Monkeypox (Mpox): Evolution of Transmission and Comprehensive Review

Abstract

The human monkeypox (mpox) virus is an orthopox virus that can be transmitted to humans. Though the disease has been endemic in Africa, the recent mpox outbreak since May 2022. We attempted to examine differences between the endemic form of mpox and the current outbreak. Review of electronic medical database with relevant keywords. The current outbreak of mpox has disproportionately impacted the gay, bisexual and other men who have sex with men (MSM) community. This is also the first time that widespread semen testing has turned up evidence of mpox viral deoxyribonucleic acid (DNA). Cases in the present outbreak are more likely to affect adults, involve the genitalia, and have no prodrome. Close diagnostic differentials include varicella and hand-foot-mouth disease. The disease is usually self-limiting; though secondary infections, anorectal pain, pharyngitis, ocular lesions and rarely, renal injury and myocarditis may occur. This review focuses primarily on the novel clinical characteristics and emerging sexual transmission route of the mpox virus, which, although unconfirmed, appears extremely likely as the route of spread. Dermatologists have an important role in this health emergency, as early diagnosis can cause a significant reduction in disease transmission.

Introduction

Human monkeypox (mpox) is an evolving zoonosis caused by the monkeypox virus (MPXV), a member of the Poxviridae family and orthopox virus genus, that derives its name from first being detected in research monkey colonies kept in captivity.[1] Monkeypox virus is a 200–250 nm sized, brick or oval-shaped double-stranded Deoxyribonucleic acid (DNA) virus with a 197-kbps genome.[2] Although the precise reservoir of the virus is unknown, it is believed that rodents (squirrels, Gambian pouched rats and dormice) play a role in its transmission in endemic countries.[3] Other members of the poxvirus family that can infect humans are variola (smallpox), vaccinia, camelpox and cowpox. These viruses are antigenically highly similar and have considerable cross-immunity.[4] The effectiveness of previous smallpox vaccination in preventing mpox was estimated to be 85 percent; however, the long-term effectiveness is unknown.[5,6] The first human mpox infection was recorded in 1970 in the Democratic Republic of the Congo (Central Africa) in a nine-month-old baby during a smallpox surveillance program, who was the sole unvaccinated member of his household.[7] It is the cessation of smallpox vaccination and turnover of the immune population that seems to have heralded the outbreak today.

Materials and Methods

We searched the major academic electronic databases PubMed/MEDLINE, Google/Google Scholar for relevant articles, using the terms: “poxvirus”, “orthopoxvirus”, “smallpox virus”, “variola virus”, “vaccinia virus”, “monkeypox”, “monkeypox virus”, “sperm”, “seminal”, “semen”, “anogenital lesions”, “solitary lesion”, “sexual transmission”, “skin to skin contact”, “Male having sex with male”, “Monkeypox vaccine”, “Monkeypox differential diagnosis”, “Monkeypox treatment”. We searched medical subject headings and wildcards in relevant articles. A total of 120 articles were reviewed and 76 articles were shortlisted for inclusion in this review after removing duplicated data and smaller studies, the data from which had been included in larger studies subsequently.

Epidemiology of the current 2022 global mpox outbreak

From January 2022 to 10 April 2023, WHO has reports of 86,930 confirmed cases of mpox in 110 countries/territories, from all six WHO regions, with 116 reported deaths [Figure1].[8] The first case was discovered in London on 6 May 2022, in a patient with a recent travel history to Nigeria.[9] Numerous early cases across Europe were attributed to men identifying as MSM, returning from the international lesbian, gay, bisexual and transgender (LGBT) + Pride festival “Maspalomas” at Gran Canaria, Spain;[10] however, by the end of the month, locally acquired illnesses and community transmission dominated in every impacted country. On 23 July 2022, in response to the increasing number of confirmed cases around the world, the WHO declared the outbreak of mpox to be a Public Health Emergency of International Concern (PHEIC), highlighting early detection and containment of mpox as global concerns of utmost importance.[11,12]

Figure 1.

Geographic distribution of confirmed cases of mpox reported to or identified by WHO from official public sources from 1 January 2022 to 10 April 2023 17:00 CEST

Figure 2.

