Factsheet for health professionals on monkeypox
Last reviewed/updated on: 21 September 2022
Human monkeypox (MPX) is a zoonotic disease caused by the Monkeypox virus (MPXV) [1,2].The disease is endemic in some regions of Central and West Africa; outbreaks outside of the African continent have also occurred.
Human monkeypox is not a notifiable disease in the EU/EEA ; similarly, monkeypox infections in animals are not notifiable at the EU/EEA level, as per the European Commission’s Implementing Regulation 2018/1882.
The first outbreak of MPX reported outside of Africa [4,5] was linked to an importation of infected mammals in 2003 into the United States. For the first time in 2022, multiple cases of monkeypox with no epidemiological link to travel or imported mammals were identified in several non-endemic countries worldwide, including EU/EEA countries.
Monkeypox virus (MPXV) is an enveloped virus with a double‐stranded DNA genome of around 190 kb. It belongs to the Orthopoxvirus genus of the Poxviridae family. The Orthopoxvirus genus also includes Vaccinia virus, Cowpox virus, Variola virus and several other animal pathogen poxviruses . There are two genetically distinct clades described for MPXV, Clade I (formerly called the Central African (Congo Basin) clade) and Clade II (formerly called the West African clade), with sub-clades IIa and IIb [7,8]. Genetic differences between the viral genomes of the two clades might explain differences in viral clearance and pathogenesis [7,9,10]. Clade I has been associated with more severe disease and higher mortality [2,4,11,12].
Poxviruses show extraordinary resistance to drying , and increased temperature and pH tolerance when compared with other enveloped viruses. These characteristics strongly impact their environmental persistence. Viruses of the Orthopoxvirus genus are known to have a long-lasting stability in the environment , and viable MPXV can be detected on household surfaces at least 15 days after contamination of the surfaces . In a personal communication it was suggested that vaccinia virus (the virus contained in the smallpox vaccine) is rapidly inactivated in sewage . Despite these characteristics, poxviruses are sensitive to common disinfectants, although they can be less sensitive to organic disinfectants compared to other enveloped viruses.
MPXV is not considered a biological agent of concern for biosecurity according to the United States’ Centers for Disease Control and Prevention’s (CDC) list of bioterrorism agents , but it is considered an ‘agent with high threat for deliberate release’ using the matrix developed by the EU task force on Bioterrorism (BICHAT) .
Clinical features and sequelae
From studies in endemic settings, the incubation period for MPX is described as usually lasting six to 13 days but able to range from five to 21 days . Human monkeypox often begins with a combination of the following symptoms: fever, headache, chills, exhaustion, asthenia, lymph node swelling (lymphadenopathy), back pain, and muscle aches [12,20]. In cases in endemic areas (Africa), within three days after onset of these prodrome symptoms, a centrifugal maculopapular rash starts from the site of primary infection and rapidly spreads to other parts of the body. Palms and soles are involved in cases of the disseminated rash, which was indicated as characteristic of the disease.
Studies on the current multi-country outbreak which started in May 2022 show an incubation period of seven to eight days (IQR 5–10) [21,22], with shorter incubation periods of two to four days also being observed . Additionally, a somewhat different clinical presentation of symptoms compared with those previously reported in endemic areas has also arisen. In this outbreak, systemic prodrome symptoms do not always precede the onset of rash and may be absent in up to almost 50% of cases [21,24,25]. A majority of cases presented with rash in the anogenital region and inguinal lymphadenopathy [26,27], however, in some cases, the number of lesions is quite limited, including cases of single cutaneous or mucosal anogenital or oral lesion . In a number of cases, the presenting symptoms are proctitis with severe rectal pain and diarrhoea, with no skin lesions, which makes diagnosis more challenging. Oropharyngeal involvement including oral lesions, tonsillitis and peritonsillar abscess causing pain and difficulty swallowing, and epiglottitis affecting breathing, also occurred . No difference in the presenting symptoms has been described between HIV positive and HIV negative MPX cases in this current outbreak .
