The globalization of monkeypox

By Warren R. Heymann, MD, FAAD
May 25, 2022
Vol. 4, No. 21

Here we go again. I have not thought much about monkeypox (MP) since 2003 when a documented case appeared in a 3-year-old girl from central Wisconsin. Investigations implicated a shipment of 800 small animals from Ghana to Texas as the probable means of entry of the MP virus into the United States. According to Sale et al: “A sick Gambian giant-pouched rat (Cricetomys gambianus) from this shipment was subsequently sold to an Illinois animal vendor where it was kept in close proximity to prairie dogs (a native North American rodent [Cynomys species]). Prairie dogs that became infected were sold to a second animal distributor, and eventually to two pet shops and at a pet swap meet in northern Wisconsin. Additional animals from the Texas shipment, including dormice and rope squirrels, tested positive for monkeypox virus. As of July 2003, 72 cases of human monkeypox were under investigation in Illinois, Indiana, Kansas, Missouri, Ohio, and Wisconsin with 37 cases confirmed through laboratory analysis.” (1)

As of today, a case has been identified in Massachusetts along with two in Canada. (2) Kozlov states: “More than 120 confirmed or suspected cases of monkeypox, a rare viral disease seldom detected outside of Africa, have been reported in at least 11 non-African countries in the past week. The emergence of the virus in separate populations across the world where it doesn’t usually appear has alarmed scientists — and sent them racing for answers.” (3)

(The image above shows monkeypox on a darker skin tone. NPR recently published an image of monkeypox on white skin, which can be seen in a recent article.)

There is no need for panic — MP is not analogous to COVID-19. A pandemic from MP is not in the offing. Regardless, dermatologists must be familiar with all aspects of MP in order to identify possible cases which may assist in limiting contagion of this potentially fatal disease. This scenario reminds me of the anthrax scare following 9/11. I did not see a single case but had to evaluate dozens of patients who were convinced they were infected with Bacillus anthracis. (Most of those patients had impetigo or insect bites). Regardless, dermatologists needed to be prepared for the possibility of encountering the disease. The same holds true for MP. This commentary will take a question and answer format, followed by an expert opinion by Misha Rosenbach, MD, FAAD.

What is MP?

MP is a rare, potentially life-threatening zoonotic infection that occurs predominantly in West and Central Africa. It is caused by the monkeypox virus, a double-stranded DNA orthopoxvirus similar to the variola virus (the causative agent of smallpox) and vaccinia virus (the live virus component of orthopoxvirus vaccines). (4,5)

When was MP first recognized?

MP was first detected in 1958 in an outbreak of a vesicular disease in captive monkeys transported to Copenhagen, Denmark from Africa for research purposes. The term is actually a misnomer because the largest animal reservoirs of the MP virus are found in rodents, not monkeys. (5) The first human case of MP was reported in 1970, in a 9-year-old boy from Zaire (now known as the Democratic Republic of Congo), presenting with a smallpox-like disease from which MP virus was isolated. (5)

Where is MP usually found?

Ultimately, several thousand human cases of monkeypox have been confirmed in 15 different countries, with 11 of them in African countries. Monkeypox was imported to the United Kingdom, the U.S., Israel, and Singapore. (6) The increasing incidence of human MP cases in Central and West Africa is considered a function of diminished cross-protective immunity after smallpox vaccination was discontinued in the early 1980s following the eradication of smallpox. (5)

Are there variants of the MP virus?

According to Moore and Zohra: “There are two distinct clades of the monkeypox virus. The West African clade has a more favorable prognosis with a case fatality rate below 1%. On the other hand, the Central Basin clade (Central African clade) is more lethal, with a case fatality rate of up to 11% in unvaccinated children.” (7) Preliminary genetic data suggests that the MP virus is related to a viral strain predominantly found in western Africa. (3)

How is the MP virus transmitted?

The mode of transmission of the MP virus from animals to humans is unknown. Direct or indirect contact with live or dead animals is presumed to be responsible for most MP infections in humans. (5) Mahase states: “Transmission between people mostly occurs through large respiratory droplets, normally meaning prolonged contact face to face. But the virus can also spread through bodily fluids. The latest cases have mainly been among men who have sex with men. The UK Health Security Agency said that, although monkeypox has not previously been described as a sexually transmitted infection, it can be passed on by direct contact during sex. It can also be passed on through other close contact with a person who has monkeypox or contact with clothing or linens used by a person who has monkeypox.” (8) Compared to the SARS-CoV-2 virus, which spreads by aerosol particles that stay aloft for minutes, the MP virus spreads through large droplets which fall to the ground within a few feet. (2)

What are the clinical manifestations of MP?