Schematic diagram of cutaneous lesions in endemic mpox, showing generalised distribution with facial and acral predominance, lesions in the same stage of evolution and generalized lymphadenopathy

Figure 3.

Schematic diagram of cutaneous lesions in the current mpox pandemic, showing “bipolar” distribution in the form of perioral and anogenital lesions, lesions in different stages of evolution and inguinal lymphadenopathy

Figure 4.

(a) Endemic monkeypox from patients from Zambia and Democratic Republic of Congo (taken during 1980s). Multiple vesicles with crusting over the neck and back in a child; all lesions appear to be in a similar phase of evolution. (Courtesy: Dr Subhash Hira, Mumbai, India) (b) Endemic monkeypox from patients from Zambia and Democratic Republic of Congo (taken during 1980s). Umbilicated crusted papules. Lesions are larger and further apart than (2a). (Courtesy: Dr Subhash Hira, Mumbai, India)

Figure 5.

(a) Current outbreak: multiple penile ulcers (b) Current outbreak: pustules with central crust over genital with perigenital region. One can note the variable size, tendency to coalesce and significant perilesional erythema (c) Current outbreak: Deep ulcers (two) over labia majora-perineum (arrow) (d) Current outbreak: Multiple mucocutaneous lesions over genitals (e) Current outbreak A single lesion genital ulcer

Clinical presentation

In the ongoing outbreak in non-endemic countries, nearly all cases have been detected among men, a majority (96.6%) identifying as MSM, with a median age of 34 years (IQR: 29-41), having mild to moderate symptoms.[13] Most individuals had no history of travel to endemic areas or contact with a traveler, suggesting an unidentified transmission chain contributing to the continued spread of the virus.[14] The differences in the clinical presentation of endemic mpox and the current pandemic are tabulated in Table 1.

Table 1.

Comparison of clinical features of endemic mpox and the current outbreak

	Endemic monkeypox	Current monkeypox outbreak
Age group	Children Median age 10–11.9 years (range: 4–70 years)	Young adults Median age 34 years (range: 29–41 years), <1% pediatric cases[8]
Gender	No gender predilection	Men: 96.6% Majority MSM (84.3%) (source: WHO global trends)[8]
Incubation period	Mean 13 days (range 5 days to 3 weeks)	Shorter, 7-10 days[74,16,17]
Number of skin lesions [Figures 1 and 2]	● Few hundreds (Figure)	● Most present with 1–20 skin lesions, with >100 lesions being seen only in 0–4% of cases[39,41]  ● Single lesion in 10–12% of cases[48]
Site of cutaneous lesions[18,19] [Figures 2 and 3]	● Face (95%)  ● Palms and soles (75%) (Centrifugal distribution)  ● Trunk  ● Mucous membranes (70%)  ● Least frequently over the genitals	● Most patients had multiple lesions localized to the anogenital (90-94%) and perioral areas (bipolar distribution)[39,40,41,47]  ● Perioral and oral lesions: 43.1%[41]
Morphology and evolution of cutaneous lesions[20,21] [Figures 4 and 5]	● First to appear in eruptive phase: oral mucosal enanthem  ● Macules 2–10mm ® Papules and vesicles with central umbilication ® Deep-seated firm pustules; synchronously over 3–7 days  ● Scab formation in two weeks  ● Asymptomatic, painful or pruritic  ● Heal with hypo- or hyperpigmentation/atrophy/pitted/varioliform scars  ● Complete resolution by week 4	● Genital lesions often first to occur[43]  ● Similar morphology  ● Presenting symptoms may include anorectal (pain/proctitis/tenesmus/diarrhoea) in 12%, or oropharyngeal/pharyngitis (5%) in relation to oral and anal sex  ● Faster evolution with lesions in various phases of evolution exist simultaneously[22]
Systemic features	● Prodrome of 1–3 days: fever, chills, headache, lethargy, myalgia  ● Lymphadenopathy common, usually generalised, esp in the head and neck region  ● Usually a self-limited disease  ● Complications (~50%): most commonly secondary bacterial infections, rarely respiratory distress, bronchopneumonia, sepsis, encephalitis, keratitis, pneumonitis, ocular injection with a risk for vision loss[37]	● Prodrome absent, majority present with cutaneous features  ● Inguinal lymphadenopathy predominates over cervical, generalised lymphadenopathy is uncommon[39,49]  ● Complications requiring treatment: 39% (n=181)   ●Proctitis (25%)   ● Tonsillitis (10%)   ● Penile edema (8%)   ● Abscess (3%)[48]

