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Year : 2023  |  Volume : 19  |  Issue : 1  |  Page : 2-8

Re-emergence of monkeypox: Changing epidemiology, clinical manifestations, and preventive strategies

Department of General Medicine, Division of Infectious Diseases, Amrita Institute of Medical Sciences (Amrita Hospital) (AIMS), Kochi, Kerala, India

Date of Submission02-Nov-2022
Date of Acceptance27-Dec-2022
Date of Web Publication28-Mar-2023

Correspondence Address:
Dipu Thareparambil Sathyapalan
Department of General Medicine, Division of Infectious Diseases, Amrita Institute of Medical Sciences (Amrita Hospital) (AIMS), Kochi, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/AMJM.AMJM_43_22

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Monkeypox (MPX), a zoonotic disease caused by an orthopoxvirus, results in a smallpox-like disease in humans. The Democratic Republic of the Congo (DRC) reported the first human cases of MPX in 1970. Before 2000, outbreaks of MPX were regularly reported in Africa Apart from the outbreaks in Congo (2007–2011) and Nigeria (2017–2018), the current outbreak includes mostly men who identified themselves as gay, bisexual or other men who have sex with men. Along with the COVID-19 pandemic, the recent rise in the number of MPX cases reported from non-endemic nations has sounded global concerns and warnings. The current outbreak of MPX in Western countries seems to be a milder disease with reported mortality only of 0.04%. However, according to the World Health Organization, rates of MPX deaths have been between 3% and 6% in recent years, and have reached 11% in the past. This review examines the existing scientific understanding of the disease and highlights the key difference from the classic description of MPX to that of the current epidemic and to provide insight into its changing epidemiology and clinical manifestations.

Keywords: Emerging infectious diseases, monkeypox, MPXV, orthopoxvirus, outbreak
Key Messages: This review examines the existing scientific understanding of the disease and highlights the key difference from the classic description of monkeypox to that of the current epidemic and to provide insight into its changing epidemiology and clinical manifestations

How to cite this article:
Babu A, Nair CV, Moni M, Sathyapalan DT. Re-emergence of monkeypox: Changing epidemiology, clinical manifestations, and preventive strategies. Amrita J Med 2023;19:2-8

How to cite this URL:
Babu A, Nair CV, Moni M, Sathyapalan DT. Re-emergence of monkeypox: Changing epidemiology, clinical manifestations, and preventive strategies. Amrita J Med [serial online] 2023 [cited 2023 Jun 4];19:2-8. Available from: https://ajmonline.org.in/text.asp?2023/19/1/2/372706

  Introduction Top

Although the struggle of humanity to curtail the COVID-19 pandemic is continuing, on July 23, 2022 the World Health Organization (WHO) declared another infectious disease “monkeypox” as a “Global Health Emergency of International Concern.” The double-stranded DNA monkeypox (MPX) virus is a member of the Poxviridae family and belongs to the Orthopoxvirus genus. much like the age-old, eradicated smallpox virus. MPX originally described as a zoonotic disease has had two documented clades, the Congo Basin (Central African) and the West African clade. Historically, the disease has rarely been reported outside of Africa,[1] except for rare instances of the outbreak, where there had been an established epidemiological link to the African continent. The ill-sustained outbreaks outside Africa had given way to an epidemic that has involved more than 50 countries and all the continents, suggesting an epidemiological shift.[2] This review focuses on the evolution of the present MPX epidemic, changes in epidemiology, and clinical characteristics.

