Monkeypox: What Do Experts Actually Think?

Robert D. Glatter, MD; Paul D. Biddinger, MD; Angela L. Rasmussen, MA, MPhil, PhD


May 25, 2022

This discussion was recorded on May 20, 2022. This transcript has been edited for clarity.

Robert D. Glatter, MD: Welcome. I'm Dr Robert Glatter, medical advisor for Medscape Emergency Medicine. Today, we have a distinguished panel joining us to discuss a recent outbreak of the rare and potentially fatal monkeypox virus that initially began in clusters in the United Kingdom in early May, with confirmed cases now in Portugal, Italy, Sweden, and Canada, along with suspected cases in Spain. News of the first US case recently diagnosed in Massachusetts has now been linked to a patient traveling back from Canada. There is also a case under investigation at Bellevue Hospital in New York City currently. The Massachusetts case is the first report of monkeypox this year in the US. Officials in Texas and Maryland recorded one case each last year, but this new case follows a series of unusual clusters in other countries that have begun to alarm public health officials.

Joining me to discuss this outbreak is Dr Paul Biddinger, chief preparedness and continuity officer at Mass General Brigham and director of the Center for Disaster Medicine, Massachusetts General Hospital, along with Dr Angela Rasmussen, virologist at the Vaccine and Infectious Disease Organization (VIDO) at the University of Saskatchewan. Welcome, and thank you both for taking time to discuss this important outbreak.

Paul D. Biddinger, MD: Thank you so much.

Angela L. Rasmussen, MA, MPhil, PhD: Thanks for having me, Dr Glatter.

Glatter: Paul, I want to start with you, to get a little bit of the clinical presentation of patients with monkeypox virus in general. Most have never seen a case in their lifetime and need some education on this. I'll let you start. I'm looking for symptoms, rash, incubation time, and the types of precautions that you would initiate in an emergency department first off.

Biddinger: Obviously, most clinicians are not familiar with monkeypox. Many have not even heard of it before. It's a disease that was first discovered in animals in 1958, with the first human cases documented in 1970. It's an uncommon virus around the world and is endemic in Africa in certain parts of the middle of the continent. It is an orthopoxvirus, so the same family as the smallpox virus, but thankfully it has a lower lethality than the smallpox virus. Around the world, we have not seen cases that are not related to travel to West Africa or contact with infected animals. And I think that's what's unique here.

The disease begins like so many viral illnesses, with a nonspecific prodromal fever; muscle aches; and potentially a viral exanthem — a general rash, often in the mouth or on the face. The rash progresses to be a more diffuse macular or flat rash than a papular or raised bumpy rash. The papules progress to vesicles, so they're fluid-filled lesions and then pustules, ultimately, at the end. When the pustules crust over, the patient is no longer thought to be infectious. The process can take a while. It has an incubation period of 7-14 days. Typically, 21 days is what's been described, and the whole process of illness can take 2-4 weeks and can be kind of lengthy.

Glatter: In terms of the actual presentation of the patient to your emergency department, what was the concerning symptom? Did someone notice a pustular rash along with fever? Was there any change in mental status? What was the presenting or chief complaint?

Biddinger: That's a great question. I think it's an example of why we still need the astute clinician in the modern age. Obviously, I can't talk about the specific details of the patient's care, but I think what's public is that he presented to our hospital on May 12, when only the very first cases from the UK — I believe only one at that point — was public, without a travel history. Over the next couple of days, as the UK had publicized more cases without a travel history, our clinical team suspected it. The patient was appropriately isolated at that point because monkeypox had entered the differential. Then the patient was confirmed by lab testing to have monkeypox. Historically, we haven't suspected this disease, even in patients with fever and a rash, if there wasn't travel to Africa or an animal contact history. What's changing for all of us is that we have to suspect it now when we have patients with fever; with a rash without other explanation, particularly a pustular vesicular rash; and potentially contact with other suspect cases or other infected individuals.