Evolution of transmission

Since 1970, mpox has been endemic in both West and Central Africa, with a fatality rate ranging from 1 to 10%.[2,15] No cases had been reported outside of Africa until 2003, when a cluster of 71 confirmed and probable mpox cases was reported in the United States; this was found to be related to infected pet prairie dogs in contact with imported rodents from Ghana.[23] Other travel-related epidemics have subsequently been recorded in the United Kingdom, North America, Israel and Singapore.[24,25,26,27]

Two separate genetic clades of the mpox virus have since been identified based on geographic distribution, clinical presentation and genomic sequencing (0.5% variation)[28] results: Clade I, formerly the Central African/Congo Basin clade (more virulent and higher case fatality rate of 1–12%), and Clade II, formerly the West African clade (case fatality <1%).[29,30] Endemic mpox is transmitted from animals to humans by direct contact with blood, bodily fluids or mucocutaneous lesions of an infected species (prairie dogs, rats and squirrels) or consumption of food containing their meat.[31] It tends to affect children, with numerous generalised lesions. Clade I of the mpox virus produced multiple such outbreaks in the Democratic Republic of the Congo between 1981 and 2017.[32,33,34,35] During this time, only a few cases of human mpox were documented in West Africa; however, in 2017, Nigeria saw a significant outbreak with 122 cases of the mpox virus Clade II and the possibility of human-to-human transmission, as well as speculation of sexual transmission with 68% patients having genital involvement, was raised for the first time.[36,37] The reappearance of mpox in Nigeria in 2017 was attributed to the cessation of smallpox vaccination in 1980 and consequent waning immunity, frequent hunting of bushmeat for subsistence, and the spread of urbanisation with encroachment into forests and swamps.[38]

In the current outbreak, the transmission of infection during sexual intercourse has been speculated to be the predominant mode of transmission.[39,40,41] The male predominance as well as clustering of cases in the MSM population, the novel clinical presentation with mainly genital, peri-anal and peri-oral lesions along with inguinal lymphadenopathy strongly supports this hypothesis.[40,42,43,44] Unprotected sexual contact in the last 3 weeks was reported by as many as 94% (n = 2891) patients in one study from the United States, and was identified as a significant risk factor.[45] The hypothesis was strengthened by vaginal and anal lesion samples testing positive for MPXV DNA by real-time polymerase chain reaction (PCR), similar to samples from a skin lesion, feces, seminal fluid, nasopharynx, serum and plasma, yielding further credence to sexual transmissibility.[11,46,47,48] In a large multicenter study on 528 confirmed MPX cases from 16 countries, 98% of patients identified as homosexual or bisexual with many of them reporting multiple or anonymous partners. On semen analysis, 29/32 were positive for MPXV.[39] Moreover, MPXV often coexists with other sexually transmitted infections, such as chlamydia, genital herpes, syphilis, gonorrhea or human immune-deficiency virus (HIV), seen in 25–50% of cases.[39,40,44,46] There is, however, a gradual spread into the general population beyond specific population groups.

In a recent Google Form-based survey of physicians from all six WHO regions, 45% of doctors, all noted to be from African, the East-Mediterranean and South-East Asian regions, reported a heterosexual predominance. The authors commented that the non-genital involvement, cervical lymphadenopathy and a predominantly extracutaneous presentation were reported in these regions.[49] Though there has been a disproportionately small number of female patients in the 2022 mpox pandemic (3.4%), the majority of them were heterosexual (88%) (source: WHO global trends).[8]