According to Petersen et al: “The incubation period has been estimated at 5 to 21 days, and duration of [signs and symptoms] at 2 to 5 weeks. The illness begins with nonspecific [manifestations] that include fever, chills, headaches, lethargy, asthenia, lymph node swellings, back pain, and myalgia (muscle ache) and begins with a fever before rashes appear. Within 1 to 5 days after the onset of fever, rashes of varying sizes appear, first on the face, then across the body, hands, and legs and feet. The rash undergoes several stages of evolution from macules, papules, vesicles (fluid-filled blisters), and pustules, followed by resolution over time with crusts and scabs, which drop off on recovery. Various stages of the rash may show at the same time. Areas of erythema and/or skin hyperpigmentation are often seen around discrete lesions. Detached scabs may be considerably smaller than the original lesion. Inflammation of the pharyngeal, conjunctival, and genital mucosae may also be seen.” (5)

The main clinical differential diagnosis is smallpox. The lesions of MP appear monomorphic and pea-sized. The crop-like appearance of MP lesions, its less strong centrifugal spread, and presence of lymphadenopathy are important signs that differentiates MP from smallpox. (6)

What are potential complications of MP?

Complications may include secondary bacterial infections, sepsis, pneumonia, encephalitis, dehydration, cutaneous scarring, corneal scarring, post-inflammatory hyper or hypopigmentation, and death. (7)

What laboratory tests confirm the diagnosis of MP?

PCR (RT-PCR), serology (IgM and IgG), and electron microscopy have been utilized to confirm the diagnosis of MP. (6)

How are cases of MP treated?

As with most viral diseases, treatment is mostly supportive. Patients should be isolated with appropriate personal protective equipment (PPE). According to Moore and Zohra, “For severe cases, investigational use can be considered for compounds with demonstrated benefit against orthopoxviruses in animal studies and severe vaccinia vaccine complications. The oral DNA polymerase inhibitor brincidofovir, oral intracellular viral release inhibitor tecovirimat, and intravenous vaccinia immune globulin have unknown efficacy against the monkeypox virus.”

People exposed to the virus should be monitored for 21 days. There is no need for isolation unless they become symptomatic. In some cases, post-exposure vaccination with modified vaccinia, Ankara vaccine (smallpox and monkeypox vaccine, live, non-replicating) is recommended. “Contact between broken skin or mucous membranes and an infected patient’s body fluids, respiratory droplets, or scabs is considered a ‘high risk’ exposure that warrants post-exposure vaccination as soon as possible. According to the CDC, vaccination within four days of exposure may prevent disease onset, and vaccination within 14 days may reduce disease severity.” (7) Because human-to-human transmission appears to be limited, “ring” vaccination of close contacts is a more likely scenario than vaccination of the public at large. (2)

What should dermatologists be doing about the increase of MP cases?

According to the CDC (9):

• If health care providers identify patients with a rash that looks like monkeypox, consider monkeypox, regardless of whether the patient has a travel history to central or west African countries.

• Do not limit concerns to men who report having sex with other men. Those who have any sort of close personal contact with people with monkeypox could potentially also be at risk for the disease.

• Some patients have had genital lesions and the rash may be hard to distinguish from syphilis, herpes simplex virus (HSV) infection, chancroid, varicella zoster, and other more common infections [such as molluscum contagiosum]. [WRH – perform appropriate tests to rule out these clinical entities]

• Isolate any patients suspected of having monkeypox in a negative pressure room, and ensure staff understand the importance of wearing appropriate PPE and that they wear it each time they are near suspected cases.

• Consult the state health department or CDC’s monkeypox call center through the CDC Emergency Operations Center (770-488-7100) as soon as monkeypox is suspected. In the coming weeks we will be learning about the extent of MP infections, and the science propagating the outbreaks. We need to be honest about what we know and what we do not.

Point to Remember: There have been an increasing number of cases of monkeypox beyond Africa. Dermatologists should familiarize themselves with the disease and establish an in-office protocol for suspected cases.

