Etiology
Mpox is caused by the monkeypox virus (MPXV; family Poxviridae; genus Orthopoxvirus), a double-stranded DNA virus. The virus was first isolated in 1958 following an investigation into a pox-like disease occurring in monkeys. It was first detected in humans in 1970.[5][11]
Virology
There are two distinct clades of the virus:[54][55]
Clade I: formerly known as the Central African (Congo Basin) clade. Consists of subclades Ia (previously clade I) and Ib.[11] Clade Ib is a new lineage first identified in 2023 in an outbreak in the Democratic Republic of Congo (DRC) where sexual transmission was a key driver of transmission.[33]
Clade II: formerly known as the West African clade. Consists of subclades IIa and IIb; clade II is associated with milder disease, fewer deaths, and limited human-to-human transmission compared with clade I.[5]
The group of variants circulating in the 2022 global clade II mpox outbreak belong to clade IIb. The clade IIb virus has been characterized with the lineages A.1, A.1.1, A.2, A.2.1, A.2.2, A.3, and B.1.[54][56][57][58]
The majority of cases in the outbreak are in lineage B.1 (or its descendants), which has been estimated to have emerged in March 2022. However, a small number of cases are in lineage A.2. A small amount of diversity has developed within lineage B.1.
There is evidence suggestive of sustained human transmission prior to the outbreak, but not clear evidence of adaptation for improved human transmission.[57][59][60]
Further research is required to determine whether the observed genomic changes lead to phenotypic changes (e.g., enhanced transmissibility, virulence, immune escape, antiviral resistance).
Animal-to-human transmission
Zoonotic transmission was the predominant route of transmission (occurring in 62% of cases), particularly in endemic countries, prior to the 2022 global clade II mpox outbreak.[61][62]
The virus can be transmitted to humans from wild animals, such as monkeys and rodents, although its natural host reservoir is unknown. Animal-to-human transmission can occur from the bite or scratch of an infected animal; during activities such as hunting, trapping, skinning, cooking, or ingestion of infected animals; or from contact with infected bodily fluids. The extent of viral circulation in animal populations is currently unknown.[1]
Human-to-animal transmission (reverse zoonosis) has not been reported, but is a theoretical risk.[63]
Human-to-human transmission
Human-to-human transmission occurs through direct contact with infectious skin or mucocutaneous lesions and respiratory droplets (possibly short-range aerosols requiring prolonged close contact). Fomite transmission (e.g., from contaminated clothing or linens) and perinatal transmission are also possible.[1][64]
Sexual contact has been a key driver of transmission in more recent outbreaks. Almost all cases in the 2022 global clade II mpox outbreak had a history of human contact, especially sexual contact, although the transmission route was unknown for a small number of cases.[62][65] A cluster of clade Ib infections related to sexual contact (heterosexual transmission linked to commercial sex work, as well as small clusters of cases among men who have sex with men) was reported for the first time in November 2023 in the DRC.[28][66][67]
Transmission via direct contact with lesions
Available evidence suggests that the principal mode of transmission in the 2022 global clade II mpox outbreak has been close contact with skin or mucosal lesions during sexual activity.[65][68]
Approximately 74% of patients reported sexual activity in the 21 days prior to diagnosis.[15] However, there have been a small number of cases with no history of sexual exposure.[69][70] In women, 25% of infections have not been related to sexual transmission (i.e., household or occupational transmission), a significantly higher proportion compared with men.[43] Household contact is the most common route of transmission in children.[71][72]
Skin-to-skin contact is likely the dominant mode of transmission, rather than transmission via the respiratory route or contact with body fluids, as viral load is higher in skin and anogenital samples compared with throat, nasopharyngeal, blood, and urine samples.[73][74][75][76]
Prior to the more recent outbreaks, there was little data available about sexual transmission.[15]
Transmission via contact with body fluids
More information is needed to better understand transmission via contact with bodily fluids.[1] While it is known that close physical contact during sex can lead to transmission, it is not yet clear what role sexual bodily fluids play in transmission, if any.[77][78]
The virus has been detected in a number of body fluids including semen, seminal fluid, blood, serum, plasma, feces, urine, and saliva.[65][79] An analysis of samples found shedding of the virus in a range of bodily fluids during the first 2 weeks of illness and up to 16 days after symptom onset. The viral load in semen was generally low throughout the course of infection.[80][81] Further research on the infectious potential of these bodily fluids and their potential role in disease transmission is required.
