Open Forum Infectious Diseases
REVIEW ARTICLE INVITED
Monkeypox: A Contemporary Review for Healthcare
Professionals
Boghuma K. Titanji,1, Bryan Tegomoh,2 Saman Nematollahi,3 Michael Konomos,4 and Prathit A. Kulkarni5,6
1
Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, USA, 2Nebraska Department of Health and Human Services, Lincoln, Nebraska, USA, 3Department of
Medicine, University of Arizona College of Medicine, Tucson, Arizona, USA, 4Visual Medical Education, Emory University School of Medicine, Atlanta, Georgia, USA, 5Infectious Diseases Section,
Department of Medicine, Baylor College of Medicine, Houston, Texas, USA, and 6Medical Care Line, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
The ongoing 2022 multicountry outbreak of monkeypox is the largest in history to occur outside of Africa. Monkeypox is an
emerging zoonotic disease that for decades has been viewed as an infectious disease with significant epidemic potential because
Downloaded from https://academic.oup.com/ofid/article/9/7/ofac310/6615388 by guest on 15 August 2024
of the increasing occurrence of human outbreaks in recent years. As public health entities work to contain the current outbreak,
healthcare professionals globally are aiming to become familiar with the various clinical presentations and management of this
infection. We present in this review an updated overview of monkeypox for healthcare professionals in the context of the
ongoing outbreaks around the world.
Keywords. emerging infectious diseases; monkeypox; outbreak.
The 2022 outbreak of monkeypox involving multiple countries knowledge of this zoonotic infection, including its prevention,
in both endemic and nonendemic regions has generated signif clinical management, prophylaxis, and basics of infection control,
icant international interest [1, 2]. A once-neglected zoonotic vi to understand the broader implications of the current outbreak. In
rus endemic to West and Central Africa, monkeypox virus was this review, we provide an overview of monkeypox virus infection
first identified in 1958 [3] in nonhuman primates kept for re to serve as a primer for healthcare professionals who may encoun
search in Denmark [3]. The first case in humans was reported ter this condition in their practice.
in 1970 in the Democratic Republic of Congo [4]. Over the past
50 years, sporadic outbreaks have been reported mainly in
VIROLOGY
African countries, with several thousand human cases recorded
to date. Occasional cases and limited outbreaks linked to travel The Poxviridae family are double-stranded deoxyribonucleic
or importation of animals harboring the virus have also been acid viruses which infect a range of animals including birds,
described in nonendemic countries [5]. It has long been a the reptiles, insects and mammals. The family consists of 2 subfam
oretical concern that monkeypox virus and other zoonotic pox ilies: Chordopoxvirinae (with 18 genera and 52 species) and
viruses could over time expand to fill the ecological niche once Entomopoxvarinae (with 4 genera and 30 species).
occupied by the closely related variola virus [6, 7]. The com Monkeypox belongs to the Poxviridae family, the
bined effects of deforestation, population growth, encroach Chordopoxvirinae subfamily, and the genus Orthopoxvirus
ment on animal reservoir habitats, increasing human [9–11]. Several poxvirus species have been shown to cause hu
movement, and enhanced global interconnectedness have man infections including Variola (smallpox), Cowpox,
made this possibility more real in the last 20 years [6–8]. Monkeypox, Vaccinia, Camelpox, Alaskapox, Yaba monkey tu
With increasing case numbers being reported in the current mor virusTanapox virus, Orf virus, Pseudocowpox virus, Bovine
outbreak, it is important for clinicians everywhere to update their papular stomatitis virus, Buffalopox and Molluscum contagio
sum. Humans are the reservoir host of Variola and
Molluscum contagiosum viruses [11]. Monkeypox virus
Received 01 June 2022; editorial decision 21 June 2022; accepted 21 June 2022; published (MPXV) has a wide range of potential host organisms, which
online 23 June 2022
Correspondence: Boghuma K. Titanji, MD, PhD, Division of Infectious Diseases, Emory has allowed it to circulate in wild animals for a prolonged peri
University School of Medicine, 100 Woodruff Circle, Atlanta, Georgia 30322 (btitanj@emory. od of time while sporadically causing human disease through
edu).
