Abstract
Syphilis was nearly eradicated in the United States by year 2000, 1 and gonorrhea reached its lowest incidence in 2009. 2 However, not all demographic groups saw equal progress. Historically, the highest rates of sexually transmitted infections (STIs) have occurred among men who have sex with men (MSM), with “repeaters,” those suffering two or more STIs, accounting for an increasing percentage of syphilis diagnoses. 1 But cases among MSM in the United States actually declined slightly in 2020, whereas instances among heterosexual women rose 21% from 2019 to 2020, a dynamic attributed, in part, to the increasing prevalence of opioid and crystal meth abuse. 2,3 Yet new data released from the Centers for Disease Control and Prevention (CDC) surveillance group document a dramatic rise in most STIs post-early 2020. 4 These statistics almost certainly reflect an undercount during the COVID-19 pandemic, as competing public health priorities shifted resources away from COVID-19 units. 4
This surge in STIs strikes the United States in a milieu already disrupted by reallocation of funding for clinics providing free STI testing and treatment, the growth of online dating services that greatly expanded sexual networks, and a decline in condom use among MSM taking HIV pre-exposure prophylaxis. 2,3,5
Specifically, the 2.4 million cases of STIs recorded in the United States in 2020 reflected a 45% increase in gonorrhea, a 52% increase in syphilis, and a 235% increase in congenital syphilis over the past 5 years. 4,6 Only chlamydia declined in that interval, by 1.2%, most likely due to changes in screening, as chlamydial disease is usually asymptomatic. 4 More than half of the STIs occurred in those aged 15–24 years, with the greatest rise among non-Hispanic Blacks and African Americans. 4 If these disturbing trends are to be reversed, then recommitment to public health initiatives, along with the normalization of STI screening in all healthcare settings, is required. The very recent outbreak of monkeypox worldwide, predominantly among MSM, is a clear example of failure to support such a commitment. In late July the World Health Organization (WHO) declared monkeypox a “global emergency.” 7 As of August 1, the CDC designated monkeypox a nationally notifiable condition.
Human monkeypox virus (MPXV), a member of the Poxviridae family, is manifest by mucocutaneous lesions. It is sexually transmissible, if not yet officially classified as an STI. Since April 2022, an outbreak has been ongoing in non-endemic areas, with over 16,000 cases in 75 countries, including 3000 in the United States as of early July. 7,8 The fact that at least two MPXV variants have been identified in the United States suggests that multiple simultaneous outbreaks have occurred. 9 New York City cases have been expanding particularly rapidly. As of July 15th, 839 cases of clinical MPXV have been reported in New York City, representing about one quarter of total US cases, 7 with most instances not associated with international travel.
MPXV is poised to exploit vulnerabilities in public health-based STI surveillance, testing, and treatment. Although heterosexuals are not in the current network of MPXV infection—a very high proportion of cases have occurred among MSM, with 99% of all cases reported in the United Kingdom involving men—no one is immune. The WHO has cautioned that MPXV could quickly move into high-risk groups, including children, pregnant women, and the immunocompromised. Several MSM who developed clinical monkeypox had HIV infections well controlled on antiretroviral therapy and did not appear to have worse outcomes than those without HIV. 10 –13 But given the dissemination of other viruses in those with advanced or uncontrolled HIV infection, this possibility requires close scrutiny.
Although there have only been five recorded deaths since the outbreak in non-endemic countries, there have been over 1500 cases and 66 deaths from monkeypox in endemic countries in the past 6 months. 14 This dichotomy appears to be virus type dependent, but the distinction may not persist for long. That is, most people infected with the West African clade of MPXV, source of the current worldwide outbreak, recover within a few weeks, with a fatality rate of <1%, 15 reflecting current European and US statistics. But the endemic Congo Basin clade can be lethal, leading to a 10% fatality rate. 15
A Brief Primer on Monkeypox
MPXV is a double-stranded DNA virus with a very large genome, some 7 times that of SARS-CoV-2 and 20 times larger than HIV. 15 It was first identified in Asian monkeys in 1958 in a polio vaccine research facility in Denmark. 16 It was detected in humans in the Congo in 1970 and is now endemic in West and Central Africa. The first recognized outbreak outside Africa occurred in six US states in 2003, traced to pet prairie dogs that had been infected by wild rodents imported from Ghana. 15,16
MPXV was found in seminal fluid, genital and anal lesions, and feces of four MSM involved in a recent outbreak in Italy. 12 It has been known for decades that MPXV has the potential for inter-human transmission through close contact with lesions (which need not be weeping), body fluids, respiratory droplets, and contaminated materials, including towels and, potentially, fomites such as sex toys. 16,17 Genital ulcers were reported in 52 of the first 2677 confirmed cases worldwide (1.9%), 16 but as reviewed below this is probably a significant underestimation. Whether MPXV increases the risk for HIV acquisition is uncertain but, given the fact that common bacterial and viral STIs facilitate HIV spread, this is a highly likely scenario. 16,18
The average incubation period for MPXV is 7–14 days, but it may range from 5 days to 3 weeks. “Probable case” definitions have been proposed based on historical monkeypox data, but recent observational studies suggest those definitions need to be revisited, with current cases having generally milder illness with lower rates of prodromal symptoms. 19,20 Classically, initial findings of fever, chills, fatigue, headache, myalgias, pharyngitis, and lymphadenopathy occur 1–2 days before recognition of cutaneous or mucosal lesions. These systemic symptoms may also start after such lesions erupt. An initial enanthem followed by a cutaneous rash that spreads to all parts of the body within 24 h, becoming most concentrated on the face, arms, and legs (“centrifugal distribution”), was typical. Skin or mucous membrane lesions often occur first at the probable site of virus entry and evolve from macules and papules to vesicles and pustules that ulcerate and then crust before healing over several weeks. 16 Symptoms usually persist for 2–4 weeks.