The current global outbreak of 2022 has shown milder symptoms and increased human transmissibility. Apart from sexual transmission, human-to-human transmission can also occur by respiratory droplets, direct contact with body fluids or skin lesions or fomites, as well as vertical transmission.[50] On genetic evaluation, a novel lineage B.1, designated as Clade IIb (or Clade III) due to its close affinity to Clade II, was identified.[51,52] This variant has been linked to strains circulating in Nigeria during the 2017 outbreak.[36,53,54] However, there has been a significant divergence of up to 50 single nucleotide polymorphisms, representing a mutation rate 6–12 times higher than previously predicted.[52] The current PHEIC of mpox may be attributable to DNA mutations induced by host response proteins such apolipoprotein B mRNA-editing catalytic polypeptide-like 3 (APOBEC3). These cause reduced pathogenicity (and consequently, milder symptoms) in mpox, allowing cryptic transmission, thus reflecting an adaptive evolution of the mpox virus.[55]

It is well known that poxviruses such as vaccinia, variola and molluscum contagiosum transmit through skin-to-skin contact easily, causing autoinoculation, household spread and also manifesting as a sexually transmitted infection when predominantly genital, as in the case of molluscum.[56] Monkeypox may fall into a similar category. At the same time, the evolution of an endemic, generalised form to a sexually transmitted disease with localised lesions is reminiscent of the shift in syphilis centuries back. Now well-established as a sexually transmitted infection, treponemes predominant today have been phylogenetically hypothesised to have evolved from Treponema pallidum subspecies pertenuae (causing yaws in hot and humid climate), which gave rise to Treponema pallidum subspecies endemicum (causing bejel in cooler and drier civilisations) and then to Treponema pallidum subspecies pallidum. When syphilis (subspecies pertenue) first arose in the Old World (African region), it affected children and adolescents in the form of a non-venereal, highly contagious disease. It is speculated to have disseminated along with humans to the Middle East and Eastern Europe as endemic syphilis, and then to the New World. The descriptions of these New World pertenue strains in South America had a “transitional” presentation that has been supported by genetic analysis; they presented as a chancre similar to that in venereal syphilis, but found in children and in extragenital locations.[57] The emergence of venereal syphilis in Europe is closely linked to the Colombian voyage, bringing back a pathogen from the New World that adapted a different cultural and environmental context. Although different schools of thought exist on the exact sequence of evolution,[58] it is the shift in the presentation of the same pathogen in the context of international travel and dissemination that is reminiscent of the mpox pandemic today.

Without stigmatising a particular community, it is vital to recognise that even if there is insufficient evidence that MPXV is sexually transmitted, it is definitely sexually transmissible, i.e., transmitted by physical contact during sexual activity. World Health Organisation has described one of the risk factors of mpox as unprotected sexual contact, especially with multiple or different sexual partners in 21 days before symptom onset. Additionally, in recognition of the potential preclinical transmission of the disease, known contacts of confirmed or probable cases are advised to avoid sexual contact and non-essential travel for 21 days from the last contact with the case.[13]

Differential diagnosis

Although an acral-predominant vesiculopustular rash is a hallmark of mpox, a similar rash can be a sign of more common diseases such as hand-foot-mouth disease (HFMD), chickenpox, scabies and rarer ones such as Gianotti-Crosti syndrome (GCS).[59,60,61] Table 2 describes points to differentiate between mpox and its close differentials. Mpox as a single genital ulcer has been described in literature and must be distinguished from other sexually transmitted diseases presenting with genital ulcers, like syphilis, genital herpes and chancroid.[62]

Table 2.

Features differentiating between mpox and its differential diagnoses

Characteristics	Monkeypox	Chickenpox	HFMD	GCS
Lesion Distribution	Centrifugal (face, trunk, hands and feet),b Bipolar (oral and anogenital involvement)	Centripetal (Trunk to proximal extremities)	Acral, oral, rarely genitals, buttocks, knees and elbows	Face, extremities and buttocks
Rash period	14–28 days	5–10 days	7–10 days	2–8 weeks and can last up to 6 months
Fever	a1–3 days before onset of rash bConcomitant or later	Fever with each new lesion	1–3 days before onset of rash	Mild fever prior or during the onset of rash
Lymphadenopathy	Cervical and inguinal > axillary	Rare	Rare	Common
Morphology	aMonomorphic; macules, then papules, then pustules, then scabs bLesions in different phases of evolution; morphologically same as endemic mpox	Monomorphic superficial blisters with surrounding erythema (dew drop on rose petal)	Erythematous macules rapidly evolve to small blisters surrounded by erythema	Papules and papulovesicles
Sequelae	Scarring present	Scarring present	No scarring	No scarring
Complications	Secondary skin infections, dehydration, pneumonia, proctitis, encephalitis, eye infections	Bacterial infections of skin and soft tissues, dehydration, pneumonia, encephalitis, cerebellar ataxia and hemorrhagic complications. Later in life, herpes zoster	Dehydration, encephalitis, fingernail and toenail loss, viral meningitis	Acute viral hepatitis

