History and exam

Key diagnostic factors

common

rash/lesions (typical)

Shortly after the prodromal period, a characteristic rash develops. The rash usually presents 1 to 3 days after the onset of the acute febrile illness, and typically spreads to all parts of the body within 24 hours. The rash often affects the palms and soles. The skin rash (exanthem) is preceded by a rash affecting the oropharynx and tongue (enanthem) in the 24 hours prior that often passes unnoticed.[14][74][138][149]

Lesions are all of a similar stage of maturation on any part of the body, and tend to be more concentrated on the face and extremities (centrifugal) rather than on the trunk. Lesions range in size from 0.5 to 1 cm in diameter (but can be larger), and there may be few or several thousand. Lesions may be inflamed causing mild erythema and/or skin hyperpigmentation, and may be discrete or confluent. Lesions are typically described as painful until the healing phase when they become itchy. They may occur in the oral cavity, which can cause difficulties with eating and drinking, which may lead to dehydration and malnutrition.[14][74][138][149]

Lesions simultaneously progress through four stages (macular, papular, vesicular, and pustular) before scabbing over and resolving, typically over a period of 2 to 4 weeks. The vesicles are well-circumscribed and located deep in the dermis, so individual vesicles do not readily rupture (unlike varicella and herpes simplex vesicles). Pustules subsequently umbilicate before scabbing over and gradually separating after approximately 2 weeks. Once the scab drops off, the person is no longer considered contagious. A depressed scar or areas of pigmentation may remain, most notably on the face.[14][74][138][149]

Lesions may affect oral mucous membranes (in 70% of cases), genitalia (30%), and conjunctivae (20%), as well as the cornea (eyeball). In severe disease, lesions can coalesce until large sections of skin slough off.[133]

Skin lesion severity can be determined by the number of lesions: mild (<25 lesions); moderate (25-99 lesions); severe (100-250 lesions); very severe (>250 lesions).[14]

[Figure caption and citation for the preceding image starts]: Characteristic maculopapular cutaneous rashWorld Health Organization (WHO)/Brian W.J. Mahy, BSc, MA, PhD, ScD, DSc [Citation ends].com.bmj.content.model.Caption@45be852f

rash/lesions (2022 outbreak)

Rash has been reported in 95% to 100% of patients.[39][139] Data from the largest study of confirmed cases to date indicate that: 64% had <10 lesions; 73% had anogenital lesions; 41% had mucosal lesions (e.g., anogenital, oropharyngeal, urethral, nasal, eye); and 10% had only a single genital lesion.[39] Oesophageal lesions have been reported.[162]

Rash lesions in the current ongoing outbreak are atypical. Lesions tend to be localised to the genital, perineal/perianal, or perioral areas and often do not spread further. This suggests transmission occurs as a result of contact during sexual intercourse, with lesions possibly starting at the site of inoculation.[44][138][150][151][152][153][154] Lesions on the external genitalia have caused severe swelling and pain. Although most patients are men, localised genital lesions (vulvar and intravaginal) and cervical lesions have been reported in women.[155][156][157] Vulvovaginal lesions predominated in cisgender women and anorectal features predominated in transgender women, anatomically reflecting sexual practices.[51]

Other atypical presentations include: presentation of only a few lesions (or even just a single lesion) and may not be disseminated; absence of skin lesions with anal pain and bleeding; lesions appearing at different stages of development (asynchronous); rash does not always appear on palms and soles; and appearance of lesions before the prodrome.[44][138][158] Approximately one third of patients presented with cutaneous manifestations at different stages of evolution at a single time point in one study.[140] Atypical single lesions can mimic abscesses and other deep-tissue phenomena.[137]

Oral lesions may be observed in different parts of the oral mucosa including the lips, tongue, and, most commonly, the tonsils. Oral lesions may manifest as papules, vesicles, pustules, or ulcers.[161]

