccinated against smallpox decades earlier [55,56,58]. In a report of 181 cases of confirmed mpox in Spain, 32 (18 percent) had a history of smallpox vaccination in their childhood [58].
2003 United States outbreak — Between May 15 and June 2003, an outbreak of 71 cases (confirmed and probable) of human mpox in six states (Illinois, Indiana, Kansas, Missouri, Ohio, and Wisconsin) was investigated by the CDC; 35 cases were laboratory confirmed [13-15]. Prior to this cluster of cases, mpox 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 or had contact with pet prairie dogs. The prairie dogs appeared to have acquired the virus from African rodents from Ghana when the two species were housed at a distribution center in Illinois.
Mpox 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 [13]. Direct exposure to animals (including exposure to ill prairie dogs' urine and feces) without personal protection equipment (PPE) was felt to be the likely source of transmission [62], although person-to-person transmission could not be entirely 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 (range 7 to 67 percent) [63].
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 US Food and Drug Administration (FDA) [15]. There have been no other United States outbreaks related to imported animals since the time of this prohibition.
Cases related to travel from endemic countries — Prior to the 2022 global outbreak, several sporadic cases of mpox have been reported after travel to endemic areas [64-68]. In one study evaluating the 2017 outbreak in Nigeria, a small pool of related isolates was the likely source for the exported infections [69].
Between 2018 and 2021, seven cases of mpox were diagnosed in the United Kingdom; four cases were related to travel from endemic countries, two cases resulted from household transmission from one of the index cases, and one case occurred in a health care worker who acquired infection nosocomially [70,71].
In July 2021, a patient was diagnosed with mpox in Dallas, Texas [72,73]. This patient developed symptoms during his return trip from Nigeria. In November 2021, another travel-related case was reported in a United States resident in Maryland who had recently returned from Nigeria [68]. No additional cases were linked to these two patients.
Several cases of travel-related mpox due to clade 1 virus have been associated with the outbreak in Central and Eastern Africa that started in 2023. Cases have been identified in Canada, Germany, India, Kenya, Sweden, Thailand, the United Kingdom, Zambia, and Zimbabwe. In the United States, the first case of mpox due to clade 1 virus was diagnosed in November 2024 [20]. Updated statistics can be found on the CDC website. More detailed information on this outbreak is found above. (See 'Africa' above.)
Transmission — Animal-to-human and human-to-human transmission can occur.
Animal-to-human transmission — MPXV can be acquired through contact with an infected animal's bodily fluids or through a bite. It can also be acquired through preparation of bushmeat (raw or minimally processed meat that comes from wild animals in certain regions of the world, including Africa).
In Africa, evidence of MPXV infection has been found in many types of animals, including rope squirrels, tree squirrels, Gambian pouched rats, dormice, and different species of monkeys [74]. Monkeys and humans are incidental hosts; the reservoir remains unknown but is likely to be rodents [32].
Findings from the 2003 United States prairie dog outbreak highlighted the importance of type of exposure and risk of infection (eg, bite wound versus touching an infected animal) as well as severity of clinical manifestations of mpox, presumably related to level of exposure. As an 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) [75]. Patients with complex exposures were more likely than patients with noninvasive exposures to develop signs of systemic illness. (See 'Global multi-country outbreak' above.)
Human-to-human transmission
Routes of person-to-person transmission — Human-to-human transmission of MPXV can occur in several ways:
●Direct contact – Spread of MPXV is thought to occur primarily through direct contact with infectious sores, scabs, or body fluids [76]. As such, mpox can spread during activities that include close, personal contact with an infected individual. Transmission may be facilitated by touching infectious material and then the facial mucous membranes or any breach in the skin of the recipient. (See 'Pathophysiology' below.)
During the multi-country outbreak of mpox that started in 2022, close contact with infectious material from skin or lesions on mucous membranes (eg, occurring during sexual and/or close intimate contact) is considered the main risk factor for acquisition [16,49,77-79].
In most cases, transmission occurs from persons who are already symptomatic; however, some people can spread MPXV to others from one to four days before symptoms onset [80,81]. Data from the Netherlands reported five cases where transmission occurred before the person who transmitted the infection developed symptoms [82].
The risk of transmission after specific types of nonsexual exposures is discussed separately. (See "Treatment and prevention of mpox (formerly monkeypox)", section on 'Exposure definition and risk stratification'.)
●Indirect contact through fomites – Transmission can occur through contact with materials or fomites that have become contaminated with infected material in the household or patient care environment, such as clothing or linens contaminated with infectious material from body fluids or sores [76,83,84]. In one report that investigated respiratory isolation rooms, viral DNA was found in rooms, bathrooms, anterooms, and on nontouch surfaces (eg, >1.5 meters from the bed) as well as on health care workers' PPE [85].
It is unclear whether contact through fomites is a common source of transmission however, the widespread surface contamination of the patient care environment calls for a systematic approach to the use of infection prevention precautions in the home and healthcare settings, which is discussed elsewhere. (See "Treatment and prevention of mpox (formerly monkeypox)", section on 'Infection prevention and control in health care and community settings'.)
●Respiratory secretions – It is unclear to what degree mpox is spread through respiratory secretions [72]. Most of the mpox transmission studies in humans before 2022 were conducted in African households, and while droplet transmission was thought to have played a role, household settings involve various modes of acquisition such as caregiving and bed-sharing [86,87]. In addition, in a health care setting investigation in 2022 in the United States, none of the 313 health care personnel exposed to patients with mpox became infected [88]. This included seven individuals reportedly exposed during aerosol-generating procedures, four of whom did not wear an N95 respirator.
However, activities resulting in resuspension of dried material from lesions (eg, shaking contaminated linens) may present a risk and should be avoided. During the multi-country outbreak, a study evaluating 181 mpox cases found that samples from skin lesions contain much more viral DNA than do those from the throat [58].
