Master the latest knowledge on the ongoing monkeypox outbreak with Dr. Boghuma Titanji (@Boghuma)! Learn how to recognize monkeypox in the clinic, how to test for monkeypox, how to approach management (including options for antiviral agents), and more.
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Monkeypox is a DNA virus in the genus Orthopox, and is a cousin of the smallpox virus (variola) (Lum et al 2022). It is well-established as a cause of infection in humans. The first cases of human monkeypox infections were documented in the 1970s in the Democratic Republic of Congo, and since that time it has circulated in an endemic manner in West / Central Africa (Lum et al 2022, Titanji et al 2022). Historically, human monkeypox infection primarily occurred in the setting of zoonotic exposure to animal reservoirs, such as exposure through hunting or manipulating animals (Titanji et al 2022, Di Gennaro et al 2022). Previous outbreaks tended to be very restricted, generally among household contacts of index cases.
The current global outbreak of monkeypox was first recognized when clusters were noted across Europe. The current outbreak prompted concern due to several key differences from historic outbreaks. In particular, cases were being observed in individuals without links to endemic regions or zoonotic exposures. Additionally, clusters of cases were found to map onto sexual networks, suggesting that the virus may be spreading in a new manner that had not been noted previously.
Monkeypox does not transmit very efficiently in humans. Person-to-person transmission primarily occurs through sustained skin-to-skin contact (Di Gennaro et al 2022, CDC guidance.) Sex allows for sustained skin exposure that can facilitate transmission. The virus can also be transmitted through prolonged contact with contaminated materials / objects, such as clothing or bedding (Morgan et al 2022, Atkinson 2022, Vaughn et al 2020). According to Dr. Titanji, active cutaneous lesions shed the most virus (Tarin-Vicente et al 2022), and risk of transmission declines once a lesion has healed and a new layer of healthy skin has formed.
Risk Factors for Monkeypox
Clinical Presentation of Monkeypox
According to Dr. Titanji, it is important for providers to be aware of the spectrum of how monkeypox can present. Clinical manifestations of monkeypox may differ from the classic textbook presentation of monkeypox, which may lead to missed diagnoses.
The classic textbook presentation of monkeypox based on historic outbreaks generally involves a prodromal phase of non-specific symptoms such as fever, myalgias, and fatigue that precede the emergence of a rash (Di Gennaro et al 2022, Titanji et al 2022). Historically, the incubation period from the time of exposure to the development of prodromal symptoms has been fairly long, on the order of ~5-17 days, even reaching up to 21 days, according to Dr. Titanji. The textbook evolution of a monkeypox lesion involves five phases: 1) initial macule, 2) development into a papule / vesicle, 3) evolution of the lesion into a pustule with a distinctive central umbilication classic for orthopoxviruses, 4) erosion of the pustule to form an ulcer, and 5) scabbing over of the lesion and sloughing off of the scab, with full healing usually requiring 2-4 weeks (CDC guidance, Titanji et al 2022). The classic monkeypox rash in prior outbreaks was usually generalized, often accompanied by lymphadenopathy, and usually involves lesions in the same phase of development (unlike chickenpox).
However, the clinical manifestations of monkeypox in the ongoing outbreak exhibit several key differences from the historic textbook presentation (Di Gennaro et al 2022, Titanji et al 2022). In the current outbreak, the incubation period is ~5-12 days (with a median of 7 days), which is shorter than what has been observed historically (Thornhill et al 2022). Prodromal symptoms appear less likely in the current outbreak. Additionally, cases of single lesions or several lesions (as opposed to the classic generalized rash) are more common in the current outbreak (Thornhill et al 2022). Finally, the current outbreak is notable for cases of isolated proctitis (with severe rectal pain and tenesmus) and isolated pharyngitis. These manifestations tend to track with relevant sexual exposure (e.g. oral sexual exposure associated with oral / pharyngeal lesions, and receptive unprotected anal sex associate with proctitis), underscoring the importance of taking a thorough history.