In contrast to those observations, a recent review of 54 confirmed MPXV cases among MSM, 24% of those also living with HIV and seen at one sexual health center in London, suggest additional scenarios. 19 All men presented with mucocutaneous lesions, 94% of which were anogenital. They can be very painful and pruritic. Four (7%) had oropharyngeal lesions. One in four had a concurrent STI. Fever or chills were reported in 57%, a much lower finding than the 85–100% found in prior outbreaks in the United States and Africa, and 10 (18.5%) had no systemic symptoms preceding the eruptive phase of infection. Whether asymptomatic MPXV infections among MSM can lead to sexual transmission is unclear. A recent study from Europe found that 3 of 224 men with anorectal and oropharyngeal swabs taken in May 2022 for STI screening, and retrospectively analyzed with a monkeypox-specific polymerase chain reaction (PCR) test, were positive despite the fact that all 3 were asymptomatic. 21 But none of their contacts developed clinical monkeypox. 21
Serious complications seen in earlier outbreaks included pneumonia, encephalitis, and eye disease, 17 but are infrequent among contemporary cases. The diagnosis must be confirmed by screening polymerase chain reaction (PCR). Until mid-July, this was available only at state public health departments, but it can now be accessed by physicians through commercial laboratories.
Monkeypox Vaccines and Therapeutics
The CDC recommends that persons exposed to monkeypox and who have not received the smallpox vaccine within the past 3 years should get vaccinated. Two vaccines are available as pre- or postexposure prophylaxis against clinical MPXV disease per Advisory Committee on Immunization Practices guidelines. Only one, Jynneos (also known as Imvamune or Imvanex), is FDA approved for such use. 17 There is an ample supply of the second ACAM2000 vaccine, produced by Emergent BioSolutions; doses in the millions have been stockpiled. It has an efficacy against smallpox of >95%, and protection extends for 3–5 years. 22
However, ACAM2000 should not be administered to those with several health conditions, including immunodeficiencies, eczema, and pregnancy, as it contains a live attenuated vaccinia virus. 8,15 Its use during smallpox epidemics was associated with a mortality rate of 1 in 1 million. 15 The second vaccine, Jynneos, manufactured by Bavarian Nordic, has few side effects and consists of a replication-incompetent form of vaccinia. It requires two doses given 4 weeks apart. 15 Based on pre-clinical studies, it appears to protect against MPXV if given within 4 days of exposure, with an efficiency rate of up to 85%. 15,17
People are not considered vaccinated until 2 weeks after they receive the second dose of this vaccine. Unlike ACAM2000, its efficacy against monkeypox is based on pre-clinical animal studies and human immunogenicity data, not clinical trials. It is being utilized in the United States and Europe, but is in very short supply, currently administered in a “ring vaccination” strategy targeting health care workers, contacts of known cases, and those at high risk for such contacts, as well as MSM with multiple sexual partners. 8,15,23 Until production and distribution is accelerated, some public health officials are advocating for administering initial doses of Jynneos to a larger number of high-risk MSM, rather than reserving second doses for a complete vaccination. Also because of the shortage, the vaccine is being offered only as a preventative, despite the fact that it can mitigate symptoms if administered within a few days after exposure.
In terms of antiviral therapies, there are two FDA-approved drugs for the treatment of smallpox. Tecovirimat (TPOXX) led to a decrease in viremia and possibly improved clinical recovery in a case report of one patient with monkeypox. 19 The second agent, brincidofovir, had no clinical benefit and significant toxicity in three patients with monkeypox. 19 Whether TPOXX can be used as a pre-exposure prophylaxis is unknown.
Additional Considerations to Suppress a Pandemic
Apart from immediately accelerating vaccine production, how else might we intervene to prevent a monkeypox pandemic? CDC guidelines updated in early June advises those who may have become infected with monkeypox to refrain from sexual activity entirely. Recognizing this is impractical, they do offer some alternatives, including “Have virtual sex with no in-person contact” and “Avoid kissing and consider having sex with your clothes on.” Dr. Jay Varma, director of a pandemic screening program at Weill Cornell Medicine, suggested more practical initiatives.
First, “Public health agencies need to greatly increase collaboratives with community groups and with hookup apps, party promoters and travel companies that specialize in gay, bisexual and other men who have sex with man to promote self-screening for skin changes. … unchecked transmission means a virus will not stay limited to any one subset of the population and will lead to unpredictable health complications.” 9 A rising number of public health experts argue for encouraging high-risk MSM to temporarily change their sexual behaviors while the disease spreads, noting that this is not equivalent to advocating for abstinence or monogamy. 23
Second, “The general public needs to demand that elected officials recognize the urgency of having a strong national strategy and budget focused on sexual health. By making sexual health a routine part of wellness and by funding it sufficiently, we can lower the barrier to essential serves and protect everyone from emerging health threats, such as monkeypox.” 9