●Vertical transmission – The virus can cross the placenta from the mother to her fetus, which can lead to congenital mpox, although the rate of transmission or risk by trimester is not known [74]. In a report of four pregnant women with mpox from the DRC, one gave birth to a healthy infant, two had miscarriages in the first trimester, and one had fetal death with the stillborn showing diffuse cutaneous maculopapular skin lesions consistent with vertical transmission [89]. During the multi-country outbreak, one case of perinatal transmission was reported [90], but pregnancy has not always resulted in transmission to the baby [91].
●Percutaneous inoculation – There have been case reports of transmission via needlestick injuries from supplies used to collect cutaneous lesion samples [92,93]. The mpox lesions appeared at the site of the needlestick. Transmission has also been associated with piercing or tattooing; in some of these cases patients presented with a systemic cutaneous rash [94].
●Risk of spread through other body fluids – At this time, it is not known if mpox can spread through semen, vaginal fluids, or other body fluids, although viral DNA has been detected in semen [46,55,95]. In a report of 12 cases from Spain during the multi-country outbreak, there were high rates of PCR positivity in specimens collected from saliva (12 of 12), semen (7 of 9), urine (9 of 12), and feces (8 of 12) [96]. In a multi-country study, 29 of 32 semen samples had detectable MPXV DNA [46]. In at least one case, MPXV isolated from a semen sample was replication competent in cell culture, but it is still unknown if semen can transmit an infection [97]. Thus, testing of semen should not be used to guide precautions after recovery or assessing the risk of onward transmission given lack of data. (See "Treatment and prevention of mpox (formerly monkeypox)", section on 'When to discontinue isolation'.)
Risk of transmission in different settings — The risk of transmission may vary depending upon the setting.
●In the community – In the outbreak that started in 2022, the vast majority of cases have been associated with community transmission due to direct intimate contact. (See 'Routes of person-to-person transmission' above.)
One study found that the reproductive number of the virus ranged from 1.40 to 1.80, which implies a potential for sustainable local transmission [98]. Prior to this outbreak, transmission outside of a household and sustained human-to-human spread had been rare. (See 'Cases related to travel from endemic countries' above.)
●In the household – Transmissibility from person to person within the household can vary. In one report from the DRC, the secondary attack rate in households has been reported to be as high as 9 percent [86]. By contrast, a very limited number of transmission chains have been linked to households during the multi-country outbreak that began in 2022. As an example, in a study of 528 mpox cases from multiple countries, 0.8 percent were likely due to nonsexual close contact, and 0.6 percent were due to household contact [46]. Similarly, in another study of 181 cases from Spain, 3 percent of infections resulted from household contact [58].
●In congregate living situations – There are limited data on the risk of MPXV transmission in congregate living situations. In March 2022, an outbreak of mpox was described among 28 persons in a prison in Nigeria [99]. By contrast, in a report from the United States, no known cases developed in 57 jail residents who had a potential intermediate-risk exposure to a resident with mpox, even though MPXV DNA was detected on at least one surface in the living quarters [100]. However, in this report there was loss of follow-up in about a third of the residents and receipt of post-exposure vaccination among almost a third of those who were followed. (See "Treatment and prevention of mpox (formerly monkeypox)", section on 'Indications for post-exposure vaccination'.)
●In health care facilities – The risk of MPXV transmission in well-resourced health care settings is low [70,88]. During the 2003 outbreak in the United States, there were no instances of nosocomial transmission in health care facilities. In a study of 57 health care personnel who were exposed to patients with mpox, none reported signs and symptoms of disease [101].
In a report that evaluated nosocomial transmission of MPXV outside endemic regions during the 22 years prior to the global outbreak reported in May 2022, only one transmission event was reported [70]. Since 2022, several cases have been reported in HCP, including exposure after needlestick injury from supplies used to collect samples from cutaneous lesion samples [92,93]. (See 'Routes of person-to-person transmission' above.)
A detailed discussion of infection prevention measures for persons with mpox in healthcare settings is presented separately. (See "Treatment and prevention of mpox (formerly monkeypox)", section on 'Infection prevention and control in health care and community settings'.)
Viral shedding, period of infectiousness, and secondary attack rate — Historically, a person is considered infectious from the onset of clinical manifestations until all skin lesions have scabbed over and re-epithelialization has occurred. (See "Treatment and prevention of mpox (formerly monkeypox)", section on 'Infection prevention and control in health care and community settings'.)
Variations in viral shedding, the period of infectiousness, and the secondary attack rate are likely to be influenced by the clade and the mode of transmission. Viral shedding and the period of infectiousness determine isolation duration and contact definitions, while the secondary attack rate identifies high-risk groups for targeted interventions and guides contact tracing and quarantine policies.
During the multi-country outbreak that began in 2022, several studies evaluated viral shedding, and estimated viral loads appear higher in skin lesions than at other sites [58,96,102]. As an example, in a prospective study of 181 patients with mpox, higher viral DNA loads were found on skin than on pharyngeal swabs [58]. In another report, higher viral DNA loads were consistently found in skin lesions and anogenital samples compared with throat, blood, urine or semen samples [102]. The infectiousness of individuals who have no symptoms is uncertain, as discussed below. (See 'Rare asymptomatic infection' below.)
The duration of viral shedding can vary [71,102,103]. In an analysis of 1663 samples taken from 77 patients during the outbreak that began in 2022, the median time from symptom onset to viral clearance was 25 days in the skin lesions, 16 days in the oropharynx, 16 days in the rectum, 13 days in semen, and 1 day in blood; the time from symptom onset to viral clearance was approximately 40 days for 90 percent of cases [103]. In a different report, which followed seven patients who were hospitalized with moderate-to-severe mpox in the United Kingdom between 2018 and 2021, PCR positivity in blood and upper respiratory tract samples was detected for at least three weeks in three of the patients [71]. The correlation of PCR positivity and infectivity was not established in these studies, and pending additional data, the duration of isolation should continue to be based on clinical evaluation. (See "Treatment and prevention of mpox (formerly monkeypox)", section on 'When to discontinue isolation'.)