Glatter: One of your colleagues made a comment on Twitter about "when you hear hoofbeats, you expect horses, not unicorns," and I included that because I think this probably has been circulating.

I want to bring Angie into this. This virus is here, and there are certainly clusters that we can't quite figure out. How unusual is it for this zoonotic type of illness to be seen in this context?

Rasmussen: I don't think that zoonotic diseases emerging is particularly unusual. But then again, I'm probably biased because I study emerging viruses. It actually happens all the time. It just doesn't necessarily make the news.

What's different about this particular outbreak is that typically monkeypox outbreaks are very self-limiting. They occur in parts of Africa where monkeypox is endemic, and the virus is not very efficient at transmitting human to human. It requires prolonged, close physical proximity to transmit it from one person to another. Historically, a lot of the human-to-human transmission for monkeypox has been household transmission or transmission in other congregate settings, such as a prison or a hospital, where people are at very close contact for long periods of time. It's sufficient for them to get sufficient exposure dose.

In this case, what's really different is that these clusters are showing up all around the world. That suggests one or two things to me. One, perhaps there is something different about this particular isolate of monkeypox that makes it more efficiently transmitted from person to person. I don't actually think we have a lot of data to support that possibility right now. I think the other possibility is that conditions were just correct for this to spread by close contact and, coupled with travel, potentially to spread around the world and establish clusters in different countries.

We'll have to wait for the results of all the epidemiology that's going on right now. Right now, to me, that is the leading hypothesis for why this monkeypox outbreak is different from the ones that preceded it, which were limited to the African continent.

Glatter: The West African clade is certainly less concerning. The mortality rate is quoted at 3.6%, with the Congo basin at 10.6%. But in reality, the mortality is really low for this virus in general from what I've read and from my understanding of this. How worried should the average person be if someone were to come in contact with the virus?

Biddinger: I don't think the average person should be worried about this. This is not the sort of thing where walking around the grocery store or being in public you're at risk, for all the reasons that Angie well outlined. I think it is something different. We're always humble, especially after 3 years of COVID, about what we know and don't know as viruses change. But right now, what we do know and what I think the data that's available so far suggest, is you do need prolonged contact with individuals to be particularly at risk yourself. So, for the general public standpoint, no. As we learn more about who's at risk and the circumstances that make people at risk, I think we're going to have more to share about what people need to do to protect themselves if they're in an at-risk population.

Rasmussen: I completely agree with that. I think that the average person does not need to rush out and get a smallpox vaccine. I personally don't feel that I need to rush out and get one. We're going to talk about vaccination in a minute, so I don't want to get too far ahead of myself. But the average person should know that the precautions that they should be taking to reduce the risk from COVID-19 — standard hand hygiene and disinfection hygiene — all of those things will further reduce their risk for infection on the off chance that they are actually exposed to monkeypox. But in general, for the public, the real risk is very, very low.

Glatter: Well, that's good to hear. I think it really makes us feel better. But healthcare providers could get exposed. And in Paul's emergency department, he had a case. How do you handle exposures, perhaps in people who were not wearing adequate personal protective equipment? What's your protocol?

Biddinger: Again, things are changing because this isn't the disease they would have suspected, even 1 or 2 weeks ago, in the circumstances we now do. The recommended personal protective equipment is eye protection, N95 masks, gowns, and gloves and putting the patient in an airborne infection isolation room ─ a negative pressure room. That's because there is the possibility of respiratory transmission of monkeypox. That's probably not what we think the dominant mode is right now, with what we're seeing. But that's the isolation procedure for a patient. As with so much with infectious disease, early suspicion is the key.