  Change in Epidemiology Top

Before 2000, outbreaks of MPX were regularly reported in Africa. The United States recorded the first incidence of MPX in a human outside of Africa, and a link to prairie dogs was established. These dogs had been exposed to dormice and Gambian gophers imported from Ghana. Seventy cases of MPX resulted from this outbreak in the USA, but fortunately no deaths. From 2007 to 2011 there was an outbreak in Congo. In 2017, Nigeria had a large outbreak that affected about 500 people and had a mortality rate of 3%. Other nations have also reported cases, especially after 2018. There were 1376 confirmed cases of endemic human MPX illness worldwide from 1970 to 2021[3] [Table 1] and [Figure 1] and [Figure 2].
Table 1: Monkeypox confirmed cases of the Central and West African Clade in endemic regions from 1970 to 2021[3]

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Figure 1: Monkeypox confirmed cases in endemic regions from 1970 to 2021[3]

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Figure 2: Total monkeypox cases in the year 2022 in comparison to earlier years

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In outbreaks in the Congo Basin, case fatality rates have been reported to range from 1% to 10%, and the viral lineage that is prevalent there seems to be more virulent. Comparatively, the recent outbreaks in Nigeria are caused by the west African lineage, which is linked to a generally lower fatality rate that is typically less than 3%. The reason for this increased mortality in the Congo Basin MPXV infection is due to the selective downregulation of favorable host responses including growth factors and apoptotic factors.[4],[5] The mortality was predominantly reported among young children and HIV patients.

In early 2022, an ongoing outbreak of MPX was confirmed in 52 non-African/non-endemic countries in Europe, America, Asia, North Africa, Australia, and the Middle East. The outbreak marked the first time MPX had spread widely outside Central and West Africa. The earliest cluster of instances was discovered in the United Kingdom, where the first case was discovered on May 6, 2022, in a person having connections to Nigeria through travel (where the disease is endemic). From 18 May onwards, cases were reported from an increasing number of countries and regions, predominantly in Europe but also in North and South America, Asia, Africa, and Oceania.[7]

The current outbreak includes mostly men who identified themselves as gay, bisexual or other men who have sex with men.[8] As of October 26, 2022, a total of 76,510 laboratory-confirmed cases including 36 deaths have been reported worldwide [Figure 3] and [Figure 4], roughly equating to a mortality rate of 0.4 per 1000 confirmed cases. Among the total number of cases, 75,619 have been in countries where MPX has not been reported in the past and 891 cases reported in countries where MPX has been endemic. The magnitude of the current epidemic in comparison to the cases which have been reported till the end of the year 2021 is depicted in [Figure 1] and [Figure 2]. The first case of MPX in the WHO Southeast Asia region was reported in Kerala, India, in a man aged 35 years, who arrived from the Middle East. Currently, there are 17 reported cases of MPX in the country and one death.[9],[10]
Figure 3: Monkeypox: Daily confirmed cases in 2022 globally[6]

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Figure 4: Monkeypox: Cumulative confirmed deaths 2022 globally[9]

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In a study done by Luna et al.,[11] three monophyletic clades were identified from all MPXV genome analyses, which included a newly emerging clade harboring genomes from the ongoing 2022 multi-country outbreak. In a study done by Billioux et al.,[12] MPXV clades have been renamed to make the naming conventions less stigmatizing and they have been renamed as clade 1 (Congo Basin clade), clades 2 (west African clade) and 3 (formerly a subset of the West African clade). Sequencing analysis identified the MPXV clade 3 viruses as the cause of an unprecedented flare-up of MPX in May 2022. The new nomenclature consists of Clade I, Clade IIa, and Clade IIb, with Clade IIb specifically referring to the group of variants that were prevalent during the 2022 global outbreak.[7]

  Monkeypox among Different ages, Gender, and Geographic Locations Top

In a pooled data analysis and literature review conducted by Bragazzi et al.,[13] Data from six clusters in Australia, Italy, the Czech Republic, the United Kingdom, and Portugal, were combined, totaling 124 cases. All of the participants in the analysis of the pooled data were males, with most persons reporting having sex with people of the same gender (97.14%). There was only one instance of a male having sex with a woman. The overall rate of MSM was calculated to be 87.72%. A total of 54.29% of the people were in their 30s, 20.00% were in their 20s, 8.57% are above 40 and 2.86% are above 50. 33 years was the median age of the Portuguese cohort, which ranged from 22 to 51 years, with the majority being aged from 30-39 years (n = 13, 48.15%). Similarly, the median age of the English population was 38 years, with a range of 32 to 43 years. Combining this information with that provided by Vivancos et al.,[14] the current outbreak is distinct from other outbreaks in terms of sex/gender (most cases are male), age (54.29% of people are in their thirties), risk factors, and mode of transmission, with sexual transmission being particularly likely than a respiratory route as suggested by the local genital and anal lesions

