Abstract
Human monkeypox is a zoonotic Orthopoxvirus resembling smallpox in
clinical course, making it difficult to distinguish it from smallpox and
varicella. Laboratory diagnostics are critical components of illness
identification and surveillance, and novel tests are required for more
precise and quick diagnosis. The majority of human infections occur in
Central Africa, where monitoring in remote regions with little
infrastructure is challenging but may be performed using evidence-based
methods and teaching materials that educate public health personnel on
the fundamental principles of this infection. New medications and
vaccinations showed promising results for the treatment and prevention
of the disease, but more studies are required to show their efficacy in
the actual endemic settings. Thus, more studies are needed on the
virus’s epidemiology, ecology, and biology in endemic locations to
better understand and prevent human infections. This review discussed
the etiology, epidemiology, and clinical course of the monkeypox and
indicated diagnostic and treatment approaches for this disease.
Keywords: Monkeypox; Orthopoxvirus; Smallpox; Outbreak;
Infectious Disease
Introduction
Concerns about annual epidemics, such as influenza, had waned in the
shadow of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
infection. However, outbreaks of a reemerging virus have recently
brought about concerns in many world regions (Leong, 2020). Monkeypox
virus (MPXV) is a zoonotic infection with sporadic involvement in
humans. The clinical manifestation of monkeypox infection resembles that
of smallpox. Therefore, vaccination against smallpox could also protect
against this virus. Routine smallpox vaccination, which was developed to
prevent smallpox, ceased in 1980 along with global smallpox eradication.
Therefore, outbreaks were expected with the waning cross-immunity
(Reynolds & Damon, 2012). With new cases appearing in other parts of
the world, concerns have arisen about the forthcoming pandemic. Thus,
the Centers for Diseases Control and Prevention (CDC) has announced that
any smallpox-like infection, manifesting as skin eruptions and fever,
added to lymphadenopathy should be suspected of MPXV (Walensky, 2022).
In the past, most people, especially in the endemic areas, had gotten
vaccinated against smallpox. This vaccine is cross-protected against
MPXV and other related orthopoxviruses, eradicating universal smallpox.
With time passing and immunity waning, susceptibility to MPXV increased.
Accordingly, viral mutations have also increased.
On the other hand, ecological changes have given more human exposure to
animals. MPXV has a broad range of small animal hosts whose control is
challenging. Climate change, deforestation, urbanization, transboundary
migration, poverty, unsafe traditional practices, and civil wars are
other causes of monkeypox reemergence. Underreporting and
under-recognition of cases, insufficient access to healthcare
facilities, inexperienced staff, and poor laboratory diagnosis would
promote epidemic evolution (Edghill-Smith et al., 2005; Nguyen,
Ajisegiri, Costantino, Chughtai, & MacIntyre, 2021; Reynolds, Carroll,
& Karem, 2012; Simpson et al., 2020). Therefore, in this review, we aim
to discuss the data on the monkeypox virus.
Etiology
Monkeypox virus (MPXV) is a double-stranded DNA virus and one of the
most virulent members of the Orthopoxvirus genus, the Poxviridae family.
Other members of this genus include vaccinia virus (the live virus
component of orthopoxvirus vaccines), variola virus (the causative agent
of smallpox), and cowpox, all pathogenic to humans. There are two clades
of the MPXV species, the West African clade, and the Congo Basin clade.
MPXV is a virus of various mammalian species, including squirrels, mice,
monkeys, and dogs, with African rodents as the reservoirs, but it
sporadically involved humans in regional outbreaks (Babkin, Babkina, &
Tikunova, 2022; Mauldin et al., 2022).
