boghuma-k-titanji-monkeypox-a-contemporary-review-for (1).pdf

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, Atl...

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 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 in nonhuman primates kept for re­ to serve as a primer for healthcare professionals who may encoun­ search in Denmark. The first case in humans was reported ter this condition in their practice. in 1970 in the Democratic Republic of Congo. 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. 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. 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. 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%. 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. 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 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 ) 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 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. 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. 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. 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. 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. 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. 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. Infection over the last 15 years. 2 OFID Titanji et al Figure 1. Transmission of human monkeypox. In endemic countries, spillover events occur from zoonotic animal reservoirs into humans, potentially leading to limited outbreaks usually facilitated by close human contact. Outbreaks can also occur in nonendemic regions through introduction of the virus via human travel or importation of animals harboring the virus. Subsequent human-to-human transmission can then occur via household contacts and via other close contacts. CLINICAL PRESENTATION with other infections, including chickenpox, molluscum conta­ In the context of exposure and in the sylvatic setting persons are giosum, herpes simplex virus, syphilis, impetigo, measles in the at increased risk for developing monkeypox if they live in forested early stages, and rickettsial diseases. areas and are male gender, are less than 15 years of age, and are In the current 2022 outbreak, the presentation of monkey­ not immune to smallpox. Historically, patients have typically pox has had atypical features in many patients. For example, presented with prodromal symptoms, including fever, headaches, the characteristic rash is still present, but it can be limited to chills, malaise, and lymphadenopathy, followed by development the genital, perigenital, and perianal areas and present at differ­ of a characteristic rash (Figure 2). The rash usually starts in the ent stages of development. In addition, patients may pre­ mouth, and then spreads to the face and extremities, including sent with only mild or absent prodromal symptoms which may the palms and soles. Each lesion begins as a macule and then pro­ begin afteerr onset of a localised rash. Therefore, it is cru­ gresses to papules, vesicles, pustules, and scabs (Figure 3). Pain cially important to consider a wide spectrum of disease presen­ can be prominent, but it is not universally present, and pruritus tations as clinicians aim to accurately diagnose patients while can occur when the lesions are in the healing stage. Unlike chick­ the world attempts to contain the outbreak. enpox, skin lesions due to monkeypox tend to be similar in size DIAGNOSIS and typically present at the same stage. The number of lesions can range from 10 to 150 and can persist for up to 4 weeks It is important to have a high index of suspicion for monkeypox. Patients are infectious from the time symptoms start (pre­ infection and to be aware of the sometimes atypical presenta­ sumed to include prodromal symptoms before the appearance tions of the infection that have been described in the ongoing of the rash) until the lesions scab and fall off, with a new layer 2022 outbreak. When there is clinical suspicion for monkey­ of skin being formed. In rare instances, patients can experi­ pox, clinicians should ask about travel and sexual history and ence complications of monkeypox, such as bacterial superinfec­ about any close contacts with people with a similar rash or sus­ tion, encephalitis, pneumonitis, and conjunctivitis/keratitis pected or confirmed monkeypox infection. Behaviors associat­ [8, 40]. The timeframe for developing complications and their ed with close contact include sleeping in the same room, rates have not been systematically determined. drinking or eating from the same container, living in the Many features of monkeypox are similar to smallpox ; same residence, etc. More importantly, absence of travel however, in contrast to smallpox, monkeypox is often milder history or absence of a specific known close contact with a and presents with lymphadenopathy, which was typically ab­ rash or with suspected or confirmed monkeypox infection sent in smallpox infection. It is also important to note that should not exclude the possibility of this diagnosis. A thorough the cutaneous manifestations of monkeypox can be confused skin examination should also be performed. Monkeypox: A Contemporary Review for Healthcare Professionals OFID 3 Table 1. Outbreaks of Monkeypox: 1970–2021 Decade 1970–1979 1980–1989 1990–1999 2000–2009 2010–2019 2020–2021 Endemic Countries Number of Cases Reported* by Decade Total Cases Deaths References a b Cameroon 1 1 — — 16 — 18 N/A [28–32] Central African Republic — 8 — — 61 — 69 0 [7, 21, 33–38] Côte d’Ivoire 1 — — — — — 2 0 [4, 39] DRC* 38 343 511 10 027 18 788 7374 37 081 N/A [4, 18, 22, 39–50] Gabon — 4 9 — — — 13 N/A [51–53] Liberia 4 — — — 6 — 10 N/A [54, 55] Nigeria 4 — — — 228 42 274 N/A [6, 56, 57] Republic of the Congo — — — 73 24 — 97 N/A [58–60] Sierra Leone 1 — — — 2 — 3 0 [61–64] South Sudan — — — — 19 — 19 0 Nonendemic Countries Israel — — — — 1 — 1 0 Singapore — — — — 1 — 1 0 United Kingdom — — — — 4 — 4 0 [68, 69] United States — — — 47 — 2 49 0 [5, 19, 70, 71] Abbreviations: DRC, Democratic Republic of the Congo; N/A, data not available or unclear. *Reported cases include confirmed, probable, and/or suspected. All DRC cases from 2000 to 2009 and 2010 to 2019 were suspected cases.. a Cameroon is the only country where both viral clades have been reported in humans. b Dash denotes a period without reported outbreaks. The optimal diagnostic procedure for a patient with suspect­ of the possibility of increased insensible fluid losses from the ed active monkeypox infection is to obtain a specimen from a skin, decreased oral intake, and vomiting or diarrhea). Other skin lesion to send for molecular testing by PCR. Ideally, measures such as hemodynamic support, supplemental oxygen, more than 1 specimen should be obtained from 2 separate le­ or other respiratory support and treatment of bacterial superin­ sions on different parts of the body, and lesions should be un­ fections of skin lesions should be considered where indicated. roofed to adequately sample virus containing secretions. Another aspect of supportive care that has been described Certain laboratories can perform direct PCR testing for with previous OPXV infections is management of ocular infec­ MPXV specifically, whereas others perform generic OPXV test­ tion/complications, specifically resulting in corneal scarring ing that requires confirmatory testing for MPXV at a reference and/or loss of vision. Potential approaches to consider in laboratory. However, in the context of the current outbreak, a this situation include early involvement of ophthalmology ex­ positive OPXV test can reasonably be concluded to represent perts, application of lubricants, topical antibiotics, and possibly a diagnosis of monkeypox infection before results from confir­ topical antivirals such as trifluridine. matory testing are available. Testing plans should ideally be co­ At the present time, there are no US Food and Drug ordinated with public health authorities in advance of specimen Administration (FDA)-approved treatments specifically for collection. monkeypox. However, there are antiviral agents that have ac­ Cell culture provides virus strains for further characteriza­ tivity against MPXV , including cidofovir, brincidofovir tion, but it is restricted to accredited biosafety level 3 reference (a lipid-conjugate prodrug of cidofovir), and tecovirimat. laboratories. Serological testing can potentially be helpful In addition to antiviral agents, vaccinia immune globulin intra­ in epidemiologic investigations, retrospective diagnosis of venous (VIGIV) has been previously approved by the FDA for past infections, and diagnosis of late clinical manifestations, treatment of complications due to vaccinia vaccination, such as such as encephalitis. MPXV serology can cross-react with prior progressive vaccinia and severe generalized vaccinia. A smallpox vaccination, but this is not a concern in unvaccinated summary of these treatment options is presented in Table 2. individuals. Currently, tecovirimat, cidofovir, and VIGIV are available from the Strategic National Stockpile under Expanded Access Investigational New Drug (EA-IND) protocols held by the CLINICAL MANAGEMENT Centers for Disease Control and Prevention (CDC) for treat­ The mainstay of clinical management for typical monkeypox ment of OPXV infections in an outbreak scenario. In the infection is supportive care (Figure 2). Supportive care United States, these medications can be accessed through the includes maintenance of adequate fluid balance (because CDC via requests from state and territorial health departments. 4 OFID Titanji et al Figure 2. Clinical protocols and infection control during monkeypox outbreaks. Recognizing the clinical presentation and having a high index of suspicion are crucial for identifying potential cases. Rapid confirmation through testing and isolation of individuals with suspected or confirmed disease are necessary. These actions should be taken alongside notification of public health authorities for contact tracing and other components of the public health response. Although treatment for monkeypox infection is primarily supportive, antiviral agents and immune therapies could be considered for individuals with moderate to severe symptoms or who are at high risk for progression to severe disease. Vaccinating close contacts with high-risk exposures and at-risk individuals is also important for interrupting transmission chains and containing monkeypox outbreaks. Appropriate personal protective equipment (PPE) for medical settings consists of gown, gloves, a fit-tested N-95 or equivalent, and eye protection. Monkeypox: A Contemporary Review for Healthcare Professionals OFID 5 Figure 3. Stages of skin presentation and progression of monkeypox rash. Table 2. Potential Treatment Options for Monkeypox Infection Side Effects and Adverse Therapy Mechanism of Action Typical Dosing Formulation FDA Approval Status Events Cidofovir Blocks viral DNA synthesis through 5 mg/kg per dose once IV; off-label: CMV retinitis in patients Nephrotoxicity; neutropenia; competitive inhibition of DNA weekly for ≥2 doses topical, with AIDS (1996) decreased intraocular polymerase (with concomitant intravesicular pressure, nausea, vomiting probenecid) Brincidofovir Lipid conjugate prodrug of cidofovir 4 mg/kg once weekly for Oral Smallpox (2021) Abdominal pain, nausea, 2 doses (max 200 mg/ vomiting, diarrhea, elevated dose) liver transaminases and bilirubin Tecovirimat Inhibits activity of the protein VP37, IV: 35 to