Human Atypical Monkeypox: Early Warning for Global Outbreak? : Infectious Diseases & Immunity

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Human Atypical Monkeypox: Early Warning for Global Outbreak?

Wang, Hui-Fang1,2; Zhang, Yang2; Zhang, Ji-Yuan2,∗; Wang, Fu-Sheng2,∗

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Infectious Diseases & Immunity: October 2022 - Volume 2 - Issue 4 - p 239-241
doi: 10.1097/ID9.0000000000000068
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The first outbreak of monkeypox out of Africa occurred in the United States in 2003. During this outbreak, monkeypox cases were infected by monkeypox virus (MPXV) through native prairie dogs housed with infected African rodents imported from Ghana.[1] From that, sporadic travel-associated cases were reported in nonendemic countries, including Israel, United Kingdom, and Singapore.[2] This year since May 7, most increasing monkeypox cases without any travel history to endemic areas have been diagnosed out of Africa. As per the latest reports from the Centers for Disease Control and Prevention on June 16, a total of 2027 confirmed cases have been reported in 39 countries or regions. The World Health Organization (WHO) warned that this endemic is an atypical, human-to-human transmission among human population.[3,4] More recently, the Centers for Disease Control and Prevention declaimed that there are at least two distinct monkeypox outbreaks underway outside Africa.[5] Whether monkeypox can became a global health threat or not has drawn attention worldwide. In this review, we summarize the general clinical features of current outbreak to better understand the management and guard against the potential threaten.

Characteristics of the pathogen and disease


Monkeypox virus is an enveloped double-stranded DNA virus belonging to the Orthopoxvirus genus, Chordopoxvirinae subfamily, Poxviridae family.[6] Under the electron microscope, MPXVs are relatively large particles, with brick shape, approximately 200 to 250 nm in size.[7,8] In 1958, MPXV was isolated and identified for the first time in monkeys shipped from Singapore to Denmark. However, the first human case was reported in 1970 from a child who was suspected of having smallpox in the DRC (Democratic Republic of the Congo).[9] Although MPXV was first identified in monkeys, rodents such as squirrels and Gambian rats are most likely to be the natural host of MPXV.[10] Monkeypox virus has two distinct genetic clades, the Central African clade and the West African clade.[11] In this outbreak, several teams from Portugal, Belgium, the United States, and so on, have reported the genome sequences of the recent MPXV and found that the DNA sequences of MPXVs are homologous, all belonging to the mild West African clade, and closely related to the MPXVs discovered in the United Kingdom, Singapore, and Israel in 2018 and 2019.[3,8,12–14]


Animal-to-human transmission can occur from direct contact with the infected animals. The first outbreak out of endemic countries in 2003 was due to the shipment of rodents from Ghana to America.[1] Human-to-human transmission can occur through direct or indirect contact with an infected person's bodily fluids, skin lesions, or respiratory droplets through contaminated fomites. In 2018, a health care worker caring for confirmed cases was diagnosed with monkeypox in the United Kingdom, which provided indisputable evidence of human-to-human transmission of MPXV.[15,16] On May 21, the WHO issued a statement that there was a human-to-human transmission among the population who had close contact with symptomatic patients.[3]

What is particularly noteworthy in this outbreak is that many of the reported monkeypox cases are occurring within sexual networks, and the vast majority of confirmed cases in the United Kingdom, Portugal, and Spain are gay, bisexuals, or other men who have sex with men.[3,17] The case clusters include men aged 20 to 50 years, and most of them have no immunity against MPXV.

Clinical features and diagnosis

Monkeypox is usually an acute self-limited disease with symptoms lasting 2 to 4 weeks. There was an overall case fatality rate of 8.7%, with a significant difference between clades. Generally, the Central African MPXV is associated with more severe disease and a higher mortality rate of 10.6%, whereas the West African branch has a mortality rate of approximately 3.6%.[2] The incubation period of monkeypox ranges from 5 to 21 days. Symptoms can include fever, headache, muscle aches, backache, chills, and exhaustion. Typically, the rash often starts on the face but then spread to other areas. The rash will go through different stages before forming a scab and finally falls off.[18] Cases with the above clinical manifestations are laboratory confirmed for monkeypox either by real-time polymerase chain reaction or DNA sequencing from a patient specimen. Optimal clinical specimens include specimens from skin lesions such as swabs of vesicular lesions, exudate, or crusts stored in a dry, sterile tube and kept cold.[19] The clinical differential diagnosis must be considered such as other rash illnesses, such as smallpox, chickenpox, measles, syphilis, and so on.[3] Lymphadenopathy is a distinctive feature of monkeypox compared with other diseases.[10]

Despite potential scarring and skin discoloration, convalescent individuals could gain long-term immunity against MPXV. Complications of monkeypox include secondary infections, bronchopneumonia, sepsis, and encephalitis.[11] Of note, children and immunocompromised individuals are more prone to develop severe forms of the disease.