During the multi-country outbreak, challenges in tracing contacts prevented accurate determination of the secondary attack rate, particularly among sexual partners. Limited data from endemic areas of central and west Africa during both clade 1 and clade 2 outbreaks have reported secondary attack rates as high as 9 percent in household contacts [86].
PATHOGENESIS
Pathophysiology — Infections caused by orthopoxviruses can be classified as either systemic or localized (at the site of virus entry). The type of infection depends on the species of orthopoxvirus and the route of entry. Generalized disease usually manifests as a diffuse rash. In contrast, after cutaneous inoculation, a localized rash may appear at the site of virus entry, followed or not by disseminated lesions due to a viremia [104,105].
●Infection via cutaneous inoculation – Monkeypox virus (MPXV) can enter the human host through microabrasions in the skin (figure 1) [106]. The pathogenesis of human mpox following skin inoculation is felt to be similar to that of smallpox and other orthopoxviruses. Several orthopoxviruses can cause infection in animals after being introduced through the skin as well; this includes MPXV and variola virus in nonhuman primates and ectromelia virus (ECTV) in mice [107].
Using a MPXV animal model, after subcutaneous inoculation of a West African strain, viral replication was observed only in the skin and lymphatic system, while intranasal inoculation resulted in diffuse viral replication throughout the body tissues, including the lungs [106]. Human data are limited to those obtained from accidental or intentional skin inoculations of the vaccinia virus or variola virus (ie, variolation), which was observed to result in locally restricted lesions around the point of entry [107].
●Infection via respiratory route – MPXVes can enter through the respiratory system in experimental models [106,108,109]. These types of animal models were a way to study pathogenesis and effectiveness of new drugs and vaccines, but it is unclear how closely these experimental models correspond to MPXV transmission and pathogenesis in humans. (See 'Human-to-human transmission' above.)
Using a nonhuman primate model of respiratory MPXV with histopathological examinations at several time points postchallenge, it was demonstrated that during the incubation period, the virus is first seen in respiratory bronchioles and alveoli in the lungs (postchallenge day 4) [109]. The virus then spreads to the regional lymph nodes and organs of the reticuloendothelial system (day 6), including the tonsils, spleen, liver, and colon, where it replicates. Virus was ultimately detected in the blood on day 8, and its concentration increased through day 10 along with widespread lesions in the skin.
Immunology — Mpox infection stimulates an adaptative immune response comprising activated effector CD4+ and CD8+ T-cells [110]; neutralizing antibodies (IgM and IgG); and the production of Th1-inflammatory cytokines (gamma interferon [IFN-γ], IL-1ra, IL-6, IL-8, and TNF) [111]. These immune responses restrict viral replication and induce prolonged immunity in recovering patients. However, it is unknown whether the pauci-symptomatic or localized presentation seen in the multi-country outbreak compared to the disseminated presentation of mpox disease is associated with a lower degree of the immune response following infection.
Histopathology — Mpox skin lesions in the vesicular stage consist of epidermal acanthosis and spongiosis with exocytosis of lymphocytes and neutrophils. In the center of the lesion, a vesicle affecting the entire epidermis is formed by ballooning degeneration of keratinocytes and accumulation of intercellular fluid [112]. A mixed inflammatory infiltrate is present at the dermal-epidermal junction at the base of the vesicle composed of lymphocytes, eosinophils, and neutrophils.
The lesion develops into a pustule containing apoptotic keratinocyte debris, a few viable keratinocytes, and inflammatory cells. Viable keratinocytes may be multinucleated or exhibit cytopathic damage, such as eosinophilic inclusion bodies, prominent nucleoli, and "ground glass" chromatin. A mixed inflammatory infiltrate is also present in the perivascular, perieccrine, and dermal regions. Finally, the pustule becomes desiccated and forms a crust.
Immunohistochemistry shows no virus in the nonaffected epidermis, but the virus is present in the cytoplasm all keratinocytes within the affected epidermis. The lymphocytic infiltrate is predominantly T-cell with CD4- and CD-8-positive elements [113].
The histologic features of mpox are very similar to those described in the literature for smallpox, vaccinia, and cowpox. Herpesviridae, including herpes simplex virus (HSV) and varicella, have been historically differentiated by the appearance of the viral cytopathic effect and further differentiated by immunohistochemistry.
CLINICAL MANIFESTATIONS
Findings common in all outbreaks — Mpox has traditionally caused a systemic illness that includes fevers, chills, and myalgias, with a characteristic rash that is important to differentiate from that of other vesicular eruptions (eg, varicella, smallpox). However, during the 2022 to 2023 multi-country outbreak, some patients presented with genital, anal, and/or oral lesions without the systemic illness [43].
Incubation period — The incubation period of mpox is usually from 5 to 13 days but can range from 4 to 21 days [43]. The 2003 United States outbreak described above allowed estimation of time from exposure to onset of symptoms [114]. 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 only tactile exposures (9 versus 13 days, respectively) [75].
During the outbreak that began in 2022, the incubation period generally ranged from 7 to 10 days following exposure [58,115-117]. In an initial study of 18 cases in the Netherlands, the mean incubation period was found to be 8.5 days (5th to 95th percentiles: 4.2 to 17.3) [115]. Later in the outbreak, an analysis of 144 patients in Spain reported an incubation period of seven days (range 5 to 10) [58].
Systemic illness — Systemic symptoms are common and may occur before the rash appears (prodromal stage) or shortly thereafter (early clinical stage). These symptoms are attributable to a viremic phase of illness. (See 'Pathophysiology' above.)
Systemic symptoms typically last one to five days and are characterized by fever, headache, sore throat, back pain, myalgia, and fatigue.
●In endemic regions, these symptoms are common with fever in 85 to 90 percent of cases, myalgias in 65 to 85 percent, headache in 80 percent, and lymphadenopathy in 70 to 100 percent [35,114,118]. (See 'Clinical features in endemic countries in Africa and imported infections' below.)