The lesions progress, usually within 12 days, simultaneously from the stage of macules to papules, vesicles, pustules, crusts, and scabs, before falling off . This is different in chickenpox (varicella), where progression is more varied. The lesions are deep-seated, may be centrally depressed (umbilicated) and can be accompanied by pruritus and/or pain. Scratching may facilitate secondary bacterial infections. In endemic settings, the number of lesions may range from a few to thousands , and increasing number of lesions is correlated with increased disease severity. Lesions on the oral mucosa (enanthem) or ophthalmic mucosa may also be present. Prior to and concomitant with the rash, lymphadenopathy is observed in many patients, which is usually not observed in smallpox or varicella [2,4]. Clinical manifestations in travel-related cases previously detected in western countries have usually been mild, sometimes with very few lesions .
The clinical presentation of MPX includes symptoms and lesions that may be difficult to distinguish from smallpox, other orthopoxvirus, parapoxvirus and molluscipoxvirus infections, and, to some extent, chickenpox (Varicella) and secondary syphilis. The main difference between smallpox, chickenpox and MPX is that MPXV causes lymphadenopathy (e.g. in the cervical or inguinal region) while Smallpox virus and Human alphaherpesvirus 3 (the causative agent of chickenpox) usually do not . Other orthopoxviruses (e.g., Cowpox virus, Camelpox virus, Buffalopox virus), parapoxviruses (e.g. Orf virus, Pseudocowpox virus, Bovine opular stomatitis virus) and molluscipoxviruses usually cause localised skin lesions in humans. However, MPX can also present with localised skin lesions. Lesions on palms and soles might be similar to the manifestation of secondary syphilis too, although the morphology of the lesions is different.
The majority of human MPX cases experience mild to moderate symptoms typically lasting two to four weeks followed by complete recovery with supportive care . Disease severity may vary depending on transmission route, host susceptibility, and the quantity of virus inoculated , with invasive modes of exposure causing more severe disease and a shorter incubation period . A minority of cases (10–13%) in the 2022 outbreak have been hospitalised for management of pain or complications such as secondary skin infections, abscesses, difficulty swallowing or for isolation purposes [25,27]. Serious complications are rare and include epiglottitis, myocarditis and encephalitis . Sporadic fatal cases have been reported .
Complications in endemic countries include encephalitis, secondary skin bacterial infections, dehydration, conjunctivitis, keratitis, and pneumonia. The case-fatality rate of MPX ranges from 0% to 11% in outbreaks in endemic areas, with mortality mostly affecting young children . People living in or near tropical forested areas may have indirect or low-level exposure to infected animals, possibly leading to subclinical (asymptomatic) infection [19,34]. In endemic areas, immunocompromised individuals were reported being especially at risk of severe disease . In the outbreak in Nigeria in 2017, patients with concurrent HIV infection had more severe disease with more skin lesions and associated genital ulcers compared to HIV-negative individuals. No deaths were reported among HIV-positive patients . In Nigeria, from September 2017 to June 2022, 257 confirmed cases were identified, including nine deaths (CFR=3.5%), at least five of which were immunosuppressed [37,38]. Major disease sequelae are usually disfiguring scars and permanent corneal lesions . However, little information is available on MPX in immunocompromised patients in the 2022 multi-country outbreak so far.
Complications such as respiratory distress, secondary bacterial infections and encephalitis, and sequelae were found to be less common in patients vaccinated against smallpox . In addition, the MPX secondary attack rate among household members was significantly lower among those who had had prior smallpox vaccination . However, a history of smallpox vaccination decades prior to infection had no effect on the duration of illness or disease severity [32,40].
Since May 2022, a large multi-country outbreak of MPX has been ongoing [41,42]and all EU countries have reported cases. The outbreak is driven by human-to-human transmission via close contact. The majority ofcases are men who have sex with men (MSM). More information about the 2022 outbreak in the EU/EEA is available on ECDC website: https://www.ecdc.europa.eu/en/monkeypox-outbreak.