Dr. Titanji notes that pruritus and pain can be significant with monkeypox lesions. Intensive pruritus tends to develop in the pustular / ulcerative phase, when parts of the lesion are beginning to heal. The rash is typically also accompanied by considerable pain. Pain is particularly notable with mucosal lesions: pharyngeal manifestations can involve severe sore throat causing inability to control saliva and profound difficulty swallowing, and cases of proctitis can involve severe rectal pain requiring inpatient admission for pain management . In fact, uncontrolled pain is the most common reason for hospitalization (Thornhill et al, 2022). In terms of other complications, Dr. Titanji notes there have been cases of pharyngeal monkeypox complicated by bacterial super-infection.
Testing for Monkeypox
Testing for monkeypox involves collecting swabs from lesions and sending to a lab for PCR testing to detect viral DNA (CDC guidance). Swabs should be collected from the site at which the patient has symptoms (e.g. skin, rectum, oropharynx.) For skin lesions, a sterile, dry cotton swab should be used. Swabs should be collected from at least 2 lesions (if >1 lesion is present), with a separate swab used for each lesion. According to Dr. Titanji, for lesions that are not already open /ulcerated, the provider should gently unroof the lesion to make sure they are able to get inside the lesion, and then vigorously swab the lesion. For rectal swabs, it can sometimes be difficult to acquire a sample due to pain. Studies support the use of self-collection for rectal swabs, with a recent non peer-reviewed paper indicating that self-collected rectal swabs for monkeypox testing are as good as provider-collected rectal swabs (Ubals et al 2022, preprint). In terms of the turn-around time, PCR tests generally take 48 hours to result, though there are still logistical barriers in place, and currently monkeypox tests take 5-7 days to come back in most locations. According to Dr. Titanji, some labs will initially perform a generic DNA test that detects any orthopox virus and then reflex to a confirmatory monkeypox-specific PCR if the initial test if positive; in the setting of an outbreak, a positive initial orthopox PCR should be considered indicative of a presumptive monkeypox diagnosis while awaiting confirmation.
In addition to monkeypox, other causes for genital lesions should be kept on the differential, including syphilis, HSV, and lymphogranuloma venereum. Thus, in addition to monkeypox testing, Dr. Titanji recommends obtaining an RPR, HSV swabs, and chlamydia testing. Additionally, an HIV test should be performed if the patient’s HIV status is not already known.
Management of Monkeypox
Supportive care is crucial in the management of monkeypox (CDC guidance), and a large proportion of patients with monkeypox require supportive care alone. Fevers can be treated with antipyretics. Proper hydration should be ensured to counteract insensible losses in patients with multiple skin lesions, similar to burn patients. Skin protectants such as petroleum jelly can also be used. NSAIDs can be helpful for pain, and antihistamines can be used for pruritis. Notably, Dr. Titanji stresses that topical steroids should not be used, as they promote viral replication and interfere with proper skin healing; similarly, steroid enemas / suppositories are discouraged in patients with proctitis. For patients with severe pain, opiate-based medications may be necessary; additionally, IV NSAIDs have been observed to be helpful in decreasing inflammation for patients admitted to the hospital (expert opinion). For patients with severe pain due to proctitis, there is anecdotal evidence for use of steroid-sparing local anti-inflammatory agents such as mesalamine suppositories (expert opinion). Additionally, lidocaine-based preparations and sitz baths can be used for patients with peri-anal lesions (WHO Interim rapid response guidance, CDC guidance). Finally, if there is evidence of bacterial super-infection, the appropriate antibiotics should be used.
Patients with severe disease (e.g. large number cutaneous lesions such that confluent, mucocutaneous lesions that could scar/stricture or limiting function, bacterial superinfection), as well as patients at high risk for disease, are considered candidates for antiviral medications (CDC guidance). Currently, there are three available antiviral agents: tecovirimat, brincidofovir, and cidofovir (Titanji et al 2022). Notably, Dr. Titanji points out that for all three of these antiviral agents, while there is evidence supporting their efficacy in vitro and in animal models (Huggins et al 2009, Hutson et al 2021, Stittelaar et al 2006), to date there have been no randomized controlled trials (RCTs) conducted in humans on their efficacy in treating monkeypox.