●During the global outbreak that started in 2022, systemic symptoms have been less frequent, with fever in 50 to 70 percent of cases, myalgias in 25 to 80 percent, and headache in 25 to 50 percent [46,58,119]. Some patients presented with lesions without the systemic illness [43]. In addition, generalized swelling of the lymph nodes has not been commonly seen during the prodromal or early clinical stages, although regional lymphadenopathy is often associated with skin rash. (See 'Clinical features specific to the multi-country outbreak in 2022' below.)
Rash — The skin eruption usually occurs between one to two days before and three to four days after the onset of the systemic symptoms and continues for two to three weeks, although rashes without systemic illness have been reported [43].
The rash associated with mpox progresses through several stages:
●The rash typically begins as 2 to 5 mm diameter macules.
●The lesions subsequently evolve to papules, vesicles, and then pseudo-pustules (papules that simulate pustules but are predominantly filled with cell debris and do not contain fluid or pus) [119]. Lesions are well circumscribed, deep seated, and often develop umbilication (a central depression on the top of the lesion). Additional images can be found on the CDC website.
●The lesions eventually crust over, and these crusts dry up and then fall off. This typically occurs 7 to 14 days after the rash begins.
The lesions typically begin to develop simultaneously and evolve together on any given part of the body [120]. However, during the global outbreak of mpox beginning in May 2022, not all lesions were in the same stage of development [121].
The rash associated with mpox is often described as painful, but in the healing phase (crusts), it can become itchy [120].
The number of lesions varies from a few to more than one thousand. During the multi-country outbreak, there are most commonly 1 to 20 lesions on the skin, and cases with more than 100 lesions have been extremely rare [59]. In endemic regions, patients commonly present with more than 10 lesions and more than a third with 100 to 1000 lesions.
The location of the rash has varied in the different outbreaks. As an example, in the early outbreaks with clades 1a and 2a, lesions were widely distributed across the body. By contrast, for clade 2b, the rash is mainly seen in the anogenital area (see 'Location of rash' below). Patients with clade 1b show a mixed presentation with both localized (primarily genital) and generalized rashes [23,122]. (See 'Clinical features specific to the multi-country outbreak in 2022' below and 'Clinical features in endemic countries in Africa and imported infections' below.)
Clinical features specific to the multi-country outbreak in 2022
Location of rash — Patients who have developed mpox during the global outbreak of mpox that started in 2022 frequently present with lesions concentrated in the anogenital, oral, and perioral areas. There are data to suggest that location of the lesions is consistent with the site of inoculation [49,58].
●Genital lesions may present in the form of one or two solitary penile lesions (picture 2) or multiple lesions that affect the penis, scrotum, and pubis. Females may present with vulvar lesions [48,49].
Genital lesions are commonly accompanied by surrounding edema (picture 3), which in some instances may progress to severe swelling of the penile glans or foreskin so that the retracted foreskin cannot be returned to its normal position (ie, paraphimosis). Large ulcers or necrotic crusts have also been reported as complications.
●Lesions in the perianal region may present in the form of lesions in the buttocks and/or lesions involving the anal margin and perianal skin (picture 4). The latter are often associated with rectal pain or pain on defecation.
●Perioral lesions can occur. These can present as circular white lesions with a depression in the center or ulcerated lesions of the oral mucosa or lips. Lesions of the tongue have also been reported (picture 5) [123].
In some cases, a small number of lesions developed in the trunk, face, or acral areas of the body [42,58,59]. In other cases, the lesions did not involve the face or extremities at all. The lesions in distant regions can sometimes be in different stages of progression than the rash at the site of inoculation. Some cases can present with solitary primary lesions in the face or fingers in the absence of lesions in the genital and oral mucosa.
Sometimes coalescing lesions result in large plaques, ulcerations, or crusts which are most commonly seen in immunocompromised individuals [61]. Some severe complications seen during the 2022 outbreak include the evolution of genital, perianal, or facial lesions into a coalescing large plaque, ulceration, or crust and superimposed cellulitis requiring antibiotic treatment (range of 3 to 4 percent of mpox cases in the largest series published) [46,58,59,119]. In some cases, surgical debridement of an affected extremity was required [60].
Proctitis/tonsillitis — During the outbreak that started in 2022, patients with mpox have presented with proctitis or tonsillitis.
●Proctitis – Some patients have presented with clinical manifestations of proctitis (eg, anorectal pain, tenesmus, and purulent discharge or bleeding), which may or may not be associated with visible vesicular or pustular lesions on the perianal area; in some instances, hospitalization has been required for management of pain [46,58,59,119]. Patients with proctitis usually have a history of engaging in anal-receptive sex and have more often early systemic symptoms before developing skin lesions [59].
In patients with proctitis, proctoscopy may show evidence of mucosal inflammation or friability, though with visual inspection alone it is difficult to distinguish mpox from other infections (eg, lymphogranuloma venereum, herpes simplex virus [HSV], or syphilis) (see 'Differential diagnosis' below). However, we do not routinely perform proctoscopy in patients with suspected mpox proctitis since proctitis is often associated with severe pain. If rectal wall perforation is suspected (severe pain or sepsis), a rectal magnetic resonance imaging (MRI) should be performed as part of the evaluation.
●Ulcerative pharyngitis or tonsillitis – Some patients have presented with sore throat and difficulty swallowing that may limit or prevent oral intake. Ulcerative lesions may be seen on the palatine tonsils or the pharynx. The presence of these symptoms with a negative result on the Strep A rapid test suggests mpox as a possible cause, particularly in individuals with epidemiologic risk factors for mpox (table 1).
Ocular manifestations — Ocular mpox can present as conjunctivitis, blepharitis, periocular cellulitis, keratitis, and loss of vision [124]. Subconjunctival nodules have also been described [125]. In a report of five patients with ocular manifestation, all had concurrent nonocular manifestations [126].
Consultation with an ophthalmologist should be obtained if ocular infection is suspected. Some cases can be severe. As an example, in one report, a patient presented with necrotizing conjunctivitis requiring repeated tissue debridement with amniotic membrane grafting [127]. Severe oculocutaneous manifestations have also been described in people with advanced HIV [128].
