Human monkeypox: An updated appraisal on epidemiology, evolution, pathogenesis, clinical manifestations, and treatment strategies

Abstract

Monkeypox (Mpox) is a zoonotic viral disease caused by the monkeypox virus (MPXV), a member of the Orthopoxvirus genus. The recent occurrence of Mpox infections has become a significant global issue in recent months. Despite being an old disease with a low mortality rate, the ongoing multicountry outbreak is atypical due to its occurrence in nonendemic countries. The current review encompasses a comprehensive analysis of the literature pertaining to MPXV, with the aim of consolidating the existing data on the virus's epidemiological, biological, and clinical characteristics, as well as vaccination and treatment regimens against the virus.

Full text

Received: 7 August 2023
|
Revised: 13 September 2023
|
Accepted: 4 October 2023
DOI: 10.1002/jobm.202300455
REVIEW
Human monkeypox: An updated appraisal on
epidemiology, evolution, pathogenesis, clinical
manifestations, and treatment strategies
Mohammad Ejaz
1,2
|Momina Jabeen
3
|Mehmoona Sharif
2
|
Muhammad Ali Syed
4
|Pir T. Shah
5
|Rani Faryal
2
1
Department of Microbiology, Government Postgraduate College Mandian, Abbottabad, Pakistan
2
Department of Microbiology, Quaid‐i‐Azam University, Islamabad, Pakistan
3
National Center for Bioinformatics, Quaid‐i‐Azam University, Islamabad, Pakistan
4
Department of Microbiology, The University of Haripur, Haripur, Pakistan
5
Institute of Biomedical Sciences, Shanxi University, Taiyuan, Shanxi, China
Correspondence
Mohammad Ejaz, Department of
Microbiology, Quaid‐i‐Azam University,
Islamabad 45320, Pakistan.
Email: m.ejaz@bs.qau.edu.pk
Abstract
Monkeypox (Mpox) is a zoonotic viral disease caused by the monkeypox virus
(MPXV), a member of the Orthopoxvirus genus. The recent occurrence of
Mpox infections has become a significant global issue in recent months.
Despite being an old disease with a low mortality rate, the ongoing
multicountry outbreak is atypical due to its occurrence in nonendemic
countries. The current review encompasses a comprehensive analysis of the
literature pertaining to MPXV, with the aim of consolidating the existing data
on the virus's epidemiological, biological, and clinical characteristics, as well
as vaccination and treatment regimens against the virus.
KEYWORDS
clinical manifestations, global health, monkeypox, Orthopoxvirus, zoonosis
1|INTRODUCTION
Monkeypox (Mpox) is a zoonotic viral illness caused by
the monkeypox virus (MPXV). Since the first human case
of Mpox was detected in the Demographic Republic of
Congo (DRC) in 1970, sporadic outbreaks were consis-
tently reported from endemic countries of Africa with
some outbreaks outside Africa including the US outbreak
in 2003 and few cases from the United Kingdom,
Singapore, and Israel in 2018–2019 [1–3]. Mpox cases
started being reported from all across the world since
May 2022 and a Public Health Emergency of Interna-
tional Concern was declared by the World Health
Organization [4]. MPXV belongs to the Orthopoxvirus
genus of the Poxviridae family that has enveloped,
double‐stranded DNA genome. Genome size is approxi-
mately 197 kb having 190 open‐reading frames (ORFs)
with the conserved central core region having multiple
housekeeping genes [5, 6].
The disease is mainly transmitted by direct/indirect
contact with infected animals/humans' body fluids,
lesions, or respiratory droplets [7, 8]. Fomite transmission
J Basic Microbiol. 2023;1–14. www.jbm-journal.com © 2023 Wiley‐VCH GmbH.
|
1
Abbreviations: CFR, case fatality rate; CPE, cytopathic effect; FDA, Food and Drug Administration; ITR, inverted terminal repeats; Mpox,
monkeypox; MPXV, monkeypox virus; NAAT, nucleic acid amplification test; ORF, open‐reading frame; WHO, World Health Organization.

of Mpox is occasional, occurring through shared items
such as bedding and linens infected with MPXV [9].
Similarly, respiratory transmission is less efficient and
occurs only after prolonged exposure to infected droplets
or close contacts [8].
The genome of MPXV is estimated to be ~197 kb in
size and harbors approximately 190 genes. The terminal
end of the genome is bordered by inverted terminal
repeats (ITRs). The virus can be classified into two
distinct clades based on genetic differences. Clade 1
MPXV, also referred to as the Congo Basin (Central
African) clade, is characterized by a higher mortality
rate. On the other hand, clade 2 MPXV, also known as
the West African clade, is associated with less severe
infections and a lower mortality rate [10]. Following an
incubation period ranging from 7 to 14 days, with an
average duration of 5–13 days, the disease manifests as
an initial flu‐like illness accompanied by lymphadenopa-
thy. Subsequently, rashes emerge and spread outward
from the center occasionally affecting the palms, face,
oral mucosa, and soles [11, 12]. Currently, there is no
officially approved treatment specifically designed for the
management of Mpox infections. However, antiviral
drugs effective against the smallpox virus have demon-
strated efficacy in mitigating the severity of the
associated illness.
2|HISTORY AND
EPIDEMIOLOGY
Monkeypox was initially identified in a colony of the
crab‐eating macaque (Cynomolgus spp.) being used for
research in Copenhagen, Denmark in 1958 [13]. Between
1960 and 1968, several sporadic outbreaks were reported
among colonies of monkeys in research captivity in the
United States and the Netherlands [14]. The first human
Mpox case emerged in 1970 in a 9‐month‐old
unvaccinated young boy from the DRC, as part of the
national surveillance and eradication program of small-
pox disease [15]. In 1971/1972, six other human Mpox
cases were reported in DRC, Liberia, and Sierra Leone.
All of the cases reported in 1971/1972 were of young
children with no vaccination coverage against smallpox
[16, 17]. Although Mpox was uncommon in humans, the
case rate has increased since the 1980s, possibly because
of waning immunity against poxvirus due to the stoppage
of routine smallpox vaccination [18]. Surveillance of
poxvirus infection in DRC by WHO between 1981 and
1986 recorded 338 confirmed cases with a case fatality
rate (CFR) of 7.8% [19]. Mpox remains endemic in DRC
with >500 cases reported in 1991–1999, including 88%
cases of human‐to‐human transmission [19, 20]. The
reported cases in DRC and other central African
countries belong to clade I of the disease, which has a
higher CFR compared to other reported clades [15]. The
disease has been documented in 11 African countries
since its first origin in the 1970s including DRC, Central
African Republic, Liberia, Nigeria, Sierra Leone, South
Sudan, Cote d'Ivoire, Gabon, Benin, Republic of Congo,
and Cameroon [21, 22].
Mpox disease remains endemic in Central and
Western Africa and is considered exclusively an African
disease but the first case of Mpox disease emerged in
2003 outside Africa in the United States [23]. In 2003, the
first case of Mpox was identified in a young child in
Wisconsin (US) after being bitten by a prairie dog [23]. In
total, >81 cases were reported from different states of the
United States including Wisconsin, Ohio, Indiana,
Missouri, Illinois, and Kansas [24]. All of the cases in
the multistate outbreak of Mpox in the United States
were traced back to Gambian pouched rats imported
from Ghana [25]. Afterward, another significant out-
break emerged in Sudan in 2005 affecting 49 individuals
with no case fatalities [26]. The genetic analysis of the
MPXV in Sudan revealed that Mpox did not originate in
Sudan but rather imported from DRC [27]. The disease
remains endemic in African countries reporting sporadic
outbreaks, particularly in DRC and very few human
cases reported in West Africa [19].
In Nigeria, the MPXV re‐emerged after 39 years of its
last reported case. In 2017–2018, outbreaks arose in
several cities of Nigeria with 122 PCR confirmed cases
(CFR 6%) of MPXV clade 2 [28, 29]. The outbreak started
in September 2017 in Bayelsa state and makes its way
across multiple states of Nigeria by May 2019 [30]. A few
cases were also reported between September 2018 and
November 2019 in nonendemic countries. All of the cases
were associated with traveling to Nigeria (West African
clade 2) including seven cases in the United Kingdom,
two in the United States, and one case each in Singapore
and Israel [31, 32].
By May 2022, several cases of Mpox started being
reported from the United Kingdom since the first case
was on May 6, 2022 in a patient with a travel history of
Nigeria. Contact tracing identified a few other cases in
his house. Afterward, a series of unlinked cases were
reported with no travel history to any endemic country
from Italy, Portugal, and the United States. Mpox started
to spread to several countries and WHO declared a Public
Health Emergency of International Concern on July 23,
2022 [33]. The current outbreak has reported cases from
America, Europe, Africa, and even Asia and Oceania
[34, 35]. The genome sequence of the current outbreak
(clade 3) originated from the West African clade (lineage
B.1) [15]. The CFR of previous outbreaks was 3%–6%,
2
|
EJAZ ET AL.

