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Monkeypox: history, clinical manifestations, and treatment Review of the New England Journal of Medicine

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Since the first case of the current monkeypox epidemic was confirmed in the UK on 6 May 2022, the outbreak has spread to 109 countries and territories
around the world.
Compared with endemic monkeypox confined to African countries, this monkeypox outbreak has unique epidemiological characteristics, clinical manifestations, and population, such as clinical features ranging from previously centrifugally distributed facial and extremity lesions to penile rash, perianal lesions, ulcerative lesions, inguinal lymphadenopathy and pain, pharyngitis, and proctitis
.

On Thursday, the New England Journal of Medicine (NEJM) published an online review of monkeypox history, virology, animal reservoir, clinical features, epidemiology, vaccination and treatment
.
We present this review
here.

Monkeypox virus was first isolated in Copenhagen in late 1958 when a cynomolgus monkey colony suffered two outbreaks of smallpox-like disease
.
Monkeypox has no clinical signs
prior to the eruption phase (characterized by a maculopapular rash).
Because it is very similar to other known pox viruses, the virus was named monkeypox virus
.

Between 1960 and 1968, several monkeypox outbreaks occurred in captive monkey populations in the United States and the Netherlands
.
Despite the death of many infected animals, no human cases have been detected in these outbreaks, suggesting that humans are not susceptible to monkeypox
.

In 1970, a 9-month-old boy from the Democratic Republic of the Congo (DRC) became the first human case of monkeypox
.
From September 1970 to March 1971, another six human
cases of monkeypox were detected in West African countries.
Most of the patients were young children and none of them were vaccinated
against smallpox.

Human cases of monkeypox were initially found only in Africa
.
Sporadic cases have been diagnosed in forest areas of Central or West Africa, and small outbreaks occur mainly in DRC
.
Human monkeypox cases
were first reported outside Africa in2003.
These cases occurred in the United States and were associated
with the Gambian giant rat (Pouched Rat) imported from Ghana to Texas.
Rodents spread the virus to prairie dogs and rats raised in the same wildlife institution, after which prairie dogs infected humans, mostly young people and children
.

In May 2022, a series of monkeypox cases were detected in the United Kingdom, Portugal and Italy, mostly involving men who have sex with men (MSM).

Health authorities quickly identified these series of cases as a sign of the beginning of a new monkeypox outbreak
.

Virology

monkeypox virus belongs to the pox virus family, the vertebrate pox virus subfamily (chordopoxvirinae), and the genus Orthopoxvirinae (Figure 1).

The genus contains a variety of other pox viruses, such as smallpox, vaccinia and camel
poxviruses.
These double-stranded DNA viruses are very similar in terms of genes and antigens, so cross-immunity
exists.
Smallpox vaccination usually prevents monkeypox
to some extent.
Since the smallpox vaccine was stopped in 1980, herd immunity has continued to decline
.
This is one of the factors that favors the appearance of
monkeypox.

Monkeypox virus has two genetic branches with genomic differences of less than 1%.

The first clade is endemic in Central Africa and the second in West Africa
.
Monkeypox virus has emerged outside Africa, so the name change and the definition of the three clades are being discussed (Figure 1).

This article adopts the revised naming
.
The monkeypox genome sequence of the 2022 case (we call it clade 3) originated in the West African clade (lineage B.
1).

Figure 1 Monkeypox virus structure, African geographical distribution, and virus lineage nomenclature
.

Electron micrographs of several monkeypox virus species (panel A on the left) show their characteristic rectangular or oval, brick shape
.
The map (figure B) shows sporadic cases of monkeypox and monkeypox outbreak areas
reported in Africa.
Purple dots indicate Central African (clade 1) strains and green dots indicate West African (clade 2) strains
.
Dots vary in size, with larger dots indicating more
monkeypox cases.
The table next to the map lists the original taxonomy and the newly proposed taxonomy for the three clades of monkeypox virus, as well as their epidemiological characteristics
.
CAR stands for Central African Republic and DRC for Democratic Republic of Congo
.

Monkeypox, the animal reservoir that transmits monkeypox to humans, is a zoonotic disease, but its animal reservoir

remains unknown
.
Various rodents from the tropical rainforests of Central and West Africa, including tree squirrels and Gambian giant rats, are currently considered likely hosts (Figure 2).

African apes can be infected, and they are thought to be intermediate hosts
.
Many animals, such as rabbits, prairie dog mice, other rodents and monkeys, are susceptible to infection in captivity, including laboratory animals
.

