Factsheet for health professionals on monkeypox
Human monkeypox (MPX) is a zoonotic viral disease caused by the Monkeypox virus (MPXV) [1,2]. The clinical presentation is similar to smallpox. Human monkeypox causes outbreaks in the tropical rainforest regions of Central and West Africa and is not a notifiable disease at the EU/EEA level. Human monkeypox was recognised as a human disease in 1970 [3,4].
The first outbreak of MPX reported outside of Africa [5,6] was an outbreak linked to an importation of infected mammals in 2003 in the United States. More recently, in 2018 and 2019, in the context of a large MPX outbreak in Nigeria, two travellers from the United Kingdom , one from Israel , and one from Singapore [9,10], all with travel history in Nigeria were diagnosed with MPX. A healthcare worker from the United Kingdom caring for one of the cases was secondarily infected . This was the first time that travellers were associated with MPXV transmission outside of an outbreak setting. These MPX cases serve as a reminder to remain vigilant about emerging zoonoses .
Monkeypox virus is an enveloped double‐stranded DNA virus with a genome size 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-related, poxviruses . Two phylogenetically distinct clades of MPXV have been identified through genomic sequencing: the Central African (Congo Basin) clade and the West African clade. Typically, the Central African MPXV is associated with more severe disease, higher mortality, and more frequent human-to-human transmission [2,5,14,15]. Genetic differences between the viral genomes of the two clades might explain differences in viral clearance and pathogenesis [16-18]. Differences in disease severity may also be affected by transmission route, host susceptibility, and the quantity of virus inoculated .
Clinical features and sequelae
Human monkeypox often begins with a combination of the following symptoms: fever, headache, chills, exhaustion, asthenia, lymph node swelling, back pain and muscle aches [15,19]. Commonly, within one to three days after onset of fever, the patient develops a rash, which tends to first appear on the face and then spreads to other parts of the body, including hands and feet [2,20-22]. The cutaneous lesions often first present as macules, evolving successively to papules, vesicles, pustules, crusts and scabs . The number of lesions may range from a few to thousands . Cutaneous lesions generally all appear at the same stage which is a hallmark characteristic of smallpox and MPX, and distinguishes them from chickenpox (varicella). For most people, MPX is a self-limited disease, typically lasting two to four weeks and resulting in complete recovery .
The clinical presentation of MPX includes symptoms and lesions that may be difficult to distinguish from smallpox, other orthopoxvirus and parapoxvirus infections, and, to some extent, chickenpox. The main difference between smallpox and MPX is that MPXV causes lymphadenopathy (e.g. in the cervical or inguinal region) while smallpox virus and chickenpox virus usually do not . Other orthopoxviruses (i.e. cowpox virus, camelpox virus buffalopox virus) and parapoxviruses (i.e. Orf virus, pseudocowpox virus bovine papular stomatitis virus) usually cause localised skin lesions in humans, and animal contacts are often identified in the case histories. Although the clinical manifestation of MPX is milder than that of smallpox, the case fatality can still reach up to 11%. Mortality is higher among children and young adults, and immunocompromised individuals are especially at risk of severe disease . 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 .
People living in or near tropical forested areas may have indirect or low-level exposure to infected animals, possibly leading to subclinical (asymptomatic) infection [21,25].
Monkeypox is regarded as the most important orthopoxvirus infection in humans since the eradication of smallpox . Human monkeypox virus was first isolated in 1958 from pox lesions during an outbreak of vesicular disease among captive cynomologus 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 . Similar to humans, monkeys are considered disease hosts . 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 the Gambian giant rats (Cricetomys gambianus) and squirrels might be a natural reservoir of the virus [26,27].
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 [4,28].
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 ecologic studies were undertaken . This led to a major increase in the reported incidence of MPX.
In 1996–1997, the largest outbreak of MPX ever was reported in the Kasai Oriental region of the DRC. After a follow-up investigation in 1997, a total of 511 human cases were identified . Analysis of these cases showed that the proportion of secondary cases was much higher and the case fatality was much lower than in earlier surveillance periods .