I want to be careful that if you're confident the patient has cellulitis and you have other much more plausible rashes in your differential, that does not mean every single patient needs to be to be placed in an airborne infection isolation room. But when you see fever and a rash of unknown etiology, and other epidemiologic risk factors, which so far have been described as travel to an endemic area or contact with a known or suspected case, [then consider isolation]. Right now, what's been identified as men who have sex with men and as an at-risk population should be considered in the differential diagnosis. I would caution that that's just what we know right now. And certainly, if you have a fever, or an undiagnosed rash in a female patient or in any patient that you're concerned about, the same rules apply.

Latest on Vaccination for Monkeypox

Glatter: Let's get into vaccination a little bit, as Angie earlier referred to. Who would qualify for vaccinations in the setting of someone who's immunocompromised, someone who's well, and in terms of exposure?

Rasmussen: I'll start with the way that the vaccines are theoretically being used. I'm not sure how they're being used in the US or Canada, but in the UK, they're being used in this way. This is the paradigm for using them in this way, and that is a ring vaccination strategy. This is a strategy of vaccination that is coupled with contact tracing, isolation, and quarantine. The idea here is that when you identify a case, you isolate them, you find out who all of their primary contacts are, you find out all of the secondary contacts, and then you vaccinate all of those people. We know that if you give the smallpox vaccine within a short window of time after exposure, there's a very good chance that you'll be able to prevent infection that way.

This strategy has been used for other viruses. It's been used very successfully to control and contain Ebola outbreaks, both in West and Central Africa. It has been used in the past to contain smallpox and other monkeypox outbreaks. This is something we know how to do very well. Right now, my understanding is that, at least in the UK, that's who's receiving the vaccine. You will vaccinate all the primary, secondary, and sometimes even the tertiary contacts of the cases that you are able to identify and thus prevent onward transmission from all those potentially exposed people.

Biddinger: Ring vaccination is a very effective strategy in the right circumstances. Obviously, I cannot speak for the Centers for Disease Control and Prevention (CDC) and what their approach is going to be. What I know so far is that the opportunity to offer vaccination is going to be based on an analysis of the individual's risk and exposure to confirmed cases or suspect cases. You have 4 days, give or take, from the exposure to offer a vaccination to prevent illness, but 14 days to lessen the consequences of severe disease. The good news is that we have got a little bit of time.

In general, the approach right now has been to offer a vaccination to those who are higher-level risk exposure rather than lower-level risk exposure. Symptom monitoring for anyone who's had any degree of contact — so, 21 days of watching for fever, rash, any other symptoms, and then prompt evaluation of someone who develops those symptoms is what's recommended. That's appropriate, given that right now what we know is a not a low, but a lower, mortality than what we've seen with Ebola and other significant viral diseases.

Glatter: So, you're monitoring your staff at Mass General that was in the ED during this time, and I assume things are stable.

Biddinger: Exactly. We're working closely with our city and state health officials, as well as the CDC. We've identified staff and anyone else that may have come in contact with the patient as the diagnosis was being entertained. And, exactly as we just talked about, monitoring for 3 weeks, making sure that we're actively checking in with people about their symptoms for that entire period.

Rasmussen: I just want to add one thing, Rob. Many people have said to me on social media, "Well, I thought the US had a stockpile of smallpox vaccine for every American. Why aren't we vaccinating the population now because this is a potentially lethal disease, and we want to nip it in the bud? And there's clearly undetected chains of transmission."

The original-recipe smallpox vaccine is a miraculous vaccine, no question. But it also does come with significant side effects, including a potentially disfiguring rash or dermatologic conditions if you have had common diseases like psoriasis or eczema. It also includes a fairly high rate of myocarditis upon getting that vaccine. That vaccine is not necessarily something that we want to roll out at scale for people who are not at high risk of being exposed to monkeypox.

The good news is that there is a new vaccine — a next-generation vaccine that has been developed — and the US has ordered doses of it. However, we don't have that many doses of that particular vaccine in the stockpile right now. Until we do get a vaccine that has a little bit more acceptable of a side-effect profile, I think that it makes sense to not offer smallpox vaccines on demand to people who may be worried about the relatively low risk of being exposed to monkeypox.