HFMD: Hand-foot-mouth disease, GCS: Gianotti-Crosti syndrome, ^aEndemic disease, ^bCurrent Outbreak

Diagnosis

Whom to test: Case definitions [Table 3] provided by various organisations can be utilised as a guide to testing “suspect” or “probable” cases.[63,64,65] If one suspects they might have mpox, they should self-isolate and contact a healthcare worker immediately.

Table 3.

Case definitions of monkeypox/mpox

Case	CDC (Oct’22)[63]	WHO (Sept’22)[64]	MoHFW (India) (Aug’22)[65]
Suspected case	New onset characteristic rash OR High clinical suspicion of mpox (presentation consistent with common differentials) AND Any of epidemiological criteria (<21 days of onset) - Contact with confirmed case/case with similar presentation -Contact with high-risk groups - Travel to endemic countries/countries with confirmed cases - Contact with endemic African animal species or their products	Acute onset of fever (>38.5°C), headache, myalgia, back pain, profound weakness or fatigue AND Contact with confirmed/probable case<21d OR Unexplained acute skin rash, mucosal lesions or lymphadenopathy since 1 Jan 2022 AND Common differentials of papular or vesicular rash ruled out (clinically)	Unexplained acute rash AND One or more of - Lymphadenopathy - Fever -Headache - Body ache -Profound weakness AND Travel to affected countries <21 days
Probable case	Orthopoxvirus demonstration by PCR/immunohistochemistry/electron microscopy OR detectable anti-orthopoxvirus IgM (day 4–56) AND No other recent orthopoxvirus exposure	Unexplained acute skin rash, mucosal lesions or lymphadenopathy AND (any of) - <21 days of onset  ● Multiple/casual sexual partners  ● Contact with probable or confirmed case of monkeypox -Identifies as gay/bisexual/MSM - detectable anti-orthopoxvirus IgM (day 4–56) or four-fold rise in IgG (day 21 vs day1-7) - positive orthopoxvirus-specific PCR	Suspected case AND (any of) Epidemiological link - Face-to-face exposure including HCW without appropriate PPE -Direct contact including sexual contact - Contact with fomites
Confirmed case	RT-PCR/Next-generation sequencing of monkeypox virus DNA or culture of monkeypox virus on clinical specimen	RT-PCR/sequencing of monkeypox viral DNA	PCR/sequencing of monkeypox viral DNA

MoHFW: Ministry of Health and Family Welfare, Government of India

Samples to obtain for laboratory diagnosis:[66] Skin samples are the main specimen for diagnosis. Swabs (dry or Viral Transport Medium (VTM) swabs) can be collected from the skin lesion surface or exudate/roof of the lesion/lesion crust. A vigorous movement of the swabs is recommended to ensure the collection of sufficient viral DNA. Lesion fluid can be collected using an intradermal syringe, whereas the lesion base may be scraped with a sterile polyester swab. The specimen should be collected from multiple sites, and one type of specimen should be placed in one tube without mixing with another type of sample. Biopsy of a skin lesion in the macular stage may be done in research settings. An oropharyngeal swab may be collected in a dry plain tube in case of mucosal lesions. Depending on symptoms and research practices, urine, semen, rectal or genital swabs may be collected. If other samples are inconclusive, serum or plasma samples (2–5 ml) may be collected for antibody detection. This is not recommended alone for diagnosis, but day 4–56 IgM or paired IgG samples may aid in diagnosis.

Transportation of sample: Samples should be refrigerated (2–8 degrees Celsius) within an hour of collection. If transport to the laboratory is anticipated to be delayed more than seven days, it should be kept frozen (≤20°C).