Human monkeypox was reported outside of Africa for the first time in 2003 when a MPX outbreak occurred in the United States [5,6]. Importation of the disease was traced back to rodents from Ghana shipped to Texas, US and housed close to prairie dogs upon importation . All human cases of MPX fell ill following contact with the infected prairie dogs.
While the majority of documented MPX cases have occurred in the DRC, the number of cases in other West and Central African countries have been increasing during the last decade . Since 2016, confirmed MPX cases have been reported from Central African Republic, the DRC, Liberia, Nigeria, the Republic of the Congo and Sierra Leone [1,30,31]. In September 2017, Nigeria experienced its largest outbreak of MPX, with 311 suspected and 132 confirmed cases, 38 years after the last reported case [15,21,32–35].
The increase in reported incidence of MPX 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 of ecosystems that may have caused the natural reservoir’s population density to rise .
In September 2018, three individual patients in the United Kingdom were diagnosed with MPX; two had recently travelled to Nigeria, and the third case was a healthcare worker caring for one of the cases . The notification of three imported cases in a relatively short period of time could indicate an enhanced circulation of MPXV in western Africa, notably in southern Nigeria in 2017 and 2018. This is supported by continuing reports of sporadic cases in Nigeria after the 2017 outbreak and by the first notified outbreak in southern Cameroon in 2018 [35,36]. One of the primary cases reported contact with a person with suspected rash at a family gathering and consuming bush meat in Nigeria. The case of the healthcare worker provides indisputable evidence of human-to-human transmission from an infected patient with a MPXV belonging to the West African clade . In October 2018, Israel reported an imported MPX case from Nigeria . In May 2019, an additional case imported from Nigeria was reported by Singapore [9,10].
In December 2019, a new case of MPX imported from Nigeria was reported by the United Kingdom as reported in the ECDC Communicable Disease Threats Report (CDTR), week 49.
MPXV is transmitted to humans through contact with an infected animal or human, or with material contaminated with the virus [1,37]. The virus enters the body through broken skin, the respiratory tract or the mucous membranes . The incubation period is typically 6 to 16 days, but can range from 5 to 21 days . Immune markers provided evidence of asymptomatic MPX infections in individuals vaccinated against smallpox and others that had not been vaccinated [38,39].
Virus transmission through direct or indirect contact with live or dead animals is assumed to be the main factor for human MPX infections . This 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 .
Human-to-human transmission is rare, but serial transmission events have been reported . Similar to smallpox, human-to-human transmission of MPXV occurs mostly through large respiratory droplets during direct and prolonged face-to-face contact. In addition, MPXV can be transmitted by direct contact with body fluids of an infected person or with contaminated objects, such as bedding or clothing [2,21,37].
Other transmission routes, such as mother-to-child transmission  or nosocomial infection [11,42] 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.
The capacity for detection of the MPXV DNA genome from suspected skin lesions by real-time polymerase chain reaction (real-time PCR, known also as quantitative polymerase chain reaction (qPCR)) is well established in several laboratories in Europe (see EVD-LabNet Directory Search) . Scabs, swabs and aspirated lesion fluid are preferable over blood samples, due to limited duration of viremia. Results from these specimens show the best correlation with both infectivity and the clinical course of infection. Recent real-time PCR approaches can discriminate not only MPXV from other orthopoxviruses but also the two MPXV clades described above.
Serology has limited value due to the immunological cross-reactivity between human-pathogenic orthopoxviruses, although it can be useful for excluding recent 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. Immunohistochemistry can be used to identify antigens in biopsy samples and to exclude or identify other suspicious agents.
Diagnostic procedures on, and manipulation of, specimens suspected to contain MPXV should be performed in BSL-2 facilities as a minimum [45,46]. MPXV is classified as a 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
There is no specific vaccine or treatment available for MPX. Treatment is symptomatic and supportive, including prevention and treatment of secondary bacterial infections . There is currently no vaccine that is specifically licensed for use against MPX. First- and second-generation smallpox vaccines, comprised of live replication-competent vaccinia virus and administered during the smallpox eradication programme, elicit effective protection against MPX [24,47]. While these vaccines, due to concerns about adverse events [48,49], have generally not been used to control MPX, in the United States in 2003, 30 individuals did receive smallpox vaccine during that outbreak . A third-generation smallpox vaccine (MVA-BN/Imvanex) developed for individuals, in which previous versions of smallpox vaccine are contraindicated, is derived from Modified Vaccinia Ankara (MVA), a virus that has lost the ability to replicate in primate cells. This vaccine has a much more favourable safety profile than previous generations of smallpox vaccines. It has been approved in Europe for immunisation against smallpox in adults and was employed in the United Kingdom in 2018 following the identification of MPX cases . Smallpox vaccination was also offered to close contacts in Israel and in Singapore in 2018 and 2019, respectively [51,52].