Epidemiology
Monkeypox was first discovered in laboratory monkeys in 1958 after two
outbreaks of a pox-like disease. Twelve years later, the first human
case of monkeypox was identified as a human pathogen in the Democratic
Republic of the Congo (DRC) in 1970. Since then, the disease has been
endemic in Africa. Until the 2003 outbreak in the United States (US),
nearly all cases were from Africa. Nevertheless, international travel or
importing animals has led to monkeypox infection outbreaks outside
Africa. The origin of the US 2003 outbreak was determined as a shipment
of rodents, like squirrels, rats, and mice, from Ghana to Texas (Reed et
al., 2004). Subsequently, outbreaks took place periodically due to
travels across the world. The largest West monkeypox outbreak
originating from some travelers from Nigeria began in 2017 (Bunge et
al., 2022; Yinka-Ogunleye et al., 2019). This human-to-human
transmission continued to be increasingly reported, especially in
immunocompromised patients in different parts of the world, including
Israel, Singapore, the United Kingdom (UK), and lastly, the US in
November 2021 (Erez et al., 2019; Ng et al., 2019; Agam K Rao et al.,
2022; Vaughan et al., 2018a; Vaughan et al., 2020; Yinka-Ogunleye et
al., 2019). A summary of the reported cases of the monkeypox is
indicated in Table 1.
Interestingly, no epidemiologic link to Nigeria was identified in more
recent outbreaks as no correspondent case had been found there. Since
then, no human case has been reported out of Africa until lately in May
2022, when one US resident was diagnosed with monkeypox after returning
from Canada. Subsequently, several cases have been reported from Spain,
Portugal, Canada, the UK, Italy, and others. Interestingly, many
detected patients have had no travel history to Africa or no
epidemiologic connection with confirmed cases (Mahase, 2022a, 2022b).
The epidemiology of monkeypox infection has changed between different
outbreaks as the number and the median age of the cases have increased.
Younger individuals are expected to be the most susceptible population
to monkeypox, as people born after 1980 had not received the smallpox
vaccine. Therefore, it is expected to demonstrate more infection reports
in individuals younger than 40 years (Bunge et al., 2022; E. Petersen et
al., 2019).
Risk factors like a history of travel, gender, or sexual orientation
should be considered in suspecting monkeypox infection. Other risk
factors include living in rural or forested areas of central and western
Africa, being involved in preparing bushmeat, recent exposure to an
infected patient, and absence of smallpox vaccination (Nolen et al.,
2015; Quiner et al., 2017; Reynolds et al., 2007). It has been rumored
that men who have sex with men (MSM) comprise most monkeypox cases in
the current outbreak, but the issue should be verified. Monkeypox is not
a gay-related infection, but it was first identified in gay and bisexual
men in the UK and in two raves held in Spain and Belgium. Moreover, the
virus also transmits via close contact, including during sexual affairs.
Therefore, this population should be warned to monitor for compatible
symptoms. Nevertheless, it is important not to direct stigmas toward
these people during this process (Mahase, 2022a, 2022b).
Another important issue is the mode of transmission. Human-to-human
transmission usually occurs through exposure to body fluids, wounds, or
respiratory particles of wild animals or infected patients, and
sometimes infectious fomites (Walker, 2022). Patients are contagious
from the beginning of the prodromal phase to the desquamation phase.
However, the most significant phase would be the prodromal phase which
might last up to 3 weeks without any cutaneous eruption, and the
infected patient may unwantedly transmit the virus to several people
during this prolonged prodromal period (Erez et al., 2019; Reynolds et
al., 2006). It has been acknowledged in many articles and news that
droplets are the main respiratory route of spread; therefore, it is
emphasized that prolonged face-to-face contact is necessary for disease
spread. However, some authorities and the literature point out the
airborne route as a possible transmission route. Thus, considering
appropriate precautions and isolation measures is vital (Brown &
Leggat, 2016; Fleischauer et al., 2005; B. W. Petersen, Karem, & Damon,
2014).