Diagnostic tests: Monkeypox is confirmed by nucleic acid amplification testing, such as real-time or conventional PCR assays.[66,67] A generic PCR test for the orthopoxvirus coupled with a confirmatory PCR test for MPXV can confirm the diagnosis in 97% of cases, particularly from the blister fluid of vesicular lesions. Loop-mediated isothermal amplification diagnostic tests could be useful in rural health clinics or regional hospitals in low-income countries with limited access to high-precision PCR instruments.[68] Electron microscopy and viral culture are not routinely used.

Centers for testing in India: These include the National Institute of Virology, Pune; and samples are sent through the Integrated Disease Surveillance Program of the respective district/state. There are 15 designated viral research and diagnostic laboratories in India trained to test for mpox: Government Medical College, Trivandrum; Kasturba Hospital for Infectious Disease, Mumbai; Government Medical College, Gauhati; Gandhi Medical College, Secunderabad; All India Institute of Medical Sciences, Delhi; Bangalore Medical College and Research Institute, Bangalore; National Institute of Virology Field Unit, Kerala; All India Institute of Medical Sciences, Nagpur; The King Institute of Preventive Medicine and Research, Chennai; National Institute of Cholera and Enteric Diseases, Kolkata; SMS Medical College, Jaipur; Sher-e-Kashmir Institute of Medical Sciences, Srinagar; Government Medical College, Amritsar; King George’s Medical University, Lucknow; and B.J. Medical College, Ahmedabad.[65,69]

Treatment and vaccination

Treatment is largely supportive, with symptomatic management of fever and pain, and can be managed well at home under isolation, provided healthcare support is readily accessible. The WHO has released a detailed resource for patients, with “red flag signs” such as worsening symptoms, inability to eat or drink, secondary infection of the rashes and breathlessness or dizziness.[70] Patients should keep rashes uncovered, avoid scratching and take bath in warm water with Epsom salt or baking soda. An equal emphasis is placed on mental healthcare. However, if isolation is not possible, the rashes must be covered to avoid the spread of infection.

There is currently no approved specific treatment for mpox; the smallpox antivirals cidofovir,[71] brincidofovir[72] and tecovirimat,[73] all show effectiveness against the disease. There is a lack of any peer-reviewed studies on the efficacy of any of the smallpox vaccines (MVA-BN, LC16 and ACAM200) as compared to no vaccination; their recommendations are based on indirect evidence, animal studies and a pre-print of a single longitudinal study of 1970 subjects (44% vaccinated) for a minimum of 25 days; it showed an estimated vaccine efficacy of 79%. To summarise, mass vaccination is not recommended, and priority groups (high-risk groups, immunosuppressed individuals, healthcare/lab personnel working with mpox patients/samples) are eligible to receive pre-exposure vaccination. Post-exposure prophylaxis for contacts is recommended within 4 (but up to 14) days of first exposure, with prioritisation of children, pregnant women and immunocompromised persons. MVA-BN (third generation, non-replicating) appears to be safer than ACAM200 (second generation, live), with markedly lower rate of adverse effects, which are less severe when they do occur. MVA-BN is preferred in children, pregnant and breastfeeding women, and immunocompromised individuals due to its non-replicating nature.

Conclusion

Monkeypox was once only a problem in Africa but has now spread across the world. While early cases in the current outbreak were almost exclusively in MSM/bisexual patients, with a high likelihood of sexual transmission, recent data suggest a spillover into the heterosexual population in some countries. The guidelines addressing this predominance have inadvertently worsened the stigma towards the LGBTQI+ population, like in the initial years of the HIV outbreak. However, transmission is not exclusively through sexual contact and close physical contact is not exclusive to these societies, either; it is a basic human need and hence seen throughout human populations, unrelated to a person’s gender or sexual orientation. However, it should be highlighted that this disease can also be transferred by other means, and effective disease prevention efforts must target all modes of disease transmission. This includes issuing clear vaccination and quarantine guidelines, educating the public on transmission, decreasing the stigma associated with sexually transmitted infections and providing proper care for individuals who are diagnosed with mpox. Numerous elements of the epidemiology of human mpox, particularly those pertaining to the natural reservoirs, mechanisms of transmission and clinical disease course predictions, remain largely unexplored. The information gaps must be addressed through additional studies and interventions, including subjects pertinent to African nations. A widespread outbreak of mpox is imminent and requires focused attention to help reduce its repercussions.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.