No confirmed cases of transmission through substances of human origin have been documented.[82]
Transmission via respiratory droplets and aerosols
More information is needed to better understand transmission via respiratory droplets and aerosols.[1]
Airborne transmission is a theoretical concern, but no confirmed cases of airborne transmission have been reported. Although possible, the risk of respiratory transmission appears to be low.[57][65][83]
Transmission via fomites
Fomite transmission is infrequent but possible. The risk of infection through contact with contaminated surfaces or objects is thought to be low. Fomite transmission may be suspected in cases without any epidemiologic risk factors, but is difficult to confirm.[84]
Viral DNA has been detected on objects, surfaces, and air samples (from skin particles in the air during bedding changes) in household and hospital settings of infected cases, with viable virus detected in some studies but not others.[85][86][87][88][89][90][91] However, detection of replication-competent virus in samples does not mean that transmission or infection would occur, and further research is required.
Peripartum transmission
Asymptomatic and presymptomatic transmission
The extent to which asymptomatic or presymptomatic transmission may occur is unknown.[77][95]
Replication-competent viral shedding has been documented in the presymptomatic phase, and presymptomatic transmission has been documented.[96][97][98] Asymptomatic infection has been described, but the extent to which asymptomatic infection may occur is unknown.[99][100]
Small observational studies have identified cases of asymptomatic infection in a small number of men with a positive anorectal polymerase chain reaction test.[101][102][103]
Asymptomatic infections may play a role in sustaining circulation of the virus resulting in sporadic cases and clusters.[104] However, screening of high-risk asymptomatic populations detected a very low prevalence of infection, suggesting that undetected infection is unlikely to be a main driver of transmission.[105][106][107][108]
Viral transmission factors
Incubation period: typically 6 to 13 days (range 1 to 21 days). Transmission was not formerly known to occur in the incubation period.[1][11] Data from the 2022 global clade II mpox outbreak indicates a mean incubation period of approximately 7 days (range 3 to 20 days), shorter than previous outbreaks.[109][110]
R₀ (number of secondary cases expected to arise from a single primary case in a naive population): historically estimated to be 0.8, based on limited data, meaning a human-to-human epidemic is always likely to die out because transmission is inefficient.[5] However, in the 2022 global clade II mpox outbreak the R₀ has been estimated to be >1 in men who have sex with men (MSM).[111][112]
Secondary attack rate: historically reported as 0.3% to 10.2% dependent on the virus clade. However, more than half of the studies available reported a secondary attack rate of 0%.[4] In the 2013 outbreak in the DRC, the household contact secondary attack rate was 50% among 16 households.[113] The secondary attack rate for nonsexual close contacts of cases has been reported to be 1% to 1.6%.[114] Secondary attack rates are likely to be overestimates due to case ascertainment bias during outbreaks.[5] The risk for transmission aboard commercial aircraft appears to be low, with no secondary cases identified among passengers seated near infected travelers.[115] However, there is limited evidence available to assess this risk.
Pathophysiology
Data on pathophysiology are limited.[99] Following viral entry, the virus replicates at the site of inoculation (e.g., skin or respiratory route). The virus can infect epithelial cells, dendritic cells, and macrophages in the respiratory tract, or keratinocytes, fibroblasts, Langerhans cells, dendritic cells, and macrophages in the skin. The virus binds to host cell surface glycosaminoglycans and undergoes endocytosis to enter the cell. Infected cells travel to nearby draining lymph nodes (primary viremia). The virus reaches distant lymph nodes and organs via the circulation. This phase of the infection is asymptomatic. During the prodromal stage, secondary viremia occurs from the lymphoid organs to the skin and other organs (e.g., eyes, lungs, gastrointestinal tract, gonads), and nonspecific symptoms develop from the immune system being triggered. Infection of skin and mucosa leads to appearance of pustules and ulcers.[116][117][118] A detailed discussion of the pathophysiology is beyond the scope of this topic.
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