Aetiology

Monkeypox is caused by the monkeypox virus (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] The name of the virus is currently under review by the International Committee on the Taxonomy of Viruses.[32]

Virus clades

  • There are two distinct clades of the virus. A group of global experts convened by the World Health Organization has recommended that virus clades be named using Roman numerals to align names with current best practices.[32][33]

  • Clade one (I)

    • Formerly known as the Central African (Congo Basin) clade.

  • Clade two (II)

    • Formerly known as the West African clade.

    • Consists of subclades IIa and IIb; Clade IIb refers to the group of variants largely circulating in the 2022 global outbreak.

    • Associated with milder disease, fewer deaths, and limited human-to-human transmission compared with Clade I.[5]

Transmission dynamics

  • There are limited data available that describe the transmission of the virus, and most of the information to date is from endemic areas.

  • The virus can be transmitted to humans from different wild animals, such as monkeys and rodents (e.g., squirrels, rats, dormice), although its natural host reservoir is unknown. While animal-to-human transmission is the more common mode of transmission, human-to-human transmission does occur and has led to small, but contained, human outbreaks in the past.

  • 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.[14]

  • Human-to-human transmission occurs through direct contact with infectious skin or mucocutaneous lesions and respiratory droplets (and possibly short-range aerosols requiring prolonged close contact). Fomite transmission can also occur (e.g., from contaminated clothing or linens). Perinatal transmission has been reported. More information is needed to better understand other possible modes of transmission via contact with other bodily fluids (e.g., semen, vaginal fluid, breast milk, blood, amniotic fluid), and to better understand transmission by respiratory droplets and aerosols.[14] No cases of transmission through substances of human origin have been documented.[34]

  • Human-to-animal transmission (reverse zoonosis) has not been reported, but is a theoretical risk.[35]

Viral transmission factors

  • The incubation period is 6 to 13 days (range 5 to 21 days).[14] 

  • The secondary attack rate has been reported as 0.3% to 10.2%, and depends on the virus clade. However, more than half of the studies available report a secondary attack rate of 0%.[4] In the 2013 outbreak in the Democratic Republic of Congo, the household contact secondary attack rate was 50% among 16 households.[36] Secondary attack rates are likely to be overestimates due to case ascertainment bias during outbreaks.[5]

  • The R₀ (number of secondary cases expected to arise from a single primary case in a naive population) has been estimated as 0.8; however, data are limited.[5] This means that a human-to-human epidemic is always likely to die out because transmission is inefficient.

Multi-country outbreak (2022)

  • Virus clades

    • The genome sequence of the virus obtained in several countries shows some divergence from the Clade IIa virus and has mutations of unknown significance.

    • The newly emerging Clade IIb virus has been characterised with newly classified lineages (A.1, A.1.1, A.2, and B.1). The B.1 lineage includes all of the genomes from the current outbreak and has been estimated to have emerged in March 2022.[33][37] The majority of outbreak cases are currently in the B.1 lineage or descendants; however, a small number of cases are in lineage A.2. A small amount of diversity has developed within lineage B.1.[38]

    • Further research is required to determine whether the observed genomic changes lead to phenotypic changes (e.g., enhanced transmissibility, virulence, immune escape, antiviral resistance).

  • Transmission dynamics

    • Current evidence suggests person-to-person community spread is occurring primarily in gay, bisexual, or other men who have sex with men (MSM). Data from the largest study of confirmed cases to date indicate that 98% of cases were in MSM.[39]

    • Available evidence indicates that the principal mode of transmission in this outbreak is through close contact with monkeypox lesions on the skin or mucosal surfaces of a person with monkeypox during sexual activity.[40][41] However, there are a small number of cases with no history of sexual exposure.[42][43] 

    • The modes of transmission during sexual contact remain unknown. 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.[44][45] Viral load is higher in skin and anogenital samples compared with nasopharyngeal, blood, and urine samples.[46] This indicates that skin-to-skin contact is likely the dominant mode of transmission, rather than transmission via the respiratory route or contact with body fluids.[47] No confirmed cases of airborne transmission have been reported.[38] While monkeypox viral DNA has been detected in seminal fluid, its presence does not equate to evidence of infectivity.[48] Non-human primate studies have detected the monkeypox virus in the interstitial cells and seminiferous tubules of the testes (sites of sperm production and maturation) during the acute phase of infection.[49] However, further research is required to determine the significance of these findings.

    • Concomitant STIs were reported in 29% of patients who were tested in the largest study of confirmed cases to date.[39] However, it is unclear whether STIs contribute to transmission of monkeypox virus or alter its clinical expression at this stage.[50]

    • Approximately 25% of infections in women were not related to sexual transmission (89% in transgender women), a significantly higher proportion compared with men. Non-sexual routes of transmission (i.e., household and occupational exposures) were only reported by cisgender women and non-binary people, but not transgender women.[51]

    • Household contact is the most common route of transmission in children.[10][13][52] Peripartum transmission has been reported.[11] There is insufficient evidence to determine whether transmission can occur via breastfeeding.[53] However, a case has been reported in a breastfeeding infant, most likely via skin-to-skin contact.[54]

    • The extent to which pre-symptomatic or asymptomatic infection may occur is unknown.[44] Small observational studies have identified cases of asymptomatic infection in a small number of men with a positive anorectal monkeypox polymerase chain reaction test.[55][56][57] Positive anorectal tests have also been documented in symptomatic men without specific anorectal symptoms.[58] No cases of transmission have been definitively linked to exposure to asymptomatic people.[40] There is evidence for pre-symptomatic transmission.[59]

    • The risk of infection through contact with contaminated surfaces or objects is considered to be low.[40] Monkeypox virus 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.[60][61][62][63][64][65][66] However, detection of replication-competent virus in samples does not mean that transmission or infection would occur. Further research is required.

    • Transmission is unlikely during brief interactions (e.g., brief conversations), between people in close proximity for prolonged periods (e.g., passengers seated next to a confirmed case on an airplane), or during healthcare encounters.[67]

    • There are a small number of cases with no identified route of acquisition.[38]

    • There is evidence suggestive of sustained human transmission prior to the 2022 outbreak but not clear evidence of adaptation for improved human transmission.[38][68][69]

  • Viral transmission factors

    • Data from the largest study of confirmed cases to date indicates a mean incubation period of approximately 7 days (range 3 to 20 days).[39] 

    • The R₀ has been estimated to be >1 in MSM populations.[70][71] The mean serial interval has been estimated to be 5.6 days (with a reproduction number of 1.33).[72]

    • Data on viral shedding is limited. However, monkeypox virus has been detected in semen, blood, faeces, urine, and saliva. An analysis of samples from 12 patients found shedding of monkeypox virus in a range of bodily fluids during the first 2 weeks of illness and up to 16 days after symptom onset. Further research on the infectious potential of these bodily fluids and their potential role in disease transmission is required.[73]

Pathophysiology

Data on pathophysiology are limited.[74] 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 viraemia). The virus reaches distant lymph nodes and organs via the circulation. This phase of the infection is asymptomatic. During the prodromal stage, secondary viraemia occurs from the lymphoid organs to the skin and other organs (e.g., eyes, lungs, gastrointestinal tract, gonads), and non-specific symptoms develop from the immune system being triggered. Infection of skin and mucosa leads to appearance of pustules and ulcers.[75][76][77] A detailed discussion of the pathophysiology is beyond the scope of this topic.

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