Monkeypox is regarded as the most significant orthopoxvirus infection affecting humans since the eradication of smallpox . Monkeypox virus was first isolated in 1958 from pox lesions during an outbreak of vesicular disease among captive cynomolgus macaques imported from Singapore into Denmark for polio-vaccine-related research .
Although the disease name suggests that monkeys are the primary host, the specific animal reservoir of MPXV remains unknown . In nature, many animal species were found to be infected with MPXV, including rope and tree species of squirrels, Gambian giant rats, striped mice, dormice, and primates . Some evidence suggests that native African rodents such as Gambian giant rats (Cricetomys gambianus) and squirrels might be a natural reservoir of the virus [44,45].
In 1970, the first human isolate of MPXV was reported in a child in the equatorial region of the Democratic Republic of the Congo (DRC), nine months after the eradication of smallpox in that country . Subsequently, sporadic cases were reported from the rainforest areas of central and western Africa, and large outbreaks were identified, mainly in the DRC, where the disease is currently considered endemic [46,47].
Following the declaration of smallpox eradication in 1980 by the World Health Assembly, the World Health Organization sponsored enhanced MPX surveillance efforts in the central regions of the DRC and some limited animal and human ecological studies were undertaken . This led to a major increase in the reported incidence of MPX.
Human MPX was reported outside of Africa for the first time in 2003, when a MPX outbreak occurred in the United States [5,48]. A total of 81 human MPX cases in several states were reported among people who had reported close contacts with pet prairie dogs; those prairie dogs were housed with MPXV-infected rodents imported from Ghana. No human-to-human transmission was identified, and no deaths were reported. Following this outbreak, there is no evidence that the virus became enzootic in wildlife in the United States.
While the majority of documented MPX cases have occurred in DRC, the number of cases in other West and Central African countries have increased during the last decade . Since 2016, confirmed MPX cases have been reported from the following African countries: Cameroon (Clade II) , Central African Republic (Clade I), the DRC (Clade I), Liberia (Clade II), Nigeria (Clade II), the Republic of the Congo (Clade I) and Sierra Leone (Clade II) [1,50-52].
Until 2022, imported human cases have been reported among others by the United Kingdom [53-55], Israel  and Singapore [57,58]. All these cases had travelled from Nigeria. In 2021, the United Kingdom reported one family cluster: the primary case was exposed in Nigeria and subsequently infected his family members back in the United Kingdom [59,60].
The increase in reported incidence of MPX in Africa may be partly attributable to decreasing herd immunity in the population following the cessation of the smallpox vaccination program in the early 1980s. Other explanatory factors might be changes in the virus itself and modifications to ecosystems that may have caused the natural reservoir’s population density to rise  and more frequent human-wildlife interactions.
MPXV is transmitted to humans through close contact with an infected animal or human, or contact with material contaminated with the virus [1,61]. The virus enters the body through broken skin or the mucous membranes .
Virus transmission through direct or indirect contact with live or dead animals may occur by bite or scratch, bush meat preparation, direct contact with body fluids, or lesions from an infected animal or contaminated material (indirect contact) . Eating inadequately cooked meat of an infected animal is an additional possible risk factor .
The onset of the rash is considered the start of the infectious period; however, it is believed that people with prodrome symptoms can also transmit MPXV .
Human-to-human transmission of MPX occurs through close contact with infectious material from skin lesions of an infected person, through respiratory droplets in prolonged face-to-face contact and through fomites [2,19,61]. Human-to-human transmission also occurs during sexual contact . Whether transmission of MPXV through genital secretions can occur is currently unclear. MPXV DNA was identified in seminal fluid samples of young adult male patients in Italy who reported condomless sexual intercourse . The presence of MPXV nucleic acid alone cannot be considered definitive evidence of infectivity.