Glatter: What about the vaccinia, the immunoglobulin VIG (vaccinia IG)? Would that be something to consider if you can't qualify for vaccination and for some who have immunodeficiency or some other condition? Would you recommend VIG or an antiviral for that matter? Could you discuss that?

Rasmussen: I'm going to probably pass this one over to Paul, being that this really is a clinical question, but I would imagine that we don't have widespread supplies of VIG and that does require an intravenous infusion, I think. So that's not something that's necessarily going to be practical to do at scale unless somebody has had an exposure risk. The drugs that are available for treating monkeypox are certainly fantastic for people who've actually gotten monkeypox. But as far as I know, they're not used prophylactically.

Biddinger: That's correct. In general, there is no FDA-approved direct treatment for monkeypox. You would be using a drug off-label. The thinking has been that those drugs are reserved for individuals with severe disease.

Glatter: The antivirals have been described by the CDC on their website (cidofovir and brincidofovir). There's been some work with these antivirals in animals especially, and in vitro. But until we had a real major outbreak, there would be no indication for any antivirals. Is that correct at this point?

Biddinger: Again, there's one antiviral that that is FDA approved, but not for monkeypox. So off label use is possible, but that probably would be reserved for individuals with severe illness. The other requires an emergency use approval, which could be considered, if necessary, but would be more appropriate in severe disease.

Glatter: This is all new territory. Talking this language to the average practitioner in the US, this is something they would have to certainly look up and get familiar with. You know, someone in North Dakota or out in the Midwest who may present with symptoms like this, or in North Carolina. Angie, you tweeted an article, there's no cases there yet, but discussion about what are we going to do, and the next steps.

Biddinger: I do think we're really in a tough spot with regard to diagnostics. As Angie said, there are going to be people who have to investigate for this as we learn more, probably in lots of places around the country. For the most part, we have to send our diagnostics to state laboratories. This is not testing that's available in hospitals generally, and there's a limited bandwidth. As we are trying to figure out who we test, individuals with a fever and unusual rash, there are some echoes to the challenges we faced early in COVID. I really don't think this is that kind of threat. But from a diagnostic perspective, it highlights how much work we still have to do at being able to diagnose emerging infectious diseases quickly at scale.

Rasmussen: I completely agree with all of that. One of the things that's the most challenging going forward for monkeypox or any other zoonotic disease is our ability to rapidly diagnose things at the point of care or in the field. We tend to stick to these standard diagnostic assays where, again, we're looking for horses, not unicorns. It would be great to have to have more unbiased diagnostic methods in our toolkit for people who are seeing patients who have these symptoms that actually could be a lot of things. Most people come into the hospital with a fever and a headache and the physician treating them is not going to think Ebola or monkeypox or even yellow fever — things that all have these symptoms in common, particularly early in the disease. It would be great to have more unbiased point-of-care diagnostics to allow practitioners to distinguish what their patients are actually coming in with and potentially catch those rare, unusual diseases very early.

Testing for Monkeypox

Glatter: To my own understanding, the PCR of fluid from a pustule would be the way this is first diagnosed. What is the turnaround time on such a test, to your knowledge?

Rasmussen: PCR turnaround time is quite low, but the problem is you have to be doing the right PCR assay. PCR is very specific for whatever you're testing for, and monkeypox is not in the standard diagnostic PCR panels.

Biddinger: Don't forget that there's packaging, transport, and other times involved. This has to get to a state lab, and it depends on where the patient is and where the lab is. Exactly as Angie said, the runtime might be a little bit shorter, but we're talking many hours typically to get to a diagnosis. It could be longer.

Glatter: Right. With serum PCR, in terms of detecting viremia, that would be inaccurate too from my understanding, not that you couldn't trust that. Just a point in time in catching that viremic phase.

Rasmussen: That's true for any virus.