Neurologic manifestations — Neurologic complications (eg, encephalitis/encephalomyelitis) have been described in the outbreak that started in 2022 [129]. In some cases, deaths have been reported in patients who developed encephalitis. (See 'Prognosis and risk for severe disease' below.)
However, it is unclear if encephalitis/encephalomyelitis represents MPXV invasion of the central nervous system (CNS) or a parainfectious autoimmune process [61]. In one report of two patients who presented with encephalomyelitis within five and nine days of their initial mpox infection, radiographic imaging was consistent with acute demyelinating encephalitis, but polymerase chain reaction (PCR) testing of cerebrospinal fluid (CSF) was negative for poxvirus DNA [130]. By contrast, other reports have described cases of encephalitis with positive PCR results in the CSF [131].
Complications in immunocompromised patients — Severe disease, including a necrotizing form of mpox, may be seen in the context of advanced HIV. The disease is reminiscent of progressive vaccinia that was seen when replication-competent smallpox vaccines were inadvertently given to patients with immunodeficiencies. (See "Vaccines to prevent smallpox, mpox (monkeypox), and other orthopoxviruses", section on 'Complications'.)
In a study of 382 people from 19 countries with advanced HIV disease (CD4 <350 cells/microL) and mpox, 107 (28 percent) were hospitalized, of whom 27 died [61]. All deaths occurred in people with CD4 counts of <200 cells/microL. In addition, some patients developed widespread, large, necrotizing skin lesions (picture 6 and picture 7 and picture 8) and unusual nodular lung lesions (picture 9). Fulminant dermatological and systemic complications were more common in those with CD4 cell counts <100 cells/microL compared with those with CD4 cell counts >300 cells/microL, including necrotizing skin lesions (58 versus 9 percent), bacterial infections (44 versus 9 percent), ocular complications (15 versus 1 percent), pulmonary involvement (29 versus 0 percent), and death (27 versus 0 percent). Among the 85 people who started or restarted antiretroviral therapy (ART), 21 (25 percent) had suspected immune reconstitution inflammatory syndrome as a cause for clinical deterioration and 12 (57 percent) died.
In a different report that described 13 patients with advanced HIV (CD4 <200 cells/microL) and severe mpox, 6 of the 12 hospitalized patients died, and of the remaining six, the median duration of hospitalization was 56 days [132]. These outcomes occurred despite extended tecovirimat courses and/or the use of additional agents (eg, vaccinia immune globulin, cidofovir, and brincidofovir).
Mpox has also been seen in patients who had prior solid organ transplantation. In a review of 11 transplant patients with mpox, 8 of 11 were hospitalized and one patient died [133]. All patients were treated with tecovirimat. The patient who died had pneumonitis and was treated with intravenous tecovirimat and cidofovir as well as broad-spectrum antibiotics.
Other complications — Several severe complications of mpox have been reported, in addition to the ones listed above. These include bowel lesions that are exudative or cause significant tissue edema leading to obstruction [60]. Preputial edema or gross edema of the penile glans resulting in paraphimosis has also been reported. (See "Paraphimosis: Clinical manifestations, diagnosis, and treatment".)
Other complications include bronchopneumonia, sepsis, myocarditis, parotitis, epiglottitis, peritonsillar abscess, severe lymphadenopathy that can be necrotizing or obstructing, rectal wall perforation in patients with mpox proctitis, and hemophagocytic lymphohistiocytosis [46,59,60,74,134-136]. In addition, some patients have presented with a morbilliform rash of pink-to-red spots on the trunk, arms, and legs following administration of certain antibiotics (eg, ampicillin or amoxicillin) [58].
Presentation in people with past infection or complete vaccination course — Patients with mpox tend to develop milder symptoms if they have been previously vaccinated or have had prior infection. In a report of 37 people with either mpox reinfection or infection post-vaccination, clinical features and outcomes appeared to be less severe than those initially described during the global multi-country outbreak that started in 2022 [137]. People with prior infection had a shorter disease course with less mucosal disease upon reinfection compared with their initial infection, and infection post-vaccination was characterized by few lesions, little mucosal disease, and minimal analgesia requirements.
Clinical features in endemic countries in Africa and imported infections — Many reports describing the clinical features of mpox are based on cases in endemic areas of Africa [35,118].
Timing of systemic symptoms — Systemic signs and symptoms typically occur before the skin rash, last one to five days, and include fever, myalgias, headache, and lymphadenopathy. A more detailed discussion of the systemic illness associated with mpox is described above. (See 'Systemic illness' above.)
Location of rash — In endemic regions, lesions are distributed across the body but are more concentrated on areas away from the trunk, such as the head, face, arms, hands, legs, and feet. Lesion counts peak first and are highest on the head/face and then spread to the extremities in a centrifugal pattern.
During the 2017 to 2018 outbreak in Nigeria, a report of 122 confirmed or probable cases of human (likely clade 2) mpox were described [35]. The rash was present in all patients and involved all parts of the body, with the face being most affected. In a report of 216 confirmed cases (likely clade 1) from the Democratic Republic of the Congo (DRC; 2007 to 2011), the mean count of lesions at presentation was 370, and progression of lesions from one stage to another occurred in order [118].
In the 2024 outbreak in South Kivu, DRC, patients with infection due to Clade 1b virus showed a mixed presentation, with both localized (primarily genital) and generalized rashes [122]. Among 314 confirmed cases in adults, 89 percent had genital involvement, with the mean lesion density highest in that area. Of the 84 children under 15 years of age with confirmed disease, 42 percent had genital involvement, but this was typically part of their generalized rash.
Additional findings during specific outbreaks — During the 2003 United States outbreak related to imported infected animals, a detailed review of 34 patients reported that the predominant signs and symptoms were rash (97 percent), fever (85 percent), chills (71 percent), lymphadenopathy (71 percent), headache (65 percent), and myalgias (56 percent) [114]. 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 10A-D).
In a case series of seven patients diagnosed with mpox between 2018 and 2021 in the United Kingdom, the clinical features were similar to those seen in outbreaks of the West African clade of MPXV in Nigeria [71].