spillover events [9]. More importantly, Orthopoxviruses
Open Forum Infectious Diseases®
© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases (OPXV) exhibit immunological cross-reactivity and cross-
Society of America. This is an Open Access article distributed under the terms of the protection, and infection with any member of the genus confers
Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.
org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of some protection from infection with any other members of the
the work, in any medium, provided the original work is not altered or transformed in any way, same genus [12, 13].
and that the work is properly cited. For commercial re-use, please contact journals.permissions
@oup.com
Orthopoxviruses are large (size range:140–450 nm) viruses
https://doi.org/10.1093/ofid/ofac310 with a brick-like structure and a genome consisting of
Monkeypox: A Contemporary Review for Healthcare Professionals • OFID • 1
, approximately 200-500kbp kb [6, 9, 10] that codes for over 200 with the West African clade typically results in a more self-
genes. Many of the genes encoded by the OPXV genome are limited disease, with case-fatality ratios estimated to be ap
not essential for virus replication in cell culture but might play im proximately 3–6%, whereas the Central African (Congo
portant roles in the host antiviral response [10, 14]. All poxviruses Basin) clade has historically been associated with higher
complete their replication cycle in the cytoplasm of infected transmissibility and case-fatality ratios as high as 10% [8].
cells via complex molecular pathways [10, 15]. This intracellular Cameroon is the only country where both clades
replication cycle has been well characterized for Vaccinia virus, have been confirmed [20, 21]. Cumulatively, more
which was used to develop the vaccine that helped to eradicate suspected cases of the Central African clade have been re
smallpox globally; key features of this replication cycle are ported to date than cases due to the West African clade
similar for all poxviruses [10, 15]. The infection cycle can be due to the high number of cases recorded in historical and
initiated by two distinct forms of the virus: the intracellular ongoing outbreaks in the DRC [21]. The West African clade
mature virion and the extracellular enveloped virion, which differ of MPXV has been isolated from cases in newly affected
in their expression of surface glycoproteins. Glycosaminoglycans, countries in the 2022 multi-country outbreaks
Downloaded from https://academic.oup.com/ofid/article/9/7/ofac310/6615388 by guest on 15 August 2024
which are ubiquitously expressed on the surface of mammalian The transmission of monkeypox in endemic and nonendemic
cells, are thought to be crucial for binding of the virion to the settings is summarized in Figure 1. Animal-to-human transmis
cell membrane, although all cellular receptors have not been fully sion occurs via bites and scratches from infected animals.
characterized [10, 15]. A detailed description of the replication Preparation and handling of infected animal products (bush
cycle is beyond the scope of this review but has been described meat [22]) may also result in transmission. The definitive animal
previously [10, 15]. reservoir of MPXV has not been identified. The virus has been
Smallpox is estimated to have caused millions of fatalities isolated from several animal species including small mammals
worldwide [13] and was one of the most dreaded infectious dis and nonhuman primates. In the reported instances in which
eases in human history. The impact of smallpox serves as a re MPXV has been isolated from wild animals, the animals demon
minder that OPXV can be formidable pathogens. Although the strated pox-like lesions consistent with active infection [23–26].
origins of smallpox are not known, there is some evidence It is not known whether asymptomatic carriage of MPXV occurs
which suggests that Variola virus may have evolved from an an in animal reservoir. Serological surveys have been conducted
cient rodent poxvirus thousands of years ago [16]. The increas on wild mammals in endemic regions. These studies have found
ing danger of zoonotic OPXV infections such as MPXV has several animal species with detectable antibodies to OPXV in the
been recognized for a long time [17, 18]. As a consequence of absence of detectable viremia on polymerase chain reaction
immunization programs against smallpox ending over 40 years (PCR) testing. This suggests exposure to and circulation of
ago, a significant proportion of the global population does not zoonotic OPXV in many wild animal species [27].