Biddinger: And we're testing multiple samples. You test for viremia, you test the lesions themselves, you try and swab multiple sites, and it's that approach of multiple samples that hopefully gets us to the right answer. Typically, it's a two-stage process. We will confirm that it's in the orthopox family and then, secondarily, that it's actually monkeypox.

Transmission of the Virus

Glatter: I want to get to one area where people keep saying that there's a category of men having sex with men. That being a concern and the sexual transmission aspect of this has been brought up. Maybe you can both comment on that and describe what your thoughts are on the current understanding of that.

Biddinger: From public health authorities in the UK and in Europe, that's been described as an epidemiologic risk factor. It's something they're seeing as they're doing their contact tracing and individual investigation of cases. It's important in any changing presentation of disease that we identify what the epidemiology is and how might a disease be transmitted. I think that's why that's been shared, so that we do a better job of identifying cases and know who might be at risk.

On the converse side, there's a really unfortunate history, particularly with HIV, of stigma and of a lot of unfortunate behaviors in the medical system when any one population is singled out. We're trying really hard to avoid stigma. We definitely don't want to be myopic and only focus on men who have sex with men as an at-risk population. We're just trying to learn more right now about who's at risk and how can we protect anyone who's at risk.

Rasmussen: I agree with everything Paul just said. It's really important to emphasize that just like with HIV, just because men who have sex with men might be the first group that's infected, that doesn't mean that it doesn't impact other groups or that it can't be transmitted by other groups. We don't know that this is actually a bona fide sexually transmitted infection — meaning that we don't actually know if monkeypox is in the semen or the vaginal secretions and that it's been transmitted by sexual intercourse. The act of having sex really does create ideal conditions for transmission of this virus, which can be transmitted by aerosols, by direct contact, and by indirect contact. All three of those are after exposure through prolonged physical proximity and potentially direct physical contact, which are all conditions that are met by anybody having sex.

People really do need to understand that this isn't something that's specific or unique to men who have sex with men. This is definitely something that can be transmitted between anybody who's having sex, as well as anybody who's just in physical proximity to another person who happens to be infected, such as within a household.

Glatter: Angie, I wanted to just clarify the aerosol aspect. Are there models that describe this in terms of airborne transmission? I think a lot of people are confused. Droplets, obviously 1 or 2 feet at that point with prolonged contact, that's certainly a concern. But in terms of aerosols, what is the current literature in terms of the field of virology, epidemiology, and infectious disease on monkeypox virus in this respect?

Rasmussen: To be honest, I'm not sure that there is a lot of literature to support that. It's very clear that smallpox was transmitted by the aerosol route. Centuries ago, when people were practicing variolation to prevent smallpox outbreaks, one method of variolation was to actually inhale ground up smallpox scabs. You can certainly transmit orthopoxviruses by inhalation.

Now, what we don't have much information on — and I don't think much work has been done on, whether it be modeling or direct experimental work — is trying to look at things like range of aerosol transmission and what the dose is that you would need to be exposed to get infected. I think the other issue is that, as Paul pointed out earlier, those pustules, that vesicular rash, once it becomes pussy for lack of a better term, is full of virus. This can be spread by direct skin-to-skin contact with somebody who has those vesicles or pustules on them. This also can be spread by fomites very efficiently. You are at risk if someone is infected and you're sleeping in bedding that somebody else has used, if you're sharing a towel, if you're in contact with clothing that somebody who's been infected has been wearing, or if you're in contact with a surface that potentially has virus all over it. That's another route of transmission.

In the real world, it becomes very difficult to uncouple one mode of transmission from another because the overall dose that somebody needs to be exposed to is so high, because this virus isn't transmitted person-to-person very efficiently. Without doing more experiments in the laboratory — and even then, you'd be really restricted to understanding how that works in animals — it's very difficult to try to figure out how much aerosol transmission contributes vs direct contact transmission versus fomites. The best we can do right now is to say that it is a viable mode of transmission. But given the epidemiologic patterns, I would also say that we'd expect to see a lot more people infected if this were something that was efficiently transmitted via the aerosol route, and we're not seeing that. That's good news, at least for now. We might identify more cases, but it doesn't appear that this is more airborne than prior outbreaks of monkeypox.