An erythematous maculopapular rash of varying distribution and rapid onset, separate to areas of blistering or pustules, has also been reported in some patients.[140] A generalised purpuric rash has also been reported.[159]

The presentation may easily be confused with some STIs (e.g., syphilis, herpes, lymphogranuloma venereum) or other aetiologies of proctitis.[142] 

Skin lesion severity can be determined by the number of lesions: mild (<25 lesions); moderate (25-99 lesions); severe (100-250 lesions); very severe (>250 lesions).[14]

[Figure caption and citation for the preceding image starts]: Images of individual lesions (multi-country outbreak 2022)UKHSA [Citation ends].com.bmj.content.model.Caption@16611ba7

anorectal symptoms (2022 outbreak)

Some patients may present with severe/intense anorectal pain (including severe pain on defecation), tenesmus, rectal bleeding, or purulent or bloody stools, associated with perianal/rectal lesions and proctitis (initial skin lesions may be absent).[138][139][140][142][143] Patients presenting with proctitis may have no signs of a rash.[144]

Data from the largest study of confirmed cases to date indicate that 73% of patients had anogenital lesions and 14% had proctitis or anorectal pain.[39]

Men who engaged in anal-receptive sex presented with proctitis more frequently than men who did not engage in anal-receptive sex.[145]

The presentation may easily be confused with some STIs or other aetiologies of proctitis.[142]

fever

Typically a symptom of the prodromal period (usually preceding the appearance of the rash), but may present after the rash or not at all.

Historically, fever has been reported in 85% of cases, and chills in 71% of cases.[26]

Reported in 62% of patients in the current ongoing multi-country outbreak.[39]

lymphadenopathy

May be generalised or localised to several areas. Typically occurs with onset of fever preceding the rash or, rarely, with rash onset. May be submandibular and cervical, axillary, or inguinal, and occur on both sides of the body or just one side.[138]

Enlarged lymph nodes are approximately 1 to 4 cm in diameter, firm, tender, and sometimes painful.

Lymphadenopathy is a common distinguishing feature (71% to 98.6% of cases), but is rare in smallpox and other diseases in the differential diagnosis.[14][26][74][149]

Reported in 56% of patients in the current ongoing multi-country outbreak.[39]

Painful cervical lymphadenopathy causing dysphagia may be a sign of severe or complicated disease.[14] Severe lymphadenopathy that can be obstructing (e.g., in airways) or necrotising has been reported.[100]

Other diagnostic factors

common

headache

Typically a symptom of the prodromal period (usually preceding the appearance of the rash), but may present after the rash or not at all.

Historically, headache has been reported in 65% of cases.[26]

Reported in 27% of patients in the current ongoing multi-country outbreak.[39]

backache

Typically a symptom of the prodromal period (usually preceding the appearance of the rash), but may present after the rash or not at all.

Historically, backache has been reported in 30% of cases.[26]

Reported in 10.7% of patients in the current ongoing multi-country outbreak.[140]

myalgia

Typically a symptom of the prodromal period (usually preceding the appearance of the rash), but may present after the rash or not at all.

Historically, myalgia has been reported in 56% of cases.[26]

Reported in 31% of patients in the current ongoing multi-country outbreak.[39]

pharyngitis/cough

Typically a symptom of the prodromal period (usually preceding the appearance of the rash), but may present after the rash or not at all.

Oropharyngeal symptoms may cause severe pain or difficulty swallowing (odynophagia).

Historically, pharyngitis has been reported in 60% of cases.[26]

Pharyngitis has been reported in 21% of patients in the current ongoing multi-country outbreak.[39]

asthenia

Typically a symptom of the prodromal period (usually preceding the appearance of the rash), but may present after the rash or not at all.

Lethargy has been reported in 41% of patients in the current ongoing multi-country outbreak.[39]

malaise

Typically a symptom of the prodromal period (usually preceding the appearance of the rash), but may present after the rash or not at all.