Clinical manifestation
The period between being infected and the onset of manifestations ranges
from 5 to 21 days. Then, mucocutaneous lesions arise after a short
prodrome of fever, headache, myalgia, malaise, lymphadenopathy, and
sometimes cough, nasal congestion, and sore throat. Initially, enanthems
appear in the oropharynx, and then skin eruptions become evident,
beginning with macular lesions, evolving to papular, vesicular, and
pustular (usually umbilicated) and ultimately crusted lesions within 3-4
weeks. Skin eruptions are usually well-circumscribed and might be
generalized or localized, discrete or confluent. Lesions have a
centrifugal distribution, beginning on the face and extremities and then
involving the genitalia and the trunk. Unlike many infections with
cutaneous involvement, monkeypox is among the rare ones that involve
palms and soles. Each evolutional cutaneous phase takes 2-3 days to
transform to the subsequent phase, except the pustular phase, which
lasts 5-7 days before switching to scabs. The desquamation phase
continues for about 1-2 weeks, and the total duration of eruptions is
estimated to be 3-4 weeks. In brief, after an incubation period of 5-21
days, a 1-4-day febrile stage occurs, followed by the rash stage of 2-4
weeks duration, and lastly, the recovery takes days to weeks (Breman,
2000; D. Ogoina et al., 2020; Parker, Nuara, Buller, & Schultz, 2007;
Weinstein, Nalca, Rimoin, Bavari, & Whitehouse, 2005). A summary of the
clinical presentations of this infection is illustrated in Figure 1.
Differential diagnosis
The vesicular phase of monkeypox infection can readily be diagnosed as
few infectious diseases manifest with vesiculopustular lesions. However,
clinical diagnosis is more challenging in the early macule and papule
phases. Monkeypox infection’s most important differential diagnoses
include smallpox, chickenpox, generalized vaccinia, disseminated zoster,
disseminated herpes simplex, and eczema herpeticum. Nonetheless,
syphilis, scabies, measles, and drug eruption should also be considered.
The main distinguishing feature of monkeypox from smallpox includes the
presence of lymphadenopathy in the former. Moreover, symptoms of
monkeypox are milder than those of smallpox. However, the incubation and
prodromal periods and the total length of the disease are of the same
duration in both infections. In addition, the distribution pattern of
skin lesions is centrifugal, and eruptions are homogenous in both
conditions (Weinstein et al., 2005).
The common characteristics of both chickenpox and monkeypox include
their airborne transmission and vesicle formation. However, chickenpox
is well-known for its eruptions in various developmental stages
(macules, papules, vesicles, and crusts) simultaneously, while monkeypox
lesions change synchronously. Cutaneous eruptions of chickenpox are soft
and superficial with irregular borders, while those of monkeypox are
firm, deep-seated, well-circumscribed, and umbilicated. Every cutaneous
eruptions stage of monkeypox takes 1-2 days, or even 5-7 days for the
pustular phase, while rashes of chickenpox rapidly evolve from macules
to crusts within one day. Therefore, the total duration of skin lesions
is much longer in monkeypox than in chickenpox. Chickenpox is contagious
until the last skin lesions become crusted, for a maximum of 3 weeks,
while monkeypox might be transmittable for weeks or even months. Also,
the incubation period of monkeypox is much longer than that of
chickenpox, so the index patient can infect much more individuals before
being identified as infected. Other distinguishing features of monkeypox
from varicella include prodromal high-grade fever and the presence of
lymphadenopathy in monkeypox.
Furthermore, palms and soles involvement is more common in monkeypox
infection than chickenpox. Apart from the clinical differentiating
criteria, epidemiological patterns can also help us distinguish the two
infections; monkeypox is a zoonosis and has an animal reservoir with
animal-to-human and human-to-human transmission capability, while
chickenpox has only a human reservoir and is only spread among humans.
In addition, the secondary attack rate is much higher for chickenpox
than for monkeypox. Varicella predominantly involves younger pediatrics,
while monkeypox is more common in adulthood (Macneil, Reynolds, Braden,
et al., 2009; MacNeil, Reynolds, Carroll, et al., 2009; Seguin & Stoner
Halpern, 2004; Wardiana, Rahmadewi, & Sawitri, 2021). Those with herpes
and chancroid can mistake Monkeypox genital sores (D. Ogoina et al.,
2020), and generalized eruption and palms and soles are mostly
misdiagnosed as secondary syphilis or involvement rickettsia infections
(Tabasi, 2018). It is important to consider that monkeypox co-infection
with other pathogens is also likely, as reported for varicella, human
immunodeficiency virus (HIV), or SARS-CoV-2 co-infections (Bhunu,
Mushayabasa, & Hyman, 2012; Echekwube, Mbaave, Abidakun, Utoo, &
Swende, 2020; Hoff et al., 2017; C. M. Hughes et al., 2021; Uwishema et
al., 2021).