while the CFR in 2022 was less than 1% [36]. By February
2023, Mpox have been documented in 110 countries with
over 85,000 cases and 97 deaths, resulting in a pandemic‐
like situation [37, 38]. Several studies suggested the
novelty in epidemiology and clinical characteristics of
disease [39–41]. The most affected countries include the
United States, the United Kingdom, Brazil, Columbia,
Peru, France, Germany, Mexico, and Canada accounting
for >84% of total cases worldwide [37]. The global
situation is now under control and a decline in cases is
seen since October 2022 [37, 38]. Although the incidence
rate has significantly declined, the outbreak still persists
in many countries and poses global public health
concerns [42, 43] (Figure 1).
3|TRANSMISSION
Mpox is a zoonotic disease transmitted through animals
to humans but animal reservoirs are still unknown.
Various species of rodents and nonprimate animals
including tree squirrels, rope squirrels, monkeys,
Gambian pouched rats, and dormice from West and
Central African tropical rainforests are considered as
strong candidates for being reservoirs [44, 45]. Moreover,
animals like rabbits, rodents, nonhuman primates, and
prairie dogs in captivity for laboratory experiments are
also susceptible to getting infected [45, 46]. It has been
suggested that humans and monkeys are incidental hosts
of MPXV [47]. Several studies on genomic analyses have
reported the zoonotic spillover of the MPXV to human
populations, suggesting the persistence of Mpox in
wildlife reservoirs [48–50]. Further studies are needed
to find the exact reservoir and circulation cycle of
the Mpox.
Animal‐to‐human transmission could occur from
direct contact with an infected animal's body fluids or
lesions [51]. The transmission of infection to humans
typically occurs through noninvasive means, such as
engaging in activities like cleaning animal enclosures,
direct contact with infected animals, participating in
hunting activities, handling and processing infected
animal meat, and consuming undercooked meat or being
exposed to scratches or bites from infected animals
FIGURE 1 Map of monkeypox (Mpox) cases. (a) Current situation of Mpox 2022 outbreak across the world. (b) History of Mpox
emergence in endemic countries.
EJAZ ET AL.
|
3

[52, 53]. Several studies have reported animal contact
with index patients and animals as possible cause of
interspecies transmission [54]. However, virologic confir-
mation of interspecies transmission has not been
reported to date.
Human‐to‐human transmission of infection occurs
via direct contact with bodily fluids, lesions, or crusts of
the infected individuals, as well as indirect exposure to
contaminated objects, respiratory droplets, percutaneous
transmission, and vertical transmission [55, 56]. The
respiratory transmission of the MPXV is facilitated
through the inhalation of substantial respiratory droplets
emitted by infected individuals [57]. The principal mode
of transmission entails direct contact with infected sores/
lesions on mucous membranes; however, the infection
may also disseminate through close interpersonal contact
with infected individuals [44, 58]. Transmission occurs
through the facilitation of cuts, breaches, or abrasions in
the recipient's mucosa or skin during intimate or direct
contact [40, 58]. It is noteworthy that the estimated
secondary attack rate in unvaccinated individuals ex-
ceeds 9% [59].
In the 2022 outbreak of Mpox, DNA is mostly found
in skin samples and is less frequently been detected from
other parts of the body such as from semen samples
(50%), blood and urine samples (20%), and anus and
throat samples (60%–70%) [40, 44, 60]. Furthermore, viral
load in skin samples was comparatively higher by
twofolds than in other body parts [61, 62]. Transmission
of Mpox varies greatly in different settings including
healthcare settings, households, communities, and mass
gatherings. In previous outbreaks before 2022, transmis-
sion is mostly restricted to households or congregate
living settings. The secondary attack rate in the
1996–1997 outbreak in DRC was 9.3% in households,
while the attack rate of household transmission in 2022
was only 0.6%–3.0% [39, 40]. The majority of the
infections in 2022 outbreaks were of community‐
associated transmission with reproductive numbers of
approximately 1.4–1.8, showing great potential for local
transmission [63].
4|MORPHOLOGY AND
GENOMIC ORGANIZATION
The morphological features of MPXV are like other
related orthopoxviruses and have ovoid‐or brick‐shaped
particles with a diameter of about 200–250 nm [64]. The
virion encloses a biconcave dumbbell‐shaped nucleo-
protein core containing a double‐stranded DNA genome
with a covalently closed hairpin loop on each side,
FIGURE 2 Schematic representation of monkeypox virus (MPXV) morphology and genomic architecture. Schematics of MPXV
morphology and genomic architecture indicate that it contains distinct structural components, that is, surface membranes, surface tubules,
two lateral bodies, and a nucleoprotein core that encapsulates the viral genome and viral proteins. MPXV genome possesses conserved
central region and variable terminal regions. Left and right terminal regions contain 6379‐bp‐long inverted terminal repeat (ITR) regions.
ITR region is composed of a hairpin loop, tandem repeats, NR1 and NR2, short repeats, and four open‐reading frames.
4
|
EJAZ ET AL.

