Monkeypox: a brief overview (7 July 2022)
As the COVID-19 pandemic crosses the two-and-a-half-year mark, another unrelated virus is now garnering international attention and generating some consternation. Since 13 May 2022, and as of 5 July 2022, 6,924 laboratory confirmed cases of monkeypox have been reported by the World Health Organization (WHO), the U.S. Centers for Disease Control and Prevention (CDC), the European CDC, and Ministries of Health from countries in which monkeypox is not endemic [1]. Included among these is the United States; and as of 5 July 2022, 560 cases were reported in the U.S., with the highest number of cases reported in California (111), New York (96), Florida (64), Illinois (62), and the District of Columbia (53) [2]. Considering the unprecedented scope of this recent outbreak, I thought a précis of this virus hitherto known only to infectious disease physicians, veterinarians, virologists, and the like would be helpful.
Monkeypox belongs to the Orthopoxvirus genus, which also includes variola virus (which causes smallpox), vaccinia virus (used in the smallpox vaccine), and cowpox virus, among others [3]. Monkeypox was first described in 1958–1959 after it was isolated from a colony of laboratory monkeys shipped from Singapore to Denmark for polio research [4] and was first identified as a human pathogen in 1970 in a child in the Democratic Republic of the Congo (formerly Zaire) who was thought to have smallpox [5]. In the ensuing years, there have been sporadic outbreaks, mostly in the rain forests of central and western Africa and mostly associated with exposure to infected forest animals (e.g., through the preparation of bushmeat). However, the incidence of monkeypox infection is increasing, possibly because of waning immunity to closely related smallpox (resulting from the eradication of smallpox in 1977 and subsequent discontinuation of routine smallpox immunization); and in 2022, the WHO reported that monkeypox was endemic in eleven African countries [6, 7]. There have also been outbreaks in nonendemic countries, including 71 cases in 2003 in six U.S. states (the first documented outbreak in the Western hemisphere), which was attributed to exposure to pet prairie dogs that had been housed near infected rodents from Ghana [8]. The first cases in this current outbreak were reported in England in May 2022 [9]. They do not appear to be travel related or associated with animal exposure, but instead appear to involve community-based human-to-human transmission, particularly among men who have sex with men [10].
Infection with monkeypox virus typically occurs after exposure to infected fluid (e.g., saliva or blister fluid) either directly or by contact with a contaminated inanimate object (i.e., a fomite). The virus then replicates locally before spreading to the lymphatic system, followed by several rounds of viremia (i.e., virus in the blood). The incubation period (i.e., the time from exposure to symptom onset) is typically 7 to 14 days with a mean incubation period of 8.5 days observed in the current outbreak [11]. Symptoms generally begin with a prodrome of fever, headache, lymphadenopathy (which may be generalized or regional), myalgia, and prostration lasting up to five days [12]. One to two days after symptom onset, a rash typically develops. Lesions generally appear first on the tongue and oral mucosa (enanthem) before spreading to the skin (exanthem), and tend to concentrate on the face, arms, and legs (i.e., centrifugal distribution), and may involve the palms and soles [13]. However, some cases described in the current outbreak started instead with a genital rash [14]. The natural evolution of lesions is from macule to papule to vesicle to pustule and then to scab (a process that takes about 7–14 days); and an infected person is generally considered to be contagious from the onset of the enanthem to the scabbing of lesions. Of note, the monkeypox rash may be umbilicated (i.e., having a pit or navel-like depression), is typically (but not invariably) synchronous (i.e., in the same stage of development, which is in contrast to chickenpox), has been described as painful and then becoming pruritic (itchy), and is associated with lymphadenopathy (in contrast to smallpox).
The mortality associated with monkeypox has been reported to vary between 0 percent in the 2003 U.S. outbreak to 10 percent in several Central Africa outbreaks [15]. This variability has been attributed to availability of supportive care, strain-associated virulence, and other factors [16]. As of 8 June 2022, 72 deaths were reported among 59 confirmed and 1,536 suspected cases in 8 endemic African countries, equating to a 4.5% case fatality rate [17]; and as of mid-June 2022, no deaths had been reported in nonendemic countries including the U.S.