Other (rare) transmission routes, such as mother-to-child transmission  or nosocomial infection [64,65] have been documented. While transmission through substances of human origin has never been reported, transmission during pregnancy and through invasive bite or scratch from an ill animal  suggest that this transmission mode is theoretically possible.
Considering varicella as the most relevant differential diagnosis, electron microscopy was traditionally used in the past to distinguish herpesviruses from orthopoxviruses. Currently, real-time polymerase chain reaction (real-time PCR) on suspected skin lesions is used to diagnose ongoing MPXV infections. Several real-time PCR assays for specific detection of MPXV or for generic orthopoxvirus detection are available [66-72] and MPX laboratory diagnostics is well established in several laboratories in Europe (see EVD-LabNet ). Scabs, swabs, and aspirated lesion fluid are preferable over blood samples, due to limited duration of viraemia. Results from these specimens show the best correlation with both infectivity and the clinical course of infection.
Serological tests have limited value in MPX diagnostics due to immunological cross-reactivity between human-pathogenic orthopoxviruses , although they can be useful for excluding a recent or past orthopoxvirus infection. For contact investigations and population serosurveys, IgM and IgG detection by enzyme-linked immunosorbent assay (ELISA) or immunofluorescent antibody assay is available in some laboratories.
Diagnostic procedures on, and manipulation of specimens suspected to contain MPXV should be performed in BSL-2 facilities as a minimum [75,76]. MPXV is classified as a safety group 3 biological agent. Activities involving the handling of MPVX should therefore only be done in working areas corresponding to at least containment level three .
Case management and treatment
Newly-identified cases of MPX should undergo a medical assessment for severity and risk factors (e.g., underlying conditions or medications affecting immune competence, untreated HIV infection etc.). Those at increased risk of severe disease from MPX may require hospitalisation and/or treatment with antivirals. People at increased risk for severe disease include infants and young children, pregnant women, the elderly and severely immunocompromised persons.
Cases should be instructed to isolate until their rash heals completely, which indicates the end of infectiousness, including mainly the following:
- They should remain in their own room, when at home, use designated household items (clothes, bed linen, towels, eating utensils, plates, glasses), which should not be shared with other members of the household.
- They should avoid contact with immunocompromised and persons at risk for severe disease (infants, pregnant women) until their rash heals completely.
- They should be monitored by public health authorities (e.g., via telephone calls or other means, according to national guidance) and can temporarily leave their home (e.g., for medical appointments and necessary exercise for their mental health stability), provided they wear a medical facemask and their rash is covered (e.g., long sleeves and pants).
- They should practice careful hand and respiratory hygiene for themselves and everyone in the household; a medical face mask is recommended when in contact with other people.
- They should abstain from sexual activity until their rash heals completely (no new lesions appear; scabs have fallen off and new skin has formed).
- They should avoid contact with any mammalian animals (see also section on human-to-animal transmission).
Treatment is primarily symptomatic and supportive (alleviation of fever, pruritus and pain, and hydration), including prevention and treatment of secondary bacterial infections. Tecovirimat is the only antiviral drug with an indication for the treatment of orthopoxvirus infections, including MPX, authorised by the EMA . Brincidofovir and cidofovir are other antiviral drug options for severe MPX cases, but have significant side effects .
Public health control measures
Public health authorities can take several public health measures to mitigate transmission:
- Raise awareness by appropriately targeted communication to those most at risk for transmission or severe disease, including active involvement of key stakeholders at the community level.
- Facilitate early diagnosis of cases through easy access to health services with well-informed clinicians and accessible diagnostics and management guidance.
- Facilitate early detection of cases by contact tracing in outbreak settings ;
- Facilitate isolation of MPX cases,
- Implement appropriate infection prevention and control measures in healthcare settings .
- Implement a national vaccination strategy against MPX.