covered with bilayer membranes having ~10‐nm‐long
tubules on the outer membrane (Figure 2)[30].
The genomic architecture of MPXV is comprised of
~197‐kb‐long double‐stranded DNA that contains about
190 ORFs [48, 65]. MPXV contains a highly conserved
central core region that contains the housekeeping genes
involved in viral transcription, replication, and virion
assembly, and highly variable left and right terminal
regions that encode the proteins associated with host
range and pathogenicity [48, 66]. The left and right ends
contain 6397‐kb‐long ITRs, which are composed of an
80‐bp‐long hairpin loop, short tandem repeats, NR1 and
NR2 region, and some open‐reading frames (ORFs)
(Figure 2)[22].
5|EVOLUTIONARY
PERSPECTIVE OF MPXV
Since the discovery of MPXV, it has undergone evolution,
which led to the emergence of different genetic variants
[67]. The virus has previously been classified into two
clades: the Central African clade or Congo Basin clade
and the West African clade [68, 69]. However, recently a
novel nomenclature has been proposed that segregated
the MPXV into three distinct clades: clade 1/clade I
formerly known as Central African Clade (includes
isolates from Central African countries), clade 2/clade
IIa formerly West African Clade (includes isolates from
West African countries detected before 2017), and clade
3/clade IIb also known as West African Clade (includes
isolates from 2017 to 2019 outbreaks and from the
current multicountry outbreak of 2022) (Figure 3)
[68, 69]. MPXV clades 2 and 3 have a CFR of <1%,
while clade 1 is known to be more virulent with
CFR > 10% [68, 69]. The distinction among the MPXV
clades is majorly due to the nucleotide divergence in
immunomodulatory or host range determination protein‐
encoding ORFs found within the left and right termini
regions of the genome [68–70].
Moreover, multiple sublineages of MPXV clade
3/clade IIb have been identified such as A or hMPXV‐
1A, A.1, A.1.1, A.2, and B.1 (Figure 3)[69, 71]. The MPXV
strain causing the 2017–2018 outbreak in Nigeria belongs
to lineage A, which is further subdivided into two clades
A.1 and A.2, the former causing outbreak in the United
Kingdom, Singapore, and Israel, while the latter causing
2021–2022 outbreak in the United States [71]. However,
the MPXV strain causing the multicountry outbreak of
2022 belongs to lineage B.1, which diverged from lineage
A.1 [71]. Additionally, the B.1 lineage accumulated
further mutations and formed new sublineages such as
B.1.1, B.1.2, B.1.3, B.1.4, B.1.5, B.1.6, B.1.7, and B.1.8 [72].
MPXV has undergone microevolution, allowing it to
disperse to other geographical locations and potentially
adapt to new hosts across the regions [73]. Notably, 46
mutations have been found in the B.1 lineage in
comparison with the closest reference strain from which
the clade diverges. Among these mutations, three amino
acid replacements occur in the immunogenic surface
glycoprotein B21 protein, which facilitates transmission
and alters the host interaction [71, 73]. Furthermore, 10
other proteins such as OPG210, OPG071, OPG188,
OPG153, A27L‐like, OPG023, OPG109, OPG105, D2L‐
like, and OPG047 are more prone to accumulate
mutations [74]. In addition, evolution is driven by the
action of apolipoprotein mRNA‐editing catalytic
polypeptide‐like 3 (APOBEC3) enzymes in viral genome
editing, that is, 15 out of 46 mutations are the
consequence of APOBEC3 activity [73, 75]. Wolf et al.
evaluated the molecular evolution in MPXV and reported
that B.1 clade is the most circulating strain in the world
(93.9%; n= 415) [12]. The other circulating strains are 1A
(2.9%; n= 13), A.1 (2.3%; n= 10), A.1.1 (0.2%; n= 1), and
A.2 (0.7%; n= 3). The overall divergence observed in the
nucleotide sequence of MPXV was 5.59 × 10
−5
[12].
6|PATHOGENESIS AND
CLINICAL MANIFESTATIONS
MPXV infects the hosts through nasal or oral cavities as
well as hypodermic portals. Viruses multiply at their
point of entry in the host and then spread to nearby
lymph glands. The viral burden increases in primary
viremia before disseminating to the surrounding lymph
glands. Afterward, MPXV spread to the distant lymph
nodes and other organs subsequently resulting in
systemic infection [76]. Historically, the incubation
period usually ranges from 4 to 14 days but could take
up to 17 days [16, 77]. Charniga et al. determined the
mean incubation period in a multistate outbreak in the
United States and documented a mean incubation period
of 7.6 days from the moment of exposure to the onset of
initial symptoms, while the manifestation of distinctive
rashes occurs at a mean of 8.7 days [78]. The incubation
period is not contagious and clinical manifestations do
not appear during this phase. The prodromal stage is
associated with the clinical signs, symptoms, and
manifestations of MPox. During the prodromal phase,
secondary viremia occurs, which disseminates the virus
from the lymphatic system to the skin and other tertiary
organs including the eyes, gastrointestinal tract, lungs,
and so forth [1].
According to the US Centers for Disease Control and
Prevention, the incubation time for Mpox infection is 1–2
EJAZ ET AL.
|
5

weeks, and the duration of illness is typically 2–4 weeks.
The severity of infection is affected by the patient's
current health, the route of infection, and the specific
virus strain. The Central African clade exhibits a higher
severity of symptoms and a higher fatality rate than the
West African clade [46]. The Mpox cases linked to the
2022 epidemic present clinically differently than those
previously reported [28]. The incubation period for
MPXV before the epidemic in 2022 was on average
5–13 days (range 4–21 days) [79]. The incubation period
may be shorter for people who have previously been
bitten or scratched by an animal (9 vs. 13 days,
respectively) compared to those who have only had
tactile exposures. During the 2022 pandemic, the typical
incubation time is approximately 7–10 days after
exposure to the pathogen [35, 80]. Sexual transmission
may provide a shorter incubation period due to direct
virus injection [40].
MPXV has been linked to systemic manifestations
resulting from the viremic phase of infection. This
particular phase typically lasts for a span of 1–5 days,
during which affected individuals may experience fever,
myalgias, sore throat, and generalized lymphadenopathy.
Subsequently, the emergence of cutaneous lesions
becomes evident [29]. The duration of Mpox skin lesion
eruption typically spans a period of 2–3 weeks, progress-
ing through distinct phases as illustrated in Figure 4.
The macules transform and subsequently advance
into papules, vesicles, and pustules, respectively. Over
time, the pustules undergo a process of structural
FIGURE 3 Phylogenetic characterization of monkeypox virus (MPXV) based on the whole‐genome sequences. Phylogenetic tree
demonstrating the distinct clades and sublineages of MPXV. Each clade and sublineage is represented with different colors and designated
according to the nomenclature proposed by Happi et al. [69]. The phylogenetic tree was constructed in MEGA11 by employing the
maximum‐likelihood method with the Tamura–Nei substitution model. The phylogenetic analysis involved 37 whole‐genome sequences of
MPXV strains.
6
|
EJAZ ET AL.

development, acquiring an umbilicated formation, which
leads to the formation of a scab [82]. The most often
affected areas are the face (98%), the palms and soles
(95%), the oral mucous membranes (70%), the genitalia
(28%), and the conjunctiva (20%) [83]. The quantity of
cutaneous lesions resulting from the infection caused by
the MPXV may vary, spanning from a small number to
approximately 1000. In regions where the disease is
naturally prevalent, it has been observed that a notable
proportion of individuals (20%–42%) exhibit a count of
lesions exceeding 100. However, it is worth noting that
individuals with compromised immune systems may
present with an even higher count, surpassing 1000
lesions. The majority of individuals affected during the
2022 epidemic exhibit a range of 1–20 cutaneous
lesions while occurrences with over 100 lesions have
been exceedingly rare, accounting for only 0%–4% of
cases [40, 41].
Previously, rashes were more common on the face,
trunk, and extremities but can appear on the whole body
[28, 29]. However, during the 2022 pandemic, lesions
were primarily located in the perioral and anogenital
regions [39, 40]. It is not uncommon for male patients to
have many genital lesions affecting the penis, scrotum,
and pubis. In addition to typical edema around genital
sores, substantial enlargement of the penile glans or
foreskin may also occur. Proctitis (muscle spasms, pain
during feces, serosanguinous drainage, or bleeding) is
caused by lesions in the perineal area, which can affect
the buttocks, the anal margin, or the rectum mucosa.
Tonsil lesions are unpleasant and can make swallowing
difficult, while tongue lesions are often round, white, and
concave. Ulcers and crusts are common perioral lesions,
as are lesions of the oral mucosa and lips. Abscesses are
sometimes caused by secondary bacterial infections, and
large plaques or ulcerations can form wherever lesions
have coalesced [44].
The devastating consequences of Mpox infections
have been documented throughout history and they
include bronchopneumonia, septicemia, eye infection,
and neurological symptoms [84]. Ocular involvement
includes conditions such as ophthalmitis, lid lesions,
keratitis (which can leave scars on the cornea and lead to
blindness), and keratitis. Neurological clinical signs such
as encephalitis, seizures, and disorientation were re-
ported in 2% of cases of Mpox according to a systematic
review of research conducted between 2003 and 2021
[85]. Among the novel severe consequences reported in
the 2022 outbreak are myocarditis, epiglottitis, quincy
(peritonsillar abscess), bowel perforation with accompa-
nying abscess in individuals with rectal inflammation,
and macrophage activation syndrome [39–41]. Finally,
some individuals may develop a morbilliform rash after
taking specific drugs (such as ampicillin or amoxicil-
lin) [40].
7|DIAGNOSIS
The primary consideration for the diagnosis of MPXV
infection is the evaluation of clinical and epidemiological
data. The utilization of nucleic acid amplification testing
(NAAT) employing either real‐time or classical polymer-
ase has been employed for the purpose of verifying the
existence of the MPXV. It is recommended that
individuals who exhibit symptoms indicative of Mpox
infection undergo NAAT testing, either of a generic
nature for orthopoxviruses or one that is specifically
FIGURE 4 Appearance of the monkeypox rash and its progression through its different stages (adapted from Hutin et al. [81]).
EJAZ ET AL.
|
7