have immunity against smallpox and zoonotic OPXV. All of Human-to-human transmission is thought to occur via direct
this raises the possibility that given the right conditions, such skin-to-skin contact with lesions on the skin, as well as through
as increasing incidence of human infections and long-term ab indirect contact with contaminated fomites, such as bedding or
sence of vaccine immunity, a zoonotic orthopoxvirus like clothing [8]. Transmission can also occur at close proximity
MPXV could acquire the ability to more efficiently transmit be through exchange of respiratory secretions containing live virus.
tween humans and cause larger outbreaks [17]. In the last 5 decades, the DRC has been most affected by
monkeypox outbreaks, whereas the second and third most af
fected countries have been Nigeria and Republic of the
EPIDEMIOLOGY AND HISTORICAL OUTBREAKS
Congo, respectively. Table 1 shows a timeline of outbreaks of
Monkeypox is endemic in the tropical rainforest regions of human monkeypox cases reported since 1970, when the first
Central and West African countries, notably Cameroon, human case was detected in a 9-months-old patient in a remote
Central African Republic, Cote d’Ivoire, Democratic village in the DRC [4]. After the historical success of the global
Republic of the Congo (DRC), Gabon, Liberia, Nigeria, eradication of smallpox during the 1970s, surveillance for pox-
Republic of the Congo and Sierra Leone. Most cases arise like diseases was enhanced in tropical rainforest areas, which
sporadically or occur in the context of localized outbreaks has aided in identifying monkeypox outbreaks as they have oc
[6–8]. Cases outside of endemic countries are typically curred over time. More importantly, smallpox vaccination,
linked to international travel or importation of animals in which stopped being universally administered in the 1970s,
fected with MPXV [5, 19]. Before 2022, cases outside of confers cross-protection against MPXV infection. It is possible
Africa had previously been reported in the United States, that the progressive loss of immunity against smallpox over
United Kingdom (UK), Israel, and Singapore [7]. There time combined with the other factors described above has con
are 2 distinct genetic clades of the MPXV: the Central tributed to the increase in sporadic cases and outbreaks globally
African clade and the West African clade [8]. Infection over the last 15 years [18].
2 • OFID • Titanji et al
REVIEW ARTICLE INVITED
Monkeypox: A Contemporary Review for Healthcare
Professionals
Boghuma K. Titanji,1, Bryan Tegomoh,2 Saman Nematollahi,3 Michael Konomos,4 and Prathit A. Kulkarni5,6
1
Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, USA, 2Nebraska Department of Health and Human Services, Lincoln, Nebraska, USA, 3Department of
Medicine, University of Arizona College of Medicine, Tucson, Arizona, USA, 4Visual Medical Education, Emory University School of Medicine, Atlanta, Georgia, USA, 5Infectious Diseases Section,
Department of Medicine, Baylor College of Medicine, Houston, Texas, USA, and 6Medical Care Line, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
The ongoing 2022 multicountry outbreak of monkeypox is the largest in history to occur outside of Africa. Monkeypox is an
emerging zoonotic disease that for decades has been viewed as an infectious disease with significant epidemic potential because
Downloaded from https://academic.oup.com/ofid/article/9/7/ofac310/6615388 by guest on 15 August 2024
of the increasing occurrence of human outbreaks in recent years. As public health entities work to contain the current outbreak,
healthcare professionals globally are aiming to become familiar with the various clinical presentations and management of this
infection. We present in this review an updated overview of monkeypox for healthcare professionals in the context of the
ongoing outbreaks around the world.
Keywords. emerging infectious diseases; monkeypox; outbreak.
The 2022 outbreak of monkeypox involving multiple countries knowledge of this zoonotic infection, including its prevention,
in both endemic and nonendemic regions has generated signif clinical management, prophylaxis, and basics of infection control,
icant international interest [1, 2]. A once-neglected zoonotic vi to understand the broader implications of the current outbreak. In
rus endemic to West and Central Africa, monkeypox virus was this review, we provide an overview of monkeypox virus infection
first identified in 1958 [3] in nonhuman primates kept for re to serve as a primer for healthcare professionals who may encoun
search in Denmark [3]. The first case in humans was reported ter this condition in their practice.