During the outbreak of mpox in the DRC that started in 2023, patients commonly experienced systemic manifestations such as fever, myalgias, headache, and lymphadenopathy before the onset of the rash [138]. The skin rash typically begins on the face and extremities, following a centrifugal pattern, and progresses through distinct stages from macules to scabs. Most severe cases have occurred in children.
In the DRC, there have been some cases associated with sexual contact. In this setting, lesions have appeared on the genital, oral, or anal areas, similar to those seen in patients with clade 2b in other regions of the world. In one report, a 19-year-old woman presented with a macular skin rash, dysphagia, dysuria, and genital lesions following sexual contact [139].
More detailed information on the different outbreaks is described above. (See 'Africa' above.)
Laboratory findings — Multiple nonspecific laboratory findings can be seen in patients with mpox. These include abnormal aminotransferases, leukocytosis, thrombocytopenia, and hypoalbuminemia [114]. Diagnostic testing for mpox is described below. (See 'Diagnostic testing' below.)
Prognosis and risk for severe disease — For most individuals, mpox is a self-limited disease with the symptoms lasting from two to four weeks. However, some patients may develop complications or severe disease. (See 'Other complications' above.)
●Hospitalization rate – Few hospitalizations have been reported during the multi-country global outbreak, and many were for the purpose of isolating the patient [140]. Other reasons for hospitalization included provision of adequate pain management and the need to treat secondary infections [41,44,46].
During the 2003 outbreak in the United States, 9 of the 34 patients had been hospitalized for a variety of reasons, including nausea, vomiting, and dysphagia [44,114]. 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.
●Mortality – The mortality associated with mpox varies in different outbreaks.
In the ongoing outbreaks in Africa that started in 2023, the case fatality rate with clade 1a virus was 4 percent, compared with 0.6 percent with clade 1b [23]. The rate is higher in children under five years of age [138,141]. In earlier studies, the fatality rate in Central Africa was reported as approximately 10 percent, with deaths generally occurring in the second week of illness [28,142]. (See 'Africa' above.)
In West Africa, where clade 2 is prevalent, the historical case fatality rates are <0.1 percent, except for the 2017 to 2018 outbreak in Nigeria that resulted in a fatality rate of 3.6 percent, with several deaths occurring in immunocompromised persons with HIV [35,143].
There were no deaths in the 2003 outbreak in the United States, which was likely due to clade 2 [114]. In addition, in the case series of seven patients diagnosed with mpox between 2018 and 2021 in the United Kingdom, all patients made a full recovery [71].
During the multi-country 2022 to 2023 outbreak in previously nonendemic areas, the case fatality rate is generally below 0.1 percent [144]. Reported deaths primarily occurred in immunocompromised persons [61,145] and in those who developed encephalitis [146,147].
●Risk factors for severe disease – Historically, severe disease has been more likely to occur in children [114,148]. Although this trend was not observed during the global outbreak that started in 2022, severe disease in children has been observed in the 2023 to 2024 outbreak in DRC [138,141].
Underlying immune deficiencies may lead to worse outcomes. Although data in immunocompromised patients with mpox are lacking, severe complications have been historically seen in immunocompromised patients who have had smallpox or have received smallpox vaccination with a replication-competent vaccinia virus. (See "Variola virus (smallpox)" and "Vaccines to prevent smallpox, mpox (monkeypox), and other orthopoxviruses" and 'Clinical features specific to the multi-country outbreak in 2022' above.)
In persons with HIV, data from endemic countries indicate that those with advanced and uncontrolled HIV infection might be at higher risk for severe or prolonged mpox following infection [35,145]. During the outbreak that began in 2022, persons with HIV and CD4 counts <200 cells/microL with severe manifestations of mpox have been particularly difficult to manage, some have presented with severe manifestations and some have died (see 'Complications in immunocompromised patients' above) [60,61,145]. In certain cases, this may have been due in part to delays in antiviral therapy to treat mpox. In one report, some patients experienced delays of up to four weeks from the time of presentation to when treatment was initiated [145]. A number of patients with other immunocompromising conditions, either solid organ transplantation or hematologic malignancy, have also experienced severe manifestations [145].
However, in reports where most people living with HIV and mpox are receiving effective ART, there has been no evident excess in complications, hospitalizations, or deaths [57,58]. As an example, in two studies that together included 313 people living with controlled HIV, there were no differences in clinical features or clinical outcomes between those with or without HIV [46,58]. Another report found that patients with HIV were more likely to have a higher rash burden, but there was no association between HIV status and severe illness [149].
Rare asymptomatic infection — Asymptomatic infections have been reported but appear to be rare [41,150-152]. Seroepidemiological studies in Africa suggest some patients may have subclinical or asymptomatic mpox [151]. In a study from France, PCR testing was performed on 200 samples from asymptomatic men and 13 (6.5 percent) were positive for MPXV; two patients subsequently developed symptoms [152]. The potential for transmission from an individual with asymptomatic infection is uncertain [152]. In a study performed at the beginning of the 2022 outbreak in Europe, stored anogenital and oropharyngeal specimens from 224 men who had been tested for gonorrhea and chlamydia were PCR tested for mpox; three men had anorectal specimens positive for MPXV DNA despite absence of symptoms or exposure to a person with mpox [150]. MPXV was able to be grown from two samples. A more detailed discussion of transmission is presented above. (See 'Human-to-human transmission' above.)
EVALUATION AND DIAGNOSIS —
The diagnosis of mpox takes into account epidemiologic, clinical, and laboratory findings. Several authorities have put forth case definitions for suspected mpox during the 2022 to 2023 multi-country outbreak. Definitions from the World Health Organization (WHO) and the United States Centers for Disease Control and Prevention (CDC) can be found on their websites.