Unlike previous outbreaks, most MPXV-associated cases do not seem to be connected to travel histories to endemic regions or known exposure to the infected subject, suggesting that this recent multi-country outbreak is following a unique trend. The unusual increase in cases and the wider geographical spread suggest that multifactorial factors are driving the current outbreak dynamics. These factors could include the discontinuation of smallpox vaccination, a different mode of transmission as suggested by its potential spread across a specific network of people, and an emergence of a newer clade[7]

  Pathophysiology Top

The MPX virus replicates at the site of inoculation and in person-to-person transmission, the respiratory tract, oropharynx, and anogenital areas are the common sites of inoculation. Following inoculation, the virus spreads to regional lymph nodes and subsequent primary viremia resulting in spread and multiplication in the reticuloendothelial system.[14] The entire progression constitutes the incubation period, which usually lasts seven to fourteen days, with a maximum reported duration of 21 days. During this period an individual remains non-infectious. The multiplication in the reticuloendothelial system culminates in secondary viremia and spread to other organ systems including skin, eyes, lungs, and gastrointestinal tract among other organs. Secondary viremia coincides with the prodromal phase and a person is considered particularly contagious starting from this period for the next two weeks until the lesions are crusted.[15]

  Clinical Spectrum of the Disease, Historically and in the Current Outbreak Top

Classical Clinical presentation

The clinical presentation of MPX is classically divided into two phases: invasive and cutaneous phases. The invasive phase precedes the cutaneous eruptions and is characterized by prodromal symptoms including fever, headache, chills, malaise, limb pain, vomiting, and regional lymphadenopathy. Cutaneous manifestations were observed 1-3 days after the onset of fever and are characterized by a diffused vesiculopustular rash that appears over 2–3 weeks in the following order of macules, papules, vesicles, pustules, crusts, and scars. Lesions were monomorphic, the rash usually appears first in the head and neck region and then migrates to other parts of the body. The characteristic feature of MPX which helps to distinguish it from chicken pox is the non-pleomorphic nature of the skin eruptions and the preferential involvement of the cutaneous lesions over limbs, palms, and soles over that of the trunks. Chickenpox rashes are pleomorphic and predominantly involve the face and trunk and spare the palms and soles. MPX rashes persist for a longer duration of 2–3 weeks in comparison to chicken pox rashes, which last only for a week.[16] Once crusted, a person is no longer regarded as contagious, and then the crusted lesions fall off and fresh skin is seen underneath, this is termed as desquamation phase. Up until the desquamation stage, the lesions are painful at all times, and with crusting the pain gives way to extreme itching.

  Clinical Presentation in the Current Outbreak Top

The current MPX outbreak in Western countries appears to be a mild disease with some significant differences from the classic depiction of MPX. The majority of skin eruptions are restricted to the site of inoculation, including the genital, perianal, and oral regions. The clinical presentation suggests that the genital area is a primary infection site, resulting in a localized rash that is sometimes followed by a secondary disseminated infection. According to reports from Nigeria up to 2020 and the United States in 2003, the majority of patients have monomorphic lesions., whereas clinicians in the UK anecdotally report predominantly pleomorphic lesions at different stages of eruption at the same time in the current outbreak.[11]

In addition, the presenting symptom may be skin lesions, as opposed to the usual prodromal presentation with fewer systemic symptoms. Limited Lymphadenopathy mainly involves the inguinal regions, Asynchronous lesions, and fewer cutaneous lesions are also observed in this outbreak.[17] According to the study by Patel et al.,[8] rectal pain and penile swelling (edema) is being commonly seen in the current outbreak as compared to the previous outbreak. The change in the clinical symptom profile implies a new clinical course for the disease and the need for physicians across the globe to familiarise themselves with the changing trend of the clinical spectrum.