in 1970 in the Democratic Republic of Congo [4]. Over the past
50 years, sporadic outbreaks have been reported mainly in
VIROLOGY
African countries, with several thousand human cases recorded
to date. Occasional cases and limited outbreaks linked to travel The Poxviridae family are double-stranded deoxyribonucleic
or importation of animals harboring the virus have also been acid viruses which infect a range of animals including birds,
described in nonendemic countries [5]. It has long been a the reptiles, insects and mammals. The family consists of 2 subfam
oretical concern that monkeypox virus and other zoonotic pox ilies: Chordopoxvirinae (with 18 genera and 52 species) and
viruses could over time expand to fill the ecological niche once Entomopoxvarinae (with 4 genera and 30 species).
occupied by the closely related variola virus [6, 7]. The com Monkeypox belongs to the Poxviridae family, the
bined effects of deforestation, population growth, encroach Chordopoxvirinae subfamily, and the genus Orthopoxvirus
ment on animal reservoir habitats, increasing human [9–11]. Several poxvirus species have been shown to cause hu
movement, and enhanced global interconnectedness have man infections including Variola (smallpox), Cowpox,
made this possibility more real in the last 20 years [6–8]. Monkeypox, Vaccinia, Camelpox, Alaskapox, Yaba monkey tu
With increasing case numbers being reported in the current mor virusTanapox virus, Orf virus, Pseudocowpox virus, Bovine
outbreak, it is important for clinicians everywhere to update their papular stomatitis virus, Buffalopox and Molluscum contagio
sum. Humans are the reservoir host of Variola and
Molluscum contagiosum viruses [11]. Monkeypox virus
Received 01 June 2022; editorial decision 21 June 2022; accepted 21 June 2022; published (MPXV) has a wide range of potential host organisms, which
online 23 June 2022
Correspondence: Boghuma K. Titanji, MD, PhD, Division of Infectious Diseases, Emory has allowed it to circulate in wild animals for a prolonged peri
University School of Medicine, 100 Woodruff Circle, Atlanta, Georgia 30322 (btitanj@emory. od of time while sporadically causing human disease through
edu).
spillover events [9]. More importantly, Orthopoxviruses
Open Forum Infectious Diseases®
© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases (OPXV) exhibit immunological cross-reactivity and cross-
Society of America. This is an Open Access article distributed under the terms of the protection, and infection with any member of the genus confers
Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.
org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of some protection from infection with any other members of the
the work, in any medium, provided the original work is not altered or transformed in any way, same genus [12, 13].
and that the work is properly cited. For commercial re-use, please contact journals.permissions
@oup.com
Orthopoxviruses are large (size range:140–450 nm) viruses
https://doi.org/10.1093/ofid/ofac310 with a brick-like structure and a genome consisting of
Monkeypox: A Contemporary Review for Healthcare Professionals • OFID • 1
, approximately 200-500kbp kb [6, 9, 10] that codes for over 200 with the West African clade typically results in a more self-
genes. Many of the genes encoded by the OPXV genome are limited disease, with case-fatality ratios estimated to be ap
not essential for virus replication in cell culture but might play im proximately 3–6%, whereas the Central African (Congo
portant roles in the host antiviral response [10, 14]. All poxviruses Basin) clade has historically been associated with higher
complete their replication cycle in the cytoplasm of infected transmissibility and case-fatality ratios as high as 10% [8].
cells via complex molecular pathways [10, 15]. This intracellular Cameroon is the only country where both clades
replication cycle has been well characterized for Vaccinia virus, have been confirmed [20, 21]. Cumulatively, more
which was used to develop the vaccine that helped to eradicate suspected cases of the Central African clade have been re
smallpox globally; key features of this replication cycle are ported to date than cases due to the West African clade
similar for all poxviruses [10, 15]. The infection cycle can be due to the high number of cases recorded in historical and
initiated by two distinct forms of the virus: the intracellular ongoing outbreaks in the DRC [21]. The West African clade
mature virion and the extracellular enveloped virion, which differ of MPXV has been isolated from cases in newly affected
in their expression of surface glycoproteins. Glycosaminoglycans, countries in the 2022 multi-country outbreaks
Downloaded from https://academic.oup.com/ofid/article/9/7/ofac310/6615388 by guest on 15 August 2024
which are ubiquitously expressed on the surface of mammalian The transmission of monkeypox in endemic and nonendemic
cells, are thought to be crucial for binding of the virion to the settings is summarized in Figure 1. Animal-to-human transmis
cell membrane, although all cellular receptors have not been fully sion occurs via bites and scratches from infected animals.