Figure 2 Natural history
of monkeypox.
The monkeypox virus reservoir is not fully understood
.
Rodents are the most likely hosts
.
Monkeypox virus is transmitted by contact with biological fluids or lesions between a host animal or an incidentally infected host (e.
g.
, monkey) and an index case (human
).
The exact circumstances of the virus spill are unclear, but it is thought that contamination occurs during hunting (bitten by an infected animal) and during transport, slaughter, or consumption of infected animals
.
Human-to-human transmission follows
.
Human-to-human transmission can lead to sporadic cases or epidemics (generally moderate) because the virus has relatively low transmission in endemic areas, so it disappears
naturally within weeks or months.
The 2022 outbreak was when infected people brought the monkeypox virus out of Africa, leading to the virus entering men who have sex with men in 2022, where monkeypox spread rapidly and widely, eventually leading to the largest monkeypox epidemic
ever recorded.

Clinical features of monkeypox outbreaks

in African countries Monkeypox can infect both children and adults and usually occur in three stages: incubation, prodromal and eruption
.
After the initial infection, the average incubation period is 13 days (range, 3~34 days).

The prodromal period lasts 1~4 days and is typically characterized by high fever, headache, fatigue, and usually lymphadenopathy, especially in the neck and maxillary area (Table 1).

Swollen lymph nodes are characteristic
of monkeypox that distinguishes it from chickenpox.
In the eruption period lasting 14~28 days, the skin lesions are centrifugally distributed and divided into several stages: macules, papules, blisters, and finally pustules
.
Lesions are firm, well-demarcated, and indented in the middle (figure 3).

Table 1 Characteristics of classic monkeypox and clinically epidemiological novel monkeypox
.

Figure 3 Typical cutaneous and mucous membrane manifestations
of monkeypox.

Figure A shows a lesion on the left hand of a girl with confirmed monkeypox infection in the Central African Republic, presenting as a centrally indented papule
.
In Figure B, a girl has extensive disseminated papular lesions
on her hands, arms, and face.
Figure C shows a girl with disseminated lesions in her abdomen at different stages, including papules and crusts
.
In Figure D, a woman with confirmed monkeypox infection has a large number of lesions on her left hand, manifested by hyperpigmentation, crusting, and exfoliation
.
Figure E shows a synchronized lesion on the right hand of a man who has sex with a confirmed man
.
Neopustules may be seen, as well as central pitted papules with progressive central ulceration
.
Figure F shows penile edema, erythema, and swelling extending into the left groin area
in men who have sex with a confirmed man.
In Figure G, a man who has sex with a man presents with genital lesions, including scrotal and penile lesions
.
Figure H shows pharyngitis
in a man who has sex with a man.

Lesions crust and fall off, followed by hypopigmentation of the corresponding area, followed by hyperpigmentation
.
Patients range from a few to several thousand lesions and are mainly located on the face, trunk, arms, and legs (figure 3).

Lesions often occur on the palms and soles of the feet, which is a manifestation
of monkeypox as distinct from chickenpox.
In a few cases, lesions may involve other sites (e.
g.
, genitals) or are associated
with oral ulcers and conjunctival injury.
Usually, all skin lesions are at the same stage, which is another feature
that distinguishes monkeypox from other skin symptom disorders such as chickenpox.
Patients often have pruritus and myalgia
.

Symptom severity and duration of disease are proportional
to lesion density.
The disease is most severe
in children and pregnant women.
Monkeypox usually has a self-limited course, but clinical sequelae, including depressed scarring of the face, are common
.
The overall case fatality rate appears to be lower in patients infected with the West African strain (clade 2) than in patients
infected with the Central African strain (clade 1).
The case fatality rate in Nigeria is 6%, while the case fatality rate in DRC and Central African Republic is 10~15%.

The main infection considered in the differential diagnosis is chickenpox
.
Chickenpox and monkeypox epidemics can occur at the same time, and it is common
to be infected with both diseases at the same time.
In a DRC study from 2009 to 2014, out of 1107 suspected monkeypox cases, 134 were detected with both monkeypox and chickenpox
.

Epidemiological characteristics Human monkeypox infection has now been reported in 10 African countries, and the number of cases has increased
significantly over the past 30 years.
DRC is by far the most affected country, with Nigeria, the Republic of Congo and the Central African Republic being several other severely affected countries, each reporting hundreds of cases
.

Both animal-to-human transmission and human-to-human transmission have been reported in Africa (Figure 2).

Animal-to-human transmission occurs when a person comes into contact with skin lesions or biological fluids
of an infected animal.
Human-to-human transmission is mainly due to contact with the patient's biological fluids and infected skin lesions
.
Contaminated items, such as bedding, can also be contagious
.
The basic regeneration number (R0) of the Central African clade was estimated to be 0.
6~1, while the R0 of the West African clade was low
.