  Complications Top

Known complications of the disease include severe dehydration due to GI loss secondary to vomiting and diarrhea in the second week of the illness along with painful oral ulcers resulting in reduced fluid intake. In immunocompromised hosts, the infection can involve the lungs resulting in bronchopneumonia, systemic spread, and immune response resulting in sepsis and central nervous system involvement resulting in Encephalitis. During this outbreak, three cases of encephalitis were reported in two male Spanish patients and one young male Indian patient, all of whom died.[10] Corneal infection is a major complication of MPX, Eye infections can lead to corneal scarring and permanent loss of vision. Ano-genital pain, proctitis, and odynophagia secondary to oral and pharyngeal ulceration were observed to be crippling complications of MPX in the current outbreak and a leading cause of hospitalization. Patients with bronchopneumonia are to be screened for secondary bacterial and viral infections including influenza. Other rare complications observed in the current outbreak include Epiglottitis and Myocarditis.[18],[19],[20]

  Monkeypox in Children, Pregnancy, and Acquired immunodeficiency syndrome Top

Even in high-income nations like the United States, previous outbreaks of MPX have raised the mortality and hospitalization rates among children., these were the only two severe presentations during the 2003 outbreak that occurred in children.[20] Complications are more common in children than in healthy adults, with an increased risk of bacterial superinfection, keratitis, sepsis, respiratory complications due to pneumonia and pharyngeal abscess, or encephalitis. Miscarriages and fetal deaths have occurred as a result of MPX transplacental transmission. Similar to smallpox, the illness is anticipated to affect pregnant women more severely than healthy non-pregnants, particularly during the third trimester.[21],[22] As with many viral illnesses, those who are immunocompromised are thought to be more vulnerable. To date, most deaths in endemic countries have been reported in children, persons with HIV/AIDS, and other immunocompromised hosts.[19] But in the current outbreak, MPX was not particularly severe among the People living in the HIV community in comparison to those who do not have HIV.

  Transmission Top

MPX is transmitted both zoonotically and from person to person. Zoonotic transmission occurs through direct contact with MPX lesions, body fluids, or blood from diseased animals.[23] Various animal species have been identified as susceptible to the MPX virus. This includes tree squirrels, dormice, rope squirrels, non-human primates, Gambian pouched rats, and other species. Insufficiently cooked meat may also contribute to transmission. Person-to-person transmission occurs often via sustained physical contact and is almost exclusively associated with sexual contact in the current outbreak. There have also been reports of intrauterine transmission.[24],[25]

Human MPX typically manifests as a generalized monomorphic pustular rash, with genital lesions being uncommon. In the current international outbreak, including in Nigeria, the majority of cases develop an ulcerating genital rash. The clinical picture now suggests that the genital area is a primary infection site. The MPX virus appears to spread through a primarily localized rash. Transmission via primary rash (primary transmission) eliminates the need for the virus to establish a widely disseminated infection, which may aid in the evolution of variants. A transmission path of this type could also allow for the co-transmission of multiple variants.[26]

  Laboratory Diagnosis Top

Though the diagnosis of MPX in humans is mainly clinical, with the characteristic clinical presentation with skin rashes along with epidemiological links including travel, exposure risk/ occupational risk, the definitive diagnosis is by viral DNA detection by polymerase chain reaction (PCR). Skin lesion material, such as lesion crusts, exudate/or swabs of the lesion surface and roofs from many lesions, are the preferred specimen type for laboratory confirmation of MPX.[27],[28] In India, All the clinical specimens should be transported to the Apex laboratory of ICMR-NIV Pune routed through the Integrated Disease Surveillance Programme network of the respective district/state. Nucleic-acid amplification testing (NAAT), using real-time or conventional polymerase chain reaction, is used to confirm MPXV infection (PCR). According to the WHO’s recommendations for the general management of patients with MPX, all patients should undergo serology or PCR testing through their local health department until commercial testing becomes available.[7]