Our expert’s viewpoint

Misha Rosenbach, MD, FAAD
Associate Professor of Dermatology at the Hospital of the University of Pennsylvania

Thank you, as always, Warren, for rapidly distilling critical information for dermatologists, and thank you, too, for inviting me to comment. First — I am not an expert on monkeypox! I am, however, an ‘expert’ on reading, reviewing the literature, medical education, and communicating things to different audiences. Second — no one should panic about monkeypox. This is not COVID. However, lessons learned — and ignored — over the past 2 years are important to keep in mind as we frame any discussion around this new (to us, in the U.S.) pathogen.

As with COVID, clear messaging to ensure people are aware of what they need to know, in a timely fashion, is essential. Early in the COVID pandemic, physicians used social media to share information quickly, particularly dermatologists in Italy and across the EU, through use of WhatsApp, which led to an incredible atlas of the spectrum of cutaneous morphologies that were being observed early in the first wave of the pandemic. (10) Similarly, social media has allowed rapid alerts across the globe so that folks who may encounter monkeypox are thinking about the infection. Rapid diagnosis is essential, as recognizing the infection allows isolation and (potentially) treatment of cases; moreover, it helps public health officials identify contacts, evaluate their risk for exposure, monitor them for symptoms, and (potentially) roll out ring vaccination. Notably, the mainstays of management are: informed frontline providers making a rapid diagnosis; trust and engagement with the health care system by cases and contacts; strong public health; adoption of vaccination by contacts. All of these have been eroded to some degree during the pandemic, whether due to fatigue, misinformation, or both. Some of that misinformation has come from physicians, which highlights the critical need for the field of medicine, including licensing boards, to actively combat medical misinformation (11, 12).

As an inpatient dermatologist who is frequently called to consult on new rashes in the emergency department, and founder of our urgent care access clinic in a major urban center and tertiary care academic referral center, I’m acutely aware of the need to disseminate accurate, up-to-date information to our colleagues and trainees. First, rapid recognition is essential. Dermatologic manifestations are common, and according to some papers, may be the initial signs of monkeypox infection. Warren reviewed this quite nicely up above — I will highlight that the CDC notes that manifestations start in the mouth and on the tongue, then progress outwards, generally evolving through stages together at each site. The morphologic evolution is reported to go from macules (1-2 days) to papules (1-2 days) to vesicles (1-2 days) to pustules (5-7 days) to eroded/crusted lesions. Patients frequently have a prodrome of fevers and other nonspecific symptoms, though lymphadenopathy is common (as opposed to smallpox). Lesions may be painful. The entire illness can last 2-4 weeks. Patients may also frequently have genital involvement. Note that many dermatologists are facile with the bedside diagnostic technique of Tzanck smears. We have employed these to distinguish herpes-family infections, such as HSV/VZV, from molluscum — another pox virus. Tzanck preparations performed on herpes infections will demonstrate multinucleated keratinocytes with nuclear molding and margination of chromatin. I have not seen a photograph of a Tzanck performed on monkeypox; however, Tzanck of molluscum can show oval-shaped bodies correlating with the Henderson-Patterson bodies seen on H&E stains of histologic sections (13). Importantly, use of high quality masks (N95 or equivalent), goggles, and contact precautions should protect the medical team during patient evaluation — and are another reminder of the importance of clear, accurate messaging around appropriate PPE.

A few important notes that were not covered above. First — it is true that some of the emerging groups of infection have been clustered in the MSM community. Monkeypox is not a gay disease, and it is essential to avoid stigmatization (14). Monkeypox is spread by contact or droplets — sexual contact is of course a risk factor. I would encourage readers to be thoughtful of potential issues around this, particularly in light of the various attacks and laws that are expanding against the LGBTQ community, and consider only careful messaging around this issue. Second — monkeypox is not a new disease. Our colleagues in Africa have been dealing with rolling outbreaks for years, and have extensive experience in managing the disease from a supportive care and public health standpoint. This is a good time to remind ourselves that humanity is interconnected — and to consider refocusing on neglected diseases, potential emerging pathogens, and issues of medical disparities. As the impact of the COVID pandemic still (and will) dwarf that of monkeypox, this is also a good time to remind readers about vaccine disparities, and the need to vaccinate the world against COVID. Many nations with experience battling monkeypox still lack sufficient vaccines against SARS-CoV-2, for instance.