tailored to detect the MPXV, in cases where there is
suspicion or probability of infection. It is also recom-
mended to obtain skin lesion specimens, such as swabs of
the lesion surface or exudate and lesion crusts, to confirm
the presence of monkeypox through laboratory analysis.
A crucial aspect of the diagnostic process involves the
meticulous swabbing of the lesion to ensure adequate
retrieval of viral DNA. The solid material present in
the lesions caused by the MPXV poses a challenge in the
process of unroofing them, unlike the lesions caused by
herpes simplex, which are typically filled with fluid, as
evidenced by histological examination [86]. The utiliza-
tion of DNA testing via a throat swab for the MPXV could
also prove to be valuable for research or epidemiological
objectives. Nevertheless, it is not conventionally em-
ployed within a clinical context. Certain blood specimens
exhibit a favorable NAAT outcome, albeit the clinical
significance of viremia remains inadequately scrutinized
[62, 87].
The diagnostic challenges encountered in remote
regions of western and central Africa, coupled with the
requirement for a cold chain to maintain sample
integrity, have resulted in limited access to NAAT
platforms. This has impeded the confirmation of cases
and hindered the comprehension of Mpox epidemiology
in these areas. In resource‐limited settings, loop‐
mediated isothermal amplification diagnostic assays
may serve as a feasible substitute for high‐precision
PCR equipment in rural clinics or regional hospitals [88].
The aforementioned technique has been proposed as a
diagnostic modality for various tropical illnesses that
have been overlooked and has exhibited favorable results
in the context of other newly emerging viral infections
[89]. An additional approach to detecting the onset of a
rash illness epidemic involves the utilization of a field
analytical facility to conduct PCR assays on blotting
papers that have been imbued with pustular exudate and
procured from a geographically isolated region [90].
The confirmation of Mpox diagnosis can be facilitated
through serological examination for the MPXV, particu-
larly in situations where NAAT testing is not feasible.
The identification of IgM in individuals experiencing
acute illness within 4–56 days of rash onset or IgG in
paired serum samples, with the first sample collected
during the first week of infection and subsequent
samples collected at least 21 days apart, may assist in
the diagnosis. This information is supported by previous
research [91]. Skin tissue biopsies represent supplemen-
tary clinical specimens that may be employed for
diagnostic purposes, albeit exclusively in cases of clinical
necessity. The histological features of Mpox exhibit a
striking resemblance to those of smallpox, vaccinia, and
cowpox. However, these features can be utilized to
differentiate it from other ailments such as varicella and
herpes simplex virus. The manifestation of mucosal
inflammation may be observed upon proctoscopy in
individuals afflicted with proctitis. The performance of
routine proctoscopy is often impeded by the presence of
severe pain. In addition, it is recommended that rectal
magnetic resonance imaging be conducted as an integral
component of the assessment in cases where there is
suspicion of rectal wall perforation [44].
The utilization of viral culture remains an essential
technique in the identification of infrequent or nascent
viral illnesses, particularly in instances where specimens
with elevated viral loads are easily obtainable. The MPXV
exhibited rapid multiplication in cell culture, leading to
the manifestation of detectable cytopathic effects (CPEs)
within a median of 2 days. The CPE was observed to
affect more than 50% of the monolayer in various cell
lines, including RMK, BGM, A549, and MRC‐5. Electron
microscopy reveals the presence of oval to spherical
inclusions and sausage‐shaped intracytoplasmic struc-
tures [86]. The cytoplasm of keratinocytes in
glutaraldehyde‐fixed skin biopsy human tissues has been
observed to contain both immature and mature phases of
assembled virions under transmission electron micros-
copy. The morphological features of mature virions are
characterized by dumbbell‐shaped cross‐sections, as
evidenced by negative‐stain electron microscopy images
that reveal brick‐shaped virions with regularly spaced,
thread‐like ridges on their exposed surfaces.
8|TREATMENT
Primarily, symptomatic treatments and supportive care
are the only treatment strategies for Mpox infection at
this time [92]. There is no specific antiviral drug
approved to combat Mpox infection; however, several
antiviral drugs that have therapeutic potential against
orthopoxvirus species are used to treat infection [87].
HPMPC (Cidofovir), a pharmacological agent employed
in the treatment of various viral infections, exerts its
therapeutic effects through the mechanism of DNA
polymerase inhibition. Due to the nephrotoxic effects
induced by cidofovir, there is ongoing development of
CMX‐001 (Brincidofovir), an orally administered antivir-
al medication that acts by inhibiting DNA polymerase
[93]. Another oral drug, ST‐246 (Tecovirimat), is
currently being used, which inhibits the internal release
of the virus and has demonstrated encouraging effective-
ness against many species of orthopoxviruses, including
the Variola virus [94, 95]. In addition to antiviral drugs,
the Food and Drug Administration (FDA) has already
authorized the use of vaccinia immune globulin
8
|
EJAZ ET AL.

intravenous for the treatment of side effects from the
vaccinia vaccination, such as progressive vaccinia and
severe widespread vaccinia [96]. The antiviral substances
for MPXV and related orthopoxviruses are listed in
Table 1.
9|VACCINATION
Due to similar genetic and antigenic characteristics of
MPXV with other orthopoxvirus species, prior infec-
tion to OPXV can confer cross‐immunity against the
future infection by other viruses of the same genus
[103, 104]. Therefore, previous vaccination against
smallpox can offer some level of protection against
monkeypox [105]. However, because of the 40‐year‐
old WHO‐managed and validated smallpox eradica-
tion, most countries no longer prescribe routine
smallpox immunization. Thus, it is estimated that
more than 70% of the global population does not have
adequate immunity to orthopoxviruses, which led to
the surge in MPXV infection [106]. Thus, to control
the monkeypox outbreak, smallpox vaccination was
considered as one of the adequate treatment ap-
proaches, as there was no vaccine specifically
designed for MPXV [107]. Currently, there are two
types of vaccines approved in the United States and
Europe against Mpox, that is, ACAM2000 and MVA‐
BN [108–110].
From 2015 to 2019, ACAM2000 was the only FDA‐
approved orthopoxvirus vaccine in the United States
[110]. A single dose of ACAM2000 (replication‐
competent vaccinia virus vaccine) is delivered per-
cutaneously and provides protection within 28 days of
administration [110, 111]. As ACAM2000 is a replication‐
competent vaccinia virus, it can demonstrate the
potentially adverse outcome in immunocompromised
persons. Furthermore, the vaccinia virus can also be
transmitted from a vaccinated person to an unvaccinated
person via close contact with a vaccination site [112].
In 2019, FDA approved MVA‐BN (trade names:
Jynneos/Imvanex/Imvamune), a modified vaccinia An-
kara virus vaccine, which contains weakened vaccinia
virus that has reduced replication abilities of the virus
[109, 111]. Two doses of the MVA‐BN vaccine are
delivered subcutaneously, spaced 4 weeks, providing
protection after 2 weeks following the administration of
the second dose [111]. Moreover, CDC's Advisory
Committee on Immunization Practices also recom-
mended MVA‐BN (Jynneos) as an alternative to
ACAM2000, as the vaccine contains nonreplicating
vaccinia virus and cannot spread. Thus, it can be used
for individuals with immunocompromised conditions
TABLE 1 Treatment strategies for the management of monkeypox infection.
Antivirals Mode of action Mode of administration Dosage Side effects References
Cidofovir (HPMPC or Vistide) Block DNA synthesis by inhibiting
DNA polymerase
Injection 5 mg/kg per week for two doses or more Nephrotoxic, nausea, and vomiting [97]
Brincidofovir (CMX001 or
HDP‐cidofovir)
Prodrug of cidofovir combined with
lipid
Capsule 4 mg/kg per week for two doses Dizziness, vomiting, diarrhea, increased
level of transaminase, and bilirubin in
the liver
[98, 99]
Tecovirimat (ST‐246) Inhibit virion assembly by blocking
the activity of VP37 protein
Both injection and capsule IV: 30–120 kg weight: 600 mg/12 h
120 kg or more weights: 300 mg/12 h
Oral: 40–120 kg weigh: 600 mg/12 h
120 kg or more weight: 600 mg/8 h
All doses for 14 days
Extravasation along with redness and
inflammation at the infusion site
[100, 101]
Vaccinia immune globulin
intravenous (VIGIV)
Smallpox vaccine produces
antibodies, which provide
passive immunity
Injection 6000 U/kg to symptomatic individual; it may be repeated
depending on the severity of symptoms and response to
treatment; 9000 U/kg, if the patient does not respond to
the initial dose
Headache, dizziness, and nausea [102]
EJAZ ET AL.
|
9