  Prevention Top

The following recommendations are based on the US CDC[29] for the prevention of MPX. It is recommended that MPX patients be separated from healthy people and should avoid close contact with people who have an MPX-like rash. Handling clothes, sheets, blankets, or other materials that have been in contact with an infected animal or person should be avoided. Washing hands with soap and water after any contact with an infected person or animal also helps to prevent the disease.

  Vaccine Strategies to Prevent Monkeypox Top

Data suggest that smallpox vaccination may have a protective role against the MPX virus and improve clinical signs of infection. In September 2019 the U.S. Food and Drug Administration (FDA) approved JYNNEOS, a live viral vaccine, and is now indicated in individuals 18 years of age and older who are at high risk for contracting smallpox or MPX infection. ACAM2000 is another vaccine licensed under FDA that contains live vaccinia virus (a “pox”-type virus) to protect against smallpox disease. According to historical data, smallpox immunization with the vaccinia virus has a roughly 85% effectiveness rate against MPX. Currently, The Advisory Committee on Immunization Practices (ACIP) recommends pre-exposure prophylaxis for individuals at high risk for acquiring infection like immunocompromised patients, persons with severe disease, pregnant women, and children younger than 8 years of age.[30]

  Indian Vaccine Scenario Top

India has chosen to delay purchasing the MPX vaccine on an emergency basis for the time being because the number of cases reported across the nation has not increased. The Indian Council of Medical Research (ICMR) is embarking on a project to help local vaccine researchers produce the MPX vaccine locally and has called for EOI as of now, vaccination is not recommended in a generalized way in any of the countries.

  Post-Exposure Prophylaxis Top

The first vaccine dose has to administer within 4 days of exposure to prevent illness as recommended by CDC. If administered 4-14 days post-exposure, vaccination can relieve disease symptoms but cannot prevent disease onset.[31],[32]

  Treatment Top

Since there is presently no specific antiviral treatment for MPX, treatment focuses largely on symptom management. Considering the similarity of the MPX virus to the smallpox virus, the antiviral drug tecovirimat developed against smallpox is likely to be effective to treat MPX. Tecovirimat prevents viral envelope formation by inhibiting a highly conserved protein called p37, which is necessary for the replication of viral particles. In 2018 FDA approved Tecovirimat for the treatment of smallpox, and the US-CDC has an Expanded-Access Investigational New Drug protocol (EA-IND) that allows its use in non-variable orthopoxviruses such as MPX virus. Three patients were treated with tecovirimat in the US consistent with human safety studies and no significant side effects were noticed in this limited series. One patient experienced a slight rise in ALT that went away without tecovirimat being stopped. Patients’ lesions improved throughout treatment, and none of them developed a serious disease while using tecovirimat.[33] The usefulness of brincidofovir in treating human infections with the MPX virus is unknown. However, in vitro and animal investigations have shown that it is effective against orthopoxviruses.[34],[35]

For patients with severe MPX infection or those exposed to T-cell immunodeficient individuals for whom smallpox vaccination is contraindicated, intravenous vaccinia immunoglobulin is also a possibility. It is still unknown if the treatment of these MPX patients with antiviral drugs or VIGIV will be beneficial and will require further studies.[36]

  Conclusion Top

Following the current multinational outbreak of MPX, it is clear that many aspects of this disease remain unknown. Given the current climate of pandemic threats, the public health significance of MPX disease should not be underestimated. Increased international surveillance and detection of MPX cases are critical tools for understanding the ever-changing epidemiology of this resurgent disease.


The authors would like to thank all the professionals of the Infectious disease department in the hospital.

Financial support and sponsorship

Not applicable.

Conflicts of interest

There are no conflicts of interest.

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