Glatter: In a tweet, you had said COVID-19 is more of a concern right now in the general sense than having to worry about monkeypox for the average person in the urban or even rural settings at this point.

Rasmussen: There's a lot more SARS-CoV-2 out there right now than there is monkeypox. Even if we find a bunch more monkeypox cases, there's still a much higher prevalence of SARS-CoV-2 out in the community. If people are thinking about what their own individual risk is likely to be or for the vast majority of people, they're going to be more likely exposed to SARS-CoV-2 than to monkeypox virus.

Glatter: Absolutely. Could you provide us with a few takeaways? Just a couple of pearls that our audience should take from this whole discussion.

Rasmussen: The first thing that people always want to know is what is my risk, my family's risk, my community's risk? Right now, what people should take away from this is that risk is low, although I would caution that there's still quite a lot of uncertainty. We're still finding cases. It may seem as though there's so many more cases every day. Turn on the news, and there's more cases. But that's what happens in outbreak investigation. If you go looking for something, you're probably going to find it, especially if we already suspect that it's already out there.

I just tell people that what to take away from this right now, given all the information that we have, is individual risk is very low. Then on a larger scale, I would say that this is still very concerning and it's something that people really should keep in mind. Zoonotic spillover is something that happens pretty frequently. Just because it often happens in another country or continent, it doesn't mean that it doesn't affect us. This is a good example of why these zoonotic diseases that are very rare can quickly become a problem that we all have to deal with.

Therefore, it's really important that people continue to demand that as we move out of the coronavirus pandemic, we continue to put sustained efforts and make sustained investments in pandemic and epidemic prevention and preparedness. Monkeypox is not going to be the last rare disease that we all see emerging in unexpected ways, potentially even in the very near future.

Glatter: Your reference to the national stockpile made me concerned that we don't have adequate supplies of tests or even therapeutics at this point if there were to be a large-scale outbreak. So here we go again. We're in this situation of preparedness and we have to put the dollars in there and invest in it.

Rasmussen: That's exactly right. We need to be thinking about next-generation solutions. For years, the national stockpile of smallpox vaccines has relied on the old vaccinia-based vaccination. It's actually how vaccination came about after vaccinia virus, which was the original smallpox vaccine. As I said, that vaccine works very well, but we could make a vaccine that's safer, and we actually have.

We need to continually update things. Even if they work, we need to make them better. We need to make sure that we have access to them so that we can roll them out when they're needed. That also means developing new countermeasures — new vaccines, such as panviral family vaccines like pan-coronavirus vaccines and pan-influenza vaccines —so that we don't have to wait until the virus actually emerges before we can protect ourselves from it.

Glatter: Well, thank you, Angie and Paul. It's been a pleasure having you. This has been very informative. We'll have to see where this outbreak goes and how this plays out in the next several weeks and months. Again, thank you both for your time and your knowledge.

Robert D. Glatter, MD, is assistant professor of emergency medicine at Lenox Hill Hospital in New York City and at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He is an editorial advisor and hosts the Hot Topics in EM series on Medscape. He is also a medical contributor for Forbes.

Paul D. Biddinger, MD, is an associate professor of emergency medicine at the Harvard Medical School. He is also a director at the Center for Disaster Medicine and vice chairman of the department of emergency medicine at Massachusetts General Hospital in Boston, Massachusetts.

Angela L. Rasmussen, MA, MPhil, PhD, has studied a variety of viruses, including Ebola, using systems biology and genomics to examine the virus and host responses. In the current pandemic, she's used Twitter to counter misinformation and misinterpretation of data.

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