Tecoviromat, which is available through emergency use authorization (EUA), acts by inhibiting a key protein in the viral replication cycle and thus blocks formation of new virion particles. It is available in IV and oral formulations, and prescribed by weight-based dosing for a 14-day course. Patients should be advised to take tecovirimat with food, preferably fatty meals. Anecdotal evidence suggests that tecovirimat is associated with alleviation of symptoms and reduction in the emergence of new lesions (Adler et al 2022); however, the medication has yet to be evaluated in an RCT, and it is unclear if this observation is simply a result of the natural history of the disease. The results of multiple ongoing clinical trials, including the STOMP trial, are eagerly anticipated (NIH News Release). Possible side effects of tecovirimat include nausea, abdominal pain, and headache, though in general it is quite well tolerated.
The two other available antivirals are brincidofovir and cidofovir, which work by inhibiting DNA synthesis. Infectious disease should be involved if these medications are being prescribed. Brincidofovir (a prodrug of cidofovir) is FDA approved for the treatment of smallpox, and has activity against other orthopoxviruses. It is given orally once per week for 2 weeks. Elevated LFTs are a common side effect, and should be monitored (Adler et al 2022). Importantly, brincidofovir is a known teratogen, and additionally may impact male fertility . Cidofovir is given as an IV infusion once a week for 2 weeks. It is a potent nephrotoxin, and is co-administered with probenecid for renal protection. Neither of these agents has been studied in RCTs for monkeypox treatment.
Monkeypox in patients with HIV
There is a strong association between HIV infection and monkeypox infection in the current outbreak. In the U.S. ~41% of patients diagnosed with monkeypox are people with HIV (Philpott et al 2022). It is unclear whether this is simply due to shared risk factors that result in co-occurrence, or whether immune system dysfunction in HIV infection predisposes to a higher chance of acquiring monkeypox if exposed.
If an individual has well-controlled HIV, management is the same as in patients without HIV. In fact, recent cohort studies demonstrate that monkeypox outcomes in patients with well-controlled HIV are similar to those in patients without HIV (Tarin-Vicente et al 2022, Thornhill et al 2022, Patel et al 2022). However, in patients with HIV who are more immunocompromised (e.g. not on antiretroviral therapy, depleted CD4+ T cell count, detectable viral load), historic reports indicate that these patients are at a higher risk for more severe, disseminated monkeypox and are more likely to experience complications (Yinka-Ogunleye et al 2019, Ogoina et al 2020). A recently published report by the CDC observed higher rates of hospitalization for monkeypox in patients with HIV compared to those without HIV (Curran et al 2022). Patients with uncontrolled HIV should be considered for use of an antiviral medication for monkeypox treatment. Additionally, these patients should be connected with infectious disease for antiretroviral therapy initiation.
Monkeypox in pregnancy
Pregnancy is considered an immunosuppressed state, and treatment with an antiviral agent should be considered in pregnant patients with monkeypox. Of note, brincidofovir and cidofovir are both teratogenic (CDC guidance). Tecovirimat has not shown evidence of teratogenicity in mice, but there is minimal human data (CDC guidance); thus, use of tecovirimat for monkeypox during pregnancy should be based on shared decision-making. Another option for pregnant patients who prefer not to receive tecovirimat is vaccinia immunoglobulin (CDC guidance), which consists of antibodies collected from patients who have received smallpox vaccination. There is not yet data for vaccinia immunoglobulin for monkeypox, and use should occur with expert consultation.
Vaccination should be considered for post-exposure prophylaxis in patients without lesions who have been exposed to an individual with monkeypox. The hope is that if an individual is vaccinated ideally within 4 days of exposure, an antibody response can be generated that can prevent the virus from establishing infection or reduce the severity of disease if infection does occur.
Vaccination is also an important prevention strategy for outbreak control and protecting those groups at highest risk, including men who have sex with men (multiple partners, or recent STD), sex at a commercial venue, and those with significant occupational risk like research lab personnel handling the virus (CDC 2022)
There are currently two available vaccines for monkeypox (Poland et al 2022), both of which were originally developed for smallpox and both of which are based on the vaccinia virus (another orthopox virus that is not as virulent as smallpox.) The immunogenicity of these two options has been shown to be similar in trials (Pittman et al, 2019).
Listeners will learn to recognize common presentations of monkeypox infection, and learn how to manage it once diagnosed.
After listening to this episode listeners will…
Dr. Titanji reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures.
Williams PN, Titanji B, Gandhi MM, Roberts SP, Grant K, Watto MF. #359 Monkeypox with Dr. Titanji. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list. October 10, 2022.
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