Diagnosis
Monkeypox infection should be suspected in any individual with
compatible presentations, including fever, skin eruptions, new
lymphadenopathy, perianal or genital lesions, and compatible
epidemiology, including a recent travel history to endemic areas,
exposure to wild animals, or contact with an infected animal or human.
MSMs should be of particular attention as having a significant risk
factor for this infection. Diagnostic assays should be done to detect
and contain the infection early in any suspected case. Different
diagnostic tests can diagnose different phases of monkeypox infection.
Nasopharyngeal or oropharyngeal swab samples are the best ones for
diagnosis in the febrile phase, while the infection can be best
diagnosed by examining eruptions (fluid or crust) during the rash
period. Both samples, best to be dry, can be sent for viral culture.
Nevertheless, molecular tests such as PCR are readily available and more
rapid in giving the results (Damon, 2011). Serologic tests for antibody
detection, if conclusive, only help in the near-to-recovery period and
are merely used for epidemiological and research purposes.
Anti-orthopoxvirus IgM indicates recent exposure, while its IgG
counterpart is suggestive of prior exposure or vaccination. The
radioimmunoassay absorption (RIAA) test is the gold standard serologic
diagnostic test for monkeypox (Karem et al., 2005). Other diagnostic
tests, including visualization on electron microscopy, and
immunohistochemical staining, might rarely be utilized (Bayer-Garner,
2005).
Treatment
Since there has been no proven therapeutic for treating monkeypox,
supportive and symptomatic therapy is the basis of management like many
other viral infections (Durski et al., 2018). The US utilized
antivirals, the smallpox vaccine, and vaccinia immune globulin (VIG) in
the previous epidemics to control the outbreak. Since monkeypox virus
and vaccinia virus are genetically related, medications effective on
smallpox might also be beneficial in managing monkeypox. Antivirals
suggested to defend against monkeypox include brincidofovir and
tecovirimat (Jabeen & Umbreen, 2017).
Brincidofovir (CMX001), a lipophilic conjugate of cidofovir with less
toxicity, is an oral DNA polymerase inhibitor with anti-poxvirus
activity (Hutson et al., 2021). Tecovirimat (ST-246), an oral
intracellular viral release inhibitor, is another antiviral agent with
potential therapeutic effects on monkeypox (Berhanu et al., 2015). VIG
is also proposed to treat monkeypox complications as it had been used
for such circumstances in the smallpox outbreaks. Moreover, it can be
considered a post-exposure prophylactic agent in exposed
immunocompromised individuals who are contraindicated to receiving the
smallpox vaccine as a post-exposure preventive measure (Baker, Bray, &
Huggins, 2003; Sejvar et al., 2004; Xiao & Isaacs, 2010).
Complications and prognosis
Monkeypox infection usually lasts for 2−4 weeks. The severity of
infection varies considerably. Nevertheless, complications may
intervene, such as bacterial skin superinfection, skin discoloration or
scarring, sepsis, and encephalitis (Kabuga & El Zowalaty, 2019).
Despite not being lethal, cutaneous scars and the associated stigma may
be physically and psychologically annoying, with a case of suicide had
been reported in a patient affected by monkeypox in a 2017 outbreak
(Dimie Ogoina, Mohammed, Yinka-Ogunleye, & Ihekweazu, 2022). Vision
loss resulting from permanent corneal scarring is one of its most severe
complications (C. Hughes et al., 2014). Mortality occurs in 1 to 10% of
the affected patients, less in the West African and more in Central
African clades. Unvaccinated individuals, younger children, and
immunocompromised people are more likely to develop fatal infections
(Anderson, Frenkel, Homann, & Guffey, 2003; Huhn et al., 2005).