and has a greater safety profile and fewer adverse
effects [113].
In the current outbreak of MPXV, vaccination can be
administered either as pre‐exposure prophylaxis to pre-
vent infection or postexposure prophylaxis to treat
infection and disease. Pre‐exposure prophylaxis is
recommended for those associated with occupational
exposure to orthopoxvirus such as laboratory personnel
performing diagnostic testing of MPXV or other OPXV.
While postexposure prophylaxis is recommended for
those who are at risk of exposure due to contact with
symptomatic individuals. Postexposure vaccination
should ideally be administered within 4 days of exposure
to MPXV [114, 115].
10 |CONCLUSION
MPXV historically confined to specific regions in
Africa has now emerged as a worldwide issue, as cases
have been reported and verified from all around the
world. Human‐to‐human transmission primarily oc-
curs through respiratory droplets or direct contact
with the mucocutaneous lesions of an infected
individual. Therefore, the implementation of social
distancing measures and contact tracing becomes
crucial in mitigating the spread of the infection.
There is a growing number of confirmed cases of
Mpox among individuals in the middle age range. The
observed phenomenon can be ascribed to the dimin-
ished cross‐immunity resulting from the smallpox
vaccine in elderly individuals. Moreover, evolution in
MPXV genome allows it to disperse to other geograph-
ical locations and potentially adapt to new hosts
across the regions. The genomic and phylogenetic
analyses have elucidated the evolutionary dynamics of
Mpox, providing insights into its origins and the
underlying factors propelling its diversification. Cur-
rently, there is no officially approved treatment
specifically designed for the management of MPXV
infections. Therefore, the comprehensive understand-
ing of Mpox's intricate pathogenesis and dynamics
between the virus and the host immune system
highlights the imperative for ongoing investigation
into therapeutic interventions.
The OneHealth framework should be tailored to
address the endemic regions, focusing on implementing
targeted measures. These measures include epidemiolo-
gical investigations in areas with high risk, enhanced
capacity for surveillance based on laboratory methods,
improved laboratory diagnostics, the establishment of
regional capabilities to effectively respond at the local
level, and intensified research endeavors needed to be
adopted to mitigate the rapid spread of disease. Numer-
ous inquiries pertaining to human disease, animal
reservoirs, and the virus itself remain unresolved.
Advances in understanding this significant zoonotic
phenomenon will facilitate the more effective direction
of prevention strategies and mitigation of human disease.
The future research endeavors for the MPXV exhibit a
complex and interconnected nature, encompassing vari-
ous facets of investigation. These include the develop-
ment of vaccines, exploration of antiviral therapies,
in‐depth genomic studies, analysis of transmission
dynamics, advancements in diagnostics, implementation
of surveillance measures, and the pursuit of clinical
research. Moreover, the imperative for fostering interna-
tional cooperation in surveillance, prevention, and
response strategies necessitates a symbiotic alliance
among researchers, healthcare professionals, and
policymakers.
AUTHOR CONTRIBUTIONS
Mohammad Ejaz: Conceptualization; data curation;
formal analysis; investigation; methodology; project
administration; resources; software; validation; visualiza-
tion; writing—original draft; writing—review and edit-
ing. Momina Jabeen: Writing—original draft; writing—
review and editing. Mehmoona Sharif: Writing—
original draft. Muhammad Ali Syed: Supervision;
validation; visualization. Pir T. Shah: Formal analysis;
writing—review and editing. Rani Faryal: Supervision;
validation; visualization.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.
DATA AVAILABILITY STATEMENT
All the data presented in the article is available within
the manuscript.
ORCID
Mohammad Ejaz http://orcid.org/0000-0002-
1339-5537
Rani Faryal http://orcid.org/0000-0003-3018-0404
REFERENCES
[1] Kaler J, Hussain A, Flores G, Kheiri S, Desrosiers D.
Monkeypox: a comprehensive review of transmission,
pathogenesis, and manifestation. Cureus. 2022;14:e26531.
[2] Tang H, Zhang A. Human mpox: biology, epidemiology,
therapeutic options, and development of small molecule
inhibitors. Med Res Rev. 2023;43:1019–37.
[3] McCollum AM, Shelus V, Hill A, Traore T, Onoja B,
Nakazawa Y, et al. Epidemiology of human Mpox—
worldwide, 2018–2021. Morb Mortal Wkly Rep. 2023;72:
68–72.
10
|
EJAZ ET AL.