Prevention and treatment


To interrupt the transmission of MPXV, confirmed and suspected cases require early detection, early isolation, early diagnosis, and early treatment. Belgium health authorities have mandated on May 19 that monkeypox cases should self-quarantine for 21 days.[20] Close contacts of a confirmed case should be isolated and monitored as well.

The genus Orthopoxvirus is immunologically cross-reactive and cross-protective.[21] A previous study showed the smallpox vaccine was 85% effective against monkeypox and was still effective against monkeypox for more than 25 years.[10] Jynneos (also named Imvamune or Imvanex), a smallpox vaccine developed by Bavarian Nordic in Denmark, was approved by the US Food and Drug Administration in 2019 to prevent smallpox and monkeypox infections.[10] The monkeypox vaccine that was first approved globally has not been widely administered yet. Currently, a “ring vaccination” strategy is recommended for high-risk individuals and close contacts to contain the spread of the virus.[22] The Centers for Disease Control and Prevention had stated that vaccination within 4 days of exposure may prevent disease onset, and vaccination within 14 days may reduce disease severity.[11]


To date, there is no special treatment available for monkeypox. Supportive treatment should be fully optimized to alleviate symptoms, manage complications, and prevent long-term sequelae. Infected individuals should remain isolated and cared for carefully, wear a surgical mask, and cover the lesions as much as possible until all scabs naturally slough off and form a new layer of skin. Patients should be offered fluids and food to maintain good nutritional status. Complications should be treated as indicated.[3,11]

For severe cases, antiviral compounds are optional. Several compounds have shown promise as antiviral therapeutics against Orthopoxvirus species. Tecovirimat, a potent inhibitor of Orthopoxvirus VP37 protein required to form infectious viral particles, was approved in 2022 by the European Medicines Agency to treat smallpox, monkeypox, and cowpox. Brincidofovir, a DNA polymerase inhibitor approved by the Food and Drug Administration for smallpox in all age groups, may be efficient for monkeypox.[10] A retrospective observational study recently reported that monkeypox patients treated with brincidofovir have developed elevated liver enzymes and resulted in cessation of therapy, whereas one patient treated with tecovirimat has experienced no adverse effects and had a shorter duration of viral shedding and illness.[16] However, further clinical research is required to clarify the effectiveness of tecovirimat and brincidofovir in large cohort of human monkeypox cases. Immunotherapy, such as intravenous vaccinia immune globulin, was experience-based and needed to be supported by clinical efficacy.[10] New strategies for monkeypox treatment are required to be developed.


Human monkeypox cases had been increasing over the past 50 years. This new outbreak gives an early warning for global outbreak. Government officials, clinicians, and scientists should pay attention to the new situation of this disease. Government officials should be aware that robust surveillance and awareness worldwide, as recommended by WHO, could help to prevent the spread of monkeypox. Clinicians should be alert to any possible cases of monkeypox and then provide optimal clinical care, isolate cases to prevent further spread, identify and manage contacts, and develop effective control to avoid close contact with infected people and animals and potentially contaminated materials. Collaboration among clinicians and scientists is critical to conducting basic, translational, and clinical studies of monkeypox in the further. For example, further insight into the MPXV biology, epidemiology, transmission, and pathogenesis will facilitate precise prevention and treatment of monkeypox, in practically specific vaccines and antiviral drugs.


This study was supported in part by the National Natural Science Foundation Innovation Research Group Project (81721002).

Author Contributions

Fu-Sheng Wang and Ji-Yuan Zhang conceived this study. Hui-Fang Wang and Yang Zhang drafted the manuscript. Fu-Sheng Wang and Ji-Yuan Zhang made critical revision of the manuscript. All authors read and approved the final manuscript.

Conflicts of Interest


Editor note: Fu-Sheng Wang is the editor of Infectious Diseases & Immunity. The article was subject to the journal's standard procedures, with peer review handled independently by this editor and his research group.


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Monkeypox; Atypical; Human-to-human transmission; Zoonosis

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