Prevention
Early detection, management, and isolation of the infected individuals
would be the main strategy to contain the epidemic. Educating healthcare
workers and the public about the potential manifestations of this
infection can help in early recognition and prevention of further
transmission. All the population, particularly health care workers,
media, travel airlines, and stakeholders, should be warned about the
importance of reporting suspected cases to health officials (Silenou et
al., 2020). The main barrier to restricting further spread among humans
is monkeypox’s relatively long incubation period, which leads to
asymptomatic viral spread. Therefore, contacts of suspected patients
should be monitored for developing symptoms (Grant, Nguyen, & Breban,
2020). Standard preventive measures, including avoiding contact with
suspected animals or humans, practicing proper hand hygiene after any
potential exposure, and using personal protective equipment (PPE) when
close to the patients, are the cornerstone of primary prevention. Due to
the airborne transmission as the main spreading route, isolating the
patient in a negative pressure room with full PPE is required besides
taking standard, contact, and droplet precautions (Angelo, Petersen,
Hamer, Schwartz, & Brunette, 2019; Vaughan et al., 2020).
Smallpox’s eradication by vaccination turns back to the virus-host, as
smallpox had only a human host and was transmitted from human to human.
On the other hand, eradicating the monkeypox virus through human
vaccination seems to be quite difficult as this virus has several
various animal hosts that are hard to control and monitor (Reynolds &
Damon, 2012). Nonetheless, vaccination has always been the best and
cost-beneficial preventive measure to limit infection, especially for
healthcare personnel who are more likely to have occupational exposure.
Fortunately, other orthopoxvirus vaccines, such as the smallpox vaccine,
have cross-protection against monkeypox. Currently, two live
orthopoxvirus vaccines are available from CDC, which had been considered
for high-risk occupational exposure: the JYNNEOS and the ACAM2000
vaccines. Although the former has been licensed for smallpox and
monkeypox and the latter was intended only for smallpox, both can be
utilized to prevent monkeypox (Keckler et al., 2020; B. W. Petersen,
2021).
Recommendations for post-exposure prophylaxis depend upon the exposure
risk level. High-risk exposure is defined as 1) contact with damaged
skin, mucous membranes, lesions, or body fluids of an infected patient;
or 2) exposure to aerosol-generating procedures without PPE.
Intermediate-risk exposure is defined as 1) contact with intact skin,
lesions, or body fluids of an infected patient; 2) being less than 6
feet close to the patient for more than 3 hours; or 3) taking care of a
patient without donning appropriate PPE. Low-risk exposure is defined as
taking care of a patient with full PPE. Post-exposure prophylaxis is
indicated in high-risk and often intermediate-risk exposures.
Individuals with low-risk exposures should only be monitored for signs
and symptoms of monkeypox, such as fever, new lymphadenopathy, and new
eruptions, until 21 days after the exposure (Agam K Rao et al., 2022).
Post-exposure prevention of monkeypox can sometimes be feasible by
post-exposure smallpox vaccination, which should be done as soon as
possible, ideally within 4 days up to 2 weeks of exposure, to prevent
disease onset or decrease disease severity. This strategy can confer up
to 85% protection against monkeypox. The only contraindications of
smallpox vaccination include allergy to any of the vaccine components
and its use in immunocompromised individuals and populations with a high
prevalence of HIV infection because of potential complications (Heraud
et al., 2006; Russo et al., 2020; Smith et al., 2009).
Conclusion
The spreading of monkeypox across West Africa over the last decade, as
well as the current outbreaks in many nations, indicate that it is no
longer an uncommon viral zoonotic disease found only in remote areas of
Central and West Africa. Its potential for additional regional and
worldwide spreading continues to be a major issue. The ecological,
zoonotic, epidemiologic, clinical, and public health aspects of
monkeypox are still poorly understood. The cessation of the smallpox
vaccination program has produced an ecological gap in which an
increasing proportion of the population has diminishing or nonexistent
protection against the monkeypox virus. A global effort should be
undertaken to develop better diagnostic and treatment options for this
viral illness to avert new epidemics.