According to the WHO and the CDC, monkeypox should be suspected in any patient who has recently traveled to an area with a known outbreak or who has been exposed to someone diagnosed with monkeypox and who presents with the typical rash or with genital vesicles or pustules that do not respond to herpes-directed treatment (e.g., acyclovir or valacyclovir). The differential diagnosis of monkeypox infection includes infection with other pox viruses (e.g., varicella and smallpox) as well as some non-pox viruses (e.g., herpes simplex virus). However, the presence of lymphadenopathy should increase one’s suspicion for monkeypox over varicella and smallpox. The diagnosis is confirmed either by detection of monkeypox virus DNA in a skin lesion by polymerase chain reaction amplification, by detection of anti-orthopoxvirus antibodies, or by direct visualization of the brick-shaped virus by electron microscopy [18].
For most individuals, monkeypox is a mild, self-limiting infection with symptoms lasting from two to four weeks. This contrasts with chickenpox, which usually runs its course in five to ten days [19]. Most patients can be treated at home with supportive therapy (e.g., fluids, analgesics, and rest). However, antiviral therapy may be indicated for certain groups including those at risk for severe disease (e.g., immunocompromised or pregnant individuals or those at the extremes of age) or those with oral, ocular, or genital lesions. There are several antiviral medications that appear to have activity against the monkeypox virus including tecovirimat, cidofovir, and brincidofovir. To date, most of the data for these medications are from in vitro or animal studies. However, a small number of human clinical trials suggest that they are safe and effective [20, 21].
As stated previously, immunity between smallpox and monkeypox is cross-protective, and vaccination against the former confers ~85% protection against infection with the latter [22]. However, except for military personnel, routine smallpox vaccination of the American public against smallpox stopped in 1972 after the disease was eradicated in the United States [23]. That notwithstanding, several vaccines are available for both smallpox and monkeypox, including the Ankara (MVA) vaccine (sold under the trade name Jynneos in the United States), which is made from a highly attenuated, nonreplicating vaccinia virus and is administered as a subcutaneous injection at zero and four weeks [24]. The safety and efficacy of the modified vaccinia Ankara (MVA) vaccine was demonstrated in several clinical trials [25, 26]. Currently, the CDC is not recommending universal vaccination against monkeypox; rather, the Advisory Committee on Immunization Practices (ACIP) recommends the vaccine be used as pre-exposure prophylaxis for certain high-risk groups (e.g., researchers and laboratorians working with orthopoxviruses and for certain healthcare personnel) and as post-exposure prophylaxis for people exposed to infected individuals [27].
Currently, one can only speculate about the ultimate scope and magnitude of the 2022 monkeypox outbreak. The only prior large-scale outbreak in a Western country with which to compare it was the 2003 outbreak in the Midwestern United States. That event, which ran from 15 May through 20 June and consisted of 71 nonfatal cases, was eventually curbed with the help of targeted smallpox vaccination. The monkeypox clade responsible for the current outbreak appears to be the same as that of the 2003 outbreak (i.e., West African) and is associated with an overall lower case fatality rate than that associated with the other known monkeypox clade (i.e., Congo Basin). Indeed, only one death has been associated with the current outbreak to date. However, the two outbreaks do differ in that human-to-human transmission (especially through sexual contact), which was not documented in 2003, features prominently in the current outbreak [28], something that will inform the public health response to this outbreak.
As with my prior infectious disease-themed posts, my intention here is not to politicize, sensationalize, or trivialize the topic, but only to provide timely information and thoughtful commentary.
Until my next update — regards.
Michael Zapor, MD, PhD, CTropMed, FACP, FIDSA
(7 July 2022)
References
1. https://www.cdc.gov/poxvirus/monkeypox/response/2022/world-map.html (Accessed on 6 July 2022).
2. https://www.cdc.gov/poxvirus/monkeypox/response/2022/us-map.html (Accessed on 6 July 2022).
3. https://www.ncbi.nlm.nih.gov/books/NBK574519/ (Accessed on 6 July 2022).
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