[4] Bhagavathula AS, Raubenheimer JE. A real‐time infode-
miology study on public interest in Mpox (Monkeypox)
following the World Health Organization Global Public
Health Emergency Declaration. Information. 2022;14:5.
[5] Luo Q, Han J. Preparedness for a monkeypox outbreak.
Infect Med. 2022;1:124–34.
[6] Goyal R, Devi M, K. Gautam R, Gupta S. A comprehensive
review on rising concern of transmission potential of mon-
keypox virus on healthcare system. Indo Glob J Pharmaceutical
Sci. 2022;12:265–72.
[7] Amir M, Vohra M, Osoro I, Sharma A, Kumar R.
Monkeypox (Mpox) re‐emergence: prevalence, diagnostics,
countermeasures, and its global effect. J Zoonotic Dis.
2023;7:199–206.
[8] Sukhdeo S, Mishra S, Walmsley S. Human monkeypox: a
comparison of the characteristics of the new epidemic to the
endemic disease. BMC Infect Dis. 2022;22:928.
[9] Fleischauer AT, Kile JC, Davidson M, Fischer M, Karem KL,
Teclaw R, et al. Evaluation of human‐to‐human transmis-
sion of monkeypox from infected patients to health care
workers. Clin Infect Dis. 2005;40:689–94.
[10] Roshdy WH, El‐Shesheny R, Moatasim Y, Kamel MN,
Showky S, Gomaa M, et al. Whole‐genome sequence of a
human monkeypox virus strain detected in Egypt.
Microbiol Resour Announc. 2023;12:e00006–23.
[11] van Nispen C, Reffett T, Long B, Gottlieb M, Frawley TC.
Diagnosis and management of monkeypox: a review for the
emergency clinician. Ann Emerg Med. 2023;81:20–30.
[12] Wolf JM, Wolf LM, Fagundes PP, Tomm DMS, Petek H,
Brenner A, et al. Molecular evolution of the human
monkeypox virus. J Med Virol. 2023;95:e28533.
[13] Magnus P, Andersen EK, Petersen KB, Birch‐Andersen A. A
pox‐like disease in cynomolgus monkeys. Acta Pathol
Microbiol Scand. 1959;46:156–76.
[14] Arita I, Henderson DA. Smallpox and monkeypox in non‐
human primates. Bull World Health Organ. 1968;39:277–83.
[15] Gessain A, Nakoune E, Yazdanpanah Y. Monkeypox.
N Engl J Med. 2022;387:1783–93.
[16] Breman JG, Kalisa‐ruti M, Steniowski MV, Zanotto E,
Gromyko AI, Arita I. Human monkeypox, 1970‐79. Bull
World Health Organ. 1980;58:165–82.
[17] Cho CT, Wenner HA. Monkeypox virus. Bacteriol Rev.
1973;37:1–18.
[18] McCollum AM, Damon IK. Human monkeypox. Clin Infect
Dis. 2014;58:260–7.
[19] Sklenovská N, van Ranst M. Emergence of monkeypox as
the most important orthopoxvirus infection in humans.
Front Public Health. 2018;6:241.
[20] Heymann DL, Szczeniowski M, Esteves K. Re‐emergence of
monkeypox in Africa: a review of the past six years. Br Med
Bull. 1998;54:693–702.
[21] Meyer H, Perrichot M, Stemmler M, Emmerich P,
Schmitz H, Varaine F, et al. Outbreaks of disease suspected
of being due to human monkeypox virus infection in the
Democratic Republic of Congo in 2001. J Clin Microbiol.
2002;40:2919–21.
[22] Saxena SK, Ansari S, Maurya VK, Kumar S, Jain A,
Paweska JT, et al. Re‐emerging human monkeypox: a major
public‐health debacle. J Med Virol. 2023;95:e27902.
[23] Xiang Y, White A. Monkeypox virus emerges from the
shadow of its more infamous cousin: family biology matters.
Emerg Microbes Infect. 2022;11:1768–77.
[24] Control for Disease Control and Prevention. Update:
multistate outbreak of monkeypox—Illinois, Indiana,
Kansas, Missouri, Ohio, and Wisconsin. 52. 2003. Atlanta:
Control for Disease Control and Prevention; 2003; 561–4.
[25] Davidson W, Regnery RL, Reynolds MG, Hutson CL, Li Y,
Damon IK, et al. Monkeypox zoonotic associations: insights
from laboratory evaluation of animals associated with the
multi‐state US outbreak. Am J Trop Med Hyg. 2007;76:757–68.
[26] Damon IK, Roth CE, Chowdhary V. Discovery of monkey-
pox in Sudan. N Engl J Med. 2006;355:962–3.
[27] Nakazawa Y, Emerson GL, Carroll DS, Zhao H, Li Y,
Reynolds MG, et al. Phylogenetic and ecologic perspectives
of a monkeypox outbreak, southern Sudan, 2005. Emerging
Infect Dis. 2013;19:237–45.
[28] Yinka‐Ogunleye A, Aruna O, Dalhat M, Ogoina D,
McCollum A, Disu Y, et al. Outbreak of human monkeypox
in Nigeria in 2017–18: a clinical and epidemiological report.
Lancet Infect Dis. 2019;19:872–9.
[29] Ogoina D, Iroezindu M, James HI, Oladokun R,
Yinka‐Ogunleye A, Wakama P, et al. Clinical course and
outcome of human monkeypox in Nigeria. Clin Infect Dis.
2020;71:e210–4.
[30] Alakunle E, Moens U, Nchinda G, Okeke MI. Monkeypox
virus in Nigeria: infection biology, epidemiology, and
evolution. Viruses. 2020;12:1257.
[31] Yong SEF, Ng OT, Ho ZJM, Mak TM, Marimuthu K,
Vasoo S, et al. Imported monkeypox, Singapore. Emerging
Infect Dis. 2020;26:1826–30.
[32] Mauldin MR, McCollum AM, Nakazawa YJ, Mandra A,
Whitehouse ER, Davidson W, et al. Exportation of
monkeypox virus from the African continent. J Infect Dis.
2022;225:1367–76.
[33] Second meeting of the International Health Regula-
tions (IHR). Emergency Committee regarding the multi‐
country outbreak of monkeypox. 2005 [2023 Feb 26].
Available from: https://www.who.int/news/item/23-07-
2022-second-meeting-of-the-international-health-
regulations-(2005)-(ihr)-emergency-committee-regarding-
the-multi-country-outbreak-of-monkeypox
[34] Ejaz H, Junaid K, Younas S, Abdalla AE, Bukhari SNA,
Abosalif KOA, et al. Emergence and dissemination of
monkeypox, an intimidating global public health problem.
J Infect Public Health. 2022;15:1156–65.
[35] Miura F, van Ewijk CE, Backer JA, Xiridou M, Franz E,
Op de Coul E, et al. Estimated incubation period for
monkeypox cases confirmed in the Netherlands, May 2022.
Euro Surveill. 2022;27:2200448.
[36] deWitt ME, Polk C, Williamson J, Shetty AK, Passaretti CL,
McNeil CJ, et al. Global monkeypox case hospitalisation
rates: a rapid systematic review and meta‐analysis.
EClinicalMedicine. 2022;54:101710.
[37] 2022–23 Mpox (monkeypox) outbreak: global trends.
2023 [2023 Feb 27]. Available from: https://worldhealthorg.
shinyapps.io/mpx_global/
[38] 2022 Global map & case count. 2023 [2023 Feb 27]. Available
from: https://www.cdc.gov/poxvirus/monkeypox/index.html
EJAZ ET AL.
|
11