characterized [10, 15]. A detailed description of the replication Preparation and handling of infected animal products (bush
cycle is beyond the scope of this review but has been described meat [22]) may also result in transmission. The definitive animal
previously [10, 15]. reservoir of MPXV has not been identified. The virus has been
Smallpox is estimated to have caused millions of fatalities isolated from several animal species including small mammals
worldwide [13] and was one of the most dreaded infectious dis and nonhuman primates. In the reported instances in which
eases in human history. The impact of smallpox serves as a re MPXV has been isolated from wild animals, the animals demon
minder that OPXV can be formidable pathogens. Although the strated pox-like lesions consistent with active infection [23–26].
origins of smallpox are not known, there is some evidence It is not known whether asymptomatic carriage of MPXV occurs
which suggests that Variola virus may have evolved from an an in animal reservoir. Serological surveys have been conducted
cient rodent poxvirus thousands of years ago [16]. The increas on wild mammals in endemic regions. These studies have found
ing danger of zoonotic OPXV infections such as MPXV has several animal species with detectable antibodies to OPXV in the
been recognized for a long time [17, 18]. As a consequence of absence of detectable viremia on polymerase chain reaction
immunization programs against smallpox ending over 40 years (PCR) testing. This suggests exposure to and circulation of
ago, a significant proportion of the global population does not zoonotic OPXV in many wild animal species [27].
have immunity against smallpox and zoonotic OPXV. All of Human-to-human transmission is thought to occur via direct
this raises the possibility that given the right conditions, such skin-to-skin contact with lesions on the skin, as well as through
as increasing incidence of human infections and long-term ab indirect contact with contaminated fomites, such as bedding or
sence of vaccine immunity, a zoonotic orthopoxvirus like clothing [8]. Transmission can also occur at close proximity
MPXV could acquire the ability to more efficiently transmit be through exchange of respiratory secretions containing live virus.
tween humans and cause larger outbreaks [17]. In the last 5 decades, the DRC has been most affected by
monkeypox outbreaks, whereas the second and third most af
fected countries have been Nigeria and Republic of the
EPIDEMIOLOGY AND HISTORICAL OUTBREAKS
Congo, respectively. Table 1 shows a timeline of outbreaks of
Monkeypox is endemic in the tropical rainforest regions of human monkeypox cases reported since 1970, when the first
Central and West African countries, notably Cameroon, human case was detected in a 9-months-old patient in a remote
Central African Republic, Cote d’Ivoire, Democratic village in the DRC [4]. After the historical success of the global
Republic of the Congo (DRC), Gabon, Liberia, Nigeria, eradication of smallpox during the 1970s, surveillance for pox-
Republic of the Congo and Sierra Leone. Most cases arise like diseases was enhanced in tropical rainforest areas, which
sporadically or occur in the context of localized outbreaks has aided in identifying monkeypox outbreaks as they have oc
[6–8]. Cases outside of endemic countries are typically curred over time. More importantly, smallpox vaccination,
linked to international travel or importation of animals in which stopped being universally administered in the 1970s,
fected with MPXV [5, 19]. Before 2022, cases outside of confers cross-protection against MPXV infection. It is possible
Africa had previously been reported in the United States, that the progressive loss of immunity against smallpox over
United Kingdom (UK), Israel, and Singapore [7]. There time combined with the other factors described above has con
are 2 distinct genetic clades of the MPXV: the Central tributed to the increase in sporadic cases and outbreaks globally
African clade and the West African clade [8]. Infection over the last 15 years [18].
2 • OFID • Titanji et al