Infection control, personal protection and prevention
Populations at increased risk of infection
Sexual contact seems to be a particular risk factor driving the 2022 monkeypox outbreaks. Cases have been identified primarily but not exclusively among men who have sex with men. Particular sexual practices (e.g., having multiple and frequent anonymous sexual contacts, receptive anal sex) may put people at higher risk of infection. People who closely interact with someone who is infectious, including healthcare workers, household members, sexual partners and commercial sex workers are at greater risk for infection[41,42] [21,41,42]. Occupational exposure and infection from orthopoxviruses have been occasionally reported among laboratory personnel handling virus-containing specimens .
Vaccine and vaccination strategies
Previous vaccination against smallpox can confer some level of cross-protection against MPX, which was estimated from older studies to reach 85% . The protective effect of smallpox vaccination wanes with time, although serosurveys indicate that it can last more than 20 years. However, despite the waning effect, it is believed that smallpox vaccine confers lifelong protection against severe disease due to memory B and T cells and therefore some degree of protection should be expected in the population of adults in the EU/EEA currently over 50 years of age . In one case series in the 2022 multi-country outbreak, 18% of cases developed MPX despite smallpox vaccination in their childhood 
On 27 July 2022, EMA’s human medicines committee (CHMP) recommended extending the indication of the 3rd generation smallpox vaccine ImvanexTM (Modified Vaccinia Ankara – MVA) to include protecting adults from MPX . Scientific evidence on vaccine effectiveness of MVA in preventing MPX is currently limited.
MVA is administered as a subcutaneous injection, preferably in the upper arm, with a two-dose regimen, with the second dose given at least 28 days after the first. However, data from human and animal studies suggest that a single dose of MVA shows rapid increase of antibodies which could translate into fast protection against MPX in the very short term, and that the second dose serves to achieve optimal immunogenicity and extend the durability of protection .
Use of a smaller quantity of MVA administered intradermally in the forearm (0.1mL vs. 0.5mL subcutaneously) has been recently approved in the US, based on data showing immunological non-inferiority [86,87]. On 19 August 2022, EMA announced that its Emergency Task Force (ETF), after reviewing available data, suggested that national authorities may decide to use MVA as an intradermal injection at a lower dosage (fractional dose) as a temporary measure to protect at-risk individuals during the current monkeypox outbreak while supply of the vaccine is limited .
MPX vaccination strategy could include post-exposure, pre-exposure or combined (pre- and post-exposure) preventive vaccination.
Primary Preventive Vaccination (PPV) in the 2022 outbreak
Primary preventive (pre-exposure) vaccination (PPV) refers to the vaccination of individuals at risk of exposure to MPX.
Mathematical modelling indicates that vaccination, if uptake is sufficiently high and when used in addition to effective isolation of cases and tracing of contacts, would substantially increase the potential to control the 2022 multi-country outbreak . PPV would be the most efficient vaccination strategy when there is less effective contact tracing. Targeting PPV to smaller groups of individuals at high risk of exposure and/or at risk of transmitting the disease may increase vaccine efficiency in outbreak control. Therefore, the prioritisation of individuals at substantially higher risk of exposure can be considered. For instance, men who have sex with men or other at-risk groups may be offered PPV based on a risk assessment according to certain criteria and behaviour (i.e., recent history of multiple casual sexual contacts and/or sexual partners, attending sex on premises venues, or group sex or chemsex practices, or a proxy marker such as recent bacterial STI).
PPV for occupational risk exposure can also be considered for staff members who work in sex on premises venues, such as saunas, if they are regularly exposed to items (i.e., linens) or surfaces likely to be contaminated with body fluids or skin cells. Also, professionals in healthcare or laboratory settings and outbreak response team members may be targeted for PPV based on a risk assessment.
Post-exposure Preventive Vaccination (PEPV) in the 2022 outbreak
Post-exposure vaccination (PEPV) refers to the immunisation against MPX of close contacts of cases to prevent the onset of disease or mitigate disease severity.