Reported in 57% of patients in the current ongoing multi-country outbreak.[139]

nausea/vomiting

Typically a symptom of the prodromal period (usually preceding the appearance of the rash), but may present after the rash or not at all.

Historically, nausea/vomiting has been reported in 32% of cases.[26]

May contribute to severe dehydration, and be a sign of severe or complicated disease.[14]

uncommon

diarrhoea

Typically a symptom of the prodromal period (usually preceding the appearance of the rash), but may present after the rash or not at all.

Historically, diarrhoea has been reported in 6% of cases.[26]

May contribute to severe dehydration.

delirium/confusion

Typically a symptom of the prodromal period (usually preceding the appearance of the rash), but may present after the rash or not at all.

Historically, confusion has been reported in 6% of cases.[26]

May be a sign of severe or complicated disease.[14]

seizures

Typically a symptom of the prodromal period (usually preceding the appearance of the rash), but may present after the rash or not at all.

Historically, seizures have been reported in 3% of cases.[26]

Risk factors

strong

recent travel to/living in endemic country or country with outbreak

Patients may report recent travel to (or living in) endemic countries (Central or West Africa) or a country with a current outbreak in the 21 days prior to symptom onset.

Multi-country outbreak (2022): there is currently an outbreak across several countries. Cases are predominantly, but not exclusively, in gay, bisexual, and other men who have sex with men participating in extended sexual networks, and transmission is primarily linked to recent sexual contacts.[7]

WHO: 2022 monkeypox outbreak - global trends Opens in new window

CDC: 2022 monkeypox outbreak global map Opens in new window

contact with suspected, probable, or confirmed case

Human-to-human transmission occurs rarely, but serial transmission events have been reported.[4][36] People who are younger than 40 to 50 years of age (depending on the country) may be more susceptible as a result of the termination of routine smallpox vaccination worldwide after the eradication of smallpox.[14] 

The World Health Organization defines a contact as a person who has been exposed to an infected person during the infectious period (i.e., the period beginning with the onset of the index case’s first symptoms, and ending when all scabs have fallen off) and has had one or more of the following exposures with a probable or confirmed case (including health workers potentially exposed in the absence of proper use of appropriate protective personal equipment): direct skin-to-skin and skin-to-mucosal physical contact; contact with contaminated materials; prolonged face-to-face respiratory exposure in close proximity; or respiratory exposure or eye mucosal exposure to lesion material from an infected person.[78]

Healthcare workers have a low overall risk for infection (with or without proper personal protective equipment). The risk is considered to be moderate in healthcare workers performing aerosol-generating procedures without proper personal protective equipment.[34] A small number of cases have been reported among health workers in the current ongoing multi-country outbreak, with most cases being infected in the community rather than via occupational exposure.[6] In practice, the risk for healthcare workers appears to be very low even with incomplete adherence to recommended personal protective equipment.[79][80] However, there have been reports of transmission via needlestick injuries, and likely fomite transmission.[81][82][83][84][85]

The risk among staff and students after exposure to a confirmed case in educational settings appears to be low.[86] The risk for the general population is considered to be low.[34]

Case definitions vary between regions. Consult your local public health authority for more information and guidance. See Criteria.

random one-time sexual encounters or multiple sexual partners

Multi-country outbreak (2022): the predominance of cases among men who have sex with men in the current outbreak, and the nature of the presenting lesions in some cases, suggest transmission occurred during sexual intercourse. Therefore, the probability of further spread among men who have sex with men with random one-time sexual encounters or multiple sexual partners is currently assessed as moderate.[34]

recent tattoo or piercing

Outbreaks related to piercing and tattoo establishments have been reported. In one outbreak, 37% of contacts developed the infection, and most cases developed a rash at the tattoo/piercing site.[87][88]

contact with infected animal

An animal reservoir is often the initial source of human infection. There may be a history of contact with non-human primates or rodents (e.g., squirrels, rats, dormice) originating from Africa.[14] It is difficult to eradicate because of the presence of animal reservoirs in West and Central Africa.