[39] Thornhill JP, Barkati S, Walmsley S, Rockstroh J,
Antinori A, Harrison LB, et al. Monkeypox virus infection
in humans across 16 countries—April–June 2022. N Engl J
Med. 2022;387:679–91.
[40] Tarín‐Vicente EJ, Alemany A, Agud‐Dios M, Ubals M,
Suñer C, Antón A, et al. Clinical presentation and
virological assessment of confirmed human monkeypox
virus cases in Spain: a prospective observational cohort
study. Lancet. 2022;400:661–9.
[41] Patel A, Bilinska J, Tam JCH, Da Silva Fontoura D,
Mason CY, Daunt A, et al. Clinical features and novel
presentations of human monkeypox in a central London
centre during the 2022 outbreak: descriptive case series.
BMJ. 2022;378:e072410.
[42] Otu A, Ebenso B, Walley J, Barceló JM, Ochu CL. Global
human monkeypox outbreak: atypical presentation de-
manding urgent public health action. Lancet Microbe.
2022;3:e554–5.
[43] Hasan S, Saeed S. Monkeypox disease: an emerging public
health concern in the shadow of COVID‐19 pandemic: an
update. Trop Med Infect Dis. 2022;7:283.
[44] Mitjà O, Ogoina D, Titanji BK, Galvan C, Muyembe JJ,
Marks M, et al. Monkeypox. Lancet. 2023;401:60–74.
[45] Monkeypox. 2023 [cited 2023 Feb 28]. Available from:
https://www.who.int/news-room/fact-sheets/detail/
monkeypox
[46] Sah R, Abdelaal A, Reda A, Katamesh BE, Manirambona E,
Abdelmonem H, et al. Monkeypox and its possible sexual
transmission: where are we now with its evidence?
Pathogens. 2022;11:924.
[47] Ježek Z, Fenner F. Human monkeypox. 17. Basel: Karger
AG; 1988; 17:32.
[48] Kugelman JR, Johnston SC, Mulembakani PM, Kisalu N,
Lee MS, Koroleva G, et al. Genomic variability of
monkeypox virus among humans, Democratic Republic of
the Congo. Emerg Infect Dis. 2014;20:232.
[49] Berthet N, Descorps‐Declère S, Besombes C, Curaudeau M,
Nkili Meyong AA, Selekon B, et al. Genomic history of
human monkey pox infections in the Central African
Republic between 2001 and 2018. Sci Rep. 2021;11:13085.
[50] Alakunle EF, Okeke MI. Monkeypox virus: a neglected
zoonotic pathogen spreads globally. Nat Rev Microbiol.
2022;20:507–8.
[51] Ahmed M, Naseer H, Arshad M, Ahmad A. Monkeypox in
2022: a new threat in developing. Ann Med Surg.
2022;78:103975.
[52] Reynolds MG, Davidson WB, Curns AT, Conover CS,
Huhn G, Davis JP, et al. Spectrum of infection and risk
factors for human monkeypox, United States, 2003.
Emerg Infect Dis. 2007;13:1332–9.
[53] Reynolds MG, Yorita KL, Kuehnert MJ, Davidson WB,
Huhn GD, Holman RC, et al. Clinical manifestations of
human monkeypox influenced by route of infection. J Infect
Dis. 2006;194:773–80.
[54] Doshi RH, Alfonso VH, Morier D, Hoff NA, Sinai C,
Mulembakani P, et al. Monkeypox rash severity and animal
exposures in the Democratic Republic of the Congo.
EcoHealth. 2020;17:64–73.
[55] Soheili M, Nasseri S, Afraie M, Khateri S, Moradi Y,
Mahdavi Mortazavi SM, et al. Monkeypox: virology,
pathophysiology, clinical characteristics, epidemiology, vac-
cines, diagnosis, and treatments. J Pharm Pharm Sci.
2022;25:297–322.
[56] Elsayed S, Bondy L, Hanage WP. Monkeypox virus
infections in humans. Clin Microbiol Rev. 2022;35:
e00092‐22.
[57] Beeson A, Styczynski A, Hutson CL, Whitehill F,
Angelo KM, Minhaj FS, et al. Mpox respiratory transmis-
sion: the state of the evidence. Lancet Microbe. 2023;4:
e277–83.
[58] Vivancos R, Anderson C, Blomquist P, Balasegaram S,
Bell A, Bishop L, et al. Community transmission of
monkeypox in the United Kingdom, April to May 2022.
Euro Surveill. 2022;27:2200422.
[59] Damon IK. Status of human monkeypox: clinical disease,
epidemiology and research. Vaccine. 2011;29:D54–9.
[60] Lapa D, Carletti F, Mazzotta V, Matusali G, Pinnetti C,
Meschi S, et al. Monkeypox virus isolation from a semen
sample collected in the early phase of infection in a patient
with prolonged seminal viral shedding. Lancet Infect Dis.
2022;22:1267–9.
[61] Palich R, Burrel S, Monsel G, Nouchi A, Bleibtreu A,
Seang S, et al. Viral loads in clinical samples of men with
monkeypox virus infection: a French case series. Lancet
Infect Dis. 2023;23:74–80.
[62] Suñer C, Ubals M, Tarín‐Vicente EJ, Mendoza A,
Alemany A, Hernández‐Rodríguez Á, et al. Viral dynamics
in patients with monkeypox infection: a prospective cohort
study in Spain. Lancet Infect Dis. 2023;23:445–53.
[63] Kwok KO, Wei WI, Tang A, Wong SYS, Tang JW.
Estimation of local transmissibility in the early phase of
monkeypox epidemic in 2022. Clin Microbiol Infect.
2022;28(1653):1653.e1–3.
[64] Kumar N, Acharya A, Gendelman HE, Byrareddy SN. The
2022 outbreak and the pathobiology of the monkeypox
virus. J Autoimmun. 2022;131:102855.
[65] Sereewit J, Lieberman NAP, Xie H, Bakhash SAKM,
Nunley BE, Chung B, et al. ORF—interrupting mutations
in monkeypox virus genomes from Washington and Ohio,
2022. Viruses. 2022;14:2393.
[66] Esteban DJ, Hutchinson AP. Genes in the terminal regions
of orthopoxvirus genomes experience adaptive molecular
evolution. BMC Genomics. 2011;12:261.
[67] Babkin IV, Babkina IN, Tikunova NV. An update of
orthopoxvirus molecular evolution. Viruses. 2022;14:388.
[68] Luna N, Ramírez AL, Muñoz M, Ballesteros N, Patiño LH,
Castañeda SA, et al. Phylogenomic analysis of the mon-
keypox virus (MPXV) 2022 outbreak: emergence of a novel
viral lineage? Travel Med Infect Dis. 2022;49:102402.
[69] Happi C, Adetifa I, Mbala P, Njouom R, Nakoune E,
Happi A, et al. Urgent need for a non‐discriminatory and
non‐stigmatizing nomenclature for monkeypox virus. PLoS
Biol. 2022;20:e3001769.
[70] Likos AM, Sammons SA, Olson VA, Frace AM, Li Y, Olsen‐
Rasmussen M, et al. A tale of two clades: monkeypox
viruses. J Gen Virol. 2005;86:2661–72.
12
|
EJAZ ET AL.