Based on mathematical modelling results, PEPV of contacts of cases of the 2022 multi-country outbreak would be the most efficient vaccination strategy (i.e., increasing the probability of outbreak control per vaccinated individual) in settings with more effective tracing and higher vaccine uptake levels. The absolute probability of outbreak control per vaccinated individual is expected to be lower with PEPV than with PPV vaccination.
The priority target groups for PEPV are close contacts of cases i.e., sexual partners, household contacts, HCWs and individuals with other prolonged physical or high-risk contact as defined in the recent ECDC publication on contact tracing . Among these, contacts with a high risk of developing severe disease like children, pregnant women and immunocompromised individuals should be prioritised for PEP vaccination, even if there are uncertainties with respect to vaccine effectiveness in these groups to a larger extent than in the general population.
PEPV of contacts and of contacts of contacts, according to a ring vaccination scheme as conducted during recent Ebola outbreaks, could also be considered. The time of vaccination should be as close as possible to the potential date of exposure.
Ideally, PEPV should be administered within four days of first exposure (and up to 14 days in the absence of symptoms). Community engagement efforts for the identification of contacts around cases should be put in place to achieve a significant impact in terms of lowering disease burden and transmission. Data on effectiveness and safety of PEPV are needed to refine benefits and risks in the context of MPX prevention strategies.
Combined (pre- and post-exposure preventive vaccination) in the 2022 outbreak
A suitable option to prevent infection in the context of limited vaccine supply and mild symptoms, would be to offer PEPV to close contacts of cases and, in addition, to consider targeted PPV of individuals at substantially higher risk of exposure.
Special considerations in healthcare settings and home isolation
The principal mode of transmission is thought to be direct contact with MPX lesions or with objects contaminated with lesion material such as clothing and bed linen. Therefore, caregivers and relatives should avoid touching skin lesions with their bare hands, wear disposable gloves, and observe strict hand hygiene.
In healthcare settings, prevention of transmission is based on standard, contact, and droplet infection control precautions during the care of symptomatic suspected and confirmed MPX patients . More detailed options are available in guidance documents developed by the World Health Organization  and the UK Health Security Agency . Monkeypox infection prevention and control guidance for primary and acute care settings have also been developed by ECDC .
Safety of Substances of Human Origin
All potential donors should be carefully interviewed regarding contacts with infected (confirmed or suspected) MPX cases, infected animals, or travels to affected areas. Medical history data on these risk factors should be collected in the case of deceased donors.
Based on the incubation period of MPX, it is recommended to defer asymptomatic donors that have been in contact with (confirmed or suspected) MPX cases from substances of human origin donation for a minimum of 21 days from the last day of exposure.
Since the MPX prodromal stage varies in duration (one to four days ) and symptoms can be non-specific and mild [39,91-93] or absent , careful examination for any possible signs of infection should be performed even after the expiration of the deferral period (at least 21 days from the last day of exposure). Examination should not overlook mild and non-specific signs like headache or fatigue or anogenital skin lesions.
Special considerations to mitigate the risk of animal-to-human and human-to-animal transmission
To reduce animal-to-human transmission in an area with active MPXV circulation among wildlife animals, it is recommended to avoid contact with animal reservoirs as well as any materials that have been in contact with a potentially sick animal.
Similarly, human MPX cases should avoid close direct contact with animals including pet animals, livestock and wild (captive) animals. Similarly, close contacts of cases should avoid being in close direct contact with animals for 21 days after the last exposure to the virus. To mitigate the risk of wild animals entering in contact with the virus, waste, including medical waste, should be disposed of in a safe manner and should not be accessible to rodent and other scavenger animals. Implementing actions to minimise the presence of the virus in the sewage system, where numerous rodents live, should be considered.
Disclaimer: The information contained in this fact sheet is intended for the purpose of general information and should not substitute individual expert advice or judgement of healthcare professionals.
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