Animals that can be infected with monkeypox include prairie dogs, squirrels, marmots and groundhogs, chinchillas, giant-pouched rats, hedgehogs, shrews, monkeys, and apes. Mice, rats, and domestic rabbits can possibly be infected, although this may vary by species. It is currently unknown whether other animals (e.g., dogs, cats, gerbils, guinea pigs, hamsters) can be infected.[89]

The risk of establishment of an enzootic cycle and spill-over events to humans is considered to be low.[34] 

children, pregnant women, immunocompromised (severe disease)

Children, pregnant women, and immunocompromised people may be at increased risk of severe disease.[14][5][74] 

Most reported deaths have occurred in younger children and immunocompromised people.[14] In the early years of human infection, 100% of deaths were in children <10 years of age. However, between 2000 and 2019, children <10 years of age accounted for only 37.5% of deaths.[4] 

Data regarding monkeypox infection in children are limited. There is evidence from patients infected with the Clade I virus that children <8 years of age and those who are immunocompromised or have skin conditions (e.g., eczema) may be at increased risk of severe disease. Data in children infected with the Clade II virus are lacking. It is unknown whether children are more susceptible than adults to infection, or whether clinical outcomes differ from those in adults.[90] In children, the infection is usually acquired in the household setting or following close contact with an infected animal.[91]

Data regarding monkeypox infection in pregnancy are limited. It is unknown if pregnant women are more susceptible to infection or if disease is more severe in pregnancy. However, adverse pregnancy outcomes including spontaneous pregnancy loss and stillbirth, preterm delivery, and neonatal infection have been reported in Africa. Perinatal transmission is possible.[5][92][93] Infection in pregnancy is associated with a high risk of perinatal loss and vertical transmission.[94]

HIV infection (severe disease)

There is limited evidence as to how HIV infection impacts the risk of infection or its disease course, and it is currently unknown whether HIV status affects a person’s risk of infection or severe disease.[26][95]

Limited data indicate that people with advanced and uncontrolled HIV can be at a higher risk of severe or prolonged disease. In one retrospective review of 40 cases in Nigeria, people with HIV co-infection experienced more prolonged illness, larger lesions, and higher rates of secondary bacterial skin infections and ulcers.[96] 

Emerging data from the current ongoing multi-country outbreak suggest that HIV positivity may be a risk factor for infection. Available data report that 28% to 51% of patients, for whom HIV status is known, are HIV-positive.[97][98] Although women account for a minority of cases, the proportion of women with HIV is estimated to be 27% (50% in transgender women).[51] Data from the largest study of confirmed cases to date indicate HIV infection was not linked to disease severity.[39] However, data from the US indicate that people with HIV may have a higher rate of hospitalisation compared with those without HIV infection, particularly those with low CD4 counts or without viral suppression.[99] The majority of patients with severe manifestations had HIV with CD4 counts <200 cells/microlitre.[100] Patients with advanced HIV infection or AIDS are at increased risk of severe complications, intensive care unit admission, and death.[101]

People living with HIV who are on antiretroviral therapy with suppressed viral load are not considered to be immunocompromised.[14] A suppressed/undetectable viral load may protect against a more severe disease course.[102]

Observational evidence suggests that the immune response to childhood smallpox vaccination declined faster among people who subsequently became infected with HIV, and that antigen-specific CD4+ T-cell memory to vaccinations or infections prior to HIV infection did not recover after immune reconstitution in patients on antiretroviral therapy.[103]

acute or chronic skin conditions (severe disease)

People with a history or presence of atopic dermatitis or other active exfoliative skin conditions (e.g., eczema, burns, impetigo, shingles, herpes simplex infection, severe acne, severe nappy rash, psoriasis, keratosis follicularis) may be at increased risk for severe disease or complications (e.g., secondary bacterial infection).[14][104] People with atopic dermatitis may be more susceptible to infection.[105]

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