Public health control measures
Public health control measures are aimed to reduce human-to-human transmission through:
- Early recognition by specialist assessment and laboratory investigation
- Isolation of infected patients
- Implementation of appropriate infection prevention and control measures in healthcare settings (standard, contact, and droplet precautions)
- Early detection of possible new cases by contact tracing in outbreak settings.
Smallpox vaccine can be offered to contacts including i) healthcare workers caring for patients, ii) first-line responders and iii) individuals with close contact exposure to MPX which can be considered in outbreak settings [1,5,7]. The protective effect of smallpox vaccine against MPXV infection has been demonstrated in studies in the 1980s which showed up to 85% effectiveness . WHO suggests that national health authorities should consider offering the smallpox vaccine to healthcare workers and those treating, or exposed to, patients with MPX or their samples [21,53,54]. According to the United States Centers for Disease Control and Prevention (US CDC), early post-exposure vaccination with the smallpox vaccine within 14 days after close contact exposure is an option to consider to reduce symptoms of MPX [54,55].
Following the worldwide eradication of smallpox, the smallpox vaccine is not available to the general public, but vaccine stockpiles are maintained by several countries and WHO . Smallpox vaccines manufactured using older technologies should not be administered to immunocompromised persons [21,56].
To reduce the risk of animal-to-human transmission, control measures should include activities to control the importation of potential carrier species (e.g. limit or ban the movement of suspect species, apply quarantine or discard potentially infected species) .
Infection control, personal protection and prevention
The principal mode of transmission is thought to be direct contact with MPX lesions or with the patient’s belongings that have been in contact with the lesions. Therefore, caregivers and relatives should avoid touching skin lesions with 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 care of symptomatic suspected and confirmed MPX patients . More detailed options are available in guidance documents developed by Public Health England (PHE) during the response to travel- associated MPX cases: ‘Monkeypox: information for primary care’  and ‘Monkeypox: Guidance for environmental cleaning and decontamination’ .
To reduce animal-to-human transmission in an area with active MPXV circulation, it is recommended that contact with potential animal reservoirs (e.g. rodents and non-human primates) and with materials that have been in contact with a potentially sick animal or animal blood is avoided. Additionally, meat should be appropriately cooked prior to consumption .
Substances of Human Origin
Substances of Human Origin (SoHO) safety authorities should be aware that travellers returning from affected areas may pose a risk of MPXV infection. According to EU Directive 2004/33/EC, asymptomatic blood donors returning from malaria risk areas should be deferred from blood donation for at least four months . As there is an overlap between the areas at risk for malaria and MPX, this should also prevent possible blood donations from MPXV-infected travellers. Although donor deferral for malarial risk is not required when the donation is used exclusively for plasma for fractionation, multiple pathogen reduction steps used in the fractionation process have been effectively used for the inactivation of vaccinia virus and may also provide safety assurance against the presence of poxviruses like MPXV in plasma-derived medicinal products. Therefore, deferral of asymptomatic donors of plasma for fractionation who are returning from MPX-affected areas is not recommended by the authorities.
According to EU directives, cell, tissue and organ donors returning from malaria-endemic areas are only deferred when laboratory screening for malaria is positive [60,61]. Therefore, prudent practice would be to defer cell, tissue and organ donors for a minimum of 21 days after returning from an area affected by MPX. Based on the incubation period, the US CDC have recommended that asymptomatic close contacts of infected people or animals be placed under fever surveillance for 21 days . The 21 days would be a minimum deferral from SoHO donation if such contact had occurred.
Recipients of attenuated smallpox vaccine for the prevention of MPXV infection should be deferred from blood donation for eight weeks after vaccination.
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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.