I would encourage every dermatologist to add monkeypox to the differential diagnosis when evaluating patients with new papulovesicular or vesiculopustular lesions. Particularly if they’re occurring in crops, with a prodrome of fever and concurrent lymphadenopathy. Patients should be evaluated for exposure history, and infectious disease and public health colleagues engaged rapidly if the diagnosis is suspected or confirmed. In an ideal world, this new international outbreak should be rapidly contained. Doing so requires dermatologists to help make diagnoses quickly, and requires cases and their contacts to positively engage with the public health system. While it may seem premature to share information about monkeypox with only approximately 100 cases internationally, I hope we have all learned that early intervention and rapid containment is the best way to prevent pathogens from spiraling out of control. With the widespread emergence of monkeypox in multiple countries, if we react appropriately right now, at worst we might be accused of having overreacted — and that is the future I want. Accurate and timely information is essential — and I thank Warren, and the Dermatology World Insights & Inquiries team, for creating this so quickly.

1. Sale TA, Melski JW, Stratman EJ. Monkeypox: an epidemiologic and clinical comparison of African and US disease. J Am Acad Dermatol. 2006 Sep;55(3):478-81. doi: 10.1016/j.jaad.2006.05.061. PMID: 16908354.

2. Avril T. Monkeypox is almost nothing like COVID. Here’s what to know, from two Phill scientists who’ve studied it. Philadelphia Inquirer, May 19, 2022.

3. Kozlov M. Monkeypox goes global: why scientists are on alert. Nature. 2022 May 20. doi: 10.1038/d41586-022-01421-8. Epub ahead of print. PMID: 35595996.

4. Rao AK, Schulte J, Chen TH, Hughes CM, Davidson W, Neff JM, Markarian M, Delea KC, Wada S, Liddell A, Alexander S, Sunshine B, Huang P, Honza HT, Rey A, Monroe B, Doty J, Christensen B, Delaney L, Massey J, Waltenburg M, Schrodt CA, Kuhar D, Satheshkumar PS, Kondas A, Li Y, Wilkins K, Sage KM, Yu Y, Yu P, Feldpausch A, McQuiston J, Damon IK, McCollum AM; July 2021 Monkeypox Response Team. Monkeypox in a Traveler Returning from Nigeria - Dallas, Texas, July 2021. MMWR Morb Mortal Wkly Rep. 2022 Apr 8;71(14):509-516. doi: 10.15585/mmwr.mm7114a1. PMID: 35389974; PMCID: PMC8989376.

5. Petersen E, Kantele A, Koopmans M, Asogun D, Yinka-Ogunleye A, Ihekweazu C, Zumla A. Human Monkeypox: Epidemiologic and Clinical Characteristics, Diagnosis, and Prevention. Infect Dis Clin North Am. 2019 Dec;33(4):1027-1043. doi: 10.1016/j.idc.2019.03.001. Epub 2019 Apr 11. PMID: 30981594.

6. Alakunle E, Moens U, Nchinda G, Okeke MI. Monkeypox Virus in Nigeria: Infection Biology, Epidemiology, and Evolution. Viruses. 2020 Nov 5;12(11):1257. doi: 10.3390/v12111257. PMID: 33167496; PMCID: PMC7694534.

7. Moore M, Zahra F. Monkeypox. 2022 Feb 28. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 34662033.

8. Mahase E. Monkeypox: What do we know about the outbreaks in Europe and North America? BMJ. 2022 May 20;377:o1274. doi: 10.1136/bmj.o1274. PMID: 35595274.

9. https://www.cdc.gov/media/releases/2022/s0518-monkeypox-case.html

10. Galván Casas C, Català A, Carretero Hernández G, et al. Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases. Br J Dermatol. 2020;183(1):71-77. doi:10.1111/bjd.19163

11. Baron RJ, Ejnes YD. Physicians Spreading Misinformation on Social Media — Do Right and Wrong Answers Still Exist in Medicine? [published online ahead of print, 2022 May 18]. N Engl J Med. 2022;10.1056/NEJMp2204813. doi:10.1056/NEJMp2204813

12. Rubin R. When Physicians Spread Unscientific Information About COVID-19. JAMA. 2022;327(10):904-906. doi:10.1001/jama.2022.1083

13. Wanat KA, Dominguez AR, Carter Z, Legua P, Bustamante B, Micheletti RG. Bedside diagnostics in dermatology: Viral, bacterial, and fungal infections. J Am Acad Dermatol. 2017;77(2):197-218. doi:10.1016/j.jaad.2016.06.034

14. https://speakingofmedicine.plos.org/2022/05/19/monkeypox-is-not-a-gay-disease/