When to suspect the diagnosis — The diagnosis of mpox should be suspected in patients who:
●Present with a rash or other symptoms that could be consistent with mpox (eg, proctitis) (see 'Clinical manifestations' above)
and
●Have epidemiologic risk factors for infection (eg, close or intimate in-person contact with individuals who have suspected or confirmed mpox or are part of a social network or community experiencing mpox; recent travel to Central or West Africa or other areas where large outbreaks of mpox have been reported) (table 1). If testing is done on lesions from a patient at low risk for mpox disease, false-positive results can be seen [153].
If the diagnosis of mpox is being considered, infection prevention and control measures should be implemented to reduce the risk of transmission. These include standard and droplet precautions and are discussed in detail separately. (See "Treatment and prevention of mpox (formerly monkeypox)".)
Diagnostic testing — If the diagnosis of mpox is suspected, providers should send specimens for testing [154]. This can be done either through consultation with public health authorities or by sending swabs to a commercial laboratory that performs testing for mpox.
A confirmed or probable diagnosis requires supporting laboratory evidence such as detection of virus or the development of immunoglobulin (Ig)M antibodies (table 1).
●Viral testing – Polymerase chain reaction (PCR) testing for orthopoxvirus DNA should be performed on lesion samples. In the United States, this testing can be done at a Laboratory Response Network site or certain commercial and clinical laboratories [155].
Lesions should be vigorously swabbed to collect skin cells that come off the lesion [156]. Unlike the lesions seen in herpes simplex virus, which are usually filled with fluid and easily unroofed, mpox lesions can be filled with solid material, making them difficult to unroof with a swab. As discussed above, sharps should not be used to collect samples for testing due to the risk of infection via percutaneous inoculation. (See 'Routes of person-to-person transmission' above.)
If there are multiple lesions, a few of them can be sampled (using separate swabs). It is recommended to take two swabs from each specimen. Additional information on laboratory testing, including the approach to specimen collection, can be found on the CDC website; clinicians should also verify any specific specimen collection instructions with their local public health department.
There are PCR assays for monkeypox virus that can differentiate between clade 1 and clade 2. However, some of these assays may fail to detect clade 1b due to genetic deletions, such as the loss of the C3L homolog gene. If it is important to distinguish between clades, testing strategies should incorporate multiple genetic targets to ensure accurate detection, particularly in regions where clade 1b is circulating or in cases of imported infections.
Viral testing of a throat swab may also be performed for epidemiologic purposes but is generally not used to confirm the diagnosis in the clinical setting unless visible throat lesions are present. Similarly, although a positive PCR result has been found in some blood specimens, the clinical significance of viremia is not established.
●Serologic testing – Serologic testing for mpox can be used to support a diagnosis of mpox (table 1) and may be particularly helpful if viral testing is not able to be performed. The decision to obtain serologic testing is generally made in conjunction with public health officials.
Patients with mpox typically have detectable levels of antiorthopoxvirus IgM antibody during the period of 4 to 56 days after rash onset. The CDC developed an IgM capture and an IgG enzyme-linked immunosorbent assay (ELISA) that demonstrated recent mpox infection. Serum IgM and IgG antibodies were detected five and eight days after onset of rash, respectively [157]. People presenting higher IgM and IgG levels have shown faster viral clearance and more rapid clinical resolution [158].
Orthopoxvirus can also be identified through electron microscopy, in which characteristic brick-shaped poxvirus virions can be seen. (See 'Virology' above.)
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 [112]. (See 'Histopathology' above.)
DIFFERENTIAL DIAGNOSIS —
Several infections need to be considered in the differential diagnosis of mpox [154]; these include:
●Varicella – Given the worldwide eradication of smallpox, the most likely diagnostic consideration in a patient presenting with a vesicular rash is varicella (chickenpox). In several outbreaks, it has been difficult to distinguish the two [24,27,86,159]. One feature that historically helped distinguish these infections is lymphadenopathy, which is often a distinctive feature of mpox compared with varicella. In addition, unlike varicella lesions, which are vesicular fluid filled lesions, mpox lesions are typically pseudo-pustules, which are papules that simulate pustules but do not contain fluid or pus. Furthermore, varicella lesions are usually in different stages of development and healing, whereas mpox lesions are typically at the same stage. However, during the global mpox outbreak that started in May 2022, some reports describe lesions that were in different stages of development [121]. Detailed discussions of the clinical manifestations and diagnosis of varicella infection are presented elsewhere. (See "Clinical features of varicella-zoster virus infection: Chickenpox".)
●Herpes simplex virus – Herpes simplex virus (HSV) can present with both oral and genital lesions similar to mpox. Although persons with primary HSV may present with systemic symptoms such as fever and myalgias, those with recurrent HSV typically have milder symptoms. The best way to confirm the diagnosis of HSV infection is through polymerase chain reaction (PCR) testing of the lesions, which is readily available. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection" and "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection".)
●Other sexually transmitted infections – In addition to genital herpes, other sexually transmitted infections may present with signs and symptoms that overlap with those of mpox. For those who present with penile, vaginal, or perianal ulcerated lesions, primary syphilis, lymphogranuloma venereum, or Haemophilus ducreyi should be considered in the differential diagnosis. In patients with inflammation of the rectum (ie, proctitis), lymphogranuloma venereum, chlamydia, gonorrhea, and syphilis should be considered. Throat features of mpox may be mistaken for bacterial tonsillitis or primary syphilis. (See "Approach to the patient with genital ulcers" and "Evaluation of anorectal symptoms in men who have sex with men", section on 'Proctitis'.)
●Impetigo – Impetigo presents with vesicles, pustules, and golden adherent crusts caused by infection with group A Streptococcus (GAS; Streptococcus pyogenes) and Staphylococcus aureus. Recognition of the characteristic golden crust should raise suspicion for impetigo. (See "Impetigo".)
●Molluscum contagiosum – Molluscum contagiosum is a localized skin infection that is typically seen in children but can also occur in adults. Similar to mpox, it is caused by a poxvirus and is transmitted through direct skin contact or fomites. Molluscum contagiosum infection in the genital region may result from transmission during sexual activity. This infection most commonly presents as single or multiple small, skin-colored papules with central umbilication (picture 11A-G). Immunocompromised individuals have an increased risk for larger lesions and more widespread disease (picture 12A-B). The diagnosis is usually based upon the clinical appearance of skin lesions, but a biopsy can confirm the diagnosis when necessary. (See "Molluscum contagiosum".)