Current monkeypox outbreak On 6 May 2022, the first case of the current multi-country monkeypox outbreak

was confirmed in the United Kingdom, a man
from Nigeria.
Close contacts have identified other cases
in their families.
However, in the following days, the UK reported unassociated cases that had not travelled to monkeypox-endemic countries, suggesting unidentified local transmission
.
Portugal, the United States and several other countries have also detected new cases
quickly.
The first confirmed case in the UK was initially thought to be a possible index case, but this hypothesis was later overturned due to the earlier date of symptom onset in Portugal and other confirmed cases in the UK (late April).

In addition, detection of monkeypox in a clearly unassociated population suggests asymptomatic transmission
.

Given the unusual geographical distribution of cases, the World Health Organization (WHO) and other public health agencies issued an alarm
as early as 16 May 2022.
This monkeypox outbreak was caused
by what we call clade 3 monkeypox virus (originating from the West African clade).
The WHO declared monkeypox a global public health emergency on 23 July 2022
.

Epidemiological characteristicsAs of 7 October 2022, a total of 71,096 cases of monkeypox infection have been reported in 107 countries and territories worldwide, of which 70,377 cases have occurred in countries that
have never historically reported monkeypox.
The United States reported the highest number of cases, followed by Brazil and Spain
.

As of October 4, 2022, the analysis of 24,677 monkeypox cases conducted by the European Centre for Disease Prevention and Control (ECDC) and WHO showed that men accounted for the majority (24,235 out of 24,616 cases, 98.
5%), especially men aged 31~40 years (9725 cases out of 24,638 cases, 39.
5%)
.
The sexual orientation of 10,729 male patients was known, of whom 10,300 (96.
0%) reported MSM
.

At the time of writing, current monkeypox outbreaks appear to be circulating mainly among gay, bisexual, or MSM sex networks, although there is some evidence that monkeypox transmission
occurs outside these populations.
In fact, more and more
cases are being reported in women and children.
Patients often report a sexually transmitted infection (STI) in the past year (54.
2% of UK patients) and ≥10 sexual partners in the past 3 months (31.
8% of UK patients), suggesting that monkeypox has been mainly transmitted
in sexual networks associated with STI transmission to date.

The epidemiological characteristics of this outbreak are particularly unusual
.
Not only do monkeypox cases far exceed the number previously detected outside monkeypox-endemic areas, but transmission of the virus is mostly human-to-person, regardless
of travel to these areas.
Patterns of sexual contact-related transmission now dominate in countries where new cases are emerging
.

Infection rates are higher in people reporting multiple sexual partners, and the distribution pattern of lesions is unusual, often occurring in the genital,, and perianal regions, which may reflect transmission of the virus through close contact during sexual activity or through sexual transmission
.
The detection of monkeypox DNA in a patient's semen is not considered definitive evidence of infectiousness, but it does indicate that viral excretion has occurred, which may have contributed to virus transmission
.
It is unclear whether these unusual features reflect changes
in monkeypox virus transmission.

Clinical features It may be too early
to accurately describe the clinical features of this monkeypox outbreak.
However, this time appears to be largely consistent with the clinical features of the classic monkeypox outbreak described above, but there are some differences
.

The UK Health Security Agency analysed the national cases in this monkeypox outbreak and estimated the average incubation period to be 9.
22 days
.
The ECDC-WHO analysis of 660 patients with at least one typical prodromal symptom showed that 71.
4% of patients had systemic symptoms (e.
g.
, fever and headache) and 49.
0% had localized lymphadenopathy
.
In the above analysis, 97.
7% of patients had a rash during the eruption phase, 70.
5% had anogenital lesions and mucosal lesions, and 7.
0% had oral lesions and mucosal lesions (Table 1).

However, in the current monkeypox outbreak, most patients develop lesions
without a prodromal phase.
In one analysis, mucocutaneous manifestations were present in 13.
7% of patients, but no systemic manifestations
.

The number of lesions varies widely between patients, with some patients having only a few painless lesions
.
Unlike the synchronized progression pattern previously described, the lesions in the current monkeypox outbreak appear to be out of sync, with a single or group of spots, and intermediate indented papules with progressive central ulcers and finally crusting (Figure 3).

In addition, the pattern of lesion distribution is unusual, often located in the genital,, and perianal regions, without typical centrifugal distribution (Table 1), and case reports of proctitis and pharyngitis (Figure 3)
have been reported.

In one study, mucosal lesions
were reported in 41% of patients.
Anorectal mucosal involvement has been reported as the predominant symptom in 12% of cases, with anorectal pain, proctitis, tenesmus, diarrhoea, or a combination of
these.
Reports of rectal pain or defecation pain are common
.
In this study, oropharyngeal symptoms (including pharyngitis, phagia, epiglottitis, and oral or tonsillar lesions) were initial symptoms
in 5% of cases.
In another study reported in Spain, 43.
1% of patients had lesions in and around the oral cavity
.