[71] Desingu PA, Rubeni TP, Sundaresan NR. Evolution of
monkeypox virus from 2017 to 2022: in the light of point
mutations. Front Microbiol. 2022;13:1037598.
[72] Chakraborty C, Bhattacharya M, Sharma AR, Dhama K.
Evolution, epidemiology, geographical distribution, and
mutational landscape of newly emerging monkeypox virus.
GeroScience. 2022;44:2895–911.
[73] Isidro J, Borges V, Pinto M, Sobral D, Santos JD, Nunes A,
et al. Phylogenomic characterization and signs of micro-
evolution in the 2022 multi‐country outbreak of monkeypox
virus. Nat Med. 2022;28:1569–72.
[74] Wang L, Shang J, Weng S, Aliyari SR, Ji C, Cheng G, et al.
Genomic annotation and molecular evolution of monkey-
pox virus outbreak in 2022. J Med Virol. 2023;95:e28036.
[75] Chen Y, Li M, Fan H. The monkeypox outbreak in 2022:
adaptive evolution associated with APOBEC3 may account
for. Signal Transduct Target Ther. 2022;7:323.
[76] Saied AA, Dhawan M, Metwally AA, Fahrni ML,
Choudhary P, Choudhary OP. Disease history, patho-
genesis, diagnostics, and therapeutics for human monkey-
pox disease: a comprehensive review. Vaccines. 2022;10:
2091.
[77] Nolen LD, Osadebe L, Katomba J, Likofata J, Mukadi D,
Monroe B, et al. Extended human‐to‐human transmission
during a monkeypox outbreak in the Democratic Republic
of the Congo. Emerg Infect Dis. 2016;22:1014–21.
[78] Charniga K, Masters NB, Slayton RB, Gosdin L, Minhaj FS,
Philpott D, et al. Estimating the incubation period of
monkeypox virus during the multi‐national outbreak.
MedRxiv. 2022;2022–06.
[79] Minhaj FS, Ogale YP, Whitehill F, Foote M, Davidson W,
Hughes CM, et al. Monkeypox outbreak—Nine states, May
2022. Morb Mort Wkly Rep. 2022;21(23):764–9.
[80] Suárez Rodríguez B, Guzmán Herrador BR, Díaz Franco A,
Sánchez‐Seco fariñas MP, del Amo Valero J, Aginagalde
Llorente AH, et al. Epidemiologic features and control
measures during monkeypox outbreak, Spain, June 2022.
Emerg Infect Dis. 2022;28:1847–51.
[81] Hutin YJF, Williams RJ, Malfait P, Pebody R, Loparev VN,
Ropp SL, et al. Outbreak of human monkeypox, Democratic
Republic of Congo, 1996 to 1997. Emerg Infect Dis. 2001;7:
434–8.
[82] The Lancet Infectious Diseases. Monkeypox: a neglected old
foe. Lancet Infect Dis. 2022;22:913.
[83] Singhal T, Kabra SK, Lodha R. Monkeypox: a review. Indian
J Pediatr. 2022;89:955–60.
[84] Hughes C, McCollum A, Pukuta E, Karhemere S, Nguete B,
Shongo Lushima R, et al. Ocular complications associated
with acute monkeypox virus infection, DRC. Int J Infect Dis.
2014;21:276–7.
[85] Badenoch JB, Conti I, Rengasamy ER, Watson CJ, Butler M,
Hussain Z, et al. Neurological and psychiatric presentations
associated with human monkeypox virus infection: a
systematic review and meta‐analysis. EClinicalMedicine.
2022;52:101644.
[86] Bayer‐Garner IB. Monkeypox virus: histologic, immuno-
histochemical and electron‐microscopic findings. J Cutan
Pathol. 2005;32:28–34.
[87] Adler H, Gould S, Hine P, Snell LB, Wong W, Houlihan CF,
et al. Clinical features and management of human
monkeypox: a retrospective observational study in the UK.
Lancet Infect Dis. 2022;22:1153–62.
[88] Iizuka I, Saijo M, Shiota T, Ami Y, Suzaki Y, Nagata N, et al.
Loop‐mediated isothermal amplification‐based diagnostic
assay for monkeypox virus infections. J Med Virol. 2009;81:
1102–8.
[89] Bharadwaj M, Bengtson M, Golverdingen M, Waling L,
Dekker C. Diagnosing point‐of‐care diagnostics for neglec-
ted tropical diseases. PLoS Neglected Trop Dis. 2021;15:
e0009405.
[90] Dumont C, Irenge LM, Magazani EK, Garin D,
Muyembe JJT, Bentahir M, et al. Simple technique for in
field samples collection in the cases of skin rash illness and
subsequent PCR detection of orthopoxviruses and varicella
zoster virus. PLoS One. 2014;9:e96930.
[91] Karem KL, Reynolds M, Braden Z, Lou G, Bernard N,
Patton J, et al. Characterization of acute‐phase humoral
immunity to monkeypox: use of immunoglobulin M
enzyme‐linked immunosorbent assay for detection of
monkeypox infection during the 2003 North American
outbreak. Clin Vaccine Immunol. 2005;12:867–72.
[92] Reynolds M, McCollum A, Nguete B, Shongo Lushima R,
Petersen B. Improving the care and treatment of monkeypox
patients in low‐resource settings: applying evidence from
contemporary biomedical and smallpox biodefense
research. Viruses. 2017;9:380.
[93] Chittick G, Morrison M, Brundage T, Nichols WG. Short‐
term clinical safety profile of brincidofovir: a favorable
benefit–risk proposition in the treatment of smallpox.
Antiviral Res. 2017;143:269–77.
[94] Russo AT, Grosenbach DW, Chinsangaram J,
Honeychurch KM, Long PG, Lovejoy C, et al. An overview
of tecovirimat for smallpox treatment and expanded anti‐
orthopoxvirus applications. Expert Rev Anti Infect Ther.
2021;19:331–44.
[95] Grosenbach DW, Honeychurch K, Rose EA,
Chinsangaram J, Frimm A, Maiti B, et al. Oral tecovirimat
for the treatment of smallpox. N Engl J Med. 2018;379:
44–53.
[96] Wittek R. Vaccinia immune globulin: current policies,
preparedness, and product safety and efficacy. Int J Infect
Dis. 2006;10:193–201.
[97] Song H, Janosko K, Johnson RF, Qin J, Josleyn N, Jett C,
et al. Poxvirus antigen staining of immune cells as a
biomarker to predict disease outcome in monkeypox and
cowpox virus infection in non‐human primates. PLoS One.
2013;8:e60533.
[98] Rice AD, Adams MM, Lampert B, Foster S, Lanier R,
Robertson A, et al. Efficacy of CMX001 as a prophylactic
and presymptomatic antiviral agent in New Zealand white
rabbits infected with rabbitpox virus, a model for ortho-
poxvirus infections of humans. Viruses. 2011;3:63–82.
[99] Stabenow J, Buller RM, Schriewer J, West C, Sagartz JE,
Parker S. A mouse model of lethal infection for evaluating
prophylactics and therapeutics against monkeypox virus.
J Virol. 2010;84:3909–20.
EJAZ ET AL.
|
13

[100] Duraffour S, Andrei G, Snoeck R. Tecovirimat, a p37
envelope protein inhibitor for the treatment of smallpox
infection. Invest Drugs J. 2010;13:181–91.
[101] Priyamvada L, Alabi P, Leon A, Kumar A, Sambhara S,
Olson VA, et al. Discovery of retro‐1 analogs exhibiting
enhanced anti‐vaccinia virus activity. Front Microbiol.
2020;11:603.
[102] FDA. FDA approves VIG for smallpox shot complications.
Silver Spring: FDA; 2023. Available from: https://www.
cidrap.umn.edu/news-perspective/2005/02/fda-approves-
vig-smallpox-shot-complications
[103] Moss B. Poxvirus cell entry: how many proteins does it take?
Viruses. 2012;4:688–707.
[104] Dubey A, Singh R, Kumar A, Mishra G, Gupta A, Sonker A,
et al. A critical review on changing epidemiology of human
monkeypox—a current threat with multi‐country outbreak.
J Pharm Negat. 2022;13:660–71.
[105] Edghill‐Smith Y, Golding H, Manischewitz J, King LR,
Scott D, Bray M, et al. Smallpox vaccine‐induced antibodies
are necessary and sufficient for protection against mon-
keypox virus. Nat Med. 2005;11:740–7.
[106] Simpson K, Heymann D, Brown CS, Edmunds WJ,
Elsgaard J, Fine P, et al. Human monkeypox—after 40
years, an unintended consequence of smallpox eradication.
Vaccine. 2020;38:5077–81.
[107] Lozano JM, Muller S. Monkeypox: potential vaccine
development strategies. Trends Pharmacol Sci. 2023;44:
15–9.
[108] Lum FM, Torres‐Ruesta A, Tay MZ, Lin RTP, Lye DC,
Rénia L, et al. Monkeypox: disease epidemiology, host
immunity and clinical interventions. Nat Rev Immunol.
2022;22:597–613.
[109] Rao AK, Petersen BW, Whitehill F, Razeq JH, Isaacs SN,
Merchlinsky MJ, et al. Use of JYNNEOS (smallpox and
monkeypox vaccine, live, nonreplicating) for preexposure
vaccination of persons at risk for occupational exposure to
orthopoxviruses: recommendations of the advisory commit-
tee on immunization practices—United States, 2022. Morb
Mortal Wkly Rep. 2022;71:734–42.
[110] Petersen BW, Harms TJ, Reynolds MG, Harrison LH. Use of
vaccinia virus smallpox vaccine in laboratory and health
care personnel at risk for occupational exposure to
orthopoxviruses—recommendations of the advisory com-
mittee on immunization practices (ACIP), 2015. Morb
Mortal Wkly Rep. 2016;65:257–62.
[111] Letafati A, Sakhavarz T. Monkeypox virus: a review. Microb
Pathog. 2023;176:106027.
[112] Titanji BK, Tegomoh B, Nematollahi S, Konomos M,
Kulkarni PA. Monkeypox: a contemporary review for
healthcare professionals. Open Forum Infect Dis. 2022;9:
ofac310.
[113] Kuehn BM. Newer poxvirus vaccine is recommended.
JAMA. 2022;328:123.
[114] Rizk JG, Lippi G, Henry BM, Forthal DN, Rizk Y.
Prevention and treatment of monkeypox. Drugs. 2022;82:
957–63.
[115] Poland GA, Kennedy RB, Tosh PK. Prevention of mon-
keypox with vaccines: a rapid review. Lancet Infect Dis.
2022;22:e349–58.
How to cite this article: Ejaz M, Jabeen M, Sharif
M, Syed MA, Shah PT, Faryal R. Human
monkeypox: an updated appraisal on epidemiology,
evolution, pathogenesis, clinical manifestations, and
treatment strategies. J Basic Microbiol. 2023;1–14.
https://doi.org/10.1002/jobm.202300455
14
|
EJAZ ET AL.