●Smallpox – Because of concerns regarding bioterrorism, it is also important to consider the possibility of smallpox in the differential diagnosis of a patient presenting with a pox-like rash [26]. (See "Identifying and managing casualties of biological terrorism" and "Variola virus (smallpox)".)
●Vaccinia virus – The replication-competent smallpox vaccine (ACAM2000) generates local skin lesions that could be spread to other areas of the body. As such, it may be unclear if the patient is experiencing breakthrough mpox versus an adverse event related to the vaccine. (See "Vaccines to prevent smallpox, mpox (monkeypox), and other orthopoxviruses", section on 'Complications'.)
●Other pox viruses – 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 (PCR testing) of a biopsied skin lesion in an American college student who had worked in the Republic of the Congo for eight weeks caring for chimpanzees; none of the others working with these animals developed the infection [160].
Orf and bovine stomatitis (also caused by parapoxviruses) can produce localized skin lesions similar to those of mpox but are difficult to distinguish clinically. It is possible to differentiate between these conditions based on their epidemiological characteristics and previous animal contact history. In research laboratories, they 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. (See "Orf virus infection".)
Other novel orthopoxvirus infections can also be considered. These include Alaskapox virus, camelpox, cowpox, Orthopoxvirus Abatino, and Akhmeta virus [161-163].
The lesions associated with mpox can also be confused with noninfectious etiologies. These are discussed in detail elsewhere. (See "Vesicular, pustular, and bullous lesions in the newborn and infant" and "Approach to the patient with pustular skin lesions" and "Approach to the patient with cutaneous blisters" and "Skin lesions in the returning traveler" and "Approach to adult patients with anorectal complaints".)
INFORMATION FOR PATIENTS —
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Mpox (monkeypox) (The Basics)")
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Orthopoxvirus (smallpox and mpox)".)
SUMMARY AND RECOMMENDATIONS
●Virology – Mpox (previously referred to as monkeypox) is a viral zoonotic disease that is caused by monkeypox virus (MPXV). (See 'Terminology' above.)
MPXV is an orthopoxvirus that is in the same genus as variola virus (the causative agent of smallpox) and vaccinia virus (the virus used in the available smallpox vaccines). Distinct strains of MPXV (clade 1 and clade 2) exist in different geographic regions. (See 'Virology' above.)
●Geographic distribution – In Central and East Africa, an ongoing outbreak of mpox due to clade 1 virus started in early 2023; the World Health Organization declared this a global public health emergency in August 2024. This outbreak differs from the global multi-country outbreak that started in 2022, which is due to clade 2 virus. (See 'Outbreak in Central and East Africa starting in 2023' above and 'Global multi-country outbreak' above.)
Prior to 2022, most cases of mpox occurred in Central and West Africa. Cases in nonendemic countries were primarily reported in travelers returning from endemic regions. There was also an outbreak of human mpox in the United States in 2003 associated with infected prairie dogs who were exposed to imported animals from Africa. (See 'Geographic distribution' above.)
●Transmission – Human-to-human transmission of MPXV can occur through several routes. These include (see 'Human-to-human transmission' above):
•Close contact with infectious skin lesions. The global outbreak in nonendemic countries that started in 2022 has been primarily associated with close intimate contact, such as during sexual activity.
•Indirect contact with infectious fluid (eg, on contaminated linens).
•Percutaneous inoculation via needlestick injuries from supplies used to collect cutaneous lesion samples.
•Large respiratory droplets. For this to occur, prolonged face-to-face contact may be required (eg, within a six-foot radius for ≥3 hours in the absence of personal protection equipment [PPE]). Activities resulting in resuspension of dried material from lesions (eg, shaking contaminated linens) may also present a risk and should be avoided.
Mpox can also been acquired through contact with an infected animal's bodily fluids or through a bite. Monkeys and humans are incidental hosts; the reservoir is likely to be certain rodents. (See 'Animal-to-human transmission' above.)
●Clinical features – In patients with mpox, the incubation period from time of exposure to clinical illness is usually 5 to 13 days. During the global mpox outbreak in 2022, the incubation period has generally ranged from 7 to 10 days. (See 'Incubation period' above.)
Patients often present with a systemic illness that includes fevers, chills, and myalgias followed by a characteristic rash. The rash typically begins as macules and evolves to papules, vesicles, and then pseudo-pustules. The lesions eventually crust over, and these crusts dry up and then fall off. (See 'Rash' above.)
During the outbreak of mpox that began in 2022, some patients presented with genital, rectal, and/or oral lesions without the initial prodrome (figure 1). Patients have also presented with proctitis, tonsillitis, ocular disease, and/or other complications (eg, encephalomyelitis). (See 'Clinical features specific to the multi-country outbreak in 2022' above.)
●Disease course – Most patients with mpox have a self-limited illness. In the 2022 global outbreak, rare deaths have been reported. By contrast, in Central Africa, where infection is caused by a different strain (clade 1), the fatality rate has been reported to be as high as 10 percent; severe disease is more commonly seen in children. (See 'Prognosis and risk for severe disease' above.)
●Evaluation and diagnosis – The diagnosis of mpox should be suspected in patients who present with a rash or other symptoms that could be consistent with mpox and have epidemiologic risk factors for infection (table 1). (See 'Evaluation and diagnosis' above.)
A diagnosis of mpox infection can be made through demonstration of orthopoxvirus DNA (eg, by polymerase chain reaction [PCR] testing or next-generation sequencing of a clinical specimen) or through isolation of MPXV in culture from a clinical specimen.
●Differential diagnosis – When evaluating a patient with suspected mpox, varicella zoster virus (presenting as chickenpox or herpes zoster), herpes simplex, syphilis, smallpox, and other poxvirus infections should be included in the differential diagnosis. (See 'Differential diagnosis' above.)