Previous studies have shown that branches2 Monkeypox virus causes milder disease with a case fatality rate of less than 1%, consistent with
the lower hospitalization and mortality rates reported so far in this monkeypox outbreak.
The hospitalization rate is estimated at 5%~10%.

hospitalization associated with cellulitis, particularly genital and perineal region involvement; Severe anal and digestive involvement is associated with rectal pain, penile edema, severe angina, and epiglottitis, and ocular involvement with blepharitis, conjunctivitis, and keratitis (figure 3).

Two recent deaths reported in young, healthy, non-immunodeficient MSM appear to be associated with encephalitis, and the details are still under investigation
.

The monkeypox treatment currently authorized for vaccination and treatment

in the United States and Europe is tecovirimat, and the only one authorized in the United States is brincidofovir
。 Tecovirimat efficacy has been demonstrated in preclinical studies, with Phase 1 and Phase 2 clinical trials evaluating the safety and side effects
of Tecovirimat for use in humans.
A recent observational study including a very small number of monkeypox patients suggests that tecovirimat may shorten viral excretion and duration of
disease.

Mouse and rabbit studies have demonstrated brincidofovir's efficacy
in improving survival after infection.
In clinical trials of CMV disease in hematopoietic stem cell transplant recipients, researchers have evaluated its safety
for use in humans.
Brinci Dofovir has toxic effects on the gastrointestinal tract and liver, and its safety profile is inferior to tecovirimat
.

Regardless of the authorization status of both drugs, randomized clinical trials are warranted to evaluate their efficacy
.
The WHO and several countries are conducting such trials, especially for tecovirimat
.
These assessments should be conducted not only in the countries involved in the current monkeypox outbreak, but also in areas where endemic is endemic
.
Since the virus may become resistant to first-line treatments, the development of second-line treatments may be of great significance
.

Vaccinia immunoglobulin, a plasma γ globulin obtained and purified from live vaccinia virus vaccine recipients, is licensed in the United States for the treatment of complications
following smallpox vaccination.
Other therapies
such as compounds and monoclonal antibodies are currently being developed.
NIOCH-14 is a synthetic tecovirimat analog that has passed Phase 1 trials
.
Several laboratories are currently developing monoclonal antibodies, and preclinical trials have begun
.

The vaccines available to respond to current monkeypox outbreaks are ACAM2000 and MVA-BN
.
ACAM2000 (Emergent BioSolutions) is a second-generation live attenuated live pox-virus vaccine that the U.
S.
Food and Drug Administration (FDA) has approved for vaccination
before or after exposure to monkeypox.
The vaccine is effective, but there is a risk of
developing heart complications.

MVA-BN is a third-generation attenuated, modified live vaccine of the Ankara strain (non-replicating) of the vaccinia virus developed by Bavarian
Nordic.
The vaccine has been approved in the United States and Europe for smallpox prevention and was approved by the FDA in 2019 for monkeypox
prevention.
LC16m8 (KM Biologics), a third-generation highly attenuated pox-virus vaccine, is also licensed for smallpox prevention, but is not currently authorized for monkeypox
prevention.

MVA-BN has received emergency authorization from several national health authorities, including France, for post-exposure prophylaxis in monkeypox to administer ring-vaccination strategies to contacts at high risk of infection in current monkeypox outbreaks
.
Given the increasing incidence of monkeypox and difficulties in diagnosing cases and tracing contacts, some countries, including the United Kingdom and France, are now recommending the provision of third-generation smallpox vaccines
to men at high risk of exposure.

ConclusionsThe

gradual decline in immunity to smallpox may partly explain the increased
incidence of monkeypox in some areas other than endemic areas.
However, the current monkeypox epidemic reminds us that the emergence of viruses is a perpetual phenomenon that knows no borders, and that its nature, target population and size are often unpredictable
.
This monkeypox outbreak shows how diseases affecting one part of the world can strongly affect other regions outside endemic areas, with different target populations and new clinical manifestations
.

To stop the continuation of the current monkeypox epidemic, including in endemic African and newly affected areas, the priorities are clear: first, raising awareness and education, especially among high-risk groups, to prevent viral infections and reduce transmission and spread; second, to develop rapid, sensitive point-of-care tests to improve disease diagnosis and ultimately prevention; Third, assess the effectiveness of existing therapeutics, vaccines and vaccination strategies, and scale up efforts to make vaccines and therapeutics
available to all affected populations and regions.

References

Gessain A, Nakoune E, and Yazdanpanah Y.
Monkeypox.
N Engl J Med 2022 October 26 (Epub ahead of print).

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.
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.
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.
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